Tasaki Masako, Umemura Takashi, Inoue Tomoki, Okamura Toshiya, Kuroiwa Yuichi, Ishii Yuji, Maeda Machiko, Hirose Masao, Nishikawa Akiyoshi
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Toxicology. 2008 Sep 4;250(2-3):143-50. doi: 10.1016/j.tox.2008.07.003. Epub 2008 Jul 15.
Tocotrienol is an antioxidant which has found commercial application as a food additive and health supplement all over the world. Since there have been no reports regarding toxicological effects of long-term exposure, we performed a 52-week chronic study using Wistar Hannover rats of both sexes given the compound at doses of 0, 0.08, 0.4 or 2% in powdered basal diet. Since 6 animals in the 2% male group died of hemorrhage of several organs by week 50, the maximum dose level was changed to 1% in both sexes for the last 2 weeks. Decrease of body weight gain was observed in the 2% males from week 5 and females from week 10, this persisting to the end of the study. With the high dose, prolongation of prothrombin time and increase of serum ALT in males, and increase of serum ALP in both sexes were observed with statistical significance. In male and female rats receiving 0.4% or less, there were no toxicological changes in any of the parameters examined. At necropsy, multiple cyst-like nodules on the liver surface were macroscopically pronounced in both sexes receiving 2%. On histopathological examination, hepatocellular nodules were evident with distortion of hepatic cords and compression of the surrounding tissue, almost all including areas of spongiosis hepatis. The constituent hepatocytes were immunohistochemically stained with proliferation cell nuclear antigen at high rates. Nevertheless, they did not exhibit overt atypia and the basic lobular architecture remained intact. Additionally, they were consistently negative for glutathione S-transferase placental form (GST-P). Accordingly, we propose the newly categorized but previously used name 'nodular hepatocellular hyperplasia', which may not necessarily have a neoplastic or regenerative nature. However, quantitative GST-P analysis of the liver sections overall showed numbers of GST-P foci in the high dose females to be significantly elevated as compared to the control value. Based on the present data demonstrating nodular liver lesions only at the high dose of both sexes, we conclude that the no-observed-adverse-effect level (NOAEL) is 0.4% (303 mg/kg/day for males, and 472 mg/kg/day for females).
生育三烯酚是一种抗氧化剂，已在全球范围内作为食品添加剂和健康补充剂得到商业应用。由于尚无关于长期接触其毒理学影响的报告，我们使用Wistar Hannover大鼠进行了一项为期52周的慢性研究，给雌雄两性大鼠喂食添加了0%、0.08%、0.4%或2%该化合物的粉状基础日粮。由于2%雄性组中有6只动物在第50周时死于多个器官的出血，因此在最后2周将两性的最大剂量水平均改为1%。在第5周时观察到2%雄性组的体重增加减少，在第10周时雌性组的体重增加减少，这种情况一直持续到研究结束。高剂量组雄性大鼠的凝血酶原时间延长、血清谷丙转氨酶升高，两性血清碱性磷酸酶均升高，且具有统计学意义。在接受0.4%及以下剂量的雄性和雌性大鼠中，所检测的任何参数均未出现毒理学变化。尸检时，接受2%剂量的两性大鼠肝脏表面均可见多个囊肿样结节，肉眼可见。组织病理学检查显示，肝细胞结节明显，肝索扭曲，周围组织受压，几乎所有结节都包括肝海绵样变区域。组成肝细胞的增殖细胞核抗原免疫组化染色阳性率较高。然而，它们并未表现出明显的异型性，基本小叶结构保持完整。此外，它们的谷胱甘肽S-转移酶胎盘型（GST-P）始终为阴性。因此，我们提出新分类但之前已使用过的名称“结节性肝细胞增生”，其不一定具有肿瘤性或再生性。然而，对肝脏切片进行的GST-P定量分析总体显示，高剂量雌性大鼠的GST-P病灶数量与对照值相比显著升高。基于目前仅在两性高剂量组出现结节性肝脏病变的数据，我们得出结论，未观察到有害作用水平（NOAEL）为0.4%（雄性为303毫克/千克/天，雌性为472毫克/千克/天）。
