Applicability of generic PBK modelling in chemical hazard assessment: A case study with IndusChemFate

Styliani Fragki*, Aldert H. Piersma, Joost Westerhout, Anne Kienhuis, Nynke I. Kramer, Marco J. Zeilmaker

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Toxicology is moving away from animal testing towards in vitro tools to assess chemical safety. This new testing framework requires a quantitative method, i.e. kinetic modelling, which extrapolates effective concentrations in vitro to a bioequivalent human dose in vivo and which can be applied on “high throughput screening” of a wide variety of chemicals. Generic physiologically based kinetic (PBK) models help account for the role of toxicokinetics in setting human toxic exposure levels. Furthermore these models may be parameterized only on in silico QSARs and in vitro metabolism assays, thereby circumventing the use of in vivo toxicokinetics for this purpose. Though several such models exist their applicability domains have yet to be comprehensively assessed. This study extends previous evaluations of the PBK model IndusChemFate and compares it with its more complex biological complement (“TNO Model”). Both models were evaluated with a broad span of chemicals, varying regarding physicochemical properties. The results reveal that the “simpler” performed best, illustrating that IndusChemFate can be a useful first-tier for simulating toxicokinetics based on QSARs and in vitro parameters. Finally, proper quantitative in vitro to in vivo extrapolation conditions were illustrated starting with acetaminophen induced in vitro cytotoxicity in human HepaRG cells.

Original languageEnglish
Article number105267
JournalRegulatory Toxicology and Pharmacology
Publication statusPublished - Dec 2022


  • Applicability domain
  • Generic PBK models
  • In vitro
  • IndusChemFate
  • QSAR
  • TNO Model
  • Toxicokinetics


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