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Recent Advances in Nervous System Toxicology PDF

383 Pages·1988·11.475 MB·English
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Recent Advances in Nervous System Toxicology NATO ASI Series Advanced Science Institutes Series A series presenting the results of activities sponsored by the NA TO Science Committee, which aims at the dissemination of advanced scientific and technological knowledge, with a view to strengthening links between scientific communities. The series is published by an international board of publishers in conjunction with the NATO Scientific Affairs Division A Life Sciences Plenum Publishing Corporation B Physics New York and London C Mathematical D. Reidel Publishing Company and Physical Sciences Dordrecht, Boston, and Lancaster o Behavioral and Social Sciences Martinus Nijhoff Publishers E Engineering and The Hague, Boston, and Lancaster Materials Sciences F Computer and Systems Sciences Springer-Verlag G Ecological Sciences Berlin, Heidelberg, New York, and Tokyo Recent Volumes in this Series Volume 95-Drugs Affecting Leukotrienes and Other Eicosanoid Pathways edited by B. Samuelsson, F. Berti, G. C. Folco, and G. P. Velo Volume 96-Epidemiology and Quantitation of Environmental Risk in Humans from Radiation and Other Agents edited by A. Castellani Volume 97-lnteractions between Electromagnetic Fields and Cells edited by A. Chiabrera, C. Nicolini, and H. P. Schwan Volume 98-Structure and Function of the Genetic Apparatus edited by Claudio Nicolini and PaulO. P. Ts'o Volume 99-Cellular and Molecular Control of Direct Cell Interactions edited by H.-J. Marthy Volume tOO-Recent Advances in Nervous System Toxicology edited by Corrado L Galli, Luigi Manzo, and Peter S. Spencer Volume tOt-Chromosomal Proteins and Gene Expression edited by Gerald R. Reeck, Graham H_ Goodwin, and Pedro Puigdomemech Series A: Life Sciences Recent Advances in Nervous System Toxicology Edited by Corrado L. Galli Institute of Pharmacology and Pharmacognosy Milan, Italy Luigi Manzo Institute of Pharmacology Pavia, Italy and Peter S. Spencer Albert Einstein College of Medicine of Yeshiva University Bronx, New York Plenum Press New York and London Published in cooperation with NATO Scientific Affairs Divison Proceedings of a NATO Advanced Study Institute on Toxicology of the Nervous System, held September 10-20, 1984, in Belgirate, Italy Library of Congress Cataloging in Publication Data NATO Advanced Study Institute on Toxicology of the Nervous System (1984: Belgirate, Italy) Recent advances in nervous system toxicology. (NATO ASI series. Series A, Life sciences; v. 100) "Proceedings of a NATO Advanced Study Institute on Toxicology of the Ner- vous System, held September 10-20, 1984, in Belgirate, Italy"-Verso of Lp. "Published in cooperation with NATO Scientific Affairs Division." Bibliography: p. Includes index. 1. Nervous system-Diseases-Congresses. 2. Neurotoxic agents-Congress es. 3. Toxicology-Congresses. I. Galli, C. L. (Corrado L.) II. Manzo, L. III. Spencer, Peter S. IV. Title. V. Series. RC347.N37 1984 616.8 85-25805 ISBN-13: 978-1-4612-8229-7 e-ISBN-13: 978-1-4613-0887-4 001: 10.1007/978-1-4613-0887-4 © 1988 Plenum Press, New York A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y. 10013 Softcover reprint of the hardcover 1s t edition 1988 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher PREFACE This volume addresses some facets of the adverse actions of chemical agents on the central and peripheral nervous systems in developing and mature states. Some of the effects of these chemicals are short-lasting and rapidly reversible; others, especially those that cause structural damage to the nervous system, may result in permanent damage to the organism. The nervous system has several levels of vulnerability to toxic substances. Some substances perturb ion channels or synaptic mechanisms required for the orderly transfer of electrochemical information within the nervous system. Others disrupt sites required for the maintenance of cellular integrity, and these variably result in degenerative responses of neurons and myelinating cells. Further sites of vulnerability include the delicate neural vasculature and neurohumeral mechanisms responsible for physiological homeostasis. The science of neurotoxicology inevitably is a multidisciplinary endeavor, with contributions from biochemistry, physiology, morphology and behavior, to name a few. The challenge is to apply appropriate techniques to investigate neurotoxic phenomena. The first logical step in this analysis is to determine from the point of view of the nervous system the nature of the exposure. Is the chemical a single or multiple entity; is it metabolized; how does it gain access to neural tissue? Once these factors are understood, changes induced by the exposure can be described at various levels from the biochemical to the behavioral. Here one must strive to correlate the findings from one level of analysis to another, otherwise time is wasted in describing phenomena that are unrelated to the problem at hand. Is this biochemical alteration connected with the observed pathological change? Does this experimentally observed behavioral alteration relate to clinical neurological findings in similarly exposed humans? Do these tissue-culture changes really represent alterations that occur in the whole organism? Care in addressing these types of questions will ensure that neurotoxicology is kept on track in its principal mission of predicting, preventing, and ameliorating toxic disorders that plague mankind. v CONTENTS NEUROTOXIC EFFECTS OF PROLONGED EXPOSURE TO TOXIC AGENTS The Nervous System as a Target for Toxic Agents S Norton 3 Towards the Molecular Basis of Toxic Neuropathies J B Cavanagh 23 Biochemical Contributions to Neurotoxicology S C Bondy 43 Metabolic Activation of Neurotoxicants E Perucca, L Manzo 67 Membrane Effects of Neurotoxic Chemicals J van den Bercken 87 Mode of Action of Pyr~throid Insecticides J van den Bercken, H P M Vijverberg 91 Excitotoxins and Animal "Models" of Human Disease E G McGeer, P L McGeer 107 Retinotoxic Agents and Its Pathogenesis W Meier-Ruge 133 NEUROTOXIC AGENTS IN THE HUMAN ENVIRONMENT Analysis of Neurotoxic Disease: The Acrylamide Experience P S Spencer, H H Schaumburg 163 Neurotoxic Effects of Metals and Their Interactions J B Cavanagh 177 Organophosphorus Compounds L G Costa 203 vii viii CONTENTS The Delayed Polyneuropathy Caused by Some Organophosphorus Esters M Lotti 247 Central Nervous System Effects of Lead: a Study Model in Neurotoxicology S Govoni, F Battaini, R A Rius, C Fernicola, L Coniglio, M Trabucchi 259 EXPERIMENTAL MODELS AND ASSESSMENT OF NEUROTOXIC MECHANISMS Criteria and Strategies for Neurobehavioral Assessment S Norton 279 The Role of Neurochemistry in Behavioural Teratology and Toxicology V Cuomo, G Racagni 297 Receptor Binding Techniques in Neurotoxicology L G Costa, M Marinovich, C L Galli 307 The Use of Neurotransmitter Indices and the Deoxyglucose Technique to Assess Neurotoxic Effects E G McGeer 351 Recent Electrophysiological Techniques in Experimental Neurotoxicology P L Chambers 365 Index 377 NEUROTOXIC EFFECTS of PROLONGED EXPOSURE to TOXIC AGENTS THE NERVOUS SYSTEM AS A TARGET FOR TOXIC AGENTS Stata Norton Pharmacology, Toxicology and Therapeutics University of Kansas College of Health Sciences Kansas City, Kansas INTRODUCTION Damage to cells from toxic agents is of most serious con sequence in those tissues where restoration of function through cell division or regeneration of cell processes is difficult or impossible. This situation is most characteristic of the nervous system. Mature neurons undergo cell division either rarely or not at all and restoration of complex cell processes interacting with other cell processes may be impossible even if the neuron does not die. In addition the large size and specialized biochemistry of some of the neurons makes them uniquely susceptible to specific toxic agents, especially those interfering with availability of oxygen. The focus of this discussion will be on the effect of toxic agents which cause irreversible damage to the nervous system, although functional recovery following exposure to these agents may occur through partial regrowth ofaxons and dendritic processes. Other neuronal pathways may take over the function. Damage to, or death of, some neurons may not result in detectable loss of function if remaining neurons can adapt to carrying out the function. Usually complete recovery of function can occur at one exposure level, while larger doses result in permanent func tional damage. Acute, reversible effects of toxic agents, resembling the brief response to therapeutic actions of most orugs will not be the major consideration here. Because of the potential breadth of the topic of this presen tation, only a survey will be attempted. Subsequent presentations 3 4 S. NORTON by others will cover, in depth and sophistication, areas just touched upon briefly at this point. PERIPHERAL NERVOUS SYSTEM The peripheral nervous system is a target for various toxic chemicals. Neuropathies usually are a result of repeated expo sure, although neuropathy may result from single large doses of some of these chemicals. Acute, pharmacological effects are characteristic of chemi cals interacting reversibly at the neuromuscular junction. Neuropathy is more likely to result from effects on components of axons, myelin or nerve cell bodies in sensory ganglia or the spinal cord. Morphology The typical peripheral nerve contains nerve fibers of various sizes, from the very large myelinated sensory fibers and large myelinated motor fibers to small, unmyelinated sensory and motor fibers. The designation of fiber size is more determined by thickness of myelin than by difference in cross-sectional size of the axon in different nerve fibers. Nevertheless some of the largest nerve fibers are associated with the largest cell bodies, such as the alpha motor neurons in the ventral horn of the spinal cord. Some cell bodies associated with large fibers are small, such as the granule cells of the dorsal root sensory ganglia. One characteristic of large fibers is that they carry impulses for long distances and this function is tied to the presence of thick myel ill sheaths. Irreversible damage to the myelin sheath eventually results in loss of the axon and vice versa. There is a post-damage period during which slow regrowth of damaged axons may occur if the myelin sheath has not degenerated or if the pathway to the periph eral target can be followed by the regenerating axon. The axons contain large quantities of neurofilaments, demon strable with electron microscopy, and showing characteristic alterations with some tuxic agents. Biochemistry As noted above, the neuromuscular junction and associated neurotransmi tter, acetylcholine, are not the primary targets of most agents causing irreversible neuropathies. However, bio chemical interest has focused recently on an enzyme in the axonal membrane which interacts with various esterases. This enzyme is

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