GULF WAR and HEALTH
VOLUME 11
Generational Health Effects
of Serving in the Gulf War
Committee on Gulf War and Health, Volume 11:
Generational Health Effects of Serving in the Gulf War
Board on Population Health and Public Health Practice
Health and Medicine Division
A Consensus Study Report of
THE NATIONAL ACADEMIES PRESS
Washington, DC
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This activity was supported by Contract Number VA701-16-C-0029 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 organization or agency that provided support for the project.
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2018. Gulf War and health, volume 11: Generational health effects of serving in the Gulf War. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25162.
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COMMITTEE ON GULF WAR AND HEALTH, VOLUME 11: GENERATIONAL HEALTH EFFECTS OF SERVING IN THE GULF WAR
KENNETH S. RAMOS (Chair), Associate Vice President for Precision Health Sciences, Professor of Medicine and Director, Center for Applied Genetics and Genomic Medicine, University of Arizona Health Sciences
TRACY L. BALE, Professor and Director, Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine
JOHN R. BALMES, Professor of Medicine, University of California, San Francisco
BRENDA ESKENAZI, Jennifer and Brian Maxwell Professor of Maternal and Child Health and Epidemiology, Director, Center for Environmental Research and Children’s Health, University of California, Berkeley
ELAINE M. FAUSTMAN, Professor and Director, Institute for Risk Analysis and Risk Communication, Department of Environmental and Occupational Health Sciences, University of Washington
MARI S. GOLUB, California National Primate Research Center, University of California, Davis
RAFAEL A. IRIZARRY, Professor of Biostatistics, Dana-Farber Cancer Institute, Harvard University
TAMARRA JAMES-TODD, Mark and Catherine Winkler Assistant Professor of Environmental Reproductive and Perinatal Epidemiology, Harvard T.H. Chan School of Public Health
STEPHEN A. KRAWETZ, Associate Director, C.S. Mott Center for Human Growth and Development, Charlotte B. Failing Professor of Fetal Therapy and Diagnosis, Department of Obstetrics and Gynecology, Center for Molecular Medicine and Genetics, Wayne State University
LINDA A. McCAULEY, Dean, Nell Hodgson Woodruff School of Nursing, Emory University
JACOB D. McDONALD, Senior Scientist, Vice President, Chief Science Officer, Lovelace Respiratory Research Institute
DYLAN S. SMALL, Professor, Department of Statistics, The Wharton School, University of Pennsylvania
JACQUETTA TRASLER, Senior Scientist, Research Institute of the McGill University Health Centre, James McGill Professor in Pediatrics, Human Genetics, and Pharmacology and Therapeutics, McGill University
CHERYL LYN WALKER, Director, Center for Precision Environmental Health, Professor, Department of Molecular and Cell Biology and Medicine, Baylor College of Medicine
CAROL S. WOOD, Staff Scientist, Toxicology and Hazard Assessment Group, Environmental Sciences Division, Oak Ridge National Laboratory
ROBERT O. WRIGHT, Ethel H. Wise Professor of Pediatrics, Chair, Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai
Study Staff
ROBERTA WEDGE, Study Director
CARY HAVER, Program Officer
T. CHERI BANKS, Associate Program Officer
PAMELA RAMEY-McCRAY, Senior Program Assistant
ROSE MARIE MARTINEZ, Senior Board Director, Board on Population Health and Public Health Practice
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Reviewers
This report has been 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 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:
Bruce A. Barron, University of Rochester Medical Center
Joseph Braun, Brown University
Dana C. Dolinoy, University of Michigan School of Public Health
Seth Eisen, Washington University School of Medicine
David Korn, Harvard Medical School
Nancy E. Lane, University of California, Davis, School of Medicine
Germaine Buck Louis, George Mason University
Donald R. Mattison, Risk Sciences International, Ottawa
Reza J. Rasoulpour, Dow AgroSciences
Laura N. Vandenberg, University of Massachusetts
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 Nancy F. Woods, University of Washington, and Maryellen L. Giger, The University of Chicago. They were 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
Veterans of the 1990–1991 Gulf War and the Post-9/11 conflicts in Iraq and Afghanistan were exposed to a variety of biological, chemical, radiological, psychosocial, and physical stressors during their deployments. Over the past 20 years the National Academies of Sciences, Engineering, and Medicine (the National Academies) has convened more than 10 committees of experts to assess the health effects that might be linked to those exposures. Some of the health effects identified by past committees include post-traumatic stress disorder, other mental health disorders, Gulf War illness, respiratory effects, and self-reported sexual dysfunction. Veterans’ concerns regarding the impacts of deployment-related exposures on their health have grown to include potential adverse effects on the health of their children and grandchildren. These concerns now increasingly involve female veterans, as more women join the military and are deployed to war zones and areas that pose potential hazards. The committee notes that veterans’ harmful exposures are not restricted to deployment; such exposures may occur during military service in general or even outside of active duty (for example, exposure to trichloroethylene in contaminated drinking water at Camp Lejeune). As such, the need for data and knowledge to protect the health of the children and grandchildren of veterans who may have experienced harmful exposures during deployment has become urgent.
The exposure of male and female veterans to toxicants during their deployments may pose unknown risks to their future children, whether conceived during or after deployment. Harmful exposures may affect germ cells in both men and women and compromise the reproductive health of veterans and the future health of their children. For female veterans who may be deployed before they are aware they are pregnant, there may also be a risk to the developing fetus. The impact of exposures experienced during these periods on the developing embryo is largely unknown. Given these inherent risks, and in light of several public reports linking a parent’s or even a grandparent’s exposure to a toxicant to negative health outcomes in their descendants, veterans’ concerns about generational effects continue to escalate. While the public reporting of generational effects has garnered considerable attention, the scientific evidence to support those links is not compelling at this time.
To address these gaps in data and knowledge, the Department of Veterans Affairs (VA) requested this eleventh update of the Gulf War and Health series of reports. This volume addresses two major tasks: evaluating the scientific and medical literature on reproductive and developmental effects and health outcomes associated with Gulf War and Post-9/11 exposures, and determining those research areas requiring further scientific study on potential health effects in the descendants of veterans of any era.
To accomplish these tasks, the National Academies established a committee of 16 members representing a broad range of areas of scientific and medical expertise. Its work was informed by two public meetings at which the committee heard from key stakeholders, including veterans, veterans’ service organizations, research scientists, and representatives from VA, the Department of Defense, and other governmental organizations that are also attempting to determine what, if any, generational health effects may result from a veteran’s exposures prior to or during pregnancy. The committee completed a comprehensive evaluation of relevant literature and integrated its findings with the large amounts of data on reproductive and developmental health outcomes reviewed in previous updates. The synthesis of the evidence was then used to craft a path forward for VA to address veteran concerns related to multigenerational health effects, particularly as they relate to veterans’ children conceived during and after deployment, their grandchildren, and even future generations.
The Volume 11 committee thanks those who presented valuable information to the committee, including Fred Tyson, National Institute of Environmental Health Sciences; Vicki Walker, National Toxicology Program; Antonia Calafat, Centers for Disease Control and Prevention; John Greally, Albert Einstein School of Medicine; Colleen Baird, U.S. Army Public Health Command; R. Loren Erickson, Peter Rumm, and Aaron Schneiderman, Department of Veterans Affairs; and the many veterans who shared their deployment experiences with the committee. The committee is most grateful to Roberta Wedge, our outstanding study director, who helped us navigate through the report process and ensured that progress was made at all times. The committee is also indebted to Cary Haver and Cheri Banks for their hard work in support of committee functions and to Pam Ramey-McCray for her graceful administrative support of our activities. The committee acknowledges the expert assistance provided by Daniel Bearss of the National Academies Research Center helping to create and execute a detailed literature search strategy and for fact-checking the lengthy and sometimes complicated chapters included in the volume. A heartfelt thank-you to my fellow committee members for their collegiality, insights, hard work, thoughtfulness, and outstanding service over the past 2 years.
The committee is optimistic that the recommendations contained in this report will help answer many of the critical questions facing VA and the nation as a whole regarding the complex interactions between genes, environment, and lifestyle that may influence health outcomes across multiple generations. The report also provides specific guidance on the development of a health monitoring research program that can help gather the data required to evaluate generational effects and to establish a path forward in continuing to meet our responsibility to veterans of all conflicts.
Kenneth S. Ramos, Chair
Committee on Gulf War and Health, Volume 11: Generational Health Effects of Serving in the Gulf War
Timing of Exposures and Outcomes
Epidemiologic Generational and Epigenetic Studies
4 DEPLOYMENT-RELATED EXPOSURES
DEET (N,N-Diethyl-3-Methylbenzamide)
6 COMBUSTION PRODUCTS AND FUELS
8 OUTCOMES TOWARD HERITABLE EFFECTS
Health Outcomes Associated with Gulf War Deployment
9 HEALTH MONITORING AND RESEARCH PROGRAMS
Overview of VA and DoD Health Care Systems
Framework for a Health Monitoring and Research Program
Program Scope and Study Design
Effects of Genetic and Epigenetic Alterations on Descendants
Inter- and Transgenerational Health Effects
Collection of Baseline and Longitudinal Data
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Acronyms and Abbreviations
αGSU | glycoprotein hormone α-subunit |
γ-HCH | gamma-hexachlorocyclohexane (lindane) |
ΣDAP | sum of DAP |
1-N | 1-naphthol |
1-OHNa | 1-hydroxynaphthalene |
1-OHP | 1-hydroxypyrene |
2-MMA | 2-methoxyacetic acid |
2-OHF | 2-hydroxyfluorene |
2-OHNa | 2-hydroxynapthalene |
4-OHPh | 4-hydroxyphenanthrene |
9-OHFlu | 9-hydroxyfluorene |
9-OHPh | 9-hydroxyphenanthrene |
AChE | acetylcholinesterase |
ADHD | attention deficit–hyperactivity disorder |
AHLTA | Armed Forces Health Longitudinal Technology Application system (of DoD) |
AhR | aryl hydrocarbon receptor |
ALL | acute lymphoblastic leukemia |
AMH | anti-Müllerian hormone |
AML | acute myeloid leukemia |
APC | adenomatous polyposis coli |
aPR | adjusted prevalence ratio |
ASD | autism spectrum disorder |
ATSDR | Agency for Toxic Substances and Disease Registry |
AVA | anthrax vaccine absorbed |
BaP | benzo[a]pyrene |
BASC | Behavior Assessment System for Children |
BDNF | brain-derived neurotrophic factor |
BMI | body mass index |
BN-1MN | binucleated cells with one micronucleus |
BNBAS | Brazelton Neonatal Behavioral Assessment Scale |
BPA | 3-phenoxybenzoic acid |
BRIEF | Behavior Rating Inventory of Executive Functioning |
BSID-II | Bayley Scales of Infant Development II |
BTEX | benzene-toluene-ethylbenzene-xylene |
BuChE | butyrylcholinesterase |
CARC | chemical agent-resistant coating |
CBCL | Child Behavior Checklist |
CCCEH | Columbia Center for Children’s Environmental Health (study) |
CD3+ | cluster of differentiation 3 |
CD4+ | cluster of differentiation 4 |
CD19+ | cluster of differentiation 19 |
CDCCA | cis-3-(2,2- dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid |
CHAMACOS | Center for the Health Assessment of Mothers and Children of Salinas (study) |
CHARGE | Childhood Autism Risks from Genetics and Environment (study) |
ChE | cholinesterase |
CHEAR | Children’s Health Exposure Analysis Resource (of NIEHS) |
CI | confidence interval |
CIA | Central Intelligence Agency |
CO | carbon monoxide |
CO2 | carbon dioxide |
CPF | chlorpyrifos |
CpG | cytosine-adjacent-to-guanine (sites in the human genome) |
CPT-II | Conners’ Continuous Performance Test-II |
Cr6 | hexavalent chromium |
CYP1A1 | cytochrome P450 1A1 |
CYP2E1 | cytochrome P450 2E1 |
DAG | directed acyclic graph |
DAP | dialkylphosphate |
DBCA | cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-carboxylic acid |
DCA | dichloroacetate |
DEDTP | diethyldithiophosphate |
DEP | diethylphosphate |
DETP | diethylthiophosphate |
DFI | DNA fragmentation index |
DLA | Defense Logistics Agency |
DLC | dioxin-like chemical |
DMDC | Defense Manpower Data Center |
DMDTP | dimethyldithiophosphate |
DMP | dimethylphosphate |
DMSS | Defense Medical Surveillance System |
DMTP | dimethylthiophosphate |
DNA | deoxyribonucleic acid |
DNAm | DNA methylation |
DNMT | DNA methyltransferase |
DNMT3B | DNA methyltransferase 3 beta |
DoD | Department of Defense |
DOEHRS | Defense Occupational and Environmental Health Readiness System |
DOHaD | developmental origins of health and disease |
DSM-IV | Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition |
DU | depleted uranium |
E2 | estradiol |
EAA | ethoxyacetic acid |
ECHA | European Chemicals Agency |
EGBE | ethylene glycol monobutyl ether (2-butoxyethanol) |
EGEE | ethylene glycol monoethyl ether (2-ethoxythanol) |
EGMBE | ethylene glycol monobutyl ether (2-butoxyethanol) |
EGME | ethylene glycol monomethyl ether (2-methoxyethanol) |
EHR | electronic health record |
ELEMENT | Early Life Exposures in Mexico to Environmental Toxicants (study) |
EPA | U.S. Environmental Protection Agency |
EU | enriched uranium |
FAI | free androgen index |
FDA | Food and Drug Administration |
FeNO | fractional exhaled nitric oxide |
FSH | follicle-stimulating hormone |
FT4/FT3 | free thyroxin/triiodothyronine ratio |
FT4 | free thyroxine |
FVC | forced vital capacity |
GD | gestational day |
GnRH | gonadotropin-releasing hormone |
GSTM1 | glutathione S-transferase mu 1 (M1) |
GSTT1 | glutathione S-transferase theta 1 (T1) |
GWAS | genome-wide association study |
H2S | hydrogen sulfide |
Hmlh1 | human mutL homolog 1 |
HMRP | health monitoring and research program |
HOME | Health Outcomes and Measures of the Environment (study) |
HR | hazard ratio |
HRMS | high-resolution mass spectrometry |
HSD11B2 | 11β-hydroxysteroid dehydrogenase type 2 |
IARC | International Agency for Research on Cancer |
ICM | inner cellular mass |
IDR | incidence density ratio |
IFNγ | interferon gamma |
IGC | immature germ cell |
IgE | immunoglobulin E |
ILER | individual longitudinal exposure record |
IOM | Institute of Medicine |
iPSC | induced pluripotent stem cell |
IQR | interquartile range |
IRIS | Integrated Risk Information System |
IRR | incidence rate ratio |
JBB | Joint Base Balad |
JP-4 | jet fuel 4 |
JP-5 | jet fuel 5 |
JP-8 | jet fuel 8 |
KIDS | Kinder Infant Development Scale |
LBW | low birth weight |
LEP | leptin |
LH | luteinizing hormone |
md | mean difference |
MDA | malathion dicarboxylic acid |
MDI | mental development index |
MGMT | methyl guanine methyl transferase |
MHS | Military Health System |
MilCo | Millennium Cohort (DoD study) |
miRNA | microribonucleic acid |
MLH1 | mutL homolog 1 |
mRNA | messenger ribonucleic acid |
Mt. Sinai | Mount Sinai Children’s Environmental Health Cohort Study |
mtDNA | mitochondrial DNA |
MVP | Million Veteran Program (VA study) |
NAS | National Academy of Sciences |
NBDPS | National Birth Defects Prevention Study |
NBNA | Neonatal Behavioral Neurological Assessment |
ncRNA | noncoding RNA |
NHL | non-Hodgkin’s lymphoma |
NIEHS | National Institute of Environmental Health Sciences |
NIH | National Institutes of Health |
NK | natural killer (cell) |
NMDA | N-methyl-D-aspartate |
NO | nitrogen oxide |
NO2 | nitrogen dioxide |
NRC | National Research Council |
NTD | neural tube defect |
O3 | ozone |
OEF | Operation Enduring Freedom |
OIF | Operation Iraqi Freedom |
OND | Operation New Dawn |
OP | organophosphate |
OR | odds ratio |
OSAGWI | Office of the Special Assistant for Gulf War Illnesses |
PAH | polycyclic aromatic hydrocarbon |
PB | pyridostigmine bromide |
PBA | 3-phenoxybenzoic acid |
PCDD | polychlorinated dibenzo-p-dioxin |
PCDF | polychlorinated dibenzofuran |
PCE | tetrachloroethylene (perchloroethylene) |
PCOS | polycystic ovary syndrome |
PDI | psychomotor development index |
PGC | primordial germ cell |
piRNA | Piwi-interacting RNA |
PM | particulate matter |
PND | postnatal day |
PNET | pancreatic neuroendocrine tumor |
PON1 | paraoxonase 1 |
PR | progesterone receptor |
PROGRESS | Programming Research in Obesity, Growth, Environment and Social Stressors |
PTB | preterm birth |
RNA | ribonucleic acid |
ROS | reactive oxygen species |
RR | relative risk |
SDQ | Strengths and Difficulties Questionnaire |
SES | socioeconomic status |
SGA | small for gestational age |
SHBG | sex hormone binding globulin |
SIR | standardized incidence ratio |
SM | sulfur mustard |
SO2 | sulfur dioxide |
sRR | summary relative risk |
SRS | Social Responsiveness Scale |
SSVS | stochastic search variable selection |
TBDD | 2,3,7,8-tetrabromodibenzo-p-dioxin |
TBG | thyroxin-binding globulin |
TCA | trichloroacetate |
TCDD | 2,3,7,8-tetrachlorodibenzodioxin |
TCE | trichloroethylene |
TCPy | trichloro-2-pyridinol |
TDCCA | trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid |
TDG | thymine DNA glycosylase |
TDM | tail distributed moment |
TET2 | Tet methylcytosine dioxygenase 2 |
TGCT | testicular germ cell tumor |
THREE | Tracking Health Related to Environmental Exposures |
tRNA | transfer RNA fragment |
TSH | thyroid-stimulating hormone |
TTP | time to pregnancy |
VA | Department of Veterans Affairs |
VAERS | Vaccine Adverse Event Reporting System |
VAO | Veterans and Agent Orange |
VHEMBE | Venda Health Examination of Mothers, Babies and Their Environment |
VISTA | Veterans Information Systems and Technology Architecture (of VA) |
VOC | volatile organic compound |
VSO | veterans service organization |
WBC | white blood cell |
WHO | World Health Organization |
WISC-IV | Weschler Intelligence Scale for Children, 4th edition |
WPPSI-III | Weschler Preschool and Primary Scales of Intelligence-III |
XIST | X-inactive specific transcript |