Ton T T, Elwell M R, Morris R W, Maronpot R R
National Institute of Environmental Health Sciences, Laboratory of Experimental Pathology, Research Triangle Park, NC 27709, USA.
Cancer Lett. 1995 Aug 16;95(1-2):167-73. doi: 10.1016/0304-3835(95)03883-x.
In a previous 13-week study of o-nitrotoluene, a chemical-related increase in liver weight, hepatocellular vacuolization, and oval cell hyperplasia in male F344 rats was reported. In this study, the occurrence and change in number and size of hepatic foci in male F344 rats fed a diet containing 5000 ppm o-nitrotoluene or a control diet for 13 weeks, 26 weeks, and 13 weeks followed by a 13-week recovery period (26-week stop-exposure) were evaluated. The livers were stained immunohistochemically for placental glutathione S-transferase (PGST), a marker of hepatic preneoplasia, and quantified stereologically using computer-assisted image analysis. Exposure to o-nitrotoluene induced PGST-positive (PGST-positive (PGST+) liver foci in all treatment groups. The 26-week continuous-exposure group produced more PGST+ liver foci (961.4 foci/cm3 versus 445.4 foci/cm3) and greater mean focus volume (4.34 microns3 versus 1.34 microns3) than the 13-week continuous-exposure group. In the 26-week stop-exposure group, there were fewer PGST+ liver foci (181.4 foci/cm3) than observed with continuous exposure at 13 weeks or 26 weeks; however, the mean focal volume in the stop-exposure group at 26 weeks (5.33 microns3) was greater than that at 13 weeks (1.34 microns3) or 26 weeks of continuous exposure (4.34 microns3). These findings demonstrate that (1) PGST+ foci are observed after only 13 weeks of exposure to o-nitrotoluene; (2) the number and size of foci increase with continued exposure for 26 weeks; and (3) although the number of PGST+ foci decreases with time after chemical exposure is discontinued, many PGST+ foci do not regress but increase in size during the recovery of 13 weeks. The persistence and increase in size of these foci, even in the absence of chemical exposure, suggest the potential for a hepatocarcinogenic effect in long-term studies for o-nitrotoluene.
在之前一项为期13周的邻硝基甲苯研究中，据报道雄性F344大鼠出现了与化学物质相关的肝脏重量增加、肝细胞空泡化以及卵圆细胞增生。在本研究中，评估了雄性F344大鼠在喂食含5000 ppm邻硝基甲苯的饲料或对照饲料13周、26周以及13周后接着13周恢复期（26周停止暴露）期间肝脏病灶数量和大小的发生及变化情况。对肝脏进行免疫组织化学染色，检测胎盘型谷胱甘肽S -转移酶（PGST），这是一种肝脏癌前病变的标志物，并使用计算机辅助图像分析进行立体定量分析。所有处理组中，暴露于邻硝基甲苯均诱导产生了PGST阳性（PGST +）肝脏病灶。与13周连续暴露组相比，26周连续暴露组产生了更多的PGST +肝脏病灶（961.4个病灶/cm³ 对 445.4个病灶/cm³）且平均病灶体积更大（4.34立方微米 对 1.34立方微米）。在26周停止暴露组中，PGST +肝脏病灶数量（181.4个病灶/cm³）比13周或26周连续暴露时观察到的要少；然而，26周停止暴露组的平均病灶体积（5.33立方微米）大于13周（1.34立方微米）或26周连续暴露时的（4.34立方微米）。这些发现表明：（1）仅在暴露于邻硝基甲苯13周后就观察到了PGST +病灶；（2）随着连续暴露26周，病灶数量和大小增加；（3）尽管在停止化学物质暴露后PGST +病灶数量随时间减少，但在13周的恢复期内，许多PGST +病灶并未消退反而体积增大。这些病灶的持续存在及大小增加，即使在没有化学物质暴露的情况下，也提示邻硝基甲苯在长期研究中具有潜在的致癌作用。
