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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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