Environmental Neurotoxicology

Committee on Neurotoxicology and Models for Assessing Risk

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
Washington, D.C.
1992



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Environmental Neurotoxicology Environmental Neurotoxicology Committee on Neurotoxicology and Models for Assessing Risk Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1992

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Environmental Neurotoxicology NATIONAL ACADEMY PRESS 2101 Constitution Ave., N.W. Washington, D.C. 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 competencies 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 Institute of Medicine. 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 government. 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 National 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 congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth Shine is president of the Institute of Medicine. Environmental neurotoxicology / Committee on Neurotoxicology and Models for Assessing Risk, Commission on Life Sciences, National Research Council p. cm. Includes bibliographical references and index. ISBN 0-309-04531-2 1. Neurotoxicology. 2. Environmental monitoring. 3. Health risk assessment. I. National Research Council (U.S.). Committee on Neurotoxicology and Models for Assessing Risk. [DNLM: 1. Environmental Exposure. 2. Nervous System--drug effects. WL 100 E61] RC347.5.E58 1991 615.9--dc20 DNLM/DLC for Library of Congress 91-43537 CIP Additional copies of this report are available from the National Academy Press, 2101 Constitution Avenue, N.W., Washington, D.C. 20418 S538 Printed in the United States of America First Printing, January 1992 Second Printing, August 1992

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Environmental Neurotoxicology Committee on Neurotoxicology and Models for Assessing Risk PHILIP J. LANDRIGAN, Chairman, Mt. Sinai School of Medicine, New York DOYLE G. GRAHAM, Vice Chairman, Duke University Medical Center, Durham, North Carolina W. KENT ANGER, Oregon Health Sciences University, Portland JEFFERY BARKER, National Institutes of Health, Bethesda, Maryland TERRI DAMSTRA, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina DALE HATIIS, Massachusetts Institute of Technology, Cambridge WILLIAM LANGSTON, California Parkinson Foundation, San Jose HERBERT E. LOWNDES, Rutgers University, Piscataway, New Jersey JOE MARWAH, National Institutes of Health, Bethesda, Maryland PIERRE MORELL, University of North Carolina, Chapel Hill TOSHIO NARASHI, Northwestern University Medical School, Chicago PHILLIP P. NELSON, National Institutes of Health, Bethesda, Maryland LAWRENCE W. REITER, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina PATRICIA RODIER, University of Rochester, Rochester, New York JOSEPH RODRICKS, Environ Corporation, Arlington, Virginia ELLEN K. SILBERGELD, University of Maryland at Baltimore, Baltimore PETER S. SPENCER, Oregon Health Sciences University, Portland BERNARD WEISS, University of Rochester, Rochester, New York RONALD WYZGA, Electric Power Research Institute, Palo Alto, California DONALD MATTISON, Liaison, Board on Environmental Studies and Toxicology JOHN L. EMMERSON, Liaison, Board on Environmental Studies and Toxicology Staff RICHARD D. THOMAS, Program Director KATHLEEN R. STRATTON, Project Director MARY B. PAXTON, Senior Staff Officer MARVIN A. SCHNEIDERMAN, Senior Staff Scientist ANDREW M. POPE, Senior Staff Officer NORMAN GROSSBLATT, Editor ANNE M. SPRAGUE, Information Specialist GARY J. BENNETT, Technical Adviser IAN C.T. NISBET, Technical Adviser HUGH TILSON, Technical Adviser LINDA V. LEONARD, Senior Project Assistant Sponsor Agency for Toxic Substances and Disease Registry, U.S. Public Health Service

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Environmental Neurotoxicology Board on Environmental Studies and Toxicology PAUL G. RISSER (Chairman), University of New Mexico, Albuquerque GILBERT S. OMENN (Immediate Past Chairman), University of Washington, Seattle FREDERICK R. ANDERSON, Washington School of Law, American University JOHN C. BAILAR, III, McGill University School of Medicine, Montreal LAWRENCE W. BARNTHOUSE, Oak Ridge National Laboratory, Oak Ridge GARRY D. BREWER, Yale University, New Haven EDWIN H. CLARK, Department of Natural Resources & Environmental Control, State of Delaware, Dover YORAM COHEN, University of California, Los Angeles JOHN L. EMMERSON, Lilly Research Laboratories, Greenfield, Indiana ROBERT L HARNESS, Monsanto Agricultural Company, St. Louis ALFRED G. KNUDSON, Fox Chase Cancer Center, Philadelphia GENE E. LIKENS, The New York Botanical Garden, Millbrook PAUL J. LIOY, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey JANE LUBCHENCO, Oregon State University, Corvallis DONALD MATTISON, University of Pittsburgh, Pittsburgh GORDON ORIANS, University of Washington, Seattle NATHANIEL REED, Hobe Sound, Florida MARGARET M. SEMINARIO, AFL/CIO, Washington, DC I. GLENN SIPES, University of Arizona, Tucson WALTER J. WEBER, JR., University of Michigan, Ann Arbor Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Program Director for Applied Ecology and Natural Resources RICHARD D. THOMAS, Associate Director and Program Director for Human Toxicology and Risk Assessment LEE R. PAULSON, Program Director for Information Systems and Statistics RAYMOND A. WASSEL, Program Director for Environmental Sciences and Engineering

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Environmental Neurotoxicology Commission on Life Sciences BRUCE M. ALBERTS (Chairman), University of California, San Francisco BRUCE N. AMES, University of California, Berkeley J. MICHAEL BISHOP, Hooper Research Foundation, University of California Medical Center, San Francisco MICHAEL T. CLEGG, University of California, Riverside GLENN A. CROSBY, Washington State University, Pullman LEROY E. HOOD, California Institute of Technology, Pasadena DONALD F. HORNIG, Harvard School of Public Health, Boston MARIAN E. KOSHLAND, University of California, Berkeley RICHARD E. LENSKI, University of California, Irvine STEVEN P. PAKES, Southwestern Medical School, University of Texas, Dallas EMIL A. PFITZER, Hoffman-LaRoche, Inc., Nutley, New Jersey THOMAS D. POLLARD, Johns Hopkins Medical School, Baltimore JOSEPH E. RALL, National Institutes of Health, Bethesda, Maryland RICHARD D. REMINGTON, University of Iowa, Iowa City PAUL G. RISSER, University of New Mexico, Albuquerque HAROLD M. SCHMECK, JR., Armonk, New York RICHARD B. SETLOW, Brookhaven National Laboratory, Upton, New York CARLA J. SHATZ, Stanford University School of Medicine, Stanford TORSTEN N. WIESEL, Rockefeller University, New York, NY JOHN E. BURRIS, Executive Director

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Environmental Neurotoxicology The National Research Council was organized by the National Academy of Sciences 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 the 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 Research Council. The project was supported by the Environmental Protection Agency; the National Institute of Environmental Health Sciences; and the Comprehensive Environmental Response, Compensation, and Liability Act Trust Fund through cooperative agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service, Department of Health and Human Services.

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Environmental Neurotoxicology Preface There is convincing evidence that chemicals in the environment can alter the function of the nervous system. The number of people afflicted with neurotoxic disease can only be estimated, because the number of neurotoxic substances is unknown but probably plentiful, and the effects on the nervous system are many and varied. Despite increasing attention to neurotoxicity in recent years, much work still needs to be done. The Board on Environmental Studies and Toxicology of the National Research Council's Commission on Life Sciences convened the Committee on Neurotoxicology and Models for Assessing Risk. Support was provided by the Agency for Toxic Substances and Disease Registry of the U.S. Public Health Service. The charge to the committee was to 1) assess the biologic bases of neurotoxicity with regard to establishing underlying principles relevant to risk assessment and extrapolation across species; 2) review existing models and indicators of neurotoxic action and disease, including structure-activity relationships, with respect to their efficacy in identifying neurotoxicants from environmental, occupational, and other potential sources; and 3) develop critical hypotheses for future research in neurotoxicology, particularly research that will lead to models for assessing the risks of neurotoxic disease. Committee members represented the breadth of disciplines involved in environmental neurotoxicology. Their expertise served the committee well as it endeavored to meet its charge. The committee met seven times over 2 years. It focused on the magnitude of the problem, the use of biologic markers, neurotoxicity testing, surveillance and epidemiology, and risk assessment. This report presents the views of the committee members, and the conclusions and recommendations reflect the committee's deliberations. The committee concluded that research is needed to improve understanding of the mechanisms of neurotoxic action and the extent of neurotoxic disease. The committee encouraged the development of a coherent, tiered testing strategy and the improvement of surveillance programs. The committee acknowledges the tireless efforts of those without whom the report would never have been completed. The committee thanks Hugh Tilson for his expertise and insight. The committee also acknowledges NRC staff for their work in organizing and managing this undertaking. Devra Davis was instrumental in conceptualizing the study initially. James Reisa, director of the Board on Environmental Studies and Toxicology, provided much welcomed guidance and encouragement. In addition to his contributions as program director, Richard

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Environmental Neurotoxicology Thomas served as interim project director and gave invaluable support to the committee and staff. The committee thanks senior staff officers Andrew Pope and Mary Paxton for their work in the formative stages of the committee process and in helping with early drafts of the report, and Kathleen Stratton for seeing the report through its final stages. The committee recognizes the tireless efforts of Anne Sprague of the Toxicology Information Center and Linda Leonard, project assistant. Norman Grossblatt and Lee Paulson served as editors. On behalf of the committee, I thank all who assisted in completing this report. Philip J. Landrigan, Chairman Committee on Neurotoxicology and Models for and Assessing Risk

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Environmental Neurotoxicology Contents     EXECUTIVE SUMMARY   1     Magnitude of the Problem   1     Neurotoxicity Testing   2     Surveillance and Epidemiologic Studies in Environmental Neurotoxicology   4     Biologic Markers in Environmental Neurotoxicology   5     Neurotoxicity Risk Assessment   5 1   INTRODUCTION: DEFINING THE PROBLEM OF NEUROTOXICITY   9     Neurologic Responses to Environmental Toxicants   9     Magnitude of the Problem of Neurotoxicity   17     Detection and Control of Exposure to Neurotoxicants   18     Scope of this Report   19 2   BIOLOGIC BASIS OF NEUROTOXICITY   21     Cellular Anatomy and Physiology   21     General Aspects of Nervous System Structure and Function   27     Vulnerability of the Nervous System to Chemical Toxicants   30     Examples of Neurotoxic Mechanisms   33     MPTP   39     Summary   40 3   BIOLOGIC MARKERS IN NEUROTOXICOLOGY   43     Concepts and Definitions   43     Validation of Biologic Markers   48     Use of Biologic Markers in Risk Assessment   53     Summary   51 4   TESTING FOR NEUROTOXICITY   53     Approach to Neurotoxicity Testing   54

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Environmental Neurotoxicology     Current Methods Based on Structure-Activity Relationships   58     Current In Vitro Procedures   59     Current In Vivo Procedures   65     Current Regulatory Approaches   86     Strategies for Improved Neurotoxicity Testing   88 5   SURVEILLANCE TO PREVENT NEUROTOXICITY IN HUMANS   95     Neurobehavioral Test Batteries   97     Current Exposure-Surveillance Efforts   104     Current Disease-Surveillance Efforts   105 6   RISK ASSESSMENT   111     Approaches to Risk Assessment for Neurotoxicity   114     Curve-Fitting in Risk Assessment for Neurotoxicity   116     Mechanistic Models for Risk Assessment for Neurotoxicity   117     Summary   120 7   CONCLUSIONS AND RECOMMENDATIONS   123     REFERENCES   129     INDEX   149

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Environmental Neurotoxicology Tables and Figures TABLES 1-1   Partial List of Neurotoxicants   10 1-2   Human and Animal Neurobehavioral Effects Attributed to at Least 25 Chemicals   11 1-3   Selected Major Neurotoxicity Events   12 2-1   Nonneuronal (Glial) Cells of the Nervous System and Their Function   22 2-2   Neuron Type Classified by Neurochemical Released for Synaptic Transmission   27 3-1   Examples of Characteristics of Exogenous; Agents, Organisms, or Targets That Influence Choice of Biologic Marker   44 3-2   Selected Markers of Neurotoxicity in Nervous System   45 4-1   In Vitro Neurobiologic Test Systems   62 4-2   Markers for Assessing Neurotoxicity in In Vitro Systems   63 4-3   Proposed Protocol for Developing and In Vitro Neurotoxicity Screening System   65 4-4   Neurotoxic Effects of Representative Agents in Humans and Animals   67 4-5   Examples of Behavioral Measures of Functional Neurotoxicity   69 4-6   End Points That Might be Included in a Functional Observational Battery   71 4-7   Areas of the Nervous System to be Used in Neuropathologic Evaluation   81 4-8   Tissues of the Nervous System to be Used in Neuropathologic Evaluation   82 4-9   Tests Used in NCTR Collaborative Study   83 4-10   Proposed Components for Evaluating In Vitro Neurotoxicity Screening Tests   92 5-1   Characteristics of Responses to Exposure to Some Neurotoxicants   98 5-2   Components of Clinical Neurologic Examination   100 5-3   Test Batteries   102 6-1   Some Neurotoxicants That Act on Receptors   118

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Environmental Neurotoxicology FIGURES 2-1   Diagrammatic representation of neuronal structure   23 2-2   Events in chemical synaptic transmission   26 2-3   Structures of type I and type II pyrethroids   34 2-4   Metabolism of hexane   37 2-5   Diagram of MPTP toxicity   39 3-1   Simplified classification of biologic markers   46 4-1   Biologic markers in the stages between formation and degneration of neural circuits   91 6-1   Effect of a shift in mean IQ score on the population distribution   113 6-2   Estimated developmental scores at various ages for three blood-level concentrations   115 6-3   Percentage of severe mental retardation among those exposed in utero by dose and gestational age in Hiroshima and Nagasaki   119