多功能醫(yī)用護(hù)理床設(shè)計(jì)【說(shuō)明書+CAD+PROE】

多功能醫(yī)用護(hù)理床設(shè)計(jì)【說(shuō)明書+CAD+PROE】,說(shuō)明書+CAD+PROE,多功能醫(yī)用護(hù)理床設(shè)計(jì)【說(shuō)明書+CAD+PROE】,多功能,醫(yī)用,護(hù)理,設(shè)計(jì),說(shuō)明書,仿單,cad,proe S.N. Mahnik a,b , K. Lenz a , N. Weissenbacher a , R.M. Mader b , M. Fuerhacker a, * be the major elimination pathway, as up to 30% of the radio-labelled equivalents of the drugs amount was detected in the solid phase. tal euents partially transformed or even unchanged via urine and faeces of patients under medical treatment. Therefore, they are assumed to be environmentally relevant compounds. As hospital euents reach the municipal sewer network generally without any preliminary treat- ment, hospitals may represent an incontestable release * Corresponding author. Address: Institute of Sanitary Engineering and Water Pollution Control, Department of Water, Atmosphere and Envi- ronment, University of Natural Resources and Applied Life Sciences Vienna, Muthgasse 18, A-1190 Vienna, Austria. Tel.: +43 1 36006 5821; fax: +43 1 368 9949. E-mail address: maria.fuerhackerboku.ac.at (M. Fuerhacker). Chemosphere 66 (2007) Our results indicate that the investigated anticancer drugs are eliminated by sewage treatment plants, either by biodegradation or adsorption. C211 2006 Elsevier Ltd. All rights reserved. Keywords: Anthracyclines; 5-Fluorouracil; Hospital euents; Monitoring; Elimination; Activated sludge 1. Introduction During the last years, the growing use of antineoplastic drugs in cancer therapy is an emerging issue in environ- mental research and it can be expected, that consumption will increase due to a developing health care system and a higher life expectancy. Cytostatics belong to the CMR (carcinogenic, muta- genic and reprotoxic) drugs. They usually enter the hospi- 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-fluorouracil (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 8.6 to 124 lgl C01 for 5-FU and from 0.26 to 1.35 lgl C01 for DOX were determined. The concentrations analysed fitted the lower ranges calculated by an inputoutput model. Treatment of oncologic wastewater in the membrane bio-reactor as well as the analysis of the euents of the Vienna University Hospital resulted in concentrations below the limit of detection. Investigations with radio-labelled compounds showed that 5-FU is eliminated from the liquid phase below the limit of detection. But, up to 25% of radio-labelled equivalents of the drugs amount were found in the gaseous phase and only a marginal part in the solid phase, this indicates that at least one part of the drug is biode- graded. For the anthracyclines more than 90% was eliminated from the liquid phase. In this case, adsorption to suspended solids seems to Fate of 5-fluorouracil, doxorubicin, in hospital wastewater and their and treatment in a membrane-bio-react 0045-6535/$ - see front matter C211 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.chemosphere.2006.05.051 epirubicin, and daunorubicin elimination by activated sludge or system 3037 source of anticancer agents. In the Vienna University Hos- pital (VUH) nearly 80% of cancer therapies are adminis- tered in the out-patient treatment ward, i.e. patients leave the hospital after drug application. Subsequently, the drugs are also directly excreted into the municipal sewer network. Their quantification in hospital euents may serve as a starting point to individualise the magnitude of putative pollution problems. Especially in Germany, investigators have been active in monitoring the fate of cytostatics in treatment of haematological and solid neoplasms, includ- ing acute leukaemia, high grade lymphoma, breast cancer, and bladder cancer (Dorr and Von Ho, 1994). Anthra- cyclines are administered in dosages ranging from 15 120 mg m C02 body surface. Approximately 3.55.7% of administered DOX, 11% of EPI, and 1315% of DAUN are excreted unmetabolised via urine within 24 h. Metabo- lites include toxic compounds such as doxorubicinol, daunorubicinol or epirubicinol and non-toxic agents such 2- 14 C 5-FU was purchased from ARC (American Radio Labelled Chemicals Inc., St. Louis, MO) and 14- 14 C S.N. Mahnik et al. / Chemosphere 66 (2007) 3037 31 the environment after administration to patients. Steger- Hartmann et al. (1996) determined the antineoplastics cyclophosphamide and ifosfamide in sewage water samples at concentrations of 146 ng l C01 and 24 ng l C01 , respectively. Kummerer (2000) found concentrations of 0.0061.9 lgl C01 ifosfamide and 0.024.5 lgl C01 cyclophosphamide in eu- ents from an oncologic hospital. In the influents of the receiving municipal sewage treatment plants ifosfamide and cyclophosphamide were measured at concentrations of 0.010.03 lgl C01 for ifosfamide and 0.0060.14 lgl C01 for cyclophosphamide, without observing any significant reduction during sewage treatment. These results are approved by investigations of Kummerer et al. (1997).In this study average concentrations of 109 ng l C01 ifosfamide were determined in hospital euents. In the influent of municipal sewage treatment plants concentration levels from 6.28.5 ng l C01 were found, in the euent levels from 6.5 to 9.3 ng l C01 . One of the most frequently used drugs in cancer therapy is 5-fluorouracil (5-FU) of the group of antimetabolites. Therefore, it may be regarded as a pilot substance for the assessment of environmental contamination originat- ing from hospital euents. The consumption of 5-FU amounted to 119 kg in 1997 in Austria (Sattelberger, 1999)andto4.74 kgin2001intheVUH.Thedrugisadmin- istered in the treatment of breast, skin, bladder, and lung cancer in dosages ranging from 200 to 1000 mg m C02 body surface (Dorr and Von Ho, 1994). Approximately 235% oftheadministereddrugisexcretedunmetabolisedviaurine within 24 h (Diasio and Harris, 1989; Schalhorn and Kuhl, 1992; Dorr and Von Ho, 1994). The International Agency ontheResearch ofCancerindicates5-FUasnotclassifiable as to its carcinogenicity to humans (IARC, 1987). Doxorubicin (DOX), epirubicin (EPI), and daunorubi- cin (DAUN) belong to the group of anthracyclines. The consumption of these drugs amounted to 0.25 kg in 2001 in the VUH. The compounds are frequently used in the Fig. 1. Chemical structures of the selected cytostatics 5-fluorouracil, DOX hydrochloride from Amersham (Buckingham- shire, England). The chemical structures of the selected compounds are shown in Fig. 1. The scintillation liquid Opti-Fluorwas obtainedfrom Packard(PerkinElmer,Bos- ton, MA). Fresh municipal wastewater was pumped from the local sewer at the BOKU University of Nature ResourcesandAppliedLifeSciencesandcollectedinastor- age tank. Activated sludge was taken from a sequencing batch reactor which is fed with wastewater from the local municipal sewer of the BOKU University of Nature Resources and Applied Life Sciences. The average concen- tration of suspended solids was 817.6 g l C01 for the tests with radio-labelled drugs. Determination was carried out according to German guidelines (DEV, 2003). as 7-hydroxy and 7-deoxy aglycones (Dorr and Von Ho, 1994). The International Agency on the Research of Can- cer classifies DOX and DAUN as category 2 (A and B), whereby 2A means probably carcinogenic and 2B means possibly carcinogenic (IARC, 1987). The primary aim of this research was to determine the concentrations of selected cytostatics in the sewer system of the oncologic in-patient treatment ward of the VUH by calculation of the wastewater concentration, to monitor the actual concentrations and to investigate the elimination of the parent substances in a membrane-bio-reactor sys- tem. Another purpose of this study was to provide a better understanding of their fate in wastewater and their elimina- tion by activated sludge. 2. Materials and methods 2.1. Materials For the experiments with radio-labelled compounds doxorubicin, epirubicin and daunorubicin. 3. Experimental set-up 3.1. Monitoring of the sewage of the oncologic in-patient- treatment-ward and VUH euent The sewer system of the oncologic in-patient-treatment ward of the VUH was reconstructed in a way to allow the collection of the full amount of wastewater from 18 patients (3 toilets and 3 showers) over 24 h (Lenz et al., 2005). The sewer pipes were separated from the central col- lection system and connected to two 1000 l tanks in the technical area of the VUH (see Fig. 2). A pilot treatment plant, a membrane-bio reactor system, was aliated to the 1000 l tanks. The system consists of a 140 l mixing tank with a 1 mm screen, an 150 l aeration tank, an ultrafiltra- tion module and an euent tank after filtration. The bioreactor system is run with a hydraulic load of 100 200 l d C01 which means a hydraulic retention time of 2024 h. The membrane bioreactor consists of the aera- tion tank and an external, tubular ultrafiltration module (MOLSEP C210 , Nadir Filtration GmbH, Germany). The con- centration of suspended solids in the aeration tank (sampling device 2) and at the sampling device of the eu- ent (sampling device 3). The samples were stored atC020 C176C until analysis. Additionally raw wastewater samples of the VUH were measured at two dierent time periods. Pooled samples were taken at all 4 discharge points before entering the municipal sewer system. 3.2. Calculation of the wastewater concentration To spot a correlation between the results of the monitor- ing and the administered dosages, human excretion rates and administered drug amounts were applied to calculate minimal and maximal concentration ranges in the sewer of the oncologic in-patient treatment ward (Mahnik et al., 2003). 3.3. Analytical methods for the determination of the selected cytostatics All wastewater samples were centrifuged 10 min at 5000g and the liquid filtered through sterile filters with 32 S.N. Mahnik et al. / Chemosphere 66 (2007) 3037 amounted to 11.815.2 g l C01 . The ultrafiltration module operates with a polysulfonmembrane (active surface = 1m 2 , nominal cut-o = 100 kD) in the cross-flow mode. Four monitoring periods (monitoring 14) were carried out at dierent times of the year over a time period of 98 d in total. During monitoring 1 the 1000 l storage tanks were sampled at sampling device 1. During monitoring 24, wastewater samples were taken at dierent sample sites: at the sampling device of the 1000 l tank after blending the content for 15 min (sampling device 1), at the sampling device of raw water after the screen in the mixing tank Fig. 2. Design of the sampling at the 0.22 lm pore size to remove suspended solids. For the analysis of 5-FU, the pH of the samples (50 ml) was adjusted to 4.5 by acetic acid. The solid-phase-extrac- tion columns were preconditioned by MeOH, water and a sodium acetate buer. 5-FU was eluted with 8 ml MeOH (pH = 9). The solvent of the eluate was evaporated to dry- ness and the residue dissolved in a disodium tetraborate buer (pH = 9). When analysed by capillary electrophore- sis, 5-FU was monitored at 265 nm with a typical migra- tion time of 21 min and a limit of quantification (LOQ) of 8.6 lgl C01 (Mahnik et al., 2004). Vienna University Hospital. Fortheanalysisoftheanthracyclines,thepHofthesam- ples was adjusted to 7.5 by NaOH. The solid phase extrac- tion columns (C8 columns) were preconditioned by MeOH, water and phosphate buered saline containing 2% bovine serum albumin (BSA, w/v). As standard curves in water did not show linear regression, we added BSA, thus exploit- ing the high protein binding capacity of anthracyclines. The drugs were eluted with 1.5 ml MeOH/CHCl 3 (1:2, v/v). The solvent of the eluate was evaporated to dryness and the residue dissolved in 100 ll 30% acetonitrile/70% 10 mM K-di-hydrogenphosphate buer. The analysis by high performance liquid chromatography was carried out using a 10 mM K-di-hydrogenphosphate buer and aceto- nitrile as eluent. Substances were identified by their reten- tion time in the fluorescence scan and quantified by peak area (Mahnik et al., in press). The LOQ for EPI and DOX was 0.26 lgl C01 , for daunorubicin it was 0.29 lgl C01 . 3.4. Batch experiments with radio-labelled compoundsfate in wastewater and elimination by activated sludge For the investigation of the fate in wastewater and the elimination tests by activated sludge two concentrations of 2- 14 C 5-FU (5 and 500 lgl C01 ) and one concentration of 14- 14 C DOX hydrochloride (2500 lgl C01 ) were tested. The mentioned concentrations were incubated with 9 ml wastewater or activated sludge in a 24 h kinetics. When incubating the substances with activated sludge, the pro- duced carbon dioxide was collected by a 1 g soda lime trap. To optimize the analysis, the soda lime was split in 3 por- tions for counting. From the samples, agitated by a shaker (KS 501 D Janke Kummerer, 2000), investigating degradation by determina- tion of O 2 or 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 (excretion rate 2%) and DOX (excretion rate 0.5%). Ta ble 1 C oncentra tion of activat ed sludge in the aera tion tank, admin istere d amou nts of 5-FU and DOX at the oncolo gic in-patien t-treatment ward, calc ulate d and ana lysed conc entrations in the sewe r C oncentra tion of activ ated sludge (g l C0 1 ) 5-FU DO X Administ ered amount (mg) Conce ntration s i n the sewe r o f the oncolo gic in-patien t- treatmen t ward ( l gl C0 1 5-flu orourac il) Admin istered amou nt (mg) C oncentra tions i n the sewe r o f the on cologic in-p atient tr eatment ward ( l gl C0 1 doxorub icin) Calculate d Analyse d C alculate d Ana lysed Min. Max. (2% excretio n rate) Min. M ax. Mean Samples Min. Max. (0.5% exc retion rate) M in. Max. Mean Sam ples M onitoring 1 1800 6083 36122 11.5 122 55.6 28 16.8 265 0.08 1.3 0 .26 (LOQ) 1.35 0.6 28 M onitoring 2 11.8 790 3555 15.871.1 8.6 (LOQ ) 40.1 21.0 25 M onitoring 3 14.4 1010 4905 20.298.1 18 123.5 91.0 30 40.2 244 0.21 .22 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- 14 C 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 ere 66 (2007) 3037 35 be eliminated by adsorption, it has to be considered that adsorption to sewage sludge represents only a displacement 36 S.N. Mahnik et al. / Chemosph 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 eects. Fig. 4. Fate of 2-C 14 5-FU and Fig. 5. Elimination of 2-C 14 5-FU and ere 66 (2007) 3037 Acknowledgements This work has been supported by the Federal Ministry of Agriculture, Forestry, Environment and Water Manage- 14-C 14 DOX in wastewater. 14-C 14 DOX by activated sludge. ment (project number GZ a 301482), 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-fluorouracil. Clin. Pharmacokinet. 16, 215237. 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