Ultrahigh-performance liquid chromatography-tandem mass spectrometry quantitation of o-cresol in hydrolyzed human urine to assess toluene exposure.

RATIONALE: Toluene is a volatile organic compound used in domestic and industrial applications. The main routes of workplace exposure to toluene are inhalation and dermal contact. As toluene exposure can cause severe nervous system damage, its quantification is crucial to prevent occupational illness. Toluene is metabolized mainly as hippuric acid, S-benzylmercapturic acid and epoxides. These are rapidly converted to o-/p-cresol, which is then excreted in the urine as conjugated glucuronides and sulfates. o-Cresol and its conjugates can be chemically hydrolyzed to form free o-cresol, which can then serve as a urinary biomarker of toluene exposure. Current analytical methods for quantifying o-cresol in hydrolyzed urine are, however, either weakened by interference, are not sensitive enough or require water-sensitive sample preparation. Development of a liquid chromatography-tandem mass spectrometry method for assessing exposure to toluene is thus required. METHOD: Urine samples were acidified and heated to form free o-cresol and then derivatized with dansyl chloride and diluted. Extracts were separated by reverse-phase chromatography on a BEH phenyl column and then analyzed using a triple quadrupole instrument in selected reaction monitoring mode. RESULTS: The dansyl chloride derivatization step was optimized to produce the derivative within a reaction time of 3 min. Hydrolysis efficiency in forming free o-cresol from conjugated metabolites was evaluated using o-cresol-ß-d-glucuronidespiked human urine: complete hydrolysis occurred in 45 min. Dynamic range was 0.4 to 40 µM, and the method was useful for toluene monitoring in non-occupational (0.1 µmol/mmol creatinine) as well as occupational (0.3 µmol/mmol creatinine) exposure. The calculated limit of detection and limit of quantitation of the method were 0.06 and 0.21 µM, respectively. Intraday and interday precisions were 3.2% and 4.4%, respectively. Method accuracy was established as 99% using ClinChek® urine controls. CONCLUSION: An ultrahigh-performance liquid chromatography-tandem mass spectrometry method for analysis of o-cresol was developed for biological monitoring of toluene exposure in human urine. This is the method of choice used by occupational health and safety practitioners in the province of Québec, Canada.

Comprehensive methylene diphenyl diisocyanate (MDI) evaluation method comparison using a laboratory generation system.

Isocyanates are reactive semivolatile contaminants that must be assessed in occupational environments, and specific evaluation methods are required to address the challenges related to isocyanate emission characteristics. Several standard methods exist, but significant differences remain regarding the diversity of industrial isocyanate emissions. This study presents a method to establish a baseline comparison of three sampling principles. A fine aerosol (mass median aerodynamic diameter of 250 nm) of pure methylene diphenyl diisocyanate (MDI) was produced (5-60 µg m-3) using a laboratory generation system (n = 31 generation experiments). Airborne MDI was measured with the following four methods, with an emphasis on the spatial distribution of the collected MDI within the sampler: (1) Swinnex cassette 13 mm, glass fibre filter (GFF), 9-(N-methylaminomethyl) anthracene (MAMA-Swin); (2) closed-face cassette (CFC) 37 mm, GFF (end filter and inner walls), MAMA-37; (3) impinger and backup GGF, 1,2-methoxyphenylpiperazine (MP) (ISO 16702/MDHS 25); and (4) denuder and GFF (Asset EZ4-NCO), dibutylamine (DBA) (ISO 17334-1). Bland and Altman analyses determined that there were no significant bias between the methods although Asset was not in agreement with MAMA-Swin (95% confidence interval above the ±20% criteria). Significant correlations (P < 0.05) were observed between airborne MDI concentration levels and their distribution within the Asset (denuder vs. end filter) and impinger (collecting solution vs. backup filter) subsections. The presence of impregnated inner walls in the CFC did not increase collection efficiency for the generated MDI aerosol. Non-uniform MAMA impregnation on GFF was demonstrated, whereas the collected MDI was evenly distributed in the air samples. These results provided the basis of comparison for other studies involving more complex isocyanate emissions.

Occupational health and safety, metal exposures and multi-exposures health risk in Canadian electronic waste recycling facilities.

Electronic waste recycling (e-recycling) involves manual operations that expose workers to toxic metals. We aim to describe occupational health and safety practices and workers' exposures to metals in the Canadian formal e-recycling industry, and to estimate the health risk associated with multiple exposures. This cross-sectional study documented practices through observations and questionnaires, and assessed metal exposures using personal air samples and biomarkers. Health risks were estimated relative to recognised occupational exposure guidelines, and using an additive approach for consideration of multiple exposures. Six e-recycling and one commercial recycling facilities were investigated, and the metal exposures of 99 workers (23 women) were measured. In most facilities, dust control was inadequate and personal protective equipment was improperly worn. In e-recycling, lead was detected in all air samples and in most blood samples, up to 48 µg/m3 and 136 µg/l, respectively. Other quantified metals included beryllium, mercury, arsenic, barium, cadmium, chrome, cobalt, copper, indium, manganese, nickel and yttrium. When handling cathode ray tube screens, workers were 4.9 times and 8.5 times more likely to be exposed to lead and yttrium, respectively, than workers who were not assigned to a specific type of electronics. Overall, exposures were largely associated with facility size and airborne dust concentration. The additive hazard indices for airborne exposures raised concerns for kidney disorders, for peripheral and central nervous systems, and for the male reproductive system. Minimizing airborne dust through collective control methods and adequately using personal protection should reduce metal exposures and associated health risks in this growing industry.

Development of a new SPE UPLC-MS/MS method for extraction and quantitation of toluene diamine on gloves following toluene diisocyanate exposure.

RATIONALE: Toluene diisocyanate (TDI) is a highly reactive isocyanate commonly used as a mixture of 2,4- and 2,6- isomers in the production of flexible foams. Exposure to TDI occurs primarily through vapour inhalation in workplaces where TDI is produced or used, but dermal exposure is also possible during some tasks. To ensure workplace safety, accurate monitoring of TDI and toluene diamine (TDA) levels is required. Methods of quantifying field effectiveness of gloves in preventing dermal exposure have not been established. Therefore, there is a need to develop a new practical method for assessing glove effectiveness for TDI/TDA. METHOD: A new offline SPE UPLC-MS/MS method for the quantitation of TDA isomers from TDI-exposed gloves was developed. Gloves were dipped in a solution of 1% acetic acid leading to a full conversion to TDA. TDA-free amine compounds were derivatized with acetic anhydride to increase chromatographic retention and signal intensity. RESULTS: 2,4-Diaminotoluene-α, α, α-d3 (2,4-d3 -TDA) was selected as a surrogate standard to minimise the variability in sample preparation and instrumental sensitivity. The choice of UPLC-MS/MS operated in multiple reaction monitoring (MRM) mode allowed to reach much lower limits of detection (LOD). The LOD of the method was 6.86 and 2.83 ng/mL (0.03 and 0.01 µg) for 2,6-TDA and 2,4-TDA, respectively. The limit of quantitation (LOQ) was 22.85 and 9.42 ng/mL (0.11 and 0.05 µg) for 2,6-TDA and 2,4-TDA, respectively. CONCLUSION: A new UPLC-MS/MS analytical method has been developed to determine field effectiveness of gloves for preventing dermal exposure to TDI/TDA. The new technique overcomes some limitations for measuring putative dermal exposure to isocyanates and may be useful in exposure monitoring and future research on isocyanate health risks.

Transconjunctival XEN45 Implantation for Glaucoma Performed at the Slit Lamp: A Pilot Study.

PRCIS: This pilot study of ab externo implantation of a gel microstent is a novel, minimally invasive glaucoma surgery performed at the slit lamp that is effective for lowering intraocular pressure in patients with uncontrolled glaucoma. PURPOSE: To evaluate the intraocular pressure (IOP)-lowering effect of gel microstent (XEN Gel Stent, Allergan, Irvine, CA) implantation using an ab externo approach in an office setting. PATIENTS AND METHODS: This retrospective, multicenter chart review examined outcomes in patients with uncontrolled glaucoma receiving maximally tolerated medical therapy, who underwent slit lamp ab externo gel stent implantation. At postoperative visit, the IOP, the number of glaucoma medications, the final position of the stent, and the needling rate were analyzed. Assessments were conducted 1 day, 1 week and 1, 3, 6, and 12 months after the implantation. Treatment success was defined as IOP ≥6 mm Hg and ≤18 mm Hg with ≥20% reduction from presurgical IOP, with or without medications. RESULTS: Thirty-four eyes from 28 patients were included. Mean preoperative IOP was 24.1±8.0 mm Hg on 3.2±0.9 glaucoma medications. At 12 months postoperative, IOP was reduced to 15.4±4.7 mm Hg on 0.6±1.0 medications; 46.9% and 81.3% of eyes achieved complete and partial success, respectively. The gel stent was properly positioned in 94.1% of eyes after 1 attempt at implantation and in 100% of eyes after a second attempt. In addition to malpositioning, observed complications included occlusion, erosion, and endophthalmitis following anterior chamber reformation. Adjunctive needling was required in 21% of implanted eyes. CONCLUSION: Slit-lamp-based transconjunctival XEN45 implantation reduced intraocular pressure in glaucoma patients in the first year of this pilot study and was most commonly associated with wound leak and hypotony among other adverse events.

Surface contamination with nine antineoplastic drugs in 109 canadian centers; 10 years of a monitoring program.

INTRODUCTION: Healthcare workers exposure to antineoplastic drugs can lead to adverse health effects. Guidelines promote the safe handling of antineoplastic drugs, but no safe exposure limit was determined. Regular surface sampling contributes to ensuring workers safety. METHODS: A cross-sectional monitoring is conducted once a year with voluntary Canadian centers, since 2010. Twelve standardized sampling sites were sampled. Samples were analyzed by high performance mass coupled liquid chromatography. The limits of detection (in ng/cm2) were: 0.001 for cyclophosphamide and gemcitabine; 0.3 for docetaxel and ifosfamide; 0.04 for 5-fluorouracil and paclitaxel; 0.003 for irinotecan; 0.002 for methotrexate; 0.01 for vinorelbine. RESULTS: The surfaces from 109 centers were sampled between 01/01/2020-18/06/2020. Twenty-six centers delayed their participation because of the COVID-19 pandemic. 1217 samples were analyzed. Surfaces were frequently contaminated with cyclophosphamide (34% positive, 75th percentile 0.00165 ng/cm2) and gemcitabine (16% and <0.001 ng/cm2). The armrest of patient treatment chairs (84% to at least one drug), the front grille inside the biological safety cabinet (BSC) (73%) and the floor in front of the BSC (55%) were frequently contaminated. Centers that prepared ≥5000 antineoplastic drugs annually had higher concentration of cyclophosphamide on their surfaces (p < 0.0001). Contamination measured on the surfaces was reduced from 2010 to 2020. CONCLUSIONS: This large-scale study showed reproducible long term follow up of the contamination of standardized sites of Canadian centers and a reduction in surface contamination from 2010 to 2020. Periodic surface sampling help centers meet their continuous improvements goals to reduce exposure as much as possible. The COVID-19 pandemic had a limited impact on the program.

Development and characterization of an adaptable aerosolized methylene diphenyl diisocyanate generation system.

Reactive semivolatile contaminants, such as isocyanates, can be particularly difficult to assess in occupational environments. While standard methods exist for isocyanates, there are still significant differences between the results they provide for various occupational environments or processes. This study presents the validation of a laboratory system for the generation of controlled atmospheres of isocyanates. A system consisting of different modules generated airborne methylene diphenyl diisocyanate (MDI) by nebulizing a solution into mixing and exposure chambers with control of flow rate, temperature, and relative humidity. Sampling was performed through an eight-port flow splitter that allowed only very slight within-test variability. MDI was measured using the Asset EZ4-NCO® and a modified version of the Iso-Chek® sampling system. MDI specific particle-size distribution was measured by a Marple Sierra cascade. Aerosol real-time monitoring was performed using a condensation particle counter, an electrical low-pressure impactor (ELPI+), and an aerosol optical spectrometer, providing additional information on system stability and particle-size distribution of the generated aerosol. The system was able to generate MDI concentration levels ranging from 4 to 233 µg m-3, with a steady-state level reached within 5 minutes, and with well-documented intra-test and inter-test variability (RSD of 4% and 15%, respectively). Accuracy and representativeness of MDI data were confirmed by the agreement between MAMA and Asset EZ4-NCO (used as reference), with a mean bias of 3%. Using the Asset EZ4-NCO capability, the vapor-particle partitioning of MDI was evaluated to be 8% and 92%, respectively, at a concentration ranging from 20 to 25 µg m-3. The system may therefore be used for exhaustive method intercomparison studies and could also be adapted to generate other emission types of semivolatile compounds.

Direct LC-MS/MS and indirect GC-MS/MS methods for measuring urinary bisphenol A concentrations are comparable.

BACKGROUND: Bisphenol A (BPA) is typically measured in urine using an indirect method that involves enzymatic deconjugation and extraction. In contrast, the direct method measures free and conjugated BPA concurrently and sums them to estimate urinary BPA concentrations. Statistical comparison of total BPA results using the direct and indirect methods is necessary to accurately interpret biomonitoring data for risk assessments. OBJECTIVES: To compare urinary BPA concentrations estimated from the indirect and direct methods in duplicate first trimester urine samples collected from 1879 pregnant women from the MIREC Study. METHODS: For the indirect method, we measured urinary BPA concentrations using GC-MS/MS. For the direct method, we summed free and conjugated BPA concentrations measured using LC-MS/MS. We evaluated deviation between the two methods using the Bland-Altman analysis in the total sample and stratified (1) by specific gravity and (2) at the limit of quantification (LOQ). RESULTS: Median urinary BPA concentrations for the direct and indirect methods were 0.89 µg BPA equivalents/L and 0.81 µg/L respectively. Concentrations from the direct method were, on average, 8.6% (95% CI: 6.7%, 10.5%) higher than the indirect method in a Bland-Altman analysis. The percent differences between the two methods was 4.0% in urines with specific gravities < 1.02 (n = 1348, 72%) and 20.3% in urine with specific gravity ≥ 1.02. In values below the LOQ (n = 663, 35%), we observed smaller average percent deviation (4.8%) between the two methods but wider limits of agreement. DISCUSSION: Results from this study, based on the largest statistically rigorous comparison of the direct and indirect methods of BPA measurement, contrast previous findings reporting that the indirect method underestimates total BPA exposure. The difference in urinary BPA concentrations we observed with the indirect and direct methods is unlikely to alter the interpretation of health outcome data.

Evaluation of decontamination efficacy of four antineoplastics (ifosfamide, 5-fluorouracil, irinotecan, and methotrexate) after deliberate contamination.

The main objective was to determine the decontamination efficacy of quaternary ammonium, 0.1% sodium hypochlorite, and water after deliberate contamination with four antineoplastics (ifosfamide, 5-fluorouracil, irinotecan, methotrexate). A stainless-steel surface was deliberately contaminated with ifosfamide (15 µg), 5-fluorouracil (10 µg), irinotecan (1 µg), and methotrexate (1 µg). First, a single decontamination step with either water, quaternary ammonium, or 0.1% sodium hypochlorite was tested. Then, the effect of up to four successive decontamination steps with either quaternary ammonium or 0.1% sodium hypochlorite was tested. Commercial wipes consisting of two layers of non-woven microfibers with an inner layer of highly absorbent viscose fibers were used. Triplicate surface samples were obtained and tested by ultra-performance liquid chromatography tandem mass spectrometry. The limits of detection were 0.004 ng/cm2 for ifosfamide, 0.040 ng/cm2 for 5-fluorouracil, 0.003 ng/cm2 for irinotecan, and 0.002 ng/cm2 for methotrexate. After a single decontamination step, the 0.1% sodium hypochlorite eliminated 100% of contamination with 5-fluorouracil, irinotecan, and methotrexate and 99.6 ± 0.5% of ifosfamide contamination. Quaternary ammonium and water also removed 100% of the 5-fluorouracil, and 99.5% to 99.9% of the other three antineoplastics. For ifosfamide, irinotecan, and methotrexate, the decontamination efficacy increased with successive decontamination steps with quaternary ammonium. 5-fluorouracil was undetectable after a single decontamination step. Methotrexate was the only drug for which decontamination efficacy was less than 100% after four decontamination steps. 100% decontamination efficacy was achieved from the decontamination step with 0.1% sodium hypochlorite for 5-fluorouracil, irinotecan, and methotrexate. For ifosfamide, 100% efficacy was achieved only after the third decontamination step. It was possible to make all traces of antineoplastic undetectable after deliberate contamination with 5-fluorouracil, irinotecan, and methotrexate with a 0.1% chlorine solution; up to three decontamination steps were needed to make ifosfamide undetectable. Water or quaternary ammonium removed more than 99.5% of deliberate contamination. In several scenarios, it was necessary to repeat the decontamination to eliminate residual traces. More work is needed to identify the optimal decontamination approach for all of the antineoplastic drugs used.

On-site comparison of the OSHA 47, Asset EZ4-NCO, Iso-Chek, DAN, and CIP10 methods for measuring methylene diphenyl diisocyanate (MDI) at an oriented-strand board (OSB) factory.

Diisocyanates are occupational contaminants and known sensitizers causing irritation (skin and respiratory tract) as well as occupational asthma. Because of their physicochemical properties (semi-volatile and high reactivity) and low occupational limits, diisocyanate exposure evaluation is still a challenge nowadays for industrial hygienists and laboratories. The objective of this study was to compare the methylene diphenyl diisocyanate (MDI) concentrations measured by five methods using different collection or derivatization approaches in an oriented-strand board (OSB) factory. The methods used were: OSHA 47 (filter, 1-(2-pyridyl)piperazine) (OSHA), Asset EZ4-NCO (denuder and filter, dibutylamine) (Asset), Iso-Chek (double-filter, 9-(N-methylaminomethyl) anthracene and 1,2-methoxyphenylpiperazine), DAN (filter, 1,8-diaminonaphthalene), and CIP10 (centrifugation, 1,2-methoxyphenylpiperazine). Real-time monitoring of particle concentration and size distribution was performed to explain the potential bias between methods. The comparison study was performed over 3 consecutive days, generating at least 18 replicates for each of the 5 methods. The results of each methods were compared using linear mixed effect modeling. Compared to Asset, which yielded the highest concentrations overall, the OSHA method provided the smallest bias with -18% (95% CI [-61;24]) (not significant) for MDI monomer and the DAN method provided the smallest bias with -30 (95% CI [-70;9]) (not significant) for Total Reactive Isocyanate Group (TRIG). The CIP10 and Iso-Chek methods provided the largest biases for MDI monomer (-83% (95% CI [-115;-51]) and -78% (95% CI [-110;-46]), respectively) as well as for TRIG (-87% (95% CI [-120;-55]) and -75% (95% CI [-107;-44]), respectively). The underestimations of the CIP10 and Iso-Chek were explained by its inefficient sampling principle for fines particles and the use of a non-impregnated filter to collect aerosol MDI, respectively. This study confirms that impregnated filter, including denuding device such as the Asset EZ4-NCO sampler, collects the MDI-coated wood particles and MDI vapor with similar efficiency. It also demonstrates for the first time in this type of MDI emission a significant agreement for TRIG concentration between the DAN method in the impregnated filter configuration and an international standard one such as Asset.

Surgical Approaches for Implanting Xen Gel Stent without Conjunctival Dissection.

The XEN Gel Stent (Allergan Inc., an Abbvie company) is an implant that lowers intraocular pressure by creating a filtration pathway from the anterior chamber to the subconjunctival space, using the same pathway as trabeculectomy. While the primary method for implantation is via ab interno approach, it is also possible to implant the device ab externo. This technique paper details the surgical steps for closed conjunctival implantation of the Gel Stent and provides surgical pearls for enhancing outcomes.

On site comparison of the OSHA 42, Asset EZ4-NCO, Iso-Chek, DAN and CIP10 methods for measuring toluene diisocyanate (TDI) at a polyurethane foam factory.

Because of the semi-volatile nature of diisocyanates (being airborne in both physical vapor and particulate phases), their high reactivity and low occupational exposure limits, diisocyanate exposure evaluation has been challenging for industrial hygienists and laboratories. The objective of this study was to compare the toluene diisocyanate (2,4 and 2,6 isomers, TDI) concentration measured by five methods in a flexible polyurethane foam factory using different collection or derivatization approaches. The methods used were: OSHA 42 modified (filter, 1-(2-pyridyl)piperazine) (OSHA), Asset EZ4-NCO (denuder and filter, dibutylamine) (Asset), Iso-Chek (double-filter, 9-(N-methylaminomethyl) anthracene and 1,2-methoxyphenylpiperazine), DAN (filter, 1,8-diaminonaphthalene), and CIP10 (centrifugation, 1,2-methoxyphenylpiperazine). Particle real-time monitoring for concentration and size distribution was performed in parallel to improve the understanding of the potential bias between methods. The comparison study was performed over 3 days, providing 18 replicates for each of the 5 methods. Isocyanate concentrations collected for each sampling method were compared using linear mixed effect modeling. Compared to OSHA, which yielded the highest concentrations overall, the Asset and DAN methods provided the smallest biases (-29% (95% CI [-52;-6]) and -45% (95% CI [-67;-23]), respectively), while the CIP10 and Iso-Chek methods provided the largest biases (-82% (95% CI [-105;-66]) and -96% (95% CI [-118;-75]), respectively). The substantial bias of Iso-Chek and CIP10 seemed to be explained by the predominance of TDI in the form of sub-micron particles that were inadequately captured by these two methods due to their sampling principle, which are particle filtration without derivatizing agent and centrifugation respectively. Asset and DAN performance seemed to decrease as the sampling time increased. While DAN's bias could be related to a reagent deficiency on the filter, the disparities between OSHA and Asset, both considered as reference methods, highlight the fact that the mechanisms of collection, derivation and extraction do not seem to be completely controlled. Finally, an upward trend has been observed between concentrations of particles below 300 nm in size and concentration levels of TDI. It has also been observed that TDI levels increased with the TDI foam index produced at the facility.

Cross-sectional evaluation of surface contamination with 9 antineoplastic drugs in 93 Canadian healthcare centers: 2019 results.

INTRODUCTION: The primary objective was to describe environmental contamination with National Institute for Occupational Safety and Health Group 1 hazardous drugs in oncology pharmacies and outpatient clinics in Canada in 2019, as part of an annual surveillance project. METHODS: In each participating center, 12 standardized sites (6 in the oncology pharmacy and 6 in outpatient clinic) were sampled. Each sample was prepared to allow quantification of six antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, gemcitabine, 5-fluorouracil, and irinotecan) by ultra-performance liquid chromatography-tandem mass spectrometry. Samples were also tested for three additional antineoplastic drugs (docetaxel, paclitaxel, and vinorelbine) without quantification. The impact of certain characteristics of the sampling sites was evaluated with a Kolmogorov-Smirnov test for independent samples. RESULTS: Ninety-three Canadian centers participated in 2019, with a total of 1045 surfaces sampled. Cyclophosphamide was the drug most often found in the surface samples (32.4% of samples with positive result), followed by gemcitabine (20.3%). The front grille inside the biological safety cabinet (81.5% of samples positive for at least one antineoplastic drug) and the armrest of a treatment chair (75.8%) were the most frequently contaminated surfaces. Centers with more oncology inpatient and outpatient beds, those that prepared more antineoplastic drugs each year, and those that used more cyclophosphamide each year had higher concentrations of cyclophosphamide contamination on the surfaces tested (p < 0.0001). CONCLUSION: Traces of dangerous drugs were found in oncology pharmacies and oncology outpatient clinics in 93 Canadian hospitals in 2019. However, the quantities measured were very small. Every healthcare worker should consider these work areas to be contaminated and should wear appropriate protective equipment.

Development of a method for quantification of toluene diisocyanate and methylenediphenyl diisocyanate migration from polyurethane foam sample surface to artificial sweat by HPLC-UV-MS.

The US Environmental protection agency (EPA) has published guidance that includes test procedures for evaluating indoor exposure to chemicals from products. One of the test procedures represents the migration test for evaluating potential dermal exposure from home furniture. Such an evaluation involves the chemical measurement of the sweat which is currently unavailable in the literature. The objective of this project was to develop and validate an analytical method for quantification of migration of 4,4'-methylenediphenyl diisocyanate (MDI), 2,6-toluene diisocyanate (2,6-TDI) and 2,4-toluene diisocyanate (2,4-TDI) from a polyurethane (PU) flexible foam to artificial sweat that meets the recommendations of the EPA test protocol. Following the EPA protocol, six synthetic sweat solutions were prepared and used in evaluation of isocyanate recovery performance. The migration tests were conducted using five foam types that were chosen and supplied by PU foam manufacturers to represent the types most commonly found in commercial products, and with formulations anticipated to have the highest potential residual TDI or MDI. Migration tests were conducted using glass fiber filters (GFF) coated with 1-(2-methoxyphenyl)piperazine (1,2-MP) and analyzed using HPLC equipped with a UV detector for quantification and a MS detector to qualify peaks. The detection limits of the method were 0.002 µg/mL for 2,6-TDI, 0.011 µg/mL for 2,4-TDI, and 0.003 µg/mL for MDI. Quantification limits were 0.006 µg/mL, 0.037 µg/mL, and 0.010 µg/mL, respectively. The recovery tests on a Teflon surface for 5 of the 6 EPA-recommended synthetic sweat solutions indicate the recovery percentage was approximately 80% for diisocyanates. Recovery for the sixth sweat solution was low, approximately 30%. TDI and MDI migration was not observed when testing was conducted on foam samples.

Quantification of healthcare workers' exposure to cyclophosphamide, ifosfamide, methotrexate, and 5-fluorouracil by 24-h urine assay: A descriptive pilot study.

PURPOSE: The objective of this pilot study was to determine the frequency of urination and the concentration of four hazardous drugs (cyclophosphamide, ifosfamide, methotrexate, and fluorouracil) in workers' 24-h urine samples in relation to exposure to traces with hazardous drugs. METHODS: The study was conducted in three healthcare centers in the region of Montréal, Quebec, Canada. We recruited healthcare workers (nurses and pharmacy technicians) assigned to the hematology-oncology department. Each participant was asked to collect all urine voided during a 24-h period, to fill out an activity journal documenting tasks performed and to document the use of personal protective equipment. Samples were analyzed for cyclophosphamide, ifosfamide, methotrexate, and alpha-fluoro-beta-alanine (FBAL, the main urinary metabolite of 5-fluorouracil). Drugs were quantified by ultra-performance liquid chromatography-tandem mass spectrometry (positive electrospray MRM mode). RESULTS: Eighteen healthcare workers (10 nurses and 8 technicians) were recruited and provided consent to participate. Urine samples were obtained between 1 September and 30 September 2019. The number of urinations over the 24-h collection period ranged from 3 to 11 per participant. A total of 128 urine samples were analyzed for the 18 workers. All urine samples were negative for the four antineoplastics tested. CONCLUSION: No traces of cyclophosphamide, ifosfamide, methotrexate, or FBAL were found in the 24-h urine samples of 18 healthcare workers practicing in three healthcare facilities in Quebec. Although it was feasible to collect 24-h urine samples in this research project, it appears unrealistic to do so recurrently as part of a large-scale surveillance program.

A validated UPLC-MS/MS method for the determination of aliphatic and aromatic isocyanate exposure in human urine.

4,4'-Methylenediphenyldiisocyanate (MDI), toluenediisocyanate (2,4-TDI and 2,6-TDI), and 1,6'-hexamethylenediisocyanate (HDI) are all commonly used in the production of polyurethane-containing materials in different application areas. Workers exposed occupationally to these compounds may develop sensitization with the potential to lead to asthma. Isocyanates are metabolized in vivo by conjugation to macromolecules and/or by acetylation prior to being eliminated in urine. The hydrolysis of urine samples releases free amine compounds from these metabolites as biomarkers of exposure, specific to each parent isocyanate: 4,4'-methylenedianiline (MDA), toluenediamine (2,4-TDA and 2,6-TDA), and hexamethylenediamine (HDA). To address the need for a validated method that could be used for the simultaneous determination of biomarkers of aliphatic and aromatic isocyanates to monitor occupational exposure based on recommended thresholds, we have developed an UPLC-MS/MS method for the quantitation of MDA, TDA isomers, and HDA following acid hydrolysis, solid-phase extraction, and derivatization of urine samples. Free amine compounds were derivatized with acetic anhydride to augment chromatographic retention and signal intensity. The method was developed considering the biological guidance value (BGV) of MDA at 10 µg L-1, and biological exposure indices (BEI) of TDA isomers and HDA at 5 µg g-1 and 15 µg g-1 creatinine, respectively. Limits of detection allowed monitoring down to 6% of BGV/BEI, with precision within 8%. The accuracy and reliability of the method were assessed using inter-laboratory reference samples and deemed acceptable based on three rounds of measurements. This novel method has therefore been proven as useful for occupational safety and health assessments. Graphical Abstract.

Cross-Sectional Evaluation of Surface Contamination with Antineoplastic Drugs in Canadian Health Care Centres.

BACKGROUND: Surfaces in health care centres are often contaminated with traces of antineoplastic drugs. Such contamination should be limited as much as possible, to reduce workers' exposure. OBJECTIVES: The primary objective was to monitor environmental contamination with 9 antineoplastic drugs in oncology pharmacy and patient care areas of Canadian health care centres. The secondary objective was to explore the use of sodium hypochlorite as a cleaning agent for cyclophosphamide contamination. METHODS: This cross-sectional evaluation was conducted from January to April 2018. Twelve standardized sites were sampled at each participating centre: 6 in the oncology pharmacy and 6 in patient care areas. Six of the antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, gemcitabine, 5-fluorouracil, and irinotecan) were quantified by ultra-performance liquid chromatography - tandem mass spectrometry. For the other 3 antineoplastic drugs (docetaxel, paclitaxel, and vinorelbine), samples were screened for contamination but not quantified. The effect of using sodium hypochlorite as a cleaning agent was evaluated with a Kolmogorov-Smirnov test for independent samples. RESULTS: Of 202 Canadian centres invited, 79 participated. A total of 887 surface samples were analyzed, 467 from pharmacy areas and 420 from patient care areas. Cyclophosphamide was the drug most often found as a contaminant (32.2% [286/887] of samples positive, 75th percentile of measured contamination 0.0017 ng/cm2, 90th percentile 0.021 ng/cm2). The front grille inside the hood (80.8% [63/78] of samples positive for at least one antineoplastic drug), treatment chair armrest (78.9% [60/76]), storage shelf in pharmacy (61.5% [48/78]), and floor in front of the hood (60.3% [47/78]) were the most frequently contaminated surfaces. Cleaning with a sodium hypochlorite solution was highly variable. Among centres that reported using sodium hypochlorite to clean armrests on patient chairs, the concentration of cyclophosphamide was lower (0.00866 versus 0.0300 ng/cm2, p = 0.014). CONCLUSIONS: Despite growing awareness and implementation of new safe-handling guidelines, surfaces in health care centres were contaminated with traces of many antineoplastic drugs. Providing centres with attainable goals (e.g., 75th to 90th percentile relative to other similar centres) would help in identifying the sampling sites where improvements are needed and in achieving lower surface contamination.

CONTEXTE: Les surfaces dans les centres de santé sont souvent contaminées par des traces de médicaments antinéoplasiques. Une telle contamination devrait être limitée autant que faire se peut afin de réduire l'exposition des employés à ces produits. OBJECTIFS: L'objectif principal consistait à mesurer la contamination environnementale provenant de neuf médicaments antinéoplasiques dans la section de la pharmacie oncologique et celle des soins offerts aux patients dans des centres de soins de santé canadiens. L'objectif secondaire consistait à explorer l'action nettoyante de l'hypochlorite de sodium pour éliminer la contamination par la cyclophosphamide. MÉTHODES: Cette évaluation transversale a été menée de janvier à avril 2018. Des échantillons ont été prélevés dans douze endroits standardisés de chaque centre participant : six dans la section de la pharmacie oncologique et six dans celle des soins donnés aux patients. La présence de six des médicaments antinéoplasiques examinés (cyclophosphamide, ifosfamide, méthotrexate, gemcitabine, 5-fluorouracil et irinotécan) a été quantifiée par chromatographie liquide à haute performance (HPLC) avec spectrométrie de masse en tandem. Quant aux trois autres échantillons de médicaments antinéoplasiques (docetaxel, paclitaxel et vinorelbine), ils ont été analysés pour rechercher la présence d'une contamination qui n'a pas été quantifiée. L'action nettoyante de l'hypochlorite de sodium a été évaluée à l'aide d'un test de Kolmogorov-Smirnov pour les échantillons indépendants. RÉSULTATS: Sur 202 centres canadiens invités à participer à l'étude, 79 ont répondu à l'invitation. L'analyse a porté sur 887 échantillons de surfaces des lieux sélectionnés : 467 dans la section de la pharmacie et 420 dans la section des soins donnés aux patients. La cyclophosphamide était le médicament contaminant le plus souvent décelé (32,2 % d'échantillons positifs [286/887], 75e percentile de contamination mesurée 0,0017 ng/cm2, 90e percentile 0,021 ng/cm2). La grille frontale à l'intérieur de la hotte de laboratoire (80,8 % des échantillons [63/78] étaient positifs pour au moins un médicament antinéoplasique), l'accoudoir de la chaise du patient (78,9 % [60/76]), l'étagère de stockage dans la pharmacie (61,5 % [48/78]) et le sol en face de la hotte (60,3% [47/78]) étaient les surfaces le plus souvent contaminées. L'usage d'une solution d'hypochlorite de sodium pour le nettoyage variait grandement d'un centre à l'autre. Dans les centres qui indiquaient utiliser cet agent pour nettoyer les accoudoirs des chaises du patient, la concentration de cyclophosphamide sur les accoudoirs était moins élevée (0,00866 contre 0,0300 ng/cm2, p = 0,014). CONCLUSIONS: Malgré la prise de conscience et la mise en place croissantes de nouvelles lignes directrices en matière de manipulation sécuritaire, les surfaces de certains endroits des centres de santé sont contaminées par des traces de nombreux médicaments antinéoplasiques. La fixation d'objectifs atteignables pour les centres (p. ex., entre le 75e et le 90e percentile par rapport aux autres centres similaires) aide à déterminer les sites d'échantillonnage où des améliorations sont nécessaires et à diminuer la contamination des surfaces.

A validated liquid chromatography/tandem mass spectrometry method for 4,4'-methylenedianiline quantitation in human urine as a measure of 4,4'-methylene diphenyl diisocyanate exposure.

RATIONALE: 4,4'-Methylene diphenyl diisocyanate (MDI) is a highly reactive isocyanate used in the production of polyurethanes. Workers exposed to these products may develop sensitization to the diisocyanate compounds, leading to occupational asthma. Quantifying MDI levels is necessary to ensure workplace safety. MDI is metabolized by acetylation and/or conjugation to macromolecules for excretion into urine. All metabolites can be chemically hydrolyzed to form the free diamine 4,4'-methylenedianiline (MDA) as a urinary biomarker of MDI exposure. Current methods involve long sample preparation, or have been designed using costly automation. There is therefore a need to develop a new practical method for assessing exposure to MDI. METHODS: Urine samples were acidified and heated to form MDA, followed by neutralization and liquid-liquid extraction. Extracts were separated by reversed-phase chromatography on a HSS T3 column followed by analysis on a triple quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode. RESULTS: 13 C15 N-MDA was selected as the internal standard (IS) of choice following an investigation of internal standard stability. The hydrolysis efficiency, forming free MDA from conjugated metabolites in vivo, was evaluated using 4,4'-methylenebis(acetanilide) spiked into urine and complete hydrolysis occurred after 1 h. A dynamic range of 5 to 500 nM was achieved, and was useful for monitoring MDI exposure considering the biological guidance value (BGV) of 10 µg/L (~50 nM) proposed by the German Research Foundation (DFG). The limit of detection (LOD) and limit of quantification (LOQ) of the method were 0.8 and 2.7 nM, respectively. The intra-day and inter-day precisions were 4.33% and 4.27%, respectively. Finally, the method was tested with inter-laboratory samples from the German External Quality Assessment Scheme (G-EQUAS) program and the results submitted were all within the allowable tolerance range. CONCLUSIONS: A practical and validated method for the analysis of small- to medium-sized batches of samples has been developed for the biological monitoring of MDI exposure in human urine.

Standardized Procedure for the Simultaneous Determination of the Matrix Effect, Recovery, Process Efficiency, and Internal Standard Association.

The matrix effects (MEs) on the quantification of an analyte can be significant and should not be neglected during development and validation of an analytical method. According to this premise, we developed a standardized procedure based on a set of six tests performed on six different sample matrices to detect and characterize the effects of the matrix for single and multiple analytes methods. The link between the matrix effect, recovery, process efficiency, accuracy, precision, and calibration curve was underscored by calculations performed with peak areas, ratios of standard/internal standard peak area, and concentrations. The terms instrumental ME and global ME were introduced, and the term recovery was subdivided for clarity. The test accounts for the presence of ubiquitous and endogenous analytes through background subtraction. The results showed the necessity for using samples with an original concentration in the same range and that the concentration selected for the addition had a definite impact on the results. The use of six-sample matrices provided a standard deviation on the results, and this information could be inserted in a method performance result to show precision. The tool also allows for testing of different analytes/internal standard combinations, which helps with the selection of the association with minimum MEs. A UPLC-MS/MS method for the quantification of several phthalate metabolites in urine was developed and validated with this test. This methodology responds to a scientific need for homogeneity, clarity, and understanding of the results and facilitates the decision-making process while lowering the required costs and time.