elucidation of carcinogenesis (Fraumeni, 1975; IARC, 1980; Kennaway, 1942; National Research Council, 1977; Pershagen, 1981). Squibb and Fowler (1983) state emphatically, "The question as to whether arsenic is a direct carcinogen ... remains unanswered at this time. Epidemiological data clearly indicate that exposure to arsenic increases the incidence of skin, lung, liver and lymphoid cancer in humans, however, animal studies designed to confirm the carcinogenic potential of arsenic and its compounds have been, for the most part, negative." Goldman and Dacre (1989) state, "There is still reservation about accepting arsenic as a carcinogen because of the failure to demonstrate that arsenic in any form has resulted in an increased incidence in the production of tumors in experimental animals."
The most often quoted evidence of Lewisite-induced cutaneous cancer is a case of Bowen's disease that developed 8 years after Lewisite-produced injury (Krause and Grussendorf, 1978) and the multiple keratoses and skin cancers in the group of Japanese "war-gas" factory workers described above (Inada et al., 1978). The questions regarding the Japanese study in terms of sulfur mustard effects also apply here.
Arsenic has been linked to the production of human cancer by many investigators (Allen, 1967; Graham and Helwig, 1959; Graham et al., 1961; Montgomery and Waisman, 1941). Roth (1956) described arsenic-induced cancers among vineyard workers, as well as a striking multiplicity of arsenic-induced cancers. Sommers and McManus (1953) also called attention to the multiplicity of lesions and the involvement of internal organs as well as skin. Arsenic may produce keratoses (keratinized protuberances of skin, particularly on the palms and soles), squamous cell cancer, basal cell cancer, multicentric intraepithelial basal cell carcinoma, and Bowen's intraepidermal squamous cell cancer.
Convincing proof of the etiologic linkage of arsenic to neoplasms is the demonstration of arsenic in tumors. Two fairly simple tests have been used: (1) the Osborne test, which demonstrates the presence of yellowish-green crystals in specially stained histologic sections of skin; and (2) the direct differential chemical analysis of fragments of tissue for arsenic. Montgomery and Waisman (1941) have shown that normal skin will contain 0.00008 mg of arsenic per gram of tissue; whereas, cancerous skin will contain 0.00024 to 4.3 mg of arsenic per gram of tissue. Arsenic has been recovered from human skin up to 30 or more years after administration of the compound. Graham and colleagues (1961) in