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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 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 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


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

    Trends in Analytical Chemistry, 2011


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

    Trends in Analytical Chemistry, 2011


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

    Trends in Analytical Chemistry, 2011


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

    Trends in Analytical Chemistry, 2011


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

    Trends in Analytical Chemistry, 2011


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

    Trends in Analytical Chemistry, 2011


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

    Trends in Analytical Chemistry, 2011


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