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.

1,2-Dibromoethane or ethylene dibromide (EDB) is a recognized mutagen in several in vitro test systems and a carcinogen in rodents after oral, dermal, or inhalation exposure. EDB is metabolized in vitro by both the microsomal polysubstrate monooxygenase system and the cytosolic glutathione-S-transferases. The goal of this project was to determine which, or if both of these enzyme systems form a metabolite(s) responsible for the genotoxic effects observed in vivo. In order to distinguish the contribution of each enzyme system in vivo, the metabolism of tetradeutero-1,2-dibromoethane (dEDB) was examined. Metabolism of EDB or dEDB by either enzyme system releases bromide ion. The deuterium substitution of EDB reduced the amount of bromide released by microsomal enzymes by over 60%. The rate of bromide release by cytosolic enzymes was unaffected by deuterium substitution. The metabolism of EDB and dEDB were compared in male Swiss Webster mice. Three hours after intraperitoneal injection of EDB or dEDB (50 mg/kg), measurement of the serum bromide ion concentration indicated a 42% reduction in dEDB metabolism compared to EDB. These results demonstrated the importance of microsomal metabolism to the disposition of EDB and suggested that dEDB would be a useful tool in delineating the bioactivation pathway responsible for the genotoxic effects of EDB. Hepatic nuclei were isolated from mice exposed to EDB or dEDB and damage to the DNA was assessed by the alkaline elution technique. EDB (25-75 mg/kg) caused a dose dependent increase in DNA single-strand breaks. More DNA single-strand breaks were detected when lysed nuclei were preincubated in the alkaline eluting solution prior to analysis. The presence of these alkali-labile sites suggest that the DNA strand breaks result, in part, from the lability of DNA sites alkylated by EDB. There was no evidence of EDB induced DNA-DNA cross-links or DNA-protein cross-links. While the metabolism of dEDB three hours after exposure was less than EDB, the amount of DNA damage caused by both analogs was not significantly different at this time point. At later time points (8, 24, 72 hours) dEDB caused significantly greater DNA damage than EDB. Since the decreased metabolism of dEDB was due to inhibition of microsomal oxidation, these data support the hypothesis that glutathione conjugation of EDB results in formation of a genotoxic metabolite.

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