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dc.contributor.authorFragki, Styliani
dc.contributor.authorPiersma, Aldert H
dc.contributor.authorRorije, Emiel
dc.contributor.authorZeilmaker, Marco J
dc.date.accessioned2018-01-09T12:05:50Z
dc.date.available2018-01-09T12:05:50Z
dc.date.issued2017
dc.identifier.citationIn vitro to in vivo extrapolation of effective dosimetry in developmental toxicity testing: Application of a generic PBK modelling approach. 2017, 332:109-120 Toxicol. Appl. Pharmacol.en
dc.identifier.issn1096-0333
dc.identifier.pmid28760446
dc.identifier.doi10.1016/j.taap.2017.07.021
dc.identifier.urihttp://hdl.handle.net/10029/621051
dc.description.abstractIncorporation of kinetics to quantitative in vitro to in vivo extrapolations (QIVIVE) is a key step for the realization of a non-animal testing paradigm, in the sphere of regulatory toxicology. The use of Physiologically-Based Kinetic (PBK) modelling for determining systemic doses of chemicals at the target site is accepted to be an indispensable element for such purposes. Nonetheless, PBK models are usually designed for a single or a group of compounds and are considered demanding, with respect to experimental data needed for model parameterization. Alternatively, we evaluate here the use of a more generic approach, i.e. the so-called IndusChemFate model, which is based on incorporated QSAR model parametrization. The model was used to simulate the in vivo kinetics of three diverse classes of developmental toxicants: triazoles, glycol ethers' alkoxyacetic acid metabolites and phthalate primary metabolites. The model required specific input per each class of compounds. These compounds were previously tested in three alternative assays: the whole-embryo culture (WEC), the zebrafish embryo test (ZET), and the mouse embryonic stem cell test (EST). Thereafter, the PBK-simulated blood levels at toxic in vivo doses were compared to the respective in vitro effective concentrations. Comparisons pertaining to relative potency and potency ranking with integration of kinetics were similar to previously obtained comparisons. Additionally, all three in vitro systems produced quite comparable results, and hence, a combination of alternative tests is still preferable for predicting the endpoint of developmental toxicity in vivo. This approach is put forward as biologically more plausible since plasma concentrations, rather than external administered doses, constitute the most direct in vivo dose metric.
dc.language.isoenen
dc.rightsArchived with thanks to Toxicology and applied pharmacologyen
dc.subject.meshAnimals
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshEmbryonic Development
dc.subject.meshEmbryonic Stem Cells
dc.subject.meshFeasibility Studies
dc.subject.meshMice
dc.subject.meshModels, Animal
dc.subject.meshModels, Biological
dc.subject.meshModels, Molecular
dc.subject.meshPhthalic Acids
dc.subject.meshRats
dc.subject.meshRats, Wistar
dc.subject.meshToxicity Tests
dc.subject.meshTriazoles
dc.subject.meshZebrafish
dc.titleIn vitro to in vivo extrapolation of effective dosimetry in developmental toxicity testing: Application of a generic PBK modelling approach.en
dc.typeArticleen
dc.identifier.journalToxicol Appl Pharmacol 2017, 332:109-20en
html.description.abstractIncorporation of kinetics to quantitative in vitro to in vivo extrapolations (QIVIVE) is a key step for the realization of a non-animal testing paradigm, in the sphere of regulatory toxicology. The use of Physiologically-Based Kinetic (PBK) modelling for determining systemic doses of chemicals at the target site is accepted to be an indispensable element for such purposes. Nonetheless, PBK models are usually designed for a single or a group of compounds and are considered demanding, with respect to experimental data needed for model parameterization. Alternatively, we evaluate here the use of a more generic approach, i.e. the so-called IndusChemFate model, which is based on incorporated QSAR model parametrization. The model was used to simulate the in vivo kinetics of three diverse classes of developmental toxicants: triazoles, glycol ethers' alkoxyacetic acid metabolites and phthalate primary metabolites. The model required specific input per each class of compounds. These compounds were previously tested in three alternative assays: the whole-embryo culture (WEC), the zebrafish embryo test (ZET), and the mouse embryonic stem cell test (EST). Thereafter, the PBK-simulated blood levels at toxic in vivo doses were compared to the respective in vitro effective concentrations. Comparisons pertaining to relative potency and potency ranking with integration of kinetics were similar to previously obtained comparisons. Additionally, all three in vitro systems produced quite comparable results, and hence, a combination of alternative tests is still preferable for predicting the endpoint of developmental toxicity in vivo. This approach is put forward as biologically more plausible since plasma concentrations, rather than external administered doses, constitute the most direct in vivo dose metric.


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