title: BK/TD models for analyzing in vitro impedance data on cytotoxicity.
abstract: The ban of animal testing has enhanced the development of new in vitro technologies for cosmetics safety assessment. Impedance metrics is one such technology which enables monitoring of cell viability in real time. However, analyzing real time data requires moving from static to dynamic toxicity assessment. In the present study, we built mechanistic biokinetic/toxicodynamic (BK/TD) models to analyze the time course of cell viability in cytotoxicity assay using impedance. These models account for the fate of the tested compounds during the assay. BK/TD models were applied to analyze HepaRG cell viability, after single (48 h) and repeated (4 weeks) exposures to three hepatotoxic compounds (coumarin, isoeugenol and benzophenone-2). The BK/TD models properly fit the data used for their calibration that was obtained for single or repeated exposure. Only for one out of the three compounds, the models calibrated with a single exposure were able to predict repeated exposure data. We therefore recommend the use of long-term exposure in vitro data in order to adequately account for chronic hepatotoxic effects. The models we propose here are capable of being coupled with human biokinetic models in order to relate dose exposure and human hepatotoxicity.
authors.affiliation: INERIS (METO), Verneuil-en-Halatte 60550, France. Electronic address: sophie.teng-etudiant@ineris.fr.
authors.forename: S
authors.initials: S
authors.lastname: Teng
authors.affiliation: ODESIA Neosciences, Sophia Antipolis F- 31076, France. Electronic address: s.barcellini@odesia-neosciences.com.
authors.forename: S
authors.initials: S
authors.lastname: Barcellini-Couget
authors.affiliation: INERIS (METO), Verneuil-en-Halatte 60550, France. Electronic address: remy.beaudouin@ineris.fr.
authors.forename: R
authors.initials: R
authors.lastname: Beaudouin
authors.affiliation: INERIS (METO), Verneuil-en-Halatte 60550, France. Electronic address: celine.brochot@ineris.fr.
authors.forename: C
authors.initials: C
authors.lastname: Brochot
authors.affiliation: INRA Toxalim, Sophia Antipolis F- 31076, France. Electronic address: desousa@sophia.inra.fr.
authors.forename: G
authors.initials: G
authors.lastname: Desousa
authors.affiliation: INRA Toxalim, Sophia Antipolis F- 31076, France. Electronic address: roger.rahmani@sophia.inra.fr.
authors.forename: R
authors.initials: R
authors.lastname: Rahmani
authors.affiliation: INERIS (METO), Verneuil-en-Halatte 60550, France; AgroParisTech, UMR 1402 INRA-AgroParisTech EcoSys, Thiverval-Grignon F- 78850, France. Electronic address: alexandre.pery@ineris.fr.
authors.forename: A R R
authors.initials: AR
authors.lastname: Pery
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D001577:Benzophenones / Q000493:pharmacokinetics / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D003358:Cosmetics / Q000493:pharmacokinetics* / Q000633:toxicity*; D003374:Coumarins / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D005054:Eugenol / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D016014:Linear Models; D008954:Models, Biological; D015203:Reproducibility of Results; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*; D066007:Toxicokinetics
chemical_list: D001577:Benzophenones; D003358:Cosmetics; D003374:Coumarins; D005054:Eugenol; C036643:isoeugenol; C030123:coumarin; C035476:2,2',4,4'-tetrahydroxybenzophenone
keywords: Acute to chronic extrapolation; Cell viability; Hepatotoxicity; Impedance; In vitro modeling