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Physiologically-based pharmacokinetic (PBPK) modeling of two binary mixtures: metabolic activation of carbon tetrachloride by trichloroethylene and metabolic inhibition of chloroform by trichloroethylene.
Citation:
EVANS, M. V., H. M. Yang, K. A. Yokley, A. MdDonald, Y. Sey, C. R. Eklund, AND J. E. SIMMONS. Physiologically-based pharmacokinetic (PBPK) modeling of two binary mixtures: metabolic activation of carbon tetrachloride by trichloroethylene and metabolic inhibition of chloroform by trichloroethylene. Presented at Society of Toxicology (SOT) Annual meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
Illustrates how PBPK modeling can be used to examine the Mode of Action underlying nonadditive interactions
Description:
The interaction between trichloroethylene (TCE) and chloroform (CHCI3) has been described as less than additive, with co-exposure to TCE and CHC13 resulting in less hepatic and renal toxicity than observed with CHCl3 alone. In contrast, the nonadditive interaction between TCE and carbon tetrachloride (CCI4) results in increased hepatotoxicity when compared with CCl4 alone. To explore the mode of action underlying these nonadditive interactions, male F-344 rats were exposed in vapor uptake inhalation chambers to TCE alone, CHC13 alone, CCl4 alone, both TCE and CHCl3 or both TCE and CCI4. Metabolic inhibition was observed as a slower rate of decay in the vapor uptake data, while increased decay in the data represented metabolic activation. In the presence of TCE, uptake of CHCl3 decreased while uptake of CCl4 increased.Physiologically-based pharmacokinetic (PBPK) models for each chemical alone were developed and used to construct and evaluate PBPK models describing the influence of concurrent exposure to TCE on the uptake and metabolism of CHC13 or CCl4 as well as the influence of concurrent exposure to CHCl3 or CCl4 on clearance of TCE. The model simulations indicated that TCE had opposing effects on the metabolism of CHCl3 and CCI4, decreasing the metabolism of CHC13 and increasing the metabolism of CCI4 Computer simulations of the various types of metabolic inhibition suggest competitive inhibition best describes the metabolic interaction between TCE and CHC13. For TCE and CCI4, a novel metabolic hypothesis describing activation of CCl4 by TCE best fit the data. In summary, different modes of action for the nonadditive interactions resulting from co-exposure to TCE and CHCl3 and from co-exposure to TCE and CCl4 have been described by PBPK modeling. (This abstract does not reflect EPA policy.)