Toxicity of exposure to binary mixtures of four anti-neoplastic drugs in Daphnia magna and Ceriodaphnia dubia

Abstract

Anticancer drugs, interfering with DNA in every living organism, may pose a threat to aquatic environment, even more when they occur as complex mixtures. We investigated the combined long term toxic potential of four anti-neoplastic drugs (5-fluorouracil [5-FU], cisplatin [CDDP], etoposide [ET] and imatinib mesylate [IM]) testing their binary mixtures on two primary consumers of the freshwater aquatic chain with close phylogenetic relationship: Daphnia magna and Ceriodaphnia dubia. The combined toxicities were assessed using two distinct effect sizes that should be observed if Bliss independence holds. Direct statistical comparison by analysis of variance of single and combined toxicities under the assumption of Bliss independence allowed to accept or reject the independency hypothesis. Independency was confirmed for all mixtures both in D. magna and in C. dubia, except for IM+ ET and IM+CDDP in D. magna and for ET+CDDP and ET+5-FU in C. dubia which at the highest concentrations showed an antagonistic interaction. A synergic tendency was found testing IM+CDDP on C. dubia at the lowest concentration selected. Thus, the chronic ecotoxicological data evaluated in this study show not only a potential environmental risk of anticancer drugs, especially considering their potential synergistic effects, but also the necessity to integrate statistical models with experimental data to establish the real environmental impact of such compounds.

Prediction and assessment of ecogenotoxicity of antineoplastic drugs in binary mixtures

“…Although the duration of exposure plays a key role in detecting environmental effects of xenobiotics, our results indicated that the short exposure used for the comet assay could approximate the effects shown in chronic toxicity tests (inhibition of reproduction in 7 or 21 days for C. dubia and D. magna, respectively). Indeed, comparing our results with those of a previous study (Parrella et al 2014b), in D. magna, a Bliss independence was shown by most of the mixtures except some binary combinations with IM for which antagonism was observed, while in C. dubia, an antagonistic action was shown for ET+CDDP and ET+5-FU. Despite these similarities between genotoxicity results and chronic toxicity, differences occurred probably due to the more difficult prediction of combined effects of chemicals with genotoxic modes of action.…”

Fate and effects of the residues of anticancer drugs in the environment

“…This corroborate the findings of a previous reproductive toxicity study with D. magna and C. dubia revealing that the majority of these binary mixtures exerted an independent action (Parrella et al, 2014a). When comparing the effective concentrations of a binary mixture to those of the single compounds (Parrella et al, 2014b), combinations of anticancer drugs could be of environmental concern because their effects occur at very low concentrations that are in the range of concentrations encountered in aquatic systems. Eleršek et al (2016) tested the effect of a mixture of 5-FU + IM + ET on the growth inhibition of green alga Pseudokirchneriella subcapitata and cyanobacterium Synechococcus leopoliensis.…”

Ecotoxicity and genotoxicity of cyclophosphamide, ifosfamide, their metabolites/transformation products and their mixtures

“…Therefore it is important to study both, the effects of pure compounds and even more the effects of their mixtures (Brain et al, 2004). Recently published studies describe toxic activities of mixtures of several cytostatic drugs (Brezov sek et al, 2013(Brezov sek et al, , 2014Parrella et al, 2014), however, to the best of our knowledge, the toxic potential of mixture of CP, IF and their metabolites/TPs has not been investigated yet.…”