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INTRODUCTION
Attempts to stop or reverse the growth of malignant cells began in the late 1940s when nitrogen mustard and its derivatives were rst used therapeutically.1 Signicant medical benets result from the use of these drugs. However, they may be harmful to those who handle, prepare, administer, and dispose of these drugs.1 In general, cytotoxic drugs have been classied as potentially carcinogenic, teratogenic and mutagenic.1 Adverse health effects from both acute and chronic exposures have been demonstrated in health care personnel. Over a long term, almost all of these drugs have the potential of damaging cells or adversely affecting cellular growth and reproduction. The drugs bind directly to genetic material in the cell nucleus or affect cellular protein synthesis.1 The risks to workers handling cytotoxic drugs are a result of the inherent toxicity of the drugs themselves, and the actual dose that a worker receives. The dose is dependent on the concentration of the drug, the duration of the exposure, and the route of entry. The possibility of adverse health effects as a result of exposure to a particular drug may depend on whether the drug enters the body through inhalation, absorption through the skin or ingestion.9 Celeste Caskey, Daniel J. Hurley, MS, CIH and Raymond R. Liguori, CIH are afliated with Wake Forest University Health Sciences, Environmental Health & Safety, Medical Center Boulevard, Winston-Salem, NC 27157, USA (Tel.: 336 716 1226; fax: 336 716 0588; e-mail: lcaskey@wfubmc.edu).
The chemotherapy nurses subject to this investigation mix and prepare chemotherapy drugs in both in-patient and out patient settings. Approximately 80100 patients are treated daily in the outpatient clinic settings
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Division of Chemical Health and Safety of the American Chemical Society Elseiver Inc. All rights reserved.
1074-9098/$30.00 doi:10.1016/j.chs.2004.11.016
that the thickness of the gloves used in handling hazardous drugs is more important than the type of material. Thicker, longer latex gloves that cover the gown cuff are recommended for use with hazardous drugs.1 OSHA recommends disposable gowns which are lint free, low permeability fabric with a closed front, long sleeves and elastic or knit closed cuffs.1 The recent NIOSH Alert has recommended disposal gowns made of polyethylenecoated polypropylene instead of polypropylene gowns.
LITERATURE REVIEW
Monitoring efforts for cytotoxic drugs have detected measurable air levels when exhausted biological safety cabinets (BSC) were not used for preparation or when monitoring was performed inside the BSC. Concentrations of uorouracil ranging from 0.12 to 82 ng/m3 have been found during monitoring of drug preparation without a BSC.1 This indicated a potential for respiratory exposure. Elevated concentrations of cyclophosphamide were found in previous studies with and without the use of a BSC.1 Cyclophosphamide has also been detected on the HEPA lters of ow hoods used in cytotoxic drug preparation, demonstrating aerosolization of the drug and an exposure opportunity mitigated by effective engineering controls.1 A recent study has reported wipe samples of cyclophosphamide on surfaces of work stations in an oncology pharmacy and outpatient treatment areas. Concentrations ranged from 0.05 to 0.35 mg/cm2, documenting potential for dermal exposure.1
METHODOLOGY
Several studies have attempted to measure concentrations of airborne chemotherapy drugs in healthcare settings. However, in most cases the percent of samples demonstrating the presence of drug particulate was low and the concentration of the drugs was low.9 This may be due to technical problems because of the lter material
being used or that drugs are in a vapor phase instead of a particulate phase.9 For this study, wipe sampling was selected as a method to detect surface contamination. Wipe sampling is commonly used to assess surface contamination from cytotoxic drugs.2,5,9 Surface contamination may be an indicator of the efcacy of personal protective equipment use and operation techniques.9 Since the early 1990s, fourteen studies have examined environmental contamination of drug preparation and administration areas in healthcare facilities. Using wipe samples, most studies measured detectable levels of one or more cytotoxic drugs in various locations. All of the studies reported some level of contamination with at least one drug and several reported contamination with all the drugs for which assays were performed.9 All studies that examined surface wipe samples have determined that surface contamination of the workplace is common and widespread.9 Wipe sampling method for monitoring surface contamination by selected cytotoxic drugs is sufciently accurate and sensitive to evaluate surfaces.5 However, calculations assume 100% recovery of all spilled cyclophosphamide and 5-uorouracil of the drugs analyzed. Since 100% recovery of contamination is not possible, the calculations result in an underestimate of the actual contamination present.5 At Wake Forest University Health Sciences, Cytotoxic drugs are prepared and mixed in three different locations. Location 1 is utilized for in-patients; Location 2 and Location 3 are outpatient clinics. At each location, the interior of the biological safety cabinet (BSC, Class II, Type B2), oor underneath the biological safety cabinet and cabinets or tables in the proximity of the biological safety cabinet were sampled. The sample areas at each location were selected as potential areas of contamination based on previous studies.4 Fifteen wipe samples were taken from areas in the three different locations. Due to insufcient testing materials, wipe sampling was not performed for etoposide in the chemotherapy/mixing area in Location 3.
Cyclophosphamide (CP), ifosfamide (IP) and 5-uorouracil (5-FU) were sampled by using 17-mL solution of sodium hydroxide (0.03 M) was spread over each of the surface areas with a pipette.2,5 Etoposide was sampled by using a 17-mL solution of ethanol (50%) and water was spread over each of the various surface areas with a pipette.3,4 After spreading the appropriate solution over the surface area, the area was wiped with two absorbent tissues (Scott 130, Kimberly Clark). The tissues were stored in numbered 125-mL plastic screw top containers.5 Samples were stored at 0 8C and shipped on dry ice to Exposure Control, Netherlands for analysis. Cyclophosphamide (CP) and ifosfamide (IP) were analyzed by Gas Chromatography in tandem with mass spectroscopy-mass spectroscopy (GC-MS-MS Method) system.2,5 Analysis of 5-uorouracil (5-FU) and etoposide were performed using reverse phase high-performance liquid chromatography with ultraviolet detection.3,4 The analytical detection limit for cyclophosphamide and ifosfamide was 0.1 ng/mL of extract, for 5-uorouracil, 20 ng/mL of extract and 50 ng/mL of extract for etoposide.2,3,4
RESULTS
Table 1 represents the results of the samples taken in the chemotherapy preparation/mixing area in Location 1. Results indicated there was no environmental contamination from 5-uorouracil (5-FU) or etoposide. There was environmental contamination from the cyclophosphamide (CP) and ifosfamide (IP). The results for CP ranged from 0.08 to 3.36 ng/cm2 while IP ranged from 0.04 to 2.14 ng/cm2. Table 2 represents the results of the samples taken in the chemotherapy preparation/mixing area in Location 2. Results indicated that there was no environmental contamination from the use of ifosfamide (IP) and etoposide. The results indicated that there was environmental contamination from the cyclophosphamide (CP) and 5-uorouracil (5-FU). The results for CP ranged from 0.04 to 4.51 ng/cm2
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Table 1. Location 1
Drugs Analyzed Result (ng/cm ) Sample Location BSC #1 BSC #1 BSC #2 BSC #2 Countertop Countertop Floor under BSC #1 Floor under BSC #2 Control CP 0.08 NS 3.36 NS 0.09 NS 0.17 NS ND IP 2.14 NS 0.56 NS 0.04 NS 0.06 NS ND 5-FU NS NS ND NS ND NS ND NS ND Etoposide NS ND NS ND NS ND NS ND ND
off blower may allow contaminated dust to recirculate back into workroom8 and swabbing of the nal product before removing it from the BSC.5 To further this investigation of contamination, the path forward includes: observing techniques to determine source of contamination in the preparation and mixing areas, urine sampling utilized to determine if workers are being exposed to cytotoxic drugs, further wipe sampling to determine if training improved techniques and housekeeping aid in the reduction of environmental contamination. References
Drugs Analyzed Result (ng/cm2) Sample Location BSC BSC Desk Floor under BSC Countertop Control CP NS 0.60 4.51 1.05 0.04 ND IP NS ND ND ND ND ND 5-FU NS 2.27 11.15 2.73 3.45 ND Etoposide ND NS NS NS NS ND
Drugs Analyzed Result (ng/cm2) Sample Location Floor under BSC BSC Control CP 0.03 0.56 ND IP NS NS ND 5-FU 2.37 1.36 ND
while 5-FU ranged from 2.27 to 11.15 ng/cm2. Table 3 represents the results of the samples taken in the chemotherapy preparation/mixing area in Location 3. Results indicated there was no environmental contamination from the use of ifosfamide (IP). Results indicated that there was environmental contamination from the cyclophosphamide (CP) and 5-uorouracil (5-FU). The results for CP ranged from 0.03 to 0.56 ng/cm2 while 5-FU ranged from 1.36 to 2.37 ng/cm2.
exposed to cytotoxic agents. The results indicated that there is a potential exposure to 5-uorouacil, cyclophosphamide and ifosfamide. However, there was no evidence of environmental contamination with etoposide. Based on surface contamination found in the chemotherapy mixing/preparation areas sampled, the following recommendations were suggested. The frequency of cleaning should be daily.1 The frequency of decontamination of the BSC and other work areas should be when a spill occurs, weekly, and when the biosafety cabinet is serviced or certied.1,7,8 Quaternary ammonium cleaners should be avoided since they are hazardous to humans and the possibility of vapor build-up in the recirculated air if not using Class II, Type B2 biological safety cabinets.1,8 Isopropyl alcohol should not be used as the rst step in cleaning or decontamination, since anticancer agents are not inactivated by isopropyl alcohol.6,10 The following biosafety cabinet practices are recommended to ensure operating efciency: the biosafety cabinet (BSC) should not be overcrowded; do not block grill work of the BSC5; do not turn off the blower of the BSC; turning
1. Occupational Safety and Health Administration, Controlling Occupational Exposure to Hazardous Drugs, Section VI: Chapter 2; U.S. Department of Labor, 1995. http://www.osha-slc.gov/ dts/osta/otm /otm_vi/otm_vi_2 . html (2/27/03). 2. Sessink, P. J.; Anzion, R. B.; Van den Broek, P. H.; Bos, R. P. Pharm. Weekbl. Sci. 1992, 21(14(1)), 16. 3. Sessink, P. J.; Boer, K. A.; Scheefhals, A. P.; Anzion, R. B.; Bos, R. P. Int. Arch. Occup. Environ. Health, 1992, 64(2), 105. 4. Sessink, P. J. M.; Scholtes, M. M.; Anzion, R. B. M.; Bos, R. P. J. Chromatogr. 1993, 616, 333. 5. Connor, T. H.; Anderson, R. W.; Broadeld, L.; Sessink, P. J. M.; Power, L. A. Am. J. Health Syst. Pharm. 1999, 56, 1427. 6. Dorr, R. T. Oncol. Nurs. Forum, April 2002. 7. National Institute for Occupational Safety and Health (NIOSH), Recommended Guidelines for Controlling Noninfectious Health Hazards in Hospitals, 1998. http://www.cdc.gov/ niosh/hcwold5a.html (4/11/03). 8. American Journal of Hospital Pharmacy. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am. J. Hosp. Pharm. 1990, 47, 1033. 9. National Institute for Occupational Safety and Health (NIOSH), Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings. http:// www.cdc.gov/niosh/docs/2004-165/ (6/7/2004). 10. Bevenuto, J. A.; Connor, T. H.; Monteith, D. K.; Laidlaw, J. L.; Adams, S. C.; Matney, T. S.; Theiss, J. C. J. Pharm. Sci. 1993, 82(10), 988.
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