Principles for Evaluating Health Risks to Reproduction With Exposure to Chemicals

CONTENTS......Page 5
PREAMBLE......Page 11
ACRONYMS AND ABBREVIATIONS......Page 22
1.1 Summary......Page 25
1.2 Recommendations......Page 28
2. INTRODUCTION......Page 31
3.2.1 Gonadal function......Page 35
3.2.2 Basic elements underlying normal development......Page 40
3.3.1 Ovarian development and oogenesis......Page 41
3.3.2 Functional morphology of the ovary......Page 42
3.3.3 Neuroendocrine regulation of ovarian function and reproductive cycling......Page 48
3.3.4 Effects of hormones on reproductive tract and breast......Page 49
3.4.1 Testes......Page 50
3.4.2 Spermatogenesis......Page 51
3.5 Mating behaviour......Page 53
3.6 Gamete transport......Page 55
3.7 Fertilization......Page 56
3.8.1 Blastogenesis......Page 57
3.8.2 Implantation......Page 58
3.8.3 Placentation......Page 59
3.9 Embryogenesis......Page 62
3.10 Fetal development......Page 70
3.12.1 Gamete development......Page 73
3.12.2 Gonadal and genital development......Page 74
3.14 Lactation......Page 75
3.15 Maturation (postnatal)......Page 76
3.17 Summary......Page 78
4.2.1 In vivo experimental data......Page 80
4.2.2 In vitro experimental data......Page 95
4.2.3 Structure–activity relationships......Page 97
4.3.2 Fecundity and fertility......Page 98
4.4 Summary......Page 104
5.1 Introduction......Page 105
5.2.1 Critical periods during development......Page 106
5.2.2 Pharmacokinetics and pharmacodynamics......Page 108
5.2.3 Gene–environment interactions......Page 112
5.2.4 Site and mechanism of action......Page 113
5.2.5 Nutrition......Page 115
5.3.1 In vivo experimental data: structural and functional aspects......Page 116
5.3.2 In vitro systems......Page 123
5.3.3 Human developmental toxicity studies......Page 127
5.3.4 Special considerations for developmental toxicity studies in humans......Page 132
5.4 Summary......Page 133
6.1 Introduction......Page 134
6.2 Testing strategies and protocols......Page 135
6.2.1 Pharmaceutical agents......Page 136
6.2.2 Chemicals......Page 137
6.3 Sources of data on reproductive toxicity......Page 138
6.4 Hazard identification......Page 140
6.5 Human studies......Page 141
6.5.1 Criteria for establishing causality......Page 143
6.5.2 Potential bias in data collection......Page 144
6.5.3 Collection of data on other risk factors, effect modifiers and confounders......Page 145
6.5.5 Community studies and surveillance programmes......Page 146
6.6 Evaluation of dose–response relationships......Page 148
6.6.2 Determination of the NOAEL, LOAEL, BMD and guidance levels......Page 150
6.6.3 Low-dose estimation/extrapolation......Page 152
6.7 Exposure assessment......Page 153
6.8.1 Characterization of the database......Page 155
6.8.2 Risk descriptors......Page 158
6.9 Summary......Page 160
REFERENCES......Page 162
APPENDIX: TERMINOLOGY......Page 193
RESUME ET RECOMMANDATIONS......Page 198
RESUMEN Y RECOMENDACIONES......Page 205