Veterans and Agent Orange: Update 2010 (2012)

Summary

From 1962 to 1971, the US military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4- dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed. The herbicide mixtures used were named according to the colors of identification bands painted on the storage drums; the main chemical mixture sprayed was Agent Orange (a 50:50 mixture of 2,4-D and 2,4,5-T). At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form of dioxin, was an unintended contaminant generated during the production of 2,4,5-T and so was present in Agent Orange and some other formulations sprayed in Vietnam; it is important to remember that Agent Orange is not synonymous with TCDD or dioxin.

Complaints from returning Vietnam veterans about their own health and that of their children combined with emerging toxicologic evidence of adverse effects of phenoxy herbicides and TCDD in animal studies and some positive epidemiologic studies resulted in sustained controversy. In 1991, because of continuing uncertainty about long-term health effects of the sprayed herbicides in Vietnam veterans, Congress passed Public Law (PL) 102-4, the Agent Orange Act of 1991. That legislation directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. The legislation also instructed the Secretary

to ask NAS to conduct updates every 2 years for 10 years from the date of the first report to review newly available literature and draw conclusions from the overall evidence.

In response to the first request, the Institute of Medicine (IOM) convened a committee, whose conclusions IOM published in 1994 in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO). The work of later committees resulted in the publication of biennial updates (Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008) and of focused reports on the scientific evidence regarding type 2 diabetes, acute myeloid leukemia in children, and the latent period for respiratory cancer.

Enacted in 2002, PL 107-103, the Veterans Education and Benefits Expansion Act of 2001, mandated that the VAO biennial updates continue through 2014. Update 2006 was the first report published under that legislation. The current update presents this committee’s review of peer-reviewed scientific reports concerning associations between health outcomes and exposure to TCDD and other chemicals in the herbicides used in Vietnam that were published in October 2008–September 2010 and the committee’s integration of this information with the previously established evidence database.

CHARGE TO THE COMMITTEE

In accordance with PL 102-4 and PL 107-103, the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Eighth Biennial Update) was asked to “determine (to the extent that available scientific data permit meaningful determinations)” the following regarding associations between specific health outcomes and exposure to TCDD and other chemicals in herbicides used by the military in Vietnam:

A) whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiological methods used to detect the association;

B) the increased risk of disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and

C) whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease.

The committee notes that, as a consequence of congressional and judicial history, both its congressional mandate and the statement of task are phrased with the target of evaluation being “association” between exposure and health outcomes. The rigor of the evidentiary database needed to support a finding of statistical association is weaker than that needed to establish causality, but posi-

tive findings for any of the aspects of scientific evidence supportive of causality enhance conviction that an observed statistical association is reliable. Such scientific evidence, of course, would include any information assembled in relation to plausible biologic mechanisms as directed in Article C. In accord with its charge, the committee examined outcome measures commonly used to evaluate statistical associations, while assessing the adequacy of control for bias and confounding and the likelihood that an observed association could be explained by chance. Additionally, the committee assessed evidence concerning biologic plausibility derived from laboratory findings in cell-culture or animal models. In particular, associations found to have multiple supportive lines of evidence were interpreted as having stronger scientific support.

In conducting its study, the present committee operated independently of the Department of Veterans Affairs (VA) and other government agencies. The committee was not asked to make and did not make judgments regarding specific cases in which individual Vietnam veterans have claimed injury from herbicide exposure. This report provides scientific information for the Secretary of Veterans Affairs to consider as VA exercises its responsibilities to Vietnam veterans. The committee was not charged to focus on broader issues, such as the potential costs of compensation for veterans or policies regarding such compensation.

In addition to the above charge, the VA made an additional request arising from the decision-making at VA necessitated by the findings of Update 2008. The sponsor asked that, when summarizing the evidence available to support the association of a health effect with exposure to the components of the herbicides used by the military in Vietnam, the committee address whether or not all the points that have rather imprecisely become known as the Bradford Hill (1965) “criteria” for causality (strength, consistency, specificity, temporality, biologic gradient, plausibility, coherence, experiment, and analogy) had been satisfied by the information available

COMMITTEE’S APPROACH TO ITS CHARGE

Following the pattern established by prior VAO committees, the present committee concentrated its review on epidemiologic studies to fulfill its charge of assessing whether specific human health effects are associated with exposure to at least one of the herbicides sprayed in Vietnam or to TCDD. The committee also considered controlled laboratory investigations that provided information on whether association between the chemicals of interest and a given effect is biologically plausible.

The VAO committees began their evaluation presuming neither the presence nor the absence of association for any particular health outcome. Over the sequence of reviews, evidence of various degrees of association, lack of association, or persisting indeterminacy with respect to a wide array of disease

states has accrued. For many conditions, however, particularly ones that are very uncommon, any association with the chemicals of interest has remained unaddressed in the medical research literature; for these (unless the condition is logically subsumed under a broader disease category that has been evaluated), the committee remains neutral, abiding by the maxim that “absence of evidence is not evidence of absence.”

In accord with Congress’s mandated presumption of herbicide exposure for all Vietnam veterans, VAO committees have treated Vietnam-veteran status as a proxy for some herbicide exposure when no more specific exposure information is available. To obtain information potentially relevant to the evaluation of health effects related to herbicide exposure in addition to that available from studies of Vietnam veterans, the committee reviewed studies of other groups potentially exposed to the constituents of the herbicide mixtures used in Vietnam (2,4-D, 2,4,5-T, TCDD, cacodylic acid, and picloram). In addition to retrieving articles identified on the basis of keywords specifying the compounds and chemical classes of interest, literature searches for the earliest reports in the VAO series had been structured to retrieve all studies of several occupational groups, including chemical, agricultural, pulp and paper, sawmill, and forestry workers. To the extent that studies of those workforces were recovered in new searches directed at particular agents of exposure, they were incorporated into the database. Some occupational and environmental cohorts that received exceptionally high exposures (such as the International Agency for Research on Cancer [IARC] and Seveso cohorts discussed in this report) are now well characterized and are producing a stream of informative results. A continuing prospective cohort study of agricultural populations with specific information on the chemicals of interest is also steadily contributing new findings to the database. Most important, the Vietnam veterans themselves are advancing in age and, when studied, are capable of providing substantial information on chronic health conditions directly. As the information in the database on populations with established exposures to the chemicals of interest has grown, the committee has come to depend less on data from studies with nonspecific exposure information and has been able to focus more on findings of studies with refined exposure specificity.

In this update, the committee endeavored to emphasize and clarify the relationship among the succession of publications that have provided ever increasing insight into the health responses of particular exposed populations that have been studied for many years. The information in the results tables for individual health outcomes has grown over eight cycles of revision, but this committee found that the presentation of new findings in update-specific clusters obscured the interdependent nature of many of the studies on a given cohort. Therefore, the findings in the results tables have been rearranged and grouped by study population. In addition, the cohorts themselves have been ordered on these tables to reflect the hierarchical nature of many of these study populations (for example, workers at the Dow plant in Midland, Michigan, are one of several cohorts composing the

National Institute for Occupational Safety and Health cohort, which in turn is one of the many international cohorts making up the IARC cohort). Lastly, the exposure of interest for each cohort has been explicitly noted on the tables to facilitate judgments about when consistency might be expected among populations experiencing the same exposure.

The original legislation, PL 102-4, did not provide a list of specific diseases and conditions suspected of being associated with herbicide exposure. Such a list was developed on the basis of diseases and conditions that had been mentioned in the scientific literature or in other documents identified through the original VAO’s extensive literature searches. The VAO list has been augmented in response to developments in the literature, requests by VA, and concerns of Vietnam veterans.

The information that the present committee reviewed was identified through a comprehensive search of relevant databases, including databases covering biologic, medical, toxicologic, chemical, historical, and regulatory information. The search of literature published through September 30, 2010, identified more than 6,600 potentially relevant citations. Screening of those retained about 1,300 for closer consideration, and about 65 papers on epidemiologic studies and several score of toxicology studies ultimately contributed new information to this review. Additional information came from veterans and other interested people who testified at public hearings and offered written submissions.

To determine whether there is an association between exposure and a health outcome, epidemiologists estimate the magnitude of an appropriate measure (such as the relative risk or the odds ratio) that describes the relationship between exposure and disease in a defined population or group. In evaluating the strength of the evidence linking herbicide exposure with a particular outcome, the committee considered whether such estimates of risk might be incorrect (because of confounding, chance, or bias related to errors in selection and measurement) or might accurately represent true associations; although they are not required, data supporting biologic plausibility serve to strengthen confidence that an association is not spurious. It has been the practice of all VAO committees to evaluate all studies according to the same criteria and then to weight findings of similar strength and validity equivalently, whether or not the study subjects are Vietnam veterans, when drawing conclusions. The committee recognizes that an absolute conclusion about the absence of association might never be attained, because, as is generally the case in science, studies of health outcomes after herbicide exposure cannot demonstrate that a purported effect is impossible, only that it is statistically improbable.

EVIDENCE REVIEWED BY THE COMMITTEE

The sections below summarize new epidemiologic information evaluated in this update and integrated with that previously assembled. The epidemiologic studies have been divided, both here and in the health-outcome chapters, into

three categories—Vietnam-veteran, occupational, and environmental—depending on the population addressed.

Vietnam-Veterans Studies

Three studies of Vietnam veterans published since Update 2008 were reviewed by the committee. One study on Army Chemical Corp personnel produced findings related to all cause mortality, while another study on Australian Vietnam veterans evaluated the prevalence of a multitude of self-reported health outcomes, including cancers, circulatory diseases, respiratory diseases, diabetes, and digestive disorders. A third study examined the progression of prostate cancer in a case–control study of veterans with previous Agent Orange exposure.

Occupational Studies

Several occupational studies have been published since Update 2008. Recent reports from the Agricultural Health Study examined the incidence of pancreatic cancer, hearing loss, melanoma, thyroid disease, adult onset asthma, myocardial infarction, and rhinitis in private pesticide applicators (farmers), their spouses, and commercial pesticide applicators. The incidence of Parkinson disease (PD) was investigated in an expanded cohort of farmers occupationally exposed to 2,4-D from Washington State and in three newly defined case–control studies assembled from Texas, France, and eight clinics in North America. All cause mortality incidence was reported from two different subcohorts of the IARC cohort. Circulatory diseases and neurologic outcomes were studied in a 40-year follow-up of Czech production workers who were exposed to TCDD during the production of 2,4,5-T.

Environmental Studies

Numerous studies from environmental exposures to the chemicals of interest have been published since Update 2008. Reproductive outcomes, including birth weight, birth defects, childhood cancer, neonatal thyroid function, and development of childhood obesity were studied in offspring of mothers exposed to TCDD and other chemicals with dioxin-like biologic activity from incinerator emissions in France, the industrial accident at Seveso, Italy, and dietary intake in Taiwan, Italy, Belgium, the Netherlands, and Japan. Cancer outcomes were evaluated in follow-up studies of residents of Seveso, Italy, farmers and pesticide applicators/ users in Canada and the US. Diabetes and conditions associated with metabolic syndrome were assessed in Great Lakes sport-fish consumers, Taiwanese residents near a pentachlorophenol factory, Finnish fisherman, Japanese men and women, and the general US population via the National Health and Nutrition Ex-

amination Survey. New case–control studies examined environmental exposures to the chemicals of interest and endometriosis and Parkinson disease.

THE COMMITTEE’S CONCLUSIONS

Health Outcomes

The present committee weighed the strengths and limitations of the epide-miologic evidence reviewed in this report and in previous VAO reports. Although the studies published since Update 2008 are the subject of detailed evaluation in this report, the committee drew its conclusions in the context of the entire body of literature. The contribution of recent publications to the evidence database was substantial, but the committee did not weigh them more heavily merely because they were new. Epidemiologic methods and analytic capabilities have improved, but many of the recent studies were also particularly useful for this committee’s purpose because they produced results in terms of serum TCDD concentrations or the total amount of exposure from all dioxin-like chemicals. Of course, observations on the health of our population of primary concern, Vietnam veterans, are increasingly informative as they age.

Table S-1 defines four categories of association and gives criteria for assigning health outcomes to them. On the basis of its evaluation of veteran, occupational, and environmental studies, the committee allocated particular health outcomes to categories of relative certainty of association with exposure to the herbicides that were used in Vietnam or to any of their components or contaminants (with no intention of specifying particular chemicals). The committee notes that experimental data related to biologic plausibility of conditions statistically associated with exposure to Agent Orange have gradually emerged since the beginning of this series of VAO reports and that these findings can inform the decisions about how to categorize the degree of association for individual conditions; a footnote to this effect has been added to Table S-1.

The terminology of “early-onset transient peripheral neuropathy” was adopted in Update 2004 as a replacement for the terminology of “acute and subacute peripheral neuropathy” used in Update 1996. Update 1996, the first VAO report to find “limited or suggestive evidence of association” with exposure to the chemicals of interest for this health outcome, also noted in the body of the report that this was a “transient” effect. When VA declared this outcome to be presumptively associated with service in Vietnam, its definition included the temporal constraints that symptoms develop shortly after herbicide exposure and that recovery from those symptoms occurs within 2 years of their initial development. Thus, currently qualifying cases are contingent upon when symptoms arise relative to when exposure occurred and that the symptoms are transitory in nature. A thorough review of the existing literature in populations with members

TABLE S-1 Summary of Eighth Biennial Update of Findings of Veterans, Occupational, and Environmental Studies Regarding Associations Between Exposure to Herbicides and Specific Health Outcomes^a

experiencing early-onset peripheral neuropathy, however, indicated that some individuals continue to manifest neuropathy symptoms long after external exposure has ceased, demonstrating that early-onset peripheral neuropathy is not necessarily a transient condition. Based on this literature, the committee chose to delete the word transient to recognize that symptoms of early-onset peripheral neuropathy may be protracted and recovery from those symptoms may be incomplete. This change to the classifications made since the previous update is bolded in Table S-1.

As mandated by PL 102-4, the distinctions among categories are based on statistical association, not on strict causality. The committee was directed to review the scientific data, not to recommend VA policy; therefore, conclusions reported in Table S-1 are not intended to imply or suggest policy decisions. The conclusions are related to associations between exposure and outcomes in human populations, not to the likelihood that any individual’s health problem is associated with or caused by the herbicides in question.

This committee gave careful consideration to the request from VA that, in addition to its usual discussion of biologic plausibility, the committee should state the degree to which each of the other “Hill criteria for causality” are satisfied by the existing scientific information. As well known as these standards or those developed by the US Surgeon General when first assessing the health consequences of smoking are, there is in fact no sufficient set of criteria for declaring that causality has been established. In accord with the current thinking of epidemiologists, the committee concluded that adopting a checklist approach would be inappropriate.

Risk in Vietnam Veterans

There have been numerous health studies of Vietnam veterans, but most have been hampered by relatively poor measures of exposure to herbicides or TCDD and by other methodologic problems. In light of those problems, many conclusions regarding associations between exposure to the chemicals of interest and disease have been based on studies of people exposed in various occupational and environmental settings rather than on studies of Vietnam veterans, although studies of health consequences in the maturing veterans themselves have now begun to generate more informative findings. The committee believes that there is sufficient evidence to reach general or qualitative conclusions about associations between herbicide exposure and health outcomes, but the lack of adequate exposure data on Vietnam veterans themselves makes it difficult to estimate the degree of increased risk of disease in Vietnam veterans as a group or individually. Without information on the extent of herbicide exposure of Vietnam veterans and quantitative information about the dose–time–response relationship for each health outcome in humans, estimation of the risks experienced by veterans exposed to the chemicals of interest during the Vietnam War is not possible.

Because of those limitations, only general assertions can be made about risks to Vietnam veterans, depending on the category of association into which a given health outcome has been placed. If there were “limited or suggestive evidence of no association” between herbicide exposure and a health outcome, the evidence would suggest no increased risk of the outcome in Vietnam veterans attributable to exposure to the chemicals of interest (at least for the conditions, exposures, and lengths of observation covered by the studies reviewed). Even qualitative estimates are not possible when there is “inadequate or insufficient” evidence of an association. For outcomes categorized as having “sufficient” or “limited or suggestive” evidence of an association with herbicide exposure, the lack of exposure information on Vietnam veterans prevents calculation of precise risk estimates.

The information needed for assigning risk estimates continues to be absent despite concerted efforts to model the exposure of the troops in Vietnam, to measure the serum TCDD concentrations of individual veterans, and to model the dynamics of retention and clearance of TCDD in the human body. Accordingly, several successive VAO committees have stated as a general conclusion that, at least for the present, it was not possible to derive quantitative estimates of any increased risks of various adverse health effects that Vietnam veterans may have experienced in association with exposure to the herbicides sprayed in Vietnam. Given the amount of time that has passed since the Vietnam era, the current committee has concluded that the necessary information to perform such estimation for Vietnam veterans is extremely unlikely ever to become available.

COMMITTEE RECOMMENDATIONS

IOM has been asked to make recommendations concerning the need, if any, for additional scientific studies to resolve continuing scientific uncertainties about the health effects of the herbicides used in Vietnam and their contaminants. Great strides have been made over the past several years in understanding the health effects of exposure to the herbicides used in Vietnam and to TCDD and in elucidating the mechanisms that underlie the effects, but there are still subjects on which increased knowledge could be very useful.

This committee recommends that VA should more actively query its own medical databases to identify potential associations between Vietnam service and specific health outcomes, particularly for those outcomes that are less common. Moreover, if a perceived conflict of interest exists in surveying its own databases, it is recommended that an external advisory group be formed to determine the best mechanism for mining this information so that these medical databases could be available for external study.

The committee for Update 2008 concluded that it was plausible that exposure to the herbicides sprayed in Vietnam could cause paternally mediated effects in offspring as a result of epigenetic changes, and such potential would most likely be attributable to the TCDD contaminant in Agent Orange. There is a growing body of evidence that TCDD, and also arsenicals, can induce epigenetic changes in animal models, but there remains extremely limited data on the risk of paternal exposure to xenobiotics in general, and the VAO chemicals of interest in particular, resulting in adverse effects on their offspring. Consequently, this committee continues to recommend that laboratory research be conducted to characterize TCDD’s potential for inducing epigenetic modifications. Further, the committee recommends development of epidemiologic protocols to address the logistical challenge of determining whether adverse effects are being manifested in the adult children and grandchildren of Vietnam veterans as a result of paternal exposure. The best cohorts for revealing potential associations would be those with known, well-characterized exposure information. Another alternative would be to adopt a case–control approach and 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. To hone in on a paternal effect, however, it will be necessary to establish that the mothers did not have the opportunity for exposure above background levels to the chemicals of interest.

As in previous years, this committee recommends the pursuit of additional research in toxicology. The development of animal models of various chronic health conditions and their progression would be useful for understanding the possible contributions of the chemicals of interest to compromise the health of aging Vietnam veterans. Specifically, determining the mechanism by which dioxin-like chemicals induce B cell cancers and how this exposure alters the sus-

ceptibility to developing obesity and components of metabolic syndrome would fill important knowledge gaps. Health problems, such as metabolic syndrome, chronic obstructive pulmonary disease (COPD), and measuring meaningful bio-markers of immune/inflammatory disease merit study in human populations.

The committee notes that the earlier investment in studying several exposed populations is now producing useful findings; the National Institute for Occupational Safety and Health, Seveso, Air Force Health Study, and Army Chemical Corps cohorts all merit continuing follow-up or more comprehensive analysis. It is especially important that longitudinal analyses be conducted on cancer, cardiovascular, and reproductive outcomes represented in the complete database assembled in the course of the Air Force Health Study. The committee endorses VA’s actions toward restarting the congressionally mandated National Vietnam Veterans Longitudinal Study, derived from the cohort originally studied in the National Vietnam Veterans Readjustment Study.

The committee notes that its recommendations are similar to those offered in previous updates and that there has been little activity in several critical areas. The fate of the assemblage of data and biologic samples from the Air Force Health Study remains unsettled; in the interim, critical integrative analyses such as longitudinal evaluation of the cancer data have not yet been made public, and the unique potential of this resource languishes. It is the committee’s conviction that work needs to be undertaken promptly to resolve questions regarding several health outcomes, importantly COPD, tonsil cancer, melanoma, Alzheimer disease, and paternally transmitted effects to their offspring. Creative analysis of VA’s own data resources and further work on cohorts that have already been established may well be the most effective way to address those outcomes and to gain a better understanding of the role of herbicide exposure in development of PD in Vietnam veterans.