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are included because there is a dearth of experiments on sulfur mustard. Further, the similarity of action of nitrogen mustard to sulfur mustard provides information that is useful in assessing the types and sites of malignancy that may occur from exposure to sulfur mustard.

In what follows, in accordance with historical usage, we use the term sulfur mustard, although the terms HS, HD, or H were often used in past experimental literature. HD and HS refer to distilled sulfur mustard (approximately 96 percent pure), while H refers to an impure preparation known as Levinstein mustard. Experiments have been conducted with two nitrogen mustards, HN2 [methylbis(b-chloroethyl)amine or the hydrochloride] and HN3 [tris(b-chloroethyl)amine]. By far the most data are available for HN2, which is a common chemotherapeutic agent, usually in combination with other chemicals (see Medical and Therapeutic Exposure section of this chapter). The designations HN2 and HN3 are used as appropriate.

Early Studies in Mice and Rats

One of the earliest reports of the carcinogenic effect of the nitrogen mustards is an interim report describing preliminary results on the intravenous, intraperitoneal, and subcutaneous injections of HN2 and HN3 into Swiss mice and albino rats (Griffin et al., 1950). At the time of the report, tumors had developed in 15 to 20 percent of treated animals, whereas no tumors had appeared in controls. The tumors included fibrosarcomas, lymphosarcomas, and adenocarcinomas (no sites or numbers were given), and administration of a single dose proved as effective in inducing tumors as multiple injections.

Another early study on the carcinogenicity of mustard compounds was conducted at the Chester Beatty Research Institute in London (Boyland and Horning, 1949). Aqueous solutions of HN2 or HN3 were administered by subcutaneous injection weekly for 50 weeks to two groups of 20 stock mice each. The weekly dose of each substance was 1 mg/kg body weight. This dose was toxic and led to a high early mortality; only 10 animals administered HN2, and 4 animals administered HN3, survived 150 days. These 14 survived from 284 to 580 days. At autopsy, among the 10 injected with HN2, there were 3 lung carcinomas, 1 lung adenoma, and 1 with ''early bronchogenic tumors." One animal had a liver lymphosarcoma and another had a uterine fibromyoma. Three were free of tumors. Among the 4 administered HN3, there were 2 lung carcinomas and 1 lung adenoma. One of the animals with carcinoma also had a spindle-celled sarcoma at the site of injection. Substantial other non- or premalignant pathology was described in all of the treated animals. Of 40 untreated mice sacrificed between 14 and 18 months of age, 6 had lung adenomas and 2



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