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This paper explores the degree to which heterodox economics can contribute to the development and use of climate-economy integrated assessment models. To do so, it introduces the field of integrated assessment modeling, with a focus on the core economic methodology used by various types of models. It then summarizes some of the literature critiquing these models and how they inform policy. The paper then provides an extended classification of ways in which heterodox economics could be applied to climate-economy models and presents a number of storylines, or pathways, which could be created using insights and methods from heterodox schools. The paper concludes with an assessment of the scope for heterodox economics to answer the criticisms of climate-economy models, finding that despite not resolving all issues, the heterodoxy has a substantial role to play.

The aim of this study was to investigate whether biomarkers of exposure (BoE) and potential harm (BoPH) are modified when smokers switch from smoking cigarettes to exclusive use of a tobacco heating product (THP) in an ambulatory setting. Participants in this randomised, controlled study were healthy volunteer smokers assigned either to continue smoking or switch to a THP, and a control group of smokers who abstained from cigarette smoking. Various BoE and BoPH related to oxidative stress, cardiovascular and respiratory diseases, and cancer were assessed at baseline and up to 180 days. In continuing smokers, BoE and BoPH remained stable between baseline and day 180, while THP users’ levels of most BoE reduced significantly, becoming similar to those in controls abstaining from cigarette smoking. Also at 180 days, significant changes in numerous BoPH, including total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, 8-epi-prostaglandin F2α type III, fractional concentration of exhaled nitric oxide and white blood cell count, were directionally consistent with lessened health impact. Our findings support the notion that the deleterious health impacts of cigarette smoking may be reduced in smokers who completely switch to using THPs. Supplementary Information The online version contains supplementary material available at 10.1007/s11739-021-02798-6.

Objective: We evaluated the potential population health impact of launching heated tobacco products (HTP) in Japan. Method: We use a modeling approach to project the effects of HTP use in overall mortality up to 2100 and compare those projections against a baseline scenario based on smoking rates pre-HTP launch, ie, smoking only. The model was informed using data from publicly available sources and the literature, including population size, yearly deaths, and smoking prevalence with the initial year of 2004, and births and migration from 2004 to 2065. Transitions between products were estimated from cross-sectional population surveys in Japan. Result: In a worst-case scenario, population health gains would be seen with HTPs risk about 50% lower risk than smoking. Assuming equal risk for dual use and smoking, HTP risk would need to be at least 10% lower than smoking to achieve a population health benefit by 2100. Potential reduction in life-years lost with the introduction of HTPs was 13 million by 2100 compared with smoking only. Conclusions: In credible scenarios, substantial population harm reduction will follow the introduction of HTPs in Japan.

Graphical abstract, Highlights • Cigarettes compared to tobacco heating product and e-cigarette in a clinical study. • Biomarkers of Exposure were analysed over five days of switching. • Electronic cigarettes and tobacco heating products substantially reduce exposure. • The evidence enables placement of these products on an exposure continuum., Background Cigarette smoking is associated with a number of diseases, such as cancer and cardiovascular diseases. Recently, there has been an increase in the use of electronic cigarettes (ECs) and tobacco-heating products (THPs) as an alternative to cigarettes, which may reduce the health burden associated with smoking. However, an exposure continuum when smokers switch to ECs or THPs compared to complete smoking cessation is not well established. Methods 148 healthy smokers were randomized to either continue smoking cigarettes, switch to using the glo THP or a prototype EC, or completely quit any nicotine or tobacco product use for 5 days, after a 2-day baseline period. During this study breath and 24-h urine samples were collected for Biomarker of Exposure (BoE) analysis. Results After a 5-day switching period BoE levels showed a substantial significant decrease in levels from baseline in the groups using the glo THP, the prototype EC, and having quit all nicotine and tobacco use. On an exposure continuum, smokers who completely quit nicotine had the lowest levels of assessed BoEs, followed by those who switched to the EC and then those who switched to glo THP use. Participants who continued to smoke had the highest levels of BoEs. Conclusions THP or EC use over a 5-day period resulted in significant reductions in exposure to smoke toxicants, in some cases to levels similar to those for nicotine cessation. These results show that on an exposure continuum, nicotine cessation gives the greatest reduction in exposure to tobacco smoke toxicants, closely followed by the EC and the glo THP. These significant reductions in exposure to toxicants suggest that the glo THP and EC have the potential to be Reduced Risk Products. Study Registration ISRCTN80651909.

Smokers who switch completely to e-cigarettes may reduce their relative risk of tobacco-related disease. Effective nicotine delivery from e-cigarettes is important in consumer acceptance. We assessed whether protonated nicotine and e-cigarette devices delivering greater aerosol mass increase nicotine delivery and product liking. A randomised controlled non-blinded eight-arm crossover study was used to assess plasma nicotine pharmacokinetics and product liking for two e-cigarettes (Vype ePen3 and Vype ePen) with various nicotine e-liquid formulations and a conventional cigarette among 24 healthy dual-users of cigarettes and e-cigarettes. Product use and puff count were also assessed. Results show that nicotine bioavailability was greater for Vype ePen3 with greater aerosol mass delivery than for Vype ePen (Cmax, p = 0.0073; AUC0–120 min, p = 0.0102). Protonated nicotine (18 mg/mL, medium protonation) e-liquid yielded higher nicotine bioavailability than unprotonated nicotine (18 mg/mL) e-liquid (Cmax, p = 0.0001; AUC0–120 min, p = 0.0026). There was no significant difference in Tmax between e-liquids. Nicotine bioavailability did not differ between nicotine benzoate formulation (30 mg/mL nicotine, high protonation) and combustible cigarettes (Cmax, p = 0.79; AUC0–120 min, p = 0.13). Vype ePen3 with protonated nicotine delivers nicotine more efficiently with the potential to increase product liking relative to earlier devices using unprotonated e-liquid.

Introduction Tobacco 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 Methods This 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. Results In 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. Conclusion glo is a reduced-exposure tobacco product. Implications This 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 registration ISRCTN81075760.

Tobacco Heating Products (THPs) are tobacco products that heat rather than burn tobacco with temperatures less than 350 °C. Because of this operating principle, they produce substantially fewer and lower levels of tobacco smoke toxicants than combustible cigarette smoke produced when tobacco is burnt, which occurs at much higher temperatures of around 900 °C. This paper analyses data on a THP, glo™, and assesses whether its use would result in reduced health risks compared to the health risks of smoking cigarettes. It also looks at the possibility of bridging datasets across the different variants of the glo™ product.The approach is to consider whether datasets from behavioural, chemical, toxicological and clinical studies provide consistent findings of reductions in toxicant exposure with glo™ use by subjects who switch completely from smoking cigarettes to using glo™ and whether these reductions are similar to those who stop smoking cigarettes without switching to glo™ or any other tobacco or nicotine product. We also examine the similarities and differences of different versions of the glo™ product and benchmark it against a THP from another manufacturer.The studies indicate that the use of the glo™ results in substantial and prolonged reductions in toxicant exposure for smokers who switch to glo™ completely. A long-term clinical study shows substantial reductions in toxicant exposure over a period of time, similar to reduction of some biomarkers of exposure found following smoking cessation without switching to glo™ or any other tobacco product, and biomarkers of potential harm trending in a favourable manner for both groups that switch to glo™ and that quit all tobacco and nicotine use. Data suggests that all iterations of glo™ result in substantial reductions in toxicant exposure compared to smoking cigarettes and that bridging across datasets is feasible.Given the accumulated scientific data summarised in this paper, and particularly the findings from a long-term clinical study, the data demonstrate that glo™ is a reduced exposure product compared to combustible cigarettes and is reasonably deemed to reduce the risk of smoking-related diseases and supports the conclusion that smokers who would have otherwise continued to smoke and instead switch entirely to THP glo™ use, will reduce their relative risk of developing smoking-related diseases as compared to continued smoking. The extent of reduction in risk compared to continuing to smoke is likely to vary by smoking-related disease and by an individuals' smoking history, other risk factors and an individual's susceptibility to disease. Use of the THP will present some level of increased health risk as compared to cessation of tobacco and nicotine products and will cause dependence. As long as the principles of heat-not-burn are maintained, THP use will result in substantially reduced exposure to smoke toxicants as compared to continued conventional cigarette smoking. It is possible to use bridging or read across to apply these conclusions to new iterations of the glo™ product, extending the utility and validity of the evidence generated through study of prior iterations.

Introduction The number and variety of alternative tobacco and nicotine products that can potentially provide reduced-risk choices for cigarette smokers who switch completely to such products instead of continued smoking have grown substantially in the past decade. Innovation and choice are likely to improve the prospects of smokers making the switch, but this provides challenges to regulators and manufacturers to ensure that changes to regulations and products promote and do not hinder contributions to tobacco harm reduction. Aims and Methods This paper looks at where bridging data sets for tobacco heating products, closed system vaping products, and oral nicotine products might enable innovation while protecting the interests of consumers. Results We review product data from chemical studies and a toxicological study showing how bridging can be applied and consider what product development changes might allow bridging from existing datasets or trigger the need for new ones. Conclusions Bridging across specific product ranges can increase the speed of innovation, foster competition, and limit the burden of assessment for regulators while maintaining product safety and quality. Implications Bridging partial data sets is an established practice within other industries, that aims to improve efficiency with regulatory approvals, accepts natural product variation, and supports product innovation. We review product data from chemical studies and a toxicological study showing how bridging can be applied and consider what product development changes might allow bridging from existing datasets or trigger the need for new ones. This in turn can increase the speed of innovation, foster competition, and limit the burden of assessment for regulators while maintaining product safety and quality.

In vitro testing can facilitate the rapid assessment of next generation nicotine delivery products (NGPs) with comparisons to combustible tobacco products. In vitro assays for cytotoxicity and oxidative stress were employed at BAT (UK) and JT (Japan) to test total particulate matter (TPM) of a scientific reference cigarette and aerosol collected mass (ACM) of a commercially available E-cigarette and two tobacco heating products (THP). 3R4F TPMs were generated using the Health Canada intense (HCI) regimen, a modified regime (mHCI) for the THP ACMs and the CORESTA recommended method no. 81 for the E-cigarette ACM. Human lung cells were exposed to the test product TPM/ACMs at concentrations between 0–200 μg/ml followed by the employment of commercially available assays for endpoint analysis that included reactive oxygen species (ROS) generation, the glutathione ratio (GSH:GSSG), activation of the antioxidant response elements (ARE) and cellular viability. TPM/ACM nicotine concentrations were quantified using a UPLC-PDA technique. At both laboratories the 3R4F TPM induced significant and dose-dependent responses in all in vitro assays, whereas no significant responses could be measured for the NGP ACMs. In conclusion, both laboratories obtained comparable results across all endpoints therefore demonstrating the utility of the in vitro techniques combined with standardised test products to support the assessment of NGPs.

This publication is part of a series of 3 publications and describes the clinical assessment performed to fulfill the regulatory requirement per Art. 6 (2) of the EU Tobacco Products Directive 2014/40/EU under which Member States require manufacturers and importers of cigarettes and Roll Your Own tobacco containing an additive that is included in the priority list established by Commission Implementing Decision (EU) 2016/787 to carry out comprehensive studies (European Union, 2016). In our clinical study, two distinct end points were investigated, namely measuring plasma nicotine pharmacokinetics as a measure of nicotine uptake, and analyses of changes in smoker puffing behavior as a measure of cigarette smoke inhalation. This clinical study indicated that the inclusion of none of the priority additives either as single additive or as part of a chemical mixture, facilitated nicotine uptake. Furthermore, the data did not suggest that differences in the inhalation pattern of cigarette smoke of any of the Priority Additives tested occurred when compared to the additive-free reference cigarette. Finally, it is concluded that neither the scientific literature nor our study gave circumstantial indications of increased addictiveness for cigarettes containing these priority additives.

Tobacco heating products (THPs) are a potentially safer alternative to combustible cigarette smoking. Through continued use, THPs may reduce smoking-related disease risk, whilst maintaining the sensorial experience and nicotine delivery sought by smokers. While literature evidence of the biological effects of THP aerosol exposure is increasing, there remains a knowledge gap with respect to substantiation of THP reduced risk potential in longer term real-life use. This randomized, multi-centre, controlled clinical study will test the hypotheses that following a switch from combustible cigarettes to a THP for 1 year, participants will experience a sustained reduction in exposure to tobacco-related toxicants that will lead to favourable changes in health effect indicators associated with smoking-related disease development. Changes in such indicators will be contextualized against smoking cessation and never-smoker cohorts. Up to 280 participants who do not intend to quit smoking will be randomized to continued combustible smoking (arm A, up to n = 80) or a commercially available THP (arm B n = 200). Furthermore, up to 190 participants with a high intent to quit smoking will undergo smoking cessation (arm D), and 40 never smokers will serve as a control group (arm E). Recruitment numbers were determined to be sufficient to achieve n = 50 in arms A, B and D, at study end. Enrolment started in March 2018 and the trial is scheduled to be completed in March 2020. Data from this study will be a valuable addition to the growing body of evidence in the field of understanding the individual and public health impact of THPs. Clinical Trial Registration: https://www.isrctn.com/ISRCTN81075760 Electronic supplementary material The online version of this article (10.1007/s11739-019-02090-8) contains supplementary material, which is available to authorized users.

Few data are available on the health impact of tobacco heating products (THPs) at the population level. We used systems dynamics modelling to estimate effects in the established THP market in Japan. We projected effects of THP use in overall mortality up to 2100 and compare those projections against a baseline scenario based on smoking rates pre-THP launch, i.e., smoking only. The model was informed using data from publicly available sources and the literature, including population size, yearly deaths and smoking prevalence with initialisation year (2004) and, births and migration from 2004 to 2065. Transitions between products were estimated from cross-sectional population surveys in Japan. Potential life-years saved with the introduction of THPs was 13 million by 2100 compared with smoking only. In worst-case scenario, population health gains would be seen with THPs risk 10–50% lower risk than smoking. Assuming equal risk for dual use and smoking, THP risk would need to be at least 10% lower than smoking to achieve a population health benefit by 2100. In credible scenarios, substantial population health gains will follow the introduction of THPs in Japan in a relatively short time frame.

Background For novel tobacco products that potentially reduce the risk of tobacco harm, post-market surveillance is important to observe population usage and behaviours associated with everyday use. This pilot study was performed to examine the use of tobacco products in three Japanese urban regions. Methods This study was a cross-sectional epidemiological survey administered in Sendai, Tokyo and Osaka, Japan, from May 19th to June 25th, 2018. Participants were selected with a three-stage probability random sampling process that first identified primary sampling units, then households and finally individuals. Eligible participants were aged at least 20 years who were willing to participate after information about the study was provided. People younger than 20 years and those living in institutions were excluded. Questionnaires were paper based and administered door to door. Results Responses were obtained from 4154 participants. Sixty-five percent self-reported being never, 19% current and 16% former users of any tobacco product at the time of the survey. Combustible tobacco products (almost all being cigarette) were used most (16%) followed by HTPs (5%). In the categories of combustible tobacco users and HTP users, 70% and 16%, respectively, used these products exclusively. Dual use was reported by 11% of respondents. Compared with 12 months before the survey, 12% of sole combustible tobacco products users were using HTPs exclusively or as dual users and 6% had quit tobacco products completely; 94% of sole HTP users remained sole users and 4% had quit tobacco products completely; and amongst dual users 12% had reverted to exclusive use of combustible tobacco products, 14% had switched to sole use of HTPs and 4% had quit tobacco products completely. Conclusion HTPs seem to be accepted as an alternative tobacco product amongst combustible tobacco users. Given complex findings for dual use, improved understanding of the motivations underlying this behaviour would be of interest.

Actual use studies play a key part in evaluating the reduced risk potential of tobacco and nicotine products. This study was undertaken to determine the puffing topography, mouth level exposure (MLE) and average daily consumption (ADC) relating to two commercially available tobacco heating products (THPs) and a prototype electronic cigarette (or e-cigarette) among Italian non-mentholated 7 mg ISO tar cigarette smokers. The study was conducted in Milan, Italy, with three groups of approximately 50 participants. Groups 1 and 3 included adult smokers of 7 mg ISO tar tobacco cigarettes, and Group 2 consisted of both solus vapers and dual users of vapour and tobacco products. Amongst smokers, e-cigarette mean puff volumes (41.6 mL vs 41.3 mL) and mean puff durations (1.4 s vs 1.5 s) were similar to that of the cigarette, although the average usage session was significantly longer (1064.8 s vs 289.5 s) with a higher total number of puffs (58.6 vs 17.3), however this may be attributable to differences in product operation. There were no significant differences across puffing topography measurements observed between smokers (Group 1) and regular vapers/dual users (Group 2) when using the e-cigarette. As consistent with previous research, users took, on average, larger mean puff volumes when using a THP compared to the reference cigarette (C651), although puff numbers and puff durations remained similar. The average interval between puffs was considerably shorter for THP1.0(T) compared to THS2.4(T) (11.0 s vs 17.1 s). MLE to nicotine-free dry particulate matter and nicotine was significantly reduced for THP1.0(T) and THS2.4(T) compared to the tobacco cigarette (C651). MLE to nicotine was also significantly reduced for the e-cigarette (IS1.0(T)) compared to C651. The average daily consumption (ADC) of cigarettes by groups 1 and 3 were higher than the respective ADCs of both THP consumables. There were no significant differences in ADC when comparing the same product between different groups. Differences seen between sensory scores for each of the product categories may be attributed to fundamental differences in design and mode of operation resulting in very different characteristics of the aerosol generated.

ISO 4387 Standard determines the main aerosol constituents (total particulate matter, water, nicotine, and nicotine-free-dry-particulate matter, referred to as "tar") in cigarette mainstream smoke (ISO, 2000). Heated Tobacco Products (also called Tobacco Heating Products or Heat-not-Burn Products) are designed to form aerosol by heating tobacco rather than burning like in combustible cigarettes. In this study we have evaluated the suitability of ISO 4387 Standard to be adapted for quantifying main aerosol constituents for HTP aerosol. HTP emissions have much higher levels of water and humectants (e.g., glycerol) in dynamic equilibria between gaseous and particulate phases. Several modifications to ISO 4387 Standard on aerosol collection were tested to improve the accuracy and reliability of aerosol capturing, with minimal deviation to the standard method. The proposed modifications are readily adoptable by laboratories already practicing the Standard for cigarette smoke analyses. Taking collectively with other available aerosol chemistry and biological results on HTPs in the literature, they show a fundamentally different aerosol in HTPs and call for category-specific product standards and terminology.

We designed a novel tobacco-heating product (THP) that heats tobacco to release nicotine and aerosolised components, such as glycerol and tobacco volatiles from a tobacco rod (Neostik). Heating tobacco significantly reduces levels of combustion-derived toxicants in the aerosol compared to cigarette smoke. This study was conducted to determine whether the inclusion of potential flavourings in the THP would add to the levels of toxicants in the emissions or alter in vitro responses. Levels of measured toxicants were similar in the flavoured and unflavoured Neostik emissions and significantly less than emissions from the reference cigarette, 3R4F. No mutagenicity was observed with the Neostiks in the Ames test or in the mouse lymphoma assay. There was evidence of a weak genotoxic response in the in vitro micronucleus test using V79 cells from both Neostiks and these responses were less than 3R4F. They did not show tumour-promoting potential in the Bhas 42 cell transformation assay and were not cytotoxic in the Neutral Red uptake assay. 3R4F elicited toxic responses in all assays at significantly lower concentrations. The addition of flavourings to the Neostik tested did not alter the chemical profile of THP emissions or change in vitro responses relative to the unflavoured Neostik.

The concept of a risk continuum for tobacco and nicotine products has been proposed, which differentiates products according to their propensity to reduce toxicant exposure and risk. Cigarettes are deemed the most risky and medicinal nicotine the least. We assessed whether a Reduced-Toxicant Prototype (RTP) cigarette could sufficiently reduce exposure to toxicants versus conventional cigarettes to be considered a distinct category in the risk continuum. We present findings from both pre-clinical and clinical studies in order to examine the potential for reduced smoke toxicant emissions to lower health risks associated with cigarette smoking. We conclude that current toxicant reducing technologies are unable to reduce toxicant emissions sufficiently to manifest beneficial disease-relevant changes in smokers. These findings point to a minimum toxicant exposure standard that future potentially reduced risk products would need to meet to be considered for full biological assessment. The RTP met WHO TobReg proposed limits on cigarette toxicant emissions, however the absence of beneficial disease relevant changes in smokers after six months reduced toxicant cigarette use, does not provide evidence that these regulatory proposals will positively impact risks of smoking related diseases. Greater toxicant reductions, such as those that can be achieved in next generation products e.g. tobacco heating products and electronic cigarettes are likely to be necessary to clearly reduce risks compared with conventional cigarettes.

A four-arm study was undertaken in Japan to determine the puffing topography, mouth level exposure and average daily consumption by consumers of the tobacco heating products (THPs): the non-mentholated THP1.0(T), the mentholated THP1.0(M) and a tobacco heating system (THS). The extent of lip blocking of air inlet holes while using THP1.0(T) was also assessed. Groups 1, 2, and 4 included smokers, and group 3 included regular THP users. Smokers of 7–8 mg ISO nicotine free dry particulate matter (NFDPM) non-mentholated cigarettes took on average larger mean puff volumes from THPs than from conventional cigarettes, but puff numbers and durations were similar. Mouth level exposure to NFDPM and nicotine levels were significantly lower when using THPs than conventional cigarettes. Similar trends were observed among smokers of 7–8 mg ISO NFDPM mentholated cigarettes who used mentholated cigarettes and THP1.0(M). Regular users of commercial THS had similar puffing behaviours irrespective of whether they were using THS or THP1.0(T), except for mean puff volume which was lower with THP1.0(T). No smokers blocked the air inlet holes when using THP1.0(T). The puffing topography results support the machine puffing regime used to generate toxicant emissions data and in vitro toxicology testing.

The tobacco heating product THP1.0, which heats but does not burn tobacco, was tested as part of a modified-risk tobacco product assessment framework for its impacts on indoor air quality and residual tobacco smoke odour. THP1.0 heats the tobacco to less than 240 °C ± 5 °C during puffs. An environmentally controlled room was used to simulate ventilation conditions corresponding to residential, office and hospitality environments. An analysis of known tobacco smoke constituents, included CO, CO 2 , NO, NO 2 , nicotine, glycerol, 3-ethenyl pyridine, sixteen polycyclic aromatic hydrocarbons, eight volatile organic compounds, four carbonyls, four tobacco-specific nitrosamines and total aerosol particulate matter. Significant emissions reductions in comparison to conventional cigarettes were measured for THP1.0. Levels of nicotine, acetaldehyde, formaldehyde and particulate matter emitted from THP1.0 exceeded ambient air measurements, but were more than 90% reduced relative to cigarette smoke emissions within the laboratory conditions defined Residual tobacco smoke odour was assessed by trained sensory panels after exposure of cloth, hair and skin to both mainstream and environmental emissions from the test products. Residual tobacco smoke odour was significantly lower from THP1.0 than from a conventional cigarette. These data show that using THP1.0 has the potential to result in considerably reduced environmental emissions that affect indoor air quality relative to conventional cigarettes.

In vitro studies have been widely used to support the toxicological evaluation of chemicals and complex mixtures including cigarette smoke. In this study, the total particulate matter and whole aerosol from a Kentucky reference 3R4F cigarette and two commercially available tobacco heating products (THPs) were assessed using in vitro mutagenicity, cytotoxicity and tumour-promoting activity assays. The Ames assay assessed mutagenicity using Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537 and TA102 ± metabolic activation (S9). The mouse lymphoma assay was used with short 3 h and longer 24 h exposures. The Bhas 42 cell transformation assay was incorporated as an in vitro alternative for detecting tumour promoters, and the neutral red uptake cell viability assay provided an acute measure of cytotoxicity. To complement the approach, the Ames assay was also employed with S. typhimurium tester strains TA98, TA100, TA1535, TA97 and TA102 using a scaled down methodology for the assessment of aerosols. All the in vitro techniques employed produced a clear positive response with cigarette smoke and in contrast, a negative response to THPs at doses equivalent to or higher than a cigarette smoke test matrix. The data show little difference between the THPs assessed suggesting parity between products.

This series of nine papers described the operation and pre-clinical assessment of a tobacco heating product THP1.0. This last paper contextualises the pre-clinical assessment data on THP1.0 with data from other next generation products relative to cigarette smoke. The tobacco and nicotine risk continuum is a concept that ranks products according to their potential harm, with cigarettes at the highest risk extreme and Nicotine Replacement Therapy at the least risky extreme. Data generated in pre-clinical studies on THP1.0 and a range of Next Generation Products (NGPs) may provide some initial indication of potential ranking of these products, although importantly, data from such studies are limited and cannot take into consideration several important aspects for risk such as long term product use patterns. In each of the studies, the responses to the emissions from THP1.0 were substantially reduced relative to cigarette smoke. Additionally, responses from THP1.0 were very similar to those from the other NGP emissions. A comparison of the results clearly showed the emissions from all the NGPs were considerably lower than those from cigarettes and all in around the same emissions level. These results show that THP1.0 could have the potential to be a reduced risk product compared to cigarettes, though further studies assessing the exposure, individual and population risk reduction profile would be required to substantiate this potential.

Tobacco heating products (THPs) represent a subset of the next-generation nicotine and tobacco product category, in which tobacco is typically heated at temperatures of 250-350 °C, thereby avoiding many of the harmful combustion-related toxicant emissions of conventional cigarettes. In this study, we have assessed aerosol generation and cytotoxicity from two commercially available THPs, THP1.0 and THS, relative to tobacco smoke from 3R4F reference cigarettes, using an adapted Borgwaldt RM20S Smoking Machine. Quantification of nicotine in the exposed cell-culture media showed greater delivery of nicotine from both THPs than from the cigarette. Using Neutral Red Uptake assay, THPs demonstrated reduced in vitro cytotoxicity in H292 human bronchial epithelial cells as compared with 3R4F cigarette exposure at the air-liquid interface (p 0.0001). Both THPs demonstrated a statistically similar reduction in biological response, with87% viability relative to 3R4F at a common aerosol dilution (1:40, aerosol:air). A similar response was observed when plotted against nicotine; a statistical difference between 3R4F and THPs (p 0.0001) and no difference between the THPs (p = 0.0186). This pre-clinical in vitro biological testing forms part of a larger package of data to help assess the safety and risk reduction potential of next-generation tobacco products relative to cigarettes, using a weight of evidence approach.

For a tobacco heating product (THP), which heats rather than burns tobacco, the emissions of toxicants in the aerosol were compared with those in cigarette smoke under a machine-puffing regimen of puff volume 55 ml, puff duration 2 s and puff interval 30 s. The list of toxicants included those proposed by Health Canada, the World Health Organization Study Group on Tobacco Product Regulation (TobReg), the US Food and Drug Administration and possible thermal breakdown products. In comparison to the University of Kentucky 3R4F reference cigarette the toxicant levels in the THP1.0 emissions were significantly reduced across all chemical classes. For the nine toxicants proposed by TobReg for mandated reduction in cigarette emissions, the mean reductions in THP1.0 aerosol were 90.6–99.9% per consumable with an overall average reduction of 97.1%. For the abbreviated list of harmful and potentially harmful constituents of smoke specified by the US Food and Drug Administration Tobacco Products Scientific Advisory Committee for reporting in cigarette smoke (excluding nicotine), reductions in the aerosol of THP1.0 were 84.6–99.9% per consumable with an overall average reduction of 97.5%.

Background Smoking is a leading cause of numerous human disorders including lung cancer, chronic obstructive pulmonary disease, and atherosclerotic cardiovascular disease. The development of modified risk tobacco products (MRTPs) has been suggested as a possible way to reduce the risks of tobacco smoking by reducing exposure to cigarette smoke toxicants. This study is designed to investigate whether biomarkers of such exposure are reduced when smokers switch from smoking commercial cigarettes to using either a novel or a commercially-available tobacco heating product (THP). Design and Methods This study will assess biomarkers of exposure in current smokers who either remain smoking, switch to THP use, or quit all tobacco use completely, for 5 days. The study is an in-clinic (confinement) two-centre, randomised controlled clinical study with a forced-switching design. Subjects of either gender will be aged 23–55 years (minimum legal smoking age plus 3 years), of Japanese origin and with a verified smoking status (assessed by exhaled breath carbon monoxide and urinary cotinine levels). Subjects will have a usual brand cigarette within the International Organisation for Standardisation (ISO) tar band of 6-8 mg and will be judged to be healthy by medical history, physical examination, vital signs, electrocardiography (ECG), clinical biochemistry and lung function tests. The primary objective of this study is to assess changes within groups in selected biomarkers of exposure (BoE) and of biological effect (BoBE) after a forced switch from a commercial control cigarette to either a menthol or a non-menthol THP. Secondary objectives are to assess between-group differences, to determine nicotine pharmacokinetics for cigarettes and THPs, to assess subject’s satisfaction with the study products, and to monitor additional endpoints related to safety and product use. Discussion Data from this study will advance our scientific understanding of the changes in exposure to cigarette smoke toxicants in smokers who switch to using a THP. Trial registrations UMIN000024988 (25th November 2016); ISRCTN14301360 (14th December 2016) Electronic supplementary material The online version of this article (doi:10.1186/s12889-017-4678-9) contains supplementary material, which is available to authorized users.

The WHO Tobacco Product Regulation Study Group (TobReg) has proposed three regulatory models for cigarettes, each creating mandatory limits for emissions of nine smoke toxicants. One approach proposes country-specific limits, using median or 1.25× median toxicant/nicotine emission ratios. A second model provides fixed toxicant-ratio limits. The third model limits were three times the lowest toxicant emission on a market. Currently, the practical implications of these models are largely unknown. An impact assessment was conducted using cigarette data from 79 countries to identify four diverse test markets. We sampled all products from each market but limited product availability led to incomplete (80–97%) sourcing. Analysis showed that the country-specific model led to diverse (up to threefold) toxicant limits across the four markets. 70%–80% of products were non-compliant, rising to 100% in some countries with the second and the third models. With each regulatory model the main drivers of non-compliance were the tobacco-specific nitrosamines, the simultaneous application of limits for nine poorly correlated smoke toxicants, and analytical variability. Use of nicotine ratios led to compliance of some high toxicant emission products due to high nicotine emissions. Our findings suggest that these proposals would have greater impact on global markets than TobReg's stated aims.

Objectives E-cigarettes could potentially play a major role in tobacco harm reduction by delivering nicotine in a vapor containing significantly fewer toxicants than cigarette smoke and may aid smoking behavior changes such as reduction or cessation. Methods We examined blood nicotine levels in smokers who were non-accustomed to e-cigarette use (Study 1) and accustomed e-cigarette users (Study 2). We compared nicotine levels when participants used a closed modular system e-cigarette to those when participants smoked a cigarette. Results In Study 1, Cmax (geometric mean (CV)) during a 5-minute puffing period (10 puffs, 30 seconds apart) was 13.4 (51.4) ng/ ml for a regular cigarette. The e-cigarette Cmax was significantly lower (p .05) at 2.5 (67.8) ng/ml. In Study 2, during a 5-minute ad libitum puffing period, cigarette Cmax was 7.2 (130.8) ng/mL, and it was 7.8 (108.2) ng/mL for the e-cigarette. Conclusions Our data demonstrate heterogeneity of nicotine deliveries both between products and also with the same products used by different cohorts, eg, accustomed users versus smokers. Such differences must be taken into account when determining the likely behavioral impact, on smoking reduction and cessation, of nicotine delivery data and when planning e-cigarette nicotine pharmacokinetic studies.

We have recently developed a Tobacco Heating Product (THP) comprising an electrical heating device, commercially known as Glo™, and consumable tobacco rods, commercially known as Kent Neostiks™. We refer to this system as THP1.0; Bright tobacco-flavoured variant THP1.0(T), or THP1.0(M) Menthol-flavoured variant. In this issue, we present a series of seven pre-clinical studies conducted on THP1.0,covering the following aspects of its design, development, safety and toxicological assessment, and a paper on placing THPs on an emissions continuum.

There is interest in the relative toxicities of emissions from electronic cigarettes and tobacco cigarettes. Lists of cigarette smoke priority toxicants have been developed to focus regulatory initiatives. However, a comprehensive assessment of e-cigarette chemical emissions including all tobacco smoke Harmful and Potentially Harmful Constituents, and additional toxic species reportedly present in e-cigarette emissions, is lacking. We examined 150 chemical emissions from an e-cigarette (Vype ePen), a reference tobacco cigarette (Ky3R4F), and laboratory air/method blanks. All measurements were conducted by a contract research laboratory using ISO 17025 accredited methods. The data show that it is essential to conduct laboratory air/method measurements when measuring e-cigarette emissions, owing to the combination of low emissions and the associated impact of laboratory background that can lead to false-positive results and overestimates. Of the 150 measurands examined in the e-cigarette aerosol, 104 were not detected and 21 were present due to laboratory background. Of the 25 detected aerosol constituents, 9 were present at levels too low to be quantified and 16 were generated in whole or in part by the e-cigarette. These comprised major e-liquid constituents (nicotine, propylene glycol, and glycerol), recognized impurities in Pharmacopoeia-quality nicotine, and eight thermal decomposition products of propylene glycol or glycerol. By contrast, approximately 100 measurands were detected in mainstream cigarette smoke. Depending on the regulatory list considered and the puffing regime used, the emissions of toxicants identified for regulation were from 82 to99% lower on a per-puff basis from the e-cigarette compared with those from Ky3R4F. Thus, the aerosol from the e-cigarette is compositionally less complex than cigarette smoke and contains significantly lower levels of toxicants. These data demonstrate that e-cigarettes can be developed that offer the potential for substantially reduced exposure to cigarette toxicants. Further studies are required to establish whether the potential lower consumer exposure to these toxicants will result in tangible public health benefits.

Tobacco harm reduction strategies aim to substitute smoking with potentially reduced risk products (PRRPs) such as e-cigarettes and tobacco-heating products (THPs). The health benefits of switching from smoking to PRRPs is unknown. A randomised controlled trial is being conducted to increase understanding of the health effects of switching from smoking to a THP in a 12-month long ambulatory study (ISRCTN81075760). Here we describe the study endpoints and the statistical analysis plan. Endpoints are divided into biomarkers of exposure (BoE) to tobacco smoke constituents and health effect indicators related to risk of lung cancer, cardiovascular and obstructive lung disease. These have been selected on the basis of extensive literature evidence. Three primary endpoints, augmentation index (risk factor for cardiovascular disease), total NNAL (linked to lung cancer) and 8-Epi-PGF2α type III (indicator of oxidative stress linked to various diseases), and multiple secondary endpoints will be analysed at 90, 180, and 360 days. Changes from baseline will be compared between study arms by specific contrasts in mixed models. Study wise multiple comparisons adjustments will be performed to account for multiplicity of timepoints and comparisons within timepoints. Generalisability of outcomes will be tested by a sensitivity analysis adjusting for age and gender. Importantly, an ancillary analysis will be performed to assess product compliance during the study based on plasma levels of CEVal, a surrogate marker for acrylonitrile exposure. The rationale underlying the selection of BoEs and health effect indicators, coupled with the statistical analysis plan will be central to understanding the potential health effects of replacing smoking with THP use for one year. Keywords: Nicotine, Biomarker, Tobacco heating product, THP, MRTP

To evaluate in vitro enamel sample discoloration following exposure to a scientific reference cigarette (3R4F) or emissions from next generation tobacco and nicotine products (NGPs) such as electronic cigarettes (EC) and tobacco heating products (THP).Bovine enamel blocks (6.5 × 6.5 mm) were prepared and pre-incubated with human or artificial saliva, to form a pellicle layer before exposure to either particulate matter (PM) or whole aerosols. PM was prepared by capturing 3R4F cigarette smoke (CS), a commercial THP (THP1.0) or a novel vapor product (NVP)/next generation e-cigarette aerosols on Cambridge filter pads followed by elution with dimethyl sulfoxide (DMSO). Ten enamel samples were exposed to each PM for 14 days. For aerosol exposure, 12 enamel samples were exposed (200 puffs per day, for 5 consecutive days) to 3R4F CS or THP1.0 and NVP aerosols. Control samples were incubated with DMSO (PM study) or phosphate buffered saline (PBS, aerosol study). Individual enamel sample color readings (L*, a*, b*) were measured at baseline and on each exposure day. Mean ΔL*, Δa*, Δb* and ΔE values were calculated for each product or control. A one-way ANOVA was used to assess the differences between the products and controls. The Tukey procedure for pairwise comparisons was also used.At all timepoints, 3R4F PM and CS induced enamel discoloration that was statistically significant (0.0001) when compared to THP1.0 or NVP. After 14-day PM exposure, mean ΔE values were 29.4± 3.6, 10.5 ± 2.3, 10.7 ± 2.6 and 12.6 ± 2.0 for 3R4F, THP1.0, NVP and DMSO control respectively. After 5-day CS or aerosol exposure, mean ΔE values were 26.2 ± 3.2, 3.6 ± 1.9, 3.4 ± 1.3, 5.3 ± 0.8 for 3R4F CS, THP1.0, NVP or PBS control, respectively. Both exposure methods demonstrated that THP1.0 and NVP induced minimal staining, mean ΔL* , Δa* , Δb* and ΔE values were comparable to DMSO or PBS controls.For the first time, diverse NGPs across the risk continuum were assessed in vitro for their impact on enamel staining. CS exposure significantly increased the level of bovine enamel sample discoloration, whereas THP1.0 or NVP exposure resulted in values comparable to the controls.

A framework for the assessment of novel next-generation tobacco and nicotine products with the potential to reduce health risks compared with cigarettes should integrate scientific studies incorporating nonclinical, clinical, and population studies approaches. These products should have lower emissions and exhibit reduced biological effects compared with those of cigarettes, ideally approaching those of smoking cessation. The products should also be acceptable cigarette alternatives for current smokers, while not appealing to nonsmokers or former smokers. Validating harm reduction and promoting regulatory acceptance of the assessment methods require a collaborative approach by industry, independent reviewers, the public health community, and regulatory agencies. This article summarizes the science and approaches applied and considered to substantiate tobacco harm reduction in the light of regulatory requirements, presented at the 53rd Congress of the European Societies of Toxicology, 2017.

Background Smoking 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. Methods This 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). Results On 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. Conclusions glo™ 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. Implications This 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 Registrations ISRCTN14301360 and UMIN000024988.

Approximately 100 toxicants have been identified in cigarette smoke, to which exposure has been linked to a range of serious diseases in smokers. Smoking machines have been used to quantify toxicant emissions from cigarettes for regulatory reporting. The World Health Organization Study Group on Tobacco Product Regulation has proposed a regulatory scenario to identify median values for toxicants found in commercially available products, which could be used to set mandated limits on smoke emissions. We present an alternative approach, which used quantile regression to estimate reference percentiles to help contextualise the toxicant yields of commercially available products with respect to a reference analyte, such as tar or nicotine. To illustrate this approach we examined four toxicants (acetone, N′-nitrosoanatabine, phenol and pyridine) with respect to tar, and explored International Organization for Standardization (ISO) and Health Canada Intense (HCI) regimes. We compared this approach with other methods for assessing toxicants in cigarette smoke, such as ratios to nicotine or tar, and linear regression. We concluded that the quantile regression approach effectively represented data distributions across toxicants for both ISO and HCI regimes. This method provides robust, transparent and intuitive percentile estimates in relation to any desired reference value within the data space.

Background: Assessment of health-related quality of life (HRQoL) is well established in clinical research, but ceiling effects in validated tools might prevent detection of changes in well respondents. Tobacco Quality of Life Impact Tool (TQOLITv1) uses conceptual and psychometric advances to enhance detection of HRQoL changes. Methods: In a 6-month, forced-switch study, the German TQOLITv1 was assessed in healthy adult (age 23–55 years) current and matched former-smokers. At baseline, smokers were switched to reduced toxicant prototype (RTP) or conventional cigarette for 6 months. TQOLITv1 responses were collected at baseline, 3 and 6 months from current smokers whilst former smokers completed it at the latter two time points. TQOLITv1 includes SF-36v2 and new smoking-specific, physical and general-health measures. Results: Reliability at baseline was good (Cronbach’s coefficient alpha > 0.70) for all measures. The baseline percentage with the best possible score (ceiling effect) for former and current smokers was substantially better for the new physical function than SF-36 physical function measure (35% vs. 59% at ceiling, respectively). New smoking-specific measures discriminated current from former smokers better than general health measures. Smoking-specific symptoms ( r = 0.73) were more stable from baseline to 6 months than other measures (r = 0.38–0.54) particularly more than the SF-36 mental component score (r = 0.24). Although both product smoking groups worsened in most HRQoL measures, changes in general and smoking-specific HRQoL impact measures favored RTP smokers. Conclusions: The German TQOLITv1 is sufficiently reliable and valid to assess HRQoL and may be more useful than SF-36v2 in evaluation of interventions in well smoking populations including those consuming RTPs.

Cigarette smoking is a major risk factor for many adverse health conditions. Novel tobacco heating products (THPs) heat tobacco, reducing exposure to many of the harmful combustion toxicants in conventional cigarette emissions. In vitro studies have been employed to support the toxicological evaluation of chemicals and complex mixtures, including cigarette smoke. The use of automated robotics platforms for in vitro toxicological screening complements traditional testing approaches. Multiparametric toxicity and oxidative stress endpoints were used to assess in vitro biological responses elicited after exposure to total particulate matter (TPM) from two commercially available THPs, and the reference tobacco product 3R4F, in human bronchial epithelial cells. A luciferase-based reporter gene assay was used to assess antioxidant response element (ARE) transcriptional activation in stably transfected H292 cells after 6 and 24 h exposures. High-content screening was used to assess 10 endpoints normal human bronchial epithelial cells after 4 or 24 h exposures. 3R4F TPM stimulated significant increases in ARE activation (p 0.005) and moderate activity in HCS cell-based assays compared to THP at comparable doses. THPs showed little or no activity in all assays. HCS techniques can extend safety assessments providing information quickly in the early stages of product innovation and development.

A novel tobacco heating product, THP1.0, that heats tobacco below 245 °C is described. It was designed to eliminate tobacco combustion, while heating tobacco to release nicotine, tobacco volatiles and glycerol to form its aerosol. The stewardship assessment approach behind the THP 1.0 design was based on established toxicological principles. Thermophysical studies were conducted to examine the extent of tobacco thermal conversion during operation. Thermogravimetric analysis of the tobacco material revealed the major thermal behaviour in air and nitrogen up to 900 °C. This, combined with the heating temperature profiling of the heater and tobacco rod, verified that the tobacco was not subject to combustion. The levels of tobacco combustion markers (CO, CO2, NO and NOx) in the aerosol of THP1.0 were significantly lower than the levels if there were any significant pyrolysis or combustion. Quantification of other tobacco thermal decomposition and evaporative transfer markers showed that these levels were, on average, reduced by more than 90% in THP1.0 aerosol as compared with cigarette smoke. The physical integrity of the tobacco consumable rod showed no ashing. Taken together, these data establish that the aerosol generated by THP1.0 is produced mainly by evaporation and distillation, and not by combustion or pyrolysis.