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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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