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pounds is probably the lesion that produces lethality at the lowest frequency of occurrence and at the lowest concentration of the agent. However, cell death from this lesion is delayed for a number of hours, until the cell replicates its DNA or undergoes division. At higher cellular exposures, mechanisms other than DNA cross-linking become important and produce more rapid cell death. The acute damage to the cornea, mucous membranes, and skin seen with sulfur mustard is probably generated by one or more of these other mechanisms.

One mechanism that may be involved in acute damage is nicotinamide adenine dinucleotide (NAD) depletion. The nuclear enzyme poly-(adenosine diphosphoribose) polymerase is activated by DNA strand breaks, such as those produced by sulfur and nitrogen mustards. The enzyme cleaves NAD between nicotinamide and adenine diphosphoribose (ADP) and joins the ADP molecules into polymers of ADP-ribose, which are then linked to nuclear proteins, including the enzyme itself. This process can rapidly deplete cellular pools of NAD, which is required for ATP synthesis. The subsequent depletion of ATP rapidly produces loss of energy-dependent functions in the cell and results in cell death.

Other potential mechanisms of rapid cell death are related to the rapid inactivation of sulfhydryl peptides, especially glutathione, and proteins. These sulfhydryl compounds are critical to maintaining the appropriate oxidation-reduction state of cellular components. In particular, enzymes that maintain calcium homeostasis are sulfhydryl dependent, and sulfhydryl depletion may lead to elevated cellular calcium levels and cell death. Glutathione is also thought to be critical in reducing reactive oxygen species in the cell and preventing lipid peroxidation and loss of membrane integrity.

The toxicities of sulfur mustard to specific organs and tissues are described in detail in subsequent sections of this report. Essentially all of the data on the effects of sulfur mustard on humans are derived from either gas exposure or topical application to the skin. Because of the extensive use of nitrogen mustards in cancer chemotherapy, there is an extensive body of literature on these compounds in man after systemic administration, with doses and clinical follow-up. Since the fundamental mechanisms of interaction of sulfur mustard and nitrogen mustards with biological molecules are very similar, it should be useful to consider the major effects of nitrogen mustards, especially the long-term effects, in trying to ascertain the long-term clinical effects of sulfur mustard. The acute effects of nitrogen mustard are initially nausea and vomiting, followed in a few days by hematopoietic depression. At higher doses, neurotoxicity and damage to the gastrointestinal epithelium are seen. The major delayed effect of nitrogen mustards has been carcinogenesis, especially the development of myelocytic leukemia, although an in-



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