Veterans and Agent Orange

Herbicide/Dioxin Exposure and Type 2 Diabetes

Committee to Review the Evidence Regarding the Link Between Exposure to Agent Orange and Diabetes

Division of Health Promotion and Disease Prevention

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.



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Veterans and Agent Orange Herbicide/Dioxin Exposure and Type 2 Diabetes Committee to Review the Evidence Regarding the Link Between Exposure to Agent Orange and Diabetes Division of Health Promotion and Disease Prevention INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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NATIONAL ACADEMY PRESS • 2101 Constitution Avenue, N.W. • Washington, DC 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 Insti- tute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. Support for this project was provided by the Department of Veterans Affairs. The views presented in this report are those of the Institute of Medicine Committee to Review the Evidence Regarding the Link Between Exposure to Agent Orange and Diabetes and are not necessarily those of the funding agency. International Standard Book No. 0-309-07198-4 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, D.C. 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP’s home page at www.nap.edu. The full text of this report is available at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2000 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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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. William 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 re- sponsibility 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. Kenneth I. Shine 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 Na- tional 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. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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COMMITTEE TO REVIEW THE EVIDENCE REGARDING THE LINK BETWEEN EXPOSURE TO AGENT ORANGE AND DIABETES David Tollerud, MD, MPH (Chair),1,2,3 Professor of Public Health and Medi- cine and Director, Center for Environmental and Occupational Health, Drexel University School of Public Health Michael Aminoff, MD,2,3 Professor, Department of Neurology, University of California at San Francisco, School of Medicine Steven Goodman, MD, MHS, PhD,3 Associate Professor, Department of Oncol- ogy, Division of Biostatistics, Johns Hopkins University School of Medicine Robert Herrick, PhD, CIH,3 Lecturer on Industrial Hygiene, Department of Environmental Health, Harvard School of Public Health Irva Hertz-Picciotto, PhD,3 Associate Professor, Department of Epidemiology, University of North Carolina at Chapel Hill David Hoel, PhD, 3 Distinguished University Professor, Medical University of South Carolina Andrew Olshan, PhD,1,2,3 Associate Professor, Department of Epidemiology, University of North Carolina at Chapel Hill Howard Ozer, MD, PhD,3 Eason Chair and Chief of the Hematology/Oncology Section, Director of the Cancer Center, and Professor of Medicine, Univer- sity of Oklahoma Kenneth Ramos, PhD,2,3 Professor, Department of Physiology and Pharmacol- ogy, Texas A&M University College of Veterinary Medicine Noel Rose, MD, PhD,2,3 Professor, Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health Arthur Rubenstein, MBBCh, Dean and Executive Vice President, Mount Sinai School of Medicine Michael Stern, MD, Professor, Department of Medicine, and Chief, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio Susan Woskie, PhD, CIH,3 Associate Professor, Department of Work Envi- ronment, University of Massachusetts at Lowell Staff David A. Butler, Study Director James Bowers, Research Assistant Jennifer A. Cohen, Research Assistant Rose Marie Martinez, Director, Division of Health Promotion and Disease Prevention 1 Member of the committee responsible for Veterans and Agent Orange (1994). 2 Member of the committee responsible for Veterans and Agent Orange: Update 1996. 3 Member of the committee responsible for Veterans and Agent Orange: Update 1998. v

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Kathleen Stratton, Acting Director (1997–1999), Division of Health Promotion and Disease Prevention Donna D. Thompson and Rita Gaskins, Division Assistants Melissa Goodwin, Financial Associate Staff Consultants Susan Thaul, Senior Project Officer, Institute of Medicine Florence Poillon, Contract Editor vi

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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, enacted on February 6, 1991). This call resulted in the creation of the first NAS Institute of Medicine Committee to Re- view the Health Effects in Vietnam Veterans of Exposure to Herbicides in 1992. The committee published its initial findings in the 1994 report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Public Law 102-4 also tasked the NAS to conduct biennial updates that would review newly published scientific literature regarding statistical associa- tions between health outcomes and exposure to dioxin and other chemical com- pounds in these herbicides. The results of the first two of these efforts were published in Veterans and Agent Orange: Update 1996 and Update 1998. Work on the Update 2000 report is presently under way. This report is the result of a 1999 request from the Department of Veterans Affairs (DVA) under the aegis of the Veterans and Agent Orange research pro- gram. DVA asked the Institute of Medicine to call together a committee to con- duct a focused review of the scientific evidence regarding one of the medical conditions addressed in the report series in advance of the next scheduled bien- nial report. Specifically, DVA asked the committee to examine evidence re- garding the association, if any, between Type 2 diabetes and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. David A. Butler served as the study director for this project and deserves credit for drafting the report. The committee would also like to acknowledge the vii

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viii PREFACE excellent work of IOM staff members James Bowers and Jennifer Cohen, and extend a special thanks to Susan Thaul for her work on this report. Thanks are also extended to Melisssa Goodwin, who handled the finances for the project; Florence Poillon who provided excellent editorial skills; Susan Fourt, who conducted data base searches; Michael Edington, who supervised the report through the editorial and publication phases; and Donna Thompson 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 Drs. Geoffrey Calvert (National Institute for Occupational Safety and Health), Marilyn Fingerhut (National Institute for Occupational Safety and Health), Philip Kern (University of Arkansas for Medical Sciences), Bonnie LaFleur (The George Washington University School of Public Health and Health Serv- ices), Matthew Longnecker (National Institute for Environmental Safety and Health), Joel Michalek (Air Force Research Laboratory, Brooks Air Force Base), and Michael Stoto (The George Washington University School of Public Health and Health Services). This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures ap- proved by the NRC’s Report Review Committee. The purpose of this independ- ent review is to provide candid and critical comments that will assist the institu- tion in making the 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 confi- dential to protect the integrity of the deliberative process. We wish to thank the following individuals for their participation in the review of this report: John C. Bailar, The University of Chicago; Daniel W. Foster, University of Texas Southwestern Medical Center at Dallas; Kristine M. Gebbie, Columbia Univer- sity; Barbara C. Hansen, University of Maryland at Baltimore; Paul D. Stolley, University of Maryland at Baltimore; Martha Vaughan, National Heart, Lung, and Blood Institute; M. Donald Whorton, M. Donald Whorton, Inc. While the individuals listed above have provided constructive comments and suggestions, it must be emphasized that responsibility for the final content of this report rests entirely with the authoring committee and the institution. David Tollerud Chair

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Contents EXECUTIVE SUMMARY .............................................................................. 1 INTRODUCTION ........................................................................................... 4 Background, 4 Organization and Framework, 5 Methodologic Considerations in Evaluating the Evidence, 6 Publication Bias, 9 Exposure Assessment, 9 Issues Related to the Epidemiologic Study of Exposure to Herbicides and Type 2 Diabetes, 10 SUMMARIES OF EPIDEMIOLOGIC EVIDENCE ...................................... 11 Occupational Cohorts, 11 Vietnam Veteran Cohorts, 22 Environmental Cohorts, 33 SYNTHESIS..................................................................................................... 35 CONCLUSIONS .............................................................................................. 36 Strength of Evidence in Epidemiologic Studies, 36 Increased Risk of Diabetes Among Vietnam Veterans, 37 Biologic Plausibility, 38 REFERENCES ................................................................................................ 38 ix

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x CONTENTS APPENDIXES A Summary of Workshops on the Evidence Regarding a Link Between Exposure to Agent Orange and Diabetes, 45 B Excerpts from the Discussion of Type 2 Diabetes in Veterans and Agent Orange: Update 1998, 47 C Committee and Staff Biographies, 61