Lijinsky W, Kovatch R M, Riggs C W, Walters P T
National Cancer Institute-Frederick Cancer Research Facility, Biometics Research, Inc.-Basic Research Program, Maryland 21701.
Cancer Res. 1988 Apr 15;48(8):2089-95.
A dose-response study in carcinogenesis was carried out with N-nitrosomorpholine in female F344 rats. The compound was administered in drinking water, which was supplied in controlled amounts of 20 ml per day per rat, 5 days a wk. At the two highest dose rates, 100 mg/liter and 40 mg/liter, treatment lasted 25 and 40 wk, respectively. At the other dose rates, which differed by a factor of 2.5, treatment lasted 50 or 100 wk. The average total dose received by each rat ranged from 250 mg to 0.7 mg. There were 100 animals per group at the lowest dose rates and 24 animals per group at the highest dose rates. Total doses of nitrosomorpholine above approximately 30 mg per rat caused a statistically significant decrease in survival, but at lower doses survival was similar to that of untreated controls. In nearly all of the treated groups there was a statistically significant increase in the incidence of benign or malignant hepatocellular neoplasms, with a highly significant dose-related trend. At the higher doses there was a significant incidence of hemangiosarcomas of the liver. Both hepatocellular carcinomas and hemangiosarcomas metastasized to the lungs and other organs. At the highest doses there was a significant incidence of neoplasms of the tongue and esophagus, which were rarely seen at the lower doses. The results suggest that even the lowest dose of nitrosomorpholine received by the rats, 0.7 mg or approximately 3 mg/kg body weight, was not a no-effect dose during the 2-yr lifetime of a rat. Probit analysis of the results indicate a dose estimated to cause tumors in 50% of the population of 25 mg nitrosomorpholine for liver neoplasms.
在雌性F344大鼠中开展了一项关于N-亚硝基吗啉致癌作用的剂量反应研究。该化合物通过饮用水给药，每只大鼠每天的饮水量控制为20毫升，每周5天。在两个最高剂量率下，即100毫克/升和40毫克/升，处理分别持续25周和40周。在其他剂量率下，剂量相差2.5倍，处理持续50周或100周。每只大鼠接受的平均总剂量范围为250毫克至0.7毫克。最低剂量率组每组有100只动物，最高剂量率组每组有24只动物。每只大鼠亚硝基吗啉总剂量超过约30毫克会导致存活率出现统计学显著下降，但较低剂量时存活率与未处理对照组相似。几乎所有处理组中，良性或恶性肝细胞肿瘤的发生率都有统计学显著增加，且存在高度显著的剂量相关趋势。在较高剂量时，肝脏血管肉瘤的发生率显著。肝细胞癌和血管肉瘤都会转移至肺部和其他器官。在最高剂量时，舌和食管肿瘤的发生率显著，而在较低剂量时很少见。结果表明，即使大鼠接受的亚硝基吗啉最低剂量，即0.7毫克或约3毫克/千克体重，在大鼠2年寿命期间也不是无作用剂量。对结果进行的概率分析表明，估计导致50%群体发生肝脏肿瘤的亚硝基吗啉剂量为25毫克。
