Benzene Metabolism Is Dominated by a High-Affinity Pathway at Ambient Exposures with Implications for Cancer Risks

Benzene is a ubiquitous environmental pollutant that induces blood cancers via its complex metabolism. Since cancer risks to the general public involve toxic benzene metabolites derived from the inhalation of benzene at ppb air concentrations, questions remain regarding low-dose metabolism. Using previously published data from 389 Chinese workers, we fit Michaelis–Menten-like models to predict urinary concentrations of E,E-muconic acid (the most discriminating urinary metabolite) as functions of urinary benzene levels between 0.0001 μM and 54 μM, equivalent to benzene air concentrations between 0.1 ppb and more than 100 ppm. When we compared models having either one or two metabolic pathways, weights of evidence favoring two pathways were essentially 100 percent for nonsmoking males and females and 58 percent for smoking males. At ppb exposure levels, metabolic rates for the high-affinity pathway were 43-fold greater than those for the low-affinity pathway in nonsmoking males, 6.5-fold greater in nonsmoking females, and 4.9-fold greater in smoking males. Thus, the high-affinity pathway is most efficient in nonsmoking males and is inhibited by smoking. The characteristics of the two-pathway model implicate lung metabolism of benzene via CYP2A13 and/or CYP2F1 at ppb air levels and liver metabolism by CYP2E1 above one ppm. Since ambient benzene concentrations are typically less than 10 ppb, blood-cancer risks predicted from workers exposed to above 1 ppm likely underestimate risks to the general public by many fold, and these risks may be modulated by smoking. Also, since the lung is the site of initial metabolism upon inhalation, the respiratory bioactivation of benzene could contribute to lung-cancer incidence, including that for lung adenomas in never smokers.