Modeling the population health impact of accurate and inaccurate perceptions of harm from nicotine.

BACKGROUND: Scientific evidence clearly demonstrates that inhaling the smoke from the combustion of cigarettes is responsible for most of the harm caused by smoking, and not the nicotine. However, a majority of U.S. adults who smoke inaccurately believe that nicotine causes cancer which may be a significant barrier, preventing switching to potentially reduced risk, non-combustible products like electronic nicotine delivery systems (ENDS) and smokeless tobacco (ST). We assessed the population health impact associated with nicotine perceptions. METHODS: Using a previously validated agent-based model to the U.S. population, we analyzed nationally representative data from the Population Assessment of Tobacco and Health (PATH) study to estimate base case rates of sustained (maintained over four waves) cessation and switching to non-combustible product use, by sex. Nicotine perception scenarios were determined from PATH data. The overall switch rate from smoking in Wave 4 to non-combustible product use in Wave 5 (3.94%) was stratified based on responses to the nicotine perception question "Do you believe nicotine is the chemical that causes most of the cancer caused by smoking cigarettes?", (four-item scale from "Definitely not" to "Definitely yes"). The relative percent change between the overall and stratified rates, corresponding to each item, was used to adjust the base case rates of switching, to determine the impact, if all adults who smoke exhibited switching behaviors based on responses to the nicotine perceptions question. The public health impact of nicotine perceptions was estimated as the difference in all-cause mortality between the base case and the four nicotine perception scenarios. RESULTS: Switch rates associated with those who responded, "Definitely not" (8.39%) resulted in a net benefit of preventing nearly 800,000 premature deaths over an 85-year period. Conversely switch rates reflective of those who responded, "Definitely yes" (2.59%) resulted in a net harm of nearly 300,000 additional premature deaths over the same period. CONCLUSIONS: Accurate knowledge regarding the role of nicotine is associated with higher switch rates and prevention of premature deaths. Our findings suggest that promoting public education to correct perceptions of harm from nicotine has the potential to benefit public health.

Assessment of the Exposure to NNN in the Plasma of Smokeless Tobacco Users.

N-Nitrosonornicotine (NNN) is a human carcinogen present in cigarette smoke and smokeless tobacco. Urinary NNN is usually measured in order to assess the exposure to this toxicant for tobacco users. NNN excretion in urine can be highly biased due to the formation of NNN by nitrosation of nornicotine under acidic conditions, both endogenously and exogenously. Hence, urinary NNN levels may not necessarily correctly reflect the product-specific exposure. Measurement of plasma NNN may be less prone to endogenous formation due to the stable pH (7.4) of blood. We developed an LC-MS/MS method for the quantification of NNN using 1 mL of human plasma. Validation according to FDA guidelines proved that the method is selective and highly sensitive with an LLOQ of 0.3 pg/mL. Accuracy and precision averaged to 98.7 and 7.5% (CV), respectively. The assay was applied to plasma samples collected from 10 experienced moist smokeless tobacco users during and after a single use of 2 g of the product for 40 min under controlled use conditions. Blood was drawn at 15 time points over a 6 h time course. The maximum NNN concentration (Cmax) ranged from 3.5 to 10 pg/mL (mean: 7.1 pg/mL) at a tmax of 32 min. Plasma NNN and nicotine were found to have similar time courses. In conclusion, the determination of NNN in plasma may be fit-for-purpose to evaluate the product-use-specific exposure to this carcinogen.

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.

INTRODUCTION: Long-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. METHODS: Adult 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. RESULTS: Total 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 ß2, 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. CONCLUSIONS: We 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. IMPLICATIONS: Cigarette 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.

Understanding heterogeneity among individuals who smoke cigarettes and vape: assessment of biomarkers of exposure and potential harm among subpopulations from the PATH Wave 1 Data.

INTRODUCTION: People who both smoke cigarettes and vape are often considered as a homogenous group even though multiple subgroups may exist. We examined biomarkers of exposure (BOE) and biomarkers of potential harm (BOPH) to differentiate between subgroups of people who smoke and vape based on PATH Study Wave 1 (2013-2014) data. METHODS: We compared people who only smoke cigarettes everyday (Group A, n = 2442) and people who only vape everyday (Group C, n = 169) against people who smoke and vape segmented into subgroups of people who frequently smoke and vape (Group B1, n = 169), frequently smoke and infrequently vape (Group B2, n = 678), frequently vape and infrequently smoke (Group B3, n = 57), and infrequently smoke and vape (Group B4, n = 66). Eighteen BOEs (representing exposure to TSNAs, nicotine, heavy metals, PAHs, and volatile organic compounds) and four BOPHs (representing inflammation and oxidative stress) were compared within the subgroups. RESULTS: Levels of many BOEs/BOPHs were higher among Group B2 relative to Groups B1, B3, and B4. Compared to Group A, many BOEs were significantly lower in Groups B3 (15/18) and B4 (17/18), and some BOEs were higher among B2 (4/18). Compared to Group C, significantly lower BOEs were observed for Group B4 (2/18). CONCLUSIONS: Overall, the levels of BOEs and BOPHs in people who smoke and vape are associated with frequency of cigarette smoking. Our findings indicate that not all people who smoke and vape are the same, and tobacco product use frequency should be considered when categorizing people who smoke and vape.

Assessment of the potential vaping-related exposure to carbonyls and epoxides using stable isotope-labeled precursors in the e-liquid.

The formation of carbonyls and epoxides in e-cigarette (EC) aerosol is possible due to heating of the liquid constituents. However, high background levels of these compounds have inhibited a clear assessment of exposure during use of ECs. An EC containing an e-liquid replaced with 10% of 13C-labeled propylene glycol and glycerol was used in a controlled use clinical study with 20 EC users. In addition, five smokers smoked cigarettes spiked with the described e-liquid. Seven carbonyls (formaldehyde, acetaldehyde, acrolein, acetone, crotonaldehyde, methacrolein, propionaldehyde) were measured in the aerosol and the mainstream smoke. Corresponding biomarkers of exposure were determined in the user's urine samples. 13C-labeled formaldehyde, acetaldehyde and acrolein were found in EC aerosol, while all seven labeled carbonyls were detected in smoke. The labeled biomarkers of exposure to formaldehyde (13C-thiazolidine carboxylic acid and 13C-N-(1,3-thiazolidine-4-carbonyl)glycine), acrolein (13C3-3-hydroxypropylmercapturic acid) and glycidol (13C3-dihydroxypropylmercapturic acid) were present in the urine of vapers indicating an EC use-specific exposure to these toxicants. However, other sources than vaping contribute to a much higher extent by several orders of magnitude to the overall exposure of these toxicants. Comparing data for the native (unlabeled) and the labeled (exposure-specific) biomarkers revealed vaping as a minor source of user's exposure to these toxicants while other carbonyls and epoxides were not detectable in the EC aerosol.

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.

INTRODUCTION: Real-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. METHODS: In 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. RESULTS: The 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). CONCLUSIONS: This 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. IMPLICATIONS: Cigarette 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.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. IMPLICATIONS: 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.

Smokeless tobacco mortality risks: an analysis of two contemporary nationally representative longitudinal mortality studies.

BACKGROUND: Assessments supporting smokeless tobacco (SLT) disease risk are generally decades old. Newer epidemiological data may more accurately represent the health risks associated with contemporary US-based SLT products, many of which contain lower levels of hazardous and potentially hazardous chemicals compared to previously available SLT products. METHODS: Data from two longitudinal datasets (National Longitudinal Mortality Study-NLMS, and the National Health Interview Survey-NHIS) were analyzed to determine potential associations between SLT use and/or cigarette smoking and all-cause and disease-specific mortality. Mortality hazard ratios (HR) were estimated using a Cox proportional hazards regression model applied to various groups, including never users of any tobacco or SLT product, and current and former SLT users and/or cigarette smokers. RESULTS: The two datasets yielded consistent findings with similar patterns evident for the specific causes of death measured. All-cause mortality risk for exclusive SLT users was significantly lower than that observed for exclusive cigarette smokers and dual SLT/cigarette users. Similar trends were found for mortality from diseases of the heart, chronic lower respiratory diseases, and malignant neoplasms. Mortality risk for lung cancer in exclusive cigarette smokers was increased by about 12-fold over never-tobacco users but was rarely present in exclusive SLT users in either survey (NHIS, < 5 cases/1,563 observations; NLMS, 3 cases/1,863 observations). While the data in the surveys are limited, SLT use by former cigarette smokers was not associated with an increase in the lung cancer risk HR compared to that by former cigarette smokers who never used SLT. CONCLUSIONS: Emerging epidemiological data provides a new perspective on the health risks of SLT use compared to risks associated with cigarette smoking. HR estimates derived from two current US datasets, which include data on contemporary tobacco products, demonstrate a clear mortality risk differential between modern SLT products and cigarettes. Cigarette smokers had an increased overall mortality risk and risk for several disease-specific causes of death, while SLT users consistently had lower mortality risks.

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 ±â€¯18.2 ml volume, 2.3 ±â€¯0.8 s duration, and 21.5 ±â€¯4.6 ml/s flow rate. EC puffs averaged 53.4 ±â€¯19.2 ml volume, 3.0 ±â€¯1.3 s duration, and 19.6 ±â€¯5.0 flow rate. CS average e-liquid use was 292 ±â€¯214 mg and EC averaged 415 ±â€¯305 mg over 7 h. When compared to a single use of their own brand cigarettes, CS took longer (2.3 ±â€¯0.8 vs.1.7 ±â€¯0.4 s) puffs with similar puff volume (47.9 ±â€¯18.2 vs. 44.1 ±â€¯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.

Evaluating the relationship between biomarkers of potential harm and biomarkers of tobacco exposure among current, past, and nonsmokers: data from the National Health and Nutrition Examination Survey 2007-2012.

Potential long-term health effects from tobacco products can be estimated by measuring changes in biochemical indicators of disease mechanisms like inflammation. This study assesses the potential relationships between biomarkers of potential harm (BOPH) and biomarkers of cigarette smoke exposure (BOE) based on data from the NHANES (2007-2012, n = 17,293 respondents). Statistically significant relationships were observed between white blood cells (WBC) and high-density lipoprotein (HDL) and BOE; between WBC and high-sensitivity C-reactive protein and smoking status; and between WBC and HDL and smoking intensity. This analysis suggests that WBC and HDL are useful BOPH in studies assessing the health risks of cigarette smoking.

Development/verification of methods for measurement of exhaled breath and environmental e-vapor product aerosol.

Concerns have been raised about the potential health effects of potential bystander exposure to exhaled aerosols from e-vapor products (EVPs). An exhaled breath collection system (EBS) was developed and analytical methods were verified for collection and analysis of exhaled breath from users of EVPs. Analytical methods were adapted and verified for collection of environmental air samples during EVP use in an exposure chamber. Analysis of constituents in exhaled breath focused on nicotine, propylene glycol, and glycerin (because these are reported as the major constituents in EVPs) and selected carbonyl compounds (acetaldehyde, acrolein, and formaldehyde). Analysis of environmental samples included nicotine, propylene glycol, glycerin, 12 volatile organic compounds (VOCs), 15 carbonyl compounds and 4 metals. The EBS and analytical methods used were found to be suitable for collection and analysis of the target constituents in exhaled breath. Environmental sampling for background levels of VOCs and carbonyl compounds found only acetone, acetaldehyde, benzene, ethylbenzene, formaldehyde, isoprene, methyl ethyl ketone, hexaldehyde, propionaldehyde, and toluene above the limit of quantification in some samples. None of the targeted metals were detected. Background levels of VOCs and carbonyl compounds were consistent with levels previously reported for ambient air.

Insights from two industrial hygiene pilot e-cigarette passive vaping studies.

While several reports have been published using research methods of estimating exposure risk to e-cigarette vapors in nonusers, only two have directly measured indoor air concentrations from vaping using validated industrial hygiene sampling methodology. Our first study was designed to measure indoor air concentrations of nicotine, menthol, propylene glycol, glycerol, and total particulates during the use of multiple e-cigarettes in a well-characterized room over a period of time. Our second study was a repeat of the first study, and it also evaluated levels of formaldehyde. Measurements were collected using active sampling, near real-time and direct measurement techniques. Air sampling incorporated industrial hygiene sampling methodology using analytical methods established by the National Institute of Occupational Safety and Health and the Occupational Safety and Health Administration. Active samples were collected over a 12-hr period, for 4 days. Background measurements were taken in the same room the day before and the day after vaping. Panelists (n = 185 Study 1; n = 145 Study 2) used menthol and non-menthol MarkTen prototype e-cigarettes. Vaping sessions (six, 1-hr) included 3 prototypes, with total number of puffs ranging from 36-216 per session. Results of the active samples were below the limit of quantitation of the analytical methods. Near real-time data were below the lowest concentration on the established calibration curves. Data from this study indicate that the majority of chemical constituents sampled were below quantifiable levels. Formaldehyde was detected at consistent levels during all sampling periods. These two studies found that indoor vaping of MarkTen prototype e-cigarette does not produce chemical constituents at quantifiable levels or background levels using standard industrial hygiene collection techniques and analytical methods.

Effect of cigarette design on biomarkers of exposure, puffing topography and respiratory parameters.

Despite the lack of evidence, many reports exist which have implied that smokers inhale low-yield cigarette smoke more deeply than that of high-yield cigarettes. The objective of this study was to investigate the effect of short-term switching between smoker's own brand and test cigarettes with different smoke yields on puffing topography, respiratory parameters and biomarkers of exposure. Participants were randomly assigned to smoke either a Test Cigarette-High Tar (TCH), for two days, and then switched to a Test Cigarette-Low Tar (TCL), for two days or the reverse order (n = 10 each sequence). Puffing topography (CReSS microdevice), respiratory parameters (inductive plethysmography) and biomarkers of exposure (BOE, urinary nicotine equivalents - NE and blood carboxyhemoglobin - COHb) were measured at baseline and on days 2 and 4. The average puffs per cigarette, puff volume and puff durations were statistically significantly lower, and inter-puff interval was significantly longer for the TCH compared to the TCL groups. Respiratory parameters were not statistically significantly different between the TCH and TCL groups. Post-baseline NE and COHb were statistically significantly lower in the TCL compared to the TCH groups. Under the conditions of this study, we found no indication of changes in respiratory parameters, particularly inhalation time and volume, between study participants smoking lower versus higher yield cigarettes. Likewise, the BOE provides no indication of deeper inhalation when smoking low- versus high-yield cigarettes. These findings are consistent with the published literature indicating smoking low-yield cigarettes does not increase the depth of inhalation.

Characterization of Ad Libitum Use Behavior of On! Nicotine Pouches.

Objectives: Actual use of nicotine pouch products is not well studied. The objectives of this study were to characterize on ® nicotine pouch (Test Products (TP)) use behavior, including association with cigarette and smokeless tobacco (ST) product use. Methods: Adults who smoke cigarettes (AS) and/or adults who use ST (ASTU) (N=1147) that were not planning to quit and had expressed interest in trying and using TP after a 5-day trial were offered ad libitum use of TPs (7 flavors at 5 nicotine levels) for 6 weeks. Results: Participants used a median of ~5-6 pouches/day of a variety of flavors and nicotine levels. In the final week of the study, 27% of AS and 71% of ASTU reported no use of cigarettes or ST respectively, while reporting continued use of TPs. Additionally, 39% of AS and 14% of ASTU reduced consumption of cigarettes or ST products respectively by 50%-99%, compared to reported use at screening. We found a statistically significant inverse relationship between TP flavor varieties and number of cigarettes/ST. Conclusions: These data suggest that TPs can be potential substitutes for cigarettes/ST products, and complete switching may offer harm reduction potential for AS and ASTU not interested in quitting.

A Randomized, Controlled Study to Assess Changes in Biomarkers of Exposures Among Adults Who Smoke That Switch to Oral Nicotine Pouch Products Relative to Continuing Smoking or Stopping All Tobacco Use.

The purpose of this open-label, randomized, controlled, in-clinic, 5-parallel-group study was to assess biomarkers of exposure (BoE) to select harmful and potentially harmful constituents in adults who smoke (N = 144) switching to oral tobacco products (on!® mint nicotine pouches; test products) compared to continuing smoking cigarettes (CS) and completely quitting all tobacco products (NT). Changes in 20 BoE to select harmful and potentially harmful constituents, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), were evaluated. Adult smokers smoked their usual brand of cigarettes for 2 days (baseline assessments) and then were randomly assigned to ad libitum use of 2, 4, or 8 mg test products, CS, or NT for 7 days. Analysis of covariance was used to assess the Day 7 BoE levels between each group using test products, CS, and NT. The creatinine-adjusted total urinary NNAL and other 18 of 19 BoE levels (except nicotine equivalents [NEs]) were significantly lower (P < .05) on Day 7, among all test product groups compared to CS. Geometric least-square means were reduced for all biomarkers of exposure, except NEs, in test product groups by approximately 42%-96% compared to the CS group, and reductions were comparable to the NT group. The geometric least-square means for urinary NE between the test product and the CS groups, although not significantly different, the Day 7 mean change relative to the CS group were 49.9%, 65.8%, and 101% for the 2, 4, and 8 mg test product groups, respectively. The substantial reduction in harmful and potentially harmful constituent exposure suggests complete switching from cigarettes to test products may present a harm reduction opportunity for adults who smoke.

Intra- and inter-individual variability in urinary nicotine excretion and plasma cotinine in adult cigarette smokers.

Urinary nicotine equivalents (NE) and plasma cotinine are widely used as a biomarker for exposure to tobacco products, but there is limited information on intra- and inter-individual variability in the literature. Data were gathered from 13 randomized controlled clinical studies sponsored by Philip Morris USA, with study durations between 2 and 8 days for the short term (ST) and 3-12 months for the long term (LT) studies. Coefficients of variation (CV) were compared and a linear mixed model was used to partition the total study variability into inter- and intra-individual variability. In the ST and LT studies respectively, the root-mean-square (RMS) intra-individual CV was 19% and 29% for NE (mg/24 h); 19% and 33% for NE (mg/cig) and 13% and 22% for plasma cotinine. The RSM inter-individual CV was 38% and 38% for NE (mg/24h), 25% and 32% for NE (mg/cig) and 38% and 37% for plasma cotinine, in ST and LT study, respectively. Intra-individual CV was smaller in ST studies than in LT studies, and was significantly less than inter-individual CV in ST studies. Daily cigarette consumption alone could not explain all the variability in NE and plasma cotinine. The variability estimates could be used for clinical study design of clinical and developing regulatory guidance.

A Randomized, Controlled Study to Assess Biomarkers of Exposure in Adult Smokers Switching to Oral Nicotine Products.

This open-label, randomized, controlled, in-clinic, 6-parallel-group study evaluated changes in biomarkers of exposure (BoEs) to select harmful and potentially harmful constituents in adult smokers (N = 213) not planning to quit smoking. Adult smokers were randomized to continue smoking (CS), reduce smoking by 50% and dual use oral tobacco-derived nicotine (OTDN) products (VERVE chews/discs), stop smoking and exclusively use discs or chews, or stop using all tobacco products (NT). The primary objective compared 24-hour urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; a biomarker for the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) in dual and exclusive use of discs and chews to continue smoking and NT on day 7. NNAL levels on day 7 were significantly lower (P < .05) among dual and exclusive users of discs/chews compared to continue smoking; median percent reductions were ≈30% and ≈73%, respectively. NNAL levels were not significantly different between those who used discs/chews and the NT group. Many of the additional secondary biomarkers of exposure were significantly lower in dual users (10/19) and exclusive users of discs/chews (17/19) compared to the continue smoking group. Overall, reductions in secondary biomarkers of exposure were greater in exclusive users than dual users. The 24-hour urinary nicotine equivalents were significantly lower (P < .05) among exclusive users of discs/chews compared to continue smoking. The discs/chews appeared to be well tolerated. These results demonstrate that while switching completely to discs/chews substantially reduces exposure to select harmful and potentially harmful constituents, dual use with 50% reduction in cigarette consumption also reduces exposure. oral tobacco-derived nicotine products like discs/chews may present a harm reduction opportunity for adult smokers, particularly those not intending to quit smoking.

Computational modeling method to estimate secondhand exposure potential from exhalations during e-vapor product use under various real-world scenarios.

Potential secondhand exposure of exhaled constituents from e-vapor product (EVP) use is a public health concern. We present a computational modeling method to predict air levels of exhaled constituents from EVP use. We measured select constituent levels in exhaled breath from adult e-vapor product users, then used a validated computational model to predict constituent levels under three scenarios (car, office, and restaurant) to estimate likely secondhand exposure to non-users. The model was based on physical/thermodynamic interactions between air, vapor, and particulate phase of the aerosol. Input variables included space setting, ventilation rate, total aerosol amount exhaled, and aerosol composition. Exhaled breath samples were analyzed after the use of four different e-liquids in a cartridge-based EVP. Nicotine, propylene glycol, glycerin, menthol, formaldehyde, acetaldehyde, and acrolein levels were measured and reported based on a linear mixed model for analysis of covariance. The ranges of nicotine, propylene glycol, glycerin, and formaldehyde in exhaled breath were 89.44-195.70 µg, 1199.7-3354.5 µg, 5366.8-6484.7 µg, and 0.25-0.34 µg, respectively. Acetaldehyde and acrolein were below detectable limits; thus, no estimated exposure to non-EVP users is reported. The model predicted that nicotine and formaldehyde exposure to non-users was substantially lower during EVPs use compared to cigarettes. The model also predicted that exposure to propylene glycol, glycerin, nicotine and formaldehyde among non-users was below permissible exposure limits.

Nicotine pharmacokinetics and subjective responses after using nicotine pouches with different nicotine levels compared to combustible cigarettes and moist smokeless tobacco in adult tobacco users.

RATIONALE: Oral tobacco-derived nicotine products include on!® nicotine pouches (NPs) which are tobacco-leaf free and available in multiple flavors and nicotine levels. Switching completely to NPs from cigarettes and moist smokeless tobacco (MST) has the potential to reduce harm for adult tobacco consumers. However, the dependence potential of NPs is not established. Therefore, we characterized the abuse potential of NPs with different nicotine levels compared to cigarettes and MST. OBJECTIVES: To evaluate nicotine pharmacokinetics (PK) and subjective effects of NPs (ranging from 1.5 to 8 mg nicotine) compared to own brand cigarettes (OBCs) and MST (OBMST). METHODS: We used a randomized, in-clinic, partial single-blind, 7-way crossover design to assess nicotine PK and subjective effects in dual users of cigarettes and MST. RESULTS: The mean nicotine Cmax for NPs increased with nicotine level, ranging from 3.5 ng/mL (1.5 mg NP) to 15.4 ng/mL (8 mg NP), compared with 12.2 ng/mL for OBCs and 9.8 ng/mL for OBMST. Nicotine tmax was much longer for all NPs and OBMST (32.5-34.4 min) compared to OBCs (8.5 min). Reductions in urges to smoke after use of the 2 mg, 3.5 mg, and 8 mg NPs were not statistically different (p > 0.05) relative to OBC. Also, NPs resulted in lower ratings of positive subjective effects relative to OBCs and OBMST. CONCLUSIONS: Overall, based on the study results and literature reported nicotine PK values for cigarettes and MST, the abuse potential of NPs is not likely to be higher than OBCs and OBMST. NPs may be potentially acceptable switching products for users of cigarettes and MST products.

A comprehensive physiologically based pharmacokinetic (PBPK) model for nicotine in humans from using nicotine-containing products with different routes of exposure.

Physiologically based pharmacokinetic (PBPK) modeling can be a useful tool for characterizing nicotine pharmacokinetics (PK) from use of tobacco products. We expand a previously published PBPK model to simulate a nicotine PK profile, following single or multiple use of various tobacco products [cigarettes, smokeless tobacco, and electronic nicotine delivery systems, or a nicotine inhaler (NICOTROL)] The uptake route in the model was designed to allow for three uptake compartments: buccal cavity (BC), upper respiratory tract (URT) (conducting and transitional airways) and lower respiratory tract (alveolar region). Within each region, the model includes product-specific descriptions of the flux of nicotine into plasma, as well as the flux of nicotine from the BC and URT to the gastrointestinal tract. These descriptions are based on regional deposition and diffusion models of nicotine into plasma, which depends on the product type. Regional deposition flux combined with regional differences in physiological parameters (e.g., blood perfusion ratio and tissue thickness) play a key role in the product-specific PK profile of nicotine. The current model describes the slower flux of nicotine into plasma across the BC and URT, as well as the rapid flux known to occur in the alveolar region. Overall, the addition of the BC and respiratory tract compartments to the nicotine model provided simulation results that are comparable to the nicotine time-course plasma concentrations reported from clinical studies for the four product categories simulated.