Veterans |
Update 11 (2018)
Committee to Review the Health Effects in Vietnam Veterans
of Exposure to Herbicides
(Eleventh Biennial Update)
Board on Population Health and Public Health Practice
Health and Medicine Division
A Consensus Study Report of
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
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This activity was supported by Contract/Task Order No. VA701-16-C-0040 between the National Academy of Sciences and the Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organizations or agency that provided support for this project.
International Standard Book Number-13: 978-0-309-47716-1
International Standard Book Number-10: 0-309-47716-6
Digital Object Identifier: https://doi.org/10.17226/25137
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25137.
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COMMITTEE TO REVIEW THE HEALTH EFFECTS IN VIETNAM VETERANS OF EXPOSURE TO HERBICIDES (ELEVENTH BIENNIAL UPDATE)
IRVA HERTZ-PICCIOTTO (Chair), Director of Environmental Health Sciences Center, Professor of Epidemiology and Environmental Health, Department of Public Health Sciences, School of Medicine, University of California, Davis
NANCY BERLINER, Chief, Division of Hematology, Brigham and Women’s Hospital
WENDY B. BERNSTEIN, Associate Professor of Medicine, Uniformed Services University of the Health Sciences, and Attending Physician, Department of Hematology Oncology, Walter Reed National Military Medical Center
MICHAEL J. CARVAN III, Shaw Professor, School of Freshwater Sciences, University of Wisconsin–Milwaukee
ARAVINDA CHAKRAVARTI, Director, Center for Human Genetics and Genomics, New York University School of Medicine
DANA C. DOLINOY, NSF International Chair and Professor, Department of Environmental Health Sciences, University of Michigan School of Public Health
MARY A. FOX, Assistant Professor, Health Policy and Management, Co-Director, Risk Sciences and Public Policy Institute, Johns Hopkins Bloomberg School of Public Health
KARL T. KELSEY, Professor of Epidemiology, Professor of Pathology and Laboratory Medicine, Brown University
MOLLY L. KILE, Associate Professor, Environmental and Occupational Health, Oregon State University
ANDREW F. OLSHAN, Barbara Sorenson Hulka Distinguished Professor, Department of Epidemiology, University of North Carolina
BEATE R. RITZ, Professor of Epidemiology, Center for Occupational and Environmental Health, University of California, Los Angeles, School of Public Health
LORI A. WHITE, Associate Professor, Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey
Staff
DAVID A. BUTLER, Scholar, Study Director
ANNE N. STYKA, Senior Program Officer
T. CHERI BANKS, Research Associate
ELIZABETH BARKSDALE BOYLE, Program Officer, Board on Environmental Studies and Toxicology (from October 2017)
PAMELA RAMEY-MCCRAY, Senior Program Assistant
HELENA J. CHAPMAN, Christine Mirzayan Science and Technology Policy Fellow (January–April 2017)
ROSE MARIE MARTINEZ, Senior Director, Board on Population Health and Public Health Practice
Acknowledgments
The study committee and the Health and Medicine Division (HMD) project staff take this opportunity to recognize and thank the many individuals who shared their time and expertise to support the committee’s work and inform its deliberations.
This study was sponsored by the Department of Veterans Affairs. We thank Dr. Peter Rumm and Dr. Loren Erickson for their guidance and support.
The committee benefited greatly from discussions with the individuals who presented at and attended the committee’s open sessions: Victoria Davey, Ralph L. Erickson, Russ Hauser, C. Ola Landgren, Paul S. Mischel, Quinn T. Ostrom, Peter R. Rumm, Aaron I. Schneiderman, and Thaddeus (Thad) Schug. The committee would also like to thank all participants who attended the committees open sessions, including Ann Brazeau, Carla Dean, Maynard Kaderlik, Mokie Porter, Pegi Scarlett, Sidath Vranga, Deborah Watkins, and the many others who attended the September 7, 2017, Minneapolis open session; and all others who made or submitted comments or materials for the committee’s consideration. The committee is grateful to these presenters for volunteering to share their expertise, knowledge, data, and opinions not only with the committee, but also with the members of the public who participated in the committee’s open sessions. The committee also appreciates the efforts of numerous individuals who assisted project staff in identifying the presenters.
Furthermore, we acknowledge the many staff within the HMD who provided support in various ways to this project, including Julie Wiltshire, financial associate for the project; Daniel Bearss, senior research librarian, who conducted and compiled all of the literature searches; and Robert Pool for his editorial assistance provided in preparing the final report.
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Reviewers
This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, 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 individuals for their review of this report:
Alvaro Alonso, Rollins School of Public Health, Emory University
Kate M. Applebaum, Milken Institute School of Public Health, The George Washington University
Linda Birnbaum, National Institute of Environmental Health Sciences and National Toxicology Program
Bruce Blumberg, University of California, Irvine
Melissa L. Bondy, Baylor College of Medicine
Victoria A. Cassano, Performance Medicine Consulting, LLC
David C. Christiani, Harvard T.H. Chan School of Public Health
David L. Eaton, University of Washington School of Public Health
S. Katharine Hammond, University of California, Berkeley, School of Public Health
Elaine S. Jaffe, Center for Cancer Research, National Cancer Institute
Patricia A. Janulewicz, Boston University School of Public Health
Stephen H. Safe, Texas A&M University
Judith T. Zelikoff, New York University School of Medicine
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by Sandro Galea, Boston University School of Public Health, and Martin A. Philbert, University of Michigan. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.
Contents
Previous Veterans and Agent Orange Reports
The Current Population of Vietnam Veterans
Military Use of Herbicides in Vietnam
Exposure of Different Groups of Vietnam Veterans
Determining Increased Risk in Vietnam Veterans
3 EVALUATION OF THE EVIDENCE BASE
Phenoxy Herbicides: 2,4-Dichlorophenoxy Acid and 2,4,5-Trichlorophenoxyacetic Acid
2,3,7,8-Tetrachlorodibenzo-p-dioxin
Overarching Toxicologic Issues Related to the Chemicals of Interest
5 BACKGROUND ON SELECTED EPIDEMIOLOGIC STUDIES AND POPULATIONS
Categories of Immune Dysfunction
Conclusions from VAO and Previous Updates
Update of Epidemiologic Literature
Current Views of Cancer Mechanisms
Overview of Studies That Report Multiple Cancer Outcomes
Studies of Overall Cancer Mortality or Incidence
Oral, Nasal, and Pharyngeal Cancers
Cancers of the Digestive Organs
8 REPRODUCTIVE HEALTH EFFECTS AND EFFECTS ON DESCENDANTS
Biologic Plausibility of Reproductive Health Effects
Gestation and Neonatal Effects in Offspring
Effects Occurring Later in Offspring’s Lives
Biologic Plausibility of Possible Effects in Subsequent Generations
Nervous System Disorders Reported Overall
Neurobehavioral, Cognitive, and Neuropsychiatric Disorders
Chronic Peripheral Nervous System Disorders
10 METABOLIC AND CARDIOVASCULAR DISORDERS
11 OTHER CHRONIC HEALTH OUTCOMES
Non-Cancerous Respiratory Disorders
Gastrointestinal and Digestive Diseases, Including Liver Toxicity
Thyroid Homeostasis and Other Endocrine Functions
12 CONCLUSIONS AND RECOMMENDATIONS
Synopsis of Committee Conclusions
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Boxes, Figures, and Tables
BOXES
1-1 Committee’s Statement of Task
3-2 Criteria for Excluding Scientific Articles from Further Consideration
3-3 Statistical Terms Used in This Report
FIGURES
2-2 Median serum TCDD levels in various study populations
4-2 Structures of selected arsenic-containing compounds
4-3 Structures of 2,4-D and 2,4,5-T
4-4 Chemical structure of 2,3,7,8-tetrachlorodibenzo-p-dioxin
4-5 Mechanisms of gene regulation by the AHR following activation by TCDD
5-1 Overview of the individual study populations reviewed in the VAO series
TABLES
2-1 Estimates of the Vietnam Veteran Population
2-2 Military Use of Herbicides in Vietnam (1961–1971)
4-1 World Health Organization Toxicity Equivalence Factors (TEFs) for Dioxin-Like Chemicals
5-1 Distribution of Perceived Herbicide Exposure Among 114,562 Korean Vietnam Veterans
Acronyms and Abbreviations
2,4-D |
2,4-dichlorophenoxyacetic 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, Silvex |
8-OHdG |
8-hydroxydeoxyguanosine |
ABC-2 |
Assessment Battery for Children-2 |
ACC |
U.S. Army Chemical Corps |
ACS |
American Cancer Society |
AD |
Alzheimer disease |
ADM |
adrenomedullin |
AFHS |
Air Force Health Study (also referred to as the “Ranch Hand Study”) |
AHR |
aryl hydrocarbon receptor |
AHRE |
AHR-responsive element |
AHS |
U.S. Agricultural Health Study |
AL amyloidosis |
amyloid light-chain amyloidosis |
ALL |
acute lymphocytic leukemia |
ALS |
amyotrophic lateral sclerosis (Lou Gehrig’s disease) |
ALT |
alanine aminotransferase |
AML |
acute myeloid leukemia (previously called “acute myelogenous leukemia”) |
ARNT |
aryl hydrocarbon nuclear translocator |
ASQ |
Ages and Stages Questionnaire |
ASRS |
Autism Spectrum Rating Scale |
B[a]P |
benzo[a]pyrene |
BMI |
body mass index |
BPA |
bisphenol A |
BRIEF |
Behavior Rating Inventory of Executive Function–Preschool version |
CDC |
U.S. Centers for Disease Control and Prevention |
CI |
confidence interval |
CLL |
chronic lymphocytic leukemia (now regarded as same disease as small lymphocytic leukemia) |
CML |
chronic myeloid leukemia |
CNS |
central nervous system |
COI |
chemical of interest to VAO series (TCDD, 2,4,5-T, 2,4-D, picloram, or cacodylic acid) |
COPD |
chronic obstructive pulmonary disease |
CT |
computed tomography |
CVD |
cardiovascular disease |
DHA |
docosahexaenoic acid |
DHEA |
dehydroepiandrosterone |
DMA |
dimethyl arsenic acid |
DMBA |
dimethylbenzanthracene |
DMMTAV |
dimethylmonothioarsinic acid |
DNA |
deoxyribonucleic acid |
DoD |
Department of Defense |
ECG |
electrocardiography |
EOI |
exposure opportunity index |
EPA |
U.S. Environmental Protection Agency |
ER |
estrogen receptor |
F1, F2, F3 |
offspring, descendants (later generations: F2 and F3) |
GGT |
γ-glutamyl transferase |
GIS |
geographic information system |
GSH |
glutathione |
HbA1c |
hemoglobin A1c |
HCB |
hexachlorobenzene |
HCH |
hexachlorocyclohexane |
HCL |
hairy-cell leukemia |
HIV |
human immunodeficiency virus |
HL |
Hodgkin lymphoma (previously referred to as Hodgkin’s disease in VAO series) |
HPV |
human papilloma virus |
HR |
hazard ratio |
HSP90 |
heat shock protein 90 |
IARC |
International Agency for Research on Cancer |
ICD |
International Classification of Diseases |
Ig |
immunoglobulin antibodies |
IgE |
immunoglobulin E |
IHD |
ischemic heart disease |
IL |
interleukin (a cytokine) |
IL-1RA |
interleukin-1 receptor antagonist |
IOM |
Institute of Medicine |
KABC-II |
Kaufman Assessment Battery for Children, 2nd Edition |
KGF |
keratinocyte growth factor |
LBW |
low birth weight |
LD50 |
dose lethal to 50% of exposed animals |
LHC |
lymphohematopoietic cancer |
MCPA |
2-methyl-4-chlorophenoxyacetic acid |
MCPP |
2-(2-methyl-4-chlorophenoxy) propionic acid |
MDS |
myelodysplastic syndrome |
MGUS |
monoclonal gammapathy of undertermined significance |
MIP-1α |
macrophage-inflammatory protein-1 α |
MMA |
methylarsonous acid |
MPN |
myeloproliferative neoplasm |
MPTP |
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine |
MRI |
magnetic resonance imaging |
n |
number of study participants |
NBDPS |
National Birth Defects Prevention Study |
NCI |
National Cancer Institute |
NHANES |
National Health and Nutrition Examination Survey |
NHL |
non-Hodgkin lymphoma |
NIOSH |
National Institute for Occupational Safety and Health |
NK |
natural killer cells |
NPC |
neural progenitor cells |
NTIS |
National Technical Information Service |
NTP |
National Toxicology Program |
OC |
organochlorine |
OR |
odds ratio |
PAH |
polycyclic aromatic hydrocarbon |
PBDE |
polybrominated diphenyl ethers |
PCB |
polychlorinated biphenyl |
PCDD |
polychlorinated dibenzodioxin |
PCDD/Fs |
polychlorinated dioxins and furans combined |
PCDF |
polychlorinated dibenzofuran |
PCP |
pentachlorophenol |
PCT |
porphyria cutanea tarda |
PD |
Parkinson disease |
PDI |
Psychomotor Developmental Index |
picloram |
4-amino-3,5,6 trichloropicolinic acid |
PIVUS |
Prospective Investigation of the Vasculature in Uppsala Seniors |
PL |
Public Law |
PNS |
peripheral nervous system |
POP |
persistent organic pollutant |
ppm |
parts per million |
ppt |
parts per trillion (pg/g) |
PTSD |
posttraumatic stress disorder |
RANTES |
regulated on activation, normal T cell expressed and secreted |
RISC |
RNA-induced silencing complex |
RITS |
RNA-induced initiation of transcriptional silencing |
RNA |
ribonucleic acid |
RR |
relative risk |
SDQ |
Strengths and Difficulties Questionnaire |
SEER |
Surveillance, Epidemiology, and End Results program (National Cancer Institute) |
SHR |
standardized hospitalization ratio |
SIR |
standardized incidence ratio |
SMR |
standardized mortality ratio |
SNP |
single-nucleotide polymorphism |
STS |
soft-tissue sarcoma |
SWHS |
Seveso Women’s Health Study |
T3 |
L-3,5,3'-triiodothyronine |
T4 |
L-3,5,3',5'-tetraiodothyronine |
TCDD |
2,3,7,8-tetrachlorodibenzo-p-dioxin |
TCP |
trichlorophenol |
TDS |
total difficulties score |
TEF |
toxicity equivalency factor, i.e., potency of a dioxin-like chemical relative to TCDD |
TEQ |
(total) toxic equivalent |
TGF |
transforming growth factor |
TH |
thyroid hormones |
TIPA |
Triisopropanolamine |
TNF |
tumor necrosis factor |
TRH |
thyrotropin-releasing hormone |
TSH |
thyroid-stimulating hormone |
UMHS |
Upper Midwest health study |
UV |
ultraviolet radiation |
VA |
U.S. Department of Veterans Affairs; previously, Veterans Administration |
VAO |
Veterans and Agent Orange (refers to series of committees and reports; italicized VAO refers to the initial comprehensive review, published in 1994) |
VE-HEROeS |
Vietnam Era Health Retrospective Observational Study |
WHO |
World Health Organization |