TITLE -- COPYRIGHT -- CONTENTS -- NOTE TO READERS OF THE CRITERIA MONOGRAPHS -- PREAMBLE -- WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA ON PRINCIPLES FOR EVALUATING HEALTH RISKS IN CHILDREN ASSOCIATED WITH EXPOSURE TO CHEMICALS -- PREFACE -- ACRONYMS AND ABBREVIATIONS -- 1. SUMMARY, CONCLUSIONS, AND RECOMMENDATIONS -- 1.1 Summary -- 1.2 Conclusions and recommendations -- 2. INTRODUCTION AND BACKGROUND -- 2.1 Introduction -- 2.2 Purpose and scope of document -- 2.3 Global burden of disease in children -- 2.4 Major environmental threats to children -- 2.4.1 Economic and nutritional factors -- 2.4.2 Social, cultural, demographic, and lifestyle factors -- 2.4.3 Chemical hazards -- 2.5 Intrinsic factors -- 2.6 The significance of a developmental stage approach -- 2.7 Summary and conclusions -- 3. UNIQUE BIOLOGICAL CHARACTERISTICS OF CHILDREN -- 3.1 General physical growth of children -- 3.1.1 Body weight and height -- 3.1.2 Organ weights/volumes -- 3.1.3 Skin -- 3.2 Anatomical and functional characteristics -- 3.3 Physiological characteristics -- 3.3.1 Breathing rate -- 3.3.2 Cardiac output -- 3.3.3 Blood flow to organs -- 3.3.4 Body composition -- 3.3.5 Tissue composition -- 3.3.6 Bone growth and composition -- 3.4 Metabolic characteristics -- 3.5 Toxicokinetics -- 3.5.1 Absorption, distribution, metabolism, and elimination -- 3.5.2 Physiological changes in mothers and their influence on toxicokinetics -- 3.5.2.1 Pregnancy -- 3.5.2.2 Lactation and breast milk -- 3.5.3 Dose to target -- 3.6 Normal development -- 3.6.1 Basic principles of normal development -- 3.6.2 Nervous system -- 3.6.3 Reproductive system -- 3.6.4 Endocrine system -- 3.6.4.1 Hypothalamic-pituitary axis -- 3.6.4.2 Thyroid gland -- 3.6.4.3 Adrenal glands -- 3.6.4.4 Gonads -- 3.6.4.5 Somatotropin (growth hormone), calcium homeostasis, and bone development -- 3.6.4.6 Pancreas.

3.6.5 Cardiovascular system -- 3.6.6 Immune system -- 3.6.7 Respiratory system -- 3.6.8 Kidney -- 3.7 Summary and conclusions -- 4. DEVELOPMENTAL STAGE-SPECIFIC SUSCEPTIBILITIES AND OUTCOMES IN CHILDREN -- 4.1 Introduction -- 4.2 Mortality, growth restriction, and birth defects -- 4.2.1 Mortality -- 4.2.2 Growth restriction -- 4.2.3 Birth defects (structural malformations) -- 4.2.3.1 Etiology -- 4.2.3.2 Functional developmental toxicity -- 4.3 Specific organ systems -- 4.3.1 Nervous system -- 4.3.1.1 Periods of susceptibility and consequences of exposures -- 4.3.1.2 Specific examples -- 4.3.2 Reproductive system -- 4.3.2.1 Periods of susceptibility -- 4.3.2.2 Consequences of exposures -- 4.3.3 Endocrine system -- 4.3.3.1 Periods of susceptibility -- 4.3.3.2 Consequences of exposures -- 4.3.4 Cardiovascular system -- 4.3.4.1 Periods of susceptibility -- 4.3.4.2 Consequences of exposures -- 4.3.5 Immune system -- 4.3.5.1 Periods of susceptibility -- 4.3.5.2 Consequences of exposures -- 4.3.6 Respiratory system -- 4.3.6.1 Periods of susceptibility -- 4.3.6.2 Consequences of exposures -- 4.3.7 Kidney -- 4.3.7.1 Periods of susceptibility -- 4.3.7.2 Consequences of exposures -- 4.4 Cancer -- 4.4.1 Childhood cancers that may have environmental causes -- 4.4.1.1 Lymphoid tissues -- 4.4.1.2 Liver -- 4.4.1.3 Thyroid -- 4.4.1.4 Brain and nervous system -- 4.4.1.5 Other organ sites -- 4.4.2 Adult cancers related to childhood exposures -- 4.4.2.1 Brain and nervous system -- 4.4.2.2 Thyroid -- 4.4.2.3 Female breast -- 4.4.2.4 Female reproductive tract -- 4.4.2.5 Integument -- 4.4.2.6 Other organ sites -- 4.4.3 Chemical exposures of special concern -- 4.5 Summary and conclusions -- 5. EXPOSURE ASSESSMENT OF CHILDREN -- 5.1 Introduction -- 5.2 General principles of exposure assessments -- 5.3 Methods for conducting exposure assessments -- 5.3.1 Direct methods.

5.3.2 Biomarkers of exposure -- 5.3.3 Modelling -- 5.4 Unique characteristics of children that affect exposure -- 5.5 Exposure as it relates to children around the world -- 5.5.1 Sources/geographical location -- 5.5.2 Pathways of exposure -- 5.5.2.1 Ambient air exposure pathway -- 5.5.2.2 Indoor exposure pathways -- 5.5.2.3 Water exposure pathway -- 5.5.2.4 Soil exposure pathway -- 5.5.2.5 Food-chain exposure pathway -- 5.5.2.6 Human to human exposure pathways -- 5.5.3 Settings/microenvironments -- 5.5.3.1 Residential -- 5.5.3.2 School -- 5.5.3.3 Child-care centres -- 5.5.3.4 Recreational -- 5.5.3.5 Special settings -- 5.5.4 Environmental equity factors (vulnerable communities) -- 5.6 Special considerations for children's exposure: case-studies -- 5.6.1 Influence of activities -- 5.6.1.1 Arsenic -- 5.6.1.2 Insecticides -- 5.6.1.3 Environmental tobacco smoke (ETS) -- 5.6.1.4 Lead -- 5.6.2 Hazardous waste sites -- 5.6.3 Aggregate exposure -- 5.6.3.1 Chlorpyrifos -- 5.6.3.2 Smelter areas -- 5.6.3.3 Malarious areas -- 5.6.4 Cumulative exposure -- 5.7 Summary and conclusions -- 6. METHODOLOGIES TO ASSESS HEALTH OUTCOMES IN CHILDREN -- 6.1 Introduction -- 6.1.1 Methodological approaches for children's health studies -- 6.1.1.1 Epidemiological methods -- 6.1.1.2 Comparison of study designs -- 6.1.1.3 Descriptive designs -- 6.1.1.4 Analytic designs -- 6.1.1.5 Unique methodological considerations -- 6.1.2 Methodological approaches for animal studies -- 6.1.2.1 Developmental stage susceptibility, dosing periods, and assessment of effects -- 6.1.2.2 Dosing of fetuses and pups -- 6.2 Growth and development -- 6.2.1 Human studies -- 6.2.1.1 Puberty -- 6.2.1.2 Birth defects -- 6.2.2 Animal studies -- 6.2.2.1 Body weight and postnatal growth -- 6.2.2.2 Pre-, peri-, and postnatal death -- 6.2.2.3 Physical and functional developmental landmarks.

6.2.2.4 Birth defects and malformations -- 6.3 Reproductive development and function -- 6.3.1 Human studies -- 6.3.2 Animal studies -- 6.3.2.1 Malformations of reproductive organs -- 6.3.2.2 Anogenital distance -- 6.3.2.3 Nipple/areola retention -- 6.3.2.4 Sexual maturation and puberty -- 6.3.2.5 Fertility -- 6.3.2.6 Histopathology of reproductive organs -- 6.3.2.7 Sperm quality and estrous cyclicity -- 6.4 Neurological and behavioural effects -- 6.4.1 Human studies -- 6.4.2 Animal studies -- 6.4.2.1 Motor activity -- 6.4.2.2 Motor and sensory functions -- 6.4.2.3 Learning and memory -- 6.4.2.4 Evaluation of effects -- 6.5 Cancer -- 6.5.1 Human studies -- 6.5.2 Animal studies -- 6.6 Immune system effects -- 6.6.1 Human studies -- 6.6.2 Animal studies -- 6.7 Respiratory system effects -- 6.7.1 Human studies -- 6.7.2 Animal studies -- 6.8 Haematopoietic/cardiovascular, hepatic/renal, skin/musculoskeletal, and metabolic/endocrine system effects -- 6.8.1 Human studies -- 6.8.2 Animal studies -- 6.9 Summary and conclusions -- 7. IMPLICATIONS AND STRATEGIES FOR RISK ASSESSMENT FOR CHILDREN -- 7.1 Introduction -- 7.2 Problem formulation -- 7.3 Hazard identification -- 7.3.1 End-points and critical periods of exposure -- 7.3.2 Human studies -- 7.3.3 Relevance of animal studies for assessing potential hazards to children -- 7.3.4 Reversibility and latency -- 7.3.5 Characterization of the health-related database -- 7.4 Dose-response assessment -- 7.4.1 Application of health outcome data -- 7.4.2 Quantitative evaluation -- 7.4.2.1 Tolerable daily intake (TDI) and reference dose (RfD)/reference concentration (RfC) approaches -- 7.4.2.2 Benchmark dose (BMD)/benchmark concentration (BMC) approach -- 7.4.2.3 Biologically based dose-response models -- 7.4.2.4 Duration adjustment -- 7.4.2.5 Toxicokinetics -- 7.5 Exposure assessment -- 7.5.1 Age-specific exposures.

7.5.2 Assessment methods -- 7.6 Risk characterization -- 7.7 Summary and conclusions -- REFERENCES -- ANNEX 1: WORKING DEFINITIONS OF KEY TERMS -- RESUME, CONCLUSIONS ET RECOMMANDATIONS -- RESUMEN, CONCLUSIONES Y RECOMENDACIONES.