Across the world availability of flavour accessories for tobacco products.

OBJECTIVE: This study aimed to provide an inventory of different types of flavour accessories for combustible tobacco products in eight countries varying in their approaches to flavour legislation and cultural aspects, including tobacco use. METHODS: A standardised search protocol was developed and shared with local informants to acquire information on the availability and marketing of flavour accessories in web shops accessible from Brazil, India, Italy, Singapore, South Africa, Switzerland, the UK and the USA. Characteristics of the products and web shops were reported, and flavours were categorised in a flavour wheel. RESULTS: Flavour accessories were available in all participating countries. Reported types are flavour capsules, cards, filter tips and tubes for make-your-own cigarettes, drops, sprays, rolling paper, aroma markers, a flavour stone and a flavour powder. In total, 118 unique flavours were reported, which were mostly fruity and sweet. Marketing of these products was often associated with (menthol) flavour bans. CONCLUSIONS: The wide availability and variety of flavour accessories raise significant public health concerns, as they have attractive flavours, and thus hinder the regulatory aim of flavour bans. Flavour accessories are not tobacco products and thus not regulated as such. Therefore, it is recommended that policymakers include these products in comprehensive flavour bans, to close this loophole in existing tobacco control measures.

Circumventing cigarette regulation: Product characteristics of cigarette-like cigarillos on the Dutch market.

INTRODUCTION: Cigarillos have been reported to provide an alternative to cigarettes with a characterizing flavor, which are banned in the European Union. Additionally, they are cheaper than cigarettes. To better inform policy making, we wanted to gain better insight into the market situation for cigarillos in the Netherlands. METHODS: We analyzed product data notified by manufacturers via the European Common Entry Gate system (EU-CEG), as extracted on the 1 June 2022. First, we identified parameters that allowed classifying cigarillos into cigar-like, cigarette-like and intermediate-type cigarillos. Next, we compared product characteristics for these groups. RESULTS: We identified five parameters that allowed classifying cigarillos into subtypes: product weight, filter presence, leaf tobacco percentage in the product, flue-cured tobacco percentage in the product, and the number of flavorings. Almost a quarter (71/285) of the cigarillos on the Dutch market were classified as cigarette-like. Compared to other cigarillo types, these have a high number of flavorings (average n=43), including many sweet and fruity flavorings. The package types of cigarette-like cigarillos resemble those of cigarettes. However, 85% of the cigarette-like cigarillos are available in smaller pack sizes than allowed for cigarettes. When comparing data over the period 2019-2022, we found a decrease in the number of cigar-like cigarillos and an increase in the number of cigarette-like cigarillos, which hints at a shift in the market composition. CONCLUSIONS: Cigarette-like cigarillos can provide a way to evade cigarette regulation. Moreover, their characteristics make them attractive for consumers, including young people. Regulators should consider amending regulations to close the regulatory loopholes that allow evading tobacco legislation.

Sensory appeal and puffing intensity of e-cigarette use: Influence of nicotine salts versus free-base nicotine in e-liquids.

BACKGROUND: In the US, nicotine salts (with protonated nicotine instead of free-based nicotine) have been reported to lower the harshness and bitterness of e-cigarette aerosols, making it easier to inhale high levels of nicotine. This study aimed to determine whether nicotine salts also increase sensory appeal at lower concentrations (< 20mg/mL). Moreover, and novel, inhalation intensity of both types of e-liquids was compared. METHODS: In a randomized, double-blinded, within-participants design, healthy adults who use e-cigarettes (n=68) vaped tobacco-flavored e-liquids containing 12mg/mL of free-based nicotine or nicotine salt ad libitum, using their own device, during two online sessions (June-July 2021, Utrecht, The Netherlands). The sensory parameters perceived liking, nicotine intensity, harshness, and pleasantness were rated on a 100-unit visual analog scale. The intensity of use was determined by the recorded puff number, duration and interval. RESULTS: Test scores on appeal, harshness and puffing behavior parameters showed no significant differences between the nicotine salt and the free-base condition. The average inhalation time was 2.5seconds. Additional analyses found no significant effect of liquid order, age, gender, smoking status, vaping frequency and familiarity with nicotine salts. Significant positive correlations were found between the sensory parameters except for harshness. CONCLUSIONS: Contrary to a previous study that used higher nicotine concentrations and standardized puffing conditions in a laboratory setting, we did not observe the effects of nicotine salts on sensory appeal in our real-life study paradigm. Moreover, we did not see effects on study parameters related to puffing intensity.

Variations in cigarette brand characteristics: can consumers tell the difference?

OBJECTIVES: Sensory experience is an important determinant of smoking initiation, brand choice and harm perception, but little is known about how cigarette design shapes sensory experience. This study reports which variations in tobacco blend and design characteristics available on the market are likely to be perceived as different by consumers. METHODS: Truth Tobacco Industry Documents was reviewed for studies showing noticeable sensory differences resulting from variations in tobacco blend and design characteristics. These differences were compared with tobacco product data as available in the Dutch section of the European Common Entry Gate (EU-CEG) system on 30 April 2020. RESULTS: Industry documents identified discrimination thresholds for ventilation, pressure drop, tobacco weight, filter length, and tar and nicotine levels in smoke while evidence for other design characteristics was less conclusive. In the 103 different cigarette varieties in the EU-CEG database, five main types of cigarettes could be identified by principal component analysis, differing in (combinations of) design characteristics. The most significant differences between brand varieties were tar, nicotine and carbon monoxide emissions and associated parameters filter ventilation, filter length, cigarette length and tobacco weight. CONCLUSIONS: While some clusters of brand varieties provided a noticeably different product for consumers, in many cases design differences within these clusters did not exceed the expected discrimination threshold. This indicates that many products on the market are not discernibly different for consumers, and that proliferation of brand varieties has a non-sensory purpose, such as marketing. Policy makers should consider limiting available brand varieties and regulating design characteristics to reduce product appeal.

Comprehensive Dutch market data analysis shows that e-liquids with nicotine salts have both higher nicotine and flavour concentrations than those with free-base nicotine.

OBJECTIVES: Recent years have seen an increase in e-liquids containing nicotine salts. Nicotine salts are less harsh and bitter than free-base nicotine and therefore can facilitate inhalation. Because inhalation-facilitating ingredients are banned in the European Union, we assessed the occurrence and characteristics of nicotine salt-containing e-liquids notified for the Netherlands. METHODS: We analysed data for 39 030 products, submitted by manufacturers in the European Union Common Entry Gate system, as extracted on 30 June 2020. RESULTS: Nicotine salts were present in 13% of e-liquids, especially in pod-related e-liquids (73%) and e-liquids registered from 2018 onwards (over 25%). We found six nicotine salt ingredients (NSIs): nicotine lactate, salicylate, benzoate, levulinate, ditartrate and malate. Nicotine salts also occurred as nicotine-organic acid ingredient combination (NAIC), like nicotine and benzoic acid. Nicotine concentrations were twofold higher in e-liquids with NSI (median 14 mg/mL) and NAIC (11 mg/mL) than for free-base nicotine (6 mg/mL). E-liquids with NSI contained a fourfold higher number (median n=17) and concentration (median 31.0 mg/mL) of flavour ingredients than e-liquids with free-base nicotine (n=4, 7.4 mg/mL). In NAIC-containing e-liquids, these were threefold higher (n=12, 21.5 mg/mL). E-liquids with nicotine salts were less often tobacco flavoured but more often had fruity or sweet flavours. CONCLUSIONS: A substantial and increasing share of e-liquids in the Netherlands contains nicotine salts. Their characteristics can make such e-liquids more addictive and more attractive, especially to young and beginning users. Policymakers are advised to consider regulating products containing nicotine salts.

Review of industry reports on EU priority tobacco additives part A: Main outcomes and conclusions.

The European Union Tobacco Products Directive (EU TPD) mandates enhanced reporting obligations for tobacco manufacturers regarding 15 priority additives. Within the Joint Action on Tobacco Control (JATC), a review panel of independent experts was appointed for the scientific evaluation of the additive reports submitted by a consortium of 12 tobacco manufacturers. As required by the TPD, the reports were evaluated based on their comprehensiveness, methodology and conclusions. In addition, we evaluated the chemical, toxicological, addictive, inhalation facilitating and flavoring properties of the priority additives based on the submitted reports, supplemented by the panel's expert knowledge and some independent literature. The industry concluded that none of the additives is associated with concern. Due to significant methodological limitations, we question the scientific validity of these conclusions and conclude that they are not warranted. Our review demonstrates that many issues regarding toxicity, addictiveness and attractiveness of the additives have not been sufficiently addressed, and therefore concerns remain. For example, menthol facilitates inhalation by activation of the cooling receptor TRPM8. The addition of sorbitol and guar gum leads to a significant increase of aldehydes that may contribute to toxicity and addictiveness. Titanium dioxide particles (aerodynamic diameter <10 µm) are legally classified as carcinogenic when inhaled. For diacetyl no report was provided. Overall, the industry reports were not comprehensive, and the information presented provides an insufficient basis for the regulation of most additives. We, therefore, advise MS to consider alternative approaches such as the precautionary principle.

Review of industry reports on EU priority tobacco additives part B: Methodological limitations.

The Tobacco Products Directive (TPD) defines enhanced reporting obligations applying to 15 priority additives added to cigarettes and roll-your-own tobacco. A consortium of 12 international tobacco companies submitted 14 reports that were reviewed by an independent scientific body within the Joint Action on Tobacco Control (JATC). The reports were evaluated in accordance with the TPD with regard to their comprehensiveness, methodology and conclusions. Here we present their significant identified methodological limitations. The toxicological and chemical evaluation in the industry reports was mainly based on comparative testing, which lacks discriminative power for products with high toxicity and variability, like cigarettes. The literature reviews were biased, the comparative chemical studies did not assess previously identified pyrolysis products, the toxicological evaluation did not include the assessment of inhalation toxicity, and pyrolysis products were not assessed in terms of toxicity, including their genotoxic and carcinogenic potential. For both chemistry and toxicity testing, the statistical approach applied to test the difference between test and additive-free control cigarettes resulted in a high chance of false negatives. The clinical study for inhalation facilitation and nicotine uptake had limitations concerning study design and statistical analysis, while addictiveness was not assessed. Finally, the methodology used to assess characterizing flavors was flawed. In conclusion, there are significant limitations in the methodology applied by the industry. Therefore, the provided reports are of insufficient quality and are clearly not suitable to decide whether a priority additive should be banned in tobacco products according to the TPD.

"It's Like Jogging Next to the Highway": A Qualitative Analysis of the Motivations and Experiences of Single-, Dual-, and Ex-Users of IQOS in The Netherlands.

The popularity of heated tobacco products (HTPs) is of concern, as most users are dual users exposed to emissions of both HTPs and conventional cigarettes. Furthermore, HTPs may appeal to young people and non-smokers. This study aims to build intelligence on user experiences in order to inform policy development. We conducted five semi-structured focus group interviews with single-, dual-, and ex-users of the HTP IQOS. The discussions focused on initiation and use, experiences and perception, and knowledge and information needs. We performed a thematic analysis of the transcripts. All users smoked cigarettes and/or roll your own (RYO) tobacco before using HTP. We found that almost all users started using IQOS after being introduced to it by others. Single users successfully quit smoking cigarettes using the IQOS, liked the taste, and experienced physical benefits. Dual users experienced more satisfaction from smoking cigarettes and used the IQOS for specific occasions, such as social situations or in places with smoking bans. All IQOS users described themselves as smokers and considered using the IQOS as an alternative way of smoking. Regulators may consider providing reliable and easily accessible information and regulating points of sale, promotional activities, and product properties such as flavors and devices in order to reduce product attractiveness and discourage use.

Awareness, use and perceptions of cigarillos, heated tobacco products and nicotine pouches: A survey among Dutch adolescents and adults.

OBJECTIVES: Many tobacco and related products (TRPs) are less strictly regulated and marketed as less harmful than cigarettes. Little is known about their awareness, use, user profile, use behavior, reasons for use and risk perception, especially for the newest products. In an exploratory survey study among Dutch adolescents and adults, we have investigated three examples of non-cigarette TRPs available on the worldwide market. METHODS: In a two-step web-based design, data on cigarillos, heated tobacco products (HTPs) and nicotine pouches were collected. In the first step (N = 5805), a representative sample (≥13 years) was studied to quantify their awareness, ever and current use in the Dutch population. In the second step (N = 526), in-depth data regarding use behavior, reasons for use and risk perception were collected among users and non-users. RESULTS: Awareness (<50%) and use (<15% ever use and <2% current use) is relatively low for all three products, but overall higher among men, (e-)cigarette users and respondents with higher education and social economic status. Most participants became aware of the products through people they knew. Reasons for use were mainly curiosity, pleasant taste, flavour variety, and lower harmfulness. All products were perceived as (slightly) less harmful and addictive than cigarettes. CONCLUSIONS: This study is one of the first to investigate awareness and use of cigarillos, HTPs and nicotine pouches. To prevent increased use, we recommend regulators to extend flavour and smoking bans to these products. In addition, public information may discourage use by increasing awareness of health risks.

Smoking regular and low-nicotine cigarettes results in comparable levels of volatile organic compounds in blood and exhaled breath.

Smokers are exposed to more than 6000 (toxic) smoke components including volatile organic compounds (VOCs). In this study VOCs levels in headspace of blood and exhaled breath, in the mainstream smoke of three types of cigarettes of one brand varying in declared tar, nicotine and carbon monoxide (TNCO) yields are investigated. The objective was to identify whether VOC levels correlate with TNCO yields of cigarettes smoked according to ISO 3308. Our data show that smoking regular and low-TNCO cigarettes result in comparable levels of VOCs in blood and exhaled breath. Hence, declared TNCO-yields as determined with the ISO 3308 machine smoking protocol are irrelevant for predicting VOC exposure upon human smoking. Venous blood and exhaled breath were sampled from 12 male volunteers directly before and 10 min after smoking cigarettes on 3 d (day 1 Marlboro Red (regular), day 2 Marlboro Prime (highly ventilated, low-TNCO), day 3 Marlboro Prime with blocked filter ventilation (taped)). Upon smoking, the levels of toluene, ethylbenzene, m/p-xylene, o-xylene, and 2,5-dimethylfuran in both headspace of venous blood and exhaled breath increase within the same range for all three cigarette types smoked. However, no strong correlation was found between VOC levels in exhaled breath and VOC levels in headspace of blood because of variations between the individual smoking volunteers. More research is required in order to use exhaled breath sampling as a non-invasive quantitative marker for volatile toxicants from cigarette smoke exposure of different brands.

Characteristic Human Individual Puffing Profiles Can Generate More TNCO than ISO and Health Canada Regimes on Smoking Machine When the Same Brand Is Smoked.

Human smoking behavior influences exposure to smoke toxicants and is important for risk assessment. In a prospective observational study, the smoking behavior of Marlboro smokers was measured for 36 h. Puff volume, duration, frequency, flow and inter-puff interval were recorded with the portable CReSSmicro™ device, as has often been done by other scientists. However, the use of the CReSSmicro™ device may lead to some registration pitfalls since the method of insertion of the cigarette may influence the data collection. Participants demonstrated consistent individual characteristic puffing behavior over the course of the day, enabling the creation of a personalized puffing profile. These puffing profiles were subsequently used as settings for smoking machine experiments and tar, nicotine and carbon monoxide (TNCO) emissions were generated. The application of human puffing profiles led to TNCO exposures more in the range of Health Canada Intense (HCI)-TNCO emissions than for those of the International Standardization Organization (ISO). Compared to the ISO regime, which applies a low puff volume relative to human smokers, the generation of TNCO may be at least two times higher than when human puffing profiles were applied on the smoking machine. Human smokers showed a higher puffing intensity than HCI and ISO because of higher puffing frequency, which resulted in more puffs per cigarette, than both HCI and ISO.

Tar, nicotine and carbon monoxide yield of UK cigarettes and the risk of non-muscle-invasive and muscle-invasive bladder cancer.

Cigarette smoking is a major risk factor for bladder cancer (BC); however, the impact of cigarette content remains unclear. This study aims to investigate tar, nicotine and carbon monoxide (TNCO) yields of different filtered cigarettes in relation to BC risk. From the Bladder Cancer Prognosis Programme 575 non-muscle-invasive bladder cancer (NMIBC) cases, 139 muscle-invasive bladder cancer (MIBC) cases and 130 BC-free controls with retrospective data on smoking behaviour and cigarette brand were identified. Independently measured TNCO yields of cigarettes sold in the UK were obtained through the UK Department of Health and merged with the Bladder Cancer Prognosis Programme dataset to estimate the daily intake of TNCO. BC risk increased by TNCO intake category for NMIBC cases (P <0.050 in all multivariate models), but only for the daily intake of tar for MIBC cases (P=0.046) in multivariate models. No difference in risk was observed between smokers of low-tar/low-nicotine and high-tar/high-nicotine cigarettes compared with never smokers, either for NMIBC (P=0.544) or MIBC (P=0.449). High daily intake of TNCO additionally increases the risk of both NMIBC and MIBC compared with low daily intake. However, as there is no difference in BC risk between low-tar/low-nicotine and high-tar/high-nicotine cigarette smokers, it remains unclear whether smoking behaviour or TNCO yield of cigarettes explains this association.

Cigarette Filter Ventilation and Smoking Protocol Influence Aldehyde Smoke Yields.

The WHO study group on tobacco product regulation (TobReg) advised regulating and lowering toxicant levels in cigarette smoke. Aldehydes are one of the chemical classes on the TobReg smoke toxicants priority list. To provide insight in factors determining aldehyde yields, the levels of 12 aldehydes in mainstream cigarette smoke of 11 Dutch brands were quantified. Variations in smoking behavior and cigarette design affecting human exposure to aldehydes were studied by using four different machine testing protocols. Machine smoking was based on the International Standardization Organization (ISO) and Health Canada Intense (HCI) regime, both with and without taping the filter vents. The 11 cigarette brands differed in (i) design and blend characteristics; (ii) tar, nicotine, and carbon monoxide (TNCO) levels; (iii) popularity; and (iv) manufacturer. Cigarette smoke was trapped on a Cambridge filter pad and carboxen cartridge. After being dissolved in methanol/CS2 and derivatization with DNPH, the aldehyde yields were determined using HPLC-DAD. Using an intense smoking regime (increased puff volume, shorter puff interval) significantly increased aldehyde yields, following the pattern: ISO < ISO-taped < HCI-untaped < HCI. For all of the regimes, acetaldehyde and acrolein yields were strongly correlated ( r = 0.804). The difference in TNCO and aldehyde levels between regular and highly ventilated low-TNCO cigarettes (as measured using ISO) diminished when smoking intensely; this effect is stronger when combined with taping filter vents. The highly ventilated low-TNCO brands showed six times more aldehyde production per mg nicotine for the intense smoking regimes. In conclusion, acetaldehyde and acrolein can be used as representatives for the class of volatile aldehydes for the different brands and smoking regimes. The aldehyde-to-nicotine ratio increased when highly ventilated cigarettes were smoked intensely, similar to real smokers. Thus, a smoker of highly ventilated low-TNCO cigarettes has an increased potential for higher aldehyde exposures compared to a smoker of regular cigarettes.

Home-based cycling program tailored to older people with lumbar spinal stenosis: Barriers and facilitators.

BACKGROUND: Lumbar-flexion-based endurance training, namely cycling, could be effective in reducing pain and improving function and health-related quality of life in older people with chronic low back pain. OBJECTIVES: To assess barriers and facilitators to home-based cycling in older patients with lumbar spinal stenosis (LSS). METHODS: We conducted a retrospective mixed-method study. Patients≥50 years old followed up for LSS from November 2015 to June 2016 in a French tertiary care center were screened. The intervention consisted of a single supervised session followed by home-based sessions of cycling, with dose (number of sessions and duration, distance and power per session) self-determined by patient preference. The primary outcome was assessed by a qualitative approach using semi-structured interviews at baseline and 3 months and was the identification of barriers and facilitators to the intervention. Secondary outcomes were assessed by a quantitative approach and were adherence monitored by a USB stick connected to the bicycle, burden of treatment assessed by the Exercise Therapy Burden Questionnaire (ETBQ) and clinical efficacy assessed by change in lumbar pain, radicular pain, disability, spine-specific activity limitation and maximum walking distance at 3 months. RESULTS: Overall, 15 patients were included and data for 12 were analyzed at 3 months. At baseline, the mean age was 70.9 years (95% CI: 64.9-76.8) and 9/15 patients (60.0%) were women. Barriers to cycling were fear of pain and fatigue, a too large bicycle, burden of hospital follow-up and lack of time and motivation. Facilitators were clinical improvement, surveillance and ease-of-use of the bicycle. Adherence remained stable overtime. The burden of treatment was low [mean ETBQ score: 21.0 (95% confidence interval: 11.5-30.5)]. At 3 months, 7/12 patients (58.3%) self-reported clinical improvement, with reduced radicular pain and disability [mean absolute differences: -27.5 (-43.3 to -11.7), P<0.01 and -17.5 (-32.1 to -2.9), P=0.01, respectively]. CONCLUSIONS: For people with LSS, home-based cycling is a feasible intervention.

A Human Proximal Tubular Epithelial Cell Model to Explore a Knowledge Gap on Neonatal Drug Disposition.

BACKGROUND: Finding the right drug-dosage for neonates is still a challenge. Until now, neonatal doses are extrapolated from adults and children doses. However, there are differences between neonatal and adult kidney physiology that should be considered, especially when it comes to drug metabolism and/or transport. Studying renal drug disposition in neonates is limited by the lack of reliable human cell models. OBJECTIVE: To illustrate the feasibility of developing an in vitro model for neonatal proximal tubule epithelial cells (nPTECs) to study renal drug disposition at this age. METHOD: nPTECs were isolated from urine samples of neonates of different gestational ages and were conditionally immortalized using a temperature sensitive SV40T antigen and human telomerase hTERT. Cell clones were characterized on gene expression level for PTEC markers such as P-glycoprotein (ABCB1), aquaporin1 (AQP1), and organic cation transport protein 2 (SLC22A2), and for kidney progenitor cell and podocyte markers. In addition, protein expression and functional assessment were performed for P-gp and OCT2. RESULTS: We established 101 clonal cell lines of conditionally immortalized nPTECs derived from neonatal urines. Characterization of primary cells lines showed expression of genes from different cell types such as progenitors, PTECs and podocytes, however the developed conditionally immortalized nPTECs only expressed proximal tubule markers. Quantitative PCR analysis confirmed the expression of proximal tubule markers in nPTECs similar to the adult control PTECs. P-gp was expressed in nPTECs derived from the different gestational ages with a similar functionality compared with adult derived PTECs. In contrast, OCT2 functionality was significantly lower in nPTEC cell lines compared with adult PTECs. CONCLUSION: We demonstrate the feasibility of culturing proximal tubule epithelial cells with high efficiency from urine of neonates. These cells expressed PTEC-specific genes and functional drug transporters. The cell model presented is a valuable tool to study proximal tubule physiology and pharmacology in newborns. In addition, we demonstrate the physiological differences between the neonatal and adult kidney, which emphasizes the importance of studying drug disposition in neonatal models instead of extrapolating from adult data.

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation.

Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/- heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/- knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/- and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/- mice in the Visual Discrimination &Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/- mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/- mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability.