In vitro to in vivo extrapolation of effective dosimetry in developmental toxicity testing: Application of a generic PBK modelling approach.

2.50
Hdl Handle:
http://hdl.handle.net/10029/621051
Title:
In vitro to in vivo extrapolation of effective dosimetry in developmental toxicity testing: Application of a generic PBK modelling approach.
Authors:
Fragki, Styliani; Piersma, Aldert H; Rorije, Emiel; Zeilmaker, Marco J
Abstract:
Incorporation 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.
Citation:
In 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.
Journal:
Toxicol Appl Pharmacol 2017, 332:109-20
Issue Date:
2017
URI:
http://hdl.handle.net/10029/621051
DOI:
10.1016/j.taap.2017.07.021
PubMed ID:
28760446
Type:
Article
Language:
en
ISSN:
1096-0333
Appears in Collections:
Miscellaneous

Full metadata record

DC FieldValue Language
dc.contributor.authorFragki, Stylianien
dc.contributor.authorPiersma, Aldert Hen
dc.contributor.authorRorije, Emielen
dc.contributor.authorZeilmaker, Marco Jen
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.en
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
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