METABOLISM AND TOXICITY OF HALOGENATED ALKYL PHOSPHATES

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The overall objective of the proposed research is to determine those structural features of halogenated alkyl compounds which render them either highly toxic or relatively non-toxic. To this end the mechanisms of metabolic activation of tris(2,3-dibromoprpyl)phosphate (Tris-BP) and structurally related compounds will be examined with regard to their genotoxic and cytotoxic effect. Specifically deuterated and radiolabeled analogs of Tris-BP will be used to probe the mechanism of nephrotoxicity caused by this brominated alkyl phosphate in rats and in preparations of isolated kidney cells from rats. Stereoisomers of Tris-BP will be synthesized to determine if the relative configuration of the adjacent alkyl bromines is a determinant of mutagenicity. 2-Bromoacrolein, a major mutagenic metabolite of Tris-BP and other halogenated compounds, will be reacted with nucleosides and glutathione to investigate the nature of adducts with DNA or protein that may cause structural damage. Gonadal toxic effects of Tris-BP will be compared to those of tris(1,3-dichloro-2-propyl) phosphate (Tris-CP) in mice using an assay for abnormal sperm. This is important inasmuch as Tris-CP has been detected in the semen of male college students. Finally, specifically deuterated analogs of 1,2-dibromo-3-chloropropane (DBCP) will be synthesized to investigate mechanisms for activation of this nematocide to mutagenic products. DBCP is structurally related to the halogenated alkyl phosphates and several synthetic male antifertility agents, and it causes similar genotoxic and cytotoxic effects. Results of these studies should provide a stronger basis for making benefit/risk assessments for halogenated alkyl phosphates and other halogenated compounds that are related in structure.