Toxicology studies

      Toxicology studies on smoke-free products

      After a product has been developed and has been shown to generate lower levels of harmful chemicals compared with levels found in cigarette smoke, we can then conduct toxicology studies. In the case of smoke-free tobacco products, the aim of this research is to confirm whether the reduction we see in the levels of harmful chemicals released by a smoke-free product, such as the Tobacco Heating System (THS), translates to reduced toxicity and shows the potential for reduced risk of smoking-related diseases in laboratory models. 

      Toxicological studies are one piece of overall product assessment

      Toxicological studies provide a good indication of the risk reduction and the confidence to move forward with clinical studies. From a regulatory standpoint, the main purpose of certain toxicology assays is to provide data for regulatory agencies on whether our products meet the defined acceptability criteria. These criteria include requirements for manufacturing and are prerequisites to clinical studies.

      Clinical studies, and later steps in the assessment program, are key to understanding the reduced-risk potential of a smoke-free product. We also take toxicology assessment a step further by using systems toxicology, which seeks to explain the relationship, or mechanism, that connects the initial exposure to the resulting effects.

      Of course, just as aerosol assessment alone is not enough, toxicological data are also not sufficient to prove that switching to a smoke-free product is of reduced risk compared with continued cigarette smoking. Specially designed clinical studies are required to answer such questions and, combined with an understanding of how people perceive and use these products, we can see what kind of impact these products will have on population health. We expect that our long-term studies will demonstrate that this impact is a beneficial one. 

      You can find a summary of our entire product assessment program in the PMI Science Booklet, and our publications, most of which are open-access, can be found via the publications library.

      Jump to a specific result from our toxicological studies on THS, or learn more about our methods:

      • Less toxic than smoke

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      • No increase in lung tumors, emphysema, or atherosclerosis

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      • Less teeth discoloration

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      • Toxicology methods

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      Tobacco Heating System aerosol was observed to have substantially reduced toxicity compared with cigarette smoke

      We have conducted a series of tests to compare the toxicity of THS aerosol with that of the smoke from a standard reference cigarette (3R4F). In our laboratories, we observed a substantial reduction in toxicity of THS aerosol compared with cigarette smoke.

      This result is part of our regulatory toxicology assessment which is performed under Good Laboratory Practice (GLP). GLP ensures uniformity, consistency, reliability, reproducibility, quality, and integrity in the methodology of the tests and therefore the results. The assays we use for this assessment include the Ames Assay, the Mouse Lymphoma Assay, the Neutral Red Assay, and OECD 28-day and 90-day studies.

      Read about the research that supports our conclusions on reduced toxicity:

      Evaluation of the Tobacco Heating System 2.2. Part 2: Chemical composition, genotoxicity, cytotoxicity, and physical properties of the aerosol
      Evaluation of the Tobacco Heating System 2.2. Part 4: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects compared with cigarette smoke
      In vitro systems toxicology assessment of a candidate Modified Risk Tobacco Product shows reduced toxicity compared to that of a conventional cigarette
      Evaluation of the Tobacco Heating System 2.2. Part 6: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of a mentholated version compared with mentholated and non-mentholated cigarette smoke
      Evaluation of the Tobacco Heating System 2.2. Part 6: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of a mentholated version compared with mentholated and non-mentholated cigarette smoke

      Tobacco Heating System aerosol does not increase the incidence and number of lung tumors, emphysema, or atherosclerosis in mouse models, as compared with cigarette smoke

      These systems toxicology studies relied on the A/J mouse, which is frequently used in cancer research because it is highly susceptible to lung tumor development, and on the Apoe-/- mouse that is susceptible to developing diseases like emphysema and atherosclerosis. Find the specific details of these studies and their relevant publications below.

      PMI follows the 3Rs principle in animal experimentation to replace, reduce, and refine the use of animals in research. As part of this, we have developed multiple different organ-on-a-chip technologies, and we have even received an award from PETA for contributions to a public knowledge base whose aim is to phase out animal testing by better understanding the chain of cause and effect between initial exposure and the ultimate effects on human health.

       

      Unlike cigarette smoke, the Tobacco Heating System aerosol does not lead to increased lung tumor incidence and multiplicity in a mouse model

      A study was conducted to compare carcinogenic effects of THS aerosol with 3R4F cigarette smoke over the lifetime (18 months) of A/J mice. The number of mice who developed tumors (incidence) and the number of tumors per animal (multiplicity) were significantly lower in THS aerosol exposed mice than in those exposed to smoke. Incidence and multiplicity were similar in the mice exposed to fresh air and those exposed to THS aerosol.

      Review the publications that support this research:

      Respiratory effects of exposure to aerosol from the candidate modified-risk tobacco product THS 2.2 in an 18-month systems toxicology study with A/J mice
      Reduced chronic toxicity and carcinogenicity in A/J mice in response to life-time exposure to aerosol from a heated tobacco product compared with cigarette smoke

      Unlike cigarette smoke, Tobacco Heating System aerosol does not cause emphysema in mice

      Emphysema is the destruction of lung tissue which occurs in up to 25% of smokers. This pathology can be mimicked in Apoe-/- mice by exposing them to cigarette smoke for up to 8 months. Unlike smoke from a standard reference cigarette (3R4F), the aerosol of THS did not induce emphysema in mice during this period. We also simulated smoking cessation by switching the exposure to air after an initial 2 months of exposure to cigarette smoke. We observed that switching from cigarettes to THS yields comparable results to cessation in mice. 

      Find the details of these results in the publications below:

      An 8-month systems toxicology inhalation/cessation study in Apoe−/− mice to investigate cardiovascular and respiratory exposure effects of a candidate Modified Risk Tobacco Product, THS 2.2, compared with conventional cigarettes
      Effects of cigarette smoke, cessation, and switching to two heat-not-burn tobacco products on lung lipid metabolism in C57BL/6 and Apoe−/− mice—An integrative systems toxicology analysis
      A six-month systems toxicology inhalation/cessation study in ApoE-/- mice to investigate cardiovascular and respiratory exposure effects of Modified Risk Tobacco Products, CHTP1.2 and THS2.2, compared with conventional cigarettes

      Unlike cigarette smoke, Tobacco Heating System aerosol does not increase atherosclerosis in mice

      Atherosclerosis is the deposition of fatty plaques in the arteries that occurs in up to 30% of smokers, which is higher than in nonsmokers. The disease can be mimicked by exposing Apoe-/- mice to cigarette smoke for 8 months. Unlike smoke from a standard reference cigarette (3R4F), the aerosol of THS did not increase atherosclerotic plaques in mice during this period. As mentioned in the results on emphysema above, we simulated smoking cessation by switching the exposure to air after an initial 2 months of exposure to cigarette smoke. Again, we observed that switching from cigarettes to THS yields comparable results to cessation in mice.

      Learn more from the publications supporting the above conclusions:

      An 8-month systems toxicology inhalation/cessation study in Apoe−/− mice to investigate cardiovascular and respiratory exposure effects of a candidate Modified Risk Tobacco Product, THS 2.2, compared with conventional cigarettes
      A six-month systems toxicology inhalation/cessation study in ApoE-/- mice to investigate cardiovascular and respiratory exposure effects of Modified Risk Tobacco Products, CHTP1.2 and THS2.2, compared with conventional cigarettes

      Tobacco Heating System aerosol discolors teeth significantly less than cigarette smoke

      Our studies on human teeth demonstrate the reduced discoloration effects of THS aerosol compared with the smoke of a 3R4F cigarette. Teeth that had cavities filled with dental resins were exposed to cigarette smoke or THS aerosol for 4 days a week, followed by brushing and incubation. After 3 weeks of such exposure, smoke exposure caused an overall larger color change compared with THS aerosol exposure. Exposure to smoke also caused mismatches between the tooth and the dental resins while THS aerosol exposure did not.

      Read the research studies presenting our dental health results:

      Effects of cigarette smoke and tobacco heating aerosol on color stability of dental enamel, dentin, and composite resin restorations
      Effects of cigarette smoking on color stability of dental resin composites

      Toxicology methods

      In addition to toxicology studies required by regulatory bodies, Philip Morris International has emerged as a pioneer in research to substantiate its smoke-free product portfolio. Learn more about the methods we use to generate, process, store, and analyze our toxicology data.

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      Reduced Risk Products ("RRPs”) is the term we use to refer to products that present, are likely to present, or have the potential to present less risk of harm to smokers who switch to these products versus continuing smoking. PMI has a range of RRPs in various stages of development, scientific assessment and commercialization. All of our RRPs are smoke-free products that deliver nicotine with far lower quantities of harmful and potentially harmful constituents than found in cigarette smoke.