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Published on 13 December 2007

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Occupational exposure to cytotoxic drugs

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Wouter Fransman
MSc PhD

Occupational Epidemiologist

Institute for Risk Assessment Sciences
Utrecht University
Utrecht
The Netherlands

E: wouter.fransman@tno.nl

Several studies have shown that exposure to antineoplastic drugs can have toxic effects on reproduction as well as carcinogenic effects. The presence of these drugs in the urine of hospital personnel has been widely studied and dermal exposure has been suggested as being the main route of exposure.

Exposure to cytotoxic drugs in hospitals
In a pilot study, potential and actual dermal exposure was assessed for several common hospital tasks.[1] Dermal exposure to cyclophosphamide – a frequently used antineoplastic drug – was determined in three Dutch hospitals during five tasks (preparation, decanting urine, washing the patient, removing bedsheets and cleaning toilets) using pad samples on ten body locations. The results showed that hospital personnel (pharmacy technicians and oncology nurses) were dermally exposed to ­cyclophosphamide while performing their daily duties. The results of this pilot study were used to derive an optimal measurement strategy for a larger exposure study, which measured dermal exposure to cyclophosphamide on hands, forearms and forehead during preparation, nursing and cleaning activities.[2] Pharmacy technicians, oncology nurses and cleaners showed actual and potential dermal exposure to cyclophosphamide while performing their daily duties. Exposure occurred predominantly on the hands and sporadically on the forehead and forearms.

Although all nurses used gloves while handling patients’ urine and sometimes during other nursing tasks, the skin underneath gloves was repeatedly contaminated. Results of tests on bulk and surface contamination samples confirmed that patients intravenously treated with cyclophosphamide excrete the unmetabolised drug, which could lead to dermal exposure by hospital personnel. A clear relationship was found between dermal exposure levels and direct sources of exposure for all tasks, except for handling patients’ urine. Pharmacy technicians and cleaners, on the other hand, may also be exposed to cyclophosphamide, but the protection provided by gloving seemed to be sufficient.

Exposure to cytotoxics outside hospitals
Eight sectors outside the hospital environment were identified as potentially laying staff open to exposure to antineoplastic drugs: the pharmaceutical industry, pharmacies, universities, veterinary medicine, nursing homes, homecare, laundry facilities and waste treatment.[3] Four sectors – veterinary medicine, home care, nursing homes and industrial laundries – were of primary concern. In these sectors, potentially exposed populations vary considerably in size – they range from several tens to thousands of workers – and in exposure levels. Indicative exposure measurements collected in these four sectors showed that workers outside hospitals are indeed exposed to antineoplastic drugs. Exposure levels may be higher than in the hospital environment because exposure routes are complex and awareness of the hazard (and therefore use of protective measures) is limited.

Trends in exposure to cytotoxic drugs
Data from three cross-sectional surveys were pooled.[4] Nurses’ urine samples were analysed, surface contamination was determined and gloves that had been used during preparation or while handling patients’ urine were collected. The percentage of urine samples with detectable amounts of cyclophosphamide decreased fourfold between 1997 and 2000. Median cyclophosphamide levels in the positive urine samples were threefold lower in 2000 than in 1997. Surface and glove contamination also decreased significantly between 1997 and more recent years. The study showed that oncology nurses in the Netherlands are still being exposed to cyclophosphamide, but their exposure decreased considerably between 1997 and 2000−2.

In addition, a task-based exposure model was used to estimate dermal exposure of the hands among oncology nurses in nonacademic hospitals in the Netherlands.[5] Monte Carlo simulation was used to integrate information from available exposure studies and generate exposure distributions for the total population of oncology nurses in both pre- and post-intervention situations. The results of the analysis show that the interventions did not affect the median exposure of the total population of oncology nurses, but the number of individuals with very high and very low total dermal exposures decreased substantially in the post-intervention situation.

Health effects related to exposure
In an epidemiological study, self-administered questionnaires were completed by exposed and non-exposed nurses employed between 1990 and 1997 (79% response rate).[6] Questions related to pregnancy outcome, work-related exposures and lifestyle. Exposure to antineoplastic drugs was estimated using task-based dermal exposure measurement results and self-reported task frequencies. There was evidence suggestive of an increased risk of prolonged time to pregnancy (on average one month) among nurses with relatively high exposure to antineoplastic agents compared with referent nurses (hazard ratio = 0.8; 95% CI 0.6–0.9). Positive log-linear relations were apparent between exposure to antineoplastic drugs and premature delivery. Spontaneous abortion, stillbirth, gender of offspring and congenital anomalies did not appear to be related to prevailing levels of exposure to antineoplastic drugs. This study was the first to show quantitative relations between dermal exposure to antineoplastic drugs among oncology nurses and reproductive health effects.

In addition to toxicity to reproduction, anti­neoplastic drugs have been found to have carcinogenic potential. Nine antineoplastic drugs (including cyclophosphamide) have been classified as ­carcinogenic to humans by the International Agency for Research on Cancer.

We aimed to assess the carcinogenic risks of occupational exposure to cyclophosphamide, which was assumed to account for 25% of all antineoplastic drug treatments.[7] Average task frequencies from the total population of oncology nurses in the Netherlands and dermal exposure intensities for each task were used to calculate oncology nurses’ dermal exposure levels. A dermal absorption model in combination with a physiologically based pharmacokinetic model was used to accurately assess the delivered dose of cyclo­phosphamide and its active metabolites in the primary target organ: bone marrow.

This delivered dose was subsequently related to pharmacodynamic information from a study with cyclophosphamide-treated patients to estimate the risk of leukaemia for oncology nurses after 40 years’ exposure to cyclophosphamide. The ­leukaemia risk of an oncology nurse after 40 years of dermal exposure to cyclophosphamide (with average task-frequency and average exposure-intensity for each task) was estimated to be on average 0.3 extra cases per million oncology nurses. This risk could increase to a worst-case maximum of 40 extra cases per million if a nurse performs all cyclo­phosphamide-related tasks with the maximum frequency (observed in this population) and is exposed to the maximum exposure intensity for each task without using protective gloves for 40 years. This study concluded that the risk of an oncology nurse exposed to average levels cyclophosphamide is below the target risk of one extra cancer case per 10 million per year, but that this level may be exceeded in a worst-case scenario.

Conclusion
Oncology nurses are exposed via the skin of their hands during daily work activities, even when protective gloves are being used. The introduction of new guidelines and regulations on working with antineoplastic drugs, the use of more closed preparation and infusion systems and the consequent growing awareness of nurses working with anti­neoplastic drugs has decreased exposure to anti­neoplastic drugs considerably. The identification of the patient as a source of contamination and exposure makes it very complicated to further reduce nurses’ exposure to antineoplastic drugs. The identification of occupational exposure to antineoplastic drugs in sectors outside the hospital environment showed that the number of workers potentially exposed to anti­neoplastic drugs is larger than previously estimated.

A five-year forecast would require:

  • Improvement and implementation of guidelines and regulations on working safely with cytotoxic drugs.
  • Additional research to identify occupational exposure in sectors outside the hospital environment.
  • Elucidation of potential exposure to cytotoxic drugs in the home environment of patients (human and animal) treated with these drugs.
  • Extension of risk assessment to other cytotoxic drugs, with the aim of limiting values for working with cytotoxic drugs.

This research was partly facilitated by the Dutch Ministry of Social Affairs and Employment, the European Union, and participating hospitals and non-­hospital sectors.

References
1. Fransman W, Vermeulen R, Kromhout H. Occupational dermal exposure to cyclophosphamide in Dutch hospitals: a pilot study. Ann Occup Hyg 2004;48(3):237-4.

2. Fransman W, Vermeulen R, Kromhout H. Dermal exposure to cyclophosphamide in hospitals during preparation, nursing and cleaning activities. Int Arch Occup Environ Health 2005;78(5):403-12.

3. Meijster T, Fransman W, Veldhof R, Kromhout H. Exposure to antineoplastic drugs outside the hospital environment. Ann Occup Hyg 2006;50(7):657-64.

4. Fransman W, Peelen S, Hilhorst S, et al. A pooled analysis to study trends in exposure to antineoplastic drugs among nurses.
Ann Occup Hyg 2007;51:231-9.

5. Meijster T, Fransman W, Van Hemmen J, et al. A probabilistic assessment of the impact of interventions on the exposure to antineoplastic agents of oncology nurses. Occup Environ Med 2006;63:530-7.

6. Fransman W, Roeleveld N, Peelen S, et al. Nurses with dermal exposure to antineoplastic drugs: reproductive outcomes. Epidemiology 2007;18(1):112-19.

7. Fransman W, Kager H, Meijster T, et al. Pharmacokinetic model for assessment of leukemia risk associated with dermal exposure to cyclophosphamide among nurses. Submitted for publication.



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