The committee’s findings for deployment-related exposures, pesticides, combustion products, and solvents, as detailed in Chapters 4 through 7, are summarized here. During the evaluation process, the committee identified important data and knowledge gaps and methodological constraints that hinder an understanding of how veterans’ exposures during deployment might affect their children and grandchildren. The committee emphasizes the need to interpret the conclusions in these chapters and also any future research within the broader context of both the veterans’ and their descendants’ exposures over their lifecourses. In addition to the committee’s findings on the basis of the epidemiologic literature, there is a growing body of research on potentially acquired generational effects induced by epigenetic changes. Evidence linking epigenetic changes to health effects in descendants is being developed but is currently insufficient to identify specific associations with the deployment exposures discussed in this report. The committee emphasizes that it reviewed the literature on the exposures indicated in the Gulf War legislation and in other relevant reports (see Chapter 1). However, the literature on each toxicant was not consistent in terms of quantity, quality, or the health effects that were examined and, therefore, the lack of information on some toxicants should not be taken to mean that there are no effects from those toxicants, only that the effects may not have been studied or identified in the published literature.
The committee was charged with summarizing the strength of the scientific evidence regarding exposure to the deployment toxicants identified in the Gulf War legislation (P.L. 105-277 and P.L. 105-368, see Chapter 1) and the reproductive, developmental, and generational effects that may be associated with them, with a particular focus on the health of children of deployed veterans. While both epidemiologic and toxicologic studies were evaluated for health outcomes from the exposures of concern, as described in Chapters 4 through 7, the committee identified categories of association based only on the human data. Mechanistic animal model studies provided additional data that were not available from the human studies. The associations identified by the committee in its review of the literature are provided in Table 8-1 for reproductive effects in men and women and adverse pregnancy outcomes and in Table 8-2 for developmental effects.
TABLE 8-1 Summary of Categories of Association for Reproductive Effects and Adverse Pregnancy Outcomes*
|Toxicant||Categories of Association|
|Deployment||Reproductive effects in men or women; adverse pregnancy outcomes|
|Sarin/cyclosarin||Reproductive effects in men or women; adverse pregnancy outcomes|
|Sulfur mustard||Reproductive effects in men||Reproductive effects in women; adverse pregnancy outcomes|
|Leishmaniasis||Adverse pregnancy outcomes||Reproductive effects in men or women|
|Anthrax vaccine||Reproductive effects in men or women; adverse pregnancy outcomes|
|Depleted uranium||Reproductive effects in men or women; adverse pregnancy outcomes|
|Pyridostigmine bromide||Reproductive effects in men; adverse pregnancy outcomes|
|Hexavalent chromium||Reproductive effects in men||Adverse pregnancy outcomes||Reproductive effects in women|
|Organophosphate pesticides||Reproductive effects in men||Reproductive effects in women; adverse pregnancy outcomes|
|Carbamate pesticides||Reproductive effects in men||Reproductive effects in women; adverse pregnancy outcomes|
|Pyrethroids||Reproductive effects in men||Reproductive effects in women; adverse pregnancy outcomes|
|Lindane||Reproductive effects in women||Reproductive effects in men; adverse pregnancy outcomes|
|DEET||Reproductive effects in men or women; adverse pregnancy outcomes|
TABLE 8-1 Continued
|Toxicant||Categories of Association|
|Particulate matter||Adverse pregnancy outcomes||Pregnancy-induced hypertensive disorders||Reproductive effects in men or women|
|Polycyclic aromatic hydrocarbons||Reproductive effects in men; adverse pregnancy outcomes||Reproductive effects in women|
|Polychlorinated dibenzodioxins/furans||Reproductive effects in men or women; adverse pregnancy outcomes|
|Exhaust||Reproductive effects in men or women; adverse pregnancy outcomes|
|Fuels||Reproductive effects in men or women; adverse pregnancy outcomes|
|Benzene||Reproductive effects in men||Reproductive effects in women; adverse pregnancy outcomes|
|Toluene||Reproductive effects in men or women; adverse pregnancy outcomes|
|Xylenes||Reproductive effects in men or women; adverse pregnancy outcomes|
|Trichloroethylene||Reproductive effects in men; adverse pregnancy outcomes||Reproductive effects in women|
|Tetrachloroethylene||Reproductive effects in men or women; adverse pregnancy outcomes|
|Glycols and glycol ethers||Reproductive effects in men||Reproductive effects in women; adverse pregnancy outcomes|
* There were no toxicants for which sufficient evidence of a causal association was found between exposure to that toxicant and reproductive effects, nor were there any toxicants for which there was limited/suggestive evidence of no association between exposure and reproductive effects.
TABLE 8-2 Summary of Categories of Association for Developmental Effects*
|Toxicant||Categories of Association|
|Sulfur mustard||Developmental effects|
|Depleted uranium||Developmental effects|
|Pyridostigmine bromide||Developmental effects|
|Hexavalent chromium||Developmental effects|
|Organophosphate pesticides||Neurodevelopmental effects||Other developmental effects|
|Carbamate pesticides||Developmental effects|
|Pyrethroid insecticides||Developmental effects|
|Particulate matter||Respiratory effects; neurodevelopmental effects||Other developmental effects in children|
|Polycyclic aromatic hydrocarbons||Birth defects; childhood cancer; neurodevelopmental effects; respiratory effects||Other developmental effects|
|Polychlorinated dibenzodioxins/furans||Developmental effects|
|Benzene||Leukemia||Other developmental effects|
|Glycols and glycol ethers||Birth defects||Other developmental effects|
* There were no toxicants for which sufficient evidence was found of a causal association between prenatal exposure to that toxicant and developmental effects, nor were there any toxicants for which there was limited/suggestive evidence of no association between prenatal exposure and developmental effects.
None of the toxicants examined by the committee were found to have a causal relationship with reproductive or developmental effects. The toxicants that were considered to have sufficient evidence of an association with reproductive effects were hexavalent chromium (Cr6), carbamate pesticides, and particulate matter (PM). Cr6 exposures were found to be associated with pregnancy loss and broad changes in semen parameters. Carbamate pesticide exposures were found to be associated with reproductive effects in men, and PM exposure was associated with preterm birth and low birth weight.
There was limited/suggestive evidence for several toxicants having associations with reproductive effects in either men or women. Male reproductive effects, particularly altered semen parameters, were associated with sulfur mustard, organophosphate (OP) and pyrethroid pesticides, polycyclic aromatic hydrocarbons (PAHs), benzene, trichloroethylene (TCE), and glycols and glycol ethers. Female reproductive effects, specifically changes in endometrial tissue, were associated with lindane. Limited/suggestive evidence of associations specific to adverse pregnancy or birth outcomes was found for infection with Leishmaniasis during pregnancy, PAHs, TCE, and glycols and glycol ethers, and pregnancy-induced hypertensive disorders with PM.
Toxicants considered by the committee to have sufficient evidence of associations with developmental effects in children were limited to prenatal Cr6 exposure with structural defects and delayed sexual maturation, prenatal exposure to OP pesticides with neurodevelopmental effects, and prenatal benzene exposure with childhood leukemia. Conclusions of limited/suggestive evidence of associations with developmental effects were found for pyrethroid insecticide exposures and also TCE and tetrachloroethylene exposures, whereas congenital malformations were associated with glycols and glycol ethers. The committee also found limited/suggestive evidence of associations between exposure to PM and PAH and respiratory and neurodevelopmental effects in children, with additional associations between PAH exposure and birth defects and childhood cancer. All these associations are limited to prenatal exposures.
The committee considered associations between deployment exposures and reproductive and developmental effects on the basis of human data. For some toxicants, human data were lacking, but there was a relative abundance of animal data. The toxicants for which animal data were robust, but a lack of human data precluded the committee from assigning a stronger category of association, are 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;
- Xylenes and developmental effects in offspring;
- TCE and reproductive effects in females; and
- Dioxin and reproductive effects in males and females.
On one hand, the use of animal models permits greater control with defined exposures. On the other hand, these models may lack temporal resolution since only specific points in time are considered. Often, they do not model the cumulative effect of exposures to mixtures that are observed in humans. In addition, adsorption, distribution, metabolism, and excretion processes can vary widely between humans and other species, and effects seen in one species might not be seen in another.
The committee’s conclusions are limited by the availability of pertinent evidence. In its review of the literature, the committee identified data and knowledge gaps that were used to inform the research agenda detailed in Chapter 9. Some of the priorities for research are discussed below. Data were often not available for an evaluation of the critical windows of exposure for developmental and male and female reproductive effects. Very limited data were found on actual exposure assessment and epidemiological research, the majority of which consisted of civilian-based studies that did not mimic deployment exposures. How these data gaps resulted in a lack of knowledge with which to inform associations between deployment exposures and outcomes is discussed briefly below.
Developmental and Reproductive Effects
Developmental effects were almost exclusively studied with prenatal exposures. Studies of preconception exposures are virtually nonexistent for all the toxicants reviewed in Chapters 4 through 7. Most of the evidence gathered by the committee was on long-term, continuous occupational and environmental exposures, none of which mimic the potential short-term exposures experienced by veterans during deployment. Such gaps limited the committee’s ability to draw conclusions about the potential health effects specific to veterans and their descendants.
The effects of toxicants on female reproductive capacity and function from oocyte to the birth of a child and the ability of that child to reproduce have not been studied in depth. Although effects on sperm have been evaluated for many toxicants, few studies have assessed the reproductive effects in women (Krulewitch, 2016). One area that has been studied in animal models is the apparent link between benzo[a]pyrene (BaP) exposure and effects on endometrial and ovarian function (Li et al., 2017; Luderer et al., 2017).
Unlike Gulf War and Post-9/11 veterans, Vietnam veterans have been extensively studied for the existence of reproductive and developmental health effects. Despite the vast amount of data available from this population, no definitive effects on male or female reproductive endpoints have been identified (NASEM, 2016). The Volume 11 committee acknowledges that limited data on 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) exposures in nonveteran populations show altered semen parameters in men and increased time to pregnancy in women, but those exposures are not similar to what most veterans experienced (e.g., low levels of exposure associated with combustion from burn pits). Although animal studies support specific TCDD effects on reproduction, the effects are highly species-specific, and animal responses do not consistently predict human responses because of differing sensitivities and susceptibilities. Furthermore, previous research has not addressed specific windows of susceptibility for adverse reproductive effects. Therefore, the committee has a residual concern that adverse reproductive effects may occur with different exposure scenarios, and it identifies this area as a major priority for future monitoring and research (see Chapters 9 and 10).
As noted above, many toxicants have been evaluated for their effects on semen. These evaluations typically rely on measurements of physical and morphological sperm parameters, including volume, total count, vitality, motility, and abnormalities (Cooper et al., 2010), but the particular set of measurements used varies across laboratories and studies (Auger et al., 2000). Furthermore, semen parameters are not a good surrogate for determining infertility. As Guzick et al. (2001) concluded, “Threshold values for sperm concentration, motility, and morphology can be used to classify men as subfertile, of indeterminate fertility, or fertile. None of the measures, however, are diagnostic of infertility.” Taken together, all of this results in a variability that clouds the relationship between semen parameters and
fertility (Khatun et al., 2018; Patel et al., 2017); furthermore, the studies provide no information about the health of a resulting fetus or what long-term clinical outcomes might result from toxic exposures. New and objective omics-based tests—using, for example, RNAs, proteins, and DNA methylation profiles—may provide consistent and standardized analytical methods and measures to help define a suite of parameters that better predict fertility and a father’s contribution to the birth and lifecourse of his child. Greater consistency, validity, and biological resolution of measures that are better correlated with clinical outcomes than semen parameters are needed to assess the full impact of toxicants on sperm and male reproduction and their effects on descendants.
The evidence demonstrates the potential risks to children posed by prenatal exposures to toxicants; however, as few female service members are pregnant while deployed in the theater of operation, the applicability of those conclusions to female veterans is unknown. For the few female veterans who were pregnant during deployment—as far back as Vietnam and up to the Post-9/11 era—there has been little follow-up of those pregnancies or of the children.
To understand how prenatal exposures may influence the health of children as they grow, the postnatal environment must also be considered. Prenatal exposures may be modified by postnatal exposures (and vice versa) or, alternatively, by cumulative lifecourse exposures (e.g., throughout pre- and postnatal life). A few of the studies of prenatal exposures discussed in Chapters 4 through 7 assessed the health of the children in their teenage years, but in general the studies have not assessed or controlled for the confounding effects of postnatal exposures on the child’s development and health later in life. Important health outcomes that become apparent in adolescence or adulthood (e.g., mental health conditions or illicit drug use with early life exposure to tetrachloroethylene; Aschengrau et al., 2016; Sagiv et al., 2018; and Yang et al., 2016, who assessed children up to age 14) are being studied; however, the link from prenatal exposure to adult disease requires substantial development. Thus, there is a need to assess and adjust for prenatal and postnatal experiences in future studies of preconception exposures and developmental outcomes to be able to differentiate between effects of certain exposures or windows of susceptibility.
In the absence of exposure data, biomarkers may be used as a proxy for exposure assessment. Not all chemical exposures in the human body can be measured with biomarkers, especially a long time after the exposure has taken place, and specificity may be lost. Some exposures can be measured in blood products, but other biomarkers of exposure are better measured in urine or other bodily fluids. And sometimes exposures can be determined only by measuring the breakdown products of the original chemicals—for example, dialkylphosphates (DAPs) as metabolites of OPs—which can lead to a loss of specificity since, for instance, DAPs are nonspecific metabolites of a number of OPs. Additionally, many chemicals have a relatively short half-life in the body and they can be measured only within hours or days after exposure. Therefore, a single measurement may not accurately reflect an exposure that took place over a critical window of development or reproduction, especially if the exposure scenario is variable. For many chemicals there are no laboratory methods to measure them, or the method is not considered to be of sufficient reliability or sensitivity to accurately measure relevant levels of exposure. Thus, exposure assessment especially when conducted after a long period of time—for example, after a member of the military has returned from deployment—can be a major limitation of epidemiologic investigations. Assessment issues are further discussed in Chapter 9. Another challenge is that the effects of multiple, simultaneous, or successive exposures have rarely been studied in human population, yet they more likely reflect the actual exposure scenarios. Deployed military personnel may be exposed
to environmental chemicals such as pesticides and PAHs as well as cigarette smoke and nonchemical stressors such as extreme heat, psychological stress, and radiation. Some may act on the same receptors (e.g., nicotine and OPs both act on acetylcholine neurotransmission), raising the possibility that they could enhance toxicity (see Coker et al., 2017; Woods et al., 2017).
Most of the epidemiologic research reviewed in Chapters 4 through 7 was of environmentally or occupationally exposed populations. In those populations exposure typically occurred continuously, from before conception through the development of health effects during childhood and the entire lifecourse. Veterans’ exposures happened during defined time periods, generally several months at a time, and occurred generally with little, if any, direct monitoring. The long-term health risks associated with toxicant exposures over the period of deployment generally have not characterized risks after the exposure ended, with the exception of a few occupational studies. The presentation of long-term health effects may change over time (i.e., it may appear after many years), it may stay the same for some outcomes, or it may decrease over time or be negligible soon after exposure ceases. An overview of epidemiological studies is provided in Chapter 9.
One major limitation of epidemiologic studies is the presence of modifiers of effect. Common modifiers may include lifestyle factors such as cigarette smoking and exercise, diet, a family history of the disease or condition, and sociodemographic characteristics. The difficulty in controlling for modifiers is compounded when multiple generations are evaluated over a long period of time.
The committee’s review recognizes the potential for a veteran’s preconception or prenatal exposures to result in intergenerational effects, particularly effects in his or her children (the F1 generation). Although transgenerational effects are less certain in humans, some animal studies have found effects in second (F2) and third (F3) generation offspring. The toxicants that have been studied for transgenerational effects in animals include PM, BaP, dioxin, permethrin + DEET, pesticides, stress, and fuels; none of the toxicants of concern for this report have been studied for transgenerational effects in humans (Walker et al., 2018).
Epigenetic effects resulting from a variety of prenatal exposures to PM, PAHs, polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/PCDFs), fuels, Cr6, and pesticides have been observed in various tissues and systems. To date, however, few human studies have included measures of epigenetic alterations. The presence of some epigenetic effects has been shown in toxicological studies of PCDD/PCDFs, BaP, and OP pesticides (Walker et al. 2018) and in human studies—for example, studies of the effects of PM exposure. The epigenetic literature in humans, as illustrated by studies of PM effects, relies on relatively large sets of samples and studies, such as ENVIRONAGE (ENVIRonmental influence ON early AGEing; Grevendonk et al., 2016; Janssen et al., 2012, 2013, 2015); the Children’s Health Study (Breton et al., 2016; Salam et al., 2012); PROGRESS (Programming Research in Obesity, Growth, Environment and Social Stressors; Rosa et al., 2017); and MAMC (Metropolitan Area of Mexico City; Alvarado-Cruz et al., 2017). Until recently, the majority of epigenetic studies of PM had not accounted for the variability that arises from the use of heterogeneous cell types in cord blood, placenta, and peripheral blood lymphocyte samples (see Chapter 3). Although epigenetic changes might result in clinically relevant health effects, little is understood about these mechanisms or about how the various changes—and what specific types of changes—modify the presentation of health effects.
The complexity of assessing gene x environment interactions increases when exposure to mixtures (Silva da Silva et al., 2015) and the stage of development (Soto-Martinez and Sly, 2010) are considered. A challenge to interpreting results from observational studies is that the estimates of effects are often confounded by other potential modifiers of the epigenome. Potential confounders, such as smoking, have been associated with altered DNA (Jenkins et al., 2017; Knopik et al., 2012) and are often not accounted for in analyses.
Although no human data directly describe the transgenerational effects of these exposures, there is evidence from intergenerational and transgenerational effects in animal studies that prenatal exposures, such as to BaP, can affect the development of reproductive organs and stem cells (EPA, 2017). None of the exposures considered by this committee had been studied for their potential transgenerational effects in humans, although some animal studies are discussed in earlier chapters (PM, BaP, PCDD/PCDFs, the jet fuel JP-8, permethrin + DEET mixture; Walker et al., 2018). However, there is research examining the transgenerational effects of prenatal exposures to some of the environmental stresses and toxicants that are not considered in this report. These studies include the Avon Longitudinal Study of Parents and Children, the Swedish Överkalix cohorts, and studies of the 1944–1945 Dutch famine (Pembrey et al., 2014).
The Volume 11 committee notes that pesticides, including OPs, are routinely tested for reproductive and developmental toxicity in animals and that these studies provide information on intergenerational (F0→F1) effects—that is, the effects of parental exposures in their offspring. However, studies of the transgenerational effects of OPs—that is, the effects in unexposed offspring—have not yet been conducted in animal models. In approaching the issue of pesticide transgenerational effects, the first pesticides chosen for study (e.g., vinclozolin) are well-characterized reproductive toxicants with known genetic or epigenetic effects (Walker et al., 2018). As research progresses, knowledge of the developmental and reproductive toxicity of OPs is likely to guide transgenerational studies in animal models. Nevertheless, in spite of a growing evidence base on the reproductive and developmental toxicity of OPs, such as chlorpyrifos, the exposures most relevant to Gulf War and Post-9/11 deployments—that is, preconception for both men and women and early pregnancy—have not been well studied in human populations.
Throughout the time the committee spent reviewing and evaluating the epidemiologic and toxicologic literature on deployment toxicants, as described earlier in this chapter, it identified data and knowledge gaps. These gaps included the need for better exposure assessment methods, for identifying the windows of exposure that pose the greatest risk, and for elucidating possible epigenetic effects that may result in heritable effects. Addressing these gaps using both human and animal studies will be a crucial part of helping improve our understanding of generational health effects. Approaches to conducting human studies in veterans and their children and grandchildren are described in Chapter 9, and the use of animal and mechanistic studies is discussed in Chapter 10.
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