Influence of oral administration of a quaternary mixture of trihalomethanes on their blood kinetics in the rat.

Trihalomethanes (THMs; chloroform, bromoform, bromodichloromethane, dibromochloromethane), formed as by-products of chlorine disinfection, are found to occur in combination in drinking water supplies. THMs are metabolized by cytochromes P-450 and are likely substrates of CYP2E1. Therefore, it is possible that mixed exposure results in toxicokinetic interactions among THMs. The toxicokinetics of THMs during mixed exposures has not been investigated previously. The purpose of this study was to characterize the blood kinetics of the four THMs administered singly or in combination in the rat. A single dose of 0.25 mmol/kg or 0.5 mmol/kg b.w., of each THM alone, or of a quaternary mixture containing 0.25 mmol/kg of each THM (total dose of 1.0 mmol/kg) was administered by gavage. The venous blood concentrations of the THMs were measured by headspace gas chromatography (GC) at 20, 40, 60, 120, 180, 270 and 360 min post-administration. Results showed a nonlinear relationship between the area under the blood concentration versus time curves (AUCs) and administered doses of THMs, suggesting that metabolism is saturated in this dose range. The venous blood concentrations of THMs following administration of the quaternary mixture were significantly higher compared to single exposures. The altered kinetics of THMs during combined exposures is consistent with the occurrence of mutual inhibition of their hepatic metabolism. Simulation exercises conducted with physiologically based toxicokinetic models support metabolic inhibition as the possible mechanism of the interaction among THMs. The data reported in this study provide the starting point for evaluating the significance of interactions among THMs in the risk assessment process.