lack of association, or persistent indeterminacy with respect to a wide array of disease states has accrued. For many conditions, however, particularly ones that are very uncommon, associations with the chemicals of interest have remained unaddressed in the medical research literature; for these, the committee remains neutral on the basis of the understanding that “absence of evidence is not evidence of absence.”


Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophen-oxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed in Vietnam. At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, one form of dioxin) was an unintended contaminant from the production of 2,4,5-T and so was present in Agent Pink, Agent Green, Agent Purple, Agent Orange, and Agent Orange II, which all contained 2,4,5-T. It is important to note that TCDD and Agent Orange are not the same. Databases have been searched for the names of those compounds, their synonyms and abbreviations, and their Chemical Abstracts Service (CAS) numbers. The evidence indicates that a single protein, the aryl hydrocarbon receptor (AHR), mediates essentially all the toxicity of TCDD, so aryl hydrocarbon receptor also was used as a keyword, as were dioxin, Agent Orange, and Vietnam veteran.

One of the herbicides used in Vietnam was cacodylic acid, or dimethylar-sinic acid of valency 5 (DMAV), an organic form of arsenic. In addition to being synthesized as a herbicide, DMAV is a metabolite of inorganic arsenic exposure in humans. DMAV was long thought to be a biologically inactive metabolite, but evidence suggests that methylated forms such as MMAIII (Aposhian et al., 2000), and perhaps DMAIII and DMAV (Cohen et al., 2006), might be responsible for some of the adverse effects of inorganic arsenic. The committee carefully reconsidered that evidence but again determined that it does not support a conclusion that exposure to cacodylic acid (DMAV) would be expected to result in the same adverse health effects as would exposure to toxic concentrations of inorganic arsenic. Therefore, as in prior VAO reports, the literature on the health effects of inorganic arsenic was not considered here. Further details on the effects of inorganic arsenic can be found in Arsenic in Drinking Water (NRC, 1999) and Arsenic in Drinking Water: 2001 Update (NRC, 2001). For cacodylic acid and picloram, the search terms were the chemical names, synonyms, and CAS numbers of the herbicides.

This report concentrates on the evidence published after the completion of work on Veterans and Agent Orange: Update 2008 (IOM, 2009). Relevant new contributions to the literature made during the period October 1, 2008–September 30, 2010, were sought. The information that the committee used was compiled from a comprehensive electronic search of public and commercial databases— biologic, medical, toxicologic, chemical, historical, and regulatory—that pro-

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