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workers could be identified and studied, which would contribute additional information.

The second gap concerns the limited information available on exposure levels. Historical records vary considerably in their detail. Exposure measurements, if any, were usually done to determine levels for particularly troublesome parts of the manufacturing process or were collected for specific areas of the plant, which limits their value in characterizing particular jobs.

The third gap concerns assessment of risk. The available epidemiologic studies focus on determining whether exposure is associated with a increased rate of malignancy in the exposed workers. This endeavor is complicated, and its conclusions—whether or not war gases are carcinogenic—are not the most appropriate questions to be addressed by this committee. Even if one concludes that the studies demonstrate a relationship between exposure and human cancer, the question remains: What would be the likely rate of cancer in the chamber and field test volunteers, or those who worked with these agents, exposed at levels different from the battlefield or occupational situations in Japan or Great Britain? This question requires a quantitative risk assessment, which cannot be developed from the data available in the literature.

Conclusions

Mustard agents are well known to be monofunctional and bifunctional DNA alkylating agents. They are extremely cytotoxic at low doses. They alkylate RNA and proteins and produce DNA lesions, which may be repaired only at low doses. The sulfur mustards also alkylate the 0-6 position of guanine. DNA alkylation is likely primarily responsible for the mutagenic consequence of cellular exposure. The sulfur mustards induce a wide variety of genetic lesions in many types of mammalian cells in vitro in a dose-related fashion. They also induce genetic damage in vivo in peripheral blood lymphocytes at low doses.

In contrast to mustard agents, the genetic toxicology of Lewisite has been poorly studied. Lewisite induces chromosome aberration in one type of cellular assay. It appears not to be mutagenic in Salmonella.

Sulfur mustard produces a variety of cancers through different exposure routes. It produced skin malignancies in chamber exposure in rats. Intravenous injection produced a significant increase in pulmonary tumors in highly susceptible strain A mice. Subcutaneous injections produced sarcomas and other tumors at the injection site in C3H, C3Hf, and strain A mice, but did not produce an increase of tumors at other sites.

Nitrogen mustard, particularly HN2, was more widely tested and



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