Developmental Toxicology PDF
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Developmental Toxicology Developmental Toxicology Edited by Keith Snell 'If Croom Helm London ©1982 Keith Snell Softcover reprint of the hardcover 1s t edition 1982 Croom Helm Ltd, 2-10 St John's Road, London SWll British Library Cataloguing in Publication Data Snell, Keith Developmental toxicology. 1. Abnormalities, Human I. Title 616'.043 RG626 ISBN-13: 978-1-4615-9792-6 e-ISBN-13: 978-1-4615-9790-2 DOl: 10.1007/978-1-4615-9790-2 Typesetting by Elephant Productions, London SE1S Biddies Ltd, Guildford and King's Lynn Contents Preface 1. Model Systems in Teratology Research Felix Beck 11 2. The In Vitro Approach to Teratogenicity Testing Nigel A. Brown and Sergio E. Fabro 31 3. The Use of Cell Culture Methods for Exploring Teratogenic Susceptibility Ruth M. Clayton and Ahmet Zehir 59 4. Biochemical Mechanisms of Teratogenesis Kenneth E. Williams 93 5. The Distribution of Drugs and Other Agents in the Fetus Sven Ullberg, Lennart Dencker and Bengt Danielsson 123 6. The Differentiation of Drug Metabolism in Relation to Developmental Toxicology Olavi Pelkonen 165 7. The Role of the Placenta in Developmental Toxicology Mont R. luchau 187 8. Developmental Carcinogenicity Paul Kleihues 211 9. Behavioural Teratogenicity Charles V. Vorhees and Richard E. Butcher 247 10. Developmental Enzyme Pathology Keith Snell 299 Notes on Contributors 340 Index 341 Preface Since the 1930s and the work of Hale and Warkany on birth defects produced by variations in dietary vitamin A, it has been recognised that the developing fetus is particularly vulnerable to adverse influences in the environment. . Studies of malformations at birth remained largely in the hands of paediatricians who, for instance, quickly established the con nection between rubella infection in early pregnancy and the birth of severely affected infants. However, it was through the tragic events of 1962, when dramatic increases in the incidence of phocomelia in newborn infants in Germany, the United Kingdom, Japan, and other countries were traced to the use of the apparently non-toxic sedative thalidomide by pregnant women, that toxicologists were brought face to face with the devastating possibility of chemically-induced developmental abnormalities. It had been shown earlier that chemotherapeutic agents could cause damage to the developing organism, but the absence of any known examples of drug-induced birth defects had produced an air of complacency which was reinforced by the lack of any specific regulatory requirements for safety evaluation in this area. The magnitude of the thalidomide tragedy, affecting some 10000 malformed children, was sufficient to cause an immediate, and some would say hasty, reaction by government drug regulatory agencies throughout the world to construct a test protocol which would detect potential teratogenic substances that might give rise to anatomical malformations. Such empirically based protocols paid scant attention to the spectrum of possible developmental abnormalities that may befall the developing organism and more recent revised regulatory guidelines require investigations that include reproduction studies, tera tology studies and postnatal studies. The latter category is noteworthy in that it raises two fundamental issues in developmental toxicology. One is the recognition that develop ment, and the susceptibility of the developing organism, is not confined to the prenatal phase of life but continues during postnatal life. This is a particularly significant concept for toxicology in the light of the known Preface transmission of therapeutic agents and environmental pollutants to the suckling infant in the breast milk of the nursing mother, the so-called translactational route of exposure (cf. transplacental exposure). The other is the question of the latency of developmental toxic responses which may only become overtly manifest as maturation proceeds. Thus, although the critical toxic event itself may have occurred during gestation, the defect or disturbance may be functional rather than structural and may not be revealed until these functions and other associated processes are brought into action at a later maturational stage, often in the postnatal period. Moreover, for toxic interactions which are initiated postnatally, the eventual derangement may not occur until much later in life. In these cases, where cause and effect are temporally separated, it is difficult to explore the mechanisms just by examining the end-results. It is equally difficult to devise testing procedures which would be able to detect the full range of possible developmental toxic phenomena. The aim of this book is to provide a forum for a discussion of the inter actions between toxic agents and developmental processes. It is not a recipe book for test procedures for detecting teratogenicity or develop mental toxicity. Rather it seeks to show the current status of various aspects of research in developmental toxicology which should comprise the background knowledge required to approach the problem of the detection of such hazards in a rational fashion governed by scientific rather than empirical considerations. It is axiomatic in toxicology, and developmental toxicology is no exception, that the discipline as a whole is made up of many varied specialist areas of expertise. It is important for the scientific advancement of the subject that these individual specialisms should be intelligible to each other so that their contributions can be properly evaluated. In this spirit the various contributors to the book have been charged with the task of presenting a review of their specialist area which should not only describe the current research efforts in that area and the concepts which are emerging, but also place these in perspective and discuss them in a way which will allow them to be appreciated by the non-specialist in that area. The book, then, is aimed at a broad readership which will include practising toxicologists, especially those concerned with evaluating develop mental hazards whether their role is in the laboratory or in the legislative departments of government and industry. It will also include those research scientists who are interested in the effect of toxic agents on the processes of mammalian development and the mechanisms of such interactions. Hopefully, this book will also be read by those members of the medical Preface profession, particularly paediatricians, who are faced with the consequences of the untoward effects of therapeutic and environmental agents on the developing human organism. Finally, it is intended that the book should prove useful to those students in universities and young scientists in industrial training who are embarking on a career in toxicology and who would benefit from an overview of the current preoccupations of develop mental toxicology. The book begins with a consideration of various aspects of teratology, particularly the use of model systems using techniques in vitro. These are proving useful in dissecting the mechanistic events of teratogenesis free from the secondary events which can lead to ambiguity with studies in vivo (Beck). The applications of some of these in vitro systems for use in testing chemicals for teratogenic potential are described by Brown and Fabro. The use of in vitro cell culture systems for exploring the nature and timing of teratogenic susceptibility is illustrated with reference to examples of known teratogens by Clayton and Zehir. Williams discusses the biological and biochemical bases for teratogenic actions. One of the factors deter mining the susceptibility of the developing organism to developmental toxicity in general is the manner and extent to which chemical substances are distributed (Ullberg et al.) or undergo bioactivation or detoxification (Pelkonen; Juchau) in the materno-placental-fetal unit. Bioactivation is a key factor in determining the carcinogenicity of many agents and Kleihues discusses the effect of carcinogens on the developing organism, with particular emphasis on tumours of the nervous system and the mechanisms which determine carcinogenic susceptibility. Functional developmental aberrations which only become manifest at later periods after the original toxic insult are illustrated by examples of behavioural teratogenicity (Vorhees and Butcher) and of biochemical or metabolic teratogenesis and developmental toxicity (Snell). This final chapter also describes the possible use of developmental biochemical parameters (particularly enzymes) in the early detection of developmental aberrations induced by developmental toxicants and carcinogens (Snell). As editor of the book I am indebted to my colleagues and co-authors for the enthusiastic and diligent manner in which they approached their various contributions. Even if, in certain cases, the gestation period proved somewhat longer than expected, the finished articles more than justified their conception. I am grateful to Tim Hardwick of Croom Helm for prompting the initial implantation and for guiding the whole conceptus on its journey into life. I should also like to acknowledge with thanks the ministering efforts and secretarial co-operation ofPrue Levers and Janet Cole Preface in assisting with the delivery. In the end of course, as with any newly created being, this book must justify its existence on its own merits. It is my hope that they approach closely the original aspirations. Keith Snell Toxicology Division, Biochemistry Department, University of Surrey, Guild ford CHAPTER ONE MODEL SYSTEMS IN TERATOLOGY RESEARCH Felix Beck CONTENTS I Introduction 13 II. In Vivo Systems 14 A. Screening for Potentially Embryopathic Agents 14 B. The Study of Teratogenic Mechanisms 16 III. Some Model Systems to Study Teratogenic Mechanisms Using Surgical Techniques 20 IV. Some Model Systems Using In Vitro Techniques 24 A. Embryo Culture 24 B. Organ Culture 25 C. Cell Culture 27 V. Conclusion 27 References 28 I. Introduction Broadly speaking, teratology research falls into two main categories. The first is essentially concerned with identifying extrinsic and intrinsic factors responsible for embryopathies. In pursuing such objectives account is taken not only of the biological effects of potentially embryotoxic agents in isolation but also of the so-called dramatype of the experimental animal used (i.e. the combination of the maternal phenotype with the multiple environmental f,!ctors which play upon it) as well as a consideration of the embryonic genotype and its contribution in facilitating or hindering the action of agents which tend to disturb development. Clearly the widest application of this type of work is in the testing of drugs and other con sumer products for possible embryopathic effects. A quartet of effects are relevant in this context; namely, fetal death (with consequent resorption or abortion), fetal malformation (true teratologies in the morphological sense) abnormalities of function (perhaps associated with faulty histo genesis) and intra-uterine growth retardation. The second principal aim of teratology research is the precise elucidation of the natural history of a congenital disorder. Here Wilson's (1977) subdivision of the process into an initial mechanism (such as a gene mutation) which leads to a pathogenic event (for example impeded morpho genetic movement) with a subsequent final defect being produced by a restricted number of common pathways (such as too few cells to effect localised morphogenesis) is a useful concept, though it is probably in complete and oversimplified. Teratology research, therefore, is a wide field with an important unifying 13
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