Neurotoxicity: Identifying and Controlling Poisons of the Nervous System April 1990 OTA-BA-436 NTIS order #PB90-252511 Recommended Citation: U.S. Congress, Office of Technology Assessment, Neurotoxicity: Identifying and Controlling Poisons of the Nervous System, OTA-BA-436 (Washington, DC: U.S. Government Printing Office, April 1990). For sale by the Superintendent of Documents U.S. Government Printing Office, Washington, DC 20402-9325 (order form can be found in the back of this report) . Foreword Extraordinary developments in the neuroscience in recent years have been paralleled by a growing congressional interest in their policy implications. The designation of the 1990s by the 101st Congress as the “Decade of the Brain” is one indication of the promise shown by scientific advances for treating diseases of the nervous system and for increased general understanding of the human mind. Other advances, however, have led us to the disturbing realization that many commonly used chemicals can adversely affect the human nervous system. Concern about this issue provided the motivation for hearings held in October 1985 on ‘‘Neurotoxins in the Home and in the Workplace’ by the Subcommittee on Investigations and Oversight of the House Committee on Science and Technology. Another result of heightened congressional interest was a request that OTA undertake a series of assessments on major public policy issues related to the neuroscience. Requesting committees included the House Committees on Science, Space, and Technology; Energy and Commerce; Appropriations; and Veterans’ Affairs; and the Senate Subcommittee on Science, Technology, and Space of the Committee on Commerce, Science, and Transportation. In addition, the Senate Committee on Environment and Public Works recently requested a study of the noncancer health risks posed by toxic substances. This Report, the first of the neuroscience series, discusses the risks posed by neurotoxic substances—substances that can adversely affect the nervous system—and evaluates the Federal research and regulatory programs now in place to address these risks. One finding of this Report is that considerably more research and testing are necessary to determine which substances have neurotoxic potential. Neurotoxic effects can often go unrecognized because symptoms are varied and may not appear for months or even years. Adverse effects range from impaired movement, anxiety, and confusion to memory loss, convulsions, and death. Another important finding is the need for greater public awareness. Neurotoxic chemicals constitute a major public health threat; the social and economic consequences of excessive exposure to them are potentially very large. Minimizing exposure requires action not just by regulatory and other public officials, but also by individual citizens who can take steps to avoid these substances both at home and in the workplace. Many individuals and institutions contributed their time and expertise to the project. Scientists and regulatory officials in several Federal agencies and experts in academia and industry served on the project’s advisory panel, in workshop groups, and as reviewers. OTA gratefully acknowledges the assistance of these contributors. As with all OTA assessments, however, responsibility for the content of the Report is OTA’s alone and does not necessarily constitute the consensus or endorsement of the advisory panel or the Technology Assessment Board. JOHN H. GIBBONS Director . .,. Ill New Developments in Neuroscience Advisory Panel Peter S. Spencer, Chair Oregon Health Sciences University, Portland, OR Robert H. Blank Laurane G. Mendelssohn Northern Illinois University Lilly Research Laboratories DeKalb, IL Indianapolis, IN James F. Childress Franklin E. Mirer University of Virginia United Auto Workers Charlottesville, VA Detroit, MI Fred H. Gage Albert S. Moraczewski University of California-San Diego Pope John XXIII Center La Jolla, CA Houston, TX Bernice Grafstein Herbert Paroles Cornell University Columbia University New York, NY New York, NY Ronald Kartzine} Richard M. Restak CIBA-GIGY Corp. Neurological Associates, P.C. Summit, NJ Washington, DC Alan Kraut American Psychological Association Washington, DC Neurotoxic Substances Study Panel Stanley H. Abramson Marion Moses King & Spalding University of California-San Francisco Washington, DC San Francisco, CA Louis W. Chang John O’Donoghue University of Arkansas Eastman Kodak Co. Little Rock, AR Rochester, NY Alan M. Goldberg Bernard Weiss Johns Hopkins University University of Rochester Baltimore, MD Rochester, NY NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the advisory and study panel members. The panels do not, however, necessarily approve, disapprove, or endorse this report. OTA assumes full responsibility for the report and the accuracy of its contents. iv Neurotoxicity Roger C. Herdman, Assistant Director, OTA, Health and Life Sciences Division Gretchen S. Kolsrud, Biological Applications Program Manager1 OTA Project Staff Mark Schaefer, Study & Project Director Timothy P. Condon, Project Director2 Peter R. Andrews, Research Assistant Joyce Ann Brentley, Analyst Claire L. Pouncey, Research Assistant E. Blair Wardenburg, Research Analyst3 Monica Bhattacharyya, Research Assistant Catherine A. Laughlin, NIH Detailee4 Gladys B. White, Analyst5 Support Staff Cecile Parker, Office Administrator Linda Rayford-Journiette, Administrative Secretary Jene Lewis, Secretary Sharon Oatman, Administrative Assistant6 Lori B. Idian, Secretary7 Contractors Zoltan Annau, Johns Hopkins University Jacqueline Courteau, Hampshire Research Associates Warren R. Muir, Hampshire Research Associates George Provenzano, University of Maryland at Baltimore Brenda Seidman, Environ Corp. Ellen Widess, University of Texas Ronald Wood, New York University Medical Center John S. Young, Hampshire Research Associates Jeffrey L. Fox, Washington, DC Blair Potter (editor), Bethesda, MD Julie Phillips (indexer), Vienna, VA Raymond Driver (graphics artist), Damascus, MD OTA Publishing Staff Kathie Boss, Publishing Officer Dorinda Edmondson, Desktop Publishing Christine Onrubia, Graphic Designer/Illustrator Susan Zimmerman, Graphic Artist lmou~ September 1989. 2mou@ August 1989. 3~ou~ August 1989. 4Th17Nl@ hdy 1989. fThrough June 1989. %ough February 1989 7ThOU#l July 1989. Contents Page Chapter 1. Summary, Policy Issues, and Options for Congressional Action . 3 Chapter 2. Introduction . 43 Chapter 3. Fundamentals of Neurotoxicology . 63 Chapter 4. Research and Education Programs . 81 Chapter 5. Testing and Monitoring . 105 Chapter 6. Assessing and Managing Risk . 145 Chapter 7. The Federal Regulatory Response . 159 Chapter 8. Economic Considerations in Regulating Neurotoxic Substances . 211 Chapter 9. International Regulatory and Research Activities . 237 Chapter 10. Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace . 267 Appendix A, The Food Additive Approval Process: A Case Study . 315 Appendix B. Workshop on Federal Interagency Coordination of Neurotoxicity Research and Regulatory Programs . 321 Appendix C. Decade of the Brain . 330 Appendix D. Acknowledgments . 332 Appendix E. List of Contractor Documents . 335 Appendix F. Glossary of Terms and List of Acronyms . 336 Index . 343 Chapter 1 Summary, Policy Issues, and Options for Congressional Action CONTENTS Page SUMMARY .. ... .. .. ... .. .. .. .. ... .,. .....+. .....,, . 3 Scope of This Study . .. .. .. .. .. .. .. .. +.. ... .+.+..., 4 What Is Neurotoxicity? . .+ .. .. .. .. .. ..+. 4 Who Is At Risk? ... ... ...+.... 8 Research and Education Programs . 9 Testing and Monitoring .. .. .. .. .. .. .. .. ... ....+... .. .. .. .. .. .. .. .. ... ... ... ...~. 12 Risk Assessment . .. .. .. .. .. ... ... +...... ,...,.. 13 Federal Regulatory Response . .. .. .. .. .. .. ... +.. ....+... 15 Federal Interagency Coordination . 19 Economic Considerations in Regulation . 19 ~ . A c. t i. 6 N International Issues . oR 60ieki loN k . 21 POLICY ISSUES AND OPTIONS . 22 Boxes Box Page I-A. Vulnerability of the NervousSystem to Toxic Substances . 5 l-13. MPTP and Parkinson’s Disease ......+..........++.. .. .. .. .+ . 6 l-C. had: A Continuing Threat to the Nation’s Children . 8 l-1). Cocaine and the Developing Fetus . .+ . 10 l-E. Neurotoxic Pesticides . 26 l-F. Limitations of FDA’s Postmarked Monitoring System for Adverse Drug Reactions: Halcyon . .29 I-G. Organic Solvents in the Workplace . ..+.. 30 Figures Figure Page l-1. Average Annual Motor Neuron Disease Mortality in the United States, White Males . ,..,.... 3 l-2. The Fundamental Structure of the Nerve Cell . 5 l-3. Neurotoxic Effect of MDMA on Serotonin Nerve Fibers in the Cerebral Cortex of the Monkey . + . +........ 9 l-4.Neurotoxic Substances Are Prominent Among the Toxics Release Inventory’s Top 25 Chemicals Emitted Into the Air 1987 .. .. .. .. .. .. .. .. .. .. ... ... ..+...+ 14 Tables Table Page l-1. Federal Funding for Civilian Neurotoxicity-Related Research . 11 l-2+ Major Federal Laws Controlling Toxic Substances . 16 Chapter 1 Summary, Policy Issues, and Options for Congressional Action SUMMARY substantial number of therapeutic drugs have neurotoxic potential. Chemicals are an integral part of our daily lives and are responsible for substantially im- In recent years, concern about the neurotoxic proving them. Chemicals can also endanger our effects of chemicals has increased as evidence health, even our survival. This assessment