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Fate of 5-fl uorouracil, doxorubicin, epirubicin, and daunorubicin in hospital wastewater and their elimination by activated sludge and treatment in a membrane-bio-reactor system S.N. Mahnik a,b, K. Lenza, N. Weissenbachera, R.M. Maderb, M. Fuerhackera,* a Institute of Sanitary Engineering and Water Pollution Control, Department of Water, Atmosphere and Environment, University of Natural Resources and Applied Life Sciences Vienna, Muthgasse 18, A-1190 Vienna, Austria b Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Austria Received 4 November 2005; received in revised form 22 May 2006; accepted 24 May 2006 Available online 12 July 2006 Abstract Antineoplastic agents are applied in cancer therapy and end up in hospital wastewater by human excretions. In this study, the raw wastewater of the sewer of the oncologic in-patient treatment ward of the Vienna University Hospital was monitored for 98 d over 2 years for the cytostatics 5-fl uorouracil (5-FU), doxorubicin (DOX), epirubicin, and daunorubicin. In a next step, the elimination of the drugs by a membrane-bio-reactor system was investigated. In addition, their fate in wastewater and elimination by activated sludge was investigated with radio-labelled substances. During the monitoring periods, concentration levels ranging from 90% over time of 24 h, i.e. the concentration in the liquid phase remained stable over time of 24 h. DOX was adsorbed to suspended solids in wastewater and to the tube walls since from the beginning of the experiment the concentration in the liquid phase amounted only to 41% compared to the start concentration (see Fig. 4). Together with the experimental data of the monitoring it can be assumed, that 5-FU is expected to be biodegraded or at least metabolized by microorganisms as it did not adsorb to suspended solids in wastewater. For the anthra- cyclines adsorption to suspended solids seems to be the major elimination pathway. 4.3. Batch experiments with radio-labelled compounds elimination by activated sludge To assess the elimination of 5-FU and DOX by acti- vated sludge, kinetic investigations with 5 and 500 lg l?1 2-14C 5-FU and 2 500 lg l?114-14C DOX were carried out. The results of these tests are demonstrated in Fig. 5. The investigations showed that 5-FU was eliminated from the liquid phase below LOD within 24 h. The tests indi- cated that the minor part of the drug was found in the sludge over time of 24 h, since recoveries amounted only to 25%. Up to 25% of the whole amount of 5-FU was trapped by the soda lime, which suggests a biodegradation, partly a fi nal degradation or metabolization by micro- organisms of a major part of the substance. Although we counted the soda lime in several portions, we hypothesised, that parts of the signals were suppressed. Also Kiff meyer et al. (1998) observed a biodegradation up to 92% for 5- FU in the OECD Confi rmatory Test. The degradation rate was directly proportional to the initial concentration. In contrast, degradation was not observed in the Closed- Bottle-Test (OECD 301 D) and in the Zahn-Wellens- Test (OECD 302 B) (Ku mmerer and Al-Ahmad, 1997; Ku mmerer, 2000), investigating degradation by determina- tion of O2or dissolved organic carbon (DOC). The tests with radio-labelled DOX resulted in a total elimination of 90% from the liquid phase. Over time the recovery for DOX ranged between 2040% in the sludge, but only between 612% in the liquid phase. Analysis of the soda lime indicated, that elimination of DOX is mainly Fig. 3. Analysed and calculated concentrations of 5-FU (excretion rate 2%) and DOX (excretion rate 0.5%). 34S.N. Mahnik et al. / Chemosphere 66 (2007) 3037 caused by adsorption, as only 1.7% of the total amount could be determined when soda lime was counted. Litera- tureresultsindicatethatEPIiseliminatedinthe Zahn-Wellens-Test (OECD 302 B), but not in the Closed- Bottle-Test (OECD 301 D). Both tests investigate the degradation by determination of DOC and O2, respec- tively. The Zahn-Wellens-Test (OECD 302 B) is carried out with a higher concentration of bacteria and a higher concentration of test substance, furthermore, the concen- trations used for these tests were 67 orders of magnitude higher than concentrations expected in sewage of hospitals (Ku mmerer et al., 1996; Ku mmerer, 1999). Due to the high adsorption capacity of sludge for EPI, neither biodegra- dation in sewage treatment plants nor emission to surface water is supposed. The radio-labelling was carried out at the most stable part of the drug. The ring structure of the prodrug 5-FU is opened very easily when degraded by anabolism and catabolism, whereas the ring structure of DOX remains stable when degraded (Diasio and Harris, 1989; Dorr and Von Hoff , 1994). 5. Conclusions The present paper shows that the pilot substance 5-FU is administered in considerable amounts and that the calcu- lated concentrations could be monitored in the sewer of the oncologic in-patient treatment ward of the VUH. The drug is eliminated from the liquid phase below LOD when incu- bated with activated sludge in batch experiments or treated in a membrane-bio-reactor system. Although there was no diff erence in the elimination, the combination of activated sludge treatment and membrane fi ltration in the mem- brane-bio-reactor system enabled a total retention of sew- age sludge and a high sludge retention time. Combined with adsorption processes in the system, the degradation of trace contaminants, e.g. endocrine modulators, is forced as already shown by Scha fer (2001). The elimination of the investigated substances in this study is mainly caused by biodegradation or metabolization, as the experiments with 2-14C 5-FU indicate. The amount of anthracyclines observed in the sewer of oncologic in patient treatment ward of the VUH is also comparable to the administered quantity. Incubation with activated sludge yielded in an elimination of 90% from the liquid phase, treatment in the membrane-bio-reactor system resulted in concentra- tions below LOD in the liquid phase. In case of the anthra- cyclines adsorption to sewage sludge seems to be the major elimination pathway from the wastewater as the tests with 14-14C DOX show. As 5-FU is expected to be biodegraded in sewage treat- ment plants, the environmental impact is of minor impor- tance provided that a failure (e.g. leaking) or direct emission of wastewater to a small receiving water can be inhibited. For the anthracyclines, as they are assumed to be eliminated by adsorption, it has to be considered that adsorption to sewage sludge represents only a displacement Table 1 Concentration of activated sludge in the aeration tank, administered amounts of 5-FU and DOX at the oncologic in-patient-treatment ward, calculated and analysed concentrations in the sewer Concentration of activated sludge (g l?1) 5-FUDOX Administered amount (mg) Concentrations in the sewer of the oncologic in-patient- treatment ward (lg l?1 5-fl uorouracil) Administered amount (mg) Concentrations in the sewer of the oncologic in-patient treatment ward (lg l?1doxorubicin) CalculatedAnalysedCalculatedAnalysed Min.Max.(2% excretion rate) Min.Max.MeanSamplesMin.Max.(0.5% excretion rate) Min.Max.MeanSamples Monitoring 1180060833612211.512255.62816.82650.081.30.26 (LOQ)1.350.628 Monitoring 211.8790355515.871.18.6 (LOQ)40.121.025 Monitoring 314.41010490520.298.118123.591.03040.2246 (LOQ)0.50.330 Monitoring 415.2648276812.955.414 S.N. Mahnik et al. / Chemosphere 66 (2007) 303735 of the drugs from the liquid to the solid phase. On the basis of the current knowledge, much is yet to be understood regarding fate and the transport of cytostatics and their ultimate environmental eff ects. Acknowledgements This work has been supported by the Federal Ministry of Agriculture, Forestry, Environment and Water Manage- Fig. 4. Fate of 2-C14 5-FU and 14-C14 DOX in wastewater. Fig. 5. Elimination of 2-C14 5-FU and 14-C14 DOX by activated sludge. 36S.N. Mahnik et al. / Chemosphere 66 (2007) 3037 ment(projectnumberGZa301482),Austrian Kommunalkredit AG and the FFF. References DEV German Standard procedures for the analysis of water, wastewater and sewage sludge (Deutsche Einheitsverfahren zur Wasser-, Abwas- ser- und Schlammuntersuchung, Physikalische, chemische, biologische und bakteriologische Verfahren), 2003. WileyVCH Verlag GmbH & Co, Weinheim. Diasio, R.B., Harris, B.E., 1989. Clinical pharmacology of 5-fl uorouracil. Clin. Pharmacokinet. 16, 215237. Dorr, R.T., VonHoff , D.D., 1994. Cancer Chemotherapy Handbook, second ed. Norwalk, Appleton & Lange, Norwalk, Connecticut. IARC, 1987. Monographs on the Evaluation of Cancerogenic Risks to Humans.InternationalAgencyforResearchofCancer,Lyon(Suppl.7). Kiff meyer, T., Go tze, H.-J., Jursch, M., Lu ders, U., 1998. Trace enrich- ment, chromatographic separation and biodegradation of cytostatic compounds in surface water. Fresenius J. Anal. Chem. 361, 185191. Ku mmerer, K., 1999. Epirubicin hydrochloride in the aquatic environ- mentbiodegradation and bacterial toxicity (Epirubicinhydrochlorid in der aquatischen UmweltBiologische Abbaubarkeit und Wirkung auf aquatische Bakterien). In: Proceedings 7, Nordwestdeutscher Zytostatikaworkshop, Hamburg-Harburg 2931.1. 1999, pp. 1011. Ku mmerer, K., 2000. Laboratory scale degradation of pharmaceuticals and emission control (Abbau von Arzneimitteln in Testsystemen und Mo glichkeiten zur Emissionsreduktion). In: Weigert, B., Steinberg, Chr., Bru ggemann, R., (Eds). Chemische Stressfaktoren in aquatischen Systemen. Schriftenreihe Wasserforschung 6, Wasserforschung e.V., Berlin, pp. 165177. Ku mmerer, K., Al-Ahmad, A., 1997. Biodegradability of the anti-tumour agents 5-fl uorouracil, cytarabine, and gemcitabine: impact of the chemical structure and dynergistic toxicity with hospital effl uents. Acta Hydroch. Hydrob. 25, 166172. Ku mmerer, K., Al-Ahmad, A., Steger-Hartmann, T., 1996. Epirubicin hydrochloride in the aquatic environmentbiodegradation and bac- terial toxicity (Verhalten des Zytostatikums EpirubicinHydrochlorid in der aquatischen Umwelt). Umweltmedizin Forschung Praxis 1, 133 137. Ku mmerer, K., Steger-Hartmann, T., Meyer, M., 1997. Biodegradability of the anti-tumour agent ifosfamide and its occurrence in hospital effl uents and communal sewage. Water Res. 31, 27052710. Lenz, K., Hann, S., Koellensperger, G., Stefanka, Z., Stingeder, G., Weissenbacher, N., Mahnik, S., Fuerhacker, M., 2005. Presence of cancerostatic platinum compounds in hospital wastewater and possible elimination by adsorption to activated sludge. Sci. Total Environ. 345, 141152. Mahnik, S., Mader, R.M., Fuerhacker, M., 2003. Cytostatic agents in the wastewater of the Vienna University Hospital. In: 4th IWA Specialized Conference on Assessment and Control of Hazardous Substances in Water: Ecohazard 2003 Conference 1417.9. 2003, Aachen University Germany. Mahnik, S., Rizovski, B., Fuerhacker, M., Mader, R., 2004. Determina- tion of 5-fl uorour