Toxicological Risk Assessment of Chemicals A Practical Guide ß 2007 by Taylor & Francis Group, LLC. ß 2007 by Taylor & Francis Group, LLC. Toxicological Risk Assessment of Chemicals A Practical Guide Elsa Nielsen • Grete Østergaard • John Christian Larsen New York London ß 2007 by Taylor & Francis Group, LLC. Cover: Theophrastus Phillippus Aureolus Bombastus von Hohenheim, known as “Paracelsus” 1493–1541 (“the equal of Celsus”, an early Roman physician). Paracelsus is often called “the father of toxicology.” His famous quotation forms the central dogma of regulatory toxicology: “All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy.”—Paracelsus Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2008 by Informa Healthcare USA, Inc. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Ostergaard, Grete. Toxicological Risk Assessment of Chemicals : a practical guide / Elsa Nielsen, Grete Ostergaard, and John Christian Larsen. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-0-8493-7265-0 (hardcover : alk. paper) ISBN-10: 0-8493-7265-8 (hardcover : alk. paper) 1. Toxicology. 2. Toxicity testing. 3. Health risk assessment. 4. Environmental risk assessment. I. Nielsen, Elsa. II. Larsen, John Christian. III. Title. [DNLM: 1. Hazardous Substances toxicity. 2. Environmental Exposure prevention & control. 3. Risk Assessment methods. 4. Risk Assessment standards. WA 670 O845p 2008] RA1190.O88 2008 615.9 dc22 2007034227 Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com ß 2007 by Taylor & Francis Group, LLC. Contents Preface Acknowledgment Authors Abbreviations and Acronyms Chapter 1 Introduction Reference Chapter 2 International and Federal Bodies Involved in Risk Assessment of Chemical Substances 2.1 World Health Organization 2.1.1 International Programme on Che mical Safety 2.1.2 Food and Agriculture Organization of the United Nations 2.1.3 Joint FAO=WHO Expert Committee on Food Additives 2.1.4 Joint FAO=WHO Meeting on Pesticide Residues 2.1.5 Inter-Organization Programme for the Sound Management of Chemicals 2.1.6 International Agency for Research on Cancer 2.1.7 IPCS: Chemicals Assessment 2.1.7.1 Environmental Health Criteria 2.1.7.2 Concise International Chemical Assessment Document 2.1.7.3 Health and Safety Guide 2.1.7.4 International Chemical Safety Card 2.1.7.5 Pesticide Safety Data Sheet 2.1.7.6 The WHO Recommended Classification of Pesticides by Hazard 2.2 Organisation for Economic Co-operation and Development 2.2.1 The OECD Chemicals Program 2.2.2 Mutual Acceptance of Data 2.2.3 The OECD Existing Chemicals Program 2.2.4 The OECD New Chemicals Program 2.2.5 The OECD Pesticides and Biocides Program 2.2.6 OECD Test Guidelines 2.3 United States of America 2.3.1 United States Environmental Protection Agency 2.3.1.1 Office of Pollution Prevention and Toxics 2.3.1.2 Toxic Substances Control Act 2.3.1.3 Existing Chemicals 2.3.1.4 High Production Volume Challenge Program 2.3.1.5 New Chemicals 2.3.1.6 Integrated Risk Information System 2.3.1.7 Harmonization of US-EPA Risk Assessment 2.3.1.8 US-EPA Risk Assessment Guidelines 2.3.1.9 US-EPA Test Guidelines 2.3.2 Agency for Toxic Substances and Disease Registry ß 2007 by Taylor & Francis Group, LLC. 2.3.3 National Toxicology Program 2.3.4 United States Food and Drug Administration 2.4 The European Union 2.4.1 EU Chemicals Program 2.4.1.1 Actors Involved in Chemical Legislation 2.4.1.2 Current EU Regulatory Framework for Chemicals 2.4.1.3 New EU Regulatory Framework for Chemicals 2.4.1.4 Existing Substances 2.4.1.5 New Substances 2.4.1.6 International Uniform ChemicaL Information Database 2.4.1.7 Biocides and Plant Protection Products 2.4.1.8 Classification and Labeling of Chemical Substances 2.4.1.9 EU Test Guidelines 2.4.2 Harmonization of Risk Assessment in DG SANCO 2.4.2.1 Scientific Committee on Health and Environmental Risks 2.4.2.2 Scientific Committee on Consumer Products 2.4.2.3 Scientific Committee on Emerging and Newly Identified Health Risks 2.4.2.4 EFSA Committees 2.5 Globally Harmonized System of Classification and Labeling of Chemicals 2.6 Precautionary Principle References Chapter 3 Data for Hazard Assessment 3.1 Introduction 3.2 Human Data 3.2.1 Case Reports 3.2.2 Clinical and Physiological Investigations 3.2.3 Studies in Volunteers 3.2.4 Occupational Experience 3.2.5 Epidemiological Studies 3.2.6 Meta-Analysis 3.3 Data from Studies in Experimental Animals 3.3.1 Animal Toxicity Studies 3.3.2 Test Guidelines for Animal Toxicity Studies 3.3.3 Good Laboratory Practice 3.3.4 OECD Test Guidelines 3.3.5 US-EPA Test Guidelines 3.3.6 EU Test Guidelines 3.3.7 Nonguideline Animal Toxicity Studies 3.4 In Vitro Methods 3.4.1 United States Interagency Coordinating Committee on the Validation of Alternative Methods 3.4.2 United States National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods 3.4.3 ICCVAM Review Process 3.4.4 In Vitro Tests Undergoing Validation by ICCVAM 3.4.5 European Center for the Validat ion of Alternative Methods 3.4.6 In Vitro Tests Undergoing Validation by ECVAM ß 2007 by Taylor & Francis Group, LLC. 3.4.7 In Vitro Test Guideline Methods 3.4.7.1 OECD In Vitro Test Guideline Methods 3.4.7.2 EU In Vitro Test Guideline Methods 3.5 Nontesting Data 3.5.1 Physico-Chemical Properties 3.5.2 Use of Structure–Activity Relationships 3.5.3 Quantitative Structure–Act ivity Relationship 3.6 Data Collection 3.6.1 Criteria Documents and Monographs from International Bodies 3.6.1.1 Environmental Health Criteria 3.6.1.2 Monographs from the International Agency for Research on Cancer 3.6.1.3 Monographs from the Joint FAO=WHO Expert Committee on Food Additives and from the Joint FAO=WHO Meeting on Pesticide Residues 3.6.1.4 WHO Guidelines for Drinki ng-Water Quality 3.6.1.5 WHO Air Quality Guidelines for Europe 3.6.1.6 Toxicological Profiles from Agency for Toxic Substances and Disease Registry 3.6.1.7 EU Risk Assessment Reports on Existing Chemicals 3.6.1.8 Publications from the International Life Sciences Institute 3.6.1.9 Publications from the European Centre for Ecotoxicology and Toxicology of Chemicals 3.6.1.10 BUA Reports from the German Chemical Society 3.6.1.11 American Conference on Governmental Industrial Hygienists 3.6.1.12 Criteria Documents from the Nordic Expert Group 3.6.2 Databases 3.6.2.1 IPCS INCHEM 3.6.2.2 International Uniform ChemicaL Information Database 3.6.2.3 US-EPA Integrated Risk Information System 3.6.2.4 U.S. National Library of Medicine TOXNET References Chapter 4 Hazard Assessment 4.1 Introduction 4.2 General Aspects 4.2.1 Systemic Effects versus Local Effects 4.2.2 Adverse Effects versus Non-Adverse Effects 4.2.3 Dose–Response Relationships 4.2.4 No-Observed-Adverse-Effect Level, Lowest-Observed-Adverse-Effect Level 4.2.5 The Benchmark Dose Concept 4.2.6 Toxicological Modes of Action 4.2.7 Critical Effects 4.3 Toxicokinetics 4.3.1 Definitions 4.3.2 Objectives for Assessing the Toxicokinetics of a Substance 4.3.3 Test Guidelines 4.3.3.1 In Vivo Tests 4.3.3.2 In Vitro Tests 4.3.4 Guidance Documents ß 2007 by Taylor & Francis Group, LLC. 4.3.5 Use of Toxicokinetics in Hazard Assessment 4.3.5.1 Human and Animal Data 4.3.5.2 In Vitro Data 4.3.5.3 Other Data 4.3.6 PBPK=PBTK Models 4.4 Acute Toxicity 4.4.1 Definitions 4.4.2 Objectives for Assessing the Acute Toxicity of a Substance. 4.4.3 Test Guidelines 4.4.3.1 In Vivo Tests 4.4.3.2 In Vitro Tests 4.4.4 Guidance Documents 4.4.4.1 WHO 4.4.4.2 OECD 4.4.4.3 US-EPA 4.4.4.4 EU 4.4.5 Use of Acute Toxicity Data in Hazard Assessment 4.4.5.1 Human Data 4.4.5.2 Animal Data 4.4.5.3 In Vitro Data 4.4.5.4 Other Data 4.5 Irritation and Corrosion 4.5.1 Definitions 4.5.1.1 OECD 4.5.1.2 US-EPA 4.5.1.3 EU 4.5.2 Objectives for Assessing Irritation and Corrosion of a Substance 4.5.3 Test Guidelines 4.5.3.1 In Vivo Tests 4.5.3.2 In Vitro Tests 4.5.4 Guidance Documents 4.5.5 Use of Information on Irritation and Corrosion in Hazard Assessment 4.5.5.1 Human Data 4.5.5.2 Animal Data 4.5.5.3 In Vitro Data 4.5.5.4 Other Data 4.6 Sensitization 4.6.1 Definitions 4.6.2 Objectives for Assessing Sensitization of a Substance 4.6.3 Test Guidelines 4.6.3.1 In Vivo Tests for Skin Sensitization 4.6.3.2 In Vivo Tests for Respiratory or Oral Sensitization 4.6.3.3 In Vitro Tests 4.6.4 Guidance Documents 4.6.4.1 WHO 4.6.4.2 OECD 4.6.4.3 US-EPA 4.6.4.4 EU 4.6.5 Use of Information on Sensitization in Hazard Assessment 4.6.5.1 Human Data 4.6.5.2 Animal Data ß 2007 by Taylor & Francis Group, LLC. 4.6.5.3 In Vitro Data 4.6.5.4 Other Data 4.7 Repeated Dose Toxicity 4.7.1 Definitions 4.7.1.1 OECD 4.7.1.2 US-EPA 4.7.1.3 EU 4.7.2 Objectives for Assessing the Repeated Dose Toxicity of a Substance 4.7.3 Test Guidelines 4.7.3.1 In Vivo Tests 4.7.3.2 In Vitro Tests 4.7.4 Guidance Documents 4.7.4.1 WHO 4.7.4.2 OECD 4.7.4.3 US-EPA 4.7.4.4 EU 4.7.5 Use of Information on Repeated Dose Toxicity in Hazard Assessment 4.7.5.1 Human Data 4.7.5.2 Animal Data 4.7.5.3 In Vitro Data 4.7.5.4 Other Data 4.7.6 Immunotoxicity 4.7.6.1 Definitions 4.7.6.2 Test Guidelines 4.7.6.3 Guidance Documents 4.7.6.4 Use of Information from Repeated Dose Toxicity Studies in the Hazard Assessmen t of Immunotoxicity 4.7.7 Neurotoxicity 4.7.7.1 Definitions 4.7.7.2 Test Guidelines 4.7.7.3 Guidance Documents 4.7.7.4 Use of Information from Repeated Dose Toxicity Studies in the Hazard Assessmen t of Neurotoxicity 4.7.8 Nasal Toxicity 4.8 Mutagenicity 4.8.1 Definitions 4.8.1.1 OECD 4.8.1.2 US-EPA 4.8.1.3 EU 4.8.2 Objectives for Assessing the Mutagenicity of a Substance 4.8.3 Test Guidelines 4.8.3.1 In Vivo Tests 4.8.3.2 In Vitro Tests 4.8.4 Guidance Documents 4.8.4.1 WHO 4.8.4.2 OECD 4.8.4.3 US-EPA 4.8.4.4 EU 4.8.5 Use of Information on Mutagenicity in Hazard Assessment 4.8.5.1 Human Data 4.8.5.2 Animal Data ß 2007 by Taylor & Francis Group, LLC. 4.8.5.3 In Vitro Data 4.8.5.4 Other Data 4.9 Carcinogenicity 4.9.1 Definitions 4.9.2 Objectives for Assessing the Carcinogenicity of a Substance 4.9.3 Test Guidelines 4.9.3.1 In Vivo Tests 4.9.3.2 In Vitro Tests 4.9.4 Guidance Documents 4.9.4.1 WHO 4.9.4.2 OECD 4.9.4.3 US-EPA 4.9.4.4 EU 4.9.4.5 IARC 4.9.5 Use of Information on Carcinogenicity in Hazard Assessment 4.9.5.1 Human Data 4.9.5.2 Animal Data 4.9.5.3 In Vitro Data 4.9.5.4 Other Data 4.9.6 Effects in Experimental Animals of Disputed Relevance for Humans 4.9.6.1 Leukemia (Mononuclear Cell Type) in the Fischer Rat 4.9.6.2 Kidney Tumors in Male Rats 4.9.6.3 Liver Tumors in Mice and Rats 4.9.6.4 Leydig Cell Tumors in Rats 4.9.6.5 Thyroid Tumors in the Rat 4.9.6.6 Urinary Bladder Tumors in the Rat and Mouse 4.9.6.7 Forestomach Tumors in Mice and Rats 4.9.6.8 Other Types of Tumors 4.9.7 Categorization for Carcinogenicity 4.9.7.1 IARC 4.9.7.2 US-EPA 4.9.7.3 EU 4.9.8 The Carcinogenic Potency Database 4.10 Reproductive Toxicity 4.10.1 Definitions 4.10.2 Objectives for Assessing the Reproductive Toxicity of a Substance 4.10.3 Test Guidelines 4.10.3.1 In Vivo Tests 4.10.3.2 In Vitro Tests 4.10.4 Guidance Documents 4.10.4.1 WHO 4.10.4.2 OECD 4.10.4.3 US-EPA 4.10.4.4 EU 4.10.5 Use of Information on Reproductive Toxicity in Hazard Identification 4.10.5.1 Human Data 4.10.5.2 Animal Data 4.10.5.3 In Vitro Data 4.10.5.4 Other Data 4.11 Endocrine Disrupters 4.11.1 Definitions ß 2007 by Taylor & Francis Group, LLC. [...]... Lewis–Lynch–Nikiforov Approach 5.2 .1. 5 EU TGD Approach 5.2 .1. 6 ECETOC Approach 5.2 .1. 7 Dutch Approaches 5.2 .1. 8 Kalberlah and Schneider Approach 5.2 .1. 9 UK Approach 5.2 .1. 10 Swedish National Chemicals Inspectorate’s Approach 5.2 .1. 11 Danish EPA’s Approach 5.2 .1. 12 Chemical-Specific Assessment Factors 5.2 .1. 13 Children-Specific Assessment Factor Interspecies Extrapolation (Animal-to-Human) 5.3 .1 Biological Variation... Polymorphism 5.4 .1. 4 Health and Disease 5.4 .1. 5 Lifestyle 5.4.2 Assessment Factor for Intraspecies Variation (Human-to-Human): Default Value 5.4.3 Intraspecies Extrapolation (Human-to-Human): Summary and Recommendations 5.5 Route-to-Route Extrapolation 5.5 .1 Route-to-Route Extrapolation: Summary and Recommendations 5.6 Duration of Exposure Extrapolation 5.6 .1 Duration of Exposure Extrapolation: Summary and Recommendations... Statistical Designs Toxicological Test Methods Approaches Used in the Hazard Assessment of Chemical Mixtures 10 .5 .1 Procedures Used to Assess Cumulative Effects of Chemicals That Act by a Common Mechanism of Action: Cumulative Risk Assessment by Dose Addition 10 .5 .1. 1 Hazard Index 10 .5 .1. 2 Weight -of- Evidence Modification to the Hazard Index 10 .5 .1. 3 Point of Departure Index 10 .5 .1. 4 Toxicity Equivalency Factors... Recommendations 5.7 Dose–Response Curve (LOAEL-to-NOAEL Extrapolation) 5.7 .1 Dose–Response Curve (LOAEL-to-NOAEL Extrapolation): Summary and Recommendations 5.8 Nature and Severity of Effects 5.8 .1 Nature and Severity of Effects: Summary and Recommendations 5.9 Confidence in the Database 5.9 .1 Confidence in the Database: Summary and Recommendations 5 .10 Overall Assessment Factor 5 .10 .1 Overall Assessment Factor:... Effect Levels by an Uncertainty Factor 6.2.4 Acceptable/Tolerable Lifetime Cancer Risk 6.3 Quantitative Dose–Response Assessment: Currently Used Approaches 6.3 .1 WHO Approach: Drinking Water and Air Quality Guidelines 6.3 .1. 1 Drinking-Water Guidelines 6.3 .1. 2 Air Quality Guidelines 6.3.2 US-EPA: General Approach 6.3.3 EU Approach: Industrial Chemicals 6.4 JECFA and EFSA: New Approach, Margin of Exposure... by Taylor & Francis Group, LLC Abbreviations and Acronyms ACGIH ADD ADI ADME AF ALARA AOEL AR ARfD ARI ATC ATRA ATSDR AUC BEI BIAC BMD BMDL BMR BUA CA CAA CAFE CAS CCOHS CCPR CDC CDER CED CEFIC CEM TF CERCLA CES CF CG=HCCS CHAD CHMP CICAD CNS CPDB CPF CPSC CRI CSAF American Conference on Governmental Industrial Hygienists Average Daily Dose Acceptable Daily Intake Absorption, Distribution, Metabolism,... (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 Detailed examination of anything complex, made in order to understand its nature or to determine its essential features Adverse Effect Analysis Assessment Assessment Endpoint Evaluation or appraisal of an analysis of facts... (Chapter 6) Exposure assessment (Chapter 7) and risk characterization (Chapter 8) Regulatory standards set by various bodies (Chapter 9) and combined actions of chemicals in mixture (Chapter 10 ) Risk assessment is a process by which regulatory and scientific principles are applied in a systematic fashion in order to describe the hazard associated with human exposure to chemical substances The information... assessment, and risk characterization It is the first component in a risk analysis process.’’ The Risk Assessment process, from data collection to risk characterization, is illustrated in Figure 1. 2 Chemical risk assessments are carried out by many national and international bodies, including major actors such as the World Health Organization (WHO) - particularly the International Programme on Chemical Safety... Project: Applicability of TTC within REACH 4 .13 .4.3 TTC Concept within EU REACH: Dutch Document 4 .14 Probabilistic Methods for Hazard Assessment References Chapter 5 5 .1 5.2 5.3 Standard Setting: Threshold Effects Introduction Assessment Factors: General Aspects 5.2 .1 Assessment Factors: Various Approaches 5.2 .1. 1 US-EPA Approach 5.2 .1. 2 Calabrese and Gilbert Approach 5.2 .1. 3 Renwick Approach 5.2 .1. 4 Lewis–Lynch–Nikiforov . Approach 5.2 .1. 11 Danish EPA’s Approach 5.2 .1. 12 Chemical-Specific Assessment Factors 5.2 .1. 13 Children-Specific Asse ssment Factor 5.3 Interspecies Extrapolation (Animal-to-Human) 5.3 .1 Biological. Identification 4 .10 .5 .1 Human Data 4 .10 .5.2 Animal Data 4 .10 .5.3 In Vitro Data 4 .10 .5.4 Other Data 4 .11 Endocrine Disrupters 4 .11 .1 Definitions ß 2007 by Taylor & Francis Group, LLC. 4 .11 .2 Strategies. Assessment Factors: General Aspects 5.2 .1 Assessment Factors: Various Approaches 5.2 .1. 1 US-EPA Approach 5.2 .1. 2 Calabrese and Gilbert Approach 5.2 .1. 3 Renwick Approach 5.2 .1. 4 Lewis–Lynch–Nikiforov Approach 5.2 .1. 5