New data presented at the Society of Toxicology Annual Meeting (SOT) have demonstrated the potential of two different heat-not-burn tobacco products and e-cigarettes to reduce the risk of smoking-related diseases, in comparison to continued use of conventional cigarettes. A range of studies have investigated the toxicological impact of Philip Morris International (PMI)’s Tobacco Heating System 2.2 (THS 2.2), Carbon Heated Tobacco Product 1.2 (CHTP 1.2) and prototype e-cigarette products in the context of respiratory disease, cardiovascular disease, and lung cancer using several different approaches. In each case, the aerosols produced by the alternative products resulted in significantly reduced levels of biological impact as compared to cigarette smoke (CS).
One six-month, multi-arm exposure study compared the effects of CS with those of the aerosol from the two heat-not-burn tobacco products THS 2.2 and CHTP 1.2 using a mouse model.1 In both THS 2.2 and CHTP 1.2, tobacco is heated rather than burned, resulting in significantly reduced levels of harmful chemicals emitted and inhaled as compared with CS. Through a systems toxicology approach, combining physiological, histological, and omics endpoints, the study found that exposure to THS 2.2 and CHTP 1.2 aerosols had minimal adverse respiratory and cardiovascular effects in comparison to exposure to CS, not much different from the effects of fresh air alone. The findings are in line with a previous assessment of THS 2.2, demonstrating reproducibility of the results obtained.2 In addition, both cessation and switching to CHTP 1.2 aerosol exposure after three months exposure to CS reversed inflammatory lung responses, halted the progression of aortic plaque growth and reduced the perturbations of biological pathways in heart tissue, again to levels typically seen following exposure to fresh air alone.
Another study presented at SOT assessed lung inflammation, emphysema and the underlying molecular changes typically associated with lung cancer following up to 18 months of exposure to either CS or THS 2.2 aerosol.3 The study used a combination of traditional toxicology endpoints as well as systems toxicology techniques including histological, transcriptomic, and proteomic analysis of the lungs. In all endpoints, the biological impact of THS 2.2 aerosol was significantly lower than that of CS.
In line with the principles of 21st century toxicology, PMI is also developing novel in vitro methods for toxicity testing using human cells. Such models have the potential to reduce the necessity for animal testing and offer more cost-efficient and timely results, as well as a detailed understanding of the biological processes underlying toxicity. In collaboration with the Institute for In Vitro Sciences (IIVS), one study presented at the SOT evaluated the performance and reproducibility of three new in vitro assays.4 Six laboratories conducted comparison of the assays and found that these non-animal test systems may provide consistent human-relevant data corresponding to key events involved in respiratory disease. A further in vitro methodology using human bronchial epithelial cells was used in a study assessing the effects of THS 2.2 aerosol and CS.5
“The multi-lab comparison of these non-animal systems paves the way for more robust and meaningful strategies for toxicity testing,” said Dr. Holger Behrsing, Principal Scientist, IIVS. “They allow us to generate human-relevant data that will be of interest not just to industry and research scientists, but also to regulatory bodies. In order to develop these assays and ensure they reach their fullest potential, collaboration is key. Working with PMI and a range of different laboratories has allowed us to leverage expertise across the field and demonstrate the reproducibility of our findings. In the spirit of open science, we hope that this will open the door to further collaborations in the investigation, development, and validation of novel in vitro systems.”
In the assessment of three prototype e-cigarettes, biological changes following three-week’s exposure to the either the e-cigarette aerosols or CS were assessed using traditional and systems toxicology endpoints.6 CS exposure was found to induce biological responses associated with smoking-related diseases in the respiratory tract, while e-cigarette aerosol exposures, even at higher levels of nicotine delivery, resulted in substantially reduced molecular and microscopic changes. Two additional e-cigarette studies assessed the biological effects of flavor compounds typically added to e-cigarette liquids, demonstrating the potential to establish a scientifically substantiated list of minimally-toxic flavor ingredients.7,8
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1. Phillips, B. et al. A 6-month systems toxicology inhalation/cessation study in Apoe−/− mice to investigate cardiovascular and respiratory exposure effects of two candidate modified risk tobacco products compared with conventional cigarettes. Society of Toxicology Annual Meeting, March 11-15, 2018, San Antonio, Texas, USA.
2. Phillips, B. et al. An 8-month systems toxicology inhalation/cessation study in Apoe-/- mice to investigate cardiovascular and respiratory exposure effects of candidate modified risk tobacco product, THS 2.2, compared with conventional cigarettes. Toxicological Sciences: An Official Journal of the Society of Toxicology. 2016;149:411-32. Available online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725610/
3. Wong, ET. et al. Lung inflammation and emphysema in A/J mice in response to chronic exposure to aerosol from a candidate modified risk tobacco product and mainstream cigarette smoke. Society of Toxicology Annual Meeting, March 11-15, 2018, San Antonio, Texas, USA.
4. Frentzel, S. et al. Human in-vitro models for respiratory toxicology: evaluation of goblet cell hyperplasia, mucus production, and ciliary beating assays. Society of Toxicology Annual Meeting, March 11-15, 2018, San Antonio, Texas, USA.
5. van der Toorn, M. et al. Characterization of clones derived from human bronchial epithelial cells after long-term treatment with TPM from reference cigarettes versus THS 2.2. Society of Toxicology Annual Meeting, March 11-15, 2018, San Antonio, Texas, USA.
6. Lee, KM. et al. Biological changes in C57BL/6 mice following 3 weeks of inhalation exposure to cigarette smoke or e-vapor aerosols. Society of Toxicology Annual Meeting, March 11-15, 2018, San Antonio, Texas, USA.
7. Marescotti, D. et al. Systems toxicology assessment of flavors compounds present in E-vapor products using human primary bronchial epithelial cells. Society of Toxicology Annual Meeting, March 11-15, 2018, San Antonio, Texas, USA.
8. Ho, J. et al. Toxicological assessment of aerosol from flavored e-liquids in Sprague-Dawley rats; a 90-day sub-chronic inhalation study. Society of Toxicology Annual Meeting, March 11-15, 2018, San Antonio, Texas, USA.
9. Philip Morris International, 2016. United Nations Global Compact Communication on Progress 2015. Available online at: https://www.unglobalcompact.org/participation/report/cop/create-and-submit/active/245741