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


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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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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

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

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 environment1

CYTOSTATICS IN THE ENVIRONMENT

Estimation for IF, CF: 1 to 10 µgL-1

Toxicity: parent compounds, human metabolites, TPs


Cytostatics in the environment2

Human metabolites

CYTOSTATICS IN THE ENVIRONMENT

Parentcompounds

Environmental transformationproducts

Estimation for IF, CF: 1 to 10 µgL-1

Toxicity: parent compounds, human metabolites, TPs


Carmustine

CP

IF

melphalan

chlorambucil

5-FU

CAP

MET

gemcitarabine

cytarabine

carmustine

etoposide

vincristine

vinblastine

procarbazine

cisplatin

epirubicin

doxorubicin

daunorubicin


Physico chemical characteristics

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

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

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

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

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 the environment


Occurence in ww and in the environment1

Occurence in WW and in the environment


Occurence in ww and in the environment2

Occurence in WW and in theenvironment

Kosjek andHeath, Trendsin Analytical Chemistry, 30 (2011) 1065-1087


Transformation of cytostatics

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


    Transformation of cytostatics1

    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


    Cytostatic p harmaceuticals in the e nvironment o ccurrence f ate and d etermination

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


    Acknowledgements

    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"


    Cytostatic p harmaceuticals in the e nvironment o ccurrence f ate and d etermination

    Alkylatingagents

    CP

    IF

    5-FU

    CAP

    MET

    Antimetabolic agents

    cytarabine

    Plantalkaloids

    vinblastine

    cisplatin

    Cytotoxicantibiotics

    doxorubicin


    Cytostatic p harmaceuticals in the e nvironment o ccurrence f ate and d etermination

    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

    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

    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

    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

    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

    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

    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

    Kosjek and Heath, Cytostatic pharmaceuticals in the environment: occurrence, fate and determination

    Trends in Analytical Chemistry, 2011


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