Radiation-induced double-strand breaks by internal ex vivo irradiation of lymphocytes: Validation of a Monte Carlo simulation model using GATE and Geant4-DNA.

This study describes a method to validate a radiation transport model that quantifies the number of DNA double-strand breaks (DSB) produced in the lymphocyte nucleus by internal ex vivo irradiation of whole blood with the radionuclides ⁹⁰Y, ^99mTc, ¹²³I, ¹³¹I, ¹⁷⁷Lu, ²²³Ra, and ²²⁵Ac in a test vial using the GATE/Geant4 code at the macroscopic level and the Geant4-DNA code at the microscopic level.

Methods: The simulation at the macroscopic level reproduces an 8 mL cylindrical water-equivalent medium contained in a vial that mimics the geometry for internal ex vivo blood irradiation. The lymphocytes were simulated as spheres of 3.75 µm radius randomly distributed, with a concentration of 125 spheres/mL. A phase-space actor was attached to each sphere to register all the entering particles. The simulation at the microscopic level for each radionuclide was performed using the Geant4-DNA tool kit, which includes the clustering example centered on a density-based spatial clustering of applications with noise (DBSCAN) algorithm. The irradiation source was constructed by generating a single phase space from the sum of all phase spaces. The lymphocyte nucleus was defined as a water sphere of a 3.1 µm radius. The absorbed dose coefficients for lymphocyte nuclei (d_Lymph) were calculated and compared with macroscopic whole blood absorbed dose coefficients (d_Blood). The DBSCAN algorithm was used to calculate the number of DSBs. Lastly, the number of DSB∙cell^-1∙mGy^-1 (simulation) was compared with the number of radiation-induced foci per cell and absorbed dose (RIF∙cell^-1∙mGy^-1) provided by experimental data for gamma and beta emitting radionuclides. For alpha emitters, d_Lymph and the number of α-tracks∙100 cell^-1∙mGy^-1 and DBSs∙µm^-1 were calculated using experiment-based thresholds for the α-track lengths and DBSs/track values. The results were compared with the results of an ex vivo study with ²²³Ra.

Results: The d_Lymph values differed from the d_Blood values by -1.0% (⁹⁰Y), -5.2% (^99mTc), -22.3% (¹²³I), 0.35% (¹³¹I), 2.4% (¹⁷⁷Lu), -5.6% (²²³Ra) and -6.1% (²²⁵Ac). The number of DSB∙cell^-1∙mGy^-1 for each radionuclide was 0.015 DSB∙cell^-1∙mGy^-1 (⁹⁰Y), 0.012 DSB∙cell^-1∙mGy^-1 (^99mTc), 0.014DSB∙cell^-1∙mGy^-1 (¹²³I), 0.012 DSB∙cell^-1∙mGy^-1 (¹³¹I), and 0.016 DSB∙cell^-1∙mGy^-1 (¹⁷⁷Lu). These values agree very well with experimental data. The number of α-tracks∙100 cells^-1∙mGy^-1 for ²²³Ra and ²²⁵Ac where 0.144 α-tracks∙100 cells^-1∙mGy^-1 and 0.151 α-tracks∙100 cells^-1∙mGy^-1, respectively. These values agree very well with experimental data. Moreover, the linear density of DSBs per micrometer α-track length were 11.13 ± 0.04 DSB/µm and 10.86 ± 0.06 DSB/µm for ²²³Ra and ²²⁵Ac, respectively.

Conclusion: This study describes a model to simulate the DNA DSB damage in lymphocyte nuclei validated by experimental data obtained from internal ex vivo blood irradiation with radionuclides frequently used in diagnostic and therapeutic procedures in nuclear medicine.