vide citations of the scientific literature. In addition, the reference lists of some review and research articles, books, and reports were examined for potentially relevant articles. As noted above, the terms used in the search strategy included the chemical names, synonyms, and CAS numbers of the specific chemicals of interest—2,4-D, 2,4,5-T, TCDD, cacocylic acid, and picloram (see Figure 2-1 for chemical structures and CAS numbers)—and the more generic terms involved with this project: Vietnam veteran, Agent Orange, aryl hydrocarbon receptor, dioxin, herbicide, and phenoxy. Results on other specific phenoxy herbicides are also of interest: 2-methyl-4-chlorophenoxyacetic acid (MCPA) and 2-(2-methyl-4 -chlorophenoxy) propionic acid (MCPP or Mecoprop) for 2,4-D and 2-(2,4,5-trichlorophenoxy) propionic acid (2,4,5-TP or Silvex) for 2,4,5-T (see Figure 2-1); although the benzoate herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) is not always categorized with the phenoxy herbicides, it has structural similarities with this class, and measures of its association with various adverse health outcomes have been factored into the evidence. Because some polychlorinated biphenyls (PCBs) and polychlorodibenzofurans (PCDFs) have dioxin-like biologic activity, studies of populations exposed to PCBs or PCDFs were reviewed when results were presented in terms of TOTSL toxic equivalents (TEQs). Findings related only to exposure to the diverse chemical families of pesticides were considered too nonspecific for inclusion in the evidence database used to draw conclusions about associations. (An ancillary analysis conducted during preparation of Update 2008 determined that the term pesticide did not identify any relevant citation that was not picked up by more specific terms, and so it was eliminated from the searches conducted for the current update, and this reduced the number of extraneous hits to be culled.)

(With the structural representation at hand in Figure 2-1, the committee will respond to an assertion it has heard repeatedly from individual Vietnam veterans that “benzene is contained in TCDD.” Indeed, the two rings at the ends of the three-ring structure constituting the basic structure of dioxin compounds, to which chlorine molecules or other chemical radicals can be attached, do have the molecular structure of a single benzene molecule and “dibenzo-dioxin” in TCDD’s chemical name does mean the molecule is indeed a benzene-substituted dioxane. The benzene ring structure is a basic building block of a vast number of organic compounds, both industrial [such as polyaromatic hydrocarbons, the phenoxy herbicides, picloram, and PCBs] and natural [such as estradiol, a hormone present in both men and women]. However, the biologically active compound benzene does not emerge from dioxin, whose three-ring structure is extremely stable and very resistant to metabolism.)

Because they are the target population of the charge to the VAO committees, studies of Vietnam veterans (serving in any of the armed forces, American or otherwise) have always been accorded considerable weight in the committees’ deliberations, whether or not estimation of exposure to herbicide-related substances has been attempted. Characterization of exposure in studies of the



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