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Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

SUPPORTING INFORMATION

Mass flows of X-ray contrast media and cytostatics in hospital wastewater

David Weissbrodt1, Lubomira Kovalova1,2, Christoph Ort1, Vinitha Pazhepurackel3, Ruedi Moser3, Juliane Hollender1, Hansruedi Siegrist1, Christa S. McArdell1,*

1 Eawag, Swiss Federal Institute of Aquatic Science and Technology, CH-8600 Duebendorf, Switzerland 2 RWTH Aachen University, Institute of Hygiene and Environmental Health, D-52074 Aachen, Germany 3 Hunziker Betatech AG, CH-8411 Winterthur, Switzerland * Corresponding author phone: +41 44 823 5483; fax: +41 44 823 5311; e-mail address: [email protected]

Number of pages: 17 Number of Figures: 3 Number of Tables: 8

Environmental Science & Technology Manuscript ID es-2008-036725

Page S1 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

S1 Biosafety Hospital wastewater is highly contaminated. It contains concentrated amounts of pharmaceuticals, disinfectants, and pathogen agents such as multiresistant bacteria and viruses. Considerations of full safety measures (1) are recommended for the work with hospital wastewater during the sampling and filtration. For the sampling phase, overall protection of the operator, protection of the sampling area, and protection of the sampling instruments were considered. In particular, single use FFP3 valved respirators (Type 9332, 3M™, Rüschlikon, Switzerland) were worn to avoid the operator contamination through bioaerosols. Two types of gloves, a single use nitrile lab glove (Type 92-500, 0.12 mm Touch N Tuff®, Ansell Ltd, Richmond, Australia) and a reusable nitrile protection glove (Type 37-185, 0.56 mm, Sol-Vex®, Ansell Ltd, Richmond, Australia), were worn superimposed. The work within the confined area of the hospital canalization had to be reduced to the strict minimum, and second collaborator had to be present on the sampling site. As samples could not be thermo sterilized because of the instability of organic compounds at elevated temperature, the sterilization was done by filtration. The raw samples were filtrated, in a biological safety class 2 sterile bench under laminar flow, successively on a 0.7 μm GF/F glass micro fiber circle filter (90 mm diameter, Whatman, Maidstone, UK) and on a 0.2 μm cellulose acetate filter (90 mm diameter, Sartorius AG, Goettingen, Germany). All instruments were autoclaved or chemically disinfected when thermal sterilization was not applicable. The glass bottles were inserted each in plastic freezer bags as safety in case of bottle breakage.

S2 Hospital wastewater sampling scheme and flow profile The sampling scheme is shown in Tab.S1. The hospital wastewater flow profile (Fig.S1) measured during the sampling phase, under dry weather conditions, is typical for the daily activities of an institution. One rain event occurred over the whole day of Saturday 05th of May. Between 6:00-8:00 am, the flow rate is increasing rapidly from 5 m3/h (1.4 l/s) to reach 20 m3/h (5.5 l/s), due to the beginning of the first activities at the

Page S2 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

hospital and to the awakening of the patients. Successive peaks are present at 11:30, between 14:00-17:00, and at 21:00. As many hospital departments are also active during the week-end, the daily flow profile is similar during the week and during the week-end. The average wastewater flow rate over the whole sampling period was 15.8±14.8 m3/h, with minimal and maximal instantaneous values of 4.0 m3/h and 205.7 m3/h at the rainy day, respectively. An average flow rate of 17.2±8.8 m3/h was measured over the eighteen hours day periods (05:00-23:00) and 11.9±6.1 m3/h over the six hours night periods (23:00-5:00). Under dry weather conditions the wastewater flow rate amounted in average to 13.7±8.1 m3/h, which gives an effective amount of wastewater per hospital bed of 0.8 m3/(bed·day) during the sampling period. During the test phase, peaks up to 130-140 m3/h were regularly detected in the night. The hospital sanitary service explained these periodic peaks as back flushes from reverse osmosis installations and from warm baths. During the sampling phase, however, these peaks were no more present.

Table S1. Sampling scheme: 18h-day (05:00-23:00) and 6h-night (23:00-05:00) flow proportional composite samples were collected during one week, and 2h- to 4h- composite samples were collected during one day.

18h-day and 6h-night 2h- to 4h- composite samples composite samples Monday, 30.4.2007 06:55-09:35 Tuesday, 1.5.2007 09:35-11:45 Wednesday, 2.5.2007 12:05-14:25 Thursday, 3.5.2007 14:25-17:05

Friday, 4.5.2007 17:05-20:35 Saturday, 5.5.2007 20:35-00:05 Sunday, 6.5.2007 00:05-04:25

Monday, 7.5.2007 Monday, 7.5.2007 04:25-07:55 Tuesday, 8.5.2007 07:55-09:55

Page S3 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

400

380 Test phase Sampling phase

50 360 45 340 40 /h) 320 3 35 300

/h) 30 3 280 25 260 20 240 15 05.05 Rain event 220 10 (m flow wastewater Hospital

200 5

180 0 00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00 03 06:00 09:00 12:00 15:00 18:00 21:00 00 03 06:00 09:00 12:00 15:00 18:00 21:00 00:00 :00 :00 :0 :00 :00 160 0 Mon 07.05.2007 Tue 08.05.2007 Wed 09.05.2007 140 120

100 Hospital wastewater flow (m 80 60 40 20 0 17.04 18.04 19.04 20.04 21.04 22.04 23.04 24.04 25.04 26.04 27.04 28.04 29.04 30.04 01.05 02.05 03.05 04.05 05.05 06.05 07.05 08.05 09.05 10.05 11.05 Monday Monday Monday

Figure S1. Hospital wastewater flow rate at the sampling point during the test phase (18.04-23.04) and the sampling phase (29.04-10.05).

Page S4 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

Table S2. Input data for the sampling optimization modelling (adapted from Ort and Guier (2)). Information Source Values used in this study Initial duration of hydraulic Assumption 3-5 seconds toilet flush σinit Duration of toilet flush in Tracer experiment at a 5-30 seconds (to cover a reasonable sewer σup house connection resulted range). in a duration of 10 seconds (single standard deviation of a gaussian pulse) Average flow distance in Sewer layout from hospital 200 m (no buffer or retention tank in sewer (L) map hospital sewer network) Dispersion coefficient (D) Assumption for average 0.1 m2/s conditions, (3) Average velocity in sewer Measured 0.5 m/s (u) Duration of toilet flush in Calculated with: 20-35 seconds sewer at the sampling point (95% of a total toilet flush can pass the 2 t σ = σ + 2D σdown down up u 2 sampling point in 4 σdown, i.e. in a time of 80-140 seconds) With t = L/u Number of patients Assumption or hospital Z, can be calculated for each drug for excreting in the hospital details each day with the following information:

number of patients receiving drug: see Table 1 half-live and excretion rate from pharmacokinetic information: see Table 2 number of out-patients: ICM: 50% on average cytostatics: 70% on average, details in Table 1 Number of toilet flushes Assumption: 4.5 toilet Z * 4.5 containing drugs flushes per person per day for a normal, healthy person (4,5). Consumed amount of drugs hospital details see Table 1 during sampling period Elimination in hospital ICM: negligible (persistent compounds) sewer (hydrolysis, Cytostatics: unknown biodegradation, sorption)

Page S5 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

S3 Analytical methods The wastewater samples were brought daily to the laboratory and stored at 0-5 °C for maximal 8 hours. After the successive filtrations to 0.7 and 0.2 μm under a sterile bench (S1), the samples were stored at -20°C until analysis. The analytical sample preparation was done within two months after the end of the sampling phase. All samples were prepared in duplicate. The analytical method for the measurement of iodinated X-ray contrast media (ICM) was adapted from Ternes et al. (6). Characteristics of the selected compounds are given in Tab.S3. The homogeneous hospital wastewater samples were diluted by a factor 1:100 (w:w) with uncontaminated tap water (pH 7.4, TOC 0.8 mg/L, 12.7 mg/L Cl-), while WWTP wastewater samples were taken undiluted (100 mL), because hospital wastewater is about 100 times more concentrated than urban wastewater. The constitution of 24h- composite samples was done by flow proportional mixing of the composite 18h- day and 6h- night samples. The pH of the samples was adjusted to pH 2.80 drop by drop with a ~ 0.32%- HCl solution and a ~ 0.50%- NaOH solution, resulting in an added volume of around 5 mL. For each series, a method blank (tap water) was prepared identically to the samples. For each wastewater matrix - i.e. hospital wastewater, WWTP influent, WWTP effluent - 4 different concentrations in the range of 50 to 2’250 ng/mL of the following analyte standards were spiked (standard addition) in one sample: iopromide and diatrizoate (courtesy of Bayer Schering Pharma, Berlin, Germany), iopamidol, iomeprol and ioxitalamic acid (courtesy of Byk Gulden, Singen, Germany), iohexol (Fluka, Sigma-Aldrich, Buchs, Switzerland). 200 ng absolute of desmethoxyiopromide (DMI, courtesy of Bayer Schering Pharma, Berlin, Germany) were added in each sample as surrogate standard. The analytes were extracted and enriched by solid phase extraction (SPE) on Isolute ENV+ cartridges 200 mg (3 ml volume, IST International Sorbent Technology, Mid Glamorgan, UK), in series of 10 samples plus one method blank per SPE box. The SPE method consisted of successive procedures: cartridges conditioning (1x 2 mL hexane, 1x 2 mL acetone, 3x 2 mL methanol, 4x 2 mL tap water pH 2.80), analytes extraction (~ 100 mL / 30 min, ~ 600 mbar), cartridges drying (under N2(g) flow, 1 h), analytes elution (4x 1 mL methanol), solvent evaporation

Page S6 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

to 100 μL (under N2(g) flow, 50°C), adjustment of the final volume to 500 μL with eluent A (see below). The 500 μL of extracted enriched samples were then caped in 1.5mL- amber HPLC vials and stored at 0-5°C until analysis. The extracts were analyzed by HPLC-MS/MS. The chromatographic separation was done with a Hewlett Packard instrument (Series 1100, Agilent Technologies AG, Basel, Switzerland) on a Phenomenex Polar-RP column (150 x 3.00 mm, 4 μm, 80 Å, 30 cm; Phenomenex, Aschaffenburg, Germany). Two eluents were used: eluent A (1% acetonitrile + 0.5% formic acid + 0.1% ammonium formiate 5 M in HPLC-grade water) and eluent B (acetonitrile). The HPLC gradient mode was programmed as following. The analysis started isocratically at 5% eluent B. After 8 min, it changed to 15% eluent B in a 7min- linear gradient. At 15 min, the initial condition was then reestablished through a 0.5min- linear gradient, followed by an equilibration time of 6.5 min. The total elution time amounted to 22 min. The flow rate was kept constant at 400 μL/min. The temperature of the column was set to 30°C. After the chromatographic separation, the target compounds were detected on a triple quadrupole mass spectrometer API 4000 (Applied Biosystems, Rotkreuz, Switzerland) with electrospray ionisation source, set in electrospray positive ionisation mode (spray voltage 5000 V, temperature 390°C). The chromatographic retention times and the mass spectrometry tuning parameters of the respective substances are summarized in Tab.S4. The chromatograms were retreated with the software Analyst v.1.4.1 (Applied Biosystems, Rotkreuz, Switzerland). The absolute extraction recovery of the internal standard DMI was calculated by dividing the measured DMI peak areas in the extracted samples by the average DMI peak area measured in 22 samples of the external calibration. Absolute and relative recoveries over the whole analytical method were determined for each analyte and for each wastewater matrix from four spiking experiments. For absolute recoveries, the measured peak areas were not corrected by the areas of the internal standard DMI, whereas for relative recoveries the correction was done. The limits of quantification (LOQ) were estimated from the signal-to-noise ratio of 10 of a real sample. Parameters of quality assurance (recoveries and LOQ) are summarized in Tab. S5.

Page S7 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

For the analysis of cytostatics, the analytical method of Kovalova et al. (7) was used. 50 mL of wastewater from hospital or WWTP were pre-concentrated by solid phase extraction on ENV+ (1000 mg / 6 mL) cartridges connected on top of SA-DVB disc cartridges (200 mg / 6 mL). Compounds were separated on a hydrophilic interaction chromatography column ZIC-HILIC (150 x 2.1 mm, 4.5 μm, 100 Å; Sequant, Marl, Germany) and detected on a triple quadrupole mass spectrometer API 4000 (Applied Biosystems, Rotkreuz, Switzerland) with electrospray ionisation source either in positive (gemcitabine) or negative (5-fluorouracil and dFdU) mode. Table S4 lists the measured transition for all the analytes as well as the employed labeled internal standards. Relative SPE recoveries were determined by spiking the analytes and internal standards in wastewater shortly before it was loaded on the cartridge. Absolute recoveries were determined by spiking the analytes shortly before it was loaded on the cartridge and internal standards after evaporation, prior to analysis. Limits of quantification (LOQ) were estimated from the signal to noise ratio (S/N = 10) of a real sample.

Page S8 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

Table S3. Iodinated X-ray contrast media and cytostatic compounds selected for the present study. These compounds are used in specific radiology applications, such as computer tomography (CT), emergency computer tomography (ECT), angiography and intervention (A&I), radiography (RAD) and arthrography (ARTH). Iobitridol and iodixanol were not analyzed during the study, but are consumed at the hospital.

Iodinated X-ray contrast media Active compound Chemical structure Speciality

Iopamidol OH Iopamiro™ C17H22I3N3O8 O Usage: ARTH MW = 777.09 I NH

OH H CAS: 60166-93-0 NH I

O I O

Iomeprol H Iomeron™ O N OH C17H22I3N3O8 Usage: ECT I I MW = 777.09 O OH

H CAS: 78649-41-9 HO N OH N

I O

Iopromide OH Ultravist™ O N OH C18H24I3N3O8 Usage: CT and A&I I I MW = 791.11 O OH

H CAS: 73334-07-3 O N OH N H I O

Iohexol H Accupaque™ O N OH C19H26I3N3O9 Usage: CT MW = 821.14 I I OH

CAS: 66108-95-0 H N OH HO N OH I O O

Ioxitalamic acid O Telebrix Gastro™ I OH C12H11I3N2O5 Usage: CT and RAD

MW = 643.94 HN I OH

CAS: 28179-44-4 O Telebrix 12™ I NH Usage: RAD O

Amidotrizoic acid O Gastrografin™ I OH (diatrizoate) Usage: RAD

C11H9I3N2O4 HN I

MW = 613.91 O CAS: 131-49-7 I HN O

Page S9 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

Iobitridol OH Xenetix™ O N OH C20H28I3N3O9 Usage: CT

MW = 835.16 I I CAS: 136949-58-1 OH O HO N N OH H

O I OH

OH OH Iodixanol H H Visipaque™ HO N O O N OH C35H44I6N6O15 Usage: A&I

I I I I MW = 1550.18 OH OH H H CAS: 92339-11-2 HO N N OH N N O I OH I O O O

Cytostatics Active compound Chemical structure Speciality

5-fluorouracil O Efudix™ C4H3FN2O2 F Fluorouracil-Teva™ MW = 130.08 NH Fluoro-uracil Valeant™ CAS: 51-21-8 Verrumal™ N O H Usage: Oncology

Gemcitabine NH2 Gemzar™ 2',2'-difluoro-deoxycytidine Usage: Oncology (dFdC) N C9H11F2N3O4 MW = 263.20 HO N O F CAS: 95058-81-4 O

OH F

2',2'-difluoro-deoxyuridine O Deaminated human meta- (dFdU) bolite of gemcitabine. NH C9H10F2N2O5 MW = 264.18 CAS: 114248-23-6 HO N O F O

OH F

Page S10 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

Table S4. LC/MS/MS parameter. Chromatographic retention times and mass spectrometry tuning parameters for iodinated X-ray contrast media and cytostatics. DMI, 15 13 15 ’ N2 5-fluorouracil and C N2 5-deoxy-5-fluorocytidine are the internal standard. The mass for determination is underlined in the Q3 mass column. Other tuning parameters of the mass spectrometer (API 4000, Applied Biosystems) are the declustering potential (DP), the collision energy (CE), and the cell exit potential (CXP).

Iodinated X-ray contrast media analytical parameters Retention Q1 mass Q3 mass DP CE CXP Substance time (min) (amu) (amu) Desmethoxyiopromide (DMI) 9.9 761.9 528.8/743.7 64 32 33 Iopamidol 4.3 777.9 386.9/558.9 64 32 33 Iomeprol 7.0 777.9 531.7/687.0 62 40 18 Iopromide 9.7 792.0 558.7/572.9 60 35 16 Iohexol 5.85 822.1 602.7/803.9 56 28 21 Ioxitalamic acid 3.75 644.8 408.0/583.6 58 25 26 Diatrizoate (amidotrizoic acid) 5.0 614.7 337.1/361.0 72 25 21

Cytostatics analytical parameters Retention Q1 mass Q3 mass DP CE CXP Substance time (min) (amu) (amu) 15 N2 5-fluorouracil 5.8 131.0 43.1/87.3 -40 -30 -5 5-fluorouracil 5.8 129.0 42.0/58.9 -40 -30 -5 2',2'-difluorodeoxyuridine 6.0 262.8 110.9/220.0 -40 -22 -5 13 15 ’ C N2 5 -deoxy-5-fluorocytidine 5.8 249.0 115.1/132.7 20 28 15 Gemcitabine 7.1 264.0 95.0/112.0 20 19 15

Page S11 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

Table S5. Quality assurance parameters. Limits of quantification (LOQ), absolute recoveries (AR) and relative recoveries (RR) over the whole method for each compound specific to the wastewater matrix: hospital wastewater, WWTP influent (WWTP in), WWTP effluent (WWTP out). The LOQs refer to the absolute sample volume taken (see section S3).

Iodinated X-ray contrast media Cytostatics

Iopromide Iopamidol Iomeprol Iohexol Ioxitalamic acid Diatrizoate 5-fluorouracil Gemcitabine 2',2'-difluorodeoxyuridine

-3 -3 -3 5 10 10 20 5 0.2 5⋅10 0.9⋅10 9⋅10 LOQ (μg/l)

82±45 83±48 91±62 120±28 77±54 75±41 46±7 79±3 40±5 AR (%)

Hospital Hospital wastewater 91±12 93±12 93±11 88±16 89±13 85±12 95±2 118±18 54±13 RR (%)

0.04 0.1 0.3 0.2 0.05 0.01 n/a n/a n/a LOQ (μg/l)

105±14 102±15 121±19 138±18 123±19 67±11 n/a n/a n/a AR (%)

WWTP in 99±8 95±8 113±9 129±11 114±13 65±7 n/a n/a n/a RR (%)

Wastewater matrix Wastewater 0.04 0.01 0.2 0.2 0.05 0.01 n/a n/a n/a LOQ (μg/l)

80±56 93±91 86±66 93±57 93±57 76±44 n/a n/a n/a AR (%)

WWTP out 83±5 91±14 90±4 95±5 100±13 80±5 n/a n/a n/a RR (%)

Page S12 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

Table S6. ICM consumption in Switzerland in 2004 and in the Cantonal Hospital in 2005 and 2006.

Substance Consumption in Consumption in Consumption in all Swiss hospitals cantonal hospital cantonal hospital (2004) (2005) (2006)

[g/day] [g/day] [g/day] Iopromide 18’985 157 138 Iopamidol 7’504 240 212 Iomeprol 4’520 0 215 Iohexol 12’640 0 170 Ioxitalamic acid 9’944 125 160 Sum ICM 53’593 523 895

Table S7. Cytostatics excreted in the highest amounts in the Cantonal Hospital in 2006.

Substance Amount Excretion rate Calculated (g) (%) excreted amounts in urine and faeces Urine Faeces (g) 5-Fluorouracil 1623.8 10% 0% 5-Fluorouracil (from 4518.0 0.54% 0% 186.8 Capecitabine) Methotrexate 92.4 81% 15% 88.4 Cyclophosphamide 415.3 20% 0% 83.1 Carboplatin 99.8 70% 0% 69.9 Gemcitabine 498.4 5% 0% 24.9 Etoposide 49.0 50% 0% 24.5 Irinotecan 27.6 22% 33% 15.2 Ifosfamide 41.0 34% 0% 13.9 Cisplatin 31.5 40% 0% 12.6 Doxorubicin 22.0 10% 45% 12.1

Page S13 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

Work week Week-end 1400 35 ICM sum 1300 ICM sum (week average) 1200 Iomeprol 30 Iohexol 1100 Ioxitalamic acid /h) Iopamidol 3 1000 Iopromide 25 Diatrizoate 900 Average wastewater flow 800 20 700 600 15

Mass flow (g/d) flow Mass 500

400 10 300 Average wastewater flow (m 200 5 100

0 0 29.04 30.04 01.05 02.05 03.05 04.05 05.05 06.05 07.05 08.05 Monday Monday

Work week Week-end 300 40 280 5-fluorouracil Gemcitabine 260 35 2',2'-difluorodeoxyuridine 240 Average wastewater flow /h) 220 30 3 200 25 180 160 20 140 120 15

Mass flow (mg/d) flow Mass 100

80 10

60 Average wastewater flow (m

40 5 20 0 0 29.04 30.04 01.05 02.05 03.05 04.05 05.05 06.05 07.05 08.05 09.05 Monday Monday

Figure S2. Mass flow profile of ICM (top) and of cyostatics (bottom) in the wastewater of the Cantonal Hospital (from Monday 30.04.2007 to Monday 07.05.2007). The continuous dark line (top) is the sum of the six ICM mass flows. The average hospital wastewater flow corresponds to 24 h for ICM (24h-composite samples) and to 18 h for cytostatics (18h- composite samples).

Page S14 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

4000 y = 468.56x - 12.045 2 3500 R = 0.9749

3000

2500

2000

1500

Consumption at hospital (mg/d) hospital at Consumption 1000

500

0 012345678 Mass flow in hospital wastewater (mg/d)

Figure S3. Linear correlation between the intravenous consumption of 5-fluorouracil at the hospital and the measured emission of this compound in hospital wastewater. The point of the last Tuesday was rejected (x,y) = (0 mg/d, 3793 mg/d).

Page S15 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

S4 Overall measurement uncertainty The overall uncertainties for the measured mass flows of ICM and cytostatics represented in Fig. 2 and Tab. 2 are composed of three parts. (1) The precision of the instantaneous flow rate measurement device is ±20%. (2) The sampling uncertainty is related to the estimation of the number of toilet pulses containing the substances of interests emitted by hospitalized patients (4.5 pulses) and out-patients who excrete also partly on the hospital site (1 pulse). This uncertainty is specific for each day and analyte, and constitutes the highest fraction of the overall uncertainty. The sampling uncertainty was determined from the 68%-quantile (see section Assessment of Sampling Uncertainty in the main article) and lays between ±30% and ±120% (Tab. S8). For cytostatics, the number of hospitalized and out-patients is known and were taken as bases for the calculations. For ICM, 50% hospitalized and 50% out-patients were assumed for each day. (3) The variation of the analyzed duplicates was taken as the precision of the analytical method, what contributes only by a minor fraction to the overall uncertainty. For ICM the analytical precision is 4.5±4.6%; for cytostatics 10.0±7.6%. The overall uncertainties were then computed following the Gaussian error propagation for multiplications given in Eq. S1, as the square root of the sum of the squared relative standard deviations.

2 2 2 s ⎛ s ⎞ ⎛ s ⎞ ⎛ s ⎞ y = x ⋅ x ⋅ x , y = ⎜ x1 ⎟ + ⎜ x2 ⎟ + ⎜ x3 ⎟ (Eq. S1) 1 2 3 ⎜ ⎟ ⎜ ⎟ ⎜ ⎟ y ⎝ x1 ⎠ ⎝ x2 ⎠ ⎝ x3 ⎠

where xi and y are absolute values, sxi and sy the absolute standard deviations of the values, and (sxi/xi) the relative standard deviation.

Page S16 Supporting Information to Weissbrodt D., Kovalova L., Ort C., Pazhepurackel V., Moser R., Hollender J., Siegrist H., McArdell C.S., “Mass flows of X-ray contrast media and cytostatics in hospital wastewater”, Environ. Sci. Technol. 2009.

Table S8. Average sampling uncertainty coefficients (68%-quantile) computed as a function of the number of toilet pulses emitted into the hospital canalization.

Number of toilet pulses 1 2 3 4 5 6 7 8 9 10 Sampling uncertainty ±120% ±110% ±110% ±110% ±100% ±100% ±90% ±80% ±70% ±70% Number of toilet pulses 11 12 13 14 15 16 17 18 19 20 Sampling uncertainty ±70% ±70% ±60% ±60% ±60% ±60% ±50% ±50% ±50% ±50% Number of toilet pulses 21 22 23 24 25 26 27 28 29 30 Sampling uncertainty ±50% ±50% ±50% ±50% ±50% ±50% ±40% ±40% ±40% ±40% Number of toilet pulses 50 Sampling uncertainty ±30%

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