Chemical studies on tobacco smoke. 52. Reaction of nicotine and sodium nitrite: formation of nitrosamines and fragmentation of the pyrrolidine ring

Hecht, Stephen S.; Chen, Chi hong B.; Ornaf, Raphael M.; Jacobs, Eugenia; Adams, John; Hoffmann, Dietrich

doi:10.1021/jo00395a017

Cited by 66 publications

(33 citation statements)

References 19 publications

(44 reference statements)

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“…A mechanism to explain the in situ formation of surface-bound TSNAs measured in this study is proposed below. The predominance of NNA is consistent with results by Hecht et al (25), who showed that NNA was the main product of nicotine nitrosation in acidic NaNO 2 solution (pH 5.4-5.9). We hypothesize that similar processes occur on indoor surfaces exposed to ambient HONO.…”

Section: Resultssupporting

confidence: 91%

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Formation of carcinogens indoors by surface-mediated reactions of nicotine with nitrous acid, leading to potential thirdhand smoke hazards

Sleiman

Gundel

Pankow

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

365

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This study shows that residual nicotine from tobacco smoke sorbed to indoor surfaces reacts with ambient nitrous acid (HONO) to form carcinogenic tobacco-specific nitrosamines (TSNAs). Substantial levels of TSNAs were measured on surfaces inside a smoker's vehicle. Laboratory experiments using cellulose as a model indoor material yielded a >10-fold increase of surface-bound TSNAs when sorbed secondhand smoke was exposed to 60 ppbv HONO for 3 hours. In both cases we identified 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal, a TSNA absent in freshly emitted tobacco smoke, as the major product. The potent carcinogens 4-(methylnitrosamino)-1-(3-pyridinyl)-1-butanone and N-nitroso nornicotine were also detected. Time-course measurements revealed fast TSNA formation, with up to 0.4% conversion of nicotine. Given the rapid sorption and persistence of high levels of nicotine on indoor surfaces-including clothing and human skin-this recently identified process represents an unappreciated health hazard through dermal exposure, dust inhalation, and ingestion. These findings raise concerns about exposures to the tobacco smoke residue that has been recently dubbed "thirdhand smoke." Our work highlights the importance of reactions at indoor interfaces, particularly those involving amines and NO x /HONO cycling, with potential health impacts.exposure | indoor environment | nitrosamine | nitrogen oxides | heterogeneous chemistry

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Section: Resultssupporting

confidence: 91%

“…An alternative mechanism, similar to that proposed by Hecht et al (25) is presented in SI Text and leads to identical products. The acidity of the aqueous surface layer [pH ∼5-6 in the absence of HONO (29)] plays a key role by inducing the formation of NO þ and affecting regioselectivity.…”

Section: Resultsmentioning

confidence: 60%

Formation of carcinogens indoors by surface-mediated reactions of nicotine with nitrous acid, leading to potential thirdhand smoke hazards

Sleiman

Gundel

Pankow

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

365

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“…5 are shown in eq. [5]. The spectrum assigned to It is very similar to that recorded in a nonhydroxylic solvent (8).…”

Section: Nature Of the Acid Speciessupporting

confidence: 52%

Kinetic and equilibrium study of the ring opening of 2-aryl-1-methyl-1-pyrrolinium ions in aqueous solution

McClelland¹,

Seaman²

1987

Can. J. Chem.

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. Can. J. Chem. 65, 1689 (1987). Ultraviolet spectral and kinetic measurements are reported for the transformations in aqueous solution undergone by the cyclic iminium ion, the 2-aryl-1-methyl-1-pyrrolinium ion I+. In solutions with pH < 9.5 this ion equilibrates with a ring-opened hydrated form, the protonated 4-methylaminobutyrophenone SH'. The concentration of the latter at equilibrium is small, but it can be observed using nuclear magnetic resonance spectroscopy. A kinetic analysis provides a measure of the I' + SH+ equilibrium constant. Values range from 0.06 for 4-methoxyphenyl to 0.17 for 3-chlorophenyl. In acid solutions (pH < 5) the equilibration is slow (half-life = 20 min for phenyl) and pH independent. Above pH 5 this process becomes first order in hydroxide ion. In strongly basic solutions a neutral species is formed in equilibrium with these two cations, with pK(app) for the transformation cations + neutral + H' ranging from 11.8 to 11.3. Spectral arguments imply that the base species is the ring-opened 4-methylaminobutyrophenone S, with less than ten percent of the pseudobase of I' present.ROBERT A. MCCLELLAND et N. ESTHER SEAMAN. Can. J. Chem. 65, 1689 (1987) On a mesure les spectres ultraviolets et la cinetique des transformations que subit I'ion cyclique iminium, I'ion aryl-2 methyl-I pyrrolinium I+, dans des solutions aqueuses. Dans des solutions de,pH < 9 3 , cet ion s'equilibre avec la forme hydratie qui est ouverte, soit la methylamino-4 butyrophinone protonee SH'. A l'equilibre, la concentration de ce compose est faible; toutefois, on peut l'observer par rmn. Une analyse cinetique fournit une mesure de la constante d'iquilibre I+ + SH'. Les valeurs de cette constante varient de 0,06 pour le methoxy-4 phenyle i 0,17 pour le chloro-3 phenyle. Dans des solutions acides (pH < 5), I'equilibre est lent (demi-vie .= 20 min pour le phinyle) et ne depend pas du pH. Au-dessus d'un pH de 5, ce processus devient du premier ordre en ions hydroxydes. Dans des solutions fortement basiques, il se forme une espkce neutre qui est en Cquilibre avec ceux deux cations; le pK(app) pour la transformation des cations + forme neutre + H+ varie de 11,8 B 11,3. Les arguments bases sur les spectres indiquent que I'espkce basique est la methylamino-4 butyrophenone B chaine ouverte S ; il y aurait moins de dix pourcent de la pseudobase de I+ qui serait prisente.[Traduit par la revue]The reversible addition of hydroxide ion to heterocyclic cations is well documented (1). The pseudobase product of this reaction is usually also the tetrahedral adduct of an intramolecular nucleophilic addition to a carbonyl (or acyl) group. Assuch, the pseudobase frequently exists in equilibrium with a ring-opened form, a phenomenon which has been termed "ringchain tautomerism" (I). As part of a program of study of tetrahedral intermediates (2,3) we have investigated a series of cyclic iminium ions I+. This study was prompted by suggestions that nitrosamines derived from nicotine are forming by way of iminium salts, one of which has a st...

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“…1 is a tobacco-specific nitrosamine formed by nitrosation of the tobacco alkaloids nornicotine and nicotine (Hu et al, 1974;Hecht et al, 1978). It is the most prevalent strongly carcinogenic nitrosamine in smokeless tobacco products, such as chewing tobacco and snuff, and occurs in substantial quantities in cigarette smoke (Hoffmann et al, 1994).…”

Section: Nnnmentioning

confidence: 99%

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Upadhyaya¹,

Zimmerman

Hecht³

2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:N-Nitrosonornicotine (NNN) is present in significant quantities in tobacco and tobacco smoke and is believed to play an important role as a cause of cancer in people who use tobacco products. Biomarkers of NNN uptake in humans such as urinary metabolites would be useful for assessing cancer risk. Previous studies, carried out almost exclusively in rodents, have characterized urinary metabolites of NNN, but none of these would be suitable as a biomarkers of NNN uptake in humans. Therefore, we studied NNN metabolism in the patas monkey. Monkeys were treated intravenously with

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Chemical studies on tobacco smoke. 52. Reaction of nicotine and sodium nitrite: formation of nitrosamines and fragmentation of the pyrrolidine ring

Cited by 66 publications

References 19 publications

Formation of carcinogens indoors by surface-mediated reactions of nicotine with nitrous acid, leading to potential thirdhand smoke hazards

Formation of carcinogens indoors by surface-mediated reactions of nicotine with nitrous acid, leading to potential thirdhand smoke hazards

Kinetic and equilibrium study of the ring opening of 2-aryl-1-methyl-1-pyrrolinium ions in aqueous solution

Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

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