2-Bromoacrolein (2-BA) and 2,3-dibromopropanal (2,3-DBPA), an identified and a postulated reactive metabolite of tris(2,3-dibromopropyl)phosphate (Tris-BP), respectively, were found to cause mutations in Salmonella typhimurium TA 100 both in the absence and presence of a metabolic system. 2-BA, as well as 2,3-DBPA, caused extensive DNA single-stranded breaks as evidenced by alkaline elution of DNA from exposed Reuber hepatoma cells in culture. The data with Syrian hamster embryo cells suggest that both 2-BA and 2,3-DBPA were more potent than Tris-BP in transforming these cells in culture. On the other hand, neither 2-BA, nor 2,3-DBPA, was found to cause increased unscheduled DNA repair synthesis in isolated rat hepatocytes in monolayer cultures, whereas Tris-BP had a significant effect at low concentrations (10-50 microM). There was no correlation between the observed mutagenic effects of 2-BA and 2,3-DBPA and their alkylating activities using the nitrobenzyl-pyridine test. The genotoxic effects associated with 2-BA and its detection in microsomal incubations makes it a likely candidate for a role in the mutagenicity of Tris-BP.

1,2-Dibromo-3-chloropropane (DBCP) and a number of halogenated propane analogs induced DNA damage in rat hepatocytes in vitro measured by an automated alkaline elution method. Short-term (2 hrs) cytotoxic effects of DBCP were not observed until the DBCP concentration exceeded 1 mM. The short-term cytotoxicity of all the DBCP analogs occurred in the same concentration range. Significant membrane damage, measured as cell detachment, was observed after extended exposure to lower concentrations of DBCP (100 microM) for 20 hrs. The relative, delayed cytotoxic effect of DBCP and analogs correlated with their ability to cause DNA damage. In general, the halogenated propanes with more bromines relative to chlorines were the more potent compounds. Propane analogs lacking the third halogen had little cytotoxic activity. The addition of the proposed specific poly(ADP-ribosyl)transferase inhibitor 3-aminobenzamide (3-ABA) protected against DBCP-induced cytotoxic effects and NAD+ depletion. However, 3-ABA also reduced DBCP-induced DNA damage, DBCP metabolic loss, and the formation of water soluble and covalently bound DBCP metabolites. Thus, 3-ABA may block DBCP-induced cell death by decreasing the formation of reactive DBCP-metabolites.

Selectively deuterated and methylated analogues of the flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) and its nephrotoxic metabolite bis(2,3-dibromopropyl)phosphate (Bis-BP) were compared to Tris-BP and Bis-BP in inducing acute renal damage in rats. None of the deuterated Tris-BP or Bis-BP analogues significantly altered morphological evidence of nephrotoxicity compared to the protio compounds. On the other hand, some of the selectively methylated analogues were much less nephrotoxic. Although the C1-methyl analogues of both Tris-BP and Bis-BP were as potent nephrotoxicants as Tris-BP and Bis-BP, respectively, neither the C2-methyl nor the C3-methyl analogues were significantly nephrotoxic. Interestingly, whereas the 3,4-dibromobutyl homologue of Tris-BP was not nephrotoxic, the corresponding 3,4-dibromobutyl-Bis homologue was as nephrotoxic as Bis-BP. Additional investigations with treatments that are known to decrease nephrotoxicity caused by several halogenated alkenes, showed that L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) and aminooxyacetic acid were without effects on Tris-BP induced renal damage. Probenecid pretreatment led to a reduction in Tris-BP and Bis-BP tubular necrosis, these effects may be related to inhibition of Bis-BP uptake in the kidney. It appears that the cysteine conjugate beta-lyase pathway is not involved in the generation of nephrotoxic metabolites of Tris-BP.