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Combination experiments with very low doses of three genotoxic N-nitrosamines with similar organotropic
M R Berger1, D Schmähl, H Zerban
1Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, FRG.
Abstract:
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.
Insights
Very low doses of N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR), and N-nitrosodiethanolamine (NDElA) caused dose-dependent liver cancer in rats. Combining these nitrosamines linearly increased carcinogenic effects, even at low exposure levels.
Area of Science:
- Toxicology
- Carcinogenesis
- Environmental Health
Background:
- N-nitrosamines are known carcinogens, but their effects at very low doses, especially in combination, require further investigation.
- Understanding the syncarcinogenic activity of multiple low-dose carcinogens is crucial for public health risk assessment.
Purpose of the Study:
- To assess the syncarcinogenic activity of very low doses of N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR), and N-nitrosodiethanolamine (NDElA) in Sprague-Dawley rats.
- To determine the dose-dependent incidence of liver cancer and other tumors following individual and combined exposure to these nitrosamines.
Main Methods:
- 1800 male Sprague-Dawley rats were administered NDEA, NPYR, and NDElA individually and in combination via drinking water for their lifetime.
- Three logarithmically spaced dose levels were used for each nitrosamine and their combinations, with dose escalation factors of 3.16.
- Tumor incidence in the liver and other organs was recorded and analyzed for dose-dependency and synergistic effects.
Main Results:
- Individual nitrosamines showed a dose-dependent incidence of liver cancer, with NDEA being the most potent.
- Combined administration of NDEA, NPYR, and NDElA resulted in a linear summation of carcinogenic effects, indicating additive syncarcinogenesis.
- Tumor incidences increased in other tissues (gastrointestinal, neurogenic, urinary, hematopoietic, lymphatic) but without a clear dose dependency.
Conclusions:
- Liver tumor formation is dose-dependent even at very low exposure levels of individual hepatotropic N-nitrosamines.
- The carcinogenic effects of these nitrosamines are additive when administered in combination, posing a significant cancer risk.
- Low-dose combinations of agents, individually non-carcinogenic, can collectively induce significant cancer risk.