Chloracne has been used as a marker of exposure in epidemiologic studies of populations exposed to TCDD and related chemicals. It is one of the few findings in humans that are consistently associated with such exposure, and it is a well-validated indicator of high-dose exposure to TCDD and related chemicals (Sweeney et al., 1997/98). If chloracne occurs, it appears shortly after the chemical exposure, not after a long latent period; therefore, new cases of chloracne among Vietnam veterans would not be the result of exposure during the Vietnam War. It should be noted that absence of chloracne does not necessarily indicate absence of substantial exposure to TCDD, as is apparent from studies of people who had documented exposure to TCDD after the Seveso incident (Baccarelli et al., 2005a), nor is there necessarily a correlation between serum TCDD concentration and the occurrence or severity of chloracne. Susceptibility to the development of chloracne varies among individuals.

Conclusions from VAO and Previous Updates

The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (referred to as VAO; IOM, 1994) determined that there was sufficient evidence of an association between exposure to at least one chemical of interest (TCDD) and chloracne. Additional information available to the committees responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), and Update 2006 (IOM, 2007) has not modified that conclusion.

Even in the absence of full understanding of the cellular and molecular mechanisms that lead to the disease, several notable reviews (Panteleyev and Bickers, 2006; Sweeney and Mocarelli, 2000) have deemed the clinical and epidemiologic evidence of dioxin-induced chloracne to be strong. The occupational epidemiologic literature has many examples of chloracne in workers after reported industrial exposures (Beck et al., 1989; Bond et al., 1987, 1989a,b; Cook et al., 1980; Goldman, 1972; May, 1973, 1982; Oliver, 1975; Pazderova-Vejlupkova et al., 1981; Poland et al., 1971; Suskind and Hertzberg, 1984; Suskind et al., 1953; Zober et al., 1990). With relative-risk estimates as high as 5.5 in exposed workers compared with referent nonexposed workers, Bond et al. (1989a) identified a dose–response relationship between probable exposure to TCDD and chloracne. Not everyone exposed to relatively high doses develops chloracne, and some with lower exposure may acquire it (Beck et al., 1989).

Almost 200 cases of chloracne were recorded in those residing in the vicinity of the accidental industrial release of dioxin in Seveso, Italy. Most cases occurred in children, particularly in people who lived in the highest-exposure zone, and most cases resolved within 7 years (Assennato et al., 1989a,b; Caramaschi et al., 1981; Mocarelli et al., 1991). No cases of chloracne were identified in conjunc-



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