Contaminations chimiques par les anticancéreux en pharmacie hospitalière : Suède

O. Nygren Department of Chemistry, Umeå University, Umeå, Sweden

Rules and regulations in Sweden

Already in 1980-ies, the Swedish Work Health Authority paid attention to the problem with occupational exposure to cytotoxic drugs. The first ordinance on handling cytotoxic drugs was issued in 1984. The current ordinance was issued in 2005 [1] and do also cover other drugs with permanent toxic effects, e.g., some antibiotics and antiviral drugs. The ordinance state that the health risks should be evaluated and relevant and appropriate precau­tions shall be undertaken before any work, that could cause exposure, can commence. This app­lies to all groups of pharmacy staff that could be exposed (e.g., also cleaning and maintenance staff). The risk evaluation shall be made together with the staff concerned. Based on the risk evaluation, handling instructions shall be made and be avail­able for the staff in their maternal language. The staff shall get ade­qu­ate and appropriate edu­cation for their work tasks. Adequate protective clothes and devices shall be used. The prepara­tion shall be car­ried out so spill and leakage are mini­mi­zed and, if it occurs, it should not be dispersed uncontrolled. The ordinance recommends that prepa­ra­tions are carried out inside a biological safety cabinet (BSC) or similar technical device. Closed sys­tems can also be used, if shown to functioning for the specific work task. All preparation systems shall be tested annually during the normal way (method) of working. Garba­ge shall be placed in specific containers appropri­ately marked and should be kept closed to mini­mize emissions of possible vaporized drug com­ponents.

Measurements methods used in Sweden

Sampling has been focused on

  • collecting wipe samples (benches, wall, floor, drug vials, prepared infusion bags) ;
  • collecting possible contaminated materials (bench cover sheets, disposal gloves) ;
  • collecting biological samples (blood or urine samples).

Platinum (Pt) has been analysed as tracer for Cisplatin and similar drugs using adsorptive cathodic stripping voltammetry (AdCSV) [2] or portable X-ray fluorescence (XRF) [3] [4]. Cyclophosphamide (CP) and ifosfamide (IF) has been analysed in the samples using liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) [5]. In Sweden the radioisotope Technetium m-99 (m99Tc) has been used in a test method (Tc-method) for evaluation of preparation systems [6]. The Tc-test is not valid for testing release of vaporised compounds since m99Tc is not volatile.

Investigations in Sweden

Here follows a short and not complete summary of investigations carried out at Swedish pharmacies during recent time.

One investigation was carried out in a drug preparation room using a special test set-up. At the experiments, each test subject made six preparations with m99Tc prepared vials using the pump (milking) technique and a closed system (PhaSeal) [7]. The leakage onto gloves and the bench cover was about 3-4 orders of magnitude lower using the closed system, compared with the pump technique. All of the test subjects also showed a large variation of the leakage using the traditional technique. With the closed system even inexperienced test subjects generally performed preparations with low or no spill.

CP and ifosfamide (IF) contamination in a hospital pharmacy was investigated using wipe sampling [8]. Both Cp and IF were found the the samples. On the floor in the preparation and dressing rooms the CP level ranged from 100 – 1000 pg cm-2, while in offices and on benches the level was below 20 pg cm-2. After changing the cleaning routines all locations were below 60 pg cm-2. Another authentic work environment at a hospital pharmacy in Sweden was investigated [9]. The hospital pharmacy prepared cytotoxic drugs to many different departments at the hospital. All cytotoxic drugs were prepared inside BSC. Wipe samples were collected in the BSC after preparation of an infusion mixture containing 1000 mg CP. CP was detected in the samples and corresponded to a level between 3.3 and 3.5 pg cm-2.

In a preparation room Cisplatin drug preparation was performed in a BSC. There was, however, concern that spill and leakage inside the cabinet would be emitted into the room. Portable-XRF was used on-site to measure the Pt level in wipe samples [10]. The Pt-level was highest inside the BSC and decreased with increasing distance from the cabinet. This simple screening, taking less than an hour, showed how the drug had been spread around in the preparation room in spite that all handling of the drug was carried out in a BSC.

Contamination of drug vials has been studied. Drug vials from three different manufacturers of Cisplatin were investigated [11]. Wipe samples were collected by thoroughly wipe the outside of ten randomly picked vials from newly opened packages. Elevated platinum amounts were found on two of the ten vials. In another study, outer packages of Sendoxan (CP) and Holoxan (IF) were studied [12]. CP was found on all packages in the range 0.2-5.1 ng/package. Low amounts of IF (<0.08 ng) was found on a few packages. Also most of the vials were contaminated on the outside up to 200 ng/vial.

The new handling system, TevadaptorTM, has been tested using the Tc-method [13]. The test results showed that the spill was lower than 100 nL for all 75 preparations in the test and was below 1 nL for 70 of the preparations. This is comparable with other tested closed drug handling systems.

Biological sampling has mainly been carried out on nurses in Sweden and there is limited information on pharmacists. In one study we followed two test subjects during one week where they made 10 daily CP preparations [14]. We collected 24 h voided urine volume during the whole week. No CP was detected on Monday and Tuesday but from Wednesday to Fridayand CP in urine was detected in both subjects and increased during the week from detection limit (< 0.1 µg L-1) up to 0.21 µg L-1 on Friday.

Blood and urine samples have also been collected from pharmacists preparing infusion bags with Cisplatin [15]. These samples were spot samples and they were analysed using AdCSV. Pt above normal values was detected in the several samples, but not as high as samples from nurses doing similar preparations.

Measures to reduce exposure in Sweden

In many Swedish hospitals preparation of cytotoxic drugs has been centralized to special facili­ties at the hospital pharmacy. Work in BSC is standard for preparation of cytotoxic drugs. In some cases the systems regarded as closed (e.g., PhaSeal, Tevadaptor) or filter spikes are used as extra precaution. In one hospital, the PhaSeal system has been used on open bench for several years without any monitored spill or leakage in the regular tests. More focus has also been put on cleaning routines to avoid spreading drugs during cleaning. There is also an increasing attention paid on the use of closed systems for preparation of antibiotics and other reactive drugs.

[1ASF Ordinance 2005:5, Work Health Authority, Solna, Sweden, 2005

[2Nygren O, Vaughan G T, Florence M T, Morrison G M P, Warner I M and Dale L S. Determination of platinum in blood by adsorptive voltammetry. Anal Chem 62 (1990), 1637-1640

[3Nygren, O. New approaches for assessment of occupational exposure to metals using on-site measurements. J Environ Monit 4 (2002), 623 - 627

[4Nygren O and Aspman O. Validation and application of wipe sampling and portable XRF analysis as an on-site screening method for assessment of deposited aerosols on workplaces. Aust J Chem 37 (2004), 1021-28

[5Hedmer M, Jönsson B A, Nygren O. Development and validation of methods for environmental monitoring of cyclophosphamide in workplaces. J Environ Monit 6 (2004), 979-84

[6Nygren O, Gustavsson B, Eriksson R. A test method for assessment of spill and leakage from drug preparation systems. Ann Occup Hyg, 49 (2005), 711 - 718

[7Nygren O, Gustavsson B, Ström L, Eriksson R, Jarneborn L, Friberg A. Exposure to anti-cancer drugs during preparation and administration. Investigations of an open and a closed system. J Environ Monit 4 (2002), 739 - 742

[8Hedmer M, Monitoring of Occupational exposure to antineoplastic drugs. Faculty of Medicine Doctoral Disseration Series 2006:56, Lunds University, Lund, 2006

[9Nygren O. Development of measuring methods based on wipe sampling for assessment of emission and distribution of cytotoxic drugs in indoor environments. Proc 10th Intl Conf Indoor Air Quality and Climate, pp 2756-2761, 4-9th Sept, Beijing, China, 2005


[11Nygren O, Gustavsson B, Eriksson R, Friberg A. Cisplatin contamination observed on the outside of drug vials. Ann Occup Hyg 46 (2002), 555-557

[12Hedmer M, Monitoring of Occupational exposure to antineoplastic drugs. Faculty of Medicine Doctoral Disseration Series 2006:56, Lunds University, Lund, 2006

[13Nygren O, Olofsson E and Johansson L. Spill and leakage using a drug preparation system based on
double filter technology. Ann Occup Hyg, submitted 2007

[14Nygren, O. Unpublished data


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