IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

Transcription

1 IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ILO UNEP Environmental Health Criteria 240 Principles and Methods for the Risk Assessment of Chemicals in Food Front Matters Preamble, Preface, Table of Content A joint publication of the Food and Agriculture Organization of the United Nations and the World Health Organization

2 This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization or the World Health Organization. Environmental Health Criteria 240 PRINCIPLES AND METHODS FOR THE RISK ASSESSMENT OF CHEMICALS IN FOOD A joint publication of the Food and Agriculture Organization of the United Nations and the World Health Organization Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. F I A T I S PA N Food and Agriculture Organization of the United Nations

3 The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO) and the World Health Organization (WHO). The overall objec tives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organiza tion of the United Nations, WHO, the United Nations Industrial Development Organi zat ion, the United Nations Institute for Training and Research and the Organisa tion for Economic Co-operation and Development (Participating Organizations), followi ng recommendations made by the 1992 UN Conference on Environment and Develop ment to strengthen coop era tion and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organi zations, jointly or separately, to achieve the sound manage ment of chemicals in relation to human health and the environment. WHO Library Cataloguing-in-Publication Data Principles and methods for the risk assessment of chemicals in food. (Environmental health criteria ; 240) 1. Risk assessment. 2. Hazard assessment. 3. Exposure assessment. 4. Dose-response assessment. 5. Chemicals. 6. Food safety. 7. Food additives. 8. Contaminants. 9. Pesticide residues. 10. Veterinary drug residues. I.World Health Organization. II.Food and Agriculture Organization of the United Nations. ISBN (NLM classification: WA 712) ISSN X World Health Organization 2009 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: ; fax: ; bookorders@who.int). Requests for permission to reproduce or translate WHO publications whether for sale or for noncommercial distribution should be addressed to WHO Press, at the above address (fax: ; permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This document was technically and linguistically edited by Marla Sheffer, Ottawa, Canada. Printed by Wissenchaftliche Verlagsgesellschaft mbh, Stuttgart, Germany.

4 CONTENTS ENVIRONMENTAL HEALTH CRITERIA ON PRINCIPLES AND METHODS FOR THE RISK ASSESSMENT OF CHEMICALS IN FOOD PREAMBLE PREFACE ACRONYMS AND ABBREVIATIONS SUMMARY xix xxxiii xxxv xliii 1. INTRODUCTION The need for updated guidance on risk assessment Development of the monograph Purpose, scope and outline of the monograph Purpose Scope Outline Historical background to the work of JECFA and JMPR JECFA JMPR Relevant activities since the publication of EHC 70 and EHC Evaluation of veterinary drug residues Dietary exposure assessments Assessment of acute toxicity Evaluation of flavouring agents Framework for identification, evaluation, development and incorporation of new principles and methods References 1-17 iii

5 EHC 240: Principles for Risk Assessment of Chemicals in Food 2. RISK ASSESSMENT AND ITS ROLE IN RISK ANALYSIS Introduction Definitions of hazard and risk Role of risk assessment in risk analysis for food chemicals The four steps of risk assessment for food chemicals Hazard identification Hazard characterization Exposure assessment Risk characterization Interactions between risk assessment and risk management Problem formulation Priority setting for JECFA and JMPR Periodic reviews and specific re-evaluations References CHEMICAL CHARACTERIZATION, ANALYTICAL METHODS AND THE DEVELOPMENT OF SPECIFICATIONS Introduction Criteria for the review of analytical methods and required technical competence of testing laboratories The significance of multilaboratory method trials and collaborative studies Food additive specifications General considerations Formulation of specifications and information requirements Stability and fate of additives in food Analytical methods Pesticide characterization General considerations Identity and purity Stability Physical and chemical properties 3-15 iv

6 3.5.5 Analytical methods Veterinary drug residues General considerations Analytical methods Contaminants General considerations Analytical methods Substances consumed in large amounts References HAZARD IDENTIFICATION AND CHARACTERIZATION: TOXICOLOGICAL AND HUMAN STUDIES Introduction Nature of substances to be evaluated Knowledge requirements for substances to be tested and evaluated Role of structure activity relationships and metabolic fate Integrating data on dietary exposure General approach to toxicity testing Role of in silico and in vitro studies Digestion and impact on gut flora Absorption, distribution, metabolism and excretion (ADME) Considerations in the selection of appropriate in vivo studies and relevant species (models) Types of animal studies and their role in safety assessment Role of human studies Absorption, distribution, metabolism and excretion (including residues of toxicological concern) Introduction Absorption Distribution Metabolism 4-26 v

7 EHC 240: Principles for Risk Assessment of Chemicals in Food Excretion Overall elimination from the body The role of toxicokinetic studies in the design of animal toxicity tests The role of toxicokinetic studies in the interpretation of data from animal toxicity studies Route-to-route extrapolation General systemic toxicity Introduction Tests for general systemic toxicity Testing strategies Study design and data interpretation Good Laboratory Practice Test substance Species, number and sex Dose selection Administration of the test substance Observations and measurements Mortality Observations of test animals Body weight and feed intake data Ophthalmology Haematology Clinical chemistry Urinalyses Necropsy Organ weight Histological examination Neurotoxicity and immunotoxicity Reversibility Other considerations Acute toxicity Introduction Guidance for a single-dose study Genotoxicity Introduction Tests for genetic toxicity Test categories 4-53 vi

8 Commonly used tests Testing strategy Data assessment Cytogenetic assays in vivo and in vitro Germline and somatic cell in vivo cytogenetic assays In vivo gene mutation assays in germline cells Genetic toxicity in relation to carcinogenicity Validation of genetic toxicity tests for the prediction of carcinogenicity Evidence of mode of action Conclusions Carcinogenicity Introduction Mechanisms of carcinogenicity and mode of action Genotoxic or DNA-reactive mechanisms Non-genotoxic mechanisms Chronic bioassays for the identification and characterization of cancer risk Statistical methods Evaluation Interpretation Alternative methods for carcinogenicity testing Initiation/promotion models Neonatal mouse model Transgenic mouse models Interpretation of the data from alternative methods End-points in carcinogenicity studies Spontaneous neoplasms Pathological classification of neoplasms Benign and malignant neoplasms Preneoplastic lesions 4-70 vii

9 EHC 240: Principles for Risk Assessment of Chemicals in Food Characterization of carcinogenic effects Mechanisms relevant to humans Mechanisms not relevant to humans Assessment of carcinogenic response Nature of the test substance Relevance of study design Are the tumours substance related? Can a mode of action for the tumour response be established? Is the mode of action relevant to humans? Historical control data Reproductive and developmental toxicity Introduction End-points of concern Study design Overview Reproductive toxicity Developmental toxicity Tiered and combined approaches to reproductive and developmental toxicity testing Endocrine toxicity Issues specific to category of chemical Interpretation of data Other considerations In vitro tests Paternally mediated effects Information gaps Neurotoxicity Introduction Nervous system features Evaluation of neurotoxicity Morphological evaluations Neurobehavioural evaluation Developmental neurotoxicity Tiered testing strategy Cholinesterase-inhibiting compounds Alternative test methods viii

10 4.8.7 Interpretation of data Immunotoxicity Introduction Assessment of immunotoxicity Laboratory animal studies Human studies Interpretation of data on immunotoxicity Conclusions Food allergy and other food hypersensitivities Introduction Prevalence IgE-mediated food allergy Sensitization Symptoms and diagnosis Common characteristics of food allergens Thresholds Risk assessment in food allergy Evaluating potential allergenicity of genetically modified food Non-IgE-mediated food allergy Coeliac disease Non-immune-mediated food hypersensitivity Metabolic disorders Other General principles of studies in humans Introduction Lessons learnt from pharmaceutical development Types of studies in humans Short-term clinical laboratory studies More prolonged clinical laboratory studies Post-marketing surveillance and epidemiological studies Other sources of information about effects in humans Poisoning ix

11 EHC 240: Principles for Risk Assessment of Chemicals in Food Human tissues and other preparations in vitro Ethical, legal and regulatory issues Gastrointestinal tract considerations, including effects on the gut flora General considerations Effects of the gut microflora on the chemical Effects of the chemical on the gut microflora Decision tree approach for determining the potential adverse effects of residues of veterinary antimicrobial drugs on the human intestinal microflora References DOSE RESPONSE ASSESSMENT AND DERIVATION OF HEALTH-BASED GUIDANCE VALUES Dose response assessment Basic concepts of dose response assessment Dose Response Dose response modelling (DRM) Overview Mathematical models Dose response models for continuous data Dose response models for quantal data Model fitting and estimation of parameters Modelling with covariates Biologically based dose response models Uncertainty Issues of extrapolation Setting health-based guidance values Introduction Data Safety/uncertainty factors 5-24 x

12 5.2.4 The NOAEL approach to deriving healthbased guidance values Benchmark dose approach to deriving health-based guidance values Acceptable daily intakes Food additives Pesticides Veterinary drug residues Tolerable intakes Group ADIs/TIs Setting of acute reference doses (ARfDs) General considerations Practical cut-off value for ARfDs Biological and toxicological considerations Stepwise process for setting ARfDs Toxicological end-points relevant for ARfD derivation Uncertainty factors for ARfDs Different ARfDs for population subgroups Use of human data in setting ARfDs Intake considerations in relation to ARfDs Specific guidance on the derivation of ARfDs References DIETARY EXPOSURE ASSESSMENT OF CHEMICALS IN FOOD Introduction General considerations Dietary exposure assessment methods Presentation of results of dietary exposure assessment Data sources Data on concentrations of chemicals in food, including water 6-7 xi

13 EHC 240: Principles for Risk Assessment of Chemicals in Food Use of maximum levels (MLs) or maximum residue limits (MRLs) in dietary exposure assessments (preregulation) Use of other concentration data sources for dietary exposure assessments (preregulation and post-regulation) Approaches for obtaining food chemical concentration data Sampling Analysis Deriving concentration data for use in estimating dietary exposures Uncertainty in food chemical concentration data Available food composition databases Food consumption data Food consumption data requirements Approaches for food consumption data collection Data reporting and use Usual food consumption patterns Food consumption databases Estimating dietary exposure Introduction Considerations when undertaking an exposure assessment Stepwise approach to exposure assessment Deterministic/point estimates of dietary exposure Screening methods More refined deterministic/point estimates Further examples of point estimates using model diets Specialized studies designed to answer specific questions 6-60 xii

14 6.3.5 Refined dietary exposure assessments (probabilistic distributional analyses) Overview of probabilistic estimates of exposure Probabilistic models Applicability of a probabilistic approach at the international level Specific considerations for modelling approaches for acute and chronic dietary exposure assessments Chronic dietary exposure assessments Acute dietary exposure assessments Aggregate/cumulative exposures Biomarkers of exposure References 6-77 Appendix 6.1: Acute dietary exposure estimates currently used by JMPR RISK CHARACTERIZATION Introduction Risks at estimated levels of exposure General considerations Uncertainty and variability analysis Sensitivity analysis Risks from exposure to multiple substances General considerations Toxic equivalency factor (TEF) approach Surrogate approach The formulation of advice on compounds that are both genotoxic and carcinogenic Subpopulations at risk References MAXIMUM RESIDUE LIMITS FOR PESTICIDES AND VETERINARY DRUGS Introduction Overview of current principles and practice of JMPR and JECFA for residue evaluation 8-3 xiii

15 EHC 240: Principles for Risk Assessment of Chemicals in Food JMPR assessment processes for pesticide residues JECFA assessment processes for residues of veterinary drugs Comparison of JMPR and JECFA approaches Identification and description of residues and methods Residue definition, chemical identity and physicochemical properties Marker residue Definition of residues for dietary intake Pharmacokinetic, toxicokinetic and metabolic data used to determine the residue definition Pharmacokinetics, toxicokinetics and metabolism Purpose of livestock metabolism studies for veterinary drug and pesticide evaluation Purpose of plant metabolism studies Analytical methods and residue stability in stored analytical samples Method performance requirements Analyte stability Fate of residues during commercial food processing Field study data used to identify the MRL: livestock feeding studies and animal treatments Criteria for selecting data, species and commodities Comparability of definitions for species, tissues and commodities of foods of animal origin Meat and muscle Milk Eggs Aquatic species 8-41 xiv

16 Edible offal Data evaluation based on the application of GLP, GAP and GPVD JMPR JECFA Direct external animal treatment dossier submissions to JMPR and JECFA Extrapolation issues Proposal for expanding the scope of MRLs Pesticide residues Residues of veterinary drugs Possible extension of MRLs to other animal species Honey Geographic extrapolation Pesticide residues Veterinary drug residues References PRINCIPLES RELATED TO SPECIFIC GROUPS OF SUBSTANCES Special considerations for substances consumed in small amounts Threshold of toxicological concern (TTC) Flavouring agents The JECFA procedure for safety evaluation Consideration of dietary exposure estimates Food contact materials/packaging migrants Processing aids Solvents Enzymes Immobilizing agents Special considerations for nutrients and substances consumed in large amounts Introduction Chemical composition, specifications and impurities 9-22 xv

17 EHC 240: Principles for Risk Assessment of Chemicals in Food Nutritional studies Toxicity studies Nutrients and related substances Adverse health effects of nutrients and related substances general concepts Deriving the UL Foods from novel sources Chemical composition Nutritional considerations Toxicological evaluations Human data History of use Exposure assessment Risk characterization References 9-45 Annex 1: Glossary of terms A-1 Annex 2: Dose conversion table A-43 Résumé R-1 Resumen R-35 Index I-1 xvi

18 NOTE TO READERS OF THIS CRITERIA MONOGRAPH The individual chapters of this monograph can largely stand alone; hence, a table of contents and reference list are included in each chapter, and some duplication may occur in the overall text. This publication will also be made available electronically, and individual chapters will be independently updated when the need arises. Every effort has been made to present the information in this criteria monograph as accurately as possible without unduly delaying its publication. In the interest of all users of this Environmental Health Criteria monograph, readers are requested to communicate any errors that may have occurred to the Director of the Department of Food Safety and Zoonoses, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda. xvii

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20 Environmental Health Criteria PREAMBLE Objectives In 1973, the WHO Environmental Health Criteria Programme was initiated with the following objectives: (i) to assess information on the relationship between exposure to environmental pollutants and human health, and to provide guide lines for setting exposure limits; (ii) to identify new or potential pollutants; (iii) to identify gaps in knowledge concerning the health effects of pollutants; (iv) to promote the harmonization of toxicological and epidemiological methods in order to have internationally comparable results. The first Environmental Health Criteria (EHC) monograph, on mercury, was published in 1976, and since that time an ever-increasing number of assessments of chemicals and of physical effects have been produced. In addition, many EHC monographs have been devoted to evaluating toxicological methodology, e.g. for genetic, neurotoxic, teratogenic, and nephrotoxic effects. Other publications have been concerned with epidemiological guidelines, evaluation of short-term tests for carcinogens, biomarkers, effects on the elderly, and so forth. Since its inauguration, the EHC Programme has widened its scope, and the importance of environmental effects, in addition to health effects, has been increasingly emphasized in the total evaluation of chemicals. The original impetus for the Programme came from World Health Assembly resolutions and the recommendations of the 1972 UN Conference on the Human Environment. Subsequently, the work became an integral part of the International Programme on Chemical Safety (IPCS), a cooperative programme of WHO, ILO, and UNEP. In xix

21 EHC 240: Principles for Risk Assessment of Chemicals in Food this manner, with the strong support of the new partners, the importance of occupational health and environmental effects was fully recognized. The EHC monographs have become widely established, used, and recognized throughout the world. The recommendations of the 1992 UN Conference on Environment and Development and the subsequent establishment of the Intergovernmental Forum on Chemical Safety with the priorities for action in the six programme areas of Chapter 19, Agenda 21, all lend further weight to the need for EHC assessments of the risks of chemicals. Scope Two different types of EHC documents are available: 1) on specific chemicals or groups of related chemicals; and 2) on risk assessment methodologies. The criteria monographs are intended to provide critical reviews on the effect on human health and the environment of chemicals and of combinations of chemicals and physical and biological agents and risk assessment methodologies. As such, they include and review studies that are of direct relevance for evaluations. However, they do not describe every study carried out. Worldwide data are used and are quoted from original studies, not from abstracts or reviews. Both published and unpublished reports are considered, and it is incumbent on the authors to assess all the articles cited in the references. Preference is always given to published data. Unpublished data are used only when relevant published data are absent or when they are pivotal to the risk assessment. A detailed policy statement is available that describes the procedures used for unpublished proprietary data so that this information can be used in the evaluation without compromising its confidential nature (WHO (1990) Revised Guidelines for the Preparation of Environmental Health Criteria Monographs. PCS/90.69, Geneva, World Health Organiza tion). In the evaluation of human health risks, sound human data, whenever available, are preferred to animal data. Animal and in vitro studies provide support and are used mainly to supply evidence missing from human studies. It is mandatory that research on human subjects is conducted in full accord with ethical principles, including the provisions of the Declaration of Helsinki. xx

22 The EHC monographs are intended to assist national and international authorities in making risk assessments and subsequent risk management decisions. They represent a thorough evaluation of risks and are not, in any sense, recommendations for regulation or standard setting. These latter are the exclusive purview of national and regional governments. Procedures The procedures described below were followed in the development and publication of this EHC. A designated WHO Staff Member, Dr Sam Page and subsequently Dr A. Tritscher, served as the Responsible Officer (RO) at WHO. At the Food and Agriculture Organization of the United Nations (FAO), the ROs were Dr M. Lützow and subsequently Dr A. Wennberg. These ROs are responsible for the scientific content of the document. The editor was responsible for layout and language. A public web site was created to inform progress on the project. FAO and WHO held a planning meeting of international experts with experience in the risk assessment activities of the Joint FAO/ WHO Expert Committee on Food Additives (JECFA) and the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) on November 2001 at WHO Headquarters in Geneva, Switzerland, to define the scope of the project and develop a project plan. A steering group was then formed, which accompanied and guided the project until its completion. A series of workshops were held to develop the basis for the key chapters. In addition, drafters were commissioned for certain subchapters, and these drafts were subsequently peer reviewed by the steering group and/or by invited experts. Once all chapters had been drafted, four experts familiar with the project as well as with the methods and procedures applied by JECFA and JMPR were commissioned for an overall review. Subsequently, two experts were commissioned to compile and write the first draft of the monograph based on existing chapters and taking into account comments from reviewers and the steering group. This draft monograph was then made available on the IPCS web site for external review and comment. Comments received are available on request from the WHO Secretariat. They were reviewed by an expert meeting held on November 2008 in Seoul, Republic of xxi

23 EHC 240: Principles for Risk Assessment of Chemicals in Food Korea, and necessary additions and revisions to the document were made. All experts who contributed to this monograph served as individual scientists, not as representatives of any organization, government or industry. Every attempt was made to ensure that all individuals who, as authors, consultants or advisers, participated in the preparation of this EHC monograph informed the WHO Secretariat if at any time a conflict of interest, whether actual or potential, could be perceived in their work. xxii

24 TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA ON PRINCIPLES AND METHODS FOR THE RISK ASSESSMENT OF CHEMICALS IN FOOD Dr S. Page, IPCS, and Dr A. Tritscher, Department of Food Safety and Zoonoses, served as the Responsible Officers (ROs) for WHO, and Dr M. Lützow and Dr A. Wennberg served as the ROs for FAO. The ROs were responsible for the preparation of the final document and for its overall scientific content. Marla Sheffer, Ottawa, Canada, was the IPCS editor responsible for layout and language. * * * Risk assessment activities of IPCS are supported financially by the Department of Health, Department for Environment, Food & Rural Affairs and Food Standards Agency, United Kingdom; Environmental Protection Agency, Food and Drug Administration and National Institute of Environmental Health Sciences, United States of America (USA); European Commission; German Federal Ministry of Environment, Nature Conservation and Nuclear Safety; Health Canada; Japanese Ministry of Health, Labour and Welfare; and Swiss Agency for Environment, Forests and Landscape. Specific support for this project was received from the United Kingdom Food Standards Agency, the United States Food and Drug Administration, the Republic of Korea Food and Drug Administration and the Netherlands National Institute for Public Health and the Environment. Steering group members * * * Dr D. Arnold, Federal Institute for Health Protection of Consumers & Veterinary Medicine, Berlin, Germany Professor J. Bend, Department of Pathology, Siebens-Drake Medical Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada Dr M. Bolger, Food and Drug Administration, United States Department of Health and Human Services, College Park, Maryland, USA xxiii

25 EHC 240: Principles for Risk Assessment of Chemicals in Food Dr E. Boutrif, Food Quality and Standards Service, Food and Nutrition Division, Food and Agriculture Organization of the United Nations, Rome, Italy Mr D. Hamilton, Department of Primary Industries, Brisbane, Australia Dr J.-L. Jouve, Chief, Food Quality and Standards Service, Food and Nutrition Division, Food and Agriculture Organization of the United Nations, Rome, Italy (retired) Dr M. Lützow, Consultant, Neuenhof, Switzerland Dr T. Meredith, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Dr B. Petersen, Exponent, Inc., Washington, DC, USA Dr G. Vaagt, Pesticide Management Group, Food and Agriculture Organization of the United Nations, Rome, Italy Professor R. Walker, School of Biological Sciences, Guildford, Surrey, England Dr Y. Yamada, National Food Research Institute, Tsukuba, Japan Secretariat Dr M. Choi, Department of Food Safety and Zoonoses, World Health Organization, Geneva, Switzerland Dr S. Page, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Dr A. Tritscher, Department of Food Safety and Zoonoses, World Health Organization, Geneva, Switzerland Dr A. Wennberg, Nutrition and Consumer Protection Division, Food and Agriculture Organization of the United Nations, Rome, Italy Other contributors The contributors to this monograph are listed below. Those who submitted written comments in response to a request for public comments are also acknowledged below. xxiv

26 Invited reviewers of the draft chapters were Dr S. Barlow, Dr A. Boobis, Dr J. Herrman and Dr J. Weatherwax. Dr S. Barlow and Professor A. Renwick compiled and prepared the first draft of the monograph based on the draft chapters and taking into account comments from reviewers and the steering group. Legend 1 Participant in: Workshop I, London, 9 13 December 2002: Joint FAO/WHO Project to Update Principles and Methods for the Risk Assessment of Chemicals in Food (basis for chapter 4) 2 Participant in: Joint FAO/WHO Expert Consultation: Dietary Exposure Assessment of Chemicals in Food, Annapolis, Maryland, USA, 2 6 May 2005 (basis for chapter 6) 3 Participant in: Joint FAO/WHO Expert Consultation: MRLs for Pesticides and Veterinary Drugs, Bilthoven, the Netherlands, 7 10 November 2005 (basis for chapter 9) 4 Participant in: Workshop on Principles for Modelling Dose Response for the Risk Assessment of Chemicals, Geneva, September 2004 (basis for chapter 5) 5 Participant in: Final Expert Meeting, November 2008, Seoul, Republic of Korea 6 Drafter of section or chapter (chapter indicated in parentheses) Dr A. Ambrus, Hungarian Food Safety Office, Budapest, Hungary Professor A. Anadón, Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, Spain Dr D. Arnold, Consultant, Berlin, Germany (formerly Federal Institute for Health Protection of Consumers & Veterinary Medicine, Berlin, Germany) (3: Chair) Dr S.A. Assimon, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD, USA Ms J. Baines, Evaluation and Surveillance, Food Standards Australia New Zealand, Canberra, Australia (2: Rapporteur) 2, 3 1 1, 3, 5, 6 (chapter 3) 6 (section 4.10) 2, 5 Dr S. Barlow, Consultant, Brighton, England (5: Chair) 5, 6 (section 4.7) Dr L. Barraj, Exponent, Inc., Washington, DC, USA 2 xxv

27 EHC 240: Principles for Risk Assessment of Chemicals in Food Dr D. Bellinger, Harvard Medical School Children s Hospital, Boston, MA, USA Dr D. Benford, Food Standards Agency, London, England 1, 5 Dr M. Bolger, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD, USA (4: Rapporteur) Professor A. Boobis, Experimental Medicine & Toxicology Division of Investigative Science, Faculty of Medicine, Imperial College, London, England (1,4: Chair) (5: Rapporteur) Dr A. Bruno, FAO Codex Secretariat, Food and Agriculture Organization of the United Nations, Rome, Italy Professor E. Calabrese, University of Massachusetts, Amherst, MA, USA Dr E. Caldas, University of Brasilia, College of Health Sciences, Pharmaceutical Sciences Department, Campus Universitàrio Darci Ribeiro, Brasilia, Brazil Dr C. Carrington, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD, USA Dr C. Cerniglia, Division of Microbiology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA Mrs R. Charrondiere, Nutrition Planning, Assessment and Evaluation Service, Nutrition and Consumer Protection Division, Food and Agriculture Organization of the United Nations, Rome, Italy Professor B. Chen, School of Public Health, Shanghai Medical University, Shanghai, China Dr M.-H. Cho, National Institute of Toxicological Research, Korean Food and Drug Administration, Seoul, Republic of Korea Dr M. Choi, Korean Food and Drug Administration, Seoul, Republic of Korea (formerly Department of Food Safety and Zoonoses, World Health Organization, Geneva, Switzerland) Dr V. Cogliano, Carcinogen Identification and Evaluation, International Agency for Research on Cancer, World Health Organization, Lyon, France Dr J. Cohen, Harvard Center for Risk Analysis, Boston, MA, USA 1 1, 2, 4 1, 4, 5, 6 (sections 4.1, 4.6) 3 4 2, 3 2, 4, 5, 6 (chapter 5) 1, 6 (section 4.12) xxvi

28 Dr R. Crebelli, Unit of Genetic Toxicology, Department of Environment and Primary Prevention, Istituto Superiore di Sanita, Rome, Italy 6 (section 4.5) Professor A. Dayan, Consultant, London, England 1, 6 (section 4.11) Dr D. Deuk Jang, National Institute of Toxicological Research, Korean Food and Drug Administration, Seoul, Republic of Korea Dr M. DiNovi, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD, USA Professor E. Dybing, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway (retired) (4: Rapporteur) Dr L. Edler, Biostatistics Unit, German Cancer Research Center, Heidelberg, Germany Ms S.K. Egan, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD, USA (2: Rapporteur) Dr R. Ellis, Consultant, South Carolina, USA (formerly Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD, USA) (3: Rapporteur) Professor P. Farmer, Department of Biochemistry and Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, England Professor E. Faustman, Department of Environmental and Occupational Health Sciences, School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA (section 4.5) Dr C. Fisher, Consultant, Cambridge, England 1, 6 (chapter 3) Dr S. Funk, Health Effects Division, United States Environmental Protection Agency, Washington, DC, USA Dr G. Gallhoff, Health and Consumer Protection Directorate-General, European Commission, Brussels, Belgium Dr W. Gelderblom, Programme on Mycotoxins and Experimental Carcinogenesis (PROMEC), Tygerberg, South Africa Dr D. Germolec, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA Dr K. Greenlees, Toxicology Team, Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD, USA 4 2, (section 4.9) 3 xxvii

29 EHC 240: Principles for Risk Assessment of Chemicals in Food Mr D. Hamilton, Consultant, Brisbane, Australia (formerly Biosecurity, Department of Primary Industries and Fisheries, Brisbane, Australia) (3: Rapporteur) Dr C.A. Harris, Exponent International Ltd, Harrogate, England Dr G.J. Harry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA Dr M. Healy, Food Standards Australia New Zealand, Canberra, Australia 1, 3, 5, 6 (chapters 1, 8) 3 1, 6 (section 4.8) Dr J. Herrman, Consultant, Placerville, CA, USA 1, 6 (chapter 1) Dr J. Hlywka, Cantox Health Sciences International, Mississauga, Ontario, Canada Mr J. Howlett, Consultant, Surrey, England 4 Dr T. Inoue, Biological Safety Research Centre, National Institute of Health Sciences, Tokyo, Japan Dr S.-H. Jeong, Toxicology Division, National Veterinary Research and Quarantine Service, Ministry of Agriculture & Forestry, Anyang City, Republic of Korea Dr J.-L. Jouve, Food Quality and Standards Service, Food and Nutrition Division, Food and Agriculture Organization of the United Nations, Rome, Italy (retired) Dr M. Kaethner, Bayer CropScience AG, Monheim, Germany Dr R. Kavlock, United States Environmental Protection Agency, Research Triangle Park, NC, USA Dr J. Kleiner, European Food Safety Authority, Parma, Italy 4 Dr A. Knaap, Center for Substances and Integrated Risk Assessment, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands (retired) 4 1, 6 (sections 4.10, 4.11) , 6 (section 4.7) Dr P. Kuznesof, Silver Spring, MD, USA 6 (chapter 3) Dr J. Larsen, National Food Institute, Technical University of Denmark, Soborg, Denmark Dr J.-C. Leblanc, Department for the Evaluation of Nutritional and Health Risks, French Food Safety Agency (AFSSA), Maisons Alfort, France Dr C. Leclercq, Research Group on Food Safety Exposure Analysis, National Institute for Food and Nutrition Research (INRAN), Rome, Italy xxviii

30 Dr H.M. Lee, Risk Assessment Research Team, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Republic of Korea Professor P. Lees, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, England Dr D. Lovell, Postgraduate Medical School, University of Surrey, Surrey, England Dr R. Luebke, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA Dr M. Luster, National Institute for Occupational Safety and Health, Morgantown, WV, USA Dr M. Lützow, Consultant, Neuenhof, Switzerland 1, 3, 5 Dr D. MacLachlan, Australian Quarantine and Inspection Service, Australian Department of Agriculture, Fisheries and Forestry, Kingston, Australia Dr J.D. MacNeil, Center for Veterinary Drug Residues, Canadian Food Inspection Agency, Saskatoon, Saskatchewan, Canada Dr C. Madsen, Institute of Food Safety and Toxicology, Danish Veterinary and Food Administration, Copenhagen, Denmark Dr A. Mattia, Division of Biotechnology and GRAS Notice Review, Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD, USA (section 4.9) 6 (section 4.9) 3 3, 6 (chapter 3) 6 (section 4.10) 1, 6 (section 4.3) Dr D. McGregor, Consultant, Aberdour, Scotland 1, 6 (section 4.5) Dr T. Meredith, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Mr D.J. Miller, United States Environmental Protection Agency, Washington, DC, USA Professor E. Mitema, Department of Public Health, Pharmacology and Toxicology, Faculty of Veterinary Medicine, College of Agriculture and Veterinary Sciences, University of Nairobi, Kenya Dr A. Moretto, Department of Environmental and Occupational Health, University of Milan, International Centre for Pesticides and Health Risk Prevention (ICPS), Milano, Italy Dr G. Moy, Consultant, Geneva, Switzerland (previously Department of Food Safety and Zoonoses, World Health Organization, Geneva, Switzerland) , 2 xxix

31 EHC 240: Principles for Risk Assessment of Chemicals in Food Dr I. Munro, Cantox Health Sciences International, Mississauga, Ontario, Canada (1: Rapporteur) Dr J.L. Nappier, Pfizer Animal Health, Kalamazoo, MI, USA 3 Dr B.C. Ossendorp, Centre for Substances and Integrated Risk Assessment, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands (3: Co-Chair) Dr S. Page, Consultant, New Castle, USA (formerly International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland) Dr B. Petersen, Exponent, Inc., Washington, DC, USA (2: Chair) Professor R. Pieters, University of Utrecht, Utrecht, the Netherlands Dr C. Portier, National Institute for Environmental Health Sciences, Research Triangle Park, NC, USA Professor A. Renwick, Consultant, Ulverston, Cumbria, England Professor F. Reyes, Department of Food Science, State University of Campinas, Campinas, Brazil Ms A. Richter, Federal Institute for Risk Assessment, Berlin, Germany Dr R. Roberts, AstraZeneca R&D, Safety Assessment, Alderly Park, England Dr J.C. Rühl, DuPont Crop Protection, Newark, NJ, USA 2 Professor T. Sanner, Laboratory for Environmental and Occupational Cancer, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway Dr J. Schefferlie, Centre for Substances and Integrated Risk Assessment, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands Dr S. Scheid, Federal Office of Consumer Protection and Food Safety, Berlin, Germany Dr J. Schlatter, Consumer Protection Directorate, Food Safety Division, Nutritional and Toxicological Risks Section, Swiss Federal Office of Public Health, Zürich, Switzerland Dr R. Setzer, Jr, Experimental Toxicology Division, Pharmacokinetics Branch, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, NC, USA 1, 6 (sections 4.1, 9.1) 2, 3 1, 2, 3, 4, 6 (chapters 1, 2) 1, 2 6 (section 4.10) 4 1, 4, 5, 6 (section 4.2, chapters 5, 7) (section 4.6) , 4 4 xxx

32 Professor W. Slob, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands Dr R. Solecki, Safety of Substances and Preparations, Coordination and Overall Assessment, Federal Institute for Risk Assessment, Berlin, Germany Dr A.F. Suárez, Instituto Nacional de Tecnología Agropecuaria, Centro de Agroalimentos, Buenos Aires, Argentina Dr S.F. Sundlof, Center for Food Safety and Applied Nutrition (formerly Center for Veterinary Medicine), Food and Drug Administration, Rockville, MD, USA Dr C. Taylor, Institute of Medicine, The National Academies, Washington, DC, USA Dr A. Tejada, Pesticide Management Group, Plant Protection Service, Plant Production and Protection Division, Food and Agriculture Organization of the United Nations, Rome, Italy (retired) Dr A. Tritscher, Department of Food Safety and Zoonoses (formerly International Programme on Chemical Safety), World Health Organization, Geneva, Switzerland Dr W. van Eck, The Food and Consumer Product Safety Authority, The Hague, the Netherlands Dr R.W. Vannoort, ESR Christchurch Science Centre, Christchurch, New Zealand Dr P. Verger, National Institute for Agricultural Research (INRA), Paris, France Dr J. Vos, Laboratory for Pathology and Immunology, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands Dr A. Wadge, Food Standards Agency, London, England 4 Professor R. Walker, Consultant, Guildford, Surrey, England (formerly School of Biological Sciences, Guildford, Surrey, England) Dr A. Wennberg, FAO Joint Secretary, Food Quality and Standards Service, Nutrition and Consumer Protection Division, Food and Agriculture Organization of the United Nations, Rome, Italy Professor C.P. Wild, International Agency for Research on Cancer, World Health Organization, Lyon, France (formerly University of Leeds, Leeds, England) 4 4, 6 (sections 4.4, 5.2.8) (section 9.2) 1, 2 3, 4, 5, 6 (chapters 1, 2) 6 (chapter 1) 2 2 1, 6 (section 4.9) 1, 5, 6 (section 4.12, chapter 5) 3, 5, 6 (chapter 3) 1 xxxi

33 EHC 240: Principles for Risk Assessment of Chemicals in Food Professor G. Williams, Environmental Pathology and Toxicology, New York Medical College, Valhalla, NY, USA Dr Y. Yamada, Ministry of Agriculture, Forestry and Fisheries, Tokyo, Japan Professor J.-H. Yang, Catholic University of Taegu, Department of Pharmacology/Toxicology, School of Medicine, Namgu Taegu, Republic of Korea Dr H.J. Yoon, Korean Food and Drug Administration, Seoul, Republic of Korea (formerly Department of Food Safety, Zoonoses and Foodborne Diseases, World Health Organization, Geneva, Switzerland) 1, 4, 6 (section 4.6) 1, 6 (chapter 1) The following individuals submitted written comments in response to the request for public comments on the final draft monograph: 5 3 B. Amzal (European Food Safety Authority) Dr K.C. Angelova (Bulgaria) Dr D. Benford (England) A. Bulder (RIKILT Institute of Food Safety, Wageningen, the Netherlands) R. Crebelli (European Food Safety Authority) S. Fabiansson (European Food Safety Authority) Professor P.B. Farmer (England) D. Hamilton (Biosecurity Queensland, Australia) J. Hopkins (Consultant, England) O. Lindtner (Federal Institute for Risk Assessment, Germany) C. Madsen (Denmark) Dr H. Marvin (RIKILT Institute of Food Safety, Wageningen, the Netherlands) D. Morris (New Zealand) J. Nicholas (Committee for Medicinal Products for Veterinary Use) B. Ossendorp (National Institute for Public Health and the Environment, the Netherlands) Dr R.H. Waring (European Food Safety Authority) xxxii

34 PREFACE The International Programme on Chemical Safety (IPCS) was initiated in 1980 as a collaborative programme of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). One of the major objectives of IPCS is to improve scientific methodologies for assessing the effects of chemicals on human health and the environment. As part of this effort, IPCS publishes a series of monographs, called Environmental Health Criteria (EHC) docu ments, that evaluate the scientific principles underlying method ologies and strategies to assess risks from exposure to chemicals. This EHC was prepared in response to a recommendation that the Food and Agriculture Organization of the United Nations (FAO) and WHO should consider updating and harmonizing all the common principles used by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) in the toxicological evaluation of food chemicals and publish the information in a single consolidated document. It updates, harmonizes and consolidates principles and methods for the risk assessment of food additives, food contaminants, natural toxicants and residues of pesticides and veterinary drugs. The efforts of all who helped in the preparation, review, and finalization of the monograph are gratefully acknowledged. Special thanks are due to Health Canada, the Ministry of Health of Japan, the United Kingdom Food Standards Agency and the United States National Institute of Environmental Health Sciences for their financial support of the project. xxxiii