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Behavioral
Measures
OF
Neuro toxicity
Report of a Symposium
Roger W. Russell, Pamela Ebert Flattau,
and Andrew M. Pope, editors
U.S. National Committee for the International
Union of Psychological Science
Commission on Behavioral and
Social Sciences and Education
National Research Council
NATIONAL ACADEMY PRESS
Washington, D.C. 1990
OCR for page R2
National Academy Press · 2101 Constitution Avenue, NW · Washington, DC 20418
NOTICE: The project that is the subject of this report was approved by the Governing
Board of the National Research Council, whose members are drawn from the councils
of the National Academy of Sciences, the National Academy of Engineering, and the
Institute of Medicine. The members of the committee responsible for the report were
chosen for their special competences and with regard for appropriate balance.
This report has been reviewed by a group other than the authors according to
procedures approved by a Report Review Committee consisting of members of the
National Academy of Sciences, the National Academy of Engineering, and the Insti-
tute of Medicine.
Library of Congress Cataloguing-in-Publication Data
Behavioral measures of neurotoxicity: report of a symposium / Roger
W. Russell, Pamela Ebert Flattau, and Andrew M. Pope, editors.
p. cm.
Based on the Workshop on Behavioral Aspects of Neurotoxicity,
Critical Issues, held in Aug. 1988 at the Australian National
University in Canberra; sponsored by the U.S. National Committee for
the International Union of Psychological Science (USNC/IUPsyS).
Includes bibliographical references.
Includes index.
ISBN 0-309-04047-7
1. Neurotoxicology—Congresses. 2. Pollutants—Toxicology-
Congresses. 3. Nervous system Diseases Environmental aspects-
Congresses. 4. Neuropsychological tests—Congresses. I. Russell,
Roger W. II. Flattau, Pamela Ebert. III. Pope, Andrew MacPherson,
1950- . IV. U.S. National Committee for the International Union
of Psychological Science. V. Workshop on Behavioral Aspects of
Neurotoxicity: Critical Issues (1988: Australian National
University)
[DNLM: 1. Behavior drug effects—congresses. 2. Nervous System
Diseases—chemically induced congresses. 3. Neurotoxins adverse
effects congresses. WL 103 B419 1988]
RC347.5.B44 1990
616.8- dc20
DNLM/DLC
for Library of Congress
Copyright ~ 1990 by the National Academy of Sciences
Printed in the United States of America
90-6565
CIP
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U.S. NATIONAL COMMITTEE FOR THE
INTERNATIONAL UNION OF
PSYCHOLOGICAL SCIENCE
JAMES L. MCGAUGH (Chair), Center for the Neurobiology of
Learning and Memory, University of California, Irvine
DOROTHEA JAMESON Vice Chair), Department of Psychology,
University of Pennsylvania
ALBERT BANDURA, Department of Psychology, Stanford
University
ROCHEL GELMAN, Department of Psychology, University of
California, Los Angeles
ROBERT GLASER, Learning Research and Development Center,
University of Pittsburgh
WILLARD W. HARTUP, Institute of Child Development, University
of Minnesota
GEORGE MANDLER, Department of Psychology, University of
California, San Diego
MARK R. ROSENZWEIG, Department of Psychology, University of
California, Berkeley
ROBERT B. ZAJONC, Research Center for Group Dynamics,
University of Michigan
ROBERT MCC. ADAMS Sex officio>, Chair, Commission on
Behavioral and Social Sciences and Education
WILLIAM E. GORDON Rex officios, Foreign Secretary, National
Academy of Sciences
WAYNE H. HOLTZMAN Vex officios, President, International Union
of Psychological Science
PAMELA EBERT FLATTAU, Staff Officer
CAROL METCALF, Administrative Secretary
. . .
tit
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The National Academy of Sciences is a private, nonprofit, self-perpetuating society
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Upon the authority of the charter granted to it by the Congress in 1863, the Academy
has a mandate that requires it to advise the federal government on scientific and
technical matters. Dr. Frank Press is president of the National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of
the National Academy of Sciences, as a parallel organization of outstanding engineers.
It is autonomous in its administration and in the selection of its members, sharing with
the National Academy of Sciences the responsibility for advising the federal govern-
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aimed at meeting national needs, encourages education and research, and recognizes
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The National Research Council was organized by the National Academy of Sci-
ences in 1916 to associate the broad community of science and technology with the
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search Council.
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SYMPOSIUM CONTRIBUTORS
W. KENT ANGER, National Institute of Occupational Safety and
Health, Cincinnati, Ohio, U.S.A.
ELAINE L. BAILEY, School of Biological Science, The Flinders
University, Australia
JOHN GRAHAM BEAUMONT, Department of Psychology,
University College of Swansea, United Kingdom
M.G. CASSITTO, Institute of Occupational Health, Milan, Italy
DEBORAH A. CORY-SLECHTA, School of Medicine and Dentistry,
University of Rochester, New York, U.S.A.
PAMELA EBERT FLATTAU, National Research Council,
Washington, D.C., U.S.A.
FRANCESCO GAMBERALE, Division of Psychophysiology,
National Institute of Occupational Safety and Health, Solna, Sweden
RENATO GILIOLI, Institute of Occupational Health, Milan, Italy
HELENA HANNINEN, Institute of Occupational Health, Helsinki,
Finland
WAYNE H. HOLTZMAN, Hogg Foundation for Mental Health,
University of Texas, Austin, U.S.A.
ANDERS IREGREN, Division of Psychophysiology, National
Institute of Occupational Safety and Health, Solna, Sweden
ANDERS KlELLBERG, Division of Psychophysiology, National
Institute of Occupational Safety and Health, Solna, Sweden
NORMAN KRASNEGOR, National Institute of Child Health and
Human Development, Bethesda, Maryland, U.S.A.
BEVERLY M. KULIG, Medical Biological Laboratories, TNO,
Rijswijk, The Netherlands
ROBERT MACPHAIL, Environmental Protection Agency, Research
Triangle Park, North Carolina, U.S.A.
MANNA MICHALEK, Laboratory of Pharmacology, Instituto
Superiore di Sanita, Rome, Italy
DAVID H. OVERSTREET, School of Biological Science, The Flinders
University, Australia
~Affiliations of contributors are as of 1988.
V
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ANNITA PINTOR, Laboratory of Pharmacology, Instituto Superiore
di Sanita, Rome, Italy
ANDREW M. POPE, National Research Council, Washington, D.C.,
U.S.A.
DEBORAH C. RICE, Toxicology Research Division, Bureau of
Chemical Safety, Ottawa, Canada
ROGER W. RUSSELL, Department of Pharmacology, University of
California, Los Angeles, U.S.A.
VINOD BEHARI SAXENA, Department of Psychology, P.P.N.
College, Kanpur University, India
GEORGE SINGER, Brain-Behavior Research Institute, La Trobe
University, Australia
PETER S. SPENCER, Center for Research on Occupational and
Environmental Toxicology, Oregon Health Sciences University,
Portland, U.S.A.
BERNARD WEISS, School of Medicine and Dentistry, University of
Rochester, New York, U.S.A.
ANN M. WILLIAMSON, National Institute of Occupational Health
and Safety, Sydney, Australia
GERHARD WINNEKE, Medical Institute for Environmental
Hygiene, Dusseldorf, West Germany
LIANG YOU-XIN, Department of Occupational Health, Shanghai
Medical University, The People's Republic of China
vz
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Preface
The U.S. National Committee for the International Union of Psy-
chological Science (USNC/IUPsyS) is a standing committee of the
National Research Council's (NRC) Commission on Behavioral and
Social Sciences and Education. Established in 1985, the committee
promotes the advancement of the science of psychology in the United
States and throughout the world. It does so by advising the Presi-
dent of the National Academy of Sciences on matters pertaining to
U.S. participation in the Union and by planning and sponsoring sci-
entific meetings in the United States and abroad in accordance with
the objectives of the International Union of Psychological Science.
A continuing concern of the committee has been U.S. participation
in the International Congress of Psychology. Although the USNC/
IUPsyS is a relatively young committee by NRC standards (the oldest
were established in the early 1920s), U.S. representatives have been
active in the affairs of the Union since its inception in 1952. Thus, in
its establishment by the NRC in 1985, the role of the committee was
to continue U.S. participation in Union affairs. One of the first items
of committee business was the exchange of correspondence with the
Australian scientific program committee regarding possible topics for
inclusion in the XXIV International Congress of Psychology held in
Sydney in August 1988. The committee recommended that U.S. psy-
chologists both organize and participate in symposia in scientific
psychology.
One area that emerged during committee deliberations as a topic
. ~
v''
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· ~ ~
Vlll
PREFACE
of significant scientific interest was behavioral analysis of the action
of environmental toxicants on neural tissue. The committee noted
that numerous researchers in the United States and abroad were engaged
in the development of neurobehavioral tests of toxic exposure. With
funds provided by the U.S. Environmental Protection Agency (EPA),
the committee organized a meeting in 1987 to develop the agenda for
an invitational workshop to be held in conjunction with the XXIV
International Congress, drawing speakers from the diverse array of
behavioral scientists planning to attend the congress.
In August 1988, the committee convened the "Workshop on Be-
havioral Aspects of Neurotoxicity: Critical Issues." Workshop par-
ticipants, drawn from 12 countries, met for three days at the Austra-
lian National University in Canberra; Vice Chancellor L.W. Nichol
kindly welcomed participants on behalf of the University. The 20
specialists participating in the workshop met to review progress to-
ward the development of behavioral tests of neurotoxicity. The meeting
began with a report of the findings from field work studies by Pro-
fessor Peter Spencer. Spencer's research has led to a new understanding
of the direct relationship between environmental toxicants and the
occurrence of neurodegenerative disease arising from the health and
social practices of Pacific Islanders. Papers by the remaining workshop
participants provided a state-of-the-art review of behavioral measures
of neurotoxicity and suggested new directions, given emerging knowledge
of the interactive effects of environmental toxicants and neurodegenerative
disorders.
Five panels were assembled to address separate but interrelated
topics: (1) assessment of neurobehavioral tests now in use; (2) animal
models: what has worked and what is needed; (3) "chemical time
bombs": environmental causes of neurodegenerative diseases; (4) re-
gional issues in neurobehavioral toxicity testing; and (5) recommendations
for further research and testing. The Appendix contains a list of
conference participants and the detailed program. Background papers
were prepared by each participant and circulated well in advance of
the meeting. Discussants similarly prepared a response to panelists'
papers, with the preliminary responses also circulated prior to the
meeting. This report presents those papers in a collected volume.
Funding for the workshop was provided by several U.S. sources,
including EPA, the National Institute for Occupational Safety and
Health, the National Institute of Child Health and Human Development,
and a consortium of private contributors (Rohm & Haas Co., Abbott
Laboratories, Lilly-Research Laboratories, Burroughs Wellcome Co.,
Hoffmann-La Roche).
In addition to the workshop participants, a number of people con-
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PREFACE
lo
tributed in important ways to the success of the workshop and to this
report. Roger Russell, Emeritus Professor, University of California,
Los Angeles, has served as a wise and enthusiastic consultant to the
committee, helping to shape the workshop program, meeting logistics,
and the final report. The committee is deeply indebted to Professor
Russell for these contributions. Andrew M. Pope, staff officer with
the NRC Board on Environmental Studies and Toxicology, provided
valuable technical assistance in organizing the workshop. Pamela
Ebert Flattau, the committee's study director, planned the workshop
and played a significant role in overseeing the development of this
volume. Carol Metcalf, the committee's administrative secretary, worked
tirelessly to coordinate the production of the workshop papers. To
all these people, we express our gratitude for their efforts.
lames L. McGaugh, Chair
U.S. National Committee for the International
Union of Psychological Science
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Contents
Introduction
Are Neurotoxins Driving Us Crazy? Planetary
Observations on the Causes of Neurodegenerative
Diseases of Old Age ............................
Peter S. Spencer
· ~
PART I. ASSESSMENT OF NEUROBEHAVIORAL
TESTS NOW IN USE
Methods in Behavioral Toxicology: Current Test
Batteries and Need for Development.......
Helena Hanninen
The Current Status of Test Development in
Neurobehavioral Toxicology ..............
Ann M. Williamson
Human Neurobehavioral Toxicology Testing
W. Kent Anger
Neurobehavioral Tests: Problems, Potential, and
Prospects . .
I. Graham Beaumont
· · · · · · · 11
.
·
x'
39
. . . . . 56
69
86
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Xil
PART II. ASSESSMENT OF ANIMAL MODELS:
WHAT HAS WORKED AND WHAT IS NEEDED
Exposure to Neurotoxins Throughout the Life Span:
Animal Moclels for Linking Neurochemical Effects to
Behavioral Consequences ......................
Hanna Michalek and Annita Pintor
Animal Models of Dementia: Their Relevance to
Neurobehavioral Toxicology Testing.............
David H. Overstreet and Elaine L. Bailey
· —
Bridging Experimental Animal and Human Behavioral
Toxicology Studies .....................................
Deborah A. Cory-Slechta
Methods and Issues in Evaluating the Neurotoxic
Effects of Organic Solvents..............................
Beverly M. Kulig
Animal Moclels: What Has Worked and
What Is Needed........................................
Robert C. MacPhai]
PART III. CHEMICAL TIME BOMBS: ENVIRONMENTAL
CAUSES OF NEURODEGENERATIVE DISEASES
On the Identification and Measurement of Chemical
Time Bombs: A Behavior Development Perspective
Norman A. Krasnegor
Neurobehavioral Time Bombs: Their Nature and
Their Mechanisms...............................
Roger W. Russell
Neurobehavioral Toxicity of Selected Environmental
Chemicals: Clinical and Subclinical Aspects ........
Gerhard Winneke
The Health Effects of Environmental Lead Exposure:
Closing Pandora's Box..........................
Deborah C. Rice
Chemical Time Bombs: Environmental Causes of
Neurodegenerative Diseases ............
Peter S. Spencer
CONTENTS
....... 101
. . . . . . . 124
137
159
184
.191
. 206
. 226
243
268
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CONTENTS
PART IV. BEHAVIORAL ASPECTS OF NEUROTOXICITY:
REGIONAL ISSUES
. . .
x'''
Neurobehavioral Toxicity Testing in China 287
7=iang You-Xin
Regional Issues in the Development of the
Neurobehavioral Core Test Battery 312
Renato Gilioli and Maria G. Cassitto
Issues in the Development of Neurobehavioral Toxicity
Tests in India
Vinod Behari Saxena
Regional Issues in Neurobehavioral Testing:
An Overview
Ann M. Williamson
PART V. RECOMMENDATIONS FOR FURTHER
RESEARCH AND TESTING
Environmental Modulation of Neurobehavioral
· —
Toxicity .. ................ ~ ~
322
337
Robert C. MacPhai]
Computerized Performance Testing in Neurotoxicology:
Why, What, How, and Whereto? 359
Francesco Gamberale, Andlers Iregren, and Anders KjeZ]berg
The Scope and Promise of Behavioral Toxicology 395
Bernard Weiss
Appendix: Symposium Agenda 415
Index .
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Behav loran
Measures
OF
Neuro toxicity
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