Cytostatic P harmaceuticals in the E nvironment : O ccurrence , F ate and D etermination

Cytostatic Pharmaceuticals in the Environment: Occurrence, Fate and Determination Ester Heathand Tina Kosjek Jožef Stefan Institute, Ljubljana, Slovenia

CYTOSTATIC AGENTS IN THE ENVIRONMENT • One major class/often overlooked in the environment • Interaction with DNA  preventing growth & proliferation of tumor cells • Importance: • Cytotoxicity • Genotoxicity • Mutagenicity • Teratogenicity • Potentialrisk for humans and the environment • Synergistic toxic effects of certain cytostatic agents with certain antibiotics (hospital effluents, ww)

CYTOSTATICS IN THE ENVIRONMENT • Impact in the environment? • Consumption: low • Globally (50): 5-FU, gemc, IF, CP, MET • Unselective on all growing cells • Carcenogenic potency • All eucariotic organisms vulnerable (teratogenicity, ng L-1) Data courtesy of INSTITUTE OF ONCOLOGY, Ljubljana (2009)

CYTOSTATICS IN THE ENVIRONMENT Estimation for IF, CF: 1 to 10 µgL-1 Toxicity: parent compounds, human metabolites, TPs

Human metabolites CYTOSTATICS IN THE ENVIRONMENT Parentcompounds Environmental transformationproducts Estimation for IF, CF: 1 to 10 µgL-1 Toxicity: parent compounds, human metabolites, TPs

CP IF melphalan chlorambucil 5-FU CAP MET gemcitarabine cytarabine carmustine etoposide vincristine vinblastine procarbazine cisplatin epirubicin doxorubicin daunorubicin

Physico-Chemical Characteristics Kosjek and Heath, CytostaticPharmaceuticalsin the Environment: Occurrence, Fate and Determination Trends in Analytical Chemistry, 30 (2011) 1065-1087

Environmental Fate of the Cytostatics / Biodegradability • Buerge et al (2006): • reviewed → high concentrations (750 mg/L) • performed at envconc → no biodeg • Some: significant biodeg: • Cytarabine: 70 • % • Mixture: less efficient (MIXTURE EFFECTS!) • MET, 5-FU: rate dependent on intialconc • 5-FU • contradictory results • CAP (YES) – prodrug 5-FU • high conc: cytotoxiceff (false neg results) • Vinca alkaloids and anthracyclines → no biodeg (sorption) • SUMMARY: not significantly removed in WWTP (ads, halogens, toxic) • Most: low biodegradability: CP, IF • (std.tests, simulated WWTP, sewage water) Kosjek and Heath, Trendsin Analytical Chemistry, 30 (2011) 1065-1087

Environmental Fate of the Cytostatics /Adsorption onto sludge / sediments • CP, IF, 5-FU, CAP: sorption onto sludge negligable • MET: sorption of polar pollutants to WW solids by hydrphobic interactions important for organic cations (aromaticamines =MET) • anthracyclines: adsorb to glass, steel, plastics • Mahnik et al (2007) confirmed in 5-FU+ anthracyclne test (removal: 5-FU biodeg, anthracycline ads) • vinblastine: log Kow 3,7, log Koc 2400, BCF 140 → potential (studies needed) • Displacement to another compartment • (not removal) Kosjek andHeath, Trendsin Analytical Chemistry, 30 (2011) 1065-1087

Environmental Fate of the Cytostatics /Photolysis • absorption in the 200 to 800 nmregion • chromophores: C=C, C≡C, C=O, N=O and C-X (X =I, Br) • oxygen non-bonding electrons in alcohols and ethers no absorption above 160 nm • common antineoplastics MET, vinblastine and etoposide • dearth of data on this topic • MET: absorbing UV light Kosjek andHeath, Trendsin Analytical Chemistry, 30 (2011) 1065-1087

Environmental Fate of the Cytostatics / Indirect photolysis • CP, IF: ·OH radicals -succesfull photooxidants • promissing for most cytostatics • furtherreserach needed • degradation by ·OH radicals - alternative for AOP of WW containing cytostatics Kosjek andHeath, Trendsin Analytical Chemistry, 30 (2011) 1065-1087

Occurence in WW and in the environment

Occurence in WW and in theenvironment Kosjek andHeath, Trendsin Analytical Chemistry, 30 (2011) 1065-1087

Transformation of cytostatics • Human metabolites together with parent compounds • Hospital effluent: Gemcytarabine human metabolite (2',2'-didefluorodeoxyuridine) • - Cytarabine: abiotic hydrolytic deamination • (→ uracilarabinoside) • - Methotrexate:biotransformation→7-hydroxymethotrexate • (also human metabolite, non biodeg → env) • LACK OF ENVIRONMENTAL STUDIES (PARENT COMPOUNDS, METABOLITES AND TPs) • Kosjek andHeath,Trendsin AnalyticalChemistry, 30 (2011) 1065-1087

Human metabolites Parentcompounds Environmental transformationproducts Transformation of cytostatics • Human metabolites together with parent compounds • Hospital effluent: Gemcytarabine human metabolite (2',2'-didefluorodeoxyuridine) • - Cytarabine: abiotic hydrolytic deamination • (→ uracilarabinoside) • - Methotrexate:biotransformation→7-hydroxymethotrexate • (also human metabolite, non biodeg → env) • LACK OF ENVIRONMENTAL STUDIES (PARENT COMPOUNDS, METABOLITES AND TPs) • Kosjek and Heath, Trendsin AnalyticalChemistry, 30 (2011) 1065-1087

Conclusions: WhyCytostatics? Whynow?- awareof „emerging/emergedcontaminants“- improvedtechnologies (samplepreparation, analyticalinstrumentation) allowlowleveldetection- cytostatics: not sufficientconclusivedata- EC FP7 „CytoThreat“ and „Pharmas“ (2011)

ACKNOWLEDGEMENTS • Slovenian Research Agency, Research Program P1-0143 – »Cycling of nutrients and contaminants inthe environment, mass balances and modeling of environmentalprocesses and risk analysis« • ECFP7“CytoThreat”: “Fate and effects of cytostatic pharmaceuticals in theenvironment and the identification of biomarkers for improved riskassessment on environmental exposure” (2011-2014) • PharmaCluster "This project received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n. 265264"

Alkylatingagents CP IF 5-FU CAP MET Antimetabolic agents cytarabine Plantalkaloids vinblastine cisplatin Cytotoxicantibiotics doxorubicin

Kosjek and Heath, Cytostatic pharmaceuticals in the environment: occurrence, fate and determination Trends in Analytical Chemistry, 2011

Cytostatic P harmaceuticals in the E nvironment : O ccurrence , F ate and D etermination