Annals of Occupational Hygiene Advance Access originally published online on June 17, 2005
Annals of Occupational Hygiene 2005 49(7):603-610; doi:10.1093/annhyg/mei023
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Original Article |
Exposure to Antineoplastic Drugs in Two UK Hospital Pharmacy Units
1 Health and Safety Laboratory, Buxton UK; 2 Fife Primary Care NHS Trust, formerly Occupational Health Department, Addenbrooke's Hospital, Cambridge, UK; 3 Occupational Health Department, Addenbrooke's Hospital, Cambridge, UK; 4 Baxter Healthcare Ltd, Compton, Berks, UK
* Author to whom correspondence should be addressed. Tel: +44 1298 218 413; fax: +44 1298 218 172; e-mail: howard.mason{at}hsl.gov.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study objectives: To carry out an environmental and biological monitoring study in two UK hospital pharmacy units involved in the preparation of antineoplastic drugs.
Participants and methods: The two units studied used isolators for drug preparation. One used isolators operating at positive pressure relative to external atmospheric pressure, whereas the other used negative pressure isolators. Monitoring utilized the measurements of methotrexate, ifosfamide, cyclophosphamide and platinum reflecting the platino-coordinated drugs, such as cisplatin and carboplatin. Personal and static atmospheric and floor wipe samples were collected together with preshift and post-shift urine samples over a 4-day consecutive monitoring period. During the study period both units operated to their normal procedures.
Results: Measurable amounts of cytotoxic drugs were detected on the floors of both units and on the disposable gloves worn by staff preparing the drugs. There was also evidence in both units of some very low-level drug absorption from urine measurements, using the most sensitive analytical technique of platinum analysis. The absorption of platinum containing drugs in the unit using negative-pressure isolators was significantly higher, even though less platinum containing drug was prepared per day. Urine measurements in both units were below the detection limit for the other measured drugs.
Although the unit using positive-pressure isolators handled daily approximately five times the drug quantities handled with the negative pressure unit, the general levels of external contamination and urine measurements did not reflect this difference. Comparison of the relative levels of glove and floor contamination between the two units was not clear-cut and appeared to depend on the specific cytotoxic drug being monitored.
Conclusions: The levels of external contamination on the floor and gloves, and absorbed dose from urine measurements found in this study showed considerable improvement over many earlier, non-UK studies using comparable exposure measurements. These earlier studies were in facilities using laminar flow/microbiological safety cabinets and where staff were likely to be involved in both drug preparation and administration. Our data did not suggest that the differential pressure of the isolator to the pharmacy atmosphere was an overarching factor in the risk of operator exposure under normal operation. There remains a need to investigate the sources of the low-level drug contamination found in the pharmacies even when using isolators to prepare cytotoxic drugs. This study, and related studies of hospital oncology ward staff, appear to be the only recent UK studies of occupational cytotoxic drug exposure using environmental and biological monitoring techniques.
Keywords: biological monitoring • cytotoxic drugs • environmental monitoring
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The last 10–15 years have seen changes in the way the cytotoxic drugs are prepared in UK hospitals. These include the separation of any drug reconstitution or preparation activity from administration of the prepared drug to the patient. Best practice is that the former is a pharmacy-based activity, leading to a formulated product that needs an absolute minimum amount of manipulation on the ward. There has also been a move towards establishing purpose designed units for cytotoxic drug preparation within the overall pharmacy structure and using isolators rather than laminar flow cabinets or other containment devices to manipulate the drugs. A recent unpublished survey of UK pharmacies undertaken by us suggests that 86% use only isolators for cytotoxic drug preparation.
Although there is a considerable UK routine testing data for product sterility and patient protection reasons, there appears to be little monitoring data on potential cytotoxic exposure to staff. A number of published occupational hygiene and biological monitoring studies have attempted to document the level of occupational cytotoxic drug exposure in pharmacies. A recent extensive analytical review (Turci et al., 2003
) also details these surveys in pharmacies. A variety of exposure-control measures and operating procedures were in place in these international studies; none was a UK study.
There has been UK debate about the use of positively or negatively pressurized isolators in the preparation of cytotoxic drugs. In current practice, it seems that most pharmacy units undertaking this type of work use negatively pressurized systems.
Given the lack of any current UK data on occupational cytotoxic drug exposure, it was decided to carry out a small study of pharmacy units where good working practices were in place, but where differently pressurized isolator systems were being used. The study attempted to describe possible exposure under real-life operation and was designed such that the data could be compared with some of the earlier published studies.
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STUDY DESIGN |
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TOPABSTRACTINTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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A small number of pharmacy units preparing cytotoxic drugs were selected by an experienced occupational hygienist. Criteria were that the units were relatively new purpose-designed facilities, and that there was documentary evidence of implementation of the UK regulations on the Control of Substances Hazardous to Health (COSHH 1998) with good working practices (Goodman 1998
; Allwood et al., 2002). Only a few units were known to be using positively pressurized isolators. Two units agreed to participate; the other using negatively-pressurized isolators and the other using several positively-pressurized isolators. The amount of cytotoxic drugs formulated by the positive pressure unit was considerably more than the other unit and was supplying the specialist cancer hospital in which it was located and other cytotoxic-using medical facilities in the area. The negatively pressurized isolator unit serviced a large, district teaching hospital.
The panel of marker cytotoxic drugs monitored consisted of cyclophosphamide (CP), methotrexate (MTX), and both cisplatin (cis-Pt) and carboplatin (Carb-Pt) monitored by measurement of platinum (Pt). Later, ifosfamide (Ifos) was added to the panel of marker drugs. The defined toxicokinetics of excretion of these parent drugs and Pt also allows the same measurements for biological monitoring using urine samples (Seideman et al., 1993; Ota et al., 1994; Schierl et al., 1995; Chladek et al., 1998), as well as in investigating air levels or surface contamination.
Each unit was studied longitudinally over four working days. A combination of environmental and biological monitoring was employed; daily static atmospheric sampling and surface contamination monitoring using floor wipes were undertaken. A number of disposable gloves worn by staff were also collected rather than being discarded. Staff using the isolators to prepare formulations gave daily preshift and post-shift urine samples and underwent personal atmospheric sampling. All samples were measured for the marker drugs. Where possible, the daily amounts of the marker drugs prepared during the study period were noted. An HSL scientist was present during the study to observe unit operations. The study was approved by the HSE Ethics Research Committee and all participants gave informed consent.
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DESCRIPTION OF PHARMACIES |
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TOPABSTRACTINTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The unit using positive pressure isolators (PPIU) was operated by a large multinational health care firm. On-site management of the unit was overseen by the parent firm taking specific responsibilities for production and quality management, health and safety, environmental systems and occupational health provision. All isolators in use were of the flexible skin type. Three single operator isolators (La Calhene, model 514503; +40 Pa with turbulent air flow), housed in a European class D clean-room environment, were available for drug reconstitution, two other isolators were used for sterilizing or compounding with one half-suit isolator for storage of sterilized product. A product transfer system between isolators maintained product sterility. Daily floor cleaning used a chlorine-based bleaching agent (<5%) containing 5–15% anionic surfactant.
Work-flow was as follows. Drugs, fluids, devices and other items were delivered from stores, then placed in an isolator for sterilizing with peracetic acid and subsequently to a storage isolator. Items were then taken for compounding against individual prescriptions. Once complete, the formulated drugs were passed out of the isolator through a heat-sealing, high-grade polythene sleeving system to maintain sterility. Formulated drugs then underwent labelling and inspection in the same room as the isolators, and finally signed-off against the prescription. Products were individually heat-sealed in polythene for protection and despatched in specialized containers. Waste from within the isolator was double-polythene wrapped using the sleeving system and the outer bag heat-sealed on removal. This waste was kept in lidded containers until removed on a daily basis.
Approximately six staff were directly involved in drug compounding. Staff rotated between drug preparation, checking and other administrative tasks. Fully-fastening lab coats were worn at all times and disposable latex gloves worn during sterilizing, compounding using the isolator gauntlets, labelling and checking. Overshoes were not worn. All staff undergo prior training, covering the use of standard operating procedures, cytotoxic awareness, handling and compounding techniques, and use of isolators. Staff are re-assessed annually. All staff are under health surveillance.
Isolator leak testing was performed every two weeks by over-pressurizing and searching for escaping detector gas. The gloves and sleeves attached to the isolators were visually inspected and washed daily, and changed every two weeks or when a hole was detected. Daily cleaning of the inside of the preparation isolators used sterile water and every two weeks they were cleaned with mild detergent prior to a sterilization cycle using peracetic acid. Isolator pressure was monitored to +40 Pa on a daily basis. Isolators exhaust externally through an HEPA exhaust filter.
The second, smaller pharmacy unit, using negatively pressurized isolators (NPIU), was a self-contained unit located next to the oncology outpatients and day-treatment centre. Two adult wards and a pediatric oncology ward were also serviced by the unit. A single rigid isolator with four glove ports was used within an 
40 m2, European class D clean room; most of the input air was taken by the isolator with a small amount as overspill. A Bassaire model BC141 isolator operated at –215 Pa, exhausting externally via an HEPA filter. A transfer box with dual doors on the isolator was used to transfer drugs. The clean room had two hatches through which primary and prepared drugs were passed to the adjoining office. Staff entering the clean room put on a clean full body suit, overshoes and caps. Disposable vinyl gloves were worn at all times that drugs may be handled, including while preparing drugs using the isolator gauntlets. Personal protective equipment was discarded on leaving the clean room; lab coats were worn within the office. The clean-room floor was cleaned three times a week with a proprietary product containing quartenary ammonium compounds and amphoteric surfactant. Contaminated waste material was removed hourly from the isolator and stored within receptacles in the clean room before being removed daily for incineration.
Work-flow was as follows. On receipt of a prescription the unit assembled on a tray the necessary drugs and disposables from pharmacy stores. These were sterilized by an IMS or 70% ethanolic spray as passed through the hatch into the clean room, and then into the isolator via the transfer box for compounding. The prepared products were labelled and heat-sealed in polythene in the clean-room and then passed through the out-hatch into the office area for final checking. Dispatch of the prepared prescriptions were by designated pharmacy or ward staff in clearly labelled containers.
The isolator was cleaned with 70% ethanol at the beginning of any compounding session and at regular intervals during use. The gauntlets attached to the sleeves of the isolator glove-ports were changed daily or as required. The unit had a manager and three or four qualified pharmacy technicians who undertook drug preparation regularly and had been trained on aseptic techniques. Unit staff were under health surveillance by the hospital's occupational health department and did not involve any biological monitoring.
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SAMPLING STRATEGY |
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TOPABSTRACTINTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Over the 4-day monitoring period, the staff using isolators to compound drugs were requested to give preshift and post-shift urine samples and undergo personal atmospheric monitoring on each day. The potential for contamination of the urine samples collected was minimized by discarding any protective clothes worn in the pharmacy and by hand washing prior to urine collection. Full-shift, personal atmospheric monitoring undertaken for these staff used GFA filters in IOM heads, pumped at 2 l min–1. Not all of the sampling times were attributable to actual time spent working at a preparation isolator. A daily background air sample was taken over the working day using a static sampler, pumping at 15 l min–1 through a GFA filter. Calibration of pumps was performed prior to, and rechecked after the completion of the study.
Surface wipe tests of two standardized floor areas in the drug preparation room were carried out daily. Areas of 0.5 m2 were cleaned thoroughly with a set of folded wipes (Kimberley Clark) wetted with 10 ml of 30 mM sodium hydroxide. Blank wipes had been tested at HSL. The standardized sampling sites were one located directly under the glove ports of preparation isolator(s) and a second one 1 m to the side of the isolator. A number of disposable latex gloves were collected on an ad hoc basis from technicians who had been working on the isolators, they were collected at the time that technicians were going to change or remove their disposable gloves.
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ANALYTICAL METHODS |
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TOPABSTRACTINTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Static atmospheric filters, floor-wipes and gloves were extracted for analysis by addition of 20 ml of ultrapure water and mixed continuously for at least 2 h; personal atmospheric filters were extracted in 5 ml of water. Preliminary experiments had investigated the efficiency of drug extraction from spiked GFA filters, being
100% for CP/Ifos, 96% for Carb-Pt/cis-Pt and 70–75% for MTX. Extraction efficiencies for wipes and gloves have already been reported (Ziegler et al., 2002).
CP and Ifos were measured by the same analytical procedure using GC–MS in electrochemical ionization mode (Evelo et al., 1986; Sessink et al., 1993; Ziegler et al., 2002). In brief, after extraction of urine, aqueous filter and wipe extracts using ether liquid–liquid extraction, drug is derivitized using trifluoroacetic anhydride. The analytical detection limits were 1 nM in urine, 10 ng m–2 on surface wipes, 5 ng per glove and 0.8–1.0 ng m–3 for air samples.
Pt was measured by inductively coupled plasma mass spectrometry (ICP-MS). For urine measurements electrothermal vaporization coupled to ICP-MS was used for increased sensitivity (Schramel et al., 1995). This method cannot distinguish between Pt as platino-coordinated drug and its elemental form. Both 194Pt and 195Pt isotopes were monitored. The limit of detection for Pt in this study was 22 pM for urine, 0.2 ng m–2 on surface wipes, 0.1 ng per glove and 0.01–0.02 ng m–3 for static and personal air samples. We participate and perform satisfactorily in an international quality assurance scheme for urine platinum at occupational and environmental levels.
MTX was measured by an in-house enzyme-linked immunosorbent assay. Owing to potential cross-reaction of the MTX antibody in the different sampling media, limits of quantitation for MTX were derived for the specific types of sample analysed. For urine the lower limit of quantitation for MTX was set at 10 nM after measurement in 40 unexposed control subjects, for surface wipes, gloves and air filters, the detection limits were 10 ng m–2 5 ng per glove and 0.5–1 ng m–3, respectively.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Table 1 shows the amount of the marker cytotoxic drugs which each unit formulated during the study period. The atmospheric and surface contamination results from the two sets of sampling are shown in Table 2. There were no spills or incidents over the study period which led to deviation from standard operating conditions. One subject from the NPIU failed to provide urine samples on the first day of the study. One floor wipe sample was missed at the PPIU on the last day of sampling.
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All urinary CP, Ifos and MTX results were less than the detection limits of the assays. However, the urinary creatinine-corrected, post-shift Pt results from both units were significantly higher (P < 0.01, Mann–Whitney test) than unexposed, office-based hospital workers (control group) who included those living in both urban and non-urban environments (Fig. 1). The median post-shift urine Pt found in the PPIU and NPIU units were 8.2 nmol mol–1 creatinine (range = 6–32.1) and 23.2 nmol mol–1 creatinine (range = 6–82.4), respectively, whereas the control group gave a median value of 1.3 nmol/mol creatinine (range = ND–14.5). Comparison between preshift and post-shift samples in individuals in both NPIU and PPIU suggested that post-shift urine levels were significantly high (P = 0.006, Wilcoxon test) and that urine levels in the NPIU were significantly higher than the PPIU (P = 0.003, Mann–Whitney test).
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However, this significant difference in urine Pt levels between pharmacies was not reflected in the levels measured in personal atmospheric samples (Mann–Whitney test, P = 0.25) or static atmospheric levels (Mann–Whitney test, P = 0.49). Interestingly, it was reflected in the differing levels of floor Pt contamination (medians 5 ng in PPIU, versus 90 ng in NPIU, Mann–Whitney test, P = 0.0003) and glove contamination (means 5 ng in PPIU, versus 31 ng in NPIU, Mann–Whitney test, P = 0.0022). These data may suggest that any low-level Pt absorption may be by dermal exposure.
The general level of glove contamination by MTX and Pt-containing drugs seemed to run counter to the relative quantities of drugs handled by the pharmacies, but for CP and Ifos the level of glove contamination was similar between pharmacies (Table 2). Interestingly, the floor contamination for MTX and Pt was also higher in the NPIU, whereas floor contamination with CP and Ifos paralleled the relative amounts handled by the units.
We estimated the percentage of drug formulated per day which is found on the units' floor area, assuming a simple homogeneous distribution over the surface area. Percentages of marker drug formulated each day, found on the units' floor, were between 2 x 10–5% and 1.3 x 10–3% (mean = 2.8 x 10–4%). The highest value was for MTX in the NPIU and may be reflecting an occurrence on one day when one personal atmospheric sample (215 ng m–3) and floor swab (674 ng m–2) under the glove ports of the isolator suggested some abnormal MTX leakage. Personal atmospheric samples were mostly non-detected for any of the marker drugs (74% in NPIU and 81% in PPIU).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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This study, although of only two pharmacy units, appears to be the only recent UK investigation that has attempted to quantify the probable exposure and uptake of cytotoxic drugs in pharmacy staff undertaking reconstitution, while describing the workpractices and control measures in place. It also allows some comparison with earlier published, non-UK studies. Although a large number of different antineoplastic drugs are formulated in hospital pharmacies, we have chosen a small number of marker drugs to investigate in this and other studies. These were chosen for a number of reasons; they are formulated in relatively large amounts, the toxicokinetics of urinary excretion are relatively well established and interpretable in terms of dose. Finally, several of the marker drugs have been applied in earlier studies and therefore, allow comparison of the influence of changes in exposure control measures.
Importantly, this study suggests that workers in both units continue to be exposed to cytotoxic drugs at very low levels, despite the use of isolators rather than vertical laminar flow units and biological safety cabinets. Urinary Pt, which is the most analytically sensitive measure of absorbed cytotoxic drug, suggests some very low level absorption of drug, but below the detection limit for the other drugs. We calculate that the increase in median urine Pt in both pharmacy units over unexposed populations could suggest the equivalent uptake of 0.1–0.3 µg of Carbo-pt or cis-pt in the previous 24 h (Gorodetsky et al., 1993; Ota et al., 1994). Low levels of Pt in urine have been proven to be related to dental gold restorative work (Schierl, 2001); the upper limit for urine Pt found in our control group is comparable with the upper level presented by Schierl for individuals with dental gold alloys. Thus, although we did not collect data on the prevalence of dental gold restorative in controls or pharmacy staff, we feel that it does not explain the increased urine Pt in the pharmacy staff.
In comparison, the urinary detection limits for CP and MTX could equate to an internal dose of 5 and 10 µg, respectively, in the previous 24 h (Sessink et al., 1991; Ensslin et al., 1994). Although these are extrapolations from pharmacokinetic studies involving clinical doses, we consider that the urine biological monitoring measurements would largely reflect recent exposure over the previous 8–24 h (Colvin and Hilton 1981; Sessink et al., 1991; Gorodetsky et al., 1993; Seideman et al., 1993; Ota et al., 1994; Chladek et al., 1998).
Pt-containing cytotoxics appeared to be the only detectable absorbed drug in both the PPIU and NPIU, but with negligible measurable Pt levels in personal or static air samples. Thus low-level Pt absorption may not be occurring via inhalation. However, some caution concerning the airborne cytotoxic levels in this and other published studies using air filter samples needs to be applied. Kiffmeyer (Kiffmeyer et al., 2002) suggested significant vapor pressure for several cytotoxic drugs, including CP, leading to air levels of such drugs volatilized from contaminated surfaces and not detectable using air filter samples. However, it has also been suggested that any vaporized CP is subsequently efficiently attached to surfaces (Hedmer et al., 2004). The significantly higher urinary Pt, floor-wipe and glove contamination found in the smaller unit using the negative pressure isolators suggests that these workers are at increased risk of dermal exposure over their colleagues in the PPIU. There is evidence that the outer surfaces of unopened drug vials as delivered by the manufacturer may not be completely free from contamination (Nygren et al., 2002; Mason et al., 2003). This may indicate that differences in workpractices between the units may be important. The PPIU pharmacy used a relatively sophisticated transfer and sterilization system for the primary product prior to formulation. Staff were less directly in contact with the surface of drug containing vials and the disposable gloves worn by staff remained dry. In comparison, the NPIU pharmacy used a sanitization technique spraying 70% IMS onto the vials and products while holding them in a gloved hand. In this way, cytotoxic drug exposure and external contamination could conceivably occur through IMS removal of drug from the vial surface onto the glove, but also owing to a possible reduction in drug breakthrough times because of the effect of the solvent-based spray on the glove material. The same gloved hands may also be placed inside the gauntlets of the isolator to perform drug reconstitution. Hands would thereby be inside latex gloves, potentially contaminated with solvent and cytotoxics for an extended period.
Much of the earlier published work using environmental and/or biological monitoring and documented by Turci (Turci et al., 2003) suggest higher level of external contamination and more risk of absorption of the drugs by staff than is indicated in our study. For example in Minoia's study (Minoia et al., 1998) floor contamination levels were orders of magnitude higher than the floor contamination found in our study and internal surfaces of disposable gloves were substantially more contaminated than we found on the total surfaces of gloves. Above all, these studies suggest comparable or lower amount of drugs being handled compared with our study. McDevitt (McDevitt et al., 1993) concluded the need to reduce surface contamination as an exposure route for staff and recently Fransman (Fransman et al., 2004) showed that dermal exposure to CP is common in Dutch hospital personnel. Recent data from pharmacies employing laminar flow cabinets (Pethran et al., 2003) has shown measurable urinary levels of cytotoxic drugs, including CP in 7–40% of samples.
There are two clear differences between these earlier published data and the units we studied. First, in the earlier studies laminar flow cabinets rather than isolators were in use, and second, in some of the earlier studies the preparation and formulation of the drugs and their administration to the patients were often carried out by the same personnel or that both tasks tended to be co-located. The current good practice in UK is to use isolators, which exhaust externally, for the preparation and to perform all drug manipulation and formulation in specialized pharmacy units by staff whose training and activity focuses on both aseptic technique and handling of hazardous drugs. Therefore on ward or outpatient facilities an absolute minimum level of drug manipulation is done, excepting for putting up lines, drips etc. (Ziegler et al., 2002). These conclusions are substantiated by a relatively recent study (Turci et al., 2002) which indicated measurable CP and Pt above our reported data, on a number of occasions in hospital staff using laminar flow cabinets and involved in both preparation and administration. We note that recent US guidance (NIOSH, 2004) also stresses many of the workpractices and control measures found in the two pharmacies in this study, including the use of isolators rather than laminar flow cabinets.
The prognostic health significance of any measured low levels of cytotoxic drugs in pharmacy staff is not clear, but health risk calculations from biological measurements (Sessink et al., 1995; Sorsa and Anderson, 1996) suggest that the continuing uptake of CP commensurate with our current urine detection limit may represent an additional annual cancer risk of between 3 and 20 per million for this drug alone. There are a few recent epidemiological studies of the health risk from occupational cytotoxic drug exposure. These studies suggest a significant risk of leukemia with no increased reproductive effects (Skov et al., 1992), an increase of non-melanoma skin cancer and non-Hodgkin's lymphoma (Hansen and Olsen, 1994) and significant reproductive effects (Valanis et al., 1999). However, the time frame of the dataset in the Valanis study appears to be at least 14 years old and notes a frequency of direct drug–skin contact that seems wholly inappropriate with the protective measures currently used in UK. By their very nature, these non-UK epidemiological studies reflect health outcomes from historical and ill-defined exposures when protective measures and workpractices were significantly different to current UK practices. However, given that some cytotoxic drugs, such as CP, may be carcinogens themselves and potential exposure is to a cocktail of drugs, control measures should be applied to keep exposure down to as low a level as practicable. Therefore, biological or environmental monitoring of cytotoxic drugs may be used as a means of ensuring that risk is controlled by reducing exposure to as low as reasonably practical rather than attempting to interpret on a health risk basis.
This report has applied some of the tools that could be used routinely to monitor exposure in hospital staff potentially exposed to cytotoxic drugs, quantify improvements made through changes in workpractices or control measures, and also to identify major sources of exposure. Surface wipe testing and biological monitoring of a panel of cytotoxic drugs, including the platino-coordinated and cyclophosphamide, may be useful. This study was carried out in only two pharmacy units, albeit with facilities and working practices deemed to be good. A wider study of UK pharmacies may help further identify best practice or identify the need for improvements in exposure control.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Our thanks to all the staff at Baxter Healthcare Cytotoxic Unit, Christie Hospital, Manchester and the cytotoxic unit within the pharmacy department of Addenbrooke's Hospital, Cambridge. The valuable contributions and suggestions of many staff at HSL, HSE (Dr M. Stear and C. Davy), Baxter Healthcare (Dr A. Mason) and Addenbrooke's Hospital (I. Wray) are also gratefully acknowledged.
Received December 5, 2004; in final form March 27, 2005
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSTUDY DESIGNDESCRIPTION OF PHARMACIESSAMPLING STRATEGYANALYTICAL METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Allwood M, Stanley A, Wright P. (2002) The Cytotoxics Handbook. Abingdon, Oxon: Radcliffe Medical Press Ltd.
Chladek J, Martinkova J, Simkova M et al. (1998) Pharmacokinetics of low doses of methotrexate in patients with psoriasis over the early period of treatment. Eur J Clin Pharmacol; 53: 437–4.[CrossRef][Web of Science][Medline]
Colvin M, Hilton J. (1981) Pharmacology of cyclophosphamide and metabolites. Cancer Treat Rep; 65: 89–95.
Ensslin A, Stoll Y, Pethran A et al. (1994) Biological monitoring of cyclophosphamide and ifosfamide in urine of hospital personnel occupationally exposed to cytostatic drugs. Occup Environ Med; 51: 229–33.
Evelo C, Bos R, Peters J et al. (1986) Urinary cyclophosphamide assay as a method for biological monitoring of occupational exposure to cyclophosphamide. Int Arch Occup Environ Health; 58: 151–5.[CrossRef][Web of Science][Medline]
Fransman W, Vermeulen R, Kromhout H. (2004) Occupational dermal exposure to cyclophosphamide in Dutch hospitals: a pilot study. Ann Occup Hyg; 48: 237–44.
Goodman I. (1998) Clinical practice guidelines: the administration of cytotoxic chemotherapy. Technical report. Oxford: Royal College of Nursing.
Gorodetsky R., Mou X, Vexler A et al. (1993) Non-invasive follow-up of platinum pharmacokinetics in the skin of patients on cisplatin chemotherapy. Cancer; 72: 446–54.[CrossRef][Medline]
Hansen J, Olsen J. (1994) Cancer mordidity among Danish female pharmacy technicians. Scand J Work Environ Health; 20: 22–6.[Web of Science][Medline]
Hedmer M, Johnsson B, Nygren O. (2004) Development and validation of methods for environmental monitoring of cyclophosphamide in workplaces. J Environ Monit; 6: 979–84.[CrossRef][Web of Science][Medline]
Kiffmeyer T, Kube C, Opioka S et al. (2002) Vapour pressures, evaporation behaviour and airborne concentrations of hazardous drugs: implications for occupational safety. The Pharmaceutical Journal; 26: 331–7.
Mason H, Morton J, Garfitt S et al. (2003) Cytotoxic drug contamination on the outside of vials delivered to a hospital pharmacy. Ann Occup Hyg; 47: 681–5.
McDevitt J, Lees P, McDiarmid M. (1993) Exposure of hospital pharmacists and nurses to antineoplastic drugs. J Occup Med; 36: 57–60.
Minoia C, Turci R, Sottani C et al. (1998) Application of hplc-tandem MS in the environmental and biological monitoring of health care personnel occupationally exposed to cyclophosphamide and ifosfamide. Rapid Commun Mass Spectrom; 12: 1485–93.[CrossRef][Web of Science][Medline]
NIOSH. (2004) Preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings. NIOSH Alert. Cincinnati, OH: NIOSH. pp. 1–61.
Nygren O, Gustavsson B, Strom L et al. (2002) Cisplatin contamination observed on the outside of drug vials. Ann Occup Hyg; 46: 555–7.
Ota K, Oguma T, Shimamura K. (1994) Pharmacokinetics of platinum in cancer patients following intravenous infusion of cis diammine(glycolato)platinum 254-S. Anticancer Res; 14: 1383–8.[Medline]
Pethran A, Schierl R, Hauff K et al. (2003) Uptake of antineoplastic agents in pharmacy and hospital personnel. Part 1: monitoring of urinary concentrations. Int Arch Occup Environ Health; 76: 5–10.[Web of Science][Medline]
Schierl, R. (2001) Urinary platinum levels associated with dental gold alloys. Arch Environ Health; 56: 283–6.[Medline]
Schierl R, Rohrer B, Hohnloser J. (1995) Long-term platinum excretion in patients treated with cisplatin. Cancer Chemother Pharmacol; 36: 75–8.[Medline]
Schramel P, Wendler I, Lustig S. (1995) Capability of ICP-MS-ETV for Pt analysis in different matrices at ecologically relevent concentrations. Fresenius J Anal Chem; 353: 115–18.[CrossRef]
Seideman P, Beck O, Eksborg S et al. (1993) The pharmacokinetics of methotrexate and its 7 hydroxy metabolite in patients with rheumatoid arthritis. Br J Clin Pharmacol; 35: 409–12.[Medline]
Sessink P, Anzion R, van der Broek P et al. (1991) Urinary cyclophosphamide excretion in rats after intratracheal, dermal, oral and intravenous administration of cyclophosphamide. J Appl Toxicol; 11: 125–8.[Web of Science][Medline]
Sessink P, Scholtes M, Anzion R et al. (1993) Determination of cyclophosphamide in urine by gas-chromatography. J Chromatogr; 616: 333–7.[Web of Science][Medline]
Sessink P, Kroese E, van Kranen H. (1995) Cancer risk assessment for health care workers occupationally exposed to cyclophosphamide. Int Arch Occup Environ Health; 67: 317–23.[CrossRef][Web of Science][Medline]
Skov T, Marrup B, Olsen J et al. (1992) Leukemia and reproductive outcome among nurses handling anti-neoplastic drugs. Br J Ind Med; 44: 855–61.
Sorsa M, Anderson D. (1996) Monitoring of occupational exposure to cytostatic anticancer agents. Mutat Res; 355: 253–61.[Web of Science][Medline]
Turci R, Sottani C, Ronchi A et al. (2002) Biological monitoring of hospital personnel occupationally exposed to antineoplastic agents. Toxicology Lett; 134: 57–64.[CrossRef][Web of Science][Medline]
Turci R, Sottani C, Spagnoli G et al. (2003) Biological and environmental monitoring of hospital personnel exposed to antineoplastic agents: a review of analytical methods. J Chromatogr B; 78: 169–209.
Valanis B, Vollmer W, Steele P. (1999) Occupational exposure to antineoplastic agents: self-reported miscarriages and stillbirths among nurses and pharmacists. J Occup Environ Med; 41: 632–8.[Web of Science][Medline]
Ziegler E, Mason H, Baxter P. (2002) Occupational exposure to cytotoxics drugs in two UK oncology wards. Occup Environ Med; 59: 608–12.
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