Veterans and Agent Orange

Update 2004

Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fifth Biennial Update)

Board on Health Promotion and Disease Prevention

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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Veterans and Agent Orange: Update 2004 Veterans and Agent Orange Update 2004 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fifth Biennial Update) Board on Health Promotion and Disease Prevention INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Veterans and Agent Orange: Update 2004 THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, D.C. 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 No. V101(93)P-1637, TO#30 between the National Academy of Sciences and the US Department of Government 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 0-309-09598-0 (book) International Standard Book Number 0-309-54892-6 (PDF) Library of Congress Control Number 2005924080 Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, N.W., Box 285, Washington, D.C. 20055; call (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 2005 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 2004 “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Adviser to the Nation to Improve Health

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Veterans and Agent Orange: Update 2004 THE NATIONAL ACADEMIES Advisers to the Nation on Science, 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. 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. 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. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Veterans and Agent Orange: Update 2004 COMMITTEE TO REVIEW THE HEALTH EFFECTS IN VIETNAM VETERANS OF EXPOSURE TO HERBICIDES (FIFTH BIENNIAL UPDATE) JOHN J. STEGEMAN, (Chair), Senior Scientist, Woods Hole Oceanographic Institution, Department of Biology, Woods Hole, Massachusetts KIROS T. BERHANE, Associate Professor, Department of Preventive Medicine, University of Southern California, Los Angeles, California PAUL F. ENGSTROM, Senior Vice President and Medical Director, Fox Chase Network, Philadelphia, Pennsylvania RICHARD A. FENSKE, Professor of Environmental and Occupational Health Sciences and Director of the Pacific Northwest Agricultural Safety and Health Center, University of Washington, Seattle, Washington JORDAN FIRESTONE, Assistant Professor of Neurology, Clinic Director of Occupational and Environmental Medicine, University of Washington, Seattle, Washington THOMAS A. GASIEWICZ, Professor and Chair of Environmental Medicine and Director of the Environmental Health Sciences Center, University of Rochester, Rochester, New York CLAUDIA HOPENHAYN, Assistant Professor, College of Public Health, University of Kentucky, Lexington, Kentucky LOREN D. KOLLER, Consultant, Environmental Health and Toxicology, Corvallis, Oregon NANCY I. KERKVLIET, Professor, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon JOEL MCCULLOUGH, Medical Director of Environmental Health, Chicago Department of Health, Chicago, Illinois DAVID S. STROGATZ, Associate Professor and Chair of Epidemiology, School of Public Health, State University of New York at Albany, New York Staff Michelle C. Catlin, Study Director (through October 2004) Mary Burr Paxton, Study Director (as of November 2004) Jennifer A. Cohen, Senior Program Associate Rose Marie Martinez, Director, Board on Health Promotion and Disease Prevention David Butler, Senior Program Officer Sonia J. Cheruvillil, Senior Program Assistant (as of October 2004) Joseph A. Esparza, Senior Program Assistant (through May 2004) Peter James, Senior Program Assistant Kate Kelly, Senior Editor

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Veterans and Agent Orange: Update 2004 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 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: Hans Berkel, President and CEO, Cancer Prevention Institute, Dayton, Ohio Linda S. Birnbaum, Director, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina Margit L. Bleecker, Director, Center for Occupational and Environmental Neurology, Baltimore, Maryland Norman Breslow, Professor, Department of Biostatistics, University of Washington, Seattle, Washington Mark R. Cullen, Professor, Occupational and Environmental Medicine Program, Yale University School of Medicine, New Haven, Connecticut Chris Gennings, Professor, Department of Biostatistics, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia Russ B. Hauser, Associate Professor, Occupational Health Program, Harvard School of Public Health, Boston, Massachusetts

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Veterans and Agent Orange: Update 2004 Robert F. Herrick, Senior Lecturer on Industrial Hygiene, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts Howard M. Kipen, Director, Occupational Health Division, Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey Stephen H. Safe, Professor, Texas A&M Institute for Biosciences and Technology, College Station, Texas Herbert H. Schaumburg, Professor, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York Bailus Walker, Jr., Professor, Howard University Cancer Center, Washington DC 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 Dan Blazer, Duke University Medical Center, Durham, North Carolina. Appointed by the Institute of Medicine, he 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 author committee and the institution.

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Veterans and Agent Orange: Update 2004 Preface In 1991, because of continuing uncertainty about the long-term health effects on Vietnam veterans who where exposed to herbicides during their service in Vietnam (mixtures of 2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], picloram, and cacodylic acid), Congress passed Public Law 102-4, the Agent Orange Act of 1991. That legislation directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various chemical components of those herbicides, including TCDD. The resulting report, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO) was published by the NAS Institute of Medicine (IOM) in 1994. The Secretary also asked that NAS conduct updates at least every 2 years for 10 years from the date of the first report to review newly available literature and draw conclusions from the overall evidence. PL 107-103, The Veterans Education and Benefits Expansion Act of 2001, extended the updates until 2014. The first report in the resulting series was Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (abbreviated as VAO in this report). It evaluated and integrated the scientific evidence regarding statistical associations between health outcomes and exposure to TCDD or other compounds in these herbicides that had accumulated prior to 1994. Public Law 102-4 also required the NAS to conduct biennial updates that would review newly published scientific literature regarding such associations. 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 pub-

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Veterans and Agent Orange: Update 2004 lished in 1999. The third, Veterans and Agent Orange: Update 2000 (Update 2000) was published in 2001. The fourth, Veterans and Agent Orange: Update 2002 (Update 2002) was published in 2003. The focus of this fifth updated review is on scientific studies published since the release of Update 2002. To conduct the review, the IOM established a committee of 11 members representing a wide range of expertise to take a fresh look at the studies reviewed in VAO, Update 1996, Update 1998, Update 2000, and Update 2002, along with the newest scientific evidence. To provide a link to the experience and expertise developed by the previous committees, seven of the members of the committee responsible for this report were recruited from the committee responsible for Update 2002. 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 TCDD exposure. Biographical sketches of committee members and staff appear in Appendix D. 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 NAS procedures, the committee met in a series of closed sessions in which members could freely examine, characterize, and weigh the strengths and limitations of the evidence. It also convened open meetings in May and July 2004 to provide the opportunity for veterans and veterans’ service organizations, researchers, policy-makers, 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 listed in Appendix B. The committee thanks the individuals who provided valuable insights into the health problems experienced by Vietnam veterans. The committee is grateful to Michelle Catlin and Mary Paxton, who skillfully served as study directors for this project. The committee would also like to acknowledge the excellent work of IOM staff members Jennifer Cohen, Joe Esparza, Peter James, Sonia Cheruvillil, and David Butler. Thanks are also extended to Jim Banihashemi and Christie Bell, who handled the finances for the project; Kate Kelly, who provided editorial skills; and William McLeod, who conducted database searches. 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 Dr. Joel Michalek (Air Force Research Laboratory, Brooks Air Force Base, Texas) for presenting his most recent data at a public session. John Stegeman, Chair

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Veterans and Agent Orange: Update 2004 Contents     EXECUTIVE SUMMARY   1 1   INTRODUCTION   11      Charge to the Committee,   12      Conclusions of Previous Veterans and Agent Orange Reports,   13      Organization of this Report,   18      References,   18 2   EVALUATING THE EVIDENCE   20      Choice of Health Outcomes,   20      Identification of Relevant Literature,   20      Committee’s Approach,   22      Evaluation of the Evidence,   25      References,   31 3   TOXICOLOGY   33      Highlights of Previous Reports,   34      Toxicity Profile Update of 2,4-D,   34      Toxicity Profile Update of 2,4,5-T,   41      Toxicity Profile Update of Cacodylic Acid,   41      Toxicity Profile Update of Picloram,   43      Toxicity Profile Update of TCDD,   44      Summary of Toxicity Profiles,   88      Relevance to Human Health,   93      References,   94

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Veterans and Agent Orange: Update 2004 4   EPIDEMIOLOGY   118      Occupational Studies,   120      Environmental Studies,   129      Vietnam-Veteran Studies,   134      References,   142 5   EXPOSURE ASSESSMENT   165      Exposure Assessment for Epidemiology,   165      Occupational Exposure to Herbicides and TCDD,   169      Environmental Exposure to Herbicides and TCDD,   177      Military Use of Herbicides in Vietnam,   182      Exposure Assessment in Studies of Vietnam Veterans,   186      References,   191 6   CANCER   201      Gastrointestinal Tract Cancers,   203      Hepatobiliary Cancers,   221      Oral, Nasal, and Pharyngeal Cancer,   226      Laryngeal Cancer,   230      Lung Cancer,   234      Bone and Joint Cancer,   242      Soft-Tissue Sarcomas,   245      Skin Cancer—Melanoma,   251      Skin Cancer—Basal-Cell and Squamous-Cell (Non-melanoma),   261      Breast Cancer,   265      Cancers of the Female Reproductive System,   270      Prostate Cancer,   275      Testicular Cancer,   283      Urinary Bladder Cancer,   286      Renal Cancer,   292      Brain Tumors,   296      Non-Hodgkin’s Lymphoma,   303      Hodgkin’s Disease,   313      Multiple Myeloma,   319      Leukemia,   325      Chronic Lymphocytic Leukemia,   334      Summary,   337      References,   342

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Veterans and Agent Orange: Update 2004 7   REPRODUCTIVE AND DEVELOPMENTAL EFFECTS   354      Birth Defects,   355      Fertility,   365      Spontaneous Abortion,   372      Stillbirth, Neonatal Death, and Infant Death,   378      Birthweight and Preterm Delivery,   379      Childhood Cancer,   383      Sex Ratio,   389      Summary,   394      References,   398 8   NEUROLOGIC DISORDERS   404      Neurobehavioral Disorders (Cognitive or Neuropsychiatric),   406      Movement Disorders,   410      Peripheral Neuropathy,   423      Summary,   429      References,   431 9   OTHER HEALTH EFFECTS   436      Chloracne,   437      Porphyria Cutanea Tarda,   439      Respiratory Disorders,   440      Immune System Disorders,   443      Diabetes,   448      Lipid and Lipoprotein Disorders,   457      Gastrointestinal and Digestive Disease, Including Liver Toxicity,   463      Circulatory Disorders,   467      AL Amyloidosis,   471      Endometriosis,   473      Thyroid Homeostasis,   478      Summary,   481      References,   486 10   RESEARCH RECOMMENDATIONS   491      Vietnam Veteram Studies,   491      Studies of Vietnamese,   493      Other Research,   493      References,   494

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Veterans and Agent Orange: Update 2004     APPENDIXES     A   EPIDEMIOLOGIC TABLES FOR CHAPTER 4   495 B   AGENDAS OF PUBLIC MEETINGS   569 C   INTERNATIONAL CLASSIFICATION OF DISEASES (ICD-9) CODES FOR CANCERS OF INTEREST   571 D   COMMITTEE AND STAFF BIOGRAPHIES   575     INDEX   580

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Veterans and Agent Orange: Update 2004 Veterans and Agent Orange Update 2004

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