Extrahepatic metabolism by CYP2E1 in PBPK modeling of lipophilic volatile organic chemicals: impacts on metabolic parameter estimation and prediction of dose metrics.

Physiologically based pharmacokinetic (PBPK) models are increasingly available for environmental chemicals and applied in risk assessments. Volatile organic compounds (VOCs) are important pollutants in air, soil, and water. CYP2E1 metabolically activates many VOCs in animals and humans. Despite its presence in extrahepatic tissues, the metabolism by CYP2E1 is often described as restricted to the liver in PBPK models, unless target tissue dose metrics in extrahepatic tissues are needed for the model application, including risk assessment. The impact of accounting for extrahepatic metabolism by CYP2E1 on the estimation of metabolic parameters and the prediction of dose metrics was evaluated for three lipophilic VOCs: vinyl chloride, trichloroethylene, and carbon tetrachloride. Metabolic parameters estimated from fitting gas uptake data with and without extrahepatic metabolism were similar. The impact of extrahepatic metabolism on PBPK predictions was evaluated using inhalation exposure scenarios relevant for animal toxicity studies and human risk assessment. Although small, the relative role of extrahepatic metabolism and the differences in the predicted dose metrics were greater at low exposure concentrations. The impact was species dependent and influenced by Km for CYP2E1. The current study indicates that inhalation modeling for several representative VOCs that are CYP2E1 substrates is not affected by the inclusion of extrahepatic metabolism, implying that liver-only metabolism may be a reasonable simplification for PBPK modeling of lipophilic VOCs. The PBPK predictions using this assumption can be applied confidently for risk assessment, but this conclusion should not necessarily be applied to VOCs that are metabolized by other enzymes.