title: In silico cytotoxicity assessment on cultured rat intestinal cells deduced from cellular impedance measurements.
abstract: Early and reliable identification of chemical toxicity is of utmost importance. At the same time, reduction of animal testing is paramount. Therefore, methods that improve the interpretability and usability of in vitro assays are essential. xCELLigence's real-time cell analyzer (RTCA) provides a novel, fast and cost effective in vitro method to probe compound toxicity. We developed a simple mathematical framework for the qualitative and quantitative assessment of toxicity for RTCA measurements. Compound toxicity, in terms of its 50% inhibitory concentration IC50on cell growth, and parameters related to cell turnover were estimated on cultured IEC-6 cells exposed to 10 chemicals at varying concentrations. Our method estimated IC50values of 113.05, 7.16, 28.69 and 725.15 μM for the apparently toxic compounds 2-acetylamino-fluorene, aflatoxin B1, benzo-[a]-pyrene and chloramphenicol in the tested cell line, in agreement with literature knowledge. IC50values of all apparent in vivo non-toxic compounds were estimated to be non-toxic by our method. Corresponding estimates from RTCA's in-built model gave false positive (toxicity) predictions in 5/10 cases. Taken together, our proposed method reduces false positive predictions and reliably identifies chemical toxicity based on impedance measurements. The source code for the developed method including instructions is available at https://git.zib.de/bzfgupta/toxfit/tree/master.
authors.affiliation: Department of Mathematics and Informatics, Freie Universität Berlin, Arnimallee 6, Berlin 14195, Germany; Department of Mathematics for Life and Materials Sciences, Zuse Institute Berlin, Takustrasse 7, Berlin 14195, Germany. Electronic address: gupta@math.fu-berlin.de.
authors.forename: P
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Department of Veterinary Biochemistry, Freie Universität Berlin, Oertzenweg 19b, Building 12, Berlin 14163, Germany. Electronic address: annikagramatke@gmx.de.
authors.forename: A
authors.initials: A
authors.lastname: Gramatke
authors.affiliation: Department of Veterinary Biochemistry, Freie Universität Berlin, Oertzenweg 19b, Building 12, Berlin 14163, Germany. Electronic address: Ralf.Einspanier@fu-berlin.de.
authors.forename: R
authors.initials: R
authors.lastname: Einspanier
authors.affiliation: Department of Mathematics and Informatics, Freie Universität Berlin, Arnimallee 6, Berlin 14195, Germany; Department of Mathematics for Life and Materials Sciences, Zuse Institute Berlin, Takustrasse 7, Berlin 14195, Germany. Electronic address: Christof.Schuette@fu-berlin.de.
authors.forename: C
authors.initials: C
authors.lastname: Schütte
authors.affiliation: Department of Mathematics and Informatics, Freie Universität Berlin, Arnimallee 6, Berlin 14195, Germany. Electronic address: vkleist@zedat.fu-berlin.de.
authors.forename: M
authors.initials: M
authors.lastname: von Kleist
authors.affiliation: Department of Veterinary Biochemistry, Freie Universität Berlin, Oertzenweg 19b, Building 12, Berlin 14163, Germany. Electronic address: Jutta.Sharbati@fu-berlin.de.
authors.forename: J
authors.initials: J
authors.lastname: Sharbati
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D020128:Inhibitory Concentration 50; D007422:Intestines / Q000166:cytology; D008954:Models, Biological; D009153:Mutagens / Q000633:toxicity; D051381:Rats; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D009153:Mutagens
keywords: IC(50); Mathematical modeling; Real-time cell analyzer; Toxicity