Annals of Occupational Hygiene Advance Access originally published online on August 26, 2005
Annals of Occupational Hygiene 2005 49(7):619-628; doi:10.1093/annhyg/mei045
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© 2005 British Occupational Hygiene Society Published by Oxford University Press
Original Article |
Environmental Contamination with Cytotoxic Drugs in Healthcare Using Positive Air Pressure Isolators
1 University of Pharmacy Paris 5 René Descartes, Pharmacie Galénique, 4 avenue de l'Observatoire 75006 Paris, France; 2 CHI Saint Germain-en-Laye, Pharmacy department, 20, rue Armagis, 78105 Saint Germain-en-Laye, France; 3 Exposure Control B.V., P.O. Box 467, 6600, AL Wijchen, The Netherlands; 4 CH Pau, Pharmacy department, 4 bd Hauterive, 64000, Pau, France; 5 GERPAC (Group of Evaluation and Research for Protection in Controlled Area), ZI de saux, 6 rue Ampère, 65100 Lourdes, France
* Author to whom correspondence should be addressed. Tel: +33 (0)1 39 27 42 71; fax: +33 (0)1 39 27 44 70; e-mail: sylvie.crauste-manciet{at}univ-paris5.fr
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Occupational exposure to cytotoxic drugs of hospital personnel involved in their preparation and administration is a major issue: ever since the introduction of protective measures in recent decades, the handling of these drugs has always been referred to as an occupational health hazard. Isolator technology was one of the protective equipments aimed at providing safe handling, but it has not yet been studied regarding contamination. The present study evaluates surface contamination with four cytotoxic drugs [cyclophosphamide (CP), ifosfamide (IF), 5 fluorouracil (5FU) and methotrexate (MTX)] by wipe sampling in two hospital pharmacies. Wipe samples were taken from work surfaces both located inside and outside the isolators. In addition, working gloves, the surface of infusion bags filled with 5FU or CP, and gloves used in simulation of drug administration were analyzed. Contamination was routinely found inside the isolators but rarely outside the isolators, indicating that the isolator technology is offering good protection of the cytotoxic drug handlers as well as the environment during preparation. On the other hand, contamination was found on the surfaces of infusion bags and gloves in contact with infusion bags filled with cytotoxic drugs. Consequently, personal protective equipment is still recommended during the manipulation and administration of the drugs because of potentially contaminated drug vials and final products.
Keywords: antineoplastic drugs • cytotoxic drugs • surface contamination
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The extensive treatment of cancer with cytotoxic drugs, which are recognized to be carcinogenic and/or to have mutagenic and teratogenic effects on humans (IARC, 1997
), has been referred to as an occupational health hazard. It was demonstrated for nurses who handled cytotoxics without protective measures at the end of the 1970s (Falck et al., 1979). Ever since this discovery, worldwide attempts have been made to prevent exposure of healthcare workers. The first measure was to centralize the preparation of cytotoxic drugs in hospital pharmacies using specific guidelines and protective measures, such as using vertical laminar airflow safety hoods, wearing disposable protective gowns and double pairs of gloves. In France, in hospital pharmacies, almost 15 years ago, protective measures were focused on the use of a specific isolator technology especially developed to protect both handlers and products (Larrouturou et al., 1992; Cazin and Gosselin, 1999). The concept of isolator was developed under three main considerations: (i) The physical barrier and a permanently closed working environment which avoid direct skin contact between handlers and toxic products. (ii) The air is released through an air exhaust system outside the preparation room directly into the atmosphere, which avoids inhalation risks of the cytotoxic drugs. (iii) The sterility of the closed work area and the positive air pressure both guarantee the sterility of the injectable cytotoxic drugs prepared. In addition, several international studies were carried out to assess the exposure of healthcare workers involved in the preparation and the administration of antineoplastic agents by measuring drug airborne levels, residues in wipe samples, gloves, mask and urinary excretion (Sorsa et al., 1988; Sessink et al., 1992a,b, 1994, 1997; Ensslin et al., 1994a,b).
Environmental contamination with cytotoxic drugs has been shown in a number of recent publications. Contamination was found at measurable levels in the working areas even though drug preparation was carried out in biological safety cabinets (BSCs) (Sessink et al., 1992a,b; Connor et al., 1999; Schmaus et al., 2002; Turci et al., 2003; Wick et al., 2003). Despite the availability of methods for monitoring surface contamination in hospital pharmacies, only one French study has evaluated surface contamination with 5-Fluorouracil in workplaces using isolator technology (Favier et al., 2001).
The present study was carried out to determine the level of surface contamination with the cytotoxic drugs cyclophosphamide (CP), ifosfamide (IF), 5 fluorouracil (5FU) and methotrexate (MTX) in two hospital pharmacies using positive air pressure isolators.
The aim of this study was to evaluate the potential risk of occupational exposure for cytotoxic drug handlers using isolator technology by taking wipe samples inside and outside the isolator and collecting glove samples. In addition, wipe samples were taken from the infusion bags and gloves to investigate the potential risk for nurses.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Study sites
The study was conducted in two French hospital pharmacies (Saint Germain-en-Laye and Pau) selected for having the same isolator design. The characteristics of the centers are shown in Table 1.
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Isolator design
Isolators (Isoconcept®, A.R.F.L., Neuilly sur Marne, France) used correspond to the definition of ‘closed isolator intended for asepsis and containment’ given by the PDA technical report N 34 (Agalloco and Akers, 2001
). Totally enclosed sterile isolators (Fig. 1) are ventilated by positive air pressure (+35 Pa) and filtered without any recirculation through high efficiency particulate air (HEPA) filters. One HEPA filter is used for air admission into the isolator and one HEPA filter is used for air exhaust to the outside of the isolator. Exhausted air is vented outside the room. The soft plastic wall isolators (Fig. 1a) (5 m3) investigated in both centers have the same design including a sterile storage area, one central half suit (Fig. 1b), and two workstations fitted with two sleeves and neoprene gloves. A rigid ventilated pass-through chamber (0.3 m3) (Fig. 1c) which is permanently connected to the isolator is used for contact sterilization (peracetic acid) of products and preparation devices before introduction into the isolator. The removal of the final preparations and waste is in both cases permitted by an interlocking door (Biosafe® door, IDC, Lourdes, France) fitted to a non-reusable sterile soft plastic container (Biosafe® container, IDC) (Fig. 1d). Each preparation is removed from the main isolator inside that plastic sterile container and individually sealed (Fig. 1e), allowing no contact with the external environment. In both centers, the isolator is located in a normal room environment.
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Collection of samples
Wipe samples were taken from six locations inside the isolator and from six locations outside the isolator, according to the method of Sessink et al. (1992a
,b). Approximately, the same locations were chosen in both centers to allow comparison (Fig. 2a and b). Inside the isolators, samples were taken from the two work surfaces (left and right), the surface in front of the entrance of drugs (between pass-through chamber and half suit), surface of a transfer plate and surfaces of 5FU and CP storage boxes. Outside the isolators, samples were taken from surfaces of desks (two locations) and floor (two locations) inside the preparation rooms. The surfaces of the desks located outside the preparation rooms were also sampled. In both centers, samples were taken at the end of the working day just before the cleaning procedure.
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In addition, two sets of two vials and the whole surface of an infusion bag prepared with 5FU (Merck Générique, Lyon, France) and CP (Baxter, Maurepas, France) were wiped at each center. In both centers, gloves were collected: one entire neoprene glove (Piercan, Paris, France), a pair of vinyl gloves (POLYSEM, Rambouillet, France for Center 1 and EUROMEDIS, Neuilly sous Clermont, France for Center 2) in contact with 5FU and CP prepared infusion bags, and for Center 2 a pair of latex outer gloves (ANSELL, Cergy Pontoise, France) used for a 5FU and a CP preparation were also collected.
For the locations to be sampled, the sizes of the locations were measured and the areas were calculated (range: 625–4500 cm2 for the working surfaces and range: 900–6400 cm2 for floors). The wipe samples were taken with two tissues (
1000 cm2 per tissue) (Scott 130, Kimberly-Clark Corporation, Koblenz, FGR) using 17 ml of a 0.03 M NaOH solution. All samples were stored frozen after sampling and during transport until sample preparation and analysis.
Drug analysis
All samples were extracted as previously described (Sessink et al., 1992a,b). CP and IF were analyzed with gas chromatography in combination with tandem mass spectroscopy (GC-MSMS) (Sessink et al., 1993; Sessink, 1996). Deuterium-labelled CP was used as internal standard. 5FU and MTX were analyzed by reverse-phase high-performance liquid chromatography with ultraviolet-light detection (HPLC-UV) (Sessink et al., 1992a,b). The detection limits for CP, IF, 5FU and MTX were 0.1, 0.1, 20 and 10 ng/ml extract, respectively. Detectable amounts of CP, IF, 5FU and MTX were individually reported in nanograms per square centimeter (ng/cm2) of surface area sampled and compared descriptively by site and location. For the gloves, the total amounts of drug per pair were reported in nanograms.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Preparation
Surface contamination inside the isolators
In Center 1, chemical contamination with all four drugs investigated was found on all surfaces tested inside the isolator except for MTX on one location (Table 2). A substantial level of contamination was found on the working surfaces. The contamination ranges were for CP (0.16–6.55 ng/cm2), IF (0.03–0.85 ng/cm2), 5FU (9.73–83.76 ng/cm2) and MTX (ND–8.61 ng/cm2). The storage boxes were contaminated with the drug that was contained in them, especially with 5FU. On the other hand, the vials were not contaminated with the drugs they contained (CP and 5FU).
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In Center 2, lower levels of contamination were found inside the isolator. MTX was not detected on all locations investigated. The contamination ranges were for CP (0.07–2.53 ng/cm2), IF (ND–0.05 ng/cm2) and 5FU (ND–37.28 ng/cm2). The storage boxes and vials were not contaminated with the containing drug.
Surface contamination outside the isolators
In Center 1, no contamination was observed outside the isolator except in one location where CP was detected on the surface of a table used for entrance of the drugs (0.22 ng/cm2) (Table 3). No contamination was found in this location (same surface sampled) after usual cleaning (isopropyl alcohol) and after special cleaning using a detergent disinfectant (Anios Détergent Désinfectant Surfaces Hautes, Anios, Lille, France).
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In Center 2, only the worktop and floor in front of the isolator were found to be contaminated with CP (0.11 and 0.03 ng/cm2, respectively) and for IF only the floor (0.26 ng/cm2) showed contamination. Both locations are next to the isolator entering zone where cytotoxic vials were transferred before entering the sterilizing pass-through chamber.
Preparation gloves
The whole latex outer gloves used in Center 2 for the preparation of CP and 5FU were highly contaminated with the corresponding drug and especially with 5FU (Table 4).
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In both centers, the whole neoprene gloves were contaminated with all the drugs investigated except for MTX in Center 2. The contamination was only found on the isolator side of the gloves (external surface of the glove). The surfaces of the neoprene gloves in contact with the hand of the cytotoxic drug handler (inside surface) were not contaminated.
Administration
The outsides of the infusion bags were contaminated with the corresponding drug, both for CP and 5FU in Center 1 and only with CP in Center 2 (Table 5). Contamination of gloves in contact with infusion bags filled with 5FU or CP was only found for CP in Center 1.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The results in general show contamination with CP, IF and 5FU in both centers and with MTX in Center 1. The levels of contamination outside the isolators were far lower than the levels of contamination inside the isolators.
Levels of contamination inside the isolators are comparable with the results of the studies performed inside BSCs (Table 6) (Sessink et al., 1992a; Minoia et al., 1998; Connor et al., 1999; Turci et al., 2003). Results are also comparable with the single French study performed inside an isolator (Favier et al., 2001), where the range of contamination with 5FU was 0.11–187.8 ng/cm2. The origin of the contamination can be related to the preparation process and to external vials contamination (Delporte et al., 1999; Favier et al., 2003; Mason et al., 2003; Nygren et al., 2003; Connor et al., 2005). With regard to the preparation process, one study simulating the conventional preparation process using needles and syringes with fluorescein found multiple sources of leakage during the preparation process (Spivey and Connor, 2003). Leakages can result from several activities: withdrawing needles from vials and from the port of an intravenous infusion bag resulted in drape and glove contamination. Withdrawing the needle from an overpressurized vial was found to produce the largest spots. In our study, the use of air vent needles to equilibrate pressure was recognized to minimize the leakage and aerosolization risks while withdrawing drugs from vials (Christienson and Jansson, 1983). Despite the use of air vent needles, spillage may occur during transfer operations (removal of liquid from vials or injection into infusion bags). Moreover, air vent needles are unable to prevent leakage of gaseous substances, i.e. CP which was found to vaporize and pass through HEPA filters (Kiffmeyer et al., 2002) and for other cytotoxics which are also recognized to be able to vaporize (Connor et al., 2000). Then, gaseous substances may condensate on surface areas and thereby contribute to surface contamination. The very high contamination of outer gloves found in Center 2 and whole neoprene glove contamination confirm that the preparation process contributes to the spread of contamination inside the isolator. Studies performed with a closed system (Phaseal®) have shown its benefit for decreasing chemical contamination in the workplace (Sessink et al., 1999; Vandenbroucke and Robays, 2001; Connor et al., 2002; Spivey and Connor, 2003; Wick et al., 2003). Nevertheless, contamination was not totally removed. Wick et al. (2003) still found positive samples of CP and IF after implementation of Phaseal®. Vandenbroucke and Robays (2001) showed that contamination decreased by using the Phaseal® device, but positive points still existed, including all locations outside the BSCs. Connor et al. (2002), concluded that closed-system devices reduce contamination but have to be combined with other safe handling practices.
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Regarding the results outside the isolator, it is expected that isolators will effectively protect cytotoxic drug handlers from contact with the contaminated inside of the isolator and exposure to the drugs will not occur. The few positive points outside the isolator could be due to the external contamination of vials (Delporte et al., 1999
; Favier et al., 2003; Mason et al., 2003; Nygren et al., 2003). In this study, vials were not found to be contaminated, but the number of samples (two vials per center) was probably insufficient to conclude that there was no vial contamination. Delporte et al. (1999) found only 3 contaminated vials among the 90 sampled. Moreover, the contamination hypothesis can be relevant regarding surface contamination found in storage boxes. Surface contamination can be related to the location of the drug vials. Mason et al. (2003) found contamination of the floor area directly in front of the shelves used for storing cytotoxic drugs. Schmaus et al. (2002) also found contamination of the storage shelves (CP, 5.106 ng/cm2; IF, 1.86 ng/cm2; 5FU, 1.378 ng/cm2) in 14 hospital pharmacies. In this study, two positive points were found only where cytotoxic vials were transferred before entering the sterilizing pass-through chamber. These included the worktop, where cytotoxic drugs are placed before entering the sterilizing pass-through chamber and the floor directly in front of the pass-through chamber of the isolator. Favier et al. (2001) found low levels of 5FU contamination on the surrounding area of isolators for the floor (ND–0.625 ng/cm2) and the area where the vial packaging was removed (ND–0.352). A recent investigation confirms the external vial contamination, especially with CP (Connor et al., 2005) and showed the importance of specific methods for decreasing contamination during the manufacturing process. In addition to the vials themselves, the removal of the vial cap cover can contribute to the spreading of contamination. Nygren et al. (2003) found substantial contamination of the vial cap covers of cisplatin. It can be related to the floor positive point found in Center 2 which is located around the waste bin where the vial cap covers are placed (sometimes not in the bin but next to the bin on the floor). The very few positive points found in the environment (Table 7) compared with studies published in BSC rooms (Minoia et al., 1998; Connor et al., 1999; Micoli et al., 2001; Vandenbroucke and Robays, 2001; Schmaus et al., 2002; Wick et al., 2003) confirm that permanently enclosed isolators may guarantee the protection of the healthcare workers who are handling cytotoxic drugs. Rajan-Sithamparanadarajah et al. (2004) identified different tasks that resulted in dermal exposure (Riskoderm program) which showed that the mixing/diluting task produced exposure of the legs that was seven times higher than the rest of body and exposure of the hands was sixty times higher. Because of the use of a barrier isolator, the body is not exposed to contamination, but hands could be the major relevant route for contamination if permeation of cytotoxic drugs through the gloves occurred.
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No contamination was found on the part of the neoprene gloves that is in contact with the hands of the cytotoxic drug handlers. This is in opposition to published data where the inner part of gloves was found contaminated with cytotoxic drugs (Table 8). Simulated models which assessed surgical and examination glove permeation to antineoplastic drugs found low levels or no permeation over short periods (1–3 h). When low permeation occurred, permeation has been related to glove thickness (Slevin et al., 1984
), to time of exposure (Stoikes et al., 1987), to drug (Slevin et al., 1984; Stoikes et al., 1987; Connor, 1999; Klein et al., 2003) and to glove composition (Stoikes et al., 1987; Connor, 1999; Klein et al., 2003). Neoprene isolator gloves have not previously been assessed for simulated permeation tests. Regarding the above parameters, Connor (1999) found permeation with surgical neoprene gloves for paclitaxel at 120 min and Klein et al. (2003), found low levels of carmustine permeation through neoprene gloves. In both studies, the thickness of neoprene gloves assessed (0.13–0.15 mm) and (0.19–0.20 mm), respectively were less than neoprene isolator gloves (0.4 and 0.5 mm, current study). Regarding thickness, isolator neoprene gloves should provide good protection, but the extended use (several days to one month), risk of permeation cannot be discarded. Nevertheless, in our study, in real conditions of use, isolator neoprene gloves used for 15 days were not contaminated on the inner side. This suggests that the good maintenance of the neoprene gloves with regular changes (twice a month, current study) avoids skin contamination during the preparation of the drugs.
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In addition, hand washing procedures when handling cytotoxic drugs must be applied (National Institute for Occupational Safety and Health, 2004
).
With regard to the administration results, we found that surfaces of infusion bags filled with CP or 5FU and gloves in contact with infusion bags can be contaminated with the corresponding drug. Because of the contamination inside the isolator, contamination is probably transferred to the prepared infusion bags. Nevertheless, the prepared infusion bags are transported in a sealed container to the administration areas in the hospital. Moreover, no contamination of the container (Biosafe® container) was found. Therefore, contamination should not happen during transportation because the infusion bags are protected with the container which acts as an outer wrap. However, a potential risk occurs after the sealed container is opened to administer the drug. Hands are recognized to be the major route of contamination (Fransman et al., 2004). Previous studies using simulating models of glove permeation by cytotoxic drugs found low glove permeation (Singleton and Connor, 1999; Klein et al., 2003) over a period of 2 or 3 h. Taking into account the very short period of exposure during administration, gloves should be able to protect nurses from cytotoxic drug exposure.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Results indicate that the configuration of isolators provides protection of the cytotoxic drug handlers who work in the pharmacy. An advantage of isolator technology is to create a small, confined environment, and then only the breakage of the airtight seal may compromise the safety of the healthcare workers. A critical point for drug handlers is the containment of the potential outside contamination of the vials with the drugs before entering the isolator. The use of personal protective equipment during manipulation of vials and surface protection with non-reusable drapes must be applied. Moreover, good preventive maintenance of the isolator must be done regularly to prevent any potential leakage, including neoprene glove changes.
Development of specific decontamination procedures of the drug vials during the manufacturing process should be extended to the whole pharmaceutical companies. Due to the high level of contamination inside the isolator, which can be contained during transportation to the ward, contamination can be transferred to the administration area. Modifying the preparation process using close transfer systems might contribute to a decrease in the level of contamination inside the isolator.
Received April 20, 2005; in final form July 9, 2005
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Section 1 Introduction Journal of Oncology Pharmacy Practice, September 1, 2007; 13(3_suppl): 3 - 6. [PDF]
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 T. H. Connor and M. A. McDiarmid Preventing Occupational Exposures to Antineoplastic Drugs in Health Care Settings CA Cancer J Clin, November 1, 2006; 56(6): 354 - 365. [Abstract] [Full Text] [PDF]
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