Berger M R, Schmähl D, Zerban H
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, FRG.
Carcinogenesis. 1987 Nov;8(11):1635-43. doi: 10.1093/carcin/8.11.1635.
The study was designed to assess the syncarcinogenic activity of very low doses of N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR) and N-nitrosodiethanolamine (NDElA) in the liver of 1800 male Sprague-Dawley rats. The N-nitrosamines were administered throughout the rats' lives individually and in combination at three logarithmically spaced dose levels contained in drinking water. The dose levels in the individual dose-response experiments ranged from the lowest concentrations of previous experiments (NDEA, 0.1 mg/kg; NPYR, 0.4 mg/kg; NDElA, 2.0 mg/kg) to dosages 10 times lower and comprised a high, medium and low dose (escalation factor: 3.16). The high dose of the combination contained the three nitrosamine concentrations used as the medium doses of the individual nitrosamines. The medium combination dose resulted from the combined administration of the three lowest dosages, and the low combination dose consisted of three nitrosamine dosages which amounted to one-third of the low dosages respectively. Administration of these dosages was associated with a dose-dependent incidence of liver cancer: NDEA induced 45, 3.8 and 2.5%; NPYR caused 21.3, 5 and 1.3%; NDElA generated 7.5, 1.3 and 2.5%; and the combinations induced 16, 4.2 and 1.7% respectively. Untreated controls showed 0.6% liver cancer incidence. Besides the liver, the gastrointestinal tract, the neurogenic tissue, the urinary tract and the hematopoietic and lymphatic tissue were affected by tumor incidences increased over that of controls. There was, however, no well-defined dose dependency as with the liver tumors. These results indicate dose dependency of liver tumor formation even at very low exposure levels of the individual agents. The carcinogenic effects of the hepatotropic N-nitrosamines summed up in combination. The observed additivity was linear. Dose levels, which alone would presumably not have been carcinogenic, effected a significant cancer risk in combination.
本研究旨在评估极低剂量的N-亚硝基二乙胺（NDEA）、N-亚硝基吡咯烷（NPYR）和N-亚硝基二乙醇胺（NDElA）对1800只雄性斯普拉格-道利大鼠肝脏的协同致癌活性。这些N-亚硝胺在大鼠的整个生命过程中通过饮用水以三种对数间隔的剂量水平单独或联合给药。在各个剂量反应实验中，剂量水平范围从前一实验的最低浓度（NDEA为0.1mg/kg；NPYR为0.4mg/kg；NDElA为2.0mg/kg）到低10倍的剂量，并包括高、中、低剂量（递增因子：3.16）。联合给药的高剂量包含用作各个亚硝胺中剂量的三种亚硝胺浓度。联合给药的中剂量由三种最低剂量联合给药产生，低剂量联合给药由三种亚硝胺剂量组成，分别相当于低剂量的三分之一。给予这些剂量与肝癌的剂量依赖性发生率相关：NDEA诱导的发生率分别为45%、3.8%和2.5%；NPYR导致的发生率分别为21.3%、5%和1.3%；NDElA产生的发生率分别为7.5%、1.3%和2.5%；联合给药诱导的发生率分别为16%、4.2%和1.7%。未处理的对照组肝癌发生率为0.6%。除肝脏外，胃肠道、神经组织、泌尿系统以及造血和淋巴组织的肿瘤发生率也高于对照组。然而，与肝脏肿瘤不同，没有明确的剂量依赖性。这些结果表明，即使在单个药物极低暴露水平下，肝脏肿瘤形成也存在剂量依赖性。亲肝性N-亚硝胺的致癌作用在联合给药时具有相加性。观察到的相加性是线性的。单独使用时可能不会致癌的剂量水平，联合使用时会产生显著的癌症风险。
