Congenital Diseases and the Environment

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3 Congenital Diseases and the Environment

4 Environmental Science and Technology Library VOLUME 23

5 Congenital Diseases and the Environment Edited by P. Nicolopoulou-Stamati National and Kapodistrian University of Athens, Medical School, Department of Pathology, Athens, Greece L. Hens Vrije Universiteit Brussel, Human Ecology Department, Brussels, Belgium and C.V. Howard Bioimaging Research Group, Centre for Molecular Biosciences, University of Ulster, Coleraine, United Kingdom

6 A C.I.P. Catalogue record for this book is available from the Library of Congress. ISBN (HB) ISBN (HB) ISBN (e-book) ISBN (e-book) Published by Springer, P.O. Box 17, 3300 AA Dordrecht, The Netherlands. Printed on acid-free paper Desktop publishing by Dao Kim Nguyen Thuy Binh and Vu Van Hieu. Editorial Statement It is the policy of AREHNA, EU SANCO project, to encourage the full spectrum of opinions to be represented at its meetings. Therefore it should not be assumed that the publication of a paper in this volume implies that the Editorial Board is fully in agreement with the contents, though we ensure that contributions are factually correct. Where, in our opinion, there is scope for ambiguity we have added notes to the text, where appropriate. Cover Images 2006 JupiterImages Corporation. All Rights Reserved 2007 Springer No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work.

7 TABLE OF CONTENTS PREFACE...xvii ACKNOWLEDGEMENTS...xxi LIST OF CONTRIBUTORS... xxv LIST OF FIGURES...xxxi LIST OF TABLES...xxxiii LIST OF BOXES...xxxvii INTRODUCTION: CONCEPTS IN THE RELATIONSHIP OF CONGENITAL DISEASES WITH THE ENVIRONMENT P. NICOLOPOULOU-STAMATI Summary Introduction The changing concepts of environmental influences in the causation of congenital anomalies Methods to study congenital anomalies and their links to the environment EUROCAT: Surveillance of environmental impact Endpoints for prenatal exposures in toxicological studies Evidence from wildlife Epidemiology Clinical teratology Chemicals and exposure conditions associated with congenital anomalies Congenital diseases related to environmental exposure to dioxins Association of intra-uterine exposure with drugs: the thalidomide effect Endocrine disrupter exposure and male congenital malformations Links between in utero exposure to pesticides and their effects on human progeny. Does European pesticide policy protect health? Phthalates Environmental congenital anomalies Testicular dysgenesis syndrome Endocrine disrupters, inflammation and steroidogenesis v

8 vi TABLE OF CONTENTS 5.3. Environmental impact on congenital diseases: the case of cryptorchidism Policy aspects Raising awareness of information society on impact of EU policies and deployment aspects The concerns of NGO s related to congenital diseases Environmental impacts on congenital anomalies information for the non-expert professional Conclusions References SECTION 1: METHODS ENDPOINTS FOR PRENATAL EXPOSURES IN TOXICOLOGICAL STUDIES A. MANTOVANI AND F. MARANGHI Summary Introduction An overview of regulatory tests in developmental toxicology Prenatal development toxicity study (OECD guideline 414) Two-generation reproduction toxicity study (OECD 416) In vitro alternative tests for developmental toxicity Developmental toxicity testing of environmental contaminants. The example of endocrine disrupters Recommendations for further research in developmental toxicology Acknowledgements References CONGENITAL DEFECTS OR ADVERSE DEVELOPMENTAL EFFECTS IN VERTEBRATE WILDLIFE: THE WILDLIFE-HUMAN CONNECTION G. LYONS Summary Introduction: The animal human connection and epigenetic reprogramming Summary of pollutant-related defects reported in wildlife Fish Deformities of sex-linked structures in fish Poor reproductive success / reduced hatching in fish Thyroid disruption in fish... 47

9 TABLE OF CONTENTS vii Immunosuppression in fish Altered osmoregulation in migrating fish Birds Abnormal VTG production in male birds Deformities of the reproductive tract, and ovo-testes in birds Embryonic mortality and reduced reproductive success in birds Altered thyroid function in birds Immunosuppression in birds Eggshell thinning in birds Deformities of the bill and bone in birds Reptiles Effects in alligators Effects on turtles Amphibians Mammals Feral rodents Otters Mink Seals and sea lions: Reproductive problems, immunosuppression, adrenal and other effects in seals Whales and other cetaceans Polar bears Black and brown bears Florida panther Sitka black tail deer White tailed deer Mule deer Eland Summary of some effects found in both humans and wildlife Testicular dysgenesis syndrome / Intersex Thyroid disruption Immunotoxicity Congenital defects of jaw, beak, claw, nails or teeth Conclusions References EPIDEMIOLOGICAL METHODS A. ROSANO AND E. ROBERT-GNANSIA Summary Introduction Sources of data, coding and classification... 92

10 viii TABLE OF CONTENTS 2.1. Source of data for congenital anomalies Coding and classification of congenital anomalies Accuracy of diagnosis and ascertainment of congenital anomalies Source of data, coding and assessment of environmental exposures Study designs Cohort or follow-up study Case-control studies Ecological designs Exploratory studies Multiple-group comparison study Space-time cluster study Case reports Genetic epidemiology Study designs in genetic epidemiology Problems in environmental epidemiology when studying its effects on reproduction Living status of cases Genetic susceptibility Rare diseases, low-level exposures, and small effects Identifying, quantifying, and timing exposures Sources of errors Conclusions References EUROCAT: SURVEILLANCE OF ENVIRONMENTAL IMPACT H. DOLK Summary EUROCAT: What and why? The prevalence of congenital anomalies Environmental causes of congenital anomalies EUROCAT surveillance of environmental impact Approaches to surveillance Assessment of trends in congenital anomaly prevalence Routine detection of and response to clusters without a well defined a priori exposure hypothesis Systematic evaluation of environmental exposures Envirovigilance References

11 TABLE OF CONTENTS ix CLINICAL TERATOLOGY M. CLEMENTI AND E. DI GIANANTONIO Summary Introduction Teratogens Basic principles of clinical teratology Animal studies Pharmacokinetics in pregnancy Methods to identify human teratogens Classification of drugs used in pregnancy Criteria for proof of human teratogenicity Teratogen Information Services (TIS) in Europe Conclusions References SECTION 2: TERATOGENS DIOXINS AND CONGENITAL MALFORMATIONS J.G. KOPPE, M. LEIJS, G. TEN TUSSCHER AND P.D. BOER Summary Introduction Acute dioxin poisoning Animal studies Acute dioxin toxicity in man Yushchenko Two secretaries Hormones Thrombocytopenia Hotspots of dioxin pollution Amsterdam Diemerzeedijk Yusho-disaster Yucheng-disaster Seveso-disaster Vietnam: Agent Orange spraying Bashkortostan: Chapaevsk Prematurity Intra-uterine growth retardation Congenital morphogenetic conditions Congenital malformations Congenital hydrocephaly without spina bifida

12 x TABLE OF CONTENTS Increasing type 1 diabetes The role of vitamin A Conclusion References LINKS BETWEEN IN UTERO EXPOSURE TO PESTICIDES AND EFFECTS ON THE HUMAN PROGENY. DOES EUROPEAN PESTICIDE POLICY PROTECT HEALTH? C. WATTIEZ Summary Introduction Congenital disorders Congenital malformations Several birth defects Central nervous system defects Cardiovascular defects Orofacial clefts Urogenital defects Limb defects Other congenital disorders Intrauterine growth retardation Neurodevelopmental impairments Does European pesticide policy protect our health? The plant protection product authorisation directive Regulatory testing shortcomings No consideration for combined effects Toxic properties of the formulated products are not properly evaluated No systematic review of the scientific literature is required No exclusion criteria are defined for active substances, based on intrinsic properties Exposure evaluation deficits The substitution principle and comparative assessment are not considered The thematic strategy on the sustainable use of pesticides Conclusions References

13 TABLE OF CONTENTS xi ASSOCIATION OF INTRA-UTERINE EXPOSURE TO DRUGS WITH CONGENITAL DEFECTS: THE THALIDOMIDE EFFECT M. CLEMENTI, K. LUGWIG AND A. ANDRISANI Summary Introduction Pharmacokinetics Mechanism of action Thalidomide side-effects New indications Leprosy Human Immunodeficiency Virus (HIV) Beucet disease Dermatological and autoimmune disorders Cancer complications STEPS programme (System for thalidomide education and prescribing safety) Lessons for environmental teratology Conclusions References SECTION 3: CONGENITAL DISEASES ENDOCRINE DISRUPTER EXPOSURE AND MALE CONGENITAL MALFORMATIONS M.F. FERNÁNDEZ AND N. OLEA Summary Introduction Review of the epidemiological evidence The case of Southern Spain Difficulties in exposure assessment: Implications for future research Acknowledgements References TESTICULAR DYSGENESIS SYNDROME AS A CONGENITAL DISEASE H.E. VIRTANEN AND J. TOPPARI Summary Introduction

14 xii TABLE OF CONTENTS 2. Semen quality and testicular cancer Birth rates of cryptorchidism and hypospadias Discussion Acknowledgements References ENDOCRINE DISRUPTERS, STEROIDOGENESIS AND INFLAMMATION K. SVECHNIKOV, V. SUPORNSILCHAI, I. SVECHNIKOVA, M. STRAND, C. ZETTERSTRÖM, A. WAHLGREN, O. SÖDER Summary Introduction The role of androgens in male fetal differentiation Functions of the fetal Leydig cell Impact of endocrine disrupters on male reproductive health Effects of environmental anti-androgens on the reproductive development and hormonal functions of Leydig cells Procymidone Linuron Vinclozolin p,p DDT and its derivatives Effects of phthalates on Leydig cell function and reproductive development Effects of dioxin on androgen production by Leydig cells and on reproductive health Effects of endocrine disrupters on adrenal function Effects of endocrine disrupters on the hormonal functions of ovarian cells Endocrine disrupters, inflammation and androgen production Conclusions Acknowledgements References ENVIRONMENTAL IMPACT ON CONGENITAL DISEASES: THE CASE OF CRYPTORCHIDISM. WHERE ARE WE NOW, AND WHERE ARE WE GOING? P.F. THONNEAU, E. HUYGHE AND R. MIEUSSET Summary Background Has the incidence of cryptorchidism increased? Increasing evidence of a link between various male reproductive health issues

15 TABLE OF CONTENTS xiii 4. Toxic effect of anti-androgenic compounds on male reproductive health The evidence-based central role of Sertoli cells and androgen production in testis and male reproductive tract development A potential role of Insulin-like growth factor (Insl3) A non-exhaustive list of environmental chemicals with anti-androgenic effects Limited data on environmental impact of cryptorchidism in humans DES Epidemiological studies (occupational and environmental conditions) Bioaccumulation of chemical compounds Where do we go from here, and how can we answer the question? References ENVIRONMENTAL RISK AND SEX RATIO IN NEWBORNS M. PETERKA, Z. LIKOVSKY AND R. PETERKOVA Summary Introduction Basic manifestations of developmental damage Lethality - prenatal loss Major malformations Prenatal extinction of major malformations Minor malformations usually manifest as functional defects Intrauterine growth retardation and low birth weight Dose response in teratology Substances with teratogenic and lethal effects Substances with a predominantly lethal effect Substances with neither a teratogenic nor a lethal effect Residual teratogenesis and the epidemiology of malformations Sex ratio Sex determination Newborn sex ratio Newborn sex ratio and the vulnerability of male embryos/fetuses Chernobyl Radioactive clouds and whole body radioactivity Newborn sex ratio November Critical period for radiation Hypothesis about the reasons for the selective abortion of male fetuses after the Chernobyl disaster Conclusion References