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

Česen, Marjeta; Eleršek, Tina; Novak, Matjaž; Žegura, Bojana; Kosjek, Tina; Filipič, Metka; Heath, Ester

doi:10.1016/j.envpol.2015.12.017

Cited by 62 publications

(26 citation statements)

References 55 publications

(58 reference statements)

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“…Acting unselectively on DNA, it has been hypothesized that anticancer drugs may harm all eukaryotic organisms by cytotoxic, genotoxic, mutagenic and carcinogenic effects (Johnson et al, 2008;Vyas et al, 2014). The biological risk posed by these anticancer molecules and their metabolites in aquatic species is not well elucidated (Mater et al, 2014), with few data on acute and chronic ecotoxicological assessments in algae Tetrahymena pyriformis (Bonnet et al, 2003), Pseudomonas putida (Zounková et al, 2007) and Pseudokirchneriella subcapitata (Zounková et al, 2007;Brezovsek et al, 2014;Česen et al, 2016); polychaete Nereis diversicolor (Fonseca et al, 2017); bivalve mollusc Mytilus galloprovincialis (Trombini et al, 2016); cladocera crustaceans Daphnia pulex (DellaGreca et al, 2007;Borgatta et al, 2015Borgatta et al, , 2016, D. magna (Zounková et al, 2007;Parrella et al, 2014aParrella et al, , 2014bParrella et al, , 2015 and Ceriodaphnia dubia (DellaGreca et al, 2007;Parrella et al, 2014aParrella et al, , 2014bParrella et al, , 2015; crustacean amphipod Ampelisca brevicornis (Moreira et al, 2016); and the fishes Danio rerio (Kovacs et al, 2015), Pimephales promelas (Winter et al, 2007) and Oryzias latipes (Sun et al, 2011). Limited information exists regarding Environmental risk assessment (ERA) for anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

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Environmental relevant levels of the cytotoxic drug cyclophosphamide produce harmful effects in the polychaete Nereis diversicolor

Fonseca

Auguste

Ribeiro

et al. 2018

Science of The Total Environment

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Cytotoxic drugs applied in chemotherapy enter the aquatic environment after patient's metabolism and excretion, in both main compounds and their respective metabolites. The increased consumption and discharge of these drugs raise concern on the genotoxic burden to non-target aquatic species, due to their unselective action on DNA. Settlement and adsorption of cytotoxic drugs to aquatic sediments pose risks to benthic species through chronic exposure. The aim of the present study was to assess the effects induced by the anticancer drug cyclophosphamide (CP) on the polychaete Nereis diversicolor, after 14 days of exposure to environmental relevant concentrations (10, 100, 500 and 1000 ng L). Burrowing impairment, neurotoxicity (Acetylcholinesterase - AChE activity), oxidative stress (superoxide dismutase - SOD; catalase - CAT; glutathione peroxidases - GPXs activities), biotransformation (glutathione-S-transferases - GST), oxidative damage (lipid peroxidation - LPO) and genotoxicity (DNA damage) were assessed. Burrowing impairments were higher at the lowest CP concentrations tested. The higher CP levels tested (500 and 1000 ng L) induced a significant inhibition on the enzymatic antioxidant system (SOD, GPx) and on GST activity. DNA damage was also significant at these concentrations as an outcome of CP metabolism, and high levels of oxidative damage occurred. The results showed that the prodrug CP was metabolically activated in the benthic biological model N. diversicolor. In addition to the potential cytotoxic impact likely to be caused in aquatic species with similar metabolism, N. diversicolor proved to be reliable and vulnerable to the cytotoxic mode of action of CP, even at the lower doses.

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Section: Introductionmentioning

confidence: 99%

“…The levels of CP detected in hospital effluents, WWTPs influents and effluents, surface waters and sediments are indicated in Table 1. Data suggests that this drug and its metabolites are likely to contribute to overall toxicity in receiving waters (Kiffmeyer et al, 1998;Yasunaga et al, 2006;Kosjek and Heath, 2011;Česen et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Environmental relevant levels of the cytotoxic drug cyclophosphamide produce harmful effects in the polychaete Nereis diversicolor

Fonseca

Auguste

Ribeiro

et al. 2018

Science of The Total Environment

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“…At chronic exposure, 5-fluorouracil produced in zebrafish histopathological changes, and genotoxic effects at environmental concentrations (Kovacs et al, 2015). It is crucial, therefore, to consider the possible toxic/genotoxic effects in organisms exposed over their life span to the continuous presence and possible accumulation of not just the parent anticancer drugs, but also their metabolites and transformation products (Toolaram et al, 2014;Cesen et al, 2016b). Hospital wastewaters are a major source of anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

Chemical and toxicological characterisation of anticancer drugs in hospital and municipal wastewaters from Slovenia and Spain

Isidori¹,

Lavorgna²,

Russo³

et al. 2016

Environmental Pollution

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138

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Anticancer drugs are continuously released into hospital and urban wastewaters, where they, most commonly, undergo conventional treatment in wastewater treatment plants (WWTPs). Wastewaters contain complex mixtures of substances including parent compounds, their metabolites and transformation products (TPs). In this study, samples of hospital effluents and WWTP influents and effluents from Slovenia and Spain were analyzed for twenty-two selected anticancer drugs, their metabolites and transformation products. Acute and chronic toxicity tests were performed on the crustacean Ceriodaphnia dubia, genotoxicity was determined with Tradescantia and Allium cepa micronucleus (MN) assays and in vitro comet assay in zebrafish (Danio rerio) liver cell line (ZFL cells). Sixty of the two hundred-twenty determinations revealed detectable levels of anticancer drug residues. Among the targeted compounds, platinum based were most frequently detected (90%). Furthermore, erlotinib was detected in 80%, cyclophosphamide and tamoxifen in 70% and methotrexate in 60% of the samples. Seven of ten samples were toxic to C. dubia after acute exposure, whereas after chronic exposure all samples reduced reproduction of C. dubia at high sample dilutions. Allium cepa proved insensitive to the potential genotoxicity of the tested samples, while in Tradescantia increased MN frequencies were induced by a hospital effluent and WWTP influents. In ZFL comet assay all but one sample induced a significant increase of DNA strand breaks. Correlations of chemotherapeutics or their TPs were detected for all bioassays except for Allium cepa genotoxicity test, however for each test the highest correlations were found for different substances indicating differential sensitivities of the test organisms.

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“…Thus, CP metabolism is probably different in bacteria cells in comparison to human cells. Maybe, as a result of CP biochemical changes, other intermediate metabolites are formed, which can also generate free radical production [47][48][49][50]57].…”

Section: Antimicrobial Activity Studymentioning

confidence: 99%

Using an <i>Escherichia Coli</i> K-12/<i>recA-gfpmut2</i> Microbial Biosensor to Assess the Impact of Cyclophosphamide and L-ascorbic Acid Residues on Living Bacteria Cells

Matejczyk¹,

Świsłocka²,

Lewandowski³

2020

Pol. J. Environ. Stud.

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Pharmaceutical residues and their transformation products (TPs) have been found in wastewaters and aquatic environments, and they cause adverse effects in aquatic organisms, especially upon chronic exposure and even at very low doses. Cyclophosphamide (CP) is a common alkylating agent that is effective against a wide variety of tumors. L-ascorbic acid is a known water-soluble vitamin that has antioxidant properties. The pharmaceutical residues of both drugs are detected in the environment, and as biologically active molecules they have the ability to affect organisms. In this work we presented the use of a microbiological biosensor E. coli K-12/recA-gfpmut2 in the assessment of the effects of residues of cyclophosphamide and vitamin C and their mixtures on living cells. In our studies, we have shown that mixtures of CP and vitamin C in the highest CP concentrations are more toxic to E. coli strain compared to parent chemicals. In addition, we also found that drug mixtures, especially at the highest CP concentrations, more strongly stimulate the recA promoter and gfp gene expression. We showed that an Escherichia coli K-12/recA-gfpmut2 microbial biosensor is a useful tool in assessing the impact of pharmaceutical residues of cyclophosphamide and L-ascorbic acid and their mixture on living bacteria cells. A stronger impact and toxicity of the mixtures of both tested chemical compounds was found in comparison to parent chemicals.

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

Cited by 62 publications

References 55 publications

Environmental relevant levels of the cytotoxic drug cyclophosphamide produce harmful effects in the polychaete Nereis diversicolor

Environmental relevant levels of the cytotoxic drug cyclophosphamide produce harmful effects in the polychaete Nereis diversicolor

Chemical and toxicological characterisation of anticancer drugs in hospital and municipal wastewaters from Slovenia and Spain

Using an <i>Escherichia Coli</i> K-12/<i>recA-gfpmut2</i> Microbial Biosensor to Assess the Impact of Cyclophosphamide and L-ascorbic Acid Residues on Living Bacteria Cells

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