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 microg/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.

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

“…1A, B and SM-3). The observed results for CP on P. subcapitata (SM-3) are in the agreement with literature (Grung et al, 2008;Zounkova et al, 2007), whereas to our knowledge the effects of IF towards these species are yet to be reported. Since prokaryotic organisms (cyanobacteria belongs to prokaryotes) are more abundant in biological water treatment than eukaryotic organisms (Wagner and Loy, 2002) and because the alga and cyanobacteria did not differ in the susceptibility towards exposure to CP and IF, all following experiments involving metabolites/TPs, mixtures of compounds and toxicity of the CP and IF after UV irradiation were performed using only S. leopoliensis.…”

“…Freshwater Alga and Cyanobacteria, Growth Inhibition Test) are commonly performed (OECD TG 201, 2011). A literature overview revealed that only two CP growth inhibition studies have been performed using the alga Pseudokirchneriella subcapitata, both showing low toxicity with no observed effect concentration (NOEC) > 100 mg L À1 (Grung et al, 2008;Zounkova et al, 2007). No published ecotoxicity studies, to the authors knowledge, have included IF and the human metabolites/TPs of CP and IF.…”

Degradation of 5-FU by means of advanced (photo)oxidation processes: UV/H2O2, UV/Fe2+/H2O2 and UV/TiO2 — Comparison of transformation products, ready biodegradability and toxicity

“…As one can see in Tables 5, 3 positive alerts from the different models of the ICH M7 guideline conformal set from CASE Ultra indicate possible mutagenic and genotoxic activities of 5-FU in the Ames test with different strains of Salmonella and E. coli. These results are in line with previous in vivo studies which have already reported the potential mutagenic and genotoxic effects of 5-FU (Zounkova et al (2007); Yasunaga et al (2006)). …”

Evaluation of the toxic effects of four anti-cancer drugs in plant bioassays and its potency for screening in the context of waste water reuse for irrigation

“…Zounkova et al (2007) performed genotoxicity assays with 5 cytotoxic compounds using Escherichia coli SOS chromotest (with and without the use of metabolic activator) and Saccharomyces cerevisiae (eukaryotic yeast GreenScreen Assay (GSA)). The results indicated 5-FU as the most genotoxic compound for S. cerevisiae (Minimal Genotoxic Concentration -MGC = 0.02 mg/L) and very toxic in the assays involving E. coli without metabolic activation (MGC = 1.4 mg/L).…”