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

• Published in: Regulatory toxicology and pharmacology 2022-12, Vol.136, p.105267-105267, Article 105267
• Main Authors: Fragki, Styliani, Piersma, Aldert H., Westerhout, Joost, Kienhuis, Anne, Kramer, Nynke I., Zeilmaker, Marco J.
• Format: Article
• Language: English
• Subjects: Applicability domain; Generic PBK models; In vitro; IndusChemFate; QIVIVE; QSAR; TNO Model; Toxicokinetics
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2022.105267

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. •IndusChemFate model was shown to predict chemical kinetics in data-poor environments.•IndusChemFate was compared to a more complex biological PBK model.•The simpler performed best and it can be useful for first-tier toxicokinetics' simulations.•A case study illustrates how it may be used for QIVIVE in chemical safety.•The prediction accuracy needs agreement for the wider acceptance of generic PBK models.