Urine biomonitoring of occupational exposure to methotrexate using a highly sensitive UHPLC-MS/MS method in MRM3 mode.

Methotrexate (MTX) is widely used as antineoplastic drug (AD) and as an immunosuppressive. As a result, many healthcare professionals are exposed to this drug which is classified as dangerous to handle due to its reproductive toxicity in humans. Since the 1990 s, cases of internal contamination of professionals handling this molecule have been reported in the literature and even recently MTX was detected in the urine of professionals. To date, there is no toxicological reference value for occupational exposure to MTX. Given the toxicity of this molecule, the internal contamination of professionals must be reduced and kept as low as possible according to the ALARA principle (as low as reasonably achievable). The aim of this work was to develop an UHPLC-MS/MS method in MRM (Multiple Reaction Monitoring) and MRM3 modes for routine application in MTX occupational biomonitoring. Good linearity (r greater than 0.997), precision (CV < 15 %), and accuracy (94.97-97.80% of the nominal value in MRM mode; 105.90-112.25% in MRM3 mode) were achieved. This method is reliable with high specificity and high sensitivity especially in MRM3 mode and has better LOD and LLOQ (1 ng/L and 2.5 ng/L) than published methods to date. The MRM3 mode increases the signal-to-noise ratio compared to the MRM mode. It was then applied routinely for the biological monitoring of healthcare professionals exposed to methotrexate. One hundred and seventeen urine samples from 93 healthcare professionals occupationally exposed to methotrexate were analyzed. Fifteen healthcare professionals (16.1 %) were found to be contaminated with methotrexate. Urine concentration levels ranged from 2.5 to 380 ng/L with a median value of 8.9 ng/L. Such efficient analytical tool is essential for the routine biological monitoring of healthcare professionals exposed to methotrexate. It also enables the traceability of occupational exposure to this molecule and the evaluation of the effectiveness of preventive measures such as individual and collective protective equipment.

A highly sensitive UHPLC-MS/MS method for urine biological monitoring of occupational exposure to anthracycline antineoplastic drugs and routine application.

Anthracycline antineoplastic drugs (doxorubicin, epirubicin, daunorubicin) are "hazardous drugs for handling" by healthcare professionals. To monitor their occupational exposure, a highly sensitive ESI-UHPLC-MS/MS method for the assay of anthracyclines in urine was developed. The urine extraction consisted of SPE extraction method. A good linearity (r > 0.996), precision (CV < 14.4%), and accuracy (bias < 13.6%) were achieved for the three drugs. The lower limit of quantification (LOQ) was 10 ng/L. This LOQ value is equal to the LOQ of published methods except for epirubicin, for which the LOQ value is better by a factor of 10 (best published LOQ value: 100 ng/L). Applying this method in routine, more than 77 healthcare professionals occupationally exposed to anthracyclines were monitored and 77 urines were analyzed. Two healthcare professionals (2.6%) were found to be contaminated to doxorubicin and/or epirubicin. The measured concentrations ranged from 17.7 to 218 ng/L. Such an efficient analytical tool, combining both high specificity and sensitivity is essential for reliable highlight of contamination during biological monitoring of healthcare professionals widely exposed to these drugs. This anthracycline antineoplastic drugs exposure monitoring allows healthcare professionals for assessing effectiveness individual and collective protective measures and for ensuring traceability of occupational exposure to these drugs.