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PHYSIOLOGICALLY BASED PHARMACOKINEITC (PBPK) MODELING OF METABOLIC INHIBITION FOR INTERACTION BETWEEN TRICHLOROETHYLENE AND CHLOROFORM
Citation:
EVANS, M. V., H. M. YANG, T. A. MCDONALD, Y. M. SEY, AND J. E. SIMMONS. PHYSIOLOGICALLY BASED PHARMACOKINEITC (PBPK) MODELING OF METABOLIC INHIBITION FOR INTERACTION BETWEEN TRICHLOROETHYLENE AND CHLOROFORM. Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.
Description:
Trichloroethylene (TCE) and chloroform (CHCl3) are two of the most common environmental contaminants found in water. PBPK models have been increasingly used to predict target dose in internal tissues from available environmental exposure concentrations. A closed inhalation (or gas uptake) system was used to estimate metabolic parameters using male F344 rats at different initial concentrations. Individual chemicals were first tested separately using the following initial concentrations: 100, 500, 1000, and 3000 ppm. The decrease in chamber concentration reflecting metabolism was measured for up to 6 hours. A PBPK model was then used for each individual data set to obtain the metabolic parameters describing saturable metabolism, Vmax (maximum velocity of reaction) and Km (affinity constant). The next set of experiments described co-exposure of different binary combinations, including 500 ppm for both chemicals, 500 ppm TCE and 10 ppm of CHCl3, and 500 ppm TCE with 2000 ppm CHCl3. PBPK modeling was used to test three types of different metabolic inhibition: competitive, uncompetitive and noncompetitive. Results of the simulations suggest that competitive inhibition gives the closest agreement between the inhalation data and the simulations, resulting in an inhibition constant (Ki) of 0.33 mg/liter, which is similar to the Km value of 0.36 mg/liter. This interaction model was used to identify sensitive parameters for the design of future experiments. In summary, PBPK modeling results were consistent with competitive inhibition for TCE and CHCl3 co-exposure, leading to an overall decrease in metabolism when both chemicals are present simultaneously. (This abstract does not reflect EPA policy. Research support for Karen Yokley is provided by grants EPA T829472 and EPA CT833237.).