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 237 PRINCIPLES FOR EVALUATING HEALTH RISKS IN CHILDREN ASSOCIATED WITH EXPOSURE TO CHEMICALS First drafts prepared by Dr Germaine Buck Louis, Bethesda, USA; Dr Terri Damstra, Research Triangle Park, USA; Dr Fernando Díaz- Barriga, San Luis Potosi, Mexico; Dr Elaine Faustman, Washington, USA; Dr Ulla Hass, Soborg, Denmark; Dr Robert Kavlock, Research Triangle Park, USA; Dr Carole Kimmel, Washington, USA; Dr Gary Kimmel, Silver Spring, USA; Dr Kannan Krishnan, Montreal, Canada; Dr Ulrike Luderer, Irvine, USA; and Dr Linda Sheldon, Research Triangle Park, USA 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. 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 Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen coop- eration 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 Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment. WHO Library Cataloguing-in-Publication Data Principles for evaluating health risks in children associated with exposure to chemicals (Environmental health criteria ; 237) “First drafts prepared by Dr Germaine Buck Louis [et al.].” 1.Environmental health. 2.Risk assessment. 3.Child. 4.Organic chemicals - adverse effects. 5.Inorganic chemicals - adverse effects. 6.Environmental exposure. I.Louis, Germaine Buck. II.World Health Organization. III.Inter-Organization Programme for the Sound Management of Chemicals. IV.Series. ISBN 92 4 157237 X (NLM classification: WA 30.5) ISBN 978 92 4 157237 8 ISSN 0250-863X ©World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, 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 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 prefer- ence 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 WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either express or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organi- zation be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication. This document was technically and linguistically edited by Marla Sheffer, Ottawa, Canada, and printed by Wissenchaftliche Verlagsgesellschaft mbH, Stuttgart, Germany. Switzerland (tel: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). address (fax: +41 22 791 4806; e-mail: permissions@who.int). iii CONTENTS ENVIRONMENTAL HEALTH CRITERIA ON PRINCIPLES FOR EVALUATING HEALTH RISKS IN CHILDREN ASSOCIATED WITH EXPOSURE TO CHEMICALS PREAMBLE xi PREFACE xvii ACRONYMS AND ABBREVIATIONS xix 1. SUMMARY, CONCLUSIONS, AND RECOMMENDATIONS 1 1.1 Summary 1 1.2 Conclusions and recommendations 4 2. INTRODUCTION AND BACKGROUND 7 2.1 Introduction 7 2.2 Purpose and scope of document 9 2.3 Global burden of disease in children 12 2.4 Major environmental threats to children 14 2.4.1 Economic and nutritional factors 15 2.4.2 Social, cultural, demographic, and lifestyle factors 16 2.4.3 Chemical hazards 17 2.5 Intrinsic factors 19 2.6 The significance of a developmental stage approach 20 2.7 Summary and conclusions 21 3. UNIQUE BIOLOGICAL CHARACTERISTICS OF CHILDREN 22 3.1 General physical growth of children 22 3.1.1 Body weight and height 22 3.1.2 Organ weights/volumes 23 3.1.3 Skin 25 3.2 Anatomical and functional characteristics 25 3.3 Physiological characteristics 26 EHC 237: Principles for Evaluating Health Risks in Children iv 3.3.1 Breathing rate 26 3.3.2 Cardiac output 26 3.3.3 Blood flow to organs 27 3.3.4 Body composition 28 3.3.5 Tissue composition 29 3.3.6 Bone growth and composition 29 3.4 Metabolic characteristics 29 3.5 Toxicokinetics 31 3.5.1 Absorption, distribution, metabolism, and elimination 31 3.5.2 Physiological changes in mothers and their influence on toxicokinetics 33 3.5.2.1 Pregnancy 33 3.5.2.2 Lactation and breast milk 35 3.5.3 Dose to target 36 3.6 Normal development 39 3.6.1 Basic principles of normal development 39 3.6.2 Nervous system 40 3.6.3 Reproductive system 42 3.6.4 Endocrine system 44 3.6.4.1 Hypothalamic–pituitary axis 44 3.6.4.2 Thyroid gland 46 3.6.4.3 Adrenal glands 47 3.6.4.4 Gonads 48 3.6.4.5 Somatotropin (growth hormone), calcium homeostasis, and bone development 48 3.6.4.6 Pancreas 48 3.6.5 Cardiovascular system 49 3.6.6 Immune system 49 3.6.7 Respiratory system 50 3.6.8 Kidney 52 3.7 Summary and conclusions 53 4. DEVELOPMENTAL STAGE–SPECIFIC SUSCEPTIBILITIES AND OUTCOMES IN CHILDREN 55 4.1 Introduction 55 4.2 Mortality, growth restriction, and birth defects 60 4.2.1 Mortality 60 4.2.2 Growth restriction 63 4.2.3 Birth defects (structural malformations) 64 v 4.2.3.1 Etiology 66 4.2.3.2 Functional developmental toxicity 67 4.3 Specific organ systems 68 4.3.1 Nervous system 68 4.3.1.1 Periods of susceptibility and consequences of exposures 69 4.3.1.2 Specific examples 72 4.3.2 Reproductive system 78 4.3.2.1 Periods of susceptibility 79 4.3.2.2 Consequences of exposures 80 4.3.3 Endocrine system 85 4.3.3.1 Periods of susceptibility 85 4.3.3.2 Consequences of exposures 92 4.3.4 Cardiovascular system 95 4.3.4.1 Periods of susceptibility 96 4.3.4.2 Consequences of exposures 96 4.3.5 Immune system 97 4.3.5.1 Periods of susceptibility 98 4.3.5.2 Consequences of exposures 101 4.3.6 Respiratory system 105 4.3.6.1 Periods of susceptibility 105 4.3.6.2 Consequences of exposures 106 4.3.7 Kidney 113 4.3.7.1 Periods of susceptibility 113 4.3.7.2 Consequences of exposures 114 4.4 Cancer 115 4.4.1 Childhood cancers that may have environmental causes 116 4.4.1.1 Lymphoid tissues 116 4.4.1.2 Liver 118 4.4.1.3 Thyroid 118 4.4.1.4 Brain and nervous system 119 4.4.1.5 Other organ sites 119 4.4.2 Adult cancers related to childhood exposures 120 4.4.2.1 Brain and nervous system 120 4.4.2.2 Thyroid 121 4.4.2.3 Female breast 122 4.4.2.4 Female reproductive tract 122 4.4.2.5 Integument 122 4.4.2.6 Other organ sites 123 Contents EHC 237: Principles for Evaluating Health Risks in Children vi 4.4.3 Chemical exposures of special concern 123 4.5 Summary and conclusions 126 5. EXPOSURE ASSESSMENT OF CHILDREN 129 5.1 Introduction 129 5.2 General principles of exposure assessments 129 5.3 Methods for conducting exposure assessments 133 5.3.1 Direct methods 133 5.3.2 Biomarkers of exposure 136 5.3.3 Modelling 137 5.4 Unique characteristics of children that affect exposure 139 5.5 Exposure as it relates to children around the world 144 5.5.1 Sources/geographical location 144 5.5.2 Pathways of exposure 145 5.5.2.1 Ambient air exposure pathway 145 5.5.2.2 Indoor exposure pathways 150 5.5.2.3 Water exposure pathway 152 5.5.2.4 Soil exposure pathway 153 5.5.2.5 Food-chain exposure pathway 154 5.5.2.6 Human to human exposure pathways 155 5.5.3 Settings/microenvironments 156 5.5.3.1 Residential 157 5.5.3.2 School 157 5.5.3.3 Child-care centres 157 5.5.3.4 Recreational 158 5.5.3.5 Special settings 159 5.5.4 Environmental equity factors (vulnerable communities) 161 5.6 Special considerations for children’s exposure: case-studies 162 5.6.1 Influence of activities 162 5.6.1.1 Arsenic 162 5.6.1.2 Insecticides 162 5.6.1.3 Environmental tobacco smoke (ETS) 162 5.6.1.4 Lead 163 5.6.2 Hazardous waste sites 163 5.6.3 Aggregate exposure 164 5.6.3.1 Chlorpyrifos 164 vii 5.6.3.2 Smelter areas 165 5.6.3.3 Malarious areas 165 5.6.4 Cumulative exposure 165 5.7 Summary and conclusions 166 6. METHODOLOGIES TO ASSESS HEALTH OUTCOMES IN CHILDREN 168 6.1 Introduction 168 6.1.1 Methodological approaches for children’s health studies 168 6.1.1.1 Epidemiological methods 171 6.1.1.2 Comparison of study designs 171 6.1.1.3 Descriptive designs 176 6.1.1.4 Analytic designs 178 6.1.1.5 Unique methodological considerations 180 6.1.2 Methodological approaches for animal studies 181 6.1.2.1 Developmental stage susceptibility, dosing periods, and assessment of effects 184 6.1.2.2 Dosing of fetuses and pups 190 6.2 Growth and development 190 6.2.1 Human studies 190 6.2.1.1 Puberty 194 6.2.1.2 Birth defects 195 6.2.2 Animal studies 195 6.2.2.1 Body weight and postnatal growth 195 6.2.2.2 Pre-, peri-, and postnatal death 196 6.2.2.3 Physical and functional developmental landmarks 196 6.2.2.4 Birth defects and malformations 198 6.3 Reproductive development and function 198 6.3.1 Human studies 198 6.3.2 Animal studies 202 6.3.2.1 Malformations of reproductive organs 202 6.3.2.2 Anogenital distance 203 6.3.2.3 Nipple/areola retention 204 6.3.2.4 Sexual maturation and puberty 204 Contents viii 6.3.2.5 Fertility 204 6.3.2.6 Histopathology of reproductive organs 206 6.3.2.7 Sperm quality and estrous cyclicity 207 6.4 Neurological and behavioural effects 207 6.4.1 Human studies 207 6.4.2 Animal studies 208 6.4.2.1 Motor activity 208 6.4.2.2 Motor and sensory functions 209 6.4.2.3 Learning and memory 209 6.4.2.4 Evaluation of effects 210 6.5 Cancer 211 6.5.1 Human studies 211 6.5.2 Animal studies 212 6.6 Immune system effects 212 6.6.1 Human studies 212 6.6.2 Animal studies 213 6.7 Respiratory system effects 213 6.7.1 Human studies 213 6.7.2 Animal studies 213 6.8 Haematopoietic/cardiovascular, hepatic/renal, skin/musculoskeletal, and metabolic/endocrine system effects 214 6.8.1 Human studies 214 6.8.2 Animal studies 214 6.9 Summary and conclusions 214 7. IMPLICATIONS AND STRATEGIES FOR RISK ASSESSMENT FOR CHILDREN 217 7.1 Introduction 217 7.2 Problem formulation 220 7.3 Hazard identification 221 7.3.1 End-points and critical periods of exposure 223 7.3.2 Human studies 224 7.3.3 Relevance of animal studies for assessing potential hazards to children 225 7.3.4 Reversibility and latency 229 7.3.5 Characterization of the health-related database 230 7.4 Dose–response assessment 230 7.4.1 Application of health outcome data 232 EHC 237: Principles for Evaluating Health Risks in Children ix 7.4.2 Quantitative evaluation 233 7.4.2.1 Tolerable daily intake (TDI) and reference dose (RfD)/reference concentration (RfC) approaches 233 7.4.2.2 Benchmark dose (BMD)/benchmark concentration (BMC) approach 236 7.4.2.3 Biologically based dose–response models 236 7.4.2.4 Duration adjustment 237 7.4.2.5 Toxicokinetics 237 7.5 Exposure assessment 238 7.5.1 Age-specific exposures 238 7.5.2 Assessment methods 240 7.6 Risk characterization 242 7.7 Summary and conclusions 244 REFERENCES 247 ANNEX 1: WORKING DEFINITIONS OF KEY TERMS 310 RESUME, CONCLUSIONS ET RECOMMANDATIONS 315 RESUMEN, CONCLUSIONES Y RECOMENDACIONES 323 Contents x NOTE TO READERS OF THE CRITERIA MONOGRAPHS Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication. In the interest of all users of the Environmental Health Criteria monographs, readers are requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corri- genda. [...]... guidelines, or protocols for the conduct of specific tests and studies In addition to the documents cited in the introduction to this chapter, it builds on two previous 11 EHC 237: Principles for Evaluating Health Risks in Children EHCs addressing methodologies for assessing risks in children: EHC 30, Principles for Evaluating Health Risks to Progeny Associated with Exposure to Chemicals during Pregnancy... methodologies and strategies to assess risks from exposure to chemicals Since its inception, IPCS has been concerned about the effects of chemical exposures on susceptible populations, including children Past EHC publications addressing methodologies for risk assessment in children include EHC 30, Principles for Evaluating Health Risks to Progeny Associated with Exposure to Chemicals during Pregnancy (IPCS,... this document is specifically on exposure to environmental chemicals This document evaluates the scientific principles to be considered in assessing health risks in children from exposures to environmental chemicals during distinct developmental stages and provides information for public health officials, research and regulatory scientists, and other experts responsible for protecting children s health. .. forwarded to an IPCS editor for language editing, reference checking, and preparation of camera-ready copy After approval by the Director, IPCS, the manuscript was submitted to the WHO Office of Publications for printing It will also be available on the IPCS web site xiv WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA ON PRINCIPLES FOR EVALUATING HEALTH RISKS IN CHILDREN ASSOCIATED WITH EXPOSURE TO CHEMICALS. .. and test guidelines on reproductive and developmental toxicity currently xvii EHC 237: Principles for Evaluating Health Risks in Children available However, this document does not provide specific guidelines or protocols for the application of risk assessment strategies or the conduct of specific tests Specific testing guidelines for assessing reproductive toxicity from exposure to chemicals have been... Argentina, assessed major environmental threats to children in Central and Latin American countries and identified priority areas for research collaboration Many countries have also established specific regulations to protect children from exposure to certain environmental hazards, including toxic chemicals Examples include banning of heavy metals in toys, strict limit setting for persistent toxic... in assessing health risks in children from exposures to environmental agents during distinct stages of development The developmental stages used throughout this document are defined in Table 1 and are considered temporal intervals with distinct anatomical, physiological, behavioural, or functional characteristics that contribute to potential differences in vulnerability to environmental exposures Exposure. .. throughout the document for more detailed information on environmental threats to children A list of WHO web sites relevant to children s health is provided in Box 1 These WHO web sites also provide links to other sites relevant to children s health Box 1 WHO web site resources relevant to children s health WHO Child and Adolescent Health and Development: http://www.who.int/child-adolescent -health/ WHO Children s... assessment approaches In recognition of this new scientific knowledge, IPCS was asked to provide an up -to- date EHC on scientific principles and approaches to assessing risks in children associated with exposures to environmental chemicals IPCS is producing this monograph as a tool for use by public health officials, research and regulatory scientists, and risk assessors It is intended to complement the... young children (e.g infant mortality, asthma, neurobehavioural and immune impairment), and in adolescents (e.g precocious or delayed puberty) Emerging evidence suggests that an increased risk of certain diseases in adults (e.g 3 EHC 237: Principles for Evaluating Health Risks in Children cancer, heart disease) can result in part from exposures to certain environmental chemicals during childhood While . World Health Organization. Environmental Health Criteria 237 PRINCIPLES FOR EVALUATING HEALTH RISKS IN CHILDREN ASSOCIATED WITH EXPOSURE TO CHEMICALS First drafts prepared by Dr Germaine Buck. Evaluating Health Risks to Progeny Associated with Exposure to Chemicals during Pregnancy (IPCS, 1984), and EHC 59, Principles for Evaluating Health Risks from Chemicals during Infancy and Early. separately, to achieve the sound management of chemicals in relation to human health and the environment. WHO Library Cataloguing -in- Publication Data Principles for evaluating health risks in children