Extending the microdosimetry gamma model (MGM) to estimate induced DNA damage and its complexity at macroscopic scale...

Objective.DNA damage, particularly double-strand break (DSB), is the primary mechanism for cell death in radiation therapy. High-linear energy transfer particles, like protons and helium ions, induce more complex DSB than photons, increasing their biological effectiveness. Simulating particle transport at the DNA level with Monte Carlo (MC) codes is computationally intensive, often limiting studies to single cells. This study presents an efficient method using the microdosimetric gamma model (MGM) to estimate DSB numbers and complexity in macroscopic setups.Approach.The MGM analytically predicts the number of DSBs and their complexity induced by protons orα-particles. We integrated it into the TOPAS MC toolkit (TOPAS-MGM), enabling the calculation of DNA damage at macroscale scenarios. We have calculated DNA damage distributions inin-vitro-like geometries and water phantoms with proton and helium beams.Results.Cross-comparisons with TOPAS-nBio show that the DNA damage outputs from macroscopic simulations are consistent and 100 000 times faster than DNA scale simulations. We tested DNA damage induction with proton and helium ion beams and alpha-emitting radiopharmaceuticals. For clinical beams, the DNA along the beam path showed a significant increase in the number of induced DSB and their complexity at the Bragg peak, especially with helium ions. Radiopharmaceuticals induced a markedly heterogeneous number of damages compared to beams.Significance. This work offers a method to simulate DNA damage and its complexity in macroscale scenarios for protons andα-particles. The output could potentially be used to predict cell killing based on DNA repair models or to assess the biological effectiveness of particle therapy using DNA damage and complexity as key metrics.