Benzene is an important industrial chemical. At certain levels, benzene has been found to produce aplastic anemia, pancytopenia, myeloblastic anemia and genotoxic effects in humans. Metabolism by cytochrome P450 monooxygenases and myeloperoxidase to hydroquinone, phenol, and other metabolites contributes to benzene toxicity. Other xenobiotic substrates for cytochrome P450 can alter benzene metabolism. At high concentrations, toluene has been shown to inhibit benzene metabolism and benzene-induced toxicities. The present study investigated the genotoxicity of exposure to benzene and toluene at lower and intermittent co-exposures. Mice were exposed via whole-body inhalation for 6h/day for 8 days (over a 15-day time period) to air, 50 ppm benzene, 100 ppm toluene, 50 ppm benzene and 50 ppm toluene, or 50 ppm benzene and 100 ppm toluene. Mice exposed to 50 ppm benzene exhibited an increased frequency (2.4-fold) of micronucleated polychromatic erythrocytes (PCE) and increased levels of urinary metabolites (t,t-muconic acid, hydroquinone, and s-phenylmercapturic acid) vs. air-exposed controls. Benzene co-exposure with 100 ppm toluene resulted in similar urinary metabolite levels but a 3.7-fold increase in frequency of micronucleated PCE. Benzene co-exposure with 50 ppm toluene resulted in a similar elevation of micronuclei frequency as with 100 ppm toluene which did not differ significantly from 50 ppm benzene exposure alone. Both co-exposures - 50 ppm benzene with 50 or 100 ppm toluene - resulted in significantly elevated CYP2E1 activities that did not occur following benzene or toluene exposure alone. Whole blood glutathione (GSH) levels were similarly decreased following exposure to 50 ppm benzene and/or 100 ppm toluene, while co-exposure to 50 ppm benzene and 100 ppm toluene significantly decreased GSSG levels and increased the GSH/GSSG ratio. The higher frequency of micronucleated PCE following benzene and toluene co-exposure when compared with mice exposed to benzene or toluene alone suggests that, at the doses used in this study, toluene can enhance benzene-induced clastogenic or aneugenic bone marrow injury. These findings exemplify the importance of studying the effects of binary chemical interactions in animals exposed to lower exposure concentrations of benzene and toluene on benzene metabolism and clastogenicity. The relevance of these data on interactions for humans exposed at low benzene concentrations can be best assessed only when the mechanism of interaction is understood at a quantitative level and incorporated within a biologically based modeling framework.

译文

:苯是重要的工业化学品。在某些水平上,已发现苯会在人类中产生再生障碍性贫血,全血细胞减少,骨髓小球性贫血和遗传毒性作用。细胞色素P450单加氧酶和髓过氧化物酶代谢为氢醌,苯酚和其他代谢物会导致苯毒性。细胞色素P450的其他异质底物可以改变苯的代谢。在高浓度下,甲苯已显示出抑制苯代谢和苯诱导的毒性的作用。本研究调查了在较低和间歇性共同暴露下暴露于苯和甲苯的遗传毒性。通过全身吸入将小鼠暴露于空气,50 ppm苯,100 ppm甲苯,50 ppm苯和50 ppm甲苯或50 ppm苯和100 ppm的空气中,每天吸入6小时/天,持续8天(在15天的时间内)。甲苯。与暴露于空气的对照组相比,暴露于50 ppm苯的小鼠的微核多色红细胞(PCE)的频率增加(2.4倍),尿代谢产物(t,t-粘康酸,对苯二酚和s-苯基巯基尿酸)的含量增加。 。苯与100 ppm甲苯的共同暴露导致尿液代谢产物水平相似,但微核PCE的频率增加了3.7倍。苯与50 ppm甲苯的共同暴露导致微核频率的升高与100 ppm甲苯的相似,这与单独暴露于50 ppm的苯没有显着差异。两种共同暴露-50 ppm苯与50或100 ppm甲苯-均导致CYP2E1活性显着升高,而单独暴露于苯或甲苯后并未发生。暴露于50 ppm苯和/或100 ppm甲苯后,全血谷胱甘肽(GSH)水平同样降低,而同时暴露于50 ppm苯和100 ppm甲苯则显着降低GSSG水平并增加GSH / GSSG比。与仅暴露于苯或甲苯的小鼠相比,苯和甲苯共同暴露后微核PCE的发生频率更高,这表明,在本研究中使用的剂量下,甲苯可以增强苯诱导的可致瘤性或非成因性骨髓损伤。这些发现证明了研究动物中二元化学相互作用对苯和甲苯的较低暴露浓度对苯代谢和致突变性的影响的重要性。仅当在定量水平上理解相互作用机理并将其纳入基于生物学的建模框架中时,才能最好地评估这些数据对与低苯浓度暴露的人的相互作用的相关性。

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