Formation of Redox-Active Duroquinone from Vaping of Vitamin E Acetate Contributes to Oxidative Lung Injury.

In late 2019, the outbreak of e-cigarette or vaping-associated lung injuries (EVALIs) in the United States demonstrated to the public the potential health risks of vaping. While studies since the outbreak have identified vitamin E acetate (VEA), a diluent of tetrahydrocannabinol (THC) in vape cartridges, as a potential contributor to lung injuries, the molecular mechanisms through which VEA may cause damage are still unclear. Recent studies have found that the thermal degradation of e-liquids during vaping can result in the formation of products that are more toxic than the parent compounds. In this study, we assessed the role of duroquinone (DQ) in VEA vaping emissions that may act as a mechanism through which VEA vaping causes lung damage. VEA vaping emissions were collected and analyzed for their potential to generate reactive oxygen species (ROS) and induce oxidative stress-associated gene expression in human bronchial epithelial cells (BEAS-2B). Significant ROS generation by VEA vaping emissions was observed in both acellular and cellular systems. Furthermore, exposure to vaping emissions resulted in significant upregulation of NQO1 and HMOX-1 genes in BEAS-2B cells, indicating a strong potential for vaped VEA to cause oxidative damage and acute lung injury; the effects are more profound than exposure to equivalent concentrations of DQ alone. Our findings suggest that there may be synergistic interactions between thermal decomposition products of VEA, highlighting the multifaceted nature of vaping toxicity.

Cigarette smoke preparations, not electronic nicotine delivery system preparations, induce features of lung disease in a 3D lung repeat-dose model.

Cigarette smoking is a risk factor for several lung diseases, including chronic obstructive pulmonary disease, cardiovascular disease, and lung cancer. The potential health effects of chronic use of electronic nicotine delivery systems (ENDS) is unclear. This study utilized fully differentiated primary normal human bronchial epithelial (NHBE) cultures in a repeat-dose exposure to evaluate and compare the effect of combustible cigarette and ENDS preparations. We show that 1-h daily exposure of NHBE cultures over a 10-day period to combustible cigarette whole smoke-conditioned media (WS-CM) increased expression of oxidative stress markers, cell proliferation, airway remodeling, and cellular transformation markers and decreased mucociliary function including ion channel function and airway surface liquid. Conversely, aerosol conditioned media (ACM) from ENDS with similar nicotine concentration (equivalent-nicotine units) as WS-CM and nicotine alone had no effect on those parameters. In conclusion, primary NHBE cultures in a repeat-dose exposure system represent a good model to assess the features of lung disease. This study also reveals that cigarette and ENDS preparations differentially elicit several key endpoints, some of which are potential biomarkers for lung cancer or chronic obstructive pulmonary disease (COPD).

Understanding potential mechanisms of harm: the drivers of electronic cigarette-induced changes in alveolar macrophages, neutrophils, and lung epithelial cells.

Electronic (e-) cigarettes are growing in popularity despite uncertainties regarding their long-term health implications. The link between cigarette smoking and initiation of chronic lung disease took decades to unpick so in vitro studies mimicking e-cigarette exposure aim to detect early indicators of harm. In response to e-cigarette exposure, alveolar macrophages adopt a proinflammatory phenotype of increased secretion of proinflammatory cytokines, reduction in phagocytosis, and efferocytosis and reactive oxygen species generation. These effects are largely driven by free radical exposure, changes in PI3K/Akt signaling pathways, nicotine-induced reduction in phagocytosis receptors, and impaired lipid homeostasis leading to a foam-like lipid-laden phenotype. Neutrophils exhibit disrupted chemotaxis and transmigration to chemokines, reduced phagocytosis and bacterial killing, and an increase in protease secretion without corresponding antiproteases in response to e-cigarette exposure. This is driven by an altered ability to respond and to polarize toward chemoattractants, an activation of the p38 MAPK signaling pathway and inability to assemble NADPH oxidase. E-cigarettes induce lung epithelial cells to display decreased ciliary beat frequency and ion channel conductance as well as changes in chemokine secretion and surface protein expression. Changes in gene expression, mitochondrial function, and signaling pathways have been demonstrated in lung epithelial cells to explain these changes. Many functional outputs of alveolar macrophages, neutrophils, and lung epithelial cells have not been fully explored in the context of e-cigarette exposure and the underlying driving mechanisms are poorly understood. This review discusses current evidence surrounding the effects of e-cigarettes on alveolar macrophages, neutrophils, and lung epithelial cells with particular focus on the cellular mechanisms of change.

An updated overview of e-cigarette impact on human health.

The electronic cigarette (e-cigarette), for many considered as a safe alternative to conventional cigarettes, has revolutionised the tobacco industry in the last decades. In e-cigarettes, tobacco combustion is replaced by e-liquid heating, leading some manufacturers to propose that e-cigarettes have less harmful respiratory effects than tobacco consumption. Other innovative features such as the adjustment of nicotine content and the choice of pleasant flavours have won over many users. Nevertheless, the safety of e-cigarette consumption and its potential as a smoking cessation method remain controversial due to limited evidence. Moreover, it has been reported that the heating process itself can lead to the formation of new decomposition compounds of questionable toxicity. Numerous in vivo and in vitro studies have been performed to better understand the impact of these new inhalable compounds on human health. Results of toxicological analyses suggest that e-cigarettes can be safer than conventional cigarettes, although harmful effects from short-term e-cigarette use have been described. Worryingly, the potential long-term effects of e-cigarette consumption have been scarcely investigated. In this review, we take stock of the main findings in this field and their consequences for human health including coronavirus disease 2019 (COVID-19).

Short halt in vaping modifies cardiorespiratory parameters and urine metabolome: a randomized trial.

Propylene glycol and glycerol are e-cigarette constituents that facilitate liquid vaporization and nicotine transport. As these small hydrophilic molecules quickly cross the lung epithelium, we hypothesized that short-term cessation of vaping in regular users would completely clear aerosol deposit from the lungs and reverse vaping-induced cardiorespiratory toxicity. We aimed to assess the acute effects of vaping and their reversibility on biological/clinical cardiorespiratory parameters [serum/urine pneumoproteins, hemodynamic parameters, lung-function test and diffusing capacities, transcutaneous gas tensions (primary outcome), and skin microcirculatory blood flow]. Regular e-cigarette users were enrolled in this randomized, investigator-blinded, three-period crossover study. The periods consisted of nicotine-vaping (nicotine-session), nicotine-free vaping (nicotine-free-session), and complete cessation of vaping (stop-session), all maintained for 5 days before the session began. Multiparametric metabolomic analyses were used to verify subjects' protocol compliance. Biological/clinical cardiorespiratory parameters were assessed at the beginning of each session (baseline) and after acute vaping exposure. Compared with the nicotine- and nicotine-free-sessions, a specific metabolomic signature characterized the stop-session. Baseline serum club cell protein-16 was higher during the stop-session than the other sessions (P < 0.01), and heart rate was higher in the nicotine-session (P < 0.001). Compared with acute sham-vaping in the stop-session, acute nicotine-vaping (nicotine-session) and acute nicotine-free vaping (nicotine-free-session) slightly decreased skin oxygen tension (P < 0.05). In regular e-cigarette-users, short-term vaping cessation seemed to shift baseline urine metabolome and increased serum club cell protein-16 concentration, suggesting a decrease in lung inflammation. Additionally, acute vaping with and without nicotine decreased slightly transcutaneous oxygen tension, likely as a result of lung gas exchanges disturbances.

Cell-specific toxicity of short-term JUUL aerosol exposure to human bronchial epithelial cells and murine macrophages exposed at the air-liquid interface.

BACKGROUD: JUUL, an electronic nicotine delivery system (ENDS), which first appeared on the US market in 2015, controled more than 75% of the US ENDS sales in 2018. JUUL-type devices are currently the most commonly used form of ENDS among youth in the US. In contrast to free-base nicotine contained in cigarettes and other ENDS, JUUL contains high levels of nicotine salt (35 or 59 mg/mL), whose cellular and molecular effects on lung cells are largely unknown. In the present study, we evaluated the in vitro toxicity of JUUL crème brûlée-flavored aerosols on 2 types of human bronchial epithelial cell lines (BEAS-2B, H292) and a murine macrophage cell line (RAW 264.7). METHODS: Human lung epithelial cells and murine macrophages were exposed to JUUL crème brûlée-flavored aerosols at the air-liquid interface (ALI) for 1-h followed by a 24-h recovery period. Membrane integrity, cytotoxicity, extracellular release of nitrogen species and reactive oxygen species, cellular morphology and gene expression were assessed. RESULTS: Crème brûlée-flavored aerosol contained elevated concentrations of benzoic acid (86.9 µg/puff), a well-established respiratory irritant. In BEAS-2B cells, crème brûlée-flavored aerosol decreased cell viability (≥ 50%) and increased nitric oxide (NO) production (≥ 30%), as well as iNOS gene expression. Crème brûlée-flavored aerosol did not affect the viability of either H292 cells or RAW macrophages, but increased the production of reactive oxygen species (ROS) by ≥ 20% in both cell types. While crème brûlée-flavored aerosol did not alter NO levels in H292 cells, RAW macrophages exposed to crème brûlée-flavored aerosol displayed decreased NO (≥ 50%) and down-regulation of the iNOS gene, possibly due to increased ROS. Additionally, crème brûlée-flavored aerosol dysregulated the expression of several genes related to biotransformation, inflammation and airway remodeling, including CYP1A1, IL-6, and MMP12 in all 3 cell lines. CONCLUSION: Our results indicate that crème brûlée-flavored aerosol causes cell-specific toxicity to lung cells. This study contributes to providing scientific evidence towards regulation of nicotine salt-based products.

Characterization of Volatile Organic Compound Metabolites in Cigarette Smokers, Electronic Nicotine Device Users, Dual Users, and Nonusers of Tobacco.

INTRODUCTION: Limited research exists about the possible cardiovascular effects of electronic nicotine delivery systems (ENDS). We therefore sought to compare exposure to known or potentially cardiotoxic volatile organic compounds (VOCs) in ENDS users, smokers, and dual users. METHODS: A total of 371 individuals from the Cardiovascular Injury due to Tobacco Use study, a cross-sectional study of healthy participants aged 21-45 years, were categorized as nonusers of tobacco (n = 87), sole ENDS users (n = 17), cigarette smokers (n = 237), and dual users (n = 30) based on 30-day self-reported tobacco product use patterns. Participants provided urine samples for VOC and nicotine metabolite measurement. We assessed associations between tobacco product use and VOC metabolite measures using multivariable-adjusted linear regression models. RESULTS: Mean (SD) age of the population was 32 (±6.8) years, 55% men. Mean urinary cotinine level in nonusers of tobacco was 2.6 ng/mg creatinine, whereas cotinine levels were similar across all tobacco product use categories (851.6-910.9 ng/mg creatinine). In multivariable-adjusted models, sole ENDS users had higher levels of metabolites of acrolein, acrylamide, acrylonitrile, and xylene compared with nonusers of tobacco, but lower levels of most VOC metabolites compared with cigarette smokers or dual users. In direct comparison of cigarettes smokers and dual users, we found lower levels of metabolites of styrene and xylene in dual users. CONCLUSION: Although sole ENDS use may be associated with lower VOC exposure compared to cigarette smoking, further study is required to determine the potential health effects of the higher levels of certain reactive aldehydes, including acrolein, in ENDS users compared with nonusers of tobacco. IMPLICATIONS: ENDS use in conjunction with other tobacco products may not significantly reduce exposure to VOC, but sole use does generally reduce some VOC exposure and warrants more in-depth studies.

Associations Between Self-Reported and Biological Measures of Nicotine Consumption Among Young Adult Nondaily Cigarette Smokers.

BACKGROUND AND OBJECTIVES: Intermittent, dual use of cigarettes and e-cigarettes is a common pattern among youth and young adults. However, little is known about the validity of self-report measures of nicotine consumption in these populations. The goal of the present study was to examine associations between self-reported frequency of cigarette and e-cigarette use and nicotine levels in hair samples at two assessments 1 year apart. METHODS: Participants (n = 90; 65% female) were 19- to 25-year-old intermittent cigarette smokers recruited from the community for a longitudinal study of tobacco use. They submitted hair samples via mail, 1 and 2 years after enrollment in the parent study. RESULTS: Findings indicated that days of use of both cigarettes and e-cigarettes in the past 30 days independently predicted hair nicotine in the full sample, and when examining only timepoints at which any cigarette use was reported. Timepoints when any e-cigarette use was reported, hair nicotine was positively associated with e-cigarette but not cigarette frequency. DISCUSSION AND CONCLUSIONS: Data suggest that self-report measures are valid methods of assessing intermittent use of both cigarettes and e-cigarettes. Findings also suggest that dual users may tend to consume more nicotine and thus be at greater risk for dependence than single product users. SCIENTIFIC SIGNIFICANCE: These results are among the first to indicate that hair analysis can be used to detect intermittent nicotine exposure via both cigarettes and e-cigarettes. (Am J Addict 2020;29:471-475).

Determining the impact of flavored e-liquids on aldehyde production during Vaping.

1,2-Propylene glycol and glycerin, principal components of e-liquids, can thermally degrade to form acetaldehyde, acrolein, and formaldehyde when heated in electronic nicotine delivery systems (ENDS). Recently the flavors in e-liquids were suggested to be the major source of these aldehydes. We used the same 10 ENDS devices to test 5 e-liquid formulations (four flavored & one corresponding non-flavored) and measured device mass loss and levels of acetaldehyde, acrolein, and formaldehyde (30 replicate measurements per formulation). Despite finding reasonable variability in measurements of device mass loss, two out of 10 ENDS devices tested produced outlier values for aerosol levels acetaldehyde, acrolein, and formaldehyde. After removing these devices from further analysis, acceptable variability (≤20% RSD) in aerosol levels of acetaldehyde, and formaldehyde were found. The flavored formulations tested resulted in a consistent and selective increase of 150%-200% in acetaldehyde, no increase or decrease in acrolein and depending on the flavor formulation, an increase, a decrease or no change in formaldehyde levels. Comparison of our results to the literature illustrates the need for development of a standardized ENDS testing protocol. Our results further support that device variability must be fully characterized and considered before assessing the impact of e-liquid formulations.

A Summary of In Vitro and In Vivo Studies Evaluating the Impact of E-Cigarette Exposure on Living Organisms and the Environment.

Worldwide use of electronic cigarettes has been rapidly expanding over recent years, but the long-term effect of e-cigarette vapor exposure on human health and environment is not well established; however, its mechanism of action entails the production of reactive oxygen species and trace metals, and the exacerbation of inflammation, which are associated with potential cytotoxicity and genotoxicity. The present study examines the effects of selected liquid chemicals used in e-cigarettes, such as propylene glycol/vegetable glycerin, nicotine and flavorings, on living organisms; the data collected indicates that exposure to e-cigarette liquid has potentially detrimental effects on cells in vitro, and on animals and humans in vivo. While e-liquid exposure can adversely influence the physiology of living organisms, vaping is recommended as an alternative for tobacco smoking. The study also compares the impact of e-cigarette liquid exposure and traditional cigarette smoke on organisms and the environmental impact. The environmental influence of e-cigarette use is closely connected with the emission of airborne particulate matter, suggesting the possibility of passive smoking. The obtained data provides an insight into the impact of nicotine delivery systems on living organisms and the environment.

Behavior-based yield for electronic cigarette users of different strength eliquids based on natural environment topography.

Introduction: The extent to which electronic cigarette users will compensate for lower nicotine eliquids has implications on the risk associated with regulating eliquid composition. This article elucidates topography as a compensatory mechanism by investigating the impact of nicotine strength on total particulate matter (TPM) and nicotine consumed per puff.Methods: Thirty-three experienced vape pen users were assigned an NJOY™ VapePen and AVAIL™ brand Tobacco Row eliquid with their usual nicotine strength (L = 6 mg/mL, M = 12 mg/mL, H = 18 mg/mL) and vaped through RIT's wPUMTM vape pen monitor to record every puff during 1 week. Nicotine and TPM yield per puff was determined accounting for the impact of topography characteristics on emissions and used to compute participant-specific mean yield per puff.Results: Nicotine yields ranged from 0.01 to 0.05 mg/puff and varied widely within each group (L, M, and H nicotine strength). Group-wise mean flow rate was lower for L compared to M (p = 0.2) and duration was higher compared to M (p = 0.09). Larger TPM was consumed per puff for L compared to M (p = 0.07), yet nicotine per puff for L was less than M (p = 0.3). H users took smaller volumes than L (p = 0.1) or M (p = 0.17), and there was little difference between L and M (p = 0.47).Conclusions: Evidence was provided for topography as a compensatory mechanism. Use of low nicotine strength eliquids can increase TPM, which can lead to increase in HPHC. Regulatory review of new products should consider natural use topography and realistic use exposures to nicotine, TPM and HPHCs.

E-cigarette use results in suppression of immune and inflammatory-response genes in nasal epithelial cells similar to cigarette smoke.

Exposure to cigarette smoke is known to result in impaired host defense responses and immune suppressive effects. However, the effects of new and emerging tobacco products, such as e-cigarettes, on the immune status of the respiratory epithelium are largely unknown. We conducted a clinical study collecting superficial nasal scrape biopsies, nasal lavage, urine, and serum from nonsmokers, cigarette smokers, and e-cigarette users and assessed them for changes in immune gene expression profiles. Smoking status was determined based on a smoking history and a 3- to 4-wk smoking diary and confirmed using serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) levels. Total RNA from nasal scrape biopsies was analyzed using the nCounter Human Immunology v2 Expression panel. Smoking cigarettes or vaping e-cigarettes resulted in decreased expression of immune-related genes. All genes with decreased expression in cigarette smokers (n = 53) were also decreased in e-cigarette smokers. Additionally, vaping e-cigarettes was associated with suppression of a large number of unique genes (n = 305). Furthermore, the e-cigarette users showed a greater suppression of genes common with those changed in cigarette smokers. This was particularly apparent for suppressed expression of transcription factors, such as EGR1, which was functionally associated with decreased expression of 5 target genes in cigarette smokers and 18 target genes in e-cigarette users. Taken together, these data indicate that vaping e-cigarettes is associated with decreased expression of a large number of immune-related genes, which are consistent with immune suppression at the level of the nasal mucosa.

Molecular and neuronal mechanisms underlying the effects of adolescent nicotine exposure on anxiety and mood disorders.

Tobacco addiction is highly co-morbid with a variety of mental health conditions, including schizophrenia, mood and anxiety disorders. Nicotine, the primary psychoactive compound in tobacco-related products is known to functionally modulate brain circuits that are disturbed in these disorders. Nicotine can potently regulate the transmission of various neurochemicals, including dopamine (DA), γ-amino-butyric acid (GABA) and glutamate, within various mesocorticolimbic structures, such as the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC), all of which show pathologies in these disorders. Many neuropsychiatric diseases have etiological origins during neurodevelopment, typically occurring during vulnerable periods of adolescent or pre-natal brain development. During these neurodevelopmental periods, exposure to extrinsic drug insults can induce enduring and long-term pathophysiological sequelae that ultimately increase the risk of developing chronic mental health disorders in later life. These vulnerability factors are of growing concern given rising rates of adolescent nicotine exposure via traditional tobacco use and the increasing use of alternative nicotine delivery formats such as vaping and e-cigarettes. A large body of clinical and pre-clinical evidence points to an important role for adolescent exposure to nicotine and increased vulnerability to developing mood and anxiety disorders in later life. This review will examine current clinical and pre-clinical evidence that pinpoints specific mechanisms within the mesocorticolimbic circuitry and molecular biomarkers linked to the association between adolescent nicotine exposure and increased risk of developing mood and anxiety-related disorders. This article is part of the special issue on 'Vulnerabilities to Substance Abuse'.

Breath analysis of smokers, non-smokers, and e-cigarette users.

Solid phase micro extraction-Gas Chromatography/Mass Spectrometry (SPME-GC/MS) analysis was performed in exhaled breath samples of 48 healthy volunteers: 20 non-smokers, 10 smokers and 18 e-cigarette (EC, vape) users. Each volunteer provided 1 L of exhaled breath in a pre-cleaned Tedlar bag, in which an SPME fiber was exposed to absorb the emitted breath volatile organic compounds (VOCs). The acquired data were processed using multivariate data analysis (MDA) methods in order to identify the characteristic chemicals of the three groups. The results revealed that the breath of non-smokers demonstrated inverse correlation with a variety of molecules related to the breath from smokers including furan, toluene, 2-butanone and other organic substances. Vapers were distinguished from smokers by the chemical speciation of the e-liquids, such as that of esters (e.g. ethyl acetate), terpenes (e.g. α-pinene, ß-pinene, d-limonene, p-cymene, etc.) and oxygenated compounds (e.g. 3-hexen-1-ol, benzaldehyde, hexanal, decanal, etc). Two classification models were developed (a) using principal component analysis (PCA) with hierarchical cluster analysis (HCA) and (b) using partial least squares-discriminant analysis (PLS-DA). Both models were validated using 8 new samples (4 vapers and 4 smokers), collected in addition to the 48 samples of the calibration set. The combination of GC/MS breath analysis and MDA contributed successfully in classifying the volunteers into their respective groups and highlighted the relevant characteristic VOCs. The respective dynamic combination (SPME-GC/MS and MDA) provides a means for long term non-invasive monitoring of the population's health status for early detection purposes.

The Association Between E-Cigarette Use Behaviors and Saliva Cotinine Concentration Among Healthy E-Cigarette Users in Malaysia.

Electronic cigarettes (e-cigarettes) have rapidly increased in popularity within the last 2 years in Malaysia. The study aims to understand the association between e-cigarette use behaviors and salivary cotinine (a CYP2AA metabolite of nicotine) concentration to inform the development of future e-cigarette control policies. A convenience sample of saliva from 144 e-cigarette users was obtained between November and December 2015. The study participants used refill liquid containing between 0 and 12 mg/ml of nicotine. The overall median cotinine concentration of the study participants was 81.1 ng/ml (interquartile range = 8.5-195.8). Among the zero-nicotine and single e-cigarette users, the median cotinine level was 51.1 (interquartile range = 8.20-125.35) ng/ml. Factors significantly associated with a higher salivary cotinine concentration were dual use of e-cigarettes and tobacco cigarettes, regular and daily e-cigarette use, a longer duration of e-cigarette use, using a higher amount of e-liquid, and a shorter duration to finish a refill. Multivariate analysis revealed that e-cigarette use of 1-6 and 6-12 months (but not 1 month and below) was significantly associated with a higher cotinine concentration. Cotinine found in zero-nicotine e-liquids implies the importance of stringent regulatory governance for the consistency of labeled nicotine content of e-cigarette liquid in the market. Zero-nicotine e-cigarette users should also be informed of the likelihood of environmental exposure to tobacco smoke. Future studies conducted on larger samples are warranted to validate the association between duration of e-cigarette use and salivary cotinine concentration as well as to investigate underlying mechanisms.

Replacing smoking with vaping during pregnancy: Impacts on metabolic health in mice.

Smoking is a significant risk factor for the development of metabolic diseases. Due to social pressures to quit smoking, many pregnant women are vaping as an alternative nicotine source. However, the metabolic consequences of replacing tobacco cigarettes with e-cigarettes during pregnancy are unknown. Therefore, in the mothers and their offspring, we investigated the metabolic and hepatic impacts of replacing cigarette smoke with e-vapour during pregnancy. Female BALB/c mice were either air-exposed or cigarette smoke-exposed (SE) from six weeks before pregnancy until lactation. At mating, a subset of the SE mice were instead exposed to e-vapour. Markers of glucose and lipid metabolism were measured in the livers and plasma, from the mothers and their male offspring (13 weeks). In the SE mothers, plasma insulin levels were reduced, leading to downstream increases in hepatic gluconeogenesis and plasma non-esterified fatty acids (NEFA). In the e-vapour replacement mothers, these changes were not as significant. In the SE offspring, there was impaired glucose tolerance, and increased plasma NEFA and liver triglyceride concentrations. E-vapour replacement restored lipid homeostasis but did not improve glucose tolerance. Therefore, in a murine model, low dose e-cigarette replacement during pregnancy is less toxic than cigarette smoke.

Effect of Pod e-Cigarettes vs Cigarettes on Carcinogen Exposure Among African American and Latinx Smokers: A Randomized Clinical Trial.

Importance: Fourth-generation nicotine salt pod system (NSPS) electronic cigarettes (e-cigarettes) are the leading class of e-cigarettes. They contain high nicotine concentrations, which may facilitate switching among smokers, but could also lead to increased exposure to nicotine and biomarkers of potential harm. African American and Latinx smokers experience significant tobacco-related health disparities. The potential of NSPS e-cigarettes to reduce smoking-related harm among these groups is unknown. Objective: To compare the harm reduction potential of NSPS e-cigarette vs combustible cigarettes. Design, Setting, and Participants: This unblinded randomized clinical trial compared 6 weeks of e-cigarette use vs cigarettes as usual from to 2018 to 2019 among smokers in the San Diego, California, and Kansas City, Missouri, areas. Participants included African American and Latinx adult combustible cigarette smokers who smoked at least 5 cigarettes/d on at least 25 of the past 30 days for at least 6 months and were interested in switching to e-cigarettes. Data were analyzed from September 18, 2019, to September 4, 2020. Interventions: 6 weeks of e-cigarette use in a choice of pod flavors (5% nicotine) along with brief education, training, and action planning to completely switch to e-cigarettes from combustible cigarettes. The control group smoked combustible cigarettes as usual. Main Outcomes and Measures: The primary outcome was reduction in urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentration at week 6. Secondary outcomes were change in urinary cotinine, expired carbon monoxide (CO), respiratory symptoms, lung function, blood pressure, past 7-day consumption of combustible cigarettes, and switching rates (e-cigarette group only) at weeks 2 and 6. Results: This study included 186 participants, including 92 African American participants and 94 Latinx participants. The mean (SD) age was 43.3 (12.5) years, and 75 (40.3%) were women. Participants smoked a mean (SD) of 12.1 (7.2) cigarettes/d on 6.8 (0.6) d/wk at baseline. A total of 125 participants were randomized to the e-cigarette group and 61 were randomized to the control group. At baseline, median (interquartile range) NNAL was 124 (45-197) pg/mL in the e-cigarette group and 88 (58-197) pg/mL in the control group. At week 6, the e-cigarette group had significantly greater reductions in NNAL (relative risk [RR], 0.36 [95% CI, 0.23-0.54]; P < .001), CO (RR, 0.53 [95% CI, 0.42-0.68]; P < .001), respiratory symptoms (RR, 0.63 [95% CI, 0.47-0.85]; P = .002), and number of cigarettes smoked in the past 7 days among those still smoking (RR, 0.30 [95% CI, 0.20-0.43]; P < .001) than the control group and maintained their cotinine levels (RR, 0.80 [95% CI, 0.58-1.10]; P = .17). Lung function and diastolic and systolic blood pressure remained unchanged and did not differ between groups. For participants randomized to receive e-cigarettes, 32 participants (28.1%) were exclusively using e-cigarettes at week 6, while 66 participants (57.9%) were dual using and 16 participants (14%) resumed exclusively using cigarettes. Conclusions and Relevance: These findings suggest that e-cigarettes may be an inclusive harm reduction strategy for African American and Latinx smokers. Trial Registration: ClinicalTrials.gov Identifier: NCT03511001.

Recent findings in the pharmacology of inhaled nicotine: Preclinical and clinical in vivo studies.

INTRODUCTION: The rise of vaping in adolescents, the recent entrance of new inhaled nicotine products such as iQOS on the market and e-cigarette or vaping product use-associated lung injury cases has created concern for the use of inhaled non-combustible nicotine products. This narrative review discusses recent experimental in vivo studies that utilize human, rat and mouse models to understand the pharmacological impact of nicotine from non-combustible products. METHODS: The search engine PubMed was utilized with the following search terms: inhaled nicotine, nicotine e-cigarette, heated tobacco products, iQOS, electronic cigarette, nicotine inhaler, nicotine vaping. This review highlights recent primary in vivo studies of inhaled nicotine administration experimental paradigms that occurred in laboratory settings using human and rodent (rats and mice) models that have been published from January 2017-December 2019. RESULTS: The pharmacokinetics of nicotine via e-cigarettes is influenced by the PG/VG and flavor constituents in e-liquids, the presence of nicotine salts in e-liquids, puff topography of nicotine and tobacco product users and the power of the e-cigarette device. The pharmacodynamic impact of inhaled nicotine has cardiovascular, pulmonary and central nervous system implications. CONCLUSION: The articles reviewed here highlight the importance of both animal and human models to fully understand the impact of inhaled nicotine pharmacology There is a need for more rodent pharmacokinetic inhaled nicotine studies to understand the influences of factors such as flavor and nicotine salts. Additionally, consensus on nicotine measurement in both human and rodent studies is greatly needed.

Nicotine absorption from e-cigarettes over 12 months.

BACKGROUND: Research indicates that, over time, exclusive e-cigarette users (vapers) gradually reduce the nicotine concentration in their e-liquid and transition to more sophisticated devices. Alongside this, consumption of e-liquid increases and constant cotinine levels are maintained. AIMS: We aimed to confirm these observations in 27 experienced vapers tested at baseline and 12 months later, by measuring nicotine absorption (via salivary levels of the nicotine metabolite cotinine; ng/mL), nicotine concentrations in e-liquid (mg/mL), volume of e-liquid consumed (mL per day), device types and flavours used, both at baseline and 12 months. RESULTS: Vapers reduced both their nicotine concentrations in e-liquid over 12 months (from 13.83 mg/mL at baseline to 9.91 at follow up) but significantly increased their e-liquid consumption (from 4.44 to 6.84 mL). No significant changes in salivary cotinine concentrations (370.88 ng/mL at baseline and 415.78 ng/mL at follow up) were observed. There was an increase in sub-ohming (using an atomiser coil with resistance of <1â€¯Ω with increased power) at 12 months, and in the use of fruit flavoured e-liquids. CONCLUSIONS: Our sample of experienced vapers reduced the concentration of nicotine in their e-liquid over time, but maintained their nicotine intake possibly through self-titration via more intensive puffing. Findings suggest there may be little benefit in reducing nicotine e-liquid concentration since this appears to result in higher e-liquid consumption which may incur both a financial and health cost. Gaining an understanding of underlying reasons for lowering e-liquid concentration would be a useful line of empirical enquiry.

The relationship between nicotine metabolism and nicotine and carcinogen exposure among American Indian commercial cigarette smokers and electronic nicotine delivery system users.

BACKGROUND: In American Indian (AI) tobacco users from the southern plains region of the US, we examined the relationship between nicotine and carcinogen exposure and nicotine metabolism. METHODS: Smokers (n = 27), electronic nicotine delivery system (ENDS) users (n = 21), and dual users (n = 25) of AI descent were recruited from a southern plains state. Urinary biomarkers of nicotine metabolism (nicotine metabolite ratio [NMR]), nicotine dose (total nicotine equivalents [TNE]), and a tobacco-specific lung carcinogen (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides [total NNAL] were measured. RESULTS: The geometric mean of NMR was 3.35 (95% Confidence Interval(CI): 2.42, 4.65), 4.67 (95% CI: 3.39, 6.43), and 3.26 (95% CI: 2.44, 4.37) among smokers, ENDS users, and dual users. Each of the three user groups had relatively low levels of TNE, indicative of light tobacco use. Among smokers, there were inverse relationships between NMR and TNE (r = -0.45) and between NMR and NNAL (r = -0.50). Among dual users, NMR and TNE, and NMR and NNAL were not associated. Among ENDS users, NMR and TNE were not associated. CONCLUSIONS: AI tobacco users with higher NMR did not have higher TNE or NNAL exposure than those with lower NMR. This supports prior work among light tobacco users who do not alter their tobacco consumption to account for nicotine metabolism. IMPACT: The high prevalences of smoking and ENDS among AI in the southern plains may not be related to nicotine metabolism. Environmental and social cues may play a more important role in light tobacco users and this may be particularly true among AI light tobacco users who have strong cultural ties.