Risk Assessment of Prenatally-Induced Adverse Health Effects

555 Pages·1992·26.42 MB·English

by  Diether Neubert

Diether Neubert Robert J. Kavlock
Hans-Joachim Merker Jane Klein (Eds.)
Risk Assessment
of Prenatally-Induced
Adverse Health Effects
With 106 Figures and 100 Tables
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
Professor Dr. Diether Neubert
Institut fur Toxikologie und Embryopharmakologie
Universitlitsklinikum Rudolf Virchow
Freie Universitat Berlin
Garystrasse 5, W-lOOO Berlin 33, FRG
Dr. Robert J. Kavlock, Director
Developmental Toxicology Division
US Environmental Protection Agency
Health Effects Research Laboratory (MD-71)
Research Triangle Park, NC 27711, USA
Professor Dr. Hans-Joachim Merker
Institut fUr Anatomie
Freie Universitat Berlin
Konigin-Luise-Strasse 15, W-lOOO Berlin 33, FRG
Jane Klein
Institut fUr Toxikologie und Embryopharmakologie
Freie Universitat Berlin
Garystrasse 5, W-lOOO Berlin 33, FRG
Library of Congress Cataloging-in-Publication Data
Risk assessment of prenatally-induced adverse health effects / Diether Neubert ... let al.l, hrsg. "Compiles the
presentations and discussion of a symposium organized by the Institute of Toxicology and Embryopharmacology, Free
University of Berlin, on May 21-23 1991, in Berlin-Dahlem". - Pref. Includes bibliographical references and index.
ISBN-13: 978-3-642-77755-4 e-ISBN-13: 978-3-642-77753-0
DOl: 10.1007/ 978-3-642-77753-0
I. Reproductive toxicology-Congresses. 2. Developmental toxicology-Congresses. 3. Human reproduction-Effect
of chemicals on-Congresses. 4. Health risk assessment-Congresses. I. Neubert, D. (Dieter) RA
1224.2.R44 1992 618.3'2-dc20
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© Springer-Verlag Berlin Heidelberg 1992
Softcover reprint of the hardcover 1st edition 1992
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Preface
This publication compiles the presentations and discussion of a symposium
organized by the Institute o/Toxicology and Embryophannacology, Free Univer
sity of Berlin on May 21-23, 1991, in Berlin-Dahlem. Participants from seyen
countries from university institutions, industry and regulatory agencies joined in
these discussions.
This compilation has been supplemented with some contributions which were not
presented at the symposium but which fit into the framework of the topic of the
meeting, therefore, allowing us to include new information. Some authors
updated their original manuscripts, thus making this a current presentation of the
data. Where available, a short protocol of the podium discussions have also been
included at the end of each contribution.
Our institute has regularly organized symposia dealing with topics from the field
of Reproductive Biology and Toxicology for the last 20 years. This the 9th sym
posium of this kind.
The Institute of Toxicology and Embryopharmacology at the Free University of
Berlin is unique in its size (about 120 coworkers, including 35 scientists) and re
search orientation, and for more than 20 years has concentrated on problems of
reproductive biology and toxicology.
The Institute of Toxicology is the center of a Special Research Association
("Sonderforschungsbereich 174") devoted to: Risk Assessment 0/ Prenataliy
Induced Lesions. In Germany, "Special Research Associations" are local
concentrations of 10 to 25 intensively cross-linked groups concentrating their
research on a defined topic. They represent the highest level of funding by the
VI Preface
Deutsche Forschungsgemeinschaft (DFG), controlled by an extensive peer-review
procedure. Predominantly located within the Universitlitsklinikum Rudolf Virchow
of the Free University of Berlin, problems of the above mentioned research area
are presently studied jointly by eight clinical and twelve experimental groups,
also collaborating with one group from the Bundesgesundheitsamt (Federal
Health Office).
Our institute has also been selected as WHO Collaborative Centre for develop
mental toxicology.
We want to thank the Free University of Berlin and the Deutsche Forschungs
gemeinschafi for the financial help in organizing this symposium. The financial
support received from Bayer AG, Wuppertal and the Verband der Chemischen
Industrie is also greatly appreciated.
Of course, the success of such a meeting results from the joint effort of many
(not to say all) members of the institute. While the contribution of each single
member of the department is highly appreciated, the main load of the
organization always rests on a few. In this case our special thanks go to Doris
Webb for the general organization of the meeting and her help during the work
on this book, and to Peter Abt for taking care of all the financial details.
We hope that this publication will aid in recognizing and perhaps solving the
many problems connected with risk assessment in the area of reproductive and
developmental toxicology.
Berlin, May 1992 Diether Neuben
Roben J. Kavlock
Hans-Joachim Merker
Jane Klein
Contents
Introduction
Diether Neubert and Robert J. Kavlock 1
Risk Assessment for Pharmaceutical Products
Jeanne M. Manson .................................................... ....................... 27
Reproductive Toxicity Risk Assessment -Some Questions
Anthony K. Palmer ........................................................................... 45
Biomarkers of Developmental Neurotoxicity
Andrew C. Scallet and William Slikker, Jr. .......................................... 63
A Call for Increased Flexibility in Current
Teratogenicity Testing
William J. Scott, Jr. ......................................................................... 79
Specific and Non-Specific Developmental Effects
Ludwig Machemer, Ulrich Schmidt and Beate Holzum ........................... 85
Assessment of Reproductive Toxicology of Drugs
at the Food and Drug Administration
Judi Weissinger .............................................................................. 103
New Approaches to Developmental Toxicity Risk Assess
ment at the U.S. Environmental Protection Agency
Robert J. Kavlock and Carole A. Kimmel ............................................ 113
Scientific Basis for Risk Assessment (Reproductive Toxicity)
for Pesticides as Practiced by the Bundesgesundheitsamt
(BGA)
Wolfgang Lingk, Maged Younes, Rudolf Pfeil
and Roland Solecki . ......................................................................... 127
VIII Contents
Scientific Basis for Risk Assessment (Reproductive Toxicity)
in Ecotoxico1ogy as Practiced by the Federal Environmental
Agency (Umweltbundesamt)
Wolfgang Heger ..........................................................." ................... 141
General Discussion: Choice of Species ............................................... 149
Scientific Basis for Risk Assessment (Reproductive Toxicity)
for Medicinal Products as Practiced in Germany and the
European Community (BC)
Rolf Bafl and Beate Ulbrich .............................................................. 153
Risk Assessment in Reproductive Toxicology
as Practiced in South America
Francisco J.R. Paumgartten, Eduardo E. Castilla,
and Roque Monteleone Neto ............................................................. 163
Reproductive Hazard Evaluation and Risk Assessment
under California's Proposition 65
Gerald F. Chernoff and Steven A. Book .............................................. 181
General Discussion: Risk Assessment ................................................. 191
Statistical Problems (and Some Solutions) Associated
with Testing for Effects in Developmental Toxicology
R. Woodrow Setzer .......................................................................... 197
Aspects of Concentration-Response Analysis
Reinhard Meister ............................................................................ 211
Dose-Response Relationships in Reproductive Toxicology:
Importance of Skeletal Variations
Ibrahim Chahoud, Gerd Boehert and Diether Neubert ........................... 227
Prenatal-Toxic Risk Estimation Based on Dose-Response
Relationships and Molecular Dosimetry
Thomas Platzek, Gerd Boehert, Reinhard Meister
and Diether Neubert ........................................................................ 245
Kinetic Problems Arising in a Multigeneration Study
Elisabeth Koch, Ibrahim Chahoud
and Diether Neubert ........................................................................ 267
Contents IX
Application of Mathematical Dose-Response Models vs.
Physiological Models in Risk Assessment in Reproductive
Toxicology
G.A. de S. Wzckramaratne ................................................................ 279
General Discussion:
Use of Biologically Based Models 289
Pharmacokinetics and Drug Metabolism in the Design and
Interpretation of Developmental Toxicity Studies
Heinz Nau ...................................................................................... 293
Feasibility of Studying Effects on the Immune System
in Non-Human Primates
Reinhard Neubert, Ana Cristina Nogueira, Hans Helge,
Ralf Stahlm ann, and Diether Neubert ................................................. 313
Marmosets (Callithrixjacchus) as Useful Species
for Toxicological Risk Assessments
Diether Neubert, Stephan Klug, Georg Golor,
Reinhard Neubert and Annegret Felies ... ..... .......... ......... .... ........... ...... 347
Planning and Performance of Segment I, II and III
Experiments: Practical Aspects and General Comments
Helmut Sterz ................................................................................... 377
Significance of Postnatal Manifestations of
Prenatally-Induced Effects (Behaviour)
RolfB aft and Beate Ulbrich .............................................................. 389
Significance of Prenatally or Early Postnatally-Induced
Organ Dysfunctions - Other than CNS Defects
Ralf Stahlmann, Ibrahim Chahoud, Hans-Joachim Merker
and Diether Neubert ........................................................................ 397
Quantitative Morphological Tests for Evaluation
of Testicular Toxicity
Gabriele M. Rune, Jutta Hartmann
and Philippe De Souza ..................................................................... 419
Morphological Changes in Cultures of Hippocampus
Following In Vitro Irradiation
Jorge Cerv6s-Navarro, Gundula Hamdoif, Angela Becker
and Andreas Scheffler ...................................................................... 433
x Contents
Possible Contribution of In Vitro Methods to Risk Assess
ment in Reproductive and Developmental Toxicology
Stephan Klug and Diether Neubert ..................................................... 449
Morphological Endpoints in In Vitro Testing
Hans-Joachim Merker, Jamaledin Ghaida
and Dieter Blottner .......................................................................... 475
Significance of Epidemiological Studies for Risk Assessment
in Prenatal Toxicity
Janine Goujard .... ...... ......... ..... ............... ........... ...... .... ................ ... 489
Maternal Thyroid Autoantibodies and Fetal Thyroid Growth
Annette Graters, Ulrich Bogner, Petra Schumm-Draeger
and Hans Helge .............................................................................. 503
Pre- and Postnatal Risk Factors for the Development of
Atopy in Childhood
Ulrich Wahn, Renate Bergmann, Maria-Elisabeth Herrmann,
Annette Graters, Werner Luck and Markos Schmitt ............................... 513
Does Smoking During Pregnancy Alter Brain Perfusion in
the Neonate? A Doppler Study
Hashem Abdul-Khaliq, Hugo Segerer
and Michael Obladen ....................................................................... 519
Risk Assessment of Tocolytic Therapy in Pregnancy
Ruth Hildebrandt ............................................................................ 527
Histochemical and Immunocytochemical Investigations of
the Fetal Extravascular and Vascular Contractile System
in the Normal Placenta and During Preeclampsia
Renate Gra/, Hans-Georg Frank and Taylan Oney ............................... 537
Some Data on the Pattern of Lymphocyte Subsets
in Blood During the Perinatal Period
Reinhard Neubert, Isabella Delgado, Ursula Jacob-Muller,
Joachim Wolfram Dudenhausen and Diether Neubert ............................ 551
Subject Index .................................................................................................... 561
List of First Authors and Discussants
Hashem Abdul-Khaliq Dr. Ibrahim Chahoud
Universitiitsklinikum Rudolf Virchow Institut flir Toxikologie
Kinderklinik und Poliklinik und Embryopharmakologie
Abteilung fiir Neonatologie der Freien Universitiit Berlin
Kaiserin Auguste Viktoria Haus Garystr.5
Heubnerweg 6 W-IOOO Berlin 33
W-IOOO Berlin 19
Dr. Gerald F. Chernoff
Dr. Elizabeth Anderson California Dept. of Health Services
President Reproductive and Cancer Hazard
Clement International Corporation Assessment Section
9300 Lee Highway Health Hazard Assessment Division
Fairfax., Virginia 714 P Street, Room 476
USA 22031 Sacramento, California
USA 95814
Prof. Dr. Rolf BaS
Institut fiir Arzneimittel Prof. Dr. Jean R. Claude
des Bundesgesundheitsamtes Faculte des Sciences Pharmaceutiques
Seestra6e 10 6, avenue de l'Observatoire
W -1000 Berlin 65 75006 PARIS
France
Prof. Dr. Dr. H.M. Bolt
Institut fiir Arbeitsphysiologie Prof. Dr. Joachim W. Dudenhausen
ArdeystraSe 67 Universitiitsklinikum Rudolf Virchow
D-4600 Dortmund 1 Abt. Geburtsmedizin
PulsstraSe 4
Dr. Jochen Buschmann W-loo0 Berlin 19
ITA - Frauenhofer-Institut
fiir Toxikologie und Prof. Dr. med. Harald Frohberg
Aerosolforschung Direktor
Nikolai-Fuchs-Stra6e 1 E. Merck
D-3000 Hannover 61 Frankfurter StraSe 250
D-6100 Darmstadt 1
Prof. Dr. Dr. Jorge Cerv6s-Navarro
Institut flir Neuropathologie Dr. Janine Goujard
der Freien Universitiit Berlin INSERM Unite 149
Hindenburgdamm 30 123, Boulevard de Port Royal
W-lOoo Berlin 45 F-75014 PARIS