WHO Technical Report Series 989
WHO STUDY GROUP ON TOBACCO PRODUCT REGULATION Report on the Scientific Basis of Tobacco Product Regulations: Fifth Report of a WHO Study Group
WHO Technical Report Series 989
WHO STUDY GROUP ON TOBACCO PRODUCT REGULATION Report on the Scientific Basis of Tobacco Product Regulations: Fifth Report of a WHO Study Group
WHO Library Cataloguing-in-Publication Data WHO study group on tobacco product regulation : report on the scientific basis of tobacco product regulation : fifth report of a WHO study group. (WHO Technical report series ; 989) 1.Tobacco Use Disorder - prevention and control. 2.Tobacco Industry - legislation. 3.Tobacco Control Campaigns. 4.Tobacco - chemistry. 5.Metals, Heavy - adverse effects. 6.Metals, Heavy - toxicity. 7.Metals, Heavy - standards. I.World Health Organization. II.WHO Study Group on Tobacco Product Regulation. III.Series. ISBN 978 92 4 120989 2 ISSN 0512-3054 (NLM classification: QV 137)
© World Health Organization 2015 All rights reserved. Publications of the World Health Organization are available on the WHO website (www.who.int or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the policies of the World Health Organization. Printed in Switzerland
Contents Participants in the seventh meeting of the WHO Study Group on Tobacco Product Regulation, Rio de Janeiro, Brazil, 4–6 December 2013 Acknowledgements 1. Introduction 2. Novel tobacco products, including potential reduced exposure products: research needs and regulatory recommendations 2.1 Introduction 2.2 Results of the WHO tobacco products survey, 2014 2.3 Impact on public health 2.4 Research needs 2.4.1 Monitoring 2.4.2 Framework for risk assessment 2.4.3 Marketing and consumer perception 2.4.4 Risk communication 2.4.5 Regulatory issues 2.5 Regulatory recommendations 2.6 References 9 11 15 19 19 20 22 23 23 24 26 27 27 28 29
3. Smokeless tobacco products: research needs and regulatory recommendations 33 3.1 Introduction 33 3.1.1 Wide range of products 34 3.1.2 Limited data 35 3.1.3 Novel products and marketing 35 3.1.4 Impact on young people and development of tobacco use 36 3.1.5 Limited treatment options 36 3.1.6 Tobacco “harm reduction” 36 3.2 Results of the WHO tobacco products survey, 2014 37 3.3 Current regional and national regulations 38 3.3.1 WHO African Region 38 3.3.2 WHO Region of the Americas 39 3.3.3 WHO Eastern Mediterranean Region 39 3.3.4 WHO European Region 39 3.3.5 WHO South-East Asia Region 40 3.3.6 WHO Western Pacific Region 41 3.4 Conclusions 41 3.5 Research needs 43 3.5.1 Surveillance and monitoring 43 3.5.2 Product characterization 43 3.5.3 Health effects 43 3.5.4 Economics and marketing 44 3.5.5 Interventions 44 3.6 Regulatory recommendations 44 3.6.1 Interventions and policy 44
3.6.2 Challenges and recommendations for creating a regulatory framework 3.6.3 Building capacity 3.7 References 4. Reduced ignition propensity cigarettes: research needs and regulatory recommendations 4.1 Introduction 4.2 Background 4.3 Findings 4.3.1 New studies since the previous report 4.3.2 Country and regional experiences in legislation and its implementation 4.3.3 Data on product compliance 4.3.4 Risk assessment and perceptions of safety and risk 4.3.5 Trends in cigarette-ignited fires before and after adoption of the standard 4.3.6 Relevance and shortcomings of the standard 4.4 Conclusions 4.5 Results of the WHO tobacco products survey, 2014 4.6 Research needs 4.7 Regulatory recommendations 4.8 References Appendix 4.1. Methods Appendix 4.2. Summary of ISO 12863 Appendix 4.3 Recent CORESTA presentations by industry relevant to the technology of reduced ignition propensity cigarettes 5. Non-exhaustive priority list of toxic contents and emissions of tobacco products 5.1 Introduction 5.2 Findings of the review 5.3 Recommendations 5.4 Non-exhaustive list of priority toxic contents and emissions of tobacco products 5.5 References 6. Overall recommendations 6.1 Novel tobacco products 6.1.1 Main recommendations 6.1.2 Significance for public health policies 6.1.3 Implications for WHO programmes 6.2 Smokeless tobacco 6.2.1 Main recommendations 6.2.2 Significance for public health policies 6.2.3 Implications for WHO programmes 6.3 Reduced ignition propensity cigarettes 6.3.1 Main recommendations 6.3.2 Significance for public health policies 6.3.3 Implications for WHO programmes 6.4 Non-exhaustive list of toxic contents and emissions of tobacco products
47 47 49 53 53 54 54 55 55 56 58 60 63 63 64 65 66 66 68 69 70 73 73 74 75 76 77 79 79 79 80 80 80 80 81 81 81 81 81 81 82
6.4.1 Main recommendation 6.4.2 Significance for public health policies 6.4.3 Implications for WHO programmes 7. Regulation of tobacco smoke: commentary on the status quo 7.1 Background 7.2 Proposed actions 7.3 Issues relevant to setting upper limits 7.4 References
82 82 82 83 83 86 87 89
Annex 1. Novel tobacco products, including potential reduced exposure products: research needs and recommendations 91 Abstract 92 Background 93 Concept of “harm reduction” 94 Methods 95 Data sources 95 Selection criteria 95 Data extraction and synthesis 96 New marketed and test-marketed products and products with emerging use 96 Oral tobacco products 97 Modified or alternative smoked products 108 Waterpipes 121 Notable alterations to traditional products 124 Technologies under development 127 Substitution of traditional tobacco burning by heating 128 Combination of changed tobacco processing and filter structure 128 Modification of filter structure 134 Research in progress as presented at the 2013 CORESTA meeting 136 Summary 138 Non-combustible oral products 138 Cigarettes and cigarette-like devices 141 Conclusions 145 Acknowledgements 145 References 147 Appendix. Questionnaire on new tobacco products, including products with potentially “modified risk” 159 Annex 2. Role of ammonia in delivery of free nicotine: recent work and analytical challenges Introduction Recent publications on nicotine transfer to smoke Recent publications on nicotine uptake Current role of ammonia technology References Annex 3. Reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction Introduction Tobacco addictiveness model 163 163 164 166 168 171
175 176 177
Nicotine addiction Individual variation in response to nicotine Delivery of nicotine from tobacco Dual reinforcement model of addiction Drug expectancy Social and contextual factors Summary Establishing a threshold for addiction Nicotine self-administration Acquisition of nicotine dependence Reinforcing effects of low-nicotine cigarettes Addiction threshold versus reinforcement threshold Threshold for conditioned stimulus Summary Feasibility of reducing nicotine Cigarette nicotine delivery Methods for reducing nicotine in tobacco Denicotinized or reduced-nicotine cigarettes Free-base nicotine in low-delivery cigarettes Products that lead to compensatory smoking Product formulation and approaches to nicotine reduction Summary Potential behavioural and population outcomes Potential effects on cigarette consumption Potential effects on topography and smoking behaviour Potential effects on abstinence and quitting Potential effects on acquisition of cigarette use Potential unintended behavioural consequences Potential population differences Potential health effects Potential illicit sales of nicotine-containing cigarettes Models of population effects Summary Policy approaches to nicotine reduction Comprehensive regulation of nicotine Performance standards Gradual versus sudden reduction Alternative forms of nicotine Cessation and behavioural treatment Surveillance Consumer education and beliefs Public support for a reduced nicotine policy Unintended market consequences Summary Conclusions Recommendations References
178 179 180 181 183 183 184 185 185 187 187 188 189 190 191 191 192 193 194 195 196 197 198 199 199 200 201 202 202 203 204 204 206 207 207 208 209 210 210 211 212 212 213 214 215 216 217
8
Participants in the seventh meeting of the WHO Study Group on Tobacco Product Regulation Rio de Janeiro, Brazil, 4–6 December 2013
Members
Dr D.L. Ashley, Director, Office of Science, Center for Tobacco Products, US Food and Drug Administration, Rockville, Maryland, United States of America Professor O.A. Ayo-Yusuf, Dean, School of Oral Health Sciences, Sefako Makgatho Health Sciences University, Pretoria, South Africa Professor A.R. Boobis, Biochemical Pharmacology, Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College, London; Director, Public Health England Toxicology Unit, Imperial College, London, United Kingdom Dr Vera Luiza da Costa e Silva, Independent Consultant, Senior Public Health Specialist, Rio de Janeiro, Brazil Dr M.V. Djordjevic, Program Director/Project Officer, Tobacco Control Research Branch, Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, United States of America Dr N. Gray, Honorary Senior Associate, Cancer Council Victoria, Melbourne, Australia† Dr P. Gupta, Director, Healis Sekhsaria Institute for Public Health, Mumbai, India Dr S.K. Hammond, Professor of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California, United States of America Dr D. Hatsukami, Professor of Psychiatry, University of Minnesota, Minneapolis, Minnesota, United States of America Dr J. Henningfield, Professor (Adjunct), Behavioral Biology, The Johns Hopkins University School of Medicine; Vice President, Research, Health Policy, and Abuse Liability Pinney Associates, Bethesda, Maryland, United States of America Dr A. Opperhuizen, Director, Office for Risk Assessment and Research, Utrecht, The Netherlands Dr G. Zaatari (Chair), Professor and Chairman, Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon
9
Facilitors of the WHO FCTC Conference of the Parties Working Group on Articles 9 and 10 Dr P. Altan, Tobacco Control Department, Ministry of Health, Ankara, Turkey Ms A.C. Bastos de Andrade, Head of Tobacco Products Control Department, Agência Nacional de Vigilância Sanitária, Rio de Janeiro, Brazil Dr Katja Bromen, Policy Officer, Tobacco Control Team, European Commission, Directorate-General for Health and Consumers, Unit D4, Substances of Human Origin and Tobacco Control, Brussels, Belgium Mr D. Choinière, Director, Tobacco Products Regulatory Office, Controlled Substances and Tobacco Directorate, Health Canada, Ottawa, Ontario, Canada
Presenters
Dr G. Ferris Wayne, California, United States of America Dr R. Grana, Postdoctoral Fellow, Center for Tobacco Control Research and Education, University of California, San Francisco, California, United States of America Dr M. Parascandola, Epidemiologist, Tobacco Control Research Branch, Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Maryland, United States of America Dr R. Talhout, National Institute for Public Health and Environment, Centre for Health Protection, Bilthoven, The Netherlands
Convention Secretariat of the WHO FCTC (Geneva, Switzerland) Ms K. Brown, Programme Officer
WHO Regional Office for the Americas
Dr A. Blanco, Regional Advisor, Tobacco Control, Washington DC, United States of America
WHO Secretariat (Prevention of Noncommunicable Diseases, Geneva, Switzerland) Dr A. Peruga, Programme Manager, Tobacco Free Initiative Dr V.M. Prasad, Project Manager, Tobacco Free Initiative Ms G. Vestal, Technical Officer (Legal), Tobacco Free Initiative
Ms M. Aryee-Quansah, Administrative Assistant, Tobacco Free Initiative
10
Acknowledgements
WHO has many people to thank for the production of this fifth report of the WHO Study Group on Tobacco Product Regulation (TobReg). Ms Gemma Vestal coordinated the production, with the supervision and support of Dr Armando Peruga and Dr Douglas Bettcher. Work on the report began shortly after the fifth session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control (FCTC) in Seoul, Republic of Korea, 12–17 November 2012, and continued after the sixth session, in Moscow, Russian Federation, 13–18 October 2014. This report will be presented by the Director-General of WHO to the 136th session of the Executive Board in Geneva, Switzerland, to be held 25 January–3 February 2015. We thank all the members of TobReg for their full, whole-hearted dedication, time and unfailing commitment to fulfilling their mandate to advise WHO on tobacco product regulation, a highly complex area of tobacco control. As independent experts, members of TobReg serve WHO without remuneration. In response to the requests to WHO made by the Conference of the Parties at its fifth session, TobReg members provided guidance in drafting the terms of reference for commissioning a series of reviews to serve as background documents and as a basis for discussions at TobReg’s seventh meeting, held in Rio de Janeiro, Brazil, in December 2013. We thank the authors of the background paper on novel tobacco products, Dr Irina Stepanov, Dr Lya Soeteman-Hernández and Dr Reinskje Talhout, for their highly informative document. Their work was overseen by Dr Mirjana Djordjevic (TobReg). The full background paper is appended as Annex 1 to this report. We also recognize our colleagues Dr Samira Asma, United States Centers for Disease Control and Prevention, and Dr Mark Parascandola, United States National Cancer Institute, for providing WHO with a draft of their report
11
entitled Smokeless tobacco and public health: a global perspective. This authoritative, voluminous report, published in 2014, was ably synthesized by Dr Dorothy Hatsukami (TobReg) and Ms Lindsay Pickell, BLH Technologies, and subsequently presented to TobReg at its seventh meeting. We also acknowledge the authors of the background paper on reduced ignition propensity cigarettes, Dr Greg Connolly and Dr Hillel Alpert, both at the Harvard School of Public Health. They thoroughly and enthusiastically updated the original TobReg paper on reduced ignition propensity cigarettes, which was published in 2008. The work on this background paper was overseen by Dr Alan Boobis (TobReg) and Professor O.A. Ayo-Yusuf (TobReg). The background paper on reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction was written by Mr Geoff Ferris Wayne. It is appended as Annex 3 to this report. WHO thanks Mr Wayne for the time and effort invested in writing the paper, which was presented to TobReg in December 2013, and for continuing to work with TobReg in finalizing their conclusions and recommendations on this important topic. Work on the background paper was overseen by Dr Jack Henningfield, who unfortunately resigned from TobReg in January 2014. WHO would like to take the opportunity to express its deepest gratitude to Dr Henningfield for his years of dedicated, effective service to TobReg. He was one of TobReg’s “thought leaders” and a prolific writer. The Conference of the Parties at its fifth session also requested WHO to draw up a non-exhaustive priority list of toxic contents and emissions of tobacco products. Work on this chapter was led by three TobReg members, Dr David Ashley, former Chair of the WHO Tobacco Laboratory Network (TobLabNet), Dr Antoon Opperhuizen, current Chair of TobLabNet, and Dr Ghazi Zaatari, current Chair of TobReg. At its seventh meeting, TobReg discussed the role of ammonia in increasing the rate of delivery of nicotine to the brain. The background paper on this topic was written by Ms Christina Watson, United States Centers for Disease Control and Prevention. For the benefit of academics and policy-makers, this paper is appended to the report as Annex 2. Work on this paper was overseen by Dr David Ashley (TobReg). The report also includes a commentary by Dr Nigel Gray, one of the pioneers of TobReg, on regulation of tobacco smoke and the status quo. Dr Gray, in his ninth decade, passed away peacefully on 20 December 2014. Dr Gray was renowned in the international tobacco control community as an activist, scholar and visionary. As a TobReg member, Dr Gray provided leadership and invaluable insight in an area that is often highly complex, as most studies have been conducted by the tobacco industry, and many Member States did
12
not have the capacity to analyse them thoroughly. The WHO Tobacco Free Initiative considered that inclusion of Dr Gray’s commentary in this report was a fitting tribute to the life of a prime “thought leader” in TobReg. Dr Gray’s legacy can be found in the many TobReg recommendations that have been published throughout the years. To ensure that WHO delivered the information requested on tobacco product regulation to the Conference of the Parties, through the Convention Secretariat, WHO and TobReg worked closely with the facilitators of the Working Group on Articles 9 and 10 of the WHO FCTC. WHO acknowledges the significant contributions of Ms Ana Claudia Bastos de Andrade (Brazil), Mr Denis Choinière (Canada), Dr Katja Bromen (European Union) and Dr Peyman Altan (Turkey). WHO also acknowledges the assistance of colleagues of the Convention Secretariat throughout production of this document, namely: Ms Karlie Brown, Ms Guangyuan Liu and Dr Tibor Szilagyi (Technical Officers), Dr Haik Nikogosian (former Head of the Convention Secretariat) and Dr Vera da Costa e Silva (current Head of the Convention Secretariat). Administrative support throughout the years of production was provided by WHO colleagues Ms Miriamjoy Aryee-Quansah, Mr Gareth Burns, Ms Elaine Alexandre Caruana, Mr Luis Madge, Ms Elizabeth Tecson and Ms Rosane Serrao. Special thanks go to Dr Adriana Blanco, Tobacco Control Regional Adviser, WHO Regional Office for the Americas, for ensuring a smooth TobReg meeting in Brazil. We also sincerely thank Ms Ana Claudia Bastos de Andrade, Agência Nacional de Vigilância Sanitária (ANVISA), Brazil, for heroically hosting the seventh meeting of TobReg in Rio de Janeiro, Brazil, in December 2013, while at the same time defending ANVISA from a number of lawsuits instigated by the tobacco industry. In addition, ANVISA provided much needed financial assistance to make the meeting become a reality. We also express our appreciation to the WHO editor, copy-editor and proofreader and to the layout and typesetter company, Talk Infosystems, in India, for their eye for detail and their patience with the various rounds of editing. Last but not least, WHO expresses its profound gratitude to former interns at the Tobacco Free Initiative who contributed large amounts of their internship time to the fruition of this document: Ms Aurelie Abrial, Ms Colleen Ciciora, Mr Adrian Diaz, Dr Richelle Duque, Ms Mary Law, Ms Christina Menke, Ms Hannah Patzke and Ms Angeli Vigo. It is our hope that they continue to work passionately in some aspects of tobacco control, regardless of the bright careers they follow in the future.
13
Undoubtedly, many people to whom we are indebted are not mentioned here, because there were so many people involved in production of this report. We apologize for any omission. We therefore thank both those who are named and those who are not named. Without your assistance and support, none of this would have been possible. Thank you very much.
14
1. Introduction
The WHO Study Group on Tobacco Product Regulation (TobReg)1 is mandated to provide the WHO Director-General with scientifically sound, evidence-based recommendations for Member States about tobacco product regulation. In line with the provisions of Articles 9 and 10 of the WHO Framework Convention on Tobacco Control (FCTC), TobReg identifies approaches for regulating tobacco products that pose significant public health issues and raise questions for tobacco control policy. Regulation of tobacco products is essential for tobacco control and is endorsed by the WHO FCTC in provisions of its Articles 9, 10 and 11. Regulation serves public health goals by meaningful surveillance of the manufacture, packaging, labelling and distribution of tobacco products. Scientifically based principles for implementing the provisions create synergy and mutual reinforcement of the regulatory practices described in each article. Tobacco product regulation includes regulating their contents and emissions by testing, measuring and mandating disclosure of the results and regulating their packaging and labelling. Government supervision is required for manufacture and for enforcement of regulations on the design, contents and emissions of tobacco products, as well as their distribution, packaging and labelling, with the aim of protecting and promoting public health. Chemical consumer products are usually regulated after a review of the scientific evidence on the hazards associated with them, the probable exposure, the patterns of use and the marketing messages of the manufacturer. Many jurisdictions require manufacturers to classify and label products according to their hazardous properties, to control the hazardous content or to limit the advertising, promotion and sponsorship of such products. TobReg reviews the scientific evidence on topics related to tobacco product regulation and identifies the research necessary to fill regulatory gaps in 1
http://www.who.int/tobacco/industry/product_regulation/tobreg/en/
15
tobacco control. It is composed of national and international scientific experts on product regulation, treatment of tobacco dependence and laboratory analysis of tobacco contents and emissions. As a formalized entity of WHO, TobReg reports to the WHO Executive Board through the Director-General to draw the attention of Member States to the Organization’s work in tobacco product regulation, which is a complex area of tobacco control. The seventh meeting of TobReg was held in Rio de Janeiro, Brazil, on 4–6 December 2013. The discussions mainly addressed the request of the Conference of the Parties (COP) of the WHO FCTC at its fifth session (Seoul, Republic of Korea, 12–17 November 2012) to WHO to: • Monitor and follow closely the evolution of new tobacco products, including products with potentially “modified risks”, and to report any relevant development to the COP. Direct some of its activities towards aspects of addictiveness (or dependence liability) of both smoked and smokeless tobacco products that remain to be studied. Monitor and research country experience and scientific developments with respect to reduced ignition propensity cigarettes. Identify measures likely to reduce the toxicity of both smoked and smokeless tobacco products, and describe the evidence supporting the effectiveness of such measures and the experience of Parties on the matter for consideration by the COP. Compile, make available to Parties and update a non-exhaustive list of the toxic contents and emissions of tobacco products, and provide advice on how such information could be best used by Parties. Prepare draft fact sheets on measures recommended in the partial guidelines for implementation of Articles 9 and 10 of the WHO FCTC. Continue and report on progress in validation of analytical chemical methods for testing and measuring cigarette contents and emissions.
•
• •
•
• •
Subsequent to this request, a number of background documents were commissioned. In addition, information on the availability and regulation of novel tobacco products, smokeless tobacco products and reduced ignition propensity cigarettes was collected in a WHO survey of tobacco products sent to all Member States. Ninety countries responded, representing approximately 77% of the world’s population. This report focuses on four main topics for which TobReg has issued clear recommendations: novel tobacco products, smokeless tobacco, reduced ignition propensity cigarettes and a non-exhaustive priority list of toxic contents
16
and emissions of tobacco products. The document that served as the basis for discussions on novel tobacco products is included in this report as Annex 1, and a background paper on the industry practice of adding ammonia to increase the rate of delivery of nicotine to the brain is included as Annex 2. At its eighth meeting, TobReg will review the topic of “reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction”, as the discussions on this topic did not result in fully agreed recommendations for research and regulation. The background document for the discussion at the seventh meeting in December 2013 is nevertheless provided as Annex 3 for the information of researchers and policy-makers. The report also includes a commentary, which is based on a paper written independently by Dr Nigel Gray, one of the pioneers of TobReg, on regulation of tobacco smoke and the status quo, which was presented at the seventh meeting in December 2013. Unfortunately, Dr Gray, in his ninth decade, passed away peacefully on 20 December 2014.2 TobReg members unanimously recommended that his thoughtful commentary be included in recognition of the importance of its content and goals and of Dr Gray as a leader and visionary in public health and tobacco control. TobReg hopes that the conclusions, recommendations and advisory notes contained in this report will be useful to countries in implementing the product regulation provisions of the WHO FCTC.
See WHO’s tribute to Dr Nigel Gray at http://www.who.int/tobacco/communications/ highlights/nigelgray/en/. 2
17
18
2. Novel tobacco products, including potential reduced exposure products: research needs and regulatory recommendations 2.1 Introduction 2.2 Results of the WHO tobacco products survey, 2014 2.3 Impact on public health 2.4 Research needs 2.4.1 Monitoring 2.4.2 Framework for risk assessment 2.4.3 Marketing and consumer perception 2.4.4 Risk communication 2.4.5 Regulatory issues 2.5 Regulatory recommendations 2.6 References
2.1 Introduction This section of the report is based on a background paper commissioned by WHO (appended as Annex 1 to this report), which served as the basis for discussion on the topic at the seventh meeting of the WHO Study Group on Tobacco Product Regulation (TobReg) in Rio de Janeiro, Brazil, in December 2013. A wide variety of novel tobacco product types and technologies have entered world markets since 2000. According to WHO, “new” or “novel” tobacco products, in addition to containing tobacco, must meet at least one of the following criteria: • • • New or unconventional technology is used, such as vaporization of tobacco into the lungs or use of menthol pellets in a cigarette filter. The product type has been on the market for less than 12 years; these include dissolvable tobacco products. The product type has been on the market for longer, but the market share has increased in areas in which the type was not traditionally used, such as smokeless tobacco products being introduced into countries where they were not previously available. The product is marketed, or work has been published to allow it to be marketed, with the claim that it could reduce exposure to harmful chemicals.
•
Some novel products are designed for oral use, such as dissolvable tobacco products and “snus” manufactured in the USA (1–3). Others are in essence modified cigarettes that may include specially treated tobaccos, novel filters or
19
novel ways of delivering inhaled tobacco (e.g. at a lower burning temperature or by heating rather than burning tobacco) (4–6). At least some novel products reflect an industry effort to reduce exposure to harmful tobacco or smoke constituents and have been marketed with corresponding implicit or explicit health claims. Industry research suggests that more novel products are likely to be introduced in the near future (7, 8). New tobacco products and types and their unique physical or chemical characteristics may alter consumers’ exposure to harmful and addictive tobacco constituents. The results of these changes, whether positive or negative, may be difficult to anticipate. The characteristics of novel products and any associated health claims may potentially increase their addictiveness and appeal, thereby promoting continued use. Even when a novel product is relatively less toxic than conventional cigarettes, it may be marketed or adopted primarily as an adjunct to smoking, delaying cessation for some people by providing a means to relieve nicotine craving temporarily when smoking is not possible (3, 9). Novel products may also appeal to new users, including adolescents who would not otherwise initiate tobacco use (2, 3). In order to address the public health issues related to novel products adequately, all products that can be used as a means to facilitate cessation, lead to initiation and addiction or result in maintenance of smoking through dual use—both those that contain tobacco and those that do not—should be regulated to maximize any benefits and minimize harm. A systematic approach to monitoring novel tobacco products entering international markets is instrumental to guiding tobacco control and assessing their potential public health impact. Basic principles for the evaluation of new and potentially reduced-harm tobacco products require consideration of the actual exposure to and intake of the constituents, behavioural adaptation to the product, marketing approaches, consumer perceptions and modes and populations of use (5, 10). 2.2 Results of the WHO tobacco products survey, 2014 A questionnaire on smokeless tobacco products, electronic nicotine delivery systems, reduced ignition propensity (RIP) cigarettes and novel tobacco products3
3
Products that represent variations on cigarettes, cigars, pipe tobacco, roll-your-own tobacco or oral tobacco in markets that traditionally carry these types of products were excluded. Also, for the purposes of this report, electronic nicotine delivery systems, such as electronic cigarettes, and herbal cigarettes are not included; a specific document covers such products (document FCTC/COP/6/10 Rev., http://apps.who.int/gb/fctc/PDF/cop6/FCTC_COP6_10Rev1-en.pdf, accessed on 10 December 2014).
20
was sent to all WHO Member States in 2013.4 Novel tobacco products were found to be available for sale in 13 Member States representing 28% of the world population. Regulation of novel products may be one factor in their limited availability, as regulations govern the production (in 26 Member States, representing 26% of the world population), distribution (33 Member States, 32%) and sale (39 Member States, 32%) of these products. Only three of the Member States in which novel products are sold reported domestic manufacture; seven reported that all such products are imported, and three did not report the origin of manufacture. Government sales licences for novel products are required by 11 Member States (28% of the world population), and 44 (34%) have policies restricting the sale of these products to minors; when specified, the minimum age for sale to minors was 16–21 years. Regulation of marketing and promotion of novel products is only slightly more widespread than regulation of sales. Comprehensive bans on tobacco advertising, promotion and sponsorship of novel tobacco products are in place in 41 Member States (35% of the world population), while 32 Member States (38%) reported no such ban. Claims on the packaging of these products that they modify or reduce risk or harm were reported by nine Member States (26%), but the characteristics or contents of these products were regulated for their potential to cause harm in only one of the nine Member States; no health claims were reported in five Member States. Overall, the worldwide sale of novel products is limited; however, more than half of all Member States, representing more than half the world population, remain open to the introduction of novel products with no restriction on sales, marketing or product characteristics.
4
A total of 90 countries, including 86 Parties to the WHO FCTC, had responded to the survey as of 9 April 2014. These countries, representing 77% of the world’s population, are: • WHO African Region: Botswana, Congo, Gabon, Ghana, Kenya, Mali, Mauritania, South Sudan, Zambia; • WHO Region of the Americas: Barbados, Belize, Bolivia (Plurinational State of), Brazil, Canada, Chile, Colombia, Costa Rica, Dominica, Ecuador, Guatemala, Honduras, Jamaica, Nicaragua, Panama, Paraguay, Peru, Suriname, Uruguay, United States of America; • WHO European Region: Austria, Belarus, Belgium, Croatia, Czech Republic, Estonia, Finland, France, Georgia, Hungary, Iceland, Latvia, Lithuania, Netherlands, Norway, Poland, Slovakia, Spain, Sweden, Russian Federation, Turkey, Uzbekistan; • WHO Eastern Mediterranean Region: Bahrain, Djibouti, Egypt, Iran (Islamic Republic of), Iraq, Jordan, Kuwait, Lebanon, Morocco, Oman, Pakistan, Qatar, Sudan, Syrian Arab Republic, Tunisia, United Arab Emirates; • WHO South-East Asia Region: Bangladesh, Bhutan, India, Indonesia, Maldives, Myanmar, Thailand; and • WHO Western Pacific Region: Australia, Brunei Darussalam, Cambodia, China, Fiji, Japan, Lao People’s Democratic Republic, Malaysia, Mongolia, New Zealand, Palau, Philippines, Republic of Korea, Tonga, Tuvalu, Viet Nam.
21
2.3 Impact on public health Development of new tobacco products that are less toxic or less addictive could be a component of a comprehensive approach to reducing tobacco-related deaths and disease, particularly among tobacco users who are unwilling to quit or are unable to break their dependence on tobacco. However, new products that increase the risk for exposure or encourage tobacco use could result in greater harm to individual users or to the population as a whole (11). Evidence of the population impact of novel products is limited. The United States (US) Food and Drug Administration Tobacco Product Scientific Advisory Committee (12) reviewed information on dissolvable tobacco products and concluded that the likelihood of abuse of these products may be lower than that for conventional smoked and smokeless tobacco products, and that exclusive use of dissolvable products should be less hazardous than cigarette smoking. The report noted, however, that no epidemiological data were available to assess absolute or population risks. Dissolvable tobacco products have undergone significant transformation in both formulation and packaging since they were first introduced onto the US market, but with little commercial success, and it is not clear whether these products will persist in the USA or internationally. In contrast, novel snus products appear to be gaining popularity in the USA (13). These products are differentiated from traditional smokeless products in advertising (9, 13) and are often promoted as versions of popular cigarette brands that can be used discreetly in public, in bars, offices and airplanes, where smoking is banned (9). Both novel snus and dissolvable products can suppress symptoms of smoking abstinence, although products with different nicotine content have different effects (14–16). Surveys in Scandinavia show that snus has been used effectively for cessation, predominantly among male smokers (17–19), but the extent to which these products can substitute completely for cigarettes in smokers in other countries is unknown because of differences in the context of tobacco use and in populations. While smokers in the USA are generally dissatisfied with the taste of snus and dissolvable products, they may use these products to reduce their risk (20, 21) or to satisfy nicotine craving in locations where smoking is banned. More thorough surveillance of population responses to dissolvable products and snus in test market areas will be essential to provide tobacco control professionals with the data necessary to recommend policy (22). Modified cigarettes or alternative tobacco-burning or -heating devices developed and marketed as potential harm-reducing devices have generated little public awareness or acceptance (23). Previous studies on use of cigarettes modified to yield fewer toxicants did not find a substantial reduction in actual exposure to these toxicants (e.g. 24). Furthermore, decreasing the content
22
of a limited number of carcinogens may not decrease the overall health risk and could potentially affect the concentrations of other carcinogens in smoke (23). The introduction of new materials in product construction, in cigarette filler or elsewhere, might generate new chemicals with unknown health consequences. Some other novel cigarette devices, such as those that heat rather than burn tobacco, appear to generate lower yields of toxic constituents than conventional products and lower levels of biomarkers (25); however, no studies have been conducted to determine whether use of these products results in a significantly lower disease burden than use of cigarettes. These types of product may also indirectly encourage cigarette consumption by promoting a safer image of cigarette use overall (5). Population effects are difficult to assess in view of the lack of market penetration and short market life of alternative cigarette designs. 2.4 Research needs 2.4.1 Monitoring
Systematic global surveillance should provide accurate, timely data on new tobacco products and products with emerging or expanding use, including when, where, how and what types of products have been introduced, which populations are targeted, how the products are used and their impact on the use of other tobacco products. The aim of surveillance should be not only to identify novel products but also to assess the likelihood that such products will gain a market share. The data to be collected should include: • a description of the product (composition, physical parameters, design features, package) from a random sample (e.g. by the International Standards Organization [ISO] method) to account for factors such as storage conditions and differences per production batch; marketing and promotion; their cost relative to that of other tobacco products; awareness and perception of the product and attitudes toward tobacco control policies; the prevalence and patterns of use, including use with other products; the results of cognitive testing and/or focus groups to determine the best way to describe the product to respondents for full comprehension; uptake by young people and whether its use leads to use of other tobacco products; development of dependence;
• • • • • • •
23
• • • •
reasons for use; groups targeted for product use, such as young people, women and populations with co-morbid medical and mental disorders; behavioural measures (e.g. topography); and exposure to toxicants and nicotine in the product.
2.4.2 Framework for risk assessment
A global regulatory framework should be drawn up for assessing new products, in order to evaluate the validity of claims made by industry and to assess potential harm. General guidelines for assessing the risks associated with modified tobacco products have been proposed by the Tobacco Product Scientific Advisory Committee (10) and by the Society for Research on Nicotine and Tobacco (5). The main issues are outlined below. Conventional machine measurements are not sufficient to assess the delivery of toxicants by novel smoke- or vapour-generating products. Traditional methods, such as smoking machine measurements, used for conventional cigarettes may have to be adapted or new methods developed, because puffing behaviour and the physical and chemical characteristics of new products vary, particularly those with inhaled aerosols, and because exposure time may be different. Human behavioural studies should be conducted to understand better the smoking behaviour associated with each potential reduced-exposure product (PREP). Use of standardized machine-generated yields per milligram of nicotine would minimize the variation among methods (26).5 In contrast to smoking machines, smokers tend to adjust their puff volume and inter-puff interval to attain the desired biological level of nicotine. Adjustment of the toxicant level per milligram of nicotine as obtained from smoking machines to a smoker’s nicotine intake can provide a better estimate of the actual level of toxicants to which smokers are exposed (27). This approach was an important factor in an assessment of the reduction in risk associated with titanate nanoparticles (7, 28), while a reduction in toxicant levels was not seen after standardization per milligram of nicotine. A reduction in the toxicant level in mainstream cigarette smoke per milligram of nicotine does not necessarily reduce risk. Even when toxicant levels are normalized to nicotine, product design may alter user behaviour and result in different risks. Taking larger puffs can result in smoke particles being drawn deeper The available standards for machine yields are those of ISO and TobLabNet, which pertain only to cigarettes. Although there are tests for yields from e-cigarettes, they have not yet been standardized. 5
24
into the lungs. Normalization by level of nicotine does not address these behavioural differences. For example, studies of smoking behaviour of Eclipse cigarettes showed that, in comparison with estimates made from smoking machines, smokers took larger puff volumes and more frequent puffs than of conventional cigarettes (4, 29). Variations in puffing behaviour and in physical and chemical characteristics, particularly of inhaled aerosols, and the differences in exposure time should be considered when evaluating new products. A method is required to assess changes in risk associated with each PREP. There is no agreed method for assessing the risks associated with toxicants in a complex mixture such as mainstream smoke. At present, the “margin-of-exposure” approach is considered the most appropriate for estimating the risks associated with individual smoke components (30, 31). The margin of exposure is defined as the ratio of a critical toxicological end-point (e.g. a no-observed-adverse-effect level or a benchmark dose) to an appropriate exposure dose metric: the higher the margin of exposure, the lower the risk. Although interpretation of this measure depends on extrapolation (e.g. between and within species and types of exposure), it has been used successfully to assess novel tobacco products (30, 31). A limitation of the margin-of-exposure approach is that it is intended for single compounds, not exposure to mixtures; additive effects can be calculated, but, as synergistic effects cannot be taken into account, the risks may be underestimated. If the margin of error increases because the concentration has decreased in a PREP, the synergistic effects are expected to decrease and the risk will be reduced disproportionately; on the other hand, if the margin of error decreases, the overall outcome is unknown because the impact of synergistic effects cannot be determined without carefully designed studies. Biomarkers of exposure are toxicant-specific; therefore, biomarkers of effect are needed to assess the health effects of PREPs. Wide variation in the concentrations of biomarkers of exposure are found among individuals using the same PREP, which is presumed to reflect both individual smoking and tobacco use behaviour and inter-individual differences in metabolism. Therefore, while group mean biomarkers of exposure tend to be reduced when comparing the use of a PREP and smoking, the wide variation may result in some users not experiencing a decrease in exposure. Often, only a few biomarkers of exposure are measured, and the possibility of increased levels of unmeasured toxicants in PREPs cannot be excluded. For instance, in a study of a British American Tobacco process (tobacco-blend treatment), the levels of carcinogens such as formaldehyde and benzo[a]pyrene were increased (32). Correlations between reduced yields and biomarkers of disease (effect) must be studied to properly assess potential long-term health risks and the full range of tobacco-related diseases, including cardiovascular disease, pulmonary disease, cancer and fetal toxicity (25, 33).
25
Post-market surveillance of novel products is crucial for determining their effects on population health. Pre-market evaluation cannot fully remove uncertainty about how products will be used and their effects once they are introduced onto the market. Post-market surveillance can help to identify emerging issues once a product is being used by the broader population, such as consumer response, potential for abuse, use by minors, dual use, long-term effects of use or accidental ingestion by children (34). A post-market regulatory framework is also required for monitoring ingredients and constituents, as for conventional cigarettes. Consideration should be given to which contents and emissions of novel products are priorities. For instance, in methods for measuring waterpipe emissions, priority should be given to nicotine, polycyclic aromatic hydrocarbons (PAH), aldehydes and carbon monoxide (CO). New products should also be assessed for their potential to recruit new users, their potential to discourage smoking cessation and their effects on other forms of tobacco use. Considerations in evaluating the potential public health impact of novel tobacco products include their potential to recruit new consumers who previously did not use tobacco, potential progression to smoking conventional cigarettes, potential to discourage smoking cessation, and whether the products will be used exclusively or will lead to significant dual (or multi-) tobacco product use. 2.4.3 Marketing and consumer perception
Recently, companies have changed the way in which they interact with both current and prospective customers. Web sites promoting specific brands of tobacco are a relatively new form of marketing for tobacco companies (35). Research should be conducted to determine how web sites and other new media are being used to communicate brand identity, advertise brand events and promotions and introduce new products. Social media should also be monitored for new trends. Packaging plays a significant role in shaping perceptions of novel products. Brand extension of traditional products to novel products may enhance their acceptability through a recognizable brand name. Some novel products may be less expensive than the traditional products, which may favour their acceptance. Research should be conducted on how tobacco users perceive newly introduced products and the accompanying direct and implicit health claims made by tobacco manufacturers. For example, analysis of smokers’ responses to advertisements for potential reduced-exposure cigarettes (Omni, Eclipse and Advance) showed that, although the advertisements did not explicitly state that the products were healthy or safe, smokers perceived them as being associated
26
with lower health risks and fewer carcinogens than other cigarettes (36). Effective regulation must take into account the perceptions arising from advertisements in addition to the explicit content of the advertising text. An important aspect of novel tobacco products is whether they are marketed as products as such, as a means of reducing cigarette smoking or for use when smoking is not possible. These different approaches may have substantial effects on the use and public health impact of a new product. 2.4.4 Risk communication
Effective approaches for providing accurate, understandable information to health professionals and the general public should be identified in order to prevent or reverse any misperceptions about novel products. General communication rules with regard to the content of messages, the type of media, the messenger and timing should be considered, and messages should be tailored to different target groups. Correct health information can be effective in changing consumers’ and tobacco control professionals’ perceptions of products (37, 38). Counter-marketing messages may also be effective in discouraging current and former smokers from becoming dual users of smokeless tobacco and cigarettes (39). 2.4.5 Regulatory issues
Although marketing in the USA has emphasized the Swedish origin of snus (9), snus manufactured in the USA differs from that made in Sweden with regard to moisture content, pouch size and the content of nicotine and other constituents (40–42). Furthermore, the higher levels of tobacco-specific nitrosamines (TSNA) in the latest versions of Camel Snus indicate that either the tobacco type or the tobacco processing method (or both) used in manufacturing this product is different from that for Swedish snus. Therefore, those researchers who advocate replication of the “Swedish experience” in other countries should be cautious. Analysis of the characteristics of these products should be country-specific. Regulation of tobacco product nomenclature would require tobacco manufacturers to justify the use of existing tobacco product names for newly developed products. Individual and public health may be harmed if brand extension perpetuates use of multiple tobacco products with the same name. The carcinogenic potential of smokeless tobacco products varies worldwide with the nature of the product used. Promotion of novel smokeless tobacco products as a harm-reduction strategy in countries where the locally marketed products are highly toxic could be particularly detrimental (43–45).
27
Tobacco control measures such as taxation, smoke-free workplaces and clean air laws may stimulate the development and adoption of novel product types. Research should be conducted on the impact of tobacco control measures on marketed products, such as their toxicity or addictiveness. Changes in tobacco use from conventional cigarettes to products that do not involve the burning of tobacco suggest that the focus on exposure to “second-hand smoke” should evolve to the more inclusive concept of “second-hand tobacco”. Both psychological and behavioural considerations, such as social acceptability by non-users and initiation by new users, and biochemical aspects, such as accidental ingestion or experimentation by children and exposure to tobacco constituents at home, must be considered. For instance, it has been shown that non-smoking residents, including children, living with smokeless tobacco users can be exposed to high levels of nicotine and other constituents of tobacco by contact with contaminated household surfaces (46). 2.5 Regulatory recommendations All new and emerging tobacco products should be regulated under the WHO FCTC. The regulatory framework could be extended to include not only existing and emerging tobacco products but also products that are “gateways” to or substitutes for smoking, such as non-tobacco shisha, electronic cigarettes, herbal cigarettes and herbal snuff. When regulation under the WHO FCTC is not feasible, novel products should at least be monitored to determine their effects. A notification or premarket authorization should be required for all novel products. When feasible, a regulatory body should determine which products are allowed on the market, on the basis of scientific evidence of potential public health benefit. In line with criteria developed by the US Food and Drug Administration, the burden of proof should lie with manufacturers, while the established regulatory body should have the authority to decide whether the information provided is sufficient. Any other required scientific data should be provided by manufacturers and audited by independent scientists. The financial burden for establishing such a system should be borne by the industry. Regulatory strategies developed by the US Food and Drug Administration could be used as a basis for deciding on best practices (10). The prevalence of new tobacco products and their use should be monitored in each country to determine whether a product is a priority for regulation or other tobacco control measures. Novel products that are introduced onto the market should be monitored for unanticipated population outcomes, including • unrecognized toxicity;
28
•
increased or sustained prevalence of tobacco use by recruitment of new users, relapse of ex-smokers or maintenance of tobacco use in current smokers who might otherwise have quit; dual use with cigarettes or another conventional tobacco product; and initiation of tobacco use with a novel product by adolescents or other populations at risk and eventual switching to cigarette smoking (“gateway” effect).
• •
Regulatory bodies should prepare strategies for clearly communicating information about novel products to both professionals (such as general practitioners) and the general public. 2.6 References 1. 2. Rainey CL, Conder PA, Goodpaster JV. Chemical characterization of dissolvable tobacco products promoted to reduce harm. J Agric Food Chem 2011;59:2745–51. Romito LM, Saxton MK, Coan LL, Christen AG. Retail promotions and perceptions of R.J. Reynolds’ novel dissolvable tobacco in a US test market. Harm Reduction J 2011;8:10. Southwell BG, Kim AE, Tessman GK, MacMonegle AJ, Choiniere CJ, Evans SE et al. The marketing of dissolvable tobacco: social science and public policy research needs. Am J Health Promot 2012;26:331–2. Slade J, Connolly GN, Lymperis D. Eclipse: does it live up to its health claims? Tob Control 2002;11(Suppl 2):ii64–70. Hatsukami DK, Henningfield JE, Kotlyar M. Harm reduction approaches to reducing tobacco-related mortality. Annu Rev Public Health 2004;25:377–95. Kleinstreuer C, Feng Y. Lung deposition analyses of inhaled toxic aerosols in conventional and less harmful cigarette smoke: a review. Int J Environ Res Public Health 2013;10:4454–85. Deng Q, Huang C, Zhang J, Xie W, Xua H, Wei M. Selectively reduction of tobacco specific nitrosamines in cigarette smoke by use of nanostructural titanates. Nanoscale 2013;5:5519–23. Dittrich DJ, Fieblekorn RT, Bevan MJ, Rushforth D, Murphy JJ, Ashley M, et al. Approaches for the design of reduced toxicant emission cigarettes. SpringerPlus 2014;3:374. Bahreinifar S, Sheon NM, Ling PM. Is snus the same as dip? Smokers’ perceptions of new smokeless tobacco advertising. Tob Control 2013;22:84–90.
3.
4. 5. 6.
7.
8.
9.
10. Tobacco Product Scientific Advisory Committee. Modified risk tobacco product applications. Draft guidance. Rockville, Maryland: US Food and Drug Administration; 2012. 11. Zeller M, Hatsukami D, Strategic Dialogue on Tobacco Harm Reduction Group. The Strategic Dialogue on Tobacco Harm Reduction: a vision and blueprint for
29
action in the US. Tob Control 2009;18:324–32. 12. Tobacco Product Scientific Advisory Committee. Summary: TPSAC report on dissolvable tobacco products (Rep. No. March 1, 2012). Rockville, Maryland: US Food and Drug Administration; 2012. 13. Delnevo CD, Waskowski OA, Giovenco DP, Bover Manderski MT, Hrywna M, Ling PM. Examining market trends in the United States smokeless tobacco use: 2005–2011. Tob Control 2014;23(2):107–12. 14. Blank MD, Eissenberg T. Evaluating oral noncombustible potential-reduced exposure products for smokers. Nicotine Tob Res 2010;12:336–43. 15. Cobb CO, Weaver MF, Eissenberg T. Evaluating the acute effects of oral, noncombustible potential reduced exposure products marketed to smokers. Tob Control 2010;19:367–73. 16. Hatsukami DK, Jensen J, Anderson A, Broadbent B, Allen S, Zhang Y, et al. Oral tobacco products: preference and effects among smokers. Drug Alcohol Depend 2011;118:230–6. 17. Ramstrom LM, Foulds J. Role of snus in initiation and cessation of tobacco smoking in Sweden. Tob Control 2006;15:210–4. 18. Lund KE, McNeill A, Scheffels J. The use of snus for quitting smoking compared with medicinal products. Nicotine Tob Res 2010;12:817–22. 19. Scheffels J, Lund KE, McNeill A. Contrasting snus and NRT as methods to quit smoking. an observational study. Harm Reduction J 2012;9:10. 20. Pederson LL, Nelson DE. Literature review and summary of perceptions, attitudes, beliefs, and marketing of potentially reduced exposure products: communication implications. Nicotine Tob Res 2007;9:525–34. 21. O’Connor RJ, Norton KJ, Bansal-Traves M, Mahoney MC, Cummings KM, Borland R. US smokers’ reactions to a brief trial of oral nicotine products. Harm Reduction J 2011; 8:1. 22. Biener L, McCausland K, Curry L, Cullen J. Prevalence of trial of snus products among adult smokers. Am J Public Health 2011;101(10):1870–6. 23. McNeill A, Hammond D, Gartner C. Whither tobacco product regulation? Tob Control 2012;21:221–6. 24. Hatsukami DK, Joseph AM, LeSage M, Jensen J, Murphy SE, Pentel P, et al. Developing the science base for reducing tobacco harm reduction. Nicotine Tob Res 2007;9(Suppl 4):S537–53. 25. Hatsukami DK, Feuer RM, Ebbert JO, Stepanov I, Hecht SS. Changing smokeless tobacco products: new tobacco delivery systems. Am J Prev Med 2007;33:S368–78. 26. Burns DM, Dybing E, Gray N, Hecht S, Anderson C, Sanner T, et al. Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal. Tob Control 2008;17:132–41. 27. Djordjevic MV, Stellman SD, Zang E. Doses of nicotine and lung carcinogens delivered to cigarette smokers. J Natl Cancer Inst 2000;92(2):106–11.
30
28. Deng Q, Huang C, Xie W, Xu H, Wei M. Significant reduction of harmful compounds in tobacco smoke by the use of titanite nanosheets and nanotubes. Chem Commun (Camb) 2011;47:6153–5. 29. Lee EM, Malson JL, Moolchan ET, Pickworth WB (2004) Quantitative comparisons between a nicotine delivery device (Eclipse) and conventional cigarette smoking. Nicotine Tob Res 2004;6:95–102. 30. Cunningham FH, Fiebelkorn S, Johnson M, Meredith C. A novel application of the margin of exposure approach: segregation of tobacco smoke toxicants. Food Chem Toxicol 49:2921–33. 31. Hernandez LG, Bos PM, Talhout R. Tobacco smoke-related health effects induced by 1,3-butadiene and strategies for reduction. Toxicol Sci 2013;136:566–80. 32. Liu C, DeGrandpre Y, Porter A, Griffiths A, McAdam K, Voisine R et al. The use of a novel tobacco treatment process to reduce toxicant yields in cigarette smoke. Food Chem Toxicol 2011;49:1904–17. 33. Hatsukami DK, Giovino GA, Eissenberg T, Clark P, Lawrence D, Leischow S. Methods to assess potential reduced exposure products. Nicotine Tob Res 2005;7(6):827–44. 34. O’Connor RJ. Postmarketing surveillance for “modified-risk” tobacco products. Nicotine Tob Res 2012;14:29–42. 35. Wackowski OA, Lewis MJ, Delnevo CD. Qualitative analysis of Camel Snus’ website message board—users’ product perceptions, insights and online interactions. Tob Control 2011;20:e1. 36. Hamilton WL, DiStefano NJ, Ouellette TK, Rhodes WM, Kling R, Connolly GN. Smokers’ responses to advertisements for regular and light cigarettes and potential reduced-exposure tobacco products. Nicotine Tob Res 2004;6:S353–62. 37. Biener L, Bogen K, Connolly G. Impact of corrective health information on consumers’ perceptions of “reduced exposure” tobacco products. Tob Control 2007;16:306–11. 38. Biener L, Nyman AL, Stepanov I, Hatsukami D. Public education about the relative harm of tobacco products: an intervention for tobacco control professionals. Tob Control 2013;22(6):412–7. 39. Popova L, Neilands TB, Ling PM. Testing messages to reduce smokers’ openness to using novel tobacco products. Tob Control 2014;23(4):313–21. 40. Foulds J, Furberg H. Is low-nicotine Marlboro snus really snus? Harm Reduction J 2008;5:9. 41. Stepanov I, Jensen J, Hatsukami D, Hecht SS. New and traditional smokeless tobacco: comparison of toxicant and carcinogen levels. Nicotine Tob Res 2008;10:1773–82. 42. Stepanov I, Biener L, Knezevich A, Nyman AL, Bliss R, Jensen J et al. Monitoring tobacco-specific N-nitrosamines and nicotine in novel Marlboro and Camel smokeless tobacco products: findings from round I of the New Product Watch. Nicotine Tob Res 2012;14:274–81.
31
43. Hatsukami DK, Lemmonds C, Tomar SL. Smokeless tobacco use: harm reduction or induction approach? Prev Med 2004;38:309–17. 44. Bedi R, Scully C. Tobacco control—debate on harm reduction enters new phase as India implements public smoking ban. Lancet Oncol 2008;9:1122–3. 45. Ayo-Yusuf OA, Burns DM. The complexity of “harm reduction” with smokeless tobacco as an approach to tobacco control in low-income and middle-income countries. Tob Control 2012;21:245–51. 46. Whitehead TP, Metayer C, Park JS, Does M, Buffler PA, Rappaport SM. Levels of nicotine in dust from homes of smokeless tobacco users. Nicotine Tob Res 2013;15(12):2045–52.
32
3. Smokeless tobacco products: research needs and regulatory recommendations6 3.1 Introduction 3.1.1 Wide range of products 3.1.2 Limited data 3.1.3 Novel products and marketing 3.1.4 Impact on young people and development of tobacco use 3.1.5 Limited treatment options 3.1.6 Tobacco “harm reduction” 3.2 Results of the WHO tobacco products survey, 2014 3.3 Current regional and national regulations 3.3.1 WHO African Region 3.3.2 WHO Region of the Americas 3.3.3 WHO Eastern Mediterranean Region 3.3.4 WHO European Region 3.3.5 WHO South-East Asia Region 3.3.6 WHO Western Pacific Region 3.4 Conclusions 3.5 Research needs 3.5.1 Surveillance and monitoring 3.5.2 Product characterization 3.5.3 Health effects 3.5.4 Economics and marketing 3.5.5 Interventions 3.6 Regulatory recommendations 3.6.1 Interventions and policy 3.6.2 Challenges and recommendations for creating a regulatory framework 3.6.3 Building capacity 3.7 References
3.1 Introduction Smokeless tobacco products present a complex, widespread challenge to public health that has so far received limited attention from researchers and policy-makers. In many regions of the world, such as India, it is the predominant form of tobacco use; and data from the Global Youth Tobacco Survey in 2006 showed that students aged 13–15 surveyed in 132 countries were more likely to report using non-cigarette tobacco products, including smokeless tobacco (11.2%), than smoking cigarettes (8.9%) (2). Data from household surveys, 6 The background paper that was the basis for the TobReg deliberations on this issue was a synopsis of a then unpublished report entitled Smokeless tobacco and public health: a global perspective, which was published in 2014 (1).
33
including the Global Adult Tobacco Survey, in a few countries show that use of smokeless tobacco tends to be more frequent among women and people in lower socioeconomic strata, making these populations even more vulnerable to the health and economic consequences of these products. Yet, international tobacco control has focused mainly on cigarettes, with only limited attention to other types of products, including smokeless tobacco. Smokeless tobacco products have been used worldwide for hundreds of years, and today over 300 million adults worldwide use these products; nearly 270 million of these users live in the WHO South-East Asia Region (3). The serious health effects of smokeless tobacco have been documented: users are at high risk for death from all causes (4–7) and from specific diseases (8–12). In 2004, a working group convened by the International Agency for Research on Cancer (IARC) found that there was sufficient epidemiological and experimental evidence to conclude that smokeless tobacco causes oral cancer, oesophageal cancer and pancreatic cancer in humans (13, 14). At least 28 carcinogens have been identified in smokeless tobacco products, including TSNA, which cause tumours of the nasal cavity, lung, trachea, pancreas, liver and oesophagus in animal models (15). Smokeless tobacco also causes adverse oral health effects, including oral mucosal lesions, leukoplakia and periodontal disease (16, 17). Use of smokeless tobacco increases the risk for cardiovascular diseases (18, 19) and causes adverse reproductive outcomes when used by pregnant women (20, 21). As smokeless tobacco products contain nicotine, users show signs of dependence similar to those of cigarette smokers, including tolerance with repeated use and symptoms of withdrawal upon cessation of use (22). Although smokeless tobacco use, like tobacco smoking, can cause serious damage, it poses substantial challenges for science and public health that are distinct from those presented by tobacco smoking. For example, the extent of health effects may vary by country, with the highest risks in countries including India and lower health risks in Sweden (23), due in part to the types and toxicity of the products used in different countries. 3.1.1 Wide range of products
Understanding the use and effects of smokeless tobacco products is complicated by the diversity of products and the related behaviour. The wide range includes chewing tobacco, snuff, gutka, betel quid with tobacco, snus, toombak, iqmik and tobacco lozenges. Yet, limited data are available on the properties of these products, how they are used and the prevalence of their use in different population groups. It is therefore inappropriate to make generalizations about them as a class. Additionally, the ways in which these products are produced, sold, used and controlled (such as through taxes or marketing restrictions) differ widely by country and region.
34
3.1.2 Limited data
Although the biological effects of smokeless tobacco are known, the public health impact of its use depends on various factors, including the prevalence and patterns of use of different products, the impact of marketing messages and the effectiveness of prevention and cessation activities. While certain groups have been identified as being at increased risk for use, limited data are available on why particular populations begin to use smokeless tobacco and what factors are most important in preventing or promoting initiation. 3.1.3 Novel products and marketing
Tobacco manufacturers have introduced a new generation of smokeless tobacco products that may have broad consumer appeal because of the addition of attractive flavourings, such as mint or fruit, and new delivery methods, such as lozenges. Products have also been developed that appeal to novice users, new target populations (such as women) or smokers by placing smokeless tobacco in small pouches, thus eliminating the need to spit. Major multinational cigarette companies such as Philip Morris and RJ Reynolds have introduced snus products carrying the well-known Marlboro and Camel brand names, with the marketing expertise of those companies now in the service of smokeless tobacco products. Tobacco control experts warn that increased marketing of these products may have an adverse impact on population health by appealing to young, new users or by inciting current smokers to maintain their nicotine dependence (24). Novel nicotine delivery devices, such as electronic cigarettes, in which heat, rather than combustion, is used to release a vapour containing nicotine, are also being marketed in many countries as an alternative to conventional cigarettes. These products are not addressed in this report, but they may also affect the patterns of tobacco use (25). Some tobacco companies responded to the widespread smoke-free indoor air laws by advertising smokeless tobacco products to smokers as a temporary alternative to cigarettes for use in situations in which they cannot smoke, using slogans such as “Enjoy tobacco inside the office? You bet” and “Enjoy tobacco on a 4-hour flight? You bet” (26). In addition to increasing smokeless tobacco use, this marketing strategy may impede smoking cessation efforts by making it easier for smokers to maintain their nicotine addiction between cigarettes. This is an example of how progress made in one area of tobacco control, such as through smoke-free indoor air laws, has been followed by adaptation by the tobacco manufacturers, this time by introducing new products and marketing strategies.
35
3.1.4 Impact on young people and development of tobacco use
Increased initiation of smokeless tobacco use by young people poses a major public health challenge. Smokeless tobacco use amobyng adolescents and young adults rose substantially in the USA during the 1970s after the introduction of products that were more accessible to new users (27). These products had a lower nicotine content and attractive flavourings; evidence suggests that users who begin with low-nicotine “starter” products are more likely to “graduate” subsequently to products with a higher nicotine content (28). In India, marketing of a new smokeless tobacco product, gutka, led to increases in the incidences of oral submucous fibrosis and mouth cancer among young people (29, 30). Moreover, a number of studies suggest that smokeless tobacco use is associated with and reinforces use of other tobacco products, including cigarettes. Thus, adolescents who use smokeless tobacco may also be more likely to move on to cigarette smoking (31, 32). The 2014 US Surgeon General’s Report (33) shows that, although US cigarette consumption has decreased substantially, both the consumption and the sale of smokeless tobacco have risen since 2000, with increased use among young adults (18–25 years of age), an overall prevalence of 5.5% and far more common current use among males (10.5%) than females (0.5%). 3.1.5 Limited treatment options
Strategies for cessation of smokeless tobacco use have had mixed success. Behavioural intervention studies in India were successful in rural populations (34, 35) and among schoolteachers (36). Clinical trials of behavioural interventions in settings such as dental offices showed increased abstinence rates among smokeless tobacco users, although the evidence is insufficient to recommend specific intervention components (37, 38). Trials of pharmacotherapy, including nicotine patches, nicotine gum and bupropion, showed no effect on long-term (> 6 months) abstinence rates (39); however, pharmacotherapy may reduce symptoms associated with cessation, such as craving and weight gain (40). Moreover, people who use both cigarettes and smokeless tobacco have higher exposure to nicotine and find cessation more difficult than those who use only smokeless tobacco or who only smoke (41–43). Very few countries have a cessation intervention for smokeless tobacco users in their national programmes. Recently, the National Tobacco Control Programme in India scaled up cessation services for both cigarette and smokeless tobacco users (44). 3.1.6 Tobacco “harm reduction”
The response to the hazards of smokeless tobacco use is complicated by discussions about the possibility of using this form of tobacco as a means to reduce
36
harm in cigarette smokers. Some forms of smokeless tobacco could provide an alternative to cigarettes; as smokeless tobacco is not associated with the same risks for lung cancer and respiratory diseases as cigarette smoking, it might reduce the overall risk. Although all forms of smokeless tobacco are harmful and cause cancer and other diseases, some forms, including some snus products, have lower concentrations of TSNA and other toxicants than cigarettes and may pose lower overall risks. This inference requires a number of assumptions, as the health effects of the most widely used forms of smokeless tobacco in a number of Asian countries have not been fully documented, and some smokeless tobacco products used in Bangladesh and India have not been tested. Some products called “snus” in India are highly toxic (45).7 Given the wide diversity of smokeless tobacco products and patterns of use around the world, it is inappropriate to make any broad generalization about the level of harm associated with these products as a category, as little is known about their toxic constituents or the exposure of users. Will smokers who begin using smokeless tobacco products completely replace cigarettes, or will they instead become dual product users, which could increase their risk? Additionally, it is essential to consider the overall population impact of increased smokeless tobacco use. For example, will increased promotion of these products increase initiation of tobacco use or adversely affect smoking cessation efforts? While the body of evidence on this topic is growing, definitive studies to answer key questions are lacking, and more research is needed. 3.2 Results of the WHO tobacco products survey, 2014 The WHO questionnaire on smokeless tobacco, electronic nicotine delivery systems, reduced ignition propensity (RIP) cigarettes and novel tobacco products was sent to all WHO Member States in 2013.8 The responses indicated that smokeless tobacco products are available in 70 Member States in which 73% of the world population lives. Snuff is widely available in 52 Member States (65% of the world population), snus in 21 (55%), chewing tobacco in 55 (51%), tobacco gum in 17 (49%), dissolvable tobacco in 7 (44%), topical tobacco paste in 5 (40%), dipping tobacco in 10 (29%), creamy snuff in 6 (23%), tobacco water in 8 (20%), gutka in 11 (10%), orbs in 3 (6%) and blackbull (iqmik) in 3 Member States (5%) (dissolvable tobacco products were not distinguished from dissolvable tobacco in the questionnaire). Flavoured smokeless tobacco is also widely available in 34 Member States (61%), the most popular flavours 7 See also http://en.schweden-snus.com/chaini-khaini.html and https://www.youtube.com/ watch?v=HqOfA7tXhwY. 8 A total of 90 countries, including 86 Parties to the WHO FCTC, had responded to the survey as of 9 April 2014, representing 77% of the world population.
37
being menthol and mint. It is made available by local manufacturers in three Member States (1%), by cottage industries in 8 (2%), by importation from other countries in 30 (8%), by local manufacture and cottage industries in 5 (26%), by local manufacture and importation in 6 (24%), by cottage industries and importation in 7 (1%) and by local manufacture, cottage industries and importation in 6 Member States (9%). The main countries from which smokeless tobacco products were imported were India, Sweden and the USA. Smokeless tobacco products are regulated under tobacco laws in 46 Member States (26%), under both tobacco and food safety laws in 8 Member States (19%) and under other laws in 9 (23%); the laws under which these products are regulated were unknown in the remaining Member States. Comprehensive bans on advertising, promotion and sponsorship of smokeless tobacco products are in place in 58 Member States (40%), while there are partial bans in 11 (29%). The production, distribution and sale of smokeless tobacco products are regulated to some extent in 54 Member States (66%). The production of commercially manufactured smokeless tobacco products is regulated in 41 (60%), the distribution in 43 (59%) and sale in 51 (63%); the production of smokeless tobacco products manufactured in cottage industries is regulated in 24 (31%) Member States, distribution in 30 (33%) and sale in 36 (41%). The content and ingredients of smokeless tobacco products on the market are regulated in 9 Member States (22%). Governmental sales licences are required in 26 Member States (30%); policies regulating the sale of smokeless tobacco products to minors exist in 64 Member States (72%), and the minimum age for buying these products ranged from 16 to 21 years, when this information was specified. Taxes are levied on these products as follows: no excise tax in 24 Member States (13%), a uniform ad valorem excise tax in 8 Member States (21%), a uniform specific excise tax in 11 (8%), a mix of uniform ad valorem and uniform specific excise taxes in 4 Member States (2%), uniform ad valorem with minimum specific floors in 3 Member States (1%), a tiered system in 1 Member State (1%), value added tax in 34 Member States (53%) and import duty in 31 (53%). 3.3 Current regional and national regulations 3.3.1 WHO African Region
The introduction of smokeless tobacco products into many eastern and southern sub-Saharan African countries in the past decade or so has gone mainly unnoticed by health and revenue authorities. A number of countries in the Region are now adopting comprehensive tobacco control policies and legislation
38
to cover all tobacco products, including smokeless products. Sale of these products was officially banned in the United Republic of Tanzania in 2006, although it has been suggested that more stringent monitoring and enforcement are needed. Seychelles has legally mandated pictorial health warnings covering 50% or more of the principal display areas on smokeless tobacco product packaging. 3.3.2 WHO Region of the Americas
In Brazil, smokeless tobacco products may be sold if they are registered with the national health regulatory agency, ANVISA; as none are registered, however, the sale of any such product in Brazil is currently illegal. In Canada, smokeless tobacco products generally fall under broader tobacco product regulations, including prohibition of sale to minors, restrictions on promotion and requirements for manufacturer reporting. Labelling regulations for smokeless tobacco products exist but apply only to chewing tobacco, nasal snuff and oral snuff. In the USA, laws have been enacted that include provisions for product registration, warning labels on all products and enforcement of a minimum age for sale. In addition, under US law, the Food and Drug Administration is authorized to establish limits on the amounts of nicotine, toxicants and additives in smokeless tobacco products, but it has not yet issued any specific regulation on product performance standards. Many countries in the Region, including Chile, Costa Rica, Ecuador, El Salvador, Honduras, Nicaragua, Panama, Peru and Uruguay, have legally mandated pictorial health warnings covering 50% or more of the principal display areas on smokeless tobacco product packaging. 3.3.3 WHO Eastern Mediterranean Region
While the Islamic Republic of Iran has banned importation of smokeless tobacco products and Bahrain has adopted policies banning both the sale and importation of these products, few relevant regulatory controls exist in the Region. Heavy fines have been used to enforce the existing laws. Many countries in the Region, such as Egypt, the Islamic Republic of Iran, Kuwait, Morocco, Oman, Qatar and the United Arab Emirates, have legally mandated pictorial health warnings covering 50% or more of the principal display areas on tobacco product packaging. 3.3.4 WHO European Region
The European Union provides leadership on regulatory practices, including through the recently revised Tobacco Products Directive, which governs the manufacture, presentation and sale of tobacco and related products. The 28
39
member states of the European Union regulate smokeless tobacco products by prohibiting the sale of tobacco for oral use, which includes all products for oral consumption made of tobacco except those intended for smoking or chewing. Sweden, however, is exempted from this regulation. In many non-European Union countries in Europe, smokeless tobacco is regulated in accordance with regulations on advertising and health warnings similar to those applicable to smoked tobacco products. Turkey has legally mandated pictorial health warnings covering 50% or more of the principal display areas on smokeless tobacco product packaging. 3.3.5 WHO South-East Asia Region
Many Parties in the Region have taken steps to regulate smokeless tobacco (3). Bhutan introduced a policy to ban the manufacture and sale of tobacco products, including smokeless products, in 2004 and in 2010 introduced comprehensive legislation to implement the 2004 policy. Thailand also has provisions to ban the import and sale of these products. Legislation in Bangladesh, India and Nepal requires the display of graphic health warnings on smoked and smokeless products, covering 50%, 85% and 90% of the display area, respectively. Bangladesh, Bhutan, India, Maldives, Myanmar, Nepal, Sri Lanka and Thailand have banned advertisement of smokeless tobacco products. India invoked food safety laws in 2011 to ban gutka and pan masala containing tobacco, some of the most common forms of smokeless tobacco used in the country. A few states in India, including Maharashtra, have banned production and sale of scented smokeless tobacco products. India has also strengthened pictorial health warnings, used intensive mass media campaigns to inform people of the harm of smokeless tobacco and introduced smokeless tobacco cessation into tobacco dependence treatment guidelines and into the National Tobacco Control Programme. To control illicit trade, India introduced presumptive taxes on smokeless tobacco, based on production capacity; revenue collection on smokeless tobacco products increased by more than fourfold in the past 5 years. Myanmar banned importation of all types of tobacco products, including smokeless tobacco, but illicit trade from neighbouring countries remains a problem. Nepal has banned the use of smokeless tobacco products in public places, and Myanmar banned the sale of these products in certain metropolitan areas and their use in Government workplaces. India, Myanmar and Nepal have policies to prohibit sales of smokeless tobacco products within 100 m of educational facilities. Enforcement is, however, still weak in many countries, and the Region lacks adequate laboratory capacity to test for constituents of smokeless tobacco. The lower taxes on smokeless tobacco than on smoking products lead tobacco users to switch to smokeless tobacco whenever the tax on cigarettes is increased.
40
3.3.6 WHO Western Pacific Region
In 2010, because of concern about the increasing use of areca (betel nut) and chewing tobacco, the WHO Regional Office for the Western Pacific supported Parties to the WHO FCTC in the Region in preparing a regional action plan, in which specific indicators and actions were identified to reduce betel nut and tobacco use. The report, issued in 2012 (46) was prepared in consultation with countries and territories in which use of betel nut and chewing tobacco is particularly common (Cambodia, Guam, Kiribati, Marshall Islands, Micronesia (Federated States of), Mariana Islands, Palau, Solomon Islands and Vanuatu). The report found that use of betel nut is widespread in parts of Melanesia, principally Papua New Guinea, the Solomon Islands and the Northern Province of Vanuatu, and in the Federated States of Micronesia, particularly in the Northern Mariana islands, the Marshall Islands and Palau and also in the US territory Guam. It recommended that evidence on the harm caused by this type of smokeless tobacco be shared with policy-makers and that community-based strategies be designed to change behaviour in use of smokeless tobacco. Some Parties, such as Singapore, have banned smokeless tobacco products such as chewing tobacco, new tobacco-derivative products such as dissolvable tobacco and nicotine-based products. Singapore has a laboratory for measuring nicotine content in smokeless tobacco products such as chewable tobacco, betel quid and khaini. Mongolia and Viet Nam require pictorial health warnings covering 50% or more of the principal display areas on smokeless tobacco product packaging. 3.4 Conclusions Smokeless tobacco is a global problem, in that the products are used in at least 70 low-, middle- and high-income countries by more than 300 million people. The highest prevalence of use is in South-East Asia, with 89% of users, which also has the highest attributable disease burden and the greatest diversity of product types and forms of use. In Bangladesh, more women use these products than men. In India, use of smokeless tobacco exceeds tobacco smoking among both men and women. The disease risks directly associated with smokeless tobacco use differ by country and region, due in part to differences in the products and patterns of use. Laboratory analyses have shown widely varying levels of known carcinogens and nicotine in products from different regions, and epidemiological studies have yielded risk estimates for cancer and cardiovascular disease that vary from country to country. Yet data are lacking to quantify these differences in disease risk precisely and to identify the factors that drive them.
41
Smokeless tobacco use and marketing are public health challenges in a number of countries and regions. While some high-income countries, such as Sweden, have a high prevalence of use of smokeless tobacco with a low nitrosamine content, a reduced prevalence of smoking and strong tobacco control and regulatory frameworks, most countries in which smokeless tobacco is used are low- or middle-income such as Bangladesh, India and other countries in the South-East Asia Region. In these countries, smokeless tobacco products often have very high levels of harmful constituents, marketing of cigarettes is increasing, and a large unorganized business sector makes product control and regulation difficult. Changes in product marketing, patterns of use and tobacco control programmes and interventions may have widely different effects in these different environments. Changing tobacco industry marketing strategies may influence the future public health impact of smokeless tobacco use. In some high-income countries where restrictions on public smoking have increased and the prevalence of smoking has decreased, tobacco companies have been marketing oral tobacco products to smokers. The impact of this trend on smoking behaviour and possible use of one or more tobacco products together remains uncertain. Multinational tobacco companies are increasingly present, introducing both smoked and smokeless products in low- and middle-income countries. In many regions, even those in which smokeless tobacco use is highly prevalent, the policies and programmes for prevention and cessation of smokeless tobacco use are generally weaker than those for smoked tobacco products: the prices are lower, the warning labels are weaker, surveillance is less well developed, fewer proven interventions are available, and fewer resources are devoted to prevention and control. The challenges in monitoring the use and health effects of smokeless tobacco include the diversity of products and types of use, lack of information on the products and their use, the informal, unorganized nature of the market in some regions and limited attention to tailored educational and intervention programmes. Many gaps remain in research on smokeless tobacco products, including surveillance data, characterization of products, the health consequences of use of the products, including fetal exposure and reproductive outcomes, the economic policies related to smokeless tobacco products and their use and effective region-specific education, prevention and treatment interventions. Various policies have been proposed or implemented in some countries, but data are often lacking on their impact or effectiveness. More evidence-based policies are needed to control smokeless tobacco use, which could include: obliging tobacco companies to disclose the content of smokeless tobacco products; establishing product performance standards for toxicants and maximum pH levels; banning flavourings; requiring effective, relevant health warning
42
labels; increasing taxes on these products; banning or restricting promotion, sponsorship and marketing of smokeless tobacco; and raising public awareness about the toxicity and health effects of these products. In sum, prevention and cessation of smokeless tobacco use should form an integral part of any comprehensive tobacco control effort. Capacity for research and public health action on smokeless tobacco is limited in many countries, especially those in which the public health burden is greatest. International infrastructure for research and information-sharing could improve the ability of many countries to reduce the consequences of smokeless tobacco use. 3.5 Research needs 3.5.1 Surveillance and monitoring
Comprehensive surveillance should be conducted to assess the extent of smokeless tobacco use and changes in patterns of use and to evaluate the effectiveness of policies, interventions and other steps that could be taken to reduce its use, even in countries where the products are banned or the prevalence of use is very low. Surveillance and monitoring of trends in use should include information on the populations and subpopulations that use the products, the types of products used, the patterns and intensity of use, combined use with other tobacco products and attitudes, beliefs and perceptions about the products. Surveillance should also include monitoring of changes in use and cessation in use of other tobacco products, including cigarettes. 3.5.2 Product characterization
Given the diversity of products and modes of manufacture around the world, the properties of different products, their constituents and methods of manufacture should be characterized comprehensively. Where the resources are available, biomarker studies to determine actual human uptake (absorption and excretion) of nicotine and other toxicants after active and second-hand exposure (e.g. fetal) to smokeless tobacco would be valuable. Studies should also be conducted on non-tobacco products that are frequently used in conjunction with tobacco, such as areca nut. Products should be tested regularly in order to assess national and regional variations and changes in products over time. 3.5.3 Health effects
The diversity of products, practices and patterns of use also precludes broad generalizations about their health effects. Most studies of health effects have been conducted in India, the Nordic countries and the USA. Because of 43
differences in the levels of nicotine and other toxicants in smokeless tobacco products, the results from one country cannot be applied to another; even within a country, the products may vary widely. Data are not available for estimating the relative risks for disease associated with the different products, although assessment of country-specific health effects is essential for determining the global burden of disease associated with use of smokeless tobacco. 3.5.4 Economics and marketing
Data on pricing, tax structures and sales of smokeless tobacco products and marketing strategies are limited, and there is no information on the cost of health care for treating the diseases caused by use of these products. Such information is necessary to devise policies and programmes for different countries. In view of the high prevalence of smokeless tobacco use in some low- and middle-income countries and among poor and rural populations, information on pricing would be especially important for designing effective public health interventions. Information on prices, taxes, affordability and trade should be collected routinely. 3.5.5 Interventions
Population and individual interventions for the prevention and cessation of smokeless tobacco use should be developed and tested, especially interventions tailored to specific populations of users, taking into account cultural differences. Most of the current evidence base for the effectiveness of interventions applies to high-income countries; therefore, interventions designed for use in low- and middle-income countries and in diverse health care settings are necessary. 3.6 Regulatory recommendations 3.6.1 Interventions and policy
Tobacco control policies, programmes and interventions applied to cigarettes and smoked tobacco products should also be applied, enforced and monitored, with equal rigor, to smokeless tobacco products, particularly in regions where the prevalence of use is high. Prevention and cessation of smokeless tobacco use should be an integral part of a comprehensive tobacco control programme. Nevertheless, these products pose distinct challenges, and specific policies might depend on the products, patterns of use, marketing and the tobacco control environment. The aspects of smokeless tobacco product regulation listed below should be addressed in particular.
44
Pay greater attention to smokeless tobacco. The public health challenge of smokeless tobacco warrants far greater attention and action than it has received so far, considering the extent and complexity of the problem, marketing, trends in patterns of use and lack of effective treatment. Much of the scientific basis for policy to control cigarette use also applies to controlling use of smokeless tobacco. Make country-specific and product-specific interventions. No intervention strategy will apply to all countries: approaches must be tailored to the social context, prevalence and trends in consumption of all tobacco products. Furthermore, because of the heterogeneity of the products and how they are made, policy interventions should be specific for each type of product, both manufactured and custom-made. Apply WHO FCTC requirements to smokeless tobacco products. Tobacco control policy interventions for cigarettes and other forms of smoking tobacco should also apply to smokeless tobacco products. These interventions include: • health warnings on product packaging that cover a major proportion of the package and that include text and pictorial depictions, are rotated and are located on the top principal display (Article 11) (Although many countries require health warnings on smokeless tobacco packaging, most labels have only text warnings and lack the graphic images that have been used on cigarette labels.); restrictions or bans on advertising, promotion and sponsorship (Article 13); restriction of sales to minors (Article 16); taxation and pricing policies, with effective compliance, to discourage smokeless tobacco use and to lower demand, including consideration of using taxation of tobacco leaves or a presumptive tax (compounded levy per manufacturing machine), because of the challenge of traditional markets (Article 6); obligatory disclosure of the constituents of smokeless tobacco products by manufacturers, comprising all the ingredients and harmful and potentially harmful constituents of the products (Article 10); public education about the harms of smokeless tobacco (Article 12), with information, education and communication to raise awareness of the harmful health effects and to dispel myths (Education should be targeted to health professionals, policy-makers, community leaders and the public, with particular attention to young people and women of child-bearing age, especially in geographical areas where tobacco products are made in cottage industries or custom-made at home or at the point of sale.);
• • •
•
•
45
• •
a tracking and tracing mechanism for smokeless tobacco products and prevention of illicit trade (Article 15); and promotion and provision of evidence-based interventions for smokeless tobacco cessation (Article 14).
Reduce the hazard associated with smokeless tobacco products. • Reduce toxicity: The levels of known toxicants in smokeless tobacco products vary widely, as do the effects of storage and processing on toxicant levels (25). Requirements that could be introduced to prevent greater toxicity of pre-made and custom-made products include: reducing the use of Nicotiana rustica; limiting bacterial contamination, which can promote nitrosation and carcinogen formation; requiring that tobacco be flue- or sun-cured rather than fire- or air-cured; killing bacteria by pasteurization; improving storage conditions, such as refrigerating products before sale; affixing a date of manufacture; and eliminating ingredients such as areca nut and tonka bean, which are known to be carcinogenic (14). • Impose product standards (Article 9): As proposed by TobReg (25), upper limits on toxicants should be mandated for smokeless tobacco products manufactured by industry, with an upper limit for N-nitrosonornicotine (NNN) plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at 2 µg/g of dry tobacco and an upper limit for benzo[a]pyrene at 5 ng/g. Regulatory authorities should require monitoring of levels of arsenic, cadmium and lead in tobacco (47). Implementing such standards does not mean that a product is less hazardous, and tobacco companies should not be allowed to promote products as such. Reduce appeal and addictiveness: A variety of flavours and other additives are used to enhance the appeal of tobacco products and facilitate uptake (48, 49). Steps to reduce the appeal of and addiction to tobacco products should include banning or regulating sweeteners and flavourings (including herbs, spices and flowers) and setting limits on free nicotine and pH. Apply uniform standards for transnational products: Exported smokeless tobacco products should be held to the same (or a higher) standard as in the country in which they were manufactured.
•
•
No health claim or claim of reduced exposure or harm should be allowed on the basis of currently available evidence. Scientific evidence introduced to support a health claim must be reviewed by an independent, scientific, government regulatory agency (Article 10).
46
3.6.2
Challenges and recommendations for creating a regulatory framework
Conducting surveillance and research and implementing new policies and interventions to address smokeless tobacco use will require greater scientific and public health capacity in low- and middle-income countries, particularly those with high levels of smokeless tobacco use. Major challenges, however, impede implementation of effective policies and programmes. Gaps in the evidence base and information Limited data are available for quantifying the risks associated with smokeless tobacco use, including the burden on health, the economy, the environment and society, in regions and countries. Furthermore, there is almost no information on progress or challenges in smokeless tobacco control. Recommendation: The Global Tobacco Surveillance System of the US Centers for Disease Control and Prevention and WHO STEP surveys could be extended to provide greater coverage of smokeless tobacco. Smaller, targeted surveys are needed to understand patterns in specific subgroups.
Laboratory testing Most countries in which smokeless tobacco is widely used lack the technical and financial capacity to evaluate the content and toxicant levels in smokeless tobaccos. Methods, product performance standards and testing regimens should be improved to facilitate inter-country comparisons and to monitor products in countries over time. Recommendation: Testing methods should be standardized and, ideally, coordinated by region through the WHO Tobacco Laboratory Network (TobLabNet).9 Methods for determining nicotine, TSNA and benzo[a]pyrene in smokeless tobacco products should be validated. Laboratory capacity should be improved in low- and middle-income countries by partnerships, such as with WHO collaborating centres. 3.6.3 Building capacity
Communication and collaboration among countries are increasingly important. As tobacco use changes, innovative policies and interventions are being introduced in various countries, and the tobacco industry is adopting new marketing strategies. This enormous “natural experiment” provides unique opportunities for research and evaluation, which will require coordinated surveillance, information-sharing and research. With this in mind, the following recommendations are made to enhance collaboration and infrastructure (some of which are described in Article 20 of the WHO FCTC). 9
The WHO Tobacco Laboratory Network (TobLabNet) is a global network of government, academic and independent laboratories for strengthening national and regional capacity for testing and research on the contents and emissions of tobacco products, in accordance with Article 9 of the WHO FCTC (http://www.who.int/tobacco/industry/product_regulation/toblabnet/en/).
47
Create regional knowledge hubs or clearing-houses. Create regional information hubs or clearing-houses for information on tobacco products, especially smokeless tobacco, that can be readily accessed electronically by people throughout the world. Clearing-houses could provide information about global “best practice” and country experience in regulating smokeless tobacco, product characteristics, patterns of use, policies and interventions and the results of research and evaluations. Establish an infrastructure for networking, communication and collaboration. A web portal could be established that would be a repository and index of information on global, regional and country best practice in regulating smokeless tobacco, product characteristics, constituents and ingredients, manufacturing and promotion methods, prices, packaging and marketing. The portal could also bring together the regional hubs or clearing-houses described above and provide a forum for discussion about successes and challenges in smokeless tobacco product regulation, operational and policy research, clinical research design and results and policies. Encourage collaboration among scientists, tobacco control advocates and policy-makers. Such collaboration is critical for translating research into policy and ensuring that policy needs inform research. Collaboration among countries and regions will be especially important for comparing different products, environments and interventions. Countries with more mature tobacco control programmes could provide expertise and assistance to countries with newer programmes and policies. Build research capacity. Research capacity should be built by better use of existing resources, such as the TobLabNet, the Global Adult Survey and the Global Youth Tobacco Survey. Research capacity could also be enhanced by attracting and training new researchers—especially from middle- and low-income countries—and encouraging collaboration between new and more experienced researchers. Enhance opportunities for smokeless tobacco product regulation. Opportunities for evidence-based smokeless tobacco regulation and policy can be increased by international coordination of technical assistance, training and capacity-building; surveillance and enforcement of existing regulations; development and dissemination of testing protocols and product performance standards; and revising existing tobacco control programmes to better address smokeless tobacco.
48
3.7 References 1. National Cancer Institute and Centers for Disease Control and Prevention. Smokeless tobacco and public health: a global perspective. Bethesda, Maryland: Department of Health and Human Services, Centers for Disease Control and Prevention and National Institutes of Health, National Cancer Institute (NIH Publication No. 14-7983); 2014 (http://nccd.cdc.gov/GTSSData/Ancillary/ Publications.aspx). Centers for Disease Control and Prevention. Use of cigarettes and other tobacco products among students aged 13–15 years—worldwide, 1999–2005. Morb Mortal Wkly Rep 2006;55:553–6. WHO Regional Office for South-East Asia. Expert group meeting on smokeless tobacco control and cessation, New Delhi, India, 16–17 August 2011. New Delhi. Gupta PC, Bhonsle RB, Mehta FS, Pindborg JJ. Mortality experience in relation to tobacco chewing and smoking habits from a 10-year follow-up study in Ernakulam District, Kerala. Int J Epidemiol 1984;13:184–7. Gupta PC, Mehta FS, Pindborg JJ. Mortality among reverse chutta smokers in south India. Br Med J 1984;289:865–6. Gupta PC, Mehta HC. Cohort study of all-cause mortality among tobacco users in Mumbai, India. Bull World Health Organ 2000;78:877–83. Gupta PC, Pednekar MS, Parkin DM, Sankaranarayanan R. Tobacco associated deaths in Mumbai (Bombay) India. Results of the Bombay Cohort Study. Int J Epidemiol 2005;34:1395–402, Rahman MA, Zaman MM. Smoking and smokeless tobacco consumption: possible risk factors for coronary heart disease among young patients attending tertiary care cardiac hospital in Bangladesh. Public Health 2008;122:1331–8. Lee PN, Hamling J. Systematic review of the relation between smokeless tobacco and cancer in Europe and North America. BMC Med 2009;29:36.
2.
3. 4.
5. 6. 7.
8.
9.
10. Lee CH, Lee KW, Fang FM, Wu DC, Shieh TY, Huang HL, et al. The use of tobacco-free betel-quid in conjunction with alcohol/tobacco impacts early-onset age and carcinoma distribution for upper aerodigestive tract cancer. J Oral Pathol Med 2011;40:684–92. 11. Mateen FJ, Carone M, Alam N, Streatfield PK, Black RE. A population-based case–control study of 1250 stroke deaths in rural Bangladesh. Eur J Neurol 2012;19:999–1006. 12. Rahman MA, Spurrier N, Mahmood MA, Rahman M, Choudhury SR, Leeder S et al. Is there any association between use of smokeless tobacco products and coronary heart disease in Bangladesh? PLoS One 2012;7:e30584. 13. Cogliano V, Straif K, Baan R, Grosse Y, Secretan B, El Ghissassi F. Smokeless tobacco and tobacco-related nitrosamines. Lancet Oncol 2004;5:708. 14. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 85. Betel quid and areca nut chewing. Lyon: International Agency for Research on Cancer; 2004 (http://monographs.iarc.fr/ENG/Monographs/vol85/mono85-6.
49
pdf, accessed 1 August 2012). 15. Smokeless tobacco or health: an international perspective (Smoking and Tobacco Control Monograph No. 2). Bethesda, Maryland: National Cancer Institute, Department of Health and Human Services; 1992 (Publication No. 923461) (http://www.cancercontrol.cancer.gov/tcrb/monographs/2/index.html). 16. Shulman JD, Beach MM, Rivera-Hidalgo F. The prevalence of oral mucosal lesions in US adults: data from the Third National Health and Nutrition Examination Survey, 1988–1994. J Am Dent Assoc 2004;135:1279–86. 17. Fisher MA, Bouquot JE, Shelton BJ. Assessment of risk factors for oral leukoplakia in West Virginia. Community Dent Oral Epidemiol 2005;33:45–52. 18. Boffetta P, Straif K. Use of smokeless tobacco and risk of myocardial infarction and stroke: systematic review with meta-analysis. BMJ 2009;339:b3060. 19. Gupta R, Gupta N, Khedar RS. Smokeless tobacco and cardiovascular disease in low and middle income countries. Indian Heart J 2013;65;369–77. 20. England LJ, Kim SY, Tomar SL, Ray CS, Gupta PC, Eissenberg T, et al. Noncigarette tobacco use among women and adverse pregnancy outcomes. Acta Obstet Gynaecol Scand 2010;89:454–64. 21. Willis D, Popovech M, Gany F, Zelikoff J. Toxicology of smokeless tobacco: implications for immune, reproductive, and cardiovascular systems. J Toxicol Environ Health Crit Rev 2012;15:317–31. 22. Henningfield JE, Fant RV, Tomar SL. Smokeless tobacco: an addicting drug. Adv Dent Res 1997;11:330–5. 23. Boffetta P, Hecht S, Gray N, Gupta P, Straif K. Smokeless tobacco and cancer. Lancet Oncol 2008;9:667–75. 24. Henningfield JE, Rose CA, Giovino GA. Brave new world of tobacco disease prevention: promoting dual product use? Am J Prev Med 2002;23:226–8. 25. WHO Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation: third report of a WHO study group (WHO Technical Report Series, No. 955). Geneva: World Health Organization; 2009 (http://www.who.int/tobacco/global_interaction/tobreg/publications/tsr_955/en/ index.html). 26. O’Hegarty M, Richter P, Pederson LL. What do adult smokers think about ads and promotional materials for PREPs? Am J Health Behav 2007;31:526–34. 27. Connolly GN. The marketing of nicotine addiction by one oral snuff manufacturer. Tob Control 1995;4:73–9. 28. Tomar SL, Giovino GA, Eriksen MP. Smokeless tobacco brand preference and brand switching among US adolescents and young adults. Tob Control 1995;4:67–72. 29. Gupta PC, Sinor PN, Bhonsle RB, Pawar VS, Mehta HC. Oral submucous fibrosis in India: a new epidemic? Natl Med J India 1998;11:113–6. 30. Gupta PC. Mouth cancer in India—a new epidemic? J Indian Med Assoc 1999;97:370–3.
50
31. Tomar S. Is use of smokeless tobacco a risk factor for cigarette smoking? The US experience. Nicotine Tob Res 2003;5:561–9. 32. Hatsukami DK, Lemmonds C, Tomar SL. Smokeless tobacco use: harm reduction or induction approach? Prev Med 2004;38:309–17. 33. The health consequences of smoking—50 years of progress. A report of the Surgeon General. Rockville, Maryland: Department of Health and Human Services; 2014. 34. Gupta PC, Mehta FS, Pindborg JJ, Bhonsle RB, Murti PR, Daftary DK, et al. Primary prevention trial of oral cancer in India: a 10-year follow-up study. J Oral Pathol Med 1992;21:433–9. 35. Anantha N, Nandakumar A, Vishwanath N, Venkatesh T, Pallad YG, Manjunath P, et al. Efficacy of an anti-tobacco community education program in India. Cancer Causes Control 1995;6:119–29. 36. Sorensen G, Pednekar MS, Sinha DN, Stoddard AM, Nagler E, Aghi MB, et al. Effects of a tobacco control intervention for teachers in India: results of the Bihar School Teachers Study. Am J Public Health 2013;103:2035–40. 37. Severson HH. What have we learned from 20 years of research on smokeless tobacco cessation? Am J Med Sci 2003;326:206–11. 38. Carr AB, Ebbert JO. Interventions for tobacco cessation in the dental setting. Cochrane Database Syst Rev 2006:CD005084. 39. Ebbert JO, Rowland LC, Montori V, Vickers KS, Erwin PC, Dale LC, et al. Interventions for smokeless tobacco use cessation. Cochrane Database Syst Rev 2004:CD004306. 40. Dale LC, Ebbert JO, Glover ED, Croghan IT, Schroeder DR, Severson HH, et al. Bupropion SR for the treatment of smokeless tobacco use. Drug Alcohol Depend 2007;90:56–63. 41. Hatsukami DK, Severson HH. Oral spit tobacco: addiction, prevention and treatment. Nicotine Tob Res 1999;1:21–44. 42. Spangler JG, Michielutte R, Bell RA, Knick S, Dignan MB, Summerson JH. Dual tobacco use among Native American adults in southeastern North Carolina. Prev Med 2001;32:521–8. 43. Wetter DW, McClure JB, de Moor C, Cofta-Gunn L, Cummings S, Cinciripini PM, et al. Concomitant use of cigarettes and smokeless tobacco: prevalence, correlates, and predictors of tobacco cessation. Prev Med 2002;34:638–48. 44. Varghese C, Kaur J, Desai NG, Murthy P, Malhotra S, Subbakrishna DK, et al. Initiating tobacco cessation services in India: challenges and opportunities. WHO South-East Asia J Public Health 2012;1:159–68. 45. Mukherjea A. Tobacco industry co-optation of culture? Converging culturally specific and mainstream tobacco products in India. Tob Control 2012;21:63–4. 46. Review of areca (betel) nut and tobacco use in the Pacific. A technical report. Manila: WHO Regional Office for the Western Pacific; 2012 (http://www.wpro. who.int/tobacco/documents/201203_Betelnut/en/).
51
47. WHO Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation. Fourth report of a WHO study group (WHO Technical Report Series, No. 967). Geneva: World Health Organization; 2012 (http://www.who.int/tobacco/global_interaction/tobreg/publications/tsr_967/en/ index.html). 48. Henningfield JE, Hatsukami DK, Zeller M, Peters E. Conference on abuse liability and appeal of tobacco products: conclusions and recommendations. Drug Alcohol Depend 2011;116(1–3):1–7. 49. Menthol cigarettes and the public health: review of the scientific evidence and recommendations. Washington DC: Tobacco Products Scientific Advisory Committee, Food and Drug Administration; 2011 (http://www. fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ TobaccoProductsScientificAdvisoryCommittee/UCM269697.pdf).
52
4. Reduced ignition propensity cigarettes: research needs and regulatory recommendations 4.1 Introduction 4.2 Background 4.3 Findings 4.3.1 New studies since the previous report 4.3.2 Country and regional experiences in legislation and its implementation 4.3.3 Data on product compliance 4.3.4 Risk assessment and perceptions of safety and risk 4.3.5 Trends in cigarette-ignited fires before and after adoption of the standard 4.3.6 Relevance and shortcomings of the standard 4.4 Conclusions 4.5 Results of the WHO tobacco products survey, 2014 4.6 Research needs 4.7 Regulatory recommendations 4.8 References Appendix 4.1 Methods Appendix 4.2 Summary of ISO 12863 Appendix 4.3 Recent CORESTA presentations by industry relevant to the technology of reduced ignition propensity cigarettes
4.1 Introduction This section addresses emerging issues and provides an update of the work of TobReg on reduced ignition propensity (RIP) cigarettes published in 2008. The document was prepared for the Sixth Session of the Conference of the Parties of the WHO FCTC in October 2014. Laws have been enacted on the basis of laboratory research conducted by the US National Institute of Standards and Technology, and coalitions of scientists, consumer groups and public health and fire officials have been formed. Countries are enacting legislation and have introduced product-reporting systems for RIP, the costs of testing being paid for by the manufacturers. Despite early claims to the contrary, the marketplace responded by producing reduced-ignition paper and adequate, certified laboratory testing facilities. The costs of manufacture have been minimal. Compliance has been monitored in various countries, and the results are available. Canadian data indicate substantial, sustained compliance by large manufacturers and increasing compliance by smaller ones. Risk assessments indicate little evidence that people smoking RIP cigarettes increased their fire risk-related behaviour and limited evidence of
53
increased exposure of smokers to toxicants. Evaluations of the impact on fire incidence and casualties are limited by the quality of fire reporting systems, the short time the RIP standard has been in force, secular trends to fewer fires and reduced flammability (e.g. of mattresses and upholstered furniture). Still, the most rigorous evaluations indicate an approximately 30% reduction in fires due to smoking as a result of the RIP regulations. In 2010, the ISO adopted a global standard based on the standard of the US National Institute of Standards and Technology and the American Society for Testing and Materials (1). The scientific evidence from experimental research and emerging population studies show that the current standard is effective in reducing fires and fire deaths. Legislation for RIP cigarettes should nevertheless allow flexibility in improving the standard as the science base grows, particularly with regard to population effectiveness. Countries should adopt the 2010 ISO standard, and manufacturers should all voluntarily adopt RIP cigarette design as part of good manufacturing processes. 4.2 Background The report of TobReg (2) on the scientific basis for regulating tobacco products included an advisory note on “fire safer” cigarettes. The report concluded that deaths in fires caused by burning cigarettes are a major global problem and that cigarettes with RIP should be mandatory. Standards exist, including the American Society for Testing and Materials E2187 (3), and laboratories accredited according to ISO 17025 are capable of testing RIP cigarettes, the cost being borne by tobacco manufacturers. The report cautioned that, although claims that RIP cigarettes reduce risk should be allowed, the effectiveness of the standard in reducing fires and fire-related deaths should be monitored as the standards are implemented. Any legislation with regard to RIP cigarettes should allow flexibility for strengthening the standard as new research results become available. The report called for international collaboration among interested agencies. In preparation for the Sixth Session of the Conference of the Parties, TobReg reviewed activities and research since the previous report, including on RIP standards, their adoption, monitoring, their effect on consumer perceptions of the overall risk associated with cigarettes and the effectiveness of RIP cigarettes in reducing fires. As part of this exercise, TobReg requested comments on the relevance of the standard, its shortcomings and areas in which more research is needed (see Appendix 4.1 for details). 4.3 Findings The regulations for RIP cigarettes are based on a test derived from work performed at the US National Institute for Standards and Technology under the
54
Cigarette Fire Safety Act of 1991 (4), which led to the development of a repeatable, reproducible test for ignition strength on filter paper, with full-length burn as an indicator of ignition propensity. The method, in which a cigarette is placed flat on a varying number of layers of filter paper in an enclosed chamber, is called the “cigarette extinction method” and is described in detail in the previous report. The test is based on an earlier performance standard, the “mock up furniture ignition method”, in which a burning cigarette was placed on furniture material and tested for fire ignition. The simpler filter paper method correlates well with the furniture test and was codified by ASTM International (1) as ASTM E2187. In 2010, ISO adopted the method as 12863:2010 (5). Neither the National Institute of Standards and Technology nor the ISO standard proscribes the design of the cigarette necessary to meet the standard. The two standards are similar. Appendix 4.2 summarizes the procedure. 4.3.1 New studies since the previous report
Alpert and colleagues (6) reviewed existing patents and literature on RIP-related technologies. Seidenberg et al. (7) conducted tests according to the ASTM method and reported that cigarettes bought in countries that had regulations tended to comply, while those bought in other markets tended to have more full-length burns. Recent meetings of groups on smoke science and product technology of the Cooperative Centre for Scientific Research Relative to Tobacco (CORESTA) in Paris, France, considered a number of abstracts related to RIP (Appendix 4.3), mainly on testing parameters and methods and comparisons of the emissions of RIP cigarettes and other products. Most of the studies on emissions reported no substantial difference between products (8, 9). Studies conducted by independent researchers on changes in toxic emissions of RIP, risk perceptions and population effects are reviewed below. 4.3.2 Country and regional experiences in legislation and its implementation
New York State (USA) was the first jurisdiction to enact RIP regulation, in June 2004. Canada implemented its regulation in October 2005. At the time of the previous report (2), Canada and 18 US states (with 38% of the US population) were the only jurisdictions with active RIP regulations. Since 2008, RIP standards have been implemented in four countries and by all member states of the European Union (10). In South Africa, RIP standards were published as regulations in 2011.10 In the USA, where 18 states had already adopted the standards, the remaining states did so between 2009 and 2011. Australia adopted the standards in 2010. http://www.tobaccocontrollaws.org/files/live/South%20Africa/South%20Africa%20-%20 RIP%20Regs%20-%20national.pdf. See also link to BAT’s communication to customers when the law was implemented in 2012: http://www.batsa.co.za/group/sites/BAT_7N3ML8.nsf/ vwPagesWebLive/DO8QVAU2?opendocument&SKN=1. 10
55
This experience illustrates a number of legislative strategies for passing RIP laws (11). A coalition including scientists, “burn” advocates, legislators, consumer groups and public health and fire safety officials should be formed to collect data on fires related to cigarette use and the scientific basis of the standard; they should then formulate comprehensive, consistent legislation, conduct public education campaigns and interact with policy-makers. The coalition should be closely advised by experts in science and legislation and take note of progress in other jurisdictions and public information, including information to refute tobacco industry opposition (11, 12). In the USA, first, a series of international meetings and workshops attended by representatives of countries that later adopted RIP legislation was convened, including scientists, consumer groups, legislators, public health and fire safety officials, to exchange information and form policy. The meetings were supported by grants and contracts from fire and public health agencies. Secondly, use of a uniform standard in all states facilitated adoption of and research on RIP laws and eliminated the industry argument that they would have to design several types of RIP cigarette. Thirdly, hard data were available on the actual harm caused by cigarette fires, and, in some campaigns, “heroes” who had been injured in fires caused by cigarettes were spokespersons. Finally, consensus was achieved that uniform, comprehensive laws must be drafted and reviewed by legal experts; the actual design of the cigarette should not be dictated, but a uniform standard should be complied with. Legislation should allow alteration of the standard in the light of new findings, require that fees for testing be paid by the tobacco industry, prohibit claims of reduced risk and require fees for national implementation and follow-up research. A centralized rapid response team was formed to track progress, refute industry arguments and prevent attempts to weaken legislation. These activities facilitated passage and implementation of RIP laws and eased the passage of subsequent laws. Once the law was passed, states shared their methods of implementation; however, data on actual fires, which would improve the RIP standard, have not yet been shared or reported. A European Union directive has been adopted, requiring the ISO standard but not compliance of industry with laboratory testing. The laws requiring RIP cigarettes in Australia, the European Union and South Africa cover approximately 20% of the world’s population, who consume approximately 20% of the world’s manufactured cigarettes. Most are high-income countries; adoption by low- and middle-income countries has been limited. 4.3.3 Data on product compliance
Health Canada’s website shows the results of RIP testing in the period 2005– 2011, with test results for specific brand styles (13). For simplicity, TobReg has 56
classified manufacturers as the three major companies (Imperial, Rothmans and JTI) and “other” (which encompasses small importers and local manufacturers). The three major manufacturers have about 97% of the market share (14). Figure 4.1 shows raw data on full-length burns. A clear difference in RIP compliance can be seen between the major manufacturers and others: the products of the major manufacturers have been well under the RIP standard from the beginning, while the others took longer. The results of binary logistic regression (events/trials) analysis to model the effects of manufacturer group and sampling year (2005–2011) on full-length burns are illustrated in Figure 4.2, which confirms the initial finding that the rate of change in full-length burns was greater for other manufacturers than for the major companies (manufacturer ´ year interaction, χ2 (6) = 241.6, p < 0.001). It is unclear, however, whether this is due to the effectiveness of the regulation or the number of fires observed, as the major manufacturers hold such a dominant share of the market. Gray lines, major manufacturers 50 Dotted line, “other” manufacturers
40 Full-lenght burn (%)
30
20
10
00 2005 2006 2007 2008 Year 2009 2010 2011
Figure 4.1. Proportions of tested brands showing full-length burn in the ASTM E2187 test method, by manufacturer, Canada, 2006–2011. RIP legislation was introduced in October 2005. Horizontal line, RIP standard (25% full-length burn)
57
60
Imperial RBH/JTI
Other Manufacturers / Importers
50
Full-lenght burn (%)
40
30
RIP standard
20
10
00
2005
2006
2007
2008 Year
2009
2010
2011
Figure 4.2. Estimated proportions of tested brands with full-length burns in the ASTM E2187 test, by binomial regression on year and manufacturer, Canada, 2006–2011. RIP legislation was introduced in October 2005. Horizontal line, RIP standard (25% full-length burn)
4.3.4 Risk assessment and perceptions of safety and risk
The behavioural and health correlates of introducing RIP cigarettes have been addressed in a few studies. O’Connor et al. (15) examined Canadian smokers’ beliefs and behaviour before and 1 year after implementation of the regulation. Using random-digit dialling telephone surveys, they obtained information from 435 smokers aged ≥ 18 years (73% follow-up rate) and found similar levels of fire-risk behaviour, such as smoking in bed (14.7% before and 13.1% after the legislation) and dozing off while smoking (2.3% versus 2.1%). No difference was found in worry about starting a fire with a cigarette. Smokers more frequently reported that their cigarettes self-extinguished “often” after implementation of the law (3.7% before and 14.7% after; p < 0.001), but there was no difference in reports of “coal drop-off ” (36.4% before, 31.3% after). Seidenberg et al. (16) reported a similar study among smokers in Massachusetts, USA, before and after implementation of the law and found a broadly similar pattern. Of 620 initial respondents, 352 (57%) completed both surveys. The frequency of reports of leaving a cigarette unattended (26.5% vs 28.1%, p = 0.567) and smoking in bed (19.2% vs 19.6%, p = 1.000) was unchanged; the
58
proportion of respondents who smoked more than 20 cigarettes per day decreased (21.5% vs 15.6, p < 0.001), reports of self-extinction “often” increased (22.3% vs 44.2%, p < 0.001), while no increase was reported in “coal drop-off ” (43.2% vs 33.7%). There was no change in reported intention to quit. Adkison et al. (17) studied the effects of RIP cigarette regulation on consumer behaviour and intention to quit between 2004 and 2011 from data obtained in a survey conducted in Australia, Canada, the United Kingdom and the USA (total N = 12 492). This dataset is unique, as it allows assessment of both initial and time-lagged effects, since laws were introduced at different times in each (and in the USA, within) country. Perceptions of cigarette self-extinction increased concurrently with RIP cigarette legislation (odds ratio = 2.7, p < 0.001), as did the intention to quit smoking (odds ratio = 1.02, p < 0.05), but no effect was seen on the number of cigarettes smoked per day. The intention to quit was more frequent among people who reported that their cigarettes selfextinguished (odds ratio = 1.02, p < 0.05). Overall, the RIP safety standards did not have an impact on consumer acceptability, and the study did not indicate any “wear-out” effect (i.e. loss of market share because of implementation of RIP safety standards). O’Connor et al. (18) reported the results of an 18-day study among 160 smokers in two US cities, in which smokers in one city switched from their usual brand to the RIP version, while those in the other city smoked RIP cigarettes throughout the study. The outcomes of interest included the number of cigarettes smoked per day, smoking topography (puff volume, duration, interval), exhaled CO, saliva cotinine and urine metabolites of selected PAH (pyrene, naphthalene, phenanthrene and fluorene). The authors reported no significant difference in smoking topography, exhaled CO, PAH metabolites (with the exception of phenanthrene) or cotinine as a result of switching to RIP versions. The smoking rate decreased by approximately two cigarettes per day, from 18 to 16. There was a 35% increase in the level of urinary metabolites of phenanthrene, which is an irritant but is not known to be carcinogenic. June et al. (19) reported the findings of a study of the behaviour and exposure of 42 daily smokers before and 18 months after introduction of the Canadian RIP regulation. The outcomes of interest were the same as in the study of O’Connor et al. (18). No significant differences were seen in smoking topography, exhaled CO, the number of cigarettes smoked per day or urinary cotinine. Significant increases of 14–25% in selected PAH metabolites were noted; if this result is confirmed, it would be a concern because these biomarkers indicate the presence of benzo[a]pyrene, a known human carcinogen. Côté et al. (20) conducted a study supported by Imperial Tobacco Canada of oral exposure to tar and nicotine, using machine smoking estimates and the “part-filter” method (21). Half of the total of 1086 smokers who used 10
59
specific brands were recruited before and half after introduction of the RIP regulation. Participants were given up to two packs of their usual brand and a kit for collecting filters and were asked to smoke ad libitum but to return the kit when 15 filters had been collected. The filters were tested for nicotine retention by gas chromatography with a flame ionization detector, and the results were used to estimate exposure by comparison with calibration curves for each brand, generated from machine smoking parameters. Although the mean number of cigarettes smoked per day was significantly higher before introduction of the law than after (22.1 vs 20.6, p = 0.0003), no difference in oral exposure to tar or nicotine was observed. It should be noted that this was a cross-sectional and not a cohort study. 4.3.5 Trends in cigarette-ignited fires before and after adoption of the standard
Research on the effects of the RIP standard on the frequency of cigarette-ignited fires is essential for validating the effectiveness of a laboratory standard in reducing cigarette-related fires and deaths. Studies on the causes of and casualties due to fires confirm that cigarette-associated fires are more likely than other causes to result in injury or death (22–24). Such studies are difficult to conduct because of the quality and number of fire-reporting systems, the short time the RIP standard has been in force and other trends that affect the incidence of fires, including increased resistance of mattresses and upholstery to ignition, smoke detectors, public education, decreased smoking prevalence and changes in where people smoke because of indoor smoking restrictions (25). Such research is also difficult to conduct because legislation on RIP does not require that such studies be conducted or funded, and there is no centralized reporting system in which compliance with the RIP standard is linked to reports of fires. At the time this report was written, neither Australia nor the European Union had published data on fire incidents. The US National Fire Protection Association reported in 2013 that incidents and deaths in fires related to smoking were at their lowest levels since monitoring began, in 1980 (26). Furthermore, the report commented that adoption of the RIP standard by the 50 US states appeared to be the “principal reason for a 30% decline in smoking material fire deaths from 2003 to 2011”, taking into account the percentage of smokers covered and changes in the resistance of mattresses and upholstery to ignition. Figure 4.3 illustrates the trends in incidents, deaths and injuries found in the study.
60
Fires 400 000 350 000
Deaths
Injuries
Number of smoking materials fires
5 000
300 000 250 000 200 000 150 000 100 000 50 000 0 1 000 4 000
3 000
2 000
0
Figure 4.3. Incidents, deaths and injuries related to fires ignited by smoking materials, USA, 1980–2011. The shading indicates the increasing number of states that adopted the standard after 2004. Adapted from Hall (26)
A report prepared by TriData on behalf of Philip Morris International examined the impact of the RIP laws in Ontario and Alberta, Canada, and in New York State, USA, up to 2008–2009 (27). The authors concluded that there was “no substantive decrease attributable to reduced ignition propensity cigarettes”. Trends in Ontario and Alberta are shown in Figure 4.4. Their analysis has a number of serious flaws (D. Hemenway, personal communication); broadly speaking, their evaluation appears to be designed to find no effect (28). Evaluations of regulatory policies must include a counterfactual approach (i.e. What would have happened in the absence of the law?), because there is no control group. Epidemiological approaches and statistical analyses were not, however, used. A major problem in the TriData analyses is the assumption of a straightline trend, with the absolute number of incidents on the vertical axis, which is then projected to continue unabated. This assumes a rapidly increasing rate of decrease and indeed leads to the inference that the number of incidents will fall to zero within a few years and become negative, which is clearly absurd (see their figures 18 and 22). Note, however, that when the trend before RIP implementation is upwards (in New York), they do not draw a trend line for comparison (their figures 36 and 37). They also overlook evidence of possible beneficial effects in Vermont, Massachusetts, New York (their figure 34) and Alberta (their figures 18, 20 and 29).
19 8 19 0 19 81 1982 1983 1984 1985 8 19 6 19 87 1988 1989 9 19 0 19 91 1992 1993 1994 1995 9 19 6 19 97 1998 20 99 2000 20 01 20 02 20 03 20 04 20 05 2 00 6 2 0 07 20 08 0 20 9 1 20 0 11
Year
Number of smoking materials fire deaths and injuries
6 000
61
ON Fires
AL Fires
ON Death
ON Injury
AL Death
AL Injury
800
Number of smoking materials fires
750
90 80 70 60 50 40 30 20 10 0
700
650 550
600 500 450 350 250 150
400 300 200 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Figure 4.4. Incidents, deaths and injuries from fires associated with smoking materials in Alberta and Ontario, Canada, 2000–2008 or 2009. Shading indicates implementation of the RIP law. Adapted from Frazier et al. (27)
Year
Perhaps the best evidence to date on the population effect of the RIP standard comes from a recent evaluation by Alpert et al. (29) of the effectiveness of the Massachusetts (USA) Fire Safe Cigarette Law in preventing residential fires. The analysis effectively controlled for most potential sources of confounding, other than an increased use of flame retardants, on which information was not available. Massachusetts already had one of the best fire-reporting systems in the USA, and the reporting characteristics did not change after the law came into effect on 1 January 2008. Unintentional residential fires reported to the system in 2004–2010 were analysed to determine which of them were caused by cigarettes, and effect modification by fire scenario factors was analysed in an interrupted time series regression model. Poisson regression was used to analyse the effect of the law on monthly fire rates. Cigarettes caused 1629 unintentional fires during the period. The greatest reductions were in fires in which human factors were involved: ignited on furniture, bedding or soft goods, occurred in living areas or occurred in summer or winter (rather than in spring or autumn). The authors concluded that the RIP standard adopted into law and enforced in Massachusetts had decreased the likelihood of residential fires by 28% (95% confidence interval, 12–41%), particularly in the scenarios for which the RIP standard was set. This study is one of only a few high-quality, reliable population studies on the impact of the RIP standard on cigarette fires.
62
Number of smoking materials fire deaths and injuries
850
100
In summary, despite the difficulty of conducting research on the population effects of the standard, particularly in view of the short time it has been in force and the quality of fire-reporting systems, the RIP standard appears to be effective in reducing the incidence of cigarette-associated fires by approximately one third; however, more research is needed to validate this initial finding. 4.3.6 Relevance and shortcomings of the standard
The current standard is based on over 30 years of research, beginning with the “mock-up upholstery method”, the cell paper ignition method and emerging research on population health. More research is needed, including on the possible effects of changes in smoking behaviour and increased resistance of substrates to ignition. In high-income countries, the standard has been found to be effective, regardless of national factors; however, the standard could be altered as new scientific results, testing standards and cigarette features emerge. 4.4 Conclusions Experience in countries in which RIP laws have been introduced suggests that the steps necessary for successful passage of such laws are: • constitution of a coalition of relevant groups, including scientists, consumer groups and public health and fire safety officials, to collect data on cigarette-related fires, to formulate appropriate legislative proposals and to interact with policy-makers; a uniform standard for all legislative entities to facilitate adoption and to eliminate industry arguments that multiple RIP cigarettes would have to be designed; hard data on the actual harm caused by cigarette fires; and legislation that requires compliance with a uniform standard but does not dictate actual cigarette design.
•
• •
Data on compliance have been collected in countries in which RIP laws have been introduced. Studies in Canada indicate substantial, sustained compliance by large manufacturers and increasing compliance by smaller ones. The three large manufacturers, which comprise 97% of the market in Canada, readily met the performance target of ≤ 25% of cigarettes in a sample that failed to meet the standard, soon after the RIP law was implemented. For all manufacturers, 10% or less of samples failed to reach the standard within a few years of the RIP law being enacted. Few studies have been conducted on behavioural and health effects after introduction of RIP cigarettes. There is little, if any evidence of any change in
63
smoking topography (puff volume, puff duration, interval between puffs) or any increase in fire risk-related behaviour, such as leaving a burning cigarette unattended or smoking in bed. A consistent observation was that RIP cigarettes self-extinguish more often, but there was no difference in the reported frequency in coal drop-off. Inconsistent evidence was presented that more people who smoke RIP cigarettes express an intention to quit smoking and smoke fewer cigarettes per day. The yields of CO, tar and nicotine are similar in RIP and non-RIP cigarettes. In two studies in which urinary biomarkers of exposure to hydrocarbons were measured, use of RIP cigarettes was associated with a modest (≤ 25%) increase in metabolites of pyrene, fluorenes and phenanthrenes; however, the data were not consistent, and the significance of the finding is unclear. Evaluation of the impact of RIP laws on the incidence of cigarette-caused fires and the related casualties is limited by factors including lack of or poor quality data on fires, the relatively short time the RIP standard has been in force, particularly in some regions, such as the European Union, a general decrease in the prevalence of fires in recent decades, the introduction of clean air laws and the reduced flammability of substrates such as mattresses and soft furnishings. Despite these limitations, some rigorous studies have been conducted in high-income countries, which indicate an approximate 30% reduction in cigarette-caused fires as a result of RIP regulations. While it is anticipated that the numbers of deaths and injuries would be decreased as a result, there is only limited evidence in support of this assumption. It has been noted that the effectiveness of RIP cigarettes in reducing fire-related harm would vary with the effectiveness of fire-fighting departments. No information was available on the impact of RIP legislation on the frequency of outdoor fires or the resulting human or environmental impact. 4.5 Results of the WHO tobacco products survey, 2014 The WHO questionnaire on smokeless tobacco products, electronic nicotine delivery systems, RIP cigarettes and novel tobacco products was sent to all WHO Member States.11 Eighteen Member States (5%) reported that they had a legal mandate requiring cigarettes sold to have RIP characteristics; and 19 Member States (5%)—18 with a mandate and one without—in four of the six WHO regions (the African Region, the Region of the Americas, the European Region and the Western Pacific Region) reported having adopted technical standards for RIP. RIP cigarettes are made available by commercial manufacturers in 13 Member States (8%) and by importation in 19 (8%). The exporting countries identified in the survey were Canada, China, the Czech Republic, Hungary, Lithuania, the Netherlands, New Zealand, the Republic of Korea and the USA. 11 A total of 90 countries, including 86 Parties to the WHO FCTC, had responded to the survey as of 9 April 2014, representing 77% of the world’s population.
64
Fires or deaths in fires due to smoking materials were recorded in 24 Member States (7%). Of those Member States in which reliable data were available over a 10-year period (2003–2012), the Czech Republic reported a total of 8129 fires due to cigarettes and 177 deaths, while Norway reported 74 deaths in the same period. Lithuania reported an average of 79 deaths per year, Oman reported an average of 48 fires per year, and Sweden reported an average of 25 deaths due to smoking-related fires each year. In general, 30% of all residential fire deaths in high-income nations are attributable to smoking. 4.6 Research needs Research should be conducted at national, subnational or combined levels to predict population effects, including: • factors that contribute to a general reduction in the number of fires, with specific studies on the effects of educational campaigns, sprinkler systems and reducing the flammability of substrates (upholstery, mattresses, etc.); cigarette-related issues, such as the impact of changes in smoking behaviour, including decreasing prevalence, the impact of clean indoor air laws on where people smoke, the number of cigarettes smoked and their disposal; emerging paper design techniques to enhance RIP performance, standards and possible alterations in emissions and toxicity; fires lit by cigarettes in settings not addressed by the standard (outdoors, brush fires, outdoor rubbish bins); and the applicability of the standard to novel RIP cigarettes that are not wrapped in paper.
•
• • •
Regarding infrastructure, research capacity, funding and support for universal RIP standards for all cigarettes, FCTC Parties and fire officials should be surveyed about the significance of the RIP standard in their overall tobacco control or fire safety plans and asked to assess the resources required and potential funding. In order for RIP standards to be considered good manufacturing process, the cost–benefit of having one global design rather than multiple designs should be calculated, including the time required to develop manufacturing capacity and compliance costs. Research should be conducted to find simpler compliance testing methods at the site of manufacture rather than in individual markets, thus reducing industry costs, and to determine the applicability to cigarettes of good manufacturing processes already recommended by WHO for drugs and other products.
65
4.7 Regulatory recommendations • • • Universal RIP standards should be applied to all cigarettes. The RIP design should be adopted universally by manufacturers as standard manufacturing practice for cigarettes. All costs for implementation of the RIP standard should be borne by manufacturers. Countries with limited capacity for compliance testing should consider asking manufacturers to file a statement of conformity with the government or to use third-party certification. Implementation of these recommendations will require close collaboration between agencies and fire departments, the establishment of a central clearing-house for RIP standards, a survey of FCTC Parties and fire officials on the impact of RIP standards, introduction of a consistent standard for reporting fires and determining how these activities will be funded. Research should be continued to obtain data on the population impact of RIP legislation on cigarette-associated fires, deaths and injuries in all countries and regions in which RIP laws have been implemented.
•
•
4.8 References 1. 2. Standard test method for measuring the ignition strength of cigarettes. West Conshohocken, Pennsylvania: ASTM International; 2004. WHO Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation: second report of a WHO study group (WHO Technical Report Series, No. 951). Geneva: World Health Organization; 2008 (http://www.who.int/tobacco/global_interaction/tobreg/publications/tsr_951/en/ index.html). Gann RG, Hnetkovsky EJ. Modification of ASTM E 2187 for measuring the ignition propensity of conventional cigarettes. Fire Technol 2011;47:69–83. Barillo DJ, Brigham PA, Kayden DA, Heck RT, McManus AT. The fire-safe cigarette: a burn prevention tool. J Burn Care Rehabilit 2000;21:162–70. Standard testing method for assessing the ignition propensity of cigarettes. Geneva: International Organization for Standardization; 2010. Alpert HR, O’Connor RJ, Spallette R, Connolly GN, Rees VW, Alpert HR, O’Connor RJ, Connolly GN. Recent advances in cigarette ignition propensity research and development. Fire Technol 2010;46: 275–89. Seidenberg AB, Rees VW, Alpert HR, O’Connor RJ, Connolly GN. Ignition strength of 25 international cigarette brands. Tob Control 2011;20:77–80. Connolly GN, Alpert HR, Rees V, Carpenter C, Wayne GF, Vallone D, et al. Effect of the New York State cigarette fire safety standard on ignition propensity, smoke constituents, and the consumer market. Tob Control 2005;14:321–7.
3. 4. 5. 6.
7. 8.
66
9.
Pang Y, Jing Y, Jiang X, Chen Z, Tang G, Xing J. Effects of low ignition propensity cigarette paper on deliveries of harmful components in mainstream cigarette smoke (in Chinese). Tob Sci Technol 2013;2:52–6.
10. Arnott D, Berteletti F. Europe: agreement on reducing cigarette fires. Tob Control 2008;17:4–5. 11. Goldstein AO, Grant E, McCullough A, Cairns B, Kurian A. Achieving fire-safe cigarette legislation through coalition-based legislative advocacy. Tob Control 2010;19:75–9. 12. Barbeau EM, Kelder G, Ahmed S, Mantuefel V, Balbach ED. From strange bedfellows to natural allies: the shifting allegiance of fire service organisations in the push for federal fire-safe cigarette legislation. Tob Control 2005;14:338–45. 13. Laboratory analysis of cigarette for ignition propensty. Ottawa: Health Canada; 2012 (http://www.hc-sc.gc.ca/hc-ps/tobac-tabac/legislation/reg/ignition-alllumage/ analys-eng.php, accessed 20 November 2013). 14. Smoking and Health Action Foundation, Non-smokers’ Rights Association. Backgrounder on the Canadian tobacco market. Toronto, Ontario:; 2013 (http://www.nsra-adnf.ca/cms/file/files/2013_Canadian_Tobacco_Market.pdf, accessed 20 November 2013). 15. O’Connor RJ, Fix BV, Hammond D, Giovino GA, Hyland A, Fong GT, et al. The impact of reduced ignition propensity cigarette regulation on smoking behaviour in a cohort of Ontario smokers. Inj Prev 2010;16:420–2. 16. Seidenberg AB, Rees VW, Alpert HR, O’Connor RJ, Giovino GA, Hyland A, et al. Smokers’ self-reported responses to the introduction of reduced ignition propensity (RIP) cigarettes. Tob Control 2012;21:337–40. 17. Adkison SE, O’Connor RJ, Borland R, Yong HH, Cummings KM, Hammond D, et al. Impact of reduced ignition propensity cigarette regulation on consumer smoking behavior and quit intentions: evidence from 6 waves (2004–11) of the ITC Four Country Survey. Tob Induced Dis 2013;11:26. 18. O’Connor RJ, Rees VW, Norton KJ, Cummings KM, Connolly GN, Alpert HR, et al. Does switching to reduced ignition propensity cigarettes alter smoking behavior or exposure to tobacco smoke constituents? Nicotine Tob Res 2010;12:1011–8. 19. June KM, Hammond D, Sjödin A, Li Z, Romanoff L, O’Connor RJ. Cigarette ignition propensity, smoking behavior, and toxicant exposure: a natural experiment in Canada. Tob Induced Dis 2011;9:13. 20. Côté F, Letourneau C, Mulland G, Voisine R. Estimation of nicotine and tar yields from human-smoked cigarettes before and after the implementation of the cigarette ignition propensity regulations in Canada. Regul Toxicol Pharmacol 2011;61(3 Suppl):S51–9. 21. Shepperd CJ, Eldridge AC, Mariner DC, McEwan M, Errington G, Dikon M. A study to estimate and correlate cigarette smoke exposure in smokers in Germany as determined by filter analysis and biomarkers of exposure. Regul Toxicol Pharmacol 2009;55:97–109.
67
22. Mulvaney C, Kendrick D, Towner E, Brussoni M, Hayes M, Powell J. Fatal and non-fatal fire injuries in England 1995–2004: time trends and inequalities by age, sex and area deprivation. J Public Health 2009;31:154–61. 23. Smith J, Bullen C, Laugesen M, Glover MP. Cigarette fires and burns in a population of New Zealand smokers. Tob Control 2009;18:29–33. 24. Anderson A, Ezekoye OA. A comparative study assessing factors that influence home fire casualties and fatalities using state fire incident data. J Fire Prot Eng 2013;23:51–75. 25. Markowitz S. Where there’s smoking, there’s fire: the effects of smoking policies on the incidence of fires in the USA. Health Econ 2013;25:1353–73. 26. Hall JR Jr. The smoking-material fire problem. Quincy, Masachusetts: National Fire Protection Association; 2013:54. 27. Frazier P, Schaenman P, Jones E. Initial evaluation of the effectiveness of reduced ignition propensity cigarettes in reducing cigarette-ignited fires: case studies of the North American experience. Arlington, Virginia: TriData Division, System Planning Corp; 2011 (http://www.fdma.go.jp/html/life/yobou_contents/ info/pdf/tabaco/kentou01/sanko04.pdf). 28. Hemenway D. How to find nothing. J Public Health Policy 2009;30:260–8. 29. Alpert HR, Christiani D, Orav EJ, Dockery D, Connolly GN. Effectiveness of the cigarette ignition propensity standards in preventing unintentional residential fires in Massachusetts. Am J Public Health 2014;104:e56–61.
Appendix 4.1. Methods For this review, we searched a number of publicly accessible databases, including PubMed, the Africa Index Medicus, the Index Medicus for the Eastern Mediterranean Region, the Index Medicus for the Western Pacific Region, the Pan American Health Organization Library, Biblioteca virtual em Saûde, the Index Medicus for the South-East Asia Region, the Web of Science and Engineering Village, using the search terms “cigarette” and “fire” or “burn”, published since 2008. This search of the published literature was supplemented with a search on Google to identify “grey” literature, such as conference abstracts, consultant organization reports and news reports. Public health and fire safety officials in countries that were known to have adopted or were considering adopting RIP standards for cigarettes were contacted, and information was collected from the WHO regional offices. Interviews were conducted with key informants in countries in which RIP laws have been adopted. A total of 26 relevant publications were identified.
68
Appendix 4.2. Summary of ISO 12863 1 test = 40 determinations, one cigarette per determination Outcome = full-length burn (lit cigarette burns past the end of the tipping paper for filter-tipped cigarettes, or past metal pins placed in non-filter cigarettes) Environmental conditions: humidity 55% ± 5%, temperature 23 °C ± 3 °C Polymethylmethacrylate test chamber dimensions: height, 340 ± 25 mm; width, 292 ± 6 mm; depth, 394 ± 6 mm; chimney height, 165 ± 13 mm with inside diameter 152 ± 6 mm Polymethylmethacrylate substrate holder dimensions: outer diameter, 165 ± 1 mm; inner diameter, 127 ± 1 mm; height, 50 ± 1 mm; a recess in the top, 10 ± 2.5 mm deep, extending the inner diameter to 152 ± 1 mm; three or four legs to raise the bottom holder approximately 20 ± 1 mm above the chamber floor; a metal rim made of brass, with an outer diameter of 150 ± 1 mm Filter papers (Whatman #2) should be selected such that the combined mass of 15 sheets is 24.7 ± 0.5 g. Test procedure: 1. Before testing, mark cigarettes in pencil at 5 mm and 15 mm from the lighting end to establish a uniform pre-burn period. 2. Light cigarette, and place with seam facing upwards in the holder. Close chamber door and remove chimney cover. 3. If cigarette goes out in the holder (i.e. between 5-mm and 15-mm marks), record as self-extinguished. 4. If cigarette burns to the 15-mm mark, remove from holder and place seam up on substrate. 5. Record stopping point of burn. If burn has reached tipping paper (or metal reference pins for non-filter cigarettes), record as full-length burn; otherwise, record as non-full-length burn. 6. Remove cigarette and filter papers, and dispose of them. 7. Repeat procedure until 40 determinations have been made. 8. Calculate proportion of determinations in which a full-length burn was observed.
69
Appendix 4.3 Recent CORESTA presentations by industry relevant to the technology of reduced ignition propensity cigarettes 2013 Wilkinson P, Colard S, Verron T, Cahours X, Pritchard J. Control or monitoring of the LIP testing process: the fitness for purpose of the LIP standard products. Wanna J. Alternate test substrate for ASTM test method E2187-09. Mayr M, Vizee H. Impact of using a metal sheet as an “alternative substrate for ISO 12863” on SE performance. Verron T, Cahours X, Colard S. LIP cigarettes: proposal for an alternative sampling design. Gleinser M, Bachmann S, Rohregger I, Vizee H, Volgger D. Puff-by-puff analysis of mainstream smoke constituents of non-LIP and LIP-cigarettes. Verron T, Cahours X, Colard S, Taschner P. Some key points to assess LIP regulation impact.
2012 Bachmann S, Gleinser M, Möhring D, Rohregger I, Volgger D. Puff-by-puff analysis of mainstream smoke constituents of non-LIP/FSC and LIP/FSC cigarettes. Guyard A, Meier D, Ceccketto A, Hofer R, Li P. Impact of cigarette paper properties on smoke constituents’ delivery under Health Canada Intense smoking regime. Hesford MJ, Volgger D, Case P, Vanhala A. A further experimental design to investigate the influence of the LIP test substrate parameters on LIP pass rates and residual length measurements. Mayr M, Volgger D. Influence of band width and band material coverage rate (total band area / total paper area) on smoke yields, SE test and free burn. Verron T, Cahours X, Colard S. LIP cigarettes: effect of band positioning. Verron T, Cahours X, Colard S. Trend analysis: a relevant tool to assess postregulation impacts. Wanna J, Le Moigne C, Le Bec L. Tobacco column influence on cigarette paper.
2011 Hesford M. A 24 factorial experimental design to investigate the influence of LIP testing substrate parameters (basis weight, permeability and roughness) on LIP pass rates and residual length measurements. Mayr M, Volgger D. The impact of different physical and chemical cigarette paper base sheet parameters on smoke yields, and testing of an alternative substrate for Whatman #2 using the ASTM method E.2187-09. Inoue Y, Hasegawa Y, Kominami T. Study of heat transfer of a cigarette relating to the ignition propensity. 70
Loureau JM, Le Bec L, Kraker T, Le Moigne C, Wanna J, Le Bourvellec G. Influence of base paper citrate and filler amount and of band diffusion on smoke deliveries, ASTM and FASE.
2010 Eitzinger B, Volgger D. Some statistical considerations regarding the testing of LIP cigarettes. Hesford M, Case P, Coburn S, Larochelle J, Cabral JC, DeGrandpré Y, Wanna J. A factorial experimental design to investigate the influence of band diffusivity and filler, fibre and citrate contents on the machine smoking yields and LIP performance of banded LIP papers. Wanna J. Influence of humidity, number of filter papers, and orientation of the filter paper on ASTM results. Hampl V Jr. Effect on ASTM test results and carbon monoxide deliveries when sodium alginate bands are on the outside of cigarettes. Mason T, Tindall I. Correlation between manual and semi automatic measurements of ignition propensity to ASTM E2187-04. Vincent J, Tindall I. Factors affecting the design of paper diffusivity measurement apparatus with particular reference to the design of transfer standards.
71
72
5. Non-exhaustive priority list of toxic contents and emissions of tobacco products 5.1 Introduction 5.2 Findings of the review 5.3 Recommendations 5.4 Non-exhaustive list of priority toxic contents and emissions of tobacco products 5.5 References
5.1 Introduction This document was prepared in response to a request by the Conference of the Parties at its Fifth Session (Seoul, Republic of Korea, 12–17 November 2012) to the Convention Secretariat to “compile, make available for Parties and update jointly with WHO’s Tobacco Free Initiative a non-exhaustive list of toxic contents and emissions of tobacco products and advise how such information could best be used by Parties” for consideration at the Sixth Session of the Conference of the Parties (decision FCTC/COP5(6)) (1). In the same decision, the Conference of the Parties further decided to mandate the Working Group on Articles 9 and 10 to submit draft partial guidelines or a progress report on testing and measuring contents and emissions with analytical chemical methods validated by WHO, for consideration at the Sixth Session of the Conference of the Parties. TobReg, at its meeting in Rio de Janeiro, Brazil, on 4–6 December 2013, selected a priority list of 38 toxicants from among more than 7000 chemicals found in cigarette smoke on the basis of qualitative and quantitative analyses. The list of toxicants was based on eight non-exhaustive lists of toxicants: from Health Canada,12 the National Institute for Public Health and the Environment in The Netherlands (2), the US Food and Drug Administration (3), Counts et al. (4), Fowles and Dybing (5), the “Hoffman analytes” (6), Philip Morris Australian brands13 and Philip Morris Canadian brands14 in order to balance the identified concerns with the practical reality of a regulatory structure. The list of tobacco contents and emissions of cigarette smoke was drawn up on the basis of the following criteria: For constituents: http://laws-lois.justice.gc.ca/eng/regulations/SOR-2000-273/page-13. html; for emissions (mainstream smoke): http://laws-lois.justice.gc.ca/eng/regulations/SOR2000-273/page-14.html. 13 http://www.health.gov.au/internet/main/publishing.nsf/Content/health-tobaccoingredients-philip-2013. 14 Available from Health Canada upon request or at tfi@who.int. 12
73
• •
the presence of specific chemicals in cigarette smoke at levels that are toxic for smokers as determined by well-established scientific toxicity indices; variations in concentrations among cigarette brands that are substantially greater than the variation in repeated measurements of the toxicant in a single brand; and the availability of technology to reduce the concentration of a given toxicant in smoke, should an upper limit be mandated.
•
The 7000 chemicals in cigarette smoke were analysed according to the same criteria when sufficient data on smoke emissions and data on toxicity relevant to humans were available. The Conference of the Parties at its Third Session requested the Convention Secretariat to invite the WHO Tobacco Free Initiative to validate the analytical chemical methods for testing and measuring priority emissions and contents in cigarette smoke (decision FCTC/COP3(9) (7). TobLabNet has undertaken validation of the methods for three contents (nicotine, ammonia and humectants) and four emissions (aldehydes, benzo[a]pyrene, TSNA and volatile organic compounds). To date, validation of the methods for CO, humectants, benzo[a]pyrene, nicotine and TSNA has been completed, while the methods for ammonia, volatile organic compounds (benzene and 1,3-butadiene) and aldehydes (acetaldehyde, acrolein and formaldehyde) are still being validated. 5.2 Findings of the review TobReg evaluated the lists of harmful and toxic chemicals associated with cancer, cardiovascular and pulmonary diseases published by several regulatory bodies, including Health Canada, the National Institute for Public Health and the Environment in The Netherlands and the US Food and Drug Administration, and reviewed the list of toxicants in the report of TobReg (8). TobReg subsequently drew up a modified non-exhaustive list of priority toxic contents and emissions of tobacco products, as outlined in section 5.4; however, it should be noted that this list represents only a small fraction of the total complex mixture of chemicals present in combustible tobacco products and that the overall toxicity of the emissions of tobacco products is not necessarily related to the toxicity of the individual chemicals. Experience gained by the Agéncia Nacional de Vigilância Sanitária in Brazil, Health Canada and the US Food and Drug Administration should be used by Parties and non-Parties to the WHO FCTC to urge the tobacco industry to disclose information about the emissions of tobacco products, in accordance with the Partial Guideline for Articles 9 and 10.
74
While several Parties include tar in their regulatory policies, it is not on the priority list of toxicants in tobacco smoke emissions, as the composition of tar varies qualitatively and quantitatively in each type of product, limiting the possibility for validated testing and measurement. TobReg previously expressed concern about the presence of cadmium, lead, nickel, arsenic and polonium in tobacco smoke. Although these metals present a high risk when present in smoke, there are no currently interlaboratory-validated standardized methods for testing and monitoring them (9). Because of the increasing worldwide use of waterpipes (shisha), TobReg concludes that there is an urgent need for an interlaboratory-validated method for determining nicotine in waterpipe smoke and that the relative concentrations of nicotine and other priority emissions in the smoke should be studied. Some of the emissions from smoked tobacco products on the priority list are irrelevant or less relevant for smokeless tobacco products. For example, CO is produced during burning and is thus not present in smokeless tobacco. The priority list for smokeless products is currently limited to nicotine, TSNA and benzo[a]pyrene; however, no standardized, interlaboratory-validated methods are available for measuring these chemicals in smokeless products. TobReg concludes that methods for testing these components in smokeless tobacco should be fully validated. TobReg concludes that the upper limits of emissions of toxicants from tobacco products should be regulated on the basis of the scientific knowledge and principles that have been applied to food and other consumer products, often on the basis of the principle of reasonable assurance of safety. TobReg concludes that the same principle should apply to tobacco products. 5.3 Recommendations • The Conference of the Parties should request WHO to mandate TobLabNet to develop standardized methods for determining the arsenic, cadmium and lead content of tobacco products. Tar need not be measured, as it is not a sound basis for regulation, and the levels can be misleading. Although the recommended priority list of contents and emissions was drawn up for standard cigarettes, TobReg recommends use of the same list for other smoked tobacco products, such as non-standard cigarette (slims, for example), cigars, waterpipes, pipes and roll-your-own or “make-yourown” cigarettes.
• •
75
•
For both standardized cigarettes and other tobacco products, the concentration of a chemical in emissions should also be reported relative to the concentration of nicotine in the smoke, as advocated previously (8). The Conference of the Parties should request WHO to mandate TobLabNet to issue a validated method for the determination of nicotine in the smoke of waterpipes (shishas). Countries should regulate nicotine, TSNA and benzo[a]pyrene in smokeless tobacco products. The Conference of the Parties should request WHO to mandate TobLabNet to develop validated methods for determining nicotine, TSNA and benzo[a]pyrene in smokeless tobacco products. The list of priority contents and emissions should be used, with validated TobLabNet methods, as a basis for regulating contents and emission, as stated in Article 9 of the WHO FCTC. As an initial step in regulating contents and emissions, as stipulated in Article 9, Parties may start monitoring the priority contents and emissions of cigarettes on their markets. Data on each brand and each content and emission should be made available by the tobacco industry, and the cost of compliance testing should be covered by the tobacco industry, as agreed in the Partial Guideline of Article 10. Regulatory steps should include setting upper limits for emissions of toxicants in tobacco products on the basis of established toxicological principles. Tobacco emissions contain many chemicals; therefore, the list of priority emissions and contents is only a first step to help Parties fulfil the requirements of Articles 9 and 10. The priority list of contents and emissions in cigarettes, other smoked tobacco products and smokeless tobacco products should be re-evaluated periodically, as appropriate, on the basis of new scientific knowledge.
•
• •
•
•
•
•
•
5.4 Non-exhaustive list of priority toxic contents and emissions of tobacco products15 Acetaldehyde Acetone Acrolein 15 This list contains one compound more than the 38 listed in the WHO report to the Sixth Session of the Conference of the Parties to the WHO FCTC (10), because, on the basis of the weight of the scientific evidence and further deliberations by TobReg, arsenic was added to the list.
76
Acrylonitrile 1-Aminonaphthalene 2-Aminonaphthalene 3-Aminobiphenyl 4-Aminobiphenyl Ammonia Arsenic Benzene Benzo[a]pyrene 1,3-Butadiene Butyraldehyde Cadmium Carbon monoxide Catechol m-Cresol p-Cresol o-Cresol Crotonaldehyde Formaldehyde Hydrogen cyanide Hydroquinone Isoprene Lead Mercury Nicotine Nitric oxides
N-Nitrosoanabasine N-Nitrosoanatabine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) N´-Nitrosonornicotine (NNN) Phenol Propionaldehyde Pyridine Quinoline Resorcinol Toluene 5.5 References 1. Decision FCTC/COP5(6). In: Decisions. Fifth Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control. Geneva: World Health Organization; 2012 (document FCTC/COP/5/DIV/5) (http://apps.who.int/
77
gb/fctc/PDF/cop5/FCTC_COP5%286%29-en.pdf). 2. Talhout R, Schulz T, Florek E, van Benthem J, Wester P, Opperhuizen A. Hazardous compounds in tobacco smoke. Int J Environ Res Public Health 2011;8:613–28. Harmful and potentially harmful constituents in tobacco products and tobacco smoke: established list. Silver Spring, Maryland: Food and Drug Administration; 2012. Counts ME, Morton MJ, Laffoon SW, Cox RH, Lipowicz PJ. Smoke composition and predicting relationships for international commercial cigarettes smoked with three machine-smoking conditions. Regul Toxicol Pharmacol 2005;41:185–227. Fowles J, Dybing E. Application of toxicological risk assessment principles to the chemical toxicants of cigarette smoke. Tob Control 2003;12:424–30. Thielen A, Klus H, Müller L. Tobacco smoke: unraveling a controversial subject. Exp Toxicol Pathol 2008;60:141–56. Decision FCTC/COP3(9). In: Decisions. Third Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control. Geneva: World Health Organization; 2008 (document FCTC/COP/3/DIV/3) (http://apps.who.int/ gb/fctc/PDF/cop5/FCTC_COP5%286%29-en.pdf). Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation. Geneva: World Health Organization; 2008 (WHO Technical Report Series, No. 951) (http://www.who.int/tobacco/publications/ prod_regulation/trs_951/en/). Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation. Fourth report of a WHO study group. Geneva: World Health Organization; 2012 (WHO Technical Report Series, No. 967) (http://www. who.int/tobacco/publications/prod_regulation/trs_967/en/).
3.
4.
5. 6. 7.
8.
9.
10. Work in progress in relation to Articles 9 and 10 of the WHO FCTC. Report by WHO. In: Sixth Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control. Geneva: World Health Organization; 2014 (document FCTC/COP/6/14).
78
6. Overall recommendations 6.1 Novel tobacco products 6.1.1 Main recommendations 6.1.2 Significance for public health policies 6.1.3 Implications for WHO programmes 6.2 Smokeless tobacco 6.2.1 Main recommendations 6.2.2 Significance for public health policies 6.2.3 Implications for WHO programmes 6.3 Reduced ignition propensity cigarettes 6.3.1 Main recommendations 6.3.2 Significance for public health policies 6.3.3 Implications for WHO programmes 6.4 Non-exhaustive list of toxic contents and emissions of tobacco products 6.4.1 Main recommendations 6.4.2 Significance for public health policies 6.4.3 Implications for WHO programmes
TobReg commissioned a series of reports to provide a scientific foundation for tobacco product regulation. In line with Articles 9 and 10 of the WHO FCTC,16 these reports identify approaches on which to base the regulation of tobacco products, which pose significant public health threats. The seventh meeting focused on issues critical to advancing the regulation of tobacco products, particularly as outlined at the Fifth Session of the Conference of the Parties to the WHO FCTC.17 The topics discussed included the evolution of novel tobacco and related products, smokeless tobacco, reduced ignition propensity (RIP) cigarettes, nicotine reduction and addictiveness and a non-exhaustive priority list of toxicants. 6.1 Novel tobacco products 6.1.1 Main recommendations
A tobacco product is considered novel if it contains tobacco and if at least one of the following applies: it has been on the market for less than 12 years; it has been on the market for a longer time but with market share increases in countries or regions that traditionally did not use the product; it is based on a new technology; and it is marketed as being less hazardous to health than other tobacco products. 16 For more information, see: http://www.who.int/fctc/text_download/en/ (accessed 28 November 2014). 17 For more information, see decision FCTC/COP5(6), paragraph 3(b) and decision FCTC/ COP5(10), paragraphs 1– 4 (http://www.who.int/fctc/cop/en/ (accessed 28 November 2014).
79
Novel tobacco products should be evaluated for toxicity, association with disease risk, consumer awareness and perception, pattern of use and the demographics of use. Standardized evaluation of such products is needed, and regulators should approve them only if pre-market testing shows a probably public health benefit. The concept of “harm reduction” used by the industry and the impact and effectiveness of strategies promoting the use of products that are allegedly less hazardous to health should be evaluated and communicated effectively to the general public in order to prevent misperceptions. 6.1.2 Significance for public health policies
The main concern related to the use of novel tobacco products includes unknown toxicity, changes in product use behaviour, decreased cessation, increased initiation, sustained prevalence of tobacco “dual use”18 and public misunderstanding about the actual risk associated with allegedly less hazardous products. 6.1.3 Implications for WHO programmes
The approach to monitoring should be more comprehensive and consistent and the collection of research data on novel tobacco products more systematic. 6.2 Smokeless tobacco 6.2.1 Main recommendations
Clearer policy is required to address the challenges presented by smokeless tobacco products. In comparison with smoked tobacco products, smokeless tobacco products are more readily affordable, they carry weaker warning labels, and fewer resources are spent on their surveillance, prevention and control. Evidence-based control policies must be strengthened, such as ensuring disclosure of product content, establishing performance standards for toxicants and maximum pH levels, banning flavourings, using effective, relevant health warning labels, increasing product taxes, restricting or banning marketing of such products and increasing public awareness of the harm associated with their use.
18
Concomitant use of two forms of tobacco is an increasing public health concern. As yet, however, there is no consensus on a consistent definition of such “dual use”. For the present purposes, the term refers to use of both cigarettes and smokeless tobacco or of cigarettes and a novel tobacco product, either product being used daily or not daily.
80
6.2.2
Significance for public health policies
More attention should be given to the overall impact of smokeless tobacco products, including their use by adolescents, dual use, “poly-use” and the growth in targeted marketing for indoor use. 6.2.3 Implications for WHO programmes
Additional data are needed on the use, surveillance and characteristics of smokeless tobacco products, as well as on the health consequences of the use of individual products. Further, better understanding is required of the market for such products and on effective region-specific education, prevention and treatment interventions. Resources and collaborative work are required to obtain such data. 6.3 Reduced ignition propensity cigarettes 6.3.1 Main recommendations
Laws relating to RIP have now been enacted in Australia, Canada, South Africa, the USA and the European Union, but this pattern has yet to be followed in many middle- and low-income countries. Ideally, this technology would be applied to all cigarette manufacture; to achieve this, testing must be standardized in accredited laboratories, paid for by the tobacco industry. Claims of reduced risk to health should not be allowed. Monitoring should be established to determine whether this technology is effective in reducing the numbers of fires, deaths and injuries related to cigarettes. Monitoring should also be conducted for toxicity and for behavioural changes related to a heightened awareness of RIP in cigarette manufacture. 6.3.2 Significance for public health policies
Fires caused by smoking are a major public health risk and cause many deaths. A reduction of approximately 30% in smoking-related fires was shown in areas with RIP laws, when data were available. Testing has shown no consistent difference in smoke emissions between cigarettes manufactured by RIP technology and classical cigarettes. These findings refute the claims of the tobacco industry. 6.3.3 Implications for WHO programmes
More research is needed on the toxicity and emissions of RIP cigarettes, on possible changes in smoking behaviour and on the potential reduction in the numbers of fires and deaths associated with cigarettes.
81
6.4 Non-exhaustive list of toxic contents and emissions of tobacco products 6.4.1 Main recommendation
From among the chemicals found in cigarette contents and emissions (as many as 7000), TobReg identified a non-exhaustive priority list of 39 contents and emissions of cigarette smoke and recommended that these 39 toxicants be monitored in all tobacco products. The criteria included their potential toxicity to smokers and variation in concentrations among cigarette brands. As the scientific basis grows, this list is likely to be modified or extended. 6.4.2 Significance for public health policies
The list will guide regulation of contents and emissions, as stated in Articles 9 and 10 of the WHO FCTC. The list should be re-evaluated periodically as new knowledge becomes available. 6.4.3 Implications for WHO programmes
The contents and emissions of tobacco products should be monitored and regulated by the validated methods of TobLabNet. Laboratories in the Network have already validated methods for measuring tar, nicotine, CO, TSNA, benzo[a]pyrene and humectants, and validation of methods for measuring ammonia, volatile organic compounds and aldehydes is under way. Priority should be given to laboratories in the Network that are developing standardized methods for measuring cadmium and lead in tobacco, nicotine in the smoke of waterpipes and nicotine, TSNA and benzo[a]pyrene in smokeless tobacco products.
82
7. Regulation of tobacco smoke: commentary on the status quo19 7.1 Background 7.2 Proposed actions 7.3 Issues relevant to setting upper limits 7.4 References
7.1 Background This commentary addresses those elements of cigarette design that are well understood, for which there is clear evidence of harm and which could certainly be reduced on the basis of existing evidence. Nicotine delivery systems have evolved over the centuries, leaving the cigarette as the victor since the development of efficient machinery in 1880. Not a great deal changed between the two world wars, but, since then, the cigarette has remained the nicotine delivery system of choice. It has been developed into a highly sophisticated chemical melange of tobacco and additives that is certainly more addictive (1), more adenocarcinogenic (2, 3) and more “attractive” (1) than the relatively simple “gasper” that addicted the troops during the First and Second World Wars. The cigarette’s competitors in the western world have universally failed to displace it as first choice. In the developing world, there is a galaxy of smokeless products that are highly toxic and carcinogenic and also have a high nicotine content, but even these cannot challenge the cigarette. Even in India, where the mixtures are diverse and abundant, the cigarette has claimed 40% of the smoking market (4). There are probably two reasons for this situation: the existence of a globally powerful group of corporate bodies with a serious vested interest in the cigarette, which is cheap to make and sell, and the technical brilliance of the modern cigarette. 19
This commentary by Dr Nigel Gray is based on the thoughtful paper that he independently produced for the seventh TobReg meeting in December 2013 without commission by WHO. It does not necessarily represent the views of WHO or TobReg. However, TobReg members unanimously recommended that it be included as a commentary recognizing the thought-provoking nature of its content and goals, and recognizing Dr Gray as a public health and tobacco control leader and visionary. Dr Gray served TobReg since its inception in 2000 as SACTob (Scientific Advisory Committee on Tobacco Product Regulation) and he significantly guided its direction and reports. WHO TobReg has been honoured by his service, and global tobacco control has advanced significantly by his contributions. Dr Nigel Gray passed away peacefully on 20 December 2014 surrounded by his loved ones. WHO’s tribute to Dr Gray can be found at: http://www.who.int/tobacco/communications/highlights/nigelgray/en/.
83
In developed countries, public health authorities have considered alternatives, with the expensive development of therapeutic nicotine and, in some cases, other alternatives, such as snus and, more recently, electronic cigarettes. None of these has made a significant inroad into the market of the cigarette, which dominates the battlefield of nicotine addiction and probably has about 65–85% of the global market (5). Much of the literature on harm reduction involves comparisons of cigarette alternatives, such as smokeless tobacco and therapeutic nicotine, with “the cigarette” (6–8). The implication of many such comparisons is that “the cigarette” is a standard form of product. This is patently not true, as shown in Table 7.1. Although comparisons between “cigarettes” and less toxic products such as snus are reasonable for promoting the possibility of harm reduction by change of product, they avoid the reality that the cigarette of today is a highly variable product, which presumably causes various degrees of harm. As cigarette recipes are not published but certainly change over time and users also change brands, there has been, and can be, no study in which specific brands are compared with specific disease outcomes. As a result, there is no precise way of determining whether Marlboro is more or less carcinogenic, adenocarcinogenic or squamocarcinogenic than Virginia Slims. Modern epidemiology was built on use of “the cigarette” as the unit of dose, with occasional studies of differences in levels of tar. It is probable that the main findings of the major studies have withstood the test of time because they are actually serious understatements. Table 7.1. Levels of carcinogens and other toxins found in cigarettes Toxin NNK (ng/cigarette) NNN (ng/cigarette) Benzo[a]pyrene Acetaldehyde (µg/cigarette) Acrolein (µg/cigarette) Benzene (µg/cigarette) Butadiene (µg/cigarette) Formaldehyde (µg/cigarette) CO (mg/cigarette) Lowest 12.4 5.0 6.6 32 2.4 6.1 6.4 1.6 1.1 Highest 107.8 195 29.3 643 61.9 45.2 54.1 52.1 13.4 Variation (fold) 9 19 4 20 24 7 8 30 13 Threefold 37.2 15 19.8 94 7.2 18.3 19.2 4.8 3.3
The passage of legislation permitting interference with cigarette design in Canada and the USA offers hope but has so far produced only changes in flavourings. This is probably a reflection of the relative powers of the manufacturers and of government agencies. A side-effect of that relative power has
84
been a consequential failure by public health authorities to establish actual rather than theoretical control of product design. Even more serious is the disconnection between the excellent research done by non-industry scientists and the development of public health policy that could have led to changes in cigarette design. There is an obvious role for TobReg and WHO in this situation, where they could reasonably aspire to establish some parameters for cigarette design that could be introduced immediately in those countries that do not have sophisticated public health establishments or tobacco research facilities. Such countries need advice about immediate action on cigarette design that is research-based, scientifically solid and unarguable. WHO has the deficiency that it cannot make laws and can only advise Member States. It has the parallel virtue, however, that its advice is widely accepted. Within WHO, only TobReg has independent expertise in the field of tobacco product design. For this reason, it is proposed that TobReg establish a set of parameters for cigarette design that could be accepted routinely and immediately by interested countries, just as WHO advice on influenza vaccines is accepted. The report of TobReg (1) covered virtually all the qualities and chemicals that are known to contribute to dependence on cigarettes. Although they were named and described, TobReg did not suggest any action. That publication does, however, set the stage for specific regulatory actions, which can now be recommended. It should be noted that the manufacturers have shown extraordinary skill in using chemical changes to achieve alterations in qualities. A review of the text of the TobReg document reveals the following qualities. The proposals are fully referenced in WHO (1), and some new references are added. Factors (qualities) that affect initiation and maintenance of addiction: • • • • • • • • • • • • attractiveness smell flavour taste coolness smoothness filter ventilation speed of delivery efficiency of absorption pH particle size starter products with low nicotine and high flavour
Factors (qualities) that affect the strength of the “fix”:
85
Chemicals that facilitate dependence: • • • • • • • • • • • • • • • • • • • nicotine anabasine nornicotine menthol acetaldehyde ammonia laevulinic acid monoamine oxidase inhibitors urea chocolate NNK NNN acetaldehyde acrolein benzene benzo[a]pyrene 1,3-butadiene CO formaldehyde
WHO (1) list of carcinogens and toxicants for which upper limits could be set:
Now is an ideal time to consider the actions that should be taken on the basis of what we know. 7.2 Proposed actions As an initial step in regulating cigarettes, the following measures, which have a strong evidence base, could be taken. • Cigarettes should contain a relatively standard dose of nicotine, delivered to the smoker with a minimum of carcinogens and other toxins. This is not discussed further here, as the issue of nicotine dosing, including the alternative approach of reduction of nicotine to non-addictive levels, is addressed in Annex 3 of this report. Elements that facilitate compensatory smoking should be discouraged; filter ventilation is an obvious example. Additives that increase the addictiveness or the attractiveness of tobacco smoke should be prohibited. There is a strong case for prohibiting all additives, unless there is a public health reason for their presence, such as the additives required to make RIP cigarettes.
• • •
86
•
Upper limits should be set for those carcinogens and other toxins about which there is knowledge and for which the necessary technology is available. A measuring system that gives consistent results is needed. The current Canadian system (9) meets this need and has the advantage that the filter is taped over, thereby reducing the incentive to use filter ventilation. Manufacturers should be required to meet the performance standards proposed here and should disclose relevant levels of carcinogens and other toxins. The current Canadian system also meets this need. Nitrosamines: The tobacco industry has established a standard method for reducing the levels of nitrosamines, the Gothatiek standard (10, pp. 23–41), pioneered by Swedish Match. It is used for such products as snus and could be accepted as an initial step, although the levels of these carcinogens could be reduced still further (S.S. Hecht, personal communication). PAH: The levels of these compounds could also be reduced significantly with the standard Gothatiek procedure.
•
•
This leads to the consideration of the following performance standards: •
•
Other major carcinogens and other toxins that were considered by TobReg (11) are listed in Table 7.1, which shows the high and low levels in cigarettes on the international market in 2002, as reported by Counts et al. (12). The range of levels is astonishing; conveniently, it covers an international sample, although it is limited by the choice only of Philip Morris brands. 7.3 Issues relevant to setting upper limits There are no precedents for setting limits for carcinogens and other toxins in a consumer product, for the simple reason that the normal public health approach would be to set these at zero. Any regulator would require considerable persuasion to accept that a limit other than that which is the lowest achievable would be acceptable. Acceptance of levels that are multiples of the lowest levels achievable would be clearly ridiculous, as shown in Table 7.1: e.g. eightfold for NNK, 19-fold for acetaldehyde, 24-fold for acrolein, sevenfold for benzene, sixfold for butadiene, 30-fold for formaldehyde and 12-fold for CO. If the upper limit was set at three times the lowest level achieved on the market, it would be up to the manufacturer to prove that such a (generous) limit should be increased. Thus, the onus of proof that any such limit should be exceeded should lie with the manufacturer, and the only acceptable reason for any increase would be that achieving the set limit is biochemically impossible. Permitting a threefold variation above the lowest level achievable, while
87
clearly generous, would establish a precedent and should be established for a trial period of 2 years, after which time the levels would be reviewed and, where practical, set lower. These simple actions would: • • • • • reduce the incentive for compensatory smoking, as the cigarette would provide the smoker’s chosen dose; remove much of the sophistication that underlies addictiveness; be consistent with fire risk reduction; reduce the relative risk for adenocarcinoma (which has been clearly related to exposure to nitrosamines: 2, 3); and reduce the total carcinogenic burden by removing nitrosamines and PAH.
Ten nitrosamines could be almost completely removed, and the levels of nine PAH would be substantially reduced. This change, with those in the levels of the other substances shown in the table, might well be described as dramatic, but it actually reflects the views first stated 6 years ago (11). While it cannot and should not be denied that cigarettes that meet these performance standards would be less dangerous than current products, there is nothing here that could allow “health” claims to be made, as the benefits cannot be quantified, nor could the period over which effects would be seen be firmly established in any ethical trial. The cigarette will still be the most dangerous consumer product in the world as well as, probably, the greatest cause of tobacco-related disease. Nevertheless, we should be clear that what we are attempting to do is “harm reduction” applied to the cigarette. This principle was the basis for the low-tar cigarette campaign, which started with harm reduction as an objective but was a failure because the industry cheated and public health authorities lacked the knowledge and laboratory facilities to call them to account. Times have changed. Thus, these changes are justified not only by the precautionary principle, which is a normal feature of public health regulation, but also because there can be no doubt that the substantial changes proposed would reduce cancer rates and addictiveness over time. The fact that we do not know by how much or over what time is no excuse for accepting the status quo.
88
7.4 References 1. WHO Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation. Fourth report of a WHO study group (WHO Technical Report Series, No. 967). Geneva: World Health Organization; 2012. Burns DM, Anderson CM, Gray N. Has the lung cancer risk from smoking increased over the last fifty years? Cancer Causes Control 2011;22:389–97. Burns DM, Anderson CM, Gray N. Do changes in cigarette design influence the rise in adenocarcinoma of the lung? Cancer Causes Control 2011;22:13–22. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 89. Smokeless tobacco and some tobacco-specific N-nitrosamines. Lyon: International Agency for Research on Cancer; 2007. Jha P, Chaloupka F. Tobacco control in developing countries. Oxford: Oxford University Press; 2000. Fox BJ, Cohen JE. Tobacco harm reduction: a call to address the ethical dilemmas. Nicotine Tob Res 2002;4(Suppl 2):S81–7. Gilpin EA, Pierce JP. The California tobacco control program and potential harm reduction through reduced cigarette consumption in continuing smokers. Nicotine Tob Res 2002;4(Suppl 2):S157–66. Foulds J, Ramstrom L, Burke M, Fagerstrom K. Effect of smokeless tobacco (snus) on smoking and public health in Sweden. Tob Control 2003;12:349–59. Canadian tobacco reporting regulations. Ottawa: Health Canada; 2003.
2. 3. 4.
5. 6. 7.
8. 9.
10. WHO Study Group on Tobacco Product Regulation. Report on setting regulatory limits for carcinogens in smokeless tobacco. Geneva: World Health Organization; 2010 (WHO Technical Report Series No. 955). 11. WHO Study Group on Tobacco Product Regulation. Contents and design features of tobacco products: their relationship to dependence potential and consumer appeal. Geneva: World Health Organization; 2007 (WHO Technical Report Series, No. 945). 12. Counts ME, Morton MJ, Laffoon SW, Cox RH, Lipowicz PJ. Smoke composition and predicting relationships for international commercial cigarettes smoked with three machine-smoking conditions. Regul Toxicol Pharmacol 2005;41:185–227.
89
90
Annex 1
Novel tobacco products, including potential reduced exposure products: research needs and recommendations
Dr I. Stepanov, Division of Environmental Health Sciences and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
Dr L. Soeteman-Hernández, Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, The Netherlands Dr R. Talhout, Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
Abstract Background Concept of “harm reduction” Methods Data sources Selection criteria Data extraction and synthesis New marketed and test-marketed products and products with emerging use Oral tobacco products Dissolvable tobacco Novel snus products Oral tobacco types resembling snus on the market in the European Union Modified or alternative smoked products Potential reduced exposure cigarettes “Low-tar” cigarettes promoted in some countries as “less harmful” products Reduced-nicotine cigarettes Super-slim cigarettes Little cigars and cigarillos Herbal-tobacco cigarettes Bidis Waterpipes Product description and marketing strategies Consumer awareness, product use and perceptions Constituents, toxicity and disease risk Addictive potential Regulatory considerations Notable alterations to traditional products Swedish snus with reduced tobacco content
91
Moist snuff with bioactive additives Menthol capsules in filters No-additive, or organic, cigarettes Branding with a brand name Less-smoke-smell cigarettes Technologies under development Substitution of traditional tobacco burning by heating Combination of changed tobacco processing and filter structure Tobacco substitute sheet with a carbon or cellulose acetate filter Tobacco-blend treatment and filters containing functionalized resin or carbon Combination of tobacco substitute sheet and a two-segment carbon filter Modification of filter structure An amine functionalized ion-exchange resin in filters Titanate nanosheets, nanotubes and nanowires in filters Charcoal filters Research in progress as presented at the 2013 CORESTA meeting Tobacco additives Filter additives Precursor studies Summary Non-combustible oral products Cigarettes and cigarette-like devices Conclusions Acknowledgements References Appendix. Questionnaire on new tobacco products, including products with potentially “modified risk”
Abstract This annex provides an overview of novel marketed and test-marketed products and products with emerging use, including oral tobacco products, modified or alternative cigarettes, waterpipes and notable alterations to traditional products. New technologies in development, such as substituting traditional burning of tobacco by heating, changing tobacco processing and alterations to filter structure are also discussed. Analysis of published research on these products brought us to the conclusion that the impact of the newest tobacco products on public health is not clear. Potential unrecognized toxicity, increased or sustained prevalence of tobacco use by recruitment of new users, relapse of ex-smokers or maintenance of tobacco use by current smokers who might otherwise have quit, dual use of a novel tobacco product and cigarettes and potential initiation with a novel product followed by switching to cigarette smoking are major concerns voiced
92
by many public health researchers and advocates. The current state of research does not provide sufficient evidence to dismiss any of these concerns. We recommend improved systematic global surveillance of new tobacco products and development of a standard approach to assess the risks associated with their use, research on marketing and on consumer perceptions of novel products, development of effective approaches to communicate information on these products to professionals and the general public, introduction of consistent nomenclature and assessment of the impact of policies on the prevalence of novel product use. We also suggest that regulatory bodies consider expanding their regulatory framework to include not only all existing and emerging tobacco products but also products that are used in similar ways (such as herbal cigarettes) and accessories for tobacco use (such as waterpipe charcoal), establish requirements for premarket authorization of novel products, monitor the prevalence of new tobacco product use in each country in order to prioritize tobacco control and regulation measures properly, and develop regulatory strategies to decrease the toxicity, attractiveness and addictiveness of new products.
Background During the past decade, a range of new tobacco products and product types has been introduced onto markets worldwide. Some of the new products, such as dissolvable tobacco products and “snus” manufactured in the USA, are designed for oral use. Other innovations are in essence modified cigarettes that contain specially treated tobacco or novel filters or deliver inhaled tobacco in novel ways, such as at a lower burning temperature or by heating instead or burning the tobacco. Some of these products may be the result of attempts by the tobacco industry to manufacture and market products that decrease exposure to harmful tobacco constituents, and some have been or are being marketed with corresponding implicit or explicit health claims. While the general concept of exposure reduction is constructive, use of such products or misperception of the health benefit of using a “reduced exposure” product could have unintended health consequences. For instance, marketing of “light” cigarettes raised false expectations of reduced exposure, and they have not decreased health risks. Cigarettes with reduced nicotine content are another innovation in tobacco products; such cigarettes could be less addictive and lead to a decrease in smoking prevalence. Other innovations, such as menthol capsules in cigarette filters, are not associated with reduced risk. Further alterations to or processing of tobacco plants and new tobacco delivery products may be developed. The emerging use of some tobacco products in countries where those products have not been used previously, with potential unrecognized consequences, is another concern.
93
The increase in the diversity of new tobacco products should be accompanied by rigorous research on their effects at both individual and population level. A significant amount of independent research has been conducted on some of these products during the past decade, and tobacco companies publish the results of testing of products that may appear on the market. Summarizing existing knowledge on the toxicity and marketing of these products is important for understanding the current state of science and for identifying any gaps and future directions, thus providing an adequate basis for tobacco control policies and regulations. Our objective was to systematically identify and evaluate published peer-reviewed publications and other sources on the types, properties and effects of new and emerging tobacco products, including those with potentially “modified risks”.
Concept of “harm reduction” A “harm reduction” strategy to develop tobacco products that are less toxic and addictive could be an effective element of a comprehensive approach to reducing tobacco-related deaths and disease. Such a strategy might not only be beneficial on a population scale but might also be necessary to reduce the risk for disease of tobacco users who are unwilling or unable to break their dependence on tobacco. The concept of “harm reduction” may have different meanings for the tobacco industry and for researchers in public health and tobacco control. Until now, the industry has focused on reducing the measured yields of harmful constituents in cigarette smoke; however, from a public health perspective, marketing of such tobacco products might imply reduced exposure and risk on the basis of insufficient or unverified information. The history of the manufacture and marketing of “light” or “low-tar” cigarettes is a well-known example in which consumers were misled by invalid assurances of reduced harm. Public health researchers and tobacco control professionals are therefore concerned about the actual exposure and intake of consumers to constituents, the possible recruitment of new users and the addictive potential of products (1, 2). As both addiction and the risks for many tobacco use-associated diseases are related to the level of exposure to tobacco constituents, reducing exposure should be an important component of tobacco control. Several basic principles have been proposed by the Society for Research on Nicotine and Tobacco (3) for approaches to exposure reduction. • • The purpose of the approach must be to reduce deaths and disease caused by tobacco. The long-term goal of the approach should be to make smokers both tobacco- and nicotine-free.
94
• • • • • •
The approach should not add any risk, and the data on safety should be extensive, including in long-term use. The approach should not exacerbate individual nicotine dependence. It should not reduce the likelihood of eventual cessation of tobacco use. The approach should not increase the population prevalence of tobacco dependence. It should not appeal to adolescents or increase the risk for misuse or abuse by adolescents. Any promotion or marketing of this approach should provide consistent messages about smoking cessation and offers of help in quitting smoking and in terminating use of the product.
Use of these basic principles in designing exposure reduction approaches might accelerate assessment of products with reduced toxicant levels and provide consumers with less harmful options than the currently available conventional cigarettes.
Methods Data sources
Literature was sought primarily on the PubMed database and with the SciFinder search tool, which retrieves data from the Medline and CAplus databases. Relevant articles cited in publications obtained from the databases were also included. In addition, the Internet was searched for websites that provide product characteristics and marketing information, the websites of major tobacco manufacturers, tobacco research websites, blogs and news articles. Information was obtained from 2002 on, as the background document on new or modified tobacco products (4) was finalized in November 2002 and issued in 2003. A period of around 11 years is therefore covered. In addition, experts in the field, including regulators and tobacco scientists, were consulted through a questionnaire (see Appendix). Contributors are listed in the acknowledgements. The Internet was searched for products identified in the questionnaire survey. Selection criteria
We used the following criteria to define “new” or “novel” tobacco products: • The product contains tobacco (e.g. e-cigarettes and herbal cigarettes were not included). 95
• • •
The product is manufactured by a new or unconventional technology and/ or is marketed as a “reduced harm” product. The product type has been on the market for less than 12 years. The product type has been on the market for longer, but its market share has increased in countries or regions in which this type was not used previously. Emerging use of unconventional tobacco products jeopardizes tobacco control efforts worldwide.
While some of the products described are no longer available, we summarized the research on those products to improve understanding of current and future innovations in tobacco product development and for interpreting any health claims by the industry. We excluded products that are just variations of traditional or regular cigarettes, cigars, pipe tobacco, roll-your-own or oral tobacco in markets that carry these types of product. Data extraction and synthesis
The search was performed with the initial keywords “snus”, “waterpipe”, “dissolvable tobacco”, “low nicotine cigarette”, “reduced (tobacco product or cigarette)”, “modified (tobacco product or cigarette)”, “tobacco harm reduction” and “novel (tobacco or cigarettes)”, followed by the “snowball” method. We collected information on the products, approaches used in marketing them, including health claims, how the products are used and perceived, their chemical composition and toxicity, their addictive potential, their effectiveness in suppressing withdrawal symptoms (which may hinder smoking cessation or complete substitution) and any regulations specific to the product.
New marketed and test-marketed products and products with emerging use Although some of the products described in this section have been discontinued by their manufacturers and are no longer available, a substantial amount of research has been done, which is important for understanding current and future innovations in tobacco product development and for evaluating the potential public health impact of future modified products. Products that do not involve new technologies but are beginning to be used in new markets are also included, as expanding use by new types of consumer raises new challenges and new questions that must be addressed by rigorous scientific research.
96
The majority of the published papers included in this report originated in Europe and the USA. Furthermore, the feedback to the questionnaires did not provide sufficient information for a geographically comprehensive overview, as some respondents reported no information on new or emerging tobacco products in their region. Therefore, information is provided on product type rather than on trends by geographical region. Oral tobacco products Dissolvable tobacco
Product description and marketing strategies Dissolvable tobacco products appeared on the US market in 2001, with the introduction of Ariva and Stonewall (Figure A1.1). Figure A1.1. Examples of dissolvable tobacco products
Their manufacturer, Star Scientific, made only a limited investment in marketing and promoting these products (5). In 2009, RJ Reynolds introduced Camel dissolvable products, and in 2011 Philip Morris introduced Marlboro and Skoal dissolvable tobacco (Figure A1.1). These products are made from finely milled tobacco and are sold in the form of pellets, sticks or strips. For example, Camel Orbs are small, oval-shaped pellets, Camel Sticks are rods of dissolvable tobacco that resemble toothpicks, and Camel Strips are brown tobacco strips similar to breath-freshening strips (6). Dissolvable Camel
97
products were initially introduced in mellow and fresh flavours, but the latest version has been reformulated and has a single mint flavour (7). Dissolvable tobacco products of a size, shape and packaging similar to those of the Camel dissolvable series were introduced into markets of Taiwan, China, under the brand name Revo in 2010 (8). Marlboro Sticks and Skoal Sticks produced by Philip Morris differ from Camel Sticks in that they contain a toothpick-like wooden rod covered with a layer of finely milled tobacco. Figure A1.1 demonstrates the evolution of this category of product. Camel dissolvable products were test-marketed in several US states, including Indiana, which has the highest tobacco use and the second highest adult smoking rate in the USA (9, 10). Advertising in shops carrying dissolvable tobacco products included phrases such as “dissolvable tobacco”, “free trial”, “special price” and “What’s your style?”, and the products were shelved near smokeless tobacco, cigarettes or sweets (10). Like the approaches for promoting US snus, some of the advertisements for dissolvable products emphasize their unique features (for example, do not require spitting or disposal after use), their discreet nature and the ease of use in bars, airplanes and other places where smoking is not permitted (5). Although the primary audience for retail advertising of these products appears to be current smokers, some researchers raised the concern that their promotion, the fact that they can be used discreetly and the packaging, which many refer to as “candy-like”, may appeal to new, young users who have not previously used tobacco (5, 10). The study by Romito et al. (10) in Indiana showed that most shops that sold Camel dissolvables carried promotional items, including offers of free trial packs with another Camel purchase. The authors also reported that various university campuses held events at which dissolvable products were promoted, with free samples, coupons and other promotional items. Of participants who had received any promotion, 11% had tried the products, whereas only 3% of the total sample had done so. Consumer awareness, product use and perceptions Early research on Ariva showed little appeal or uptake by smokers, although some research participants thought the products would appeal to groups such as new smokers, young adults and women (5, 11). Concern has been raised that the “candy-like” appearance of these products and the added flavours might be attractive to young children (12). Analysis of data from Florida, USA, suggested that 18- to 34-year-old smokers are more likely to have tried dissolvables than older adult smokers (5). Another study of consumer awareness, interest and perception of Camel dissolvables in Indiana, USA, showed that consumer interest was very low, but respondents < 40 years were more familiar with Camel dissolvables (60%) than those > 40 years (45%; p < 0.01). As for snus,
98
males and current and former smokers showed more interest and more often tested dissolvable products. Both smokers and nonsmokers perceived that the advertisements targeted smokers (10). Constituents, toxicity and disease risk The first versions of dissolvable products, Ariva and Stonewall, contained the lowest levels of tobacco-specific N-nitrosamines (TSNA)—a major group of tobacco carcinogens—of all US commercial tobacco products (13). For instance, the N’-nitrosonornicotine (NNN) content of Ariva was 19 ng/g, and that of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was 37 ng/g, whereas the traditional moist snuff Kodiak Wintergreen contained 2200 ng/g NNN and 410 ng/g NNK. In a study of Ariva and medicinal nicotine, the TSNA intake of smokers who switched to Ariva was comparable to that of a nicotine lozenge (14). Slightly higher TSNA levels have been reported in more recent Ariva and Stonewall products, although they are still much lower than those in traditional moist snuff (15, 16). The TSNA levels in the dissolvable Camel products that initially appeared on the market were generally comparable to those of Ariva and Stonewall, Camel Strips having the lowest TSNA content, followed by Camel Orbs and Sticks (15). More recent versions of Camel dissolvables, however, contain higher levels of TSNA (17). The new dissolvable products Marlboro Sticks and Skoal Sticks contained TSNA at the levels found in conventional US moist snuff (16, 17). Table A1.1 summarizes the concentrations of nicotine and TSNA reported in dissolvable tobacco products. Table A1.1. Concentrations of nicotine and tobacco-specific N-nitrosamines in dissolvable tobacco products Nicotine (mg/g) 4.4–6.3 6.8–8.7 2.7–4.1 3.1–4.7 2.2–4.1 5.9–7.1 Free nicotine (mg/g) 0.3–1.5 0.7–1.6 1.2–1.8 1.4–1.9 1.1–2.0 2.7–3.5 0.8–1.1 NNN (ng/g) 19–98 56–133 NNK (ng/g) 37–71 43–73
Product Ariva Stonewall Camel Orbs Camel Sticks Camel Strips Marlboro Sticks
Skoal Sticks 4.5–5.9
References 13, 15, 16, 18 13, 15, 16, 18 15, 16, 18; Stepanov, 190–280 260–1060 unpublished data 15, 16; Stepanov, 221–260 220–780 unpublished data 15, 16; Stepanov, 150–340 194–780 unpublished data 16; Stepanov, 1760–2070 472–800 unpublished data 16; Stepanov, 1820–2420 485 – 790 unpublished data
99
Extensive chemical screening of Camel dissolvable tobacco products showed that they contain mainly tobacco, mixed with binders, fillers and flavours (6, 7). The chemical composition of the version of Camel dissolvable products released in 2010 showed a changed flavour (mint instead of fresh and mellow flavours); thus, all the new products contained menthol but no cinnamaldehyde or coumarin, which were previously present in mellow-flavoured dissolvables, and threitol instead of glycerol. The level of free nicotine (biologically available form) was statistically significantly higher in the new Orbs than in the older version, but no significant change was found in sticks or strips. More comprehensive screening showed the presence of 163 chemicals in dissolvable Camel Orbs, indicating their chemical complexity (16). Because of the suggested resemblance of dissolvable tobacco products to “candies” (sweets), there is concern that children might accidentally ingest these products. Connolly et al. (12) analysed data on child poisoning due to ingestion of tobacco products and found an increasing rate of ingestion of smokeless tobacco between 2006 and 2008, with a case of ingestion of Orbs by a 3-year-old child and two cases of mild poisoning in children aged 2 and 3 years resulting from ingestion of snus. Addictive potential: effectiveness in smoking substitution or cessation According to the promotional literature, Camel Orbs contain 1 mg of nicotine per pellet, Camel Sticks contain 3.1 mg of nicotine per stick, and Camel Strips contain 0.6 mg of nicotine per strip. Connolly et al. (12) analysed Camel Orbs (fresh and mellow flavours) sold in three test markets in the USA and found that they contained an average of 0.83 mg of nicotine per pellet. The average pH was 7.9, which resulted in an average of 42% nicotine in the biologically available free, or unprotonated, form. Analysis of Camel dissolvable products in another study (6) showed that the nicotine content was 0.82 mg in Orbs mellow flavour, 0.77 mg in Orb fresh flavour, 0.91 mg in sticks and 0.21 mg in strips; the pH of these products ranged from 7.50 to 8.02. These products have much lower levels of total and free nicotine than traditional smokeless tobacco, which is likely to determine their acceptability by current or new tobacco users. Low-nicotine products may have lower addictive potential and thus may be more readily accepted by young people who are initiating tobacco use, but they may be rejected by smokers who are seeking a good substitute for cigarette smoking. Smokeless products with a higher nicotine content potentially lead to abuse and sustain addiction but may more effectively satisfy smokers and more completely substitute for cigarettes than those with less nicotine (19, 20). Dissolvable products can provide gradually increasing levels of biologically available free nicotine, so that different formulations may appeal to different potential consumers (Figure A1.2).
100
Figure A1.2. Nicotine gradient in dissolvable tobacco products Star Scientific 0.40 Unprotonated nicotine mg/portion 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 Ariva Stonewall Unprotonated nicotine mg/portion RJ Reynolds 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 Camel Orbs Camel Strips Camel Sticks
Free nicotine levels have been intentionally maintained in various smokeless tobacco products in order to offer low-nicotine products to new users and also products with gradually higher levels of nicotine to sustain the addiction of established consumers (“graduation strategy”) (21). It is important to understand how differing free nicotine levels in new dissolvable products affect their use by consumers. Studies of switching from smoking to the use of dissolvable tobacco show that the physiological and subjective effects of some dissolvable products on withdrawal and craving may be comparable to those of medicinal nicotine (14). These products may, however, delay cessation by providing a means for smokers to relieve their nicotine craving temporarily when they cannot smoke rather than to quit tobacco use completely (5). US Food and Drug Administration Tobacco Products Scientific Advisory Committee report on dissolvable tobacco products In March 2012, this Committee reviewed the published material, submissions and presentations relevant to dissolvable products and submitted a report to the Food and Drug Administration on “…the nature and impact of the use of dissolvable tobacco products on the public health, including such use among children” (22). The Committee concluded that (i) products vary in the content of various constituents, including nicotine and TSNA; (ii) the liability for abuse of dissolvable tobacco products may be lower than that of conventional
101
US cigarettes and most conventional smokeless tobacco products; (iii) use of dissolvable tobacco products may reduce cigarette consumption but does not completely substitute for smoking by most regular cigarette smokers; (iv) while exclusive use of dissolvable tobacco products should be less hazardous than regular smoking of cigarettes, no epidemiological data are available on the absolute health risks posed by these products as they are currently used in the population; (v) data on consumer perceptions and response are limited, but, in general, consumers have not responded positively to current products; and (vi) few cases of accidental ingestion with serious consequences have been reported. Novel snus products
Snus traditionally manufactured in Scandinavia is a finely ground moist tobacco snuff usually processed by pasteurization, which leads to lower levels of carcinogenic TSNA than in other traditional moist snuff. Snus is placed between the cheek and gum, and the juices produced in the mouth are swallowed rather than expectorated. In this section, we focus on the novel versions of snus manufactured and marketed in the USA. Product description and marketing strategies In 2006, two leading US cigarette manufacturers, RJ Reynolds and Philip Morris, began to market new smokeless tobacco products also called “snus” (Figure A1.3). Figure A1.3. Examples of US-manufactured snus
The US version of snus is also produced from pasteurized tobacco and differs from traditional US chewing tobacco, dip and snuff in that it does not require spitting and is packaged in small teabag-like pouches that are placed under the upper lip and are relatively unobtrusive (23). Differentiation of US snus from
102
traditional smokeless products was part of the product advertising (24, 25). The marketing of US snus has emphasized the Swedish origins, but US snus products have been promoted as extensions of the popular cigarette brands Camel and Marlboro. With increasing application of clean indoor air laws, snus has been marketed as a product that can be used discreetly in public and in bars, offices and airplanes “when smoking isn’t an option” (24). Therefore, although much of snus advertising appears to position the product as an alternative to smoking (25), there is concern that snus is marketed primarily as an adjunct to smoking rather than a replacement (24). Examination of Camel snus advertisements (26) indicated that, while between 2007 and 2009 this product was promoted to cigarette smokers, the marketing strategy shifted in October 2009, when new “Break free” advertisements appeared in magazines. The authors suggested that the new advertisements give an ambiguous message that could appeal to a broader spectrum of consumers, including young potential new users. A limited study of a small sample of neighbourhoods and schools in New York City, USA, showed that about 20% of probable tobacco-selling businesses around schools sold snus (27). Since the restriction of traditional broadcast tobacco advertising in the USA, snus has been promoted by tobacco companies to consumers by direct mail, e-mail and other means and also by promotions and free samples in bars and clubs and magazine advertising (23, 24, 28, 29). Direct mailing has been used to promote Marlboro and Camel snus, with coupons and free packages of the product (24). The marketing also included new websites, such as www. camelsnus.com for Camel snus (28). The messages posted on the message board of the Camel snus brand website by consumers during test-marketing may have influenced RJ Reynolds’ decisions on product modifications, such as discontinuing Spice flavour and revising pouch size (28. Delnevo et al. (25) suggested that the ranking of Camel snus as one of the top 10 selling US smokeless brands after only a few years on the market might be attributable to this aggressive marketing. Snus products carrying popular cigarette brand names such as Lucky Strike and Peter Stuyvesant have also been promoted in Canada, Japan and South Africa (24). Consumer awareness, product use and perceptions Biener et al. (30) reported that 10% of smokers in test markets had tried snus in 2010, the trial rate among young adult men being as high as 29%. Products were tested more frequently by whites than by minorities, by respondents with lower education than by those with higher education and by those without immediate plans to quit smoking than by those intending to quit within the next 30 days. Similar results were obtained in a study of snus use in 8472 pupils 103
aged 11–18 in Texas, USA: 7.1% reported ever trying snus, and, of these, 77% were male, 68% were in school, and 46% were white (31). In a study of the awareness, use and perception of snus among 2607 young adults aged 20–28 after snus became available nationwide, 64.8% of participants were aware of snus, 14.5% had ever used it, and 3.2% had used it in the past 30 days; all three outcomes were associated with being male and having smoked > 100 cigarettes in a lifetime (p < 0.05) (29). In a study of the Camel snus website message board, marketing was found to play a significant role in deciding to try this product; many participants said that they had tried the product after receiving a free sample (28). Most smokers viewed using smokeless tobacco products such as Camel snus and Marlboro snus as a temporary rather than a complete substitution for smoking; furthermore, trying snus was reported to reinforce a preference for smoking (24). The participants considered the main benefits of snus to be its use in smoke-free environments and avoiding the social stigma attached to second-hand smoke. Participants were sceptical of the idea that snus is safer than cigarettes and did not consider it an acceptable substitute for cigarettes or as a cessation aid. In other studies, however, snus users and people exposed to snus marketing in bars and clubs were more likely to agree that snus is less harmful than cigarettes (29, 31). The overall market share of snus in the USA increased from 0.1% in 2007 to 3.7% in 2011 (25). Camel, Marlboro and Skoal snus accounted for 99.7% of all snus sales in 2011 (63.3% Camel, 24.2% Marlboro and 12.3% Skoal snus). Most snus sold in 2011 (86.7%) was spearmint or mint flavoured. Habitual users of Camel snus reported using other tobacco products concurrently and consumed an average of 3.3 ± 1.9 pouches/day. Some users reported using two or more pouches simultaneously (32). Constituents, toxicity and disease risk The levels of TSNA, nicotine, benzo[a]pyrene (a representative of carcinogenic polycyclic aromatic hydrocarbons [PAH]) and several metals in Camel snus were reported by RJ Reynolds researchers (32). In an independent study, Stepanov et al. (2012a) analysed TSNA and nicotine levels in various novel products, including Camel and Marlboro snus, purchased in various parts of the USA in 2010. Camel snus had significantly higher TSNA levels than Marlboro snus, while the levels of unprotonated nicotine in the two products varied significantly by region. The amounts of total nicotine, unprotonated nicotine and the sum of NNN and NNK in Camel and Marlboro snus determined in the authors’ laboratory between 2006 and 2010 were significantly higher in in the large Camel snus pouches released in 2010 than in the original, smaller
104
pouches that entered the market in 2006, due to the increase in pouch size. The total and unprotonated nicotine contents of the later version of Marlboro snus pouches were also higher, but the sum of NNN and NNK was lower than in the original version (33). Table A1.2 summarizes the concentrations of nicotine and TSNA reported in US-manufactured snus. Table A1.2. Concentrations of nicotine and tobacco-specific N-nitrosamines in USmanufactured snus Nicotine (mg/g) 14.0–18.3 11.5–19.7 Free nicotine NNN (mg/g) (ng/g) 0.7–1.1 822–933 0.3–1.0 1.6–6.1 0.6–1.6 0.6–1.0 330–2950 369–1320 929–4750 1410– 1710 NNK (ng/g) 67–84
Product Taboka Marlboro Snus
Camel Snus 8.7–13.9 Skoal Dry 10.1–11.4 Skoal Snus 17.2–19.0
References 18, 34 15, 34; Stepanov, 100–233 unpublished data 15, 18, 34; Stepanov, 84–480 unpublished data 80–323 18, 34 Stepanov, unpublished 246–378 data
Mouth-level exposure to various constituents of Camel snus was studied in a group of adult habitual snus users (32). On average, 60–90% of the nicotine, TSNA and benzo[a]pyrene initially present in a snus pouch remained in the pouch after use. The calculated mean mouth-level exposure was 9.4 mg/day for nicotine, 527.7 ng/day for TSNA and 0.68 ng/day for benzo[a]pyrene. In contrast, researchers at the British American Tobacco in Sweden reported that only 33–38% of nicotine and TSNA were extracted from Swedish snus by habitual users (35). The Camel snus studied by Caraway and Chen (32) is, however, different from the Lucky Strike snus tested by Digard et al., with a lower moisture content, a smaller portion size and perhaps other differences in content and manufacture. Potential changes in the exposure of smokers who switched to snus were investigated in a comparison of Taboka, an early version of a US snus-like product, Camel snus and medicinal nicotine. The concentrations of exhaled CO, urinary cotinine, urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a biomarker of exposure to the tobacco-specific lung carcinogen NNK, and urinary total NNN were lower after 4 weeks of product use in each group. The decrease in total NNAL concentration was greater in the group given medicinal nicotine than in that given Camel snus (20). Switching to Marlboro snus was investigated in a study that included partial substitution, complete switching and control groups of smokers who continued to smoke or
105
did not use any tobacco products (36). Metabolites of TSNA, nicotine (urine and plasma), aromatic amines, benzene and PAH, urine mutagenicity and carboxyhaemoglobin were measured at baseline and at various times after switching or quitting. Significant reductions were found in all urinary biomarkers in both the “complete” and “partial” substitution groups as compared with smokers who continued to smoke. Epidemiological evidence indicates that people who use exclusively low-TSNA Swedish snus have a lower overall risk for cancer than regular cigarette smokers (37–39). An increased risk for pancreatic cancer was reported in snus users as compared with people who never used tobacco, but the risk for oral cancer was low or inexistent (38, 39). Snus-induced leukoplakia is common in Scandinavian snus users, but the risk for subsequent development of cancer is not clear (40). Use of smokeless tobacco may increase the risk for death after a myocardial infarct, but it does not increase the risk for myocardial infarction. The data on the reproductive effects of smokeless tobacco use during pregnancy are too sparse to allow conclusions. No information on these health effects is available for users of US-manufactured snus; however, the individual risks of exclusive users may be similar to those of Swedish snus users. Addictive potential; effectiveness in smoking substitution or cessation In a study in which smokers were asked to stop smoking and to choose General snus (a Swedish product), Camel snus, Marlboro snus, Stonewall or Ariva and use it for 2 weeks, Camel snus was generally associated with greater relief from craving, greater satisfaction, reduced use of cigarettes and longer abstinence during follow-up than the other products (19). The dissolvable products Ariva and Marlboro snus were least effective in encouraging abstinence, suppressing cigarette use and lowering the rate of product use. These differences could be due to the levels of nicotine in the products studied: the free nicotine content of a single portion of Camel snus was 1.74–1.97 mg, while that of Ariva was 0.24–0.25 mg and that of Marlboro snus was 0.14–0.38 mg. In a study of pharmacokinetics, the intake of nicotine tended to parallel the nicotine content of the products: use of Camel snus resulted in a higher peak plasma concentration of nicotine (7.7 ng/mL) than Ariva (3.4 ng/mL) or Marlboro snus (2.9 ng/mL) (41). Measures of craving and intention to smoke were significantly decreased with use of Camel snus but not with the lower-nicotine Ariva or Marlboro snus. In a pilot comparison of medicinal oral nicotine replacement with Camel snus and Taboka, Camel snus was associated with less cigarette smoking, greater product use and greater abstinence than the lower-nicotine Taboka (20). The effect of the level of nicotine in snus products on subjective responses to the products is not clear. In one study of the pharmacokinetics of different oral
106
tobacco products, products with a higher nicotine content resulted in greater relief of craving (42), while another study involving 5 days of product administration showed no difference in craving or anticipation of withdrawal relief between Ariva and Camel snus (43). Similarly, in a study with randomization of smokers to Taboka, Camel snus or medicinal nicotine, no difference in craving or withdrawal was seen (20). In general, snus products have not been found to be superior to medicinal nicotine in reducing withdrawal symptoms (19, 20). Oral tobacco types resembling snus on the market in the European Union
According to Article 8 of the European Tobacco Product Directive 2001/37/ EC (44), selling tobacco for oral use, except for chewing tobacco, is forbidden in the European Union, except in Sweden. “Tobacco for oral use” means all products for oral use, except those intended to be smoked or chewed, made wholly or partly of tobacco, in powder or in particulate form or in any combination of those forms, particularly those presented in sachet portions or porous sachets, or in a form resembling a food product. In our questionnaire survey, Austria, the Czech Republic, Germany and Switzerland reported products that resemble both chewing tobacco and snus. For instance, Thunder Chewing Tobacco (Figure A1.4A), a strongly flavoured tobacco paste manufactured by V2 Tobacco in Denmark (http://www.v2tobacco. com/), contains 41% tobacco and 59% of “texture agent”; this is a relatively low tobacco content. The same manufacturer produces Thunder Chewing Bags (Figure A1.4B), consisting of cut tobacco in small sachets that are strongly flavoured with aroma of spearmint. Figure A1.4. Examples of products that resemble snus A. Chewing tobacco
107
B. Chewing bags
Another product of this type is Makla Africaine reported in Switzerland and the United Kingdom (e.g. http://www.sifaco.be/Engl/Site_engl.htm and http:// www.makla-ifrikia.com/shop/kautabak-makla-ifrikia-kautabakshop.html). On a snus consumer forum (http://www.snuson.com/forum/archive/index. php/t-16456.html, accessed 5 October 2013), Thunder Chewing Tobacco is described as unsuitable for chewing, but “Its technically makla, which is classed as chewing tobacco, European chewing tobacco is different to US chewing tobacco, if it wasn’t intended to be chewed, it would be banned by the EU”. As the product resembles snus, its regulatory status must be assessed. In Germany, authorities are examining whether the product falls under the Tobacco Law (implemented from Article 8 of Directive 2001/37/EC). Switzerland considers that the product is not a typical chewing tobacco product but is similar to snus, although it does not fit the definition, as it is more a paste than a powder. In Finland, the authorities are assessing whether a similar product should be regarded as snuff or as chewing tobacco. Modified or alternative smoked products In this section, we review information on cigarettes and cigarette-like products and devices that have either recently been introduced onto the market or have an expanding market share in regions in which they were not used previously. Research on cigarettes designed to reduce the exposure of smokers to toxins and on reduced-nicotine cigarettes is described. Alternative size cigarettes (super-slim), herbal tobacco cigarettes and other products are also described briefly.
108
Potential reduced exposure cigarettes
Product description and marketing strategies Several attempts have been made by the tobacco industry to develop cigarettes that result in lower exposure to toxins than traditional cigarettes, potentially reducing the health risks of smokers and nonsmokers associated with smoking (3, 45). Three main approaches are used in the manufacture of such cigarettes. Substituting burning for heating of tobacco. Examples are Eclipse cigarettes, introduced by RJ Reynolds, and Accord, developed by Philip Morris. Eclipse consists of a filter, tobacco (in two plugs) and a carbon-based heating element wrapped in aluminium foil surrounded by a fibreglass insulator at the tip, which is lit like a conventional cigarette but does not burn the tobacco (46). Once it is heated, the carbon element transfers heat along the wrapped core, first reaching a light reconstituted tobacco high in glycerine and then reaching the tobacco; thus, the smoke is rich in glycerol and water (47). Eclipse was claimed to potentially “reduce the risks of smoking-associated cancers and lower the risk of lung disease” (48). Other advertisements stated that Eclipse “may present less risk”, “may present less risk of cancer”, “reduces levels of carcinogenic compounds”, “produces less respiratory inflammation” and is less offensive to passive smokers because it releases vapour instead of smoke (45). Accord consists of a filter plug, a hollow tube and a segment filled with pressed tobacco; the tube is inserted into a hand-held chamber that heats the tobacco without burning it (46). Accord was marketed as a product intended to reduce second-hand smoke and which may decrease the mutagenicity and cytotoxicity associated with normal tobacco smoke (48). While Accord has been discontinued, Eclipse is still available on the US market. A recent prototype of cigarettes that heat rather than burn tobacco is the Ploom modelTwo (Figure A1.5), a combination of an electronic cigarette (e-cigarette) and a conventional cigarette, which vaporizes actual tobacco rather than the propylene glycol used in e-cigarettes (49; http://www.ploom.com/modeltwo). Figure A1.5. Ploom
109
The motto of the Ploom company is “It’s time to rethink tobacco”, and their most popular product, the Ploom modelTwo, is advertised as a “revolutionary way to enjoy real tobacco in style”. It is a handheld device for warming tobacco pods in many different flavours and inhaling the warm tobacco vapour. According to the product description, the Ploom modelTwo takes 20–30 s to heat up, and each tobacco pod is designed to be smoked over 5–10 min rather than being puffed steadily for a longer time. The vapour generated appears to be appreciated by consumers due to its similarity to conventional tobacco smoke: “The vapor is great, thick and milky, almost like actual smoke…” (49). A reported disadvantage is that the heating element is placed close to the mouthpiece, which becomes very hot (49). Changing tobacco processing. This approach was used in AdvanceTM and Omni cigarettes, released by Brown & Williamson and Vector Tobacco, respectively, which have been discontinued. AdvanceTM was marketed as a product with “all of the taste…less of the toxins” and, according to the manufacturer’s claims, was made of tobacco cured by a special process that “significantly inhibits the formation of tobacco-specific nitrosamines” (50, 51). Omni was made with tobacco treated with palladium to increase its burning efficiency, which was expected to reduce the levels of toxic and carcinogenic products of incomplete combustion in the smoke (52). Omni was marketed as containing significantly reduced levels of PAH, TSNA and catechols, which are “among the most potent and dangerous substances in tobacco smoke in relation to lung cancer incidence” (51). Modifying filter structure. For example, Marlboro UltraSmooth, which entered the US commercial test market in 2005, had a filter that contained activated carbon. While carbon was already used in US cigarettes, the novelty of Marlboro UltraSmooth was that it contained more carbon than other brands (53), suggesting enhanced potential to reduce toxic smoke constituents. This brand was also discontinued. Consumer awareness, product use and perceptions In studies of smokers’ and ex-smokers’ reactions to Eclipse cigarettes, most smokers believed that they were safer than regular, low-tar or low-nicotine cigarettes or even “completely safe”, for the health of both smokers and those around them (45, 54, 55). In one study, many smokers viewed Eclipse as a step towards quitting (45). Another group showed that Eclipse appealed to smokers who were contemplating quitting but that claims of reduced risk appeared to reduce their readiness to quit (54). Thus, such claims can undermine adult cessation and prevention of uptake by young people, possibly increasing harm even if the products are less toxic. A study by the same group in the United
110
Kingdom had similar findings, indicating that the effects of such products and of the claims of quitting by smokers and relapse by ex-smokers must be evaluated as a matter of public health urgency worldwide (55). Despite smokers’ perception that Eclipse cigarettes are “safer”, they rated Eclipse as less satisfying and less rewarding than their own brand of cigarettes (56). Constituents, toxicity and disease risk According to industry investigations, the lower pyrolysis temperature of electrically heated cigarette smoking systems like Accord leads to a significant reduction (25–90%) in the measured concentrations of 44 mainstream smoke (MSS) constituents, including nicotine and carbon monoxide (CO), in comparison with a standard reference cigarette (46, 57). When tested with the Federal Trade Commission method, Accord yields 0.1 mg nicotine and 2 mg tar, and Eclipse yields 0.2 mg nicotine and 4.0 mg tar (46); however, because of differences in design and potential differences in human smoking topography from that of conventional cigarettes, the requirements for measuring the doses of chemicals and toxicants delivered from this type of product must be carefully evaluated. For instance, although the machine-measured nicotine yield of Eclipse was reduced, the levels of nicotine in the blood of smokers were similar to those after smoking conventional cigarettes (58). An evaluation of exposure based on urinary biomarkers, however, showed that switching to Eclipse reduced exposure to nicotine and NNK (59). Early research reported by the manufacturer RJ Reynolds showed that, in comparison with regular cigarettes, the MSS condensate of Eclipse was less genotoxic in a mouse dermal application study (47) and caused less inflammation and pulmonary toxicity in the rat nasal inhalation model (60); they also reported that switching to Eclipse reduced the mutagenicity of the urine of smokers (61). An independent study of the acute effects of Eclipse in smokers who had switched to these cigarettes showed that their exposure to CO was approximately 30% higher than that from regular cigarettes (46). Other studies showed that smokers take larger puff volumes and more frequent puffs when smoking Eclipse than with conventional cigarettes and confirmed the increase in exhaled CO (56, 59, 62). Long-term smokers of Eclipse exhaled 45% more CO than people who used a Nicorette oral inhaler (63, 64). Rennard et al. (65) investigated the effect in heavy smokers of switching from regular cigarettes to Eclipse for 2 months on lower respiratory tract inflammation and observed a significant reduction, although the improvement did not reach the state found in nonsmokers. In a study of the effect on pulmonary epithelial permeability, airway inflammation and blood leukocyte activation in current smokers, switching to Eclipse reduced alveolar epithelial injury in some smokers but may have increased carboxyhaemoglobin levels and oxidative stress (66). In
111
the same study, Accord reduced exposure to CO from that with regular cigarettes, even though smokers take larger, longer puffs when using Accord (46). Smoking AdvanceTM cigarettes produced a lower CO “boost” but increased the heart rate, like regular cigarettes (67). Modest reductions in the uptake of tobacco toxins were observed when smokers switched for 4 weeks from their usual conventional cigarette brand to Omni cigarettes; the total level of NNAL, but not that of 1-hydroxypyrene (a PAH biomarker), was statistically significantly reduced. The overall mean total NNAL level of smokers who used a nicotine patch was statistically significantly lower than that of smokers who used the Omni cigarette (68). Tests in mouse embryonic stem cells showed that smoke from AdvanceTM cigarettes was as toxic as smoke from a traditional brand (Marlboro Red) (69). In a study of the effect of Omni and AdvanceTM cigarettes on oviduct functioning in hamsters, it was found that these cigarettes contain sufficient amounts of oviductal toxicants to inhibit biological processes, potentially affecting reproductive outcomes (70). Like “low tar” cigarettes, Marlboro UltraSmooth was shown to lead to compensatory smoking, although it produced a lower CO “boost” than regular cigarettes. Measures of salivary cotinine and cardiac function after smoking Marlboro UltraSmooth were similar to those with conventional brands, suggesting that switching to this brand is unlikely to reduce exposure to smoke constituents (53). Effectiveness in smoking substitution or cessation In a study in which smokers of regular cigarettes abstained overnight and then smoked Eclipse or Accord, withdrawal symptoms were suppressed fully with Eclipse, while Accord was less effective (46). Studies on the long-term effects of Eclipse showed that it can decrease cigarette consumption without causing withdrawal symptoms, decreasing nicotine concentrations or decreasing the motivation to quit altogether (63, 64). AdvanceTM produced withdrawal suppression and higher plasma nicotine concentrations, similar to those produced by regular cigarettes (67). “Low-tar” cigarettes promoted in some countries as “less harmful” products
Product description and marketing strategies These cigarettes—currently banned from being designated as “light”—include several elements (for example filter ventilation and paper porosity) that reduce smoking machine-measured tar and nicotine yields by diluting the smoke with air. Because smokers increase their intensity of smoking in response to
112
the reduced nicotine content of the smoke, however, these cigarettes did not reduce smokers’ exposure to tobacco carcinogens and did not lower the risks for smoking-induced diseases (71–73). Nevertheless, this type of cigarette is being promoted actively in China. For example, analysis of the annual reports of the State Tobacco Monopoly Administration and the Chinese National Tobacco Corporation after 2000 shows a proposal to “actively proceed with ‘less harmful, low-tar’ cigarettes” (74). Consumer awareness, product use and perceptions Since the tobacco industry launched the “less harmful, low-tar” strategy in China, overall tobacco production was reported to have increased by nearly 40% between 2000 and 2009, due largely to the production and sale of low-tar cigarettes. During the first 10 months of 2011, low-tar cigarette production in China increased by 408%, and sales increased by 386% over those in 2010 (74). Constituents, toxicity and disease risk Cigarettes with low tar and low nicotine yields are designed to produce lower levels of smoke constituents than regular cigarettes in smoking machine measurements. It is well established that the smoker–cigarette interaction is driven primarily by the smoker’s pursuit of nicotine and is therefore much more complex than any machine-based regimen (75–77). To control their nicotine intake, smokers adjust their puff volume, duration, frequency and depth of inhalation, which affects their exposure to other constituents present in cigarette smoke. Smokers also regulate their nicotine intake by blocking filter ventilation holes, which reduces dilution of cigarette smoke with air (78). Therefore, smoking low-tar cigarettes does not reduce smokers’ exposure to tobacco carcinogens and does not lower their risk for smoking-induced diseases (71–73). Addictive potential Smokers adjust their smoking intensity, for example by drawing larger volumes of smoke and inhaling more deeply, when smoking low-tar cigarettes. Therefore, as “low-tar, low-nicotine” cigarettes deliver regular doses of nicotine to the user, their addictive potential is similar to that of regular cigarettes. Regulatory considerations Misleading labelling of these cigarettes as “lights” has been banned in many countries. Article 5 of the law of China’s Tobacco Monopoly states that “The 113
State shall strengthen the scientific research and technical development of tobacco monopoly commodities, so as to improve the quality of tobacco products and reduce the content of tar and other hazardous ingredients in such products”. As a result of this requirement, the Chinese Cigarette Science and Technology Development Outline was developed in 2003, and manufacturers were ordered to reduce the tar level in cigarettes to an average of 12 mg by 2010. A report of the State Tobacco Monopoly Administration annual meeting in 2010 stated that implementing the “less harmful, low-tar” strategy would be the overall approach to improving competitiveness in China (74). Reduced-nicotine cigarettes
Product description and marketing strategies Unlike the “reduced-yield” cigarettes, in which the nicotine yield in smoke is modified by changing the cigarette or filter structure, low-nicotine cigarettes are made with tobacco that contains less nicotine than traditional tobaccos. For example, a brand of low-nicotine cigarettes named Quest, introduced onto the US market in 2003, was available in three varieties—low nicotine, extra-low nicotine and nicotine free. They contained genetically modified low-nicotine tobacco blended with normal tobacco to provide nicotine levels of 0.6–0.05 mg/cigarette (79), offering smokers the opportunity to reduce their nicotine intake gradually. The yields of other constituents in such cigarettes are expected to be similar to those of regular commercial cigarettes; therefore, from the point of view of exposure to toxicants and carcinogens, these cigarettes should not be considered “harm reduction” products. Analysis of internal industry documents, however, reveals that the tobacco industry has invested substantial resources in the development of low-nicotine cigarettes (80) because of their consumer appeal and their economic importance in a highly competitive cigarette market for “healthier” products. Investigation of smokers’ reactions to Quest advertisements showed that some held false beliefs about these cigarettes, such as “lower in tar”, “healthier” and “less likely to cause cancer” (81). Dutch Magic, a brand of cigarettes with virtually no nicotine (< 0.04 mg) but a “normal” level of tar, is expected to enter the Dutch market (http://www. dutch-magic.com/). According to the manufacturer’s website, the product allows smokers the experience of smoking a cigarette with the characteristic tobacco taste but without the addictive effects of nicotine. The website also cites specific target consumer groups: people who want to quit smoking with an aid, occasional smokers, people who would like to try smoking but do not want to get addicted and cannabis smokers who do not otherwise smoke tobacco or currently use nicotine-containing tobacco to roll their joints but do not want to get addicted. Dutch Magic is prepared under license of 22nd Century, which
114
is, according to their website, committed to developing and commercializing consumer-acceptable reduced-risk tobacco products and a prescription-based smoking cessation aid consisting of a kit of very low-nicotine cigarettes (http:// www.xxiicentury.com/). The company offers to supply cigarettes with virtually any nicotine content level, from very low (approximately 0.50 mg/cigarette) to high (approximately 30 mg/cigarette). Consumer response In studies of switching to commercially available low-nicotine Quest cigarettes, study participants reported that the research cigarettes were less satisfying and of poorer quality than their usual brands (82–84). Constituents, toxicity and disease risk The level of nicotine in Quest cigarettes reported by the manufacturer ranged from 0.05 to 0.6 mg/cigarette, with a tar content of 10 mg tar/cigarette (85). Chen et al. (86) generally confirmed these values, although, interestingly, they found that the level of NNN was higher in the smoke of nicotine-free than low-nicotine Quest. Analysis of the tobacco filler revealed no significant difference in NNN levels among Quest varieties with different nicotine levels (13). One possibility is that the levels of nornicotine in nicotine-free cigarettes are higher, resulting in formation of more NNN during combustion. A comparison of regular cigarettes with non-commercial reduced-nicotine cigarettes provided by Philip Morris for research purposes did not, however, show significant differences in the levels of constituents other than nicotine (82–84). Several studies addressed the exposure to cigarette smoke constituents of smokers who switched to reduced-nicotine cigarettes. In a small study of 20 smokers who progressively reduced their nicotine level over 10 weeks by changing the type of cigarette smoked, biomarkers of exposure to CO and PAH and markers of cardiovascular end-points were not affected, while urinary excretion of NNAL decreased (83). In a similar study by the same authors but with 135 smokers and progressive nicotine reduction over 6 months (84), the results for smokers who were randomized to reduced-nicotine cigarettes were similar to those in the first trial. In a study by Hatsukami et al. (2010), switching to 0.05-mg nicotine Quest cigarettes for 6 weeks reduced exposure to carcinogens to a greater extent than switching to 0.3-mg nicotine cigarettes, due to the compensatory behaviour associated with smoking 0.3-mg nicotine cigarettes, which was not observed with those containing 0.05 mg nicotine. The reduction in levels of urinary total NNAL and NNN was consistent with the lower levels of TSNA found in Quest cigarettes than in regular cigarettes (13).
115
Smokers of the 0.05-mg cigarettes also showed reduced exposure to acrolein and benzene, which the authors attributed to the observed reduction in cigarette intake; by the end of the study, the levels of most biomarkers in the 0.05mg group were not significantly different from those in a group given nicotine lozenges. Hatsukami et al. (87) confirmed significant reductions in nicotine and NNK intake in smokers who switched to reduced-nicotine cigarettes. Benowitz et al. (82) measured the heart rate and skin temperature (measure of vascoconstriction) of smokers who smoked single cigarettes with different nicotine contents and found a plateau of increased heart rate and decreased skin temperature at about 8 mg nicotine per cigarette, suggesting that there is a cut-off level of nicotine beyond which the effect on cardiovascular risk does not change significantly. Girdhar et al. (88) showed, however, that smoking nicotine-free Quest 3 cigarettes resulted in higher platelet activation (marker of cardiovascular risk) than smoking nicotine-containing Quest 1. They proposed that nicotine modulates platelet activation by non-nicotine smoke components. In mouse embryonic stem cells and normal human bronchial epithelial cells, smoke from Quest cigarettes was as toxic as smoke from regular cigarettes (69, 86, 89). In an animal model of atherosclerosis, mice exposed to smoke from Quest 3 cigarettes developed smaller lesions than those treated with Quest 1 or regular cigarette smoke (85). Addictive potential; effectiveness in smoking substitution or cessation A reduction in the nicotine content of cigarettes has been proposed as an approach for reducing their addictiveness (90) (see also Annex 2). While smoking commercial cigarettes in which the reduced nicotine yields are due to smoke dilution is known to cause compensatory behaviour, this may not be true for smoking cigarettes with a reduced nicotine content, or such behaviour may not be effective. Benowitz et al. (82) investigated the intake of nicotine, the degree of compensation and the dose–response relations for various effects of nicotine when people smoked cigarettes made from reduced-nicotine tobacco. Levels of 1, 2, 4, 8 and 12 mg nicotine/cigarette were shown to correlate with systemic exposure to nicotine. Little compensation was made with the lower-nicotine cigarettes (1, 2 and 4 mg), ranging from 0% to 5% in comparison with the usual brand; this was confirmed by the levels of exposure to CO and tar. At higher nicotine levels, however, compensation increased to 34% for 8 mg nicotine and 127% for 12 mg nicotine, supporting the hypothesis that the ease of obtaining nicotine is a determinant of the extent of compensation. Benowitz et al. (83) also studied progressive switching to cigarettes with a gradually decreasing nicotine content over 10 weeks. Five of 20 smokers (25%) spontaneously quit smoking. In a larger, longer trial with the same cigarettes and design, however, only 2 of 53 smokers who switched to lower-nicotine
116
cigarettes eventually quit (84). Compensation for the lack of nicotine was greater than in the earlier single-cigarette trial (82), ranging from 20% to 60% for the cigarettes with the lowest nicotine content (1, 2 and 4 mg). Hatsukami et al. (79) suggested that cigarettes with nicotine levels below those tested by Benowitz et al. (82–84) may be effective in eliminating compensatory behaviour and facilitating cessation. Cigarettes containing nicotine at a level of 0.05 mg did not result in compensatory smoking behaviour, in contrast to those containing 0.3 mg, and were associated with reduced nicotine dependence, product withdrawal and a significantly higher rate of cessation. Lack of compensation when smoking high-tar, very low-nicotine cigarettes (0.02 mg) was reported in another study (91). In contrast, Strasser et al. (92) observed behavioural compensation with smoking very low-nicotine cigarettes; the total puff volume was greatest for the 0.05 mg Quest cigarette. The effect of very low-nicotine cigarettes on smoking abstinence was studied in a large randomized controlled trial in New Zealand, in which standard Quitline care alone was compared with Quitline plus an instruction to smoke Quest 3 cigarettes when participants had the urge to smoke (93). In comparison with the group receiving usual Quitline care, participants assigned to Quest 3 had higher abstinence rates at the 6-month follow-up (33% compared with 28%) and higher continuous abstinence rates (23% compared with 15%). Furthermore, the median time to relapse was 2 months for the group assigned to Quest 3 cigarettes and 2 weeks with usual care. These results suggest that adding very low-nicotine cigarettes to standard Quitline smoking cessation support might help some smokers to become abstinent. Several studies have been conducted of the use of very low-nicotine cigarettes in combination with a nicotine patch. In one small study, participants were assigned to nicotine or a placebo patch in combination with reduced-nicotine cigarettes (94). Participants assigned to the very low-nicotine cigarettes (0.08 mg) and a nicotine patch reported smoking only three cigarettes of their usual brand during the 2 weeks of the study, while those assigned to the same cigarettes but a placebo patch reported smoking 46 cigarettes of their usual brand during the same period. No difference was observed in craving or withdrawal symptoms with addition of the nicotine patch or placebo. In another study, participants were randomly assigned to supplement low-nicotine cigarettes with patches containing various levels of nicotine (95). People assigned to patches with higher doses of nicotine (7 or 21 mg) showed greater decreases in the number of cigarettes smoked, the total volume of cigarette smoke inhaled and the level of CO than those assigned to low-nicotine cigarettes without medicinal nicotine supplement (placebo patch); greater relief of withdrawal symptoms during an abstinence period was also observed. In a recent study, Hatsukami et al. (87) examined the feasibility of using very low-nicotine cigarettes to reduce smoking behaviour significantly and the effect of adding a
117
nicotine patch with these cigarettes. Both the nicotine patch and the combination of very low-nicotine cigarettes (≤ 0.09 mg/cigarette) plus patch led to a greater increase in nicotine intake than switching to the low-nicotine cigarettes. The combination condition also reduced withdrawal symptoms as compared with an individual patch or low-nicotine cigarettes. No difference in withdrawal symptoms was found with a nicotine patch or low-nicotine cigarettes, and craving did not differ among groups after cessation of the assigned product. The results indicate that combining very low-nicotine cigarettes with a nicotine patch might ameliorate the acute effects that result from switching to either of these products alone. Regulatory considerations Reduction of the nicotine content (but not complete elimination) of cigarettes has been discussed in the USA as a potential regulatory approach for making cigarettes non-addictive. This could lead to cessation by smokers who are the no longer addicted, with a significant public health benefit. Such a policy measure might include supplementation with nicotine replacement therapy to facilitate tobacco cessation. Super-slim cigarettes
Super-slim cigarettes have a significantly smaller circumference than regular cigarettes. They have been sold in some countries, such as the USA, for a long time (e.g. Virginia Slims Superslims), but their introduction in other countries is relatively recent. Many such brands were launched from 2007 in Canada (96). The circumference of these cigarettes is 17 mm, while that of regular cigarettes is approximately 25 mm, and they are sold in slimmer packs. These cigarettes are not marketed with explicit health claims; however the “slim” pack profile and the thinner design of super-slim brands are likely to be perceived by consumers as emitting lower levels of toxins and being “less harmful” (96, 97). Analysis of super-slim cigarettes sold in Canada showed that the yields of many constituents, including CO, carbonyls, volatiles and aromatic amines, were significantly lower due to the reduced circumference and thus lower tobacco weight; however, the yields of other constituents, including formaldehyde and ammonia, were significantly higher. As for regular-size cigarettes, the measured constituent yields depended on the smoking machine regimen used. It was shown that super-slim cigarettes sold in Canada can contain as much nicotine as other Canadian cigarettes, and their addiction potential may be similar. The introduction of these cigarettes in Canada, where virtually all advertising and promotion of tobacco products have been prohibited by law,
118
represents an attempt by the tobacco industry to use new designs and packaging to promote and market tobacco products to specific audiences (96). A ban on slim cigarettes was included in the original European Commission proposal for a revision of the European Tobacco Products Directive. The Council and the European Parliament decided, however, to delete this prohibition, and no regulation on slim cigarettes is included in the final version of the Directive, other than the statement that market developments and consumer perceptions of some products, including slim cigarettes, should be monitored (98). Little cigars and cigarillos
Dramatic increases in the sales of this type of product have been reported in many countries, with the largest increases in China, Germany and the USA (99). Unlike cigarettes, little cigars and cigarillos are wrapped in tobacco leaves or brown tobacco-based paper. Little cigars are similar in size to cigarettes, while cigarillos are intermediate between a cigarette and a large cigar (99, 100). No health claims are made for these products. The Maxwell Report (101) showed that sales in the USA, the largest market for little cigars and cigarillos, increased by 316% for little cigars and by 255% for cigarillos between 1995 and 2008, and more young adults in the USA have ever smoked little cigars and cigarillos (26%) than the general US population (5.2%) (cited in 99). A study of dual use of cigarettes and cigars showed that approximately 12.5% of cigarette smokers used cigars and that dual users were more likely to be young males, non-Hispanic or black, with lower educational attainment and either unemployed or out of the work force (102). The study also showed that dual users were less likely than cigarette-only smokers to smoke cigarettes daily (odds ratio, 0.57), more likely to have made a recent attempt to quit (odds ratio, 2.39) and more likely to have used at least one other product, such as snus, e-cigarettes, dissolvable products or chewing tobacco (odds ratio, 2.26). A limitation of the study is that little cigars and cigarillos were not differentiated from large cigars in the assessment of current and prior use of cigars; however, smokers of little cigars and cigarillos may not identify these products as cigars, and the questionnaire used in the study cited popular brands, which may have increased self-reported cigar use. Both the lower prices of little cigars and cigarillos than cigarettes and the variety of flavours may explain their appeal to young people (as for flavoured cigarettes). The Family Smoking Prevention and Tobacco Control Act in the USA (103) provided an unprecedented opportunity to regulate tobacco in the country; however, it contains no restrictions on little cigars, cigarillos or large cigars. After the ban on flavourings in cigarettes by the Food and Drug Administration in 2009, a study among young adults showed that 18.5% currently
119
used a flavoured tobacco product (104). Almost 50% of little-cigar smokers used a flavoured brand. The smoke of little cigars, with or without filters, contains the same toxic chemicals that are present in the smoke of cigarettes sold in Canada (105). Furthermore, the smoke of little cigars and cigarillos is inhaled more deeply than that of large cigars, similarly to the smoke of cigarettes (106). Herbal-tobacco cigarettes
In 2000, several Asian countries started producing cigarettes containing both traditional medicinal herbs and tobacco. Chen et al. (107) collected information on the availability of herbal-tobacco cigarettes between 1999 and 2005 and identified 23 brands. Most were produced in China; after 2000, however, tobacco companies in China (Taiwan), the Republic of Korea and Thailand began producing similar products. These cigarettes are commonly produced by adding herbal extracts to or mixing herbs with tobacco leaves, spraying herbal extracts on shredded tobacco or adding herbal extracts to the cigarette filter material. Most of these cigarettes are claimed to have reduced contents of harmful substances (nicotine, tar, CO, carcinogens and mutagens), and some are claimed to relieve respiratory symptoms, protect internal organs, boost immunity or aid in smoking cessation. Herbal-tobacco cigarette brands in the Republic of Korea have been promoted as reducing the harm of smoking via special filtering of the smoke, addition of green tea catechins, not “hurting smokers’ lungs and throat” or as a smoking cessation aid. In Thailand, a herbal-tobacco cigarette brand, Herbal Krongthip, contained a herbal oil traditionally used to treat cold symptoms; sale of this brand was reportedly stopped in 2002. These cigarettes are widely available on Asian markets. In 2005, two herbal-tobacco cigarette brands, Jinsheng and Zhongnanhai, were identified by the State Tobacco Monopoly Association of China as two of the “top 36 Chinese cigarette brands” designated for development. While no data on the market share of herbal-tobacco cigarettes in China are available, Jinsheng already had an annual production of 3.5 billion cigarettes in 2003, and the Zhongnanhai brand name had reached “US$ 244 million in its intangible assets in 2001”. The Chinese herbal-tobacco cigarette brand Wuyeshen was reported also to be sold in San Francisco, California, USA (107). Some herbal-tobacco cigarette brands available in Asia list a primary herbal ingredient, while others contain a mixture of herbs, which are not necessarily disclosed. Only four of 23 brands identified by Chen et al. (107) contained herbs only. The study showed that 18 medicinal herbs were listed as ingredients in such cigarettes, ginseng being the most common, followed by Apocynum
120
venetum. The effects of herb-derived bioactive compounds in these cigarettes are unknown. For example, datura flower, an anticholinergic herb present in the Chinese YangJinHua brand, is thought to be responsible for most cases of poisoning due to Chinese herbal medicine, while some ginseng preparations might be adulterated with scopolamine. Tobacco control groups in China (Taiwan), Japan and Thailand have expressed concern about the health claims made for herbal-tobacco products (107). Bidis
Bidi cigarettes are manufactured primarily in India but are imported in the USA, where a surprisingly high rate of use by young adults has been reported (108–110. Bidis are small, brown, hand-rolled cigarettes consisting of tobacco flakes rolled in a temburni (Diospyros melanoxylon) or tendu (Diospyros ebenum) leaf and tied with a small string. As they are hand-rolled, the amount of tobacco in each cigarette varies. Bidis come in unfiltered and filtered varieties, the filter consisting of a small wad of cotton inside the wrapper. Bidis are highly flavoured and sold in brightly coloured packaging almost exclusively for the US market. The flavours include grape, wild cherry, strawberry, clove, vanilla, cinnamon, cardamom, dewberry, black liquorice, lemon–lime, raspberry, mango, menthol and chocolate (109, 110). The “novelty” aspect of bidi smoking in the USA, particularly for children and young adults, is a concern. Nearly two thirds of US adults who reported current bidi use were under the age of 25. Among young adults, higher rates of any and current bidi use were seen for males, blacks and current cigarette smokers (110). A significant number of consumers reported that bidi cigarettes tasted better and were less expensive, easier to buy (12%) and safer (13%) than regular cigarettes (109). Analysis of the smoke of bidi cigarettes showed that they deliver substantial amounts of tar, nicotine and CO. In contrast to traditional filtered cigarettes, filters did not reduce the tar, nicotine or CO delivery in smoke. Bidi smokers may be at higher risk than smokers of traditional cigarettes for lung cancer and several other cancers, including of the oral cavity, pharynx and oesophagus (109). Waterpipes Waterpipes are used in many cultures in various forms, including narghile, hookah, shisha, goza, hubble-bubble and argeela. They are a traditional method of tobacco use by indigenous peoples of Africa and Asia.
121
Product description and marketing strategies
A common feature of all types of waterpipe is that smoke passes through water before it reaches the smoker. Very moist flavoured tobacco is often used, which is placed in the “head” of the waterpipe, and charcoal is placed on top. Drawing on the waterpipe creates a vacuum above the water and causes charcoal-heated air to pass through the tobacco, so that the MSS contains evaporated tobacco constituents as well as charcoal combustion products (111). Alternatively, electrical “coals” are used (in products found on several internet sites, e.g. http://www.hookah-shisha.com/p-15165-blazn-burner-fast-hookah-charcoalburner.html). Waterpipe tobacco is often sweet and flavoured (111), making it taste good and smooth, mild and easy to inhale (112, 113). The tobacco for waterpipes is sold at a very low price, often without a health warning and with misleading information about the content. It is frequently designed to look like a harmless product, such as tea, coffee, chewing-gum or sweets. Substances without tobacco are also smoked in waterpipes (112); for example, steam stones, small porous stones containing aroma and no nicotine, are used in some brands (e.g. Starbuzz, Shiazo, Bigg, Om, Angel, Bump ’n Grind). Consumer awareness, product use and perceptions
Waterpipe smoking has become increasingly widespread among young people in the Middle East during the past decade and is rapidly spreading elsewhere (114). The prevalence is also high in groups of Middle Eastern descent in Australia and the USA and is high although not specifically in people of Middle Eastern descent in European countries such as Denmark, Estonia, Germany and Sweden (115). According to a European Union survey, waterpipes are regularly used by 1% of European Union citizens (range, 0–2%), occasionally by 4% (range, 0–10%) and were tried once or twice by 11% (range, 3–30%) (116). Many European Union countries reported an increase in waterpipe use on our questionnaire but did not quantify it. Waterpipe tobacco smoking is particularly popular among school and university students (115). A national survey in the United Kingdom showed that waterpipe smoking was popular among medical students, irrespective of their descent. Students and adults generally stated that waterpipe smoking was less harmful than cigarette smoking (113, 117). The popularity of waterpipe tobacco smoking may reflect a trend of age-specific prevalence, which should be investigated in longitudinal studies (115). Waterpipe smoking fills a social function among young people, most of whom share waterpipes and smoke in company (112, 113).
122
Constituents, toxicity and disease risk
Constituents are transferred to smoke by absorption in the charcoal-heated air that passes through the tobacco and are the same as those in cigarette smoke, including nicotine, propylene glycol, glycerol, TSNA, CO, PAH (118) and the aldehydes formaldehyde, acetaldehyde and acrolein (119). The levels of CO and PAH are particularly high, due to the charcoal used to heat the air that passes through the tobacco. The CO levels have been reported to be 30 times higher in waterpipe smoke than in cigarette smoke (118), and carboxyhaemoglobin levels in blood, a biomarker of CO exposure, have been reported to be fourfold higher in waterpipe smokers than in cigarette smokers (120). By 2011, six cases of CO poisoning had been reported as a consequence of waterpipe smoking; these patients had carboxyhaemoglobin levels of 20–30% (121). Although nicotine is found at higher levels than in cigarette smoke, the blood levels of nicotine measured over 24 h were lower, probably because smokers consume several cigarettes a day (118). Studies of biomarkers in dual users also showed that waterpipe use was associated with significantly lower intake of nicotine, higher exposure to CO and a different pattern of exposure to carcinogens when compared with cigarette smoking (122). Waterpipe smoking also produces large amounts and high concentrations of harmful particles in environmental smoke, contributing to the risks associated with passive smoking (112). Waterpipe tobacco smoking is significantly associated with lung cancer, respiratory illness and low birth weight, and associations with cancers of the bladder, throat and mouth have also been suggested (115). The carcinogenic potential of waterpipe tobacco smoke is not surprising, as it contains aldehydes such as formaldehyde, which is a human carcinogen (123) and acetaldehyde, which is possibly carcinogenic to humans (124). The presence of propylene glycol and glycerol in waterpipe tobacco smoke at levels much higher than those that trigger adverse effects in experimental studies is a concern. Their effects include increases in mucus-producing goblet cells in the respiratory tract and throat irritation (118). Addictive potential
Waterpipe use results in tobacco and nicotine dependence but is often more intermittent than cigarette smoking (113, 125). Although the level of nicotine in waterpipe tobacco smoke is higher than that in cigarette smoke, the blood levels of nicotine measured over 24 h were lower (118).
123
Regulatory considerations
Waterpipe use appears to be increasing in groups that did not previously smoke this product. Users perceive waterpipe smoking to be relatively harmless and not addictive, whereas in reality they are exposed to the same toxicants as in cigarette smoke, some at dangerously high levels, most notably CO. Their perceptions could be affected by educating them about harm, addiction and exposure to toxicants in waterpipe tobacco (126). Although waterpipe tobacco is usually subject to regulation, waterpipes and their accessories are not (114). In addition, herbal waterpipe tobacco is not subject to laws governing tobacco and clean indoor air, so that in most countries it can be smoked indoors. The exceptions are Canada and Turkey. Notable alterations to traditional products Many elements have been introduced into the composition or structure of traditional tobacco products. Thus, while the product itself, for example moist snuff or cigarettes, is not novel, alterations made to a specific brand may present new risks to individual users or to public health. Timely knowledge of emerging modifications can predict any substantial changes in the tobacco product inventory, so that forward-looking strategies can be introduced for tobacco product regulation. Below, we describe some recently introduced modifications of traditional products. Swedish snus with reduced tobacco content
In our survey, a report was received from Sweden about a new brand of snus called Loonic in forms containing gradually decreasing proportions of tobacco: 75% (Loonic No.1), 50% (Loonic No.2), 25% (Loonic No.3) and 0% (Loonic No.4) tobacco in the total product mass. The product website (http://www. loonic.se/index.php/en) indicates that the remainder of the product mass is tea leaves. The decreasing tobacco content in the Loonic series results in gradually decreasing levels of nicotine. Like the Quest series of cigarettes, the Loonic series is advertised for “snus users who want to taper off or quit completely”. The product description states that Loonic No.4, the tobacco-free version, “contains neither tobacco nor nicotine, but guarana, B12, and folic acid have been added”. The product appears to be advertised to current snus users and does not include health claims. Moist snuff with bioactive additives
Revved Up Energy Dip was introduced in 2008 by the Southern Smokeless tobacco company based in Georgia, USA. According to the description provided
124
on the product website (http://www.southernsmokeless.com/Revved-up.html), Revved Up is a long-cut smokeless tobacco with vitamin B, vitamin C, caffeine, ginseng and taurine added and comes in mint and wintergreen flavours. The blend is claimed to increase alertness, focus and energy. As in the promotion of US snus, Revved Up is described as a discreet way of enjoying smokeless tobacco. The product description states that it is intended for current tobacco users; however, it is promoted mainly for its purported ability to increase focus and energy. The suggested users listed on the product website include military service members, civil servants (police officers, fire-fighters) and athletes. The description claims that the tobacco blend used in Revved Up contains “65% less carcinogens than found in dark fire cured tobaccos”, implying reduced exposure or risk. Menthol capsules in filters
Cigarettes with a new technology for delivering an additive are available in Japan and the USA and have been marketed in several European Union member states (127). A capsule filled with a flavouring solution is embedded in the cigarette filter, which the smoker can crush to release the flavour into the smoke. The capsule contains menthol, but other additives could be used. The innovation seems to be particularly appealing to young people, and advertising for these products is directed at this target group. In Turkey, cigarettes with menthol capsules were allowed on the market, as they comply with the technical requirements of the Tobacco and Alcohol Market Regulatory Authority. The scientific commission authorized by the Authority to evaluate the ingredients according to the WHO Framework Convention on Tobacco Control and national legislation is, however, investigating the status of this product. The National Supervisory Authority for Welfare and Health (Valvira) in Finland reported that cigarette brands that release a fresh taste (menthol and spearmint) by a click-on function were promoted by local retailers who agreed with tobacco companies to offer them as a first choice to consumers. The new European Union Tobacco Products Directive 2014/40/EU (98) includes a ban on the sale of tobacco products containing flavourings in any of their components, such as filters, papers, packages, capsules or any technical features that allow modification of the smell or taste of the products or their smoke intensity. In addition, filters, papers and capsules shall not contain tobacco or nicotine. The new Directive entered into force in May 2014, and European member Member States have 2 years to bring their national legislation into line with the rules.
125
No-additive, or organic, cigarettes
In several countries, “natural” tobacco products are being advertised as containing no additives (128). “Natural American Spirit” (http://www.von-eicken.com/en/) and “Manitou” (https://www.nascigs.com/), bearing pictures of a tipi and of a native American smoking a peace pipe, respectively, on their packages, have been on the market for many years as cigarettes and fine-cut tobacco. A similar product is Sioux (http://www.von-eicken.com/en/). All these brands contain exclusively Virginia tobacco leaves. Flue-cured tobacco leaves, such as Virginia, contain up to 20% of natural sugars, which largely determine consumer acceptance (128–130). Pueblo tobacco is, according to its website (www.poeschl-tobacco.com), a traditional blend of premium-quality tobaccos. The name Pueblo, like Natural American Spirit, Manitou and Sioux, refers to the native American culture, from which tobacco originated before it became an industrialized product. The names therefore evoke a traditional, authentic, natural feeling. Spain provided data on the sales of Pueblo products, showing that the market share of the cigarettes is only 0.1% (ranking 68 out of 176), whereas the fine cut tobacco Pueblo Burley Blend is more popular, with 9.6% of the market (ranking 3 out of 112). A website (http://yesmoke.eu/blog/tobacco-shag-natural-organic/) indicated that this is also the most popular fine-cut tobacco brand in Italy. Spain also notified a cigarette brand, Yuma Organic, which contains 100% organic tobacco, without pesticides or additives. According to their website (http://www.yumaorganic.com/), “by choosing organic products you help to protect the environment”. Yuma supports organic farming. The product is not popular, with 0.0001% of the market (ranking 162 out of 176). A few years ago, Camel and Lucky Strike also launched brands without additives: Camel natural flavour and Lucky Strike additive-free, in brownish paper packages. The no-additive pure tobacco trend appears to cater for consumers interested in natural products. Some consumers perceive additive-free cigarettes as being “less unhealthy” (see e.g. http://answers.yahoo.com/question/ index?qid=20090212111736AAiemjg); however, the smoke emitted still contains carcinogens and other toxic compounds from the tobacco (129). Branding with a brand name
Spain reported two fine-cut tobacco products with brand names: “Roll your own American blend for people who don’t need a brand to tell other people who they are” and “Roll your own Virginia blend for people who don’t need a brand to tell other people who they are”. The commercial name is used as
126
an advertising and promotional element to attract people pretending to be “self-confident” and independent. As the commercial names were authorized by the European Patent Office, it was difficult for health authorities to refuse their commercialization. Less-smoke-smell cigarettes
A study of patent records revealed more than 100 patents related to side-stream smoke, including improved smoke odour and reduced visibility (131). One country reported that Japan Tobacco International has requested authorization to place a new tobacco product, Winston XS, on the market, consisting of cigarettes with “less smoke smell” (see http://www.cigarettestime.com/ cigarettes-articles/winston-xs). Technologies under development An increasing number of new tobacco products, especially cigarettes, are being or will be marketed with the claim that they can reduce exposure to harmful chemicals in tobacco smoke. These potential reduced-exposure products (PREPs) include modifications in tobacco processing, filters or design. Many of the studies that support the claims of risk reduction are performed and published by the industry. Independent studies should be conducted to investigate claims that such products can lower the levels of smoke components or toxicants in MSS, can reduce toxicity, can modify biomarkers of human exposure, can modify biomarkers of disease outcome and can pass sensory evaluation such as test panels in controlled clinical studies. In evaluating estimates from smoking machines, account must be taken of human smoking behaviour, which is a complex process involving puff volume, puff duration, inter-puff interval, number of puffs per cigarette and total puff volume (132). Thus, human smoking behaviour can differ from commonly used smoking machine regimes such as the International Organization for Standardization (ISO) and the Canadian Intense protocols. The ISO method involves a puff volume of 35 mL, a puff frequency of 60 s, a total puff volume of 455 mL and open ventilation. The Canadian Intense method involves a puff volume of 55 mL, a puff frequency of 30 s, a total puff volume of 715 mL and 100% blocked ventilation. Standardization of machine-generated yields per milligram of nicotine has been suggested in order to minimize the variation between standardized methods (133). Below, several PREPs are evaluated to determine whether these products could reduce the levels of harmful toxicants in MSS and whether these reductions might lower disease outcomes. As most of these products are not on the market, they are described, and information is given on their constituents, toxicity
127
and potential risk. No information was available on the addictive potential of these new products. In regulatory terms, PREPs are tobacco products with modified tobacco processing, filter and/or design and are therefore subject to tobacco product regulation. Substitution of traditional tobacco burning by heating
Product description: One of the world’s largest tobacco companies, Phillip Morris International, plans to market a new type of cigarette by 2017 that allegedly poses lower risks to health (134). According to the company, the toxic components of this new prototype, which heats tobacco rather than burning it, will be reduced by 95%. The company states that “the most promising lower-risk products” heat tobacco or generate an aerosol that consumers inhale, and the new prototype is ready for clinical testing (134). Our survey indicated that Italy, the Netherlands and Romania were soon expecting the release of a new product by Phillip Morris International. The company argues that the 2014 European Tobacco Product Directive regarding pictorial health warnings on packages should not apply to this type of product, and that a textual warning about, for instance, addictive potential will suffice (135). Cigarettes similar to those that Phillip Morris International plans to place on the market are those sold by Ploom and the Premier and Eclipse cigarettes marketed by RJ Reynolds (see above). Overall, convincing evidence has yet to be provided for the claims of risk reduction and health benefits of products that heat rather than burn tobacco, and better ways are needed to assess the validity of these claims (136). The methods used for conventional cigarettes, such as smoking machine measurements, might have to be adapted or new methods developed, because the puffing behaviour, physical and chemical characteristics (particularly of inhaled aerosols) and longer exposure to these new products are different. Some scientists consider that these new cigarette products are just as harmful as conventional cigarettes (137). Combination of changed tobacco processing and filter structure Tobacco substitute sheet with a carbon or cellulose acetate filter
Product description British American Tobacco has designed several PREP prototypes, one of which is an experimental cigarette with a tobacco substitute sheet (TSS) that releases glycerol on heating. The components of the TSS are calcium carbonate, glycerol, sodium alginate and caramel. It has a dual function: it decreases the amount of tobacco in the overall blend, thus reducing smoke toxicants, and it releases glycerol into MSS to dilute the concentration of particulate constituents,
128
including toxicants, from tobacco combustion. These experimental cigarettes also have filters that contain a dispersion of activated dual-segment carbon or cellulose acetate. Unlike “light” cigarettes, in which the filter differentiates them from conventional cigarettes, the experimental cigarettes have less tobacco (40–70%), contain 30–60% TSS and filters that vary in design (dual-segment carbon or cellulose acetate filters with 0–55% ventilation) (137). Constituents, toxicity and disease risk Studies of smoke chemistry, toxicological investigations and preliminary human studies have been conducted on experimental cigarettes made with TSS (138). British American Tobacco claims that experimental cigarettes with TSS plus dual-segment carbon or cellulose acetate filters have reduced levels of smoke components in MSS and that the filters also reduce the amount of particulate matter: cellulose acetate filters selectively reduce the levels of some phenolic compounds, and dual-segment carbon reduces additional volatile smoke components. No health claims have been made. Analysis of MSS from these experimental cigarettes showed reduced yields of most measured constituents, other than some volatile species. Several studies were conducted of toxicity in vitro, including cytotoxicity, mutagenicity and chromosomal damage. In all the studies, Silk Cut King Size filtered cigarettes with the same yield of machine-smoked nicotine-free dry particulate matter were used as controls. The four experimental cigarettes consisted of 60% TSS/cellulose acetate filter, 60% TSS/dual-segment carbon filter, 50% TSS with a tobacco blend containing 2.5% glycerol and a dual-segment carbon filter. Total particulate matter from the four experimental cigarettes induced less cytotoxicity and mutagenicity in bacterial cells and chromosomal damage in mammalian cells than that from the control cigarettes. The greatest reduction in mutagenicity was observed with experimental cigarettes with 60% TSS and a cellulose acetate filter. The total particulate matter used in these tests did not include all compounds, such as volatiles. Human exposure was evaluated by analysing cigarette filters from smoked commercial cigarettes and an experimental cigarette (60% TSS/cellulose acetate filter) with a similar level of machine smoked nicotine-free dry particulate matter and also analysing biomarkers of exposure in urine 24 h after smoking. Smokers were given 1 day’s supply of either product, a container for collecting a urine sample and a container for collecting smoked cigarette filters. The estimated daily mean exposure of the mouth to nicotine was statistically significantly lower in smokers of the experimental cigarettes. Exposure to nicotine was reduced by a daily mean of 18% as determined from the filters and by 14% as determined from 24-h urinary biomarkers. Exposure to smoke particulates was reduced by a mean of 29% as determined from the filters and
129
exposure to NNK by a similar degree as determined from the urinary NNAL concentration. Urinary excretion of nicotine metabolites and of NNAL was decreased. These biomarkers of exposure are considered to be representative of each smoke toxicant and are relevant for exposure to tobacco smoke. No biomarkers of effect have been reported. In a sensory evaluation in which participants were allowed to smoke the experimental cigarette or their own brand ad libitum, the experimental cigarettes were found to be inferior to the smokers’ own brand. Although reduced in-vitro cytotoxicity and genotoxicity were reported, no method is available to predict whether such reductions would ultimately reduce the risk for disease and whether the observed dilution effect would have any biological relevance to the health risks of smokers. Several models have been proposed, but progress in this area is still necessary (139–141). The results of the biomarker studies suggest that a longer switching period and perhaps more participants would be required to evaluate urinary biomarkers in smokers of experimental cigarettes. The levels of only some smoke toxicants were reduced, and the sensory attributes of the smoke were less acceptable than those of conventional cigarettes. Tobacco-blend treatment and filters containing functionalized resin or carbon
Product description British American Tobacco has developed an experimental cigarette prototype based on treatment of the tobacco blend, involving aqueous extraction, treatment with protease, filtration of the extract to remove peptides, amino acids and polyphenols, and recombination of the extract and treated tobacco (142). This treatment is claimed to reduce the levels of toxicants in MSS. Selective filters containing activated carbon and/or resin adsorbents were effective in reducing the yields of volatile toxicants. Constituents, toxicity and disease risk In comparison with matched control Silk Cut King Size filtered cigarettes of the same machine smoked nicotine-free dry particulate matter yield, the tobacco-blend treated cigarettes had lower levels of protein nitrogen (59%), polyphenols (33–78%) and nicotine (12%) but 16% more sugars. The ISO yields of 43 toxicants were measured in MSS from cigarettes containing treated tobacco, adjusted per milligram of nicotine. Lower yields of the toxicants ammonia (27%), aromatic amines (34–38%), pyridine (23%), quinolone (21%), hydrogen cyanide (41%), TSNA (10–18%), phenol (42%) and cadmium (21%) were obtained; however, significantly increased yields of formaldehyde (79%),
130
benzo[a]pyrene (13%), acetaldehyde (16%), acetone (12%), acrolein (26%), propionaldehyde (21%), crotonaldehyde (12%), methyl ethyl ketone (16%), isoprene (4%), styrene (19%) and chromium (42%) were found. Reduced sidestream yields of nitrogenous smoke toxicants and increased side-stream yields of several carbonyls, benzo[a]pyrene and isoprene were also observed. Tobacco-blend treatment was associated with increased yields of volatile aldehydes (particularly formaldehyde and isoprene), PAH (benzo[a]pyrene) and some heavy metals (chromium). Selective filters containing activated carbon and/ or resin adsorbents were effective in reducing the yields of these volatile toxicants. Only ISO yields were reported; a comparison with Canadian Intense MSS yields would have been interesting. Toxicity was not tested. Biomarkers of exposure were evaluated in a 6-week, single-centre, single-blinded, controlled, forced switch clinical study conducted with 1-mg tar cigarettes that had undergone tobacco-blend treatment (143). Smoke yields (MSS under ISO conditions) and biomarkers of exposure were generally reduced, sometimes substantially (> 80%). The reductions in MSS yields and biomarkers of three of the four TSNA were in agreement, with reductions in MSS of 85–96% and reductions in biomarkers of exposure of 81–87%; however, the reduction in NNK in smoke yield of 83% did not correspond to the average reduction in biomarkers of exposure of 49%. This difference is probably due to the long halflife of NNAL and the shorter half-lives of the other, un-metabolized TSNA. No end-points to assess the impact of these findings on long-term health risks (i.e. no biomarkers of effect) were evaluated. In a sensory analysis in terms of acceptability, satisfaction and taste, the treated tobacco-blend, reduced toxicant prototype scored lower than the control in most sensory categories. Acceptability appeared to improve over 4 weeks but was still slightly lower than that of the control cigarette. The 43 toxicants analysed represent a small fraction of the approximately 5000 chemical constituents identified in MSS. There is no scientific consensus about the relations between smoke toxicants and the health risks associated with smoking. To assess the impact of reduced toxicant prototypes on health risks, comprehensive toxicity testing and clinical studies must be conducted. Wide variations between individuals were observed in the study of biomarkers of exposure, reflecting both differences in individual smoking behaviour and inter-individual variation in metabolism. Biomarkers of exposure to tobacco smoke are needed, as the currently accepted, most widely used biomarkers are specific only for families of compounds. Although significant reductions in some toxicants in MSS and in biomarkers of exposure were reported, the levels of many carcinogens in MSS from the treated tobacco-blend cigarettes were elevated, and there is no convincing evidence for risk reduction with this prototype.
131
Combination of tobacco substitute sheet and a two-segment carbon filter
Product description The most promising of the experimental cigarettes developed by British American Tobacco by combining technological applications to reduce machine-measured MSS yields of specific toxicants or groups of toxicants was a combination of 80% US blend tobacco, 20% tobacco substitute sheet and a two-segment filter containing 80 mg polymer-derived carbon (20% TSS/80 mg carbon filter) (144). Constituents, toxicity and disease risk ISO and Canadian Intense MSS yields showed overall reductions in toxicant yields from this experimental cigarette when compared with published values for control cigarettes (144). To assess the effects of reduced MSS yields on disease, Fearon et al. (139) used an in vitro model of cardiovascular disease to test the prototype cigarette, which had a 6-mg ISO tar yield. In this assay of endothelial damage repair, endothelial cell migration was inhibited by cigarette smoke particulate matter generated from control cigarettes, with a concentration-dependent decrease in wound recovery, whereas particulate matter from the prototype cigarette had a 22% lower effect on endothelial migration, with better wound recovery (59). Cigarette smoke particulate matter does not include compounds such as volatiles, and only one reduced toxicant prototype was analysed. Because of the complexity of cardiovascular disease, these results cannot be extrapolated to humans, and more studies are needed to determine whether these biological changes seen in vitro reflect disease outcomes in vivo. Biomarkers of exposure were evaluated in a 6-week, single-centre, single-blinded, controlled, forced-switch clinical study. A 1-mg ISO tar cigarette in which TSS was incorporated into the tobacco blend, combined with a three-stage filter containing carbon, amine functionalized resin and cellulose acetate (TSS1), was compared with a 6-mg ISO tar cigarette prototype with TSS in the tobacco blend combined with a two-stage filter without the amine functionalized resin (TSS6) (143). The yields of all toxicants from the TSS1 were reduced in comparison with the control (Silk Cut King Size filtered cigarettes with the same machine-smoked nicotine-free dry particulate matter), although the extent of the reduction varied by toxicant. The responses in biomarkers of exposure also varied, with some reasonable increases. The changes in MSS yield and in biomarkers of exposure were often not in agreement; for example, the yield of some TSNA, such as NNK, was reduced, while others, such as NNAL, showed an increase. With the TSS6 cigarette, all biomarkers
132
of exposure showed reductions from baseline levels at the end of study, except for total nicotine equivalents and 4-hydroxyphenanthrene. The reductions were significant except those in 4-aminobiphenyl, 1-hydroxypyrene, 2-hydroxyphenanthrene, 3-hydroxyphenanthrene and 4-hydroxyphenanthrene. Total nicotine equivalents were significantly higher at end of the study than at baseline, with no significant increase in the number of cigarettes smoked per day. The greatest reductions were seen in volatile compounds, with reductions of 75% for crotonaldehyde, 45% for acrolein and 63% for 1,3-butadiene. Biomarkers of exposure to TSNA were reduced by 10–26%. Thus, biomarkers of exposure generally showed reductions with smoking the TSS1 or the TSS6 prototype, but reductions in MSS yields did not always correspond to reductions in biomarkers of exposure. The measured biomarkers of exposure varied widely among individuals. Although no biomarkers of effect have been reported, a method has been proposed for assessing toxicant-induced changes in risk associated with smoking PREPs by evaluating changes in the risks for cancer and other diseases related to 1,3-butadiene (130). This compound was chosen because it is one of the toxicants proposed for mandated lowering by WHO TobReg (133). The 20% TSS/80 mg carbon filter prototype resulted in the most significant change in risk for health effects. Although a significant change in risk for cancer (leukaemia) was found, it was not sufficient to make this a “low health concern”. For non-neoplastic effects (ovarian atrophy), the 20% TSS/80 mg carbon filter prototype resulted in 1,3-butadiene levels that would be of no health concern (130). In a sensory analysis as part of a 6-week, single-centre, single-blinded, controlled, forced switch clinical study, the TSS reduced-toxicant prototype scored lower than the control in terms of acceptability, satisfaction and taste (143). Generally, participants reported equivalent or substantially lower acceptability of the cigarette prototype for most sensory categories. The acceptability appeared to improve over the 4 weeks of the study but was still slightly lower than that of the control cigarette. Despite the low overall machine yields of toxicants from the TSS1 and TSS6 prototypes, their performance against commercial cigarettes and published data on toxicant yields, much more scientific evidence would be required to determine whether these products are associated with lower health risks. More studies of biomarkers in volunteers smoking PREPs and further refinement of the technologies used in their manufacture are needed. With regard to toxicity in vitro, little information is available on the specific cigarette smoke toxicants involved in the pathogenesis of cardiovascular disease and how the results reflect human health risks. In the study of biomarkers, wide variation was seen among individuals, presumably reflecting both smoking behaviour
133
and inter-individual differences in metabolism. Thus, while the group mean levels of biomarkers of exposure may be reduced, not all the members of the group would experience decreases. As no health end-points were evaluated in this study, the impact on long-term health risks remains unknown. Modification of filter structure An amine functionalized ion-exchange resin in filter
Product description: Another experimental prototype developed by British American Tobacco contains an amine functionalized ion-exchange resin in the filter (145). The filter thus contains a macroporous, polystyrene-based ion-exchange resin (Diaion®CR20) with a surface amine group that reacts with aldehydes and hydrogen cyanide in an aerosol stream. The company claims that the resin in the filter reduces the yields of toxicants with high vapour pressure (in particular formaldehyde) in MSS. Constituents, toxicity and disease risk: In tests with an experimental prototype developed by British American Tobacco containing 60 mg of Diaion®CR20 in a cigarette cavity filter, the yields in ISO and Canadian Intense smoking machine protocols showed a ≥ 50% reduction in formaldehyde (estimated to represent > 80 % of the formaldehyde present in the smoke vapour phase) and removal of substantial proportions of hydrogen cyanide (> 80 %) and acetaldehyde (> 60 %). The performance of the resin was consistent throughout the 6-month test period. Diaion®CR20 is especially designed to trap smoke toxicants with high vapour pressure at ambient temperature, such as formaldehyde, acetaldehyde and hydrogen cyanide; its ability to remove other compounds is unknown. Although reductions in the levels of some toxicants were reported, those of other toxicants, such as acetone and 2-butanone, were increased in the Canadian Intense smoking machine protocol. The cigarette has not been tested for toxicity, biomarkers of exposure or effect or sensory quality. Titanate nanosheets, nanotubes and nanowires in filters
The Fujian Tobacco Industrial Corporation in China has evaluated use of titante nanosheets, titanate nanotubes and titanate nanowires in filters for reducing toxicant levels in MSS (146, 147). Although reductions in the levels of toxicants were reported in both publications, when the yields were standardized per milligram of nicotine, no reduction was found with the nanosheet and the levels of only a few toxicants (ammonia, hydroquinone, catechol and phenol) were reduced with the nanotubes (146). As nicotine levels were not reported in the second paper, the efficiency of nanowires in capturing TSNA cannot be assessed.
134
No tests of toxicity, biomarkers of exposure or effect or sensory acceptability were performed. More research is needed to determine whether these nanoparticles are transferred to MSS and, if so, the potential health effects of direct exposure to titanate nanoparticles in the lung and other organs. Charcoal filters
Product description The US Centers for Disease Control and Prevention evaluated the industry’s claim that charcoal-containing filters reduce toxicant levels in MSS (148, 149). The industry claims that, because charcoal has long been used to remove volatile organic compounds from water and air, it should have the same effect in MSS. Cigarettes containing charcoal in their filters at levels of 45–180 mg, either dispersed in the filter material or contained in a small cavity in the filter segment, were evaluated (148). Constituents, toxicity and disease risk Tar, nicotine, CO, acetaldehyde, acrolein, benzene, styrene and the sum of 22 volatile organic compounds were measured in MSS. The cigarettes with charcoal filters showed reduced machine-generated MSS delivery (ISO and Canadian Intense protocols) of a wide range of volatile organic compounds as compared with a similar, non-charcoal filtered cigarette. The reduction depended, however, not only on the amount of charcoal present but also on the volume of smoke drawn through the filter. While a brand with 45 mg charcoal reduced the delivery of volatile organic compounds under ISO smoking conditions, charcoal saturation and breakthrough occurred under more intense smoking conditions (Canadian Intense protocol). Overall, the brands with the most charcoal were more effective in reducing the delivery of volatile organic compounds, even under intense smoking conditions. A brand with a 33-mm filter, 43% filter ventilation, 0.5 g tobacco and 120 mg of charcoal yielded consistently lower levels of analytes in both smoking machine regimes. The preliminary results indicated that the levels of other important but less volatile toxic constituents (for example, TSNA and PAH) were not affected or were reduced to a lesser extent than that of volatile organic compounds (148). Hearn et al. (149) showed that, while charcoal-containing filters selectively removed lower molecular mass PAH from MSS, they did not significantly remove the heavier, more toxic PAH studied, such as benzo[a]pyrene, a known carcinogen. Likewise, charcoal-containing filters removed phenols and TSNA from MSS to varying degrees, depending on the compound, filter design and smoking regimen. The presence of sufficient charcoal in cigarette filters is known to
135
remove many volatile compounds and can potentially reduce the deliveries of certain semi-volatile compounds in some machine smoking regimens. Less volatile compounds, with a significant portion in the particulate phase, are less freely available for selective filtration by charcoal-containing filters than the more volatile compounds that reside predominantly in the gas phase. The industry has not reported any toxicity tests with these cigarettes. The effects of charcoal-filtered cigarettes on biomarkers of exposure were examined in a randomized, crossover, 2-week brand-switching study with 39 smokers (150). Twenty participants smoked cellulose acetate filter-tipped cigarettes, and the other 19 participants smoked charcoal-filtered cigarettes during week 1 of the study. The two types of cigarette had similar smoking machine-derived tar and nicotine yields. In week 2, the participants switched to the brand with the other filter type. Daily cigarette consumption, CO in exhaled breath, salivary cotinine and urinary nicotine equivalents (molar sum of nicotine plus five major metabolites) did not change significantly with switching. The rates of urinary excretion of 3-hydroxy-1-methylpropylmercapturic acid (a metabolite of crotonaldehyde), monohydroxybutenylmercapturic acid (a metabolite of 1,3-butadiene) and S-phenylmercapturic acid (a metabolite of benzene) were significantly lower in samples from participants who smoked charcoal-filtered cigarettes; the reduction in the amount of 3-hydroxypropylmercapturic acid (a metabolite of acrolein) was of borderline significance. The levels of other mercapturic acids and thioethers (the latter being a summary measure of exposure to electrophilic compounds) were not or only slightly reduced in samples from participants smoking charcoal-filtered cigarettes (143). Overall, smoking charcoal-filtered cigarettes did not change the uptake of CO or nicotine from that with cellulose acetate-tipped cigarettes with similar tar and nicotine yields, but it significantly reduced exposure to toxicologically relevant smoke constituents such as acrolein, crotonaldehyde, 1,3-butadiene and benzene (150). The health benefits of reducing the levels of selected compounds in MSS by the addition of charcoal filters are still not clear. The only study of biomarkers (150) was an uncontrolled field study. Acrolein and crotonaldehyde are also products of endogenous lipid peroxidation, and it is not known which smoke components are responsible for increasing their concentrations. Only a limited number of people (39) were evaluated, whereas a large sample size would be required to confirm the results of the biomarker study. The industry has not reported any studies of biomarkers or sensory quality. Research in progress as presented at the 2013 CORESTA meeting
Research on harm reduction presented at the meeting on smoke science and product technology organized by the Cooperation Centre for Scientific
136
Research Relative to Tobacco (CORESTA) in Seville, Spain, in 2013 is summarized below. The summaries do not give complete or definitive overviews of the results but signal trends in research on tobacco product technology, including filter materials, TSS and mechanisms of formation of toxicants. Tobacco additives
The Yunnan Reascend Tobacco Technology (Group) Company in China presented a study on the effect of introducing nanomaterials such as particles of iron oxide into reconstituted tobacco sheet to reduce smoke components such as tar, CO, benzo[a]pyrene and NNK (lecture 16, poster 13). The type of cigarette used and whether the reduction was still present after nicotine levels were normalized were not reported. The Company also reported that the addition of stem granules reduced the delivery of several smoke components but did not affect the sensory quality of the product (lecture 52). Addition of 8% stem granules reduced the levels of tar (32%), nicotine 32%), chromium (28%), nickel (17%), cadmium (53%), lead (28%) and mercury (17%) in MSS. As nicotine was usually reduced to a greater extent than the other toxicants, it could be argued that a smoker titrating a desired amount of nicotine is actually exposed to more toxicants when smoking the product with stem granules. Filter additives
The Yunnan Reascend Tobacco Technology (Group) Company also made a presentation on polyamidoamine-grafted silica gels in cigarette filters (lecture 17). The absorbent was reported to selectively reduce the levels of phenol, crotonaldehyde and hydrogen cyanide; effects on nicotine were not reported. The China Tobacco Hunan Industrial Company and the Zhengzou Tobacco Research Institute reported that common acetate filters selectively reduced the levels of seven phenolic compounds as compared with nicotine (lecture 31). The China Tobacco Jiangsu Industrial Company showed the results of applying several activated carbon fibres with surfaces modified by metal oxides such as palladium chloride (poster 12). Depending on the product, reductions in tar, phenol, catechol and crotonaldehyde were observed; nicotine levels were not reported. Precursor studies
The Zhengzou Tobacco Research Institute presented some results from studies of the main precursors of hydrogen cyanide (mainly proteins) and of
137
4-aminobiphenyl (lecture 56), and the Japan Tobacco Inc. described the effect of pyrolysis conditions on formation of these compounds (lecture 57). Knowledge of the precursors and mechanisms of pyrolysis could indicate potential harm reduction products. Summary A wide spectrum of new tobacco products and technologies has been introduced onto international markets during the past decade. The new products include non-combustible products, such as dissolvable tobacco and novel snus, and modified cigarettes and cigarette-like products that heat rather than burn tobacco. Non-combustible oral products
Dissolvable tobacco products have undergone significant transformation since they were first introduced onto the US market, with changes in both their packaging and formulations (Figure 1). It is not clear whether these products will persist on the US market or spread internationally. In contrast, novel snus products appear to be gaining popularity in the USA (25). Snus products manufactured in USA and potentially in other countries should, however, be distinguished from traditional Swedish snus. US-manufactured snus differs from Swedish snus in moisture content, pouch size and the content of nicotine and other constituents (15, 34, 151). Furthermore, the higher TSNA levels in the latest versions of Camel snus suggest that either the tobacco type or the tobacco processing method (or both) used in the manufacture of this product are different from those of Swedish snus. Researchers who advocate replication of “Swedish experience” in the USA and other countries should therefore exercise caution. Furthermore, the levels of constituents in novel non-combustible products have been shown to vary widely (15, 33), perhaps as a result of test-marketing experimentation and/or reformulation. This category of products must continue to be monitored as the products are test-marketed and modified and new products are introduced. The marketing used to promote some novel tobacco products in the USA, such as snus and dissolvable tobacco, includes distribution of free samples, “teaching” new consumers to use the products and messages suggesting that the products will be used only temporarily. These tactics indicate that current snus campaigns are targeting new users and encouraging dual use. Information about consumer research by the tobacco industry in previously secret industry documents strongly supports this hypothesis (152–154). While manufacturers insist that their dissolvable products are neither marketed nor attractive to youth, the research community is concerned that the “candy”-like appearance
138
of these products and the fact that they can be used discreetly may appeal to children and adolescents, potentially increasing their tobacco use and accidental poisoning (10). The products are also offered in various flavours, and it has been shown that younger adults are more likely to use flavoured tobacco products (104). Product packaging appears to play an important role in the tobacco industry’s overall marketing strategy. In the USA, awareness and use of novel products is more frequent among non-Hispanic, white, male, young smokers (155–158). Young adults apparently tend to perceive some novel snus and dissolvable products as accessible, convenient, attractive, modern, fun, recreational and concealable (159). Both smokers and nonsmokers reported that they would use them when the opportunity arose. Little is known about who uses the dissolvable tobacco products on sale and who will use them if they are widely marketed. For instance, certain demographic groups, such as young people and pregnant women, might be more likely to use dissolvable tobacco than others. If so, it is important to better understand the factors related to product design and marketing that could make these products appealing to certain groups. Limited studies show that, while awareness, testing and interest in dissolvable products are quite low, they were highest among young adults and male smokers (5). Smokers tend to believe in the relative safety of products that are directly or implicitly marketed as less harmful (160–162). Thus, while smokers are generally dissatisfied with the taste of snus and dissolvable products, they may be interested in using these products to reduce their risk (162, 163). The availability of dissolvable tobacco and snus might also attract new users who would have not otherwise have used tobacco. More thorough surveillance of the population response to dissolvable tobacco products and snus in test market areas is essential to obtain the data necessary for tobacco control professionals to formulate policy recommendations (30). A national assessment of users of both cigarettes and smokeless tobacco in the USA showed that such dual users tend to be young white males—the same category of the population that appears to be interested in such novel products as snus and dissolvable tobacco (164, 165). Most of these dual users were not planning to quit and used smokeless tobacco in places where they could not smoke. Snus advertising actually appears to promote dual use of cigarettes and snus, such as the promotion of smokeless tobacco products as extensions of established cigarette brands. Dual use of cigarettes and smokeless tobacco has unclear consequences for public health but may increase the risks for tobacco-related morbidity and mortality (24). The initial versions of dissolvable and snus products contained less TSNA than more recent versions (13, 15, 18, 33). Thus, comparison of Ariva and medicinal nicotine lozenges in two small pilot studies showed that the uptake
139
of tobacco-specific carcinogens was comparable (14). In the rat lip canal model of the mucosal changes induced by chronic daily exposure, all four brands of smokeless tobacco induced dysplasia; however, Stonewall caused less severe dysplasia than conventional moist snuff, consistent with the hypothesis that tobacco with low levels of nitrosamines might induce fewer carcinomas in human users (166). Non-combustible products such as snus and dissolvable tobacco deliver less nicotine than cigarettes and do not expose smokers to CO, implying lower exposure to toxicants (41). The levels of TSNA and other harmful chemicals in dissolvable products, however, were found to range from very low to the levels found in traditional smokeless tobacco products (13, 15–17). The frequency of use of alternative tobacco products, including snus and dissolvables, and the association of use with attempts and intention to quit was studied in a nationally representative probability-based sample of 1836 current or recently former smokers in the USA. No indication was found that these products promote cessation (167). Novel snus and dissolvable products are generally not particularly effective in suppressing symptoms of abstinence (41, 43), although oral tobacco products containing more nicotine are more effective in suppressing cigarette smoking and leading to abstinence than those with lower nicotine levels. Studies should be conducted to determine whether use of snus products containing higher nicotine levels leads to dependence on the product, as in Scandinavian smokers who use snus to quit smoking (168). Many studies have shown that use of such products results in lower nicotine concentrations and equivalent or smaller reductions in subjective measures, such as craving and withdrawal symptoms, than medicinal nicotine (42). Until the health effects of such products are better understood, medicinal nicotine should be recommended for smokers who are willing to quit or to switch to lower-risk products. In Europe, the sale of snus is prohibited by the Tobacco Product Directive, except in Sweden. New products have appeared on the market that resemble snus but are advertised as chewing tobacco, which is allowed in Europe. Several Member States are discussing the regulatory status of this product type. Most researchers in the field of tobacco control agree that use of low-nitrosamine, non-combustible tobacco products such as snus could reduce the harm to individual smokers who switched entirely to these products (169). For instance, epidemiological evidence suggests that exclusive use of Swedish snus is associated with a relatively low risk for cancer (37, 38). A panel of experts reviewed the risk for mortality associated with use of low-nitrosamine smokeless tobacco marketed for oral use and concluded that the median relative risk for mortality of individual users was 5–9%, depending on the age of the smoker (169). The median risks associated with smoking were estimated to be 2–3% for lung cancer, 10% for heart disease and 15–30% for oral cancer.
140
The experts estimated a reduction of at least 90% in the relative risk of users of low-nicotine smokeless tobacco products in comparison with smoking. An expert evaluation of the potential impact of low-nitrosamine smokeless tobacco products on the prevalence of cigarette smoking concluded that introduction of a well-regulated smokeless tobacco product might reduce smoking and increase smokeless tobacco use in the USA only modestly (170). The effects of such products may, however, be modified by factors such as the willingness of smokers to switch, the potential for recruiting new tobacco users and the robust regulation of product chemistry. Smokeless tobacco products around the world vary in carcinogenic potential, and promotion of smokeless tobacco for reducing harm in countries where the locally marketed products have high contents of cancer-causing chemicals would be inappropriate (171–173). The results of epidemiological studies of smokeless tobacco use and disease risk depend on the product and the population studied (174). Furthermore, the effects of harm reduction strategies may differ according to cultural, social and economic differences among countries, especially between low- and middle-income countries and wealthier countries (173). Cigarettes and cigarette-like devices
The tobacco industry has developed a number of PREP cigarettes and cigarette-like devices, such as those that heat rather than burn tobacco. Although use of some of these products results in reduced levels of biomarkers, they have not been shown to reduce the disease burden or addictive potential significantly in comparison with usual cigarettes. Overall, these products have been market failures, with little public awareness of them (175). Nevertheless, marketing of “reduced exposure” cigarettes in the USA raised substantial interest among smokers, indicating that “health conscious” smokers and heavy smokers who are not planning to quit may be especially vulnerable to the industry’s marketing messages that such products are an alternative to smoking cessation (176). The peer-reviewed literature on “potential reduced exposure” cigarettes that involve heating of tobacco instead of burning shows that these products are not effective in reducing exposure. Exposure to CO from some of these cigarettes may be higher than from regular smoking. Furthermore, as tobacco smoke has over 4000 constituents, 60 of which are known carcinogens, decreasing the content of a limited number of carcinogens may not decrease the overall health risk and could affect the concentrations of other carcinogens in the smoke (175). Introduction of new materials into cigarette fillers and filters raises similar concern, potentially adding risks from new chemicals with unknown consequences for smokers’ health.
141
The spread of the “low-tar” cigarette market in some regions is another concern. The levels of exposure to tar are similar from cigarettes with different yields, and no health benefit has been found of smoking cigarettes with lower yields. Nevertheless, the tar reduction strategy is still being promoted in some countries, such as China. Reduced-nicotine cigarettes are considered a promising approach for reducing the addictive properties of cigarettes and thus reducing exposure to the harmful constituents of smoke. Switching to cigarettes with a very low nicotine content (< 0.05 mg) may be accompanied by minimal compensatory behaviour, reduce cigarette consumption, decrease dependence and facilitate abstinence by smokers (87). It is not clear, however, whether accustomed smokers would compensate for the lack of nicotine, as all the available evidence is from small trials of switching. In addition, reference to cigarettes as “low-nicotine” may be misinterpreted by consumers as indicating “low-risk” or “healthier”. Perusal of tobacco industry documents shows that such consumer misconceptions were the basis for the development of reduced-nicotine cigarettes (80). Apparently, the tobacco companies sought to define and lead a new market for “healthier”’ cigarettes that might appeal to “quitters”. Few brands of low-nicotine cigarettes are available, but the market may expand in the near future. The introduction of super-slim cigarettes to new markets is a concern, because the design appears to be tailored specifically for female users and because the slimmer design may be interpreted as that of a less harmful cigarette (96). Tobacco industry documents on the effect of cigarette pack shape, size and openings on consumer perceptions show that packaging not only communicates such attributes as premium quality and smooth taste but also influences perceptions of reduced harm. Furthermore, slim, rounded, oval, booklet and generally novel packs were found to be particularly appealing to young adults (177). Herbal cigarettes are an issue of concern, particularly in Asia, where medicinal plants have been used for centuries, making the population more vulnerable to misleading claims of health benefits than in countries where herbal medicine is less widely accepted; furthermore, unconfirmed scientific evidence is being widely cited in the Asian media to support the health claims. Adequate research and strict control of such claims are essential. Young urban males, particularly students, are more likely to use alternative products such as bidis (108, 178). The rates of bidi use among young adults may be a consequence of experimentation during adolescence; therefore, bidis may serve as a gateway to regular cigarette smoking. Tobacco prevention and control programmes must be aware of such emerging products. A waterpipe delivers charcoal-heated smoke that is first passed through sweet, flavoured tobacco and then through water before being inhaled by the smoker.
142
Waterpipe tobacco smoking is increasingly widespread; it is traditionally popular in Africa and the Middle East and is now spreading globally. It is particularly popular among school and university students. Longitudinal studies should be conducted to investigate whether the popularity of waterpipe tobacco smoking is a trend of age-specific prevalence. Waterpipe tobacco smoke contains numerous toxicants and carcinogens that are also found in cigarette smoke; therefore, it is not harmless but is significantly associated with various diseases, including cancer. A particular concern is the high level of CO inhaled when smoking waterpipes with or without tobacco, as the exposure is due mainly to charcoal combustion. Cases of CO poisoning after waterpipe smoking have been reported. The First International Conference on Waterpipe Tobacco Smoking held in October 2013 (179) made several recommendations to stop the global spread of waterpipe tobacco smoking: education and communication on the dangers of waterpipe smoking and misperceptions; support and evaluation of programmes to prevent initiation of young people and encourage smoking cessation; banning of flavoured waterpipe products; inclusion of waterpipe smoking in clean indoor air regulations; more effective warning labels, increased taxes, restricted access of young people and elimination of advertising and marketing of waterpipe tobacco products. Notable changes in cigarette design and marketing have been observed in Europe. Cigarettes and fine-cut tobacco brands that are advertised as containing only natural tobacco and no additives have been on the market for years. Recently, large brands such as Camel and Lucky Strike have also launched no-additive variants. This trend may be due to increasing social interest in natural, organic products, the fact that cigarette additives are associated with product manipulation and the expectation that tobacco additives will be regulated more strictly in the future. Cigarettes are available with capsules in their filters that release a flavour, usually menthol-like, to smoke; however, additives may no longer be allowed in filters, including capsules, in the tobacco product directive that is being negotiated. Cigarettes with “less smoke smell” are being marketed, which may increase the acceptability of smoking by bystanders. An increasing number of new tobacco products are being or will be marketed with the claim that they can reduce exposure to harmful chemicals in tobacco smoke. These PREPs include modifications in tobacco processing, filters and design. Many of the studies that support claims of risk reduction are performed and published by the industry. There is some evidence that adaptations in product design, such as TSS and the tobacco-blend treatment in conjunction with various filters (Diaion®CR20, carbon, cellulose acetate, CR20L and polymer-derived carbon), reduce toxicant levels in MSS and biomarkers of exposure. The most promising PREP was a combination of 20% TSS with an 80-mg carbon filter, which significantly reduced biomarkers of exposure; generally, participants reported equivalent or substantially poorer
143
acceptability of the experimental cigarette for most sensory categories. The acceptability appeared to improve over 4 weeks but was still slightly lower than for the control cigarette. No effect on MSS toxicant levels was observed when titanate nanoparticles were added to the filters of cigarettes. Charcoal filters specifically remove compounds present in the gas phase, such as volatile organic compounds, phenols and TSNA, but are less efficient in removing less volatile compounds in the particulate phase. In general, smoking charcoal-tipped cigarettes did not reduce the uptake of CO or nicotine when compared with cellulose acetate filter-tipped cigarettes with similar tar and nicotine yields, but it significantly reduced exposure to toxicologically relevant smoke constituents such as acrolein, crotonaldehyde, 1,3-butadiene and benzene. Biomarkers of exposure were measured in only a few studies, and only a limited number of biomarkers were measured. As tobacco smoke has over 5000 compounds, measurement of only a few biomarkers of exposure is insufficient to capture exposure to all the toxicants in MSS. Biomarkers of effect may provide a better indication of whether reductions in the levels of a few toxicants in MSS reduces tobacco-related diseases. A limitation of this approach is that it is not known whether reduced toxicant levels in MSS and biomarkers of exposure result in reduced disease outcomes. Although lower machine yields of toxicants in MSS were found with PREPs than with conventional cigarettes, substantial scientific data would be required to conclude that such products are associated with lower health risks. When evaluating the efficacy of PREPs in reducing human risk, consideration must be given to how people smoke, in terms of the level of toxicity and whether a design change actually results in reduced exposure or only a false sense of safety. The evidence that the PREPs evaluated can reduce risk is insufficient. Reductions in smoking machine-measured toxicant levels in MSS are not consistently reflected in reduced biomarkers of exposure, and the relations between biomarkers of exposure and disease outcomes should be investigated further. To date, there is insufficient evidence that any of the currently marketed modified cigarettes or alternative tobacco-burning or -heating devices can be used as “harm reduction” products. Pankow et al. (51), using risk assessment modelling, estimated that switching to a PREP cigarette would reduce the risk for lung cancer by < 2% as compared with conventional cigarettes. Smokers have accepted none of the tobacco-containing alternative cigarettes, and their market life has generally been short, so that it is impossible to assess any effect of these products on smoking-attributable morbidity and mortality. The general public, policy-makers and health professionals must be educated. For example, a study of harm reduction perceptions among US nurses revealed a widespread belief in the relative safety of “light” or additive-free cigarettes and other misperceptions about tobacco, which may have led them to make inaccurate recommendations during medical encounters (180).
144
Reductions in both exposure to toxic compounds and the addictive potential of tobacco products are important for harm reduction strategies. It must be remembered, however, that exposure reduction may encourage cigarette consumption by promoting a safer image, and reducing addictiveness may encourage compensatory smoking. Research indicates that cigarettes with a very low nicotine content do not lead to compensatory smoking and may be a viable approach for reducing exposure. In a study of the health impact of reductions in product addictiveness and toxicity, estimated in a computer model of changes in age- and gender-specific smoking behaviour in the US population over time, it was found that such reductions would produce net gains in population health and cumulative quality-adjusted life-years (181).
Conclusions Novel tobacco product types and technologies that have entered worldwide markets during the past decade vary substantially. Tobacco industry research indicates that more products may be introduced in the near future. A better approach is required for monitoring these novel tobacco products, with systematic collection of data to guide tobacco control and to understand the implications for public health. The impact of most novel tobacco products on public health is not clear. The major concerns include their potential unrecognized toxicity; increased or sustained prevalence of tobacco use by recruitment of new users, relapse of ex-smokers and maintenance of tobacco use by current smokers who might otherwise have quit; dual use of novel tobacco products and cigarettes; and initiation with a novel “gateway” product and eventual switching to cigarette smoking. Future research should focus on issues such as the toxicity of novel products (by analysis of the products and measurement of biomarkers of tobacco-related exposure and toxicity), their addictive potential and how they are perceived and used. Such information will help to determine whether they reduce or induce harm in individuals and at a population level.
Acknowledgements We thank Dr Anne Kienhuis (Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands) for her contribution to the paragraph on waterpipes.
145
We thank Mr Robert Carlson (University of Minnesota, Minneapolis, USA) for editorial assistance. The following people are acknowledged for their contributions to the background paper by sharing valuable information on new products in their countries in response to our questionnaire: Michael Anderegg, Federal Department of Home Affairs, Federal Office of Public Health, Consumer Protection Directorate, Bern, Switzerland Teresa Cepeda, Secretariat General for the Promotion of Health and Epidemiology, Directorate General of Public Health, Quality and Innovation, Ministry of Health, Social Services and Equality, Madrid, Spain Nuan Ping Cheah, Cigarette Testing Laboratory, Pharmaceutical Division, Applied Sciences Group, Health Sciences Authority, Singapore. Magda Ciobanu, Ministry of Health, Bucharest, Romania. Dr Daniela Galeone, Ministry of Health, Department of Public Health and Innovation, Rome, Italy Dorianne Grech, Environmental Health Policy Co-ordination Unit, Environmental Health Directorate, Valletta, Malta Prakash C. Gupta, Healis Sekhsaria Institute for Public Health, Mumbai, India Jürgen Hahn, Chemical and Veterinary Investigation Office, Sigmaringen, Germany Tiiu Härm, National Institute for Health Development, Tallinn, Estonia Dr Antero Heloma, National Institute for Health and Welfare, Helsinki, Finland Herodotos Herodotou, Medical and Public Health Services, Ministry of Health, Nicosia, Cyprus Lenka Kostelecka, Ministry of Health, Department of Health Services, Prague, Czech Republic Sofia Kuitunen and Linda-Maria Viitala, National Supervisory Authority for Welfare and Health (Valvira), Helsinki, Finland Rita Lindbak, Norwegian Directorate of Health, Oslo, Norway Lee McGill, Department of Health, London, United Kingdom Karin Molander Gregory, Swedish National Institute of Public Health, Department of Supervision, Östersund, Sweden Dr Ljiljana Muslić, Croatian National Institute of Public Health, Zagreb, Croatia Emília Nunes, National Programme for the Prevention and Control of Tobacco Use, Directorate General for Health, Lisbon, Portugal Helen O’Brien, Health Promotion Unit, Department of Health, Dublin, Ireland
146
Andre Luiz Oliveira da Silva, National Health Surveillance Agency, Brasilia, Brazil Stela Ondrušová, Department of European Union Affairs and International Relations, Ministry of Health, Bratislava, Slovak Republic Dr Helga Osiander-Fuchs, Bavarian State Office for Health and Food Safety, Erlangen, Germany Nuray Akan Yaltirakli, Tobacco and Alcohol Market Regulatory Authority, Ankara, Turkey
References 1. Zeller M, Hatsukami D, Strategic Dialogue on Tobacco Harm Reduction Group. The Strategic Dialogue on Tobacco Harm Reduction: a vision and blueprint for action in the US. Tob Control 2009;18:324–32. Colilla S. An epidemiologic review of smokeless tobacco health effects and harm reduction potential. Regul Toxicol Pharmacol 2010;56:197–211. Hatsukami DK, Henningfield JE, Kotlyar M. Harm reduction approaches to reducing tobacco-related mortality. Annu Rev Public Health 2004;25:377–95. Statement of principles guiding the evaluation of new or modified tobacco products. Geneva: Scientific Advisory Committee on Tobacco Product Regulation, World Health Organization; 2003 (http://apps.who.int/iris/handle/10665/42648, accessed October 2014). Southwell BG, Kim AE, Tessman GK, MacMonegle AJ, Choiniere CJ, Evans SE, et al. The marketing of dissolvable tobacco: social science and public policy research needs. Am J Health Promot 2012;26:331–2. Rainey CL, Conder PA, Goodpaster JV. Chemical characterization of dissolvable tobacco products promoted to reduce harm. J Agric Food Chem 2011;59:2745–51. Rainey CL, Berry JJ, Goodpaster JV. Monitoring changes in the chemical composition of dissolvable tobacco products. Anal Methods 2013;5:3216–21. Seidenberg AB, Rees VW, Connolly GN. RJ Reynolds goes international with new dissolvable tobacco products. Tob Control 2012;21:368–9. Centers for Disease Control and Prevention. State-specific secondhand smoke exposure and current cigarette smoking among adults—United States, 2008. Morbid Mortal Wkly Rep 2009;58(44).
2. 3. 4.
5.
6. 7. 8. 9.
10. Romito LM, Saxton MK, Coan LL, Christen AG. Retail promotions and perceptions of RJ Reynolds’ novel dissolvable tobacco in a US test market. Harm Reduction J 2011;8:10. 11. Caraballo RS, Pederson LL, Gupta N. New tobacco products: do smokers like them? Tob Control 2006;15:39–44. 12. Connolly GN, Richter P, Aleguas A, Pechachek TF, Stanfill SB, Alpert HR. Unintentional child poisonings through ingestion of conventional and novel
147
tobacco products. Pediatrics 2010;125:896–9. 13. Stepanov I, Jensen J, Hatsukami D, Hecht SS. Tobacco-specific nitrosamines in new tobacco products. Nicotine Tob Res 2006;8:309–13. 14. Mendoza-Baumgart MI, Tulunay OE, Hecht SS, Zhang Y, Murphy SE, Le CT, et al. Pilot study on lower nitrosamine smokeless tobacco products compared to medicinal nicotine. Nicotine Tob Res 2007;9:1309–23. 15. Stepanov I, Biener L, Knezevich A, Nyman AL, Bliss R, Jensen J, et al. Monitoring tobacco-specific N-nitrosamines and nicotine in novel Marlboro and Camel smokeless tobacco products: findings from round I of the New Product Watch. Nicotine Tob Res 2012;14:274–81. 16. Watson C. Quantitative and qualitative analysis of dissolvable tobacco products. Report to the Food and Drug Administration Tobacco Scientific Advisory Committee, 18–22 January 2012. Rockville, Maryland: Food and Drug Administration; 2012. 17. Stepanov I. Toxic and carcinogenic constituents in dissolvable tobacco products. Report to the Food and Drug Administration Tobacco Scientific Advisory Committee, 18–22 January 2012. Rockville, Maryland: Food and Drug Administration; 2012. 18. Lawler TS, Stanfill SB, Zhang L, Ashley DL, Watson CH. Chemical characterization of domestic oral tobacco products: total nicotine, pH, unprotonated nicotine and tobacco-specific N-nitrosamines. Food Chem Toxicol 2013;57:380–6. 19. Hatsukami DK, Jensen J, Anderson A, Broadbent B, Allen S, Zhang Y et al. Oral tobacco products: preference and effects among smokers. Drug Alcohol Depend 2011;118:230–6. 20. Kotlyar M, Hertsgaard LA, Lindgren BR, Jensen JA, Carmella SG, Stepanov I, et al. Effect of oral snus and medicinal nicotine in smokers on toxicant exposure and withdrawal symptoms: a feasibility study. Cancer Epidemiol Biomarkers Prev 2011;20:91–100. 21. Connolly GN. The marketing of nicotine addiction by one oral snuff manufacturer. Tob Control 1995;4:73–9. 22. Summary: TPSAC Report on Dissolvable Tobacco Products (Rep. No. March 1, 2012). Silver Spring, Maryland: Food and Drug Administration, Tobacco Scientific Advisory Committee; 2012. 23. Biener L, Bogen K. Receptivity to Taboka and Camel Snus in a US test market. Nicotine Tob Res 2009;11:1154–9. 24. Bahreinifar S, Sheon NM, Ling PM. Is snus the same as dip? Smokers’ perceptions of new smokeless tobacco advertising. Tob Control 2013;22:84–90. 25. Delnevo CD, Wackowski OA, Giovenco DP, Bover Manderski MT, Hrywna M, Ling PM. Examining market trends in the United States smokeless tobacco use: 2005–2011. Tob Control 2013;22:266–73. 26. Timberlake DS, Pechmann C, Tran SY, Au V. A content analysis of Camel Snus advertisements in print media. Nicotine Tob Res 2011;13:431–9.
148
27. Gany F, Rastogi N, Suri A, Hass C, Bari S, Leng J. Smokeless tobacco: how exposed are our children? J Community Health 2013;38:750–2. 28. Wackowski OA, Lewis MJ, Delnevo CD. Qualitative analysis of Camel Snus’ website message board—users’ product perceptions, insights and online interactions. Tob Control 2011;20:e1. 29. Choi K, Forster J. Awareness, perceptions, and use of snus among young adults from the upper Midwest region of the USA. Tob Control 2012;102:208893. 30. Biener L, McCausland K, Curry L, Cullen J. Prevalence of trial of snus products among adult smokers. Am J Public Health 2011;101:1874–6. 31. Loukas A, Batanova MD, Velazquez CE, Lang WJ, Sneden GG, Pasch KE, et al. Who uses snus? A study of Texas adolescents. Nicotine Tob Res 2012;14:626–30. 32. Caraway JW, Chen PX. Assessment of mouth-level exposure to tobacco constituents in US snus consumers. Nicotine Tob Res 2013;15:670–7. 33. Stepanov I, Jensen J, Biener L, Bliss RL, Hecht SS, Hatsukami DK. Increased pouch sizes and resulting changes in the amounts of nicotine and tobaccspecific N-nitrosamines in single pouches of Camel Snus and Marlboro Snus. Nicotine Tob Res 2012;14:1241–5. 34. Stepanov I, Jensen J, Hatsukami D, Hecht SS. New and traditional smokeless tobacco: comparison of toxicant and carcinogen levels. Nicotine Tob Res 2008;10:1773–82. 35. Digard H, Gale N, Errington G, Peters N, McAdam K. Multi-analyte approach for determining the extraction of tobacco constituents from pouched snus by consumers during use. Chem Central J 2013;7:55. 36. Sarkar M, Liu J, Koval T, Wang J, Feng S, Serafin R, et al. Evaluation of biomarkers of exposure in adult cigarette smokers using Marlboro Snus. Nicotine Tob Res 2010;12:105–16. 37. Foulds J, Ramstrom L, Burke M, Fagerstrom K. Effect of smokeless tobacco (snus) on smoking and public health in Sweden. Tob Control 2003;12:349–59. 38. Luo J, Ye W, Zandehdel K, Adami J, Adami HO, Boffetta P, et al. Oral use of Swedish moist snuff (snus) and risk for cancer of the mouth, lung, and pancreas in male construction workers: a retrospective cohort study. Lancet 2007;369:2015–20. 39. Greer RO Jr. Oral manifestations of smokeless tobacco use. Otolaryngol Clin N Am 2011;44:31–56. 40. Health effects of smokeless tobacco products. Brussels: European Commission, Scientific Committee on Emerging and Newly Identified Health Risks; 2008. 41. Cobb CO, Weaver MF, Eissenberg T. Evaluating the acute effects of oral, noncombustible potential reduced exposure products marketed to smokers. Tob Control 2010;19:367–373. 42. Kotlyar M, Mendoza-Baumgart MI, Li Z, Pentel PR, Barnett BC, Feuer RM, et al. Nicotine pharmacokinetics and subjective effects of three potential reduced exposure products, moist snuff and nicotine lozenge. Tob Control 2007;16:138–42.
149
43. Blank MD, Eissenberg T. Evaluating oral noncombustible potential-reduced exposure products for smokers. Nicotine Tob Res 2010;12:336–43. 44. European Commission. Directive 2001/37/EC of the European Parliament and of the Council of 5 June 2001 on the approximation of the laws, regulations and administrative provisions of the Member States, concerning the manufacture, presentation and sale of tobacco products. Off J L 2013;194:26. 45. Hughes JR, Keely JP, Callas PW. Ever users versus never users of a “less risky” cigarette. Psychol Addictive Behav 2005;19:439–42. 46. Breland AB, Evans SE, Buchhalter AR, Eissenberg T. Acute effects of Advance: a potential reduced exposure product for smokers. Tob Control 2002;11:376–8. 47. Brown B, Kolesar J, Lindberg K, Meckley D, Mosberg A, Doolittle D. Comparative studies of DNA adduct formation in mice following dermal application of smoke condensates from cigarettes that burn or primarily heat tobacco. Mutat Res 1998;414:21–30. 48. Buchhalter AR, Schrinel L, Eissenberg T. Withdrawal-suppressing effects of a novel smoking system: comparison with own brand, not own brand, and denicotinized cigarettes. Nicotine Tob Res 2001;3:111–8. 49. Tarantola A. Ploom modelTwo E-Cig review: welcome to flavor country. Gizmodocom; 2013 (http://gizmodo.com/ploom-modeltwo-e-cig-review-welcome -to-flavor-country-586563052, accessed October 2014). 50. Breland AB, Acosta MC, Eissenberg T. Tobacco specific nitrosamines and potential reduced exposure products for smokers: a preliminary evaluation of AdvanceTM. Tob Control 2003;12:317–21. 51. Pankow JF, Watanabe KH, Toccalino PL, Luo W, Austin DF. Calculated cancer risks for conventional and “potentially reduced exposure product” cigarettes. Cancer Epidemiol Biomarkers Prev 2007;16:584–592. 52. Hughes JR, Hecht SS, Carmella SG, Murphy SE, Callas P. Smoking behavior and toxin exposure during six weeks use of a “less risky” cigarette—Omni. Tob Control 2004;13:175–9. 53. Rees VW, Wayne GF, Connolly GN. Puffing style and human exposure minimally alltered by switching to a carbon-filtered cigarette. Cancer Epidemiol Biomarkers Prev 2008;17:2995–3003. 54. Shiffman S, Pillitteri JL, Burton SL, DiMarino ME. Smoker and ex-smoker reactions to cigarettes claiming reduced risk. Tob Control 2004;13:78–84. 55. Shiffman S, Jarvis MJ, Pillitteri JL, DiMarino ME, Gitchell JG, Kemper KE. UK smokers’ and ex-smokers’ reactions to cigarettes promising reduced risk. Addiction 2007;102:156–60. 56. Lee EM, Malson JL, Moolchan ET, Pickworth WB. Quantitative comparisons between a nicotine delivery device (Eclipse) and conventional cigarette smoking. Nicotine Tob Res 2004;6:95–102. 57. Stabbert R, Voncken P, Rustemeier K, Haussmann HJ, Roemer E, Schaffernicht H, et al. Toxicological evaluation of an electrically heated cigarette. Part 2: Chemical composition of mainstream smoke. J Appl Toxicol 2003;23:329–39.
150
58. Fowles J. Novel tobacco products: health risk implications and international concerns (Client report FW0175). Auckland: Ministry of Health; 2001 (www.moh.govt. nz/moh.nsf/.../noveltobaccoproductshealthrisk.doc, accessed October 2014). 59. Breland AB, Kleykamp BA, Eissenberg T. Clinical laboratory evaluation of potential reduced exposure products for smokers. Nicotine Tob Res 2006;8:738. 60. Ayres PH, Hayes JR, Higuchi MA, Mosberg AT, Sagartz JW. Subchronic inhalation by rats of mainstream smoke from a cigarette that primarily heats tobacco compared to a cigarette that burns tobacco. Inhal Toxicol 2001;13:149–86. 61. Bowman DL, Smith CJ, Bombick BR, Avalos JT, Davis RA, Morgan WT, et al. Relationship between FTC “tar” and urine mutagenicity in smokers of tobaccoburning or Eclipse cigarettes. Mutat Res 2002;521:137–49. 62. Slade J, Connolly GN, Lymperis D. Eclipse: does it live up to its health claims? Tob Control 2002;11(Suppl 2):ii64–70. 63. Fagerstrom KO, Hughes JR, Callas PW. Long-term effects of the Eclipse cigarette substitute and the nicotine inhaler in smokers not interested in quitting. Nicotine Tob Res 2002;4(Suppl 2):S141–5. 64. Fagerstrom KO, Hughes JR, Rasmussen T, Callas PW. Randomised trial investigating effect of a novel nicotine delivery device (Eclipse) and a nicotine oral inhaler on smoking behaviour, nicotine and carbon monoxide exposure, and motivation to quit. Tob Control 2000;9:327–33. 65. Rennard SI, Umino T, Millatmal T, Daughton DM, Manouilova LS, Ullrich FA, et al. Evaluation of subclinical respiratory tract inflammation in heavy smokers who switch to a cigarette-like nicotine delivery device that primarily heats tobacco. Nicotine Tob Res 2002;4:467–76. 66. Stewart JC, Hyde RW, Boscia J, Chow MY, O’Mara RE, Perillo I, et al. Changes in markers of epithelial permeability and inflammation in chronic smokers switching to a nonburning tobacco device (Eclipse). Nicotine Tob Res 2006;8:773–83. 67. Breland AB, Buchhalter AR, Evans SE, Eissenberg T. Evaluating acute effects of potential reduced-exposure products for smokers: clinical laboratory methodology. Nicotine Tob Res 2002;4(Suppl 2):S131–40. 68. Hatsukami DK, Lemmonds C, Zhang Y, Murphy SE, Le C, Carmella SG et al. Evaluation of carcinogen exposure in people who used “reduced exposure” tobacco products. J Natl Cancer Inst 2004;96:844–52. 69. Lin S, Tran V, Talbot P Comparison of toxicity of smoke from traditional and harm-reduction cigarettes using mouse embryonic stem cells as a novel model for preimplantation development. Hum Reprod 2009;24:386–97. 70. Riveles K, Tran V, Roza R, Kwan D, Talbot P. Smoke from traditional commercial, harm reduction and research brand cigarettes impairs oviductal functioning in hamsters (Mesocricetus auratus) in vitro. Hum Reprod 2007;22:346–55. 71. Benowitz NL. Compensatory smoking of low-yield cigarettes. In: Risks Associated with Smoking Cigarettes with Low Machine-measured Yields of Tar and Nicotine (Smoking and Tobacco Control Monograph No. 13). Bethesda, Maryland: US Department of Health and Human Services, National Institutes of
151
Health, National Cancer Institute; 2001:39–63. 72. Harris JE, Thun MJ, Mondul AM, Calle EE. Cigarette tar yields in relation to mortality from lung cancer in the Cancer Prevention Study II prospective cohort, 1982–8. BMJ 2004;328:72–9. 73. Hecht SS, Murphy SE, Carmella SG, Li S, Jensen J, Le C, et al. Similar uptake of lung carcinogens by smokers of regular, light, and ultra-light cigarettes. Cancer Epidemiol Biomarkers Prev 2005;14:693–8. 74. Yang G Marketing “less harmful, low-tar” cigarettes is a key strategy of the industry to counter tobacco control in China. Tob Control 2013;23:167–72. 75. Djordjevic MV, Stellman SD, Zang E. Doses of nicotine and lung carcinogens delivered to cigarette smokers. J Natl Cancer Inst 2000;92:106–11. 76. Benowitz NL. Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 2008;83:531–41. 77. Benowitz NL. Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol 2009;49:57–71. 78. Strasser AA, Ashare RL, Kozlowski LT, Pickworth WB. The effect of filter vent blocking and smoking topography on carbon monoxide levels in smokers. Pharmacol Biochem Behav 2005;82:320–9. 79. Hatsukami DK, Kotlyar M, Hertsgaard LA, Zhang Y, Carmella SG, Jensen JA et al. Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation. Addiction 2010;105:343–55. 80. Dunsby J, Bero L. A nicotine delivery device without the nicotine? Tobacco industry development of low nicotine cigarettes. Tob Control 2004;13:362–9. 81. Shadel WG, Lerman C, Cappella J, Strasser AA, Pinto A, Hornik R. Evaluating smokers’ reactions to advertizing for new lower nicotine Quest cigarettes. Psychol Addict Behav 2006;20:80–4. 84. Benowitz NL, Dains KM, Hall SM, Stewart S, Wilson M, Dempsey D, et al. Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 2012;21:761–9. 82. Benowitz NL, Jacob PIII, Herrera B. Nicotine intake and dose response when smoking reduced-nicotine content cigarettes. Clin Pharmacol Ther 2006;80:703–14. 90. Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction— the implications for tobacco regulation. N Engl J Med 1994;331:123–5. 85. Catanzaro DF, Zhou Y, Chen R, Yu F, Catanzaro SE, DeLorenzo MS et al. Potentially reduced exposure cigarettes accelerate atherosclerosis: evidence for the role of nicotine. Cardiovasc Toxicol 2007;7:192–201. 86. Chen J, Higby R, Tian D, Tan D, Johnson MD, Xiao Y et al. Toxicological analysis of low-nicotine and nicotine-free cigarettes. Toxicology 2008;249:194–203. 87. Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS et al. Reduced nicotine content cigarettes and nicotine patch. Cancer Epidemiol Biomarkers Prev 2013;22:1015–24.
152
88. Girdhar G, Xu S, Bluestein D, Jesty J. Reduced-nicotine cigarettes increase platelet activation in smokers in vivo: a dilemma in harm reduction. Nicotine Tob Res 2008;10:1737–44. 83. Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P III. Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 2007;16:2479–85. 89. Lin S, Fonteno S, Weng JH, Talbot P. Comparison of the toxicity of smoke from conventional and harm reduction cigarettes using human embryonic stem cells. Toxicol Sci 2010;118:202–12. 91. Rose JE, Behm FM. Effects of low nicotine content cigarettes on smoke intake. Nicotine Tob Res 2004;6:309–19. 92. Strasser AA, Lerman C, Sanborn PM, Pickworth WB, Feldman EA. New lower nicotine cigarettes can produce compensatory smoking and increased carbon monoxide exposure. Drug Alcohol Depend 2007;86:294–300. 93. Walker N, Howe C, Bullen C, Grigg M, Glover M, McRobbie H, et al. The combined effect of very low nicotine content cigarettes, used as an adjunct to usual Quitline care (nicotine replacement therapy and behavioural support), on smoking cessation: a randomized controlled trial. Addiction 2012;107:1857–67. 94. Rose JE, Behm FM, Westman EC, Kukovich P. Precessation treatment with nicotine skin patch facilitates smoking cessation. Nicotine Tob Res 2006;8:89–101. 95. Donny EC, Jones M. Prolonged exposure to denicotinized cigarettes with or without transdermal nicotine. Drug Alcohol Depend 2009;104:23–33. 96. Siu M, Mladjenovic N, Soo E. The analysis of mainstream smoke emissions of Canadian “super slim” cigarettes. Tob Control 2012;22:e10. 97. Hammond D, Doxey J, Daniel S, Bansal-Travers M. Impact of female-oriented cigarette packaging in the United States. Nicotine Tob Res 2011;13:579–88. 98. European Commission. Directive 2014/40/EU of the European Parliament and of the Council of 3 April 2014 on the approximation of the laws, regulations and administrative provisions of the Member States concerning the manufacture, presentation and sale of tobacco and related products and repealing Directive 2001/37/EC Text with EEA relevance. Off J L 2014;127:1–38. 99. Richardson A, Vallone DM. YouTube: a promotional vechicle for little cigars and cigarillos? Tob Control 2012;23:21–6. 100. Kozlowski LT, Dollar KM, Giovino GA. Cigar/cigarillo surveillance: limitations of the US Department of Agriculture system. Am J Prev Med 2008;34:424–6. 101. Maxwell JC. The Maxwell report. Cigar industry in 2008. Richmond, Virginia; 2008. 102. Richardson A, Xiao H, Vallone DM. Primary and dual users of cigars and cigarettes: profiles, tobacco use patterns, and relevance to policy. Nicotine Tob Res 2012;14:927–32. 103. Family Smoking Prevention and Tobacco Control Act (7-22-2009). Public Law 1131, H.R. 1256. Washington DC: Government Printing Office, US Congress; 2009
153
( http://www.gpo.gov/fdsys/pkg/PLAW-111publ31/pdf/PLAW-111publ31.pdf, accessed October 2014). 104. Villanti AC, Richardson A, Vallone DM, Rath JM. Flavored tobacco product use among US young adults. Am J Prev Med 2013;44:388–91. 105. Little cigars—big concerns. Ottawa: Health Canada; 2011. 106. Henningfield JE, Fant RV, Radzius A, Frost S. Nicotine concentration, smoke pH and whole tobacco aqueous pH of some cigar brands and types popular in the United States. Nicotine Tob Res 1999;1:163–8. 107. Chen A, Glantz S, Tong E. Asian herbal-tobacco cigarettes: “not medicine but less harmful”? Tob Control 2007;16:e3. 108. Soldz S, Huyser DJ, Dorsey E. Characteristics of users of cigares, bidis, and kreteks and the relationship to cigarette use. Prev Med 2003;37:250–8. 109. Watson CH, Polzin GM, Calafat AM, Ashley DL. Determination of tar, nicotine, and carbon monoxide yields in the smoke of bidi cigarettes. Nicotine Tob Res 2003;5:747–53. 110. Delnevo CD, Pevzner ES, Hrywna M, Lewis MJ. Bidi cigarette use among young adults in 15 states. Prev Med 2004;39:207–11. 111. Waterpipe tobacco smoking: health effects, research needs and recommended actions by regulators. Geneva: World Health Organization; 2005. 112. Vattenpipa—rök utan risk? Hälsoeffekter, vanor, attityder och tillsyn [Hookah— smoke without risk? Health effects, habits, attitudes and supervision]. Östersund: Statens Folkhälsoinstitut; 2010. 113. Morton J, Song Y, Fouad H, Awa FE, Abou El Naga R, Zhao L, et al. Crosscountry comparison of waterpipe use: nationally representative data from 13 low and middle-income countries from the Global Adult Tobacco Survey (GATS). Tob Control 2013;23:419–27. 114. Maziak W. The global epidemic of waterpipe smoking. Addict Behav 2011;36:1–5. 115. Akl EA, Gunukula SK, Aleem S, Obeid R, Abou Jaoude P, Honeine R, et al. The prevalence of waterpipe tobacco smoking among the general and specific populations: a systemic review. BMC Public Health 2011;11:244. 116. Attitudes of Europeans towards tobacco (Special Eurobarometer 385, Wave EB77.1). Brussels: European Commission; 2012. 117. Jawad M, Abass J, Hariri A, Rajasooriar KG, Salmasi H, Millett C, et al. Waterpipe smoking: prevalence and attitudes among medical students in London. Int J Tuberc Lung Dis 2013;17:137–40. 118. Schubert J, Hahn J, Dettbarn G, Seidel A, Luch A, Schulz TG. Mainstream smoke of the waterpipe: does this environmental matrix reveal as significant source of toxic compounds? Toxicol Lett 2011;205:279–84. 119. Al Rashidi M, Shihadeh A, Saliba NA. Volatile aldehydes in the mainstream smoke of the narghile waterpipe. Food Chem Toxicol 2008;46:3546–9. 120. Cobb CO, Shihadeh A, Weaver MF, Eissenberg T. Waterpipe tobacco smoking and cigarette smoking: a direct comparison of toxicant exposure and subjective
154
effects. Nicotine Tob Res 2011;11:78–87. 121. La Fauci G, Weiser G, Steiner IP, Shavit I. Carbon monoxide poisoning in nagrhile (water pipe) tobacco smokers. Can J Emerg Med 2012;14:57–9. 122. Jacob P III, Abu Raddaha AH, Dempsey D, Havel C, Peng M, Yu L, et al. Comparison of nicotine and carcinogen exposure with water pipe and cigarette smoking. Cancer Epidemiol Biomarkers Prev 2013;22:765–72. 123. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 71, Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide. Lyon: International Agency for Research on Cancer; 1999. 124. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 88, Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropan-2-ol. Lyon: International Agency for Research on Cancer; 2006. 125. Maziak W, Eissenberg T, Ward KD. Patterns of waterpipe use and dependence: implications for intervention development. Pharmacol Biochem Behav 2005;80:173–9. 126. Lipkus IM, Eissenberg T, Schwartz-Bloom RD, Prokhorov AV, Levy J. Affecting perceptions of harm and addiction among college waterpipe tobacco smokers. Nicotine Tob Res 2011;13:599–610. 127. Menthol capsules in cigarette filters—incrreasing the attractiveness of a harmful product. Heidelberg: German Cancer Research Center; 2012. 128. Addictiveness and Attractiveness of Tobacco Additives. Brussels: European Commission, Scientific Committee on Emerging and Newly Identified Health Risks; 2010. 129. Tobacco additives. Bilthoven: National Institute for Public Health and the Environment; 2012. 130. Soeteman-Hernandez LG, Bos PM, Talhout R. Tobacco smoke-related health effects induced by 1,3-butadiene and strategies for reduction. Toxicol Sci 2013;136:566–80. 131. Kennedy RD, Millstein RA, Rees VW, Connolly GN. Tobacco industry strategies to minimize or mask cigarette smoke: opportunities for tobacco product regulation. Nicotine Tob Res 2013;15:596–602. 132. Marian C, O’Connor RJ, Djordjevic MV, Rees VW, Hatsukami DK, Shields PG. Reconciling human smoking behavior and machine smoking patterns: implications for understanding smoking behavior and the impact on laboratory studies. Cancer Epidemiol Biomarkers Prev 2009;18:3305–20. 133. Burns DM, Dybing E, Gray N, Hecht S, Anderson C, Sanner T et al. Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal. Tob Control 2008;17:132–41. 134. Mulier T. Philip Morris to introduce lower-risk cigarette by 2017. Bloombergcom; 2013 (http://www.bloomberg.com/news/2012-06-21/philip-morris-to-introducenext-generation-cigarette-by-7.html, accessed October 2014). 135. Smeltsigaret op komst [Melt cigarette arriving]. SP!TS; 2013 (http://www.
155
spitsnieuws.nl/archives/binnenland/2013/10/smeltsigaret-op-komst, accessed 5 October 2013). 136. Rees VW, Kreslake JM, O’Connor RJ, Cummings KM, Parascandola M, Hatsukami D, et al. Methods used in internal industry clinical trials to assess tobacco risk reduction. Cancer Epidemiol Biomarkers Prev 2009;18:3196–208. 137. Kleinstreuer C, Feng Y. Lung deposition analyses of inhaled toxic aerosols in conventional and less harmful cigarette smoke: a review. Int J Environ Res Public Health 2013;10:4454–85. 138. McAdam KG, Gregg EO, Liu C, Dittrich DJ, Duke MG, Proctor CJ. The use of a novel tobacco-substitute sheet and smoke dilution to reduce toxicant yields in cigarette smoke. Food Chem Toxicol 2011;49:1684–96. 139. Fearon IM, Acheampong DO, Bishop E. Modification of smoke toxicant yields alters the effects of cigarette smoke extracts on endothelial migration: an in vitro study using a cardiovascular disease model. Int J Toxicol 2012;31:572–83. 140. Fearon IM, Gaca MD, Nordskog BK. In vitro models for assessing the potential cardiovascular disease risk associated with cigarette smoking. Toxicol in Vitro 2013;27:513–22. 141. St Charles FK, McAughey J, Shepperd CJ. Methodologies for the quantitative estimation of toxicant dose to cigarette smokers using physical, chemical, and bioanalytical data. Inhal Toxicol 2013;25:363–72. 142. Liu C, DeGrandpre Y, Porter A, Griffiths A, McAdam K, Voisine R, et al. The use of a novel tobacco treatment process to reduce toxicant yields in cigarette smoke. Food Chem Toxicol 2011;49:1904–17. 143. Shepperd CJ, Eldridge A, Camacho OM, McAdam K, Proctor CJ, Meyer I. Changes in levels of biomarkers of exposure observed in a controlled study of smokers switched from conventional to reduced toxicant prototype cigarettes. Regul Toxicol Pharmacol 2013;66:147–62. 144. McAdam KG, Gregg EO, Bevan M, Dittrich DJ, Hemsley S, Liu C, et al. Design and chemical evaluation of reduced machine-yield cigarettes. Regul Toxicol Pharmacol 2012;62:138–50. 145. Branton PJ, McAdam KG, Winter DB, Liu C, Duke MG, Proctor CJ. Reduction of aldehydes and hydrogen cyanide yields in mainstream smoke using an amine functionalised ion exchange resin. Chem Central J 2011;5:15. 146. Deng Q, Huang C, Xie W, Xu H, Wei M. Significant reduction of harmful compounds in tobacco smoke by the use of titanite nanosheets and nanotubes. Chem Commun (Camb) 2011;47:6153–5. 147. Deng Q, Huang C, Zhang J, Xie W, Xu H, Wei M. Selectively reduction of tobacco specific nitrosamines in cigarette smoke by use of nanostructural titanates. Nanoscale 2013;5:5519–23. 148. Polzin GM, Zhang L, Hearn BA, Tavakoli AD, Vaughan C, Ding YS, et al. Effect of charcoal-containing cigarette filters on gas phase volatile organic compounds in mainstream cigarette smoke. Tob Control 2008;17(Suppl 1):i10–6. 149. Hearn BA, Ding YS, Vaughan C, Zhang LQ, Polzin G, Caudill SP, et al. Semi-
156
volatiles in mainstream smoke delivery from select charcoal-filtered cigarette brand variants. Tob Control 2010;19:223–30. 150. Scherer G, Urban M, Engl J, Hagedorn HW, Riedel K. Influence of smoking charcoal filter tipped cigarettes on various biomarkers of exposure. Inhal Toxicol 2006;18:821–9. 151. Foulds J, Furberg H. Is low-nicotine Marlboro snus really snus? Harm Reduction J 2008;5:9. 152. Carpenter CM, Connolly GN, Ayo-Yusuf OA, Wayne GF. Developing smokeless tobacco products for smokers: an examination of tobacco industry documents. Tob Control 2009;18:54–9. 153. Rees VW, Kreslake JM, Cummings KM, O’Connor RJ, Hatsukami DK, Parascandola M, et al. Assessing consumer responses to potential reducedexposure tobacco products: a review of tobacco industry and independent research methods. Cancer Epidemiol Biomarkers Prev 2009;18:3225–40. 154. Mejia AB, Ling PM. Tobacco industry consumer research on smokeless tobacco users and product development. Am J Public Health 2010;100:78–87. 155. Parascandola M, Augustson E, Rose A. Characteristics of current and recent former smokers associated with the use of new potential reduced-exposure tobacco products. Nicotine Tob Res 2009;11:1431–8. 156. Regan AK, Dube SR, Arrazola R. Smokeless and flavored tobacco products in the US 2009 Styles survey results. Am J Prev Med 2012;42:29–36. 157. Wray RJ, Jupka K, Berman S, Zellin S, Vijaykumar S. Young adults’ perceptions about established and emerging tobacco products: results from eight focus groups. Nicotine Tob Res 2012;14:184–90. 158. Shaikh RA, Siahpush M, Singh GK. Socioeconomic, demographic and smokingrelated correlates of the use of potentially reduced exposure to tobacco products in a national sample. Tob Control 2013;23:353–8. 159. Choi K, Fabian L, Mottey N, Corbett A, Forster J. Young adults’ favorable perceptions of snus, dissolvable tobacco products, and electronic cigarettes: findings from a focus group study. Am J Public Health 2012;102:2088–93. 160. O’Connor RJ, Hyland A, Giovino GA, Fong GT, Cummings KM. Smoker awareness of and beliefs about supposedly less-harmful tobacco products. Am J Prev Med 2005;29:85–90. 161. O’Connor RJ, McNeill A, Borland R, Hammond D, King B, Boudreau C, et al. Smokers’ beliefs about the relative safety of other tobacco products: findings from the ITC Collaboration. Nicotine Tob Res 2007;9:1033–42. 162. Pederson LL, Nelson DE. Literature review and summary of perceptions, attitudes, beliefs, and marketing of potentially reduced exposure products: communication implications. Nicotine Tob Res 2007;9:525–34. 163. O’Connor RJ, Norton KJ, Bansal-Traves M, Mahoney MC, Cummings KM, Borland R. US smokers’ reactions to a brief trial of oral nicotine products. Harm Reduction J 2011;8:1.
157
164. Tomar SL, Alpert HR, Connolly GN. Patterns of dual use of cigarettes and smokeless tobacco among US males: findings from national surveys. Tob Control 2010;19:104–9. 165. McClave-Regan AK, Berkowitz J. Smokers who are also using smokeless tobacco products in the US: a national assessment of characteristics, behaviours and beliefs of “dual users”. Tob Control 2011;20:239–42. 166. Schwartz JL, Brunnemann KD, Adami AJ, Panda S, Gordon SC, Hoffmann D, et al. Brand specific responses to smokeless tobacco in a rat lip canal model. J Oral Pathol Med 2010;39:453–9. 167. Popova L, Ling PM. Alternative tobacco product use and smoking cessation: a national study. Am J Public Health 2013;103:923–30. 168. Lund KE, McNeill A, Scheffels J. The use of snus for quitting smoking compared with medicinal products. Nicotine Tob Res 2010;12:817–22. 169. Levy DT, Mumford EA, Cummings KM, Gilpin EA, Giovino G, Hyland A, et al. The relative risks of a low-nitrosamine smokeless tobacco product compared with smoking cigarettes: estimates of a panel of experts. Cancer Epidemiol Biomarkers Prev 2004;13:2035–42. 170. Levy DT, Mumford EA, Cummings KM, Gilpin EA, Giovino GA, Hyland A, et al. The potential impact of a low-nitrosamine smokeless tobacco product on cigarette smoking in the United States: Estimates of a panel of experts. Addict Behav 2006;31:1190–200. 171. Hatsukami DK, Lemmonds C, Tomar SL. Smokeless tobacco use: harm reduction or induction approach? Prev Med 2004;38:309–17. 172. Bedi R, Scully C. Tobacco control—debate on harm reduction enters new phase as India implements public smoking ban. Lancet Oncol 2008;9:1122–3. 173. Ayo-Yusuf OA, Burns DM. The complexity of “harm reduction” with smokeless tobacco as an approach to tobacco control in low-income and middle-income countries. Tob Control 2012;21:245–51. 174. Benowitz NL. Smokeless tobacco as a nicotine delivery device: harm or harm reduction? Clin Pharmacol Ther 2011;90:491–3. 175. McNeill A, Hammond D, Gartner C. Whither tobacco product regulation? Tob Control 2012;21:221–6. 176. Parascandola M, Augustson E, O’Connell ME, Marcus S. Consumer awareness and attitudes related to new potential reduced-exposure tobacco product brands. Nicotine Tob Res 2009;11:886–95. 177. Kotnowski K, Hammond D. The impact of cigarette pack shape, size and opening: evidence from tobacco company documents. Addiction 2013;108:1658–68. 178. Tomar SL. Trends and patterns of tobacco use in the United States. Am J Med Sci 2003;326:248–54. 179. Declaration. First International Conference on Waterpipe Tobacco Smoking: Building Evidence for Intervention and Policy. Abu Dhabi: American University of Beirut, NYU Abu Dhabi; 2013.
158
180. Borrelli B, Novak SP. Nurses’ knowledge about the risk of light cigarettes and other tobacco “harm reduction” strategies. Nicotine Tob Res 2007;9:653–61. 181. Ahmad S, Billimek J. Estimating the health impacts of tobacco harm reduction policies: a simulation modeling approach. Risk Anal 2005;24:801–12.
Appendix. Questionnaire on new tobacco products, including products with potentially “modified risk” This questionnaire has been prepared in the context of a background paper for the 7th Meeting of WHO TobReg, entitled “Research and monitoring the evolution of new tobacco products, including products with potentially “modified risks”. This assignment has been commissioned by WHO Tobacco Free Initiative. One of the objectives of the paper is to provide an update on regional and country level activity including, but not limited to, availability, policy and regulation of contents, sale, advertisement and promotion. To this purpose, we kindly ask you to complete the questionnaire below. Any information you provide will be helpful for our inventory, and enable evidence-based future regulation of these products where necessary. If you cannot or do not want to answer all these questions, leave them open. Please indicate if you want (part of) your information to be treated confidentially. We welcome any other information regarding these issues that is not covered by the questions asked. We are looking for information on products that contain tobacco and meet one or more of the following criteria: • • • • Product is NOT just another variation or flavor of a traditional/regular cigarette, cigar, pipe tobacco, roll-your-own, or oral tobacco Product contains new technology and/or is marketed as a reduced harm product Product type has been on the market for less than fifteen years (for example dissolvable tobacco), with an emphasis on the last few years. Product type has been on the market for a longer time, but market share increases in areas where it was not used traditionally (for example waterpipe and snus)
159
Examples of products we are interested in: • • • • Chewing tobacco called “Thunder”. It is a strongly flavoured tobacco paste filled into round plastic tins, manufactured by V2 Tobacco, Denmark. “Dutch Magic”. This is a cigarette that contains virtually no nicotine in tobacco, but average level of tar (not a “light” cigarette). Dissolvable tobacco. Products considered/promoted as “reduced harm”, for example low-nitrosamine cigarettes.
Questionnaire: General Country Contact person Contact information (phone or email) Which new or modified tobacco products have come to your attention in the last few years, in shops, via internet, news, request for license, or otherwise? Per product, please answer the following questions. Kindly provide references to sources that document this information, if available. E.g. Internet sources with examples of advertisements or discussions, reports on market shares. Product description: 1. Brand name (e.g. “Thunder”) 2. Manufacturer (e.g. V2 Tobacco, Denmark) 3. Product type as indicated by manufacturer (e.g. “chewing tobacco”) 4. Description (e.g. a strongly flavoured tobacco paste) 5. Package (e.g. filled into round plastic tins, containing 37g) 6. Contents and emissions as indicated on package or from other sources (e.g. ingredient lists, chemical analysis)
160
7. Pictures of product, if available, or link to internet site 8. Any other information Policy and regulation in your country 9. How are these products regulated in your country? 10. Are there regulations on contents and emissions of this specific product? 11. Any other information Market 12. Are they popular? 13. Do you know their market share? 14. Do specific groups use them? E.g. young people, women? 15. Any other information Promotion 16. What is the promotion strategy? 17. Are there specific target groups? 18. How is the product advertised? Do you have examples from e.g. internet? 19. Any other information Any other remarks
161
162
Annex 2
Role of ammonia in delivery of free nicotine: recent work and analytical challenges
C.V. Watson, Research Chemist, Tobacco Products Laboratory, Tobacco & Volatiles Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
Introduction Recent publications on nicotine transfer to smoke Recent publications on nicotine uptake Current role of ammonia technology References
Introduction While ammonia occurs naturally at relatively low levels in tobacco leaves, the tobacco industry often adds ammonia for various reasons. From a public health perspective, the most significant reason for adding ammonia is to increase the rate of delivery of nicotine to the brain. Unprotonated, “free-base” nicotine is more lipophilic than protonated nicotine and can therefore be absorbed more quickly. It has been reported that ammonia is responsible for the pH shift required to deprotonate a portion of the nicotine molecule, which can then be perceived more quickly by smokers, a phenomenon known as “impact” (1). Publically, the tobacco industry denies this, although numerous internal documents refer to the “impact”, “strength” and “kick” of smoke. The Tobacco Master Settlement Agreement of 1998 provided the public health community with a rich source of information on the history of ammonia technology from the tobacco industry’s internal documents. A simple search of these documents brought to light dozens of references to the “discovery” of ammonia technology and how it was extensively researched and tested on panels of smokers to derive subjective feedback on sensory elements such as taste and “impact.” Philip Morris appears to have “discovered” ammonia technology in the 1960s while attempting to engineer a better reconstituted tobacco sheet. At the time, Philip Morris was the smallest of the four largest cigarette manufacturers and was struggling to reduce costs. They seized on the idea of using 100% of the tobacco lamina (rather than the normal 80%) by taking
163
the scraps, ribs, stems and “fines” and making a tobacco sheet with band cast technology (similar to older paper making techniques). To add mechanical strength to the sheet, diammonium phosphate was added to break down the calcium ion bridges found in protopectins in the leaf and to bind the calcium to phosphate so that the bridges could not immediately re-form (2). The free pectin then became available to re-link, giving strength to the new sheet, or to form complexes with other molecules, like nicotine. Philip Morris scientists also discovered that the addition of diammonium hydrogen phosphate to reconstituted tobacco sheets gave the final product much better sensory “impact” and taste. At the time, Philip Morris did not know exactly why the impact was improved, but they quickly realized its importance and capitalized on this technology. The new, improved smoke flavour, the higher impact and a massive marketing campaign centred on the “Marlboro Man” quickly made Marlboro the top selling cigarette brand in the USA (3). Competing manufacturers scrambled to reverse-engineer the Marlboro cigarette in order to understand its sudden rise in popularity. In 1973, RJ Reynolds concluded that the free nicotine content correlates most closely with share performance (4). After extensive research, British American Tobacco concluded that the band-cast reconstituted tobacco sheet produced with ammonia technology was the “heart and soul” of the Marlboro cigarette (3, 5). Continued use of a product known to be responsible for hundreds of thousands of deaths annually is a major concern for the public health community. The main explanation for the habitual use of cigarettes is the addictive potential of nicotine. As reported by Ashley et al. (6), two steps are involved in nicotine delivery: transfer of nicotine from the filler to smoke and uptake of nicotine from the smoke by the user. The role of ammonia in these steps has been addressed in a number of studies, some funded by Philip Morris. The following text discusses concern about the analysis of these studies and a discussion of the difficulty for researchers of elucidating the role of ammonia in pH manipulation and the subsequent impact on the delivery of free nicotine. Recent publications on nicotine transfer to smoke Although nicotine is a natural component of tobacco plants, the levels in the leaves, the amount transferred to cigarette smoke and the amount available as the free base can be closely controlled, as indicated in most of the industry documents cited. In tobacco leaves and cured tobacco filler, most nicotine is in the non-volatile, protonated salt form; however, a slight shift in pH can cause deprotonation of a large portion, making it more volatile. The volatile form is thought to be more readily bioavailable because it is lipophilic, allowing more rapid penetration into lung membranes, and because it is more rapidly available than nicotine diffusing from the particulate phase (7, 8). Industry
164
documents indicate that only a small amount of free nicotine is needed to have a favourable sensory effect; too much free nicotine due to a higher pH would make the smoke “harsher” and difficult to inhale (9, 10). During production of reconstituted sheets, pectins can be freed from protopectins by diammonium phosphate and can form a complex with nicotine that decomposes at temperatures more favourable to smoking, thereby increasing the efficiency with which nicotine is transferred to smoke. Increasing the temperature also increases the free nicotine levels in smoke, as hydrolysis of nicotine is temperature-dependent (11, 12). Seeman and Carchman (13) reported that the temperature in a burning cigarette is more than enough to volatilize nicotine and its salts. If nicotine present in the reconstituted tobacco sheets forms stable complexes with pectins, thus increasing the heat required to evaporate nicotine, these complexes remain on the sheet longer and are thereby exposed to much higher temperatures as the burning zone approaches, which could increase the fraction of free-base nicotine in the smoke. Callicutt et al. (14) studied nicotine transfer efficiency in test cigarettes containing various levels of ammonia. An interesting aspect of this study is the ability of the investigators to design and manufacture cigarettes that differed only in their ammonia content; however, there are questions about the test cigarettes analysed. Of the four test cigarettes produced, one that was supposedly additive-free still contained about 1.7 mg/g of “soluble ammonia”; this was acknowledged but not adequately explained by the authors. Although tobacco type, agricultural practices and processing differences can result in differences in ammonia content, this concentration appears to be high for an “additive-free” cigarette. No information was provided about use of a reconstituted tobacco sheet in making the additive-free cigarette; only the lack of ammonia-forming ingredients was mentioned. Reconstituted tobacco sheets can be made without these chemicals, although industry research indicates that they are more difficult to produce and less pleasant for smokers (15). As research cigarettes are not meant for human consumption, this would not be a concern. The presence of a reconstituted tobacco sheet potentially containing nicotine–pectin complexes could shift the amount of free-base nicotine to the levels smokers perceive as “strength” or “impact”. Callicutt et al. (14) found no significant difference in nicotine transfer among the cigarettes analysed. They stated that the main goal of the study was to examine the rate of total nicotine transfer according to ammonia level; however, the total nicotine content can remain constant while free nicotine delivery changes (14, 16). A greater concern is physical or chemical changes made to cigarettes that can change the level of free nicotine by changing the ratio of free to total nicotine. A limitation of this study is lack of data on free nicotine concentrations, although industry methods for analysing free nicotine have been available since the 1930s (17). A more meaningful question that could have been answered in this study is
165
the extent to which use of ammonia technology in the manufacture of reconstituted tobacco sheets alters the amount of free nicotine in smoke. Recent publications on nicotine uptake A study, funded by Philip Morris, was conducted on the pharmacokinetics of nicotine in relation to ammonia in mainstream smoke, which provides information on the usefulness of measuring ammonia in smoke. McKinney et al. (18) concluded that differences in ammonia levels in mainstream smoke do not affect the pharmacokinetics of nicotine. The procedure involved rapid arterial blood sampling from smokers receiving puffs of smoke through an inhalation device from one of two cigarettes, delivering 10 or 19 µg/cigarette of ammonia to the smoke. Unpublished data from the US Centers for Disease Control and Prevention on measures of ammonia in mainstream smoke particulate and vapour phases suggest that the difference between brands containing 10 and 19 µg/cigarette is insignificant; a difference of 10 µg was even found between two brands of “light”, unmentholated cigarettes made by different manufacturers. Therefore, a statistically significant difference in the plasma nicotine concentration–time curve would not be expected between cigarettes delivering similar ammonia levels in smoke. The cigarettes designated as “low ammonia” also contained higher percentages of Burley tobacco and stems, which can increase the pH of smoke and therefore compensate for the slightly lower ammonia level (19, 20). Information on the levels of ammonia in the fillers would have been helpful for determining whether there were true differences between the two brands. The complex smoke inhalation system was not adequately described in terms of delivery to the smoker. Smoke can be diluted in a number of ways. First, there is no mention that ventilation holes were blocked, whereas unblocked ventilation holes do not accurately mimic human smoking. Secondly, according to the diagram, more clean air could have been introduced through the transducer, although the mechanics and requirement for this are not explained. Finally, loss of free-base nicotine and ammonia due to moisture accumulation in the tubing is not addressed. There has been some discussion of the significance of puff count. In the study of McKinney et al. (18), only the fourth puff from each cigarette was sampled, so that subjects may have been exposed to lower concentrations of free-base nicotine than those in the initial puffs (21). Industry documents indicate that excess ammonia imparts negative sensory affects to smokers, and most of the added ammonia is intended to react in various ways before or in the first few milliseconds of smoking (22–24). According to the Handbook for leaf blenders and product developers (16), ammonia reacts with known irritants, immediately reducing their effects. This ameliorating activity might also liberate more free nicotine by binding acids that could form salts with nicotine (25). The
166
cellulose acetate filter also effectively traps ammonia during smoking, and another large percentage is lost to side-stream smoke (26). Further, ammonia reacts immediately with irritants such as aldehydes in smoke, thereby reducing its harshness (23–25). Ammonia detected in smoke is probably the pyrolysis product of nitrogenous compounds such as amino acids and nicotine rather than the result of direct migration of added ammonia from the filler to smoke. Little free ammonia is available for analysis, as indicated by the low values for ammonia in smoke; therefore, ammonia in mainstream smoke is a poor indicator of smoke pH and of the delivery of free nicotine. This study would have been more informative if the rate of change in nicotine concentration in arterial blood had been compared with the levels of free nicotine and smoke pH. The total amount of nicotine absorbed is less pertinent than the rate of nicotine absorption, as the human body effectively absorbs most of the nicotine introduced by smoking. A study of nicotine absorption by van Amsterdam et al. (27) illustrates this point. Venous blood samples were taken from subjects who smoked two test cigarettes with different measured levels of ammonia in the filler (0.89 and 3.43 mg/g). The first sample was taken 2.5 min after the last puff. As expected, no difference was seen between the two brands in “nicotine exposure”, as a sample drawn 2.5 min after smoking would not reflect the rate of absorption of free-base nicotine. Rose et al. (28), in a study of nicotine accumulation in the brain, found that nicotine can reach the brain as little as 7 s after entry into the mouth. Henningfield et al. (29) emphasized that the most important parameter in reinforcing nicotine dependence is the uptake rate and the concentration spike within 10–15 s of the first puff, not the total nicotine absorbed. Furthermore, while there was a large difference in the ammonia content of the two brands used in the study of van Amsterdam et al., levels of 1 mg/g are found in “full-flavour” mentholated cigarettes, which is still considered a significant amount of detectable ammonia. As in the study by Callicutt et al. (14), the level of ammonia in the test cigarettes does not appear to have been below 0.9 mg/g, which is about that found in some mentholated cigarettes. The significance of this amount of ammonia in filler is currently unknown. In the paper by van Amsterdam et al. (27), there was no mention of the presence of reconstituted tobacco sheet in the blend, although this is one of the main sources of ammonia and could affect the efficiency of transfer of free nicotine. A major limitation for independent researchers wishing to compare different cigarettes is the inability to produce test cigarettes that differ only in the ammonia content of the tobacco. A more interesting comparison would be between a fully ammoniated cigarette containing reconstituted sheets and an “additive-free” brand with a low Burley tobacco content, slightly acidic smoke and no reconstituted tobacco sheet.
167
Current role of ammonia technology The timeline of ammonia technology is well known. What was once considered one of the “greatest triumphs in the history of modern drug design” (3) can now be considered a legacy technology. The question of the current role of ammonia technology in cigarette design remains. The available industry research on ammonia is at least 20 years old and does not reflect chemical and biotechnological advances for manipulating and controlling smoke pH and free nicotine delivery. Further, the smoke aerosol is a complex mixture of chemicals in a dynamic state. Thus, attempting to correlate ammonia in filler or smoke directly with smoke pH or free nicotine delivery, while a logical, necessary start, vastly oversimplifies the smoke matrix. Ammonia is only one of many compounds that could deprotonate nicotine and form Maillard reaction products, and the industry has had ample time to devise, refine and test alternative technologies and approaches. Aside from ammonia–diammonium phosphate alternatives, a myriad of bases are present in smoke that can create an alkaline environment favourable to the formation of free nicotine. Many other means of manipulation are also possible: the levels of certain constituents in leaves can be altered by biotechnological methods; additives and changes in the design of cigarette filters can be used to create an alkaline smoke or to change the particle size to enhance “off-gassing” of free-base nicotine from the particle; bronchodilators and menthol can be used to enhance nicotine uptake by smokers; and physical characteristics like paper porosity and filter ventilation can be altered to change smoke chemistry. By the late 1980s, a ban on use of diammonium phosphate in some countries led the tobacco industry to investigate alternative means of making diammonium phosphate-free sheets that still delivered the sugar–diammonium phosphate reaction products to smoke. Brown & Williamson investigated use of solid pineapple extract, caramel and high-maltose corn syrup as substitutes for diammonium phosphate in reconstituted sheets. They found that use of sheets without diammonium phosphate “yielded cigarettes with less irritation, more body, and better tobacco taste” than control samples (15, 30). Industry documents also make reference to the urea–urease system, indicating that urea can dramatically increase smoke pH and the extractable nicotine content and has the added benefit of remaining chemically inert until the cigarette is smoked (31). Urea is, however, difficult to analyse, and urease breaks down urea into ammonia and carbon dioxide in the presence of water. If water-based extraction is used during analysis, urea in filler is analysed as ammonia. In another industry document, Johnson (2) stated “you will never find all the urea you added to tobacco”; this was not explained but might indicate that urea reacts fully once in the system and is therefore not found.
168
In 1977, the Lorillard Tobacco Company investigated whether addition of inorganic cations, such as potassium and calcium, would raise the smoke pH and increase impact (32). The report stated that, as these compounds occur naturally in tobacco, extensive toxicity studies would not be necessary. Another industry study showed that treating tobacco with potassium carbonate raised the smoke pH without increasing the level of total volatile bases, as ammonia does (33). The potassium ion is a stronger base than ammonia, and potassium and calcium are present in popular brands in the USA. In Germany, where diammonium phosphate is banned, organic or inorganic compounds that can decompose thermally to bases, like calcium carbonate, are used to enhance nicotine delivery (34). Alkali metals like potassium and calcium do not have to be added to tobacco blends, as the levels in leaves can be easily manipulated with fertilizers or by curing practices. Naturally occurring compounds that are used as additives are difficult to analyse, as the levels present in untreated, unmodified tobacco are unknown, and there is no reliable way to differentiate between natural and added levels without a blank tobacco matrix. In a discussion of nicotine delivery at RJ Reynolds (35), industry scientists expressed concern about a potential “severe ingredients issue for the cigarette industry” and discussed achieving the same smoothness of Philip Morris cigarettes by using chemicals that occur naturally in tobacco in order to avoid having to reformulate products in order to meet possible future regulations. One way of obtaining desirable elements in a blend without additives (particularly those that are banned in some countries) is manipulating the tobacco leaf. References to genetic modification in industry documents include production of a high-nicotine Burley tobacco by somaclonal variation and hybrid sorting (36) and a high-nicotine flue-cured tobacco (37–39). A genetically modified, virtually nicotine-free tobacco species was engineered for use in the Quest cigarette (40). A “worldwide biotech assessment” by Philip Morris (41) identified several areas of interest, including improving flavour and quality, but there was no discussion of whether the improvements were meant to replace additives such as ammonia by increasing the basic properties of leaves. A report from the Philip Morris Tobacco Biotechnology Working Group in 1999 addressed the possibility of increasing the level of reducing sugars in tobacco by enzymatic modification (42). In 2003, Philip Morris provided significant financial support to researchers at North Carolina State University for mapping the tobacco genome. In response to a media inquiry, they claimed that the purpose of the research was to reduce harmful constituents of tobacco (43). It stands to reason that, through either genetic engineering or enzymatic modification, novel tobaccos could be engineered to achieve target deliveries and ensure the delicate balance of taste and “impact” necessary to keep smokers using the product without the use of additives that might be problematic in a regulated market.
169
The chemistry of cigarette smoke is complex. The low level of ammonia present in the smoke of most modern brands sold in the USA could not alone bring about the pH shift necessary to create the alkaline environment most favourable to free-nicotine formation. Hundreds of bases have been identified in tobacco smoke, many of which are nitrogen heterocyclic compounds, which could be responsible for tobacco flavours (44, 45). In older industry documents, ammonia in smoke was measured separately and included in a measure of total volatile bases. These bases are listed as free ammonia, nicotine, pyridine, alkaloids, pyrazines, pyrrole derivatives and volatile amines that may form Schiff bases with aldehydes present in smoke, which are then further pyrolysed to “basic nitrogen compounds which contribute to the alkalinity of the smoke” (46). The documents state that a measure of total volatile bases gives the most “linear plot with smoke pH, with total alkaloid and total nitrogen also showing strong correlations” (47). Interestingly, pyrolysis of deoxyfructazines formed in the diammonium phosphate–sugar reaction produces several of the pyridines and pyrazines present in smoke (2, 48). Amino acids, which are present at high levels in Burley tobacco, can also react with sugars to create similar, weakly basic compounds (49, 50). Nicotine, one of the most abundant compounds in tobacco leaves, can decompose thermally to ammonia, amines and pyridines. In a review from Philip Morris (51) of the effects of filters on smoke chemistry, smoke was characterized in terms of the total basic fraction (pyrazines, pyridines and alkaloids) and the total acidic fraction (organic acids, phenyl acids, phenolic acids and fatty acids), the larger fraction being basic. Sufficient compounds are therefore present, in addition to ammonia, to create an alkaline smoke, and ammonia should not be considered the sole contributor to smoke alkalinity. Ammonia technology is nevertheless still largely responsible, albeit indirectly, for a large portion of the weak bases present in tobacco smoke. Several other ways of manipulating free nicotine delivery and uptake are described in industry documents. Cocoa and menthol, two common cigarette additives, have been implicated as potential bronchodilators, thereby increasing inhalation depth and volume and allowing better nicotine absorption (52). Filter additives such as calcium carbonate and sodium carbonate can increase the pH of smoke, possibly eliminating the need to add bases to tobacco filler (53). Increased paper porosity and filter ventilation could also influence smoke particle size or raise the smoke pH. Highly ventilated cigarettes could have a lower aerosol particle density so that their normal coalescence rate is slower (the particles stay smaller longer, with more surface area to facilitate “off-gassing”). Another potential mechanism by which filter ventilation plays an important role is that the air drawn through filter ventilation holes acts as a “drying gas”. A reduction in the water content of aerosol particles effectively increases pH, thereby favouring formation of free-base nicotine in the gas
170
phase. Differences in blends, the use of expanded tobaccos and the position of the tobacco leaf on the stalk can all alter smoke pH and chemistry, without chemical additives (19, 46). While ammonia technology may have shown the tobacco industry that nicotine delivery can be manipulated, the industry has had 50 years to study, design and perfect other techniques for controlling the dose of nicotine while maintaining a product “pleasing” to the “dedicated” smoker while still appealing to the novice smoker. Ammonia addition can be viewed as an older technology, still used in some products and in the manufacture of reconstituted sheet, but it does not appear to be a necessary design factor in modern US blended cigarettes. Many variables affect free nicotine delivery, obviating a direct correlation between ammonia and free nicotine. Questions remain regarding the role of ammonia and ammonia alternatives in free nicotine delivery, the most important being whether ammonia affects the alkalinity of the smoke, thereby affecting free nicotine delivery. Does the presence of the reconstituted tobacco sheet without use of ammonia technology affect free nicotine delivery? And do differences in the rate of nicotine uptake within the first 5–20 s reflect differences in free nicotine delivery? We consider these to be some the most important questions, and none of the studies conducted to date has adequately addressed these critical research gaps.
References 1. 2. 3. Schori TR. Free nicotine: its implications on smoke impact. Bates: 542001986– 96; 1979 (http://legacy.library.ucsf.edu/tid/rlk46b00). Johnson R. Ammonia technology conference minutes. Bates: 508104012–164; 1989 (http://legacy.library.ucsf.edu/tid/cfl36b00). Stevenson T, Proctor RN. The secret and soul of Marlboro: Phillip Morris and the origins, spread, and denial of nicotine freebasing. Am J Public Health 2008;98:1184–94. Blevins RA. Letter: Free nicotine. Bates: 500917503; 1973 (http://legacy.library. ucsf.edu/tid/gnq46b00). Backhurst JD. A relation between “strength” of a cigarette and the “extractable nicotine” in the smoke. Bates: 620364222; 1965 (http://legacy.library.ucsf.edu/ tid/kgt83f00). Ashley DL, Pankow JF, Tavakoli AD, Watson CH. Approaches, challenges, and experience in assessing free nicotine. In: Henningfield JE, London ED, Pogun S, editors. Nicotine psychopharmacology (Handbook of Experimental Pharmacology, No. 192). Berlin: Springer-Verlag; 2009:437–56. RJ Reynolds. Nicotine toxicity. Bates: 511194087–114; 1977 (http://legacy. library.ucsf.edu/tid/ggg53d00).
4. 5.
6.
7.
171
8. 9.
Reininghaus W. Bioavailability of nicotine. Bates: 3990473388–93; 1994 (http:// legacy.library.ucsf.edu/tid/jgn13j00). Ireland MS. Research proposal—development of assay for free nicotine. Bates: 00044522–3; 1976 (http://legacy.library.ucsf.edu/tid/nts76b00).
10. Larson TM, Morgan JP. Application of free nicotine to cigarette tobacco and the delivery of that nicotine in the cigarette smoke. Bates: 00781406; 1976 (http:// legacy.library.ucsf.edu/tid/pts76b00). 11. Riehl TF. Project SHIP main technical conclusions 840400–841100. Bates: 650554484–8; 1984 (http://legacy.library.ucsf.edu/tid/gxq23f00). 12. Philip Morris. Bates: 2060554039; 1999 (http://legacy.library.ucsf.edu/tid/ iqf13e00). 13. Seeman JI, Carchman RA. The possible role of ammonia toxicity on the exposure, deposition, retention, and the bioavailability of nicotine during smoking. Food Chem Toxicol 2008;46:1863–81. 14. Callicutt CH, Cox RH, Hsu F, Kinser RD, Laffoon SW, Lee PN, et al. The role of ammonia in the transfer of nicotine from tobacco to mainstream smoke. Regul Toxicol Pharmacol 2006;46: 1–17. 15. Tang JY. DAP-free recon development update. Bates: 508102219–224; 1991 (http://legacy.library.ucsf.edu/tid/dtm51f00). 16. Aulbach PL, Black RR, Chakraborty BB, Diesing AC, Gonterman RA, Johnson RR, et al. Root technology: a handbook for leaf blenders and product developers. Louisville, Kentucky: Brown & Williamson. Bates: USX47046–105; 1991 (http:// legacy.library.ucsf.edu/tid/nqz36b00). 17. Vickery HB, Pucher GW. The determination of “free nicotine” in tobacco: the apparent dissociation constants of nicotine. J Biol Chem 1929;84(1): 233–41. 18. McKinney DL, Gogova M, Davies BD, Ramakrishnan V, Fisher K, Carter WH. Evaluation of the effect of ammonia on nicotine pharmacokinetics using rapid arterial sampling. Nicotine Tob Res 2012;14:586–95. 19. Hellams RD. pH determination of mainstream cigarette smoke. Bates: 2050871031; 1984 (http://legacy.library.ucsf.edu/tid/jgu46b00). 20. British American Tobacco. How does pH affect transfer of nicotine to smoke? Bates: 566630379–83; 1995 (http://legacy.library.ucsf.edu/tid/ajs46b00). 21. Pankow JF, Tavakoli AD, Luo W, Isabelle LM. Percent free base nicotine in the tobacco smoke particulate matter of selected commercial and reference cigarettes. Chem Res Toxicol 2003;16(8): 1014–8. 22. Routh WE. Ammonia treatment of tobacco. Bates: 00044858–79; 1977 (http:// legacy.library.ucsf.edu/tid/jtm99d00). 23. Johnson R (1984) The unique differences of Phillip Morris cigarette brands— R&D-B016-84. Bates: 103281081–112; 1984 (http://legacy.library.ucsf.edu/tid/ ton66b00). 24. Crellin RA (1985) Project Ship (examination of branded and experimental products from the USA). Bates: 570316962 (http://legacy.library.ucsf.edu/tid/pls46b00).
172
25. Christopher FH Jr (1978) Free nicotine/ammonia treatment of tobacco. Bates: 505197081 (http://legacy.library.ucsf.edu/tid/cru46b00). 26. Kusama M, Matsuki T, Sakuma H, Sugawara S, Yamaguchi K. The distribution of cigarette smoke components between mainstream and sidestream smoke II. Bases. Bates: 501523990–4006; 1983 (http://legacy.library.ucsf.edu/tid/ kpm77c00). 27. van Amsterdam J, Sleijffers A, van Spiegel P, Blom R, Witte M, van de Kassteele J, et al. Effect of ammonia in cigarette tobacco on nicotine absorption in human smokers. Food Chem Toxicol 2011;49:3025–30. 28. Rose JE, Mukhin AG, Lokitz SJ, Turkington TG, Herskovic J, Behm FM, et al. Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine. Proc Natl Acad Sci U S A 2010;107:5190–5. 29. Henningfield JE, Stapleton JM, Benowitz NL, Grayson RF, London ED. Higher levels of nicotine in arterial than in venous blood after cigarette smoking. Drug Alcohol Depend 1993;33(1): 23–9. 30. Alford ED, Hsieh TC. A major sugar/ammonia reaction product in Marlboro 85’s. Bates: 510001069–79; 1983 (http://legacy.library.ucsf.edu/tid/ylh23f00). 31. Newton P, Johnson R. Urea development. Bates: 620136145–9; 1971 (http:// legacy.library.ucsf.edu/tid/gmd43f00). 32. Ihrig AM. Inorganic additives for the improvement of tobacco. Bates: 00382055– 62; 1977 (http://legacy.library.ucsf.edu/tid/fku61e00). 33. Glock E. Leaf services monthly report for June: increasing nicotine transfer in smoke. Bates: 514804804–9; 1980 (http://legacy.library.ucsf.edu/tid/tja87h00). 34. Wigand JS. Additives, cigarette design and tobacco product regulation. A report to World Health Organization Tobacco Free Initiative Tobacco Product Regualtion Group. Bates: 3990512671–715; 2006 (http://legacy.library.ucsf. edu/tid/ccj13j00). 35. RJ Reynolds. Regarding means to achieve nicotine balance and deliveries. Bates: 508408649–770; 1992 (http://legacy.library.ucsf.edu/tid/ikv46b00). 36. Brown & Williamson. High nicotine Burley flavor development. Bates: 589100515–9; 1996 (http://legacy.library.ucsf.edu/tid/ewm41f00/). 37. Brown & Williamson. Y1 product. Bates: 661071395A–6 (http://legacy.library. ucsf.edu/tid/uql66b00). 38. Brown & Williamson. The Y1 story. Bates: 682727985–90 (http://legacy.library. ucsf.edu/tid/eqv70f00). 39. Fisher PR. Y1 product development. Bates: 620017189–91; 1990 (http://legacy. library.ucsf.edu/tid/chf93f00). 40. Lightner JG. Cigarette information highlights: Quest Menthol Lights. Bates: 3039591093; 2004 (http://legacy.library.ucsf.edu/tid/uko91g00). 41. Gadani F, Rossi L. Worldwide biotechnology assessment: inventory of research activities. Bates: 2073337017–9; 1997 (http://legacy.library.ucsf.edu/tid/wyz27d00).
173
42. Philip Morris. Final report tobacco biotechnology: a worldwide technology assessment. Bates: 2065359566–9631; 1999 (http://legacy.library.ucsf.edu/tid/ itb29h00). 43. Philip Morris. Response to media inquiry—genome technology 2.271 RWL.doc. Bates: 3008849132–4; 2004 (http://legacy.library.ucsf.edu/tid/vde30i00). 44. Schmeltz I, Stedman RL, Chamberlain WJ, Burdick B. Composition studies on tobacco. XX. Bases of cigarette smoke. Tob Sci 1964;8:82–91. 45. Heckman RA, Best FW. An investigation of the lipophilic bases of cigarette smoke condensate. Bates: 620398463–70; 1981 (http://legacy.library.ucsf.edu/ tid/xvz90c00). 46. Ihrig AM. pH of particulate phase. Bates: 87644270–81; 1973 (http://legacy. library.ucsf.edu/tid/iwr46b00). 47. Creighton DE. The significance of pH in tobacco and tobacco smoke. Bates: 500104402; 1988 (http://legacy.library.ucsf.edu/tid/edk86b00). 48. Anonymous. Ammonia process comparisons fructose conversion vs. tobacco temperature. Bates: 681915855 (http://legacy.library.ucsf.edu/tid/pek46b00). 49. Wang MX. Analytical results of the experimental flavor samples. Bates: 583150454–5; 1986 (http://legacy.library.ucsf.edu/tid/qar03f00). 50. Evans RJ, Nimlos MR. Kinetics and mechanisms of the pyrolysis of amino acids. Bates: 3003669136; 2002 (http://legacy.library.ucsf.edu/tid/fnh95g00). 51. Lin SS. Basic flavor investigation low tar / high flavor literature review. Bates: 2050878148–90; 1990 (http://legacy.library.ucsf.edu/tid/wgu46b00). 52. Ferris Wayne G, Connolly GN. Application, function, and effects of menthol in cigarettes: a survey of tobacco industry documents. Nicotine Tob Res 2004;6(Suppl 1):S43–54. 53. Irwin WDE. Comment by W.D.E. Irwin on Handbook for leaf blenders and product developers. Bates: 400820196–7; 1983 (http://legacy.library.ucsf.edu/ tid/ogc54a99).
174
Annex 3
Reducing the dependence potential of manufactured cigarettes by reducing their nicotine content to levels that cannot cause or sustain addiction
G. Ferris Wayne, WHO Consultant
Introduction Tobacco addictiveness model Nicotine addiction Individual variation in response to nicotine Delivery of nicotine from tobacco Dual reinforcement model of addiction Drug expectancy Social and contextual factors Summary Establishing a threshold for addiction Nicotine self-administration Acquisition of nicotine dependence Reinforcing effects of low-nicotine cigarettes Addiction threshold versus reinforcement threshold Threshold for conditioned stimulus Summary Feasibility of reducing nicotine Cigarette nicotine delivery Methods for reducing nicotine in tobacco Denicotinized or reduced-nicotine cigarettes Free-base nicotine in low-delivery cigarettes Products that lead to compensatory smoking Product formulation and approaches to nicotine reduction Summary Potential behavioural and population outcomes Potential effects on cigarette consumption Potential effects on topography and smoking behaviour Potential effects on abstinence and quitting Potential effects on acquisition of cigarette use Potential unintended behavioural consequences Potential population differences Potential health effects Potential illicit sales of nicotine-containing cigarettes Models of population effects
175
Summary Policy approaches to nicotine reduction Comprehensive regulation of nicotine Performance standards Gradual versus sudden reduction Alternative forms of nicotine Cessation and behavioural treatment Surveillance Consumer education and beliefs Public support for a reduced nicotine policy Unintended market consequences Summary Conclusions Recommendations References
Introduction Nearly two decades ago, Benowitz and Henningfield (1) proposed a gradual reduction of the nicotine content of cigarettes as a strategy for harm reduction. A number of health scientists have since concluded that such an approach could have a significant positive impact on public health (2–8). The goals of a nicotine reduction policy are to reduce the pharmacological addiction of smokers, making it easier for them to quit or encouraging them to change to less harmful sources of nicotine, and also to prevent novice smokers from moving from experimental or occasional smoking to cigarette addiction (2, 6). This strategy is consistent with Article 9 of the WHO Framework Convention on Tobacco Control (FCTC), which calls for guidelines for regulating the contents and emissions of tobacco products (9, 10). A nicotine reduction strategy is based on the assumption that it is nicotine that is primarily responsible for cigarette use and that a threshold level of nicotine can be identified, below which the acquisition and maintenance of cigarette dependence will be substantially reduced (2). Both theoretical and practical questions must be addressed in evaluating the probable outcomes of this approach: the role of nicotine in initiating and sustaining tobacco addiction, the amount of nicotine necessary for addiction, differences associated with the chemical form or mechanism of delivery of nicotine, variation in the response to nicotine among individuals or vulnerable populations such as children and people with mental illness, processes for reducing nicotine in tobacco and their potential effects, behavioural responses to reduced-nicotine cigarettes (such as compensatory or increased smoking by nicotine-addicted smokers) and the relative toxicity of reduced-nicotine cigarettes.
176
An early obstacle to evaluating the potential outcomes of a nicotine reduction strategy was the lack of a scientific basis. For example, an initial concern was that reduced-nicotine products might increase the harmful effects of cigarette use as a result of more intense or more frequent smoking (11, 12). Recent clinical studies appear to address this concern, demonstrating substantial reductions in smoking and less exposure to toxins, with little compensation, even at very low doses of nicotine (13–15). In this annex, I review the state of the science with respect to tobacco and nicotine addiction, the concept of a threshold for nicotine addiction and the practical feasibility of reducing nicotine in cigarettes below the threshold for addiction. Environmental factors are also known to affect the adoption and use of tobacco products and would be likely to play a role in the effectiveness of a nicotine reduction strategy. The factors to be considered include the availability of alternative sources of nicotine, the extent of regulation of alternative products, the potential growth of illicit sales of high-nicotine cigarettes, the availability of treatment for dependence, education of smokers and potential smokers about use, withdrawal and treatment, and public support for regulation of nicotine. For example, barriers to access to less toxic nicotine delivery systems and treatment medications are likely to spur illicit sales or drive smokers to other potentially harmful tobacco products (16). In this annex, I review the anticipated population outcomes of a nicotine reduction strategy and policy approaches for supporting such a strategy and for minimizing any unintended or negative health consequences of nicotine reduction. The report by the Institute of Medicine in the USA, Clearing the smoke (17), provides a useful framework for assessing the harm of tobacco products due to both their toxicity and the factors that encourage experimentation and use (see also 5, 18). Cigarettes and other burnt tobacco are not only much more toxic than alternatives such as medicinal nicotine but also have unmatched potential for harm due to their greater availability, addictiveness and appeal. A nicotine reduction strategy could substantially reduce population harm, even if it did not reduce toxicity, by removing incentives to begin or continue use of these deadly products (5). In this annex, I assess the likelihood of such an outcome on the basis of the available scientific evidence and identify areas in which additional research is needed. Tobacco addictiveness model Early attempts to reduce the disease burden associated with tobacco smoking were based on reducing the smoke delivery from cigarette products, mainly by the introduction of filter ventilation to dilute the smoke and use of expanded tobacco and other product changes (19). However, smokers simply compensated for the reduced delivery by altering their smoking behaviour: puffing longer
177
and more frequently or increasing the number of cigarettes they smoked per day, maintaining their exposure to both nicotine and toxins (20, 21). Parascandola (22) observed that the failure of past attempts to reduce the harm of tobacco use was due to incomplete understanding by the public health community of the factors that control smoking behaviour and in particular the role of nicotine in driving that behaviour. A nicotine reduction strategy is based directly on the assumption that nicotine is the primary psychoactive drug in tobacco and is the key to continuing tobacco use. Scientific understanding of both nicotine addiction and tobacco use is evolving. Anticipating the consequences—both intended and unintended—of product regulation requires clear, complete understanding of dependence on nicotine and tobacco. Nicotine addiction
Nicotine is a highly addictive, potent drug, which has psychoactive rewarding effects at an acutely administered dose of < 1 mg (23). Low doses of nicotine stimulate the central and peripheral nervous systems and cause arousal, mood enhancement and increased heart rate or blood pressure; high doses may cause bradycardia, hypotension and depressed mental status. Nicotine improves motor reflexes and cognitive performance, including attention and memory (24). Tolerance to the behavioural and cardiovascular effects of nicotine develops rapidly with repeated exposure. Thus, the pharmacological basis of nicotine addiction is a combination of positive reinforcement (arousal, mood, performance) and avoidance of the withdrawal symptoms that occur in the absence of nicotine (23, 25). The addictive potential of a nicotine delivery system depends on its dosing mechanism, including the speed with which it delivers nicotine and the ease with which nicotine can be extracted (26, 27). Cigarettes are a particularly effective form of delivery. When an individual inhales smoke from a cigarette, nicotine from the tobacco is carried in smoke particles into the lungs, where it is rapidly absorbed and carried to the brain. Nicotine diffuses readily into brain tissue, where it binds to nicotinic cholinergic receptors. The gradual absence of nicotine after smoking results in subnormal release of dopamine and other neurotransmitters, which is experienced as malaise and inability to experience pleasure. Other symptoms of nicotine withdrawal include irritability, restlessness, anxiety, difficulty in concentrating, decreased heart rate, increased appetite and inability to sleep (23). Cigarette addiction is maintained by repeated behaviour. The first cigarette of the day produces a substantial pharmacological effect and enhanced mood; the next cigarettes cause accumulation of nicotine in the body, resulting in greater tolerance, and withdrawal symptoms become more pronounced between
178
successive cigarettes. Most smokers tend to absorb the same amount of nicotine each day and to adjust their smoking behaviour to compensate for changes in the availability of nicotine or in the rate of its elimination from the body in order to regulate their level of nicotine (23). Compulsion is a core feature of tobacco addiction; it is characterized by a craving to smoke that recurs after each cigarette (28). When compulsion is defined as including withdrawal symptoms, it has a sensitivity of 99% for identifying which novice smokers will progress to established smoking (29–31). Individual variation in response to nicotine
Most tobacco use begins in adolescence. While many young people try cigarette smoking, only 20–25% of those who try cigarettes become addicted adult smokers (32). Genetic vulnerability to nicotine dependence may explain tobacco use by some people. Studies of twins indicate > 50% heritability in the prevalence of cigarette smoking, the number of cigarettes smoked per day, the ability to quit smoking and the nature of the withdrawal symptoms experienced on quitting (33). Other risk factors for smoking include peer and parental influences, individual personality traits and conditions such as depression and anxiety (32). Early exposure to nicotine is associated with more severe dependence and increased smoking among adult smokers (1, 34–37). These results are corroborated by studies in animal models, in which exposure during the period corresponding to human adolescence resulted in higher levels of self-administration (38–44). These findings suggest that the developing brain is more susceptible to permanent changes due to nicotine that support addiction (23, 45). An approximately fourfold individual variation in the rate of metabolism of nicotine has been observed (45, 46). Women metabolize nicotine faster than men (23, 47), which may contribute to greater addiction. Women are also more sensitive to nicotine than men (48) and have more difficulty in quitting smoking (49–53). The smoking behaviour of women is more strongly influenced by conditioned cues and by negative affect, while men are more likely to smoke in response to pharmacological cues and to regulate their nicotine intake (54–57). Individuals with psychiatric and/or substance abuse disorders have much higher rates of nicotine dependence, smoke more cigarettes per day and have more difficulty in quitting (58–62). Nicotine may be used as a form of self-medication for some disorders (63), particularly schizophrenia, as nicotine can improve deficient sensory gating (64, 65), and depression, as nicotine may desensitize nicotinic receptors in a manner functionally similar to many
179
antidepressant drugs (66, 67). In addition, smoking (but not nicotine) inhibits brain monoamine oxidase, which could contribute to antidepressant activity (68). Smokers with mental illness constitute more than a third of all smokers and more than half of nicotine-dependent smokers (58, 69, 70). A subset of light or occasional smokers consume five or fewer cigarettes per day or non-daily and appear to smoke primarily for the positive reinforcing effects of nicotine (23) They often use cigarettes in association with specific activities, such as after meals or with alcohol, and less in response to negative affect; they may be more reactive to smoking cues (71). Although they experience minimal or no withdrawal symptoms, many of these occasional smokers have difficulty in quitting, suggesting a form of dependence distinct from that of daily smokers. Delivery of nicotine from tobacco
Tobacco smoke is a complex mixture of several thousand compounds (19, 26) that may contribute to a cigarette’s addictive properties either independently (72) or in combination with nicotine (73, 74). Nicotine in its unprotonated or free-base form is readily absorbed through the oral mucosa and upper respiratory tract, as occurs from smokeless tobacco products or cigars. When taken in this form, nicotine gives a stinging sensation or “bite” in the upper respiratory tract, which may be considered irritating or unpalatable. In cigarette smoke, however, a large percentage of nicotine remains in the protonated or bound form, in which it is more easily inhaled and carried deep into the respiratory tract. Bound nicotine is not absorbed as quickly or readily as unprotonated nicotine and does not provide the same sensory stimulus (26, 75). The aim of modern cigarette construction is to provide an ideal balance between the efficiency and palatability of nicotine delivery. For example, a high ammonia content can increase the proportion of unprotonated nicotine in cigarette smoke, allowing more rapid or efficient absorption of nicotine (76). Sugars and other additives may then be added to offset the harshness of unprotonated nicotine and facilitate deeper inhalation (26). The sensory characteristics (taste, aroma, tracheobronchial sensations) of tobacco smoke provide direct cues to the smoker, guiding smoking behaviour at the level of the individual puff (77, 78). The motor aspects of cigarette use (handling, puffing, inhaling) do not elicit significant satisfaction in smokers in the absence of sensory components, as indicated in studies with unlit cigarettes (79). Variations in sensory components, such as taste and impact, may, however, have significant effects on measures of smoking reward (77, 80). For example, attenuation of olfactory and taste cues diminishes both the
180
enjoyment and behaviourally reinforcing effects of cigarette smoke, particularly among female smokers (77, 81). Nicotine plays a central role in the sensory composition of cigarette smoke. Nicotine-containing cigarettes are consistently rated as stronger than denicotinized cigarettes in terms of perceived respiratory tract sensations (81, 82). Inhalation of nicotine aerosol has strong irritant effects (83), and even intravenous nicotine infusions can elicit respiratory tract sensations (27, 84). A balance of smoke constituents is necessary to offset the excessive harshness of nicotine and make tobacco smoke palatable. “Tar” is a common measure of the total particulates in smoke except nicotine, and the ratio of tar : nicotine has been found to be a key determinant of the overall harshness of smoke (77, 85). Other tobacco constituents may provide additional stimuli, either with or in place of nicotine (26). Menthol, which has strong sensory stimulant properties, is a common tobacco additive and has been used to compensate for reduced nicotine in products with extremely low delivery (86, 87). Menthol may also attenuate some of the irritant effects of nicotine by virtue of its local anaesthetic properties (88) and increase the permeability of biological membranes (89), which could influence nicotine absorption. Smoke components other than nicotine may have direct pharmacological effects on the brain or interact with the reinforcing effects of nicotine. Brody et al. (90) found significant occupancy of α4β2 nicotinic cholinergic receptors in individuals smoking denicotinized cigarettes, suggesting that, even in the absence of nicotine, tobacco smoke may have measurable pharmacological effects. Various minor tobacco alkaloids are reinforcing on their own (nornicotine) or by potentiating the effects of nicotine (anabasine, nornicotine, anatabine, cotinine and myosmine) (91, 92). Acetaldehyde is self-administered in animal models (72) and has been shown to potentiate the reinforcing effects of nicotine, especially in adolescent animals (73, 93–95). Harman and salsolinol are condensation products of acetaldehyde that inhibit monoamine oxidase (73), and they increase self-administration of nicotine substantially when given to rats (74, 96, 97), possibly by exerting antidepressant effects or by potentiating the reinforcing effects of nicotine by increasing the lifetime of neurotransmitters such as dopamine after their release by nicotine (98). Dual reinforcement model of addiction
Although the addictive properties of tobacco are often attributed exclusively to nicotine (99), nicotine alone, in the absence of tobacco, has not been shown conclusively to have reinforcing effects in studies with blinded protocols (100,
181
101). Like other psychostimulants, nicotine has unconditioned effects that increase conditioned reinforcing by non-drug stimuli, independently of a direct association between nicotine administration and presentation of the stimulus (102–108). The critical role of non-drug stimuli has been demonstrated in studies in rodents, in which discontinuation of environmental stimuli associated with intravenous nicotine injection decreased self-administration almost as effectively as removal of nicotine (102, 109). In experiments in rats (110) and squirrel monkeys (111), the response rate maintained by light stimuli associated with nicotine was equivalent to that maintained by nicotine. Behavioural interventions without environmental stimuli paired directly with nicotine delivery resulted in very little self-administration (112). A new hypothesis is that nicotine addiction, seen as high rates of self-administration by laboratory animals or as cigarette smoking by humans, is supported by the reinforcing stimuli that accompany nicotine intake and the capacity of nicotine to enhance the reinforcing effects of such stimuli. In this dual-reinforcement model, nicotine acts first as a primary reinforcer, establishing a concurrent neutral stimulus as a conditioned reinforcer by association, and then as a reinforcement enhancer, magnifying the incentive of the nicotine-associated conditioned reinforcement (113). As the effects of nicotine become associated with various non-nicotine stimuli, the stimuli acquire conditional value or serve as cues for future nicotine delivery. As a result, the conditional stimuli for tobacco can alter behaviour in a manner to maintain smoking or result in lapse or relapse after sustained abstinence. Thus, proximal stimuli usually associated with smoking, such as a lit cigarette, can induce craving in smokers but not in non-smokers (114). This hypothesis explains the importance of sensory stimuli relative to nicotine in determining subjective responses to tobacco smoke (77, 84) and the reduction in subjective reports of craving for tobacco, desire to smoke and tobacco withdrawal symptoms of people given placebo cigarettes (115). Rees et al. (116) observed that sensory cues may be highly characteristic of individual tobacco products and suggested that such brand-specific cues acquire incentive salience, reinforcing use on the basis of brand characteristics. They suggested that the limited commercial appeal of denicotinized cigarettes such as Quest is due in part to disruption of the established chemosensory cue–nicotine dose contingency. While nicotine administration increases the salience of sensory cues, it does not alter palatability (117). Thus, the incentive-amplifying effect of nicotine may be most effective for familiar sensory stimuli that already have positive associations, such as flavours like cocoa or menthol.
182
Drug expectancy
Drug expectancy plays an important role in smokers’ responses (118–121), particularly in women (56). According to expectancy theory, a smoker’s urge is reduced when smoking a placebo cigarette if he or she has the stimulus (or dose) expectancy of smoking an active-nicotine cigarette and has the response expectancy that nicotine reduces the urge to smoke (122, 123). The expectation of receiving nicotine increases the “likeability” and clinical efficacy of nicotine replacement products, and this expectation interacts with pharmacological factors to produce overall subjective and behavioural responses (120, 124, 125). In a study with a balanced placebo design, smokers who expected smoking to relieve the negative affect of an anxious mood induction had improved mood even when they smoked a placebo cigarette (126). Telling smokers that they are smoking nicotine attenuates their urge to smoke a placebo cigarette but has little effect in the context of nicotine administration, indicating that either nicotine or the belief that one is smoking a nicotine-containing cigarette is sufficient to attenuate the urge to smoke but that dose expectancy is not additive with the effects of nicotine (121). Drug expectancy may be informed by sensory stimuli that indicate to a smoker the likelihood of a given nicotine dose due to conditioned associations. Such cues may be expressed by a smoker as the “strength” of the cigarette and reflect some combination of nicotine-derived impact and other smoke compounds that interact with oral, trigeminal or other receptors (26, 127, 128). Expectancy can also be separated from non-pharmacological stimuli. For example, the same denicotinized cigarette smoked with a different dose expectancy has different effects (129). Information on nicotine content plays a role in smokers’ subjective response to nicotine inhalers, particularly with respect to the craving associated with positive reinforcement (i.e. intention to smoke) but not to the craving associated with negative reinforcement (i.e. withdrawal relief) (120, 130). Although smokers expect pleasurable effects from smoking, they show less expectancy of positive effects from less familiar formulations (123). Social and contextual factors
Dependence is not limited to physiological experience, but is also shaped by behavioural practices and by the environmental factors that support them. The social context of tobacco use is clearly relevant to understanding the patterns of use of various tobacco products, as is the extent of external pressure to abstain or quit. De Leon et al. (131) called for measures of tobacco use that account for contextual factors in determining smoking behaviour and dependence. These would include where it is permissible to use tobacco products (both legally
183
and in terms of social norms); the cost of tobacco use, both individually and to families; and the degree of stigmatization of tobacco use with respect for example to gender, religious affiliation and social status. Knowledge of these factors might be useful for understanding experimentation with tobacco before tobacco dependence, the processes that lead to the choice to quit and quitting outcomes. Summary
• • •
Tobacco addiction is maintained by nicotine. Cigarettes that do not deliver nicotine do not sustain addiction. Nicotine addiction is supported both by positive reinforcement (e.g. mood, performance) and avoidance of withdrawal symptoms. There is considerable individual variation in the response to nicotine. Women differ from men in metabolizing nicotine and are more responsive to conditioned cues. Nicotine dependence initiated in adolescence has implications for dependence in adulthood. Nicotine delivered by tobacco smoke is distinct from other forms of nicotine. Key determinants of the addictiveness of tobacco-delivered nicotine include the form of nicotine, ease of inhalation, related sensory stimulus and the addictive or reinforcing effects of other smoke constituents. Denicotinized tobacco more effectively reduces craving and produces pleasure in smokers than nicotine without tobacco. Evidence supports the validity of the dual-reinforcement model of addiction, in which the conditioned stimulus (tobacco smoke) strengthens dependence beyond that produced by unconditioned nicotine. Drug expectancy alters responses to nicotine and non-nicotine cigarettes. Expectancy may reflect cues within the delivery mechanism (sensory stimuli) as well as information received from advertising, packaging or other forms of communication. Development of dependence is associated with social context and environmental factors that determine product access and appeal.
• • •
• •
•
•
184
Establishing a threshold for addiction The concept of a threshold for nicotine addiction implies that a minimum intake of nicotine is required for acquisition and maintenance of addiction. In their original proposal, Benowitz and Henningfield (1) estimated that the threshold for addiction to nicotine was 5 mg/day, associated with a plasma cotinine level of 50–70 ng/mL per day. The estimate was based on observation of experienced smokers rather than on empirical studies in which exposure to nicotine was manipulated. It was intended for use as a starting-point for critical research and discussion. Since that initial proposal, the widespread availability of denicotinized cigarettes has led to a significant body of research on the effects of reduced exposure to nicotine on smoking behaviour and subjective measures (45, 132). Self-administration of nicotine and the related behaviour have also been studied in experimental animals (8, 113, 133, 134). Together, these studies provide insight into the potential reinforcing effects of cigarettes with extremely low levels of nicotine. Nicotine self-administration
Henningfield and colleagues (27, 135) studied intravenous self-administration of nicotine in smokers. The overall response rates for nicotine did not reliably exceed those for saline, although responses for nicotine tended to be more regularly spaced. Harvey et al. (136) gave abstinent male cigarette smokers access to both nicotine (0.75, 1.5 and 3 mg/injection) and saline by intravenous injection during a 3-h session. Smokers preferred the nicotine injections at all three doses. These doses are higher than the usual nicotine intake of smokers, which is 1–4 mg/h from an average of one or two cigarettes per hour (21). Self-administration of nicotine at doses within the range of the average intake by smokers was studied in male and female smokers who were asked to choose an intravenous dose of 0.1, 0.4 or 0.7 mg nicotine or saline (137). The 0.1-mg dose represents approximately half the amount of nicotine inhaled in a typical cigarette puff. The 0.4- and 0.7-mg doses were preferred to the placebo, indicating that the reinforcing threshold dose of nicotine for smokers is between 0.1 and 0.4 mg. The findings are consistent with research on nicotine discrimination, which indicates that the threshold for nicotine discrimination is well below the typical level of nicotine delivered by most cigarette brands. No difference was found between smokers and non-smokers, with median thresholds of 3 and 2 μg/kg, respectively (about 0.23 and 0.15 mg nicotine) (80). As noted by Hatsukami et al. (45), however, more than 100-fold individual variation in nicotine discrimination has been reported.
185
More studies of nicotine self-administration have been conducted in animal models than in humans, with similar conclusions for the nicotine threshold. Smith et al. (8) reported significantly decreased nicotine self-administration by rats when the nicotine dose was reduced to ≤ 3.75 µg/kg per infusion, while doses ≥ 7.5 µg/kg per infusion resulted in similar or higher rates of self-administration relative to maintenance at 60 µg/kg. In this study, nicotine was administered with a cocktail of other tobacco constituents in order to mirror the effects of tobacco use. Donny et al. (133) examined the dose–response curves from a number of studies of both acquisition and maintenance of nicotine self-administration. They placed the peak of the acquisition curve at 20–30 µg/kg. Similar results were obtained in rats, dogs, monkeys and humans (136, 138). At lower unit doses (3.75–10 µg/kg), the mean response rate increased with dose but with considerable individual variation; few participants acquired nicotine self-administration when compared with saline controls (139, 140). During maintenance of nicotine self-administration, the peak of the dose–response curve was typically between 10 and 30 µg/kg (141–146). Again, nicotine self-administration decreased and variation increased when unit doses < 10 µg/kg were substituted. The threshold reinforcing dose at the low end of the dose range has rarely been determined; however, doses as low as 3 µg/kg maintain nicotine self-administration rates above those for saline in studies of both limited and extended access. The findings suggest that a reinforcement threshold for maintenance of nicotine self-administration in adult animals might lie between 3 and 7.5 μg/kg nicotine (0.23 and 0.56 mg), consistent with (although marginally higher than) those indicated by studies in humans. In most studies, however, the number and range of doses were small, limiting their accuracy. Moreover, in some studies, manipulated doses were given to participants. This would not reflect the change in dose for individual smokers that would follow implementation of a nicotine reduction policy (132) Most research on nicotine self-administration involved rapid infusions of high unit doses of nicotine (15–30 µg/kg per infusion). Sorge and Clarke (147) compared self-administration of nicotine in rats at a duration of infusion of 3, 30, 60 or 120 s and found that slow infusion was preferred to fast infusion; self-administration was seen at doses as low as 3 µg/kg. Their findings indicate that slower self-administration differs pharmacologically from the usual procedure and suggest that the time course of dose delivery plays a role in determining a nicotine reinforcement threshold.
186
Acquisition of nicotine dependence
The dose of nicotine necessary for maintaining smoking may differ from that for acquisition of dependence (7). Despite the lack of data directly relevant to the question, Donny et al. (133) concluded from a comparison of studies that the threshold for maintenance is probably lower than that for acquisition. This conclusion would be consistent with the observation that pre-exposure to nicotine can increase acquisition of nicotine self-administration (42, 143, 148). Acquisition of dependence among adolescents may be different from acquisition among adults. As noted previously, adolescent rats and mice appear to be more vulnerable than adults to the reinforcing effects of nicotine (41, 44, 149), with faster acquisition of nicotine self-administration and higher baseline rates than adults (40, 43, 150, 151). Evidence that adult male rats are more likely than rats in early adolescence to acquire nicotine self-administration at a low dose of nicotine conflicts, however, with this conclusion (140, 152, 153). Cross-sectional and longitudinal studies indicate that young people who smoke less than daily report the onset of dependence symptoms (31, 154–158). Adolescent smokers self-administer physiologically active doses of nicotine despite taking smaller puffs than adults (159–162). Expectancy plays a significant role in the smoking behaviour and motivation to smoke of adolescents. Specifically, a stronger expectancy of the ability of cigarettes to reduce negative affect predicts escalation of smoking, although, as expectancy becomes stronger with increased smoking experience, its effect stabilizes (163, 164). In a study among adolescent smokers of high-yield and denicotinized cigarettes, smoking resulted in reduced negative affect regardless of the nicotine content of the cigarette smoked. This effect was moderated by affect-related expectancy; thus, participants who smoked a high-yield cigarette and held a strong expectancy that smoking would alleviate negative affect experienced the greatest reduction in negative affect. No change in affect was found among non-smoking adolescents (165). The onset of smoking and subsequent exposure to nicotine during adolescence, even at levels below that for daily reinforcement, may lower the threshold for nicotine dependence in adulthood, despite highly attenuated rewarding or reinforcing effects (35, 37, 151). Reinforcing effects of low-nicotine cigarettes
Evidence from clinical studies indicates that denicotinized tobacco can provide significant subjective satisfaction and an immediate reduction in craving (84, 115, 166–172), although ratings may rely on the level of dependence of the smokers (173). Suppression of craving appears to be a particularly robust effect that is less sensitive to extinction procedures (115). Nicotine-containing and denicotinized smoke suppress craving and ad-libitum smoking equally,
187
but intravenous nicotine has only a small effect in suppressing ad-libitum smoking (174, 175). Cigarettes with very low levels of nicotine may be sufficient to maintain smoking behaviour. Brain imaging showed that smoking a single very low-nicotine cigarette resulted in significant (23%) occupancy of α4β2 nicotinic receptors, which are considered the primary receptor subtype that mediates the reinforcing and other behavioural effects of nicotine (90). The effects of low levels of nicotine may be further reinforced by non-nicotine elements of tobacco. Use of denicotinized tobacco was associated with a greater feeling of relaxation than use of a nicotine inhaler, suggesting that non-nicotine factors are partially or even largely responsible for the calming effect of tobacco smoking (172). Dependence on cigarettes could be generated in other ways, even with an extremely low intake of nicotine, for example through desensitization of receptors, which can occur with chronic exposure to even very low levels of nicotine (176). Desensitization of receptors mediates the acute reinforcing effect of nicotine (177, 178). Environment is also likely to play a role in the behaviour of smokers. For example, Donny and Jones (179) found that denicotinized cigarettes maintained their reinforcing properties throughout a 9-day outpatient assessment, whereas in a similar study of inpatients (115) both motivation to smoke and the number of denicotinized cigarettes smoked decreased somewhat over time. It was hypothesized that extinction may proceed more slowly in a natural setting, possibly because of the presence of numerous stimuli associated with smoking (180). Addiction threshold versus reinforcement threshold
There is no universally accepted definition of nicotine or tobacco addiction. WHO (181) defined drug dependence in terms of compulsion, that is, a behavioural pattern in which use of a drug is given priority over other behaviour to an extent that is considered detrimental to the individual or to others. The US Surgeon General’s report on nicotine addiction (99)EC also required that the drug produce psychoactive effects and that drug-taking behaviour be clearly reinforced by the effects of the drug. Although most cigarette smokers meet these criteria, not all do so (23). The diagnostic criteria widely used to identify nicotine addiction include those of the fourth edition of the Diagnostic and statistical manual of mental disorders (DSM-IV), published by the American Psychiatric Association, for assessing general drug dependence, and the Fagerström test of nicotine dependence, used to assess tolerance and the severity of dependence. Concern has been
188
raised about the validity of these instruments for measuring addiction. They correlate poorly with each other, and neither consistently predicts other indices of smoking behaviour or the outcome of treatment of smokers (182–185). They may also not be sensitive for assessing addiction in smokers who are in the early stages of nicotine use, as they were developed and validated for evaluating adult end-stage smokers (186, 187). DiFranza et al. (25) argued that the diagnostic criteria for addiction should, at the very least, differentiate between individuals who can and cannot abstain when they decide to do so. They proposed that self-assessment of addiction should be the gold standard, as it correlates strongly with self-rated difficulty in quitting (r = 0.89) and correlates better than the DSM-IV with the number of cigarettes smoked per day and the time to the first morning cigarette (183). Self-assessment may also better identify emerging dependence in children than other measures. In one study (188), self-assessment of addiction by adolescents predicted neurophysiological responses to smoking more successfully than the Fagerström test. Sofuoglu and LeSage (189) found that the lack of a consensus about valid methods for assessing nicotine addiction is a significant challenge to nicotine reduction strategies. They noted that the concept of a reinforcement threshold is not synonymous with an addiction threshold, although the terms are sometimes used interchangeably, and might be a preferable basis for establishing a threshold level of nicotine. The reinforcement threshold would be defined as the lowest dose of nicotine that increases or maintains nicotine self-administration (i.e. tobacco use). A nicotine reinforcement threshold would have a number of practical advantages. First, it is more clearly defined and would be easier to measure than an addiction threshold, as a drug is considered to be reinforcing if it is self-administered to a greater extent than a vehicle or placebo (190). Secondly, because dependence does not occur if a drug is not reinforcing, a nicotine reinforcement threshold is likely to be lower than a nicotine addiction threshold and may be a more sensitive index for predicting tobacco use below the threshold for addiction (190, 191). Thirdly, a reinforcement threshold could be measured in short-term studies of self-administration in either humans or experimental animals and could easily be adapted to assessment of individual differences (in e.g. age, gender, genetic factors) and of environmental factors (e.g. stress, peer influence) (192). Threshold for conditioned stimulus
Given the importance of conditioned stimuli in reinforcing smoking behaviour and the primary role of nicotine in enhancing salience, consideration should be given to whether there is a separate nicotine threshold for the acquisition of reinforcing properties in non-nicotine stimuli.
189
Rats trained on a dose of 0.4 mg/kg nicotine readily acquire conditioned response to an unconditioned reward (193–195). Groups assigned to a training dose of 0.1, 0.2 or 0.4 mg/kg nicotine showed similar acquisition of conditioned response, but the groups given the two higher doses showed greater resistance to extinction (196). The similarity of the acquisition rate among groups might suggest that 0.1 mg/kg nicotine is as salient as the higher doses. A non-salience explanation involves the rich schedule of sucrose delivery in nicotine sessions; that is, less nicotine was necessary to prompt conditioned responding because of the large number of nicotine–sucrose pairings (193, 195). Palmatier et al. (197) compared the effects of a lower (0.03 mg/kg) and a higher nicotine dose (0.09 mg/kg), reasoning that the new conditioned properties of an associated stimulus should be based in part on the strength or intensity of the primary reinforcer. They concluded that the conditional reinforcing properties acquired by the stimulus are a direct function of increased dose. These findings imply that stimulus control of tobacco-seeking behaviour will be most potent in people exposed to high levels of nicotine and is likely to be greatly reduced with exposure to very low-nicotine products. The strength of conditional stimuli is also driven, however, by the frequency with which the stimulus is paired with nicotine, how closely it is correlated with nicotine and how closely related it is in time and space. Thus, as suggested by Murray and Bevins (196), if there are enough pairings, even a nicotine dose that would otherwise have been a weaker conditional stimulus could become a strong conditioned exciter. Summary
•
Threshold reinforcement studies in experimental animals and in humans show strong agreement. These studies allow a preliminary estimate of the reinforcing threshold for nicotine at 0.1–0.5 mg. The threshold for reinforcement is lower when a self-administration mechanism that more accurately models cigarette nicotine delivery is used. The threshold for discrimination of nicotine in humans is approximately 0.2 mg, although there is wide individual variation. In adults, the threshold for maintenance appears to be lower than that for acquisition of reinforcing behaviour. Acquisition of nicotine use by adolescents may differ from that by adults. Adolescent smokers have low daily rates of cigarette use but appear to self-administer physiologically active doses of nicotine. Expectation of reduced negative affect is a primary motivation for smoking among adolescents.
• • • •
190
• •
Cigarettes with nicotine yields of 0.05–0.1 mg can provide significant subjective satisfaction and an immediate reduction in craving. The low levels of nicotine present in denicotinized cigarettes may be sufficient to maintain smoking behaviour. Alternatively, responses to denicotinized cigarettes may reflect conditioned reinforcing effects or imply that some non-nicotine constituents have primary effects. The goal of reducing nicotine levels below the threshold for addiction requires a reliable measure of addiction. No readily accepted measure of addiction is applicable to establishing a nicotine threshold. Common measures of dependence do not apply to all smokers and may fail to capture adolescent smoking. The alternative definitions proposed are self-assessment of addiction (25) and a reinforcement threshold (189). A high nicotine dose has a stronger conditioned reinforcing effect than a low dose; however, even a low nicotine dose may be sufficient for conditioned reinforcement, particularly in the context of many highly correlated pairings (as in the case of long-term smoking).
•
• •
Feasibility of reducing nicotine Most studies of the behavioural effects of nicotine reduction have been conducted with commercially available low-nicotine products, including so-called denicotinized cigarettes such as Quest. These studies provide valuable insight into the behavioural responses of smokers, but they do not necessarily reflect the commercial products that are likely to become available with mandated nicotine reduction. Internal tobacco industry documents, although potentially less reliable than published clinical studies, may provide insight into the commercial manipulation of cigarette-delivered nicotine and the range of product approaches that are likely to be used by tobacco product manufacturers (26, 198). Cigarette nicotine delivery
Tobacco manufacturers have used brain imaging to determine the effective ranges of nicotine delivery from cigarettes under controlled smoking conditions (198). A comparison of cigarettes delivering no nicotine, low nicotine (0.14 mg) or high nicotine (1.34 mg) showed a statistically significant decrease in the amplitude of evoked potentials only with the high-nicotine cigarette (p < 0.05) (199). In a similar comparison of six cigarettes delivering 0.12–1.1 mg nicotine, the electrophysiological effect of smoking the 0.12-mg delivery cigarette was indistinguishable from that of a nicotine-free cigarette, while cigarettes delivering ≥ 0.21 mg had measurable effects (200).
191
A theoretical best-fit curve relating the latency of the measured brain response to cigarette-delivered nicotine showed that the decrease in latency as a function of nicotine was greatest up to 0.4 mg delivered nicotine per cigarette, with no further shift beyond approximately 1.4 mg per cigarette. This implies that reductions in smoke nicotine to ≤ 0.4 mg are likely to have the greatest overall effect on smoking behaviour (201). In a comparison of latency effects during controlled and ad-libitum smoking of commercial cigarettes delivering 0.11–1.04 mg nicotine per cigarette, smokers showed central nervous system effects comparable to that elicited by full-flavour cigarettes, due to compensation, even with the lowest nicotine delivery (201). In a study to determine whether the effects of a cigarette with high nicotine delivery (0.9 mg) could be replicated by smoking three cigarettes with lower delivery (0.3 mg), latency effects were successfully mimicked, whereas the amplitude effects required a single, relatively large intake of nicotine over a short interval. When the effect of three 0.1-mg nicotine cigarettes was compared with that of a single 0.3-mg cigarette, the latency was no longer similar (p < 0.05). The author concluded that the neurophysiological effects of nicotine exhibit “a threshold […] somewhere between 0.1 and 0.3 mg” (201)—a result consistent with the findings described under “Nicotine self-administration”, above. Methods for reducing nicotine in tobacco
The concentration of nicotine in tobacco is significantly correlated with the nicotine yield of smoke (202) and can readily be altered and controlled by manufacturers (26, 203–205). Type, grade and the position of leaves on the stalk can significantly affect the nicotine concentration of tobacco. By blending different tobaccos, manufacturers can balance tobacco characteristics and adjust for natural variations in nicotine content in order to meet production standards for specific brands and styles (206). Differences of a factor of 10 are found in tobacco types, and factors of 5 and 6 are common; e.g. oriental tobacco has a 1% nicotine content by weight, while Burley tobaccos have 5% by weight (207). Differences in products achieved by tobacco selection are not limited to nicotine but include sugar and ammonia content, aroma and taste characteristics and relative harshness and irritation (207, 208). Strains of tobacco with extremely high and low nicotine were developed for research purposes with the assistance of public research agencies in both Canada and the USA (209–212). For example, Brown & Williamson compared three strains of Burley tobacco containing approximately 1/20, 1⁄2 and 9/10 of the normal levels of nicotine and showed that the level of nicotine in smoke was proportional to that in the tobacco (213). In other cases, bacteria were used to degrade nicotine while leaving other components of the leaf intact (214, 215). Tobacco derived by this process was as acceptable as untreated tobacco (216).
192
The earliest tobacco processing included steam extraction of Burley tobacco and stems in order to reduce the irritation commonly associated with their high nicotine content. Later, ammonia and similar compounds were incorporated during extraction (217, 218). Treatment of tobacco disassociates the naturally occurring nicotine salts into free nicotine and free acid. In heat or steam treatment, free nicotine is driven from the tobacco (219). Other treatments, such as use of a solvent (e.g. freon) allow easier extraction of free nicotine, after which the denicotinized extract may or may not be added back. Extraction processes can result in significant reductions in smoke nicotine delivery and have significant effects on the subjective or sensory characteristics of smoke (220). Research conducted by Philip Morris on nicotine reduction, before development of the denicotinized brand Next, included genetic modification, enzymatic processes and nicotine-extracted tobacco (205). While none of these methods completely eliminated nicotine, reductions of 80–98% were achieved. Quest cigarettes, produced by Vector Tobacco in 2003, were made from genetically modified tobacco. Denicotinized or reduced-nicotine cigarettes
Although in principle it should be possible to make cigarettes with tobacco completely free of nicotine, in most cases the term “denicotinized” indicates tobacco with a concentration of ≤ 1 mg nicotine. When they are smoked on a standard smoking machine, they produce nicotine yields of 0.05–0.1 mg, equivalent to 5–10% of the nicotine yield of standard commercial brands (6). The main technical challenge of producing denicotinized cigarettes is not reducing the nicotine content but maintaining the sensory characteristics and appeal of the smoke. The earliest nicotine-extracted tobaccos, derived by techniques such as solvent or steam extraction, were perceived as “stinging” and “numbing” and had extremely low acceptability, regardless of tobacco type and despite use of flavourings (221). The differences were not due simply to lack of nicotine, as adding extracted nicotine back to test cigarettes did not restore the taste of unextracted cigarettes. Other tobacco materials were removed incidentally during extraction, including waxes, heavy hydrocarbons and essential oils, which, when added back after extraction, improved the subjective acceptability. Thus, elements other than nicotine determine product acceptance (221, 222). For the brand Next, Philip Morris used the supercritical extraction technique that is used to decaffeinate coffee to remove nicotine from tobacco (205). Despite attempts to improve selectivity and limit the underlying effects of extraction, the process altered the taste characteristics of the tobacco. Many
193
post-extraction flavouring and casing systems were tested (223); the most successful were menthol-based prototypes, which covered much of the unusual taste while providing some of the impact lost by removal of nicotine (86, 224). An extended test of the Next prototype conducted by an internal expert panel showed that, although the extracted cigarettes were appealing initially, continued smoking of a pack of the cigarettes led to increasingly poor acceptability ratings. When nicotine was added back to the extracted cigarette, the level of acceptability did not decrease over time (225). In a study conducted with highly motivated smokers, “liking” ratings for the extracted cigarettes improved over time, indicating that smokers may adjust their expectations under some conditions (222). Free-base nicotine in low-delivery cigarettes
Pankow (75) and others (76, 226) identified the fraction of free-base nicotine in tobacco smoke as critical to the rate of transfer of nicotine from both tobacco to smoke and smoke to nicotine receptors in the back of the throat and lungs. Standard measures of smoke nicotine delivery do not differentiate between forms of nicotine (227); however, internal industry documents suggest that comparisons of free-base nicotine delivery may provide a more accurate measure of subjective response to products, particularly in low-yield brands (26, 226). Products that appear to differ significantly in total smoke nicotine can resemble each other in terms of free nicotine delivery. Brown & Williamson compared the smoke yields of Marlboro (1.15 mg nicotine) and the high-impact, low-yield product Merit (0.64 mg) and found essentially the same free nicotine (about 0.3 mg) in each brand. The authors concluded that a person would have difficulty in differentiating the two brands physiologically (228). Similarly, although smoke from a Marlboro had less nicotine than that from a Winston, it had higher levels of weaker bases, such as pyrazines. These bases “accounted for the pH being slightly higher” of Marlboro, indicating equivalent levels of volatile or “free” nicotine, despite the fact that the level of nicotine was not as high (229). Limited published measures of free-base nicotine in cigarette smoke suggest that differences between commercial brands are not identified in standard smoking protocols (230, 231). The concentrations of free-base nicotine are similar within but differ between nicotine delivery categories of full-flavoured, light and ultralight cigarette brands. The degree of filter ventilation increases the proportion of free-base nicotine in mainstream smoke, suggesting that, even without compensatory behaviour, a ventilated cigarette delivers a greater proportion of total nicotine in free-base form (231).
194
Products that lead to compensatory smoking
Smokers adjust their smoking behaviour when they switch from regular to light (or low-yield) cigarettes in order to maintain their desired nicotine intake (20, 166, 232). Unlike conventional low-yield cigarettes, reduced-nicotine cigarettes do not require ventilation for reduced smoke yields and do not appear to lead to compensation as readily (13, 14, 83). Rose and Behm (82) compared smoking a cigarette with a smoke yield of 0.2 mg nicotine and 14 mg tar with smoking a commercial, highly ventilated low-yield cigarette (0.2 mg nicotine and 1 mg tar) in a single-session ad-libitum crossover study and found substantial compensation for the commercial low-nicotine cigarette but no appreciable compensation for the low-nicotine cigarette with 14 mg of tar. Benowitz et al. (233) compared smoking behaviour with the smoker’s usual brand of cigarette with that of a cigarette with an adjusted nicotine content of 1–12 mg. Strong compensatory behaviour was seen with cigarettes with moderate levels of nicotine but minimal compensation and a significant reduction in exposure to nicotine for cigarettes with 1, 2 or 4 mg nicotine (0.1, 0.2, 0.3 mg nicotine yields). The lowest-nicotine cigarette resulted in an average nicotine intake of 0.26 mg, while the usual brand delivered 1.47 mg. A longer study of cigarettes with the same range of nicotine levels (1–12 mg), which was decreased at monthly intervals over 6 months, gave similar results, with a high level of compensation for the 12-mg cigarette but little compensation for the cigarette with lowest nicotine content (15). Hatsukami et al. (14) assigned smokers to cigarettes with either 0.3 or 0.05 mg nicotine yield or to 4-mg nicotine lozenges in a 6-week switching study. For participants who smoked the 0.3-mg cigarettes, the number of cigarettes smoked per day increased significantly in each of the first 5 weeks of treatment over that of the usual brand, while for participants assigned the 0.05mg cigarettes, the number of cigarettes smoked per day (relative to baseline) decreased significantly. These studies suggest that, for cigarettes with a reduced nicotine content, there may be a threshold below which compensation is less likely. This threshold appears to be 0.05–0.1 mg smoke nicotine yield. At less extreme levels of reduced nicotine (0.2–0.3 mg), compensatory behaviour is significantly increased. A similar threshold may exist for commercial, ventilated low-yield cigarettes. In a 10-week study of commercially available cigarettes, Benowitz et al. (234) found that forced switching from regular cigarettes to popular low-yield cigarettes with machine-determined yields of ≥ 0.6 mg nicotine resulted in complete or nearly complete compensation, with no reduction in exposure to nicotine or tobacco smoke toxins. When participants switched to ultralow-yield
195
cigarettes delivering 0.1–0.2 mg nicotine, exposure to nicotine and tobacco smoke toxins was substantially although not entirely decreased (by about 40%, with a 90% reduction in nominal yields). Product formulation and approaches to nicotine reduction
Differences in formulation play a key role in the likelihood that a product will be abused and in determining the threshold for reinforcement. For example, the risk for addiction to oral smokeless tobacco products appears to be somewhat lower than that to cigarettes (235, 236), and the risk for becoming addicted to nicotine replacement medication appears to be small (99, 237), even though the absolute nicotine delivery may be similar. Currently, most manufactured cigarettes contain 10–15 mg of nicotine per cigarette, of which approximately 10% is delivered in smoke. This leads to a typical systemic intake of 1–2 mg nicotine per cigarette (6). Setting a threshold for nicotine at 0.1–0.2 mg per cigarette would result in an overall reduction in nicotine intake of about 90%. Various approaches can be considered to achieve such a reduction. The nicotine concentration in tobacco could be reduced such that the total content per cigarette remained at or below the intake threshold. This would ensure that the nicotine consumption per cigarette remained below the threshold regardless of behavioural changes by the smoker (i.e. increased frequency or volume of puffs) or manipulation of the form of nicotine delivery, although it would not prevent the smoker from increasing the number of cigarettes smoked to obtain more nicotine. For construction of such a cigarette, the nicotine concentration in tobacco would have to be reduced approximately 10 times more than that in the commercial denicotinized brands Next and Quest. The reduction would probably result in significant changes in the sensory or taste characteristics of the tobacco. No studies have been conducted on the probable behavioural responses to cigarettes with this range of nicotine. The reduction in the nicotine concentration of tobacco could alternatively be such that the machine-measured smoke yield is likely to be at or below the nicotine threshold. This is the approach of the commercial products Next and Quest, which have a smoke nicotine yield of < 0.1 mg and a total nicotine content of tobacco of < 1 mg. The existence of saleable brands containing this level of nicotine provides strong evidence that the approach is technically feasible. Most research on behavioural responses to nicotine reduction has been conducted with cigarettes containing such levels of nicotine. A third alternative to meeting a threshold for smoke nicotine intake would be to alter product parameters other than nicotine concentration of the tobacco or in combination with reduced-nicotine tobacco. This approach could include
196
extreme filter ventilation, high levels of expanded tobacco and lower tobacco content. The technical feasibility of this approach has also been demonstrated commercially, in cigarettes at the extreme end of the ultralight category, i.e. those yielding approximately 0.1 mg nicotine and 1 mg tar under machine smoking conditions. Cigarettes manufactured by this approach would probably maintain nicotine : tar ratios that are similar to or greater than those in current commercial cigarettes, while cigarettes with a reduced nicotine concentration would produce smoke with extremely low nicotine : tar ratios. They might lead to more frequent compensatory behaviour, such as covering vent holes and altering puffing behaviour. Manufacturers could manipulate the physical or chemical parameters of cigarette construction to alter the characteristics of smoke and offset reductions in nicotine delivery. For example, new filters could be added to alter the form of nicotine (by addition of an acid or base) or to change the size distribution of the aerosol particles that determine deposition and absorption of nicotine and other constituents (26, 127, 238). Changes in tobacco processing, use of additives and physical construction parameters, including length, width, moisture and packing density, could alter the combustion or pyrolysis conditions of the cigarette and change the composition and sensory characteristics of smoke; or new compounds could be introduced with unique behavioural or sensory effects or that interact with or alter nicotine (26, 78, 128). Thus, regulators must be attentive to other product factors in addition to nicotine delivery. Summary
•
Cigarettes may be pharmacologically active above a certain threshold of smoke nicotine yield, whereas below this threshold (somewhere between 0.1 and 0.3 mg) they are no longer as effective. A single intake of nicotine from a single cigarette over a short time is more effective than a series of smaller intakes from many cigarettes, particularly when they have a lower level of nicotine. Reduction of the total nicotine concentration of tobacco is a common practice in the tobacco industry. A wide range of techniques has been used, including selection and processing of tobacco, genetic selection, microbial or enzymatic treatment and selective extraction of nicotine. Both selective extraction and genetic modification have been shown to produce tobaccos in which the nicotine content is reduced by 80–95%. Reduced-nicotine tobacco has different sensory characteristics from unmodified tobacco, due in part to the absence of nicotine but also to the loss of incidental compounds such as waxes, hydrocarbons and essential oils.
•
•
• •
197
•
Total nicotine intake is only one measure of the overall sensory and pharmacological effects of nicotine and does not differentiate between forms of nicotine. Free-base nicotine is primarily responsible for the sensory impact of nicotine, and the level of free-base nicotine might be a more accurate measure of subjective or physiological effects, particularly from low- or reduced-nicotine products. For cigarettes with a reduced nicotine content, there may be a threshold below which compensation is less likely. This threshold appears to be in the range of 0.05–0.1 mg nicotine yield. At a less extreme level of reduced nicotine (0.2–0.3 mg), compensatory behaviour is significantly increased. Similar findings are reported from studies of switching to denicotinized cigarettes (0.05 mg nicotine) or conventional cigarettes with extremely low nicotine levels (0.1–0.2 mg), despite differences in construction and the greater available nicotine in the rod. Reduction of the nicotine content in cigarettes below the 0.1 mg threshold would require a reduction 10-fold greater than that of current denicotinized products. The feasibility of and behavioural responses to such a product are unknown. Most research on behavioural responses has been conducted with cigarettes made with reduced-nicotine tobacco that have machine-measured smoke yields of nicotine near the 0.1 mg threshold. The physical and chemical parameters of cigarettes can be manipulated, including the introduction of new compounds, to alter basic characteristics such as the size distribution of particles, combustion and pyrolysis. Attention must be paid to product factors other than nicotine delivery.
•
•
•
•
•
Potential behavioural and population outcomes Smoking denicotinized cigarettes can reduce smoking of conventional cigarettes by providing a temporary behavioural substitute and by removing the primary reinforcing effects of nicotine, resulting in less craving over time (239). The evidence presented above indicates that, while smokers prefer nicotine-containing cigarettes, reduced-nicotine cigarettes can provide subjective satisfaction and reduce immediate craving. Some individuals may continue to smoke after mandated nicotine reduction, either because of the strong substitution effects reported above or because the nicotine content of cigarettes remains greater than their individual threshold for reinforcement (45, 240).
198
In behavioural models, evidence on the effects of reduced-nicotine cigarettes in individuals is used to predict population outcomes. There are, however, few studies on the acquisition of reduced-nicotine cigarette use in non-smoking populations and on the long-term effects of reduced-nicotine cigarette use. Potential effects on cigarette consumption
Research in behavioural economics provides information on smokers’ consumption. For example, DeGrandpre et al. (241) conducted a “demand curve” meta-analysis of 17 studies of the effects of nicotine yield on smoking behaviour. They found a strong relation between consumption and nicotine yield, suggesting that decreasing smokers’ usual nicotine yield increased their smoking behaviour. Studies of the use of nicotine-containing and denicotinized cigarettes indicate a similar elasticity, as an increase in unit price resulted in a similar reduction in self-administration. When the two cigarette types were available at the same range of unit prices, however, the nicotine-containing cigarettes were reliably preferred. The study showed that the act of smoking has reinforcing value in regular smokers, regardless of the nicotine content of cigarettes, and that denicotinized cigarettes serve as an effective behavioural economic substitute for nicotine-containing cigarettes (242, 243). Increasing the unit price of nicotine-containing cigarettes while holding the price of denicotinized cigarettes or nicotine chewing-gum constant increases consumption of the latter (244). When both alternatives are available, however, consumption of nicotine chewing-gum diminishes but that of denicotinized cigarettes does not (245). Increasing the price of both denicotinized and nicotine-containing cigarettes results in increased chewing-gum consumption. These findings suggest that the availability of nicotine substitutes such as medications, oral tobacco or nicotine-containing electronic cigarettes may directly affect self-administration of cigarettes, regardless of the cigarette nicotine content. Potential effects on topography and smoking behaviour
Switching to cigarettes with a reduced nicotine content can elicit modest withdrawal symptoms (13, 14, 234, 246, 247), suggesting that withdrawal symptoms might motivate an increase in smoking. There is little evidence, however, that cigarettes yielding 0.05–0.1 mg nicotine lead to compensatory smoking, as indicated under “Products that lead to compensatory smoking”, above. Strasser et al. (248) found that participants who smoked reduced-nicotine cigarettes (Quest 3, with 0.05 mg yield) increased their total puff volume. The response
199
of the participants was, however, evaluated only at first use of the study cigarettes. Studies of use of reduced-nicotine cigarettes over several days or weeks consistently found no increase in compensatory smoking and in fact showed a tendency to decreased smoking over time, as would be expected during behavioural extinction. Measurement of smoking behaviour over 9 days showed initial differences in puff volume, which dissipated as the study progressed, suggesting that puffing behaviour may be disrupted only temporarily by a switch to reduced-nicotine cigarettes (179). In an 11-day assessment, participants smoking reduced-nicotine cigarettes showed less ad-libitum smoking than those smoking nicotine-containing cigarettes (115). Hatsukami et al. (14) found a similar reduction over a 6-week treatment period. In a 26-week study of stepped reduction in nicotine content from 12 mg to 1 mg (15), cigarette consumption remained unchanged between baseline and week 14, when the nicotine content had reached 4 mg; from this point to the end of the study, cigarette consumption decreased significantly by four cigarettes per day, and the nicotine intake, as measured by plasma cotinine, decreased to 30% of the baseline level. In a study of self-administration in rats, dose reduction did not elicit withdrawal symptoms for the group as a whole; however, it elicited symptoms in some individuals, the severity of which did not determine differences in compensation (249). These results complement a report that a large partial reduction in brain nicotine levels induced by administration of nicotine-specific antibodies was not sufficient to elicit withdrawal in rats that were dependent on a chronic nicotine infusion (250). These findings suggest that withdrawal is not a prominent adverse consequence of reduced nicotine intake for most individuals and that significant compensatory smoking behaviour in the form of greater intensity of smoking or smoking more cigarettes per day is not a likely outcome at very low (0.1 mg) levels of nicotine. Potential effects on abstinence and quitting
Studies in both laboratory and outpatient research settings demonstrate that use of reduced-nicotine cigarettes over 1–2 weeks weakens the reinforcing effects of smoking (82, 115). In clinical trials conducted over 6 weeks or more (14, 15, 234), smokers consistently reported less dependence after use of reduced-nicotine cigarettes. Reduced-nicotine cigarettes may serve as a coping mechanism for the initial stages of abstinence by replacing some of the conditioned rituals associated with smoking, such as the hand-to-mouth action, the tactile action of puffing on a cigarette and the sensation of smoke in the mouth and throat (251). Among smokers seeking to quit, continuous abstinence at week 6 was 13.5%
200
for smokers who switched to a 0.3-mg cigarette and 30.2% for those assigned to a 0.05-mg cigarette. This suggests that a nicotine reduction policy would be more likely to help smokers to achieve abstinence when they are making an active attempt to quit (14). Reduced-nicotine cigarettes may, however, support quitting not only in smokers seeking treatment but also in those who have not previously expressed an interest in quitting. Benowitz et al. (13) found that 25% of participants had stopped smoking 4 weeks after the end of a progressive 6-week reduction in the nicotine content of their cigarettes. In a similarly designed study, 10% of participants who had not previously expressed an interest in quitting had quit smoking after progressive reduction of the nicotine content of their cigarettes (234). After progressive reduction in nicotine over 6 months, a quit rate of 4% was found at completion (15). The effects of reduced-nicotine cigarettes on quitting may be increased by nicotine-based treatment. When smokers were switched to reduced-nicotine cigarettes (0.05–0.09 mg nicotine yield) with or without nicotine patches for 6 weeks, the group without patches smoked significantly more cigarettes per day than those assigned patches and had more withdrawal symptoms, although the scores for craving were similar in the two groups. At follow-up at 36 weeks, continued abstinence was achieved by 18% of smokers who had used the reduced-nicotine cigarettes alone and 20% of those who had used the combination of reduced nicotine and patches (252). In another study, smokers assigned a nicotine patch with reduced-nicotine cigarettes smoked fewer cigarettes, inhaled a smaller total volume of cigarette smoke and had greater relief of withdrawal symptoms than those without a patch (179). Walker et al. (251) conducted a randomized controlled trial of use of denicotinized cigarettes with or without usual Quitline care (nicotine replacement therapy and behavioural support). The quit rates were higher with the combination, with a shorter time to relapse and good acceptability. The trial provides strong evidence that the combination of reduced-nicotine cigarettes with nicotine replacement therapy and behavioural support is an effective smoking cessation strategy. Potential effects on acquisition of cigarette use
The impact of a reduced-nicotine policy on smoking initiation has not been quantified. Studies cited under “Acquisition of nicotine dependence”, above, suggest that the expectancy that cigarettes can reduce negative affect plays a primary role in acquisition of smoking by adolescents (163, 164) and that the reduction in negative affect with denicotinized cigarettes is comparable to that with a nicotine-containing cigarette among adolescent smokers. No change
201
in affect was found, however, among non-smoking adolescents who used a reduced-nicotine cigarette (165). This suggests that non-smoking adolescents are unlikely to escalate their smoking behaviour in the absence of acute effects of nicotine. Establishment of a threshold for reducing negative affect in non-smoking adolescents would confirm this hypothesis. The effect of a reduced-nicotine policy on the acquisition of reduced-nicotine cigarette use by adult non-smokers has not been studied separately. Self-administration of a nicotine nasal spray was similar in dependent and non-dependent smokers and was more frequent in both groups than in ex-smokers or non-smokers. In non-smokers, self-administration is related directly to pleasurable effects but inversely to aversive effects (253). Expectancy of both positive and negative reinforcement changed significantly after initiation of smoking (254). Exposure to reduced nicotine in adolescence is likely to reduce their vulnerability to nicotine dependence in adulthood (see “Individual variation in response to nicotine”, above). More research should be conducted on the effects of reduced-nicotine cigarette use among non-smokers and non-dependent smokers. Potential unintended behavioural consequences
Experimentation with reduced-nicotine cigarettes by adolescents might increase their risk for addiction to other drugs of abuse (45). In experimental animals, very brief intravenous exposure of adolescent rats to nicotine (two infusions of 0.03 mg/kg daily for 4 days) sensitized them to the reinforcing effects of cocaine (255). This daily dose is comparable to the nicotine intake from four standard cigarettes (4.2 mg) or approximately 40 reduced-nicotine cigarettes. Reduced-nicotine cigarettes might serve as starter products for higher-nicotine products, in a manner similar to that demonstrated for smokeless tobacco products with low levels of free-base nicotine (254). Dual use of reduced-nicotine cigarettes and tobacco products with higher nicotine contents, such as oral tobacco or small cigars, could also result in greater exposure to toxicants (45). Potential population differences
As observed under “Individual variation in response to nicotine”, above, factors other than nicotine may determine tobacco dependence in women. Women are less responsive than men to manipulations of nicotine exposure and more responsive than men to manipulation of non-nicotine components of cigarette smoking, such as sensory cues (52, 56, 125). At least some of the difference precedes the onset of dependence caused by chronic exposure to nicotine from
202
smoking (125). Reduced-nicotine cigarettes relieve craving to a greater extent (172), have more positive subjective effects (satisfaction, relaxation, reduced anxiety) and result in a greater reduction in the intention to smoke in women than in men (257). These observations suggest that women are at greater risk for maintaining long-term use of reduced-nicotine tobacco than men; however, in a study of cessation, tapered reduction of nicotine in combination with nicotine replacement therapy had a greater effect on continuous abstinence at 4 weeks for women than for men (239). Walker et al. (251) observed no difference by gender in the effect of the paired Quitline intervention. The potential adverse effects of nicotine reduction in people with severe psychiatric disorders remain a concern. Tidey et al. (258) studied the effects of reduced-nicotine cigarettes among smokers with schizophrenia. Denicotinized cigarettes reduced craving for cigarettes, nicotine withdrawal symptoms, smoking withdrawal symptoms and smoking of usual brands and were well tolerated; there was no indication that the reduction in nicotine affected psychiatric symptoms. Nevertheless, denicotinized cigarettes substituted less effectively for nicotine-containing cigarettes in smokers with schizophrenia than in control smokers, suggesting that long-term use of reduced-nicotine cigarettes by patients with schizophrenia would be less likely if nicotine-containing alternatives were available. Further studies of reduced nicotine should be conducted among people with depression or other serious mental health disorders. Potential health effects
Hatsukami et al. (14) reported significant reductions in the exposure to toxicants of smokers who switched to reduced-nicotine cigarettes, including tobacco-specific nitrosamines, acrolein and benzene, although no measured reduction in exposure to polycyclic aromatic hydrocarbons was found. The reductions in nitrosamines were consistent with the reduced levels measured in the tobacco, while the differences in other toxicants were considered to reflect reductions in smoking. These findings indicate that a reduced-nicotine policy might reduce health risks not only among people who quit or do not acquire tobacco dependence but also among people who continue to use tobacco products despite the lower nicotine (259). The probable reduction in nicotine intake is another potential health benefit (82, 259). Although components of tobacco other than nicotine are the main causes of tobacco-related disease, nicotine may contribute to the development of cardiovascular disease by causing vasoconstriction, promoting thrombosis and atherosclerosis and impairing sensitivity to insulin (260, 261). Nicotine may also promote arteriogenesis (262), which could increase the blood supply
203
to tumours and inhibit apoptosis (263), promoting carcinogenesis. Girdhar et al. (264) postulated that nicotine moderates the risk for cardiovascular disease caused by other smoke components by reducing platelet activation. A reduction in cigarette nicotine content would therefore increase the risk for cardiovascular disease; however, use of pure nicotine as a tobacco substitute has not been reported to be harmful, suggesting that the direct health effects of nicotine use are minimal. No significant difference in adverse health events was identified between people assigned to a reduced-nicotine cigarette and those assigned to nicotine replacement therapy only in the Quitline intervention conducted in New Zealand (251). The weight of the evidence suggests that the health risks associated with switching to reduced-nicotine cigarettes are similar to or lower than those associated with conventional cigarettes, but more studies are needed. Potential illicit sales of nicotine-containing cigarettes
A number of studies have shown the importance of smuggling to cigarette manufacturers as a means of promoting their products in low- and middle-income countries (265, 266). Most illicit cigarette sales are supply-driven and remain commonplace even when prices and excise taxes remain low (267). The rate of smuggling may be represent as much as 10–15% of all sales (268, 269, 270). There have been no published studies of the likelihood of illicit sales of higher-nicotine cigarettes in a reduced-nicotine market. Givel (271) described the outcome of a sales ban enacted in 2004 to end tobacco consumption in Bhutan, which allowed only small quantities of tobacco to be imported for personal consumption. Smuggling and black market sales increased in the years following the ban, sufficient to support a smoking rate of 10% among Bhutanese men. In the event of a nicotine reduction policy, both the appeal of reduced-nicotine cigarettes and the availability and appeal of alternative forms of nicotine are likely to affect the extent of illicit tobacco sales (272). In Canada, contraband cigarettes were rated by young people as less appealing than leading brands, suggesting that the availability of contraband cigarettes might have greater appeal for addicted smokers than for novice or experimenting users (273). The availability of contraband cigarettes has also, however, been associated with a reduced likelihood of cessation and fewer attempts to quit (274–276). Models of population effects
Tengs et al. (4) simulated the population effects of a reduced-nicotine mandate in the USA over 6 years. Assuming an 80% decrease in smoking prevalence,
204
a 10% increase in mortality among current smokers due to compensatory behaviour and entry of 10% of smokers into the black market annually, they estimated a cumulative gain of 157 million quality-adjusted life years over 50 years. They then varied the model parameters in several ways and concluded that, as long as smoking cessation increased by 10% or more, relapse and initiation of smoking decreased by 10% or more and compensatory behaviour increased the mortality rates of smokers by no more than 80%, there would still be a net gain in quality-adjusted life years. Significantly, over a range of plausible estimates (0–50% of all smokers), quality-adjusted life years were uniformly gained rather than lost, regardless of the extent of entry into the black market. In another simulated model, health outcomes were estimated on the assumption that a reduction in nicotine would reduce the probability of initiating smoking for people of every age and gender, that the probability of cessation would increase and that former smokers would be less likely to relapse (277). The authors also simulated the possibility that promotion of reduced-nicotine cigarettes as “safer” would worsen all three outcomes. Outcome estimates were created for the probability of behaviour change in increments of 10% from −80% to +80%. They concluded that a 60% reduction in smoking (initiation, use, relapse) would offset any plausible increase (≤ 50%) in harm resulting from compensatory smoking or other unintended health consequences among people who continued to smoke. A modest 20% reduction in initiation, use and relapse, with a 20% reduction in disease risk among continuing smokers, would result in a cumulative gain of 165 million quality-adjusted life years, while a significant 80% reduction in initiation, use and relapse, with no change in disease risk for people who continued to smoke, would result in an estimated gain of 281 million quality-adjusted life years. A study was commissioned by Health Canada to model the potential effects in Canada of a nicotine-reduction policy for all tobacco products (278). The study was based on a literature review and on interviews with health experts. The outcomes considered were smoking initiation and cessation, increased black market sales, substitution of other tobacco products for cigarettes and potential compensatory behaviour. It was estimated that the impact of such a policy on initiation and cessation, in the absence of effects on black market sales, substitution and compensation, would reduce the cost of treating tobacco-related illness by 19% after 30 years. Assumption of an increase in the black market share from 15% to 50% would decrease the benefit by 40%. The benefits of a reduced-nicotine standard for mortality were due mainly to the effect on cessation, while the benefits for morbidity were due mainly to the effect on initiation.
205
Summary
•
The act of smoking has a reinforcing effect in addicted smokers, regardless of the nicotine content. Denicotinized cigarettes can serve as an effective behavioural economic substitute for nicotine-containing cigarettes. The availability of alternative nicotine substitutes, such as nicotine medication, oral tobacco and nicotine-containing electronic cigarettes, may directly affect self-administration of cigarettes, whether or not the cigarettes themselves contain nicotine. Withdrawal symptoms are not a prominent adverse consequence of a reduction in nicotine intake for most individuals, and significant compensatory smoking behaviour in the form of greater intensity of smoking or smoking more cigarettes per day is not a likely outcome at very low (< 0.1 mg) levels of nicotine. A nicotine reduction policy may be more likely to help smokers achieve abstinence when they make an active attempt to quit. Use of reduced-nicotine cigarettes improved quit rates in a number of studies. Non-smoking adolescents are unlikely to escalate their smoking behaviour in the absence of acute effects of nicotine. Identification of a threshold for reducing negative affect in non-smoking adolescents would confirm this hypothesis. The use and effects of reduced-nicotine cigarettes in non-smokers and non-dependent smokers have not been studied adequately. In non-smokers, self-administration of reduced-nicotine cigarettes is related directly to pleasurable effects and inversely to aversive effects. Exposure of adolescents to low levels of nicotine could increase their risk for addiction to other drugs of abuse. Low-nicotine products could also serve as starter products for other forms of tobacco or other forms of nicotine delivery. Women may be more likely than men to sustain long-term use of reduced-nicotine tobacco. Nicotine reduction had no aversive effects on mental health symptoms in patients with schizophrenia; more studies should be conducted in other populations at risk. Reduced nicotine may reduce health risks not only in people who quit or do not acquire tobacco dependence but also in people who continue to use tobacco products despite reduced nicotine. More studies are needed. Illicit tobacco sales may undermine the health goals of a nicotine reduction policy. Although no formal estimates have been made, both the appeal of reduced-nicotine cigarettes and the availability and appeal of
•
•
•
•
•
•
•
•
•
206
alternative forms of nicotine are likely to affect the extent of illicit tobacco sales significantly. • Various models have been designed to estimate the likely effects of a nicotine reduction policy. All indicate a significant positive effect on health outcomes.
Policy approaches to nicotine reduction A number of authors have proposed reducing the nicotine content of cigarettes in the context of a harm reduction model in which safer products are made more appealing than more toxic products (272, 279–284). A regulatory framework is essential to support a nicotine reduction policy, both with respect to the resulting commercial marketplace in which smokers and non-smokers develop and sustain use of tobacco or nicotine and the social environment that influences and supports this behaviour. Comprehensive regulation of nicotine
The effects of a policy to reduce the nicotine content of cigarettes would depend significantly on the availability, toxicity and appeal of alternative nicotine delivery systems, including other forms of (combustible or incombustible) tobacco, medicinal nicotine and commercial non-tobacco nicotine products (45). Therefore, a successful nicotine reduction policy must be part of comprehensive regulation of all tobacco- and nicotine-containing products (3, 5, 7, 280, 281). A single institution with authority for tobacco and nicotine regulation would allow coordination of approaches for different products (280). This institution would be responsible for deciding how tobacco and nicotine products are regulated, setting performance standards, authorizing health or other claims for products, evaluating products on the market and evaluating their population effects. A comprehensive surveillance system would be essential for responding quickly to any unanticipated change in nicotine use or health outcomes (7, 280). The main goals of comprehensive regulation of nicotine would be to minimize use of the most toxic nicotine-containing products, to encourage the development of new, improved nicotine delivery systems as alternatives to more toxic products and to continue to monitor and regulate less toxic products for health effects (3, 6, 280). Policy approaches could be considered to incentivize smokers to adopt less hazardous forms of tobacco or nicotine use, including restrictions on access, marketing and use, as well as differential taxation, such
207
that taxes on cigarettes and combusted tobacco are much higher than those on cleaner nicotine-delivery products (6, 281, 285). Performance standards
Performance standards are necessary to ensure implementation of a reduced-nicotine policy (284, 285). A number of approaches could be considered for determining standards for nicotine products, such as restricting delivered or inhaled nicotine or restricting individual doses of nicotine defined at the level of a single puff. The most promising approach, however, is to focus on the total nicotine available in an unburnt cigarette, because it is more easily measured and less subject to behavioural manipulation and individual variation (see “Product formulation and approaches to nicotine reduction”, above). The evidence presented in this annex suggests that a reduction of the nicotine content of cigarettes to < 1 mg would be sufficient to reduce dependence in a proportion of the smoking population, with minimal adverse effects. This evidence comes from studies of cigarettes constructed with very low-nicotine tobacco and design parameters similar to those of standard conventional cigarettes. It is possible and even likely that performance standards exclusively for the nicotine content of tobacco would encourage development of cigarettes that contain little tobacco nicotine but that are otherwise quite different in form and function from conventional cigarettes. Examples might include products that release nicotine in a more readily available (free-base) form, that alter the particle formation or deposition of nicotine, that release the full amount of nicotine in a single dose, that encourage and enable use of many cigarettes to maintain nicotine dose or that contain nicotine analogues and other pharmacologically active compounds to enhance or replace the effects of nicotine. Performance standards must respond to the changing marketplace (7, 18, 22, 285). Initial standards should require that products resemble conventional cigarettes in various basic physical characteristics, including tobacco weight, length, circumference, filter, paper and ventilation (286). New products and technologies must be carefully evaluated and their commercial introduction permitted only once their reduced risk, addictiveness and appeal have been sufficiently demonstrated (7, 18, 287, 288). Global standards for addiction and harm should ultimately be set through the WHO FCTC (281). Such global standards could include further product standards, such as restrictions on toxicants (e.g. nitrosamines), on physical design parameters that lead to or support compensatory behaviour (e.g. ventilation) and on flavourings and other factors that increase product appeal (e.g. menthol). The effects of each of these standards would have to be carefully evaluated (18, 281, 284, 285).
208
Gradual versus sudden reduction
In their original proposal, Benowitz and Henningfield (1) called for a reduction in nicotine levels over 10–15 years, in order to minimize potential withdrawal symptoms, among other practical concerns. A gradual reduction in nicotine could, however, have negative health consequences (45). First, individuals would be exposed for an extended period to doses of nicotine that maintained their smoking behaviour. Secondly, a gradual market-wide shift in nicotine levels might alter smokers’ relation to nicotine in unanticipated ways, potentially adjusting the threshold for addiction (8); for example, in early work on nicotine self-administration, addiction in rats that were switched to saline extinguished more slowly if they received an intermediate dose reduction before saline substitution (139). There is no model of the effects of reducing nicotine over the course of years. Studies of progressive reduction in nicotine over weeks or months, however, showed that nicotine consumption can be decreased gradually without significant compensation. Further, once tapering is completed, the nicotine intake remains below the baseline level, suggesting reduced nicotine dependence (13, 15, 234). A strong association was found between the extent of reduction of daily smoking and nicotine dependence, supporting the idea that a gradual reduction in intake may reduce nicotine dependence (289). After reviewing the literature, Walker et al. (290) concluded that a progressive reduction in the level of nicotine in cigarette tobacco could reduce nicotine dependence in smokers, with minimal compensatory smoking (at a smoke nicotine level < 0.1 mg) and no adverse effects. Even immediate reductions in nicotine may be successful in decreasing both smoking rates and dependence. Smokers who switched abruptly from their own cigarettes to reduced-nicotine cigarettes for 6 weeks showed reduced exposure, decreased consumption and higher rates of cessation (14). Similarly, in an 11-day switching study, cigarette consumption declined immediately and motivation to smoke decreased (115). Gradual and immediate reductions in the dose of nicotine resulted in similar self-administration behaviour in rats, with no compensation in either group (8) A meta-analysis of the effect on quit rates of an intermediate reduction in consumption before quitting showed no difference between reducing the number of cigarettes smoked before “quit day” and quitting abruptly with no prior reduction (291). Taken together, the results of these studies suggest that the dose of nicotine from cigarettes could be reduced quickly with no significant adverse effects among smokers.
209
Alternative forms of nicotine
Some cigarette smokers faced with reduced-nicotine products are likely to switch to products that contain more nicotine. The appeal of alternative tobacco products, such as oral and smokeless tobacco, waterpipes, pipes and cigars, may increase if they can substitute for conventional cigarettes more effectively than reduced-nicotine cigarettes (see “Potential effects on cigarette consumption”, above). Combusted tobacco is significantly more harmful than un-combusted tobacco, which is itself more harmful than clean nicotine products such as patches and chewing-gum (17). In view of this continuum of harm, it might be advisable to mandate nicotine reduction not only in cigarettes but in all combusted tobacco products, thus minimizing the risks associated with switching to the most harmful products (285). Pharmaceutical products for dispensing nicotine, while much safer than tobacco products, are designed to be unappealing in order to avoid abuse and are not intended for long-term use (287, 288). Although these products may help smokers through withdrawal, they do not produce sufficient positive reward (particularly fast, effective nicotine delivery) to be reasonable alternatives to tobacco products (292). Electronic cigarettes were designed with the express purpose of replicating the act of smoking, without tobacco (285, 293). These and similar products may be more viable alternatives to cigarettes (294), and evidence is rapidly accumulating on their use and acceptance (293, 295–297). Electronic cigarettes produce a vapour of nicotine and other constituents, usually including glycerine or propylene glycol. Currently, they are used primarily for smoking cessation, although for longer than nicotine replacement therapy (297). Users believe them to be safer than smoking (297). Electronic cigarettes deliver nicotine more effectively and more rapidly than a nicotine inhaler (298) but somewhat less effectively than a conventional cigarette (293, 298). They significantly reduce craving, due at least in part to the physical sensory characteristics of the cigarette, independently of nicotine delivery (293, 299). At least some electronic cigarettes deliver reliable blood levels of nicotine (mean, 6.77 ng/mL 10 min after 10 puffs; mean maximum, 13.91 ng/mL by the end of the ad-libitum puffing period). They reduce tobacco-related withdrawal symptoms and the urge to smoke, provide direct positive effects and have few adverse effects (295). Cessation and behavioural treatment
As nicotine is reduced to non-addictive levels, there will probably be a sharp increase in the number of smokers who want to quit (2, 6). Many smokers will visit physicians seeking nicotine replacement or behavioural therapy to
210
aid cessation or relief from withdrawal symptoms. The availability of effective, affordable treatment offered by health care professionals will be invaluable in ensuring the success of the policy (5, 6, 285). Coverage by insurance programmes is critical, as are individualized services for populations who may have greater adverse effects, such as people with co-morbid psychiatric disorders (2). The widespread availability of pharmacological treatment might not only limit the discomfort associated with reduced nicotine in cigarettes but also substantially reduce cigarette smoking and possibly lead to cessation of all tobacco and nicotine products by some or many current smokers. Surveillance
The public health community has been slow to recognize the potential limitations of regulatory or harm-reduction approaches, despite early evidence of their ineffectiveness (22, 281). An adequate surveillance system will permit regulators to monitor the effects of tobacco products on the prevalence and initiation of their use and the associated harm and to address unintended outcomes (7). Mandatory reporting regulations for all nicotine and tobacco products, as adopted in Canada and described in Articles 9 and 10 of the WHO FCTC, are a necessary condition of adequate surveillance. Reporting should include physical design components (tobacco weight, nicotine concentration, filter ventilation), tobacco and added constituents, emissions (for combustible products) and measures of the likelihood of abuse (7, 18, 281, 287). Hatsukami et al. (7) and Stratton et al. (17) described a comprehensive approach for evaluating tobacco products that could be effective for continuous evaluation of reduced-nicotine cigarettes. The approach includes: preclinical tests in experimental animals to assess the likelihood of abuse, acquisition of nicotine self-administration by both adolescent and adult animals and neurophysiological changes that affect function; imaging, laboratory tests and clinical trials in humans to determine the likelihood of abuse, tobacco use patterns, exposure to toxicants and potential health risks in general and vulnerable populations; and assessment of moderating factors, including how the consumer perceives the product and its appeal, its packaging, price and promotion (7). Although testing for biomarkers in large studies of smokers is a promising method for evaluating disease risk, it may not be feasible in countries with few resources (281). The complexity of tobacco products and the expertise required to assess toxicological results, the likelihood of abuse or other outcome measures, may prove to be additional barriers. McNeill et al. (281) called for a global data repository to facilitate implementation of tobacco product regulations and surveillance worldwide. The repository would ease the burden
211
of regulators for collecting and analysing data, allow global comparisons and make information and recommendations available to national regulators in a readily understandable form. Consumer education and beliefs
The effects of a reduced nicotine policy will depend in part on how effectively risks are communicated and on the relative appeal of reduced-nicotine and of other tobacco or nicotine products. Beliefs about the greater safety of reduced-nicotine products could reduce the likelihood of quitting or switching to safer alternatives and could encourage greater experimentation with cigarettes. Limited evidence suggests that smokers believe that reduced-nicotine cigarettes are less harmful. Shadel et al. (300) evaluated beliefs after exposure to a single print advertisement for a nicotine-free product (Quest). Smokers made a number of false inferences about the product: that it had a lower tar content and was “healthier” and less likely to cause cancer. The denicotinized Philip Morris brand Next was developed in response to interest in no-nicotine products in focus groups that perceived the product as healthier and as potentially facilitating quitting (205). Despite interest in reduced-exposure products, smokers express doubt about health claims for reduced-exposure products, about whether they would actually switch to such a product and whether the product would taste as good as conventional cigarettes (301). These and other responses are likely to be affected by marketing and communication by manufacturers, public health communication strategies in support of nicotine reduction and the availability and public knowledge of other tobacco or nicotine products. Both smokers and non-smokers must be educated about the health risks of tobacco without nicotine, the relative harm of the available products and opportunities for treatment. Marketing of tobacco and nicotine products must be strongly regulated (7, 281) Public support for a reduced nicotine policy
Studies in the USA showed strong public support for mandated nicotine reduction. In a survey of 511 non-smokers and 510 smokers, 65% supported a reduction in nicotine in cigarettes to non-addictive levels; these comprised 73% of the non-smokers and 58% of the smokers. More than three in four participants (77%), including 81% of non-smokers and 74% of smokers, said that they would support a reduction in nicotine if it resulted in fewer children becoming addicted to cigarettes. Non-smokers were significantly more likely
212
than smokers to support a reduction of nicotine levels in cigarettes (302). In another survey, 67% of smokers said they would support a Food and Drug Administration regulation that made cigarettes less addictive if “nicotine was made easily available in non-cigarette form” (303). In a cross-sectional survey of 2649 adults, nearly half supported a reduction in nicotine, comprising 46% of people who had never smoked, 49% of former smokers and 46% of current smokers. Among smokers, support was greatest among those who intended to quit within the next 6 months (304). This survey was the only one of the three that included a neutral response option, and nearly 27% of respondents chose this option, which might explain the closer agreement in the other surveys. Unintended market consequences
Reduced access to nicotine-containing cigarettes might increase the demand for contraband cigarettes among addicted smokers (6). Minimizing illicit cigarette sales will require effective surveillance strategies (7) and policies to limit the contraband market (268). Most worldwide smuggling is on a large scale and well organized, in which containers of cigarettes are exported by tobacco manufacturers to countries in which they have no legal market (267, 268). Successful attempts to control smuggling have involved making manufacturers liable for the safe transport of cigarettes to legitimate markets. Chain-of-custody markings would require manufacturers to print legibly, on all packages of tobacco products, a unique serial number to identify the manufacturer and the date and location of manufacture and another identifier to show the chain of custody—wholesaler, exporter, distributor and end market. Other successful anti-smuggling measures include scanners for detecting containers, prominent fiscal marks on packs, stronger punishment, more customs officers and parliamentary hearings to expose tobacco industry export practices. These approaches have resulted in reductions in cigarette smuggling from around 15% to 1–2% in Italy and Spain and significant reductions in the United Kingdom (268). Voluntary approaches have had no measurable effect. Besides large-scale, organized smuggling, illegal trade also includes bootlegged or counterfeit products. These products could contain extremely low-grade tobaccos with high levels of toxins or present other, unanticipated risks for the subset of smokers who use them. As noted by Benowitz and Henningfield (6), however, it is difficult to imagine growth of a bootlegged cigarette industry operating outside of regulatory control that would be sufficient in scale to rival the present cigarette market. Unregulated combustible tobacco, such as roll-your-own, could become a substitute for manufactured cigarettes. Other possibilities include significant dual use of reduced-nicotine cigarettes in conjunction with nicotine delivery
213
devices, pH modification or additives to increase the pharmacological effect of manufactured products and significant unanticipated behavioural changes in use of reduced-nicotine products as a result of long-term use. The availability of more appealing alternative nicotine products would be likely to function as a check on these unintended market outcomes (6, 7). Summary
•
Comprehensive, coordinated regulation of all tobacco- and nicotine-containing products is necessary for successful implementation of a nicotine reduction policy. Regulating the total nicotine available in unburnt cigarettes is the most promising approach to nicotine reduction, as it is both more easily measured and less subject to behavioural manipulation and variation. Performance standards exclusively for the nicotine content of tobacco would be likely to encourage the development of cigarettes that contain relatively little tobacco nicotine but are quite different in form and function from conventional cigarettes. New products and technologies must be carefully evaluated and their commercial introduction permitted only once the reduced risk, addictiveness and appeal of the products have been sufficiently demonstrated. A gradual reduction in nicotine over a course of years might have unintended consequences, which have yet to be studied. Neither progressive reduction over months nor immediate reduction had adverse effects or led to compensatory smoking. Smokers are likely to switch to alternative products. The most promising of these are electronic cigarettes and other devices that both provide nicotine and have the sensory characteristics of cigarettes, in the absence of tobacco. Behavioural counselling and pharmacotherapy to assist smokers with significant withdrawal symptoms and those who wish to quit should be made more widely available to support nicotine reduction. An adequate surveillance system is necessary to enable regulators to monitor the impact of reduced-nicotine cigarettes on the prevalence and initiation of use, and to assess the associated harm and unintended outcomes. Countries that cannot support a large-scale surveillance system might require assistance. Beliefs about the greater safety of reduced-nicotine products might reduce the likelihood of quitting or switching to safer alternatives. Public health
•
•
•
•
•
•
•
•
214
communication strategies and regulation of marketing are critical. • Public support for reducing nicotine in cigarettes is high among both smokers and non-smokers in the USA, particularly if other forms of nicotine were made available. Successful attempts to control smuggling have involved making manufacturers liable for the safe transport of cigarettes to their legitimate markets. Health might be threatened by contraband cigarettes sold on a smaller scale, unregulated forms of tobacco, dual use and modifications made to reduced-nicotine cigarettes to increase or replace the effectiveness of nicotine.
• •
Conclusions Although scientific research on nicotine reduction and the use of reduced-nicotine cigarettes remains limited, the agreement among the available studies is striking. The findings of studies in experimental animals and humans are broadly comparable: they show similar thresholds for self-administration, effects of both sensory stimuli and broad classes of tobacco compounds (monoamine oxidases, alkaloids) on nicotine reinforcement, the importance of acquisition of dependence in adolescence rather than adulthood and a relative lack of withdrawal or adverse effects with a progressive reduction in nicotine. On the basis of the weight of the evidence presented above, the most likely consequences of mandated nicotine reduction include: • • • • a reduction in the acquisition of smoking and progression to addiction among novice smokers; a reduction in smoking by some proportion of addicted smokers as a result of behavioural extinction; an increase in the rate of quitting and a reduction in the number of quitters who relapse; increased use and availability of alternative forms of nicotine, including oral or smokeless tobacco products, nicotine aerosol or vapour products and medicinal nicotine; and a reduction in the health risks of most smokers, reflecting reduced consumption, reduced exposure to tobacco smoke and reduced levels of toxicants in tobacco (e.g. tobacco-specific nitrosamines, nicotine). Possible consequences of mandated nicotine reduction, for which there is currently too little information to make judgements, include:
•
•
215
• • •
an increased proportion of smokers using black market cigarettes with a high nicotine content; an increased proportion of some smokers using both nicotine-containing products and reduced-nicotine cigarettes; changes in the design or construction of reduced-nicotine products, by manufacturers or by smokers, that alter the delivery characteristics of the product, with unanticipated effects on toxicity, addiction and appeal; increased use of nicotine-containing products by non-smokers and people who would not have smoked, because of their greater availability and appeal and the lower perceived risk of disease; and greater long-term use of reduced-nicotine cigarettes by women than men. Other potential but less likely outcomes of a mandated nicotine reduction include: increased smoke intake (more puffing or more cigarettes per day) by some proportion of smokers as a compensatory response to lack of nicotine; an increased risk for cardiovascular disease among continuing smokers as a result of exposure to tobacco smoke in the absence of nicotine; increased use of other drugs of abuse potentiated by exposure to reduced-nicotine cigarettes; and a significant black market for high-nicotine cigarettes replacing or supplanting the regulated cigarette market.
•
• • • • • •
Recommendations A nicotine reduction policy is technically feasible, is supported by smokers and non-smokers and is likely to have a significant positive impact on population health. It should therefore be supported by comprehensive regulation of all nicotine- and tobacco-containing products. Comprehensive regulation should encourage the use of products that are less toxic, such as medicinal nicotine and nicotine delivery devices, and should reduce the availability and appeal of more toxic products. There is strong evidence that the threshold level of nicotine in cigarettes required for reinforcement is 0.1–0.2 mg of delivered nicotine. This level is at or below the level of nicotine self-administered by smokers (0.1–0.4 mg) and animal models (0.2–0.5 mg) and at or below the threshold for discrimination of nicotine by both smokers and non-smokers. It is consistent with studies of the threshold for latency effects of cigarette nicotine yield conducted by manufacturers (0.1–0.3 mg).
216
Mandated nicotine reduction over a relatively short time had few adverse withdrawal or behavioural effects. A more gradual reduction might have unintended behavioural and health consequences. The availability of effective, affordable treatment and of alternative forms of nicotine will help dependent smokers who experience adverse effects. Population outcomes in a number of areas have not been predicted. Research should be conducted to determine the likelihood of use and the effects of reduced-nicotine cigarettes by non-smoking adolescents, non-smoking adults and non-dependent smokers. Further studies should be done among populations at risk, such as people with moderate or severe depression, and on the relative health effects of reduced-nicotine and nicotine-containing cigarettes. Studies should also be performed on long-term use of reduced-nicotine cigarettes.
References 1. 2. Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction. The implications for tobacco regulation. N Engl J Med 1994;331:123–5. Henningfield JE, Benowitz NL, Slade J, Houston TP, Davis RM, Deitchman SD. Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American Medical Association. Tob Control 1998;7:281–93. Gray N, Henningfield JE, Benowitz NL, Connolly GN, Dresler G, Fagerstrom K, et al. Toward a comprehensive long term nicotine policy. Tob Control 2005;14:161–5. Tengs TO, Ahmad S, Savage JM, Moore R, Gage E. The AMA proposal to mandate nicotine reduction in cigarettes: a simulation of the population health impacts. Prev Med 2005;40:170–80. Zeller M, Hatsukami D, Strategic Dialogue on Tobacco Harm Reduction G. The Strategic Dialogue on Tobacco Harm Reduction: a vision and blueprint for action in the US. Tob Control 2009;18:324–32. Benowitz NL, Henningfield JE. Reducing the nicotine content to make cigarettes less addictive. Tob Control 2013;22(Suppl 1):i14–7. Hatsukami DK, Benowitz NL, Donny E, Henningfield J, Zeller M. Nicotine reduction: strategic research plan. Nicotine Tob Res 2013;15:1003–13. Smith TT, Levin ME, Schassburger RL, Buffalari DM, Sved AF, Donny EC. Gradual and immediate nicotine reduction result in similar low-dose nicotine self-administration. Nicotine Tob Res 2013;15:1918–25. Framework Convention on Tobacco Control. Geneva: World Health Organization; 2013 (http://www.who.int/fctc/en/).
3. 4.
5.
6. 7. 8.
9.
10. Report on the Scientific Basis of Tobacco Product Regulation: Fourth Report of
217
a WHO Study Group (WHO Technical Report Series, No. 967). Geneva: World Health Organization; 2012 (http://www.who.int/tobacco/publications/prod_ regulation/trs_967/en/index.html). 11. Jarvis MJ, Bates C. Eliminating nicotine in cigarettes. Tob Control 1999;8:106–7; author reply 107–9. 12. Shatenstein S. Eliminating nicotine in cigarettes. Tob Control 1999;8:106; author reply 107–9. 13. Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P 3rd. Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarette. Cancer Epidemiol Biomarkers Prev 2007;16:2479–85. 14. Hatsukami DK, Kotlyar M, Hertsgaard LA, Zhang Y, Carmella SG, Jensen JA, et al. Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation. Addiction 2010;105:343–55. 15. Benowitz NL, Dains KM, Hall SM, Stewart S, Wilson M, Dempsey D, et al. Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 2012;21:761–9. 16. Henningfield JE, Benowitz N, Connolly G, Davis R, Gray N, Myers M, et al. Reducing tobacco addiction through tobacco product regulation. Tob Control 2004;13:132–5. 17. Stratton K, Shetty P, Wallace R, Bondurant S. Clearing the smoke: the science base for tobacco harm reduction—executive summary. Tob Control 2001;10:189–95. 18. Hatsukami DK, Biener L, Leischow SJ, Zeller MR. Tobacco and nicotine product testing. Nicotine Tob Res 2012;14:7–17. 19. Hoffmann D, Hoffmann I. The changing cigarette, 1950–1995. J Toxicol Environ Health 1997;50:307–64. 20. Risks associated with smoking cigarettes with low tar machine-measured yields of tar and nicotine (Monograph 13). Bethesda, Maryland: National Cancer Institute; 2001. 21. Benowitz NL, Jacob P 3rd. Intravenous nicotine replacement suppresses nicotine intake from cigarette smoking. J Pharmacol Exp Ther 1990;254:1000–5. 22. Parascandola M. Tobacco harm reduction and the evolution of nicotine dependence. Am J Public Health 2011;101:632–41. 23. Benowitz NL. Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 2008;83:531–41. 24. Heishman SJ, Kleykamp BA, Singleton EG. Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology 2010;210:453–69. 25. DiFranza J, Ursprung WW, Lauzon B, Bancej C, Wellman RJ, Ziedonis D, et al. A systematic review of the Diagnostic and Statistical Manual diagnostic criteria for nicotine dependence. Addict Behav 2010;35:373–82.
218
26. Wayne GF, Carpenter CM. Tobacco industry manipulation of nicotine dosing. Handb Exp Pharmacol 2009;192:457–85. 27. Henningfield JE, Goldberg SR. Control of behavior by intravenous nicotine injections in human subjects. Pharmacol Biochem Behav 1983;19:1021–6. 28. DiFranza JR, Ursprung WW, Carson A. New insights into the compulsion to use tobacco from an adolescent case-series. J Adolesc 2010;33:209–14. 29. Wellman RJ, DiFranza JR, Savageau JA, Dussault GF. Short term patterns of early smoking acquisition. Tob Control 2004;13:251–7. 30. DiFranza JR, Savageau JA, Fletcher K, O’Loughlin JE, Pbert L, Ockene JK, et al. Symptoms of tobacco dependence after brief intermittent use: the Development and Assessment of Nicotine Dependence in Youth-2 study. Arch Pediatr Adolesc Med 2007;161:704–10. 31. DiFranza JR, Savageau JA, Fletcher K, Pbert L, O’Loughlin J, McNeill AD, et al. Susceptibility to nicotine dependence: the Development and Assessment of Nicotine Dependence in Youth 2 study. Pediatrics 2007;120:e974–83. 32. Lynch BS, Bonnie RJ, editors. Growing up tobacco free—preventing nicotine addiction in children and youths. Washington DC: Institute of Medicine, The National Academies; 1994:28–68. 33. Lessov-Schlaggar CN, Pergadia ML, Khroyan TV, Swan GE. Genetics of nicotine dependence and pharmacotherapy. Biochem Pharmacol 2008;75:178–95. 34. Taioli E, Wynder EL. Effect of the age at which smoking begins on frequency of smoking in adulthood. N Engl J Med 1991;325:968–9. 35. Breslau N, Peterson EL. Smoking cessation in young adults: age at initiation of cigarette smoking and other suspected influences. Am J Public Health 1996;86:214–20. 36. Lando HA, Thai DT, Murray DM, Robinson LA, Jeffery RW, Sherwood NE, et al. Age of initiation, smoking patterns, and risk in a population of working adults. Prev Med 1999;29:590–8. 37. Cui Y, Wen W, Moriarty CJ, Levine RS. Risk factors and their effects on the dynamic process of smoking relapse among veteran smokers. Behav Res Ther 2006;44:967–81. 38. Trauth JA, Seidler FJ, McCook EC, Slotkin TA. Adolescent nicotine exposure causes persistent upregulation of nicotinic cholinergic receptors in rat brain regions. Brain Res 1999;851:9–19. 39. Trauth JA, Seidler FJ, Slotkin TA. Persistent and delayed behavioral changes after nicotine treatment in adolescent rats. Brain Res 2000;880:167–72. 40. Adriani W, Macri S, Pacifici R, Laviola G. Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence. Neuropsychopharmacology 2002;27:212–24. 41. Vastola BJ, Douglas LA, Varlinskaya EI, Spear LP. Nicotine-induced conditioned place preference in adolescent and adult rats. Physiol Behav 2002;77:107–14. 42. Adriani W, Spijker S, Deroche-Gamonet V, Laviola G, Le Moal M, Smit AB,
219
et al. Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats. J Neurosci 2003;23:4712–6. 43. Levin ED, Lawrence S, Petro A, Horton K, Rezvani AH, Seidler FJ, et al. Adolescent vs adult-onset nicotine self-administration in male rats: duration of effect and differential nicotinic receptor correlates. Neurotoxicol Teratol 2007;29:458–65. 44. Kota D, Martin BR, Damaj MI. Age-dependent differences in nicotine reward and withdrawal in female mice. Psychopharmacology 2008;198:201–10. 45. Hatsukami DK, Perkins KA, LeSage MG, Ashley DL, Henningfield JE, Benowitz NL, et al. Nicotine reduction revisited: science and future directions. Tob Control 2010;19:e1–10. 46. Hukkanen J, Jacob P 3rd, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev 2005;57:79–115. 47. Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P 3rd. Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther 2006;79:480–8. 48. Sofuoglu M, Mooney M. Subjective responses to intravenous nicotine: greater sensitivity in women than in men. Exp Clin Psychopharmacol 2009;17:63–9. 49. Fant RV, Everson D, Dayton G, Pickworth WB, Henningfield JE. Nicotine dependence in women. J Am Med Womens Assoc 1996;51:19–20, 22–4, 28. 50. Gritz ER, Nielsen IR, Brooks LA. Smoking cessation and gender: the influence of physiological, psychological, and behavioral factors. J Am Med Womens Assoc 1996;51:35–42. 51. Eissenberg T, Adams C, Riggins EC 3rd, Likness M. Smokers’ sex and the effects of tobacco cigarettes: subject-rated and physiological measures. Nicotine Tob Res 1999;1:317–24 52. Perkins KA, Donny E, Caggiula AR. Sex differences in nicotine effects and self-administration: review of human and animal evidence. Nicotine Tob Res 1999;1:301–15. 53. Wetter DW, Kenford SL, Smith SS, Fiore MC, Jorenby DE, Baker TB. Gender differences in smoking cessation. J Consult Clin Psychol 1999;67:555–62. 54. Perkins KA, Sanders M, D’Amico D, Wilson A. Nicotine discrimination and selfadministration in humans as a function of smoking status. Psychopharmacology 1997;131:361–70. 55. Carpenter CM, Wayne GF, Connolly GN. Designing cigarettes for women: new findings from the tobacco industry documents. Addiction 2005;100:837–51. 56. Perkins KA, Doyle T, Ciccocioppo M, Conklin C, Sayette M, Caggiula A. Sex differences in the influence of nicotine dose instructions on the reinforcing and selfreported rewarding effects of smoking. Psychopharmacology 2006;184:600–7. 57. Bevins RA, Caggiula AR. Nicotine, tobacco use, and the 55th Nebraska Symposium on Motivation. Nebr Symp Motiv 2009;55:1–3. 58. Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH.
220
Smoking and mental illness: a population-based prevalence study. JAMA 2000;284:2606–10. 59. Williams JM, Ziedonis D. Addressing tobacco among individuals with a mental illness or an addiction. Addict Behav 2004;29:1067–83. 60. Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 2008;10:1691–715. 61. Lawrence D, Considine J, Mitrou F, Zubrick SR. Anxiety disorders and cigarette smoking: results from the Australian Survey of Mental Health and Wellbeing. Aust N Z J Psychiatry 2010;44:520–7. 62. McClave AK, McKnight-Eily LR, Davis SP, Dube SR. Smoking characteristics of adults with selected lifetime mental illnesses: results from the 2007 National Health Interview Survey. Am J Public Health 2010;100:2464–72. 63. Schroeder SA, Morris CD. Confronting a neglected epidemic: tobacco cessation for persons with mental illnesses and substance abuse problems. Annu Rev Public Health 2010;31:297–314 1p following 314. 64. Leonard S, Adler LE, Benhammou K, Berger R, Breese CR, Drebing C, et al. Smoking and mental illness. Pharmacol Biochem Behav 2001;70:561–70. 65. Leonard S, Adams CE. Smoking cessation and schizophrenia. Am J Psychiatry 2006;163:1877. 66. Mineur YS, Picciotto MR. Biological basis for the co-morbidity between smoking and mood disorders. J Dual Diagn 2009;5:122–30. 67. Mineur YS, Picciotto MR. Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis. Trends Pharmacol Sci 2010;31:580–6. 68. Lewis A, Miller JH, Lea RA. Monoamine oxidase and tobacco dependence. Neurotoxicology 2007;28:182–95. 69. Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA. Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry 2004;61:1107–15. 70. Lawrence D, Mitrou F. One-third of adult smokers have a mental illness. Aust N Z J Psychiatry 2009;43:177–8. 71. Watson NL, Carpenter MJ, Saladin ME, Gray KM, Upadhyaya HP. Evidence for greater cue reactivity among low-dependent vs. high-dependent smokers. Addict Behav 2010;35:673–7. 72. Plescia F, Brancato A, Marino RA, Cannizzaro C. Acetaldehyde as a drug of abuse: insight into AM281 administration on operant-conflict paradigm in rats. Front Behav Neurosci 2013;7:64. 73. Talhout R, Opperhuizen A, van Amsterdam JG (2007) Role of acetaldehyde in tobacco smoke addiction. Eur Neuropsychopharmacol 17:627–36. 74. Villégier AS, Lotfipour S, McQuown SC, Belluzzi JD, Leslie FM. Tranylcypromine enhancement of nicotine self-administration. Neuropharmacology 2007;52:1415–25.
221
75. Pankow JF. A consideration of the role of gas/particle partitioning in the deposition of nicotine and other tobacco smoke compounds in the respiratory tract. Chem Res Toxicol 2001;14:1465–81. 76. Henningfield J, Pankow J, Garrett B. Ammonia and other chemical base tobacco additives and cigarette nicotine delivery: issues and research needs. Nicotine Tob Res 2004;6:199–205. 77. Rose JE. Nicotine and nonnicotine Psychopharmacology 2006;184:274–85. factors in cigarette addiction.
78. Carpenter CM, Wayne GF, Connolly GN. The role of sensory perception in the development and targeting of tobacco products. Addiction 2007;102:136–47. 79. Breland AB, Buchhalter AR, Evans SE, Eissenberg T. Evaluating acute effects of potential reduced-exposure products for smokers: clinical laboratory methodology. Nicotine Tob Res 2002;4(Suppl 2):S131-40. 80. Perkins KA, Gerlach D, Broge M, Grobe JE, Sanders M, Fonte C, et al. Dissociation of nicotine tolerance from tobacco dependence in humans. J Pharmacol Exp Ther 2001;296:849–56. 81. Rose JE, Behm FM. Extinguishing the rewarding value of smoke cues: pharmacological and behavioral treatments. Nicotine Tob Res 2004;6:523–32. 82. Rose J, Behm F. Effects of low nicotine content cigarettes on smoke intake. Nicotine Tob Res 2004;6:309–19. 83. Lee LY, Gerhardstein DC, Wang AL, Burki NK. Nicotine is responsible for airway irritation evoked by cigarette smoke inhalation in men. J Appl Physiol 1993;75:1955–61. 84. Rose JE, Behm FM, Westman EC, Johnson M. Dissociating nicotine and nonnicotine components of cigarette smoking. Pharmacol Biochem Behav 2000;67:71–81. 85. Rose JE, Behm FM, Westman EC, Coleman RE. Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction. Drug Alcohol Depend 1999;56:99–107. 86. Ferris Wayne G, Connolly GN. Application, function, and effects of menthol in cigarettes: a survey of tobacco industry documents. Nicotine Tob Res 2004;6(Suppl 1):S43–54. 87. Celebucki CC, Wayne GF, Connolly GN, Pankow JF, Chang EI. Characterization of measured menthol in 48 US cigarette sub-brands. Nicotine Tob Res 2005;7:523–31. 88. Galeotti N, Ghelardini C, Mannelli L, Mazzanti G, Baghiroli L, Bartolini A. Local anaesthetic activity of (+)- and (–)-menthol. Planta Med 2001;67:174–6. 89. Shojaei AH, Khan M, Lim G, Khosravan R. Transbuccal permeation of a nucleoside analog, dideoxycytidine: effects of menthol as a permeation enhancer. Int J Pharm 1999;192:139–46. 90. Brody AL, Mandelkern M, Costello MR, Abrams AL, Scheibal D, Farahi J, et al. Brain nicotinic acetylcholine receptor occupancy: effect of smoking a
222
denicotinized cigarette. Int J Neuropsychopharmacol 2009;12:305–16. 91. Bardo MT, Green TA, Crooks PA, Dwoskin LP. Nornicotine is self-administered intravenously by rats. Psychopharmacology 1999;146:290–6. 92. Clemens KJ, Caille S, Stinus L, Cador M. The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats. Int J Neuropsychopharmacology 2009;12:1355–66. 93. Rodd-Henricks ZA, Melendez RI, Zaffaroni A, Goldstein A, McBride WJ, Li TK. The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of alcohol-preferring rats. Pharmacol Biochem Behav 2002;72:55–64. 94. Belluzzi JD, Wang R, Leslie FM.Acetaldehyde enhances acquisition of nicotine selfadministration in adolescent rats. Neuropsychopharmacology 2005;30:705–12. 95. Cao J, Belluzzi JD, Loughlin SE, Keyler DE, Pentel PR, Leslie FM. Acetaldehyde, a major constituent of tobacco smoke, enhances behavioral, endocrine, and neuronal responses to nicotine in adolescent and adult rats. Neuropsychopharmacology 2007;32:2025–35. 96. Guillem K, Vouillac C, Koob JF, Cador M, Stinus L. Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats. J Neurosci 2005;25:8593–600. 97. Guillem K, Vouillac C, Koob GF, Cador M, Stinus L. Monoamine oxidase inhibition dramatically prolongs the duration of nicotine withdrawal-induced place aversion. Biol Psychiatry 2008;63:158–63. 98. Rose JE, Behm FM, Ramsey C, Ritchie JC Jr. Platelet monoamine oxidase, smoking cessation, and tobacco withdrawal symptoms. Nicotine Tob Res 2001;3:383–90. 99. The health consequences of smoking: nicotine addiction. A report of the Surgeon General. Rockville, Maryland: Department of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health; 1988. 100. Dar R, Frenk H. Do smokers self-administer pure nicotine? A review of the evidence. Psychopharmacology 2004;173:18–26. 101. Fulton HG, Barrett SP. A demonstration of intravenous nicotine self-administration in humans? Neuropsychopharmacology 2008;33:2042–3; author reply 2044. 102. Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved AF. Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav 2002;77:683–7. 103. Olausson P, Jentsch JD, Taylor JR. Repeated nicotine exposure enhances reward-related learning in the rat. Neuropsychopharmacology 2003;28:1264–71. 104. Olausson P, Jentsch JD, Taylor JR. Nicotine enhances responding with conditioned reinforcement. Psychopharmacology 2004;171:173–8. 105. Chaudhri N, Caggiula AR, Donny EC, Palmatier MI, Liu X, Sved AF. Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement. Psychopharmacology 2006;184:353–66.
223
106. Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, et al. Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule. Psychopharmacology 2007;190:353–62. 107. Palmatier MI, Liu X, Caggiula AR, Donny EC, Sved AF. The role of nicotinic acetylcholine receptors in the primary reinforcing and reinforcement-enhancing effects of nicotine. Neuropsychopharmacology 2007;32:1098–108. 108. Palmatier MI, Liu X, Matteson GL, Donny EC, Caggiula AR, Sved AF. Conditioned reinforcement in rats established with self-administered nicotine and enhanced by noncontingent nicotine. Psychopharmacology 2007;195:235–43. 109. Le Foll B, Goldberg SR. Control of the reinforcing effects of nicotine by associated environmental stimuli in animals and humans. Trends Pharmacol Sci 2005;26:287–93. 110. Cohen C, Perrault G, Griebel G, Soubrie P. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology 2005;30:145–55. 111. Le Foll B, Wertheim C, Goldberg SR. High reinforcing efficacy of nicotine in nonhuman primates. PloS One 2007;2:e230. 112. Donny EC, Chaudhri N, Caggiula AR, Evans-Martin FF, Booth S, Gharib MA, et al. Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology 2003;169:68–76. 113. Caggiula AR, Donny EC, Palmatier MI, Liu X, Chaudhri N, Sved AF. The role of nicotine in smoking: a dual-reinforcement model. Nebr Symp Motiv 2009;55:91– 109. 114. Carter BL, Tiffany ST. Cue-reactivity and the future of addiction research. Addiction 1999;94:349–51. 115. Donny EC, Houtsmuller E, Stitzer ML. Smoking in the absence of nicotine: behavioral, subjective and physiological effects over 11 days. Addiction 2007;102:324–34. 116. Rees VW, Kreslake JM, Wayne GF, O’Connor RJ, Cummings KM, Connolly GN. Role of cigarette sensory cues in modifying puffing topography. Drug Alcohol Depend 2012;124:1–10. 117. Palmatier MI, Lantz JE, O’Brien LC, Metz SP. Effects of nicotine on olfactogustatory incentives: preference, palatability, and operant choice tests. Nicotine Tob Res 2013;15:1545–54. 118. Perkins KA, Jacobs L, Ciccocioppo M, Conklin C, Sayette M, Caggiula A. The influence of instructions and nicotine dose on the subjective and reinforcing effects of smoking. Exp Clin Psychopharmacol 2004;12:91–101. 119. Perkins KA, Ciccocioppo M, Conklin CA, Milanak ME, Grottenthaler A, Sayette MA. Mood influences on acute smoking responses are independent of nicotine intake and dose expectancy. J Abnorm Psychol 2008;117:79–93.
224
120. Darredeau C, Barrett SP. The role of nicotine content information in smokers’ subjective responses to nicotine and placebo inhalers. Hum Psychopharmacol 2010;25:577–81. 121. Juliano LM, Fucito LM, Harrell PT. The influence of nicotine dose and nicotine dose expectancy on the cognitive and subjective effects of cigarette smoking. Exp Clin Psychopharmacology 2011;19:105–15. 122. Kirsch I, Lynn SJ. Automaticity in clinical psychology. Am Psychol 1999;54:504–15 123. Perkins K, Sayette M, Conklin C, Caggiula A. Placebo effects of tobacco smoking and other nicotine intake. Nicotine Tob Res 2003;5:695–709. 124. Hughes JR, Gulliver SB, Amori G, Mireault GC, Fenwick JF. Effect of instructions and nicotine on smoking cessation, withdrawal symptoms and self-administration of nicotine gum. Psychopharmacology 1989;99:486–91. 125. Perkins KA, Coddington SB, Karelitz JL, Jetton C, Scott JA, Wilson AS, et al. Variability in initial nicotine sensitivity due to sex, history of other drug use, and parental smoking. Drug Alcohol Depend 2009;99:47–57. 126. Juliano LM, Brandon TH. Effects of nicotine dose, instructional set, and outcome expectancies on the subjective effects of smoking in the presence of a stressor. J Abnorm Psychol 2002;111:88–97. 127. Wayne GF, Connolly GN, Henningfield JE. Assessing internal tobacco industry knowledge of the neurobiology of tobacco dependence. Nicotine Tob Res 2004;6:927–40. 128. Megerdichian CL, Rees VW, Wayne GF, Connolly GN. Internal tobacco industry research on olfactory and trigeminal nerve response to nicotine and other smoke components. Nicotine Tob Res 2007;9:1119–29. 129. Darredeau C, Stewart SH, Barrett SP. The effects of nicotine content information on subjective and behavioural responses to nicotine-containing and denicotinized cigarettes. Behav Pharmacol 2013;24:291–7. 130. Perkins KA, Grottenthaler A, Ciccocioppo MM, Conklin CA, Sayette MA, Wilson AS. Mood, nicotine, and dose expectancy effects on acute responses to nicotine spray. Nicotine Tob Res 2009;11:540–6. 131. De Leon E, Smith KC, Cohen JE. Dependence measures for non-cigarette tobacco products within the context of the global epidemic: a systematic review. Tob Control 2013;23:197–203. 132. Hatsukami DK, Joseph AM, LeSage M, Jensen J, Murphy SE, Pentel PR, et al. Developing the science base for reducing tobacco harm. Nicotine Tob Res 2007;9(Suppl 4):S537–53. 133. Donny EC, Taylor TG, LeSage MG, Levin M, Buffalari DM, Joel D, et al. Impact of tobacco regulation on animal research: new perspectives and opportunities. Nicotine Tob Res 2012;14:1319–38. 134. Palmatier MI, O’Brien LC, Hall MJ. The role of conditioning history and reinforcer strength in the reinforcement enhancing effects of nicotine in rats. Psychopharmacology 2012;219:1119–31.
225
135. Henningfield JE, Miyasato K, Jasinski DR Cigarette smokers self-administer intravenous nicotine. Pharmacol Biochem Behav 1983;19:887–90. 136. Harvey DM, Yasar S, Heishman SJ, Panlilio LV, Henningfield JE, Goldberg SR. Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Psychopharmacology 2004;175:134–42. 137. Sofuoglu M, Yoo S, Hill KP, Mooney M. Self-administration of intravenous nicotine in male and female cigarette smokers. Neuropsychopharmacology 2008;33:715–20. 138. Matta SG, Balfour DJ, Benowitz NL, Boyd RT, Buccafusco JJ, Caggiula AR, et al. Guidelines on nicotine dose selection for in vivo research. Psychopharmacology 2007;190:269–319. 139. Cox BM, Goldstein A, Nelson WT. Nicotine self-administration in rats. Br J Pharmacol 1984;83:49–55 140. Shram MJ, Li Z, Le AD. Age differences in the spontaneous acquisition of nicotine self-administration in male Wistar and Long-Evans rats. Psychopharmacology 2008;197:45–58. 141. Corrigall WA, Coen KM. Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology 1989;99:473–8 142. Donny EC, Caggiula AR, Knopf S, Brown C. Nicotine self-administration in rats. Psychopharmacology 1995;122:390–4 143. Shoaib M, Schindler CW, Goldberg SR. Nicotine self-administration in rats: strain and nicotine pre-exposure effects on acquisition. Psychopharmacology 1997;129:35–43. 144. Watkins SS, Epping-Jordan MP, Koob GF, Markou A. Blockade of nicotine selfadministration with nicotinic antagonists in rats. Pharmacol Biochem Behav 1999;62:743–51. 145. Brower VG, Fu Y, Matta SG, Sharp BM. Rat strain differences in nicotine selfadministration using an unlimited access paradigm. Brain Res 2002;930:12–20. 146. DeNoble VJ, Mele PC. Intravenous nicotine self-administration in rats: effects of mecamylamine, hexamethonium and naloxone. Psychopharmacology 2006;184:266–72. 147. Sorge RE, Clarke PB. Rats self-administer intravenous nicotine delivered in a novel smoking-relevant procedure: effects of dopamine antagonists. J Pharmacol Exp Ther 2009;330:633–40. 148. Hanson HM, Ivester CA, Morton BR. Nicotine self-administration in rats. In: Krasnegor NA, editor. Cigarette smoking as a dependence process (NIDA Research Monograph 23). Washington DC: National Instiute on Drug Abuse; 1979:70–90. 149. Kota D, Martin BR, Robinson SE, Damaj MI. Nicotine dependence and reward differ between adolescent and adult male mice. J Pharmacol Exp Ther 2007;322:399–407. 150. Levin ED, Rezvani AH, Montoya D, Rose JE, Swartzwelder HS. Adolescent-
226
onset nicotine self-administration modeled in female rats. Psychopharmacology 2003;169:141–9. 151. Chen H, Matta SG, Sharp BM. Acquisition of nicotine self-administration in adolescent rats given prolonged access to the drug. Neuropsychopharmacology 2007;32:700–9. 152. Shram MJ, Funk D, Li Z, Le AD. Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence. Neuropsychopharmacology 2008;33:739–48. 153. Shram MJ, Siu EC, Li Z, Tyndale RF, Le AD. Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats. Psychopharmacology 2008;198:181–90. 154. DiFranza JR, Savageau JA, Rigotti NA, Fletcher K, Ockene JK, McNeill AD, et al. Development of symptoms of tobacco dependence in youths: 30 month follow up data from the DANDY study. Tob Control 2002;11:228–35. 155. O’Loughlin J, Gervais A, Dugas E, Meshefedjian G. Nicotine-dependence symptoms are associated with smoking frequency in adolescents. Am J Prev Med 2003;25:219–25. 156. Gervais A, O’Loughlin J, Meshefedjian G, Bancej C, Tremblay M. Milestones in the natural course of onset of cigarette use among adolescents. Can Med Assoc J 2006;175:255–61. 157. Kandel DB, Hu MC, Griesler PC, Schaffran C. On the development of nicotine dependence in adolescence. Drug Alcohol Depend 2007;91:26–39. 158. Caraballo RS, Novak SP, Asman K. Linking quantity and frequency profiles of cigarette smoking to the presence of nicotine dependence symptoms among adolescent smokers: findings from the 2004 National Youth Tobacco Survey. Nicotine Tob Res 2009;11:49–57. 159. Corrigall WA, Zack M, Eissenberg T, Belsito L, Scher R. Acute subjective and physiological responses to smoking in adolescents. Addiction 2001;96:1409– 17. 160. Aung AT, Pickworth WB, Moolchan ET. History of marijuana use and tobacco smoking topography in tobacco-dependent adolescents. Addict Behav 2004;29:699–706. 161. Wood T, Wewers ME, Groner J, Ahijevych K. Smoke constituent exposure and smoking topography of adolescent daily cigarette smokers. Nicotine Tob Res 2004;6:853–62. 162. Kassel JD, Greenstein JE, Evatt DP, Wardle MC, Yates MC, Veilleux JC, et al. Smoking topography in response to denicotinized and high-yield nicotine cigarettes in adolescent smokers. J Adolesc Health 2007;40:54–60. 163. Wahl SK, Turner LR, Mermelstein RJ, Flay BR. Adolescents’ smoking expectancies: psychometric properties and prediction of behavior change. Nicotine Tob Res 2005;7:613–23.
227
164. Heinz AJ, Kassel JD, Berbaum M, Mermelstein R. Adolescents’ expectancies for smoking to regulate affect predict smoking behavior and nicotine dependence over time. Drug Alcohol Depend 2010;111:128–35. 165. Kassel JD, Evatt DP, Greenstein JE, Wardle MC, Yates MC, Veilleux JC. The acute effects of nicotine on positive and negative affect in adolescent smokers. J Abnorm Psychol 2007;116:543–53. 166. Baldinger B, Hasenfratz M, Battig K. Switching to ultralow nicotine cigarettes: effects of different tar yields and blocking of olfactory cues. Pharmacol Biochem Behav 1995;50:233–9. 167. Butschky MF, Bailey D, Henningfield JE, Pickworth WB. Smoking without nicotine delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacol Biochem Behav 1995;50:91–6. 168. Westman EC, Behm FM, Rose JE. Dissociating the nicotine and airway sensory effects of smoking. Pharmacol Biochem Behav 1996;53:309–15. 169. Gross J, Lee J, Stitzer ML. Nicotine-containing versus de-nicotinized cigarettes: effects on craving and withdrawal. Pharmacol Biochem Behav 1997;57:159–65. 170. Pickworth WB, Fant RV, Nelson RA, Rohrer MS, Henningfield JE. Pharmacodynamic effects of new de-nicotinized cigarettes. Nicotine Tob Res 1999;1:357–64. 171. Buchhalter AR, Schrinel L, Eissenberg T. Withdrawal-suppressing effects of a novel smoking system: comparison with own brand, not own brand, and denicotinized cigarettes. Nicotine Tob Res 2001;3:111–8. 172. Barrett SP. The effects of nicotine, denicotinized tobacco, and nicotine-containing tobacco on cigarette craving, withdrawal, and self-administration in male and female smokers. Behav Pharmacol 2010;21:144–52. 173. Brauer LH, Behm FM, Lane JD, Westman EC, Perkins C, Rose JE. Individual differences in smoking reward from de-nicotinized cigarettes. Nicotine Tob Res 2001;3(2):101–9. 174. Dallery J, Houtsmuller EJ, Pickworth WB, Stitzer ML. Effects of cigarette nicotine content and smoking pace on subsequent craving and smoking. Psychopharmacology 2003;165:172–80. 175. Rose JE, Behm FM, Westman EC, Bates JE, Salley A. Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav 2003;76:243–50. 176. Grady SR, Marks MJ, Collins AC. Desensitization of nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes. J Neurochem 1994;62:1390–8. 177. Lu Y, Marks MJ, Collins AC. Desensitization of nicotinic agonist-induced [3H]gamma-aminobutyric acid release from mouse brain synaptosomes is produced by subactivating concentrations of agonists. J Pharmacol Exp Ther 1999;291:1127–34. 178. Picciotto MR, Addy NA, Mineur YS, Brunzell DH. It is not “either/or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors
228
related to nicotine addiction and mood. Prog Neurobiol 2008;84:329–42. 179. Donny EC, Jones M. Prolonged exposure to denicotinized cigarettes with or without transdermal nicotine. Drug Alcohol Depend 2009;104:23–33. 180. Bouton ME. Context and behavioral processes in extinction. Learn Mem 2004;11:485–94. 181. International statistical classification of diseases and related health problems, 10th revision. Geneva: World Health Organization; 1992. 182. Moolchan ET, Radzius A, Epstein DH, Uhl G, Gorelick DA, Cadet JL, et al. The Fagerstrom test for nicotine dependence and the Diagnostic Interview Schedule: do they diagnose the same smokers? Addict Behav 2002;27:101–13. 183. Hughes JR, Oliveto AH, Riggs R, Kenny M, Liguori A, Pillitteri JL, et al. Concordance of different measures of nicotine dependence: two pilot studies. Addict Behav 2004;29:1527–39. 184. Hendricks PS, Prochaska JJ, Humfleet GL, Hall SM. Evaluating the validities of different DSM-IV-based conceptual constructs of tobacco dependence. Addiction 2008;103:1215–23. 185. Hughes JR, Baker T, Breslau N, Covey L, Shiffman S. Applicability of DSM criteria to nicotine dependence. Addiction 2011;106:894–5; discussion 895–7. 186. Colby SM, Tiffany ST, Shiffman S, Niaura RS. Measuring nicotine dependence among youth: a review of available approaches and instruments. Drug Alcohol Depend 2000;59(Suppl 1):S23–39. 187. Rose JS, Dierker LC. DSM-IV nicotine dependence symptom characteristics for recent-onset smokers. Nicotine Tob Res 2010;12:278–86. 188. Rubinstein ML, Luks TL, Moscicki AB, Dryden W, Rait MA, Simpson GV. Smoking-related cue-induced brain activation in adolescent light smokers. J Adolesc Health 2011;48:7–12. 189. Sofuoglu M, LeSage MG. The reinforcement threshold for nicotine as a target for tobacco control. Drug Alcohol Depend 2012;125:1–7. 190. Audrain-McGovern J, Rodriguez D, Epstein LH, Rodgers K, Cuevas J, Wileyto EP. Young adult smoking: what factors differentiate ex-smokers, smoking cessation treatment seekers and nontreatment seekers? Addict Behav 2009;34:1036-41. 191. Glautier S. Measures and models of nicotine dependence: positive reinforcement. Addiction 2004;99(Suppl 1):30–50. 192. Comer SD, Ashworth JB, Foltin RW, Johanson CE, Zacny JP, Walsh SL. The role of human drug self-administration procedures in the development of medications. Drug Alcohol Depend 2008;96:1–15. 193. Besheer J, Palmatier MI, Metschke DM, Bevins RA. Nicotine as a signal for the presence or absence of sucrose reward: a Pavlovian drug appetitive conditioning preparation in rats. Psychopharmacology 2004;172:108–17. 194. Bevins RA, Palmatier MI. Extending the role of associative learning processes in nicotine addiction. Behav Cogn Neurosci Rev 2004;3(3):143–58. 195. Wilkinson JL, Murray JE, Li C, Wiltgen SM, Penrod RD, Berg SA, Bevins RA.
229
Interoceptive Pavlovian conditioning with nicotine as the conditional stimulus varies as a function of the number of conditioning trials and unpaired sucrose deliveries. Behav Pharmacol 2006;17:161–72. 196. Murray JE, Bevins RA. Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus. Eur J Pharmacol 2007;561:91–104. 197. Palmatier MI, Coddington SB, Liu X, Donny EC, Caggiula AR, Sved AF. The motivation to obtain nicotine-conditioned reinforcers depends on nicotine dose. Neuropharmacology 2008;55:1425–30. 198. Panzano VC, Wayne GF, Pickworth WB, Connolly GN. Human electroencephalography and the tobacco industry: a review of internal documents. Tob Control 2010;19:153–9. 199. Gullotta FP, Hayes C. The effects of cigarette smoking on pattern reversal evoked potentials (preps). Philip Morris. Bates No. 2028817734–40; 1981 (http://legacy.library.ucsf.edu/tid/rfp12e00). 200. Gullotta FP, Hayes CS, Martin BR. Electrophysiological and subjective effect of cigarettes delivering varying amounts of nicotine. Philip Morris. Bates No. 2062374615–22; 1990 (http://legacy.library.ucsf.edu/tid/izy26c00). 201. Charles JL, Gullotta FP, Schultz CJ. Electrophysiological studies—820000 annual report. Philip Morris. Bates No. 2056128455–504; 1982 (http://legacy. library.ucsf.edu/tid/bra52e00). 202. Connolly GN, Alpert HR, Wayne GF, Koh H. Trends in nicotine yield in smoke and its relationship with design characteristics among popular US cigarette brands, 1997–2005. Tob Control 2007;16(5):e5. 203. Slade J, Bero LA, Hanauer P, Barnes DE, Glantz SA. Nicotine and addiction. The Brown and Williamson documents. J Am Med Assoc 1995;274:225–33. 204. Hurt RD, Robertson CR. Prying open the door to the tobacco industry’s secrets about nicotine: the Minnesota Tobacco Trial. J Am Med Assoc 1998;280:1173–81. 205. Dunsby J, Bero L. A nicotine delivery device without the nicotine? Tobacco industry development of low nicotine cigarettes. Tob Control 2004;13:362–9. 206. British American Tobacco. Research and Development Department: Progress in 1972—Plans for 1973. Bates No. 402409855–89; 1972 (http://legacy.library. ucsf.edu/tid/qdb84a99/). 207. British American Tobacco. Introductory notes on leaf blending. Bates No. 102638105–66; 1969 (http://legacy.library.ucsf.edu/tid/qmy36a99/). 208. Browne CL. The design of cigarettes. Charlotte, North Carolina: Hoechst Celanese; 1990. 209. Cohen N. Minutes of meeting on May 6 1971. British American Tobacco. Bates No. 103551202–4; 1971 (http://legacy.library.ucsf.edu/tid/rng84a99/). 210. Gibb RM. [Memo from RM Gibb to EP Gage regarding low nicotine]. Bates No. 103408473–4; 1974 (http://legacy.library.ucsf.edu/tid/kly06a99/). 211. Johnson DP. Low nicotine tobacco. RJ Reynolds. Bates No. 511040740; 1977 (http://legacy.library.ucsf.edu/tid/xsk53d00/).
230
212. Kentucky Tobacco Research Board. 1977 annual review. Bates No. 9809; 1977 (http://legacy.library.ucsf.edu/tid/omd76b00). 213. Smith TE. Tobacco and smoke characteristics of low nicotine strains of Burley. British American Tobacco. Bates No. 402379156–69; 1972 (http://legacy.library. ucsf.edu/tid/dly54a99/). 214. Geiss VL. Bw process. I Reductions of tobacco nicotine using selected bacteria. British American Tobacco. Bates No. 402350891–915; 1972 (http://legacy. library.ucsf.edu/tid/jlw84a99). 215. Geiss VL. Bw process. VI Metabolism of nicotine and other biochemistry of the Bw process. British American Tobacco. Bates No. 107474767–70; 1975 (http:// legacy.library.ucsf.edu/tid/gpx86a99/). 216. Gravely LE, Newton RP, Geiss VL. Bw process: IV Evaluation of low nicotine cigarettes used for consumer product testing. British American Tobacco. Bates No. 402371546–59; 1973 (http://legacy.library.ucsf.edu/tid/zso05a99/). 217. York JE. Control of nicotine in tobacco and cigarette smoke. American Tobacco. Bates No. 950796661–6; 1977 (http://legacy.library.ucsf.edu/tid/ywy90a00/). 218. Rickett FL, Pedersen PM. A review of methods for reduction of nicotine in tobacco. American Tobacco. Bates No. 950643646–55; 1980 (http://legacy. library.ucsf.edu/tid/rgd90a00/). 219. Ashburn G. Vapor-phase removal of nicotine from smoke. RJ Reynolds. Bates No. 500937661–714; 1961 (http://legacy.library.ucsf.edu/tid/cyo59d00). 220. Green CR. Denicotinization of low nicotine, high sugar flue cured tobacco. RJ Reynolds. Bates No. 504804962–3; 1979 (http://legacy.library.ucsf.edu/tid/ jwm55d00). 221. Kassman AJ, Knudson DB, Lilly AC, Sherwood JF. Alkaloid reduced Tobaco (ART) Program Current Status and Plans for 1987. Philip Morris. Bates No. 2051841630–44; 1986 (http://legacy.library.ucsf.edu/tid/xth52e00). 222. Philip Morris. Alkaloid reduced tobacco (ART) program. Philip Morris. Bates No. 2063096617–51; 1995 (http://legacy.library.ucsf.edu/tid/xus47d00). 223. Houghton KS. Monthly development summary—May, 1990. Philip Morris. Bates No. 2022156219–42; 1990 (http://legacy.library.ucsf.edu/tid/ggx44e00). 224. Gullotta F, Hayes C, Martin B. The effects of nicotine and menthol on electrophysiological and subjective responses. Philip Morris. Bates No. 2029213006–18; 1991 (http://legacy.library.ucsf.edu/tid/ezc69e00). 225. Philip Morris. Study concept: the electrophysiological and subjective effects of smoking cigarettes with constant nicotine but varying tar levels. Philip Morris. Bates No. 2025988473–5; 1995 (http://legacy.library.ucsf.edu/tid/vlo46b00). 226. Ferris Wayne G, Connolly GN, Henningfield JE. Brand differences of free-base nicotine delivery in cigarette smoke: the view of the tobacco industry documents. Tob Control 2006;15:189–98. 227. Ashley DL, Pankow JF, Tavakoli AD, Watson CH. Approaches, challenges, and experience in assessing free nicotine. Handb Exp Pharmacol 2009;192:437–56.
231
228. Gregory CF. Observation of free nicotine changes in tobacco smoke/528. Brown & Williamson. Bates No. 510000667–70; 1980 (http://legacy.library.ucsf.edu/tid/ zds24f00). 229. Shannon D, Walker RJ, Smith NA, Perfetti T, Ingebrethsen B, Saintsing B, et al. We Are Looking at Smoothness from a Different Perspective. RJ Reynolds. Bates No. 508408649–770; 1992 (http://legacy.library.ucsf.edu/tid/mcq93d00). 230. Pankow JF, Tavakoli AD, Luo W, Isabelle LM. Percent free base nicotine in the tobacco smoke particulate matter of selected commercial and reference cigarettes. Chem Res Toxicol 2003;16:1014–8. 231. Watson CH, Trommel JS, Ashley DL. Solid-phase microextraction-based approach to determine free-base nicotine in trapped mainstream cigarette smoke total particulate matter. J Agric Food Chem 2004;52:7240–5. 232. Benowitz NL, Jacob P III, Bernert JT, Wilson M, Wang L, Allen F, et al. Carcinogen exposure during short-term switching from regular to “light” cigarettes. Cancer Epidemiol Biomarkers Prev 2005;14:1376–83. 233. Benowitz NL, Jacob P 3rd, Herrera B. Nicotine intake and dose response when smoking reduced-nicotine content cigarettes. Clin Pharmacol Ther 2006;80: 703–14. 234. Benowitz NL, Dains KM, Hall SM, Stewart S, Wilson M, Dempsey D, et al. Progressive commercial cigarette yield reduction: biochemical exposure and behavioral assessment. Cancer Epidemiol Biomarkers Prev 2009;18:876–83. 235. Henningfield JE, Fant RV, Tomar SL. Smokeless tobacco: an addicting drug. Adv Dental Res 1997;11:330–5. 236. Hatsukami DK, Lemmonds C, Tomar SL. Smokeless tobacco use: harm reduction or induction approach? Prev Med 2004;38:309–17. 237. Henningfield JE, Shiffman S, Ferguson SG, Gritz ER. Tobacco dependence and withdrawal: science base, challenges and opportunities for pharmacotherapy. Pharmacol Ther 2009;123:1–16. 238. Wayne GF, Connolly GN, Henningfield JE, Farone WA. Tobacco industry research and efforts to manipulate smoke particle size: implications for product regulation. Nicotine Tob Res 2008;10:613–25. 239. Becker KM, Rose JE, Albino AP. A randomized trial of nicotine replacement therapy in combination with reduced-nicotine cigarettes for smoking cessation. Nicotine Tob Res 2008;10:1139–48. 240. Rose JE. Disrupting nicotine reinforcement: from cigarette to brain. Ann N Y Acad Sci 2008;1141:233–56. 241. DeGrandpre RJ, Bickel WK, Hughes JR, Higgins ST. Behavioral economics of drug self-administration. III. A reanalysis of the nicotine regulation hypothesis. Psychopharmacology 1992;108:1–10 242. Shahan TA, Bickel WK, Madden GJ, Badger GJ. Comparing the reinforcing efficacy of nicotine containing and de-nicotinized cigarettes: a behavioral economic analysis. Psychopharmacology 1999;147:210–6.
232
243. Shahan TA, Bickel WK, Badger GJ, Giordano LA. Sensitivity of nicotine-containing and de-nicotinized cigarette consumption to alternative non-drug reinforcement: a behavioral economic analysis. Behav Pharmacol 2001;12:277–84. 244. Shahan TA, Odum AL, Bickel WK. Nicotine gum as a substitute for cigarettes: a behavioral economic analysis. Behav Pharmacol 2000;11:71–9. 245. Johnson MW, Bickel WK, Kirshenbaum AP. Substitutes for tobacco smoking: a behavioral economic analysis of nicotine gum, denicotinized cigarettes, and nicotine-containing cigarettes. Drug Alcohol Depend 2004;74:253–64. 246. West RJ, Jarvis MJ, Russell MA, Carruthers ME, Feyerabend C. Effect of nicotine replacement on the cigarette withdrawal syndrome. Br J Addict 1984;79:215–9. 247. Zacny JP, Stitzer ML. Cigarette brand-switching: effects on smoke exposure and smoking behavior. J Pharmacol Exp Ther 1988;246:619–27. 248. Strasser AA, Lerman C, Sanborn PM, Pickworth WB, Feldman EA. New lower nicotine cigarettes can produce compensatory smoking and increased carbon monoxide exposure. Drug Alcohol Depend 2007;86:294–300. 249. Harris AC, Pentel PR, Burroughs D, Staley MD, Lesage MG. A lack of association between severity of nicotine withdrawal and individual differences in compensatory nicotine self-administration in rats. Psychopharmacology 2011;217:153–66. 250. Roiko SA, Harris AC, LeSage MG, Keyler DE, Pentel PR. Passive immunization with a nicotine-specific monoclonal antibody decreases brain nicotine levels but does not precipitate withdrawal in nicotine-dependent rats. Pharmacol Biochem Behav 2009;93:105–11. 251. Walker N, Howe C, Bullen C, Grigg M, Glover M, McRobbie H, et al. The combined effect of very low nicotine content cigarettes, used as an adjunct to usual Quitline care (nicotine replacement therapy and behavioural support), on smoking cessation: a randomized controlled trial. Addiction 2012;107:1857–67. 252. Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS, et al. Reduced nicotine content cigarettes and nicotine patch. Cancer Epidemiol Biomarkers Prev 2013;22:1015–24. 253. Perkins KA, Gerlach D, Broge M, Fonte C, Wilson A. Reinforcing effects of nicotine as a function of smoking status. Exp Clin Psychopharmacol 2001;9:243–50. 254. Doran N, Schweizer CA, Myers MG. Do expectancies for reinforcement from smoking change after smoking initiation? Psychol Addict Behav 2011;25:101–7. 255. McQuown SC, Belluzzi JD, Leslie FM. Low dose nicotine treatment during early adolescence increases subsequent cocaine reward. Neurotoxicol Teratol 2007;29:66–73. 256. Connolly GN. The marketing of nicotine addiction by one oral snuff manufacturer. Tob Control 1995;4: 73–9. 257. Barrett SP, Darredeau C. The acute effects of nicotine on the subjective and behavioural responses to denicotinized tobacco in dependent smokers. Behav Pharmacol 2012;23:221–7.
233
258. Tidey JW, Rohsenow DJ, Kaplan GB, Swift RM, Ahnallen CG. Separate and combined effects of very low nicotine cigarettes and nicotine replacement in smokers with schizophrenia and controls. Nicotine Tob Res 2013;15:121–9. 259. Joel DL, Denlinger RL, Dermody SS, Hatsukami DK, Benowitz NL, Donny EC. Very low nicotine content cigarettes and potential consequences on cardiovascular disease. Curr Cardiovasc Risk Rep 2012;6:534–41. 260. Benowitz NL. Toxicity of nicotine: implications with regard to nicotine replacement therapy. Prog Clin Biol Res 1988;261:187–217. 261. Assali AR, Beigel Y, Schreibman R, Shafer Z, Fainaru M. Weight gain and insulin resistance during nicotine replacement therapy. Clin Cardiol 1999;22:357–60. 262. Heeschen C, Weis M, Cooke JP. Nicotine promotes arteriogenesis. J Am Coll Cardiol 2003;41:489–96 263. Suzuki J, Bayna E, Dalle Molle E, Lew WY. Nicotine inhibits cardiac apoptosis induced by lipopolysaccharide in rats. J Am Coll Cardiol 2003;41:482–8. 264. Girdhar G, Xu S, Bluestein D, Jesty J. Reduced-nicotine cigarettes increase platelet activation in smokers in vivo: a dilemma in harm reduction. Nicotine Tob Res 2008;10:1737–44. 265. Legresley E, Lee K, Muggli ME, Patel P, Collin J, Hurt RD. British American Tobacco and the “insidious impact of illicit trade” in cigarettes across Africa. Tob Control 2008;17:339–46. 266. Lee S, Ling PM, Glantz SA. The vector of the tobacco epidemic: tobacco industry practices in low and middle-income countries. Cancer Causes Control 2012;23(Suppl 1):117–29. 267. Joossens L, Raw M. Turning off the tap: the real solution to cigarette smuggling. Int J Tuberc Lung Dis 2003;7:214–22. 268. Joossens L, Raw M. Progress in combating cigarette smuggling: controlling the supply chain. Tob Control 2008;17:399–404. 269. Pavananunt P. Illicit cigarette trade in Thailand. Southeast Asian J Trop Med Public Health 2011;42:1531–9. 270. Mecredy GC, Diemert LM, Callaghan RC, Cohen JE. Association between use of contraband tobacco and smoking cessation outcomes: a population-based cohort study. Can Med Assoc J 2013;185:E287–94. 271. Givel MS. History of Bhutan’s prohibition of cigarettes: implications for neoprohibitionists and their critics. Int J Drug Policy 2011;22:306–10. 272. Borland R. Minimising the harm from nicotine use: finding the right regulatory framework. Tob Control 2013;22(Suppl 1):i6–9. 273. Czoli CD, Hammond D. Cigarette packaging: youth perceptions of “natural” cigarettes, filter references, and contraband tobacco. J Adolesc Health 2013;54:33–9. 274. Hyland A, Higbee C, Li Q, Bauer JE, Giovino GA, Alford T, et al. Access to low-taxed cigarettes deters smoking cessation attempts. Am J Public Health 2005;95:994–5.
234
275. Hyland A, Laux FL, Higbee C, Hastings G, Ross H, Chaloupka FJ, et al. Cigarette purchase patterns in four countries and the relationship with cessation: findings from the International Tobacco Control (ITC) Four Country Survey. Tob Control 2006;15(Suppl 3):iii59–64. 276. Licht AS, Hyland AJ, O’Connor RJ, Caloupka FJ, Borland R, Fong GT. How do price minimizing behaviors impact smoking cessation? Findings from the International Tobacco Control (ITC) Four Country Survey. Int J Environ Res Public Health 2011;8:1671–91. 277. Ahmad S, Billimek J. Estimating the health impacts of tobacco harm reduction policies: a simulation modeling approach. Risk Anal 2005;25:801–12. 278. Modeling the health benefits of a nicotine standard for tobacco products sold in Canada. Cambridge, Massachusetts: Industrial Economics Inc.; 2013. 279. Hall W, West R. Thinking about the unthinkable: a de facto prohibition on smoked tobacco products. Addiction 2008;103:873–4. 280. Le Houezec J, McNeill A, Britton J. Tobacco, nicotine and harm reduction. Drug Alcohol Rev 2011;30:119–23. 281. McNeill A, Hammond D, Gartner C. Whither tobacco product regulation? Tob Control 2012;21:221–6. 282. Arnott D. There’s no single endgame. Tob Control 2013;22(Suppl 1):i38–9. 283. Britton J, McNeil A. Nicotine regulation and tobacco harm reduction in the UK. Lancet 2013;381:1879–80. 284. Hatsukami DK. Ending tobacco-caused mortality and morbidity: the case for performance standards for tobacco products. Tob Control 2013;22(Suppl 1):i36–7. 285. O’Connor RJ. Non-cigarette tobacco products: what have we learnt and where are we headed? Tob Control 2012;21:181–90. 286. Wayne GF, Connolly GN. Regulatory assessment of brand changes in the commercial tobacco product market. Tob Control 2009;18:302–9. 287. Carter LP, Stitzer ML, Henningfield JE, O’Connor RJ, Cummings KM, Hatsukami DK. Abuse liability assessment of tobacco products including potential reduced exposure products. Cancer Epidemiol Biomarkers Prev 2009;18:3241–62. 288. Henningfield JE, Hatsukami DK, Zeller M, Peters E. Conference on abuse liability and appeal of tobacco products: conclusions and recommendations. Drug Alcohol Depend 2011;116:1–7. 289. Mooney ME, Johnson EO, Breslau N, Bierut LJ, Hatsukami DK. Cigarette smoking reduction and changes in nicotine dependence. Nicotine Tob Res 2011;13:426–30. 290. Walker N, Bullen C, McRobbie H. Reduced-nicotine content cigarettes: Is there potential to aid smoking cessation? Nicotine Tob Res 2009;11:1274–9. 291. Lindson-Hawley N, Aveyard P, Hughes JR. Reduction versus abrupt cessation in smokers who want to quit. Cochrane Database Syst Rev 2012;11:CD008033. 292. Rooke C, McNeill A, Arnott D. Regulatory issues concerning the development and circulation of nicotine-containing products: a qualitative study. Nicotine Tob
235
Res 2013;15(6):1052–9. 293. Cahn Z, Siegel M. Electronic cigarettes as a harm reduction strategy for tobacco control: a step forward or a repeat of past mistakes? J Public Health Policy 2011;32:16–31. 294. Le Houezec J, Aubin HJ. Pharmacotherapies and harm-reduction options for the treatment of tobacco dependence. Expert Opin Pharmacother 2013;14:1959–67. 295. Dawkins L, Corcoran O. Acute electronic cigarette use: nicotine delivery and subjective effects in regular users. Psychopharmacology 2013;231:401–7. 296. Dawkins L, Turner J, Crowe E. Nicotine derived from the electronic cigarette improves time-based prospective memory in abstinent smokers. Psychopharmacology 2013;227:377–84. 297. Dawkins L, Turner J, Roberts A, Soar K “Vaping” profiles and preferences: an online survey of electronic cigarette users. Addiction 2013;108:1115–25. 298. Eissenberg T. Electronic nicotine delivery devices: ineffective nicotine delivery and craving suppression after acute administration. Tob Control 2010;19:87–8. 299. Bullen C, McRobbie H, Thornley S, Glover M, Lin R, Laugesen M. Effect of an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross-over trial. Tob Control 2010;19:98–103. 300. Shadel WG, Lerman C, Cappella J, Strasser AA, Pinto A, Hornik R. Evaluating smokers’ reactions to advertising for new lower nicotine quest cigarettes. Psychol Addict Behav 2006;20:80–4. 301. Parascandola M, Augustson E, O’Connell ME, Marcus S. Consumer awareness and attitudes related to new potential reduced-exposure tobacco product brands. Nicotine Tob Res 2009;11:886–95. 302. Connolly GN, Behm I, Healton CG, Alpert HR. Public attitudes regarding banning of cigarettes and regulation of nicotine. Am J Public Health 2012;102:e1–2. 303. Fix BV, O’Connor RJ, Fong GT, Borland R, Cummings KM, Hyland A. Smokers’ reactions to FDA regulation of tobacco products: findings from the 2009 ITC United States survey. BMC Public Health 2011;11:941. 304. Pearson JL, Abrams DB, Niaura RS, Richardson A, Vallone DM. Public support for mandated nicotine reduction in cigarettes. Am J Public Health 2013;103:562–7.
236
237
This report presents the conclusions reached and recommendations made by the members of the WHO Study Group on Tobacco Product Regulation (TobReg) at its seventh meeting, in December 2013, during which it reviewed background papers specially commissioned for the meeting, which dealt, respectively, with the following four themes: 1. 2. 3. 4. Novel tobacco products, including potential reduced exposure products Smokeless tobacco products: research needs and regulatory recommendations Reduced ignition propensity cigarettes: research needs and regulatory recommendations Non-exhaustive priority list of toxic contents and emissions of tobacco products
The Study Group’s recommendations in relation to each theme are set out at the end of the section dealing with that theme; its overall recommendations are summarized in Chapter 6.
本书英文版于 2015 年由世界卫生组织（World Health Organization）出版，书名 为 WHO study group on tobacco product regulation: report on the scientific basis of tobacco product regulation: fifth report of a WHO study group (WHO technical report series; no. 989) http://www.who.int/tobacco/publications/prod_regulation/trs989/en/ © World Health Organization 2015 世界卫生组织（World Health Organization）授权中国科技出版传媒股份有限公 司（科学出版社）翻译出版本书中文版。中文版的翻译质量和对原文的忠实性 完全由科学出版社负责。当出现中文版与英文版不一致的情况时，应将英文版 视作可靠和有约束力的版本。 中文版《烟草制品管制科学基础报告 : WHO 研究组第五份报告》 © World Health Organization 2015 如翻译或复制世界卫生组织的健康信息产品，无论是以营利为目的的销售还是 非营利性的发行，都必须事先联系 WHO Press（Email: permissions@who.int）以 获得许可。
WHO技术报告系列
989
WHO烟草制品管制研究小组
烟草制品管制科学基础报告 WHO研究组第五份报告
·3·
图字：01-2015-3385 号 内 容 简 介 本报告呈现了 WHO 烟草制品管制研究小组于 2013 年 12 月在其第七次会 议上达成的结论和给出的建议。在第七次会议期间，研究组审议了四份受会议 特别委托而撰写的背景文章，分别阐述以下四个议题：①包括潜在降低暴露量 产品在内的新型烟草制品；②无烟烟草制品：研究需求和管制建议；③降低引 燃能力的卷烟：研究需求和管制建议；④烟草制品有害成分及释放物的非详尽 优先清单。本报告第 2~5 章分别阐述这四个议题，在各章结尾处给出研究组的 建议；第 6 章为总体建议；第 7 章阐述烟草管控现状。 本报告会引起吸烟与健康、烟草化学以及公共卫生学等诸多领域研究人员 的兴趣，可以为从事烟草科学研究的科技工作者和烟草管制研究的决策者提供 权威性参考，还对烟草企业的生产实践有重要的指导作用。 图书在版编目(CIP)数据 烟草制品管制科学基础报告: WHO研究组第五份报告 / WHO烟草制品管制研究 小组著； 胡清源等译 — 北京： 科学出版社， 2015.9 （WHO技术报告系列989） 书名原文: WHO study group on tobacco product regulation: report on the scientific basis of tobacco product regulation: fifth report of a WHO study group (WHO technical report series; no. 989) ISBN 978-7-03-044751-7 Ⅰ. ①烟… Ⅱ. ①W… ②胡… Ⅲ. ①烟草制品－科学研究－研究报告 Ⅳ. ①TS45 中国版本图书馆CIP数据核字（2015）第124325号 责任编辑：刘 冉 / 责任校对：赵桂芬 责任印制：徐晓晨 / 封面设计：铭轩堂
北京教图印刷有限公司印刷 科学出版社发行 各地新华书店经销 * 2015年9月第 一 版 开本：890×1240 A5 2015年9月第一次印刷 印张：10 1/4 字数：300 000
定价：120.00元 ( 如有印装质量问题，我社负责调换 )
译 者 序
译 者 序 2003 年 5 月， 第 56 届世界卫生大会 * 通过了 《烟草控制框架公约》 （FCTC） ， 迄今已有包括我国在内的 180 个缔约方。 根据 FCTC 第 9 条和第 10 条的规定， 授权世界卫生组织（WHO） 烟草制品管制研 究小组（TobReg）对可能造成重要公共健康问题的烟草制品管制措 施进行鉴别，提供科学合理的、有根据的建议，用于指导成员国进 行烟草制品管制。 自 2007 年起，WHO 陆续出版了五份烟草制品管制科学基础报 告，分别是 945，951，955，967 和 989。WHO 烟草制品管制科学基 础系列报告阐述了降低烟草制品的吸引力、致瘾性和毒性等烟草制 品管制相关主题的科学依据， 内容涉及烟草化学、 代谢组学、 毒理学、 吸烟与健康等烟草制品管制的多学科交叉领域，是一系列以科学研 究为依据、对烟草管制发展和决策有重大影响意义的技术报告。将 其引进并翻译出版，可以为相关烟草科学研究的科技工作者提供科 学性参考。希望引起吸烟与健康、烟草化学和公共卫生学等诸多应 用领域科学家的兴趣，为客观评价烟草制品的管制和披露措施提供 必要的参考。 第一份报告（945） 由胡清源、 侯宏卫、 韩书磊、 陈欢、 刘彤、 * 世界卫生大会（World Health Assembly，WHA）是世界卫生组织的最高权力机构， 每年召开一次。
·i·
烟草制品管制科学基础报告： WHO 研究组第五份报告
付亚宁翻译，全书由韩书磊负责统稿 ； 第二份报告（951） 由胡清源、 侯宏卫、 刘彤、 付亚宁、 陈欢、 韩书磊翻译，全书由刘彤负责统稿 ； 第三份报告（955）由胡清源、侯宏卫、付亚宁、陈欢、韩书磊、 刘彤翻译，全书由付亚宁负责统稿 ； 第四份报告（967） 由胡清源、 侯宏卫、 陈欢、 刘彤、 韩书磊、 付亚宁翻译，全书由陈欢负责统稿 ； 第五份报告（989） 由胡清源、 侯宏卫、 陈欢、 刘彤、 韩书磊、 付亚宁翻译，全书由陈欢负责统稿。 由于译者学识水平有限，本中文版难免有错漏和不当之处，敬 请读者批评指正。
2015 年 4 月
·ii·
目 录
目 录
WHO 烟草制品管制研究组第七次会议··············································· xi 致谢 ·········································································································xv 1. 前言 ······································································································ 1 2. 包括潜在降低暴露量产品在内的新型烟草制品 研究需求 和管制建议 ·························································································· 4 4 2.1 引言 ···································································· 4 2.2 2014 年 WHO 烟草制品调查结果 ································ 6 2.3 对公众健康的影响 ·················································· 8 2.4 研究需求 ······························································ 9 2.4.1 监测 2.4.2 风险评估框架 2.4.3 营销与消费者认知 2.4.4 风险披露 2.4.5 管制问题 9 10 13 14 14 ·iii·
烟草制品管制科学基础报告： WHO 研究组第五份报告
2.5 管制建议 ·····························································15 2.6 参考文献 ·····························································16 3. 无烟烟草制品 研究需求和管制建议··············································23 3.1 引言 ···································································24 3.1.1 产品范围广 3.1.2 数据有限 3.1.3 新型产品及其营销 3.1.4 对年轻人及烟草使用发展的影响 3.1.5 应对选择有限 3.1.6 烟草“减害” 25 26 26 27 28 28
3.2 2014 年 WHO 烟草制品调查结果 ·······························29 3.3 当前的地区与国家管制 ···········································31 3.3.1 WHO 非洲地区 3.3.2 WHO 美洲地区 3.3.3 WHO 地中海东部地区 3.3.4 WHO 欧洲地区 3.3.5 WHO 东南亚地区 3.3.6 WHO 西太平洋地区 31 31 32 32 33 34
3.4 结论 ···································································34 3.5 研究需求 ·····························································36 3.5.1 监督与监测 3.5.2 产品表征 3.5.3 健康效应 3.5.4 经济与市场营销 3.5.5 干预措施 ·iv·
36 37 37 37 38
目 录
3.6 管制建议 ·····························································38 3.6.1 干预措施与政策 3.6.2 建立管制框架的挑战与建议 3.6.3 能力建设 4. 低引燃倾向卷烟 38 41 42
3.7 参考文献 ····························································································43 研究需求和监管建议··········································51 4.1 引言 ···································································52 4.2 背景 ···································································53 4.3 结果 ···································································53 4.3.1 上述报告后的新研究 4.3.2 国家和地区的立法经验及其执行 4.3.3 产品符合性数据 4.3.4 风险评估以及对安全与风险的认知 4.3.5 采用标准前后卷烟引发火灾的动态 4.3.6 标准的实用性与不足 54 54 56 57 60 64
4.4 结论 ···································································64 4.5 2014 年 WHO 烟草制品调查结果 ·······························66 4.6 研究需求 ·····························································66 4.7 管制建议 ·····························································67 4.8 参考文献 ·····························································68 附录 4.1 方法 ····························································72 附录 4.2 ISO12863 概述 ···············································73 附录 4.3 低引燃倾向卷烟技术相关企业最近的 CORESTA 简报 ··························································· 74 ·v·
烟草制品管制科学基础报告： WHO 研究组第五份报告
5. 烟草制品有害成分和释放物的非详尽优先清单 ······························78 5.1 引言 ···································································78 5.2 结果综述 ·····························································80 5.3 建议 ···································································81 5.4 烟草制品有害成分和释放物的非详尽优先清单 ·············83 5.5 参考文献 ·····························································84 6. 总体建议 ·····························································································87 6.1 新型烟草制品 ·······················································88 6.1.1 主要建议 6.1.2 对公众健康政策的意义 6.1.3 对 WHO 方案的启示 6.2.1 主要建议 6.2.2 对公众健康政策的意义 6.2.3 对 WHO 方案的启示 6.3.1 主要建议 6.3.2 对公众健康政策的意义 6.3.3 对 WHO 方案的启示 6.4.1 主要建议 6.4.2 对公众健康政策的意义 6.4.3 对 WHO 方案的启示 88 89 89 89 90 90 90 91 91 91 92 92
6.2 无烟烟草制品 ·······················································89
6.3 低引燃倾向卷烟 ····················································90
6.4 烟草制品有害成分和释放物的非详尽清单 ···················91
7. 烟草烟气管制 现状评述 ·································································93 7.1 背景 ···································································93 ·vi·
目 录
7.2 建议的措施 ··························································98 7.3 设定上限相关问题 ·················································99 7.4 参考文献 ··························································· 100 附录 1 包括潜在降低暴露量产品在内的新型烟草制品 研究需求和建议 ···································································103 103 A1.1 摘要 ······························································· 106 A1.2 背景 ······························································· 107 A1.3 “减害”的概念 ················································ 108 A1.4 方法 ······························································· 109 A1.4.1 数据来源 A1.4.2 选择标准 A1.4.3 数据提取和合成 A1.5.1 口含烟 A1.5.2 改良或替代型抽吸产品 A1.5.3 水烟 A1.5.4 对传统烟草制品的显著改变 A1.6.1 代替传统卷烟燃烧的加热技术 A1.6.2 烟草加工工艺和滤嘴结构的改变 A1.6.3 滤嘴结构的改良 A1.6.4 2013 年 CORESTA 会议所展现的研究进展 A1.7.1 非燃烧型口用产品 A1.7.2 卷烟和类卷烟装置 109 110 110 111 126 141 144 149 150 156 160 162 166 ·vii·
A1.5 新上市和试销产品以及新兴用途产品 ····················· 111
A1.6 发展中的技术 ··················································· 148
A1.7 总结 ······························································· 162
烟草制品管制科学基础报告： WHO 研究组第五份报告
A1.8 结论 ······························································· 170 A1.9 致谢 ······························································· 171 A1.10 参考文献 ······················································· 173 附录 包括潜在“减害”产品在内的新型烟草制品调查问卷···· 197 附录 2 氨在游离态烟碱传输中的作用 近期研究及分析挑战 ·····200 A2.1 引言 ······························································· 200 A2.2 烟碱向烟气传输的近期研究成果 ··························· 202 A2.3 烟碱摄入的近期研究成果 ···································· 204 A2.4 当前加氨技术的作用 ·········································· 206 A2.5 参考文献 ························································· 211 附录 3 通过降低烟碱释放量至不会引起或维持成瘾的 水平来降低卷烟产品的潜在依赖性···································· 218 A3.1 引言 ······························································· 220 A3.2 烟草致瘾模式 ··················································· 222 A3.2.1 烟碱成瘾 A3.2.2 烟碱响应的个体差异 A3.2.3 烟草中的烟碱传输 A3.2.4 成瘾的双重强化模式 A3.2.5 药物期望 A3.2.6 社会和环境因素 A3.2.7 小结 A3.3.1 烟碱的自我给药 A3.3.2 烟碱依赖的形成 ·viii·
222 223 225 226 228 229 229 231 232
A3.3 成瘾阈值的建立 ················································ 230
目 录
A3.3.3 低烟碱卷烟的增强作用 A3.3.4 成瘾阈值与强化阈值 A3.3.5 条件刺激的阈值 A3.3.6 小结 A3.4.1 卷烟烟碱传输 A3.4.2 降低烟草中烟碱的方法 A3.4.3 去烟碱化或低烟碱卷烟 A3.4.4 低传输率卷烟中的游离态烟碱 A3.4.5 引起补偿抽吸的产品 A3.4.6 降低烟碱的产品配方和途径 A3.4.7 小结 A3.5.1 对卷烟消费量的潜在影响 A3.5.2 对吸烟行为的潜在影响 A3.5.3 对戒烟的潜在影响 A3.5.4 对卷烟使用购买的潜在影响 A3.5.5 潜在的不可预料的行为后果 A3.5.6 潜在的人群差异 A3.5.7 潜在的健康影响 A3.5.8 非法销售含烟碱卷烟产品的可能性 A3.5.9 人群影响模型 A3.5.10 小结
233 234 236 237 238 239 240 241 242 243 245 247 248 249 250 250 251 252 253 253 255
A3.4 降低烟碱的可行性 ············································· 238
A3.5 潜在的行为效果和人群效果 ································· 246
A3.6 降低烟碱的政策手段 ·········································· 256 ·ix·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A3.6.1 对烟碱的全面管制 A3.6.2 绩效标准 A3.6.3 逐渐性降低与急剧性降低 A3.6.4 烟碱的可替代形式 A3.6.5 戒烟与行为治疗 A3.6.6 监测 A3.6.7 消费者教育和信念 A3.6.8 公众对降低烟碱政策的支持 A3.6.9 未知的市场影响 A3.6.10 小结
257 257 258 260 261 261 262 263 264 265
A3.7 结论 ······························································· 266 A3.8 建议 ······························································· 267 A3.9 参考文献 ························································· 268
·x·
WHO烟草制品管制研究组第七次会议
WHO 烟草制品管制研究组第七次会议 巴西里约热内卢，2013 年 12 月 4 ～ 6 日 参加者 D. L. Ashley 博士，美国食品药品管理局（马里兰州罗克维尔）烟草 制品中心科学办公室主任 O. A. Ayo-Yusuf 教授 , Sefako Makgatho 卫生科学大学（南非比勒陀 利亚）口腔卫生科学学院院长 A. R. Boobis 教授，英国伦敦帝国学院医学系药理学与治疗学中心生 化药理学专业 ； 伦敦帝国学院公共卫生英格兰毒理学课题组组长 Vera Luiza da Costa e Silva 博士，巴西里约热内卢高级公共卫生专家， 独立顾问 M. V. Djordjevic 博士， 美国国家癌症研究所（美国马里兰州贝塞斯达） 癌症控制与人口科学部烟草控制研究课题组行为研究项目负责人 N. Gray 博士，维多利亚癌症委员会（澳大利亚墨尔本）高级荣誉合 伙人 P. Gupta 博士，Healis Sekhsaria 公共卫生研究所（印度孟买）所长 S. K. Hammond 博士，加利福尼亚大学伯克利分校（美国加利福尼亚 州伯克利）公共卫生学院环境卫生学教授 D. Hatsukami 博士，明尼苏达大学（美国明尼苏达州明尼阿波利斯） ·xi·
烟草制品管制科学基础报告： WHO 研究组第五份报告
精神病学教授 J. Henningfield 博士， 约翰 霍普金斯大学医学院行为生物学兼职教授； · Pinney 协会（美国马里兰州贝塞斯达）研究与健康政策部副总裁 A. Opperhuizen 博士，荷兰乌得勒支省风险评估与研究办公室主任 G. Zaatari 博士，WHO 烟草制品管制研究小组主席 ； 贝鲁特美国大 学（黎巴嫩贝鲁特）病理学与实验医学系教授 WHO FCTC 第 9 条和第 10 条工作组会议专家 P. Altan 博士，土耳其卫生部（土耳其安卡拉省）烟草控制司 A. C. Bastos de Andrade 博士， 巴西国家卫生监督管理局（Agência Nacional de Vigilância Sanitária） （巴西里约热内卢）烟草制品控制 司司长 Katja Bromen 博士， 欧盟健康与消费者理事会（ 比利时布鲁塞尔 ） D4 单元人类起源物质与烟草控制组政策官员 D. Choinière 先生，加拿大卫生部（加拿大安大略省渥太华）管制物 质与烟草理事会烟草制品管制办公室主任 发言人 G. Ferris Wayne 博士，美国加利福尼亚州 R. Grana 博士，加利福尼亚大学（美国加利福尼亚州圣弗朗西斯科） 烟草控制研究与教育中心博士后 M. Parascandola 博士，美国国家癌症研究所（美国马里兰州）癌症控 制与人口科学部行为研究项目烟草控制研究课题组流行病学专业 R. Talhout 博士， 荷兰国家公共卫生与环境研究所（荷兰比尔特霍芬） 健康防护中心 ·xii·
WHO烟草制品管制研究组第七次会议
WHO FCTC 公约秘书处（瑞士日内瓦） K. Brown 女士，项目官员 WHO 美洲地区办公室 A. Blanco 博士，烟草控制地区顾问，美国华盛顿特区 WHO 秘书处（非传染疾病预防，瑞士日内瓦） M. Aryee-Quansah 女士，无烟草行动司行政助理 A. Peruga 博士，无烟草行动司计划理事 V. M. Prasad 博士，无烟草行动司项目理事 G. Vestal 女士，无烟草行动司法定技术官员
·xiii·
致 谢
致 谢 WHO 要感谢许多人对烟草制品管制研究小组（TobReg） 第五 份报告的贡献。Gemma Vestal 女士负责协调，Armando Peruga 博士 和 Douglas Bettcher 博士负责监督和支持。 本报告的工作开始于 2012 年 11 月 12~17 日在韩国首尔召开的 WHO《 烟草控制框架公约 》 （FCTC） 第五次缔约方会议， 2014 年 10 月 13~18 日在俄罗斯莫斯科又继续召开了第六次会议。本报告由 WHO 总干事提交给将于 2015 年 1 月 25 日至 2 月 3 日在瑞士日内瓦 召开的第 136 届执行委员会会议。 衷心感谢所有 TobReg 成员，感谢他们全心奉献，付出时间，一 直履行就烟草制品管制这一烟草管控最复杂领域向 WHO 提供咨询 的承诺。作为独立的专家成员，TobReg 免费向 WHO 提供服务。为 了回应缔约方会议在其第五次会议上向 WHO 提出的请求，TobReg 成员为 2013 年 12 月在巴西里约热内卢召开的 TobReg 第七次会议起 草了参考条款用于指导一系列述评，并作为背景文件和会议讨论的 基础。 衷心感谢关于新型烟草制品的背景文章的作者 Irina Stepanov 博 士、Lya Soeteman-Hernández 博士和 Reinskje Talhout 博士等，感谢他 们提供的翔实的资料。 他们的工作由 Mirjana Djordjevic 博士 （TobReg） 监督。完整的背景文章作为附录 1 附在本报告中。 ·xv·
烟草制品管制科学基础报告： WHO 研究组第五份报告
向我们的同事， 来自美国疾病控制与预防中心的 Samira Asma 博士和来自美国国家癌症研究所的 Mark Parascandola 博士致谢，感 谢他们为 WHO 起草题为“无烟烟草与公众健康： 全球视角”的报告。 这一权威、详细的报告，发表于 2014 年，随后由 Dorothy Hatsukami 博士（TobReg）和 BLH 科技的 Lindsay Pickell 女士提交给 TobReg 第 七次会议。 向关于低引燃倾向卷烟的背景文章的作者，来自哈佛大学公共 卫生学院的 Greg Connolly 博士和 Hillel Alpert 博士致谢。 他们踊跃 并完全地更新了 TobReg 于 2008 年出版的关于低引燃倾向卷烟的原 创文章。 该背景文章的工作由 Alan Boobis 博士（TobReg） 和 O. A. Ayo-Yusuf 教授（TobReg）监督。 Geoff Ferris Wayne 先生撰写了通过降低烟碱释放量至不会引起 或维持成瘾的水平来降低卷烟潜在致瘾性的背景文章。该文章作为 附录 3 附在本报告中。WHO 感谢 Wayne 先生在撰写 2013 年 12 月 提交给 TobReg 的文章中所付出的时间和精力， 并感谢他继续参与 TobReg 工作以完成关于这一重要议题的结论和建议。 背景文章的 工作由 Jack Henningfield 博士监督， 很遗憾他于 2014 年 1 月辞去了 TobReg 的工作。WHO 想借此机会来向 Henningfield 博士表达最诚 挚的感谢，感谢他多年来专注、高效地服务于 TobReg。他是 TobReg 的“思想领袖”之一，也是一位多产的作者。 第五次缔约方会议还要求 WHO 起草一个烟草制品有害成分 和释放物的非详尽优先清单。这部分工作由三个 TobReg 成员领导， 分 别 是 烟 草 实 验 室 网 络（TobLabNet） 前 主 席 David Ashley 博 士， TobLabNet 现 任 主 席 Antoon Opperhuizen 博 士 和 TobReg 现 任 主 席 Ghazi Zaatari 博士。 ·xvi·
致 谢
TobReg 第七次会议讨论了氨在增加烟碱向大脑传输中的作用。 关于这一主题的背景文章由美国疾病控制与预防中心的 Christina Watson 女士撰写。该文章作为附录 2 附在本报告中，以方便学者和 政策制定者。该文章的工作由 David Ashley 博士（TobReg）监督。 本报告还包括 TobReg 的先驱之一 Nigel Gray 博士对于烟草烟气 管制及现状的评论。Gray 博士于 2014 年 12 月 20 日去世， 享年 90 岁。 Gray 博士是国际社会烟草控制领域著名的活动家、 学者和远见者。 作为 TobReg 成员，Gray 博士在许多高度复杂的领域具有领导力和 宝贵的洞察力，这些复杂性来源于大多数的研究是由烟草行业进行 的，而且许多成员国没有对其进行透彻分析的能力。WHO 无烟草行 动司认为将 Gray 博士的评论收录在这份报告中， 是向 TobReg 首要 “思想领袖”的致敬。Gray 博士的遗作可见于许多这些年来已出版的 TobReg 建议。 为了确保 WHO 通过公约秘书处向缔约方会议提交烟草制品管 制的需求信息，WHO 和 TobReg 与 WHO FCTC 第 9 条和第 10 条工 作组的协调组密切合作。WHO 感谢 Ana Claudia Bastos de Andrade 女士（巴西） Denis Choinière 先生（加拿大） Katja Bromen 博士（欧 、 、 盟）和 Peyman Altan 博士（土耳其）的重大贡献。 WHO 还感谢公约秘书处的同事在本报告的制作中提供的协助， 分别是 ： Karlie Brown 女士、Guangyuan Liu 女士和 Tibor Szilagyi 博 士（ 技术官员 ） 、Haik Nikogosian 博士（ 公约秘书处前负责人 ） 和 Vera da Costa e Silva 博士（公约秘书处现负责人） 。 感谢多年的制作过程中 WHO 同事提供的行政支持， 分别是 Miriamjoy Aryee-Quansah 女士、Gareth Burns 先生、Elaine Alexandre Caruana 女 士、Luis Madge 先 生、Elizabeth Tecson 女 士 和 Rosane ·xvii·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Serrao 女士。 特 别 感 谢 WHO 美 洲 地 区 办 事 处 烟 草 控 制 地 区 顾 问 Adriana Blanco 博士确保 TobReg 会议在巴西的顺利召开。真诚地感谢巴西国 家卫生监督管理局（Agência Nacional de Vigilância Sanitária，ANVISA） 的 Ana Claudia Bastos de Andrade 女士在为 ANVISA 同烟草行业煽动 的多起诉讼进行辩护的同时， 还毅然主办了 2013 年 12 月巴西里约 热内卢的 TobReg 第七次会议。 此外， ANVISA 提供了急需的财政援助， 使得会议得以召开。 也衷心感谢 WHO 的编辑、 审稿和校对以及印度的排版公司 Talk Infosystems，感谢他们对细节的关注和对多轮编校的耐心。 最后，WHO 深深地向无烟草行动司的前实习生表示深切感谢， 感谢他们为本报告的完成贡献了大量的实习时间， 他们是 ： Aurelie Abrial 女士、Colleen Ciciora 女士、Adrian Diaz 先生、Richelle Duque 博士、Mary Law 女士、Christina Menke 女士、Hannah Patzke 女士和 Angeli Vigo 女士。我们希望他们在未来的光明职业生涯之外，能继 续充满激情地在烟草控制的某些方面工作。 无疑，还有许多人我们没有提到，因为有如此多的人参与本报 告的制作。我们为任何遗漏道歉。因此，我们要感谢那些提到的和 没有提到的人。没有你们的帮助与支持，就没有这份报告。非常感 谢你们。
·xviii·
1.前 言
1. 前 言 WHO 烟草制品管制研究小组（TobReg）a 被授权向 WHO 总 干事提供给予成员国关于烟草制品管制的科学合理、 有依据的建 议。与 WHO《烟草控制框架公约》 （FCTC）第 9 条和第 10 条一致， TobReg 识别用以管制构成重大的公众健康问题并为烟草控制政策带 来挑战的烟草制品的方法。 烟 草 制 品 管 制 对 于 烟 草 控 制 至 关 重 要， 得 到 WHO FCTC 第 9,10,11 条规定的支持。管制通过对烟草制品制造、包装、标识和分 发的有意义的监督服务于公众健康目的。用于实施条款的科学原则 在每一条款描述的管制实践之间产生协同强化效应。 烟草制品管制包括通过测试、测量和强制披露结果来监管其成 分和释放物，以及包装和标识。烟草制品生产和执行烟草制品设计、 成分和释放物的规定，以及它们的分发、包装和标识等都需要政府 监管，以保护和促进公众健康。 化工消费产品的监管通常在审查其相关风险、可能暴露量、适 用类型和生产商的营销信息等之后进行。许多行政区要求生产商根 据产品危险特性进行分类和标识，以控制有害成分或限制该产品的 广告、促销和赞助。
a
http://www.who.int/tobacco/industry/product_regulation/tobreg/en.
·1·
烟草制品管制科学基础报告： WHO 研究组第五份报告
TobReg 审议了与烟草制品管制相关主题的科学依据，并识别了 填补烟草控制管制空白的研究需要。TobReg 由国内和国际上产品管 制、烟草依赖治疗以及烟草成分和释放物实验室分析方面的专家组 成。作为 WHO 的一个正式实体，TobReg 通过总干事向 WHO 执行 委员会报告，以引起成员国对 TobReg 在复杂的烟草控制领域，即烟 草制品管制方面工作的关注。 TobReg 第七次会议于 2013 年 12 月 4~6 日在巴西里约热内卢举 行。讨论的主要问题是针对 WHO FCTC 缔约方会议（COP）第五次 会议（韩国首尔，2012 年 11 月 12~17 日）上向 WHO 提出的要求 ： • • 监测并密切跟踪新烟草制品的演变情况，包括可能“改良风 险”的制品，并向缔约方会议报告任何相关发展 ； 针对背景文件（文件 FCTC/COP/5/9 附件 3）第 12 节有关仍 需研究的有烟和无烟烟草制品致瘾性（依赖性倾向）方面的 内容开展一些活动 ； • • 监测和研究降低点燃倾向卷烟方面的国家经验和科学发展 ； 确认可能会减少有烟和无烟烟草制品毒性的措施，介绍支持 此类措施有效性的证据以及缔约方在此事项方面的经验，供 缔约方会议审议 ； • • • 编纂，向缔约方提供以及更新烟草制品有害成分和释放物的 非详尽清单， 并就缔约方可如何最佳利用此类信息提出意见； 就《 世界卫生组织框架公约第 9 条和第 10 条实施准则的部 分案文》所建议的措施撰写实况报道草案 ； 继续对用于检测和测定卷烟成分及释放物的分析化学方法进 行验证，并报告进展情况。 继这一要求之后，会议还委托撰写了一些背景文章。此外，通 ·2·
1.前 言
过世界卫生组织向所有成员国提交的一次性烟草制品调查，收集了 关于新型烟草制品和降低点燃倾向的卷烟可得性和管制的信息。有 90 个国家答复，占世界人口的 77% 左右。 本报告侧重于四个 TobReg 已发布明确建议的主要议题 ： 新型烟 草制品、无烟烟草制品、低引燃倾向卷烟和烟草制品有害成分和释 放物的非详尽清单。作为新型烟草制品讨论基础的背景文章收录在 本报告中（附录 1） ，关于添加氨以增加烟碱向大脑传输的行业实践 的背景文章作为本报告附录 2。 在其第八次会议上，TobReg 将审议 的主题定为“通过降低卷烟烟碱释放量至不会引起或维持成瘾的水 平来降低卷烟的潜在致瘾性” ，因为对这一主题的讨论尚未得到完全 一致的研究和监管建议。 这份在 2013 年 12 月第七次会议上讨论的 背景文章作为附录 3 提供给研究人员和政策制定者。 本报告还包括一个评论， 该评论是基于 TobReg 的先驱之一， Nigel Gray 博士独立撰写的一篇关于烟草烟气管制及现状的文章， 该文章是在 2013 年的第七会议上提出的。 不幸的是，Gray 博士在 2014 年 12 月 20 日去世， 享年 90 岁。b 因为其内容和目标的重要性， TobReg 成员一致推荐收录 Gray 博士这篇深思熟虑的评论， 还一致 认为 Gray 博士是公共卫生和烟草控制领域的领导者和远见者。 TobReg 希望本报告中的结论、建议和咨询说明能够有助于成员 国实施 WHO FCTC 的产品监管条款。
b
WHO 对 Nigel Gray 博士的致敬请见 http://www.who.int/tobacco/communications/
highlights/nigelgray/en.
·3·
烟草制品管制科学基础报告： WHO 研究组第五份报告
2. 包括潜在降低暴露量产品在内的新型 烟草制品 ： 研究需求和管制建议 2.1 引言 2.2 2014 年 WHO 烟草制品调查结果 2.3 对公众健康的影响 2.4 研究需求 2.4.1 监测 2.4.2 风险评估框架 2.4.3 营销与消费者认知 2.4.4 风险披露 2.4.5 管制问题 2.5 管制建议 2.6 参考文献
2.1 引 言 本报告的这部分是基于 WHO 委托的一个背景文章（ 附录 1） ， 该文章作为 2013 年 12 月在巴西里约热内卢召开的 WHO 烟草制品 ·4·
2.包括潜在降低暴露量产品在内的新型烟草制品：研究需求和管制建议
管制研究小组（TobReg）第七次会议议题的讨论基础。 2000 年以来，多种多样的新型烟草制品类型和技术进入世界市 场。根据 WHO，除了含有烟草以外， “新的”或“新型”烟草制品 必须至少满足下列条件中的一个 ： • • • 应用新的或非常规的技术，例如使烟草汽化进入肺部或卷烟 滤嘴中使用薄荷丸。 上市不足 12 年的产品类型 ； 包括可溶烟草制品。 上市已久的产品类型，但市场份额在按传统不使用此类制品 的区域中增加，例如无烟烟草制品被引入原本不具有此类制 品的国家。 • 营销制品或发表文章的目的是在营销该制品时能够声称这些 制品有潜力减少接触烟草烟雾中发现的有害化学品。 一些新型产品被设计用于口服，如可溶烟草制品和美国制造的 可能包括特殊处理的烟草、 “snus”[1-3]。其他的大体上是改良的卷烟， 新型滤嘴或传输吸入烟草的新方法（如在一个较低的燃烧温度或通 过加热而不是燃烧烟草）[4–6]。至少有一些新型产品反映了行业减少 有害烟草或烟气成分暴露的努力，且一些隐含或具有明确健康声明 的新型产品已上市。行业研究表明，不久的将来可能出现更多的新 型产品 [7,8]。 新的烟草制品和类型及其独特的物理或化学特性可能会改变 消费者对有害和致瘾的烟草成分的暴露。这些变化的结果，无论是 积极的还是消极的， 都很难预测。 新型产品的特性和任何相关的 健康声明都可能会增加它们的致瘾性和吸引力， 从而促进持续使 用。即使一个新型产品相对传统卷烟具有较少毒性，其可能作为吸
·5·
烟草制品管制科学基础报告： WHO 研究组第五份报告
烟的附属物来销售或使用，为一些人提供无法吸烟时临时缓解烟碱 需求的手段， 从而延缓这些人的戒烟 [3,9]。 新型产品也可能吸引新 用户， 包括可能本来不会开始吸烟的青少年 [2,3]。 为了充分解决新 型产品相关的公众健康问题，所有可作为一种促进戒烟手段，引起 开始使用和烟草成瘾或通过双重使用维持吸烟的产品，都应受到管 制，以使收益最大化和危害最小化，包括含有烟草的和不含烟草的 产品。 监控新型烟草制品进入国际市场的系统方法有助于指导烟草控 制并评估其潜在的公众健康影响。评估新型和潜在低危害烟草制品 的基本原则需要考虑成分的实际暴露和摄入量、针对产品的行为调 整、营销手段、消费者的观念和模式及使用人群 [5,10]。
2.2 2014 年 WHO 烟草制品调查结果 一份关于无烟烟草制品、 电子烟碱传输系统、 低引燃倾向（RIP） 卷 烟 和 新 型 烟 草 制 品 c 的 调 查 于 2013 年 被 送 往 所 有 WHO 成 员
c
排除了在传统具有卷烟、雪茄、斗烟、自卷烟或口嚼烟等产品的市场上代表这
些产品变化的情况。同时，为了本报告的目的， 也排除了电子烟碱传输系统， 如电子烟 和草本卷烟 ； 一份特别文件涵盖了这类产品（document FCTC/COP/6/10 Rev., http://apps. who.int/gb/fctc/PDF/cop6/FCTC_COP6_10Rev1-en.pdf,accessed on 10 December 2014）.
·6·
2.包括潜在降低暴露量产品在内的新型烟草制品：研究需求和管制建议
国。d 新型烟草制品在 13 个成员国可获得， 代表世界人口的 28%。 监管控制新型产品的生产 占世界人口的 26%） 分发 （26 个成员国， 、 （33 个成员国，32%）和销售（39 个成员国，32%） ， 可能是其可获得性 有限的一个因素。有新型产品销售的成员国中只有三个报道国内生 产，七个报道这类产品是进口的，另有三个没有报道来源。11 个成 员国（占世界人口的 28%）要求新型产品销售的政府许可证，44 个 国家（34%）有政策限制向未成年人销售这些产品，具体来说，这些 产品的最低可购买年龄为 16~21 岁不等。 对新型产品的营销和推广的监管仅比对销售的监管略宽泛。41 个成员国（ 占世界人口的 35%） 全面禁止烟草广告、 新型烟草制品 的促销和赞助， 而 32 个成员国（38%） 报告说没有这样的禁令。9 个成员国 报道这些产品的包装声称其改良或降低风险或危害， （26%） 但这 9 个成员国中只有 1 个对这些产品的特性或成分造成危害的潜 d 截至 2014 年 4 月 9 日， 共有 90 个国家（ 包括 86 个 WHO FCTC 缔约方 ） 对调
查作出回应。这些国家占世界人口的 77%，分别是 ： • WHO 非洲地区： 博茨瓦纳， 刚果， 加蓬， 加纳， 肯尼亚， 马里， 毛里塔尼亚， 南苏丹， 赞比亚 ； • WHO 美洲地区： 巴巴多斯，伯利兹，玻利维亚（多民族国家） ，巴西，加拿大，智利， 哥伦比亚，哥斯达黎加，多米尼加，厄瓜多尔，瓜地马拉，洪都拉斯，牙买加，尼加拉瓜， 巴拿马，巴拉圭，秘鲁，苏里南，乌拉圭，美国 ； • WHO 欧洲地区 ： 奥地利，白俄罗斯，比利时，克罗地亚，捷克共和国，爱沙尼亚， 芬兰，法国，格鲁吉亚，冰岛，匈牙利，拉脱维亚，立陶宛，荷兰，挪威，波兰，斯洛伐克， 西班牙，瑞典，俄罗斯，土耳其，乌兹别克斯坦 ； • WHO 地中海东部地区： 巴林， 吉布提， 埃及， 伊朗（伊斯兰共和国） 伊拉克， 科威特， ， 黎巴嫩，乔丹，摩洛哥，阿曼，巴基斯坦，卡塔尔，苏丹，阿拉伯叙利亚共和国，突尼斯， 阿拉伯联合酋长国 ； 孟加拉国，不丹，印度，印度尼西亚，马尔代夫，缅甸，泰国 ； • WHO 东南亚地区 ： • WHO 西太平洋地区 ： 澳大利亚，文莱，柬埔寨，中国，斐济，日本，老挝人民民 主共和国，马来西亚，蒙古，新西兰，菲律宾，帕劳共和国，韩国，汤加，图瓦卢，越南。
·7·
烟草制品管制科学基础报告： WHO 研究组第五份报告
力进行了监管 ； 5 个成员国报道无健康声明。 总体而言，新型产品在全球的销售是有限的 ； 然而，超过半数 成员国（占世界人口的一半以上）还存在引入新型产品而不限制其 销售、营销或产品特性的可能性。
2.3 对公众健康的影响 发展毒性较小或不致瘾的新型烟草制品，可能是一个减少烟草 相关死亡和疾病的全面方法，特别对于那些不愿意戒断或无法戒断 其对烟草依赖的烟草使用者。然而，具有增加暴露和鼓励烟草使用 风险的新型产品可能会导致对个人或整个群体产生更大的危害 [11]。 关于新型产品影响的证据很有限。美国食品药品管理局烟草制 品科学咨询委员会 [12] 回顾了可溶烟草制品的信息并得出结论，这些 产品滥用的可能性可能会比传统的抽吸型和无烟烟草制品低，而只 使用可溶产品应该比抽烟更安全。然而，报告指出还没有评估绝对 风险或人群风险的流行病学数据。 由于最初可溶烟草制品引入美国市场并未取得商业上的成功， 这类产品的配方和包装经历了重大转变，目前尚不清楚这些产品是 否能在美国或国际上持续下去。相比之下，新型 snus 似乎在美国流 行起来 [13]。 这些产品的广告有别于传统无烟烟草制品 [9,13]， 且经常 作为可在公共场所、酒吧、办公室和飞机上等禁烟的地方使用的流 行卷烟品牌的变体来进行推广 [9]。 新型 snus 和可溶产品可以抑制戒烟症状，尽管不同烟碱含量的 产品有不同效果 [14–16]。斯堪的纳维亚半岛的调查表明 snus 可用于有效 ·8·
2.包括潜在降低暴露量产品在内的新型烟草制品：研究需求和管制建议
戒烟，主要是在男性吸烟者中 [17–19]，但在其他国家的吸烟者中这些产 品能够完全取代卷烟的程度还是未知的，因为烟草使用情况和使用人 群存在差异。在美国， 虽然吸烟者通常不满意 snus 和可溶产品的口味， 但他们可能使用这些产品以减少风险 [20,21] 或在禁烟场合满足对烟碱的 渴求。更彻底地调查试验市场人群对可溶烟草制品和 snus 的反应对于 向烟草控制专家提供数据和政策建议是不可或缺的 [22]。 作为潜在减害装置来开发并营销的改良卷烟或替代烟草燃烧或 加热装置的公众认知度或接受度都很有限 [23]。之前关于产生较少有 害物质的改良卷烟的研究并未发现这些有害物质实际暴露的大幅减 少（如 [24]） 。此外，减少有限数量的致癌物质的释放量可能不会降 低整体的健康风险并有可能影响烟气中其他致癌物质的浓度 [23]。在 产品结构、卷烟滤嘴或其他部位引入新材料，可能会产生新的具有 未知健康后果的化学物质。一些其他新型卷烟装置，如加热不燃烧 烟草制品，相比传统产品似乎产生较少有害成分，并产生较低水平 然而，还没有研究能确定使用这些产品相比卷烟 的生物标志物 [25] ； 会引起的疾病负担是否显著降低。这些类型的产品也可能通过宣传卷 烟使用整体的安全形象，从而会间接鼓励卷烟消费 [5]。由于缺乏市场 渗透和作为卷烟设计替代品的销售时间较短，很难评价人群影响。
2.4 研 究 需 求 2.4.1 监测 全球监视系统应该提供关于新型烟草制品和新的或扩展用途产 ·9·
烟草制品管制科学基础报告： WHO 研究组第五份报告
品的准确及时的数据，包括何时、何地、何种方式以及何种类型的产 品得以引入以及如何引入，针对哪一群体，产品如何使用，以及它们 对其他烟草制品使用的影响。监视的目的不仅是识别新型产品，也应 对该类产品获得市场份额的可能性进行评估。收集的数据应包括 ： • 来自随机样本 [ 例如通过国际标准组织（ISO）方法 ] 的产品 说明（组成、物理参数、设计特征、包装）来解释如存储条 件等因素和每批产品的差异 ； • • • • • • • • • • • 营销和推广 ； 相对于其他烟草制品的成本 ； 产品的认知度及对烟草管控政策的态度 ； 流行率和使用方式，包括以其他产品的方式使用 ； 认知测试的结果和 / 或分组讨论以确定向受访者描述产品使 其完全理解的最佳方式 ； 年轻人摄入以及是否其使用会导致其他烟草产品的使用 ； 依赖性的发展 ； 使用的原因 ； 产品使用的目标群体，如年轻人、女人以及并发症和精神疾 病人群 ； 行为测量（如行为学） ； 对产品中有害物质和烟碱的暴露。
2.4.2 风险评估框架 为了评估新型产品应建立全球管制框架，以评估行业声明的有 效性及评估潜在危害。评估改良烟草制品风险的一般指导原则已由 ·10·
2.包括潜在降低暴露量产品在内的新型烟草制品：研究需求和管制建议
烟草制品科学咨询委员会 [10] 和烟碱和烟草研究协会 [5] 提出。主要问 题如下 ： 。用于传统卷烟的传统方法，如吸烟机测量，可能必须进 行调整，或开发新方法，因为新型产品的抽吸行为、物理和化学特 性的变化，特别是那些具有可吸入气溶胶的产品，因为暴露时间可 能存在不同。应进行人体行为研究以更好地理解与每一种潜在降低 暴露量产品（PREP）相关的抽吸行为。 [26]
。e 与吸烟机相比，吸烟者往往会调整自己抽吸的量以
及抽吸间隔以获取所需生物水平的烟碱。将吸烟机获得的每毫克烟 碱有害物质水平调整为吸烟者烟碱摄入，可以提供对有害物质吸烟 者实际暴露水平的更好估计 [27]。该方法是评估钛酸纳米粒子相关的 风险降低的重要因素 [7,28]，然而以每毫克烟碱标准化后未发现有害成 分水平降低。 。即使根据烟碱标准化有害物质水平，产品设计也可能会改 变使用者的行为并带来风险。更大口抽吸会导致烟气颗粒被吸到肺 部深处。烟碱水平标准化无法解决行为差异。例如，对 Eclipse 卷烟 抽吸行为的研究表明，相较于根据吸烟机做出的估计，吸烟者相比 传统卷烟抽吸量更大且抽吸更频繁 [4,29]。在评估新型产品时应考虑抽 吸行为以及物理和化学特性的变化，尤其是可吸入气溶胶，还有暴
e
可用的吸烟机释放量标准有 ISO 标准和 TobLabNet 标准， 均只适用于卷烟。 尽
管已有电子烟释放量测试，但尚未标准化。
·11·
烟草制品管制科学基础报告： WHO 研究组第五份报告
露时间的差异。 PREP 。 还没有一致 的方法用以评估复杂混合物如主流烟气中有害物质相关的风险。目 前， “ 暴露限值法 ” 被认为最适用于评价单个烟气成分的风险 [30,31]。 暴露限值被定义为适当暴露剂量指标的关键毒理学终点（例如，未 观察到不良效应水平或基准剂量） 暴露限值越高，则风险越低。虽 ： 然对这一测量的解读取决于外推 （如物种间和物种内以及暴露类型） ， 其已被成功地用于评估新型烟草制品 [30,31]。 暴露限值法的局限性是 其只适用于单一化合物， 而不适用于混合物暴露； 可以计算添加效应， 但无法考虑协同效应， 从而会导致低估风险。 如果因为 PREP 中浓 度降低导致误差界限增大，协同效应预期将减少，风险将不成比例 地降低 ； 另一方面，如果误差界限减小，由于没有精心设计的研究， 则协同效应无法确定，因此总体结果未知。 ； PREP ， 。 使用相同 PREP 的个体间的暴露生
物标志物浓度变化范围很大，据推测，这体现了个体吸烟和烟草使 用行为，以及个体间代谢过程的差异。因此，虽然相比吸烟，使用 PREP 组的暴露生物标志物平均值往往较低，但较大的变异可能会导 致一些使用者未体验到暴露的降低。通常，只有很少的暴露生物标 志物得以测量， 不能排除 PREP 中未检测的有害物质水平增加的可 能性。例如， 英美烟草公司加工过程（烟草混合处理）的一项研究中， 致癌物如甲醛和苯并 [a] 芘的水平均升高 [32]。释放量减少和疾病（效 应）型生物标志物之间的相关性必须进行研究，以准确评估潜在的 长期健康风险以及与烟草相关的全部疾病，包括心血管疾病、肺部 疾病、癌症和胎儿毒性 [25,33]。 ·12·
2.包括潜在降低暴露量产品在内的新型烟草制品：研究需求和管制建议
。 上市前评价不能完全消除产品上市后使用方式及其效应的不确定性。 上市后监测可以帮助识别产品被更广泛人群使用后新出现的问题， 如消费者反应、滥用倾向、未成年人使用、双重使用、长期使用的 影响或儿童误食 [34]。同传统卷烟一样，还需要上市后管制框架来监 测配方和成分。 应考虑新型产品中成分和释放物的优先级。 例如， 水烟释放物的测量方法中，应优先考虑烟碱、多环芳烃（PAH） 、醛 类和一氧化碳（CO） 。 、 。对新型烟草制品潜在公众健康影响的评 价的考虑包括其吸引之前不使用烟草的新消费者的潜力，对抽吸传 统卷烟的潜在促进，阻碍戒烟的潜力，以及这类产品会单一使用还 是会导致显著双重（或多重）烟草制品使用。 2.4.3 营销与消费者认知 最近， 烟草公司已经改变了他们与现有和潜在消费者的互动方式。 推广特定烟草品牌的网站是烟草公司一个相对较新的营销形式 [35]。应 进行研究以确定网站和其他新媒体如何被用来传达品牌形象、宣传 品牌活动和促销活动以及推出新型产品。还应该监测社交媒体的新 趋势。 包装在塑造新产品认知中起着重大作用。传统产品品牌延伸到 新型产品可以通过一个知名品牌来提高新产品的接受度。一些新型 产品可能比传统产品更便宜，这可能有利于它们的接受度。 应研究烟草使用者如何认知新引入的产品以及伴随而来的烟草 ·13·
烟草制品管制科学基础报告： WHO 研究组第五份报告
生产商做出的直接或隐含健康声明。例如，吸烟者对潜在降低暴露 量卷烟（Omni、Eclipse 和 Advance） 广告的反应的分析表明， 虽然 广告没有明确声称产品是健康或安全的，吸烟者仍认为它们相比其 他卷烟具有较低的健康风险和较少的致癌物质 [36]。有效的监管除了 广告文本的明确内容以外，还必须考虑到广告所产生的认知。 新型烟草制品的一个重要方面是它们是否作为减少吸烟或可在 戒烟场合使用的产品进行营销。这些不同的方法可能对新型产品的 使用和公众健康影响有实质性的影响。 2.4.4 风险披露 应确定能够向卫生专业人员和公众提供准确、可理解的信息的 有效方法，以防止或扭转对新型产品的任何误解。应考虑关于信息 内容、媒体类型、信使和时机的一般交流规则，并应根据不同目标 群体定制信息。正确的健康信息可以有效改变消费者和烟草控制专 家对于产品的认知 [37,38]。 反营销信息也可能有效阻止当前或曾经的 吸烟者成为无烟烟草和卷烟的双重使用者 [39]。 2.4.5 管制问题 虽然美国市场的营销一直强调 snus 起源于瑞典 [9]，然而美国制 造的 snus 同瑞典制造的 snus 在水分含量、包装袋尺寸以及烟碱和其 他成分含量上都有区别 [40–42]。此外，最新版的骆驼 snus 中的烟草特 有亚硝胺（TSNA）表明用于制造该产品的烟草类型或烟草处理方法 （或两者）均不同于瑞典 snus。因此，那些倡导在其他国家复制“瑞 ·14·
2.包括潜在降低暴露量产品在内的新型烟草制品：研究需求和管制建议
典经验”的研究者们应当谨慎。对这些产品特性应该具体国家具体 分析。 对烟草制品命名规则的管制将要求烟草制造者对使用现有烟草 制品名称命名新开发产品进行充分论证。如果品牌延伸导致具有相 同名称的多种烟草制品的长期使用，个人和公众健康可能受到损害。 无烟烟草制品的致癌潜力在世界范围随产品的性质而变化。在 当地市场销售的产品具有高毒性的国家推广新型无烟烟草制品作为 减害策略，可能会尤其有害 [43–45]。 烟草控制措施，如税收，无烟场所和清洁空气法律可能会刺激 新型产品的开发和使用。应该对烟草控制措施对市场产品的影响进 行研究，如其毒性或致瘾性。 使用传统卷烟向不燃烧烟草制品的转变表明对“二手烟”暴露 的关注应进化到更广泛的概念“二手烟草” 。还必须考虑心理和行为 因素，如非吸烟者的社会接受度和新用户开始吸烟，以及生物化学 方面，如儿童误食或误试以及在家里暴露于烟草成分。例如，与无 烟烟草使用者生活在一起的非吸烟者，包括儿童，可能通过接触受 到污染的家具表面从而暴露于高水平的烟碱和其他烟草成分 [46]。
2.5 管 制 建 议 所有新型和新兴烟草制品， 应受 WHO FCTC 管制。 管制框架 可以扩展到不仅包括现有和新兴烟草产品，而且包括“门户”或吸 烟替代产品， 如非烟草 shisha、 电子烟、 草本卷烟和草本鼻烟。 当 基于 WHO FCTC 的管制不可行时， 至少应监测新型产品以确定其 ·15·
烟草制品管制科学基础报告： WHO 研究组第五份报告
效应。 对所有新型产品都应要求通报或在上市前获得授权。如果可能， 管制机构应基于潜在公众健康效益的科学证据来确定哪些产品可被 允许上市。同美国食品药品管理局开发标准一致，举证责任应归于 生产商，而建立的管制机构应有权决定提供的信息是否充分。任何 其他所需的科学数据应由生产商提供并由独立科学家审核。建立这 样一个系统的财务负担应该由行业承担。美国食品药品管理局开发 的管制策略可作为确定最佳做法的基础 [10]。 每个国家都应监测新型烟草制品及其使用的流行率，以确定产 品是否应优先管制或进行其他烟草控制措施。引入市场的新型产品 市场应监测不可预料的人群效果，包括 ： • • • • 未意识到的毒性 ； 通过吸引新用户、使曾吸烟者复吸或维持可能本会戒烟的当 前用户的使用，来增加或维持烟草使用的流行率 ； 与卷烟或另一种传统烟草制品的双重使用 ； 引发青少年或其他高危人群从新型产品开始使用烟草，并最 终转为吸烟（ “门户”效应） 。 管制机构应该准备向专业人士（如全科医生）和一般公众明确 交流信息的策略。
2.6 参 考 文 献 [1] Rainey CL, Conder PA, Goodpaster JV. Chemical characterization of dissolvable tobacco products promoted to reduce harm. J Agric Food ·16·
2.包括潜在降低暴露量产品在内的新型烟草制品：研究需求和管制建议
Chem 2011;59:2745–51. [2] Romito LM, Saxton MK, Coan LL, Christen AG. Retail promotions and perceptions of R.J. Reynolds ’novel dissolvable tobacco in a US test market. Harm Reduction J 2011;8:10. [3] Southwell BG, Kim AE, Tessman GK, MacMonegle AJ, Choiniere CJ, Evans SE et al. The marketing of dissolvable tobacco: social science and public policy research needs. Am J Health Promot 2012;26:331–2. [4] Slade J, Connolly GN, Lymperis D. Eclipse: does it live up to its health claims? Tob Control 2002;11(Suppl 2):ii64–70. [5] Hatsukami DK, Henningfeld JE, Kotlyar M. Harm reductionapproaches to reducing tobacco-related mortality. Annu Rev Public Health 2004;25:377–95. [6] Kleinstreuer C, Feng Y. Lung deposition analyses of inhaled toxic aerosols in conventional and less harmful cigarette smoke: a review. Int J Environ Res Public Health 2013;10:4454–85. [7] Deng Q, Huang C, Zhang J, Xie W, Xua H, Wei M. Selectively reduction of tobacco specifc nitrosamines in cigarette smoke by use of nanostructural titanates. Nanoscale 2013;5:5519–23. [8] Dittrich DJ, Fieblekorn RT, Bevan MJ, Rushforth D, Murphy JJ, Ashley M, et al. Approaches for the design of reduced toxicant emission cigarettes. SpringerPlus 2014;3:374. [9] Bahreinifar S, Sheon NM, Ling PM. Is snus the same as dip? Smokers’perceptions of new smokeless tobacco advertising. Tob Control 2013;22:84–90. [10] Tobacco Product Scientifc Advisory Committee. Modifed risk ·17·
烟草制品管制科学基础报告： WHO 研究组第五份报告
tobacco product applications. Draft guidance. Rockville, Maryland: US Food and Drug Administration; 2012. [11] Zeller M, Hatsukami D, Strategic Dialogue on Tobacco Harm Reduction Group. The Strategic Dialogue on Tobacco Harm Reduction: a vision and blueprint for action in the US. Tob Control 2009;18:324–32. [12] Tobacco Product Scientifc Advisory Committee. Summary: TPSAC report on dissolvable tobacco products (Rep. No. March 1, 2012). Rockville, Maryland: US Food and Drug Administration; 2012. [13] Delnevo CD, Waskowski OA, Giovenco DP, Bover Manderski MT, Hrywna M, Ling PM. Examining market trends in the United States smokeless tobacco use: 2005–2011. Tob Control 2014;23(2):107–12. [14] Blank MD, Eissenberg T. Evaluating oral noncombustible potential-reduced exposure products for smokers. Nicotine Tob Res 2010;12:336–43. [15] Cobb CO, Weaver MF, Eissenberg T. Evaluating the acute effects of oral, non-combustible potential reduced exposure products marketed to smokers. Tob Control 2010;19:367–73. [16] Hatsukami DK, Jensen J, Anderson A, Broadbent B, Allen S, Zhang Y, et al. Oral tobacco products: preference and effects among smokers. Drug Alcohol Depend 2011;118:230–6. [17] Ramstrom LM, Foulds J. Role of snus in initiation and cessation of tobacco smoking in Sweden. Tob Control 2006;15:210–4. [18] Lund KE, McNeill A, Scheffels J. The use of snus for quitting smoking compared with medicinal products. Nicotine Tob Res 2010;12:817– ·18·
2.包括潜在降低暴露量产品在内的新型烟草制品：研究需求和管制建议
22. [19] Scheffels J, Lund KE, McNeill A. Contrasting snus and NRT as methods to quit smoking. an observational study. Harm Reduction J 2012;9:10. [20] Pederson LL, Nelson DE. Literature review and summary of perceptions, attitudes, beliefs, and marketing of potentially reduced exposure products: communication implications. Nicotine Tob Res 2007;9:525–34. [21] O’ Connor RJ, Norton KJ, Bansal-Traves M, Mahoney MC, Cummings KM, Borland R. US smokers’ reactions to a brief trial of oral nicotine products. Harm Reduction J 2011; 8:1. [22] Biener L, McCausland K, Curry L, Cullen J. Prevalence of trial of snus products among adult smokers. Am J Public Health 2011;101(10):1870–6. [23] McNeill A, Hammond D, Gartner C. Whither tobacco product regulation? Tob Control 2012;21:221–6. [24] Hatsukami DK, Joseph AM, LeSage M, Jensen J, Murphy SE, Pentel P, et al. Developing the science base for reducing tobacco harm reduction. Nicotine Tob Res 2007;9(Suppl 4):S537–53. [25] Hatsukami DK, Feuer RM, Ebbert JO, Stepanov I, Hecht SS. Changing smokeless tobacco products: new tobacco delivery systems. Am J Prev Med 2007;33:S368–78. [26] Burns DM, Dybing E, Gray N, Hecht S, Anderson C, Sanner T, et al. Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal. Tob Control ·19·
烟草制品管制科学基础报告： WHO 研究组第五份报告
2008;17:132–41. [27] Djordjevic MV, Stellman SD, Zang E. Doses of nicotine and lung carcinogens delivered to cigarette smokers. J Natl Cancer Inst 2000;92(2):106–11. [28] Deng Q, Huang C, Xie W, Xu H, Wei M. Signifcant reduction of harmful compounds in tobacco smoke by the use of titanite nanosheets and nanotubes. Chem Commun (Camb) 2011;47:6153–5. [29] Lee EM, Malson JL, Moolchan ET, Pickworth WB (2004) Quantitative comparisons between a nicotine delivery device (Eclipse) and conventional cigarette smoking. Nicotine Tob Res 2004;6:95–102. [30] Cunningham FH, Fiebelkorn S, Johnson M, Meredith C. A novel application of the margin of exposure approach: segregation of tobacco smoke toxicants. Food Chem Toxicol 49:2921–33. [31] Hernandez LG, Bos PM, Talhout R. Tobacco smoke-related health effects induced by 1,3-butadiene and strategies for reduction. Toxicol Sci 2013;136:566–80. [32] Liu C, DeGrandpre Y, Porter A, Griffths A, McAdam K, Voisine R et al. The use of a novel tobacco treatment process to reduce toxicant yields in cigarette smoke. Food Chem Toxicol 2011;49:1904–17. [33] Hatsukami DK, Giovino GA, Eissenberg T, Clark P, Lawrence D, Leischow S. Methods to assess potential reduced exposure products. Nicotine Tob Res 2005;7(6):827–44. [34] O ’ Connor RJ. Postmarketing surveillance for“ modifed-risk ” tobacco products. Nicotine Tob Res 2012;14:29–42. ·20·
2.包括潜在降低暴露量产品在内的新型烟草制品：研究需求和管制建议
[35] Wackowski OA, Lewis MJ, Delnevo CD. Qualitative analysis of Camel Snus’ website message board—users’product perceptions, insights and online interactions. Tob Control 2011;20:e1. [36] Hamilton WL, DiStefano NJ, Ouellette TK, Rhodes WM, Kling R, Connolly GN. Smokers’responses to advertisements for regular and light cigarettes and potential reduced-exposure tobacco products. Nicotine Tob Res 2004;6:S353–62. [37] Biener L, Bogen K, Connolly G. Impact of corrective health information on consumers’perceptions of “reduced exposure” tobacco products. Tob Control 2007;16:306–11. [38] Biener L, Nyman AL, Stepanov I, Hatsukami D. Public education about the relative harm of tobacco products: an intervention for tobacco control professionals. Tob Control 2013;22(6):412–7. [39] Popova L, Neilands TB, Ling PM. Testing messages to reduce smokers’openness to using novel tobacco products. Tob Control 2014;23(4):313–21. [40] Foulds J, Furberg H. Is low-nicotine Marlboro snus really snus? Harm Reduction J 2008;5:9. [41] Stepanov I, Jensen J, Hatsukami D, Hecht SS. New and traditional smokeless tobacco: comparison of toxicant and carcinogen levels. Nicotine Tob Res 2008;10:1773–82. [42] Stepanov I, Biener L, Knezevich A, Nyman AL, Bliss R, Jensen J et al. Monitoring tobacco-specifc N-nitrosamines and nicotine in novel Marlboro and Camel smokeless tobacco products: fndings from round I of the New Product Watch. Nicotine Tob Res 2012;14:274–81. ·21·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[43] Hatsukami DK, Lemmonds C, Tomar SL. Smokeless tobacco use: harm reduction or induction approach? Prev Med 2004;38:309–17. [44] Bedi R, Scully C. Tobacco control—debate on harm reduction enters new phase as India implements public smoking ban. Lancet Oncol 2008;9:1122–3. [45] Ayo-Yusuf OA, Burns DM. The complexity of“harm reduction” with smokeless tobacco as an approach to tobacco control in lowincome and middle-income countries. Tob Control 2012;21:245–51. [46] Whitehead TP, Metayer C, Park JS, Does M, Buffer PA, Rappaport SM. Levels of nicotine in dust from homes of smokeless tobacco users. Nicotine Tob Res 2013;15(12):2045–52.
·22·
3.无烟烟草制品：研究需求和管制建议
3. 无烟烟草制品 ： 研究需求和管制建议 3.1 引言 3.1.1 产品范围广 3.1.2 数据有限 3.1.3 新型产品及其营销 3.1.4 对年轻人及烟草使用发展的影响 3.1.5 应对选择有限 3.1.6 烟草“减害” 3.2 2014 年 WHO 烟草制品调查结果 3.3 当前的地区与国家管制 3.3.1 WHO 非洲地区 3.3.2 WHO 美洲地区 3.3.3 WHO 地中海东部地区 3.3.4 WHO 欧洲地区 3.3.5 WHO 东南亚地区 3.3.6 WHO 西太平洋地区 3.4 结论
f
f
作为 TobReg 审议这个议题基础的背景文章是一份发表于 2014 年的题为“ 无烟
烟草与公众健康 ： 全球视角”的报告 [1]。
·23·
烟草制品管制科学基础报告： WHO 研究组第五份报告
3.5 研究需求 3.5.1 监督与监测 3.5.2 产品表征 3.5.3 健康效应 3.5.4 经济与市场营销 3.5.5 干预措施 3.6 管制建议 3.6.1 干预措施与政策 3.6.2 建立管制框架的挑战与建议 3.6.3 能力建设 3.7 参考文献
3.1 引 言 无烟烟草制品对公众健康呈现出复杂的、广泛的挑战，到目前 为止研究人员和政策对其关注有限。在世界上许多地区，例如印度， 其是主要的烟草使用形式 ； 2006 年全球青少年烟草调查的数据表明， 132 个被调查国家年龄在 13~15 岁的学生相比卷烟（8.9%）更有可能 使用非卷烟烟草制品，包括无烟烟草制品（11.2%）[2]。一些国家家庭 调查数据表明，包括全球成人烟草调查，无烟烟草制品的使用在女性 和处于较低社会经济阶层的人群中更普遍，使这些群体更易受到这些 产品健康和经济后果的危害。然而， 国际烟草控制主要集中在卷烟上， 只有有限的注意力放在包括无烟烟草制品的其他产品类型上。 ·24·
3.无烟烟草制品：研究需求和管制建议
无烟烟草制品已经在全世界使用了几百年，今天，世界范围内 超过 3 亿成年人在使用这些产品 ； 近 2.7 亿使用者生活在 WHO 东南 亚地区 [3]。无烟烟草的严重健康影响已被记录在案 ： 使用者因各种 原因 [4–7] 和特定疾病 [8–12] 死亡的风险很高。2004 年， 国际癌症研究 机构（IARC）的一个工作组发现，有足够的流行病学和实验证据表 明， 无烟烟草可导致人体口腔癌、 食道癌和胰腺癌 [13,14]。 无烟烟草 制品中至少发现 28 种致癌物质，包括 TSNA，动物模型中 TSNA 会 导致鼻、气管、肺、肝、胰腺和食道肿瘤 [15]。无烟烟草也造成了不 良的口腔健康影响， 包括口腔黏膜损伤、 白斑和牙周疾病 [16,17]。 使 用无烟烟草会增加心血管疾病风险 [18,19] 并导致孕妇的不良生殖结 果 [20,21]。 由于无烟烟草制品含有烟碱， 使用者表现出类似于吸烟者 的依赖性，包括对重复使用的耐受性和停用时的戒断症状 [22]。虽然 无烟烟草的使用，像吸烟一样，可以造成严重的损害，但它给科学 和公众健康带来了有别于烟草抽吸的实质性挑战。例如，对健康的 影响程度可能因国家而异，在包括印度的一些国家中风险最高，而 在瑞典的健康风险较低 [23]，部分原因是由于不同国家使用的产品类 型和毒性不同。 3.1.1 产品范围广 无烟烟草制品和相关行为的多样性使得了解其使用的影响变 得很复杂。 其范围包括嚼烟、 鼻烟、gutka、 含烟草的槟榔咀嚼物、 snus、toombak、iqmik 和烟草含片。 然而， 关于这些产品特性、 它 们如何使用以及它们在不同人群中流行率的数据很有限。因此，将 其概括为一个类别是不恰当的。此外，这些产品的生产、销售、使 ·25·
烟草制品管制科学基础报告： WHO 研究组第五份报告
用和控制方式 在不同国家和地区区别很大。 （如通过税收或营销限制） 3.1.2 数据有限 虽然无烟烟草的生物效应是已知的，其使用的公众健康影响取 决于多种因素，包括不同产品的流行率和使用模式，营销信息的影 响以及预防和戒烟活动的有效性。虽然某些类别已被确认为使用的 风险增加，但关于为何特定人群开始使用无烟烟草以及何种因素对 于预防或促进启动最关键等问题的数据仍然有限。 3.1.3 新型产品及其营销 烟草生产商已推出新一代无烟烟草制品，由于增加了有吸引力 的口味，如薄荷味或水果味，并采用了新的传输方法，如含片，可 能会吸引更广泛的消费者。还开发了产品，通过用小包装袋包装无 烟烟草，消除了吐出的需要，以吸引新用户、新的目标人群（如女 性）或吸烟者。主要跨国卷烟公司如菲利普·莫里斯公司和雷诺公 司在其知名品牌万宝路、 骆驼中引入了 snus 产品， 并且这些公司 市场营销方面的专长现在也服务于无烟烟草制品。 烟草控制专家 警告说， 这些产品营销的增加可能通过吸引年轻人、 新用户或刺 激当前吸烟者维持其对烟碱的依赖， 从而对人群健康造成不良影 响 [24]。 新型烟碱传输装置， 如电子烟， 其通过加热而不是燃烧来 释放含烟碱的蒸汽，也在许多国家上市作为一种对传统卷烟的替代 品。 这些产品不在本报告中讨论， 但它们也可能影响烟草使用的 模式 [25]。 ·26·
3.无烟烟草制品：研究需求和管制建议
一些烟草公司为应对普遍的无烟室内空气法律，向吸烟者广告 无烟烟草制品可在无法吸烟场合作为临时替代，使用诸如“想在办 公室享受烟草吗？当然啦”以及“想在 4 小时的飞行过程中享受烟 草吗？当然啦”之类的口号 [26]。除了增加无烟烟草使用，这种营销 策略可能会通过使得吸烟者在抽烟以外更容易维持其对烟碱的依赖 从而阻碍戒烟的努力。这样一个例子说明了烟草控制在一个领域有 所进展后， 如通过室内无烟空气法律， 烟草生产商如何进行适应， 这次是通过引进新型产品和新的市场营销策略。 3.1.4 对年轻人及烟草使用发展的影响 开始使用无烟烟草的年轻人的增多给公共卫生带来了巨大挑战。 美国在 20 世纪 70 年代引入更易被新用户接受的无烟烟草产品后， 青少年和年轻人当中无烟烟草的使用大幅上升 [27]。这些特色产品有 较低的烟碱含量和诱人的口味 ； 证据表明从低烟碱“初吸型”产品 开始的用户随后更容易“升级”为使用烟碱含量较高的产品 [28]。在 印度， 对一种新型无烟烟草制品 gutka 的市场营销， 导致年轻人口 腔黏膜下纤维化和口腔癌的发生率增加 [29,30]。此外，一些研究表明， 无烟烟草使用与包括卷烟在内的其他烟草产品的强化使用相关。因 此使用无烟烟草的青少年可能也更容易继续吸烟 [31,32]。2014 年美国 外科医学报告 [33] 显示， 尽管美国的卷烟消费量已显著下降， 但自 2000 年以来无论是无烟烟草的消费还是销售都增多，年轻人（18~25 岁）中使用增加， 总流行率为 5.5%， 男性（10.5%）中远比女性（0.5%） 更流行。
·27·
烟草制品管制科学基础报告： WHO 研究组第五份报告
3.1.5 应对选择有限 无烟烟草使用的戒断策略喜忧参半。印度行为干预研究在农村 人群 [34,35] 和教师 [36] 中是成功的。在如牙科诊所等环境中的行为干预 临床试验表明无烟烟草使用者戒断率增加，尽管证据不足以推荐具 体干预内容 [37,38]。 药物治疗试验， 包括烟碱贴片、 烟碱口香糖和安 非他酮，对长期（＞ 6 个月）戒断率无影响 [39] ； 然而，药物治疗可 能减少戒断相关症状，如渴求和体重增加 [40]。此外，相比只使用无 烟烟草或只吸烟的人，两者都使用的人暴露于烟碱的风险更高，且 更难戒断 [41–43]。很少国家有国家计划对无烟烟草使用者进行戒断干 预。最近，印度的国家烟草控制项目规模扩大至对卷烟和无烟烟草 使用者的戒断服务 [44]。 3.1.6 烟草“减害” 使用无烟烟草作为吸烟者减害手段的可行性分析，使得对使用 无烟烟草危害的反应变得很复杂。无烟烟草的某些类型可作为卷烟 替代品 ； 由于无烟烟草不像卷烟抽吸那样同肺癌和呼吸道疾病风险 存在关联，这可能会降低整体风险。虽然所有类型的无烟烟草都是 有害的，且可导致癌症和其他疾病，一些类型，包括 snus，相比卷 烟具有较低的 TSNA 和其他有害物质的浓度，整体风险可能较低。 要做出上述推理需要一系列的假设， 因为在一些亚洲国家使 用最广泛的无烟烟草类型的健康影响尚未得到充分记录，并且孟加 拉国和印度使用的一些无烟烟草产品还没有测试。 印度一些被称
·28·
3.无烟烟草制品：研究需求和管制建议
为“snus”的产品有剧毒 [45]。g 考虑到世界范围无烟烟草制品及使用 方式的广泛多样性，不适合将这些产品作为一类来概括与其相关的 危害水平，因为关于其有害成分或使用者暴露还所知尚少。吸烟者 开始使用无烟烟草产品完全取代卷烟，或将成为双重产品用户，是 否会增加他们的风险？此外，还必须考虑无烟烟草使用增加对人群 整体的影响。例如，对这些产品推广的增多是否会使得开始使用烟 草增多或对戒烟努力造成不利影响？虽然关于这一主题的证据越来 越多，但能回答关键问题的明确研究还很缺乏，尚需要进行更多的 研究。
3.2 2014 年 WHO 烟草制品调查结果 2013 年 WHO 关于无烟烟草、电子烟碱传输系统，低引燃倾向 （RIP） 卷烟和新型烟草制品的问卷被发往所有 WHO 成员国。h 结 果表明，无烟烟草制品可见于 70 个成员国，占世界人口的 73%。鼻 烟在 52 个成员国被广泛使用（占世界人口的 65%） ，snus 在 21 个成 员国（55%） ，嚼烟在 55 个成员国（51%） ，烟草口香糖在 17 个成员 国（49%） ，可溶烟草在 7 个成员国（44%） ，外用烟草膏在 5 个成员 国（40%） ， 浸渍烟草在 10 个成员国（29%） ， 奶油鼻烟在 6 个成员 国（23%） ，水烟在 8 个成员国（20%） ，gutka 在 11 个成员国（10%） ， g h 参 见 http://en.schweden-snus.com/chaini-khaini. html 和 https://www.youtube.com/ 截 至 2014 年 4 月 9 日， 一 共 有 90 个 国 家 对 问 卷 做 出 了 回 应， 其 中 86 个 是
watch?v=HqOfA7txhwY. WHO FCTC 缔约国，代表了世界人口的 77%。
·29·
烟草制品管制科学基础报告： WHO 研究组第五份报告
orbs 在 3 个成员国（6%）以及 blackbull（iqmik）在 3 个成员国（5%） 可见（可溶烟草制品未从问卷中的可溶烟草中区分出来） 。调味的无 烟烟草在 34 个成员国（61%）被广泛使用，最受欢迎的口味是薄荷。 3 个成员国 中的无烟烟草来源于本地生产商，8 个成员国 （1%） （2%） 是家庭作坊生产，30 个成员国（8%）是从其他国家进口，5 个成员 国（26%）是本地生产商和家庭作坊生产，6 个成员国（24%）是本 地生产商和进口，7 个成员国（1%）是家庭作坊生产和进口，6 个成 员国（9%）是本地生产商、家庭作坊生产和进口。无烟烟草制品主 要从印度、瑞典和美国进口。 无烟烟草制品在 46 个成员国（26%） 受烟草法律规范，8 个成 员国（19%）受烟草和食品安全法律规范，在 9 个成员国（23%）受 其他法律规范 ； 在其余成员国无烟烟草制品受何种法律规范尚属未 知。58 个成员国（40%） 全面禁止无烟烟草广告、 促销和赞助，11 个（29%）部分禁止。 54 个成员国（66%） 在某种程度上管制无烟烟草制品的生产、 分发和销售。 41 个成员国（60%） 管制商业生产的无烟烟草制品， 43 个成员国（59%） 管制分发，51 个成员国（63%） 管制销售 ； 24 个成员国（31%） 管制家庭作坊生产的无烟烟草制品，30 个成员国 （33%）管制其分发，36 个成员国（41%）管制其销售。 9 个成员国（22%）管制市场上无烟烟草制品的配方和成分。26 个成员国（30%）要求政府出具的销售许可证 ； 64 个成员国（72%） 有政策限制向未成年人销售无烟烟草，具体来说这些产品的最低可 购买年龄为 16~21 岁不等。 对这些产品征收的税如下 ： 24 个成员国（13%）不征收消费税， 8 个成员国（21%） 征收统一计价消费税，11 个成员国（8%） 征收 ·30·
3.无烟烟草制品：研究需求和管制建议
统一特定消费税，4 个成员国（2%） 混合征收统一计价消费税和统 一特定消费税，3 个成员国（1%）征收最低的统一计价消费税，1 个 成员国（1%）分层征税，34 个成员国（53%）征收增值税，31 个成 员国（53%）征收进口关税。
3.3 当前的地区与国家管制 3.3.1 WHO 非洲地区 过去的十年左右无烟烟草制品被引入许多东部和南部的撒 哈拉以南非洲国家， 却被主要卫生和税收部门忽视了。 该地区许 多国家现在采用全面的烟草控制政策和法规， 覆盖所有的烟草制 品， 包括无烟烟草制品。 2006 年这些产品的销售在坦桑尼亚联合 共和国被正式禁止，虽然还需要更严格的监督和执行。塞舌尔法律 强制规定健康警告图案应覆盖无烟烟草包装的主要区域的 50% 或 以上。 3.3.2 WHO 美洲地区 巴西规定如果无烟烟草制品在国家卫生监督管理局（ANVISA） 进行登记则可以出售 ； 然而由于还没有产品进行登记，当前此类产 品在巴西的销售是违法的。在加拿大，无烟烟草制品普遍受广泛的 烟草制品管制规范，包括禁止向未成年人出售、对促销的限制以及 对生产商报告的要求。无烟烟草制品标识规范已存在，但只适用于 ·31·
烟草制品管制科学基础报告： WHO 研究组第五份报告
嚼烟、 鼻烟和口服 snuff。在美国， 已经颁布的法律包括产品登记规定、 所有产品的警示标识以及强制最低可售年龄。此外，根据美国法律， 美国食品药品管理局有权建立无烟烟草制品的烟碱、有害物质和添 加剂含量限量，但尚未发布任何具体的产品性能标准规定。该地区 的许多国家，包括智利、哥斯达黎加、 厄瓜多尔、 萨尔瓦多、 洪都 拉斯、尼加拉瓜、巴拿马、秘鲁和乌拉圭，法律强制规定健康警告 图案应覆盖无烟烟草包装的主要区域的 50% 或以上。 3.3.3 WHO 地中海东部地区 伊朗伊斯兰共和国已经禁止进口无烟烟草制品，巴林出台政策 禁止这些产品的销售和进口，本地区几乎没有相关监管控制。高额 罚款被用来加强现有法律。许多该地区的国家，如埃及、伊朗伊斯 兰共和国、 科威特、 摩洛哥、 阿曼、 卡塔尔和阿拉伯联合酋长国， 法律强制规定健康警告图案应覆盖烟草产品包装的主要区域的 50% 或以上。 3.3.4 WHO 欧洲地区 欧盟提供对烟草管制实践的领导，包括通过最近修订的烟草制 品指令，管理烟草和相关产品的制造、展示和销售。欧盟 28 个成员 国通过禁止口用烟草的销售来管制无烟烟草制品，其中包括除了用 于抽吸或口嚼以外的所有由烟草制成的口用产品。然而，瑞典免除 本规范。在许多非欧盟欧洲国家，无烟烟草按照抽吸烟草产品的广 告和健康警告规定来进行监管。土耳其法律强制规定健康警告图案 ·32·
3.无烟烟草制品：研究需求和管制建议
应覆盖烟草产品包装的主要区域的 50% 或以上。 3.3.5 WHO 东南亚地区 该地区许多缔约方已经采取措施来规范无烟烟草 [3]。不丹 2004 年引进政策禁止烟草制品的制造和销售，包括无烟烟草制品，2010 年 全面立法落实 2004 年的政策。泰国也有规定禁止这些产品的进口和 销售。孟加拉国、印度和尼泊尔立法分别要求健康警告图案覆盖抽吸 和无烟烟草产品包装展示区域的 50%、85% 和 90%。孟加拉国、不丹、 印度、马尔代夫、缅甸、尼泊尔、斯里兰卡和泰国已禁止无烟烟草制 品的广告。印度援引 2011 年的食品安全法禁止含烟草的 gutka 和 pan masala，这是该国使用的无烟烟草的最常见形式。印度的一些州，包 括马哈拉施特拉邦，禁止生产、销售有香味的无烟烟草制品。印度还 加强了健康警告图案，用大众媒体密集宣传，告知人们无烟烟草的危 害，并将无烟烟草戒断纳入烟草依赖治疗指南和国家烟草控制计划。 为控制非法贸易，印度出台了无烟烟草推定税，根据生产能力征收 ； 从无烟烟草制品征收的税款在过去 5 年增加了 4 倍多。缅甸禁止所有 类型烟草产品的进口，包括无烟烟草，但来自邻国的非法贸易仍很成 问题。尼泊尔已经禁止在公共场合使用无烟烟草制品，缅甸禁止在某 些城市地区销售这些产品，并禁止其在政府工作场所的使用。印度、 缅甸、尼泊尔政策禁止无烟烟草制品在教育设施 100 米范围内的销售。 但是，许多国家的执行仍然薄弱，并且该地区缺乏足够的实验室能力 来检测无烟烟草的成分。每当卷烟税增加，无烟烟草税率低于抽吸产 品，用户就开始改用无烟烟草制品。
·33·
烟草制品管制科学基础报告： WHO 研究组第五份报告
3.3.6 WHO 西太平洋地区 2010 年， 由于对槟榔和嚼烟的日益关注，WHO 西太平洋地区 办公室支持该地区 WHO FCTC 缔约方准备一项区域行动计划，其中 具体指标和行动是为了减少槟榔和烟草的使用。2012 年发表的技术 报告 [46] 咨询了槟榔和嚼烟使用特别常见的国家和地区（柬埔寨、关 岛、 基里巴斯、 马绍尔群岛、 密克罗尼西亚联邦、 马里亚纳群岛、 帕劳群岛、所罗门群岛和瓦努阿图） 。报告发现，美拉尼西亚部分地 区，主要是巴布亚新几内亚、所罗门群岛、瓦努阿图北部省份，以 及密克罗尼西亚联邦特别是在北马里亚纳群岛、马绍尔群岛和帕劳 还有关岛槟榔的使用很广。建议应向决策者共享这种无烟烟草造成 伤害的证据，应设计基于社区的策略来改变无烟烟草使用行为。一 些缔约方，如新加坡，已经禁止无烟烟草制品如嚼烟、新型烟草衍 生产品如可溶烟草和含烟碱产品。新加坡有实验室测量无烟烟草产 品如嚼烟、 槟榔、khaini 中的烟碱含量。 蒙古和越南要求健康警告 图案应覆盖烟草产品包装的主要区域的 50% 或以上。
3.4 结 论 无烟烟草是一个全球性的问题 ； 至少 70 个低、中、高收入国家 超过 3 亿人使用这类产品。流行率最高的是东南亚，有 89% 的使用 者，这里也有最高相关疾病负担和最多样性的产品使用类型和形式。 在孟加拉国，使用这些产品的女性比男性更多。在印度，使用无烟 烟草的男性和女性超过吸烟者。 ·34·
3.无烟烟草制品：研究需求和管制建议
与使用无烟烟草相关的疾病风险随国家和地区而不同，部分原 因是由于不同的产品和使用模式。实验室分析显示不同地区产品中 已知致癌物质和烟碱水平变化很大，流行病学研究得出的癌症和心 血管疾病风险评估也随国家而不同。然而，缺乏数据来量化疾病风 险中的这些差异以及准确地识别驱动因素。 在许多国家和地区，无烟烟草的使用和销售都是公共卫生挑战。 在一些高收入国家，如瑞典，低亚硝胺含量无烟烟草的流行率较高， 吸烟率降低且具有强大的烟草控制管制框架，然而大多数使用无烟 烟草的国家是低或中等收入国家，如孟加拉国、印度和东南亚地区 的其他国家。在这些国家，无烟烟草制品经常含有很高水平的有害 成分，卷烟销售在增加，并且大而无组织的业务部门使得很难进行 产品的控制和监管。产品营销的变化、使用模式以及烟草控制计划 和干预在这些不同环境可能会有大不相同的影响。 烟草行业营销策略的改变可能影响未来无烟烟草使用的公共卫 生影响。一些公共场所吸烟限制增加且吸烟流行率有所减少的高收 入国家，烟草公司已开始向吸烟者营销口含烟。这一趋势对吸烟行 为和使用一种或同时使用多种烟草制品的影响仍然不确定。跨国烟 草公司越来越多地在低收入和中等收入国家推出、引入抽吸和无烟 烟草制品。 在许多地区，甚至那些无烟烟草使用非常流行的地区，相比抽 吸烟草制品，用于预防和戒断无烟烟草使用的政策和计划通常较弱 ： 价格更低，警告标记更无力，行之有效的干预措施更少，并且投入 预防和控制的资源更少。 监测无烟烟草使用和健康影响的挑战包括产品及其使用类型的 多样性，产品及其用途信息的缺乏，一些地区非正式的无序的市场， ·35·
烟草制品管制科学基础报告： WHO 研究组第五份报告
以及对定制教育和干预方案的关注有限。 无烟烟草制品的研究中仍存在许多空白，包括监测数据、产品 表征、使用产品的健康影响（包括胎儿暴露与妊娠结果） 、无烟烟草 制品及其使用相关的经济政策、有效的区域特异性教育以及预防和 治疗干预。一些国家已经提出或实施各项政策，但通常缺乏关于影 响或有效性的数据。需要更多基于证据的政策来控制无烟烟草的使 用，其中可包括 ： 要求烟草公司披露无烟烟草制品的成分 ； 建立有 害物质和最大 pH 的产品性能标准 ； 禁止调味 ； 需要有效的相关健 康警告标识 ； 增加这些产品的税收 ； 禁止或限制无烟烟草赞助和营销 ； 以及提高关于这些产品毒性及健康影响的公众意识。总之，预防与 戒断无烟烟草使用应成为任何全面烟草控制努力不可分割的一部分。 许多国家无烟烟草研究和公共卫生行动的能力很有限，特别是 那些公共卫生负担最大的国家。研究与信息共享的国际基础设施可 提高许多国家减少无烟烟草使用后果的能力。
3.5 研 究 需 求 3.5.1 监督与监测 应该进行全面监督以评估无烟烟草使用的程度以及使用模式的 变化，来评价即使是在那些无烟烟草被禁用或流行率很低的国家也 可以采取的减少无烟烟草使用的政策、 干预和其他步骤的有效性。 对使用趋势的监督和监测应包括使用产品的人群和亚人群信息、使 用的产品类型、使用模式和使用强度，与其他烟草产品的混合使用 ·36·
3.无烟烟草制品：研究需求和管制建议
情况，以及对产品的态度、信任和认知。监督应包括对使用变化以 及对包括卷烟在内的其他烟草制品使用的戒断的检测。 3.5.2 产品表征 鉴于世界各地产品和制造模式的多样性，应综合表征不同产品 的特性及其成分和制造方法。在可能的情况下，用以确定主动或二 手（如胎儿）无烟烟草暴露后烟碱和其他有害物质实际人体吸收（吸 收和排泄）的生物标志物研究将很有价值。对经常和烟草一起使用 的非烟草制品， 如槟榔， 也应进行研究。 应对产品进行定期测试， 以评估国家和地区差异，以及产品随时间的变化。 3.5.3 健康效应 产品以及使用实践和使用方式的多样性也妨碍对其健康影响的 广泛概括。 大多数的健康影响研究是在印度、 北欧国家和美国进行的。 因为无烟烟草制品中烟碱和其他有害物质的含量差异，一个国家的 结果不能应用到另一个国家 ； 即使在一个国家内，产品也可能有很 大的不同。虽然要确定与使用无烟烟草相关疾病的全球负担，对具 体国家的健康影响评估必不可少，但目前尚无数据可对不同产品相 关的疾病的相对风险进行估计。 3.5.4 经济与市场营销 关于无烟烟草制品价格、税收结构、销售以及营销策略的数据 ·37·
烟草制品管制科学基础报告： WHO 研究组第五份报告
有限，目前还没有关于治疗这些产品使用引起的疾病的医疗卫生成 本的信息。这类信息对不同国家设计政策和计划很有必要。鉴于无 烟烟草使用在一些中低收入国家以及贫困地区和农村人口中流行率 很高，价格信息对设计有效的公共卫生干预措施尤为重要。应定期 收集价格、税收、支付能力和贸易信息。 3.5.5 干预措施 应开发并测试用于预防和戒断无烟烟草使用的人群和个体干预 措施，特别是考虑文化差异对特定用户群体量身定制干预措施。当 前大多数证据是以高收入国家干预措施的有效性为基础的 ； 因此， 有必要设计用于低收入和中等收入国家以及不同医疗卫生环境的干 预措施。
3.6 管 制 建 议 3.6.1 干预措施与政策 应用于卷烟和抽吸烟草制品的烟草控制政策、方案和措施也应 该同样严谨地在无烟烟草制品中被应用、执行和监测，特别是在流 行率高的地区。无烟烟草使用的预防和戒断应该是全面烟草控制计 划不可分割的组成部分。然而，这些产品呈现不同的挑战，而具体 政策也许取决于产品、使用模式、营销和烟草控制环境。应特别对 待下面列出的无烟烟草制品管制层面。 ·38·
3.无烟烟草制品：研究需求和管制建议
鉴于问题、 营销、 使用模式的趋势以及有效治疗的缺乏的程 度和复杂性，无烟烟草带来的公共卫生挑战要远大于其受到的关注 和举措。大多数控制卷烟的政策的科学依据也适用于控制无烟烟草 使用。 没有干预策略能适用于所有国家 ： 必须根据社会环境、所有烟 草制品的流行率和消费趋势来制定方法。此外，由于产品以及其制 作方式的异质性， 政策干预措施应该针对每一个具体的产品类型， 不管是生产的还是定制的。
WHO FCTC 应用于卷烟和其他抽吸烟草形式的烟草控制政策干预措施也应 适用于无烟烟草制品。这些干预措施包括 ： • 覆盖产品包装主要部分的健康警告， 包括文字和图形描述， 位于主印刷面并轮换（第 11 条） （尽管许多国家要求无烟烟 草包装上要有健康警告，但多数标记只有文字警告，缺乏一 直用于卷烟标记的图形图像） ； • • • 限制或禁止烟草广告、促销和赞助（第 13 条） ； 限制向未成年人销售（第 16 条） ； 由于传统市场的挑战，制定具有有效依从性的税收和价格政 策，来阻止无烟烟草的使用和降低需求，包括考虑对烟叶征 税或推定税（对每台制造机器混合征税） （第 6 条） ； • • 强制生产商披露无烟烟草制品的成分，包括产品的所有组成 以及有害和潜在有害的成分（第 10 条） ； 对无烟烟草危害的公共教育（第 12 条） ，用信息、教育和交 ·39·
烟草制品管制科学基础报告： WHO 研究组第五份报告
流来提高对有害健康影响的认识并消除谬见（教育要针对卫 生专业人员、决策者、社区领袖和公众，特别要注意年轻人 和育龄女性，特别是在烟草制品由家庭作坊制作或在家里或 销售点定制的地区） ； • • 无烟烟草制品的追溯机制以及对非法贸易的预防（第 15 条） ； 基于证据的无烟烟草戒断的干预措施的推广与规定（ 第 14 条） 。 • 无烟烟草制品中已知有害物质的水平有很大不同， ： 存储和处理对有害物质水平的影响也存在很大不同 [25]。能够 用于防止预先制作和定制产品产生更大毒性的要求包括 ： 减 少使用黄花烟草（Nicotiana rustica） 限制细菌污染，细菌污 ； 染可促进烟硝胺和致癌物质的形成 ； 烟草应火管烤制或晒制 而不是明火烤制或晾制 ； 通过巴氏杀菌法杀死细菌 ； 改进存 储条件，如在销售前将产品冷藏 ； 标识生产日期 ； 消除如槟 榔和零陵香豆等组成成分，它们是已知的致癌物质 [14]。 • （ 9 TobReg 提出 [25]，行业生产的 ） ： 无烟烟草制品应强制实行有害物质上限，N′- 亚硝基降烟碱 （NNN）与 4-(N- 甲基亚硝胺基 )-1-(3- 吡啶 )-1- 丁酮（NNK） 的上限为 2 μg/g 干重烟草， 苯并 [a] 芘的上限为 5 ng/g。 管 制当局还应要求监测烟草中砷、镉和铅的水平 [47]。实施这些 标准并不意味着某个产品是较安全的，不应允许烟草公司如 此宣传以促销产品。 • ·40·
各种香料和其他添加剂被用于提高烟 ： 草制品的吸引力并促进吸收 [48,49]。降低烟草制品吸引力和成
3.无烟烟草制品：研究需求和管制建议
瘾应包括禁止或调节甜味剂和香料（ 包括本草、 香料和花 ） 以及对游离态烟碱和 pH 设置限值。 • 出口的无烟烟草制品应采用和制 ： 造国相同（或更高）的标准。 基于现有证据基础，不应允许任何降低暴露或危害的健康声明 或主张。用于支持健康声明的科学依据必须经独立的、科学的政府 管制机构审核（第 10 条） 。 3.6.2 建立管制框架的挑战与建议 进行监测和研究并实施新的政策和干预措施以应对无烟烟草使 用将需要低收入和中等收入国家更大的科学和公共卫生能力，特别 是那些无烟烟草使用水平高的国家。但是，主要挑战阻碍了有效政 策和方案的实施。 只有有限的数据可用于定量无烟烟草使用相关的风险，包括国 家和地区的健康、经济、环境和社会负担。此外，几乎没有任何关 于无烟烟草控制进展或挑战的信息。 ：美 国 疾 病 控 制 与 预 防 中 心 的 全 球 烟 草 监 控 系 统 以 及 WHO STEP 调查可以扩展以覆盖无烟烟草。还需要较小的、有针对 性的调查以理解特定亚组的模式。 广泛使用无烟烟草的大多数国家都缺乏技术和财政能力来评估 无烟烟草制品中的成分和有害物质水平。应进一步完善方法、产品 性能标准和测试方案，以促进跨国比较并最终监控的各国产品。 ·41·
烟草制品管制科学基础报告： WHO 研究组第五份报告
应规范测试方法， 如果理想的话， 通过 WHO 烟草实验 ： 室网络（TobLabNet）进行区域协调。i 应验证检测无烟烟草制品中 烟碱、TSNA 和苯并 [a] 芘的方法。应通过伙伴关系，如 WHO 合作 中心，来提高低收入和中等收入国家的实验室能力。 3.6.3 能力建设 国家间的交流与合作越来越重要。由于烟草使用的变化，创新 政策和干预措施正被引入不同国家，而烟草行业也在采用新的营销 策略。这一庞大的“天然实验”提供了独一无二的研究和评估机会， 这将需要协调监测、信息共享与研究。出于这种考虑，做出如下建 议以加强协作和基础设施（ 其中一些在 WHO FCTC 第 20 条中有 描述） 。 创建可以使全世界的人通过网络轻松访问的关于烟草制品特别 是无烟烟草制品信息的区域知识中心或信息资源库。信息资源库可 以提供关于无烟烟草管制、产品特性、使用模式、政策和干预措施 以及研究和评估结果的全球“最佳实践”和国家经验。
、 可以建立一个门户网站作为全球、区域和国家最佳实践的信息 索引和资源库，包括无烟烟草管制、产品特性、成分和组成、制造 和促销手段、价格、包装和营销等方面。该入口可同时汇集上面提 i WHO 烟草实验室网络（TobLabNet）是一个政府的、学术的和独立的实验室组
成的全球网络，目的是根据 WHO FCTC 第 9 条加强国家和地区检测和研究烟草制品成分 和释放物的能力（http://www.who.int/tobacco/industry/product_regulation/toblabnet/en/） 。
·42·
3.无烟烟草制品：研究需求和管制建议
到的区域中心或资源库，并提供一个论坛用于讨论无烟烟草制品管 制、运营和政策研究、临床研究设计和结果以及政策等方面的成就 与挑战。
、 这样的合作对将研究转化为政策并确保政策需求反馈给研究来 说至关重要。国家和地区之间的合作对比较不同的产品、环境与干 预来说特别重要。具有较成熟烟草控制计划的国家可以为新计划和 新政策的国家提供专业知识和帮助。 研究能力的建设应该通过更好地利用现有的资源， 如 TobLabNet、 全球成人调查和全球青少年烟草调查。研究能力也可以通过吸引和 培训新的研究人员，特别是中低收入国家，并鼓励新的和有经验的 研究人员之间的合作来增强。 基于证据的无烟烟草法规和政策的时机可通过技术援助的国际 协调、培训和能力建设得以增强 ； 监督和执行现有规章制度 ； 开发 和传播的测试规范和产品性能标准 ； 修订现有的烟草控制计划以更 好地处理无烟烟草。
3.7 参 考 文 献 [1] National Cancer Institute and Centers for Disease Control and Prevention. Smokeless tobacco and public health: a global perspective. Bethesda, Maryland: Department of Health and Human Services, ·43·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Centers for Disease Control and Prevention and National Institutes of Health, National Cancer Institute (NIH Publication No. 147983); 2014 (http://nccd.cdc.gov/GTSSData/Ancillary/Publications. aspx). [2] Centers for Disease Control and Prevention. Use of cigarettes and other tobacco products among students aged 13–15 years—worldwide, 1999–2005. Morb Mortal Wkly Rep 2006;55:553–6. [3] WHO Regional Offce for South-East Asia. Expert group meeting on smokeless tobacco control and cessation, New Delhi, India, 16–17 August 2011. New Delhi. [4] Gupta PC, Bhonsle RB, Mehta FS, Pindborg JJ. Mortality experience in relation to tobacco chewing and smoking habits from a 10year follow-up study in Ernakulam District, Kerala. Int J Epidemiol 1984;13:184–7. [5] Gupta PC, Mehta FS, Pindborg JJ. Mortality among reverse chutta smokers in south India. Br Med J 1984;289:865–6. [6] Gupta PC, Mehta HC. Cohort study of all-cause mortality among tobacco users in Mumbai, India. Bull World Health Organ 2000;78:877–83. [7] Gupta PC, Pednekar MS, Parkin DM, Sankaranarayanan R. Tobacco associated deaths in Mumbai (Bombay) India. Results of the Bombay Cohort Study. Int J Epidemiol 2005;34:1395–402. [8] Rahman MA, Zaman MM. Smoking and smokeless tobacco consumption: possible risk factors for coronary heart disease among young patients attending tertiary care cardiac hospital in Bangladesh. ·44·
3.无烟烟草制品：研究需求和管制建议
Public Health 2008;122:1331–8. [9] Lee PN, Hamling J. Systematic review of the relation between smokeless tobacco and cancer in Europe and North America. BMC Med 2009;29:36. [10] Lee CH, Lee KW, Fang FM, Wu DC, Shieh TY, Huang HL, et al. The use of tobacco-free betel-quid in conjunction with alcohol/tobacco impacts early-onset age and carcinoma distribution for upper aerodigestive tract cancer. J Oral Pathol Med 2011;40:684–92. [11] Mateen FJ, Carone M, Alam N, Streatfeld PK, Black RE. A population-based case–control study of 1250 stroke deaths in rural Bangladesh. Eur J Neurol 2012;19:999–1006. [12] Rahman MA, Spurrier N, Mahmood MA, Rahman M, Choudhury SR, Leeder S et al. Is there any association between use of smokeless tobacco products and coronary heart disease in Bangladesh? PLoS One 2012;7:e30584. [13] Cogliano V, Straif K, Baan R, Grosse Y, Secretan B, El Ghissassi F. Smokeless tobacco and tobacco-related nitrosamines. Lancet Oncol 2004;5:708. [14] IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 85.Betel quid and areca nut chewing. Lyon: International Agency for Research on Cancer; 2004 (http://monographs.iarc.fr/ENG/ Monographs/vol85/mono85-6.pdf, accessed 1 August 2012). [15] Smokeless tobacco or health: an international perspective (Smoking and Tobacco Control Monograph No. 2). Bethesda, Maryland: National Cancer Institute, Department of Health and ·45·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Human Services; 1992 (Publication No. 92-3461) (http://www. cancercontrol.cancer.gov/tcrb/monographs/2/index.html). [16] Shulman JD, Beach MM, Rivera-Hidalgo F. The prevalence of oral mucosal lesions in US adults: data from the Third National Health and Nutrition Examination Survey, 1988–1994. J Am Dent Assoc 2004;135:1279–86. [17] Fisher MA, Bouquot JE, Shelton BJ. Assessment of risk factors for oral leukoplakia in West Virginia. Community Dent Oral Epidemiol 2005;33:45–52. [18] Boffetta P, Straif K. Use of smokeless tobacco and risk of myocardial infarction and stroke: systematic review with meta-analysis. BMJ 2009;339:b3060. [19] Gupta R, Gupta N, Khedar RS. Smokeless tobacco and cardiovascular disease in low and middle income countries. Indian Heart J 2013;65;369–77. [20] England LJ, Kim SY, Tomar SL, Ray CS, Gupta PC, Eissenberg T, et al. Non-cigarette tobacco use among women and adverse pregnancy outcomes. Acta Obstet Gynaecol Scand 2010;89:454–64. [21] Willis D, Popovech M, Gany F, Zelikoff J. Toxicology of smokeless tobacco: implications for immune, reproductive, and cardiovascular systems. J Toxicol Environ Health Crit Rev 2012;15:317–31. [22] Henningfeld JE, Fant RV, Tomar SL. Smokeless tobacco: an addicting drug. Adv Dent Res 1997;11:330–5. [23] Boffetta P, Hecht S, Gray N, Gupta P, Straif K. Smokeless tobacco and ·46·
3.无烟烟草制品：研究需求和管制建议
cancer. Lancet Oncol 2008;9:667–75. [24] Henningfeld JE, Rose CA, Giovino GA. Brave new world of tobacco disease prevention: promoting dual product use? Am J Prev Med 2002;23:226–8. [25] WHO Study Group on Tobacco Product Regulation. Report on the scientifc basis of tobacco product regulation: third report of a WHO study group (WHO Technical Report Series, No. 955). Geneva: World Health Organization; 2009 (http://www.who.int/ tobacco/global_interaction/tobreg/publications/tsr_955/en/index. html). Hegarty M, Richter P, Pederson LL. What do adult smokers think [26] O’ about ads and promotional materials for PREPs? Am J Health Behav 2007;31:526–34. [27] Connolly GN. The marketing of nicotine addiction by one oral snuff manufacturer. Tob Control 1995;4:73–9. [28] Tomar SL, Giovino GA, Eriksen MP. Smokeless tobacco brand preference and brand switching among US adolescents and young adults. Tob Control 1995;4:67–72. [29] Gupta PC, Sinor PN, Bhonsle RB, Pawar VS, Mehta HC. Oral submucous fibrosis in India: a new epidemic? Natl Med J India 1998;11:113–6. [30] Gupta PC. Mouth cancer in India—a new epidemic? J Indian Med Assoc 1999;97:370–3. [31] Tomar S. Is use of smokeless tobacco a risk factor for cigarette smoking? The US experience. Nicotine Tob Res 2003;5:561–9. ·47·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[32] Hatsukami DK, Lemmonds C, Tomar SL. Smokeless tobacco use: harm reduction or induction approach? Prev Med 2004;38:309–17. [33] The health consequences of smoking—50 years of progress. A report of the Surgeon General. Rockville, Maryland: Department of Health and Human Services; 2014. [34] Gupta PC, Mehta FS, Pindborg JJ, Bhonsle RB, Murti PR, Daftary DK, et al. Primary prevention trial of oral cancer in India: a 10-year follow-up study. J Oral Pathol Med 1992;21:433–9. [35] Anantha N, Nandakumar A, Vishwanath N, Venkatesh T, Pallad YG, Manjunath P, et al. Efficacy of an anti-tobacco community education program in India. Cancer Causes Control 1995;6:119–29. [36] Sorensen G, Pednekar MS, Sinha DN, Stoddard AM, Nagler E, Aghi MB, et al. Effects of a tobacco control intervention for teachers in India: results of the Bihar School Teachers Study. Am J Public Health 2013;103:2035–40. [37] Severson HH. What have we learned from 20 years of research on smokeless tobacco cessation? Am J Med Sci 2003;326:206–11. [38] Carr AB, Ebbert JO. Interventions for tobacco cessation in the dental setting. Cochrane Database Syst Rev 2006:CD005084. [39] Ebbert JO, Rowland LC, Montori V, Vickers KS, Erwin PC, Dale LC, et al. Interventions for smokeless tobacco use cessation. Cochrane Database Syst Rev 2004:CD004306. [40] Dale LC, Ebbert JO, Glover ED, Croghan IT, Schroeder DR, Severson HH, et al. Bupropion SR for the treatment of smokeless tobacco use. Drug Alcohol Depend 2007;90:56–63. ·48·
3.无烟烟草制品：研究需求和管制建议
[41] Hatsukami DK, Severson HH. Oral spit tobacco: addiction, prevention and treatment. Nicotine Tob Res 1999;1:21–44. [42] Spangler JG, Michielutte R, Bell RA, Knick S, Dignan MB, Summerson JH. Dual tobacco use among Native American adults in southeastern North Carolina. Prev Med 2001;32:521–8. [43] Wetter DW, McClure JB, de Moor C, Cofta-Gunn L, Cummings S, Cinciripini PM, et al. Concomitant use of cigarettes and smokeless tobacco: prevalence, correlates, and predictors of tobacco cessation. Prev Med 2002;34:638–48. [44] Varghese C, Kaur J, Desai NG, Murthy P, Malhotra S, Subbakrishna DK, et al. Initiating tobacco cessation services in India: challenges and opportunities. WHO South-East Asia J Public Health 2012;1:159–68. [45] Mukherjea A. Tobacco industry co-optation of culture? Converging culturally specifc and mainstream tobacco products in India. Tob Control 2012;21:63–4. [46] Review of areca (betel) nut and tobacco use in the Pacific. A technical report. Manila: WHO Regional Offce for the Western Pacific; 2012 (http://www.wpro.who.int/tobacco/documents/201203_Betelnut/en/). [47] WHO Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation. Fourth report of a WHO study group (WHO Technical Report Series, No. 967). Geneva: World Health Organization; 2012 (http://www.who.int/ tobacco/global_interaction/tobreg/publications/tsr_967/en/index. html). ·49·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[48] Henningfield JE, Hatsukami DK, Zeller M, Peters E. Conference on abuse liability and appeal of tobacco products: conclusions and recommendations. Drug Alcohol Depend 2011;116(1–3):1–7. [49] Menthol cigarettes and the public health: review of the scientifc evidence and recommendations. Washington DC: Tobacco Products Scientific Advisory Committee, Food and Drug Administration; 2011 (http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoProduc tsScientifcAdvisoryCommittee/UCM269697.pdf).
·50·
4.低引燃倾向卷烟：研究需求和监管建议
4. 低引燃倾向卷烟 ： 研究需求和监管建议 4.1 引言 4.2 背景 4.3 结果 4.3.1 上述报告后的新研究 4.3.2 国家和地区的立法经验及其执行 4.3.3 产品符合性数据 4.3.4 风险评估以及对安全与风险的认知 4.3.5 采用标准前后卷烟引发火灾的动态 4.3.6 标准的实用性与不足 4.4 结论 4.5 2014 年 WHO 烟草制品调查结果 4.6 研究需求 4.7 管制建议 4.8 参考文献 附录 4.1 方法 附录 4.2 ISO 12863 概述 附录 4.3 低引燃倾向卷烟技术相关企业最近的 CORESTA 简报
·51·
烟草制品管制科学基础报告： WHO 研究组第五份报告
4.1 引 言 这部分针对新出现的问题并更新了 2008 年发表的 TobReg 关于 低引燃倾向（RIP） 卷烟的工作。 文件为 2014 年 10 月召开的 WHO FCTC 缔约方第六次会议准备。 基于美国国家标准与技术研究所的实验室研究制定了法规，且 形成了科学家、消费者团体、公共卫生和消防安全官员的联盟。一 些国家试图立法并引入 RIP 产品报告系统，测试费用由生产商支付。 尽管与早期声明相反，市场通过提供低引燃纸张以及充足且经认证 的实验室测试设施进行了反应。制造成本已经最小。不同国家中的 依从性已经得以监测，结果也可获得。加拿大的数据表明大型生产 商的实质和持续的依从，较小生产商的依从也不断增加。风险评估 表明几乎没有证据表明抽吸 RIP 卷烟增加人们火灾风险相关的行为， 且关于吸烟者对有害物质暴露风险增加的证据有限。对火灾发生率 和人员伤亡的影响的评估受限于火灾报告系统的质量、RIP 标准生 效时间较短、火灾减少且可燃性（如床垫和软垫家具）降低的长期 趋势。尽管如此，最严格的评估表明 RIP 管制带来吸烟相关火灾约 30% 的减少。2010 年，ISO 采用基于美国国家标准与技术研究所和 美国材料与测试协会标准的全球标准 [1]。来自实验研究和新兴的人 群研究的科学证据表明，当前标准对于减少火灾和火灾死亡行之有 效。然而对 RIP 卷烟立法应当允许随科学基础增长而提高标准的弹 性，特别是关于人群有效性。国家应采用 ISO 2010 标准，生产商应 主动采取 RIP 卷烟设计作为良好制造过程的一部分。
·52·
4.低引燃倾向卷烟：研究需求和监管建议
4.2 背 景 关于烟草制品管制科学基础的 TobReg 报告 [2] 包括一个 “防火型” 卷烟的咨询说明。报告认为，卷烟燃烧引起的火灾死亡是一个全球 性的重大问题，RIP 卷烟应该是强制性的。 包括美国材料与测试协 会 E2187[3]，以及根据 ISO 17025 的实验室认可等标准能够用于测试 RIP 卷烟， 成本由烟草生产商负担。 报告警告说， 虽然 RIP 卷烟降 低风险的声称应该被允许，但减少火灾和火灾相关死亡的标准的有 效性应随着标准的实施得以监测。任何关于 RIP 卷烟的立法应允许 当新的研究结果可用时对标准进行加强。报告呼吁有权益的机构进 行国际合作。 为了准备缔约方会议第六次会议，TobReg 审议了上述报告发布 以来的活动和研究，包括 RIP 标准及其采用、 监测、其对消费者认 知卷烟相关整体风险的影响以及 RIP 卷烟降低火灾的有效性。作为 这项工作的一部分，TobReg 要求评论标准的关联性、其存在的不足 和有必要进行进一步研究的领域（详见附录 4.1） 。
4.3 结 果 RIP 卷烟管制基于源自美国国家标准与技术研究所在 1991 年卷 烟消防安全法案下进行的一项测试 [4]，其带来了可重复用于滤纸上 的引燃倾向的测试，使用燃烧全长作为引燃倾向的指标。该方法中 卷烟被平放于密闭室内不同数量的滤纸层上，该方法被称为“卷烟 ·53·
烟草制品管制科学基础报告： WHO 研究组第五份报告
熄灭法” ，在以前的报告中有过详细描述。 “模拟家具引燃法”测试 基于先前的性能标准，该方法是将一个燃烧的卷烟放在家具材料上 并测试引燃倾向。简单的滤纸方法与家具测试关联性很好，并由美 国材料与测试协会 [1] 编号为 ASTM E2187。2010 年， ISO 采用该方法， 并编号为 12863:2010[5]。无论是美国国家标准与技术研究所还是 ISO 标准都规定卷烟设计必须符合标准。这两个标准很相似。附录 4.2 对 其程序进行了总结。 4.3.1 上述报告后的新研究 Alpert 和他的同事 [6] 综述了现有的 RIP 相关技术的专利和文献。 Seidenberg 等 [7] 根据 ASTM 方法进行了测试， 报道称在有规定的国 家购买的卷烟趋向依从，而其他市场购买的往往趋向全长燃烧。烟 草科学研究合作中心（CORESTA） 最近在法国巴黎的关于烟气科 学和产品技术的会议研究了一些与 RIP 相关的摘要（ 附录 4.3） ，主 要关于测试参数和方法，比较 RIP 卷烟和其他产品的释放物。大多 数的研究报道产品释放物之间无实质性的差异 [8,9]。 独立研究人员 进行的关于 RIP 有害释放物、 风险认知和人群影响的研究综述见 后文。 4.3.2 国家和地区的立法经验及其执行 美国纽约州是第一个颁布 RIP 规定的行政区， 于 2004 年 6 月 颁布。 加拿大于 2005 年 10 月实施管制。 上述报告发布时 [2]， 加拿 大和美国的 18 个州（占美国人口的 38%）是仅有的具有有效 RIP 规 ·54·
4.低引燃倾向卷烟：研究需求和监管建议
定的行政区。自 2008 年以来，RIP 标准已在四个国家和欧盟全体成 员国实施 [10]。在南非，RIP 标准于 2011 年作为规定发布。j 在已有 18 个州采用标准的美国，其余的州在 2009~2011 年间也采取了标准。 澳大利亚于 2010 年采用了标准。 这些经验说明了一些通过 RIP 法律的立法策略 [11]。应构建一个 包括科学家、 “燃烧”拥护者、立法者、消费者组织、公共卫生和消 防安全官员的联盟，以收集卷烟使用相关火灾的数据以及标准的科 学依据 ； 随后应制定全面、一致的立法，进行公共教育活动并与决 策者互动。联盟应该由科学和立法方面的专家密切建议，并注意其 他行政区取得的进展，并关注公共信息，包括用于驳斥烟草行业反 对的信息 [11,12]。 首先，在美国召开一系列由随后采用 RIP 立法的国家代表参加 的国际会议和研讨会，包括科学家、消费群体、立法者、公共卫生 和消防官员，以进行信息交换并形成政策。会议由公共卫生机构的 赠款和赞助支持。其次，在所有国家使用统一的标准，消除行业内 所谓不得不设计多种 RIP 卷烟类型的说法。第三，获取卷烟火灾造 成的实际危害的确实数据，在一些活动中，由在卷烟引起火灾中受 伤的“英雄”作为代言人。最后，达成共识，即必须起草统一全面 的法律并由法律专家审查 ； 卷烟的实际设计不应该确定，但应符合 一个统一的标准。立法应允许依据新发现改变标准，要求测试费用 由烟草行业支付，禁止宣称低风险并要求支付国家实施法律和后续 研究的经费。成立一个集中且快速响应的团队来跟踪进展，反驳行 j http://www.tobaccocontrollaws.org/fles/live/South%20Africa/South%20Africa%20-%20
RIP%20Regs%20-%20national.pdf. 也可参见 2012 年法律实施时 BAT 向客户交流的链接 : http:// www.batsa.co.za/group/sites/BAT_7N3ML8.nsf/vwPagesWebLive/DO8QVAU2?opendocument&SKN=1。
·55·
烟草制品管制科学基础报告： WHO 研究组第五份报告
业争论并防止削弱立法的尝试。这些活动促进了 RIP 法律的通过和 实施，并使得随后法规的通过更容易。一旦法律通过，各国应分享 他们实施的方法 ；然而， 关于实际火灾的数据（ 可提高 RIP 标准 ） 尚未得以共享或报道。 一项欧盟指令已经通过，要求 ISO 标准但不要求行业依从实验 室测试。 法律在澳大利亚、欧盟和南非对 RIP 卷烟有要求，这些国 家占约 20% 的世界人口，并消耗大约 20% 世界上生产的卷烟。大多 数是高收入国家 ； 低收入和中等收入国家采用的很少。 4.3.3 产品符合性数据 加拿大卫生部网站上展示了 2005~2011 年 RIP 测试的结果， 包 括特定品牌风格的测试结果 [13]。为简单起见，TobReg 决定将生产商 分为三大公司（帝国、Rothmans 和 JTI）以及“其他” （包括小进口 商和当地生产商） 。三大厂商占有约 97% 的市场份额 [14]。 图 4.1 显示了全长燃烧的原始数据。 可以在主要生产商的产品 和其他产品之间发现 RIP 依从性的明显差异 ： 主要生产商的产品从 一开始就很好地符合 RIP 标准，而其他的则需要更长的时间来符合。 二元 logistic 回归 分析生产商群体和采样年份 （事件 / 试验） （2005~2011 年）对全长燃烧的影响的结果如图 4.2 所示，证实了一开始的发现， 即其他公司的全长燃烧的变化率大于大型公司（生产商的年际交互 作用，χ2(6)= 241.6，P ＜ 0.001） 。然而，目前尚不清楚这是由于管制 的有效性还是由于观察到的火灾数量，因为各大厂商占有市场的主 导地位。
·56·
4.低引燃倾向卷烟：研究需求和监管建议
ᅲ㒓˖Џ㽕⫳ѻଚ 50
㰮㒓˖݊Ҫ⫳ѻଚ
40
ܼ䭓➗⚻˄%˅
30
20
10
00 2005 2006 2007 2008 ᑈӑ 2009 2010 2011
图 4.1 2006~2011 年加拿大生产商利用 ASTM E2187 方法测试的品牌中全长燃 烧的比例 RIP 立法于 2005 年 10 月确立。水平线表示 RIP 标准（25% 全长燃烧）
4.3.4 风险评估以及对安全与风险的认知 引入 RIP 卷烟的行为和健康关联已在一些研究中得以解决。 O’ Connor 等 [15] 检测了加拿大吸烟者在法规实施前后一年的观念和 行为。采用随机拨号电话调查，他们获得了来自 435 位烟龄在 18 年 以上的吸烟者的信息（随访率 73%） ，发现了类似的火灾危险行为水 ·57·
烟草制品管制科学基础报告： WHO 研究组第五份报告
RBH/JTI 60
/
50
ܼ䭓➗⚻˄%˅
40
30 RIP 20
10
0 2005 2006 2007 2008 ᑈӑ 2009 2010 2011
图 4.2 2006~2011 年加拿大 ASTM E2187 测试中全长燃烧的测试品牌的比例， 根据年限和生产商二元回归的结果 RIP 立法于 2005 年 10 月确立。虚线表示 RIP 标准（25% 全长燃烧）
平，如躺在床上吸烟（立法前 14.7%，立法后 13.1%）和吸烟时打瞌 睡（ 立法前 2.3%， 立法后 2.1%） 。 未发现担心卷烟引起火灾方面的 不同。吸烟者更频繁地报告他们的卷烟在法规实施后“经常”自熄 P ＜ 0.001） （ 实施前 3.7%， 实施后 14.7% ； ， 但在报道“ 烟灰掉落 ” 方面没有差异（ 立法前 36.4%， 立法后 31.3%） 。Seidenberg 等 [16] 报 道了类似的研究，美国马萨诸塞州吸烟者在法规实施前后发现了一 个类似的模式。最初的 620 名受访者中，352 名（57%）完成了调查。 报道的任由卷烟无人看管的频率（ 立法前 26.5%， 立法后 28.1%， ·58·
4.低引燃倾向卷烟：研究需求和监管建议
P =0.567） 和躺在床上吸烟的频率（ 立法前 19.2%， 立法后 19.6%， P = 1.000）保持不变 ； 受访者每天吸烟超过 20 支的比例下降（立法 前 21.5%，立法后 15.6，P ＜ 0.001） ，报告“经常”自熄的情况增加 （立法前 22.3%，立法后 44.2%，P ＜ 0.001） ，而报告“烟灰掉落”的 情况没有增加（立法前 43.2% ，立法后 33.7%） 。报告中戒烟的打算 没有变化。 Adkison 等 [17] 研究了 2004~2011 年间 RIP 卷烟管控对消费者行 为和戒断意向的影响，数据来源于在澳大利亚、加拿大、英国和美 国进行的一项调查（N = 12 492） 。 该数据是独一无二的， 这是由于 法律引入不同国家（以及美国国内）的时间不同，数据可支持对初 始和时间滞后效应的评估。对卷烟自熄的认知随 RIP 卷烟立法而增 P<0.001） P ＜ 0.05） 加（OR= 2.7， 戒烟意愿也一样增加（OR= 1.02， ， ， 但没有影响到吸烟者每天抽吸的数量。报道卷烟自熄的人戒断意向 更频繁（OR= 1.02，P ＜ 0.05） 。 总的来说，RIP 安全标准对消费者 可接受性没有影响，且研究没有表明任何“磨损”效应（即因为 RIP 安全标准的实施而失去市场份额） 。 O’Connor 等 [18] 报道了在两个美国城市的 160 名吸烟者中开展 的 18 天研究的结果，其中一个城市的吸烟者从通常品牌转为 RIP 类 型，而另一个城市的吸烟者在整个研究期间都抽吸 RIP 卷烟。目标 结果包括每天抽吸的卷烟数量、 吸烟行为（ 每口体积、 持续时间、 间隔） 、呼出 CO、唾液中可替宁和选定 PAH（芘、萘、菲和芴）的 尿液代谢物。作者报道吸烟行为、呼出 CO、PAH 代谢物（除了菲） 或可替宁未因转换到 RIP 卷烟而产生显著变化。吸烟率下降了约两 支 / 天，从 18 支降到了 16 支。菲的尿液代谢物水平增加 35%，而菲 被认为是一种刺激剂而不是致癌物质。 ·59·
烟草制品管制科学基础报告： WHO 研究组第五份报告
June 等 [19] 报道了关于加拿大 RIP 法规引入前和 18 个月后 42 名 每日吸烟者行为和暴露的研究结果。目标结果与 O’Connor 等 [18] 的 研究相同。未在吸烟行为、呼出 CO、每天吸烟的数量或尿液可替宁 等发现显著差异。发现选定 PAH 的代谢物有 14%~25% 的显著增加 ； 如果该结果得以证实，这将是一个问题，因为这些生物标志物表明 苯并 [a] 芘（一种已知的人类致癌物）的存在。 CôTé 等 [20] 进行了一项由加拿大帝国烟草公司支持的研究， 利 用吸烟机估计和“ 部分滤嘴 ” 法研究了焦油和烟碱的口腔暴露 [21]。 总共 1086 名使用 10 个特定品牌的吸烟者， RIP 管控前后各招募一半。 参与者被给予两包他们一贯的品牌以及一个用于收集滤嘴的工具盒， 并被要求随意抽吸但在收集了 15 个滤嘴后放入该盒子。利用火焰离 子检测器气相色谱检测滤嘴的烟碱截留，结果通过与每个品牌的校 正曲线比较而被用来估计暴露， 校正曲线从吸烟机抽吸参数得出。 虽然法规引入前平均每天吸烟的数量显著高于引入后（引入前 22.1， 引入后 20.6，P = 0.0003） ，但未观察到焦油和烟碱口腔暴露的显著性 差异。应该指出的是，这是一项横断面研究而不是队列研究。 4.3.5 采用标准前后卷烟引发火灾的动态 关于 RIP 标准对卷烟引发火灾的频率影响的研究对于验证一项 实验室标准在降低卷烟引起的火灾和死亡的有效性方面至关重要。 对火灾原因和火灾伤亡的研究证实卷烟相关火灾相比其他成因更可 能导致伤害或死亡 [22–24]。 由于火灾报告系统的质量和数量，RIP 标 准实施的时间较短，以及影响火灾发生率的其他趋势，包括床垫和 内饰等抗引燃能力的增加、烟雾探测器、公共教育、吸烟率降低和 ·60·
4.低引燃倾向卷烟：研究需求和监管建议
由于室内吸烟限制引起的人们吸烟地点的变化等原因，这种研究很 难开展 [25]。这种研究很难进行也因为 RIP 立法不需要进行或资助此 类研究，且没有集中报告系统可将 RIP 标准的依从性与火灾报告联 系起来。在本报告撰写时，澳大利亚和欧盟均未公布火灾事故数据。 美国国家消防协会报道 2013 年与吸烟有关火灾的死亡人数为 1980 年有监测以来的最低水平 [26]。 此外， 报道还说， 美国 50 个州 采用 RIP 标准似乎是“ 从 2003 年至 2011 年烟草制品火灾死亡下降 30% 的主要原因” ，已经考虑到吸烟者覆盖的比例以及床垫和内饰抗 引燃能力的变化。 图 4.3 说明了该研究发现的事故、 死亡和受伤的 趋势。 400 000 350 000 300 000 250 000 200 000 150 000 100 000 50 000 0 1 000 0 ᑈӑ 4 000 3 000 2 000 6 000 ⚳㤝ࠊક☿♒ᓩ䍋ⱘ⅏ѵফӸҎ᭄
5 000
⚳㤝ࠊકᓩথ☿♒᭄䞣
图 4.3 1980~2011 年美国与烟草制品引燃火灾相关的事故数量及死亡和受伤人数 阴影部分表示 2004 年后采用 RIP 标准的州的数量增加 资料来源 ： Hall[26]
19 1980 19 81 1982 1983 1984 1985 1986 1987 1988 1989 1990 19 91 1992 1993 1994 1995 1996 19 97 1998 20 99 2 00 0 20 01 20 02 20 03 20 04 20 05 2 00 6 2 0 07 20 08 2009 2010 11
·61·
烟草制品管制科学基础报告： WHO 研究组第五份报告
850 800 750 700 650 ⚳㤝ࠊકᓩথ☿♒᭄䞣 600 550 500 450 400 350 300 250 200 150 2000
ON☿♒᭄䞣 ONফӸҎ᭄
AL☿♒᭄䞣 AL⅏ѵҎ᭄
ON⅏ѵҎ᭄ ALফӸҎ᭄
100 90 ⚳㤝ࠊક☿♒ᓩ䍋⅏ѵফӸᆇҎ᭄ 80 70 60 50 40 30 20 10
2001
2002
2003
2004 2005 ᑈӑ
2006
2007
2008
2009
0
图 4.4 2000~2008 年或 2009 年加拿大阿尔伯塔省（AL）和安大略省（ON）烟 草制品火灾的事故数量及死亡和受伤人数 阴影部分表示 RIP 法案的实施 资料来源 ： Frazier 等 [27]
TriData 为 菲 利 普· 莫 里 斯 国 际 公 司 做 的 一 份 报 告 检 测 了 2008~2009 年加拿大安大略省和阿尔伯塔省以及美国纽约州 RIP 法 案的影响 [27]。 作者的结论是， “ 没有因为低引燃倾向卷烟而产生实 质性的减少。 ” 安大略省和阿尔伯塔省趋势如图 4.4 所示。 他们的 分析有一些严重缺陷（D. Hemenway， 个人通信 ） ；大体上说， 他 们的评价的设计目的似乎就是为了发现没有影响 [28]。 因为没有对 照组，评价管制政策必须包括一个相反事实的方法（即如果法案不 存在会发生什么情况？） 。 然而， 统计分析和流行病学方法未被使 ·62·
4.低引燃倾向卷烟：研究需求和监管建议
用。TriData 分析的主要问题是线性趋势的假设， 纵坐标轴上事件 的绝对数量被预测继续趋势而无衰减。假设降低速度快速增加，甚 至得出推论事故的数量会在一些年内降至零并成为负数，这显然很 荒谬（见他们的图 18 和图 22） 。然而，注意到 RIP 法案实施前趋势 是向上的（ 纽约 ） ， 而他们没有画趋势线进行比较（ 他们的图 36 和 图 37） 。他们也可能忽略了佛蒙特州、马萨诸塞州、纽约州（他们的 图 34）和阿尔伯塔省（他们的图 18， 图 20 和图 29）可能有利影响的 证据。 也许到目前为止最好的关于 RIP 标准影响的证据来自 Alpert 等 [29] 最近的一项关于美国马萨诸塞州消防安全卷烟法案对于防止住宅火 灾有效性的评价。该分析有效控制了混杂的最主要的潜在来源，其 他阻燃剂的使用增加除外，由于这方面的信息不可用。马萨诸塞州 已具有美国最好的火灾报告系统之一，报道特征并未在 2008 年 1 月 1 日法案生效后改变。 对报告给系统的 2004~2010 年间的非故意的 住宅火灾进行了分析，以确定哪些是由卷烟引起的，并在中断的时 间序列回归模型中分析了火灾情景因素改变的影响。采用泊松回归 分析了法律对每月火灾发生率的影响。这期间卷烟造成 1629 起非故 意的火灾。最大的减少是涉及人的因素的火灾 ： 点燃家具、床上用 品或纺织品，发生在居住区或在夏天或冬天发生（而不是在春季或 秋季） 。作者认为，将 RIP 标准纳入法律并在马萨诸塞州执行减少了 28%（95% 置信区间，12%~41%）的住宅火灾的可能性，特别是在标 准确定的情况下。这项研究是仅有的一些高质量可靠的关于 RIP 标 准对卷烟火灾影响的人群研究之一。 总之，尽管进行标准对人群影响的研究很困难，特别是考虑到 标准生效的时间较短并考虑到火灾报告系统的质量，RIP 的标准似 ·63·
烟草制品管制科学基础报告： WHO 研究组第五份报告
乎能有效降低卷烟相关火灾三分之一的发生率 ； 然而，需要更多的 研究来验证这一初步调查。 4.3.6 标准的实用性与不足 目前的标准是基于超过 30 年的研究， 开始于“ 模拟家具法 ” ， 单位纸张引燃法和新兴的人群健康研究。还需要更多的研究，包括 吸烟行为变化的可能影响和基质防火性能的增加。 在高收入国家， 该标准已被发现是有效的，无关国家因素 ； 然而，该标准可以随新 的科学结果、检测标准和卷烟特征的出现而进行改变。
4.4 结 论 已引入 RIP 法案的国家的经验表明， 这些法案成功的必要步 骤是 ： • 建立相关群体的联盟，包括科学家、消费者组织以及公共卫 生和消防安全官员，以收集卷烟引起火灾的数据，制定相应 的立法建议并与决策者互动 ； • • • 对所有立法机构采用统一标准以推动法案采纳并消除行业里 需要设计多种 RIP 卷烟的争论 ； 卷烟火灾造成的实际危害的确切数据 ； 需要遵循一个统一标准但又不指定实际卷烟设计的立法。
已从引入 RIP 法案的国家收集了依从性数据。加拿大的研究表 明大型生产商实质的持续的依从性，以及较小生产商依从性的增加。 ·64·
4.低引燃倾向卷烟：研究需求和监管建议
三家大型生产商占据加拿大 97% 的市场， 在 RIP 标准实施后不久 就很轻易地达到了性能目标，即一批样品中不能有超过 25% 的卷烟 不符合标准。对于所有生产商，在 RIP 法案制定后的数年内实现了 10% 或更少样品未能满足标准。 RIP 卷烟引入后， 只有较少关于行为和健康影响的研究。 几乎 没有任何吸烟行为（抽吸体积、抽吸时间、抽吸间隔）任何变化的 证据，或者火灾风险相关行为的任何增加，如任由燃烧的卷烟不顾 或在床上吸烟。一个一致的观察是 RIP 卷烟更经常自熄，但是报道 中烟灰掉落频率不存在差异。抽吸 RIP 卷烟的人更倾向于戒烟或每 天抽较少的烟，这方面的证据存在不一致。CO、焦油和烟碱的释放 量在 RIP 卷烟和非 RIP 卷烟中相似。 在两个研究中， 测量了暴露于碳氢化合物的尿液生物标志物， 使用 RIP 卷烟与芘、菲和芴代谢产物增加适度相关（≤ 25%） 然而， ； 数据存在不一致，且这一发现的意义尚不清楚。 对于 RIP 法案对卷烟引起的火灾发生率与相关伤亡影响的评价 受限于诸多因素， 如缺乏火灾数据或数据质量差，RIP 标准生效时 间相对较短，特别是在欧盟等最近几十年的火灾发生率普遍下降的 地区，清洁空气法案的引入以及如床垫和室内装饰品等基质易燃性 的降低。 尽管有这些限制， 还是在高收入国家进行了一些严谨的研究， 结果表明 RIP 管制引起卷烟引起火灾约 30% 的减少。虽然预计死亡 和受伤人数将因此下降，但这种假设只有有限的证据支持。人们已 经注意到 RIP 卷烟降低火灾相关伤害的有效性会随消防部门效力的 不同而不同。尚没有关于 RIP 立法对室外火灾的影响或由此产生的 人类或环境影响等方面的信息。
·65·
烟草制品管制科学基础报告： WHO 研究组第五份报告
4.5 2014 年 WHO 烟草制品调查结果 WHO 关于无烟烟草制品、电子烟碱传输系统、RIP 卷烟和新型 烟草制品等的问卷被发送到所有 WHO 成员国。k 其中 18 个成员国 WHO （5%）报告说他们具有法律强制要求所售卷烟具备 RIP 特性 ； 六大地区中的四个（非洲地区、 美洲地区、 欧洲地区和西太平洋地区） 的 19 个成员国（5%） 报告已采用 RIP 技术标准（18 个具有强制性 而 1 个非强制性） 。13 个成员国（8%）由商业生产商提供 RIP 卷烟， 而 19 个（8%）来自进口。调查识别出的出口国家有加拿大、中国、 捷克共和国、匈牙利、立陶宛、荷兰、新西兰、韩国和美国。24 个 成员国（7%） 有烟草制品引发的火灾或火灾死亡的记录。 有 10 年 （2003~2012 年）可靠数据的成员国中，捷克共和国共报告了 8129 起 卷烟引起的火灾和 177 人死亡，而挪威报告同期 74 人死亡。立陶宛 报告平均每年 79 人死亡， 阿曼报告每年平均 48 起火灾， 瑞典报告 每年平均 25 人因吸烟引起的火灾死亡。一般来说，高收入国家 30% 的火灾死亡是由于吸烟。
4.6 研 究 需 求 应在国家、地方及其组合层面进行研究以预测人群影响，包括 ： • k
有助于普遍降低火灾数量的因素， 特别是对教育活动影响、 总共 90 个国家， 包括 86 个 WHO FCTC 缔约国， 于 2014 年 4 月 9 日前对问卷
做出回应，代表全世界 77% 的人口。
·66·
4.低引燃倾向卷烟：研究需求和监管建议
自动喷水灭火系统以及减少基质易燃性（家具、床垫等）的 研究 ； • 卷烟有关的问题，如吸烟行为变化的影响，包括降低流行率， 室内空气清洁法案对人们在何处抽烟、抽多少烟以及怎么处 理的影响 ； • • • 用以提高 RIP 性能、标准以及可能改变释放物和毒性的新兴 的纸张设计技术 ； 在标准没有涉及的环境中由卷烟引起的火灾（户外、森林大 火、户外垃圾桶） ； 未用纸包裹的新型 RIP 卷烟标准的适用性。 关于基础设施、 研究能力、 资助和支持用于所有卷烟的通用 RIP 标准， 应对 FCTC 缔约方和消防官员进行关于 RIP 标准在其烟 草整体管控或消防计划中的重要性的调查，并要求其评价需要的资 源和潜在的资助。 为了使 RIP 标准被认为是良好的制造工艺，应计算具有一个全 球性设计而不是多个设计的成本效益，包括开发所需的时间和制造 能力以及依从成本。应进行研究以发现在生产商处而不是在个体市 场处的更简单的依从性测试方法，因而降低生产成本，并确定已被 WHO 推荐用于药物和其他产品的良好生产过程对于卷烟的适用性。
4.7 管 制 建 议 • • 通用 RIP 标准应用于所有的卷烟。 生产商应采用 RIP 设计作为标准的卷烟生产实践。 ·67·
烟草制品管制科学基础报告： WHO 研究组第五份报告
•
实施 RIP 标准的所有成本应由生产商承担。测试能力有限的 国家应考虑要求生产商向政府提交一致性声明或使用第三方 认证。
•
实施这些建议将需要机构和消防部门之间的密切合作，建立 一个 RIP 标准信息交流中心，调查 FCTC 缔约方和消防官员 对 RIP 标准的影响，引入一项一致的报告火灾的标准，并确 定这些活动将如何被资助。
•
应该继续研究以获得所有已实施 RIP 法案的国家和地区中 RIP 立法对卷烟相关火灾、死亡和伤害的人群影响的数据。
4.8 参 考 文 献 [1] Standard test method for measuring the ignition strength of cigarettes. West Conshohocken, Pennsylvania: ASTM International; 2004. [2] WHO Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation: second report of a WHO study group (WHO Technical Report Series, No. 951). Geneva: World Health Organization; 2008 (http://www.who.int/tobacco/global_ interaction/tobreg/publications/tsr_951/en/index.html). [3] Gann RG, Hnetkovsky EJ. Modifcation of ASTM E 2187 for measuring the ignition propensity of conventional cigarettes. Fire Technol 2011;47:69–83. [4] Barillo DJ, Brigham PA, Kayden DA, Heck RT, McManus AT. The fre-safe cigarette: a burn prevention tool. J Burn Care Rehabilit ·68·
4.低引燃倾向卷烟：研究需求和监管建议
2000;21:162–70. [5] Standard testing method for assessing the ignition propensity of cigarettes. Geneva: International Organization for Standardization; 2010. [6] Alpert HR, O ’ Connor RJ, Spallette R, Connolly GN, Rees VW, Alpert HR, O’ Connor RJ, Connolly GN. Recent advances in cigarette ignition propensity research and development. Fire Technol 2010;46: 275–89. [7] Seidenberg AB, Rees VW, Alpert HR, O’ Connor RJ, Connolly GN. Ignition strength of 25 international cigarette brands. Tob Control 2011;20:77–80. [8] Connolly GN, Alpert HR, Rees V, Carpenter C, Wayne GF, Vallone D, et al. Effect of the New York State cigarette fire safety standard on ignition propensity, smoke constituents, and the consumer market. Tob Control 2005;14:321–7. [9] Pang Y, Jing Y, Jiang X, Chen Z, Tang G, Xing J. Effects of low ignition propensity cigarette paper on deliveries of harmful components in mainstream cigarette smoke (in Chinese). Tob Sci Technol 2013;2:52– 6. [10] Arnott D, Berteletti F. Europe: agreement on reducing cigarette fires. Tob Control 2008;17:4–5. [11] Goldstein AO, Grant E, McCullough A, Cairns B, Kurian A. Achieving fire-safe cigarette legislation through coalition-based legislative advocacy. Tob Control 2010;19:75–9. [12] Barbeau EM, Kelder G, Ahmed S, Mantuefel V, Balbach ED. ·69·
烟草制品管制科学基础报告： WHO 研究组第五份报告
From strange bedfellows to natural allies: the shifting allegiance of fire service organisations in the push for federal fire-safe cigarette legislation. Tob Control 2005;14:338–45. [13] Laboratory analysis of cigarette for ignition propensty. Ottawa: Health Canada; 2012 (http://www.hc-sc.gc.ca/hc-ps/tobac-tabac/legislation/ reg/ignition-alllumage/ analys-eng.php, accessed 20 November 2013). [14] Smoking and Health Action Foundation, Non-smokers’Rights Association. Backgrounder on the Canadian tobacco market. Toronto, Ontario:; 2013 (http://www.nsra-adnf.ca/cms/file/ files/2013_Canadian_Tobacco_Market.pdf, accessed 20 November 2013). [15] O’ Connor RJ, Fix BV, Hammond D, Giovino GA, Hyland A, Fong GT, et al. The impact of reduced ignition propensity cigarette regulation on smoking behaviour in a cohort of Ontario smokers. Inj Prev 2010;16:420–2. [16] Seidenberg AB, Rees VW, Alpert HR, O ’ Connor RJ, Giovino GA, Hyland A, et al. Smokers’self-reported responses to the introduction of reduced ignition propensity (RIP) cigarettes. Tob Control 2012;21:337–40. [17] Adkison SE, O’ Connor RJ, Borland R, Yong HH, Cummings KM, Hammond D, et al. Impact of reduced ignition propensity cigarette regulation on consumer smoking behavior and quit intentions: evidence from 6 waves (2004–11) of the ITC Four Country Survey. Tob Induced Dis 2013;11:26. ·70·
4.低引燃倾向卷烟：研究需求和监管建议
[18] O’ Connor RJ, Rees VW, Norton KJ, Cummings KM, Connolly GN, Alpert HR, et al. Does switching to reduced ignition propensity cigarettes alter smoking behavior or exposure to tobacco smoke constituents? Nicotine Tob Res 2010;12:1011–8. [19] June KM, Hammond D, Sjödin A, Li Z, Romanoff L, O’ Connor RJ. Cigarette ignition propensity, smoking behavior, and toxicant exposure: a natural experiment in Canada. Tob Induced Dis 2011;9:13. [20] Côté F, Letourneau C, Mulland G, Voisine R. Estimation of nicotine and tar yields from human-smoked cigarettes before and after the implementation of the cigarette ignition propensity regulations in Canada. Regul Toxicol Pharmacol 2011;61(3 Suppl):S51–9. [21] Shepperd CJ, Eldridge AC, Mariner DC, McEwan M, Errington G, Dikon M. A study to estimate and correlate cigarette smoke exposure in smokers in Germany as determined by filter analysis and biomarkers of exposure. Regul Toxicol Pharmacol 2009;55:97– 109. [22] Mulvaney C, Kendrick D, Towner E, Brussoni M, Hayes M, Powell J. Fatal and non-fatal fire injuries in England 1995–2004: time trends and inequalities by age, sex and area deprivation. J Public Health 2009;31:154–61. [23] Smith J, Bullen C, Laugesen M, Glover MP. Cigarette fires and burns in a population of New Zealand smokers. Tob Control 2009;18:29–33. ·71·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[24] Anderson A, Ezekoye OA. A comparative study assessing factors that influence home fire casualties and fatalities using state fire incident data. J Fire Prot Eng 2013;23:51–75. [25] Markowitz S. Where there’ s smoking, there’s fire: the effects of smoking policies on the incidence of fires in the USA. Health Econ 2013;25:1353–73. [26] Hall JR Jr. The smoking-material fire problem. Quincy, Masachusetts: National Fire Protection Association; 2013:54. [27] Frazier P, Schaenman P, Jones E. Initial evaluation of the effectiveness of reduced ignition propensity cigarettes in reducing cigarette-ignited fires: case studies of the North American experience. Arlington, Virginia: TriData Division, System Planning Corp; 2011 (http://www.fdma.go.jp/html/life/yobou_contents/info/ pdf/tabaco/kentou01/sanko04.pdf). [28] Hemenway D.How to find nothing. J Public Health Policy 2009;30:260–8. [29] Alpert HR, Christiani D, Orav EJ, Dockery D, Connolly GN. Effectiveness of the cigarette ignition propensity standards in preventing unintentional residential fires in Massachusetts. Am J Public Health 2014;104:e56–61.
附录 4.1 方 法 为 了 本 文， 我 们 搜 索 了 一 些 可 公 开 访 问 的 数 据 库， 包 括 ·72·
4.低引燃倾向卷烟：研究需求和监管建议
PubMed 、 Africa Index Medicus 、 Index Medicus for the Eastern Mediterranean Region、Index Medicus for the Western Pacifc Region、 Pan American Health Organization Library 、 Biblioteca virtual em Saûde、Index Medicus for the South-East Asia Region、Web of Science 和 Engineering Village，搜索词为“卷烟”和“火”或“燃烧” ，搜索 了自 2008 年以来发表的文献。这次对已发表文献的检索还补充了谷 歌搜索来识别“灰色”文献， 如会议摘要、 咨询组织报道和新闻报道。 联络了已采用或考虑采用 RIP 卷烟标准的国家的公共卫生和消防安 全官员， 并从 WHO 地区办公室收集了信息。 对采用 RIP 法律的国 家中的关键知情人进行了采访。共确定了 26 个相关的出版物。
附录 4.2 ISO 12863 概述 1 测试 = 40 测定，每支卷烟一次测定。 结果 = 燃烧全长（点燃卷烟烧过的滤嘴烟的接装纸，或烧过非 滤嘴烟的金属针） 。 环境条件 ： 湿度 55%±5%，温度 23℃ ±3℃。 有机玻璃试验箱尺寸 ： 高 340 mm±25 mm ； 宽 292 mm±6 mm ； 深 394 mm±6 mm ； 烟囱高度 165 mm±13 mm，内径 152 mm±6 mm。 有机玻璃基板支架尺寸 ： 外径 165 mm±1 mm ； 内径 127 mm±1 m ； 高 50 mm±1 mm ； 顶部凹槽深 10 mm±2.5 mm，延伸内径至 152 mm 三或四条腿抬高底座至房间地板约 20 mm±1 mm 以上 ； ±1 mm ； 黄铜制金属环外径 150 mm±1 mm。 滤纸 应根据组合质量选择， 如 15 张 24.7 g±0.5 g。 （Whatman # 2） ·73·
烟草制品管制科学基础报告： WHO 研究组第五份报告
测试步骤 ： 1. 测试之前， 用铅笔在卷烟点燃端 5 mm 和 15 mm 进行标记， 建立统一的燃烧前时期。 2. 点燃卷烟，接缝朝上放置在支架中。关闭室门并移开烟囱盖。 3. 如果卷烟在支架中熄灭（即在 5 mm 和 15 mm 标志之间） ，记 录自熄。 4. 如果卷烟烧至 15 mm 标记，从支架中取出，接缝朝上放至基 板上。 5. 记录燃烧停止点。如果燃烧至接装纸（或非滤嘴烟的金属参 考针） 否则，记录为非全长燃烧。 ，记录为全长燃烧 ； 6. 去除卷烟和滤嘴纸张并处理掉。 7. 重复步骤直至进行 40 次测定。 8. 计算观察到全长燃烧测定的比例。
附录 4.3 低引燃倾向卷烟技术相关企业最近的 CORESTA 简报 2013 Wilkinson P, Colard S, Verron T, Cahours X, Pritchard J. Control or monitoring of the LIP testing process: the fitness for purpose of the LIP standard products. Wanna J. Alternate test substrate for ASTM test method E2187-09. Mayr M, Vizee H. Impact of using a metal sheet as an“ alternative substrate for ISO 12863” on SE performance. ·74·
4.低引燃倾向卷烟：研究需求和监管建议
Verron T, Cahours X, Colard S. LIP cigarettes: proposal for an alternative sampling design. Gleinser M, Bachmann S, Rohregger I, Vizee H, Volgger D. Puff-bypuff analysis of mainstream smoke constituents of non-LIP and LIPcigarettes. Verron T, Cahours X, Colard S, Taschner P. Some key points to assess LIP regulation impact. 2012 Bachmann S, Gleinser M, Möhring D, Rohregger I, Volgger D. Puff-bypuff analysis of mainstream smoke constituents of non-LIP/FSC and LIP/FSC cigarettes. Guyard A, Meier D, Ceccketto A, Hofer R, Li P. Impact of cigarette paper properties on smoke constituents ’delivery under Health Canada Intense smoking regime. Hesford MJ, Volgger D, Case P, Vanhala A. A further experimental design to investigate the influence of the LIP test substrate parameters on LIP pass rates and residual length measurements. Mayr M, Volgger D. Influence of band width and band material coverage rate (total band area / total paper area) on smoke yields, SE test and free burn. Verron T, Cahours X, Colard S. LIP cigarettes: effect of band positioning. Verron T, Cahours X, Colard S. Trend analysis: a relevant tool to assess post-regulation impacts. Wanna J, Le Moigne C, Le Bec L. Tobacco column influence on cigarette paper. ·75·
烟草制品管制科学基础报告： WHO 研究组第五份报告
2011 Hesford M. A 24 factorial experimental design to investigate the infuence of LIP testing substrate parameters (basis weight, permeability and roughness) on LIP pass rates and residual length measurements. Mayr M, Volgger D.The impact of different physical and chemical cigarette paper base sheet parameters on smoke yields, and testing of an alternative substrate for Whatman #2 using the ASTM method E.218709. Inoue Y, Hasegawa Y, Kominami T. Study of heat transfer of a cigarette relating to the ignition propensity. Loureau JM, Le Bec L, Kraker T, Le Moigne C, Wanna J, Le Bourvellec G. Influence of base paper citrate and filler amount and of band diffusion on smoke deliveries, ASTM and FASE. 2010 Eitzinger B, Volgger D. Some statistical considerations regarding the testing of LIP cigarettes. Hesford M, Case P, Coburn S, Larochelle J, Cabral JC, DeGrandpré Y, Wanna J. A factorial experimental design to investigate the influence of band diffusivity and filler, fibre and citrate contents on the machine smoking yields and LIP performance of banded LIP papers. Wanna J. Influence of humidity, number of filter papers, and orientation of the filter paper on ASTM results. Hampl V Jr. Effect on ASTM test results and carbon monoxide deliveries ·76·
4.低引燃倾向卷烟：研究需求和监管建议
when sodium alginate bands are on the outside of cigarettes. Mason T, Tindall I. Correlation between manual and semi automatic measurements of ignition propensity to ASTM E2187-04. Vincent J, Tindall I. Factors affecting the design of paper diffusivity measurement apparatus with particular reference to the design of transfer standards.
·77·
烟草制品管制科学基础报告： WHO 研究组第五份报告
5. 烟草制品有害成分和释放物的非详尽 优先清单 5.1 引言 5.2 结果综述 5.3 建议 5.4 烟草制品有害成分和释放物的非详尽优先清单 5.5 参考文献
5.1 引 言 本 文 件 是 针 对 第 五 次 缔 约 方 会 议（ 韩 国 首 尔， 2012 年 12 月 12~17 日）向大会秘书处提交的，为便于第六次缔约方会议考虑的请 求而准备 [FCTC/COP5 决议 ]， 即 （6） “编制一份所有缔约方可获得的、 与 WHO 无烟草行动共同更新的烟草制品有害成分和释放物的非详 尽清单，并对缔约方如何最佳使用该信息提出建议”[1]。在同一个决 议中，缔约方会议进一步决定授权第 9 条和第 10 条工作组提交关于 经 WHO 验证的测试分析成分和释放物的分析化学方法的部分实施 准则起草文件或进展报告，以供第六次缔约方会议审议。 ·78·
5.烟草制品有害成分和释放物的非详尽优先清单
2013 年 12 月 4~6 日在巴西里约热内卢召开的 TobReg 会议中， 在卷烟烟气中已发现的基于定性和定量分析的 7000 种化学成分中挑 选了 38 种优先清单。该有害成分清单是基于 8 个非详尽的有害物质 清单 ： 加拿大卫生部 l，荷兰国家公共卫生与环境研究所 [2]，美国食 品药品管理局 [3]， Counts 等 [4]， Fowles 和 Dybing[5]， “霍夫曼清单”[6]， 菲利浦·莫里斯澳大利亚品牌 m 和菲利浦 为了 莫里斯加拿大品牌 n， · 平衡被识别的管制结构的现实情况的担忧。 烟草成分和卷烟烟气释放物清单是基于以下标准草拟的 ： • • • 基于已确认的科学毒性因子，确定卷烟烟气中特定化合物的 释放量水平对吸烟者是有害的 ； 有害物质在卷烟品牌间的浓度变异远大于在同一品牌内反复 测定的差异 ； 已有可用技术降低烟气中特定有害物质的浓度，应强制执行 上限。 当可获得烟气释放物的充足数据和对人体相关毒性的数据时， 对卷烟烟气中 7000 种化合物根据相同标准进行分析。 缔约方会议第三次会议要求大会秘书处邀请 WHO 无烟草行 动司验证用于卷烟烟气优先释放物和成分测试分析的分析化学方 法 [FCTC/COP3（9） 决 议 ][7]。TobLabNet 已 验 证 了 三 种 成 分（ 烟 碱、 氨和保润剂 ） 和四种释放物（ 乙醛、 苯并 [a] 芘、TSNA 和挥
l m n
成分 : http://laws-lois.justice.gc.ca/eng/regulations/SOR-2000-273/page-13.html; 释放 http://www.health.gov.au/internet/main/publishing.nsf/C ontent/health咨询加拿大卫生部或在 tfi@who.int 获得。
物 ( 主流烟气 ): http://laws-lois.justice.gc.ca/eng/regulations/SOR-2000-273/page-14.html。 tobaccoingredients- philip-2013。
·79·
烟草制品管制科学基础报告： WHO 研究组第五份报告
发性有机化合物）的方法。到目前为止，对 CO、保润剂、苯并 [a] 芘、 烟碱和 TSNA 的方法验证已经完成， 对氨、 挥发性有机化合物 （苯和 1,3- 丁二烯）和醛类（乙醛、丙烯醛和甲醛）的方法还正在验 证中。
5.2 结 果 综 述 TobReg 评估了加拿大卫生部、 荷兰国家公共卫生与环境研究所、 美国食品药品管理局等几个监管主体发表的，与癌症、心血管疾病 和肺病相关的有害和有害化合物清单，也回顾了 TobReg 报告中的有 害物质清单 [8]。TobReg 随后起草了一份修订的烟草制品有毒成分和 释放物的非详尽清单，见 5.4 节 ； 但是，应当注意的是，该清单仅代 表了燃烧型烟草制品全部复杂混合物中的一小部分，且烟草制品释 放物的总体毒性不一定与单一化合物毒性相关。 巴西国家卫生监督管理局、加拿大卫生部和美国食品药品管理 局的前期经验应在 WHO FCTC 的缔约国和非缔约国应用，以敦促烟 草行业依据第 9 条和第 10 条部分实施准则的要求披露烟草制品释放 物信息。 一些缔约国在管制政策中包括了焦油，其并未列入烟气释放物 的有害成分优先清单中，因为每种类型产品的焦油成分都存在定性 和定量的差异，限制了测试分析验证的可能性。 TobReg 以前曾表达过对卷烟烟气中镉、铅、镍、砷和钋的关注。 尽管这些金属在卷烟烟气中存在时表现出极高的风险，但目前还没 有经多个实验室验证的标准方法来测试和检测它们 [9]。 ·80·
5.烟草制品有害成分和释放物的非详尽优先清单
因 为 世 界 范 围 内 水 烟（shisha） 使 用 的 增 加，TobReg 得 出 结 论 ：迫切需要一个经多个实验室验证的方法， 实现水烟烟气中烟 碱的测定， 烟气中烟碱和其他优先级释放物的相对浓度也应开展 研究。 优先清单中所列的抽吸型烟草制品的一些释放物与无烟烟草制 品无关或相关性较小。例如，CO 由燃烧产生，因此在无烟烟草制品 中并不存在。无烟烟草制品的优先清单目前仅包括烟碱、TSNA 和苯 并 [a] 芘，但是没有标准的经多个实验室验证的方法可用于无烟烟草 制品中这些化合物的测定。TobReg 得出结论 ： 无烟烟草制品中这些 成分的测试方法应进行充分的验证。 TobReg 得出结论 ：应基于科学知识和已广泛应用于食品和其 他消费品的原则（ 通常基于合理地确保安全性的原则 ） ， 规定烟草 制品有害释放物成分的上限。TobReg 认为相同原则应适用于烟草 制品。
5.3 建 议 • • • 缔约方会议应请求 WHO 授权 TobLabNet 建立烟草制品中砷、 镉、铅释放量的标准方法。 无需检测焦油，因为其不是管制的合理基础，且其水平会产 生误导。 尽管建议的成分和释放物优先清单是为标准卷烟起草，TobReg 建议对其他抽吸型烟草制品使用相同的清单， 例如非标准 卷烟（ 如细支烟 ） 、 雪茄、 水烟、 烟枪和手卷烟或“ 自制 ” ·81·
烟草制品管制科学基础报告： WHO 研究组第五份报告
卷烟。 • 对于标准卷烟和其他烟草制品，正如之前所提倡的 [8]，释放 物中的化学成分释放量应以相对于烟气烟碱浓度的形式进行 报告。 • • • • 缔约方会议应请求 WHO 授权 TobLabNet 发布经验证的水烟 （shishas）烟气中烟碱测定方法。 各国应管制无烟烟草制品中的烟碱、TSNA 和苯并 [a] 芘。 缔约方会议应请求 WHO 授权 TobLabNet 建立经验证的无烟 烟草制品中的烟碱、TSNA 和苯并 [a] 芘的测定方法。 成分和释放物的优先级清单应与经验证的 TobLabNet 方法一 起使用， 作为 WHO FCTC 第 9 条中所述的对成分和释放物 管制的基础。 • 作为成分和释放物管制的初始步骤，按照第 9 条的规定，缔 约方应开始监测各自市售卷烟的优先级成分和释放物。按照 第 10 条部分实施准则的约定， 每个牌号、 每个成分和释放 物的数据应由烟草行业提供，验证测试的费用应由烟草行业 承担。 • • • 管制步骤应包括基于已建立的毒理学原则对烟草制品有害成 分释放物设定上限。 烟草释放物包括许多化学物质 ； 因此，成分和释放物的优先 清单仅是帮助缔约方履行第 9 条和第 10 条要求的第一步。 卷烟成分和释放物的优先清单，其他抽吸型烟草制品和无烟 烟草制品应基于新的科学知识，适时地定期重新评估。
·82·
5.烟草制品有害成分和释放物的非详尽优先清单
5.4 烟草制品有害成分和释放物的非详尽优先清单 o 乙醛 丙酮 丙烯醛 丙烯腈 1- 氨基萘 2- 氨基萘 3 - 氨基联苯 4- 氨基联苯 氨 砷 苯 苯并 [ a ] 芘 1,3- 丁二烯 丁醛 镉 一氧化碳 邻苯二酚 间甲酚 对甲酚 邻甲酚 o 该清单比向 WHO FCTC 第六次缔约方会议提交的 WHO 报告 [10] 中 38 种清单多
1 种化合物，因为，基于充分的科学证据和 TobReg 的进一步审议，砷被加入该清单。
·83·
烟草制品管制科学基础报告： WHO 研究组第五份报告
巴豆醛 甲醛 氰化氢 对苯二酚 异戊二烯 铅 汞 烟碱 氮氧化物 N′- 亚硝基假木贼碱（NAB） N′- 亚硝基新烟草碱（NAT） 4-(N- 甲基亚硝胺基 )-1-(3- 吡啶基 )-1- 丁酮（NNK） N′- 亚硝基降烟碱（NNN） 苯酚 丙醛 吡啶 喹啉 间苯二酚 甲苯
5.5 参 考 文 献 [1] Decision FCTC/COP5(6). In: Decisions. Fifth Session of the Conference of the Parties to the WHO Framework Convention ·84·
5.烟草制品有害成分和释放物的非详尽优先清单
on Tobacco Control. Geneva: World Health Organization; 2012 (document FCTC/COP/5/DIV/5) (http://apps.who.int/gb/fctc/PDF/ cop5/FCTC_COP5%286%29-en.pdf). [2] Talhout R, Schulz T, Florek E, van Benthem J, Wester P, Opperhuizen A. Hazardous compounds in tobacco smoke. Int J Environ Res Public Health 2011;8:613–28. [3] Harmful and potentially harmful constituents in tobacco products and tobacco smoke: established list. Silver Spring, Maryland: Food and Drug Administration; 2012. [4] Counts ME, Morton MJ, Laffoon SW, Cox RH, Lipowicz PJ. Smoke composition and predicting relationships for international commercial cigarettes smoked with three machine-smoking conditions. Regul Toxicol Pharmacol 2005;41:185–227. [5] Fowles J, Dybing E. Application of toxicological risk assessment principles to the chemical toxicants of cigarette smoke. Tob Control 2003;12:424–30. [6] Thielen A, Klus H, Müller L. Tobacco smoke: unraveling a controversial subject. Exp Toxicol Pathol 2008;60:141–56. [7] Decision FCTC/COP3(9). In: Decisions. Third Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control. Geneva: World Health Organization; 2008 (document FCTC/COP/3/DIV/3) (http://apps.who.int/ gb/fctc/PDF/ cop5/FCTC_COP5%286%29-en.pdf). [8] Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation. Geneva: World Health ·85·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Organization; 2008 (WHO Technical Report Series, No. 951) (http:// www.who.int/tobacco/publications/ prod_regulation/trs_951/en/). [9] Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation. Fourth report of a WHO study group. Geneva: World Health Organization; 2012 (WHO Technical Report Series, No. 967) (http://www. who.int/tobacco/publications/ prod_regulation/trs_967/en/). [10] Work in progress in relation to Articles 9 and 10 of the WHO FCTC. Report by WHO. In: Sixth Session of the Conference of the Parties to the WHO Framework Convention on Tobacco Control. Geneva: World Health Organization; 2014 (document FCTC/COP/6/14).
·86·
6.总 体 建 议
6. 总 体 建 议 6.1 新型烟草制品 6.1.1 主要建议 6.1.2 对公众健康政策的意义 6.1.3 对 WHO 方案的启示 6.2 无烟烟草制品 6.2.1 主要建议 6.2.2 对公众健康政策的意义 6.2.3 对 WHO 方案的启示 6.3 低引燃倾向卷烟 6.3.1 主要建议 6.3.2 对公众健康政策的意义 6.3.3 对 WHO 方案的启示 6.4 烟草制品有害成分和释放物的非详尽清单 6.4.1 主要建议 6.4.2 对公众健康政策的意义 6.4.3 对 WHO 方案的启示 TobReg 受委托提供一系列报告， 为烟草制品管制提供科学基础。 ·87·
烟草制品管制科学基础报告： WHO 研究组第五份报告
这些报告对造成重要公 根据 WHO FCTC 第 9 条和第 10 条的规定 p， 众健康威胁的烟草制品管制的基础措施进行鉴别。 第 七 次 会 议 聚 焦 于 推 进 烟 草 制 品 管 制 的 关 键 问 题， 特 别 是 WHO FCTC 第五次缔约方会议上概括的问题。q 讨论的主题包括新 型烟草制品和相关产品的进展，无烟烟草制品，低引燃倾向（RIP） 卷烟，降低烟碱、致瘾性以及非详尽有害成分优先清单。
6.1 新型烟草制品 6.1.1 主要建议 除了含有烟草以外，被认为是“新型”的烟草制品还必须至少 满足下列条件中的一个 ： 上市不足 12 年 ； 上市已久的产品类型，但 市场份额在传统上不使用该类型产品的区域增加 ； 应用新技术 ； 以 比其他烟草制品有较低健康危害的身份上市。 应该对新型烟草制品毒性、疾病关联、消费者认知和看法、使 用形式和使用人口统计资料进行评估。此类产品需要标准的评估方 法，管制者只有当其上市前测试中表现出可能的公众健康益处时才 能批准。烟草行业使用的“降低危害”的概念和促进宣称有低健康 危害产品使用的措施效果和效力，均应被评估和与公众进行有效沟 通，以避免错误认知。 p q 更多信息可参见 : http://www.who.int/fctc/text_download/en/ (2014 年 11 月 28 日 )。 更多信息可参见见 FCTC/COP5(6) 决议 3(b) 段和 FCTC/COP5(10) 决议 1~4 段 ：
http://www.who.int/fctc/cop/en/ (2014 年 11 月 28 日 )。
·88·
6.总 体 建 议
6.1.2 对公众健康政策的意义 对新型烟草制品使用的主要担忧包括未知毒性、产品使用行为 以 的改变、 戒烟率下降、 初吸增加、 维持烟草使用的“双重使用”r， 及公众对宣称低危害产品相关的实际风险的误解。 6.1.3 对 WHO 方案的启示 监督措施应更全面和一致，关于新型烟草制品研究数据的收集 应更系统。
6.2 无烟烟草制品 6.2.1 主要建议 需要更加清晰的政策来处理无烟烟草制品面临的挑战。与抽吸 型烟草制品相比，无烟烟草制品价格更低，警语标识更弱，仅较少 资源用于其监督、预防和控制。应加强基于证据的控制措施，例如 确保产品成分的披露， 对有害成分和最大 pH 水平设定性能标准， 禁用香料，使用有效的相关健康警语标识，增加产品税，限制或禁 止此类产品，增加公众对其使用相关危害的认知。 r 两种形式烟草同时使用是越来越受关注的公共卫生热点。 但是， 到目前为止，
没有关于“双重使用”的一致定义。出于目前的目的，该术语指同时使用卷烟和无烟烟草 制品，或同时使用卷烟和新型烟草制品，每种产品可以是每天使用或间断使用。
·89·
烟草制品管制科学基础报告： WHO 研究组第五份报告
6.2.2 对公众健康政策的意义 应该对无烟气烟草制品总体影响给予更多关注，包括未成年人 使用，双重使用， “多重使用” ，以及室内使用定向营销的增加。 6.2.3 对 WHO 方案的启示 关于无烟烟草制品的使用、监督和特征，以及每个产品使用可 产生的健康后果都需要补充数据。此外，需要更好地了解此类产品 的市场和有效的区域性教育、预防和干预治疗。需要资源和协作工 作来获得这些数据。
6.3 低引燃倾向卷烟 6.3.1 主要建议 RIP 相关法律已经在澳大利亚、 加拿大、 南非、 美国和欧盟颁 布，但该模式尚未在许多中、低收入国家跟进。理想状态下，该技 术将应用于所有卷烟加工 ； 为实现该目标，测试必须在认可的实验 室进行标准化， 费用由烟草行业承担。 不应允许降低健康风险的宣称。 应该设定监测以确定该技术在降低卷烟相关的火灾数、死亡数和伤 病数中的有效性。应该对卷烟生产中与 RIP 意识提高相关的毒性和 行为改变设定监测。
·90·
6.总 体 建 议
6.3.2 对公众健康政策的意义 吸烟引起的火灾是重要的公众健康风险，导致大量死亡。根据 可获得的数据，在 RIP 法规实施区域，吸烟相关火灾降低了约 30%。 测试显示基于 RIP 技术制造的卷烟与传统卷烟相比，释放物之间并 无一致性差异。这些发现反驳了烟草行业的宣称。 6.3.3 对 WHO 方案的启示 关于 RIP 卷烟毒性和释放物、可能造成的吸烟行为的改变、减 少卷烟相关火灾数和死亡数的可能性均需要更多的研究。
6.4 烟草制品有害成分和释放物的非详尽清单 6.4.1 主要建议 根据卷烟成分和释放物中已发现的化学成分（ 多达 7000 种 ） ， TobReg 确定了一份含有 39 种卷烟烟气成分和释放物的非详尽优先 清单，并建议在所有烟草制品中监测这 39 种有害物质。该标准包括 其对吸烟者的潜在毒性和不同卷烟品牌间的浓度变化。随着科学基 础的进步，很可能会修订或扩展该清单。
·91·
烟草制品管制科学基础报告： WHO 研究组第五份报告
6.4.2 对公众健康政策的意义 如 WHO FCTC 第 9 条和第 10 条所述，该清单将引导成分和释 放物的管制。随着可用新技术的发展，该清单应定期重新评估。 6.4.3 对 WHO 方案的启示 烟草制品成分和释放物应采用经 TobLabNet 验证的方法进行检 测和管制。网络中的实验室已验证了焦油、 烟碱、 CO、 TSNA， 苯并 [a] 芘和保润剂的测试方法，对氨、挥发性有机化合物和醛类测试方法 的验证正在进行中。应对网络中正在建立烟草中镉和铅、水烟烟气 中烟碱、无烟烟草制品中烟碱、TSNA 和苯并 [a] 芘测试方法的实验 室给予优先权。
·92·
7.烟草烟气管制：现状评述
7. 烟草烟气管制 ： 现状评述 s 7.1 背景 7.2 建议的措施 7.3 设定上限相关问题 7.4 参考文献
7.1 背 景 本评论指出了那些广泛熟知的卷烟设计元素，已有明显证据显 示其有害性，且基于现有技术其有害性一定可以降低。
s
这是 Nigel Gray 博士基于深入思考的论文所发表的评论，其创作独立于 2013 年
12 月的 TobReg 第七次会议，也未受到 WHO 委任。其并不代表 WHO 或 TobReg 的观点。 但是认识到本文发人深省的内容和目标，以及鉴于 Gray 博士是公共卫生和烟草控制领导 者和有远见者，TobReg 成员一致同意推荐其作为评论收录于本报告。 Gray 博士自从 2000 年 SACTob（ 烟草制品管制科学咨询委员会 ） 成立起即为 TobReg 服务， 他大大引领了 TobReg 的方向和报告。WHO TobReg 以能得到他的服务为荣，全球烟草控制在他的贡献 下得到显著进步。2014 年 12 月 20 日，Nigel Gray 博士在其亲属陪伴下平静去世。WHO 对 Gray 博 士 的 悼 文 见 ： http://www.who.int/tobacco/communications/highlights/nigelgray/ en/。
·93·
烟草制品管制科学基础报告： WHO 研究组第五份报告
经过了几个世纪，烟碱传输系统已经得到了发展，随着 1880 年 高效机械化的发展，卷烟成为赢家。两次世界大战之间没有发生较 大改变，但是，从那时起，卷烟成为烟碱传输系统的首选。它已经 发展成由烟草和添加剂制成的高度复杂的化学混合物，比一战和二 战期间部队喜好使用的简单的“廉价卷烟” 显然更具致瘾性 [1]、腺 癌致癌性 [2,3] 和“吸引力 [1]” 。 在西方， 卷烟的竞争者普遍在替代其作为首选的比赛中失败。 在发展中国家，有大量的具有高毒性、高致癌性、高烟碱含量的无 烟烟草制品，但这些也无法挑战卷烟。即使在产品种类多样且丰富 的印度，卷烟仍声称占有 40% 的消费市场 [4]。这种情况可能有两个 原因 ： 全球法人团体的实力集团对投资制作和销售都非常廉价的卷 烟产品感兴趣，以及现代卷烟的技术光辉。 在发达国家， 公共卫生机构已经考虑了发展昂贵的烟碱替代 疗法作为替代选择，有些情况下，还采用其他选择，例如鼻烟和近 期的电子烟。 但没有任何一种产品对卷烟市场造成重要影响， 卷 烟控制了烟碱成瘾的战场， 并在全球市场中占有大约 65%~85% 的 份额 [5]。 大量文献报道了卷烟替代品与“卷烟”对比下的毒性降低，例 如无烟烟草制品和烟碱替代疗法 [6-8]。 许多这些对比都隐含“ 卷烟 ” 是标准的产品。显然，这不是事实，如表 7.1 所示，尽管将“卷烟” 和低毒性产品（例如鼻烟）进行对比，对于通过产品改变来提高减 害的可能性来说是合理的，但这回避了一个事实，即当今卷烟是一 个高度变异的产品，可能引起不同程度的危害。对卷烟的配方未见 报道，但一定会随着时间改变，消费者也会更换品牌，这些已经发 生或可能发生， 没有关于特定品牌和特定疾病结果相比较的研究。 ·94·
7.烟草烟气管制：现状评述
因此， 没有精确的方法能确定是否 Marlboro 致癌性、 腺癌致癌性、 鳞屑致癌性比 Virginia Slims 更高或更低。现代流行病学是建立在 “卷 烟”使用作为剂量单位上的，个别研究了焦油水平的差异。很可能 大多数研究的主要结果都已经受了时间的考验，因为它们实际上都 是严谨的保守的陈述。 表 7.1 卷烟中致癌物和其他有害物质的水平 有害物质 NNK（ng/ 支卷烟） NNN（ng/ 支卷烟） 苯并 [a] 芘 乙醛（µg/ 支卷烟） 丙烯醛（µg/ 支卷烟） 苯（µg/ 支卷烟） 丁二烯（µg/ 支卷烟） 甲醛（µg/ 支卷烟） CO（mg/ 支卷烟） 最低值 12.4 5 6.6 32 2.4 6.1 6.4 1.6 1.1 最高值 107.8 195 29.3 643 61.9 45.2 54.1 52.1 13.4 变异（倍数） 9 19 4 20 24 7 8 30 13 3倍 37.2 15 19.8 94 7.2 18.3 19.2 4.8 3.3
美国和加拿大的立法通道允许干涉卷烟设计，这为相关领域的 管制提供了希望，但截至目前仅对香料使用进行了改变。这很可能 反映了制造商和政府机关的相对权利。相对权利的副作用就是导致 公共卫生当局没能对产品设计设定实际的而不是理论的控制。更严 重的是造成非烟草企业科学家那些本应引起卷烟设计改变的出色研 究与公众健康政策脱节。 在这种情况下，TobReg 和 WHO 的一个明显的任务是应该合理 地期望制定更多卷烟设计参数，并且这些参数可以立刻在尚无富有 经验公共卫生机构或烟草研究设施的国家引用。这些国家需要关于 那些基于研究的、科学严谨的、无可争辩的卷烟设计的立即执行的 ·95·
烟草制品管制科学基础报告： WHO 研究组第五份报告
建议。WHO 的不足是不能制定法律， 仅能建议缔约方。 但是， 也 有一个相应的优点， 即其建议是受广泛认可的。 在 WHO 内部， 仅 TobReg 有独立的烟草制品设计领域的专家。 因此， 建议 TobReg 设 立一系列可被感兴趣国家例行的、快速接受的卷烟设计参数，就像 接受 WHO 对流感疫苗的建议一样。 TobReg 的报告 [1] 几乎覆盖了所有已知的对卷烟依赖性有贡献的 “品质”和化合物。尽管对其进行了命名和描述，但 TobReg 并没有 任何建议措施。然而，出版物为特定的管制措施打好了基础，可以 在此处进行推荐。应当注意的是，制造商在使用化学品改变来实现 品质改变方面已表现出非凡的才能。对 TobReg 文件文本的回顾揭示 了以下品质。 这些建议被 WHO 全面参考， 并加入了一些新的参考 文献。 （ • • • • • • • • • • • ·96·
）
吸引力 气味 香味 吃味 凉爽度 柔和性 “ ” （ ） 滤嘴通风 传输速率 吸收效率 pH 颗粒尺寸
7.烟草烟气管制：现状评述
• • • • • • • • • • • • • • • • • • • • 时机 。
具有低烟碱和丰富香味的初吸型产品 ： 烟碱 假木贼碱 降烟碱 薄荷醇 乙醛 氨 乙酰丙酸 单胺氧化酶抑制剂 尿素 巧克力 [1]
WHO
：
NNK NNN 乙醛 丙烯醛 苯 苯并 [a] 芘 1,3- 丁二烯 CO 甲醛
基于目前我们所掌握的知识 ， 现在正是考虑采取措施的理想
·97·
烟草制品管制科学基础报告： WHO 研究组第五份报告
7.2 建议的措施 作为卷烟管制的初始步骤 ， 可以采取下述已具有有力证据的 措施 。 • 卷烟应包含相对标准的烟碱剂量，向吸烟者传输时伴随有最 少量的致癌物和其他毒物。此处不做进一步讨论，因为关于 烟碱剂量的问题，包括可供选择的将烟碱降低至不致瘾水平 的方法，在本报告的附录 3 中有介绍。 • • • • • 有利于补偿抽吸的因素不应鼓励， 滤嘴通风就是典型的例子。 增加烟气致瘾性或吸引力的添加剂应被禁止。 强烈主张禁用所有添加剂，除非是出于公众健康原因进行使 用，例如制作 RIP 卷烟时要求使用的添加剂。 对那些已知且必要技术可行的致癌物和其他有害物质设定 上限。 需要可提供一致结果的测量体系。目前的加拿大系统 [9] 满足 该要求，且具有使用胶带包裹滤嘴，以降低滤嘴通风的影响 的优势。 • 制造商应被要求满足此处建议的性能标准，应披露相关致癌 物和其他有害物质的水平。目前加拿大系统也满足该要求。 由此引出对下述性能标准的考虑 ： 亚硝胺 ： 烟气行业已经建立了标准方法用于降低亚硝胺水平， 即由瑞典火柴开创的 Gothatiek 标准 [10]pp.23-41。 其被用于如 snus 等产品， 可以被作为初始步骤，尽管这些致癌物的水平仍可以被进一步降低 （S. S. Hecht，个人联系） 。 ·98·
7.烟草烟气管制：现状评述
PAH ： 这类化合物的水平也可使用 Gothatiek 标准而被显著降低。 TobReg[11] 考虑的其他主要致癌物和有害物质由表 7.1 列出， 展 示了 2002 年 Counts 等 [12] 报道的国际市场卷烟中的高水平和低水平。 水平的范围跨度惊人地大，恰好覆盖了国际样品，尽管其局限于仅 选择菲利浦·莫里斯公司的牌号。
7.3 设定上限相关问题 对于消费品中致癌物和其他有害物质设定限量并无先例，其简 单原因是通常的公众健康措施会将其设定为 0。任何管制者都应需要 相当大的说服力才能接受设定一个不是最低可实现的可接受的限量。 允许的水平是最低水平的数倍无疑是非常荒谬的，如表 7.1 所示 ： 例 如，NNK 为 8 倍， 乙醛为 19 倍， 丙烯醛为 24 倍， 苯为 7 倍， 丁二 烯为 6 倍，甲醛为 30 倍，CO 为 12 倍。 如果上限设定为市场上获得的最低水平的 3 倍，将轮到制造商 证明如此（宽宏大量的）限量应该增加。因此，超出该限量的举证 责任应该由制造商承担，对任何提高限量的唯一可以接受的理由只 能是实现该设定限量是生物化学上不可行的。允许最低高于可实现 最低水平的 3 倍变异，显然已是非常宽宏大量，可以设立先例并应 该设定两年的试用期，之后对限量进行评估，根据实际情况，设定 更低限量。 这些简单措施应 ： • • 减少补偿抽吸诱因，因为卷烟应提供消费者选择的剂量 ； 去除大量的成为致瘾性基础的复杂因素 ； ·99·
烟草制品管制科学基础报告： WHO 研究组第五份报告
• • •
与降低火灾风险一致 ； 降低腺癌相关风险（已明确与亚硝胺暴露有关 [2,3]） ； 通过降低亚硝胺和 PAH 降低总体致癌性负担。
10 种亚硝胺几乎可以全部去除，9 种 PAH 水平也将大幅度降低。 该改变连同表格中所示其他物质的水平，可被称为激动人心的，但 其实际反映的是 6 年前首次提出的观点 [11]。 不能也不应否认卷烟在符合这些性能标准时将会比现有产品危 害性更低，此处绝不是指可以允许进行“健康”宣称，因为其收益 尚未量化，且未在任何伦理学试验中确认该效果在一段时期后是否 可见。卷烟仍将是烟草相关疾病的最大起因。 然而， 我们应该清楚我们正在尝试做的事情是适用于卷烟的“降 低危害” 。该原理是低焦油卷烟运动的基础，起初将降低危害作为目 标，但因为烟草行业的欺骗和公共卫生机构缺乏相关知识和试验设 施让其进行说明，而最终失败。 时代已经改变了。 因此，这些改变不仅仅是基于公众健康管制常规的预防原则进 行调整，也是因为大量改变无疑将随时间降低癌症发病率和致瘾性。 事实上我们不知道该降低有多大程度或需要多长时间，但这不能作 为我们接受现状的理由。
7.4 参 考 文 献 [1] WHO Study Group on Tobacco Product Regulation. Report on the scientific basis of tobacco product regulation. Fourth report of a WHO ·100·
7.烟草烟气管制：现状评述
study group (WHO Technical Report Series, No. 967). Geneva: World Health Organization; 2012. [2] Burns DM, Anderson CM, Gray N. Has the lung cancer risk from smoking increased over the last fifty years? Cancer Causes Control 2011;22:389–97. [3] Burns DM, Anderson CM, Gray N. Do changes in cigarette design influence the rise in adenocarcinoma of the lung? Cancer Causes Control 2011;22:13–22. [4] IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 89. Smokeless tobacco and some tobacco-specific N-nitrosamines. Lyon: International Agency for Research on Cancer; 2007. [5] Jha P, Chaloupka F. Tobacco control in developing countries. Oxford: Oxford University Press; 2000. [6] Fox BJ, Cohen JE. Tobacco harm reduction: a call to address the ethical dilemmas. Nicotine Tob Res 2002;4(Suppl 2):S81–7. [7] Gilpin EA, Pierce JP. The California tobacco control program and potential harm reduction through reduced cigarette consumption in continuing smokers. Nicotine Tob Res 2002;4(Suppl 2):S157–66. [8] Foulds J, Ramstrom L, Burke M, Fagerstrom K. Effect of smokeless tobacco (snus) on smoking and public health in Sweden. Tob Control 2003;12:349–59. [9] Canadian tobacco reporting regulations. Ottawa: Health Canada; 2003. [10] WHO Study Group on Tobacco Product Regulation. Report on setting regulatory limits for carcinogens in smokeless tobacco. Geneva: World Health Organization; 2010 (WHO Technical Report ·101·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Series No. 955). [11] WHO Study Group on Tobacco Product Regulation. Contents and design features of tobacco products: their relationship to dependence potential and consumer appeal. Geneva: World Health Organization; 2007 (WHO Technical Report Series, No. 945). [12] Counts ME, Morton MJ, Laffoon SW, Cox RH, Lipowicz PJ. Smoke composition and predicting relationships for international commercial cigarettes smoked with three machine-smoking conditions. Regul Toxicol Pharmacol 2005;41:185–227.
·102·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
附录 1 包括潜在降低暴露量产品在内的新型烟 草制品 研究需求和建议
I. Stepanov 博士 , 明尼苏达大学 （美国明尼苏达州明尼阿波利斯） 环境卫生科学学部与共济会癌症中心 L. Soeteman-Hernández 博士 , 荷兰国家公共卫生研究院（ 荷兰 比尔特霍芬）健康防护中心 R. Talhout 博士 , 荷兰国家公共卫生研究院（ 荷兰比尔特霍芬 ） 健康防护中心 A1.1 摘要 A1.2 背景 A1.3 “减害”的概念 A1.4 方法 A1.4.1 数据来源 A1.4.2 选择标准 A1.4.3 数据提取和合成 A1.5 新上市和试销产品以及新兴用途产品 A1.5.1 口含烟 A1.5.1.1 可溶解烟草制品 ·103·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A1.5.1.2 新型鼻烟产品 A1.5.1.3 欧盟市场上模仿 snus 的口含烟 A1.5.2 改良或替代型抽吸产品 A1.5.2.1 潜在降低暴露量卷烟 A1.5.2.2 在一些国家作为“减害”产品推广的“低 焦油”卷烟 A1.5.2.3 低烟碱卷烟 A1.5.2.4 超细卷烟 A1.5.2.5 小雪茄 A1.5.2.6 含本草卷烟 A1.5.2.7 比迪烟 A1.5.3 水烟 A1.5.3.1 产品描述和营销策略 A1.5.3.2 消费者意识、产品使用和认知 A1.5.3.3 成分、毒性和疾病风险 A1.5.3.4 潜在致瘾性 A1.5.3.5 管制方面的考虑 A1.5.4 对传统烟草制品的显著改变 A1.5.4.1 降低烟草含量的瑞典鼻烟 A1.5.4.2 含有生物活性添加剂的湿鼻烟 A1.5.4.3 滤嘴中的薄荷醇胶囊 A1.5.4.4 无添加卷烟或有机卷烟 A1.5.4.5 产品名称的品牌化 A1.5.4.6 低烟味卷烟
·104·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
A1.6 发展中的技术 A1.6.1 代替传统卷烟燃烧的加热技术 A1.6.2 烟草加工工艺和滤嘴结构的改变 A1.6.2.1 含碳纤维或醋酸纤维滤嘴的烟草替代薄片 A1.6.2.2 烟草混合物处理及含有功能化树脂或碳的 滤嘴 A1.6.2.3 烟草替代薄片和两段式碳滤嘴的结合 A1.6.3 滤嘴结构的改良 A1.6.3.1 滤嘴中的氨基功能化离子交换树脂 A1.6.3.2 滤嘴中的钛酸盐纳米片、 纳米管和纳米线 材料 A1.6.3.3 活性炭滤嘴 A1.6.4 2013 年 CORESTA 会议所展现的研究进展 A1.6.4.1 烟草添加剂 A1.6.4.2 滤嘴添加剂 A1.6.4.3 前体研究 A1.7 总结 A1.7.1 非燃烧型口用产品 A1.7.2 卷烟和类卷烟装置 A1.8 结论 A1.9 致谢 A1.10 参考文献 附录 包括潜在“减害”产品在内的新型烟草制品调查问卷
·105·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A1.1 摘 要 本附录提供了新上市和试销产品以及新兴用途产品的概述，包 括口含烟、改良或替代型卷烟、水管烟和显著改变传统的产品。对 发展中的新技术，例如通过加热替代传统烟草燃烧，改变烟草加工 工艺和滤嘴结构也进行了讨论。 通过研究这些产品已发表的研究我们得出结论 ： 新型烟草制品 对公众健康的影响是不明确的。潜在的无法识别的毒性，通过招募 初吸者，戒烟者复吸，有可能戒烟的吸烟者维持烟草使用等形式增 加或持续烟草使用的流行性， 双重使用一种新型烟草产品和卷烟， 通过初吸一种新型烟草制品后转为抽吸卷烟的可能性，是许多公共 卫生研究者和倡导者的主要担忧。目前的研究状况没有提供足够的 证据排除其中任何担忧。 我们建议提高对新烟草制品的系统性全球监督，开发评估其使 用相关风险的标准方法，研究新产品的营销和消费者认知，发展向 专业人士和公众传达这些产品信息的有效途径，介绍一致的命名法 和评估政策对新产品使用流行的影响。我们还建议监管机构考虑扩 大其监管框架，不仅包括所有现有的和新兴的烟草制品，也包括使 用类似方法的产品（如草本卷烟）和烟草使用的配件（如水烟炭） ， 建立新产品上市前的批准要求， 监测每个国家新烟草制品的流行， 恰当地按轻重缓急发展烟草控制和管制措施，并制定降低新产品毒 性、吸引力和成瘾性的管制策略。 ·106·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
A1.2 背 景 在过去的十年中，一系列新的烟草制品和产品类型已经投入到 全球市场。设计一些口用的新产品，例如可溶解烟草制品和在美国 制造的“snus” 。其他的创新点本质上都是改良卷烟，含有特殊处理 的烟草或新型滤嘴或以新的方式传输可吸入烟草，例如在一个较低 的燃烧温度或加热代替燃烧烟草。这些产品中的一些可能是烟草行 业尝试生产和销售的低有害烟草成分暴露的产品，一些已经或正在 伴随暗示或明确的健康宣传上市。而减少暴露的一般概念是推测的， 使用此类产品或误解使用“减少暴露”产品的健康益处可能会产生 意想不到的健康后果。例如， “light”卷烟的上市增加了降低暴露的 错误期望，它们没有降低健康风险。降低卷烟中烟碱的含量是烟草 制品的另一个创新 ； 此类卷烟有较低的致瘾性，从而导致吸烟流行 率的下降。其他创新，如卷烟滤嘴中的薄荷胶囊，与降低风险无关。 进一步改变或加工烟草作物和新的烟草传输产品可能被研发。一些 国家以前没有使用过的一些烟草制品的新兴用途，可能带来的未知 后果，是另一个值得关注的问题。 随着新烟草制品多样性的增加，应该开展对个体和种群水平影 响的严谨研究。在过去的十年里已经对一些产品进行了大量的独立 研究， 烟草公司发表了可能已经在市场上出现的产品的测试结果。 总结关于产品毒性的现有知识和产品的市场销量，对于了解科学现 状、识别空白领域和未来方向具有重要作用，从而为烟草控制政策 和法规提供充足基础。我们的目的是系统地识别并评估发表的同行 评议出版物和关于新兴烟草制品类型、性能和影响的其他资料，包 ·107·
烟草制品管制科学基础报告： WHO 研究组第五份报告
括那些潜在的“风险改良” 。
A1.3 “减害”的概念 通过“减害”措施发展低毒性和低致瘾性的烟草制品，可能是 用于减少烟草相关的死亡和疾病的综合方案中的一个有效部分。这 种策略不仅在群体规模上有益，而且对那些不愿意或无法打破烟草 依赖的使用者可能也起到必要的降低风险的作用。 “减害”概念对于烟草行业和公众健康和烟草控制中的研究人员 可能有不同的含义。直到现在，行业主要集中在降低卷烟烟气中有 害成分的测定量上 ； 然而，从公众健康的角度来看，在不充分或未 经核实的信息基础上，营销此类烟草制品可能暗示着减少暴露和风 险。 “淡味”或“低焦油”卷烟的生产和销售历史是一个众所周知的 例子，消费者被减少危害的无效保证误导。公众健康研究人员和烟 草控制专家因此担心实际暴露量和消费者对成分的摄入量、引入新 消费者的可能性和烟草制品的潜在致瘾性 [1,2]。因为成瘾和许多与烟 草使用相关的疾病风险都与烟草成分的暴露水平相关，降低暴露应 该是烟草控制的一个重要组成部分。烟碱和烟草研究学会 [3] 已为减 少暴露的方法提出了几项基本原则。 • • • • ·108·
方法的目的必须是减少烟草引起的死亡和疾病。 这种方法的长期目标应该是让吸烟者不使用烟草和烟碱。 方法不应引入任何风险，关于安全性的数据应广泛，包括长 期使用的数据。 方法不应加重个人烟碱依赖。
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
• • • •
不应该降低最终停止使用烟草的可能性。 方法不应增加烟草依赖性人群流行率。 不应该具有对青少年的吸引力或增加其误用或滥用的风险。 任何对该方法的推广或营销，都应该提供关于戒烟的一致性 信息并提供戒烟和终止产品使用的帮助。
在设计减少暴露的方法时，使用这些基本原则可能会加快低毒 性水平产品的评估，给消费者提供比目前可用的传统卷烟危害小的 选择。
A1.4 方 法 A1.4.1 数据来源 文献主要在 PubMed 数据库和使用 SciFinder 搜索工具寻求，从 MEDLINE 和 CAplus 数据库检索数据， 也包括从数据库获得的在出 版物中引用的相关文章。此外，互联网搜索可提供产品特点和营销 信息的网站、主要烟草制造商的网站、烟草研究网站、博客和新闻 文章。获得从 2002 年至今的信息，因为新的或改良烟草制品的背景 文件 [4] 于 2002 年 11 月定稿， 2003 年发行， 因此跨越了约 11 年的 时间。 此外，该领域的专家，包括监管者和烟草科学家，通过调查问 卷进行咨询（见附录） 。贡献者列在致谢中。对调查问卷确定的产品 展开互联网搜索。
·109·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A1.4.2 选择标准 我们用以下的标准来定义“新兴”或“新型”烟草制品 ： • • • • 产品含有烟草（例如电子卷烟和草本卷烟不包括在内） 产品是由一个新的或非常规的技术制造，和 / 或作为“减害” 产品销售。 产品类型上市不超过 12 年。 产品类型已上市很久，但在以前没有用过该类型产品的国家 或地区市场份额增加。非常规烟草制品的新兴用途危害了全 球烟草控制的努力。 但一些描述的产品已不能再获得，我们总结了那些产品的相关 研究，以提高对烟草制品开发中当前和未来创新点的理解，并解释 行业的任何健康声明。我们排除了那些仅仅是市场上已有的传统或 普通卷烟、雪茄、烟斗、手卷烟或口用烟草的变型产品。 A1.4.3 数据提取和合成 搜索最初的关键词为“snus” ， “ 水烟 ” ， “ 可溶解烟草 ” ， “ 低烟 碱卷烟 ” ， “ 减少（烟草制品或卷烟） ” ， “改良（ 烟草制品或卷烟） ” ， “ 烟草减害 ” “ 新型（ 烟草或卷烟 ） ” ， 随后按照“ 滚雪球 ” 的方法。 我们收集产品上的信息， 其市场营销方法， 包括健康宣称， 如何 使用和感知产品，其化学成分和毒性，其潜在致瘾性，其抑制戒断 症状的有效性（ 这可能会阻碍戒烟或完全替代 ） 和针对该产品的 管制。
·110·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
A1.5 新上市和试销产品以及新兴用途产品 虽然本节中所描述的一些产品已经被制造商中止生产且不能再 获得，但大量的研究已经完成，这对于理解烟草制品开发中当前和 未来的创新点，以及和评估未来改良产品潜在的公众健康影响非常 重要。不涉及新技术但开始在新市场应用的产品也包括在内，因为 新类型的消费者扩大使用所引起的新挑战和新问题，必须通过严谨 的科学研究来解决。 本报告中包括的大多数已发表论文源自欧洲和美国。此外，调 查问卷的反馈也没能提供为地域上的全面概述提供足够的信息，因 为一些受访者表示在他们的地区没有新兴的或新型烟草产品的信息。 因此，按照产品类型提供信息而不是按地域趋势。 A1.5.1 口含烟 A1.5.1.1 可溶解烟草制品
2001 年美国市场上，以 Ariva 和 Stonewall 品牌引入了可溶解烟 草制品（图 A1.1） 。 他们的制造商 Star Scientific 在这些产品的营销和推广方面投 资有限 [5]。 2009 年， 雷诺公司推出 Camel 可溶解烟草制品， 2011 年， 菲 利 浦· 莫 里 斯 公 司 推 出 Marlboro 和 Skoal 可 溶 解 烟 草（ 图 A1.1） 。 这些产品是由精细研磨的烟草制成， 以丸、 棒或条的形式 出售。 例如，Camel Orbs 是椭圆形小丸，Camel Sticks 是牙签状的 ·111·
烟草制品管制科学基础报告： WHO 研究组第五份报告
可溶解烟草棒，Camel Strips 是类似口气清新片的褐色烟草条 [6]。最 初推出的可溶性的 Camel 产品有柔和的清新风味，但最新的版本进 行了配方重组， 仅有单一的薄荷风味 [7]。 与 Camel 可溶性系列的尺 寸、 形状和包装均类似的可溶性烟草制品， 在 2010 年以 Revo 的品 牌名称推向中国台湾市场 [8]。 菲利普·莫里斯公司生产的 Marlboro Sticks 和 Skoal Sticks 与 Camel Sticks 不同， 它们包含一个牙签状的 木棒，上面覆盖了一层精细研磨的烟草。图 A1.1 描述了这类产品的 演变。
图 A1.1 可溶解烟草制品样品
在美国的几个州对 Camel 可溶解烟草制品进行了试销，包括在 美国烟草使用率最高和成人吸烟率第二高的印第安纳州 [9,10]。 商店 ·112·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
里关于可溶解烟草制品的广告中包括以下短语，如“可溶解烟草” ， “ 免费试用 ” ， “ 特价 ” 和“ 什么是你的风格？” ， 而且产品的摆放邻 近无烟烟草、 卷烟或糖果 [10]。 像促销美国鼻烟的方法， 有些可溶 性产品广告强调其独特的功能（例如，使用后不需要吐掉或扔掉） ， 其严谨的特性，以及在酒吧、飞机以及其他不允许吸烟的地方使用 方便 [5]。虽然这些产品零售广告的主要受众似乎是当前吸烟者，一 些研究人员对它们的促销提出担忧， 事实上它们可能被谨慎使用， 其包装中许多提到“糖果类似物” ，可能会吸引新的、以前没有使用 过烟草的年轻使用者 [5,10]。Romito 等 [10] 在印第安纳州的研究表明， 大多数商店出售 Camel 可溶解烟草制品时附送促销品，包括购买另 一种 Camel 产品时提供免费试用品。作者也报道了各种大学校园举 行的活动中有可溶性产品的推广、 免费样品、 优惠券和其他赠品。 收到任何推广的参与者中，11% 尝试了该产品，而总样本中只有 3% 这样做了。
、 对 Ariva 的早期研究显示， 其对吸烟者几乎没有吸引力， 但是 一些研究者认为产品会对其他群体有吸引力，例如新吸烟者、年轻 人和妇女 [5,11]。相关担忧已经指出这些产品“类似糖果”的外观和添 加的香味可能会增加对少年儿童的吸引力 [12]。来自美国佛罗里达州 的数据分析认为，18~34 岁的吸烟者比年长的成年吸烟者更可能尝 试可溶解烟 [5]。在美国印第安纳州开展的对 Camel 可溶解烟草制品 的兴趣和感知的另一个消费者认知研究表明， 消费者的兴趣很低， 但 40 岁以下的受访者比 40 岁以上的受访者更熟悉 Camel 可溶解烟 P ＜ 0.01） （60%） （45% ； 。至于鼻烟，男性、当前吸烟者和既往吸烟 者表现出更多的兴趣，也更经常试用可溶解产品。吸烟者和非吸烟 ·113·
烟草制品管制科学基础报告： WHO 研究组第五份报告
者都认为广告的目标是吸烟者 [10]。
、 第一代可溶性产品，Ariva 和 Stonewall，包含所有美国市售烟草制品 中最低水平的烟草特有亚硝胺（TSNA）——一组主要的烟草致癌物 [13]。 例如，Ariva 中 N ′- 亚硝基降烟碱（NNN）含量为 19 ng/g，4 -(N- 甲基 亚硝胺基 )- 1 -(3- 吡啶基 )- 1- 丁酮（NNK）为 37 ng/g，而传统的湿鼻 烟 Kodiak Wintergreen 含 有 2200 ng/g NNN 和 410 ng/g NNK。 在 一 个关于 Ariva 和药用烟碱的研究中，转为使用 Ariva 的吸烟者摄入的 TSNA 和戒烟糖水平相当 [14]。 最近报道的 Ariva 和 Stonewall 产品中 的 TSNA 水平稍微增高， 但仍远低于传统的湿鼻烟 [15,16]。 率先出现 在市场上可溶性 Camel 产品中的 TSNA 水平与 Ariva 和 Stonewall 相当， Camel Strips 含有的 TSNA 含量最低，其次是 Camel Orbs 和 Sticks[15]。 然而， 最新一代的可溶解 Camel 含有更高水平的 TSNA[17]。 新的可 溶解产品 Marlboro Sticks 和 Skoal Sticks 含有的 TSNA 水平与传统的 美国湿鼻烟相当 [16,17]。表 A1.1 总结了报道的可溶解烟草制品中烟碱 和 TSNA 浓度。 表 A1.1 可溶解烟草制品中烟碱和 TSNA 的浓度 产品 Ariva Stonewall Camel Orbs Camel Sticks Camel Strips Skoal Sticks 烟碱 4.4~6.3 6.8~8.7 2.7~4.1 3.1~4.7 2.2~4.1 4.5~5.9 游离态烟碱 0.3~1.5 0.7~1.6 1.2~1.8 1.4~1.9 1.1~2.0 2.7~3.5 0.8~1.1 NNN （ng/g） 19~98 56~133 190~280 221~260 150~340 1760~2070 NNK （ng/g） 37~71 43~73 220~780 194~780 472~800 （mg/g） （mg/g） 参考文献 [13, 15, 16, 18] [13, 15, 16, 18] [15, 16]; Stepanov, 未发表数据 [15, 16]; Stepanov, 未发表数据 [16]; Stepanov, 未发表数据 [16]; Stepanov, 未发表数据
260~1060 [15, 16, 18]; Stepanov, 未发表数据
Marlboro Sticks 5.9~7.1
1820~2420 485 ~ 790
·114·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
对 Camel 可溶解烟草制品广泛的化学物筛查显示它们主要含 有烟草， 混合有黏合剂、 填料和香味剂 [6,7]。 在 2010 年推出的一代 Camel 可溶解产品的化学组成显示了风味的改变（ 薄荷味代替清新 柔和香味） 因此，所有的新产品都含有薄荷醇但没有以前柔和香型 ； 可溶解产品中使用的肉桂醛或香豆素，且用苏糖醇代替了甘油。游 离态烟碱（生物可利用形式）的含量在新一代的 Orbs 产品中统计学 显著高于旧款型，但在棒状或条状产品中没有发现显著的变化。更 多的全面筛查显示，目前可溶性 Camel Orbs 中有 163 种化学物质存 在，表明其化学成分的复杂性 [16]。 基于提到的可溶解烟草制品和“糖果” （甜品）的相似性，有人 担心孩子会不小心吞下这些产品。Connolly 等 [12] 对儿童中因为摄入 烟草制品中毒的数据进行分析， 发现 2006~2008 年间摄入无烟烟草 的案例递增， 3 岁儿童吞下 Orbs 的有一例，2 岁儿童由于摄入鼻烟造 成轻度中毒的有两例。
： 根据促销资料，Camel Orbs 每丸含有 1 mg 烟碱，Camel Sticks 每棒含有 3.1 mg 烟碱，Camel Strips 每条含有 0.6 mg 烟碱。Connolly 等 [12] 分析了美国三个市销市场上的 Camel Orbs（ 清新柔和风味 ） ， 发现平均每丸含有 0.83 mg 烟碱。 平均 pH 为 7.9， 导致其生物可利 用的游离或非质子化形式的烟碱平均占 42%。另一项 Camel 可溶解 产品分析研究 [6] 表明柔和风味的 Orbs 中烟碱含量为 0.82 mg，清新 风味的 Orbs 中为 0.77 mg， 棒状产品中为 0.91 mg， 条状产品中为 0.21 mg ； 这些产品的 pH 范围为 7.50~8.02。这些产品与传统的无烟烟草 制品相比，总的游离态烟碱含量更低，这很可能决定其在现有的或 新的烟草使用者中的接受度。烟碱含量低的产品可能有较低的潜在 ·115·
烟草制品管制科学基础报告： WHO 研究组第五份报告
致瘾性，也因此更容易被刚开始吸烟的年轻人接受，但它们可能被 正在寻求好的吸烟替代品的吸烟者拒绝。烟碱含量较高的无烟产品 可能导致滥用和持续成瘾，但相比那些烟碱更少的产品，能更有效 地满足吸烟者和更完全的替代卷烟 [19,20]。 可溶性的产品可以提供逐 步增加生物可利用游离态烟碱水平，所以不同的配方可能会吸引不 同的潜在消费者（图 A1.2） 。 Star Scientific 0.40 0.35 䴲䋼ᄤ࣪⚳⺅˄mg/ḋᴀ˅ 0.30 0.25 0.20 0.15 0.10 0.05 0.00 Ariva Stonewall 䴲䋼ᄤ࣪⚳⺅˄mg/ḋᴀ˅ RJ Reynolds 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00
Camel Orbs
Camel Strips
Camel Sticks
图 A1.2 可溶解烟草制品中烟碱梯度
各种无烟烟草制品中有意保持一定的游离态烟碱水平，以给新 使用者提供低烟碱产品，同时具有渐进的更高剂量烟碱水平的产品 可以维持现有消费者的成瘾（分级策略）[21]。了解新的可溶解产品 中不同游离态烟碱水平是怎样影响消费者的使用非常重要。 通过研究人们由吸烟转向消费可溶解烟草制品的行为，一些可 ·116·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
溶性产品对戒烟及烟草渴求的生理及心理影响可能与那些医用烟碱 产品类似 [14]。然而，当吸烟者不能吸烟时，这些产品可能提供了一 种临时降低吸烟者对烟碱渴望度的方式，从而使他（她）们推迟戒 烟进程，而不是彻底戒烟 [5]。
（FDA） 在 2012 年 3 月，该委员会总结了所发表的关于可溶解烟草制品 的资料、 意见和描述等， 并向 FDA 提交了一份报告， 该报告是关于 “消 费可溶解烟草制品（包括在儿童中的消费行为）的性质及其对公众 健康的影响”[22]。该委员会总结到 ： ①该产品的多种化学成分含量 都不同，包括烟碱和 TSNA ； ②可溶解烟草制品滥用的可能性可能比 传统美国卷烟及大多数传统无烟烟草制品低 ； ③消费可溶解烟草制 品可能降低卷烟的消费量，但对于大多数老烟民来说，这种产品还 不能完全替代卷烟 ； ④尽管可溶解烟草制品比传统卷烟的危害性小， 但还没有足够的流行病学数据能表明这些产品对现有消费人群的影 响； ⑤关于消费者对这些产品的认知及反应的研究还很有限，但是， 一般说来，消费者对现有产品的反应是消极的 ； ⑥很少有由于吞咽 这些产品而导致严重后果的报告。 A1.5.1.2 新型鼻烟产品 斯堪的纳维亚地区的传统鼻烟是一种通常经过湿法灭菌并加以 仔细研磨的湿鼻烟，这种鼻烟与其他传统的湿鼻烟相比，致癌性的 TSNA 含量较低。鼻烟被放在脸颊及牙龈之间，口腔所产生的液体会 吞下而不是吐出。在这一节中，我们集中讨论在美国生产及销售的 新型鼻烟产品。 ·117·
烟草制品管制科学基础报告： WHO 研究组第五份报告
2006 年，美国的两家领先的卷烟生产商，雷诺公司和菲利浦 莫 · 里斯公司，开始推出新型无烟气烟草产品，也叫“鼻烟” （图 A1.3） 。
图 A1.3 美国制造鼻烟示例
美国鼻烟也是由巴氏灭菌的烟草制造的，但和传统的美国嚼烟、 “dip” 及鼻烟不同， 这种烟不需要吐出， 包装在小的类似于茶叶袋 的袋子中，放在上嘴唇下，其消费方式具有相对隐蔽性 [23]。美国鼻 烟与传统无烟烟草制品的不同是产品营销的一部分 [24,25]。 美国鼻烟 在营销过程中强调与瑞典鼻烟的渊源，但是美国鼻烟产品却是以人 们熟知的卷烟品牌“骆驼”和“万宝路”延伸品牌的形式来进行推 广。随着室内空气清洁法令实施力度的进一步增强， 生产商宣称， “在 不能吸烟的地方 ” ， 如公共场合、 酒吧、 办公室和机场， 鼻烟是一 种可以用来谨慎消费的产品 [24]。因此，尽管很多鼻烟广告想将鼻烟 作为一种可替代卷烟的产品 [25]，人们仍担心鼻烟会主要以吸烟的补 充产品而不是替代产品来推广 [24]。通过对骆驼鼻烟的广告调查发现 [26]
， 从 2007 年到 2009 年， 该产品主要向吸烟人群推广， 但是， 在
·118·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
2009 年 10 月，当新的“Break free”广告在杂志上出现时，表示该产 品营销策略的转变。作者认为，新的广告传达了一种模棱两可的信 息，会吸引更大范围的消费者，包括潜在的年轻消费人群。在美国 纽约开展的一项小规模居民区及学校的有限调查表明，学校周围大 约 20% 的可能销售卷烟的商家销售鼻烟 [27]。 由于美国限制传统卷烟广告，烟草公司会通过直接邮寄、电子 邮件及其他途径，以及在酒吧和俱乐部中提供免费样品及杂志广告 等方式来向消费者推广鼻烟 [23,24,28,29]。万宝路及骆驼牌鼻烟曾通过直 接邮寄的方式来推广其产品，包括优惠券和免费产品包裹等 [24]。营 [28] 销措施还包括新的网页， 如骆驼牌鼻烟网站 （www.camelsnus.com） 。
在产品市场测试时期，消费者在骆驼牌鼻烟网站留言板上的留言还 会影响到雷诺公司对产品的设计决定，如他们就通过这种途径抛弃 了香料口味，并重新设计了包装大小 [25]，这说明，骆驼牌鼻烟仅用 数年的时间就位列美国无烟烟草制品品牌榜十强之一，这种强势的 营销手段功不可没。 具有流行卷烟品牌名称的鼻烟产品， 如“Lucky Strike”和“Peter Stuyvesant” ，也在加拿大、日本和南非得到推广 [24]。
、 Biener 等 [30]
报道， 在 2010 年， 在作为试点的市场上， 有 10%
的吸烟者尝试过鼻烟， 而这个比例在年轻人中高达 29%。 相比较而言， 白人、教育程度较低的人以及不想立刻戒烟的人群分别比少数人种、 教育程度较高的人以及想在接下来的 30 天内戒烟的人更经常使用这 些产品。在一项包括美国得克萨斯州 8472 名年龄在 11~18 岁的学生 的鼻烟消费情况调查中，也发现了类似的结果 ： 7.1% 的调查人群标 识曾经尝试过鼻烟， 其中 77% 是男性， 68% 是在校生， 46% 是白人 [31]。 ·119·
烟草制品管制科学基础报告： WHO 研究组第五份报告
鼻烟在全国范围内开始流行后，一项包括 2607 名年龄在 20~28 岁的 年轻人的关于鼻烟认知、 消费及看法的研究中，64.8% 的受访者知 道鼻烟，14.5% 曾经使用过，3.2% 在过去的 30 天曾经使用过 ； 所有 的三项调查结果都和男性有关， 并在一生中抽吸过大于 100 支卷烟 （P < 0.05）[29]。 在一项对骆驼牌鼻烟网站信息板的调查中发现， 在 人们决定选择这种产品的过程中，广告起着很重要的作用 ； 许多参 与者表示，他们收到一个免费的产品后，就会尝试这种产品 [28]。 大多数受访的吸烟者表示，使用无烟烟草制品，如骆驼牌鼻烟 和万宝路牌鼻烟， 是一种权宜之计， 而不是想作为吸烟的完全替代品； 而且，使用鼻烟会增强吸烟者对吸烟的偏爱 [24]。受访者认为，鼻烟 最大的好处是可以在无烟环境中使用，并可避免产生二手烟气的愧 疚感。受访者怀疑鼻烟比卷烟更安全的观点，且并不认为鼻烟是一 种卷烟的可接受的替代品， 或是一种戒烟手段。然而， 在其他研究中， 那些在酒吧或俱乐部的受到鼻烟广告影响的消费者，更可能相信鼻 烟比卷烟的危害性低 [29,31]。 美国市场使鼻烟的总市场占有率从 2007 年的 0.1% 升高到 2011 年的 3.7%[25]。2011 年， 骆驼、 万宝路和 Skoal 三大品牌占据的市场 份额达到 99.7%（ 骆驼牌是 63.3%， 万宝路牌是 24.2%，Skoal 牌为 12.3%） 。2011 年，绝大多数（86.7%）市售鼻烟是绿薄荷或薄荷口味 的。骆驼牌鼻烟的习惯消费人群表示会同时使用其他类型的烟草产 品， 并会平均每天消费 3.3±1.9 包的鼻烟。 一些消费者表示会同时 使用两包或更多的鼻烟 [32]。
、 雷诺公司的研究人员报道了骆驼牌鼻烟中的 TSNA、 烟碱、 苯 并 [a] 芘 [ 稠环芳烃 (PAH) 的代表性致癌物 ] 及部分金属元素含量水 ·120·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
平 [32]。2010 年，在一项第三方研究中，Stepanov 等（2012a）分析了 多种新型产品中的 TSNA 和烟碱含量，包括骆驼牌及万宝路牌鼻烟， 这些产品从美国多个地区购买。骆驼牌鼻烟的 TSNA 含量水平比万 宝路牌高很多，但是两种品牌中游离态烟碱含量随地域而显著不同。 在 2006~2010 年之间， 作者实验室对骆驼牌及万宝路牌鼻烟的总烟碱、 游离态烟碱及总 NNN 和 NNK 含量进行了测定，结果发现，2010 年 大的骆驼牌包装的上述成分含量比原有的于 2006 年进入市场中的小 包装产品的含量高很多，这是由于包装大小造成的。后来的万宝路 牌鼻烟中总烟碱及游离态烟碱含量也高，但是现有包装中的总 NNN 和 NNK 含量要比原有包装低 [33]。表 A1.2 总结了美国制造鼻烟的烟 碱和 TSNA 含量。 表 A1.2 美国制造鼻烟的烟碱和烟草特有亚硝胺含量 产品 Taboka 万宝路鼻烟 骆驼鼻烟 Skoal Dry Skoal 鼻烟 烟碱 （mg/g） 14.0~18.3 11.5~19.7 8.7~13.9 10.1~11.4 17.2~19.0 游离态烟碱 （mg/g） 0.7~1.1 0.3~1.0 1.6~6.1 0.6~1.6 0.6~1.0 NNN （ng/g） 822~933 330~2950 369~1320 929~4750 1410~1710 NNK （ng/g） 67~84 100~233 84~480 80~323 246~378 参考文献 [18, 34] [15, 34]; Stepanov, 未发表 [15,18, 34]; Stepanov, 未发表 [18, 34] Stepanov, 未发表
在一项对一组成年老鼻烟消费者的研究中，研究人员对多种骆 驼牌鼻烟的多种成分口腔暴露量进行了测定 [32]。一般来讲，鼻烟包 装中原有 60%~90% 的烟碱，TSNA 和苯并 [a] 芘在消费后依然在包 装中存在。 烟碱的平均口腔暴露量为 9.4 mg/d，TSNA 为 527.7 ng/ d， 苯并 [a] 芘为 0.68 ng/d。 相比而言， 瑞典的英美烟草公司研究 人员报道，老鼻烟消费者对瑞典鼻烟中烟碱及 TSNA 的吸收量只有 ·121·
烟草制品管制科学基础报告： WHO 研究组第五份报告
33%~38%[35]。然而，Caraway 和 Chen[32] 对骆驼牌鼻烟的研究结果与 Digard 等对“Lucky Strike” 鼻烟的研究结果不同， 前者的水分含量 较低，包装袋较小，而且还存在其他成分及生产方式的不同。 当吸烟者转而消费鼻烟时， 人们研究了其潜在暴露量的改变， 并比较了三种产品的不同，包括 Taboka（一种美国的类似鼻烟的早 期产品 ） 、 骆驼牌鼻烟以及医用烟碱等。 在每组受试者人群中， 在 对这些产品使用 4 周后， 其呼出二氧化碳含量、 尿液可替宁含量、 NNAL（一种烟草特有致癌物 NNK 的暴露生物标志物）以及尿液总 NNN 含量都会降低。 使用医用烟碱的总 NNAL 降低量要比骆驼牌 鼻烟的降低量高 [20]。一项研究报道了吸烟者消费鼻烟后结果，这项 研究包括三组研究对象，一组为吸烟者除鼻烟还有其他替代品，一 组是吸烟者完全使用鼻烟，一组是对照组，该组中的吸烟者会继续 吸烟或不再使用任何烟草产品 [36]。 在受试者使用鼻烟之前以及使 用鼻烟或戒烟后的多个时间段里， 研究人员对其 TSNA、 烟碱（ 尿 液或血液中 ） 、 芳香胺、 苯和 PAH 的代谢物、 尿液致突变性及碳氧 血红蛋白的含量进行了测定。结果发现，与继续吸烟人群相比，那 些完全戒烟或有部分替代品的人群的总尿液生物标志物含量有明显 降低。 流行病学研究表明， 相对于传统卷烟消费者， 那些只使用低 TSNA 含量瑞典鼻烟的人群的患癌风险要低 [37-39]。 相对于那些从来 不使用烟草的人来说，鼻烟消费人群的胰腺癌发病率较高，但是其 口腔癌发病率较低或基本持平 [38,39]。 对于斯堪的纳维亚地区鼻烟消 费人群，其由鼻烟而引起的黏膜白斑病很普遍，但是还不清楚这是 否会发展成癌症 [40]。无烟烟草制品的消费人群发生心肌梗死后的死 亡率会升高，但不会增加心肌梗死的发生率。至于女人怀孕期间使 ·122·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
用无烟烟草制品对生殖系统的影响，由于相关数据太少，还无法得 出最终结论。还不清楚使用美国制造的鼻烟后对健康的影响 ； 但是， 个体只使用鼻烟的后果与瑞典鼻烟的影响可能是类似的。
： 在一项研究中，吸烟者被要求停止吸烟，并选择“General”鼻 烟（ 一 种 瑞 典 产 品 ） 、 骆 驼 牌 鼻 烟、 万 宝 路 牌 鼻 烟、Stonewall 或 Ariva 等产品，并继续使用 2 周，结果发现，与其他产品相比，骆驼 牌鼻烟更能减轻吸烟渴望，满足感更强，吸烟量减少量大，戒烟时 间更长 [19]。可溶解烟草制品“Ariva”和万宝路鼻烟在促进戒烟、减 少吸烟量及降低吸烟频率等方面的效果最弱。这些差异可能是由这 些产品中烟碱含量的差异所造成的 ： 单包骆驼牌鼻烟的游离态烟碱 含量为 1.74~1.97 mg，Ariva 为 0.24~0.25 mg，万宝路鼻烟为 0.14~0.38 mg。在一项代谢组学研究中，人体对烟碱的摄入量与产品烟碱含量 有关 ： 使用骆驼牌鼻烟比 Ariva 和万宝路鼻烟的血液烟碱含量高（分 别为 7.7 ng/mL，3.4 ng/mL 和 2.9 ng/mL）[41]。 在抽烟渴望度及意向 的研究中，骆驼牌鼻烟的相关指标明显降低，但是，对于烟碱含量 较低的 Ariva 及万宝路鼻烟，这些指标变化不明显。在医用口腔烟碱 替代疗法与骆驼牌鼻烟及 Tobaka 的对比实验中，相比烟碱含量较低 的 Taboka，骆驼牌鼻烟更能降低卷烟抽吸量，产品消费量高，戒烟 率高 [20]。 鼻烟中烟碱含量对人们对鼻烟主观反应的影响还不清楚。在一 项对不同口用烟草的代谢动力学研究中，产品烟碱含量越高，对人 们吸烟渴望度的减轻效果越好 [42]，但是，其他包括 5 天产品使用过 程的研究表明，Ariva 和骆驼牌鼻烟对吸烟渴望度及戒烟的影响差异 不大 [43]。一项类似的研究表明，在吸烟者随机选择使用 Taboka、骆 ·123·
烟草制品管制科学基础报告： WHO 研究组第五份报告
驼牌鼻烟及医用烟碱时，其对吸烟渴望度与戒烟的影响差异不大 [20]。 总之，在降低戒烟不适症状方面，与医用烟碱相比，鼻烟产品也不 具有优势 [19,20]。 A1.5.1.3 欧盟市场上模仿 snus 的口含烟 根据欧盟烟草指令 2001/37/EC 第 8 条，在欧盟地区，除瑞典外， 禁止销售除嚼烟之外的口含烟 [44]。
“ ，
” ， ， ， ，
。 在我们的问卷调查中，奥地利、捷克共和国、德国和瑞士都报 告有产品模仿嚼烟和 snus。例如，一种丹麦 V2 烟草公司生产的经强 烈调味的“Thunder” 嚼烟 (http://www.v2tobacco.com/)（ 图 A1.4A） ， 含有 41% 的烟草和 59% 的 这种产品的烟草含量相对较低。 “填充剂” ； 同一家公司还生产“Thunder”嚼烟包（图 A1.4B） ，这种产品含有小 包装的切丝烟，并经过荷兰薄荷进行强烈调味。 另外一种这类产品是瑞士和英国的“MaklaAfricaine” （如 http:// www.sifaco.be/Engl/Site_engl.htm 和 http://www.makla-ifrikia.com/shop/ kautabak-makla-ifrikia-kautabakshop.html） 。 在一个鼻烟消费者论坛中（(http://www.snuson.com/forum/archive/ index.php/t-16456.html， 2013-10-05） ， “Thunder” 嚼 烟 被 认 为 不 适 合咀嚼，但是， “欧盟嚼烟不同于美国嚼烟，在技术上归类为嚼烟的 makla，如果它不是用来咀嚼的，欧盟就会将其禁止” 。
·124·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
A
B
图 A1.4 模仿 snus 的产品示例
·125·
烟草制品管制科学基础报告： WHO 研究组第五份报告
由于一些产品在模仿 snus， 就必须在管制政策上对其进行评 估。在德国，官方在评估这些产品是否在烟草法令的管制范围之内 （2001/37/EC 法令第 8 条 ） 。 瑞士认为， 该产品不是典型的嚼烟， 但 类似于 snus， 尽管这种产品不符合 snus 的定义， 因为它是膏状而 不是粉末状的。在芬兰，官方在评估一种类似的产品是否应被看作 snus 或嚼烟。 A1.5.2 改良或替代型抽吸产品 在本节，我们将对卷烟及类似卷烟的产品及装置进行综述，这 些产品或是刚引入到市场，或是已经在一些本没有这些产品的地区 中占据了较大的市场份额。本节还将介绍通过卷烟设计来降低烟气 有害物质暴露量及低烟碱释放量卷烟的研究。本节还将简要介绍不 同尺寸卷烟（超细卷烟） 、草本卷烟和其他产品。 A1.5.2.1 潜在降低暴露量卷烟 烟草公司一直在尝试开发能够使有害物质暴露量比传统卷烟低 的卷烟，以降低与吸烟相关的吸烟和非吸烟人群的健康风险 [3,45]。主 要有三种方式来制造这类卷烟。 加 热 非 燃 烧 产 品。 实 例 有 雷 诺 公 司 生 产 的 Eclipse 卷 烟 和 菲利浦 · 莫里斯公司开发的 Accord 卷烟。Eclipse 含有滤嘴、 烟草 （ 双堵头 ） 以及通过顶端的绝缘玻璃丝包裹在铝箔纸中的碳基加热 模块，这种产品加热而不是燃烧烟草 [46]。一旦被加热，碳模块就会 通过包装芯传递热量，并首先达到富含甘油的再造烟叶，进而到达 ·126·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
烟草 ；因此， 烟气会富含甘油和水分 [47]。Eclipse 宣称可潜在“ 降 低吸烟相关的癌症风险，并降低肺部疾病风险”[48]。其他广告宣称 Eclipse“ 可能危害性较低 ” ， “ 可能患癌的风险低 ” ， “ 降低致癌物释 放量水平” ， “相对降低呼吸系统炎症” ，而且对被动吸烟者的影响较 低，因为该产品释放的是蒸汽而不是烟气。Acoord 包括一个过滤插 件、 一个空管及填有压缩烟草的部件； 该管子被插到手持式加热管中， 然后通过加热而不是燃烧的方式来加热烟草 [46]。Accord 被作为一种 可降低二手烟释放量的产品而推向市场，并可能降低烟气的致突变 性和细胞毒性 [48]。 尽管 Accord 已退出市场， 但 Eclipse 依旧出现在 美国市场上。 一 个 最 近 的 加 热 而 不 是 燃 烧 烟 草 的 卷 烟 类 型 是“Ploom modelTwo” （图 A1.5） ，这种产品是电子烟和传统卷烟的结合体，这 种产品加热烟草，而不是电子烟产品的丙二醇 [49]（http://www.ploom. com/modeltwo） 。
图 A1.5 Ploom
Ploom 公司的座右铭是“是时候重新看待烟草了” ，其最流行的 产品“Ploom modelTwo”的广告语是“一种享受烟草的全新方式” 。 ·127·
烟草制品管制科学基础报告： WHO 研究组第五份报告
这是一种手持式装置，可加热具有多种不同风味的烟草，并吸入温 热的烟草蒸汽。根据产品描述， “Ploom modelTwo”在 20~30 秒内完 成加热，而且每一种烟草模块可抽吸 5~10 分钟，而不是一直不停抽 吸很长时间。这种蒸汽和传统卷烟烟气类似，所以消费者比较喜欢 ： “蒸汽很棒，浑厚而柔和，几乎和真的烟气一样……”[49]。该种产品 的一种缺点是加热模块距离口腔较近，也很热 [49]。 改变烟草加工过程。布朗和威廉姆森烟草公司和 Vector 烟草公 司分别推出的“AdvanceTM” 和“Omni” 卷烟， 就是这一类型， 但 都已经退出市场。AdvanceTM 宣称“ 拥有所有口味 …… 有害成分释 放量低” ，而且，根据生产商的声明，这种产品使用的烟草经过特殊 的加工过程，该过程“能够显著降低烟草特有亚硝胺的形成”[50,51]。 Omni 使用的烟草经过钯处理，能提高烟草燃烧效率，进而能够降低 烟气中由于烟草不完全燃烧而造成的有害物质和致癌物质释放量 [52]。 Omni 宣称能够显著降低烟气中的 PAH、TSNA 和邻苯二酚释放量， 这些化合物“是卷烟烟气中和肺癌发生率相关的毒性最强、最危险 的化合物之一”[51]。 改变滤嘴结构。 例如， 万宝路的“UltraSmooth” 在 2005 年进 入美国测试市场，其滤嘴中含有活性炭。尽管活性炭已经在美国卷 烟中得到应用，但是该产品的创新点在于它比其他品牌含有更多的 活性炭 [53]，这可能会增强降低烟气有害成分释放量的能力。该产品 也退出了市场。
、 在吸烟者和戒烟者对 Eclipse 卷烟的反应研究中，大多数吸烟者 认为它们比常规、低焦油和低烟碱卷烟对吸烟者和他们周围人的健 康更安全，或甚至是“完全”安全 [45,54,55]。在一项研究中，很多吸烟 ·128·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
者认为 Eclipse 是戒烟的一步 [45]。 另一组显示 Eclipse 对正在考虑戒 烟的吸烟者有吸引力， 但其声称降低风险， 会减少他们戒烟的意愿 [54]。 因此，这样的声明可能会破坏成人戒烟和对年轻人使用的预防，即 使产品的毒性较低，也可能增加伤害。在英国的同一组研究中也有 类似的结果，表明这种产品对声称戒烟的吸烟者和戒烟者复吸的作 用必须作为世界范围一个公众健康紧急事件进行评估 [55]。尽管吸烟 者认为 Eclipse 卷烟“是更安全的” ，但他们认为 Eclipse 与比自己的 卷烟品牌满意度和奖赏作用更低 [56]。
、 根据行业调查， 如 Accord 等电加热卷烟抽吸系统较低的裂解 温度会导致 44 种主流烟气成分测定量比标准参考卷烟的浓度显著降 低（25%~90%） （MSS） ， 包括烟碱和一氧化碳（CO）[46,57]。 在使用 联邦贸易委员会方法测定时，Accord 产生 0.1 mg 烟碱和 2 mg 焦油， Eclipse 产生 0.2 mg 烟碱和 4.0 mg 焦油 [46] ； 然而，因为设计不同，且 人的吸烟行为与传统卷烟可能存在差异，要求对这类产品传输的化 学物质和有害成分剂量测定必须进行仔细评估。例如，尽管吸烟机 测定的 Eclipse 中烟碱释放量减少了，吸烟者血液中的烟碱水平与那 些抽吸传统卷烟的类似 [58]。然而，基于尿液中生物标志物的暴露评 价表明，转换到 Eclipse 降低了对烟碱和 NNK 的暴露 [59]。 由制造商雷诺公司报道的早期研究表明，与普通卷烟相比，在 小鼠皮肤中的应用研究中，Eclipse 主流烟气冷凝物的遗传毒性更低 [47]
他们也报道 ，在大鼠鼻腔吸入模型引起的炎症和肺毒性更小 [60] ；
称传换到 Eclipse 降低了吸烟者尿液的致突变性 [61]。在转换到 Eclipse 吸烟者急性效应的一个独立研究中， 吸烟者对 CO 的暴露比普通卷 烟大约增加 30%[46]。 其他的研究表明， 抽吸 Eclipse 烟比传统卷烟 ·129·
烟草制品管制科学基础报告： WHO 研究组第五份报告
吸烟者的抽吸容量更大且频率更高， 已确认呼出 CO 增加 [56,59,62]。 Eclipse 的长期使用者比那些使用此口腔吸入器的人呼出的 CO 高 45% 以 上 [63,64]。Rennard 等 [65] 调 查 了 重 度 吸 烟 者 从 普 通 卷 烟 转 到 Eclipse 2 个月后， 上下呼吸道炎症减轻和显著减少， 虽然该改善还 没有达到非吸烟者的状态。在对当前吸烟者肺上皮细胞通透性、气 道炎症和血白细胞激活的影响研究中，转换到 Eclipse 会降低一些吸 烟者肺泡上皮损伤，但是可能增加碳氧血红蛋白水平和氧化应激 [66]。 在同一研究中，Accord 比普通卷烟降低对 CO 的暴露， 尽管吸烟者 使用 Accord 时，抽吸容量更大，时间更长 [46]。 抽吸 AdvanceTM 卷烟产生更低的 CO“ 呼出 ” ， 但像普通卷烟一 样增加心率 [67]。 从他们平时的常规卷烟品牌转换到 Omni 卷烟 4 周 后，观察到烟草有害物质的摄入量适度的降低 ； 总的 NNAL 水平统 计学显著降低， 但并不包括 1- 羟基芘（PAH 的生物标志物 ） 。 使用 烟碱贴片的吸烟者中总 NNAL 的整体平均水平显著低于用 Omni 卷 烟的吸烟者 [68]。 小鼠胚胎干细胞试验显示 AdvanceTM 烟和传统品牌 卷烟（万宝路红）烟气的毒性相当 [69]。Omni 和 AdvanceTM 卷烟对仓 鼠输卵管功能影响的研究发现，这些卷烟中含有足够量的可抑制生 物学过程的输卵管毒物，很可能会影响生殖结果 [70]。 类似“低焦油”卷烟，Marlboro UltraSmooth 表现出会引起补偿 性抽吸， 尽管它比普通卷烟产生更低的 CO“呼出” 。吸万宝路卷烟 后唾液中可替宁和心脏功能测定与传统的品牌类似，这表明转换到 该品牌不太可能减少对烟气成分的暴露 [53]。 一项整夜停止抽吸普通卷烟， 然后开始抽吸 Eclipse 或 Accord 的研究中，Eclipse 可完全抑制脱瘾症状，而 Accord 效果较差 [46]。对 ·130·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
Eclipse 长期效果的研究表明，它可以减少卷烟消费而不引起脱瘾症 状，降低烟碱释放量或减少整体戒烟的动力 [63,64]。AdvanceTM 产生对 脱瘾症状的抑制，且血浆中烟碱浓度更高，和普通卷烟产品类似 [67]。 A1.5.2.2 在一些国家作为“减害”产品推广的“低焦油”卷烟
目前被禁止的所谓“淡味”的卷烟，包括通过利用空气稀释烟 气来降低吸烟机测定焦油和烟碱释放量的几种要素（例如滤嘴通风 和纸张孔隙率） 。但是，由于吸烟者在烟气烟碱释放量降低时会增加 抽吸强度，这些卷烟没有减少吸烟者对烟草致癌物的暴露，也没有 降低吸烟相关疾病的风险 [71–73]。然而，此类型的卷烟正在中国积极 推进。例如，国家烟草专卖局和中国烟草总公司 2000 年之后的年度 报告提出了“积极推进减害、降焦”的提案 [74]*。
、 自从中国烟草行业推出“ 减害降焦 ” 战略， 据报道 2000~2009 年间全部烟草产量增加了近 40%，主要是由于低焦油卷烟的生产和 销售。在 2011 年的前 10 个月，在中国低焦油卷烟的产量比 2010 年 增加了 408%，而销量增长了 386%[74]。
、 低焦油和低烟碱释放量卷烟的设计是为了在吸烟机的测试时产 生比普通卷烟更低的烟气成分水平。已得到广泛认可的是，吸烟者 和卷烟的相互作用主要是受到吸烟者对烟碱的追求驱使的，因此比 任何基于机器的方案更复杂 [75–77]。为了控制烟碱摄入量，吸烟者调 * 年度报告原文为“减害、降焦” ，该原文的英文译文为“Reducing Harmful Components and Tar in Cigarette Smoke.” ——译注
·131·
烟草制品管制科学基础报告： WHO 研究组第五份报告
整抽吸容量、持续时间、抽吸频率和吸入深度，这影响他们对卷烟 烟气中其他成分的暴露。吸烟者通过封堵滤嘴通风孔减少了空气对 卷烟烟气的稀释，控制他们的烟碱摄入量 [78]。因此，抽吸低焦油卷 烟不能减少吸烟者对烟草致癌物的暴露量，不能降低吸烟引起的疾 病风险 [71–73]。 吸烟者可调整他们的吸烟强度，例如当吸低焦油卷烟时，吸入 更大体积的烟气且吸入更深。因此，由于“低焦油、低烟碱” 卷烟向 用户提供常规烟碱剂量，其致瘾潜力和普通卷烟类似。 在许多国家已经禁止这些卷烟的误导性标识，如“淡味” 。中国 烟草专卖法 5 条规定， “国家应加强对烟草专卖品的科学研究和技术 开发，从而提高烟草制品的质量，降低产品中焦油和其他有害成分 的释放量。 ” 鉴于该要求， 在 2003 年发布的中国卷烟科学技术发展 纲要中，要求制造商截止到 2010 年将卷烟中的焦油水平降低到平均 12 mg。2010 年国家烟草专卖局年度会议报告指出，中国实施“减害 降焦”的战略是提高竞争力的整体方法 [74]*。 A1.5.2.3 低烟碱卷烟
和通过卷烟或滤嘴结构改变实现烟气烟碱释放量改变的“低释 放量”卷烟不同，低烟碱卷烟是使用比传统烟草烟碱含量更低的烟 草制造的。 例如， 一个名为 Quest 低烟碱卷烟，2003 年引入到美国 * 该处文献介绍了 2010 年国家烟草专卖局年度会议报告，内容为“以提高中国烟草整 体竞争力为目标，……，积极实施减害、降焦战略。 ”——译注
·132·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
市场，有三个品种——低烟碱、超低烟碱和自由烟碱。它们含有转 基因修饰的低烟碱烟草， 与正常烟叶混合后的烟碱水平为 0.6~0.05mg/ 支卷烟 [79]，为吸烟者提供逐渐减少烟碱摄入量的机会。此类卷烟中 其他成分的释放量预计与普通市售卷烟类似 ； 因此，从对暴露于有 害物质和致癌观点来看，这些卷烟应该不被视为“减害”产品。然 而，内部的行业文件的分析揭示了烟草行业投入了大量资源发展低 烟碱卷烟 [80] 的原因是其对消费者的吸引力和其在争夺“更健康”产 品的高度竞争卷烟市场中的经济重要性。 吸烟者对 Quest 广告反应 的研究显示了一些关于此类卷烟的虚假信念， 如“低焦油” 、 “更健康” 和“不太可能导致癌症”[81]。 Dutch Magic，一个几乎无烟碱但焦油“正常”水平的卷烟品牌 （＜ 0.04 mg） ， 有望进入荷兰市场（http:/ / www.dutch-magic.com/） 。 根据制造商网站，该产品允许烟民体验抽吸烟草特征味道的卷烟但 没有烟碱成瘾性的影响。该网站还引用了特定目标消费群体 ： 想在 援助下戒烟的人群、偶尔吸烟者、想尝试吸烟但不想上瘾的人，以 及不吸烟或其他目前使用的含烟碱的烟草作为过渡但也不想上瘾的 大麻使用者。Dutch Magic 在 22 世纪公司旗下，根据其公司网站，致 力于开发和商业化消费者可接受的降低烟草产品风险和基于处方的由 一套非常低烟碱卷烟组成的戒烟援助（http ： //www.xxiicentury. com/） 。 该公司试图供应几乎任何烟碱释放量水平的卷烟， 从非常低（约 0.50 mg/ 支卷烟）至高（约 30 mg/ 支卷烟） 。 在转换使用市售低烟碱 Quest 卷烟的研究中， 受试者报道测试 卷烟与他们使用的正常品牌相比，满足感不足且质量较差 [82–84]。
·133·
烟草制品管制科学基础报告： WHO 研究组第五份报告
、 制造商报告 Quest 卷烟中烟碱水平范围在 0.05~0.6 mg/ 支卷烟， 焦油释放量为 10 mg/ 支卷烟 [85]。Chen 等 [86] 基本证实了这些数据， 但有趣的是， 他们发现无烟碱 Quest 烟气中 NNN 水平高于低烟碱 Quest。 对烟草填料的分析发现不同烟碱水平 Quest 产品之间 NNN 水平无显著差异 [13]。一种可能性是，无烟碱卷烟中降烟碱水平更高， 导致在燃烧过程中形成更多的 NNN。然而，将普通卷烟与菲利浦· 莫里斯公司提供的科研用非商业性低烟碱卷烟比较，除了烟碱外的 其他成分水平没有显著差异 [82–84]。 几项研究涉及了转换抽吸低烟碱卷烟吸烟者的卷烟烟气成分暴 露。 在一个 20 名吸烟者的小规模研究中， 在超过 10 周的周期内， 通过改变所抽吸卷烟的类型逐渐减少烟碱水平，CO 和 PAH 的暴露 生物标志物和心血管终点指标不受影响，而排出尿中 NNAL 下降 [83]。 由同一作者的类似研究中使用了 135 名吸烟者和在超过 6 个月的周 期内逐渐减少烟碱 [84]，使用低烟碱卷烟的随机吸烟者的结果与第一 次实验类似。在 Hatsukami 等（2010）的一项研究中，转换使用 0.05 mg 烟碱 Quest 卷烟达 6 周， 可减少致癌物暴露的程度比转换使用 0.3 mg 烟碱卷烟更大。 因为抽吸 0.3 mg 烟碱卷烟有补偿性行为， 而含 有 0.05 mg 烟碱的卷烟未观察到该情况。 尿液中总 NNAL 和 NNN 水平的降低和 Quest 卷烟与普通卷烟相比下 TSNA 水平的降低是一 致的 [13]。0.05 mg 卷烟吸烟者也显示减少暴露于丙烯醛和苯，作者将 其归因于卷烟摄入量的减少 ； 在研究结束时，0.05 mg 组大多数生物 标志物水平与戒烟糖组没有明显差异。Hatsukami 等 [87] 证实了转换 至低烟碱卷烟的吸烟者烟碱和 NNK 摄入量显著减少。 Benowitz 等 [82] 测量抽吸含有不同烟碱单支卷烟吸烟者的心率和 ·134·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
皮肤温度（心血管收缩的测量） ，发现在大约每根卷烟中含 8 mg 烟 碱时，心率增加和皮肤温度降低达到平台，这表明了一个节点水平， 当烟碱水平更高时， 对心血管风险的影响没有明显的变化。 然而， Girdhar 等 [88] 表明吸无烟碱 Quest 3 卷烟比含有烟碱的 Quest 1 导致 更高的血小板活化（心血管风险标志物） 。他们提出烟碱通过非烟碱 烟气成分调节血小板活化。在小鼠胚胎干细胞和正常人支气管上皮 细胞中，Quest 卷烟和常规卷烟毒性一样 [69,86,89]。在动脉粥样硬化的 动物模型中， 暴露于 Quest 3 卷烟的小鼠比 Quest1 卷烟或普通卷烟 烟气 [85] 发展成较小规模的病变。
： 已经提出将降低卷烟中烟碱释放量作为降低其致瘾性的方法 [90] （ 也见附录 2） 。 抽吸利用烟气稀释低烟碱释放量的市售卷烟时， 众 所周知会引起补偿抽吸行为，在抽吸降低烟碱释放量的卷烟时情况 可能不同，或这样的行为可能不是有效的。Benowitz 等 [82] 研究了人 们抽吸低烟碱烟草制备卷烟时，烟碱的摄入量、补偿程度和不同烟 碱效果的剂量—效应关系。每支卷烟 1mg、2mg、4mg、8mg 和 12mg 水平显示与系统烟碱暴露相关。 低烟碱卷烟（1mg、 2mg 和 4mg） 时几乎没有补偿抽吸，与通常品牌相比变化范围从 0% 到 5% ； 这点 通过一氧化碳和焦油的暴露水平得到确认。然而，在更高的烟碱水 平下，8mg 烟碱相应的补偿抽吸增加到 34%，12mg 烟碱的补偿抽吸 增加到 127%，支持如下假设 ： 获得烟碱的难易程度是补偿抽吸程度 的决定因素。Benowitz 等 [83] 在超过 10 周时间内， 也开展了转换到 逐渐降低烟碱释放量卷烟的研究。20 名吸烟者中的 5 人（25%） 自 发戒烟。然而，在更大规模的、使用相同卷烟和设计的长期试验中， 53 名吸烟者中只有 2 名吸烟者转向低烟碱卷烟并最终退出 [84]。因为 ·135·
烟草制品管制科学基础报告： WHO 研究组第五份报告
缺乏烟碱引起的补偿抽吸比早期的单支卷烟试验更严重 [82]，在最低 烟碱释放量卷烟（1mg、2mg 和 4mg）时范围从 20% 到 60%。 Hatsukami 等 [79] 建议，烟碱水平低于 Benowitz 等测试所用水平 的卷烟 [82–84] 可以有效消除补偿行为和促进戒烟。和那些含有 0.3 mg 烟碱的卷烟相比， 卷烟中含有 0.05 mg 水平烟碱不会引起补偿抽吸 行为，且和减少烟碱依赖性，产品脱瘾和显著较高的戒烟率有关联。 在另一项研究报告， 抽吸高焦油、 非常低烟碱卷烟（0.02mg） 时没 有补偿抽吸 [91]。 相反地，Strasser 等 [92] 观察到抽吸极低烟碱卷烟的 补偿抽吸行为 ； 对 0.05 mg Quest 卷烟总的抽吸容量最大。在新西兰 一个大规模的随机对照试验中研究了极低烟碱卷烟对戒烟的效果， 对有意愿戒烟的志愿者，采取单独的标准戒烟治疗与标准戒烟治疗 附加抽吸 Quest 3 卷烟用法进行比较 [93]。 与接受常规戒烟治疗组相 比，分派到 Quest 3 组的志愿者在后续 6 个月的随访中有较高的戒烟 率（33% 比 28%）和较高的持续戒烟率（23% 比 15%） 。此外，分配 给 Quest 3 卷烟组发生复吸的中位值时间为 2 个月，而常规治疗组为 2 周。这些结果表明将极低烟碱卷烟添加到标准戒烟治疗中可能帮助 一些吸烟者戒烟。 已经开展了一些将极低烟碱卷烟和烟碱贴片组合使用的研究。 在一个小规模研究中，志愿者被指定将烟碱或安慰剂贴片和低烟碱 卷烟结合使用 [94]。 分配到极低烟碱卷烟（0.08 mg） 和烟碱贴片的 志愿者报告，两周的研究期间他们仅抽吸了三支他们的正常品牌卷 烟，而那些分配到相同的卷烟但和安慰剂贴片结合使用的志愿者报 告，在同一期间他们抽吸了 46 支正常品牌卷烟。辅助烟碱贴片或安 慰剂时，渴求或脱瘾症状无显著性差异。在另一项研究中，志愿者 被随机分到含有不同水平烟碱贴片并辅以低烟碱卷烟 [95]。分到更高 ·136·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
剂量烟碱贴片的志愿者 表现出吸烟的数量减少更多， （7 mg 或 21 mg） 总的烟气摄入体积和 CO 水平比那些分配到低烟碱卷烟没有药用烟 碱补充剂（安慰剂）相比更高 ； 也观测到在禁欲期能更好地缓解脱 瘾症状。 在最近的一项研究中，Hatsukami 等 [87] 考察了使用极低烟 碱卷烟显著减少吸烟行为的可行性，以及这些卷烟添加烟碱贴剂的 效果。无论是烟碱贴片，还是极低烟碱卷烟（≤ 0.09 mg/ 支卷烟）和 贴片的组合，均导致烟碱摄入比转换到低烟碱卷烟极大增加。和单 独贴片或低烟碱卷烟相比，组合情况也减少脱瘾症状。没有发现烟 碱贴片或低烟碱卷烟对脱瘾症状有差异，分配产品戒烟后各组对渴 望无差异。结果表明极低烟碱卷烟和烟碱贴片组合时可能改善单独 转向任一这些产品的急性效应。 降低卷烟烟碱释放量（但不是完全消除）已经在美国作为一个 发展非致瘾卷烟的潜在管制方法进行探讨。这可能会导致那些不会 再成瘾的吸烟者戒烟，有重要的公众健康益处。这样的政策措施可 能包括对烟碱替代疗法进行补充以促进戒烟。 A1.5.2.4 超细卷烟 超细卷烟比传统卷烟的周长要小很多。超细卷烟在一些国家已销 售很长时间，如美国（如弗吉尼亚州的“Slims Superslims” ） ，但在一 些国家，它们才刚刚出现。在加拿大，许多超细卷烟品牌在 2007 年 开始出现 [96]。超细卷烟的圆周约 17 mm，而传统卷烟的圆周大约为 25 mm，这两种卷烟的包装类似。超细卷烟在销售时没有明显的健康 声明 ； 但是，超细卷烟“细”的包装特征及其更薄的超细品牌设计极 易让消费者认为它们释放物的有害成分释放量低且“危害性小”[96,97]。 ·137·
烟草制品管制科学基础报告： WHO 研究组第五份报告
对加拿大所销售超细卷烟的分析结果表明，由于圆周低、烟草 含量少，超细卷烟的许多成分释放量都要小得多，如一氧化碳、羰 基化合物、挥发性成分及芳香胺等 ； 然而，其他成分的释放量要高 很多，如甲醛和氨等。对于常规尺寸的卷烟来说，所测试成分的释 放量取决于所采用的吸烟机模式。加拿大销售的超细卷烟的烟碱释 放量和其他加拿大品牌差不多，致瘾性也类似。在加拿大，法律已 完全禁止烟草制品所有的广告及推销，这些超细卷烟的引入说明烟 草公司试图利用新的设计和包装及营销手段来吸引消费者 [96]。 欧盟委员会原先提议的欧盟烟草指令对细支烟发布了禁令。然 而，此项禁令已被欧盟议会及理事会废止，最终的欧盟烟草指令没 有对细支烟的管制内容，除了声称要监控包括细支烟在内的一些产 品的营销及消费者认知 [98]。 A1.5.2.5 小雪茄 这种类型的烟草制品在许多国家的销量呈现大幅增长，增长最 大的有中国、德国及美国 [99]。与卷烟不同，小雪茄烟和小雪茄用烟 叶或棕色烟纸卷制而成。 的大小和卷烟类似， 而 “小雪茄烟” “小雪茄” 的大小在卷烟和大雪茄之间 [99,100]。这些产品都没有健康警语。 Maxwell 报 告 [101] 表 明， 世 界 上 最 大 的 小 雪 茄 市 场 —— 美 国， 在 1995~2008 年 间， “little cigars” 增 长 了 316%， “cigarillos” 增 长 了 255%，美国年轻人吸过小雪茄的比例是 26%，这样比小雪茄在整个美 国人中吸过的比例（5.2%）高 [99]。一项对同时消费卷烟及雪茄的情况 调查表明，大约 12.5% 的卷烟消费者使用雪茄，而同时消费卷烟及雪 茄的群体最可能是教育程度较低，失业或失去劳动能力的年轻男人， 非西班牙裔或黑人等 [102]。该研究还表明，同时抽卷烟及雪茄的人比 ·138·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
那些只抽卷烟的人更不易每天抽吸卷烟（比例为 0.57） ，更容易尝试 戒烟（ 比例为 2.39） ， 更容易消费不止一种产品， 如鼻烟、 电子烟、 可溶解烟草制品及嚼烟等（比例为 2.26） 。该研究的不足是，在评估 当前及过去对雪茄的消费情况时，没有将小雪茄和大雪茄区分开 ； 然 而，抽吸小雪茄的人并不认为这些产品是雪茄，而且，该研究使用的 调查问卷使用了知名品牌，这可能提高了调查问卷中雪茄的消费量。 小雪茄比卷烟价格低，风味多样，所以，这可能是它们对年轻 人更有吸引力的原因（相比卷烟来说） 。美国家庭吸烟预防与烟草控 制法案 [103] 为该国烟草制品的管制提供了空前的机遇 ； 然而， 该法 案对小雪茄及雪茄没有限制。2009 年，美国食品药品管理局（FDA） 禁止卷烟中添加调味剂以后，一项针对年轻人的研究表明，18.5% 的 年轻人当前使用经调味的烟草制品 [104]。接近 50% 的“little cigar”消 费者使用调味烟草品牌。 有无滤嘴的小雪茄的烟气中有害物质的水平与加拿大市售卷烟相 同 [105]
。此外，小雪茄烟气相比大雪茄吸入更深，和卷烟烟气类似 [106]。
A1.5.2.6 含本草卷烟 2000 年，多个亚洲国家开始生产同时含有传统本草及烟草的卷 烟。Chen 等 [107] 搜集了 1999~2005 年的多种含本草卷烟 23 种。这些 产品大多在中国生产 ； 然而，2000 年以后，中国台湾地区、韩国及 泰国的烟草公司都开始制作类似的产品。这些产品一般通过向烟叶 中添加本草提取物、将烟叶与本草混合、向烟丝中喷洒本草提取物 或向卷烟过滤材料中添加本草提取物等方式制成。这些卷烟产品大 多宣称可降低有害成分（烟碱、焦油、一氧化碳、致癌物和诱变剂） ， 一些产品声称可减轻呼吸系统不适、保护内脏组织、促进免疫力及 ·139·
烟草制品管制科学基础报告： WHO 研究组第五份报告
辅助戒烟。韩国的含本草烟草宣称可通过烟气的特殊过滤手段，如 添加绿茶儿茶酚，来降低烟气危害性，并“不对吸烟者的肺及喉部 造成危害” ，或可作为一种戒烟手段。在泰国，一种含本草卷烟品牌 据报道，在 “Herbal Krongthip”含有一种传统的本草油来治疗感冒 ； 2002 年，该品牌的销售已停止。 这些卷烟在亚洲市场普遍存在。2005 年，两种含本草卷烟—— 金圣和中南海，被中国国家烟草专卖局列为重点发展的“中国卷烟 36 个重点品牌” 之一。 尽管含本草烟草制品在中国市场的份额还未知， 但是“金圣”品牌 2003 年在中国的年产量为 35 亿支， “中南海”品 牌“ 在 2001 年的无形资产达到 2.44 亿美元” 。 据报道， 中国含本草 卷烟品牌“五叶神”也在美国加利福尼亚州旧金山市销售 [107]。 亚洲的一些含本草烟草品牌含有一系列主要的添加剂，而其他 品牌含有多种本草的混合物，而这些都没有被披露。Chen 等鉴别的 23 种含本草品牌中，只有四种只含有本草 [107]。该研究表明，在这些 卷烟中，有 18 种本草列有添加剂名单，而“金圣”是最普遍的，其 次是“Apocynumvenetum” 。这些卷烟中本草含有的生物活性成分的 效力是未知的。例如，洋金花 *（中国“洋金花”品牌中含有的一种 抗胆碱本草）被认为是中草药引发的大多数中毒事件的原因，而一 些人参的制备过程中可能掺入东莨菪碱。 中国台湾地区、日本及泰国的控烟机构也开始关注含本草烟草 制品的健康声明 [107]。 A1.5.2.7 比迪烟 比迪烟原产于印度，但也向美国出口，据报道，在美国年轻人 * 洋金花，1959 年至 20 世纪 70 年代早期药材公司委托以适量的洋金花等中药材配以 烟叶卷制而成，用于治疗哮喘。——译注
·140·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
中比迪烟的消费比例高得惊人 [108-110]。比迪烟是一种较小的手工制作 的褐色卷烟， 含有烟草薄片， 由 或 “temburni” （一种硬木） “tendu” （一 种乌木）的叶子卷制而成，并由小线绳绑起来。因为比迪烟是由人 工卷制而成，它们之间的烟草含量是不同的。比迪烟有过滤型和非 过滤型，过滤型的包装纸中含有少量的棉花。比迪烟风味十足，包 装鲜艳亮丽，在美国市场上基本没有其他类似产品。这些风味包括 葡萄、樱桃、草莓、 丁香、香草、肉桂、 豆蔻、悬钩子、 黑甘草、柠檬、 覆盆子、芒果、薄荷和巧克力等 [109,110]。 在美国， 人们特别是小孩和年轻人对抽吸比迪烟的“ 新鲜感 ” 已经引起注意。据报道，当前比迪烟的美国成年消费人群中，接近 三分之二的年龄低于 25 岁。在这些年轻人中，男人、黑人及当前吸 烟者的比迪烟消费比例较高 [110]。大量消费者认为，比迪烟比传统卷 烟口感更好，价格便宜，易于购买（12%） ，且更安全（13%）[109]。 比迪烟的烟气分析结果表明，其烟气焦油、烟碱和一氧化碳的 释放量很高。相比传统过滤型卷烟，比迪烟滤嘴并不能较少烟气中 的焦油、烟碱和一氧化碳释放量。抽吸比迪烟比传统卷烟的肺癌及 其他癌症的风险更大，如口腔癌、咽癌和食道癌等。 A1.5.3 水烟 在许多文化中， 水烟有多种消费形式， 如水烟筒（narghile） 、 水烟袋（hookah） 、阿拉伯水烟（shisha） 、 “goza” 、 “hubble-bubble” 、 “argeela”等。它们是非洲和亚洲原住民的烟草消费传统方法。 A1.5.3.1 产品描述和营销策略 所有类型水烟的普遍特性是烟气被人体吸收之前会经过水。水 ·141·
烟草制品管制科学基础报告： WHO 研究组第五份报告
烟一般使用高度调味的烟草， 并将其放到水烟的“ 头部 ” ， 上面再 放置木炭。抽吸水烟时，会在水上产生一个真空环境，使经木炭加 热的空气通过烟草，所以吸入气体会含有蒸发的烟草成分和木炭燃 烧产物 [111]。电加热的“木炭”也可作为木炭的替代品（一些网站上 有 发 现， 如 http://www.hookah-shisha.com/p-15165-blazn-burner-fasthookah-charcoalburner.html)。水烟通常是甜味的，并加入有调味剂， 所以它们的口感较好，平顺，柔和，并易于吸入 [112,113]。水烟的烟草 价格很低，一般没有健康警示，还含有其成分的误导信息。它们通 常被设计成一个看似无害的产品， 如茶叶、 咖啡、 口香糖或糖果。 人们在抽吸水烟时， 还抽吸非烟草成分 [112] ；例如， 一些品牌（ 如 Starbuzz, Shiazo, Bigg, Om, Angel, Bump’n Grind 等 ） ， 含有蒸汽核和 多孔核，这些核含有香气，但不含烟碱。 A1.5.3.2 消费者意识、产品使用和认知 过去的十年里，在中东国家，水烟在年轻人中愈发流行，并向 其他国家快速传播 [114]。 水烟在澳大利亚及美国中东部地区也很流 行，在欧洲地区也是这样，尽管在欧洲中东部的一些国家不太流行， 如丹麦、爱沙尼亚、德国和瑞典 [115]。根据欧盟的一项调查，欧盟有 1% 的人经常使用水烟（0%~2%） ，4% 的人偶尔使用（0%~10%） ，有 11% 的人尝试过一到两次（3%~30%）[116]。在我们的调查问卷中，许 多欧盟国家报告水烟的消费量有增长，但没有定量。 水烟在学校及大学学生中特别流行 [115]。 英国的一个国家调查显示， 水烟在医学院的学生之中较流行，这和他们的地域无关。学生及成年 人一般认为，水烟的危害性比卷烟小 [113,117]。水烟的流行可能反映出与 年龄相关的流行趋势，这需要开展进一步研究 [115]。水烟在年轻人之间 ·142·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
还有社交功能，大部分这些年轻人在公司中分享并抽吸水烟 [112,113]。 A1.5.3.3 成分、毒性和疾病风险 水烟的烟气由木炭加热过的空气通过烟草后形成，其成分和卷 烟烟气中的成分类似， 包括烟碱、 丙二醇、 丙三醇、 烟草特有亚硝 胺、一氧化碳、稠环芳烃 [118] 及醛酮类化合物如甲醛、乙醛和丙烯醛 等 [119]。由于木炭燃烧加热并通过烟草，水烟的一氧化碳和稠环芳烃释 放量尤其高。水烟烟气中的一氧化碳释放量比卷烟烟气高 30 倍 [118]， 而水烟消费人群血液中一氧化碳的生物标志物（碳氧血红蛋白）的 含量要比卷烟消费人群含量 4 倍 [120]。 到 2011 年， 由抽吸水烟引起 的一氧化碳中毒事件有 6 件 ；这些病人的碳氧血红蛋白含量达到 20%~30%[121]。尽管水烟烟气中的烟碱浓度比卷烟烟气高，但 24 小时 血液烟碱含量反而比卷烟低，这很可能是因为消费者每天也抽几根 卷烟 [118]。生物标志物研究也表明，和卷烟相比，水烟和超低烟碱摄 入量、高一氧化碳暴露量及不同的致癌物暴露模式相关 [122]。水烟还 会产生大量高浓度有害颗粒物的环境烟气，并导致了二手烟风险。 水烟和肺癌、呼吸系统疾病及低出生率紧密相关，并和膀胱癌、 喉癌和口腔癌也有关系 [115]。水烟烟气的致癌性并不让人感到意外， 因为它含有甲醛和乙醛等羰基化合物，甲醛是一种人体致癌物 [123]， 而乙醛是一种可能的人体致癌物 [124]。丙二醇和丙三醇在水烟烟气中 的释放量比实验研究中能引起不良反应的释放量要高很多，这应引 起注意。这两种化合物能引起呼吸系统中的黏液分泌杯状细胞含量 增高，并会刺激喉部 [118]。 A1.5.3.4 潜在致瘾性 水烟会导致烟草及烟碱致瘾，但比卷烟更具有间歇性 [113,125]。尽 ·143·
烟草制品管制科学基础报告： WHO 研究组第五份报告
管水烟烟气中的烟碱释放量比卷烟烟气中高，但其血液中的 24 小时 烟碱浓度却更低 [118]。 A1.5.3.5 管制方面的考虑 在原本不抽水烟的人群中，水烟的使用量似乎在增加。消费者 以为水烟危害性小，没有致瘾性，但实际上水烟烟气和卷烟烟气的 一些有害物质释放量差别不大， 一些释放量甚至还高出安全范围， 如一氧化碳。可告知这些人水烟的危害性、致瘾性和有害物质的暴 露量，以期能影响这些人对水烟的看法 [126]。尽管水烟烟草通常受到 管制，但水烟烟管及其配件却没有管制 [114]。此外，本草水烟烟草不 受控烟及室内空气清洁等相关法律的管制，所以，在大多数国家里， 水烟都可以在室内抽吸。加拿大和土耳其是例外。 A1.5.4 对传统烟草制品的显著改变 许多元素都被引入传统烟草制品的组成和结构改变中。 因此， 被监管的产品（如湿鼻烟或卷烟）本身不是新的，但特定品牌所做 出的改变可能会对个人及公众健康带来新的风险。现在可以对预测 烟草制品改变造成的影响，所以烟草制品管制提出具有前瞻性的措 施。下面，我们将探讨一些近期传统烟草制品的改变。 A1.5.4.1 降低烟草含量的瑞典鼻烟 在我们的调查中，我们收到了一项来自瑞典的报告，该报告声 称， 一种名为“Loonic” 的鼻烟中含有多种烟草含量占产品总重量 逐渐降低的型号： 75% (Loonic No.1)，50% (Loonic No.2)，25% (Loonic ·144·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
No.3) 和 0% (LoonicNo.4)。该产品的网址（http://www.loonic.se/index. php/en）显示，该产品的其他物质是茶叶。 “Loonic”中，烟草含量 降低， 烟碱含量也随之降低。就像“Quest”系列卷烟那样， “Loonic” 的广告语是 “为那些减少吸烟或彻底戒烟的人而生” 。产品描述声称， 不含烟碱的型号“Loonic No.4” 但加入了瓜拿纳、 “不含烟草或烟碱， 维生素 B12 和叶酸” 。这种产品似乎是针对现在的鼻烟消费者，且并 没有健康声明。 A1.5.4.2 含有生物活性添加剂的湿鼻烟 “Revved Up Energy Dip” 在 2008 年 由 位 于 美 国 佐 治 亚 州 的 南 方 无 烟 气 烟 草 公 司 引 入。 根 据 产 品 网 站 的 介 绍（http://www. southernsmokeless.com/Revved-up.html） ， “Revved Up”是一种含有维 生素 B、 维生素 C、 咖啡因、 人参及牛磺酸的长条状无烟气烟草制 品， 有薄荷和冬青口味。该产品声称能够提高灵敏度、 注意力及活力。 在美国鼻烟的推销过程中， “Revved Up” 被描述成“ 谨慎享受无烟 气烟草制品” 但是，它却被主要宣传成能够提高注意力和活力。浏 ； 览该网站产品的人主要有军人、公务员（警察、消防员等）以及运 动员。该产品声称“Revved Up”使用的烟草“比烤烟中的致癌物含 量低 65%” ，这意味着它们能够降低暴露量或风险。 A1.5.4.3 滤嘴中的薄荷醇胶囊 具有传输致瘾性物质新技术的卷烟已经在日本和美国出现，并 在一些欧盟国家中有销售 [127]。卷烟滤嘴中嵌入进一个含有风味成分 的胶囊，吸烟者可通过挤压这个胶囊将调味剂释放到烟气中。这种 新颖的设计好像对年轻人有特殊的吸引力，而这种产品的营销也主 ·145·
烟草制品管制科学基础报告： WHO 研究组第五份报告
要针对这些人群。 在土耳其，含有薄荷醇胶囊的卷烟是允许销售的，因为它们符 合烟草及酒精市场管制机构的技术要求。然而，官方授权的科学委 员会正在根据 WHO FCTC 及国家法律对这类产品进行调查。 芬兰国家福利及健康监管机构报告，地方零售商在推出可以通 过按压来释放清新口味（薄荷及绿薄荷）的卷烟品牌，并与烟草公 司达成一致，将这些产品最先推销给消费者。 新的欧盟烟草指令 2014/40/EU(98) 禁止销售那些在其任何部位含 有调味剂的烟草制品，如滤嘴、纸、包装、胶囊或任何能改变该产 品或其烟气气味及口味的技术。此外，滤嘴、纸盒胶囊不能含有烟 草或烟碱。新法案于 2014 年 5 月开始实施，欧盟成员国有两年的时 间对本国的法律进行修改，以符合新法案的要求。 A1.5.4.4 无添加卷烟或有机卷烟 在一些国家， “天然”卷烟广告声称无添加剂 [128]。 “Natural American Spirit”(http://www.von-eicken.com/en/) 和 “Manitou”(https://www.nascigs.com/) 的包装上分别有美国印第安人 圆锥形帐篷及印第安人抽吸长杆烟斗的照片，以示卷烟和细切烟草 已经在美国市场上存在很多年了。一个类似的产品是 “Sioux” （http:// www.von-eicken.com/en/） 。所有这些品牌都只含有弗吉尼亚烟叶。烤 烟叶，如弗吉尼亚烟叶，含有 20% 的天然糖分，这在很大程度上决 定了消费者的接受度 [128-130]。 根 据 它 的 网 站 介 绍（www.poeschl-tobacco.com)， 普 韦 布 洛 （Pueblo） 烟草是一种高质量的混合烟草。 它的名字“Pueblo” 就 像“Natural American Spirit” ， “Manitou” 和“Sioux” ，都代表一种 ·146·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
传统的美国文化，这个文化包含烟草在成为工业品之前的起源。因 此，这种名字能引起一种传统、真实和自然的感觉。西班牙提供了 Pueblo 的销售情况，表明该产品的市场份额只有 0.1%（在 176 种品 牌中排 68 位 ） ， 然而细切卷烟 Pueblo- 白肋烟混合型产品要更受欢 迎， 市场份额达到 9.6%（在 112 种品牌中排 3 位） 。网络显示（http:// yesmoke.eu/blog/tobacco-shag-natural-organic/） ，这种产品也是意大利 最受欢迎的细切卷烟品牌。 西班牙也有一种卷烟品牌， 名叫“Yuma Organic” ， 含有 100% 的 有 机 烟 草， 不 含 杀 虫 剂 和 添 加 剂。 它 们 的 网 站（http://www. yumaorganic.com/） 宣传到 ： “ 选择有机产品， 保护环境。 ” “Yuma” 支持有机农业。该产品并不受欢迎，只占到市场份额的 0.0001%（在 176 种品牌中排 162 位） 。 几 年 前，Camel 和 Lucky Strike 也 推 出 过 不 加 添 加 剂 的 品 牌 ： “Camelnatural flavour”和“Lucky Strikeadditive-free” ，并使用褐色纸 包装。不含添加剂的纯烟草品牌似乎在迎合那些对自然有机产品感 兴趣的消费者。一些消费者认为那些不含添加剂的卷烟“对身体危 害小 ” （ 如 http://answers.yahoo.com/question/index?qid=200902121117 36AAiemjg） 然而，这类产品依然释放来自烟草中的致癌物和其他有 ； 害化合物 [129]。 A1.5.4.5 产品名称的品牌化 西班牙报道了两种有品牌名称的细切烟草产品 ： “自卷式美国混 合型烟草， 给那些不需要该品牌告诉其他人它是什么的人们”和“自 卷式弗吉尼亚混合型烟草，给那些不需要该品牌告诉其他人它是什 么的人们” 。这种品牌名称作为广告和促销手段来吸引人们假装“自 ·147·
烟草制品管制科学基础报告： WHO 研究组第五份报告
信”和独立。因为这些品牌名称已经被欧洲专利局授权，所以卫生 部门也难以阻止这些产品的营销行为。 A1.5.4.6 低烟味卷烟 关于专利记录的一项研究表明， 有超过 100 项和测流烟气相 关的专利， 包括改善烟气气味和降低能见度等 [131]。 有关国家报 道， 日本烟草国际公司曾要求官方允许其向市场推出一种新的产 品： “Winston XS” ， 这种卷烟产品“ 烟气味较淡 ” （ 见 http://www. cigarettestime.com/cigarettes-articles/winston-xs） 。
A1.6 发展中的技术 越来越多的烟草制品， 特别是卷烟， 正在或将要被推向市场， 并声明它们能降低烟气中有害物质的暴露量。这些潜在降低暴露量 产品（PREP）包括烟草生产过程、滤嘴或设计的改变。烟草公司开 展并发布了很多研究，以证明其减害声明。应该开展独立研究，以 对这些声明进行调查研究，如产品可以降低烟气有害物质释放量水 平的声明，降低毒性的声明，降低人体暴露生物标志物含量的声明， 降低疾病发生生物标志物的声明，以及在对比临床试验的实验组中 能够通过感官评价的声明等。在评估吸烟机测试结果时，需要考虑 个体真实的吸烟行为，因为人的吸烟过程是一个复杂的过程，包括 抽吸容量、抽吸时间、抽吸间隔、每支烟的抽吸次数及总抽吸体积 等 [132]。 因此， 人的抽吸行为与普遍使用的吸烟机模式都不同， 如 ISO 模式和加拿大深度抽吸模式。ISO 模式为 ： 抽吸体积为 35 mL， ·148·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
抽吸间隔为 60 s，总抽吸体积为 455 mL，不堵塞通风口。加拿大深 度抽吸模式为 ： 抽吸体积为 55 mL，抽吸间隔为 30 s，总抽吸体积为 715 mL，堵塞通风口。建议通过单位毫克烟碱释放量来校正吸烟机 抽吸结果，以降低标准方法之间的差异 [133]。 接下来将评估一系列 PREP，以考察这些产品是否会降低卷烟主 流烟气中的有害物质释放量，以及释放量的降低是否会降低疾病风 险。由于这些大部分产品都不在市售，所以会基于它们的成分、毒 性和潜在风险对其进行描述和说明。不对这些产品的致瘾性进行说 明。PREP 是在烟草制造过程中滤嘴和 / 或设计改变的烟草制品，因 此也归烟草制品管制。 A1.6.1 代替传统卷烟燃烧的加热技术 产品描述 ： 世界上最大的烟草公司之一，菲利浦·莫里斯国际 公司，计划到 2017 年推出一种据说能够降低健康风险的新型卷烟产 品 [134]。该公司声称，这种新型产品加热而不是燃烧烟草，其有害物 质释放量会降低 95%。该公司宣称该“最有前途的低危害产品”通过 加热烟草产生气溶胶供消费者吸入，并准备好接受临床试验 [134]。我 们的研究表明，荷兰和罗马尼亚期待菲利浦·莫里斯国际公司新产品 的问世。该公司认为 2014 年欧盟烟草指令中在包装上标注健康声明 的要求不适用于此产品，只用文字表示产品具有致瘾性就已足够 [135]。 和菲利浦·莫里斯国际公司计划投入市场的产品类似的卷烟是 Ploom 销售的产品及雷诺公司销售的“Premier”和“Eclipse”卷烟。 总的来说，还需要提供加热非燃烧产品减害和有益健康声明的令人 信服的证据，以及支持这些声明的更好的方式 [136]。用于传统卷烟的 ·149·
烟草制品管制科学基础报告： WHO 研究组第五份报告
方法，如吸烟机测试方法，可能需要加以改变或开发新的方法，因 为这些新产品的抽吸行为、物理和化学性质（特别是吸入的气溶胶） 及更长的暴露时间和传统卷烟是不同的。一些科学家认为这些新的 卷烟产品的危害性和传统卷烟是一样的 [137]。 A1.6.2 烟草加工工艺和滤嘴结构的改变 A1.6.2.1 含碳纤维或醋酸纤维滤嘴的烟草替代薄片
英美烟草公司设计了几种 PREP，其中之一是一种含有烟草替代 薄片（TSS）的实验卷烟，该卷烟在加热的时候会释放出甘油。TSS 的成分包括碳酸钙、甘油、海藻酸钠和焦糖。这种产品有双重功能 ： 降低产品中的烟草含量，从而降低烟气有害物质释放量 ； 释放到卷 烟主流烟气中的甘油会稀释卷烟燃烧产生的包含有害物质的粒相物。 这些实验卷烟还有包含分散的活化双层碳纤维或醋酸纤维的滤嘴。 和仅靠滤嘴区分于传统卷烟的“淡味型”卷烟不同，这些实验卷烟 烟草含量低 含有 30%~60% 的 TSS 和不同设计的滤嘴 （40%~70%） ， （双 层碳纤维或醋酸纤维滤嘴，通风率为 0%~55%） 。
、 烟气化学、毒理学评估及初级人群实验已经用来对 TSS 制成的 实验卷烟进行测试 [138]。英美烟草公司宣称，含有双层碳纤维或醋酸 纤维及 TSS 的实验卷烟可降低主流烟气的烟气成分释放量水平，而 且，滤嘴也能降低粒相物释放量 ： 醋酸纤维滤嘴能选择性降低一些 酚类化合物的释放量，而双层碳纤维能够降低额外的挥发性化学成 分。这种产品没有健康声明。这些实验卷烟主流烟气的分析结果表 ·150·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
明，除了一些挥发性成分外，大部分所测定成分的释放量都有降低。 进行了一些研究时体外毒理学研究，如细胞毒性试验、诱变实验及 染色体损伤实验等。在所有的实验中， “Silk Cut King Size”过滤嘴卷 烟都被用来做对照卷烟，这种卷烟在吸烟机模式下的无水粒相物释 放量和实验卷烟相同， 且不含烟碱。4 种实验卷烟分别含有 60% 的 TSS/ 醋酸纤维滤嘴、60% 的 TSS/ 双层碳纤维滤嘴、 含 50%TSS 及 2.5% 甘油的烟草混合物以及双层碳纤维滤嘴。在诱变实验中降低程度最 高的是含有 60%TSS 及醋酸纤维素滤嘴的实验卷烟。 这些实验中所 用的总粒相物并没有包含所有的化合物，如挥发性化合物。 人体暴露量是通过分析抽吸市售卷烟和实验卷烟的滤嘴， 以 及分析抽吸卷烟后的 24 小时暴露生物标志物来进行评估的， 实验 卷烟的无水粒相物释放量与市售卷烟相近， 且不含烟碱， 并含有 60%TSS/ 醋酸纤维滤嘴。 所提供给吸烟者的东西包括一天的卷烟产 品，搜集尿液样品的的容器以及搜集吸烟滤嘴的容器。据估计，抽 吸实验卷烟人群的每日口腔烟碱暴露量要在统计上低很多。滤嘴测 试结果表明，烟碱每日暴露量降低了 14%，而 24 小时尿液生物标志 物测试显示降低了 14%。滤嘴测试结果表明， 烟气成分暴露量平均 降低了 29%，尿液 NNAL 测试结果表明，NNK 暴露量降低程度与滤 嘴类似。尿液的烟碱生物标志物及 NNAL 的代谢量也有所降低。这 些暴露生物标记物代表相应的每种烟气有害成分，并和烟气暴露量 有关。没有效应生物标志物的报道。在一个感官评价实验中，允许 受试者抽吸实验卷烟或者是他们自己的品牌“ad libitum” 结果发现， ， 实验卷烟的接受度不如吸烟者自己的品牌。 尽管有报道声称这种卷烟降低了体外细胞毒性和基因毒性，但 是，还没有现成方法可以用来预测这种降低能否根本上降低疾病风 ·151·
烟草制品管制科学基础报告： WHO 研究组第五份报告
险，以及这种稀释效应能否和吸烟者的健康风险有生物相关性。尽 管已经提出了几种模式， 但是还需对这些模式进行进一步研究 [139-141]。 生物标志物研究表明，需要更长时间以及可能更多的参与者来评估 实验卷烟吸烟者尿液中的生物标志物。与传统卷烟相比，实验卷烟 只有一部分烟气有害物质释放量下降，且其感官接受度较低。 A1.6.2.2 烟草混合物处理及含有功能化树脂或碳的滤嘴
英美烟草公司开发了一种实验卷烟，这种产品对烟草混合物进 行了处理，包括加入水提取物、蛋白酶处理、过滤掉提取物的多肽、 氨基酸以及多酚等，并将提取物和处理过的烟草再次结合 [142]。该公 司宣称这种处理方式能够降低卷烟主流烟气中的有害物质释放量。 含有活性炭和 / 或树脂吸附剂的选择性滤嘴能有效降低挥发性有害 物质释放量。
、 “Silk Cut King Size” 过滤嘴卷烟和实验卷烟具有相同释放量的 吸烟机生成的不含烟碱的干燥粒相物成分，和这种卷烟相比，烟草 混合物经处理的卷烟中蛋白氮（59%） 、多酚（33%~78%）及烟碱 [12] 释放量低，但糖类释放量高（16%） 。测定了 ISO 模式下含有再造烟 叶的卷烟主流烟气中的 43 种有害成分释放量。结果发现，下列成分 的释放量较低 ： 氨类（27%） 、芳香胺（34% ～ 38%） 、吡啶（23%） 、 喹 啉（21%） 、 氰 化 氢（41%） 、TSNA（10% ～ 18%） 、 酚 类（42%） 及镉（79%） ；然而， 下列成分释放量显著增高 ：甲醛（79%） 、苯 并 [a] 芘（13%） 、乙醛（16%） 、丙酮（12%） 、丙烯腈（26%） 、丙醛 （21%） 、巴豆醛（12％） 、甲基乙基酮（16％） 、异戊二烯（4％） 、苯 ·152·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
乙烯（19％）和铬（42％） 。该产品测流烟气中的含氮有害成分、醛 酮类化合物、苯并 [a] 芘及异戊二烯释放量升高。烟草混合物的处理 和挥发性化合物及醛酮类化合物（特别是甲醛和异戊二烯） PAH（苯 、 并 [a] 芘）以及一些重金属（镉）释放量的升高有关。含有活性炭和 / 或树脂吸附剂的选择性滤嘴能有效降低这些挥发性有害成分的释放 量。但这些实验只报告了 ISO 模式，有必要和加拿大深度抽吸模式 进行对比。此外，也没有开展毒理学测试。 暴露生物标志物是通过 6 周、 单中心、 单盲、 有对照、 强制 交换的临床试验来进行评估的，所使用样品为经过混合烟草处理的 焦油释放量为 1 mg 的卷烟 [143]。 实验发现， 烟气生成量（ISO 模式 下的主流烟气）及暴露生物标志物都有所减少，有时候甚至明显降 低（ > 80%） 。 主流烟气及 4 种 TSNA 中的 3 种生物标志物含量的降 低和主流烟气释放量降低 85%~96% 以及暴露生物标志物含量降低 81%~87% 是一致的 ； 然而， 烟气中 NNK 的释放量降低 83% 和其暴 露生物标志物平均含量降低 49% 不一致。造成这种差异的原因可能 是由于 NNAL 半衰期比较长，而其他未代谢的 TSNA 的半衰期较短。 这些发现对长期健康风险 的评估将不会停止。 （不是效应生物标志物） 在开展接受度、满意度及口感等感官评吸过程中，再造烟叶的多数 感官评吸项目中得分都很低。接受度在 4 周后好像有所改善，但仍 不及参比卷烟。 检测的 43 种有害物质只代表卷烟主流烟气中大约 5000 种化学 成分的一小部分。烟气有害成分释放量和健康风险的关系还没有科 学共识。为评估降低有害成分释放量对健康风险的关系，需要开展 毒理学评估及临床实验。在暴露生物标志物研究中，不同个体之间 的差异很大，这说明个体吸烟行为和代谢行为都有差异。我们需要 ·153·
烟草制品管制科学基础报告： WHO 研究组第五份报告
烟气的暴露生物标志物，就像我们当前所接受的那样，大多数广泛 使用的生物标志物只针对几种化合物。尽管有报道声称这类产品中 卷烟主流烟气中的一些有害物质释放量及暴露生物标志物含量显著 降低，但是，通过评估这些再造烟叶卷烟中主流烟气的大部分致癌 物释放量，目前尚无让人信服的证据证明这类产品能降低风险。 A1.6.2.3 烟草替代薄片和两段式碳滤嘴的结合
为了降低吸烟机模式下卷烟主流烟气中特定有害物质或一组 有害物质释放量， 英美烟草公司通过整合相关技术， 开发了一种 最具有希望的实验卷烟， 这种卷烟包括 80% 美国混合型烟草，20% 烟 草 替 代 薄 片 以 及 一 种 含 有 80 mg 聚 合 物 碳 纤 维 的 两 段 式 滤 嘴 （20%TSS/80 mg 碳滤嘴） 。
、 这种实验卷烟在 ISO 模式和加拿大深度抽吸模式下的主流烟气 总有害物质释放量要比对照卷烟低 [144]。未评估这种主流烟气释放量 降低的卷烟对疾病的影响，Fearon 等 [139] 使用了一种心血管疾病的 体外毒理学试验对一种原型卷烟进行了测试，这种原型烟在 ISO 模 式下的焦油释放量为 6 mg。在这种内皮损伤修复实验中，参比卷烟 主流烟气粒相物对内皮细胞的迁移有抑制，其创伤修复与烟气浓度 呈负相关关系，然而，原型烟的粒相物对内皮细胞迁移的影响比参 比卷烟降低了 22%，其创伤修复效果也更好 [59]。在这个实验中，卷 烟主流烟气粒相物不包括诸如挥发性成分在内的化合物，而且只是 用了一种减害评估模式。由于心血管疾病的复杂性，这些实验结果 不能被外推到人类，而且需要更多的研究来确定这些体外生物变化 ·154·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
能否反映生物有机体内的疾病变化。 暴露生物标志物是通过 6 周、单中心、 单盲、有对照、 强制交 换的临床试验来进行评估的。 有研究比较了两种卷烟， 一种是 ISO 模式下的 1 mg 焦油卷烟（TSS1） ，该卷烟含有烟草替代薄片以及含 有碳、 氨基功能化树脂和醋酸纤维素的三级滤嘴， 一种卷烟是 ISO 模式下的 6 mg 焦油卷烟（TSS6） ，该卷烟含有烟草替代薄片以及没 有氨基功能化树脂的两级滤嘴 [143]。和参比卷烟（ “Silk Cut King Size” 过滤嘴卷烟，吸烟机模式下的粒相物释放量相同且不含烟碱）相比， TSS1 所测定所有有害成分释放量都较低，尽管每种有害物质的降低 程度不同。暴露生物标志物的降低程度也不同，且一部分含量有所 升高。主流烟气成分家暴露生物标志物的变化一般是不一致的 ； 例 如，一些 TSNA，如 NNK，其中的释放量降低，而 NNAL 的含量却 升高。对于 TSS6 来说，在研究末期，除了总烟碱当量和 4- 羟基菲， 所有暴露生物标志物含量都有所降低。除了 4- 氨基联苯、1- 羟基芘、 2- 羟基菲、3- 羟基菲和 4- 羟基菲外，所有化合物的降低程度都很明 显。降低最明显的是挥发性化合物，如巴豆醛降低 75％，丙烯醛降 低 45 ％，1,3- 丁二烯降低 63 ％。TSNA 暴露生物标志物含量降低了 10%~26%。 由此可知， 抽吸 TSS1 和 TSS6 后暴露生物标志物含量一 般是降低的，但是卷烟主流烟气的成分降低情况往往与暴露生物标 志物的降低情况不一样。个体间所测定暴露生物标志物差异很大。 尽管没有效应生物标志物的报道，曾有方法通过评估和 1,3- 丁 二烯相关的癌症及其他疾病变化来评估抽吸 PREP 时化合物所引起 的风险改变 [130]。选择这种化合物的原因是该化合物是 WHO 提议降 低释放量的有害成分之一 [133]。20%TSS/80 mg 碳滤嘴所引起的健康 风险的改变最明显。尽管癌症（白血病）的变化最明显，但是还不 ·155·
烟草制品管制科学基础报告： WHO 研究组第五份报告
足以因此说该产品（减低疾病风险） 。对于非致癌作用（如子宫萎缩 等） ，20%TSS/80 mg 碳纤维模式所产生的 1,3- 丁二烯释放量对健康 没有影响 [130]。 作为 6 周、单中心、单盲、有对照、 强制交换的临床试验的一 部分，通过 TSS 降低有害成分释放量的模式在接受度、满足感及口 味等感官评析中不如对比卷烟 [143]。一般来说，对大部分评吸模式来 说，参与者所反馈的结果是该卷烟的接受度与参比卷烟持平或略低。 研究 4 周之后，这种卷烟的接受度有所升高，但依旧比参比卷烟低。 尽管与传统卷烟相比，TSS1 和 TSS6 在吸烟机模式下的有害成分释 放量较低，还需要更多的研究来确定这些产品是否能降低健康风险。 还需要更多的抽吸 PREP 的志愿者的生物标志物研究， 并需要改善 其制造工艺。至于体外毒理学试验，我们对与心脑血管疾病发病相 关的特定烟气成分以及实验结果对身体健康影响的了解还很少。在 生物标志物研究中，个体间差异较大，这可能是由于个体吸烟行为 及个体间代谢行为的差异所造成的。因此，就算群体暴露生物标志 物平均含量可能降低，但这并不意味着群体所有成员的疾病风险都 会降低。因为该研究是无止境的，所以这些产品的长期健康效应依 旧是未知的。 A1.6.3 滤嘴结构的改良 A1.6.3.1 滤嘴中的氨基功能化离子交换树脂
英美烟草公司开发的另一种实验卷烟是在滤嘴中加入氨基修饰 的离子交换树脂 [145]。该滤嘴中含有一种基于聚苯乙烯的多孔阳离子 ·156·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
交换树脂（Diaion®CR20） ， 这种树脂表面含有能与烟气中的醛酮类 化合物和氰化氢反应的氨基官能团。该公司宣称，滤嘴中的树脂能 够升高卷烟主流烟气中的蒸汽压（ 特别是甲醛 ） ， 并降低有害成分 释放量。
、 英美烟草公司对其开发的实验卷烟进行了测试，这种卷烟的滤 嘴中含有 60 mg 的 Diaion®CR20， 在 ISO 模式和加拿大深度抽吸模 式下，其主流烟气中甲醛释放量降低量超过 50%（估计代表烟气气 相物中超过 80% 的甲醛总量 ） ， 氰化氢释放量降低超过 80%， 乙醛 释放量降低超过 60%。在 6 个月的试验周期中，树脂活性保持不变。 Diaion®CR20 是被特别设计来捕获常温下具有高蒸汽压的烟气有害成 分，例如甲醛、乙醛和氰化氢 ； 尚不清楚这种材料能否降低其他化 合物的释放量。尽管报道表明一些烟气成分释放量会降低，但是一 些其他有害成分的释放量在加拿大深度抽吸模式下会升高，如丙酮 和 2- 丁酮。这种卷烟也没有经过毒理学评估、暴露或效应生物标志 物测试和感官质量评价。 A1.6.3.2 滤嘴中的钛酸盐纳米片、纳米管和纳米线材料 中国福建中烟工业有限公司对滤嘴中添加钛酸盐纳米片、纳米 管和纳米线材料来降低卷烟主流烟气中的有害成分释放量进行了评 估 [146,147]。尽管两篇文献都报道了有害成分释放量的降低，但是，将 有害成分释放量通过单位毫克烟碱标准化后，纳米片材料没有降低 有害成分释放量效果，纳米管材料只降低了一部分有害物质释放量 （如氨、对苯二酚、邻苯二酚和苯酚等）[146]。因为第二篇文献没有报 道烟碱释放量，所以纳米线材料对 TSNA 的吸附效果还无法评估。 ·157·
烟草制品管制科学基础报告： WHO 研究组第五份报告
这种卷烟没有经过毒理学评估、暴露或效应生物标志物测试和 感官接受度评价。需要进一步研究这些纳米颗粒是否会被转移到主 流烟气中，而如果转移的话，还需评估钛酸盐纳米颗粒对肺部及其 他器官直接暴露的健康效应。 A1.6.3.3 活性炭滤嘴
烟草公司宣称活性炭滤嘴能够降低卷烟主流烟气中的有害物 质释放量， 美国疾病控制与预防中心对其进行了评估 [148,149]。 烟草 公司宣称，因为活性炭长期以来都被用于除去水及空气中的挥发性 有机化合物，所以它对卷烟主流烟气应该会有同样的效果。美国疾 病控制与预防中心对这种活性炭滤嘴进行了评估，其活性炭含量在 45 ～ 180 mg，并分散在滤嘴中或在滤嘴的小腔体中。
、 测定对象为卷烟主流烟气中的焦油、烟碱、一氧化碳、乙醛、丙 烯醛、苯、苯乙烯和总共 22 种挥发性有机化合物。和类似的不含活 性炭的过滤性卷烟相比，活性炭滤嘴卷烟的主流烟气中总挥发性有 机化合物的释放量降低（在 ISO 模式和加拿大深度抽吸模式下） 。然 而，释放量的降低并不仅仅取决于添加活性炭的含量，还取决于通过 滤嘴的烟气量。尽管一种含有 45 mg 活性炭的品牌在 ISO 模式下烟气 挥发性有机化合物释放量有所降低，在更深度抽吸模式下（如加拿大 深度抽吸模式） ，其活性炭含量会达到饱和并有质的改变。总的来说， 即使在深度抽吸模式下，活性炭含量最高的品牌能最有效降低挥发性 有机物释放量。在 ISO 和加拿大深度抽吸模式下，含有 33 mm 滤嘴、 43% 滤嘴通风率，0.5 g 烟草及 120 mg 活性炭的品牌，其测定烟气成 ·158·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
分释放量相对较低。初步研究结果表明，和挥发性有机化合物相比， 其他重要但挥发性不强的成分（如 TSNA 和 PAH）释放量不受影响， 或释放量降低程度相对较小 [148]。Hearn 等 [149] 指出，活性炭滤嘴选择 性地除去卷烟主流烟气中的低相对分子质量 PAH，但不能显著去除更 重更有害的 PAH，如一种已知的致癌物，苯并 [a] 芘。同样地，活性 炭滤嘴可不同程度地除去卷烟主流烟气中的酚类化合物和 TSNA，这 取决于化合物特性、滤嘴设计及抽吸模式。在一定的抽吸模式下，卷 烟滤嘴中足量的活性炭能够除去很多挥发性有机物，并可能降低特定 半挥发性化合物的释放量。挥发性不强的化合物在粒相物中占有很大 比例，和主要在气相物中的挥发性成分相比，并不容易被活性炭滤嘴 选择性去除。 烟草公司没有报道任何关于这些卷烟的毒理学测试结果。 活性炭滤嘴对暴露生物标志物的影响在一个含有 39 名吸烟者的 随机、正交、2 周可品牌调换的研究中加以评估 [150]。20 名参与者抽 吸醋酸纤维滤嘴卷烟，其他 19 名参与者抽吸活性炭滤嘴卷烟。这两 种类型卷烟含有相近的吸烟机抽吸焦油和烟碱。在第 2 周，参与者互 相交换卷烟。 交换卷烟过程中， 每日抽烟支数、 呼出气体一氧化碳含量、 唾液可替宁含量以及尿液烟碱当量 （烟碱和 5 种主要代谢物的总含量） 并没有明显变化。抽活性炭滤嘴卷烟的志愿者尿液中的 3- 羟基 -1- 甲 基丙基硫醚氨酸（巴豆醛的代谢物） 、单羟基丁烯基硫醚氨酸（1,3- 丁 二烯的代谢产物）和 S- 丙基硫醚氨酸（苯的代谢产物）明显较低 ； 3羟基丙基硫醚氨酸（丙烯醛的代谢物）含量的降低并不显著。其他硫 醚氨酸和硫醚（硫醚用于测定对亲电性化合物的暴露总量） ，在抽吸 活性炭滤嘴卷烟人群样品中的含量没有降低或略有降低 [143]。总的来 说，与含有类似焦油或烟碱释放量的醋酸纤维滤片卷烟相比，活性炭 滤嘴卷烟并不能改变一氧化碳或烟碱摄入量，但能显著降低烟气毒性 ·159·
烟草制品管制科学基础报告： WHO 研究组第五份报告
相关成分如丙烯醛、巴豆醛、1,3- 丁二烯和苯的释放量 [150]。活性炭滤 嘴能否通过降低卷烟主流烟气中的特定化合物释放量来降低健康风险 仍是未知的。仅有的生物标志物实验 [150] 还是一项没有参照组的研究。 丙烯醛和丁烯醛也是内源性脂质过氧化的产物，但还不清楚哪种烟气 成分会提高它们的浓度。研究评估的人数很有限 [39]，因此还需要更多 的志愿者参与，以确定生物标志物的研究结果。烟草公司没有对使生 物标志物和感官质量进行评估。 A1.6.4 2013 年 CORESTA 会议所展现的研究进展 2013 年，烟草制品科学研究合作中心（CORESTA）烟草科学及 产品技术会议在西班牙塞维利亚召开，并就烟草减害问题展开讨论， 其内容总结如下 *。这些总结并不给出全面或绝对的综述结果，但给 出了烟草制品技术研究的主要趋势， 包括滤嘴技术、TSS 及有害物 质的形成机理等。 A1.6.4.1 烟草添加剂 中国云南瑞升烟草技术（集团）公司展示了一项研究，该研究 通过向烟草再造薄片引入氧化铁等纳米材料来降低烟气成分释放量， 如焦油、 一氧化碳、 苯并 [a] 芘和 NNK 墙报 13） 。但是， （口头报告 16， 该研究没有列出卷烟类型以及成分释放量通过烟碱归一化后是否还 会降低。 该公司还报告，通过添加烟梗颗粒物，可以降低一些烟气成分 * 从烟草制品科学研究合作中心（CORESTA） 网站发布的摘要中获得。http://www. coresta.org/Meetings/CORESTA-Abstracts/Seville2013-SmokeTech.pdf. ——译注
·160·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
释放量， 但不影响产品感官质量（口头报告 52） 。添加 8% 的梗颗粒， 可以将主流烟气中的焦油释放量降低 32%， 烟碱释放量降低 32%， 铬释放量降低 28%， 镍释放量降低 17%， 镉释放量降低 53%， 铅释 放量降低 28%， 汞释放量降低 17%。 因为烟碱的降低幅度比其他有 害成分都大，如果吸烟者渴求摄入一定量的烟碱，在抽吸此类含有 颗粒梗的卷烟时，实际上会暴露于更多的有害物质。 A1.6.4.2 滤嘴添加剂 云南瑞升烟草技术（集团）公司还做了一项关于向卷烟滤嘴中 添加聚酰胺桥连硅胶的报告（口头报告 17） 。这种吸附剂能够选择性 降低苯酚、巴豆醛和氰化氢的释放量 ； 但对烟碱的影响没有报道。 中国湖南中烟工业有限责任公司和郑州烟草研究院报告，但相 对于烟碱来说，常规的醋酸纤维滤嘴能够选择性地降低七种酚类化 合物的释放量（口头报告 31） 。 中国江苏中烟工业有限责任公司报告了在卷烟中应用一些表面 经氯化钯等金属氧化物修饰的活性炭纤维滤嘴（ 墙报 12） 。 根据该 类产品的研究结果，其焦油、苯酚、邻苯二酚及巴豆醛释放量下降 ； 但没有列出烟碱释放量变化情况。 A1.6.4.3 前体研究 郑州烟草研究院报告了氰化氢形成的前体物质（主要是蛋白质） 和 4- 氨基联苯的一些主要前体物质（口头报告 56） ，日本烟草国际 公司报告了热裂解条件对这些化合物形成的影响（口头报告 57） 。关 于热裂解前体物质及机理的研究可对开发新的减害产品提供帮助。
·161·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A1.7 总 结 在过去的十年里，一系列新型烟草制品及技术被推向国际市场。 这些新型烟草制品包括非加热型产品，如可溶解烟草产品及新型鼻 烟，以及加热非燃烧的改进型卷烟产品和类卷烟产品。 A1.7.1 非燃烧型口用产品 自可溶解烟草制品第一次引入美国市场以来，这些产品变化明 显， 包括包装及配方等（ 图 1.1） 。 尚不清楚这些产品是否能在美国 市场上长期存在或向国际市场传播。相比较而言，新型鼻烟在美国 市场上越来越受欢迎 [25]。 然而， 在美国或其他国家可能制造的鼻 烟产品应和传统的瑞典鼻烟区别开来。美国生产的鼻烟与瑞典制造 的鼻烟在含水率、包装袋大小、烟碱含量以及其他成分含量都不同 [15,34,151]
。此外，最近骆驼（Camel）鼻烟产品较高的 TSNA 含量表明，
美国制造的这种鼻烟产品在烟草类型或 / 和烟草加工过程都和瑞典 鼻烟不同。一些研究人员建议在美国和其他国家复制“瑞典经验” ， 这需要谨慎对待。此外，新型非燃烧烟草制品之间成分含量相差较 大 [15,33]，这可能是由于试销市场实验方法和 / 或产品重复生产的不同 造成的。必须对这类产品继续加以监控，因为该类产品只是处于市 场测试阶段，会不断加以改变，并有新产品被不断引入。 在美国，一些新兴烟草制品，如鼻烟和可溶解烟草制品的营销 手段包括产品分配， “教育”新消费者如何使用该类产品，以及发布 让人觉得该类产品只是试用品的信息。这些策略表明，现有鼻烟营 ·162·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
销手段在吸引新的消费人群，并鼓励消费者长期使用该产品。在原 来的烟草公司秘密文件中显示，这些公司所作的消费者调查坚定地 支持我们这一假设 [152-154]。尽管制造商坚称没有对其可溶性产品进行 营销，或吸引消费者，这些研究关注那些类似“糖果”的烟草产品， 并提醒消费者谨慎使用这类产品，这些说法可能吸引儿童或未成年 人，并可能提升此类产品的消费量及毒性 [10]。这些产品也含有多种 口味，以前的研究表明，年轻人更容易消费经调味的烟草产品 [104]。 产品包装可能在烟草公司的营销策略中发挥重要作用。 在美国，非西班牙裔、白人、男人及年轻吸烟者更倾向于使用 新型烟草制品 [155-158]。年轻人倾向于注意那些接受度高、方便、有吸 引力、现代、有趣、有娱乐功能以及便于隐藏的新型鼻烟和可溶解 烟草制品 [159]。吸烟者和非吸烟者都声称， 有机会时会使用这些产品。 尚不清楚哪些人正在使用这些市售可溶解烟草产品，以及这些产品 大规模上市时哪些人会使用它们。例如，人群统计结果表明，年轻 人和怀孕的妇女可能会比其他人更可能使用可溶解烟草制品。如果 是这样的话，需要更好地理解哪些和产品设计和营销因素会使这些 产品吸引特定人群。有限的研究表明，可溶解烟草制品尽管在人群 中具有一定的知名度，但对其尝试和感兴趣的人还很少，知道这些 产品最多的人群是年轻人和男性吸烟者 [5]。吸烟者倾向于信任那些 直接或间接暗示危害小、相对安全的的产品 [160-162]。因此，尽管吸烟 者普遍对鼻烟和可溶解烟草产品的口味不满意，但是他（她）们还 是可能愿意使用这些产品，以降低产品的危害性 [162,163]。可溶解烟草 制品和鼻烟也可能吸引那些不使用烟草的新消费人群。需要对测试 市场上人们对可溶解烟草制品和鼻烟的态度进行严格的监督，并给 控烟专家提供相关数据，以制定相应的管制政策 [30]。 ·163·
烟草制品管制科学基础报告： WHO 研究组第五份报告
对美国市场上使用卷烟及无烟烟草制品人群的国家级评估表明， 这些同时使用两种产品的消费者一般是年轻白人男性，这和对鼻烟 和可溶解烟草产品感兴趣的人群类型是一样的 [164,165]。这些同时使用 两种产品的消费者没有打算戒烟，并在不能吸烟的场所使用无烟烟 草制品。鼻烟广告实际上鼓励同时使用卷烟和鼻烟，例如促使无烟 烟草制品作为现有卷烟品牌的补充。同时使用两种产品对公众健康 的影响尚不清楚，但可能会增加烟草相关发病率和死亡率的风险 [24]。 最 开 始 的 可 溶 解 烟 草 制 品 和 鼻 烟 的 TSNA 含 量 比 近 期 型 号 低 [13,15,18,33]
。因此，通过比较“Ariva”和医药烟碱贴片，两者烟草特
有致癌物的含量是类似的 [14]。在老鼠口腔黏膜变化的长期暴露实验 中，所有 4 种无烟烟草制品都能引起异常 ； 然而， “Stonewall”比传 统的湿鼻烟引起的黏膜变化异常都要低，这和具有低亚硝胺含量的 烟草可能引起人体较少的癌症发生率的推断是一致的 [166]。例如鼻烟 和可溶解产品等火燃烧型烟草制品相比卷烟传输更少烟碱，使其使 用者避免暴露于 CO， 表明较少的有害物质暴露 [41]。 然而， 和传统 无烟烟草制品相比，可溶解烟草制品中的 TSNA 和其他有害成分含 量从低很多到含量相当的产品都存在 [13,15-17]。 美国开展了一项国家级的有代表性的研究，这项研究选取了 1836 名有代表性的当前或以前吸烟者，并对替代烟草制品，如鼻烟和可溶 解烟草制品的使用情况，以及这类产品的消费及戒烟目的和意愿之间 的关系展开了研究。没有证据表明这些产品能够促进戒烟 [167]。新型 鼻烟即可溶解烟草制品通常在消除戒断症状方面不是特别有效 [41,43]， 尽管含有更多烟碱的口含型烟草制品在减少和停止卷烟抽吸方面比 那些烟碱含量少的产品更有效。还需要开展研究来确定含有更多烟 碱的鼻烟会使人上瘾，就像斯堪的纳维亚吸烟者使用鼻烟来戒烟那 ·164·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
样 [168]。许多研究表明，与烟碱疗法相比，使用这些产品的烟碱暴露 量低，对烟碱渴望及戒断症状的缓解程度相当或更小 [42]。在人们对 这种产品的健康影响更了解之前，应该向那些渴望戒烟或使用低危 害产品的消费者推荐烟碱疗法。 在欧洲，除瑞典外，烟草制品指令禁止了鼻烟。欧洲允许那些 外观上和鼻烟类似但作为口嚼烟草制品售卖的新型产品。一些欧盟 成员国正在讨论管制这类烟草制品。 戒烟领域的大多数研究人员认为，使用如鼻烟之类的低亚硝胺 含量、非燃烧烟草制品能降低对那些完全转向消费此类产品的吸烟 者的危害性 [169]。例如，流行病学研究表明，只是用瑞典鼻烟和低的 癌症风险有关 [37,38]。 一组专家对与使用低亚硝胺含量口含无烟烟草 制品相关的死亡风险进行了综述，并得出结论 ： 消费者的死亡风险 相对平均值为 5%~9%，这取决于吸烟者的年龄 [169]。和吸烟相关的平 均风险约为 ： 肺癌为 2%~3%，心脏病为 10%，口腔癌为 15%~30%。 专家估计，使用低烟碱无烟烟草制品消费者与吸烟者相比，其 相对健康风险降低至少 90%。一组专家通过评估低亚硝胺含量无烟烟 草制品对卷烟消费的潜在影响，总结认为，经过较好管制的无烟烟草 制品的引入，可能只在一定程度上降低吸烟量，并增加美国对无烟气 烟草制品的消费量 [170]。然而，这种产品的影响力受多种因素的影响， 如吸烟者使用该产品的意愿，扩大该产品消费人群的可能性，以及对 该类产品化学物质的有力管制等。世界范围内的无烟烟草制品的致癌 性特征不同，在那些地方市售产品中致癌化学成分含量较高的国家， 如果要推广无烟烟草制品来进行减害，是不合适的 [171-173]。对无烟烟 草使用和疾病风险的流行病学研究的结果取决于所用的产品和研究的 人群。此外，不同国家，其文化、社会和经济情况不同，推进减害策 ·165·
烟草制品管制科学基础报告： WHO 研究组第五份报告
略的影响也不同，特别是在中低收入及高收入国家之间 [173]。 A1.7.2 卷烟和类卷烟装置 烟草公司开发出了很多种 PREP 卷烟和类似卷烟的装置， 如那 些加热非燃烧烟草制品。与传统卷烟相比，尽管这些产品中的一部 分能够降低生物标志物水平， 但不能明显降低疾病风险和致瘾性。 总的来说， 这些产品的营销是失败的， 很少人关注它们 [175]。然而， 美国“降低暴露量”卷烟的营销在吸烟者之间引起了高度关注，这 表示那些不愿意戒烟的“ 关注健康 ” 的吸烟者以及重度吸烟者可 能特别受烟草公司宣传的影响，这些产品也会成为他们戒烟的替代 品 [176]。 从以前关于“潜在降低暴露”卷烟的综述文献中我们可以看到， 这些产品通过加热而不是燃烧烟草，不能有效降低暴露量。这些产 品一氧化碳的暴露量可能比传统卷烟还要高。此外，因为烟草烟气 含有超过 4000 种化学成分， 其中 69 种是已知致癌物， 通过降低有 限数量的致癌物含量，可能并不能够降低健康风险，并可能会影响 烟气中其他致癌物的释放量水平 [175]。向卷烟滤嘴中引入新材料也引 起类似的关注，这可能引入的新化合物对吸烟者健康风险的影响还 未知。 一些地区市场中“低焦油”卷烟的流行也应受到关注。不同释 放量卷烟的实际焦油暴露水平类似，也没有发现抽吸低焦油释放量 卷烟有健康益处。然而，一些国家依旧在推行降焦策略，如中国。 低烟碱卷烟被认为是一种降低卷烟致瘾性的有价值尝试，并会 降低烟气有害成分的暴露量。吸烟者通过抽吸极低烟碱释放量的卷 ·166·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
烟（< 0.05 mg） ，可能会使吸烟者补偿抽吸最低， 卷烟消费量减少， 成瘾性降低，并有利于戒烟 [87]。然而，并不清楚这些常年的吸烟者 会由于缺乏烟碱而进行补偿抽吸，因为所有的证据都是来自小规模 实验。此外， “低烟碱”卷烟可能会误导消费者，使其认为这种卷烟 “低害”或“更健康” 。对烟草公司的资料进行详细阅读发现，这种 对消费者认知上的误导是发展低烟碱卷烟的基础 [80]。可以明显看到， 烟草公司在寻找定义并引导一个“更健康”卷烟的新的市场，这个 市场对那些“懒人”可能具有吸引力。当前低烟碱释放量卷烟很少， 但是在不久的将来，其市场可能扩大。 细支烟这一新兴市场应受到关注，因为细支烟的外观主要为女 性吸烟者设计，其外观容易被人误认为是一种低危害卷烟 [96]。烟草 公司在卷烟包装形状、 大小及开口对消费者感知影响的文件表明， 包装不仅和一流品质和顺和口感有关，还会影响消费者对减害的感 知。此外，细的、圆形的、椭圆形的、小包装及一般的新包装对年 轻人有特别的吸引力 [177]。 含本草卷烟应受到关注，特别是在亚洲，该地区药用作物的使 用已经持续了几个世纪，这使该地区的人们比其他本草接受度低的 国家更容易受到这类产品健康声明的影响和误导 ； 此外，亚洲媒体 广泛引用那些未经证实的科学依据， 来支持这类卷烟的健康声明。 必须对这些声明进行充分研究和严格控制。 城市里的年轻男人， 特别是学生， 更容易使用那些替代产品， 如比迪烟 [108,178]。年轻人中比迪烟的使用率偏高可能是这种群体处于 青春期，对新产品比较好奇的结果 ； 因此，比迪烟可能是卷烟管制 的一个尝试。戒烟及控烟必须考虑到这些新兴的产品。 水烟中的烟气在吸烟者吸入之前，首先通过甜的经调味的烟草， ·167·
烟草制品管制科学基础报告： WHO 研究组第五份报告
然后通过水。水烟消费量在普遍增长 ； 这类产品传统上在非洲和中 东地区很流行，现在正在传播到全世界。它在在校大学生中特别流 行。应该开展不同年龄组的研究，以确定水烟的流行是否和年龄有 关。水烟中含有许多卷烟中也有的大量的有害物质和致癌物 ； 因此， 水烟不是无害的，而是和包括癌症在内的许多疾病有关。需要特别 关注水烟在有烟草和无烟草状态下的高一氧化碳释放量，因为一氧 化碳主要是由于炭的燃烧引起的。使用水烟后的一氧化碳中毒事件 也有报道。2013 年 10 月召开的首届国际水烟大会 [179] 为阻止水烟的 全球化发展， 提出了几项建议 ： 对水烟抽吸及误解的教育和沟通 ； 支持和评估阻止年轻人抽吸水烟及鼓励戒烟的计划 ； 禁止调味水烟 产品 ； 在清洁室内空气法案中添加水烟的内容 ； 更有效的警示标识， 增加税收，限制年轻人获取水烟，禁止水烟广告以及营销行为。 欧洲已经出现了卷烟设计及营销行为的明显变化。宣称只含有 自然烟草、不含添加剂的卷烟及细切烟草品牌已经在市场上存在多 年。 近期， 如骆驼及“Lucky Strike” 等大品牌也开始推出不含添加 剂的品牌。这种趋势可能是由于人们对天然、有机产品的不断关注， 以及卷烟添加剂和产品制作有关，且预计在将来烟草添加剂将会被 更严厉地管制。有些卷烟产品在滤嘴中添加有胶囊，而这种胶囊能 向烟气中释放调味剂，如薄荷醇等 ； 然而，在正在制定中的新的烟 草产品法令中，包括这种胶囊的添加剂可能不再允许添加到滤嘴中。 具有“较淡烟气气味”的卷烟正在市场上销售，这可能提高不吸烟 人群对吸烟的接受度。 不断增多的新型烟草制品正在或将要被推向市场，这些产品声 称能够降低烟草烟气中的有害成分暴露量。 这些 PREP 包括对烟草 加工工艺、滤嘴及设计的改变。大多数支持这些产品减害声明的研 ·168·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
究都是烟草公司开展并发表的。有一些证据证明，产品设计的改变， 如加入 TSS、混合烟草的处理及不同类型的滤嘴（Diaion®CR20、碳 纤维、醋酸纤维、CR20L 和聚合物碳纤维等） ，能够降低卷烟主流烟 气中的有害物质及暴露生物标志物含量。 最受关注的 PREP 是一种 含有 20%TSS 和 80 mg 碳纤维滤嘴的卷烟， 这种卷烟能够显著降低 暴露生物标志物含量 ； 然而，这些实验卷烟在大多数感官评析种类 中的接受度和参比卷烟相比要接近或明显较低。这种卷烟在 4 周后 的接受度又提高，但依然比参比卷烟稍低。当钛酸盐纳米颗粒加入 到卷烟滤嘴中后，主流烟气中的有害物质释放量没有变化。活性炭 滤嘴能够显著去除气相物中的化合物，如挥发性有机物、酚类化合 物和 TSNA， 但是在去除粒相物中的挥发性不强的成分时， 其效果 不太好。总的来说，和含有类似焦油和烟碱释放量的醋酸纤维滤嘴 卷烟相比，抽吸活性炭滤嘴卷烟并不能降低一氧化碳及烟碱的释放 量，但能显著降低烟气中的毒性相关成分，如丙烯醛、巴豆醛、1,3丁二烯和苯。仅有几项研究对生物标志物进行了测定，而且所测定 生物标志物的数量也很少。因为卷烟烟气中含有超过 5000 种化合物， 仅测定一部分暴露生物标志物不足以评估卷烟主流烟气中的所有有 害物质暴露量。效应生物标志物可能能够更好地判定降低卷烟主流 烟气中的一部分有害成分能否降低烟草相关疾病。这种方法的局限 性在于不能够判定能否通过降低卷烟主流烟气中的有害成分及暴露 生物标志物释放量来降低疾病风险。 尽管吸烟机模式下这些 PREP 主流烟气中的有害成分释放量比传统卷烟低，但还需要更多的研究 来证明这些产品和低的健康风险有关。 在评估 PREP 降低健康风险 的效力时，必须考虑人们的抽吸行为，有害成分释放量，以及设计 改变能否真正降低暴露量，还是仅仅是对安全性能的错误认识。 ·169·
烟草制品管制科学基础报告： WHO 研究组第五份报告
PREP 降低危害性的证据还不充分。吸烟机模式下主流烟气有害 成分释放量的降低并不相应反映出暴露生物标志物的降低，而且还 需要进一步研究暴露生物标志物和疾病风险之间的关系。 到目前为止，还没有足够证据表明当前市场上的改进型卷烟或 加热不燃烧产品等是一种“减害”产品。Pankow 等使用风险评估模 式对吸烟者转而消费 PREP 卷烟的结果进行评估， 发现这种产品和 传统卷烟相比，其肺癌发生率降低 2%。消费者没有接受任何一种含 有烟草的替代卷烟产品，这些产品的市场周期都很短，所以不可能 评估这些产品对吸烟引起死亡率和致病率的任何影响。必须对普通 大众、政策制定者及卫生专家们进行培训教育。例如，对美国护士 的一项烟草减害感知研究中，这些人普遍认为“淡”的卷烟和不含 添加剂的卷烟相对安全，并还有一些其他对烟草的误解，这会使他 （她）们在治病过程中对患者提供一些错误的建议 [180]。 在烟草减害过程中，降低烟草制品有害成分暴露量及致瘾性都 是很重要的。但是，必须注意的是，降低暴露量可能提供给消费者 一个卷烟安全的错觉，进而可能推动卷烟消费，而降低致瘾性可能 会导致补偿抽吸的发生。有研究表明，含有极低烟碱释放量的卷烟 不会导致补偿抽吸，并可能是降低暴露量的一个可行的途径。一项 就烟草制品致瘾性和有害性的健康影响研究建立了美国人口随时间 的年龄及性别特征吸烟行为变化的计算模型，研究发现，烟草制品 致瘾性及危害性的降低将会对公众健康及寿命产生重大影响 [181]。
A1.8 结 论 在过去的十年里，进入全球市场的新型烟草制品及技术之间差 ·170·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
异很大。烟草公司研究表明，在将来，会有更多的产品产生。需要 开发能够评估这些新型烟草产品的更好的方法，进而开展相关研究， 来为控烟提供指导，并了解这些产品对公众健康的影响。 大部分烟草制品对公众健康的影响是不清楚的。 对这些产品 的主要关注方面有 ： 潜在的没有被发现的毒性 ； 对新的消费者不断 增强或持续的吸引力，对已戒烟者复吸的影响和现在可能戒烟的吸 烟者的消费行为的影响 ；新型烟草制品和卷烟的同时使用 ；通过 一种新型的“入门”烟草制品使人们开始吸烟，进而使之开始抽吸 卷烟。 未来的研究需要关注新型烟草制品的毒性（通过产品分析、烟 草相关暴露及毒性生物标志物的测定） 、致瘾性及它们是如何被接受 及消费的。这些研究成果将帮助决定这些产品是否会在一个人群水 平降低或引起个体的危害。
A1.9 致 谢 我们感谢荷兰国家公共卫生与环境研究所（RIVM，荷兰比尔特 霍芬）健康防护中心 Anne Kienhuis 博士在水烟相关段落中的贡献。 我们感谢明尼苏达大学（美国明尼阿波利斯）Robert Carlson 先 生在编辑方面给予的帮助。 感谢以下人士对背景文章撰写的贡献，感谢他（她）们在我们 的问卷调查中给我们提供的其国家新型烟草制品的有价值的信息， 他（她）们是 ： 瑞士联邦家庭事务部（伯尔尼）公共卫生办公室消费者保护委 ·171·
烟草制品管制科学基础报告： WHO 研究组第五份报告
员会 Michael Anderegg 西班牙平等、卫生与社会服务部（马德里）公共卫生、质量与 改革理事会健康促进与流行病学处秘书长 Teresa Cepeda 新加坡卫生科学局应用科学组药学分部卷烟测试实验室 Nuan Ping Cheah 罗马尼亚卫生部（布加勒斯特）Magda Ciobanu 意大利卫生部（罗马）公共卫生与改革司 Daniela Galeone 博士 马耳他环境卫生部（ 瓦莱塔 ） 环境卫生政策协作司 Dorianne Grech 印度 Healis Sekhsaria 公共卫生研究所（孟买） Prakash C. Gupta 德国化学品与兽医调查办公室（锡格马林根）Jürgen Hahn 爱沙尼亚国家卫生发展研究所（塔林）Tiiu Härm 芬兰国家卫生与福利研究所（赫尔辛基）Antero Heloma 博士 塞浦路斯卫生部医疗与公共卫生服务司（尼科西亚）Herodotos Herodotou 捷克共和国卫生部卫生服务司（布拉格）Lenka Kostelecka 芬兰国家福利与卫生监督管理局（赫尔辛基）Sofia Kuitunen 和 Linda-Maria Viitala 挪威卫生部（奥斯陆）Rita Lindbak 英国卫生部（伦敦）Lee McGill 瑞典国家公共卫生研究所（ 厄斯特松德 ） 监督管理部 Karin Molander Gregory 南斯拉夫国家公共卫生研究所（萨格勒布）Ljiljana Musli 博士 葡萄牙国家烟草消费预防与控制计划健康理事会（ 里斯本 ） Emília Nunes ·172·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
爱尔兰卫生部（都柏林）健康促进司 Helen O’Brien 巴西国家卫生监督管理局（ 巴西利亚 ）Andre Luiz Oliveira da Silva 斯洛伐克共和国卫生部（布拉迪斯拉发）欧盟事务与国际关系 司 Stela Ondrušová 德 国 卫 生 与 食 品 安 全 巴 伐 利 亚 州 办 公 室（ 埃 朗 根 ）Helga Osiander-Fuchs 博士 土耳其烟草与酒精销售管制局（安卡拉）Nuray Akan Yaltirakli
A1.10 参 考 文 献 [1] Zeller M, Hatsukami D, Strategic Dialogue on Tobacco Harm Reduction Group.The Strategic Dialogue on Tobacco Harm Reduction: a vision and blueprint for action in the US. Tob Control 2009;18:324– 32. [2] Colilla S. An epidemiologic review of smokeless tobacco health effects and harm reduction potential. Regul Toxicol Pharmacol 2010;56:197– 211. [3] Hatsukami DK, Henningfield JE, Kotlyar M. Harm reduction approaches to reducing tobacco-related mortality. Annu Rev Public Health 2004;25:377–95. [4] Statement of principles guiding the evaluation of new or modified tobacco products. Geneva: Scientific Advisory Committee on Tobacco Product Regulation, World Health Organization; 2003 (http://apps. ·173·
烟草制品管制科学基础报告： WHO 研究组第五份报告
who.int/iris/handle/10665/42648,accessed October 2014). [5] Southwell BG, Kim AE, Tessman GK, MacMonegle AJ, Choiniere CJ, Evans SE, et al. The marketing of dissolvable tobacco: social science and public policy research needs. Am J Health Promot 2012;26:331–2. [6] Rainey CL, Conder PA, Goodpaster JV. Chemical characterization of dissolvable tobacco products promoted to reduce harm. J Agric Food Chem 2011;59:2745–51. [7] Rainey CL, Berry JJ, Goodpaster JV. Monitoring changes in the chemical composition of dissolvable tobacco products. Anal Methods 2013;5:3216–21. [8] Seidenberg AB, Rees VW, Connolly GN. RJ Reynolds goes international with new dissolvable tobacco products. Tob Control 2012;21:368–9. [9] Centers for Disease Control and Prevention. State-specific secondhand smoke exposure and current cigarette smoking among adults—United States, 2008.Morbid Mortal Wkly Rep 2009;58(44). [10] Romito LM, Saxton MK, Coan LL, Christen AG. Retail promotions and perceptions of RJ Reynolds’novel dissolvable tobacco in a US test market.Harm Reduction J 2011;8:10. [11] Caraballo RS, Pederson LL, Gupta N. New tobacco products: do smokers like them? Tob Control 2006;15:39–44. [12] Connolly GN, Richter P, Aleguas A, Pechachek TF, Stanfill SB, Alpert HR.Unintentional child poisonings through ingestion of conventional and novel tobacco products. Pediatrics 2010;125:896–9. [13] Stepanov I, Jensen J, Hatsukami D, Hecht SS. Tobacco-specific ·174·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
nitrosamines in new tobacco products. Nicotine Tob Res 2006;8:309– 13. [14] Mendoza-Baumgart MI, Tulunay OE, Hecht SS, Zhang Y, Murphy SE, Le CT, et al. Pilot study on lower nitrosamine smokeless tobacco products compared to medicinal nicotine. Nicotine Tob Res 2007; 9:1309–23. [15] Stepanov I, Biener L, Knezevich A, Nyman AL, Bliss R, Jensen J, et al.Monitoring tobacco-specific N-nitrosamines and nicotine in novel Marlboro and Camel smokeless tobacco products: findings from round I of the New Product Watch. Nicotine Tob Res 2012;14:274– 81. [16] Watson C. Quantitative and qualitative analysis of dissolvable tobacco products. Report to the Food and Drug Administration Tobacco Scientific Advisory Committee, 18–22 January 2012. Rockville, Maryland: Food and Drug Administration; 2012. [17] Stepanov I. Toxic and carcinogenic constituents in dissolvable tobacco products. Report to the Food and Drug Administration Tobacco Scientific Advisory Committee, 18–22 January 2012. Rockville, Maryland: Food and Drug Administration; 2012. [18] Lawler TS, Stanfill SB, Zhang L, Ashley DL, Watson CH. Chemical characterization of domestic oral tobacco products: total nicotine, pH, unprotonated nicotine and tobacco-specific N-nitrosamines. Food Chem Toxicol 2013;57:380–6. [19] Hatsukami DK, Jensen J, Anderson A, Broadbent B, Allen S, Zhang Y et al.Oral tobacco products: preference and effects among smokers. ·175·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Drug Alcohol Depend 2011;118:230–6. [20] Kotlyar M, Hertsgaard LA, Lindgren BR, Jensen JA, Carmella SG, Stepanov I,et al. Effect of oral snus and medicinal nicotine in smokers on toxicant exposure and withdrawal symptoms: a feasibility study. Cancer Epidemiol Biomarkers Prev 2011;20:91–100. [21] Connolly GN. The marketing of nicotine addiction by one oral snuff manufacturer. Tob Control 1995;4:73–9. [22] Summary: TPSAC Report on Dissolvable Tobacco Products (Rep. No. March 1, 2012). Silver Spring, Maryland: Food and Drug Administration, Tobacco Scientific Advisory Committee; 2012. [23] Biener L, Bogen K. Receptivity to Taboka and Camel Snus in a US test market.Nicotine Tob Res 2009;11:1154–9. [24] Bahreinifar S, Sheon NM, Ling PM. Is snus the same as dip? Smokers’ perceptions of new smokeless tobacco advertising. Tob Control 2013;22:84–90. [25] Delnevo CD, Wackowski OA, Giovenco DP, Bover Manderski MT, Hrywna M,Ling PM. Examining market trends in the United States smokeless tobacco use:2005–2011. Tob Control 2013;22:266–73. [26] Timberlake DS, Pechmann C, Tran SY, Au V. A content analysis of Camel Snus advertisements in print media.Nicotine Tob Res 2011;13:431–9.149. [27] Gany F, Rastogi N, Suri A, Hass C, Bari S, Leng J. Smokeless tobacco: how exposed are our children? J Community Health 2013;38:750–2. [28] Wackowski OA, Lewis MJ, Delnevo CD. Qualitative analysis of Camel Snus’ website message board—users’product perceptions, insights ·176·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
and online interactions. Tob Control 2011;20:e1. [29] Choi K, Forster J. Awareness, perceptions, and use of snus among young adults from the upper Midwest region of the USA. Tob Control 2012;102:208893. [30] Biener L, McCausland K, Curry L, Cullen J. Prevalence of trial of snus products among adult smokers. Am J Public Health 2011;101:1874–6. [31] Loukas A, Batanova MD, Velazquez CE, Lang WJ, Sneden GG, Pasch KE, et al.Who uses snus? A study of Texas adolescents. Nicotine Tob Res 2012;14:626–30. [32] Caraway JW, Chen PX. Assessment of mouth-level exposure to tobacco constituents in US snus consumers. Nicotine Tob Res 2013;15:670–7. [33] Stepanov I, Jensen J, Biener L, Bliss RL, Hecht SS, Hatsukami DK. Increased pouch sizes and resulting changes in the amounts of nicotine and tobacco specific N-nitrosamines in single pouches of Camel Snus and Marlboro Snus.Nicotine Tob Res 2012;14:1241–5. [34] Stepanov I, Jensen J, Hatsukami D, Hecht SS. New and traditional smokeless tobacco: comparison of toxicant and carcinogen levels. Nicotine Tob Res 2008;10:1773–82. [35] Digard H, Gale N, Errington G, Peters N, McAdam K. Multi-analyte approach for determining the extraction of tobacco constituents from pouched snus by consumers during use. Chem Central J 2013;7:55. [36] Sarkar M, Liu J, Koval T, Wang J, Feng S, Serafin R, et al. Evaluation of biomarkers of exposure in adult cigarette smokers using Marlboro Snus. Nicotine Tob Res 2010;12:105–16. [37] Foulds J, Ramstrom L, Burke M, Fagerstrom K. Effect of smokeless ·177·
烟草制品管制科学基础报告： WHO 研究组第五份报告
tobacco(snus) on smoking and public health in Sweden. Tob Control 2003;12:349–59. [38] Luo J, Ye W, Zandehdel K, Adami J, Adami HO, Boffetta P, et al. Oral useof Swedish moist snuff (snus) and risk for cancer of the mouth, lung, and pancreas in male construction workers: a retrospective cohort study. Lancet 2007;369:2015–20. [39] Greer RO Jr. Oral manifestations of smokeless tobacco use. Otolaryngol Clin N Am 2011;44:31–56. [40] Health effects of smokeless tobacco products. Brussels: European Commission, Scientific Committee on Emerging and Newly Identified Health Risks; 2008. [41] Cobb CO, Weaver MF, Eissenberg T. Evaluating the acute effects of oral, non-combustible potential reduced exposure products marketed to smokers. Tob Control 2010;19:367–373. [42] Kotlyar M, Mendoza-Baumgart MI, Li Z, Pentel PR, Barnett BC, Feuer RM, et al. Nicotine pharmacokinetics and subjective effects of three potential reduced exposure products, moist snuff and nicotine lozenge. Tob Control 2007;16:138–42. [43] Blank MD, Eissenberg T. Evaluating oral noncombustible potentialreduced exposure products for smokers. Nicotine Tob Res 2010; 12:336–43. [44] European Commission. Directive 2001/37/EC of the European Parliament and of the Council of 5 June 2001 on the approximation of the laws, regulations and administrative provisions of the Member States, concerning the manufacture,presentation and sale of tobacco ·178·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
products. Off J L 2013;194:26. [45] Hughes JR, Keely JP, Callas PW. Ever users versus never users of a “less risky”cigarette. Psychol Addictive Behav 2005;19:439–42. [46] Breland AB, Evans SE, Buchhalter AR, Eissenberg T. Acute effects of Advance:a potential reduced exposure product for smokers. Tob Control 2002;11:376–8. [47] Brown B, Kolesar J, Lindberg K, Meckley D, Mosberg A, Doolittle D. Comparative studies of DNA adduct formation in mice following dermal application of smoke condensates from cigarettes that burn or primarily heat tobacco. Mutat Res 1998;414:21–30. [48] Buchhalter AR, Schrinel L, Eissenberg T. Withdrawal-suppressing effects of a novel smoking system: comparison with own brand, not own brand, and denicotinized cigarettes. Nicotine Tob Res 2001;3:111–8. [49] Tarantola A. Ploom model Two E-Cig review: welcome to flavor country.Gizmodocom; 2013 (http://gizmodo.com/ploom-modeltwoe-cig-review-welcome -to-flavor-country-586563052, accessed October 2014). [50] Breland AB, Acosta MC, Eissenberg T. Tobacco specific nitrosamines and potential reduced exposure products for smokers: a preliminary evaluation of AdvanceTM. Tob Control 2003;12:317–21. [51] Pankow JF, Watanabe KH, Toccalino PL, Luo W, Austin DF. Calculated cancer risks for conventional and“potentially reduced exposure product”cigarettes.Cancer Epidemiol Biomarkers Prev 2007;16:584–592. ·179·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[52] Hughes JR, Hecht SS, Carmella SG, Murphy SE, Callas P. Smoking behavior and toxin exposure during six weeks use of a“less risky” cigarette—Omni. Tob Control 2004;13:175–9. [53] Rees VW, Wayne GF, Connolly GN. Puffing style and human exposure minimally alltered by switching to a carbon-filtered cigarette. Cancer Epidemiol Biomarkers Prev 2008;17:2995–3003. [54] Shiffman S, Pillitteri JL, Burton SL, DiMarino ME. Smoker and exsmoker reactions to cigarettes claiming reduced risk. Tob Control 2004;13:78–84. [55] Shiffman S, Jarvis MJ, Pillitteri JL, DiMarino ME, Gitchell JG, Kemper KE.UK smokers’ and ex-smokers’ reactions to cigarettes promising reduced risk.Addiction 2007;102:156–60. [56] Lee EM, Malson JL, Moolchan ET, Pickworth WB. Quantitative comparisons between a nicotine delivery device (Eclipse) and conventional cigarette smoking.Nicotine Tob Res 2004;6:95–102. [57] Stabbert R, Voncken P, Rustemeier K, Haussmann HJ, Roemer E, Schaffernicht H, et al. Toxicological evaluation of an electrically heated cigarette. Part 2:Chemical composition of mainstream smoke. J Appl Toxicol 2003;23:329–39. [58] Fowles J. Novel tobacco products: health risk implications and international concerns(Client report FW0175). Auckland: Ministr y of Health; 2001 (w w w.moh.govt.nz/moh.nsf/.../ noveltobaccoproductshealthrisk.doc, accessed October 2014). [59] Breland AB, Kleykamp BA, Eissenberg T. Clinical laboratory evaluation of potential reduced exposure products for smokers. ·180·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
Nicotine Tob Res 2006;8:738. [60] Ayres PH, Hayes JR, Higuchi MA, Mosberg AT, Sagartz JW. Subchronic inhalation by rats of mainstream smoke from a cigarette that primarily heats tobacco compared to a cigarette that burns tobacco. Inhal Toxicol 2001;13:149–86. [61] Bowman DL, Smith CJ, Bombick BR, Avalos JT, Davis RA, Morgan WT, et al.Relationship between FTC“tar”and urine mutagenicity in smokers of tobacco burning or Eclipse cigarettes. Mutat Res 2002;521:137–49. [62] Slade J, Connolly GN, Lymperis D. Eclipse: does it live up to its health claims?Tob Control 2002;11(Suppl 2):ii64–70. [63] Fagerstrom KO, Hughes JR, Callas PW. Long-term effects of the Eclipse cigarette substitute and the nicotine inhaler in smokers not interested in quitting.Nicotine Tob Res 2002;4(Suppl 2):S141–5. [64] Fagerstrom KO, Hughes JR, Rasmussen T, Callas PW. Randomised trial investigating effect of a novel nicotine delivery device (Eclipse) and a nicotine oral inhaler on smoking behaviour, nicotine and carbon monoxide exposure, and motivation to quit. Tob Control 2000;9:327–33. [65] Rennard SI, Umino T, Millatmal T, Daughton DM, Manouilova LS, Ullrich FA, et al. Evaluation of subclinical respiratory tract inflammation in heavy smokers who switch to a cigarette-like nicotine delivery device that primarily heats tobacco.Nicotine Tob Res 2002;4:467–76. [66] Stewart JC, Hyde RW, Boscia J, Chow MY, O’ Mara RE, Perillo I, et al. ·181·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Changes in markers of epithelial permeability and inflammation in chronic smokers switching to a nonburning tobacco device (Eclipse). Nicotine Tob Res 2006;8:773–83. [67] Breland AB, Buchhalter AR, Evans SE, Eissenberg T. Evaluating acute effects of potential reduced-exposure products for smokers: clinical laboratory methodology. Nicotine Tob Res 2002;4(Suppl 2):S131–40. [68] Hatsukami DK, Lemmonds C, Zhang Y, Murphy SE, Le C, Carmella SG et al.Evaluation of carcinogen exposure in people who used “ reduced exposure ” tobacco products. J Natl Cancer Inst 2004;96:844–52. [69] Lin S, Tran V, Talbot P Comparison of toxicity of smoke from traditional and harm-reduction cigarettes using mouse embryonic stem cells as a novel model for preimplantation development. Hum Reprod 2009;24:386–97. [70] Riveles K, Tran V, Roza R, Kwan D, Talbot P. Smoke from traditional commercial,harm reduction and research brand cigarettes impairs oviductal functioning in hamsters (Mesocricetus auratus) in vitro. Hum Reprod 2007;22:346–55. [71] Benowitz NL. Compensatory smoking of low-yield cigarettes. In: Risks Associated with Smoking Cigarettes with Low Machinemeasured Yields of Tar and Nicotine (Smoking and Tobacco Control Monograph No. 13). Bethesda,Maryland: US Department of Health and Human Services, National Institutes of 152Health, National Cancer Institute; 2001:39–63. [72] Harris JE, Thun MJ, Mondul AM, Calle EE. Cigarette tar yields in ·182·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
relation to mortality from lung cancer in the Cancer Prevention Study II prospective cohort,1982–8. BMJ 2004;328:72–9. [73] Hecht SS, Murphy SE, Carmella SG, Li S, Jensen J, Le C, et al. Similar uptake of lung carcinogens by smokers of regular, light, and ultralight cigarettes. Cancer Epidemiol Biomarkers Prev 2005;14:693–8. [74] Yang G Marketing cigarettes is a key strategy “less harmful, low-tar” of the industry to counter tobacco control in China. Tob Control 2013;23:167–72. [75] Djordjevic MV, Stellman SD, Zang E. Doses of nicotine and lung carcinogens delivered to cigarette smokers. J Natl Cancer Inst 2000;92:106–11. [76] Benowitz NL. Clinical pharmacology of nicotine: implications for understanding,preventing, and treating tobacco addiction. Clin Pharmacol Ther 2008;83:531–41. [77] Benowitz NL. Pharmacology of nicotine: addiction, smoking-induced disease,and therapeutics. Annu Rev Pharmacol Toxicol 2009;49:57– 71. [78] Strasser AA, Ashare RL, Kozlowski LT, Pickworth WB. The effect of filter vent blocking and smoking topography on carbon monoxide levels in smokers.Pharmacol Biochem Behav 2005;82:320–9. [79] Hatsukami DK, Kotlyar M, Hertsgaard LA, Zhang Y, Carmella SG, Jensen JA et al. Reduced nicotine content cigarettes: effects on toxicant exposure,dependence and cessation. Addiction 2010;105:343–55. [80] Dunsby J, Bero L. A nicotine deliver y device without the ·183·
烟草制品管制科学基础报告： WHO 研究组第五份报告
nicotine?Tobacco industry development of low nicotine cigarettes. Tob Control 2004;13:362–9. [81] Shadel WG, Lerman C, Cappella J, Strasser AA, Pinto A, Hornik R. Evaluating smokers’ reactions to advertizing for new lower nicotine Quest cigarettes.Psychol Addict Behav 2006;20:80–4. [82] Benowitz NL, Jacob P III, Herrera B. Nicotine intake and dose response when smoking reduced-nicotine content cigarettes. Clin Pharmacol Ther 2006;80:703–14. [83] Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P III. Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 2007;16:2479–85. [84] Benowitz NL, Dains KM, Hall SM, Stewart S, Wilson M, Dempsey D, et al.Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 2012;21:761–9. [85] Catanzaro DF, Zhou Y, Chen R, Yu F, Catanzaro SE, DeLorenzo MS et al.Potentially reduced exposure cigarettes accelerate atherosclerosis: evidence for the role of nicotine. Cardiovasc Toxicol 2007;7:192–201. [86] Chen J, Higby R, Tian D, Tan D, Johnson MD, Xiao Y et al. Toxicological analysis of low-nicotine and nicotine-free cigarettes. Toxicology 2008;249:194–203. [87] Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS et al. Reduced nicotine content cigarettes and nicotine patch. Cancer Epidemiol Biomarkers Prev 2013;22:1015–24. ·184·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
[88] Girdhar G, Xu S, Bluestein D, Jesty J. Reduced-nicotine cigarettes increase platelet activation in smokers in vivo: a dilemma in harm reduction. Nicotine Tob Res 2008;10:1737–44. [89] Lin S, Fonteno S, Weng JH, Talbot P. Comparison of the toxicity of smoke from conventional and harm reduction cigarettes using human embryonic stem cells.Toxicol Sci 2010;118:202–12. [90] Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction—the implications for tobacco regulation. N Engl J Med 1994;331:123–5. [91] Rose JE, Behm FM. Effects of low nicotine content cigarettes on smoke intake.Nicotine Tob Res 2004;6:309–19. [92] Strasser AA, Lerman C, Sanborn PM, Pickworth WB, Feldman EA. New lower nicotine cigarettes can produce compensatory smoking and increased carbon monoxide exposure. Drug Alcohol Depend 2007;86:294–300. [93] Walker N, Howe C, Bullen C, Grigg M, Glover M, McRobbie H, et al. The combined effect of very low nicotine content cigarettes, used as an adjunct to usual Quitline care (nicotine replacement therapy and behavioural support), on smoking cessation: a randomized controlled trial. Addiction 2012;107:1857–67. [94] Rose JE, Behm FM, Westman EC, Kukovich P. Precessation treatment with nicotine skin patch facilitates smoking cessation. Nicotine Tob Res 2006;8:89–101. [95] Donny EC, Jones M. Prolonged exposure to denicotinized cigarettes with or without transdermal nicotine. Drug Alcohol Depend ·185·
烟草制品管制科学基础报告： WHO 研究组第五份报告
2009;104:23–33. [96] Siu M, Mladjenovic N, Soo E. The analysis of mainstream smoke emissions of Canadian“ super slim ”cigarettes. Tob Control 2012;22:e10. [97] Hammond D, Doxey J, Daniel S, Bansal-Travers M. Impact of femaleoriented cigarette packaging in the United States. Nicotine Tob Res 2011;13:579–88. [98] European Commission. Directive 2014/40/EU of the European Parliament and of the Council of 3 April 2014 on the approximation of the laws, regulations and administrative provisions of the Member States concerning the manufacture,presentation and sale of tobacco and related products and repealing Directive 2001/37/EC Text with EEA relevance. Off J L 2014;127:1–38. [99] Richardson A, Vallone DM. YouTube: a promotional vechicle for little cigars and cigarillos? Tob Control 2012;23:21–6. [100]Kozlowski LT, Dollar KM, Giovino GA. Cigar/cigarillo surveillance: limitations of the US Department of Agriculture system. Am J Prev Med 2008;34:424–6. [101]Maxwell JC. The Maxwell report.Cigar industry in 2008.Richmond, Virginia;2008. [102]Richardson A, Xiao H, Vallone DM. Primary and dual users of cigars and cigarettes: profiles, tobacco use patterns, and relevance to policy. Nicotine Tob Res 2012;14:927–32. [103]Family Smoking Prevention and Tobacco Control Act (7-22-2009). Public Law 11-31, H.R. 1256. Washington DC: Government Printing ·186·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
Office, US Congress; 2009154(http://www.gpo.gov/fdsys/pkg/PLAW111publ31/pdf/PLAW-111publ31.pdf,accessed October 2014). [104] Villanti AC, Richardson A, Vallone DM, Rath JM. Flavored tobacco product use among US young adults. Am J Prev Med 2013;44:388– 91. [105] Little cigars—big concerns. Ottawa: Health Canada; 2011. [106]Henningfield JE, Fant RV, Radzius A, Frost S. Nicotine concentration, smoke pH and whole tobacco aqueous pH of some cigar brands and types popular in the United States. Nicotine Tob Res 1999;1:163–8. [107] Chen A, Glantz S, Tong E. Asian herbal-tobacco cigarettes:“not medicine but less harmful”? Tob Control 2007;16:e3. [108]Soldz S, Huyser DJ, Dorsey E. Characteristics of users of cigares, bidis, and kreteks and the relationship to cigarette use. Prev Med 2003;37:250–8. [109]Watson CH, Polzin GM, Calafat AM, Ashley DL. Determination of tar, nicotine,and carbon monoxide yields in the smoke of bidi cigarettes. Nicotine Tob Res 2003;5:747–53. [110]Delnevo CD, Pevzner ES, Hrywna M, Lewis MJ.Bidi cigarette use among young adults in 15 states. Prev Med 2004;39:207–11. [111]Waterpipe tobacco smoking: health effects, research needs and recommended actions by regulators. Geneva: World Health Organization; 2005. [112] Vattenpipa—rök utan risk? Hälsoeffekter, vanor, attityder och tillsyn [Hookah—smoke without risk? Health effects, habits, attitudes and supervision]. Östersund:Statens Folkhälsoinstitut; 2010. ·187·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[113] Morton J, Song Y, Fouad H, Awa FE, Abou El Naga R, Zhao L, et al. Cross-country comparison of waterpipe use: nationally representative data from 13 low and middle-income countries from the Global Adult Tobacco Survey (GATS).Tob Control 2013;23:419–27. [114] Maziak W. The global epidemic of waterpipe smoking. Addict Behav 2011;36:1–5. [115] Akl EA, Gunukula SK, Aleem S, Obeid R, Abou Jaoude P, Honeine R, et al.The prevalence of waterpipe tobacco smoking among the general and specific populations: a systemic review. BMC Public Health 2011;11:244. [116] Attitudes of Europeans towards tobacco (Special Eurobarometer 385, Wave EB77.1). Brussels: European Commission; 2012. [117] Jawad M, Abass J, Hariri A, Rajasooriar KG, Salmasi H, Millett C, et al. Waterpipe smoking: prevalence and attitudes among medical students in London. Int J Tuberc Lung Dis 2013;17:137–40. [118] Schubert J, Hahn J, Dettbarn G, Seidel A, Luch A, Schulz TG. Mainstream smoke of the waterpipe: does this environmental matrix reveal as significant source of toxic compounds? Toxicol Lett 2011;205:279–84. [119] Al Rashidi M, Shihadeh A, Saliba NA. Volatile aldehydes in the mainstream smoke of the narghile waterpipe. Food Chem Toxicol 2008;46:3546–9. [120] Cobb CO, Shihadeh A, Weaver MF, Eissenberg T. Waterpipe tobacco smoking and cigarette smoking: a direct comparison of toxicant exposure and subjective155 effects. Nicotine Tob Res 2011;11:78–87. ·188·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
[121]La Fauci G, Weiser G, Steiner IP, Shavit I. Carbon monoxide poisoning in nagrhile (water pipe) tobacco smokers. Can J Emerg Med 2012;14:57–9. [122] Jacob P III, Abu Raddaha AH, Dempsey D, Havel C, Peng M, Yu L, et al.Comparison of nicotine and carcinogen exposure with water pipe and cigarette smoking. Cancer Epidemiol Biomarkers Prev 2013;22:765–72. [123]IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 71,Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide.Lyon: International Agency for Research on Cancer; 1999. [124]IARC monographs on the evaluation of carcinogenic risks to humans. Vol.88, Formaldehyde, 2-butoxyethanol and 1-tertbutoxypropan-2-ol. Lyon:International Agency for Research on Cancer; 2006. [125] Maziak W, Eissenberg T, Ward KD. Patterns of waterpipe use and dependence:implications for intervention development. Pharmacol Biochem Behav 2005;80:173–9. [126] Lipkus IM, Eissenberg T, Schwartz-Bloom RD, Prokhorov AV, Levy J. Affecting perceptions of harm and addiction among college waterpipe tobacco smokers.Nicotine Tob Res 2011;13:599–610. [127] Menthol capsules in cigarette filters—incrreasing the attractiveness of a harmful product. Heidelberg: German Cancer Research Center; 2012. [128] Addictiveness and Attractiveness of Tobacco Additives. Brussels: ·189·
烟草制品管制科学基础报告： WHO 研究组第五份报告
European Commission, Scientific Committee on Emerging and Newly Identified Health Risks; 2010. [129] Tobacco additives. Bilthoven: National Institute for Public Health and the Environment; 2012. [130] Soeteman-Hernandez LG, Bos PM, Talhout R. Tobacco smokerelated health effects induced by 1,3-butadiene and strategies for reduction. Toxicol Sci 2013;136:566–80. [131] Kennedy RD, Millstein RA, Rees VW, Connolly GN. Tobacco industr y strategies to minimize or mask cigarette smoke: opportunities for tobacco product regulation. Nicotine Tob Res 2013;15:596–602. [132] Marian C, O’ Connor RJ, Djordjevic MV, Rees VW, Hatsukami DK, Shields PG. Reconciling human smoking behavior and machine smoking patterns:implications for understanding smoking behavior and the impact on laboratory studies. Cancer Epidemiol Biomarkers Prev 2009;18:3305–20. [133] Burns DM, Dybing E, Gray N, Hecht S, Anderson C, Sanner T et al. Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal. Tob Control 2008;17:132–41. [134] Mulier T. Philip Morris to introduce lower-risk cigarette by 2017. Bloombergcom;2013(http://www.bloomberg.com/news/2012-0621/philip-morris-to-introducenext-generation-cigarette-by-7.html, accessed October 2014). [135] Smeltsigaret op komst [Melt cigarette arriving]. SP!TS; 2013 (http:// ·190·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
www.156 spitsnieuws.nl/archives/binnenland/2013/10/smeltsigaretop-komst, accessed 5October 2013). [136] Rees VW, Kreslake JM, O’ Connor RJ, Cummings KM, Parascandola M,Hatsukami D, et al. Methods used in internal industry clinical trials to assess tobacco risk reduction. Cancer Epidemiol Biomarkers Prev 2009;18:3196–208. [137] Kleinstreuer C, Feng Y. Lung deposition analyses of inhaled toxic aerosols in conventional and less harmful cigarette smoke: a review. Int J Environ Res Public Health 2013;10:4454–85. [138] McAdam KG, Gregg EO, Liu C, Dittrich DJ, Duke MG, Proctor CJ. The use of a novel tobacco-substitute sheet and smoke dilution to reduce toxicant yields in cigarette smoke. Food Chem Toxicol 2011;49:1684–96. [139] Fearon IM, Acheampong DO, Bishop E. Modification of smoke toxicant yields alters the effects of cigarette smoke extracts on endothelial migration: an in vitro study using a cardiovascular disease model. Int J Toxicol 2012;31:572–83. [140] Fearon IM, Gaca MD, Nordskog BK. In vitro models for assessing the potential cardiovascular disease risk associated with cigarette smoking. Toxicol in Vitro 2013;27:513–22. [141] St Charles FK, McAughey J, Shepperd CJ. Methodologies for the quantitative estimation of toxicant dose to cigarette smokers using physical, chemical, and bioanalytical data. Inhal Toxicol 2013; 25:363–72. [142] Liu C, DeGrandpre Y, Porter A, Griffiths A, McAdam K, Voisine R, ·191·
烟草制品管制科学基础报告： WHO 研究组第五份报告
et al. The use of a novel tobacco treatment process to reduce toxicant yields in cigarette smoke. Food Chem Toxicol 2011;49:1904–17. [143] Shepperd CJ, Eldridge A, Camacho OM, McAdam K, Proctor CJ, Meyer I.Changes in levels of biomarkers of exposure observed in a controlled study of smokers switched from conventional to reduced toxicant prototype cigarettes.Regul Toxicol Pharmacol 2013;66:147– 62. [144] McAdam KG, Gregg EO, Bevan M, Dittrich DJ, Hemsley S, Liu C, et al. Design and chemical evaluation of reduced machine-yield cigarettes. Regul Toxicol Pharmacol 2012;62:138–50. [145] Branton PJ, McAdam KG, Winter DB, Liu C, Duke MG, Proctor CJ. Reduction of aldehydes and hydrogen cyanide yields in mainstream smoke using an amine functionalised ion exchange resin. Chem Central J 2011;5:15. [146] Deng Q, Huang C, Xie W, Xu H, Wei M. Significant reduction of harmful compounds in tobacco smoke by the use of titanite nanosheets and nanotubes.Chem Commun (Camb) 2011;47:6153–5. [147] Deng Q, Huang C, Zhang J, Xie W, Xu H, Wei M. Selectively reduction of tobacco specific nitrosamines in cigarette smoke by use of nanostructural titanates.Nanoscale 2013;5:5519–23. [148] Polzin GM, Zhang L, Hearn BA, Tavakoli AD, Vaughan C, Ding YS, et al. Effect of charcoal-containing cigarette filters on gas phase volatile organic compounds in mainstream cigarette smoke. Tob Control 2008;17(Suppl 1):i10–6. [149] Hearn BA, Ding YS, Vaughan C, Zhang LQ, Polzin G, Caudill SP, ·192·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
et al. Semi-volatiles in mainstream smoke delivery from select charcoal-filtered cigarette brand variants. Tob Control 2010;19:223– 30. [150] Scherer G, Urban M, Engl J, Hagedorn HW, Riedel K. Influence of smoking charcoal filter tipped cigarettes on various biomarkers of exposure. Inhal Toxicol 2006;18:821–9. [151] Foulds J, Furberg H. Is low-nicotine Marlboro snus really snus? Harm Reduction J 2008;5:9. [152] Carpenter CM, Connolly GN, Ayo-Yusuf OA, Wayne GF. Developing smokeless tobacco products for smokers: an examination of tobacco industry documents.Tob Control 2009;18:54–9. [153] Rees VW, Kreslake JM, Cummings KM, O’ Connor RJ, Hatsukami DK,Parascandola M, et al. Assessing consumer responses to potential reduced-exposure tobacco products: a review of tobacco industry and independent research methods. Cancer Epidemiol Biomarkers Prev 2009;18:3225–40. [154] Mejia AB, Ling PM. Tobacco industry consumer research on smokeless tobacco users and product development. Am J Public Health 2010;100:78–87. [155] Parascandola M, Augustson E, Rose A. Characteristics of current and recent former smokers associated with the use of new potential reduced-exposure tobacco products. Nicotine Tob Res 2009;11:1431–8. [156] Regan AK, Dube SR, Arrazola R. Smokeless and flavored tobacco products in the US 2009 Styles survey results. Am J Prev Med ·193·
烟草制品管制科学基础报告： WHO 研究组第五份报告
2012;42:29–36. [157] Wray RJ, Jupka K, Berman S, Zellin S, Vijaykumar S. Young adults’ perceptions about established and emerging tobacco products: results from eight focus groups. Nicotine Tob Res 2012;14:184–90. [158] Shaikh RA, Siahpush M, Singh GK. Socioeconomic, demographic and smoking-related correlates of the use of potentially reduced exposure to tobacco products in a national sample. Tob Control 2013;23:353–8. [159] Choi K, Fabian L, Mottey N, Corbett A, Forster J. Young adults’ favorable perceptions of snus, dissolvable tobacco products, and electronic cigarettes:findings from a focus group study. Am J Public Health 2012;102:2088–93. [160] O’ Connor RJ, Hyland A, Giovino GA, Fong GT, Cummings KM. Smoker awareness of and beliefs about supposedly less-harmful tobacco products. Am J Prev Med 2005;29:85–90. Connor RJ, McNeill A, Borland R, Hammond D, King B, [161] O ’ Boudreau C, et al.Smokers’ beliefs about the relative safety of other tobacco products: findings from the ITC Collaboration. Nicotine Tob Res 2007;9:1033–42. [162]Pederson LL, Nelson DE. Literature review and summary of perceptions,attitudes, beliefs, and marketing of potentially reduced exposure products:communication implications. Nicotine Tob Res 2007;9:525–34. Connor RJ, Norton KJ, Bansal-Traves M, Mahoney MC, [163]O ’ Cummings KM,Borland R. US smokers’ reactions to a brief trial of ·194·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
oral nicotine products. Harm Reduction J 2011;8:1. [164] Tomar SL, Alpert HR, Connolly GN. Patterns of dual use of cigarettes and smokeless tobacco among US males: findings from national surveys. Tob Control 2010;19:104–9. [165] McClave-Regan AK, Berkowitz J. Smokers who are also using smokeless tobacco products in the US: a national assessment of characteristics, behaviours and beliefs of “dual users”. Tob Control 2011;20:239–42. [166] Schwartz JL, Brunnemann KD, Adami AJ, Panda S, Gordon SC, Hoffmann D,et al. Brand specific responses to smokeless tobacco in a rat lip canal model. J Oral Pathol Med 2010;39:453–9. [167] Popova L, Ling PM. Alternative tobacco product use and smoking cessation: a national study. Am J Public Health 2013;103:923–30. [168] Lund KE, McNeill A, Scheffels J. The use of snus for quitting smoking compared with medicinal products. Nicotine Tob Res 2010;12:817–22. [169] Levy DT, Mumford EA, Cummings KM, Gilpin EA, Giovino G, Hyland A, et al.The relative risks of a low-nitrosamine smokeless tobacco product compared with smoking cigarettes: estimates of a panel of experts. Cancer Epidemiol Biomarkers Prev 2004;13:2035– 42. [170] Levy DT, Mumford EA, Cummings KM, Gilpin EA, Giovino GA, Hyland A, et al. The potential impact of a low-nitrosamine smokeless tobacco product on cigarette smoking in the United States: Estimates of a panel of experts. Addict Behav 2006;31:1190–200. ·195·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[171] Hatsukami DK, Lemmonds C, Tomar SL. Smokeless tobacco use: harm reduction or induction approach? Prev Med 2004;38:309–17. [172] Bedi R, Scully C. Tobacco control—debate on harm reduction enters new phase as India implements public smoking ban. Lancet Oncol 2008;9:1122–3. [173] Ayo-Yusuf OA, Burns DM. The complexity of“harm reduction” with smokeless tobacco as an approach to tobacco control in lowincome and middle-income countries. Tob Control 2012;21:245–51. [174] Benowitz NL. Smokeless tobacco as a nicotine delivery device: harm or harm reduction? Clin Pharmacol Ther 2011;90:491–3. [175] McNeill A, Hammond D, Gartner C. Whither tobacco product regulation? Tob Control 2012;21:221–6. [176] Parascandola M, Augustson E, O’ Connell ME, Marcus S. Consumer awareness and attitudes related to new potential reduced-exposure tobacco product brands. Nicotine Tob Res 2009;11:886–95. [177] Kotnowski K, Hammond D. The impact of cigarette pack shape, size and opening:evidence from tobacco company documents. Addiction 2013;108:1658–68. [178] Tomar SL. Trends and patterns of tobacco use in the United States. Am J Med Sci 2003;326:248–54. [179] Declaration. First International Conference on Waterpipe Tobacco Smoking:Building Evidence for Intervention and Policy. Abu Dhabi: American University of Beirut, NYU Abu Dhabi; 2013. [180] Borrelli B, Novak SP. Nurses’knowledge about the risk of light cigarettes and other tobacco“harm reduction”strategies. Nicotine ·196·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
Tob Res 2007;9:653–61. [181] Ahmad S, Billimek J. Estimating the health impacts of tobacco harm reduction policies: a simulation modeling approach. Risk Anal 2005;24:801–12.
附录 包括潜在“减害”产品在内的新型烟草制品 调查问卷 本调查问卷是在撰写 WHO TobReg 第七次会议的背景文章的时 候准备的，名为“包括潜在‘减害’产品在内的新型烟草制品发展 研究和监督” 。本调查问卷受 WHO TFI 委托分配。本调查问卷的目 的之一是提供一个地区及国家水平上的包括但不仅限于烟草制品成 分、 销售、 广告及发展的可行性、 政策及管制情况。 为了达到这个目的， 我们诚挚地要求您能够完成下列的调查问卷。您提供的任何信息都 对我们的研究有帮助，并使未来基于科学证据的相关产品的管制成 为可能。 如果您不能或不想回答下列所有问题，可不回答。请确定您是 否想要您的（部分）信息进行保密处理。我们欢迎其他关于这些问 题但不在本调查问卷中包含的任何信息。 我们想知道含有烟草及符合以下原则中的一条或多条的产品 信息 ： • • 不只是传统 / 常规卷烟、雪茄、烟斗、自卷烟或口含烟的其 他改变或添加调料的产品 ； 拥有新技术和 / 或宣称减害的产品 ； ·197·
烟草制品管制科学基础报告： WHO 研究组第五份报告
• •
已经在市场上存在超过 15 年（如可溶性烟草） ，且在近年来 加以强化的产品 ； 已经在市场上存在很长时间，但在不将其作为传统烟草制品 的市场里，其份额增加的产品（如水烟和鼻烟） 。
举例说明我们感兴趣的产品 ： • 名为“Thunder” 的嚼烟。 这种产品经高度调味， 并装入到 圆形的塑料罐中，由丹麦 V2 烟草公司制造。 • “Dutch Magic” 。这种卷烟烟草中不含有烟碱，但其焦油释放 量和普通卷烟类似（不是“低焦油”卷烟） 。 • • 可溶性烟草制品。 可能或宣传的“减害”产品，如亚硝胺释放量较低的卷烟。
问卷 ： 基本情况 国家 联系人 联系方式（电话或邮箱） 在过去的几年内，哪种新型或改进型烟草产品在商店里或通过 互联网、新闻、执照申请或其他途径引起了您的注意？ 对于每种产品，请回答以下问题 ： 如果可能的话， 请提供能证明所提供信息的参考文献或资料， 如有广告、讨论或有市场份额报告的产品的网址等。 产品描述 ： 1. 品牌名称（如“Thunder” ） ； 2. 制造商（如丹麦 V2 烟草公司） ； 3. 制造商所标注的烟草类型（如“嚼烟” ） ； ·198·
附录1 包括潜在降低暴露量产品在内的新型烟草制品：研究需求和建议
4. 产品描述（如这类烟草产品调味浓郁） ； 5. 包装（如圆形塑料罐包装，含有 37 g） ； 6. 在包装或其他途径中显示的成分及释放物（ 如添加剂清单、 化合物分析） ； 7. 如果可能的话，请提供产品图片或网站链接 ； 8. 其他任何信息。 贵国的政策及管制 9. 这些产品在贵国是如何管制的？ 10. 这种产品在成分和释放物方面有没有管制政策？ 11. 其他任何信息。 市场 12. 这些产品是否流行？ 13. 你知道这些产品的市场份额吗？ 14. 是否有一些特定群体在使用这些产品？如年轻人、女性等。 15. 其他任何信息。 产品营销情况 16. 这些产品营销策略是什么？ 17. 营销手段是否针对特定群体？ 18. 这些产品是如何做广告的？ 你能举例说明吗（ 例如通过网 络）？ 19. 其他任何问题。 其他任何说明
·199·
烟草制品管制科学基础报告： WHO 研究组第五份报告
附录 2 氨在游离态烟碱传输中的作用 近期研究 及分析挑战
C. V. Watson， 美国疾病控制与预防中心 （美国佐治亚州亚特兰大） 烟草与挥发物课题组烟草制品实验室研究化学家 A2.1 引言 A2.2 烟碱向烟气传输的近期研究成果 A2.3 烟碱摄入的近期研究成果 A2.4 当前加氨技术的作用 A2.5 参考文献
A2.1 引 言 尽管氨在烟叶中的自然含量相对较低，但是烟草公司经常基于 各种原因向烟草产品中人为添加。从公共卫生领域的角度来看，添 加氨最重要的原因是增加烟碱向大脑的传输速率。非质子化（ “游离 态” 故而能被更快吸收。据报道， ）的烟碱比质子化烟碱亲脂性更强， 氨在烟碱的去质子化过程中与 pH 改变有关， 这种去质子化能使吸 烟者对烟碱的吸收更快，这个现象叫做“影响”[1]。然而，烟草公司 ·200·
附录2 氨在游离态烟碱传输中的作用：近期研究及分析挑战
公开反对这一说法， 尽管大量的内部资料提到烟气的“影响” ， “力量” 及“冲击” 。 1998 年的烟草大和解协议从烟草公司内部资料中向公共卫生团 体提供了含有大量关于加氨技术的历史信息。通过对这些文件的简 单查找，可发现数十份文献并“发现”加氨技术，以及这种技术是 如何基于多名吸烟者被广泛研究和测试，以取得关于感官元素的主 观反馈结果， 例如口味和“ 影响 ” 。 菲利浦·莫里斯公司似乎在 20 世纪 60 年代“发现”了加氨技术，并尝试生产一种更好的再造烟叶 薄片。在那个时候，菲利浦·莫里斯公司是四大烟草公司中最小的 一个，并在努力降低成本。该公司尝试使用薄片压制技术（和过去 的的造纸技术类似 ） ， 并利用烟草废料、 根、 茎及“ 粉末 ” 来制造 100% 的烟草薄片（而不是通常的 80%） 。为了增强薄片的机械强度， 加入了磷酸氢二铵来破坏烟叶中原果胶的钙离子络合，并使钙离子 和磷酸根相结合，这样钙离子原有的络合就不能很快地重新结合 [2]。 这样，游离态的原果胶就能够重新络合，进而增加了新薄片的强度， 或与其他分子重新络合，如烟碱。菲利浦·莫里斯公司的科学家还 发现， 向再造烟叶薄片中添加磷酸氢二铵使最后的产品的感官 “影响” 和口味大大改善。在那时，菲利浦·莫里斯公司还不知道这是为什 么，但他们很快意识到了它的重要性，并采用了此项技术。 “万宝路” 牌卷烟新型的、改进的烟气风味，高的感官质量，以及大规模的营 销活动使万宝路成为美国最畅销的卷烟产品 [3]。 菲利浦·莫里斯公 司的竞争对手们希望通过对万宝路卷烟的剖析来搞清楚为什么该产 品突然这么受欢迎。在 1973 年，雷诺公司总结为，游离烟碱含量和 该品牌的特征关系最紧密 [4]。经过大量研究后英美烟草公司总结出， 能够产生氨的再造烟叶薄片技术是万宝路卷烟的“核心和灵魂”[3,5]。 ·201·
烟草制品管制科学基础报告： WHO 研究组第五份报告
对一种已知每年造成成千上万人死亡的产品的持续使用是公共 卫生领域的主要顾虑。卷烟习惯性消费的一个主要解释是烟碱的潜 在致瘾性。如 Ashley 等 [6] 报道的那样，烟碱传输分两步进行 ： 卷烟 向烟气的传输以及消费者从烟气中吸收烟碱。大量实验研究了氨在 这些步骤中的作用，其中一部分研究是菲利浦·莫里斯公司资助的。 下文将讨论这些研究的分析结果以及研究人员对阐明氨在 pH 调节 和以后烟碱传输中作用的困难。
A2.2 烟碱向烟气传输的近期研究成果 尽管烟碱是烟草的一种天然成分，但是其在烟叶中的含量、向 烟气的传输量以及游离态烟碱含量都是可以精确控制的，正如大部 分烟草公司资料所指出的那样。在烟叶及醇化烟丝中，大部分烟碱 处于非挥发质子态 ； 但是， 通过 pH 的轻微调节可实现烟碱的去质 子化，从而使之更容易吸收。烟碱的挥发态生物活性更强，因为这 种状态是亲脂态，更容易迅速穿过肺泡细胞膜，而且比粒相物中的 烟碱吸收更快 [7,8]。烟草行业研究结果显示，只需要一小部分游离态 烟碱就能达到一个令人愉快的感官效果 ； 高 pH 所致的高含量游离 态烟碱会使烟气“刺激” ，并难以吸入 [9,10]。再造薄片的制造过程中， 果胶会在磷酸二铵盐的作用下从原果胶中释放出来，并与烟碱络合， 该络合物在吸烟时的温度下更容易分解，因此提高了烟碱向烟气中 转移的效率。提高温度还会提高烟气中的游离烟碱浓度，因为烟碱 的水解作用是取决于温度的 [11,12]。Seeman 和 Carchman 报道 [13]， 卷 烟燃烧所产生的温度将烟碱及其盐汽化绰绰有余。如果再造烟叶薄 ·202·
附录2 氨在游离态烟碱传输中的作用：近期研究及分析挑战
片中的烟碱和果胶形成稳定的化合物，则提高了汽化烟碱所需的热 量，因此，这些络合物在薄片上停留的时间就更长，并且暴露于更 高的温度直到靠近卷烟燃烧区，这会提高烟气中的游离烟碱比例。 Callicutt 等 [14] 研究了含有不同浓度氨的实验卷烟的烟碱传输 效率。该实验的一个有趣的地方在于研究人员设计并制造出了仅氨 含量不同的卷烟 ；尽管如此， 也有对这些实验卷烟的质疑。 在这 四种实验卷烟中， 有一种被认为不含添加剂的卷烟仍含有大约 1.7 mg“ 可溶氨 ” 作者指出了这点， 但没有对其进行详细说明。 尽管 ； 烟草类型、 烟草种植方法及烟草加工工艺都会引起氨含量的不同， 但对于一个“不含添加剂”的卷烟来说，这种氨浓度水平似乎还是 有点偏高。 尚无使用再造烟草薄片来制作不含添加剂卷烟的报道 ； 有报道只提到不含有氨的添加剂。再造烟草薄片可不含这些化合物， 尽管烟草行业研究表明这样的薄片难以制造且消费者不喜欢 [15]。因 为实验卷烟不是用来供消费者使用的，所以不用考虑这个问题。可 能含有烟碱 - 果胶络合物的再造烟草薄片的存在， 可使游离态烟碱 的含量发生变化， 从而使吸烟者感到“ 力度 ” 或“ 冲击 ” 。Callicutt 等发现 [14]，这些卷烟的烟碱传输没有明显的差别。他们称这项研究 的主要目的是考察一定氨浓度下的总烟碱传输速率 ； 然而，在游离 态烟碱传输量改变时， 总烟碱释放量保持不变 [14,16]。 更加需要关注 的是，通过卷烟的物理或化学变化，可改变游离态烟碱在总烟碱中 的比例，进而改变游离态烟碱含量水平。这项研究的局限性在于缺 少游离态烟碱含量水平的分析数据， 尽管烟草行业自 20 世纪 30 年 代就已经建立了分析游离态烟碱含量的方法 [17]。该研究可以回答的 一个更有意义的问题是，通过再造烟草薄片制造中的加氨技术，究 竟可以使烟气中的烟碱含量改变到什么程度。 ·203·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A2.3 烟碱摄入的近期研究成果 菲利浦· 莫里斯公司资助了一项烟碱与主流烟气中的氨释放 量关系的代谢组学研究， 提供了测定烟气中氨释放量的有用信息。 McKinney 等 [18]
总结到， 主流烟气中的氨释放量差异并不影响烟
碱的代谢。该方法通过一个吸入装置使吸烟者吸入一到两支卷烟的 烟气，并对吸烟者的动脉血液进行取样，每支卷烟能向烟气中传输 10 μg 或 19 μg 的氨。美国疾病控制及预防中心有一项未发表的关于 主流烟气粒相物及气相物中氨的测定研究，该研究表明，含有 10 μg 及 19 μg 氨的卷烟之间的差异并不大 ； 在两个“ 淡味 ” 品牌中， 其 氨释放量差别都可高达 10 μg，更不用说那些由不同生产商制造的卷 烟品牌了。因此，在烟气中含有相似氨释放量的卷烟之间，吸烟者 血液中烟碱含量随时间的变化曲线图不会差异很大。设计成“低氨” 的卷烟也包括高比例的白肋烟及烟梗，这会提高烟气的 pH，并会导 致吸烟者对氨释放量稍低的卷烟进行补偿抽吸 [19,20]
。 卷烟烟丝中的
氨含量有助于判定两种卷烟品牌之间是否有真正差别。当吸烟者吸 入烟气时，这种烟气吸入系统的复杂性还没有得到充分阐述。烟气 可以通过多种途径被稀释。首先，没有提到通风口是否被堵上，不 堵塞的通风口并不能准确模拟真实的吸烟行为。其次，根据该图表， 更清洁的空气会通过传感器进来， 尽管没有解释相关机理和要求。 最后，没有介绍由于管路受潮而引起的游离态烟碱和氨的损失。 有一些关于抽吸口数重要性的描述。McKinney 等 [18] 的研究中， 每支卷烟只测定了第四口，所以，对比那些取前几口样的吸烟者来 说，这些个体的游离态烟碱暴露量可能偏低 [21]。烟草行业的研究表 ·204·
附录2 氨在游离态烟碱传输中的作用：近期研究及分析挑战
明，过量的氨会给吸烟者带来负面的感官影响，而在吸烟的前几毫 秒内或之前，大部分加入的氨都会通过各种途径反应掉 [22-24]。根据 Handbook for leaf blenders and product developers 一书介绍 [16]，氨会和 一些已知刺激物反应并立刻减弱其效力。氨还会通过和与烟碱成盐 的酸的结合而释放更多地游离态烟碱 [25]。在吸烟过程中，醋酸纤维 滤嘴也会有效捕集烟气中的氨，因此，侧流烟气会减少另外一大部 分的氨 [26]。此外， 氨还会和烟气中的一些刺激物 快速反应， （如乙醛） 并降低其刺激性 [23-25]。烟气中的氨很可能是含氮化合物（如氨基酸 及烟碱）的分解产物，而不是来源于烟丝中的氨向烟气中的直接迁 移。烟气中的氨释放量很低，不会将游离态氨用于分析，因此，主 流烟气中的氨释放量不是烟气 pH 及游离态烟碱传输量的好的指标。 如果将动脉血液中的烟碱浓度和游离烟态碱含量及烟气 pH 相比较， 该研究将会更有意义。 人体对烟碱的吸收总量与烟碱吸收速率的相关性不强，因为人 体能有效吸收烟气中的大部分烟碱。Van Amsterdam 等 [27] 对烟碱吸 收的研究说明了这一点。该实验采集了抽吸两种不同实验卷烟的吸 烟者的静脉血液样品，这两种实验卷烟烟丝中的氨含量不同（分别 是 0.89 mg/g 和 3.43 mg/g） 。 第一个样品在抽吸最后一口 2.5 分钟后 进行采集。正如所预料的那样，两种卷烟品牌的“烟碱暴露量”没 有差别， 因为抽吸卷烟 2.5 分钟后采集的血液样品不反映游离态烟 碱的吸收速率。Rose 等 [28] 在一项对烟碱脑部蓄积作用的研究中发 现，在进入口腔后，烟碱仅需 7 秒就会到达脑部。Henningfield 等 [29] 强调，增强烟碱致瘾性最重要的因素是在抽吸第一口后 10~15 秒内 烟碱的摄入量及摄入浓度， 而不是总烟碱摄入量。 此外， 尽管 Van Amsterdam 等研究中使用的两种品牌卷烟的氨释放量有巨大差异， ·205·
烟草制品管制科学基础报告： WHO 研究组第五份报告
“充分调味”的薄荷卷烟中的氨释放量达到 1 mg/g，这种释放量水平 是很高的。Callicutt 等 [14] 的研究表明，实验卷烟中的氨释放量不低 于 0.9 mg/g， 这和一些薄荷卷烟中的氨释放量类似。 烟丝中氨含量 的重要性尚未知。Van Amsterdam 等 [27] 的研究中，没有提到混合型 卷烟中的再造烟草薄片，尽管这是氨的主要途径，并会影响游离态 烟碱的传输效率。对那些希望比较不同卷烟的研究者来说，一个主 要局限性是不能制造烟草只有中氨释放量不同的实验卷烟。比较含 有再造薄片的氨浓度很高的卷烟和所含白肋烟浓度低、烟气酸性弱、 不含再造烟草薄片的“不含添加剂”品牌，将会很有意思。
A2.4 当前加氨技术的作用 人们对加氨技术的时间年表都比较熟知了。曾经被认为是“现 代药物设计历史的最大胜利”之一的技术，现在已经成了一个技术 遗产。当前在卷烟设计中加氨技术作用的疑问依旧存在。氨的工业 应用已经研究了至少 20 年， 且并不反映调节及控制烟气 pH 及游 离态烟碱传输的化学与生物技术进步。 此外， 烟气气溶胶是一个 动态的化合物复杂混合体。因此，如果试图将烟丝或烟气的氨含量 和烟气 pH 或游离态烟碱传输量直接联系起来， 就极大地低估了烟 气的复杂程度。氨只是那些能够使烟碱游离化并产生美拉德反应的 众多化合物中的一种，烟草行业拥有足够的时间来设计、改善和测 试替代技术和方法。 除了氨 - 磷酸二铵盐替代物， 烟气中还存在大 量的碱性化合物， 这些成分能够创造一个适宜游离态烟碱组成的 碱性环境。 许多其他途径也是可能的 ：通过生物技术来改变烟叶 ·206·
附录2 氨在游离态烟碱传输中的作用：近期研究及分析挑战
中特定成分的含量 ； 通过卷烟滤嘴添加剂及设计的改变来创造一个 碱性环境或改变颗粒大小来提高颗粒中游离态烟碱的含量 ；可利 用支气管扩张剂及薄荷醇来增加吸烟者对烟碱的摄入量 ；还可以 通过纸张的孔隙率及滤嘴的通风率等物理性质来改变烟气的化学 性质。 到 20 世 纪 80 年 代 晚 期， 一 些 国 家 禁 止 了 磷 酸 二 铵 盐 的 使 用，这促使烟草企业研究制作不含磷酸二铵盐的薄片的新方法，但 那仍能产生糖 - 磷酸二铵盐反应产物并释放到烟气中。Brown 和 Williamson 研究使用菠萝固态提取物， 焦糖和高麦芽糖含量的玉米 糖浆来作为再造薄片中磷酸二铵盐的替代品。他们发现，不含磷酸 二盐的薄片的卷烟与参比卷烟相比“刺激性小，丰满度好，烟草口 感佳 ”[15,30]。 行业文件还提及尿素 - 尿酶体系， 并指出， 尿素能够 显著提高烟气的 pH， 并增加游离态烟碱含量， 并在吸烟之前的化 学惰性比较强 [31]。然而，尿素分析起来比较困难，且尿酶在水的作 用下能分解为氨和二氧化碳。如果在分析过程中使用到水萃取，那 么烟丝中尿素的测定就以氨的形式来进行。在另外一份行业文件中， Johnson[2] 声称， 作者没有 “你不会发现所有加入到烟草中的尿素” ； 对其进行解释， 但可能是要指出， 尿素一旦加入， 就会完全反应， 因此不会被发现。 在 1977 年，Lorillard 烟草公司研究了加入钾离子或钙离子等无 机阴离子是否能够提高烟气 pH， 并增强卷烟的效果 [32]。该报告声称， 因为这些化合物在烟草中天然存在，不必对其进行大量毒理学研究。 另一项行业研究声称，使用碳酸钾处理烟草，会提高烟气的 pH，但 不像氨那样增加挥发性碱的的总量 [33]。钾离子比氨的碱性强，而且 钾离子和钙离子在美国的流行卷烟品牌中都存在。在德国，磷酸二 ·207·
烟草制品管制科学基础报告： WHO 研究组第五份报告
铵盐是禁止使用的，那些能够热分解成碱的有机或无机化合物，如 碳酸钙，被用来提高烟碱的传输量 [34]。钾或钙等碱金属并不一定要 人为加入到烟草中，因为其在烟叶中的含量水平可通过肥料或纯化 过程来调节。那些被用来作为添加剂的自然生成的化合物不易进行 分析， 因为这些化合物在未被处理或改造的烟叶中的含量未知， 所以， 在没有空白烟草基质的情况下，尚无一个可靠的方法来区分自然生 成和外部添加的化合物的含量差异。 在雷诺公司关于烟碱传输的一个讨论中 [35]，烟草公司的科学家 对潜在的“对卷烟企业来说严重的添加剂事件”表示了担忧，并希 望通过使用烟草中自然生长的化学物质来达到与菲利浦·莫里斯公 司卷烟类似的柔和度，以避免以后不得不对产品进行改造，来满足 未来可能的管制措施。不使用添加剂（特别是在部分国家中禁用的 添加剂）而达到混合型卷烟令人满意的效果的一个途径是对烟叶进 行调节。行业文件所涉及的基因调节有通过体细胞克隆变异和混合 排序的高烟碱含量白肋烟 [36]， 以及高烟碱含量的烤烟 [37-39]。Quest 卷烟加入了经过基因修饰不含烟碱的烟草 [40]。菲利浦·莫里斯公司 召开的“ 世界范围生物技术评估会 ”[41] 列出了几个感兴趣的领域， 如增加香味和质量等，但没有讨论质量的提高是否包括通过烟叶碱 性的增加来代替诸如氨这类添加剂。1999 年，菲利浦·莫里斯烟草 生物技术研究组的报告讨论了通过酶修饰技术来提高烟草中还原性 糖含量的可能性 [42]。2003 年，菲利浦·莫里斯公司给予北卡罗来纳 州立大学的研究人员大量研究经费，以绘制烟草基因图谱。对于媒 体的质疑，菲利浦·莫里斯公司声称这项研究是为了降低烟草的有 害成分 [43]。这似乎也合情合理，因为不管是通过基因工程还是酶修 饰技术，都可以生产出新型烟草，从而达到期待的多样性，并保证 ·208·
附录2 氨在游离态烟碱传输中的作用：近期研究及分析挑战
在口味和“冲击力”之间找到微妙的平衡，来使消费者使用该产品， 而不使用那些因使用添加剂而可能在未来的管制市场中存在问题的 产品。 卷烟烟气化学是复杂的。在美国市场上销售的大部分现代卷烟 品牌， 其烟气中的氨释放量较低， 不会是改变烟气 pH 并创造出最 适合游离态烟碱形成的碱性环境的唯一原因。烟草烟气中已经鉴定 出了数百种碱性成分，其中大部分是氮杂环化合物，这些化合物可 能是烟草香气的来源 [44,45]。 在早期的行业文件中， 烟气中的氨是单 独测定的，并被包括在总挥发性碱的测定之中。这些碱包括游离氨、 烟碱、吡啶、生物碱、吡嗪、吡咯衍生物和挥发性氨， 这些化合物 能和烟气中的醛类化合物形成席夫碱，并被进一步热解为“引起烟 气碱性的碱性氮化合物 ”[46]。 该文件声称， 总挥发性碱的测定“ 与 烟气 pH 有线性关系， 而且与总生物碱和总氮也有强相关性 ”[47]。 有意思的是， 在磷酸二铵盐 - 糖反应中形成的双氧果糖吖嗪生成烟 气中的几种吡啶及吡嗪类化合物 [2,48]。在白肋烟中含量很高的氨基酸 类化合物， 也能和糖反应生成相似的弱碱性化合物 [49,50]。 烟碱作为 烟叶中含量最高的化合物之一，能热分解为氨、胺类和吡啶。在菲 利浦·莫里斯公司的一篇关于滤嘴对烟气化学成分影响的综述中 [51]， 烟气被描述为总碱部分（吡嗪、 吡啶和生物碱）和总酸部分（有机酸、 苯基酸、酚酸和脂肪酸） ，而总碱部分含量要高些。因此，除氨外， 还有很多化合物创造碱性烟气成分，而氨不能被看做唯一的导致烟 气碱性的成分。然而，尽管不是直接导致，加氨技术还是在很大程 度上是导致烟气弱碱性的重要原因。 行业文件中还有其他一些调节游离态烟碱传输和摄入的方式。 可可和薄荷是两种常用的卷烟添加剂，可作为潜在的支气管扩张药， ·209·
烟草制品管制科学基础报告： WHO 研究组第五份报告
因此可以增加吸入深度和体积， 并可以实现对烟碱更好的吸收 [52]。 碳酸钙和碳酸钠等滤嘴添加剂能提高烟气的 pH，可能会免除向烟丝 中添加碱性物质的需要 [53]。增加纸的孔隙率及滤嘴通风率也能够影 响烟气的粒径或提高烟气的 pH。 高度通风卷烟的气溶胶离子浓度 相对较小，所以它们正常的合并速率就慢（保持粒子小的时间越长， 就有越大的表面积以有利于“排气” ） 。滤嘴通风孔起重要作用的另 外一个机理是通过滤嘴通风孔的空气是一种“干燥气体” 。气溶胶中 水含量的降低能够显著提高烟气 pH，这更有利于烟气中游离态烟碱 的形成。烟草混合物的不同、膨胀烟丝的使用以及烟叶在烟茎中位 置的不同， 都会在不使用化学添加剂的情况下， 改变烟气 pH 及其 化学和成分。 尽管加氨技术已经表明烟草行业可以调节烟碱传输量，烟草行 业已经花费了 50 年来研究、设计和完善其他技术，以期能够控制烟 碱的剂量，在烟草制品对新吸烟者保持吸引力的同时，还能保持“老 烟民”具有“愉悦感” 。加氨技术可以被视为一种较老的技术，该技 术还在一些产品和再造薄片中利用， 但在现代美国混合型卷烟中， 该技术并不是一个必要的设计因素。许多变数会影响游离态烟碱的 传输，这说明氨和游离态烟碱之间并没有直接联系。氨及氨添加剂 在烟碱传输中的作用依然存在疑问，其中最重要的是氨是否会影响 烟气的碱性， 进而影响游离态烟碱的传输。 如果再造烟草薄片不 使用加氨技术，那么它的存在还会影响游离态烟碱的传输么？在前 5~20 秒内烟碱吸收速率的不同是否会反映游离态烟碱传输的不同？ 我们认为这些问题是最重要的问题之一，而且迄今为止还没有对这 些问题进行充分研究的报告。
·210·
附录2 氨在游离态烟碱传输中的作用：近期研究及分析挑战
A2.5 参 考 文 献 [1] Schori TR. Free nicotine: its implications on smoke impact. Bates:542001986-96; 1979 =(http://legacy.library.ucsf.edu/tid/ rlk46b00). [2] Johnson R. Ammonia technology conference minutes. Bates: 508104012–164;1989 (http://legacy.library.ucsf.edu/tid/cfl36b00). [3] Stevenson T, Proctor RN. The secret and soul of Marlboro: Phillip Morris and the origins, spread, and denial of nicotine freebasing. Am J Public Health 2008;98:1184–94. [4] Blevins RA. Letter: Free nicotine. Bates: 500917503; 1973(http://legacy. library.ucsf.edu/tid/gnq46b00). [5] Backhurst JD. A relation between“ strength ”of a cigarette and the in the smoke. Bates: 620364222; 1965 (http:// “extractable nicotine” legacy.library.ucsf.edu/tid/kgt83f00). [6] Ashley DL, Pankow JF, Tavakoli AD, Watson CH. Approaches, challenges, and experience in assessing free nicotine. In: Henningfield JE, London ED, Pogun S, editors. Nicotine psychopharmacology (Handbook of Experimental Pharmacology, No. 192). Berlin: SpringerVerlag; 2009:437–56. [7] RJ Reynolds. Nicotine toxicity. Bates: 511194087–114; 1977 (http:// legacy.library.ucsf.edu/tid/ggg53d00). [8] Reininghaus W. Bioavailability of nicotine. Bates: 3990473388–93; 1994 (http://legacy.library.ucsf.edu/tid/jgn13j00). ·211·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[9] Ireland MS. Research proposal — development of assay for free nicotine. Bates:00044522–3; 1976 (http://legacy.library.ucsf.edu/tid/ nts76b00). [10] Larson TM, Morgan JP. Application of free nicotine to cigarette tobacco and the delivery of that nicotine in the cigarette smoke.Bates: 00781406; 1976 (http://legacy.library.ucsf.edu/tid/pts76b00). [11] Riehl TF. Project SHIP main technical conclusions 840400–841100. Bates:650554484–8; 1984 (http://legacy.library.ucsf.edu/tid/ gxq23f00). [12] Philip Morris. Bates: 2060554039; 1999 (http://legacy.library.ucsf.edu/ tid/iqf13e00). [13] Seeman JI, Carchman RA. The possible role of ammonia toxicity on the exposure,deposition, retention, and the bioavailability of nicotine during smoking. Food Chem Toxicol 2008;46:1863–81. [14] Callicutt CH, Cox RH, Hsu F, Kinser RD, Laffoon SW, Lee PN, et al. The role of ammonia in the transfer of nicotine from tobacco to mainstream smoke. Regul Toxicol Pharmacol 2006;46: 1–17. [15] Tang JY. DAP-free recon development update. Bates: 508102219–224; 1991(http://legacy.library.ucsf.edu/tid/dtm51f00). [16] Aulbach PL, Black RR, Chakraborty BB, Diesing AC, Gonterman RA, JohnsonRR, et al. Root technology: a handbook for leaf blenders and product developers.Louisville, Kentucky: Brown & Williamson. Bates: USX47046–105; 1991 (http://legacy.library.ucsf.edu/tid/ nqz36b00). [17] Vickery HB, Pucher GW. The determination of“free nicotine”in ·212·
附录2 氨在游离态烟碱传输中的作用：近期研究及分析挑战
tobacco: the apparent dissociation constants of nicotine. J Biol Chem 1929;84(1): 233–41. [18] McKinney DL, Gogova M, Davies BD, Ramakrishnan V, Fisher K, Carter WH.Evaluation of the effect of ammonia on nicotine pharmacokinetics using rapid arterial sampling. Nicotine Tob Res 2012;14:586–95. [19] Hellams RD. pH determination of mainstream cigarette smoke. Bates:2050871031; 1984 (http://legacy.library.ucsf.edu/tid/jgu46b00). [20] British American Tobacco. How does pH affect transfer of nicotine to smoke?Bates: 566630379–83; 1995 (http://legacy.library.ucsf.edu/tid/ ajs46b00). [21] Pankow JF, Tavakoli AD, Luo W, Isabelle LM. Percent free base nicotine in the tobacco smoke particulate matter of selected commercial and reference cigarettes. Chem Res Toxicol 2003;16(8): 1014–8. [22] Routh WE. Ammonia treatment of tobacco. Bates: 00044858–79; 1977 (http://legacy.library.ucsf.edu/tid/jtm99d00). [23] Johnson R (1984) The unique differences of Phillip Morris cigarette brands—R&D-B016-84. Bates: 103281081–112; 1984 (http://legacy. library.ucsf.edu/tid/ton66b00). [24] Crellin RA (1985) Project Ship (examination of branded and experimental products from the USA). Bates: 570316962 (http:// legacy.library.ucsf.edu/tid/pls46b00). [25] Christopher FH Jr (1978) Free nicotine/ammonia treatment of tobacco. Bates:505197081 (http://legacy.library.ucsf.edu/tid/ ·213·
烟草制品管制科学基础报告： WHO 研究组第五份报告
cru46b00). [26] Kusama M, Matsuki T, Sakuma H, Sugawara S, Yamaguchi K. The distribution of cigarette smoke components between mainstream and sidestream smoke II. Bases. Bates: 501523990–4006; 1983 (http:// legacy.library.ucsf.edu/tid/kpm77c00). [27] van Amsterdam J, Sleijffers A, van Spiegel P, Blom R, Witte M, van de Kassteele J, et al. Effect of ammonia in cigarette tobacco on nicotine absorption in human smokers. Food Chem Toxicol 2011;49:3025–30. [28] Rose JE, Mukhin AG, Lokitz SJ, Turkington TG, Herskovic J, Behm FM, et al. Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine. Proc Natl Acad Sci U S A 2010;107:5190–5. [29] Henningfield JE, Stapleton JM, Benowitz NL, Grayson RF, London ED. Higher levels of nicotine in arterial than in venous blood after cigarette smoking. Drug Alcohol Depend 1993;33(1): 23–9. [30] Alford ED, Hsieh TC. A major sugar/ammonia reaction product in Marlboro 85’s.Bates: 510001069–79; 1983 (http://legacy.library.ucsf. edu/tid/ylh23f00). [31] Newton P, Johnson R. Urea development. Bates: 620136145–9; 1971 (http://legacy.library.ucsf.edu/tid/gmd43f00). [32] Ihrig AM. Inorganic additives for the improvement of tobacco. Bates: 00382055–62; 1977 (http://legacy.library.ucsf.edu/tid/fku61e00). [33] Glock E. Leaf services monthly report for June: increasing nicotine transfer in smoke. Bates: 514804804–9; 1980 (http://legacy.library. ucsf.edu/tid/tja87h00). ·214·
附录2 氨在游离态烟碱传输中的作用：近期研究及分析挑战
[34] Wigand JS. Additives, cigarette design and tobacco product regulation. A report to World Health Organization Tobacco Free Initiative Tobacco Product Regualtion Group. Bates: 3990512671– 715; 2006 (http://legacy.library.ucsf.edu/tid/ccj13j00). [35] RJ Reynolds. Regarding means to achieve nicotine balance and deliveries.Bates: 508408649–770; 1992 (http://legacy.library.ucsf.edu/ tid/ikv46b00). [36] Brown & Williamson. High nicotine Burley flavor development. Bates:589100515–9; 1996 (http://legacy.library.ucsf.edu/tid/ ewm41f00/). [37] Brown & Williamson. Y1 product. Bates: 661071395A–6 (http:// legacy.library.ucsf.edu/tid/uql66b00). [38] Brown & Williamson. The Y1 story. Bates: 682727985–90 (http:// legacy.library.ucsf.edu/tid/eqv70f00). [39] Fisher PR. Y1 product development. Bates: 620017189–91 ; 1990 (http://legacy.library.ucsf.edu/tid/chf93f00). [40] Lightner JG. Cigarette information highlights: Quest Menthol Lights. Bates:3039591093; 2004 (http://legacy.library.ucsf.edu/tid/ uko91g00). [41] Gadani F, Rossi L. Worldwide biotechnology assessment: inventory of research activities. Bates: 2073337017–9; 1997 (http://legacy.library. ucsf.edu/tid/wyz27d00). [42] Philip Morris. Final report tobacco biotechnology: a worldwide technology assessment. Bates: 2065359566–9631; 1999 (http://legacy. library.ucsf.edu/tid/itb29h00). ·215·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[43] Philip Morris. Response to media inquiry—genome technology 2.271 RWL.doc.Bates: 3008849132–4; 2004 (http://legacy.library.ucsf.edu/ tid/vde30i00). [44] Schmeltz I, Stedman RL, Chamberlain WJ, Burdick B. Composition studies ontobacco. XX. Bases of cigarette smoke. Tob Sci 1964;8:82– 91. [45] Heckman RA, Best FW. An investigation of the lipophilic bases of cigarette smoke condensate. Bates: 620398463–70; 1981 (http:// legacy.library.ucsf.edu/tid/xvz90c00). [46] Ihrig AM. pH of particulate phase. Bates: 87644270–81; 1973 (http:// legacy.library.ucsf.edu/tid/iwr46b00). [47] Creighton DE. The significance of pH in tobacco and tobacco smoke. Bates:500104402; 1988 (http://legacy.library.ucsf.edu/tid/edk86b00). [48] Anonymous. Ammonia process comparisons fructose conversion vs. tobacco temperature. Bates: 681915855 (http://legacy.library.ucsf. edu/tid/pek46b00). [49] Wang MX. Analytical results of the experimental flavor samples. Bates: 583150454–5; 1986 (http://legacy.library.ucsf.edu/tid/ qar03f00). [50] Evans RJ, Nimlos MR. Kinetics and mechanisms of the pyrolysis of amino acids.Bates: 3003669136; 2002 (http://legacy.library.ucsf.edu/ tid/fnh95g00). [51] Lin SS. Basic flavor investigation low tar / high flavor literature review. Bates:2050878148–90; 1990 (http://legacy.library.ucsf.edu/ tid/wgu46b00). ·216·
附录2 氨在游离态烟碱传输中的作用：近期研究及分析挑战
[52] Ferris Wayne G, Connolly GN. Application, function, and effects of menthol in cigarettes: a survey of tobacco industry documents. Nicotine Tob Res 2004;6(Suppl 1):S43–54. [53] Irwin WDE. Comment by W.D.E. Irwin on Handbook for leaf blenders and product developers. Bates: 400820196–7; 1983 (http:// legacy.library.ucsf.edu/tid/ogc54a99).
·217·
烟草制品管制科学基础报告： WHO 研究组第五份报告
附录 3 通过降低烟碱释放量至不会引起或维持成 瘾的水平来降低卷烟产品的潜在依赖性
G. Ferris Wayne，WHO 顾问 A3.1 引言 A3.2 烟草致瘾模式 A3.2.1 烟碱成瘾 A3.2.2 烟碱响应的个体差异 A3.2.3 烟草中的烟碱传输 A3.2.4 成瘾的双重强化模式 A3.2.5 药物期望 A3.2.6 社会和环境因素 A3.2.7 小结 A3.3 成瘾阈值的建立 A3.3.1 烟碱的自我给药 A3.3.2 烟碱依赖的形成 A3.3.3 低烟碱卷烟的增强作用 A3.3.4 成瘾阈值与强化阈值 A3.3.5 条件刺激的阈值 A3.3.6 小结 ·218·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
A3.4 降低烟碱的可行性 A3.4.1 卷烟烟碱传输 A3.4.2 降低烟草中烟碱的方法 A3.4.3 去烟碱化或低烟碱卷烟 A3.4.4 低传输率卷烟中的游离态烟碱 A3.4.5 引起补偿抽吸的产品 A3.4.6 降低烟碱的产品配方和途径 A3.4.7 小结 A3.5 潜在的行为效果和人群效果 A3.5.1 对卷烟消费量的潜在影响 A3.5.2 对吸烟行为的潜在影响 A3.5.3 对戒烟的潜在影响 A3.5.4 对卷烟使用购买的潜在影响 A3.5.5 潜在的不可预料的行为后果 A3.5.6 潜在的人群差异 A3.5.7 潜在的健康影响 A3.5.8 非法销售含烟碱卷烟产品的可能性 A3.5.9 人群影响模型 A3.5.10 小结 A3.6 降低烟碱的政策手段 A3.6.1 对烟碱的全面管制 A3.6.2 绩效标准 A3.6.3 逐渐性降低与急剧性降低 A3.6.4 烟碱的可替代形式 A3.6.5 戒烟与行为治疗 ·219·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A3.6.6 监测 A3.6.7 消费者教育和信念 A3.6.8 公众对降低烟碱政策的支持 A3.6.9 未知的市场影响 A3.6.10 小结 A3.7 结论 A3.8 建议 A3.9 参考文献
A3.1 引 言 近二十年以前，Benowitz 和 Henningfield[1] 提出逐渐减少卷烟烟 碱释放量作为一种减害策略。此后，一些公共卫生科学家认为，这种 做法可能会对公众健康产生重大的积极影响 [2–8]。减少烟碱政策的目 标是减少吸烟者的药理成瘾，这也帮助他们戒烟或鼓励他们转向危害 性较小的烟碱来源，还可防止初吸者从尝试或偶尔吸烟转向成瘾 [2,6]。 这一策略符合 WHO《烟草控制框架公约》 （FCTC）第 9 条的要求， 即对烟草制品成分和释放物的监管指南 [9,10]。 降低烟碱策略是基于如下的假设 ： 烟碱是烟草使用的主要原因， 且烟碱释放量阈值能被确定，低于该阈值的卷烟依赖性的产生和维 持会大大降低 [2]。在评估这种方法可能的效果时，必须解决理论和 实践两方面的问题 ： 烟碱在引发和维持烟草成瘾中的作用，烟碱成 瘾所必需的剂量，与烟碱化学形态或传输机制相关的差异性，在个 ·220·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
体或易感群体（例如儿童或有精神类疾病人群）中烟碱响应的不同， 降低烟草中烟碱的过程及其潜在影响， 对低烟碱卷烟的行为反应（如 烟碱成瘾的吸烟者补偿性抽吸或增量抽吸） ，以及低烟碱卷烟的相对 毒性。 最初评估降低烟碱策略效果的障碍是缺乏科学依据。例如，最 受关注的是，低烟碱的产品可能由于被更深度地抽吸或频率更高地 抽吸而增加危害性 [11,12]。 最近的临床研究似乎解决了这一问题， 即 使在非常低剂量的烟碱水平，也显示大大减少了抽吸和有害物质的 暴露，几乎没有补偿性 [13–15]。在本附录中，作者综述了有关烟草和 烟碱成瘾的科学现状，烟碱成瘾阈值的概念，以及将卷烟中烟碱降 低到致瘾阈值之下的实际可行性。 环境因素也能影响烟草制品的可接受度和使用性，可能在降低 烟碱策略的有效性中发挥作用。需要考虑的因素包括是否有烟碱替 代来源，替代产品的管制范围，高烟碱释放量卷烟的非法销售的潜 在性增长， 依赖治疗的有效性， 对吸烟者和潜在吸烟者关于使用、 戒断和治疗的教育，以及公众对烟碱管制的支持。例如，得到低毒 性烟碱传输系统和治疗药物的障碍可能会刺激非法销售或驱使吸烟 者选择其他可能有害的烟草产品 [16]。在本附录中，作者综述了降低 烟碱策略预期的人群效果，以及支持这一策略的政策手段，并最大 限度地减少降低烟碱所造成的任何意料之外或负面的健康影响。 在美国医学研究院的报告《清洁烟气》[17] 中，从烟草制品毒性 和促进吸烟尝试和使用的因素两方面（参见 [5,18]） ，提供了一个有 用的危害性评估框架。卷烟和其他燃烧类烟草不仅比其他替代产品 （如药用烟碱）有更大的毒性，还由于其有效性、致瘾性和吸引力更 大而具有无与伦比的潜在危害。即使没有降低毒性，通过去除开始 ·221·
烟草制品管制科学基础报告： WHO 研究组第五份报告
或继续使用这些致命产品的诱因 , 降低烟碱策略可以大大减少人群危 害 [5]。本附录中， 作者在现有科学证据的基础上评估这一后果的可 能性，并确定在哪些领域还需要开展更多的研究。
A3.2 烟草致瘾模式 早期尝试减少与吸烟相关的疾病负担是基于减少卷烟产品的烟 气传输，主要通过引入滤嘴通风孔稀释烟气、使用膨胀烟丝以及改 变产品的其他方面 [19]。然而，吸烟者通过改变他们的吸烟行为对减 少的传输进行简单地补偿 ： 抽吸更长和更频繁或增加他们每天吸烟 的数量，以维持对烟碱和有害物质的暴露 [20,21]。 Parascandola[22] 观察到，过去减少烟草使用危害的尝试的失败是 由于公共卫生界不完全理解控制吸烟行为的因素，特别是烟碱在这 种行为中的驱动作用。降低烟碱策略是直接基于以下假设，即烟碱 是烟草中主要的精神类药物，是持续使用烟草的关键。对烟碱成瘾 和烟草使用的科学理解是不断发展的。对产品管制效果（无论意料 中还是意料外）的预期需要对烟碱和烟草依赖的明确、完全的理解。 A3.2.1 烟碱成瘾 烟碱是有很高致瘾性的强效药物，精神奖赏效应的急性给药剂 量小于 1 mg[23]。 低剂量的烟碱刺激中枢神经系统和周围神经系统， 引起兴奋、情绪改善及增加心率和血压 ； 高剂量可能引起心动过缓、 低血压和情绪低落。烟碱可提高运动反射和感知能力，包括注意力 ·222·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
和记忆力 [24]。通过重复暴露烟碱对行为上影响和心血管影响的耐受 性迅速形成。 因此， 烟碱成瘾的药理学基础是积极性强化（ 激励、 情绪、表现）的结合，以及避免出现烟碱缺乏时的戒断症状 [23,25]。 烟碱传输系统致瘾的可能性取决于它的剂量机制，包括烟碱的 传输速率和烟碱能被吸收的容易程度 [26,27]。 卷烟就是烟碱传输的特 别有效的形式。当个体从卷烟吸入烟气，烟草中的烟碱通过烟气粒 相物携带进入肺部，在肺部被迅速吸收并运送到大脑。烟碱快速扩 散到脑组织，并与烟碱胆碱受体结合。在吸完烟之后，烟碱的逐渐 减少会导致多巴胺等神经递质的释放低于正常值，使人感觉不适和 不愉快。其他的烟碱断瘾症状包括易怒、 烦躁、 焦虑、 注意力不集中、 心率降低、食欲增加和失眠 [23]。 烟瘾是由重复的行为维持的。每天的第一支卷烟产生很大的药 理作用使情绪高涨 ； 接下来的卷烟，由于烟碱在体内累积，造成更 大的耐受量，在相继的卷烟之间戒断症状变得更加明显。大多数吸 烟者倾向于每天吸入相同的烟碱量，并调整他们的吸烟行为来补偿 获得烟碱或烟碱从体内清除率的变化，从而调节烟碱的水平 [23]。 强迫性是烟草成瘾的核心特征 ； 其特点是抽吸每支卷烟之后再 出现吸烟的渴望 [28]。既然强迫被定义为包括断瘾症状，对鉴定初吸 者将要发展到确定的吸烟者具有 99% 的灵敏度 [29–31]。 A3.2.2 烟碱响应的个体差异 大多数的烟草使用开始于青少年时期。虽然许多青少年尝试吸 烟， 但只有 20%~25% 的尝试吸烟者成为上瘾的成人吸烟者［32］ 。烟 碱依赖的遗传脆弱性也许可以解释某些人使用烟草。对双胞胎的研 ·223·
烟草制品管制科学基础报告： WHO 研究组第五份报告
究表明，在吸烟的流行性、每天吸烟的数量、戒烟的能力，以及在 戒烟中戒断症状的特征等方面， 遗传性大于 50%[33]。 吸烟的其他风 险因素包括同伴和父母的影响、个体个性特质和疾病，如抑郁和焦 虑 [32]。 早期的烟碱暴露与更严重的依赖以及成年吸烟者吸烟增多相 关 [1,34–37]
。动物模型研究佐证了这些结果，其中在人类青春期暴露相
应地导致更高的自身给药 [38–44]。这些结果表明，发育中的大脑更容 易受到来自烟碱的永久性改变造成的对成瘾的支持 [23,45]。 已观察到烟碱代谢率个体差异大约为四倍 [45,46]。女性比男性代 谢烟碱更快 [23,47]， 这可能有助于提高成瘾。 女性也比男性对烟碱更 敏感 [48] 且更难戒烟 [49–53]。女性的吸烟行为更大程度上受到条件性暗 示和负面因素影响，而男性则更可能是响应药理性提示吸烟并调节 他们的烟碱摄入 [54–57]。 有精神类疾病和 / 或物质滥用障碍的个体烟碱依赖的发生率也高 得多，每天抽更多烟，并更难戒烟 [58–62]。烟碱可作为一些机能失调的 自我药疗的一种方式 [63]，尤其是精神分裂症，因为烟碱可以提高感觉 门控的不足 [64,65]，对于抑郁，因为烟碱可以脱敏烟碱受体，功能上类 似于许多抗抑郁药物 [66,67]。此外， 吸烟 抑制单胺氧化酶， （但不是烟碱） 其能促进抗抑郁药物活性 [68]。患有精神疾病的吸烟者在总吸烟者中占 三分之一以上，并且超过一半是烟碱依赖吸烟者 [58,69,70]。 轻度或偶尔吸烟者的人群每天抽吸五支或更少的卷烟或者不是 每天吸烟，且似乎吸烟主要是为了积极性强化烟碱作用 [23]。他们使 用卷烟经常与特定活动相联系，例如饭后或饮酒时，而且很少对负 面作用产生响应 ； 他们可能对吸烟提示有更多反应 [71]。虽然他们很 少或没有感受戒断症状，但许多的偶尔吸烟者戒烟困难，意味着依 ·224·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
赖形式有别于每日吸烟者。 A3.2.3 烟草中的烟碱传输 烟草烟气是有几千种化合物的复杂混合物 [19,26]，可能不是独立 的 [72] 就是与烟碱结合 [73,74] 来促进卷烟的致瘾能力。 非质子化或游离态的烟碱很容易通过口腔黏膜和上呼吸道吸收， 比如从无烟烟草产品或雪茄中。当以这种形式摄入，烟碱在上呼吸 道产生刺感或“叮咬感” ，可能会被认为是刺激性的或令人不适的。 然而，在卷烟烟气中，很大比例的烟碱是质子化或结合态，它更容 易吸入并被带入呼吸道深处。结合态烟碱不像非质子化烟碱一样迅 速或容易地被吸收， 不能提供相同的感官刺激 [26,75]。 现代卷烟构造 的目标是在烟碱释放效率和适口性之间提供一个理想平衡。 例如， 氨含量高可以增加卷烟烟气中非质子化烟碱的比例，产生更快速或 更有效地吸收烟碱 [76]。糖和其他添加剂可能会增加对非质子化烟碱 粗糙感的补偿，促时更深地吸入 [26]。 烟气的感官特征（口味、香气、气管 / 支气管的感受）向吸烟者 提供直接提示，指导吸烟行为处于个性化的抽吸水平 [77,78]。在缺乏感 官成分时吸烟的运作特征（夹持、抽吸、吸入）对吸烟者不能产生明 显的满足感，如在不燃烧卷烟的研究所显示的 [79]。但是，感官成分的 变化，如吃味和冲击，可能对吸烟奖赏的比较有显著影响 [77,80]。例如， 嗅觉和味觉提示的减弱对卷烟烟气的愉悦感和行为增强作用都减少 了，特别是在女性吸烟者中 [77,81]。 在卷烟烟气感官构成中烟碱发挥核心作用。依据呼吸道感受到 的感官作用， 含烟碱的卷烟一贯比去除烟碱的卷烟强烈 [81,82]。 吸入 ·225·
烟草制品管制科学基础报告： WHO 研究组第五份报告
烟碱气溶胶具有较强的刺激作用 [83]，甚至静脉注射烟碱也能引起呼 吸道感官作用 [27,84]。 烟气组分的平衡对抵消烟碱过度的粗糙感并使烟气可口是必要 的。 “焦油”是烟气中除烟碱外研究总粒相物的一种常用测量方法， 焦油与烟碱的比被认为是烟气整体粗糙感的一个决定性因素 [77,85]。 其他的烟草成分可提供另外的刺激， 不是与烟碱协同就是替代烟碱 [26]。 薄荷醇具有强烈的感官刺激特性，是一种常见的烟草添加剂，并被 用于在烟碱传输极低的产品中补偿减少的烟碱 [86,87]。 薄荷醇因其本 身的麻醉特性 [88] 以及可增加生物膜的渗透性 [89] 也可以减轻一些烟 碱的刺激作用，会影响烟碱的吸收。 烟碱以外的烟气成分可能对大脑有直接的药理作用或与烟碱相 互作用加强烟碱的影响。Brody 等 [90] 发现在抽吸去烟碱化卷烟的个 体体内明显存在 α4β2 烟碱胆碱受体，这表明，即使不含烟碱，卷烟 烟气也可能有明显的药理作用。各种微量烟草生物碱自身有强化作 用（降烟碱） ，或者具有增强烟碱的效果（假木贼碱、降烟碱、新烟 草碱、可替宁和麦司明）[91,92]。在动物模型中乙醛是自我给药的 [72]， 已表明其对烟碱有潜在的强化作用，尤其是在未成年动物中 [73,93–95]。 哈尔满和去甲猪毛菜碱是乙醛 的缩合产物 [73]， （抑制单胺氧化酶） 当给予大鼠时，它们大幅增加烟碱的自我给药 [74,96,97]，可能是通过发 挥抗抑郁作用，或通过增加烟碱释放的神经递质（如多巴胺）寿命 来增强烟碱的强化作用 [98]。 A3.2.4 成瘾的双重强化模式 虽然烟草的致瘾作用往往仅归因于烟碱 [99]， 单独只有烟碱而 ·226·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
不出现烟草时，在双盲方案的研究中并没有被证明确实具有强化作 用 [100,101]。像其他兴奋剂一样，烟碱具有通过非药物刺激来增加条件 强化的非条件作用，烟碱强化和刺激物的存在之间有独立的直接关 联 [102–108]。 非药物刺激的重要作用已经在啮齿类动物研究中证明，其中中 止与静脉注射烟碱相关联的环境刺激会减少自我给药，几乎与去除 烟碱的效果一样 [102,109]。 在大鼠 [110] 和松鼠猴 [111] 试验中， 与烟碱关 联的轻微刺激维持的响应速率与由烟碱维持的相当。没有环境刺激 的行为干预，直接传输烟碱，产生非常小的自我给药 [112]。 一个新的假说是，被视为实验室动物高比例的自我给药或人类 吸烟的烟碱成瘾，是通过伴随烟碱摄入的强化刺激，以及烟碱增加 对这些刺激强化作用来支撑的。在这种双重强化模型中，烟碱首先 作为一个初始强化剂，作为条件强化剂通过关联建立中性刺激，然 后作为增强强化剂，放大烟碱关联条件强化的刺激 [113]。随着烟碱的 影响与各种非烟碱的刺激产生关联，刺激获得条件值或作为未来烟 碱传输的提示。因此，烟草的条件刺激可以用维持吸烟或持续戒烟 后失败或复吸的方式改变行为。因此，通常与吸烟有关联的接近的 刺激，例如一支点燃的卷烟，可以引发吸烟者而不是非吸烟者的渴 求 [114]。这一假说解释了在决定对烟气的主观性反应 [77,84] 以及对烟草 渴望、想要吸烟和给予安慰剂卷烟人群的烟草戒断症状 [115] 的主观性 报告的减少中，与烟碱相关的感官刺激的重要性。 Rees 等 [116] 观察到，某种类型烟草产品感官提示可能非常特别， 表明这样的特殊品牌提示获得的激励显著，依据品牌特性强化使用。 他们认为，除去烟碱的卷烟（如 Quest）商业吸引力有限的部分原因 是已建立的化学感官提示——烟碱剂量突然被破坏。尽管烟碱给药 ·227·
烟草制品管制科学基础报告： WHO 研究组第五份报告
增加明显的感觉提示，但它不改变适口性 [117]。因此，烟碱的刺激放 大效应可能对已经有积极的关联的熟悉的感官刺激最有效，比如类 可可或薄荷醇的味道。 A3.2.5 药物期望 药物期望在吸烟者的反应中起着重要作用 [118–121]，尤其是在女性 中 [56]。 根据期望理论， 如果吸烟者有抽吸有效烟碱卷烟的刺激期望 （或 剂量）且有烟碱降低吸烟冲动的期望反应，则当他（或她）抽吸安 慰剂卷烟时，欲望降低 [122,123]。得到烟碱的期望增加了“好感度”和 烟碱替代品的临床疗效，这一期望与药理因素相互作用产生综合的 主观性和行为反应 [120,124,125]。 在使用平衡的安慰剂设计的一项研究中，期望用吸烟来缓解焦 虑情绪诱发负面影响的吸烟者，即使他们抽吸安慰剂卷烟，心情也 有所改善 [126]。告诉吸烟者其抽吸的是烟碱，这会降低其抽安慰剂卷 烟的欲望，但对烟碱给药的影响不大，这表明不是烟碱就是抽吸了 含烟碱的卷烟的信念，足以减轻吸烟的欲望，但剂量期望不增加烟 碱的作用 [121]。 药物期望可由指示吸烟者已被给定一定烟碱剂量可能性的感官 刺激获知，因为存在条件性关联。这些提示可能被吸烟者表达为卷 烟的“强度” ，反映了烟碱产生的冲击与其他烟气成分的一些组合作 用，在口腔、三叉神经或其他受体间相互作用 [26,127,128]。 期望也可以从非药物刺激中分开。例如，抽吸同样去烟碱化的 卷烟， 带着不同的剂量预期， 有不同的影响 [129]。 烟碱释放量的信 息对吸烟者吸入烟碱的主观反应发挥作用，特别是对积极性强化关 ·228·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
联的渴望（ 如打算抽烟 ） ， 而不是对负面强化关联的渴望（ 即消除 断瘾 ） [120,130]。 尽管吸烟者期望抽烟获得愉快感受， 但他们不预期 从不太熟悉的配方中获得积极性影响 [123]。 A3.2.6 社会和环境因素 依赖不局限于生理体验， 也通过行为习惯形成， 受环境因素支持。 烟草使用的社会背景显然与了解各种烟草制品的使用模式有关系， 这是对获取或戒断的外部压力程度。De Leon 等 [131] 呼吁对烟草使用 采取措施，因为环境因素决定吸烟行为和依赖性。这些将包括使用 烟草制品中哪些是被允许的（包括法律上的和从社会准则方面的） ； 烟草使用的成本， 包括个人和家庭两方面； 烟草使用相关的描述程度， 例如性别、宗教信仰和社会地位。了解这些因素可能对了解在烟草 依赖之前的烟草尝试是有用的，导向选择戒断的过程以及戒断效果。 A3.2.7 小结 • • • • • • 烟草成瘾由烟碱维持。不传输烟碱的卷烟不维持成瘾。 烟碱成瘾由积极性强化（即情绪、性能）和避免断瘾症状两 方面支持。 对烟碱的反应有相当大的个体差异。女性对烟碱的代谢与男 性不同，对条件性提示更敏感。 在青少年时期开始的烟碱依赖会影响成年后的依赖。 烟草烟气传输的烟碱不同于其他形式的烟碱。 烟草传输的烟碱的致瘾性的关键因素包括烟碱的形态、便于 ·229·
烟草制品管制科学基础报告： WHO 研究组第五份报告
吸入、 相关的感官刺激以及其他烟气组分的致瘾性或强化 作用。 • • • 除去烟碱的烟草比没有烟草的烟碱对减少吸烟者渴望和产生 的愉悦感更有效。 证据支持双重强化模型的有效性， 其中条件刺激的（ 烟气 ） 强化依赖超过由非条件烟碱产生的依赖。 药物期望改变对含烟碱和不含烟碱卷烟的反应。期望可能反 映了在传输机制内（感官刺激）中的提示以及来自广告、包 装或其他形式传播的信息。 • 依赖的发展与决定产品接受性和吸引力的社会背景和环境因 素有关。
A3.3 成瘾阈值的建立 烟碱成瘾阈值的概念指获得和维持成瘾所需要的最小烟碱摄入 量。在他们最初的建议中，Benowitz 和 Henningfield[1] 估计烟碱成瘾 阈值为 5 mg/d， 血浆可替宁水平对应每天 50~70 ng/mL 的水平。 这 种估计是基于观察实际的吸烟者，而不是操控烟碱暴露的实证性研 究。它可被看作是重要的研究和讨论的起点。 这项最初的方案之后，大量可用的去烟碱化的卷烟已成为降低 烟碱暴露对吸烟行为和主观性措施研究的重要主体 [45,132]。烟碱自我 给药及相关行为已对试验动物进行了研究 [8,113,133,134]。 总之， 这些研 究提供了深入了解极低烟碱水平卷烟的潜在强化作用。 ·230·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
A3.3.1 烟碱的自我给药 Henningfield 及其同事 [27,135] 研究了吸烟者静脉烟碱自我给药。 烟碱的总体反应速率没有可靠地超过那些对生理盐水的反应，尽管 对烟碱的反应倾向于更规律性的间隔。Harvey 等 [136] 为戒烟的男性 吸烟者在 3 小时中， 静脉注射烟碱（0.75 mg/ 注射液、1.5 mg/ 注射 液和 3 mg/ 注射液 ） 和生理盐水。 吸烟者更喜欢所有三个剂量的烟 碱注射。这些剂量高于吸烟者通常的烟碱摄入量，即 1~4 mg/h，从 每小时平均一到两支的卷烟获得 [21]。 烟碱自我给药剂量在吸烟者的平均摄入量范围内，受试的男性 和女性吸烟者被要求选择静脉注射剂量为 0.1 mg、0.4 mg 或 0.7 mg 的烟碱或生理盐水 [137]。0.1 mg 剂量表示了典型卷烟抽吸吸入烟碱 量的近似值。 0.4 mg 和 0.7 mg 剂量比安慰剂更受欢迎， 表明吸烟 者的烟碱强化剂量阈值在 0.1~0.4 mg 之间。 该发现与烟碱识别研究 的结果一致，表明烟碱识别阈值远远低于大多数卷烟品牌传输的烟 碱典型水平。吸烟者和非吸烟者之间没有差异，阈值中位值分别为 3 μg/kg 和 2 μg/kg（ 约 0.23 mg 烟碱和 0.15 mg 烟碱 ）[80]。 但是， 如 Hatsukami 等 [45] 指出， 已报道在烟碱识别中有 100 倍以上的个体 差异。 更多的烟碱自我给药研究是在动物模型中开展而不是在人体中， 烟碱阈值具有类似的结论。Smith 等 [8] 报道烟碱剂量减少到每次输 液 ≤ 3.75 μg/kg 时， 大鼠的烟碱自我给药显著降低， 而每次输液剂 量≥ 7.5 μg/kg 时，相对于维持在 60 μg/kg，自我给药率接近或更高。 在该项研究中，烟碱与其他烟草成分调配以反映烟草使用的影响。 Donny 等 [133] 从大量包括获得及维持烟碱自我给药的研究中考 ·231·
烟草制品管制科学基础报告： WHO 研究组第五份报告
察了剂量 - 效应曲线。他们把获得曲线的峰值设为 20~30 μg/kg。在 大鼠、狗、猴子和人体中得到了类似的结果 [136,138]。在较低的单位剂 量（3.75~10μg/kg） 水平， 平均响应率随着剂量而增加， 但有相当 大的个体差异 ； 一些受试者与生理盐水对照组相比获得烟碱自我给 药 [139,140]。在维持烟碱自我给药期间，通常剂量 - 效应曲线的峰值在 10~30 μg/kg 之间 [141–146]。此外，当单位剂量 <10 μg/kg 时，烟碱自我 给药降低而且差异性增加。在低剂量范围的强化剂量阈值很少被测 定； 然而，在低至 3 μg/kg 的剂量，烟碱的自我给药率超过生理盐水 的，不管是在限制性获得还是在扩展性获得情况下。结果表明在成 年动物中，维持烟碱自身给药的强化阈值可能在 3~7.5 μg/kg 烟碱之 间（0.23~0.56 mg） 符合（虽然略高于）人类研究中所显示的。然而， ， 在大多数研究中，数量和剂量范围很小，限制了准确性。此外，在 一些研究中，给受试者的是受操控的剂量。这不表示吸烟者个体剂 量变化会影响烟碱降低策略的实行 [132]。 大多数烟碱自我给药研究， 包括快速注射高单位剂量的烟碱（每 次注射 15~30μg/kg） 。Sorge 和 Clarks[147] 比较了大鼠的烟碱自我给药， 持续注射 3 秒、30 秒、60 秒或 120 秒，发现缓慢注射优于快速注射； 自我给药被认为在低至 3 μg/kg 的剂量。他们的结果表明，缓慢自我 给药药理上不同于正常过程，并认为剂量传输过程的时间在确定烟 碱强化阈值时发挥着作用。 A3.3.2 烟碱依赖的形成 维持吸烟需要的烟碱剂量可能不同于产生依赖的剂量 [7]。对于 这个问题，尽管缺乏直接的数据，Donny 等 [133] 从比较研究得到的结 ·232·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
论是，维持阈值可能低于产生阈值。这一结论符合观察结果，即对 烟碱的前期暴露能增加烟碱自我给药的产生阈值 [42,143,148]。在青少年 中依赖的产生可能不同于成人。如前所述，未成年大鼠和小鼠似乎 比成年的更容易受到烟碱的强化作用 [41,44,149]， 烟碱自我给药更快产 生且基线水平高于成年的 [40,43,150,151]。 成年雄性大鼠比未成年大鼠在 低剂量烟碱更可能产生烟碱自我给药的证据与结论相矛盾 [140,152,153]。 横截面和纵向研究表明，少于每天吸烟的年轻人报告了依赖症状的 开始 [31,154–158]。尽管比成人每口抽吸小，青少年吸烟者存在生理性地 自我给药烟碱活性剂量 [159–162]。 在青少年吸烟行为与动机中，期望发挥了重要作用。具体来说， 卷烟减少负面影响能力的强烈期望预示着吸烟的增加，不过，由于 期望随着吸烟经验增加而变得更强，它的效果趋稳 [163,164]。在青少年 吸烟者中进行的一项高烟碱释放量及去除烟碱卷烟的研究中，无论 所抽吸卷烟的烟碱释放量是多少，吸烟都减少了负面影响。这种作 用由期望相关的影响所调节 ； 因此，抽吸高烟碱释放量卷烟并具有 强烈的吸烟会减轻负面影响期望的受试者负面影响的降低最大。在 非吸烟的青少年中发现影响没有变化 [165]。在青少年时期开始吸烟并 在随后暴露于烟碱，即使是在日常强化水平之下，可以降低在成年 后对烟碱依赖的阈值，尽管奖赏和强化作用大大减弱 [35,37,151]。 A3.3.3 低烟碱卷烟的增强作用 临床研究证据表明，去烟碱化的烟草可以提供显著的主观满足 感， 并立即减少渴望 [84,115,166–172]， 虽然比例与吸烟者的依赖水平有 关 [173]。 抑制渴望似乎是一个特别稳健的影响， 对消退过程不敏感 [115]。 ·233·
烟草制品管制科学基础报告： WHO 研究组第五份报告
含烟碱和去烟碱化的烟气抑制渴望与随意抽烟相同，但静脉注射烟 碱对抑制随意抽烟只有很少的效果 [174,175]。 烟碱水平非常低的卷烟可能足以维持吸烟行为。大脑成像表明， 抽吸一支烟碱水平非常的卷烟导致显著存在 α4β2 烟碱受体（23%） ， 这种受体被认为是最主要的调节烟碱强化和其他行为影响的受体亚 型 [90]。 低烟碱水平卷烟的作用可能更多被烟草的非烟碱因素强化。 使用去烟碱化的烟草与产生放松感的相关性大于使用烟碱吸入器， 表明非烟碱因素是吸烟镇静作用的部分甚至是主要原因 [172]。 对卷烟依赖能以其他方式产生，即使以极低的烟碱摄入量，例 如通过受体脱敏，长期暴露于即使是极低含量的烟碱也能发生 [176]。 受体脱敏传达了灵敏的烟碱强化作用 [177,178]。 环境也可能在吸烟行为中发挥作用。 例如，Donny 和 Jones[179] 发现去烟碱化的卷烟在 9 天的门诊评估中继续其强化特性，而在住 院患者的类似研究中 [115]，吸烟动机和抽吸去烟碱化卷烟的数量随着 时间的推移有所下降。有人推测减退过程在自然环境中可放慢，可 能是因为有许多与吸烟有关的刺激存在 [180]。 A3.3.4 成瘾阈值与强化阈值 没有普遍接受的烟碱或烟草成瘾的定义。 世界卫生组织 [181] 依 据强制性来定义药物依赖，即在某种程度上使用药物优先于其他行 为的行为模式，被认为是对个体或对其他人有损害。美国卫生部部 长关于烟碱成瘾的报告中 [99] 也要求药物产生精神类影响，吸毒行为 是由药物影响明显强化的。尽管大多数吸烟者符合这些标准，但不 是所有的 [23]。 ·234·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
广泛用于识别烟碱成瘾的诊断标准包括《 精神疾病诊断与统 计手册 》 （ 第四版 ） （DSM-IV） ， 由美国精神病学协会出版， 用于评 估常见药物依赖， 而 Fagerström 烟碱依赖测试是用来评估耐受性 和依赖程度。 关于这些工具测量成瘾的有效性已被关注。 它们之 间相关性差， 也不能一致地预测吸烟行为的其他指标或吸烟者的 治疗结果 [182–185]。 它们可能也不能在使用烟碱的早期阶段敏感地评 估吸烟者的成瘾性， 因为它们被开发并验证用于评价末期成年吸 烟者 [186,187]。 DiFranza 等 [25] 认为成瘾的诊断标准应该至少当个体决定戒烟 时在他们之间区分能或不能戒烟。他们建议成瘾的自我评估应该是 黄金标准，因为它与戒烟时自测困难强烈相关（r=0.89） ，与每天吸 烟的数量和早晨抽吸第一支卷烟的时间的相关性比 DSM-IV 好 [183]。 而且，在儿童中确认刚出现的依赖，自我评估比其他方法更好。在 一项研究中 [188]， 青少年成瘾的自我评估预测吸烟的神经反应比 Fagerström 测试更成功。 Sofuoglu 和 LeSage[189] 发现关于评价烟碱成瘾的有效方法缺乏共 识是降低烟碱策略的一个重大挑战。他们指出，强化阈值的概念不 等于成瘾阈值，虽然这些术语有时被互换使用，以及建立一个烟碱 阈值水平可能是一个更好的方法。强化阈值会定义为增加或维持烟 碱自身给药（即烟草使用）的最低烟碱剂量。烟碱强化阈值会有许 多实用优势。 首先， 它的定义更清晰， 并且比成瘾阈值易于测量， 因为如果自我给药的程度大于一种工具或安慰剂，这种药物被认为 是被强化的 [190]。其次，因为如果某种药物不是强化性的，依赖不会 发生，烟碱强化阈值可能会低于烟碱成瘾阈值，可能是更敏感的指 标，用于预测低于成瘾阈值的烟草使用 [190,191]。第三，强化阈值可以 ·235·
烟草制品管制科学基础报告： WHO 研究组第五份报告
在人或试验动物的自我给药短期研究中测量，而且可以很容易地进 行调整来评估个体差异（例如年龄、 性别、 遗传因素）与环境因素（例 如压力、同伴影响）[192]。 A3.3.5 条件刺激的阈值 鉴于在吸烟行为强化中条件性刺激的重要性，以及在强化显著 性中烟碱的主要作用，应考虑对于非烟碱刺激的强化特性产生是否 有一个单独的烟碱阈值。 被训练的大鼠对剂量为 0.4 mg/kg 的烟碱容易对无条件奖赏产生 条件反射 [193–195]。按 0.1 mg/kg、0.2 mg/kg 或 0.4 mg/kg 烟碱剂量分组 训练，显示产生类似的条件反射，但两个高剂量组显示出反应更难 以减退 [196]。 在各组中发生率的相似性可能意味着 0.1 mg/kg 与高剂 量烟碱一样显著。一种无显著性的解释包含在烟碱环节中丰富的蔗 糖传输调度 ； 也就是说， 因为有大量的烟碱 - 蔗糖配对只需要少量 烟碱来促进条件反射 [193,195]。 Palmatier 等 [197] 比较烟碱较低剂量 和较高剂量 （0.03 mg/kg） （0.09 mg/kg）的影响，推论刺激关联的新的条件特性应在一定程度上依靠 最初强化剂的力量或强度。他们得出结论，刺激产生的条件强化特 性是剂量增加的直接作用。 这些发现说明刺激控制着烟草寻求行为，将在暴露于高剂量烟 碱人群中最有效，并很可能在暴露于烟碱极低产品时大大减少。然 而，条件刺激的强度也是由烟碱匹配的刺激的频率驱动的，它与烟 碱的相关性有多紧密， 那么它与时间和空间的相关性有多紧密。 因此， Murray 和 Bevins[196] 建议，如果有足够多的配对，即使本来条件刺激 ·236·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
较弱的烟碱剂量，也可能成为一个强有力的刺激物。 A3.3.6 小结 • • • • • 试验动物和人体的强化阈值研究显示很强的一致性。这些研 究给出烟碱强化阈值的初步估计在 0.1~0.5 mg。 当一个自我给药机制的强化阈值更低时，使用卷烟烟碱传输 模型更准确。 人体的烟碱识别阈值约为 0.2 mg，尽管有大的个体差异。 在成年人中，维持阈值似乎低于产生强化行为的阈值。 青少年使用烟碱的产生阈值可能不同于成年人。青少年吸烟 者每天吸烟率低， 但似乎生理上有自我给药烟碱活性剂量。 减少负面影响的期望是青少年吸烟的一个主要动机。 • 去烟碱化卷烟中低水平的烟碱可能足以维持吸烟行为。 另外， 对去烟碱化卷烟的响应可能反映条件性强化作用或表明一些 非烟碱成分有重要作用。 • 减少烟碱释放量到低于成瘾阈值的目标需要测量成瘾的可靠 方法。没有容易被接受的测量成瘾的方法适用于建立烟碱阈 值。依赖的常用测量方法不适用于所有吸烟者，可能无法测 量青少年吸烟。 • • 提议的可供选择的定义是成瘾的自我评估 [25] 和强化阈值 [189]。 高剂量烟碱比低剂量有更强的条件强化作用 ； 然而，即便是 低剂量烟碱对条件性强化可能也是足够的，特别是在有许多 高度相关性匹配的环境中（如长期吸烟的情况下） 。
·237·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A3.4 降低烟碱的可行性 大多数降低烟碱行为性影响研究中，使用了商业化的低烟碱产 品，包括称为去烟碱化卷烟的产品，如 Quest。这些研究对吸烟者的 行为反应提供了有价值的认识，但未必表示这些商业产品有可能成 为授权的降低烟碱产品。烟草企业内部资料虽然可能比公开发布的 临床研究可靠性差，但可以提供深入了解可能被烟草制品制造商所 使用的、商业上操纵卷烟产品烟碱传输和范围的方法 [26,198]。 A3.4.1 卷烟烟碱传输 烟草生产商在可控吸烟条件下利用大脑成像来确定从卷烟中传 输烟碱的有效范围 [198]。比较不提供烟碱、低烟碱量（0.14 mg）或高 烟碱量（1.34 mg）的卷烟，只有高烟碱释放量的卷烟，激发潜能的 波动统计学上呈显著减少（P<0.05）[199]。 在一项对烟碱传输剂量范 围在 0.12~1.1 mg 范围的六种卷烟类似比较中，传输 0.12 mg 烟碱的 卷烟的吸烟电生理效应与无烟碱卷烟是无法区分的， 而传输 ≥ 0.21 mg 的卷烟有显著的影响 [200]。 卷烟传输烟碱与测量大脑反应的潜能相关性的理论最佳拟合曲 线表明， 当烟碱作用潜能降低在每支卷烟传输烟碱 0.4 mg 时最大， 超出每支卷烟大约 1.4 mg 时没有更进一步的变化。这说明烟气烟碱 降低到 ≤ 0.4 mg 可能对吸烟行为有最大的整体影响 [201]。 在比较限 制性和随意抽吸每支商品卷烟传输 0.11~1.04 mg 烟碱的潜能影响中， 显示吸烟者中枢神经系统影响相当于全香味卷烟所诱发的，由于存 ·238·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
在补偿性，甚至于是最低的烟碱传输 [201]。在一项确定高烟碱传输卷 烟（0.9 mg）的影响是否等于三支低烟碱传输卷烟（0.3 mg）的影响研 究中，在要求很短间隔内摄入单一、相对较大剂量烟碱的放大效应时， 潜能影响被成功地模拟。在三支 0.1 mg 烟碱卷烟与一支 0.3 mg 烟碱卷 烟的影响相比时，潜能不再相似（P< 0.05） 。作者认为，烟碱的神经 生理学作用显示“阈值 […] 介于 0.1~0.3 mg 之间”[201]——结果符合上 述的在“烟碱自我给药”水平之下的结论。 A3.4.2 降低烟草中烟碱的方法 烟草中烟碱的含量与烟气烟碱释放量呈显著性相关 [202]， 可以 很容易地由制造商改变和控制 [26,203–205]。烟叶的类型、等级和在烟茎 上的部位可以显著地影响烟草中烟碱的含量。通过混合不同的烟叶， 制造商可以平衡烟草特性，对烟碱含量存在的差异进行调整，以满 足特定品牌和风格的产品标准 [206]。在不同烟草类型中发现差异有 10 倍，常见的是差 5~6 倍 ； 例如，香料烟烟碱含量 1%，而白肋烟烟碱 含量 5%[207]。产品差异通过选择烟草来实现，差异性并不限于烟碱， 还包括糖和氨的含量、香气和吃味特点，以及相对的粗燥感和刺激 性 [207,208]。 在加拿大和美国公共研究机构的协助下，为研究目的开发了具 有极高、极低烟碱的烟草品系 [209–212]。例如，布朗和威廉姆森公司比 较含有正常烟碱水平的 1/20、1/2、9/10 的三个白肋烟品系，显示烟 气中烟碱水平与烟草中成正比 [213]。在其他情况下，细菌降解烟碱而 烟叶的其他成分不受影响 [214,215]。通过这一过程获得的烟草作为未经 处理的烟草被认可 [216]。 ·239·
烟草制品管制科学基础报告： WHO 研究组第五份报告
最早的烟草加工包括蒸汽萃取白肋烟及其烟茎，来减少通常由 高含量烟碱带来的刺激性。 后来， 氨及类似化合物也被萃取 [217,218]。 处理烟草使天然存在的烟碱盐转变为游离态烟碱和游离态酸。在加 热或蒸汽处理中， 游离态烟碱从烟草中脱离出来 [219]。其他处理方法， 如使用溶剂（如 freon*）很容易萃取游离态烟碱，之后，去烟碱化的 提取物可能不会再添加回去。萃取过程可以显著减少烟气中烟碱释 放，对烟气的主观或感官特性有显著影响 [220]。 在去烟碱化品牌 Next 开发之前，菲利普·莫里斯公司进行了降 低烟碱研究，包括转基因、酶处理法和提取烟草中烟碱 [205]。虽然这 些方法没有完全消除烟碱， 但达到了 80%~98% 的降低。2003 年由 Vectoe 烟草公司生产的 Quest 牌卷烟，是用转基因烟草制造的。 A3.4.3 去烟碱化或低烟碱卷烟 虽然原则上能够生产完全不含烟碱的卷烟，但在大多数情况下， 术语“去烟碱化”表明卷烟中烟碱浓度≤ 1 mg。当在标准吸烟机上 抽吸时，它们产生的烟碱释放量为 0.05~0.1 mg，相当于标准商业品 牌烟碱释放量的 5%~10%[6]。 生产去烟碱化卷烟的主要技术挑战不是降低烟碱释放量，而是 维持感官特性和烟气吸引力。最早的提取烟碱的烟草，使用溶剂或 蒸汽提取技术，被视为“刺激的”和“无味的” ，可接受性极低，无 论是哪种烟草类型，尽管使用了加香技术 [221]。差异性不只是由于缺 乏烟碱，如果将提取的烟碱添加回所试验的卷烟，仍不能还原未被 提取的卷烟的味道。其他烟草成分在提取期间，顺带被除去了，包 * 氟利昂，几种氟氯代甲烷和氟氯代乙烷的总称。——中文版注
·240·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
括蜡质、重烃和精油，而在提取后重新添加时，提高了主观的可接 受性。因此，烟碱以外的因素决定了产品的接受性 [221,222]。 为了 Next 品牌，菲利普·莫里斯公司使用除去咖啡中的咖啡因 的超临界萃取技术，从烟草中除去烟碱 [205]。尽管尝试提高选择性以 及限制提取的潜在影响，但这个过程改变了烟草的味道特征。烟草 提取后的加香和加料体系进行了许多试验 [223] ； 最成功的是基于薄荷 的模型，它掩盖了大部分不正常的口味，同时弥补了一些除去烟碱 后损失的冲击力 [86,224]。 一个内部专家小组进行的 Next 原型扩展测试表明，虽然经烟草 提取后的卷烟刚开始是有吸引力的，但持续抽吸一包卷烟导致了接 受度差的比例越来越高。当烟碱被添加回烟草提取的卷烟，随着时 间的推移，接受度水平没有下降 [225]。在对吸烟积极性高的吸烟者所 做的一项研究中，对经烟草提取的卷烟的“嗜好”比例随着时间的 推移有所改善，表明吸烟者在一定条件下可以调整他们的期望 [222]。 A3.4.4 低传输率卷烟中的游离态烟碱 Pankow[75] 和其他人 [76,226] 发现烟气中游离态烟碱的比例对于烟 碱传输速率，在从烟草传输到烟气及从烟气传输到喉部后部和肺部 的烟碱受体都是关键性的。烟气烟碱释放的标准测量方法不区分烟 碱的形态 [227] ； 但是，企业内部文件表明，比较游离态烟碱释放可以 更准确地测量对产品的主观反应，特别是在低释放量品牌中 [26,226]。 烟气总烟碱显著差异的产品在游离态烟碱传输中相互接近。布 朗和威廉姆森公司与万宝路（1.15 mg 烟碱）和高冲击、低释放量产 品 Merit（0.64 mg）烟释放量相比，发现每个品牌的游离态烟碱实质 ·241·
烟草制品管制科学基础报告： WHO 研究组第五份报告
上相同（约 0.3 mg） 。作者认为，一个人在生理上很难区分这两个品 牌 [228]。同样地，虽然万宝路的烟气烟碱比云丝顿少，但后者弱碱性 物质水平较高，如吡嗪类。这些碱性物质使万宝路“pH 略高” ，表 明等效于挥发性的或 烟碱， 尽管事实上其烟碱水平不高 [229]。 “游离的” 发表的卷烟烟气中游离态烟碱的测定方法很有限，表明商业品 牌之间的差异用标准吸烟方案是不能确定的 [230,231]。游离态烟碱浓度 在全香型、淡味的和超淡味的卷烟品牌各类型内是相似的、在类型 之间是不同的。滤嘴的通风性增加卷烟主流烟气中的游离烟碱的比 例，表明即使没有补偿行为，有通风孔的卷烟提供的总游离态烟碱 仍比例较高 [231]。 A3.4.5 引起补偿抽吸的产品 当吸烟者从常规卷烟转换到淡味（或低释放量）卷烟时，他们 调整吸烟行为，以维持所需的烟碱摄入量 [20,166,232]。与传统的低释放 量卷烟不同，降低烟碱卷烟不需要通风孔来降低烟气释放量，不出 现补偿性，因为容易 [13,14,83]。Rose 和 Behm[82] 在单次随意交叉研究中 将烟气释放量为 0.2 mg 烟碱、 14 mg 焦油的卷烟， 与商品化、 高通风率、 低释放量（0.2 mg 烟碱、1 mg 焦油）的卷烟比较，发现商品化低烟 碱卷烟有大量补偿性，而 14 mg 低烟碱卷烟没有明显的补偿性。 Benowitz 等 [233] 对吸烟者常用品牌卷烟与调整烟碱释放量为 1~12 mg 的卷烟比较吸烟行为。 对于烟碱中等水平的卷烟观察到强 烈的补偿行为， 但对 1 mg、2 mg 或 4 mg 烟碱（0.1 mg、0.2 mg 或 0.3 mg 烟碱释放量）的卷烟补偿性很小，且烟碱暴露量大大地降低。最 低烟碱水平卷烟产生平均 0.26 mg 的烟碱摄入量， 而正常品牌传输 1.47 ·242·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
mg 烟碱。对相同烟碱释放量范围（1~12 mg）的卷烟进行较长期的 研究，在 6 个月中每月降低烟碱，得出了相似的结果，12 mg 卷烟具 有较高的补偿性水平，但最低烟碱释放量卷烟补偿性很少 [15]。 Hatsukami 等 [14] 在 6 周的转换研究中分配给吸烟者烟碱释放量 为 0.3 mg 或 0.05 mg 的卷烟或 4 mg 的烟碱口香糖。抽吸 0.3 mg 卷烟 的受试者，在前 5 周的治疗中与普通品牌相比，每天吸烟的数量显 著增加，而抽吸 0.05 mg 卷烟的受试者，每天吸烟的数量（相对于基 线）显著下降。 这些研究表明，对于减少烟碱释放量的卷烟，可能会有一个阈 值，低于此阈值补偿性是不太可能的。这个阈值似乎是烟碱释放量 为 0.05~0.1 mg 的卷烟。在没有极度减少烟碱水平（0.2~0.3 mg）时， 补偿行为显著增加。 一个类似的阈值可能存在于商品化的、有通风孔的、低释放量 的卷烟。在对商品化卷烟为期 10 周的研究中，Benowitz 等 [234] 发现 从普通卷烟强制转换到流行的低释放量卷烟（机测烟碱释放量≥ 0.6 mg） ， 产生完全的或接近完全的补偿性， 而对烟碱或烟气有害物质 的暴露量没有降低。 当受试者转换到传输 0.1~0.2 mg 烟碱的超低释 放量卷烟时，烟碱和烟气有害物质暴露明显下降，虽然不能完全降 低（降低约 40%，而标准释放量减少 90%） 。 A3.4.6 降低烟碱的产品配方和途径 配方差异在产品被滥用的可能性以及在强化阈值的确定中发挥 了关键作用。例如，口用无烟烟草制品的致瘾性风险似乎稍稍低于 卷烟 [235,236]，而替代烟碱药物的成瘾风险似乎很小 [99,237]，即使绝对烟 ·243·
烟草制品管制科学基础报告： WHO 研究组第五份报告
碱传输量可能是相似的。目前，大多数卷烟包含 10~15 mg 烟碱 / 支 卷烟，其中大约 10% 是被释放到烟气中。这产生一种典型的每支卷 烟 1~2 mg 的系统性摄入量 [6]。设置每支卷烟 0.1~0.2 mg 的烟碱阈值 会整体减少约 90% 的烟碱摄入量。 可以考虑各种方法来实现这种减少。可以减少烟草中的烟碱含 量，这样每支卷烟的总释放量保持或低于摄入阈值。这将确保每支 卷烟的烟碱消耗量低于阈值，无论吸烟者行为怎样变化（即增加频 率或抽吸容量）或操纵释放的烟碱的形态，虽然这并不能阻止吸烟 者增加吸烟数量来获得更多的烟碱。为制造这样一种卷烟，烟草中 烟碱的含量必须比商品化的去烟碱化的品牌（ 如 Next 和 Quest） 降 低大约 10 倍。这种降低可能会对烟草的感官或吃味特征产生重大改 变。还没有对烟碱在这个范围内的卷烟的可能的行为响应进行研究。 烟草中烟碱含量的减少也可能是机测烟气释放量可能处在或低 于这一烟碱阈值。这是商品化卷烟产品 Next 和 Quest 的方法，其烟 气烟碱释放量 <0.1 mg，烟草总烟碱含量 <1 mg。含有这种烟碱水平 的畅销品牌的存在提供了强有力的证据，说明该方法在技术上是可 行的。对降低烟碱的行为反应开展的大多数研究使用了含有这种烟 碱水平的卷烟。 符合烟气烟碱摄入量阈值的第三种选择，是改变除了烟草烟碱 含量之外的，或与降低烟草烟碱相结合的产品参数。这种方法包括 极大的滤嘴通风率、膨胀烟丝含量高、降低烟草含量。这种方法的 技术可行性已在商业上被证明，那些极低的超淡型卷烟，即吸烟机 条件下的释放大约 0.1 mg 烟碱和 1 mg 焦油。由这种方法制造的卷烟 可能维持烟碱 / 焦油比类似于或大于那些目前销售的卷烟， 而降低 烟碱含量的卷烟会产生极低的烟气烟碱 / 焦油比。 它们可能会引起 ·244·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
更频繁的补偿行为，例如封闭通风孔和改变抽吸行为。 制造商可以操纵卷烟物理或化学参数来改变烟气特性，补偿烟 碱释放量的降低。例如，可以添加新型滤嘴改变烟碱的形态（通过 加酸或碱 ） ， 或改变气溶胶颗粒的大小分布， 确定烟碱和其他成分 的沉积和吸收 [26,127,238]。烟草加工工艺的变化，使用添加剂和物理结 构参数，包括长度、宽度、水分和堆积密度，可能改变卷烟的燃烧 或热解条件，改变烟气的成分和感官特性 ； 或者加入具有独特的行 为或感官作用，或与烟碱相互作用或改变烟碱的新的化合物 [26,78,128]。 因此，监管机构必须注意除了烟碱释放的其他产品因素。 A3.4.7 小结 • • • 在某一烟气释放量阈值以上的卷烟可能具有药理活性，而低 于此阈值（介于 0.1~0.3 mg 之间）不再有效果。 在短时间内从一支卷烟的一次烟碱摄入比从多支卷烟的一系 列较小的摄入更有效，特别是当它们的烟碱水平较低时。 降低烟草的总烟碱含量是烟草行业常见的一种做法。广泛的 技术应用包括烟草的选用和加工、遗传选择、微生物或酶处 理和选择性萃取烟碱。 • • 选择性萃取和转基因都能生产烟碱含量减少了 80%~95% 的 烟草。 降低烟碱的烟草不同于未改性烟草的感官特性，部分原因是 缺乏烟碱，而且还附带损失了一些化合物，如蜡质、烃类和 精油。 • 总烟碱摄入量只是烟碱整体感官和药理作用的一个测量方 ·245·
烟草制品管制科学基础报告： WHO 研究组第五份报告
法，且不区分烟碱的形态。游离态烟碱主要负责烟碱的感官 影响，可能是一个更准确的主观或生理影响的测量方法，特 别是对低的或降低烟碱的产品。 • 减少烟碱释放量的卷烟，可能会有一个阈值，低于此阈值补 偿是不太可能的。 这个阈值似乎在 0.05~0.1 mg 的烟碱范围内。 在不是极端地减少烟碱的水平（0.2~0.3 mg） 的情况下， 补 偿行为显著增加。 • 转换到除去烟碱的卷烟（0.05 mg 烟碱 ） 或烟碱释放量极低 的传统卷烟（0.1~0.2 mg） 的研究中， 报道了类似的结果， 尽管在结构上有差异，从烟丝中能获得更多烟碱。 • • • 降低卷烟中烟碱释放量到低于 0.1 mg 的阈值需要将目前去烟碱 化产品再减少 10 倍。此类产品的可行性和行为反应是未知的。 大多数关于行为反应的研究使用了降低烟碱烟草制成的卷 烟，它的机测烟气烟碱释放量在 0.1 mg 阈值附近。 卷烟的物理和化学参数可以被操纵， 包括加入新的化合物， 来改变颗粒的尺寸分布、燃烧和热解等基本特征。一定要注 意产品除了烟碱释放之外的其他因素。
A3.5 潜在的行为效果和人群效果 去烟碱化卷烟可以减少抽吸传统卷烟，提供一个暂时性替代行 为，消除烟碱主要强化效果，从而在一段时间内减少渴望 [239]。上述 证据表明，尽管吸烟者更喜欢含烟碱的卷烟，但减少烟碱的卷烟能 提供主观满足感，立即减少渴望。有些人在强制减少烟碱后可能继 ·246·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
续吸烟，是因为上述强的替代效应，或是因为卷烟的烟碱释放量仍 然大于他们的强化阈值 [45,240]。 在行为模型中，减少烟碱卷烟对个体影响的证据被用于预测人 群效果。然而，几乎没有开展低烟碱卷烟在非吸烟人群中使用和使 用低烟碱卷烟长期影响的研究。 A3.5.1 对卷烟消费量的潜在影响 行 为 经 济 学 研 究 提 供 了 关 于 吸 烟 者 消 费 的 信 息。 例 如， DeGrandpre 等 [241] 关于烟碱释放量对吸烟行为的影响进行了 17 项研 究的“需求曲线”元分析。他们发现消费和烟碱释放量存在强相关 性，表明降低吸烟者通常的烟碱释放量增加他们的吸烟行为。 使用含烟碱和去烟碱化卷烟的研究表明了类似的变化 ， 增加 单位价格导致类似的自我给药减少 。 不过 ， 当这两种类型卷烟在 同一单位价格范围内时 ， 含烟碱卷烟是确实的首选 。 研究表明 ， 吸烟动作对经常性吸烟者有强化作用 ， 无论卷烟的烟碱释放量 ， 并指出 ， 去烟碱化卷烟充当含烟碱卷烟的一种有效的行为上的经 济的替代品 [242,243]。 增加含有烟碱卷烟单价的同时保持去烟碱化卷烟或烟碱口香糖 的价格，后者的消费不断增加 [244]。但是，当两个替代品都可获得时， 烟碱口香糖的消费减少，但去烟碱化卷烟不减少 [245]。同时增加去烟 碱化及含烟碱卷烟的价格，会导致口香糖消费增加。这些结果表明， 烟碱替代品比如药品、口含烟草或含烟碱电子烟的供应，可能会直 接影响到卷烟的自我给药，无论卷烟的烟碱释放量。
·247·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A3.5.2 对吸烟行为的潜在影响 转换到降低烟碱释放量卷烟能引起温和的戒断症状 [13,14,234,246,247]， 表明戒断症状可能激发吸烟的增加。然而，很少有证据表明烟碱释 放量 0.05~0.1 mg 的卷烟导致补偿性吸烟，像上述的“导致补偿性吸 烟产品” 显示的。Strasser 等 [248] 发现抽吸降低烟碱卷烟 （Quest3，0.05 mg 烟气释放量 ） 的受试者增加了他们的总抽吸容量。 然而， 受试 者的反应只在第一次使用研究的卷烟时进行了评价。使用减少烟碱 的卷烟在数天或数周的研究中一致发现补偿性吸烟没有增加，事实 上吸烟随着时间的推移呈下降的趋势，可以预期行为上的消除过程。 超过 9 天的吸烟行为的测量显示初始抽吸容量的差异随着研究的进 展而消失，表明通过转换为减少烟碱的卷烟抽吸行为可能只是暂时 性中断 [179]。 在 11 天的评估中， 受试者抽吸减少烟碱的卷烟显示非 限制性吸烟少于含烟碱的卷烟 [115]。Hatsukami 等 [14] 发现在 6 周治疗 期间有类似的减少。 在 26 周的研究中从 12 mg 到 1 mg 逐步减少烟 碱释放量 [15]，卷烟消费基线与 14 周之间的（烟碱释放量达到 4 mg） 保持不变 ； 从这个点到研究结束时，卷烟消费明显下降到每天 4 支 卷烟，通过测量血浆可替宁，烟碱的摄入量降至基线水平的 30%。 在大鼠自我给药的研究中，减少剂量整组没有引起戒断症状 ； 然 而，在某些个体引起戒断症状、补偿性的严重程度不能确定差异 [249]。 这些结果补充了报告，很大部分减少由烟碱特异性抗体诱导的大脑 烟碱水平， 不足以引起慢性烟碱注入产生依赖的大鼠的戒断症状 [250]。 这些研究结果表明，对于大多数个体断瘾症状不是减少烟碱摄入量 的突出的负面后果，在非常低的烟碱水平（0.1 mg） ，抽吸强度增大、 每天吸烟更多等形式的明显的补偿性吸烟行为是不可能造成的后果。 ·248·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
A3.5.3 对戒烟的潜在影响 在实验室和门诊环境的研究表明，使用减少烟碱的卷烟 1~2 周削 弱了吸烟的强化作用 [82,115]。在进行了 6 周或以上的临床试验中 [14,15,234]， 吸烟者在使用减少烟碱的卷烟后，报告始终显示有较少依赖性。 减少烟碱的卷烟可作为戒烟初始阶段的应对机制，取代一些与 吸烟有关的条件性仪式，如手到嘴的动作，吸烟的触觉动作、抽烟 在口腔和喉咙的感官 [251]。在开始戒烟的吸烟者中，对转换到 0.3 mg 卷烟的吸烟者持续戒烟到第 6 周是 13.5%，0.05 mg 卷烟组是 30.2%。 这意味着减少烟碱政策将帮助吸烟者，当他们正在积极试图戒烟时 更有可能实现戒烟 [14]。 然而，减少烟碱卷烟可能不仅对寻求治疗的烟民，而且也在以 前没有表示愿意戒烟的人群中帮助戒烟。Benowitz 等 [13] 发现，25% 的受试者 6 周逐步减少烟碱释放量的卷烟试验结束后戒烟 4 周。 在 同样设计的研究中，10% 的以前没有兴趣戒烟的受试者在逐步减少 烟碱释放量后戒烟 [234]。在逐渐减少烟碱 6 个月后，戒烟率为 4%[15]。 减少烟碱的卷烟对戒烟的影响可能会增加基于烟碱的治疗。当吸 烟者被转换到减少烟碱的卷烟（0.05~0.09 mg 烟碱） 、有或没有烟碱贴 片 6 周，无贴片组比贴片组每天抽更多的烟，有更多的戒断症状，虽 然两组渴望的分数相似。在 36 周的后续观测中，那些仅使用减少烟 碱卷烟的吸烟者继续戒烟达到 18%，使用减少烟碱卷烟和贴片组合的 是 20%[252]。在另一项研究中， 使用减少烟碱卷烟和烟碱贴片的吸烟者， 吸入卷烟烟气的总量较小，比没有贴片组戒断症状减轻更多 [179]。 Walker 等 [251] 在有或没有通常的戒烟热线服务（ 烟碱替代疗法 和行为上的支持）的情况下，使用去烟碱化的卷烟进行了一项随机 ·249·
烟草制品管制科学基础报告： WHO 研究组第五份报告
对照试验。二者结合的戒烟率高， 复吸时间较短， 有良好的可接受性。 试验提供了强有力的证据，烟碱替代治疗和行为支持与减少烟碱卷 烟的结合是一种有效的戒烟策略。 A3.5.4 对卷烟使用购买的潜在影响 减少烟碱政策对开始吸烟的影响尚未被量化描述。引用上述对 “烟碱依赖的产生”研究，说明卷烟可以减少负面影响的期望对引起 青少年吸烟方面起着主要作用 [163,164]，在青少年吸烟者中，去烟碱化 卷烟对负面影响的减少可以比得上含烟碱的卷烟。但是，在不吸烟 的青少年中，减少烟碱的卷烟的影响无明显变化 [165]。这表明，在没 有烟碱急性影响的情况下，不太可能加剧不吸烟青少年的吸烟行为。 建立不吸烟青少年减少负面影响的阈值，将会证实这个假设。 减少烟碱政策对成人不吸烟者使用低烟碱卷烟的影响尚未研究。 烟碱鼻喷雾剂的自我给药在依赖性和非依赖性吸烟者中是相似的， 两组都比前吸烟者和非吸烟者更频繁。在不吸烟者中，自我给药直 接关系到愉悦的效果，但与负面影响相反 [253]。在开始吸烟后，积极 性和消极性的强化预期都明显变化 [254]。在青春期接触被降低的烟碱 可能会减少在成年后对烟碱依赖的脆弱性（见上述的“烟碱响应的 个体差异” ） 。应对不吸烟者和非依赖性吸烟者使用减少烟碱卷烟的 效果进行更多的研究。 A3.5.5 潜在的不可预料的行为后果 青少年试验减少烟碱的卷烟可能会增加他们滥用其他药物的 ·250·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
成瘾风险 [45]。 在试验动物中 ， 未成年大鼠非常短地静脉暴露于烟 碱 （ 4 天中每天注射两次 0.03 mg/kg ） 使它们对可卡因的强化作 用更敏感 [255]
。 这一每日剂量相当于从 4 个标准卷烟（4.2 mg）或大
约 40 支减少烟碱的卷烟的烟碱摄入量。 减少卷烟的烟碱可作为高烟碱产品的启动产品，方式相似于游 离态烟碱水平低的无烟烟草制品所显示的 [254]。减少烟碱的卷烟和烟 碱释放量较高的烟草制品同时使用，如口嚼烟草或小雪茄，还可能 产生对有害物质更大的暴露 [45]。 A3.5.6 潜在的人群差异 如在上述“对烟碱响应的个体差异”观察到的，烟碱以外的因 素可能决定女性的烟草依赖。女性对操控烟碱暴露做出的反应比男性 更少，对操控非烟碱烟气成分比男性更敏感，如感官提示 [52,56,125]。至 少有一些差异比来自吸烟的慢性烟碱暴露引起依赖的发生更重要 [125]。 降低烟碱卷烟在更大程度上缓解愿望 [172]， 有更多积极的主观影响 （满 足感、 放松、 减少焦虑 ） ， 且与男性相比， 在女性中产生的吸烟意 向减少更多 [257]。这些观察表明，女性比男性更容易存在长期持续使 用降低烟碱的烟草的风险 ； 不过， 在一项戒烟研究中，4 周连续戒 烟，结合烟碱替代疗法的锥形减少烟碱对女性比对男性有很大的影 响 [239]。Walker 等 [251] 观察到在结合戒烟热线干预的影响中，没有性 别差异。 在患有严重精神疾病的人群中，减少烟碱的潜在不利影响仍然 令人担忧。Tidey 等 [258] 研究了在患有精神分裂症的吸烟者中低烟碱 卷烟的影响。去烟碱化卷烟与抽吸普通品牌卷烟相比减少了对卷烟 ·251·
烟草制品管制科学基础报告： WHO 研究组第五份报告
的渴求、烟碱戒断症状、吸烟戒断症状，且耐受性好 ； 没有迹象表 明烟碱的减少影响精神症状。然而，去烟碱化卷烟替代含烟碱卷烟 对患有精神分裂症吸烟者与对照组吸烟者相比很少有效，表明如果 含烟碱的替代品是可用的，精神分裂症患者长期使用低烟碱卷烟是 不太可能的。在抑郁症或其他严重的精神健康障碍患者中，应开展 减少烟碱的进一步研究。 A3.5.7 潜在的健康影响 Hatsukami 等 [14] 报告了转换为减少烟碱卷烟的吸烟者的有害物 质暴露显著减少，包括烟草特有亚硝胺、丙烯醛和苯，虽然多环芳 烃暴露没有被测量到减少。亚硝胺的减少与烟草中测量的水平降低 相一致，而其他有害物质的差异被认为反映了吸烟的减少。这些结 果表明， 减少烟碱政策可能会减少健康风险， 不仅在戒烟人群中， 也在未产生烟草依赖的人群中，还在无论是否降低烟碱继续使用烟 草制品的人群中 [259]。 烟碱的摄入量可能的减少是另一个潜在的健康好处 [82,259]。虽然烟 碱以外的烟草成分是引起烟草相关疾病的主要原因，烟碱通过使血管 收缩可能有助于心血管疾病的发展， 促进与动脉粥样硬化血栓的形成， 影响胰岛素的敏感性 [260,261]。烟碱还能促进侧支血管 [262]，这可能会增 加肿瘤的血液供应，抑制细胞凋亡，促进肿瘤 [263]。Girdhar 等 [264] 提 出假说，烟碱通过降低血小板活化调节其他烟气成分产生的心血管 疾病风险。减少卷烟中的烟碱释放量会因此增加心血管疾病的风险 ； 然而，使用纯烟碱作为烟草替代品没有被报道是有害的，表明使用 烟碱的直接健康影响最小。 ·252·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
在新西兰进行的关于使用减少烟碱的卷烟的人群和那些只给烟 碱替代治疗和戒烟热线干预的人群研究表明，不良健康情况无显著 性差异 [251]。强有力的证据表明，转换到减少烟碱卷烟相关的健康风 险接近或低于传统卷烟，但需要更多的研究。 A3.5.8 非法销售含烟碱卷烟产品的可能性 一些研究显示走私作为促进其产品在低收入和中等收入国家销 售的一种手段对卷烟制造商的重要性 [265,266]。大多数非法卷烟销售是 供应驱动的，仍很常见，即使价格和消费税很低 [267]。走私率可能高 达所有销售量的 1%~15%[268-270]。 没有已发表的在减少烟碱的卷烟市场非法销售的高烟碱卷烟的 可能性研究。Givel[271] 描述了于 2004 年在不丹颁布的终止烟草消费 的销售禁令的后果，仅允许少量用于个人消费的烟草进口。走私和 黑市销售在禁止后增加，足以在不丹男性中满足 10% 的吸烟率。 在减少烟碱政策中，同时呼吁减少烟碱的卷烟，以及烟碱替代 产品的可用性和吸引力， 会影响非法烟草销售的程度 [272]。 在加拿 大，走私卷烟的吸引力被年轻人认为低于畅销品牌，表明走私卷烟 的可用性可能对成瘾吸烟者的吸引力大于新手或尝试吸烟者 [273]。然 而，走私卷烟的可用性也与戒烟可能性降低和尝试戒烟减少有相关 性 [274–276]。 A3.5.9 人群影响模型 Tengs 等 [4] 模拟减少烟碱的人口影响在美国进行了超过 6 年的 ·253·
烟草制品管制科学基础报告： WHO 研究组第五份报告
时间。 假设吸烟率下降了 80%， 由于补偿行为， 在现有吸烟者中死 亡率增长 10%， 每年 10% 的吸烟者进入黑市， 他们估计 50 年中累 计获得 1.57 亿的质量调整寿命。然后，他们以多种方式改变模型参 数，并得出结论 ： 只要戒烟率提高 10% 或以上，复吸和开始吸烟减 少 10% 或以上，补偿行为增加吸烟者的死亡率不超过 80%，则对于 质量调整寿命仍为净增加。 值得注意的是， 经过一系列合理的估计 （所 有吸烟者的 0%~50%） ，无论进入黑市的程度，质量调整寿命一致地 增加而不是减少。 另一个模拟模型中所估计的健康后果，假设减少烟碱会降低每 个年龄段和性别的人群引发吸烟的概率，戒烟的概率会增加，有吸 烟史者不太可能复吸 [277]。作者还模拟了减少烟碱卷烟作为 “更安全” 卷烟促销的可能性， 将恶化所有三个后果， 是从 –80% 到 +80% 以 10% 增量改变行为的可能性来估计后果。他们得出结论，吸烟减少 60%（开始、使用、复吸）会抵消在继续吸烟的人群中的补偿性吸烟 造成的伤害，或其他不能预料的健康后果的任何合理增加（≤ 50%） 。 开始吸烟、 使用、 复吸适度减少 20%， 在继续吸烟者中的疾病风险 降低 20%， 将导致累计 1.65 亿质量调整寿命， 而开始吸烟、 使用、 复吸大幅降低 80%，在不改变继续吸烟的人群的疾病风险的情况下， 将会导致估计 2.81 亿涨幅的质量调整寿命。 由加拿大卫生部委托研究了在加拿大降低所有烟草制品烟碱政 策潜在影响模型 [278]。这项研究基于文献审查和与卫生专家的访谈。 所考虑的后果是开始和停止吸烟，黑市销售增加，替代卷烟的其他 烟草制品，以及潜在的补偿行为。据估计，这一政策评估了对开始 和停止吸烟的影响，在不存在对黑市销售的影响、替代品和补偿性 的情况下，30 年后，将减少烟草相关疾病治疗费用 19%。假设在黑 ·254·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
市份额从 15% 增加到 50%，则使利润降低 40%。减少烟碱标准对死 亡率的好处主要是由于对戒烟的影响，而对发病率的好处主要是由 于对开始吸烟的影响。 A3.5.10 小结 • 吸烟的行为对成瘾的吸烟者有强化作用，无论烟碱释放量是 多少。去烟碱化卷烟可以作为一种有效的行为上的含烟碱卷 烟的经济替代品。 • 是否有可选择的烟碱替代品，如烟碱药物、口含烟草和含烟 碱的电子卷烟，会直接影响到卷烟的自我给药，不管卷烟本 身是否含有烟碱。 • 对于大多数个体，减少烟碱摄入量，戒断症状不是一个突出 的不良后果，更大的抽吸强度或每天吸烟更多等形式的重要 补偿性吸烟行为，在非常低的烟碱水平（<0.1 mg）是不可能 产生的后果。 • • 当吸烟者作出积极尝试戒烟时，减少烟碱政策更有可能帮助 他们实现戒烟。 一些研究中使用减少烟碱卷烟提高了戒烟率。 非吸烟的青少年在没有烟碱的急性影响时不太可能加剧他们 的吸烟行为。确定不吸烟青少年的减少负面影响的阈值，将 会证实这个假设。 • 尚未对非吸烟者和非依赖性吸烟者对减少烟碱卷烟的使用和 影响开展充分研究。 不吸烟者对减少烟碱卷烟的自我给药， 与愉悦感直接相关，和负面影响成反比。 ·255·
烟草制品管制科学基础报告： WHO 研究组第五份报告
•
青少年接触低浓度的烟碱会增加他们滥用其他药物的成瘾风 险。低烟碱产品也可以作为其他形式的烟草产品或其他形式 的烟碱传输的初吸型产品。
•
女性比男性更有可能维持减少烟碱烟草的长期使用。减少烟 碱对精神分裂症患者心理健康症状没有负面影响 ； 在其他人 群中的风险应进行更多的研究。
•
减少的烟碱不仅可以在戒烟或未产生烟草依赖的人群中，还 在尽管减少了烟碱仍然继续使用烟草产品的人群中减少健康 风险。需要更多的研究。
•
烟草非法销售可能破坏烟碱降低政策的健康目标。虽然还没 有进行正式的估计， 但减少烟碱的卷烟的吸引力、 烟碱替 代品的可用性和吸引力都可能影响到烟草非法销售的显著 程度。
•
已设计了各种模型来估计减少烟碱政策可能的影响。都显示 出对健康后果显著的积极影响。
A3.6 降低烟碱的政策手段 许多作者提出了在减害模型中更安全产品比毒性大的产品更有吸 引力的背景下，减少卷烟的烟碱释放量 [272,279–284]。监管框架是支持减 少烟碱政策的关键，同样尊重吸烟者和非吸烟者发展和维持使用烟草 或烟碱所产生的商业市场，以及影响和支持这种行为的社会环境。 ·256·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
A3.6.1 对烟碱的全面管制 减少卷烟烟碱释放量政策的影响将很大程度上取决于可用性、 毒性和替代烟碱传输系统的吸引力，包括其他形式的烟草（可燃或 不燃的） 、烟碱药品和商品化非烟草类烟碱产品 [45]。因此，一个成功 的减少烟碱政策必须综合监管所有烟草类和含烟碱的制品 [3,5,7,280,281]。 监管烟草和烟碱的单一机构将允许协调对于不同产品的方法 [280]。 这个机构将负责决定如何管制烟草和烟碱产品，制定性能标准，授 权产品的健康或其他声明， 评估市场上的产品， 以及评估其人口影响。 全面的监察系统必须快速响应任何意料之外的烟碱使用或健康后果 的变化 [7,280]。 综合监管烟碱的主要目标是减少使用最有害的烟碱产品，鼓励 发展新的、改进的烟碱传输系统作为毒性强的产品的替代品，并且 继续监察和监管毒性较低的产品对健康的影响 [3,6,280]。政策手段可被 视为是激励吸烟者采用危险性减少的烟草产品或烟碱的使用，包括 限制准入、销售和使用，以及差别课税，如对卷烟和燃烧类烟草的 税收远高于清洁的烟碱传输产品 [6,281,285]。 A3.6.2 绩效标准 绩效标准是必要的，以确保实施减少烟碱政策 [284,285]。许多办法 可以用来考虑确定烟碱产品的标准，如限制烟碱的传输或吸入，或 在每口抽吸的水平上定义所限制的单口烟碱剂量。然而，最有前景 的方法， 是关注未燃烧卷烟中可用的总烟碱含量， 因为它更容易测量， 且不受制于行为上的操控及个体差异（参见上述“减少降低的产品 ·257·
烟草制品管制科学基础报告： WHO 研究组第五份报告
配方和途径” ） 。 本附录提出的证据表明， 减少卷烟的烟碱释放量到 <1 mg 就 足以减少吸烟人口的依赖比例，不利的影响最少。这个证据来自于 研究使用烟草烟碱含量极低的卷烟， 其设计参数和构造类似于传 统卷烟的标准。可能甚至很有可能为烟草的烟碱含量制定的专门绩 效标准，将鼓励发展烟草烟碱含量极低的卷烟，但在形式和功能上 完全不同于传统卷烟。例子可能包括以更容易被利用的形式（游离 态 ） 释放烟碱的产品， 改变粒相的形成或烟碱的沉积， 以单个剂 量完全释放烟碱的量， 鼓励并使许多卷烟的使用能够维持烟碱剂 量，或包含烟碱类似物和其他活性药物成分，以增强或替代烟碱的 影响。 绩效标准必须应对不断变化的市场 [7,18,22,285]。初始标准应对传统 卷烟相似的产品的各个基本物理特征的， 包括烟草重量、 长度、 圆周、 滤嘴、纸和通风孔方面进行要求 [286]。必须仔细评估新产品和技术， 只有当它们降低风险、致瘾性和吸引力已被充分证明时才能获得商 业销售许可 [7,18,287,288]。 成瘾和伤害的全球标准最终应通过 WHO《烟草控制框架公约》 设置 [281]。这种全球标准可能包括进一步的产品标准，如对有害物质 （例如亚硝胺类）的限制，对物理设计参数的限制，如导致支持补偿 性行为（例如通风） 、增加产品吸引力（例如薄荷醇）的香料和其他 因素。每个标准的影响必须仔细地评估 [18,281,284,285]。 A3.6.3 逐渐性降低与急剧性降低 在 Benowitz 和 Henningfield[1] 最初的建议中， 呼吁在 10~15 年 ·258·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
中减少烟碱释放量， 以尽量减少潜在的戒断症状及其他实际问题。 然而，逐渐减少烟碱可能有负面健康影响 [45]。首先，个体会在较长 时期暴露于维持他们吸烟行为的烟碱剂量。其次，渐进的市场范围 的烟碱释放量的转变可能会以无法预料的方式改变吸烟者与烟碱的 关系，可能会调整成瘾的阈值 [8]； 例如，在烟碱自我给药奏效的初期， 如果它们在盐水替代以前接收到中等程度的剂量降低，则改用生理 盐水的大鼠能更缓慢地消除成瘾 [139]。 没有经过多年过程降低烟碱的影响模型。但是，在几周或几个 月逐渐减少烟碱的研究中，表明烟碱消费可以逐渐减少而无显著补 偿性。此外，当锥形减量完成时，烟碱摄入量保持在低于基线的水 平， 表明减少了对烟碱的依赖 [13,15,234]。 每天吸烟减少的程度与烟碱 依赖之间发现有强的相关性，这种观点支持下逐步减少烟碱摄入可 以减少依赖 [289]。回顾文献，Walker 等 [290] 得出结论，逐步减少卷烟 烟草中的烟碱水平可以减少吸烟者对烟碱依赖， 补偿性吸烟最小（烟 气烟碱水平 <0.1 mg 时） ，且无不良影响。 即使立即减少烟碱可能也会在减少吸烟率和依赖性方面都很成 功。吸烟者突然从自己的卷烟转换到减少烟碱卷烟 6 周，显示出暴 露降低、 消费减少以及戒烟率较高 [14]。同样， 在 11 天的转换研究中， 卷烟消费立即下降，吸烟的动机降低 [115]。 逐渐和立即减少烟碱的剂量导致大鼠产生相似的自我给药行为， 两组都无补偿性 [8]。在戒烟之前中等程度地减少消费对戒烟率的影 响进行无分析表明， “戒烟日”之前减少吸烟数量与之前没有减少而 突然戒烟之间没有区别 [291]。总之，这些研究结果表明，卷烟中烟碱 的剂量可以迅速减少而在吸烟者中无显著性不利影响。
·259·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A3.6.4 烟碱的可替代形式 面对减少烟碱的产品，有些吸烟者有可能转换到包含更多烟碱 的产品。替代烟草产品的吸引力可能增加，如口含和无烟烟草制品、 水烟、斗烟和雪茄，如果它们能比减少烟碱的卷烟更有效地替代传 统卷烟（参见上述“对卷烟消费量的潜在影响” ） 。燃烧类烟草比非 燃烧类烟草更有害，后者比清洁烟碱产品（如贴片和口香糖）更有 害 [17]。 鉴于这种全体产品的危害性， 似乎不只强制减少卷烟中的烟碱， 而且是减少所有燃烧类烟草产品的烟碱更可取，从而最小化转换到 最有害产品的风险 [285]。 释放烟碱的药品，比烟草产品更安全，但设计上不具吸引力以 避免滥用，不适合长期使用 [287,288]。虽然这些产品可以帮助吸烟者克 服戒断症状，但它们不提供足够的积极性奖赏作用（特别是快速地、 有效地传输烟碱） ，是合理的烟草产品替代品 [292]。 电子烟设计具有复制吸烟动作的明确目的，不含烟草 [285,293]。这 些产品及类似产品可能是更切实的卷烟替代品 [294]，对其使用性和接 受度的证据正在快速地积累 [293,295–297]。电子烟产生烟碱和其他成分的 蒸气，通常包括甘油和丙二醇。目前，它们主要用于戒烟，虽然时 间比烟碱替代疗法长 [297]。使用者认为它们比抽烟更安全 [297]。 电子烟比烟碱吸入剂更有效和更迅速地传输烟碱 [298]，但不如传 统卷烟有效 [293,298]。它们显著地减少渴望，由于至少部分具有卷烟的 物理感官特征，仅在烟碱传输方面 [293,299]。至少有一些电子烟提供可 靠的血液烟碱水平（在抽吸 10 口之后 10 分钟时，平均值为 6.77 mg/ mL ； 在随意抽吸结束时，最高平均值为 13.91 mg/mL） 。它们减少与 烟草有关的戒断症状和抽烟的冲动，提供直接的积极影响，有很少 ·260·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
的不良影响 [295]。 A3.6.5 戒烟与行为治疗 当烟碱降低到非致瘾水平，可能想戒烟的吸烟者人数会急剧增 加 [2,6]
。很多吸烟者会看医生进行烟碱替代治疗或行为治疗来辅助戒
烟或缓解戒断症状。医疗保健专业人士提供的具有有效性、可负担 得起的治疗，会在确保政策成功中是极有用的 [5,6,285]。保险方案的覆 盖范围是至关重要的， 为有较大不利影响的人群提供个性化服务， 如有精神障碍并发症的人群 [2]。药物治疗的广泛性不仅减少了降低 烟碱卷烟相关的不适，也大大降低了卷烟的抽吸，并可能引起一些 或许多的现有吸烟者戒掉所有烟草和烟碱产品。 A3.6.6 监测 公共卫生团体已经慢慢认识到监管或减害方法潜在的限制，尽 管刚出现它们无效性的证据 [22,281]。适当的监测系统会准许监管机构 监督烟草产品对流行性和初学者的影响、相关的危害性以及处理意 料之外的后果 [7]。对所有烟碱和烟草制品强制性报告的规定， 如在 加拿大采用的，以及 WHO《烟草控制框架公约》第 9 条和第 10 条 中所述的，是适当监督的必要条件。报告应包括物理设计参数（烟 草重量、烟碱含量、过滤通风） 、烟草和添加成分、释放物（对燃烧 类产品） 、滥用可能性的措施 [7,18,281,287]。 Hatsukami 等 [7] 和 Stratton 等 [17] 描述了一个综合评价烟草产品 的方法，它可以有效地对减少烟碱的卷烟进行不断地评价。该方法 ·261·
烟草制品管制科学基础报告： WHO 研究组第五份报告
包括 ： 实验动物的临床前测试，以评估滥用的可能性，未成年和成 年动物烟碱自我给药的产生， 以及影响功能的神经生理学变化； 成像、 实验室试验和人体临床试验，以确定滥用的可能性，烟草使用模式， 有害物质暴露，以及在普通人群和易感人群中潜在的健康风险 ； 调 节因素的评估，包括消费者对产品的认知，产品吸引力，产品包装、 价格和促销 [7]。 虽然在大规模吸烟者研究中测试生物标志物是评价疾病风险的 一个大有前途的方法，但它在缺乏资源的国家是不可行的 [281]。烟草 产品的复杂性以及评估毒理学结果需要专门知识，滥用的可能性或 对其他后果的评估， 可能是另外的障碍。McNeil 等 [281] 呼吁建立全 球数据库，以促进实现全球烟草产品的监管和监测。该数据库将减 轻监管机构收集和分析数据的负担，能进行全球化对比，以容易理 解的形式使国家监管机构了解信息和建议。 A3.6.7 消费者教育和信念 减少烟碱政策的影响在一定程度上取决于如何有效地沟通风险， 取决于降低烟碱卷烟与其他烟草或烟碱产品吸引力的比较。减少烟 碱产品更安全的信念会减少戒烟或切换到更安全替代品的可能性， 并鼓励更多地尝试卷烟。 有限的证据表明， 吸烟者认为减少烟碱的卷烟危害性较低。 Shadel 等 [300] 评估了暴露于一张无烟碱产品（Quest） 的平面广告之 后的看法。 吸烟者得出了一些有关产品的错误推论： 焦油释放量更低， 是“更健康的” ，也不太可能导致癌症。菲利普·莫里斯公司的去烟 碱化品牌 Next 的开发是针对对无烟碱产品感兴趣的人群，这些人认 ·262·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
为这类产品是更健康的并且可能使戒烟更容易的 [205]。 尽管吸烟者对减少曝露的产品感兴趣，但对降低暴露产品的健 康声明表示怀疑，怀疑是否真的会转换到这类产品，以及产品口味 是否和传统卷烟一样好 [301]。这些以及其他的反应可能受制造商对市 场营销，和在支持减少烟碱、烟草和其他烟碱产品的可用性和公众 的了解等方面宣传策略的影响。吸烟者和非吸烟者都必须了解不含 烟碱烟草的健康风险，可用产品的相对危害性，及对于治疗的作用。 烟草和烟碱产品的营销必须坚决被监管 [7,281]。 A3.6.8 公众对降低烟碱政策的支持 在美国进行的研究显示公众对强制减少烟碱有较强的支持。在 一项 511 名非烟者和 510 名吸烟者的调查中，65% 支持将卷烟中烟 碱降低到不致瘾的水平 ；其中包括 73% 的非吸烟者和 58% 的吸烟 者。超过 3/4 人以上（77%）的受访者，包括 81% 的非吸烟者和 74% 的吸烟者说，如果能减少儿童对卷烟的成瘾，他们会支持减少烟碱。 非吸烟者比吸烟者更可能支持降低卷烟中的烟碱水平 [302]。在另一项 调查中，67% 的吸烟者说他们会支持食品药物管理局（FDA） 的监 管， 使卷烟减少致瘾性， 如果“非卷烟形式的烟碱是容易获得的”[303]。 采用横断面方法对 2649 名成年人的调查中， 近半数支持减少烟碱， 包括 46% 的不吸烟者，49% 的有吸烟史者和 46% 的现吸烟者。在那 些打算在未来 6 月内戒烟的吸烟者中支持度最大 [304]。这项调查是三 项中唯一的一个，包括一个中立的反应选项，近 27% 的受访者选择 此选项，这可能解释与其他调查的接近的一致看法。
·263·
烟草制品管制科学基础报告： WHO 研究组第五份报告
A3.6.9 未知的市场影响 缩减含烟碱卷烟的供应可能会在上瘾的吸烟者中增加对走私卷 烟的需求 [6]。减少非法卷烟销售需要有效的监控策略 [7] 以及限制走 私市场的政策 [268]。大多数世界范围的走私是大规模、有组织的，烟 草制造商出口卷烟集装箱到没有合法市场的国家 [267,268]。对控制走私 成功的尝试包括生产厂家承担安全运输卷烟到合法市场的责任。 产销监管链标识要求生产商在所有烟草制品包装上清楚地印 刷标识制造商的唯一的序列号、日期和生产商地址及其他显示产销 链——批发商、出口商、经销商和终端市场的识别符。其他成功的 反走私措施包括用于检测的扫描仪、包装上醒目的财税标识、更强 的处罚力度、更多的海关官员和议会听证会揭露烟草行业出口活动 等做法。这些方法在意大利、西班牙大约分别减少走私卷烟 15% 和 1%~2%，在英国显著地减少 [268]。自愿的办法没有可衡量的影响。 除了大规模、 有组织走私， 非法贸易还包括假冒伪劣产品。 这 些 产 品 可 能 含 有 等 级 很 差 的 烟 草， 有 害 物 质 水 平 很 高， 或 对 使 用 它 们 的 吸 烟 者 存 在 其 他 意 外 风 险。 但 是， 正 如 Benowitz 和 Henningfield[6] 指出的，很难想象经营监管之外的假冒卷烟产品企业 的增长在规模上足以匹敌现有的卷烟市场。 未被监管的可燃烧类烟草，如自卷烟，可以成为商品化卷烟的 一种替代品。其他可能性包括大量同时使用减少烟碱卷烟结合烟碱 传输装置， 改变 pH 或添加剂来提高商品化产品的药理作用， 长期 使用减少烟碱产品产生的重要的、不可预料的行为上的变化。更有 吸引力的替代烟碱产品的可用性可能会起到检查这些意想不到的市 场效果的作用 [6,7]。 ·264·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
A3.6.10 小结 • • 全面协调地监管所有烟草和含烟碱的产品是减少烟碱政策成 功执行的必要条件。 调节在卷烟烟丝中含有的总烟碱释放量是减少烟碱的最有希 望的方法，因为它更容易被测量，减少行为操控和变化的主 观影响。 • 专门为烟草烟碱含量制定的绩效标准可能会鼓励研发包含较 少烟草烟碱的卷烟， 其在形式和功能上与传统卷烟十分不 相同。 • • 必须仔细评估新产品和技术及其商品上市许可，仅对已被充 分证明降低风险、致瘾性和吸引力的产品。 在几年的过程中逐渐减少烟碱可能会产生意想不到的后果， 还有待研究。无论是在几个月中逐步减少还是立即减少，均 存在不良影响或导致补偿性吸烟。 • • • 吸烟者可能会转向替代产品。其中最有前途的是电子烟和其 他装置，能提供烟碱并具有卷烟的感官特性，但并没有烟草。 行为辅导和药物治疗以协助有明显戒断症状和希望戒烟的吸 烟者，应为减少烟碱提供更广泛的支持。 适当的监测体系是必要的，使监管机构监督减少烟碱的卷烟 对流行性和初吸的影响，并评估相关危害性和意外后果。不 能支持大规模监测体系的国家可能需要援助。 • 降低烟碱产品更安全的信念可能会降低戒烟或切换到更安全 的替代产品的可能性。公众健康传播策略和市场监管是很重 要的。 ·265·
烟草制品管制科学基础报告： WHO 研究组第五份报告
• • •
在美国吸烟者和不吸烟者对减少卷烟中的烟碱都有很高的公 众支持，特别是如果提供其他形式的烟碱产品。 控制走私成功的尝试包括制造商承担安全运输卷烟到其合法 市场的责任。 健康可能会受到以下威胁 ： 小规模出售的走私卷烟，未被管 制的烟草制品形式，双重使用，以及为增加或替换烟碱有效 性而减少烟碱的卷烟进行的改变。
A3.7 结 论 虽然减少烟碱和使用减少烟碱卷烟的科学研究仍然有限 ， 在 现有研究中的结果仍是惊人的 。 动物和人体试验的研究结果大致 相若 ：它们显示出类似的自我给药阈值 ， 感官刺激和许多类烟草 化合物 （ 单胺氧化酶 、 生物碱 ） 都对烟碱强化有影响 ， 在青少年 时期依赖性产生的重要性大于成年后 ， 逐渐减少烟碱戒断症状或 不良影响相对较少 。 依据以上提出的证据，强制减少烟碱最可能的后果包括 ： • • • • • ·266·
初学者开始吸烟和发展到成瘾的减少 ； 由于行为上的消除使部分成瘾的吸烟者减少吸烟 ； 戒烟率增加和戒烟者复吸的数量减少 ； 增加烟碱替代形式的使用和可用性，包括口含烟或无烟烟草 产品、烟碱气溶胶或蒸气制品以及药用烟碱 ； 减少大多数吸烟者的健康风险，反映了消费量减少，烟气暴 露减少和减少烟草中有害物质的水平 （例如烟草特有亚硝胺、
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
烟碱） 。 强制减少烟碱可能产生的后果，目前用于做出判断的信息太少， 包括 ： • • • 使用高烟碱释放量黑市卷烟的吸烟者的比例增加 ； 同时使用含有烟碱产品和减少烟碱卷烟的吸烟者的比例增 加； 由生产商或由吸烟者对减少烟碱产品的设计或构造的改变， 改变产品的传输特性，对毒性、致瘾性和吸引力存在不能预 料的影响 ； • • • • • • 非吸烟者对含烟碱产品使用的增加， 因为其更高的可用性、 吸引力和疾病风险较低的认知 ； 女性比男性更长期地使用减少烟碱的卷烟。 作为缺乏烟碱的补偿反应，一些吸烟者增加摄入量（更多抽 吸或每天更多的卷烟） ； 由于暴露于缺乏烟碱的烟气，在继续吸烟者中心血管疾病的 风险增加 ； 暴露于减少烟碱的卷烟增加了其他滥用药物的使用 ； 替换或取代规范的卷烟市场的高烟碱释放量的卷烟黑市大 大增加 。 强制减少烟碱的其他潜在的不太可能的后果包括 ：
A3.8 建 议 减少烟碱政策在技术上是可行的，吸烟者和非吸烟者都是支持 ·267·
烟草制品管制科学基础报告： WHO 研究组第五份报告
的，并有可能对人群健康产生重大的积极影响。因此，应该支持全 面地监管所有含烟碱和烟草的产品。 全面监管应鼓励使用毒性较低的产品，如药用烟碱和烟碱传输 装置，并应减少毒性更大的产品的可用性和吸引力。 有确凿的证据表明， 卷烟烟碱强化所需的阈值水平是传输 0.1~0.2 mg 的烟碱。 此级别等于或低于吸烟者（0.1~0.4 mg） 和动物模型中 （0.2~0.5 mg）的自我给药烟碱水平， 等于或低于吸烟者和非吸烟者 对烟碱的识别阈值。它符合由制造商进行的关于卷烟烟碱延时作用 阈值（0.1~0.3 mg）的研究。 在较短时间强制减少烟碱几乎没有戒断作用或行为上的不良影 响。而逐渐地减少烟碱可能产生意想不到的行为和健康影响。提供 有效的、负担得起的治疗和替代形式的烟碱将帮助经历不良反应的 依赖性吸烟者。 在一些地区人群后果没有进行预测。应进行研究以确定使用的 可能性和减少烟碱卷烟对非吸烟的青少年、不吸烟的成年人和非依 赖性吸烟者的影响。应在风险人群中做进一步研究，如有中度或重 度抑郁症的人， 以及研究减少烟碱和含烟碱卷烟相对的健康影响。 还应对长期使用减少烟碱的卷烟进行研究。
A3.9 参 考 文 献 [1] Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction.The implications for tobacco regulation. N Engl J Med 1994;331:123–5. ·268·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
[2] Henningfield JE, Benowitz NL, Slade J, Houston TP, Davis RM, Deitchman SD.Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American Medical Association. Tob Control 1998;7:281–93. [3] Gray N, Henningfield JE, Benowitz NL, Connolly GN, Dresler G, Fagerstrom K, et al. Toward a comprehensive long term nicotine policy. Tob Control 2005;14:161–5. [4] Tengs TO, Ahmad S, Savage JM, Moore R, Gage E. The AMA proposal to mandate nicotine reduction in cigarettes: a simulation of the population health impacts. Prev Med 2005;40:170–80. [5] Zeller M, Hatsukami D, Strategic Dialogue on Tobacco Harm Reduction G. The Strategic Dialogue on Tobacco Harm Reduction: a vision and blueprint for action in the US. Tob Control 2009;18:324–32. [6] Benowitz NL, Henningfield JE. Reducing the nicotine content to make cigarettes less addictive. Tob Control 2013;22(Suppl 1):i14–7. [7] Hatsukami DK, Benowitz NL, Donny E, Henningfield J, Zeller M. Nicotine reduction: strategic research plan. Nicotine Tob Res 2013;15:1003–13. [8] Smith TT, Levin ME, Schassburger RL, Buffalari DM, Sved AF, Donny EC.Gradual and immediate nicotine reduction result in similar lowdose nicotine self-administration. Nicotine Tob Res 2013;15:1918–25. [9] Framework Convention on Tobacco Control. Geneva: World Health Organization;2013 (http://www.who.int/fctc/en/). [10] Report on the Scientific Basis of Tobacco Product Regulation: Fourth Report of a WHO Study Group (WHO Technical Report Series, No. ·269·
烟草制品管制科学基础报告： WHO 研究组第五份报告
967). Geneva: World Health Organization; 2012 (http://www.who. int/tobacco/publications/prod_regulation/trs_967/en/index.html). [11] Jarvis MJ, Bates C. Eliminating nicotine in cigarettes. Tob Control 1999;8:106–7;author reply 107–9. [12] Shatenstein S. Eliminating nicotine in cigarettes. Tob Control 1999;8:106; author reply 107–9. [13] Benowitz NL, Hall SM, Stewart S, Wilson M, Dempsey D, Jacob P 3rd. Nicotine and carcinogen exposure with smoking of progressively reduced nicotine content cigarette. Cancer Epidemiol Biomarkers Prev 2007;16:2479–85. [14] Hatsukami DK, Kotlyar M, Hertsgaard LA, Zhang Y, Carmella SG, Jensen JA, et al. Reduced nicotine content cigarettes: effects on toxicant exposure,dependence and cessation. Addiction 2010;105:343–55. [15] Benowitz NL, Dains KM, Hall SM, Stewart S, Wilson M, Dempsey D, et al.Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively reduced nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 2012;21:761–9. [16] Henningfield JE, Benowitz N, Connolly G, Davis R, Gray N, Myers M, et al.Reducing tobacco addiction through tobacco product regulation. Tob Control 2004;13:132–5. [17] Stratton K, Shetty P, Wallace R, Bondurant S. Clearing the smoke: the science base for tobacco harm reduction—executive summary. Tob Control 2001;10:189–95. [18] Hatsukami DK, Biener L, Leischow SJ, Zeller MR. Tobacco and ·270·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
nicotine product testing. Nicotine Tob Res 2012;14:7–17. [19] Hoffmann D, Hoffmann I. The changing cigarette, 1950–1995. J Toxicol Environ Health 1997;50:307–64. [20] Risks associated with smoking cigarettes with low tar machinemeasured yields of tar and nicotine (Monograph 13). Bethesda, Maryland: National Cancer Institute; 2001. [21] Benowitz NL, Jacob P 3rd. Intravenous nicotine replacement suppresses nicotine intake from cigarette smoking. J Pharmacol Exp Ther 1990;254:1000–5. [22] Parascandola M. Tobacco harm reduction and the evolution of nicotine dependence. Am J Public Health 2011;101:632–41. [23] Benowitz NL. Clinical pharmacology of nicotine: implications for understanding,preventing, and treating tobacco addiction. Clin Pharmacol Ther 2008;83:531–41. [24] Heishman SJ, Kleykamp BA, Singleton EG. Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology 2010;210:453–69. [25] DiFranza J, Ursprung WW, Lauzon B, Bancej C, Wellman RJ, Ziedonis D, et al.A systematic review of the Diagnostic and Statistical Manual diagnostic criteria for nicotine dependence. Addict Behav 2010;35:373–82. [26] Wayne GF, Carpenter CM. Tobacco industry manipulation of nicotine dosing.Handb Exp Pharmacol 2009;192:457–85. [27] Henningfield JE, Goldberg SR. Control of behavior by intravenous nicotine injections in human subjects. Pharmacol Biochem Behav ·271·
烟草制品管制科学基础报告： WHO 研究组第五份报告
1983;19:1021–6. [28] DiFranza JR, Ursprung WW, Carson A. New insights into the compulsion to use tobacco from an adolescent case-series. J Adolesc 2010;33:209–14. [29] Wellman RJ, DiFranza JR, Savageau JA, Dussault GF. Short term patterns of early smoking acquisition. Tob Control 2004;13:251–7. [30] DiFranza JR, Savageau JA, Fletcher K, O ’ Loughlin JE, Pbert L, Ockene JK, et al.Symptoms of tobacco dependence after brief intermittent use: the Development and Assessment of Nicotine Dependence in Youth-2 study. Arch Pediatr Adolesc Med 2007;161:704–10. [31] DiFranza JR, Savageau JA, Fletcher K, Pbert L, O’ Loughlin J, McNeill AD, et al. Susceptibility to nicotine dependence: the Development and Assessment of Nicotine Dependence in Youth 2 study. Pediatrics 2007;120:e974–83. [32] Lynch BS, Bonnie RJ, editors. Growing up tobacco free—preventing nicotine addiction in children and youths. Washington DC: Institute of Medicine, The National Academies; 1994:28–68. [33] Lessov-Schlaggar CN, Pergadia ML, Khroyan TV, Swan GE. Genetics of nicotine dependence and pharmacotherapy. Biochem Pharmacol 2008;75:178–95. [34] Taioli E, Wynder EL. Effect of the age at which smoking begins on frequency of smoking in adulthood. N Engl J Med 1991;325:968–9. [35] Breslau N, Peterson EL. Smoking cessation in young adults: age at initiation of cigarette smoking and other suspected influences. Am J ·272·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
Public Health 1996;86:214–20. [36] Lando HA, Thai DT, Murray DM, Robinson LA, Jeffery RW, Sherwood NE, et al.Age of initiation, smoking patterns, and risk in a population of working adults.Prev Med 1999;29:590–8. [37] Cui Y, Wen W, Moriarty CJ, Levine RS. Risk factors and their effects on the dynamic process of smoking relapse among veteran smokers. Behav Res Ther 2006;44:967–81. [38] Trauth JA, Seidler FJ, McCook EC, Slotkin TA. Adolescent nicotine exposure causes persistent upregulation of nicotinic cholinergic receptors in rat brain regions. Brain Res 1999;851:9–19. [39] Trauth JA, Seidler FJ, Slotkin TA. Persistent and delayed behavioral changes after nicotine treatment in adolescent rats. Brain Res 2000;880:167–72. [40] Adriani W, Macri S, Pacifici R, Laviola G. Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence. Neuropsychopharmacology 2002;27:212–24. [41] Vastola BJ, Douglas LA, Varlinskaya EI, Spear LP. Nicotine-induced conditioned place preference in adolescent and adult rats. Physiol Behav 2002;77:107–14. [42] Adriani W, Spijker S, Deroche-Gamonet V, Laviola G, Le Moal M, Smit AB,et al. Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats. J Neurosci 2003;23:4712–6. [43] Levin ED, Lawrence S, Petro A, Horton K, Rezvani AH, Seidler FJ, et al.Adolescent vs adult-onset nicotine self-administration in male rats: duration of effect and differential nicotinic receptor correlates. ·273·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Neurotoxicol Teratol 2007;29:458–65. [44] Kota D, Martin BR, Damaj MI. Age-dependent differences in nicotine reward and withdrawal in female mice. Psychopharmacology 2008;198:201–10. [45] Hatsukami DK, Perkins KA, LeSage MG, Ashley DL, Henningfield JE, Benowitz NL, et al. Nicotine reduction revisited: science and future directions. Tob Control 2010;19:e1–10. [46] Hukkanen J, Jacob P 3rd, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev 2005;57:79–115. [47] Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P 3rd. Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther 2006;79:480–8. [48] Sofuoglu M, Mooney M. Subjective responses to intravenous nicotine: greater sensitivity in women than in men. Exp Clin Psychopharmacol 2009;17:63–9. [49] Fant RV, Everson D, Dayton G, Pickworth WB, Henningfield JE. Nicotine dependence in women. J Am Med Womens Assoc 1996;51:19–20, 22–4, 28. [50] Gritz ER, Nielsen IR, Brooks LA. Smoking cessation and gender: the influence of physiological, psychological, and behavioral factors. J Am Med Womens Assoc 1996;51:35–42. [51] Eissenberg T, Adams C, Riggins EC 3rd, Likness M. Smokers’sex and the effects of tobacco cigarettes: subject-rated and physiological measures. Nicotine Tob Res 1999;1:317–24. [52] Perkins KA, Donny E, Caggiula AR. Sex differences in nicotine effects ·274·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
and self-administration: review of human and animal evidence. Nicotine Tob Res 1999;1:301–15. [53] Wetter DW, Kenford SL, Smith SS, Fiore MC, Jorenby DE, Baker TB. Gender differences in smoking cessation. J Consult Clin Psychol 1999;67:555–62. [54] Perkins KA, Sanders M, D ’ Amico D, Wilson A. Nicotine discrimination and self-administration in humans as a function of smoking status. Psychopharmacology 1997;131:361–70. [55] Carpenter CM, Wayne GF, Connolly GN. Designing cigarettes for women: new findings from the tobacco industry documents. Addiction 2005;100:837–51. [56] Perkins KA, Doyle T, Ciccocioppo M, Conklin C, Sayette M, Caggiula A. Sex differences in the influence of nicotine dose instructions on the reinforcing and self-reported rewarding effects of smoking. Psychopharmacology 2006;184:600–7. [57] Bevins RA, Caggiula AR. Nicotine, tobacco use, and the 55th Nebraska Symposium on Motivation. Nebr Symp Motiv 2009;55:1–3. [58] Lasser K, Boyd JW, Woolhandler S, Himmelstein DU, McCormick D, Bor DH.Smoking and mental illness: a population-based prevalence study. JAMA 2000;284:2606–10. [59] Williams JM, Ziedonis D. Addressing tobacco among individuals with a mental illness or an addiction. Addict Behav 2004;29:1067–83. [60] Ziedonis D, Hitsman B, Beckham JC, Zvolensky M, Adler LE, Audrain-McGovern J, et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob ·275·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Res 2008;10:1691–715. [61] Lawrence D, Considine J, Mitrou F, Zubrick SR. Anxiety disorders and cigarette smoking: results from the Australian Survey of Mental Health and Wellbeing.Aust N Z J Psychiatry 2010;44:520–7. [62] McClave AK, McKnight-Eily LR, Davis SP, Dube SR. Smoking characteristics of adults with selected lifetime mental illnesses: results from the 2007 National Health Interview Survey. Am J Public Health 2010;100:2464–72. [63] Schroeder SA, Morris CD. Confronting a neglected epidemic: tobacco cessation for persons with mental illnesses and substance abuse problems. Annu Rev Public Health 2010;31:297–314 1p following 314. [64] Leonard S, Adler LE, Benhammou K, Berger R, Breese CR, Drebing C, et al.Smoking and mental illness. Pharmacol Biochem Behav 2001;70:561–70. [65] Leonard S, Adams CE. Smoking cessation and schizophrenia. Am J Psychiatry 2006;163:1877. [66] Mineur YS, Picciotto MR. Biological basis for the co-morbidity between smoking and mood disorders. J Dual Diagn 2009;5:122–30. [67] Mineur YS, Picciotto MR. Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis. Trends Pharmacol Sci 2010;31:580–6. [68] Lewis A, Miller JH, Lea RA. Monoamine oxidase and tobacco dependence.Neurotoxicology 2007;28:182–95. [69] Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA. Nicotine ·276·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry 2004;61:1107–15. [70] Lawrence D, Mitrou F. One-third of adult smokers have a mental illness. Aust N Z J Psychiatry 2009;43:177–8. [71] Watson NL, Carpenter MJ, Saladin ME, Gray KM, Upadhyaya HP. Evidence for greater cue reactivity among low-dependent vs. highdependent smokers.Addict Behav 2010;35:673–7. [72] Plescia F, Brancato A, Marino RA, Cannizzaro C. Acetaldehyde as a drug of abuse: insight into AM281 administration on operantconflict paradigm in rats.Front Behav Neurosci 2013;7:64. [73] Talhout R, Opperhuizen A, van Amsterdam JG (2007) Role of acetaldehyde in tobacco smoke addiction. Eur Neuropsychopharmacol 17:627–36. [74] Villégier AS, Lotfipour S, McQuown SC, Belluzzi JD, Leslie FM. Tranylcypromine enhancement of nicotine self-administration. Neuropharmacology 2007;52:1415–25. [75] Pankow JF. A consideration of the role of gas/particle partitioning in the deposition of nicotine and other tobacco smoke compounds in the respiratory tract. Chem Res Toxicol 2001;14:1465–81. [76] Henningfield J, Pankow J, Garrett B. Ammonia and other chemical base tobacco additives and cigarette nicotine delivery: issues and research needs. Nicotine Tob Res 2004;6:199–205. [77] Rose JE. Nicotine and nonnicotine factors in cigarette addiction. Psychopharmacology 2006;184:274–85. ·277·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[78] Carpenter CM, Wayne GF, Connolly GN. The role of sensory perception in the development and targeting of tobacco products. Addiction 2007;102:136–47. [79] Breland AB, Buchhalter AR, Evans SE, Eissenberg T. Evaluating acute effects of potential reduced-exposure products for smokers: clinical laboratory methodology. Nicotine Tob Res 2002;4(Suppl 2):S131-40. [80] Perkins KA, Gerlach D, Broge M, Grobe JE, Sanders M, Fonte C, et al.Dissociation of nicotine tolerance from tobacco dependence in humans. J Pharmacol Exp Ther 2001;296:849–56. [81] Rose JE, Behm FM. Extinguishing the rewarding value of smoke cues:pharmacological and behavioral treatments. Nicotine Tob Res 2004;6:523–32. [82] Rose J, Behm F. Effects of low nicotine content cigarettes on smoke intake.Nicotine Tob Res 2004;6:309–19. [83] Lee LY, Gerhardstein DC, Wang AL, Burki NK. Nicotine is responsible for airway irritation evoked by cigarette smoke inhalation in men. J Appl Physiol 1993;75:1955–61. [84] Rose JE, Behm FM, Westman EC, Johnson M. Dissociating nicotine and nonnicotine components of cigarette smoking. Pharmacol Biochem Behav 2000;67:71–81. [85] Rose JE, Behm FM, Westman EC, Coleman RE. Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction. Drug Alcohol Depend 1999;56:99–107. [86] Ferris Wayne G, Connolly GN. Application, function, and effects ·278·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
of menthol in cigarettes: a survey of tobacco industry documents. Nicotine Tob Res 2004;6(Suppl 1):S43–54. [87] Celebucki CC, Wayne GF, Connolly GN, Pankow JF, Chang EI. Characterization of measured menthol in 48 US cigarette sub-brands. Nicotine Tob Res 2005;7:523–31. [88] Galeotti N, Ghelardini C, Mannelli L, Mazzanti G, Baghiroli L, Bartolini A. Local anaesthetic activity of (+)- and (–)-menthol. Planta Med 2001;67:174–6. [89] Shojaei AH, Khan M, Lim G, Khosravan R. Transbuccal permeation of a nucleoside analog, dideoxycytidine: effects of menthol as a permeation enhancer. Int J Pharm 1999;192:139–46. [90] Brody AL, Mandelkern M, Costello MR, Abrams AL, Scheibal D, Farahi J, et al. Brain nicotinic acetylcholine receptor occupancy: effect of smoking a denicotinized cigarette. Int J Neuropsychopharmacol 2009;12:305–16. [91] Bardo MT, Green TA, Crooks PA, Dwoskin LP. Nornicotine is self-administered intravenously by rats. Psychopharmacology 1999;146:290–6. [92] Clemens KJ, Caille S, Stinus L, Cador M. The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats. Int J Neuropsychopharmacology 2009;12:1355–66. [93] Rodd-Henricks ZA, Melendez RI, Zaffaroni A, Goldstein A, McBride WJ, Li TK.The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of alcohol-preferring rats. Pharmacol Biochem ·279·
烟草制品管制科学基础报告： WHO 研究组第五份报告
Behav 2002;72:55–64. [94] B elluzzi JD, Wang R , Leslie FM. Acetaldehyde enhances acquisition of nicotine self-administrationin adolescent rats. Neuropsychopharmacology 2005;30:705–12. [95] Cao J, Belluzzi JD, Loughlin SE, Keyler DE, Pentel PR, Leslie FM.Acetaldehyde, a major constituent of tobacco smoke, enhances behavioral,endocrine, and neuronal responses to nicotine in adolescent and adult rats.Neuropsychopharmacology 2007;32:2025– 35. [96] Guillem K, Vouillac C, Koob JF, Cador M, Stinus L. Monoamine oxidase inhibition dramatically increases the motivation to selfadminister nicotine in rats. J Neurosci 2005;25:8593–600. [97] Guillem K, Vouillac C, Koob GF, Cador M, Stinus L. Monoamine oxidase inhibition dramatically prolongs the duration of nicotine withdrawal-induced place aversion. Biol Psychiatry 2008;63:158–63. [98] Rose JE, Behm FM, Ramsey C, Ritchie JC Jr. Platelet monoamine oxidase,smoking cessation, and tobacco withdrawal symptoms. Nicotine Tob Res2001;3:383–90. [99] The health consequences of smoking: nicotine addiction. A report of the Surgeon General. Rockville, Maryland: Department of Health and Human Services,Public Health Service, Centers for Disease Control, Office on Smoking and Health; 1988. [100] Dar R, Frenk H. Do smokers self-administer pure nicotine? A review of the evidence. Psychopharmacology 2004;173:18–26. [101] Fulton HG, Barrett SP. A demonstration of intravenous nicotine ·280·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
self-administration in humans? Neuropsychopharmacology 2008; 33:2042–3; author reply 2044. [102] Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved AF. Importance of nonpharmacological factors in nicotine self-administration.Physiol Behav 2002;77:683–7. [103] Olausson P, Jentsch JD, Taylor JR. Repeated nicotine exposure enhances reward-related learning in the rat. Neuropsychopharmacology 2003;28:1264–71. [104] Olausson P, Jentsch JD, Taylor JR. Nicotine enhances responding with conditioned reinforcement. Psychopharmacology 2004; 171:173–8. [105] Chaudhri N, Caggiula AR, Donny EC, Palmatier MI, Liu X, Sved AF. Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement. Psychopharmacology 2006;184:353–66. [106] Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, et al.Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule.Psychopharmacology 2007;190:353–62. [107] Palmatier MI, Liu X, Caggiula AR, Donny EC, Sved AF. The role of nicotinic acetylcholine receptors in the primary reinforcing and reinforcement-enhanci ng effects of nicotine. Neuropsychopharmacology 2007;32:1098–108. [108] Palmatier MI, Liu X, Matteson GL, Donny EC, Caggiula AR, Sved AF. Conditioned reinforcement in rats established with self·281·
烟草制品管制科学基础报告： WHO 研究组第五份报告
administered nicotine and enhanced by noncontingent nicotine. Psychopharmacology 2007;195:235–43. [109] Le Foll B, Goldberg SR. Control of the reinforcing effects of nicotine by associated environmental stimuli in animals and humans. Trends Pharmacol Sci 2005;26:287–93. [110] Cohen C, Perrault G, Griebel G, Soubrie P. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal:reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716).Neuropsychopharmacology 2005;30:145–55. [111] Le Foll B, Wertheim C, Goldberg SR. High reinforcing efficacy of nicotine in non human primates. PloS One 2007;2:e230. [112] Donny EC, Chaudhri N, Caggiula AR, Evans-Martin FF, Booth S, Gharib MA, et al. Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology 2003;169:68–76. [113] Caggiula AR, Donny EC, Palmatier MI, Liu X, Chaudhri N, Sved AF. The role of nicotine in smoking: a dual-reinforcement model. Nebr Symp Motiv 2009;55:91–109. [114] Carter BL, Tiffany ST. Cue-reactivity and the future of addiction research.Addiction 1999;94:349–51. [115] Donny EC, Houtsmuller E, Stitzer ML. Smoking in the absence of nicotine:behavioral, subjective and physiological effects over 11 days. Addiction 2007;102:324–34. ·282·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
[116] Rees VW, Kreslake JM, Wayne GF, O’ Connor RJ, Cummings KM, Connolly GN.Role of cigarette sensory cues in modifying puffing topography. Drug Alcohol Depend 2012;124:1–10. [117] Palmatier MI, Lantz JE, O’ Brien LC, Metz SP. Effects of nicotine on olfactogustatory incentives: preference, palatability, and operant choice tests.Nicotine Tob Res 2013;15:1545–54. [118] Perkins KA, Jacobs L, Ciccocioppo M, Conklin C, Sayette M, Caggiula A. The influence of instructions and nicotine dose on the subjective and reinforcing effects of smoking. Exp Clin Psychopharmacol 2004;12:91–101. [119] Perkins KA, Ciccocioppo M, Conklin CA, Milanak ME, Grottenthaler A, Sayette MA. Mood influences on acute smoking responses are independent of nicotine intake and dose expectancy. J Abnorm Psychol 2008;117:79–93. [120] Darredeau C, Barrett SP. The role of nicotine content information in smokers’ subjective responses to nicotine and placebo inhalers. Hum Psychopharmacol 2010;25:577–81. [121] Juliano LM, Fucito LM, Harrell PT. The influence of nicotine dose and nicotine dose expectancy on the cognitive and subjective effects of cigarette smoking.Exp Clin Psychopharmacology 2011;19:105– 15. [122] Kirsch I, Lynn SJ. Automaticity in clinical psychology. Am Psychol 1999;54:504–15. [123] Perkins K, Sayette M, Conklin C, Caggiula A. Placebo effects of tobacco smoking and other nicotine intake. Nicotine Tob Res ·283·
烟草制品管制科学基础报告： WHO 研究组第五份报告
2003;5:695–709. [124] Hughes JR, Gulliver SB, Amori G, Mireault GC, Fenwick JF. Effect of instructions and nicotine on smoking cessation, withdrawal symptoms and self-administration of nicotine gum. Psychopharmacology 1989;99:486–91. [125] Perkins KA, Coddington SB, Karelitz JL, Jetton C, Scott JA, Wilson AS, et al.Variability in initial nicotine sensitivity due to sex, history of other drug use, and parental smoking. Drug Alcohol Depend 2009;99:47–57. [126] Juliano LM, Brandon TH. Effects of nicotine dose, instructional set, and outcome expectancies on the subjective effects of smoking in the presence of a stressor. J Abnorm Psychol 2002;111:88–97. [127] Wayne GF, Connolly GN, Henningfield JE. Assessing internal tobacco industry knowledge of the neurobiology of tobacco dependence. Nicotine Tob Res 2004;6:927–40. [128] Megerdichian CL, Rees VW, Wayne GF, Connolly GN. Internal tobacco industr yresearch on olfactory and trigeminal nerve response to nicotine and other smoke components. Nicotine Tob Res 2007;9:1119–29. [129] Darredeau C, Stewart SH, Barrett SP. The effects of nicotine content informationon subjective and behavioural responses to nicotinecontaining and denicotinized cigarettes. Behav Pharmacol 2013;24:291–7. [130] Perkins KA, Grottenthaler A, Ciccocioppo MM, Conklin CA, Sayette MA, Wilson AS. Mood, nicotine, and dose expectancy effects on ·284·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
acute responses to nicotine spray. Nicotine Tob Res 2009;11:540–6. [131] De Leon E, Smith KC, Cohen JE. Dependence measures for noncigarette tobacco products within the context of the global epidemic: a systematic review.Tob Control 2013;23:197–203. [132] Hatsukami DK, Joseph AM, LeSage M, Jensen J, Murphy SE, Pentel PR, et al. Developing the science base for reducing tobacco harm. Nicotine Tob Res 2007;9(Suppl 4):S537–53. [133] Donny EC, Taylor TG, LeSage MG, Levin M, Buffalari DM, Joel D, et al. Impact of tobacco regulation on animal research: new perspectives and opportunities.Nicotine Tob Res 2012;14:1319–38. [134] Palmatier MI, O’ Brien LC, Hall MJ. The role of conditioning history and reinforcer strength in the reinforcement enhancing effects of nicotine in rats.Psychopharmacology 2012;219:1119–31. [135] Henningfield JE, Miyasato K, Jasinski DR Cigarette smokers selfadminister intravenous nicotine. Pharmacol Biochem Behav 1983;19:887–90. [136] Harvey DM, Yasar S, Heishman SJ, Panlilio LV, Henningfield JE, Goldberg SR.Nicotine serves as an effective reinforcer of intravenous drug-taking behavior inhuman cigarette smokers. Psychopharmacology 2004;175:134–42. [137] Sofuoglu M, Yoo S, Hill KP, Mooney M. Self-administration of intravenous nicotine in male and female cigarette smokers. Neuropsychopharmacology 2008;33:715–20. [138] Matta SG, Balfour DJ, Benowitz NL, Boyd RT, Buccafusco JJ, Caggiula AR, et al.Guidelines on nicotine dose selection for in vivo ·285·
烟草制品管制科学基础报告： WHO 研究组第五份报告
research. Psychopharmacology 2007;190:269–319. [139] Cox BM, Goldstein A, Nelson WT. Nicotine self-administration in rats. Br JPharmacol 1984;83:49–55. [140] Shram MJ, Li Z, Le AD. Age differences in the spontaneous acquisition of nicotine self-administration in male Wistar and Long-Evans rats. Psychopharmacology 2008;197:45–58. [141] Corrigall WA, Coen KM. Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology 1989; 99:473–8 [142] Donny EC, Caggiula AR, Knopf S, Brown C. Nicotine selfadministration in rats.Psychopharmacology 1995;122:390–4. [143] Shoaib M, Schindler CW, Goldberg SR. Nicotine self-administration in rats:strain and nicotine pre-exposure effects on acquisition. Psychopharmacology 1997;129:35–43. [144] Watkins SS, Epping-Jordan MP, Koob GF, Markou A. Blockade of nicotine self-administration with nicotinic antagonists in rats. Pharmacol Biochem Behav 1999;62:743–51. [145] Brower VG, Fu Y, Matta SG, Sharp BM. Rat strain differences in nicotine self-administration using an unlimited access paradigm. Brain Res 2002;930:12–20. [146] DeNoble VJ, Mele PC. Intravenous nicotine self-administration in rats: effects of mecamylamine, hexamethonium and naloxone. Psychopharmacology 2006;184:266–72. [147] Sorge RE, Clarke PB. Rats self-administer intravenous nicotine delivered in a novel smoking-relevant procedure: effects of ·286·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
dopamine antagonists. J Pharmacol Exp Ther 2009;330:633–40. [148] Hanson HM, Ivester CA, Morton BR. Nicotine self-administration in rats. In:Krasnegor NA, editor. Cigarette smoking as a dependence process (NIDA Research Monograph 23). Washington DC: National Instiute on Drug Abuse;1979:70–90. [149] Kota D, Martin BR, Robinson SE, Damaj MI. Nicotine dependence and reward differ between adolescent and adult male mice. J Pharmacol Exp Ther 2007;322:399–407. [150] Levin ED, Rezvani AH, Montoya D, Rose JE, Swartzwelder HS. Adolescent onset nicotine self-administration modeled in female rats. Psychopharmacology2003;169:141–9. [151] Chen H, Matta SG, Sharp BM. Acquisition of nicotine selfadministration in adolescent rats given prolonged access to the drug. Neuropsychopharmacology2007;32:700–9. [152] Shram MJ, Funk D, Li Z, Le AD. Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence.Neuropsychopharmacology 2008;33:739–48. [153] Shram MJ, Siu EC, Li Z, Tyndale RF, Le AD. Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats. Psychopharmacology 2008;198:181–90. [154] DiFranza JR, Savageau JA, Rigotti NA, Fletcher K, Ockene JK, McNeill AD,et al. Development of symptoms of tobacco ·287·
烟草制品管制科学基础报告： WHO 研究组第五份报告
dependence in youths: 30 month follow up data from the DANDY study. Tob Control 2002;11:228–35. [155] O ’ Loughlin J, Gervais A, Dugas E, Meshefedjian G. Nicotinedependence symptoms are associated with smoking frequency in adolescents. Am J Prev Med 2003;25:219–25. [156] Gervais A, O’ Loughlin J, Meshefedjian G, Bancej C, Tremblay M. Milestones in the natural course of onset of cigarette use among adolescents. Can Med Assoc J 2006;175:255–61. [157] Kandel DB, Hu MC, Griesler PC, Schaffran C. On the development of nicotine dependence in adolescence. Drug Alcohol Depend 2007;91:26–39. [158] Caraballo RS, Novak SP, Asman K. Linking quantity and frequency profiles of cigarette smoking to the presence of nicotine dependence symptoms among adolescent smokers: findings from the 2004 National Youth Tobacco Survey.Nicotine Tob Res 2009;11:49–57. [159] Corrigall WA, Zack M, Eissenberg T, Belsito L, Scher R. Acute subjective and physiological responses to smoking in adolescents. Addiction 2001;96:1409–17. [160] Aung AT, Pickworth WB, Moolchan ET. History of marijuana use and tobacco smoking topography in tobacco-dependent adolescents. Addict Behav 2004;29:699–706. [161] Wood T, Wewers ME, Groner J, Ahijevych K. Smoke constituent exposure and smoking topography of adolescent daily cigarette smokers. Nicotine Tob Res 2004;6:853–62. [162] Kassel JD, Greenstein JE, Evatt DP, Wardle MC, Yates MC, Veilleux ·288·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
JC, et al. Smoking topography in response to denicotinized and high-yield nicotine cigarettes in adolescent smokers. J Adolesc Health 2007;40:54–60. [163] Wahl SK, Turner LR, Mermelstein RJ, Flay BR. Adolescents ’ smoking expectancies: psychometric properties and prediction of behavior change.Nicotine Tob Res 2005;7:613–23. [164] Heinz AJ, Kassel JD, Berbaum M, Mermelstein R. Adolescents’ expectancies for smoking to regulate affect predict smoking behavior and nicotine dependence over time. Drug Alcohol Depend 2010;111:128–35. [165] Kassel JD, Evatt DP, Greenstein JE, Wardle MC, Yates MC, Veilleux JC. Theacute effects of nicotine on positive and negative affect in adolescent smokers.J Abnorm Psychol 2007;116:543–53. [166] Baldinger B, Hasenfratz M, Battig K. Switching to ultralow nicotine cigarettes:effects of different tar yields and blocking of olfactory cues. Pharmacol Biochem Behav 1995;50:233–9. [167] Butschky MF, Bailey D, Henningfield JE, Pickworth WB. Smoking without nicotine delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacol Biochem Behav 1995;50:91–6. [168] Westman EC, Behm FM, Rose JE. Dissociating the nicotine and airway sensory effects of smoking. Pharmacol Biochem Behav 1996;53:309–15. [169] Gross J, Lee J, Stitzer ML. Nicotine-containing versus de-nicotinized cigarettes:effects on craving and withdrawal. Pharmacol Biochem Behav 1997;57:159–65. ·289·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[170] Pickworth WB, Fant RV, Nelson RA, Rohrer MS, Henningfield JE.Pharmacodynamic effects of new de-nicotinized cigarettes. Nicotine Tob Res1999;1:357–64. [171] Buchhalter AR, Schrinel L, Eissenberg T. Withdrawal-suppressing effects of a novel smoking system: comparison with own brand, not own brand, and denicotinizedcigarettes. Nicotine Tob Res 2001;3:111–8. [172] Barrett SP. The effects of nicotine, denicotinized tobacco, and nicotine-containing tobacco on cigarette craving, withdrawal, and self-administration in male and female smokers. Behav Pharmacol 2010;21:144–52. [173] Brauer LH, Behm FM, Lane JD, Westman EC, Perkins C, Rose JE. Individual differences in smoking reward from de-nicotinized cigarettes. Nicotine Tob Res 2001;3(2):101–9. [174] Dallery J, Houtsmuller EJ, Pickworth WB, Stitzer ML. Effects of cigarette nicotine content and smoking pace on subsequent craving and smoking.Psychopharmacology 2003;165:172–80. [175] Rose JE, Behm FM, Westman EC, Bates JE, Salley A. Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav 2003;76:243–50. [176] Grady SR, Marks MJ, Collins AC. Desensitization of nicotinestimulated[3H]dopamine release from mouse striatal synaptosomes. J Neurochem 1994;62:1390–8. [177] Lu Y, Marks MJ, Collins AC. Desensitization of nicotinic agonistinduced[3H]gamma-aminobutyric acid release from mouse brain ·290·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
synaptosomes is produced by subactivating concentrations of agonists. J Pharmacol Exp Ther 1999;291:1127–34. [178] Picciotto MR, Addy NA, Mineur YS, Brunzell DH. It is not “either/ or ” : activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol 2008;84:329–42. [179] Donny EC, Jones M. Prolonged exposure to denicotinized cigarettes with or without transdermal nicotine. Drug Alcohol Depend 2009;104:23–33. [180] Bouton ME. Context and behavioral processes in extinction. Learn Mem 2004;11:485–94. [181] International statistical classification of diseases and related health problems,10th revision. Geneva: World Health Organization; 1992. [182] Moolchan ET, Radzius A, Epstein DH, Uhl G, Gorelick DA, Cadet JL, et al. The Fagerstrom test for nicotine dependence and the Diagnostic Interview Schedule:do they diagnose the same smokers? Addict Behav 2002;27:101–13. [183] Hughes JR, Oliveto AH, Riggs R, Kenny M, Liguori A, Pillitteri JL, et al.Concordance of different measures of nicotine dependence: two pilot studies.Addict Behav 2004;29:1527–39. [184] Hendricks PS, Prochaska JJ, Humfleet GL, Hall SM. Evaluating the validities of different DSM-IV-based conceptual constructs of tobacco dependence.Addiction 2008;103:1215–23. [185] Hughes JR, Baker T, Breslau N, Covey L, Shiffman S. Applicability of DSM criteria to nicotine dependence. Addiction 2011;106:894–5; ·291·
烟草制品管制科学基础报告： WHO 研究组第五份报告
discussion 895–7. [186] Colby SM, Tiffany ST, Shiffman S, Niaura RS. Measuring nicotine dependence among youth: a review of available approaches and instruments. Drug Alcohol Depend 2000;59(Suppl 1):S23–39. [187] Rose JS, Dierker LC. DSM-IV nicotine dependence symptom characteristics for recent-onset smokers. Nicotine Tob Res 2010; 12:278–86. [188] Rubinstein ML, Luks TL, Moscicki AB, Dryden W, Rait MA, Simpson GV.Smoking-related cue-induced brain activation in adolescent light smokers. J Adolesc Health 2011;48:7–12. [189] Sofuoglu M, LeSage MG. The reinforcement threshold for nicotine as a target for tobacco control. Drug Alcohol Depend 2012;125:1–7. [190] Audrain-McGovern J, Rodriguez D, Epstein LH, Rodgers K, Cuevas J, Wileyto EP.Young adult smoking: what factors differentiate exsmokers, smoking cessation treatment seekers and nontreatment seekers? Addict Behav 2009;34:1036-41. [191] Glautier S. Measures and models of nicotine dependence: positive reinforcement.Addiction 2004;99(Suppl 1):30–50. [192] Comer SD, Ashworth JB, Foltin RW, Johanson CE, Zacny JP, Walsh SL. The role of human drug self-administration procedures in the development of medications. Drug Alcohol Depend 2008;96:1–15. [193] Besheer J, Palmatier MI, Metschke DM, Bevins RA. Nicotine as a signal for the presence or absence of sucrose reward: a Pavlovian drug appetitive conditioning preparation in rats. Psychopharmacology 2004;172:108–17. ·292·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
[194] Bevins RA, Palmatier MI. Extending the role of associative learning processesin nicotine addiction. Behav Cogn Neurosci Rev 2004;3(3):143–58. [195] Wilkinson JL, Murray JE, Li C, Wiltgen SM, Penrod RD, Berg SA, Bevins RA.Interoceptive Pavlovian conditioning with nicotine as the conditional stimulus varies as a function of the number of conditioning trials and unpaired sucrose deliveries. Behav Pharmacol 2006;17:161–72. [196] Murray JE, Bevins RA. Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus. Eur J Pharmacol 2007;561:91–104. [197] Palmatier MI, Coddington SB, Liu X, Donny EC, Caggiula AR, Sved AF. The motivation to obtain nicotine-conditioned reinforcers depends on nicotine dose.Neuropharmacology 2008;55:1425–30. [198] Panzano VC, Wayne GF, Pickworth WB, Connolly GN. Human electroencephalography and the tobacco industry: a review of internal documents. Tob Control 2010;19:153–9. [199] Gullotta FP, Hayes C. The effects of cigarette smoking on pattern reversal evoked potentials (preps). Philip Morris. Bates No. 2028817734–40; 1981(http://legacy.library.ucsf.edu/tid/rfp12e00). [200] Gullotta FP, Hayes CS, Martin BR. Electrophysiological and subjective effect of cigarettes delivering varying amounts of nicotine. Philip Morris. Bates No.2062374615–22; 1990 (http:// legacy.library.ucsf.edu/tid/izy26c00). [201] Charles JL, Gullotta FP, Schultz CJ. Electrophysiological studies— ·293·
烟草制品管制科学基础报告： WHO 研究组第五份报告
820000 annual report. Philip Morris. Bates No. 2056128455–504; 1982 (http://legacy.library.ucsf.edu/tid/bra52e00). [202] Connolly GN, Alpert HR, Wayne GF, Koh H. Trends in nicotine yield in smoke and its relationship with design characteristics among popular US cigarette brands, 1997—2005. Tob Control 2007;16(5):e5. [203] Slade J, Bero LA, Hanauer P, Barnes DE, Glantz SA. Nicotine and addiction.The Brown and Williamson documents. J Am Med Assoc 1995;274:225–33. [204] Hurt RD, Robertson CR. Prying open the door to the tobacco industry’ s secrets about nicotine: the Minnesota Tobacco Trial. J Am Med Assoc 1998;280:1173–81. [205] Dunsby J, Bero L. A nicotine delivery device without the nicotine? Tobacco industry development of low nicotine cigarettes. Tob Control 2004;13:362–9. [206] British American Tobacco. Research and Development Department: Progress in 1972—Plans for 1973. Bates No. 402409855–89; 1972 (http://legacy.library.ucsf.edu/tid/qdb84a99/). [207] British American Tobacco. Introductory notes on leaf blending. Bates No.102638105–66; 1969 (http://legacy.library.ucsf.edu/tid/ qmy36a99/). [208] Browne CL. The design of cigarettes. Charlotte, North Carolina: Hoechst Celanese; 1990. [209] Cohen N. Minutes of meeting on May 6 1971. British American Tobacco. Bates No. 103551202–4; 1971 (http://legacy.library.ucsf. ·294·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
edu/tid/rng84a99/). [210] Gibb RM. [Memo from RM Gibb to EP Gage regarding low nicotine]. Bates No.103408473–4; 1974 (http://legacy.library.ucsf. edu/tid/kly06a99/). [211] Johnson DP. Low nicotine tobacco. RJ Reynolds. Bates No. 511040740; 1977(http://legacy.library.ucsf.edu/tid/xsk53d00/). [212] Kentucky Tobacco Research Board. 1977 annual review. Bates No. 9809; 1977(http://legacy.library.ucsf.edu/tid/omd76b00). [213] Smith TE. Tobacco and smoke characteristics of low nicotine strains of Burley.British American Tobacco. Bates No. 402379156–69; 1972 (http://legacy.library.ucsf.edu/tid/dly54a99/). [214] Geiss VL. Bw process. I Reductions of tobacco nicotine using selected bacteria.British American Tobacco. Bates No. 402350891– 915; 1972 (http://legacy.library.ucsf.edu/tid/jlw84a99). [215] Geiss VL. Bw process. VI Metabolism of nicotine and other biochemistry of the Bw process. British American Tobacco. Bates No. 107474767–70; 1975 (http://legacy.library.ucsf.edu/tid/ gpx86a99/). [216] Gravely LE, Newton RP, Geiss VL. Bw process: IV Evaluation of low nicotine cigarettes used for consumer product testing. British American Tobacco. Bates No. 402371546–59; 1973 (http://legacy. library.ucsf.edu/tid/zso05a99/). [217] York JE. Control of nicotine in tobacco and cigarette smoke. American Tobacco.Bates No. 950796661–6; 1977 (http://legacy. library.ucsf.edu/tid/ywy90a00/). ·295·
烟草制品管制科学基础报告： WHO 研究组第五份报告
[218] Rickett FL, Pedersen PM. A review of methods for reduction of nicotine in tobacco. American Tobacco. Bates No. 950643646–55; 1980 (http://legacy.library.ucsf.edu/tid/rgd90a00/). [219] Ashburn G. Vapor-phase removal of nicotine from smoke. RJ Reynolds. Bates No. 500937661–714; 1961 (http://legacy.library. ucsf.edu/tid/cyo59d00). [220] Green CR. Denicotinization of low nicotine, high sugar flue cured tobacco. RJ Reynolds. Bates No. 504804962–3; 1979 (http://legacy. library.ucsf.edu/tid/jwm55d00). [221] Kassman AJ, Knudson DB, Lilly AC, Sherwood JF. Alkaloid reduced Tobaco(ART) Program Current Status and Plans for 1987. Philip Morris. Bates No.2051841630–44; 1986 (http://legacy.library.ucsf. edu/tid/xth52e00). [222] Philip Morris. Alkaloid reduced tobacco (ART) program. Philip Morris. Bates No.2063096617–51; 1995 (http://legacy.library.ucsf. edu/tid/xus47d00). [223] Houghton KS. Monthly development summary—May, 1990. Philip Morris. Bates No. 2022156219–42; 1990 (http://legacy.library.ucsf. edu/tid/ggx44e00). [224] Gullotta F, Hayes C, Martin B. The effects of nicotine and menthol on electrophysiological and subjective responses. Philip Morris. Bates No.2029213006–18; 1991 (http://legacy.library.ucsf.edu/tid/ ezc69e00). [225] Philip Morris. Study concept: the electrophysiological and subjective effects of smoking cigarettes with constant nicotine but varying tar ·296·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
levels. Philip Morris.Bates No. 2025988473–5; 1995 (http://legacy. library.ucsf.edu/tid/vlo46b00). [226] Ferris Wayne G, Connolly GN, Henningfield JE. Brand differences of free-base nicotine delivery in cigarette smoke: the view of the tobacco industry documents.Tob Control 2006;15:189–98. [227] Ashley DL, Pankow JF, Tavakoli AD, Watson CH. Approaches, challenges, and experience in assessing free nicotine. Handb Exp Pharmacol 2009;192:437–56. [228] Gregory CF. Observation of free nicotine changes in tobacco smoke/528. Brown& Williamson. Bates No. 510000667–70; 1980 (http://legacy.library.ucsf.edu/tid/zds24f00). [229] Shannon D, Walker RJ, Smith NA, Perfetti T, Ingebrethsen B, Saintsing B, et al. We Are Looking at Smoothness from a Different Perspective. RJ Reynolds.Bates No. 508408649–770; 1992 (http:// legacy.library.ucsf.edu/tid/mcq93d00). [230] Pankow JF, Tavakoli AD, Luo W, Isabelle LM. Percent free base nicotine in the tobacco smoke particulate matter of selected commercial and reference cigarettes. Chem Res Toxicol 2003;16:1014–8. [231] Watson CH, Trommel JS, Ashley DL. Solid-phase microextractionbased approach to determine free-base nicotine in trapped mainstream cigarettesmoke total particulate matter. J Agric Food Chem 2004;52:7240–5. [232] Benowitz NL, Jacob P III, Bernert JT, Wilson M, Wang L, Allen F, et al. Carcinogen exposure during short-term switching from ·297·
烟草制品管制科学基础报告： WHO 研究组第五份报告
regular to“light”cigarettes. Cancer Epidemiol Biomarkers Prev 2005;14:1376–83. [233] Benowitz NL, Jacob P 3rd, Herrera B. Nicotine intake and dose response when smoking reduced-nicotine content cigarettes. Clin Pharmacol Ther 2006;80:703–14. [234] Benowitz NL, Dains KM, Hall SM, Stewart S, Wilson M, Dempsey D, et al.Progressive commercial cigarette yield reduction: biochemical exposure and behavioral assessment. Cancer Epidemiol Biomarkers Prev 2009;18:876–83. [235] Henningfield JE, Fant RV, Tomar SL. Smokeless tobacco: an addicting drug.Adv Dental Res 1997;11:330–5. [236] Hatsukami DK, Lemmonds C, Tomar SL. Smokeless tobacco use: harm reduction or induction approach? Prev Med 2004;38:309–17. [237] Henningfield JE, Shiffman S, Ferguson SG, Gritz ER. Tobacco dependence and withdrawal: science b ase, challenges and opportunities for pharmacotherapy.Pharmacol Ther 2009;123:1–16. [238] Wayne GF, Connolly GN, Henningfield JE, Farone WA. Tobacco industry research and efforts to manipulate smoke particle size: implications for product regulation. Nicotine Tob Res 2008;10:613–25. [239] Becker KM, Rose JE, Albino AP. A randomized trial of nicotine replacement therapy in combination with reduced-nicotine cigarettes for smoking cessation.Nicotine Tob Res 2008;10:1139–48. [240] Rose JE. Disrupting nicotine reinforcement: from cigarette to brain. Ann N Y Acad Sci 2008;1141:233–56. [241] DeGrandpre RJ, Bickel WK, Hughes JR, Higgins ST. Behavioral ·298·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
economics of drug self-administration. III. A reanalysis of the nicotine regulation hypothesis.Psychopharmacology 1992;108:1– 10. [242] Shahan TA, Bickel WK, Madden GJ, Badger GJ. Comparing the reinforcing efficacy of nicotine containing and de-nicotinized cigarettes: a behavioral economic analysis. Psychopharmacology 1999;147:210–6. [243] Shahan TA, Bickel WK, Badger GJ, Giordano LA. Sensitivity of nicotine-containing and de-nicotinized cigarette consumption to alternative non-drug reinforcement:a behavioral economic analysis. Behav Pharmacol 2001;12:277–84. [244] Shahan TA, Odum AL, Bickel WK. Nicotine gum as a substitute for cigarettes: a behavioral economic analysis. Behav Pharmacol 2000;11:71–9. [245] Johnson MW, Bickel WK, Kirshenbaum AP. Substitutes for tobacco smoking:a behavioral economic analysis of nicotine gum, denicotinized cigarettes, and nicotine-containing cigarettes. Drug Alcohol Depend 2004;74:253–64. [246] West RJ, Jarvis MJ, Russell MA, Carruthers ME, Feyerabend C. Effect of nicotine replacement on the cigarette withdrawal syndrome. Br J Addict 1984;79:215–9. [247] Zacny JP, Stitzer ML. Cigarette brand-switching: effects on smoke exposure and smoking behavior. J Pharmacol Exp Ther 1988;246:619–27. [248] Strasser AA, Lerman C, Sanborn PM, Pickworth WB, Feldman EA. ·299·
烟草制品管制科学基础报告： WHO 研究组第五份报告
New lower nicotine cigarettes can produce compensatory smoking and increased carbon monoxide exposure. Drug Alcohol Depend 2007;86:294–300. [249] Harris AC, Pentel PR, Burroughs D, Staley MD, Lesage MG. A lack of association between severity of nicotine withdrawal and individual differences in compensatory nicotine self-administration in rats. Psychopharmacology 2011;217:153–66. [250] Roiko SA, Harris AC, LeSage MG, Keyler DE, Pentel PR. Passive immunization with a nicotine-specific monoclonal antibody decreases brain nicotine levels but does not precipitate withdrawal in nicotine-dependent rats. Pharmacol Biochem Behav 2009; 93:105–11. [251] Walker N, Howe C, Bullen C, Grigg M, Glover M, McRobbie H, et al. The combined effect of very low nicotine content cigarettes, used as an adjunct to usual Quitline care (nicotine replacement therapy and behavioural support), on smoking cessation: a randomized controlled trial. Addiction 2012;107:1857–67. [252] Hatsukami DK, Hertsgaard LA, Vogel RI, Jensen JA, Murphy SE, Hecht SS, et al. Reduced nicotine content cigarettes and nicotine patch. Cancer Epidemiol Biomarkers Prev 2013;22:1015–24. [253] Perkins KA, Gerlach D, Broge M, Fonte C, Wilson A. Reinforcing effects of nicotineas a function of smoking status. Exp Clin Psychopharmacol 2001;9:243–50. [254] Doran N, Schweizer CA, Myers MG. Do expectancies for reinforcement from smoking change after smoking initiation? ·300·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
Psychol Addict Behav 2011;25:101–7. [255] McQuown SC, Belluzzi JD, Leslie FM. Low dose nicotine treatment during early adolescence increases subsequent cocaine reward. Neurotoxicol Teratol 2007;29:66–73. [256] Connolly GN. The marketing of nicotine addiction by one oral snuff manufacturer.Tob Control 1995;4: 73–9. [257] Barrett SP, Darredeau C. The acute effects of nicotine on the subjective and behavioural responses to denicotinized tobacco in dependent smokers. Behav Pharmacol 2012;23:221–7. [258] Tidey JW, Rohsenow DJ, Kaplan GB, Swift RM, Ahnallen CG. Separate andcombined effects of very low nicotine cigarettes and nicotine replacement insmokers with schizophrenia and controls. Nicotine Tob Res 2013;15:121–9. [259] Joel DL, Denlinger RL, Dermody SS, Hatsukami DK, Benowitz NL, Donny EC. Very low nicotine content cigarettes and potential consequences on cardiovascular disease. Curr Cardiovasc Risk Rep 2012;6:534–41. [260] Benowitz NL. Toxicity of nicotine: implications with regard to nicotine replacement therapy. Prog Clin Biol Res 1988;261:187–217. [261] Assali AR, Beigel Y, Schreibman R, Shafer Z, Fainaru M. Weight gain and insulin resistance during nicotine replacement therapy. Clin Cardiol 1999;22:357–60. [262] Heeschen C, Weis M, Cooke JP. Nicotine promotes arteriogenesis. J Am CollCardiol 2003;41:489–96 [263] Suzuki J, Bayna E, Dalle Molle E, Lew WY. Nicotine inhibits cardiac ·301·
烟草制品管制科学基础报告： WHO 研究组第五份报告
apoptosis induced by lipopolysaccharide in rats. J Am Coll Cardiol 2003;41:482–8. [264] Girdhar G, Xu S, Bluestein D, Jesty J. Reduced-nicotine cigarettes increase platelet activation in smokers in vivo: a dilemma in harm reduction. Nicotine Tob Res 2008;10:1737–44. [265] Legresley E, Lee K, Muggli ME, Patel P, Collin J, Hurt RD. British American Tobacco and the“insidious impact of illicit trade”in cigarettes across Africa. Tob Control 2008;17:339–46. [266] Lee S, Ling PM, Glantz SA. The vector of the tobacco epidemic: tobacco industry practices in low and middle-income countries. Cancer Causes Control 2012;23(Suppl 1):117–29. [267] Joossens L, Raw M. Turning off the tap: the real solution to cigarette smuggling.Int J Tuberc Lung Dis 2003;7:214–22. [268] Joossens L, Raw M. Progress in combating cigarette smuggling: controlling the supply chain. Tob Control 2008;17:399–404. [269] Pavananunt P. Illicit cigarette trade in Thailand. Southeast Asian J Trop Med Public Health 2011;42:1531–9. [270] Mecredy GC, Diemert LM, Callaghan RC, Cohen JE. Association between useof contrab and tobacco and smoking cessation outcomes: a population-based cohort study. Can Med Assoc J 2013; 185:E287–94. [271] Givel MS. History of Bhutan’ s prohibition of cigarettes: implications for neo-prohibitionistsand their critics. Int J Drug Policy 2011;22:306–10. [272] Borland R. Minimising the harm from nicotine use: finding the right ·302·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
regulatory framework. Tob Control 2013;22(Suppl 1):i6–9. [273] Czoli CD, Hammond D. Cigarette packaging: youth perceptions of “natural”cigarettes, filter references, and contraband tobacco. J Adolesc Health 2013;54:33–9. [274] Hyland A, Higbee C, Li Q, Bauer JE, Giovino GA, Alford T, et al. Access to low-taxed cigarettes deters smoking cessation attempts. Am J Public Health 2005;95:994–5. [275] Hyland A, Laux FL, Higbee C, Hastings G, Ross H, Chaloupka FJ, et al. Cigarette purchase patterns in four countries and the relationship with cessation: findings from the International Tobacco Control (ITC) Four Country Survey. Tob Control 2006;15(Suppl 3): iii59–64. [276] Licht AS, Hyland AJ, O’ Connor RJ, Caloupka FJ, Borland R, Fong GT. How do price minimizing behaviors impact smoking cessation? Findings from the International Tobacco Control (ITC) Four Country Survey. Int J Environ Res Public Health 2011;8:1671–91. [277] Ahmad S, Billimek J. Estimating the health impacts of tobacco harm reduction policies: a simulation modeling approach. Risk Anal 2005;25:801–12. [278] Modeling the health benefits of a nicotine standard for tobacco products sold in Canada. Cambridge, Massachusetts: Industrial Economics Inc.; 2013. [279] Hall W, West R. Thinking about the unthinkable: a de facto prohibition on smoked tobacco products. Addiction 2008;103:873–4. [280] Le Houezec J, McNeill A, Britton J. Tobacco, nicotine and harm ·303·
烟草制品管制科学基础报告： WHO 研究组第五份报告
reduction. Drug Alcohol Rev 2011;30:119–23. [281] McNeill A, Hammond D, Gartner C. Whither tobacco product regulation? Tob Control 2012;21:221–6. [282] Arnott D. There’ s no single endgame. Tob Control 2013;22(Suppl 1):i38–9. [283] Britton J, McNeil A. Nicotine regulation and tobacco harm reduction in the UK.Lancet 2013;381:1879–80. [284] Hatsukami DK. Ending tobacco-caused mortality and morbidity: the case for performance standards for tobacco products. Tob Control 2013;22(Suppl 1):i36–7. [285] O’ Connor RJ. Non-cigarette tobacco products: what have we learnt and where are we headed? Tob Control 2012;21:181–90. [286] Wayne GF, Connolly GN. Regulatory assessment of brand changes in the commercial tobacco product market. Tob Control 2009;18:302– 9. [287] Carter LP, Stitzer ML, Henningfield JE, O’Connor RJ, Cummings KM, Hatsukami DK. Abuse liability assessment of tobacco products including potential reduced exposure products. Cancer Epidemiol Biomarkers Prev 2009;18:3241–62. [288] Henningfield JE, Hatsukami DK, Zeller M, Peters E. Conference on abuse liability and appeal of tobacco products: conclusions and recommendations.Drug Alcohol Depend 2011;116:1–7. [289] Mooney ME, Johnson EO, Breslau N, Bierut LJ, Hatsukami DK. Cigarette smoking reduction and changes in nicotine dependence. Nicotine Tob Res2011;13:426–30. ·304·
附录 3 通过降低烟碱释放量至不会引起或维持成瘾的水平来降低卷烟 产品的潜在依赖性
[290] Walker N, Bullen C, McRobbie H. Reduced-nicotine content cigarettes: Is there potential to aid smoking cessation? Nicotine Tob Res 2009;11:1274–9. [291] Lindson-Hawley N, Aveyard P, Hughes JR. Reduction versus abrupt cessationin smokers who want to quit. Cochrane Database Syst Rev 2012;11:CD008033. [292] Rooke C, McNeill A, Arnott D. Regulatory issues concerning the development and circulation of nicotine-containing products: a qualitative study. Nicotine Tob Res 2013;15(6):1052–9. [293] Cahn Z, Siegel M. Electronic cigarettes as a harm reduction strategy for tobacco control: a step forward or a repeat of past mistakes? J Public Health Policy 2011;32:16–31. [294] Le Houezec J, Aubin HJ. Pharmacotherapies and harm-reduction options for the treatment of tobacco dependence. Expert Opin Pharmacother 2013;14:1959–67. [295] Dawkins L, Corcoran O. Acute electronic cigarette use: nicotine delivery and subjective effects in regular users. Psychopharmacology 2013;231:401–7. [296] Dawkins L, Turner J, Crowe E. Nicotine derived from the electronic cigarette improves time-based prospective memory in abstinent smokers.Psychopharmacology 2013;227:377–84. [297] Dawkins L, Turner J, Roberts A, Soar K“Vaping”profiles and preferences: an online survey of electronic cigarette users. Addiction 2013;108:1115–25. [298] Eissenberg T. Electronic nicotine delivery devices: ineffective nicotine ·305·
烟草制品管制科学基础报告： WHO 研究组第五份报告
delivery and craving suppression after acute administration. Tob Control 2010;19:87–8. [299] Bullen C, McRobbie H, Thornley S, Glover M, Lin R, Laugesen M. Effect of an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross-over trial.Tob Control 2010;19:98–103. [300] Shadel WG, Lerman C, Cappella J, Strasser AA, Pinto A, Hornik R. Evaluating smokers’ reactions to advertising for new lower nicotine quest cigarettes.Psychol Addict Behav 2006;20:80–4. [301] Parascandola M, Augustson E, O’ Connell ME, Marcus S. Consumer awareness and attitudes related to new potential reduced-exposure tobacco product brands. Nicotine Tob Res 2009; 11:886–95. [302] Connolly GN, Behm I, Healton CG, Alpert HR. Public attitudes regarding banning of cigarettes and regulation of nicotine. Am J Public Health 2012;102:e1–2. [303] Fix BV, OC onnor RJ, Fong GT, Borland R, Cummings KM, Hyland A. ’ Smokers’ reactions to FDA regulation of tobacco products: findings from the 2009 ITC United States survey. BMC Public Health 2011;11:941. [304] Pearson JL, Abrams DB, Niaura RS, Richardson A, Vallone DM. Public support for mandated nicotine reduction in cigarettes. Am J Public Health 2013;103:562–7.
·306·