Theoretical model for predicting rates of nitrosamine and nitrosamide formation in the human stomach

A mathematical model has been developed to estimate the rates of formation of nitrosamines and nitrosamides in the human stomach, under a variety of physiological and environmental conditions. The model combines a detailed description of the kinetics of N-nitrosation with mass balance equations which account for gastric emptying, dilution and absorption. The simulations were based on a typical schedule of dietary inputs, and included variations in gastric pH and in the volume of the stomach contents over a 24-h period. Consideration of these transient phenomena allowed a distinction to be made between amines or amides present in the diet and in gastric or salivary secretions. A comparison of the theoretical results with available data on the nitrosation of proline suggests that the model accurately predicts gastric rates of nitrosamine formation under control conditions, and correctly represents the strong catalytic effects of thiocyanate and the inhibitory effects of ascorbic acid or ascorbate ion. The results further suggest that nitrosoproline (NPro) excretion is not an accurate index of gastric nitrosation under physiological (low-dose) conditions, even when corrections are made for dietary intake of NPro. The predicted rates of formation of N-nitrosodimethylamine (NDMA), even for a diet high in dimethylamine, were found to be a factor of approximately 10(2) to 10(3) lower than published estimates of the dietary exposure to preformed NDMA. Thus, these findings do not support the hypothesis that gastric formation of NDMA from dietary dimethylamine poses a serious additional health risk. The results are presented in a graphical and tabular form which makes it possible to readily estimate the rates of formation of other nitrosamines or nitrosamides in the stomach, under various assumed conditions.