Ecotoxicity and Genotoxicity Assessment of Cytostatic Pharmaceuticals

Abstract

The fate and effects of cytostatic (anticancer or antineoplastic) pharmaceuticals in the environment are largely unknown, but they can contaminate wastewater treatment effluents and consequently aquatic ecosystems. In this paper, we have focused on five cytostatic compounds used in high amounts (cyclophosphamide, cisplatin, 5‐fluorouracil, doxorubicin, and etoposide), and we have investigated their ecotoxicity in bacterial Pseudomonas putida growth‐inhibition test, algal Pseudokirchneriella subcapitata growth‐inhibition test, and Dapnia magna acute immobilization test. Genotoxicity also was assessed with Escherichia coli SOS‐chromotest (with and without metabolic activation) and the GreenScreen Assay using yeast S. cerevisiae. All tested compounds showed significant effects in most of the assays with lowest‐observed‐effect concentrations and concentrations causing 50% effects (EC50s) values ranging within μg/L to mg/L. The most toxic compound was 5‐fluorouracil in the assays with P. putida (EC50 = 0.027 mg/L) and P. subcapitata (EC50 = 0.11 mg/L), although cisplatin and doxorubicin were the most toxic to D. magna (EC50 = 0.64 and 2.0 mg/L, respectively). These two chemicals were also the most genotoxic in the SOS‐chromotest (minimum genotoxic concentrations [MGC] = 0.07–0.2 mg/L), and 5‐fluorouracil was the most genotoxic in the eukaryotic yeast assay (MGC = 0.02 mg/L). Our investigation seems to indicate generally lower risks of acute effects at concentrations expected in the environment. However, some effective concentrations were relatively low and chronic toxicity of cytostatics (and/or their transformation products), as well as specific sources of human pharmaceuticals such as hospital effluents, require research attention.

Evaluation of Cytotoxic and Cytostatic Effects in Saccharomyces cerevisiae by Poissoner Quantitative Drop Test

“…3C). The cytostatic effect of 5‐fluorouracil in mammalian cells is well described [13], and yeast cells are currently being used to study its mechanisms of action in the cell cycle and metabolism [14,15]. However, the exponential decay curve reported here for 5‐fluorouracil in yeast is new and has not been shown for other antitumoral drugs.…”

Non conventional biological treatment based on Trametes versicolor for the elimination of recalcitrant anticancer drugs in hospital wastewater

“…The occurrences of these drugs in the aquatic environment could be 78 especially critical since they are intrinsically hazardous. Several ecotoxicological studies 79 have shown that in some cases such as for the cancer drug 5-Fluorouracil, the lowest 80 observed-effect concentration values (in algal and bacterial assays) were close to the 81 concentration found in sewage effluents (Zounkova et al, 2007) . More recently, studies 82 have revealed that mixtures of anticancer drugs in real samples possess an important 83 toxicological effect comparing with the individual drug (Mater et al, 2014).…”

Toxicological evaluation of the topoisomerase inhibitor, etoposide, in the model animal Caenorhabditis elegans and 3T3‐L1 normal murine cells

“…Environmental concerns relating to the use of topoisomerase inhibitors have increased. Topoisomerase inhibitors exert detrimental effects to diverse wild life, including bacteria, aquatic organisms (planktons and primary consumers), and plants . However, in these reports, the toxicological evaluation is limited to growth inhibition; the detailed cellular and molecular mechanisms underlying the toxicity of topoisomerase inhibitors have not yet been fully elucidated.…”