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ments using pigskin, labeled Lewisite was deposited primarily in the hair and hair follicle, with a small amount within the epidermis. Ferguson and Silver (1947) described similar experiments using the skin of guinea pigs: Lewisite could be found within the epidermis in 2 minutes and the dermis within 10; it remained concentrated within the dermis for about 30 minutes and then began to disappear; only traces were detectable in the skin after 24 hours.

The histopathologic changes in skin after Lewisite exposure have been described by Davis (1944), Cameron and colleagues (1946), and McGown and colleagues (1985, 1987). Unlike sulfur mustard exposure, Lewisite causes early and complete necrosis of the epidermis in humans. The necrotic process also involves the dermis where it is principally vascular in location. Capillary degeneration and perivascular leukocyte infiltration accompany Lewisite vesiculation. Feister and colleagues (1989) state that there is evidence to show that, like vesication after sulfur mustard exposure, vesication subsequent to Lewisite injury occurs within the lamina lucida. However, it is not clear which anatomical structures are disrupted to cause epidermal-dermal separation. Studies in the human skin-grafted nude mouse system  suggest that epidermal-dermal necrosis precedes epidermal-dermal separation.

It is assumed that upon entry of Lewisite into the aqueous medium of the intact skin it is rapidly hydrolyzed to a stable, water-soluble, but highly toxic derivative 2-chlorovinylarsine oxide (Lewisite oxide) and hydrochloric acid. Feister and colleagues (1989) postulate that Lewisite oxide may be the principal metabolite and major cytotoxic form  of Lewisite within tissues. It is also believed that the trivalent form of arsenic, which is highly reactive in biological systems, is responsible for the overt toxicity of all arsenicals, including Lewisite, to living systems. Trivalent arsenicals exert their toxic effects through interactions with active tissue sulfhydryl groups (Peters, 1955; Peters et al., 1946; Squibb and Fowler, 1983). Trivalent arsenicals interact directly with protein sulfhydryl or thiol (sulfhydryl attached to a carbon) groups.

Because a vast array of critical enzymes contain thiol groups that interact with arsenicals, the end result of this interaction is enzyme inactivity. This ability of arsenicals to inhibit tissue enzyme activity in a variety of animal systems has made them valuable tools in the study of the biochemistry of specific enzymes, their mechanisms of action, and sites of action. A body of work, beginning with the separate investigations of R.A. Peters and C. Voegtlin in the 1920s, supports the concept that cell death from Lewisite results from the inhibition of the pyruvate-dehydrogenase complex, causing energy depletion within the cell (Peters, 1955; also see Feister et al., 1989). Numerous studies have shown that addition of arsenic to isolated mitochondria produces an inhibition of cellular respiration, the oxidation of tricar-



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