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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite
mechanism within the DNA-binding domain of the relevant protein (Simons et al., 1990).
Recent work of Wiencke and Yager (1992) hypothesized that arsenite might interact with DNA repair proteins that are known to contain so-called zinc fingers. These zinc fingers, which contain closely spaced dithiols, are likely important in gene regulation. Proteins that contain zinc fingers include the UVRA protein (Husain et al., 1986), polyadenosine diphosphoribose polymerase (Cherney et al., 1987; Uchida et al., 1987), the RAD-18 protein (Jones et al., 1988), and the XPAC protein (Tanaka et al., 1990). All of these are proteins that are thought to be central to DNA repair of genetic lesions. Wiencke and Yager showed that arsenite alone induced both SCEs and chromosome aberrations. However, when the DNA cross-linking agent diepoxybutane (DEB) was added to human lymphocyte culture in the presence of arsenite, the induction of chromosome aberrations was synergistically enhanced. The induction of SCEs was only additively increased. Interestingly, the synergistic enhancement of chromosome aberrations was most pronounced in individual lymphocytes previously known to be relatively more sensitive to the clastogenic action of DEB (Wiencke et al., 1991). Wiencke and Yager concluded that the specific co-clastogenic effects of arsenite were mediated by its interference with DNA repair activities. All of this work may indicate that arsenicals could interact with DNA-alkylating agents when they are given concomitantly. Although there is no direct evidence that the genetic effects of sulfur mustard exposure are enhanced by concomitant Lewisite exposure, it remains a possibility.
In contrast to mustard agents, the genetic toxicology of Lewisite has been poorly studied. Its hydrolysis has been examined and arsenite is one significant product likely produced in man after exposure. Lewisite itself clearly induces chromosome aberration in one type of cellular assay. It appears not to be mutagenic in Salmonella. Arsenicals in general and arsenite have been shown to be clastogenic and to induce SCE in human and other mammalian cells. Arsenite synergistically enhances the clastogenic action of alkylating agents, perhaps through binding to DNA repair proteins.
EVIDENCE OF LONG-TERM HEALTH EFFECTS
This section reviews the results of the published experimental carcinogenesis studies of sulfur mustard and nitrogen mustard. The latter