E-vapor Products Research Articles

Assessing Product Use Behavior and Exposure: Definitions and Methods

Summary In recent years, the tobacco- and/or nicotine-containing product (TNP) portfolio has expanded to include products such as e-vapor products, heated tobacco products, and nicotine pouches. Although scientific papers and regulatory requirements/recommendations related to the assessment of product use behavior and exposure to product use have been published for these novel TNPs, there is great diversity in the terminology used to characterize and assess these types of products. The aim of this paper is to define the terms and methods used for assessing product use behavior and exposure, with the objective to suggest a uniform application of terms used by scientists working in this field of research. This publication is the work product of a cross-industry work item commissioned by the Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) Product Use Behaviour and Biomarkers Subgroups.

Pitfalls in the Detection of Volatiles Associated with Heated Tobacco and e-Vapor Products When Using PTR-TOF-MS.

We investigated the applicability of proton transfer reaction-time-of-flight mass spectrometry (PTR-TOF-MS) for quantitative analysis of mixtures comprising glycerin, acetol, glycidol, acetaldehyde, acetone, and propylene glycol. While PTR-TOF-MS offers real-time simultaneous determination, the method selectivity is limited when analyzing compounds with identical elemental compositions or when labile compounds present in the mixture produce fragments that generate overlapping ions with other matrix components. In this study, we observed significant fragmentation of glycerin, acetol, glycidol, and propylene glycol during protonation via hydronium ions (H3O+). Nevertheless, specific ions generated by glycerin (m/z 93.055) and propylene glycol (m/z 77.060) enabled their selective detection. To thoroughly investigate the selectivity of the method, various mixtures containing both isotope-labeled and unlabeled compounds were utilized. The experimental findings demonstrated that when samples contained high levels of glycerin, it was not feasible to perform time-resolved analysis in H3O+ mode for acetaldehyde, acetol, and glycidol. To overcome the observed selectivity limitations associated with the H3O+ reagent ions, alternative ionization modes were investigated. The ammonium ion mode proved appropriate for analyzing propylene glycol (m/z 94.086) and acetone (m/z 76.076) mixtures. Concerning the nitric oxide mode, specific m/z were identified for acetaldehyde (m/z 43.018), acetone (m/z 88.039), glycidol (m/z 73.028), and propylene glycol (m/z 75.044). It was concluded that considering the presence of multiple product ions and the potential influence of other compounds, it is crucial to conduct a thorough selectivity assessment when employing PTR-TOF-MS as the sole method for analyzing compounds in complex matrices of unknown composition.

Blood and urine multi-omics analysis of the impact of e-vaping, smoking, and cessation: from exposome to molecular responses

Cigarette smoking is a major preventable cause of morbidity and mortality. While quitting smoking is the best option, switching from cigarettes to non-combustible alternatives (NCAs) such as e-vapor products is a viable harm reduction approach for smokers who would otherwise continue to smoke. A key challenge for the clinical assessment of NCAs is that self-reported product use can be unreliable, compromising the proper evaluation of their risk reduction potential. In this cross-sectional study of 205 healthy volunteers, we combined comprehensive exposure characterization with in-depth multi-omics profiling to compare effects across four study groups: cigarette smokers (CS), e-vapor users (EV), former smokers (FS), and never smokers (NS). Multi-omics analyses included metabolomics, transcriptomics, DNA methylomics, proteomics, and lipidomics. Comparison of the molecular effects between CS and NS recapitulated several previous observations, such as increased inflammatory markers in CS. Generally, FS and EV demonstrated intermediate molecular effects between the NS and CS groups. Stratification of the FS and EV by combustion exposure markers suggested that this position on the spectrum between CS and NS was partially driven by non-compliance/dual use. Overall, this study highlights the importance of in-depth exposure characterization before biological effect characterization for any NCA assessment study.

An in vitro evaluation of e-vapor products: The contributions of chemical adulteration, concentration, and device power.

Homemade e-liquids and power-adjustable vaping devices may carry higher risks than commercial formulations and fixed-power devices. This study used human macrophage-like and bronchial epithelial (NHBE) cell cultures to investigate toxicity of homemade e-liquids containing propylene glycol and vegetable glycerin (PG/VG), nicotine, vitamin E acetate (VEA), medium-chain fatty acids (MCFAs), phytol, and cannabidiol (CBD). SmallAir™ organotypic epithelial cultures were exposed to aerosols generated at different power settings (10-50 W). Carbonyl levels were measured, and endpoints reflecting epithelial function (ciliary beating frequency [CBF]), integrity (transepithelial electrical resistance [TEER]), and structure (histology) were investigated. Treatment with nicotine or VEA alone or with PG/VG did not impact cell viability. CBD, phytol, and lauric acid caused cytotoxicity in both culture systems and increased lipid-laden macrophages. Exposure of SmallAir™ organotypic cultures to CBD-containing aerosols resulted in tissue injury and loss of CBF and TEER, while PG/VG alone or with nicotine or VEA did not. Aerosols generated with higher power settings had higher carbonyl concentrations. In conclusion, the presence and concentration of certain chemicals and device power may induce cytotoxicity in vitro. These results raise concerns that power-adjustable devices may generate toxic compounds and suggest that toxicity assessments should be conducted for both e-liquid formulations and their aerosols.

Toxicological Assessment of Flavor Ingredients in E-Vapor Products.

Many flavor ingredients are often used in potentially reduced-risk tobacco products (such as e-vapor products). Although most are “generally recognized as safe (GRAS)” when used in food, there is limited information available on their long-term health effects when delivered by inhalation. While obtaining route-of-exposure-specific toxicological data on flavor ingredients is critical to product evaluation, the large number of individual flavor ingredients available and their potential combinations render classical toxicological assessment approaches impractical, as they may require years of preclinical investigations and thousands of laboratory animals. Therefore, we propose a pragmatic approach in which flavor ingredients are initially assigned to groups of structurally related compounds (Flavor Groups), from which flavor group representatives (FGR) are then selected and tested individually and as a mixture in vitro and in vivo. The premise is that structurally related compounds would have comparable metabolic and biological activity and that the data generated using FGRs could support the toxicological assessment of other structurally related flavor ingredients of their respective Flavor Groups. This approach is explained in a step-wise manner and exemplified by a case study, along with its strengths, limitations as well as recommendations for further confirmatory testing. Once completed, this FGR approach could significantly reduce the time and resources required for filling the data gap in understanding the health risks of many flavor ingredients while also minimizing the need for laboratory animals.

Biomarkers of Exposure and Biomarkers of Potential Harm in Adult Smokers Who Switch to e-Vapor Products Relative to Cigarette Smoking in a 24-week, Randomized, Clinical Trial.

IntroductionLong-term health effects of e-vapor products (EVPs) are not well-established. We compared biomarkers of exposure (BoE) to select harmful and potentially harmful constituents and biomarkers of potential harm (BoPH) in adult smokers who switched to EVPs versus continued smoking for 24 weeks.MethodsAdult smokers (n = 450, >10 cigarettes per day for ≥10 years) were randomly assigned to continue smoking (control) or switch to one of two cartridge-based EVPs (test 1: classic; test 2: menthol, 4% nicotine). BoE and BoPH were measured at baseline and 12 weeks. The results presented here are from a subset of 150 control and EVP subjects (switchers with exhaled carbon monoxide <8 ppm and <10% baseline cigarettes per day) followed for 24 total weeks.ResultsTotal 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and carboxyhemoglobin were significantly reduced (p < .0001) in tests 1 and 2 at 24 weeks. Urinary nicotine equivalents were not statistically significantly different between the control and EVP groups. At week 24, statistically significant reductions (p < .05) were observed for white blood cell counts, 11-dehydrothromboxane β2, and sICAM in both test groups, and there were several significant changes in measures of pulmonary function. High-density lipoprotein cholesterol and 8-epi-prostaglandin-F2α were directionally favorable in both EVP groups versus control.ConclusionsWe demonstrate that significant reductions of selected harmful and potentially harmful constituents in EVP aerosol results in significant reductions in BoEs and favorable changes in BoPHs after switching to EVPs for 24 weeks. These changes approached those reported for smoking cessation, suggesting that switching to exclusive use of the EVPs may be less harmful than continuing smoking.ImplicationsCigarette smoking causes serious diseases. Switching from cigarettes to a noncombustible product is a potential harm reduction pathway for adult smokers unable or unwilling to quit. Long-term health effects of e-vapor products (EVPs) compared with continued smoking have not been extensively studied. We present biomarker of exposure evidence on select harmful and potentially harmful constituents and biomarkers of potential harm related to inflammation and oxidative stress in adult smokers switching to two EVPs. This study demonstrates significant reductions in biomarkers of exposure (except for nicotine) accompanied with favorable changes in various biomarkers of potential harm, including pulmonary function. The totality of evidence suggests that exclusive EVP use may present lower health risks compared with smoking cigarettes.

Non-Targeted Analysis Using Gas Chromatography-Mass Spectrometry for Evaluation of Chemical Composition of E-Vapor Products.

The Premarket Tobacco Product Applications (PMTA) guidance issued by the Food and Drug Administration for electronic nicotine delivery systems (ENDSs) recommends that in addition to reporting harmful and potentially harmful constituents (HPHCs), manufacturers should evaluate these products for other chemicals that could form during use and over time. Although e-vapor product aerosols are considerably less complex than mainstream smoke from cigarettes and heated tobacco product (HTP) aerosols, there are challenges with performing a comprehensive chemical characterization. Some of these challenges include the complexity of the e-liquid chemical compositions, the variety of flavors used, and the aerosol collection efficiency of volatile and semi-volatile compounds generated from aerosols. In this study, a non-targeted analysis method was developed using gas chromatography-mass spectrometry (GC-MS) that allows evaluation of volatile and semi-volatile compounds in e-liquids and aerosols of e-vapor products. The method employed an automated data analysis workflow using Agilent MassHunter Unknowns Analysis software for mass spectral deconvolution, peak detection, and library searching and reporting. The automated process ensured data integrity and consistency of compound identification with >99% of known compounds being identified using an in-house custom mass spectral library. The custom library was created to aid in compound identifications and includes over 1,100 unique mass spectral entries, of which 600 have been confirmed from reference standard comparisons. The method validation included accuracy, precision, repeatability, limit of detection (LOD), and selectivity. The validation also demonstrated that this semi-quantitative method provides estimated concentrations with an accuracy ranging between 0.5- and 2.0-fold as compared to the actual values. The LOD threshold of 0.7 ppm was established based on instrument sensitivity and accuracy of the compounds identified. To demonstrate the application of this method, we share results from the comprehensive chemical profile of e-liquids and aerosols collected from a marketed e-vapor product. Applying the data processing workflow developed here, 46 compounds were detected in the e-liquid formulation and 55 compounds in the aerosol sample. More than 50% of compounds reported have been confirmed with reference standards. The profiling approach described in this publication is applicable to evaluating volatile and semi-volatile compounds in e-vapor products.

Thirteen-week nose-only inhalation exposures of propylene glycol aerosols in Sprague Dawley rats with a lung systems toxicology analysis

The objectives of this study were to increase PG exposure above concentrations tested by Suber et al. and use systems toxicology analysis of lung tissue to understand molecular events. Sprague Dawley rats were exposed to filtered air (sham), propylene glycol/water (PG/W; 90:10) or a propylene glycol/vegetable glycerin/water (PG/VG/W; 50:40:10) reference. The reference group was added at the high dose to observe any changes that might be associated with a carrier more in line with e-vapor products. Macroscopic examinations and terminal organ weights revealed no observations associated with exposure to PG/W or reference. Food consumption and body weights were unaffected by PG/W or reference when compared to sham. No exposure related alterations were observed in serum chemistry, hematology, coagulation, urinalysis or BALF cytology and clinical chemistry. Although clinical observations of dried red material around the nose in the high dose PG/W group were reported, histopathology showed no nasal hemorrhaging which was previously reported by Suber et al. Non-adverse PG/W and reference related findings of minimal mucous cell hyperplasia were noted in nasal cavity section II. No other exposure-related findings were noted in the primary or recovery necropsies. A systems toxicology analysis on lung tissue showed no statistically significant differentially expressed transcripts or proteins compared to the sham group. The endpoints measured from the PG/W high dose group did not differ significantly from those in the more common carrier PG/VG/W. As anticipated, exposure to PG aerosols was slightly irritating but well tolerated. Accordingly, the highest PG exposure (5 mg/L, 6 hrs/day) was regarded as the NOAEC, corresponding to a PG delivered dose of 1,152 mg/kg/day in rats.

A 7-month inhalation toxicology study in C57BL/6 mice demonstrates reduced pulmonary inflammation and emphysematous changes following smoking cessation or switching to e-vapor products

Cigarette smoking causes serious diseases, including lung cancer, atherosclerotic coronary artery disease, peripheral vascular disease, chronic bronchitis, and emphysema. While cessation remains the most effective approach to minimize smoking-related disease, alternative non-combustible tobacco-derived nicotine-containing products may reduce disease risks among those unable or unwilling to quit. E-vapor aerosols typically contain significantly lower levels of smoke-related harmful and potentially harmful constituents; however, health risks of long-term inhalation exposures are unknown. We designed a 7-month inhalation study in C57BL/6 mice to evaluate long-term respiratory toxicity of e-vapor aerosols compared to cigarette smoke and to assess the impact of smoking cessation (Cessation group) or switching to an e-vapor product (Switching group) after 3 months of exposure to 3R4F cigarette smoke (CS). There were no significant changes in in-life observations (body weights, clinical signs) in e-vapor groups compared to the Sham Control. The 3R4F CS group showed reduced respiratory function during exposure and had lower body weight and showed transient signs of distress post-exposure. Following 7 months of exposure, e-vapor aerosols resulted in no or minimal increase in pulmonary inflammation, while exposure to 3R4F CS led to impairment of lung function and caused marked lung inflammation and emphysematous changes. Biological changes observed in the Switching group were similar to the Cessation group. 3R4F CS exposure dysregulated the lung and nasal tissue transcriptome, while these molecular effects were substantially lower in the e-vapor group. Results from this study demonstrate that in comparison with 3R4F CS, e-vapor aerosols induce substantially lower biological responses including pulmonary inflammation and emphysematous changes, and that complete switching from CS to e-vapor products significantly reduces biological changes associated with CS in C57BL/6 mice.

Viscosity Model for Liquid Mixtures of Propylene Glycol, Glycerol, and Water

The viscosity of liquid mixtures in e-vapor products (EVPs) is key to their performance and is sensitive to mixture composition and temperature. To date, no accurate model exists for the viscosities of said mixtures. Herein, we report an empirical model for the viscosity of liquid mixtures containing propylene glycol (PG), glycerol (GL), and water (W), representative of the mixtures in EVPs. The model captures the interactions between component liquids and makes accurate viscosity predictions for liquid mixtures of PG, GL, and W, as well as such mixtures containing small amounts of menthol, from 20 to 80 °C. The model is calibrated to new experimental data for PG–GL–W ternary mixtures and may be extended to incorporate different or additional liquids or a wider temperature range given additional fitting data. The model should also prove beneficial for food, cosmetic, and pharmaceutical products containing aqueous solutions of PG and GL.

Comparison of the biological impact of aerosol of e-vapor device with MESH® technology and cigarette smoke on human bronchial and alveolar cultures

Exposure to aerosol from electronic vapor (e-vapor) products has been suggested to result in less risk of harm to smokers than cigarette smoke (CS) exposure. Although many studies on e-vapor products have tested the effects of liquid formulations on cell cultures, few have evaluated the effects of aerosolized formulations. We examined the effects of acute exposure to the aerosol of an e-vapor device that uses the MESH® technology (IQOS® MESH, Philip Morris International) and to CS from the 3R4F reference cigarette on human organotypic bronchial epithelial culture and alveolar triculture models. In contrast to 3R4F CS exposure, exposure to the IQOS MESH aerosol (Classic Tobacco flavor) did not cause cytotoxicity in bronchial epithelial cultures or alveolar tricultures despite its greater concentrations of deposited nicotine (3- and 4-fold, respectively). CS exposure caused a marked decrease in the frequency and active area of ciliary beating in bronchial cultures, whereas IQOS MESH aerosol exposure did not. Global mRNA expression and secreted protein profiles revealed a significantly lower impact of IQOS MESH aerosol exposure than 3R4F CS exposure. Overall, our whole aerosol exposure study shows a clearly reduced impact of IQOS MESH aerosol relative to CS in bronchial and alveolar cultures, even at greater nicotine doses.

Ceramide ratios are affected by cigarette smoke but not heat-not-burn or e-vapor aerosols across four independent mouse studies

AimsSmoking is an important risk factor for the development of chronic obstructive pulmonary disease and cardiovascular diseases. This study aimed to further elucidate the role of ceramides, as a key lipid class dysregulated in disease states. Main methodsIn this article we developed and validated LC–MS/MS method for ceramides (Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1(15Z)) for the absolute quantification. We deployed it together with proteomics and transcriptomic analysis to assess the effects of cigarette smoke (CS) from the reference cigarette as well as aerosols from heat-not-burn (HnB) tobacco and e-vapor products in apolipoprotein E-deficient (ApoE−/−) mice over several time points. Key findingsIn the lungs, CS exposure substantially elevated the ratios of Cer(d18:1/24:0) and Cer(d18:1/24:1) to Cer(d18:1/18:0) in two independent ApoE−/− mouse inhalation studies. Data from previous studies, in both ApoE−/− and wild-type mice, further confirmed the reproducibility of this finding. Elevation of these ceramide ratios was also observed in plasma/serum, the liver, and—for the Cer(d18:1/24:1(15Z)) to Cer(d18:1/18:0) ratio—the abdominal aorta. Also, the levels of acid ceramidase (Asah1) and glucocerebrosidase (Gba)—lysosomal enzymes involved in the hydrolysis of glucosylceramides—were consistently elevated in the lungs after CS exposure. In contrast, exposure to HnB tobacco product and e-vapor aerosols did not induce significant changes in the ceramide profiles or associated enzymes. SignificanceOur work in mice contributes to the accumulating evidence on the importance of ceramide ratios as biologically relevant markers for respiratory disorders, adding to their already demonstrated role in cardiovascular disease risk assessment in humans.

Formation of Diacetyl and Other α-Dicarbonyl Compounds during the Generation of E-Vapor Product Aerosols.

Exposure to diacetyl (DA) has been linked to the respiratory condition bronchiolitis obliterans. Previous research has demonstrated that DA and other α-dicarbonyl compounds can be detected in both the e-liquids and aerosols of e-vapor products (EVPs). While some EVP manufacturers may add these compounds as flavor ingredients, the primary objective of this work was to determine the potential for the formation of α-dicarbonyl compounds during the generation of aerosols from EVPs where no DA or other α-dicarbonyl compounds are added to the e-liquid. A novel ultraperformance liquid chromatography-mass spectrometry-based analytical method for the determination of DA, acetyl propionyl, glyoxal, and methylglyoxal was developed and validated. Next, eight commercially available cig-a-like-type EVPs were evaluated for α-dicarbonyl formation. Increased levels of α-dicarbonyls were observed in the aerosols of all evaluated EVPs compared to their respective e-liquids. Mechanistic studies were conducted using a model microwave reaction system to identify key reaction precursors for DA generated from propylene glycol (PG) and carbon-13-labeled glycerin (GLY). These studies, along with the corresponding retrosynthetic analysis, resulted in the proposed formation pathway where hydroxyacetone is generated from PG and/or GLY. Hydroxyacetone then participates in an aldol condensation with formaldehyde where formaldehyde can also be generated from PG and/or GLY; the resultant product then dehydrates to form DA. This proposed pathway was further investigated through in situ synthetic organic experiments within the model microwave reaction system. This work establishes that DA is formed in the aerosol generation process of the EVPs tested though at levels below toxicological concern.

E-vapor aerosols do not compromise bone integrity relative to cigarette smoke after 6-month inhalation in an ApoE\u2013/\u2013 mouse model

Cigarette smoke (CS) exposure is one of the leading risk factors for human health. Nicotine-containing inhalable products, such as e-cigarettes, can effectively support tobacco harm reduction approaches. However, there are limited comparative data on the effects of the aerosols generated from electronic vapor products (e-vapor) and CS on bone. Here, we report the effects of e-vapor aerosols and CS on bone morphology, structure, and strength in a 6-month inhalation study. Eight-week-old ApoE–/– mice were exposed to aerosols from three different e-vapor formulations—CARRIER (propylene glycol and vegetable glycerol), BASE (CARRIER and nicotine), TEST (BASE and flavor)—to CS from 3R4F reference cigarettes at matched nicotine concentrations (35 µg/L) or to fresh air (Sham) (N = 10 per group). Tibiae were analyzed for bone morphology by µCT imaging, biomechanics by three-point bending, and by histological analysis. CS inhalation caused a significant decrease in cortical and total bone volume fraction and bone density relative to e-vapor aerosols. Additionally, CS exposure caused a decrease in ultimate load and stiffness. In contrast, bone structural and biomechanical parameters were not significantly affected by e-vapor aerosol or Sham exposure. At the dissection time point, there was no significant difference in body weight or tibia bone weight or length among the groups. Histological findings revealed microcracks in cortical bone areas among all exposed groups compared to Sham control. In conclusion, because of the bone-preserving effect of e-vapor aerosols relative to CS exposure, e-vapor products could potentially constitute less harmful alternatives to cigarettes in situations in which bone health is of importance.

State-of-the-art methods and devices for generation, exposure, and collection of aerosols from e-vapor products

E-vapor products (EVP) have become popular alternatives for cigarette smokers who would otherwise continue to smoke. EVP research is challenging and complex, mostly because of the numerous and rapidly evolving technologies and designs as well as the multiplicity of e-liquid flavors and solvents available on the market. There is an urgent need to standardize all stages of EVP assessment, from the production of a reference product to e-vapor generation methods and from physicochemical characterization methods to nonclinical and clinical exposure studies. The objective of this review is to provide a detailed description of selected experimental setups and methods for EVP aerosol generation and collection and exposure systems for their in vitro and in vivo assessment. The focus is on the specificities of the product that constitute challenges and require development of ad hoc assessment frameworks, equipment, and methods. In so doing, this review aims to support further studies, objective evaluation, comparison, and verification of existing evidence, and, ultimately, formulation of standardized methods for testing EVPs.

CARDIORESPIRATORY IMPACT OF E-VAPOR AEROSOLS AND CIGARETTE SMOKE EXPOSURE IN THE APOE KNOCKOUT MOUSE MODEL

Chronic exposure to cigarette smoke (CS) causes cardiorespiratory diseases in smokers. Considerable attention has been given to the reduced harm potential of alternative e-vapor products. ApoE-/- mice were used to evaluate lung inflammation, emphysematous changes, atherosclerosis development, and cardiovascular function upon chronic (6-month) exposure to fresh air (Sham), CS, or e-vapor aerosols. Mice were exposed to CS from 3R4F reference cigarettes or e-vapor aerosols generated using capillary aerosol generators from various e-liquids (“CARRIER” containing humectants [propylene glycol, glycerin], “BASE” containing humectants and nicotine, and “TEST” containing humectants, nicotine, and flavors) via a whole-body inhalation system. Exposure to CS at a nicotine concentration of 35 μg/L causes adverse effects on the lungs (including increased lung volume and inflammation), accelerates atherosclerotic plaque formation, and alters the cardiorespiratory transcriptome. CS exposure causes an impairment of both systolic and diastolic cardiac function, as assessed by ejection fraction, fractional shortening, isovolumic relaxation time, and E/A ratio. In comparison with CS, exposure to e-vapor aerosols lower atherosclerotic plaque formation, was associated with limited to absent inflammatory cells in the lung tissue, and induced substantially less molecular changes in cardiorespiratory transcriptomes. Ultrasound analysis highlighted that cardiac dysfunction and aortic stiffness were less prominent in nicotine-containing e-vapor aerosol-exposed groups than in the CS-exposed group. This study suggests that in comparison with CS, e-vapor aerosols induce substantially lower biological responses associated with smoking-related cardiovascular and pulmonary diseases.

Real-World Evidence of Differences in Biomarkers of Exposure to Select Harmful and Potentially Harmful Constituents and Biomarkers of Potential Harm Between Adult E-Vapor Users and Adult Cigarette Smokers

IntroductionReal-world evidence regarding likely long-term health effects of e-vapor products (EVP) under actual use conditions relative to cigarette smoking is not well studied.MethodsIn this cross-sectional, observational study, biomarkers of exposure (BOE) to select harmful and potentially harmful constituents and biomarkers of potential harm (BOPH) relevant to smoking-related diseases were measured in exclusive adult EVP users (AEVP, n = 144) and exclusive adult cigarette smokers (AS, n = 73). AEVP used their own brand of EVP for 6+ months following 10+ years of cigarette smoking and AS smoked own brand of cigarettes for 10+ years. Subject recruitment and informed consent were obtained online and urine/blood samples were collected at local clinical laboratories, representing a new paradigm for collecting real-world evidence.ResultsThe levels of total NNAL (NNK metabolite), 3-hydroxypropyl mercapturic acid (acrolein metabolite), and carboxyhemoglobin (carbon monoxide measure) were 46% to 86% lower in AEVP compared with AS (p ≤ .0001) as was nicotine equivalents (nicotine and its five metabolites; 36%, p < .01). The levels of some BOPH were significantly lower in AEVP compared with AS for 11-dehydrothromboxane-B2 (29%, p = .04; platelet activation), 8-epi-prostaglandin F2α (23%, p = .02; oxidative stress) and soluble intercellular adhesion molecule-1 (16%, p = .02; endothelial function). ConclusionsThis study demonstrates the feasibility of a new approach for collecting real-world evidence. Substantially lower levels of BOEs (NNK, nicotine, acrolein, carbon monoxide) and favorable differences in BOPHs (platelet activation, oxidative stress, endothelial function) suggest EVP users may have lower health risks than cigarette smokers.ImplicationsCigarette smoking causes serious diseases. Switching from a combustible tobacco product to a noncombustible product is a potential harm reduction pathway for adult smokers unable or unwilling to quit. Real-world evidence regarding the relative risk of EVP use compared with cigarettes is not well established. This study provides data specific to BOE to tobacco smoke constituents and biomarkers of potential harm collected under actual use conditions in a real-world setting. The totality of evidence suggests that exclusive EVP use may present lower health risk compared with smoking cigarettes.

Biomarkers of Exposure Specific to E-vapor Products Based on Stable-Isotope Labeled Ingredients.

An important basis for risk estimation for e-cigarette (e-cig) users is a well-founded dosimetry. The objective of this study was to assess the applicability of stable-isotope e-liquid ingredients for exposure studies in vapers. E-cigs with 10% of labeled propylene glycol (PG), glycerol (G), and nicotine was used by 20 experienced vapers under controlled (Part A) and free (Part B) conditions. In Part A, 10 subjects vaped at 10 W and another 10 subjects at 18 W power setting of the e-cig. In Part B, the same subjects used the same product ad libitum in their usual environment. Five smokers, smoking 10 non-filter cigarettes, spiked with labeled PG, G, and nicotine, served as positive control during Part A. PG, G, nicotine and its metabolites were measured in plasma, urine, and saliva. Peak nicotine levels (sum of measured labeled and unlabeled) in plasma were lower in vapers (15.8 to 19.6 ng/mL) than in smokers (36 ng/mL). The labeled plasma nicotine levels were ten times lower than the unlabeled, reflecting the ratio in the e-liquid. PG levels in plasma and urine also reflected the vaping activities in Part A, while G in these body fluids showed no association with vaping. This proof of concept study shows that the application of labeled e-liquid ingredients allows the accurate quantification of the dose of nicotine and PG when other nicotine and tobacco products were used simultaneously. Unchanged G was not assessable by this approach. This approach allows the investigations of the absorption of potential PG-, G-, and nicotine-derived vapor constituents (eg, aldehydes and epoxides) by vaping. Appropriate studies are in progress in our laboratory.

Characterization of puff topography of a prototype electronic cigarette in adult exclusive cigarette smokers and adult exclusive electronic cigarette users

Puff topography is an important measure of how consumers use e-vapor products. The purpose of this study was to evaluate the feasibility of using SODIM Smoking Puff Analyzer Mobile Device (SPA/M) to measure puff topography during use of a prototype e-cigarette (e-cig) in exclusive cigarette smokers (CS) and e-cig users (EC) under ad lib conditions in a clinic. Adult CS (n = 13) and EC (EC; n = 10) completed a 7-hr use session with the e-cig (2% tobacco-derived nicotine by weight, cartridge based system approximately the size of a king size cigarette). E-liquid usage was determined from cartridge weight. CS also smoked a single cigarette with the SPA/M. The SPA/M reliably recorded puff parameters throughout the study period, with CS puffs averaging 47.9 ± 18.2 ml volume, 2.3 ± 0.8 s duration, and 21.5 ± 4.6 ml/s flow rate. EC puffs averaged 53.4 ± 19.2 ml volume, 3.0 ± 1.3 s duration, and 19.6 ± 5.0 flow rate. CS average e-liquid use was 292 ± 214 mg and EC averaged 415 ± 305 mg over 7 h. When compared to a single use of their own brand cigarettes, CS took longer (2.3 ± 0.8 vs.1.7 ± 0.4 s) puffs with similar puff volume (47.9 ± 18.2 vs. 44.1 ± 10.5 ml) from the e-cig prototype. The puff duration, flow rate and peak flow were significantly lower (p < 0.05) with the e-cigs compared to cigarettes. Experienced EC and CS appeared to use the e-cig prototype differently, which is consistent with the literature. The SPA/M could be a useful tool in assessing e-cig use behavior for regulatory purposes.

A distributed computational model for estimating room air level of constituents due to aerosol emission from e-vapor product use

Most indoor air quality models reported in the literature are well-mixed models. A well-mixed model estimates the room average concentration of constituents from sources. It does not provide information on (1) how far and how fast the emitted chemicals travel in the indoor space? And (2) how the concentration changes as a function of distance from the emission source? We developed a distributed model, using computational fluid dynamics and thermodynamics principles, which allows for aerosol dispersion in an indoor space and includes evaporation and condensation of constituents in a multi-compound aerosol mixture. The distributed model can estimate the spatial and temporal variations of the concentration of individual constituents present in the emitted aerosol in vapor and particulate phases separately. Results from the model were compared with the published experimental data and were found to be in good agreement. A sensitivity analysis was performed to evaluate the impact of various parameters that affect the air level of the emitted constituents within an indoor space, including rate of emission, the rate of air exchange, etc. The model can also be used to estimate the level of second hand exposure in a confined space where e-vapor products (EVPs) are used.