Occupational exposure to cyclophosphamide in nurses at a single center.

ORIGINAL ARTICLE

Occupational Exposure to Cyclophosphamide in Nurses at a Single Center Raveena Ramphal, MBChB, MPH, Tejinder Bains, BSc (Pharm), Régis Vaillancourt, B Pharm, Pharm D, Martin H. Osmond, MDCM, and Nicholas Barrowman, PhD Objective: To evaluate biological and environmental exposure to cyclophosphamide in nurses at a single institution. Methods: Biological exposure to cyclophosphamide in nurses administering cyclophosphamide compared with two control groups: nononcology nurses not administering cyclophosphamide and community members without recent hospital exposure. Environmental exposure to chemotherapy was measured using surface wipes taken from oncology and nononcology areas in the hospital. Results: More than one third of all nurses and no community controls tested positive for urinary cyclophosphamide. Oncology and nurse controls tested positive in equal numbers. Surface wipes were positive only in the oncology ward. Conclusion: We have demonstrated elevated levels of cyclophosphamide in one third of all nurses and cyclophosphamide contamination of surfaces within the oncology patient environment. This suggests that environmental contamination plays a major role in biological exposure to cyclophosphamide.

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yclophosphamide is one of the most commonly used chemotherapy drugs worldwide, with increasingly higher doses and quantities being used each year. Throughout the world, many thousands of individuals are engaged in the manufacture, preparation, handling, and administration of this drug and are therefore at risk of long-term, low-grade exposure. Moreover, environmental contamination within hospitals may potentially expose all hospital workers and visitors to this drug. The effect of long-term, low-grade exposure has not been fully established. Nevertheless, cyclophosphamide has been classified as a group 1 carcinogen by the International Agency for Research on Cancer.1 This means that it is known to be carcinogenic to humans and is considered a “nonthreshold toxicant,” which implies no safe lower-dose threshold can be assumed. It has also been associated with mutagenic, teratogenic, and reproductive effects.2–10 Exposure can occur through several different methods— dermal, inhalation, or ingestion. Contact with cyclophosphamide can occur through environmental contamination, drug preparation and administration, or handling of secretions that contain the active metabolites of cyclophosphamide. Exposure can be measured biologically by looking for the metabolites of cyclophosphamide in urine or environmentally by wiping surfaces with special surface wipes and analyzing these wipes for the drug. Several studies, mainly done in Europe, have shown biological and environmental exposure of health care workers to cyclophosphamide.11–29 There does seem to be a correlation between the stringency of protection strategies in place and levels

From the Department of Pediatrics (Drs Ramphal and Osmond), University of Ottawa, Ottawa, Ontario, Canada; and Pharmacy Department (Ms Bains and Dr Vaillancourt) and Clinical Research Unit (Dr Osmond and Dr Barrowman), Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada. The authors declare no conflicts of interest. Address correspondence to: Raveena Ramphal, MBChB, MPH, 2631-401 Smyth Rd, Division of Hematology/Oncology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada ([email protected]). C 2014 by American College of Occupational and Environmental Copyright Medicine DOI: 10.1097/JOM.0000000000000097

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of exposure to cyclophosphamide, with some institutions showing a significant decrease in exposure levels after implementing more stringent protective measures.13,16,27,30–35 Therefore, it may be misleading to extrapolate findings from one part of the world to another where protective measures may be considerably different. A few studies done in North America, most quite small, demonstrated environmental contamination and biological exposure in health care workers.11,27,29–31,34,36–39 Nevertheless, only one study used a control group of health care workers who do not handle chemotherapy, and no studies have used a control group not exposed to the hospital environment.36 Therefore, we undertook to investigate the extent of environmental and biological exposure to cyclophosphamide in nurses administering cyclophosphamide at a single Canadian institution and compared this with the exposure in two control groups— health care workers at the same institution who do not handle chemotherapy and members of the local community who have had no recent exposure to a hospital environment.

MATERIALS AND METHODS Study Design This was a cross-sectional study conducted at a single pediatric hospital and the surrounding local community. The first aim was to determine the extent of biological exposure to cyclophosphamide in nurses administering cyclophosphamide (oncology nurses) compared with a group of nononcology nurses not administering cyclophosphamide (nurse controls) and a smaller group of community controls who were members of the local community. The number of subjects with detectable amounts of urinary cyclophosphamide in each arm was compared. The second aim was to determine the degree of surface contamination with cyclophosphamide in the oncology ward and clinic, where chemotherapy is administered, compared with the same areas in a nononcology ward and clinic where no chemotherapy is administered (control areas). This was done using special surface wipes to sample prespecified areas in all four locations.

Study Participants Forty-one oncology nurses, 39 nononcology nurse controls, and 10 community controls participated in the study over a 4-month period (Table 1). Exclusion criteria were as follows: any participant who had themselves received chemotherapy in the past 1 year; any participant who had previously participated in this study; control nurses who had administered any chemotherapy in the past 1 month or who had worked in an oncology area in the 7 days before study participation; community controls who had any physical contact with a hospital or any known exposure to cyclophosphamide in the 1 month before study participation; and oncology nurses who were not administering cyclophosphamide on the day of study participation. Oncology nursing tasks that may have resulted in chemotherapy exposure were administration of chemotherapy and handling of body fluids that contained active metabolites of chemotherapy. Nevertheless, they did not mix chemotherapy, crush tablets, or perform any similar activities that may have resulted in additional exposure to chemotherapy. During the performance of any tasks that may have resulted in exposure to chemotherapy, oncology nurses were expected JOEM r Volume 56, Number 3, March 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

JOEM r Volume 56, Number 3, March 2014

Exposure to Cyclophosphamide in Nurses

TABLE 1. Demographic Characteristics of Study Population Total Sex Male Female Job description Oncology nurse Nononcology nurse Community control

All (90)

Exposed (27)

Nonexposed (63)

7 83

0 27

7 56

41 39 10

14 13 0

27 26 10

to wear personal protective equipment, that is, chemotherapy gowns, chemotherapy gloves, and fluid-resistant masks with eye shields and goggles. Control nurses were based in separate wards and completely segregated from the oncology ward. They did not share common nursing stations or other common working areas and did not handle any chemotherapy drugs. Occasionally, nurses from other wards are asked to work a shift in the oncology ward if staffing levels in the oncology ward are low. In this study, control nurses who had worked a shift in the oncology ward or clinic for 7 days before study participation were excluded. All participants gave their informed consent to study participation, and the study protocol was approved by the research ethics board of the Children’s Hospital of Eastern Ontario.

Data Collection Questionnaires All nurse participants completed a study questionnaire (the Appendix) that included demographic data such as sex as well as questions about location of their shift in the hospital on the day of study participation, years of experience as a nurse, and years of experience administering chemotherapy. Only oncology nurses were required to complete section B of the questionnaire, which asked about work practices on the day of study participation, for example, use of personal protective equipment such as gloves, gowns, and respiratory and eye protection during both administration of cyclophosphamide and handling of patient secretions; details of activities that may have resulted in cyclophosphamide exposure, such as connecting and disconnecting of intravenous tubing, accidental spillage of cyclophosphamide, exposure to patient secretions (urine, stool, saliva, vomit, or bathing of patient); documentation of dose of cyclophosphamide administered during that shift; and ingestion of food in an oncology area.

Exposure Assessment Biological Measures of Exposure to Cyclophosphamide Urine Collection Strategy Urine samples were collected from all nurses, starting halfway through their shift and continuing until 24 hours after the end of the shift. Starting halfway though a shift allowed time for absorption and metabolism of the drug before excretion of the active metabolites by the kidney. The sampling duration took into account the 3- to 12-hour half-life of cyclophosphamide; a 28- to 30-hour collection period captured between 2.5 to 10 half-lives of the drug.40 For the community controls, urine samples were collected over any 24-hour period that the participant found convenient. Written standardized instructions that accompanied the kit were provided to each participant.

Urine sampling procedure Each participant used a specialized kit provided by the research laboratory that did the analysis. Each kit consisted of a measuring cup to collect one entire void and 10 small tubes. A sample from each void was drawn into 1 tube with a suction device. The samples were stored in a designated hospital freezer at −20◦ C during a work shift. For samples collected at home, the participants stored the sample in their home freezer and placed the samples in the designated hospital freezer when they returned to work for their next shift. Community controls stored all samples in their home freezer and brought them to the hospital for storage in the hospital freezer once sample collection was completed. Samples were transported from the home to hospital in cooler boxes with ice packs. All urine samples from each individual were placed together in a sealed plastic bag so there was no risk of direct contact between urine tubes from different participants. Samples were batched and shipped to the Netherlands once per month for analysis and were transported on dry ice at −80◦ C.

Analysis of urine samples Analysis of all samples was done at the Exposure Control toxicology laboratory in the Netherlands. Technicians were blinded with regard to the group from which each urine sample was obtained. This laboratory specializes in the biological and environmental monitoring of occupational exposure to antineoplastic agents in hospitals and the pharmaceutical industry. Analysis was done by gas chromatography–mass spectrometry as described by Sessink et al.41 Both the lower limit of determination and the lower limit of quantification for urinary cyclophosphamide for this laboratory was 0.01 ng cyclophosphamide per milliliter of urine. Because most studies to date have used this laboratory for analysis, the method of both collection and analysis was standardized, making studies more comparable. There is no commercial center in North America, that the authors are aware of, that does urine testing for cyclophosphamide.

Environmental Measures of Exposure to Cyclophosphamide Surface Wipe Sampling Strategy Surface wipe samples, to detect the presence of cyclophosphamide, were collected from six areas in the oncology ward and clinic and in the same areas in a nononcology ward and clinic, used as controls. Sampling locations were selected on the basis of published reports that have shown the highest yield in health care settings, suggestions accompanying the kit and the researchers’ own assessments as to the locations most likely to be contaminated. Each area was sampled once. The ward areas sampled were the medication room counter and floor, the nursing station desk, a patient room floor (before and after being cleaned), and a patient bathroom floor. The clinic areas sampled were the nursing counter, the nursing floor below the nursing counter, the clinic counter, a patient room floor (before and after being cleaned), and a patient bathroom floor. The medication room is where chemotherapy bags are spiked, chemotherapy lines are primed and discarded, and chemotherapy drugs are stored; the clinic counter is where chemotherapy bags are kept before use; the nursing counter is where chemotherapy is checked; the patient room is where chemotherapy is administered, diapers, vomit, and sweat containing chemotherapy may be present, and chemotherapy spills may occur; sampling a patient room after it has been cleaned allows for assessment of the effectiveness of our cleaning policies for cytotoxic agents; a patient bathroom is where urine containing chemotherapy is present and toilet flushing can aerosolize urine; and the nursing station desk is where nurses complete their chemotherapy checking procedures, consume food, and answer telephones. The

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oncology clinic surface wipes were done in a newly built clinic that had been in use for only 1 month.

Wipe Sampling Procedure Surface wipes were done by a single pharmacist in all locations, following the standardized instructions accompanying the kit. Each kit contained 17 mL of sodium hydroxide solution, two tissues, and a container. The sodium hydroxide solution was dripped over a premarked 0.5 m2 surface, the first tissue was then used to spread the solution over the area, and the second was used to wipe it to dryness. Both tissues were then placed in a container (provided in the kit) and stored at −20◦ C in a freezer dedicated to this research project. Samples were sent for analysis within 1 month of collection to the Exposure Control toxicology laboratory in the Netherlands. Samples were transported to the laboratory on dry ice at −80◦ C and were received in good condition.

Extraction of Wipe Samples Samples were extracted using the procedure described by Sessink et al.26,42

Analysis of Wipe Samples Wipe samples were analyzed for cyclophosphamide content by gas chromatography in tandem with mass spectroscopy–mass spectroscopy.4,41 The limit of determination for cyclophosphamide in surface wipe samples for this laboratory was 16 ng of cyclophosphamide per milliliter extract, and the limit of quantification was 0.10 ng cyclophosphamide per milliliter extract.

Statistical Methods Statistical Analysis Descriptive statistics were used to summarize the characteristics of the study participants, including sex, the number of years working as a nurse, and the number of years handling chemotherapy. Continuous variables were summarized using mean, standard deviation, median, interquartile range, and range. Dichotomous variables were summarized using frequency and percentage. Presence of cyclophosphamide in at least one of each participant’s urine samples was tabulated. The proportion of nurses in which urinary cyclophosphamide is detected was estimated for each group, together with a 95% confidence interval, calculated using the Wilson score method. A two-sided Fisher exact test was used to test for a difference in these proportions between the oncology nurses and the control nurses. Two-sided P values less than 0.05 were deemed statistically significant. In addition, the Fisher exact test was used to test for a difference in these proportions between all the nurses and the community controls, between the oncology nurses and the community controls, and between the control nurses and the community controls. For each participant for whom at least one urine sample tested positive for cyclophosphamide, a graphical examination of changes over time in the rate of excretion of cyclophosphamide was performed. The excretion rate corresponding to each sample was defined to be the mass of cyclophosphamide detected (nanogram) divided by the time in minutes since the participant’s last void. If the first sample was positive for cyclophosphamide, then the excretion rate was indeterminate, because the number of minutes since the participant’s last void was not available. For nurses who administered intravenous cyclophosphamide, the graphs were annotated with the times of initiation and termination of cyclophosphamide administration. The use of personal protective equipment (gloves, gown, mask, eye protection) and practices (handwashing, hand sanitizer) 306

was summarized by potential exposure type (urine, stool, vomit, saliva, bathing). In nurses in whom cyclophosphamide was detected, total detected cyclophosphamide was examined. Because the distribution of total detected cyclophosphamide was skewed, a log transformation was applied. A t test was then used to compute log-transformed total detected cyclophosphamide between cyclophosphamide-positive oncology nurses and cyclophosphamide-positive nononcology nurses.

RESULTS Urine Samples Men accounted for 4 of 41 oncology nurses (10%), 2 of 39 nurse controls (5%), and 1 of 10 community controls (10%). Nursing experience was more than 5 years in 55 of 80 (69%), 1 to 5 years for 20 of 80 (25%), and less than 1 year in 4 of 80 (5%); data were missing for 1 participant. For oncology nurses, experience administering chemotherapy was more than 5 years for 25 of 41 (61%), 1 to 5 years for 10 of 41(24%), and less than 1 year for 5 of 41 (12%), and 1 of 41 (2%) was administering chemotherapy for the first time. One oncology nurse who had already started the urine collection did not administer cyclophosphamide on that day, because the chemotherapy administration for that patient was cancelled. In the analysis, she was considered an oncology nurse rather than a control nurse because she spent the day in the oncology clinic and was therefore potentially exposed to environmental contamination in the clinic. Cyclophosphamide was detected in at least 1 urine sample in 14 of 41 oncology nurses (34%) and 13 of 39 control nurses (33%) (P = 1.0). No cyclophosphamide was detected in any of the urine samples of the 10 community controls (Table 2). There was a statistically significant difference in the proportion of participants who tested positive between the nurses (combined oncology and control nurses) and the community controls (P = 0.03), between the control nurses and the community controls (P = 0.04), and between the oncology nurses and the community controls (P = 0.05). For the oncology nurses, there was no clear-cut correlation between the timing of the peak cyclophosphamide excretion rate and the timing of administration of cyclophosphamide. For both oncology and nononcology nurses, there were some individuals who showed marked spikes in peak cyclophosphamide excretion rates, suggesting a discrete exposure. One cyclophosphamidepositive oncology nurse did not record the total volumes of each urine void; therefore, it was not possible to calculate peak cyclophosphamide levels for her. Excluding this nurse, we examined the total cyclophosphamide detected in cyclophosphamide-positive oncology nurses and cyclophosphamide-positive nononcology nurses (Table 3).

TABLE 2. Percentage of Subjects With Detectable Levels of Urinary Cyclophosphamide*

Oncology nurses Control nurses Community controls

n

Cyclophosphamide Detected (%)

95% CI

41 39 10

14 (34) 13 (33) 0 (0)

22–49 21–50 0–28

*The Fisher exact test, not corrected for multiple testing: oncology nurses versus control nurses: P = 1.0; oncology nurses versus community controls: P = 0.05; control nurses versus external controls: P = 0.04; nurses versus external controls: P = 0.03. CI, confidence interval.





TABLE 3. Analysis of Participants With Detectable Levels of Urinary Cyclophosphamide

Cyclophosphamide, ng/24 hrs

CyclophosphamidePositive* Oncology Nurses (n = 13)

CyclophosphamidePositive* Nononcology Nurses (n = 13)

162 39 170 12 474 33 298

88 52 87 18 286 24 114

Mean Median Standard deviation Minimum level detected Maximum level detected First quartile Third quartile

TABLE 4. Amount of Cyclophosphamide Measured in Surface Wipes Collected From Areas in the Oncology and Nononcology Ward Description of Surface Medication room counter Medication room floor Nursing station desk Patient room floor (before cleaning) Patient room floor (after cleaning) Patient bathroom floor

*Cyclophosphamide positive: Participants with cyclophosphamide detected in at least one urine sample.

For oncology nurses administering chemotherapy, direct exposure to cyclophosphamide can occur at the time of connection and disconnection of the intravenous tubing to the cyclophosphamide bag. Excluding the nurse who did not administer chemotherapy, all 40 oncology nurses connected the tubing to the bag themselves, and 32 of 40 (80%) disconnected the bag themselves. During connection, all nurses wore gloves and a gown, 38 of 40 (95%) wore a mask, and 33 of 40 (83%) wore eye protection. During disconnection, all 32 nurses wore gloves, 26 of 32 (81%) wore a gown, 24 of 32 (75%) wore a mask, and 21 of 32 (66%) wore eye protection. Active metabolites of cyclophosphamide are known to be detected in secretions/excretions of patients receiving cyclophosphamide; therefore, indirect exposure to cyclophosphamide can occur at the time of contact with secretions/excretions from patients receiving cyclophosphamide (urine, saliva, vomit, stool, and bathing patient). Twenty-three of 40 oncology nurses (58%) handled urine, 1 of 40 (3%) handled stool, and no nurses handled saliva, vomit, or bathed a patient receiving cyclophosphamide. Among the 23 oncology nurses who handled urine, 1 (4%) reported direct contact of urine with skin. When handling urine, all 23 wore gloves, 10 of 23 (43%) washed their hands, 19 of 23 (83%) used a bacterial disinfectant, 4 of 23 (17%) wore a gown, 9 of 23 (39%) wore a mask, 3 of 23 (13%) wore eye protection, 21 of 23 (91%) measured urine volumes, and 16 of 23 (70%) flushed the toilet after depositing the urine in it and of these 8 of 16 (50%) covered the toilet bowl when flushing.

Surface Wipe Samples Three of six areas tested positive for cyclophosphamide in the oncology ward; results are summarized in Table 4. Surface wipe testing in the same six areas in the nononcology control ward and surface wipe testing in all six areas in both the oncology and control clinic were all negative.

DISCUSSION This study has several important findings. It demonstrated that one third of all nurses tested were positive for urinary cyclophosphamide, whereas all community controls (who had no recent exposure to the hospital environment) tested negative. This suggests that exposure to the hospital environment is the main source of exposure to cyclophosphamide. Moreover, one third of nononcology nurses (not exposed to oncology areas) tested positive, similar in number to the oncology nurses. As expected, the mean and maximum concentration of urinary cyclophosphamide were higher in the oncology nurses; however, the median concentration was slightly higher in the control nurses. This suggests that environmental contamination is

Oncology Ward Cyclophosphamide, ng/cm2

Nononcology Ward Cyclophosphamide, ng/cm2

ND ND ND 0.82

ND ND ND ND

0.79

ND

22.17

ND

ND, not detected.

widespread within the hospital and is not confined to areas where cyclophosphamide is administered. This would mean that anyone exposed to the hospital environment, including cleaners, physicians, administrators, other patients, and visitors, are all potentially at risk of exposure to cyclophosphamide and possibly other chemotherapy agents. Possible reasons for environmental contamination within the hospital may have been lack of use of closed system devices at the time of the study. Moreover, at the time of the study, chemotherapy was reconstituted by the pharmacy in a room without negative pressure. Both of these practices may have resulted in increased aerosilization of chemotherapy to work surfaces and therefore increased spread of chemotherapy throughout the hospital. Transport bins, used only for the transport of chemotherapy, were also sometimes left in patient rooms for a period of time. These contaminated bins may have resulted in further contamination of patient rooms. In addition, bathrooms contaminated with urine and other secretions that contained chemotherapy may have been spread to other parts of the hospital through cleaning practices. For example, using the same cleaning equipment in bathrooms of patients that received chemotherapy and those that did not receive chemotherapy, as well as using the same cleaning equipment in oncology and nononcology wards, may have resulted in spread of chemotherapy to “clean” bathrooms. The study also demonstrated that environmental traces of cyclophosphamide were present in some areas of the oncology ward, specifically in patient areas. A pilot study done at the same institution several months before this study showed similar findings of environmental contamination with chemotherapy mainly in patient areas. In the pilot study, 12 samples from multiple areas in the oncology ward were tested for cyclophosphamide, ifosfamide, and methotrexate. Each area was sampled once. Seven of 12 areas sampled tested positive for cyclophosphamide and ifosfamide. These areas were a patient bathroom floor, the floor below the chemotherapy bag in two patient rooms, one patient room floor at the entrance to the room, the medication room floor (where chemotherapy bags are spiked, chemotherapy lines are primed and discarded, and chemotherapy drugs are stored), and two transport bins (used to transport chemotherapy from the oncology pharmacy, where it is prepared, to the ward). An additional three samples taken from the oncology ward medication room, one sample from the nursing table (where chemotherapy is checked), and one additional sample from a transport bin tested negative for both cyclophosphamide and ifosfamide. Methotrexate was detected in a patient bathroom floor and two transport bins; the other areas tested negative. One unused wipe, also sent to enable blinded



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analysis, tested negative for all the three drugs. Pilot study results are summarized in Table 5. Health care workers have different types of exposure to chemotherapy, depending on their job description. Pharmacy personnel, especially pharmacy technicians, are exposed to a very concentrated form of the drug. However, they often have the most protection (such as biological safety cabinets and protective gear) and may be more vigilant about complying with safety precautions than health care workers who handle a more diluted form of the drug. Nurses are potentially exposed during administration of chemotherapy and when handling patient secretions. The current literature has concentrated mainly on exposure during preparation and administration of chemotherapy. There has been less focus on exposure when handling secretions of patients receiving chemotherapy and exposure through this route may be underestimated. Although the drug at this point is more dilute, the relative lack of attention to protective measures may result in significant exposure. In this study, one patient bathroom floor had more than 22 ng/cm2 of cyclophosphamide on a surface wipe. This was 27 times higher than any other area sampled. Data from the previous pilot study mentioned earlier also showed concentrations that were several fold higher for all three drugs (cyclophosphamide, ifosfamide, and methotrexate) in patient bathroom floors compared with other sites. Nursing exposure to the relatively high concentrations of chemotherapy detected in areas containing patient secretions may be particularly relevant in the pediatric setting. Pediatric nurses are more likely to be in direct contact with bodily secretions than nurses working in the adult setting, because they are required to perform tasks such as changing diapers. To the best of our knowledge, this is the first report of occupational exposure to chemotherapy exclusively in the pediatric setting. Unique issues, such as the challenge of controlling bodily secretions, may play an important role in higher exposure rates in the pediatric setting. Moreover, others in contact with these secretions (such as cleaning staff, caregivers who are changing diapers, others sharing the same bathroom as the patient) are also at increased risk of exposure, especially because the use of protective gear in these situations is minimal at best.19,23,24 Pregnant women handling secretions containing cyclophosphamide may expose their unborn fetus as well. This study also demonstrated that even after cleaning a contaminated patient room with Hospira Surface Safe pads, which consists of 2% sodium hypochlorite as the cleaning ingredient, the concentration of cyclophosphamide was almost unchanged, suggesting

that cleaning was ineffective. Moreover, the cleaning equipment used to clean the room or bathroom of a patient receiving chemotherapy is often then used to clean other nononcology patient rooms. This could potentially spread the drug to other “clean” rooms and bathrooms. It is worth noting that implementation of measures such as closed system transfer devices has no effect on reducing exposure related to secretions. This study demonstrated that cyclophosphamide continues to be secreted in the urine of health care workers for 24 hours or longer after exposure. The duration that chemotherapy is present in the urine of patients will likely be even longer, because they receive chemotherapy in concentrations that are usually more than 1000 times the concentration to which health care workers are exposed. Biological exposure may occur through the skin, inhalation, or ingestion. Therefore, it is possible that exposure may be occurring in areas not tested by surface wipes or may be occurring by means other than absorption through skin, such as inhalation of aerosolized drug particles or ingestion after skin contamination. A study by Yoshida et al43 demonstrated positive wipe samples for cyclophosphamide from the air-conditioning filter of two hospitals, and one could postulate that central air heating systems, connected to various parts of a hospital, may be similarly affected. There are three comprehensive policies at our institution for the safe handling of cytotoxic drugs. The policies are administration and safe handling of cytotoxic agents, exposure to cytotoxic agents, and safe handling of bodily fluids during the administration of cytotoxic agents. These policies fully encompass the safe handling of cytotoxic drugs, including preparation and administration of chemotherapy, as well as dealing with bodily secretions. These policies include elements of engineering controls (biological safety cabinet), personal protective equipment (chemotherapy gowns, gloves, and fluid-resistant masks), management of chemotherapy spills (spill kits, procedures), work practice requirements for pharmacy, nursing, and environmental services staff (equipment, procedures, checklists), and specific methods of disposal of contaminated fluids/supplies (flushing toilets, linens, tubing, needles, and diaper disposal). All staff working with chemotherapy are educated on these policies and procedures to reduce the risk of occupational exposure. In spite of these policies, there is considerable exposure to cyclophosphamide. This may be due, in part, to suboptimal compliance with these policies. This study revealed that full compliance with personal protective equipment is relatively high when nurses connect intravenous tubing to the cyclophosphamide bag, lower during disconnection of tubing from the bag, and very low when handling

TABLE 5. Results of Surface Wipes Collected From the Oncology Ward: Pilot Study Area Wiped Medication room floor Transport bin 1 Transport bin 2 Transport bin 3 Patient room bathroom floor Patient room 1 floor* Patient room 2 floor* Patient room floor entrance Medication room 1 Medication room 2 Medication room 3 Nursing table Unused wipe

Cyclophosphamide, ng/cm2

Ifosfamide, ng/cm2

Methotrexate, ng/cm2

0.007 ND 0.050 0.042 0.130 0.008 0.024 0.14 ND ND ND ND ND

0.036 ND 0.590 0.043 0.340 0.009 0.013 0.09 ND ND ND ND ND

ND 0.053 0.041 ND 0.340 ND ND ND ND ND ND ND ND

*Surface wipe sample taken from floor below intravenous pole holding chemotherapy bag. ND, not detected.

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secretions. It is possible that nurses view secretions as having a lower risk of exposure than the chemotherapy itself and are therefore less likely to comply with full personal protective equipment measures when handling secretions. Both this study and our pilot study have shown the opposite; the highest concentrations of chemotherapy were found in areas contaminated with body fluids. It is noteworthy that, in this study, more than 90% of nurses measured urine volumes during their shift, further increasing their exposure to cyclophosphamide. Moreover, half the nurses who flushed the toilet after depositing urine in it did not cover the toilet bowl when flushing. This omission may account, in part, for the high levels of cyclophosphamide detected in patient bathrooms. Additional measures that may help reduce environmental contamination include the following: reducing aerosolization of chemotherapy during preparation and administration (eg, by using a closed system device), finding more effective methods to clean patient rooms and changing cleaning policy (eg, by using separate cleaning equipment to clean the rooms and bathrooms of patients receiving chemotherapy, thereby preventing spread of chemotherapycontaining secretions to clean, nonchemotherapy rooms), and using disposable covers on transport bins. Given that several dozen chemotherapy drugs are routinely prepared and administered in hospitals, implementing measures to reduce both environmental contamination and biological exposure to all chemotherapy agents should be a priority at health care institutions to ensure the safety of hospital employees and members of the public who use and visit these institutions. Surface wipe testing demonstrated environmental contamination in the oncology ward but not in the oncology clinic, control ward, or control clinic. The oncology clinic was a new clinic that had been opened only 1 month before surface wipe testing. There may not have been sufficient time for detectable amounts of contamination to have occurred. Moreover, a lower total volume and lower doses of cyclophosphamide are administered in the clinic than that in the ward. This may have influenced the degree of surface contamination. For the control ward and clinic, levels of contamination may not have been high enough to be detected by surface wipe testing or, given the limited number of wipe samples taken, contaminated areas may have been missed. Alternatively, the control nurses may have been exposed either when they visited other parts of the hospital during their shift or through inhalation of aerosolized drug particles. Therefore, exposure may have occurred even if the unit they were assigned to was not contaminated. This study is different from most published studies in several important ways. It is the second-largest study to date that investigates biological exposure of nurses to chemotherapy. The larger study by Connor et al36 had 68 participants actively handling chemotherapy, of whom 47 were nurses, and 53 control participants not involved with the handling of chemotherapy, of whom 33 were nurses. They found no biological exposure in the control group and that 3 of 68 oncology personnel had detectable levels of cyclophosphamide in their urine. This study had a much higher number of participants with detectable levels of cyclophosphamide in their urine. Possible reasons for this difference may have been differences in protection guidelines between the institutions, differences in the setting (pe-

diatric compared with an adult hospital), differences in laboratory analytical techniques, or differences in sample collection. However, the limit of detection of cyclophosphamide in urine samples was similar for both studies. This was 0.01 ng cyclophosphamide per milliliter of urine in this study and 0.015 ng cyclophosphamide per milliliter of urine in the Connor study. This is the only study, of which the authors are aware, that includes two control arms: nurses not working in an area where chemotherapy is administered and community participants not exposed to the hospital environment. By including participants not exposed to the hospital environment, this study was able to demonstrate that exposure to the hospital environment is the likely source of exposure to cyclophosphamide. The study by Connor et al34 referenced earlier had one control group of health care workers not involved with the handling of chemotherapy but no community control group. A few other studies have included a small number of participants who tested positive for chemotherapy in their urine even though they did not handle the drug. However, all these participants worked in close proximity to an area handling chemotherapy.13,26,28,33,44 There are very few North American studies investigating occupational exposure of health care workers to cyclophosphamide or any other chemotherapy agent. Apart from the study by Connor et al,36 only three other small North American studies have investigated biological exposure to chemotherapy in health care workers, none of them using control groups.11,27,30 Several other small studies have looked exclusively at environmental contamination in the North American setting.29,31,34,37–39 Therefore, this large study provides new and useful information about chemotherapy exposure in the North American setting. The effect of long-term, low-grade exposure to cyclophosphamide and other chemotherapy agents has not been established. However, McDiarmid et al45 demonstrated an excess of structural and total abnormalities of chromosome 5 in health care workers handling chemotherapy compared with a control group not handling chemotherapy. This abnormality is known to be associated with therapy-related myelodysplastic syndrome and therapy-related acute myeloid leukemia.

CONCLUSION This study has demonstrated cyclophosphamide contamination of surfaces within the oncology patient environment and elevated levels of cyclophosphamide in the urine of one third of oncology and nononcology nurses. This exposure poses potential risks to all health care staff, patients, and visitors; therefore, reducing occupational exposure of chemotherapy to as low a level as possible should be a priority at all health care institutions. Further research to clarify the potential health risks, including possible increased cancer risk in exposed health care workers, is also warranted.

ACKNOWLEDGMENTS We thank Dr Paul JM Sessink (PhD) and the laboratory Exposure Control Sweden AB for analysis of the urine and surface wipe samples, Geneviève Goulet for assistance with surface wipe testing, and Melissa Morrison for assistance with the preparation of the manuscript.

APPENDIX Questionnaire: Occupational Exposure to Chemotherapy Study Participant number ____________ You are eligible to participate in this study if you are (check applicable box): A nurse at CHEO. Yes No Have not yourself taken any form of chemotherapy in the past 1 year. Yes No Have not participated in this study previously. Yes No

If you are in the control group, have not handled cyclophosphamide in the past 1 month, AND have not worked in the oncology ward, oncology clinic, or oncology pharmacy in the past 7 days. Yes No If you answered YES to all of the questions above, please CONTINUE.



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SECTION A. 1. Date and time that you started to complete questionnaire: Date: ______________ Time: _________ 2. Time shift started: __________ 3. Where did you work today? (check all that are applicable) Oncology clinic Oncology ward Nononcology clinic Nononcology ward Other, please specify __________ 4. Are you: Male Female 5. Number of years working as a nurse: 5 years 6. Number of years handling chemotherapy: Not applicable 5 years 7. Did you visit or work in any oncology area (oncology pharmacy, clinic, or ward) in the past 1 week? Yes No Unsure 8. Were you in contact with any chemotherapy in the past 1 month? Yes No Unsure For Participants who have NOT handled cyclophosphamide or the excretions/secretions of patients receiving cyclophosphamide today, you have completed the questionnaire. Thank you. For Participants who HAVE handled cyclophosphamide or the excretions/secretions of patients receiving cyclophosphamide today, please complete Section B.

SECTION B. Please complete separately for each patient who received cyclophosphamide.

Patient 1 Question 1: 1.1 Name of patient: ______________________________ 1.2 Route of administration of cyclophosphamide: Intravenous _______ Other. Please specify ______ 1.3 Time of administration __________ to __________ 1.4 Dose administered today Actual dose: ____________ Dose in mg per m2 : ____________

Question 2: 2.1 Did you connect the cyclophosphamide bag to tubing? Yes No If yes, At what time: _____________ Did you wear gloves? Yes No Unsure Did you gown? Yes No Unsure Did you wear a mask? Yes No Unsure Did you have eye protection? Yes No Unsure 2.2 Did you disconnect the cyclophosphamide infusion system? Yes No If yes, At what time: _____________ Did you wear gloves? Yes No Unsure Did you gown? Yes No Unsure Did you wear a mask? Yes No Unsure Did you have eye protection? Yes No Unsure 2.3 At any time during the shift, was there any direct contact of cyclophosphamide with your skin? Yes No Unsure

Question 3: URINE: 3.1 Did you handle the patient’s urine or urine soaked diapers? Yes No Unsure 310

If yes, Did you perform this task with: No gloves Single pair of gloves Double pair of gloves Unsure Did you Purell your hands after removing the gloves? Yes No Unsure Not applicable Did you wash your hands after removing gloves? Yes No Unsure Not applicable Was there any direct contact of urine with your skin? Yes No Unsure Did you gown when handling the patient’s urine? Yes No Unsure Did you mask when handling the patient’s urine? Yes No Unsure Did you use any form of eye protection when handling the patient’s urine? Yes No Unsure Did you measure urine volumes? Yes No Unsure Did you flush urine down the toilet? Yes No Unsure If yes, was the toilet bowl covered? Yes No Unsure

Question 4: SALIVA: 4.1 Did you handle patient’s saliva? Yes No Unsure If yes, Did you perform this task with: No gloves Single pair of gloves Double pair of gloves Did you Purell your hands after removing the gloves? Yes No Unsure Not applicable Did you wash your hands after removing the gloves? Yes No Unsure Not applicable Was there any direct contact of patient’s saliva with your skin? Yes No Unsure Did you gown when handling the patient’s saliva? Yes No Unsure Did you mask when handling the patient’s saliva? Yes No Unsure Did you use any form of eye protection when handling the patient’s saliva? Yes No Unsure

Question 5: VOMIT: 5.1 Did you handle the patient’s vomit? Yes No Unsure If yes, Did you perform this task with: No gloves Single pair of gloves Double pair of gloves Unsure Did you Purell your hands after removing gloves? Yes No Unsure Not applicable Did you wash your hands after removing gloves? Yes No Unsure Not applicable Any direct contact of patient’s vomit with your skin? Yes No Unsure Did you gown when handling patient’s vomit? Yes No Unsure Did you mask when handling patient’s vomit? Yes No Unsure Did you use any form of eye protection when handling patient’s vomit? Yes No Unsure





Question 6: STOOL: 6.1 Did you handle patient’s stool? Yes No Unsure If yes, Did you perform this task with: No gloves Single pair of gloves Double pair of gloves Unsure Did you Purell your hands after removing gloves? Yes No Unsure Not applicable Did you wash your hands after removing gloves? Yes No Unsure Not applicable Was there any direct contact of stool with your skin? Yes No Unsure Did you gown when handling patient’s stool? Yes No Unsure Did you mask when handling patient’s stool? Yes No Unsure Did you use any form of eye protection when handling patient’s stool? Yes No Unsure

Question 7: BATHING: 7.1 Did you bathe the patient? Yes No Unsure If yes, Did you perform this task with: No gloves Single pair of gloves Double pair of gloves Unsure Did you Purell your hands after removing gloves? Yes No Unsure Not applicable Did you wash your hands after removing gloves? Yes No Unsure Not applicable Was there any direct contact of bath water with your skin? Yes No Unsure Did you gown when bathing the patient? Yes No Unsure Did you mask when bathing the patient? Yes No Unsure Did you use any form of eye protection when bathing the patient? Yes No Unsure

Question 8: CYCLOPHOSPHAMIDE SPILLAGE: 8.1 Was there any accidental spillage of cyclophosphamide? Yes No If yes, Did this occur while you were wearing: No gloves Single pair of gloves Double pair of gloves Unsure Did you Purell your hands after removing gloves? Yes No Unsure Not applicable Did you wash your hands after removing gloves? Yes No Unsure Not applicable At the time of the spillage were you: Wearing a gown? Yes No Unsure Wearing a mask? Yes No Unsure Wearing any form of eye protection? Yes No Unsure

Question 9: FOOD:

9.1 Did you eat any food on the ward or the clinic area today? Yes No Unsure

Question 10: 10.1 In general, if a task involves contact with cyclophosphamide or the secretions/excretions of patients receiving cyclophosphamide that takes >15 minutes to complete, would you change gloves every 15 minutes or less? Yes No Only if gloves are soiled Unsure

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