Principles For Evaluating Health Risks To Reproduction Associated With Exposure To C...Page 1 of 141 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 225 Principles For Evaluating Health Risks To Reproduction Associated With Exposure To Chemicals Initial drafts prepared by Dr P. Foster, Research Triangle Park, NC, USA; Dr W. Foster, Los Angeles, CA, USA; Dr C. Hughes, Los Angeles, CA, USA; Dr C. Kimmel, Washington, DC, USA; Dr S. Selevan, Washington, DC, USA; Dr N. Skakkebaek, Copenhagen, Denmark; Dr F. Sullivan, Brighton, England; Dr S. Tabacova, Sofia, Bulgaria; Dr J. Toppari, Turku, Finland; and Dr B. Ulbrich, Berlin, Germany 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. World Health Organization Geneva, 2001 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 objectives 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 cooperation 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 http://www.inchem.org/documents/ehc/ehc/ehc225.htm 6/1/2007 Principles For Evaluating Health Risks To Reproduction Associated With Exposure To C...Page 2 of 141 Principles for evaluating health risks to reproduction associated with exposure to chemicals. (Environmental health criteria ; 225) 1.Reproduction – physiology 2.Reproduction – drug effects 3.Fertility – drug effects 4.Fetal development – drug effects 5.Environmental exposure 6.Risk assessment I. International Programme for Chemical Safety II.Series ISBN 92 4 157225 6 (NLM classification: QZ 59) ISSN 0250-863X The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available. ©World Health Organization 2001 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. 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 Secretariat 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. 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. CONTENTS Environmental Health Criteria For Principles For Evaluating Health Risks To Reproduction Associated With Exposure To Chemicals http://www.inchem.org/documents/ehc/ehc/ehc225.htm 6/1/2007 Principles For Evaluating Health Risks To Reproduction Associated With Exposure To C...Page 3 of 141 PREAMBLE ACRONYMS AND ABBREVIATIONS 1. SUMMARY AND RECOMMENDATIONS 1.1 Summary 1.2 Recommendations 2. INTRODUCTION 3. PHYSIOLOGY OF HUMAN REPRODUCTION 3.1 Introduction 3.2 Reproductive endocrinology 3.2.1 Gonadal function 3.2.2 Basic elements underlying normal development 3.3 Female reproductive physiology 3.3.1 Ovarian development and oogenesis 3.3.2 Functional morphology of the ovary 3.3.2.1 Folliculogenesis 3.3.2.2 Intraovarian signalling 3.3.3 Neuroendocrine regulation of ovarian function and reproductive cycling 3.3.3.1 Hypothalamus 3.3.3.2 Pituitary 3.3.3.3 Patterns of ovarian response 3.3.4 Effects of hormones on reproductive tract and breast 3.4 Male reproductive physiology 3.4.1 Testes 3.4.2 Spermatogenesis 3.4.3 Intratesticular signalling 3.5 Mating behaviour 3.6 Gamete transport 3.7 Fertilization http://www.inchem.org/documents/ehc/ehc/ehc225.htm 6/1/2007 Principles For Evaluating Health Risks To Reproduction Associated With Exposure To C...Page 4 of 141 3.8 In utero development 3.8.1 Blastogenesis 3.8.2 Implantation 3.8.3 Placentation 3.8.3.1 Yolk sac placenta 3.8.3.2 Chorioallantoic placenta 3.8.3.3 Placental steroidogenesis 3.9 Embryogenesis 3.10 Fetal development 3.11 Gestation 3.12 Gametogenesis and gonadogenesis 3.12.1 Gamete development 3.12.2 Gonadal and genital development 3.13 Parturition 3.14 Lactation 3.15 Maturation (postnatal) 3.16 Reproductive senescence 3.17 Summary 4. EVALUATION OF ALTERED SEXUAL FUNCTION AND FERTILITY 4.1 Introduction 4.2 Experimental data 4.2.1 In vivo experimental data 4.2.1.1 Introduction 4.2.1.2 General evaluation of sexual function and fertility 4.2.1.3 Evaluation of male-specific end-points of sexual function and fertility 4.2.1.4 Evaluation of female-specific end-points of sexual function and fertility 4.2.2 In vitro experimental data http://www.inchem.org/documents/ehc/ehc/ehc225.htm 6/1/2007 Principles For Evaluating Health Risks To Reproduction Associated With Exposure To C...Page 5 of 141 4.2.2.1 Introduction 4.2.2.2 Cell and tissue culture systems 4.2.2.3 In vitro fertilization studies 4.2.2.4 Other in vitro systems 4.2.3 Structure–activity relationships 4.2.4 Methods to assess endocrine disruption 4.3 Human data 4.3.1 Introduction 4.3.2 Fecundity and fertility 4.3.2.1 Male end-points 4.3.2.2 Female end-points 4.4 Summary 5. EVALUATION OF DEVELOPMENTAL TOXICITY 5.1 Introduction 5.2 Background information on abnormal development 5.2.1 Critical periods during development 5.2.1.1 Prenatal toxicity and structural defects 5.2.1.2 Fetal and postnatal developmental defects 5.2.2 Pharmacokinetics and pharmacodynamics 5.2.3 Gene–environment interactions 5.2.4 Site and mechanism of action 5.2.4.1 Mechanisms of developmental toxicity 5.2.4.2 Site of action of developmental toxicants 5.2.5 Nutrition 5.3 Experimental data 5.3.1 In vivo experimental data: structural and functional aspects 5.3.1.1 Prenatal observations 5.3.1.2 Postnatal manifestations http://www.inchem.org/documents/ehc/ehc/ehc225.htm 6/1/2007 Principles For Evaluating Health Risks To Reproduction Associated With Exposure To C...Page 6 of 141 5.3.1.3 Male-mediated developmental toxicity and transplacental carcinogenesis 5.3.2 In vitro systems 5.3.2.1 Embryonic stem cell test 5.3.2.2 Whole embryo culture 5.3.2.3 Organ culture systems 5.3.2.4 Cell and tissue culture 5.3.3 Human developmental toxicity studies 5.3.3.1 Outcomes measured in the newborn period 5.3.3.2 Outcomes measured in infancy and childhood 5.3.3.3 Outcomes measured in adulthood 5.3.4 Special considerations for developmental toxicity studies in humans 5.4 Summary 6.0 RISK ASSESSMENT STRATEGIES FOR REPRODUCTIVE TOXICITY 6.1 Introduction 6.2 Testing strategies and protocols 6.2.1 Pharmaceutical agents 6.2.2 Chemicals 6.3 Sources of data on reproductive toxicity 6.4 Hazard identification 6.5 Human studies 6.5.1 Criteria for establishing causality 6.5.2 Potential bias in data collection 6.5.3 Collection of data on other risk factors, effect modifiers and confounders 6.5.4 Examination of clusters, case reports or series 6.5.5 Community studies and surveillance programmes 6.6 Evaluation of dose–response relationships http://www.inchem.org/documents/ehc/ehc/ehc225.htm 6/1/2007 Principles For Evaluating Health Risks To Reproduction Associated With Exposure To C...Page 7 of 141 6.6.1 Quantitative dose–response assessment 6.6.2 Determination of the NOAEL, LOAEL, BMD and guidance levels 6.6.3 Low-dose estimation/extrapolation 6.7 Exposure assessment 6.8 Risk characterization 6.8.1 Characterization of the database 6.8.2 Risk descriptors 6.9 Summary REFERENCES APPENDIX: TERMINOLOGY RESUME ET RECOMMANDATIONS RESUMEN Y RECOMENDACIONES 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 corrigenda.