Salivary excretion of N-nitrosodimethylamine in dogs

Carcinogenic N-nitroso compounds (NOCs) are not only ingested from the environment but are also formed endogenously from precursors. It has been reported that nitrate, an NOC precursor, has an enterosalivary cycle and that the cycle increases the chance of exposure to NOCs. However, there is no information on the salivary excretion of NOCs. In the present study, the toxicokinetics of N-nitrosodimethylamine (NDMA) in dogs was evaluated, focusing on the salivary excretion. Following intravenous injection of 2 mg/kg NDMA, the plasma concentration showed a monoexponential decline, and the total body clearance and apparent distribution volume were greatly in excess of the hepatic plasma flow and total body water, respectively. A high concentration of NDMA was immediately detected in the plasma after oral administration of the same dose, and the oral bioavailability was almost 100%. NDMA was rapidly excreted into the saliva after both treatments, and the concentration in saliva was higher than that in the plasma. These results suggest that NDMA also has an enterosalivary cycle: NDMA is partially excreted from blood into saliva, delivered into the gastrointestinal tract by swallowing the saliva, and then completely reabsorbed into the systemic circulation. This concept was also supported by kinetic analysis based on a compartment model. The enterosalivary cycle of NDMA cannot be ignored in the risk assessment of carcinogenesis.