Ann. occup. Hyg., Vol. 46, No. 6, pp. 555-557, 2002
© 2002 British Occupational Hygiene Society
Published by Oxford University Press
Cisplatin Contamination Observed on the Outside of Drug Vials
1 National Institute for Working Life, Program for Chemical Exposure Assessment, PO Box 7654, SE-907 13 Umeå; 2 Östra Hospital, Surgical Department, SE-416 85 Göteborg; 3 Östra Hospital, Hospital Pharmacy, SE-416 85 Göteborg, Sweden
Received 20 December 2001; in final form 7 May 2002
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONSREFERENCES |
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Exposure to cytotoxic drugs is of great concern today. Special regulations for handling these drugs during preparation and administration have been implemented in most countries. Concern has also been raised as to whether exposure to these drugs can occur due to contaminated drug vials. In this investigation, wipe samples were taken from drug vials used for platinum-containing drugs, e.g. cisplatin and related drugs. The vials were randomly picked from unbroken packages from different manufacturers. The results showed that drug vials may already be contaminated on the outside when delivered from the manufacturer.
Keywords: cytotoxic drugs; vial contamination; cisplatin
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONSREFERENCES |
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There has been concern about exposure to cytotoxic drugs (Sessink et al., 1992; Baker and Connor, 1996; Sorsa and Anderson, 1996). Many cytotoxic drugs are known to be carcinogens and antibiotics are known to cause pulmonary and skin allergies. Most concern has been focused on drug preparation and administration. Extensive safety precautions using biological safety cabinets (BSCs) as well as protective clothing have been described for handling cytotoxic drugs (Harrison, 1981; Kolmodin-Hedman et al., 1983; Valanis et al., 1992; Canadian Society of Hospital Pharmacists, 1993; Davis et al., 1997) and have also been introduced to a varying extent in drug-handling guidelines in many countries.
Several studies have shown that cyclophosphamide can be found in urine from occupationally exposed workers (Sessink et al., 1994). Cyclophosphamide, 5-fluorouracil and methotrexate have, furthermore, been found in the air and on the floor and workbenches in drug preparation rooms, although preparations had been carried out in BSCs (Ensslin et al., 1994; Sessink et al., 1994; Connor et al., 1999). Moreover, increased levels of platinum have also been found in blood samples from nurses and nurses’ assistants, who worked with patients treated with cisplatin (Nygren et al., 1990; Nygren and Lundgren, 1997). These reported findings show that exposure does occur during handling of drugs, even when preparation is carried out in BSCs as well as during administration to patients. The route of exposure, however, is not evident. Beside airborne drug emission and skin exposure due to leakage, contamination of the drug substance on the outside of the vials must also be considered as a possible source of skin exposure. In a Dutch study, contamination on the outside of cyclophosphamide drug vials was investigated (Ros et al., 1997). They found a significant contamination by cyclophosphamide on the outside of the drug vials.
This paper presents an investigation of the possible contamination on the outside of cisplatin drug vials taken from unbroken packages. Platinum was used as a tracer and was analysed using adsorptive voltammetry.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONSREFERENCES |
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Chemicals and materials
All chemicals were of analytical or higher quality and the water was purified in a Milli-RQ Water Purifier (Millipore Corp., Bedford, MA). A commercial AAS Pt-standard (Spectrascan 1.000 g/l, Teknolab A/S, Oslo, Norway) was used as platinum standard.
Wipe sampling of drug vials
Drug vials from three different manufacturers were investigated. The vials (20 ml) were delivered in sixes packed in sealed styrolite foam boxes. One vial was taken at random from two different drug packages from each manufacturer. A wipe sample was collected by thoroughly wiping the outside of each vial with a 3 x 3 cm cellulose pad (Apoteksbolaget, Stockholm, Sweden), moistened with 0.25 ml of water. The vial cap cover on each vial was then removed. Another wipe sample was then collected by wiping the inside of the cap cover in the same way. Each pad was placed in a plastic bag and stored at +4°C prior to analysis. As blanks, four unused pads, two dry and two wetted with 0.25 ml of water, were placed in plastic bags and stored with the samples prior to analysis.
Analytical procedures
Platinum on the wipe pads was determined using adsorptive voltammetry (Nygren and Lundgren, 1997; Nygren et al., 1990). In short, the pads were placed in silica crucibles. To fit into the bottom of the crucibles, the pads had to be cut into four pieces. To avoid cross-contamination, each pad was cut on separate glass plates using separate scalpels. The samples were then ashed in a muffle furnace employing a temperature programme up to a final temperature of 800°C. The residues were dissolved in aqua regia and taken to dryness before dissolving in concentrated hydrochloric acid. Each sample was then transferred to the measuring cell, and hydrazine and formaldehyde were added to form a Pt–formazone complex. The Pt concentration in the sample was determined using a polarograph (640 VA-Processor and 647 VA-Stand, Methrom, Herisau, Switzerland). The Pt-complex was adsorbed on a hanging mercury drop electrode at –800 mV versus a silver/silver chloride [Ag/AgCl (3 M KCl)] electrode, followed by stripping at 25 mV/s to –1050 mV in differential pulse mode. Standard additions to each sample, using a daily prepared Pt standard, were used for quantification. The detection limit was 0.1 ng/sample.
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RESULTS AND DISCUSSIONS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONSREFERENCES |
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The dry and wet blanks did not show any significant difference and the average of all four blanks (±SD) was 2.8 ± 1.3 ng. A Pt level higher than three times the SD above the blank was regarded as an elevated level (
6.6 ng). The results of the wipe sampling are shown in Table 1. For one of the six vials (no. 2), elevated Pt levels were found both on the pad used for wiping the outside the vial (37 ng) and on the pad used for wiping the vial cap cover (21 ng). On vial no. 4, 99 ng was found on the pad used for wiping the outside of that vial. No other samples were found to have elevated Pt levels.
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These elevated Pt levels show that the vials were most probably contaminated with the Pt-containing drug during the manufacture or packing process. Although this investigation only comprises a limited number of samples, these results indicate that contaminated drug vials may be delivered from manufacturers. However, the possible contamination and its source need to be elucidated further before any extended conclusions can be drawn.
Acknowledgements—We thank Mrs Ewa Kragh and Ms Cecilia Lundgren for technical assistance with platinum analyses. The Swedish Council for Work Life Research (former Swedish Work Health Fund) is acknowledged for financial support.
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FOOTNOTES |
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* Author to whom correspondence should be addressed. Tel: +46-90-176039; fax: +46-90-16-176123; e-mail: olle.nygren{at}niwl.se
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONSREFERENCES |
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Baker ES, Connor TH. (1996) Monitoring occupational exposure to cancer chemotherapy drugs. Am J Health-Syst Pharm; 53: 2713–23.
Canadian Society of Hospital Pharmacists. (1993) Guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs). Ottawa.
Connor TH, Anderson RW, Sessink PJM, Broadfield L, Power LA. (1999) Surface contamination with antineoplastic agents in six cancer treatment centers in Canada and the United States. Am J Health-Syst Pharm; 56: 1427–32.
Davis J, Jackson J, Kirsa S et al. (1997) SHPA standards of practice for the safe handling of cytotoxic drugs in pharmacy departments. SHPA Practice Standards; 8–1: 8–10.
Ensslin AS, Pethran A, Schierl R, Fruhmann G. (1994) Urinary platinum in hospital personnel occupationally exposed to platinum-containing antineoplastic drugs. Int Arch Occup Environ Health; 65: 339–42.[Web of Science][Medline]
Harrison RB. (1981) Developing guidelines for working with antineoplastic drugs. Am J Hosp Pharm; 38: 1686–93.[Abstract]
Kolmodin-Hedman B, Hartvig P, Sorsa M et al. (1983) Occupational handling of cytostatic drugs. Arch Toxicol; 54: 25–33.[Web of Science][Medline]
Nygren O, Lundgren C. (1997) Determination of platinum in workroom air and in blood and urine from nursing staff working with patients receiving cisplatin chemotherapy. Int Arch Occup Environ Health; 70: 209–14.[Web of Science][Medline]
Nygren O, Vaughan GT, Florence M et al. (1990) Determination of platinum in blood by adsorptive voltammetry. Anal Chem; 62: 1637–40.[Medline]
Ros JJW, Simons KA, Verzijl JM et al. (1997) Practical applications of a validated method of analysis for the detection of traces of cyclophosphamide on injection bottles and at oncological outpatient center. Ziekenhuisfarmacie; 13: 168–71.
Sessink PJM, Anzion RB, Van den Broek PHH, Bos RP. (1992) Detection of contamination with antineoplastic agents in a hospital pharmacy department. Pharm Weekbl (Sci); 14: 16–22.
Sessink PJM, van de Kerkhof MCA, Anzion RBM et al. (1994) Environmental contamination and assessment of exposure to anti-neoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians: is skin absorption an important exposure route? Arch Environ Health; 49: 165–9.[Web of Science][Medline]
Sorsa M, Anderson D. (1996) Monitoring of occupational exposure to cytostatic anticancer agents. Mutat Res; 355: 253–61.
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