Veterans and Agent Orange

Update 1996

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.
1996



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--> Veterans and Agent Orange Update 1996 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. 1996

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--> National Academy Press 2101 Constitution Avenue, N.W. 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. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. 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). Veterans and Agent Orange: Update 1996 is available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Lock Box 285, Washington, DC, 20055. Call 800-624-6242 or 202-334-3938 (in the Washington Metropolitan Area). The Executive Summary of Veterans and Agent Orange: Update 1996 is available on-line at http://www.nap.edu/nap/online/veterans/. Library of Congress Catalog Card Number 96-68761 International Standard Book Number 0-309-05487-7 Copyright 1996 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 logo-type by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatlichemusseen in Berlin. First Printing, June 1996 Second Printing, April 1997

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--> Committee To Review The Health Effects In Vietnam Veterans Of Exposure To Herbicides DAVID TOLLERUD (Chairman), Associate Professor and Chief, Occupational and Environmental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania MICHAEL AMINOFF, Professor, Department of Neurology, University of California at San Francisco, School of Medicine, San Francisco, California JESSE BERLIN, Research Associate Professor, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania KAREN BOLLA, Associate Professor, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland GRAHAM COLDITZ, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts CHRISTOPHER GOETZ, Professor, Department of Neurologic Sciences, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois SEYMOUR GRUFFERMAN, Professor and Chairman, Department of Family Medicine and Clinical Epidemiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania S. KATHARINE HAMMOND, Associate Professor, Department of Environmental Health Sciences, School of Public Health, University of California at Berkeley, Berkeley, California DAVID KRIEBEL, Associate Professor, Department of Work Environment, University of Massachusetts, Lowell, Massachusetts BRYAN LANGHOLZ, Associate Professor of Research, Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California WILLIAM NICHOLSON, Professor, Mount Sinai School of Medicine, New York, New York PETER NOWELL,* Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania ANDREW OLSHAN, Assistant Professor, Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina MALCOLM PIKE,* Chairman, Preventative Medicine, University of Southern California School of Medicine, Los Angeles, California *   Member, Institute of Medicine

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--> KEN RAMOS, Associate Professor, Department of Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, Texas NOEL ROSE, Professor, Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland Project Staff MICHAEL A. STOTO, Director, Division of Health Promotion and Disease Prevention DAVID A. BUTLER, Study Director (as of January 1996) KELLEY BRIX, Study Director (through November 1995) CYNTHIA ABEL, Program Officer DEBORAH KATZ, Research Assistant AMY NOEL O'HARA, Project Assistant DONNA D. THOMPSON, Division Assistant MONA BRINEGAR, Financial Associate Staff Consultants CAROL MACZKA, Director of Toxicology and Risk Assessment, Institute of Medicine DIANE J. MUNDT, Senior Program Officer, Institute of Medicine CATHARYN LIVERMAN, Program Office, Institute of Medicine TOM BURROWS, Contract Editor

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--> 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, signed 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 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 original 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 the original committee on recent research results and studies still under way. This information provided a meaningful backdrop for the numerous scientific articles that the original committee reviewed and evaluated. In its 1994 report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, the committee 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 and provided the committee's findings to the Secretary of Veterans Affairs to consider as the Department of Veterans Affairs carried out its responsibilities to Vietnam veterans. The report also described areas in which the available

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--> scientific data were insufficient to determine whether an association exists and provided the committee's recommendations for future research. Public Law 102-4 also asked the IOM 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 focus of this first updated review is on new scientific studies published since the release of Veterans and Agent Orange (VAO) and on updates of scientific studies previously reviewed in VAO. To conduct this review, the IOM established a new committee of 16 members representing a wide range of expertise to take a fresh look at the studies reviewed in VAO and new scientific studies to determine whether an association exists between herbicide exposure and specific health outcomes. In order to provide a link to VAO, half of the committee members had also served on the original 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 goals of seeking the most accurate information and advice from the widest possible range of knowledgeable sources. Consistent with procedures of the IOM, 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. Given the nature of the controversy surrounding this issue, the committee deemed it vital to convene an open meeting as well. The public meeting was held in conjunction with the committee's first meeting, in April 1995, and provided 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. To solicit broad participation, the committee sent announcements to nearly 1,300 individuals and organizations 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 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. These interactions included meetings with representatives of veterans service organizations, congressional committees, federal agencies, and scientific organizations. The committee also heard from the public through telephone calls and letters, each of which received a response from the IOM staff. Most of the committee's work involved reviewing the scientific literature bearing on the association between herbicides or dioxin and various health outcomes. The literature included studies of people exposed in occupational and

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--> environmental settings to the types of herbicides used in Vietnam, as well as studies of Vietnam veterans. The committee reviewed the original publications themselves rather than summaries or commentaries. Such secondary sources were used to check the completeness of the review. The committee also reviewed the primary and secondary literature on basic toxicological and animal studies related to dioxin and other herbicides in question. As explained in the Executive Summary on page 14, the committee found that, in general, it is not possible to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. Two members of the committee believe that there are certain circumstances under which the risk to veterans can be quantified. Appendix B presents their analysis and estimates; it represents their opinion alone. Kelley Brix served as the original 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 the staff members, David Butler, Deborah Katz, and Amy Noel O'Hara. The committee would also like to thank Michael Stoto, Cynthia Abel, Diane Mundt, and Catharyn Liverman, who also served as staff members for the original committee; their knowledge of the subject was helpful in completing the report. Thanks are also extended to Mona Brinegar, who handled the finances for the project; Thomas Burroughs, who provided excellent editorial skills; Michael Edington, who supervised the report through the editorial and publication phases; and Donna Thompson, who provided assistance with editorial changes to the manuscript. DAVID TOLLERUD, CHAIRMAN

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--> Contents 1   EXECUTIVE SUMMARY   1     Organization and Framework   2     Toxicology Summary   3     Exposure Assessment   4     Conclusions about Health Outcomes   5        Health Outcomes with Sufficient Evidence of an Association   5        Health Outcomes with Limited/Suggestive Evidence of Association   8        Health Outcomes with Inadequate/Insufficient Evidence to Determine Whether an Association Exists   11        Health Outcomes with Limited/Suggestive Evidence of No Association   12     The Relationship Between the Length of Time Since Exposure and the Possible Risk of Cancer Development   13     Increased Risk of Disease in Vietnam Veterans   14 2   VETERANS AND AGENT ORANGE: THE INITIAL IOM REPORT   17     Background   17        Conclusions About Health Outcomes   19        Research Recommendations   23     Impact of the Report   24        DVA Task Force   24     Military Use of Herbicides in Vietnam   26     Federal Government's Response to Concerns Over the Military Use of Herbicides in Vietnam   27

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-->        U.S. Congress   27        Department of Veterans Affairs   29        Department of the Air Force   31        Environmental Protection Agency   32 3   TOXICOLOGY   35     Summary   35        Introduction   35     Summary of VAO   37        Chemistry   38        Toxicokinetics   38        Disease Outcomes and Mechanisms of Toxicity   39     Literature Update   43        Overview   43     Update of Toxicity Profiles   45        Toxicity Profile Update of 2,4-D   46        Toxicity Profile Update of 2,4,5-T   49        Toxicity Profile Update of Cacodylic Acid   50        Toxicity Profile Update of Picloram   51        Toxicity Profile Update of TCDD   51 4   METHODOLOGIC CONSIDERATIONS IN EVALUATING THE EVIDENCE   88     Questions to Be Addressed   88        Are Herbicides Statistically Associated with the Health Outcome?   90        What Is the Increased Risk of the Disease in Question Among Those Exposed to Herbicides in Vietnam?   91        Is There a Plausible Biologic Mechanism?   92     Issues in Evaluating the Evidence   92        Experimental Studies   92        Epidemiologic Studies   93        The Role of Case Studies and Other Studies with No Comparison Groups   94        Publication Bias   95        The Role of Judgment   96        Integration of New Evidence   96     Summary of the Evidence   97        Categories of Association   97 5   EXPOSURE ASSESSMENT   99     Exposure Assessment in the Evaluation of Epidemiologic Studies   99     Estimates of Exposure to Herbicides and TCDD During Vietnam Service   101

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-->     Review of the Recent Literature   104        TCDD Half-Life Investigations   104        TCDD Exposure Levels for Selected Epidemiologic Studies   105        Other Dioxin Congeners   106        Development of Exposure Indices   107 6   EPIDEMIOLOGIC STUDIES   112     Occupational Studies   113        Production Workers   128        Agricultural Workers   135     Environmental Studies   140        Seveso   141        Vietnam   148        Other Environmental Studies   148     Vietnam Veterans   149        United States   150 7   CANCER   175     Introduction   175        Plausibility Data   176        Expected Number of Cancer Cases Among Vietnam Veterans in the Absence of Any Increase in Risk Due to Herbicide Exposure   176     Gastrointestinal Tract Tumors   177        Background   177        Summary of VAO   177        Update of the Scientific Literature   178        Summary   180        Conclusions   181     Hepatobiliary Cancers   181        Background   181        Epidemiologic Studies   182        Summary   185        Conclusions   185     Nasal/Nasopharyngeal Cancer   187        Background   187        Epidemiological Studies   188        Summary   189        Conclusions   189     Respiratory Cancers   189        Background   189        Epidemiologic Studies   191        Epidemiologic Studies of Laryngeal Cancer   202

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-->        Summary   203        Conclusions   203     Bone Cancer   204        Background   204        Summary of VAO   204        Update of the Scientific Literature   204        Summary   205        Conclusions   205     Soft-Tissue Sarcomas   205        Background   205        Summary of VAO   205        Update of the Scientific Literature   206        Summary   208        Conclusions   208     Skin Cancers   209        Background   209        Epidemiologic Studies   209        Summary   210        Conclusions   210     Cancers of the Female Reproductive System   211        Background   211        Summary of VAO   211        Update of the Scientific Literature   212        Summary   213        Conclusions   213     Breast Cancer   213        Background   213        Epidemiologic Studies   214        Summary   217        Conclusions   217     Prostate Cancer   217        Background   217        Epidemiologic Studies   219        Summary   221        Conclusions   223     Renal, Bladder, and Testicular Cancers   223        Background   223     Renal Cancer   224        Summary of VAO   224        Update of the Scientific Literature   224        Summary   225        Conclusions   225     Bladder Cancer   225

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-->        Summary of VAO   225        Update of the Scientific Literature   226        Summary   227        Conclusions   227     Testicular Cancer   227        Summary of VAO   227        Update of the Scientific Literature   227        Summary   228        Conclusions   228     Brain Tumors   228        Background   228        Summary of VAO   229        Update of the Scientific Literature   229        Summary   230        Conclusions   230     Malignant Lymphomas and Myeloma   231        Background   231     Non-Hodgkin's Lymphoma   231        Summary of VAO   231        Update of the Scientific Literature   232        Summary   234        Conclusions   234     Hodgkin's Disease   235        Summary of VAO   235        Update of the Scientific Literature   235        Summary   236        Conclusions   236     Multiple Myeloma   236        Background   236        Epidemiologic Studies   237        Summary   244        Conclusions   244     Leukemia   245        Background   245        Summary of VAO   245        Update of Scientific Literature   245        Summary   246        Conclusions   247     Overall Summary for Cancer   247        Health Outcomes with Sufficient Evidence of an Association   247        Health Outcomes with Limited/Suggestive Evidence of Association   247        Health Outcomes with Inadequate/Insufficient Evidence to Determine Whether an Association Exists   249

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-->        Health Outcomes with Limited/Suggestive Evidence of No Association   250        Increased Risk in Vietnam Veterans   251 8   LATENCY AND CANCER RISK   260     Analysis of Latency in Epidemiologic Studies   261        Questions Addressed by the Committee   264     Results of the Literature Review of Herbicide Exposure and Cancer   266        Limitations of the Literature Review Approach   266        Overview of the Findings   267     Respiratory Cancer   268        Background   268        Conclusions   271     Prostate Cancer   273        Background   273        Conclusions   274     Relevance of the Latency Issue in Assessing the Effect of Herbicides on Cancer Risk in Vietnam Veterans   276 9   REPRODUCTIVE EFFECTS   278     Introduction   278     Fertility   279        Background   279        Summary of VAO   280        Update of the Scientific Literature   280        Conclusions   282     Spontaneous Abortion   282        Background   282        Summary of VAO   283        Update of the Scientific Literature   283        Conclusions   284     Stillbirth   284        Background   284        Summary of VAO   285        Update of the Scientific Literature   285        Conclusions   285     Birth Defects   286        Background   286        Epidemiologic Studies of Birth Defects   286        Summary   295        Conclusions   298     Childhood Cancer   298        Background   298

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-->        Summary of VAO   299        Update of Scientific Literature   299        Conclusions   300     Conclusions for Reproductive Effects   300 10   NEUROBEHAVIORAL DISORDERS   304     Introduction   304     Cognitive and Neuropsychiatric Effects   307        Summary of VAO   307        Update of the Scientific Literature   307        Conclusions   308     Motor/Coordination Dysfunction   309        Summary of VAO   309        Update of the Scientific Literature   309        Conclusions   310     Chronic Persistent Peripheral Neuropathy   310        Summary of VAO   310        Update of the Scientific Literature   310        Conclusions   311     Acute and Subacute Transient Peripheral Neuropathy   311        Review of the Scientific Literature   312        Summary of Acute and Subacute Transient Peripheral Neuropathy   313        Conclusions   314     Conclusions for Neurobehavioral Disorders   314 11   OTHER HEALTH EFFECTS   317     Introduction   317     Chloracne   317        Summary of VAO   318        Update of the Scientific Literature   318        Conclusions   320     Porphyria Cutanea Tarda   321        Summary of VAO   321        Update of the Scientific Literature   322        Conclusions   323     Respiratory Disorders   324        Summary of VAO   324        Update of the Scientific Literature   325        Conclusions   325     Immune System Disorders   326        Immune Suppression   326        Allergy and Autoimmunity   327        Summary of VAO   327

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-->        Update of the Scientific Literature   328        Conclusions   329     Other Metabolic and Digestive Disorders   330        Diabetes Mellitus   330        Liver Toxicity   331        Lipid Abnormalities   333        Gastrointestinal Ulcers   334        Conclusions   334     Circulatory Disorders   335        Summary of VAO   335        Update of the Scientific Literature   336        Conclusions   337     APPENDIXES         A Information Gathering   343     B Risk of Disease in Vietnam Veterans by Bryan Langholz and Malcolm Pike   349     C Committee and Staff Biographies   360

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Veterans and Agent Orange Update 1996

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