Reemtsma

Data from pre-clinical and clinical studies form part of an integrated assessment of the tobacco harm reduction (THR) potential of novel products that may act as cigarette alternatives for adult smokers. We report data from pre-clinical (emissions chemistry and in vitro toxicology) and clinical (nicotine pharmacokinetics and subjective effects) studies conducted with the iSENZIA™ heated herbal system (HHS; PULZE™ 2.0 device with iSENZIA™ sticks), which utilizes electronic heating of a tea-based substrate to generate an inhalable nicotine-containing aerosol. The aerosols from the iSENZIA™ HHS contained significantly lower levels, by up to 99.8%, of the nine World Health Organization Study Group on Tobacco Product Regulation (WHO TobReg) analytes compared with 1R6F reference cigarette smoke and elicited significantly lower in vitro cytotoxicity, genotoxicity, and mutagenicity responses. The clinical study demonstrated that the iSENZIA™ HHS delivers satisfactory levels of nicotine to users and has lower abuse liability than cigarettes. Overall, our data suggest that iSENZIA™ has the potential to offer substantially reduced toxicant exposure, as well as a reduction in toxicity, compared to cigarettes, while delivering satisfactory levels of nicotine. These findings support the THR potential of the iSENZIA™ HHS as a reduced-risk, acceptable alternative product for adult smokers.

Nicotine delivery and subjective effects are determinants of the ability of potentially less harmful tobacco products such as heated tobacco products (HTPs) to support adult smokers in switching away from cigarettes, and therefore to support tobacco harm reduction. This open-label, randomised, crossover, clinical study in 24 healthy adult smokers study assessed nicotine pharmacokinetics and subjective effects of the Pulze Heated Tobacco System (HTS; Pulze HTP device and three iD stick variants—Intense American Blend, Regular American Blend and Regular Menthol) compared with subjects’ usual brand cigarettes (UBC). Cmax and AUCt were highest for UBC and significantly lower for each Pulze HTS variant. Cmax and AUCt were significantly higher for Intense American Blend compared with Regular American Blend, while AUCt was significantly higher for Intense American Blend compared with Regular Menthol. Median Tmax was lowest (i.e., nicotine delivery was fastest) for subjects’ usual brand cigarettes and similar across the iD stick variants, although no between-product differences were statistically significant. All study products reduced urges to smoke; this effect was greatest for cigarettes although this was not statistically significant. Product evaluation scores for each Pulze HTS variant in the domains of ‘satisfaction’, ‘psychological reward’ and ‘relief’ were similar, and lower than those for UBC. These data demonstrate that the Pulze HTS effectively delivers nicotine and generates positive subjective effects, including satisfaction and reduced urge to smoke. This supports the conclusion that the Pulze HTS may be an acceptable alternative to cigarettes for adult smokers while having a lower abuse liability than cigarettes.

Tobacco harm reduction (THR) involves providing adult smokers with potentially reduced harm modes of nicotine delivery as alternatives to smoking combustible cigarettes. Heated tobacco products (HTPs) form a category with THR potential due to their ability to deliver nicotine and flavours through heating, not burning, tobacco. By eliminating burning, heated tobacco does not produce smoke but an aerosol which contains fewer and lower levels of harmful chemicals compared to cigarette smoke. In this study we assessed the in vitro toxicological profiles of two prototype HTPs' aerosols compared to the 1R6F reference cigarette using the 3D human (bronchial) MucilAir™ model. To increase consumer relevance, whole aerosol/smoke exposures were delivered repeatedly across a 28 day period (16, 32, or 48 puffs per exposure). Cytotoxicity (LDH secretion), histology (Alcian Blue/H&E; Muc5AC; FoxJ1 staining), cilia active area and beat frequency and inflammatory marker (IL-6; IL-8; MMP-1; MMP-3; MMP-9; TNFα) levels were assessed. Diluted 1R6F smoke consistently induced greater and earlier effects compared to the prototype HTP aerosols across the endpoints, and in a puff dependent manner. Although some significant changes across the endpoints were induced by exposure to the HTPs, these were substantially less pronounced and less frequently observed, with apparent adaptive responses occurring over the experimental period. Furthermore, these differences between the two product categories were observed at a greater dilution (and generally lower nicotine delivery range) for 1R6F (1R6F smoke diluted 1/14, HTP aerosols diluted 1/2, with air). Overall, the findings demonstrate the THR potential of the prototype HTPs through demonstrated substantial reductions in toxicological outcomes in in vitro 3D human lung models.

In vitro testing is important to characterise biological effects of consumer products, including nicotine delivery products such as cigarettes, e-cigarettes and heated tobacco products. Users' cells are exposed to these products' aerosols, of variant chemical compositions, as they move along the respiratory tract. In vitro exposure systems are available to model such exposures, including delivery of whole aerosols to cells, and at the air-liquid interface. Whilst there are clear advantages of such systems, factors including time to aerosol delivery, aerosol losses and number of cell cultures that can be exposed at one time could be improved. This study aimed to characterise a custom-built smoke/ aerosol exposure in vitro system (SAEIVS) using 1R6F reference cigarette smoke. This system contains five parallel smoking chambers and delivers different dilutions of smoke/ aerosol to two separate cell culture exposure chambers in <10 s. Using two dosimetry measures (optical density 400 nm [OD400 ]; mass spectrometric nicotine quantification), the SAEIVS demonstrated excellent linearity of smoke dilution prior to exposure (R2 = 0.9951 for mass spectrometric quantification; R2 = 0.9965 for OD400 ) and consistent puff-wise exposures across 24 and 96 well plates in cell culture relevant formats (e.g., within inserts). Smoke loss was lower than previously reported for other systems (OD400 : 16%; nicotine measurement: 20%). There was good correlation of OD400 and nicotine measurements, indicating that OD was a useful surrogate for exposure dosimetry for the product tested. The findings demonstrated that the SAEIVS is a fit-for-purpose exposure system for the reproducible dose-wise exposure assessment of nicotine delivery product aerosols.