Induction of Chromosomal Aberrations at Fluences of Less Than One HZE Particle per Cell Nucleus

Abstract

The assumption of a linear dose response used to describe the biological effects of high LET radiation is fundamental in radiation protection methodologies. We investigated the dose response for chromosomal aberrations for exposures corresponding to less than one particle traversal per cell nucleus by high energy and charge (HZE) nuclei. Human fibroblast and lymphocyte cells where irradiated with several low doses of <0.1 Gy, and several higher doses of up to 1 Gy with O (77 keV/m), Si (99 keV/m), Fe (175 keV/m), Fe (195 keV/m) or Fe (240 keV/m) particles. Chromosomal aberrations at first mitosis were scored using fluorescence in situ hybridization (FISH) with chromosome specific paints for chromosomes 1, 2 and 4 and DAPI staining of background chromosomes. Non-linear regression models were used to evaluate possible linear and non-linear dose response models based on these data. Dose responses for simple exchanges for human fibroblast irradiated under confluent culture conditions were best fit by non-linear models motivated by a non-targeted effect (NTE). Best fits for the dose response data for human lymphocytes irradiated in blood tubes were a NTE model for O and a linear response model fit best for Si and Fe particles. Additional evidence for NTE were found in low dose experiments measuring H2AX foci, a marker of double strand breaks (DSB), and split-dose experiments with human fibroblasts. Our results suggest that simple exchanges in normal human fibroblasts have an important NTE contribution at low particle fluence. The current and prior experimental studies provide important evidence against the linear dose response assumption used in radiation protection for HZE particles and other high LET radiation at the relevant range of low doses.

Non-Targeted Effects Models Predict Significantly Higher Mars Mission Cancer Risk than Targeted Effects Models

“…Important evidence in support of NTEs as contributing to both cancer initiation and promotion is suggested by a large number of both in-vitro and in-vivo mechanistic studies 15–17, 44–46 , and studies with broad-beam irradiation such as alpha-particles 25, 26 or HZE particles 19, 20 . The main limitation of the current NTE model predictions is the lack of an additional tumor type to understand the possible generality of our results.…”

“…Analysis of the Harderian gland studies 9, 14, 18 and experiments for chromosomal aberrations at low dose 19, 20 suggests a model based on NTEs is favored over a targeted effects (TE) model, where the later assumes a linear dose response model consistent with DNA damage and misrepair assumptions, while the former suggests a supra-linear dose response occurs which increases the risk at low doses compared to the TE model. The NTE model is supported by many mechanistic studies 15–17 using micro-beams to direct radiation to targeted cells, medium transfer from irradiated to unirradiated cells, and inhibitors of reactive oxygen species, gap junctions and signaling pathways.…”

A comparison of mechanism‐inspired models for particle relative biological effectiveness (RBE)

“…For very high‐LET radiation types in which the mean‐specific energy () becomes comparable to the absorbed dose, the DSB distribution among a group of uniformly irradiated cells is poorly approximated by a Poisson distribution . A non‐Poisson distribution of initial DSB (or PLL in the MK model) gives rise to so‐called over‐ and underdispersion effects in the formation of chromosome aberrations and lethal damage . The conceptual and computational approaches taken in the LEM IV, MK, and RMF to model the density of potentially lethal DSB along individual tracks and among cells differ significantly but are nevertheless comparable in many ways, for example, the RBE for cell survival initially tends to increase in monotonic fashion with increasing LET.…”

“…19,44,48,52,98 A non-Poisson distribution of initial DSB (or PLL in the MK model) gives rise to so-called over-and underdispersion effects in the formation of chromosome aberrations and lethal damage. 122,123 The conceptual and computational approaches taken in the LEM IV, MK, and RMF to model the density of potentially lethal DSB along individual tracks and among cells differ significantly but are nevertheless comparable in many ways, for example, the RBE for cell survival initially tends to increase in monotonic fashion with increasing LET.…”

Late-occurring chromosome aberrations and global DNA methylation in hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon (28Si) ions

“…Only a few in vitro studies have been conducted to examine the effects of these ions with different energies (ranging from 170 to 1000 MeV/n, at doses ranging from less than 0.1-2 Gy) using various biological endpoints such as cytogenetics in human fibroblasts [4,5] and lymphocytes [5], including human bronchial epithelial cells [6]; or cell transformation in Syrian Hamster embryo cells [7]; or cell survival in human skin fibroblasts [8]; or the ␥-histone-2AX assay in human fibroblasts [9]. The results from these in vitro studies clearly indicate that 28 Si ions can be harmful to cells in culture even at low doses (as low as 2 cGy).…”