Kano Hirokazu, Umeda Yumi, Saito Misae, Senoh Hideki, Ohbayashi Hisao, Aiso Shigetoshi, Yamazaki Kazunori, Nagano Kasuke, Fukushima Shoji
Japan Bioassay Research Center, Japan Industrial Safety and Health Association, Hadano, Kanagawa, Japan.
J Toxicol Sci. 2008 May;33(2):141-53. doi: 10.2131/jts.33.141.
Subchronic oral toxicity of 1,4-dioxane was examined by administering 1,4-dioxane in drinking water at 6 different concentrations of 0 (control), 640, 1,600, 4,000, 10,000 or 25,000 ppm (wt/wt) to F344 rats and BDF(1)mice of both sexes for 13 weeks. Food and water consumption and terminal body weight were decreased dose-dependently in rats and mice. A dose-dependent increase in the relative weights of kidney and lung was noted in rats and mice, while the relative liver weight was increased only in rats. Increases in plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and a decrease in plasma glucose were noted primarily in the rats and mice dosed 25,000 ppm. Histopathological examination revealed that 1,4-dioxane affected the upper and lower respiratory tracts, liver, kidneys and brain in rats, while only the former two organs were affected in mice. Nuclear enlargement occurred in the respiratory, olfactory, tracheal and bronchial epithelia of the 1,4-dioxane-dosed rats and mice. The 1,4-dioxane-induced hepatic lesions were characterized by centrilobular swelling and necrosis in rats and mice and by glutathione S-transferase placental form (GST-P)-positive altered hepatocellular foci in rats, which are known as preneoplastic lesions. A no-observed-adverse-effect-level (NOAEL) was determined at 640 ppm for both rats and mice, since the nuclear enlargement in the nasal respiratory epithelium and the centrilobular swelling of hepatocytes in rats and the nuclear enlargement in the bronchial epithelium in mice were observed at 1,600 ppm. The NOAEL value corresponded to the estimated 1,4-dioxane intake of 52 mg/kg/day in rats and 170 mg/kg/day in mice.
通过给F344大鼠和BDF(1)小鼠饮用含1,4 - 二氧六环的水，浓度分别为0（对照）、640、1,600、4,000、10,000或25,000 ppm（重量/重量），持续13周，来检测1,4 - 二氧六环的亚慢性经口毒性。大鼠和小鼠的食物和水消耗量以及终末体重均呈剂量依赖性下降。大鼠和小鼠的肾脏和肺相对重量呈剂量依赖性增加，而相对肝脏重量仅在大鼠中增加。主要在给予25,000 ppm剂量的大鼠和小鼠中，观察到天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）血浆水平升高以及血糖降低。组织病理学检查显示，1,4 - 二氧六环影响大鼠的上、下呼吸道、肝脏、肾脏和大脑，而在小鼠中仅影响前两个器官。在给予1,4 - 二氧六环的大鼠和小鼠的呼吸道、嗅觉、气管和支气管上皮中出现核肿大。1,4 - 二氧六环诱导的肝脏病变在大鼠和小鼠中表现为小叶中心肿胀和坏死，在大鼠中还表现为谷胱甘肽S - 转移酶胎盘形式（GST - P）阳性的肝细胞灶改变，这些被认为是癌前病变。大鼠和小鼠的未观察到有害作用水平（NOAEL）均确定为640 ppm，因为在1,600 ppm时观察到大鼠鼻呼吸上皮细胞核肿大和肝细胞小叶中心肿胀以及小鼠支气管上皮细胞核肿大。该NOAEL值相当于大鼠中1,4 - 二氧六环估计摄入量为52 mg/kg/天，小鼠中为170 mg/kg/天。
