Quantitative modeling of carcinogenesis induced by single beams or mixtures of space radiations using targeted and non-targeted effects

Igor Shuryak,Rainer K Sachs,David J Brenner

doi:10.1038/s41598-021-02883-y

Abstract

Ionizing radiations encountered by astronauts on deep space missions produce biological damage by two main mechanisms: (1) Targeted effects (TE) due to direct traversals of cells by ionizing tracks. (2) Non-targeted effects (NTE) caused by release of signals from directly hit cells. The combination of these mechanisms generates non-linear dose response shapes, which need to be modeled quantitatively to predict health risks from space exploration. Here we used a TE + NTE model to analyze data on APC(1638N/+) mouse tumorigenesis induced by space-relevant doses of protons, 4He, 12C, 16O, 28Si or 56Fe ions, or γ rays. A customized weighted Negative Binomial distribution was used to describe the radiation type- and dose-dependent data variability. This approach allowed detailed quantification of dose–response shapes, NTE- and TE-related model parameters, and radiation quality metrics (relative biological effectiveness, RBE, and radiation effects ratio, RER, relative to γ rays) for each radiation type. Based on the modeled responses for each radiation type, we predicted the tumor yield for a Mars-mission-relevant mixture of these radiations, using the recently-developed incremental effect additivity (IEA) synergy theory. The proposed modeling approach can enhance current knowledge about quantification of space radiation quality effects, dose response shapes, and ultimately the health risks for astronauts.

Highlights

Ionizing radiations encountered by astronauts on deep space missions produce biological damage by two main mechanisms: (1) Targeted effects (TE) due to direct traversals of cells by ionizing tracks. (2) Non-targeted effects (NTE) caused by release of signals from directly hit cells
Ionizing radiations cause biological damage in multiple ways, which can be usefully classified into two categories: (1) Targeted effects (TE), involving the consequences of direct traversals of cells by ionizing tracks leading to DNA double strand breaks and other lesions
These curves clearly indicate that Si and Fe ions were the most effective at tumorigenesis, among the studied radiation types (Fig. 2A)

Summary

Introduction

Ionizing radiations encountered by astronauts on deep space missions produce biological damage by two main mechanisms: (1) Targeted effects (TE) due to direct traversals of cells by ionizing tracks. (2) Non-targeted effects (NTE) caused by release of signals from directly hit cells. (2) Non-targeted effects (NTE) caused by release of signals from directly hit cells The combination of these mechanisms generates non-linear dose response shapes, which need to be modeled quantitatively to predict health risks from space exploration. Ionizing heavy ions are important in this context because they produce spatially clustered ionizations along defined tracks[4], whereas sparsely ionizing γ rays generate more random distributions of ionizations Such energy deposition differences between radiation types influence their biological effectiveness. A given cell nucleus is unlikely to be traversed by a heavy ion track core more than once during a space mission such as a trip to Mars and back, and most cell nuclei will not be traversed at all In such stochastic exposure scenarios, where the probability of TE induced by heavy ion track cores is relatively low, NTE are likely to be the dominant mechanism producing adverse health effects associated with heavy ions[1]. We assume that NTE responses can induce susceptible cells to switch from a normal state to an “activated” state, e.g. of persistent oxidative stress[15,16,17,18]

Methods

Results

Conclusion