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10 Research Recommendations As part of its charge, the committee was asked to make recommendations concerning the need, if any, for additional scientific studies to resolve uncer- tainties 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 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid. This chapter summarizes the committee’s research recommendations. Although great strides have been made over the last several years in un- derstanding the health effects of exposure to the chemicals of interest and in elucidating the mechanisms underlying them, gaps in our knowledge remain. The scope of potential research on the chemicals is wide, and what follows in this chapter is not an exhaustive listing of future research that might have value. There are many additional opportunities for progress in such subjects as toxicol- ogy, exposure assessment, the conduct of continuing or additional epidemiologic studies, and systematic and comprehensive integration of existing data that have not been explicitly noted here. • There is a need for new animal models to elucidate mechanisms of diseases and disease progression. The committee believes that experimental research in the mechanisms that underlie human health outcomes (particularly cardiovascular disease) could pro- vide valuable information related to the risk of disease in Vietnam veterans. The central role of the aryl hydrocarbon receptor (AhR) in animal models is clear, and AhR gene differences in animals clearly affect susceptibility to the effects of TCDD. Although work to date on the AhR in humans has been sparse, variations 699

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700 VETERANS AND AGENT ORANGE: UPDATE 2006 in this specific genetic factor alone are likely to affect human susceptibility to the toxic effects of TCDD, other dioxin-like chemicals, and herbicide formula- tions containing these chemicals. In addition, recent research makes clear that variations in the genetic regulation of the expression or activity of other factors, including proteins that interact with the AhR and the gene products that are regulated by the AhR, are critical in determining susceptibility to the effects of TCDD and the types of toxic effects observed. Studies addressing the identifica- tion, distribution, and functional consequences of polymorphisms of the AhR and the other cofactors in human populations should be pursued. • A biphasic physiologically based pharmacokinetic (PBPK) model for TCDD is needed. The committee recognizes the importance of accurate back-extrapolation of serum TCDD concentrations to predict exposure levels at the time of Vietnam service and to categorize veterans accurately into appropriate exposure classifi- cations. As noted in Chapter 3, new human PBPK models have been developed in an effort to incorporate the increasing evidence that TCDD exhibits dose- dependent elimination. The models seriously challenge the paradigm of a one- compartment, first-order elimination model for back-extrapolation of estimates of earlier exposures; however, it remains unclear which type of model should be used for dose reconstruction. Thus, the committee recommends additional valida- tion of the PBPK models and direct comparisons of the resulting exposure clas- sifications when the new models and the standard first-order elimination models are applied to large data sets. • Potential emergence of metabolic syndrome should be analyzed. The committee recognized that, within the study populations reviewed in preparing Update 2006, the values of serum components and specific health outcomes may be interrelated, including hypertriglyceridemia, type 2 diabetes mellitus, hypertension, and ischemic heart disease. The first three of those out- comes are key criteria for the diagnosis of metabolic syndrome, and the fourth is a major consequence of it. Thus, the committee recommends that—in addition to analysis of the association of exposure to the chemicals of interest with indi- vidual health outcomes—the incidence of multiple health outcomes that define metabolic syndrome should be analyzed as a group. • Possible effects in offspring merit further investigation. The assessment of any link between exposure of Vietnam veterans to the chemicals of interest and birth defects or developmental disease in their offspring presents distinct challenges. The Department of Veterans Affairs (VA) should re- view all the possible cognitive and developmental effects in offspring of veterans. Such a review should include the possibility of effects in grandchildren, which are of growing concern to veterans and their families. A recent review of the lit- erature and meta-analysis by Ngo et al. (2006) noted a significant association for

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RESEARCH RECOMMENDATIONS 701 veterans, who served in Ranch Hand, pointing to the need to examine closely both the biologic plausibility of paternally mediated birth defects and existing epide- miologic evidence. In addition, reviews have focused on epidemiologic studies of data from birth-defect registries or parental reports of birth defects. Those studies often exclude alterations in function that could appear later in a child’s life, such as in neurologic function, endocrine function, or reproductive capacity. The find- ings of the Air Force Health Study (AFHS) on birth defects in veterans’ offspring have not yet been (and, if funding is not provided, may never be) formally and systematically integrated and analyzed in a longitudinal fashion. Most etiologic research has focused on the effects of maternal and fetal exposures, but some work addressing paternal exposures has been discussed in previous reviews. With increasing concern about male reproductive function, increasing numbers of epidemiologic studies of the role of paternal exposures in the risk of birth defects among offspring are being published. This work is particularly relevant in assessing health outcomes in offspring among a largely male service population. The plausibility of birth defects arising from parental exposure, especially from paternal exposure, merits a careful review in light of newly hypothesized mechanisms (such as heritable forms of gamete imprinting) that might make paternal transmission of a TCDD effect more plausible. The committee recommends that an ad hoc group be established to review current mechanistic studies that could further knowledge of a possible paternally medi- ated link between exposure to the chemicals of interest and health conditions (including birth defects) among offspring. Given the rarity of birth defects, the committee also recommends that the ad hoc group conduct a meta-analysis of the current epidemiologic studies of male populations exposed to the chemicals of interest and the risk of birth defects among offspring. • Available information should be gleaned from existing cohort studies. Members of the Army Chemical Corps constitute the largest cohort of Viet- nam veterans exposed directly to herbicides and TCDD. They were involved in the handling and distribution of the chemicals in Vietnam. Army Chemical Corps veterans who reported spraying herbicides as part of their duties have been demonstrated to have increased serum TCDD concentrations; that more highly exposed population (herbicide sprayers) has also been shown to be at increased risk for several diseases. The population should be the focus of additional study, with new resources devoted to it, because it represents our best opportunity to understand the health effects of exposure to TCDD and the herbicides used in Vietnam. The present VAO committee concurs with the recommendations of the recent Committee on the Disposition of the Air Force Health Study (IOM, 2006). That committee concluded that the various assets of the study should be retained, that a custodian should be identified to house and administer the data, and that the data should be made available for future research. The future availability of the

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702 VETERANS AND AGENT ORANGE: UPDATE 2006 data implies that full longitudinal analysis using the data collected in the various medical cycle examinations, data on medical interventions (such as hospitaliza- tions and emergency-department visits), cancer incidence, mortality, and other data on exposure could be used profitably to investigate further some of or all the endpoints that may be associated with the exposures under consideration in the present report. The present VAO committee concurs with the AFHS-disposition committee that prioritizing which endpoints to investigate ought to be left to in- dependent investigators making appropriate choices based on scientific criteria. There is regrettably little data available on the women who served in Vietnam. The cohort of nurses studied in Kang et al. (2000) largely exhausted the source population, but now that an additional 10 years has elapsed following up the health status of this group and determining their TCDD levels would be worthwhile. At the direction of Congress, the National Vietnam Veterans Readjustment Study (1986–1988) investigated primarily psychiatric sequellae in a representa- tive cohort of about 1,600 men and women. In 2000, Congress mandated (Public Law 106-419) that the VA assess the current physical and mental well-being of the individuals in that cohort. In 2001, VA contracted for the work, named the National Vietnam Veterans Longitudinal Study, but unfortunately progress ceased within 2 years. The VA Office of Inspector General (2005) ruled that “the Study was not properly, planned, procured, or managed,” but directed that the study be completed, making provisions to avoid the previous problems. Because baseline information is available on symptoms and chronic health problems in the original cohort, the committee thinks completion of this study could generate meaningful information for future updates and concurs that serious consideration should be given to restarting the National Vietnam Veterans Longitudinal Study. Starting in 1978, the National Institute for Occupational Safety and Health (NIOSH) began to study US workers potentially exposed to TCDD. A total of 5,132 workers in 12 large manufacturing companies were included in the cohort. The NIOSH cohort has been an extremely valuable source of data in assessing the health effects associated with TCDD exposure. The studies have included high-quality exposure assessment, and evaluations of a wide array of health outcomes have been published. Given its value as an important source of epide- miologic data, the committee recommends that studies of the NIOSH cohort be extended. The committee also notes that future analyses of health outcomes in those and other important study populations should be as specific as possible because generic findings, such as for “all respiratory outcomes,” are not useful in address- ing this committee’s charge of determining associations of herbicide exposures with specific health conditions. • VA should evaluate possibilities for studying health outcomes among Vietnam-era veterans by using the existing administrative and health- services databases.

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RESEARCH RECOMMENDATIONS 703 The original VAO committee recommended that the Department of Defense and VA identify Vietnam service in the computerized index of records. By linking that information with the VA electronic medical-record and associated administra- tive databases, such as discharge-diagnosis and pharmacy-use records, it should be possible to assemble epidemiologic information on common health conditions for evaluation of possible associations with military service in Vietnam. Particular attention should be paid to the feasibility of conducting epide- miologic studies of conditions that have been noted to be of special interest but on which the current evidence is inadequate or insufficient to determine whether there is an association with herbicide exposure (such as tonsil and breast cancers, melanoma, Parkinson’s disease, amyotrophic lateral sclerosis, lupus, ischemic heart disease, and stroke). For very uncommon health outcomes, a case–control design would probably be most appropriate. 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, an effort to use existing VA information should include a more systematic review of the distribution of health outcomes in the database. • Exposure-reconstruction study should be put to use. The Institute of Medicine’s Committee on the Assessment of Wartime Expo- sure to Herbicides in Vietnam oversaw the development of an herbicide-exposure model for Vietnam veterans (the “Stellman model”), which was described in detail in recent publications (IOM, 2003a,b). That committee concluded that the model was adequate for use in epidemiologic studies. The present commit- tee recommends that the model be incorporated into new epidemiologic studies where feasible, as is being investigated by a newly convened IOM committee, the Committee on Making Best Use of the Agent Orange Reconstruction Model. • Studies of the Vietnamese population would be worthwhile. As discussed in earlier updates, the Vietnamese are an understudied popu- lation. Although there are likely to be serious logistical challenges, the many Vietnamese people with substantial exposure constitute a potentially informative study sample. It will be important to include appropriate exposure measures, such as tissue TCDD concentrations, when studying Vietnamese residents. Because such research has the potential to close a number of gaps in understanding of the long-term health consequences of exposure to TCDD and herbicides used in Vietnam, the committee supports any further steps that can be taken to develop collaborative programs of research.

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704 VETERANS AND AGENT ORANGE: UPDATE 2006 REFERENCES1 IOM. 2003a. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Interim Findings and Recommendations. Washington, DC: The National Academies Press. IOM. 2003b. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Final Report. Washington, DC: The National Academies Press. IOM. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. Kang HK, Mahan CM, Lee KY, Magee CA, Mather SH, Matanoski G. 2000. Pregnancy out- comes among US women Vietnam veterans. American Journal of Industrial Medicine 38(4):447–454. Ngo AD, Taylor R, Roberts CL, Nguyen TV. 2006. Association between Agent Orange and birth defects: Systematic review and meta-analysis. International Journal of Epidemiology 35(5):1220−1230. VA Office of Inspector General, Department of Veterans Affairs. 2005. Audit of VA Acquisition Practices for the National Vietnam Veterans Longitudinal Study (Report No. 04-02330-212). Washington, DC. 1Throughout the report the same alphabetic indicator following year of publication is used con- sistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.