GULF WAR and HEALTH

VOLUME 4

HEALTH EFFECTS OF SERVING IN THE GULF WAR

Committee on Gulf War and Health: A Review of the Medical Literature Relative to the Gulf War Veterans’ Health

Board on Population Health and Public Health Practice

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu



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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 GULF WAR and HEALTH VOLUME 4 HEALTH EFFECTS OF SERVING IN THE GULF WAR Committee on Gulf War and Health: A Review of the Medical Literature Relative to the Gulf War Veterans’ Health Board on Population Health and Public Health Practice INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 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 study was supported by Contract V101(93)P-2155 between the National Academy of Sciences and the Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-10: 0-309-10176-X International Standard Book Number-13: 978-0-309-10176-9 Library of Congress Control Number: 2006934960 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2006 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: Health Effects of Serving in the Gulf War, Volume 4 “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Advising the Nation. Improving Health.

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 THE NATIONAL ACADEMIES Advisers to the National on Sciences, Engineering, and 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. Ralph J. Cicerone 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. Wm. 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. Harvey V. Fineberg 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. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 COMMITTEE ON GULF WAR AND HEALTH: A REVIEW OF THE MEDICAL LITERATURE RELATIVE TO GULF WAR VETERANS’ HEALTH LYNN R. GOLDMAN, MD, MPH, (chair) Professor, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD MARCIA ANGELL, MD, Senior Lecturer on Social Medicine, Department of Social Medicine, Harvard Medical School, Boston, MA W. KENT ANGER, PhD, Associate Director for Occupational Research, Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, OR MICHAEL BRAUER, ScD, Professor, School of Occupational and Environmental Hygiene, University of British Columbia, Vancouver, British Columbia DEDRA S. BUCHWALD, MD, Director, Harborview Medical Center, University of Washington, Seattle, WA FRANCESCA DOMINICI, PhD, Associate Professor, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD ARTHUR L. FRANK, MD, PhD, Professor, Chair, Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, PA FRANCINE LADEN, ScD, Assistant Professor of Medicine, Channing Laboratory, Harvard Medical School, Boston, MA DAVID MATCHAR, MD, Director, Center for Clinical Health Policy Research, Duke University Medical Center, Durham, NC SAMUEL J. POTOLICCHIO, MD, Professor, Department of Neurology, George Washington University Medical Center, Washington, DC THOMAS G. ROBINS, MD, MPH, Professor, Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI GEORGE W. RUTHERFORD, MD, Professor, Vice-Chair, Department of Epidemiology and Biostatistics, Division of Preventive Medicine and Public Health, School of Medicine, University of California, San Francisco, CA CAROL A. TAMMINGA, M.D., Professor, Department of Psychiatry, University of Texas, Southwestern Medical Center, Dallas, TX

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 STAFF CAROLYN FULCO, Senior Program Officer ABIGAIL MITCHELL, Senior Program Officer DEEPALI PATEL, Senior Program Associate MICHAEL SCHNEIDER, Senior Program Associate JUDITH URBANCZYK, Senior Program Associate HOPE HARE, Administrative Assistant PETER JAMES, Research Associate DAMIKA WEBB, Research Assistant RENEE WLODARCZYK, Intern NORMAN GROSSBLATT, Senior Editor ROSE MARIE MARTINEZ, Director, Board on Population Health and Public Health Practice CONSULTANTS MIRIAM DAVIS, Independent Medical Writer, Silver Spring, MD ANNE STANGL, Tulane School of Public Health and Tropical Medicine, New Orleans, LA

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 REVIEWERS This report has been reviewed in draft form by persons 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 its 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 for their review of this report: ARTHUR K. ASBURY, MD, Department of Neurology, University of Pennsylvania, Philadelphia, PA SHARON COOPER, PhD, Professor and Chair, Department of Epidemiology and Biostatistics, Texas A & M University School of Rural Public Health, College Station, TX PETER J. DYCK, MD, Director, Peripheral Nerve Research Laboratory, Mayo Clinic College of Medicine, Rochester, MN DAVID GAYLOR, PhD, MS, President, Gaylor & Associates, LLC, Eureka Springs, AR JACK M. GORMAN, MD, President and Psychiatrist in Chief, McLean Hospital, Belmont, MA PHILIP GREENLAND, MD, Executive Associate Dean for Clinical and Translational Research, Northwestern University Feinberg School of Medicine, Chicago, IL HOWARD KIPEN, MD, MPH, Director, Clinical Research and Occupational Medicine Division, Environmental & Occupational Health Sciences Institute, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ JOSEPH LADOU, MD, Editor, International Journal of Occupational and Environmental Health, Professor, Division of Occupational and Environmental Medicine, University of California, San Francisco, CA ELLEN REMENCHIK, MD, MPH, Assistant Professor, Occupational and Environmental Medicine, The University of Texas Health Center, Tyler, TX KATHERINE S. SQUIBB, PhD, Associate Professor & Head, Division of Environmental Epidemiology & Toxicology, University of Maryland School of Medicine, Baltimore, MD 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 David J. Tollerud, Professor and Chair, Department of Environmental and Occupational Health Sciences, University of Louisville and by Harold Sox, editor, Annals of Internal Medicine, American College of Physicians of Internal Medicine. Appointed by the National Research Council, Dr. Sox was responsible 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: Health Effects of Serving in the Gulf War, Volume 4 PREFACE The 1990-1991 Persian Gulf War was brief and entailed few US casualties in comparison with other wars, and yet it had a profound impact on the lives of many of the troops. Among the 700,000 US military personnel deployed in the battle theater, many veterans have reported chronic symptoms and illnesses that they have attributed to their service in the gulf. Numerous studies have been conducted to characterize the long-term adverse health consequences of deployment to the Persian Gulf. Potential exposures to numerous hazardous substances have been identified in association with the Gulf War. Most alarming are the smoke from oil-well fires that were set by Iraqis as they retreated at the end of the war and the potential exposures arising from the US military bombing of a poison-gas munitions dump at a location called Khamisiyah. Military personnel have also been reported to have had other exposures, such as to fuels, vaccines, pharmaceuticals, and pathogens. Most recently, the Department of Defense published a report documenting a large amount of pesticide use in the war theater. For most of those exposures, it is difficult or impossible to reconstruct doses because of lack of exposure measurements on either the individual or group level. The situation is compounded by the stress experienced by many veterans during deployment and in some cases after deployment. Stress is known to have serious acute and chronic health effects, but at the time of the Gulf War relatively little attention was given to reduction of stress and its consequences. The Department of Veterans Affairs (VA) and the US Congress have secured the assistance of the Institute of Medicine (IOM) in evaluating the scientific literature regarding possible health outcomes associated with exposures that might have occurred in the Gulf War, IOM has published several volumes that review the clinical diseases that might be associated with exposures, such as exposure to sarin gas, depleted uranium, pesticides, solvents, rocket propellants, fuels, and combustion products. Such reviews continue and will provide information about illnesses related to exposure to pathogens, stress, and chemical agents. The congressional request regarding the possible association between illness and exposures in the gulf is similar to the approach Congress took after the Vietnam War to address the potential adverse health effects of exposure to Agent Orange. The current report, however, takes a different approach, which is to identify the adverse health effects, if any, that are occurring among Gulf War veterans and thus might warrant further attention, either on the individual level or for the Gulf War veterans as a whole. Many of the relevant studies are limited by the lack of objective exposure information. Although there is a blood test that can provide an indication of exposure to Agent Orange and dioxin that occurred many years ago, there is not biological measure that can be employed today to assess exposures during the Gulf War. Another limitation is that most studies have relied on self-reports of symptoms and symptom-based case definitions to determine whether rates of diseases were increased among Gulf War veterans. Nonetheless, some studies do point to psychiatric disorders and neurologic end points that might be associated with Gulf War service and for which it might be possible to develop new approaches to prevention and clinical treatment that could benefit not only Gulf War veterans but also veterans of later conflicts. Our committee does not recommend

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 that more such studies be undertaken for the Gulf War veterans, but, there would be value in continuing to monitor the veterans for some health end points, specifically, cancer, especially brain and testicular cancers, neurologic diseases including Amyotrophic Lateral Sclerosis (ALS), and causes of death. Therefore, despite the serious limitations of the available studies as a group, they do point the way to actions that might benefit Gulf War and other combat veterans. I am deeply appreciative of the expert work of our committee members: Marcia Angell, W. Kent Anger, Michael Brauer, Dedra S. Buchwald, Francesca Dominici, Arthur L. Frank, Francine Laden, David Matchar, Samuel J. Potolicchio, Thomas G. Robins, George W. Rutherford, and Carol Tamminga. Although our committee developed conclusions independently of input from IOM and its staff, we deeply appreciate their hard work and attention to detail and the extensive research that they conducted to ensure that we had all the information that we needed from the outset. It has been a privilege and a pleasure to work with the IOM staff directed by Carolyn Fulco and with our consultant, Miriam Davis. Without them, this report would not have been possible. Most of all, our committee appreciates the veterans who served in the Gulf War and who have volunteered again and again to participate in the health studies that we reviewed. It is for them that we do this work. We hope this report will inform those who have given so much to our nation about what researchers have been able to learn about their health. LYNN R. GOLDMAN, MD, MPH PROFESSOR JOHNS HOPKINS UNIVERSITY

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 CONTENTS     Summary   1      Charge to the Committee   1      Committee’s Approach to Its Charge   1      Limitations of the Gulf War Studies   2      Overview of Health Outcomes   2      Outcomes Based Primarily on Symptoms or Self-Reports   3      Outcomes with Objective Measures or Diagnostic Medical Tests   5      Recommendations   7      Predeployment and Postdeployment Screening   7      Exposure Assessment   7      Surveillance for Adverse Outcomes   8      Brief Summary of Findings and Recommendations   9 1   Introduction   11      Background   11      The Gulf War Setting   12      Deployment   12      Living Conditions   13      Environmental and Chemical Exposures   13      Threat of Chemical and Biologic Warfare   14      Charge to the Committee   15      Committee’s Approach to Its Charge   15      Inclusion Criteria   15      Complexities in Resolving Gulf War and Health Issues   16      Multiple Exposures and Chemical Interactions   16      Limitations of Exposure Information   16      Individual Variability   17      Unexplained Symptoms   17      Organization of the Report   18      References   18 2   Exposures in the Persian Gulf   21      Exposure Assessment in Epidemiologic Studies   21      Studies Assessing Exposures with Questionnaires   21      Exposure to Oil-Well Fire Smoke   22      Exposure to Vaccination   22

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4      Exposure to Pyridostigmine Bromide   23      Exposure to Depleted Uranium   24      General Cohort Studies (Prevalence Studies)   25      Studies Using Simulation to Assess the Potential Magnitude of Exposures   26      Tent Heaters   26      Khamisiyah Demolition and Potential Exposure to Sarin and Cyclosarin   26      Epidemiologic Studies Using Fate and Transport Models to Assess Exposure to Sarin and Cyclosarin   35      Studies Using Environmental Fate and Transport Models for Specific Exposures   37      Studies Using Biologic Monitoring for Specific Exposures   39      Depleted Uranium   39      Oil-Well Fire Smoke   40      Summary and Conclusions   41      References   41 3   Considerations in Identifying and Evaluating the Literature   45      Types of Epidemiologic Studies   45      Cohort Studies   45      Case-Control Studies   47      Cross-Sectional Studies   47      General Remarks   48      Defining a New Syndrome   48      Statistical Techniques Used to Develop a Case Definition   49      Inclusion Criteria   51      Additional Considerations   51      Bias   52      Confounding   52      Chance   52      Multiple Comparisons   52      Assignment of Causality   53      Limitations of Gulf War Veteran Studies   53      Summary   53      References   54 4   Major Cohort Studies   55      General Limitations of Gulf War Cohort Studies and Derivative Studies   56      Organization of This Chapter   58      Population-Based Studies   58      The Iowa Study   58      Department of Veterans Affairs Study   60      Oregon and Washington Veteran Studies   63      Kansas Veteran Study   64      Canadian Veteran Study   65      United Kingdom Veteran Studies   65

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4      Danish Peacekeeper Studies   68      Australian Veteran Studies   69      Military-Unit-Based Studies   70      Ft. Devens and New Orleans Cohort Studies   70      Seabee Reserve Battalion Studies   71      Larger Seabee Cohort Studies   73      Pennsylvania Air National Guard Study   74      Other Cohort Studies   75      Hawaii and Pennsylvania Active Duty and Reserve Study   76      New Orleans Reservist Studies   76      Air Force Women Study   76      Connecticut National Guard   77      References   105 5   Health Outcomes   115      Cancer (ICD-10 C00-D48)   115      Primary and Secondary Studies   116      Summary and Conclusion   118      Mental and Behavioral Disorders (ICD-10 F00-F99)   122      Primary Studies   123      Secondary Studies   127      Summary and Conclusion   127      Neurobehavioral and Neurocognitive Outcomes (ICD-10 F00-F99)   131      Neurobehavioral Tests and Confounding Factors   131      Studies That Respond to Question 1 (Outcomes in Gulf War-Deployed Veterans vs Veterans Deployed Elsewhere or Not Deployed)   132      Studies That Respond to Question 2 (Symptomatic vs Nonsymptomatic Veterans)   135      Related Findings: Malingering and Association of Symptoms with Objective Test Results   140      Summary and Conclusion   140      Diseases of the Nervous System (ICD-10 G00-G99)   153      Amyotrophic Lateral Sclerosis   153      Summary and Conclusion   155      Peripheral Neuropathy and Other Neurologic Outcomes   157      Summary and Conclusion   159      Chronic Fatigue Syndrome   161      Primary Studies   162      Secondary Studies   162      Summary and Conclusion   163      Diseases of the Circulatory System (ICD-10 I00-I99)   166      Primary Studies   166      Secondary Studies   167      Summary and Conclusion   168      Diseases of the Respiratory System (ICD-10 J00-J99)   170      Associations of Respiratory Outcomes with Deployment in the Gulf War Theater   170

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4      Associations of Respiratory Outcomes with Specific Exposures Experienced by Gulf War Veterans During Their Deployment   172      Summary and Conclusion   174      Diseases of the Digestive System (ICD-10 K00-K93)   180      Primary Studies   180      Secondary Studies   181      Summary and Conclusion   181      Diseases of the Skin and Subcutaneous Tissue (ICD-10 L00-L99)   183      Primary Studies   183      Secondary Studies   183      Summary and Conclusion   183      Diseases of the Musculoskeletal System and Connective Tissue (ICD-10 M00-M99)   185      Arthritis and Arthralgia   185      Summary and Conclusion   186      Fibromyalgia   188      Primary Studies   188      Secondary Studies   189      Summary and Conclusion   190      Birth Defects and Adverse Pregnancy Outcomes (ICD-10 O00-Q99)   192      Birth Defects   192      Summary and Conclusion   194      Adverse Pregnancy Outcomes   195      Summary and Conclusion   195      Male Fertility Problems and Infertility   196      Symptoms, Signs, and Abnormal Clinical and Laboratory Findings (ICD-10 R00-R99)   202      Unexplained Illness   202      Hospitalizations for Unexplained Illness   202      Factor-Analysis Derived Syndromes   203      Cluster Analysis   212      Summary and Conclusion   213      Injury and External Causes of Morbidity and Mortality (ICD-10 S00-Y98)   219      Primary Studies   219      Secondary Studies   220      Summary and Conclusion   220      All-Cause Hospitalization Studies   223      Primary Studies   223      Summary and Conclusion   224      Multiple Chemical Sensitivity   227      Primary Studies   227      Secondary Studies   228      Summary and Conclusion   229      References   232

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Gulf War and Health: Health Effects of Serving in the Gulf War, Volume 4 6   Conclusions and Recommendations   247      Quality of the Studies   247      Overview of Health Outcomes   247      Outcomes Based Primarily on Symptoms and Self-Reports   248      Outcomes with Objective Measures or Diagnostic Medical Tests   251      Recommendations   254      Predeployment and Postdeployment Screening   254      Exposure Assessment   254      Surveillance for Adverse Outcomes   254      References   255     Index   261

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