title: Measured and modeled toxicokinetics in cultured fish cells and application to in vitro-in vivo toxicity extrapolation.
abstract: Effect concentrations in the toxicity assessment of chemicals with fish and fish cells are generally based on external exposure concentrations. External concentrations as dose metrics, may, however, hamper interpretation and extrapolation of toxicological effects because it is the internal concentration that gives rise to the biological effective dose. Thus, we need to understand the relationship between the external and internal concentrations of chemicals. The objectives of this study were to: (i) elucidate the time-course of the concentration of chemicals with a wide range of physicochemical properties in the compartments of an in vitro test system, (ii) derive a predictive model for toxicokinetics in the in vitro test system, (iii) test the hypothesis that internal effect concentrations in fish (in vivo) and fish cell lines (in vitro) correlate, and (iv) develop a quantitative in vitro to in vivo toxicity extrapolation method for fish acute toxicity. To achieve these goals, time-dependent amounts of organic chemicals were measured in medium, cells (RTgill-W1) and the plastic of exposure wells. Then, the relation between uptake, elimination rate constants, and log KOW was investigated for cells in order to develop a toxicokinetic model. This model was used to predict internal effect concentrations in cells, which were compared with internal effect concentrations in fish gills predicted by a Physiologically Based Toxicokinetic model. Our model could predict concentrations of non-volatile organic chemicals with log KOW between 0.5 and 7 in cells. The correlation of the log ratio of internal effect concentrations in fish gills and the fish gill cell line with the log KOW was significant (r>0.85, p = 0.0008, F-test). This ratio can be predicted from the log KOW of the chemical (77% of variance explained), comprising a promising model to predict lethal effects on fish based on in vitro data.
authors.affiliation: Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland; ETH Zürich, Institute of Biogeochemistry and Pollutant Dynamics, Zürich, Switzerland; EPF Lausanne, School of Architecture, Civil and Environmental Engineering, Lausanne, Switzerland.
authors.forename: Julita
authors.initials: J
authors.lastname: Stadnicka-Michalak
authors.affiliation: Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland; Ecosens AG, Wallisellen, Switzerland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Tanneberger
authors.affiliation: Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland; ETH Zürich, Institute of Biogeochemistry and Pollutant Dynamics, Zürich, Switzerland; EPF Lausanne, School of Architecture, Civil and Environmental Engineering, Lausanne, Switzerland.
authors.forename: Kristin
authors.initials: K
authors.lastname: Schirmer
authors.affiliation: Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland; Environment Department, University of York, Heslington, York, United Kingdom.
authors.forename: Roman
authors.initials: R
authors.lastname: Ashauer
mesh_terms: D000818:Animals; D005399:Fishes; D008962:Models, Theoretical; D009930:Organic Chemicals / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity
chemical_list: D009930:Organic Chemicals; D014874:Water Pollutants, Chemical