Cyclophosphamide exposure factors in family caregivers for pediatric cancer patients.

The exposure of family caregivers to anticancer drugs for pediatric patients with malignancy is a potential health risk that needs to be minimized. We monitored the amount of cyclophosphamide (CPM) that had adhered to the undershirts of patients and the personal protective equipment (PPE) of family caregivers as well as the caregivers' urine levels of CPM within the first three days after the first and second courses of high-dose CPM therapy. Liquid chromatography/mass spectrometry (LC/MS/MS) detected >0.03 ng/ml of CPM in 26% (23/88) of urine samples from 8 of 11 (72.7%) patients' family caregivers, with a peak of 0.7 ng/ml from 24 to 48 h after administration. Since urine CPM concentrations in family caregivers varied after the first and second courses, the exposure risk factors were analyzed by scoring the PPE-wearing time index (caring minutes × PPE points from wearing masks, gloves, and/or gowns) and CPM adhesion of PPE items with the caring patterns of diaper change, washing body care, oral care, eating assistance, emotional support, and co-sleeping. The closest association was observed for CPM adhesion between oral care gloves and undershirts (correlation coefficient 0.67, p = 0.001). The mixed-effect model analysis indicated only a significant correlation between the PPE-wearing time index and emotional care (playing, cuddling, and physical contact) (p = 0.016). These results suggest that prolonged emotional support results in poor PPE protection, which increases the risk of exposure in family caregivers. Strict PPE care within 48 h after high-dose CPM controls the exposure to high-risk anticancer drugs in caregivers of pediatric patients.

Factors associated with internal contamination of nurses by antineoplastic drugs based on biomonitoring data from a previous study.

Internal contamination of healthcare professionals by antineoplastic drugs (ADs) remains a current occupational health issue, particularly because these compounds are classified as dangerous to handle by the NIOSH. In order to improve preventive actions, a study of the factors associated with this internal contamination was conducted among nursing staff in health care institutions. This study is a statistical analysis of metadata from a cross-sectional observational study conducted among nurses in two French hospitals. The internal contamination of each nurse was assessed in a previous study and was defined by whether or not at least one studied AD was detected in at least one urine sample. Three urine samples and a self-questionnaire were collected for each participant. Analysis of five ADs (cyclophosphamide, ifosfamide, metabolite of 5-fluorouracil, methotrexate, doxorubicin) were performed by liquid chromatography coupled to tandem mass spectrometry. A multivariate stepwise descending regression model was used to determine factors associated with internal contamination by coupling data from a self-questionnaire with internal contamination data. A total of 74 nurses participated to the study and 68 were included for this work: 39 nurses with and 29 without detectable internal ADs contamination. Two protective factors of internal contamination could be identified: a high "glove wearing score" (OR: 0.957; 95%CI: 0.93-0.98; p < 0.01) and a high "total number of years handling ADs and/or caring for patients treated with ADs" (OR: 0.797; 95%CI: 0.67-0.91; p < 0.01). In addition, three factors contributing to internal contamination were identified, namely "feeling sufficiently informed about tasks exposing to ADs" (OR: 9.585; 95%CI: 2.23-57.05; p < 0.01), "disposal of a waste bin containing equipment used for administration of the ADs studied" (OR: 8.04; 95%CI: 1.87-46.08; p < 0.01) and "changing sheets and/or making bed of a patient treated by one of the ADs studied" (OR: 10.479; 95%CI: 1.43-133.30; p < 0.05). Thus, the use of gloves when handling ADs directly or indirectly and the contaminating nature of certain tasks should be taken into account when (1) implementing preventive actions in health care services and (2) training and informing exposed staff. Further studies would be desirable to confirm these results and extend them to other professional categories.

Nurses' internal contamination by antineoplastic drugs in hospital centers: a cross-sectional descriptive study.

OBJECTIVE: The aim of this study was to assess internal antineoplastic drugs (ADs) contamination in the nursing staff in French hospital centers, using highly sensitive analytical methods. METHODS: This cross-sectional study included nurses practicing in care departments where at least one of the five ADs studied was handled (5-fluorouracil, cyclophosphamide, doxorubicin, ifosfamide, methotrexate). The nurses study participation lasted 24 h including collection of three urine samples and one self-questionnaire. All urine samples were assayed by ultra-high-performance liquid chromatography-tandem mass spectrometry methods with very low value of the lower limit of quantification (LLOQ). RESULTS: 74 nurses were included, 222 urine samples and 74 self-questionnaires were collected; 1092 urine assays were performed. The percentage of nurses with internal AD contamination was 60.8% and low levels of urinary concentrations were measured. Regarding nurses with internal contamination (n = 45), 42.2% presented internal contamination by methotrexate, 37.8% by cyclophosphamide, 33.3% by ifosfamide, 17.8% by 5-fluorouracil metabolite and 6.7% by doxorubicine. Among the positive assays, 17.9% (n = 26/145) were not explained by exposure data from the self-questionnaire but this could be due to the skin contact of nurses with contaminated work surfaces. CONCLUSIONS: This study reported high percentage of nurses with internal ADs contamination. The low LLOQ values of the used analytical methods, allowed the detection of ADs that would not have been detected with the current published methods: the percentage of contamination would have been 17.6% instead of the 60.8% reported here. Pending toxicological reference values, urine ADs concentrations should be reduced as low as reasonably achievable (ALARA principle).

Biomonitoring of pharmacists and nurses at occupational risk from handling antineoplastic agents.

OBJECTIVE: The objective of this study was to evaluate the frequency of genetic lesions in pharmacists and nurses who prepare and/or handle antineoplastic agents and to evaluate whether there are traces of contaminants in the urine of these professionals. METHODS: A total of 59 professionals participated in the study, of which 10 were non-exposed professionals (controls), 25 were pharmacists, and 24 were nurses. KEY FINDINGS: There was a significant increase in genetic damage in lymphocytes and cells of the oral mucosa in both pharmacists and nurses. The levels of cyclophosphamide and ifosfamide were also increased in the urine samples from those individuals. CONCLUSIONS: These results demonstrate the growing need for genetic biomonitoring and biomonitoring of trace antineoplastic agents in the urine of health professionals who prepare and/or handle antineoplastic agents.

Study protocol for the assessment of nurses internal contamination by antineoplastic drugs in hospital centres: a cross-sectional multicentre descriptive study.

INTRODUCTION: Antineoplastic drugs (AD) are potentially carcinogenic and/or reprotoxic molecules. Healthcare professionals are increasingly exposed to these drugs and can be potentially contaminated by them. Internal contamination of professionals is a key concern for occupational physicians in the assessment and management of occupational risks in healthcare settings. Objectives of this study are to report AD internal contamination rate in nursing staff and to identify factors associated with internal contamination. METHODS AND ANALYSIS: This trial will be conducted in two French hospital centres: University Hospital of Bordeaux and IUCT-Oncopole of Toulouse. The target population is nurses practicing in one of the fifteen selected care departments where at least one of the five studied AD is handled (5-fluorouracil, cyclophosphamide, doxorubicin, ifosfamide, methotrexate). The trial will be conducted with the following steps: (1) development of analytical methods to quantify AD urine biomarkers, (2) study of the workplace and organization around AD in each care department (transport and handling, professional practices, personal and collective protection equipments available) (3) development of a self-questionnaire detailing professional activities during the day of inclusion, (4) nurses inclusion (urine samples and self-questionnaire collection), (5) urine assays, (6) data analysis. ETHICS AND DISSEMINATION: The study protocol has been approved by the French Advisory Committee on the Treatment of Information in Health Research (CCTIRS) and by the French Data Protection Authority (CNIL). Following the opinion of the Regional Committee for the Protection of Persons, this study is outside the scope of the provisions governing biomedical research and routine care (n°2014/87). The results will be submitted to peer-reviewed journals and reported at suitable national and international meetings. TRIAL REGISTRATION NUMBER: NCT03137641.

Closed-system drug-transfer devices plus safe handling of hazardous drugs versus safe handling alone for reducing exposure to infusional hazardous drugs in healthcare staff.

BACKGROUND: Occupational exposure to hazardous drugs can decrease fertility and result in miscarriages, stillbirths, and cancers in healthcare staff. Several recommended practices aim to reduce this exposure, including protective clothing, gloves, and biological safety cabinets ('safe handling'). There is significant uncertainty as to whether using closed-system drug-transfer devices (CSTD) in addition to safe handling decreases the contamination and risk of staff exposure to infusional hazardous drugs compared to safe handling alone. OBJECTIVES: To assess the effects of closed-system drug-transfer of infusional hazardous drugs plus safe handling versus safe handling alone for reducing staff exposure to infusional hazardous drugs and risk of staff contamination. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, OSH-UPDATE, CINAHL, Science Citation Index Expanded, economic evaluation databases, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to October 2017. SELECTION CRITERIA: We included comparative studies of any study design (irrespective of language, blinding, or publication status) that compared CSTD plus safe handling versus safe handling alone for infusional hazardous drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and extracted data. We calculated the risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models. We assessed risk of bias according to the risk of bias in non-randomised studies of interventions (ROBINS-I) tool, used an intracluster correlation coefficient of 0.10, and we assessed the quality of the evidence using GRADE. MAIN RESULTS: We included 23 observational cluster studies (358 hospitals) in this review. We did not find any randomised controlled trials or formal economic evaluations. In 21 studies, the people who used the intervention (CSTD plus safe handling) and control (safe handling alone) were pharmacists or pharmacy technicians; in the other two studies, the people who used the intervention and control were nurses, pharmacists, or pharmacy technicians. The CSTD used in the studies were PhaSeal (13 studies), Tevadaptor (1 study), SpikeSwan (1 study), PhaSeal and Tevadaptor (1 study), varied (5 studies), and not stated (2 studies). The studies' descriptions of the control groups were varied. Twenty-one studies provide data on one or more outcomes for this systematic review. All the studies are at serious risk of bias. The quality of evidence is very low for all the outcomes.There is no evidence of differences in the proportion of people with positive urine tests for exposure between the CSTD and control groups for cyclophosphamide alone (RR 0.83, 95% CI 0.46 to 1.52; I² = 12%; 2 studies; 2 hospitals; 20 participants; CSTD: 76.1% versus control: 91.7%); cyclophosphamide or ifosfamide (RR 0.09, 95% CI 0.00 to 2.79; 1 study; 1 hospital; 14 participants; CSTD: 6.4% versus control: 71.4%); and cyclophosphamide, ifosfamide, or gemcitabine (RR not estimable; 1 study; 1 hospital; 36 participants; 0% in both groups).There is no evidence of a difference in the proportion of surface samples contaminated in the pharmacy areas or patient-care areas for any of the drugs except 5-fluorouracil, which was lower in the CSTD group than in the control (RR 0.65, 95% CI 0.43 to 0.97; 3 studies, 106 hospitals, 1008 samples; CSTD: 9% versus control: 13.9%).The amount of cyclophosphamide was lower in pharmacy areas in the CSTD group than in the control group (MD -49.34 pg/cm², 95% CI -84.11 to -14.56, I² = 0%, 7 studies; 282 hospitals, 1793 surface samples). Additionally, one interrupted time-series study (3 hospitals; 342 samples) demonstrated a change in the slope between pre-CSTD and CSTD (3.9439 pg/cm², 95% CI 1.2303 to 6.6576; P = 0.010), but not between CSTD and post-CSTD withdrawal (-1.9331 pg/cm², 95% CI -5.1260 to 1.2598; P = 0.20). There is no evidence of difference in the amount of the other drugs between CSTD and control groups in the pharmacy areas or patient-care areas.None of the studies report on atmospheric contamination, blood tests, or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction.None of the studies report short-term health benefits such as reduction in skin rashes, medium-term reproductive health benefits such as fertility and parity, or long-term health benefits related to the development of any type of cancer or adverse events.Five studies (six hospitals) report the potential cost savings through the use of CSTD. The studies used different methods of calculating the costs, and the results were not reported in a format that could be pooled via meta-analysis. There is significant variability between the studies in terms of whether CSTD resulted in cost savings (the point estimates of the average potential cost savings ranged from (2017) USD -642,656 to (2017) USD 221,818). AUTHORS' CONCLUSIONS: There is currently no evidence to support or refute the routine use of closed-system drug transfer devices in addition to safe handling of infusional hazardous drugs, as there is no evidence of differences in exposure or financial benefits between CSTD plus safe handling versus safe handling alone (very low-quality evidence). None of the studies report health benefits.Well-designed multicentre randomised controlled trials may be feasible depending upon the proportion of people with exposure. The next best study design is interrupted time-series. This design is likely to provide a better estimate than uncontrolled before-after studies or cross-sectional studies. Future studies may involve other alternate ways of reducing exposure in addition to safe handling as one intervention group in a multi-arm parallel design or factorial design trial. Future studies should have designs that decrease the risk of bias and enable measurement of direct health benefits in addition to exposure. Studies using exposure should be tested for a relevant selection of hazardous drugs used in the hospital to provide an estimate of the exposure and health benefits of using CSTD. Steps should be undertaken to ensure that there are no other differences between CSTD and control groups, so that one can obtain a reasonable estimate of the health benefits of using CSTD.

Antineoplastic drug residues inside homes of chemotherapy patients.

Chemotherapy treatment of cancer patients has shifted from inpatient to outpatient administration. Thus, family members are potentially exposed to cytotoxic drug residues from patients' excretions inside their homes. The study's aim was to evaluate the surface contamination and the potential uptake of antineoplastic drug residues by family members at home of chemotherapy patients. Overall, 265 wipe samples from 13 homes were taken at two times after chemotherapy from different surfaces (toilet, bathroom, kitchen). 62 urine samples were collected from patients and family members on three days. Samples were analyzed for cyclophosphamide, 5-fluorouracil (urine: FBAL) and platinum (as marker for cis-, carbo- and oxaliplatin). Substantial contamination was found on every surface type (PT: 0.02-42.5pg/cm2, 5-FU: ND-98.3pg/cm2, CP: ND-283.3pg/cm2) with highest concentrations on toilet and bathroom surfaces. While patients' urinary drug concentrations often were elevated for more than 48h after administration, no drug residues were detectable in the family members' urine. This study provided an insight in the exposure situation against antineoplastic drug residues at home of chemotherapy patients. As contamination could be found on various surfaces adequate hygienic and protective measures are necessary to minimize the exposure risk for cohabitants.

Pilot study of biological monitoring of four antineoplastic drugs among Canadian healthcare workers.

Purpose There are health risks to workers occupationally exposed to antineoplastic drugs. We hypothesized that implementing a biological monitoring program would be feasible. The goal was to present the results of our pilot cross-sectional study of biological monitoring of four antineoplastic drugs. Methods We recruited workers from the hematology-oncology department and control workers in a mother-child university health center. This study was preceded by an information period during which we aimed at enhancing the workers' awareness and knowledge of the risks of occupational exposure. Participants filled out a journal containing activities performed and personal protective equipment worn. One urine sample was collected at the end of their shift. Samples were analyzed by UPLC/MS-MS for the presence of cyclophosphamide, ifosfamide, methotrexate, and alpha-fluoro-beta-alanine (5-fluorouracile's main urinary metabolite). Results The participation rate was 85.7% (102/119). No urine sample had detectable concentrations of any of the four drugs evaluated (0/101; 0/74 nurses, 0/11 pharmacists, 0/9 pharmacy technicians, and 0/7 doctors). In the 5 days before sampling, 67/92 (72.8%) hematology-oncology participants performed at least one activity with antineoplastic drugs. Nurses wore all of the recommended protection for technical activities (86.2%), but rarely for non-technical activities (14.9%). Pharmacists and pharmacy technicians wore all of the recommended protection for all activities (100.0%). Conclusions This pilot study had a good participation rate. The absence of positive samples was a good indication that the measures in place ensured workers' safety, even though we found areas where the worker protection can be enhanced.

Occupational exposures among nurses caring for chemotherapy patients -Quantitative analysis of cyclophosphamide and α-fluoro-ß-alanine in urine.

OBJECTIVES: The aim of this study was to measure the antineoplastic drug content in urine and verify the situation of occupational exposure of the antineoplastic drug among nurses who care for patients undergoing chemotherapy. METHODS: Ten female nurses who were caring for patients receiving chemotherapy were the subjects of this study. Urine samples were collected over 24-hour periods, and each sample was analyzed. The excretion of cyclophosphamide (CP) and α-fluoro-ß-alanine (FBAL) were measured in the urine of the 10 nurses. CP and FBAL were detected separately using gas chromatography tandem mass spectrometry (GC-MSMS) methods (Exposure Control, the Netherlands). RESULT: CP was detected in 24 urine samples of 9 nurses. The total amount of CP excreted ranged from 5.4 to 44.2 ng/24-hours. The mean amount of CP excreted per nurse was 16.8 ng/24-hours. No significant difference was observed between the hospital I and II. FBAL was not detected in any of the urine samples. CP was detected in the urine of the nurses prior to their work shift. Moreover, CP was detected in the urine of the nurses who were not caring for patients in the intravenous drip of CP. There was most what answered that there was hair loss in health condition. CONCLUSION: The results reveal that almost all nurses were exposed to cyclophosphamide. Even when the patient in the intravenous drip of CP was not being cared for, it became clear that exposure by CP existed. As the route of the exposure to CP, the inhalation or dermal absorption can be considered. To ensure minimum exposed to antineoplastic drugs, suitable personal protective equipment needs to be equipped also of various scenes of caring for chemotherapy patients. Moreover, it is important to keep an eye on the monitoring of the antineoplastic drug in the environment and a nurse's health condition periodically going forward.

Quantitation of anticancer drugs - Cyclophosphamide and ifosfamide in urine and water sewage samples by gas chromatography-mass spectrometry.

OBJECTIVES: Cyclophosphamide (CP) and ifosfamide (IF) are effective anti-cancer drugs but their genotoxicity can harm everyone contacting them occupationally or environmentally. Therefore, a sensitive method for monitoring their amounts in biological and environmental samples is needed. This has aimed to develop a method for analyzing these drugs in urine and water sewage samples. MATERIAL AND METHODS: The drug spiked samples were extracted, derivatized, and analyzed by gas chromatography-mass spectrometry and the analytical parameters were validated. RESULTS: The method gave linear calibration curves at the concentrations of 0-190 nmol/l. It had the quantitation limit of 3.8 nmol/l and showed acceptable specificity, accuracy, recovery and precision. CONCLUSIONS: The developed method can be used reliably for monitoring CP and IF concentrations in urine and water sewage. The method will be applied for preventing health risk from occupational and environmental exposures to these drugs. Int J Occup Med Environ Health 2016;29(5):815-822.

Secondary Exposure of Family Members to Cyclophosphamide After Chemotherapy of Outpatients With Cancer: A Pilot Study.

PURPOSE/OBJECTIVES: To measure the total amount of cyclophosphamide (CPA) excreted in the urine of patients with cancer and their cohabitating family members seven days after CPA administration. DESIGN: Biological monitoring.
. SETTING: Home setting with outpatients receiving chemo-therapy. SAMPLE: 8 patients administered CPA, 10 cohabitating family members, and 10 control participants. METHODS: During the first seven days after CPA administration, urine samples were collected from the participants. The samples were analyzed for the unchanged form of CPA using gas chromatography in tandem with mass spectroscopy. MAIN RESEARCH VARIABLES: CPA levels
. FINDINGS: CPA was detected in 112 of 276 patient urine samples. The last sample containing detectable CPA levels was collected after more than 48 hours in 63% of the patients, with a maximum length of five days post-treatment. In addition, 243 urine samples were collected from family members, and CPA was detected in the samples of five family members (17-252 ng per member). CPA was not detected in any control participants. CONCLUSIONS: These findings indicate that family members in close contact with patients receiving CPA are at high risk for drug exposure as many as seven days post-treatment
. IMPLICATIONS FOR NURSING: Nurses should educate patients and their family members about preventing exposure to antineoplastic drugs in the home setting.


Antineoplastic drug contamination in the urine of Canadian healthcare workers.

PURPOSE: The purpose of this study was to quantify the urine concentration of non-metabolized cyclophosphamide (CP), a commonly administered antineoplastic drug, among potentially exposed Canadian healthcare workers and to identify factors associated with the drug concentration levels. METHODS: Participants were asked to provide two sets of 24-h urine samples (at two different sampling events), and the level of CP was quantified using high-performance liquid chromatography-tandem mass spectrometry. In addition to demographic information, participants were surveyed regarding their frequency of handling of antineoplastic drugs, safe drug handling training, and known contact with CP on their work shift. Descriptive and inferential statistical analyses were performed. A backward stepwise linear mixed effect model was conducted to identify the factors associated with urine concentration levels. RESULTS: We collected 201 urine samples, and 55 % (n = 111) had levels greater than the LOD of 0.05 ng/mL. The mean urinary CP concentration was 0.156 ng/mL, the geometric mean was 0.067 ng/mL, the geometric standard deviation was 3.18, the 75th percentile was 0.129 ng/mL, and the range was

Environmental contamination, product contamination and workers exposure using a robotic system for antineoplastic drug preparation.

Environmental contamination, product contamination and technicians exposure were measured following preparation of iv bags with cyclophosphamide using the robotic system CytoCare. Wipe samples were taken inside CytoCare, in the clean room environment, from vials, and prepared iv bags including ports and analysed for contamination with cyclophosphamide. Contamination with cyclophosphamide was also measured in environmental air and on the technicians hands and gloves used for handling the drugs. Exposure of the technicians to cyclophosphamide was measured by analysis of cyclophosphamide in urine. Contamination with cyclophosphamide was mainly observed inside CytoCare, before preparation, after preparation and after daily routine cleaning. Contamination outside CytoCare was incidentally found. All vials with reconstituted cyclophosphamide entering CytoCare were contaminated on the outside but vials with powdered cyclophosphamide were not contaminated on the outside. Contaminated bags entering CytoCare were also contaminated after preparation but non-contaminated bags were not contaminated after preparation. Cyclophosphamide was detected on the ports of all prepared bags. Almost all outer pairs of gloves used for preparation and daily routine cleaning were contaminated with cyclophosphamide. Cyclophosphamide was not found on the inner pairs of gloves and on the hands of the technicians. Cyclophosphamide was not detected in the stationary and personal air samples and in the urine samples of the technicians. CytoCare enables the preparation of cyclophosphamide with low levels of environmental contamination and product contamination and no measurable exposure of the technicians.

Occupational exposure to cyclophosphamide in nurses at a single center.

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.

Evaluación de la exposición ocupacional a Ciclofosfamida en nueve hospitales del Perú / Evaluation of occupational exposure to Cyclophosphamide in nine hospitals of Peru

Objetivos. Evaluar la exposición ocupacional a ciclofosfamida en nueve hospitales del Perú. Materiales y métodos. Estudio observacional de tipo transversal realizado durante el año 2010 en el cual se colectó muestras de orina de 24 h de 96 trabajadores de las unidades de mezclas oncológicas y servicios de oncología de nueve hospitales del Perú, la cuantificación de ciclofosfamida se realizó por la metodología de GC-MS ( Gas Cromathography-Mass Spectroscopy). Se realizó, además, muestreo de superficies de trabajo utilizando paños húmedos para la determinación de ciclofosfamida. Resultados. Se detectó la presencia de ciclofosfamida en orina en 67 trabajadores (concentración promedio de excreción: 74,2 ng/24 h), lo cual representa el 70% del total de la población evaluada. Basado en la excreción se puede clasificar la exposición total entre los hospitales, en términos de exposición alta (>18,9 ng/24 h), moderada (1,725 - 18,9 ng/24 h) y baja (<1,725 ng/24 h), con una frecuencia porcentual de 31,3; 26,0 y 42,7% respectivamente. Además, como parte de la evaluación ambiental, se encontró concentraciones de ciclofosfamida de 14,72, 14,98 y 5,12 ng/cm².Conclusiones. Se evidencia una contaminación por ciclofosfamida en las áreas donde se realizan los preparados oncológicos y la presencia de ciclofosfamida en muestras de orina de trabajadores expuestos a citostáticos.

Objetives. Evaluate occupational exposure to cyclophosphamide in nine hospitals of Peru. Materials and methods. Cross-cutting observational study conducted in 2010, for which 24-hour urine samples were obtained from 96 employees of the oncologic mixture units and oncology services of nine hospitals in Peru, the quantification of cyclophosphamide was done through the GC-MS methodology ( Gas Cromathography-Mass Spectroscopy). Additionally, working surfaces were tested by obtaining samples with wet wipes for identification of cyclophosphamide. Results. Cyclophosphamide was detected in urine samples in 67 employees (average concentration of excretion: 74.2 ng/24 h), accounting for 70% of the total population to be assessed. Based on the excretion, total exposure among hospitals can be classified as high level (>18.9 ng/24 h), moderate level (1,725 - 18.9 ng/24 h) and low level (<1,725 ng/24 h), with a percent incidence of 31.3; 26.0 and 42.7% respectively. Additionally, as part of the environmental evaluation, concentrations of cyclosphamide were found in 14.72, 14.98 and 5,12 ng/cm2. Conclusions. Contamination through cyclophosphamide in areas where oncological preparations are done and the presence of cyclophosphamide in urine samples of workers exposed to cytostatics substance were observed.

Exposure of family members to antineoplastic drugs via excreta of treated cancer patients.

PURPOSES: (a) To measure the urinary excretion of antineoplastic drugs of three patients during 48 h after the administration of cyclophosphamide (two patients) and 5-fluorouracil (one patient). (b) To evaluate environmental contamination with antineoplastic drugs via excreta of patients in the home setting. (c) To evaluate exposure of family members to antineoplastic drugs by measuring the drugs in their urine during the 48 h after completion of the chemotherapy by the patients. METHODS: Two patients were administered cyclophosphamide by i.v. bolus injection. One patient was administered 5-fluorouracil by i.v. bolus injection and thereafter immediately administered the same drug by continuous infusion for 46 h. Urine samples from the patients administered cyclophosphamide and their family members, and wipe samples from their home environment, were analysed for the unchanged form of cyclophosphamide. For 5-fluorouracil, the urine samples from the patient and the family member were analysed for the 5-fluorouracil metabolite α-fluoro-ß-alanine. Wipe samples were analysed for 5-fluorouracil. Drugs were detected and quantified with gas chromatography in tandem with mass spectroscopy-mass spectroscopy or by high-performance liquid chromatography with ultraviolet-light detection. RESULTS: A total of 35 and 16 urine samples were collected from the three patients and their family members, respectively. The drugs were detected in all samples. Cyclophosphamide was detected at levels of 0.03-7.34 ng/cm(2) in 8 of the 12 wipe samples obtained from the homes of the patients administered cyclophosphamide. For the patient administered 5-fluorouracil, drug levels in his home environment were below the limit of detection. CONCLUSION: We demonstrated contamination of the home setting and exposure of family members to cyclophosphamide via the excreta of outpatient receiving chemotherapy. Exposure of the family member of the patient administered 5-fluorouracil was also demonstrated. These findings indicate the importance of strict precautions by the members of treated cancer patients as well as healthcare workers, to reduce the risk of exposure to antineoplastic drugs.

Involvement of interleukin-6-regulated nitric oxide synthase in hemorrhagic cystitis and impaired bladder contractions in young rats induced by acrolein, a urinary metabolite of cyclophosphamide.

Hemorrhagic cystitis is a common complication in children receiving cyclophosphamide, a chemotherapeutic alkylating agent. Acrolein is a urinary metabolite from cyclophosphamide and can induce hemorrhagic cystitis. Here, we investigated the effects and mechanisms of acrolein by intravesical instillation on urinary bladder muscle contractions and pathological alterations in rats. Acrolein instillation significantly increased the muscle contractions of rat bladder detrusor after 1 and 6 h but markedly decreased detrusor contractions after 24 h. Acrolein increased phosphorylated protein kinase C (pan-PKC) expressions in bladders after 1 and 6 h but inhibited it after 24 h. Inducible nitric oxide (NO) synthase (iNOS) protein expressions were markedly induced in bladders 24 h after acrolein treatment. Twenty-four-hour acrolein instillation increased the levels of nitrite/nitrate and interleukin-6 (IL-6) in the urinary bladder. The iNOS inhibitors significantly inhibited the acrolein-increased nitrite/nitrate levels, but not IL-6 levels. IL-6-neutralizing antibodies effectively inhibited the acrolein-increased NOx levels. The increased detrusor contractions by 1-h acrolein treatment were significantly reversed by the PKC inhibitor RO32-0432, and the decreased detrusor contractions by 24-h acrolein treatment were significantly reversed by the iNOS inhibitor and IL-6-neutralizing antibody. Both the iNOS inhibitor and IL-6-neutralizing antibody effectively reversed the increased iNOS expression, decreased PKC phosphorylation, increased bladder weight, and hemorrhagic cystitis in rats 24 h after acrolein treatment. Taken together, these results suggest that an IL-6-regulated iNOS/NO signaling pathway participates in the acrolein-triggered detrusor contraction inhibition and hemorrhagic cystitis. These findings may help us to find a new strategy to treat cyclophosphamide-induced hemorrhagic cystitis.

[Evaluation of occupational exposure to cyclophosphamide in nine hospitals of Peru]. / Evaluación de la exposición ocupacional a Ciclofosfamida en nueve hospitales del Perú

OBJECTIVES: Evaluate occupational exposure to cyclophosphamide in nine hospitals of Peru. MATERIALS AND METHODS: Cross-cutting observational study conducted in 2010, for which 24-hour urine samples were obtained from 96 employees of the oncologic mixture units and oncology services of nine hospitals in Peru, the quantification of cyclophosphamide was done through the GC-MS methodology ( Gas Cromathography-Mass Spectroscopy). Additionally, working surfaces were tested by obtaining samples with wet wipes for identification of cyclophosphamide. RESULTS: Cyclophosphamide was detected in urine samples in 67 employees (average concentration of excretion: 74.2 ng/24 h), accounting for 70% of the total population to be assessed. Based on the excretion, total exposure among hospitals can be classified as high level (>18.9 ng/24 h), moderate level (1,725 - 18.9 ng/24 h) and low level (<1,725 ng/24 h), with a percent incidence of 31.3; 26.0 and 42.7% respectively. Additionally, as part of the environmental evaluation, concentrations of cyclosphamide were found in 14.72, 14.98 and 5,12 ng/cm2. CONCLUSIONS: Contamination through cyclophosphamide in areas where oncological preparations are done and the presence of cyclophosphamide in urine samples of workers exposed to cytostatics substance were observed.

Biological monitoring of occupational exposure to antineoplastic drugs in hospital settings.

BACKGROUND: In view of the evidence of cytotoxicity of chemotherapic antineoplastic drugs (AD), current guidelines recommend the evaluation of the health risks of hospital personnel exposed to these compounds. Biological monitoring is the main tool to evaluate all possible drug intake and measure workers' real risk. OBJECTIVES: The aim of this study was to assess occupational exposure toAD in a large hospital in Northern Italy in order to verify the effectiveness of the structural and procedural improvements carried out over the last decade. METHODS: Three biological monitoring campaigns were performed using LC-MS/MS analysis of cyclophosphamide (CP) and metotrexate (MTX) as biomarkers of internal dose in the urine of hospital workers. In the first two campaigns, 50 and 81 workers respectively were monitored during AD preparation operations. The last campaign, concerning AD administration activity, was performed after a centralized preparation unit had been set up. Two environmental monitoring campaigns were carried out as well, to complete AD exposure assessment. RESULTS: During the first monitoring campaign we found positive urinary samples in all the wards studied (total positivity 36%), whereas in the second campaign 11% of the samples were positive and four departments showed negative results in all urine samples. The last campaign showed all urinary CP and MTX levels below the detection limit of the analytical method CONCLUSION: Exposure of oncology ward nurses considerably decreased due to the centralization of AD preparation operations together with training and education of workers. The last biological monitoring results were reassuring; nevertheless, surface contamination still occurred and safety measures should be further improved in order to achieve the lowest reasonably possible contamination levels.

Verification of surface contamination of Japanese cyclophosphamide vials and an example of exposure by handling.

PURPOSE: Cyclophosphamide (CP) contamination has been detected in Japanese hospitals. In other countries, the surface contamination of CP vials has been reported; however, the manufacturing process of Japanese CP vials is unknown, so the conditions are not necessarily the same as in other countries. This study aimed to establish whether vial surface contamination also occurs in Japan. METHOD: Contamination of vial surfaces was examined with a wipe test. Urine samples were taken from a pharmacist, engaged solely in dispensing work, for 29 h. It was also investigated whether CP vials were dispensed during the urine sampling period. In addition, vial surfaces, purposely coated with CP and then washed, were examined using wipe tests. RESULT: CP was detected at 30-60% in vials, which was 11-62 ng (0.10-0.54 ng/cm(2)). One of the urine samples was contaminated (CP 13.5 ng); this was taken on Day 2 (11:35 AM). CP was not detected among the washed vials. DISCUSSION: This study shows that the surface of Japanese CP vials was contaminated and that it was probable that healthcare workers were exposed to CP. CP absorption by the pharmacist was probably due to dermal uptake while dispensing. Washing the vial is considered effective to avoid CP exposure. Manufacturers should be more proactive to prevent contamination and healthcare workers should comply with exposure prevention rules. Cytotoxic drugs should be included in institution monitoring lists.