Veterans and Agent Orange

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Veterans and Agent Orange: Update 2000 Veterans and Agent Orange Update 2000 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Third Biennial Update) Division of Health Promotion and Disease Prevention INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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Veterans and Agent Orange: Update 2000 NATIONAL ACADEMY PRESS 2101 Constitution Avenue, NW 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 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 to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Third Biennial Update) and are not necessarily those of the funding agencies. Library of Congress Cataloging-in-Publication Data Institute of Medicine (U.S.). Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides Veterans and agent orange: update 2000/Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides, Division of Health Promotion and Disease Prevention, Institute of Medicine. p. cm. Includes index ISBN 0-309-07552-1 1. Agent Orange—Health aspects. 2. Agent Orange—Toxicology. 3. Vietnamese Conflict, 1961–1975—Veterans—Health risk assessment—United States. I. Title. RA1242.T44 I57 2001 363.17′9–dc21 2001026682 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, D.C. 20055. Call (800) 624–6242 or (202) 334–3313 (in the Washington metropolitan area), or visit the NAP’s home page at www.nap.edu. The full text of this report is available at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2001 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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Veterans and Agent Orange: Update 2000 “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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Veterans and Agent Orange: Update 2000 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. 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. 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. Wm. A.Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Veterans and Agent Orange: Update 2000 COMMITTEE TO REVIEW THE HEALTH EFFECTS IN VIETNAM VETERANS OF EXPOSURE TO HERBICIDES (THIRD BIENNIAL UPDATE) Irva Hertz-Picciotto, Ph.D. (Chair),1,2 Professor, Department of Epidemiology, University of North Carolina at Chapel Hill Margit L.Bleecker, M.D., Ph.D., Director, Center for Occupational and Environmental Neurology, Baltimore, Maryland Thomas A.Gasiewicz, Ph.D., Professor of Environmental Medicine and Deputy Director of the Environmental Health Sciences Center, University of Rochester Tee L.Guidotti, M.D., M.P.H., Professor and Chair of the Department of Environmental and Occupational Health, The George Washington University School of Public Health and Health Services Robert Herrick, Ph.D., C.I.H.,1,2 Lecturer on Industrial Hygiene, Department of Environmental Health, Harvard School of Public Health David G.Hoel, Ph.D.,1,2 Distinguished University Professor, Medical University of South Carolina Loren D.Koller, D.V.M., Ph.D., Professor, Oregon State University, College of Veterinary Medicine Howard Ozer, M.D., Ph.D.,1,2Eason Chair and Chief of the Hematology/Oncology Section, Director of the Cancer Center, and Professor of Medicine, University of Oklahoma John J.Stegeman, Ph.D., Senior Scientist and Chair of the Biology Department, Woods Hole Oceanographic Institution David S.Strogatz, Ph.D., M.S.P.H., Associate Professor and Chair of Epidemiology, School of Public Health, State University of New York at Albany Staff David A.Butler, Study Director James Bowers, Research Assistant Jennifer A.Cohen, Research Assistant Rose Marie Martinez, Director, Division of Health Promotion and Disease Prevention Marjan Najafi, Research Associate Patricia Spaulding, Project Assistant Anna Staton, Project Assistant Kathleen Stratton, Acting Director (1997–1999), Division of Health Promotion and Disease Prevention Donna D.Thompson and Rita Gaskins, Division Assistants Melissa French, Financial Associate Staff Consultants Michelle Catlin, Program Officer Florence Poillon, Contract Editor 1   Member of the committee responsible for Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes. 2   Member of the committee responsible for Veterans and Agent Orange: Update 1998.

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Veterans and Agent Orange: Update 2000 Reviewers 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 NRC’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 individuals for their review of this report: Linda S.Birnbaum, Ph.D., U.S. Environmental Protection Agency Mark R.Cullen, M.D., Yale University John Doull, Ph.D., University of Kansas Medical Center Howard M.Kippen, M.D., M.P.H., Rutgers University David Kriebel, Ph.D., University of Massachusetts Lowell Paul Lioy, Ph.D. Environmental and Occupational Health Sciences Institute 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 Kristine Gebbie, Dr.P.H., R.N., Columbia University, who 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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Veterans and Agent Orange: Update 2000 Preface In response to the concerns voiced by Vietnam veterans and their families, Congress called upon the National Academy of Sciences (NAS) to review the scientific evidence on the possible health effects of exposure to Agent Orange and other herbicides (Public Law 102–4, enacted on February 6, 1991). The creation of the first NAS Institute of Medicine committee, in 1992, underscored the critical importance of approaching these questions from a non-partisan scientific standpoint. The original Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides realized from the beginning that it could not conduct a credible scientific review without a full understanding of the experiences and perspectives of veterans. Thus, to supplement its standard scientific process, the committee opened several of its meetings to the public in order to allow veterans and other interested individuals to voice their concerns and opinions, to provide personal information about individual exposure to herbicides and associated health effects, and to educate committee members on recent research results and studies still under way. This information provided a meaningful back-drop for the numerous scientific articles that the committee considered. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (abbreviated as VAO in this report) reviewed and evaluated the available scientific evidence regarding the association between exposure to dioxin or other chemical compounds contained in herbicides used in Vietnam and a wide range of health effects. The report provided information for the Secretary of Veterans Affairs to consider as the Department of Veterans Affairs carried out its responsibilities to Vietnam veterans. It also described areas in which the available scientific data were insufficient to determine whether an association exists and provided the committee’s recommendations for future research.

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Veterans and Agent Orange: Update 2000 Public Law 102–4 also tasked the NAS to conduct biennial updates that would review newly published scientific literature regarding statistical associations between health outcomes and exposure to dioxin and other chemical compounds in these herbicides. The first of these, Veterans and Agent Orange: Update 1996 (Update 1996) was published in March of that year. The second, Veterans and Agent Orange: Update 1998 (Update 1998) was published in 1999. The focus of this third updated review is on scientific studies published since the release of Update 1998. To conduct the review, the IOM established a committee of 10 members representing a wide range of expertise to take a fresh look at the studies reviewed in VAO, Update 1996, and Update 1998 along with the newest scientific evidence. In order to provide a link to the experience and expertise developed by the previous committees, four of the members of the committee responsible for this report were recruited from the committee responsible for Update 1998. All committee members were selected because they are leading experts in their fields, have no conflicts of interest with regard to the matter under study, and have taken no public positions concerning the potential health effects of herbicides in Vietnam veterans or related aspects of herbicide or dioxin exposure. Biographical sketches of committee members and staff appear in Appendix C. The committee worked on several fronts in conducting this updated review, always with the goal of seeking the most accurate information and advice from the widest possible range of knowledgeable sources. Consistent with procedures of the NAS, the committee met in a series of closed sessions and working group meetings in which members could freely examine, characterize, and weigh the strengths and limitations of the evidence. It also convened an open meeting in May 2000 to provide the opportunity for veterans and veterans service organizations, researchers, policymakers, and other interested parties to present their concerns, review their research, and exchange information directly with committee members. The oral presentations and written statements submitted to the committee are described in Appendix A. The committee thanks these individuals who provided valuable insights into the health problems experienced by Vietnam veterans. In addition to its formal meetings, the committee actively and continuously sought information from, and explained its mission to, a broad array of individuals and organizations with interest or expertise in assessing the effects of exposure to herbicides. The committee also heard from the public through telephone calls, letters, and emails. David A.Butler served as the study director for this project. The committee would also like to acknowledge the excellent work of IOM staff members James Bowers, Michelle Catlin, Jennifer Cohen, Marjan Najafi, and Anna Staton. Thanks are also extended to Melissa French, who handled the finances for the project; Florence Poillon who provided excellent editorial skills; Susan Fourt, who conducted database searches; Paige Baldwin, Michael Edington, and Sarah Schlosser, who supervised the report through the editorial and publication phases; and Rita Gaskins, who provided administrative support to the project.

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Veterans and Agent Orange: Update 2000 The committee also benefited from the assistance of several scientists and researchers who generously lent their time and expertise to help give committee members insight on particular issues, provide copies of newly-released research, or answer queries concerning their work. Special thanks are extended to Drs. Keith Horsley (Commonwealth Department of Veterans’ Affairs, Australia) and Joel Michalek (Air Force Research Laboratory, Brooks Air Force Base, Texas). Irva Hertz-Picciotto, Chair

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Veterans and Agent Orange: Update 2000 Contents 1   EXECUTIVE SUMMARY   1     Organization and Framework,   2     Toxicology Summary,   3     Exposure Assessment,   5     Conclusions About Health Outcomes,   5     Increased Risk of Disease Among Vietnam Veterans,   12     Observations and Research Recommendations,   13 2   VETERANS AND AGENT ORANGE: PREVIOUS IOM REPORTS   15     Background,   15     Conclusions About Health Outcomes,   17     Increased Risk of Disease Among Vietnam Veterans,   20     Existence of a Plausible Biologic Mechanism or Other Evidence of a Causal Relationship,   20     Research Recommendations,   21 3   TOXICOLOGY   22     Lay Summary,   23     Overview of the Scientific Literature in Update 2000,   27     Toxicity Profile Updates,   33     Issues in Evaluating the Evidence,   85

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Veterans and Agent Orange: Update 2000 4   METHODOLGICAL CONSIDERATIONS IN EVALUATING THE EVIDENCE   103     Questions to Be Addressed,   103     Issues in Evaluating the Evidence,   106 5   EXPOSURE ASSESSMENT   110     Occupational and Environmental Exposures to Herbicides and Dioxin,   110     Military Use of Herbicides in Vietnam,   117     Exposure Assessment in Studies of Vietnam Veterans,   122 6   EPIDEMIOLOGIC STUDIES   132     Occupational Studies,   134     Environmental Studies,   147     Vietnam Veteran Studies,   150     Observations and Research Recommendations,   160 7   CANCER   248     Gastrointestinal Tract Tumors,   250     Hepatobiliary Cancers,   267     Nasal and Nasopharyngeal Cancer,   273     Laryngeal Cancer,   277     Lung Cancer,   281     Bone Cancer,   287     Soft-Tissue Sarcomas,   291     Skin Cancers—All Types,   299     Skin Cancer—Melanoma,   302     Skin Cancer—Basal and Squamous Cell (Nonmelanoma),   308     Breast Cancer,   314     Cancers of the Female Reproductive System,   320     Prostate Cancer,   326     Testicular Cancer,   335     Urinary Bladder Cancer,   339     Renal Cancer,   345     Brain Tumors,   350     Non-Hodgkin’s Lymphoma,   355     Hodgkin’s Disease,   364     Multiple Myeloma,   371     Leukemia,   377     Summary,   383

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Veterans and Agent Orange: Update 2000 8   REPRODUCTIVE EFFECTS   399     Introduction,   399     Birth Defects,   400     Fertility,   405     Spontaneous Abortion,   409     Stillbirth, Neonatal Death, and Infant Death,   412     Low Birthweight and Preterm Birth,   413     Childhood Cancers,   417     Sex Ratio,   429     Summary,   431 9   NEUROBEHAVIORAL DISORDERS   440     Introduction,   440     Cognitive and Neuropsychiatric Effects,   441     Motor/Coordination Dysfunction,   443     Chronic Persistent Peripheral Neuropathy,   454     Acute and Subacute Transient Peripheral Neuropathy,   457     Conclusions for Neurobehaviorial Disorders,   457 10   OTHER HEALTH EFFECTS   463     Introduction,   463     Chloracne,   463     Porphyria Cutanea Tarda,   466     Respiratory Disorders,   468     Immune System Disorders,   475     Diabetes,   481     Lipid and Lipoprotein Disorders,   492     Gastrointestinal and Digestive Disease, Including Liver Toxicity,   498     Circulatory Disorders,   505     Amyloidosis,   511     Summary,   513     APPENDIXES     A   SUMMARY OF WORKSHOP   523 B   ICD•9 CODES FOR CANCER OUTCOMES   524 C   COMMITTEE AND STAFF BIOGRAPHIES   527     INDEX   533

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Veterans and Agent Orange: Update 2000 Veterans and Agent Orange Update 2000

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