The current committee reviewed and updated the scientific evidence published in the 2 years following the set of new studies considered in Veterans and Agent Orange: Update 20121(IOM, 2014) regarding statistical associations between diseases and possible exposure to dioxin and other chemical compounds in herbicides used in Vietnam. The publication period reviewed for this update was from October 1, 2012, to September 30, 2014. In addition, the committee evaluated the risk of disease among individuals potentially exposed to herbicides during service in Vietnam, as well as scientific studies related to plausible biologic mechanisms or causal relationships between exposure and a disease.
The committee 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 2012 are the subject of detailed evaluation here, the committee drew its conclusions in the context of the entire body of literature. The contribution of recent publications to the evidence database is emphasized in this report, but the totality of the weight
1Despite loose usage of “Agent Orange” by many people, in numerous publications, and even in the title of this series, this committee uses “herbicides” to refer to the full range of herbicide exposures experienced in Vietnam, while “Agent Orange” is reserved for a specific one of the mixtures sprayed in Vietnam.
of the evidence was the primary consideration guiding the evaluation of health outcomes. Although the study subjects in the new literature reviewed here were not the male American Vietnam veterans who constitute most of the population affected by the VAO reports, the new studies of female American Vietnam veterans and male Vietnam veterans from Korea and New Zealand provided extremely pertinent information. The findings of these investigations are especially relevant because they consisted of observations in the aging population of primary concern, Vietnam veterans.
Epidemiologic methods and analytic capabilities have continued to improve over the period in which these 10 biennial VAO updates have been conducted. As has been the case for recent updates, a considerable number of new studies presented results in terms of serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (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. It was particularly gratifying that the literature identified for the current update contained a series of papers based on an investigation of a large cohort of Korean veterans who served in Vietnam. Their health experience was analyzed in terms of several exposure metrics, including the simple proxy for herbicide exposure of deployment status and the bias-prone measure of self-perceived exposure. In addition, however, the Korean Veterans’ Health Study is the first epidemiological application of the model for generating exposure opportunity scores based on how troop movements intersected the herbicide spray missions in time and location, the development of which was fostered by early VAO committees.
In the course of reviewing the recent epidemiology literature, the committee noticed that several studies at Department of Veterans Affairs (VA) medical centers based exposure characterization upon indications of “Agent Orange exposure” in the medical records. While it is gratifying that data generated in the course of VA’s medical services are being used for research, the committee is concerned that undue confidence may be placed upon these data given the lack of validation of exposure classifiers. The committee has been unable to obtain documentation of the source of and manner in which such exposure classifiers are coded into patients’ electronic records. In the absence of standardized designations that rely on reliable methods, herbicide exposure designations derived from medical records are no more reliable than entries based on the Agent Orange Registry or simply service during the Vietnam conflict.
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 this series of VAO reports. 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, occupational, and environmental 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. The assignments were not based on a particular one of the chemicals of interest being specified as the responsible agent. This committee’s deliberations led to the addition of two findings of “limited or suggestive” evidence of association to those of previous VAO committees and modifications to two prior findings.
The committee for Update 2014 concluded that the information now assembled constituted compelling evidence for moving both bladder cancer and hypothyroid conditions into the category of limited or suggestive evidence of association with herbicide exposure from their previous positions in the inadequate or insufficient evidence category. For each of these conditions, new results from the large study of Korean veterans who served in the Vietnam War were compellingly suggestive. In the case of hypothyroid conditions, there were also new supportive epidemiologic observations. In combination with some pre-existing supportive epidemiologic findings and substantial biologic plausibility, the new information provided enough evidence to merit a change in category of association.
There has been no additional epidemiologic evidence to support the placement of spina bifida in the category of limited or suggestive evidence of association, and plausibility for paternal transmission of health problems to their offspring remains quite uncertain. Although animal studies have shown epigenetic modifications to be passed along through the male germline, as yet, this has only been the result of perinatal exposure (in utero and by lactation) in which the exposed parent is the mother. The perinatal period clearly represents a period of susceptibility for impacts on the development of both male and female fetuses and on their germlines, but this exposure scenario is not relevant for the offspring of male Vietnam veterans who were adults when the exposure of concern would have taken place. Epigenetic research has provided insights into biologic mechanisms underlying the transmission of adverse effects to offspring when an adult female is exposed, but it has not been convincingly established that harm to offspring may arise from paternal exposures experienced as an adult. Therefore, the committee concluded that spina bifida in children of male Vietnam veterans should be moved to the insufficient category. This decision reflects the committee’s conviction that it would be inappropriate to let the very uncertain dataset on the chemicals of interest and spina bifida remain as a formally documented instance of the questionable phenomenon of paternal transmission. Although the biologic plausibility of maternal exposure to toxic agents, specifically including the chemicals of interest, is well established, there are no existing epidemiologic data supporting increased incidence of spina bifida specifically following maternal exposure to the components of the herbicides sprayed in Vietnam as is required for identifying an association under the Agent Orange Act. Consequently, spina bifida in the offspring of both male and female veterans has been moved to the category of inadequate or insufficient evidence of an association with
herbicide exposure from its prior categorization as having limited or suggestive evidence of an association.
VA also charged the committee for Update 2014 to address the specific question of whether various conditions with Parkinson-like symptoms should be considered covered under the assignment of Parkinson disease to the limited- or-suggestive category of association with herbicide exposure. The committee noted that the diagnostic standards for this condition should not be assumed to have been uniform in the epidemiologic studies that constitute the basis for this association or in the claims submitted by veterans, so there is no rational basis for exclusion of individuals with Parkinson-like symptoms from the service-related category denoted as Parkinson disease. To exclude a claim for a condition with Parkinson-like symptoms, the onus should be on VA on a case-by-case basis to definitively establish the role of a recognized etiologic factor other than the herbicides sprayed in Vietnam.
Although VA has not found hypertension [Health Effects Not Associated with Exposure to Certain Herbicide Agents, 75 Fed. Reg. 109 (June 8, 2010)] or stroke [Determinations Concerning Illnesses Discussed in National Academy of Sciences Report: Veterans and Agent Orange: Update 2012, 79 Fed. Reg. 70 (April 11, 2014)] to be presumptively related to service in Vietnam, on the basis of the total weight of available evidence the current committee reaffirmed the conclusions of previous VAO committees that these two health outcomes should be placed in the category of limited or suggestive evidence of association.
The changes made by the current committee to the categorizations determined by the committee for Update 2012 (as presented in Table 1-1) are noted in boldface in Table 14-1. As mandated by Public Law (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 14-1 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.
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 the chemicals of interest sprayed in Vietnam: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant TCDD, picloram, and cacodylic acid. Because Update 2014 is the last of the reports mandated by the Agent Orange Act (PL 102-4, and renewed as PL 107-103), this committee considered it appropriate to review the recommendations made
TABLE 14-1 Summary of Tenth Biennial Update of Findings on Vietnam-Veteran, Occupational, and Environmental Studies Regarding Scientifically Relevant Associations Between Exposure to Herbicides and Specific Health Outcomesa
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
Limited or Suggestive Evidence of an Association
Cancer of the lung, bronchus, or trachea
Cancer of the urinary bladder (category change from Inadequate or Insufficient in Update 2012)
* Multiple myeloma
* AL amyloidosis
Early-onset peripheral neuropathy
Parkinson disease (including Parkinsonism and Parkinson-like syndromes) (category clarification from Update 2012)
Porphyria cutanea tarda
Ischemic heart disease
Type 2 diabetes (mellitus)
Hypothroidism (category change from Inadequate or Insufficient in Update 2012)
Inadequate or Insufficient Evidence to Determine an Association
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 cancer
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 B-cell leukemias, including chronic lymphocytic leukemia and hairy cell leukemia)
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 (category change from Limited or Suggestive in Update 2012 for spina bifida)
Childhood cancer (including acute myeloid leukemia) 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, lipid abnormalities, and ulcers)
Immune system disorders (immune suppression, allergy, and autoimmunity)
Circulatory disorders (other than hypertension, ischemic heart disease, and stroke) Endometriosis
Disruption of thyroid homeostasis (other than hypothyroidism) (category modification from Update 2012)
|This 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
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 occupational, environmental, and veteran 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 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109529/table/T1, accessed December 2, 2015).
by prior VAO committees and, in light of the lessons learned in this process, to consider what would be the most important activities to undertake in the future. This committee has endeavored to factor the constraints of feasibility into its judgments. Table 14-2 is a compendium of the recommendations of prior committees condensed and sorted into several topic areas, with comments on what response these recommendations received from VA, Department of Defense (DOD), and other parties. In Table 14-3, this committee summarizes the future activities it considers 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.
As evidenced in Table 14-2, the recommendations of previous VAO committees fall into four primary areas:
- Management of information under the auspices of DOD and VA
- Additional epidemiologic work
- Improvement of exposure estimation
- Priority areas for toxicologic research
In instances in which the VAO committees have been aware of actions taken after a recommendation was made, the events are briefly delineated in the rightmost column of Table 14-2. After encouragement of the effort that matured into the model to estimate individual opportunity of herbicide exposure based
|Recommendation Focus||Report of Initial Recommendation||Follow-up|
|DOD and VA databases should be linked to identify, record, and/or monitor trends in diseases of aging Vietnam veterans for evaluation of possible associations with military service in Vietnam (Vietnam or in the Vietnam theater during the Vietnam era).||VAO||Although it is most probably no longer possible to do this for Vietnam veterans, this type of linkage still has not been successfully established to manage follow-up of more recent deployments (e.g., “Returning Home” [IOM, 2013])|
|The VA should make more effective use of its databases to determine health effects that may have resulted from exposures in Vietnam:||No known follow-up|
|Link the EMR and associated administrative databases, such as discharge-diagnosis and pharmacy-use records||Update 2006|
|Establish systematic review of the distribution of health outcomes||Update 2008|
|Combine information from the Neurotoxin Exposure Treatment Parkinson Research program with the resources of the VA’s appeals and medical records||Update 2008|
|Commission an independent panel to identify and assign priorities||Update 2010|
|Involve external analysts||Update 2010|
|Investigations of VA data sources should be conducted on:|
|COPD||Update 2010||Other than the work in progress on COPD in the ACC study population discussed below, the committee is not aware of epidemiologic efforts undertaken by VA to assess a possible role for herbicides in the occurrence of the other conditions listed here.|
|Brain cancer||Update 2002|
|Breast cancer||Update 2006|
|Tonsil cancer (squamous cell carcinomas of the head and neck)||Update 2006|
|Amyotrophic lateral sclerosis||Update 2002|
|Parkinson disease||Update 2002||Several small studies have been published by individual researchers using the “AO exposed” variable in VA medical records without explanation of its derivation.|
|Alzheimer disease||Update 2010|
|Metabolic syndrome||Update 2006|
|Paternally mediated effects on health of offspring||Update 2006|
|Mortality Cohort of Male Vietnam–era Veterans|
|VA should continue epidemiologic studies (morbidity and mortality) of Vietnam Veterans, especially as the VV population grows older and the incidence of many health outcomes increases with age.||Update 2004|
|Army Chemical Corps (ACC)|
|Study ACC members to increase the size of the highly exposed population of Vietnam veterans and gain greater statistical power to detect less common health outcomes.||VAO||Kang et al. (2006) examined health status of ACC VVs.|
|Cypel and Kang (2010) presented updated mortality findings on a limited number of cancers, diabetes, circulatory conditions, respiratory conditions, and cirrhosis of the liver.|
|Collect and store biological samples and determine serum TCDD levels.||VAO||TCDD serum levels were determined in a subset of the ACC cohort (Kang et al., 2006), but not aware of collection of other biospecimens|
|Augment update mortality of ACC with assembly of clinical information on morbidity associated with COPD and HT.||Update 2010||In 2010, VA launched the ACC Vietnam-era Veterans Health Study to investigate the relationship between herbicide exposure during the Vietnam War and morbidity from hypertension and COPD in ACC veterans [results have not yet been reported].|
|Recommendation Focus||Report of Initial Recommendation||Follow-up|
|Female Vietnam-era Veterans|
|Women Vietnam veterans should be included in Vietnam veteran studies whenever appropriate.||VAO||A cohort of female US Vietnam-era veterans (primarily nurses) was developed and reported on by Kang et al. (2000). Since then, Cypel and Kang (2008) and Kang et al. (2014) have updated mortality.|
|In 2009, VA announced the start of a 4-year undertaking to investigate the mental and physical health of this cohort, but any results remain outstanding.|
|US Air Force—Air Force Health Study (AFHS)|
|The AFHS could benefit from improved methods of analysis and presentation of results both for existing data and for data obtained in the future.||VAO||No known follow-up|
|Establish an independent, non-governmental scientific panel to oversee analysis of resulting data to satisfy the public’s concern about impartiality and scientific credibility.||VAO||No known follow-up|
|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 medical interventions, cancer incidence, mortality, birth defects in veterans’ offspring) making use of the available exposure data.||Update 2008||No known follow-up|
|Perform a comprehensive analysis of melanoma in the entire AFHS dataset to resolve ambiguity remaining in currently published results.||Update 2010||No known follow-up|
|Combine existing data from AFHS with new results derived by assays of the curated biological samples.||Update 2010||No known follow-up|
|Consideration should be given to whether it is appropriate to continue the AFHS study past its planned completion date because AFHS cohorts are only now reaching the age where several health outcomes of interest may be expected to manifest.||VAO||Following the last AFHS physical exam in 2002, the IOM was asked to form a committee to provide guidance on the future of the AFHS. The IOM committee’s final report, Disposition of the Air Force Health Study, concluded that the medical records, data, and biological specimens collected in the study, which closed on September 30, 2006, were a trove of valuable research material. It recommended that—after the AFHS’s scheduled end—these assets be made available to researchers, through a custodian that takes an active role in fostering their use. No matter where the AFHS materials go, that custodian would need a secure source of funding. The report also recommended that Congress allocate at least $250,000 annually for 3 years to promote research using the data and specimens.|
|Retain and maintain AFHS medical records and biological samples with oversight that could be established for future use and research, while respecting the privacy of participants.||VAO|
|Dedicated funding is required so that focused analyses can be carried out by independent investigators using the AFHS data and biospecimens.||Update 2008|
|In spring 2012, the Committee on the Management of the Air Force Health Study Data and Specimens issued a request for proposals to use the AFHS materials (data or specimens) for innovative research. Each submission was subject to an intensive review by the entire committee to ensure that it was scientifically sound and feasible. Seven proposals were approved. The investigations have begun only fairly recently, so no results are available. A second request for proposals was issued in May 2013. The committee enthusiastically supports these new and continuing research efforts.|
|Recommendation Focus||Report of Initial Recommendation||Follow-up|
|CDC—National Vietnam Veterans Readjustment Study (NVVRS )/National Vietnam Veterans Longitudinal Study (NVVLS)|
|As mandated by Congress (PL 106-419), the cohort from the NVVRS should be updated as the NVVLS. As directed by VA’s Inspector General (VAOIG, 2005), the aborted update of the NVVRS should be started again. The committee recommends that, in addition to the largely psychological outcomes that were the focus of the NVVRS, the physical health (and Alzheimer disease) of the members of this carefully selected cohort should be assessed in the NVVLS. Outcomes considered most important for data gathering are those for which current evidence is inadequate or insufficient to determine whether there is an association with herbicide exposure, such as COPD, brain cancer, tonsil cancer, melanoma (with particular attention given to ocular types), and Alzheimer disease.||Update 2010||In 2010, VA announced that a contractor had been engaged to conduct the study, with an expected completion date of 2013. Unfortunately from the perspective of VAO committees, the questionnaires and interviews are focusing on PTSD/psychologic issues rather than expanding the data gathering to include the physical health status of this well-defined cohort. Update: The NVVLS was completed in 2014—IOM is working to obtain the full report (See Schlenger et al., 2015 for methods).|
|Even an up-to-date estimate of overall mortality would be quite helpful.|
|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||No known follow-up|
|Continue the NIOSH studies.||Update 2006||No known follow-up|
|Agricultural Health Study (AHS)|
|Researchers should try to resolve known inconsistencies in results for incident and prevalent PD cases (possibly using the analytic method described in Copas and Farewell, 2008).||Update 2008||No known follow-up|
|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|
|Other Recommended Epidemiologic Studies and Analyses:|
|Studies of individual characteristics and other factors affecting TCDD metabolism are particularly important and should be encouraged.||VAO||No known follow-up|
|Biomarkers for herbicide exposure should be developed further.||VAO||No known follow-up|
|Studies of the Vietnamese population exposed to herbicides (including both those who served in the military during the war and civilians) are possible and potentially useful. Before significant resources are committed, the committee recommends that feasibility studies of both exposure reconstruction and disease outcome monitoring be conducted. The committee supports further steps toward collaborative programs of research. Studies should include sufficient exposure measures, such as tissue TCDD concentrations.||VAO||No known follow-up [Given the chronic nature of exposure of the entire population, it now seems that such studies of the Vietnamese would not be particularly enlightening (particularly for question of paternal transmission of adverse effects).]|
|Future epidemiologic studies should be as specific as possible, rather than generic findings such as “all respiratory disorders.”||Update 2006||No known follow-up|
|An ad hoc group should conduct a meta-analysis of the current epidemiologic studies of male populations exposed to the 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).]|
|Additional studies of the COIs and conditions that have been noted to be of special interest but on which the current evidence is inadequate or insufficient (such as COPD, brain cancer, breast cancer, tonsil cancer, melanoma, amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer disease). For very uncommon health outcomes, a case-control design would probably be most appropriate.||Update 2006||No known follow-up|
|Investigate possible effects in offspring of VVs (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|
|Recommendation Focus||Report of Initial Recommendation||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 last several decades (especially for very uncommon health outcomes). To hone 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 COIs.||Update 2010||No known follow-up|
|New studies in additional populations of COPD diagnosed using appropriate functional tests with adjustment for smoking status and consideration of comorbidities that could contribute to death from COPD.||Update 2010||No known follow-up|
|Epi studies to explore the relationship between exposure to the chemicals of interest and meaningful biomarkers of immune/inflammatory diseases, such as Fox p3+ T regulatory cells, Th17 cells, and dendritic cells; interleukin 6 elevations; frequency and duration of specific types of infections; and inflammatory cytokines under resting and challenged conditions.||Update 2010||No known follow-up|
|A non-governmental organization with appropriate experience in historical reconstruction should be commissioned to develop and test models of herbicide exposure for use in studies of Vietnam veterans. If it is determined that a valid exposure reconstruction model is feasible, then the VA and other government agencies should facilitate additional epidemiologic studies of veterans.||VAO||Stellman model developed|
|Animal studies of multiple exposures (for example, examining the interaction of smoking and TCDD exposure with the health outcomes of interest) would be useful for interpreting the results of epidemiologic studies.||Update 2002||No known follow-up|
|Studies are needed to examine and clarify the role of genetic factors, in particular studies addressing the identification, distribution, and functional consequences of polymorphisms of the aryl-hydrocarbon receptor.||Update 2004||Additional studies of genetic factors and AHR polymorphisms have been published.|
|Animal models are needed to elucidate disease mechanisms and progression (particularly cardiovascular disease, B-cell cancers, obesity and the components of metabolic syndrome, and transgenerational or paternally mediated effects).||Update 2006||No known follow-up|
|There is a need for a biphasic physiologically based pharmacokinetic model for TCDD. There is also a need for additional validation of the PBPK models and direct comparisons of the resulting exposure classifications when the new models and the standard first-order elimination models are applied to larger datasets.||Update 2006||Additional studies of pharmacokinetic modeling have been published.|
|An investigation of mitochondrial disease is needed and could have important implications for health effects of concern in VVs.||Update 2008||No known follow-up|
|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|
NOTE: ACC, US Army Chemical Corps; AFHS, Air Force Health Study; AHS, Agricultural Health Study; AO, Agent Orange; COI, chemical of interest; COPD, chronic obstructive pulmonary disease; DOD, US Department of Defense; EMR, electronic medical record; HT, hypertension; IARC, International Agency for Research on Cancer; IOM, Institute of Medicine; NIOSH, National Institute for Occupational Safety and Health; NVVLS, National Vietnam Veterans Longitudinal Study; NVVRS, National Vietnam Veterans Readjustment Study; PBPK model, physiologically based pharmacokinetic model; PD, Parkinson disease; PTSD, posttraumatic stress disorder; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, Veterans Administration; VAO, Veterans and Agent Orange: VV, Vietnam veteran.
|OVERSIGHT OF LONG-TERM HEALTH STATUS OF DEPLOYED SERVICE MEMBERS|
|A single overarching body is needed to review all deployment-related issues of veteran’s health regularly and in a uniform fashion. (Numerous points concerning appointment of members and other procedural matters would need to be addressed in advance.)|
|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 women now serving in the military.|
|DOD should create and maintain rosters of individuals deployed on every mission.|
|DOD should create and maintain a matrix of potentially toxic exposures by time and location for every deployment.|
|DOD’s collection of biological specimens should be expanded to occur at regular intervals for all service members, as well as before and after deployments. Storage should be established on a permanent basis, with samples being accessible to researchers|
|Documentation of vaccination and other medical procedures performed during service need to be included in the records of each service person, and automatically transferred to VA upon discharge from the military.|
|DOD and VA databases should be linked to systematically identify, record, and/or monitor trends in diseases of soldiers and veterans for evaluation of possible associations with military service deployments.|
|VA should routinely (probably quarterly) obtain frequency distributions of health conditions treated at its medical facilities for participants in each deployment in contrast to those observed among their non-deployed contemporaries.|
|It would be worthwhile to conduct similar monitoring of VA claims data even though it might be less objective than treatment records and does not have an obvious comparison group.|
|Air Force Health Study (AFHS)|
|Comprehensive longitudinal analysis of the AFHS data collected in the six intensive medical-cycle examinations (particularly concerning medical interventions, cancer incidence, mortality, 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. (See Table 14-4 from the recent report of the Committee on the Management of the Air Force Health Study Data and Specimens [IOM, 2015].)|
|Dedicated funding should be continued for focused analyses by independent investigators.|
|Army Chemical Corps (ACC)|
|Analysis and release of findings gathered by following up on the ACC mortality study to assemble clinical information on morbidity associated with COPD and HT.|
|Vietnam Era-Health Evaluation Retrospective Observational Study (VE-HEROeS)|
|VA should continue epidemiologic studies (morbidity and mortality) of Vietnam veterans, especially as this population grows older and the incidence of many health outcomes increases with age.|
|Clinical examination and collection of biologic specimens from a subsample would provide a basis for establishing the reliability of self-reported information and deepen the value of hypotheses that could be explored.|
|Foster cooperation with veterans’ service organizations in conducting studies.|
|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. Design a study to focus on specific manifestations in humans of dioxin exposure and compromised immunity, which has been so clearly demonstrated in animal models.|
|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. Continue exploration of the constellation of effects involved with the metabolic syndrome, which appear to represent a node of dioxin-related conditions.|
|Explore the role of B-cell responses to dioxin-like activity.|
|Resolve whether toxicology results for direct exposure to organic arsenic compounds are applicable to human exposure to such compounds.|
on merging records of troop movements and flight records of Operation Ranch Hand herbicide spray missions, innovative ideas for exposure assessment that might improve the evaluation of health effects in Vietnam veterans appear to have been exhausted. In the other areas, however, VAO committees repeatedly proposed variations of several suggestions. VAO committees have been gratified by some of the responses to their encouragement of following up on established cohorts of Vietnam veterans, as embodied by additional epidemiology studies of female Vietnam veterans and the Army Chemical Corps. For example, the committee for Update 2010 placed a high priority on research to address COPD from a morbidity perspective with an appropriate functional diagnosis of COPD and a collection of data to permit adjustments for smoking and other relevant confounders. The committee for Update 2012 was pleased to note that VA had started such a study on its ACC cohort; the results from any such investigation, however, were not available to the present committee for review.
Similarly, previous VAO committees strongly recommended that measures of physical health be included along with the psychological endpoints when the congressionally mandated update of the carefully selected sample of the National Vietnam Veterans Readjustment Study (1986–1988) was conducted. Although the committee asked repeatedly about the status of this effort, it was not until a terse summary of the findings of the National Vietnam Veterans Longitudinal Study appeared in the Summer 2015 issue of VA’s erratically published Agent Orange Newsletter, it became evident that this advice had not been incorporated into the experimental design.
In retrospect, it appears that the implementation of some of these suggestions was not feasible. A lack of comprehensive rosters of who had been deployed to Vietnam impeded the conducting of epidemiologic studies in an optimal fashion, and the difficulty of establishing retrospective methods to reliably estimate individual exposure has proved frustrating. With the passage of time, some opportunities have been missed and other suggestions no longer seem to have high priority, but a considerable number remain that merit serious consideration.
Although progress has been made in understanding the health effects of exposure to the chemicals of interest and the mechanisms underlying these effects, significant gaps in our knowledge remain. The scope of potential research is far-reaching, and what follows here is not an exhaustive list of future research that would be worthwhile. Many additional opportunities for progress in toxicology research, the conduct of continuing or new epidemiologic studies, and a systematic and comprehensive integration of existing datasets have not been explicitly noted here. As Table 14-2 illustrates, a number of the recommendations detailed below have been mentioned in previous VAO updates, but they are restated here to emphasize the committee’s conviction that more progress should be made in the research fields noted.
Several themes underlie the points raised for future action in Table 14-3. A uniform, equitable, and evidence-based approach to meeting this country’s obligation associated with delayed service-related health problems is a high priority not only for Vietnam veterans, but also for all US veterans. Improved cooperation between the organizations that place new recruits in service and those that are responsible for their care after discharge has been recommended repeatedly, and this represents an essential element to having a functional system. These individual suggestions fall into five categories, as discussed below.
Oversight of the Long-Term Health Status of Deployed Service Members
This is an area in which the VAO charge does not allow for specific recommendations. This committee simply notes that its experience suggests that, as the mandate of the Agent Orange Act expires, concern about service-related health problems in the Vietnam veterans continues. As adjustment to government policy about Vietnam veterans is made at this point of transition, it seems an opportune
time to allocate resources toward addressing how this issue will be handled in the future for all veterans. Rather than simply continuing regular periodic updates on literature related to the health of Vietnam veterans and addressing, on a case-by-case basis, health problems in other veterans that might involve harmful exposures suffered while in the military, a more effective approach would be a standing, overarching body to review all deployment-related issues of veteran’s health regularly and in a uniform fashion. (Of course, numerous points concerning the appointment of members and other procedural matters would need to be addressed in advance.)
More specifically, before committing extensive resources to ameliorating adverse health consequences in the descendants of veterans, both male and female, it would be appropriate to conduct a 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.
It is too late for Vietnam veterans and other more recently deployed veterans, but DOD should prepare the way for addressing the issue of delayed service-related health conditions in a more coherent and better documented fashion for future veterans. The compilation of rosters of individuals sent on various deployments is a rudimentary starting point for any subsequent epidemiologic investigations. Documentation of medical procedures such as vaccinations should also be maintained for such cohorts.
The committee endorses DOD’s efforts to improve the collection of exposure data during current deployments so that the impasses associated with missing exposure information will not impede investigations of health consequences in future veterans. It notes, however, that more regular collection of biological samples from military personnel and storage without analysis might prove a more flexible tool for investigation in the event of a health issue involving possible toxic exposure.
In general, improved data linkage and data sharing between DOD and VA would greatly enhance the conduct of military epidemiology to guide health care delivery for veterans of all conflicts.
It is recognized that those who use VA services will not constitute a representative sample of the full cohort of veterans from a given deployment. VA could make extremely substantial contributions by the identification of possible service-related health problems through regular and systematic processing of the data accumulated in the course of fulfilling its health care responsibilities. Routine comparisons of health care use by deployed veterans and suitably matched
non-deployed veterans from each deployment could provide early alerts of impending relevance in the very population of interest. Although applications for compensation and appeals constitute a non-representative, self-selected sample that is influenced by which conditions are already judged to be service-related, even a periodic determination of the distribution of health conditions for which claims are filed could be informative. More rigorous investigation could then be directed at the confirmation or dismissal of such conditions as being service-related, such as a case-control approach that addresses deployment status and other emerging risk factors nested within VA’s patient population.
Linkage of occupational, health, and socioeconomic data from DOD with VA electronic medical-record system and associated administrative databases, such as discharge diagnoses and pharmacy-use records, would afford VA the opportunity to assemble an expansive epidemiologic database for a more rigorous evaluation of possible associations with military service in Vietnam. Particular attention should be paid to the feasibility of conducting epidemiologic studies of conditions that have been noted to be of special interest, but for which the current evidence is inadequate or insufficient to determine whether there is an association with herbicide exposure (see list in Table 14-2). A creative analysis of VA’s own data resources may well be the most effective way to address those outcomes and to gain a better understanding of the role, if any, of herbicide exposure in chronic diseases of Vietnam veterans. Perceptions that VA would have a conflict of interest in surveying its own databases might be alleviated by recruiting external analysts to evaluate the contents of VA’s medical databases. For example, an independent panel could be commissioned to identify and assign priorities to database information that would aid future evaluation of the evidence.
In addition, VA should establish an external advisory group to identify effective mechanisms for mining VA medical database information and to establish guidelines for the creation of a grants program focused on proposals for the conduct of analytic studies related to specific health outcomes of interest.
The committee notes that future analyses of health outcomes in any future epidemiology studies should be as specific as possible because generic findings, such as those for “all respiratory outcomes,” are not useful in determining associations of herbicide exposures with specific health conditions.
The Institute of Medicine (IOM) Medical Follow-up Agency (MFUA) has become the custodian of the data and biologic specimens generated by the Air Force Health Study (AFHS) (PL 109-364; 120 Stat. 2290); the specimens are held in storage at the Wright–Patterson Air Force Base under MFUA’s aegis, and funding has been provided for the IOM to maintain and manage the materials and to make these invaluable data and biospecimens available to independent researchers. Such research could clarify the various issues and would generate substantial
benefits in the understanding of health issues of Vietnam veterans exposed to herbicides. Comprehensive longitudinal analyses of the data collected in the six intensive medical examinations—which include data on medical interventions (such as hospitalizations and emergency-department visits), cancer incidence, mortality, and exposures—should be conducted to investigate, if not all the health outcomes, at least those for which a possible association with herbicide exposure remains contentious. The distillation of existing data could be enhanced by the incorporation of new results derived from study of the biologic samples. For example, an analysis of banked semen samples for epigenetic markers on sperm DNA and the measurement of TCDD in seminal fluid, particularly in comparison with the subjects’ serum TCDD concentrations, could provide insight into the likelihood of male Vietnam veterans’ transmitting effects to their offspring, as well as supplementing general knowledge on paternal transmission. Through January 2015, 13 projects using the AFHS resources have been approved and initiated. Although the program does not require that these research projects necessarily investigate issues related to the health of Vietnam veterans specifically, most of them do address topics that are relevant to questions VAO committees have posed. Table 14-4 reproduces a table from the recent report of the Committee on the Management of the Air Force Health Study Data and Specimens (IOM, 2015), which summarized the diverse efforts undertaken. The committee enthusiastically supports these new and continuing research efforts and believes dedicated funding should be continued for focused analyses of these invaluable AFHS data and biospecimens by independent investigators.
Members of the ACC constitute the largest cohort of Vietnam veterans exposed directly to herbicides and TCDD. They were involved in the handling and distribution of the chemicals in Vietnam. ACC veterans who reported spraying herbicides as part of their duties have increased serum TCDD concentrations; this highly exposed population has also been shown to be at increased risk for several diseases. Previous VAO committees recommended that VA conduct additional studies of ACC veterans because the population presents a unique opportunity to examine the association between the health effects of exposure to TCDD and the herbicides used in Vietnam. Recently, VA launched the ACC Vietnam-Era Veterans Health Study to investigate the relationship between herbicide exposure during the Vietnam War and hypertension and COPD in ACC veterans. Information garnered from the study could benefit VA and future VAO committees as potential associations between exposure to the chemicals of interest and respiratory outcomes are evaluated.
Although about 250,000 US women served in the military during the Vietnam War and 5,000–7,000 women served in Vietnam, few data on the health of the deployed and non-deployed female veterans are available. More than a decade ago, Kang et al. (2000a,b) examined the prevalence of gynecologic cancers in female Vietnam veterans and of birth defects in their children. Kang et al. (2014) extended information on vital status in this population through 2010, adding
|Principal Investigator||Institution||Proposal Title||Request Type|
|Batty||University of Edinburgh||Cognitive function in middle age as a predictor of later life health: Analyses of data from the Air Force Health Study||Data only|
|Boekelheidec||Brown University||Identifying epigenetic molecular markers of dioxin exposure in Vietnam veterans||Data and biospecimens|
|Chambersc||Mississippi State University||A longitudinal study of paraoxonase 1 (PON1) in relationship to type 2 diabetes and aging||Data and biospecimens|
|Haws||ToxStrategies, Inc.||Exposure–response relationship for dioxin and cancer and non-cancer health outcomes in the Air Force Health Study cohort using physiologically based pharmacokinetic modeling of exposure and updated mortality||Data only|
|Knafl||University of North Carolina at Chapel Hill||Effects of dioxin exposure for male Air Force Vietnam veterans on reproductive outcomes||Data only|
|Mandel||Exponent, Inc.||The reanalysis of the Ranch Hand data||Data only|
|Mazur||Syracuse University||Testosterone changes||Data only|
|Mitchell||Emory University and Atlanta VA Medical Center||Identifying novel biomarkers of vulnerable coronary artery disease: The Air Force Health Study||Data and biospecimens|
|Ramosc||University of Louisville||Detection of L1 protein in Ranch Hand biospecimens||Data and biospecimens|
|Rossc||Pacific Health Research and Education Institute, VA||Parkinson’s disease and pre-motor features of Parkinson’s disease in the Air Force Health Study||Data only|
|Rothc||VA San Diego Healthcare System||Caveolin’s role during healthy aging||Data and biospecimens|
|Seldinc||Boston University||Incidence of abnormal free light chains and other markers of light chain amyloidosis in veterans exposed to Agent Orange: A pilot study||Data and biospecimens|
|Shimv||Centers for Disease Control and Prevention||Monoclonal gammopathy of undetermined significance (MGUS) and microRNAs in Ranch Hand veterans||Data and biospecimens|
aThis list represents studies approved as of February 1, 2015.
bThe date that a proposal was approved and the date that the study was able to start varied depending on the type and extensiveness of the requested assets. For example, studies that requested more biospecimens (for example, more than 100) took longer to process than those requesting fewer samples.
cDenotes studies that were awarded pilot funding.
SOURCE: IOM, 2015.
6 years of follow-up to the previous mortality study (Cypel and Kang, 2008). However, no additional information on the health status of the survivors in this group has become available. In 2009, VA announced the start of the Health of the Vietnam Era Veteran Women’s Study, a 4-year undertaking to investigate the mental and physical health of deployed and non-deployed US women who served during the Vietnam War. Although findings from the study have yet to be published, the committee supports these VA efforts and hopes that the findings will help to elucidate how military service in Vietnam may have affected the health of female veterans who served.
There has not been a sizable survey of the health of Vietnam veterans since CDC’s Vietnam Experience Study was conducted 30 years ago in the mid-1980s, so the committee was pleased to learn that VA has already done considerable preparation for a study to monitor the health of Vietnam veterans as they age, the Vietnam Era Health Evaluation Retrospective Observational Study (VE-HEROeS). Table 14-3 contains several suggestions about maximizing the rate of participation, validating self-reported health outcomes, and gathering biological samples that would strengthen and increase the utility of the results generated by this endeavor.
VAO committees have been monitoring studies of morphologic birth defects and cancers in the offspring of exposed individuals, but systematic review of defined clinical health conditions that are manifested later in the offspring’s lives remains difficult because most studies report on physiologic biomarkers that might or might not predict the potential for disease development later in life, rather than investigating specific diseases. A longstanding major concern is the possible association between the exposure of male Vietnam veterans to the chemicals of interest and health problems in their offspring, but there are few epidemiology studies of these endpoints that have addressed paternal exposure in the absence of maternal exposure. The few data on toxic contaminants in seminal fluid suggest that fetal exposure due to paternal transmission during later acts of intercourse is highly unlikely, but it now appears more physiologically possible that epigenetic modifications of sperm, including alterations in sperm mRNAs, microRNAs, and DNA after paternal exposure, might lead to changes in the offspring. The last of the few publications on birth defects in the offspring of male Vietnam veterans was published before the report on the children of female Vietnam veterans (Kang et al., 2000b), and no recently reviewed epidemiologic studies have assessed the role of paternal exposure in the occurrence of such effects. Thus, most of the available epidemiologic studies of effects in offspring are not relevant to the primary exposure group of concern: male Vietnam veterans.
The committee believes that experimental research on the mechanisms that underlie human health outcomes (particularly cardiovascular disease, B-cell
cancers, and paternally mediated effects in offspring) could provide valuable information related to the risk of disease in Vietnam veterans and their children. Specifically, determining the mechanism by which dioxin-like chemicals induce B-cell cancers and how exposure to dioxin-like chemicals alters susceptibility to obesity and components of metabolic syndrome would fill important knowledge gaps. The development of animal models of neurologic outcomes and various chronic health conditions and their progression would also be useful for understanding the possible contributions of the chemicals of interest to impacting the health of aging Vietnam veterans.
The rapidly expanding field of epigenetics is revealing the molecular mechanisms by which environmental agents can modify gene expression without changing DNA sequence long after exposure occurs, even in later generations—at least in the case of maternal exposure to some chemicals. 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 to the chemicals of interest and birth weight. There is a growing body of evidence that TCDD can induce epigenetic changes in animal models, and continuing research could characterize the timing and duration of exposure that are most critical as well as the susceptibility of specific organ systems to disease development in offspring later in life. The occurrence of adverse effects in offspring following maternal exposure to numerous agents, including TCDD, has been amply documented, and experimental results have shown that effects on male offspring following maternal exposure to TCDD can be passed even to the second generation, but to date there has been minimal investigation of whether paternal exposure poses a risk of adverse effects in their offspring, for xenobiotics in general and the VAO chemicals of interest in particular. 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. In fact, it might be wise to delay the initiation of epidemiologic studies on these endpoints until such effects have been demonstrated in the offspring of exposed male laboratory animals.