METABOLISM AND TOXICITY OF HALOGENATED ALKYL PHOSPHATES

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Halogenated alkyl compounds are used extensively as herbicides, pesticides, and fire retardants, and many are employed as intermediates in manufacturing processes. Several of these compounds have been found to be genotoxic and cytotoxic. The overall objectives of the proposed research are to determine those structural features of halogenated alkyl compounds that are important determinants of genotoxicity and acute cytotoxicity, and to understand how halogenated alkyl compounds interact with tissue components to cause toxicity. Specifically, the mechanisms of toxicity of the flame retardant chemicals tris(2,3-dibromopropyl)phosphate (Tris-BP) and tris(1,3- dichloropropyl)phosphate (Tris-CP), and of the nematocide, 1,2- dibromo-3-chloropropane (DBCP), will be investigated. Mechanisms of kidney toxicity will be examined by treating rats will agents that are known to modulate renal cytochromes P-450 and GSH concentrations to determine their role in toxication or detoxication pathways of the halogenated compounds. Both isolated kidney cells and testicular cells will be used to elucidate mechanisms of acute toxicity and genotoxicity caused by the halogenated compounds in these target cell populations. Cell membrane damage will be assessed by cell viability (trypan blue exclusion) and enzyme (LDH) leakage, and DNA damage by alkaline elution of DNA. Metabolites will be isolated by HPLC and their structures elucidated by soft ionization mass spectral techniques (FAB MS/MS). Selectively deuterated and methylated analogs of Tris-BP, Tris-CP, and DBCP that are significantly less toxic will be compared with their parent compounds to determine how the structural modifications altered toxicity and metabolism. Finally, the structures of mutagenic metabolites of Tris-BP, Tris- CP and DBCP will be determined both by characterization of trapped derivatives and by comparison with synthetic standards, whenever it is feasible. If mutagens are identified, they will be reacted with nucleosides for comparisons with DNA adducts. These studies will parallel studies that are ongoing to characterize the reactions of 2-bromoacrolein with DNA. 2- Bromoacrolein has been identified as a potent direct-acting mutagenic metabolite of Tris-BP and DBCP.