Reanalysis of Mechanism-Inspired Relative Biological Effectiveness Models Based on Track-structure Monte Carlo Simulation.

PURPOSE: Models predicting relative biological effectiveness (RBE) are essential for proton and heavy ion radiotherapy. The Microdosimetric Kinetic Model (MKM) and Local Effect Model (LEM) are two primary classes of mechanism-inspired RBE models. Rigorous model evaluations should extend beyond their ability to reproduce known experimental data. This study systematically examines the core principles of these models by establishing specific test conditions designed to assess their fundamental predictive accuracy and robustness. METHODS: Track-structure Monte Carlo (TSMC) simulations were used to calculate DNA double-strand break (DSB) in nuclear domains (core principles of them) as reference datasets. For MKM, we systematically investigated the effects of domain and nucleus sizes on RBE-LET curves and compared the results with TSMC data. For LEM, the model-assumed dose-dependent DSB pattern was verified using TSMC data. Within the LEM framework, we further derived implicit cell-independent functional relationships: one between RBE and α/β, and the other linking α/β values under low- and high-LET irradiation. These relationships were subsequently validated using multi-cell experimental data. RESULTS: The predicted trends of domain size affecting RBE peak position and magnitude from MKM were inconsistent with TSMC results. The inconsistencies are attributed to saturation correction in MKM. For LEM, the clustered DSB yield obtained from TSMC under low-LET clearly departs from the Poisson distribution assumed during model derivation. Reproducing low αX/βX requires an exceedingly large giant loop domain, which pushes the predicted RBE peak to LET values below experimental observation. Furthermore, experimental data failed to support LEM's hypothesized cell-independent relationships. Strong cross-correlations among fitting residuals indicate missing key factors. These issues are attributed to binary classification of DSBs in LEM. CONCLUSION: Both the MKM and LEM show limitations in their mechanistic derivations. These findings highlight updated RBE models with clearly defined core terms and parameters rooted in well-established physical and biological mechanisms.