Development and validation of a multicompound LLE-LC-MS/MS method for biomonitoring of hazardous medicinal products in urine of exposed workers

Antineoplastic drugs are carcinogens, mutagens, or teratogenic substances, which can pose serious risks to professionals. Concerns about chronic exposure to these hazardous medicinal products (HMPs) have led to their prominence in the EU strategic framework on health and safety at work 2021-2027. To estimate and mitigate human exposure to HMPs, regular monitoring programs and, consequently, reliable, sensitive, multicomponent methods are crucial. In this study, an unconventional liquid-liquid extraction coupled with liquid chromatography-tandem mass spectrometry analysis is proposed to simultaneously identify and quantify seven HMPs of high concern in urine: cyclophosphamide, etoposide, ifosfamide, paclitaxel, megestrol, mycophenolate mofetil, and tamoxifen, the last three for the first time. Recoveries of all drugs from urine samples were close to 100 %, and method detection limits (0.6-4.1 ng/L) were noticeably lower than most previously reported. This novel, non-invasive method for biomonitoring is thus suitable to unequivocally identify the target drugs at the expected trace levels in urine and to infer about workers' exposure. The method contributes to the conception of regular monitoring programs for antineoplastic drugs, in line with recommendations under EU Directive 2004/37/EC. This is especially relevant in Portugal, where neither analytical methods nor exposure data exist due to lack of formal surveillance.