Overview of Scientific Frameworks

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17 September 2024
CHAPTER 4 . OUR SMOKELESS SCIENCE

Overview of Scientific Frameworks

Why is there a need for a scientific assessment framework for Reduced-Risk*† Products?

Reduced-Risk*† Products (RRPs), whether they are Heated Products, Vapour Products or Oral Nicotine Pouches, are all relatively new. While we are still understanding their long-term effects, we know that in the short-term, our Smokeless Products are less risky than smoking. Absent conclusive epidemiology, there is no single test that would determine that a new product is, for certain, reduced risk compared to another. So scientists both from industry[1-5] and from public health[6,7,8] have set out a series of tests that, when taken as a whole, would help give confidence to comparative risk assessments.

Weight of evidence approaches

Most proposed scientific assessment frameworks include chemical, toxicological and clinical studies.

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Chemical studies

Chemical studies fall into two broad categories: the first measuring the level of toxicants found in the emissions of the RRP and the quantification of what reductions are seen relative to that of a reference cigarette.[9,10,11] The second examines whether there are toxicants not found in cigarette smoke present in the emissions of the RRP.[12,13,14]

 

Toxicological studies

Toxicological studies can be:

  • In silico: using computer models built on previous studies to assess the likely impact of any toxicants in RRP emissions[15] 
  • In vitro: using laboratory biological systems typically developed and validated for many different chemicals and mixtures to observe the impact of the emissions on cells cultured in the laboratory on biological changes to the cells[16,17,18] 
  • In vivo: which uses live animals and is not undertaken by BAT unless required to do so by regulators.[19] This looks at changes in organs or other biological material after exposure[20]
     

Clinical studies

Clinical studies ask people, typically regular adult smokers, to take part in studies where they attend clinics and provide samples of blood, urine or other biological samples. These are then used to measure biomarkers that either measure the amount of exposure to specific toxicants (biomarkers of exposure) or biological indicators of potential disease pathways (biomarkers of potential harm).[21,22] Other clinical studies look at nicotine uptake.[23,24]

 

The above focus is on the potential reduction of risk to a smoker as compared to continued smoking. To look at the reduction in harm to a population, other studies may be needed that look at what happens in terms of uptake, use and cessation when an RRP is commercially introduced.

 

Comparison to scientific frameworks for other product categories

The assessment of RRPs consists of some relatively unique challenges given the range of diseases associated with smoking. Assessment frameworks for other product categories provide some guidance. These are often focused on efficacy against a specific biological endpoint (such as blood pressure reduction) or disease (such as Alzheimer’s) and their evaluations are weighted to several phases of clinical study to determine what effect the new drug may have, and what side-effects might occur.[25] For functional foods, where additives may be applied that might have a biological benefit, again typically the biological endpoint (such as reduction in cholesterol levels) is reasonably closely defined.[26]

 

In each of these cases there are often regulators who set common approaches to what data is expected and how it will be judged. However, with RRPs there are, to date, few regulators who have set out an assessment framework. The U.S. Food and Drug Administration is an example of one that does have guidelines but no prescriptive approach.

References

[1] Smith, M.R., et al., Evaluation of the Tobacco Heating System 2.2. Part 1: Description of the system and the scientific assessment program. Regul Toxicol Pharmacol, 2016. 81(2): p.S17-S26. DOI: 10.1016/j.yrtph.2016.07.006

[2] Cordery, S., et al., The Product Science of Electrically Heated Tobacco Products: An Updated Narrative Review of the Scientific Literature. Cureus, 2024. 16(5): e61223. DOI: 10.7759/cureus.61223

[3] Lowe, F., et al., A framework for the assessment of reduced risk tobacco and nicotine products. Recent Adv Tob Sci, 2015. 41: p. 51-82. Available at: https://www.bat-science.com/pdfs/a-framework-for-the-assessment-of-reduced-risk-tobacco-and-nicotine-products.pdf

[4] Murphy, J., et al., Assessing modified risk tobacco and nicotine products: description of the scientific framework and assessment of a closed modular electronic cigarette. Regul Toxicol Pharmacol, 2017. 90: p. 342-357. DOI: 10.1016/j.yrtph.2017.09.008

[5] Peitsch, M.C., et al., Next-generation tobacco and nicotine products: Substantiating harm reduction and supporting tobacco regulatory science. Toxicol Res App, 2018. 2. DOI: 10.1177/2397847318773701

[6] Institute of Medicine, Clearing the smoke: Assessing the science base for tobacco harm reduction. National Academies Press, 2001. Available at: http://nap.nationalacademies.org/10029

[7] Institute of Medicine, Scientific Standards for Studies on Modified Risk Tobacco Products. National Academies Press, 2012. DOI: 10.17226/13294

[8] U.S. Food & Drug Administration, Section 911 of the Federal Food, Drug, and Cosmetic Act - Modified Risk Tobacco Products. 2018. Available at: https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/section-911-federal-food-drug-and-cosmetic-act-modified-risktobacco-products (Accessed: 2 July 2024)

[9] Margham, J., et al., Chemical composition of aerosol from an e-cigarette: a quantitative comparison with cigarette smoke. Chem Res Toxicol, 2016. 29(10): p. 1662-1678. DOI: 10.1021/acs.chemrestox.6b00188

[10] Wagner, K.A., et al., An evaluation of electronic cigarette formulations and aerosols for harmful and potentially harmful constituents (HPHCs) typically derived from combustion. Regul Toxicol Pharmacol, 2018. 95: p. 153-160. DOI: 10.1016/j.yrtph.2018.03.012

[11] Jaccard, G., et al., Comparative assessment of HPHC yields in the Tobacco Heating System THS2.2 and commercial cigarettes. Regul Toxicol Pharmacol, 2017. 90: p. 1-8. DOI: 10.1016/j.yrtph.2017.08.006

[12] Bentley, M. C., et al., Comprehensive chemical characterization of the aerosol generated by a heated tobacco product by untargeted screening. Anal Bioanal Chem, 2020. 412: p. 2675-2685. DOI: 10.1007/s00216-020-02502-1

[13] Shah, N.H., et al., Non-targeted analysis using gas chromatography-mass spectrometry for evaluation of chemical composition of E-vapor products. Front Chem, 2021. 9: 742854. DOI: 10.3389/fchem.2021.742854

[14] Rawlinson, C., et al., Chemical characterisation of aerosols emitted by electronic cigarettes using thermal desorption–gas chromatography–time of flight mass spectrometry. J Chromatogr A, 2017. 1497: p. 144-154. DOI: 10.1016/j.chroma.2017.02.050

[15] Murphy, J., et al. Assessing modified risk tobacco and nicotine products: Description of the scientific framework and assessment of a closed modular electronic cigarette. Regul Toxicol Pharmacol, 2017. 90: p. 342-357. DOI: 10.1016/j.yrtph.2017.09.008

[16] Caruso, M., et al., Screening of different cytotoxicity methods for the assessment of ENDS toxicity relative to tobacco cigarettes. Regul Toxicol Pharmacol, 2021. 125:105018. DOI: 10.1016/j.yrtph.2021.105018

[17] Miller-Holt, J., et al., In vitro evaluation of mutagenic, cytotoxic, genotoxic and oral irritation potential of nicotine pouch products. Toxicol Rep, 2022. 9: p. 1316-1324. DOI: 10.1016/j.toxrep.2022.06.008

[18] Thorne, D., et al., The genotoxicological assessment of a tobacco heating product relative to cigarette smoke using the in vitro micronucleus assay. Toxicol, 2020. 7: p. 1010-1019. DOI: 10.1016/j.toxrep.2020.08.013

[19] Clippinger, A.J., et al., Alternative approaches for acute inhalation toxicity testing to address global regulatory and non-regulatory data requirements: An international workshop report. Toxicol In Vitro, 2018. 48: p. 53-70. DOI: 10.1016/j.tiv.2017.12.011

[20] Wong, E.T., et al., 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. Toxicol Sci, 2020. 178(1): p. 44-70. DOI: 10.1093/toxsci/kfaa131

[21] Goniewicz, M.L., et al., Comparison of nicotine and toxicant exposure in users of electronic cigarettes and combustible cigarettes. JAMA Netw Open, 2018. 1(8): e185937. DOI: 10.1001/jamanetworkopen.2018.5937

[22] Gale, N., et al., Changes in biomarkers after 180 days of tobacco heating product use: a randomised trial. Intern Emerg Med, 2021. 16(8): p. 2201-2212. DOI: 10.1007/s11739-021-02798-6

[23] Fearon, I.M., et al., Nicotine pharmacokinetics of electronic cigarettes: a review of the literature. Regul Toxicol Pharmacol, 2018. 100: p.25-34. DOI: 10.1016/j.yrtph.2018.09.004

[24] Liu, J., et al., Nicotine pharmacokinetics and subjective responses after using nicotine pouches with different nicotine levels compared to combustible cigarettes and moist smokeless tobacco in adult tobacco users. Psychopharmacol, 2022. 239(9): p. 2863-2873. DOI: 10.1007/s00213-022-06172-y

[25] U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research and Center for Drug Evaluation and Research, Guidance for Industry: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. 2010. Available at: https://www.fda.gov/media/71542/download

[26] D.az, L.D., et al., An international regulatory review of food health-related claims in functional food products labeling. J Funct Foods, 2020. 68:103896. DOI: 10.1016/j.jff.2020.103896

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