# Low Dose Ionising Radiation-Induced Hormesis: Therapeutic Implications to Human Health
## 6 Discussion  
A summary of both the hormetic and detrimental effects of LDIR and its underlying cellular and molecular mechanisms have been discussed. Low-dose radiation exposures can be used as an experimental tool to induce bio-responses such as the bystander effect, adaptive response, HRS, radioresistance, and genomic instability. Notably, the distinct biological effects of LDIR can be seen to be different in normal and cancerous cells. It has been shown that LDIR exerts its hormetic effect through its increased DNA repair efficiency, the antioxidant capacity, and the stimulated immune responses--albeit confined to in vitro studies; however, in vivo evidence is currently insufficient. In view of present-day radiotherapy that utilises photon, neutron, proton, and C-ions, it should be noted that radiation hormesis is also dependent on the LET of the radiation modality [75; 86; 88; 89; 92; 97; 98]. While it is clear that very a low dose of both low and high-LET radiation can result in the perturbation of intra and inter-cellular signalling and potentially produce protective effects, such as apoptosis in transformed pre-cancerous cells [77], the pattern of energy deposition is very different. For low-LET radiation down to approximately 1 mGy, essentially all cells will be traversed, on average receiving a similar dose and therefore damage (with some variability due to the stochastic nature of the interactions). However, for high-LET particles,such as a-particles, the same average dose to the cell population would result in the vast majority of the cells not being traversed, but the small fraction of cells that are traversed will receive a significant amount of damage along the path of the traversing particle, due to the high average dose of that particular cell. Interestingly, data suggest that the fraction of cells traversed is important in determining whether signalling within the cell population as a whole is perturbed [77]. Thus, further studies are required to rigorously determine the circumstances of how the low dose radiotherapy of both low and high LET may be used to maximise its bio-positive effects while preventing the cellular and molecular signalling pathways that could potentially contribute to the bio-negative effects of LDIR treatment. Hormesis has mostly been supported using in _vitro cell_ culture and lower invertebrate models. Therefore, a survey of animal models (including vertebrate and invertebrates) and occupational radiation workers exposed to low-dose IR, demonstrating life-span changes, cancer, and other metabolic disease risks would be important to develop a consensus on IR-induced hormesis and would benefit this field by addressing the prevailing controversies. However, epidemiological studies on radiation workers will be particularly challenging due to the need to deal with multiple confounding factors and the large numbers needed. Furthermore, this aspect of radiobiology is controversial and requires further discussion and debate in order to determine how future research should be conducted. In addition to animal studies, future epidemiological investigations with large sample sizes are also required to provide further evidence of potential clinical application for treating human diseases. In particular, the development of sensitive biomarkers may be crucial for the detection of early pathophysiological changes induced by LDIR.  
Conceptualisation, Y.S.L., M.T.C., D.A.B. and A.N.; writing--original draft preparation Y.S.L., M.T.C. and D.A.B.; writing--review and editing, Y.S.L., M.T.C., D.A.B., B.J., A.N., A.A. and M.A.H.; funding acquisition, D.A.B. and A.A. All authors have read and agreed to the published version of the manuscript.  
This research and APC were funded by Sunway University Internal Grant (INT-2019-SHMS-CBP-01), and [PERSON] acknowledges support from University Iman Abdulrahman Bin Faisal.  
Not applicable.  
The authors declare no conflict of interest.