Quantitative Adverse Outcome Pathway: A New Prediction Tool to Assess Human Risk of Decreased Lung Function When Switching from Combustible Cigarettes to Heated Tobacco Products

      Mathis, C.; Sewer, A.; Calvino, F.; Luettich, K.; Iskandar, A.; Talikka, M.

      Conference date
      Sep 25, 2023
      Conference name
      6th Scientific Summit on Tobacco Harm Reduction: Novel producs, Research & Policy 2023

      Adverse outcome pathways (AOPs) are simple linear or branching paths representing a sequence of molecular, cellular, tissue, and organ level perturbations (or “key events”). They are triggered by the interaction between a particular compound and a cellular component (identified as the “molecular initiating event”) that precedes an adverse outcome (AO) at the organism or population level. AOPs integrate data from alternative test methods in line with the “3R” paradigm (to refine, reduce, and replace laboratory animals) and serve the development of new predictive tools for hazard assessment.

      Here, we took advantage of the AOP 411 that describes how increased oxidative stress, reduced ciliary beat frequency (CBF), and reduced mucociliary clearance (MCC) sequentially lead to decreased lung function to develop mathematical models reflecting the relationships between key events and allowing the quantification of AO prediction. As a case study, we evaluated the potential risk of impaired lung function associated with tobacco heating system (THS) use compared with cigarette smoking, by using data from a series of in vitro studies on the THS, employing advanced human tissue culture models, and by mapping them in the AOP 411. Our new quantitative AOP (qAOP) predicted a 48.7% reduced risk of decreased CBF based on measurement of oxidative stress indicators and 18.4% reduced risk of decreased MCC based on measurement of CBF in THS aerosol compared with cigarette smoke-exposed cultures.

      Finally, modeling based on human MCC data predicted a 79.3% reduced risk of decreased lung function in heated tobacco product switchers compared with smokers. In summary, the development and use of this new qAOP may be a potent alternative to evaluate the risk of decreased lung function in the context of tobacco harm reduction while waiting for long-term clinical studies and epidemiological data.