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Physiologically-based pharmacokinetic (PBPK) modeling to explore potential metabolic pathways of bromochloromethane in rats.
Citation:
EVANS, M. V., W. Cuello, J. Jessee, M. Venecek, M. Sawyer, AND C. R. EKLUND. Physiologically-based pharmacokinetic (PBPK) modeling to explore potential metabolic pathways of bromochloromethane in rats. Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
Application of PBPK modeling to test different metabolic hypotheses
Description:
Bromochloromethane (BCM) is a volatile organic compound and a by-product of disinfection of water by chlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications and a PBPK model for BCM, Updated with F-344 specific input parameters, is used here for hypothesis testing to provide useful information for risk assessment of this compound. Inhalation vapor uptake data for F344 rats obtained from the literature were used for PBPK development. The initial chamber concentration ranged between 200-4000 ppm to ensure that metabolic saturation was included in the experimental design. The two different metabolic hypotheses examined were: 1) a two-pathway model using both CYP2E1 and glutathione transferase systems, and 2) a two-binding site model where metabolism can occur via one enzyme, CYP2E1. Our computer simulations demonstrated that both metabolic hypotheses described the available experimental data in a similar manner. The two-pathway results were comparable to previously reported values (Vmax = 3.8 mg/hour, Km=0.35 mglliter, and KGST =4.7 Ihour). The two-binding site results use Michaelis-Menten parameters to describe the first binding site, Vmax, = 3.7 mg/hour and Km1=0.3mglliter, and a dearance rate to describe the second site, CL2 = 0.05Iiter/hour. In addition, the sensitivity of different parameters for each model was explored using our obtained optimized values. At concentrations below 2000 ppm for both metabolic hypotheses, there was a peak in sensitivity towards Vmax measurement using liver concentration. In summary, the combination of PBPK modeling and sensitivity analysis is useful when studying different kinetic hypotheses using parameters optimized with closed chamber experimental data. (This abstract does not reflect EPA policy).