Integrating in vitro testing and physiologically-based pharmacokinetic (PBPK) modelling for chemical liver toxicity assessment—A case study of troglitazone |
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Affiliation: | 1. Academy of Military Medicine, Academy of Military Sciences, 27 Taiping Road, Beijing 100850, PR China;2. Institute of Disease Control and Prevention, People’s Liberation Army, 20 Dongda Street, Beijing 100071, PR China;3. Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK;4. Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA |
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Abstract: | In vitro to in vivo extrapolation (IVIVE) for next-generation risk assessment (NGRA) of chemicals requires computational modeling and faces unique challenges. Using mitochondria-related toxicity data of troglitazone (TGZ), a prototype drug known for liver toxicity, from HepaRG, HepG2, HC-04, and primary human hepatocytes, we explored inherent uncertainties in IVIVE, including cell models, cellular response endpoints, and dose metrics. A human population physiologically-based pharmacokinetic (PBPK) model for TGZ was developed to predict in vivo doses from in vitro point-of-departure (POD) concentrations. Compared to the 200–800 mg/d dose range of TGZ where liver injury was observed clinically, the predicted POD doses for the mean and top one percentile of the PBPK population were 28–372 and 15–178 mg/d respectively based on Cmax dosimetry, and 185–2552 and 83–1010 mg/d respectively based on AUC. In conclusion, although with many uncertainties, integrating in vitro assays and PBPK modeling is promising in informing liver toxicity-inducing TGZ doses. |
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Keywords: | Troglitazone PBPK modeling Reverse dosimetry PODs Toxicity testing alternatives |
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