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CONCLUSIONS REGARDING THE CAUSAL RELATIONSHIPS OF EXPOSURE TO THE DEVELOPMENT OF SPECIFIC DISEASES

The major conclusions reached by the committee regarding the association of exposure to mustard agents or Lewisite to specific diseases in different organ systems are summarized in Table 12-1. In some cases, the data examined were found to indicate a causal relationship between exposure and a particular disease or health problem. For other health problems, the data were suggestive, but not completely clear. Finally, there were certain health problems for which very little or no data existed regarding the possible contributions of exposure to mustard agents or Lewisite. By the same token, however, there was no condition evaluated that could be removed from consideration as a health consequence of exposure to these agents. Thus, for many diseases and health problems, there remains significant doubt about whether or not exposure to these agents is a key etiological factor.

The evidence indicates a causal relation between sulfur mustard exposure and the occurrence of excess respiratory and skin cancer, and possibly leukemia. This conclusion is based upon estimates of exposure to sulfur mustard during the chamber tests, which may have approximated the battlefield exposure of surviving World War I (WWI) soldiers and WWII production workers in Japan and Great Britain. Inadequate exposure information, however, limits precise estimation of the cancer excesses that may be expected. The evidence is insufficient to indicate a causal relationship for Lewisite carcinogenesis.

Mustard agents are DNA-alkylating agents and are extremely cytotoxic at low doses. DNA alkylation is probably responsible for the mutagenicity of mustard agents. These agents also alkylate RNA and proteins and can, at moderate to high doses, produce nonrepairable DNA lesions (genotoxicity). 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 from exposed individuals at low doses. The toxicology of Lewisite has been poorly studied.

Chamber exposure to sulfur mustard has produced skin malignancies in rats, and intravenous injection has produced a significant increase in pulmonary tumors in highly susceptible strain A mice. Subcutaneous injection of sulfur mustard has been shown to cause 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, has been more widely tested than sulfur mustard and has been found to be a carcinogen, producing



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