title: Protein adducts as biomarkers of human benzene metabolism.
abstract: We used cysteinyl adducts of serum albumin (Alb) to investigate the production of two reactive benzene metabolites, namely, benzene oxide (BO) and 1,4-benzoquinone (1,4-BQ) in workers exposed to benzene. Adducts were measured in 160 benzene-exposed workers who did not use respiratory protection (based upon individual geometric mean benzene exposure levels: median=5.27 ppm, interquartile range=2.14-13.4 ppm, range=0.074-328 ppm) and 101 local controls, from populations in Shanghai and Tianjin, China. After isolation of Alb, these adducts (designated as BO-Alb and 1,4-BQ-Alb) were cleaved from the protein with methanesulfonic acid and trifluoroacetic anhydride and measured by gas chromatography-mass spectrometry. Although BO-Alb and 1,4-BQ-Alb were measured in all subjects, levels of both adducts were 2.4-fold greater (median value) in exposed subjects than in controls (interquartile-fold range=1.63-4.05 for BO-Alb and 1.64-3.69 for 1,4-BQ-Alb). Log-log plots of the individual adduct levels versus exposure were quasi-linear with straight-line slopes of about 0.3 for both BO-Alb and 1,4-BQ-Alb. Since these log-space slopes were significantly less than one, we infer that adduct production was nonlinear, i.e., less-than proportional to benzene exposure, over the indicated range. This behavior points to saturation of CYP2E1 as a critical metabolic consequence of high exposure to benzene in humans. Thus, the biologically effective dose of BO and 1,4-BQ should be proportionally greater in persons exposed to low rather than high levels of benzene.
authors.affiliation: School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7431, USA. smr@unc.edu
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Rappaport
authors.forename: Suramya
authors.initials: S
authors.lastname: Waidyanatha
authors.forename: Karen
authors.initials: K
authors.lastname: Yeowell-O'Connell
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Qu
authors.forename: Roy
authors.initials: R
authors.lastname: Shore
authors.forename: Guilan
authors.initials: G
authors.lastname: Li
authors.forename: Songnian
authors.initials: S
authors.lastname: Yin
mesh_terms: D001554:Benzene / Q000032:analysis / Q000378:metabolism*; D016227:Benzoquinones / Q000378:metabolism*; D015415:Biomarkers; D002681:China / Q000453:epidemiology; D003510:Cyclohexanes / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004784:Environmental Monitoring; D062665:Epidemiological Monitoring; D005260:Female; D006801:Humans; D008297:Male; D016273:Occupational Exposure; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D015415:Biomarkers; D003510:Cyclohexanes; D012709:Serum Albumin; C004532:quinone; D001554:Benzene; C023372:benzene oxide