The Adverse Outcome Pathway for oxidative stress-mediated EGFR activation leading to decreased lung function

The Adverse Outcome Pathway (AOP) framework provides a means to outline a knowledge-driven sequence of events from exposure to adverse outcome. As a concept, AOPs have been readily accepted by the toxicology community as a means to organize available mechanistic information linking exposures to toxic effects in a standardized way encompassing all organizational levels of a given biological system. However, there is also an inherent benefit in applying AOPs to health outcomes that are not necessarily linked to standard toxicological end points, for example, in the context of predicting disease risk or in drug development. In this study, we propose an AOP for decreased lung function that originates in oxidative stress-mediated epidermal growth factor receptor activation in the airway epithelium. This article provides an overview of the supporting evidence for key events (KEs) on the molecular, cellular, tissue/organ, and organism level and how they relate to each other through key event relationships (KERs). The essentiality of the identified KEs, as well as the biological plausibility of the KERs, is also assessed. Moreover, the envisioned application of the proposed AOP is discussed, highlighting the utility of the AOP framework for developing preclinical tests that could prove useful in public health risk assessment for long-term e-cigarette use.