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Application of tissue time course data to elucidate mechanistic details of carbon tetrachloride (CC14) transport using an updated physiologically based pharmacokinetic (PBPK) model in rats
Citation:
EVANS, M. V., C. M. Eklund, U. Y. Sanzgiri, J. V. Bruckner, AND J. E. SIMMONS. Application of tissue time course data to elucidate mechanistic details of carbon tetrachloride (CC14) transport using an updated physiologically based pharmacokinetic (PBPK) model in rats. Presented at Society of Toxicology 49th Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
Complex PBPK modeling to better predict liver toxicity
Description:
CCl4 is a common environmental contaminant in water and superfund sites, and a model liver toxicant. One application of PBPK models used in risk assessment is simulation of internal dose for the metric involved with toxicity, particularly for different routes of exposure. Time-course pharmacokinetic data for different tissues (Sanzgiri et al., 1995) were used to evaluate a rat PBPK model employing previous metabolic estimates. The flow-limited PBPK model contained: fat, liver, brain, rapidly and slowly perfused compartments. Arterial concentration data measured for 100 or 1000 ppm constant inhalation exposure lasting 2 hours were used to evaluate the initial PBPK predictions. These simulations were able to describe the time-course data well at both inhaled concentrations. However, a closer examination of tissue uptake data of 1000 ppm CCl4 revealed an inconsistency with the preliminary simulations. Upon further evaluation of tissue time-course results, the PBPK model underpredicted brain and fat tissue concentrations. Also, the peak arterial concentration was about twice that predicted by the initial calibration simulation. Further modeling is needed to incorporate physiological and structural details (i.e. diffusion) that may be taking place at higher exposure concentrations. Ongoing model refinement strategies will include: (1) addition of a blood brain barrier component (for brain tissue), and (2) a diffusion-limited compartment for fat, and (3) diffusion in the respiratory tract during the breathing cycle. Diffusion may help explain the difference between observed and predicted tissue concentrations. In summary, tissue time-course data are essential for the determination of mechanistic detail for different organs, and the accurate prediction of internal liver dose. (This abstract does not reflect EPA policy.)