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important to acknowledge a dose-response relationship—that is, the more exposure, the more effect. This is important for two reasons:

  •  If a study is small enough, or if the level of exposure in the study is low enough, the study may not detect a chemical-cancer association, even if it is present.

  •  Even if a chemical is a carcinogen at a high level of exposure, it may only rarely cause cancer at low levels of exposure.

Two further questions must therefore be addressed in order to make a contribution to the well-being of surviving experimental subjects exposed to chemical war agents. The first is whether the specific agents are likely to be carcinogens. The second is whether, at the level of exposure experienced by these subjects, the added risk that they carry is small or large.


Sulfur Mustard

Sulfur mustard has been produced primarily for its acute toxic effects. Concern has been raised, however, about the long-term health effects of exposure to sulfur mustard in humans. Because the various sulfur mustards are known to be animal carcinogens, much of this concern has centered around their potential carcinogenicity to humans. One part of the process of assessing the carcinogenic risk involves examination of the biologic fate of this compound, its potential genotoxicity, and its ability to induce mutations in living systems.

Biologic Fate and Mechanisms of Action

After absorption, sulfur mustard undergoes intermolecular cyclization to form an ethylene episulfonium ion intermediate, liberating a free chloride anion. This process is facilitated by heat and by water, a likely explanation for the vulnerability of the warm and moist regions of the body (mucous membranes, eyes, respiratory tract, etc.) to the acute toxic effects of this compound (Somani and Babu, 1989; Ward and Seider, 1984). Cyclization can occur on both ends of the molecule. The cyclic intermediate reacts rapidly with a variety of nucleophiles, according to the affinity of neighboring compounds for the reaction. In pure aqueous media, most sulfur mustard is hydrolyzed to thiodiglycol and hydrochloric acid.

Boursnell and colleagues (1946) have shown that 35S-labeled sulfur mustard diffused rapidly throughout the body after intravenous (IV) injection in experiments employing rabbits. Activity was retained chiefly

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