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

• Published in: Environmental pollution (1987) Vol. 210; pp. 192 - 201
• Main Authors: Česen, Marjeta, Eleršek, Tina, Novak, Matjaž, Žegura, Bojana, Kosjek, Tina, Filipič, Metka, Heath, Ester
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2016
• Subjects: Antineoplastic Agents, Alkylating - chemistry; Antineoplastic Agents, Alkylating - pharmacokinetics; Antineoplastic Agents, Alkylating - toxicity; Antineoplastic Combined Chemotherapy Protocols - chemistry; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - toxicity; Aquatic ecotoxicity; Chlorophyta - drug effects; Cyclophosphamide - chemistry; Cyclophosphamide - pharmacokinetics; Cyclophosphamide - toxicity; Cytostatic; DNA Damage; Environmental Pollutants - chemistry; Environmental Pollutants - pharmacokinetics; Environmental Pollutants - toxicity; Genotoxicity; Human metabolite; Humans; Ifosfamide - chemistry; Ifosfamide - pharmacokinetics; Ifosfamide - toxicity; Mixture; Mutagenicity Tests; Pseudokirchneriella subcapitata; Salmonella typhimurium; Ultraviolet Rays; NQNO; Aquatic ecotoxicity; AFLB1; Cytostatic; S9; Genotoxicity; NdCP; CPCOOH; H2O2; CP; Mixture; Human metabolite; ONPG; HEPES; DOC; EC50; NADP; NOEC; TP; IF; ketoCP
• ISSN: 0269-7491; 1873-6424
• DOI: 10.1016/j.envpol.2015.12.017

Cyclophosphamide (CP) and ifosfamide (IF) are commonly used cytostatic drugs that repress cell division by interaction with DNA. The present study investigates the ecotoxicity and genotoxicity of CP, IF, their human metabolites/transformation products (TPs) carboxy-cyclophosphamide (CPCOOH), keto-cyclophosphamide (ketoCP) and N-dechloroethyl-cyclophosphamide (NdCP) as individual compounds and as mixture. The two parent compounds (CP and IF), at concentrations up to 320 mg L−1, were non-toxic towards the alga Pseudokirchneriella subcapitata and cyanobacterium Synecococcus leopoliensis. Further ecotoxicity studies of metabolites/TPs and a mixture of parent compounds and metabolites/TPs performed in cyanobacteria S. leopoliensis, showed that only CPCOOH (EC50 = 17.1 mg L−1) was toxic. The measured toxicity (EC50 = 11.5 mg L−1) of the mixture was lower from the toxicity predicted by concentration addition model (EC50 = 21.1 mg L−1) indicating potentiating effects of the CPCOOH toxicity. The SOS/umuC assay with Salmonella typhimurium revealed genotoxic activity of CP, CPCOOH and the mixture in the presence of S9 metabolic activation. Only CPCOOH was genotoxic also in the absence of metabolic activation indicating that this compound is a direct acting genotoxin. This finding is of particular importance as in the environment such compounds can directly affect DNA of non-target organisms and also explains toxicity of CPCOOH against cyanobacteria S. leopoliensis. The degradation study with UV irradiation of samples containing CP and IF showed efficient degradation of both compounds and remained non-toxic towards S. leopoliensis, suggesting that no stable TPs with adverse effects were formed. To our knowledge, this is the first study describing the ecotoxicity and genotoxicity of the commonly used cytostatics CP and IF, their known metabolites/TPs and their mixture. The results indicate the importance of toxicological evaluation and monitoring of drug metabolites as they may be for certain aquatic species more hazardous than parent compounds. [Display omitted] •CP and IF were not toxic (<320 mgL−1) for P. subcapitata and S. leopoliensis.•The EC50 value for CPCOOH, a CP human metabolite/TP, was 17.1 mg L−1.•CPCOOH was genotoxic regardless of the metabolic activation in SOS/umuC assay.•The mixture of studied compounds was genotoxic with metabolic activation.•UV treatment of CP and IF had no influence on growth of S. leopoliensis. Carboxy-cyclophosphamide, a CP metabolite, is more toxic than its parent compound, which indicates that also metabolites/TPs should be included in human and environment risk assessment.