Table Of ContentHandbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Pharmakologie
Vol. 65
Editorial Board
G. V. R Born, London· A. Farah, Rensselaer, New York
H. Herken, Berlin· A. D. Welch, Memphis, Tennessee
Advisory Board
S. Ebashi . E. G. Erdos' V. Erspamer . U. S. von Euler' W. S. Feldberg
G. B. Koelle' M. Rocha e Silva' 1. R. Vane' P. G. Waser
Teratogenesis and
Reproductive Toxicology
Contributors
S. T. Chao' K. P. Chepenik . M. S. Christian· B. E. G. Gabel
J. H. Greenberg· R. M. Greene' H. E. Holden' D. E. Hutchings
R. P. Jensh . E. M. Johnson· M. R. Juchau . N. W Klein
D. M. Kochhar . D. W N ebert . L. M. Newman' L. J. Pierro
L. W Rampy' K. S. Rao . D. S. Salomon' C. A. Schreiner
B. A. Schwetz . J. L. Sever· S. A. Waldmann' J. F. Young
Editors
E. M. Johnson and D. M. Kochhar
Springer-Verlag Berlin Heidelberg New York 1983
Professor E. MARSHALL JOHNSON, Ph.D.
Chainnan of Department of Anatomy, Director of Daniel Baugh Institute,
Jefferson Medical College, 1020 Locust Street, Philadelphia, PA 19107jUSA
Professor DEVENDRA M. KOCHHAR, Ph.D.
Department of Anatomy, Daniel Baugh Institute, Thomas Jefferson University,
1020 Locust Street, Philadelphia, PA 19107jUSA
With 69 Figures
Library of Congress Cataloging in Publication Data. Maiu entry under title: Teratogenesis and reproductive
toxicology. (Handbook of experimental pharmacology; v. 65) Includes bibliographies and index. I. Fetus-Effect of
drugs on. 2. Teratogenesis. 3. Behavioral toxicology. 4. Behavioral assessment. I. Johnson. F. M. (Elmer Marshall),
1930-. II. Kochhar, D. M. (Devendra M.), 1938-. III. Chao, S. T. IV. Series. [DNLM: I. Abnonnalities, Drug-induced.
2. Prenatal exposure delayed effects. WI HA51L v. 65/QS 679 T313] QP905.H3 vol. 65 [QM691] 615'.Is [616'.043]
82-19581.
ISBN-13 978-3-642-81921-6 e-ISBN-13: 978-3-642-81919-3
DOT 10.1007/978-3-642-81919-3
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© by Springer-Verlag Berlin Heidelberg 1983.
Softcover reprint of the hardcover 1s t edition 1983
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Typesetting: BrilhJsche Universitiitsdruckerei Gicssen.
2122/3130-543210
List of Contributors
Dr. S. T. CHAO, Ph.D., Department of Pharmacology, SJ-30 School of Medicine,
University of Washington, Seattle, WA 98195/USA
Dr. K. P. CHEPENIK, Ph.D., Associate Professor, Department of Anatomy, Daniel
Baugh Institute of Anatomy, Jefferson Medical College, Thomas Jefferson
University, 1020 Locust Street, Philadelphia, PA 19107jUSA
Dr. M. S. CHRISTIAN, Ph.D., Director of Research, Argus Research Laboratories,
935 Horsham Road, Horsham, PA'19044/USA
Mr. B. E. G. GABEL, Department of A~atomy, Daniel Baugh Institute, Jefferson
Medical College, 1020 Locust Street, Philadelphia, PA 19107/USA
Dr. J. H. GREENBERG, Ph.D., National Institute of General Medical Sciences,
Medical Institutes Westbard, National Institutes of Health, Westwood
Building, Room 920,5333 Westbard Avenue, Bethesda, MD 20205jUSA
Dr. R. M. GREENE, Ph.D., Assistant Professor, Department of Anatomy, The
Jefferson Medical College, 1020 Locust Street, Philadelphia, PA 19107/USA
Dr. H. E. HOLDEN JR., Ph.D., Safety Evaluation Department, PfIzer Central
Research, Groton, CT 06340/USA
Dr. D. E. HUTCHINGS, Ph.D., New York State Psychiatric Institute, 722 West
168th Street, New York, NY 10032/USA
Dr. R. P. JENSH, Ph.D., Associate Professor, Anatomy and Radiology, Department
of Anatomy, 561 Jefferson Alumni Hall, Thomas Jefferson University,
1020 Locust Street, Philadelphia, PA 19107/USA
Dr. E. M. JOHNSON, Ph.D., Professor and Chairman of Department of
Anatomy, Director of Daniel Baugh Institute, Jefferson Medical College,
1020 Locust Street, Philadelphia, PA 19107/USA
Dr. M. R. JUCHAU, Ph.D., Department of Pharmacology, SJ-30, School of
Medicine, University of Washington, Seattle, WA 98195jUSA
Dr. N. W. KLEIN, Ph.D., Department of Animal Genetics, University of
Connecticut, Storrs, CT 06268jUSA
Dr. D. M. KocHHAR, Ph.D., Department of Anatomy, Daniel Baugh
Institute, Thomas Jefferson University, 1020 Locust Street, Philadelphia,
PA 19107jUSA
VI List of Contributors
Dr. D. W. NEBERT, Ph.D., Developmental Pharmacology Branch, Building 10,
Room 8C-420, National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, MD 20205jUSA
Dr. L. M. NEWMAN, Ph.D., Daniel Baugh Institute, Department of Anatomy,
Jefferson Medical College, 1020 Locust Street, Philadelphia, PA 19107jUSA
Dr. L. J. PIERRO, Ph.D., Department of Animal Genetics, University of
Connecticut, Storrs, CT 06268jUSA
Dr. L. W. RAMPY, Ph.D., Health and Environmental Sciences, Building 1803, Dow
Chemical Co., Midland, MI 48640jUSA
Dr. K. S. RAO, Ph.D., Health and Environmental Sciences, Building 1803, Dow
Chemical Co., Midland, MI 48640jUSA
Dr. D. S. SALOMON, Ph.D., Laboratory of Tumor Immunology and Biology,
National Cancer Institute, National Institute of Health, Bethesda,
MD 20205jUSA
Dr. C. A. SCHREINER, Ph.D., Supervisor Genetic Toxicology, Toxicology Division,
Mobil Oil Corporation, P.O. Box 1026, Princeton, NJ 08540jUSA
Dr. B. A. SCHWETZ, D.V.M., Ph~D., Director, Toxicology Research Laboratory,
Health and Environmental Sciences, Building 1803, Dow Chemical Co.,
Midland, MI 48640jUSA
Dr. J. L. SEVER, M.D., Ph.D., Chief, Infectious Disease Branch, IRP,
National Institute of Neurological and Communicative Disorders and
Stroke, National Institutes of Health, Building 36, Room 5D06, Bethesda,
MD 20205jUSA
Dr. S. A. WALDMANN, Ph.D., Department of Anatomy, Daniel Baugh Institute
of Anatomy, Jefferson Medical College, Thomas Jefferson University,
1020 Locust Street, Philadelphia, PA 19107 jUSA
Dr. J. F. YOUNG, Ph.D., Division of Teratogenesis Research, National Center
for Toxicological Research, DHHSjFDAjEPA, Jefferson, AR n079jUSA
Preface
The resolution of links between exposure to components of our complex
environmental and causation of reproductive effects in the population constitutes
an important problem in the field of toxicology. The focus of this volume is
developmental toxicology, which represents one aspect of reproductive toxicology
dealing with the study of adverse effects on the developing conceptus.
Developmental toxicology, which includes teratogenesis as one of its manifesta
tions, provides a fertile field for research in several basic and clinical disciplines; this
field also receives input from several disoiplines such as developmental and molecu
lar biology, pathology, pharmacology and toxicology, pediatrics and neonatology,
and epidemiology. More recently we h~ve seen an emergence of interest in other
fields such as perinatal physiology and postnatal behavior which have now become
incorporated into the mainstream of research in this discipline. The present volume
is an effort to provide a sampling of concepts currently under active investigation in
several of the above fields. The authors have endeavored to provide up-to-date in
formation on the following topics: detection and analysis of potential hazards to the
conceptus in the workplace, pharmacokinetic aspects of the maternal/placental!
fetal complex and its relationship to human birth defects, and probable mechanisms
of teratogenesis as uncovered in certain well-defined situations. Also included are
summaries of newer investigations on the emerging field of postnatal functional
evaluations, i.e., adverse effects on adult activities resultant from in utero exposure
to toxic substances. Explanation of some experimental methods in use for the
detection of hazards to in utero development under well-controlled laboratory
investigations are a further area of some uniqueness and immediate practical
interest.
This text is organized into four general segments. The first part provides a brief
yet pointed awareness of human in utero exposure in one context. The second
segment deals with several aspects of mechanisms thought to underlie abnormal
development. An important third part concentrates upon on the subtle postnatal
manifestations of prenatal exposure to toxic concentrations of specific substances.
This section is a pioneering effort to provide an awareness of the diverse nature and
extent to which in utero exposure can influence function of several organ systems in
later life. Last but not least is a section on methods presently available for the more
rapid detection of environmental hazards to the cenceptus. These systems may
prove to be germane to assessing the degree to which specific industrial and other
exposures pose a hazard to development of the next generation.
This volume will be of interest to investigators in the fields of developmental
biology and toxicology - those interested in basic mechanisms underlying abnormal
VIII Preface
development, to individuals in industry who bear responsibility for workplace
safety, to persons who face the myriad and complex considerations necessary for
regulatory decisions regarding potential hazards to the conceptus, and to informed
physicians who wish to remain conversant with advances in the field of environ
mental toxicology.
THE EDITORS
Contents
Epidemiology and Bioavailability
CHAPTER 1
Assessment of Potential Hazards to the Unborn in the Workplace
B. A. SCHWETZ, K. S. RAO, and L. W. RAMPY
A. Introduction. . . . . . . 3
B. Management of the Hazard 3
C. Environmental Agents 4
D. Protective Measures 4
E. Safety Standards. 5
F. Summary 6
References . . . . . 6
CHAPTER 2
Pharmacokinetic Modeling and the Teratologist. J. F. YOUNG. With 5 Figures
A. Introduction. . . . . . . . . . . . . . 7
B. Pharmacokinetic Modeling and Simulation 7
I. One-Compartment Open Model . . . 8
II. One-Compartment Model with Parallel Elimination. 13
III. One-Compartment Absorption Model. 15
C. Multicompartment Models . . . . . . . . 19
I. Two-Compartment Model. . . . . . . 19
II. Protein Binding and Metabolism Models 22
III. Drug-Chemical Interactions (Blood Protein and Tissue Binding) 23
D. Data Acquisition and Analysis. 25
References . . . . . . . . . . . . . . . . . . . . . . . . . .. 27
CHAPTER 3
Placental Drug Metabolism. S. T. CHAO and M. R. JUCHAU
A. Introduction. . . . 31
B. Oxidation Reactions . . 32
I. Dehydrogenases . . 32
II. Monoamine Oxidase 33
III. Monooxygenases. . 33
x
Contents
C. Reduction Reactions . 40
D. Hydrolytic Reactions. 41
E. Conjugation Reactions 42
References . . . . . . . 43
CHAPTER 4
Genetic Differences in Drug Metabolism: Proposed Relationship to Human
Birth Defects. D. W. NEBERT. With 7 Figures
A. Introduction. . . . . . . . . . . . . . . . . . . 49
I. Phase I and Phase II Drug-Metabolizing Enzymes 49
II. Fundamental Aspects of Cytochrome PA50 . . . 49
III. Assessment of Substrates Metabolized by Cytochrome PA50 . 50
B. The Ah Locus . . . . . . . . . . . . . 51
I. Genetics . . . . . . . . . . . . . . . . 51
II. Pleiotypic Response of the Ah System. . . . 52
C. Genetic Influences on Drug-Induced Birth Defects 54
D. Use of Ah Locus for Teratogenesis Studies. . . . 55
I. Genetic Differences in aaP Teratogenicity. . 55
II. Correlation of BaP-Induced Stillbirths and Resorptions with the
Ah Allele . . . . . . . . . . . . . . . . . . . . . . .. 56
III. Association of BaP-Induced Embryotoxicity with the Ah Allele. 58
IV. Correlation of BaP-Induced Teratogenesis with the Ah Allele. 58
V. Developmental Expression of Ah Allele in the Mouse Embryo. 59
E. Extrapolation of Data to the Human 60
F. Summary 61
References . . . . . . . . . . . . . 61
Mechanisms of Teratogenesis
CHAPTER 5
Viruses as Teratogens. J. L. SEVER
A. Introduction. . . 65
B. Discussion 65
I. Epidemiology 65
II. Rubella Virus 66
III. Cytomegalovirus. 68
IV. Herpes Simplex Virus. 69
V. Venezuelan Equine Encephalitis Virus. 70
VI. Varicella Virus . 71
C. Summary 72
References . . . . . . 72
Contents XI
CHAPTER 6
Hormonal Involvement in Palatal Differentiation
R. M. GREENE. With 8 Figures
A. Introduction. . . . . . . . . . . . . . . . . . . 75
B. Developmental Aspects of Secondary Palate Formation 75
C. Cyclic AMP and Palatal Differentiation . 78
D. Prostaglandins in the Secondary Palate 82
E. Summary 86
References . . . . . . . . . . . . . . 87
CHAPTER 7
Membrane Lipids and Differentiation. K. P. CHEPENIK and S. A.WALDMANN
With 2 Figures
A. Introduction. . . . . . . . . . . . . . . . . 93
B. Membrane Lipid Composition and Differentiation 94
C. Lipids as Intracellular Messengers . . . . . . . 95
D. Membrane Lipid Metabolism Duriqg Normal and Abnormal Mammalian
Embryogenesis. . . . . 96
I. Initial Studies . . . . . 96
II. Role of the Placenta . . 99
III. Experimental Approaches 100
IV. Results . . . . . . . . 10 1
I. In Vitro Enzyme Studies 101
2. In Vivo Metabolic Studies 102
3. In Vitro Metabolic Studies 103
4. Acyl Composition of Embryo and Placental Phospholipids 105
V. Vitamin A and Glucocorticoids 106
E. Conclusion 107
References . . . . . . . . . . . . . 108
CHAPTER 8
Hormone Receptors and Malformations. D. S. SALOMON. With 1 Figure
A. Introduction. . 113
B. Steroids. . . . . . . . . . 116
I. Androgens. . . . . . . 116
I. Testicular Feminization 116
II. Glucocorticoids. . 119
1. Cystic Fibrosis . 119
2. Cleft Palate . . 120
C. Cholesterol . . . . . 124
I. Low Density Lipoprotein 124
1. Familial Hypercholesterolemia 124
