title: Understanding receptor-mediated effects in rainbow trout: in vitro-in vivo extrapolation using physiologically based toxicokinetic models.
abstract: The European REACH regulation requires the use of animal experimentation to assess the risk of industrial chemicals. However, the 3R principle (reduction, replacement, refinement) demands the use of suitable alternative test methods. Many dossiers submitted for the authorization of chemicals have attempted to provide the required data without performing new experiments, relying heavily on in silico methods; in vitro assays were scarcely used. We propose a methodology that uses physiologically based toxicokinetic (PBTK) models to extrapolate in vitro data to the in vivo level. We collected experimental results for in vitro and in vivo ethoxyresorufin-O-deethylase and vitellogenin induction following chemical exposure and compared those results with model predictions. We found that the predictive power of aqueous chemical concentrations was limited; median effect concentrations (EC50s) based on internal concentrations in fish correlated better with in vitro EC50s. Our data show that in vitro assays could offer a substitute for fish studies when combined with PBTK models.
authors.affiliation: Department of Ecosystem Analysis, RWTH Aachen University, Institute for Environmental Research , Worringerweg 1, 52074 Aachen, North Rhine-Westphalia, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Brinkmann
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eichbaum
authors.forename: Sebastian
authors.initials: S
authors.lastname: Buchinger
authors.forename: Georg
authors.initials: G
authors.lastname: Reifferscheid
authors.forename: Thuy
authors.initials: T
authors.lastname: Bui
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäffer
authors.forename: Henner
authors.initials: H
authors.lastname: Hollert
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Preuss
mesh_terms: D000818:Animals; D003198:Computer Simulation; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D008954:Models, Biological; D017686:Oncorhynchus mykiss / Q000378:metabolism*; D066007:Toxicokinetics; D014819:Vitellogenins / Q000096:biosynthesis; D014874:Water Pollutants, Chemical / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D014819:Vitellogenins; D014874:Water Pollutants, Chemical; D019363:Cytochrome P-450 CYP1A1