Delayed and chronic effects of chemicals in the workplace: report on a WHO meeting, Kiev, 21–24 October 1980

EURO Reports and Studies 64 Delayed and chronic effects of chemicals in the workplace Report on a WHO Meeting REGIONAL OFFICE FOR EUROPE World Health Organization COPENHAGEN IND LA/f/0 ..rer. t: , I Re/ EURO Reports and Studies 64 ~C,tA/ "'cµ ~ - ~ Cc~l,(_f t:U. , ~~ rVe~A. ~,"ft,< - 4 r'uu, 11-t J. Delayed and chronic effects of chemicals in the workplace Report on a WHO Meeting Kiev 21-24 October 1980 REGIONAL OFFICE FOR EUROPE World Health Organization COPENHAGEN 1982 ICP/WKH 011 ISBN 92 890 1230 7 © World Health Organization 1982 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Conven- tion. For rights of reproduction or translation, in part or in 1010, of publications issued by the WHO Regional Office for Europe application should be made to the Regional Office for Europe , Scherfigsvej 8, DK-2100 Copenhagen 0, Denmark. The Regional Office welcomes such applications. The designations employed and the presentation of the material in this publica- tion do not imply the expression of any opinion whatsoever on the part of the Secretariat 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. The mention of specific companies o r of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organiza- tion in preference to others of a simi lar nature that are not mentioned . Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The views expressed in this publication are those of the participants in the Meeting and do not necessarily represent the decisions or the stated policy of the World Health Organization. PRINTED IN DENMA RK ISSN 0250-8710 Introduction . . . . National experience Bulgaria .. .. Czechoslovakia Finland ... . France .... . German Democratic Republic Federal Republic of Germany Hungary Norway Poland . USSR . United Kingdom CONTENTS Experience of the International Agency for Research on Cancer . Page 1 3 3 4 5 7 8 8 9 10 12 13 13 16 Results obtained in long-term animal tests in the absence of human data 21 Short-term tests Experimental studies . Mutagenicity .. Carcinogenicity . Embryotoxicity and teratogenicity Epidemiology and epidemiological requirements . Monitoring of exposure to carcinogens Training . .. . . .. .. . . .... . 22 23 23 23 25 25 26 29 Conclusions and recommendations . 30 Conclusions . . . . 30 Recommendations 31 Annex 1 Strengthening of occupational health services to prevent the delayed effects of occupational hazards - Y.l. Kundiev . . . . . . . . . . . . . . 34 Annex 2 List of participants . . . . . . . . . . . . . . . . . 48 INTRODUCTION A Meeting on the Delayed and Chronic Effects of Chemicals in the Work- place was convened by the WHO Regional Office for Europe, in collaboration with the Government of the USSR, in Kiev from 21 to 24 October 1980. The Ins ti tu te of Occupational Health in Kiev and the Department of Inter- national Affairs of the Ministry of Health of the USSR played a large part in organizing the Meeting, which was attended by 17 temporary advisers from 15 countries , a representative of the International Labour Organisation, a representative of the International Agency for Research on Cancer, and 5 ob- servers from the USSR. The participants were welcomed by the Vice-Minister of Health of the Ukrainian Soviet Socialist Republic, Professor A. Pavlov. Dr M. Mikheev, Regional Officer for Workers' Health, addressed the participants on behalf of the Regional Director , and mentioned that Lhe Regional Office is paying particular attention to the formulation of a long-term policy on preventing the delayed effects of chemicals in the occupational environment. He pointed out that the Meeting had been convened within the regional component of the International Programme on Chemical Safety. The objectives of the Meeting were: (a) to review the present situation with regard to the prevention of delayed effects (carcinogenic , mutagenic , teratogenic and embryotoxic) of chemicals in Member States; (b) to define and specify delayed effects in relation to health impair- ment and types of occupational exposure ; (c) to stimulate the application of existing knowledge on such de- layed effects in the practice of occupational health services, and to identify measures for strengthening the services; (d) to consider training of the specialists involved in relation to service requirements; and (e) to identify gaps in knowledge and define priorities for further research and development in this field . The Meeting confined itself to a discussion of the importance of the de- layed effects of chemicals in the area of occupational health . However , the participants recognized that such effects also arise from exposure to chemi- cals in general, and that a complete assessment of potential adverse effects must take into account total exposure from all sources . In the field of oc- cupational health there are certain well established examples of synergistic effects arising from multiple exposures. In establishing its initial terms of reference it was decided that the discussions should be restricted to considerations of mutagenic , teratogenic, embryotoxic and carcinogenic effects of chemicals, which are defined in Annex 1. It was recognized that many other delayed and chronic effects of exposure to chemicals , such as pneumoconiosis , sclerotic effects , delayed neurotoxicity and preseniJity, can also occur . These effects were not con- sidered any less important than those selected for discussion, and should form the basis for further meetings of specialized groups . The problems fal] naturally into four types , which were initially dis- cussed in depth by subgroups of experts. One subgroup was concerned with the administrative mechanisms for strengthening occupational health ser- vices, another with the experimental basis for controlling and evaluating these hazards, a third with the use of epidemiology in understanding and con- trolling the delayed effects of chemicals , and the fourth with training of personnel and the educational requirements of others involved. The various Member States from which the participants were drawn have al] recognized the importance of the delayed and chronic effects of chemicals, but there are considerable differences in approach. The Meeting began with a consideration of the modes of operation existing in various countries , and there emerged a series of central issues that formed the basis of much of the subsequent discussion . Problems concerned with variations in definitions of some of the delayed effects of chemicals are often better resolved by experts who may not be available to individual countries. The International Agency for Research on Cancer (IARC) , for example , is often able to provide guidelines based on the best available international scientific advice. Some of the newer methods that are considered to have potential for the recognition and monitoring of occupational health problems were dis- cussed at length and useful guidelines formulated. The number of trained personnel in this field is very smalJ and nowhere is the need for international cooperation more clear. Epidemiological methods are advancing as rapidly as molecular biology. In this respect the differences between countries are more marked, since adequate epidemiological surveillance requires considerable resources. The 2 availability of personnel records, of record linkage systems and of registers vary enormously from country to country. Awareness of the potential hazards of carcinogenic chemicals has been well known for some years and much useful data is available, although much remains to be done. However , as regards the other effects discussed , there is a need for new approaches to epidemiological surveillance. Furthermore, effects such as mutagenesis require further study to enable laboratory find- ings to be interpreted in terms of effects on man. Working papers describing the approaches taken in different countries to the prevention and control of the delayed and chronic effects of chemicals were presented. There were clearly many similarities as well as differences in approach, but for the purpose of this report only those parts that highlight areas in which there are differences are included. NATIONAL EXPERIENCE Bulgaria Some of the more important approaches are as follows. I . The current 5-year national plan for social and economic develop- ment includes two new programmes : (a) measures to protect the environment; and (b) a national programme for Jabour safety and hygiene. 2. There is national occupational health legislation dealing with: (a) internationally recognized regulations and conventions; (b) maximum allowable concentrations (MACs) for 285 chemicals at places of work, including those with known carcinogenic, mutagenic, teratogenic and embryotoxic properties; (c) strict regulations for protecting people from radiation; and (d) special protection of the health of women, particularly mothers and pregnant women , including prohibition of any work with toxic 3 agents after the fourth month of pregnancy until IO months after the birth of the child, and specification of certain occupations in which women cannot be employed. 3. The Ministry of Public Health operates three national specialized health services primarily concerned with occupational pathology: (a) occupational health institutes, hospitals, polyclinics, etc., many situated in large industrial plants; (b) central and regional institutes of hygiene and epidemiology; and (c) central institutes of oncology. The activities of all these national networks are coordinated to protect workers' health and control hazardous agents in the working environment, including monitoring of physical and chemical a gen ts in the workplace, monitoring workers' health , and registration of diseases. During the last few years efforts have been made to differentiate between these activities according to the requirements of the so-called "at-risk" groups. 4. Research studies relevant to the problems under discussion are carried out in various institutes and laboratories. Various parameters of malformations in the newborn were recently studied in several districts of the country. Tests on animals for carcinogenic, teratogenic and embryo- toxic effects of various products are routinely done in several laboratories under the supervision of the Laboratory of Chemical Carcinogenicity and Testing at the Institute of Oncology in Sofia. Several shortcomings in the system for control and prevention of occu- pational hazards exist : (a) there is a gap between existing knowledge and its rapid imple- mentation; (b) the coordination of relevant activities, mainly research, is still far from satisfactory and a competent and efficient coordinating body is needed;and (c) more internationally adopted regulations, instructions, models, expertise and training of specialists in international courses are clearly required. Czechoslovakia On 1 January 1981 the Czech Ministry of Health issued "Basic principles of hygienic rules for working with chemical carcinogens", according to 4 which carcinogens are divided into three groups, using the IARC guidelines : (a) chemicals and industrial processes that are demonstrably carcinogenic to humans; (b) suspected carcinogens; and (c) potential carcinogens. The first two are related specifically to data gathered from studies of occupational exposures; the third is based on the latest experimental data published by IARC . It is considered that genetic toxicology (including carcinogenicity) can be effectively detected and monitored by a series of short-term tests. In particular, tests for mutagenicity are considered to be most reliable. To ensure uniform standards for mutagenicity testing, a national reference laboratory for estimating the genetic risk of environmental chemicals has been established at the Institute of Hygiene and Epidemiology in Prague. Tests are carried out in two stages. Screening tests use microorganisms in vitro, with and without activation systems, and cytogenetic analysis of human peripheral lymphocytes. The complete set of studies would then include, in addition, cytogenetic analysis of rodent bone marrow and the dominant lethal test in mice. Epidemiological studies combined with muta- genicity tests and cytogenetic analyses are being carried out in several con- trolled studies , and it is believed that preventive and control measures can be planned on the basis of these approaches. Finland Legislation Finland has ratified ILO Convention 139° by issuing a list of chemicals posing a carcinogenic risk in the workplace. This list currently comprises about 51 chemicals divided into three categories. Compounds in category l (I 2 chemicals) are prohibited while no further regulations have as yet been issued concerning the use of those in categories 2 and 3. All workers exposed to the compounds listed are registered in a computerized data base. Biological monitoring of exposure As long as workers are exposed to carcinogens or suspected carcinogens, there is a need to monitor exposure and its early effects. A number of methods are available for the biological monitoring of exposure to genotoxic compounds. l. The compound or its metabolite can be measured from urine , blood or exhaled air. Metals can be assayed from urine or from blood . Of the organic a International Labour Organisation. Convention 139. Convention concerning prevention and control of occupational hazards caused by carcinogenic substances and agents. Geneva, International Labour Office, 1974. 5 compounds, benzene is assayed from exhaled air or , rather unspecifically, as urinary phenol. Exposure to styrene is measured as urinary mandelic acid; exposures to trichloroethylene and tetrachloroethylene are estimated as tri- chloroacetic and tetrachloroacetic acids, respectively. Modern analytical techniques are able to detect several other compounds in biological samples, but there are difficulties in application owing to a lack of pharmacodynamic data , particularly in man, for most genotoxic compounds . 2. Most genotoxic compounds are nonpolar and are conjugated before excretion. Conjugation to glutathione, glucuronic acid, sulfuric acid , glycine, etc. is known to take place, and such conjugates can thus be assayed from urine. Occupational exposure has been monitored as, for example , urinary thioethers. 3 . Most genotoxic compounds are electrophiles capable of reacting with nucleophilic groups in proteins such as haemoglobin . Alkylation of haemoglobin has been determined in occupational exposure to ethylene oxide, and used to estimate genetic risk. 4. As electrophiles, genotoxic compounds also react with nucleic acids to form covalent adducts. These adducts are removed spontaneously or enzymatically, and excreted in the urine . So far, only animal studies have been reported as an application of this method. 5. A known or unknown exposure to genotoxic compounds may lead to the excretion of mutagenic compounds. Urinary mutagenicity, correlating with a defined exposure, may be indicative of genotoxic risk. Mutagenicity has been detected in the urine of anaesthetists , rubber workers, and nurses administering cytostatic drugs. 6. Cytogenetic methods, including chromosome aberrations and sister chromatid exchanges (SCE) in human lymphocytes , have been applied in the estimation of the effects of exposure to radiation, benzene , ethylene oxide, arsine, epichlorohydrin and styrene. In exposed populations the increase in chromosome aberrations and/or SCE may correlate with cancer risk . Reproductive hazards Finnish studies on spontaneous abortion are based on hospital cases retrieved from the hospital discharge register of the National Board of Medicine. In- formation is obtained from spontaneous abortions (6000 annually), induced abortions and births . Based on these figures two proportions can be calcu- lated : rate (number of spontaneous abortions/number of pregnancies X 100) and ratio (number of spontaneous abortions/number of births X 100); these were 7 .4 and 10.7 , respectively, in 1973-75. These proportions have been calculated in various industrial populations . 6 The Finnish Register of Congenital Malformations has been used in the analysis of occupational risks in malformations. The register includes cases involving the central nervous system, oral cleft, and the musculoskeletal system, and cases of Down's syndrome. In addition to the case children, the register contains information on normal children born in the same maternity welfare district. The register contains information on the parents' occupation, and 3600 cases and controls have been analysed according to the mother's occu- pation. In two occupational groups (transport and the construction industry) a significantly higher risk for certain types of malformation was noted, whereas in scientific and technical occupations there was a decreased risk. France Carcinogenic chemicals Special medical examinations and legal provisions are available to those ex- posed to the following carcinogenic chemicals and groups of chemicals: benzene, aromatic amines, coal tar, asbestos and vinyl chloride. The fre- quency and details of medical examinations are described for individual cases. The rules for establishing permissible levels of exposure parallel those estab- lished for the control of exposure to ionizing radiation. Considerable reliance is placed on specially trained occupational health physicians, who are expected to be familiar with those chemicals that are known to be carcinogenic and with the chemicals used in the plants for which they have responsibility. The occupational health physician is empowered by law to order inspections involving chemical analysis and measurements of exposure to chemicals. He may order more complete investigations should he consider these to be necessary. More physicians are at present undergoing training in epidemiology. How- ever, studies in epidemiology are made extremely difficult in France by the anonymity of death certificates. Mutagenicity Under a decree of January 1979, all new chemicals introduced on to the market must be tested for mutagenicity by at least two tests, one of which should be performed in bacteria. The results of such tests must be made public . At present no specific regulations are in force governing the use of materials in the workplace that are currently in use and that may be found to be mutagenic. Teratogenicity and embryo toxicity At present only occupations involving the use of ionizing radiation are re- stricted for pregnant women; such regulations have not yet been extended 7 to teratogenic chemicals. However, recommendations to exclude pregnant women from occupations involving teratogenic chemicals are made by in- dividual occupational health physicians. German Democratic Republic The main concern is centred on the control of carcinogenic hazards in the occupational setting. A monitoring system for the detection of levels of known carcinogenic chemicals in the workplace is under development. At present such information is available for benzene, vinyl chloride, and benzo [a] pyrene. Considerable experience is available on the control of exposure to asbestos dusts. A great deal of reliance is placed on the IARC monographs for the definition of carcinogenicity and for information on individual carcinogens. For the purposes of a medical surveillance programme , carcinogenic chemicals have been divided into three groups using information from the !ARC monographs : (a) agents carcinogenic to man proven by epidemiological studies; (b) agents which, from case studies, are probably carcinogenic to man; and (c) agents carcinogenic in experimental animals. Specific instructions for the type of medical examination to be con- ducted have been established; these will depend on the type of exposure and the organ specificity of the compound involved. Insofar as teratogenic, mutagenic and embryotoxic effects are concerned, it is felt that there is not enough knowledge available to be a basis for legislative control. The Central Institute for Occupational Medicine, in cooperation with the Central Institutes for Cancer Research and of Toxicology, is preparing material on carcinogenic factors in the working environment as part of a coordinated effort to train physicians, technologists, managers, trade union officers and others in problems concerned with the control and pre- vention of occupational cancer. Federal Republic of Germany The German Civil Code provides detailed regulations governing the responsi- bility of the employer in matters of occupational health. Specific require- ments for medical examinations, for the appointment of plant physicians, and for compensation are laid down . Companies employing l 00 or more people are required to have a company medical officer, who is expected to have undergone special training in occupational medicine. Since 1971 an ordinance has been in effect governing the use of various carcinogenic sub- stances (the provisions of this legislation are set out in the full working paper) . Pre-employment examinations and subsequent examinations at 5-year intervals are mandatory for workers exposed to these substances. The use of the more hazardous materials is effectively banned, the only exception 8 being their unavoidable use to rectify production delays or to eliminate damage. Under these specific conditions additional supervision and pro- tective clothing must be used. Research laboratories are not subject to these restrictions. The Law on protection against hazardous substances {1980) requires pre-market testing for mutagenicity, embryotoxicity, teratogenicity and impairment of fertility, as well as carcinogenicity. It is felt that the elimina- tion of substances with adverse toxic effects of this kind prior to their coming into contact with man is the most effective means of prevention. Detection of such effects epidemiologically in workers is considered to be a demonstra- tion of failure. Hungary The principal measures taken to control the delayed toxic effects of chemi- cals are incorporated into the general statutes of the Labour Code, reinforced by the Decree on Occupational Health and Safety of the Council of Ministers. In addition to the general legislation , certain specific regulations are either in force or are in preparation . 1. Specific restrictions exist on the occupational exposure of women and young people to chemicals. Decrees promulgated by the Minister of Labour in 1962 and 1966 prohibit certain occupations for women and young people. 2. Pre-employment medical examinations with subsequent periodic reviews are compulsory. The frequency of examination depends on the type of chemical according to its toxic properties and target organs. 3. Occupational diseases are registered; 63 are notifiable and 30 of these are related to chemical exposure. 4. Biologically acceptable limits for 21 chemicals have been laid down. Special monitoring is carried out by the National Institute of Occupa- tional Health on certain chemical carcinogens labelled by IARC as human hazards. These include benzene , lead compounds, vinyl chloride, asbestos, acrylonitrile, beryllium , cadmium and chromium . It is felt that embryotoxicity, if not a result of genetic damage , can be used to determine MAC values . However , it is thought that research in the field of teratology is lacking and that, for the moment , the transfer of animal data to man would be premature . 9 Norway On I July 1977 legislation was enacted that resulted in the identification of substances and processes causing delayed effects on the health of workers . Carcinogenic effects are the primary problem involved , although teratogenic, embryotoxic and neurotoxic effects are also considered. The occupational health authorities (Directorate of Labour Inspection) in Norway have approached the problems along the following lines. 1. Criteria have been established for the carcinogenicity of chemicals . 2. Carcinogenic substances are classified in two categories. 3. Threshold limit values have been established for carcinogenic sub- stances in the working atmosphere. 4. Regulations exist for the importation, production , handling and labelling of carcinogenic substances . 5 . There is a register of substances that may have delayed effects and which are produced or handled by industry ("the 200 substances register") . This register is expected to be important for the labour inspection authorities and for the occupational health services in carrying out pre-employment and periodical medical examinations. 6. A product register will store information on all imported and pro- duced chemicals and products. 7. The 1977 legislation established the legal foundation for a com- pulsory as well as for a non-compulsory health service in industry. The occupational health services are compelled to carry out selective and speci- fied personal examinations if so required by the authorities. 8. A register of exposed workers has been in existence in some in- dustries in Norway for some 20 years. This has now been extended from the aluminium and ferro-alloy industries to include styrene, toluene , and hospital personnel handling cytostatics and general anaesthetics. The following definition of a potential occupational carcinogen has been adopted: 10 "Potential occupational carcinogen" means any substance or combination or mixture of substances which causes an increased incidence of benign and/or malig- nant neoplasms, or a substantial decrease in the latency period between exposure and onset of neoplasms in humans, or in one or more experimental mammalian species, as the result of any oral, respiratory or dermal exposure, or any other exposure which results in the induction of tumours at a site other than that of the administration . This definition also includes any substance that is metabolized into one or more potential occupational carcinogens by mammals. Positive findings in two or more of the following types of study are con- sidered to be of importance: (a) the induction of DNA damage and/or repair; (b) mutagenesis in bacteria, yeast, Neurospora or Drosophila melan- ogaster; (c) mutagenesis in mammalian somatic cells; (d) mutagenesis in mammalian germinal cells; and (e) neoplastic transformation of mammalian cells in culture . Indications for a chemical being a potential occupational carcinogen may be obtained from : (a) epidemiological cohort studies; (b) bioassays on mammalian species; (c) short-term tests; and (d) similarity of structure to a chemical recognized as being a potential occupational carcinogen. From this information known occupational carcinogens can be placed in one of two classes. Class I occupational carcinogens are substances that meet the definition of a potential carcinogen in: (a) epidemiological investigations; or (b) experimental bioassays on (i) two mammalian species, or (ii) one mammalian species if the result is confirmed in a second, separately conducted bioassay, or (iii) one mammalian bioassay, if the result is supported by a positive result in short-term tests. 11 Class II chemicals are those with suggestive carcinogenic effects. A chemical is placed in class II if: (a) it has shown suggestive carcinogenic effect in bioassays as listed for class I potential carcinogens, but the scientific reports are evaluated as not being appropriate for classification in class I; (b) the carcinogenic effect is demonstrated in one bioassay on one species but the result is not reproduced or supported by other investi- gations; or (c) positive results in short-term tests are reported and the suspected substance shows similarity in structure to a recognized potential car- cinogen, and/or if occupational exposure is suspected as being a carcino- genic risk to man. Poland In Poland there are no overall regulations governing the use of chemicals resulting in delayed toxic effects. There are, however, legal restrictions on the employment of women in certain occupations deemed potentially harmful to reproduction or the health of the progeny. Arsenic, benzene, carbon disulfide, cadmium, lead, mercury and polycyclic hydrocarbons are among the chemicals prohibited. These regulations have considerable limitations and do not take into account rapidly changing technologies, and it is felt that they should be improved. Considerable advances have al- ready been made, and it is proposed that a comprehensive plan to deal with carcinogenic hazards in the workplace will be developed within the next 5 years. It is hoped that within that period the following aims will have been achieved. 1 . Identification of the type and size of the risk from carcinogenic factors occurring in the working environment. With respect to chemicals it has been decided that evaluation of the magnitude and size of occupational exposure , i.e. the number of exposed persons, will be limited to I 5 substances for which there is sufficient experimental and epidemiological evidence of carcinogenicity. 2. Creation of methodological and theoretical bases for the system of evaluating exposure to carcinogens, together with enviromental and epidemiological studies in those branches of industry in which occupa- tional exposure to known carcinogens occurs. Accomplishment of this programme requires special training of industrial health service workers. As far as epidemiology is concerned, the closest attention will be paid to 12 asbestos, vinyl chloride , benzidine, benzidine dyes and polycyclic hydro- carbons in the coal processing and aluminium industries . 3. The Institute of Occupational Medicine in Lodz has initiated studies on the potential carcinogenic effect of new chemicals planned to be pro- duced by new industrial technologies. 4. The Institute has also undertaken the development of legal rules and regulations with respect to the prevention of occupational cancer. Apart from the main objectives of the programme, investigations on the embryotoxic and teratogenic effects of some toxic substances will be con- tinued, with special regard to structural and functional teratogenesis . USSR The prevention of the delayed effects of toxic chemicals and other occu- pational hazards is based on legislation on labour hygiene , the most important of which cover all workers. The general approach under this legislation is that all chemicals should be tested and those suspected of having delayed effects (blastomogenic , mutagenic, teratogenic or embryotoxic) are further studied according to a standard protocol. If carcinogenicity is revealed the compound should be substituted by another. When and where it is not possible to eliminate the carcinogenic compound it should be controlled , and an exposure limit should be estab- lished at the "no-effect" level. Particular attention is given to epidemi- ological data when available. Occupations involving the use of chemicals likely to induce delayed ef- fects are prohibited to pregnant women , and recommendations on the em- ployment of pregnant women have been approved by the Ministry of Health of the USSR. The occupational health services cover all places of work, providing control of workers' health and the working environment. In ad- dition , research is carried out on the evaluation of chemicals , using short- and long-term tests and epidemiological studies. United Kingdom There is a long history of legislation, from the beginning of the last century right up to the present time , but it is convenient to discuss the present position that follows the passing of the Health and Safety at Work Act of 1974 . This Act covers essentially all workers, not just those in factories , and covers the responsibility both of employers and workers. It is con- cerned not only with risks in the workplace but with risks outside arising from work activities . 13 Health and Safety Commission It is a basic principle of this legislation that there has to be involvement not only of the employers but also of employees and the Government. The main body concerned is a Government agency called the Health and Safety Commission (HSC). The Commission is composed of three representatives from the Confederation of British Industry (CBI), which is the main em- ployers' organization, three from the Trades Union Congress (TUC) repre- senting workers, and two representing local authorities. The Chairman of the Commission is appointed by the Minister. The operational arm of the Commission is the Health and Safety Executive (HSE). To advise it on special subjects or in special areas of interest the HSC has set up certain subject committees and industry committees, such as the Advisory Committee on Toxic Substances (ACTS). That Committee has representatives from the CBI , TUC and local authorities, and also includes outside experts. Another subject committee is the Medical Advisory Com- mittee which has a similar structure. There are also tripartite committees with particular reference to specific areas of industry, such as the construction industry, the railway industry, and so on. One of the most important aspects in developing occupational health policy and practice is the mechanism for standard setting. Ultimately the set- ting of control limits is the business of the HSC, advised by its various appro- priate bodies and in general by the Executive . A branch of the Employment Medical Advisory Service reviews all the scientific facts concerning a material or hazard under consideration, and the review is then presented as a paper to ACTS. Other parts of HSE then prepare similar papers dealing with the in- dustrial hygiene aspects , methods of control , the amount of use and the most effective practices, and these papers are also considered by ACTS. This process has been employed to study the setting of control limits for materials which have been of recent interest, such as vinyl chloride, acrylonitrile, 2,4,5-T, asbestos and so on. Of course , setting a standard of exposure or a limit for control does not of itself solve the problem of occupational health . Standards must recog- nize the acceptance of some level of risk and to be effective they have to be properly enforced. The regulations therefore may include guidance on health supervision, record keeping, further epidemiological follow-up , methods of measurement and other such factors that will permit effective enforcement. The basic principle of scientific assessment is to try to establish some form of dose-effect relationship and hence , if possible , some estimate of the risk. It may well be that the degree of risk will vary according to the type of operation being undertaken and the effectiveness of the control that can be imposed . In addition to the surveillance of all these procedures by the Inspectorates , great care is taken to involve the working population in the derivation and implementation of these measures. In particular there are 14 regulations called the Safety Representative Regulations 1978, requmng an employer to give to the union representatives certain rights to informa- tion and facilities to study the working environment. Under the Act there are also requirements of the employer to pass on to his employees any information on hazards of the employment, and of the manufacturer to pass on to a purchaser similar data . Occupational health services The position of occupational health services in the United Kingdom was reviewed in 1976 in a publication called The way ahead. This also made some recommendations as to possible future development. The position is that general governmental responsibility for occupational health is borne by the Health and Safety Commission , which is distinct from the involve- ment of the Department of Health and Social Security in all the health provisions of the National Health Service . There are, of course, close links between the two but the responsibility of the Commission in this field is clear. The Health and Safety Executive with its various parts , including doctors, nurses, scientists, hygienists, administrators , inspectors and re- search workers, is the main Government agency in this field, but a very large part of national resources is provided by industry and a small, but more specialized , part by the universities . The Governmental role is largely advisory and inspectorial. Occupational health doctors, hygienists, nurses and safety engineers are provided by many of the larger employers, either on a full-time or a part-time basis, and there have been attempts at provision of group services. Training Specialist tnumng for physicians is made available at various centres and the standards of training are in the process of being defined by the Faculty of Occupational Medicine , which was set up by the Royal College of Phys- icians of London in 1978. It is envisaged that there will be two main levels of training, one for the full-time consultant and one for practitioners of some other part of medicine who have obtained special knowledge in occu- pational health. As far as occupational hygienists are concerned, the British Occupa- tional Hygiene Society has set up an examining board which is producing levels of qualification of an appropriate nature. The Royal College of Nursing has for many years issued an occupational health nursing certificate. This certificate is available only to fully registered nurses , but shorter-term dip- lomas are also available. 15 EXPERIENCE OF THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER The importance of tests to prove or disprove the carcinogenicity of environ- mental chemicals resides in the possibility that the results may provide informa-- tion that would be of use in the primary prevention of cancer. A discussion on the role of experimentation should take into account certain facts. I. A proportion of cancers in man has been shown incontrovertibly to be due to exposure to identified environmental chemicals or to com- plex mixtures . 2. The number of chemicals at present in common use has been esti- mated at about 60 000 and is still rising. The rapidly increasing exploitation of man-made materials during a period in which health problems related to chemicals did not receive adequate attention is to a great extent the cause of the large backlog of chemicals for which no acute or chronic toxicity data are available . 3. The specific causal agents of a large proportion of cancers in man , in particular those occurring at some of the most frequent sites , have not been identified . This has often been taken to mean that their causes can- not be traced to one or more of the chemicals to which we are exposed or for which evidence of carcinogenicity relies solely on experimental results . However, it is not unreasonable to assume that some of the chemicals among the thousands to which we are exposed will eventually be identified as being carcinogenic to humans . 4. For those chemicals that have been shown to be causally associated with cancer in man, in most instances the cause-effect relationship has been found after high exposure of relatively small and relatively easily identifi- able population groups . Therefore , the identification of carcinogens has taken place in situations similar to those used in experimental carcinogenesis, where limited numbers of experimental animals are exposed to relatively high dose levels in order to maximize the sensitivity of the experimental models . 5. Recognition of a substance as a carcinogen in man has relied basi- cally only on the epidemiological approach to the identification of carcino- genic risk factors. This approach , however, suffers from two main pitfalls: 16 (a) individual exposures cannot be controlled, as the approach relies en- tirely on observational data in human populations; and (b) most human exposures are to such low levels as to preclude the direct measurement of risk in epidemiological surveys. 6. Finally, it should be remembered that past experience has shown that, for several environmental chemicals , experimental evidence of car- cinogenicity preceded evidence in man and would have predicted similar effects in man. It should be stressed that long-term tests on animals are today still the only means , in the absence of data on man, of providing conclusive evidence of the carcinogenic effect of a chemical. This is not to downgrade unduly other tests of much shorter duration and lower cost, but simply to serve as a reminder that the efficiency of short-tenn tests is measured by their capacity to match the results obtained in long-term bioassays. One should be careful, therefore , in replacing a diffuse discontent, or even distrust, of long-term bioassays with an uncritical enthusiasm for the much needed short-tenn tests, as if they would offer a key for making unfailing predictions. There is a certain irony in this , as it may suggest that we had forgotten that the results obtained in long-tenn tests are often not held as final evidence for carcinogenicity. What still is, in fact, badly needed today is an agreement on the validity of experimental results to predict a carcinogenic effect in man or, in its absence, a certain faith in primary prevention. The difficulties in assessing the validity of results obtained in long-tenn animal tests are both qualitative and quantitative, and raise two questions. First, are chemicals that have been shown to be carcinogenic to experi- mental animals also carcinogenic to man? Second, do experimental animals, rodents in particular, and human beings have similar susceptibilities to the carcinogenic effect of chemicals, or are rodents incomparably more suscept- ible than man? A partial answer to the first question is usually given by reversing the terms of the question : most of the chemicals that are car- cinogenic to man are carcinogenic to one or, in most cases, more than one animal species. Another partial answer is that experimental evidence of carcinogenicity has, in several cases, preceded observations in man and could have predicted them. As a basis for discussion , we may use the information accumulated over ten years in IARC through the programme on the evaluation of the carcinogenic risk of chemicals to humans . This programme is centred on the production of monographs on individual chemicals or groups of chemicals for which all available data on use and production, experimental carcino- genicity and other toxic effects , as well as epidemiological data, are critically analysed and summarized. The first 20 volumes of monographs published be- tween 1971 and 1979 considered a total of 442 chemicals.° For only 60 (14%) a A cumulative index to the chemicals evaluated during this period is provided in Monograph 20, pages 593-609. 17 of these were epidemiological studies and/ or case reports available. This is indeed a small percentage among the chemicals that have been selected a priori for consideration because (a) there was evidence of human exposure, and (b) there was some evidence of carcinogenjcity in man and/or experi- mental arumals. For 54 of these 60 chemicals, the available human and experimental data have been analysed in detail to evaluate the degree of evidence of carcino- gerucity in man. For I 8 of the 54 compounds or industrial processes the available evidence from studies on man was sufficient to establish a causal relationship with the occurrence of cancer in man. These 18 chemicals or industrial processes were therefore deemed to be causally associated with tumours in man on evidence provided by epidemiological studies or case reports, and experimental evidence of carcinogenicity was not used in the formulation of the evaluations. Among the 18 were 5 industrial processes (the manufacture of aura- mine, chromates and isopropyl alcohol, haematite mirung, and nickel re- fining) for which no direct correlation can be made between human and ex- perimental data because the chemical identity of the agent responsible for the carcinogenic effect in man is unknown. However, there is some evidence for auramine, chromates and ruckel that the animal model responds to some of the factors that might be responsible for the effect in man. Auramine (of unknown purity) produces liver tumours in rats and mice. Many chromate salts produce local sarcomas when given repeatedly by intramuscular in- jection, and cadmium chromate induces lung tumours in rats after intra- bronchial implantation . Nickel subsulfide induces malignant lung tumours in rats when given by inhalation; many nickel compounds produce local sarcomas after repeated subcutaneous injection in rats; and inhalation of ruckel carbonyl has been reported to produce a few malignant lung tumours in rats. The agent responsible for lung tumours in haematite miners has not been identified , but radon is suspected; ferric oxide was not carcinogeruc in mice, guinea pigs or hamsters when given by inhalation or intratracheally. One compound, benzene, has not been tested adequately for carcinogenicity. For arsenic , alone among the 12 other compounds, results from available carcino- genicity tests are negative , although there is sufficient evidence that arseruc compounds induce skin and lung cancer in man. Of the remaining com- pounds, one (mustard gas) was found to be carcinogenic in one arumal species, and the other 10 in several animal species. For the 11 chemicals for which a correlation can be made between human and experimental data, a comparison of organ specificities indicates that they can have the same target organ(s) in man and in at least one of the animal species tested. Although it might be thought that the chances of find- ing similar target organs would be greater if similar routes of exposure were used, chemicals that have been found to be carcinogeruc in both man and experimental animals were also carcinogenic in the latter when administered 18 by routes different from those by which humans are exposed . In addition, multiple target organs are found more often in experimental animals than in man . Of the 11 chemicals, 3 are aromatic amines, namely 4-aminobiphenyl, benzidine and 2-naphthylamine , which show a definite organ specificity for the urinary bladder in man. The most likely routes of exposure for these compounds are by inhalation and skin absorption and, to a lesser extent, by ingestion. The 3 compounds were all tested in at least 2 experimental animal species by several routes of exposure, but none by inhalation or skin absorption. When given by the oral route, urinary bladder tumours were obtained with 4-aminobiphenyl in mice, dogs and rabbits; with benzidine in dogs (but not rats or rabbits, in which it produced liver tumours); and with 2-naphthyl- amine in dogs, hamsters and monkeys (but not in rats or rabbits, in which the results were inconclusive for an effect at any site). These 3 compounds were also administered to mice and/or rats by the subcutaneous route; distant tumours were produced at sites other than the urinary bladder in all cases. These results indicate that: (a) the 3 compounds are carcinogenic in more than one animal species, producing tumours at different sites, most frequently in the bladder and the liver; (b) when the chemicals are admin- istered to certain species by the oral route (one, but not the main, route by which humans are exposed) they produce tumours of the urinary bladder, the target organ in man; and (c) there are exceptions to this rule, since benzidine given orally to rats and hamsters produced liver tumours, and inconclusive results were obtained when 2-naphthylamine was given orally to rats and rabbits. The case of these 3 compounds may also indicate that man is not necessarily more resistant than rodents to the carcinogenic effect of chemicals or , conversely, that rodents are not necessarily more susceptible than man. In fact, the incidence of bladder tumours in workers exposed to 4-aminobiphenyl was over 18%. Most of the workers in whom the tumours were found were in their late thirties or forties, and for several of them the duration of exposure was less than two years. In workers exposed to benzidine and 2-naphthylamine the incidence of bladder tumours was up to 90% when exposure lasted for more than five years. Although these may be exceptional cases the fact remains that with certain chemicals, in this case aromatic amines, when the level of exposure was high the tumour incidence was also very high. Experimental evidence for the carcinogenicity of 4-aminobiphenyl, bis( chloromethyl)ether, diethylstilbestrol , melphalan , mustard gas and vinyl chloride preceded such evidence in man. It is worth mentioning that experi- mental evidence with regard to some of these chemicals, such as 4-aminobi- phenyl and bis(chloromethyl)ether, indicated the occurrence of tumours at organs different from those which later appeared to be target(s) in man. For an additional 18 compounds among the 60 for which data on man exist, the available evidence indicates that they are probably carcinogenic to 19 man . While, for the previous group of chemicals and industrial processes assessment of their carcinogenicity to man could be based exclusively on human data since these provided sufficient and definite evidence of a causal relationship , evaluation of carcinogenic risk to man for the chemicals in the second group was made by taking into consideration evidence from both human and experimental studies. Evidence of carcinogenicity to man for chemicals in this group thus varies from being almost sufficient to suggestive. In order to reflect the range of probability, the chemicals were divided into two groups indicating higher (subgroup A) and lower (subgroup B) degrees of evidence (probability) that the chemical or group of chemicals is carcino- genic to man. For oxymetholone , no experimental data were available; for ethylene oxide, the data were inadequate; and for auramine and phenacetin, the data provided only limited evidence of carcinogenicity although recent studies indicate that phenacetin is carcinogenic to rats. For cadmium com- pounds, no correlation could be made between human and experimental data, because the chemical identity of the agent responsible for the possible carcinogenic effect in man has not been discovered. Of the remaining I 3 compounds, two (acrylonitrile and dimethylcarba- moyl chloride) were found to be carcinogenic in one animal species, and the remaining 11 in several animal species. Although in aflatoxins, beryllium, carbon tetrachloride, iron-dextran complex and nickel (and possibly phen- acetin) the putative target organ in man corresponds to the main or one of the target organs in experimental animals, there is no evidence to support the view that similarity of target organs is the rule , even when experimental animals have been exposed to the same route by which humans are exposed. For example, acrylonitrile probably induces lung and intestinal tumours in man, but induces forestomach, brain and Zymbal gland tumours in rats. A different case is that of cyclophosphamide, which probably induces bladder tumours in man and was known , until recently, to induce tumours at various sites in mice and rats , with only indicative evidence that the urinary bladder could be a target organ in mice . Recent results, however , show that cyclophosphamide produces bladder tumours in rats. For this compound, therefore , a similarity in target organ was obtained over IO years after the first experimental evidence of a carcinogenic effect became available. Eight of the 13 compounds (aflatoxins, amitrole, carbon tetrachloride, dimethyl sulfate , iron-dextran and nickel) were tested with positive results when given su bcu taneousl y. The remaining 24 compounds (chloramphenicol , chlordane/heptachlor, ortho- and para-dichlorobenzene , 3,3'-dichlorobenzidine , chloroprene , DDT, dieldrin , epichlorohydrin , haematite, hexachlorocyclohexane (BHC and lin- dane), isoniazid , isopropyl oils, lead and certain lead compounds , phenobarbi- tone, phenylbutazone , N-phenyl-2-naphthylamine, 2,3,7,8-tetrachlorodibenzo- para-dioxin , phenytoin, reserpine, styrene, ortho-toluidine, trichloroethylene and triaziquone) could not be classified as to their carcinogenicity to man, 20 owing to limitations of available human data and/or to the limited evidence of carcinogenicity provided by experimental data. For these compounds, there- fore, no comparison can be made between human and experimental data. From the limited data now at our disposal, it may be concluded that: (a) the majority of chemicals for which there is sufficient evidence of carcinogenicity in man, and those for which the available evidence indicates probable carcinogenicity in man, have been shown to be carcinogenic in experimental animals; {b) in several instances, experimental evidence of carcinogenicity pre- ceded observations on man; (c) these chemicals may have the same target organs in man and in experimental animals, but this is by no means an absolute rule; and (d) evidence of a carcinogenic effect in experimental animals is often ob- tained using a route of exposure different from that by which humans are ex- posed, or which has been associated with the occurrence of tumours in man. Results obtained in long-term animal tests in the absence of human data Chemicals for which a causal association with the occurrence of cancer in man has been proved, or is at least strongly suspected, comprise a clear case, since it is agreed that human exposure to such compounds must be avoided - even if there is disagreement on how, to what extent, and how quickly this should be done . A different and major problem is evaluation of the possible carcinogenic effect to man of chemicals for which there are no epidemi- ological studies or case reports . The good empirical correlation between human and experimental animal data for the limited number of chemicals for which both human and experi- mental data are available indicates, as shown above, that experimental animal data may predict a qualitatively similar response in man, although the validity of this empirical correlation cannot be extended to predict possible quantita- tive variations of the response in different species. The data obtained in animal tests may, however, represent different degrees of evidence of a carcinogenic effect, this drawback being due mainly to our insufficient know- ledge of the mechanisms of carcinogenesis. Of the 442 chemicals evaluated in the first 20 volumes of the IARC Mono- graphs, 143 were shown to have "sufficient evidence" of carcinogenicity in experimental animals . For 9 of these, no human data are available and they may be assumed to be reasonably good targets for epidemiological studies. If we take all chemicals among the 442 considered in the first 20 volumes of the IARC Monographs for which there is sufficient or limited evidence of carcino- genicity, their number rises to 268. For the majority of them, there is evidence of human exposure and, in most cases , this is occupational. 21 Short-term tests Although the relevance of the various biological endpoints used in short-term assays to the mechanisms of cancer induction is not known precisely, there is little doubt that the combination of short-term assays (rapid screening tests) is a promising tool for the identification of man-made and naturally-occurring carcinogens and mutagens. Short-term tests for the detection of chemical carcinogens/mutagens can be divided broadly into the following categories: mutagenic or cyto- genetic changes in submammalian or mammalian cells, induction of DNA damage or repair, and in vitro transformation of cultured mammalian cells. More recently, assays have also been developed for the detection of tumour- promoting agents, since it is recognized that cancer induction may occur in multiple steps and that some compounds may act, not as complete carcino- gens or initiating agents, but as promoters. Any test system must incorporate some aspects of mammalian metabolism; this is done in vitro either by adding a rodent or human liver fraction or by using metabolically competent cells, such as rodent embryo cells or rat hepatocytes. Whether short-term assays will eventually acquire the status of long- term animal tests in predicting human risk depends entirely on further demonstrations of their consistency with results obtained in adequately conducted animal and human epidemiological studies. Major efforts should therefore be directed at establishing their validity. Of the chemicals and industrial processes associated with cancer induc- tion in man, or considered as probably carcinogenic for man, most were positive in one or more of these tests. Of the chemicals or industrial pro- cesses associated with human cancer (with the exception of haematite mining, the manufacture of isopropyl alcohol and nickel refining, for which no results were available), arsenic, asbestos, benzidine and DES were not positive in the Salmonella test. Among the chemicals considered to be probably car- cinogenic to man, arnitrole, auramine, carbon tetrachloride and PCBs were negative in the Salmonella test. Of 110 chemicals for which it was considered there was sufficient evidence of carcinogenicity in experimental animals, 77 were tested in the Salmonella test and 83% of these were found to be mutagenic. Of the 149 chemicals having limited evidence of carcinogenicity, only 34 were tested and of these, 56% were found to be mutagenic. The number of chemicals proved to be or suspected of being human carcinogens is too small to serve as a basis for validating the significance of short-term tests as predictors of carcinogenicity. Similarly, the limited number of chemicals with sufficient and limited evidence of carcinogenicity in experi- mental animals for which reliable data from short-term tests exist does not offer as yet a sufficiently solid base on which to found a validation system. Increasing demand for quantitative carcinogenicity data for the purpose of risk assessment has stimulated further examination of whether there is 22 a quantitative relationship between the potency of a carcinogen in animals and man and its biological activity in a short-term test. At present, such a correlation is not sufficiently established for all classes of carcinogens to allow its general use. EXPERIMENT AL STUDIES Mutagenicity It is often possible to predict the mutagenicity of a compound from chemi- cal structural analogy to known mutagenic compounds. However, there are now several tests for potential mutagenicity and therefore delayed toxicity to man. These include in vitro tests that study effects on DNA replication and repair, studies using bacterial systems and cell cultures, and investigations on gene mutations, chromosomal aberrations and sister chromatid exchange. Tests in whole mammals include cytogenic analysis , the dominant lethal test , an in vivo somatic mutation test in mice known as the "spot test", and the specific locus test. In designing a test programme it is most important that the tests corres- pond as closely as possible to the routes of exposure occurring under the oc- cupational circumstances under study. If possible, the tests should be used to determine dose -response parameters. These tests should be used sequentially in order to obtain the maximum information that may assist in the setting of standards and to be useful in the monitoring of biological exposure of workers to chemicals causing delayed toxic effects. Carcinogenicity The Meeting adopted the definition of a carcinogenic chemical as used in the IARC Monographs: The widely accepted meaning of the term "chemical carcinogenesis", and that used in these monographs, is the induction by chemicals of neoplasms that are not usually observed , the earlier induction by chemicals of neoplasms that are usually observed , and/or the induction by chemicals of more neoplasms than are usually found - although fundamentally different mechanisms may be in- volved in these three situations. Etymologically, the term "carcinogenesis" means the induction of cancer, that is, of malignant neoplasms; however, the commonly accepted meaning is the induction of various types of neoplasms or of a combina- tion of malignant and benign tumours. In the monographs, the words "tumour" and "neoplasm" are used interchangeably (in scientific literature the terms "tu- mourigen", "oncogen" and "blastomogen" have all been used synonymously with "carcinogen", although occasionally "tumourigen" has been used specifically to denote the induction of benign tumours). 23 Both the interpretation and the evaluation of a particular study, as well as the overall assessment of the carcinogenic activity of a chemical, involve several qualitatively important considerations, including (a) the experimental conditions under which the chemical was tested; (b) the consistency with which the chemical has been shown to be carcinogenic; (c) the spectrum of neoplastic response; (d) the stage of tumour formation in which a chemical may be involved; and (e) the possible role of modifying factors . In general, the evidence that a chemical produces tumours in experi- mental animals is of two degrees: (a) sufficient evidence of carcinogenicity is provided by the production of malignant tumours; and (b) limited evidence of carcinogenicity reflects qualitative and/or quantitative limitations of the experimental results. For many of the chemicals evaluated in the first 20 volumes of the IARC Monographs for which there is sufficient evidence of carcinogenicity in animals, data relating to carcinogenicity in man are either insufficient or nonexistent. In the absence of adequate data on man, it is reasonable, for practical purposes, to regard such chemicals as if they presented a carcino- genic risk to man. In the present state of knowledge, it would be difficult to define a predictable relationship between the dose (mg per kg of body weight per day) of a particular chemical required to produce cancer in test animals and the dose that would produce a similar incidence of cancer in man. The available data suggest, however, that such a relationship may exist, at least for certain classes of carcinogenic chemicals. Data that provide sufficient evidence of carcinogenicity in test animals may therefore be used in an ap- proximate quantitative evaluation of the human risk at some given exposure level, provided that the nature of the chemical concerned and the physiologi- cal, pharmacological and toxicological differences between the test animals and man are taken into account. However, no acceptable methods are cur- rently available for quantifying the possible errors in such a procedure, whether it is used to generalize between species or to extrapolate from high to low doses. The methodology for such quantitative extrapolation to man requires further development. Some chemicals for which there is limited evidence of carcinogenicity in animals have also been studied in man with , in general, inconclusive results. While such chemicals may indeed be carcinogenic to man, more experimental and epidemiological investigation is required . In recent years, several short-term tests for the detection of potential carcinogens have been developed. When only inadequate experimental data are available, positive results in validated short-term tests are an indication that the compound is a potential carcinogen and that it should be tested in animals for an assessment of its carcinogenicity. Negative results from short- term tests cannot be considered sufficient evidence to rule out carcino- genicity. Whether short-term tests will eventually be as reliable as long-term 24 tests in predicting carcinogenicity in man will depend on further demon- strations of consistency with long-term experiments and with data from man. Embryotoxicity and teratogenicity Experimental studies relevant to the determination of embryotoxic or tera- togenic effects of chemicals include short-term tests such as those used for the determination of mutagenicity. In addition, epidemiological studies are of considerable importance . In extrapolating results from animals to man, mammalian studies are of great importance in determining quantitative aspects of the effect. In under- taking mammalian studies it is important that a positive control group, using a known teratogenic compound active in man , be used . Based on careful evaluation of such studies , MAC values may be lowered and occupations deemed unsafe for pregnant women . EPIDEMIOLOGY AND EPIDEMIOLOGICAL REQUIREMENTS Epidemiological data showing occupational cancer or other delayed effects reflect failures of prevention . Therefore basic scientific experimental ap- proaches must be closely linked to and related to epidemiological studies. Nevertheless , it is most important that full scientific advantage should be taken of opportunities to study the effects of any accidental occurrences and to make public the results of such studies. Data are required about (a) individuals (preferably the whole work- ing population) , and (b) special groups known to be at risk . There will be national differences in the way these data can be made available, owing both to organizational factors and public attitudes to issues of confiden- tiality. The sources may be social insurance records, reports from places of employment, or routine medical records; where possible the last should take the form of a worker's "passport" of which a copy could be held by the national authority. The basic personal data should include : name or identity number ; sex; place and date of birth; and occupation (and length of time in it). These records should, if possible, be linked to wages records and should be re- tained for at least 30 years or until the worker dies. Similar data are required for at-risk groups, though more detail may be included. Some attempt is also necessary to determine the population at risk, who will provide the denominator of any study. 25 Environmental data are required to try to correlate exposure (if possible, intake) with the personal data. In many cases these data will be incomplete for individuals, and not precise even for groups, but best estimates are essen- tial. Some records of processes and the areas of the plant in which the in- dividual has worked may be of value. Good general mortality and mor- bidity data related to occupational classifications are vital. Data are needed for answering specific questions about late or concealed effects: (a) national and regional cancer registries; (b) malformation register (problems of definition); and (c) stillbirth register (problems of definition). In addition to the desirability of these general approaches, the group stressed the importance of special local studies of these features, provided care was taken in defining control groups for such studies . It is also probable that, in the early years of national or regional regis- ters, there will be apparent increases in notifiable conditions because of increased vigilance . Review of the international literature should help in providing pointers to areas requiring special studies or surveys. A similar response should fol- low published results of animal experiments or other documented scien- tific experiments. Such studies may serve to reinforce scientific suspicion but, since nega- tives are hard to prove, may not firmly deny it. However, they act as an essential check because of interspecies variability and, even more, because of the possible unrepresentative nature of some biological experimentation . MONITORING OF EXPOSURE TO CARCINOGENS Both chemical and biological methods must be considered for the monitor- ing of the workplace for carcinogenic chemicals . In addition, newer ap- proaches suggest that it will shortly become feasible to monitor individual workers for exposure. Extremely sensitive , accurate , and well evaluated methods exist for the chemical analysis of many groups of chemical carcinogen . The deter- mination of levels of these compounds or their metabolites or conjugates excreted in the urine can also be determined using available methods . Such studies should be encouraged so that more background material may be- come available . 26 Biological monitoring includes the use of cytogenetic studies with peripheral lymphocy tes. It is possible not only to study chromosomal ab- normalities but also, to a limited extent, sister chromatid exchange. If reliance is to be placed on such studies for workers exposed to chemi- cals with delayed toxic effects, it is extremely important that large num- bers of people are used and that particular attention is paid to the careful selection of controls. Suggestions have been made that exposure to chemicals causing delayed toxic effects might be monitored by investigating the possible mutagenicity of body fluids in in vitro assays. However, such procedures have many un- known variables and negative results do not exclude exposure. Other tests that have been suggested include the determination of haemo- globin alkylation products in the blood and of nucleic acid alkylation pro- ducts in the urine, and the use of immunological markers . All these methods should be studied experimentally but cannot be recommended for routine use at this time. The fundamental basis for effective control of occupational disease resulting from chronic exposure to chemicals depends on the administra- tive design and legislative authority of the government department specifi- cally designated to accomplish this task. The designated government agency should be provided with adequate financial support. It should be properly staffed with appropriate experts, and have access to laboratories as well as facilities and staff to ensure that proper monitoring is carried out. In order to operate effectively the agency should have a work plan that should be subjected to continuous review and take into account new developments in this rapidly changing field. The work plan should include the following areas: (a) the identification of chemicals causing cancer and other delayed effects; (b) methods for the safe handling of such chemicals; (c) medical examinations; (d) epidemiological surveillance; (e) monitoring of workplaces; (J) methods of prevention ; (g) information exchange; and (h) training programmes. In more detail it is essential that the government agency in charge of this programme identify and evaluate all chemicals in the workplace that may give rise to chronic or delayed health effects. This must be done on a continuing basis taking into account new information that may be used in making such classifications. It may be that such information will be used in 27 establishing a system of registration for such toxic chemicals and in sub- sequently developing a system of certification which will detail specific uses or prohibitions of use. The agency should develop detailed instructions for industry on methods for the safe handling of such chemicals. This will require careful examination of existing practices in industry and the identification of present hazards. All workers who are actually employed or who are about to be em- ployed in occupations involving potential exposure to such toxic chemicals must be given regular medical examinations. These must be carefully designed to detect early effects of possible exposure to chemicals causing delayed and chronic effects. Records of these workers should be incorporated into registers to be used in epidemiological follow-up studies. Monitoring of workplaces for the presence of chemicals that may result in delayed or chronic effects is a complex problem requiring both specially trained personnel and access to special laboratory facilities. These require- ments are far in excess of those used to monitor other health effects of chemical exposure. It is important that a multidisciplinary group be as- sembled to be available to the government agency responsible for monitoring. This group of specialists should include physicians trained in occupational health, biochemists, biologists, biometricians, epidemiologists and engineers. In addition, the government agency should have access to specialized lab- oratory facilities capable of determining the mutagenic, teratogenic , embryo- toxic and carcinogenic effects of chemicals in in vitro and in vivo test systems. The possible occurrence of delayed neurotoxic effects, as well as delayed hypersensitivity and behavioural changes, should also be considered . As well as the above measures, the agency should undertake to study all other methods of prevention that might be applicable to special situations, and to support research designed to improve on such methods. The key to effective implementation of all these programmes resides in information dissemination . In the first instance it is essential that the responsible agency be empowered to require that manufacturers involved in the manufacture of chemicals causing delayed toxic effects reveal essential details that may be required to control health problems. In return , the agency should provide industry with guidance on the methods that should be used to ensure safe handling of these toxic materials . It is particularly important that not only management but also the workers fully comprehend the reasons for the measures taken. Special pre- cautions may have to be adopted to protect particularly susceptible groups such as pregnant women. Reasons for such measures and for the imposition of labelling requirements must be explained to all those concerned . It is clear that many Member States will not have all the necessary facil- ities and it is therefore recommended that steps be taken to develop training programmes for the various specialists required. In this instance international cooperation may be particularly important. 28 The specific measures that are required to protect workers from the effects of chemicals with delayed toxic effects have been the subject of careful consideration by both various Member States and international bodies . The approaches that may be taken include a series of different op- tions that can be recommended following careful evaluation of individual cases. These include : (a) prohibition of use; (b) use under licence with rigidly prescribed control measures; (c) substitution by less harmful chemicals; (d) use only in enclosed processes; (e) limited exposure to a limited number of workers for a limited time; (J) monitoring combined with application of corrective measures at appropriate times; (g) application of appropriate measures to limit environmental expo- sure, for example by using filters, wet processes and effective methods of local and general ventilation; and (h) provision of protective clothing and equipment. TRAINING It was stressed by the Meeting that : (a) there is a need for interdisciplinary courses for those who are to administer occupational health services in the field; (b) more specialized courses are needed for those in narrower areas - experts in laboratory work, analytical epidemiology, etc.; (c) WHO should prepare a general purpose "guidebook" on epidemi- ological methods in occupational health; (d) more financial resources need to be applied to training in this field; national authorities should encourage industry to contribute to ex- change fellowship schemes and specialized training courses, which should be developed in specialized centres in cooperation with WHO; (e) IARC should be encouraged to add supplementary bulletins to its monograph programme that could provide public health authorities with up-to-date information on occupational carcinogens; 29 (f) international organizations should continue and further develop their activities to support countries in controlling chemical hazards; (g) training programmes dealing with all aspects of the control and pre- vention of hazards from chemicals with delayed toxic effects should be provided to all personnel responsible; (h) there is room for further development of specialized and general training schemes in the field, which should provide the basis for international courses, symposia and other training activities; and (i) further preparation and publication of basic books and manuals on important aspects of this developing field of knowlege should be undertaken. CONCLUSIONS AND RECOMMENDATIONS Conclusions 1. There is a need for the competent national authorities to control the use of chemicals that can have delayed and chronic effects in workers. 2. Chemicals causing delayed and chronic hazards should be determined. The use of such chemicals should be subjected to authorization and control. 3 . The chemicals should be identified on a continuing basis, taking into ac- count the availability of new information and new technological methods for making such identifications. The basic information might be used to establish a system of registration, possibly incorporating provisions for certi- fication on the use of chemicals having delayed toxic effects. 4. The requirements for the safe handling of new chemicals introduced into industry should be detailed. Existing industrial processes should be properly supervised and efforts made to identify existing hazards . 5. Tests for embryotoxicity and genotoxicity at the submammalian level can form an important part of evaluation of the potential delayed toxic effects of chemicals to which workers are exposed. 6. Biological monitoring, including cytogenetic studies, may prove to be a feasible method for following exposure of workers to genotoxic chemicals. 7. The general principles for evaluating the carcinogenic risk of chemicals, as set out in the IARC Monographs, are considered a satisfactory basis for 30 the definition of carcinogenic chemicals . These principles provide guidelines enabling the competent authorities to establish proper protection of workers from chemicals that have only been found carcinogenic in experimental animal systems. Recommendations 1. Individual Member States should determine health hazards and make relevant regulations for controlling the production and individual use of chemicals that may have delayed health effects in workers . 2. Individual Member States should set up the required research and moni- toring services and occupational health infrastructures to assure identification and control of the chemicals. 3 . Additional personal information and clearer definition of groups at risk are needed. 4. Scrupulous attention should be paid to the safety precautions specified for the use of chemicals causing delayed effects. 5. The adoption of a worker 's "passport" recording details of all employ- ment should be encouraged . Details of environmental conditions should be included. 6. Research should be undertaken on biological monitoring of exposure of workers to genotoxic chemicals. 7. To enable the organization of effective programmes of prevention and control of chemicals having delayed toxic effects, Member States must pro- vide appropriate laboratory facilities and expert monitoring services. The facilities should be capable of determining mutagenic, teratogenic , embryo- toxic and carcinogenic effects. 8. All workers employed in the production or use of chemicals that might have delayed toxic effects should be subjected to regular medical exam- inations and epidemiological supervision. 9. The complexity of the subject requires that a multidisciplinary team of experts be available. It should include physicians, biochemists , biologists, engineers, biometricians and epidemiologists. 10. Information interchange and dissemination is a primary requirement for any effective programme in this field . The competent authorities should be 31 able to require that manufacturers involved in the use of chemicals having delayed toxic effects provide essential information required to deal with health problems. 11 . Information exchange between the health authorities and basic research institutions should be maintained . 12. The authorities should continuously provide industry with information on the safe handling of toxic chemicals. 13. The authorities should make sure that workers engaged in the handling of chemicals with delayed toxicity are provided with information on pro- cedures and safeguards to be applied. 14. Chemicals having delayed toxic effects should be appropriately labelled, and the labelling regulations should be legally enforceable . 15 . Special regulations should be established to protect any specially sus- ceptible groups of workers, such as pregnant women. 16. All Member States should ensure that appropriate resources, including funds, personnel, material and facilities, are made available for the preven- tion and control of the delayed and chronic effects of chemicals. 17. The preventive measures needed for the protection of workers may include restrictions on use . 18. More research is required to evaluate the use of submammalian tests for the determination of the genotoxicity and embryotoxicity of chemicals to which workers are exposed . 19. Training programmes dealing with all aspects of the control and preven- tion of hazards from chemicals with delayed toxic effects should be provided for all personnel responsible, and for this purpose : (a) there is room for further development of specialized and general schemes, which should form the basis of international courses, symposia and other training activities; (b) further preparation and publication of basic books and manuals on important aspects of this field should be undertaken; (c) there is a need for interdisciplinary courses for those who are to administer the relevant occupational health services; 32 (d) more specialized courses are needed for those in areas such as laboratory work and analytical epidemiology; (e) WHO should prepare a general-purpose guide on epidemiological methods in occupational health; (j) more financial resources need to be made available for training; (g) national authorities should promote industrial funding , exchange fel- lowship schemes and specialized training courses , which could be developed for international use in specialized centres in cooperation with WHO. 20. Member States should be encouraged to establish registers to record oc- cupational diseases resulting from exposure to chemicals with delayed effects. 21. IARC should be encouraged to add supplementary bulletins to its mono- graph programme so as to provide public health authorities with up-to-date information on occupational carcinogens. 22. International organizations, including WHO and ILO, should continue and further develop their activities to support countries in controlling hazards due to chemical substances. 33 ( ~('l ttt.l 1,,--. ~ tr, 'JA. ( Annex 1 ff 4AJ-f I r~ tct~ t'- ~ STRENGTHENING OF OCCUPATIONAL HEALTH SERVICES TO PREVENT THE DELA YEO EFFECTS OF OCCUPATIONAL HAZARDS Y J. Kundiev 0 (! In recent years in many industrialized countries of the world, great progress has been made in preventing acute and chronic occupational diseases. The participation of national services for occupational health is significant. WHO activities and joint WHO/ILO efforts in the field of occupational health have promoted these achievements in Member States to a great extent. The re- quired legislation has been elaborated , and medical and technical measures to prevent the adverse effects of environmental factors on workers have been carried out. Further improvement of these measures and strengthening the control of working conditions will make it possible to effectively reduce cases of occupational exposure to health hazards. However, chemical and physical factors in the working environment , even at low levels of exposure, may cause pathological processes that can be revealed not only during and immediately after exposure but later in life, after months, years or decades of exposure. Manifestations of such pro- cesses are delayed, and may even occur in subsequent generations. Changes in the delicate structures and mechanisms of metabolic processes at cellular, subcellular and molecular levels can have genetic effects that damage the regeneration process. Present knowledge allows us to assess the relationship between the mutagenic, carcinogenic and teratogenic action of working environmental agents. However, there is not enough evidence that an agent possessing one type of action may also have another type. Many authors relate a wider spectrum of pathological changes and diseases to delayed effects . Among such changes are : pneumoconiosis , earlier sclerotic changes in organs and tissues, cardiotoxic and neurotoxic (paralytic) effects of industrial poisons, pre- senility, and shortening of lifespan. The problem of preventing delayed adverse effects in many countries of the world gained extreme urgency in connection not only with exposure to environment factors at work but also with environmental contamination and a Director, Kiev Research Institute of Labour Hygiene and Occupational Diseases, USSR. 34 inadequate control of drug consumption and food additives. To solve this oc- cupational health problem, we must take many factors into consideration . The occupational health services in a number of European countries have some experience in preventing the delayed effects caused by environmental factors. However, this relates mainly to chemical carcinogens. Legislation on carcinogens adopted in various countries shows the absence of a common approach to this problem caused , among other factors, by the economic significance of different industries(}) . The strengthening of occupational health services to prevent the delayed effects of exposure to industrial factors is an urgent task , as WHO and ILO have repeatedly emphasized (2,3), and may rightly be considered as a com- ponent of the WHO strategy for health for all by the year 2000. The present situation 1n most Member Sta tes the importance of preventing delayed effects, especi- ally those of occupational etiology, is recognized not only by health services but also by the general public . Numerous publications documenting the in- crease in malignant tumours, spontaneous abortions, perinatal mortality, con- genital defects and malformations have contributed to this awareness . One can see evidence of interest in the problem on the part of specialists in very different fields: genetics , oncology, teratology, obstetrics/gynaecology, etc. Scientific institutions of various types are attempting to solve the problems of protecting the environment, including the working environment. It is natural that this trend should cause satisfaction and be given every kind of support by occupational health services , because it increases their potential and pro- vides a practical basis for refining the theoretical approach to the problem. At the same time, because of inadequate coordination , the carcinogenic , mutagenic, embryotoxic and teratogenic effects of environmental exposures are being studied separately from other types of noxious effects. The studied exposure levels (doses and concentrations) are far higher than those which might occur in actual work conditions . Unfortunately, too , the interrelation- ships of dose (concentration) , time and effect are seldom defined (4,5). As a result of this primary "screening", the substances, which are found in significantly lower doses (concentrations) in actual conditions than in studied ones, are entered in registers of carcinogens , mutagens and teratogens . On this basis earlier conclusions concerning many agents, e.g. on the carcino- genicity of ammonia , ethyl alcohol, lactose and g]utaminic acid, or the mutagenic action of albumin , caffeine, cystein, glucose and other substances , are called into question . Thus , although the volume of information on delayed effects of exposure to environmental factors is increasing, measures to evaluate the hazards (pri- marily with reference to "genetic" risk) are inadequate , in spite of the fact that in most cases the current knowledge allows them to be taken . The 35 essential limitation of many investigations lies in the fact that they do not make any distinction between the potential hazard and the actual one. Hence the results are often of a sensational nature. Investigators generally agree that the main evidence for the existence of delayed effects due to the working environment can be derived from epidemi- ological studies together with experiments where key pathogenic factors are detected. However, there are unfortunately few studies of this type. Sig- nificant experience has been gained in Sweden in studying somatic and reproductive damage in groups of workers exposed to chemicals (L. Beck- man, unpublished data, 1980). In this context several authors (6-8) have recently emphasized the need to arrange genetic (epidemiological) monitoring for people exposed to chemi- cal mutagens accidentally or during occupational contacts. The following indices are proposed: to reveal mutagenic metabolites in urine by means of bacteriological tests and to define chromosomal aberration rates and sister chromosomal metabolism in somatic cells. Authors consider that the follow- ing indices are appropriate for epidemiological monitoring: the rate of malig- nant tumour occurrence in children; the rate of congenital malformations among occupationally and non-occupationally exposed populations; and the rate of spontaneous abortion and the rate of chromosomal and structural damage in abortive material. People in different branches of science believe that only by combining the laboratory detection of mutagens, carcinogens and teratogens with monitoring of occupational groups will the delayed effects of hazards to the health of present and future generations be prevented. At the same time, the point of view of those who regard epidemiologi- cal data as belated should be recognized (9). Significant errors have often been detected in previous preventive measures. That is why importance is attached to laboratory experiments on animals before widespread occu- pational exposure occurs. Under certain conditions the results may allow the selection of technological processes and chemicals, the identification of tenta- tive safe exposure levels, and the development of additional measures for prevention. In the USSR epidemiological data and the results of periodic medical examinations are used as the basis for revising previously adopted safe exposure levels and for improving the system of preventive measures. European countries now tend to concentrate on preventing the car- cinogenic danger of chemical substances. Such studies are an integral part of national programmes on cancer control. All kinds of activities in this direction have been favoured by the action of governments and international organizations such as IARC, ILO and WHO. Convention 139 and Recom- mendation 147 of 24 June 1974 (2), concerning the prevention and con- trol of occupational hazards caused by carcinogenic substances, are of great importance. Most European countries have since ratified and adopted these instruments. 36 In most European countries there is national legislation on carcino- gens. Montesano & Tomatis (1) reviewed the legislation of 14 industri- alized countries (I l of them in Europe). Two types of legislation were considered : (a) legislation on chemical carcinogens in the working environ- ment; and (b) legislation on compensation in cases of occupational cancer. Table I gives an idea of the completeness of legislation in the countries concerned . National lists of carcinogens for 11 industrialized countries (9 of them in Europe) have also been issued by ILO (10). In all industrialized countries lung cancer is a major cause of death. Although cigarette smoking is considered to be the main risk factor, exposure to working environment factors also is of concern. During the past decade numerous data have been accumulated on the increase in lung cancer and mesothelioma among persons working in asbestos mines and wherever asbestos or asbestos products are used. The development of mesothelioma depends on the type of fibre (11, 12). Table 1. Legislation on industrial carcinogens in some countries Legislation on the Legislation General legislation prohibiting the Country on chemical production and production substances application of and import of carcinogens carcinogens Australia +a Belgium + France +a German Democratic Republic +a Germany, Federal Republic of + Ireland + + + Italy +a Japan + + + Netherlands +a Sweden + Switzerland +a USSR + + + United Kingdom + + + USA + + a Legislation does not specifically mention carcinogens . 37 Lung cancer has been shown to occur more frequently among miners than among the general population (13) . It is frequently associated with pneumoconiosis, sideroconiosis and anthracotic tuberculosis. Ferric oxide and radioactive ore and their combined action are commonly recognized in the etiology of the disease (14). The effect of exhaust gases from internal combustion engines and other engines used in mines should not be excluded . Epidemiological studies have been carried out in nickel, chromium, alu- minium and some other industries. The carcinogenic effect of chromium and nickel compounds is being actively studied (15) . As to substances possessing other types of delayed effect, it is apparent that legislation does not distinguish them, and only in some countries are specific effects (embryotoxicity, teratogenicity, etc.) taken into account when setting maximum allowable concentrations (MACs). In the USSR there has been an official call to establish thresholds of carcinogenic, mutagenic, embryotoxic and teratogenic effects for all new substances introduced in industry and agriculture. At present more than 150 industrial chemicals have been studied for possible delayed effects. Physical factors in the working environment are also important in the etiology of delayed effects. Among these factors, ionizing and nonionizing radiation as well as radioactive substances should be noted. The prevention of occupational cancer caused by exposure to ionizing radiation and radio- active substances is based on the observance of maximum allowable levels of ionizing radiation which, as distinct from MAC values for chemical sub- stances, are the same in all the countries and are revised by the International Commission on Radiological Protection as new data are accumulated. The problem of preventing occupational cancer induced by ultraviolet (UV) radiation has not been investigated sufficiently. It is known that UV at a wavelength of 260 nm has a relatively high carcinogenic effect. Maximum mutagenic effects occur in the spectral range of 260-280 nm . Allowing for the fact that the sun is a natural source of UV, it may be claimed that long-term exposure of unprotected sites of the body to solar rays may cause malignant skin tumours. There have been studies (16-18) on skin cancer among persons working outdoors according to occupation. The incidence was relatively low, which may have been connected with the retention of UV of less than 290 nm by the atmosphere. The interaction of UV, particularly at 320-400 nm, with chemical substances may result in photocarcinogenesis. The main principles in studying and assessing the delayed effects of factors in the working environment WHO activities are based on the principle that human health is a sine qua non of wellbeing. Health to a great extent depends on working conditions. There- fore, in setting standards for industrial factors, including those causing delayed effects, it is necessary to proceed not only in accordance with technical 38 criteria, no matter how evident they may be , but also with medical and bio- logical criteria . The introduction of such standards has considerable social as well as economic implications that will become more important for each new generation in decreasing the risk of delayed effects. The public health sector , occupational health services in this case, plays an important part in defining the strategy in this field and hence in establishing the priority of medical criteria . Early prevention According to the principle of early prevention, assessment of delayed effects should be performed before extensive human contact with factors in the working environment. Early prevention depends on the stage of development of research. Present research on delayed effects is considered as a synchronization of the successive phases of experimental research (oncologic, mutagenic, tera- togenic, etc.) with technological development in industry (9,19). Biological modelling of delayed effects There are two possible approaches to the identification of delayed effects caused by exposure to physical and chemical factors in the environment: (a) epidemiological investigations; and (b) biological modelling of delayed effects in animal experiments. Both present a number of difficulties. Epi- demiological investigations are possible only after a long period of time following the introduction of substances and after exposure to physical fac- tors in the working environment. This does not conform with the principle of early prevention, whereby the prognosis and assessment of delayed effects should be performed before extensive contact occurs. Also , under industrial conditions, there is as a rule a complex of factors and it is not always possible to detect the major factor. These reasons highlight the importance of bio- logical modelling as the only possible way to reveal delayed effects of new factors in the environment. It should be noted that the problem of biological modelling of carcin- ogenic, mutagenic, teratogenic and other types of delayed effect is very complicated. Although principles have been elaborated to some extent (20,21) the significance of delayed effects in models and the extrapolation of resulting data to man are still under discussion. Laboratory methods for determining carcinogenic properties of industrial factors , depending on the model, may be tentatively divided into two groups: (a) modelling on the whole organism; and (b) modelling on cultured cells and tissues and at the molecular level. In studying carcinogenic effects, it is necessary to pay attention to the choice of laboratory animals , doses and routes of entry, as well as to the time of exposure and observation . 39 Studies on the whole organism make it more possible to extrapolate the results to man, but this takes 3 -5 years, a serious problem in view of the rate of development of new processes. In this respect in recent years rapid methods using cultured cells and tissues as models have been widely used for prognosis of carcinogenesis and mutagenesis. The basis of this operation is the close connection between mutagenesis and carcinogenesis , with the possibility of transforming a normal cell into a tumour cell, and the possibility of using mutagenicity tests for identifying occupational cancer etiology in man (22-25). A number of tests may be applied for screening working environment factors. The most widely used are the Ames test, the cell transformation test , the Williams and Rubin test, and the implantation test. Recently, a cytospectrofluorometric method was proposed (26). As impairment of the DNA repair system underlies the initial cancer pro- cess, it is reasonable for the purpose of prognosis of carcinogenicity to use sys- tems based on different approaches to the assessment of this phenomenon. The need for rapid assessment of the genetic danger of hundreds of chemicals, as well as various physical factors in the environment, excludes the possibility of their all-round study in short-term test systems. In this connection the question of the choice of comparatively simple test systems is relevant. These would allow preliminary assessment of the genetic danger of a compound or factor in the environment. According to Dubinin (27), accurate qualitative assessment of the mutation danger for man requires the application of the following four systems: (a) point mutation with metabolic activation in microorganisms; (b) dominant lethal mutation in mice; (c) chromosomal changes in mammalian bone marrow; and (cl) chromosomal changes in human leucocytes. Small rodent species are usually used as models for studying embryo- genesis; here we distinguish teratogenic effects from embryotoxic effects (9,28). Impairment of embryogenesis is possible in exposure to chemical (19) as well as to physical factors or combinations of them (29). Although bio- logical modelling of delayed effects in laboratory animals is rather compli- cated, it nevertheless remains the principal approach to studying and forecast- ing the danger of delayed effects in man. Threshold exposure The problem of threshold exposure of chemical and physical factors in the environment is closely connected with the establishment of harmless levels of exposure to these factors . In considering this problem, it is necessary first 40 to differentiate the concept of the threshold of biological exposure and the threshold of harmful (toxic, carcinogenic, mutagenic, etc.) exposure. There is a practical need to determine levels of exposure to the environmental factors below which harmful effects are not shown. Sanotsky & Ulanova (30) consider that threshold exposure to all types of action (including mutagenic and carcinogenic) should be the main principle of hygiene and preventive toxi- cology. Although there are no particular objections to the principle of threshold exposure for toxic substances, a number of scientists do not agree with it in respect of carcinogens and/ or mutagens. However, the need for standardization is now recognized by everybody. The supporters of the "non-threshold" con- cept consider that the thresholds of carcinogenic and/or mutagenic effects de- fined in experiments are imaginary because they relate to a limited number of animals in which it is difficult to discover a rare phenomenon . However, epi- demiological data on new substances cannot be obtained during a short period of time, and therefore the only possibility is to determine the dose-effect relationship and to extrapolate the resulting data for small doses of practical significance. The extrapolation allows an estimation of the risk (i .e. prob- ability of the effect) for real doses. Supporters of the "non-threshold" con- cept conclude that there is a need to determine probable no-effect doses. It is important to emphasize that a level of probability should be accepted with a view to the solution of the problem. Thus when determining the no-effect doses of carcinogens, the probability of the fact that no tumours will develop due to this dose must be very high (0.997 and higher). This means that when comparing data of experiments and controls one should take into consideration the differences obtained with less probability than is usual in biological studies. Determination of threshold and no-effect con- centrations implies the need to study the total dose -effect relationship over the whole range from high doses to approximately real doses. Selective exposure Selectivity is one of the main principles in assessing the effect of chemical and physical factors on the organism. When assessing the damage effect , it is reasonable not only to study integral changes in the organism but to reveal the most vulnerable site that serves as a limiting sign of exposure to this or that factor. Thus it is necessary to define factors in the environment that cause selective damage in the fetus. If the embryotoxic effect of a substance occurs when doses are nontoxic for the mother, the substance is considered extremely toxic. This also applies to other types of delayed effect. With regard to selectivity in assessing the factors causing specific delayed effects, it is reasonable to determine the zone of specific action, i.e. the relationship of the doses causing common toxic and specific action. Cytogenetic surveillance of workers exposed to industrial contami- nants has been inadequate up to now. Meanwhile the results of cytogenetic 41 surveillance of workers exposed to potential mutagens of a chemical or physical nature supplement the experimental evidence concerning the genetic activity of these substances and provide a real basis for scientific forecasting (6) . Here, careful registration of absorbed doses of chemical or physical factors is of great importance. For this purpose it is necessary to document thoroughly the concentrations of chemical or radioactive substances in the air of the working area, and the levels of radiation, and to use chemical or radiochemical methods and biological tests to define the received dose more accurately through blood and urine analysis. Comparison of the dose burden of the organism and cytogenetic studies, in which determination of the frequency of chromosome aberrations in the lymphocytes of the peripheral blood of workers is the most widely used procedure, are of special significance in monitoring for genetic danger and cytogenetic screening for early detection of delayed effects. Strengthening of occupational health services Strengthening of occupational health services for preventing delayed effects should be based on experience in various countries. Particular attention should be paid to primary prevention, comprising a complex of measures for limiting contact of workers with agents causing delayed effects. This can be achieved at the stage of design of new technologies, using the resources of science and tech- nology. Close-<:ycled and wasteless technologies have much potential and are economically interesting. Automation of dangerous industrial processes en- sures full cessation or extensive limitation of contact with harmful agents. To realize the above measures , occupational health personnel should actively identify the main sources of contamination causing the delayed ef- fects . The extent of exposure of these sources to environmental contam- ination depends on the nature of the raw material, the means of treatment, the technological processes, the equipment capacity and other factors that must be taken into consideration when elaborating the required sanitary and technical measures together with industrial authorities . It is recognized that preventive state sanitary regulations are reasonably effective in primary prevention. They relate to newly designed production processes and technologies, and new substances and equipment. Introduction of effective recommendations on industrial production at the design stage involves less expense than investment and operation for reconstruction of an enterprise, and the effect as a rule is greater. When the approach is compre- hensive, medical needs do not conflict with economic ones. To carry out preventive supervision, it is necessary to have appropriate legislation. At present there is enough scientific information to upgrade the legislation . It must be directed first of all to primary prevention of delayed effects and cover all aspects, including production, use , domestic trade , and the import of chemicals and technology. 42 Threshold limit values of exposure in respect of mutagenic , carcinogenic, embryotoxic and teratogenic effects of working environment factors should be covered by the legislation. It is necessary to revise systematically the per- missible levels of exposure to agents causing delayed effects, using data furnished by new investigations ( epidemiological and experimental) . Supervision of working conditions is very important for primary pre- vention. The aim is to ensure effective control of working places through legislation. It is necessary to have appropriate methods for the control and assessment of harmful agents. The efficiency of supervision depends on the reliability and sensitivity of air sampling methods and analysis and other methods of quantitative detection of adverse agents. Standardization of analytical methods and all conditions for determining harmful agents at places of work should be considered obligatory. Personal protection devices (overalls, footwear, respirators) should be considered as an additional measure . Legislation on compensation for workers exposed to harmful agents should include provision for primary prevention, i.e. limiting contact with harmful agents . In some countries workers in the aniline dye industry have a shorter working day, longer leave, earlier retirement , etc. In some cases the regulations stipulate that occupational contact with a number of carcinogens is permitted only for persons over 40 , the aim being to reduce the danger of cancer in the progeny. Systematic and thorough instruction of workers in safety, and training in this field, should be a matter of constant concern for occupational health services. The issuing of detailed instructions for certain occupations and working places is common in a number of countries and has proved effective. The second group of complex measures for strengthening of occu- pational health services for prevention of delayed effects is the monitor- ing of workers' health, aimed at revealing the earliest signs of impairment. Tumours and other effects do not occur immediately; they are only the last link in a long chain of changes. The need for earlier detection of pre- cancerous diseases or states is fully recognized in helping to prevent cancer. As for embryotoxic and teratogenic effects , the question has not yet been studied sufficiently. WHO pays great attention to the earlier detection of health impair- ments caused by occupational factors (31) . Here the emphasis is placed on the need to have criteria based on earlier reversible changes, preceding the occurrence of pronounced signs and symptoms. At the same time it has been noted that there is a lack of data to promote earlier detection of pre- cancerous changes, while the medical significance of chromosomal changes has been studied insufficiently. As regards preventive measures , it is important to elaborate medical contraindications for industries and occupations where contact with agents causing delayed effects is possible . Thus, in the USSR, the contraindications 43 for workers occupied in the production and use of coal and shale tar , pitch , anthracite and creosote oil are as follows : skin diseases characterized by high photosensitivity, precancerous skin diseases, fatty seborrhoea, skin follicular diseases , and chronic diseases of the eye (anterior). Industrial and occupational regulations requiring periodic medical examinations are an essential preventive measure. Here it is necessary to state precisely the periodicity of examinations and to regulate the list of participating specialists , taking into account specific manifestations of poten- tial delayed effects. Occupational health services should constantly coordinate their activity in the prevention of delayed effects of occupational hazards with specialists in other medical sciences. Broadening of contacts with other specialists will help to promote a unification of approaches , methods and criteria in the detection of different types of delayed effect, to exchange information, and to elaborate effective joint prevention measures . The problem of prevention of the delayed effects of occupational hazards is closely connected with that of protection of the environment, so coor- dination is needed between occupational health services and environmental health specialists . Immediate tasks Today more than 60 000 different chemicals are used in the world; every year about l 000 new compounds are introduced into industry and agri- culture. New technologies often utilize different types of radiation (ion- izing and nonionizing) and radioactive substances. New biological prep- arations are also widely used and produced . Studying their common adverse effects and their ability to cause delayed effects at real levels of exposure, and establishing permissible safety levels, are extremely complicated tasks. In many countries studying the delayed effects of occupational hazards is outside the scope of health assessment. Its effectiveness depends on the complexity of the problem and the use of imperfect methods and tests. The main shortcoming is the lack of a broad international cooperation in this important field. The work of WHO , ILO, IARC and other international bodies is appreciable , but it does not suffice in view of the growing magnitude of the problem. Thus, the main task is international harmonization of major principles and approaches . It is reasonable to harmonize not only approaches and methods but also criteria for assessing the resulting data. This would give the possibility of comparing results obtained in different countries in order to reach sound theoretical conclusions and to adopt more effective practical measures. Essentially the need is to prolong and develop WHO activity with regard to methods for establishing permissible levels of exposure to occupational hazards (3). 44 Naturally, harmonization of methods should not exclude the search for new effective approaches , methods and criteria for assessment. Harmon- ization would, in fact, create favourable conditions for such work and be of value in expanding research on the delayed effects of working environment factors, with the involvement of new laboratories, specialists of different sciences, etc. This is reflected in the experience of those countries where such harmonization has been adopted . One of the main tasks for toxicologists is establishing the links between structure and physical and chemical properties of substances and their biologi- cal activity, toxicity, etc . This makes it possible to forecast the toxicity and danger of new substances and may be used in the synthesis of new substances. Threshold links have been defined for certain groups of substances, and have been successfully used in predicting safe exposure levels. However , this is not enough for forecasting delayed effects. Attempts have been made to determine the relationship between the carcinogenic action of substances and electronic configuration and the ability to form free radicals . This has provided evidence only of some conformity between biological action and physical and chemical properties. Dubinin (27) and Santosky & Fomenko (9) give classes of chemicals among which carcinogens, mutagens and teratogens appear most often. Undoubtedly the modern state of knowledge of the relationship of carcinogenic , mutagenic, embryotoxic and teratogenic effects and molecular structure of a substance has not yet been developed sufficiently. Our know- ledge of the ability of many biological factors to cause delayed effects must be considered insufficient. Data on aflotoxins, antibiotics, hormones, vitamins , some alkaloids and other products of moulds and plants , taking into account the constant increase of biological hazards in production , show that investi- gations in this field will be of a prospective nature. Working conditions in industry and agriculture are characterized by simultaneous, combined and complex action of working environment factors . This brings up the problem of synergism ( or potentiation) and the frequency of delayed effects of exposure to various factors. As the information on the problem is insufficient, there is a need to carry out research in this direction. REFERENCES 1. Montesano, R. & Tomatis, L. Legislation concerning chemical carcinogens in several industrialized countries. Cancer research, 37 : 310-316 (I 977). 2. International Labour Conference on Labour. Convention 139. Convention concerning prevention and control of occupational hazards caused by carcinogenic substances and agents. 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In: Adaptation and compensation during chronic exposures: scientific and technical results. Moscow, VlNITI, 1973 , pp. 128-145 . 20. Krasovsky, G.N. & Sobinyakova, O.R. Comparative sensitivity of man and animals to the action of different substances according to the indices of acute toxicity. Gigijena i sanitariya, l: 29-34 (1970) . 21 . Roll, D.P. Problem of extrapolation of toxicological data from labora- tory animals to man . Gigijena i sanitariya, 4 : 73-77 (1973) . 22 . Ames, B.N. et al. Methods for detecting carcinogens and mutagens with salmonella (mammalian-microsome mutagenicity test). Mutation re- search, 31: 347-364(1975). 23. Pilinskaya, M.A. Cytogenetic action of zineb and ziram on human somatic cells. In: Genetics and selection in Ukrainian SSR. Kiev, Naukova Dumka, I 971 , Part II, pp. 11-21. 24 . Pogosyants, E.E. Main trends and tasks of genetic researches in oncology. Voprosy onkologiji, 8: 8-15 {1972). 25 . Rapoport, I.A. Toxicokinetics: scientific results. Moscow, VINITI, 1966 , pp . 3 -16 . 26. Trachtenberg, I.M. et al. Application of microspectral analysis of cul- tured cells for the assessment of the comparative toxicity of new chemi- cals. Gigijena i sanitariya, 10: 54-56 (1976). 27 . Dubinin, N .P. Molecular mechanisms of genetic processes: mutagenesis and repair. Moscow, Nauka , 1976. 28. Warkany, S. Congenital malformations. Proceedings of the Royal Society of Medicine, 66(1) : 73-76 (1973). 29 . Dobrovolsky, L.A. et al. Chronic combined effect of radioactive and temperature ( or chemical) factor on fertility in rats . In: All-Union con- ference on delayed effects and estimation of risk of exposure to radia- tion. Moscow, Ministry of Health , 1978 , pp . I 38-140. 30 . Sanotsky, I.V. & Ulanova , 1.P.Criteriaofharmfuleffectsforhygieneand toxicology in assessment of the danger of chemicals. Moscow, Medicina, 1975. 31 . WHO Technical Report Series , No . 571, 1975 (Early detection of health impairment in occupational exposure to health hazards) . 47 Annex 2 LIST OF PARTICIPANTS Temporary advisers 48 Dr I. Chemozemski, Institute of Oncology, Sofia , Bulgaria Dr K.P. Duncan , Director of Medical Services , Health and Safety Execu- tive, London, United Kingdom Professor D. Furon, Institute of Occupational Health, Lille, France Dr K.I. Hemminki, Institute of Occupational Health, Helsinki, Finland (Vice-Chairman) Professor J . Indulski, Director, lnstitu te of Occupational Medicine, Lodz, Poland Professor N .F. Izmerov, Director, Institute of Industrial Hygiene and Occupational Diseases, Moscow, USSR (Chairman) Dr V. Kevshilo, Chief, Department of Hygiene, Ministry of Health of the USSR, Moscow, USSR Dr G. Konetzke, Central Institute for Occupational Health, Berlin- Lichtenberg, German Democratic Republic Professor Y.I. Kundiev, Director, Scientific Research Institute of Labour Hygiene and Occupational Diseases, Kiev, USSR Dr V. Mathies, Medical Officer, Henkel Ltd, Haan, Federal Republic of Germany Dr G. Ungvary, Head, Section of Toxicology, National Institute of Occu- pational Health, Budapest, Hungary Professor P. Shubik, Cancer Resarch Centre, Institute for Toxicology and Chemotherapy, Heidelberg, Federal Republic of Germany (Rapporteur) Dr R.J. Sram, Institute of Hygiene and Epidemiology, Prague, Czecho- slovakia Mr RM. Stern , Danish Welding Institute , Glostrup, Denmark Dr H.H. Tj~nn, Directorate of Labour Inspection, Oslo , Norway Mr L. Tomatis, International Agency for Research on Cancer, Lyon , France Dr V. Vicente Martin , Ministry of Public Health and Social Security, Madrid, Spain Representatives of other organizations Dr M. Stilon de Piro, International Labour Office, Geneva, Switzerland WHO Regional Office for Europe Dr Ml. 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