Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox Tobacco-specific nitrosamines: A literature review Evangelia Konstantinou a , Foteini Fotopoulou a , Athanasios Drosos a , Nektaria Dimakopoulou a , Zoi Zagoriti a , Athanasios Niarchos a , Dimitra Makrynioti b , Dimitrios Kouretas c , Konstantinos Farsalinos a , George Lagoumintzis a,* , Konstantinos Poulas a,** a Department of Pharmacy, Laboratory of Molecular Biology and Immunology, University of Patras, Patras, Greece b Department of Optics & Optometry, School of Health and Caring Professions, University of Applied Sciences (T.E.I. of Western Greece), Patras, Greece c Department of Biochemistry-Biotechnology, School of Health Sciences, University of Thessaly, Viopolis, Larissa, 41500, Greece ARTICLE INFO Keywords: e-liquids e-cigarette Nitrosamines Tobacco ABSTRACT Cigarette smoke is a complex mixture of chemicals, including several tobacco-specific nitrosamines (TSNA). Most TSNA are formed in tobacco during the post-harvest period, while a number are produced when a cigarette is burned. Considerable evidence supports the role of TSNA important causative factors for cancers of the lung, pancreas, esophagus, and oral cavity in people who use tobacco products. Of the known TSNA, nicotine-derived nitrosamine ketone (NNK) and N-nitrosonornicotine (NNN) are the most carcinogenic. Other TSNA include N′- nitrosoanatabine (NAT) and N-nitrosoanabasine (NAB). New tobacco products (e.g., e-cigarettes) designed to attract consumers who are concerned about the health effects of tobacco have been appearing on the market. Several studies have reported that certain TSNA have been detected in the replacement liquids and vapour of e- cigarettes, but the levels are generally considerably lower than in tobacco cigarettes. Additionally, the FDA recently announced its intention to regulate TSNA in e-cigarettes, cigar tobacco and pipe tobacco. With the rise of new technologies for reducing the use of tobacco products—such as e-cigarettes— to evaluate exposure levels to these harmful chemicals over time, researchers will be monitoring levels of TSNA in the body as a result of the use of these devices. 1. Introduction Smoking is a serious addiction and is the leading cause of lung, pancreatic and oesophageal cancer, as well as other related preventable diseases such as blindness (Wu et al., 2003; Hecht, 1998; Polosa et al., 2017a,b; Asfar et al., 2015). This is because tobacco smoke contains numerous mutagens and carcinogens, such as polycyclic aromatic hy- drocarbons (PAHs) and tobacco-specific nitrosamines (TSNAs), which are the leading causes of human cancer (Zhang et al., 2003). Smoking cessation is a desirable outcome for many people who want to eliminate the associated cancer risk (Polosa et al., 2017a,b). However, other forms of nicotine delivery, such as electronic cigarettes (ECs), are a more realistic compromise solution that can reduce exposure to tobacco smoke toxicants (Trtchounian et al., 2010). Many studies have shown that ECs contain TSNAs, but in lower amounts than conventional ci- garettes and at levels comparable to pharmaceutical nicotine products (Stepanov et al., 2006; Farsalinos et al., 2015a,b). The main tobacco specific nitrosamines, which are present in tobacco and to which we will refer in the present study, are nitrosoanabasine (NAB), nitrosoanatabine (NAT), 4-(methylnitrosamino)-1-(3-pyridyl)-1-buta- none (NNK) and nitrosonornicotine (NNN). Other nitrosamines include 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), 4-(methylni- trosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL) and 4-(methylni- trosamino)-4-3-pyridyl) butyric acid (iso-NNAC) (Moldoveanu et al., 2017). Many of the aforementioned compounds have tumourigenic and mutagenic activities (Hecht, 1998). In the current study, we will ana- lyse the effects of TSNAs in humans and how the use of ECs can reduce these effects. 1.1. Conventional cigarettes vs. ECs It is known that smoking can lead to preventable disease or even death, and therefore, efforts should be made to promote its cessation (Thornton et al., 2008; Asfar et al., 2018). ECs are thought to be an effective alternative that can lead to the cessation of tobacco cigarette use. ECs are alternative smokeless smoking devices, and as many re- searchers have proven, they are much safer because the dangerous compounds in conventional cigarettes are 9–450 times lower in EC https://doi.org/10.1016/j.fct.2018.05.008 Received 29 January 2018; Received in revised form 2 May 2018; Accepted 4 May 2018 * Corresponding author. Department of Pharmacy, University of Patras, 26504 Rio-Patras, Greece. ** Corresponding author. Department of Pharmacy, University of Patras, 26504 Rio-Patras, Greece. E-mail addresses: glagoum@upatras.gr (G. Lagoumintzis), kpoulas@upatras.gr (K. Poulas). Food and Chemical Toxicology 118 (2018) 198–203 Available online 08 May 2018 0278-6915/ © 2018 Elsevier Ltd. All rights reserved. T