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Veterans and Agent Orange: Update 2006
Veterans and Agent Orange
Update 2006
Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Sixth Biennial Update)
Board on Population Health and Public Health Practice
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 2006
THE NATIONAL ACADEMIES PRESS
500 Fifth Street, N.W. Washington, DC 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.
This study was supported by Contract No. V101 (93) P-2136, TO#3 between the National Academy of Sciences and 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 view of the organizations or agencies that provided support for this project.
International Standard Book Number-13: 978-0-309-10708-2 (Book)
International Standard Book Number-10: 0-309-10708-3 (Book)
International Standard Book Number-13: 978-0-309-10709-9 (PDF)
International Standard Book Number-10: 978-0-309-10709-1 (PDF)
Library of Congress Control Number: 2007937818
Additional copies of this report are available from the
National Academies Press,
500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (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 2007 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.
Suggested citation: IOM (Institute of Medicine). 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press.
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Veterans and Agent Orange: Update 2006
“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
—Goethe
INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES
Advising the Nation. Improving Health.
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Veterans and Agent Orange: Update 2006
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. Charles M. Vest 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. Charles M. Vest are chair and vice chair, respectively, of the National Research Council.
www.national-academies.org
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Veterans and Agent Orange: Update 2006
COMMITTEE TO REVIEW THE HEALTH EFFECTS IN VIETNAM VETERANS OF EXPOSURE TO HERBICIDES (SIXTH BIENNIAL UPDATE)
JOHN J. STEGEMAN (Chair), Senior Scientist,
Department of Biology, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts
RICHARD A. FENSKE, Professor,
School of Public Health and CommunityMedicine, University of Washington, Seattle
JORDAN FIRESTONE, Clinic Director
Haborview Medical Center, Occupational and Environmental Medicine, University of Washington, Seattle
PETER H. GANN, Professor,
Department of Pathology, University of Illinois, Chicago
MARK S. GOLDBERG, Associate Professor,
Department of Medicine, McGill University, Quebec, Canada
CLAUDIA HOPENHAYN, Professor,
College of Public Health, University of Kentucky, Lexington
NANCY I. KERKVLIET, Professor,
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis
LINDA A. MCCAULEY, Professor,
School of Nursing, University of Pennsylvania, Philadelphia
DEJURAN RICHARDSON, Professor of Mathematics and Computer Science,
Lake Forest College, Chicago, Illinois
HOLLIE I. SWANSON, Associate Professor,
College of Medicine, University of Kentucky, Lexington
MARY K. WALKER, Professor,
Pharmacology and Toxicology, University of New Mexico, Albuquerque
STEPHEN D. WALTER, Professor,
Clinical Epidemiology and Biostatistics, McMaster University, Ontario, Canada
Staff
Mary Burr Paxton, Study Director
Jennifer A. Cohen, Program Officer
Rose Marie Martinez, Director,
Board on Population Health and Public Health Practice
Tia S. Carter, Senior Program Assistant
Sonia J. Cheruvillil, Senior Program Assistant (through June 2006)
Norman Grossblatt, Senior Editor
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Veterans and Agent Orange: Update 2006
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 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:
Christine B. Ambrosone, Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York
Frederick R. Appelbaum, Fred Hutchinson Cancer Research Center, Seattle, Washington
Lesa L. Aylward, Summit Toxicology, Falls Church, Virginia
Linda S. Birnbaum, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina
Robert L. Black, Stanford University and Private Practice, Pediatrics, Monterey, California
Margit L. Bleecker, The Center for Occupational and Environmental Neurology, Baltimore, Maryland
David G. Hoel, Department of Biostatistics, Bioinformatics and Epidemiology, Medical University of South Carolina, Charleston
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Stephen H. Safe, Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station
Robert D. Sparks, TASER Foundation, El Dorado Hills, California
G. Marie Swanson, College of Public Health, University of Arizona, Tucson
Bailus Walker, Jr., Department of Community Medicine, Howard University, Washington, DC
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 this report was overseen by Kristine M. Gebbie, Columbia University School of Nursing, New York. Appointed by the National Research Council, she 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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Preface
In 1991, Congress passed Public Law (PL) 102-4, the Agent Orange Act of 1991, to address the uncertainty about the long-term health effects on Vietnam veterans who during their service in Vietnam were exposed to herbicides (mixtures of 2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], picloram, and cacodylic acid). That legislation directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various chemical components of those herbicides, including TCDD. The resulting committee report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO) was published by the NAS Institute of Medicine (IOM) in 1994. That report evaluated and integrated the scientific evidence regarding statistical associations between health outcomes and exposure to the herbicides and TCDD, based on published literature that had accumulated prior to 1994.
As required by PL 102-4, the Secretary also asked that NAS conduct updates at least every 2 years for 10 years from the date of the first report, to review newly available literature and draw conclusions from the overall evidence. The first of these updates, 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 fourth, Veterans and Agent Orange: Update 2002 (Update 2002) was published in 2003, and the fifth, Veterans and Agent Orange: Update 2004 (Update 2004) was published in 2005, concluding 10 years of updates.
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PL 107-103, the Veterans Education and Benefits Expansion Act of 2001, extended the period for biennial updates until 2014. The present report is the first of this second 10-year period of evaluation.
The focus of this update is on the scientific studies published since the release of Update 2004. To accomplish the review, the IOM established a committee of 12 members representing a wide range of expertise to evaluate the newest scientific evidence and to consider this in light of the studies reviewed in VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004. Five of the members of the committee responsible for this report were recruited from the committee responsible for Update 2004, providing a link to the experience and expertise of the previous committees. 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 TCDD exposure. Biographical sketches of committee members and staff appear in Appendix D.
Embarking on this second decade of evaluation, the committee approached a number of issues concerning the presentation of the information in the report, as well as seeking the most accurate information and advice from the widest possible range of knowledgeable sources for consideration. Consistent with NAS 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 two open meetings in March and June, 2006, 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 listed in Appendix A. The committee thanks the individuals 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. The committee would also like to acknowledge the excellent work of IOM staff members Jennifer Cohen, Tia Carter, Sonia Cheruvillil, David Butler, and Rose Marie Martinez. Thanks are also extended to Christie Bell, who handled the finances for the project; Norman Grossblatt, who provided editorial skills; and William McLeod, who conducted database searches.
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, provided copies of newly released research, or answered queries concerning their work. Dr. Maria Teresa Landi, an investigator at the National Cancer Institute, gave the committee a very informative presentation on her work on the Seveso Women’s Health Study. Dr. Michael Alavanja, also of the National Cancer Institute, was very helpful in answering questions about the conduct of the Agricultural Health Study, as were Julienell
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Robinson and Billy Jackson of Brooks Air Force Base in addressing questions about the Air Force Health Study. Special thanks are extended to Dr. Han Kang, Director of the Department of Veterans Affairs’ Environmental Epidemiology Service, for his prompt response in providing supplementary analyses on the data presented in his recent publication on Vietnam-era veterans who served in the Army Chemical Corps.
John Stegeman, Ph.D., Chair
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Contents
ABBREVIATIONS AND ACRONYMS
xvii
SUMMARY
1
1
INTRODUCTION
17
Charge to the Committee,
18
Conclusions of Previous Veterans and Agent Orange Reports,
19
Organization of This Report,
27
References,
27
2
EVALUATING THE EVIDENCE
29
Choice of Health Outcomes,
29
Identification of Relevant Literature,
29
Committee’s Approach,
34
Evaluation of the Evidence,
37
References,
46
3
TOXICOLOGY
47
Highlights of Previous Reports,
48
Update Toxicity Profile of 2,4-D,
49
Update Toxicity Profile of 2,4,5-T,
56
Update Toxicity Profile of Cacodylic Acid,
58
Update Toxicity Profile of Picloram,
61
Update Toxicity Profile of TCDD,
62
References,
117
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4
EPIDEMIOLOGIC STUDIES—NEW CITATIONS FOR UPDATE 2006 AND BACKGROUND ON REPEATEDLY STUDIED POPULATIONS
139
New Citations Reviewed in Update 2006,
140
Relevant Populations: New Reports with Multiple Endpoints or Results on Previously Studied Groups,
150
Occupational Studies,
151
Environmental Studies,
168
Vietnam-Veteran Studies,
172
References,
186
5
EXPOSURE ASSESSMENT
214
Exposure Assessment in Epidemiologic Studies,
214
Occupational Exposure to Herbicides and TCDD,
221
Environmental Exposures to Herbicides and TCDD,
232
Military Use of Herbicides in Vietnam,
237
Exposure Assessment in Studies of Vietnam Veterans,
240
References,
247
6
CANCER
261
An Exhaustive and Unambiguous System for Addressing Cancer Types,
264
Oral, Nasal, and Pharyngeal Cancer,
267
Lip Cancer,
277
Tongue Cancer,
279
Tonsil Cancer,
281
Cancers of the Digestive Organs,
283
Esophageal Cancer,
286
Stomach Cancer,
291
Colorectal Cancer,
299
Hepatobiliary Cancers,
310
Pancreatic Cancer,
318
Laryngeal Cancer,
325
Lung Cancer,
330
Bone and Joint Cancer,
342
Soft-Tissue Sarcomas,
346
Skin Cancer—Melanoma,
354
Skin Cancer—Basal-Cell and Squamous-Cell Cancer (Non-Melanoma),
366
Breast Cancer,
371
Cancers of the Female Reproductive System,
382
Prostate Cancer,
388
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Testicular Cancer,
402
Bladder Cancer,
407
Renal Cancer,
414
Cancers of the Eye and Orbit,
421
Brain Cancer,
423
Endocrine Cancers,
433
Non-Hodgkin’s Lymphoma,
443
Hodgkin’s Disease,
457
Multiple Myeloma,
465
AL Amyloidosis,
472
Leukemia,
474
Chronic Lymphocytic Leukemia,
486
Acute Myelogenous Leukemia,
490
Summary,
494
References,
498
7
REPRODUCTIVE AND DEVELOPMENTAL EFFECTS
517
Fertility,
518
Spontaneous Abortion,
525
Stillbirth, Neonatal Death, and Infant Death,
529
Birth Weight and Preterm Delivery,
531
Birth Defects,
535
Childhood Cancer,
546
Summary,
553
References,
557
8
NEUROLOGIC DISORDERS
566
Neurobehavioral (Cognitive or Neuropsychiatric) Disorders,
568
Movement Disorders,
570
Parkinson’s Disease and Parkinsonism,
570
Amyotrophic Lateral Sclerosis,
580
Peripheral Neuropathy,
585
Summary,
591
References,
593
9
OTHER HEALTH EFFECTS
599
Chloracne,
600
Porphyria Cutanea Tarda,
602
Respiratory Disorders,
604
Immune-System Disorders,
617
Diabetes,
620
Lipid and Lipoprotein Disorders,
632
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Gastrointestinal and Digestive Disease, Including Liver Toxicity,
639
Peptic Ulcer Disease,
640
Liver Disease,
640
Circulatory Disorders,
644
Hypertension,
671
Circulatory Diseases,
673
AL Amyloidosis,
675
Endometriosis,
675
Thyroid Homeostasis,
680
Summary,
686
References,
688
10
RESEARCH RECOMMENDATIONS
699
References,
704
APPENDIXES
A
Agendas of Public Meetings Held by the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Sixth Biennial Update)
705
B
Classification of Cancer Groupings Used in Reporting Results, with Correspondence to NIOSH Cause-of-Death Codes and ICD Codes for Cancers
707
C
Epidemiologic Tables for Chapter 4
717
D
Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Sixth Biennial Update) and Staff Biographies
778
INDEX
784
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Abbreviations and Acronyms
2,4-D 2,4-dichlorophenoxyacetic acid
2,4-DB 4-(2,4-dichlorophenoxy)butyric acid
2,4-DCP 2,4-dichlorophenol
2,4,5-T 2,4,5-trichlorophenoxyacetic acid
2,4,5-TCP 2,4,5-trichlorophenol
2,4,5-TP 2-(2,4,5-trichlorophenoxy)propionic acid or Silvex
4NQO 4-nitroquinolone 1-oxide
ACC Army Chemical Corps
AFHS Air Force Health Study on veterans who served in Vietnam in Operation Ranch (Ranch Hand subjects) who were compared to Vietnam-era Air Force veterans who were deployed to Southeast Asia (SEA comparisons)
AhR aryl hydrocarbon receptor
AHRE Ah-responsive element
AhRR aryl hydrocarbon receptor repressor
AHS Agricultural Health Study of commercial and private herbicide applicators and the spouses of private applicators in Iowa and North Carolina
ALL acute lymphocytic leukemia
ALS amyotrophic lateral sclerosis
AML acute myelogenous leukemia
ARNT aryl hydrocarbon nuclear translocator
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BCC basal cell carcinoma
BIRLS Beneficiary Identification and Record Locator Subsystem
BMI body-mass index
CADM concentration- and age-dependent elimination model
CAS Chemical Abstracts Service
CCR California Cancer Registry
CDC Centers for Disease Control and Prevention
CLL chronic lymphocytic leukemia
CNS central nervous system
COPD chronic obstructive pulmonary disease
CPUR California Pesticide Use Reporting Database
CRR crude rate ratio
DHT dihydrotestosterone
DMA dimethylarsinic acid or cacodylic acid
DNA deoxyribonucleic acid
DoD Department of Defense
EC50 effective concentration for 50 percent of subjects treated
EOI exposure opportunity index
EPA Environmental Protection Agency
FSH follicle-stimulating hormone
GCT germ-cell tumor
GD gestation day
GIS geographic information system
HD Hodgkin’s disease
HR hazard ratio
IARC International Agency for Research on Cancer
ICD; ICD-# International Classification of Diseases; specifies edition of ICD
IOM Institute of Medicine
IUGR intrauterine growth retardation
JEM job–exposure matrix
LD50 lethal dose to 50 percent of treated animals
LH luteinizing hormone
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M molar
MCPA 2-methyl-4-chlorophenoxyacetic acid
MCPP 2-(2-methyl-4-chlorophenoxy) propionic acid or Mecoprop
MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
NAS National Academy of Sciences
NCI National Cancer Institute
NCV nerve-conduction velocity
NHL non-Hodgkin’s lymphoma
NIOSH National Institute for Occupational Safety and Health
NMDA N-methyl-D-aspartate
NOEL no-observed-effect level
OR odds ratio
ORH Operation Ranch Hand
PBPK model physiologically based pharmacokinetic model
PCBs polychlorinated biphenyls
PCDD/Fs polychlorinated dibenzo-p-dioxins and dibenzofurans
PCT porphyria cutanea tarda
PD Parkinson’s disease
PL Public Law
PND postnatal day
PNS peripheral nervous system
ppb parts per billion (109), equivalent to µg/kg or ng/g
ppm parts per million (106), equivalent to mg/kg or µg/g
ppt parts per trillion (1012), equivalent to ng/kg or pg/g
PSD presenile dementia
PTD preterm delivery
PTSD posttraumatic stress disorder
RA rheumatoid arthritis
RBC red blood cell
RR relative risk
SCC squamous cell carcinoma
SEA Southeast Asia
SEER National Cancer Institute Surveillance Epidemiology and End Results
SES socioeconomic status
SIR standardized incidence ratio
SMP submitochondrial particle
SMR standardized mortality ratio
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SRMR standardized relative mortality ratio
STS soft-tissue sarcoma
SWHS Seveso Women’s Health Study
TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin
TCP trichlorophenol (not specifically 2,4,5-TCP)
TEF toxicity equivalency factor, potency of a dioxin-like compound relative to TCDD
TEQ total toxicity equivalency quotient, sum of TEFs for a mixture of PCDDs, PCDFs, and PCBs
TH tyrosine hydroxylase
TNFα tumor necrosis factor-alpha
TPA 12-O-tetradecanoylphorbol-13-acetate
UFW United Farm Workers of America
VA Department of Veterans Affairs
VAO Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, first report in series
VAO Veterans and Agent Orange, used to indicate this series of reports (VAO and updates) and the committees responsible for their preparation
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Veterans and Agent Orange
Update 2006
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