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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. Jesse, M. Venecek, M. Sawyer, AND C. Eklund. Physiologically-based pharmacokinetic (PBPK) modeling to explore potential metabolic pathways of bromochloromethane in rats. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 2012(2012):629781, (2012).
Impact/Purpose:
The study was done to highlight the application of PBPK modeling to test different kinetic hypotheses. The PBPK model was combined with experimental inhalation data to help choose the best description of the available data. In addition, sensitivity analysis was conducted to help determine the relative importance of different model parameters to predict outcome. The combination of both approaches provided an updated PBPK model for BCM. Future research suggested by this effort includes the inclusion of data at lower concentrations similar to those occurring in the environment.
Description:
Bromochloromethane (BCM) is a volatile compound and a by-product of disinfection of water by ofchlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications. An updated PBPKmodel for BCM is generated and applied to hypotheses testing calibrated using vapor uptake data. The two different metabolic hypotheses examined are: 1) a two-pathway model using both CYP2E1 and glutathione transferase enzymes, and 2) a two-binding site model where metabolism can occur on one enzyme, CYP2E1. Our computer simulations show that both hypotheses describe the experimental data in a similar manner. The two-pathway results were comparable to previously reported values (Vmax = 3.8 mg/hour, Km=0.35 mg/liter, and KGST =4.7 /hour). The two-binding site results were Vmaxi = 3.7 mg/hour, Kml=0.3mg/liter, and CL2 =0.05 liter/hour. In addition, we explore the sensitivity of different parameters for each model using our obtained optimized values and explore their applications to risk assessment.
