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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

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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 of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. 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- ment. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Robert M. White is president of the Na- tional Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congres- sional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Samuel O. Thier is president of the Institute of Medicine. 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 Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Frank Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National Re- 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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