Systemic biomarkers of exposure associated with ENDS use: a scoping review.

OBJECTIVE: This scoping review provides an overview of the existing literature on biomarkers of exposure from electronic nicotine delivery systems (ENDS) use and identifies gaps in existing knowledge. DATA SOURCES: We searched two international databases (PubMed and Web of Science) to identify relevant studies published from August 2013 to February 2021. DATA SELECTION: Studies were included if they assessed and compared biomarkers of exposure between exclusive ENDS users, non-users, exclusive cigarette smokers, dual users of ENDS and cigarettes or cigarette smokers who switch to ENDS. DATA EXTRACTION AND SYNTHESIS: Of the 5074 studies identified, 188 studies met criteria and were selected for full-text screening. Of these, 27 studies were selected for inclusion and data extraction. CONCLUSIONS: Consistent, although limited, evidence shows that exclusive ENDS users have elevated levels of biomarkers of certain volatile organic compounds (VOCs; eg, acrylamide and acrylonitrile), metals (eg, cadmium and selenium) and propylene glycol compared with non-users; however, evidence for biomarkers of other toxicants (eg, acrolein, benzene and chromium) is mixed. Biomarkers of most VOCs are lower in ENDS users compared with cigarette smokers, and cigarette smokers who switch to ENDS consistently show reductions in VOC biomarkers. Evidence comparing metal exposures from exclusive ENDS use, cigarette smoking and dual use is mixed and depends on the metal. ENDS and e-liquid characteristics as well as use patterns may be associated with elevated exposure to VOCs and metals. Additional rigorous, controlled studies can assess biomarker exposures from ENDS use and inform the overall risk-benefit of ENDS use for different user populations.

Formulation of smokeless tobacco products with a wide range of pH to study nicotine pharmacokinetics and pharmacodynamics.

The rate of nicotine absorption from tobacco products is a determinant of addiction potential and other detrimental health effects. Oral nicotine bioavailability from moist snuff smokeless tobacco (ST) is influenced by nicotine content, pH, flavors, and tobacco cut. For use in a clinical study testing the effect of pH on nicotine pharmacokinetics, four investigational ST products that differed only in pH were produced. A commercial ST product (Copenhagen Long Cut Original, pH 7.7) was modified with citric acid monohydrate (23 mg/g tobacco) or sodium carbonate (4.6 and 11 mg/g) to create products with pH 5.0, 8.2, and 8.6, respectively. All products - including the original product with pH 7.7 - were individually packaged (approximately 2 g) in aluminum foil pouches and stored frozen (-20 °C); pH, nicotine, tobacco-specific nitrosamines, moisture content, and mold and yeast counts were tested for up to 19 months to verify stability. Remarkable stability was demonstrated in this packaging/storage combination. For example, pH from all products were within 0.1 pH units and never exceeded 0.2 units. Nicotine concentration averaged 9.07 mg/g at baseline, maximal deviations from baseline in the four products averaged 0.30 mg/g. Similarly, TSNA, moisture content, yeast, and mold did not materially change. This study illustrates a method of investigational tobacco products formulation by manipulating a single design feature (or component) with the purpose of independently and systematically assessing its influence on nicotine bioavailability in a clinical study.

Serum Concentrations of Cotinine and Trans-3'-Hydroxycotinine in US Adults: Results From Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health Study.

INTRODUCTION: The Population Assessment of Tobacco and Health (PATH) Study is a nationally representative cohort of tobacco product users and nonusers. The study's main purpose is to obtain longitudinal epidemiologic data on tobacco use and exposure among the US population. AIMS AND METHODS: Nicotine biomarkers-cotinine (COT) and trans-3'-hydroxycotinine (HCT)-were measured in blood samples collected from adult daily tobacco users and nonusers during Wave 1 of the PATH Study (2013-2014; n = 5012; one sample per participant). Participants' tobacco product use and exposure to secondhand smoke were categorized based on questionnaire responses. Nonusers were subdivided into never users and recent former users. Daily tobacco users were classified into seven tobacco product use categories: exclusive users of cigarette, smokeless tobacco, electronic cigarette, cigar, pipe, and hookah, as well as polyusers. We calculated sample-weighted geometric mean (GM) concentrations of cotinine, HCT, and the nicotine metabolite ratio (NMR) and evaluated their associations with tobacco use with adjustment for potential confounders. RESULTS: The GMs (95% confidence intervals) of COT and HCT concentrations for daily tobacco users were 196 (184 to 208) and 72.5 (67.8 to 77.4) ng/mL, and for nonusers they were 0.033 (0.028 to 0.037) and 0.021 (0.018 to 0.023) ng/mL. Exclusive smokeless tobacco users had the highest COT concentrations of all user groups examined. The GM NMR in daily users was 0.339 (95% confidence interval: 0.330 to 0.350). CONCLUSIONS: These nationally representative estimates of serum nicotine biomarkers could be the basis for reference ranges characterizing nicotine exposure for daily tobacco users and nonusers in the US adult population. IMPLICATIONS: This report summarizes the serum nicotine biomarker measurements in Wave 1 of the PATH Study. We are reporting the first estimates of HCT in serum for daily tobacco users and nonusers in the noninstitutionalized, civilian US adult population; the first nationally representative serum COT estimates for daily exclusive users of different tobacco products and daily polyusers; and the first nationally representative estimate of the serum NMR in daily tobacco users by age, race/ethnicity, and sex.

The pH of Smokeless Tobacco Determines Nicotine Buccal Absorption: Results of a Randomized Crossover Trial.

Nicotine absorption rate influences tobacco products' addictiveness. For smokeless tobacco, nicotine buccal absorption is associated with its free-base form; the pH of smokeless tobacco defines the proportion of free-base (i.e., unprotonated) vs. protonated nicotine. This was the first study to compare nicotine pharmacokinetics (PK) and pharmacodynamics (PD) after the use of commercial smokeless tobacco products that were experimentally manipulated to differ only in pH and percent free-base nicotine. Moist snuff users (N = 40) completed four crossover visits and used a single 2 g portion of Copenhagen Original Long Cut amended to 4 pH levels: 5.0, 7.7, 8.2, and 8.6 (free-base nicotine 0.1, 32, 60, and 79%) for 30 minutes. Nicotine PK and PD were assessed for 4 hours post-use. Nicotine PK substantially depends on its free-base proportion, with more than 4-fold increases in mean plasma nicotine maximum concentration and area under the curve over 240 minutes (3.9 to 16.7 ng/mL; 385 to 1810 ng min/mL, respectively, both P < 0.001) from pH 5.0 to 8.6. The autonomic cardiovascular effects of smokeless tobacco use reflected percent free-base nicotine, with small (albeit significant) systematic increases in heart rate and blood pressure associated with free-base nicotine. Smokeless tobacco product pH and percent free-base nicotine play a major role in the rate and extent of nicotine absorption, determining product PD effects and abuse potential. Research and regulation of smokeless tobacco products should consider both total nicotine content and product pH. Further research may address the impact of modifying pH on the addictiveness of smokeless tobacco and associated use behaviors.

Biomarkers of Inflammation and Oxidative Stress among Adult Former Smoker, Current E-Cigarette Users-Results from Wave 1 PATH Study.

BACKGROUND: Former smokers who currently use e-cigarettes have lower concentrations of biomarkers of tobacco toxicant exposure than current smokers. It is unclear whether tobacco toxicant exposure reductions may lead to health risk reductions. METHODS: We compared inflammatory biomarkers (high-sensitivity C-reactive protein, IL6, fibrinogen, soluble intercellular adhesion molecule-1) and an oxidative stress marker (F2-isoprostane) among 3,712 adult participants in Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health Study by tobacco user groups: dual users of cigarettes and e-cigarettes; former smokers who currently use e-cigarettes-only; current cigarette-only smokers; former smokers who do not currently use any tobacco; and never tobacco users. We calculated geometric means (GM) and estimated adjusted GM ratios (GMR). RESULTS: Dual users experienced greater concentration of F2-isoprostane than current cigarette-only smokers [GMR 1.09 (95% confidence interval, CI, 1.03-1.15)]. Biomarkers were similar between former smokers who currently use e-cigarettes and both former smokers who do not use any tobacco and never tobacco users, but among these groups most biomarkers were lower than those of current cigarette-only smokers. The concentration of F2-isoprostane decreased by time since smoking cessation among both exclusive e-cigarette users (P trend = 0.03) and former smokers who do not currently use any tobacco (P trend = 0.0001). CONCLUSIONS: Dual users have greater concentration of F2-isoprostane than smokers. Exclusive e-cigarette users have biomarker concentrations that are similar to those of former smokers who do not currently use tobacco, and lower than those of exclusive cigarette smokers. IMPACT: This study contributes to an understanding of the health effects of e-cigarettes.

Biomarkers of Potential Harm: Summary of an FDA-Sponsored Public Workshop.

Introduction: Since 2009, the United States (US) Food and Drug Administration (FDA) Center for Tobacco Products (CTP) has had the authority to regulate the manufacture, distribution, and marketing of tobacco products in order to reduce the death and disease caused by tobacco use. Biomarkers could play an important role across a number of FDA regulatory activities, including assessing new and modified risk tobacco products and identifying and evaluating potential product standards. Methods: On April 4-5, 2016, FDA/CTP hosted a public workshop focused on biomarkers of potential harm (BOPH) with participants from government, industry, academia, and other organizations. The workshop was divided into five sessions focused on: (1) overview of BOPH; (2) cardiovascular disease (CVD); (3) chronic obstructive pulmonary disease (COPD); (4) cancer; and (5) new areas of research. Results and Conclusions: The deliberations from the workshop noted some promising BOPH but also highlighted the lack of systematic effort to identify BOPH that would have utility and validity for evaluating tobacco products. Research areas that could further strengthen the applicability of BOPH to tobacco regulatory science include the exploration of composite biomarkers as predictors of disease risk, "omics" biomarkers, and examining biomarkers using existing cohorts, surveys, and experimental studies. Implications: This paper synthesizes the main findings from the 2016 FDA-sponsored workshop focused on BOPH and highlights research areas that could further strengthen the science around BOPH and their applicability to tobacco regulatory science.

Clinical pharmacology research strategy for dissolvable tobacco products.

INTRODUCTION: Dissolvable tobacco products (DTPs) are relatively new to the market. Some researchers and manufacturers describe them as finely ground tobacco that has been compressed into sticks, strips, and orbs that dissolve or disintegrate in the mouth and do not require spitting. While the pharmacokinetic profiles of nicotine and other tobacco-associated compounds and pharmacological effects of these products are complex, their clinical pharmacology has not been systematically evaluated. We reviewed the scientific literature regarding the known pharmacokinetic (PK) characteristics and pharmacodynamic (PD) effects of DTPs with the purpose of identifying research gaps and informing future studies. OBJECTIVES: To evaluate current knowledge of the pharmacological properties of DTPs; to assess their similarities and differences with other tobacco products, especially smokeless tobacco products, and Food and Drug Administration-approved nicotine replacement therapies; to identify gaps in existing information; and to propose a strategy for future clinical pharmacology studies of DTPs. METHODS: We reviewed the peer-reviewed literature and generated research questions for future clinical pharmacology studies. RESULTS AND CONCLUSIONS: Data on the PK and PD of DTPs are sparse and inconsistent. The results of existing studies are limited and inconclusive, and their interpretation is complicated by methodological and/or study design issues. This review identifies a need for larger, comprehensive, and prospectively designed studies that include PK/PD measurements and data analyses. We propose a research agenda for future DTP studies related to the clinical pharmacology of nicotine, its metabolites, tobacco-specific nitrosamines, and other toxic compounds.

Structural transition in peptide nanotubes.

Phase transitions in organic and inorganic materials are well-studied classical phenomena, where a change in the crystal space group symmetry induces a wide variation of physical properties, permitted by the crystalline symmetry in each phase. Here we observe a conformational induced transition in bioinspired peptide nanotubes (PNTs). We found that the PNTs change their original molecular assembly from a linear peptide conformation to a cyclic one, followed by a change of the nanocrystalline structure from a noncentrosymmetric hexagonal space group to a centrosymmetric orthorhombic space group. The observed transition is irreversible and induces a profound variation in the PNTs properties, from the microscopic to the macroscopic level. In this context, we follow the unique changes in the molecular, morphological, piezoelectric, second harmonic generation, and wettability properties of the PNTs.