Emerging ENDS products and challenges in tobacco control toxicity research.

Electronic nicotine delivery systems (ENDS) continue to rapidly evolve. Current products pose unique challenges and opportunities for researchers and regulators. This commentary aims to highlight research gaps, particularly in toxicity research, and provide guidance on priority research questions for the tobacco regulatory community. Disposable flavoured ENDS have become the most popular device class among youth and may contain higher nicotine levels than JUUL devices. They also exhibit enhanced harmful and potentially harmful constituents production, contain elevated levels of synthetic coolants and pose environmental concerns. Synthetic nicotine and flavour capsules are innovations that have recently enabled the circumvention of Food and Drug Administration oversight. Coil-less ENDS offer the promise of delivering fewer toxicants due to the absence of heating coils, but initial studies show that these products exhibit similar toxicological profiles compared with JUULs. Each of these topic areas requires further research to understand and mitigate their impact on human health, especially their risks to young users.

E-Cigarette or Vaping Product Use-associated Lung Injury: Developing a Research Agenda. An NIH Workshop Report.

The NHLBI convened a working group on October 23, 2019, to identify the most relevant and urgent research priorities and prevailing challenges in e-cigarette or vaping product use-associated lung injury (EVALI). Experts across multiple disciplines discussed the complexities of the EVALI outbreak, identified research priorities, and recommended strategies to address most effectively its causal factors and improve diagnosis, treatment, and prevention of this disease. Many research priorities were identified, including the need to create national and international registries of patients with EVALI, to track accurately those affected and assess outcomes. The group concluded that biospecimens from subjects with EVALI are urgently needed to help define EVALI pathogenesis and that vaping has disease risks that are disparate from smoking, with the occurrence of EVALI highlighting the importance of broadening e-cigarette research beyond comparators to smoking-related diseases.

The Application of Commercially Available Mobile Cigarette Topography Devices for E-cigarette Vaping Behavior Measurements.

INTRODUCTION: The ability to reliably measure real-world vaping behavior is critical to understand exposures to potential toxins. Commercially available mobile topography devices were originally designed to measure cigarette puffing behavior. Information regarding how applicable these devices are to the measurement of electronic cigarette (e-cigarette) vaping topography is needed. METHODS: Clinical Research Support System (CReSS; Pocket) and Smoking Puff Analyzer Mobile (SPA-M) topography devices were tested against the calibrated laboratory-based smoking puff analyzer duplicator (SPA-D) device combined with an analytical smoking machine that generates programmable puffs with high precision. Puff topography of e-cigarettes was measured over a range of puff volumes (10-130 mL) at 2 and 5 s puff durations (using bell- and square-shaped puffs). "Real-world" topography data collected from 10 participants during 1 week of at-home vaping were also analyzed. Recording anomalies and limitations of the devices, such as accuracy of detection of the puff end, flow rate dropouts, unreported puffs, and abandoned vaping sessions for the CReSS, and multi-peak puffs for the SPA-M were defined. RESULTS: The accuracy of puff volumes and durations was determined for both devices. The error for SPA-M was generally within ±10%, whereas that for the CReSS varied more widely. The CReSS consistently underestimated puff duration at higher flow rates. CONCLUSIONS: CReSS and SPA-M topography devices can be used for real-world e-cigarette topography measurements, but researchers have to be aware of the limitations. Both devices can provide accurate measurements only under certain puff parameter ranges. The SPA-M provided more accurate measurements under a wider range of puffing parameters than the CReSS. Summary data reported by both devices require thorough analysis of the raw data to avoid misleading data interpretation. IMPLICATIONS: Results of this study provide researchers with valuable information about the capability of commercially available cigarette topography devices to measure real-world vaping behaviors. The differing measurement ranges of the two devices and puff recording limitations and anomalies should be taken into account during analysis and interpretation of real-world data.

Chemical characterization of marijuana blunt smoke by non-targeted chemical analysis.

Background: Marijuana blunts, which are tobacco cigar wrappers filled with marijuana, are commonly smoked in the US as a means of cannabis use. The use of marijuana blunts presents toxicity concerns because the smoke contains both marijuana-related and tobacco-related chemicals. Thus, it is important to understand the chemical composition of mainstream smoke (MSS) from marijuana blunts. This study demonstrates the ability to detect and identify chemical constituents exclusively associated with blunt MSS in contrast to tobacco cigar MSS (designated as 'new exposures') through non-targeted chemical analysis.Methods: Samples collected separately from blunt MSS and tobacco cigar MSS were analyzed using two-dimensional gas chromatography-time-of-flight mass spectrometry (GC × GC-TOFMS).Results and Discussion: Two new exposures, which likely represent only a subset of all new exposures, were identified by evaluating the data from thousands of detected signals and then confirming selected compound identities in analyses using authentic chemical standards. The two confirmed new exposures, mellein and 2-phenyl-2-oxazoline, are not cannabinoids and, to the best of our knowledge, have not been previously reported in association with cannabis, tobacco, or smoke of any kind. In addition, we detected and quantified three phenols (2-, 3-, and 4-ethylphenol) in blunt MSS. Given the toxicity of phenols, quantifying the levels of other phenols could be pursued in future research on blunt MSS.Conclusion: This study shows the power and utility of GC × GC-TOFMS as a methodology for non-targeted chemical analysis to identify new chemical exposures in blunt MSS and to provide data to guide further investigations of blunt MSS.

Influence of airborne particulates on respiratory tract deposition of inhaled toluene and naphthalene in the rat.

OBJECTIVE: Most studies report that inhaled volatile and semivolatile organic compounds (VOCs/SVOCs) tend to deposit in the upper respiratory tract, while ultrafine (or near ultrafine) particulate matter (PM) (∼100 nm) reaches the lower airways. The objective of this study was to determine whether carbon particle co-exposure carries VOCs/SVOCs deeper into the lungs where they are deposited. MATERIALS AND METHODS: Male Sprague-Dawley rats were exposed by inhalation (nose-only) to radiolabeled toluene (20 ppm) or naphthalene (20 ppm) on a single occasion for 1 h, with or without concurrent carbon particle exposure (∼5 mg/m3). The distribution of radiolabel deposited within the respiratory tract of each animal was determined after sacrifice. The extent of adsorption of toluene and naphthalene to airborne carbon particles under the exposure conditions of the study was also assessed. RESULTS: We found that in the absence of particles, the highest deposition of both naphthalene and toluene was observed in the upper respiratory tract. Co-exposure with carbon particles tended to increase naphthalene deposition slightly throughout the respiratory tract, whereas slight decreases in toluene deposition were observed. Few differences were statistically significant. Naphthalene showed greater adsorption to the particles compared to toluene, but overall the particle-adsorbed concentration of each of these compounds was a small fraction of the total inspired concentration. CONCLUSIONS: These studies imply that at the concentrations used for the exposures in this study, inhaled carbon particles do not substantially alter the deposition of naphthalene and toluene within the respiratory tract.

Real-Time Measurement of Electronic Cigarette Aerosol Size Distribution and Metals Content Analysis.

INTRODUCTION: Electronic cigarette (e-cigarette) use is increasing worldwide and is highest among both daily and nondaily smokers. E-cigarettes are perceived as a healthier alternative to combustible tobacco products, but their health risk factors have not yet been established, and one of them is lack of data on aerosol size generated by e-cigarettes. METHODS: We applied a real-time, high-resolution aerosol differential mobility spectrometer to monitor the evolution of aerosol size and concentration during puff development. Particles generated by e-cigarettes were immediately delivered for analysis with minimal dilution and therefore with minimal sample distortion, which is critically important given the highly dynamic aerosol/vapor mixture inherent to e-cigarette emissions. RESULTS: E-cigarette aerosols normally exhibit a bimodal particle size distribution: nanoparticles (11-25nm count median diameter) and submicron particles (96-175nm count median diameter). Each mode has comparable number concentrations (10(7)-10(8) particles/cm(3)). "Dry puff" tests conducted with no e-cigarette liquid (e-liquid) present in the e-cigarette tank demonstrated that under these conditions only nanoparticles were generated. Analysis of the bulk aerosol collected on the filter showed that e-cigarette emissions contained a variety of metals. CONCLUSIONS: E-cigarette aerosol size distribution is different from that of combustible tobacco smoke. E-cigarettes generate high concentrations of nanoparticles and their chemical content requires further investigation. Despite the small mass of nanoparticles, their toxicological impact could be significant. Toxic chemicals that are attached to the small nanoparticles may have greater adverse health effects than when attached to larger submicron particles. IMPLICATIONS: The e-cigarette aerosol size distribution is different from that of combustible tobacco smoke and typically exhibits a bimodal behavior with comparable number concentrations of nanoparticles and submicron particles. While vaping the e-cigarette, along with submicron particles the user is also inhaling nano-aerosol that consists of nanoparticles with attached chemicals that has not been fully investigated. The presence of high concentrations of nanoparticles requires nanotoxicological consideration in order to assess the potential health impact of e-cigarettes. The toxicological impact of inhaled nanoparticles could be significant, though not necessarily similar to the biomarkers typical of combustible tobacco smoke.

Comparative iron oxide nanoparticle cellular dosimetry and response in mice by the inhalation and liquid cell culture exposure routes.

BACKGROUND: Toxicity testing the rapidly growing number of nanomaterials requires large scale use of in vitro systems under the presumption that these systems are sufficiently predictive or descriptive of responses in in vivo systems for effective use in hazard ranking. We hypothesized that improved relationships between in vitro and in vivo models of experimental toxicology for nanomaterials would result from placing response data in vitro and in vivo on the same dose scale, the amount of material associated with cells. METHODS: Balb/c mice were exposed nose-only to an aerosol (68.6 nm CMD, 19.9 mg/m(3), 4 hours) generated from of 12.8 nm superparamagnetic iron oxide particles (SPIO). Target cell doses were calculated, histological evaluations conducted, and biomarkers of response were identified by global transcriptomics. Representative murine epithelial and macrophage cell types were exposed in vitro to the same material in liquid suspension for four hours and levels of nanoparticle regulated cytokine transcripts identified in vivo were quantified as a function of measured nanoparticle cellular dose. RESULTS: Target tissue doses of 0.009-0.4 µg SPIO/cm(2) in lung led to an inflammatory response in the alveolar region characterized by interstitial inflammation and macrophage infiltration. In vitro, higher target tissue doses of ~1.2-4 µg SPIO/ cm(2) of cells were required to induce transcriptional regulation of markers of inflammation, CXCL2 & CCL3, in C10 lung epithelial cells. Estimated in vivo macrophage SPIO nanoparticle doses ranged from 1-100 pg/cell, and induction of inflammatory markers was observed in vitro in macrophages at doses of 8-35 pg/cell. CONCLUSIONS: Application of target tissue dosimetry revealed good correspondence between target cell doses triggering inflammatory processes in vitro and in vivo in the alveolar macrophage population, but not in the epithelial cells of the alveolar region. These findings demonstrate the potential for target tissue dosimetry to enable the more quantitative comparison of in vitro and in vivo systems and advance their use for hazard assessment and extrapolation to humans. The mildly inflammogentic cellular doses experienced by mice were similar to those calculated for humans exposed to the same material at the existing permissible exposure limit of 10 mg/m(3) iron oxide (as Fe).

Comparison of emissions across tobacco products: A slippery slope in tobacco control.

In this narrative review, we highlight the challenges of comparing emissions from different tobacco products under controlled laboratory settings (using smoking/vaping machines). We focus on tobacco products that generate inhalable smoke or aerosol, such as cigarettes, cigars, hookah, electronic cigarettes, and heated tobacco products. We discuss challenges associated with sample generation including variability of smoking/vaping machines, lack of standardized adaptors that connect smoking/vaping machines to different tobacco products, puffing protocols that are not representative of actual use, and sample generation session length (minutes or number of puffs) that depends on product characteristics. We also discuss the challenges of physically characterizing and trapping emissions from products with different aerosol characteristics. Challenges to analytical method development are also covered, highlighting matrix effects, order of magnitude differences in analyte levels, and the necessity of tailored quality control/quality assurance measures. The review highlights two approaches in selecting emissions to monitor across products, one focusing on toxicants that were detected and quantified with optimized methods for combustible cigarettes, and the other looking for product-specific toxicants using non-targeted analysis. The challenges of data reporting and statistical analysis that allow meaningful comparison across products are also discussed. We end the review by highlighting that even if the technical challenges are overcome, emission comparison may obscure the absolute exposure from novel products if we only focus on relative exposure compared to combustible products.

Analysis of the Aerosol Generated from Tetrahydrocannabinol, Vitamin E Acetate, and Their Mixtures.

E-cigarette, or vaping, product use-associated lung injury (EVALI) outbreak was linked to vitamin E acetate (VEA) used as a solvent for tetrahydrocannabinol (THC). Several studies were conducted to assess the products of VEA (and THC/VEA mixtures) thermal degradation as a result of vaporizing/aerosolizing from a traditional type (coil-cotton wick) and ceramic type coil vape pens. The particle size distribution (PSD) of VEA aerosol and the temperature VEA and THC/VEA mixtures are heated to were also measured for a few types of traditional and ceramic vape pens. The current study assessed the PSD of the aerosol generated from THC, VEA, and a number of THC/VEA mixtures using a dab-type vape pen under two different temperature settings and two puffing flow rates. Thermal degradation of THC, VEA, and THC/VEA mixtures were also assessed, and coil temperature was measured. Results showed the dependence of the PSD upon the chemical content of the aerosolized mixture as well as upon the puffing flow rate. Minimal thermal degradation was observed. Flaws in the vape pen's design, which most likely affected results, were detected. The suitability of VEA, THC, and THC/VEA mixtures with certain types of vape pens was discussed.

E-Cigarettes and Cardiopulmonary Health.

E-cigarettes have surged in popularity over the last few years, particularly among youth and young adults. These battery-powered devices aerosolize e-liquids, comprised of propylene glycol and vegetable glycerin, typically with nicotine, flavors, and stabilizers/humectants. Although the use of combustible cigarettes is associated with several adverse health effects including multiple pulmonary and cardiovascular diseases, the effects of e-cigarettes on both short- and long-term health have only begun to be investigated. Given the recent increase in the popularity of e-cigarettes, there is an urgent need for studies to address their potential adverse health effects, particularly as many researchers have suggested that e-cigarettes may pose less of a health risk than traditional combustible cigarettes and should be used as nicotine replacements. This report is prepared for clinicians, researchers, and other health care providers to provide the current state of knowledge on how e-cigarette use might affect cardiopulmonary health, along with research gaps to be addressed in future studies.

Aerosol size distribution measurement of electronic cigarette emissions using combined differential mobility and inertial impaction methods: Smoking machine and puff topography influence.

A combination of a real-time high resolution aerosol differential mobility spectrometer (DMS500) and an electrical low pressure impactor (used as a traditional impactor) was applied to simultaneously collect real-time data and analyze particle size by weighing the mass of the aerosol collected on the impactor stages. Nonrefillable fixed-power as well as refillable and power adjustable e-cigarettes (e-cigs) were tested at various puffing flow rates. Two types of smoking machines were used: a smoke cycle simulator that provides instantaneous straight sample delivery to the analyzer and a Human Profile Pump that utilizes two synchronized pistons and operates by sample pull-push mode. Chemical analysis of the major components of e-liquid (propylene glycol, vegetable glycerol, water, and nicotine) was made using a proton nuclear magnetic resonance method. Limited amounts of samples collected on impactor stages were analyzed by liquid chromatography time-of-flight mass-spectrometry to find newly formed semi- or low-volatile organic compounds in e-cig aerosol and by transmission electron microscopy to check for the presence of nanoparticles in e-cig emissions. Differential mobility and inertial impaction methods showed comparable particle size results. Method of aerosol generation (type of the smoking machine) as well as puffing topography affected the e-cig particle size. Newly formed semi- or low-volatile organic compounds as well as metal nanoparticles were found in e-cig aerosol.