INSERM U1219, Université de Bordeaux, 33076 Bordeaux, France; Consultations de Pathologie Professionnelle, Hôpital Timone, AP-HM, 13005 Marseille, France.
Laboratoire de Pharmacologie Clinique et Toxicologie, CHU de Bordeaux, 33076 Bordeaux, France.
J Chromatogr B Analyt Technol Biomed Life Sci. 2022 Oct 15;1209:123411. doi: 10.1016/j.jchromb.2022.123411. Epub 2022 Aug 6.
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 MRM 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 MRM mode) were achieved. This method is reliable with high specificity and high sensitivity especially in MRM mode and has better LOD and LLOQ (1 ng/L and 2.5 ng/L) than published methods to date. The MRM 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.
甲氨蝶呤（MTX）被广泛用作抗肿瘤药物（AD）和免疫抑制剂。因此，许多医疗保健专业人员接触到这种药物，由于其对人类的生殖毒性，该药物被归类为危险药物。自 20 世纪 90 年代以来，文献中已经报道了处理这种分子的专业人员内部污染的病例，甚至最近在专业人员的尿液中检测到 MTX。迄今为止，职业接触 MTX 的毒理学参考值尚不存在。鉴于这种分子的毒性，必须根据尽可能降低原则（尽可能低）降低并保持专业人员的内部污染尽可能低。这项工作的目的是开发一种用于常规 MTX 职业生物监测的 UHPLC-MS/MS 方法，采用 MRM（多重反应监测）和 MRM 模式。获得了良好的线性（r 大于 0.997），精密度（CV<15%）和准确度（MRM 模式下为名义值的 94.97-97.80%；MRM 模式下为 105.90-112.25%）。该方法具有高特异性和高灵敏度，特别是在 MRM 模式下，并且与迄今为止发表的方法相比，具有更好的 LOD 和 LLOQ（1ng/L 和 2.5ng/L）。MRM 模式与 MRM 模式相比，提高了信噪比。然后将其常规用于职业接触甲氨蝶呤的医疗保健专业人员的生物监测。分析了 93 名职业接触甲氨蝶呤的医疗保健专业人员的 117 份尿液样本。发现 15 名医疗保健专业人员（16.1%）被甲氨蝶呤污染。尿液浓度范围为 2.5 至 380ng/L，中位数为 8.9ng/L。这种高效的分析工具对于职业接触甲氨蝶呤的医疗保健专业人员的常规生物监测至关重要。它还使对这种分子的职业接触的可追溯性以及对个人和集体防护设备等预防措施的有效性的评估成为可能。
