Harmful and Potentially Harmful Constituents in E-Liquids and Aerosols from Electronic Nicotine Delivery Systems (ENDS).

In 2012, the U.S. Food & Drug Administration (FDA) published an established list of 93 harmful and potentially harmful constituents (HPHCs) targeting four tobacco product types (cigarettes, cigarette tobacco, roll-your-own tobacco, smokeless tobacco). In 2016, the FDA finalized the deeming rule to regulate electronic nicotine delivery systems (ENDS). However, knowledge gaps exist regarding whether certain HPHCs are present in ENDS e-liquids and aerosols. We identified and addressed these gaps by conducting literature searches and then experimentally quantifying HPHCs in the e-liquid and aerosol of 37 ENDS brands based on gaps in the literature. The literature searches identified 66 e-liquid HPHCs and 68 aerosol HPHCs that have limited to no information regarding the quantifiability of these constituents. A contracted ISO 17025 accredited laboratory performed the HPHC quantifications. The availability of validated analytical methods in the contracted laboratory determined the HPHCs included in the study scope (63/66 for e-liquids, 64/68 for aerosols). Combining the results from the quantifications and literature searches, 36 (39%) and 34 (37%) HPHCs were found quantifiable (≥limit of quantification [LOQ]) in ENDS e-liquids and aerosols, respectively, with 25 HPHCs being quantifiable in both matrices. Quantifiability results imply potential HPHC transfers between matrices, leaching from components, or formations from aerosol generation. The study results can inform the scientific basis for manufacturers and regulators regarding regulatory requirements for HPHC reporting. The HPHC quantities can also inform evaluations of the public health impact of ENDS and public communications regarding ENDS health risks.

Environmental persistence, bioaccumulation, and hazards of chemicals in e-cigarette e-liquids: short-listing chemicals for risk assessments.

BACKGROUND/METHODS: Increased use and sales of e-cigarettes raises concerns about the potential environmental impacts throughout their life-cycle. However, few available research studies focus on the environmental impacts and ecotoxicity of e-cigarettes. In this study, we short-list e-liquid chemicals from published literature that should be considered in future environmental impact and risk assessments. We used a combination of available laboratory bioassays-based data and predictive methods (eg, Structure-Activity Relationships) to characterise the hazards of the e-liquid chemicals (environmental persistence, bioaccumulation, and aquatic toxicity including hazardous concentration values (concentration affecting specific proportion of species)) for short-listing. RESULTS: Of the 421 unique e-liquid chemicals compiled from literature, 35 are US Environmental Protection Agency's hazardous constituents, 42 are US Food and Drug Administration's harmful or potentially harmful constituents in tobacco products and smoke, and 20 are listed as both. Per hazard characteristics, we short-listed 81 chemicals that should be considered for future environmental impact and risk assessments, including tobacco-specific compounds (eg, nicotine, N'-nitrosonornicotine), polycyclic aromatic hydrocarbons (eg, chrysene), flavours (eg, (-)caryophyllene oxide), metals (eg, lead), phthalates (eg, di(2-ethylhexyl)phthalate) and flame retardants (eg, tris(4-methylphenyl)phosphate). IMPLICATIONS: Our findings documenting various hazardous chemicals in the e-liquids underscore the importance of awareness and education when handling or disposing of e-liquids/e-cigarettes and aim to inform strategies to prevent and reduce hazards from e-cigarettes. This includes any scenario where e-liquids can come into contact with people or the environment during e-liquid storage, manufacturing, use, and disposal practices. Overall, our study characterises the environmental hazards of e-liquid chemicals and provides regulators and researchers a readily available list for future ecological and health risk assessments.

Harmful and Potentially Harmful Constituents in the Filler and Smoke of Tobacco-Containing Tobacco Products.

The U.S. Food and Drug Administration established a list of 93 harmful and potentially harmful constituents (HPHCs) in tobacco products. While HPHCs are required to be submitted for tobacco products, knowledge gaps exist regarding which tobacco-containing tobacco product (TCTP, i.e., tobacco products that contain tobacco(s) as a component) types (cigarettes, cigars, roll-your-own tobaccos [RYOs], pipe tobaccos [pipes], smokeless tobacco products [STPs], waterpipe tobaccos [waterpipes]) and matrices (filler, smoke) contain which HPHCs. This study identified and addressed such gaps by conducting literature searches and measuring the amount of HPHCs in TCTP types and matrices. First, literature searches, performed for cigarettes, RYOs, and STPs for publications up to 2014 and for cigars, pipes, and waterpipes for publications up to 2016, identified knowledge gaps for the 93 HPHCs (or 119 HPHCs if cresols [o-, m-, p-cresol] are counted as 3 and chlorinated dioxins/furans as 25) across TCTP types and matrices. Then, three ISO 17025 accredited laboratories including two subcontracted laboratories performed the HPHC quantifications. Inclusion of the HPHCs, TCTP types, and matrices in the study scope was also determined by the availability of validated analytical methods in each laboratory. Eleven (9%) HPHCs are quantifiable in all brands for all TCTP types and matrices, 33 (28%) HPHCs are not quantifiable in any brands of any TCTP type and matrix, and 74 (63%) HPHCs are quantifiable only in some brands across TCTP types and matrices examined. Understanding the quantifiability of HPHCs in each TCTP type and matrix can inform the scientific basis for manufacturers regarding the regulatory requirements for reporting HPHCs. The quantity of HPHCs observed can also inform the evaluation of the public health impact of HPHCs and public communications regarding the health risks of tobacco products.

A Computational Approach for Respiratory Hazard Identification of Flavor Chemicals in Tobacco Products.

Flavor chemicals contribute to the appeal and toxicity of tobacco products, including electronic nicotine delivery systems (ENDS). The assortment of flavor chemicals available for use in tobacco products is extensive. In this study, a chemistry-driven computational approach was used to evaluate flavor chemicals based on intrinsic hazardous structures and reactivity of chemicals. A large library of 3012 unique flavor chemicals was compiled from publicly available information. Next, information was computed and collated based on their (1) physicochemical properties, (2) global harmonization system (GHS) health hazard classification, (3) structural alerts linked to the chemical's reactivity, instability, or toxicity, and (4) common substructure shared with FDA's harmful and potentially harmful constituents (HPHCs) flavor chemicals that are respiratory toxicants. Computational analysis of the constructed flavor library flagged 638 chemicals with GHS classified respiratory health hazards, 1079 chemicals with at least one structural alert, and 2297 chemicals with substructural similarity to FDA's established and proposed list of HPHCs. A subsequent analysis was performed on a subset of 173 chemicals in the flavor library that are respiratory health hazards, contain structural alerts as well as flavor HPHC substructures. Four general toxicophore structures with an increased potential for respiratory toxicity were then identified. In summary, computational methods are efficient tools for hazard identification and understanding structure-toxicity relationship. With appropriate context of use and interpretation, in silico methods may provide scientific evidence to support toxicological evaluations of chemicals in or emitted from tobacco products.

Switching to Progressively Reduced Nicotine Content Cigarettes in Smokers With Low Socioeconomic Status: A Double-Blind Randomized Clinical Trial.

INTRODUCTION: The Food and Drug Administration issued an advanced notice of proposed rulemaking for setting a product standard for nicotine levels in cigarettes, with an emphasis on minimally or non-addicting very low nicotine content (VLNC). METHODS: A 33 week, two-arm, double-blind randomized trial conducted in Hershey, Pennsylvania, USA and Washington, DC, USA included adult daily cigarette smokers (≥5 cigarettes per day) with less than a college degree, and who had no plans to quit within the next six months. Participants were randomized to either reduced nicotine content (RNC) study cigarettes tapered every three weeks to a final VLNC (0.2 mg/cigarette) for six weeks or to usual nicotine content (UNC) study cigarettes (11.6 mg/cigarette). Outcomes included acceptability of study cigarettes measured by attrition (primary outcome), compliance, reduction in cigarette dependence and tobacco biomarkers, and post-intervention cessation. RESULTS: The RNC (n = 122) versus UNC (n = 123) group had higher attrition (adjusted Hazard Ratio 3.4; 95% confidence interval [CI] 1.99 to 5.81). At the end of the intervention, cotinine levels were 50% lower in the RNC group (mean group difference -137 ng/mL; 95% CI -172, -102). The RNC group smoked fewer CPD (-4.1; 95% CI -6.44, -1.75) and had lower carbon monoxide levels (-4.0 ppm; 95% CI -7.7, -0.4). Forty seven percent (29/62) of the RNC group were biochemically-confirmed compliant with smoking VLNC cigarettes (mean cotinine = 8.9 ng/ml). At three month follow-up, only compliant VLNC smokers quit with an assisted quit attempt (N = 6/22, 27%). CONCLUSIONS: This study supports a VLNC standard in cigarettes. IMPLICATIONS: Differential dropout and noncompliance indicate some smokers had difficulty transitioning to cigarettes with reduced nicotine. These smokers will benefit from supplemental nicotine in medicinal or noncombustible tobacco products if a nicotine reduction standard is established. Other smokers successfully transitioned to very low nicotine content cigarettes exclusively and substantially reduced their exposure to nicotine.

Method Validation Approaches for Analysis of Constituents in ENDS.

OBJECTIVE: We assessed how many peer-reviewed publications reporting chemical quantities and/or yields from electronic nicotine delivery systems (ENDS) have included adequate method validation characteristics in the publication for appropriate interpretation of data quality for informing tobacco regulatory science. METHODS: We searched 5 databases (Web of Knowledge, PubMed, SciFinder, Embase, EBSCOhost) for ENDS publications between January 2007 and September 2018. Of the 283 publications screened, 173 publications were relevant for analysis. We identified the publications that report a certain degree of control in data quality, ie, the publications that report marginally validated methods (MVMs). MVMs refer to the methods that: (1) report 3 or more International Conference on Harmonisation (ICH) method validation characteristics, (2) state the method was validated, (3) cite their own previous publication(s) that report MVMs, or (4) use a method within the accreditation scope of an accredited laboratory. RESULTS: Overall, 97 publications (56%) report MVMs in their studies. This percentage also reflects the publication distribution for the majority of the 28 chemicals measured by MVMs. CONCLUSIONS: This study highlights the need for reporting sufficient validation characteristics following appropriate guidance to ensure the accuracy and reliability of the published analytical data for proper data interpretations that may support policy.

Emissions of Free Radicals, Carbonyls, and Nicotine from the NIDA Standardized Research Electronic Cigarette and Comparison to Similar Commercial Devices.

E-cigarettes (e-cigs) are a diverse and continuously evolving group of products with four generations currently in the market. The National Institute on Drug Abuse (NIDA) standardized research e-cigarette (SREC) is intended to provide researchers with a consistent e-cig device with known characteristics. Thus, we conducted laboratory-based characterizations of oxidants and nicotine in aerosols produced from SREC and other closed-system, breath-activated, commercially available e-cigs (Blu and Vuse). We hypothesized that oxidant and nicotine production will be significantly affected in all devices by changes in puffing parameters. All e-cigs were machine vaped and the aerosols generated were examined for nicotine, carbonyls, and free-radicals while varying the puff-volumes and puff-durations to reflect typical human usage. The data were normalized on a per puff, per gram aerosol, and per milligram nicotine basis. We found that aerosol production generally increased with increasing puff-duration and puff-volume in all e-cigs tested. Increased puff-duration and puff-volume increased nicotine delivery for Blu and Vuse but not the SREC. We report, for the first time, reactive free-radicals in aerosols from all closed-system e-cigs tested, albeit at levels lower than cigarette smoke. Formaldehyde, acetaldehyde, acetone, and propionaldehyde were detected in the aerosols of all tested e-cigs. Carbonyl and free radical production is affected by puff-duration and puff volume. Overall, SREC was more efficient at aerosol and nicotine production than both Blu and Vuse. In terms of carbonyl and free radical levels, SREC delivered lower or similar levels to both other devices.

Free Radical, Carbonyl, and Nicotine Levels Produced by Juul Electronic Cigarettes.

INTRODUCTION: Free radicals and carbonyls produced by electronic cigarettes (e-cigs) have the potential to inflict oxidative stress. Recently, Juul e-cigs have risen drastically in popularity; however, there is no data on nicotine and oxidant yields from this new e-cig design. METHODS: Aerosol generated from four different Juul flavors was analyzed for carbonyls, nicotine, and free radicals. The e-liquids were analyzed for propylene glycol (PG) and glycerol (GLY) concentrations. To determine the effects of e-liquid on oxidant production, Juul pods were refilled with nicotine-free 30:70 or 60:40 PG:GLY with or without citral. RESULTS: No significant differences were found in nicotine (164 ± 41 µg/puff), free radical (5.85 ± 1.20 pmol/puff), formaldehyde (0.20 ± 0.10 µg/puff), and acetone (0.20 ± 0.05 µg/puff) levels between flavors. The PG:GLY ratio in e-liquids was ~30:70 across all flavors with GLY being slightly higher in tobacco and mint flavors. In general, when Juul e-liquids were replaced with nicotine-free 60:40 PG:GLY, oxidant production increased up to 190% and, with addition of citral, increased even further. CONCLUSIONS: Juul devices produce free radicals and carbonyls, albeit, at levels substantially lower than those observed in other e-cig products, an effect only partially because of a low PG:GLY ratio. Nicotine delivery by these devices was as high as or higher than the levels previously reported from cigarettes. IMPLICATIONS: These findings suggest that oxidative stress and/or damage resulting from Juul use may be lower than that from cigarettes or other e-cig devices; however, the high nicotine levels are suggestive of a greater addiction potential.

Effects of Charcoal on Carbonyl Delivery from Commercial, Research, and Make-Your-Own Cigarettes.

Previous literature has shown that adding charcoal to cigarette filters can have varying effects on the delivery of toxic carbonyls depending on filter design, amount of charcoal, and puffing profiles. However, these studies have relied on either comparisons between commercially available charcoal and noncharcoal filtered cigarettes or experimental modification of filters to insert a charcoal plug into existing cellulose acetate filters. Make-your-own (MYO) cigarettes can help obviate many of the potential pitfalls of previous studies; thus, we conducted studies using commercial charcoal cigarettes and MYO cigarettes to determine the effects of charcoal on carbonyl delivery. To do this, we analyzed carbonyls in mainstream smoke by HPLC-UV after derivatization with 2,4-dinitrophenylhydrazine (DNPH). Charcoal was added in-line after the cigarettes or through the use of MYO charcoal cigarette tubes. MYO cigarettes had carbonyl deliveries similar to that of 3R4F research cigarette, regardless of tobacco type. The greatest effect on carbonyl delivery was observed with 200 mg of charcoal, significantly reducing all carbonyls under both methods tested. However, "on-tow" design charcoal filters, available on many commercially available charcoal brands, appeared to have a minimal effect on carbonyl delivery under intense smoking methods. Overall, we found that charcoal, when added in sufficient quantity (200 mg) as a plug, can substantially reduce carbonyl delivery for both MYO and conventional cigarettes. As carbonyls are related to negative health outcomes, such reductions may be associated with reductions in carbonyl-related harm in smokers.

Little Cigars, Filtered Cigars, and their Carbonyl Delivery Relative to Cigarettes.

Introduction: Little cigars and filtered cigars are currently growing in popularity due to their low cost and wide variety of flavors while retaining an appearance similar to cigarettes. Given the health consequences associated with cigarette use, it is important to understand the potential harm associated with these similar products. This includes the potential harm associated with carbonyls (eg, acetaldehyde, acrolein, formaldehyde, etc.), an important class of toxicants and carcinogens in tobacco smoke. Our objective was to determine the carbonyl levels in mainstream smoke from little and filtered cigars compared to cigarettes. Methods: We examined two brands each of little cigars and filtered cigars, as well as two research cigarettes for carbonyl delivery using the International Organization of Standards (ISO) and the Health Canada Intense (HCI) machine-smoking protocols. Results: On a per puff basis, the levels of five of the seven carbonyls were higher from little cigars than filtered cigars and cigarettes (ISO: 56-116%; HCI: 39-85%; p < .05). On a per unit basis, most carbonyl levels were higher from both cigar types than cigarettes using the ISO method (ISO: 51-313%; p < .05) whereas only filtered cigars were higher using the HCI method (HCI: 53-99%; p < .05). Conclusion: These findings suggest that cigar smokers can be exposed to higher levels of carbonyls per cigar than cigarette smokers per cigarette. Implications: These data will increase our understanding of the relative harm from carbonyl exposure from little and filtered cigars both for cigar-only smokers and the cumulative harm among the growing population of cigarette-cigar multi-product smokers.

Effect of Charcoal in Cigarette Filters on Free Radicals in Mainstream Smoke.

The addition of charcoal in cigarette filters may be an effective means of reducing many toxicants from tobacco smoke. Free radicals are a highly reactive class of oxidants abundant in cigarette smoke, and here we evaluated the effectiveness of charcoal to reduce free radical delivery by comparing radical yields from commercially available cigarettes with charcoal-infused filters to those without and by examining the effects of incorporating charcoal into conventional cigarette filters on radical production. Commercial cigarettes containing charcoal filters produced 40% fewer gas-phase radicals than did regular cellulose acetate filter cigarettes when smoked using the International Organization of Standardization (ISO, p = 0.07) and Canadian Intense (CI, p < 0.01) smoking protocols. While mean-particulate-phase radicals were 25-27% lower in charcoal cigarettes, differences from noncharcoal products were not significant ( p = 0.06-0.22). When cellulose acetate cigarette filters were modified to incorporate different types and amounts of activated charcoal, reductions in gas-phase (>70%), but not particulate-phase, radicals were observed. The reductions in gas-phase radicals were similar for the three types of charcoal. Decreases in radical production were dose-responsive with increasing amounts of charcoal (25-300 mg) with as little as 25 mg of activated charcoal reducing gas-phase radicals by 41%. In all studies, charcoal had less of an effect on nicotine delivery, which was decreased 33% at the maximal amount of charcoal tested (300 mg). Overall, these results support the potential consideration of charcoal in cigarette filters as a means to reduce exposure to toxic free radicals from cigarettes and other combustible tobacco products.

Influence of Smoking Puff Parameters and Tobacco Varieties on Free Radicals Yields in Cigarette Mainstream Smoke.

Cigarette smoke is a major exogenous source of free radicals, and the resulting oxidative stress is one of the major causes of smoking-caused diseases. Yet, many of the factors that impact free radical delivery from cigarettes remain unclear. In this study, we machine-smoked cigarettes and measured the levels of gas- and particulate-phase radicals by electron paramagnetic resonance (EPR) spectroscopy using standardized smoking regimens (International Organization of Standardization (ISO) and Canadian Intense (CI)), puffing parameters, and tobacco blends. Radical delivery per cigarette was significantly greater in both gas (4-fold) and particulate (6-fold) phases when cigarettes were smoked under the CI protocol compared to the ISO protocol. Total puff volume per cigarette was the major factor with radical production being proportional to total volume, regardless of whether volume differences were achieved by changes in individual puff volume or puff frequency. Changing puff shape (bell vs sharp vs square) or puff duration (1-5 s), without changing volume, had no effect on radical yields. Tobacco variety did have a significant impact on free radical production, with gas-phase radicals highest in reconstituted > burley > oriental > bright tobacco and particulate-phase radicals highest in burley > bright > oriental > reconstituted tobacco. Our findings show that modifiable cigarette design features and measurable user smoking behaviors are key factors determining free radical exposure in smokers.

Differences in nicotine dependence, smoke exposure and consumer characteristics between smokers of machine-injected roll-your-own cigarettes and factory-made cigarettes.

BACKGROUND: Consumption of machine-injected roll-your-own (RYO) filtered cigarettes made from pipe tobacco increased almost 7-fold from 2008 to 2011 in the United States. METHODS: We used data from the Pennsylvania Adult Smoking Study to compare the differences in sociodemographic, smoking topography, nicotine dependence, and cotinine levels between 280 smokers using factory made (FM) cigarettes and 68 smokers using RYO cigarettes. RESULTS: RYO smokers were older (41 vs. 37, P = 0.053), had significantly lower levels of income (P < 0.001) and education (P = 0.007), and were less likely to be fully employed (P = 0.009). RYO smokers consumed more cigarettes per day [CPD] (21 vs. 15, P < 0.001), and had a higher mean score on the Fagerström Test for Cigarette/Nicotine Dependence (5.2 vs. 4.1, P < 0.001). The main reasons for choosing RYO cigarettes were the lower cost (68%) and believed they are less harmful (12%). The average cost per pack of FM cigarettes was $5.74 vs. $1.13 for RYO. In multiple regression analyses, RYO smokers had significantly lower cotinine levels across all levels of CPD. Among smokers of king-size cigarettes, mean interpuff interval (P < 0.05) and total smoke duration (P < 0.01) per cigarette was significantly greater in RYO smokers. In laboratory measurements, RYO cigarettes contained more tobacco by weight than FM cigarettes, but weight varied by both tobacco and cigarette tube brands. CONCLUSIONS: Machine-injected RYO cigarettes made from pipe tobacco are cheaper than FM cigarettes but may have higher abuse liability. Smokers who might otherwise reduce their cigarette consumption or quit altogether may continue to smoke RYO cigarettes due to their affordability.

Effect of flavoring chemicals on free radical formation in electronic cigarette aerosols.

BACKGROUND: Flavoring chemicals, or flavorants, have been used in electronic cigarettes (e-cigarettes) since their inception; however, little is known about their toxicological effects. Free radicals present in e-cigarette aerosols have been shown to induce oxidative stress resulting in damage to proliferation, survival, and inflammation pathways in the cell. Aerosols generated from e-liquid solvents alone contain high levels of free radicals but few studies have looked at how these toxins are modulated by flavorants. OBJECTIVES: We investigated the effects of different flavorants on free radical production in e-cigarette aerosols. METHODS: Free radicals generated from 49 commercially available e-liquid flavors were captured and analyzed using electron paramagnetic resonance (EPR). The flavorant composition of each e-liquid was analyzed by gas chromatography mass spectroscopy (GCMS). Radical production was correlated with flavorant abundance. Ten compounds were identified and analyzed for their impact on free radical generation. RESULTS: Nearly half of the flavors modulated free radical generation. Flavorants with strong correlations included ß-damascone, δ-tetradecalactone, γ-decalactone, citral, dipentene, ethyl maltol, ethyl vanillin, ethyl vanillin PG acetal, linalool, and piperonal. Dipentene, ethyl maltol, citral, linalool, and piperonal promoted radical formation in a concentration-dependent manner. Ethyl vanillin inhibited the radical formation in a concentration dependent manner. Free radical production was closely linked with the capacity to oxidize biologically-relevant lipids. CONCLUSIONS: Our results suggest that flavoring agents play an important role in either enhancing or inhibiting the production of free radicals in flavored e-cigarette aerosols. This information is important for developing regulatory strategies aimed at reducing potential harm from e-cigarettes.

Comparison of Biomarkers of Tobacco Exposure between Premium and Discount Brand Cigarette Smokers in the NHANES 2011-2012 Special Sample.

Background: Increased cigarette costs have inadvertently strengthened the appeal of discounted brands to price-sensitive smokers. Although smokers perceive discounted brands as having poorer quality, little is known about their delivery of toxic tobacco smoke constituents compared with premium-branded tobacco products.Methods: We investigated the differences between discount and premium brand smokers using the National Health and Nutrition Examination Survey 2011-2012 Special Smoker Sample. Our analyses focused on demographic differences and 27 biomarkers of harmful and potentially harmful constituents (HPHC) listed by the FDA, including volatile organic compounds, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol glucuronide; reported as total NNAL (tNNAL)], metals, and polycyclic aromatic hydrocarbons (PAHs). Data were analyzed using linear regression models adjusting for potential confounders.Results: A total of 976 non-tobacco users and 578 recent cigarette smokers were eligible for analysis, of which 141 (26.0% weighted) smoked discount brand cigarettes and 437 (74.0% weighted) smoked premium. Discount brand smokers were older, predominantly non-Hispanic white, and had higher serum cotinine. Discount brand smokers had significantly higher levels of 13 smoking-related biomarkers, including tNNAL, uranium, styrene, xylene, and biomarkers of exposure to PAHs (naphthalene, fluorene, and phenanthrene), compared with premium brand smokers.Conclusions: These findings suggest that discount cigarette use is associated with higher exposure to several carcinogenic and toxic HPHCs.Impact: These results may have important regulatory implications for product standards, as higher exposures could lead to a greater degree of harm. Cancer Epidemiol Biomarkers Prev; 27(5); 601-9. ©2018 AACR.

Effects of Solvent and Temperature on Free Radical Formation in Electronic Cigarette Aerosols.

The ever-evolving market of electronic cigarettes (e-cigarettes) presents a challenge for analyzing and characterizing the harmful products they can produce. Earlier we reported that e-cigarette aerosols can deliver high levels of reactive free radicals; however, there are few data characterizing the production of these potentially harmful oxidants. Thus, we have performed a detailed analysis of the different parameters affecting the production of free radical by e-cigarettes. Using a temperature-controlled e-cigarette device and a novel mechanism for reliably simulating e-cigarette usage conditions, including coil activation and puff flow, we analyzed the effects of temperature, wattage, and e-liquid solvent composition of propylene glycol (PG) and glycerol (GLY) on radical production. Free radicals in e-cigarette aerosols were spin-trapped and analyzed using electron paramagnetic resonance. Free radical production increased in a temperature-dependent manner, showing a nearly 2-fold increase between 100 and 300 °C under constant-temperature conditions. Free radical production under constant wattage showed an even greater increase when going from 10 to 50 W due, in part, to higher coil temperatures compared to constant-temperature conditions. The e-liquid PG content also heavily influenced free radical production, showing a nearly 3-fold increase upon comparison of ratios of 0:100 (PG:GLY) and 100:0 (PG:GLY). Increases in PG content were also associated with increases in aerosol-induced oxidation of biologically relevant lipids. These results demonstrate that the production of reactive free radicals in e-cigarette aerosols is highly solvent dependent and increases with an increase in temperature. Radical production was somewhat dependent on aerosol production at higher temperatures; however, disproportionately high levels of free radicals were observed at ≥100 °C despite limited aerosol production. Overall, these findings suggest that e-cigarettes can be designed to minimize exposure to these potentially harmful products.

A Survey of Nicotine Yields in Small Cigar Smoke: Influence of Cigar Design and Smoking Regimens.

Introduction: Although the popularity of small cigar brands that resemble cigarettes, including both little cigars (LC) and filtered cigars (FC), has been on the rise, little is known about the delivery of nicotine from these products. Our objective was to determine the nicotine yields of small cigars in comparison to cigarettes. Methods: Nicotine yields from LC, FC, and 3R4F and 1R6F research cigarettes were determined from mainstream smoke generated on a smoking machine under the International Organization of Standardization (ISO) and Canadian Intense (CI) methods. Market characteristics (price and package label) and physical features (filter ventilation, product weight and filter weight, product length, and diameter) were also determined for eight brands of small cigars. Results: Nicotine yields in small cigars averaged 1.24 and 3.49 mg/unit on ISO and CI regimens, respectively, compared with 0.73 and 2.35 mg/unit, respectively, for the research cigarettes. Nicotine yields per puff were similar between small cigars and cigarettes. We also found that FC did not differ from LC in nicotine yields. FC and LC differ from each other in many physical design features (unit weight, filter weight, and filter length), but are similar in others (unit length, diameter, and filter ventilation). Conclusions: Nicotine delivery from small cigars is similar to or greater than that from cigarettes. Thus, for future research and regulatory purposes, standard definitions need to be developed for small cigars, and FC and LC should be evaluated as separate entities. Implications: Small cigars are similar to cigarettes in their design and use. Although nicotine yields per puff were similar between products, small cigars delivered substantially higher amounts of nicotine per unit than cigarettes. These findings support the growing body of evidence to justify regulating all small cigars, including LC and FC in a similar fashion as cigarettes.

Correction to Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial.

CORRECTION: The title of the original publication [1] had an error; furthermore there were errors in Fig. 2. The corrected version of the title and of Fig. 2 can be found below in this Erratum.

Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial.

BACKGROUND: The Family Smoking Prevention and Tobacco Control Act gave the Food and Drug Administration jurisdiction over the regulation of all tobacco products, including their nicotine content. Under this act, a major strategy to reduce harm from cigarette tobacco is lowering the nicotine content without causing unintended adverse consequences. Initial research on reduced nicotine content (RNC) cigarettes has shown that smokers of these cigarettes gradually decrease their smoking frequency and biomarkers of exposure. The effectiveness of this strategy needs to be demonstrated in different populations whose response to RNC cigarettes might be substantially mediated by personal or environmental factors, such as low socioeconomic status (SES) populations. This study aims to evaluate the response to a reduced nicotine intervention in low SES smokers, as defined here as those with less than 16 years of education, by switching smokers from high nicotine commercial cigarettes to RNC cigarettes. METHODS/DESIGN: Adults (N = 280) who have smoked five cigarettes or more per day for the past year, have not made a quit attempt in the prior month, are not planning to quit, and have less than 16 years of education are recruited into a two-arm, double-blinded randomized controlled trial. First, participants smoke their usual brand of cigarettes for 1 week and SPECTRUM research cigarettes containing a usual amount of nicotine for 2 weeks. During the experimental phase, participants are randomized to continue smoking SPECTRUM research cigarettes that contain either (1) usual nicotine content (UNC) (11.6 mg/cigarette) or (2) RNC (11.6 to 0.2 mg/cigarette) over 18 weeks. During the final phase of the study, all participants are offered the choice to quit smoking with nicotine replacement therapy, continue smoking the research cigarettes, or return to their usual brand of cigarettes. The primary outcomes of the study include retention rates and compliance with using only research cigarettes and no use of other nicotine-containing products. Secondary outcomes are tobacco smoke biomarkers, nicotine dependence measures, smoking topography, stress levels, and adverse health consequences. DISCUSSION: Results from this study will provide information on whether low SES smokers can maintain a course of progressive nicotine reduction without increases in incidence of adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01928719 . Registered on 21 August 2013.

Effects of Topography-Related Puff Parameters on Carbonyl Delivery in Mainstream Cigarette Smoke.

Smoking topography parameters differ substantially between individual smokers and may lead to significant variation in tobacco smoke exposure and risk for tobacco-caused diseases. However, to date, little is known regarding the impact of individual puff parameters on the delivery of many harmful smoke constituents including carbonyls. To examine this, we determined the effect of altering individual puff parameters on mainstream smoke carbonyl levels in machine-smoked reference cigarettes. Carbonyls including formaldehyde, acetaldehyde, crotonaldehyde, propionaldehyde, methyl ethyl ketone (MEK), acrolein, and acetone were determined in cigarette smoke by HPLC after derivatization with 2,4-dinitrophenylhydrazine (DNPH). Deliveries of all carbonyls were nearly two-fold greater when cigarettes were smoked according to the more intense Health Canada Intense (HCI) protocol compared to the International Organization of Standardization (ISO) method, consistent with the two-fold difference in total puff volume between methods (ISO: 280-315 mL; CI: 495-605 mL). When individual topography parameters were assessed, changes in puff volume alone had the greatest effect on carbonyl delivery as predicted with total carbonyls being strongly correlated with overall puff volume (r2: 0.52-0.99) regardless of how the differences in volume were achieved. All seven of the carbonyls examined showed a similar relationship with puff volume. Minor effects on carbonyl levels were observed from vent blocking and changing the interpuff interval, while effects of changing puff duration and peak flow rate were minimal. Overall, these results highlight the importance of considering topography, especially puff volume, when the toxicant delivery and potential exposure smokers receive are assessed. The lack of an impact of other behaviors, including puff intensity and duration independent of volume, indicate that factors such as temperature and peak flow rate may have minimal overall effects on carbonyl production and delivery.