Quantitative Modeling of In Vitro Data Using an Adverse Outcome Pathway for the Risk Assessment of Decreased Lung Function in Humans

February 11, 2024


Alain Sewer, Marja Talikka , Florian Calvino-Martin, Karsta Luettich, Anita Iskandar
PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland


  • AOP 411 Oxidative Stress Leading to Decreased Lung Function is considered
  • A quantitative model (qAOP) is proposed that uses in vitro/human data as input
  • The qAOP enables assessing the risk of the adverse outcome Decreased Lung Function
  • It is applied to subjects switching from smoking to using heated tobacco products
  • The qAOP results predict the reduction of the adverse outcome risk after switching

In the absence of epidemiological data, there is a need to develop computational models that convert in vitro findings to human disease risk predictions following toxicant exposure. In such efforts, in vitro data can be evaluated in the context of adverse outcome pathways (AOPs) that organize mechanistic knowledge based on empirical evidence into a sequence of molecular-, cellular-, tissue-, and organ-level key events that precede an adverse outcome (AO). Here we combined data from advanced in vitro organotypic airway models exposed to combustible cigarette (CC) smoke or Tobacco Heating System (THS) aerosol with an AOP for increased oxidative stress leads to decreased lung function. The mathematical modeling predicted reduced risk of decreased ciliary beating frequency (CBF) based on oxidative stress measurements and reduced risk of decreased mucociliary clearance (MCC) based on CBF measurements in THS aerosol- compared with CC smoke-exposed cultures. To extend the predictions to the AO of decreased lung function, we leveraged human MCC data from current smokers, nonsmokers, former smokers, and users of heated tobacco products. This approach provided a plausible prediction of diminished reduction in lung function in response to THS use compared with continued smoking. The current approach may also present a basis for an integrated approach to testing and assessment of tobacco products for future regulatory decision-making.

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