Towards Internal Threshold for Toxicological Concern (iTTC): In Vitro Hepatocyte Metabolism Testing of 207 Chemicals using Cryopreserved Suspended Hepatocytes for PBPK Modeling

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ID: 323503
2026
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Abstract
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 two 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 4294 µL/min/106 cells at 0.1 µM and from 0 to 2351 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 two concentrations. These data contribute to establishing robust iTTC values that can be utilized for: (1) extrapolating from an oral in vivo study to dermal and inhalation exposures, (2) risk-based screening of aggregate exposures of a given substance from multiple routes of exposures, and (3) risk-based screening of human biomonitoring results.
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openalex_W7172317668 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Corie A. Ellison, A.M. Api, Richard A. Becker, Sherry Black, Kaushal Joshi, Dan Selechnik
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Journal toxicological sciences : an official journal of the society of toxicology
Year 2026
DOI
10.1093/toxsci/kfag086
URL
https://doi.org/10.1093/toxsci/kfag086
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