Toxicology VOL. VOL. 27 about the book… 27 TARGET ORGAN Highlighting latest advances in genetics and biochemistry, the completely revised Third TOXICOLOGY Edition reviews the field from basic science, clinical, epidemiological, and regulatory SERIES TARGET ORGAN TOXICOLOGY SERIES perspectives. Contributions from top opinion leaders in the field bring together developments in molecular embryology and cell biology as they apply to problems Series Editors in developmental toxicology. It covers testing of pharmaceutical and environmental agents and interpretation of developmental toxicology data, highlighting mathematical A. Wallace Hayes • John A. Thomas • Donald E. Gardner and statistical techniques, as well as the effects of toxic exposure on the functional D development of various organs. EVELOPMENTAL The relationship between maternal and developmental toxicology is examined, in addition to current techniques for studying chemical disposition, metabolism, and placental transfer. Close attention is given to the regulatory aspects of testing and risk assessment. Pre- and postconceptional clinical care and genetic factors in clinical developmental toxicology are also discussed. Key topics include: • the roles of apoptosis and signal transduction pathways T in normal and abnormal development HIRD • the role of epigenetic changes in development • the role of nutrition and individual susceptibility • the utility of bioinformatics E • global and targeted gene expression changes DION DEVELOPMENTAL about the editors... T T DEBORAH K. HANSEN is a research biologist in the Division of Genetic and Reproductive I Toxicology, the National Center for Toxicological Research, Jefferson and Adjunct OXICOLOGY TOXICOLOGY Associate Professor of Pharmacology and Interdisciplinary Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. She received her M.S. in genetics from Iowa State University, Ames, Iowa and her Ph.D. in medical genetics from Indiana University School of Medicine, Indianapolis, Indiana, USA. Dr. Hansen is a THIRD EDIONT I member of both the Teratology Society, of which she is Secretary, and the Society of Toxicology. She has contributed to numerous peer-reviewed publications on the subjects of reproductive toxicology, embryotoxicity, and developmental toxicology. BARBARA D. ABBOTT is Research Biologist in the Reproductive Toxicology Division of the U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina, USA. She received both her M.S. and Ph.D. in toxicology from North Carolina State University, Raleigh, North Carolina, USA. Dr. Abbott is a member of the Teratology Society and the Society of Toxicology. She is Associate Editor of Toxicological Sciences and serves on the editorial board of Reproductive Toxicology. Dr. Abbott has also received several Scientific and Technological Achievement awards from the U.S. EPA and has Edited by been a frequent invited lecturer at international meetings and symposiums. Her main Hansen area of interest is developmental toxicity, particularly complex, interactive signal Deborah K. Hansen transduction and receptor-mediated pathways. 54376 Abbott Printed in the United States of America Barbara D. Abbott DEVELOPMENTAL TOXICOLOGY TARGET ORGAN TOXICOLOGY SERIES Series Editors A. Wallace Hayes, John A. Thomas, and Donald E. Gardner Developmental Toxicology, Third Edition. Deborah K. Hansen and Barbara D. Abbott, editors, 408 pp., 2008 Adrenal Toxicology. Philip W. Harvey, David J. Everett, and Christopher J. Springall, editors, 336 pp., 2008 Cardiovascular Toxicology, Fourth Edition. Daniel Acosta, Jr., editor, 712 pp., 2008 Toxicology of the Gastrointestinal Tract. Shayne C. Gad, editor, 384 pp., 2007 Immunotoxicology and Immunopharmacology, Third Edition. Robert Luebke, Robert House, and Ian Kimber, editors, 676 pp., 2007 Toxicology of the Lung, Fourth Edition. Donald E. Gardner, editor, 696 pp., 2006 Toxicology of the Pancreas. Parviz M. Pour, editor, 720 pp., 2005 Toxicology of the Kidney, Third Edition. Joan B. Tarloff and Lawrence H. Lash, editors, 1200 pp., 2004 Ovarian Toxicology. Patricia B. Hoyer, editor, 248 pp., 2004 Cardiovascular Toxicology, Third Edition. Daniel Acosta, Jr., editor, 616 pp., 2001 Nutritional Toxicology, Second Edition. Frank N. Kotsonis and Maureen A. Mackey, editors, 480 pp., 2001 Toxicology of Skin. Howard I. Maibach, editor, 558 pp., 2000 Neurotoxicology, Second Edition. Hugh A. Tilson and G. Jean Harry, editors, 386 pp., 1999 Toxicant–Receptor Interactions: Modulation of Signal Transductions and Gene Expression. Michael S. Denison and William G. Helferich, editors, 256 pp., 1998 Toxicology of the Liver, Second Edition. Gabriel L. Plaa and William R. Hewitt, editors, 444 pp., 1997 Free Radical Toxicology. Kendall B. Wallace, editor, 454 pp., 1997 Endocrine Toxicology, Second Edition. Raphael J. Witorsch, editor, 336 pp., 1995 Carcinogenesis. Michael P. Waalkes and Jerrold M. Ward, editors, 496 pp., 1994 Developmental Toxicology, Second Edition. Carole A. Kimmel and Judy Buelke-Sam, editors, 496 pp., 1994 Nutritional Toxicology. Frank N. Kotsonis, Maureen A. Mackey, and Jerry J. Hjelle, editors, 336 pp., 1994 Ophthalmic Toxicology. George C. Y. Chiou, editor, 352 pp., 1992 Toxicology of the Blood and Bone Marrow. Richard D. Irons, editor, 192 pp., 1985 Toxicology of the Eye, Ear, and Other Special Senses. A. Wallace Hayes, editor, 264 pp., 1985 Cutaneous Toxicity. Victor A. Drill and Paul Lazar, editors, 288 pp., 1984 DEVELOPMENTAL TOXICOLOGY THIRD EDI T ION Edited by Deborah K. Hansen National Center for Toxicological Research Jefferson, Arkansas, USA Barbara D. Abbott U.S. Environmental Protection Agency Research Triangle Park, North Carolina, USA Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 C 2009 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10987654321 International Standard Book Number-10: 1-4200-5437-6 (Hardcover) International Standard Book Number-13: 978-1-4200-5437-8 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the conse- quence of their use. 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Library of Congress Cataloging-in-Publication Data Developmental toxicology. – 3rd ed. / edited by Deborah K. Hansen, Barbara D. Abbott. p. ; cm. – (Target organ toxicology series ; 27) Includes bibliographical references and index. ISBN-13: 978-1-4200-5437-8 (hardcover : alk. paper) ISBN-10: 1-4200-5437-6 (hardcover : alk. paper) 1. Developmental toxicology. 2. Fetus–Effect of drugs on. 3. Teratogenic agents. I. Hansen, Deborah Kay, 1952– II. Abbott, Barbara D. III. Series. [DNLM: 1. Abnormalities, Drug-Induced. 2. Embryonic Development–drug effects. 3. Fetal Development–drug effects. 4. Risk Assessment. 5. Teratogens. QS 679 D4893 2008] RA1224.45.D47 2008 618.32–dc22 2008026172 For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 7th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com Preface This Third Edition of Developmental Toxicology comes 14 years after the publi- cation of the Second Edition. Much has happened in the field of developmental toxicology over that period of time. Many of the advances have been in the areas of mechanistic examinations of developmental toxicants as well as in risk assess- ment, so these are the two general areas that we have chosen to focus on in this volume. The first two editions serve as a strong foundation on which to build. Many basic issues in the field of developmental toxicology were covered in those edi- tions, and the information provided in them still remains relevant today. How- ever, significant strides have been made in the area of mechanistic information. Potential mechanisms of developmental toxicants that are covered in this edition include apoptosis, alterations in signal transduction pathways, as well as effects on nutrition and epistasis. The role of the placenta in the transfer of developmental toxicants, nutrients, and wastes, as well as its role in metabolism of compounds is also covered. New techniques being used to address mechanistic