tion with the nonextreme environmental dioxin contamination at Times Beach, Missouri (Webb et al., 1987).

Exposures of Vietnam veterans were substantially lower than those observed in occupational studies and in environmental disasters, such as the one in Seveso. The long period since the putative exposure has imposed methodologic limitations on studies of Vietnam cohorts for chloracne. Nonetheless, the Vietnam Experience Study (CDC, 1988) found that chloracne was self-reported more often by Vietnam veterans than by Vietnam-era veterans (odds ratio [OR] = 3.9). An excess incidence was also found in Vietnam vs era veterans among subjects who were physically examined (OR = 7.3). In comparison with a nonexposed group, Air Force Ranch Hand personnel potentially exposed to Agent Orange reported a significant excess of acne (OR = 1.6) (Wolfe et al., 1990), but no cases of chloracne or postinflammatory scars were found on physical examination 20 years after possible herbicide exposure (AFHS, 1991b).

Biologic Plausibility

Previous updates have reported that chloracne-like skin lesions have been observed in several animal species in response to exposure to TCDD but not to purified phenoxy herbicides. Data accruing over the past several decades demonstrated that TCDD alters differentiation of human keratinocytes, and more recent studies have illuminated how. Geusau et al. (2005) found that TCDD accelerates the events associated with early differentiation but also obstructs completion of differentiation. Panteleyev and Bickers (2006) proposed that the major mechanism of TCDD induction of chloracne is activation of the stem cells in the basal layer of the skin to differentiate and inhibition of their ability to commit fully to a differentiated status. Ikuta et al. (2010) have investigated the expression of B-lymphocyte maturation protein 1 (Blimp1) in epidermal keratinocytes and sebocytes in mice after induction of the aryl hydrocarbon receptor (AHR). Recent work with a constitutively activated form of the AHR implicated additional inflammation-related mechanisms by which TCDD exposure may lead to chloracne (Tauchi et al., 2005). The data provide a biologically plausible mechanism for the induction of chloracne by TCDD.

Synthesis

No epidemiologic data in the past decade have refuted the conclusion of prior VAO committees that the evidence of an association between exposure to dioxin and chloracne is sufficient. The 2004 poisoning case of Ukrainian politician Victor Yuschenko has provided a high-profile instance that supports this condition as a response to high-level exposure to TCDD, and the careful monitoring of his case has demonstrated the course of chloracne’s resolution in conjunction with subsiding serum concentrations (Sorg et al., 2009). The formation of chlor-



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