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dc.contributor.authorGAJEWSKA MONIKAen_GB
dc.contributor.authorPAINI ALICIAen_GB
dc.contributor.authorSALA BENITO Jose'en_GB
dc.contributor.authorBURTON JULIENen_GB
dc.contributor.authorWORTH Andrewen_GB
dc.contributor.authorURANI Chiaraen_GB
dc.contributor.authorBRIESEN Heikoen_GB
dc.contributor.authorSCHRAMM Karl-Werneren_GB
dc.date.accessioned2015-05-28T10:14:53Z-
dc.date.available2014-12-09en_GB
dc.date.available2015-05-28T10:14:53Z-
dc.date.created2014-12-04en_GB
dc.date.issued2015en_GB
dc.date.submitted2014-07-22en_GB
dc.identifier.citationFOOD AND CHEMICAL TOXICOLOGY vol. 75 p. 39–49en_GB
dc.identifier.issn0278-6915en_GB
dc.identifier.urihttp://www.sciencedirect.com/science/article/pii/S0278691514004451en_GB
dc.identifier.urihttp://publications.jrc.ec.europa.eu/repository/handle/JRC91186-
dc.description.abstractThis work illustrates the use of Physiologically-Based Toxicokinetic (PBTK) modelling in in vitro-to-in vivo correlation (IVIVC) of kinetic measures of caffeine skin penetration and liver metabolism, as well as dose metrics of caffeine-induced HepaRG toxicity. We applied a PBTK model calibrated for the Caucasian population to quantify the differences in in vitro and in vivo skin absorption and liver metabolism rates by means of a simple correlation factor. We developed a multi-scale computational approach by linking the PBTK model with a Virtual Cell-Based (VCB) Assay to relate an external oral and dermal dose with an internal dose-dependent liver toxicity, measured in vitro as HepaRG cell viability. The results revealed higher in vivo skin permeation profiles than those determined in vitro using identical in vitro and in vivo exposure conditions. Literature in vitro liver metabolism rates were higher than the optimized in vivo rates with respect to available caffeine plasma concentrations. Finally, HepaRG cell viability was shown to decrease only slightly for external caffeine doses in the 5-200 mg range, assuming a 4.56 mg/mL in ethanol/propylene glycol vehicle after both exposure types. We modelled single human exposure to single doses of caffeine only. The approaches described in the present paper provide a promising means of performing in vitro -to- in vivo correlations that may contribute to a reduction of animal experimentation in the chemical risk assessment process.en_GB
dc.description.sponsorshipJRC.I.5-Systems Toxicologyen_GB
dc.format.mediumPrinteden_GB
dc.languageENGen_GB
dc.publisherPERGAMON-ELSEVIER SCIENCE LTDen_GB
dc.relation.ispartofseriesJRC91186en_GB
dc.titleIn vitro-to-in vivo correlation of the skin penetration, liver clearance and hepatotoxicity of caffeineen_GB
dc.typeArticles in periodicals and booksen_GB
dc.identifier.doi10.1016/j.fct.2014.10.017en_GB
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