Harmful And Potentially Harmful Constituents Research Articles

Non-targeted analytical comparison of a heated tobacco product aerosol against mainstream cigarette smoke: does heating tobacco produce an inherently different set of aerosol constituents?

Smoking-related diseases remain a significant public health concern, and heated tobacco products (HTPs) have emerged as a potential alternative to cigarettes. While several studies have confirmed that HTP aerosols contain lower levels of harmful and potentially harmful constituents (HPHCs) than cigarette smoke, less is known about constituents that are intrinsically higher in HTP aerosols. This study provides a comprehensive comparative assessment of an HTP aerosol produced with Tobacco Heating System 2.2 (THS) and comparator cigarette (CC) smoke aiming at identifying all unique or increased compounds in THS aerosol by applying a broad set of LC–MS and GC × GC–MS methods. To focus on differences due to heating versus burning tobacco, confounding factors were minimized by using the same tobacco in both test items and not adding flavorants. Of all analytical features, only 3.5%—corresponding to 31 distinctive compounds—were significantly more abundant in THS aerosol than in CC smoke. A notable subset of these compounds was identified as reaction products of glycerol. The only compound unique to THS aerosol was traced back to its presence in a non-tobacco material in the test item and not a direct product of heating tobacco. Our results demonstrate that heating a glycerol-containing tobacco substrate to the temperatures applied in THS does not introduce new compounds in the resulting aerosol compared to CC smoke which are detectable with the method portfolio applied in this study. Overall, this study contributes to a better understanding of the chemical composition of HTP aerosols and their potential impact on human health.Graphical

RISK REDUCTION ASSESSMENT: EPIDEMIOLOGY AND NOVEL APPROACHES

Introduction. Today, there are new approaches to assessing the potential impact of alternative nicotine delivery systems, such as systemic toxicology and biomarker assessment. The modern development of science and technology, including laboratory research, allows for a detailed assessment of the biological effects of a substance or complex of substances on the human body as a whole.
 The aim of the study: to compare and assess based on literature data possibility to broaden the standard approach for risk reduction assessment for lifestyle (potentially correctable) risk factors, especially tobacco smoking (TS). While epidemiology remains a golden standard for risk reduction assessment, novel approaches are based on preventive or system toxicology analysis and biomarkers of harm evaluation, thus it is crucial to understand both benefits and limitations of novel and standard approaches to complete risk reduction assessment for potentially correctable risk factors.
 Materials and methods. The thematic scientific papers, published predominantly during the last decade, constituted the study material. The research methodology involved bibliosemantic method and structural and logical analysis.
 Results and discussion. Level of modern scientific development already can help us to assess the harm made by new/emerging products based on epidemiological, toxicological data and evaluation of biomarkers of potential harm for specific risk or disease. For TS biomarkers of harm are mostly well established and include 15 Harmful and Potentially Harmful Constituents (HPHCs) of tobacco smoke and their metabolites in the body. Reduction in Total-3-OH-B[a]P, S-PMA, COHb and other can show reduction in harm and risk caused by new/emerging product. So far most comprehensive analysis of reduction in HPHCs and biomarkers manifestation was concluded for tobacco heating system as TS alternative. Switching from cigarettes to THS for 5 days resulted in 56 % to 96 % reductions in 15 exposure biomarkers in the THS group compared to the TS group. These values approached the decrease in effect observed in the group of complete refusal of TS. Similar observations were made for the 90-day studies, where the reduction observed on day 5 was maintained until the end of the three-month studies and confirmed by other 3 clinical studies.
 Conclusions. In general, the results of the risk reduction assessment based on novel approaches
 confirms that THS is an acceptable alternative to cigarettes for adult smokers, and based on the positive biological effects, the transition to THS represents a lower risk for the smoker’s body with regard to the effects of HPHCs.

In vitro permeation of nicotine and tobacco specific nitrosamines from smokeless tobacco product extracts in a 3D buccal tissue model

Tobacco product use is a risk factor in the development of oral cancer, although epidemiology studies show this risk is far less with smokeless tobacco product use than cigarette smoking. While smokeless tobacco contains harmful and potentially harmful constituents (HPHCs), the oral permeation of HPHCs in oral tobacco products is not completely understood. To improve the understanding, three different extract concentrations of the CORESTA reference products (CRP) for snus (CRP1.1) and moist snuff (CRP2.1) were applied to cellular tissue derived from two donors of EpiOral™ model, a 3D human buccal model, and permeation of nicotine and tobacco-specific nitrosamines (TSNAs) were measured over two hours. Permeation of 0.15% caffeine in complete artificial saliva and cell viability were also measured. Results showed that a consistent and concentration dependent cumulative permeation of nicotine and TSNAs was observed with high percent recovery in all conditions. A high degree of sensitivity was seen for all analytes, with minimal cytotoxicity for both CRPs. The data presented here show the EpiOral™ model is fit-for-purpose to evaluate the permeation of nicotine and TSNAs in nicotine-containing snus and moist snuff oral tobacco.

Believability of messaging concerning a hypothetical product standard to lower a constituent in cigarettes or smokeless tobacco among U.S. Adults who use tobacco

The U.S. Food and Drug Administration (FDA) has regulatory authority to implement tobacco product standards to reduce harmful and potentially harmful constituents (HPHCs). This study examines people who use tobacco products’ awareness of FDA’s tobacco regulatory authority, knowledge of HPHCs, and belief in hypothetical tobacco product standard statements. We recruited adults who reported currently using tobacco (N = 1,592) from the National Panel of Tobacco Consumer Studies and randomized them to one of four conditions. Participants viewed a stimulus which consisted of a statement about a hypothetical product standard that would reduce the level of a chemical in cigarettes or smokeless tobacco (ST) and reduce cases of cancer or heart attack and stroke. A small majority of participants correctly believed that FDA regulates tobacco; however, the percentage of participants who recognized HPHCs varied widely depending upon the chemical. People who currently use ST found chemical and health statements more believable than people who did not currently use ST. Participants found it more believable that cigarettes, not ST, could be made with fewer harm-causing chemicals, and their belief in the chemical and health statements did not differ based on the health outcome specified in the hypothetical product standard statement.

Facile preparation of sulfonated covalent triazine frameworks for effectively detection of six carcinogenic aromatic amines in cigarette smoke

FDA reported a HPHCs (Harmful and Potentially Harmful Constituents) list for tobacco products and tobacco smoke in 2012, which contained six carcinogenic aromatic amines (AAs). In this work, a sulfonated covalent triazine frameworks (CTF-SO3H) material was synthesized and used as a solid phase extraction (SPE) absorbent for highly effective enrichment and determination of six carcinogenic AAs in cigarette mainstream smoke (MSS), coupled with HPLC-MS/MS technique. The CTF-SO3H material was prepared with a rapid and facile method, which was superior to the general methods. The characterization with Nitrogen adsorption and desorption isotherm experiment, High resolution transmission electron microscopy (HTEM), etc, indicated that the CTF-SO3H material possessed sulfonic acid groups and abundant microporous structure. And the CTF-SO3H material showed good enrichment effect for AAs due to the synergistic effect of π-π stacking and electrostatic interactions. Limits of detection (LODs) of 6 AAs with the developed method were in the range of 0.01–0.11 ng cig−1. Recoveries of 6 AAs were between 80.40% and 106.00%, while the intra-day and inter-day precisions were good (i.e. RSDintra ≤ 6.40%, RSDinter ≤ 9.90%). Commercial cigarette MSS samples were analyzed with the developed method, and a commercial cation exchange SPE column was chosen for comparison. Results obtained by two methods showed a good consistency. However, the CTF-SO3H material needed less dosage, even could be reused for 4 times. Thus, the developed method not only showed high enrichment efficiency, but also was economical.

Evaluation of the 1R6F certified reference cigarette for proficiency testing of mainstream smoke parameters

A goal of the cooperative agreement between the U.S. Food and Drug Administration and the Center for Tobacco Reference Products (CTRP) at the University of Kentucky was to produce a standard reference cigarette for researchers to further tobacco science. The 1R6F certified reference cigarette for analytical testing was developed to be typical of an American blend cigarette. The cigarettes have been used in proficiency testing (PT) schemes under the supervision of the CTRP since 2016 for a variety of parameters. Data were compared from 8 rounds of PT schemes submitted by participating laboratories, which include various international stakeholders comprised of academic institutions, federal research/regulatory laboratories, tobacco product manufacturers, and independent contract testing laboratories. Evaluation of the datasets for harmful and potentially harmful constituents (HPHCs) within the mainstream smoke of the 1R6F certified reference cigarette included tobacco-specific nitrosamines (TSNA), tar, nicotine, and carbon monoxide (TNCO), and Benzo[α]pyrene (BαP). Of the datasets evaluated, less than 5 % resulted in either a warning or alert, and less than 2 % resulted in an alert. Comparisons across multiple PT rounds revealed no significant differences in the consensus means of the tested parameters. Evaluation of data submitted by participating laboratories for multiple proficiency test rounds shows that the 1R6F certified reference cigarette is an acceptable material as a control reference for the analysis of HPHCs which is imperative since some stakeholders may be required to participate in, and receive satisfactory results, from PT for accreditation purposes.

Harmful and potentially harmful constituents (HPHCs) in two novel nicotine pouch products in comparison with regular smokeless tobacco products and pharmaceutical nicotine replacement therapy products (NRTs)

BackgroundTobacco-free nicotine pouches is a novel category of oral nicotine-delivery products. Among current tobacco users such pouches may serve as a low-risk alternative to cigarettes or conventional, tobacco-based oral products e.g., snus and moist snuff. In the United States (U.S.), the market leading nicotine-pouch brand is ZYN®. However, no data on the chemical characteristics of ZYN have been published.MethodsWe screened for 43 compounds potentially present in tobacco products in seven oral nicotine-delivery products: ZYN (dry and moist), snus (General®), moist snuff (CRP2.1 and Grizzly Pouches Wintergreen), and two pharmaceutical, nicotine replacement therapy products (NRTs, Nicorette® lozenge and Nicotinell® gum). Thirty-six of the tested compounds are classified as harmful and potentially harmful constituents (HPHCs) by the Center for Tobacco Products at the U.S. Food and Drug Administration (FDA-CTP). Five additional compounds were included to cover the GOTHIATEK® product standard for Swedish snus and the last two compounds were chosen to include the four primary tobacco specific nitrosamines (TSNAs).ResultsThe tested products contained nicotine at varying levels. The two ZYN products contained no nitrosamines or polycyclic aromatic hydrocarbons (PAHs) but low levels of ammonia, chromium, formaldehyde, and nickel. In the NRT products we quantified low levels of acetaldehyde, ammonia, cadmium, chromium, lead, nickel, uranium-235, and uranium-238. The largest number (27) and generally the highest levels of HPHCs were quantified in the moist snuff products. For example, they contained six out of seven tested PAHs, and seven out of ten nitrosamines (including NNN and NNK). A total of 19 compounds, none of which were PAHs, were quantified at low levels in the snus product. NNN and NNK levels were five to 12-fold lower in snus compared to the moist snuff products.ConclusionsNo nitrosamines or PAHs were quantified in the ZYN and NRT products. Overall, the number of quantified HPHCs were similar between ZYN and NRT products and found at low levels.

Youth and adult understanding of public displays of information about harmful constituents in cigarette smoke

The U.S. FDA is required by law to publicly display a list of harmful and potentially harmful constituents (HPHCs) “by brand and by quantity in each brand and subbrand” in a format that is “understandable and not misleading to a lay person.” An online experiment examined youth and adult understanding of which HPHCs are present in cigarette smoke, understanding of health effects of smoking cigarettes, and endorsement of misleading information after viewing HPHC information displayed in one of six formats. We recruited youth (N = 1324) and adults (N = 2904) from an online panel and randomized them to one of six formats of presenting HPHC information. Participants responded to survey items before and after exposure to an HPHC format. Understanding of HPHCs in cigarette smoke and understanding of health effects of cigarette smoking significantly increased pre- to post-exposure for all formats. Respondents (20.6% to 73.5%) endorsed misleading beliefs after exposure to information about HPHCs. Endorsement of the one misleading belief that was measured pre- and post-exposure significantly increased for viewers of four formats. All formats increased understanding of HPHCs in cigarette smoke and the health effects of smoking cigarettes, but some participants endorsed each misleading belief after exposure to HPHC information.

Chemical andin vitro toxicological comparison of emissions from a heated tobacco product and the 1R6F reference cigarette.

It has previously been found that, compared with cigarette smoke, the aerosols generated by heated tobacco products contain fewer and lower harmful and potentially harmful constituents (HPHCs) and elicit lower biological activity inin vitro models and lower smoking-related exposure biomarker levels in clinical studies. It is important to accumulate such scientific evidences for heated tobacco products with a novel heating system, because different heating system may affect the quantitative aspect of the amount of HPHCs and the qualitative aspect of the biological activity of the aerosol generated. Here, the chemical properties of, and toxicological responses to aerosols emitted by DT3.0a, a new heated tobacco product with a novel heating system, and cigarette smoke (CS) were compared, using chemical analyses, in vitro battery (standardized genotoxicity and cytotoxicity) assays, and mechanistic (ToxTracker and two-dimensional cell culture) assays. Regular- and menthol-flavored DT3.0a and standard 1R6F reference cigarettes were tested. Selected HPHC yields were lower in DT3.0a aerosol than 1R6F CS. The genotoxicity-related assays indicated that DT3.0a aerosol was not genotoxic, regardless of metabolic activation. The other biological assays indicated that less cytotoxicity induction and oxidative stress response were elicited by DT3.0a aerosol compared with 1R6F CS. Similar results were found for both regular and menthol DT3.0a. Like previous reports for heated tobacco products with other heating systems, the results of this study indicated that DT3.0a aerosols have chemical and biological properties less likely to be harmful than 1R6F CS.

Physico-Chemical Aspects of the Processes During the Combustion and Heating of Tobacco under Different Conditions

Smoking cigarettes causes lung cancer, heart disease, chronic obstructive pulmonary disease (COPD) and other serious diseases. The damage caused by cigarette smoking is multifaceted and complex. Exposure to harmful and potentially harmful constituents (HPHCs), created during the process of burning tobacco, is the main reason for the development of smoking-related diseases. An alternative way to reduce the generation of toxicants from tobacco product is to heat rather than burn tobacco. Modified risk tobacco product (MRTP) are designed to significantly reduce or eliminate the release of harmful and potentially harmful chemicals while preserving, as much as possible, taste, sensory experience, nicotine delivery profile, and the ritual component of smoking cigarettes. In this review, the chemical composition of the smoke generated by conventional cigarettes to the composition of the aerosol generated by devices for controlled tobacco heating is compared. Also, critically assess the current knowledge in the field, aiming towards an objective assessment of the alternative tobacco products.

Current Evidence on Tobacco Harm Reduction in Pneumology: Interviews with Two Key Opinion Leaders

The negative impact of smoking on the lung is well documented. Cigarette smoke is the cause of 90% of cases of chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema. COPD is a progressive and debilitating condition with morbidity and mortality rates similar to myocardial infarction (MI) and stroke. Despite the widely recognised risks, millions of people continue to smoke, in some cases even after receiving a diagnosis of COPD and despite knowing that the habit will accelerate disease progression. While there is no doubt that smoking cessation is the most important health intervention for all cigarette smokers, it can be challenging. Nicotine addiction, social norms and culture, and the length of time it can take smokers to feel the adverse consequences of the habit all contribute to the high cessation failure rate. However, increasing clinical and epidemiological evidence indicates that for those who are unwilling or cannot stop smoking, harm reduction strategies can help reduce exposure to the harmful chemicals and carcinogens released during tobacco combustion. Electronic devices heat processed tobacco without combusting it to deliver an aerosol containing fewer toxic products or harmful and potentially harmful constituents (HPHC) than cigarette smoke. Clinical evidence to support their use is growing. In Japan, for example, a decrease in hospitalisations due to COPD exacerbation after the introduction of such heat-not-burn (HNB), or tobacco heating systems (THS), has been reported. In this article, Wolfgang Popp, Döbling Doctor’s Center, Privatklinik Döbling, Vienna, Austria, and Klara Szondy, Semmelweis University, Budapest, Hungary, discuss the impact of cigarette smoke on the lung, and how to support smoking cessation in those willing and able to quit smoking. They also explain when strategies that reduce the harmful effects of smoking may be useful, and outline the latest evidence supporting the use of HNB systems.

Assessment of the exposure to selected smoke constituents in adult smokers using in-market heated tobacco products: a randomized, controlled study

The objectives of this clinical study were to demonstrate a reduction in exposure to selected harmful and potentially harmful constituents (HPHCs) in Japanese healthy adult smokers who switched to four in-market heated tobacco products. Eighty-nine smokers were randomly assigned for five days to one of six study groups: four groups who switched to one of the commercially available heated tobacco products; a group who continued to smoke their own brand of combustible cigarettes (CC); or a group who stopped smoking (SS). Fifteen biomarkers of exposure (BoE) to 14 HPHCs and pyrene were measured at baseline, Day 3 and Day 5 in 24 h urine and breath, under clinical confinement. Product consumption, nicotine uptake and subjective effects were also measured before and after product switching. On Day 5, significant reductions in most BoE relative to the CC group were observed after switching to heated tobacco products. No changes in BoE were observed between baseline and Day 5 in the CC group. Significantly, the magnitude of the reduction in exposure to most of the selected HPHCs observed in the heated tobacco product groups was close to that observed in the SS group.

Chemical characterisation of the vapour emitted by an e-cigarette using a ceramic wick-based technology

Fourth-generation ‘pod’ e-cigarette devices have been driven by technological advances in electronic atomization of the e-liquid. Use of microporous ceramic as a wicking material improves heating efficiency, but how it affects the chemical emissions of these devices is unclear. We assessed the emissions of a pod e-cigarette with innovative ceramic wick-based technology and two flavoured e-liquids containing nicotine lactate and nicotine benzoate (57 and 18 mg mL−1 nicotine, respectively). Among the studied harmful and potentially harmful constituents (HPHCs) listed by the US FDA and/or WHO TobReg, only 5 (acetone, acetaldehyde, formaldehyde, naphthalene and nornicotine) were quantified at levels of 0.14 to 100 ng puff−1. In the combustible cigarette (Kentucky reference 1R6F), levels were from 0.131 to 168 µg puff−1. Nicotine levels ranged 0.10–0.32 mg puff−1 across the 3 study products. From the 19 proposed HPHCs specifically of concern in e-cigarettes, only 3 (glycerol, isoamyl acetate and propylene glycol) were quantified. The low/undetectable levels of HPHCs reflect not only the optimal operating conditions of the e-cigarette, including an efficient supply of e-liquid by the ceramic wick without overheating, but also the potential of the e-cigarettes to be used as an alternative to combustible cigarettes.

The importance of harmful and potentially harmful constituents in the implementation of the 2009 US Family Smoking Prevention and Tobacco Control Act.

Implementing the 2009 US Tobacco Control Act established a new infrastructure for tobacco and nicotine science. At its heart is the Food and Drug Administration (FDA) Center for Tobacco Products (CTP). A key challenge facing FDA CTP is determining whether nicotine products are "appropriate to the protection of the public health," and this is the central component of the Premarket Tobacco Application (PMTA) and Modified Risk Tobacco Application (MRTP) processes. CTP has granted such marketing orders for only a few products but has been consistent in its reasoning: the applicant demonstrated that the product(s) has low levels of Harmful and Potentially Harmful Constituents (HPHCs). By doing so, FDA has equated low levels of HPHCs with public health benefit. Other factors will be increasingly important, but the regulatory history indicates that no product will be granted a marketing order unless it has low levels of HPHCs. This science-driven regulatory approach has been possible due to the rapid evolution of the knowledge base and expansion of scientific human resources, including establishment of a robust CTP Office of Science to evaluate the extensive dossiers that manufacturers must submit. Companies therefore established internal regulatory science programs, and contract research organizations developed capabilities needed to support regulatory dossiers. This article focuses on the chemistry and toxicology part of the regulatory science process and also presents the industry side of the regulatory process by examining the experience of one company-Swedish Match-that was granted the first PMTA and MRTP marketing authorizations.

Composition of aerosols from thermal degradation of flavors used in ENDS and tobacco products

Aim: The cardiovascular toxicity of unheated and heated flavorants and their products as commonly present in electronic cigarette liquids (e-liquids) was evaluated previously in vitro. Based on the results of in vitro assays, cinnamaldehyde, eugenol, menthol, and vanillin were selected to conduct a detailed chemical analysis of the aerosol generated following heating of each compound both at 250 and 750 °C. Materials and Methods: Each flavoring was heated in a drop-tube furnace within a quartz tube. The combustion atmosphere was captured using different methods to enable analysis of 308 formed compounds. Volatile organic compounds (VOCs) were captured with an evacuated Summa canister and assayed via gas chromatography interfaced with mass spectrometry (GC–MS). Carbonyls (aldehydes and ketones) were captured using a 2,4-dinitrophenylhydrazine (DNPH) cartridge and assayed via a high-performance liquid chromatography-ultra-violet (HPLC-UV) assay. Polyaromatic hydrocarbons (PAHs) were captured using an XAD cartridge and filter, and extracts were assayed using GC–MS/MS. Polar compounds were assayed after derivatization of the XAD/filter extracts and analyzed via GC–MS. Conclusion: At higher temperature, both cinnamaldehyde and menthol combustion significantly increased formaldehyde and acetaldehyde levels. At higher temperature, cinnamaldehyde, eugenol, and menthol resulted in increased benzene concentrations. At low temperature, all four compounds led to higher levels of benzoic acid. These data show that products of thermal degradation of common flavorant compounds vary by flavorant and by temperature and include a wide variety of harmful and potentially harmful constituents (HPHCs).

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.

HPHC Testing of Tobacco and Smoke to Examine Cigarette Temporal Variability

Summary Commercial cigarettes were analyzed for harmful and potentially harmful constituents (HPHCs) in tobacco and smoke to investigate temporal product variability independent of analytical variability over one week, one year, and three years. Cigarettes from the worldwide market with various design features were collected over a 3-year period, stored, and tested concurrently for HPHCs to minimize analytical variability; repeat testing of reference cigarette 3R4F was included as an analytical control for the study design. Physical parameters were found to be relatively consistent. No trends in variability were noted based on blend type, smoke analyte matrix, or magnitude of an HPHC's yield. Combustion-related HPHCs generally showed low variation. Long-term batch-to-batch variability was found to be higher than short-term variability for tobacco-related compounds that have the potential to vary over time due to weather and agronomic practices. “Tar”, nicotine, and carbon monoxide were tested in multiple labs and showed greater lab-to-lab variability than batch-to-batch variability across all phases. Based on the results of this study, commercial cigarette products appear to have relatively low product variability. The low analyte variability noted in this study with products tested under unconventionally controlled analytical conditions serves to indicate that analytical variability may be a significant contributor to overall variability for general product testing over time and in interlaboratory studies. Laboratory controls and using a matched reference product across studies and between laboratories are important to assess testing differences and variability.

Effects of Common e-Liquid Flavorants and Added Nicotine on Toxicant Formation during Vaping Analyzed by 1H NMR Spectroscopy.

A broad variety of e-liquids are used by e-cigarette consumers. Additives to the e-liquid carrier solvents, propylene glycol and glycerol, often include flavorants and nicotine at various concentrations. Flavorants in general have been reported to increase toxicant formation in e-cigarette aerosols, yet there is still much that remains unknown about the effects of flavorants, nicotine, and flavorants + nicotine on harmful and potentially harmful constituents (HPHCs) when aerosolizing e-liquids. Common flavorants benzaldehyde, vanillin, benzyl alcohol, and trans-cinnamaldehyde have been identified as some of the most concentrated flavorants in some commercial e-liquids, yet there is limited information on their effects on HPHC formation. E-liquids containing flavorants + nicotine are also common, but the specific effects of flavorants + nicotine on toxicant formation remain understudied. We used 1H NMR spectroscopy to evaluate HPHCs and herein report that benzaldehyde, vanillin, benzyl alcohol, trans-cinnamaldehyde, and mixtures of these flavorants significantly increased toxicant formation produced during e-liquid aerosolization compared to unflavored e-liquids. However, e-liquids aerosolized with flavorants + nicotine decreased the HPHCs for benzaldehyde, vanillin, benzyl alcohol, and a "flavorant mixture" but increased the HPHCs for e-liquids containing trans-cinnamaldehyde compared to e-liquids with flavorants and no nicotine. We determined how nicotine affects the production of HPHCs from e-liquids with flavorant + nicotine versus flavorant, herein referred to as the "nicotine degradation factor". Benzaldehyde, vanillin, benzyl alcohol, and a "flavorant mixture" with nicotine showed lower HPHC levels, having nicotine degradation factors <1 for acetaldehyde, acrolein, and total formaldehyde. HPHC formation was most inhibited in e-liquids containing vanillin + nicotine, with a degradation factor of ∼0.5, while trans-cinnamaldehyde gave more HPHC formation when nicotine was present, with a degradation factor of ∼2.5 under the conditions studied. Thus, the effects of flavorant molecules and nicotine are complex and warrant further studies on their impacts in other e-liquid formulations as well as with more devices and heating element types.

Chemical analysis of selected harmful and potentially harmful constituents and in vitro toxicological evaluation of leading flavoured e-cigarette aerosols in the Chinese market.

Use of electronic cigarettes (e-cigarettes) has increased significantly over the past decade due to consumer perception that these products represent a less risky alternative to combustible cigarettes. E-liquids generally contain a simple mix of vegetable glycerin, propylene glycerol, nicotine, organic acids, and flavourings. Regulators require that harmful and potentially harmful constituents (HPHCs) that might cause harm to the consumer must be monitored in the aerosol generated by e-cigarettes and in cigarette smoke (CS). To quantify HPHCs in aerosols from commercial flavoured e-cigarettes in Chinese market, this study has systematically compared levels of HPHCs, including eight carbonyls, five volatile organic compounds, four tobacco-specific nitrosamines, 16 polycyclic aromatic hydrocarbons, and seven heavy metals, in the aerosols of four market-leading flavoured e-cigarettes and mainstream CS, alongside in vitro cytotoxicity and mutagenicity assays. The vast majority of HPHCs were either undetected or significantly lower in the e-cigarette aerosols than in commercial CS or reference CS (3R4F). Where HPHCs were detected, there were small variations among the different flavoured e-cigarettes. In the neutral red uptake and Ames assays, aqueous extracts of the e-cigarette aerosols did not induce obvious cytotoxicity or mutagenicity, whereas CS aqueous extract showed dose-related cytotoxicity and mutagenicity. Collectively, these results indicate that use of e-cigarettes might potentially lead to a significant reduction in exposure to harmful substances, with fewer cytotoxic and mutagenic effects, as compared with conventional smoking. Further studies based on human puffing conditions and longer evaluation periods will be needed to substantiate this potential.

Comparison of Carcinogen Biomarkers in Smokers of Menthol and Nonmenthol Cigarettes: The 2015-2016 National Health and Nutrition Examination Survey Special Sample.

The US FDA announced its commitment to prohibiting menthol as a characterizing flavor in tobacco. The relationship between cigarette menthol and exposure to toxic substances in mainstream tobacco smoke is not well characterized. Data from the National Health and Nutrition Examination Survey (NHANES) 2015 to 2016 special sample were used to study markers of 26 harmful and potentially harmful constituents (HPHC) in tobacco smoke. These include urine metabolites of polycyclic aromatic hydrocarbons (PAH), volatile organic compounds (VOC), and heavy metals in exclusive menthol (n = 162) and nonmenthol (n = 189) cigarette smokers. Urine metabolites of 7 PAHs, 15 VOCs, and 4 heavy metal biomarkers were compared by menthol status. Multivariable analyses were conducted on creatinine-adjusted concentrations. There were no significant differences in cotinine levels or in 22 of 26 HPHCs. Among the urine metabolites of PAHs, the levels of 1-hydroxyphenanthrene were about 16% lower in menthol smokers. Among the urine metabolites of VOCs, menthol cigarette smokers presented significantly lower concentrations of acrylamide, N,N-dimethylformamide, and acrylonitrile. Menthol and nonmenthol smokers presented similar levels of heavy metals. Menthol did not affect the levels of cotinine and the nicotine metabolite ratio in urine. Menthol and nonmenthol cigarettes deliver similar levels of most HPHCs. Findings on toxicity are similar for menthol and nonmenthol cigarettes.