No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Free-Base and Protonated Nicotine in Electronic Cigarette Liquids and Aerosols
Abstract
As with other tobacco aerosols, nicotine delivery from e-cigarettes (ECIG) depends on the total nicotine and its partitioning between free-base (Nic) and protonated (NicH+) forms. Previous studies of ECIG nicotine emissions have generally reported "nicotine yield" without attention to whether the methods employed resulted in quantification of the total nicotine or only one of its forms, making reported results difficult to compare across studies, or to evaluate against reported blood exposure. This study reports a convenient solvent extraction method for determining total nicotine and its partitioning in ECIG liquids and aerosols by gas chromatography. Commercial ECIG liquids and aerosols were analyzed and it was found that most of the nicotine was in the Nic form, with aerosols exhibiting higher Nic concentration than the parent liquids. Apparent pH was found to correlate with nicotine partitioning and can provide a useful indirect measure when chromatography is unavailable. Finally, labeled ECIG liquid nicotine concentration in commercial products was often inconsistent with measured nicotine.
... Te solvent extraction method is the most widely used, and there are two main strategies: one involves using water to extract free nicotine from the sample and subsequently employing an appropriate organic solvent to extract free nicotine from the water for determination [24,[29][30][31][32][33][34]. Te other approach involves initially performing organic solvent extraction and then utilizing water to wash and purify the organic extract [35][36][37][38]. ...
... Tis method relies on the fact that free nicotine and certain protonated nicotine compounds are initially extracted into the water. When both aqueous and organic phases are present, protonated nicotine remains in the aqueous phase because it readily dissolves in water, while free nicotine can be selectively extracted as it is more soluble in the organic phase, thus achieving purifcation [24,[29][30][31][32][33][34]. Another method is to extract free nicotine with an organic solvent frst and then purify the organic extract with water for analysis. ...
... El-Hellani et al. studied the determination of free nicotine content in e-cigarette liquid by dissolving 300 μL of the liquid to be measured in 5 mL water, adding 5 mL toluene, shaking for 30 min, stratifying, and then detecting the nicotine content in toluene, which was recorded as the content of free nicotine to be measured [29]. Since free nicotine had a good solubility in toluene and water, the sample also contained other acids, alkaline, and other components. ...
The accurate determination of the free nicotine content in cigarette smoke is crucial for assessing cigarette quality, studying harm and addiction, and reducing tar levels. Currently, the determination of free nicotine in tobacco products primarily relies on methods such as pH calculation, nuclear magnetic resonance (NMR) spectroscopy, headspace solid-phase microextraction (HS-SPME), and traditional solvent extraction. However, these methods have limitations that restrict their widespread application. In this study, the free nicotine in cigarette smoke was directly extracted by using cyclohexane according to the traditional solvent extraction method and detected via gas chromatography-mass spectrometry. Compared with the traditional two-phase solvent extraction, our experimental method is easy to execute and eliminates the influence of aqueous solutions on the original distribution of nicotine in cigarette smoke particulate matter. Furthermore, the presence of protonated nicotine in tobacco does not affect the determination. Compared with HS-SPME and NMR spectroscopy, our approach, which involves solvent extraction followed by chromatographic separation and instrumental detection, offers simplicity, improved precision, better detection limits, and reduced interference during the instrumental detection stage. The standard addition recoveries in the conducted experiment ranged from 96.2% to 102.5%. The limit of detection was 2.8 μg/cig, and the correlation coefficient R2 for the quadratic regression of the standard curve exceeded 0.999. The relative standard deviation for parallel samples was between 1.7% and 3.4% (n = 5), fully meeting the requirements for the determination of free nicotine in cigarette smoke. Analysis of cigarette samples from 38 commercially available brands revealed that the content of free nicotine ranged from 0.376 to 0.716 mg/cig, with an average of 0.540 mg/cig, and free nicotine accounted for 39.1%–88.8% of the total nicotine content.
... The most widespread approach is aerosol condensation on a filter. 29,31 However, the filter material is known to influence pH and equilibrium among nicotine forms. 29 Two types of filters, glass fibers (Cambridge filter 44 mm diameter (ø), Borgwaldt, Hamburg, Germany) and quartz fibers (QM-B 42 mm ø, Whatmann, Sigma-Aldrich, Saint-Quentin-Fallavier, France), were tested to select the appropriate material. ...
... 29,31 However, the filter material is known to influence pH and equilibrium among nicotine forms. 29 Two types of filters, glass fibers (Cambridge filter 44 mm diameter (ø), Borgwaldt, Hamburg, Germany) and quartz fibers (QM-B 42 mm ø, Whatmann, Sigma-Aldrich, Saint-Quentin-Fallavier, France), were tested to select the appropriate material. The impact of the filter fibers was assessed by spiking 300 μL of homemade e-liquids directly on the filter, followed by filter extraction with 5 mL of ultrapure water and agitation for 10 minutes. ...
... 5. α fb Estimation Using the Liquid−Liquid Extraction Method. The protocol was adapted from previous studies published by El-Hellani et al. and Gholap et al. 28,29 As described in those studies, this method relies on the selectivity of organic solvents for free-base nicotine. Briefly, two consecutive extraction steps (denoted "E1" and "dE1" extracts) were performed by the addition of an organic solvent. ...
Given that nicotine salts are a growing market, methods are needed to characterize nicotine forms in e-cigarette vaping products. By lowering the free-base nicotine fraction (αfb) in favor of protonated forms, the addition of organic acids to the e-liquid mix greatly modulates nicotine pharmacokinetics and improves vapers' craving. This research investigated (1) the performance of pH measurement, liquid-liquid extraction (LLE), and acid/nicotine molar ratio calculation methods for αfb estimation in 6 nicotine benzoate and nicotine salicylate e-liquids and (2) nicotine protonation in the aerosol post vaporization. Aerosols were generated with a JUUL device and another mod-pod on a vaping machine to assess device effects. E-liquid and aerosol samples were then analyzed after further analytical optimization of previous methods and careful consideration of biases. Globally, performances were comparable between methods. αfb accounted for less than 5% of nicotine content regardless of experimental conditions. αfb were consistent between e-liquids and aerosols irrespective of e-cigarette devices. Hence, e-liquids are adequate surrogates for aerosols, facilitating the establishment of regulations. pH measurement is one of the most used methods and enables the establishment of relative scales for e-liquid classification but lacks automation possibility. Until now, the extent of sample dilution remained arbitrary. The dilution factor was fixed at 10, as usually achieved, since no effect of dilution was noted. pH values ranged from 5.3 to 6.3 in accordance with the literature. By contrast, LLE relies on the specificity of organic solvent for free-base nicotine extraction, causing discrepancies in previous studies. Here, the results were similar to αfb values from pH determination. Yet, LLE presented the highest variability and was the most time-consuming protocol. Finally, αfb calculation from molar ratio was the most robust and versatile method. Estimations can be made in silico from reported composition data and/or after liquid chromatography routine analysis.
... Studies have characterized the constituents of JUUL R eliquids and documented the different proportions of propylene glycol (PG) and vegetable glycerin (VG); other constituents include flavorings, nicotine, and benzoic acid (BA) (15)(16)(17)(18)(19)(20). In the presence of BA, nicotine forms a salt, which forms protonated nicotine, rather than free-base nicotine, thereby allowing high levels of nicotine to be inhaled with less irritation or harsh "throat hit" as compared with traditional tobacco cigarettes and earlier generation (first, second, and third) EVP designs (2,17,(20)(21)(22)(23). ...
... Studies have characterized the constituents of JUUL R eliquids and documented the different proportions of propylene glycol (PG) and vegetable glycerin (VG); other constituents include flavorings, nicotine, and benzoic acid (BA) (15)(16)(17)(18)(19)(20). In the presence of BA, nicotine forms a salt, which forms protonated nicotine, rather than free-base nicotine, thereby allowing high levels of nicotine to be inhaled with less irritation or harsh "throat hit" as compared with traditional tobacco cigarettes and earlier generation (first, second, and third) EVP designs (2,17,(20)(21)(22)(23). The literature has conveyed that the presence of nicotinic salts in JUUL R e-liquids maximized nicotine uptake to the blood (8,17,(21)(22)(23)(24). ...
... As noted, the constituents of JUUL R e-liquids include PG-VG, acids, ethanol, flavorings, nicotine, and water (15,16,19,20). Talih et al. (17) reported that the ratio of PG-VG was 30:70-27:73 in both liquid and aerosol for the JUUL R products sold in the USA (17,18). ...
The current fourth generation (“pod-style”) electronic cigarette, or vaping, products (EVPs) heat a liquid (“e-liquid”) contained in a reservoir (“pod”) using a battery-powered coil to deliver aerosol into the lungs. A portion of inhaled EVP aerosol is estimated as exhaled, which can present a potential secondhand exposure risk to bystanders. The effects of modifiable factors using either a prefilled disposable or refillable pod-style EVPs on aerosol particle size distribution (PSD) and its respiratory deposition are poorly understood. In this study, the influence of up to six puff profiles (55-, 65-, and 75-ml puff volumes per 6.5 and 7.5 W EVP power settings) on PSD was evaluated using a popular pod-style EVP (JUUL® brand) and a cascade impactor. JUUL® brand EVPs were used to aerosolize the manufacturers' e-liquids in their disposable pods and laboratory prepared “reference e-liquid” (without flavorings or nicotine) in refillable pods. The modeled dosimetry and calculated aerosol mass median aerodynamic diameters (MMADs) were used to estimate regional respiratory deposition. From these results, exhaled fraction of EVP aerosols was calculated as a surrogate of the secondhand exposure potential. Overall, MMADs did not differ among puff profiles, except for 55- and 75-ml volumes at 7.5 W (p < 0.05). For the reference e-liquid, MMADs ranged from 1.02 to 1.23 μm and dosimetry calculations predicted that particles would deposit in the head region (36–41%), in the trachea-bronchial (TB) region (19–21%), and in the pulmonary region (40–43%). For commercial JUUL® e-liquids, MMADs ranged from 0.92 to 1.67 μm and modeling predicted that more particles would deposit in the head region (35–52%) and in the pulmonary region (30–42%). Overall, 30–40% of the particles aerosolized by a pod-style EVP were estimated to deposit in the pulmonary region and 50–70% of the inhaled EVP aerosols could be exhaled; the latter could present an inhalational hazard to bystanders in indoor occupational settings. More research is needed to understand the influence of other modifiable factors on PSD and exposure potential.
... Yet some consumers still prefer deprotonated nicotine because it behaves differently in the body. The neutrality of the species makes it more bioavailable, allowing higher concentrations to reach active sites in the brain (El-Hellani, et al., 2015). ...
... E-liquid producers have noticed consumer-preferences related to nicotine speciation and have altered the pH of their e-liquids accordingly. The addition of benzoic acid or citric acid to the e-liquid lowers the pH to the point where there is primarily mono-protonated nicotine (El-Hellani, et al., 2015;Jackler & Ramamurthi, 2019). As a result, there are now both "freebase nicotine" (deprotonated) and "nic salts" (mono-protonated) labeled e-liquids on the market, although the abundance of nicotine species is variable (Jackler & Ramamurthi, 2019). ...
... As a result, there are now both "freebase nicotine" (deprotonated) and "nic salts" (mono-protonated) labeled e-liquids on the market, although the abundance of nicotine species is variable (Jackler & Ramamurthi, 2019). El-Hellani, et al. (2015) concluded that freebase nicotine (as opposed to other species) accounted for 18-95% of the total nicotine content depending on the product. Marketed nicotine concentrations also change with speciation. ...
Vaping is the process of inhaling and exhaling an aerosol produced by an e-cigarette, vape pen, or personal aerosolizer. When the device contains nicotine, the Food and Drug Administration (FDA) lists the product as an electronic nicotine delivery system or ENDS device. Similar electronic devices can be used to vape cannabis extracts. Over the past decade, the vaping market has increased exponentially, raising health concerns over the number of people exposed and a nationwide outbreak of cases of severe, sometimes fatal, lung dysfunction that arose suddenly in otherwise healthy individuals. In this review, we discuss the various vaping technologies, which are remarkably diverse, and summarize the use prevalence in the U.S. over time by youths and adults. We examine the complex chemistry of vape carrier solvents, flavoring chemicals, and transformation products. We review the health effects from epidemiological and laboratory studies and, finally, discuss the proposed mechanisms underlying some of these health effects. We conclude that since much of the research in this area is recent and vaping technologies are dynamic, our understanding of the health effects is insufficient. With the rapid growth of ENDS use, consumers and regulatory bodies need a better understanding of constituent-dependent toxicity to guide product use and regulatory decisions.
... Nicotine can exist in the monoprotonated, deprotonated, and free-base forms; the latter form is absorbed by the epithelial tissues of the body, and such forms depend on the pH of the matrix. Thus, in the tobacco production process, ammonia is added to the tobacco blend to increase the pH, and consequently, the amount of bioavailable nicotine [7]. ...
... For nicotine to be absorbed by epithelial tissues, its structure needs to be in a deprotonated form, which occurs in a basic medium because it has values of pKa1 = 3.12 and pKa2 = 8.02 [7]. Thus, to change the pH to 12, K2CO3 solution was used. ...
The study of cigarette authenticity in Brazil is important due to increasing consumption of contraband cigarettes. Nicotine concentration is an important parameter reflecting the quality of tobacco used in the production of these cigarettes. Simple methods for this determination, which produce reduced waste, are environmentally and industrially important. The nicotine concentration of smuggled cigarette tobacco was determined by the QuEChERS method, requiring some modifications, such as decreasing the volume of the extractor solvent, changes in pH, and removal of the sample hydration step. Quantification was performed by gas chromatography using a flame ionization detector. The Doehlert matrix design was used to optimize the method. The extraction recoveries ranged from 97.5% to 99.6%, with relative standard deviation (RSD) ≤ 2.5% and limits of detection and quantification of 0.6 mg L-1 and 2.5 mg L-1, respectively. The method was sensitive and accurate for the detection and quantification of nicotine. The nicotine concentration in contraband cigarettes was found to be lower than that observed in legal cigarettes. The method was successfully applied to real samples of smuggled and legal cigarettes, providing a robust method for routine analysis and proving the need for more studies on quality control of smuggled cigarettes in Brazil.
... E-liquids contain nicotine in free-base (basic pH~8 to 10) or salt (acidic pH) form (El-Hellani et al., 2015). The form of nicotine in an e-liquid and resultant aerosol influences its bioavailability, which has varied with e-cigarette generation. ...
... The form of nicotine in an e-liquid and resultant aerosol influences its bioavailability, which has varied with e-cigarette generation. E-liquids used in many thirdgeneration and prior e-cigarettes contained 18 to 95% of their total nicotine in free-base form, which tended to have a more harsh throat hit (El-Hellani et al., 2015). The free-base form of nicotine differs from the acidic salt form used in fourth generation e-cigarettes (discussed below). ...
Electronic cigarettes (e-cigarettes) were introduced in the United States in 2007 and by 2014 they were the most popular tobacco product amongst youth and had overtaken use of regular tobacco cigarettes. E-cigarettes are used to aerosolize a liquid (e-liquid) that the user inhales. Flavorings in e-liquids is a primary reason for youth to initiate use of e-cigarettes. Evidence is growing in the scientific literature that inhalation of some flavorings is not without risk of harm. In this review, 67 original articles (primarily cellular in vitro) on the toxicity of flavored e-liquids were identified in the PubMed and Scopus databases and evaluated critically. At least 65 individual flavoring ingredients in e-liquids or aerosols from e-cigarettes induced toxicity in the respiratory tract, cardiovascular and circulatory systems, skeletal system, and skin. Cinnamaldehyde was most frequently reported to be cytotoxic, followed by vanillin, menthol, ethyl maltol, ethyl vanillin, benzaldehyde and linalool. Additionally, modern e-cigarettes can be modified to aerosolize cannabis as dried plant material or a concentrated extract. The U.S. experienced an outbreak of lung injuries, termed e-cigarette, or vaping, product use-associated lung injury (EVALI) that began in 2019; among 2,022 hospitalized patients who had data on substance use (as of January 14, 2020), 82% reported using a delta-9-tetrahydrocannabinol (main psychoactive component in cannabis) containing e-cigarette, or vaping, product. Our literature search identified 33 articles related to EVALI. Vitamin E acetate, a diluent and thickening agent in cannabis-based products, was strongly linked to the EVALI outbreak in epidemiologic and laboratory studies; however, e-liquid chemistry is highly complex, and more than one mechanism of lung injury, ingredient, or thermal breakdown product may be responsible for toxicity. More research is needed, particularly with regard to e-cigarettes (generation, power settings, etc.), e-liquids (composition, bulk or vaped form), modeled systems (cell type, culture type, and dosimetry metrics), biological monitoring, secondhand exposures and contact with residues that contain nicotine and flavorings, and causative agents and mechanisms of EVALI toxicity.
... 72,77 One study, however, that used toluene to extract the nicotine from the e-liquid to remove any possible interferences from the sample being injected onto the GC had a 92.1% recovery. 33 Many of the GC-MS studies described the use of internal standards to aid in the quantification of nicotine which included nicotine-d3 , 38 nicotinium-d3 , 13 naphthalene-d8 , 39 hexadecane, 33 n-heptadecane, 27 and caffeine. 41 For GC-based techniques not involving mass spectrometry, quinoline 35,75 and quinolone 36,37 have been employed as well as n-heptadecane. ...
... however, one study quantified free-base nicotine and nicotine salt in a regular e-liquid. 33 This made reported results difficult to compare across studies. The ±10% deviation from the labelled value has been adopted by AEMSA and BSI; however, many analytical methods allow for higher error, such as ±30% in toxicological validation studies. ...
Electronic cigarettes (ECs) are thought to be less harmful than traditional combustible cigarettes and were originally intended to help smokers quit. Over the past two decades, they have especially gained popularity with the younger generation. To date, there are over 7000 unique e‐liquid flavours available and over 400 different e‐cigarette brands. The accuracy of nicotine strength labelling in e‐liquids was assessed in this work. Twenty‐three studies from around the world were chosen to assess the level and frequency of nicotine mislabelling in 545 e‐liquid products. Nicotine strengths were most commonly mislabelled by between 5 and 20%, with the majority testing lower than what the label indicated. Fifteen European e‐liquids that were assessed were labelled as 20 mg/ml or less, yet when tested they contained more than 20 mg/ml of nicotine. One e‐liquid that was supposed to contain no nicotine in fact contained 23.91 mg/ml of nicotine. Furthermore, the difference between the medians of the available labelled and experimental nicotine concentrations was significant (p < 0.001, Wilcoxon Signed Ranks test). Preliminary studies show that high nicotine levels delivered via aerosol increase the risk for nicotine poisoning and cause airway inflammation. Other EC ingredients, such as flavourings, contribute to EVALI and “popcorn lung”. There is evidence that certain flavourings, such as menthol, reinforce the effects of nicotine and modify drug absorption and metabolism. There is a global need for better quality control in EC products in order to make these safe for consumers.
... The stable nicotine dependence levels over a year in e-cigarette and combined cigarette users compared to those using conventional cigarettes may be attributed to the oxidizing free-based nicotine produced by e-cigarette devices. 24) This form of nicotine, which is highly addictive and readily absorbed into the bloodstream through inhalation, can sustain nicotine dependence by activating nicotine receptors. Additionally, individuals who use e-cigarettes and combined cigarettes often find themselves in settings conducive to nicotine inhalation, such as being around other smokers, 25) thereby maintaining consistent levels of nicotine dependence. ...
... NIC and CAF are hydrophilic compounds possessing too close Log P values (1.17, and -0.07, respectively) [39]. Moreover, NIC (Fig. S1) has two basic nitrogen groups in its chemical structure, pka 1 = 3.12, pka 2 = 8.02, and hence it exists in three forms depending on the pH of the solution [40]. On the other hand, CAF (Fig. S1) contains more than two basic nitrogen groups in its chemical structure (pka 1 = 10.4, ...
The availability of well-established analytical methods is crucial to cope with the fast-ongoing research for the development of new drug delivery formulations. In this work, a rapid highly green chromatographic method was developed for the simultaneous determination of nicotine (NIC) and caffeine (CAF) to be applied for an in-vitro release study from a newly prepared quick mist mouth spray co-formula (QMS), as a complementary synergistic fast-onset relief of cravings during smoking cessation. The chromatographic resolution was accomplished on a cyano column using isocratically delivered (1.0 mL/ min) glycerol: orthophosphoric acid (OPA) (0.2 M) adjusted to pH 3.0 using 0.05 M triethylamine (5:95, v/v) and UV detection at 260 nm. Well resolved peaks of NIC and CAF were eluted at 2.1 and 3.9 min (Rs = 5.64), with linear responses between 0.1 and 20.0 µg/mL and 0.2–40.0 µg/mL, and detection limits of 0.03 and 0.07 µg/mL for NIC and CAF, respectively. The developed method showed good analytical performance (accuracy, precision, robustness, and selectivity) as well as superiority in practicality and ecological profile compared to reported methods applying GAPI, analytical eco-scale, AGREE, BAGI, and whiteness metric tool. The developed method was successfully applied for NIC and CAF determination in their pharmaceutical preparations, and artificial saliva with no significant differences from reported method results (F-test and t-test). Moreover, an in-vitro release study of NIC and CAF from QMS was performed employing the developed method that revealed diffusion-controlled release, compared to mixed diffusion/ polymer chain relaxation for marketed single component formulation, showing the superiority of QMS in reducing drug level fluctuations of NIC and CAF and improving their bioavailability.
Graphical Abstract
... A third form of diprotonated nicotine is another possible structure (Scheme 4). However, there's a lack of evidence to support the existence of the diprotonated nicotine form in any smoking products (El-Hellani et al., 2015;Pankow et al., 2003). ...
Nicotine is a chiral alkaloid; nitrogen-containing organic compound that occurs naturally. (S)-nicotine is extracted from Tobacco plants and used as the key addictive ingredient in many smoking products. Synthetic nicotine has gained the interest of many smoking product manufacturers over the last few decades due to the ease and low cost of manufacturing. Another claimed advantage of synthetic nicotine is the absence of genotoxic impurities that form during the extraction process of nicotine. These impurities are other plant alkaloids, phenolic compounds, and heavy metals. Additionally, the U. S. FDA has implemented new regulations on the quality control of synthetic nicotine. However, only a very few research articles have been published on assessing the complete impurity profile of synthetic nicotine. Therefore, the need to know the composition difference between tobacco-extracted nicotine vs. synthetic nicotine is highly necessary. In this research study, the impurity profile of thirteen different lots of synthetic nicotine was compared with fourteen lots of nicotine extracted from plants using in-house analytical methods. First, the samples were tested for other alkaloids and phenols by reversed-phase High-Performance Liquid Chromatography (HPLC). Second, the chiral purity was analyzed by normal phase HPLC. Third, lead and arsenic content were tested by atomic absorption and fluorescence spectrometry. Fourth, nicotine-specific nitrosamines were tested by LC-MS. The reversed phase HPLC data suggested similar quantities of total impurities in both synthetic and tobacco-extracted nicotine (0.1%). However, synthetic nicotine lacks some impurities such as cotinine, nornicotine, and nicotine-N-oxide. Additionally, the synthetic nicotine lots used in this study have high enantiomeric purity similar to the tobacco-extracted nicotine.
... ECs differ substantially from combustible and HTP products in that they usually do not contain tobacco leaves, but rather a nicotine solution in propylene glycol and glycerol, along with a wide variety of additives intended to regulate pH, impart flavor, and other functions 2 . ECs are also unique in the manipulation of nicotine parameters in their e-liquids: nicotine concentration, nicotine form (freebase or salt), and nicotine source (tobaccoderived or synthetic) 70,71 . As a result, while some tobacco-specific toxicants are absent in EC aerosol, thousands of chemical compounds have been detected in EC aerosol 72 , and toxicants including listed HPHCs such as carbonyls (e.g. ...
In this narrative review, we highlight the challenges of comparing emissions from different tobacco products under controlled laboratory settings (using smoking/vaping machines). We focus on tobacco products that generate inhalable smoke or aerosol, such as cigarettes, cigars, hookah, electronic cigarettes, and heated tobacco products. We discuss challenges associated with sample generation including variability of smoking/vaping machines, lack of standardized adaptors that connect smoking/vaping machines to different tobacco products, puffing protocols that are not representative of actual use, and sample generation session length (minutes or number of puffs) that depends on product characteristics. We also discuss the challenges of physically characterizing and trapping emissions from products with different aerosol characteristics. Challenges to analytical method development are also covered, highlighting matrix effects, order of magnitude differences in analyte levels, and the necessity of tailored quality control/quality assurance measures. The review highlights two approaches in selecting emissions to monitor across products, one focusing on toxicants that were detected and quantified with optimized methods for combustible cigarettes, and the other looking for product-specific toxicants using non-targeted analysis. The challenges of data reporting and statistical analysis that allow meaningful comparison across products are also discussed. We end the review by highlighting that even if the technical challenges are overcome, emission comparison may obscure the absolute exposure from novel products if we only focus on relative exposure compared to combustible products.
... Two complimentary trials. This project is based on designs, procedures, and outcome measures that have been used successfully in numerous peer-reviewed publications and extensive preliminary work on the two study sites [38][39][40][41]. ...
Introduction
Electronic cigarette (EC) use has increased rapidly in the last decade, especially among youth. Regulating nicotine delivery from ECs could help curb youth uptake and leverage EC use in harm reduction yet is complicated by varying device and liquid variables that affect nicotine delivery. Nicotine flux, the nicotine emission rate, is a parameter that incorporates these variables and focuses on the performance rather than the design of an EC. Nicotine flux therefore could be a powerful regulatory tool if it is shown empirically to predict nicotine delivery and subjective effects related to dependence.
Methods and analysis
This project consists of two complementary clinical trials. In Trial I, we will examine the relationship between nicotine flux and the rate and dose of nicotine delivery from ECs, hence, impacting abuse liability. It will also examine the extent to which this relationship is mediated by nicotine form (i.e., freebase versus protonated). At Yale School of Medicine (YSM), study participants will puff EC devices under conditions that differ by flux and form, while arterial blood is sampled in high time resolution. In Trial II, we will assess the relationship between nicotine flux, form, and subjective effects. At the American University of Beirut (AUB), participants will use EC devices with varying nicotine fluxes and forms, while dependency measures, such as the urge to use ECs, nicotine craving, and withdrawal symptoms, will be assessed. We will also monitor puffing intensity and real-time exposure to toxicants.
Ethics and dissemination
The protocol of Trial I and Trial II was approved by YSM and AUB IRBs, respectively. We will disseminate study results through peer-reviewed publications and conference presentations.
Trial registration
NCT05706701 for Trial I and NCT05430334 for Trial II.
... Separation times were not directly reported in many cases but ranged from a few minutes to over 25 minutes in studies where this was mentioned. 7,[12][13][14]17,18,[23][24][25] Plasma spectrochemistry, particularly plasma-based ambient desorption/ionization mass spectrometry (ADI-MS), represents a promising analytical approach for the direct and fast analysis of e-liquid samples. In contrast to classical analytical methods, ADI-MS approaches can provide advantages in terms of time efficiency through rapid screening capabilities. ...
Surface-assisted flowing atmospheric-pressure afterglow mass spectrometry (SA-FAPA-MS) was succesfully used for direct and rapid analysis of e-liquids including qualitative screening and accurate nicotine quantification.
... While the diprotonated form is not considered safely obtainable in eliquids, the ratio of free-base and monoprotonated is often manipulated through the addition of acidic solutions (e.g. benzoic acid) or ammonia 33,46 . The pH of e-liquids is thus a relevant manufacturing concern especially in e-liquids with higher nicotine content 47 , as protonated salts both affect the bioavailability of nicotine and lead to a less harsh sensation 48 , which can allow for tolerance of higher concentrations. ...
Electronic cigarettes are a popular nicotine consumption product that have risen in popularity as an alternative to cigarettes. However, their recent meteoric rise in market size and various controversies have resulted in the analyses of e-liquid ingredients to be focused on powerful laboratory-based slow methods such as chromatography and mass spectrometry. Here we present a complementary technology based on Raman spectroscopy combined with chemometrics as a fast, inexpensive, and highly portable screening tool to detect and quantify the propylene glycol : glycerol (PG : VG) ratio and nicotine content of e-cigarette liquids. Through this, the PG : VG ratio of 20 out of 23 commercial samples was quantified to within 3% of their stated value, while nicotine was successfully quantified to within 1 mg g-1 for 16 out of 23 samples without the need for accurate knowledge of flavonoid composition. High linearity was also achieved when flavours were kept constant. Finally, the limitations of Raman spectroscopy are discussed, and potential solutions are suggested.
... The liquid is used to produce aerosol by heating it in the tank with the help of heating elements (coils), which are surrounded by cotton wool. The aerosol formed contains nicotine, including the free base and protonated form [28], tobacco-specific nitrosamines, if initially present in the liquid [29], or diacetyl and acetyl propionyl [30]. Other compounds are also found in the aerosol, including toluene, ethyl benzene, ortho-, meta-and para-xylene [31], formaldehyde, acetaldehyde, acetone, and propenal [20,32]. ...
Refill liquids for electronic cigarettes are an important area of research due to the health safety and quality control of such products. A method was developed for the determination of glycerol, propylene glycol, and nicotine in refill liquids using liquid chromatography, coupled with tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring (MRM) mode with electrospray ionisation (ESI). Sample preparation was based on a simple dilute-and-shoot approach, with recoveries ranging from 96 to 112% with coefficients of variation < 6.4%. Linearity, limits of detection and quantification (LOD, LOQ), repeatability, and accuracy were determined for the proposed method. The proposed sample preparation and the developed chromatographic method using hydrophilic interaction liquid chromatography (HILIC) were successfully applied for the determination of glycerol, propylene glycol, and nicotine in refill liquid samples. For the first time, the developed method using HILIC-MS/MS has been applied for the determination of the main components of refill liquids in a single analysis. The proposed procedure is rapid and straightforward and is suitable for quick determination of glycerol, propylene glycol, and nicotine. The nicotine concentrations corresponded to the labelling of samples (it varied from <LOD-11.24 mg/mL), and the ratios of propylene glycol to glycerol were also determined.
... It is worth noting that the nicotine salt vaping liquids were not studied in great detail to understand the proportion of nicotine present as a free base (Nic) and as protonated forms (NicH + ); in fact, assumptions were made that the protonated forms were, as freebase, soluble in acetonitrile and methanol, as our methodology is mainly dilution-and not extraction-based. The pH of individual vaping liquids was not measured and not used to estimate ratios of different forms of nicotine in the vaping liquids, as according to a study by El-Hellani et al. [23], the correlation between pH measurements and actual vaping liquid experimental measurements of the ratio of free-base and protonated forms of nicotine is very weak and highly dependent on the presence of other constituents in the matrix. When we compared the deviances in the difference between measured concentrations and labelled concentrations of the two groups of vaping liquids (free-base-nicotine-containing liquids vs. nicotine-salt-containing liquids) using the Brown-Forsythe test of homogeneity of variances (modified Levene's test), the differences were not statistically significant (p-value = 0.051). ...
Electronic cigarettes (e-cigarettes, vaping products) have become increasingly popular, with recent increases in use associated with closed systems delivering higher concentrations of nicotine. Most vaping products designed as an alternative to combustible cigarettes contain nicotine. A number of published studies have examined the reported concentrations of nicotine in vaping liquids (e-liquids) and found discrepancies between labelled and measured levels. Some discrepancy can also be explained by the lack of stability of nicotine in these types of products. Recently, a chemical analysis method for the quantitative determination of low and high levels of nicotine in vaping liquids was developed. This method uses dilution with acetonitrile prior to analysis with gas chromatograph mass spectrometry (GC-MS) in single ion monitoring mode (SIM). The developed method was validated using a laboratory-prepared vaping liquid as well as commercially available, nicotine-free products fortified with nicotine in the laboratory. The method detection limit (MDL) and the limit of quantitation (LOQ) for nicotine were calculated to be 0.002 mg/mL and 0.006 mg/mL, respectively. The newly developed method was applied to quantify nicotine in commercially available vaping liquids of various flavour profiles and across a wide range of nicotine concentrations, including those with nicotine salts. Furthermore, a subset of vaping liquids were analyzed to elucidate nicotine stability in various product subtypes. After a period of six months of accelerated storage to mimic one year, the overall mean percent of the original nicotine concentration remaining in the salt-based vaping products was 85% (minimum 64%, maximum 99%) while in the free-base nicotine products it was 74% (minimum 31%, maximum 106%). Nicotine stability in vaping liquids was found to be influenced by the nicotine form (pH) of formulation and its chemical composition. Non-targeted, qualitative analysis of chemical composition of vaping products showed that most constituents were identified and found to be remaining in the products following stability trials; however, three new compounds were tentatively identified in some vaping liquids at the end of the stability trials. Stability studies and the accurate quantitation of nicotine in vaping products can help inform product standards related to the safety, quality and utility of vaping products as a smoking cessation tool.
... Nicotine has two basic nitrogen groups with pKa values of pKa,1 = 3.12, and pKa,2 = 8.02. Thus, aqueous phase nicotine can come in three forms, namely freebase (Nic), monoprotonated (NicH + ), and biprotonated (NicH2 2+ ) [74]. Under the basic condition (pH > pKa,2), nicotine is mostly in neutral form and volatile, and thus, can evaporate completely from e-cigarette aerosols within a few ten seconds [75]. ...
The E-cigarette has been promoted as an alternative nicotine delivery device with potentially fewer toxicant emissions. The objective of this review is to summarize the current knowledge on the particle size distribution (PSD) of e-cigarette emissions and to analyze the knowledge gaps between existing particle size measurements and the vision toward harm reduction from e-cigarette use. Here, we focus on firstly describing the physical parameters used to characterize PSD, followed by comparing particle size measurement approaches, investigating the factors that impact the PSD of e-cigarette mainstream aerosols, and conclude by linking size distribution to the respiratory dosimetry by demonstrating the modeling results of particle deposition in the respiratory tract. This review calls for a harmonized testing protocol to conduct inter-comparisons and further understand e-cigarette particle sizes. Among the influencing factors investigated, puff topography, operation power, flavorings, PG/VG ratio, and nicotine strength impose a substantial impact on the PSD, but the underlying mechanisms have not yet been fully investigated. The effects brought by the type of device refill and nicotine are yet inconclusive due to lack of evidence. Coil aging has no significant impact on the PSD of e-cigarette aerosols within the coil lifetime. Lastly, while computational models of particle deposition have been adopted to profile the deposition of e-cigarette mainstream emissions, existing models have limited applicability and generality when dealing with e-cigarette aerosols that have high volatility and hygroscopicity, which can dynamically evaporate or grow during the transport process. Additionally, the size-dependent chemical composition (e.g., nicotine and harmful and potentially harmful constituents) of e-cigarette aerosols is unknown, impeding the understanding of the health effects of e-cigarette use. Therefore, it is essential for future studies to bridge these knowledge gaps and unveil the mechanisms determining PSD and respiratory deposition.
... Three cigars of each flavor and Marlboro Red cigarettes were tested in triplicate. Adapting the nicotine extraction method from previous work (El-Hellani et al., 2015), 0.5 g of cigar wrapper and filler were extracted with 12 ml of water. To extract freebase nicotine, another 6 ml of toluene were added to the aqueous layer; this step was repeated twice and an aliquot of the organic layer was run on the GC-MS. ...
The U.S. Food and Drug Administration proposed new product standards that would ban characterizing flavors (other than tobacco) in cigars. To inform this regulatory action, we compared physiological effects, use behavior, and subjective effects of four popular cigar flavors in cigar-naïve young adult cigarette smokers. Across five laboratory visits, participants (n = 25) used and evaluated own brand (OB) cigarettes or Black & Mild cigars (original, wine, apple, and cream flavors). Linear mixed models tested differences in saliva nicotine, exhaled carbon monoxide (CO), heart rate (HR), blood pressure (BP), puff topography, and subjective effects (p < .05). Compared to all cigars, OB resulted in higher nicotine boost (953 vs. < 300 ng/ml) and lower CO boost (4 vs. 8-9 ppm). Nicotine boost for original cigars (283 ng/ml) was significantly higher than wine (190 ng/ml). All products significantly increased HR/BP relative to baseline, but across time wine and apple cigars were associated with significantly lower HR than OB and BP effects varied. Relative to OB, participants took approximately 0.5 s longer puffs for all cigars and took significantly larger puffs (+ 21%-24%) of original, wine, and apple cigars. OB was rated more positively than all cigars, which had similar subjective effects. Wine cigars were disliked most and were less effective in reducing tobacco abstinence symptoms than OB; cream cigars were harsher and had stronger flavor intensity than original. The consistency in toxicant exposure, use behavior, and subjective effects across cigar flavors, including original, highlights the need for product standards to interpret characterizing flavors subject to prohibition broadly. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
... There is a slight scatter between the percentage of protonated nicotine in the aerosol and the estimation using the Henderson− Hasselbalch equation due to the effect of polyol (i.e., PG and G mixture). 42,43 In this study, although the percentage of protonated nicotine of e-liquid B was relatively higher than that of acid-free e-liquid A based on the Henderson− Hasselbalch equation, 33 the nicotine absorption ratio of the e-liquid B with the benzoic acid was almost the same as that of the acid-free e-liquid A, as shown in Figure 5. This suggested that the equilibrium of the protonated and unprotonated states or the dissociated state of ion and salt might change from the aqueous solution in the limitation of the proton concentration in the aerosol of polyol (i.e., PG and G mixture). ...
Inhaled aerosols are absorbed across the oral cavity, respiratory tract, and gastrointestinal tract. The absorption across the oral cavity, which is one of the exposure routes, plays an important role in understanding pharmacokinetics and physiological effects. After aerosol exposure from e-cigarettes, tissue viability studies, morphological observation, and chemical analyses at the inner and outer buccal tissues were performed using organotypic 3D in vitro culture models of the buccal epithelium to better understand the deposition and absorption on the inner and outer buccal tissues. The aerosol exposures did not affect the tissue viability and had no change to the tissue morphology and structure. The deposition ratio at the buccal tissue surface is relatively low. This shows that majority of aerosol transfers to the airway tissues. The distribution from the inner tissue to the outer tissue has selectivity among various compounds, depending on the affinity with the liquid crystal structure of phospholipids and glucosylceramide. Although nicotine absorption in the aqueous solution was well known to increase as the unprotonated state of nicotine increased, the nicotine absorption after the aerosol exposure is irrelevant to the protonated-unprotonated state. Furthermore, the results showed that half of nicotine that adhered to the oral cavity transferred to the inner tissue via the oral epithelium and the other half transferred to the gastrointestinal tract accompanying multiple executions of swallowing, while majority of the water-soluble compounds with the hydroxyl group such as propylene glycol and benzoic acid that adhered to the oral cavity were eluted with the saliva and transferred to the gastrointestinal tract by swallowing.
... Furthermore, the formulations were optimized to ensure that the freebase nicotine formulation contained a minimal amount of protonated nicotine and the nicotine lactate formulation contained a minimal amount of freebase nicotine. Both formulations were also unflavored to ensure no flavoring compounds could influence nicotine protonation and hence possibly the deposition or absorption [28]. The nicotine lactate formulation had a pH of 3.98, and the freebase formulation had a pH of 9.98. ...
Smoking is a cause of serious disease in smokers. Electronic cigarettes, delivering aerosolized nicotine, offer adult smokers a potentially less harmful alternative to combustible cigarettes. This explorative PET/CT study investigated the distribution and deposition of inhaled [11C]nicotine using the mybluTM e-cigarette with two nicotine formulations, freebase and lactate salt. Fifteen healthy adult smokers participated in the two-part study to assess the distribution and accumulation of [11C]nicotine in the respiratory pathways and brain. Time-activity data for the respiratory pathways, lungs, oesophagus and brain were derived. 31–36% of both inhaled tracer formulations accumulated in the lung within 15–35 s. [11C]Nicotinefreebase exhibited higher uptake and deposition in the upper respiratory pathways. For [11C]nicotinelactate, brain deposition peaked at 4–5%, with an earlier peak and a steeper decline. A different kinetic profile was obtained for [11C]nicotinelactate with lower tracer uptake and accumulation in the upper respiratory pathways and an earlier peak and a steeper decline in lung and brain. Using nicotine lactate formulations in e-cigarettes may thus contribute to greater adult smoker acceptance and satisfaction compared to freebase formulations, potentially aiding a transition from combustible cigarettes and an acceleration of tobacco harm reduction initiatives.
... Flavorings are added to the e-liquid to impart taste and aromas to the inhaled aerosol (11)(12)(13)(14). Nicotine, when present, is in either the free-base (basic pH ∼8-10) or salt (acidic pH) form; e-liquids used in third and prior generation ecigarettes contained up to 95% of their total nicotine in free-base form (15), whereas e-liquids for fourth generation e-cigarettes contain nicotine in the acidic salt form (16)(17)(18). ...
Electronic cigarette, or vaping, products are used to heat an e-liquid to form an aerosol (liquid droplets suspended in gas) that the user inhales; a portion of this aerosol deposits in their respiratory tract and the remainder is exhaled, thereby potentially creating opportunity for secondhand exposure to bystanders (e.g., in homes, automobiles, and workplaces). Particle size, a critical factor in respiratory deposition (and therefore potential for secondhand exposure), could be influenced by e-liquid composition. Hence, the purposes of this study were to (1) test the influence of laboratory-prepared e-liquid composition [ratio of propylene glycol (PG) to vegetable glycerin (VG) humectants, nicotine, and flavorings] on particle size distribution and (2) model respiratory dosimetry. All e-liquids were aerosolized using a second-generation reference e-cigarette. We measured particle size distribution based on mass using a low-flow cascade impactor (LFCI) and size distribution based on number using real-time mobility sizers. Mass median aerodynamic diameters (MMADs) of aerosol from e-liquids that contained only humectants were significantly larger compared with e-liquids that contained flavorings or nicotine (p = 0.005). Humectant ratio significantly influenced MMADs; all aerosols from e-liquids prepared with 70:30 PG:VG were significantly larger compared with e-liquids prepared with 30:70 PG:VG (p = 0.017). In contrast to the LFCI approach, the high dilution and sampling flow rate of a fast mobility particle sizer strongly influenced particle size measurements (i.e., all calculated MMAD values were < 75 nm). Dosimetry modeling using LFCI data indicated that a portion of inhaled particles will deposit throughout the respiratory tract, though statistical differences in aerosol MMADs among e-liquid formulations did not translate into large differences in deposition estimates. A portion of inhaled aerosol will be exhaled and could be a source for secondhand exposure. Use of laboratory-prepared e-liquids and a reference e-cigarette to standardize aerosol generation and a LFCI to measure particle size distribution without dilution represents an improved method to characterize physical properties of volatile aerosol particles and permitted determination of MMAD values more representative of e-cigarette aerosol in situ, which in turn, can help to improve dose modeling for users and bystanders.
... Nicotine occurs in protonated form at acidic pH and freebase in alkaline uids [5] [20]. The nonionized form (free-based) is lipophilic and more bioavailable [21] [20]. Also avorings may affect the nicotine delivery pro le. ...
The use of electronic cigarettes referred to as “vaping” have a detrimental impact on human health, especially on the respiratory system. Depending on the chemical composition and the frequency and quantity of inhalation exposure, the severity of the symptoms may vary among patients. Here we discuss the main potential triggers for EVALI (e-cigarette or vaping product use-associated lung injury). Some vaping-related cellular response mechanisms, including inflammatory response and oxidative stress, and a correlation between vaping and the susceptibility to respiratory infections (including SARS-CoV-2), are presented. In-depth, long-term studies, especially involving cellular responses, are necessary to fully elucidate the process leading to the onset of EVALI symptoms.
... To date, no standard emissions outcome measures have been agreed upon, while a wide variety of metrics have been reported. Emissions have frequently been reported as the total condensed aerosol, commonly referred to as the Total Particulate Matter (TPM) yield per puff [Y TPM , (mg/puff)] and the Harmful and Potentially Harmful Constituents (HPHC) Yield [Y HPHC , (mg/puff), i.e., the mass of selected HPHCs per number of puffs] (2,3,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Some studies have reported emissions in terms of the HPHC mass ratio, f HPHC (mg/mg) (i.e., the mass of selected HPHCs per unit mass of TPM) (17,26,30,31,33). ...
Many Electronic Nicotine Delivery Systems (ENDS) employ integrated sensors to detect user puffing behavior and activate the heating coil to initiate aerosol generation. The minimum puff flow rate and duration at which the ENDS device begins to generate aerosol are important parameters in quantifying the viable operating envelope of the device and are essential to formulating a design of experiments for comprehensive emissions characterization. An accurate and unbiased method for quantifying the flow condition operating envelope of ENDS is needed to quantify product characteristics across research laboratories. This study reports an accurate, unbiased method for measuring the minimum and maximum aerosolization puff flow rate and duration of seven pod-style, four pen-style and two disposable ENDS. The minimum aerosolization flow rate ranged from 2.5 to 23 (mL/s) and the minimum aerosolization duration ranged from 0.5 to 1.0 (s) across the ENDS studied. The maximum aerosolization flow rate was defined to be when the onset of liquid aspiration was evident, at flow rates ranging from 50 to 88 (mL/s). Results are presented which provide preliminary estimates for the effective maximum aerosolization flow rate and duration envelope of each ENDS. The variation in operating envelope observed between ENDS products of differing design by various manufacturers has implications for development of standardized emissions testing protocols and data reporting required for regulatory approval of new products.
... For liquids that contain nicotine in the free base form, the higher the nicotine concentration, the higher the pH. 56 At higher pH, a large fraction of nicotine is in the free base form. Free base nicotine is volatile, leaves particles readily and can deposit in the mouth and upper airway, activating sensory nerves in these sites. ...
Electronic nicotine delivery systems (ENDS) such as e‐cigarettes and heated tobacco products are novel battery‐operated devices that deliver nicotine without combustion of tobacco. Because cigarette smoking is sustained by nicotine addiction and the toxic combustion products are mainly responsible for the harmful effects of smoking, ENDS could be used to promote smoking cessation while exposing users to lower levels of toxicants compared with conventional cigarettes. The currently available evidence from clinical and observational studies indicates a potential role of e‐cigarettes as smoking cessation aids, although many continue to use e‐cigarettes long after quitting smoking. Nicotine and toxicant delivery vary considerably by device and depend on the characteristics of the e‐liquid formulation. Because smokers tend to titrate their nicotine intake to maintain their desired pharmacologic effects, device and liquid characteristics need to be considered when using ENDS as an aid to quit smoking. Factors potentially limiting their use are the currently still unknown long‐term safety of these products and concerns regarding widespread use among youth. Implications of clinical pharmacology data on ENDS for the cigarette endgame and regulation by the U.S. Food and Drug administration are discussed.
... Because the JUUL device incorporates a variable voltage temperature control system that continuously adjusts voltage during each puff, we computed average power for JUUL by sampling the voltage continuously using a data acquisition system, as described in Talih et al. 21 Propylene glycol and vegetable glycerin in the liquid were measured by gas chromatography-flame ionisation detector as in El-Hellani et al. 22 Liquid nicotine concentration and form were measured using a liquid-liquid extraction method and gas chromatography-mass spectrometry (GC-MS), as in El-Hellani et al. 23 Liquid pH was measured using a Starter 3100 OHAUS pH-metre. ...
Introduction
Use of flavoured pod-mod-like disposable electronic cigarettes (e-cigarettes) has grown rapidly, particularly among cost-sensitive youth and young adults. To date, little is known about their design characteristics and toxicant emissions. In this study, we analysed the electrical and chemical characteristics and nicotine and pulmonary toxicant emission profiles of five commonly available flavoured disposable e-cigarettes and compared these data with those of a JUUL, a cartridge-based e-cigarette device that pod-mod-like disposables emulate in size and shape.
Methods
Device construction, electrical power and liquid composition were determined. Machine-generated aerosol emissions including particulate matter, nicotine, carbonyl compounds and heavy metals were also measured. Liquid and aerosol composition were measured by high-performance liquid chromatography, gas chromatography-mass spectrometry/flame ionisation detection, and inductively coupled plasma mass spectrometry.
Results
We found that unlike JUUL, disposable devices did not incorporate a microcontroller to regulate electrical power to the heating coil. Quality of construction varied widely. Disposable e-cigarette power ranged between 5 and 9 W and liquid nicotine concentration ranged between 53 and 85 mg/mL (~95% in the protonated form). In 15 puffs, total nicotine yield for the disposables ranged between 1.6 and 6.7 mg, total carbonyls ranged between 28 and 138 µg, and total metals ranged between 1084 and 5804 ng. JUUL emissions were near the floors of all of these ranges.
Conclusions
Disposable e-cigarettes are designed with high nicotine concentration liquids and are capable of emitting much higher nicotine and carbonyl species relative to rechargeable look-alike e-cigarettes. These differences are likely due to the lower quality in construction, unreliable labelling and lack of temperature control regulation that limits the power during operation. From a public health perspective, regulating these devices is important to limit user exposure to carbonyls and nicotine, particularly because these devices are popular with youth and young adults.
... Liquid nicotine concentration and form were measured using a liquid-liquid extraction method and gas chromatography-mass spectrometry (GC-MS), as in El-Hellani, El-Hage. 12 The pH was measured by diluting the liquid with deionised water to prepare an aqueous extract of 600 µg/mL of nicotine concentration in a final volume of 6 mL. The pH of this extract was measured by a pH-metre (Starter 3100 OHAUS). ...
In 2019, JUUL Labs began marketing in the European Union ‘new technology’ pods that incorporated a new wick that it claimed provided ‘more satisfaction’. In this study, we compared design and materials of construction, electrical characteristics, liquid composition and nicotine and carbonyl emissions of new technology JUUL pods to their predecessors. Consistent with manufacturer’s claims, we found that the new pods incorporated a different wicking material. However, we also found that the new pod design resulted in 50% greater nicotine emissions per puff than its predecessor, despite exhibiting unchanged liquid composition, device geometry and heating coil resistance. We found that when connected to the new technology pods, the JUUL power unit delivered a more consistent voltage to the heating coil. This behaviour suggests that the new coil-wick system resulted in better surface contact between the liquid and the temperature-regulated heating coil. Total carbonyl emissions did not differ across pod generations. That nicotine yields can be greatly altered with a simple substitution of wick material underscores the fragility of regulatory approaches that centre on product design rather than product performance specifications.
... Article nicotine in our study will be protonated, which will suppress its partitioning into the gas phase. El-Hellani et al. 103 found that some flavored e-liquids have high pH, such that a significant fraction of nicotine may exist as free base for some commercial e-liquids. ...
E-cigarette aerosol is a complex mixture of gases and particles with a composition that is dependent on the e-liquid formulation, puffing regimen, and device operational parameters. This work investigated mainstream aerosols from a third generation device, as a function of coil temperature (315-510 °F, or 157-266 °C), puff duration (2-4 s), and the ratio of propylene glycol (PG) to vegetable glycerin (VG) in e-liquid (100:0-0:100). Targeted and untargeted analyses using liquid chromatography high-resolution mass spectrometry, gas chromatography, in situ chemical ionization mass spectrometry, and gravimetry were used for chemical characterizations. PG and VG were found to be the major constituents (>99%) in both phases of the aerosol. Most e-cigarette components were observed to be volatile or semivolatile under the conditions tested. PG was found almost entirely in the gas phase, while VG had a sizable particle component. Nicotine was only observed in the particle phase. The production of aerosol mass and carbonyl degradation products dramatically increased with higher coil temperature and puff duration, but decreased with increasing VG fraction in the e-liquid. An exception is acrolein, which increased with increasing VG. The formation of carbonyls was dominated by the heat-induced dehydration mechanism in the temperature range studied, yet radical reactions also played an important role. The findings from this study identified open questions regarding both pathways. The vaping process consumed PG significantly faster than VG under all tested conditions, suggesting that e-liquids become more enriched in VG and the exposure to acrolein significantly increases as vaping continues. It can be estimated that a 30:70 initial ratio of PG:VG in the e-liquid becomes almost entirely VG when 60-70% of e-liquid remains during the vaping process at 375 °F (191 °C). This work underscores the need for further research on the puffing lifecycle of e-cigarettes.
... Some compounds, including tobacco specific nitrosamines (TSNAs) and nicotine, occur naturally in tobacco and are released during tobacco burning (Edwards et al. 2017;Konstantinou et al. 2018). Nicotine predominantly present in tobacco mainly exists in two forms-protonated nicotine and non-protonated nicotine-that are pH dependent (El-Hellani et al. 2015). Non-protonated nicotine is a free base and the more addictive form of nicotine, which is extremely bioavailable and freely absorbed into the blood system and is responsible for the pleasurable psychoactive effects (O'Connor et al. 2020). ...
Aim
The economic burden caused by death and disease in the world is credited mainly to tobacco use—currently linked to approximately 8,000,000 deaths per year with approximately 80% of these faralities reported in low and middle income economies. The World Health Organization (WHO) estimates that nearly 7,000,000 deaths are attributed to direct tobacco use, while approximately 1,200,000 non-smokers exposed to second hand cigarette smoke die every year. Accordingly, tobacco use is a major threat to the public health infrastructure; therefore, proper cessation interventions must be put in place to curb tobacco abuse and ease economic and social burdens caused by the tobacco epidemic.
Methods
A systematic review was conducted to investigate how scientific efforts have been advanced towards harm reduction among smokers and non-smokers. Relevant articles published during the period 2010–2020 in PubMed, Crossref, Google scholar, and Web of Science were used in this study. The articles were selected based on health impacts of cigarette smoking, tobacco cessation and emerging diseases, including Covid−19. Various cessation strategies have been identified although their efficiency is yet to match the desired results.
Results
A series of carcinogenic chemicals are generated during cigarette smoking resulting in serious health complications such as cancer and mutagenesis. The precursors for tobacco induced diseases are toxic and carcinogenic chemicals of the nitrosamine type, aldehydes, polonium-210 and benzo[a]pyrene, which bio-accumulate in the body system during cigarette smoking to cause disease. Rehabilitation facilities, use of drugs to diminish the desire to smoke, heavy taxation of tobacco products and warning labels on cigarettes are some of the cessation strategies employed towards curbing tobacco abuse.
Conclusion
The need for further research to develop better methods and research based policies for safe cigarette smoking and workable cessation strategies must be a priority in order to deal with the tobacco epidemic. Campaigns to promote tobacco cessation and abstinence are recommended in this review as a sure measure to mitigate against the deleterious impacts caused by cigarette smoking and tobacco abuse.
Over several years, e-liquids with “nicotine salts” have gained considerable popularity. These e-liquids have a low pH, at which nicotine occurs mostly in its monoprotonated form. Manufacturers usually accomplish this by the addition of an organic acid, such as levulinic acid, benzoic acid, or lactic acid. Nicotine in its protonated form can be more easily inhaled, enhancing the addictiveness and attractiveness of products. Several techniques have been described for measuring the protonation state of nicotine in e-liquids. However, nuclear magnetic resonance (NMR) spectroscopy is particularly suited for this purpose because it can be performed on unaltered e-liquids. In this article, we demonstrate the suitability of a benchtop NMR (60 MHz) instrument for determining the protonation state of nicotine in e-liquids. The method is subsequently applied to measure the protonation state of 33 commercially available e-liquids and to investigate whether the vaping process alters the protonation state of nicotine. For this purpose, the protonation state in the condensed aerosol obtained by automated vaping of different e-liquids was compared with that of the original e-liquids. Two distinct populations were observed in the protonation state of nicotine in commercial e-liquids: free-base (fraction of free-base nicotine αfb > 0.80) and protonated (αfb < 0.40). For 30 e-liquids out of 33, the information on the packaging regarding the presence of nicotine salt was in agreement with the observed protonation state. Three e-liquids contained nicotine salt, even though this was not stated on the packaging. Measuring the protonation state of nicotine before and after (machine) vaping revealed that the protonation state of e-liquids is not affected by vaping. In conclusion, it is possible to determine the nicotine protonation state with the described method. Two clusters can be distinguished in the protonation state of commercial e-liquids, and the protonation state of nicotine remains unchanged after vaping.
Electronic (e-) cigarette formulations containing nicotine salts from a range of organic acid conjugates and pH values have dominated the commercial market. The acids in the nicotine salt formulations may alter the redox environment in e-cigarettes, impacting free radical formation in e-cigarette aerosol. Here, the generation of aerosol mass and free radicals from a fourth-generation e-cigarette device was evaluated at 2 wt % nicotine salts (pH 7, 30:70 mixture propylene glycol to vegetable glycerin) across eight organic acids used in e-liquids: benzoic acid (BA), salicylic acid (SLA), lactic acid (LA), levulinic acid (LVA), succinic acid (SA), malic acid (MA), tartaric acid (TA), and citric acid (CA). Furthermore, 2 wt % BA nicotine salts were studied at the following nicotine to acid ratios: 1:2 (pH 4), 1:1 (pH 7), and 2:1 (pH 8), in comparison with freebase nicotine (pH 10). Radical yields were quantified by spin-trapping and electron paramagnetic resonance (EPR) spectroscopy. The EPR spectra of free radicals in the nicotine salt aerosol matched those generated from the Fenton reaction, which are primarily hydroxyl (OH) radicals and other reactive oxygen species (ROS). Although the aerosol mass formation was not significantly different for most of the tested nicotine salts and acid concentrations, notable ROS yields were observed only from BA, CA, and TA under the study conditions. The e-liquids with SLA, LA, LVA, SA, and MA produced less ROS than the 2 wt % freebase nicotine e-liquid, suggesting that organic acids may play dual roles in the production and scavenging of ROS. For BA nicotine salts, it was found that the ROS yield increased with a higher acid concentration (or a lower nicotine to acid ratio). The observation that BA nicotine salts produce the highest ROS yield in aerosol generated from a fourth-generation vape device, which increases with acid concentration, has important implications for ROS-mediated health outcomes that may be relevant to consumers, manufacturers, and regulatory agencies.
Rapid brain accumulation is critical for the acute reinforcing effects of nicotine. Although nicotine formulation (free-base vs. protonated or salt) in electronic cigarette (E-cig) liquid affects user satisfaction, its impact on brain nicotine accumulation (BNA) from E-cig use has not been evaluated in comparison with traditional combustible cigarettes (C-cigs) using a within-subjects design. BNA was directly assessed with 29 adult dual users (13 females) of E-cigs and C-cigs, using [11C]nicotine and positron emission tomography (PET). Participants underwent two 15-min upper body (from chest to head) scanning sessions during which they inhaled a single puff of [11C]nicotine-labeled vapor from E-cigs with free-base nicotine or C-cig smoke in a randomized order. Seventeen of them also went through another session during which they inhaled from E-cigs with nicotine salt. A full-body scan was also conducted at each session to measure total absorbed dose of [11C]nicotine. Mean maximum nicotine concentration (Cmax) in brain following inhalation of free-base nicotine E-cig vapor was 19% and 15% lower relative to C-cig smoke and nicotine salt E-cig vapor (ps = 0.014 and 0.043, respectively). The Cmax values did not differ significantly between the C-cig and nicotine salt E-cig. Mean values of time to the maximum concentration (Tmax) were not significantly different between the two types of E-cig, but they were 64% and 40% longer than that for C-cig smoking (ps = 0.0005 and 0.004, respectively). Mean Cmax with C-cigs and free-base nicotine E-cigs were greater in females relative to males and correlated with T1/2 of lung nicotine clearance and participants' pack-years. These results suggest that while E-cigs with free-base nicotine formulation can deliver nicotine rapidly to the brain, those with nicotine salt formulation are capable of even more efficient brain nicotine delivery closely resembling combustible cigarettes. Therefore, nicotine formulation or pH in E-liquid should be considered in evaluation of E-cigs in terms of abuse liability and potential in substituting for combustible cigarettes.
In the current scientific milieu, a plethora of studies explores the intricacies of unravelling the antioxidant capacities inherent in novel compounds, employing the sophisticated tool of quantum chemistry. However, despite the strides made in this field, it is widely acknowledged that quantum chemical computations are not immune to imperfections, particularly when applied to a diverse array of chemical systems. The challenges extend to the critical task of discerning the reliability of suspected thermodynamic data, a pivotal aspect in the assessment of antioxidant candidates. This report endeavours to address the pressing question of how to establish the trustworthiness of thermo-dynamic data derived from quantum mechanical computations. Rather than solely relying on quantum mechanical approaches, our proposed methodology advocates for an inclusive strategy that incorporates additional experimental parameters to bolster the overall credibility assessment. With a specific focus on nicotine andTrolox, we aim to transcend the limitations of singular computational methods. By juxtaposing quantum-derived data with supplementary experimental evidence, we aspire to forge a comprehensive framework capable of robustly evaluating antioxidant candidates.
With the growing number of individuals regularly using e-cigarettes, it has become increasingly important to understand the psychobiological effects of nicotine salts. Nicotine increases the release of dopamine (DA) into the nucleus accumbens (NAc), causing feelings of satisfaction. However, the differences in the DA-increasing effects of different nicotine salts have not been reported. In this study, we used a G protein-coupled receptor-activated DA fluorescent probe (GRABDA1m) and optical fiber photometric recording equipment to monitor the dynamic changes and kinetics of DA release in the NAc of mice exposed to different e-cigarette aerosols, including nicotine, nicotine benzoate, nicotine tartrate, nicotine lactate, nicotine levulinic acid, nicotine malate, and nicotine citrate. The results of this study were as follows: 1) Different types of nicotine salts could increase the release of DA in the NAc. 2) The slopes and half-effective concentrations of the fitted curves were different, suggesting that each nicotine salt had a difference in the efficiency of increasing DA release with concentration changes. 3) The absorption rates of different nicotine salts containing the same original nicotine concentration were significantly different by measuring the blood nicotine content. The effect of nicotine salts on increasing DA was directly proportional to the blood nicotine level. In conclusion, by observing the effects of nicotine salts on DA release in real time in vivo, differences in the pharmacological effects of nicotine salts are revealed to better understand the mechanism underlying the regulatory effects of nicotine salts on the brain.
Recently, many electronic cigarettes (ECIGs) manufacturers have begun offering e-liquids, known as "nicotine salts". These salts that have started gaining big popularity among users can be formed by adding weak acid to e-liquid mixtures consisting of propylene glycol (PG), vegetable glycerin (VG), flavors, and nicotine. The latter can exist in two forms: monoprotonated (mp) and freebase (fb) based on the pH of the matrix. Over the years, the determination of the fraction of fb was found important to policymakers as the prevalence of this form in ECIGs has been associated with the harshness sensory of inhalable aerosols. Liquid-liquid extraction (LLE), 1H NMR, and Henderson-Hasselback have been developed to deduce the fraction of fb; however, these methods were found to be time-consuming and have shown some challenges mainly due to the presence of a non-aqueous matrix consisting of PG and VG. This paper presents a quick non-aqueous pH measurement-based method that allows a quick determination of the fraction fb by just measuring the pH and the dielectric constant of the e-liquid. Then, by inputting these values into an established mathematical relationship, the fraction fb can be deduced. The relationship between pH, dielectric constant, and fb relies on knowing the values of the acidity dissociation constants of nicotine, which were determined for the first time in various PG/VG mixtures using a non-aqueous potentiometric titration. To validate the proposed method, the fraction fb was determined for commercials and lab-made nicotine salts utilizing the pH and LLE methods. The variation between the two methods was (<8.0%) for commercial e-liquids and lab-made nicotine salts containing lactic acid and salicylic acid. A larger discrepancy of up to 22% was observed for lab-made nicotine salts containing benzoic acid, which can be attributed to the stronger affinity of benzoic acid to toluene in the LLE method.
Currently it is not fully understood how the device settings and electronic liquid (e-liquid) composition, including their form of nicotine content, impact mouth and throat losses, and potentially lead to the variations in total nicotine delivery to the human lungs. An in situ size assessment method was developed for real-time measurements at the mouthpiece and outlet of a biorelevant mouth-throat to account for the dynamic nature of the aerosol. The aerosol size, temperature, and delivery through the mouth-throat replica and the exhaled aerosol between the puff intervals were measured at different wattages using various e-liquid compositions. The effects of body temperature and humidity on aerosol size and nicotine delivery were also explored to evaluate the importance of considering realistic in vivo conditions in in vitro measurements. Notably, in vitro tests with body temperature and humidity in mouth-throat model vs room conditions, resulted in larger aerosol size at the end of the throat (Dv50=5.83±0.33 μm vs 3.05±0.15 μm), significantly higher thoracic nicotine delivery (>90% vs 50-85%) potentially due to the lower exhaled amount (<10% vs 15-50%). Besides, higher VG/PG ratios resulted in significantly lower exhaled amount and higher mouth-throat nicotine deposition. One of the main outcomes of the study was finding significantly lower exhaled amount and higher thoracic nicotine delivery with nicotine salt form vs free-base. Considering body temperature and humidity also showed significant enhancement in nicotine delivery, so it is essential to account for biorelevant experimental conditions in benchtop testing.
Introduction:
Based on our preliminary 11C-nicotine PET imaging studies in humans, we speculated that greater deposition of nicotine in the respiratory tract from electronic cigarettes compared to combustible cigarettes could result from the alkaline pH of typical aerosol-producing electronic cigarette liquids (e-liquids). To address this hypothesis, we assessed the effect of e-liquid pH on the retention of nicotine in vitro using 11C-nicotine, PET, and a human respiratory tract model of nicotine deposition.
Methods:
A single two-second 35-mL puff was delivered to a human respiratory tract cast from a 2.8-Ohm cartomizer at 4.1 volts. Immediately after the puff, a two-second 700-mL air wash-in volume was administered. E-liquids (glycerol and propylene glycol 50/50 vol/vol) containing 24 mg/mL nicotine were mixed with 11C-nicotine. Deposition (retention) of nicotine was assessed using a GE Discovery MI DR PET/CT scanner. Eight e-liquids with different pH values (range 5.3 - 9.6) were investigated. All experiments were performed at room temperature and at a relative humidity of 70%-80%.
Results:
Retention of nicotine in the respiratory tract cast was pH-dependent and the pH-sensitive component of the retention was well described by a sigmoid curve. 50% of the maximal pH-dependent effect was observed at pH 8.0, which is close to the pKa2 of nicotine.
Conclusion:
The retention of nicotine in the respiratory tract conducting airways is dependent on the e-liquid pH. Lowering the e-liquid pH reduces retention of nicotine. Nonetheless, reduction of the pH below 7 has little effect, consistent with the pKa2 of protonated nicotine.
Implications:
Similar to combustible cigarettes, the retention of nicotine in the human respiratory tract from consumption of electronic cigarettes may have some health consequences and affect nicotine dependence. Here we demonstrated that the retention of nicotine in the respiratory tract is dependent on the e-liquid pH, and lowering pH reduces retention of nicotine in conducting airways of the respiratory tract. Therefore, e-cigarettes with low pH values would result in reduced respiratory tract nicotine exposure and faster delivery of nicotine to the CNS. The latter can be associated with e-cigarette abuse liability and the effectiveness of e-cigarettes as substitutes for combustible cigarettes.
A new generation of electronic cigarettes is exacerbating the youth vaping epidemic by incorporating additives that increase the acidity of generated aerosols, which facilitate uptake of high nicotine levels. We need to better understand the chemical speciation of vaping aerosols to assess the impact of acidification. Here we used X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy to probe the acid-base equilibria of nicotine in hydrated vaping aerosols. We show that, unlike the behavior observed in bulk water, nicotine in the core of aqueous particles was partially protonated when the pH of the nebulized solution was 10.4, with a fraction of free-base nicotine (αFB) of 0.34. Nicotine was further protonated by acidification with equimolar addition of benzoic acid (αFB = 0.17 at pH 6.2). By contrast, the degree of nicotine protonation at the particle surface was significantly lower, with 0.72 < αFB < 0.80 in the same pH range. The presence of propylene glycol and glycerol completely eliminated protonation of nicotine at the surface (αFB = 1) while not affecting significantly its acid-base equilibrium in the particle core. These results provide a better understanding of the role of acidifying additives in vaping aerosols, supporting public health policy interventions.
Background:
The JUUL electronic cigarette (e-cigarette) remains popular in the USA and has a big prevalence among youth. In response to the popularity of JUUL and similar devices among youth, the US Food and Drug Administration issued in February 2020 an enforcement policy to remove all flavoured cartridge/pod-based e-cigarettes from the market except for tobacco and menthol. Subsequent studies showed that some users of the now-removed flavoured JUUL pods (especially cool mint) switched to menthol-flavoured JUUL pods with similar satisfaction.
Methods:
We quantified menthol, nicotine, propylene glycol (PG) and vegetable glycerol (VG) in JUUL pod samples (Menthol, Classic Menthol and Cool Mint) that were purchased in 2017, 2018 and 2020 (only Menthol) to evaluate composition differences before and after the enforcement policy. We also analysed the samples to detect other cooling agents using a screening gas chromatography-mass spectrometry headspace method that we developed for this purpose.
Results:
Menthol concentration was significantly higher in 2020 products than in products from prior years. Moreover, other cooling agents varied across pods. The PG/VG volume ratio was 27/63 in all pods examined.
Conclusion:
This study highlights how regulations intended to reduce e-cigarette prevalence among youth may influence changes in tobacco product characteristics in ways that regulators may not have foreseen.
Nicotine salts, formed by nicotine and organic acids, are commonly added to electronic cigarette liquids for their ability to provide desirable sensory effects. Analytical strategies have been developed to detect the types of organic acids and nicotine levels, but methods for directly measuring nicotine salts are still desirable. Herein, a novel approach is presented for the simultaneous quantification of non-volatile and volatile nicotine salts via liquid chromatography/tandem mass spectroscopy (LC-MS/MS) and gas chromatography/mass spectroscopy (GC-MS). This approach was validated with recovery experiments, which yielded recovery values between 92.0% and 110.8%. This method is the first technique for quantifying multiple nicotine salts that could be present in commercial e-liquids. Without using derivatization steps, different nicotine salts could be detected rapidly and conveniently. This new method was demonstrated with 10 e-cigarette liquid samples, providing satisfactory outcomes. It could be used to study organic acids and protonated nicotine in e-liquids and the release behaviour of nicotine salts in electronic cigarettes.
O tabagismo é uma doença crônica associada à dependência de nicotina. Nos últimos anos, uma variedade de produtos alternativos à nicotina surgiu, destacando-se os Dispositivos Eletrônicos para Fumar (DEF), conhecidos como cigarros eletrônicos ou e-cigarro, que podem conter ou não nicotina. É fato que o consumo dos DEFs vem aumentando, constantemente, provavelmente pela maior aceitação social, a qual está relacionada à aparência contemporânea, à variedade de sabores, odores agradáveis e designs disponíveis no mercado. No entanto, não há evidências suficientes de que DEFs sejam menos prejudiciais à saúde do que o tabaco, a longo prazo. Destaca-se ainda que os DEFs podem servir como meio de entrada para o tabagismo para indivíduos não fumantes, visto que perpetuam o comportamento repetitivo e automático envolto no ato de fumar. Assim, esse artigo de reflexão sobre o uso dos DEFs na atualidade tem como objetivos esclarecer o que são os DEFs, discutir possíveis benefícios ou prejuízos relacionados ao uso dos DEFs e debater sobre a regulamentação e a comercialização destes dispositivos no Brasil.
The accurate determination of the free nicotine content in tobacco is of great importance for the quality assessment of tobacco leaves and cigarettes, as well as for the study of tar reduction and cigarette formulation. A method based on solvent extraction and gas chromatography-mass spectrometry (GC-MS) was established for direct determination of free nicotine content in tobacco. Free nicotine extraction from tobacco was optimized, using different solvents and physical techniques (shaking, ultrasonic oscillation, and static extraction). Ultimately, a 24 h static extraction with cyclohexane, followed by GC-MS analysis, gave superior results. The standard addition recovery was 98.0-104.7%, with a limit of detection of 5.3 μg/g and a relative standard deviation between 1.3 and 4.1% (n = 5). Quadratic regression of the standard curve was excellent (R 2 ≥ 0.9994). The free nicotine content was determined in 67 tobacco samples, with parallel samples showing relative deviations of 0.1-3.1%. To evaluate the effect of nicotine salts present in tobacco, malic acid, citric acid, acetic acid, and nicotine citrate were spiked into samples prior to extraction and analysis. The results show no interference from bound nicotine compounds on the method. The experimental results show that direct determination of free nicotine in tobacco was achieved using a simple static cyclohexane extraction. Moreover, the high extraction efficiency of free nicotine was also achieved with ease of operation and good repeatability.
Background
A supply of maternal thyroid hormone (thyroxine, T4) is essential for normal human fetal development. Human placental trophoblasts synthesize, secrete and take up the T4 binding protein transthyretin, providing a route for maternal T4 to enter the placenta. Transthyretin is also involved in T4 transport in other tissues such as the brain choroid plexus. Nicotine alters transthyretin synthesis and function in rat choroid plexus. If nicotine influences trophoblast turnover of transthyretin, then it may directly affect placental transfer of T4 to the developing fetus and contribute to the negative impacts of smoking on fetal growth, development and placental function.
Methods
The effect of nicotine on trophoblast uptake of Alexa-labelled transthyretin was measured using live cell imaging. The effect of nicotine on protein expression was measured by western blotting. Interactions between transthyretin, T4 and nicotine were investigated using chemical cross-linking techniques and molecular dynamic simulations.
Results
Nicotine blocks uptake of transthyretin-T4 by human placental trophoblast cells. Nicotine reduces the expression of the trophoblast scavenger receptor class B type 1 (SR-B1) that plays a role in transthyretin-T4 uptake. Molecular dynamic modelling suggests that when T4 is bound to transthyretin, nicotine binding increases tetramer stability, reducing the ability of the transthyretin-T4 complex to enter trophoblast cells.
Conclusion
Our data suggest that nicotine exposure during pregnancy reduces transplacental transport of transthyretin and T4 to the placenta and developing fetus. This may contribute to the negative effects of smoking on fetal growth, development and pregnancy viability.
Each electronic cigarette (e-cigarette) is a battery-powered system which converts electronic cigarette liquids (e-liquids) into the inhalable phase by heating the solution when it is in use. After four generations of development, e-cigarettes tend to be more customized and user-operable. The main components in the e-liquid and the aerosol are vegetable glycerin, propylene glycol, nicotine, organic acid and some flavor ingredients. Among them, nicotine is closely associated with the irritation and physiological satisfaction caused by tobacco products, and it is the core functional substance of e-cigarettes. For this reason, the quantification of nicotine content and nicotine form distribution mainly focuses on the components of the e-liquid and the released aerosol. Up to now, various technologies and methods have been applied in the analysis and research of nicotine content and nicotine form distribution in the e-liquid and its aerosol. GC-MS is often used as the most viable tool for the analysis of volatile organic compounds and can be widely applied in the measurement of nicotine related chemicals; there are a number of quantitation strategies using LC-MS, LC-MS/MS or 1H NMR for the analysis of e-cigarette samples. We also reviewed the four main methods for determining the distribution of nicotine forms, which are pH value derivation, solvent extraction, SPME and NMR methods. These research methods are of great significance to the upgrading and development of e-cigarette products.
Many new tobacco and related products (nTRP) have emerged on the market, with unknown health risks. Here, we present a conceptual model containing the factors and relations between them that contribute to the nTRP's health effects. Factors that determine attractiveness, addictiveness and toxicity of nTRP were defined based on previous assessments, literature, and expert discussions. Our model will aid in identifying key risk factors contributing to increased risk of adverse health effects for a product in a qualitative manner. Additionally, it can gauge attractiveness for specific user groups, as a determinant for population prevalence of use. Our model can be used to identify aspects of nTRP that require attention for public information or product regulation. As an example, we applied this to JUUL, a popular e-cigarette in the US. Aspects of concern for JUUL are its attractive and discrete shape, user-friendly prefilled pods, flavors, high aerosol nicotine levels, and liquids containing nicotine salts instead of free-based nicotine. The addictiveness and especially attractiveness are sufficiently high to have a large potential impact on population health due to its contribution to use and hence exposure. Products and their use can change over time; therefore market research and monitoring are crucial.
We carried out steady-state and stopped-flow photophysical measurements to determine the kinetics of a discrete disassembly driven turn-on fluorescent system. On and off rates for both DimerDye1 assembly and nicotine binding were determined. Relative rates for these competing processes provide insight on how this system can be optimized for sensing applications. Kinetics studies in artificial saliva showed that moving to more complex media has minimal effects on the sensing ability of the system.
Bei legalen Drogen handelt es sich um Substanzen, die einfach und rechtmäßig erhältlich sind. Der Konsum und Besitz von diesen Substanzen und der Handel mit ihnen sind straffrei und sie können im Supermarkt, am Kiosk oder in der Tankstelle um die Ecke erworben werden. Doch Vorsicht: Legal bedeutet auf keinen Fall, dass diese Substanzen harmlos sind, denn den Körper interessiert das kleine Wörtchen „legal“ kein bisschen, und nur weil diese Suchtmittel ohne strafrechtliche Folgen zu erwerben sind, rechtfertigt dies die negativen Folgen für Gesundheit und Lebensqualität nicht.
Nicotine in electronic cigarette (ECIG) liquids can exist in a free-base or protonated (or “salt”) form. Protonated nicotine is less aversive upon inhalation than free-base nicotine, and many ECIG manufacturers have begun marketing protonated nicotine products, often with high nicotine concentrations. Regulations intended to control ECIG nicotine delivery limit nicotine concentration but do not consider nicotine form. In this study, we systematically examined the effect of nicotine form on nicotine yield for varying powers and liquid vehicles. A Kanger Subox Mini-C tank ECIG (0.5 Ω) was used to generate aerosols at varying powers (5–45 W) from liquid solutions that contained either free-base or protonated nicotine at 15 mg/g concentration, with a liquid vehicle consisting of either propylene glycol (PG) or vegetable glycerin (VG), resulting in four different solutions (free-base/PG, free-base/VG, protonated/PG, and protonated/VG). Nicotine yield was quantified using gas chromatography-mass spectrometry. Nicotine yields were not influenced by nicotine form under any condition investigated. At each power level, PG-based liquids resulted in approximately double the nicotine yield of VG-based liquids. Nicotine concentrations in the aerosols matched those of the parent liquids for both the PG and VG conditions. Increasing power led to greater nicotine yield across all conditions. The amount of nicotine emitted by an ECIG is independent of whether the nicotine is free-base or protonated, however the liquid vehicle has a strong effect on yield. Regulations intended to limit nicotine emissions must consider not only nicotine concentration, but also liquid vehicle and device power.
The structures of three types of nicotine salts have been determined. These salts have acid to base ratios of either 1 : 1, 2 : 1, or 3 : 1. Salt formation between organic acids and nicotine is dependent upon the structure of the acids (aliphatic or aromatic) and their functionality. The 1 : 1 salts of nicotine have amino acids or benzoic-type acids bound to the N-methylpyrrolidine nitrogen of nicotine. The 2 : 1 salts are found to bind to one acid group as in the 1 : 1 salts and a second to the nitrogen of the pyridine ring. The 2 : 1 salts of nicotine are formed with formic acid, aliphatic dicarboxylic acids, and/or nitroaromatic acids. Nicotine forms 3 : 1 salts with aliphatic monocarboxylic acids starting with acetic acid. Here one acid is bound as in the 1 : 1 salts while the other two acids dimerize and bind to the nitrogen of the pyridine group. Infra-red (IR), ultra-violet (UV), proton nuclear magnetic resonance (PMR), and carbon nuclear magnetic resonance (CMR) spectroscopy as well as field desorption - mass spectroscopy (FD-MS) were used in this investigation of the structure of nicotine salts.
Electronic cigarette (e-cigarette) use is increasing dramatically in developed countries, but little is known about these rapidly evolving products. This study analyzed and evaluated the chemical composition including nicotine, tobacco alkaloids, pH, and flavors in 36 e-liquids brands from 4 manufacturers.
We determined the concentrations of nicotine, alkaloids, and select flavors and measured pH in solutions used in e-cigarettes. E-cigarette products were chosen based upon favorable consumer approval ratings from online review websites. Quantitative analyses were performed using strict quality assurance/quality control validated methods previously established by our lab for the measurement of nicotine, alkaloids, pH, and flavors.
Three-quarters of the products contained lower measured nicotine levels than the stated label values (6%-42% by concentration). The pH for e-liquids ranged from 5.1-9.1. Minor tobacco alkaloids were found in all samples containing nicotine, and their relative concentrations varied widely among manufacturers. A number of common flavor compounds were analyzed in all e-liquids.
Free nicotine levels calculated from the measurement of pH correlated with total nicotine content. The direct correlation between the total nicotine concentration and pH suggests that the alkalinity of nicotine drives the pH of e-cigarette solutions. A higher percentage of nicotine exists in the more absorbable free form as total nicotine concentration increases. A number of products contained tobacco alkaloids at concentrations that exceed U.S. pharmacopeia limits for impurities in nicotine used in pharmaceutical and food products.
© Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Introduction:
Some electronic cigarette (ECIG) users attain tobacco cigarette-like plasma nicotine concentrations while others do not. Understanding the factors that influence ECIG aerosol nicotine delivery is relevant to regulation, including product labeling and abuse liability. These factors may include user puff topography, ECIG liquid composition, and ECIG design features. This study addresses how these factors can influence ECIG nicotine yield.
Methods:
Aerosols were machine generated with 1 type of ECIG cartridge (V4L CoolCart) using 5 distinct puff profiles representing a tobacco cigarette smoker (2-s puff duration, 33-ml/s puff velocity), a slow average ECIG user (4 s, 17 ml/s), a fast average user (4 s, 33 ml/s), a slow extreme user (8 s, 17 ml/s), and a fast extreme user (8 s, 33 ml/s). Output voltage (3.3-5.2 V or 3.0-7.5 W) and e-liquid nicotine concentration (18-36 mg/ml labeled concentration) were varied. A theoretical model was also developed to simulate the ECIG aerosol production process and to provide insight into the empirical observations.
Results:
Nicotine yields from 15 puffs varied by more than 50-fold across conditions. Experienced ECIG user profiles (longer puffs) resulted in higher nicotine yields relative to the tobacco smoker (shorter puffs). Puff velocity had no effect on nicotine yield. Higher nicotine concentration and higher voltages resulted in higher nicotine yields. These results were predicted well by the theoretical model (R (2) = 0.99).
Conclusions:
Depending on puff conditions and product features, 15 puffs from an ECIG can provide far less or far more nicotine than a single tobacco cigarette. ECIG emissions can be predicted using physical principles, with knowledge of puff topography and a few ECIG device design parameters.
Background:
A major characteristic of the electronic cigarette (EC) market is the availability of a large number of different flavours. This has been criticised by the public health authorities, some of whom believe that diverse flavours will attract young users and that ECs are a gateway to smoking. At the same time, several reports in the news media mention that the main purpose of flavour marketing is to attract youngsters. The importance of flavourings and their patterns of use by EC consumers have not been adequately evaluated, therefore, the purpose of this survey was to examine and understand the impact of flavourings in the EC experience of dedicated users.
Methods:
A questionnaire was prepared and uploaded in an online survey tool. EC users were asked to participate irrespective of their current smoking status. Participants were divided according to their smoking status at the time of participation in two subgroups: former smokers and current smokers.
Results:
In total, 4,618 participants were included in the analysis, with 4,515 reporting current smoking status. The vast majority (91.1%) were former smokers, while current smokers had reduced smoking consumption from 20 to 4 cigarettes per day. Both subgroups had a median smoking history of 22 years and had been using ECs for 12 months. On average they were using three different types of liquid flavours on a regular basis, with former smokers switching between flavours more frequently compared to current smokers; 69.2% of the former subgroup reported doing so on a daily basis or within the day. Fruit flavours were more popular at the time of participation, while tobacco flavours were more popular at initiation of EC use. On a scale from 1 (not at all important) to 5 (extremely important) participants answered that variability of flavours was "very important" (score = 4) in their effort to reduce or quit smoking. The majority reported that restricting variability will make ECs less enjoyable and more boring, while 48.5% mentioned that it would increase craving for cigarettes and 39.7% said that it would have been less likely for them to reduce or quit smoking. The number of flavours used was independently associated with smoking cessation.
Conclusions:
The results of this survey of dedicated users indicate that flavours are marketed in order to satisfy vapers' demand. They appear to contribute to both perceived pleasure and the effort to reduce cigarette consumption or quit smoking. Due to the fact that adoption of ECs by youngsters is currently minimal, it seems that implementing regulatory restrictions to flavours could cause harm to current vapers while no public health benefits would be observed in youngsters. Therefore, flavours variability should be maintained; any potential future risk for youngsters being attracted to ECs can be sufficiently minimized by strictly prohibiting EC sales in this population group.
Background:
Although millions of people are using electronic cigarettes (ECs) and research on this topic has intensified in recent years, the pattern of EC use has not been systematically studied. Additionally, no comparative measure of exposure and nicotine delivery between EC and tobacco cigarette or nicotine replacement therapy (NRTs) has been established. This is important, especially in the context of the proposal for a new Tobacco Product Directive issued by the European Commission.
Methods:
A second generation EC device, consisting of a higher capacity battery and tank atomiser design compared to smaller cigarette-like batteries and cartomizers, and a 9 mg/mL nicotine-concentration liquid were used in this study. Eighty subjects were recruited; 45 experienced EC users and 35 smokers. EC users were video-recorded when using the device (ECIG group), while smokers were recorded when smoking (SM-S group) and when using the EC (SM-E group) in a randomized cross-over design. Puff, inhalation and exhalation duration were measured. Additionally, the amount of EC liquid consumed by experienced EC users was measured at 5 min (similar to the time needed to smoke one tobacco cigarette) and at 20 min (similar to the time needed for a nicotine inhaler to deliver 4 mg nicotine).
Results:
Puff duration was significantly higher in ECIG (4.2 ± 0.7 s) compared to SM-S (2.1 ± 0.4 s) and SM-E (2.3 ± 0.5 s), while inhalation time was lower (1.3 ± 0.4, 2.1 ± 0.4 and 2.1 ± 0.4 respectively). No difference was observed in exhalation duration. EC users took 13 puffs and consumed 62 ± 16 mg liquid in 5 min; they took 43 puffs and consumed 219 ± 56 mg liquid in 20 min. Nicotine delivery was estimated at 0.46 ± 0.12 mg after 5 min and 1.63 ± 0.41 mg after 20 min of use. Therefore, 20.8 mg/mL and 23.8 mg/mL nicotine-containing liquids would deliver 1 mg of nicotine in 5 min and 4 mg nicotine in 20 min, respectively. Since the ISO method significantly underestimates nicotine delivery by tobacco cigarettes, it seems that liquids with even higher than 24 mg/mL nicotine concentration would be comparable to one tobacco cigarette.
Conclusions:
EC use topography is significantly different compared to smoking. Four-second puffs with 20-30 s interpuff interval should be used when assessing EC effects in laboratory experiments, provided that the equipment used does not get overheated. Based on the characteristics of the device used in this study, a 20 mg/mL nicotine concentration liquid would be needed in order to deliver nicotine at amounts similar to the maximum allowable content of one tobacco cigarette (as measured by the ISO 3308 method). The results of this study do not support the statement of the European Commission Tobacco Product Directive that liquids with nicotine concentration of 4 mg/mL are comparable to NRTs in the amount of nicotine delivered to the user.
Electronic cigarettes (EC) deliver aerosol by heating fluid containing nicotine. Cartomizer EC combine the fluid chamber and heating element in a single unit. Because EC do not burn tobacco, they may be safer than conventional cigarettes. Their use is rapidly increasing worldwide with little prior testing of their aerosol.
We tested the hypothesis that EC aerosol contains metals derived from various components in EC.
Cartomizer contents and aerosols were analyzed using light and electron microscopy, cytotoxicity testing, x-ray microanalysis, particle counting, and inductively coupled plasma optical emission spectrometry.
The filament, a nickel-chromium wire, was coupled to a thicker copper wire coated with silver. The silver coating was sometimes missing. Four tin solder joints attached the wires to each other and coupled the copper/silver wire to the air tube and mouthpiece. All cartomizers had evidence of use before packaging (burn spots on the fibers and electrophoretic movement of fluid in the fibers). Fibers in two cartomizers had green deposits that contained copper. Centrifugation of the fibers produced large pellets containing tin. Tin particles and tin whiskers were identified in cartridge fluid and outer fibers. Cartomizer fluid with tin particles was cytotoxic in assays using human pulmonary fibroblasts. The aerosol contained particles >1 µm comprised of tin, silver, iron, nickel, aluminum, and silicate and nanoparticles (<100 nm) of tin, chromium and nickel. The concentrations of nine of eleven elements in EC aerosol were higher than or equal to the corresponding concentrations in conventional cigarette smoke. Many of the elements identified in EC aerosol are known to cause respiratory distress and disease.
The presence of metal and silicate particles in cartomizer aerosol demonstrates the need for improved quality control in EC design and manufacture and studies on how EC aerosol impacts the health of users and bystanders.
The objective of this study was to determine nicotine and the nicotine related impurities, that is, cotinine, myosmine, anatabine, anabasine, and β-nicotyrine, in electronic cigarette cartridges, the liquid used to fill the cartridges, and from smoke generated using the electronic cigarette devices. An HPLC method was validated for the determination. Samples of nicotine containing products were purchased via the internet from NJOY, Smoking Everywhere, CIXI, and Johnson Creek. Electronic cigarette devices were purchased from NJOY, Smoking Everywhere, and CIXI. The results from the testing found that (1) the nicotine content labeling was not accurate with some manufacturers, (2) nicotine is present in the “smoke” from electronic cigarettes, and (3) nicotine related impurities contents in cartridges and refills were found to vary by electronic cigarette manufacturer.
The object of the present work is to evaluate the use of toluene as an alternative solvent for nicotine extraction from aqueous-leached solutions of tobacco wastes. The liquid−liquid equilibrium data of the ternary system water + toluene + nicotine has been determined at 295, 303, and 313 K. The results have been correlated using the UNIQUAC and NRTL equations with linear temperature-dependent parameters. It is concluded that toluene is an effective agent for nicotine extraction.
Introduction:
Electronic cigarettes (ECIGs) heat a nicotine-containing solution; the resulting aerosol is inhaled by the user. Nicotine delivery may be affected by users' puffing behavior (puff topography), and little is known about the puff topography of ECIG users. Puff topography can be measured using mouthpiece-based computerized systems. However, the extent to which a mouthpiece influences nicotine delivery and subjective effects in ECIG users is unknown.
Methods:
Plasma nicotine concentration, heart rate, and subjective effects were measured in 13 experienced ECIG users who used their preferred ECIG and liquid (≥ 12 mg/ml nicotine) during 2 sessions (with or without a mouthpiece). In both sessions, participants completed an ECIG use session in which they were instructed to take 10 puffs with 30-second inter-puff intervals. Puff topography was recorded in the mouthpiece condition.
Results:
Almost all measures of the effects of ECIG use were independent of topography measurement. Collapsed across session, mean plasma nicotine concentration increased by 16.8 ng/ml, and mean heart rate increased by 8.5 bpm (ps < .05). Withdrawal symptoms decreased significantly after ECIG use. Participants reported that the mouthpiece affected awareness and made ECIG use more difficult. Relative to previously reported data for tobacco cigarette smokers using similar topography measurement equipment, ECIG-using participants took larger and longer puffs with lower flow rates.
Conclusions:
In experienced ECIG users, measuring ECIG topography did not influence ECIG-associated nicotine delivery or most measures of withdrawal suppression. Topography measurement systems will need to account for the low flow rates observed for ECIG users.
Electronic (e-)cigarettes have emerged in recent years as putative alternative to conventional tobacco cigarettes. These products do not contain typical carcinogens that are present in tobacco smoke, due to the lack of combustion. However, besides nicotine, hazards can also arise from other constituents of liquids, such as solvents, flavors, additives and contaminants. In this study, we have analyzed 28 liquids of seven manufacturers purchased in Germany. We confirm the presence of a wide range of flavors to enhance palatability. Although glycerol and propylene glycol were detected in all samples, these solvents had been replaced by ethylene glycol as dominant compound in five products. Ethylene glycol is associated with markedly enhanced toxicological hazards when compared to conventionally used glycerol and propylene glycol. Additional additives, such as coumarin and acetamide, that raise concerns for human health were detected in certain samples. Ten out of 28 products had been declared "free-of-nicotine" by the manufacturer. Among these ten, seven liquids were identified containing nicotine in the range of 0.1-15 µg/ml. This suggests that "carry over" of ingredients may occur during the production of cartridges. We have further analyzed the formation of carbonylic compounds in one widely distributed nicotine-free brand. Significant amounts of formaldehyde, acetaldehyde and propionaldehyde were only found at 150 °C by headspace GC-MS analysis. In addition, an enhanced formation of aldehydes was found in defined puff fractions, using an adopted machine smoking protocol. However, this effect was delayed and only observed during the last third of the smoking procedure. In the emissions of these fractions, which represent up to 40 % of total vapor volume, similar levels of formaldehyde were detected when compared to conventional tobacco cigarettes. By contrast, carbonylic compounds were hardly detectable in earlier collected fractions. Our data demonstrate the necessity of standardized machine smoking protocols to reliably address putative risks of e-cigarettes for consumers.
There is a lack of consensus among health experts and the tobacco control community regarding the potential population impact of the rapidly spreading use of electronic cigarettes, or e-cigarettes.1–3 Dual use of e-cigarettes with regular cigarettes and initiation in non-tobacco users are among common concerns. Some experts, however, believe that complete switching to e-cigarettes could potentially lead to significant reductions in smoking-induced morbidity and mortality among current smokers who experience difficulty giving up smoking. Indeed, the e-cigarette aerosol, which primarily consists of nicotine, humectants and flavouring agents, contains significantly lower levels of many toxic and carcinogenic chemicals that are abundant in the smoke of regular cigarettes.4
The common toxicity concerns regarding e-cigarette use include nicotine toxicity, the potential long-term effect of propylene glycol (humectant) inhalation, and the lack of quality control oversight over the production of some e-cigarettes and refill fluids.1 ,2 ,5 The latter can result in …
Electronic cigarettes (e-cigarettes) have been increasingly available and marketed in the U.S. since 2007. As patterns of product adoption are frequently driven and reinforced by marketing, it is important to understand the marketing claims encountered by consumers.
To describe the main advertising claims made on branded e-cigarette retail websites.
Websites were retrieved from two major search engines in 2011 using iterative searches with the following terms: electronic cigarette, e-cigarette, e-cig, and personal vaporizer. Fifty-nine websites met inclusion criteria, and 13 marketing claims were coded for main marketing messages in 2012.
Ninety-five percent of the websites made explicit or implicit health-related claims, 64% had a smoking cessation-related claim, 22% featured doctors, and 76% claimed that the product does not produce secondhand smoke. Comparisons to cigarettes included claims that e-cigarettes were cleaner (95%) and cheaper (93%). Eighty-eight percent stated that the product could be smoked anywhere and 71% mentioned using the product to circumvent clean air policies. Candy, fruit, and coffee flavors were offered on most sites. Youthful appeals included images or claims of modernity (73%); increased social status (44%); enhanced social activity (32%); romance (31%); and use by celebrities (22%).
Health claims and smoking-cessation messages that are unsupported by current scientific evidence are frequently used to sell e-cigarettes. Implied and overt health claims, the presence of doctors on websites, celebrity endorsements, and the use of characterizing flavors should be prohibited.
Background and aims:
Electronic cigarettes (EC) may have a potential for public health benefit as a safer alternative to smoking, but questions have been raised about whether EC should be licensed as a medicine, with accurate labelling of nicotine content. This study determined the nicotine content of the cartridges of the most popular EC brands in the United Kingdom and the nicotine levels they deliver in the vapour, and estimated the safety and consistency of nicotine delivery across batches of the same product as a proxy for quality control for individual brands and within the industry.
Methods:
We studied five UK brands (six products) with high internet popularity.
Measurements:
Two samples of each brand were purchased 4 weeks apart, and analysed for nicotine content in the cartridges and nicotine delivery in vapour.
Results:
The nicotine content of cartridges within the same batch varied by up to 12% relative standard deviation (RSD) and the mean difference between different batches of the same brand ranged from 1% [95% confidence interval (CI) = -5 to 7%] to 20% (95% CI=14-25%) for five brands and 31% (95% CI=21-39%) for the sixth. The puffing schedule used in this study vaporized 10-81% of the nicotine present in the cartridges. The nicotine delivery from 300 puffs ranged from ∼2 mg to ∼15 mg and was not related significantly to the variation of nicotine content in e-liquid (r=0.06, P=0.92). None of the tested products allowed access to e-liquid or produced vapour nicotine concentrations as high as conventional cigarettes.
Conclusions:
There is very little risk of nicotine toxicity from major electronic cigarette (EC) brands in the United Kingdom. Variation in nicotine concentration in the vapour from a given brand is low. Nicotine concentration in e-liquid is not well related to nicotine in vapour. Other EC brands may be of lower quality and consumer protection regulation needs to be implemented, but in terms of accuracy of labelling of nicotine content and risks of nicotine overdose, regulation over and above such safeguards seems unnecessary.
An apparatus has been designed and constructed to measure mutual solubilities of (water + hydrocarbon). The solubility of water in toluene, cyclohexane, methylcyclohexane, ethylcyclohexane, and (cis + trans)-1,2-dimethylcyclohexane were determined at temperatures ranging from (30 to 180) °C. Measurements obtained for toluene show good agreement with literature values and allow us to validate this new method. As expected, increasing the temperature increases the solubilities of water in the alkylcyclohexanes. Furthermore, the solubility of water in alkylcyclohexanes increases with the number of carbon atoms.
Aims:
To assess levels of nicotine, nicotine degradation products and some specific impurities in commercial refill liquids for electronic cigarettes.
Design and setting:
We analyzed 20 models of 10 of the most popular brands of refill liquids, using gas and liquid chromatography.
Measurements:
We assessed nicotine content, content of the known nicotine degradation products and impurities, and presence of ethylene glycol and diethylene glycol.
Findings:
The nicotine content in the bottles corresponded closely to the labels on the bottles. The levels of nicotine degradation products represented 0-4.4% of those for nicotine, but for most samples the level was 1-2%. Cis-N-oxide, trans-N-oxide, myosmine, anatabine and anabasine were the most common additional compounds found. Neither ethylene glycol nor diethylene glycol were detected.
Conclusion:
The nicotine content of electronic cigarette refill bottles is close to what is stated on the label. Impurities are detectable in several brands above the level set for nicotine products in the European Pharmacopoeia, but below the level where they would be likely to cause harm.
Electronic nicotine delivery systems (ENDS) initially emerged in 2003 and have since become widely available globally, particularly over the Internet.
Data on ENDS usage patterns are limited. The current paper examines patterns of ENDS awareness, use, and product-associated beliefs among current and former smokers in four countries.
Data come from Wave 8 of the International Tobacco Control Four-Country Survey, collected July 2010 to June 2011 and analyzed through June 2012. Respondents included 5939 current and former smokers in Canada (n=1581); the U.S. (n=1520); the United Kingdom (UK; n=1325); and Australia (n=1513).
Overall, 46.6% were aware of ENDS (U.S.: 73%, UK: 54%, Canada: 40%, Australia: 20%); 7.6% had tried ENDS (16% of those aware of ENDS); and 2.9% were current users (39% of triers). Awareness of ENDS was higher among younger, non-minority smokers with higher incomes who were heavier smokers. Prevalence of trying ENDS was higher among younger, nondaily smokers with a high income and among those who perceived ENDS as less harmful than traditional cigarettes. Current use was higher among both nondaily and heavy (≥20 cigarettes per day) smokers. In all, 79.8% reported using ENDS because they were considered less harmful than traditional cigarettes; 75.4% stated that they used ENDS to help them reduce their smoking; and 85.1% reported using ENDS to help them quit smoking.
Awareness of ENDS is high, especially in countries where they are legal (i.e., the U.S. and UK). Because trial was associated with nondaily smoking and a desire to quit smoking, ENDS may have the potential to serve as a cessation aid.
Objective:
Many electronic nicotine delivery systems (ENDS) are marketed as safer tobacco alternative products or effective cessation therapies. ENDS samples were evaluated for design features, including nicotine and glycols content. This could be useful in developing a legal framework to handle ENDS.
Methods:
Identification of the nicotine, glycerol and propylene glycol (PPG) contents was conducted using gas chromatography mass spectrometry with quantification performed using flame ionisation techniques.
Results:
Varying nicotine amounts were found in ENDS cartridges which were labelled with the same concentration. Chemicals such as PPG and glycerol were found to be present in the nicotine-containing liquid of the cartridges. ENDS varied in their contents and packaging information. Limited information was available on the contents of nicotine and other chemicals present in a variety of ENDS sampled.
Conclusions:
Based on samples tested in this study, many contain misleading information on product ingredients. The results show poor consistency between actual nicotine content analysed on ENDS cartridges and the amount labelled. These findings raise safety and efficacy concerns for current and would-be recreational users or those trying to quit smoking.
A considerable minority of adults remain addicted to smoking cigarettes despite substantial education and public health efforts. Nicotine replacement therapies have only modest long-term quit rates. The pulmonary route of nicotine delivery has advantages over other routes. However, there are regulatory and technical barriers to the development of pulmonary nicotine delivery devices, and hence, none are commercially available. Current knowledge about pulmonary nicotine delivery is scattered throughout the literature and other sources such as patent applications. This review draws together what is currently known about pulmonary nicotine delivery and identifies potential ways that deep lung delivery can be achieved with a simple portable device. Aims: To systematically review clinical trials of nicotine inhalers, determine whether they delivered nicotine via the lung, and identify ways that pulmonary delivery of medicinal nicotine might be achieved and the technical issues involved.
Systematic search of Medline and Embase.
Thirty-eight trials met the inclusion criteria. Cough, reflex interruption of smooth inspiration, and throat scratch limited the usefulness of nicotine inhalers. The pharmacokinetic profiles of portable nicotine inhalers were inferior to smoking, but among commercially available products, electronic cigarettes are currently the most promising. Conclusions: Pulmonary nicotine delivery might be maximized by use of nicotine salts, which have a more physiological pH than pure nicotine, by ensuring the mass of the particles is optimal for alveolar absorption, and by adding flavoring agents. Metered-dose inhalers potentially can deliver nicotine more efficiently than other nicotine products, facilitating smoking cessation and improving smokers' lives.
Objective The objective was to analyse and compare puff and exhalation duration for individuals using electronic nicotine delivery systems (ENDS) and conventional cigarettes in YouTube videos.
Methods Video data from YouTube videos were analysed to quantify puff duration and exhalation duration during use of conventional tobacco-containing cigarettes and ENDS. For ENDS, comparisons were also made between ‘advertisers’ and ‘non-advertisers’, genders, brands of ENDS, and models of ENDS within one brand.
Results Puff duration (mean =2.4 s) for conventional smokers in YouTube videos (N=9) agreed well with prior publications. Puff duration was significantly longer for ENDS users (mean =4.3 s) (N = 64) than for conventional cigarette users, and puff duration varied significantly among ENDS brands. For ENDS users, puff duration and exhalation duration were not significantly affected by ‘advertiser’ status, gender or variation in models within a brand. Men outnumbered women by about 5:1, and most users were between 19 and 35 years of age.
Conclusions YouTube videos provide a valuable resource for studying ENDS usage. Longer puff duration may help ENDS users compensate for the apparently poor delivery of nicotine from ENDS. As with conventional cigarette smoking, ENDS users showed a large variation in puff duration (range =1.9–8.3 s). ENDS puff duration should be considered when designing laboratory and clinical trials and in developing a standard protocol for evaluating ENDS performance.
Public interest in electronic nicotine delivery systems (ENDS) is undocumented.
By monitoring search queries, ENDS popularity and correlates of their popularity were assessed in Australia, Canada, the United Kingdom (UK), and the U.S.
English-language Google searches conducted from January 2008 through September 2010 were compared to snus, nicotine replacement therapy (NRT), and Chantix® or Champix®. Searches for each week were scaled to the highest weekly search proportion (100), with lower values indicating the relative search proportion compared to the highest-proportion week (e.g., 50=50% of the highest observed proportion). Analyses were performed in 2010.
From July 2008 through February 2010, ENDS searches increased in all nations studied except Australia, there an increase occurred more recently. By September 2010, ENDS searches were several-hundred-fold greater than searches for smoking alternatives in the UK and U.S., and were rivaling alternatives in Australia and Canada. Across nations, ENDS searches were highest in the U.S., followed by similar search intensity in Canada and the UK, with Australia having the fewest ENDS searches. Stronger tobacco control, created by clean indoor air laws, cigarette taxes, and anti-smoking populations, were associated with consistently higher levels of ENDS searches.
The online popularity of ENDS has surpassed that of snus and NRTs, which have been on the market for far longer, and is quickly outpacing Chantix or Champix. In part, the association between ENDS's popularity and stronger tobacco control suggests ENDS are used to bypass, or quit in response to, smoking restrictions. Search query surveillance is a valuable, real-time, free, and public method to evaluate the diffusion of new health products. This method may be generalized to other behavioral, biological, informational, or psychological outcomes manifested on search engines.
The issue of harm reduction has long been controversial in the public health practice of tobacco control. Health advocates have been reluctant to endorse a harm reduction approach out of fear that tobacco companies cannot be trusted to produce and market products that will reduce the risks associated with tobacco use. Recently, companies independent of the tobacco industry introduced electronic cigarettes, devices that deliver vaporized nicotine without combusting tobacco. We review the existing evidence on the safety and efficacy of electronic cigarettes. We then revisit the tobacco harm reduction debate, with a focus on these novel products. We conclude that electronic cigarettes show tremendous promise in the fight against tobacco-related morbidity and mortality. By dramatically expanding the potential for harm reduction strategies to achieve substantial health gains, they may fundamentally alter the tobacco harm reduction debate.
The content of free-base nicotine in cigarette smoke is a controversial subject, partly due to methodological issues. In this investigation, an improved method to measure free-base nicotine in cigarette smoke using headspace solid-phase microextraction (HS-SPME) combined with GC/MS analysis, was developed and validated for this purpose. Cigarette smoke particulate phase (PP) was collected onto a 44mm glass fiber filter pad. The pad was cut in halves with one half used to determine the concentrations of total nicotine and water. The remaining half was analyzed by HS-SPME for free-base nicotine. The following factors were found to have a significant impact on the responses of free-base nicotine: SPME fiber type, pre-equilibrium time before HS-SPME, extraction time and temperature, PP water content, and the solvent used for the preparation of standards. It was also found that the impact of PP water content on the determination of free-base nicotine from smoke sample could be corrected by a water correction factor calculated based on an experimentally determined reciprocal model. The precision of the method was evaluated with smoke samples of reference cigarettes: Canadian flue-cured monitor and Kentucky reference 2R4F. The RSD values obtained were in the 12.8-16.8% range.
Tobacco smoke is an aerosol that contains both gaseous and suspended particulate material (PM). The particles are largely liquid droplets containing a wide variety of condensed organic compounds. Each compound in the smoke will partition between the gas and PM phases and will always seek a state of gas/particle equilibrium. When tobacco smoke is inhaled, a compound such as nicotine can deposit in the respiratory tract (RT) by four different mechanisms: (1) direct gas deposition (DGD) of the portion of the compound that is initially in the gas phase of the inhaled smoke; (2) evaporative gas deposition (EGD) of PM-phase compound by evaporation to the gas phase, then deposition; (3) particle deposition, evaporation from the deposited particle, then deposition from the gas phase (PDE); and (4) particle deposition with diffusion (PDD) into RT tissue. Three of the mechanisms (DGD, EGD, and PDE) involve volatilization from the PM phase. The relative importance of all the mechanisms is therefore greatly affected by the volatility of the compound from the PM phase as it is set by the compound's gas/particle partitioning constant K(p) through the compound's vapor pressure. For a largely nonvolatile compound such as benzo[a]pyrene, only PDD will likely be important. For a semivolatile compound such as nicotine, all four mechanisms can be important. Because tobacco smoke alkaloids such as nicotine can exist in protonated as well as free-base form, the fraction alpha(fb) of the compound that is in the neutral free-base form in the PM phase plays a critical, pH-dependent role in determining the relative importance of the four mechanisms. Equations are developed that can be used to ascertain the importance of the DGD and EGD mechanisms. The value of alpha(fb) for nicotine in a tobacco smoke PM is set by pH(eff), the effective pH of the PM phase. Historically, a primary method for measuring "smoke pH" has involved the direct exposure of a pH electrode to tobacco smoke. This method cannot yield direct insight into pH(eff) or alpha(fb) values because (1) problems exist in using such an electrode to measure smoke PM-phase pH, and (2) by itself, a measurement of the pH of tobacco smoke PM says nothing about the effects of PM-phase activity coefficients of protonated and free-base nicotine on the nicotine species distribution. The "acidic" values that have typically been measured for cigarette "smoke pH" by the direct pH electrode method are therefore neither reliable nor useful in determining the relative distribution of PM-phase nicotine among the protonated and free-base forms. The dependence of the volatility of nicotine from tobacco smoke PM on alpha(fb) means that measuring the gas/particle distribution of nicotine under equilibrium conditions in a tobacco smoke by denuder samplers (or by another method) can yield information about the nicotine K(p) for that smoke. Knowledge of K(p,fb), the partitioning constant for nicotine in the free-base form, then allows calculation of alpha(fb) through the relation K(p) = K(p,fb)/alpha(fb). The available data suggest that the smoke PM from some commercial cigarettes can be characterized by alpha(fb) > or = 0.4, i.e., 40% or more of the nicotine in the free-base form. This conclusion is consistent with (1) the gas-sampling denuder results obtained by Philip Morris in which significant tobacco smoke nicotine was observed to deposit in acid-coated denuder tubes, with more depositing when the cigarette tobacco blend was treated with ammonia; (2) the view that the sensory "impact" exhibited by some tobacco smokes is caused by the deposition of gaseous nicotine in the pharynx; (3) the observed throat irritation caused by nicotine inhalers; and (4) the high overall respiratory tract deposition efficiencies for nicotine of 0.9 and greater that have been reported for some cigarette smokes. The available information combines to create a picture of nicotine in cigarette smoke that contradicts the traditional view that cigarette smoke PM is typically acidic, with little free-base nicotine typically present in the smoke PM phase. Government agencies interested in establishing a framework for the testing and monitoring of nicotine delivery may wish to consider requiring the measurement and publication of the PM-phase alpha(fb) values for the cigars and cigarettes marketed in their jurisdictions.
The gas-phase basicities (GBs) of nornicotine, nicotine, and model pyrrolidines have been measured by FT-ICR. These experimental GBs are compared with those calculated (for the two sites of protonation in the case of nicotine and nornicotine) at the B3LYP/6-311+G(3df,2p)//B3LYP/6-31G(d,p) level, or those estimated from substituent effects on the GBs of 2-substituted pyrrolidines, 2-substituted N-methylpyrrolidines, and 3-substituted pyridines. It is found that, in contrast to the Nsp(3) protonation in water, in the gas phase nornicotine is protonated on the pyridine nitrogen, because the effects of an intramolecular CH.Nsp(3) hydrogen bond and of the polarizability of the 3-(pyrrolidin-2-yl) substituent add up on the Nsp(2) basicity, while the polarizability effect of the 2-(3-pyridyl) substituent on the Nsp(3) basicity is canceled by its field/inductive electron-withdrawing effect. The same structural effects operate on the Nsp(3) and Nsp(2) basicities of nicotine, but here, the polarizability effect of the methyl group puts the pyrrolidine nitrogen basicity very close to that of pyridine. Consequently, protonated nicotine is a mixture of the Nsp(3) and Nsp(2) protonated forms.
The available evidence suggests that most of the nicotine in mainstream tobacco smoke is in the smoke particle matter (PM) phase. Nicotine can exist in protonated and free base forms in the smoke PM, and alpha(fb) is the fraction of the PM nicotine that is in the free base form. Because only the free base form can volatilize from the smoke PM phase to the gas phase of an inhaled aerosol and because gaseous nicotine deposits rapidly in the respiratory tract (RT), the magnitude and rate of nicotine deposition in the RT will depend on alpha(fb). The types of values that alpha(fb) can assume in the PM of cigarette smoke aerosols have not been well-known. The conventional view has been that mainstream cigarette smoke PM contains relatively little free base nicotine so that the cigarette smoker must absorb nicotine mostly from deposited particles. A prior study concluded that because cigarette smoke is at "pH 5.3", there is very little free base nicotine in such smoke. A 1994 internal tobacco company document discusses the view that "smoke pH" values for cigarette smoke are "approximately 6.0". This work uses volatility-based measurements to provide determinations of equilibrium nicotine alpha(fb) values for mainstream smoke PM from selected cigarettes. The effective pH (i.e., pH(eff)) of the smoke PM from selected brands of commercial cigarettes was found to span a range of 6.0-7.8 (nicotine alpha(fb) = 0.01-0.36), with all pH(eff) values much larger than 5.3 and most larger than 6.0.
A first generation smoking machine capable of reading and replicating detailed puffing behavior from recorded smoking topography data is presented. Unlike standard smoking machines, which model human puffing behavior as a steady periodic waveform with a fixed puff frequency, volume, and duration, this novel machine generates a mainstream smoke aerosol by automatically "playing-back" puff topography recordings. Because combustion chemistry is highly non-linear, representing real smoking behavior with a smoothed periodic waveform may result in a tobacco smoke aerosol with a significantly different chemical composition and physical properties than that generated by a smoker. The machine presented here utilizes a rapid closed-loop control algorithm coded in Labview to generate smoke aerosols for toxicological assessment and inhalation studies. To illustrate its use, dry particulate matter and carbon monoxide yields generated using the playback and equivalent periodic puffing regimens are compared for a single smoking session by a 26-year-old male narghile water-pipe smoker. It was found that the periodic puffing regimen yielded 20% less carbon monoxide (CO) than the played-back smoking session, indicating that steady periodic smoking regimens, which are widely used in tobacco smoke research, may not produce realistic smoke aerosols.
Changes in Unprotonated Nicotine Concentration in Cigarette Mainstream Smoke with Three Machine-Smoking Conditions Site of Protonation of Nicotine and Nornicotine in the Gas Phase: Pyridine or Pyrrolidine Nitrogen?
- J.-M Lee
- G.-C Jang
- J.-T Lee
- J.-W Park
- D.-Y Kim
- H.-K Kim
- K.-J Hwang
- Y.-K Graton
- J Berthelot
- M Gal
- J.-F Girard
- S Laurence
- C Lebreton
- Le Questel
- J.-Y Maria
- P.-C Nauš
Lee, J.-M., Jang, G.-C., Lee, J.-T., Park, J.-W., Kim, D.-Y., Kim, H.-
K., Hwang, K.-J., and Min, Y.-K. (2006) Changes in Unprotonated
Nicotine Concentration in Cigarette Mainstream Smoke with Three
Machine-Smoking Conditions. J. Kor. Soc. Tob. Sci. 28, 136−143.
(9) Graton, J., Berthelot, M., Gal, J.-F., Girard, S., Laurence, C.,
Lebreton, J., Le Questel, J.-Y., Maria, P.-C., and Nauš, P. (2002) Site of
Protonation of Nicotine and Nornicotine in the Gas Phase: Pyridine or
Pyrrolidine Nitrogen? J. Am. Chem. Soc. 124, 10552−10562.
(10) Reininghaus, W. (1994) Bioavailability of Nicotine, Philip Morris
Research Center USA, Richmond, VA.
(11) Goniewicz, M. L., Hajek, P., and McRobbie, H. (2014) Nicotine
content of electronic cigarettes, its release in vapour and its consistency
across batches: regulatory implications. Addiction 109, 500−507.
Chemical hazards present in liquids and vapors of electronic cigarettes A Systematic Review of Nicotine by Inhalation: Is There a Role for the Inhaled Route?
- C Hutzler
- M Paschke
- S Kruschinski
- F Henkler
- J Hahn
- A Luch
- B Caldwell
- W Sumner
- J Crane
Hutzler, C., Paschke, M., Kruschinski, S., Henkler, F., Hahn, J.,
and Luch, A. (2014) Chemical hazards present in liquids and vapors of
electronic cigarettes. Arch. Toxicol. 88, 1295−1308.
(16) Caldwell, B., Sumner, W., and Crane, J. (2012) A Systematic
Review of Nicotine by Inhalation: Is There a Role for the Inhaled Route?
Nicotine Tob. Res. 14, 1127−1139.
A Consideration of the Role of Gas/Particle Partitioning in the Deposition of Nicotine and Other Tobacco Smoke Compounds in the Respiratory Tract Apparatus for the Determination of Water Solubility in Hydrocarbon: Toluene and Alkylcyclohexanes (C6 to C8) from 30 to 180 °C
- J F Pankow
- C Marche
- C Ferronato
- De Hemptinne
Pankow, J. F. (2001) A Consideration of the Role of Gas/Particle
Partitioning in the Deposition of Nicotine and Other Tobacco Smoke
Compounds in the Respiratory Tract. Chem. Res. Toxicol. 14, 1465−
1481.
(19) Marche, C., Ferronato, C., De Hemptinne, J.-C., and Jose, J.
(2006) Apparatus for the Determination of Water Solubility in
Hydrocarbon: Toluene and Alkylcyclohexanes (C6 to C8) from 30 to
180 °C. J. Chem. Eng. Data 51, 355−359.
How Do I Choose Nicotine Level
- A Jha
Jha, A. How Do I Choose Nicotine Level/Strength?, http://www.
180smoke.com/blogs/e-cigarette-faq/9244123-how-do-i-choosenicotine-level-strength# (accessed on May 21, 2015).
Partition coefficients and their uses A Closed-Loop Control ″Playback″ Smoking Machine for Generating Mainstream Smoke Aerosols
- A Leo
- C Hansch
- D Elkins
(24) Leo, A., Hansch, C., and Elkins, D. (1971) Partition coefficients
and their uses. Chem. Rev. 71, 525−616.
(25) Shihadeh, A., and Azar, S. (2006) A Closed-Loop Control
″Playback″ Smoking Machine for Generating Mainstream Smoke
Aerosols. J. Aerosol Med. 19, 137−147.
Chemical Research in Toxicology Article DOI: 10.1021/acs.chemrestox.5b00107
Chemical Research in Toxicology
Article
DOI: 10.1021/acs.chemrestox.5b00107
Chem. Res. Toxicol. 2015, 28, 1532−1537
Preliminary Results of an Examination of Electronic Cigarette User Puff Topography: The Effect of a Mouthpiece-Based Topography Measurement Device on Plasma Nicotine and Subjective Effects Bringing attention to e-cigarette pH as an important element for research and regulation
- L Eissenberg
- T I Fujioka
L., and Eissenberg, T. (2015) Preliminary Results of an Examination of
Electronic Cigarette User Puff Topography: The Effect of a Mouthpiece-Based Topography Measurement Device on Plasma Nicotine and
Subjective Effects. Nicotine Tob. Res. 17, 142−149.
(30) Stepanov, I., Fujioka, N. (2015) Bringing attention to e-cigarette
pH as an important element for research and regulation. Tobacco
Control, in press. DOI: 2441310.1136/tobaccocontrol-2014-051540.
Changes in Unprotonated Nicotine Concentration in Cigarette Mainstream Smoke with Three Machine-Smoking Conditions
- J.-M Lee
- G.-C Jang
- J.-T Lee
- J.-W Park
- D.-Y Kim
- H.-K Kim
- K.-J Hwang
Lee, J.-M., Jang, G.-C., Lee, J.-T., Park, J.-W., Kim, D.-Y., Kim, H.-K., Hwang, K.-J., and Min, Y.-K. (2006) Changes in Unprotonated
Nicotine Concentration in Cigarette Mainstream Smoke with Three
Machine-Smoking Conditions. J. Kor. Soc. Tob. Sci. 28, 136−143.