Introduction 1978 1979 1997 2004 1994 2005 2005 2002 2005 2002 2005 2002 2005 2005 2003 2002 1994a b 1997 1998 2003 2003 1994 2002 1997 The relationship between prolonged exposure to small quantities of cytotoxic drugs and harmful effects is difficult to establish. Based on current scientific knowledge, it is impossible to set a level of exposure that, beyond doubt, will not cause adverse effects. Because no regulations on the maximal acceptable amount of contamination for these drugs have been set so far, hospitals should aim for the lowest contamination as is reasonably achievable. Monitoring of contamination, therefore, is essential. This can aid in the identification of the main exposure routes and in assessing the effectiveness of cleaning and working procedures. Evaluation of environmental contamination will, moreover, lead to an increase of the consciousness among personnel, concerning the handling of the chemotherapeutic agents. This can lead to an improvement of and the compliance to working and cleaning procedures. Wipe sampling is a common method to monitor surfaces for the presence of cytotoxic drugs. Hence, sensitive and validated methods are indispensable to be able to detect the relatively low quantities of drug present on surfaces. 2002 2005 2002 2002 2005 2002 2002 2000 −1 2002 In the present study, we describe the development and validation of an ICP-MS method for the evaluation of surface contamination by platinum originating from cisplatinum, oxaliplatinum, and carboplatinum. ICP-MS assures an ultra high sensitivity and specificity and requires relatively simple sample pre-treatment procedures. The validated method has been applied to measure surface contamination in seven Dutch hospital pharmacies. Experimental Chemicals −1 −1 3 −1 Instrumentation −1 Determination of platinum by ICP-MS −1 −1 115 5 −1 232 6 −1 194 5 −1 + + ++ 194 1997 Assay development The most suitable wipe material, desorption solvent, and wipe solvent were selected using one surface sampling and desorption procedure. This will be described below. Recovery data were assessed for the three most commonly used platinum agents; cisplatinum, oxaliplatinum, and carboplatinum. The different molecular structures and, as a result, the variable physical characteristics, might possibly lead to a variation in absorption and desorption characteristics. Therefore, we decided to evaluate all three compounds instead of choosing one reference compound. Surface sampling and desorption procedure Each wipe tissue was moistened with 500 μl wipe solvent. In general, sampling was performed by wiping a defined surface area of 10 cm × 10 cm. However, for surfaces for which it was not possible to take a 10 cm × 10 cm sample, the complete top of the device was sampled and the area was estimated. All wipe samples were collected with a uniform sampling procedure by wiping in three different directions (vertical, horizontal, and diagonal). Wipe samples were stored in 50 ml disposable polypropylene flasks (Falcon, Becton Dickinson Labware, Franklin Lakes, NJ, USA) at −20°C until further processing. Prior to analysis, 10 ml of desorption solvent was added to the sample and flasks were kept in an ultrasonic bath for 60 min. Then, samples were filtered to remove particles which could possibly obstruct the ICP-MS nebuliser, or could interfere with the analysis. Two millilitres of sample were, after addition of iridium as internal standard, introduced directly into the ICP-MS. Samples of locations which were expected to be highly contaminated, were diluted prior to analysis to prevent contamination of the sample introduction system of the ICP-MS. Wipe material A variety of wipe tissues are available for collecting samples of surface contaminants. These vary in type of material, surface area, and content of platinum contaminants. Three types of wipes were evaluated for this study; Kimtech Science precision wipes (Kimberley-Clark Professional, Irving, TX, USA), Whatman glass fibre filters (Schleicher&Schuell Microscience GmbH, Dassel, Germany), and Klinion non-woven gauzes (Medeco, Oud-Beijerland, The Netherlands). The tissues were checked for platinum contamination and for their ability to release platinum from stainless steel surfaces. Desorption solvent 3 3 Wipe solvent 2 Validation procedures Linearity −1 3 −1 −1 −1 Recovery and precision −1 3 −1 −3 −2 −1 2 Sensitivity The lower limit of quantitation (LLOQ) was defined as the concentration at which the analyte response was at least five times the response of a blank wipe sample. Besides, the LLOQ, when spiked on blank tissues, had to be determined with a precision less than 20% and the mean value should not deviate more than 20% of the actual value. Stability Stability of cisplatinum, oxaliplatinum, and carboplatinum spiked to tissues, at two concentration levels, was evaluated at ambient temperatures for 1 week and under storage conditions (−20°C) for up to 3 weeks. From each storage condition two wipe samples were analysed. Samples were considered stable when 80–120% of the initial concentration was recovered. Platinum determination in pharmacy facilities where no cytotoxic agents are processed 1997 Monitoring of surface contamination in seven Dutch hospital pharmacies 1 1 Table 1 Amount of platinum agents processed and years that the facilities are in service  Site 1 2 3 4 5 6 7 Cisplatinum use in 2005 (in g) 52.3 6.80 64.0 147 16.8 29.9 104 Oxaliplatinum use in 2005 (in g) 47.5 8.65 44.1 109 23.4 98.8 62.0 Carboplatinum use in 2005 (in g) 256 48.2 124 635 56.5 223 217 Total amount of platinum processed in 2005 (in g)  192 34.0 129 483 52.1 185 212 Number of years in service 5 10 18 2.5 1.5 10 15 Wipe sampling frequency Once per year 2005 first time Sporadic: last in 2004 Once per year Once per year Once per year  Twice per year Fig. 1 Sample locations in pharmacy facilities  Wipe sampling was announced in each facility in advance and was performed after the daily cleaning procedure of the LAF hoods, but before the daily cleaning procedure of the rest of the facility. Wipe sampling in all the facilities was performed by the same person. Results Assay development Wipe material As a result of high platinum backgrounds (10–20 pg platinum per filter depending on the batch analysed), Whatman glass fibre filters were found to be not suitable for platinum wipe sampling. Kimtech Science precision wipes and Klinion non-woven gauzes did not show platinum contamination. However, Kimtech Science precision wipes showed better recoveries of platinum compared to Klinion non-woven gauzes and consequently Kimtech Science precision wipes appeared to be the best choice. Desorption solvent The most effective desorption of platinum from the wipe materials was achieved by 1% HCl (94–99%). As a result 1% HCl was selected as the desorption solution of choice. Wipe solvent Recoveries were inadequate for 80% ethanol (<40% for all three compounds) and acceptable for water (50–77%) and 1% HCl (63–78%). Because 1% HCl appeared to be corrosive for some types of stainless steel, water was selected as wipe solution. Validation procedures Linearity The calibration curve was best described by linear regression, using 1/(sd of triplicate sample reading) as weight-factor, to avoid bias in favour of samples with high standard deviations. Deviations from the nominal concentration were between −10.0 and 10.2 for all concentration levels. Relative standard deviations for the calibration samples were up to 7.84%. Correlation coefficients were higher than 0.99999. Recovery and precision 2 Table 2 Within and between-run precision data for quality control samples Amount of platinum spiked to tissue (in ng) −1 Cisplatinum Oxaliplatinum Carboplatinum Within-run Between-run Within-run Between-run Within-run Between-run −3 0.500 7.75 a 8.53 a 8.01 8.75 −2 2.50 4.10 4.05 1.66 1.15 2.39 a 0.100 10.0 1.35 7.44 1.75 1.27 2.86 2.50 1.00 100 1.07 7.79 1.63 a 0.84 1.96 a 3 4 Table 3 Recovery of 1.00 ng platinum from a stainless steel surface  Cisplatinum Oxaliplatinum Carboplatinum Mean recovery (%) 50.4 73.8 77.2 Within-run precision (in %) 2.21 4.63 2.53 Between-run precision (in %) 3.36 a a Number of days 3 3 3 Number of samples per day 3 3 3 a Table 4 Recovery of 1.00 ng platinum from a linoneum surface  Cisplatinum Oxaliplatinum Carboplatinum Mean recovery (%) 76.8 77.9 81.4 Within-run precision (in %) 3.62 2.12 3.35 Between-run precision (in %) 12.2 5.41 6.82 Number of days 3 3 3 Number of samples per day 3 3 3 Sensitivity −1 −2 2 Stability Stability has now been established up to 3 weeks, but further testing is still ongoing. Sample storage at room temperature for 1 week was not possible. Tissues which were spiked with cisplatinum showed a decrease in platinum levels of 30% after 1 week. Oxaliplatinum and carboplatinum spiked tissues did not reduce under these conditions. Sample storage at −20°C was possible for at least 3 weeks. Platinum concentrations of cisplatinum spiked tissues were decreasing more obvious with time than oxaliplatinum and carboplatinum spiked tissues. However, no decrease of more than 20% of the initial concentration was observed after 3 weeks at −20°C. Platinum determination in pharmacy facilities where no cytotoxic agents are processed −1 −2 −1 −2 2 Monitoring surface contamination in seven Dutch hospital pharmacies 1 5 −2 5 Table 5 Platinum contamination in seven Dutch hospital pharmacies S.no. Sampled surface −2 Site 1 2 3 4 5 6 7 1 Middle of bench LAF hood 0.22 180 0.54 32.7 0.360 7.22 2.94  Duplicate of 1 0.189 124 0.645 18.7 0.328 8.22 2.28 2 Front edge of LAF hood a 356 3.32 99.5 0.133 28.2 5.12  Duplicate of 2 a 268 8.34 180 a 37.0 5.19 3 Floor in front of LAF hood 3.14 173 824 1,107 0.228 2.48 21.7  Duplicate of 3 3.20 232 728 2,211 0.186 1.91 12.5 4 Handle of service hatch a 22.7 a 2,055 a 1.96 11.8 5 Door handle a 3.17 a 16.8 a 21.4 16.1 6 Waste bin top a 1.02 0.392 10.1 a 7.38 c 7 Bench-top on which materials are placed 0.829 0.949 0.298 90.6 0.202 0.375 63.4 8 Floor in front of bench c 19.7 58.9 38.1 a c 11.9 9 Mouse computer 0.252 0.816 1.34 10.2 b 0.758 5.41 10 Handle telephone a 3.22 0.59 12.1 a 3.06 5.12 11 Storage shelve cisplatinum c 1.14 c 4.76 0.536 4.04 336 12 Storage shelve oxaliplatinum 0.368 0.916 c 4.10 82.7 1.15 2.21 13 Storage shelve carboplatinum 3.25 1.53 0.147 3.13 0.186 0.989 5,760 14 Transport box 74.5 a 0.285 4.44 a 0.828 b 15 Handle refrigerator 0.452 26.3 1.46 36.0 0.948 1.42 5.71 a b c Platinum was detected in 94% of the wipe samples and 88% of the samples contained levels above the threshold set. Six of the 126 samples showed raised hafmium signals which, considering a maximum oxide formation of 1%, might have accounted for up to 20% of the platinum signals of these samples. None of blank samples prepared for each facility by moistening tissues with wipe solvent, contained levels of platinum exceeding 20% of the LLOQ standard. The variation in the level of contamination between pharmacies was high. Pharmacies of site 1 and 5 showed overall low platinum contaminations. For these sites, respectively 33 and 39% did not contain platinum levels above the threshold set. Platinum levels detected at pharmacy 3 were relatively low as well, although the wipes taken from the floor were high at this site. These high values were, most probably, the result of a calamity in 2005 with a cisplatinum infusion mixture, which was spilled on the floor. Most locations wiped at the hospital pharmacies of site 2, 4, 6, and 7 showed high contaminations. Only one sample from these sites did not contain any detectable platinum. The high contamination of site 2 seemed to run counter to the quantities of drugs handled, because in this pharmacy relatively low amounts of platinum were processed. This site, however, was occasionally used, for preparation of larger amounts of cytotoxic drugs to serve another hospital. Therefore, the amount of drugs processed in 2005, was not fully representative for the amount of drugs processed in the 10 years that this site was in use. Site 4 showed the highest contamination, which paralleled the relative amount of drug handled in this unit. As expected, platinum was found in most wipe samples taken from the middle of the LAF hood bench. Notable was that, in general, wipe samples of the front edge of the LAF hood were more contaminated than samples taken from the bench-top of the LAF hood. Furthermore, floor samples usually contained the highest platinum levels. Other locations showing substantial contamination were storage shelves, door handles, and handles of service hatches. Duplicate samples of locations 1, 2, and 3 showed similar results, indicating a homogeneous distribution over de surface area. The number of years that the seven units were in use, did not parallel contamination levels and the amount of drug handled in 2005, overall, did not predict the level of contamination either. Discussion 1997 1994a 1997 1997 2003 2003 2002 −1 −2 2 2005 2003 2005 2000 2002 2002 2003 Validation of the method was performed for the three, in oncology most prominently used platinum agents, cisplatinum, oxaliplatinum, and carboplatinum. We decided not to choose one reference compound, because the different molecular structures of the platinum agents and, as a result, the variable physical characteristics, might possibly lead to a variation in absorption and desorption characteristics. Excellent reproducibility (imprecision up to 8.75%) and recoveries (86.7–103%) were demonstrated with spiked tissues, for all concentration levels and compounds. Up to 13.3% of the initial amount of platinum added to the tissues was not recovered after desorption and analysis. This could be due to variation in analysis, as well as loss due to adsorption to the tissues. Recoveries from the spiked stainless steel surface were 50.4% for cisplatinum, 73.8% for oxaliplatinum, and 77.2% for carboplatinum. Recoveries, for the three compounds, from the linoleum surface were, respectively, 76.8, 77.9, and 81.4%. These results showed that for stainless steel, depending on the compound analysed, up to 49.6% of the initial amount of platinum spiked to the surface was lost. This was, for the greater part, caused by the inability of the wipe procedure to remove all the added platinum and, for a minor part, by the variation in analysis and loss due to adsorption to the tissues. The lower recovery that was observed for cisplatinum, is, most probably, a consequence of its superior reactivity compared to oxaliplatinum and carboplatinum. This might lead to a stronger binding affinity of cisplatinum to materials and surfaces. For linoleum up to 23.2% of the initial amount of platinum spiked to the surface was not recovered. For this surface, recoveries were similar for all compounds. To evaluate the stability of spiked samples, recoveries were assessed after storage at room temperature and −20°C. Storage of spiked tissues at −20°C for at least 3 weeks was possible. However, storage of tissues spiked with cisplatinum for 1 week at room temperature led to considerable decrease in platinum levels. Even though platinum concentrations from oxaliplatinum and carboplatinum spiked tissues did not reduce under these conditions, storage at room temperature was not recommended, also because the source of elemental platinum is not known in wipe samples performed in pharmacies. Differences in recovery of the cisplatinum and the oxaliplatinum and carboplatinum spiked samples, again, could be explained by the higher reactivity of cisplatinum. −1 −2 2 5 The results of this study indicate that there is substantial variation in surface contamination of the pharmacies tested and that the amount of platinum processed in the pharmacies did not always parallel the level of contamination. The number of preparations with platinum drugs was, however, not assessed and might also be related to surface contamination. This suggests that variation in the application of or compliance to cleaning and working procedures and the incidence of calamities, rather than the amount of platinum processed, caused variation in surface contamination. In general, results reveal that the LAF hoods, the floor in front of the LAF hoods, door handles, and handles of service hatches were often contaminated. This demonstrates that contamination is often spread throughout the pharmacy. Notable was that wipe samples of the front edge of the LAF hood were more contaminated than samples from the bench-top of the LAF hood. This is thought to be due to incorrect application of working procedures or insufficient cleaning. 2005 2005 2003 2002 −2 2002 2002 2002 −1 2002 −2 −2 2005 When comparing the amounts of platinum detected on different locations in this study (up to 0.576 μg per wipe sample) with the platinum content of one vial (between 6.50 and 237 mg platinum), contamination seems to be relatively low. Furthermore, the extremely sensitive technique used in this study, leads to a high percentage of positive samples. Interpretation of these results is rather complicated. It is important to consider that the total area of the contamination is large and that pharmacy personnel are at risk to be exposed to the contamination daily. Hence, for safety precautions, it is recommended to attempt to achieve the lowest possible contamination. Environmental monitoring therefore, may be used to monitor and control contamination and thereby evaluate working and cleaning procedures, rather than to interpret potential health risks. In general, when a minimal contamination level is desired, the results of this study demonstrate that cleaning and working procedures do not sufficiently prevent contamination in most hospitals. This could be due to an inadequate compliance of personnel to these procedures. Moreover, contamination can spread out unconsciously by hands or feet of the personnel. It is also likely that cleaning procedures as applied in the different pharmacies are not fully optimised and validated, leading to contamination due to sub-optimal cleaning. With respect to the physical properties of the different cytotoxic drugs, it is recommended to consider cleaning techniques appropriate for specific agents. As was shown in this study for platinum, for instance, 80% ethanol did not effectively remove platinum from a stainless steel surface. Although water gave better recoveries for platinum, it was not capable of removing all of the added platinum from the stainless steel surface. This illustrates the importance to evaluate several cleaning procedures for the different cytotoxic agents handled and to optimise a procedure which does remove all drugs with acceptable recoveries. In conclusion we developed and validated an ultra sensitive and reliable ICP-MS method for the determination of platinum in surface samples. This method was successfully applied in the evaluation of platinum contamination in the preparation units of seven Dutch hospital pharmacies. It was demonstrated that pharmacy personnel is at risk to be exposed to platinum, despite the use of cleaning and safety procedures. As long as the consequences of long-term exposure are not known, the aim should be to achieve a contamination levels as low as possible. This study, therefore, highlights the need to further evaluate cleaning and safety procedures. Wipe sampling can be applied to quantify improvements made through changes in procedures.