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Relationship: 1977


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Energy Deposition leads to Increase, DNA strand breaks

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Deposition of energy leading to lung cancer adjacent High High Brendan Ferreri-Hanberry (send email) Open for citation & comment WPHA/WNT Endorsed
Deposition of energy leading to population decline via DNA strand breaks and follicular atresia adjacent High Evgeniia Kazymova (send email) Under development: Not open for comment. Do not cite
Deposition of energy leading to population decline via DNA strand breaks and oocyte apoptosis adjacent Agnes Aggy (send email) Under development: Not open for comment. Do not cite
Deposition of energy leading to occurrence of cataracts adjacent High High Arthur Author (send email) Open for citation & comment
Deposition of energy leads to vascular remodeling adjacent High High Cataia Ives (send email) Open for citation & comment
Deposition of Energy Leading to Learning and Memory Impairment adjacent High High Brendan Ferreri-Hanberry (send email) Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
bovine Bos taurus Low NCBI
rabbit Oryctolagus cuniculus Low NCBI
Pig Pig Low NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Direct deposition of ionizing energy refers to imparted energy interacting directly with the DNA double helix and producing randomized damage. This can be in the form of double strand breaks (DSBs), single-strand breaks, base damage, or the crosslinking of DNA to other molecules (Smith et al., 2003; Joiner, 2009; Christensen, 2014; Sage and Shikazono, 2017). Among these, the most detrimental type of DNA damage to a cell is DSBs. They are caused by the breaking of the sugar-phosphate backbone on both strands of the DNA double helix molecule, either directly across from each other or several nucleotides apart (Ward, 1988; Iliakis et al., 2015). This occurs when high-energy subatomic particles interact with the orbital electrons of the DNA causing ionization (where electrons are ejected from atoms) and excitation (where electrons are raised to higher energy levels) (Joiner, 2009). The number of DSBs produced and the complexity of the breaks is highly dependent on the amount of energy deposited on and absorbed by the cell. This can vary as a function of the dose-rate (Brooks et al., 2016) and the radiation quality which is a function of its linear energy transfer (LET) (Sutherland et al., 2000; Nikjoo et al., 2001; Jorge et al., 2012). LET describes the amount of energy that an ionizing particle transfers to media per unit distance (Smith et al., 2003; Okayasu, 2012a; Christensen et al., 2014). High LET radiation, such as alpha particles, heavy ion particles, and neutrons can deposit larger quantities of energy within a single track than low LET radiation, such as γ-rays, X-rays, electrons, and protons (Kadhim et al., 2006; Franken et al., 2012; Frankenberg et al., 1999; Rydberg et al., 2002; Belli et al., 2000; Antonelli et al., 2015). As such, radiation with higher LETs tends to produce more complex, dense structural damage, particularly in the form of clustered damage, in comparison to lower LET radiation (Nikjoo et al., 2001; Terato and Ide, 2005; Hada and Georgakilas, 2008; Okayasu, 2012a; Lorat et al., 2015; Nikitaki et al., 2016). Some data reports that low dose and low LER radiation can lead to complex lesions, which can cause unrepairable DNA damage. However, determining the actual frequency of the complexity of these lesions has proven challenging (Wilkinson et al., 2023). The complexity and yield of clustered DNA damage increases with ionizing density (Ward, 1988; Goodhead, 2006). However, clustered damage can also be induced even by a single radiation track through a cell.

While the amount of DSBs produced depends on the radiation dose (see dose concordance), it also depends on several other factors. As the LET increases, the complexity of DNA damage increases, decreasing the repair rate, and increasing toxicity (Franken et al., 2012; Antonelli et al., 2015).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The strategy for collating the evidence on radiation stressors to support the relationship is described in Kozbenko et al 2022.  Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall Weight of Evidence for this KER: High

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The biological rationale linking the direct deposition of energy on DNA with an increase in DSB formation is strongly supported by numerous literature reviews that are available on this topic (J .F. Ward, 1988; Lipman, 1988; Hightower, 1995; Terato & Ide, 2005; Goodhead, 2006; Kim & Lee, 2007; Asaithamby et al., 2008; Hada & Georgakilas, 2008; Jeggo, 2009; Clement, 2012; Okayasu, 2012b; Stewart, 2012; M. E. Lomax et al., 2013; EPRI, 2014; Hamada, 2014; Moore et al., 2014; Desouky et al., 2015; Ainsbury, 2016; Foray et al., 2016; Hamada & Sato, 2016; Hamada, 2017a; Sage & Shikazono, 2017; Chadwick, 2017; Wang et al., 2021; Nagane et al., 2021; Sylvester et al., 2018; Baselet et al., 2019). Ionizing radiation can be in the form of high energy particles (such as alpha particles, beta particles, or charged ions) or high energy photons (such as gamma-rays or X-rays). Ionizing radiation can break the DNA within chromosomes both directly and indirectly, as shown through using velocity sedimentation of DNA through neutral and alkaline sucrose gradients. The most direct path entails a collision between a high-energy particle or photon and a strand of DNA.

Additionally, excitation of secondary electrons in the DNA allows for a cascade of ionization events to occur, which can lead to the formation of multiple damage sites (Joiner, 2009). As an example, high-energy electrons will traverse a DNA molecule in a mammalian cell within 10-18 s and 10-14 s, resulting in 100,000 ionizing events per 1 Gy dose in a 10 μm cell (Joiner, 2009). The amount of damage can be influenced by factors such as the cell cycle stage and chromatin structure. It has been shown that in more condensed, packed chromatin structures such as those present in intact cells and heterochromatin, it is more difficult for the DNA to be damaged (Radulescu et al., 2006; Agrawala et al., 2008; Falk et al., 2008; Venkatesh et al., 2016). In contrast, DNA damage is more easily induced in lightly-packed chromatin such as euchromatin and nucleoids, (Radulescu et al., 2006; Falk et al., 2008; Venkatesh et al., 2016).

Of the possible radiation-induced DNA damage types, DSB is considered to be the most harmful to the cell, as there may be severe consequences if this damage is not adequately repaired (Khanna & Jackson, 2001; Smith et al., 2003; Okayasu, 2012a; M. E. Lomax et al., 2013; Rothkamm et al., 2015).

A considerable fraction of DSBs can also be formed in cells through indirect mechanisms.  In this case, deposited energy can split water molecules near DNA, which can generate a significant quantity of reactive oxygen species in the form of hydroxyl free radicals (Ward, 1988; Wolf, 2008; Desouky et al., 2015; Maier et al., 2016, Cencer et al., 2018; Bains, 2019; Ahmadi et al., 2021). Estimates using models and experimental results suggest that hydroxyl radicals may be present within nanoseconds of energy deposition by radiation (Yamaguchi et al., 2005). These short-lived but highly reactive hydroxyl radicals may react with nearby DNA. This will produce DNA damage, including single-strand breaks and DSBs (Ward, 1988; Sasaki, 1998; Desouky et al., 2015; Maier et al., 2016). DNA breaks are especially likely to be produced if the sugar moiety is damaged, and DSBs occur when two single-strand breaks are in close proximity to each other (Ward, 1988).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Uncertainties and inconsistencies in this KER are as follows:

  • Studies have shown that dose-rates (Brooks et al., 2016) and radiation quality (Sutherland et al., 2000; Nikjoo et al., 2001; Jorge et al., 2012) are factors that can influence the dose-response relationship.  
  • Low-dose radiation has been observed to have beneficial effects and may even invoke protection against spontaneous genomic damage (Feinendegen, 2005; Day et al., 2007; Feinendegen et al., 2007; Shah et al., 2012; Nenoi et al., 2015; Dalke, 2018). This protective effect has been documented in in vivo and in vitro, as reviewed by ICRP (2007) and UNSCEAR (2008) and can vary depending on the cell type, the tissue, the organ, or the entire organism (Brooks et al., 2016).
  • Depositing ionizing energy is a stochastic event; as such this can influence the location, degree and type of DNA damage imparted on a cell. As an example, studies have shown that mitochondrial DNA may also be an important target for genotoxic effects of ionizing radiation (Wu et al., 1999).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Modulating Factor 


Effects on the KER  



Increased concentration 

Decreased DNA strand breaks. 

DeGraff et al., 1992; Citrin & Mitchel, 2014 


Increased concentration 

Increased DNA strand breaks. 

De Angelis et al., 2006; Citrin & Mitchel, 2014 


Increased concentration 

Decreased DNA strand breaks. 

Milligan et al., 1995; Citrin & Mitchel, 2014 


Increased concentration 

Decreased DNA break repair. 

Sears & Turchi; Citrin & Mitchel, 2014 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

There is evidence of a response-response relationship between the deposition of energy and the frequency of DSBs. In studies encompassing a variety of biological models, radiation types and radiation doses, a positive, linear relationship was found between the radiation dose and the number of DSBs (Aufderheide et al., 1987; Sidjanin, 1993; Frankenberg et al., 1999; Sutherland et al., 2000; de Lara et al., 2001; Baumstark-Khan et al., 2003; Rothkamm & Lo, 2003; Kuhne et al., 2005; Rube et al., 2008; Grudzenski et al., 2010; Bannik et al., 2013; Shelke & Das, 2015; Antonelli et al., 2015; Hamada, 2017b; Dalke, 2018; Barazzuol et al., 2017; Geisel et al., 2012; Ungvari et al., 2013; Rombouts et al., 2013; Baselet et al., 2017). There were, however, at least four exceptions reported. When human blood lymphocytes were irradiated with X-rays in vitro, a linear relationship was only found for doses ranging from 6 - 500 mGy; at low doses from 0 - 6 mGy, there was a quadratic relationship reported (Beels et al., 2009). Secondly, simulation studies predicted that there would be a non-linear increase in DSBs as energy deposition increased, with a saturation point at higher LETs (Charlton et al., 1989). Furthermore, primary normal human fibroblasts exposed to 1.2 – 5 mGy X-rays at 5.67 mGy/min showed a supralinear relationship, indicating at low doses, the DSBs are mostly due to radiation-induced bystander effects. Doses above 10 mGy showed a positive linear relationship (Ojima et al., 2008). Finally, in the human lens epithelial cell line SRA01/04, DNA strand breaks appeared immediately after exposure to UVB (0.14 J/cm2) and were repaired after 30 minutes. They then reappeared after 60 and 90 minutes. Both were once again repaired within 30 minutes. However, the two subsequent stages of DNA strand breaks did not occur when exposed to a lower dose of UVB (0.014 J/cm2) (Cencer et al., 2018).  

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Data from temporal response studies suggests that DSBs likely occur within seconds to minutes of energy deposition by ionizing radiation. In a variety of biological models, the presence of DSBs has been well documented within 10 - 30 minutes of radiation exposure (Rogakou et al., 1999; Rube et al., 2008; Beels et al., 2009; Kuefner et al., 2009; Grudzenski et al., 2010; Antonelli et al., 2015; Acharya et al., 2010; Dong et al., 2015; Barazzuol et al., 2017; Sabirzhanov et al., 2020; Rombouts et al., 2013; Nübel et al., 2006; Baselet et al., 2017; Zhang et al., 2017; Gionchiglia et al., 2021); there is also evidence that DSBs may actually be present within 3 - 5 minutes of irradiation (Kleiman, 1990; Rogakou et al., 1999; Rothkamm & Lo, 2003; Rube et al., 2008; Grudzenski et al., 2010; Cencer et al., 2018). Interestingly, one study that focussed on monitoring the cells before, during and after irradiation by taking photos every 5, 10 or 15 seconds found that foci indicative of DSBs were present 25 and 40 seconds after collision of the alpha particles and protons with the cell, respectively. The number of foci were found to increase over time until plateauing at approximately 200 seconds after alpha particle exposure and 800 seconds after proton exposure (Mosconi et al., 2011).

After the 30 minute mark, DSBs have been shown to rapidly decline in number. By 24 hours post-irradiation, DSB numbers had declined substantially in systems exposed to radiation doses between 40 mGy and 80 Gy (Aufderheide et al., 1987; Baumstark-Khan et al., 2003; Rothkamm & Lo, 2003; Rube et al., 2008; Grudzenski et al., 2010; Bannik et al., 2013; Markiewicz et al., 2015; Russo et al., 2015; Antonelli et al., 2015; Dalke, 2018; Bains, 2019; Barnard, 2019; Ahmadi et al., 2021; Dong et al., 2015; Dong et al., 2014; Sabirzhanov et al., 2020; Rombouts et al., 2013; Baselet et al., 2017; Gionchiglia et al., 2021), with the sharpest decrease documented within the first 5 h (Kleiman, 1990; Sidjanin, 1993; Rogakou et al., 1999; Rube et al., 2008; Kuefner et al., 2009; Grudzenski et al., 2010; Bannik, 2013; Markiewicz et al., 2015; Shelke and Das, 2015; Cencer et al., 2018; Acharya et al., 2010; Park et al., 2022; Kim et al., 2014; Nübel et al., 2006). Interestingly, DSBs were found to be more persistent when they were induced by higher LET radiation (Aufderheide et al., 1987, Baumstark-Khan et al., 2003; Antonelli et al., 2015).

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not identified.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

This KER is plausible in all life stages, sexes, and organisms with DNA. The majority of the evidence is from In vivo adult mice and human In vitro models that do not specify the sex. 


List of the literature that was cited for this KER description. More help

Agrawala, P.K. et al. (2008), "Induction and repairability of DNA damage caused by ultrasoft X-rays: Role of core events.", Int. J. Radiat. Biol., 84(12):1093–1103. doi:10.1080/09553000802478083.

Ahmadi, M. et al. (2021), “Early responses to low-dose ionizing radiation in cellular lens epithelial models”, Radiation research, Vol.197/1, Radiation Research Society, United States, 

Ainsbury, E. A. et al. (2016), “Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research”, Mutation research. Reviews in mutation research, Vol. 770, Elsevier B.V., Amsterdam, 

Alexander, J. L. and Orr-Weaver, T. L. (2016), “Replication fork instability and the consequences of fork collisions from replication”, Genes & Development, Vol. 30/20, Cold Spring Harbor Laboratory Press, 10.1101/gad.288142.116 

Allen, C. H. et al. (2018), “Raman micro-spectroscopy analysis of human lens epithelial cells exposed to a low-dose-range of ionizing radiation”, Physics in medicine & biology, Vol. 63/2, IOP Publishing, Bristol, 

Antonelli, A.F. et al. (2015), "Induction and Repair of DNA DSB as Revealed by H2AX Phosphorylation Foci in Human Fibroblasts Exposed to Low- and High-LET Radiation: Relationship with Early and Delayed Reproductive Cell Death", Radiat. Res. 183(4):417-31, doi:10.1667/RR13855.1.

Acharya, M. et al. (2010), “Consequences of ionizing radiation-induced damage in human neural stem cells”, Free Radical Biology and Medicine. 49(12):1846-1855, doi:10.1016/j.freeradbiomed.2010.08.021. 

Asaithamby, A. et al. (2008), "Repair of HZE-Particle-Induced DNA Double-Strand Breaks in Normal Human Fibroblasts.", Radiat Res. 169(4):437–446. doi:10.1667/RR1165.1.

Aufderheide, E. et al. (1987), “Heavy ion effects on cellular DNA: Strand break induction and repair in cultured diploid lens epithelial cells”, International journal of radiation biology and related studies in physics, chemistry and medicine, Vol. 51/5, Taylor & Francis, London, 

Bannik, K. et al. (2013), “Are mouse lens epithelial cells more sensitive to γ-irradiation than lymphocytes?”, Radiation and environmental biophysics, Vol. 52/2, Springer-Verlag, Berlin/Heidelberg, 

Bains, S. K. et al. (2019), “Effects of ionizing radiation on telomere length and telomerase activity in cultured human lens epithelium cells”, International journal of radiation biology, Vol. 95/1, Taylor & Francis, Abingdon, 

Barazzuol, L et al. (2017), “A coordinated DNA damage response promotes adult quiescent neural stem cell activation. PLOS Biology, 15(5). 

Barnard, S. G. R. et al. (2018), “Dotting the eyes: mouse strain dependency of the lens epithelium to low dose radiation-induced DNA damage”, International journal of radiation biology, Vol. 94/12, Taylor & Francis, Abingdon, 

Barnard, S. G. R. et al. (2019), “Inverse dose-rate effect of ionising radiation on residual 53BP1 foci in the eye lens”, Scientific Reports, Vol. 9/1, Nature Publishing Group, England, 

Barnard, S. G. R. et al. (2022), “Radiation-induced DNA damage and repair in lens epithelial cells of both Ptch1 (+/-) and Ercc2 (+/-) mutated mice”, Radiation Research, Vol. 197/1, Radiation Research Society, United States, 

Baselet, B. et al. (2019), “Pathological effects of ionizing radiation: endothelial activation and dysfunction”, Cellular and molecular life sciences, Vol. 76/4, Springer Nature, 

Baselet, B. et al. (2017), “Functional Gene Analysis Reveals Cell Cycle Changes and Inflammation in Endothelial Cells Irradiated with a Single X-ray Dose”, Frontiers in pharmacology, Vol. 8, Frontiers, 

Baumstark-Khan, C., J. Heilmann, and H. Rink (2003), ‘Induction and repair of DNA strand breaks in bovine lens epithelial cells after high LET irradiation”, Advances in space research, Vol. 31/6, Elsevier Ltd, England, 

Beels, L. et al. (2009), "g-H2AX Foci as a Biomarker for Patient X-Ray Exposure in Pediatric Cardiac Catheterization", Are We Underestimating Radiation Risks?":1903–1909. doi:10.1161/CIRCULATIONAHA.109.880385.

Belli M, Cherunbini R, Vecchia MD, Dini V, Moschini G, Signoretti C, Simon G, Tabocchini MA, Tiveron P. 2000. DNA DSB induction and rejoining in V79 cells irradiated with light ions: a constant field gel electrophoresis study. Int J Radiat Biol. 76(8):1095-1104.

Brooks, A.L., D.G. Hoel & R.J. Preston (2016), "The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation.", Int. J. Radiat. Biol. 92(8):405–426. doi:10.1080/09553002.2016.1186301.

Bucolo, C. et al. (1994), “The effect of ganglioside on oxidation-induced permeability changes in lens and in epithelial cells of lens and retina”, Experimental eye research, Vol. 58/6, Elsevier Ltd, London, 

Cabrera et al. (2011), “Antioxidants and the integrity of ocular tissues”, in Veterinary medicine international, SAGE-Hindawi Access to Research, United States. DOI: 10.4061/2011/905153 

Cadet, J. et al. (2012), “Oxidatively generated complex DNA damage: tandem and clustered lesions”, Cancer letters, Vol. 327/1, Elsevier Ireland Ltd, Ireland. 

Cannan, W.J. & D.S. Pederson (2016), "Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin.", J. Cell Physiol. 231(1):3–14. doi:10.1002/jcp.25048. 

Cencer, C. S. et al. (2018), “PARP-1/PAR activity in cultured human lens epithelial cells exposed to two levels of UVB light”, Photochemistry and photobiology, Vol. 94/1, Wiley, Hoboken, 

Chadwick, K.H., (2017), Towards a new dose and dose-rate effectiveness factor (DDREF)? Some comments., J Radiol Prot., 37:422-433. doi: 10.1088/1361-6498/aa6722. 

Charlton, D.E., H. Nikjoo & J.L. Humm (1989), "Calculation of initial yields of single- and double-strand breaks in cell nuclei from electrons, protons and alpha particles.", Int. J. Rad. Biol., 53(3):353-365, DOI: 10.1080/09553008814552501 

Christensen, D.M. (2014), "Management of Ionizing Radiation Injuries and Illnesses, Part 3: Radiobiology and Health Effects of Ionizing Radiation.", 114(7):556–565. doi:10.7556/jaoa.2014.109. 

Citrin, D.E. & J.B. Mitchel (2014), "Public Access NIH Public Access.", 71(2):233–236. doi:10.1038/mp.2011.182.doi. 

Dalke, C. et al. (2018), “Lifetime study in mice after acute low-dose ionizing radiation: a multifactorial study with special focus on cataract risk”, Radiation and environmental biophysics, Vol. 57/2, Springer Berlin Heidelberg, Berling/Heidelberg, 

Day, T.K. et al. (2007), "Adaptive Response for Chromosomal Inversions in pKZ1 Mouse Prostate Induced by Low Doses of X Radiation Delivered after a High Dose.", Radiat Res. 167(6):682–692. doi:10.1667/rr0764.1. 

De Angelis, P. M. et al. (2006), “Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery”, Molecular Cancer, Vol. 5/20, BioMed Central, 

DeGraff, W. G. et al. (1992), “Nitroxide-mediated protection against X-ray- and neocarzinostatin-induced DNA damage”, Free Radical Biology and Medicine, Vol. 13/5, Elsevier, 

Desouky, O., N. Ding & G. Zhou (2015), "ScienceDirect Targeted and non-targeted effects of ionizing radiation.", J. Radiat. Res. Appl. Sci. 8(2):247–254. doi:10.1016/j.jrras.2015.03.003. 

Dong et al. (2015), “Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of Mice. International Journal of Radiation Biology, 91(3):224–239. 

Dong, X. et al. (2014), “NEMO modulates radiation-induced endothelial senescence of human umbilical veins through NF-κB signal pathway”, Radiation Research, Vol. 183/1, BioOne, 

Dubrova, Y.E. & M.A. Plumb (2002), "Ionising radiation and mutation induction at mouse minisatellite loci The story of the two generations", Mutat. Res. 499(2):143–150. 

EPRI (2014), Epidemiology and mechanistic effects of radiation on the lens of the eye: Review and scientific appraisal of the literature, EPRI, California 

Falk, M., E. Lukášová & S. Kozubek (2008), "Chromatin structure influences the sensitivity of DNA to γ-radiation.", Biochim. Biophys. Acta. - Mol. Cell. Res. 1783(12):2398–2414. doi:10.1016/j.bbamcr.2008.07.010. 

Feinendegen, L.E. (2005), "UKRC 2004 debate Evidence for beneficial low level radiation effects and radiation hormesis. Radiology.", 78:3–7. doi:10.1259/bjr/63353075. 

Feinendegen, L.E., M. Pollycove & R.D. Neumann (2007), "Whole-body responses to low-level radiation exposure: New concepts in mammalian radiobiology.", Exp. Hematol. 35(4 SUPPL.):37–46. doi:10.1016/j.exphem.2007.01.011. 

Flegal, M. et al. (2015), "Measuring DNA Damage and Repair in Mouse Splenocytes After Chronic In Vivo Exposure to Very Low Doses of Beta- and γ-Radiation.", (July):1–9. doi:10.3791/52912. 

Foray, N., M. Bourguignon and N. Hamada (2016), “Individual response to ionizing radiation”, Mutation research. Reviews in mutation research, Vol. 770, Elsevier B.V., Amsterdam, 

Franken NAP, Hovingh S, Cate RT, Krawczyk P, Stap J, Hoebe R, Aten J, Barendsen GW. 2012. Relative biological effectiveness of high linear energy transfer alpha-particles for the induction of DNA-double-strand breaks, chromosome aberrations and reproductive cell death in SW-1573 lung tumour cells. Oncol reports. 27:769-774. 

Frankenberg D, Brede HJ, Schrewe UJ, Steinmetz C, Frankenberg-Scwager M, Kasten G, Pralle E. 1999. Induction of DNA Double-Strand Breaks by 1H and 4He Ions in Primary Human Skin Fibroblasts in the LET range of 8 to 124 keV/µm. Radiat Res. 151:540-549. 

Geisel, D. et al. (2012), “DNA double-strand breaks as potential indicators for the biological effects of ionising radiation exposure from cardiac CT and conventional coronary angiography: a randomised, controlled study”, European Radiology, Vol. 22/8, Springer Nature, 

Gionchiglia, N. et al. (2021), “Association of Caspase 3 Activation and H2AX γ Phosphorylation in the Aging Brain: Studies on Untreated and Irradiated Mice,” Biomedicines. 9(9):1166. doi: 10.3390/biomedicines9091166. 

Goodhead, D.T. (2006), "Energy deposition stochastics and track structure: What about the target?", Radiat. Prot. Dosimetry. 122(1–4):3–15. doi:10.1093/rpd/ncl498. 

Grudzenski, S. et al. (2010), "Inducible response required for repair of low-dose radiation damage in human fibroblasts.", Proc. Natl. Acad. Sci. USA. 107(32): 14205-14210, doi:10.1073/pnas.1002213107. 

Hada, M. & A.G. Georgakilas (2008), "Formation of Clustered DNA Damage after High-LET Irradiation: A Review.", J. Radiat. Res., 49(3):203–210. doi:10.1269/jrr.07123. 

Hamada, N. et al. (2006), “Histone H2AX phosphorylation in normal human cells irradiated with focused ultrasoft X rays: evidence for chromatin movement during repair”, Radiation Research, Vol. 166/1, Radiation Research Society, United States, 

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