N-Nitrosamine in tobacco

Brunnemann KD, Masaryk J, Hoffmann D. 1983. Role of tobacco stems in the formation of N-nitrosamines in tobacco and cigarette mainstream and sidestream smoke. J Agric Food Chem 31 1221-1224. 

Aromatic and Cyclic Secondary Amines and N-Nitrosamines in Tobacco and Tobacco Smoke... 

N-Nitrosamines in Tobacco, Tobacco Smoke, and Tobacco Substitute Smoke... 

Hecht, S. S., 1982, N-nitrosamines in tobacco carcinogenesis, in "Banbury Report 12 Nitrosamines and Human Cancer,"... 

Nonvolatile Nitrosamines In Tobacco Smoke. Although there are more than 10 million exsmokers in the U.S.A., 53 million adults continue to smoke cigarettes and an additional 10 million still smoke cigars or pipes (39). The cigarette smokers are exposed to about 10 ng of volatile nitrosamines, 20-40 ng of NDELA and, most importantly, to 1-10 pg of tobacco specific N-nitros-amines with each cigarette smoked (Table IV). Similar quantities of the TSNA are found in sidestream smoke. The quantities of TSNA in the smoke are dependent on nitrate, nitrite, tobacco alkaloids and on NNN, NNK and NAT in the tobacco itself (31)>... 

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

N-nitrosation by oxides of nitrogen at neutral and alkaline pH has an important bearing on assessing human exposure to N-nitroso compounds, particularly as this route has been almost totally disregarded in the past. Those analytical techniques which have relied on a basic pH to inhibit nitrosation need further study to ensure the validity of the findings. For the same reason, measurements of N-nitrosamines in engine exhausts and tobacco smoke are likely to be particularly artifact prone. 

Brunnemann KD, Genoble L, Hoffmann D. 1985. N-Nitrosamine in chewing tobacco an international comparison. J Agric Food Chem 33 1178-1181. 

Hoffman D,Adams JD, Brunnemann KD. 1987. A critical look at N-nitrosamines in environmental tobacco smoke. Toxicol Lett 35 1-8. 

Janson C, Paccou A, and Osterdahl B-G (2003) Analysis of tobacco-specific N-nitrosamines in snuff by ethyl acetate extraction and fiquid chromatography-tandem mass spectrometry. Journal of Chromatography A 1008 135-143. 

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). 

N-Nitrosamines are formed during processing and smoking of tobacco products. Proteins, agricultural chemicals and alkaloids in tobacco products serve as major precursors for volatile, nonvolatile, and tobacco-specific nitrosamines (Figure 1). In this review we will summarize the progress achieved in respect to tobacco nitrosamines since the last ACS symposium in Boston in June of 1978 (J ). Additional papers will review the metabolism of cyclic N-nitrosamines, including that of N -nitrosonornicotine 1) and the correlation between tobacco and alcohol consumption and cancer of the upper alimentary tract (J ). 

NT087 Hoffmann, D., M. V. Djordjevic, A. Rivenson, E. Zang, D. Desai, and S. Amin. A study of tobacco carcinogenesis. LI. Relative potencies of tobacco-specific N-nitrosamines as inducers of lung tumours in A/J mice. Cancer Lett 1993 71(1-3) 25-30. 

Amin, and R. Hoffmann. A study of tobacco carcinogenesis XLIV. Bioassay in A/] mice of some N-nitrosamines. Cancer Lett 1989 47(1-2) 111-114. 

Since nicotine is the major precursor to NNN in tobacco and tobacco smoke, the reaction of nicotine with sodium nitrite was studied to provide information on formation of other tobacco specific nitrosamines, especially NNK and NNA, which could arise by oxidative cleavage of the l -2 bonds or l -5 bond of nicotine followed by nitrosation (26). The reaction was investigated under a variety of conditions as summarized in Table I. All three nitrosamines were formed when the reaction was done under relatively mild conditions (17 hrs, 20 ). The yields are typical of the formation of nitrosamines from tertiary amines (27). At 90 , with a five fold excess of nitrite, only NNN and NNK were detected. Under these conditions, both NNK and NNA gave secondary products. NNK was nitrosated a to the carbonyl to yield 4-(N-methyl-N-nitrosamino)-2-oximino-l-(3-pyridyl)-1-butanone while NNA underwent cyclization followed by oxidation, decarboxylation and dehydration to give l-methyl-5-(3-pyridyl)pyrazole, as shown in Figure 4. Extensive fragmentation and oxidation of the pyrrolidine ring was also observed under these conditions. The products of the reaction of nicotine and nitrite at 90 are summarized in Table II. 

Brunnemann, K. D., Adams, J. and Hofj nann, D., "Non-volatile N-Nitrosamines Analysis in Tobacco and Tobacco Smoke by HPLC-TEA", Abs. 31st Tobacco Chemists Research Conference, Greensboro, N.C., 1977. 

Substances carcinogenic to animals (polycyclic hydrocarbons and nicotine-derived N-nitrosamines) have been identified in tobacco smoke condensates from cigarettes, cigars and pipes. Polycyclic hydrocarbons are responsible for the hepatic enzyme induction that occurs in smokers. 

Brunnemann, K.D., J. Qi, G.N. Connolly, and D. Hoffmann Effects of storage on the levels of tobacco-specific nitrosamines in oral moist snuff tobacco 55th Tobacco Science Research Conference, Program Booklet and Abstracts, Vol. 55, Paper No. 40, 2001, pp. 43 44. 

Burton, H.R., N.K. Dye, and L.P. Bush Distribution of tobacco constituents in tobacco leaf tissue. 1. Tobacco-specific nitrosamines, nitrate, nitrite, and alkaloids J. Agr. 

Caldwell, W.S., J.M. Greene, G.P. Dobson, and J.D. deBethizy Intragastric nitrosation of nicotine is not a significant contributor to nitrosamine exposure in Tobacco smoking and nutrition Influence of nutrition on tobacco-associated health risks, edited by J.N. Diana and W.A. Pryor, Ann. N.Y. Acad. Sci. 686 (1992) 213-228, see www.rjrtdocs.com 514892394 -2401. 

Gilhnan, LG. Jr, J.E. Eossett, N. Finkel, and R.D. Bereman Investigations into a rapid method for determining tobacco-specific A-nitrosamines and volatile nitrosamines in sidestream tobacco smoke using LC/ MS/MS with positive ion electrospray 56th Tobacco Science Research Conference, Program Booklet and Abstracts, Vol. 56, Paper No. 36, 2002, p. 41. 

Mitacek, E.J., K.D. Brunnemann, D. Hoffmann, T. Limsila, M. Suttajit, N. Martin, and L.S. Caplan Volatile nitrosamines and tobacco-specific nitrosamines in the smoke of Thai cigarettes A risk factor for lung cancer and a suspected risk factor for liver cancer in Thailand. Carcinogenesis 20 (1999) 133-137. 

Certain compounds in tobacco are known to cause cancer. Among these are the N-nitrosamines and certain hydrocarbons. The alcohol extract of the chewing variety of tobacco tested mutagenic in a Salmonella typhimurium test (Shah et al. 1985). Administration of the extract in mice resulted in an increased incidence of lung and liver tumors. 

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