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4 Nicotine
Pages 89-154

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From page 89...
... . As with combustible tobacco cigarettes, machine-derived nicotine yield of 89
From page 90...
... Nevertheless, e-liquid nicotine concentration may be a determinant of systemic nicotine exposure. Here, the committee reviews current evidence related to the range of nicotine concentrations in commercially available e-cigarettes, whether cartridges of first-generation and closed-tank e-cigarettes or refill liquids used in other open-system e-cigarettes.
From page 91...
... Nicotine content ranged from undetected to 20.5 mg/g. The measured nicotine concentrations were 5.8–41.7 percent lower than the labeled nicotine content.
From page 92...
... Finally, the choice of preferred nicotine strength may be influenced, in part, by the characteristics of the e-cigarette used, including the power of the device. NICOTINE CONCENTRATION IN E-CIGARETTE EMISSIONS Nicotine concentration in e-cigarette emissions is an important determinant of systemic exposure to nicotine, and likely directly affects the abuse liability of e-cigarettes.
From page 93...
... The implications for variation or lack thereof in nicotine concentration per puff between combustible tobacco cigarette use versus e-cigarette use are not clear. However, this study shows that at a power of 5.7 W, e-cigarettes deliver less nicotine per puff than combustible tobacco cigarettes.
From page 94...
... reported that cartridges from three brands with various nicotine concentrations and refill liquids had pH ranging from 7.4 to 9.7. This study found wide variability in nicotine partitioning between the unprotonated and protonated states of nicotine in the e-liquid and aerosols.
From page 95...
... found elevated rates of nicotine absorption and maximum plasma nicotine concentration when participants used a strawberry e-liquid (18 mg/ml nicotine, 50/50 glycerol/PG, pH 8.29) compared with a tobacco e-liquid (18 mg/ml nicotine, 50/50 glycerol/PG, pH 9.10)
From page 96...
... In a clinical study, maximum plasma nicotine concentrations from use of three formulations of P3L, namely, 50, 80, and 150 µg/puff P3L, were 9.7, 11.2, and 9.8 ng/ml, respectively (Teichert et al., 2017)
From page 97...
... . Nicotine addiction develops as a neurobiological adaptation to chronic nicotine exposure (HHS, 2014)
From page 98...
... While nicotine exerts diverse pharmacological effects in the peripheral nervous system (e.g., stimulation in the trachea that may enhance the reinforcing effect of selfadministration) , it is generally believed that the actions of nicotine in the central nervous system are pivotal to reinforcing tobacco use (HHS, 1988)
From page 99...
... As discussed above and in detail later in this chapter under Exposure to Nicotine and Nicotine Derivatives from E-Cigarettes, e-cigarettes can deliver nicotine levels comparable to combustible tobacco cigarettes (St.Helen et al., 2016a) , and the plasma nicotine profile can resemble that of combustible tobacco cigarette smokers (Dawkins et al., 2016; Ramoa et al., 2016; St.Helen et al., 2016a; Wagener et al., 2017)
From page 100...
... . During daily smoking, typical peak blood nicotine concentrations range from 19 to 50 ng/ml, while typical trough concentrations range from 10 to 37 ng/ml; depending on how the cigarette is smoked, each cigarette increases blood nicotine concentra
From page 101...
... Nonetheless, as discussed later, e-cigarette users also administer nicotine throughout the day, likely leading to persistent systemic exposure to nicotine and associated neuroadaptation and tolerance to pharmacological effects of nicotine observed in combustible tobacco cigarette smokers. Biotransformation of Nicotine The metabolism of nicotine has been reviewed in depth elsewhere (Benowitz et al., 2009; Hukkanen et al., 2005)
From page 102...
... quantitatively the most important nicotine metabolite in mammals. About 70–80 percent of nicotine is metabolized through the cotinine pathway.
From page 103...
... . Based on measurement of blood nicotine levels after administration of a known dose, average total clearance of nicotine is about 1,200 ml/ minute.
From page 104...
... . The ratio of 3HC/cotinine in urine is also used as a proxy of CYP2A6 nicotine metabolism, with forms including unconjugated, glucuronidated, or total (unconjugated + glucuronidated)
From page 105...
... Menthol, a flavorant used in foods, toothpaste, combustible tobacco cigarettes, and e-cigarettes, moderately inhibits CYP2A6. Metabolism of nicotine to cotinine and glucuronidation of nicotine were inhibited after smoking mentholated cigarettes compared with after smoking non-mentholated cigarettes (Benowitz et al., 2004; Hukkanen et al., 2005)
From page 106...
... . Japanese are also known to have higher frequencies of null and reduced activity CYP2A6 alleles, resulting in slower nicotine metabolism.
From page 107...
... Other factors that lead to variation in nicotine metabolism include pathological conditions, medications, and tobacco smoke itself. Hepatic pathologies impact nicotine metabolism.
From page 108...
... . Other Effects of Nicotine Carcinogenesis Concerns about the potential carcinogenic risk of nicotine is important due to the growing prevalence of use of alternative forms of nicotine delivery such as e-cigarettes and other non-combustible tobacco products, as well as smokers who attempt to quit through extended use of NRT.
From page 109...
... and elevated risk of these cancers in users of smokeless tobacco products (IARC, 2012)
From page 110...
... Smokeless tobacco products used in Scandinavia have lower levels of TSNAs compared with traditional smokeless tobacco products and combustible tobacco products (HHS, 2014; Stepanov et al., 2006) , but deliver as much nicotine as combustible tobacco cigarettes (Digard et al., 2013)
From page 111...
... , and studies of smokeless tobacco users, which show increase in risk of cancers related to TSNA exposure but not an increase in risk of other cancers (Luo et al., 2007; Timberlake et al., 2017) , indicate that it is unlikely that nicotine exposure acts as a tumor promoter to increase the risk of cancer in humans.
From page 112...
... Some animal studies have reported increased platelet activation from acute exposure to nicotine, whereas long-term exposure in rodents leads to reduced platelet activation. Studies of NRT and smokeless tobacco do not show increased platelet activation following nicotine intake.
From page 113...
... . Nevertheless, based on studies showing significant decline in inflammatory markers after switching from smoking to transdermal nicotine and similar levels of inflammatory markers between smokeless tobacco users and non-tobacco users, nicotine is not believed to be the main determinant of an inflammatory response in smokers (HHS, 2010a)
From page 114...
... In short, how fast is nicotine from e-cigarettes absorbed, and what is the systemic exposure to nicotine? These questions can be answered through clinical studies that measure biomarkers of nicotine exposure after e-cigarette use, including pharmacokinetic parameters such as the maximum blood nicotine concentration (Cmax)
From page 115...
... . Comparisons of nicotine exposure from e-cigarettes with other inhaled forms of nicotine such as combustible tobacco cigarettes or nicotine inhalers can inform questions of the relative addictiveness of e-cigarettes or their ability to serve as a substitute for combustible tobacco cigarettes among smokers who want to quit (Benowitz et al., 2009)
From page 116...
... 116 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 4-2  Summary of Clinical Studies Examining Nicotine Exposure from E-Cigarette Use Study Characteristics Reference Study Product Nicotine Content Sample Size Clinical Studies with E-Cigarette–Naïve Smokers Bullen et al., 2010 Ruyan V8 16-mg cartridge  8 Eissenberg, 2010 NPRO by NJOY or 16-mg cartridge 16 Hydro by Crown (both brands) Seven Vansickel et al., NPRO by NJOY or NPRO: 18-mg 32 2010 Hydro by Crown cartridge; Hydro, Seven 16-mg cartridge Vansickel et al., Vapor King 18-mg/ml cartridge 20 2012 Flouris et al., 2013 Giant by Nobacco 11-mg/ml cartridge 15 G.P.
From page 117...
... ; 5 minutes were 30 minutes apart after last session: 7.4 (5.1) ng/ml median = 11 puffs; plasma cotinine: usual brand cigarette: no puffs varied between increased significantly significant difference in participants; took immediately after and 1 plasma cotinine between equivalent puffs to be hour after e-cigarette use e-cigarette and cigarette use equivalent to two usual brand cigarettes based on a ratio of 1.5 cigarettes to e-cigarette nicotine absorption ratio 10 puffs in 5 minutes plasma nicotine: N/A followed by ad lib use in baseline: 1.6 (0.3)
From page 118...
... 118 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 4-2 Continued Study Characteristics Reference Study Product Nicotine Content Sample Size Nides et al., 2014 King Bold by NJOY 26-mg cartridge 25 Hajek et al., 2015 Green Smoke 2.4% cartridge (24  6 mg/ml) Oncken et al., 2015 Joye eGo-C 18-mg/ml e-liquid 20 with tobacco or tobacco and menthol Yan and D'Ruiz, blu e-cigs 5 different 23 2015 formulations: 3 with 24 mg/ml and 2 with 16 mg/ml
From page 119...
... ng/ml 50-puff standardized plasma nicotine: one Marlboro Gold King session, 5-second puff, baseline: range of mean: Size: baseline: 0.03 (0.12) 30-second interval,1-hour 0.01 (0.05)
From page 120...
... 120 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 4-2 Continued Study Characteristics Reference Study Product Nicotine Content Sample Size D'Ruiz et al., 2015 Not specified (but 5 different 23 same study as Yan formulations: 3 with and D'Ruiz, 2015) 24 mg/ml and 2 with 16 mg/ml Antoniewicz et al., eGo XL 3.7-V battery 12 mg/ml e-liquid 16 2016 with dual-coil CE5 atomizer Lopez et al., 2016 eGO 3.3-V battery 4 different e-liquids: 16 with 1.5-Ω Smoktech 0, 8, 18, or 36 mg/ml cartomizer nicotine Walele et al., 2016 e-cigarette prototype 2 mg/ml nicotine 12 (flavored and unflavored)
From page 121...
... (range of mean, SD) 1-hour ad lib session plasma nicotine: range end of ad lib: 29.2 (10.86)
From page 122...
... 16 mg/ml 9 Stiles et al., 2017 Vuse Solo 14-, 29-, and 36-mg 45 cartridge Clinical Studies with Experienced E-Cigarette Users Vansickel and usual brands average of e-liquid:  8 Eissenberg, 2013 17.6 mg/ml; range: 9–24 mg/ml Dawkins and SKYCIG 18-mg cartridge 14 Corcoran, 2014
From page 123...
... minutes up to 10 minutes of ad plasma nicotine: Cmax: usual brand cigarette: Cmax: lib use of e-cigarette or 14 mg: 3.01 ng/ml; 29 17.98 ng/ml; Tmax: 8.13 cigarette; 30 minutes mg: 4.67 ng/ml; 36 mg: minutes; nicotine gum: chewing nicotine gum 5.36 ng/ml; Tmax: 14 mg: Cmax: 5.26; Tmax: 50.88 min 27.35 minutes; 29 mg: 21.83 minutes; 36 mg: 24.17 minutes 10-puff standardized plasma nicotine: N/A session, 30 seconds baseline: 2 (0) ng/ml between puffs (mean, SEM)
From page 124...
... mg/ml (mean, SD) ; range: 6–24 mg/ml Wagener et al., 2017 usual brands 2nd generation: 20 22.3 (7.5)
From page 125...
... device ng/ml 60-minute ad lib session plasma nicotine: 10 N/A minutes after first puff: 8.59 (7.52) ng/ml (mean, SD)
From page 126...
... Hajek et al., 2017 usual brand and range: 16–48 mg/ml 11 8 other common brands Spindle et al., 2017 usual battery with usual e-liquid: 18.9 29 1.5-Ω SmokTech (5.9) mg/ml (mean, cartomizer SD)
From page 127...
... 5-minute ad lib session plasma nicotine: Cmax: usual tobacco cigarette: 7.5 (5.0)
From page 128...
... Participants took 10 puffs at two separate times during each session, as described before. The participants' usual tobacco cigarette brand significantly increased plasma nicotine concentration 5 minutes after the first puff, while NPRO, Hydro, and sham smoking did not alter blood nicotine levels.
From page 129...
... By comparison, average baseline plasma nicotine concentration was 0.03 ng/ml and increased to 14.42 ng/ml after smoking one cigarette. At the end of the 1-hour ad lib session, average plasma nicotine concentration ranged from 13.70 to 22.42 ng/ml with the e-cigarettes compared with 29.23 ng/ml with the combustible tobacco cigarettes.
From page 130...
... Average plasma nicotine concentration increased significantly from baseline to 5 minutes after the first puff during both laboratory sessions. Average plasma nicotine increased from 4.2–8.2 ng/ml at session one and 4.2–9.3 at session two.
From page 131...
... . Five minutes after the first puff, plasma nicotine concentrations for the 0, 8, 18, and 36 mg/ml e-liquids were 3.8 ng/ml, 8.8 ng/ml, 13.2 ng/ml, and 17.0 ng/ml, respectively.
From page 132...
... Plasma AUC from 0 to 55 minutes was significantly higher with the combustible tobacco cigarette during the first administration, indicating higher systemic nicotine exposure from combustible tobacco cigarettes compared with e-cigarettes. It should be noted that plasma nicotine Cmax of 7.3 and 9.0 ng/ml from smoking the Marlboro cigarette are lower than typical Cmax from smoking combustible tobacco cigarettes.
From page 133...
... The change from baseline for the 0, 8, 18, and 36 mg/ml nicotine e-liquids was −4.4 ng/ml, 11.1 ng/ml, 18.1 ng/ml, and 24.1 ng/ml. This study also demonstrated that e-cigarettes can elevate blood nicotine levels in experienced users within the range of that of combustible tobacco cigarettes.
From page 134...
... This study demonstrated that the shape of the plasma nicotine concentration-time curve was, on average, similar to that of combustible tobacco cigarettes, albeit with a lower average Cmax compared with combustible tobacco cigarettes. However, there was variation, including some profiles that resembled that of smokeless tobacco, that is, slow rise to peak and sustained plasma nicotine levels, which are indicative of buccal absorption.
From page 135...
... Plasma nicotine concentration 5 minutes after the 10th puff was 7.3 ng/ml for the second-generation e-cigarettes and 17.5 ng/ml for the third-generation e-cigarettes. The study showed that third-generation devices are able to mimic the plasma nicotine concentration of combustible tobacco cigarettes, likely due to their high power levels.
From page 136...
... Plasma nicotine concentrations after the 90-minute ad lib session were 16.5 ng/ml (strawberry) , 11.3 ng/ml (tobacco)
From page 137...
... Switching Studies Studies in which tobacco cigarette smokers are given e-cigarettes to use instead of combustible tobacco cigarettes can be used to compare daily nicotine intake from combustible tobacco cigarettes and e-cigarettes, and answer whether e-cigarettes can effectively replace combustible tobacco cigarettes as a source of nicotine. The committee identified eight publications in which biomarkers of nicotine exposure were reported.
From page 138...
... The results of this study indicate that there was no significant difference in daily nicotine intake among smokers who switched completely to e-cigarettes, those who used both e-cigarettes and combustible tobacco cigarettes, and those who only smoked combustible tobacco cigarettes. In addition, the study also showed that e-cigarette–naïve smokers can titrate their nicotine intake with practice.
From page 139...
... The authors of both publications reported changes in nicotine exposure among different groups following a 5-day forced switch from usual brand of tobacco cigarette to exclusive use of commercial e-cigarettes; dual use of commercial e-cigarettes and participants' usual combustible tobacco cigarette; or discontinued use of all tobacco or nicotine products (O'Connell et al., 2016)
From page 140...
... This indicated significant reduction in nicotine exposure during e-cigarette use compared with combustible tobacco cigarette use. Furthermore, saliva cotinine did not differ between day 5 and day 10, indicating that nicotine exposure during e-cigarette use remained constant, albeit at levels lower than combustible tobacco cigarette use.
From page 141...
... On the other hand, the other four studies suggest that some e-cigarettes are ineffective nicotine delivery devices compared with combustible tobacco cigarettes. Other Studies of Nicotine Exposure A few other studies have measured nicotine exposure in long-term e-cigarette users to address the question of whether nicotine exposure from e-cigarettes matches that of combustible tobacco cigarettes.
From page 142...
... This study indicated that while e-cigarette users decrease the nicotine concentration of their e-liquids over time, they consume more e-liquid and maintain a relatively constant daily nicotine intake. The authors concluded that in experienced e-cigarette users enrolled online, cotinine levels were similar to levels usually observed in combustible tobacco cigarette smokers.
From page 143...
... . The study found statistically significant but weak positive correlations between puff duration and plasma nicotine levels after 5 minutes and after 65 minutes.
From page 144...
... SYNTHESIS This chapter reviews the literature on nicotine content in e-cigarette liquids and aerosols, e-liquid pH, nicotine pharmacokinetics and pharmacology, and nicotine exposure from e-cigarettes. The nicotine content of e-cigarettes varies widely among products, with varying degrees of agreement between nicotine content on the label and what is chemically measured.
From page 145...
... Finally, the committee reviewed human studies to examine the nicotine exposure profile of e-cigarettes. Clinical studies of acute nicotine exposure from e-cigarette use in e-cigarette–naïve smokers and experienced e-cigarette users were reviewed, as well as studies of long-term e-cigarette use in combustible tobacco cigarette smokers who switch to e-cigarettes over a study period.
From page 146...
... 2017. Cardiovascular effects of electronic cigarettes.
From page 147...
... 2016. Self-titration by experienced e-cigarette users: Blood nicotine delivery and subjective effects.
From page 148...
... 2014. Nicotine content of electronic cigarettes, its release in vapour and its consistency across batches: Regulatory implications.
From page 149...
... 2015. Nicotine intake from electronic cigarettes on initial use and after 4 weeks of regular use.
From page 150...
... 2016. Effects of electronic cigarette liquid nicotine concentration on plasma nicotine and puff topography in tobacco cigarette smokers: A preliminary report.
From page 151...
... 2016. Tobacco consumption and toxicant exposure of cigarette smokers us ing electronic cigarettes.
From page 152...
... 2017. The influence of a mouthpiece-based topography measurement de vice on electronic cigarette user's plasma nicotine concentration, heart rate, and subjec tive effects under directed and ad libitum use conditions.
From page 153...
... 2013. Electronic cigarettes: Effective nicotine delivery after acute administration.


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