10
Research Recommendations

As part of its charge, the committee makes recommendations concerning the need, if any, for additional scientific studies to resolve uncertainties 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 understanding the health effects of exposure to the chemicals of interest and in elucidating the mechanisms underlying those effects, there are still important gaps in our knowledge. The scope of potential research on these chemicals is wide, and this is not an exhaustive list of future research that might have value.

VIETNAM VETERAN STUDIES

As in prior reports (IOM, 1994, 1996, 1999, 2000, 2001, 2003) that reviewed the epidemiologic evidence and evaluated the quality of available information, this committee recommends continuation of epidemiologic studies of existing veterans cohorts. This is especially important as the veteran populations grow older and the incidence of many health outcomes (e.g., cancer, neurological disorders) increases with age. The same reasoning is applicable to other established cohorts (such as NIOSH, Seveso, and IARC). The committee considers such continued research essential for addressing diseases with long latency or



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Veterans and Agent Orange: Update 2004 10 Research Recommendations As part of its charge, the committee makes recommendations concerning the need, if any, for additional scientific studies to resolve uncertainties 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 understanding the health effects of exposure to the chemicals of interest and in elucidating the mechanisms underlying those effects, there are still important gaps in our knowledge. The scope of potential research on these chemicals is wide, and this is not an exhaustive list of future research that might have value. VIETNAM VETERAN STUDIES As in prior reports (IOM, 1994, 1996, 1999, 2000, 2001, 2003) that reviewed the epidemiologic evidence and evaluated the quality of available information, this committee recommends continuation of epidemiologic studies of existing veterans cohorts. This is especially important as the veteran populations grow older and the incidence of many health outcomes (e.g., cancer, neurological disorders) increases with age. The same reasoning is applicable to other established cohorts (such as NIOSH, Seveso, and IARC). The committee considers such continued research essential for addressing diseases with long latency or

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Veterans and Agent Orange: Update 2004 age-related incidence. In addition, a high priority should be placed on clarifying the role of genetic factors, in particular the role of aryl-hydrocarbon receptor (AhR) polymorphisms, in determining individual susceptibility to disease. Air Force Health Study The Air Force Health Study (AFHS) is an epidemiologic study whose purpose is to determine whether exposure to the herbicides used in Vietnam might underlie any adverse health conditions observed in a cohort of Air Force personnel who conducted aerial spray missions (Operation Ranch Hand). A baseline morbidity study and a matched comparison cohort study were initiated in 1982, with follow-up assessments in 1985, 1987, 1992, and 1997. In accordance with the study protocol, one additional assessment was completed in 2003, and a final report will be issued in May, 2005 (personal communication, Joel Michalek, Brooks Air Force Base, September 24, 2004). The AFHS is one of the few primary sources of information on the health of Vietnam veterans known to have been exposed to Agent Orange and other herbicides, and the study is coming to its scheduled end. A congressionally-mandated Institute of Medicine (IOM) committee has been recently formed to evaluate the future of the AFHS. That IOM committee is charged with evaluating the scientific merit of maintaining the records and samples, and how those specimens could be made available for independent researchers. That committee also will evaluate the merit of extending that study beyond its scheduled end and, if extended, what oversight would be most appropriate. Previous VAO committees have recommended extending the AFHS, and this committee encourages the newly appointed AFHS review committee to consider those recommendations in the course of its deliberation. Army Chemical Corps Study Members of the Army Chemical Corps constitute the largest cohort of Vietnam veterans exposed directly to herbicides and TCDD. They were involved in the handling and distribution of the compounds in Vietnam. Preliminary studies of this cohort by scientists in the Department of Veterans Affairs have demonstrated increased TCDD concentrations in Chemical Corps veterans who reported spraying herbicides as part of their duties. Information on health outcomes from that cohort is expected to provide insight into the effects of the chemicals of interest on the entire population of Vietnam veteran. The committee has long awaited publication of more data from this study, and reasons why it has not been forthcoming are not apparent. Issues concerning continuation similar to those being evaluated by the IOM committee reviewing the AFHS should be assessed as well for the study of the Army Chemical Corps veterans.

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Veterans and Agent Orange: Update 2004 National Institute of Occupational Safety and Health (NIOSH) Cohort Starting in 1978, NIOSH began to study US workers potentially exposed to TCDD. In total, 5,132 workers from 12 large manufacturing companies were included in this 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 range of health outcomes have been published. Given its value as an important source of epidemiological data, the committee recommends that studies of the NIOSH cohort be extended. Exposure Reconstruction Study The IOM Committee on the Assessment of Wartime Exposure to Herbicides in Vietnam oversaw the development of an herbicide exposure model for Vietnam veterans (the “Stellman model”), which was described in detail in a recent publication (IOM, 2003b,c). That committee concluded the model was adequate for use in epidemiology studies. This committee recommends that the model be validated using appropriate measures of exposure (e.g., serum TCDD concentrations) in appropriate study populations. STUDIES OF VIETNAMESE As discussed in earlier updates, the Vietnamese represent an understudied population. Although there are likely to be significant logistical challenges, the many people with substantial exposure within the Vietnamese population represent a potentially informative study sample. It will be important to include appropriate exposure measures, such as TCDD levels in tissues, when studying Vietnamese residents. Because such research has the potential to close a number of gaps in our 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. OTHER RESEARCH The committee recognizes that the study of the possible diseases associated with exposure to the chemicals of interest is complicated by the latency period related to many health outcomes. Appropriate analytic techniques are available for addressing issues of latency, as reviewed in the recent IOM report on such issues (IOM, 2004). However, most studies to date have used relatively simple approaches. Approaches such as using a predetermined lag period or assessing cumulative exposure could potentially lead to erroneous conclusions about true dose-response relationships, thereby precluding detection of important health

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Veterans and Agent Orange: Update 2004 effects. Hence, more detailed and sophisticated latency analyses should be used in future research efforts. The committee believes that experimental research into the mechanisms that underlie human health outcomes can provide valuable information related to risk of disease in Vietnam veterans. The central role of the AhR in animal models is clear, and AhR gene differences in animals clearly affect susceptibility to TCDD. Although work to date on the AhR in humans has been limited, variations in this specific genetic factor alone are likely to affect human susceptibility to the toxic effects of TCDD, other dioxin-like chemicals, and herbicide formulations containing these chemicals. However, in addition to the AhR, it is also clear from recent research that variations in the genetics regulating the expression or activity or other factors, including proteins interacting with the AhR as well as the gene products regulated by the AhR, are critical in determining susceptibility to TCDD and the type of toxic effect observed. Studies addressing the identification, distribution, and functional consequences of polymorphisms of the AhR and these other cofactors in human populations should be pursued. REFERENCES IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2000. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes. Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2003a. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. IOM. 2003b. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Interim Findings and Recommendations. Washington, DC: The National Academies Press. IOM. 2003c. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Final Report. Washington, DC: The National Academies Press. IOM. 2004. Veterans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer. Washington, DC: The National Academies Press.