Reduced-risk Tobacco Products Research Articles

Associations of individual characteristics and socioeconomic status with heated tobacco product harmfulness perceptions in Japan: A nationwide cross-sectional study (INFORM Study 2020).

IntroductionIn Japan, heated tobacco products (HTPs) are promoted by the tobacco industry as reduced-risk tobacco products despite the lack of evidence for this claim. This study determined the distribution of HTP-harmfulness perception and identify the explanatory factors associated with the perception of HTP as less harmful than conventional cigarettes.MethodsA nationwide cross-sectional survey was conducted with Japanese people aged 20 years or older (INFORM Study 2020) using a self-administered questionnaire. We performed descriptive analysis and weighted logistic regression analysis to examine the relationship between explanatory factors (e.g., individual characteristics, socioeconomic status, and trusted sources of cancer information) and the perception of HTPs as less harmful.ResultsAmong 3,420 participants (response rate: 35.2%), the proportions of those who perceived HTPs as less harmful were 40.3% and 18.3% for users and non-users of tobacco, respectively. For participants aged 20-39 years, the proportion were 49.9% and 30.4%, respectively. Among 1,160 non-tobacco users who were familiar with HTPs, male, aged under 39 years, and had lower education were associated with the perception of HTPs as less harmful. Trusted sources of cancer information were not associated with the perception of HTPs as less harmful.ConclusionsThis study showed that, among non-tobacco users, being male, aged under 39 years, and lower education were associated with a perception of HTPs as less harmful. Public health stakeholders should provide the latest evidence about HTP harmfulness in their daily practice, and strengthen the regulations on HTP marketing directed at both tobacco- and non-tobacco users.

Optimal Taxation of Cigarettes and E-Cigarettes: Principles for Taxing Reduced-Harm Tobacco Products.

As the tax base for traditional tobacco excise taxes continues to erode, policymakers have growing interest to expand taxation to novel and reduced-risk tobacco products. Chief among the latter are electronic nicotine delivery systems (ENDS; commonly known as e-cigarettes), although other reduced-risk tobacco products such as heated tobacco and smokeless tobacco products are also being considered for taxation. There are many possible rationales for taxing such products: to raise revenue, to correct for health externalities, to improve public health, to correct for internalities caused by irrationality or misinformation, and to redistribute income. Although each rationale leads to a different objective function, the conclusions regarding relative tax rates are largely the same. The relatively higher price elasticity of demand for e-cigarettes (compared to cigarettes) and the lower marginal harms from use imply in each case that taxes on e-cigarettes and other harm-reduced products should be relatively lower, and likely much lower, than those on cigarettes. Additional considerations concerning the policy goal of discouraging use of any tobacco product by youth are discussed as well.

Trends in Over-the-Counter Nicotine Replacement Therapy Sales, U.S., 2017‒2020

Few studies have examined trends in over-the-counter U.S. Food and Drug Administration‒approved nicotine replacement therapy sales data and consumer preferences for nicotine replacement therapy attributes (e.g., flavor). Examination of consumer preferences may inform both public health smoking cessation programs as well as subsequent research on consumer preferences for potentially reduced-risk tobacco products U.S. Food and Drug Administration may authorize. NielsenIQ Retail Measurement Service data were used to examine national trends in over-the-counter nicotine replacement therapy dollar sales from 2017 to 2020 and dollar sales by retail channel and product attributes for the most recent year available at the time of analysis (2020). Over-the-counter nicotine replacement therapy sales totaled about $1 billion annually between 2017 and 2020. Across the 4-year period, sales of gum and patches decreased, whereas lozenge sales increased (p<0.05 for all). In 2020, gum accounted for 52.7% ($511 million), lozenges accounted for 33.3% ($322 million), and patches accounted for 14.1% ($137 million) of over-the-counter nicotine replacement therapy sales. Drug stores were the retail channel accounting for the largest percentage of total over-the-counter nicotine replacement therapy sales (42.9%). Three leading brands-private label or store brands (62.8%), Nicorette (30.7%,), and NicoDerm CQ (5.7%)-accounted for 99.2% of the total over-the-counter nicotine replacement therapy market. Mint was the most common flavor, representing 41.2% of total gum and 73.6% of total lozenge sales. This analysis of over-the-counter nicotine replacement therapy sales sheds light on consumer preferences for attributes that can inform efforts to facilitate smoking cessation and research on preferences related to potentially reduced-risk tobacco products.

Exposure to e-cigarette health claims and association with e-cigarette use and risk perceptions: A cohort study of young adults

IntroductionE-cigarettes have been marketed illicitly as smoking cessation aids and reduced risk tobacco products in the United States. Our study assessed consumers’ exposure to such claims and evaluated their impact on relative risk perceptions and e-cigarette use. MethodsData are from the Assessment of the post-College Experience study, which followed a cohort of young adults since 2010 when they were college freshmen. We used data from survey waves 10 (fall 2017) through 14 (fall 2019) to assess past 6 month exposure to e-cigarette marketing that made smoking cessation or modified risk tobacco product (MRTP) claims. Logistic regression models examined if exposure to claims at waves 11 through 14 were predictors of e-cigarette use and relative risk perceptions at wave 14. ResultsExposure to MRTP (28.4% to 40.1%) and cessation claims (29.1% to 46.6%) increased, with participants reporting more exposure to cessation than MRTP claims at each wave. Multiple exposures were associated with perceptions that e-cigarettes are less harmful compared to cigarettes (Cessation: AOR = 1.12, CI: 1.01–1.23; p = 0.025; MRTP: AOR = 1.16; CI: 1.05–1.29; p = 0.003). Neither claim type was associated with past 30-day e-cigarette use. Claim exposure did not increase e-cigarette initiation among never e-cigarette users. However, current cigarette smokers who had never used e-cigarettes at wave 10 had 2.5 higher odds of initiating e-cigarette use by wave 14 for each exposure to a cessation claim (AOR = 2.53; CI: 1.43–4.45; p = 0.001). ConclusionsYoung adults reported increasing exposure to unauthorized e-cigarette health claims. Exposure was associated with reduced relative risk perceptions, but was not associated with past 30-day e-cigarette use. Cessation claims may motivate current cigarette smokers to try e-cigarettes.

Toxicological Assessment of Flavor Ingredients in E-Vapor Products.

Many flavor ingredients are often used in potentially reduced-risk tobacco products (such as e-vapor products). Although most are “generally recognized as safe (GRAS)” when used in food, there is limited information available on their long-term health effects when delivered by inhalation. While obtaining route-of-exposure-specific toxicological data on flavor ingredients is critical to product evaluation, the large number of individual flavor ingredients available and their potential combinations render classical toxicological assessment approaches impractical, as they may require years of preclinical investigations and thousands of laboratory animals. Therefore, we propose a pragmatic approach in which flavor ingredients are initially assigned to groups of structurally related compounds (Flavor Groups), from which flavor group representatives (FGR) are then selected and tested individually and as a mixture in vitro and in vivo. The premise is that structurally related compounds would have comparable metabolic and biological activity and that the data generated using FGRs could support the toxicological assessment of other structurally related flavor ingredients of their respective Flavor Groups. This approach is explained in a step-wise manner and exemplified by a case study, along with its strengths, limitations as well as recommendations for further confirmatory testing. Once completed, this FGR approach could significantly reduce the time and resources required for filling the data gap in understanding the health risks of many flavor ingredients while also minimizing the need for laboratory animals.

Toxicological assessment of highly mentholated reduced-risk tobacco products in Sprague Dawley rats following sub-chronic inhalation exposure

Toxicological assessment of highly mentholated reduced-risk tobacco products in Sprague Dawley rats following sub-chronic inhalation exposure

Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to the glo Tobacco Heating Product: A Randomized, Controlled Ambulatory Study.

IntroductionTobacco heating products (THPs) generate lower machine yields of toxicants compared to those found in conventional cigarette smoke. During use, these products are likely to expose users to lower levels of particulate matter and harmful and potentially harmful compounds compared with smoking cigarettes.Aims and MethodsThis randomized, controlled study is investigating whether biomarkers of exposure (BoE) to smoke toxicants are reduced when smokers switch from smoking cigarettes to using the glo THP in a naturalistic, ambulatory setting. Control groups include smokers who are abstaining from cigarette smoking and never-smokers. At a baseline study visit, 24-hour urine samples and spot blood samples were taken for BoE analysis, and exhaled carbon monoxide was also measured. N-(2-cyanoethyl) valine (CEVal) was used as a marker of compliance in subjects asked to refrain from combustible cigarette smoking. Subjects are being followed up at periodic intervals for 360 days; this article presents data following a planned interim analysis at day 90.ResultsIn continuing smokers, BoE remained stable between baseline (day 1) and day 90. In both per-protocol and CEVal-compliant analysis populations, reductions in BoE were observed in subjects switching to using glo or undergoing smoking cessation. These reductions were statistically significant for a number of BoE when switching to glo was compared with continued smoking. Furthermore, in both populations, reductions observed in subjects switching to using glo were comparable to those seen with smoking cessation and were also to levels similar to those seen in never-smokers.Conclusionglo is a reduced-exposure tobacco product.ImplicationsThis clinical study builds on a previous 5-day confinement study and demonstrates that when smokers switched from smoking combustible cigarettes to using the glo THP in a naturalistic, ambulatory setting, their exposure to tobacco smoke toxicants was significantly decreased. For most BoE examined, this was to the same extent as that seen when a control group of smokers ceased cigarette smoking, or even to levels seen in never-smoker controls. This indicates that glo is a reduced-exposure product with the potential to be a reduced-risk tobacco product, when used by smokers whose cigarette consumption is displaced completely.Clinical trial registrationISRCTN81075760.

Perceptions of Harmfulness of Heated Tobacco Products Compared to Combustible Cigarettes among Adult Smokers in Japan: Findings from the 2018 ITC Japan Survey.

In Japan, the tobacco industry promotes heated tobacco products (HTPs) as a reduced-risk tobacco product. This study examines: (1) smokers’ harm perceptions of HTPs relative to combustible cigarettes; (2) differences in relative harm perceptions between exclusive smokers and smokers who use HTPs (concurrent users) and between concurrent users based on frequency of product use; and (3) if smokers who were exposed to HTP advertising hold beliefs that are consistent with marketing messages of lower harmfulness. This cross-sectional study included 2614 adult exclusive cigarette smokers and 986 concurrent users who reported their perceptions of harmfulness of HTPs compared to cigarettes, as well as their exposure to HTP advertising in the last six months. Among all smokers, 47.5% perceive that HTPs are less harmful than cigarettes, 24.6% perceive HTPs to be equally as harmful, 1.8% perceive HTPs as more harmful, and 26.1% did not know. Concurrent users are more likely than exclusive smokers to believe that HTPs are less harmful (62.1% versus 43.8%, p < 0.0001) and less likely to report that they did not know (14.3% versus 29.4%, p < 0.0001). Frequent HTP users are more likely than infrequent users to believe that HTPs are less harmful (71.7% versus 57.1%, p ≤ 0.001). Believing that HTPs are less harmful than cigarettes was associated with noticing HTP advertising on TV (p = 0.0005), in newspapers/magazines (p = 0.0001), on posters/billboards (p < 0.0001), in stores where tobacco (p < 0.0001) or where HTPs (p < 0.0001) are sold, on social media (p < 0.0001), or in bars/pubs (p = 0.04). HTP users were significantly more likely than non-HTP users to believe that HTPs are less harmful than cigarettes, with this belief being more prominent among frequent users. Smokers who have been exposed to HTP advertising were more likely to perceive HTPs as less harmful than cigarettes.

Increased Leaf Nicotine Content by Targeting Transcription Factor Gene Expression in Commercial Flue-Cured Tobacco (Nicotiana tabacum L.).

Nicotine, the most abundant pyridine alkaloid in cultivated tobacco (Nicotiana tabacum L.), is a potent inhibitor of insect and animal herbivory and a neurostimulator of human brain function. Nicotine biosynthesis is controlled developmentally and can be induced by abiotic and biotic stressors via a jasmonic acid (JA)-mediated signal transduction mechanism involving members of the APETALA 2/ethylene-responsive factor (AP2/ERF) and basic helix-loop-helix (bHLH) transcription factor (TF) families. AP2/ERF and bHLH TFs work combinatorically to control nicotine biosynthesis and its subsequent accumulation in tobacco leaves. Here, we demonstrate that overexpression of the tobacco NtERF32, NtERF221/ORC1, and NtMYC2a TFs leads to significant increases in nicotine accumulation in T2 transgenic K326 tobacco plants before topping. Up to 9-fold higher nicotine production was achieved in transgenics overexpressing NtERF221/ORC1 under the control of a constitutive GmUBI3 gene promoter compared to wild-type plants. The constitutive 2XCaMV35S promoter and a novel JA-inducible 4XGAG promoter were less effective in driving high-level nicotine formation. Methyljasmonic acid (MeJA) treatment further elevated nicotine production in all transgenic lines. Our results show that targeted manipulation of NtERF221/ORC1 is an effective strategy for elevating leaf nicotine levels in commercial tobacco for use in the preparation of reduced risk tobacco products for smoking replacement therapeutics.

Modeling the impact of changes in tobacco use on individual disease risks

Abstract Philip Morris International has developed a Population Health Impact Model (PHIM) to estimate the effects of marketing Reduced-Risk Products on population health. The PHIM creates a disease-specific risk profile for each individual based on their age and smoking history. To create a risk profile, the PHIM calculates, at each year of age, the excess relative risk (ERR=relative risk [RR]-1) by multiplying an individual’s equivalent dose (ED) by the ERR for smoking vs. never smoking. ED is defined as 0 at birth and stays at 0 while the individual is a non-smoker. Once tobacco use starts, the individual’s ED rises toward the relative exposure (RE) corresponding to the product used. Following quitting or change of product, ED moves toward the new value of RE. The model uses estimates of age- and disease-specific current smoking RRs and ERR half-lives following cessation, derived from meta-analyses of published data. Estimates of the half-life of excess risk are also used when estimating rise in ERR following initiation or change in ERR following a change in product use. We apply the method to data for the four main smoking-related diseases; lung cancer, ischemic heart disease, stroke, and chronic obstructive pulmonary disease. For a given disease and age group, the PHIM can derive estimates of the average ERR for each individual in the population studied. Given an overall estimate of absolute population risk, the PHIM can then also be used to derive estimates of absolute risk for each individual. Key messages Health impact modeling can be used to understand the individual and population impacts of introducing reduced risk tobacco products. Footnote: *Reduced-Risk Products are products that present, are likely to present, or have the potential to present less risk of harm to smokers who switch to these products vs continued smoking.

Estimating the population health impact of introducing a reduced-risk tobacco product into Japan. The effect of differing assumptions, and some comparisons with the U.S.

We estimated, using previously described methodology, the population health impact of introducing a reduced-risk tobacco product (RRP) into Japan. Various simulations were carried out to understand the impact on the population in different situations over a 20-year period from 1990. The overall reduction in tobacco-attributable deaths from lung cancer (LC), ischemic heart disease (IHD), stroke, and chronic obstructive pulmonary disease (COPD) for men and women combined was estimated to be 269,916 over the period if tobacco use disappeared completely at baseline. In contrast, reductions ranging from 167,041 to 232,519 deaths were estimated if the RRP totally replaced smoking at baseline (assuming that switching to it had an effect equivalent to 70%–90% of the effect of quitting). If, more plausibly, the RRP were introduced at baseline, with uptake rates consistent with the known uptake of the RRP IQOS®, the reductions would still be substantial (from 65,126 to 86,885 deaths). Expressed as a percentage of attributable deaths, these proportions are larger than those for the U.S., based on likely uptake rates. We discuss various limitations of the approach, though none should affect the conclusion that the introduction of an RRP into Japan will substantially reduce tobacco-related deaths.

Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to Tobacco Heating Products: A Randomized, Controlled Study in Healthy Japanese Subjects.

BackgroundSmoking is a leading cause of numerous human disorders including pulmonary disease, cardiovascular disease, and cancer. Disease development is primarily caused by exposure to cigarette smoke constituents, many of which are known toxicants. Switching smokers to modified risk tobacco products (MRTPs) has been suggested as a potential means to reduce the risks of tobacco use, by reducing such exposure.MethodsThis randomized, controlled study investigated whether biomarkers of toxicant exposure (BoE) were reduced when smokers switched from smoking combustible cigarettes to using a novel (glo™/THP1.0) or in-market comparator (iQOS/THS) tobacco heating product (THP). One hundred eighty Japanese smokers smoked combustible cigarettes during a 2-day baseline period, followed by randomization to either continue smoking cigarettes, switch to using mentholated or non-mentholated variants of glo™, switch to using a non-mentholated variant of iQOS, or quit nicotine and tobacco product use completely for 5 days. Baseline and post-randomization 24-h urine samples were collected for BoE analysis. Carbon monoxide was measured daily in exhaled breath (eCO).ResultsOn day 5 after switching, urinary BoE (excluding for nicotine) and eCO levels were significantly (p < .05) reduced by medians between 20.9% and 92.1% compared with baseline in all groups either using glo™ or iQOS or quitting tobacco use. Between-group comparisons revealed that the reductions in the glo™ groups were similar (p > .05) to quitting in many cases.Conclusionsglo™ or iQOS use for 5 days reduced exposure to smoke toxicants in a manner comparable to quitting tobacco use. THPs are reduced exposure tobacco products with the potential to be MRTPs.ImplicationsThis clinical study demonstrates that when smokers switched from smoking combustible cigarettes to using tobacco heating products their exposure to smoke toxicants was significantly decreased. In many cases, this was to the same extent as that seen when they quit smoking completely. This may indicate that these products have the potential to be reduced exposure and/or reduced risk tobacco products when used by smokers whose cigarette consumption is displaced completely.Clinical Trial RegistrationsISRCTN14301360 and UMIN000024988.

Estimating the effect of differing assumptions on the population health impact of introducing a Reduced Risk Tobacco Product in the USA

We use Population Health Impact Modelling to assess effects on tobacco prevalence and mortality of introducing a Reduced Risk Tobacco Product (RRP). Simulated samples start in 1990 with a US-representative smoking prevalence. Individual tobacco histories are updated annually until 2010 using estimated probabilities of switching between never/current/former smoking where the RRP is not introduced, with current users subdivided into cigarette/RRP/dual users where it is. RRP-related mortality reductions from lung cancer, IHD, stroke and COPD are derived from the histories and the assumed relative risks of the RRP.A basic analysis assumes a hypothetical RRP reduces effective dose 80% in users and 40% in dual users, with an uptake rate generating ∼10% RRP and ∼6% dual users among current users after 10 years. Sensitivity study changes in tobacco prevalence and mortality from varying effective doses, current smoking risks, quitting half-lives and rates of initiation, switching, re-initiation and cessation. They also study extreme situations (e.g. everyone using RRP), and investigate assumptions which might eliminate the RRP-related mortality reduction. The mortality reduction is proportional to the dose reduction, increasing rapidly with time of follow-up. Plausible increases in re-initiation or dual users’ consumption, or decreased quitting by smokers would not eliminate the drop.

Murine lung tumor response after exposure to cigarette mainstream smoke or its particulate and gas/vapor phase fractions

Knowledge on mechanisms of smoking-induced tumorigenesis and on active smoke constituents may improve the development and evaluation of chemopreventive and therapeutic interventions, early diagnostic markers, and new and potentially reduced-risk tobacco products. A suitable laboratory animal disease model of mainstream cigarette smoke inhalation is needed for this purpose. In order to develop such a model, A/J and Swiss SWR/J mouse strains, with a genetic susceptibility to developing lung adenocarcinoma, were whole-body exposed to diluted cigarette mainstream smoke at 0, 120, and 240 mg total particulate matter per m 3 for 6 h per day, 5 days per week. Mainstream smoke is the smoke actively inhaled by the smoker. For etiological reasons, parallel exposures to whole smoke fractions (enriched for particulate or gas/vapor phase) were performed at the higher concentration level. After 5 months of smoke inhalation and an additional 4-month post-inhalation period, both mouse strains responded similarly: no increase in lung tumor multiplicity was seen at the end of the inhalation period; however, there was a concentration-dependent tumorigenic response at the end of the post-inhalation period (up to 2-fold beyond control) in mice exposed to the whole smoke or the particulate phase. Tumors were characterized mainly as pulmonary adenomas. At the end of the inhalation period, epithelial hyperplasia, atrophy, and metaplasia were found in the nasal passages and larynx, and cellular and molecular markers of inflammation were found in the bronchoalveolar lavage fluid. These inflammatory effects were mostly resolved by the end of the post-inhalation period. In summary, these mouse strains responded to mainstream smoke inhalation with enhanced pulmonary adenoma formation. The major tumorigenic potency resided in the particulate phase, which is contrary to the findings published for environmental tobacco smoke surrogate inhalation in these mouse models.

Hypotheses and fundamental study design characteristics for evaluating potential reduced-risk tobacco products. Part I: Heuristic

The risk-reducing effect of a potential reduced-risk tobacco product (PRRP) can be investigated conceptually in a long-term, prospective study of disease risks among cigarette smokers who switch to a PRRP and in appropriate comparison groups. Our objective was to provide guidance for establishing the fundamental design characteristics of a study intended to (1) determine if switching to a PRRP reduces the risk of lung cancer (LC) compared with continued cigarette smoking, and (2) compare, using a non-inferiority approach, the reduction in LC risk among smokers who switched to a PRRP to the reduction in risk among smokers who quit smoking entirely. Using standard statistical methods applied to published data on LC incidence after smoking cessation, we show that the sample size and duration required for a study designed to evaluate the potential for LC risk reduction for an already marketed PRRP, compared with continued smoking, varies depending on the LC risk-reducing effectiveness of the PRRP, from a 5-year study with 8000–30,000 subjects to a 15-year study with <5000 to 10,000 subjects. To assess non-inferiority to quitting, the required sample size tends to be about 10 times greater, again depending on the effectiveness of the PRRP.

Further considerations on the evaluation of potential reduced-risk tobacco products. Part II: Re-assessment of a heuristic using the CPS-II database

In a previous analysis (see Part I) we proposed a heuristic for assessing the efficacy of potential reduced-risk tobacco products (PRRPs) on lung cancer (LC) rates, using smoking cessation data published in a report from the Iowa Women’s Health Study (IWHS) as a basis for sample size estimates. In this study, an additional analysis was performed using cessation data from the much larger Cancer Prevention Study II (CPS-II), which also provides data on different durations of cessation. Statistical methods were used to assess whether smokers switching to a PRRP would reduce their risk of LC. Furthermore, non-inferiority tests compared the LC risk in switchers to that in smokers who had quit smoking. The present work shows that similar sample size estimates were obtained whether the analysis was based on the IWHS or the CPS-II data sets, suggesting that the heuristic may be generally applicable to prospective real-life studies to evaluate PRRPs. Non-inferiority testing of switchers compared with quitters required approximately 10-fold more subjects than did superiority testing of switchers compared with smokers. Altogether, these estimates indicate that it is feasible, in terms of study duration and sample size, to clinically assess the LC risk-reducing potential of a PRRP.

Are smokers adequately informed about the health risks of smoking and medicinal nicotine?

The present study assessed smokers' beliefs about the health risks of smoking and the benefits of smoking filtered and low-tar cigarettes, and their awareness of and interest in trying so-called reduced-risk tobacco products. Results were based on a nationally representative random-digit-dialed telephone survey of 1,046 adult (aged 18 years or older) current cigarette smokers. Data were gathered on demographic characteristics, tobacco use behaviors, awareness and use of nicotine medications, beliefs about the health risks of smoking, content of smoke and design features of cigarettes, and the safety and efficacy of nicotine medications. In addition, respondents were asked about their interest in and perceived ability to stop smoking and about their desire for more information about the health risks of smoking. Smokers were least knowledgeable about low-tar and filter cigarettes (65% of responses were incorrect or "don't know") and most knowledgeable about the health risks of smoking (39% of responses were incorrect or "don't know"). The smokers' characteristics most commonly associated with misinformation when all six indices were combined into a summary index were as follows: those aged 45 years or older, smokers of ultralight cigarettes, smokers who believe they will stop smoking before they experience a serious health problem caused by smoking, smokers who have never used a stop-smoking medication, and smokers with a lower education level. Those who believed they would stop smoking in the next year were more knowledgeable about smoking. Some 77% of respondents reported a desire for additional information from tobacco companies on the health dangers of smoking. The present findings demonstrate that smokers are misinformed about many aspects of the cigarettes they smoke and stop-smoking medications and that they want more information about ways to reduce their health risks.

Smoker and ex-smoker reactions to cigarettes claiming reduced risk

Context: The tobacco industry is introducing modified tobacco products claiming to reduce the risk of smoking (potential reduced exposure products, PREPs). If PREPs are perceived as safe, they may deter...