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Cytogenetic and Mutagenic Effects

Little in vitro genetic toxicology testing appears to have been done on Lewisite. Jostes and colleagues (1989) have completed the most extensive study in Chinese hamster ovary (CHO) cells. They found that Lewisite was cytotoxic after a one-hour exposure to micromolar amounts. Cell survival experiments yielded a D37 of 0.6 µM with an extrapolation number of 2.5. Interestingly, at the dose ranges of 0.125 to 2.0 µM no consistent significant induction of mutations at the hprt gene locus was observed. At doses of 0.25 to 1 µM, Jostes and colleagues noted no significant induction of SCEs in CHO cells, although the dose-response trend was toward a positive response. Lewisite did significantly induce chromosomal aberrations at doses of 0.5 and 0.75 µM, with a definite positive dose-response. Stewart and colleagues (1989) tested the mutagenicity of Lewisite in the Ames Salmonella assay. Four Salmonella strains were tested with and without S9 microsomal activation. This compound (S9) is used in this bioassay system to activate the agent of interest to its biologic intermediates. These intermediates are often the bioactive species and are the compounds of real interest. The strain most sensitive to killing was TA 102. No mutagenic response was observed in any strain with or without S9 activation.

No other data evaluating the genotoxicity of Lewisite appear to exist, but there have been studies of the genotoxicity of other arsenicals. Jacobson-Kram and Montalba (1985) have shown that inorganic arsenic induces both chromosome aberrations and SCEs in mammalian cells. Arsenite enhances ultraviolet light (UV) mutagenicity in bacteria (Ross-man, 1981) and viral transformation in mammalian cells (Casto et al., 1979). Arsenite synergistically enhances cis-platinum (a DNA-alkylating agent) and UV-plus-psoralen induced chromosome aberrations (Lee et al., 1986a,b). Using sulfur dioxide and arsenite, Beckman and Nordenson (1986) noted no enhanced induction of SCEs. Recent work has also shown that arsenic will induce gene amplification (an increase in the number of copies of an actively transcribed gene) in mouse cells in culture (Barrett et al., 1989; Lee et al., 1988). Arsenic exposure in vivo also has been reported to induce chromosome aberrations in human lymphocytes (Nordenson et al., 1978).

Arsenite reacts avidly with protein sulfhydryl groups. Relatively recent work has shown that arsenite is highly selective in reacting with small, closely spaced dithiol groups in proteins (Joshi and Hughes, 1981; Knowles and Benson, 1983). Dexamethasone binding to glucocorticoid receptors is inhibited by arsenite via a putative mechanism involving the formation of a stable dithioarsenite complex with a single dithiol group within the binding domain of the receptor (Lopez et al., 1990). Arsenite also blocks DNA binding by the receptor, presumably via a similar

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