Chemical and in vitro toxicological comparison of emissions from a heated tobacco product and the 1R6F reference cigarette.

It has previously been found that, compared with cigarette smoke, the aerosols generated by heated tobacco products contain fewer and lower harmful and potentially harmful constituents (HPHCs) and elicit lower biological activity in in vitro models and lower smoking-related exposure biomarker levels in clinical studies. It is important to accumulate such scientific evidences for heated tobacco products with a novel heating system, because different heating system may affect the quantitative aspect of the amount of HPHCs and the qualitative aspect of the biological activity of the aerosol generated. Here, the chemical properties of, and toxicological responses to aerosols emitted by DT3.0a, a new heated tobacco product with a novel heating system, and cigarette smoke (CS) were compared, using chemical analyses, in vitro battery (standardized genotoxicity and cytotoxicity) assays, and mechanistic (ToxTracker and two-dimensional cell culture) assays. Regular- and menthol-flavored DT3.0a and standard 1R6F reference cigarettes were tested. Selected HPHC yields were lower in DT3.0a aerosol than 1R6F CS. The genotoxicity-related assays indicated that DT3.0a aerosol was not genotoxic, regardless of metabolic activation. The other biological assays indicated that less cytotoxicity induction and oxidative stress response were elicited by DT3.0a aerosol compared with 1R6F CS. Similar results were found for both regular and menthol DT3.0a. Like previous reports for heated tobacco products with other heating systems, the results of this study indicated that DT3.0a aerosols have chemical and biological properties less likely to be harmful than 1R6F CS.

Comparing the preclinical risk profile of inhalable candidate and potential candidate modified risk tobacco products: A bridging use case.

Cigarette smoking causes major preventable diseases, morbidity, and mortality worldwide. Smoking cessation and prevention of smoking initiation are the preferred means for reducing these risks. Less harmful tobacco products, termed modified-risk tobacco products (MRTP), are being developed as a potential alternative for current adult smokers who would otherwise continue smoking. According to a regulatory framework issued by the US Food and Drug Administration, a manufacturer must provide comprehensive scientific evidence that the product significantly reduces harm and the risk of tobacco-related diseases, in order to obtain marketing authorization for a new MRTP. For new tobacco products similar to an already approved predicate product, the FDA has foreseen a simplified procedure for assessing "substantial equivalence". In this article, we present a use case that bridges the nonclinical evidence from previous studies demonstrating the relatively reduced harm potential of two heat-not-burn products based on different tobacco heating principles. The nonclinical evidence was collected along a "causal chain of events leading to disease" (CELSD) to systematically follow the consequences of reduced exposure to toxicants (relative to cigarette smoke) through increasing levels of biological complexity up to disease manifestation in animal models of human disease. This approach leverages the principles of systems biology and toxicology as a basis for further extrapolation to human studies. The experimental results demonstrate a similarly reduced impact of both products on apical and molecular endpoints, no novel effects not seen with cigarette smoke exposure, and an effect of switching from cigarettes to either MRTP that is comparable to that of complete smoking cessation. Ideally, a subset of representative assays from the presented sequence along the CELSD could be sufficient for predicting similarity or substantial equivalence in the nonclinical impact of novel products; this would require further validation, for which the present use case could serve as a starting point.

Comparison of monoamine oxidase inhibition by cigarettes and modified risk tobacco products.

The adverse effects of cigarette smoking are well documented, and the two main strategies for reducing smoking prevalence are prevention of smoking initiation and promotion of smoking cessation. More recently, a third and complementary avenue, tobacco harm reduction has emerged, which is aimed to reduce the burden of smoking-related diseases. This has been enabled by the development of novel products such as electronic cigarettes (e-cigarettes) and heated tobacco products, designed to deliver nicotine with significantly reduced levels of the toxicants that are emitted by cigarettes. Several potential modified risk tobacco products (pMRTP) have been reported to emit significantly less toxicants than cigarettes and significantly reduce toxicant exposure in smokers who switch completely to such products. These are two prerequisites for pMRTPs to reduce harm and the risk of smoking-related disease. However, concerns remain regarding the addictive nature of these products. Smoking addiction is a complex phenomenon involving multiple pharmacological and non-pharmacological factors. Although the main pharmacological substance associated with smoking addiction is nicotine, accumulating evidence suggests that nicotine mostly acts as a primary reinforcer and that other factors are involved in establishing smoking addiction. Inhibition of monoamine oxidases (MAO)-mammalian flavoenzymes with a central role in neurotransmitter metabolism-has also been suggested to be involved in this process. Therefore, we aimed to comparatively investigate the ability of several types of pMRTPs and cigarette smoke (3R4F) to inhibit MAO activity. The results showed that the heated tobacco product Tobacco Heating System (THS) 2.2 and the MESH 1.1 e-cigarette possessed no MAO inhibitory activity while 3R4F significantly inhibits the levels of MAO activity (3R4F MAO-A and B; > 2 µM nicotine). Snus products have similar inhibition profiles as 3R4F but for larger nicotine concentrations (snus MAO-A; ∼68-fold, snus MAO-B; ∼23-fold higher compared to 3R4F). These observations were confirmed by analytical datasets of potential MAO inhibitors emitted by these products. In conclusion, we have demonstrated that specific pMRTPs, namely THS 2.2 and MESH 1.1, have a significantly lower MAO-inhibitory activity than 3R4F. These findings provide a basis for further investigation of the role of MAO inhibitors in cigarette addiction as well as the implications of the findings for abuse liability of pMRTPs in comparison with cigarettes.