title: Ecotoxicity and genotoxicity assessment of cytotoxic antineoplastic drugs and their metabolites.
abstract: In spite of growing scientific concern about pharmaceuticals in the environment, there is still a lack of information especially with regard to their metabolites. The present study investigated ecotoxicity and genotoxicity of three widely used cytostatic agents 5-fluorouracil (5-FU), cytarabine (CYT) and gemcitabine (GemC) and their major human metabolites, i.e. alpha-fluoro-beta-alanine (FBAL), uracil-1-beta-D-arabinofuranoside (AraU) and 2',2'-difluorodeoxyuridine (dFdU), respectively. Effects were studied in acute immobilization and reproduction assays with crustacean Daphnia magna and growth inhibition tests with alga Desmodesmus subspicatus and bacteria Pseudomonas putida. Genotoxicity was tested with umu-test employing Salmonella choleraesius subsp. chol. Toxicity was relatively high at parent compounds with EC(50) values ranging from 44 microg L(-1) (5-fluorouracil in the P. putida test) to 200 mg L(-1) (cytarabine in D. magna acute test). In general, the most toxic compound was 5-FU. Studied metabolites showed low or no toxicity; only FBAL (metabolite of 5-FU) showed low toxicity to D. subspicatus and P. putida with EC(50) values 80 and 140 mg L(-1), respectively. All parent cytostatics showed genotoxicity with minimum genotoxic concentrations (MGC) ranging from 40 to 330 mg L(-1). From metabolites, only FBAL was genotoxic in high concentrations. To our knowledge, the present study provides some of the first ecotoxicity data for both cytostatics and their metabolites, which might further serve for serious evaluation of ecological risks. The observed EC(50) values within the microg L(-1) range were fairly close to concentrations reported in hospital sewage water, which indicates further research needs, especially studies of chronic toxicity.
authors.affiliation: RWTH Aachen University, Institute of Hygiene and Environmental Health, Pauwelsstrabetae 30, 52072 Aachen, Germany. zounkova@recetox.muni.cz
authors.forename: Radka
authors.initials: R
authors.lastname: Zounkova
authors.forename: Lubomira
authors.initials: L
authors.lastname: Kovalova
authors.forename: Ludek
authors.initials: L
authors.lastname: Blaha
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dott
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D001086:Arabinofuranosyluracil / Q000737:chemistry / Q000633:toxicity; D000460:Chlorophyta / Q000187:drug effects / Q000254:growth & development; D003561:Cytarabine / Q000737:chemistry / Q000633:toxicity*; D003621:Daphnia / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000737:chemistry / Q000633:toxicity*; D006131:Growth Inhibitors / Q000633:toxicity; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011549:Pseudomonas / Q000187:drug effects / Q000254:growth & development; D012475:Salmonella / Q000187:drug effects / Q000254:growth & development; D018675:Toxicity Tests; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D009153:Mutagens; D003561:Cytarabine; D003841:Deoxycytidine; D015091:beta-Alanine; D001086:Arabinofuranosyluracil; C032348:alpha-fluoro-beta-alanine; D005472:Fluorouracil; D000093542:Gemcitabine