Nitrosamines (or more formallyN-nitrosamines) areorganic compounds produced by industrial processes.[1][better source needed] Thechemical structure isR2N−N=O, where R is usually analkyl group.[2] Nitrosamines have anitroso group (NO+) that are "probable human carcinogens",[3] bonded to a deprotonatedamine. Most nitrosamines arecarcinogenic in animals.[4] A 2006 systematic review supports a "positive association betweennitrite and nitrosamine intake andgastric cancer, between meat and processed meat intake and gastric cancer andoesophageal cancer, and between preserved fish, vegetable and smoked food intake and gastric cancer, but is not conclusive".[5]
Metabolic activation of the nitrosamineNDMA converts it to the alkylating agentdiazomethane[6]
The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions.[7][8] They usually are produced by the reaction ofnitrous acid (HNO2) and secondary amines, although othernitrosyl sources (e.g.N 2O 4,NOCl,RONO) have the same effect:[9]
HONO + R2NH → R2N-NO + H2O
The nitrous acid usually arises from protonation of anitrite. This synthesis method is relevant to the generation of nitrosamines under some biological conditions.[10] The nitrosation is also reversible, particularly in acidic solutions ofnucleophiles.[11]Aryl nitrosamines rearrange to give apara-nitroso aryl amine in theFischer-Hepp rearrangement.[12]
With regards to structure, theC2N2O core of nitrosamines is planar, as established byX-ray crystallography. The N-N and N-O distances are 132 and 126 pm, respectively indimethylnitrosamine,[13] one of the simplest members of a large class of N-nitrosamines.
Nitrosamines are not directly carcinogenic. Metabolic activation is required to convert them to thealkylating agents that modify bases in DNA, inducing mutations. The specific alkylating agents vary with the nitrosamine, but all are proposed to featurealkyldiazonium centers.[14][6]
In 1956, two British scientists, John Barnes and Peter Magee, reported that a simple member of the large class of N-nitrosamines,dimethylnitrosamine, produced livertumours in rats. Subsequent studies showed that approximately 90% of the 300 nitrosamines tested werecarcinogenic in a wide variety of animals.[15]
A common way ordinary consumers are exposed to nitrosamines is through tobacco use and cigarette smoke.[14]Tobacco-specific nitrosamines also can be found in Americandip snuff,chewing tobacco, and to a much lesser degree,snus (127.9 ppm for American dip snuff compared to 2.8 ppm in Swedish snuff or snus).[16]
Nitroso compounds react withprimary amines in acidic environments to formnitrosamines, which human metabolism converts to mutagenicdiazo compounds. Small amounts of nitro and nitroso compounds form during meatcuring; the toxicity of these compoundspreserves the meat againstbacterial infection. After curing completes, the concentration of these compounds appears to degrade over time. Their presence in finished products has been tightly regulated since several food-poisoning cases in the early 20th century,[17] but consumption of large quantities of processed meats can still cause a slight elevation ingastric andoesophageal cancer risk today.[18][19][20][21]
The effects of nitroso compounds vary dramatically across the gastrointestinal tract, and with diet. Nitroso compounds present in stool do not induce nitrosamine formation, because stool has neutralpH.[23][24]Stomach acid catalyzes nitrosamine compound formation and is the main location of the reaction during digestion.[25]
The formation process is inhibited when amine concentration is low (e.g. a low-protein diet or no fermented food). The process may also be inhibited in the case of highvitamin C (ascorbic acid) orerythorbic acid[26] concentration (e.g. high-fruit diet).[27][28][29] However, when 10% of the meal is fat, the effect reverses, and ascorbic acid markedly increases nitrosamine formation.[25][30] Vitamin C and erythorbic acid are already commonly used in the meat industry because they enhance the binding of nitrite to myoglobin, encouraging the formation of the desired pink color.[31]
The USFood and Drug Administration published guidance about the control of nitrosamine impurities in medicines.[32][33]Health Canada published guidance about nitrosamine impurities in medications[34] and a list of established acceptable intake limits of nitrosamine impurities in medications.[35]
Altkofer, Werner; Braune, Stefan; Ellendt, Kathi; Kettl-Grömminger, Margit; Steiner, Gabriele (2005). "Migration of nitrosamines from rubber products - are balloons and condoms harmful to the human health?".Molecular Nutrition & Food Research.49 (3):235–238.doi:10.1002/mnfr.200400050.PMID15672455.
Proctor, Robert N. (2012).Golden Holocaust: Origins of the Cigarette Catastrophe and the Case for Abolition. Berkeley: University of California Press.ISBN9780520950436.OCLC784884555.
^abTricker, A.R.; Preussmann, R. (1991). "CarcinogenicN-Nitrosamines in the Diet: Occurrence, Formation, Mechanisms and Carcinogenic Potential".Mutation Research/Genetic Toxicology.259 (3–4):277–289.doi:10.1016/0165-1218(91)90123-4.PMID2017213.
^Anselme, Jean-Pierre (1979). "The Organic Chemistry ofN-Nitrosamines: A Brief Review".N-Nitrosamines. ACS Symposium Series. Vol. 101. pp. 1–12.doi:10.1021/bk-1979-0101.ch001.ISBN0-8412-0503-5.
^Vogel, A. I. (1962).Practical Organic Chemistry (3rd ed.). Impression. p. 1074.
^Krebs, Bernt; Mandt, Jürgen (1975). "Kristallstruktur desN-Nitrosodimethylamins".Chemische Berichte.108 (4):1130–1137.doi:10.1002/cber.19751080419.
^abHecht, Stephen S. (1998). "Biochemistry, Biology, and Carcinogenicity of Tobacco-SpecificN-Nitrosamines".Chemical Research in Toxicology.11 (6):559–603.doi:10.1021/tx980005y.PMID9625726.
^Gregory N. Connolly; Howard Saxner (August 21, 2001). "Informational Update Research on Tobacco Specific Nitrosamines (TSNAs) in Oral Snuff and a Request to Tobacco Manufacturers to Voluntarily Set Tolerance Limits For TSNAs in Oral Snuff".{{cite journal}}:Cite journal requires|journal= (help)
^Lee, L; Archer, MC; Bruce, WR (October 1981). "Absence of volatile nitrosamines in human feces".Cancer Res.41 (10):3992–4.PMID7285009.
^Kuhnle, GG; Story, GW; Reda, T; et al. (October 2007). "Diet-induced endogenous formation of nitroso compounds in the GI tract".Free Radic. Biol. Med.43 (7):1040–7.doi:10.1016/j.freeradbiomed.2007.03.011.PMID17761300.
^Combet, E; El Mesmari, A; Preston, T; Crozier, A; McColl, K. E. (2010). "Dietary phenolic acids and ascorbic acid: Influence on acid-catalyzed nitrosative chemistry in the presence and absence of lipids".Free Radical Biology and Medicine.48 (6):763–771.doi:10.1016/j.freeradbiomed.2009.12.011.PMID20026204.
^Pappenberger, Günter; Hohmann, Hans-Peter (2013). "Industrial Production of l-Ascorbic Acid (Vitamin C) and d-Isoascorbic Acid".Biotechnology of Food and Feed Additives.143:143–188.doi:10.1007/10_2013_243.
^Hecht, Steven S.; Borukhova, Anna; Carmella, Steven G. "Tobacco specific nitrosamines" Chapter 7; of "Nicotine safety and toxicity" Society for Research on Nicotine and Tobacco; 1998 - 203 pages
