Occurrence and Fate of the Cytostatic Drugs Cyclophosphamide and - PowerPoint PPT Presentation

Occurrence and Fate of the Cytostatic Drugs Cyclophosphamide and Ifosfamide in Wastewater and Surface Waters Ignaz J. Buerge, Hans-Rudolf Buser, Thomas Poiger, Markus D. Müller Plant Protection Chemistry Swiss Federal Research Station CH-8820 Wädenswil, Switzerland Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Cl Cl H Cl N N O O Cl P H P N O N O Cyclophosphamide Ifosfamide • cytostatic drugs • chemotherapy of bronchial-, brest-, ovarian-cancer, lymphomas, leukaemias, etc. • immunosuppression (rheumatoid arthritis, bone marrow transplantation) Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

→ metabolic activation to the mustard Cl Cl N Cl Cl N O P O HN O P H 2 N OH → unspecific alkylation A T e.g., cross-linking of guanine bases C G R R N N NH 2 G C H 2 N N N NH HN + + N N N O O O P H 2 N OH → errors in DNA replication → mutagenic, carcinogenic, teratogenic, and embryotoxic effects Crick and Watson Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

occurrence in dissipation behavior surface waters consumption/dosage occurrence in ecotoxicity/ wastewater risk assessment trace analysis Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Annual Consumption/Dosage Cyclophosphamide Ifosfamide Switzerland, 2002 55 kg 12 kg Germany, (2000) 200-400 kg Austria, 1997 39 kg 18 kg treatment ambulant or clinical ambulant or clinical typical dosage ≈ 1 g ≈ 2 g renal excretion ≈ 13 % ≈ 15 % Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Trace Analysis solid phase extraction analysis by LC-MS-MS untreated wastewater 6 ng/L Matrix Limit of Detection untreated wastewater 0.2-1 ng/L treated wastewater 0.3-0.4 ng/L surface water 0.02-0.1 ng/L spiked groundwater 0.25 ng/L → extremely sensitive analytical method Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Behavior in Wastewater Treatment Plants (WWTPs) 150 • non biodegraded in activated sludge Ifosfamide Concentration [ng/L] 100 Cyclophosphamide 50 0 0 2 4 6 8 24 10 12 Incubation Time [h] • no sorption to sewage sludge (log K OW = 0.97) • no volatilization (K H = 7 ·10 -11 atm L/mol) → high persistence in WWTPs Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Behavior in Surface Waters gas exchange water exchange flushing degradation degradation processes • biodegradation sorption/ sedimentation • hydrolysis ? • photolysis ? sediment/water- exchange Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Half-Lives under Laboratory Conditions 1.2 CP IF 1.0 Cyclophosphamide [ μ g/L] dark incubation: hydrolysis 0.8 hydrolysis 80 d > 1 year 0.6 indirect photolysis 100 d 140 d 0.4 light incubation: hydrolysis and indirect photolysis 0.2 by HO · radicals 0.0 0 10 20 30 40 50 60 7 Incubation Time [days] Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Extrapolation to Surface Waters CP IF hydrolysis 1-2 years several years indirect photolysis several years several years by HO · radicals → slow degradation in surface waters primarily by hydrolysis Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Comparison of Dissipation by Water Exchange and Hydrolysis CP IF water exchange water exchange, hydrolysis hydrolysis Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Degradation by Photochemically Formed HO . Radicals • diffusion controlled reaction • may be relevant only in shallow, clear, and nitrate-rich waterbodies • could be further exploited for elimination of CP and IF by advanced oxidation processes, e.g., in a treatment of hospital wastewater Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Predicted Concentrations (PEC) of Cyclophosphamide in WWTPs consumption in CH 55 kg renal excretion 13 % water consumption CH 500 L/(person day) degradation in sewer system not considered degradation in WWTPs none PEC untreated and treated wastewater CH 5.4 ng/L "realistic worst case" up to ≈ 100 ng/L Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Selection of WWTPs WWTP Männedorf • hospital with a relatively large oncology division • little dilution by domestic wastewater of 9000 inhabitants → "realistic worst case" situation WWTP Zürich • several hospitals, surgeries, where cytostatic drugs are administered • high dilution by domestic wastewater of 370000 inhabitants → typical situation for urban areas Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Measured Concentrations (MEC) in WWTPs WWTP Influent [ng/L] Effluent [ng/L] Zürich 2-5 2-4 ≈ 4 ≈ 2 Männedorf (no treatment in hospital) Männedorf (with treatments in hospial) 11 * 10 * PEC CH 5.4 5.4 PEC "realistic worst case" up to 100 up to 100 → persistent in WWTPs → * under dry weather conditions ≈ 40 ng/L → PEC ≈ MEC Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Measured Concentrations in Surface Waters PEC treated wastewater 5.4 ng/L degradation in lakes hydrolysis considered PEC lake Zurich 0.07-0.08 ng/L PEC "realistic worst case" surface water a few ng/L MEC lake Zurich ≈ 0.05-0.07 ng/L MEC river Limmat below WWTP Zürich 0.15-0.17 ng/L → PEC ≈ MEC Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Ecotoxicological Data: Mutagenicity to Fish • micronucleus test with erythrozytes of Anguilla anguilla : 3 d exposition, highest effects at 25 mg/L Pacheco and Santos, 1996 • sister chromatide exchange with Anguilla anguilla : 3 d exposition, effects in the mg/L range Santos and Pacheco, 1995 → toxicity-exposure ratio TER >> 1, no acute ecotoxicological risk → no ecotoxicological studies on chronic effects to aquatic organisms Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Summary • consumption CH: 55 kg CP, 12 kg IF • extremely sensitive analytical method: LODs down to 0.02 ng/L • persistent in WWTPs with activated sludge treatment • elimination in lakes by water exchange and slow hydrolysis • degradation by HO · radicals: AOP treatment of hospital wastewater • MEC wastewater: 2-11 ng/L CP, < 0.3-6 ng/L IF "realistic worst case": up to 100 ng/L • MEC surface waters: up to 0.17 ng/L CP, 0.14 ng/L IF "realistic worst case": a few ng/L • no acute ecotoxicological risk, but no ecotoxicological studies on chronic effects to aquatic organisms Buerge et al., Environ. Sci. Technol., in prep. Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

Acknowledgments • BAFU: B. Hitzfeld, U. Stämpfli, C. Studer, A. Weber • A. Heck: Universitätsspital Zürich U. Strebel: Kreisspital Männedorf T. Frösch: Bezirksspital Affoltern am Albis • T. Zobrist: Baxter Oncology • J. Weber: WWTP Männedorf P. Feusi: WWTP Werdhölzli • Amt für Abfall, Wasser, Energie und Luft (AWEL), Zürich • M. Langmeier, M. Reutlinger, S. Canonica : Eawag • M.E. Balmer, A. Bächli, A. Hauser, B. Patrian: agroscope FAW Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006

www.pch.faw.ch Buerge I.J. et al., 1st Network Conference on Persistent Organic Pollutants: Human Exposure and Impacts, University of Birmingham, March 29-30, 2006