The efficiency of antineoplastic drug contamination removal by widely used disinfectants-laboratory and hospital studies.

OBJECTIVE: Antineoplastic drugs (ADs) pose risks to healthcare staff. Surface disinfectants are used in hospitals to prevent microbial contamination but the efficiency of disinfectants to degrade ADs is not known. We studied nine disinfectants on ten ADs in the standardized laboratory and realistic in situ hospital conditions. METHODS: A survey in 43 hospitals prioritized nine most commonly used disinfections based on different ingredients. These were tested on inert stainless steel and in situ on contaminated hospital flooring. The effects against ten ADs were studied by LC-MS/MS (Cyclophosphamide CP; Ifosfamide IF; Capecitabine CAP; Sunitinib SUN; Methotrexate MET; Doxorubicin DOX; Irinotecan IRI; Paclitaxel PX; 5-Fluorouracil FU) and ICP-MS (Pt as a marker of platinum-based ADs). RESULTS: Monitoring of the floor contamination in 26 hospitals showed that the most contaminated are the outpatient clinics that suffer from a large turnover of staff and patients and have limited preventive measures. The most frequent ADs were Pt, PX, FU and CP with maxima exceeding the recommended 1 ng/cm2 limit by up to 140 times. IRI, FU, MET, DOX and SUN were efficiently removed by hydrolysis in clean water and present thus lower occupational risk. Disinfectants based on hydrogen peroxide were efficient against PX and FU (> 70% degradation) but less against other ADs, such as carcinogenic CP or IF, IRI and CAP. The most efficient were the active chlorine and peracetic acid-based products, which however release irritating toxic vapors. The innovative in situ testing of ADs previously accumulated in hospital flooring showed highly problematic removal of carcinogenic CP and showed that alcohol-based disinfectants may mobilize persistent ADs contamination from deeper floor layers. CONCLUSION: Agents based on hydrogen peroxide, peracetic acid, quaternary ammonium salts, glutaraldehyde, glucoprotamine or detergents can be recommended for daily use for both disinfection and AD decontamination. However, they have variable efficiencies and should be supplemented by periodic use of strong chlorine-based disinfectants efficient also against the carcinogenic and persistent CP.

Evaluation of the efficacy of additional measures introduced for the protection of healthcare personnel handling antineoplastic drugs.

OBJECTIVES: Due to their adverse effects, antineoplastic drugs are considered as a potential health risk to healthcare personnel. The objective of the study was to compare the surface contamination level of the conventional preparation room and outpatient clinic before and after the implementation of a set of additional protective measures. METHODS: The measures were targeted at eliminating potential sources of environmental contamination, and modification of the cleaning procedure. The measures introduced into the preparation room consisted of (i) the introduction of manual cleaning of drug vials before they enter the preparation room, (ii) the modification of the routine cleaning procedure performed at the end of each working day (i.e. shifting the cleaning of the isolators as the most contaminated objects from the beginning of the cleaning process to the end), and (iii) the introduction of regular cleaning of the work table every 2 h. The measures introduced into the outpatient clinic consisted of (i) replacement of the standard infusion sets with multichannel sets for safe drug administration, (ii) the introduction of self-cleaning seats to the patient lavatories supporting hygienic and contamination-free seated urination, and (iii) replacement of standard infusion stands with wall-mounted stands, supporting the regular and proper cleaning of the floor beneath. To determine the surface contamination level with antineoplastic drugs, cyclophosphamide and platinum were determined in wipe samples with high performance liquid chromatography with tandem mass spectrometry and inductively coupled plasma mass spectrometry. RESULTS: In the preparation room, depending on the sampling spot and analyte, median concentrations ranged from 5 to 267 pg cm(-2) and from 2 to 368 pg cm(-2) before and after implementation of the measures, respectively. In the outpatient clinic, median concentrations ranged from 5 to 5310 pg cm(-2) and from <0.2 to 574 pg cm(-2) before and after implementation of the measures, respectively. Depending on the sampling spot, median contamination of the outpatient clinic with cyclophosphamide and platinum was reduced by 57-99% and 61-98%, respectively. CONCLUSIONS: The measures implemented in the outpatient clinic were shown to reduce workplace contamination effectively. Therefore, they can be recommended also for other workplaces where antineoplastic drugs are administered. In contrast, measures implemented in the preparation room, where relatively strict regulations had already been adopted before the study, were less effective. To decrease the actual contamination of the preparation room, other protective measures (e.g. closed-system transfer devices) should be considered.

Proposals of guidance values for surface contamination by antineoplastic drugs based on long term monitoring in Czech and Slovak hospitals and pharmacies.

Introduction: The exposures to hazardous antineoplastic drugs (AD) represent serious risks for health care personnel but the exposure limits are not commonly established because of the no-threshold effects (genotoxic action, carcinogenicity) of many ADs. In this study, we discussed and derived practically applicable technical guidance values (TGV) suitable for management of AD risks. Methods: The long-term monitoring of surface contamination by eight ADs was performed in pharmacies and hospitals in the Czech Republic and Slovak Republic in 2008-2021; in total 2,223 unique samples were collected repeatedly in 48 facilities. AD contamination was studied by LC-MS/MS for cyclophosphamide, ifosfamide, methotrexate, irinotecan, paclitaxel, 5-fluorouracil and gemcitabine and by ICP-MS for total Pt as a marker of platinum-based ADs. Results: The study highlighted importance of exposure biomarkers like 5-fluorouracil and especially carcinogenic and persistent cyclophosphamide, which should be by default included in monitoring along with other ADs. Highly contaminated spots like interiors of laminar biological safety cabinets represent a specific issue, where monitoring of contamination does not bring much added value, and prevention of staff and separated cleaning procedures should be priority. Rooms and surfaces in health care facilities that should be virtually free of ADs (e.g., offices, kitchenettes, daily rooms) were contaminated with lower frequency and concentrations but any contamination in these areas should be carefully examined. Discussion and conclusions: For all other working places, i.e., majority of areas in pharmacies and hospitals, where ADs are being prepared, packaged, stored, transported, or administered to patients, the study proposes a generic TGV of 100 pg/cm2. The analysis of long-term monitoring data of multiple ADs showed that the exceedance of one TGV can serve as an indicator and trigger for improvement of working practices contributing thus to minimizing of unintended exposures and creating a safe work environment.

Levels and risks of surface contamination by thirteen antineoplastic drugs in the Czech and Slovak hospitals and pharmacies.

The consumption of hazardous antineoplastic drugs (ADs) used in anticancer chemotherapies is steadily increasing representing thus risks to both human health and the environment. Hospitals may serve as a contamination source, and pharmacists preparing the antineoplastic drugs (ADs) as well as nurses administering chemotherapy and caring for oncology patients are among the healthcare professionals being highly exposed. Here, we present the results of systematic monitoring (2018-2020) of surface contamination by 13 ADs in the pharmacies and hospitals in the Czech Republic (CZ; large-scale monitoring, 20 workplaces) and Slovak Republic (SK; pilot study at 4 workplaces). The study evaluated contamination by three commonly monitored ADs, i.e., 5-fluorouracil (FU), cyclophosphamide (CP), and platinum (total Pt representing cis-, carbo-, and oxaliplatin) together with ten less explored ADs, i.e., gemcitabine (GEM), ifosfamide (IF), paclitaxel (PX), irinotecan (IRI), docetaxel (DOC), methotrexate (MET), etoposide (ETOP), capecitabine (CAP), imatinib (IMAT), and doxorubicin (DOX). Floors and desktop surfaces in hospitals (chemotherapy application rooms, nurse working areas) were found to be more contaminated, namely with CP and Pt, in both countries when compared to pharmacies. Comparison between the countries showed that hospital surfaces in SK are generally more contaminated (e.g., CP median was 20 times higher in SK), while some pharmacy areas in the CZ were more contamined in comparison with SK. The newly studied ADs were detected at lower concentrations in comparison to FU, CP, and Pt, but some markers (GEM, IF, PX, and IRI) were frequently observed, and adding these compounds to routine monitoring is recommended.

Utilization of the solid sorbent media in monitoring of airborne cyclophosphamide concentrations and the implications for occupational hygiene.

The main objective of the study was to evaluate the applicability of two solid sorbent media (Anasorb 708 and Strata X), the impinger filled with distilled water and PTFE filters for determination of airborne cyclophosphamide (CP) in the hospital working environment. For this purpose, air contamination of Masaryk Memorial Cancer Institute (Czech Republic) was monitored using the sampling apparatus containing the samplers described above. In addition, the surface contamination was also determined using the wipe sampling technique. During the monitoring, contamination of three different workplaces (storage room, preparation room and outpatient clinic) was studied. Using Strata X solid sorbent tubes, airborne CP was determined in all (n = 5) samples collected at the outpatient clinic over a 5 day monitoring period (concentration range: 0.3-4.3 ng m(-3)). Other samplers (including PTFE filters) did not collect any detectable amount of CP (the limit of detection, LOD ≤ 0.1 ng m(-3)). Negative results detected at filter samples indicate that CP determined at Strata X samples was most probably of gaseous origin. Surface contamination ranged from <2 to 19, <8 to 418 and 133-15,500 pg cm(-2) at the storage room, preparation room and outpatient clinic, respectively. The study showed that evaporation of antineoplastic drugs should not be neglected, albeit the concentrations determined in our study are relatively low. Therefore, proper monitoring of airborne contamination should involve simultaneous sampling of both particle-bonded and gaseous phases. In this way, Strata X sorbent tubes seem to be an effective tool for the sampling of gaseous CP in the indoor air.

[Determination of airborne and surface contamination with cyclophosphamide at the Masaryk Memorial Cancer Institute, Brno, Czech Republic]. / Sledování prítomnosti cyklofosfamidu ve vnitrním ovzdusí a na povrchu materiálního vybavení Masarykova onkologického ustavu.

Manipulation with cytotoxic drugs (CDs) during the preparation and administration of chemotherapy to cancer patients can potentially lead to contamination of working areas and consequently to occupational exposure of hospital staff. This study aimed to assess the potential of inhalation and dermal contact with CDs. For this purpose, distribution of the marker drug (cyclophosphamide, CP) in the working environment of the Masaryk Memorial Cancer Institute (Czech Republic) was studied. The study determined airborne and surface contamination of the hospital pharmacy and the outpatient clinic. Determination of airborne contamination was based on active stationary sampling of air using a PTFE filter, an impinger filled with distilled water and two solid sorbent tubes (Anasorb 708 and Strata-X) as sampling devices. Surface contamination was determined by the wipe sampling method. The airborne contamination was rare and the concentrations were many times lower than the maximal value calculated from the vapour pressure (0.36 mg/m3 at 20 degrees C). Detectable airborne CP was found in Strata-X samples collected at the outpatient clinic (n = 5, all samples positive at concentrations from 0.3 to 4.3 ng/m3). Surface contamination was determined at 75% of wipe samples (n = 65) with a median concentration of 750 ng/m2. In conclusion, inhalation of CDs seems to be of low importance at our hospital, which is up to the standard specified by current legislation (drug preparation performed in a clean room equipped with negative pressure isolators). The main proportion of contamination was present on the surfaces at all workplaces studied. Consequently, attention should be given to the elimination of the sources of surface contamination and to the prevention of dermal contact with contaminated material.

Ecotoxicity and genotoxicity assessment of cytostatic pharmaceuticals.

The fate and effects of cytostatic (anticancer or antineoplastic) pharmaceuticals in the environment are largely unknown, but they can contaminate wastewater treatment effluents and consequently aquatic ecosystems. In this paper, we have focused on five cytostatic compounds used in high amounts (cyclophosphamide, cisplatin, 5-fluorouracil, doxorubicin, and etoposide), and we have investigated their ecotoxicity in bacterial Pseudomonas putida growth-inhibition test, algal Pseudokirchneriella subcapitata growth-inhibition test, and Dapnia magna acute immobilization test. Genotoxicity also was assessed with Escherichia coli SOS-chromotest (with and without metabolic activation) and the GreenScreen Assay using yeast S. cerevisiae. All tested compounds showed significant effects in most of the assays with lowest-observed-effect concentrations and concentrations causing 50% effects (EC50s) values ranging within microg/L to mg/L. The most toxic compound was 5-fluorouracil in the assays with P. putida (EC50 = 0.027 mg/L) and P. subcapitata (EC50 = 0.11 mg/L), although cisplatin and doxorubicin were the most toxic to D. magna (EC50 = 0.64 and 2.0 mg/L, respectively). These two chemicals were also the most genotoxic in the SOS-chromotest (minimum genotoxic concentrations [MGC] = 0.07-0.2 mg/L), and 5-fluorouracil was the most genotoxic in the eukaryotic yeast assay (MGC = 0.02 mg/L). Our investigation seems to indicate generally lower risks of acute effects at concentrations expected in the environment. However, some effective concentrations were relatively low and chronic toxicity of cytostatics (and/or their transformation products), as well as specific sources of human pharmaceuticals such as hospital effluents, require research attention.

Association of surface contamination by antineoplastic drugs with different working conditions in hospital pharmacies.

This study investigates the surface contamination levels of cyclophosphamide and platinum (a marker of platinum-containing drugs) in storage and preparation areas of hospital pharmacies and their relationship to working conditions surveyed by questionnaire. In total, 259 wipe samples were collected in 13 hospital pharmacies over 4 sampling campaigns. After sample extraction with acetate buffer, cyclophosphamide and platinum were determined using high-performance liquid chromatography-tandem mass spectroscopy (HPLC-MS/MS) and inductively coupled plasma mass spectrometry (ICP-MS). Depending on the sampling spot and campaign, median concentrations ranged from <2 to 61 pg/cm(2) and from <0.2 to 6.9 pg/cm(2) for cyclophosphamide and platinum, respectively. Statistical evaluation of monitoring data revealed that the contamination level was significantly influenced by laboratory throughput (expressed as number of chemotherapies prepared per week), personnel expertise (ie, participation of pharmacists with academic education in drug admixture activities), and surface material.