Adverse Outcome Pathway on deposition of energy leading to lung cancer

The present Adverse Outcome Pathway (AOP) describes the linkage between lung cancer initiated from the Deposition of Energy (DoE) into a cell by a prototypic stressor such as radon gas. The multiple ionization events from DoE can directly break DNA double strands and initiate the activation of repair machinery through non-homologous end joining, an efficient, but error-prone process. When double strand breaks occur in DNA regions that transcribe critical genes, mutations generated by faulty repair may alter the function of these genes or cause chromosomal aberrations. These events alter the functions of many gene products and affect cell growth, cycling, and apoptosis. Cell proliferation is then promoted by escaping the regulatory control and forming hyperplasia in lung epithelial cells, leading eventually to lung cancer. Although the weight of evidence for this AOP is strong, uncertainties remain on dose-effect relationships across KEs, particularly for DoE delivered at low doses and dose-rates.