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河北建筑工程学院毕业设计（论文）外文资料翻译 系别： 城市建设 专业： 环境工程 班级： 环境031 姓名： 刘志祥 学号： 2003313131 外文出处：S.N. Mahnik et al. / Chemosphere66 (2007) 3037 指导教师评语：签字： 年 月 日2、外文资料翻译译文5-氟尿嘧啶、阿霉素和柔红霉素在医院废水中的去向和通过活性污泥法的去除以及通过膜生物反应系统的治理摘要：抗肿瘤药应用于癌症的治疗,最终通过人类排泄排入医院废水。 在本文研究中，维也纳大学医院肿瘤住院病房污水管中的原废水在两年中被检测了98天，用以观测5-氟尿嘧啶(5-FU)、阿霉素(DOX)、阿霉素、柔红霉素的细胞抑制作用。在下一步工作中,消除毒品的膜生物反应系统被探讨。此外,他们在废水中的生命期和通过活性污泥法的消除效果，通过放射性同位素标记的物质来研究。在监控期间, 浓度范围8.6 124 ug/l的5-氟尿嘧啶(5-FU)和0.26 1.35ug/l的阿霉素(DOX)被测定。浓度分析与通过投入产出模型推算出来的最低范围相吻合。通过膜生物反应器治理的肿瘤废水以及在维也纳大学医院废水分析的浓度结果都低于检测限。通过对被放射性同位素标记的化合物的调查显示5-氟尿嘧啶在低于检测限浓度下，在液相阶段可以去除。但是, 高达25%的被放射性同位素标记的等量毒品在气相时被发现，只有有极少部分在固相被发现，这表明至少有一部分是可以用药物降解的。如蒽90%以上在液相可以被去除。在这种情况下,吸附悬浮固体似乎是用于消除的主要方法，因为高达30%的被放射性同位素标记的等量毒品在固相阶段被检测。 调查结果表明，我国抗癌药物在污水处理厂，用吸附或降解法去除。关键词：蒽；5-氟尿嘧啶；医院污水；监测；消除；活性污泥1.引言在过去几年，癌症治疗中越来越多的使用了抗癌药物，这是一个新兴的环保问题，可以预计，由于医疗制度的发展和人们对生命的更高的期望，这种抗癌药物的消费量会日益增长。细胞抑制属于CMR(致癌、致突变和生殖毒性的)药物。他们通常部分经转化排入医院的污水中，部分甚至没经任何转化，在药物治疗中通过病人的尿液和粪便直接排入。因此，他们被假设为和环保相关的化合物。由于医院污水到达市政污水管网时到达一般未经任何初步治理，医院不可否认的成为抗癌药物释放源的代表。在维也纳大学医院（VUH）近80%的癌症疗法是在门诊治疗病房，即病人出院后用药。随后，药品也直接排入市政污水管网。其在医院污水中测量出的数量可作为区别疑似污染问题的重要的一个起点。尤其在德国，调查一直活跃在检测在病人用药后的环境中细胞抑制的命运。Steger-Hartmann等(1996年) 在污水管中的样品中测定抗肿瘤药中，环磷酰胺和环磷酰胺的浓度分别为146ng /l和24 ng/l，Kummerer (2000) 在一家肿瘤医院废水中发现环磷酰胺的浓度为0.006-1.9ng /l，环磷酰胺的浓度为0.024.5 ng/l。在城市污水处理厂的进水口接收的环磷酰胺环磷酰胺测定的浓度为0.010.03 g/l，0.006-0.14 g/l，在污水处理的观测期间，无任何明显的减少。这些成果经Kummerer等 (1997)调查核准。这项研究中，医院污水中测定的环磷酰胺的平均浓度为109克每升。在城市污水处理厂进水口发现的浓度为6.28.5 g/l，污水中的浓度为6.59.3 g/l。其中最常用的治疗癌症的药物是抗癌药物类中的5-氟尿嘧啶。 因此，它可作为一种试验性的物质，用以评估来自医院的污水物质对环境污染。1997年在奥地利(sattelberger，1999)，5-氟尿嘧啶的消耗总额为119kg，2001年在维也纳大学医院（VUH），5-氟尿嘧啶的消耗总额为4.74kg。这种药物治疗乳腺癌、皮肤癌、膀胱癌与肺癌，每平体表的剂量从200至1000毫克不等(Dorr 和Von Hoff，1994)。约2-35%的药品在24小时内经由尿液排出。 (Diasio 和 Harris，1989； Schalhorn和Kuhl，1992； Dorr和Von Hoff，1994)。国际癌症研究机构表明5-氟尿嘧啶由于其对人体的致癌作用至今还未给予分类(癌症研究所，1987)。 阿霉素(DOX)、阿霉素(EPI)、柔红霉素(DAUN)属于蒽类。2001年，这些药物在维也纳大学医院（VUH）的消费总额为0.25 kg。 该化合物常用于血液和固体肿瘤的治疗，包括急性白血病、高档淋巴瘤、乳腺癌、膀胱癌(Dorr 和Von Hoff, 1994)。蒽的剂量范围为15-120毫克每平体表。约3.55.7的阿霉素(DOX)，11的阿霉素(EPI)和1315的柔红霉素(DAUN)在24小时内经由尿液排出。代谢物包括有毒化合物如阿霉素醇（Doxorubicinol），柔红霉素醇（daunorubicinol）或阿霉素醇（epirubicinol）和无毒物如7-羟基和7-脱氧苷(Dorr 和 Von Hoff，1994)。国际癌症研究机构将阿霉素(DOX)和柔红霉素(DAUN) 分类为第二类(包括A和B) ，2A类意味着也许可能致癌，2B类意味着很可能致癌(癌症研究所，1987年)。这项研究的主要目的是通过计算废水的浓度，来确定在维也纳大学医院（VUH）肿瘤住院病房下水道系统中选定的细胞抑制的浓度，监测实际浓度，探究在膜生物反应系统中物质的消除。这项研究的另一个目的是提供一个更好的对他们在废水中的命运的了解和通过活性污泥法将他们的消除。 图1：5-氟尿嘧啶(5-FU)、阿霉素(DOX)、阿霉素、柔红霉的化学结构2. 材料和方法2.1实验材料通过用放射性同位素标记化合物进行试验，被2-14C标记的5-氟尿嘧啶购自ARC (American RadioLabelled Chemicals Inc，St. Louis，MO)，通过14-14C标记的阿霉素盐酸盐购自Amersham公司(Buckinghamshire，England)。化合物的化学结构如图1所示。 闪烁的液体最适氟是来自惠普(明言染色体、波士顿、马)。新鲜城市污水从boku大学自然资源和应用生命科学学院当地的下水道中被泵抽出并收集到储存罐中。 活性污泥取自一个被boku大学自然资源和应用生命科学学院当地的下水道中的污水完全浸泡过的序批式反应器中。通过放射性同位素标记药物的测试，悬浮固体平均浓度为817.6 g/l。测定依据据德国指南进行(DEV, 2003)。3. 实验安排3.1 监测在肿瘤住院病房的污水和维也纳大学医院（VUH）的出水口维也纳大学医院肿瘤住院病房的下水道系统以在超过24小时后，允许收取18位病人全额废水(3个厕所和3个淋浴) (Lenz等，2005)的方式进行了改建。污水管道与中央收集系统分开，并连接到维也纳大学医院的技术研究所的两个1000升的储罐中(见图 2)。在试验处理厂，一膜生物反应器系统附属在1000升的储罐。该系统包括一个有1毫米格栅的140升搅拌池，一个150升的曝气池、 一个超滤舱和一个储存过滤后污水的污水池。这个生物反应系统在液压负荷100200 l/h，即水力停留时间为20-24小时才能起作用。膜生物反应器由曝气池和外部的管状超滤舱组成（MOLSEP，低谷过滤股份有限公司，德国)。曝气池中的悬浮物浓度为11.8-15.2 g/l。超滤舱运作有polysulfonmembrane(活跃表面=1平方米，截流面=100kd)在横流模式。在两年不同时间总共98天的时间内进行四个时段监控(监测1-4)。在1监测期间，1000升的储罐被采样器1进行采样。在2-4监测期间，废水样本在不同的地点采样：把1000升的储罐内的污水混合15分钟后进行采样(采样器1)，在原水经过搅拌池的格栅后进行采样(采样器2)，在出水口进行污水采样(采样器3)。这些样品在进行分析前均存放在零下20度的环境中。另外维也纳大学医院（VUH）的原始废水样品在两个不同的时间进行采样。在进入市政污水排放系统之前，在4个采样流出点进行汇集样本的采集。图2：维也纳大学医院设计的抽样3.2计算废水浓度为了找出监测结果和服用剂量之间的关系，人体排泄率及服用药物数量被用于计算在肿瘤住院病房下水道污水的最小和最大的浓度范围(mahnik等，2003)。3.3 测定细胞抑制的分析方法所有废水样品均在5000g的中离心10分钟，经过孔径0.22 ug的无菌过滤器来清除悬浮固体。为分析5-氟尿嘧啶，样品的pH值 (50毫升)通过醋酸调整到4.5。固相萃取柱通过甲醇进行预处理，水和醋酸钠做缓冲液。5-氟尿嘧啶在8毫升的甲醇中洗脱(pH9)。洗脱液的溶剂通过蒸发进行干燥，残渣在硼砂缓冲剂的作用下被分解(pH9)。当用毛细管电泳仪分析发现，5-氟尿嘧啶在265纳米时被监测出具有典型迁移时间21分钟，极限量化(LOQ) 18.6 ug/l (mahnik等，2004)。为了分析蒽，样品的pH值通过氢氧化钠调整到7.5。固相萃取柱(C8柱)由甲醇进行预处理， 水、磷酸盐和含2%牛血清白蛋白做缓冲液(BSA，w/v)。由于水中没有显示标准曲线的线性回归，我们加入了BSA，从而利用高蛋白与蒽的结合能力。药物在1.5毫升的甲醇/三氯甲烷（1：2，体积/体积)的溶剂中洗脱。洗脱液的溶剂通过蒸发进行干燥，残渣在100 ug30%的乙腈，10mm70的钾基磷酸氢钙缓冲液中被溶解。高效液相色谱分析使用10mm的钾基磷酸氢钙缓冲液和乙腈洗提液。物质通过它们在荧光扫描后的保留时间来鉴定，通过最高值的范围使之量化(Mahnik等，新闻)。阿霉素(EPI)和阿霉素(DOX)的LOQ为0.26 ug/l，柔红霉素为0.29 ug/l。 3.4 一批通过放射性同位素标记化合物的试点废水的命运和活性污泥法的消除为了探究废水的命运和活性污泥法消除实验的效果，两个浓度分别为5微克每升和500微克每升被2-14C 标记的5-氟尿嘧啶和一个浓度为2500微克每升被14-14C标记的阿霉素盐酸盐被用来做试验。 上述浓度的物质被培育在9毫升的废水或活性污泥中24小时动力学。当物质被培育在活性污泥中，产生的二氧化碳通过1克的装满苏打和石灰水的U形管被收集。为了优化分析，苏打石灰水为了计算被分成了三部分。把样本用搅拌器搅拌(KS 501 D Janke和 Kunkel) 在开始时，0.5小时，1小时，3小时，4小时，6小时和24小时分别采取标本。离心沉淀后(2分钟，9300g)，上层漂浮物、固体废物和苏打和石灰水通过闪烁计数器被计数了300次(wallac141液体闪烁计数器)。一比较，同等浓度的5-氟尿嘧啶倒在渗透水和阿霉素(DOX)倒在50%的渗透水和二甲基亚砜，体积/体积得到验证。4. 结果与讨论4.1. 监测肿瘤住院病房的废水为了评估肿瘤住院病房下水道中抑制细胞的浓度的数量,我们对3个废水采样器监测了98天。在图3中，分析和计算了采样器1中显示的5-氟尿嘧啶（5-FU）和阿霉素(DOX)的浓度。样本所有时期的结果在表1中显示。在监测1-4中，样本1中5-氟尿嘧啶（5-FU）的浓度从8.6ug/l变化到124ug/l。计浓度算结果与考虑排泄率2%成线性排列。总体来说，在1000升中会发现0.6-4.5%。在分析时蒽废水采样器1 时，在浓度0.26-1.39ug时，监测1和3时只有阿霉素(DOX)被监测到了。结果可以同计算考虑排泄率0.5进行对比(mahnik等,2003)。总体上管理数量的0.17-0.35%在监测器1和3中被发现了。在取样时期，EPI和DAUN仅仅偶然的或根本监测不到。分析采样的污水膜生物反应器(采样器3)的5-氟尿嘧啶（5-FU）和阿霉素(DOX)浓度的影响低于LOD，并且还分析了混合膜生物反应器系统(采样器2)浓度产量低于LOD。水池样本中维也纳大学医院（VUH）的影响的分析导致在观测期内4个样本点浓度低于LOD。下水道重建使肿瘤下水道选择性样本成为可能（见图2）。其他医药资源（如废物处置等）可以被剔除，因为根据澳大利亚知道方针抑制细胞生产从细胞毒素的药物中被分类为有毒废物（sn53510）并必须焚烧剔除。虽然化学分析的结果同计算数据成线性排列，但是下水道中的总量跟被控制的数量比却随着时间的变化一直减少。有下面集中可能的解释：1、只有75的肿瘤住院病房的厕所同储水罐相连；2、不能确保与之相连的厕所被病人使用；3、人体排泄率差异很大；4、没有经过过虑吸附的废水（24h）存储可能发生。由于存贮过程中悬浮固体的出现和生产生物数量可以孵化、减少会成为为什么5-氟尿嘧啶（5-FU）和阿霉素(DOX)都没有在取样器2中发现的原因。样本原料的吸附作用可以被5-氟尿嘧啶（5-FU）排除，正像Mahnik 等(2003)描述的那样。 Kummerer (2000)计算了在医院的影响浓度范围从3.9到112.8ug/l，这些数据排列成跟维也纳大学医院（VUH）肿瘤下水道中确定浓度的范围成相同的序列，但是，并没有被分析所证实。Kummerer (2000)进一步提到，在市政原废水和在下水道治理工厂排泄物中0.04道1.13ug/l的浓度是可以预计的，因为5-氟尿嘧啶（5-FU）可以被认为是没有经过剔除就直接通过处理厂的下水道。这个浓度范围同Mahnik 等(2003)计算的维也纳大学医院（VUH）流出物浓度范围类似（0.1-1.4ug/l）。图3：5-氟尿嘧啶(5-FU)、阿霉素(DOX)的计算浓度和分析浓度8Fate of 5-fluorouracil, doxorubicin, epirubicin, and daunorubicinin hospital wastewater and their elimination by activated sludgeand treatment in a membrane-bio-reactor systemS.N. Mahnika,b, K. Lenza, N. Weissenbachera, R.M. Maderb, M. Fuerhackera,*aInstitute 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, AustriabDepartment of Medicine I, Clinical Division of Oncology, Medical University of Vienna, AustriaReceived 4 November 2005; received in revised form 22 May 2006; accepted 24 May 2006Available online 12 July 2006AbstractAntineoplastic agents are applied in cancer therapy and end up in hospital wastewater by human excretions. In this study, the rawwastewater of the sewer of the oncologic in-patient treatment ward of the Vienna University Hospital was monitored for 98 d over 2years for the cytostatics 5-fluorouracil (5-FU), doxorubicin (DOX), epirubicin, and daunorubicin. In a next step, the elimination ofthe drugs by a membrane-bio-reactor system was investigated. In addition, their fate in wastewater and elimination by activated sludgewas investigated with radio-labelled substances. During the monitoring periods, concentration levels ranging from 8.6 to 124 lg l?1for5-FU and from 0.26 to 1.35 lg l?1for DOX were determined. The concentrations analysed fitted the lower ranges calculated by aninputoutput model. Treatment of oncologic wastewater in the membrane bio-reactor as well as the analysis of the effluents of the ViennaUniversity Hospital resulted in concentrations below the limit of detection. Investigations with radio-labelled compounds showed that5-FU is eliminated from the liquid phase below the limit of detection. But, up to 25% of radio-labelled equivalents of the drugs amountwere 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 tobe the major elimination pathway, as up to 30% of the radio-labelled equivalents of the drugs amount was detected in the solid phase.Our results indicate that the investigated anticancer drugs are eliminated by sewage treatment plants, either by biodegradation oradsorption.? 2006 Elsevier Ltd. All rights reserved.Keywords: Anthracyclines; 5-Fluorouracil; Hospital effluents; Monitoring; Elimination; Activated sludge1. IntroductionDuring the last years, the growing use of antineoplasticdrugs in cancer therapy is an emerging issue in environ-mental research and it can be expected, that consumptionwill increase due to a developing health care system anda higher life expectancy.Cytostatics belong to the CMR (carcinogenic, muta-genic and reprotoxic) drugs. They usually enter the hospi-tal effluents partially transformed or even unchanged viaurine and faeces of patients under medical treatment.Therefore, they are assumed to be environmentally relevantcompounds. As hospital effluents reach the municipalsewer network generally without any preliminary treat-ment, hospitals may represent an incontestable release0045-6535/$ - see front matter ? 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.chemosphere.2006.05.051*Corresponding author. Address: Institute of Sanitary Engineering andWater Pollution Control, Department of Water, Atmosphere and Envi-ronment, University of Natural Resources and Applied Life SciencesVienna, 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)./locate/chemosphereChemosphere 66 (2007) 3037source 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 leavethe hospital after drug application. Subsequently, the drugsare also directly excreted into the municipal sewer network.Their quantification in hospital effluents may serve as astarting point to individualise the magnitude of putativepollution problems. Especially in Germany, investigatorshave been active in monitoring the fate of cytostatics inthe environment after administration to patients. Steger-Hartmann et al. (1996) determined the antineoplasticscyclophosphamide and ifosfamide in sewage water samplesat concentrations of 146 ng l?1and 24 ng l?1, respectively.Ku mmerer (2000) found concentrations of 0.0061.9 lg l?1ifosfamide and 0.024.5 lg l?1cyclophosphamide in efflu-ents from an oncologic hospital. In the influents of thereceiving municipal sewage treatment plants ifosfamideand cyclophosphamide were measured at concentrationsof 0.010.03 lg l?1for ifosfamide and 0.0060.14 lg l?1for cyclophosphamide, without observing any significantreduction during sewage treatment. These results areapproved by investigations of Ku mmerer et al. (1997). Inthis study average concentrations of 109 ng l?1ifosfamidewere determined in hospital effluents. In the influent ofmunicipal sewage treatment plants concentration levelsfrom 6.28.5 ng l?1were found, in the effluent levels from6.5 to 9.3 ng l?1.One of the most frequently used drugs in cancer therapyis 5-fluorouracil (5-FU) of the group of antimetabolites.Therefore, it may be regarded as a pilot substance forthe assessment of environmental contamination originat-ing from hospital effluents. The consumption of 5-FUamounted to 119 kg in 1997 in Austria (Sattelberger,1999)andto4.74 kgin2001intheVUH.The drugisadmin-istered in the treatment of breast, skin, bladder, and lungcancer in dosages ranging from 200 to 1000 mg m?2bodysurface (Dorr and Von Hoff, 1994). Approximately 235%of the administered drug is excreted unmetabolisedviaurinewithin 24 h (Diasio and Harris, 1989; Schalhorn and Kuhl,1992; Dorr and Von Hoff, 1994). The International Agencyon the Research of Cancer indicates 5-FU as not classifiableas to its carcinogenicity to humans (IARC, 1987).Doxorubicin (DOX), epirubicin (EPI), and daunorubi-cin (DAUN) belong to the group of anthracyclines. Theconsumption of these drugs amounted to 0.25 kg in 2001in the VUH. The compounds are frequently used in thetreatment of haematological and solid neoplasms, includ-ing acute leukaemia, high grade lymphoma, breast cancer,and bladder cancer (Dorr and Von Hoff, 1994). Anthra-cyclines are administered in dosages ranging from 15120 mg m?2body surface. Approximately 3.55.7% ofadministered DOX, 11% of EPI, and 1315% of DAUNare excreted unmetabolised via urine within 24 h. Metabo-lites include toxic compounds such as doxorubicinol,daunorubicinol or epirubicinol and non-toxic agents suchas 7-hydroxy and 7-deoxy aglycones (Dorr and Von Hoff,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 meanspossibly carcinogenic (IARC, 1987).The primary aim of this research was to determine theconcentrations of selected cytostatics in the sewer systemof the oncologic in-patient treatment ward of the VUHby calculation of the wastewater concentration, to monitorthe actual concentrations and to investigate the eliminationof the parent substances in a membrane-bio-reactor sys-tem. Another purpose of this study was to provide a betterunderstanding of their fate in wastewater and their elimina-tion by activated sludge.2. Materials and methods2.1. MaterialsFor the experiments with radio-labelled compounds2-14C 5-FU was purchased from ARC (American RadioLabelled Chemicals Inc., St. Louis, MO) and 14-14CDOXhydrochloridefromAmersham(Buckingham-shire, England). The chemical structures of the selectedcompounds are shown in Fig. 1. The scintillation liquidOpti-Fluor was obtained from Packard (Perkin Elmer, Bos-ton, MA). Fresh municipal wastewater was pumped fromthe local sewer at the BOKU University of NatureResources and Applied Life Sciences and collected in a stor-age tank. Activated sludge was taken from a sequencingbatch reactor which is fed with wastewater from the localmunicipal sewer of the BOKU University of NatureResources and Applied Life Sciences. The average concen-tration of suspended solids was 817.6 g l?1for the testswith radio-labelled drugs. Determination was carried outaccording to German guidelines (DEV, 2003).Fig. 1. Chemical structures of the selected cytostatics 5-fluorouracil, doxorubicin, epirubicin and daunorubicin.S.N. Mahnik et al. / Chemosphere 66 (2007) 3037313. Experimental set-up3.1. Monitoring of the sewage of the oncologic in-patient-treatment-ward and VUH effluentThe sewer system of the oncologic in-patient-treatmentward of the VUH was reconstructed in a way to allowthe collection of the full amount of wastewater from 18patients (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 thetechnical area of the VUH (see Fig. 2). A pilot treatmentplant, a membrane-bio reactor system, was affiliated tothe 1000 l tanks. The system consists of a 140 l mixing tankwith a 1 mm screen, an 150 l aeration tank, an ultrafiltra-tion module and an effluent tank after filtration. Thebioreactor system is run with a hydraulic load of 100200 l d?1which means a hydraulic retention time of2024 h. The membrane bioreactor consists of the aera-tion tank and an external, tubular ultrafiltration module(MOLSEP?, Nadir Filtration GmbH, Germany). The con-centration of suspended solids in the aeration tankamounted to 11.815.2 g l?1. The ultrafiltration moduleoperates with a polysulfonmembrane (active surface =1 m2, nominal cut-off= 100 kD) in the cross-flow mode.Four monitoring periods (monitoring 14) were carriedout at different times of the year over a time period of 98 din total. During monitoring 1 the 1000 l storage tanks weresampled at sampling device 1. During monitoring 24,wastewater samples were taken at different sample sites:at the sampling device of the 1000 l tank after blendingthe content for 15 min (sampling device 1), at the samplingdevice of raw water after the screen in the mixing tank(sampling device 2) and at the sampling device of the efflu-ent (sampling device 3). The samples were stored at ?20 ?Cuntil analysis. Additionally raw wastewater samples of theVUH were measured at two different time periods. Pooledsamples were taken at all 4 discharge points before enteringthe municipal sewer system.3.2. Calculation of the wastewater concentrationTo spot a correlation between the results of the monitor-ing and the administered dosages, human excretion ratesand administered drug amounts were applied to calculateminimal and maximal concentration ranges in the sewerof the oncologic in-patient treatment ward (Mahniket al., 2003).3.3. Analytical methods for the determination of the selectedcytostaticsAll wastewater samples were centrifuged 10 min at5000g and the liquid filtered through sterile filters with0.22 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 asodium acetate buffer. 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 tetraboratebuffer (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 lg l?1(Mahnik et al., 2004).Fig. 2. Design of the sampling at the Vienna University Hospital.32S.N. Mahnik et al. / Chemosphere 66 (2007) 3037For the analysis of the anthracyclines, the pH of the sam-ples was adjusted to 7.5 by NaOH. The solid phase extrac-tion columns (C8 columns) were preconditioned by MeOH,water and phosphate buffered saline containing 2% bovineserum albumin (BSA, w/v). As standard curves in waterdid not show linear regression, we added BSA, thus exploit-ing the high protein binding capacity of anthracyclines. Thedrugs were eluted with 1.5 ml MeOH/CHCl3(1:2, v/v). Thesolvent of the eluate was evaporated to dryness andthe residue dissolved in 100 ll 30% acetonitrile/70%10 mM K-di-hydrogenphosphate buffer. The analysis byhigh performance liquid chromatography was carried outusing a 10 mM K-di-hydrogenphosphate buffer and aceto-nitrile as eluent. Substances were identified by their reten-tion time in the fluorescence scan and quantified by peakarea (Mahnik et al., in press). The LOQ for EPI andDOX was 0.26 lg l?1, for daunorubicin it was 0.29 lg l?1.3.4. Batch experiments with radio-labelled compoundsfatein wastewater and elimination by activated sludgeFor the investigation of the fate in wastewater and theelimination tests by activated sludge two concentrationsof 2-14C 5-FU (5 and 500 lg l?1) and one concentrationof 14-14C DOX hydrochloride (2500 lg l?1) were tested.The mentioned concentrations were incubated with 9 mlwastewater or activated sludge in a 24 h kinetics. Whenincubating 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 & Kunkel), specimens were taken at thebeginning and after 0.5 h, 1 h, 3 h, 4 h, 6 h and 24 h. Aftercentrifugation (2 min, 9300g), the supernatant, the solidresidue, and the soda lime were counted for 300 s in thescintillation counter (Wallac 1410 Liquid ScintillationCounter). For a comparison, equal concentrations of 5-FU in reversed osmosis water and DOX in 50% reversedosmosis water and dimethylsulfoxide, v/v were tested.4. Results and discussion4.1. Monitoring of the wastewater of the oncologic in-patienttreatment wardIn order to assess the magnitude of cytostatic concentra-tions in the sewer of the oncologic in-patient treatmentward, we monitored the wastewater for 98 d at 3 samplingdevices. In Fig. 3 analysed and calculated concentrations of5-FU and DOX are shown during monitoring 1 (at sam-pling device 1), the results of all sampling periods are pre-sented in lg l?1in Table 1. During monitoring 14, theconcentration of 5-FU at sampling device 1 ranged from8.6 lg l?1to 124 lg l?1. The results were in line withcalculated concentrations considering an excretion rate of2% (Mahnik et al., 2003). In total, 0.64.5% of the admin-istered amount was found in the 1000 l tanks.When analysing the wastewater for anthracyclines atsampling device 1, only DOX was detected during monitor-ing 1 and 3 in the range of 90% over time of 24 h, i.e. theconcentration in the liquid phase remained stable overtime of 24 h. DOX was adsorbed to suspended solids inwastewater and to the tube walls since from the beginningof the experiment the concentration in the liquid phaseamounted only to 41% compared to the start concentration(see Fig. 4).Together with the experimental data of the monitoring itcan be assumed, that 5-FU is expected to be biodegradedor at least metabolized by microorganisms as it did notadsorb to suspended solids in wastewater. For the anthra-cyclines adsorption to suspended solids seems to be themajor elimination pathway.4.3. Batch experiments with radio-labelled compoundselimination by activated sludgeTo assess the elimination of 5-FU and DOX by acti-vated sludge, kinetic investigations with 5 and 500 lg l?12-14C 5-FU and 2 500 lg l?114-14C DOX were carriedout. The results of these tests are demonstrated in Fig. 5.The investigations showed that 5-FU was eliminated fromthe liquid phase below LOD within 24 h. The tests indi-cated that the minor part of the drug was found in thesludge over time of 24 h, since recoveries amounted onlyto 25%. Up to 25% of the whole amount of 5-FU wastrapped by the soda lime, which suggests a biodegradation,partly a final degradation or metabolization by micro-organisms of a major part of the substance. Although wecounted the soda lime in several portions, we hypothesised,that parts of the signals were suppressed. Also Kiffmeyeret al. (1998) observed a biodegradation up to 92% for 5-FU in the OECD Confirmatory Test. The degradation ratewas directly proportional to the initial concentration. Incontrast, 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 totalelimination of 90% from the liquid phase. Over time therecovery for DOX ranged between 2040% in the sludge,but only between 612% in the liquid phase. Analysis ofthe soda lime indicated, that elimination of DOX is mainlyFig. 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) 3037caused by adsorption, as only 1.7% of the total amountcould be determined when soda lime was counted. Litera-tureresultsindicatethatEPIiseliminatedintheZahn-Wellens-Test (OECD 302 B), but not in the Closed-Bottle-Test (OECD 301 D). Both tests investigate thedegradation by determination of DOC and O2, respec-tively. The Zahn-Wellens-Test (OECD 302 B) is carriedout with a higher concentration of bacteria and a higherconcentration of test substance, furthermore, the concen-trations used for these tests were 67 orders of magnitudehigher than concentrations expected in sewage of hospitals(Ku mmerer et al., 1996; Ku mmerer, 1999). Due to the highadsorption capacity of sludge for EPI, neither biodegra-dation in sewage treatment plants nor emission to surfacewater is supposed.The radio-labelling was carried out at the most stablepart of the drug. The ring structure of the prodrug 5-FUis opened very easily when degraded by anabolism andcatabolism, whereas the ring structure of DOX remainsstable when degraded (Diasio and Harris, 1989; Dorr andVon Hoff, 1994).5. ConclusionsThe present paper shows that the pilot substance 5-FUis administered in considerable amounts and that the calcu-lated concentrations could be monitored in the sewer of theoncologic in-patient treatment ward of the VUH. The drugis eliminated from the liquid phase below LOD when incu-bated with activated sludge in batch experiments or treatedin a membrane-bio-reactor system. Although there was nodifference in the elimination, the combination of activatedsludge treatment and membrane filtration in the mem-brane-bio-reactor system enabled a total retention of sew-age sludge and a high sludge retention time. Combinedwith adsorption processes in the system, the degradationof trace contaminants, e.g. endocrine modulators, is forcedas already shown by Scha fer (2001). The elimination of theinvestigated substances in this study is mainly caused bybiodegradation or metabolization, as the experiments with2-14C 5-FU indicate. The amount of anthracyclinesobserved in the sewer of oncologic in patient treatmentward of the VUH is also comparable to the administeredquantity. Incubation with activated sludge yielded in anelimination of 90% from the liquid phase, treatment inthe 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 majorelimination pathway from the wastewater as the tests with14-14C 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 directemission of wastewater to a small receiving water can beinhibited. For the anthracyclines, as they are assumed tobe eliminated by adsorption, it has to be considered thatadsorption to sewage sludge represents only a displacementTable 1Concentration 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 sewerConcentration ofactivated sludge(g l?1)5-FUDOXAdministeredamount (mg)Concentrations in the sewer of the oncologic in-patient-treatment ward (lg l?15-fluorouracil)Administeredamount (mg)Concentrations in the sewer of the oncologic in-patienttreatment ward (lg l?1doxorubicin)CalculatedAnalysedCalculatedAnalysedMin.Max.(2%excretionrate)Min.Max.MeanSamplesMin.Max.(0.5%excretionrate)Min.Max.MeanSamplesMonitoring 1180060833612211.512255.62816.82650.081.30.26 (LOQ)1.350.628Monitoring 211.8790355515.871.18.6 (LOQ)40.121.025Monitoring 314.41010490520.298.118123.591.03040.2246 (LOQ)0.50.330Monitoring 415.2648276812.955.414S.N. Mahnik et al. / Chemosphere 66 (2007) 303735of the drugs from the liquid to the solid phase. On the basisof the current knowledge, much is yet to be understoodregarding fate and the transport of cytostatics and theirultimate environmental effects.AcknowledgementsThis work has been supported by the Federal Ministryof 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) 3037ment(projectnumberGZa301482),AustrianKommunalkredit AG and the FFF.ReferencesDEV German Standard procedures for the analysis of water, wastewaterand sewage sludge (Deutsche Einheitsverfahren zur Wasser-, Abwas-ser- und Schlammuntersuchung, Physikalische, chemische, biologischeund bakteriologische Verfahren), 2003. WileyVCH Verlag GmbH &Co, Weinheim.Diasio, R.B., Harris, B.E., 1989. Clinical pharmacology of 5-fluorouracil.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 toHumans.InternationalAgencyforResearchofCancer,Lyon(Suppl.7).Kiffmeyer, T., Go tze, H.-J., Jursch, M., Lu ders, U., 1998. Trace enrich-ment, chromatographic separation and biodegradation of cytostaticcompounds in surface water. Fresenius J. Anal. Chem. 361, 185191.Ku mmerer, K., 1999. Epirubicin hydrochloride in the aquatic environ-mentbiodegradation and bacterial toxic
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