Conclusions and Recommendations
This final chapter presents a synopsis of the conclusions drawn by the committee regarding statistical associations between diseases and possible exposure to dioxin and other chemical compounds in herbicides used in Vietnam. It also presents the committee’s recommendations regarding future research on Vietnam veterans’health.
SYNOPSIS OF COMMITTEE CONCLUSIONS
Under the aegis of Public Law (PL) 102-4, the current committee reviewed and evaluated the available scientific evidence regarding the associations between diseases and exposure to dioxin and other chemical compounds in herbicides used during the Vietnam War.1 In reaching its conclusions, it weighed the strengths and limitations of the epidemiologic evidence reviewed in its report and in previous Veterans and Agent Orange (VAO) reports. Although the studies published since Update 2014 are the subject of a detailed evaluation here, the committee drew its conclusions in the context of the entire body of literature. The contribution of recent publications to the scientific evidence base is emphasized in this report, but the weight of the evidence in its totality was the primary consideration guiding the evaluation of health outcomes. Although the study subjects in much of the new literature reviewed here were not the male U.S. Vietnam veterans who
1 These chemicals—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid—and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) are collectively referred to as the “chemicals of interest” (COIs) in the report.
constitute most of the population affected by the VAO reports, the new studies from U.S. and other Vietnam veteran populations provided pertinent information.
Epidemiologic methods and analytic capabilities have continued to improve over the period in which the previous VAO updates have been conducted. As has been the case for recent updates, a considerable number of the new studies presented their results in terms of serum TCDD concentrations or total toxic equivalents (TEQs), which are particularly useful for the committee’s purpose because they provide a cumulative measure of exposure to all dioxin-like chemicals.
The committee also notes that considerable experimental data related to the biologic plausibility of the health conditions statistically associated with exposure to the components of the herbicides sprayed in Vietnam have emerged since the beginning of the VAO report series. These findings help to inform decisions about how to categorize the degree of association for individual conditions. On the basis of its evaluation of epidemiology studies of Vietnam-veteran populations and of occupationally and environmentally exposed populations, and aided by experimental studies on biologic plausibility, the committee assigned each health outcome to one of four categories of relative certainty of association with exposure to the herbicides used in Vietnam or to any of their components or contaminants.
Principal Changes from Previous Updates
The application of the committee’s evaluation methodology led to three principal changes in the conclusions regarding exposure to the chemicals of interest (COIs) and adverse health outcomes reported in Update 2014. They are explicated in the preceding chapters and summarized below.
First, the current committee concluded that the information now assembled constitutes sufficient evidence of an association between exposure to at least one of the COIs and hypertension. As detailed in Chapter 10, the decision to change the classification from limited or suggestive evidence of an association was motivated in large part by the work of Cypel and colleagues (2016). These investigators conducted a study on the population of interest, U.S. Vietnam veterans (specifically, the Army Chemical Corps), that was characterized by a large sample size, appropriate controls (non-Vietnam-deployed sprayers, Vietnam-deployed non-sprayers, and non-Vietnam-deployed non-sprayers), and validated endpoints (self-reported physician-diagnosed hypertension that was confirmed by medical record reviews and serum TCDD measurements in a subset of participants). The statistical analyses conducted were robust, used state-of-the art methods, and adjusted for relevant confounders. The study clearly showed that self-reported hypertension rates were the highest among Vietnam-deployed sprayers (81.6%) followed by non-Vietnam-deployed sprayers (77.4%), Vietnam-deployed nonsprayers (72.2%), and non-Vietnam-deployed non-sprayers (64.6%), providing a significant association with exposure. Among Vietnam-deployed veterans, there was a significantly elevated association between the odds of hypertension for
sprayers versus non-sprayers that remained after adjustment for potential confounders (odds ratio [OR] = 1.77, 95% confidence interval [CI] 1.35–2.30). Similarly, for those veterans who did not deploy to Vietnam, self-reported hypertension was significantly elevated when sprayers were compared with non-sprayers (OR = 1.72, 95% CI 1.31–2.26). When considered in light of other new research and earlier papers that demonstrated a consistency in the direction and magnitude of this effect—notably Kang et al. (2006), Cypel and Kang (2010), and multiple publications from the Air Force Health Study (AFHS; AFHS, 1995, 2000, 2005)—the committee found that this body of literature constituted sufficient evidence of an association.
The committee also concluded (as detailed in Chapter 7) that there was sufficient evidence of an association between exposure to at least one of the COIs and a previously unclassified health condition, monoclonal gammopathy of undetermined significance (MGUS). MGUS is a precursor to multiple myeloma, although only an estimated 1% of cases of it progress to multiple myeloma each year. It is a clinically silent condition defined by the presence of a monoclonal antibody, antibody heavy chain, or antibody light chain in the blood or urine of a person lacking symptoms or signs of a more serious plasma cell dyscrasia. The foundation of this finding was a well-conducted study by Landgren et al. (2015) that examined data and biospecimens from a population of veterans that included participants with known exposure to herbicides in Vietnam: the AFHS cohort. Landgren and colleagues used previously measured serum levels of TCDD and performed a new assay of 958 serum samples to detect MGUS. Known confounders, including age, race, body mass index, smoking and drinking history, and a history of radiation therapy or chemotherapy, were considered. The investigators found that the prevalence of MGUS in veterans involved in herbicide spray operations (7.1%) was higher than in comparison veterans (3.1%) (adjusted OR = 2.37, 95% CI 1.27–4.44; p = 0.007). The direct relevance of the exposure and exposed population, combined with the high quality of the study and underlying database, were persuasive in convincing the committee that there was sufficient evidence of an association.
Finally, the committee—after extensive deliberations regarding the strengths and weaknesses of the new evidence and evidence from studies reviewed in previous VAO reports—could not come to a consensus on whether the available scientific information regarding exposure to the COIs and type 2 diabetes should continue to be categorized as limited or suggestive or whether it meets the criteria for sufficient evidence of an association (see Chapter 10). Newly and previously reviewed studies consistently show a relationship between well-characterized exposure to dioxin and dioxin-like chemicals and measures of diabetes health outcomes in diverse cohorts, including Vietnam veteran populations. However, the lack of exposure specificity and the potential for uncontrolled confounding that characterized many of these studies complicates any attribution of the outcome to the COIs. It was therefore not clear to the committee as a whole whether a category change was appropriate.
Health Outcomes Identified by the Department of Veterans Affairs for Specific Focus
The Department of Veterans Affairs (VA) also asked the committee to specifically focus on three health outcomes: possible generational health effects that may be the result of herbicide exposure among male Vietnam veterans, myeloproliferative neoplasms, and glioblastoma multiforme.
Chapter 8 summarizes the available literature on the effects of exposure to the COIs on the reproductive health of Vietnam veterans and on the health of their descendants. This is a burgeoning area of research, and there were several new studies for the committee to consider. Few of them address Vietnam veterans specifically, however, and almost all of those that were conducted on other populations have weaknesses—prominently, different exposures than those experienced by veterans and also poor exposure characterization—that limit their usefulness in assessing risks for veterans. Some find associations between exposures and various outcomes, but there are no circumstances for which there is a consistent and compelling body of evidence that would lead the committee to conclude that there might be limited or suggestive or sufficient evidence of an association between an exposure to a COI and a particular outcome. Transgenerational effects—those that might occur in veterans’ grandchildren and subsequent generations in which gestational exposure did not take place—are of great interest to veterans, but no epidemiological literature exists to evaluate whether exposure to the COIs might lead to such outcomes.
As further delineated below, the committee strongly believes that more work in this area is warranted. It concurs with the Update 2014 committee that it is critical that such research include animal studies in order to elucidate whether and which mechanisms for intergenerational and transgenerational effects might exist. It is, in principle, possible to do studies on the health of children and grandchildren of veterans, but it must be understood up front that such complex studies will need to be carefully planned and conducted if they are to yield meaningful results. Voluntary participation surveys and registries relying on self-reported information will not be helpful. The 2018 National Academies of Sciences, Engineering, and Medicine report Gulf War and Health, Volume 11: Generational Health Effects of Serving in the Gulf War (NASEM, 2018) addresses how studies of health outcomes in the progeny of veterans might be conducted.
Myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes, addressed in Chapter 7, are diseases of the blood cells and bone marrow. VA asked that MPNs be explicitly examined as part of the consideration of the literature concerning leukemias and related diseases. However, after conducting a targeted search of scientific and medical databases (delineated in Box 3-1), the committee was unable to identify any papers that addressed the outcome with the exception of Yi and Ohrr (2014) (reviewed in Update 2014), which assessed cancer incidence among Korean veterans who had served in Vietnam between 1964 and 1973.
Those authors reported non-significant and imprecise increased risks of myeloproliferative disease and myelodisplastic syndrome in internal comparisons of high- and low-exposure groups, based on so-called exposure opportunity scores.2 The organization MPN Advocacy and Education International presented anecdotal information on MPNs in Vietnam veterans for the committee’s consideration, but this was not usable for drawing conclusions.
The committee observes that, in general, those studies that looked at exposure to the COIs and hematological outcomes have generated much more compelling results—including results on abnormalities of lymphoid development and immune function such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma, and MGUS—than have those that examined whether myeloid neoplasms or MPNs have some relation with the COIs.
Given the absence of new studies, the paucity of epidemiologic studies in general, and the lack of information on the biologic plausibility of a connection between exposures to the COIs and abnormalities of hematopoietic cells associated with nonmalignant bone marrow–derived diseases, the committee concluded that there was inadequate or insufficient evidence of an association between exposure to the COIs and MPNs. Because the outcome has not been subject to previous research attention and is of interest to veterans, the committee recommends that investigators examine existing databases on myeloid diseases to determine whether there are data available that would allow for an evaluation of MPNs in Vietnam veterans and others who have been exposed to dioxin and the other COIs.
The scientific literature regarding exposure to the COIs and brain and other nervous system cancers, including glioblastoma multiforme (often abbreviated as glioblastoma), has been examined since the first VAO report. The body of evidence that has been developed, which is summarized in Chapter 7, has not found statistically significant associations between exposure and any relevant outcome in studies performed on Vietnam-veteran, occupational, or environmental cohorts. These studies have by and large been underpowered because of the relative rarity of these cancers. Given the limited epidemiologic data available on glioblastoma, the committee heard invited presentations from two experts on the disease. While their presentations to the committee were helpful and impressive, demonstrating that the biological understanding of glioblastoma in particular is rapidly advancing, they reinforced the absence of clear data suggesting that the COIs are associated with the occurrence of brain cancers. Information on glioblastomas in Vietnam veterans submitted for the committee’s consideration by the Sierra Valley Cancer Registry Services, Inc., was, in part, anecdotal and without documented levels of exposure and was therefore of limited usefulness for the purpose of drawing conclusions.
2 In brief, an exposure opportunity score is a means of quantifying exposure that accounts for the quantity of herbicide sprayed and the distance in time and space from the spraying (S. D. Stellman and J. M. Stellman, 2004).
Furthermore, the committee did not identify any animal studies that have reported an association between exposure to the COIs and any brain cancer. While some studies have put forward mechanisms that might explain why dioxin exposure would be associated with glioblastoma, the information reviewed by the committee along with the presentations it received from experts in the field were not sufficient to alter the conclusion of previous reports that the evidence is inadequate or insufficient to determine whether there is an association between exposure to the COIs and brain or other nervous system cancers. The committee believes it is appropriate for VA to be mindful of the concerns raised about the possible association between Vietnam service and glioblastoma, but it observes that the outcome is so rare and the information concerning herbicide exposures so imprecise that it is doubtful that any logistically and economically feasible epidemiologic study of veterans—no matter how well designed or executed—would produce meaningful results. The committee therefore recommends that epidemiologic studies of glioblastoma in Vietnam veterans should not be pursued and that VA should instead focus on fostering advancements in other areas that may be used to inform improved treatment options.
Other Health Outcomes
Table 12-1 summarizes the conclusions regarding exposure to the COIs and health outcomes, with changes to the categorizations determined by the committee for Update 2014 noted in boldface. As mandated by PL 102-4, the distinctions among categories are based on statistical association and not on strict causality. The committee was directed to review the scientific data, not to recommend VA policy, and, therefore, the conclusions presented in Table 12-1 are not intended to imply or suggest policy decisions. Instead, the conclusions are based on observed associations between exposure and health outcomes in human populations. These categorizations do not address the likelihood that the health problems of any one individual are associated with or caused by the chemicals in question.
OTHER COMMITTEE RECOMMENDATIONS
As part of their charge, all VAO committees have been asked to offer recommendations concerning the need for additional scientific studies and research to resolve areas of continuing scientific uncertainty concerning the health effects of exposure to the COIs. The previous update of the VAO series (the tenth update; Update 2014) was originally understood to be the last of the reports mandated by the Agent Orange Act (PL 102-4, renewed in PL 107-103, and subsequently extended). The committee responsible for that report thus considered it appropriate to compile the recommendations made by prior VAO committees and to consider, in light of the lessons learned in this process, what would be the most important activities to undertake in the future. They produced two tables as part of this effort:
TABLE 12-1 Summary of the Eleventh Biennial Update Findings on Vietnam-Veteran, Occupational, and Environmental Studies Regarding Scientifically Relevant Associations Between Exposure to Herbicides and Specific Health Outcomes
Sufficient Evidence of an Association
Epidemiologic evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between exposure to herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence.b For example, if several small studies that are free of bias and confounding show an association that is consistent in magnitude and direction, there could be sufficient evidence of an association. There is sufficient evidence of an association between exposure to the chemicals of interest and the following health outcomes:
Soft-tissue sarcoma (including heart)
* Non-Hodgkin lymphoma
* Chronic lymphocytic leukemia (including hairy cell leukemia and other chronic B-cell leukemias)
* Hodgkin lymphoma Chloracne
Hypertension (category change from Limited or Suggestive in Update 2014)
Monoclonal gammopathy of undetermined significance (MGUS) (newly considered condition)
The committee did not reach consensus on whether the evidence regarding type 2 diabetes (mellitus) was more properly classified as Sufficient or Limited or Suggestive.
Limited or Suggestive Evidence of an Association
Epidemiologic evidence suggests an association between exposure to herbicides and the outcome, but a firm conclusion is limited because chance, bias, and confounding could not be ruled out with confidence.b For example, a well-conducted study with strong findings in accord with less compelling results from studies of populations with similar exposures could constitute such evidence. There is limited or suggestive evidence of an association between exposure to the chemicals of interest and the following health outcomes:
Cancer of the lung, bronchus, or trachea
Cancer of the urinary bladder
* Multiple myeloma
* AL amyloidosis
Early-onset peripheral neuropathy
Parkinson disease (including Parkinsonism and Parkinson-like syndromes)
Porphyria cutanea tarda
Ischemic heart disease
The committee did not reach consensus on whether the evidence regarding type 2 diabetes (mellitus) was more properly classified as Sufficient or Limited or Suggestive.
Inadequate or Insufficient Evidence to Determine an Association
The available epidemiologic studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding, have inadequate exposure assessment, or fail to address latency. There is inadequate or insufficient evidence to determine association between exposure to the chemicals of interest and the following health outcomes that were explicitly reviewed:
Cancers of the oral cavity (including lips and tongue), pharynx (including tonsils), or nasal cavity (including ears and sinuses)
Cancers of the pleura, mediastinum, and other unspecified sites in the respiratory system and intrathoracic organs
Colorectal cancer (including small intestine and anus)
Hepatobiliary cancers (liver, gallbladder, and bile ducts)
Bone and joint cancers
Non-melanoma skin cancer (basal-cell and squamous-cell)
Cancers of reproductive organs (cervix, uterus, ovary, testes, and penis; excluding prostate)
Renal cancer (kidney and renal pelvis)
Cancers of brain and nervous system (including eye)
Endocrine cancers (thyroid, thymus, and other endocrine organs)
Leukemia (other than chronic lymphocytic leukemia, including hairy-cell leukemia and other chronic B-cell leukemias)
Other myeloid diseases (including myeloproliferative neoplasms)
Cancers at other and unspecified sites
Spontaneous abortion (other than after paternal exposure to TCDD, which appears not to be associated)
Neonatal or infant death and stillbirth in offspring of exposed people
Low birth weight in offspring of exposed people
Birth defects in offspring of exposed people, including spina bifida
Childhood cancer (including acute myeloid leukemia) or other adverse health outcomes in offspring of exposed people
Neurobehavioral disorders (cognitive and neuropsychiatric)
Neurodegenerative diseases, excluding Parkinson disease
Chronic peripheral nervous system disorders
Respiratory disorders (wheeze or asthma, chronic obstructive pulmonary disease, and farmer’s lung)
Gastrointestinal, metabolic, and digestive disorders (changes in hepatic enzymes, liver disorders including cirrhosis, lipid abnormalities, and ulcers)
Immune system disorders (immune suppression, allergy, and autoimmunity)
Circulatory disorders (other than hypertension, ischemic heart disease, and stroke)
Disruption of thyroid homeostasis (other than hypothyroidism)
Kidney and urinary disorders (including chronic kidney disorder, differences in kidney function, nephropathy, and end stage renal disorder)
Chronic skin disorders (including skin infections and changes in skin pigmentation)
The committee used a classification that spans the full array of cancers. However, reviews for non-malignant conditions were conducted only if they were found to have been the subjects of epidemiologic investigation or at the request of the Department of Veterans Affairs. By default, any health outcome on which no epidemiologic information has been found falls into this category.
Limited or Suggestive Evidence of No Association
Several adequate studies, which cover the full range of human exposure, are consistent in not showing a positive association between any magnitude of exposure to a component of the herbicides of interest and the outcome. A conclusion of “no association” is inevitably limited to the conditions, exposures, and length of observation covered by the available studies. In addition, the possibility of a very small increase in risk at the exposure studied can never be excluded. There is limited or suggestive evidence of no association between exposure to the herbicide components of interest and the following health outcome:
Spontaneous abortion after paternal exposure to TCDD
aHerbicides indicates the following chemicals of interest: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin), cacodylic acid, and picloram. The evidence regarding association was drawn from veteran, occupational, and environmental cohort studies in which people were exposed to the herbicides used in Vietnam, to their components, or to their contaminants.
bEvidence of an association is strengthened by experimental data supporting biologic plausibility, but its absence would not detract from the epidemiologic evidence.
*The committee notes the consistency of these findings with the biologic understanding of the clonal derivation of lymphohematopoietic cancers that is the basis of the World Health Organization classification system (Campo et al., 2011; see table here: www.ncbi.nlm.nih.gov/pmc/articles/PMC3109529/table/T1, accessed May 17, 2018).
- a compendium of the recommendations of prior committees condensed and sorted into topic areas, with comments on what response these recommendations received from VA, the Department of Defense, and other parties (Update 2014, Table 14-2, pp. 910–917), and
- a summary of the future activities the committee considered most important for monitoring and evaluating the health issues of Vietnam veterans and other veterans who might experience service-related health problems long after discharge (Update 2014, Table 14-3, pp. 918–919).
Generally speaking, the recommendations of previous VAO committees fell into four primary areas: better management of veterans’ health information; additional epidemiologic studies; the improvement of exposure estimation; and
priority areas for toxicologic research. Suggested future activities included initiatives in these areas plus other initiatives related to the collection and analysis of additional information on Vietnam veterans’ service, exposures, and health. Complete details may be found in Chapter 14 of the Update 2014 report.
While there have been a few laudable exceptions—notably, the initiation of additional epidemiologic studies on Vietnam veterans, the development of a herbicide exposure assessment model for use in studies of Vietnam veterans, and the fostering of additional research on the data and biospecimens collected in the course of the AFHS3—there has been no known follow-up to the vast majority of recommendations that have been offered. The current committee did not choose to revisit this issue in general, concluding that the Update 2014 committee had effectively covered it.
It does observe, though, that the very first VAO (1994) indicated that “carefully conducted epidemiologic studies—with adequate sample size to detect elevated associations—of the reproductive history of individuals with occupational or environmental exposure to herbicides and dioxin are . . . needed” (p. 731). Several subsequent volumes (Updates 2006, 2008, 2010, 2012, and 2014; summarized in Table 12-2) have echoed and expanded on this. The current committee is in agreement with these sentiments and therefore recommends further specific study of the health of offspring of male Vietnam veterans.
The Update 2014 committee also offered suggestions for research activities that should follow the end of the VAO report series. Several of these, summarized in Table 12-3, addressed reproductive outcomes. As that committee noted, although progress has been made in understanding the health effects of exposure to the COIs and the mechanisms underlying these effects, significant gaps in our knowledge remain. Many additional opportunities for progress via continuing and new toxicologic, mechanistic, and epidemiologic research exist. Such work should include efforts to gain new knowledge through the integration of existing Department of Defense and VA databases. While such research opportunities were mentioned in previous VAO updates, the Update 2014 committee restated them to emphasize its conviction that more progress should be made in the fields noted. This committee concurs in this assessment and endorses the recommendations offered in Table 12-3, noting that research in the rapidly advancing field of epigenetics appears to hold particular promise. Furthermore, the committee observes that VA’s Vietnam Era Health Retrospective Observational Study (VE-HEROeS)—a study of the health and well-being of U.S. Vietnam and Vietnam-era veterans—was under way at the time this report was completed and that it, along with other ongoing Vietnam veteran research efforts, holds the promise of adding to the body of knowledge.
3 The Institute of Medicine publications Disposition of the Air Force Health Study (IOM, 2006) and The Air Force Health Study Assets Research Program (IOM, 2015) provide details of this work.
TABLE 12-2 Compendium of Research Recommendations from Previous Veterans and Agent Orange Series Reports Related to Effects on Veterans’ Descendants (excerpted, adapted, and updated from Update 2014, Table 14-2)
|Recommendation Focus Area||Volume Initially Recommended||Follow-Up?|
|Army Chemical Corps (ACC)|
|Study paternally mediated effects on health outcomes in offspring.||Update 2006||No known follow-up|
|Air Force Health Study (AFHS)|
|Study the potential for paternally mediated effects on health outcomes in offspring.||Update 2006||No known follow-up|
|Comprehensive longitudinal analysis of the AFHS data collected in the six intensive medical-cycle examinations particularly concerning birth defects in veterans’ offspring, making use of the available exposure data.||Update 2008||No known follow-up|
|National Institute for Occupational Safety and Health (NIOSH)|
|Conduct epidemiologic studies—with adequate sample size to detect elevated associations—of the reproductive history of individuals with occupational or environmental exposure to herbicides and dioxin.||VAO||As noted in Chapter 5, NIOSH has, at its own instigation, collected data on and followed several groups of U.S. workers exposed to the committee’s COIs since the early 1990s.|
|International Agency for Research on Cancer (IARC)|
|Carefully conducted epidemiologic studies—with adequate sample size to detect elevated associations—of the reproductive history of individuals with occupational or environmental exposure to herbicides and dioxin are recommended.||VAO||No known follow-up|
|Recommendation Focus Area||Volume Initially Recommended||Follow-Up?|
|Other Recommended Epidemiologic Studies and Analyses:|
|An ad hoc group should conduct a meta-analysis of the current epidemiologic studies of male populations exposed to COIs and the risk of birth defects in offspring.||Update 2006||No known follow-up (Given the paucity of studies of only paternal transmission and the extremely heterogeneous study designs and exposures, meta-analyses no longer seems a plausible approach to evaluating birth defects [or any other health outcome].)|
|Investigate possible effects in offspring of Vietnam veterans (especially for birth defects or developmental disease, including cognitive and developmental effects in children and possibly grandchildren), especially those associated with paternal exposures.||Update 2006||No known follow-up|
|Conduct studies of defined clinical health conditions in mature offspring following exposure of either parent, rather than more investigations of physiological biomarkers that may merely be predictive of disease development later in life.||Update 2010||No known follow-up|
|Develop epidemiologic protocols to address whether adverse effects are being manifested in later generations as a result of paternal exposure (in the absence of maternal exposure, focusing on those organ systems that have shown the greatest impact following maternal exposure, including neurologic, immune, and endocrine effects). Consideration must be given to the minimum sample size needed to detect changes, if present, and to which outcome measures would be most sensitive and reliable.||Update 2010||No known follow-up|
|Case-control study should be used to explore whether information about Vietnam exposure or specific herbicide exposure could be ascertained in any of the many birth cohorts that have been established in the past several decades (especially for very uncommon health outcomes). To home in on a paternal effect, however, it will be necessary to establish that the mothers did not have the opportunity for other than background exposure to the chemicals of interest.||Update 2010||No known follow-up|
|Animal models are needed to elucidate disease mechanisms and progression, including transgenerational or paternally mediated effects.||Update 2006||No known specific follow-up of the committee’s recommendation, although numerous animal studies have been conducted since the report was published.|
|Toxicological investigations of the potential for the COIs (particularly TCDD) to induce epigenetic modifications, with special attention to the capacity for paternal transmission of such effects, should be conducted.||Update 2010||No known follow-up|
|Animal studies of the mechanisms of inhibition of fetal growth, particularly in male offspring, after maternal exposure could help to elucidate findings seen in some epidemiologic studies that examined maternal exposure and birth weight.||Update 2012||No known follow-up|
|Given the current concern among male veterans about the transmission of adverse effects to their descendants, focused use of animal models to investigate the possibility of paternal exposure contributing to the development of disease in offspring would be very informative.||Update 2014||No known follow-up|
TABLE 12-3 Suggested Activities to Follow the Completion of the Veterans and Agent Orange Report Series Mandated by the Agent Orange Act Related to Effects on Veterans’ Descendants (excerpted from Update 2014, Table 14-3)
|OVERSIGHT OF LONG-TERM HEALTH STATUS OF DEPLOYED SERVICE MEMBERS|
|Very careful review of evidence concerning whether paternal exposure to any toxicant has definitively been demonstrated to result in abnormalities in even the first generation of offspring. Careful assessment of the risks to offspring that may arise from maternal exposure is also merited, given the greatly increased number of women now serving in the military.|
|Air Force Health Study (AFHS)
Comprehensive longitudinal analysis of the AFHS data collected in the six intensive medical-cycle examinations (including birth defects in veterans’ offspring), making use of the available exposure data.
Use AFHS samples for study of epigenetic changes and definition of biomarkers of exposure and effect.*
|Other Epidemiology Goals
Pursue development of protocols that could feasibly and efficiently investigate paternal transmission of adverse effects to offspring at birth or manifesting with maturation that have sufficient power for convincing findings. The logistics of attempting to detect adverse effects in the grandchildren of Vietnam veterans would be considerably more challenging.
|Foster investigation of epigenetic changes in both somatic tissues and germ cells and during gestation.
Without sophisticated and specific markers of environmentally induced epigenetic activity, epidemiologic investigations will not be able to distinguish the mechanisms inducing any observed adverse health effects in exposed people or their offspring.
Fully investigate whether paternally transmitted adverse effects occur in animal models.
*A pilot study by Boekelheide and colleagues—described in IOM (2005)—proposed to use a “new epigenome-wide molecular approach to detect dioxin exposure-related alterations in DNA methylation in biospecimens from the Air Force Health Study” (p. 112). Proof-of-concept work was conducted, but the project was not carried forward due to lack of funding.
In the course of carrying out its Statement of Task, the committee has offered myriad criticisms of the conduct of studies of Vietnam veterans’ health, pointing out specific weaknesses and shortcomings in particular papers along with widespread (although not universal) issues such as poor exposure characterization, failure to fully control for confounding influences on outcomes, and sample sizes that are inadequate for drawing statistically meaningful results. The committee wishes to make clear, though, that the difficulty in conducting research on Vietnam veteran health issues should not act as a barrier to carrying out such work. There are many questions regarding veterans’ health that cannot be adequately answered by examining superficially analogous exposures and outcomes in other populations. It is only through research on veterans themselves that the totality of the military service experience can be properly accounted for.