Assessing the comparability of toxic emissions reduction from heated tobacco aerosols relative to cigarette smoke: a scientific approach to bridging datasets

Assessing the comparability of toxic emissions reduction from heated tobacco aerosols relative to cigarette smoke: a scientific approach to bridging datasets | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Assessing the comparability of toxic emissions reduction from heated tobacco aerosols relative to cigarette smoke: a scientific approach to bridging datasets Jacqueline MILLER HOLT, Grant O’CONNELL, Renaud BACH, Maurane CHARRIERE, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7520219/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Oct, 2025 Read the published version in Internal and Emergency Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Heated tobacco products (HTPs) offer a reduce risk potential by avoiding combustion, thereby lowering toxic emissions. This study evaluated 34 heated tobacco stick (HTS) variants, each with different tobacco blends, using two heating devices to assess the comparability of 51 toxic emission reductions compared to combustible cigarette smoke. Aerosols and 1R6F reference cigarette smoke were generated under standardized conditions, and droplet or particle size distributions were measured. Toxic emission levels were analyzed using a proposed statistical approach to determine comparability. In vitro toxicological evaluation was performed using mutagenicity, genotoxicity, and cytotoxicity assays. Additionally, published data on Biomarkers of Exposure (BoE) were reviewed to assess whether reduced emissions corresponded to reduced human exposure at the category level. Overall, HTS emissions were reduced by 93.57% compared to cigarette smoke, with consistent reductions across blends and devices. HTS aerosols consistently showed significantly reduced in vitro biological activity compared to cigarette smoke, with reductions observed across all HTS types, devices, and sample phases, even at higher concentrations than those used for cigarette samples. Toxic emissions data from other HTP technologies in published literature were also reviewed, showing comparable reduced levels leading to consistent reductions in BoE. These findings suggest that the heat-not-burn principle provides substantial exposure reduction independent of product-specific attributes. The study supports the bridging of aerosol chemistry and toxicological datasets, and leveraging published BoE results across the HTP category, to streamline product assessments. Emissions Statistics Heated Tobacco Bridging Biomarker of Exposure Harm Reduction Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Combustion of tobacco, which occurs at temperatures exceeding 400°C and can reach up to 950°C, produces a chemically complex mixture (smoke) containing thousands of constituents, including numerous toxicants known to be carcinogenic or harmful to respiratory and cardiovascular health [ 1 , 2 ]. Epidemiological data confirm that the health risks of smoking are driven by sustained and long-term exposure to these primarily combustion-derived toxicants [ 3 ]. Technological innovation has led to the development of non-combustible nicotine products such as heated tobacco products (HTPs), which aim to reduce exposure to toxic emissions by eliminating combustion [ 4 ]. HTPs heat tobacco through controlled thermal processes that produce a respirable aerosol via evaporation and distillation rather than combustion [ 5 , 6 ]. As a result, they do not generate carbonaceous solid particles and deliver nicotine-containing aerosols that are chemically less complex and substantially lower in toxicant content than combustible cigarette smoke [ 7 – 9 ]. HTPs also maintain many behavioral and sensory aspects of the cigarette smoking experience such as inhalation, hand-to-mouth action, thereby supporting their adoption by adults who smoke as a potentially less harmful alternative. Clinical studies show that switching to HTPs consistently results in marked and sustained reductions in biomarkers of exposure (BoE) to select toxic emissions, including known carcinogens and cardiovascular and pulmonary toxicants [ 10 – 14 ]. These exposure reductions have been shown to be further associated with favorable changes in biomarkers with predictive validity for several smoking-related diseases across the HTP category [ 15 ]. As such, there is growing scientific and regulatory interest in whether toxic emissions from one HTP can be used to support assessments of others, provided comparability can be demonstrated, through an approach known as bridging [ 16 , 17 ]. The present study was designed to assess whether the heat-not-burn mechanism yields comparable reductions in toxic emissions and toxicological responses across a wide range of heated tobacco stick (HTS) variants. Emissions of 51 select toxicants were quantified across 34 HTS variants and compared to levels in combustible cigarette smoke. For a subset of HTS, in vitro toxicological responses were assessed. A statistical methodology is proposed to assess the comparability of reduced toxic emissions thereby enabling an analysis of the extent to which reduced toxic emissions can be considered comparable across HTS variants and in turn which HTS variants can be considered for data bridging. In addition, the study contextualizes these findings by comparing reduced toxic emissions profiles from the tested HTS to published emissions data from HTPs using different heating technologies, further informing the applicability of bridging across the broader HTP category. Together, these efforts aim to provide a foundational scientific basis for bridging emissions, whilst also considering the consistency of reduced exposure marker trends in clinical assessments across the broader HTP category, reinforcing the role of product design anchored in the heat-not-burn principle as the consistent driver of comparable reduced toxicant exposure and likely future reduced risk Together, these efforts aim to provide a foundational scientific basis for bridging emissions, whilst also considering the consistency of reduced exposure marker trends in clinical assessments across the broader HTP category. Materials and Methods 2.1 Combustible Cigarette and HTS Test Articles To study the properties of cigarette smoke and a consistent baseline for analysis, 1R6F reference combustible cigarettes were used (University of Kentucky, Lexington, KY, USA). 34 predominantly commercially available HTS consumables were evaluated, comprising 17 regular (tobacco), 8 non-menthol, and 9 menthol variants, representing a broad range of tobacco blends (manufacturer JTI). Two heating devices (referred to as Device A and Device B; marketed under the Ploom brand (manufacturer JTI) were used in this study. Both devices operate at temperatures below 400 o C, under the reported ignition temperature of tobacco and include a temperature control system which is designed to preserve the integrity of the heat-not-burn mechanism, ensuring consistent aerosol output through precisely regulated conditions [ 2 ]. The heating element is external to the HTS tobacco matrix, termed ‘outside heating’. To represent the diversity of thermal approaches in commercially available tobacco heating technologies, published aerosol chemistry data on devices employing blade [ 18 , 19 ], induction [ 17 , 20 ], and thin-film resistive [ 17 ] heating were used for comparisons (Fig. 1 ). For the physical measurements of aerosol droplet size in the present study, the induction heating-based device iQOS ILUMA, and its corresponding HTS consumable (TEREA) were used (manufacturer Philip Morris International SA). The device was operated according to the manufacturer instructions to ensure consistency and comparability with reported data. 2.2 Smoke/Aerosol Generation and Collection HTS and 1R6F combustible cigarettes were conditioned as recommended in the International Organization for Standardization (ISO) 3402:2023 [ 21 ]. HTS aerosol was generated by machine puffing using a modified 20778:2018 puffing regime [ 22 ] recently transposed into ISO 5501-1:2024 [ 23 ]. See Supplementary Materials (Table S1 ). 2.3 Chemical Analysis of Smoke and Aerosol Emissions The yields of 51 toxic emissions were determined in aerosols produced by the HTS in combination with Device A[1] or B and cigarette smoke from 1R6F combustible cigarettes. These analytes include constituents suggested for the characterization of cigarette smoke by the scientific community and adopted by regulatory bodies (WHO [ 24 ], US FDA [ 25 ], Health Canada [ 26 ]). The assessed analytes also included the parent constituents corresponding to established biomarkers of exposure associated with tobacco product use [ 27 ] and other constituents considered of interest in heated tobacco products emissions [ 8 , 9 ]. All analyte levels were determined from one batch of each HTS and tested in a minimum of three (max five) independent replicates. The mean and 95% confidence interval for each analyte is reported. A yield was considered below the detection limit (BDL) if the mean for three or five replicate analyses was below the limit of detection (LOD). A yield was classed as not quantified (NQ) if the mean for three or five replicate analyses was below the limit of quantification (LOQ) but above the LOD. All chemical and toxicological analyses were conducted at ISO 17025 accredited laboratories, methods described in Supplementary Materials (Table S2 ). 2.4 Physical Measurements (Particle/Droplet Release) To characterize the droplet size distribution of aerosols generated by HTS with Device A or B and particle size distribution of 1R6F cigarette smoke, a cascade impactor was employed (Mini-MOUDI 135 − 10, MSP Corporation). Operating under the ISO 20778:2018. The cascade impactor separated smoke/aerosol particles/droplets based on their aerodynamic diameters, allowing for a detailed characterization of the size distribution. Each sample was tested in six independent replicates. 2.5 In Vitro Toxicological Studies The Ames, ivMN, and NRU assays were conducted in general accordance with the relevant Organization for Economic Co-operation and Development (OECD) guidelines and Health Canada official methods as previously described (Hashizume et.al., 2023) [ 7 ], with some modifications. The assays were performed with 3 independent replicates using 3 independent batches of the HTS aerosol or 1R6F cigarette smoke extract samples. 2.5.1 Sample Preparation The HTS aerosols and 1R6F cigarette smoke were generated as described in Section 2.2 . The particulate phase and gas-vapor phase of the test item aerosols/smoke were separately extracted and used in the in vitro assays. 2.5.2 Ames Assay Mutagenicity was assessed using Ames assay with Salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA1537. A test sample was classified as mutagenic if the result showed a reproducible concentration-related increase in the number of revertants and a statistically significant, as well as at least two-fold for TA98, TA100, and TA102 and three-fold for TA1535 and TA1537 increase in the number of revertants against the solvent control at one or more test concentrations [ 28 ]. 2.5.3 In Vitro Micronucleus Assay Genotoxicity was assessed using ivMN assay with Chinese Hamster Ovary – Wolff–Bloom–Litton (CHO-WBL) cell line. with Chinese Hamster Ovary – Wolff–Bloom–Litton (CHO-WBL) cell line. A test sample was classified as genotoxic if it induced a reproducible concentration-related increase in the MN frequency, exceeded the historical solvent control range in the MN frequency, and showed a statistically significant increase in the MN frequency at one or more concentrations compared to the solvent control. 2.5.4 Neutral Red Uptake Assay Cytotoxicity was assessed using NRU assay performed with CHO-WBL cell line. Cell viability for each test sample treatment concentration was calculated as the relative absorbance to the solvent control. 2.6 Estimation of Comparability 2.6.1 Physical Measurements After the particle size measurements, the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of each sample were determined by fitting the data to a lognormal distribution, as described by the following equation: $$\:\frac{{\text{d}M}_{f}\left({d}_{p}\right)}{\text{d}\text{l}\text{n}{d}_{p}}=\frac{1}{\text{l}\text{n}\left(\text{G}\text{S}\text{D}\right)\sqrt{2{\pi\:}}}\text{e}\text{x}\text{p}\left[-\frac{{\left(\text{ln}\left({d}_{p}\right)-\text{l}\text{n}\left(\text{M}\text{M}\text{A}\text{D}\right)\right)}^{2}}{2{\left(\text{l}\text{n}\left(\text{G}\text{S}\text{D}\right)\right)}^{2}}\right]$$ ​where \(\:{M}_{f}\left({d}_{p}\right)\) is the normalized mass fraction and \(\:{d}_{p}\) is the particle aerodynamic diameter. In detail, the normalized mass fraction at each stage was divided by the logarithmic width of each stage, ∆lnD_50, which was computed from the midpoints of adjacent stage cut-off diameters. Then, a non-linear least squares fitting was performed using the curve fit function from the SciPy. Optimize library in Python to obtain the MMAD and GSD. 2.6.2 Percentage Reduction Calculations Aerosol Versus Reference Cigarette Smoke The quantification results of the analytes are reported per tobacco stick/cigarette. Each individual BDL result was replaced with half the LOD, and each individual NQ result was replaced with (LOD + LOQ) / 2. The reduction of toxic emissions produced by the regular, non-menthol, and menthol blend HTS versus 1R6F combustible cigarette was calculated using the following formula: Percent reduction = \(\:\frac{HTS\:mean\:-\:1R6F\:cigarette\:mean}{1R6F\:cigarette\:mean}x100\) In cases where HTS mean value fell below the limit of quantification (LOQ) of the analytical method, a conservative approach was adopted and LOQ provided instead of the arithmetic mean. In cases where the HTS mean was below the limit of detection (LOD) of the analytical method, the value of the LOD was used as mean. If an analyte was not quantified in 1R6F cigarette smoke (below LOQ), it was excluded from the yields comparison. Having data generated at two accredited laboratories, we compared the relative differences of results to 1R6F combustible cigarette data produced within the same laboratory to mitigate any discrepancies. 2.6.3 Comparability of Aerosol Emissions To evaluate the comparability in emissions reductions between the HTS aerosols, a statistical approach was employed using Horwitz-Thompson equations [ 29 ] to define comparability margins. This allows for the integration of cigarette-derived variability and measurement uncertainty into the comparison. Comparability was assessed using a two one-sided t-test (TOST) procedure, applying a 5% significance level on each side (Fig. 4 ). 2.6.4 In Vitro Toxicological Studies For Ames and ivMN assay, the mutagenic and genotoxic potencies were estimated by the slope of the linear portion of the concentration-response curve using a generalized linear model with a Poisson distribution for tested samples that gave positive mutagenic or genotoxic responses. For NRU assay, cytotoxic potency was expressed using the half maximal inhibitory concentration (IC 50 ) estimated from the concentration-response curve using the Hill function, a four-parameter logistic mathematical model, where the model was fit. 2.7 BoE Literature Analysis and Methodology for Data Aggregation BoE data obtained from a previously published study with Device A (Nishihara et al (2024)) was reviewed to verify that the reduction in toxic emissions from HTS compared to cigarettes is reflected in human clinical data [ 10 ]. A PubMedⓇ search ( https://www.ncbi.nlm.nih.gov/pubmed/ ) was conducted in May 2025 to identify studies reporting clinical data on BoE following HTP use compared to cigarette smoking, using the search terms (“heated tobacco” AND “biomarkers of exposure”). In addition, a comprehensive published review on BoE data following HTP use by smokers (Akiyama & Sherwood, (2021)) was mined for relevant references [ 30 ]. Inclusion criteria were studies written in English, publications reporting data from randomized control trials assessing changes in BoE levels following HTP use compared to cigarette smoking, and presentation of original data. Data reported in relevant studies was tabulated for analysis as percentage change in BoE levels compared to baseline. For each biomarker, the mean percent change from baseline (with 95% confidence interval) was determined using the percentage changes for products in the same category, as reported within the selected publications. The averaged percent change for Nishihara et al (2024) was superimposed for visual comparability. Results 3.1 Size of HTS Aerosol Droplets and Cigarette Smoke Particles Across the 34 HTS test articles (with aerosols generated by Device A and B), a commercially available induction heating HTP comparator and combustible cigarette smoke, the median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the HTS aerosols and cigarette smoke were comparable, with all values falling within the respirable range (< 2.5 µm; Supplementary Materials (Table S3 )). 3.2 Reductions in Levels of Toxic Emissions from HTS Aerosols Compared to Cigarette Smoke Results showed substantial reductions in the levels of 51 toxic emissions across all 34 assessed regular, non-menthol, and menthol blend HTS, compared to cigarette smoke, whether using Device A or B (Fig. 2 A and B and raw data provided in Supplementary Material 6). On a per unit basis, levels of toxic emissions were consistently lower, with reductions ranging from at least 64% to over 99%, depending on the specific analyte measured. These reductions were consistently observed across the diverse set of HTS variants assessed, highlighting the comparability of emission reductions regardless of HTS product features such as blend, additives or device design [ 17 – 20 ]. As shown in the consolidated results in Fig. 2 C, the use of Device A or Device B did not result in any meaningful difference in the mean percentage reduction for the toxic emissions analyzed. Figure 3 presents the mean percentage reduction in 51 toxic emissions across the 34 HTS relative to combustible cigarette smoke. Fourteen analytes (indicated with triangles) were consistently below the LOD or LOQ for both Device A and Device B. This group includes two analytes from the WHO Tobacco Regulation Study Group (TobReg) 9 list of priority toxicants (1,3-butadiene and carbon monoxide) [ 24 ], underscoring the potential for meaningful reductions in exposure. Seventeen analytes (indicated with squares) were below LOD or LOQ in some, but not all, of the HTS tested, while the remaining 20 analytes (indicated with circles) were consistently quantifiable across all HTS aerosols. For these quantifiable analytes, the standard deviation of mean values was low, reflecting reproducibility of reductions across products. Even in cases where variability was observed, the reductions relative to cigarette smoke remained substantial. Figure 4 further confirms this pattern. Toxic emissions reduction values were tightly clustered around the median, demonstrating a high level of consistency across HTS aerosols. Statistical analysis showed that reductions were of comparable magnitude between Device A and Device B, with all values falling within an acceptable and scientifically relevant range. 3.3 Reductions in Levels of Toxic Emissions Across Heated Tobacco Technologies A comparative analysis of HTS aerosols demonstrated that heated tobacco technologies, regardless of the heating mechanism employed, yield substantial reductions in toxic emissions relative to combustible cigarette smoke. Mean percentage reductions ranged from 62.47–99.98% for Device A, 69.29–99.9% for Device B, 51.2-99-9% for iQOS induction heating technology and 51.61–99.9% for iQOS blade heating technology. Table 1 Comparison of percentage reductions in toxic emissions relative to reference cigarette smoke (1R6F or 3R4F), based on published data for induction heating, blade heating technologies or other heating technologies. Percent reductions are not shown when the yields of the analyte in the aerosol from the 34 HTSs in combination with Device A or B are always below the limit of detection (LOD) or limit of quantification (LOQ). Analyte (Smoke/ Aerosol) Mean % Reduction HTP Aerosol (Device A) vs. 1R6F Cigarette Smoke Mean % Reduction HTP Aerosol (Device B) vs. 1R6F Cigarette Smoke Mean % Reduction HTP Aerosol vs. 1R6F Cigarette Smoke [This Study] Reported Data on iQOS™ Induction Heating Technology [ 20 ] HTS regular / HTS menthol Reported Data on iQOS™ Blade Heating Technology [ 18 , 19 ] HTS regular / HTS menthol Reported Data glo™ Original Thin-Film Resistive Heating Technology [ 17 ] Reported Data glo™ Hyper Induction Heating Technology (Standard Mode Operation) [ 17 ] Reported Data glo™ Hyper Induction Heating Technology (Boost Mode Operation) [ 17 ] 1-Aminonaphthalene 99.57 99.85 99.62 99.9 / 99.9 > 99.85 / 99.85 - - - 2-Aminonaphthalene 99.91 99.90 99.91 99.9 / 99.9 > 99.9 / 99.9 - - - 3-Aminobiphenyl 99.85 99.85 99.85 99.8 / 99.8 99.7* - - - 4-Aminobiphenyl 99.62 99.68 99.63 99.6 / 99.6 99.72 / 99.64 - - - Acetaldehyde 92.97 93.71 93.09 89.5 / 87.9 88.49 / 88.36 94.0 91.4 91.3 Acetamide 82.11 85.65 82.68 83.8 / 84.7 73.33 / 73.9 - - - Acetone 97.89 98.18 97.94 95.4 / 95.5 95.48 / 95.34 - - - Acrolein 98.16 98.14 98.16 94.4 / 94.6 94.8 / 94.71 98.5 98.1 98.4 Acrylamide 65.30 69.29 65.95 79.2 / 78.2 62.12 / 58.43 - - - Ammonia 74.17 78.40 74.86 51.2 / 65.6 58.55 / 57.79 - - - Arsenic 78.22 71.21 77.09 89.7 / 90.6 > 85.42 / >85.42 - - - 1,3-butadiene 99.79 99.57 99.76 99.9 / 99.9 99.75 / 99.71 > 99.9 > 99.9 > 99.9 Benzene 99.86 99.77 99.85 99.5 / 99.4 99.42 / 99.32 > 99.9 99.9 99.9 Benz[a]anthracene 93.97 96.54 94.38 95.7 / 94.7 91.41 / 93.72 - - - Benzo(a)pyrene 95.01 96.90 95.31 96.2 / 95.5 93.13 / 95.63 > 97.4 > 97.8 > 98.4 Butyraldehyde 89.50 90.06 89.59 81.5 / 77.2 75.6* - - - Catechol 88.48 88.88 88.55 88.1 / 87.8 86.85 / 87.05 - - - Crotonaldehyde 94.31 97.94 94.90 92.9 / 92.9 > 94.04 / 94.04 - - - Carbon monoxide 99.20 99.10 99.18 99.1 / 99.2 > 99.78 / >99.78 > 99.5 > 99.3 99.1 Formaldehyde 95.52 97.21 95.80 90.9 / 91.1 89.89 / 89.06 95.2 95.2 95.8 Hydroquinone 96.75 96.19 96.66 91.4 / 92.2 91.9* - - - Lead 94.35 91.43 93.88 98.3 / 98.3 NA / NA - - - Mercury 62.47 72.83 64.14 72.7 / 68.0 51.61 / 56.88 - - - Methyl Ethyl Ketone 97.29 97.92 97.39 97.0 / 96.0 96.15 / 96.14 - - - NAB 82.09 86.70 82.84 88.9 / 89.1 93.6* - - - NAT 84.57 89.16 85.31 93.3 / 93.6 94.8* - - - NNK 94.14 94.97 94.27 95.5 / 96.2 96.12 / 97.02 96.8 95.9 97.8 NNN 90.64 93.20 91.05 95.0 / 96.7 94.51 / 96.57 87 83.5 88.7 NO 99.22 99.24 99.22 97.3 / 97.8 97.3* - - - NOx 99.14 99.21 99.15 97.3 / 97.8 97.5* - - - o-Cresol 99.23 98.93 99.18 99.0 / 98.8 98.91 / 98.88 - - - o-Toluidine 99.63 99.59 99.62 99.1 / 99.1 98.97 / 98.97 - - - Phenol 98.62 98.21 98.56 94.3 / 93.5 93.47 / 94.36 - - - Propionaldehyde 95.17 95.59 95.23 91.3 / 90.2 90.24 / 90.08 - - - Pyrene 91.69 95.29 92.27 93.9 / 93.0 - - - - Pyridine 92.61 93.09 92.69 83.9 / 84.0 79.3* - - - Selenium 66.45 72.29 67.39 80.8 / 80.8 NA / NA - - - Styrene 99.46 99.29 99.44 97.9 / 97.7 97.48 / 97.42 - - - Toluene 99.82 99.76 99.81 98.9 / 98.8 99.02 / 98.85 - - - Maximum device heating temperature (°C ) ≤ 320 350 350 240 250 260 * Levels for these analytes were referred to former publication on Tobacco heating System 2.2 (THS 2.2) [ 19 ] Further assessment of heated tobacco products using alternative heating technologies, including published data on glo thin-film resistive heating and glo induction (in standard and boost modes)[17], and both blade and induction variants of iQOS, revealed comparable reductions in the WHO Tobacco Product Regulation Study Group (TobReg) 9 priority toxicants (Table 1). Across all evaluated heating technologies with published datasets, the overall reduction in these priority toxicants ranged from 96.47% for glo thin-film resistive heating, 95.67% for glo induction standard mode, 96.59% for glo induction boost mode, 95.10% for iQOS blade heating, 95.56% for iQOS induction heating, and 96.27% for the outside heating evaluated in this study. The reported maximum heating temperatures of the devices ranged from 240-350 o C. 3.4 In Vitro Biological Activity Twenty-three HTS test items, representing different stick consumable varieties (regular, non-menthol, and menthol blends) in combination with two different devices (Device A and B), were assessed alongside the 1R6F cigarette. Both particulate phase (aerosol collected mass (ACM); HTS or total particulate matter (TPM); cigarette smoke) and the gas-vapor phase (GVP) samples from the HTS aerosols and cigarette smoke were evaluated. 3.4.1 Ames Assay (Mutagenicity Assessment) Detailed results for each individual HTS test item and 1R6F cigarette are provided in Supplementary Materials (Table S4-S5). The ACM and GVP samples from all HTS test items showed non-mutagenic responses under the test conditions. In contrast, the TPM sample from 1R6F cigarette induced clear and reproducible mutagenic responses in strains TA98 and TA1537 under + S9 conditions, while the GVP samples showed non-mutagenic responses under the test conditions. Due to the absence of mutagenic activity of the HTS test items, a direct comparative analysis with 1R6F cigarette was not pursued. 3.4.2 In Vitro Micronucleus Assay (Genotoxicity Assessment) Genotoxic potential was evaluated using the ivMN assay under the three treatment conditions: 3 h exposure without metabolic activation (Short -S9), a 3 h exposure with metabolic activation (short + S9), and 30 h exposure without metabolic activation (Long -S9). Detailed results, including genotoxicity assessments and genotoxic slope values for each HTS test item and 1R6F cigarette, are provided in Supplementary Materials (Table S6). Most HTS samples were classified as genotoxic in at least one treatment schedule. However, several HTS samples, irrespective of HTS stick blend or device, did not induce statistically significant increases in MN frequency compared to solvent controls, and were therefore assessed as non-genotoxic under the test conditions. These inconsistencies are likely attributable to inherent biological variability associated with ivMN assay. Such variability may influence whether a weak response meets or fails to meet all genotoxicity evaluation criteria required for a positive call, especially in borderline cases. In contrast, both TPM and GVP samples from 1R6F cigarettes demonstrated clear genotoxicity under all treatment conditions. Notably, the tested concentrations of the HTS test items were approximately 6- to 10-fold higher than those tested for the 1R6F cigarette. Overall, the genotoxic activity of HTS test items was reduced by 90–98% for ACM samples and from 86–96% for the GVP samples, relative to the 1R6F cigarette (See Supplementary Materials (Figure S1)). Across the stick types, the percentage reduction in genotoxic activity relative to 1R6F cigarette was consistent and comparable (Figure S1A, C, and E). Likewise, no significant differences were observed between the two device datasets (Figure S1B, D, and F). 3.4.3 Neutral Red Uptake Assay (Cytotoxicity Assessment) Cytotoxicity was evaluated using NRU assay. IC 50 values for each test sample from individual HTS test items and 1R6F cigarette are provided and compared in Supplementary Materials (Table S7 and Figure S2). The ACM samples from the individual HTS test items showed an 86–94% reduction in cytotoxicity compared to 1R6F cigarette TPM sample. Similarly, the GVP samples from the HTS test items demonstrated at least 93% reduction in cytotoxicity compared to the 1R6F cigarette GVP sample. These reductions in cytotoxic potential were consistent and comparable across all three HTS stick types (regular, non-menthol, and menthol; Figure S2A) and between Device A and B (Figure S2B). 3.5 Trends in Reduced Biomarkers of Exposure and Reduced Toxic Emissions in Aerosols Biomarkers of exposure (BoE) provide a direct measure of user exposure to select substances that are quantifiable in HTP aerosols [27, 31]. Clinical assessments consistently demonstrate, independently of differences in HTP designs or characteristics, adults who smoke and who switch away from combustible cigarettes to HTP experience substantial and sustained reductions in BoEs relative to continuing to smoke [10, 14]. Moreover, the magnitude of these reductions is typically not dissimilar to those observed following smoking cessation, reinforcing the relevance of BoEs as indicators of reduced toxic emissions exposure. Previous clinical data for outside heating technology (Device A) demonstrated substantial reductions in exposure to select toxic emissions after five days of complete switching from combustible cigarettes [10]. Across 15 commonly assessed BoEs, reductions relative to continued smoking ranged from 22.9–96.6%. To contextualize these findings, a pooled analysis of published clinical studies reporting data on the same 15 BoEs following HTP use among adult smokers across 25 studies, covering exposure durations from five days to one year and encompassing a range of heating technologies was conducted in the present study (see Supplementary Materials (Table S8)) for information on the included studies) [10–15, 27, 31–48]. The pooled results, represented as average percent change from baseline, indicate consistent reductions in BoEs at the HTP category level ranging from 44.6–93.9%, irrespective of device design, study duration, or study location (Fig. 5). Notably, studies conducted in Japan, United States, Poland and Germany all reported comparable reductions in BoEs among adult smokers randomized to use HTP, with effect sizes remaining within a narrow range despite differences in study populations and regulatory environments (Table S8). As illustrated in Fig. 5, the trajectory of BoE reductions from baseline observed with outside heating technology (Device A), ranging from 36.2–96.8%, closely aligns with overall HTP category BoE trends. Discussion This study evaluated the hypothesis that adherence to the core principle of heating rather than burning tobacco consistently yields substantially lower levels of toxic emissions that are comparable across HTPs, irrespective of differences in product design, tobacco blend, additive composition, or heating technology, thereby providing a foundational scientific basis for bridging datasets across the HTP category based on the comparability of reduced toxic emissions within a statistically acceptable range. To assess this, 34 HTS variants were evaluated for levels of toxicant emissions and, for a subset of HTS, the resulting in vitro biological activity response. Across all products, emissions of 51 toxic emissions were substantially reduced (average of 93.6%) compared to cigarette smoke. A proposed statistical analysis approach confirmed that the reductions fell within an acceptable range of comparability. Despite technological diversity, these findings aligned with published data from other commercial HTPs (Table 1 ), reinforcing reproducibility and reliability of toxic emissions reductions at the category level [ 17 – 20 ]. The biological relevance of these toxic emissions reductions was confirmed through three standard in vitro assays. For the subset of tested products, HTS was non-mutagenic in the Ames assay under the test conditions, contrasting with the mutagenic response observed for cigarette smoke particulate matter. Genotoxicity, as measured by the in vitro micronucleus (ivMN) assay, was reduced by 86–98%, and cytotoxicity, assessed via the neutral red uptake (NRU) assay, was reduced by 86–94%. These consistent reductions in biological activity indicate that reduced toxic emission yields translate into a meaningful reduction in toxicological risk potential. These findings confirm that comparable reductions in toxic emissions and toxicological activity are functionally relevant and attributable to the shared design principle of avoiding combustion. This shared mechanism serves as the foundation for considering data bridging across HTPs [ 16 ]. In parallel, aerosol particle size distribution was also measured to exclude differences in delivery efficiency as a confounding factor. HTS produced aerosols with mass median aerodynamic diameters (MMADs) below 2.5 µm, confirming respirability. These values were comparable to a commercial HTP comparator and combustible cigarette smoke, indicating observed reductions in toxicological activity can be attributed to differences in aerosol chemistry, not delivery characteristics or deposition efficiency. Biomarkers of exposure (BoE) provide a direct and quantitative measure of exposure to harmful substances and are closely linked to the levels of toxic emissions present in product aerosol. Given that all HTPs operate on the same fundamental principle of heating rather than burning tobacco, they consistently generate substantially lower emissions than combustible cigarettes. Therefore, it follows that BoE trends are expected to align at the product-category level, independent of individual device design, tobacco blend, or additives. Consistent with the published literature, complete switching away from combustible cigarettes to HTPs leads to substantial reductions in BoE, with reductions for outside heating technology (Device A) ranging from 36.2–96.8% compared to baseline after five days of HTP use among adult smokers [ 10 – 14 ]. When considered alongside the pooled data from 25 published studies across different heating technology devices, exposure durations and geographies, a clear pattern emerges: BoE reductions cluster at the HTP category level with reductions achieved with outside heating technology reflecting the broader category effect rather than being device specific. Importantly, this pattern is reinforced by aerosol chemistry. Comparability of reduced toxic emissions (Fig. 4 ) leads to BoE readouts that sit within category-level trends (Fig. 5 ), indicating that similarities in aerosol toxic emissions translate into consistent user exposure reductions across different heating technologies. The mechanistic basis for this consistency lies in the absence of combustion across all HTPs, which eliminate or markedly reduce the formation of many harmful substances that are characteristic of cigarette smoke. Thus, while heating technologies may vary in design, the fundamental absence of combustion provides a unifying explanation for comparable reductions in toxic emissions in product aerosols and the corresponding reproducible reductions in user exposure. The results from this study support the use of bridging approaches that link product-specific toxic emissions and toxicology data with the broader evidence base on BoE across HTP products. As such, consistency in thermal operations provides a scientific foundation for assessing the comparability of reduced toxic emissions and bridging datasets across HTPs, independently of individual HTP design provided the core thermal principle is maintained, supported by the broader HTP category-level clinical outcomes data. Bridging of emissions and toxicology datasets is a well-established scientific and regulatory practice. Frameworks such as the European Chemicals Agency’s (ECHA) read-across strategy and the UK Medicines and Healthcare products Regulatory Agency (MHRA)’s guidance on representative e-cigarette submissions endorse the use of representative data where comparability can be scientifically justified [ 49 , 50 ]. Across all HTS tested in the present study, toxic emissions and in vitro responses were consistently and substantially lower than those of combustible cigarettes, with a proposed statistical analysis approach confirming the comparability of toxic emissions reductions. Comparability of reduced toxic emissions also leads to BoE readouts that sit within category-level trends. Overall, these findings provide a scientific rationale for applying bridging assessments across HTP innovations based on demonstrating the comparability of reduced toxic emissions. This work lays the foundation for integrating product-specific HTP emissions data with broader, product-agnostic epidemiological data to assess long-term population health outcomes in the future. Abbreviations Heated Tobacco Products (HTP), Heated Tobacco Stick (HTS), Aerosol Collected Matter (ACM), Gas Vapour Phase (GVP), Below the Detection Limit (BDL), Limit of Detection (LOD), Limit of Quantification (LOQ), Not Quantified (NQ), In Vitro Micronucleus (ivMN), Neutral Red Uptake (NRU), Total Particulate Matter (TPM), Mass Median Aerodynamic Diameter (MMAD), Geometric Standard Deviation (GSD), Two One-Sided T-test (TOST), European Chemical Agency (ECHA), UK Medicines and Healthcare products Regulatory Agency (MHRA), Horwitz-Thompson Margins (HT Margins), Organization for Economic Co-operation and Development (OECD), Chinese Hamster Ovary – Wolff–Bloom–Litton (CHO-WBL), Biomarkers of Exposure (BoE). BRIEFS (Word Style “BH_Briefs”). If you are submitting your paper to a journal that requires a brief, provide a one-sentence synopsis for inclusion in the Table of Contents. SYNOPSIS (Word Style “SN_Synopsis_TOC”). If you are submitting your paper to a journal that requires a synopsis, see the journal’s Instructions for Authors for details. Declarations ACKNOWLEDGMENT The authors are grateful for the staff of Labstat International Inc, and Oekolab GmbH. for providing professional technical assistant for the study. The authors also thank Dr. Ian Jones, Dr. Javier Martinez, Dr Takashi Sekine, Dr Christelle Bonnet and Ricardo Magana for their critical review of the manuscript. ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author J. MILLER-HOLT 1 [email protected] JTI SA, 8 rue Kazem Radjavi, 1202 Geneva, Switzerland, [email protected] Author Contributions J. MILLER-HOLT: Supervision, funding acquisition, conceptualization, methodology, data curation, formal analysis, writing – original draft, review & editing G. O’CONNELL: conceptualization, methodology, formal analysis, writing-original draft, review & editing R. BACH: project administration, data acquisition, validation & visualization, writing – review & editing M. CHARRIERE: project administration, Statistical analysis, data acquisition, validation & visualization, writing – review & editing Y. KANEMARU: project administration, data acquisition, validation & visualization, writing – review & editing Z. SU: project administration, data acquisition, validation & visualization, writing – review & editing S. LARROQUE: project administration, Statistical analysis, data acquisition, validation & visualization, writing – review & editing K. JACOBSON: project administration, writing – review & editing Funding Sources This research was sponsored by JTI SA and Japan Tobacco Inc. (JT). References Baker, R.R. Product formation mechanisms inside a burning cigarette . Prog Energy Combust Sci 1981 , 7 (2), p. 135-153. DOI: 10.1016/0360-1285(81)90008-3. 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Guidance Chapter 3 - emissions from electronic cigarettes - GB, 2022, last updated 16 August 2024, https://www.gov.uk/government/publications/chapter-3-emissions-guidance-great-britain/chapter-3-emissions-from-electronic-cigarettes-gb Footnotes Device A refers to minor incremental versions of the same device, with the maximum heating temperature of each not exceeding 320°C Supplementary Files SupplementaryMaterialsTableS1toS50909.docx Supplementarymaterial6Rawdata34sticks1R6F.xlsx Cite Share Download PDF Status: Published Journal Publication published 29 Oct, 2025 Read the published version in Internal and Emergency Medicine → Version 1 posted Reviewers agreed at journal 16 Sep, 2025 Reviewers invited by journal 15 Sep, 2025 Editor assigned by journal 10 Sep, 2025 First submitted to journal 08 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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15:11:02","extension":"html","order_by":56,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":349784,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7520219/v1/276ffc8462a2587035816aef.html"},{"id":92004747,"identity":"bd6026b0-5510-48fe-a475-3abf7360f2e4","added_by":"auto","created_at":"2025-09-23 15:03:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":226064,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSchematic comparing different tobacco heating technologies: external heating, blade heating, induction heating, and thin-film resistive heating with corresponding heated tobacco consumable stick (depicted as a brown/gold cylinder) placement and direction of aerosol emissions release.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7520219/v1/897cd1436ccbc2a19f4d942a.png"},{"id":92004748,"identity":"7d42a59c-5adf-400d-a40d-cadf687f2b7b","added_by":"auto","created_at":"2025-09-23 15:03:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1186855,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePercentage reduction in toxic emissions for [A] Regular blend HTS with Device A and Device B; [B] Non-menthol blend HTS with Device A and Device B; and [C] Menthol, non-menthol, and regular HTS blends with Device A and non-menthol and regular blend HTS with Device B. Reductions are calculated relative to combustible cigarette smoke for comparable analytes on a per-unit basis.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7520219/v1/ba716ffd3540b5ea8f82d54f.png"},{"id":92005910,"identity":"50c9bb41-59b4-4f05-ab70-2fc1c0fbec9a","added_by":"auto","created_at":"2025-09-23 15:11:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":5218348,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of mean reductions in toxic emissions for 34 HTS test articles using Device A and B compared to combustible cigarette smoke. Bar at 100% represents the 1R6F reference cigarette with values representing the average percentage of the 1R6F reference cigarette level across the measured analytes on a per-unit basis. Error bars indicate the standard deviation of pooled percentage.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7520219/v1/9fb1593d8804b15e84a6891d.png"},{"id":92004764,"identity":"bc735158-94be-4a59-85ce-cc6fe2d3a456","added_by":"auto","created_at":"2025-09-23 15:03:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4068711,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStatistical comparability testing (two-one-sided t-tests [TOST], 5% level) of the difference in the 51 toxic emission reductions relative to 1R6F cigarette smoke for HTS assessed with Device A and Device B. Point estimates and 90% confidence intervals within Horwitz-Thompson (HT) margins\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7520219/v1/aad8406b4211c0e36f4705f8.png"},{"id":92008043,"identity":"bb0e800c-d115-4bc1-8614-f13202c1557e","added_by":"auto","created_at":"2025-09-23 15:27:01","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":4352919,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eConsistency of biomarkers of exposure reductions: Outside Heating (Device A) in the context of category-level HTP data.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBars represent mean percentage reductions from baseline with 95% confidence intervals for each BoE among adult smokers randomized to use HTP. Category-level reductions (grey bars) are derived from a pooled analysis of 25 published studies. Number of individual study entries per biomarker are shown in text (\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e=). Results for outside heating technology (Device A/Nishihara et al., (2024)) overlaid in green bars in comparison with the HTP category trends. Acronyms for BoEs with corresponding parent compound in aerosol: 1-AN, 1-Aminonaphthalene (1-Aminonaphthalene); 2-AN, 2-Aminonaphthalene (2-Aminonaphthalene); 3-HMPMA, 3-hydroxy-3-methylpropylmercapturic acid (crotonaldehyde); 3-HPMA, 3-hydroxypropyl-mercapturic acid (acrolein); 3-OH-BaP, 3-hydroxy-benzo[a]pyrene (benzo[a]pyrene); 4-ABP, 4-Aminobiphenyl (4-Aminobiphenyl); CEMA, 2-cyanoethylmercapturic acid (acrylonitrile); HEMA, 2-hydroxyethyl-mercapturic acid (ethylene oxide); MHBMA, monohydroxybutenyl-mercapturic acid (1,3-butadiene); S-PMA, S-phenylmercapturic acid (benzene); Total 1-OHP, Total 1-hydroxypyrene (pyrene); Total NNAL, Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK]); Total NNN, Total N-nitrosonornicotine (N-nitrosonornicotine [NNN]); eCO, exhaled carbon monoxide (carbon monoxide); o-Tol, o-Toluidine (o-Toluidine).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7520219/v1/9749f5ff864c212fa442fcb7.png"},{"id":95041394,"identity":"84970ccc-cb9b-4ddf-b3cd-49e0ae7e1ca4","added_by":"auto","created_at":"2025-11-03 16:11:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":17977363,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7520219/v1/a123206a-4deb-41fa-872f-376d895319ad.pdf"},{"id":92006326,"identity":"849511d6-4b01-4607-a09d-2df6c87f1ed6","added_by":"auto","created_at":"2025-09-23 15:19:01","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2798748,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterialsTableS1toS50909.docx","url":"https://assets-eu.researchsquare.com/files/rs-7520219/v1/afdc1e9f6694d01bb8bad220.docx"},{"id":92004751,"identity":"fb9ed3aa-e6cc-43e3-b717-fcb351032b96","added_by":"auto","created_at":"2025-09-23 15:03:01","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":45214,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial6Rawdata34sticks1R6F.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7520219/v1/88575a361753f9df28f48eca.xlsx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAssessing the comparability of toxic emissions reduction from heated tobacco aerosols relative to cigarette smoke: a scientific approach to bridging datasets\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCombustion of tobacco, which occurs at temperatures exceeding 400\u0026deg;C and can reach up to 950\u0026deg;C, produces a chemically complex mixture (smoke) containing thousands of constituents, including numerous toxicants known to be carcinogenic or harmful to respiratory and cardiovascular health [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Epidemiological data confirm that the health risks of smoking are driven by sustained and long-term exposure to these primarily combustion-derived toxicants [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTechnological innovation has led to the development of non-combustible nicotine products such as heated tobacco products (HTPs), which aim to reduce exposure to toxic emissions by eliminating combustion [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. HTPs heat tobacco through controlled thermal processes that produce a respirable aerosol via evaporation and distillation rather than combustion [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. As a result, they do not generate carbonaceous solid particles and deliver nicotine-containing aerosols that are chemically less complex and substantially lower in toxicant content than combustible cigarette smoke [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHTPs also maintain many behavioral and sensory aspects of the cigarette smoking experience such as inhalation, hand-to-mouth action, thereby supporting their adoption by adults who smoke as a potentially less harmful alternative. Clinical studies show that switching to HTPs consistently results in marked and sustained reductions in biomarkers of exposure (BoE) to select toxic emissions, including known carcinogens and cardiovascular and pulmonary toxicants [\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These exposure reductions have been shown to be further associated with favorable changes in biomarkers with predictive validity for several smoking-related diseases across the HTP category [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAs such, there is growing scientific and regulatory interest in whether toxic emissions from one HTP can be used to support assessments of others, provided comparability can be demonstrated, through an approach known as bridging [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe present study was designed to assess whether the heat-not-burn mechanism yields comparable reductions in toxic emissions and toxicological responses across a wide range of heated tobacco stick (HTS) variants. Emissions of 51 select toxicants were quantified across 34 HTS variants and compared to levels in combustible cigarette smoke. For a subset of HTS, \u003cem\u003ein vitro\u003c/em\u003e toxicological responses were assessed. A statistical methodology is proposed to assess the comparability of reduced toxic emissions thereby enabling an analysis of the extent to which reduced toxic emissions can be considered comparable across HTS variants and in turn which HTS variants can be considered for data bridging. In addition, the study contextualizes these findings by comparing reduced toxic emissions profiles from the tested HTS to published emissions data from HTPs using different heating technologies, further informing the applicability of bridging across the broader HTP category. Together, these efforts aim to provide a foundational scientific basis for bridging emissions, whilst also considering the consistency of reduced exposure marker trends in clinical assessments across the broader HTP category, reinforcing the role of product design anchored in the heat-not-burn principle as the consistent driver of comparable reduced toxicant exposure and likely future reduced risk\u003c/p\u003e\u003cp\u003eTogether, these efforts aim to provide a foundational scientific basis for bridging emissions, whilst also considering the consistency of reduced exposure marker trends in clinical assessments across the broader HTP category.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Combustible Cigarette and HTS Test Articles\u003c/h2\u003e\u003cp\u003eTo study the properties of cigarette smoke and a consistent baseline for analysis, 1R6F reference combustible cigarettes were used (University of Kentucky, Lexington, KY, USA).\u003c/p\u003e\u003cp\u003e34 predominantly commercially available HTS consumables were evaluated, comprising 17 regular (tobacco), 8 non-menthol, and 9 menthol variants, representing a broad range of tobacco blends (manufacturer JTI). Two heating devices (referred to as Device A and Device B; marketed under the Ploom brand (manufacturer JTI) were used in this study. Both devices operate at temperatures below 400\u003csup\u003eo\u003c/sup\u003eC, under the reported ignition temperature of tobacco and include a temperature control system which is designed to preserve the integrity of the heat-not-burn mechanism, ensuring consistent aerosol output through precisely regulated conditions [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The heating element is external to the HTS tobacco matrix, termed \u0026lsquo;outside heating\u0026rsquo;.\u003c/p\u003e\u003cp\u003eTo represent the diversity of thermal approaches in commercially available tobacco heating technologies, published aerosol chemistry data on devices employing blade [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], induction [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and thin-film resistive [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] heating were used for comparisons (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e). For the physical measurements of aerosol droplet size in the present study, the induction heating-based device iQOS ILUMA, and its corresponding HTS consumable (TEREA) were used (manufacturer Philip Morris International SA). The device was operated according to the manufacturer instructions to ensure consistency and comparability with reported data.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Smoke/Aerosol Generation and Collection\u003c/h2\u003e\u003cp\u003eHTS and 1R6F combustible cigarettes were conditioned as recommended in the International Organization for Standardization (ISO) 3402:2023 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. HTS aerosol was generated by machine puffing using a modified 20778:2018 puffing regime [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] recently transposed into ISO 5501-1:2024 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. See Supplementary Materials (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Chemical Analysis of Smoke and Aerosol Emissions\u003c/h2\u003e\u003cp\u003eThe yields of 51 toxic emissions were determined in aerosols produced by the HTS in combination with Device A[1]\u003ca class=\"FNLink\" href=\"#Fn1\" id=\"#FNLinkFn1\"\u003e\u003c/a\u003e or B and cigarette smoke from 1R6F combustible cigarettes. These analytes include constituents suggested for the characterization of cigarette smoke by the scientific community and adopted by regulatory bodies (WHO [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], US FDA [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], Health Canada [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]). The assessed analytes also included the parent constituents corresponding to established biomarkers of exposure associated with tobacco product use [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] and other constituents considered of interest in heated tobacco products emissions [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAll analyte levels were determined from one batch of each HTS and tested in a minimum of three (max five) independent replicates. The mean and 95% confidence interval for each analyte is reported. A yield was considered below the detection limit (BDL) if the mean for three or five replicate analyses was below the limit of detection (LOD). A yield was classed as not quantified (NQ) if the mean for three or five replicate analyses was below the limit of quantification (LOQ) but above the LOD.\u003c/p\u003e\u003cp\u003eAll chemical and toxicological analyses were conducted at ISO 17025 accredited laboratories, methods described in Supplementary Materials (Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Physical Measurements (Particle/Droplet Release)\u003c/h2\u003e\u003cp\u003eTo characterize the droplet size distribution of aerosols generated by HTS with Device A or B and particle size distribution of 1R6F cigarette smoke, a cascade impactor was employed (Mini-MOUDI 135\u0026thinsp;\u0026minus;\u0026thinsp;10, MSP Corporation). Operating under the ISO 20778:2018. The cascade impactor separated smoke/aerosol particles/droplets based on their aerodynamic diameters, allowing for a detailed characterization of the size distribution. Each sample was tested in six independent replicates.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 \u003cem\u003eIn Vitro\u003c/em\u003e Toxicological Studies\u003c/h2\u003e\u003cp\u003eThe Ames, ivMN, and NRU assays were conducted in general accordance with the relevant Organization for Economic Co-operation and Development (OECD) guidelines and Health Canada official methods as previously described (Hashizume et.al., 2023) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], with some modifications. The assays were performed with 3 independent replicates using 3 independent batches of the HTS aerosol or 1R6F cigarette smoke extract samples.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\u003ch2\u003e\u003cb\u003e2.5.1 Sample Preparation\u003c/b\u003e\u003c/h2\u003e\u003cp\u003eThe HTS aerosols and 1R6F cigarette smoke were generated as described in Section \u003cspan refid=\"Sec4\" class=\"InternalRef\"\u003e2.2\u003c/span\u003e. The particulate phase and gas-vapor phase of the test item aerosols/smoke were separately extracted and used in the \u003cem\u003ein vitro\u003c/em\u003e assays.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003e2.5.2 Ames Assay\u003c/h2\u003e\u003cp\u003eMutagenicity was assessed using Ames assay with \u003cem\u003eSalmonella typhimurium\u003c/em\u003e strains TA98, TA100, TA102, TA1535, and TA1537. A test sample was classified as mutagenic if the result showed a reproducible concentration-related increase in the number of revertants and a statistically significant, as well as at least two-fold for TA98, TA100, and TA102 and three-fold for TA1535 and TA1537 increase in the number of revertants against the solvent control at one or more test concentrations [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\u003ch2\u003e2.5.3 \u003cem\u003eIn Vitro\u003c/em\u003e Micronucleus Assay\u003c/h2\u003e\u003cp\u003eGenotoxicity was assessed using ivMN assay with Chinese Hamster Ovary \u0026ndash; Wolff\u0026ndash;Bloom\u0026ndash;Litton (CHO-WBL) cell line. with Chinese Hamster Ovary \u0026ndash; Wolff\u0026ndash;Bloom\u0026ndash;Litton (CHO-WBL) cell line. A test sample was classified as genotoxic if it induced a reproducible concentration-related increase in the MN frequency, exceeded the historical solvent control range in the MN frequency, and showed a statistically significant increase in the MN frequency at one or more concentrations compared to the solvent control.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\u003ch2\u003e2.5.4 Neutral Red Uptake Assay\u003c/h2\u003e\u003cp\u003eCytotoxicity was assessed using NRU assay performed with CHO-WBL cell line. Cell viability for each test sample treatment concentration was calculated as the relative absorbance to the solvent control.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e2.6 Estimation of Comparability\u003c/h2\u003e\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\u003ch2\u003e2.6.1 Physical Measurements\u003c/h2\u003e\u003cp\u003eAfter the particle size measurements, the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of each sample were determined by fitting the data to a lognormal distribution, as described by the following equation:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:\\frac{{\\text{d}M}_{f}\\left({d}_{p}\\right)}{\\text{d}\\text{l}\\text{n}{d}_{p}}=\\frac{1}{\\text{l}\\text{n}\\left(\\text{G}\\text{S}\\text{D}\\right)\\sqrt{2{\\pi\\:}}}\\text{e}\\text{x}\\text{p}\\left[-\\frac{{\\left(\\text{ln}\\left({d}_{p}\\right)-\\text{l}\\text{n}\\left(\\text{M}\\text{M}\\text{A}\\text{D}\\right)\\right)}^{2}}{2{\\left(\\text{l}\\text{n}\\left(\\text{G}\\text{S}\\text{D}\\right)\\right)}^{2}}\\right]$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e​where \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{M}_{f}\\left({d}_{p}\\right)\\)\u003c/span\u003e\u003c/span\u003e is the normalized mass fraction and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{d}_{p}\\)\u003c/span\u003e\u003c/span\u003e is the particle aerodynamic diameter.\u003c/p\u003e\u003cp\u003eIn detail, the normalized mass fraction at each stage was divided by the logarithmic width of each stage, ∆lnD_50, which was computed from the midpoints of adjacent stage cut-off diameters. Then, a non-linear least squares fitting was performed using the curve fit function from the SciPy. Optimize library in Python to obtain the MMAD and GSD.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003e2.6.2 Percentage Reduction Calculations Aerosol Versus Reference Cigarette Smoke\u003c/h2\u003e\u003cp\u003eThe quantification results of the analytes are reported per tobacco stick/cigarette. Each individual BDL result was replaced with half the LOD, and each individual NQ result was replaced with (LOD\u0026thinsp;+\u0026thinsp;LOQ) / 2.\u003c/p\u003e\u003cp\u003eThe reduction of toxic emissions produced by the regular, non-menthol, and menthol blend HTS versus 1R6F combustible cigarette was calculated using the following formula:\u003c/p\u003e\u003cp\u003ePercent reduction = \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\frac{HTS\\:mean\\:-\\:1R6F\\:cigarette\\:mean}{1R6F\\:cigarette\\:mean}x100\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003eIn cases where HTS mean value fell below the limit of quantification (LOQ) of the analytical method, a conservative approach was adopted and LOQ provided instead of the arithmetic mean. In cases where the HTS mean was below the limit of detection (LOD) of the analytical method, the value of the LOD was used as mean. If an analyte was not quantified in 1R6F cigarette smoke (below LOQ), it was excluded from the yields comparison.\u003c/p\u003e\u003cp\u003eHaving data generated at two accredited laboratories, we compared the relative differences of results to 1R6F combustible cigarette data produced within the same laboratory to mitigate any discrepancies.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003e2.6.3 Comparability of Aerosol Emissions\u003c/h2\u003e\u003cp\u003eTo evaluate the comparability in emissions reductions between the HTS aerosols, a statistical approach was employed using Horwitz-Thompson equations [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] to define comparability margins. This allows for the integration of cigarette-derived variability and measurement uncertainty into the comparison. Comparability was assessed using a two one-sided t-test (TOST) procedure, applying a 5% significance level on each side (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\u003ch2\u003e2.6.4 \u003cem\u003eIn Vitro\u003c/em\u003e Toxicological Studies\u003c/h2\u003e\u003cp\u003eFor Ames and ivMN assay, the mutagenic and genotoxic potencies were estimated by the slope of the linear portion of the concentration-response curve using a generalized linear model with a Poisson distribution for tested samples that gave positive mutagenic or genotoxic responses. For NRU assay, cytotoxic potency was expressed using the half maximal inhibitory concentration (IC\u003csub\u003e50\u003c/sub\u003e) estimated from the concentration-response curve using the Hill function, a four-parameter logistic mathematical model, where the model was fit.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e2.7 BoE Literature Analysis and Methodology for Data Aggregation\u003c/h2\u003e\u003cp\u003eBoE data obtained from a previously published study with Device A (Nishihara \u003cem\u003eet al\u003c/em\u003e (2024)) was reviewed to verify that the reduction in toxic emissions from HTS compared to cigarettes is reflected in human clinical data [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A PubMedⓇ search (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was conducted in May 2025 to identify studies reporting clinical data on BoE following HTP use compared to cigarette smoking, using the search terms (\u0026ldquo;heated tobacco\u0026rdquo; AND \u0026ldquo;biomarkers of exposure\u0026rdquo;). In addition, a comprehensive published review on BoE data following HTP use by smokers (Akiyama \u0026amp; Sherwood, (2021)) was mined for relevant references [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Inclusion criteria were studies written in English, publications reporting data from randomized control trials assessing changes in BoE levels following HTP use compared to cigarette smoking, and presentation of original data. Data reported in relevant studies was tabulated for analysis as percentage change in BoE levels compared to baseline.\u003c/p\u003e\u003cp\u003eFor each biomarker, the mean percent change from baseline (with 95% confidence interval) was determined using the percentage changes for products in the same category, as reported within the selected publications. The averaged percent change for Nishihara \u003cem\u003eet al\u003c/em\u003e (2024) was superimposed for visual comparability.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Size of HTS Aerosol Droplets and Cigarette Smoke Particles\u003c/h2\u003e\u003cp\u003eAcross the 34 HTS test articles (with aerosols generated by Device A and B), a commercially available induction heating HTP comparator and combustible cigarette smoke, the median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the HTS aerosols and cigarette smoke were comparable, with all values falling within the respirable range (\u0026lt;\u0026thinsp;2.5 \u0026micro;m; Supplementary Materials (Table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e)).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Reductions in Levels of Toxic Emissions from HTS Aerosols Compared to Cigarette Smoke\u003c/h2\u003e\u003cp\u003eResults showed substantial reductions in the levels of 51 toxic emissions across all 34 assessed regular, non-menthol, and menthol blend HTS, compared to cigarette smoke, whether using Device A or B (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and B and raw data provided in Supplementary Material 6). On a per unit basis, levels of toxic emissions were consistently lower, with reductions ranging from at least 64% to over 99%, depending on the specific analyte measured. These reductions were consistently observed across the diverse set of HTS variants assessed, highlighting the comparability of emission reductions regardless of HTS product features such as blend, additives or device design [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAs shown in the consolidated results in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, the use of Device A or Device B did not result in any meaningful difference in the mean percentage reduction for the toxic emissions analyzed.\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the mean percentage reduction in 51 toxic emissions across the 34 HTS relative to combustible cigarette smoke. Fourteen analytes (indicated with triangles) were consistently below the LOD or LOQ for both Device A and Device B. This group includes two analytes from the WHO Tobacco Regulation Study Group (TobReg) 9 list of priority toxicants (1,3-butadiene and carbon monoxide) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], underscoring the potential for meaningful reductions in exposure. Seventeen analytes (indicated with squares) were below LOD or LOQ in some, but not all, of the HTS tested, while the remaining 20 analytes (indicated with circles) were consistently quantifiable across all HTS aerosols. For these quantifiable analytes, the standard deviation of mean values was low, reflecting reproducibility of reductions across products. Even in cases where variability was observed, the reductions relative to cigarette smoke remained substantial.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e4\u003c/span\u003e further confirms this pattern. Toxic emissions reduction values were tightly clustered around the median, demonstrating a high level of consistency across HTS aerosols. Statistical analysis showed that reductions were of comparable magnitude between Device A and Device B, with all values falling within an acceptable and scientifically relevant range.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Reductions in Levels of Toxic Emissions Across Heated Tobacco Technologies\u003c/h2\u003e\u003cp\u003eA comparative analysis of HTS aerosols demonstrated that heated tobacco technologies, regardless of the heating mechanism employed, yield substantial reductions in toxic emissions relative to combustible cigarette smoke. Mean percentage reductions ranged from 62.47\u0026ndash;99.98% for Device A, 69.29\u0026ndash;99.9% for Device B, 51.2-99-9% for iQOS induction heating technology and 51.61\u0026ndash;99.9% for iQOS blade heating technology.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of percentage reductions in toxic emissions relative to reference cigarette smoke (1R6F or 3R4F), based on published data for induction heating, blade heating technologies or other heating technologies. Percent reductions are not shown when the yields of the analyte in the aerosol from the 34 HTSs in combination with Device A or B are always below the limit of detection (LOD) or limit of quantification (LOQ).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnalyte\u003c/p\u003e\u003cp\u003e(Smoke/\u003c/p\u003e\u003cp\u003eAerosol)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMean % Reduction HTP Aerosol (Device A) vs. 1R6F Cigarette Smoke\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMean % Reduction HTP Aerosol (Device B) vs. 1R6F Cigarette Smoke\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMean % Reduction HTP Aerosol vs. 1R6F Cigarette Smoke\u003c/p\u003e\u003cp\u003e[This Study]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReported Data on iQOS\u0026trade; Induction Heating Technology\u003c/p\u003e\u003cp\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eHTS regular / HTS menthol\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReported Data on iQOS\u0026trade; Blade Heating Technology\u003c/p\u003e\u003cp\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] HTS regular / HTS menthol\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eReported Data glo\u0026trade; Original Thin-Film Resistive Heating Technology [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReported Data glo\u0026trade; Hyper Induction Heating Technology (Standard Mode Operation) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eReported Data glo\u0026trade; Hyper Induction Heating Technology (Boost Mode Operation)\u003c/p\u003e\u003cp\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1-Aminonaphthalene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.9 / 99.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;99.85 / 99.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2-Aminonaphthalene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.9 / 99.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;99.9 / 99.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3-Aminobiphenyl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.8 / 99.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e99.7*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4-Aminobiphenyl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.6 / 99.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e99.72 / 99.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcetaldehyde\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e92.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e93.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e93.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e89.5 / 87.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e88.49 / 88.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e94.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e91.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e91.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcetamide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e82.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e85.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e83.8 / 84.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e73.33 / 73.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcetone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e95.4 / 95.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e95.48 / 95.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcrolein\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e98.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e94.4 / 94.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e94.8 / 94.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e98.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e98.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e98.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcrylamide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e65.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e69.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e65.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e79.2 / 78.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e62.12 / 58.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmmonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e74.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e78.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e74.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e51.2 / 65.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e58.55 / 57.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArsenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e78.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e71.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e77.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e89.7 / 90.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;85.42 / \u0026gt;85.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1,3-butadiene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.9 / 99.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e99.75 / 99.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;99.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;99.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;99.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBenzene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.5 / 99.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e99.42 / 99.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;99.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e99.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e99.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBenz[a]anthracene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e93.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e95.7 / 94.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e91.41 / 93.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBenzo(a)pyrene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e95.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e96.2 / 95.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e93.13 / 95.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;97.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;97.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;98.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eButyraldehyde\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e89.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e90.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e89.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e81.5 / 77.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e75.6*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCatechol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e88.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e88.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e88.1 / 87.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e86.85 / 87.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCrotonaldehyde\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e94.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e92.9 / 92.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;94.04 / 94.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCarbon monoxide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.1 / 99.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;99.78 / \u0026gt;99.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;99.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;99.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e99.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFormaldehyde\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e95.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e90.9 / 91.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e89.89 / 89.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e95.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e95.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e95.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHydroquinone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e96.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e91.4 / 92.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e91.9*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLead\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e94.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e93.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e98.3 / 98.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNA / NA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMercury\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e64.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e72.7 / 68.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e51.61 / 56.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMethyl Ethyl Ketone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e97.0 / 96.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e96.15 / 96.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNAB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e82.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e86.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e88.9 / 89.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e93.6*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNAT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e84.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e89.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e85.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e93.3 / 93.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e94.8*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNNK\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e94.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e94.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e95.5 / 96.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e96.12 / 97.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e96.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e95.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e97.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNNN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e90.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e93.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e91.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e95.0 / 96.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e94.51 / 96.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e83.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e88.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e97.3 / 97.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e97.3*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNOx\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e97.3 / 97.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e97.5*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eo-Cresol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.0 / 98.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e98.91 / 98.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eo-Toluidine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.1 / 99.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e98.97 / 98.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhenol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e98.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e94.3 / 93.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e93.47 / 94.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePropionaldehyde\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e95.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e91.3 / 90.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e90.24 / 90.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePyrene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e91.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e92.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e93.9 / 93.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePyridine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e92.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e93.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e92.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e83.9 / 84.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e79.3*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSelenium\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e67.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e80.8 / 80.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNA / NA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStyrene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e97.9 / 97.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e97.48 / 97.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eToluene\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e98.9 / 98.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e99.02 / 98.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMaximum device heating temperature (\u0026deg;C\u003c/b\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e\u0026le;\u0026thinsp;320\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e350\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e350\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e240\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e250\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e260\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003e* Levels for these analytes were referred to former publication on Tobacco heating System 2.2 (THS 2.2) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFurther assessment of heated tobacco products using alternative heating technologies, including published data on glo thin-film resistive heating and glo induction (in standard and boost modes)[17], and both blade and induction variants of iQOS, revealed comparable reductions in the WHO Tobacco Product Regulation Study Group (TobReg) 9 priority toxicants (Table 1). Across all evaluated heating technologies with published datasets, the overall reduction in these priority toxicants ranged from 96.47% for glo thin-film resistive heating, 95.67% for glo induction standard mode, 96.59% for glo induction boost mode, 95.10% for iQOS blade heating, 95.56% for iQOS induction heating, and 96.27% for the outside heating evaluated in this study. The reported maximum heating temperatures of the devices ranged from 240-350\u003csup\u003eo\u003c/sup\u003eC.\u003c/p\u003e\n\u003cdiv id=\"Sec22\"\u003e\n \u003ch2\u003e3.4 \u003cem\u003eIn Vitro\u003c/em\u003e Biological Activity\u003c/h2\u003e\n \u003cp\u003eTwenty-three HTS test items, representing different stick consumable varieties (regular, non-menthol, and menthol blends) in combination with two different devices (Device A and B), were assessed alongside the 1R6F cigarette. Both particulate phase (aerosol collected mass (ACM); HTS or total particulate matter (TPM); cigarette smoke) and the gas-vapor phase (GVP) samples from the HTS aerosols and cigarette smoke were evaluated.\u003c/p\u003e\n \u003cdiv id=\"Sec23\"\u003e\n \u003ch2\u003e3.4.1 Ames Assay (Mutagenicity Assessment)\u003c/h2\u003e\n \u003cp\u003eDetailed results for each individual HTS test item and 1R6F cigarette are provided in Supplementary Materials (Table S4-S5). The ACM and GVP samples from all HTS test items showed non-mutagenic responses under the test conditions. In contrast, the TPM sample from 1R6F cigarette induced clear and reproducible mutagenic responses in strains TA98 and TA1537 under + S9 conditions, while the GVP samples showed non-mutagenic responses under the test conditions. Due to the absence of mutagenic activity of the HTS test items, a direct comparative analysis with 1R6F cigarette was not pursued.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec24\"\u003e\n \u003ch2\u003e3.4.2 \u003cem\u003eIn Vitro\u003c/em\u003e Micronucleus Assay (Genotoxicity Assessment)\u003c/h2\u003e\n \u003cp\u003eGenotoxic potential was evaluated using the ivMN assay under the three treatment conditions: 3 h exposure without metabolic activation (Short -S9), a 3 h exposure with metabolic activation (short + S9), and 30 h exposure without metabolic activation (Long -S9). Detailed results, including genotoxicity assessments and genotoxic slope values for each HTS test item and 1R6F cigarette, are provided in Supplementary Materials (Table S6).\u003c/p\u003e\n \u003cp\u003eMost HTS samples were classified as genotoxic in at least one treatment schedule. However, several HTS samples, irrespective of HTS stick blend or device, did not induce statistically significant increases in MN frequency compared to solvent controls, and were therefore assessed as non-genotoxic under the test conditions. These inconsistencies are likely attributable to inherent biological variability associated with ivMN assay. Such variability may influence whether a weak response meets or fails to meet all genotoxicity evaluation criteria required for a positive call, especially in borderline cases.\u003c/p\u003e\n \u003cp\u003eIn contrast, both TPM and GVP samples from 1R6F cigarettes demonstrated clear genotoxicity under all treatment conditions. Notably, the tested concentrations of the HTS test items were approximately 6- to 10-fold higher than those tested for the 1R6F cigarette. Overall, the genotoxic activity of HTS test items was reduced by 90–98% for ACM samples and from 86–96% for the GVP samples, relative to the 1R6F cigarette (See Supplementary Materials (Figure S1)). Across the stick types, the percentage reduction in genotoxic activity relative to 1R6F cigarette was consistent and comparable (Figure S1A, C, and E). Likewise, no significant differences were observed between the two device datasets (Figure S1B, D, and F).\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec25\"\u003e\n \u003ch2\u003e3.4.3 Neutral Red Uptake Assay (Cytotoxicity Assessment)\u003c/h2\u003e\n \u003cp\u003eCytotoxicity was evaluated using NRU assay. IC\u003csub\u003e50\u003c/sub\u003e values for each test sample from individual HTS test items and 1R6F cigarette are provided and compared in Supplementary Materials (Table S7 and Figure S2).\u003c/p\u003e\n \u003cp\u003eThe ACM samples from the individual HTS test items showed an 86–94% reduction in cytotoxicity compared to 1R6F cigarette TPM sample. Similarly, the GVP samples from the HTS test items demonstrated at least 93% reduction in cytotoxicity compared to the 1R6F cigarette GVP sample. These reductions in cytotoxic potential were consistent and comparable across all three HTS stick types (regular, non-menthol, and menthol; Figure S2A) and between Device A and B (Figure S2B).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec26\"\u003e\n \u003ch2\u003e3.5 Trends in Reduced Biomarkers of Exposure and Reduced Toxic Emissions in Aerosols\u003c/h2\u003e\n \u003cp\u003eBiomarkers of exposure (BoE) provide a direct measure of user exposure to select substances that are quantifiable in HTP aerosols [27, 31]. Clinical assessments consistently demonstrate, independently of differences in HTP designs or characteristics, adults who smoke and who switch away from combustible cigarettes to HTP experience substantial and sustained reductions in BoEs relative to continuing to smoke [10, 14]. Moreover, the magnitude of these reductions is typically not dissimilar to those observed following smoking cessation, reinforcing the relevance of BoEs as indicators of reduced toxic emissions exposure.\u003c/p\u003e\n \u003cp\u003ePrevious clinical data for outside heating technology (Device A) demonstrated substantial reductions in exposure to select toxic emissions after five days of complete switching from combustible cigarettes [10]. Across 15 commonly assessed BoEs, reductions relative to continued smoking ranged from 22.9–96.6%.\u003c/p\u003e\n \u003cp\u003eTo contextualize these findings, a pooled analysis of published clinical studies reporting data on the same 15 BoEs following HTP use among adult smokers across 25 studies, covering exposure durations from five days to one year and encompassing a range of heating technologies was conducted in the present study (see Supplementary Materials (Table S8)) for information on the included studies) [10–15, 27, 31–48]. The pooled results, represented as average percent change from baseline, indicate consistent reductions in BoEs at the HTP category level ranging from 44.6–93.9%, irrespective of device design, study duration, or study location (Fig. 5). Notably, studies conducted in Japan, United States, Poland and Germany all reported comparable reductions in BoEs among adult smokers randomized to use HTP, with effect sizes remaining within a narrow range despite differences in study populations and regulatory environments (Table S8). As illustrated in Fig. 5, the trajectory of BoE reductions from baseline observed with outside heating technology (Device A), ranging from 36.2–96.8%, closely aligns with overall HTP category BoE trends.\u003c/p\u003e\n "},{"header":"Discussion","content":"\u003cp\u003eThis study evaluated the hypothesis that adherence to the core principle of heating rather than burning tobacco consistently yields substantially lower levels of toxic emissions that are comparable across HTPs, irrespective of differences in product design, tobacco blend, additive composition, or heating technology, thereby providing a foundational scientific basis for bridging datasets across the HTP category based on the comparability of reduced toxic emissions within a statistically acceptable range.\u003c/p\u003e\u003cp\u003eTo assess this, 34 HTS variants were evaluated for levels of toxicant emissions and, for a subset of HTS, the resulting \u003cem\u003ein vitro\u003c/em\u003e biological activity response. Across all products, emissions of 51 toxic emissions were substantially reduced (average of 93.6%) compared to cigarette smoke. A proposed statistical analysis approach confirmed that the reductions fell within an acceptable range of comparability. Despite technological diversity, these findings aligned with published data from other commercial HTPs (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), reinforcing reproducibility and reliability of toxic emissions reductions at the category level [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe biological relevance of these toxic emissions reductions was confirmed through three standard \u003cem\u003ein vitro\u003c/em\u003e assays. For the subset of tested products, HTS was non-mutagenic in the Ames assay under the test conditions, contrasting with the mutagenic response observed for cigarette smoke particulate matter. Genotoxicity, as measured by the \u003cem\u003ein vitro\u003c/em\u003e micronucleus (ivMN) assay, was reduced by 86\u0026ndash;98%, and cytotoxicity, assessed via the neutral red uptake (NRU) assay, was reduced by 86\u0026ndash;94%. These consistent reductions in biological activity indicate that reduced toxic emission yields translate into a meaningful reduction in toxicological risk potential.\u003c/p\u003e\u003cp\u003eThese findings confirm that comparable reductions in toxic emissions and toxicological activity are functionally relevant and attributable to the shared design principle of avoiding combustion. This shared mechanism serves as the foundation for considering data bridging across HTPs [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn parallel, aerosol particle size distribution was also measured to exclude differences in delivery efficiency as a confounding factor. HTS produced aerosols with mass median aerodynamic diameters (MMADs) below 2.5 \u0026micro;m, confirming respirability. These values were comparable to a commercial HTP comparator and combustible cigarette smoke, indicating observed reductions in toxicological activity can be attributed to differences in aerosol chemistry, not delivery characteristics or deposition efficiency.\u003c/p\u003e\u003cp\u003eBiomarkers of exposure (BoE) provide a direct and quantitative measure of exposure to harmful substances and are closely linked to the levels of toxic emissions present in product aerosol. Given that all HTPs operate on the same fundamental principle of heating rather than burning tobacco, they consistently generate substantially lower emissions than combustible cigarettes. Therefore, it follows that BoE trends are expected to align at the product-category level, independent of individual device design, tobacco blend, or additives.\u003c/p\u003e\u003cp\u003eConsistent with the published literature, complete switching away from combustible cigarettes to HTPs leads to substantial reductions in BoE, with reductions for outside heating technology (Device A) ranging from 36.2\u0026ndash;96.8% compared to baseline after five days of HTP use among adult smokers [\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. When considered alongside the pooled data from 25 published studies across different heating technology devices, exposure durations and geographies, a clear pattern emerges: BoE reductions cluster at the HTP category level with reductions achieved with outside heating technology reflecting the broader category effect rather than being device specific.\u003c/p\u003e\u003cp\u003eImportantly, this pattern is reinforced by aerosol chemistry. Comparability of reduced toxic emissions (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e4\u003c/span\u003e) leads to BoE readouts that sit within category-level trends (Fig.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e5\u003c/span\u003e), indicating that similarities in aerosol toxic emissions translate into consistent user exposure reductions across different heating technologies. The mechanistic basis for this consistency lies in the absence of combustion across all HTPs, which eliminate or markedly reduce the formation of many harmful substances that are characteristic of cigarette smoke. Thus, while heating technologies may vary in design, the fundamental absence of combustion provides a unifying explanation for comparable reductions in toxic emissions in product aerosols and the corresponding reproducible reductions in user exposure. The results from this study support the use of bridging approaches that link product-specific toxic emissions and toxicology data with the broader evidence base on BoE across HTP products. As such, consistency in thermal operations provides a scientific foundation for assessing the comparability of reduced toxic emissions and bridging datasets across HTPs, independently of individual HTP design provided the core thermal principle is maintained, supported by the broader HTP category-level clinical outcomes data.\u003c/p\u003e\u003cp\u003eBridging of emissions and toxicology datasets is a well-established scientific and regulatory practice. Frameworks such as the European Chemicals Agency\u0026rsquo;s (ECHA) read-across strategy and the UK Medicines and Healthcare products Regulatory Agency (MHRA)\u0026rsquo;s guidance on representative e-cigarette submissions endorse the use of representative data where comparability can be scientifically justified [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Across all HTS tested in the present study, toxic emissions and \u003cem\u003ein vitro\u003c/em\u003e responses were consistently and substantially lower than those of combustible cigarettes, with a proposed statistical analysis approach confirming the comparability of toxic emissions reductions. Comparability of reduced toxic emissions also leads to BoE readouts that sit within category-level trends.\u003c/p\u003e\u003cp\u003eOverall, these findings provide a scientific rationale for applying bridging assessments across HTP innovations based on demonstrating the comparability of reduced toxic emissions. This work lays the foundation for integrating product-specific HTP emissions data with broader, product-agnostic epidemiological data to assess long-term population health outcomes in the future.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHeated Tobacco Products (HTP), Heated Tobacco Stick (HTS), Aerosol Collected Matter (ACM), Gas Vapour Phase (GVP), Below the Detection Limit (BDL), Limit of Detection (LOD), Limit of Quantification (LOQ), Not Quantified (NQ), \u003cem\u003eIn Vitro\u003c/em\u003e Micronucleus (ivMN), Neutral Red Uptake (NRU), Total Particulate Matter (TPM), Mass Median Aerodynamic Diameter (MMAD), Geometric Standard Deviation (GSD), Two One-Sided T-test (TOST), European Chemical Agency (ECHA), UK Medicines and Healthcare products Regulatory Agency (MHRA), Horwitz-Thompson Margins (HT Margins), Organization for Economic Co-operation and Development (OECD), Chinese Hamster Ovary \u0026ndash; Wolff\u0026ndash;Bloom\u0026ndash;Litton (CHO-WBL), Biomarkers of Exposure (BoE).\u003c/p\u003e\u003cp\u003eBRIEFS (Word Style \u0026ldquo;BH_Briefs\u0026rdquo;). If you are submitting your paper to a journal that requires a brief, provide a one-sentence synopsis for inclusion in the Table of Contents.\u003c/p\u003e\n\u003cp\u003eSYNOPSIS (Word Style \u0026ldquo;SN_Synopsis_TOC\u0026rdquo;). If you are submitting your paper to a journal that requires a synopsis, see the journal\u0026rsquo;s Instructions for Authors for details.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful for the staff of Labstat International Inc, and Oekolab GmbH. for providing professional technical assistant for the study. The authors also thank Dr. Ian Jones, Dr. Javier Martinez, Dr Takashi Sekine, Dr Christelle Bonnet and Ricardo Magana for their critical review of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ASSOCIATED CONTENT\u003c/p\u003e\n\u003cp\u003eAUTHOR INFORMATION\u003c/p\u003e\n\u003cp\u003eCorresponding Author\u003c/p\u003e\n\u003cp\u003eJ. MILLER-HOLT\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\[email protected]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJTI SA, 8 rue Kazem Radjavi, 1202 Geneva, Switzerland, [email protected]\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eJ. MILLER-HOLT: Supervision, funding acquisition, conceptualization, methodology, data curation, formal analysis, writing \u0026ndash; original draft, review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eG. O\u0026rsquo;CONNELL: conceptualization, methodology, formal analysis, writing-original draft, review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eR. BACH: project administration, data acquisition, validation \u0026amp; visualization, writing \u0026ndash; review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eM. CHARRIERE: project administration, Statistical analysis, data acquisition, validation \u0026amp; visualization, writing \u0026ndash; review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eY. KANEMARU: project administration, data acquisition, validation \u0026amp; visualization, writing \u0026ndash; review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eZ. SU: project administration, data acquisition, validation \u0026amp; visualization, writing \u0026ndash; review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eS. LARROQUE: project administration, Statistical analysis, data acquisition, validation \u0026amp; visualization, writing \u0026ndash; review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eK. JACOBSON: project administration, writing \u0026ndash; review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eFunding Sources\u003c/p\u003e\n\u003cp\u003eThis research was sponsored by JTI SA and Japan Tobacco Inc. (JT).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBaker, R.R. Product formation mechanisms inside a burning cigarette\u003cem\u003e.\u003c/em\u003e \u003cem\u003eProg Energy Combust Sci\u003c/em\u003e \u003cstrong\u003e1981\u003c/strong\u003e, \u003cem\u003e7\u003c/em\u003e(2), p. 135-153. DOI: 10.1016/0360-1285(81)90008-3.\u003c/li\u003e\n\u003cli\u003eBechikhi, M.; Masson, E.; Herbinet, O.; Dufour, A. 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Changes in levels of biomarkers of exposure and biological effect in a controlled study of smokers switched from conventional cigarettes to reduced-toxicant-prototype cigarettes\u003cem\u003e.\u003c/em\u003e \u003cem\u003eRegul Toxicol Pharmacol\u003c/em\u003e \u003cstrong\u003e2015\u003c/strong\u003e, \u003cem\u003e72\u003c/em\u003e(2), p. 273-91. 10.1016/j.yrtph.2015.04.016.\u003c/li\u003e\n\u003cli\u003eOgden, M.W.; Marano, K.M.; Jones, B.A.; Morgan, W.T.; Stiles, M.F. Switching from usual brand cigarettes to a tobacco-heating cigarette or snus: Part 2. Biomarkers of exposure\u003cem\u003e.\u003c/em\u003e \u003cem\u003eBiomarkers\u003c/em\u003e \u003cstrong\u003e2015\u003c/strong\u003e, \u003cem\u003e20\u003c/em\u003e(6-7), p. 391-403. 10.3109/1354750X.2015.1094134.\u003c/li\u003e\n\u003cli\u003eRoethig, H.J.; Feng, S.; Liang, Q.; Liu, J.; Rees, W.A.; Zedler, B.K. A 12-month, randomized, controlled study to evaluate exposure and cardiovascular risk factors in adult smokers switching from conventional cigarettes to a second-generation electrically heated cigarette smoking system\u003cem\u003e.\u003c/em\u003e \u003cem\u003eJ Clin Pharmacol\u003c/em\u003e \u003cstrong\u003e2008\u003c/strong\u003e, \u003cem\u003e48\u003c/em\u003e(5), p. 580-91. 10.1177/0091270008315316.\u003c/li\u003e\n\u003cli\u003eTricker, A.R.; Stewart, A.J.; Leroy, C.M.; Lindner, D.; Schorp, M.K.; Dempsey, R. Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 3: Eight-day randomized clinical trial in the UK\u003cem\u003e.\u003c/em\u003e \u003cem\u003eRegul Toxicol Pharmacol\u003c/em\u003e \u003cstrong\u003e2012\u003c/strong\u003e, \u003cem\u003e64\u003c/em\u003e(2 Suppl), p. S35-44. 10.1016/j.yrtph.2012.08.010.\u003c/li\u003e\n\u003cli\u003eFrost-Pineda, K.; Zedler, B.K.; Oliveri, D.; Liang, Q.; Feng, S.; Roethig, H.J. 12-week clinical exposure evaluation of a third-generation electrically heated cigarette smoking system (EHCSS) in adult smokers\u003cem\u003e.\u003c/em\u003e \u003cem\u003eRegul Toxicol Pharmacol\u003c/em\u003e \u003cstrong\u003e2008\u003c/strong\u003e, \u003cem\u003e52\u003c/em\u003e(2), p. 111-7. 10.1016/j.yrtph.2008.05.015.\u003c/li\u003e\n\u003cli\u003eEuropean Chemical Agency. \u003cem\u003eGuide for enforcement of mixture classification based on bridging principles. Article 9(4) of the CLP Regulation Weight of evidence / Expert judgements, \u003c/em\u003eJuly 2024, update in September 2024, ECHA-24-H-10-EN, ISBN: 978-92-9468-390-8, Cat. Number: ED-09-24-605-EN-N, DOI: 10.2823/475106\u003c/li\u003e\n\u003cli\u003eMedicines and Healthcare products Regulatory Agency. \u003cem\u003eGuidance Chapter 3 - emissions from electronic cigarettes - GB, \u003c/em\u003e2022, last updated 16 August 2024, https://www.gov.uk/government/publications/chapter-3-emissions-guidance-great-britain/chapter-3-emissions-from-electronic-cigarettes-gb\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Footnotes","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e Device A refers to minor incremental versions of the same device, with the maximum heating temperature of each not exceeding 320\u0026deg;C\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Emissions, Statistics, Heated Tobacco, Bridging, Biomarker of Exposure, Harm Reduction","lastPublishedDoi":"10.21203/rs.3.rs-7520219/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7520219/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHeated tobacco products (HTPs) offer a reduce risk potential by avoiding combustion, thereby lowering toxic emissions. This study evaluated 34 heated tobacco stick (HTS) variants, each with different tobacco blends, using two heating devices to assess the comparability of 51 toxic emission reductions compared to combustible cigarette smoke.\u003c/p\u003e\u003cp\u003eAerosols and 1R6F reference cigarette smoke were generated under standardized conditions, and droplet or particle size distributions were measured. Toxic emission levels were analyzed using a proposed statistical approach to determine comparability. \u003cem\u003eIn vitro\u003c/em\u003e toxicological evaluation was performed using mutagenicity, genotoxicity, and cytotoxicity assays. Additionally, published data on Biomarkers of Exposure (BoE) were reviewed to assess whether reduced emissions corresponded to reduced human exposure at the category level.\u003c/p\u003e\u003cp\u003eOverall, HTS emissions were reduced by 93.57% compared to cigarette smoke, with consistent reductions across blends and devices. HTS aerosols consistently showed significantly reduced \u003cem\u003ein vitro\u003c/em\u003e biological activity compared to cigarette smoke, with reductions observed across all HTS types, devices, and sample phases, even at higher concentrations than those used for cigarette samples. Toxic emissions data from other HTP technologies in published literature were also reviewed, showing comparable reduced levels leading to consistent reductions in BoE. These findings suggest that the heat-not-burn principle provides substantial exposure reduction independent of product-specific attributes. The study supports the bridging of aerosol chemistry and toxicological datasets, and leveraging published BoE results across the HTP category, to streamline product assessments.\u003c/p\u003e","manuscriptTitle":"Assessing the comparability of toxic emissions reduction from heated tobacco aerosols relative to cigarette smoke: a scientific approach to bridging datasets","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 15:02:56","doi":"10.21203/rs.3.rs-7520219/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-09-16T07:46:05+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-15T17:52:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-10T05:13:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Internal and Emergency Medicine","date":"2025-09-09T01:02:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"04e1670e-3dd3-4c21-a981-3d0ad3ffb6ee","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T16:09:52+00:00","versionOfRecord":{"articleIdentity":"rs-7520219","link":"https://doi.org/10.1007/s11739-025-04160-6","journal":{"identity":"internal-and-emergency-medicine","isVorOnly":false,"title":"Internal and Emergency Medicine"},"publishedOn":"2025-10-29 15:57:44","publishedOnDateReadable":"October 29th, 2025"},"versionCreatedAt":"2025-09-23 15:02:56","video":"","vorDoi":"10.1007/s11739-025-04160-6","vorDoiUrl":"https://doi.org/10.1007/s11739-025-04160-6","workflowStages":[]},"version":"v1","identity":"rs-7520219","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7520219","identity":"rs-7520219","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}