Clinical Evidence of Risk: Environmental Contamination
1. Connor T, Anderson R, Sessink PJM et al. Surface contamination with antineoplastic agents in six cancer centers in Canada and the United States. Am J Health-System Pharm. 1999; 56: 1427-1432.
The level of contamination by antineoplastic agents in drug preparation and administration areas in cancer treatment centers in Canada and the United States was determined. Sampling locations at three cancer treatment centers in Canada and three centers in the United States were selected (biological safety cabinets, countertops, and floors in and adjacent to preparation areas; tabletops, chairs, and floors in administration areas). A solution of sodium hydroxide (0.03 M) was spread over the surface of each area. The surface was wiped with one or two absorbent tissues, which were then stored in plastic screw-top containers. Samples were stored at -40 degrees C before analysis of ifosfamide content (U.S. centers only) and cyclophosphamide content by gas chromatography in tandem with mass spectroscopy-mass spectroscopy and fluorouracil content by reverse-phase high-performance liquid chromatography with ultraviolet-light detection. Measurable amounts of the antineoplastic agents were detected in 75% of the pharmacy samples and 65% of the administration samples. In general, the levels of contamination were higher in the pharmacy areas than in the drug administration areas. The pharmacy area at the site with the highest number of drug preparations had considerably more drug contamination than the other sites. The results were similar for Canadian and U.S. centers. Substantial levels of contamination from three antineoplastic agents were detected on a variety of surfaces in pharmacy drug preparation areas and drug administration areas in six cancer treatment centers in Canada and the United States.
2. Connor T, Shults M, Fraser M. Determination of the vaporization of solutions of mutagenic antineoplastic agents at 23 and 37°C using a desiccator technique. Hosp Pharm. 1999; 34(11): 85-92.
This study evaluated the ability of mutagenic antineoplastic agents to vaporize at room temperature (23 degrees C) and 37 degrees C. A bacterial mutagenicity assay was used to determine the mutagenicity of these agents in the vapor phase. Open plates of bacteria were exposed to varying amounts of drug solutions in sealed glass containers for 24h. The drug solutions were prepared as they would be for patient treatment and were tested at 0.25, 0.5 and 1.0 ml of each drug solution per 10 l of air. Following exposure, the plates exposed at 23 degrees C were incubated an additional 48 h at 37 degrees C to allow for expression of mutations. Those exposed at 37 degrees C were incubated for an additional 24h at 37 degrees C. Carmustine, cyclophosphamide, ifosfamide, thiotepa, and mustargen demonstrated vaporization at 37 degrees C. Carmustine and mustargen also demonstrated significant vaporization at 23 degrees C, while cyclophosphamide demonstrated a 50% increase in revertants at this temperature. In addition, sodium azide, a known mutagen used as a control was also mutagenic as a vapor at both temperatures. Doxorubicin, cisplatin, etoposide, 5-fluorouracil and mitomycin were not detected as vaporizing in this assay. The study found that vaporization of standard solutions of some antineoplastic agents is possible at room temperature and increases as the temperature increases. Therefore, vaporization of spilled antineoplastic agents may present an additional route of exposure to healthcare workers through inhalation.
3. Sessink PJM, Bos RP. Drugs hazardous to healthcare workers (evaluation of methods for monitoring occupational exposure to cytostatic drugs). A Review Article. Drug Safety. 1999; 20(4): 347-359.
We review the literature concerning possible health risks for individuals (e.g. healthcare workers and pharmaceutical plant employees) occupationally exposed to cytostatic drugs. Cytostatic drugs possess toxic properties and may therefore cause mutagenic, carcinogenic and teratogenic effects. Hence, individuals handling these drugs in the course of their employment may face health risks. For this reason, it is important to monitor occupational exposure to these drugs. An overview of exposure monitoring methods is presented and their value is discussed. Most studies involve nonselective methods for biological monitoring and biological effect monitoring, such as the urinary mutagenicity assay and analysis of chromosomal aberrations and sister-chromatid exchanges in peripheral blood lymphocytes. The disadvantages of these biological methods are that their sensitivity is low and it cannot be proved beyond any doubt that the results found were caused by occupational exposure to cytostatic drugs. For occupational health services it is important to have sensitive and specific methods for monitoring exposure to cytostatic drugs. One of the most promising methods seems to be the determination of cyclophosphamide in urine using gas chromatography-tandem mass spectrometry. Several studies have demonstrated exposure to cyclophosphamide and other cytostatic drugs, even when protective measures were taken and safety guidelines were followed. To estimate the magnitude of any health effects arising from this exposure, we calculated the risk of cancer due to occupational exposure to cyclophosphamide on the basis of available human and animal dose-response data and the amounts of cyclophosphamide found in urine. The initial results show an extra cancer risk for pharmacy technicians and nurses.
4. Minioia C, Turci R, Sotannie C et al. Application of high performance liquid chromatography/tandem mass spectrometry in the environmental and biological monitoring of healthcare personnel occupationally exposed to cyclophosphamide and ifosfamide. Rapid Commun Mass Spectrum. 1998; 12: 1485-1493.
Twenty four workers (10 involved in the preparation and 14 in administration) exposed to cyclophosphamide (CP) and ifosfamide (IF) in two Italian hospitals were monitored. The extent of exposure was assessed by the analysis of air samples, wipe samples, pads and gloves. Urinary excretion at the beginning and at the end of the work shift was also measured by liquid-liquid extraction and analysis by high performance liquid chromatography/tandem mass spectrometry. Three out of 24 air samples were positive for CP or IF. In wipe samples, CP concentrations ranging from < 0.001 to 82.4 micrograms/dm2 in Hospital A (32 samples) and from 0.2 to 383.3 micrograms/dm2 in Hospital B (17 samples), were found. IF concentrations varied from < 0.001 to 90.9 micrograms/dm2 in Hospital A and from 0.01 to 141.5 micrograms/dm2 in Hospital B. Pads (from 11 to 13 for each operator) were contaminated with CP and IF especially on arms, legs and chest. The use of a plastic-backed liner on the working tray in the laminar flow hoods was demonstrated to compromise the containment properties of the hood. Urine samples were positive for CP in 50% of the workers (range: 0.1-2.1 micrograms/L), whereas IF was detected in 2 subjects only (range: 0.1-0.8 microgram/L). The results of this investigation demonstrate that vertical laminar airflow hoods, when incorrectly used, might represent a source of contamination and that higher risk may depend on lack of educational programmes and observance of preventive guidelines.
5. Opiolka S, Molter W, Goldschmidt R et al. Evaporation of cytostatic drugs during preparation. Gefahrstoffe-Reinhaltung der Luft. 1998; 58.
For the purpose of occupational health and safety and product safety, cytostatic drugs are prepared at enclosed and especially protected work benches. Filters (high efficiency submicron particulate air filters) make sure that particulate matter is separated, while gaseous components are not.
As far as cytostatic vapours are released during the preparation of cytostatic drugs, they might, under certain circumstances, contaminate the workplace atmosphere. This is also true for cytostatic particles on the filter which may change to the gaseous condition in the course of time. The vapour pressure values for cyclophosphamide and 5-fluorouracil were determined within the framework of research projects co-financed by the Ministries for Science and Research and for Labour and Social Affairs of North Rhine-Westphalia. A vapour pressure balance was used in accordance with Guideline 104 of the OECD. At a temperature of 20 °C, 0.0033 Pa were measured for cyclophosphamide and 0.0014 Pa for 5-fluorouracil. From this, saturation concentrations of 0.36 mg/m3 and 0.08 mg/m3 can be derived. In the mentioned cases, particles of a diameter of 50 µm are evaporated within approximately a day´s time.
6. Baker E, Connor T. Monitoring occupational exposure to cancer chemotherapy drugs. A Review Article. Am J Health-System Pharm. 1996; 53: 2713-2723.
Reports of the health effects of handling cytotoxic drugs and compliance with guidelines for handling these agents are briefly reviewed, and studies using analytical and biological methods of detecting exposure are evaluated. There is little conclusive evidence of detrimental health effects from occupational exposure to cytotoxic drugs. Work practices have improved since the issuance of guidelines for handling these drugs, but compliance with the recommended practices is still inadequate. Of 64 reports published since 1979 on studies of workers’ exposure to these drugs, 53 involved studies of changes in cellular or molecular endpoints (biological markers) and 12 described chemical analyses of drugs or their metabolites in urine (2 involved both, and 2 reported the same study). The primary biological markers used were urine mutagenicity, sister chromatid exchange, and chromosomal aberrations; other studies involved formation of micronuclei and measurements of urinary thioethers. The studies had small sample sizes, and the methods were qualitative, nonspecific, subject to many confounders, and possibly not sensitive enough to detect most occupational exposures. Since none of the currently available biological and analytical methods is sufficiently reliable or reproducible for routine monitoring of exposure in the workplace, further studies using these methods are not recommended; efforts should focus instead on wide-spread implementation of improved practices for handling cytotoxic drugs.
7. Sessink PJM, Friemel NSS, Anzion RBM et al. Biological and environmental monitoring of occupational exposure of pharmaceutical plant workers to methotrexate. Int Arch Environ Health. 1994; 65: 401-403.
The exposure of 11 pharmaceutical plant workers to methotrexate (MTX) was studied. Personal air samples were taken during the different manufacturing processes: drug compounding, vial filling, and tablet preparation. The uptake of MTX was established by the determination of MTX in urine. MTX was analyzed using the fluorescence polarization immunoassay (FPIA), a method that is frequently used for monitoring serum levels in patients treated with MTX. The FPIA method was modified in such a way that MTX could be measured quickly and efficiently in air and urine samples. MTX was detected in air samples of all workers except for those involved in the vial filling process (range: 0.8-182 micrograms/m3; median: 10 micrograms/m3). The highest concentrations were observed for workers weighing MTX (118 and 182 micrograms/m3). MTX was detected in urine samples of all workers. The mean cumulative MTX excretion over 72-96 h was 13.4 micrograms MTX-equivalents (range: 6.1-24 micrograms MTX-equivalents). A significantly lower background level of 10.2 micrograms MTX-equivalents was measured in urine of 30 control persons (range: 4.9-21 micrograms MTX-equivalents).
8. Sessink PJM, Timmermans JL et al. Assessment of occupational exposure of pharmaceutical plant workers to 5-fluorouracil. Determination of a-fluoro-b-alanine in urine. J Occup Med. 1994; 36: 79-83.
The exposure of pharmaceutical plant workers, involved in drug compounding and drug production, to 5-fluorouracil (5FU) was studied. 5FU was found by the analysis of air and wipe samples. During weighing, 5FU was detected in the air (75 micrograms/m3). 5FU was also present on the filter of the mask of the weigher (120 micrograms). Before drug compounding 5FU was found on the floor (range, < 1 to 8 ng/cm2; median, 2 ng/cm2). After routine cleaning significant higher amounts of 5FU were measured (range, 70 to 630 ng/cm2; median, 150 micrograms/cm2; P = .02). The amounts of 5FU present on several objects were lower when compared to the amounts on the floor. The gloves used were always contaminated (range, 22 to 720 micrograms/pair of gloves; median, 141 micrograms/pair of gloves). The uptake of 5FU was established by the determination of alpha-fluoro-beta-alanine, the main metabolite of 5FU, in the urine of the workers. Fifty micrograms of alpha-fluoro-beta-alanine were found in urine of the weigher.
9. Sessink PJM, Wittenhorst BCJ et al. Exposure of pharmacy technicians to antineoplastic agents; reevaluation after additional protective measures. Department of Toxicology, Faculty of Medical Sciences, University of Nijmegen, The Netherlands. Submitted 1994.
In the past, special guidelines and protective measures have been introduced to protect hospital workers during the handling of antineoplastic agents; nevertheless, it was found that they did not prevent the uptake of these toxic compounds. In response, additional protective measures were introduced, including adaptations of the laminar downflow hood, use of special masks, use of double pairs of gloves, and replacement of ampules with vials. In the current study, the authors compared the effects in these additional measures with results of a previous study. Cyclophosphamide, 5-fluorouracil, and methotrexate constituted 81% of the antineoplastic agents prepared; therefore, the investigators monitored these compounds again by personal air sampling and by determining the levels of contamination on masks and gloves. Cyclophosphamide in the urine of workers was also measured. During preparation, investigators concluded that there were lower concentrations of cyclophosphamide in the air than had occurred in the previous study. Replacement of ampules with vials (i.e., 5-fluorouracil) resulted in a significantly diminished contamination of latex gloves. Cyclophosphamide was detected in urine samples provided by six of nine technicians; the maximum amount excreted over 5 d was 2.6 microg. The mean cyclophosphamide excretion/d was not significantly lower than that found in the previous study (0.16 microg and 1.44 microg, respectively). Despite an intensified hygienic regimen, exposure to antineoplastic agents cannot be reduced if the reasons for exposure remain unknown.
10. Sessink PJM, Joost HC et al. Occupational exposure of animal caretakers to cyclophosphamide. Journal of Occupational Medicine. 1993; 35: 47-52.
Little is known about the exposure of animal caretakers to toxic agents during the administration of such chemicals to laboratory animals. In this study, we have investigated the environmental contamination with cyclophosphamide (CP) in an animal laboratory where mice were housed and injected with this compound. Also the contamination of gloves, sleeve protectors, and masks used for personal protection was studied. The uptake of CP by the animal caretakers was determined by the analysis of unmetabolized CP in urine. For the estimation of CP in the air, air samples were taken and filters of the air-circulation system were analyzed. On the filters, amounts of CP were detected corresponding with < 0.1-1.0 microgram/day. Environmental contamination was also measured by analysis of wipe samples taken from different spots (objects and surfaces). The presence of CP was not only observed in the room where the mice were housed and treated with CP but also in adjacent rooms (< 0.02-44 ng/cm2). The gloves used during the injection of CP were always contaminated (2-199 micrograms/pair). No penetration of the gloves was established. The sleeve protectors were incidentally contaminated (< 0.3-10 micrograms) and on the masks no CP was found (< 0.2 microgram). Eighty seven urine samples from four animal caretakers were analyzed for unmetabolized CP. In one sample, CP was detected (0.7 microgram). The results show that in this particular study animal caretakers are exposed to CP during their work.
11. Sessink PJM, Anzion RBM et al. Detection of contamination with antineoplastic agents in a hospital pharmacy department. Pharmaceutisch Weekblad Scientific Edition. 1992; 14: 16-22.
The contamination with Fluorouracil (5FU), cyclophosphamide (CP) and methotrexate (MTX) was studied in a hospital pharmacy department where these drugs were prepared. In the preparation room, air samples were taken before and during preparation of the drugs. MTX was detected in one sample which was collected during preparation (0.3 µg/m3). Spot samples were taken in the vertical laminar air-flow safety hood before and after preparation of the drugs and after cleaning of the hood.
Contamination of the laminar air-flow hood was: CP: 1-160 ng/cm2; 5FU: 10-62 ng/cm2 and MTX 2-623 ng/cm2. Spot samples from the floor in front of and beneath the laminar air-flow hood showed contamination with especially 5FU (48-236 µg/m2). The gloves used during preparation of the drugs were contaminated mainly with 5FU (5-980 ng/cm2). Urine samples from two workers involved in the preparation of the drugs were analysed for unmetabolized CP; it was not detected. Although no uptake of CP was established, it is shown that the methods for measurement of CP, 5FU and MTX in the preparation room are applicable for the control of occupational exposure to these drugs.
12. Sessink PJM, Boer KA, Scheefhals APH et al. Occupational exposure to antineoplastic agents at several departments in a hospital. Int Arch Occup Environ Health. 1992; 64: 105-112.
The occupational exposure to cyclophosphamide (CP), ifosfamide (IF), 5-fluorouracil (5FU), and methotrexate (MTX) of 25 pharmacy technicians and nurses from four departments of a hospital was investigated. Previously developed methods for the detection of exposure to some antineoplastic agents were validated. Exposure to CP, IF, 5FU, and MTX was measured by the analysis of these compounds in the environment (air samples and wipe samples from possible contaminated surfaces and objects). Contamination of the work environment was found not only on the working trays of the hoods and on the floors of the different rooms but also on other objects like tables, the sink unit, cleaned urinals and chamber pots, and drug vials and ampules used for preparation and packing of drugs. The gloves used during preparation of the drugs and during cleaning of the hoods were always contaminated. The uptake of CP or IF was determined by the analysis of both compounds in urine. CP or IF was detected in the urine of eight pharmacy technicians and nurses. The amounts ranged from less than 0.01 to 0.5 micrograms (median: 0.1 microgram). CP and IF were found not only in the urine of pharmacy technicians and nurses actively handling these compounds (n = 2) but also in the urine of pharmacy technicians and nurses not directly involved in the preparation and administration of these two drugs (n = 6). CP and IF were excreted during different periods ranging from 1.40 to 24.15h after the beginning of the working day, suggesting different times of exposure, different exposure routes, and/or interindividual differences in biotransformation and excretion rate for these compounds.