Speaker
Description
Rising dietary and drinking-water intake of nitrate (NO$_3^-$) and nitrite (NO$_2^-$) poses a significant public health concern. After ingestion, NO$_3^-$ enters the enterosalivary circulation, where oral bacteria reduce it to NO$_2^-$. When swallowed, NO$_2^-$ enters the acidic gastric environment, where it can react to form N-nitroso compounds (NOCs), many of which are suspected carcinogens. However, epidemiological evidence for this link remains mixed, likely due to the protective effects of antioxidants such as vitamin C. To better understand and quantify these complex interactions, we develop a dynamic, compartmental quantitative systems pharmacology model of human NO$_{3}^{-}$ and NO$_{2}^{-}$ metabolism and gastric chemistry. The framework tracks NO$_{3}^{-}$ and NO$_{2}^{-}$ fluxes across the stomach, intestine, plasma, and saliva, incorporates postprandial changes in gastric volume and pH, and includes mechanistic nitrosation pathways with vitamin C inhibition. Using this framework, we evaluate NOC formation under different dietary and water-quality contexts, demonstrating the protective effect of dietary vitamin C and examining the role of supplementation. Simulations suggest supplementation is most effective shortly after meals. These findings provide a mechanistic basis for understanding how diet, drinking-water quality, and vitamin C supplementation interact to shape endogenous NOC formation, with implications for nutritional guidelines and risk reduction.
