Creek M R, Mani C, Vogel J S, Turteltaub K W
University of California, San Francisco, Department of Pharmaceutical Chemistry 94143, USA.
Carcinogenesis. 1997 Dec;18(12):2421-7. doi: 10.1093/carcin/18.12.2421.
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.
研究了苯在跨越九个数量级的剂量范围内的组织分布和大分子结合情况，以确定剂量反应的性质，并在涵盖人类环境暴露剂量的条件下建立苯的体内剂量学。将[¹⁴C] - 苯以700 pg/kg至500 mg/kg体重的剂量给予B6C3F1雄性小鼠。通过加速器质谱法（AMS）在暴露后0至48小时（625 Ng/kg和5 μg/kg剂量）分析组织、DNA和蛋白质中的[¹⁴C] - 苯含量。肝脏中的[¹⁴C] - 苯水平最高，在暴露后0.5小时达到峰值。肝脏DNA加合物水平在0.5小时达到峰值，而骨髓DNA加合物水平在12 - 24小时达到峰值。1小时时的剂量反应评估表明，加合物和组织可利用剂量随给药剂量线性增加，直至16 mg/kg体重的剂量。在16 mg/kg剂量以上，组织可利用剂量和肝脏蛋白质加合物趋于平稳。此外，相对于肝脏，骨髓中与DNA结合的可利用剂量百分比更大。蛋白质加合物水平比DNA加合物水平高9至43倍。这些数据表明，在与人类相关的剂量下苯具有生物可利用性，并且在跨越八个数量级的剂量范围内，DNA和蛋白质加合物的形成与剂量呈线性关系。最后，这些数据表明，生物活性代谢物对骨髓的剂量大于对肝脏的剂量，并表明蛋白质加合物可能导致苯的血液毒性。
