Human nitrosamines

Inhibition of nitrosation is generally accompHshed by substances that compete effectively for the active nitrosating iatermediate. /V-Nitrosamine formation in vitro can be inhibited by ascorbic acid [50-81-7] (vitamin C) and a-tocopherol [59-02-9] (vitamin E) (61,62), as well as by several other classes of compounds including pyrroles, phenols, and a2iridines (63—65). Inhibition of iatragastric nitrosation ia humans by ascorbic acid and by foods such as fmit and vegetable juices or food extracts has been reported ia several instances (26,66,67). 

Toxicity. Many /V-nitrosamines are toxic to animals and cells in culture (4,6—8,88). /V-Nitrosodimethy1amine [62-75-9] (NDMA) is known to be acutely toxic to the Hver in humans, and exposure can result in death (89). Liver damage, diffuse bleeding, edema, and inflammation are toxic effects observed in humans as a result of acute and subacute exposure to NDMA. These effects closely resemble those observed in animals dosed with NDMA (89,90). 

There is insufficient evidence to unequivocally link nitrosamine exposure to elevated risk for human cancer (159). There are, however, a number of specific cases, especially with respect to the tobacco-related nitrosamines, in which exposure to V/-nitroso compounds is of concern. The strongest evidence in this context is probably that relating to oral cancer rates among habitual users of smokeless tobacco (snuff). Oral cancer rates among this group are significantly elevated over those of nonusers, and /V-nitrosonornicotine, and 4-(methylnitrosamino)-l-(3-pyridinyl)-l-butanone [64091 -91 both of... 

R. D. Kimbrough, in P. N. Magee, ed., Banbury Report 12 Nitrosamines and Human Cancer, Cold Spring Harhon Laboratory, Cold Spring Harbor, 1982, pp. 25-34. 

Nitrosamines. Findings that secondary amines, so common in mbber accelerators, can react with NO species to form the suspected human carcinogens, nitrosamines, have prompted active programs to develop alternative accelerators. Neither primary nor tertiary amines form stable nitrosamines and they are generally considered to be safe materials. The abiHty of each type of common mbber accelerator class to form nitrosamines has been summarized and depends on their 1°, 2°, or 3° nature (30). 

The formation of nitrosamines, e.g. n-nitrosodiedianolamine, which are possible human carcinogens, can occur in synthetic or semi-synthetic fluids which contain a nitrite salt and diethanolamine or triethanolamine. 

The symposium upon which this volume is based was organized at a turning point in nitrosamine research. Almost all types of commercial products have been tested for volatile nitrosamines, and there have been a number of outstanding accomplishments of combined university-gov-emment-private industry actions to lower or eliminate volatile nitrosamines in those products found to be contaminated. However, there is still a major gap of knowledge with regard to compounds that are not amenable to analysis by gas chromatography, and this is clearly a frontier of current research. There are also many important questions regarding chemistry, mechanism of action, and relation to human disease whose answers lie in the future of research in this field. 

Recently nitrosamines have attracted attention because of their marked carcinogenic activity in a wide variety of animal species Q, ). Nitrosamines are likely to be carcinogens in man as well human exposure to these compounds is by ingestion, inhalation, dermal contact and vivo formation from nitrite and amines Nitrite and amines react most rapidly at an acidic pH A variety of factors, however, make nitrosation a potentially important reaction above pH 7 these include the presence of microorganisms, and the possibilities of catalysis by thiocyanate, metals and phenols, and of transnitrosation by other nitroso compounds. 

There have been some preliminary reports of nitrosamines being found in normal humans, in blood (, 35), and in urine (36). The precise origin of these substances, if their presence is confirmed, is not fully understood at this time. 

An attempt to estimate human daily impact of N nitroso compounds is shown in Table I. The apparent intake from food of preformed nitrosamines is comparatively low, at least in these surveys of a Western diet in England (3). The Intake directly to the respiratory tract from smoking could be somewhat larger. However, if the blood levels reported are confirmed as correct, then inputs of up to 700 meg per day of at least N nitrosodimethylamine (NDMA) may be calculated, based on pharmacokinetic considerations of data obtained in animals and extrapolated to man. It should be emphasized that no information is available at present on nitrosamide intake or in vivo formation, largely because of analytical limitations. 

Excluding tobacco and tobacco smoke (lf f3), the largest known human exposure to N-nitrosamines is in the industrial sector (4). The area or process air samples containing the largest amount of nitrosamines are in a tire factory, NMOR at the 250 yg/m level (5, a leather tannery, NDMA at the 47 ]xg/wr level (jy, and a rocket fuel factory, NDMA at the 36 yg/m level (7). 

The complex pattern of human exposure to environmental N-nitroso compounds is summarized. Recent results are given in three areas, where a significant reduction of human exposure has been achieved after elucidation of its causes 1, N-Nitrosodimethylamine in beer. 2, Volatile N-nitrosamines in baby nipples and pacifiers and 3. occupational exposure in the rubber industry. 

A migration test was developed to simulate human exposure patterns. 5 g of rubber material was cut into 1-2 mm stripes and then immersed in 20 ml of standard test solution of artificial saliva (4.2 g NaHC03, 0.2 g K2CO3, 0.5 g NaCl, 0.03 g NaNO, ad 1000 ml with aqua dest.j. After 24 h incubation at 40 C volatile nitrosamines were determined in an aliquot and determined after destination with a standard technique (GC-TEA-method). 

Yet, except for specific cases of acute poisoning (2,10, 11), and thus mostly of liver damage, there appears to be no reliably documented evidence that there are any cases of human cancer which can be unambiguously associated with an antecedent exposure to nitrosamines In the Western world (12). 

Naturally Occurring or Endogenously Produced Nitrosamines as Human Carcinogens. 

If the concepts and facts presented in this paper are correct, a major kind of human cancer in many regions of the world, cancer of the stomach, is due to a type of nitroso compound, a nitrosoureido derivative, even though not a nitrosamine It is quite certain that the formation of such compounds can be blocked by vitamin C and vitamin E, as well as by some other substances such as gallates Thus, the primary prevention of cancer caused by nitroso compounds is readily accomplished through an adequate Intake of such harmless inhibitors with every meal from infancy onwards ... 

Other environmental properties of interest are those that govern movement of chemicals, for these properties can influence not only the possibility of human exposure but also the lifetime and fate of the chemical. Clearly, if a nitrosamine is formed in, or introduced into, the soil and stays there, it presents little threat to man, and its lifetime will depend on the chemical or microbiological properties of the soil. If it should move to the surface and volatilize into the atmosphere, on the other hand, there will exist the possibility of human exposure via inhalation and also the possibility of vapor-phase photodecomposition. If a nitrosamine were to leach from soil into water, it could perhaps be consumed in drinking water alternatively, exposure of the aqueous solution to sunlight could provide another opportunity for photodecomposition. 

Unfortunately, not all combinations of chemical additives in water-based fluids are completely compatible, and side reactions leading to various byproducts have been noted. The best known of these side reactions is the reaction between the corrosion inhibitor nitrite and the emulsifiers di- and triethanolamine (7) to form N-nitrosodiethanolamine (NDE1A), a nitrosamine reported to have carcinogenic activity (8, 9, 10). In fact, most nitrosamines are carcinogenic, and no animal species which has been tested is resistant to nitrosa mine-induced cancer. Although there is no direct evidence that firmly links human cancer to nitrosamines, it is unlikely that humans should be uniquely resistant. 

Thiocyanate, an anion normally secreted in human saliva, also catalyzes the nitrosation of amines by nitrite (22). The mechanism of the reaction is thought to proceed through the formation of nitrosylthiocyanate and subsequent reaction with amine to form the nitrosamine. This reaction, originally investigated to assess the... 

Bartsch, H., Camus, A.-M. and Malaveille, C. (1976). Comparative mutagenicity of N-nitrosamines in a semi-solid and in a liquid incubation system in the presence of rat or human tissue fractions. Mutation Res. 37 149-162. 

NOC constitute a large category of genotoxic chemical carcinogens occurring in human diet and are known to induce cancer in experimental animals. Nitrosamines are generally found in foods since they are more stable than nitrosamides. Some NOC precursors do not act directly but must be converted to other nitrosation species. 

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. 

---