Dermal exposure to cyclophosphamide in hospitals during preparation, nursing and cleaning activities

Objectives: To determine levels of potential and actual dermal exposure to cyclophosphamide (CP) during performance of oncology-related tasks in hospitals and to investigate the relationship with potential sources and surface contamination levels of CP. Methods: Dermal exposure to CP was determined for tasks with potential exposure to CP: preparation of CP, decanting of patients urine, washing of the patient, removal of bed sheets of treated patients and cleaning of patients toilets on oncology wards. Exposure was assessed by the collection of nitrile and latex protective medical gloves (potential exposure), washing of hands (actual exposure), from cotton pads attached to (un)covered forearms (potential or actual exposure) and a wipe sample of the forehead (actual exposure). Bulk samples (i.e. application fluids and patients excreta) and possible contact surfaces were monitored to assess the amount of CP available for dermal exposure. Results: Pharmacy technicians, oncology nurses and cleaning personnel showed actual and potential dermal exposure to CP during performance of their daily duties. Exposure occurred predominantly on the hands and sporadically on the forehead and forearms. Although all nurses used gloves during handling of patients urine and sometimes during the other nursing tasks, skin underneath gloves was repeatedly contaminated. Results of tests on bulk and surface contamination samples confirmed that patients intravenously treated with CP excrete the unmetabolised drug, which could subsequently lead to dermal exposure of hospital personnel. A clear relationship was found between dermal exposure levels and direct sources of exposure for all tasks, except for handling patients urine. Conclusions: We demonstrated for the first time that actual dermal exposure to CP is common among oncology nurses working with patients treated with this anti-neoplastic drug. Pharmacy technicians and cleaning personnel, on the other hand, are potentially exposed to CP, and protection provided by gloves seemed to be sufficient.     

Surface contamination of cyclophosphamide packaging and surface contamination with antineoplastic drugs in a hospital pharmacy in Sweden

Workplaces, e.g. hospital pharmacies and hospital departments, where antineoplastic drugs are handled might be contaminated with these drugs, and pharmacy personnel and health care workers may be exposed. In this study potential sources for exposure of antineoplastic drugs were investigated. Unbroken drug vials and tablet blister packages, both containing cyclophosphamide (CP) and their outer packaging were wipe sampled. Analysis was performed by liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). The result showed that almost every part of the primary packaging was contaminated with CP and ifosfamide (IF). However, the amounts of CP and IF were low, and most likely not harmful for the personnel handling these packaging in association with drug preparation. The contamination must originate from the pharmaceutical manufacturer. Different surfaces in the preparation unit of a Swedish hospital pharmacy were also investigated at two different occasions by wipe sampling. In the preparation unit CP and IF were found as contaminants on the majority of the investigated surfaces. After the first measurement the hospital pharmacy improved its routines. Lower amounts of CP and IF were detected at the second measurement. A low degree of contamination with CP and IF was also detected on the floor outside the preparation unit and this indicated a small distribution of antineoplastic drugs to the surroundings.     

Environmental contamination with cytotoxic drugs in healthcare using positive air pressure isolators

Occupational exposure to cytotoxic drugs of hospital personnel involved in their preparation and administration is a major issue: ever since the introduction of protective measures in recent decades, the handling of these drugs has always been referred to as an occupational health hazard. Isolator technology was one of the protective equipments aimed at providing safe handling, but it has not yet been studied regarding contamination. The present study evaluates surface contamination with four cytotoxic drugs [cyclophosphamide (CP), ifosfamide (IF), 5 fluorouracil (5FU) and methotrexate (MTX)] by wipe sampling in two hospital pharmacies. Wipe samples were taken from work surfaces both located inside and outside the isolators. In addition, working gloves, the surface of infusion bags filled with 5FU or CP, and gloves used in simulation of drug administration were analyzed. Contamination was routinely found inside the isolators but rarely outside the isolators, indicating that the isolator technology is offering good protection of the cytotoxic drug handlers as well as the environment during preparation. On the other hand, contamination was found on the surfaces of infusion bags and gloves in contact with infusion bags filled with cytotoxic drugs. Consequently, personal protective equipment is still recommended during the manipulation and administration of the drugs because of potentially contaminated drug vials and final products.     

Biological and environmental monitoring of occupational exposure of pharmaceutical plant workers to methotrexate

Summary 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 g/m³; median: 10 g/m³). The highest concentrations were observed for workers weighing MTX (118 and 182 g/m³). MTX was detected in urine samples of all workers. The mean cumulative MTX excretion over 72–96 h was 13.4 g MTX-equivalents (range: 6.1–24 g MTX-equiva g MTX-equivalents (range: 6.1–24 g MTX-equivalents). lents). A significantly lower background level of 10.2 g A significantly lower background level of 10.2 g MTX-equivalents was measured in urine of 30 control persons (range: 4.9–21 g MTX-equivalents).     

Environmental and biological monitoring of antineoplastic drugs in four workplaces in a Swedish hospital

Objectives Exposure to antineoplastic drugs should be avoided due to the risk of getting adverse health effects. Antineoplastic drugs such as cyclophosphamide (CP) and ifosfamide (IF) are commonly used in medical attendance. In this study the variability of surface contamination of CP and IF was investigated by repeated wipe sampling over time in four workplaces in a university hospital. The surface contamination levels were also evaluated and health care workers were biologically monitored. Methods A hospital pharmacy, two oncology wards and one oncology outpatient department were selected. Between 10 and 13 different surface areas such as work areas, floors and handles were selected in each workplace and wiped between 7 and 8 times during 9 months. Pre- and post-shift urine samples were collected from the workers in the investigated workplaces. Analysis was performed by liquid chromatography combined with tandem mass spectrometry. Results Measurable amounts of CP and IF were detected on the majority of the sampled surfaces. The highest concentrations were found on the floors in the patient lavatories and utility rooms (up to 95 ng cm⁻²). In general, the surface contamination of CP and IF on floors did not vary much over time. Work areas and handles had larger variability. Neither CP nor IF were detected in any of the collected urine samples. Conclusions The variability in surface contamination of CP and IF was rather low especially on floors. Higher concentrations of CP and IF were found on the floors compared with the work areas. The highest surface loads were found on floors (in patient lavatories and utility rooms) that were related to patient activities such as handling of patients’ urine. Although high contaminations were found, the biological monitoring showed no uptake. Wipe sampling is a good method to improve the work practices.     

Occupational dermal exposure to cyclophosphamide in Dutch hospitals: a pilot study

INTRODUCTION: Several studies have shown that exposure to antineoplastic drugs can cause reproductive toxic effects as well as carcinogenic effects. Presence of these drugs in the urine of hospital personnel has been widely studied and some work has been done on exposure by inhalation. So far, assessment of dermal exposure to antineoplastic drugs has not been extensively studied. In this pilot study we assessed potential and actual dermal exposure for several common hospital tasks. Results were used to derive an optimal measurement strategy for a currently ongoing exposure survey. METHODS: Dermal exposure to cyclophosphamide was determined in three Dutch hospitals during five tasks (preparation, decanting urine, washing the patient, removing bed sheets and cleaning the toilet) using pad samples on 10 body locations. In addition, protective medical gloves (worn during the performance of these activities) were collected to estimate potential exposure of the hands. Subsequently, hands were washed to measure actual exposure of the hands. Bulk samples (i.e. application and body fluids) were collected and possible contact surfaces were monitored to assess the amount of cyclophosphamide potentially available for exposure. RESULTS: The results show that hospital personnel (i.e. pharmacy technicians and oncology nurses) are dermally exposed to cyclophosphamide during performance of their daily duties. Exposure occurred predominantly on the hands and sporadically on other body locations (i.e. forehead and forearms). Gloves used during preparation of cyclophosphamide were more contaminated than gloves used in other tasks, however, actual exposure of the hands (underneath the gloves) was highest during decanting of urine of treated patients. Glove samples correlated significantly with handwash samples (r = 0.57, P = 0.03, n = 15). The level of protection from gloves varied between tasks, being highest for gloves used during preparation (median = 98%) and lowest for gloves used during decanting urine (median = 19%). CONCLUSION: This pilot study demonstrated that dermal exposure to cyclophosphamide is common among hospital personnel. The results showed that hands, forearms and forehead accounted for 87% of the cyclophosphamide total body exposure. Glove samples together with handwash samples enabled estimation of glove efficiency, which appeared to vary strongly between tasks observed.     

Comparison of methods for the biomonitoring of nurses handling antitumor drugs

Urinary mutagenicity, thioethers in urine, and sister chromatid exchanges and micronuclei in peripheral lymphocytes were determined for 60 nurses handling cytostatic drugs and 60 referents matched for sex, age, and smoking habits. Safety hoods were used by most of the nurses. The exposed nurses had more sister chromatid exchanges and higher urinary mutagenicity, as measured by Salmonella typhimurium TA 98, than the referents. There were no differences in the other tests. No dose-response relationship was established for any parameter. It was concluded that urinary mutagenicity with the Salmonella strain is the most sensitive test for monitoring nurses handling cytostatic drugs. Determining sister chromatid exchanges may also be a viable test, but it has the drawback of uncertainty as to whether the changes are attributable to present or past exposure. Only comparisons of rather large groups are useful, and a study design requiring matched referents would seem to be optimal.     

A review of surface wipe sampling compared to biologic monitoring for occupational exposure to antineoplastic drugs

The potential for adverse health effects from occupational exposure to antineoplastic drugs (AD) is well known. Control measures recommended by the NIOSH Alert^[3] NIOSH: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health DHHS (NIOSH) Publication No 2004 (165) (2004). [Google Scholar] include medical and biologic monitoring, and environmental monitoring where available. At present no guidelines or published best practices exist to guide EHS managers on how to carry out this biologic or environmental monitoring. Studies investigating surface wipe sampling for AD have been numerous in the past decade, but very limited research exists to correlate surface contamination with actual absorption by pharmacists and nurses.

This article reviews the studies with concurrent surface wipe sampling and urine monitoring for the same AD, and tests their correlation. Methodologic limitations are reviewed.

Twenty-one studies were identified that concurrently measured surface contamination by AD by wipe sampling and AD absorption by urine monitoring. Two studies directly evaluated the AD by wipe sampling and urine levels and neither found a statistically significant correlation. Six studies reported a decrease in both surface and urine levels following interventions to reduce contamination or exposure. Only one study directly evaluated the personal protective equipment and handling techniques employed by the studied workers, which can be viewed as a major confounder of absorption.

While no statistically significant correlation was found between wipe sampling and urine monitoring for AD, decreases in urine and wipe levels following interventions to reduce exposure were noted. Limitations in the data and recommendations for future research are reviewed.     

Evaluation of early DNA damage in healthcare workers handling antineoplastic drugs

Objectives: This study evaluates by comet assay the induction of early DNA damage in healthcare workers of an oncology hospital regularly handling antineoplastic drug mixtures. The aim was to identify a suitable biomarker of DNA damage by exposure to low levels of such drugs. Methods: We studied 12 day hospital nurses and 13 oncology ward nurses who performed up to 300 and up to 35 drug administrations per week, respectively, and five pharmacy employees who regularly prepared mixtures of antineoplastic agents. Thirty healthy subjects were selected as controls. For exposure evaluation, we performed environmental monitoring of 5-fluorouracil, cytarabine, gemcitabine, cyclophosphamide, and ifosfamide in selected work areas of pharmacy and day hospital units and biological monitoring of urine for the 5-fluorouracile metabolite, α-fluoro-β-alanine. We evaluated early DNA damage in lymphocytes and exfoliated buccal cells by comet assay measuring tail moment (TM) parameter that indirectly indicates the presence of DNA damage. Results: Environmental monitoring detected cyclophosphamide, 5-fluorouracil and ifosfamide, with higher levels of contamination in day hospital unit. The biological monitoring measured detectable levels of α-fluoro-β-alanine only in three nurses. Comet assay showed an increase on exfoliated buccal cells, even if not statistically significant, of mean TM with respect to controls in day hospital nurses (43.2 vs. 28.6, respectively) while ward nurses and pharmacy technicians did not show differences. Comet assay performed on lymphocytes did not show appreciable differences between exposed and controls. Conclusions: The employment of the sensitive comet assay, which is able to detect early the effects of a recent exposure to genotoxic substances, allowed us to find a slight DNA damage, only on exfoliated buccal cells of day hospital nurses, the group handling the highest amount of drugs during the administration process. This finding suggests that comet assay on exfoliated buccal cells could represent a useful tool to evaluate early and still repairable genotoxic effects of exposure to antineoplastic drug mixtures and then contribute to the improvement of the hospital safety practices.     

Hexahydrophthalic acid in urine as an index of exposure to hexahydrophthalic anhydride

Summary Post-shift and next-morning urine was sampled from workers exposed to hexahydrophtalic anhydride (HHPA), an epoxy hardener, sensitising at low exposure levels. Exposure levels of HHPA in air gas chromatography, GC) in the range of 30–270 g/m³ corresponded to urinary concentrations of 0.9–2.8 mol hexahydrophthalic acid (HHP acid; GC-mass spectrometry)/mmol creatinine. In the morning samples the concentrations were <0.04-0.3 mol HHP acid/mmol creatinine. In unexposed controls, the level was <0.1 mol/mmol creatinine. A correlation was found between the time-weighted levels of HHPA in air and HHP acid in the post-shift urine (r _s = 0.93; P < 0.023), indicating that the determination of HHP acid in urine is suitable for biologic monitoring of HHPA exposure.     

Biological monitoring of cobalt exposure,based on cobalt concentrations in blood and urine

Summary Cobalt exposure level and its concentrations in blood and urine were determined for 175 hard metal workers. For control data, the cobalt concentrations in blood and urine were measured for 20 office workers. The exposed workers had significantly higher cobalt concentrations in both blood and urine. The relationships between exposure level and cobalt concentrations in blood and urine were linear and positive. The results clearly showed that the cobalt concentration in the blood or urine can be used as an exposure indicator. With cobalt exposure of 100 g/m³, the cobalt concentration was 0.57 to 0.79 g/dl in blood and 59 to 78 g/l in urine with 95% confidence limits. In workers using respirators, the cobalt concentrations in the blood and urine decreased to 2/5 and 1/8, respectively, of those not using respirators.     

Significance of urinary metallothionein in workers exposed to cadmium

Summary Cadmium in blood (Cd-B) and in urine (Cd-U) and metallothionein (Mt-U) and ₂-microglobulin in urine ( ₂m-U) were measured in 94 male Cd workers. The results were examined according to the workers' current exposure to cadmium (group C, n=73, workers currently exposed to Cd; group R, n=21, Cd workers removed from exposure or retired) and according to their renal status (group N, n=66, normal ₂m-U; group 1, n=28, ₂m-U>200 g/g creatinine). The interrelationships between Mt-U, Cd-U, Cd-B and years of cadmium exposure were examined in the various subgroups. The study of the correlations between these variables demonstrates that Mt-U is directly correlated with Cd-U but not with Cd-B or years of Cd exposure. The association between Cd-U and Mt-U is independent of the status of renal function and the intensity of current exposure to cadmium. Under moderate chronic exposure to cadmium, the fraction of Cd-U which is directly influenced by recent exposure (Cd-B) is small in comparison with that influenced by the cadmium body burden.     

Knowledge, Attitude, and Practices about Biomedical Waste Management among Healthcare Personnel: A Cross-sectional Study

Background:

The waste produced in the course of healthcare activities carries a higher potential for infection and injury than any other type of waste. Inadequate and inappropriate knowledge of handling of healthcare waste may have serious health consequences and a significant impact on the environment as well.

Objective:

The objective was to assess knowledge, attitude, and practices of doctors, nurses, laboratory technicians, and sanitary staff regarding biomedical waste management.

Materials and Methods:

This was a cross-sectional study.

Setting:

The study was conducted among hospitals (bed capacity >100) of Allahabad city.

Participants:

Medical personnel included were doctors (75), nurses (60), laboratory technicians (78), and sanitary staff (70).

Results:

Doctors, nurses, and laboratory technicians have better knowledge than sanitary staff regarding biomedical waste management. Knowledge regarding the color coding and waste segregation at source was found to be better among nurses and laboratory staff as compared to doctors. Regarding practices related to biomedical waste management, sanitary staff were ignorant on all the counts. However, injury reporting was low across all the groups of health professionals.

Conclusion:

The importance of training regarding biomedical waste management needs emphasis; lack of proper and complete knowledge about biomedical waste management impacts practices of appropriate waste disposal.     

Exposure of Oncologic Nurses to Methotrexate in the Treatment of Osteosarcoma

Methotrexate is a therapeutic agent used widely for osteosarcoma. We used an extremely sensitive high-performance liquid-chromatography assay to evaluate 112 urine samples obtained from 28 hospital employees during high-dose therapy with methotrexate and during routine care of patients. The highest cumulative urinary excretion was observed when methotrexate infusions were handled in a workbench from which a portion of filtered air was emitted into the room. Remarkable urine contaminations were identified for personnel, including 1 administrative employee who had “stood by” for 2 h in the room where infusions were prepared. Lower methotrexate concentrations were detected in the urine of nurses whose exclusive function was to care for patients. The urine burden in oncologic nurses decreased after a central pharmacy unit was installed. Methotrexate was excreted in the sweat of patients who were under high-dose therapy, and its elimination half-life was 11.1 h (mean maximal concentration = 1.7 μg/ml [n = 5]). The maximal burden in spontaneous vomit from these patients was 441.5 μg/ml, and it declined to 0.24 μg/ml 19.5 h after infusion was completed. No methotrexate was detected in personnel who prepared 20-g methotrexate infusions in the central pharmacy unit. We demonstrated that occupational safety depended not only on technical precautions, but on the skills of specifically trained personnel.     

Knowledge and Practices of Healthcare Workers in Relation to Bloodborne Pathogens in a Tertiary Care Hospital,Western Saudi Arabia

To assess knowledge and practices of healthcare workers (HCWs) in relation to bloodborne pathogens in a tertiary care hospital, western Saudi Arabia. Self-administered questionnaire was distributed assessing demographic characteristics, knowledge and practices of physicians, nurses and technicians on risks of exposure and prophylaxis against human immunodeficiency virus, hepatitis B virus and hepatitis C virus infections. A total of 466 participants (151; 32.4 % physicians and 315; 67.6 % nurses/technicians) completed the questionnaire. Almost two thirds of the physicians (60.9 %) and half of the nurses/technicians (47.6 %) had history of exposure to risks of bloodborne infection. Although both physicians and nurses/technicians showed acceptable level of knowledge about risks of bloodborne infections, modest proportion knew the correct actions including reporting following exposure. Behavioral-based in-service training interventions and strict policy should be implemented to promote compliance of HCWs to the protective measures against hazards of bloodborne infection.     

Comparison between the fluorometric HPLC method and the conventional method for determining urinary δ-aminolevulinic acid and coproporphyrin as indices of lead exposure

Summary Fluorometric methods for determining -aminolevulinic acid (ALA) and coproporphyrin (CP) in urine have been recently developed by using high-performance liquid chromatography (HPLC). In the present study, urinary ALA and CP in lead-exposed workers were determined with these fluorometric HPLC methods and the conventional methods, and the results obtained were compared. In lead workers with a urinary ALA 5 mg/l, the values obtained with the fluorometric HPLC method corresponded well with those measured with the conventional colorimetric method. In contrast, in lead workers with ALA < 5 mg/l, ALA values obtained with the fluorometric HPLC method were lower than those measured with the conventional method, suggesting the possibility of matrix interference in urine. The urinary CP values obtained with the conventional method of Rimington (1971) were higher than those measured with the fluorometric HPLC method, though the correlation was good.     

Validation of urinary excretion of cyclophosphamide as a biomarker of exposure by studying its renal clearance at high and low plasma concentrations in cancer patients

Objectives Cyclophosphamide (CP) is an alkylating agent classified as a human carcinogen. Health care workers handling this drug may be exposed during, e.g., preparation or administration. Cyclophosphamide is readily absorbed by inhalation and by dermal uptake. A biomarker, CP in urine, has frequently been used to assess the occupational exposure to CP, but has not been fully validated. The aim of this study was to investigate if the proportion of the CP dose that is excreted in urine (renal clearance) is constant over different plasma drug concentrations and other pharmacokinetic parameters, e.g., urine flow. Methods Pharmacokinetics of CP were studied in 16 breast cancer patients that were treated with postoperative adjuvant chemotherapy including CP. Plasma and urine from the patients were collected at different occasions up to 12 days after the dose. Urine was collected during 4-h periods and blood was sampled at the end of each period. Analysis of CP was performed by liquid chromatography tandem mass spectrometry. The limit of detection for CP in urine and plasma was 0.01 and 0.02 ng/ml, respectively. The precisions of the developed methods were determined to ≤8%. Results The administered doses of CP in absolute amounts ranged between 800 and 2,240 mg. Mean renal clearance of CP was 8.6 (confidence interval 6.5–10.7) ml/min and was not significantly dependent of the plasma drug concentration. However, a significant correlation between renal clearance and urine flow was observed. There was a large inter-individual variation in the plasma and urine concentrations even when the same doses were given. Conclusions Cyclophosphamide in urine can be continued to be used as a biomarker to monitor occupational exposure to CP, however the inter-individual variability of excretion of CP in urine, and its dependency on urine flow must be taken into consideration in future applications.     

Attitudes,Morale, and Motivation

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 μg. The mean cyclophosphamide excretion/d was not significantly lower than that found in the previous study (0.16 μg and 1.44 μg, respectively). Despite an intensified hygienic regimen, exposure to antineoplastic agents cannot be reduced if the reasons for exposure remain unknown.