Carcinogens, N-nitrosamines

Sodium nitrite can react with proteins in the stomach or during cooking, especially in high heat (such as frying bacon), to form carcinogenic N-nitrosamines. To prevent this, ascorbic acid or erythor-bic acid is commonly added to cured meats. 

An HPLC technique has been developed [59] for volatile carcinogenic N-nitrosamines which shortens the chromatographic analysis time by a factor of five compared with GLC methods. The nitrosamines are converted into their amine reduction products which are then treated with 2,4-dinitrofluorobenzene (DNFB) in order to form the amines. The amines are then separated and detected at 340-360 nm. The reactions involved are shown in Fig.4.31. 

There is evidence that carcinogenic N-nitrosamines can be formed during the production of alcoholic beverages, fermented foods and cured meats (Steering Group on Chemical Aspects of Food Surveillance, 1992b). 

In addition to dietary sources, a significant amount of nitrate is formed endogenously by the metabolism of nitric oxide - 1 mg per kg of body weight per day (about the same as the average dietary intake), increasing 20-fold in response to inflammation and immune stimulation. There is considerable secretion of nitrate in saliva, and up to 20% of this may be reduced to nitrite by oral bacteria. Under the acidic conditions of the stomach, nitrite can react with amines in foods to form carcinogenic N-nitrosamines, although it is not known to what extent this occurs in vivo. 

Rao GS, Osborn JC, Adatia MR. 1982. Drug-nitrite interactions in human saliva effects of food constituents on carcinogenic N-nitrosamine formation. J Dent Res 61 768-771. 

Duncan, R.H., Davies, G.S. Alkylation of DNA bases by carcinogenic N-nitrosamine metabolites A theoretical study. International Journal of Quantum Chemistry 35, 665-677 (1989)... 

During the last 4 years, a considerable discussion has been building up in biochemical and oncological circles on the possible carcinogenic risk presented by exposure to N-nitrosamines(49 ). The fact that carcinogenic N-nitrosamines are present in the diet may be regarded as established (SO) though the quantities may be less thw initially thou t. Since the question of a no-effect... 

The international discussion about carcinogenic N-nitrosamines generated during or after vulcanisation of rubber products started in the late 1970s. It reached its... 

International Polymer Science and Technology 23, No. 10, 1996, p.T/27-T/29 PROBLEM OF CARCINOGENIC N-NITROSAMINES AT ENTERPRISES OF THE RUBBER AND TYRE INDUSTRY... 

An examination is made of the performance of dicyclohexyl benzothiazole sulphenamide (DCBS) as an accelerator in tyre compounds. Cure characteristics, adhesion and flow properties are discussed, and it is shown that DCBS does not form carcinogenic N-nitrosamines. 8 refs. 

Tobacco Specific N-Nitrosamines Occurrence, Carcinogenicity and Metabolism", ACS Symp. Ser, 1979, 101, 125-152,... 

Hoffmann, D. Adams, J.D. Carcinogenic Tobacco Specific N-Nitrosamines in Snuff and in the Saliva of Snuff Dippers. Submitted. 

Hoffmann D, Brunnemann KD, Prokopczyk B, Djordjevic MV. (1994). Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines chemistry, biochemistry, carcinogenicity, and relevance to humans. J Toxicol Environ Healdi. 41(1) 1-52. 

Although N-nitrosamines (l) have been known since the nineteenth century, it was not until quite recently that they became the subject of intensive investigations. This renewed interest was spurred in large part by the report of Magee and Barnes ( ) on the carcinogenicity of these compounds. Since then, research into the chemistry and biological properties of N-nitrosamines has accelerated. This brief survey is intended to serve both as a summary of some of the frontiers in this area and as an introduction to the chemistry of N-nitrosamines discussed in the remaining chapters of this Volume. 

One of the more important classes of chemical carcinogens are N-nitrosamines. They are important because practically all of the simple nitrosamines are carcinogenic, they are widely distributed in our environment and can be formed in the stomach from secondary and tertiary amines and the ubiquitous nitrite ion. Moreover, nitrosamines are very organ-specific. Thus, a given nitrosamine will produce a liver or an esophageal tumor, regardless of the route of administration of the carcinogen. This fact makes nitrosamines very useful in the study of mechanisms of tumor induction (1). 

N-nitrosodialkylamines - nitrosamines - constitute one of the most extensive series of known chemical carcinogens. Most nitrosamines can initiate tumors in at least one animal species, and all animal species which have so far been tested are susceptible to nitrosamine carcinogenesis O, 2 ). 

In summary, it appears that the differences in carcinogenic potency for both cyclic and acyclic N-nitrosodialkylamines are real and systematic, and that the potencies of environmental nitrosamines should be considered in assessing the relative hazards associated with these compounds. In addition, it can be shown that the carcinogenicity of nitrosamines can be associated... 

Most of the over 400 N-nitroso compounds that have been tested for carcinogenic activity have been found to be carcinogenic [13, 39]. It is well known that the predominant initial metabolic activation pathway for N-nitrosamines is a-hydroxyl-... 

Some critical structural features that can affect the carcinogenicity of N-nitrosamines are summarized in Table 14.4. 

Substitution at the a-carbon with acidic group(s), fluoro group(s), or bulky group (s) has been shown to diminish or abolish their carcinogenicity. This is because the initial metabolic activation pathway for N-nitrosamines is a-hydroxylation. 

It must be pointed out, however, that direct evidence of human involvement is lacking. For example, despite much publicity, N-nitrosamines have nor been proven to be causative agents on induction of human cancer. They are. however, patent carcinogens in experimental animals. 

As noted above, gastric acid serves as an important barrier to bacterial colonization of the stomach and small intestine. Increases in gastric bacterial concentrations are detected in patients taking proton pump inhibitors. An increase in nitrate-reductase positive strains could theoretically increase carcinogenic nitrites and N-nitrosamines. However, most studies do not demonstrate this. 

---