A screening tool for assessment of health risks from combined exposure to multiple chemicals in indoor air in public settings for children: methodological approach
A screening tool for assessment of health risks from combined exposure to multiple chemicals in indoor air in public settings for children: methodological approach Abstract This publication describes the methodological approach to the development of the screening tool for assessment of health risks from combined exposure to multiple chemicals in indoor air in public settings for children. The approach is based on the WHO International Programme on Chemical Safety framework for risk assessment of combined exposure to multiple chemicals. This publication includes a description of the methodology as well as assumptions and limitations/uncertainties. Its content draws in part on a series of background papers and expert consultations and meetings convened to assist and advise WHO in the development of the methodological approach. ISBN 978-92-890-5561-1 © World Health Organization 2021 Some rights reserved. 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In no event shall WHO be liable for damages arising from its use. © Cover photo: WHO/NOOR/Sebastian Liste, WHO/Andy Craggs. iii ACKNOWLEDGEMENTS .................................................................................................................. iv LIST OF ABBREVIATIONS .................................................................................................................v INTRODUCTION .................................................................................................................................1 1. TERMINOLOGY ....................................................................................................................................2 2. SCOPE, PURPOSE, CONTEXT AND LIMITATIONS OF THE SCREENING TOOL ...........................4 2.1 Hazard assessment ...................................................................................................................4 2.2 Exposure assessment ...............................................................................................................5 3. TIERED APPROACH ......................................................................................................................6 3.1 The WHO–IPCS framework for risk assessment of combined exposure to multiple chemicals ..................................................................................................................................6 3.2 Problem formulation for grouping ..............................................................................................7 3.3 Exposure and hazard tiers ........................................................................................................7 3.4 Problem formulation and tiered risk characterization within the screening tool .........................8 3.5 Considerations relevant to cancer ...........................................................................................10 4. CHEMICALS AND THE BASIS FOR THEIR SELECTION FOR INCLUSION IN THE SCREENING TOOL’S SUPPORTING DATABASE OF TOXICOLOGICAL INFORMATION .........12 5. HEALTH ENDPOINTS (ADVERSE EFFECTS OR OUTCOMES) AND THE BASIS FOR THEIR SELECTION FOR INCLUSION IN THE DATABASE .........................................................15 6. DESCRIPTION AND CRITERIA FOR SELECTION OF TIERED TOXICOLOGICAL INFORMATION IN THE SUPPORTING DATABASE ....................................................................17 7. EXPOSURE-RELATED CONSIDERATIONS ................................................................................20 REFERENCES ..................................................................................................................................21 ANNEX 1: SELECTION OF SUBSTANCES TO BE INCLUDED IN SCREENING TOOL’S SUPPORTING DATABASE OF TOXICOLOGICAL INFORMATION .................................................25 CONTENTS iv ACKNOWLEDGEMENTS The WHO Regional Office for Europe gratefully acknowledges the principal author M.E. (Bette) Meek, University of Ottawa, Canada, and co-author Katleen De Brouwere, VITO, Belgium, for preparing this publication. The Regional Office also highly appreciates the assistance provided by the following national experts in the discussion and development of the methodological approach: ♦ Guillaume Boulanger, French Agency for Food, Environmental and Occupational Health and Safety, France; ♦ Malgorzata Debiak, German Environment Agency, Germany; ♦ Marike Kolossa-Gehring, German Environment Agency, Germany; ♦ Corinne Mandin, Scientific and Technical Centre for Building, France; ♦ Lotte Mollen, VITO, Belgium; ♦ Tamas Szigeti, National Public Health Centre, Hungary; and ♦ Theo Vermeire, National Institute for Public Health and the Environment, the Netherlands. The Regional Office gratefully acknowledges the financial support of the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety. vATSDR United States Agency for Toxic Substances and Disease Registry BDE brominated diphenyl ether BMC benchmark concentration BMD benchmark dose BMR benchmark response CAS Chemical Abstracts Service C&L European Classification and Labelling inventory CEN European Committee for Standardization CO carbon monoxide CSTB Scientific and Technical Centre for Building DBE-DBCH 4-(1,2-dibromoethyl)-1,2-dibromocyclohexane) DDT 4,4’-dichloro-diphenyl-trichloroethane DEHP di(2-ethylhexyl) phthalate DEHP di-2-ethylhexyl phthalate DEP diethyl phthalate DiBP diisobutyl phthalate DiDP di-isodecyl phthalate DiNP diisononyl phthalate DnBP di-n-butyl phthalate ECEH WHO European Centre for Environment and Health ECHA European Chemicals Agency EFSA European Food Safety Authority EPA United States Environmental Protection Agency EU European Union HCH hexachlorocyclohexane HI hazard index HIAG hazard index assessment group HQ hazard quotient IARC International Agency for Research on Cancer IPCS International Programme on Chemical Safety IRIS Integrated Risk Information System ISO International Organization for Standardization ITER International Toxicity Estimates for Risk Assessment LCI lowest concentration of interest LIST OF ABBREVIATIONS vi LOAEL lowest-observed-adverse-effect level NO2 nitrogen dioxide NOAEL no-observed-adverse-effect level O3 ozone PAH polycyclic aromatic hydrocarbons PCB polychlorinated biphenyl PM1 particulate matter with a diameter of 1 µm or less PM2.5 particulate matter with a diameter of 2.5 µm or less PM10 particulate matter with a diameter of 10 µm or less POD point of departure PODadj adjusted point of departure PODIadj adjusted point of departure index QSAR quantitative structure–activity relationship RC reference concentration SAR structure–activity relationship SINPHONIE Schools Indoor Pollution and Health Observatory Network in Europe Project SO2 sulfur dioxide STOT SE specific target organ toxicity – single exposure TBEP tri-(2-butoxyethyl)-phosphate TC tumorigenic concentration TCEP tris(2-chloroethyl) phosphate TCPP tris(1-chloro-2-propyl) phosphate TD tumorigenic dose UBA German Environment Agency UF uncertainty factor VOC volatile organic compound ABBREVIATIONS contd. 1INTRODUCTION The WHO International Programme on Chemical Safety (IPCS) framework for risk assessment of combined exposure to multiple chemicals (1,2) has made an important contribution to the evolution from the current, principally single-chemical-based risk paradigm towards one which addresses co-exposures to multiple chemicals. The framework has been widely adopted internationally (3–7) and within WHO programmes, including in the development of the WHO Guidelines for Drinking Water Quality (8). WHO also addresses indoor air quality for children consistent with priorities of the Parma and Ostrava Declarations on Environment and Health (9,10) to improve the quality of indoor air and minimize the effects of hazardous chemicals on children in places where they live, learn and play. This is an important area of focus, consistent with the potentially greater exposure of children than adults based on physiological considerations and behavioural factors (11), and with increasing evidence of health effects in children associated with indoor and ambient air quality (see Section 6). To contribute to addressing these priorities, the WHO European Centre for Environment and Health (ECEH) has developed a screening tool to assess the risks to human health from indoor air chemicals in public settings for children such as schools, kindergartens and day- care centres. The screening tool comprises a database of supporting toxicological information for selected chemicals and selected adverse effects (end points) and a spreadsheet to calculate risk of combined exposures, based on specified decision rules. This publication addresses the basis for the proposed approach to assessment of combined exposure within the screening tool, including these decision rules. It includes a description of the methodology, assumptions and limitations/uncertainties. The content draws in part on a series of background papers and expert consultations and meetings convened to assist and advise WHO, which took place on 3 to 4 December 2018 in Bonn, Germany (12), on 6 May 2019 in Brussels, Belgium (an informal expert meeting), on 23 to 24 September 2019 and 9 July 2020 (virtually) in Bonn, Germany (13). A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 2 1. TERMINOLOGY The terminology and approach adopted for the screening tool are consistent with those of the IPCS programme (14) and those of the WHO–IPCS framework (1) and its application by WHO (8). The screening tool addresses combined exposure to multiple chemicals in indoor air. Substances grouped together for evaluation are an assessment group for which dose additivity is assumed, that is, relevant to chemicals acting by the same mode of action and/ or on the same target cells, tissues or organs. Exposure can be concurrent (occurring at the same time as for mixtures) or with different temporal patterns. The screening tool does not address chemicals interacting to produce an effect greater than or less than that predicted by additivity (comprising synergy and antagonism, respectively). Chemical-specific information in the supporting database for the screening tool is restricted to that on (potential) effects observed or reasonably anticipated to be associated with indoor exposure of children to chemicals, based on available data. These (observed or potential) effects are limited to those for which there is relatively consistent evidence in observational studies in children following inhalation, or which are designated as International Agency for Research on Cancer (IARC) Group 1 carcinogens. A critical effect is the first adverse effect (or its known precursor) that occurs as the chemical dose increases, and is selected as a basis to define a health-based reference value. An adverse effect is a change in the morphology, physiology, growth, development, reproduction or lifespan of an organism, system or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influences. A hazard index (HI) is the sum of the exposures to each of the component compounds of an assessment group divided by their respective reference values (for example, acceptable or tolerable concentrations). The HI represents, then, a risk-based summation of exposures to individual components, adjusted by their relative hazard. If HI > 1, the total concentration (or dose) of components in an assessment group exceeds the level considered to be acceptable. A hazard index assessment group (HIAG) is the sum of the exposures to each of the component compounds of an assessment group for one of the designated priority health effects divided by their respective reference values. A hazard quotient (HQ) is the ratio of the potential exposure to a component substance to the level at which no adverse effects are expected (for example acceptable or tolerable concentration for inhaled pollutants). HIs constitute the summation of HQs for all components in an assessment group. A reference concentration (RC) or acceptable concentration is the estimated maximum airborne concentration of an inhaled agent to which individuals in a (sub)population may be exposed without appreciable health risk. 3A point of departure (POD) is the dose or concentration selected as the point for comparison with exposure estimates as a basis for consideration of risk. Examples include the no- observed-adverse-effect-level, lowest-observed-adverse-effect level and benchmark dose/ concentration (see below). An adjusted point of departure (PODadj) is the dose or concentration selected as the point for comparison with exposure estimates adjusted to account for duration and uncertainty (non-cancer or non-genotoxic carcinogenicity) or an adequately protective margin (cancer). A no-observed-adverse-effect level (NOAEL) is the greatest concentration or amount of a substance, found by experiment or observation, that causes no adverse alteration of morphology, functional capacity, growth, development or lifespan of the target organism distinguishable from those observed in normal (control) organisms of the same species and strain under the same defined conditions of exposure. A lowest-observed-adverse-effect level (LOAEL) is the lowest concentration or amount of a substance, found by experiment or observation, that causes an adverse alteration of morphology, functional capacity, growth, development or lifespan of the target organism distinguishable from normal (control) organisms of the same species and strain under the same defined conditions of exposure. A benchmark dose (BMD) or benchmark concentration (BMC) is a dose or concentration that produces a predetermined change in the response rate of an adverse effect – called the benchmark response (BMR) – compared to background, derived generally from the modelled dose–response relationship for a substance. A margin of exposure is the ratio of the POD to exposure estimates. An adjusted point of departure index (PODIadj) is the sum of the exposures to each of the component compounds of an assessment group divided by their respective PODs, adjusted to take into account duration and uncertainty (non-cancer or non-genotoxic carcinogens) or an adequately protective margin (cancer). An uncertainty factor (UF) is the product of several factors by which the POD of the critical effect is divided to derive a reference or acceptable concentration. These factors account for adequacy of the pivotal study and the overall database, interspecies extrapolation, inter- individual variability in humans and the nature of toxicity. Often, a default 10x UF is applied to the POD to account for interspecies differences (for example, when extrapolating from experimental animal data to humans) and a further 10x UF to account for inter-individual or intraspecies variability. A tumorigenic concentration (TC) or tumorigenic dose (TD) is a BMC or BMD for induction of cancer, that is, a concentration or dose that produces a predetermined increase in tumour incidence compared to background, generally derived from the modelled dose–response relationship for specified tumours. Values included in the supporting toxicological database for the screening tool are derived from TD50s in the Carcinogenic Potency Database (15), which are defined as the chronic dose rate in milligrams per kilogram body weight per day that would induce tumours in half the test animals at the end of a standard lifespan for the species in the absence of tumours in control animals (16). A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 4 2. SCOPE, PURPOSE, CONTEXT AND LIMITATIONS OF THE SCREENING TOOL The target audience for using the screening tool to consider co-exposures is public health professionals, risk assessors at national, regional and local levels, and specialists involved in evaluating the quality of indoor air and promoting risk reduction measures in public settings for children (schools, day-care centres and kindergartens). The need to balance complexity and ease of application for the target audience has guided the development of the screening tool. It is envisaged that the screening tool will contribute as one component in an overall strategy for assessing and managing indoor air pollution in public settings for children. The specific purpose of the screening tool is to facilitate the consideration of co-exposures in assessing health risks to children in public settings in order to determine the need to refine evaluation and/or to introduce risk reduction measures. This addresses an important objective to be more proactive and protective in efficiently addressing more realistic scenarios of combined exposure to chemical pollutants in indoor air. The screening tool offers an incremental improvement on single-pollutant-based assessments, enabling a focus on the most important/feasible health effects/endpoints and co-exposures for which data are most often available. The relative paucity of available data on health effects of indoor air pollutants in humans, in addition to the need to be pragmatic in the development of the screening tool, limits the extent of the chemicals and effects it currently addresses. This is a function of the available data on effects in human populations following inhalation being restricted predominantly to a limited range of well investigated substances. 2.1 Hazard assessment For hazard, the screening tool addresses Tier 0 and Tier 1 of the WHO–IPCS framework (1), assuming dose additivity of components of assessment groups. Restriction of the screening tool to early tiers of the framework maximizes inclusiveness of relevant pollutants and effects by minimizing data demand. It also reduces complexity and facilitates communication and application. The screening tool does not currently address chemicals interacting to produce an effect greater than or less than that predicted by additivity (comprising synergy and antagonism, respectively). Analyses of empirical results for effects of combined exposure, including chemicals that induce critical effects by different modes of action, indicate that the assumption of dose additivity is conservative (3,17,18). In addition, in the small number of cases in which it has been reported that dose additivity may under-predict effects due to synergistic interaction, analyses of limited available data suggest that the magnitude of the under- prediction is less than an order of magnitude (18,19). Conservative default assumptions incorporated in the screening tool also offset the potential for under-prediction. 52.2 Exposure assessment For exposure, application of the screening tool is limited to those pollutants of indoor air, for which monitoring data are available for the target setting. In addition, to reduce complexity, the screening tool is restricted to the gaseous phase and does not yet address the particulate phase for combined exposure assessment (see also Section 8 on exposure-related considerations). Subsequent editions of the screening tool may include additional chemicals and supporting toxicological information for assessment of combined exposures in other indoor environments. Given its screening nature, an unacceptable margin of exposure or HI resulting from application of the screening tool does not always imply immediate and/or unacceptable health risk. Rather, those evaluating the quality of indoor air in public settings for children should consider the output in addition to a number of other factors, such as availability of low-cost risk-reduction measures, to assess the need for additional data generation, assessment and/or control measures. A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 6 3. TIERED APPROACH 3.1 The WHO–IPCS framework for risk assessment of combined exposure to multiple chemicals The WHO–IPCS framework includes problem formulation as a basis for considering the need for combined-exposure assessment and appropriate grouping, followed by stepwise integrated and iterative consideration of both exposure and hazard in several tiers of increasingly data-informed analyses. Each tier is more refined (that is, less conservative and uncertain than the previous one), but additionally labour- and data-intensive. At any tier, the outcome can be: management to reduce risk, no further action, generation of additional data, or further assessment (that is, additional refinement in a higher tier) based on context- specific evaluation of the adequacy of margins of exposure. The WHO–IPCS framework builds on developments in a range of programmes internationally (20), assuming dose addition and incorporating predictive approaches in early tiers and increasingly refined, more data-informed and probabilistic analyses in later tiers. For exposure, the described tiers include examples ranging from simple semi-quantitative estimates of exposure based often on crude surrogates, to conservative point estimates based on generic exposure scenarios (Tier 0), to refined estimates incorporating much more monitoring data (probabilistic, where data permit, in Tier 3). Described hazard tiers range from generic thresholds for components within known structural groups of compounds (for example, the threshold of toxicological concern in Tier 0) to more refined estimates of potency (Tiers 1 and 2), to better-informed groupings and assessments based on knowledge of mode of action and probabilistic characterization of risk (see Fig. 1). The objective of the framework analyses is “fit for purpose” assessment to ensure that no more resources are invested than are necessary to make a decision for the purpose at hand – namely, to set an assessment group aside as a non-priority for further consideration or to inform management for risk reduction. Tiering facilitates tailoring of the level of effort required for assessment to the magnitude of potential risks, the objective (for example, priority setting or screening for additional focus or risk management) and scope (for example, local, national), depending on the context (addressed in problem formulation/scoping). 7 Problem formulation for grouping Nature of exposure? Is exposure likely? Co-exposure within a relevant timeframe? Rationale for considering compounds in an assessment group? Tiered exposure assessment Tiered hazard assessment Tier 0 Simple semi- quantitative estimates of exposure Tier 1 Generic exposure scenanos using conservative point estimates Tier 2 Refined exposure assessment, increased use of actual measured data Tier 3 Probabilistic exposure estimates Tier 0 Default dose additional for all components Tier 1 Refined potency based on individual POD, refinemed of POD Tier 2 More refined potency and grouping based on mode of action Tier 3 PBPK or BBDR probabilistic estimates of risks Is the margin of exposure adequate? In cr ea si ng r efi ne m en t o f e xp os ur e m od el s Increasing refi nem ent of hazard m odels No, continue with iterative refinement as needed (i.e. more complex exposure and hazard models) Yes, no further action required Assessment 3.2 Problem formulation for grouping Problem formulation frames the extent of the need for an assessment of combined exposures and appropriate grouping based on, for example, the potential for co-occurrence and or non-temporal co-exposure to multiple chemicals. In the case that limited monitoring data are available, consideration of the nature of sources in the relevant setting is also helpful in determining the likelihood of co-occurrence to indoor air pollutants. In addition to consideration of exposure, grouping also takes into account hazard. Information relevant to the consideration of whether components are likely to act similarly includes predictive information on chemical structure, such as structure–activity relationships (SARs) and/or structural alerts and quantitative structure–activity relationship (QSAR) modelling. Where available, data on hazard or other biological data (toxicity) may be the basis for the conclusion that effects are likely to be similar. Helpful indicators for potential grouping based on hazard include answers to questions such as: Are effects observed in the same target organs? Is the biological outcome the same? Are the chemicals used for similar application potentially implying similar modes of action? 3.3 Exposure and hazard tiers Once grouping is determined in problem formulation, the analysis of risks for combined exposure is tiered to facilitate an early focus on priority pollutants as a basis to consider Fig. 1. WHO–IPCS framework for risk assessment of combined exposure to multiple chemicals (1,2) A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 8 appropriate next steps, including risk reduction management strategies and/or additional assessment and data generation. The early tiers of hazard and exposure described in the WHO–IPCS framework are as follows. Tier 0 Hazard: A conservative, very early tier assumption in the absence of information on individual components assumes that all components have the same potency as the most toxic compound known. Tier 1 Hazard: In a Tier 1 assessment, the analysis incorporates additional information on reference values (tolerable or acceptable concentrations for individual components for the common effect) and more accurate measures of PODs for hazard. For example, rather than reference values for which the timeframe of development, critical effects and uncertainty factors may not be comparable, PODs on the dose–response curve (for example, LOAELs or NOAELs) for common critical effects may be used as a basis to estimate relative potency. Use of BMDs instead of effect levels for critical effects also increases precision somewhat additionally for the POD. Tier 0 Exposure: Where the margins between very crude, conservative estimates of exposure and PODs for hazard are large, simple semi-quantitative estimates of summed exposure for the various components of an assessment group may be sufficient as a basis for an early-tier analysis. Semi-quantitative estimates require limited data and a few very simple assumptions. Often, combined information on indicators of potential exposure, such as volume, use and/or physicochemical properties, provides measures of relative ranking, quantified crudely based on comparison with more robust quantitative estimates for chemicals with similar profiles. This tier does not require monitoring data and is not included in the screening tool. Tier 1 Exposure: Summation of deterministic estimates of exposure for all components of the assessment group based on measured or modelled data, or both, may suffice as a basis for comparison with a measure of hazard to determine whether further assessment or management is necessary. This tier is included in the tool. Included tiers provide examples only. As indicated in Meek et al. (1), tiers may vary depending on available data. Tiers for specific applications may also require additional sub-tiers. 3.4 Problem formulation and tiered risk characterization within the screening tool Substances prioritized for inclusion in the supporting database for the screening tool are those for which there is greatest likelihood of co-exposure in indoor air in public settings for children (see Section 5 and Annex 1) (12,13,21). The screening tool enables grouping of these compounds by effects considered most relevant for inhalation of indoor air by children (see Section 7). The tool requires, as input, reliable monitoring data on relevant compounds for indoor air in the target setting. The construct of the screening tool described here is similar to that of the WHO–IPCS framework (see Fig. 1). However, it incorporates modified tiers relevant to the application, 9namely, consideration of combined exposures to pollutants in indoor air in public settings such as schools, kindergartens and day-care centres. It also incorporates a number of default adjustments to facilitate application. These are as follows. Tier 0: The screening tool calculates an HI, the sum of the HQs (exposures to each of the component compounds of an assessment group divided by their respective reference or acceptable concentrations for the critical effect, that is, the effect that occurs at the lowest concentration). The most recent reference values are selected by default; where there is more than one recent value, the screening tool selects the lowest value as the default approach. The HI represents an appropriate first-order, likely conservative approach, since grouping of substances does not take into consideration specific effects, but rather is based on the critical effects, often those that occur at the lowest concentration, in the derivation of reference or acceptable concentrations. An HI > 1 requires refinement of the assessment or consideration of remedial measures to reduce exposure. HI = ∑ measured concentrationx RCxx = 1 n Where x = each substance included in the assessment group, irrespective of their health effects; RC = reference concentration for inhalation based on critical effect, for example, WHO guidance values. Tier 1, Level 1: The screening tool calculates HIs as indicated above, but with chemicals grouped according to the five selected priority health effects for indoor air pollution in public settings for children (see Section 6). An HI > 1 for any of the groups requires refinement of the assessment or consideration of remedial measures to reduce exposure. HIAG= ∑ measured concentrationx RCxx = 1 n Where HIAG = the HI for an assessment group for each of the priority effects; x = each substance included in the assessment group; RC = reference concentration for inhalation for the relevant substance, for example, WHO guidance values. Tier 1, Level 2: The screening tool calculates a PODIadj for the selected effects of interest. The PODIadj is based on the lowest POD if there are data available for both humans and animals, with the value in animals being normalized to humans by a factor of 0.1 to account for interspecies differences. NOAELs are preferred; if only LOAELs are available, the screening tool adjusts the value by a factor of 3 (22). Human variability is taken into account through adjustment of the POD by an additional factor of 10. A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 10 For systemic effects, chronic exposure values are preferred. If data on chronic exposure are not available, PODs for intermediate duration exposures are adjusted by a factor of 2 to account for the shorter duration (22). There are no adjustments incorporated to account for intermittent to continuous exposure (for example, six hours per day, five days per week in animal inhalation studies to 24 hours per day, seven days per week) due to the somewhat similar pattern of exposure with that for children in schools with which the relevant POD is compared in the adjusted PODI. PODs for a limited number of substances in the supporting toxicological database are based on continuous exposure and incorporate an additional degree of conservatism. Given the conservative nature of the various default assumptions for multiple substances, additional factors to address duration (for example, variation in exposure of animals for only five to six hours per day versus continuous passive monitoring in schools), the potentially greater susceptibility of children, or study quality are not incorporated. This also maximizes simplicity in the application of the screening tool. A PODIadj > 1 for any of the effects requires additional refinement of the assessment or remedial measures. Expert advice on next steps should be sought in any additional refinement of the assessment. Where PODIAdj x = the POD adjusted for an assessment group for each of the priority effects; PODx adjusted = the POD for the relevant priority health effect for substance x adjusted by duration of exposure and an acceptable margin to account for uncertainty. Included in the supporting toxicological database for the screening tool to support the calculations in these various tiers, therefore, are reference concentrations for inhalation (occasionally based on route-to-route extrapolation) and PODs for prioritized effects for the selected chemicals. 3.5 Considerations relevant to cancer Estimates of potency (TC50s, that is, the concentration associated with a 50% increase in cancer risk) (23) are included in the supporting database of toxicological information1. TCs/TDs rather than low-dose risk estimates were included for consistency with the approach for calculation of margins of exposure for non-cancer effects. If cancer is one of the selected effects of interest (IARC Group 1; see Section 5), the screening tool also calculates a PODIadj based on TC50s divided by a margin of 50 000 if based on animal data and a margin of 5000 if derived from human data. This theoretically extrapolates 1 Values included in the supporting toxicological database for the screening tool are those for the inhalation route of exposure included in the Carcinogenic Potency Database (15). Values reported as TD50s were converted back to their corresponding inhaled concentrations, based on conversions for adults (22). PODIAdjAG= ∑ measured concentrationx PODx adjx = 1 n 11 PODIAdjAG= ∑ measured concentrationx TC50x adjx = 1 n Fig. 2. The tiered approach in the screening tool Tier 0 – no grouping by effect. Hazard Index (HI) summing the ratios of concentrations of each monitored pollutant by their respective Acceptable or Tolerable Concentrations (e.g., WHO air quality guideline) HI > 1, consider additional assessment or remedial measures Tier 1, Level 1 – grouping by five selected priority health effects; HIAGs summing the ratios of monitored pollutant concentrations by their respective Acceptable or Tolerable Concentrations (e.g., WHO air quality guideline) for each of the effect groups HI AG > 1 for any group, consider additional assessment or remedial measures Tier 1, Level 2 – grouping by five selected priority health effects and cancer; PODIadj summing the ratios of concentrations of monitored pollutants by their points of departure for the relevant effect adjusted to take into account duration and uncertainty for each of the effect groups (non-cancer or non-genotoxic carcinogenicity) or an adequately protective margin (cancer) PODIadj > 1 for any group, consider addit ional assessment or remedial measures to a risk of 1 in 105. These values are approximately consistent with the margins considered by the European Food Safety Authority (EFSA) (24) as low priorities for risk management for substances which are both carcinogenic and genotoxic. A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 12 4. CHEMICALS AND THE BASIS FOR THEIR SELECTION FOR INCLUSION IN THE SCREENING TOOL’S SUPPORTING DATABASE OF TOXICOLOGICAL INFORMATION The selection of chemicals for inclusion in the supporting database was data- and expert- informed, taking into account: ♦ the results of several literature reviews to identify the most common chemical pollutants in indoor air; ♦ input from experts convened for consultation on the development of the screening tool and the associated supporting database; and ♦ the availability of substance-specific toxicological information as well as the complexity and feasibility of their sampling and analysis. The process for developing the list of prioritized substances was iterative, and included a number of data- and expert-informed steps. An initial list for consideration by the first consultation took into account the results of a literature review of studies in public settings of children in European Union (EU) countries (2012–2017) to identify the most common indoor air pollutants (25). The search identified 90 substances prioritized by frequency of detection (see Annex 1, Table A1.1) in 26 of approximately 150 reviewed studies deemed to be relevant, following application of exclusion criteria (for example, inadequate reporting, inappropriate settings or proximity to atypical sources). In relation to co-exposure, the most frequent combinations were those for ubiquitous indoor air pollutants such as the carbonyls (for example, formaldehyde and to a lesser extent acetaldehyde), volatile organic compounds (VOCs) such as phenolic compounds (for example, benzene, toluene, ethylbenzene and xylenes, the so-called BTEX mixture) and terpenes, particulate matter, and polycyclic aromatic hydrocarbons (PAHs). In studies conducted in the preceding decade, a significant number of phthalates and brominated flame retardants in indoor air were present. More recent data (January 2014 to October 2018) on co-exposure of children in indoor air in public settings in 16 countries worldwide were compiled systematically (see Annex 1, Table A1.2). Criteria for inclusion were at least two indoor chemicals measured simultaneously in preschools, elementary schools, day-care centres or kindergartens, excluding radon and carbon monoxide (CO). Detection in 100% of samples confirmed co-exposure; if a result was less than 100%, a chemical was not considered as “systematically present”. The most commonly measured chemicals were VOCs, followed by aldehydes (n=11 studies), PAHs and flame retardants (n=6 studies) (see Table A1.2) (25). The search identified 177 compounds in 30 of approximately 73 studies, following application of exclusion criteria (for example, detection frequency or distribution of concentrations not provided or inappropriate setting). 13 A subset of 30 substances identified in these surveys was additionally prioritized for consideration at the first expert consultation (12), taking into account: ♦ substances for which there are existing guidelines for indoor or ambient air quality; ♦ substances most commonly and recently detected (as of 2017) (25); and ♦ additional expert judgment regarding potential for exposure or hazard. The additionally prioritized candidate list of 30 substances, including those identified in 19 studies in 26 countries across Europe, is presented in Annex 1, Table A1.3. Experts at the first consultation considered this candidate list and additional information to advise on appropriate inclusions, taking into account (12): ♦ an initial focus on a short list of priority chemicals for the first version of the screening tool, with consideration of additional chemicals or tier-specific lists (depending on the availability of toxicological information) as options for expanding the list at a later stage; ♦ the availability of high-confidence information on the relevant respective health effects; ♦ potential for exposure based on critical consideration of releases from outdoor and indoor sources (such as building materials or furniture) and detection in indoor air in schools; and ♦ the availability of standardized sampling and analytical methods. Three lists of chemicals were agreed (12): ♦ a short list of 19 priority substances to be included in the first version of the screening tool based on consideration of those addressed in the WHO Indoor Air Quality Guidelines (26), those investigated in the EU Schools Indoor Pollution and Health Observatory Network in Europe (SINPHONIE) Project (27) and those controlled in many European countries (see Appendix 1, Table A1.4); ♦ a so-called wish list of 36 substances and groups of substances prioritized on the basis of the availability and affordability of standardized methods relevant to consideration for inclusion in the screening tool in the future (see Appendix 1, Table A1.5); and ♦ a list of additional chemical compounds that can be measured using the same sampling and analytical methods as for chemicals from the first two lists (see Appendix 1, Table A1.6). Inclusions on these lists, in particular the short list of priority substances, were considered at the second expert consultation (Bonn, Germany, 23–24 September 2019) (13) and in post- consultation follow-up, where it was decided: ♦ to exclude CO and ozone since, while important air pollutants, they are not considered high priorities for assessing long-term effects from combined exposures; ♦ to exclude substances from the list for which adequate toxicological information has not been identified; ♦ to consider including butyl acetate, 1,2,3-trimethylbenzene and 1,4-dichlorobenzene, following confirmation of the availability of adequate toxicological information; and A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 14 ♦ to exclude phthalates due to the additional complexity of the need to actively sample, the fact that ingestion rather than inhalation is the principal route of exposure to phthalates, and the observation that concentrations in indoor air are much lower than the NOAELs for the two phthalates – di(2-ethylhexyl) phthalate (DEHP) and diisobutyl phthalate (DiBP) – for which adequate toxicological data are available. The finalized list of substances is presented in Table 1 below. Table 1. List of priority substances included in the screening tool No. Chemical family Chemical group Substances Chemical Abstracts Service (CAS) number 1 Oxygenated VOCs (oxy-VOCs) Aldehydes Formaldehyde 50-00-0 2 Acetaldehyde 75-07-0 3 VOCs Aromatic hydrocarbons Benzene 71-43-2 4 Ethylbenzene 100-41-4 5 1,2,3-trimethylbenzene 526-73-8 6 Xylene (o-, m-, p-) 95-47-6 108-38-3/106-42-3 7 Styrene 100-42-5 8 Toluene 108-88-3 9 1,4-dichlorobenzene 106-46-7 10 Terpenes Limonene 138-86-3 11 α-pinene 80-56-8 12 Chlorinated hydrocarbons Tetrachloroethylene 127-18-4 13 Trichloroethylene 79-01-6 14 Esters n-butyl acetate 126-86-1 15 PAHs Naphthalene 91-20-3 16 Semi-VOCs PAHs Benzo(a)pyrene 50-32-8 17 Inorganic compounds NO2 10102-44-0 15 5. HEALTH ENDPOINTS (ADVERSE EFFECTS OR OUTCOMES) AND THE BASIS FOR THEIR SELECTION FOR INCLUSION IN THE DATABASE The ECEH commissioned a review of information on a number of potential health effects of air pollutants on children for the expert consultations (25). This was an update of a 2013 WHO publication reviewing literature from 2001 to 2011 (21). Effects considered were those on the respiratory, cardiovascular, neurological, endocrine and immune systems. Evidence for the association between indoor air pollution and respiratory effects in children (most often allergic rhinitis, asthma development or exacerbation, chronic airway inflammation and acute respiratory infections) and impact on the neurological system (impairments in different neuropsychological development outcomes or effects on the nervous system observed by neuroimaging) was relatively consistent and convincing. Evidence of potential cardiovascular effects in children (for example, increase in arterial blood pressure and heart rate, higher levels of stress hormones and biomarkers of oxidative stress) was more limited and less consistent. Data on potential effects on the immune system of children is limited, varied and difficult to interpret, due in part to the commonly nonspecific nature of the endpoints considered (for example, infections such as pneumonia or otitis media; absenteeism from school due to sore throat, cough and cold; development of allergies). Direct observational (epidemiological) data on the potential to contribute to delayed effects such as cancer observed in later life are inadequate to draw conclusions. Experts at the first consultation (12) considered the background information prepared for the ECEH and adopted the following strategy for advising on selected effects for inclusion in the screening tool. ♦ A broad array of target endpoints was considered, including those on the respiratory, nervous, cardiovascular, immune, endocrine, blood and ocular systems; liver and kidney disorders; carcinogenicity; irritation; sensitization; and dermatological effects. ♦ The following criteria were considered in designating priorities: exposure by inhalation, likely effects of the priority substances for inclusion (see Table 1), health effects of greatest concern for which confidence in the extent of the evidence for effects in indoor air is highest, and availability of toxicological information for prioritized chemicals and endpoints. ♦ The adequacy of the selected health endpoints/effects for inclusion was cross-checked against the priority list to ensure that they include critical effects for these substances. Participants excluded effects considered uncommon following inhalation (for example, skin irritation). Effects on the kidney and liver, often critical target organs in toxicity studies, are A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 16 not commonly associated with substances prioritized for inclusion in the screening tool and occur at concentrations/doses which are commonly much higher than those in indoor air. Hematotoxic effects are not commonly critical at relatively low concentrations, though there are some exceptions (for example, benzene). Clinical manifestations of sensitization are usually allergic diseases and asthma. Irritation/respiratory system disorders partially address allergy. The limited toxicological information available on endocrine disruption and the immune system precludes their inclusion at present. Cancer is also included in the screening tool, consistent with the potential for increased risk associated with exposure during childhood and the recognized limitations of epidemiological data to detect increases in the general population. Consideration for cancer is restricted to IARC Group 1 substances consistent with the selection of critical endpoints based principally on epidemiological data in human populations (those exposed normally to higher concentrations in occupational settings). Carcinogenic potencies for the following designated substances (that is, those in Table 1 which are included in IARC Group 1) are included in the database of toxicological effects for application of the screening tool:2 ♦ formaldehyde ♦ benzene ♦ trichloroethylene ♦ benzo(a)pyrene. In conclusion, the following effects related to long- and short-term exposure were deemed as priorities for inclusion in the first version of the screening tool: ♦ effects on the respiratory system; ♦ effects on the nervous system; ♦ effects on the cardiovascular system; ♦ carcinogenicity – IARC Group 1 carcinogens, depending on the list of priority substances for inclusion; and ♦ eye and respiratory irritation – depending on the list of priority substances for inclusion. 2 Acetaldehyde is not included as IARC designation relates to consumption of alcoholic beverages for which it is a metabolic by-product (https://monographs.iarc.fr/list-of-classifications). 17 6. DESCRIPTION AND CRITERIA FOR SELECTION OF TIERED TOXICOLOGICAL INFORMATION IN THE SUPPORTING DATABASE A relevant reference or acceptable concentrations and PODs for chronic exposure for each of the five endpoints/effects are included in the supporting toxicological database for the screening tool. Where values for chronic exposure were not identified, values for intermediate exposure were included. Values have been included based on hierarchical searching of the following sources with a focus on inhalation: ♦ the WHO guidelines for indoor air (26) and ambient air quality (28); ♦ the United States Agency for Toxic Substances and Disease Registry (ATSDR) toxicological profiles (29); ♦ the United States Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) (30); ♦ the International Toxicity Estimates for Risk Assessment (ITER) database (31); ♦ the EU harmonized health-based reference values for the assessment of product emissions (EU Lowest Concentration of Interest (LCI) database) (32); ♦ the European Chemicals Agency (ECHA) Risk Assessment Committee (33); and ♦ the Carcinogenic Potency Database (15). The search strategy for populating the database is presented in Fig. 3. To facilitate assessment of combined exposure, chemicals were grouped based on evidence of similar endpoints/effects – that is, where there was a relevant LOAEL or BMD for the same effect. Chemicals were not included in an effect group if no BMD, LOAEL, NOAEL or TC was identified, or if only a NOAEL(s) value (that is, no LOAEL or BMD) for the highest test dose was reported. Grouping by similar effect in the toxicological database does not preclude grouping of substances by other characteristics, consistent with the approach described in the WHO framework for the development of combined assessment groups (1,20). These could include, for example, common sources and/or control measures. The European Classification and Labelling (C&L) inventory (34) provided support for the assignment of substances to the assessment groups “respiratory effects” (including irritation) and “eye irritation”. In the absence of a harmonized classification, non-harmonized classifications based on the majority of notifications submitted by industry, provided support. Substances included in the group “respiratory effects” had either a relevant POD identified in searched sources or a classification of STOT SE 3 (specific target organ toxicity – single exposure including respiratory tract irritation). Substances included in the group “eye irritation” A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 18 Fi g. 3 . S ea rc h st ra te gy fo r th e su pp or ti ng d at ab as e of to xi co lo gi ca l v al ue s H ea lt h eff ec t X Gu id el in e va lu e ba se d on h ea lth e ff ec t X ? X: 1. R es pi ra to ry 2. Ir ri ta tio n 3. C ar di ov as cu la r 4. N eu ro lo gi ca l 5. C an ce r W H O IA OG (I nd oo r ai r qu al ity g ui da nc e) AT S D R To xi co lo gi ca l p ro fil er s Re po rt N OA EL s or LO AE Ls a nd A F as ba si s fo r g ui de lin es va lu e N OA EL s or L OA EL s fo r X in te xt CH RO N IC Ye s N o Ye s No Re po rt N OA EL s an d LO AE Ls fo r X If nu m be r of N OA EL s (o r LO AE LS ): • ≤ 2 r ep or t a ll • ≥ 2 r ep or t m os t re ce nt A N D lo w es t ( fo r an im al s an d fo r hu m an s) M RL b as ed o n he al th e ff ec t X ? Re po rt N OA EL s or LO AE Ls u se d as b as is fo r M RL St ud ie s w ith b ot h NO AE Ls a nd L OA EL s he al th e ffe ct X in ta bl e Ye s N o Ye s No U S IP A To xi co lo gi ca l pr ofi le rs if no N OA EL s or L OA EL s IT ER if no N OA EL s or L OA EL s EU L C I if no N OA EL s or L OA EL s R A C Re po rt N OA EL s an d LO AE Ls If nu m be r of s tu di es : • ≤ 2 r ep or t a ll • ≥ 2 r ep or t m os t re ce nt A N D lo w es t ( fo r an im al s an d fo r hu m an s) N OA EL s in ta bl e Ye s No LO AE Ls in ta bl e LO AE Ls in ta bl e Ye s No Re po rt N OA EL s If nu m be r of N OA EL s: • ≤ 2 r ep or t a ll • ≥ 2 r ep or t m os t r ec en t A N D lo w es t ( fo r an im al s an d fo r hu m an s) an d LO AE Ls If n um be r of L OA EL s: • ≤ 2 r ep or t a ll • ≥ 2 r ep or t m os t r ec en t A N D lo w es t ( fo r an im al s an d fo r hu m an s) Re po rt N OA EL s If nu m be r of N OA EL s: • ≤ 2 r ep or t a ll • ≥ 2 r ep or t m os t r ec en t A N D lo w es t ( fo r an im al s an d fo r hu m an s) an d lo ok fo r LO AE Ls in in te rm ed ia te o r ac ut e ta bl e If nu m be r of L OA EL s in in te rm ed ia te or a cu te : • ≤ 2 r ep or t a ll • ≥ 2 r ep or t m os t r ec en t A N D lo w es t ( fo r an im al s an d fo r hu m an s) Ye s Re po rt L OA EL s If nu m be r of L OA EL s: • ≤ 2 r ep or t a ll • ≥ 2 r ep or t m os t r ec en t A N D lo w es t ( fo r an im al s an d fo r hu m an s) N o IN TE RM ED IA TE if no N OA EL s or L OA EL s AC U TE if no NOAELs or LOAELs in ACUTE AT SD R - U ni te d St at es Ag en cy fo r T ox ic S ub st an ce s an d Di se as e Re gi st ry IA QG - W H O Gu id el in e fo r In do or A ir Qu al ity IT ER - In te rn at io na l To xi ci ty E st im at es fo r Ri sk As se ss m en t LC I - lo w es t c on ce nt ra tio n of in te re st LO AE L - l ow es t- ob se rv ed - ad ve rs e- eff ec t l ev el M RL - m in im al r is k le ve l N OA EL - no -o bs er ve d- ad ve rs e- eff ec t l ev el RA C - C om m itt ee fo r Ri sk As se ss m en t 19 had a relevant POD identified in searched sources. Alternatively, they were classified as 1 “causes serious eye damage”, 2A “irritants” or 2B “mild irritants”. Chemicals were included in the carcinogenicity group if classified in IARC Group 1 and TCs were identified. Noted below are sources consulted and criteria for inclusion of information in the toxicological database to support the various tiers. In the screening tool, where available, WHO health- based reference or acceptable values (26,28) are preferred for Tier 0 calculations. In their absence, the most recent values from the other identified sources provide the basis for calculation, prioritized as indicated below. Tier 0 (Reference or acceptable concentrations – Inhalation): ♦ Global resources referenced in WHO documents, as below: ■ WHO guidance values for air quality (indoor (25) and ambient (28)) ■ International values for inhalation included in the ITER database, including more recent values from the ATSDR, the EPA, Health Canada, the IARC, the National Institute for Public Health and the Environment of the Netherlands and NSF International ■ Values approved by the ECHA Risk Assessment Committee and the EU-wide harmonized health-based reference values for the assessment of product emissions (lowest concentrations of interest developed by the EU LCI working group of the European Commission) Tier 1 (PODs – Inhalation): ♦ ATSDR Toxicological Profiles ■ Relatively complete source which provides information in the most accessible format on the range of PODs from identified studies for all chemical-specific effects ■ Preference for BMCs, then NO(A)ELs, then LO(A)ELs3 ○ Uninformative NOAELs where no effects at the top dose not included ○ NOAELs and LOAELs (doses where effects were seen) included Values included within the screening tool as defaults can be replaced by more appropriate national/regional values. For example, the user will be able to link to and upload repositories of approved values for inhalation from other national and/or supranational competent authorities (for example, national governments or the ECHA Risk Assessment Committee). 3 While BMCs are preferred, the extent of their inclusion in the screening tool is limited by their lack of availability in the ATSDR profiles. A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 20 7. EXPOSURE-RELATED CONSIDERATIONS A companion report addresses strategies for sampling and analysis to estimate exposure within the screening tool (35). General considerations on sampling strategy draw from the report of a WHO meeting on methods for monitoring indoor air quality in schools (36), the International Organization for Standardization (ISO) 16000-1 (Indoor air – Part 1: General aspects of sampling strategy) (37) and the SINPHONIE project (27). Continuous passive sampling is recommended, consistent with the long-term hazards of interest identified as priorities for inclusion in the screening tool and ease of implementation in public settings such as schools, kindergartens and day-care centres (generally continuous passive, 24 hours per day, five days per week; active sampling for benzo(a)pyrene only). For calculation of the HI (Tier 0 and Tier 1, Level 1) and PODIadj (Tier 1, Level 2), monitored concentrations in public spaces of children are incorporated directly, without inhalation to body weight conversions by age group, since the resulting quantitative impact of age-related variability is relatively small. There is also no adjustment for intermittent exposure (during the school day five days per week) to continuous exposure (all day seven days per week). This takes into account that the pattern of exposure in many of the critical studies that serve as the basis for the reference concentrations and PODs incorporated in the HI and PODIadj are somewhat similar to that of schoolchildren (that is, five days per week). The 24-hour sampling period for five days per week recommended for the long-term effects of interest and to facilitate implementation of passive sampling within schools is based on the reasonable assumption of similar exposures outside of school hours. While introducing an additional element of uncertainty, this is likely to be small in comparison with those addressed in the PODs, though the approach is limited to the extent that peak exposures are not well addressed in the monitoring strategy. Recommended methods of analysis were selected based on commonly used and practical methods providing adequate quantitative characterization with an appropriate detection limit at a reasonable cost. The priority of methods in decreasing order is: ♦ methods of the ISO and the European Committee for Standardization (CEN) ♦ national methods authorized according to national standards ♦ methods published in peer-reviewed journals. While benzo(a)pyrene is included in the list of priority substances, the screening tool is restricted to the gaseous phase and does not yet address particulate matter for combined exposure assessment. While requiring active sampling and being mainly particulate in nature (35), benzo(a)pyrene is considered a marker for PAHs, which are indoor air pollutants of interest, particularly in the vicinity of combustion sources. 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International Toxicity Estimates for Risk [database]. Cincinnati: Toxicology Excellence for Risk Assessment; 2020 (http://www.iter.tera.org/, accessed 15 October 2020). 32. Agreed EU-LCI values – substances with their established EU-LCI values and summary fact sheets. Luxembourg: Publications Office of the European Union; 2019 (https://ec.europa.eu/docsroom/documents/39985, accessed 15 October 2020). 33. Committee for Risk Assessment [website]. Helsinki: ECHA; 2020 (https://echa.europa. eu/about-us/who-we-are/committee-for-risk-assessment, accessed 15 October 2020). 34. European Classification and Labelling (C&L) Inventory [database]. Helsinki: ECHA; 2020 (https://echa.europa.eu/information-on-chemicals/cl-inventory-database, accessed 15 October 2020). 35. Methods for sampling and analysis of chemical pollutants in indoor air. Supplementary publication to the screening tool for assessment of health risks from combined exposure to multiple chemical in indoor air. Copenhagen: WHO Regional Office for Europe; 2020 (https://apps.who.int/iris/bitstream/hand le/10665/334389/9789289055239-eng.pdf?sequence=1&isAllowed=y, assessed 12 October 2020). 36. Methods for monitoring indoor air quality in schools. Meeting report. Copenhagen: WHO Regional Office for Europe; 2011 (http://www.euro.who.int/__data/assets/pdf_ file/0011/147998/e95417.pdf, accessed 15 October 2020). 37. ISO 16000-1:2004. Indoor air – Part 1: General aspects of sampling strategy. Geneva: International Organization for Standardization; 2020 (https://www.iso.org/ standard/39844.html, accessed 15 October 2020). 25 ANNEX 1: SELECTION OF SUBSTANCES TO BE INCLUDED THE SCREENING TOOL’S SUPPORTING DATABASE OF TOXICOLOGICAL INFORMATION Table A1.1. List of most common indoor air pollutants identified through the literature review prior to the first consultation (1) No. Substance (alphabetical order) CAS number No. Substance (alphabetical order) CAS number 1 1-butanol 71-36-3 27 Benzyl butyl phthalate 85-68-7 2 1,2,3-trimethylbenzene 526-73-8 28 Butyl acetate 123-86-4 3 1,4-dichlorobenzene 106-46-7 29 Butyraldehyde 123-72-8 4 4-(1,2-dibromoethyl)-1,2- dibromocyclohexane 3322-93-8 30 Cadmium 7440-43-9 5 4,4'-dichloro- diphenyltrichloroethane 50-29-3 31 Camphene 79-92-5 6 Acenaphthene 83-32-9 32 Carbon 124-38-9 7 Acenaphthylene 208-96-8 33 Chrysene 218-01-9 8 Acetaldehyde 75-07-0 34 CO 630-08-0 9 Alpha hexachlorocyclohexane (HCH) (or α-HCH) 319-84-6 35 d-limonene 5989-27-5 10 Anthracene 120-12-7 36 Di-isodecyl phthalate 26761-40-0 11 Arsenic 7440-38-2 37 DEHP 117-81-7 12 Brominated diphenyl ether (BDE) 28 41318-75-6 38 Dibenz[a,h]anthracene 53-70-3 13 BDE 47 5436-43-1 39 Dibenzo[a,l]pyrene 191-30-0 14 BDE 99 60348-60-9 40 DiBP 84-69-5 15 BDE 100 189084-64-8 41 Diethyl phthalate (DEP) 84-66-2 16 BDE 153 68631-49-2 42 Diisononyl phthalate 28553-12-0 17 BDE 183 207122-16-5 43 Dimethyl phthalate 131-11-3 18 BDE 209 1163-19-5 44 DnBP 84-74-2 19 Benz[a]anthracene 56-55-3 45 Ethylacetate 141-78-6 20 Benzene 71-43-2 46 Ethylbenzene 100-41-4 21 Benzo[a]pyrene 50-32-8 47 Fluoranthene 206-44-0 22 Benzo[b+ j]fluoranthene 205-99-2/205- 82-3 48 Fluorene 86-73-7 23 Benzo[b+j+k]fluoranthene 205-99-2/205- 82-3/207-08-9 49 Formaldehyde 50-00-0 24 Benzo[e]pyrene 192-97-2 50 Galaxolide 1222-05-5 25 Benzo[ghi]perylene 191-24-2 51 Gamma HCH (or γ-HCH) 134237-52-8 26 Benzo[k]fluoranthene 207-08-9 52 Heptane 142-82-5 A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 26 Table A1.1 cont. No. Substance (alphabetical order) CAS number No. Substance (alphabetical order) CAS number 53 Hexabromobenzene 201-773-9 71 PCB 138 35065-28-2 54 Hexaldehyde 66-25-1 72 Permethrin 52645-53-1 55 Indeno[1,2,3-cd]pyrene 193-39-5 73 Phenanthrene 85-01-8 56 Limonene 138-86-3 74 PM1 – 57 m,p-xylenes 108-38-3/106- 42-3 75 PM2.5 – 58 Methylacetate 79-20-9 76 PM10 – 59 n-butylbenzene 104-51-8 77 Pyrene 129-00-0 60 n-decane 124-18-5 78 SO2 7446-09-5 59 n-butylbenzene 104-51-8 79 Styrene 100-42-5 60 n-decane 124-18-5 80 Tetrachloroethylene 127-18-4 51 Naphthalene 91-20-3 81 Toluene 108-88-3 62 Nickel 7440-02-0 82 Tonalide 21145-77-7 63 NO2 10102-44-0 83 Total suspended particles – 64 o-xylene 95-47-6 84 Tri-(2-butoxyethyl)- phosphate 78-51-3 65 O3 10028-15-6 85 Tributylphosphate 126-73-8 66 Particles (number) – 86 Trichloroethylene 79-01-6 67 PCB 28 7012-37-5 87 Tris(1-chloro-2-propyl) phosphate 13674-84-5 68 PCB 31 16606-02-3 88 Tris(2-chloroethyl) phosphate 115-96-8 69 PCB 52 35693-99-3 89 Ultrafine particles – 70 PCB 101 37680-73-2 90 α-pinene 80-56-8 27 Table A1.2. List of most common co-occurring indoor air pollutants identified through the literature review prior to the first consultation (1) Chemical family Number of measured compounds Chemical family Number of measured compounds Aldehydes 15 Polycyclic aromatic hydrocarbons (PAHs) 19 Aromatic hydrocarbons 12 Organophosphates 8 Alkanes 14 Brominated flame retardants 28 Terpenes 5 Perfluorinated compounds 11 Halogenated hydrocarbons 6 Non-phthalate plasticizers 8 Ester alcohols 2 Phthalates 7 Esters 2 Polychlorinated biphenyls (PCBs) 9 Ketones 4 Musks 2 Alcohols 4 Organochlorine pesticides 7 Glycol ether 1 Pyrethroids 5 Siloxanes 3 Table A1.3. Prioritized list of substances for discussion at the first expert consultation (1,2) No. Substance Number of recordings No. Substance Number of recordings 1 Formaldehyde 24 17 Limonene 4 2 NO2 20 18 n-decane 4 3 PM10 19 19 Acetaldehyde 3 4 PM2.5 17 20 BDE 47 3 5 Benzene 11 21 Benzo(a)pyrene 3 6 O3 10 22 Naphthalene 3 7 CO 7 xx o-xylene* 3 8 m, p-xylenes 7 xx d-limonene* 2 9 Styrene 7 23 Phenanthrene 2 10 Toluene 7 24 Trichloroethylene 2 11 1,4-dichlorobenzene 6 25 DEP 2 12 Ethylbenzene 6 26 DiBP 2 13 Butyl acetate 5 27 DnBP 2 14 Tetrachloroethylene 5 28 Galaxolide 1 15 α-pinene 5 29 SO2 1 16 1,2,3-trimethylbenzene 4 30 Tonalide 1 * The two substances in grey font (o-xylene and d-limonene) are accounted respectively with m,p-xylenes and limonene. A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 28 Table A1.4. List of priority substances recommended for early inclusion in the screening tool by the first expert consultation (2) No. Chemical family Chemical group Substance CAS number 1 Oxygenated volatile organic compounds (oxi-VOCs) Aldehydes Formaldehyde 50-00-0 2 Acetaldehyde 75-07-0 3 VOCs Aromatic hydrocarbons Benzene 71-43-2 4 Ethylbenzene 100-41-4 5 o-xylenes 95-47-6 6 m,p-xylenes 108-38-3/106-42-3 7 Styrene 100-42-5 8 Toluene 108-88-3 9 Terpenes Limonene 138-86-3 10 Α-pinene 80-56-8 11 Chlorinated hydrocarbons Tetrachloroethylene 127-18-4 12 Trichloroethylene 79-01-6 13 PAHs Naphthalene 91-20-3 14 Semi-VOCs PAHs Benzo(a)pyrene 50-32-8 15 Particulate matter PM10 – 16 PM2.5 – 17 Inorganic compounds CO 630-08-0 18 NO2 10102-44-0 19 O3 10028-15-6 29 Table A1.5. List of chemicals that should be included in the tool when possible (the wish list) (2) No. Priority Chemical family Substances CAS number 1 1 Phthalates Diethyl phthalate (DEP) 84-66-2 2 Diisobutyl phthalate (DiBP) 84-69-5 3 Di-n-butyl phthalate (DnBP) 84-74-2 4 2 Musks Galaxolide 1222-05-5 5 Tonalide 21145-77-7 6 3 PAHs Acenaphthene 83-32-9 7 Acenaphthylene 208-96-8 8 Phenantrene 85-01-8 9 Anthracene 120-12-7 10 Benz[a]anthracene 56-55-3 11 Benzo[b]fluoranthene 205-99-2 12 Benzo[j]fluoranthene 205-82-3 13 Benzo[e]pyrene 192-97-2 14 Benzo[ghi]perylene 191-24-2 15 Benzo[k]fluoranthene 207-08-9 16 Chrysene 218-01-9 17 Dibenz[a,h]anthracene 53-70-3 18 Dibenzo[a,l]pyrene 191-30-0 20 Fluoranthene 206-44-0 21 Fluorene 86-73-7 22 Indeno[1,2,3-cd]pyrene 193-39-5 23 Pyrene 129-00-0 24 4 Brominated flame retardants BDE 28 41318-75-6 25 BDE 47 5436-43-1 26 BDE 99 60348-60-9 27 BDE 100 189084-64-8 28 BDE 153 68631-49-2 29 BDE 183 207122-16-5 30 BDE 209 1163-19-5 31 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (DBE-DBCH) 3322-93-8 32 Organophosphates Tributyl phosphate 126-73-8 33 Tris(2-butoxyethyl) phosphate (TBEP) 78-51-3 34 Tris(1-chloropropan-2-yl) phosphate (TCPP) 13674-84-5 35 Tris(2-chloroethyl) phosphate (TCEP) 115-96-8 36 5 Chlorinated paraffins Short-chain chlorinated paraffins (C10-13) – Medium-chain chlorinated paraffins (C14-17) – Long-chain chlorinated paraffins (C18-30) – A SCREENING TOOL FOR ASSESSMENT OF HEALTH RISKS FROM COMBINED EXPOSURE TO MULTIPLE CHEMICALS IN INDOOR AIR IN PUBLIC SETTINGS FOR CHILDREN: METHODOLOGICAL APPROACH 30 Table A1.6. Additional chemical compounds that can be determined using the same analytical methods as the priority list noted by the first consultation (2) Chemical family Substances CAS number VOCs Aldehydes Butyraldehyde 123-72-8 Hexaldehyde 66-25-1 Aromatic hydrocarbons 1,2,3-trimethylbenzene 526-73-8 1,4-dichlorobenzene 106-46-7 n-butyl benzene 104-51-8 Alcohols 1-butanol 71-36-3 Esters Ethylacetate 141-78-6 Methylacetate 79-20-9 Butyl acetate 123-86-4 Alkans Heptane 142-82-5 References 1. Literature review on chemical pollutants in indoor air in public settings for children and overview of their health effects (with a focus on schools, kindergartens and day-care centres). Supplementary publication to the screening tool for assessment of health risks from combined exposure to multiple chemicals in indoor air. Copenhagen: WHO Regional Office for Europe; 2021. 2. Towards a screening tool for assessment of cumulative risks from indoor air pollutants in public settings for children: the first expert consultation. Meeting report. Copenhagen: WHO Regional Office for Europe; 2019 (http://www.euro.who.int/__data/ assets/pdf_file/0020/410780/Indoor-air-pollutants-public-children-first-consulation- report.pdf, accessed 15 October 2020). The WHO Regional Office for Europe The World Health Organization (WHO) is a specialized agency of the United Nations creted in 1948 with the primary responsibility for international health matters and public health. The WHO Regional Office for Europe is one of six regional offices throughout the world, each with its own programme geared to the particular health conditions of the countries it serves. 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