The Adverse Outcome Pathway (AOP) framework is a valuable tool for understanding the mode of action of a stressor. While traditionally used to supplement chemical risk assessment, this concept could also be useful in disease-related toxicological risk assessment. To this end, we developed in vitro test methods as an original version of AOP148 (AO: lung function decrease) to serve as a reference for key events. Through repeated exposure of 3D-cultured bronchial epithelial cells to whole cigarette smoke, we successfully observed goblet cell hyperplasia and mucus hypersecretion. However, since the AOP framework is based on qualitative mode of action, one needs to translate AOP into quantitative model to enable risk assessment process. To address this, we developed quantitative AOP (qAOP) models using Bayesian formalism. These models allow us to evaluate the probability of adverse outcomes occurring based on in vitro test results. In this talk, we will demonstrate that although data generation with next-generation-inhalable products is still ongoing, our approach holds promise for relative risk assessment among tobacco products, effectively highlighting the differences in disease risk between combustible cigarettes and NGPs. We will also discuss the importance of investigating clinical relevance, including exposure alignment between in vitro and in vivo, to enhance the reliability of our risk assessment framework.

CORESTA SSPT2023 - NAM Symposium