1,2-Dibromoethane (DBE) is a nematocide used extensively to control fruitfly and other larvae that feed on fruit and grain and as a lead scavenger in gasoline additives. DBE is extremely toxic to animals at relatively low doses and is carcinogenic in chronic animal studies on mice and rats. The lack of good human epidermiologic data resulted in the reliance of quantitative risk assessment techniques by the Environmental Protection Agency (EPA) for severely limiting its use as a fumigant for grain in 1984, and the Occupational Safety and Health Administration (OSHA) for lowering workplace standards from 20 parts per million (ppm) to 0.1 ppm. This thesis reviews the metabolic, animal, and human studies used for the extrapolation, the mathematical models available, the assumptions made for the data and model chosen, and discusses the validity of the resultant process for setting standards for DBE exposure.

Arsine gas is a potent hemolytic agent. Early work suggested glutathione depletion preceded, and oxygen required for hemolysis to occur. This study developed an in vitro model of arsine hemolysis, using the solubility of arsine gas in aqueous solutions. A total of 75% of the arsine was taken up into the cells within 5 minutes. Hemolysis occurred after 1-2 hours and reached 40-50%. Glutathione depletion occurred, but only after hemolysis reached its maximum. Increasing intracellular glutathione did not prevent hemolysis. The use of an intracellular chelator, monomethyldimercaptosuccinic acid did not prevent hemolysis. Hemolysis occurred in an oxygen excluding atmosphere but carboxyhemoglobin prevented hemolysis. Glutathione depletion is not a critical first step in arsine induced hemolysis. The interaction of arsine with the heme site of hemoglobin is critical to hemolysis. It is likely that a free radical intermediate of oxygen or arsine is the ultimate hemolytic agent.

Acetaldehyde, the first metabolite of ethanol, has been shown to bind to proteins to form protein-acetaldehyde adducts in vivo and in vitro. The effects of acetaldehyde have been implicated in diseases associated with alcoholism. In the present study, we have extended the observations by studying three different protein-acetaldehyde adducts in vitro, and hair keratin-acetaldehyde adduct in alcohol-fed mice in vivo. Our studies reported here suggest that our enzyme-linked immunosorbent assay (ELISA) is able to detect the stable protein-acetaldehyde adducts. In our preliminary application of the indirect ELISA assay in the chronically alcohol-fed mice, we found that there were significantly increased levels of hair keratin-acetaldehyde adducts in the 5-week alcohol group, 8-week alcohol group, including different alcohol diet groups, compared to the normal control group. We suggest that our indirect ELISA assay has a potential as a biochemical parameter for alcoholism in the clinical settings, although the further study should be performed. Fluorescent techniques, including fluorescent HPLC and fluorescent spectrophotometry were also discussed.

The identification of chlorinated organic compounds in drinking supplies has resulted in an interest in the metabolism and toxicity of chlorinated aldehydes. Another possible factor in the metabolism of chloroaldehydes is the endogenaous tripeptide glutathione. The formation of glutathioneconjugates with chloroaldehydes may increase or decrease their rate of reaction with the aldehyde dehydrogenase enzyme. This study found that the rat liver aldehyde dehydrogenase isozymes lost activity with time regardless of storage conditions. In vitro assays of enzyme activity confirmed substrate specificity for the chloroaldehydes and the isozymes. The reaction rate of glutathione depletion by monochloroacetaldehyde was the highest of the aldehydes. The addition of glutathione to the activity assays resulted in a decrease in Vmax but few significant changes in the Km values. Glutathione concentration was depleted by aldehydes in solution. Glutathione effected the metabolism of aldehydes by aldehyde dehydrogenase isozymes.

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