11

Moving Forward

The Gulf War and Health series has examined the health outcomes associated with numerous harmful exposures, intentional and unintentional, to which Gulf War and Post-9/11 veterans may have been exposed during their deployments to the Persian Gulf region and Afghanistan. Some volumes in the series also evaluated the prevalence of health outcomes among veterans who deployed to the Persian Gulf region compared with veterans who did not deploy or deployed elsewhere. Each of the volumes in the series, when appropriate, attempted to ascertain which, if any, adverse reproductive effects might be occurring in male and female veterans and, when data were available, which health effects might be occurring in their children. However, none of the previous volumes considered windows of exposure during the prenatal and, particularly, the preconception periods. Generally, although deployed Gulf War veterans were more likely to self-report sexual difficulties than their nondeployed counterparts, no other adverse reproductive or developmental effects were reported in veterans or their children (NASEM, 2016a). As such, none of the Gulf War and Health volumes have specifically addressed whether generational health effects are attributable to a toxicant, other potentially harmful exposures, or deployment in general. The most recent volume in the Veterans and Agent Orange series drew attention to the possibility that exposure to dioxin, present in the herbicides sprayed in Vietnam during the war, might result in adverse health effects in the children of veterans (NASEM, 2016b). Given those concerns, coupled with the concerns of Gulf War and Post-9/11 veterans about the long-term effects of their deployment exposures on their reproductive function and on the health of their children, the Department of Veterans Affairs (VA) and Congress requested that the National Academies of Sciences, Engineering, and Medicine examine what the scientific and medical literature says about generational health effects and, importantly, how current knowledge gaps may be addressed. This volume specifically summarizes the science and provides guidance for the development of future programs that can help to fill those gaps.

In Chapters 4 through 7, the Volume 11 committee reviewed the literature on 24 toxicants or groups of toxicants and other related harmful exposures with a specific focus on reproductive and developmental health outcomes. For most exposures, there was little or no information on specific effects in veterans, so the committee relied on studies that examined other exposed populations, such as occupational or residential cohorts, in order to reach conclusions about the strength of the association between exposures

and effects. It is important to note that studies of nonveteran populations raise questions regarding the comparability of both the study population and their exposures as they relate to veterans’ experiences and their deployments. This was apparent for toxicants such as dioxins and pesticides where the preponderance of the evidence is for occupational (e.g., pesticide sprayers) and residential exposures, and not related directly to the military experience. Nevertheless, the committee is confident that nonveteran studies can help identify relevant toxicants and related exposures that need to be prioritized for future research efforts, as discussed in the following sections.

As the committee reached its conclusions regarding the categories of association for each toxicant or group of toxicants or for other exposures, it became evident that there were three areas with a substantial dearth of information. Those areas are:

• the effects that may occur in germ cells, embryos, fetuses, neonates, infants, or children following preconception exposures;
• the long-term health outcomes in children who have been prenatally exposed to potentially harmful substances; and
• the occurrence, if any, of adverse effects in grandchildren and subsequent generations as a result of veterans’ deployment exposures.

In addition, compared with studies on male reproduction, there are relatively few studies on the effects of the toxicants of concern on female reproduction. Even for exposures with a relatively robust human literature, the vast majority of information on developmental effects in embryos, fetuses, and children is based on prenatal—not preconception—exposures. In light of the Department of Defense (DoD) requirement that pregnant service members be removed from deployment as soon as possible after the pregnancy is known, preconception exposures may be more common or likely to cause problems than prenatal exposures for deployed women. For male veterans, all exposures would be considered preconception.

Several of the toxic exposures reviewed by the committee, including solvents, pesticides, and polycyclic aromatic hydrocarbons (PAHs), have been associated with health effects in children following prenatal exposures. One difficulty in assessing these studies is that no matter how much care is taken when measuring the levels of the toxicants or their metabolites in the mother’s urine or blood, the exposure of the children to the toxicants may have extended beyond their mother’s pregnancy and into their infancy and childhood. Such exposures early in childhood not only add complexity to the interpretation of findings but also can have significant impacts on the child’s health. However, some studies have continued to follow children exposed prenatally to a number of toxicants (e.g., pesticides and tetrachloroethylene), and this provides an unparalleled opportunity to monitor health outcomes throughout the children’s lifecourse.

These and other data gaps highlight the need for programs to monitor veterans prior to, during, and following deployment and to assess their children (and subsequent generations) periodically to determine what, if any, health effects they are experiencing and whether those effects might be associated with their parents’ deployment exposures. To achieve this, the committee provided a framework for the creation and implementation of a health monitoring and research program (HMRP) for veterans and their children and grandchildren as well as guidance on epidemiologic studies that might further enhance our understanding of the association between a veteran’s deployment exposures and health outcomes in their children and grandchildren. Recognizing that even a concise epidemiologic study might take several years to produce meaningful results and that conducting prospective generational studies will require even more time, the committee also provided a research agenda addressing the genetic and epigenetic

changes that underpin generational effects. That research agenda includes using animal models, target tissues, and cells, including induced pluripotent stem cells, to model observed exposures in parallel with the epidemiologic studies in order to move the science of generational health effects forward in a more expeditious and effective manner.

The proposed HMRP would establish a process for identifying service members and their families and a framework upon which specific research studies could be developed in the future. This program would also provide access to information on veterans’ military exposures (both suspected and measured); the reproductive health of the veterans and their spouses; pregnancy outcomes; and neonatal, infant, and child health outcomes. These data would allow VA to evaluate the occurrence, distribution, and overall trends of reproductive effects in veterans as well as any relevant health outcomes in their descendants, which in turn would allow researchers to investigate the biological mechanisms and epidemiologic associations of health effects and veterans’ exposures. Importantly, the committee foresees that this information will be of value not only to veterans and their children but also to the general public, given that many of the exposures, as noted earlier, are not unique to deployment but are also representative of occupational and residential exposures and, in some instances, of daily living.

There is evidence of direct reproductive and developmental effects that are related to deployment exposures, especially pesticides, particulate matter (PM), and solvents (see Tables 8-1 and 8-2). Although evidence of heritable generational effects is lacking in humans, basic research studies have provided evidence for the biological plausibility of many of the observed findings. The direct or indirect effects of prenatal exposures on the somatic cells of the embryo or fetus—that is, all the cells in the body other than reproductive cells—can lead to reproductive and developmental effects, but these should not be confused with effects on the germ cells that produce the sperm and oocytes which combine to form an embryo, for it is these changes that may give rise to transgenerational health effects. Toxicants and harmful exposures that directly or indirectly affect reproduction and development act through a variety of pathways, whereas, based on current knowledge, the toxicants capable of inducing generational effects are limited to genetic and epigenetic mechanisms in germ cells. These generational effects in turn alter normal embryonic development in ways that modify the genetic programming of one or more cell types to alter the organism’s further development. Some research has examined possible genetic and epigenetic changes in the placenta, the developing embryo, maternal blood, or cord blood as a result of deployment-related exposures, such as to PM or benzo[a]pyrene (see Chapter 6). The relationship of those changes to health outcomes, such as birth weight, has also been explored in some detail and was discussed in earlier chapters of this report. However, the committee did not identify any studies that assessed whether deployment-related exposures produced genetic or epigenetic effects in the germ cells of prenatally exposed children. This dearth of information is an important finding, because changes in the germ cells in exposed offspring represent a major pathway for the occurrence of generational inheritance of health outcomes.

A literature review by Walker et al. (2018) found that most deployment exposures of interest for this report have not been studied for potential transgenerational effects in humans. However, some toxicants, such as dioxins and permethrin in combination with DEET, have been studied in animal models. Any experimental study on chemical exposure should be combined with stress (physical or psychological) to better simulate deployment exposure scenarios.

As the committee completed its review of the epidemiologic and toxicologic literature on the Gulf War and Post-9/11 toxicants, developed a framework for an HMRP and future epidemiologic studies, and laid out an agenda for basic research on generational effects, several scientific priorities became evident. Addressing these priorities will be critical to implementing a functional and useful HMRP and a concrete agenda for answering questions about the reproductive, developmental, and generational

health effects of deployment exposures; if these priorities are not addressed, it would compromise the effectiveness and success of the proposed HMRP. These priorities are listed below and discussed in the sections that follow:

• 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.

COLLECTION OF BASELINE AND LONGITUDINAL DATA

An accurate assessment of changes in health status requires baseline data against which future data can be compared in order to properly evaluate patterns and outcomes. Thus, to determine whether any health outcomes in veterans and their children are potentially associated with the veterans’ deployments, it is essential that a properly curated and maintained database be created. The database should contain baseline exposure and health information for all new incoming service members, including biological specimens—at a minimum, blood and urine as well as sperm for men and, where feasible, oocytes for women—collected at the time of entry into the military and also before deployment. At times when it proves too difficult to collect blood and urine samples—for example, in a war zone—saliva or buccal swabs may be collected instead. The resulting extensive collection of pre-deployment data and specimens will require significant and extensive coordination, as detailed elsewhere in this volume, but it is a crucial requirement that medical staff and investigators establish a reference framework against which post-deployment exposures and health status can be evaluated.

As discussed in Chapter 9, one practical option would be to build upon the existing DoD Serum Repository. DoD already collects serum for every service member at the time of entry into the military and then every 2 years while on active duty, as well as before and after deployment. At present there are about 60 million sera samples that have been collected from about 10 million service members representing all the branches of the military and including both men and women (Lushniak et al. 2016). A well-coordinated and systematic expansion of this biobank would provide an extremely valuable resource for DoD, VA, and affiliated stakeholders. At a minimum, DoD should continue to biobank and process samples so that a longitudinal profile encompassing the baseline health status and pre- and post-deployment exposures of service members can be established. As elaborated in Chapter 9, the existing biobank could be expanded to include the collection of sperm and oocytes following defined protocols for sample collection and storage and to acquire samples immediately after a specific “incident” of potential concern.

The committee strongly believes that although the current collection of blood and urine will help with eventual exposure assessments, collecting baseline semen samples will be crucial for understanding the impacts of veterans’ exposures on their children and grandchildren. The effects of exposures on semen have been suggested as an important sentinel of environmental exposures (Montano et al., 2017); these exposures may also have impacts on the fertility of the exposed male veterans and, possibly, health effects in his offspring. Given the reports of decreasing rates of fertility in industrialized nations that have been associated with reduced semen quality, which in turn has been associated with increasing levels of environmental pollution, this issue is of significant public health relevance (Mima et al., 2018). As such, a robust, accessible, searchable, and well-curated biorepository could help provide valuable

data for answering future questions about exposure–disease associations, deployment exposures, and susceptibility to disease.

As the number of women entering the military and being deployed continues to grow, concerns regarding the possible health effects of those deployment exposures on female germ cells (oocytes) also escalate. These concerns gain added significance when one considers that women are born with a finite number of germ cells which are available throughout their reproductive period. Although the collection of oocytes when women enter the military is desirable, the committee recognizes that such biospecimens are difficult to obtain. The opportunistic collection of oocytes is feasible and might be accomplished as part of fertility preservation.

As with veterans, sample collections from infants and children will provide a baseline that can be used to create a longitudinal record of changes as a child grows. The committee suggests that blood spots be collected at birth and be maintained by the states’ newborn screening programs and that additional biological samples (e.g., saliva or meconium), also be collected from offspring to address specific goals of the HMRP. Blood and urine samples may be collected on a periodic basis from older children as well.

PRIORITIZATION OF EXPOSURES

Not all deployment exposures are equal. Some exposures during deployment may be similar to those experienced by the veteran as part of his or her military occupation specialty—diesel exhaust, for example—while others may be unique to the deployment experience, such as combat stress, chemical warfare agents, and the regular use of pesticides. Some exposures may be of particular concern because veterans are more likely to be exposed to them at higher concentrations, at a heightened frequency, or for longer periods of time than would be the case in most other occupational settings—PM and some solvents are examples—or because the substances have significant toxicity, as is the case with sarin or hexavalent chromium.

Both the overall evaluation completed by the committee and the conclusions it reached about exposure–effect associations are based on data from a wide range of exposure scenarios and populations that were not equivalent to the deployment exposures experienced by service members or veteran populations. Therefore, the committee strongly recommends that such exposures should be studied specifically in active-duty service members and in veterans in order to confirm that the associations are valid for those populations.

As discussed in Chapter 9, DoD should conduct more systematic exposure monitoring using the most appropriate, state-of-the-art analytic technologies whenever service members encounter extraordinary exposures such as sarin or depleted uranium—that is, exposures that are clearly not considered to be routine during deployment or occupational activities and for which the long-term health consequences are considerably less well characterized. The Volume 11 committee reiterates the concerns of earlier Gulf War and Health committees about the lack of precise exposure information for veterans or information on exposures at military locations, such as the Khamisiyah munitions depot containing sarin that was below the detection levels of the personal monitors yet still produced symptoms, or installations with burn pits. This uncertainty about exposures continues to significantly hamper the ability of DoD and VA to characterize hazards and to determine whether deployment exposures reached high levels of concern. The paucity of exposure data for individuals and aggregate data for military units means that future assessments will have to rely on qualitative assessments that compare “deployed versus nondeployed” rather than on precise monitoring data. The limitations of this approach are clearly substantial and greatly detract from the effectiveness with which the findings can be interpreted and followed in future investigations. Nevertheless, the committee is encouraged by steps that are being taken to improve

exposures assessments during deployment. For example, DoD conducted real-time personal breathing zone sampling of U.S. Air Force security personnel at Bagram Airfield in Afghanistan to determine pollutant levels associated with a burn pit and an incinerator. SKC Deployable Vapor samplers and SKC Deployable Particulate samplers were used to collect both breathing zone sampling and ambient air samples for 24 hours beginning with the start of each work shift at multiple sites at the airfield (Blasch et al., 2016). Similar approaches may be used in other deployment situations and military installations. This was demonstrated when the oil fields in Kuwait were set ablaze in the first Gulf War. Air monitoring of soil and air and biomonitoring of 22 service members were conducted. Blood samples were assessed for changes in PAH-DNA adducts as biomarkers of exposure. This demonstrated the feasibility of environmental monitoring when a potential threat is known (Poirier et al., 1998).

Ideally, all substances that lie at the intersection of high likelihood of exposure and great inherent toxicity would be considered a high priority for monitoring and for research on their reproductive and developmental health outcomes and toxicity. However, because the reproductive, developmental, and generational effects of many toxicants are generally not well understood, particularly in humans, it is not possible at this time to identify those particular toxicants that pose the greatest risk to veterans, their descendants, or both. A list of toxicants for which the committee concluded there is limited/suggestive or sufficient evidence of association with reproductive and developmental effects in humans is presented in Tables 8-1 and 8-2. Following those tables is a short list of toxicants for which robust animal data, but few human data, are available. Of note is that hexavalent chromium; benzene; organophosphate, carbamate, and pyrethroid pesticides; PM, PAHs; polychlorinated dibenzodioxins and furans; trichloroethylene and tetrachloroethylene; and glycols and glycol ethers all warrant further immediate research, as risks have been indicated for each. Research on generational effects from exposure to these chemicals should also be assigned top priority. Preemptively, where little or no human data are available, broad cellular, animal, and literature screening programs for early indications of concern are warranted. Compounds for which a concern is identified could then be directly assessed using biobanked resources.

DEVELOPMENT OF BIOMARKERS

Concurrent with the effort to measure veteran’s exposures during deployment, there should be research into the identification of biomarkers for those exposures, biomarkers of susceptibility, and biomarkers of various effects, including those specifically designed to evaluate reproductive effects in veterans and developmental effects in embryos, fetuses, and children. The committee notes that the assessment of generational effects will require the development of sensitive and meaningful epigenetic markers as well as biomarkers of susceptibility.

There are existing federal programs focused on biomarker research that may facilitate VA and DoD efforts in this endeavor. For example, the National Institute of Environmental Health Sciences (NIEHS) Toxicant Exposures and Responses by Genomic and Epigenomic Egulators of Transcription (TaRGET) II consortium is focused on the development of epigenetic biomarkers in animal models. These biomarkers of exposure, susceptibility, and effect will also need to discriminate with some degree of certainty, when feasible, between adverse deployment exposures and exposures that occur throughout the veteran’s lifetime as well as the lives of his or her children and grandchildren. Of particular relevance to this report is that the consortium will be collecting and analyzing target and surrogate tissues over the lifecourse following perinatal, peri-adolescent, or adult exposure to tetrachlorodibenzo-p-dioxin and to air pollution in the form of PM_2.5 (Wang et al., 2018).

The NIEHS Children’s Health Exposure Analysis Resource (CHEAR) described in Chapter 9 (see Box 9-2) is another example of efforts to develop and disseminate data on children’s exposures and provide a public resource for environmental health studies (NIEHS, 2018). Depending on the half-life of the toxicant and the timing of sample collection, biomarkers of exposure may be assessed using high-quality assays, including untargeted chemical analyses. Laboratory approaches for exposomic analysis often combine targeted and untargeted methods, with the targeted analysis providing a more accurate quantification of the untargeted screen (Cajka and Feihn, 2016; Feihn, 2016). The CHEAR program is scheduled to be converted in 2019 to a human health exposure analysis resource which will include adults. CHEAR is also at the forefront of developing untargeted chemical assays that screen hundreds to thousands of chemicals in biological samples. Untargeted chemical testing screens are based on high-resolution mass spectrometry (HRMS) and are a newer approach to assessing chemical exposures. Such assays can be used to discover which exposures from deployment are candidates for inter- and transgenerational inheritance effects. Targeted assays are more precise quantitatively, but they measure only one or a small number of chemicals in a panel.

Untargeted assays screen thousands of chemicals at once, and while they are less quantitative, they provide a more comprehensive view of the totality of chemicals within a biological sample. Untargeted assays allow researchers to discover important chemicals that drive health effects rather than subjectively choosing chemicals to test based on the published literature and available assays. No single platform captures all metabolites and exogenous chemicals, and most laboratories use multiple platforms. Gas chromatography (GC) coupled with HRMS is ideal for exogenous chemicals (Dennis et al., 2017; Feihn 2016), but methods that use both GC and liquid chromatography would be more comprehensive. Of note is that untargeted assays can capture both endogenous metabolites and exogenous chemicals (Michely et al., 2018), affording added value as measures of exposure response and exposure. A number of programs are developing assays for high-dimensional untargeted multi-chemical screens, including the Emory University HERCULES Research Center, the Mount Sinai Institute for Exposomics, the NIEHS CHEAR program, the West Coast Metabolomics Center at the University of California, Davis, and the National Institutes of Health’s Common Fund Metabolomics Program, among others. Using untargeted assays to assess thousands of chemical signatures at a time in such biological samples as urine or plasma can help identify candidate chemical exposures that may play a role in transgenerational inheritance. This approach would be the current state of the art, and it is expected that methods for both the assay and its associated bioinformatics will change and improve dramatically in the coming years, as this is an area of rapid scientific advancement.

DoD has already funded research using untargeted assays to assess exposures during deployment (Accardi et al., 2016; Jones et al., 2016; Walker et al., 2016), including for military personnel exposed at burn pits (Mallon et al., 2016), thus illustrating its interest in this line of research. Such work should be relatively easy to leverage for the HMRP proposed here and represents a logical and natural synergistic extension of the overall effort. The committee envisions that untargeted assays will be increasingly used to screen for chemical exposures during deployment and that this work will lead to the establishment of a program in exposomics¹ within the DoD and VA research portfolios. Pilot studies assessing burn pit exposures in Iraq and Afghanistan have suggested that the DoD Serum Repository is a useful

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¹Exposomics is a scientific discipline focused on the measure of all the exposures throughout a lifetime (the exposome), beginning at birth and including environmental and occupational sources, and on how they relate to health. The goal is to understand how exposures from our environment, diet, lifestyle, etc., interact with individual characteristics (i.e., genetics, physiology, and epigenetics) to affect health. The measurement of the exposome relies on internal and external exposure assessment methods. Internal exposure assessment methods frequently rely on omics approaches and biomarkers to quantify internal dose and biological effects (NIOSH, 2014).

resource for identifying nonroutine exposures using omics approaches, particularly those encountered during deployment, and that untargeted screens are now being used (Lushniak et al., 2016; Mallon et al., 2016). For example, serum microRNAs from the DoD Serum Repository are being explored as a novel biomarker of deployment exposure to dioxins (Woeller et al., 2016).

Biomarkers of exposure, susceptibility, and effect will also need to discriminate with some degree of certainty, when feasible, between adverse deployment exposures and exposures that occur throughout the veteran’s lifetime as well as the lifetimes of the veteran’s children and grandchildren.

FUNDING

As the population of veterans and their descendants continues to grow, the importance of a consistent and committed funding stream for the HMRP and its underlying basic research cannot be overemphasized. The costs of designing and conducting a HMRP for any veteran cohort will be substantial, as already demonstrated by the cost of similar programs. For example, the National Children’s Study, which attempted to examine the health of 100,000 children, had an estimated 7-year total field cost in the range of $1.3 billion to $1.6 billion (NRC/IOM, 2013). The Air Force Health Study (see Box 9-1), funded directly by Congress as a line item in the DoD budget appropriation, cost approximately $143 million as of 2006 to study more than 2,000 Ranch Hand and control veterans, including the collection of data on almost 10,000 pregnancies (IOM, 2006). The study also followed more than 20,000 Vietnam veterans for almost 25 years to gather health outcomes and mortality data.

While the programmatic costs of a HMRP, including future epidemiologic and basic research studies, may be substantial, the costs of the some of the underlying technologies have plummeted. For example, the cost of whole-genome sequencing has rapidly decreased—from an estimated $3 billion for the first human genomes sequenced in 2003 to about $1,000 per individual recently, with the cost continuing to trend downward toward the predicted $100 personal genome (NHGRI, 2018). This cost savings has expanded the use of gene sequencing for medical diagnosis and treatment to the point that this practice is now routine in many clinical medicine facilities (Krier et al., 2016). For example, sequencing is now routinely used in many cases of cancer therapy to predict response and optimize treatment (NCI, 2018), and its use has extended to personalized precision medicine, including applications in the neonatal intensive care unit (Farnaes et al., 2018; Rehm, 2017) as well as into wellness programs (Patel et al., 2013). Untargeted chemical assay costs are also declining and have been estimated to be as low at $125 per sample (Walker et al., 2016). While the effort to decode a human genome previously required substantial infrastructure, it has now been miniaturized to the size of a flash drive using nanopore sequencing technology (Jain et al., 2018). This presents a new set of opportunities for its use in research (both human and animal), clinical practice, and the theater of operation. The committee finds that the costs of an HMRP and the associated basic research efforts will be offset, at least in part, by an increased ability to identify and respond to early medical needs with treatments, interventions, and prevention.

FEASIBILITY

The Volume 11 committee concludes that new large-scale HMRPs and epidemiologic studies designed specifically to address the question of whether descendants of deployed veterans are at increased risk of adverse health effects compared with descendants of nondeployed veterans will be an ambitious undertaking. While it will be possible to generate valuable information for veterans and their descendants from this effort, several important outstanding issues need to be addressed to optimize the timing of future investments. These include the following:

• An integrated electronic health record system The need to have a fully integrated electronic health record (EHR) system between DoD and VA cannot be overstated; the committee is encouraged that VA and DoD are working toward that end. An integrated electronic health record system is needed not only to improve the transition of veterans from one health care system to the other, but also to improve access to longitudinal health data, particularly those that relate to reproductive and birth health. 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.
• Improved exposure monitoring 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 toxicological information as this relates to the complex chemical mixtures often encountered during environmental and occupational exposures.
• Collecting data on descendants It will be important but also challenging to capture health information on veterans’ partners and their children and grandchildren from health systems that are often fractured and location-specific. Countries with nationalized health care systems, such as Australia, Canada, Scandinavia, and the United Kingdom, have better infrastructure to properly follow children and obtain longitudinal data and biospecimens with which to conduct studies such as those proposed in this volume.

At present, there are numerous resource, methodologic, and organizational considerations that must be addressed across several governmental agencies—and likely private organizations as well—in order to implement a large-scale study of the magnitude envisioned and recommended by the Volume 11 committee. Some of the critical considerations for implementing and sustaining an HMRP are the following:

• sustained funding;
• legal mandates for and potential obstructions of participation by relevant government agencies such as the Social Security Administration, the Department of Health and Human Services, and DoD;
• the availability and expertise of adequately trained personnel;
• the level of technologic competencies, including an integrated EHR and data systems;
• ready accessibility to well-curated data, including biorepositories;
• maintenance of the confidentiality of human health data;
• logistical barriers to identifying descendants of veterans;
• ethical considerations regarding investigations that include parents and children; and
• the development and implementation of appropriate risk and health communication strategies between and among organizations as well as with veterans and their families.

As a result of these considerations, among many others, the committee proposes that a more practical and expedient approach to examining generational health effects may be to leverage ongoing veterans’ health research programs, such as the Million Veteran Program and the Millennium Cohort Study. Such an 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, as detailed in Chapter 9, have already enrolled large cohorts and are linked to a variety of rich big data sources, and some of them already have in place protocols for the collection of biological specimens and the participation of partners and children.

The Volume 11 committee believes that the feasibility of an HMRP and accompanying research agenda will be substantially improved by implementing the tiered approach described in Chapter 9. Building on the committee’s conclusions regarding the strength of the associations between exposures to the toxicants of interest and the reproductive and developmental effects described in Chapters 4 through 7, VA and collaborators may design a pilot HMRP to test hypotheses about associations that appear to be most important. Concurrently, those associations should also be explored by complementary animal studies to refine the scope of the problem and help to identify relevant biomarkers of exposure and effects. Results of the pilot program results would feed into an expanded HRMP encompassing potentially more participants, more data collection and analysis, and more detailed evaluation of effects. An iterative evaluation process would provide necessary course correction throughout the life of the HMRP to ensure that the program is meeting its goals and providing value to the participants.

SUMMARY

The available scientific and medical data on generational health effects associated with environmental and occupational exposures in humans are extremely limited. However, interesting and compelling findings from investigational studies in laboratory animals and in experimental model systems provide suggestive evidence that generational effects as a result of exposures associated with deployment, the military experience, or life in general are biologically plausible. On the bases of the available evidence, the Volume 11 committee concludes that systematic health monitoring coupled with epidemiologic and laboratory-based investigations are warranted and should be implemented. Although the scientific evidence is not yet sufficient to predict with confidence which exposures are most likely to result in genetic or epigenetic disturbances in a veteran’s somatic or germ cells that can compromise reproductive or generational health outcomes, progress is being made, and the mechanisms of generational inheritance are being explored. Thus, targeted epidemiologic studies combined with research using experimental models of epigenetic inheritance should be developed and promoted. Such programs can take advantage of the existing research infrastructure to establish whether adverse effects occur in the children of male and female veterans and whether these outcomes are related to their military service and, particularly, to their deployments.

As emphasized earlier, addressing the priorities outlined in this volume will require substantial resources, long-term commitment by DoD and VA and other governmental organizations, and considerable engagement by past, current, and future veterans and their families. While carrying out these priorities will be challenging, the committee firmly believes that there are actions that VA, working in partnership with DoD and other key stakeholders, partners, and collaborators, can take now and in the near future to address important health questions related to the health and well-being of future generations.

The committee commends the efforts of VA and Congress to address veterans’ concerns about generational health effects and cautions all involved that developing an increased understanding of these critical issues will be a long and complex undertaking. The committee also believes that the results and deliverables that arise from such an investment 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 generations to come.

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