IARC MONOGRAPHS VOLUME 24 The data in Table 1 demonstrate that less basic amines are much more easily nitrosated . Aldehydes such a3 formaldehyde, chloral (Keefer & Roller, 1973), benzaldehyde and, 2 pH optimum than are strongly basic amines. especially, pyridoxal (vitamin B,) (Archer at al,, 1976) Catalyse nitrosation reactions, . probably by the formation of nitrite esters via methylene-immonium intermediates. The esters then rearrange to form nitrosamine and aldehyde. t is important to note that Table 1. Rate constants of nitrosation of amines with nitrite at optimal pH and 25°C" formaldehyde catalysis also leads to nitrosamine formation in neutral and even strongly oO alkaline media (Keefer & Roller, 1973). Amine Optimal Rate constant Diphenols, such as 4-methylcatechol, are also effective catalysis (Challis & Bartlett, pH K, (mol? x sec") ~ 1975; Davies et a/., 1978; Pignatelli et a/., 1980), as are micelle-fonning surface-active Piperidine 36 0.00045 2 compounds, such as lecithin (Okun & Archer, 1976). Bacteria have also bee: shown to cata- Dimethylamine ; 34 0.0017 > | lyse nitrosation reactlons (Archer et af,, 1978}. - N-Methy!benzy!amine . 3.0 0.013 oe Morpholina . 3.4 0.42. "Inhibition Mononitrosopiperazine \ 3.0 8.7 : Piperazine . 3.0° 83 s Competition by inhibitors for the nitrosating agent may prevent nitrosamine formation or decroase reaction yields. Ascorbic acid is probably the most effective inhibitor (Mirvish et a/., 1972}; a reaction between ascorbic acid and the nitrosating agent forms NO from ; . .N,O, and dehydroascorbic acid (Dahn et a/., 1960). Another important nitrosation in- The nitrosation of weakly basic secondary amides has jn general no pH optimum: as hibitor Is a-tocopherol (Mergens et a/., 1978). a : pH changes from 3 to 1, nitrosation increases by a factor of 10 per pH unit. The nitro- ing agent is mainly the nitrosyl cation NO*, * From Mirvish, 1975 Examples of other compounds that compete with nitrosatable amines for available . . nitrite are-amino acids, urea, amidosulphonic acid and primary amines. The simultaneous Contrary to some opinion, tertiary amines may also undergo nitrosation (Hein, 1963; presence, for example, of primary and secondary amino groups in a nitrosation mixture vith & Loeppky, 1967). The reaction rate, however, is usually appreciably lower than often favours N-nitrosation over deamination (Paulsen & Mackel, 1969; Mirvish, 1971). at of the nitrosation of secondary amines and is maximal at weakly acid pH (pH 3-6). The ‘rosative. cleavage of a C-N-bond probably leads to immonium intermediates, which Ay.Nitrosation in vivo -her hydrolyse to form a secondary amine (Smith & Loeppky, 1967) or react directly with trita to form nitrite esters, which rearrange to form the nitrosamine (Lijinsky ef a/., Many experiments in animals, and some observations in humans, have shown that '72a), nitrosation reactions can occur in vive, mainly in the stomach. Their occurrence, however, depends on the relative concentrations of substrates, catalysts and inhibitors, and is in- fluenced by the inhomegeneity of the stomach contents, by pH and by many other factors. Thus, quantitative prediction of nitrosation rates and yields in vivo is impossible. Catalysis Nitrosation reactions can be catalysed by a variety of chemicals. Chloride and thio- vanate ions are simple inorganic catalysts (Boyland er a/., 1971; Fan & Tannenbaum, One substrate, nitrite, is a normal constituent of human saliva. Its concentration 173), which probably act by forming highly reactive nitrosyi helides or analogous com- depends largely on the nitrate intake in food and drinking-water. After reabsorption from sunds, such as nitrosyl thiocyamates (Challis & Butler, 1968}. Chloride is a normal com-the gut, dietary nitrate is partially secreted via the salivary glands into the mouth, where anent of the stomach fluid, and thiocyanate is present in saliva. about 20% is reduced to nitrite by bacteria (Spiegelhalder et a/., 1976; Tannenbaum et a/., 1874, 1976). Recent investigations by Tannenbaum et af, (1978) have indicated that nitrite may also be formed in the gut by heterotrophic nitrification from ammonia. The practical relevance of this nitrite source is, however, uncertain.