FEATURE

Assessing environmentalcontamination by cytoxic drugs

By Celeste Caskey, Daniel J.Hurley, Raymond R. Liguori

INTRODUCTION

Attempts to stop or reverse the growthof malignant cells began in the late1940s when nitrogen mustard and itsderivatives were first used therapeuti-cally.1 Significant medical benefitsresult from the use of these drugs.However, they may be harmful tothose who handle, prepare, administer,and dispose of these drugs.1 In general,cytotoxic drugs have been classified aspotentially carcinogenic, teratogenicand mutagenic.1

Adverse health effects from bothacute and chronic exposures havebeen demonstrated in health care per-sonnel. Over a long term, almost all ofthese drugs have the potential of dama-ging cells or adversely affecting cellulargrowth and reproduction. The drugsbind directly to genetic material inthe cell nucleus or affect cellular pro-tein synthesis.1

The risks to workers handling cyto-toxic drugs are a result of the inherenttoxicity of the drugs themselves, andthe actual dose that a worker receives.The dose is dependent on the concen-tration of the drug, the duration of theexposure, and the route of entry. Thepossibility of adverse health effects as aresult of exposure to a particular drugmay depend on whether the drugenters the body through inhalation,absorption through the skin or inges-tion.9

Celeste Caskey, Daniel J. Hurley,MS, CIH and Raymond R. Liguori,CIH are affiliated with Wake ForestUniversity 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).

26 � Division of Chemical Health and Safety of the

Elseiver Inc. All rights reserved.

TheOccupational Safety andHealthAdministration (OSHA) TechnicalManual section entitled, ControllingOccupational Exposure to HazardousDrugs, states that preparation, admin-istration and disposal of hazardousdrugs may expose healthcare workersto potentially significant workplacelevels of these drugs. It is difficult toset safe levels of exposure on the basisof current scientific information. Manyhazardous drugs are known humancarcinogens for which there is noknown safe level of exposure.1

Since OSHA standards are minimal,organizations such as NIOSH, Amer-ican Society of Hospital Pharmacists,the Oncology Nursing Society andpharmaceutical manufacturers havedeveloped guidelines for handling,preparing, mixing and administeringchemotherapy drugs. However, theadherences to these guidelines havebeen reported to be sporadic.9

Currently, there are no OSHAPermissible Exposure Limits (PELs),NIOSH Recommended ExposureLimits (RELs) or ACGIH ThresholdLimit Values (TLVs) established forhazardous drugs. As of September2004, NIOSH has published an alerton occupational exposure to che-motherapy drugs in health care set-tings.

The focus of this study was to ascer-tain environmental contaminationoccurring during the preparation andmixing of cytotoxic agents such as 5-fluorouracil, etoposide, cyclophospha-mide and ifosfamide.

ENGINEERING CONTROLS,ADMINISTRATIVE CONTROLS ANDPPE

The chemotherapy nurses subject tothis investigation mix and prepare che-motherapy drugs in both in-patientand out patient settings. Approxi-mately 80–100 patients are treateddaily in the outpatient clinic settings

American Chemical Society

and 20 patients are treated daily in aninpatient setting. The chemotherapydrugs are prepared in three differentlocations.Occupational exposure to che-

motherapy drugs can occur duringthe mixing, preparing and administra-tion. ChemotherapyNurses are trainedin the use of engineering controls suchas using biological safety cabinets;administrative controls such as rota-tion of personnel and the use of per-sonnel protective equipment (PPE) toreduce exposure whenmixing and pre-paring chemotherapy drugs.A Class II, Type B2, biological safety

cabinet (BSC) is used for mixing andpreparing the chemotherapy drugs. AClass II, Type B2 BSC has higher velo-city air inflow and exhausts the air tothe outside through HEPA filters.1

Administrative controls includerotation of personnel mixing and pre-paring drugs. Personnel protectiveequipment includes double glovingwith nitrile gloves and a chemotherapygown. Nitrile gloves were chosenbased on literature review and thedesire to avoid latex allergies. Sixteenstudies of permeability of various glovematerials to chemotherapy agents havebeen performed. The drugs, test meth-ods and procedures have varied. Thereference study evaluated gloves inresponse to latex allergies and newglove materials that have becomeavailable. The study evaluated thegloves permeability to cyclophospha-mide, ifosfamide, 5-fluorouracil andetoposide, among other agents.10

Gloves should be thin enough for com-fort and dexterity, yet provide ade-quate protection during necessaryhandling procedures.10 The study con-cluded that nitrile rubber, latex, poly-urethane and neoprene gloves wereimpermeable to the drugs tested.10

The Occupational Safety andHealthAdministration (OSHA) TechnicalManual section entitled, ControllingOccupational Exposure to HazardousDrugs, states that research indicates

1074-9098/$30.00

doi:10.1016/j.chs.2004.11.016

that the thickness of the gloves used inhandling hazardous drugs is moreimportant than the type of material.Thicker, longer latex gloves that coverthe gown cuff are recommended foruse with hazardous drugs.1 OSHArecommends disposable gowns whichare lint free, low permeability fabricwith a closed front, long sleeves andelastic or knit closed cuffs.1 The recentNIOSH Alert has recommended dis-posal gowns made of polyethylene-coated polypropylene instead of poly-propylene gowns.

LITERATURE REVIEW

Monitoring efforts for cytotoxic drugshave detected measurable air levelswhen exhausted biological safety cabi-nets (BSC) were not used for pre-paration or when monitoring wasperformed inside the BSC. Concentra-tions of fluorouracil ranging from 0.12to 82 ng/m3 have been found duringmonitoring of drug preparation with-out a BSC.1 This indicated a potentialfor respiratory exposure. Elevated con-centrations of cyclophosphamide werefound in previous studies with andwithout the use of a BSC.1

Cyclophosphamide has also beendetected on the HEPA filters of flowhoods used in cytotoxic drug prepara-tion, demonstrating aerosolization ofthe drug and an exposure opportunitymitigated by effective engineeringcontrols.1 A recent study has reportedwipe samples of cyclophosphamideon surfaces of work stations in anoncology pharmacy and outpatienttreatment areas. Concentrationsranged from 0.05 to 0.35 mg/cm2,documenting potential for dermalexposure.1

METHODOLOGY

Several studies have attempted tomea-sure concentrations of airborne che-motherapy drugs in healthcaresettings. However, in most cases thepercent of samples demonstrating thepresence of drug particulate was lowand the concentration of the drugs waslow.9 This may be due to technicalproblems because of the filter material

Chemical Health & Safety, September/Octo

being used or that drugs are in a vaporphase instead of a particulate phase.9

For this study, wipe sampling wasselected as a method to detect surfacecontamination. Wipe sampling is com-monly used to assess surface contam-ination from cytotoxic drugs.2,5,9

Surface contamination may be an indi-cator of the efficacy of personal pro-tective equipment use and operationtechniques.9

Since the early 1990s, fourteen stu-dies have examined environmentalcontamination of drug preparationand administration areas in healthcarefacilities. Using wipe samples, moststudies measured detectable levels ofone or more cytotoxic drugs in variouslocations. All of the studies reportedsome level of contamination with atleast one drug and several reportedcontamination with all the drugs forwhich assays were performed.9 All stu-dies that examined surface wipe sam-ples have determined that surfacecontamination of the workplace iscommon and widespread.9

Wipe sampling method for monitor-ing surface contamination by selectedcytotoxic drugs is sufficiently accurateand sensitive to evaluate surfaces.5

However, calculations assume 100%recovery of all spilled cyclophospha-mide and 5-fluorouracil of the drugsanalyzed. Since 100% recovery of con-tamination is not possible, the calcula-tions result in an underestimate of theactual contamination present.5

At Wake Forest University HealthSciences, Cytotoxic drugs are preparedand mixed in three different locations.Location 1 is utilized for in-patients;Location 2 and Location 3 are out-patient clinics. At each location, theinterior of the biological safety cabinet(BSC, Class II, Type B2), floor under-neath the biological safety cabinet andcabinets or tables in the proximity ofthe biological safety cabinet weresampled.The sample areas at each location

were selected as potential areas of con-tamination based on previous studies.4

Fifteen wipe samples were taken fromareas in the three different locations.Due to insufficient testing materials,wipe sampling was not performed foretoposide in the chemotherapy/mixingarea in Location 3.

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Cyclophosphamide (CP), ifosfamide(IP) and 5-fluorouracil (5-FU) weresampled by using 17-mL solution ofsodium hydroxide (0.03 M)was spreadover each of the surface areas with apipette.2,5 Etoposide was sampled byusing a 17-mL solution of ethanol(50%) and water was spread over eachof the various surface areas with apipette.3,4 After spreading the appro-priate solution over the surface area,the area was wiped with two absorbenttissues (Scott 130, Kimberly Clark).The tissues were stored in numbered125-mL plastic screw top containers.5

Samples were stored at 0 8C andshipped on dry ice to Exposure Con-trol, Netherlands for analysis.Cyclophosphamide (CP) and ifo-

sfamide (IP) were analyzed by GasChromatography in tandem withmass spectroscopy-mass spectroscopy(GC-MS-MSMethod) system.2,5 Ana-lysis of 5-fluorouracil (5-FU) and eto-poside were performed using reversephase high-performance liquid chro-matography with ultraviolet detec-tion.3,4

The analytical detection limit forcyclophosphamide and ifosfamidewas 0.1 ng/mL of extract, for 5-fluor-ouracil, 20 ng/mL of extract and50 ng/mL of extract for etoposide.2,3,4

RESULTS

Table 1 represents the results of thesamples taken in the chemotherapypreparation/mixing area in Location1. Results indicated there was no envir-onmental contamination from 5-fluor-ouracil (5-FU) or etoposide. There wasenvironmental contamination fromthe cyclophosphamide (CP) and ifos-famide (IP). The results for CP rangedfrom 0.08 to 3.36 ng/cm2 while IP ran-ged from 0.04 to 2.14 ng/cm2.Table 2 represents the results of the

samples taken in the chemotherapypreparation/mixing area in Location2. Results indicated that there was noenvironmental contamination fromthe use of ifosfamide (IP) and etopo-side. The results indicated that therewas environmental contaminationfrom the cyclophosphamide (CP) and5-fluorouracil (5-FU). The results forCP ranged from 0.04 to 4.51 ng/cm2

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Table 1. Location 1

Drugs Analyzed Result (ng/cm2)

Sample Location CP IP 5-FU Etoposide

BSC #1 0.08 2.14 NS NSBSC #1 NS NS NS NDBSC #2 3.36 0.56 ND NSBSC #2 NS NS NS NDCountertop 0.09 0.04 ND NSCountertop NS NS NS NDFloor under BSC #1 0.17 0.06 ND NSFloor under BSC #2 NS NS NS NDControl ND ND ND ND

ND, Not detected; NS, not sampled.

Table 2. Location 2

Drugs Analyzed Result (ng/cm2)

Sample Location CP IP 5-FU Etoposide

BSC NS NS NS NDBSC 0.60 ND 2.27 NSDesk 4.51 ND 11.15 NSFloor under BSC 1.05 ND 2.73 NSCountertop 0.04 ND 3.45 NSControl ND ND ND ND

ND, Not detected; NS, not sampled.

Table 3. Location 3

Drugs AnalyzedResult (ng/cm2)

Sample Location CP IP 5-FU

Floor under BSC 0.03 NS 2.37BSC 0.56 NS 1.36Control ND ND ND

ND, Not detected; NS, not sampled.

while 5-FU ranged from 2.27 to11.15 ng/cm2.Table 3 represents the results of the

samples taken in the chemotherapypreparation/mixing area in Location3. Results indicated there was no envir-onmental contamination from the useof ifosfamide (IP). Results indicatedthat there was environmental contam-ination from the cyclophosphamide(CP) and 5-fluorouracil (5-FU). Theresults for CP ranged from 0.03 to0.56 ng/cm2 while 5-FU ranged from1.36 to 2.37 ng/cm2.

RECOMMENDATIONS ANDCONCLUSIONS

Based on wipe sample results, there isa potential that employees may be

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exposed to cytotoxic agents. The resultsindicated that there is a potential expo-sure to 5-fluorouacil, cyclophospha-mide and ifosfamide. However, therewas no evidence of environmental con-tamination with etoposide.

Based on surface contaminationfound in the chemotherapymixing/pre-paration areas sampled, the followingrecommendations were suggested. Thefrequency of cleaning should be daily.1

The frequency of decontamination ofthe BSC and other work areas shouldbe when a spill occurs, weekly, andwhen the biosafety cabinet is servicedor certified.1,7,8Quaternary ammoniumcleaners should be avoided since theyare hazardous to humans and the pos-sibility of vapor build-up in the recircu-lated air if not using Class II, Type B2biological safety cabinets.1,8 Isopropylalcohol should not be used as the firststep in cleaning or decontamination,since anticancer agents are not inacti-vated by isopropyl alcohol.6,10

The following biosafety cabinet prac-tices are recommended to ensure oper-ating efficiency: the biosafety cabinet(BSC) should not be overcrowded; donot block grill work of the BSC5; do notturn off the blower of the BSC; turning

Chemical Hea

off blower may allow contaminateddust to recirculate back into work-room8 and swabbing of the final pro-duct before removing it from the BSC.5

To further this investigation of con-tamination, the path forward includes:observing techniques to determinesource of contamination in the pre-paration and mixing areas, urine sam-pling utilized to determine if workersare being exposed to cytotoxic drugs,further wipe sampling to determine iftraining improved techniques andhousekeeping aid in the reduction ofenvironmental contamination.

References1. Occupational Safety and Health Ad-

ministration, Controlling OccupationalExposure to Hazardous Drugs, SectionVI: Chapter 2; U.S. Department ofLabor, 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 denBroek, 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. Chro-matogr. 1993, 616, 333.

5. Connor, T. H.; Anderson, R. W.;Broadfield, L.; Sessink, P. J. M.; Power,L. A. Am. J. Health Syst. Pharm. 1999,56, 1427.

6. Dorr, R. T. Oncol. Nurs. Forum, April2002.

7. National Institute for OccupationalSafety and Health (NIOSH), Recom-mended Guidelines for ControllingNoninfectious Health Hazards inHospitals, 1998. http://www.cdc.gov/niosh/hcwold5a.html (4/11/03).

8. American Journal of Hospital Phar-macy. ASHP technical assistance bul-letin on handling cytotoxic andhazardous drugs. Am. J. Hosp. Pharm.1990, 47, 1033.

9. National Institute for OccupationalSafety and Health (NIOSH), Prevent-ing Occupational Exposure to Anti-neoplastic and Other Hazardous Drugsin Health Care Settings. http://www.cdc.gov/niosh/docs/2004-165/(6/7/2004).

10. Bevenuto, J. A.; Connor, T. H.; Mon-teith, 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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