On the Monte Carlo simulation of neutron-induced indirect DNA damage to estimate neutron relative biological effectiveness
Image credit: James ManaladAbstract
The exposure of patients undergoing high-energy radiotherapy to secondary neutron radiation poses a risk for iatrogenic secondary cancer induction. Ionizing radiation, such as neutrons, inflicts damage to the DNA molecule via energy depositions in DNA atoms (direct action) and via the radiolysis of nearby water molecules that results in chemical species capable of reacting with DNA segments to induce damage (indirect action). Our goal is to elucidate the underlying mechanisms of neutron-induced carcinogenesis by investigating the roles of direct and indirect action in the formation of clustered DNA lesions (especially those containing double-strand breaks or DSBs), which is believed to be a main pathway by which radiation-induced mutagenic consequences emerge. Our research group has recently explored the role of neutron direct action [1], but a similar study on neutron indirect action was outstanding. Objectives: The aims of this project were to (i) estimate the relative biological effectiveness (RBE) of neutrons for inducing DSB-containing clusters (complex DSB clusters) due to the combined effects of direct and indirect action, and (ii) to determine whether such RBE estimation may be used as a measure of neutron carcinogenic risk. Methods: In this work, the existing simulation pipeline of our research group on the direct action of ionizing radiation (built using the TOPAS and TOPAS-nBio frameworks) [1] was extended to incorporate an implementation of indirect action that has been benchmarked against published in vitro and in silico studies. Using our in-house geometric DNA model [1] and the updated simulation pipeline, we simulated irradiations of monoenergetic neutrons and reference 250 keV X-rays. The DNA damage yields obtained from these simulations were used to estimate energy-dependent neutron RBE for inducing complex DSB clusters. Results: Our results show that the majority of neutron-induced DNA damage events were isolated simple lesions due to indirect action, while most clustered lesions were hybrid (direct and indirect action) in nature. Our estimated neutron RBE for inducing complex DSB clusters was found to be smaller in magnitude than previous estimates that only considered direct action, despite our larger yields of complex DSB clusters. We suspect that this was due to the much higher density of lesions in neutron-induced damage clusters, resulting in more lesions contributing to each cluster and thus a lower increase in number of clusters relative to the reference X-rays. Conclusions: Including indirect action in the simulation of neutron-induced complex DSB clusters was found to significantly reduce neutron RBE (~50%), and thus indirect action is an important consideration when modeling neutron carcinogenic risk.
James Manalad
PhD Student, Former MSc Student
Logan Montgomery
PhD Student
