Non-linear production of benzene oxide-albumin adducts with human exposure to benzene

Benzene is initially metabolized to benzene oxide, which either undergoes further metabolism or reacts with macromolecules including proteins. Previously reported levels of benzene oxide-albumin adducts (BO-Alb) are analyzed from 30 workers exposed to 0.2-302 ppm benzene and 43 controls from Shanghai, China. Although both exposed workers and controls had significant levels of BO-Alb in their blood, exposed subjects' adduct levels (GM=378 pmol/g protein) were much greater than those of controls (GM=115 pmol/g protein). When the natural logarithm of the BO-Alb level was regressed upon the natural logarithm of exposure among the 30 exposed subjects, a strong effect of benzene exposure was observed (R(2)=0.612; p<0.0001). Because the slope of the relationship between BO-Alb and benzene exposure was significantly less than one in log-space, we infer that production of benzene oxide was less than proportional to benzene exposure. Since benzene is a substrate for CYP2E1, these results are consistent with saturation of CYP450 metabolism. They indicate that deviations from linear metabolism began at or below benzene exposures of 10 ppm and that pronounced saturation was apparent at 40-50 ppm. To our knowledge, this is the first study to investigate the linearity of human metabolism of a carcinogen based upon protein adducts.