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).
Library of Congress Cataloging-in-Publication Data
Institute of Medicine (U.S.). Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides.
Veterans and Agent Orange : health effects of herbicides used in Vietnam / Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides, Division of Health Promotion and Disease Prevention, Institute of Medicine.
Includes bibliographical references and index.
1. Agent Orange—Health aspects. 2. Agent Orange—Toxicology. 3. Vietnamese Conflict, 1961-1975—Veterans—Health risk assessment—United States. I. Title.
[DNLM: 1. Veterans. 2. War. 3. Dioxins—adverse effects. 4. Herbicides—adverse effects. 5. Environmental Exposure. WA 240 I593v 1993]
for Library of Congress 93-27237
Copyright 1994 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.
COMMITTEE TO REVIEW THE HEALTH EFFECTS IN VIETNAM VETERANS OF EXPOSURE TO HERBICIDES
HAROLD FALLON (Chairman), Dean,
University of Alabama School of Medicine, Birmingham, Alabama
DAVID TOLLERUD (Vice-Chairman), Director,
Occupational and Environmental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
NORMAN BRESLOW (Liaison to the IOM Board on Health Promotion and Disease Prevention), Professor,
Department of Biostatistics, University of Washington, Seattle, Washington
JESSE BERLIN, Research Assistant Professor of Biostatistics in Medicine,
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
KAREN BOLLA, Assistant 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 Medical School, Chicago, Illinois
NORBERT KAMINSKI, Assistant Professor,
Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, Virginia
DAVID KRIEBEL, Associate Professor,
Department of Work Environment, University of Massachusetts, Lowell, Massachusetts
N. KARLE MOTTET, Professor,
Department of Pathology and Environmental Health, University of Washington School of Medicine, Seattle, Washington
ALFRED NEUGUT, Associate Professor,
Department of Medicine and School of Public Health, Columbia University College of Physicians and Surgeons, New York, New York
WILLIAM NICHOLSON, Professor,
Mount Sinai School of Medicine, NewYork, New York
ANDREW OLSHAN, Assistant Professor,
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina
KATHLEEN RODGERS, Associate Professor,
Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles, California
NANCY SPRINCE, Associate Professor,
Department of Preventive Medicine, University of Iowa, Iowa City, Iowa
CLIFFORD WEISEL, Assistant Professor,
Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey
MICHAEL STOTO, Project Director and Director,
Division of Health Promotion and Disease Prevention
SUSAN ROGERS, Program Officer
DIANE MUNDT, Program Officer
CYNTHIA ABEL, Research Associate
CATHARYN LIVERMAN, Research Associate
CATHERINE WESNER, Project Assistant
ZOE SCHNEIDER, Project Assistant
GAIL CHARNLEY, Consultant,
Board on Environmental Studies and Toxicology, National Research Council
JANE DURCH, Program Officer,
Institute of Medicine
THOMAS BURROUGHS, Contract Science Writer
FLORENCE POILLON, Contract Editor
ANDREA POSNER, Contract Copy Editor
JANA KATZ, Student Intern
In response to decades of concern surrounding the possible long-term health consequences of exposures to herbicides and the contaminant dioxin, Congress directed the Secretary of Veterans Affairs, in Public Law 102-4 signed on February 6, 1991, to request the National Academy of Sciences (NAS) to conduct a comprehensive review and evaluation of the available scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used during the Vietnam conflict. This report from the Institute of Medicine (IOM) Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides is hereby submitted in compliance with Public Law 102-4.
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam reviews and evaluates the available scientific evidence regarding the association between exposure to dioxin or other chemical compounds in herbicides used in Vietnam and a wide range of health effects, and provides the committee's best assessment of this body of knowledge for the Secretary of Veterans Affairs to consider as the Department of Veterans Affairs exercises its responsibilities to Vietnam veterans. The report also describes areas in which the available scientific data are insufficient to determine whether an association exists and provides the committee's recommendations for areas in which future research is likely to be most productive.
That Congress would ask the NAS—a nongovernmental organization—to conduct this study reflects a time-honored tradition. Created by an act of Congress and signed into law in 1863 by President Abraham Lincoln, the NAS is dedicated to the furtherance of science and technology and to their
use for the promotion of general public welfare. A private, nonprofit society of distinguished scholars engaged in scientific and engineering research, the NAS has a mandate to advise the federal government on scientific and technical issues of pressing importance. Its members, drawn from universities and the private sector, are elected by their peers on the basis of exemplary professional achievement. Members, along with other leading experts, voluntarily participate in National Research Council and IOM studies and serve without compensation.
The IOM was chartered by the NAS in 1970 to serve as an adviser to the federal government on issues that affect the public's health, as well as to act independently in identifying important issues of medical care, research, and education. The IOM brings to this mission more than two decades of experience in conducting independent analyses of pressing health problems that involve federal policy decisions.
As described in more detail in Chapter 2 of this report, the NAS has a history of involvement with the Agent Orange issue. A major study in 1974 focused primarily on the possible ecological consequences of herbicides used in Vietnam, but an individually authored component of that report published eight years later reviewed its possible reproductive effects among the Vietnamese. In the early 1980s, two committees reviewed protocols for large, epidemiologic studies of the health effects in veterans. Between 1986 and 1990, an IOM committee reviewed protocols and the analytical methods of a series of epidemiologic studies of Vietnam veterans carried out by the Centers for Disease Control, though it did not contribute to the final conclusions reached in those studies. Thus, while the NAS and the IOM have been aware of the controversy surrounding the military use of Agent Orange and other herbicides in Vietnam, these past activities are quite different from the current study, of which the primary purpose is to determine whether there are health effects related to exposure to herbicides.
The 16 members of the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides represent a wide range of expertise including occupational and environmental medicine, toxicology, epidemiology, pathology, clinical oncology, psychology, neurology, and biostatistics. The committee was chaired by Harold Fallon, M.D., Dean of the University of Alabama Medical School, Birmingham, and a member of the IOM. David Tollerud, M.D., M.P.H., Director of Occupational and Environmental Medicine at the University of Pittsburgh, served as vice-chair. Committee member Norman Breslow, Professor of the Department of Biostatistics of the University of Washington and also a member of the IOM, served as a liaison to the IOM Board on Health Promotion and Disease Prevention, which was responsible for overseeing this study. Biographical sketches of the other committee members and the professional staff appear in Appendix D.
All committee members were selected because they are leading authorities in their scientific fields, are well-respected by their colleagues and peers, have no conflicts of interest with regard to the matters under study, and, indeed, have taken no public positions concerning the potential health effects of herbicides in Vietnam veterans or related aspects of herbicide or dioxin exposure. The committee thus has provided a fresh analysis of this issue—which is both scientifically complex and emotionally charged—and this report reflects the committee's thorough and unbiased scientific judgments. As with all reports from the IOM, the committee's work was reviewed by an independent panel of distinguished experts.
Kenneth I. Shine
President, Institute of Medicine
The use of Agent Orange and other herbicides in Vietnam has stimulated concern and controversy ever since the U.S. began the military herbicide program in 1962. Questions regarding the effects of herbicides on health and the environment have persisted over several decades. Many veterans, who served their country in Vietnam at great personal sacrifice and hardship, face continuing uncertainty about whether a myriad of diseases and health effects are associated with exposure to the herbicides used in Vietnam. Some of these veterans and their families feel that their pain and suffering have been ignored and that these questions have not been adequately addressed.
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 herbicides. The creation of the NAS Institute of Medicine's committee underscores the critical importance of approaching these questions from a scientific standpoint, yet the committee 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 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 committee on recent research results and studies still under way. This information provided a meaningful backdrop for the numerous scientific
articles that the committee reviewed and evaluated. The committee appreciates the efforts of everyone who presented information to it and acknowledges this valuable addition to the study process.
As the study progressed, two separate but interdependent themes became evident to the committee. First, this report is a scientific investigation of the potential health effects of exposure to the herbicides that were used in Vietnam and to dioxin (2,3,7,8-tetrachlorodibenzo-para-dioxin; TCDD), an unintentional contaminant of some of those herbicides. This theme is discussed first in Chapter 2, which provides a context for the investigation by relating the history of national concern about TCDD and herbicides and of efforts to address this concern. Chapter 4 reviews the toxicological data (based on laboratory studies and animal investigations) on these chemicals, with a focus on the TCDD contaminant because this area has been the object of more substantial scientific research. Most of the committee's work, however, focused on the review of epidemiologic studies. Chapters 8 through 11 analyze and present the committee's conclusions regarding the relationship between herbicide/TCDD exposure and 44 specific diseases and disorders. These diseases and disorders include different forms of cancer, reproductive and developmental effects, neurobehavioral disorders, and other health effects, including chloracne and porphyria cutanea tarda. In order to understand the committee's approach to these reviews, Chapter 5 lays out the general methodological considerations that the committee used in evaluating this evidence, and Chapter 6 addresses the question of how to assess the nature of exposure to the substances in question, a critical element in evaluating the epidemiologic studies that were reviewed. Many of these studies addressed the health effects of people who were occupationally or environmentally exposed to TCDD or the herbicides in question, and many of the studies investigated more than one health outcome. Rather than summarize the methods of these studies each time they are considered, the committee's review and summary of the health effects are preceded by a complete and thorough methodologic description of all the studies under review—organized by the nature of the population exposed and by study methods—in Chapter 7.
The second theme in this report relates to the use of herbicides in Vietnam, the effects of exposure on Vietnam veterans, and the direction of future research efforts toward learning more than is currently known about these issues. The discussion of this theme also begins in Chapter 2, but the history of military operations in Vietnam, with a special focus on the herbicide program, is described in detail in Chapter 3. In addition to addressing exposure assessment in general, Chapter 6 discusses the methods that have been used to assess exposure to herbicides in studies of Vietnam veterans and summarizes what is currently known about the nature and extent of that exposure. Chapter 6 also proposes a new method of
historical exposure reconstruction in studies of Vietnam veterans, a topic that is the focus for the committee's research recommendations in Chapter 12. In addition, Chapter 12 comments on existing studies of Vietnam veterans and makes recommendations about four specific programs mandated in Public Law 102-4.
CONDUCT OF THE STUDY
The committee worked on several fronts in conducting this study, 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 Institute of Medicine (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 available evidence. Given the nature of the controversy surrounding this issue, the committee deemed it vital to convene open meetings as well. Three public meetings were held during the course of the study, which provided timely forums for veterans and veterans service organizations, researchers, policymakers, and other interested parties to present their concerns, review their research, and exchange information directly with the committee members.
The first open meeting was held in September 1992. To solicit broad participation, the IOM committee sent announcements to nearly 1,000 persons known to have an interest in this issue. Names were gathered from veterans service organizations, scientific organizations, labor unions, environmental groups, government agencies, and numerous other sources, and news of the meeting was circulated to approximately 1,500 media outlets nationwide. During this day-long public meeting, 25 persons made oral presentations. Because some individuals were unable to attend the public meeting, written statements were given equal weight to oral presentations; by April 15, 1993, 28 additional individuals had submitted written statements. Besides these statements, the committee received specially prepared analyses from several groups. All of this material was carefully considered by the committee over the course of the study. The oral presentations and written statements submitted to the committee are described in detail in Appendix B.
The second public meeting, a ''Scientific Workshop on Exposure Assessment," took place in December 1992. The committee assembled 17 experts in various scientific fields—drawn from universities, veterans service organizations, federal agencies, and health groups—to discuss how exposure to Agent Orange, other herbicides, and TCDD is assessed in epidemiologic studies. Participants discussed records-based methods, as well as more recent biomedical research in which current dioxin levels are
measured in the blood and tissue of individuals to estimate previous levels of exposure to TCDD (see Appendix B).
A third public meeting, held in February 1993, focused on the "Vietnam Experience." The committee heard from veterans who had served in the U.S. Marines, Navy, Army, and Air Force. Some of these individuals experienced extensive combat, frequently in areas sprayed with herbicides. Others had been directly involved in spraying herbicides from aircraft or "brown water" river patrol boats. The committee also heard from the Vietnam Veterans of America on the wartime experiences of women, thousands of whom served in Vietnam, primarily as military nurses.
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 frequent meetings with representatives of veterans service organizations, congressional committees, federal agencies, and scientific organizations. The committee heard from the public through several hundred telephone calls and letters, each of which received a response from the IOM staff.
The committee also benefited from the expert advice and reviews of consultants in toxicology, environmental health, neurotoxicology, autoimmune disorders, reproductive effects, and dermatological disorders, including porphyria cutanea tarda. A list of the background papers, their authors, and the experts consulted appears in Appendix B.
During the course of the committee's work, the Environmental Protection Agency (EPA) has been in the process of carrying out an open scientific reassessment of the health risks of dioxin to guide its regulatory policy. The committee has benefited from this effort by being able to read and consider draft scientific reports prepared for the EPA by independent scientists as part of this process, and by IOM committee members' and staff's attendance at the EPA's public meetings. However, the congressional charge to the IOM committee is substantially different than the EPA's review in at least two important ways: (1) the EPA is concerned only with dioxin, whereas the IOM is concerned with all of the herbicides used in Vietnam, and (2) because of its regulatory focus, the EPA is more concerned with defining a dose-response relationship than the IOM committee felt was either necessary or feasible for Vietnam veterans.
The value of this continued, open, and wide-ranging dialogue between the IOM committee and the scientific community, veterans, policymakers, and citizens proved itself many times over and ultimately contributed to a more comprehensive report.
Most of the committee's work involved reviewing the scientific literature bearing on the association between herbicides or dioxin and various health outcomes. The committee or its staff read approximately 6,420 abstracts
of scientific or medical articles which were then entered into a computerized bibliographic data base. From these, approximately 230 epidemiologic studies were chosen for detailed review and analysis. These included studies of people exposed to the herbicides in question in occupational and environmental settings, as well as studies of Vietnam veterans. The committee relied on the original publications themselves rather than on 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 the herbicides in question. Appendix A describes the committee's literature review strategy in detail.
Controversy has surrounded the study of Agent Orange since the first questions of herbicide-related health effects in Vietnam veterans were raised more than 20 years ago. In the course of its work, the committee heard allegations of scientific misconduct and claims of a government conspiracy to suppress information on health effects, as well as serious disagreements among scientists about the interpretation of laboratory and clinical data. The committee was not charged with investigating or resolving these controversies, and it did not attempt to do so. The committee took these issues into consideration only to the extent that they had a direct bearing on the scientific results that are the subject of this review.
We believe that the committee has produced a comprehensive, unbiased scientific review of the available evidence regarding potential health effects of exposure to herbicides in Vietnam veterans. Although the conclusions and recommendations presented here will not end the controversy surrounding this issue, it is the committee's hope that this report will crystallize the current scientific information on this important topic and prompt further research to answer the remaining questions being asked by veterans and their families, the Department of Veterans Affairs, and Congress.
The committee wishes to acknowledge that this study could not have been done without the assistance of a number of people, many of whom are listed in Appendix B. A special acknowledgment is extended to Donald Whorton and Albert Munson, both of whom served for a brief period with the committee. The work of the Institute of Medicine staff deserves high praise. Thanks are extended to the professional staff, Susan Rogers, Diane Mundt, Cynthia Abel, Catharyn Liverman, Gail Charnley, and Jane Durch, for their input, advice, and support. Thanks are also extended to Catherine Wesner, the study's project assistant, who planned travel and meeting arrangements and provided assistance with editorial changes to the manuscript; Jana Katz, the committee's student intern, who assisted with literature searches and in compiling the literature data base; Thomas Burroughs, who worked with IOM staff members in drafting several sections of the report; Zoe Schneider who aided in the preparation of the final manuscript;
Andrea Posner, who proofread the final changes in the manuscript; and Florence Poillon, who provided excellent editorial skills. Finally, the committee wishes to recognize the major contributions of the study director, Michael Stoto. It is through his expert leadership that this report has come to fruition.
Harold Fallon, Chairman
David Tollerud, Vice-chairman