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Smokeless tobacco products expose adult and youth tobacco users to various addictive and carcinogenic constituents that can cause long-term nicotine dependence and oral cancers. In this study, nicotine, benzo[a]pyrene (B[a]P), N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acetaldehyde, crotonaldehyde, formaldehyde, moisture, and pH levels in 16 smokeless tobacco products were measured on a wet-weight basis (wwb). In addition, change in analytical variability with increasing replicate measurements was assessed. Total nicotine in the products varied from 6.2 to 35.5 mg/g. The percentage of total nicotine in the unprotonated form ranged from 0.1 to 62%; whereas, product moisture varied from 7.4 to 57%. The quantities of harmful and potentially harmful constituents (HPHCs) range from 0.46 to 179.9 ng/g for B [a]P, 270-12206 and 81-20716 ng/g for NNN and NNK, respectively, and 0.33-6.85 and 0.13-5.67 μg/g for acetaldehyde and formaldehyde, respectively. This study shows wide variation in smokeless tobacco product HPHC quantities. The results also show that analytical variability stabilizes after seven replicate measurements., (Published by Elsevier Inc.)

The tobacco-specific N -nitrosamines 4-( N -nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N '-nitrosonornicotine (NNN) always occur together and exclusively in tobacco products or in environments contaminated by tobacco smoke. They have been classified as "carcinogenic to humans" by the International Agency for Research on Cancer. In 1998, we published a review of the biochemistry, biology and carcinogenicity of tobacco-specific nitrosamines. Over the past 20 years, considerable progress has been made in our understanding of the mechanisms of metabolism and DNA adduct formation by these two important carcinogens, along with progress on their carcinogenicity and mutagenicity. In this review, we aim to provide an update on the carcinogenicity and mechanisms of the metabolism and DNA interactions of NNK and NNN.

Objective: To compare tobacco-specific nitrosamines (TSNAs) measured in saliva according to different types of tobacco smoked in a sample of smokers of the city of Barcelona (Spain)., Methods: We used data from a cross-sectional study of a sample of the adult smoking population of Barcelona, Spain in 2013-2014 (n = 165). We classified smokers in five groups according to the type of tobacco smoked: a) manufactured cigarettes only, b) roll-your-own (RYO) cigarettes only, c) dual smokers (both manufactured and RYO cigarettes), d) manufactured plus other types of tobacco products different from RYO and e) other types of tobacco products different from manufactured and RYO cigarettes. We calculated the geometric mean (GM) and geometric standard deviation (GSD) of TSNAs concentration in saliva (pg/mL), including N'-nitroaonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) according to the five tobacco groups. We also described all TSNAs concentration in each tobacco group stratified by the number of cigarettes smoked per day., Results: Smokers from the RYO cigarette group had higher TSNAs concentration than smokers from the manufactured cigarette group: 13 pg/mL vs 4.9 pg/mL of NNN, 1.9 pg/mL vs 1.7 pg/mL in NNK and 1.1 pg/mL vs 0.9 pg/mL of NNAL. There were significant differences in NNN concentrations between smokers of RYO vs manufactured cigarettes. The higher the number of cigarettes smoked, the higher the TSNAs concentrations. After adjusted by number of cigarettes smoked, there were not statistically significant differences in TSNAs between RYO and manufactured cigarettes., Conclusions: Our data shows that RYO cigarette is at least as hazardous as manufactured cigarettes. Regulating RYO tobacco prices could be an effective strategy to control tobacco use., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The evolution of the levels of tobacco-specific N-nitrosamines (TSNA), N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mainstream (MS) cigarette smoke is investigated based on smoke and tobacco chemistry data of cigarette brands sold by Philip Morris International (PMI) between 2000 and 2014. A total of 315 cigarette samples representing a wide range of product and design characteristics manufactured by PMI between 2008 and 2014 were analyzed and compared to a previously published dataset of PMI brands manufactured in 2000. The data indicate that there is a substantial reduction of NNN and NNK levels in tobacco fillers and MS cigarette smoke per mg of tar and per mg of nicotine using Health Canada Intense (HCI) machine-smoking regime. This observed reduction in NNN and NNK levels in MS cigarette smoke is also supported by the downward trend observed on NNN and NNK levels in USA flue-cured Virginia and Burley tobacco lots from 2000 to 2014 crops, reflecting effectiveness of measures taken on curing and agricultural practices designed to minimize TSNA formation in tobacco., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

This study reports on variation in the yields of N-nitrosonornicotine (NNN) and (4-methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) from the mainstream smoke of cigarette brands and describes factors affecting this variation. Yields of NNN and NNK from smoke and tobacco filler, which is blended and cut tobacco filled in a cigarette tube, together with cigarette design parameters, were measured for 11 commercial cigarette brands, which were available in Japan from 2009 to 2013. The ranges of the relative standard deviations (RSDs) for NNN from the smoke of each brand were 5.0%-29.9% under International Organization for Standardization (ISO) and 6.3%-26.3% under Health Canada Intense (HCI) smoking regime. When these RSDs were compared with those of tar, nicotine, and carbon monoxide yields in each brand, they were found to be much higher for all of the brands under the HCI, and higher for most of the brands under the ISO smoking regime. In addition, the RSDs of NNN and NNK in smoke were mostly higher than those of KY3R4F which was manufactured in a single batch. It was identified that variation in NNN yields from tobacco filler mainly contribute to variation in NNN yields from smoke., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The objective of this work was to characterize trends over time in urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) among cigarette smokers in the US. We identified 35 studies presenting data that either reported, or could be converted to, common units of total urinary NNAL excretion as pmol/mg creatinine. The studies spanned 18years, reported urinary NNAL excretion estimates for 61 defined populations, and included a combined total of 3941 study participants. Analyses show that urinary NNAL excretion trends downward with study publication year, and the trend is statistically significant. The trend does not appear to be accounted for by a reduction in cigarettes smoked per day by study participants over the same time period. This trend is consistent with reductions in tobacco specific nitrosamine (TSNA) levels in both cigarette tobacco filler and mainstream cigarette smoke observed over the past decade and with efforts by the tobacco industry and the agricultural community to reduce levels of TSNAs in tobacco and cigarette smoke., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

A nicotine part-filter method can be applied to estimate smokers' mouth level exposure (MLE) to smoke constituents. The objectives of this study were (1) to generate calibration curves for 47 smoke constituents, (2) to estimate MLE to selected smoke constituents using Japanese smokers of commercially available cigarettes covering a wide range of International Organization for Standardization tar yields (1-21mg/cigarette), and (3) to investigate relationships between MLE estimates and various machine-smoking yields. Five cigarette brands were machine-smoked under 7 different smoking regimes and smoke constituents and nicotine content in part-filters were measured. Calibration curves were then generated. Spent cigarette filters were collected from a target of 50 smokers for each of the 15 brands and a total of 780 filters were obtained. Nicotine content in part-filters was then measured and MLE to each smoke constituent was estimated. Strong correlations were identified between nicotine content in part-filters and 41 out of the 47 smoke constituent yields. Estimates of MLE to acetaldehyde, acrolein, 1,3-butadiene, benzene, benzo[a]pyrene, carbon monoxide, and tar showed significant negative correlations with corresponding constituent yields per mg nicotine under the Health Canada Intense smoking regime, whereas significant positive correlations were observed for N-nitrosonornicotine and (4-methylnitrosoamino)-1-(3-pyridyl)-1-butanone., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Tobacco use is a major cause of preventable morbidity and mortality globally. Tobacco products, including smokeless tobacco (ST), generally contain tobacco-specific N-nitrosamines (TSNAs), such as N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK), which are potent carcinogens that cause mutations in critical genes in human DNA. This review covers the series of biochemical and chemical transformations, related to TSNAs, leading from tobacco cultivation to cancer initiation. A key aim of this review is to provide a greater understanding of TSNAs: their precursors, the microbial and chemical mechanisms that contribute to their formation in ST, their mutagenicity leading to cancer due to ST use, and potential means of lowering TSNA levels in tobacco products. TSNAs are not present in harvested tobacco but can form due to nitrosating agents reacting with tobacco alkaloids present in tobacco during certain types of curing. TSNAs can also form during or following ST production when certain microorganisms perform nitrate metabolism, with dissimilatory nitrate reductases converting nitrate to nitrite that is then released into tobacco and reacts chemically with tobacco alkaloids. When ST usage occurs, TSNAs are absorbed and metabolized to reactive compounds that form DNA adducts leading to mutations in critical target genes, including the RAS oncogenes and the p53 tumor suppressor gene. DNA repair mechanisms remove most adducts induced by carcinogens, thus preventing many but not all mutations. Lastly, because TSNAs and other agents cause cancer, previously documented strategies for lowering their levels in ST products are discussed, including using tobacco with lower nornicotine levels, pasteurization and other means of eliminating microorganisms, omitting fermentation and fire-curing, refrigerating ST products, and including nitrite scavenging chemicals as ST ingredients. [ABSTRACT FROM AUTHOR]

Nitrate accumulation in tobacco (Nicotiana tabacum L.) leaf, particularly in the burley (BU) type, is a reservoir for the generation of nitrosating agents responsible for the formation of tobacco-specific nitrosamines (TSNAs). TSNAs are mainly produced via the nitrosation of alkaloids occurring during the curing of tobacco leaves. Additional formation of TSNAs may also occur during tobacco storage, leaf processing and in some circumstances via pyrosynthesis during combustion. Two TSNA species, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN) are found in the tobacco products and have been documented to be animal carcinogens. A previous study showed that decreasing the accumulation of nitrate in tobacco leaf via the overexpression of a deregulated form of nitrate reductase is efficient to reduce the production of TSNAs. We pursue in finding another molecular genetic target to lower nitrate in BU tobacco. Suppressing expression or knocking-out CLCNt2 has a direct impact on leaf nitrate and TSNA reduction in cured leaves without altering biomass. This study provides now a straight path toward the development of new commercial tobacco varieties with reduced TSNA levels by breeding of variants deficient in active CLCNt2 copies. [ABSTRACT FROM AUTHOR]

According to the World Health Organization, the consumption of tobacco products is the single largest cause of preventable deaths in the world, exceeding the total aggregated number of deaths caused by diseases such as AIDS, tuberculosis, and malaria. An important element in the evaluation of the health risks associated with the consumption of tobacco products is the assessment of the internal exposure to the tobacco constituents responsible for their addictive ( e.g. nicotine) and carcinogenic ( e.g. N -nitrosamines such as NNN and NNK) properties. However, the assessment of the serum levels of these compounds is often challenging from an analytical standpoint, in particular when limited sample volumes are available and low detection limits are required. Currently available analytical methods often rely on complex multi-step sample preparation procedures, which are prone to low analyte recoveries and ex-vivo contamination due to the ubiquitous nature of these compounds as background contaminants. In order to circumvent these problems, we report a facile and highly sensitive method for the simultaneous quantification of nicotine, cotinine, NNN, and NNK in serum samples. The method relies on a simple “one pot” liquid-liquid extraction procedure and isotope dilution ultra-high pressure (UPLC) hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass spectrometry. The method requires only 10 μL of serum and presents a limit of quantification of 0.02 nmol (3000 pg/mL) nicotine, 0.6 pmol (100 pg/mL) cotinine, 0.05 pmol NNK (10 pg/mL), and 0.06 pmol NNN (10 pg/mL), making it appropriate for pharmacokinetic evaluations. [ABSTRACT FROM AUTHOR]

Highlights: [•] We gathered 35years of published data of NNK and NNN levels in cigarette smoke. [•] We augmented these data with internal, unpublished data from Philip Morris USA Inc. [•] The data suggest TSNA levels have not increased in cigarette smoke over time. [•] The data suggest TSNA levels have declined in cigarette smoke over the past 10years. [ABSTRACT FROM AUTHOR]