Veterans and Agent Orange

Update 2002

Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fourth Biennial Update)

Board on Health Promotion and Disease Prevention

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C. www.nap.edu



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Veterans and Agent Orange: Update 2002 Veterans and Agent Orange Update 2002 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fourth Biennial Update) Board on Health Promotion and Disease Prevention INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Veterans and Agent Orange: Update 2002 THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, D.C. 20001 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 project was supported by Contract No. V101(93)P-1637 between the National Academy of Sciences and the US Department of Veterans Affairs. The views presented in this report are those of the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fourth Biennial Update) and are not necessarily those of the funding agencies. International Standard Book Number 0-309-08616-7 (book) International Standard Book Number 0-309-50724-3 (PDF) Library of Congress Control Number 2003103424 Additional copies of this report are available for sale from the National Academies Press , 500 Fifth Street, N.W., Box 285, Washington, D.C. 20055; call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2003 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 serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Veterans and Agent Orange: Update 2002 “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Shaping the Future for Health

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Veterans and Agent Orange: Update 2002 THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council www.national-academies.org

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Veterans and Agent Orange: Update 2002 COMMITTEE TO REVIEW THE HEALTH EFFECTS IN VIETNAM VETERANS OF EXPOSURE TO HERBICIDES (FOURTH BIENNIAL UPDATE) Irva Hertz-Picciotto, (Chair), Professor, Department of Epidemiology, University of North Carolina at Chapel Hill, North Carolina Kiros T. Berhane, Assistant Professor, Department of Preventive Medicine, University of Southern California, Los Angeles, California Margit L. Bleecker, Director, Center for Occupational and Environmental Neurology, Baltimore, Maryland Paul F. Engstrom, Senior Vice President and Medical Director, Fox Chase Network, Philadelphia, Pennsylvania Richard A. Fenske, Professor, Environmental Health, Industrial Hygiene and Safety Program, University of Washington, Seattle, Washington Thomas A. Gasiewicz, Professor of Environmental Medicine and Deputy Director of the Environmental Health Sciences Center, University of Rochester, Rochester, New York Tee L. Guidotti, Professor and Chair of the Department of Environmental and Occupational Health, The George Washington University School of Public Health and Health Services, Washington, DC Loren D. Koller, Consultant, Environmental Health and Toxicology, Corvallis, Oregon John J. Stegeman, Senior Scientist and Chair of the Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts David S. Strogatz, Associate Professor and Chair of Epidemiology, School of Public Health, State University of New York at Albany, New York Staff Michelle C. Catlin, Study Director Jennifer A. Cohen, Research Associate Anna B. Staton, Research Assistant Elizabeth J. Albrigo, Project Assistant Joe A. Esparza, Project Assistant Jakki Sears, Project Assistant (Temporary Staff) Norman Grossblatt, Senior Editor David A. Butler, Senior Program Officer Rose Marie Martinez, Director, Board on Health Promotion and Disease Prevention

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Veterans and Agent Orange: Update 2002 Reviewers 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 NRC's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its 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 review of this report: Linda S. Birnbaum, U.S. Environmental Protection Agency Chris Gennings, Virginia Commonwealth University Russ B. Hauser, Harvard School of Public Health Robert H. Herrick, Harvard School of Public Health Howard M. Kipen, University of Medicine and Dentistry of New Jersey— Robert Wood Johnson Medical School Henry C. Pitot, McArdle Cancer Research Stephen H. Safe, Texas A&M University Joseph V. Simone, Simone Consulting Bailus Walker, Jr., Howard University Cancer Center Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The

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Veterans and Agent Orange: Update 2002 review of this report was overseen by Robert B. Wallace, University of Iowa. Appointed by the National Research Council and Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Veterans and Agent Orange: Update 2002 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 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 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 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

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Veterans and Agent Orange: Update 2002 association exists and provided the committee's recommendations for future research. 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 TCDD 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 second, Veterans and Agent Orange: Update 1998 (Update 1998) was published in 1999. The third, Veterans and Agent Orange: Update 2000 (Update 2000) was published in 2001. The focus of this fourth updated review is on scientific studies published since the release of Update 2000. To conduct the review, the IOM established a committee of 10 members representing a wide range of expertise to take a fresh look at the studies reviewed in VAO, Update 1996, Update 1998, and Update 2000 along with the newest scientific evidence. In order to provide a link to the experience and expertise developed by the previous committees, seven of the members of the committee responsible for this report were recruited from the committee responsible for Update 2000. 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 TCDD 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 in April and September of 2002 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 oral presentations and written statements submitted to the committee are described in Appendix A. The committee thanks these individuals who provided valuable insights into the health problems experienced by Vietnam veterans. 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. The committee also heard from the public through telephone calls, letters, and emails. Michelle Catlin served as the study director for this project. The committee would also like to acknowledge the excellent work of IOM staff members and temporary staff members Jennifer Cohen, Anna Staton, Elizabeth Albrigo, Jakki

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Veterans and Agent Orange: Update 2002 Sears, Jonathon Kossak, and David Butler. Thanks are also extended to Jim Banihashemi, who handled the finances for the project; Norman Grossblatt, who provided excellent editorial skills; William McLeod, who conducted database searches; Jennifer Bitticks, who supervised the report through the editorial and publication phases; and Rita Gaskins, who provided administrative support to the project. 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 Dr. Joel Michalek (Air Force Research Laboratory, Brooks Air Force Base, Texas) for presenting his most recent data at a public session. Irva Hertz-Picciotto, Chair

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Veterans and Agent Orange: Update 2002 Contents     EXECUTIVE SUMMARY   1      The Charge to the Committee,   2      The Committee's Approach to Its Charge,   2      The Committee's Evaluation,   3      Research Recommendations,   10  1   INTRODUCTION   12      Charge to the Committee,   13      Conclusions of Previous Veterans and Agent Orange Reports,   13      Organization of this Report,   18      References,   19  2   CONSIDERATIONS IN EVALUATING THE EVIDENCE   20      Choice of Health Outcomes,   20      Identification of Relevant Literature,   20      Committee's Approach to Its Charge,   22      Issues in Evaluating the Evidence,   24      References,   28  3   TOXICOLOGY   30      Highlights of Previous Reports,   31      Toxicity Profile Update of 2,4-D,   31      Toxicity Profile Update of 2,4,5-T,   37

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Veterans and Agent Orange: Update 2002      Toxicity Profile Update of Cacodylic Acid,   38      Toxicity Profile Update of Picloram,   40      Toxicity Profile Update of TCDD,   40      Summary of Toxicity Profiles,   76      Relevance to Human Health,   81      References,   82  4   OVERVIEW OF EPIDEMIOLOGIC STUDIES   103      Occupational Studies,   104      Environmental Studies,   115      Vietnam-Veteran Studies,   118      References,   194  5   EXPOSURE ASSESSMENT   215      Exposure Assessment for Epidemiology,   215      Occupational Exposure to Herbicides and TCDD,   217      Environmental Exposure to Herbicides and TCDD,   226      Military Use of Herbicides in Vietnam,   229      Exposure Assessment in Studies of Vietnam Veterans,   232      References,   235  6   CANCER   242      Gastrointestinal Tract Tumors,   243      Hepatobiliary Cancers,   259      Nasopharyngeal Cancer,   264      Laryngeal Cancer,   268      Lung Cancer,   272      Bone and Joint Cancer,   278      Soft-Tissue Sarcomas,   282      Skin Cancer—Melanoma,   287      Skin Cancer—Basal-cell and Squamous-cell (Nonmelanoma),   295      Breast Cancer,   300      Cancers of the Female Reproductive System,   309      Prostate Cancer,   316      Testicular Cancer,   324      Urinary Bladder Cancer,   328      Renal Cancer,   333      Brain Tumors,   338      Non-Hodgkin's Lymphoma,   343      Hodgkin's Disease,   355      Multiple Myeloma,   361      Leukemia,   366      Chronic Lymphocytic Leukemia,   372

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Veterans and Agent Orange: Update 2002      Summary,   376      References,   381  7   REPRODUCTIVE AND DEVELOPMENTAL EFFECTS   393      Birth Defects,   393      Fertility,   405      Spontaneous Abortion,   409      Stillbirth, Neonatal Death, and Infant Death,   421      Low Birthweight and Preterm Delivery,   422      Childhood Cancer,   425      Sex Ratio,   432      Summary,   438      References,   441  8   NEUROBEHAVIORAL DISORDERS   447      Cognitive and Neuropsychiatric Effects,   448      Motor or Coordination Dysfunction,   452      Chronic Persistent Peripheral Neuropathy,   465      Acute and Subacute Transient Peripheral Neuropathy,   469      Summary,   470      References,   472  9   OTHER HEALTH EFFECTS   477      Chloracne,   477      Porphyria Cutanea Tarda,   479      Respiratory Disorders,   480      Immune System Disorders,   483      Diabetes,   485      Lipid and Lipoprotein Disorders,   493      Gastrointestinal and Digestive Disease, Including Liver Toxicity,   498      Circulatory Disorders,   502      AL Amyloidosis,   506      Endometriosis,   508      Thyroid Homeostasis,   510      Summary,   514      References,   519  10   RESEARCH RECOMMENDATIONS   523      Vietnam-Veteran Studies,   523      Studies of the Vietnamese,   526      Other Research,   526      References,   527

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Veterans and Agent Orange: Update 2002     APPENDIXES    A   AGENDAS OF PUBLIC MEETINGS   529  B   ICD-9 CODES FOR HEALTH OUTCOMES OF INTEREST   531  C   COMMITTEE AND STAFF BIOGRAPHIES   534     INDEX   539

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Veterans and Agent Orange: Update 2002 Veterans and Agent Orange Update 2002

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