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Suggested Citation:"Front Matter." Institute of Medicine. 2008. Gulf War and Health: Updated Literature Review of Depleted Uranium. Washington, DC: The National Academies Press. doi: 10.17226/12183.
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Committee on Gulf War and Health: Updated Literature Review of Depleted Uranium Board of Population Health and Public Health Practice

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(049A3)-P-0066 between the National Acad- emy of Sciences and the Department of Veterans Affairs. Any opinions, findings, conclu- sions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13:  978-0-309-11919-1 International Standard Book Number-10:  0-309-11919-7 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 2008 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. Suggested citation: IOM (Institute of Medicine). 2008. Gulf war and health: Updated literature review of depleted uranium. Washington, DC: The National Academies Press.

“Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe Advising the Nation. Improving Health.

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. Charles M. Vest 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 examina- tion 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 Na- tional 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. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

Committee on Gulf War and Health: Updated Literature Review of Depleted Uranium DAVID G. HOEL, PhD (Chair), Distinguished University Professor, Medical University of South Carolina, Charleston, SC MICHAEL ASCHNER, PhD, Gray E.B. Stahlman Professor of Neuroscience, Vanderbilt University, Nashville, TN MELISSA D. BEGG, ScD, Professor of Clinical Biostatistics and Director of Academic Programs, Mailman School of Public Health of Columbia University, New York H. TIM BORGES, PhD, Research Staff Member, Oak Ridge National Laboratory, Oak Ridge, TN (resigned February 2008) VIVIEN W. CHEN, MPH, PhD, Professor and Director of Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA HAROLD I. FELDMAN, MD, MSCE, Professor of Medicine and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA PHILIP HARBER, MD, MPH, Professor and Chief, Division of Occupational and Environmental Medicine, David Geffen School of Medicine, University of California, Los Angeles PATRICK J. HEAGERTY, PhD, Professor of Biostatistics, University of Washington School of Public Health and Community Medicine, Seattle, WA KIYOUNG LEE, MPH, ScD, Assistant Professor, University of Kentucky College of Public Health and Seoul National University School of Public Health, Republic of Korea JONATHAN LINKS, PhD, Professor and Director, Center for Public Health Preparedness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 

Staff ABIGAIL E. MITCHELL, PhD, Senior Program Officer PETER JAMES, Senior Program Associate (through May 2007) A. WEZI MUNTHALI, MPH, Senior Program Associate (through November 2007) DEEPALI M. PATEL, Senior Program Associate (through November 2007) JENNIFER E. SAUNDERS, MPP, MPH, Senior Program Associate (from November 2007) RENEE WLODARCZYK, Research Assistant JOSEPH GOODMAN, Senior Program Assistant DANIELLE K. STOLL, Intern NORMAN GROSSBLATT, Senior Editor ROSE MARIE MARTINEZ, ScD, Director, Board on Population Health and Public Health Practice vi

Reviewers T his 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 com- ments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of 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: Odile David, University of Illinois College of Medicine Fletcher Hahn, Lovelace Respiratory Research Institute, Scientist Emeritus Robert Herrick, Department of Environmental Health, Harvard School of Public Health Howard Hu, University of Michigan Schools of Public Health and Medicine Ronald L. Kathren, Washington State University, Professor Emeritus William N. Rom, Division of Pulmonary and Critical Care Medicine, New York University School of Medicine Michael J. Thun, Epidemiology and Surveillance Research, American Cancer Society Bailus Walker, Jr., Howard University Medical Center Walter Willett, Department of Nutrition, Harvard School of Public Health Judith T. Zelikoff, Department of Environmental Medicine, New York University School of Medicine vii

viii reviewers Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the conclusions or recom- mendations, nor did they see the final draft of the report before its release. The review of this report was overseen by David J. Tollerud, School of Public Health and Information Sciences, University of Louisville, and Johanna T. Dwyer, Tufts University School of Medicine and Friedman School of Nutrition Science, Tufts-New England Medical Center. Appointed by the Institute of Medicine and the National Research Council, respectively, they were responsible for making certain that an independent examination of this report was carried out in accor- dance 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.

Contents SUMMARY 1 1 INTRODUCTION 7 Summary of Findings in the Section on Depleted Uranium in Gulf War and Health, Volume 1, 9 The Department of Veterans Affairs Request for This Study, 9 The Committee’s Task, 10 Organization of This Report, 10 References, 10 2 BACKGROUND 13 Uses of Depleted Uranium, 14 Exposure of Military Personnel to Depleted Uranium, 14 Radiologic and Chemical Effects of Exposure to Depleted Uranium, 17 Dose-Response Modeling and Risk Assessment, 20 References, 21 3 TOXICOLOGY 23 Summary of Previous Report, 24 Toxicokinetics, 25 Toxicity Studies, 29 Application of the Toxicologic Data, 41 References, 66 ix

 contents 4 METHODOLOGY 73 Information-Gathering Strategy, 73 Principal Objectives of Epidemiologic Studies, 75 Factors Influencing the Relevance and Quality of Studies, 76 Epidemiologic-Study Designs, 84 Inclusion Criteria, 88 Rationale for Not Including Studies of Uranium Miners, 88 Categories of Strength of Association, 90 References, 91 5 EXPOSURE ASSESSMENT 93 Estimation of Exposure to Depleted Uranium During the Gulf War, 93 Exposure-Monitoring Methods, 100 References, 102 6 CLINICAL END POINTS OF INTEREST 105 Cancer Outcomes, 105 Noncancer Outcomes, 111 References, 115 7 COHORT DESCRIPTIONS 117 Uranium-Processing Cohorts, 118 Depleted-Uranium Studies, 143 Environmental-Exposure Studies, 153 Summary, 163 References, 190 8 CONCLUSIONS 193 Cancer Outcomes, 193 Noncancer Outcomes, 203 Summary, 214 References, 259 INDEX 263 Tables and Boxes (Note that the tables for Chapters 3, 7, and 8 are at the ends of the chapters) Tables 3-1 Uranium Compounds, by Dissolution Type, 42 3-2 Carcinogenic Effects, 43

Contents xi 3-3 Genotoxic Effects, 45 3-4 Respiratory Effects, 51 3-5 Renal Effects, 52 3-6 Neurologic Effects, 53 3-7 Hepatic Effects, 58 3-8 Reproductive and Developmental Effects, 59 3-9 Immunologic Effects, 62 3-10 Musculoskeletal Effects, 64 5-1 Comparison of Level I Exposure Estimates and Risk, 97 5-2 Comparison of Level II Exposure Estimates and Risk, 99 5-3 Comparison of Level III Exposure Estimates and Risk, 99 7-1 Studies of Uranium Processors, 164 7-2 Studies of Depleted-Uranium–Exposed Persons, 178 7-3 Studies of Environmental Exposure to Uranium, 184 8-1 Lung Cancer, 216 8-2 Lung Cancer in the Oak Ridge, Tennessee, Cohort, 220 8-3 Leukemia, 221 8-4 Hodgkin Lymphoma, 224 8-5 Non-Hodgkin Lymphoma and Other Lymphatic Cancers, 226 8-6 Bone Cancer, 230 8-7 Renal Cancer, 232 8-8 Bladder Cancer, 234 8-9 Cancers of the Central Nervous System, 236 8-10 Stomach Cancer, 238 8-11 Prostatic Cancer, 240 8-12 Testicular Cancer, 242 8-13 Mortality from Nonmalignant Renal Disease, 244 8-14 Nonmalignant Renal Disease—Morbidity Risk, 246 8-15 Mortality from Nonmalignant Respiratory Disease, 252 8-16 Nonmalignant Respiratory Disease—Morbidity Risk, 254 8-17 Mortality from Neurologic Disease, 255 8-18 Reproductive and Developmental Effects, 256 Boxes 1-1 Agents Specified in PL 105-277 and PL 105-368, 8 2-1 Units of Measurement, 18 4-1 Open-Session Presentations, June 28, 2007, 74

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The 1991 Persian Gulf War was considered a brief and successful military operation with few injuries and deaths. A large number of returning veterans, however, soon began reporting health problems that they believed to be associated with their service in the gulf. Under a Congressional mandate, the Institute of Medicine (IOM) is reviewing a wide array of biologic, chemical, and physical agents to determine if exposure to these agents may be responsible for the veterans' health problems. In a 2000 report, Gulf War and Health, Volume 1: Depleted Uranium, Sarin, Pyridostigmine Bromide, and Vaccines, the IOM concluded that there was not enough evidence to draw conclusions as to whether long-term health problems are associated with exposure to depleted uranium, a component of some military munitions and armor. In response to veterans' ongoing concerns and recent publications in the literature, IOM updated its 2000 report. In this most recent report, Gulf War and Health: Updated Literature Review of Depleted Uranium, the committee concluded that there is still not enough evidence to determine whether exposure to depleted uranium is associated with long-term health problems. The report was sponsored by the U.S. Department of Veterans Affairs.

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