Carcinogenesis, Vol 18, 2421-2427, Copyright © 1997 by Oxford University Press
MR Creek, C Mani, JS Vogel and KW Turteltaub
The tissue distribution and macromolecular binding of benzene was studied
over a dose range spanning nine-orders of magnitude to determine the nature
of the dose-response and to establish benzene's internal dosimetry at doses
encompassing human environmental exposures. [14C]-Benzene was administered
to B6C3F1 male mice at doses ranging between 700 pg/kg and 500 mg/kg body
wt. Tissues, DNA and protein were analyzed for [14C]-benzene content
between 0 and 48 h post-exposure (625 Ng/kg and 5 microg/kg dose) by
accelerator mass spectrometry (AMS). [14C]-Benzene levels were highest in
the liver and peaked within 0.5 h of exposure. Liver DNA adduct levels
peaked at 0.5 h, in contrast to bone marrow DNA adduct levels, which peaked
at 12-24 h. Dose- response assessments at 1 h showed that adducts and
tissue available doses increased linearly with administered dose up to
doses of 16 mg/kg body wt. Tissue available doses and liver protein adducts
plateau above the 16 mg/kg dose. Furthermore, a larger percentage of the
available dose in bone marrow bound to DNA relative to liver. Protein
adduct levels were 9- to 43-fold greater than DNA adduct levels. These data
show that benzene is bioavailable at human-relevant doses and that DNA and
protein adduct formation is linear with dose over a dose range spanning
eight orders of magnitude. Finally, these data show that the dose of
bioactive metabolites is greater to the bone marrow than the liver and
suggests that protein adducts may contribute to benzene's hematoxicity.
ARTICLES
Tissue distribution and macromolecular binding of extremely low doses of [14C]-benzene in B6C3F1 mice
University of California, San Francisco, Department of Pharmaceutical Chemistry 94143, USA.
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