US EPA

2278486 

Technical Report 

Interrelationships between nitrate, nitrite, and carcinogenic N-nitroso-compounds: I. Nitrate, nitrite, and nitrosable amino-compounds in food and drugs, chemistry of N-nitroso compounds 

Sander, J; Schweinsberg, F 

1973 

HEEP/73/10489 

156 

4-5 

4-5 

HEEP COPYRIGHT: BIOL ABS. A review was given on the occurrence and formation of nitrite in the human environment, foodstuffs and drugs as well as on the occurrence or use of nitrosable amino compounds. The widespread occurrence of these precursors of carcinogenic nitroso compounds made it necessary to conduct experiments to determine which conditions might influence the formation of N-nitroso compounds. In the group of secondary amines only those with a moderate or low basicity are nitrosated easily enough to induce cancer when incorporated simultaneously with nitrite. Such amines were morpholine, N-methylbenzylamine and N-methylaniline. Simple aliphatic tertiary amines which may be nitrosated at the pH prevailing in the stomach did not induce tumors when given together with nitrite. In the group of the alkylamides, alkyurethanes were of a moderate nitrosability. Alkylureas were easily nitrosated. Feeding of methylurea, ethylurea, 1,3-dimethylurea and ethyleneura resulted in the induction of cancer in rats, provided the animals received nitrite in the drinking water simultaneously. Formation of N-nitroso compounds inside the macroorganism has the same effect as the ingestion of these carcinogens themselves. If such compounds are formed in the environment or food, it will depend on the stability of the compounds, whether they are likely to be ingested or not. No tumor induction in man by N-nitroso compounds is known from the literature. There are several arguments that favor the connection between N-nitroso compounds and human cancer. The most important perhaps is the wide distribution of the precursors and the demonstrated synthesis of N-nitroso compounds under physiological and environmental conditions. With these compounds tumors were induced not only in rodents but also in fish, birds, pigs, dogs and monkeys. There is no indication that man is an exception in this respect. It was shown by Montesano and Magee that the metabolism of N-nitrosodimethylamine in human liver tissue is the same as in rat liver. After application of carcinogenic N-nitroso compounds tumors tend to occur in animals in the same organs in which they are most often found in man. This organotropy is almost completely independent of the means of application. A strong argument in favor of the significance of N-nitroso compounds as a possible cause of cancer in man would be epidemiological studies that show a correlation between the incorporation of certain N-nitroso compounds or their precursors and the occurrence of a certain kind of tumor in a population. On One in this direction was the detection of a nitrosamine in an alcoholic beverage drunk by people in South Africa that show an increased mortailty from esophageal cancer. In judging the problem of chemical carcinogenesis one must keep in mind that in animal experiments certain compounds cause cancer by synergistic effects. Each of the carcinogens must be present in the body only in trace amounts. These effects are probably very important in man since humans are exposed to a great number of carcinogens. Even if N-nitroso compounds by themselves are of no great importance as a cause of cancer in man they probably play a role together with other syncarcinogens and cocarcinogens. As consequence of what is now known about the formation of N-nitroso compounds it should be attempted to limit the amount of nitrite as well as of other precursors of these carcinogens in the environment, foodstuffs and drugs as much as possible. Of equal importance is to avoid bacterial formation of nitrite in processing, preserving and storing food.