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bination) induces mutations in vivo in human lymphocytes at the hypoxanthine phosphoribosyltransferase (hprt) enzyme gene locus (Yanagida et al., 1988).

Summary

Mustard agents are mono- and bifunctional DNA-alkylating agents that are extremely cytotoxic at low doses. They alkylate RNA and proteins and produce DNA lesions, which may be repaired only at low doses. Sulfur mustards also alkylate the 0-6 position of guanine; this lesion is likely primarily responsible for the mutagenic consequence of cellular exposure. The sulfur mustards are genotoxic in a wide variety of cells, producing chromosome aberrations and gene mutations in vitro in a dose-related fashion. They also induce SCE and hprt mutations in vivo in the peripheral blood lymphocytes of individuals exposed at low doses.

Lewisite

There are limited data in the literature on the genetic toxicology of Lewisite. Although data on many types of arsenical compounds have demonstrated significant genotoxic potential, data on Lewisite are incomplete.

Biologic Fate and Mechanism of Action

Lewisite undergoes a complex hydrolysis involving several reversible reactions. Lewisite oxide (Cl-CH=CH-AsO) is approximately 1 percent soluble in water and 2 percent soluble in a saline solution. It is slightly more soluble at an alkaline pH. At higher pH, Lewisite oxide is cleaved by hydroxyl ions to yield arsenite and acetylene.

Lewisite has labile chlorine atoms, trivalent arsenic, and multiple bonds of carbon atoms. It is a very reactive compound. It will undergo rapid nucleophilic substitution by water. In the presence of hydrogen sulfide it forms 2-chlorovinylarsine, an extremely irritating compound. Lewisite also reacts rapidly with mercaptans to form alkylarsine.

Lewisite penetrates skin rapidly on contact. It binds avidly to proteins and thiols, and the mechanism of its local and systemic toxicity is likely mediated through this binding. It is concentrated in the thiol-containing tissues throughout the body (e.g., skin and hair). The toxicity of Lewisite is reversed by administration of the dithiol compound BAL, British Anti-Lewisite, or other thiol-containing compounds. The precise chemical nature of any of the genetic lesions (DNA-based lesions) induced by cellular exposure to Lewisite appears to be unknown.



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