MEASUREMENT OF BENZENE OXIDE IN THE BLOOD OF RATS FOLLOWING ADMINISTRATION OF BENZENE

Although it is generally assumed that metabolism of benzene proceeds t hrough an initial step involving oxidation to benzene oxide (BO) by CY P450 in the liver, the production of BO has never been unambiguously c onfirmed in animals dosed with benzene, Furthermore, prevailing hypoth eses of the mechanism by which benzene causes cancer have ignored the possibility that BO might play a direct role, despite the fact that BO is electrophilic, binds covalently to cell macromolecules and is pres umably genotoxic. A likely reason for this lack of attention to the ro le of BO in the carcinogenesis of benzene is the presumption that this epoxide is too reactive to escape the hepatocyte after it is formed. We employed gas chromatography-mass spectrometry to measure BO in the blood of F344 rats, both in vitro and up to 24 h following oral admini stration of benzene. Surprisingly, BO was relatively stable in rat blo od at 37 degrees C (estimated half-life = 7.9 min) and, after administ ering a single dosage of 400 mg benzene/kg body mt, a blood concentrat ion of 90 nM BO (8.5 ng/ml) was measured for similar to 9 h, Using a p ublished PBPK model we estimate that similar to 4.3% of the metabolize d dose of benzene was released as BO from the liver into blood. This c onfirms that BO is, indeed, formed from metabolism of benzene and is s ufficiently stable to be distributed throughout the body at levels whi ch are likely to be greater than those of the other electrophilic benz ene metabolites.