title: Prediction and assessment of ecogenotoxicity of antineoplastic drugs in binary mixtures.
abstract: The combined genotoxic effects of four anticancer drugs (5-fluorouracil [5-FU], cisplatin [CDDP], etoposide [ET], and imatinib mesylate [IM]) were studied testing their binary mixtures in two crustaceans that are part of the freshwater food chain, namely Daphnia magna and Ceriodaphnia dubia. Genotoxicity was assessed using the in vivo comet assay. Assessment was based on two distinct effect sizes determined from dose-response experiments. Doses for single and combined exposures expected to result in these effect sizes were computed based on Bliss independence as reference model. Statistical comparison by analysis of variance of single and combined toxicities allowed accepting or rejecting the independency hypothesis. The results obtained for D. magna showed independent action for all mixtures except for IM+5-FU that showed an antagonistic interaction. In C. dubia, most mixtures had antagonist interactions except IM+5-FU and IM+CDDP that showed Bliss independence. Despite the antagonistic interactions, our results demonstrated that combinations of anticancer drugs could be of environmental concern because effects occur at very low concentrations that are in the range of concentrations encountered in aquatic systems.
authors.affiliation: Institute of Environmental Health, Center for Public Health, Medical University of Vienna, Kinderspitalgasse 15, 1090, Vienna, Austria. michael.kundi@meduniwien.ac.at.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-2707-3213
authors.initials: M
authors.lastname: Kundi
authors.affiliation: Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100, Caserta, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Parrella
authors.affiliation: Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100, Caserta, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Lavorgna
authors.affiliation: Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100, Caserta, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Criscuolo
authors.affiliation: Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100, Caserta, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Russo
authors.affiliation: Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100, Caserta, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Isidori
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D033361:Cladocera / Q000187:drug effects*; D020552:Comet Assay; D004249:DNA Damage; D003621:Daphnia / Q000187:drug effects; D004338:Drug Combinations; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D014874:Water Pollutants, Chemical
keywords: Anticancer drugs; Comet assay; Crustaceans; Genotoxicity; Mixtures; Surface water