Recent Advances in Nervous System Toxicology

383 Pages·1988·11.475 MB·English

by  Stata Norton (auth.), Corrado L. Galli, Luigi Manzo, Peter S. Spencer (eds.)

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