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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Gulf War and Health Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Carolyn E. Fulco, Catharyn T. Liverman, Harold C. Sox, Editors Committee on Health Effects Associated with Exposures During the Gulf War Division of Health Promotion and Disease Prevention NATIONAL ACADEMY PRESS Washington, D.C.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. 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. Support for this project was provided by the Department of Veterans Affairs. The views presented in this report are those of the Institute of Medicine Committee on Health Effects Associated with Exposures During the Gulf War and are not necessarily those of the funding agency. International Standard Book No. 0-309-07178-X Library of Congress Card Number: 00-109510 Additional copies of this publication are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP home page at www.nap.edu. The full text of this report is available on line at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2000 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE Shaping the Future for Health
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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. Bruce M. Alberts 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. William A. Wulf 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 I. Shine is president of the Institute of Medicine. 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. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines COMMITTEE ON HEALTH EFFECTS ASSOCIATED WITH EXPOSURES DURING THE GULF WAR HAROLD C. SOX (Chair), Professor and Chair, Department of Medicine, Dartmouth-Hitchcock Medical Center MICHAEL ASCHNER, Professor, Department of Physiology and Pharmacology, Wake Forest University School of Medicine PATRICIA A. BUFFLER, Professor, Department of Epidemiology, University of California at Berkeley School of Public Health LUCIO GUIDO COSTA, Professor, Department of Environmental Health, University of Washington FIRDAUS S. DHABHAR, Assistant Professor, Department of Oral Biology, Ohio State University Health Sciences Center ANTHONY L. KOMAROFF, Professor of Medicine, Harvard Medical School, and Editor-in-Chief, Harvard Health Publications JANICE L. KRUPNICK, Professor, Department of Psychiatry, Georgetown University Medical School HERBERT LOWNDES, Professor, College of Pharmacy, Rutgers University ERNEST L. MAZZAFERRI, Emeritus Professor and Chairman, Department of Internal Medicine, The Ohio State University DEMETRIOS J. MOSCHANDREAS, Professor, Department of Chemical and Environmental Engineering, Illinois Institute of Technology CHARLES E. PHELPS, Provost, University of Rochester SAMUEL J. POTOLICCHIO, Professor, Department of Neurology, George Washington University Medical Center JEAN F. REGAL, Professor, Department of Pharmacology, School of Medicine, University of Minnesota at Duluth MARC SCHENKER, Professor, Epidemiology and Preventive Medicine, University of California at Davis School of Medicine PETER H. SCHUR, Professor of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston FRANÇOISE SEILLIER-MOISEIWITSCH, Associate Professor, Department of Biostatistics, School of Public Health, University of North Carolina at Chapel Hill WALTER C. WILLETT, Professor and Chairman, Department of Nutrition, Harvard School of Public Health SCOTT L. ZEGER, Professor and Chair, Department of Biostatistics, Johns Hopkins University School of Public Health
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Staff CAROLYN E. FULCO, Study Director CATHARYN T. LIVERMAN, Study Director SANDRA AU, Research Assistant KYSA CHRISTIE, Senior Project Assistant KATHLEEN STRATTON, Acting Director (through November 1999), Board on Health Promotion and Disease Prevention ROSE MARIE MARTINEZ, Director (from December 1999), Board on Health Promotion and Disease Prevention
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Preface Although the Gulf War lasted but a few days, many combat troops have suffered lingering health problems that they attribute to their wartime service. Their health problems and illnesses have features in common with illnesses suffered by veterans of earlier wars, including the difficulty that their physicians have had in making a diagnosis. As yet, these illnesses remain unexplained by medical science, which has prompted some people to wonder if troops in the Persian Gulf theater were exposed to an agent or combination of agents that caused these illnesses. Research on this question continues. Another important question is whether an agent in the environment in the Persian Gulf theater could cause known conditions like heart disease or cancer. In an effort to respond to the health concerns of veterans and their families, the Department of Veterans Affairs contracted with the Institute of Medicine (IOM) to study the scientific evidence concerning associations between the agents to which Gulf War veterans may have been exposed and adverse health effects. To carry out this assignment, the IOM convened the Committee on Health Effects Associated with Exposures During the Gulf War. In planning its work, the committee contacted representatives of veterans’ organizations for advice in setting its priorities for this study. The veterans and their representatives advised the committee to begin the project by studying depleted uranium, sarin, pyridostigmine bromide, and vaccination against botulinum toxin and anthrax. Reports on other agents will follow, as the Institute of Medicine and the Department of Veterans Affairs have a long-term commitment to study all of the agents to which the veterans may have been exposed. Further, the IOM will issue updated reports as new evidence appears in the scientific literature.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines While the committee’s work has been rewarding, it has also been quite challenging. The rewards have been largely personal. Americans owe so much to those who go to war to protect our country, yet few of us have the opportunity to do something tangible in return. The people who served on this committee had a wonderful opportunity to use their expertise to help clarify matters that are a source of concern and suffering to those who served their country in war. We felt that privilege very deeply, largely as a result of the many opportunities we had to talk with veterans who took the time and found the means to travel to Washington to advise us of their concerns. They helped us understand both the science and the human dimension of the problem that they were living with and that we had to address. Veterans, members of their families, leaders of veterans organizations, physicians, and scientists gave freely of their time. Many struggled to find words to express the suffering that they or their family members were experiencing. Our committee responded in the only way that it could—by doing our very best, individually and collectively, to carry out our assignment. The committee sought to determine whether exposure to the agents of concern is associated with health effects in Gulf War military personnel. One of the most convincing ways to demonstrate such a relationship is to show that the magnitude of a specific health effect increases as the magnitude of the exposure increases. To achieve that goal would mean comparing the disease experience of people with differing levels of exposure to the agent. The committee soon learned that, because of extremely poor medical recordkeeping practices and limited environmental monitoring, it is not possible to document the exposure of individual Gulf War soldiers, with a few exceptions (e.g., soldiers with retained fragments of depleted uranium in their tissues). Therefore, the committee turned to studies of other populations with documented exposure to the agents of concern, including occupational-related exposure (in the case of uranium), terrorist attacks (in the case of sarin), and medical exposure (in the case of pyridostigmine bromide and vaccines). The committee can show, in some instances, that the putative agents are associated with health effects in those populations. However, the lack of information about individual Gulf War veterans’ exposure to these agents means that it is not possible to show that an individual soldier experienced a dose that is associated with an increased risk of disease. Conversely, even with limited dose information, it is not possible to demonstrate that no health effect is related to the exposure. Possible exceptions, however, may occur when the exposure is still present, as in the case of soldiers with fragments of depleted uranium in their tissues. The limitations imposed by poor troop monitoring and inadequate recordkeeping have been quite frustrating for the committee, as it will also be for the veterans. Yet our country has an obligation to understand illnesses that occur in those whom it asks to go to war. Past conflicts, from the Civil War to the Gulf War, have taught us that some veterans experience long-term health effects. Some of those health effects physicians will not find in a textbook of medicine. The military must lay the groundwork for understanding the health effects of future wars. It must carefully monitor the health of deployed forces and, con-
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines comitantly, nondeployed troops who could serve as controls. It must develop reliable methods for measuring exposure to potentially harmful agents. It must learn how to keep good medical records. For environmental exposures, the military must find ways to measure the dose experienced by individual soldiers. These tasks are technologically feasible. For this committee, one of the most important lessons of the Gulf War is the need for accurate recordkeeping of what happens to soldiers in war. The nature of the evidence and of our narrowly focused charge means that our report will not satisfy everyone. We do hope that it will reassure some people. People who read the entire report will learn something about the difficulty of forming scientific conclusions based on inadequate information. We hope that our report will lead to improved troop monitoring and better medical recordkeeping practices in future military conflicts. We urgently call upon the military to collect routinely the epidemiological evidence required to understand illnesses that occur in the wake of war. We must do better next time. Harold C. Sox, M.D. Chair
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Acknowledgments The committee wishes to acknowledge the valuable contributions that were made to this study by the many individuals who shared their experiences and their expertise. We are especially grateful for the insight provided by many veterans, veteran’s family members, representatives of veterans’ organizations, and other individuals who spoke with the committee or sent in written testimony. The committee also appreciates the efforts of the Department of Defense and Department of Veterans Affairs staff in providing materials and background documents. In addition, the committee greatly benefited from the scientific expertise provided by workshop speakers, reviewers, colleagues consulted in the course of this effort, and the technical expertise provided by Marion Ehrich, Michael Katz, Michael Ryan, and Jonathan Samet. The committee also appreciates the work of the many consultants who contributed to their effort, in particular Linda Coughlin, Miriam Davis, Janice Kirsch, and Diane Mundt. The committee greatly values the guidance of John Bailar in the early phases of this study and the continued assistance of Robert Miller. Further, we are indebted to the dedication and energy provided by the Institute of Medicine staff in coordinating and steering the committee through this extensive literature review. In particular, Cathy Liverman and Carolyn Fulco provided insight and clarity of purpose, and kept us true to our task. The committee is indebted to Kathleen Stratton for her assistance in helping us negotiate our way through various difficult issues. The committee appreciates the efforts of Susan Fourt, Sandra Au, and Kysa Christie in retrieving the numerous articles required by our charge, in maintaining the databases, and for responding to all our requests for literature. A
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines special thanks is due to the National Library of Medicine for its assistance in accessing the extensive scientific literature. The committee also appreciates the support of the sponsor of this study, the Department of Veterans Affairs. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their participation in the review of this report: John E. Casida, Professor of Entomology and Director, Environmental Chemistry Toxicology Laboratory, College of Natural Resources, University of California at Berkeley Deborah A. Cory-Slechta, Director, Environmental Health Sciences Center, Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry Daniel B. Drachman, Professor, Department of Neurology, Johns Hopkins University School of Medicine S. Katharine Hammond, Associate Professor of Environmental Health Sciences, Division of Environmental Health Sciences, University of California at Berkeley Charles Helms, Chief of Staff, University of Iowa Hospitals and Clinics Thomas A. Louis, Professor of Biostatistics, School of Public Health, University of Minnesota Beate Ritz, Assistant Professor of Epidemiology, Department of Epidemiology and Center for Occupational and Environmental Health, School of Public Health, University of California at Los Angeles Joseph V. Rodricks, The Life Sciences Consultancy, Washington, D.C. Michael A. Stoto, Professor and Chair, Department of Epidemiology and Biostatistics, School of Public Health and Health Services, The George Washington University Patrick Thomas, Bardmoor Cancer Center, Largo, Florida M. Donald Whorton, M. Donald Whorton, Inc., Alameda, California Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Donald R. Mattison, Medical Director, The March of Dimes Birth Defects Foundation, White Plains, New York, appointed by the Institute of Medicine, and Maureen M. Henderson, Professor Emerita, University of Washington, appointed by the NRC’s Report Review Committee, who were re-
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines sponsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Contents EXECUTIVE SUMMARY 1 1 INTRODUCTION 27 Addressing Gulf War Health Issues, 28 The Gulf War Setting, 32 Scope of the Report, 35 Organization of the Report, 36 2 ILLNESSES IN GULF WAR VETERANS 39 Registry Programs, 40 Epidemiologic Studies of Veterans’ Symptoms and General Health Status, 43 Epidemiologic Studies of Specific Health Endpoints, 54 Limitations of Past Studies and Ongoing Studies, 60 Conclusions, 62 3 METHODOLOGY 69 Methods of Gathering and Evaluating the Evidence, 70 Types of Evidence, 71 Considerations in Assessing the Strength of the Evidence, 78 Summary of the Evidence, 81 Comments on Increased Risk of Adverse Health Outcomes among Gulf War Veterans, 84
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 4 DEPLETED URANIUM 89 Toxicology, 94 Epidemiologic Studies: Description of the Studies, 106 Human Health Effects of Uranium, 121 Conclusions, 159 5 SARIN 169 Acute Cholinergic Syndrome, 170 Possible U.S. Troop Exposure, 172 Sarin Toxicology, 174 Cyclosarin Toxicology, 186 Summary of Toxicology, 187 Human Studies, 187 Conclusions, 198 6 PYRIDOSTIGMINE BROMIDE 207 Toxicology, 209 Human Studies, 222 Conclusions, 250 7 VACCINES 267 Issues in Identifying Adverse Effects, 268 Anthrax Vaccine, 272 Botulinum Toxoid, 287 Multiple Vaccinations, 294 Squalene, 307 Conclusions, 312 8 RESEARCH RECOMMENDATIONS 325 Depleted Uranium, 326 Sarin, 327 Pyridostigmine Bromide, 328 Vaccines, 329 APPENDIXES A Scientific Workshop Agenda, 333 B Public Meeting Agendas, 336 C Methods of Identifying and Collecting the Literature, 339 D Gulf War Illnesses and Recognizing New Diseases, 342 E Effects of Long-Term Exposure to Organophosphate Pesticides in Humans, 366 F Acronyms and Abbreviations, 378 INDEX 383
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines TABLES, FIGURES, AND BOXES Tables 1 Summary of Findings, 18 2 Research Recommendations, 21 2.1 Demographic Characteristics of U.S. Gulf War Troops, 41 2.2 Most Frequent Symptoms and Diagnoses Among 53,835 Participants in the VA Registry (1992–1997), 42 2.3 Major Studies of Gulf War Veterans’ Symptoms and Syndromes, 46 2.4 Results of the Iowa Study, 49 4.1 Percentage of Uranium Isotopes by Weight, 90 4.2 Dissolution Types of Uranium Compounds, 95 4.3 Epidemiologic Studies of Uranium Processing Workers, 112 4.4 Studies with Overlapping Cohorts, 122 4.5 Methods of Radiation Exposure Measurement, 124 4.6 Methods of Comparing Heavily Exposed Workers with Less Exposed Workers, 127 4.7 Follow-up in Studies of Exposure to Uranium, 129 4.8 Mortality from All Forms of Cancer, 131 4.9 Lung Cancer Mortality, 132 4.10 Combined Effects of External and Internal Radiation Dose on Lung Cancer Mortality, 136 4.11 Dose–Response Relationship for Lung Cancer and Radiation Exposure, 139 4.12 Lymphatic Cancer Mortality, 144 4.13 Bone Cancer Mortality, 146 4.14 Nonmalignant Renal Disease Mortality, 148 4.15 Nonmalignant Neurologic Disease Mortality, 152 4.16 Nonmalignant Respiratory Disease Mortality, 155 5.1 Examples of Organophosphates, 170 5.2 Acute Cholinergic Syndrome, 171 5.3 Acute Lethality of Sarin Administered to Various Species, 179 5.4 Delayed Neurotoxicity of Sarin, 184 5.5 Relationship Between Sarin Exposure and Symptoms 3 Years After the Matsumoto Incident, 194 7.1 Vaccinations Prescribed for Military Personnel, 295 7.2 Vaccination and Testing Schedules, 300 C.1 Bibliographic Databases Searched, 340
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines D.1 Gulf War Illnesses and Related Conditions, 351 D.2 Overlap of Symptoms, 357 E.1 Human Studies of Organophosphate Pesticide Poisonings, 371 E.2 Studies on Persons Not Previously Poisoned by Organophosphate Pesticides, 373 Figure D.1. General steps of disease recognition, 344 Boxes 1.1 Selected Past and Ongoing Committees and Panels Addressing Gulf War Health Concerns, 30 4.1 Units of Measurement, 91 6.1 Drug Interactions, 230 7.1 Genetics and the Immune Response, 273 D.1 Chronic Fatigue Syndrome, 354 D.2 Fibromyalgia, 355 D.3 Multiple Chemical Sensitivity, 356