# Low Dose Ionising Radiation-Induced Hormesis: Therapeutic Implications to Human Health
## 4 The Phenomena of LDIR
### Low-Dose Hyper-Radiosensitivity and Increased Radioresistance  
[PERSON] et al. (2001) have reported that most cell lines exhibit hyper-radiosensitivity (HRS) to very low radiation doses (<10 cGy), not being predicted by back-extrapolating the cell survival response from higher doses. Additionally, as the dose is increased above 30 cGy there is increased/(induced) radioresistance (IRR), up to doses beyond \(\sim\)1 Gy [110]. This phenomenon of HRS precedes the occurrence of IRR to cell killing by radiation over the dose range from \(\sim\)0.5 to 1 Gy, and generally HRS is observed in cell lines that are radioresistanceint to 2 Gy doses, albeit not all cell types [110]. It is therefore appropriate that we describe these two phenomena together. Briefly, HRS refers to low-dose hyper-radiosensitive cells which die from a single LDIR that is between 0.1-0.3 Gy, due to the failure of the irradiated cell to trigger the repair mechanism [111; 112; 110], resulting in cell death. However, not all cells are hyper-susceptible to radiation, mainly depending on the different types of cells and also on the cell-cycle phase. Evidence of low-dose HRS in different cell types has been shown when human embryonic lung fibroblasts and lung cancer cells are exposed to the same range of low dose X-rays (20-100 mGy) [57]. When exposed to a low dose (50 mGy), a significant cell apoptosis rate was observed in the lung cancer cells compared to the normal human lung fibroblasts, demonstrating lung cancer cells to be extremely sensitive to LDIR [57]. This low-dose HRS characteristic may have important implications in cancer radiotherapy. [PERSON] et al. (1997) [111] reported that low-dose HRS occurs in mammalian cells at doses as low as \(<\)0.3 Gy but radioresistance is found with higher doses, at 1 Gy and above [111; 112; 113]. The mechanisms involved were proposed to be associated with a three-component model, consisting of damage recognition, signal transduction, and damage repair [114]. The key control element that influences low-dose HRS in irradiated cells has been attributed to the dose-dependent pre-mitotic cell cycle checkpoint specific to G2 phase cells when exposed to an extreme low-dose radiation environment. In his review, [PERSON] conceptualised a G2-centric concept of low-dose HRS that is exclusively associated with the survival response of cells in the G2 phase of the cycle but not in G1 or S phase cells [112]. The underlying mechanism of low-dose HRS has been partly attributed to the evasion of several cellular responses to the DNA repair process, including ATM, H2 AX, PARP, 53 BP1 and HDAC4 [114; 115; 116], and presumably affecting high-fidelity recombination repair. Moreover, [PERSON] et al. (2008) reported nuclei-only irradiation rather than the irradiation of the complete cell of V79 cells using synchrotron X-ray microbeam-induced HRS, suggesting that energy deposition in the cytoplasm might suppress HRS [117]. [PERSON] et al. (2013) also show that NO, a principal mediator of the induction of bystander cell death secreted by the irradiated cells, participate in mechanisms that suppress mutagenesisby selectively killing those genetically unstable cells that have defects in their antioxidative activity [118]. Additionally, other factors such as the cellular environment, cell-to-cell contact, nutritional deprivation, and cell density have also been shown to play a significant role in the hyper-radiosensitivity of cells [65]. Conversely to the above, IRR refers to the phenomenon in which cells may become resistant to a higher radiation dose after exposure to a smaller dose of ionising radiation. A radioresistant response is seen as the radiation exposure dose is increased up to approximately 1 Gy, whilst most of the cells exhibit low-dose HRS when exposed to a single low radiation dose (below 0.1- to 0.3 Gy) [65,111].