In response to the invasion of Kuwait by Iraq in August 1990, the United States led a coalition of 34 countries in Operation Desert Shield in the Persian Gulf. This was followed by Operation Desert Storm, which began in January 1991 with an air offensive and a 4-day ground war; the war ended with a cease-fire in April 1991. Almost 700,000 U.S. troops were deployed to the Persian Gulf region during the height of the buildup.
The U.S. military engaged in further conflicts in the Middle East following the terrorist attacks of September 11, 2001. Operation Enduring Freedom began in October 2001 with troops stationed in and around Afghanistan. Operation Iraqi Freedom began in March 2003 with the invasion of Iraq, and it ended on August 31, 2010. Operation New Dawn, whose goal was to reduce the number of U.S. military personnel in Iraq, was initiated in September 2010 and ended in December 2011. The U.S. military mission in Iraq ended in 2011; the U.S. mission in Afghanistan continues.
In any war, the service members who deploy to theaters of conflict may be exposed to many hazardous agents and situations, some intentional and many unknown. Some of the exposures may be to chemicals that are, or were, used in civilian life, such as pesticides and fuels, but the duration or frequency of those exposures may be different in the deployment situations. Other potential deployment exposures are chemical and biological agents, mandatory vaccines, oil-well-fire smoke, dust, high ambient temperatures and heat stress, depleted uranium (DU), and pyridostigmine bromide (PB), a prophylactic agent against nerve agent exposure. Veterans who served in the 1990–1991 Gulf War, Post-9/11, and Vietnam conflicts, among others, were subject to a variety of exposures during deployment that have been associated with health effects in veterans and other exposed populations.
In 1998, in response to the health concerns of Gulf War veterans, Congress passed two laws: P.L. 105-277, the Persian Gulf War Veterans Act, and P.L. 105-368, the Veterans Programs Enhancement Act. Those laws directed the Secretary of Veterans Affairs to enter into a contract with the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to the toxic agents, environmental and wartime hazards, and preventive medicines and vaccines associated with Gulf War service. Since the legislation, the National Academies
of Sciences, Engineering, and Medicine (the National Academies) has prepared more than 10 reports focused on the health of Gulf War veterans.
Veterans’ concerns regarding the impact of deployment exposures on their health have grown to include concerns about whether their exposures might adversely affect the health of their children and, possibly, their grandchildren. The National Academies report Veterans and Agent Orange, Update 2014 examined the potential for such generational effects and recommended areas of research that might elucidate the biological mechanisms associated with them, specifically, the investigation of environmentally induced epigenetic mechanisms and biomarkers of effect.
This Gulf War and Health, Volume 11 report provides guidance to the Department of Veterans Affairs (VA) on addressing those research recommendations for all veterans. The report also focuses on the assessment of the available evidence on the reproductive effects related to exposures that may have occurred during the Gulf War and Post-9/11conflicts as well as on the health of veterans’ children. Finally, the report examines the mechanisms, methods, and feasibility issues of potential research approaches for determining if there are health effects in the children or grandchildren of veterans of any era related to their parents’ or grandparents’ deployment exposures.
CHARGE TO THE COMMITTEE
The full statement of task for the Gulf War and Health, Volume 11 committee is presented in Box S-1.
THE COMMITTEE’S APPROACH
The Volume 11 committee began its deliberations with public meetings to hear from representatives of VA, academic researchers, interested veterans, and veterans’ service organizations and to gather information from representatives of the National Institute for Environmental Health Sciences and its affiliated National Toxicology Program, the Centers for Disease Control and Prevention, and the Department of Defense (DoD). That input helped the committee understand VA’s needs, appreciate the veterans’ concerns, and be cognizant of complementary efforts already under way at other organizations.
The public meetings helped the committee develop an approach to identify what exposures a veteran might have experienced (e.g., lifestyle, toxicants, stress), how those exposures might be assessed (e.g., how to deal with the variability of exposures and multiple exposures), and what factors might influence the transmission of effects from parent to offspring (e.g., the concentration and timing of the exposure). The committee then considered what reproductive, developmental, and generational effects were already associated with the Gulf War toxicants and what data and knowledge gaps needed to be addressed to understand those effects. These data and information were then used to develop approaches for studying and monitoring potential health problems related to veterans’ deployments and their impact on children and grandchildren. The committee’s approach to its tasks was driven by the literature as well as by the committee’s expertise.
Identification of the Literature
The Volume 11 committee began its work with extensive searches of the scientific literature using five databases: Embase, Medline, Scopus, Proquest, and PubMed. The specific searches targeted (1) studies of the health of Gulf War or Post-9/11 veterans published since the last update, without regard for specific toxicants or outcomes; (2) studies that looked at reproductive effects associated with any
toxicants of concern; and (3) studies of developmental or other health outcomes in children or grandchildren associated with parental exposures to those toxicants. The searches included studies carried out in both human populations and animal and cellular models. The searches retrieved more than 80,000 publications that had appeared through January 2018. To help manage the large volume of data, the committee relied upon existing reviews of epidemiologic and toxicologic data published by authoritative bodies, including prior National Academies committees, the U.S. Environmental Protection Agency, and the Agency for Toxic Substances and Disease Registry.
The paucity of studies on reproductive or developmental effects specific to veterans’ exposures during deployment necessitated the identification of populations—mostly occupationally and environmentally
exposed cohorts—that had exposures to some of the same toxicants experienced by Gulf War and Post-9/11 veterans. The committee was unable to determine how relevant the exposures in these nonveteran studies are to those experienced by deployed veterans in terms of the exposure magnitude, duration, frequency, mixtures and co-exposures, and population characteristics such as gender, age, ethnicity, and lifestyle. A few studies in veterans were specific to deployment exposures such as studies of the effects of DU. Studies were categorized as reporting reproductive (including adverse pregnancy outcomes), developmental, genetic, or epigenetic effects (see Box S-2).
Categories of Association
The committee determined that it would follow the evaluation processes established by previous Gulf War and Health and other National Academies committees, including the categories of association used by those committees to draw its conclusions regarding the strength of the association between an exposure and various reproductive or developmental health effects. The five categories of association described below have gained wide acceptance by Congress, government agencies (particularly VA), researchers, and veterans groups. They present a common message: the validity of an association is likely to vary to the extent to which common sources of spurious associations can be ruled out as the reason for the observed association. Accordingly, the criteria for each category express a degree of confidence based on the extent to which sources of error were reduced. The committee discussed the evidence and reached consensus on the categorization of the evidence for each toxicant from experimental studies.
Sufficient Evidence of a Causal Relationship
Evidence is sufficient to conclude that a causal relationship exists between being exposed to a toxicant and a reproductive or developmental effect in humans. The evidence fulfills the criteria for sufficient evidence of a causal association in which chance, bias, and confounding can be ruled out with reasonable confidence. The association is supported by a consideration of the consistency of association and biologic plausibility from experimental studies.
Sufficient Evidence of an Association
Evidence suggests an association, in that a positive association has been observed between an exposure and a reproductive or developmental effect in humans; however, there is some doubt as to the influence of chance, bias, and confounding. Experimental animal and cellular studies either supported or diminished the committee’s decision in making these associations.
Limited/Suggestive Evidence of an Association
Some evidence of an association between exposure and a reproductive or developmental effect in humans exists, but this is limited by the presence of substantial doubt regarding chance, bias, and confounding. The evidence in experimental animal or cellular models was used to strengthen, or weaken the associations between exposure and effect.
Inadequate/Insufficient Evidence to Determine Whether an Association Exists
The available studies are of insufficient quantity, quality, validity, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between an exposure and a reproductive or developmental effect in humans. Evidence in experimental animal studies may have provided additional support for these assessments, but, in the absence of human data, it was not used to strengthen the categorization of the association. In some cases, the body of evidence is too small to permit conclusions, such as when there are no available studies to validate or corroborate the findings of a single study. In other cases, there is evidence from human or animal studies, but the heterogeneity
of exposures, outcomes, and methods leads to inconsistent findings that preclude the committee from identifying an association between exposure and effect.
Limited/Suggestive Evidence of No Association
There are several adequate studies, covering the full range of levels of exposure that humans are known to encounter, that are consistent in not showing an association between an exposure and a reproductive or developmental effect. A conclusion of no association is inevitably limited to the conditions, levels of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small increase in risk at the levels of exposure studied can never be excluded. Experimental animal studies were examined to support such findings.
FINDINGS AND CONCLUSIONS
The committee organized the toxicants of concern into four groups: deployment-related exposures, pesticides, combustion products and fuels, and solvents. Deployment-related exposures included deployment itself, vaccines, chemical warfare agents, infectious diseases, DU, hexavalent chromium, and PB. The committee’s conclusions for each toxicant of concern are listed in Box S-3 (reproductive effects, adverse pregnancy outcomes, and developmental effects). No toxicant had sufficient evidence of a causal association between exposure and reproductive or developmental effects, nor did any toxicant have limited/suggestive evidence of no association between exposure and reproductive or developmental effects.
The committee emphasizes the need to interpret the conclusions in this report and any future research within the broader context of both the veterans’ and their descendants’ exposures over the course of their lives. Exposures across the lifecourse, beginning in utero, can have an impact on health, including that of future children. Those exposures, such as nutritional exposure and exposure to toxicants, may interact with one another and be influenced by the genetic and epigenetic background of cells. Such changes are being studied, but at present there is insufficient evidence to link any deployment exposures to epigenetic1 effects.
The committee made its decisions concerning associations between deployment exposures and reproductive and developmental effects primarily on the basis of human data, using animal and cellular data to provide additional support. For some toxicants, however, the animal data were robust, but the lack of human data precluded the committee from assigning a category of association that reflected a stronger level of association. These toxicants include the following:
- Depleted uranium and reproductive effects in males;
- Lindane and reproductive effects in males and developmental effects in offspring;
- Toluene and developmental effects in offspring;
1Genetics is the study of deoxyribonucleic acid (DNA) and the genes it encodes, sometimes referred to as the genome when referencing the totality of the DNA (and all the genes) of an organism. Epigenetics is the study of processes that cause heritable changes in gene expression without changing DNA sequence. The epigenome is composed of chemical modifications made to DNA and the histone proteins that make up chromatin. “Heritable” in this context can refer to inheritance not only between parents and offspring (generational or meiotic inheritance of epigenetic alterations) but also between parent and daughter cells.
- Xylenes and developmental effects in offspring;
- Trichloroethylene and reproductive effects in females; and
- Dioxins and reproductive effects in males and females.
Although animal and cellular models permit defined exposures, they may lack temporal resolution since only specific points in time are considered, and they may not model the cumulative effects of exposures to mixtures that are observed in humans. In addition, adsorption, distribution, metabolism, and excretion processes and organ systems can vary widely among humans and other species, and effects seen in one species might not be seen in another. Because of these species differences, the committee cautions that even robust animal data must be interpreted with caution.
HEALTH MONITORING AND RESEARCH PROGRAM
To help determine if veterans’ descendants are at risk for health effects resulting from the veterans’ exposures during deployment, the committee has proposed creating a health monitoring and research program (HMRP) with three arms: monitoring the health of veterans and their descendants over time; epidemiologic studies to examine groups of veterans and their descendants for health outcomes of concern; and basic and translational research to help address data and knowledge gaps. The HMRP might base some of its work upon the health effects identified for the deployment toxicants considered by the committee in this report, but it would need to be tailored to specific questions.
Potential epidemiologic studies may be nested within the HMRP, make use of the data collected by the HMRP, or identify cases among HMRP participants. In addition, researchers who are not affiliated with the HMRP may also conduct epidemiologic studies simultaneously. Epidemiologic studies might focus on a specific veteran cohort (e.g., veterans who served in Vietnam) or specific exposures (e.g., sarin) or examine specific outcomes in children and grandchildren (e.g., birth defects or neurodevelopment). The pathophysiologic research program, described later, would emphasize the use of basic research studies to help elucidate cellular processes that may be responsible for generational health effects.
The committee’s framework for developing an HMRP begins with defining the program’s scope. The program scope will guide the recruiting and enrolling of the HMRP participants—active-duty service members, reservists, veterans, and their descendants—now and in the future as well as the collection and maintenance of each participant’s data. Establishing the program’s scope and goals early in the process will provide not only the overarching framework for the program but also a platform to establish communication with veterans, their descendants, and collaborators, thus helping to promote clarity and transparency, prevent redundancies, and optimize the use of resources.
The committee suggests that pilot programs be conducted to determine the feasibility of collection strategies, to establish the linkages for appropriate use of data, to assess response rates among veterans and their descendants, or to test surveys or other data collection methods. Focus groups and other exploratory strategies can help identify the specific exposures, health effects, populations, datasets, and logistics that are most appropriate for the study and that best respond to VA’s needs and veterans’ concerns.
An HMRP that includes participant recruitment at enlistment will ensure that a sufficient sample size is available to observe small effects in veterans and provide a mechanism to contact dependents (partners and children). By enrolling all new recruits as they enter DoD using an opt-out approach, a baseline of health status, including information on lifestyle and environment as well as biological samples, can be established prior to deployment. This approach will also facilitate the tracking of exposures associated with each deployment or occupational assignment. As service members transition from DoD to VA, the follow-up will be challenging and will require concerted approaches and coordination to identify and
engage the veterans in the HMRP. Not all service members are eligible for care in VA, and thus not all are captured in the VA databases. Veterans who enter the VA health care system will be easier to identify, whereas veterans who do not enter the system may be difficult to locate and recruit.
The enrollment of active-duty service members’ partners could begin with the partners’ entry into the Military Health System/TRICARE system as beneficiaries, with follow-up being carried out for the duration of their eligibility for TRICARE. Partners may provide information on their own exposures that may affect the health of veterans’ children and may also represent a valuable source of information about those children’s health.
The recruitment and enrollment of, engagement with, and collection of data from veterans, partners, and the children themselves will be essential elements of the HMRP. Recruiting the children may begin with those who are born to an active-duty service member and covered under TRICARE so as to facilitate access to the child’s health records. The recruitment and follow-up of older children will present additional feasibility and ethical challenges. All these populations will require appropriate participant consent, which may be modeled after existing long-term follow-up studies that collect data on children, including the National Health and Nutrition Examination Survey, the Environmental Influences on Child Health Outcomes program, or the Growing Up Today Study.
The analysis of biospecimens from HMRP participants will require the identification of appropriate sample collection and storage systems and equipment (e.g., laboratory facilities and biorepositories) as well as well-controlled and standardized protocols. For example, blood, urine, and semen samples should be collected from service members at their entry into the military, prior to each deployment, and after each deployment. After their separation from the military, veterans participating in the HMRP could provide additional samples on a periodic basis.
Deployment and occupational exposures may result in or contribute to a biological response that ultimately manifests itself as adverse health effects in the veteran or his or her descendants. The veterans’ exposure to stressors (nutritional, psychological, biological, physical, and chemical) during preconception and in utero development may affect the health of their descendants. Although the committee suggests that biological samples be collected periodically from service members, individual validated measures of exposure are not available for veterans of any era, and the estimates of exposure often rely on self-reported information or military records of incidents of exposure.
When children are born following a parent’s deployment, they too may be monitored during their lifecourse to determine what, if any, health effects they may experience, compared with children of veterans who were not deployed or other reference populations. Data collected directly from children can be used to document outcomes and assess the risk factors present throughout the children’s lives, such as air pollution or occupational factors. Data collection may begin with the electronic health records (EHRs) of children born in the TRICARE system, including information in the DoD Birth and Infant Health Registry.
New methodologies and efficiencies are available for identifying the population to be sampled, issuing invitations, determining the what and how of data collection and analyses, using incentives for recruiting and retaining participants, and using reminders to increase response rates. As the collected data will be both electronic and biologic, adequate preparation to receive, catalog, and maintain multiple forms of information will be important. The data analysis will require linking databases and statistical software, particularly VA and DoD EHRs and other records, and potentially other databases (e.g., of the Centers for Medicare & Medicaid Services and state cancer registries).
Program management is a critical, integral, and continuous function of an HMRP. Addressing the many requirements and opportunities of an HMRP will require the identification of lead organizations to design and implement the program and studies. These may be VA, DoD, the National Institutes of
Health, or other organizations, such as academic research centers or consortia. Close coordination and collaboration among the program partners will be critical to increase efficiency, to avoid duplicate efforts, and for accountability. Different partners may have different strengths, including the availability of subject matter experts, access to relevant data or records, and strong information technology capabilities. Limitations might include a lack of legislative mandates to participate in the program, financial constraints, and a lack of familiarity with program data requirements, each of which can be addressed through a multi-organization, nationwide, collaborative effort among the participants. In particular, sufficient information technology capabilities, combined with linked medical records from DoD and VA and potentially from other participants, will be critical elements of these research efforts.
Publishing the program’s results will ensure that veterans and their descendants are aware of the findings, positive or negative, that may affect their health and well-being. This dissemination to a broader audience, including researchers and the general public, can spur interest in the program and its activities. Finally, the HMRP needs to be evaluated on a continuing and regularly scheduled basis. Without an adequate review of all aspects of the program, resources may not be efficiently used, data collection and analysis may lag, and veterans and their descendants may be participating in a program that does not serve their needs.
The committee finds that it may be possible to implement parts of the proposed HMRP and hypothesis-driven studies by leveraging ongoing programs. The committee examined a number of ongoing research programs, including the VA-sponsored Million Veteran Program (MVP) and the DoD-sponsored Millennium Cohort (MilCo) and MilCo Family Study as well as the DoD Birth and Infant Health Registry and the DoD Serum Repository. Building on and coordinating among these existing health monitoring and epidemiologic research programs can reduce costs, expedite data collection, and provide access to already engaged study populations.
While there is a growing base of human and animal evidence concerning the reproductive and developmental effects of many of the toxicants of concern to veterans and their descendants, there is a dearth of information on the specific effects of veterans’ exposures on their children, grandchildren, and great-grandchildren. Furthermore, although targeted epidemiologic studies are being designed, it may be years or decades before the effects (if any) of parental exposures are evident in a future generation. Such studies may not capture rare events that occur only in a few descendants, as a result of a narrow range of exposures, or in those instances where specific genotypes interact with specific exposures. Basic and translational research in model systems—in vitro systems that use cells and tissues as well as whole animals—where both genetics and exposures can be controlled as well as generational animal studies that can be conducted in days or months provide powerful opportunities to assess biological plausibility, gain mechanistic insights, and address the complexities inherent in human studies. Such studies may detect subtle effects; follow genetic or epigenetic changes at the cellular and whole-animal levels, including effects on germ cells; assess impacts on reproductive function; and identify susceptible phenotypes.
The results of studies in model organisms need to be extrapolated to humans to enhance understanding of the reproductive, developmental, and generational effects of toxicant exposures across the exposure → effect → outcome pathway. Understanding the range of biological diversity across animal species—including humans—can help achieve this goal. For example, it has been shown that the gene for the aryl hydrocarbon receptor that mediates dioxin toxicity shows sensitivity differences among mouse strains; between rats, mice, and guinea pigs; and among humans. Knowledge about what those differences are makes it possible to estimate human risk from rodent studies.
Basic and translational research can also identify targets and mechanisms to help identify biomarkers of exposure, effect, and susceptibility for a toxicant or stressor; explore factors that underlie individual variation in response to an exposure, such as the impact of sex differences on response to a toxicant; and identify susceptible cell types (e.g., somatic cells, eggs, sperm) for specific exposures. Basic and translational research should include developing the following: fit-for-purpose models and reagents for generational studies; genetically engineered induced pluripotent stem cells; validated models (animal- and cell-based) that are most appropriate for studying specific exposures; and methods and databases for acquiring, curating, and analyzing the resulting datasets.
Studies should focus on deployment-specific exposures (single-agent or mixtures), although using surrogate exposures in reproductive or multigenerational studies may be adequate if that use is sufficiently responsive to research needs. Knowledge gaps to be addressed relate to the adverse reproductive effects in veterans and the developmental effects of these exposures in offspring, including details about windows of susceptibility, dose–response relationships, duration, and co-exposures (mixtures).
Both genetic and epigenetic alterations induced by environmental exposures can cause changes that result in reproductive, developmental, or generational effects. Although a few of the toxicants considered in this report are known to be reproductive or developmental toxicants or mutagens (e.g., benzene), there is little evidence that if a parent is exposed prior to the child’s conception these toxicants affect germ cells in such a way as to cause developmental effects in offspring. What effects occur in parental germ cells, what happens after exposure ceases, and if and how lifecourse events compound epigenetic alterations are crucial knowledge gaps. Focused research on the transmission, persistence, gene x environment interactions, and modifiers (e.g., stress, diet) of genetic and epigenetic effects is necessary to understand the impact of deployment exposures on veterans and their descendants.
As the committee completed its review of the epidemiologic and toxicologic literature on the Gulf War and Post-9/11 toxicants of concern, a framework for an HMRP was developed and an agenda for basic and translational research on generational effects laid out. Several scientific priorities became evident during the course of the committee’s deliberations. Addressing these priorities will be critical to implementing a functional and useful HMRP and a concrete agenda to answer questions about the reproductive, developmental, and generational health effects of deployment exposures. These priorities include the following:
- The collection, storage, and maintenance of comprehensive baseline and longitudinal data and biospecimens from veterans, their partners, and their descendants;
- A detailed characterization and assessment of exposures during and after deployment; and
- The development, evaluation, standardization, and interoperability of biomarkers of exposure, susceptibility, and biological effects.
The Volume 11 committee acknowledges that the creation of new large-scale HMRPs designed specifically to address the question of whether descendants of deployed veterans are at increased risk of adverse health effects will be an ambitious undertaking. Several important issues need to be addressed in order to optimize an HMRP, including the collection of complete and accessible health information on veterans as they enter the military and before and after deployments; developing better deployment
and occupational exposure assessments based on environmental and biological sampling; and access to and the follow-up of partners, children, and grandchildren over time.
An integrated EHR system between DoD and VA (under development) not only will improve the transition of veterans from one health care system to another but also will provide access to longitudinal health data, particularly those related to reproductive and birth outcomes. Access to electronic health data will also be essential for the large number of veterans who receive care at ancillary facilities or outside the VA system.
The lack of exposure monitoring during deployments, whether at the individual or the military-unit level, precludes an adequate assessment of the nature, duration, and frequency of deployment exposures. This limitation is exacerbated by the lack of information on lifecourse exposures and on the toxicologic effects of complex chemical mixtures that are often encountered with environmental and occupational exposures. Importantly, the capture of health information on veterans’ partners and their children and grandchildren from health systems that are often fractured and location-specific will pose unique challenges.
Implementing and maintaining an HMRP and a basic research agenda will require a consistent and committed funding stream. The costs of designing and conducting an HMRP for any veteran cohort will be considerable, as demonstrated by the cost of similar programs such as the National Children’s Study and the All of Us Research Program. However, while the costs of an HMRP may be substantial, the costs of some of the underlying technologies—such as whole-genome sequencing—have plummeted, and the preemptive health program and research results may translate into significant cost savings for the nation.
There are numerous resource, methodologic, and organizational considerations that must be addressed across several governmental agencies—and, likely, private organizations as well—to implement a large-scale HMRP of the magnitude envisioned and recommended by the Volume 11 committee. Critical considerations include financial and human resource costs, the availability and expertise of adequately trained personnel, the time required for project completion, technologic competencies, ready access to well-curated data, the maintenance of confidential human health data, ethical considerations for investigations that include parents and children, and the implementation of appropriate health and risk communication strategies between and among organizations and veterans and their families. Given these considerations, the committee proposes that a practical and expedient approach to exploring generational health effects should leverage ongoing veteran’s health research programs, such as the MVP and the MilCo study. In addition, the newly established partnership between MVP and All of Us may prove extremely useful. This approach would greatly benefit from past investments and take advantage of existing infrastructure to address some of the critical issues identified in this report. These programs have already enrolled large cohorts and are linked to a variety of large data sources, and some of them already have in place protocols for the collection of biological specimens and the participation of partners and children.
In conclusion, the committee commends the efforts of VA and Congress to address veterans’ concerns about generational health effects. The path forward demands an understanding of certain critical issues that will define the success of the program. The committee believes that the results and deliverables that arise from studying generational effects will ultimately be rewarded with new knowledge of veterans’ exposures, their reproductive health, and the health of their children and grandchildren. Importantly, the knowledge and understanding derived from these investments will be relevant to the health of all Americans now and for future generations.
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