R.P. Bos

Occupational exposure to antineoplastic agents at several departments in a hospital

SummaryThe 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 < 0.01 to 0.5 μg (median: 0.1 μg). 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 24.15 h 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. The urinary CP and IF determination method seems to be sensitive and suitable for monitoring the exposure to and measuring the uptake of these toxic compounds by pharmacy technicians and nurses during occupational activities.

Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians: is skin absorption an important exposure route?

In the Netherlands, special guidelines and safety precautions were introduced about 10 y ago for preparation and administration of antineoplastic agents. However, little is known about the effectiveness of these measures. In this study, occupational exposure to antineoplastic agents of nine pharmacy technicians who were involved in drug preparation was investigated. Cyclophosphamide, 5-fluorouracil, and methotrexate accounted for 95% of the antineoplastic agents prepared; therefore, the presence of these compounds was monitored. During preparation, cyclophosphamide was detected in the air of the work environment (< 0.04-10.1 micrograms/m3). Contamination of and permeation through latex gloves were found for each of the three compounds. The uptake of cyclophosphamide was assessed by the determination of cyclophosphamide in urine. The drug was found in urine samples of six pharmacy technicians, including three persons who were not directly involved in the preparation of cyclophosphamide. The amounts excreted ranged from 0.2 to 19.4 micrograms/24 h. The results strongly suggest that inhalation is of minor importance for internal exposure, compared with other, presumably dermal, routes.

Drugs hazardous to healthcare workers. Evaluation of methods for monitoring occupational exposure to cytostatic drugs

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 chromatographytandem 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.

Urinary cyclophosphamide excretion and micronuclei frequencies in peripheral lymphocytes and in exfoliated buccal epithelial cells of nurses handling antineoplastics

In this study, urinary cyclophosphamide (CP) excretion rate, as well as micronuclei (MN) in peripheral lymphocytes and in buccal epithelial cells were determined for 26 nurses handling antineoplastics and 14 referents matched for age and sex. In urine samples of 20 out of 25 exposed nurses CP excretion rate was found in a range of 0.02-9.14 microg CP/24 h. Our results of the analyses of CP in urine demonstrates that when the nurses were handling CP (and other antineoplastic drugs) this particular compound was observed in urine. The mean values (+/-SD) of MN frequencies (%) in peripheral lymphocytes from the nurses and controls were 0.61 (+/-0. 32) and 0.28 (+/-0.16), respectively (p<0.01). The mean value (+/-SD) of MN frequency (%) in buccal epithelial cells of nurses was 0.16 (+/-0.19) and also mean MN frequency in buccal epithelial cells for controls was found to be as 0.08 (+/-0.08), (p>0.05). Age, sex and smoking habits have not influenced the parameters analyzed in this study. Handling time of antineoplastics, use of protective equipment and handling frequency of drugs have no effect on urinary and cytogenetic parameters analyzed. No correlation was found between the urinary CP excretion and the cytogenetic findings in nurses. Neither could we find any relationship between two cytogenetic endpoints. Our results have identified the possible genotoxic damage of oncology nurses related to occupational exposure to at least one antineoplastic agent, which is used as a marker for drug handling. As a whole, there is concern that the present handling practices of antineoplastic drugs used in the several hospitals in Ankara will not be sufficient to prevent exposure.

Exposure of Pharmacy Technicians to Antineoplastic Agents: Reevaluation after Additional Protective Measures

Abstract 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 occurr...

Detection of contamination with antineoplastic agents in a hospital pharmacy department

The contamination with fluorouracil, cyclophosphamide and methotrexate 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. Methotrexate was detected in one sample which was collected during preparation (0.3μg/m3). Spot samples were taken in the vertical laminar airflow safety hood before and after preparation of the drugs and after cleaning of the hood. Contamination of the laminar airflow hood was: cyclophosphamide: 1–160 ng/cm2; fluorouracil: 10–62 ng/cm2 and methotrexate: 2–633 ng/cm2. Spot samples from the floor in front of and beneath the laminar airflow hood showed contamination with especially fluorouracil (48–236μg/m2). The gloves used during preparation of the drugs were contaminated mainly with fluorouracil (5–980 ng/cm2). Urine samples from two workers involved in the preparation of the drugs were analysed for unmetabolized cyclophosphamide; it was not detected. Although no uptake of cyclophosphamide was established, it is shown that the methods for measurement of cyclophosphamide, fluorouracil and methotrexate in the preparation room are applicable for the control of occupational exposure to these drugs.

Urinary cyclophosphamide excretion and chromosomal aberrations in peripheral blood lymphocytes after occupational exposure to antieoplastic agents

In this study we have compared the results of a method for the detection of cyclophosphamide in urine and the results of analysis of chromosomal aberrations in peripheral blood lymphocytes of four groups of subjects with various exposure statuses. These groups are 17 Dutch and 11 Czech exposed workers (mainly hospital nurses and pharmacy technicians) handling antineoplastic agents and 35 Dutch and 23 Czech controls (nurses, medical doctors, pharmacy and lab technicians) not handling these drugs. The groups were subdivided into smokers and non-smokers because of a confounding effect of smoking. Within the Dutch groups, the percentage of aberrant cells and the number of breaks per cell were increased for smokers compared to non-smokers. The percentage of aberrant cells was increased in Dutch exposed workers in comparison with Dutch control workers. Within the Czech groups the percentage of aberrant cells and the number of breaks per cell were increased in exposed workers in comparison with control workers. However, both Dutch and Czech smokers mainly contributed to the increase. The results suggest an additive effect of exposure and smoking in the Dutch subjects and a more than additive effect in the Czech subjects. In urine samples of three out of 11 Dutch exposed workers cyclophosphamide was found in a range of 0.1-0.5 micrograms/24 h. Higher levels were detected in the urine of eight out of 11 Czech exposed workers, a range of 0.1-2.9 micrograms/24 h. No correlation was observed between the amounts of cyclophosphamide excreted in urine on the one hand and the percentage of aberrant cells and the number of breaks per cell on the other hand. The present study is the first study showing that hospital workers having an increase in chromosome aberrations related to their work are exposed to at least one antineoplastic agent.

Cancer risk assessment for health care workers occupationally exposed to cyclophosphamide

In the present study a cancer risk assessment of occupational exposure to cyclophosphamide (CP), a genotoxic carcinogenic antineoplastic agent, was carried out following two approaches based on (1) data from an animal study and (2) data on primary and secondary tumors in CP-treated patients. Data on the urinary excretion of CP in health care workers were used to estimate the uptake of CP, which ranged from 3.6 to 18 μg/day. Based on data from an animal study, cancer risks were calculated for a health care worker with a body weight of 70 kg and a working period of 40 years, 200 days a year (linear extrapolation). The lifetime risks (70 years) of urinary bladder cancer in men and leukemias in men and women were found to be nearly the same and ranged from 95 to 600 per million. Based on the patient studies, cancer risks were calculated by multiplication of the 10-year cumulative incidence per gram of CP in patients by the estimated mean total uptake in health care workers over 10 years, 200 days a year. The risk of leukemias in women over 10 years ranged from 17 to 100 per million using the secondary tumor data (linear extrapolation). Comparable results were obtained for the risk of urinary bladder tumors and leukemias in men and women when primary tumor data were used. Thus, on an annual basis, cancer risks obtained from both the animal and the patient study were nearly the same and ranged from about 1.4 to 10 per million. In The Netherlands it is proposed that, for workers, a cancer risk per compound of one extra cancer case per million a year should be striven for (“target risk”) and that no risk higher than 100 per million a year (“prohibitory risk”) should be tolerated. From the animal and the patient study it appears that the target risk is exceeded but that the risk is still below the prohibitory risk.

Determination of cyclophosphamide in urine by gas chromatography—mass spectrometry

A sensitive gas chromatographic method for the determination of cyclophosphamide in urine is presented. After liquid-liquid extraction with diethyl ether and derivatization with trifluoroacetic anhydride, cyclophosphamide was identified and quantified with mass spectrometry. The method is suitable for the determination of cyclophosphamide at concentrations of more than 0.25 ng/ml, which enables the uptake of cyclophosphamide during occupational activities, such as the preparation and administration of antineoplastic agents in hospitals, to be measured. Simple preparation makes the method appropriate for routine analysis.

Assessment of genotoxic damage in nurses occupationally exposed to antineoplastics by the analysis of chromosomal aberrations

To estimate the genotoxic risk of occupational exposure to antineoplastic drugs, chromosomal aberration (CAs) frequencies in peripheral lymphocytes were determined for 20 nurses handling antineoplastics and 18 referents matched for age and sex. Urinary cyclophosphamide (CP) excretion rates, which are used as a marker for drug handling, were also measured on these nurses. We have observed significant frequencies of CAs (about 2.5-fold increase) including chromatid breaks, gaps, and acentric fragments for nurses handling antineoplastics as compared to control subjects (p<0.05, p<0.01, excluding and including gaps, respectively). The mean value of CP excretion rate for 12 nurses was 1.63 μg/24 h, suggesting that when the nurses handled CP (and other antineoplastic drugs) this particular compound was absorbed. Our study has shown that increased genetic damage was evident in nurses, at population level, due to occupational exposure to antineoplastics. Until the effects of handling antineoplastics from low-level exposure are known, it will be important to keep the exposure to a minimum.