Molecular Dynamics and Multiscale Computational Modeling of Radon Progeny-Induced DNA Damage and Repair Mechanisms in Lung Epithelial Cells

Abstract

Radon and its progeny are the leading source of natural radiation exposure and a well-established cause of lung cancer, yet the mechanistic basis linking alpha-particle track structures to population-level risk remains insufficiently resolved. In this study, we developed a multiscale computational framework that integrates spatial ionization patterns, DNA damage clustering, repair pathway kinetics, and cell fate outcomes into a biologically based dose-response (BBDR) model. Simulations revealed that alpha-particle track cores generate dense clusters of double-strand breaks prone to misrepair, while the penumbra produces more dispersed lesions largely repairable by cellular mechanisms. Protein–DNA binding kinetics distinguished repair-efficient from misrepair-prone configurations, and stochastic cell fate modeling demonstrated how mutation accumulation arises from the interplay of repair, apoptosis, and misrepair. When embedded into a multistage clonal expansion model, these mechanistic outputs reproduced excess relative risk (ERR) estimates of 8–10% per 100 Bq·m⁻³, consistent with pooled residential epidemiological data and authoritative risk assessments. This work provides a mechanistic bridge between molecular-scale damage and epidemiological observations, reducing uncertainty in low-dose extrapolation and strengthening the scientific basis for radon risk assessment and public health policy.