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Evaluation of the Potential Impact of Inhibition of Trichloroethylene Metabolism in the Liver on Extra-Hepatic Toxicity
Citation:
Eklund, C. R., M. V. EVANS, AND J. E. SIMMONS. Evaluation of the Potential Impact of Inhibition of Trichloroethylene Metabolism in the Liver on Extra-Hepatic Toxicity. Presented at Society of Toxicology (SOT) Annual Meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
Therefore, the purpose of the present study was to understand the impact of decreased TCE metabolism in the presence of CHC13 on the concentration of TCE in the blood.
Description:
The interaction between trichloroethylene (TCE) and chloroform (CHCI3) is less than additive, with co-exposure to TCE and CHCl3 resulting in less hepatic and renal toxicity than observed with CHCl3 alone. Vapor uptake data demonstrate that co-exposure to CHCl3 decreases the rate of disappearance of TCE from the vapor uptake chamber. Physiologically-based pharmacokinetic (PBPK) modeling of vapor uptake data for TCE alone, CHCl3 alone, and binary mixtures of TCE and CHCl3 indicate that competitive inhibition best describes the effect of CHCl3 on TCE metabolism. We have previously determined that the acute neurotoxic effects of TCE are predicted on the basis of the momentary concentration of TCE in either the blood or the brain. Therefore, the purpose of the present study was to understand the impact of decreased TCE metabolism in the presence of CHC13 on the concentration of TCE in the blood. The vapor-uptake, five-compartment (blood, liver, fat, slowly and rapidly perfused) PBPK model was used to estimate the concentration of TCE in blood at the end of a 10 min, 1 hr or 8 hr exposure to initial starting concentrations of either 500 ppm TCE alone, 500 ppm TCE in combination with 500 ppm CHCI3, 1000 ppm TCE alone and 1000 ppm TCE in combination with 1000 pm CHCI3. At both 500 and 1000 ppm TCE, concurrent exposure to CHCl3 resulted in small increases in blood TCE concentrations at all three time intervals. The percentage increase ranged from -5% to -15% with the largest increases seen at 500 ppm TCE with 500 ppmCHC13. These model simulations indicate that increased blood concentrations of TCE (and increased neurotoxicity) may result from co-exposure to CHCI3. Similar simulations conducted with our human model (currently under development) will allow us to evaluate the degree of increased risk at low concentrations typically seen in the environment and at high concentrations that might result from accidental or intentional chemical releases. (This abstract does not reflect EPA policy.)