1,2-dibromoethane metabolism

Two reactive intermediates are formed through 1,2-dibromoethane metabolism, 2-bromoacetaldehyde and S-(2-bromoethyl) glutathione. The 2-bromoacetaldehyde causes tissue... 

Levels of Significant Exposure to 1,2-Dibromoethane - Inhalation 2-2 Levels of Significant Exposure to 1,2-Dibromoethane - Oral 2-3 Proposed Metabolic Pathways for 1,2-Dibromoethane ... 

Renal Effects. The patient described by Letz et al. (1984) (see Section 2.2.3.1) who lived for 64 hours after exposure to toxic levels of 1,2-dibromoethane had acute renal failure as evidenced by severe oliguria 24 hours after exposure and abnormal clinical chemistry values (blood urea nitrogen, creatinine, and serum uric acid). Severe metabolic acidosis was present despite two hemodialysis procedures. 

The retention of 1,2-dibromoethane in tissues and body fluids can be altered by concurrent exposure to modifiers of enzyme activity, such as disulfiram (Plotnick et al. 1979). The concentration of radiolabeled 1,2-dibromoethane in the liver, kidneys, spleen, testes, and brain increased significantly in rats fed disulfiram in the diet for 12 days before an oral dose of 15 mg C-1,2- dibromoethane/kg compared with rats not fed disulfiram. Disulfiram, an inhibitor of P-450 metabolism (via action on acetaldehyde dehydrogenase), was found to increase the uptake of C into liver nuclei. These observations correlate well with the results of chronic studies (Wong et al. 1982) that demonstrated enhanced tumorigenic effects in the liver and testes following combined 1,2-dibromoethane and disulfiram exposure. 

Dibromoethane is metabolized to active forms capable of inducing toxic effects by either of two systems-the microsomal monooxygenase system (cytochrome P-450 oxidation) and the cytosolic activation system (glutathione conjugation). Figure 2-3 provides an overview of the metabolism of... 

In animals, 1,2-dibromoethane is rapidly metabolized after oral administration and is converted into mercapturic acid derivatives that appear in urine (Kirby et al. 1980 Nachtomi 1970 Nachtomi et al. 

Based on the rapid and extensive metabolism seen in all animals, the fate of 1,2-dibromoethane in humans would be expected to be similar. Seventy percent of the administered parent compound is excreted in the urine and feces by 48 hours. The lack of persistence of metabolites in the tissues indicate that 1,2-dibromoethane is readily removed from the body. Low-level exposure would not be expected to result in accumulation of 1,2-dibromoethane or its metabolites in human tissue. 

However, theoretically, acute high-level exposure may saturate metabolic pathways and consequently allow 1,2-dibromoethane to accumulate in the tissues for a longer period of time. 

Intraperitoneal administration of 37.6, 75, or 113 mg 1,2-dibromoethane/kg/day (0.2, 0.4, or 0.6 mmol/kg) to rats resulted in metabolic biotransformation into mercapturic acid which was strongly... 

Liver toxicity related to 1,2-dibromoethane depends on the metabolic pathway utilized and the amount of damage induced in cellular protein and membrane structures. Humans exposed to low levels of 1,2-dibromoethane are at potential risk of having toxic events occurring within hepatocytes whether these effects will be subcellular or result in cell necrosis may depend on internal dose and a variety of factors. Liver damage that is severe enough to cause clinical disease in humans from low-level exposure is unlikely. 

Principe et al. 1981 Rosenkranz 1977). The mutagenicity of 1,2-dibromoethane in bacteria was not influenced by mammalian metabolizing systems in four out of five studies (Barber et al. 1981 Moriya et al. 1983 Principe et al. 1981 Stolzenberg and Mine 1980). However, detection of its mutagenic activity is influenced by the amount of glutathione present (Kerklaan et al. 1985 Zoetemelk et al. 

Dibromoethane tested positive for mutagenicity with or without metabolic activation in fungi and mammalian cell lines in in vitro assay systems (Brimer et al. 1982 Clive et al. 1979 ... 

Primary biomarkers of exposure are the presence of 1,2-dibromoethane in blood or exhaled breath or excretion of specific metabolites in urine. In humans exposed to toxic levels of 1,2- dibromoethane (Letz et al. 1984), the parent compound was not measured in blood samples collected before death. However, two exposed individuals had elevated levels of serum bromide ions. This elevation is likely to have resulted from debromination of 1,2-dibromoethane during its metabolism. Elevated serum bromide is not specific to 1,2-dibromoethane exposure, but, rather, it is indicative of exposure to classes of brominated chemicals. 

Once absorbed, 1,2-dibromoethane is rapidly metabolized. Its metabolism may induce effects by either of two systems, the microsomal monooxygenase system or the cytosolic activation system. Animal research has shown that seventy percent of 1,2-dibromoethane is excreted in the urine and feces within 48 hours. The lack of persistent metabolites in the tissues indicate that... 

No specific antidote has been shown to be effective in treating 1,2-dibromoethane intoxication once absorption into the bloodstream has occurred (Ellenhorn and Barceloux 1988). Intravenous infusions of glucose may limit the hepatotoxicity of 1,2-dibromoethane (ERA 1989b). During the recovery phase, a diet rich in vitamin B and carbohydrates may limit liver damage (Dreisbach and Robertson 1987 Lawrence and Michaels 1984). Hemodialysis may be needed to regulate extracellular fluid and electrolyte balance and to remove metabolic waste products if renal failure occurs (ERA 1989b). 

The carcinogenic and mutagenic effects of 1,2-dibromoethane is due to its ability to bind to DNA and RNA with metabolic activation. The mechanism of action for the antispermatogenic effects is probably related to the removal of sulphur from cysteine in the nucleus of the spermatozoa. Clinical intervention to interfere with these mechanisms has yet to be developed. 

No studies in humans were found regarding excretion of 1,2-dibromoethane. Animal studies regarding the excretion of 1,2-dibromoethane following inhalation and dermal exposures are unavailable, but information is available for excretion following oral exposures (Plotnick et al. 1979). Since metabolites may contribute to the toxic effects attributed to 1,2-dibromoethane, it would be beneficial to conduct studies that would establish elimination rates for each metabolite or similar metabolic products. In addition, such studies may also provide information to facilitate the rapid removal of 1,2-dibromoethane and its metabolites in exposed people. 

Comparative Toxicokinetics. Generally, target organs and adverse effects of 1,2-dibromoethane exposure are similar across species. Toxicokinetic studies have been performed in rats, mice, and guinea pigs. There are no major differences in distribution patterns. Humans would be expected to metabolize 1,2-dibromoethane in a manner qualitatively similar to animals. However, the disposition of 1,2-dibromoethane in humans remains to be determined. 

Exposure Levels in Humans. 1,2-Dibromoethane can be measured in blood and metabolites can be detected in urine (Letz et al. 1984 Nachtomi et al. 1965). However, since the compound is rapidly and extensively metabolized in mammals, and 1,2-dibromoethane metabolites do not persist in tissues, these biomarkers have not been useful in identifying or quantifying human exposure to the compound. 

Brem H, Coward JE, Rozenkrantz HS. 1974b. 1,2-Dibromoethane Effect on the metabolism and ultrastructure of Escherichia coli. Biochem Pharmacol 23 2345-2347. 

Hunder G, Schmid A. 1988. In vivo metabolism of 1,2-dibromoethane (DBE). Arch Pharmacol 337 (suppi) R18. 

MacFarland RT, Gandolfi AJ, Sipes IG. 1984. Extra hepatic reduced GSH-dependent metabolism of 1,2-dibromoethane and 1,2-dibromo-3-chloropropane (DBCP) in the rat and mouse. Drug Chem Toxicol 7 213- 227. 

Mann AM, Darby FJ. 1985. Effects of 1,2-dibromoethane on glutathione metabolism in rat liver and kidney. Biochem Pharmacol 34 2827-2830. 

Scott BR, Sparrow AJ, Schwemmer SS, et al. 1978. Plant metabolic activation of 1,2-dibromoethane (EDB) to a mutagen of greater potency. Mutat Res 49 203-212. 

Shih TW, Hill DL. 1981. Metabolic activation of 1,2-dibromoethane by glutathione transferase and by microsomal mixed function oxidase Further evidence for formation of two reactive metabolites. Res Common Chem Pathol Pharmacol 33 449-461. 

Sipes IG, Wiersma DA, Armstrong DJ. 1986a. The role of glutathione in the toxicity of xenobiotic compounds Metabolic activation of 1,2-dibromoethane by glutathione. Adv Exp Med Biol 197 457-467. 

Tomasi A, Albano E, Dianzani MU, et al. 1983. Metabolic activation of 1,2-dibromoethane to a free radical intermediate by rat liver microsomes and isolated hepatocytes. FEES Lett 160 191-194. 

Van Bladeren PJ, Breimer DD, Van Fluijgevoort JA, et al. 1981. The metabolic formation of N-acetyl-S-2-hydroxyethyl-L-cysteine from tetradeutero-1,2-dibromoethane. Relative importance of oxidation and glutathione conjugation in vivo. Biochem Pharmacol 30 2499-2502. 

White RD, Gandolfi AJ, Bowden GT, et al. 1983. Deuterium isotope effect on the metabolism and toxicity of 1,2-dibromoethane. Toxicol AppI Pharmacol 69 170-178. 

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