Tissue distribution and macromolecular binding of extremely low doses of [14C]-benzene in B6C3F1 mice

The tissue distribution and macromolecular binding of benzene was studiedover a dose range spanning nine-orders of magnitude to determine the natureof the dose-response and to establish benzene's internal dosimetry at dosesencompassing human environmental exposures. [14C]-Benzene was administeredto B6C3F1 male mice at doses ranging between 700 pg/kg and 500 mg/kg bodywt. Tissues, DNA and protein were analyzed for [14C]-benzene contentbetween 0 and 48 h post-exposure (625 Ng/kg and 5 microg/kg dose) byaccelerator mass spectrometry (AMS). [14C]-Benzene levels were highest inthe liver and peaked within 0.5 h of exposure. Liver DNA adduct levelspeaked at 0.5 h, in contrast to bone marrow DNA adduct levels, which peakedat 12-24 h. Dose- response assessments at 1 h showed that adducts andtissue available doses increased linearly with administered dose up todoses of 16 mg/kg body wt. Tissue available doses and liver protein adductsplateau above the 16 mg/kg dose. Furthermore, a larger percentage of theavailable dose in bone marrow bound to DNA relative to liver. Proteinadduct levels were 9- to 43-fold greater than DNA adduct levels. These datashow that benzene is bioavailable at human-relevant doses and that DNA andprotein adduct formation is linear with dose over a dose range spanningeight orders of magnitude. Finally, these data show that the dose ofbioactive metabolites is greater to the bone marrow than the liver andsuggests that protein adducts may contribute to benzene's hematoxicity.