Antineoplastic drugs (ADs) play a substantial role in cancer therapy, but due to their cytotoxic properties, many ADs are considered to be hazardous to healthcare workers. The increasing number of patients receiving chemotherapy treatment and the expansion of indications for use of ADs pose especially those at exposure risk who are directly involved in cytotoxic drug preparation and application of cancer treatments (e. g. pharmacists, nurses, physicians). Independent of their concentration ADs can cause severe adverse effects such as carcinogenicity, mutagenicity and adverse reproductive outcomes [1–3]. Transdermal absorption after skin contact with contaminated surfaces is suggested to be a major route for inadvertent incorporation of the drugs [4–6], but also ingestion or inhalation are potential routes. Thus, international and national guidelines for safe AD handling and prevention of occupational exposure to hazardous drugs were introduced in many countries [7–9] and are regularly updated according to the actual state of knowledge. However, despite efforts, improved safety standards and technical development over the last decades; especially in pharmacy units, neither surface nor biological contamination by ADs has been eliminated entirely. Therefore, healthcare professionals still remain at potential exposure risk. This has been documented for nearly three decades of investigation and is nevertheless an actual issue because no health-based limit for these agents can actually be defined [10–19]. An expanded bibliography of publications on this topic has been compiled by the National Institute for Occupational Safety and Health (http://www.cdc.gov/niosh/topics/antineoplastic/pubs.html) providing a large overview of relevant literature. Obviously, although pharmacy workers are aware of the risks of occupational exposure, the adherence to published guidelines and the application of safety strategies is less effective without practical on-site monitoring at the workplace and continuous evaluation of workplace contamination. Wipe sampling of ADs is currently the method of choice to indicate workplace environmental contamination as a potential source of occupational exposure and is recommended to be part of a comprehensive hazardous drug program . Thus, long-term monitoring is an important tool to control and document the impact of exposure prevention strategies over the course of time. Moreover, it contributes to support the pharmacies to benchmark their actual exposure levels and to obtain information on possible sources of drug release, spread and routes of exposure.
The aim of the actual study was to examine long-term data of environmental contamination of 5-fluorouracil and platinum-drugs from various surfaces of AD preparation areas in pharmacies, and to investigate the contamination levels over 15 years. A summary of the large data base of surface drug concentrations is presented and results are described with respect to the development of contamination over time and to established guidance values.
Materials and methods
For more than 15 years, the Institute for Occupational, Social and Environmental Medicine of the University of Munich has developed a validated surface monitoring kit to hospital and retail pharmacies, which was designed to easily and effectively monitor contamination levels in pharmacies and health care facilities which are involved in preparation or administration of cytotoxic drugs.
Pharmacies order the monitoring kits on a voluntary basis for a variety of ADs. The monitoring is generally carried out three times per year for logistical reasons. Up to now, 168 hospital and retail pharmacies participated the monitoring varying substantially in amounts of handled antineoplastic drugs. In Germany, Austria and Switzerland, pharmacies are generally of high standard and preparation rooms in this study were equipped with various types of at least Class II BSCs (biological safety cabinets) or isolators with raisable front panels (in 10 hospital pharmacies). In hospitals, the AD preparation is usually centralized in a single pharmacy unit. General working procedures, technical and personal protective equipment as well as safety precautions are standardized. Each participating pharmacy was expected to apply local policies and procedures for all aspects of hazardous drug handling (i. e. compounding, surface cleaning, waste management etc.). However, handling practices in detail can differ largely within these requirements. No information on the amounts of antineoplastic drugs processed was collected as no significant correlation could be found between surface contamination levels and handled quantities of PT compounds and 5-FU in former studies [21, 22]. Pharmacies, which performed wipe samples at fewer than three surfaces in each monitoring event or which monitored only non-classifiable locations were excluded. Thus, overall, data of 151 of the 168 monitored pharmacies were included in this evaluation.
Investigated antineoplastic drugs
The wipe sampling technique and analytical methods were developed for the cytotoxic drugs 5-fluorouracil (FU), platinum (PT) as marker of cis-, carbo- and oxaliplatin, gemcitabine, docetaxel, paclitaxel, methotrexate, epirubicin, and doxorubicin. These drugs are suitable indicators for occupational exposure to ADs due to their frequent use in high amounts and due to the sensitive and validated analytical methods for these substances. As FU and PT were the most frequently monitored substances within this investigation, this evaluation focused on these antineoplastic substances.
Pharmacies were organized in comparable areas and workplaces for performance of defined working steps, at least in hospital pharmacies and in a large part of the retail pharmacies. For evaluation and comparison of the results, the sampled locations were classified in standard locations as described previously  selected with the aim of representing the entire workflow (Table 1). Surfaces in isolators were additionally summarised as “location 11”.
As wipe sampling was on a voluntary basis, the pharmacists themselves were free to choose which drug and which surfaces should be monitored as well as the number of samples. Areas for representative monitoring (“standard locations”: e. g.; locations for storage, preparation and packing, hoods, floor, worktops), were recommended for sampling with respect to precise classification and comparability of results. Thus, sampled locations and number of wipe samples differed between the pharmacies and FU and PT-samples were not obligatorily performed in parallel. Plans of the premises and the sampled surfaces were provided by the pharmacy personnel in most cases to facilitate classification. Only data of those surfaces were included which could be classified in the 11 standard locations, at least under the location 8 “Other surfaces”. Surfaces from the salesroom of retail pharmacies and wipe samples from vials were excluded.
Wipe sampling was performed as previously described  using a standardized sampling kit. It comprises all necessary tools (i. e. wipe filters, adequate solutions, storage containers) and a precise instruction with photos and video manual of the sampling technique enabling the pharmacy employees to perform wipe samples easily and effectively on-site. In brief, three filters (ᴓ 9 cm) were folded to quarters like a sled with two wings to grip in order to build up enough pressure for effective manual wiping. Filters were moistened with eight drops of methanol (FU sampling) or 0.01 % hydrochloric acid (PT sampling) for each wipe sample. Then, selected surfaces were consecutively wiped three times using one filter for each direction (down, left, and right) to cover an area of 20×20 cm. However, for surfaces, for which this size was not practical (e. g. doorknobs), the sampled area was exactly recorded. The three filters were combined to one sample and stored in screw-cap glass containers at 4 °C and sent back to the laboratory within 24 h.
The PT analysis was performed as described in detail by Ensslin et al.  In brief, platinum amount of the three filters was extracted with 25 ml of 2 % hydrochloric acid by shaking (1 h, 150 rpm). Organic impurities, which may disturb the voltammetry measurements, were destroyed by ultraviolet radiation from an aliquot of 0.5 ml extraction solution. PT concentrations were determined by inverse voltammetry under strict internal and external quality assurance. Twice a year the laboratory successfully participated in an external quality control scheme. The limit of detection (LOD) for PT was 0.01 ng/sample, and related to the wiping area of 400 cm² the LOD was 0.025 pg/cm². Blank samples (n=292) were taken and analysed (mean: 0.012 ng/sample, standard deviation: 0.022). As the voltammetry measures total PT, a potential input of background PT from environmental sources (e. g.; PT-containing road dust from shoes on the floors) could not be separated from PT loads deriving from surface monitoring for Cis-, Carbo- and Oxaliplatin. However, several tests showed that this impact is in an order < 0.1 pg/cm² which is in agreement with data of other investigations . Hence, we defined 0.1 pg/cm² as cut-off for “PT-positive” samples.
The FU amounts from wipe samples were analysed by gas chromatography/mass spectrometry (GC/MSMS) as described in detail previously  using methanol as organic solvent and 5-chlorouracil (CIU) as internal standard. The limit of detection (LOD) for FU was 0.2 ng/sample All 296 blank samples were below the LOD. For the wiping area of 400 cm², the LOD was 0.5 pg/cm².
Altogether, surface contamination levels of FU and PT from 151 pharmacies were determined by wipe sampling and classified in different locations. Percentiles were calculated and results of hospital pharmacies versus retail pharmacies were compared. Many pharmacies (n=120, 79.5 %) performed the surface monitoring twice or more with different time intervals from months to years. The development of surface contamination by FU and PT over the 15 years of long-term monitoring was evaluated. After each monitoring campaign, pharmacies received their individual results and – since the introduction of the proposed and in 2009 published threshold guidance values (TGVs) – also a classification (“traffic light classification”) of their contamination levels . Thus, pharmacies could compare their individual results to a collective of other pharmacies and target the sampling sites with high contaminations for corrective measures.
Statistical analyses were carried out using the software package IBM SPSS for Windows, version 21.0 (Armonk, NY). Since data were not normally distributed (Kolmogorov-Smirnov test), the median, the geometric mean (GM) and the 75th and 90th percentiles of the FU and PT concentrations are presented. For statistical calculations, FU concentrations below the LOD were set as ½ LOD. Regarding PT, only 13 samples with surfaces < 400 cm² were below the LOD (range: 0.006–0.023 pg/cm²) and were therefore included unchanged for statistical evaluations. The Spearman rank correlation test was used for correlations of those FU and PT concentrations which were measured in parallel from identical surfaces. ANOVA was performed for analysis of significant differences using sampling locations and years as fixed factors. Likewise, it was tested whether there were significant differences regarding the timespan before and after introduction of the TGVs.
In total, a number of 3,584 wipe samples for FU and 2,955 for PT were taken from 151 pharmacies. Thereof, 104 pharmacies monitored their workplaces both for FU and PT either in parallel or in seasonally/yearly change, while 26 pharmacies sampled only FU and 21 pharmacies only PT. Altogether, 55 pharmacies were retail pharmacies, and 96 were hospital pharmacies. Overall, 56 % of the FU samples were above the specific LOD of 0.5 pg/cm² and 82 % of the PT samples were “PT-positive” (≥0.1 pg/cm²). Drug concentrations of pharmacy surfaces ranged from ND to 1,725,000 pg/cm² for FU and from ND to 23,068 pg/cm², for PT with total median concentrations of 1.0 pg/cm² (GM: 1.69 pg/cm²) and 0.27 pg/cm² (GM: 0.4 pg/cm²), respectively. Tables 2 and 3 show the number of wipe samples for each location, the proportion of positive samples and the contamination levels. Median concentrations varied between ND and 4.3 pg/cm² for FU and between 0.15 and 1.8 pg/cm² for PT dependent on area within the pharmacy.
The by far highest FU contamination was found inside the BSC whereas the highest median contamination was found in the storage area for opened vials. Regarding PT, the highest concentration was located on a storage surface, but also the BSC and the waste disposal systems were strongly contaminated, which is also reflected by the median values. These findings were also confirmed by the 75th and 90th percentiles. Likewise, the percentiles of the comparatively small numbers of samples from surfaces inside isolators were also high both for FU (8 pharmacies) and PT (8 pharmacies).The GMs and the 95 % confidence intervals for all locations are shown in Figures 1 and 2. Within the 104 pharmacies, where both FU and PT were monitored, 1480 FU samples and 1480 PT samples were taken in parallel from identical locations. The FU and PT contaminations were significantly correlated (r=0.332, p < 0.01) for these locations.
Comparison of results from hospital and retail pharmacies
Altogether, 70.8 % (n=2537) of FU samples and 79.4 % (n=2346) of PT samples derived from hospital pharmacies. Median FU concentrations as well as 75th percentiles were significantly lower for hospital pharmacy samples compared to those from retail pharmacies (p < 0.001). In contrast, PT concentrations of the 50th and 75th percentiles were not different (p=0.424) between hospital and retail pharmacies (Table 4).
Surface contamination over time
The geometric means (GM) of FU contamination from all sampled surfaces per years varied between 2.1 and 12.9 pg/cm² until the year 2007 and then decreased substantially in more recent years reaching approximately a plateau concentration between the LOD and 1 pg/cm² since 2011 (Figure 3). The overall PT concentrations per year also decreased in a similar manner (Figure 4). Differences in contaminations between locations and years were significant for all locations and years both for FU and PT (p < 0.001). Likewise, separate calculation of hospital versus retail pharmacies revealed a comparable decrease of contamination over time. While retail pharmacies generally had higher contamination levels in the first monitoring period [2000–2008], surface loads with FU and PT subsequently levelled out for both pharmacy types at low and comparable ranges.
In the last years, protection and prevention strategies have been regularly updated and improved according to the state of knowledge. Pharmacy employees are more aware of the occupational exposure risk arising from AD preparation and handling than in earlier years. Thus, surface concentrations from the second study period in the more recent years 2008–2015 were additionally focused with respect to pharmacies which performed wipe sampling for their first time within this period. Wipe samples from clearly defined surfaces were compared to follow-up samples from the identical locations in order to assess the development of surface contamination. Altogether, in this period, 123 identical surfaces were sampled (at least) twice for FU and 86 for PT within 9–36 months. Compared to the primary surface concentrations at these locations, 56 % (n=69) of these surfaces were less FU-contaminated in the second sampling (38 of these results even declined < LOD) and 21 % remained < LOD in both samplings. With respect to identical surfaces which were screened for PT contamination twice, sampling results improved in 50 % of the cases (n=43) whereas 10 % (n=9) remained unchanged. Statistical tests showed that improvements between first and second sampling were significant (p < 0.001 for FU, p=0.034 for PT).
In a previous study  statistically derived threshold guidance values (TGVs) for FU and PT were proposed as educational intervention in order to help pharmacies benchmarking their contamination situation compared to other pharmacies. Those guidance values were derived by calculating the mean value of the 50th (TGV 1) and then mean value of the 75th percentiles (TGV 2) of FU and PT samples from ten defined sampling locations within the pharmacy areas and provided the basis for an easily applicable “traffic light classification” system. Comparing the results of all 3584 FU and 2955 PT samples from 2000 to 2015 to those TGVs 70.7 % of FU samples were < TGV 1 (5 pg/cm²) and 88.4 % were < TGV 2 (30 pg/cm²) while 67.3 % of the PT samples were < TGV 1 (0.6 pg/cm²) and 88.5 % were < TGV 2 (4 pg/cm²). Since summer 2008, the pharmacies received their individual monitoring results together with a classification based on the TGVs. A comparison of the median values before (first sampling period: spring 2000-spring 2008) and after (second sampling period: summer 2008-summer 2015) introduction of the TGVs displayed a significant decrease of contamination at all locations in the newer monitoring period, except for the isolators (Table 5).
This study provides a large database of long-term environmental monitoring results and presents the current contamination situation and the time course of surface contamination by FU and PT in 151 pharmacies over a period of 15 years. Although the selection of the pharmacies was not randomized, the 138 German hospital and retail facilities were spread all over Germany and thus are supposed to be representative in terms of size and type. Likewise, the 13 pharmacies from the neighboured German-speaking countries Austria and Switzerland are comparable in spatial and organizational structures of the working place. However, amounts of handled drugs were not recorded in this study. Various studies stated that number and amount of processed ADs did not correlate to the level of contamination in pharmacy areas, but conclusions of a potential relationship are inconsistent in published literature [11, 21, 22, 26–29]. We are aware that data are heterogenic due to the different frequency of monitoring per pharmacy, the individual temporal distance between the samplings and due to the range in the number of wipe samples influenced by the free choice of sampling locations. Also, the number of wipe samples increased in recent years due to a larger number of participating pharmacies with repeated monitoring. Therefore, the data evaluation was restricted to descriptive statistics.
Overall, 56 % of the quantified FU samples and nearly all PT samples were above the specific LODs due to the very sensitive analytical methods. Only few studies had comparable LODs for FU or PT [22, 26, 28] of which Brouwers et al. reported also a high percentage of 94 % positive PT-samples in hospital pharmacies. Sensitive analytical methods are an important premise as reliable evaluation is only possible when sufficient numbers of sample concentrations are quantifiable.
The surface load of the 11 locations varied remarkably between the pharmacies and the different sampling locations and ranged from ND to 1.725.000 pg/cm² (FU) and from ND to 23,068 pg/cm² (PT) with overall FU and PT median concentrations of 1.0 pg/cm² and 0.27 pg/cm², respectively. The significantly higher overall median FU load in retail pharmacies compared to hospital pharmacies (Table 4) may be attributed to constricted spatial facilities where surfaces eventually are used for different tasks. Moreover, a potentially less strict application of safety recommendations or hygiene strategies, or lack of experience in AD preparation due to smaller preparation numbers may also be reasons for higher contamination incidents. As expected, results show that BSCs and isolators were frequently contaminated, which has also been shown in other studies [12, 19, 22, 30–34], and also the waste disposal systems (e. g.; Pactosafe). At these locations, large quantities of drugs are handled and spillage is likely to happen. Isolators have been developed to ensure utmost product safety and also protection for processing pharmacy personnel during preparation. However, it has been shown that cleaning inside turned out to be difficult and drug residues often adhered to prepared infusion bags bearing the risk of contamination transfer to areas outside the pharmacy units. But interpretation of percentiles from isolator samples must be done with caution due to the comparably low numbers. Moreover, contamination can also occur due to incorrect application of working procedures or insufficient cleaning. Drug residues on the external of vials have been related to surface contamination in various studies [35–39], and this is very likely the reason for the substantial contaminations in the storage areas and other pre- and post-preparation surfaces where vials are handled or placed. The drug residues in the transport boxes and on the floors implicate that AD contamination is often spread throughout the pharmacy to surfaces not directly related to the drug preparation process. This has been supported by the results of many other studies [19, 21, 22, 27, 40, 41], and is insofar critical as gloves are often not worn in areas where no contamination is expected . Nevertheless, the present findings generally range in lower magnitudes than results from older studies [13, 33, 43, 44] and also from more recent international studies [19, 28, 31, 41, 45–47], indicating country-specific levels of contamination and pointing out the constant improvements in occupational hygiene practice in the participating pharmacies. The continuous improvement is likely to have benefitted from repeated and long-term monitoring. However, comparison to results of other studies must be done with caution due to differences in technical and analytical methods.
Long-term monitoring of surface contamination
Considering the development over the last 15 years the surface contamination has remarkably decreased and seems to level out in low concentration ranges near the LOD. Especially since 2008 (Figures 3 and 4), the FU and PT surface concentrations were often far below the proposed TGVs which were introduced to help pharmacies benchmarking their individual results and are likely the cause for this positive development. This is obviously confirmed by the significantly lower median concentrations at most locations in the second study period after TGV introduction (Table 5). But also efforts in technical equipment and hygienic strategies could have contributed to this progress. A time trend has also been reported in Canadian hospitals for other ADs with a substantial (4-5-times) decrease of the 75th percentile of contamination concentration over several years [14, 48] while the proportion of positive results remained approximately constant. Likewise, European studies described a reduction in surface contamination over time for various ADs [27, 28, 31, 49]. This is most likely related to the increased awareness of the health hazard of occupational exposure to ADs and to the implementation of international and national guidelines. Levels seem to decrease since the introduction of technical improvements such as CSTDs , standardized working and cleaning strategies and environmental contamination controls on practice quality [21, 27, 31, 32, 49, 50]. But it is also substantially dependent from the sufficient adherence to recommended practices, which are – as even shown in recent studies – often insufficiently followed [47, 51, 52].
In the present study, the participating pharmacies received a report of their individual contamination results after each monitoring and the TGV based classification together with recommendations for safer handling. The pharmacists are aware that the TGVs only reflect the individual contamination levels in comparison to a large collective of comparable pharmacies and that surface loads below the TGV 1 are not defined as “safe”. As no health-based limit of occupational exposure can be defined for cytotoxic drugs, no toxicological risk assessment can be derived from the presented data. However, classification by means of guidance values are a suitable approach when exposure limits cannot be established. The efforts in the reduction of contamination show that such challenging limits, i. e. the 75th percentile as guidance value for comparably high concentrations, are definitely applicable as guidance value and advantageous compared to the 90th percentile as proposed in other studies [18, 27]. Although it must be considered that interpersonal variability of the wiping procedure and personal experience may have influenced AD monitoring results, it is most likely that this long-term monitoring with repeated samplings has beneficially influenced working and cleaning procedures of the pharmacies, and subsequently a decrease of contamination. Long-term monitoring is supposed to support pharmacies in optimizing their working procedures, to evaluate potential sources and the effectiveness of implemented measures for reducing the potential dermal exposure risk of healthcare workers as much as possible.
The study presents a large dataset of the surface contamination by FU and PT in pharmacy areas and provides information on the development of the contamination levels over the last 15 years. Mostly contaminated areas were still the surfaces inside the BSCs/isolators and on storage shelves. The concentrations ranged widely, but altogether, overall geometric means of contaminated surfaces decreased substantially over the years to a comparably low plateau. Compared to the samplings before introduction of the TGVs, surface contamination subsequently decreased at most locations. Even if it may be impossible to remove all exposure risk during handling cytotoxic drugs, the presented results show that it is definitely possible to prepare antineoplastic drug infusions with low surface contamination and to efficiently reduce surface drug loads. Long-term monitoring of surface contamination by wipe sampling seems to have a beneficial effect on the decrease of contamination levels and is an effective screening measure to identify and promote good work and safety practices in pharmacies.
Conflict of interest statement: The authors state no conflict of interest. All authors have read the journal’s Publication ethics and publication malpractice statement available at the journal’s website and hereby confirm that they comply with all its parts applicable to the present scientific work.
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Antje Böhlandt is a MD and started her career in 2003 in an outpatient centre for dermatology and allergology. She completed her doctoral thesis at the Ludwig Maximilians University Munich in 2006. Since March 2006 she has been employed as scientific assistant at the Institute for Occupational, Social and Environmental Medicine, University Munich, and worked on various research projects on occupational exposure to allergens, heavy metals and cytotoxic drugs. Her special interest is dedicated to the evaluation and prevention of workplace contamination by antineoplastic drugs.
Dr. Rudolf Schierl (*1952) is the head of the Analytical and Monitoring Department of the Institute for Occupational, Social and Environmental Medicine, University Hospital Munich (LMU), Germany. He has a background as analytical chemist and studied during his professional career the exposure and uptake of environmental and occupational compounds. Specifically, in the field of ambient and biological monitoring of cytostatic drugs in hospital and pharmacy settings he directed several studies, doctoral theses and has published various papers. He lectures at Munich Universities LMU and TUM and is an active member of the WHO Collaborating Centre for Occupational Health.