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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 study was supported by Contract/Grant No. VA241-P-2024 between the National Academy of Sciences and the US Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project.
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Suggested citation: IOM (Institute of Medicine). 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press.
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. Ralph J. Cicerone 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. C. D. Mote, Jr. 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. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council.
COMMITTEE TO REVIEW THE HEALTH EFFECTS
IN VIETNAM VETERANS OF EXPOSURE TO
HERBICIDES (NINTH BIENNIAL UPDATE)
MARY K. WALKER (Chair), Professor, Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque
REBECCA A. BETENSKY, Professor, Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
MICHAEL J. CARVAN III, Shaw Associate Professor, School of Freshwater Sciences, University of Wisconsin–Milwaukee
SCOTT DAVIS, Professor and Chair, Department of Epidemiology, School of Public Health, University of Washington, Seattle
NAIHUA DUAN, Professor, Department of Biostatistics, Columbia University Medical Center, New York, New York
STEPHANIE M. ENGEL, Associate Professor, Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
JENNIFER R. GRANDIS, Professor and Vice Chair for Research, Department of Otolaryngology and Pharmacology, University of Pittsburgh, Pennsylvania
KARL KELSEY, Professor, Epidemiology and Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
STEPHEN B. KRITCHEVSKY, Director, J. Paul Sticht Center on Aging, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina
JAMES R. OLSON, Professor, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, New York
GAIL S. PRINS, Professor, Department of Urology, University of Illinois, Chicago
HELEN H. SUH, Associate Professor, Department of Health Sciences, Bouve School of Health Sciences, Northeastern University, Boston, Massachusetts
MARC WEISSKOPF, Associate Professor, Department of Environmental and Occupational Epidemiology, Harvard School of Public Health, Boston, Massachusetts
LORI A. WHITE, Associate Professor, Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, New Jersey
LUOPING ZHANG, Professor, School of Public Health, University of Califorina, Berkeley
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 National Research Council’s Report Review Committee. The purpose of the 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 of 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 thank the following for their review of the report:
Linda S. Birnbaum, National Institute of Environmental Health Sciences
Margit L. Bleecker, Center for Occupational and Environmental Neurology
Kim Boekelheide, Brown University
Norman E. Breslow, University of Washington
James Brophy, McGill University
David L. Eaton, University of Washington
Edward Elton George, Massachusetts General Hospital
Elaine S. Jaffe, National Cancer Institute
David W. Kennedy, University of Pennsylvania Health System
Kevin Kip, University of South Florida, College of Nursing
Roderick J.A. Little, University of Michigan
John Meeker, University of Michigan School of Public Health
Murray A. Mittleman, Harvard School of Public Health
Rosemary Polomano, University of Pennsylvania School of Nursing
Noel R. Rose, Johns Hopkins University School of Medicine
Hugh H. Tilson, University of North Carolina at Chapel Hill
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 review of the report was overseen by Kristine M. Gebbie, Flinders University School of Nursing and Midwifery, Adelaide, South Australia. Appointed by the Institute of Medicine, she was responsible for making certain that an independent examination of the 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.
Preface
This update focuses on the relevant scientific studies published from October 1, 2010, through September 30, 2012, that is, after the literature considered in Update 2010. To accomplish the review, the Institute of Medicine (IOM) established a committee of 15 members representing a wide array of expertise to evaluate the newest scientific evidence and to consider it in light of the studies reviewed in Veterans and Agent Orange (VAO), Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010. A link to the experience and expertise of previous committees was provided by recruiting eight members from committees responsible for earlier updates. All committee members were selected because they are 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 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Biographic sketches of committee members and staff appear in Appendix D.
In this second decade of evaluation, the committee sought the most accurate information and advice from the widest possible array of knowledgeable sources for consideration. To be consistent with National Academies’ procedures, the committee met in a series of closed sessions in which members could freely examine, characterize, and weigh the strengths and limitations of the evidence. The committee also convened five open meetings—in September, November, and December 2012 and in January and March 2013—to provide an opportunity for veterans and veterans service organizations, researchers, policy makers, 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 listed in Appendix A. The committee thanks the persons who provided valuable insights into the health problems experienced by Vietnam veterans.
The committee is grateful to Mary Paxton, who skillfully served as study director for this project. It also acknowledges the excellent work of IOM staff members Jennifer Cohen, Tia Carter, and Frederick (Rick) Erdtmann. Thanks are also extended to Andrea Cohen, who handled the finances for the project; Norman Grossblatt, who provided editorial skills; and William McLeod and Daniel Bearss, who conducted database searches.
The committee benefited from the assistance of several scientists and researchers who generously lent their time and expertise to give committee members insight into particular issues, provide copies of newly released research, or answer queries about their work. Lisa Cassis, a professor and chair at the University of Kentucky, discussed her research on metabolic and vascular disease. Han Kang, who recently retired as the principal investigator and director of the Environmental Epidemiology Service at the US Department of Veterans Affairs (VA), provided the committee with insight into VA’s research programs (past and present), focusing on US Vietnam veterans. Dr. Kang was again helpful, as was Brenda Eskenazi who is the chair of epidemiology at the University of California, Berkeley, in responding to the committee’s requests for additional information concerning birth weight in their published studies. Andy Olshan, the chair of epidemiology at the University of North Carolina, and Kim Boekelheide, a professor of medical science at Brown University, joined the committee via conference call to discuss issues related to paternally mediated effects.
Mary K. Walker, PhD, FAHA, Chair
Committee to Review the Health Effects
in Vietnam Veterans of Exposure to
Herbicides (Ninth Biennial Update)
Models for Characterizing Herbicide Exposure
Methodologic Issues in Exposure Assessment
4 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY
Phenoxy Herbicides: 2,4-Dichlorophenoxy Acid and 2,4,5-Trichlorophenoxyacetic Acid
2,3,7,8-Tetrachlorodibenzo-p-dioxin
Limitations of Extrapolating Results of Laboratory Studies to Human Responses
5 EPIDEMIOLOGIC STUDIES: COMPENDIUM OF NEW PUBLICATIONS
New Epidemiologic Publications
6 EPIDEMIOLOGIC STUDIES: BACKGROUND ON MULTIPLY REFERENCED POPULATIONS
Categories of Immune Dysfunction
Conclusions from VAO and Previous Updates
Update of the Epidemiologic Literature and Human Studies
Oral, Nasal, and Pharyngeal Cancer
Cancers of the Digestive Organs
Basal-Cell Cancer and Squamous-Cell Cancer (Nonmelanoma Skin Cancer)
Cancers of the Female Reproductive System
9 FERTILITY AND GESTATIONAL EFFECTS
Biologic Plausibility of Effects on Fertility and Reproduction
Spontaneous Abortion, Stillbirth, Neonatal Death, and Infant Death
Birth Weight and Preterm Delivery
10 EFFECTS ON FUTURE GENERATIONS
Effects Occurring Later in Offspring’s Life or in Later Generations
Neurobehavioral (Cognitive or Neuropsychiatric) Disorders
Chronic Peripheral System Disorders
12 CARDIOVASCULAR AND METABOLIC OUTCOMES
13 OTHER CHRONIC HEALTH OUTCOMES
Gastrointestinal and Digestive Diseases, Including Liver Toxicity
14 CONCLUSIONS AND RECOMMENDATIONS
Synopsis of Committee Conclusions
Figures and Tables
FIGURES
TABLES