Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page R1
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
OCR for page R2
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
OCR for page R3
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
OCR for page R4
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
OCR for page R5
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
OCR for page R6
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.
OCR for page R7
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
OCR for page R8
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
OCR for page R9
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
OCR for page R10
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
OCR for page R11
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
OCR for page R12
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
