From in vitro to in vivo: Integration of the virtual cell based assay with physiologically based kinetic modelling

Physiologically based kinetic (PBK) models and the virtual cell based assay can be linked to form so called physiologically based dynamic (PBD) models. This study illustrates the development and application of a PBK model for prediction of estragole-induced DNA adduct formation and hepatotoxicity in...

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Bibliographic Details
Published in:Toxicology in vitro 2017-12, Vol.45 (Pt 2), p.241-248
Main Authors: Paini, Alicia, Sala Benito, Jose Vicente, Bessems, Jos, Worth, Andrew P.
Format: Article
Language:English
Subjects:
Allylbenzene Derivatives
Anisoles - pharmacokinetics
Anisoles - toxicity
Cell culture
Cell Line
Cell Survival - drug effects
Chemical and Drug Induced Liver Injury - metabolism
Deoxyribonucleic acid
DNA
DNA adduct
DNA adducts
DNA Adducts - metabolism
Dosimeters
Dosimetry
Estragole
Flavoring Agents - pharmacokinetics
Flavoring Agents - toxicity
Hepatocytes
Hepatotoxicity
Humans
Kinetics
KNIME workflow
Liver
Liver - metabolism
Membrane Potential, Mitochondrial - drug effects
Models, Biological
Organic chemistry
PBD
PBK
Risk Assessment
VCBA
Workflow
Workflow software
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Summary:Physiologically based kinetic (PBK) models and the virtual cell based assay can be linked to form so called physiologically based dynamic (PBD) models. This study illustrates the development and application of a PBK model for prediction of estragole-induced DNA adduct formation and hepatotoxicity in humans. To address the hepatotoxicity, HepaRG cells were used as a surrogate for liver cells, with cell viability being used as the in vitro toxicological endpoint. Information on DNA adduct formation was taken from the literature. Since estragole induced cell damage is not directly caused by the parent compound, but by a reactive metabolite, information on the metabolic pathway was incorporated into the model. In addition, a user-friendly tool was developed by implementing the PBK/D model into a KNIME workflow. This workflow can be used to perform in vitro to in vivo extrapolation and forward as backward dosimetry in support of chemical risk assessment. [Display omitted] •VCBA is coupled with PBK model linking intracellular concentration to external dose.•The integrated model is applied to perform IVIVE of estragole-induced cell damage.•The IVIVE process is automated by means of a KNIME workflow.
ISSN:0887-2333
1879-3177
DOI:10.1016/j.tiv.2017.06.015