Veterans and Agent Orange

Update 1998

Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides

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 1998 Veterans and Agent Orange Update 1998 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides 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 1998 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. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under the Academy’s 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. Support for this study was provided by the Department of Veterans Affairs (contract no. V101(93)P-1331). International Standard Book Number 0-309-06326-4 Copyright 1999 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 image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatliche Musseen in Berlin.

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Veterans and Agent Orange: Update 1998 COMMITTEE TO REVIEW THE HEALTH EFFECTS IN VIETNAM VETERANS OF EXPOSURE TO HERBICIDES (SECOND BIENNIAL UPDATE) David Tollerud, MD, MPH (Chair),1,2 Professor, School of Public Health, MCP Hahnemann University Michael Aminoff, MD,2 Professor, Department of Neurology, University of California at San Francisco School of Medicine Steven Goodman, MD, MHS, PhD, Associate Professor, Department of Oncology, Division of Biostatistics, Johns Hopkins University School of Medicine Robert Herrick, PhD, CIH, Lecturer on Industrial Hygiene, Department of Environmental Health, Harvard School of Public Health Irva Hertz-Picciotto, PhD, Associate Professor, Department of Epidemiology, University of North Carolina, Chapel Hill David Hoel, PhD, Distinguished University Professor, Medical University of South Carolina Andrew Olshan, PhD,1,2 Associate Professor, Department of Epidemiology, University of North Carolina, Chapel Hill Trevor Orchard, MBBCh, MMSc, Professor, University of Pittsburgh, Rangos Research Center Howard Ozer, MD, PhD, Professor, Department of Medicine, MCP Hahnemann University Kenneth Ramos, PhD,2 Professor, Department of Physiology and Pharmacology, Texas A&M University College of Veterinary Medicine Noel Rose, MD, PhD,2 Professor, Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health Susan Woskie, PhD, CIH, Associate Professor, Department of Work Environment, University of Massachusetts, Lowell 1   Member of the committee responsible for Veterans and Agent Orange (1994). 2   Member of the committee responsible for Veterans and Agent Orange: Update 1996.

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Veterans and Agent Orange: Update 1998 Project Staff DAVID A. BUTLER, Study Director SANJAY S. BALIGA, Research Associate JAMES A. BOWERS, Research/Project Assistant KATHLEEN R. STRATTON, Director, Division of Health Promotion and Disease Prevention DONNA D. DUNCAN, Division Assistant SHARON GALLOWAY, Financial Associate Staff Consultants JANE DURCH, Senior Program Officer, Institute of Medicine CAROL MACZKA, Director of Toxicology and Risk Assessment, National Research Council FLORENCE POILLON, Contract Editor

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Veterans and Agent Orange: Update 1998 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 (IOM) 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 backdrop 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 1998 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 focus of this second updated review is on scientific studies published since the release of Update 1996. To conduct the review, the IOM established a committee of 12 members representing a wide range of expertise to take a fresh look at the studies reviewed in VAO and Update 1996 along with the newest scientific evidence. In order to provide a link to the experience and expertise developed by the previous committees, five of the members of the committee responsible for this report were recruited from the committee responsible for Update 1996; two of these individuals also served on the VAO committee. 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 two open meetings 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 first of these was held in conjunction with the committee's second meeting in June 1997 in Washington, D.C.; the second in Irvine, California, in October, 1997. To solicit broad participation, the committee sent announcements to individuals, organizations, and listserves known to have an interest in this issue. The oral presentations and written statements submitted to the committee are described in detail in Appendix A. In order to address one area of interest identified by the Department of Veterans Affairs, the committee convened a workshop on the combination and reanalysis of existing data on the health effects of herbicide and dioxin exposure. The workshop, which took place in August 1997, brought together experts in these methodologies with researchers who have developed and analyzed datasets evaluating the health of Vietnam veterans and individuals exposed to herbicides or dioxin. The results of this effort will be addressed in a separate report. 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 expo-

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Veterans and Agent Orange: Update 1998 sure to herbicides. The committee also heard from the public through telephone calls, letters, and emails. 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: Patricia Buffler, University of California, Berkeley; Graham Colditz, Harvard University; John Doull, University of Kansas; Kristine Gebbie, Columbia University; David Kriebel, University of Massachusetts, Lowell; Gilbert Omenn, University of Michigan; Jonathan Samet, Johns Hopkins University; David Strogatz, University of Albany, SUNY. While the individuals listed above have provided constructive comments and suggestions, it must be emphasized that responsibility for the final content of this report rests entirely with the authoring committee and the institution. David A. Butler served as the study director for this project and deserves credit for drafting sections of the report. The committee would also like to acknowledge the excellent work of IOM staff members Sanjay Baliga and James Bowers. Carol Maczka of the Academy's National Research Council provided invaluable help on the toxicology chapter of the report. Thanks are also extended to Sharon Galloway, who handled the finances for the project; Florence Poillon and Jane Durch, who provided excellent editorial skills; Susan Fourt, who conducted database searches; Michael Edington, who supervised the report through the editorial and publication phases; and Donna Thompson, who provided administrative support to the project. The knowledge and experience of Michael Stoto and Catharyn Liverman, who served as staff members on the original committee, were helpful in this effort. 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. Bruce Armstrong (New South Wales Cancer Council, Australia), Michael DeVito (U.S. EPA), Keith Horsley (Commonwealth Department of Veterans' Affairs, Australia), Han Kang (U.S. Department of Veterans Affairs), Stephen Katz (National Institutes of Health, DHHS), Edward McCarthy (Johns Hopkins University), Joel Michalek (Armstrong Laboratory, USAF), and Jerry Rice (International Agency for Research on Cancer). David Tollerud Chairman

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Veterans and Agent Orange: Update 1998 Contents 1   EXECUTIVE SUMMARY   1 2   VETERANS AND AGENT ORANGE: PREVIOUS IOM REPORTS   17     Background   17     Impact of the Reports   23     Federal Government's Response to Concerns over the Military Use of Herbicides in Vietnam,   25 3   TOXICOLOGY   32     Summary   32     VAO and Update 1996—Overview   36     Update of the Scientific Literature—Overview   36     Toxicity Profile Updates   43     Issues in Evaluating the Evidence   108 4   METHODOLOGIC CONSIDERATIONS IN EVALUATING THE EVIDENCE   124     Questions to Be Addressed,   124     Issues in Evaluating the Evidence,   128     Summary of the Evidence,   132 5   EXPOSURE ASSESSMENT   135     Military Use of Herbicides in Vietnam,   135     Occupational and Environmental Exposures to Herbicides and Dioxin,   141

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Veterans and Agent Orange: Update 1998     Exposure Assessment for Epidemiology,   142     Exposure Assessment in Studies of Vietnam Veterans,   146     Exposure Assessment in Occupational and Environmental Studies,   150     Review of the Scientific Literature,   157 6   EPIDEMIOLOGIC STUDIES   169     Occupational Studies,   219     Environmental Studies,   232     Vietnam Veterans Studies   236 7   CANCER   265     Introduction   265     Gastrointestinal Tract Tumors   267     Hepatobiliary Cancers   282     Nasal/Nasopharyngeal Cancer   288     Laryngeal Cancer   292     Lung Cancer   295     Bone Cancer   302     Soft-Tissue Sarcomas   304     Skin Cancers   311     Melanoma   313     Basal and Squamous Cell (Nonmelanoma) Skin Cancer   317     Breast Cancer   322     Cancers of the Female Reproductive System   329     Prostate Cancer   334     Testicular Cancer   343     Urinary Bladder Cancer   347     Renal Cancer   351     Brain Tumors   356     Non-Hodgkin's Lymphoma   362     Hodgkin's Disease   371     Multiple Myeloma   377     Leukemia   383     Summary   390 8   LATENCY AND CANCER RISK   407     Analysis of Latency in Epidemiologic Studies   408     Four Questions Addressed by the Committee   412     Review of the Scientific Literature   416     Respiratory Cancer   418     Prostate Cancer   426     Non-Hodgkin's Lymphoma   428

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Veterans and Agent Orange: Update 1998     Relevance of Latency in Assessing the Effect of Herbicides on Cancer Risk in Vietnam Veterans   430 9   REPRODUCTIVE EFFECTS   434     Introduction   434     Birth Defects   435     Fertility   444     Stillbirth, Neonatal Death, and Infant Death   451     Low Birthweight and Preterm Birth   454     Conclusions for Reproductive Effects   458 10   NEUROBEHAVIORAL DISORDERS   466     Background   466     Cognitive and Neuropsychiatric Effects   468     Motor/Coordination Dysfunction   469     Chronic Persistent Peripheral Neuropathy   470     Acute and Subacute Transient Peripheral Neuropathy   473     Conclusions for Neurobehavioral Disorders   473 11   OTHER HEALTH EFFECTS   478     Introduction   478     Chloracne   478     Porphyria Cutanea Tarda   480     Respiratory Disorders   482     Immune System Disorders   487     Diabetes   491     Lipid and Lipoprotein Disorders   503     Gastrointestinal and Digestive Disease, Including Liver Toxicity   508     Circulatory Disorders   514     Summary   518     APPENDIXES   531 A   Information Gathering   533 B   ICD·9 Codes for Cancer Outcomes   537 C   Committee and Staff Biographies   540     INDEX   547

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