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Association of Surface Contamination by AntineoplasticDrugs With Different Working Conditions in HospitalPharmaciesPavel Odraska MSc a b , Lenka Dolezalova PharmD a , Jan Kuta MSc b , Michal Oravec PhD b ,Pavel Piler MSc b , Stanislav Synek PharmD c & Ludek Blaha PhD a ba Masaryk Memorial Cancer Institute , Brno , Czech Republicb Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science,Masaryk University , Brno , Czech Republicc St. Anne's University Hospital Brno , Brno , Czech RepublicAccepted author version posted online: 08 Mar 2013.Published online: 10 Dec 2013.

To cite this article: Pavel Odraska MSc , Lenka Dolezalova PharmD , Jan Kuta MSc , Michal Oravec PhD , Pavel Piler MSc ,Stanislav Synek PharmD & Ludek Blaha PhD (2014) Association of Surface Contamination by Antineoplastic Drugs WithDifferent Working Conditions in Hospital Pharmacies, Archives of Environmental & Occupational Health, 69:3, 148-158, DOI:10.1080/19338244.2013.763757

To link to this article: http://dx.doi.org/10.1080/19338244.2013.763757

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Archives of Environmental & Occupational Health, Vol. 69, No. 3, 2014Copyright C© 2014 Taylor & Francis Group, LLC

Association of Surface Contaminationby Antineoplastic Drugs With Different

Working Conditions in HospitalPharmacies

Pavel Odraska, MSc; Lenka Dolezalova, PharmD; Jan Kuta, MSc; Michal Oravec,PhD; Pavel Piler, MSc; Stanislav Synek, PharmD; Ludek Blaha, PhD

ABSTRACT. This study investigates the surface contamination levels of cyclophosphamide andplatinum (a marker of platinum-containing drugs) in storage and preparation areas of hospital phar-macies and their relationship to working conditions surveyed by questionnaire. In total, 259 wipesamples were collected in 13 hospital pharmacies over 4 sampling campaigns. After sample extrac-tion with acetate buffer, cyclophosphamide and platinum were determined using high-performanceliquid chromatography–tandem mass spectroscopy (HPLC-MS/MS) and inductively coupled plasmamass spectrometry (ICP-MS). Depending on the sampling spot and campaign, median concentrationsranged from <2 to 61 pg/cm2 and from <0.2 to 6.9 pg/cm2 for cyclophosphamide and platinum,respectively. Statistical evaluation of monitoring data revealed that the contamination level was sig-nificantly influenced by laboratory throughput (expressed as number of chemotherapies preparedper week), personnel expertise (ie, participation of pharmacists with academic education in drugadmixture activities), and surface material.

KEYWORDS: antineoplastic agents, carcinogens, chemical exposure, cytotoxic drugs, exposureassessment, surface contamination

A ntineoplastic drugs (ADs) have an important role inthe treatment of cancer. Along with their clear ther-apeutic benefit, however, ADs have many hazardous

properties, such as genotoxicity, carcinogenicity, and repro-ductive toxicity,1–7 that make them hazardous for hospitalpersonnel. Therefore, occupational exposure to ADs shouldbe avoided or at least reduced to levels “as low as reasonablyachievable.”8 For this reason, many organizational, techni-cal, and personal protective measures along with several spe-

Pavel Odraska and Ludek Blaha are with the Masaryk Memorial Cancer Institute, Brno, Czech Republic; and the Research Centre forToxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic. Lenka Dolezalova is withthe Masaryk Memorial Cancer Institute, Brno, Czech Republic. Jan Kuta, Michal Oravec, and Pavel Piler are with the Research Centrefor Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic. Stanislav Synek iswith St. Anne’s University Hospital Brno, Brno, Czech Republic.

cial safety guidelines have been introduced during the last 2decades.

In the Czech Republic, the preparation of ADs is restrictedto a central preparation unit in all hospitals. The preparationshould be performed in a negative-pressure isolator with ver-tical laminar airflow (air purity of class A) and air leavingthe isolator should be vented outside the building. Accord-ing to legislation, the isolator should be operated in a cleanroom with air purity of class C.9 These preparation roomsshould also be used only for the preparation of ADs. Isolators

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should be certified once a year. The presence of workers inthe preparation room must be recorded and no unauthorizedpersonnel are allowed to enter. According to legislation,10

workers preparing ADs can stay in the preparation room fora maximum of 2 hours, after which they should leave theroom and take a break of at least 15 minutes before they areallowed to enter the AD preparation area again.

In addition to technical and organizational safety mea-sures, analytical methods have also been proposed in theliterature for determining ambient contamination by severaldistinct drugs. There have been numerous monitoring stud-ies showing widespread surface contamination of healthcarefacilities.11–20 However, factors affecting the contaminationlevel have not yet been fully investigated.

The objective of this study was to investigate surface con-tamination with ADs in hospital pharmacies in the CzechRepublic. Contamination levels found in different pharma-cies were compared and their association with several factors(working conditions and practices) was investigated. Timetrends regarding surface contamination were studied by re-peated sampling and assessment. For this purpose, surfacecontamination with cyclophosphamide (CP) and platinum(Pt) as a marker of Pt-containing ADs (cisplatin, oxaliplatin,and carboplatin) was determined in 4 sampling campaignsinvolving the regular participation of 13 hospital pharma-cies. In addition to the chemical analysis of samples, a sur-vey of working conditions and practices was undertaken byquestionnaire. CP and Pt were selected as markers of con-tamination because (i) CP and Pt-containing ADs are amongthe most widely used ADs6,21; (ii) their levels in the work-places were previously investigated20,22,23; and (iii) they wereshown to cause serious health occupational risks, especiallyCP.2

METHODS

Design of the study

During the years 2008 to 2010, 4 sampling campaignswere conducted (1 campaign each 6 months). The results ofchemical analyses were reported to each hospital pharmacyin the form of a review of their own values and an anonymouscomparison with other pharmacies after each campaign. Par-ticipation in the study was offered to 29 hospital pharmaciesthat are authorized to prepare ADs in the Czech Republic.From these, 13 pharmacies agreed to participate regularly inthe study. The selection covered all of the major hospitals aswell as some smaller regional hospitals.

Collection of wipe samples

Sampling was performed by workers of the individual hos-pitals according to written instructions and a video manual.Sample collection was done at the end of the working day,but before regular cleaning of the facilities was undertaken.Wiping of the same sampling spots and by the same person,if possible, throughout all campaigns was required.

In the storage area, sampling spots included (i) the work-bench for receiving ADs from the pharmaceutical supplierand (ii) the floor in front of the workbench. In the prepara-tion area, sampling spots included (iii) the postpreparationworkbench for the packing of ready-to-use infusion bags andbolus injections into plastic foil, (iv) the floor in front of theworkbench, and (v) the door of the refrigerator (the surfacearound the handle).

The area sampled was 30 × 30 cm and was highlightedwith marker or adhesive tape before each sample collection.The surfaces were sampled using a nonwoven swab (Mesoft,7.5 × 7.5 cm; Molnlycke Health Care, Goteborg, Sweden)moistened with acetate buffer (0.75 mL, 20 mM, pH = 4).Wiping was performed using a standardized sampling pro-cedure (3 repeated wipes varying in direction by one swabfolded in half after each wipe). A clean pair of gloves wasused for the collection of each sample. Besides the wipe sam-ples, 1 field blank was collected at the end of each samplingoccasion.

Chemical analyses

All samples were processed as previously described.24

Briefly, the samples were extracted in the acetate buffer(25 ml, 20 mM, pH = 4). CP and Pt were determined in theextracted samples by high-performance liquid chromatogra-phy with tandem mass spectrometry (an Agilent 1200 LCsystem coupled with a 6410 Triple-Quad MS with elec-trospray interface; Agilent Technologies, Santa Clara, CA,USA) and inductively coupled plasma mass spectrometry(Agilent 7500ce; Agilent Technologies, Tokyo, Japan), re-spectively. Internal standards were applied to correct forinjection volume errors, matrix effects, and signal drift ofthe analytical determination.2H4-labeled CP (purity 97%;Niomech, Bielefeld, Germany) was used for the quantifica-tion of CP and rhenium (185Re) and bismuth (209Bi) certifiedreference calibration solutions (Astasol; Analytika, Prague,Czech Republic) were used for the quantification of Pt. Theanalytical detection limits for CP and Pt were 2 and 0.2pg/cm2, respectively. The limit of quantification was 7 and0.7 pg/cm2, respectively. The method underwent partial vali-dation evaluating extraction efficiency as well as surface sam-pler removal efficiency. Surface sampler removal efficiencywas evaluated in terms of both single- and multiple-operatorrecovery and precision using stainless steel plates (30 ×30 cm) as representative of an ideal (smooth and nonporous)surface.25 The validation results are shown in Table 1.

Assessment of working conditions andpractices

In order to collect data on working conditions and prac-tices, a questionnaire dealing with laboratory throughput,working procedures, as well as personal, technical, andorganizational safety measures was developed. Questionswere set to receive only 1 possible answer (usually yes/noformat) or numerical information. Items recorded by the

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Table 1.—-Extraction Efficiency and Surface Sampler Removal Efficiency for Cyclophosphamide and Platinum

Variable Cyclophosphamide Platinum

Extraction procedureConcentration (pg/cm2) 18 180 1800 35 175 1750Intraday precision (RSD, %; n = 3) 6 3 3 3 1 10Interday precision (RSD, %; n = 3) 11 12 3 16 17 17Extraction recovery (mean, %; n = 6) 90 90 98 62 64 60

Entire methodConcentration (pg/cm2) 18 18

Intraoperator recovery (%; n = 8)Mean 71 56SD 11 11

Interoperator recovery (%; n = 8)Mean 72 54SD 11 8

questionnaire included (i) average number of AD prepa-rations performed per week, (ii) type of biological safetycabinet (BSC) used for AD preparation, (iii) frequency ofvalidation of the technical status of the BSC, (iv) expertise ofpersonnel preparing ADs (pharmacist vs pharmacy techni-cian), (v) use of special devices for AD preparation (spikes),(vi) use of Luer-lock syringes, and (vii) presence of spillcontrol kit in storage and preparation areas. Details on thesampling spots (surface material and cleaning frequency ofthe surfaces) and modifications to working conditions dur-ing the course of the 2-year study were assessed with a final(postmonitoring) questionnaire.

Data analyses

The monitoring data did not meet the assumptions for para-metric testing, since they showed non-normal distributionand nonhomogenous variability. Therefore, nonparametricstatistical tests were used. Differences between concentra-tions grouped by workplace, hospital, or specific workingconditions were analyzed with the Kruskal-Wallis or Mann-Whitney U test. The relation between contamination leveland laboratory throughput was investigated by the nonpara-metric Spearman correlation of pharmacy median concen-trations versus number of AD preparations performed perweek. The time trend in measured values (contamination)was evaluated by analyzing differences between the concen-trations grouped by campaign using the Friedman test fordependent samples. All statistical tests were done 2-sided atthe α = .05 significance level. Calculations were performedin Statistica 9 (StatSoft, Tulsa, OK, USA).

RESULTS

During the years 2008 to 2010, 4 monitoring campaignsat 6-month intervals were performed in 13 hospital pharma-cies, which were fairly representative of such facilities inthe Czech Republic in terms of size and laboratory through-

put (both relatively small facilities as well as the 4 largestpharmacies in the Czech Republic participated).

Working conditions and practices

The throughput of the pharmacies ranged from 45 to1,000 chemotherapy preparations per week. In all pharma-cies (A–M; see Figure 1A, B), the preparation room wasequipped with negative-pressure isolators with one excep-tion, where a vertical laminar flow hood was used for ADpreparation (pharmacy G). Regardless of the type of BSC, allcabinets underwent regular technical validation processes at1-year intervals. In 5 pharmacies (C, D, H, L, M), AD prepa-ration is usually performed by pharmacy technicians only,whereas in 8 pharmacies (A, B, E–G, I–K), ADs are pre-pared by both pharmacy technicians and pharmacists. Fourpharmacies (B, C, G, L) used only needles for AD admixtureactivities, whereas the remaining pharmacies (A, D–F, H–K,M) also used spikes (especially for high-volume vials). Nineof the pharmacies (A, B, D, F–I, K, M) used only Luer-locksyringes, whereas 4 pharmacies (C, E, J, L) used both Luer-lock and traditional syringes. Spill control kits were presentin both preparation and storage areas in all pharmacies exceptpharmacy L (kit missing in the storage room).

Characterization of the sampling spots

Several common materials were sampled during the study.The workbench of the storage area was mostly covered withlaminate with one exception (pharmacy J), where a stainlesssteel workbench was situated. The floor of the storage areawas covered with linoleum (n = 10; A–E, G–J, M) or flooringtiles (n = 3; F, K, L). In the preparation area, stainless steelpostpreparation workbenches were found in 8 pharmacies(B–E, H, J, L, M), whereas others pharmacies (n = 5; A,F, G, I, K) used laminated workbenches. The floor of thepreparation area was covered by linoleum in all pharmacieswith one exception (pharmacy A), where a concrete floor

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Fig. 1. Comparison of cyclophosphamide (A) and platinum (B) contamination levels determined in 13 Czech hospitalpharmacies (A–M). Data from all campaigns (1–4) are presented; pharmacies are ordered according to averagenumber of chemotherapies prepared per week (in parentheses).

covered with a synthetic coating was found. The refrigeratordoors were made of glass (n = 5; A, D, F, G, K), plastic witha synthetic coating (n = 6; B, E, H–J, L), or stainless steel(n = 2; C, M).

The cleaning pattern was the same in all pharmacies. Thefloors of both the storage and preparation areas were regu-larly cleaned every working day with an aqueous solutioncontaining detergent and disinfectant. The workbench of thepreparation area was cleaned with the same frequency andin the same way as the floor. The workbench of the storage

area and refrigerator door were cleaned approximately oncea week and whenever spillage occurred.

Surface contamination

During each sampling campaign, 5 wipe samples and 1field blank were collected in each pharmacy. During the firstcampaign, 1 wipe sample from the refrigerator in pharmacyB was not collected because the object was missing. In total,259 wipe samples were collected and analyzed for CP and

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Pt. Altogether, 176 (68%) samples had detectable amountsof at least 1 of the analytes and 120 (46%) samples haddetectable amounts of both of them. With respect to dis-tinct analytes, CP and Pt were found in 130 (50%) and 167(64%) samples, respectively. Median concentrations rangedfrom <2 to 61 pg/cm2 and from <0.2 to 6.9 pg/cm2 for CPand Pt, respectively, depending on the sampling spot andcampaign (Tables 2 and 3). Since method recovery has re-peatedly been shown to be affected by surface material19,22,26

and, specifically for Pt, by the proportional representation ofPt-containing drugs in the sample,22 all results are presentedas raw data without any adjustments to recovery.

Besides the wipe samples, 52 field blanks were analyzedin the study. One of these contained a trace amount of CPequal to the limit of detection and 9 of these revealed de-tectable amounts of Pt (from 0.2 to 6.0 pg/cm2). All of thesepositive field blanks originated from the pharmacies withhigh levels of contamination (pharmacies I, L, M); since theconcentrations in the blanks were negligible compared withthe results of related wipe samples (see also Figure 1A, B),no adjustments to the results were made.

Effect of working conditions

Statistical testing using the Kruskal-Wallis test revealedsignificant differences among the pharmacies with respect toboth analytes (p < .001 and p < .0001 for CP and Pt, re-spectively). Figure 1A, B shows the data from different phar-macies ordered according to laboratory throughput. Medianvalues of concentrations measured in the pharmacies signifi-cantly correlated with the throughput for both CP (Spearmanr = .746, p < .004) and Pt (r = .726, p = .005).

Further analyses of throughput-weighted monitoring data(each value divided by the average number of preparations fora specific pharmacy) revealed that the level of contaminationis also affected by the expertise of operators responsible forAD preparation. Indeed, pharmacies where pharmacists areinvolved in AD preparation activities showed significantlylower contamination with both CP (Mann-Whitney U test,p < .00001) and Pt (p = .019) than pharmacies where thepreparation was done only by pharmacy technicians (Figure2A, B). Other factors investigated by the questionnaire hadno significant effect on the levels of contamination (use ofspikes or Luer-lock syringes for AD preparation) or did notvary among the pharmacies (type and technical status of thebiological safety cabinet in use). Pharmacy G, which usedBSC class II (type B), did not show higher values than otherpharmacies with comparable throughput using isolators.

Effect of sampling spot material

Besides laboratory throughput and personnel expertise,the material of the sampled surface was also shown to affectthe results of the chemical analyses. For example, laminatedpostpreparation workbenches were found to be contaminatedwith higher levels of CP compared with stainless steel work-benches (Mann-Whitney, p = .016; Figure 3A). Higher lev-

Fig. 2. Comparison of monitoring results determinedfor pharmacies where AD preparation is performedby (i) both pharmacy technicians and pharmacists(n = 159) and (ii) pharmaceutical technicians only(n = 100). The panels present throughput-weighteddata for cyclophosphamide (A) and platinum (B)(color figure available online).

els of CP were also determined on plastic refrigerator doorscovered with a synthetic coating than on vitreous refrigera-tor doors (Mann-Whitney, p = .007; Figure 4A). Statisticallysignificant differences were found using both primary andthroughput-weighted data in both cases. Analyses of Pt con-centrations showed similar trends. However, the p value ofthe statistical analyses was just above the significance level(p = .067 [postpreparation workbench, Figure 3B] and .066[refrigerator door, Figure 4B]).

Decrease in contamination level during thestudy

Evaluating the data from all sampling spots and pharma-cies together revealed a significant decrease in contaminationlevels during the study with respect to both CP (Friedmantest, p = .0344) and Pt (p = .0043). Evaluating data groupedby sampling spot revealed a statistically significant decrease

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Table

2.—

-Cycl

ophosp

ham

ide

Conce

ntr

ations

(pg/c

m2)

on

the

Surf

ace

sof

13

Cze

chH

osp

italP

harm

aci

esSt

orag

ear

eaPr

epar

atio

nro

om

Wor

kben

chFl

oor

Wor

kben

chFl

oor

Ref

rige

rato

rTo

tal

Cam

paig

n75

th75

th75

th75

th75

th75

thno

.P.

D.a

Med

ian

perc

entil

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ax.

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edia

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rcen

tile

Max

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D.a

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edia

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ian

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entil

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.

17/

1325

6743

906/

13<

211

235

8/13

6140

717

708/

13<

758

539

6/12

842

282

35/6

4<

785

4390

24/

13<

29

203

3/13

<2

<2

135

8/13

5324

344

207/

13<

713

343

97/

13<

778

399

29/6

5<

278

4420

33/

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2<

211

24/

13<

25

229

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349

132

1440

10/1

3<

750

638

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1028

317

35/6

5<

744

1440

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25

264/

13<

25

139

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100

237

7/13

<7

6721

37/

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3212

231

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<2

2623

7Fr

iedm

ante

st(p

).2

963

.292

6.0

713

.603

9.3

916

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4

Not

e.T

hebo

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row

(Fri

edm

ante

stp)

show

sth

esi

gnifi

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chan

geof

cont

amin

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n(d

ecre

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)du

ring

the

4ca

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udy.

a Num

ber

ofpo

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esa

mpl

es/to

taln

umbe

rof

sam

ples

.

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Table

3.—

-Pla

tinum

Conce

ntr

ations

(pg/c

m2)

on

the

Surf

ace

sof

13

Cze

chH

osp

italP

harm

aci

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ear

eaPr

epar

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Wor

kben

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oor

Wor

kben

chFl

oor

Ref

rige

rato

rTo

tal

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paig

n75

th75

th75

th75

th75

th75

thno

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D.a

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ian

perc

entil

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18/

133.

26.

753

3010

/13

1.9

12.6

57.2

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914

353

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4.4

10.4

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23.

78.

122

.948

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3.7

8.9

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8.9

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3.4

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8.7

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214

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36

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342

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79.

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.537

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758

14

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101

Frie

dman

test

(p)

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357

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043

The

botto

mlin

e(F

ried

man

test

p)sh

ows

the

sign

ifica

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inth

ech

ange

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stud

y.a N

umbe

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ples

/tota

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ber

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mpl

es.

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Fig. 3. Comparison of monitoring results determinedfor postpreparation workbenches made of stainlesssteel (n = 32) and laminate (n = 20). The pan-els present throughput-weighted data for cyclophos-phamide (A) and platinum (B) (color figure availableonline).

only for Pt levels measured on the floor of the storage area (p< .05). The results of the individual sampling campaigns (in-cluding the Friedman test statistics) are presented in Table 2(CP) and Table 3 (Pt). Using the pharmacy as the groupingfactor, no significant decreases were found—most probablybecause of the low number of samples (n = 5) in the testedgroups and the resulting lack of statistical power.

COMMENT

This study evaluated surface contamination by CP and Ptat 5 selected sampling sites inside 13 hospital pharmacies.The measured concentrations showed wide ranges of values:<2 to 4420 pg/cm2 and <0.2 to 7340 pg/cm2 for CP andPt, respectively. Statistical analyses of the data revealed sig-nificant differences among the different pharmacies, and anapparent decreasing trend in the levels of contamination overthe 4 monitoring campaigns. It was demonstrated that the

Fig. 4. Comparison of monitoring results determinedfor refrigerator doors made of glass (n = 20) andplastic refrigerator doors covered with a syntheticcoating (n = 23). The panels present throughput-weighted data for cyclophosphamide (A) and plat-inum (B) (color figure available online).

contamination level was correlated with the throughput ofthe pharmacy.

Level of contamination

The preparation area was generally more contaminatedthan the storage area, which corresponds to findings ofother studies addressing the surface contamination of hos-pital pharmacies.20,23,27 With respect to literature, contam-ination levels detected in our study seem to be lower thancorresponding levels previously reported from Italy28,29 orwithin the same orders of magnitude as in Great Britain,30

Sweden,23 and The Netherlands.22 In contrast, other recentstudies from Germany have reported significantly lower val-ues,27,31 which indicates region- (or country-) specific lev-els of contamination. Direct comparison of different stud-ies is, however, complicated, since (i) the recovery of themethod used varies among the studies compared, and (ii) the

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contamination level depends on the throughput of the work-places studied, as shown in the present investigation.

It should also be noted that the results can be influencedby 2 important factors. Firstly, the results of any cited study(including the present one) can be affected by selection bias,as all studies were voluntary; therefore, it cannot be ruled outthat they failed to include institutions with the worst levelsof contamination or least effective procedures. Secondly, asthe responsibility for sample collection was devolved to in-dividual pharmacy workers, the results are also affected bythe limited sampling expertise of the operators. Although itwas verified that method precision and recovery were not af-fected by a change of operator (Table 1), the inexperience ofsome workers lacking good sampling practice led to the con-tamination of some field blanks with measurable amounts ofADs. However, this factor seems to be negligible, as positiveblanks occurred only in sample batches collected in highlycontaminated pharmacies and the contamination load of theblanks was about 2 orders of magnitude lower compared withrespective wipe samples.

Effect of laboratory throughput andpersonnel expertise

The potential association of contamination level withthroughput was previously suggested by other investiga-tors.23,32 In their studies, the highest values of average surfacecontamination were found at the workplaces where the largestquantities of the studied ADs were handled. However, manyother studies have reported contrary findings, ie, that highcontamination levels were repeatedly found in pharmacieswith relatively low AD preparation throughput.22,31,33 There-fore, it was suggested that the correct handling of cytotoxicagents (rather than the amount prepared) is more importantin minimizing contamination of the working environment18;however, to our knowledge, the influence of specific work-ing conditions affecting contamination levels has not beeninvestigated in detail.

The present study is, therefore, the first to assess statisticalrelationships between basic working conditions and the levelof contamination. Indeed, the relationship between contami-nation level and laboratory throughput was significant, whichindicates that large pharmacies are more likely to be contam-inated with higher amounts of ADs than small ones. Thecontamination level is, however, apparently also influencedby other factors such as the level of education and expertiseof relevant personnel, which was found to be an importantfactor in the present study. According to the authors’ opin-ion, the expertise of personnel is likely to determine the carewith which ADs are prepared and, therefore, the amounts ofADs that are released into the working environment. Otherfactors investigated by the current study (ie, the use of spikesor Luer-lock syringes for drug preparation) did not affect thecontamination level significantly or did not vary among thepharmacies (the type and technical status of the biological

safety cabinet in use); therefore, their influence on the resultscould not be evaluated.

Effect of sampling spot material

Interestingly, the material of the sampled surface alsoexhibited a significant effect on AD contamination levels.Laminate and synthetic coatings showed significantly higherCP contamination compared with stainless steel and glassfor postpreparation workbenches and refrigerator doors, re-spectively. Unfortunately, for the remaining 3 categories(prepreparation workbench and both floors), statistical eval-uation could not be performed due to the unbalanced dis-tribution of monitoring data into the groups according tomaterial.

As the materials with significantly lower contamination(stainless steel and glass) are supposed to be representativesof ideal materials with smooth and nonporous surfaces,25 thedifferences are unlikely to be caused by different degreesof surface sampler removal efficiency. Instead, differencesbetween the efficiencies of routine cleaning procedures forindividual surface materials and/or the different sorption po-tentials of the materials for ADs are probably the real causesof different levels of contamination of distinct surface mate-rials.

Decrease in contamination level

Interestingly, a decrease in levels of contamination wasdetermined during the course of the study (4 repeated sam-plings). Although statistical significance was only rarely ob-served regarding the specific sampling spots (p values areshown in Tables 2 and 3), data pooled together (N = 64) re-vealed significant decreases in both CP and Pt concentrations.According to the final (postmonitoring) questionnaires, theresults of the monitoring presented to pharmacy managersafter each sampling campaign contributed to an improve-ment in working conditions. For example, questionnairesfrom pharmacies B, C, E, F, K, and L reported increasedcleaning frequencies (especially in the storage area) and theintroduction of spatial sectioning of the work area into zonesfor AD handling and those for other activities. In 2 specificpharmacies (C and L), newly introduced procedures also in-cluded treatment of the work areas with oxidizing agents(active oxygen or sodium hypochlorite). All of these 6 phar-macies implementing the specified improvements revealed adecreasing trend in the contamination level during the study(see Figure 1A, B).

In general, this study seems to support the suggestionsof other reports that the systematic monitoring of contam-ination patterns (and improved awareness of the existingsituation vis-a-vis contamination on the part of pharmacymanagers) may lead to improvements in AD handling pro-cedures,5,18,33–35 which can effectively reduce surface con-tamination. Recently, long-term systematic monitoring ofGerman hospital pharmacies also led to the formulation ofthreshold guidance values used as benchmarks of tolerable

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levels of contamination.31 These values seem to be a veryuseful tool for helping hospital managers to evaluate theirown monitoring data.

Conclusions

The study revealed considerable differences in levels ofsurface contamination among pharmacies in the Czech Re-public. Contamination levels were associated with laboratorythroughput and level of personnel expertise, which under-lines the importance of education for pharmacy personneland especially for those in workplaces with high laboratorythroughput. Besides laboratory throughput and personnel ex-pertise, the surface material of the investigated areas wasalso shown to affect the contamination load. However, theresults are not conclusive and should be investigated further.Repeated monitoring (4 campaigns) promoted good practicethat led to a general decrease in contamination. Therefore, themonitoring of surface contamination seems to be an efficienttool that promotes good working practices and contributes tolower occupational exposure to hazardous ADs.

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The authors acknowledge financial support from the CYTO projectgranted by the Ministry of Education of the Czech Republic (no. NPVII2B06171). Infrastructure is supported by the European Regional Develop-ment Fund projects CETOCOEN (no. CZ.1.05/2.1.00/01.0001) and RE-CAMO (no. CZ.1.05/2.1.00/03.0101).

For comments and further information, address correspondence to PavelOdraska, MSc, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno,Czech Republic, CZ65653.

E-mail: odraska@centrum.cz

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References

1. Ensslin AS, Huber R, Pethran A, et al. Biological monitoring of hospitalpharmacy personnel occupationally exposed to cytostatic drugs: urinaryexcretion and cytogenetics studies. Int Arch Occup Environ Health.1997;70:205–208.

2. Sessink PJM, Bos RP. Drugs hazardous to healthcare workers—evaluation of methods for monitoring occupational exposure to cyto-static drugs. Drug Saf. 1999;20:347–359.

3. Schneider T, Cherrie JW, Vermeulen R, Kromhout H. Dermal exposureassessment. Ann Occup Hyg. 2000;44:493–499.

4. Hessel H, Radon K, Pethran A, et al. The genotoxic risk of hospital,pharmacy and medical personnel occupationally exposed to cytostaticdrugs—evaluation by the micronucleus assay. Mutat Res Genet ToxicolEnviron Mutagen. 2001;497:101–109.

5. Pethran A, Schierl R, Hauff K, Grimm CH, Boos KS, Nowak D. Uptakeof antineoplastic agents in pharmacy and hospital personnel. Part I:monitoring of urinary concentrations. Int Arch Occup Environ Health.2003;76:5–10.

6. Turci R, Sottani C, Spagnoli G, Minoia C. Biological and environmentalmonitoring of hospital personnel exposed to antineoplastic agents: areview of analytical methods. J Chromatogr B. 2003;789:169–209.

7. Yoshida J, Kosaka H, Tomioka K, Kumagai S. Genotoxic risks to nursesfrom contamination of the work environment with antineoplastic drugsin Japan. J Occup Health. 2006;48:517–522.

8. Turci R, Sottani C, Schierl R, Minoia C. Validation protocol and an-alytical quality in biological monitoring of occupational exposure toantineoplastic drugs. Toxicol. Lett. 2006;162:256–262.

9. Czech Ministry of Health Regulation. Vyhlaska o spravne lekarenskepraxi, blizsich podminkach zachazeni s lecivy v lekarnach, zdravotnick-

ych zarizenich a u dalsich provozovatelu a zarizeni vydavajicich lecivepripravky [Good pharmaceutical practice and drugs handling conditionsfor pharmacies, healthcare facilities and other entities emitting pharma-ceutical products to final consumers] [in Czech]. R.Lgs. n.84. 11 March2008. Available at: http://www.mzcr.cz. Accessed October 9, 2012.

10. Czech Goverment Regulation. Narizeni vlady, kterym se stanovi pod-minky ochrany zdravi pri praci [Occupational safety and health protec-tion at work] [in Czech]. R.Lgs. n.361. 12 December 2007. Availableat: http://www.mvcr.cz. Accessed October 9, 2012.

11. McDevitt JJ, Lees PSJ, McDiarmid MA. Exposure of hospital phar-macists and nurses to antineoplastic agents. J Occup Environ Med.1993;35:57–60.

12. Sessink PJM, Vandekerkhof MCA, Anzion RBM, Noordhoek J, BosRP. Environmental contamination and assessment of exposure to an-tineoplastic agents by determination of cyclophosphamide in urine ofexposed pharmacy technicians: is skin absorption an important exposureroute. Arch Environ Health. 1994;49:165–169.

13. Sessink PJM, Timmersmans JL, Anzion RBM, Bos RP. Assess-ment of occupational exposure of pharmaceutical plant workers to5-fluorouracil—determination of alpha-fluoro-beta-alanine in urine. JOccup Environ Med. 1994;36:79–83.

14. Kromhout H, Hoek F, Uitterhoeve R, et al. Postulating a dermal path-way for exposure to anti-neoplastic drugs among hospital workers. AnnOccup Hyg. 2000;44:551–560.

15. Sessink PJM, Boer KA, Scheefhals APH, Anzion RBM, Bos RP. Oc-cupational exposure to antineoplastic agents at several departments ina hospital—environmental contamination and excretion of cyclophos-phamide and ifosfamide in urine of exposed workers. Int Arch OccupEnviron Health. 1992;64:105–112.

16. Minoia C, Turci R, Sottani C, et al. Application of high performanceliquid chromatography tandem mass spectrometry in the environmen-tal and biological monitoring of health care personnel occupationallyexposed to cyclophosphamide and ifosfamide. Rapid Commun MassSpectrom. 1998;12:1485–1493.

17. Kiffmeyer T, Kube C, Opiolka S, Schmidt KG, Schoppe G, SessinkPJM. Vapour pressures, evaporation behaviour and airborne concentra-tions of hazardous drugs: implications for occupational safety. PharmJ. 2002;268:331–337.

18. Schmaus G, Schierl R, Funck S. Monitoring surface contamination byantineoplastic drugs using gas chromatography-mass spectrometry andvoltammetry. Am J Health Syst Pharm. 2002;59:956–961.

19. Hedmer M, Jonsson BAG, Nygren O. Development and validation ofmethods for environmental monitoring of cyclophosphamide in work-places. J Environ Monit. 2004;6:979–984.

20. Connor TH, DeBord G, Pretty JR, et al. Evaluation of antineoplasticdrug exposure of health care workers at three university-based US cancercenters. J Occup Environ Med. 2010;52:1019–1027.

21. Connor TH. Hazardous anticancer drugs in health care: environmentalexposure assessment. Ann N Y Acad Sci. 2006;1076:615–623.

22. Brouwers EEM, Huitema ADR, Bakker EN, et al. Monitoring of plat-inum surface contamination in seven Dutch hospital pharmacies usinginductively coupled plasma mass spectrometry. Int Arch Occup EnvironHealth. 2007;80:689–699.

23. Hedmer M, Tinnerberg H, Axmon A, Jonsson BAG. Environmentaland biological monitoring of antineoplastic drugs in four workplacesin a Swedish hospital. Int Arch Occup Environ Health. 2008;81:899–911.

24. Odraska P, Dolezalova L, Kuta J, Oravec M, Piler P, Blaha L. Evaluationof the efficacy of additional measures introduced for the protection ofhealthcare personnel handling antineoplastic drugs. Ann Occup Hyg.2013;57:240–250.

25. Occupational Safety and Health Administration. Evaluating guidelinesfor surface sampling methods. 2001. Available at: http://www.osha.gov/dts/sltc/methods/surfacesampling/surfacesampling.html. AccessedOctober 9, 2012.

26. Larson RR, Khazaeli MB, Dillon HK. Monitoring method for surfacecontamination caused by selected antineoplastic agents. Am J HealthSyst Pharm. 2002;59:270–277.

27. Funck S, Schierl R. Sicherheit bei der Zytostatikaherstellung. DtschApoth Ztg. 2004;144:1089–1094.

28. Acampora A, Castiglia L, Miraglia N, et al. A case study: surface con-tamination of cyclophosphamide due to working practices and clean-ing procedures in two Italian hospitals. Ann Occup Hyg. 2005;49:611–618.

2014, Vol. 69, No. 3 157

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29. Castiglia L, Miraglia N, Pieri M, et al. Evaluation of occupational expo-sure to antiblastic drugs in an Italian hospital oncological department.J Occup Health. 2008;50:48–56.

30. Mason HJ, Blair S, Sams C, et al. Exposure to antineoplastic drugs intwo UK hospital pharmacy units. Ann Occup Hyg. 2005;49:603–610.

31. Schierl R, Bohlandt A, Nowak D. Guidance values for surface moni-toring of antineoplastic drugs in German pharmacies. Ann Occup Hyg.2009;53:703–711.

32. Yoshida J, Koda S, Nishida S, Yoshida T, Miyajima K, Kumagai S. As-sociation between occupational exposure levels of antineoplastic drugs

and work environment in five hospitals in Japan. J Oncol Pharm Pract.2011;17:29–38.

33. Heinemann A, Hadtstein C. Mewip—Monitoring-Effekt-Studie furWischproben in Apotheken—Hinweise zur Planung eines Umge-bungsmonitorings. ASUpraxis. 2009;44:37–39.

34. Bos RP, Sessink PJM. Biomonitoring of occupational exposure to cy-tostatic anticancer drugs. Rev Environ Health. 1997;12:43–58.

35. Sessink PJM, Wittenhorst BCJ, Anzion RBM, Bos RP. Exposure ofpharmacy technicians to antineoplastic agents: reevaluation after addi-tional protective measures. Arch Environ Health. 1997;52:240–244.

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