Human Developmental Toxicants

Human Developmental Toxicants Aspects of Toxicology and Chemistry James L. Schardein & Orest T. Macina Boca Raton London New York CRC is an imprint of the Taylor & Francis Group, an informa business © 2007 by Taylor & Francis Group, LLC CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487‑2742 © 2007 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid‑free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number‑10: 0‑8493‑7229‑1 (Hardcover) International Standard Book Number‑13: 978‑0‑8493‑7229‑2 (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. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data Schardein, James L. Human developmental toxicants : aspects of toxicology and chemistry / James L. Schardein, Orest T. Macina. p. cm. Includes bibliographical references and index. ISBN 0‑8493‑7229‑1 ‑‑ ISBN 1‑4200‑0675‑4 1. Pediatric toxicology. 2. Fetus‑‑Effect of drugs on. 3. Fetus‑‑Effect of chemicals on. I. Macina, Orest T. II. Title. RG627.6.D79S35 2006 618.92’98‑‑dc22 2006044602 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com © 2007 by Taylor & Francis Group, LLC Foreword Much attention has focused on the identification of drugs and chemicals that produce malformations following human exposure during in utero development. However, as noted by the authors of this monograph, that is only one of the four types of adverse effects that may occur following exposure (or treatment) during development. Over the past several decades, clinicians and developmental scientists have established that developmental toxicity includes not only structural malformations but also growth retardation and death, as well as functional (including behavioral) abnormalities. Research by these clinicians and developmental scientists has also pointed out that vulnerable periods for developmental toxicology may begin prior to conception and extend well beyond birth. The work of Schardein and Macina in this monograph provides a unique resource that links chemistry with developmental toxicity profiles of the pharmaceuticals and industrial chemicals that represent the majority of presently known human developmental toxicants to which pregnant women may be exposed, either therapeutically or through the workplace or home environment. The use of human data as the initial source of comparison of toxicological and chemical properties is logical, because the target of toxicity of greatest priority is the human species. Human data are supplemented with available animal data for comparative purposes and to discern any “animal models” of the corresponding human effect. The chemistry component entails the chemical struc-ture as well as a set of computationally calculated physicochemical and topological parameters that represent the steric, transport, and electronic properties of the selected molecules. The inclusion of chemical property data represents a new focus on attempts to understand chemically induced developmental toxicity. As significant as this work is in assisting our understanding of developmental toxicology, it is also essential to note that we are just at the threshold. Much remains to be done to improve our ability to understand why and how a chemical may alter the many different steps occurring during development. The calculated properties presented within this monograph (and on the accompanying CD) can be utilized by interested investigators in deriving structure–activity relationship (SAR) models linking the chemical structure and properties with the observed human and animal devel-opmental toxicity data. Successful SAR models for developmental toxicity would be an invaluable adjunct to the risk assessment process as well as in the investigation of the mechanistic basis of developmental events. This critical work will improve both our ability to predict chemicals that may produce devel-opmental toxicity as well as to provide insight into the chemical properties responsible for the observed effects on human development. Donald R. Mattison, M.D. Captain, U.S. Public Health Service Senior Advisor to the Directors of the National Institute of Child Health and Human Development (NICHD) and the Center for Research for Mothers and Children (CRMC) Branch Chief, Obstetric and Pediatric Pharmacology Branch National Institutes of Health, U.S. Department of Health and Human Services © 2007 by Taylor & Francis Group, LLC Preface The Human Developmental Toxicants Database (HumDevTox) is a chemical structure–chemical property–biological activity database for 50 known agents that adversely affect human development as a result of exposure prior to conception or during prenatal and postnatal development. The developmental effects elicited include growth retardation, death, structural abnormality, and func-tional deficits. These effects vary from single endpoints of marginal or even questionable validity, to severe, proven effects of teratogenesis or death. The database also includes available animal data for each of the human developmental toxicants identified and discussed in this book. The electronic component of the database consists of three-dimensional structures and 49 calculated physicochemical and topological properties for each of the agents. The complete database is in the form of an SD file, and it includes the three-dimensional chemical structures, calculated physicochemical and topological properties, and the associated biological data in humans and animals. The construction of a database consisting of the chemical structures and properties of human developmental toxicants and the associated animal developmental data provides a valuable resource for the biomedical scientific community. To our knowledge, a detailed database such as this for human developmental toxicity does not exist in the public domain. This unique database will serve as a reference source for toxicologists, teratologists, chemists, and other scientists interested in mammalian development, and as a starting point for investigating the chemical requirements necessary for exhibiting human developmental toxicity as well as the differences in various species. DEVELOPMENTAL TOXICOLOGY With thousands of drugs already available and 300 new ones approved for marketing over the past decade alone (Lacy et al., 2004), together with >70,000 chemicals circulating in the environment (Fagin et al., 1996), there is increasing concern for the safety of pregnant women and their offspring. This is so because a high percentage of them are exposed to these agents, despite the rigorous testing of all chemical agents before they reach the marketplace. It has been established for over 30 years that there are four classes of embryo/fetal toxicity, or more properly, developmental toxicity, in mammalian species, including humans (Wilson, 1973). In simplest terms, these are growth retardation, death, malformation or terata, and functional deficit. While it has been commonplace to term those agents that induce malformations as “teratogens,” it is equally proper to term agents that affect one or more of these classes as “developmental toxicants.” This term, to our knowledge, is attributable to scientists at the U.S. Environmental Protection Agency (EPA), formulated in 1980 and publicly defined in an EPA guideline document some 6 years later (U.S. EPA, 1980, 1986). It was coined to denote those agents that induce any one or more of the four classes of developmental toxicity, as defined in those documents. The term has since been used in regulatory documents and by investigators in other publications. Adverse effects comprising these classes are shown in Table 1. The classes of developmental toxicity demonstrate a continuum, many times appearing together (e.g., growth retarded fetuses may have structural malformations, of which some may be lethal and some may be associated with functional deficiencies). While teratogens have been emphasized in importance in pregnancy studies, all classes are of equal importance in assessing developmental toxicity, whether it be in animals or in humans. The natural history of developmental parameters in humans is shown in Table 2. © 2007 by Taylor & Francis Group, LLC TABLE 1 Adverse Endpoints Comprising Classes of Developmental Toxicity in Animals and Humans Endpoints Class Growth retardation Death Malformation Functional deficit Animals Reduced fetal body weight Embryolethality, abortion, postnatal mortality Minor/major congenital (structural) abnormalities, anatomical (developmental) variations Postnatal behavioral alterations, developmental delay Humans Intrauterine growth retardation (IUGR), low birth weight, prematurity, microcephaly Spontaneous abortion, stillbirth, fetal wastage, perinatal mortality Minor/major congenital (structural) abnormalities Mental retardation/deficiency, metabolic alteration, altered social behavior, neurological deficit, developmental delay TABLE 2 Normal Incidence Patterns of Adverse Developmental Effects in Humans Normal Incidence Developmental Effect (%) Ref. Growth retardation Intrauterine growth retardation (IUGR) Low birth weight Prematurity Spontaneous abortion (<20 weeks) Early embryonic/fetal Late fetal Stillbirth Neonatal Infant Pregnancy loss (total) Minor Major Defects at birth Defects at 1 yr 3–10 7.9 6.4–9.2 Death 20 11–25 1 2 1 1.4 31 Malformation 14 2–4 2–3 6–7 Seeds, 1984 Hamilton et al., 2004 Chez et al., 1976 Abortion statistics, 1995 Hook, 1981 Hook, 1981 Rosenberg, 1984 Hook, 1981 Hook, 1981 Wilcox et al., 1988 Hook, 1981 Rosenberg, 1984; VanRegemorter et al., 1984 Hook, 1981 Hook, 1981 Functional deficit Children in need of special education Mild mental retardation Severe mental retardation 10–15 0.6 0.3–0.4 Gaddes, 1980 Hook, 1981 Hook, 1981 © 2007 by Taylor & Francis Group, LLC ... - tailieumienphi.vn