Measurement of benzene oxide in the blood of rats following administration of benzene

Although it is generally assumed that metabolism of benzene proceedsthrough an initial step involving oxidation to benzene oxide (BO) by CYP450in the liver, the production of BO has never been unambiguously confirmedin animals dosed with benzene. Furthermore, prevailing hypotheses of themechanism by which benzene causes cancer have ignored the possibility thatBO might play a direct role, despite the fact that BO is electrophilic,binds covalently to cell macromolecules and is presumably genotoxic. Alikely reason for this lack of attention to the role of BO in thecarcinogenesis of benzene is the presumption that this epoxide is tooreactive to escape the hepatocyte after it is formed. We employed gaschromatography-mass spectrometry to measure BO in the blood of F344 rats,both in vitro and up to 24 h following oral administration of benzene.Surprisingly, BO was relatively stable in rat blood at 37 degrees C(estimated half-life = 7.9 min) and, after administering a single dosage of400 mg benzene/kg body wt, a blood concentration of 90 nM BO (8.5 ng/ml)was measured for approximately 9 h. Using a published PBPK model weestimate that approximately 4.3% of the metabolized dose of benzene wasreleased as BO from the liver into blood. This confirms that BO is, indeed,formed from metabolism of benzene and is sufficiently stable to bedistributed throughout the body at levels which are likely to be greaterthan those of the other electrophilic benzene metabolites.