Toward internal threshold for toxicological concern: in vitro hepatocyte metabolism testing of 207 chemicals using...

In vitro hepatic metabolic clearance data were generated for a diverse set of 207 chemicals to advance the collaborative initiative to establish an internal Threshold of Toxicological Concern (iTTC). The data reported herein are being used for chemical-specific physiologically based pharmacokinetic (PBPK) modeling to convert oral No Observable Adverse Effect Levels (NOAELs) into estimates of internal exposure. Hepatocyte assays were conducted at 2 concentrations (0.1 and 1 µM) using cryopreserved cells from multiple species, ensuring applicability to existing mammalian toxicity studies. The metabolic clearance measurements across chemicals varied significantly, ranging from 0 to 4,294 µl/min/106 cells at 0.1 µM and from 0 to 2,351 µl/min/106 cells at 1 µM. A substantial proportion of the chemicals (68% at 0.1 µM and 62% at 1 µM) exhibited clearance values below 30 µl/min/106 cells. Additionally, we observed a strong correlation (R = 0.8) between intrinsic clearance (CLint) values determined at the 2 concentrations. These data contribute to establishing robust iTTC values that can be utilized for: (i) extrapolating from an oral in vivo study to dermal and inhalation exposures, (ii) risk-based screening of aggregate exposures of a given substance from multiple routes of exposures, and (iii) risk-based screening of human biomonitoring results.