Congenital Diseases and the Environment
Environmental Science and Technology Library
VOLUME 23
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
Congenital Diseases
and the Environment
Bioimaging Research Group,
Centre for Molecular Biosciences, University of Ulster,
Coleraine, United Kingdom
A C.I.P. Catalogue record for this book is available from the Library of Congress.
ISBN-10 1-4020-4830-0 (HB)
ISBN-13 978-1-4020-4830-2 (HB)
ISBN-10 1-4020-4831-9 (e-book)
ISBN-13 978-1-4020-4831-9 (e-book)
Published by Springer,
P.O. Box 17, 3300 AA Dordrecht, The Netherlands.
www.springer.com
Printed on acid-free paper
Cover Images © 2006 JupiterImages Corporation.
All Rights Reserved


LIST OF BOXES xxxviiINTRODUCTION: CONCEPTS IN THE RELATIONSHIP
OF CONGENITAL DISEASES WITH THE ENVIRONMENT
P. NICOLOPOULOU-STAMATI

Summary 1
1. Introduction 2
2. The changing concepts of environmental influences in the causation
of congenital anomalies 3
3. Methods to study congenital anomalies and their links to the environment 4
3.1. EUROCAT: Surveillance of environmental impact 4
3.2. Endpoints for prenatal exposures in toxicological studies 4
3.3. Evidence from wildlife 5
3.4. Epidemiology 6
3.5. Clinical teratology 6
4. Chemicals and exposure conditions associated with congenital anomalies 7
4.1. Congenital diseases related to environmental exposure to dioxins 7
4.2. Association of intra-uterine exposure with drugs: the thalidomide
effect 7

4.3. Endocrine disrupter exposure and male congenital malformations 8
4.4. Links between in utero exposure to pesticides and their effects

4.5. Phthalates 9
5. Environmental congenital anomalies 10
5.1. Testicular dysgenesis syndrome 10
5.2. Endocrine disrupters, inflammation and steroidogenesis 10

2.2. Two-generation reproduction toxicity study (OECD 416) 26
2.3. In vitro alternative tests for developmental toxicity 28
2.4. Developmental toxicity testing of environmental contaminants.
The example of endocrine disrupters. 30
3. Recommendations for further research in developmental toxicology 31
Acknowledgements 32
References 32

CONGENITAL DEFECTS OR ADVERSE DEVELOPMENTAL
EFFECTS IN VERTEBRATE WILDLIFE: THE WILDLIFE-HUMAN
CONNECTION
G. LYONS
Summary 37

1. Introduction: The animal – human connection and epigenetic
reprogramming 38

2. Summary of pollutant-related defects reported in wildlife 41
2.1. Fish 43
2.1.1. Deformities of sex-linked structures in fish 46
2.1.2. Poor reproductive success / reduced hatching in fish 47
2.1.3. Thyroid disruption in fish 47
for the non-expert pr
TABLE OF CONTENTS vii
2.1.4.
Immunosuppression in fish 48
2.1.5. Altered osmoregulation in migrating fish 48

3.1. Testicular dysgenesis syndrome / Intersex 67
3.2. Thyroid disruption 68
3.3. Immunotoxicity 69
3.4. Congenital defects of jaw, beak, claw, nails or teeth 71
4. Conclusions 71
References 72

EPIDEMIOLOGICAL METHODS
A. ROSANO AND E. ROBERT-GNANSIA

Summary 89
1. Introduction 89
2. Sources of data, coding and classification 92
TABLE OF CONTENTS

viii
2.1.
Source of data for congenital anomalies 92
2.2. Coding and classification of congenital anomalies 93
2.3. Accuracy of diagnosis and ascertainment of congenital anomalies 94
2.4. Source of data, coding and assessment of environmental exposures 95
3. Study designs 97
3.1. Cohort or follow-up study 99
3.2. Case-control studies 101
3.3. Ecological designs 103
3.3.1. Exploratory studies 105
3.3.2. Multiple-group comparison study 107
3.3.3. Space-time cluster study 107
3.4.
Case reports 109
TABLE OF CONTENTS ix
CLINICAL TERATOLOGY
M. CLEMENTI AND E. DI GIANANTONIO

Summary 147
1. Introduction 148
2. Teratogens 149
2.1. Basic principles of clinical teratology 150
2.2. Animal studies 151
2.3. Pharmacokinetics in pregnancy 152
2.4. Methods to identify human teratogens 153
2.5. Classification of drugs used in pregnancy 154
2.6. Criteria for proof of human teratogenicity 155
2.7. Teratogen Information Services (TIS) in Europe 155
3. Conclusions 157
References 15

SECTION 2
: TERATOGENS

DIOXINS AND CONGENITAL MALFORMATIONS
J.G. KOPPE, M. LEIJS, G. TEN TUSSCHER AND P.D. BOER

Summary 163
1. Introduction 164

LINKS BETWEEN IN UTERO EXPOSURE TO PESTICIDES
AND EFFECTS ON THE HUMAN PROGENY. DOES EUROPEAN
PESTICIDE POLICY PROTECT HEALTH?
C. WATTIEZ

Summary 183
1. Introduction 184
2. Congenital disorders 185
2.1. Congenital malformations 186
2.1.1. Several birth defects 186
2.1.2. Central nervous system defects 187
2.1.3. Cardiovascular defects 187
2.1.4. Orofacial clefts 188
2.1.5. Urogenital defects 188
2.1.6. Limb defects 188
2.2. Other congenital disorders 192
2.2.1. Intrauterine growth retardation 193
2.2.2. Neurodevelopmental impairments 193
3. Does European pesticide policy protect our health? 196
3.1. The plant protection product authorisation directive 196
3.1.1. Regulatory testing shortcomings 196
3.1.2. No consideration for combined effects 197
3.1.3. Toxic properties of the formulated products are not properly
evaluated 198
3.1.4. No systematic review of the scientific literature is required 198
3.1.5. No exclusion criteria are defined for active substances, based
on intrinsic properties 198
3.1.6. Exposure evaluation deficits 199
3.1.7. The substitution principle and comparative assessment are not
considered 199


7. Lessons for environmental teratology 217
8. Conclusions 218
References 218

SECTION 3
: CONGENITAL DISEASES

ENDOCRINE DISRUPTER EXPOSURE AND MALE CONGENITAL
MALFORMATIONS
M.F. FERNÁNDEZ AND N. OLEA

Summary 225
1. Introduction 226
2. Review of the epidemiological evidence 227
3. The case of Southern Spain 232
4. Difficulties in exposure assessment: Implications for future research 235
Acknowledgements 237
References 241

TESTICULAR DYSGENESIS SYNDROME AS A CONGENITAL
DISEASE
H.E. VIRTANEN AND J. TOPPARI

Summary 245
1. Introduction 246
TABLE OF CONTENTS

xii
2.

10. Endocrine disrupters, inflammation and androgen production 271
11. Conclusions 273
Acknowledgements 274
References 274ENVIRONMENTAL 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 281
1. Background 282
2. Has the incidence of cryptorchidism increased? 283
3. Increasing evidence of a link between various male reproductive health issues 285
TABLE OF CONTENTS xiii
4.
Toxic effect of anti-androgenic compounds on male reproductive health 286
4.1. The evidence-based central role of Sertoli cells and androgen
production in testis and male reproductive tract development 286
4.2. A potential role of Insulin-like growth factor (Insl3) 287
4.3. A non-exhaustive list of environmental chemicals
with anti-androgenic effects 288
5.
Limited data on environmental impact of cryptorchidism in humans 289
5.1. DES 289
5.2. Epidemiological studies (occupational and environmental conditions) 289

6.4. Hypothesis about the reasons for the selective abortion of male
fetuses after the Chernobyl disaster 312

7. Conclusion 313
References 313

TABLE OF CONTENTS

xiv
SECTION 4: COUNTRY REPORTS

CONGENITAL ABNORMALITIES IN GREECE: FUNCTIONAL
EVALUATION OF STATISTICAL DATA 1981 – 1995
E. BRILAKIS, E. FOUSTERIS AND J. PAPADOPULOS

Summary 323
1. Introduction 324
2. Method 325
3. Results 326
4. Discussion 334
4.1. Specific mortality and infant mortality ratios 334
4.2. Variations of the ratios within Greece 335
4.3. Hospitalisation due to birth defects within Greece 336
4.4. Deaths/hospitalisation ratio due to births defects in Greece 336
5. Conclusions 337
References 337

CONGENITAL ANOMALIES IN BULGARIA
E. TERLEMESIAN AND S. STOYANOV


3.1. Cluster investigations 372
3.1.1. Geographical variation in congenital anomaly rates 372
4.
Conclusion 373
Acknowledgements 374
References 374EUROPEAN UNION-FUNDED RESEARCH ON ENDOCRINE
DISRUPTERS AND UNDERLYING POLICY
T. KARJALAINEN
Summary 379

1. Introduction 380
1.1. Path to adoption of community strategy for endocrine disrupters 380
1.2. Community strategy for endocrine disrupters 381
1.2.1. Short-term strategy 381
1.2.2. Medium-term strategy 382
1.2.3. Long-term strategy 383
2. European Commission-sponsored research on endocrine disrupters 384
2.1. Research activities in the fourth research framework programme
(1994-1998) 384

2.2. Research activities in the fifth framework programme of research
(FP5: 1998-2002) 384
2.2.1. Key-action 4: environment and health 385
2.2.2. Projects funded by the Energy, Environment and Sustainable
Development (EESD) thematic programme 396
2.3. Research activities in the sixth framework programme of research
(FP6: 2002-2006) 396

5.3. Policy makers and advisors 435
5.4. Scientists and media 437
6. Discussion and conclusions 439
References 443

LIST OF ABBREVIATIONS 451LIST OF UNITS 455INDEX 457xvii
PREFACE
For many years, interest in the prevention of diseases in children was concentrated
on improvement of the postnatal environment. However, since the major problems
of infectious diseases and nutrition were solved with the help of vaccinations and
better feeding regimes, it became clear that new approaches were needed to prevent
and treat the disorders and problems we are facing now - problems mainly arising in
prenatal life.
Today’s epidemics in children are prematurity; intra-uterine growth retardation;
learning disabilities; Attention Deficit Hyperactivity Disorder (ADHD); asthma and
allergies; auto-immune diseases such as type 1 diabetes and Crohn’s disease (both
increasing in recent decades, due to so far unknown environmental factors); cancer;
obesity and hearing problems. All of these problems can have their roots in prenatal

division to develop into a full-term infant; after birth, only another five are needed to
attain adult size. Credit is due to David Barker, who brought attention to the early
origin of adult disease. Well-known are the studies done in the Netherlands on the
influence of hunger in the Dutch Hunger winter in the period of November 1944 -
May 1945. Besides a high mortality and morbidity at birth, the growth restriction of
the fetus during this period of hunger (mostly a protein deficiency) resulted fifty
years later in an abnormal glucose metabolism with a defective glucose tolerance,
abnormal lipid profile and higher blood pressure. The cohort conceived during the
peak of the hunger, in the months February until May 1945, and born in November
with normal or even higher birth-weights, showed later in life an increase in obesity
and schizophrenia.
It is fair to say that at this moment, the causes of most congenital malformations are
not known, but these are probably multi-factorial, with infinite numbers of causative
factors. A single-compound approach to testing, as is done now in classical
toxicology, is no longer sufficient in a world of multiple exposures. The
combination of different chemicals, or the combination with an infection or stress,
can result in additive, synergistic, antagonistic or neutral effects. In general, almost
nothing is yet known about fetal toxicology. Disturbances in the thyroid hormone
homeostasis causes impaired brain development, but in the first half of pregnancy, it
is the task of the mother to provide her baby with sufficient thyroid hormone and in
that period, any problem in the mother is decisive. Abnormalities in the
estrogen/androgen status in the fetal period can result in abnormal sexual
development of the brain, such as trans-sexualism.
PREFACE
PREFACE

xix
Genetic causes are becoming better known, but clear-cut genetic reasons for
congenital diseases are rare and clinical aspects can be confusing. The recognition of
epigenetics also makes it clear that the environment plays a definitive role. Genes


ACKNOWLEDGEMENTS All papers of this book have been peer reviewed. The Editors are most indebted to
the colleagues who reviewed various chapters of this book:
Ahmed Mahmoud, Laboratory of Andrologie, University of Ghent, Gent, Belgium
Alain Dupont, Clinical Pharmacology, Faculty of Medicine and Pharmacy, Vrije
Universiteit Brussel, Belgium
Antoni Duleba, Department of Obstetrics and Gynecology, Yale University School
of Medicine, USA
Arnold Schecter, University of Texas, School of Public Health, Dallas, USA
Asher Ornoy, The Israeli Teratogen Information Service, Laboratory of Teratology,
Department of Anatomy and Cell Biology, The Hebrew University – Hadassah
Medical School and Israeli Ministry of Health, Israel
Athina Tsmamadou, Teratogen Information Center, Poison Information Center,
Children’s Hospital A and P Kyriakou, Athens, Greece
Barbara D. Abbott, Developmental Toxicology Division, U.S Environmental
Protection Agency, USA
David Miller, Department of Obstetrics and Gynaecology, University of Leeds, UK
David Stone, Padiatric Epidemiology and Community Health, Yorkhill Hospital
Glasgow, Scotland
Didima M.G. de Groot, TNO Quality of Life (Location Zeist), Zeist, The Nederlands
Emmanuel Brilakis, Paediatric Surgery Department, “TZANEIO” General Hospital
of Piraeus, Piraeus, Greece
Erminio Giavini, Department of Biology, State University of Milan, Italy
Ettore Caroppo, IRCCS “S. de Bellis”, UO Fisiopatologia della Riproduzione
Umana, Castellana Grotte (Ba), Italy
Evangelos Fousteris, Department of Internal Medicine, General Hospital of
Livadeia, Piraeus, Greece

Brussels, Belgium
Marie-Christine Dewolf, EEN, EPHA Environmental Network, Hygiène Publique en
Hainaut asbl/Provincial Institute of Hygiene and Bacteriology of the Hainaut,
Belgium
Martine Vrijheid, International Agency for Research on Cancer (IARC), Lyon,
France
Maurizio Clementi, CEPIG, Genetica Clinica ed Epidemiologica, Dipartimento di
Pediatria, Università di Padova, Italy
Monique Ryan, Paediatric Neurologist, The Children’s Hospital at Westmead,
Australia
Olle Soder, Karolinska Institute and University Hospital Stockholm, Sweden
Patricia B. Hoyer, University of Arizona, Tucson, USA
Petroff D.V.M Brian, University of Kansas Medical Center, Breast Cancer
Prevention Center, USA
Ramsden David, University of Birmingham, School of Bioscience, UK
ACKNOWLEDGEMENTS

xxiii
Richard Nelson, Northern General Hospital, Sheffield, UK
Richard Sharpe, MRC Human Reproductive Sciences Unit, Centre for Reproductive
Biology, Queen’s Medical Research Institute, UK
Sándor János, University Pécs, Faculty of Health Sciences, Institute of Applied
Health Sciences, Department of Public Health. Hungary
Shigetaka Katow, CDC (Centers for Disease Control and Prevention), Department of
Viral Disease and Vaccine Control, National Institute of Infectious Diseases,
Musashi-Murayama, Japan
Stephen Safe, Department of Veterinary Physiology and Pharmacology, College
Station, University of Texas A and M, USA
Stoyan Stoyanov. University of Chemical Technology and Metallurgy, Ecology
Center, Bulgaria


P.D. BOER

Emeritus Professor of Neonatology
Ecobaby Foundation
Hollandstraat 6
3634 AT Loenersloot
The NETHERLANDS

E. BRILAKIS
Paediatric Surgery Department
“TZANEIO” General Hospital of
Piraeus
Aristofanous street 18
185 33 Piraeus
GREECE

M. CLEMENTI
CEPIG, Genetica Clinica ed
Epidemiologica
Dipartimento di Pediatria
Università di Padova
Via Giustiniani 3
35128 Padova
ITALY

E. DI GIANANTONIO
CEPIG, Genetica Clinica ed
Epidemiologica
Dipartimento di Pediatria


L. HENS
Vrije Universiteit Brussel
Human Ecology Department
Laarbeeklaan 103
B-1090 Brussel
BELGIUM
LIST OF CONTRIBUTORS

xxvi

E. HUYGHE
Human Fertility Research Group –
Reproductive Health in Developing
Countries
EA n°36 94
Hôpital Paule de Viguier
Avenue de Grande Bretagne 330
TSA 70034, 31059 Toulouse Cedex
FRANCE

T. KARJALAINEN
European Commission
Research Directorate General –Unit
E2 (Food quality)
Squre de Mecus 8
B-1049 Brussels
BELGIUM

J. G. KOPPE

35128 Padova
ITALY

G. LYONS

Toxics Policy Advisor
WWF UK
17 The Avenues
NR2 3PH
Norwich
ENGLAND

A. MANTOVANI
Department Food Safety and
Veterinary Public Health
Istituto Superiore di Sanità
viale Regina Elena 299
00161 Rome
ITALY

F. MARANGHI
Department Food Safety and
Veterinary Public Health
Istituto Superiore di Sanità
viale Regina Elena 299
00161 Rome
ITALY

R. MIEUSSET
Human Fertility Research Group –