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

Cytostatic P harmaceuticals in the E nvironment : O ccurrence , F ate and D etermination Ester Heath and Tina Kosjek Jožef Stefan Institute, Ljubljana, Slovenia. CYTOSTATIC AGENTS IN THE ENVIRONMENT. One major class/often overlooked in the environment

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

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

  2. 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)

  3. 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)

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

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

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

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

  8. 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

  9. 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

  10. 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

  11. 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

  12. Occurence in WW and in the environment

  13. Occurence in WW and in the environment

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

  15. 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

  16. 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

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

  18. 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"

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

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

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

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

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

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

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

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

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

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