Towards the characterization of neutron carcinogenesis through direct action simulations of clustered DNA damage

Abstract

Neutron exposure poses a unique radiation protection concern because neutrons have a large, energy-dependent relative biological effectiveness (RBE) for stochastic effects. Recent computational studies on the microdosimetric properties of neutron dose deposition have implicated clustered DNA damage as a likely contributor to this marked energy dependence. So far, publications have focused solely on neutron RBE for inducing clusters of DNA damage containing two or more DNA double strand breaks (DSBs). In this study, we have conducted a novel assessment of neutron RBE for inducing all types of clustered DNA damage that contain two or more lesions, stratified by whether the clusters contain DSBs (complex DSB clusters) or not (non-DSB clusters). This assessment was conducted for eighteen initial neutron energies between 1 eV and 10 MeV as well as a reference radiation of 250 keV x-rays. We also examined the energy dependence of cluster length and cluster complexity because these factors are believed to impact the DNA repair process. To carry out our investigation, we developed a user-friendly TOPAS-nBio application that includes a custom nuclear DNA model and a novel algorithm for recording clustered DNA damage. We found that neutron RBE for inducing complex DSB clusters exhibited similar energy dependence to the canonical neutron RBE for stochastic radiobiological effects, at multiple depths in human tissue. Qualitatively similar results were obtained for non-DSB clusters, although the quantitative agreement was lower. Additionally we identified a significant neutron energy dependence in the average length and complexity of clustered lesions. These results support the idea that many types of clustered DNA damage contribute to the energy dependence of neutron RBE for stochastic radiobiological effects and imply that the size and constituent lesions of individual clusters should be taken into account when modeling DNA repair. Our results were qualitatively consistent for (i) multiple radiation doses (including a low-dose 0.1 Gy irradiation), (ii) variations in the maximal lesion separation distance used to define a cluster, and (iii) two distinct collections of physics models used to govern particle transport. Our complete TOPAS-nBio application has been released under an open-source license to enable others to independently validate our work and to expand upon it.

Nanoscale Calculation of Proton-Induced DNA Damage Using a Chromatin Geometry Model with Geant4-DNA

“…We choose these distances because 10 bp was used most frequently, which is approximately one turn of the double helix, and 3 bp was used by Charlton et al [ 35 ]. A value of 30 bp causes DSBs in a dilute solution at room temperature [ 79 ], whereas 40 bp could alter the DNA repair process [ 58 ].…”

“…Geant4-DNA combined the G4DNACPA100ElasticModel with the G4DNAChampionElasticModel into a new physics constructor G4EmDNAPhysics_option8 (option8) [ 56 ]. Similarly, Lund et al, have developed a physics constructor called G4EmDNAPhysics_hybrid2and4(hereafter “option2and4”) to extract the best features of option2 and option4 [ 57 , 58 ] in TOPAS-nBio [ 59 , 60 ], which is an extension to the TOPAS [ 61 ] Monte Carlo application based on Geant4. All their work was aimed at developing a recently advanced elastic model that would perform better than any of Geant4’s electromagnetic (EM) models.…”

Neutron biological effectiveness in inducing DNA damage: a full mapping as a function of incident neutron energy and depth in a human-sized phantom

“…The statistical uncertainty of the underlying simulations as well as the deviations of analytical fits from the simulation results were below a few percent 14 . The database of simulation results includes the yield of specific DNA damage classes due to different light ions: 1 H, 4 He, 7 Li, 9 Be, 11 B, 12 C, 14 N, 16 O, 20 Ne in a wide energy range, from ≈ 0.5 GeV/u down to stopping. Included are both direct damage, from radiation interactions with the software representation of the DNA molecule, and indirect damage, mediated by radical production in the water environment surrounding the DNA.…”

“…A first model based on a fully mechanistic approach was proposed by Baiocco et al 11 , to determine the energy dependence of neutron RBE for DNA damage, specifically considering as damage endpoint clusters of Double Strand Breaks (at least 2 DSBs within a genomic lenght of 25 bp). In a recent work 12 , a similar approach has been used to model the neutron RBE for the induction of clustered DNA damage, showing a substantial agreement in the RBE energy dependence. The work presented here follows and updates the modelling strategy proposed in Baiocco et al, 2016 11 , coupling the capabilities of different simulation approaches: the Monte Carlo transport code PHITS 13 has been used to locate and analyse neutron interactions inside a biological target of human size.…”

High-Accuracy Relative Biological Effectiveness Values Following Low-Dose Thermal Neutron Exposures Support Bimodal Quality Factor Response with Neutron Energy

“…However, the high ionization density and greater DNA damage potential of the thermal neutron exposures justify use of these assays at lower absorbed doses. Neutron irradiation can cause elevated levels of complex DNA lesions, notably doublestrand break (DSB) clusters and non-DSB clusters, compared to X-ray radiation [25].…”