Cytotoxic drugs often possess 1 or more characteristics by which they should be classified as hazardous. Inherent to their mechanism of action they are carcinogenic, mutagenic, and/or reprotoxic. Healthcare workers that are exposed to cytotoxic drugs are therefore at risk of experiencing negative health effects. To combat these risks, the European Union (EU) directives on safety at work, oblige all employers to strive for the lowest level of exposure possible for their personnel.[1,2]
Numerous studies into the risk of cytotoxic exposure have been performed over the past 2 decades, resulting in recommendations on how to lower exposure. In general, the dermal route and, to a lesser extent, the inhalation route, are considered the most relevant for healthcare workers.[3,4] In hospitals, exposure can occur through a variety of different work activities—receipt, compounding and administration of cytotoxic drugs, caring for patients treated with cytotoxic drugs, and cleaning of rooms and premises where cytotoxic drugs are handled.
Determining the actual risk for healthcare workers of health effects such as the development of cancer or negative reproductive outcomes, remains an enormous challenge. Very large epidemiologic studies would be necessary, following cohorts of healthcare workers over a prolonged time period. Moreover, many confounding variables, such as life style habits or environmental influences, would be difficult to account for. Therefore, a good way of monitoring the possible risk of worker exposure is to examine contamination at the workplace. This can be done by taking wipe samples of surfaces which may have been contaminated. This approach has been incorporated into several sets of safe working guidelines.[5–7] The interpretation of the wipe sampling results evaluating the risk to workers, however, remains controversial. No actual limit values for environmental contamination, on the basis of true adverse health effects, are available, because several limitations in establishing them have not been overcome. First, the range of drugs handled in healthcare facilities is large and changes constantly because of the introduction of novel or enhanced treatment regimens. Second, the release of the cytotoxic drugs from surfaces or the rather negligible evaporation depends both on the material of the surface as well as on the physical properties of each drug. And third, the ability of drugs to penetrate through the skin or be absorbed systemically through inhalation is highly variable and for many drugs not established. Thus, only guidance values, as opposed to actual limit values, are possible and they have been independently determined in Germany, the Netherlands, and the USA.
Notwithstanding these limitations, wipe sampling remains the best tool to perform monitoring or surveillance of the risk of exposure, and can also be used to evaluate the efficacy of measures taken to reduce exposure. This has been the focus of many studies, reviewed by Kibby and Hon et al. Most of the previous studies included rather small samples or compared situations before and after implementation of safe working guidelines in a single setting. In addition, quite a large proportion of the studies were funded by manufacturers of medical devices. All previous large trials were national studies, for example, in Sweden, Switzerland, Canada, and Germany. As yet, no pan-European study has compared the levels of contamination in hospitals from a large range of drugs and correlated them with the working procedures in place.
The main goal of the MASHA (Research about Environmental Contamination by Cytotoxics and Management of Safe Handling Procedures) study is to obtain an overview of the current situation in European hospitals with regards to cytotoxic contamination at various sites, including drug preparation (pharmacy) and administration areas (ward). The secondary objective is to evaluate environmental contamination with cytotoxic drugs circulating within a facility, known as the hospital medication system (process flow of drug), and the impact of changes in local working practices. A final aim is to increase awareness among healthcare workers and their employers of the risks associated with handling hazardous drugs and to provide them with measures for protecting their health.
The MASHA study contains 3 distinct parts: in the first part (I), wipe samples of participating hospitals were taken at the pharmacy and at the wards to obtain an overview of surface contamination in the hospitals. Also general information of the safe handling procedures already in place were collected from each of the participating hospitals as well as demographic data about the number of preparations and administrations. In the second part (II), pharmacists from the participating hospitals received training about safe handling, and implemented cleaning recommendations from the European Society of Oncology Pharmacy (ESOP) at their hospital, after which wipe samples were taken again, to evaluate the impact of these changes. In part 3 (III), wipe samples were taken once more 12 months later, to assess if changes had a sustainable effect on contamination levels.
Hospitals across Europe were approached by delegates of ESOP and participation was voluntary. Hospitals could be included if they were willing to participate in the wipe sampling and if a representative pharmacist from their staff was willing to undergo wipe sample training and implement the recommendations in part II. Participating hospitals needed to supply data regarding type of hospital (general, university, oncology clinic), the type and number of chemotherapy preparations per year, a list of established local procedures and a list of ventilation type and devices used. In addition, a list of drugs handled at the days of wipe sampling had to be completed. Analysis of combined data was undertaken anonymously, but each hospital did receive a report of their own contamination outcomes from the investigating team.
Wipe sampling strategy
Wipe samples were taken at the end of a working day, before general cleaning. For wipe sampling, Pharma Monitor kits type 4 (Berner International GmbH, Elmshorn, Germany), including all materials needed for the sampling, were used. Wipe samples were taken in every participating hospital from 10 comparable surfaces (5 in preparation areas and 5 in administration areas). Each investigated surface was wiped according to the established sampling instructions using 3 tissues applied with special solvent adapted for these procedures. Samples were collected from the following surfaces:
In the pharmacy
- Sample 1—Work surface of biological safety cabinet/isolator
- Sample 2—Floor under biological safety cabinet/isolator
- Sample 3—Top of dose checking counter in the clean area
- Sample 4—Top of checking counter in the storage area
- Sample 5—Refrigerator door including handle
In the ward
- Sample 6—Top of checking counter at nurse station
- Sample 7—Lid of cytotoxic waste container
- Sample 8—Armrest of patient chair
- Sample 9—Floor area under/around the infusion stand
- Sample 10—Phone, the one most often used in the ward
Samples were frozen directly after collection and shipped in frozen state to the analytical laboratory.
Analysis of samples
Each sample was analyzed for the presence of 11 cytotoxic drugs: 5-fluorouracil (5-FU), cyclophosphamide (CP), ifosfamide, gemcitabine (Gem), methotrexate, paclitaxel (Pac), docetaxel, topotecan, irinotecan, doxorubicin, and epirubicin, using liquid chromatography–tandem mass spectrometry. The chemical analysis was done by validated and previously published analytical methods using atmospheric pressure chemical ionization for 5-FU and electrospray ionization for the other compounds. The analytical limits of detection, limits of quantification, and lower levels of quantification for each of the analyzed drugs are presented in Table 1.
Interpretation of wipe sample results and choice of reference value
Wipe sample results were reported in ng/cm2. A substance independent reference or guidance value of 0.1 ng/cm2 was initially chosen on the basis of German references and available literature[6,16] and was later confirmed by the study results as sufficiently close to the 90th percentile of the measured contamination within the MASHA project (see Section 3). Values below 0.1 ng/cm2 were included as positive results but reported to the hospitals with the notification that all values below 0.1 ng/cm2 could be regarded as below the guidance level for safety.
After part I of the study, all pharmacists were trained during a 3.5-hour workshop to increase their knowledge and awareness of the risks of handling cytotoxics. In addition, the ESOP cleaning recommendations (Figure 1) were explained and handed out on a 1-page leaflet to each pharmacist. After the workshop, the pharmacists were given the task to implement these cleaning recommendations in their own hospital.
Analysis of results
Calculations were performed using Excel (Microsoft Office 2016, Microsoft, Redmond, USA). Statistical tests were performed with SPSS (Statistical Package for the Social Sciences, SPSS Inc., Chicago, IL, USA). A P-value of 0.05 was considered statistically significant. To make comparisons between amount of contamination for different hospital characteristics, Chi-squared tests (for ordinal data), Kruskal–Wallis tests (for characteristics in 3 or more groups) and Mann–Whitney U tests (for continuous data) were used.
The study started in 2013 and was concluded in 2015. At first, 19 hospitals expressed interest in participating in the study, but 3 of those failed to complete 1 or more series of sampling and 1 hospital backed out before starting. These 4 were therefore excluded from the study. The geographical distribution of the participating hospitals is given in Figure 2. The fifteen hospitals were situated in 11 different European countries. The types of hospitals included general hospitals, university hospitals, and dedicated oncology clinics, with the amount of annual preparations ranging from 4,000 to 60,000. With regard to local procedures in the pharmacies, both isolators as well as biological safety cabinets were used, and compounding was performed with needles, spikes (devices that prevent aerosol formation and needle prick injuries) or close-system transfer devices (CSTDs, devices that by statement of the manufacturers have a completely closed connection and thereby also prevent aerosol formation and needle prick injuries). On the wards, situations where primed side lines and/or needle free multiway infusions sets were used as well as situations without these were reported. Table 2 lists the most important characteristics of the participating hospitals. For some questions, multiple results were possible. For example, some hospitals used both needles and closed-system devices, for different drugs. In that case, they were asked for which preparations or drugs they used which device.
Wipe sample results
In total, 4807 results were collected and analyzed during the study from 437 wipe samples: 1595 during part I, 1573 during part II and 1639 during part III. The presence of surface contamination was demonstrated in the preparation and administration areas of all investigated hospitals. The average contamination as well as the maximum contamination per sampling location is presented in Table 3, and the overall combined results are in Table 4.
Contamination was detected mostly on work surfaces of biological safety cabinets (BSCs)/isolators, floors (in pharmacies and wards) and the armrests of patient's chairs (Figs. 3–5). The highest number of positive results was recorded with Gem, 5-FU, CP, and Pac. The highest value was noticed for Gem (170.5 ng/cm2), 5-FU (36.9 ng/cm2) and CP (6.5 ng/cm2) in part I, part II, and part III, respectively. The floors on the wards were shown to be the most frequently contaminated (42% of samples were positive). In 11 of 15 hospitals (73%), substances were detected which were not prepared or administrated in the sampling day. Sixty-nine percent of hospitals improved or stayed at the same level in the number of positive samples after the intervention. In the last part of the study, 12 months after the intervention, the improvement had remained.
Spreading of contamination through the hospital medication system
For the pharmacy, location 1 (inside the BSC or isolator) is expected to contain the highest amounts of contamination, as this is the location where actual handling of the cytotoxics takes place. Locations 2–3 would contain contamination if traces of cytotoxics that have been released during compounding are not contained within the BSC or isolator. Locations 4 and 5 are situated even further from the actual compounding location. In part I, in 7 hospital pharmacies contamination was found at location 4 (top of the checking counter in the storage area) and in 9 hospital pharmacies at location 5 (refrigerator door including handle). Notably, in 2 and 3 of the cases, respectively, no contamination with the drugs identified to contaminate the storage room and the refrigerator was found in the compounding room. In part II, 4 hospital pharmacies showed contamination at location 4 and 5 at location 5, respectively. In 1 case, this was contamination not found in the compounding area. In part III, 4 and 2 hospital pharmacies showed contamination at locations 4 and 5, of which 2 and 1 hospitals again showed contamination in the storage room and at the refrigerator that was not identified inside the compounding area. Overall, spreading of contamination through the hospital system thus went down and stayed down after the implementation of the cleaning recommendations. The origin of the contamination in the pharmacy most likely is not always the compounding itself, because then the contamination would be found both in the compounding room as well as at the locations further away.
In the wards, the phenomenon of spreading was evaluated by looking at the contamination at locations 7 (lid of cytotoxic waste container) and 10 (phone). Cytotoxic waste containers are transported to other parts of the hospital when they are full, and outside contamination can thus cause carryover of cytotoxic traces to other departments. Location 7 was contaminated at 8, 8, and 5 hospitals respectively in part I, II, and III. Location 10 was contaminated at 5, 2, and 4 hospitals in part I, II, and III, respectively. Only 2/15 hospitals found no contamination at all at locations 7 and 10 during all parts of the study.
Correlations between contamination and hospital characteristics
The variability between hospitals was large. Overall, 3 hospitals scored continuously low (0 or 1 contaminated spot) in the pharmacy. Of these, one also scored very low on the ward (0 or 1 contaminated spot). In contrast, 2 hospitals scored continuously high (4 or 5 contaminated spots) in the pharmacy. Of these, one also scored very high on the ward (5 contaminated spots). The majority of hospitals scored in between 2–3 contaminated spots on both the wards as well as in the pharmacy. To test for possible explanations for this variability, the hospital demographics and work procedure characteristics were tested independently for correlation with the amount of contamination found. The annual number of preparations and administrations did not correlate with contamination levels. The same was observed during the MEWIP study. This shows clearly that working procedures and training are more important instead of the preparation amount. To determine a possible correlation between the use of close system transfer devices, we performed statistical testing on the amount of CP in the ventilation area (BSC or isolator) as well as in the rest of the pharmacy (to determine the possibility of spreading of contamination). We chose CP because this drug has to be dissolved which takes a relatively long time, and because most pharmacies who answered that they did use close-system devices, they all did for CP. The results are shown in Figure 5. No statistical difference was found (P = 0.201 and P = 0.730), in fact, higher total amounts of contamination with CP were found in the pharmacies that use close system devices, when compared with pharmacies using spikes. Of all other tested characteristics, the use of multiway infusion sets with an independent flushing line showed a statistically significant outcome. Hospitals who indicated they used such infusion lines had a significantly lower amount of contamination on the floor of the wards (P = 0.046). In addition, the age of the cytotoxic unit showed a negative correlation with contamination in the pharmacy, with more contamination found in the elder units (P = 0.0396).
This first pan-European large study into cytotoxic surface contamination demonstrated that contamination occurs both in hospital pharmacies as well as on wards. The variability between hospitals was large. We showed that implementation of standardized cleaning procedures substantially lowered contamination levels. A wide panel of hospital characteristics was gathered during the study and tested for possible correlations with the amount of contamination. Notably, hospitals with a high throughput of chemotherapy did not show more contamination than hospitals with more modest amounts of cytotoxic preparation and administration. Thus, the number of annual preparations is not correlated with the contamination levels. The use of close-system transfer devices did not result in lower contamination levels in the hospital pharmacies. In fact, the hospitals with the cleanest pharmacy departments did not use CSTDs. The only 2 characteristics that showed a statistically significant relation with contamination levels were hospitals where multiway needle free infusion sets with primed sidelines were used had lower contamination levels on the wards than hospitals who did not, and the age of the cytotoxic unit was negatively correlated to the amount of contamination in the pharmacies. Storage areas as well as refrigerators in storage areas of hospital pharmacies showed considerable amounts of contamination. Also in hospitals where that same contamination was absent in the compounding room. This renders the assumption that compounding is not the actual or only source of contamination, quite plausible. In fact, it is known from extensive previous studies, that vials with cytotoxics that are commercially available show contamination on the outside in 60–100% of cases.[19–21] These vials are received, unpacked and stored outside of the cleanrooms, often by personnel that is not involved in the compounding itself. Such contamination from unexpected sources can travel through the hospital system, which has been demonstrated as well in earlier studies.[9,10,22–24] The finding that elder cytotoxic units have higher contamination levels than more recent ones, may be explained either by improvement in technical design as well as by possible accumulation of cytotoxic residues on surfaces over the years.
Our results are in line with several previous studies. When comparing our study data with results from cross-sectional studies over several hospitals in the literature, the amount of contamination found is comparable, as well as the findings that floors in the wards are often contaminated,[14,15,23,24] and that in the pharmacy, the most contaminated spot is inside the BSC or isolator.[14,15,25] Thus, the use of adequate cleaning protocols, which is infact mandatory both in the EU as well as in the USA remains pivotal. We demonstrate that implementing standard protocols substantially reduced the contamination in the participating hospitals. This is in accordance with previous studies into the effectiveness of different and optimized cleaning protocols from the Czech Republic and France. In our study, we found no influence on contamination levels when comparing the use of BSCs or isolators, the use of a compounding assistant, or dispensing compounded cytotoxics in a sealed bag. This last observation is in line with a previous study from the Netherlands, where the outside of prepared cytotoxic infusion bags, were not a source of contamination.
We did show a significant reduction in contamination levels when multi-way infusion sets with independent flushing lines were used. This has been studied only once before, where a reduction in contamination on the wards was also reported. The use of CSTDs in compounding has been studied extensively though. A literature review has been published, as well as a Cochrane review. The Cochrane review concludes that there is as yet not enough evidence to draw conclusions in favor of CSTD use. Our study confirms this conclusion, as do 3 recent publications that were completed after the Cochrane review was performed. First, a very large study involving 83 hospitals in Canada, found no reduction in CP contamination in hospitals that used CSTDs versus hospitals that did not. Second, 2 recent studies into bio-monitoring, analyzing urine samples from workers for the presence of cytotoxics, found no positive samples at all in hospitals where no CSTDs were used in France and Canada. All this evidence together gives ample proof to conclude that the use of the much cheaper spikes is as good if not better in protecting healthcare workers from cytotoxic exposure than the expensive CSTDs.
Our study is the first independent pan-European study that collected a large amount of samples and demonstrated that sustainable lowering of contamination by implementing a standardized work procedure is possible. The panel of hospitals comprised a good representation of the European situation, both by geographical locations as well as by the fact that we included general, academic and specialized hospitals. The panel of analyzed drugs was also large in comparison with most previous studies. However, some limitations to our study do exist. We did not measure the recovery of the wipe sampling method in the individual hospitals. In theory, the material of the surfaces could have an impact on the recovery. However, the recovery of the standardized method has been validated previously. In addition, participation of hospitals was voluntary. This could have potentially biased the results. Finally, we measured contamination of surfaces in the workplace. This will not correlate one-on-one with the actual internal exposure of hospital staff, because internal exposure requires adsorption of drugs through the skin or through inhalation or ingestion. This is influenced by the use of personal protective equipment, so one cannot correlate internal exposure in a simple way to contamination of the surrounding. Nevertheless, our study provides a good insight in the current risk of exposure of healthcare staff.
Future studies are still needed, especially because we still found contamination after the implementation of the cleaning recommendations. This means that as yet, cleaning is still not 100% effective. No single universal cleaning solution that adequately inactivates and removes all different cytotoxic drugs is available. If such a solution were to be developed, this could potentially be of great benefit, as it would prevent the accumulation of cytotoxic residues. Furthermore, attempts to reduce workplace exposure should definitely aim at decreasing the contamination that enters the hospital system through commercial vials that are received by hospital pharmacies. Finally, a good algorithm to translate surface contaminations to actual health risks is highly warranted.
In conclusion, the MASHA project provided an overview of the local procedures for safe handling of cytotoxic drugs in European hospitals. Environmental contamination with cytotoxic drugs was seen at different levels in different hospitals. The amount of contamination can be lowered by implementing standard cleaning work procedures.
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