title: Highly sensitive LC-MS/MS methods for urinary biological monitoring of occupational exposure to cyclophosphamide, ifosfamide, and methotrexate antineoplastic drugs and routine application.
abstract: Highly sensitive ESI-LC-MS/MS methods were developed for urinary biological monitoring of occupational exposure to cyclophosphamide (CP), ifosfamide (IF), and methotrexate (MTX), which are hazardous antineoplastic drugs frequently handled by healthcare professionals. Extraction methods consisted of liquid/liquid extraction for simultaneous urinary CP and IF assays, and of solid phase extraction for the urinary MTX assay. A good linearity (r2>0.997), precision (CV<14.6%), and accuracy (bias<9.9%) were achieved for all compounds. The limit of detection (LOD) was 10pg/ml and the lower limit of quantification (LOQ) was 20pg/ml for all three drugs. Applying these methods in routine, more than 116 healthcare professionals occupationally exposed to antineoplastic drugs were monitored and 635 urines were analysed. Eleven healthcare professionals (9.5%) were found to be contaminated to at least one of the three antineoplastic drugs. Among analysed urines, 22 samples were found positives. The measured concentrations ranged from 20.1 to 1850pg/ml and, for six samples, concentrations were at CP trace level, between the LOD and LOQ values (10-20pg/ml). Such efficient analytical tools combining high specificity with high sensitivity are essential for reliable detection and routine biological monitoring of healthcare professionals occupationally exposed to these widely used antineoplastic drugs. These methods allow to monitor the healthcare professionals exposure to antineoplastic drugs in the aim to assess the effectiveness of collective and individual protective measures.
authors.affiliation: Laboratoire de Pharmacologie Clinique et Toxicologie, CHU de Bordeaux, 33076 Bordeaux, France; INSERM U1219, ISPED, Université de Bordeaux, 33076 Bordeaux, France; Service de Médecine du Travail et de Pathologies Professionnelles, CHU de Bordeaux, 33076 Bordeaux, France; Univ. of Bordeaux, 33076 Bordeaux, France. Electronic address: mireille.canal-raffin@u-bordeaux.fr.
authors.forename: Mireille
authors.initials: M
authors.lastname: Canal-Raffin
authors.affiliation: Laboratoire de Pharmacologie Clinique et Toxicologie, CHU de Bordeaux, 33076 Bordeaux, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Khennoufa
authors.affiliation: INSERM U1219, ISPED, Université de Bordeaux, 33076 Bordeaux, France; Univ. of Bordeaux, 33076 Bordeaux, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Martinez
authors.affiliation: Association d'Hygiène Industrielle Bordeaux (AHI33), 33070 Bordeaux, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Goujon
authors.affiliation: Service de Médecine du Travail et de Pathologies Professionnelles, CHU de Bordeaux, 33076 Bordeaux, France.
authors.forename: Celia
authors.initials: C
authors.lastname: Folch
authors.affiliation: Laboratoire de Pharmacologie Clinique et Toxicologie, CHU de Bordeaux, 33076 Bordeaux, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Ducint
authors.affiliation: Laboratoire de Pharmacologie Clinique et Toxicologie, CHU de Bordeaux, 33076 Bordeaux, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Titier
authors.affiliation: INSERM U1219, ISPED, Université de Bordeaux, 33076 Bordeaux, France; Service de Médecine du Travail et de Pathologies Professionnelles, CHU de Bordeaux, 33076 Bordeaux, France; Univ. of Bordeaux, 33076 Bordeaux, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brochard
authors.affiliation: INSERM U1219, ISPED, Université de Bordeaux, 33076 Bordeaux, France; Service de Médecine du Travail et de Pathologies Professionnelles, CHU de Bordeaux, 33076 Bordeaux, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Verdun-Esquer
authors.affiliation: Laboratoire de Pharmacologie Clinique et Toxicologie, CHU de Bordeaux, 33076 Bordeaux, France; INSERM U1219, ISPED, Université de Bordeaux, 33076 Bordeaux, France; Univ. of Bordeaux, 33076 Bordeaux, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Molimard
keywords: Antineoplastic drugs; Biological monitoring; Healthcare professionals; LC–MS/MS; Occupational exposure; Urine