13674-87-8ASLWPAWFJZFCKF-UHFFFAOYSA-NASLWPAWFJZFCKF-UHFFFAOYSA-N
TDCPPTris(1,3-dichloro-2-propyl)phosphate
2-Propanol, 1,3-dichloro-, phosphate (3:1)
DTXSID9026261PCO:0000001population of organismsVT:1000294egg quantityPCO:0000008population growth rate2decreasedGamma radiation2017-04-15T16:04:312017-04-15T16:04:31Ionizing Radiation<p>Ionizing radiation can vary in energy, dose, charge, and in the spatial distributions of energy transferred to other matter (linear energy transfer per unit length or LET) (ICRU 1970). At the same dose, low and high LET both generate energy deposition events, including many higher energy events (Goodhead and Nikjoo 1989). However, they differ in the spatial distribution and upper range of intensity of energy deposited. Lower LET such as gamma rays sparsely deposit many individual excitations or small clusters of excitations of low energy (Goodhead 1988). In contrast, high LET such as alpha particles have fewer tracks but readily transfer their energy to matter and therefore deposit their energy over a much smaller area (Goodhead 1994). Consequently, alpha and other high LET particles penetrate less deeply into tissue, interactions are densely focused on a narrow track, and individual energy depositions can be large (Goodhead 1988). These different energy deposition patterns can lead to differences in radiation effects including the pattern of DNA damage.</p>
<p>Exposure to ionizing radiation can come from natural and industrial sources. Space and terrestrial radiation includes a range of LET particles, while diagnostic radiation methods such as X-ray imaging, mammography and CT scans use low LET X-rays. Radiation therapy can use an external beam to direct radiation on a focused tissue area, or deposit solid or liquid radioactive materials in the body that release (mostly gamma) radiation internally. External radiotherapy typically uses X-rays but is moving towards higher LET charged particles such as protons and heavy ions (Durante, Orecchia et al. 2017).</p>
2019-05-03T12:36:362019-05-07T12:12:13Topoisomerase inhibitors2019-05-19T20:21:242019-05-19T20:21:24Radiomimetic compounds2019-05-19T20:21:422019-05-19T20:21:42Tris(1,3-dichloropropyl)phosphate - TDCPP2018-06-19T07:35:302018-06-19T07:59:12WCS_9606human10116rat10090mouse6239nematodeWCS_7955zebrafish3702thale-cress3349Scotch pineWCS_35525Daphnia magna3055Chlamydomonas reinhardtiiWCS_6396common brandling wormWCS_4472Lemna minor8030Salmo salarWikiUser_25human and other cells in cultureWCS_90988fathead minnow8078Fundulus heteroclitus8090Oryzias latipesWikiUser_22all species10095mice9913bovineWCS_9986rabbitWikiUser_24PigDeposition of EnergyEnergy DepositionMolecular<p><span style="color:#0000ff"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Deposition of energy refers to events where subatomic particles or electromagnetic radiation deposit energy in the media through which they transverse. The energy may either be sufficient (e.g. ionizing radiation) or insufficient (e.g. non-ionizing radiation) to ionize atoms or molecules (Beir, et al. 1999). </span></span></span></p>
<p><span style="color:#0000ff"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Ionizing radiation can cause the ejection of electrons from atoms and molecules, thereby </span></span></span><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">resulting in their ionization and the breakage of chemical bonds</span></span></span><span style="color:#0000ff"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">. The energy of these subatomic particles or electromagnetic waves ranges from 124 KeV to 5.4 MeV, and is dependent on the source and type of radiation (Zyla et al., 2020). Not all electromagnetic radiation is ionizing; as the incident radiation must have sufficient energy to free electrons from the atom or molecule’s electron orbitals. The energy can induce direct and indirect ionization events and </span></span></span><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">can be via internal (injections, inhalation, injection) or external exposure</span></span></span><span style="color:#0000ff"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">. Direct ionization is the principal path where charged particles interact with DNA to cause a biological damage. Photons, which are electromagnetic waves can also cause direct ionization. Indirect ionization produces free radicals of other molecules, specifically water, which can transform to damage critical targets such as DNA (Beir, et al. 1999; </span></span></span><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Balagamwala et al., 2013</span></span></span><span style="color:#0000ff"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">). Given the fundamental nature of energy deposition by nuclei, nucleons or elementary particles in material, this process is universal to all biological contexts.</span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Energy deposition is influenced by the linear energy transfer (LET) (Hall and Giaccia, 2018 UNSCEAR, 2020). High LET refers to energy above 10 keV μm-1 which produces more complex, dense structural damage than low LET radiation (below 10 keV μm-1). Low-LET particles produce sparse ionization events such as photons (X- and gamma rays), as well as high-energy protons. Low LET radiation travels farther into tissue but deposits smaller amounts of energy, whereas high LET radiation, which includes heavy ions, alpha particles and high-energy neutrons, does not travel as far but deposits larger amounts of energy into tissue at the same absorbed dose. The biological effect of the deposition of energy can be modulated by varying dose and dose rate of exposure, such as acute, chronic, or fractionated exposures (Hall and Giaccia, 2018). </span></span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px"><span style="color:#e74c3c">Non-ionizing radiation is a type of electromagnetic radiation that lacks the energy to ionize atoms or molecules. Examples of non-ionizing radiation include radio waves (wavelength: 100 km-1m), microwaves (wavelength: 1m-1mm), infrared radiation (wavelength: 1mm- 1 um), visible light (wavelengths: 400-700 nm), and ultraviolet radiation of longer wavelengths such as UVB (wavelengths: 315-400nm) and UVA (wavelengths: 280-315 nm). UVC radiation (X-X nm) is, in contrast to UVB and UVA, considered to be a type of ionizing radiation. Exposure to non-ionizing radiation occurs either from natural or anthropogenic sources, and include radio waves used for communication (broadcasting and cell phones), microwaves used in cooking food and in radar systems, infrared radiation emitted by warm objects or used in remote controls, thermal imaging and medical treatments. Visible light is the range of electromagnetic radiation that we can see and that is commonly used in photosynthesis in primary producers. UV radiation has key functions in melanisation (tanning) of a number of species, and exhibit key signalling roles in navigation and communication (e.g insects, aquatic invertebrates and fish), locomotory and predatory behavior (e.g. reptiles, birds and crustaceans) and growth and development (e.g. plants). UV radiation is also used in some medical treatments such as skin diseases (e.g. psoriasis, eczema, vitiligo and skin cancers). </span></span></span></p>
<table border="1" bordercolor="#ccc" cellpadding="5" cellspacing="0" style="border-collapse:collapse">
<tbody>
<tr>
<td style="background-color:#eeeeee; text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Radiation type</strong></span></span></td>
<td style="background-color:#eeeeee; text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Assay Name</strong></span></span></p>
</td>
<td style="background-color:#eeeeee; text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>References</strong></span></span></p>
</td>
<td style="background-color:#eeeeee; text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Description</strong></span></span></p>
</td>
<td style="background-color:#eeeeee; text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>OECD Approved Assay</strong></span></span></p>
</td>
</tr>
<tr>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ionizing radiation</span></span></td>
<td style="text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Monte Carlo Simulations (Geant4)</span></span></p>
</td>
<td style="text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Douglass et al., 2013; Douglass et al. 2012; <span style="color:#e74c3c">Zyla et al., 2020</span></span></span></p>
</td>
<td style="text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Monte Carlo simulations are based on a computational algorithm that mathematically models the deposition of energy into materials.</span></span></p>
</td>
<td style="text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">No</span></span></p>
</td>
</tr>
<tr>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ionizing radiation</span></span></td>
<td style="text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Fluorescent Nuclear Track Detector (FNTD)</span></span></p>
</td>
<td style="text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sawakuchi, 2016; Niklas, 2013; Koaira & Konishi, 2015</span></span></p>
</td>
<td style="text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">FNTDs are biocompatible chips with crystals of aluminium oxide doped with carbon and magnesium; used in conjuction with fluorescent microscopy, these FNTDs allow for the visualization and the linear energy transfer (LET) quantification of tracks produced by the deposition of energy into a material.</span></span></p>
</td>
<td style="text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">No</span></span></p>
</td>
</tr>
<tr>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ionizing radiation</span></span></td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Tissue equivalent proportional counter (TEPC)</span></span></td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Straume et al, 2015</span></span></td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Measure the LET spectrum and calculate the dose equivalent.</span></span></td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">No</span></span></td>
</tr>
<tr>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ionizing radiation</span></span></td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">alanine dosimeters/NanoDots</span></span></td>
<td style="text-align:center">
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Lind et al. 2019; Xie et al., 2022</span></span></p>
</td>
<td style="text-align:center"> </td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">No</span></span></td>
</tr>
<tr>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Non-ionizing radiation</span></span></td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">UV meters or radiameters</span></span></td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Xie et at., 2020</span></span></td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">UVA/UVB (irradiance intensity), UV dosimeters (accumulated irradiance over time), Spectrophoto meter (absorption of UV by a substance or material)</span></span></td>
<td style="text-align:center"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">No</span></span></td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Energy can be deposited into any substrate, both living and non-living; it is independent of age, taxa, sex, or life-stage. </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Taxonomic applicability: </strong>This MIE is not taxonomically specific. </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Life stage applicability: </strong>This MIE is not life stage specific. </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Sex applicability: </strong>This MIE is not sex specific. </span></span></span></p>
LowUnspecificHighAll life stagesModerateModerateModerateHighHighHighModerateHighModerateModerateHighLow<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Balagamwala, E. H. et al. (2013), “Introduction to radiotherapy and standard teletherapy techniques”,<em> Dev Ophthalmol,</em> Vol. 52, Karger, Basel, https://doi.org/10.1159/000351045 </span></span></span></p>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Beir, V. et al. (1999), “The Mechanistic Basis of Radon-Induced Lung Cancer”, in <em>Health Risks of Exposure to Radon: BEIR V</em>I, National Academy Press, Washington, D.C., https://doi.org/10.17226/5499 </span></span></span></p>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Douglass, M. et al. (2013), “Monte Carlo investigation of the increased radiation deposition due to gold nanoparticles using kilovoltage and megavoltage photons in a 3D randomized cell model”<em>, Medical Physics</em>, Vol. 40/7, American Institute of Physics, College Park, https://doi.org/10.1118/1.4808150 </span></span></span></p>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Douglass, M. et al. (2012), “Development of a randomized 3D cell model for Monte Carlo microdosimetry simulations.”, <em>Medical Physics</em>, Vol. 39/6, American Institute of Physics, College Park, https://doi.org/10.1118/1.4719963 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hall, E. J. and Giaccia, A.J. (2018), <em>Radiobiology for the Radiologist</em>, 8th edition, Wolters Kluwer, Philadelphia. </span></span></span></p>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kodaira, S. and Konishi, T. (2015), “Co-visualization of DNA damage and ion traversals in live mammalian cells using a fluorescent nuclear track detector.”, <em>Journal of Radiation Research</em>, Vol. 56/2, Oxford University Press, Oxford, https://doi.org/10.1093/jrr/rru091 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Lind, O.C., D.H. Oughton and Salbu B. (2019), "The NMBU FIGARO low dose irradiation facility", <em>International Journal of Radiation Biology</em>, Vol. 95/1, Taylor & Francis, London, https://doi.org/10.1080/09553002.2018.1516906.</span></span></p>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sawakuchi, G.O. and Akselrod, M.S. (2016), “Nanoscale measurements of proton tracks using fluorescent nuclear track detectors.”,<em> Medical Physics</em>, Vol. 43/5, American Institute of Physics, College Park, https://doi.org/10.1118/1.4947128 </span></span></span></p>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Straume, T. et al. (2015), “Compact Tissue-equivalent Proportional Counter for Deep Space Human Missions.”,<em> Health physics,</em> Vol. 109/4, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1097/HP.0000000000000334 </span></span></span></p>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Niklas, M. et al. (2013), “Engineering cell-fluorescent ion track hybrid detectors.”, <em>Radiation Oncology</em>, Vol. 8/104, BioMed Central, London, https://doi.org/10.1186/1748-717X-8-141 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">UNSCEAR (2020), <em>Sources, effects and risks of ionizing radiation</em>, United Nations. </span></span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Xie, Li. et al. (2022), "Ultraviolet B Modulates Gamma Radiation-Induced Stress Responses in Lemna Minor at Multiple Levels of Biological Organisation", <em>SSRN</em>, Elsevier, Amsterdam, http://dx.doi.org/10.2139/ssrn.4081705 .</span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Zyla, P.A. et al. (2020)<em>, Review of particle physics: Progress of Theoretical and Experimental Physics,</em> 2020 Edition, Oxford University Press, Oxford. </span></span></span></p>
<p> </p>
<p> </p>
2019-08-22T09:44:232023-04-28T08:40:04Increase, DNA strand breaksIncrease, DNA strand breaksMolecular<p>DNA strand breaks can occur on a single strand (SSB) or both strands (double strand breaks; DSB). SSBs arise when the phosphate backbone connecting adjacent nucleotides in DNA is broken on one strand. DSBs are generated when both strands are simultaneously broken at sites that are sufficiently close to one another that base-pairing and chromatin structure are insufficient to keep the two DNA ends juxtaposed. As a consequence, the two DNA ends generated by a DSB can physically dissociate from one another, becoming difficult to repair and increasing the chance of inappropriate recombination with other sites in the genome (Jackson, 2002). SSB can turn into DSB if the replication fork stalls at the lesion leading to fork collapse.</p>
<p>Strand breaks are intermediates in various biological events, including DNA repair (e.g., excision repair), V(D)J recombination in developing lymphoid cells and chromatin remodeling in both somatic cells and germ cells. The spectrum of damage can be complex, particularily if the stressor is from large amounts of deposited energy which can result in complex lesions and clustered damage defined as two or more oxidized bases, abasic sites or starnd breaks on opposing DNA strands within a few helical turns. These lesions are more difficult to repair and have been studied in many types of models (Barbieri et al., 2019 and Asaithamby et al., 2011)<span style="font-size:14px"><span style="font-family:Arial,Helvetica,sans-serif">. DSBs and complex lesions are of particular concern, as they are considered the most lethal and deleterious type of DNA lesion. If misrepaired or left unrepaired, DSBs may drive the cell towards genomic instability, apoptosis or tumorigenesis (Beir, 1999).</span></span></p>
<p> </p>
<p style="text-align:center"><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000ff">Please refer to the table below for details regarding these and other methodologies for detecting DNA DSBs.</span></span></span></p>
<p style="text-align:center"> </p>
<table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; margin-left:15px">
<tbody>
<tr>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:1px double #2b2b2b; border-right:1px double #2b2b2b; border-top:1px double #2b2b2b; height:37px; vertical-align:top; width:85px">
<p style="text-align:center"><strong><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Assay Name</span></span></strong></p>
</td>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:none; border-right:1px double #2b2b2b; border-top:1px double #2b2b2b; height:37px; vertical-align:top; width:89px">
<p style="text-align:center"><strong><span style="font-size:11px"><span style="font-family:Arial,sans-serif">References</span></span></strong></p>
</td>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:none; border-right:1px double #2b2b2b; border-top:1px double #2b2b2b; height:37px; vertical-align:top; width:228px">
<p style="text-align:center"><strong><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Description</span></span></strong></p>
</td>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:none; border-right:1px double #7f7f7f; border-top:1px double #2b2b2b; height:37px; vertical-align:top; width:46px">
<p style="margin-left:1px; margin-right:1px; text-align:center"><strong><span style="font-size:11px"><span style="font-family:Arial,sans-serif">OECD </span></span></strong><strong><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Approved Assay</span></span></strong></p>
</td>
</tr>
<tr>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:1px double #2b2b2b; border-right:1px double #2b2b2b; border-top:none; height:61px; vertical-align:top; width:85px">
<p style="margin-left:10px; margin-right:9px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Comet Assay (Single Cell Gel Eletrophoresis - Alkaline)</span></span></p>
</td>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:61px; vertical-align:top; width:89px">
<p style="margin-left:1px; margin-right:1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Collins, 2004; Olive </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">and Banath, 2006; Platel et al., 2011; Nikolova et al., 2017</span></span></p>
</td>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:61px; vertical-align:top; width:228px">
<p style="margin-left:1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">To detect SSBs or DSBs, single cells are encapsulated in agarose on a slide, lysed, and subjected to gel electrophoresis at an alkaline pH (pH >13); DNA fragments are forced to move, forming a "comet"-like </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">appearance</span></span></p>
</td>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:none; border-right:1px double #7f7f7f; border-top:none; height:61px; vertical-align:top; width:46px">
<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">Yes (No. 489)</span></p>
</td>
</tr>
<tr>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:1px double #2b2b2b; border-right:1px double #2b2b2b; border-top:none; height:61px; vertical-align:top; width:85px">
<p style="margin-left:11px; margin-right:10px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Comet Assay (Single Cell Gel Eltrophoresis - Neutral)</span></span></p>
</td>
<td style="background-color:whitesmoke; border-bottom:1px double #2b2b2b; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:61px; vertical-align:top; width:89px">
<p style="margin-left:1px; margin-right:1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Collins, 2014; Olive </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">and Banath, 2006; Anderson and Laubenthal, 2013; Nikolova et al., 2017</span></span></p>
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<p style="margin-left:1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">To detect DSBs, single cells are encapsulated in agarose on a slide, lysed, and subjected to gel electrophoresis at a neutral pH; DNA fragments, which are not denatured at the neutral pH, are forced to move, forming a "comet"-</span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">like appearance</span></span></p>
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<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">N/A</span></p>
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<p style="margin-left:1px; margin-right:-1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif"><span style="font-family:"MS UI Gothic",sans-serif">γ</span>-H2AX Foci Quantification - Flow </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Cytometry</span></span></p>
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<p style="margin-left:1px; margin-right:1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Rothkamm and Horn, 2009; Bryce et al., </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">2016</span></span></p>
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<p style="margin-left:26px; margin-right:-1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Measurement of <span style="font-family:"MS UI Gothic",sans-serif">γ</span>-H2AX immunostaining in cells by flow cytometry, normalized to total levels of H2AX</span></span></p>
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<p style="text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">N/A</span></span></p>
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<p style="margin-left:12px; margin-right:11px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif"><span style="font-family:"MS UI Gothic",sans-serif">γ</span>-H2AX Foci Quantification - </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Western Blot</span></span></p>
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<p style="margin-left:9px; margin-right:1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Burma et al., 2001; Revet et al., 2011</span></span></p>
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<p style="margin-left:14px; margin-right:9px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Measurement of <span style="font-family:"MS UI Gothic",sans-serif">γ</span>-H2AX immunostaining in cells by Western blotting, normalized to total levels of H2AX</span></span></p>
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<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">N/A</span></p>
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<p style="margin-left:12px; margin-right:11px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif"><span style="font-family:"MS UI Gothic",sans-serif">γ</span>-H2AX Foci Quantification - Microscopy</span></span></p>
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<p style="margin-left:1px; margin-right:1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Redon et al., 2010; Mah et al., 2010; Garcia-Canton et al., </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">2013</span></span></p>
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<p style="text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Quantification of <span style="font-family:"MS UI Gothic",sans-serif">γ</span>-H2AX immunostaining by counting <span style="font-family:"MS UI Gothic",sans-serif">γ</span>- H2AX foci visualized with a microscope</span></span></p>
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<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">N/A</span></p>
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<p style="margin-left:12px; margin-right:11px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif"><span style="font-family:"MS UI Gothic",sans-serif">γ</span>-H2AX Foci Detection -</span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif"> </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">ELISA and flow cytometry</span></span></p>
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<p style="text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Ji et al., 2017; </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Bryce et al., 2016</span></span></p>
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<p style="margin-right:-1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Detection of <span style="font-family:"MS UI Gothic",sans-serif">γ</span>-H2AX in cells by ELISA, normalized to total levels of H2AX; γH2AX foci detection can be high-throughput and automated using flow cytometry-based immunodetection.</span></span></p>
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<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">N/A</span></p>
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<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">Pulsed Field Gel Electrophoresis (PFGE)</span></p>
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<p style="margin-left:1px; margin-right:1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Ager et al., 1990; Gardiner et al., 1985; Herschleb et al., 2007; Kawashima et </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">al., 2017</span></span></p>
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<p style="margin-left:9px; margin-right:8px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">To detect DSBs, cells are embedded and lysed in agarose, and the released DNA undergoes gel electrophoresis in which the direction of the voltage is periodically alternated; Large DNA fragments are thus </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">able to be separated by size</span></span></p>
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<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">N/A</span></p>
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<p style="margin-left:1px; margin-right:1px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">The TUNEL </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">(Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling) Assay</span></span></p>
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<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">Loo, 2011</span></p>
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<p style="margin-left:5px; margin-right:4px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">To detect strand breaks, dUTPs added to the 3’OH end of a strand break by the DNA polymerase terminal deoxynucleotidyl transferase (TdT) are tagged with a fluorescent dye or a reporter enzyme to allow visualization (We note that this method is typically used to measure apoptosis)</span></span></p>
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<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">N/A</span></p>
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<p style="margin-left:7px; margin-right:6px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif"><em>In Vitro </em>DNA Cleavage Assays using </span></span><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Topoisomerase</span></span></p>
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<p style="text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Nitiss, 2012</span></span></p>
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<p style="margin-left:15px; margin-right:15px; text-align:center"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">Cleavage of DNA can be achieved using purified topoisomerase; DNA strand breaks can then be separated and quantified using gel electrophoresis</span></span></p>
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<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #7f7f7f; border-top:none; height:49px; vertical-align:top; width:46px">
<p style="text-align:center"><span style="font-family:Arial,sans-serif; font-size:11px">N/A</span></p>
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<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:1px double #2b2b2b; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:85px"><span style="color:#e74c3c"><span style="font-size:11px">PCR assay </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:89px"><span style="color:#e74c3c"><span style="font-size:11px">Figueroa‑González & Pérez‑Plasencia, 2017 </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:228px"><span style="color:#e74c3c"><span style="font-size:11px">Assay of strand breaks through the observation of DNA amplification prevention. Breaks block Taq polymerase, reducing the number of DNA templates, preventing amplification </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #7f7f7f; border-top:none; height:49px; text-align:center; vertical-align:top; width:46px"><span style="color:#e74c3c"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">N/A</span></span></span></td>
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<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:1px double #2b2b2b; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:85px"><span style="color:#e74c3c"><span style="font-size:11px">Sucrose density gradient centrifuge </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:89px"><span style="color:#e74c3c"><span style="font-size:11px">Raschke et al. 2009 </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:228px"><span style="color:#e74c3c"><span style="font-size:11px">Division of DNA pieces by density, increased fractionation leads to lower density pieces, with the use of a sucrose cushion </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #7f7f7f; border-top:none; height:49px; text-align:center; vertical-align:top; width:46px"><span style="color:#e74c3c"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">N/A</span></span></span></td>
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<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:1px double #2b2b2b; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:85px"><span style="color:#e74c3c"><span style="font-size:11px">Alkaline Elution Assay </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:89px"><span style="color:#e74c3c"><span style="font-size:11px">Kohn, 1991 </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:228px"><span style="color:#e74c3c"><span style="font-size:11px">Cells lysed with detergent-solution, filtered through membrane to remove all but intact DNA </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #7f7f7f; border-top:none; height:49px; text-align:center; vertical-align:top; width:46px"><span style="color:#e74c3c"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">N/A</span></span></span></td>
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<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:1px double #2b2b2b; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:85px"><span style="color:#e74c3c"><span style="font-size:11px">Unwinding Assay </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:89px"><span style="color:#e74c3c"><span style="font-size:11px">Nacci et al. 1992 </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #2b2b2b; border-top:none; height:49px; text-align:center; vertical-align:top; width:228px"><span style="color:#e74c3c"><span style="font-size:11px">DNA is stored in alkaline solutions with DNA-specific dye and allowed to unwind following removal from tissue, increased strand damage associated with increased unwinding </span></span></td>
<td style="background-color:whitesmoke; border-bottom:1px double #7f7f7f; border-left:none; border-right:1px double #7f7f7f; border-top:none; height:49px; text-align:center; vertical-align:top; width:46px"><span style="color:#e74c3c"><span style="font-size:11px"><span style="font-family:Arial,sans-serif">N/A</span></span></span></td>
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<p><span style="color:#e74c3c"><span style="font-size:11px"><strong>Taxonomic applicability: </strong>DNA strand breaks are relevant to all species, including vertebrates such as humans, that contain DNA (Cannan & Pederson, 2016). </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:11px"><strong>Life stage applicability: </strong>This key event is not life stage specific as all life stages display strand breaks. However, there is an increase in baseline levels of DNA strand breaks seen in older individuals though it is unknown whether this change due to increased break induction or a greater retention of breaks due to poor repair (White & Vijg, 2016). </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:11px"><strong>Sex applicability:</strong> This key event is not sex specific as both sexes display evidence of strand breaks. In some cell types, such as peripheral blood mononuclear cells, males show higher levels of single strand breaks than females (Garm et al., 2012). </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:11px"><strong>Evidence for perturbation by a stressor: </strong>There are studies demonstrating that increased DNA strand breaks can result from exposure to multiple stressor types including ionizing & non-ionizing radiation, chemical agents, and oxidizing agents (EPRI, 2014; Hamada, 2014; Cencer et al., 2018; Cannan & Pederson, 2016; Yang et al., 1998). </span></span></p>
HighUnspecificHighAll life stagesNot Specified<p>Ager, D. D. et al. (1990). “Measurement of Radiation- Induced DNA Double-Strand Breaks by Pulsed-Field Gel Electrophoresis.” Radiat Res. 122(2), 181-7.</p>
<p>Anderson, D. & Laubenthal J. (2013), “Analysis of DNA Damage via Single-Cell Electrophoresis. In: Makovets S, editor. DNA Electrophoresis. Totowa.”, NJ: Humana Press. p 209-218.</p>
<p>Asaithamby, A., B. Hu and D.J. Chen. (2011) Unrepaired clustered DNA lesions induce chromosome breakage in human cells. Proc Natl Acad Sci U S A 108(20): 8293-8298 .</p>
<p>Barbieri, S., G. Babini, J. Morini et a l (2019). . Predicting DNA damage foci and their experimental readout with 2D microscopy: a unified approach applied to photon and neutron exposures. Scientific Reports 9(1): 14019</p>
<p>Bryce, S. et al. (2016), “Genotoxic mode of action predictions from a multiplexed flow cytometric assay and a machine learning approach.”, Environ Mol Mutagen. 57:171-189. Doi: 10.1002/em.21996.</p>
<p>Burma, S. et al. (2001), “ATM phosphorylates histone H2AX in response to DNA double-strand breaks.”, J Biol Chem, 276(45): 42462-42467. doi:10.1074/jbc.C100466200</p>
<p><span style="color:#e74c3c">Cannan, W.J. and D.S. Pederson (2016), "Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin.", Journal of Cellular Physiology, Vol.231/1, Wiley, New York, https://doi.org/10.1002/jcp.25048. </span></p>
<p><span style="color:#e74c3c">Cencer, C. 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-Blackwell, Hoboken, https://doi.org/10.1111/php.12814. </span></p>
<p>Charlton, E. D. et al. (1989), “Calculation of Initial Yields of Single and Double Stranded Breaks in Cell Nuclei from Electrons, Protons, and Alpha Particles.”, Int. J. Radiat. Biol. 56(1): 1-19. doi: 10.1080/09553008914551141.</p>
<p>Collins, R. A. (2004), “The Comet Assay for DNA Damage and Repair. Molecular Biotechnology.”, Mol Biotechnol. 26(3): 249-61. doi:10.1385/MB:26:3:249</p>
<p><span style="color:#e74c3c">EPRI (2014), Epidemiology and mechanistic effects of radiation on the lens of the eye: Review and scientific appraisal of the literature, EPRI, California. </span></p>
<p><span style="color:#e74c3c">Figueroa‑González, G. and C. Pérez‑Plasencia. (2017), “Strategies for the evaluation of DNA damage and repair mechanisms in cancer”, Oncology Letters, Vol.13/6, Spandidos Publications, Athens, https://doi.org/10.3892/ol.2017.6002</span>. </p>
<p>Garcia-Canton, C. et al. (2013), “Assessment of the in vitro p-H2AX assay by High Content Screening asa novel genotoxicity test.”, Mutat Res. 757:158-166. Doi: 10.1016/j.mrgentox.2013.08.002</p>
<p>Gardiner, K. et al. (1986), “Fractionation of Large Mammalian DNA Restriction Fragments Using Vertical Pulsed-Field Gradient Gel Electrophoresis.”, Somatic Cell and Molecular Genetics. 12(2): 185-95.Doi: 10.1007/bf01560665.</p>
<p><span style="color:#e74c3c">Garm, C. et al. (2012), “Age and gender effects on DNA strand break repair in peripheral blood mononuclear cells”, Aging Cell, Vol.12/1, Blackwell Publishing Ltd, Oxford, https://doi.org/10.1111/acel.12019. </span></p>
<p><span style="color:#e74c3c">Hamada, N. (2014), “What are the intracellular targets and intratissue target cells for radiation effects?”, Radiation research, Vol. 181/1, The Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR13505.1. </span></p>
<p>Herschleb, J. et al. (2007), “Pulsed-field gel electrophoresis.”, Nat Protoc. 2(3): 677-684. doi:10.1038/nprot.2007.94</p>
<p>Iliakis, G. et al. (2015), “Alternative End-Joining Repair Pathways Are the Ultimate Backup for Abrogated Classical Non-Homologous End-Joining and Homologous Recombination Repair: Implications for the Formation of Chromosome Translocations.”, Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2(3): 677-84. doi: 10.1038/nprot.2007.94</p>
<p>Jackson, S. (2002). “Sensing and repairing DNA double-strand breaks.”, Carcinogenesis. 23:687-696. Doi:10.1093/carcin/23.5.687.</p>
<p>Ji, J. et al. (2017), “Phosphorylated fraction of H2AX as a measurement for DNA damage in cancer cells and potential applications of a novel assay.”, PLoS One. 12(2): e0171582. doi:10.1371/journal.pone.0171582</p>
<p>Kawashima, Y.(2017), “Detection of DNA double-strand breaks by pulsed-field gel electrophoresis.”, Genes Cells 22:84-93. Doi: 10.1111/gtc.12457.</p>
<p>Khoury, L. et al. (2013), “Validation of high-throughput genotoxicity assay screening using cH2AX in-cell Western assay on HepG2 cells.”, Environ Mol Mutagen, 54:737-746. Doi: 10.1002/em.21817.</p>
<p>Khoury, L. et al. (2016), “Evaluation of four human cell lines with distinct biotransformation properties for genotoxic screening.”, Mutagenesis, 31:83-96. Doi: <a href="https://doi.org/10.1093/mutage/gev058" target="_blank">10.1093/mutage/gev058</a>.</p>
<p><span style="color:#e74c3c">Kohn, K.W. (1991), “Principles and practice of DNA filter elution”, Pharmacology & Therapeutics, Vol.49/1, Elsevier, Amsterdam, https://doi.org/10.1016/0163-7258(91)90022-E.</span> </p>
<p>Loo, DT. (2011), “In Situ Detection of Apoptosis by the TUNEL Assay: An Overview of Techniques. In: Didenko V, editor. DNA Damage Detection In Situ, Ex Vivo, and In Vivo. Totowa.”, NJ: Humana Press. p 3-13.doi: <a href="https://doi.org/10.1007/978-1-60327-409-8_1" target="_blank">10.1007/978-1-60327-409-8_1</a>.</p>
<p>Mah, L. J. et al. (2010), “Quantification of gammaH2AX foci in response to ionising radiation.”, J Vis Exp(38). doi:10.3791/1957.</p>
<p><span style="color:#e74c3c">Nacci, D. et al. (1992), “Application of the DNA alkaline unwinding assay to detect DNA strand breaks in marine bivalves”, Marine Environmental Research, Vol.33/2, Elsevier BV, Amsterdam, https://doi.org/10.1016/0141-1136(92)90134-8. </span></p>
<p>Nikolova, T., F. et al. (2017), “Genotoxicity testing: Comparison of the γH2AX focus assay with the alkaline and neutral comet assays.”, Mutat Res 822:10-18. Doi: <a href="https://doi.org/10.1016/j.mrgentox.2017.07.004" target="_blank">10.1016/j.mrgentox.2017.07.004</a>.</p>
<p>Nitiss, J. L. et al. (2012), “Topoisomerase assays. ”, Curr Protoc Pharmacol. Chapter 3: Unit 3 3.</p>
<p>OECD. (2014). Test No. 489: “In vivo mammalian alkaline comet assay.” OECD Guideline for the Testing of Chemicals, Section 4 .</p>
<p>Olive, P. L., & Banáth, J. P. (2006), “The comet assay: a method to measure DNA damage in individual cells.”, Nature Protocols. 1(1): 23-29. doi:10.1038/nprot.2006.5.</p>
<p>Platel A. et al. (2011), “Study of oxidative DNA damage in TK6 human lymphoblastoid cells by use of the thymidine kinase gene-mutation assay and the <em>in vitro </em>modified comet assay: Determination of No-Observed-Genotoxic-Effect-Levels.”, Mutat Res 726:151-159. Doi: 10.1016/j.mrgentox.2011.09.003.</p>
<p><span style="color:#e74c3c">Raschke, S., J. Guan and G. Iliakis. (2009), “Application of alkaline sucrose gradient centrifugation in the analysis of DNA replication after DNA damage”, Methods in Molecular Biology, Vol.521, Humana Press, Totowa, https://doi.org/10.1007/978-1-60327-815-7_18. </span></p>
<p>Redon, C. et al. (2010), “The use of gamma-H2AX as a biodosimeter for total-body radiation exposure in non-human primates.”, PLoS One. 5(11): e15544. doi:10.1371/journal.pone.0015544</p>
<p>Revet, I. et al. (2011), “Functional relevance of the histone γH2Ax in the response to DNA damaging agents.” Proc Natl Acad Sci USA.108:8663-8667. Doi: 10.1073/pnas.1105866108</p>
<p>Rogakou, E.P. et al. (1998), “DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139.” , J Biol Chem, 273:5858-5868. Doi: 10.1074/jbc.273.10.5858</p>
<p>Rothkamm, K. & Horn, S. (2009), “γ-H2AX as protein biomarker for radiation exposure.”, Ann Ist Super Sanità, 45(3): 265-71.</p>
<p><span style="color:#e74c3c">White, R.R. and J. Vijg. (2016), “Do DNA Double-Strand Breaks Drive Aging?”, Molecular Cell, Vol.63, Elsevier, Amsterdam, http://doi.org/10.1016/j.molcel.2016.08.004. </span></p>
<p><span style="color:#e74c3c">Yang, Y. et al. (1998), “The effect of catalase amplification on immortal lens epithelial cell lines”, Experimental Eye Research, Vol.67/6, Academic Press Inc, Cambridge, https://doi.org/10.1006/exer.1998.0560. </span></p>
2019-05-19T16:33:202023-04-12T10:58:13Increase, Oocyte apoptosisIncrease, Oocyte apoptosisCellular2020-04-30T16:41:182020-04-30T16:41:18Decrease, OogenesisDecrease, OogenesisOrgan2017-04-15T16:20:502020-04-30T16:41:53Reduction, Cumulative fecundity and spawningReduction, Cumulative fecundity and spawningIndividual<p>Spawning refers to the release of eggs. Cumulative fecundity refers to the total number of eggs deposited by a female, or group of females over a specified period of time.</p>
<p>In laboratory-based reproduction assays (e.g., OECD Test No. 229; OECD Test No. 240), spawning and cumulative fecundity can be directly measured through daily observation of egg deposition and egg counts.</p>
<p>In some cases, fecundity may be estimated based on gonado-somatic index (<a href="http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2008)22&doclanguage=en">OECD 2008</a>).</p>
<p>Cumulative fecundity and spawning can, in theory, be evaluated for any egg laying animal.</p>
HighFemaleHighAdult, reproductively matureHighHighHigh<ul>
<li>OECD 2008. Series on testing and assessment, Number 95. Detailed Review Paper on Fish Life-cycle Tests. OECD Publishing, Paris. ENV/JM/MONO(2008)22.</li>
<li>OECD (2015), <em>Test No. 240: Medaka Extended One Generation Reproduction Test (MEOGRT)</em>, OECD Publishing, Paris.<br />
DOI: <a href="http://dx.doi.org/10.1787/9789264242258-en" target="_blank" title="http://dx.doi.org/10.1787/9789264242258-en">http://dx.doi.org/10.1787/9789264242258-en</a></li>
<li>OECD. 2012a. Test no. 229: Fish short term reproduction assay. Paris, France:Organization for Economic Cooperation and Development.</li>
</ul>
2016-11-29T18:41:222017-03-20T17:52:57Decrease, Population growth rateDecrease, Population growth ratePopulation<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">A population can be defined as a group of interbreeding organisms, all of the same species, occupying a specific space during a specific time (Vandermeer and Goldberg 2003, Gotelli 2008). As the population is the biological level of organization that is often the focus of ecological risk</span> <span style="color:black">assessments, population growth rate (and hence population size over time) is important to consider within the context of applied conservation practices.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">If N is the size of the population and t is time, then the population growth rate (dN/dt) is proportional to the instantaneous rate of increase, r, which measures the per capita rate of population increase over a short time interval. Therefore, r, is a difference between the instantaneous birth rate (number of births per individual per unit of time; b) and the instantaneous death rate (number of deaths per individual per unit of time; d) [Equation 1]. Because r is an instantaneous rate, its units can be changed via division. For example, as there are 24 hours in a day, an r of 24 individuals/(individual x day) is equal to an r of 1 individual/(individual/hour) (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). </span></span></span></span></p>
<p style="margin-left:144px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Equation 1: r = b - d</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">This key event refers to scenarios where r < 0 (instantaneous death rate exceeds instantaneous birth rate).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Examining r in the context of population growth rate:</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A population will decrease to extinction when the instantaneous death rate exceeds the instantaneous birth rate (r < 0). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black"> ● The smaller the value of r below 1, the faster the population will decrease to zero. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A population will increase when resources are available and the instantaneous birth rate exceeds the instantaneous death rate (r > 0)</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black"> ● The larger the value that r exceeds 1, the faster the population can increase over time </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A population will neither increase or decrease when the population growth rate equals 0 (either due to N = 0, or if the per capita birth and death rates are exactly balanced). For example, the per capita birth and death rates could become exactly balanced due to density dependence and/or to the effect of a stressor that reduces survival and/or reproduction (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Effects incurred on a population from a chemical or non-chemical stressor could have an impact directly upon birth rate (reproduction) and/or death rate (survival), thereby causing a decline in population growth rate. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● Example of direct effect on r: Exposure to 17b-trenbolone reduced reproduction (i.e., reduced b) in the fathead minnow over 21 days at water concentrations ranging from 0.0015 to about 41 mg/L (Ankley et al. 2001; Miller and Ankley 2004). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Alternatively, a stressor could indirectly impact survival and/or reproduction. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● Example of indirect effect on r: Exposure of non-sexually differentiated early life stage fathead minnow to the fungicide prochloraz has been shown to produce male-biased sex ratios based on gonad differentiation, and resulted in projected change in population growth rate (decrease in reproduction due to a decrease in females and thus recruitment) using a population model. (Holbech et al., 2012; Miller et al. 2022)</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Density dependence can be an important consideration:</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● The effect of density dependence depends upon the quantity of resources present within a landscape. A change in available resources could increase or decrease the effect of density dependence and therefore cause a change in population growth rate via indirectly impacting survival and/or reproduction. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● This concept could be thought of in terms of community level interactions whereby one species is not impacted but a competitor species is impacted by a chemical stressor resulting in a greater availability of resources for the unimpacted species. In this scenario, the impacted species would experience a decline in population growth rate. The unimpacted species would experience an increase in population growth rate (due to a smaller density dependent effect upon population growth rate for that species). </span> </span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Closed versus open systems:</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● The above discussion relates to closed systems (there is no movement of individuals between population sites) and thus a declining population growth rate cannot be augmented by immigration. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● When individuals depart (emigrate out of a population) the loss will diminish population growth rate. </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Population growth rate applies to all organisms, both sexes, and all life stages.</span></span></span></span></p>
<p> </p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Population growth rate (instantaneous growth rate) can be measured by sampling a population over an interval of time (i.e. from time t = 0 to time t = 1). The interval of time should be selected to correspond to the life history of the species of interest (i.e. will be different for rapidly growing versus slow growing populations). The population growth rate, r, can be determined by taking the difference (subtracting) between the initial population size, N</span><sub><span style="font-size:9pt"><span style="color:black">t=0 </span></span></sub><span style="color:black">(population size at time t=0), and the population size at the end of the interval, N</span><sub><span style="font-size:9pt"><span style="color:black">t=1 </span></span></sub><span style="color:black">(population size at time t = 1), and then subsequently dividing by the initial population size. </span></span></span></span></p>
<p style="margin-left:96px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Equation 2: r = (N</span><sub><span style="font-size:9pt"><span style="color:black">t=1 </span></span></sub><span style="color:black">- N</span><sub><span style="font-size:9pt"><span style="color:black">t=0</span></span></sub><span style="color:black">) / N</span><sub><span style="font-size:9pt"><span style="color:black">t=0</span></span></sub></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">The diversity of forms, sizes, and life histories among species has led to the development of a vast number of field techniques for estimation of population size and thus population growth over time (Bookhout 1994, McComb et al. 2021). </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● For stationary species an observational strategy may involve dividing a habitat into units. After setting up the units, samples are performed throughout the habitat at a select number of units (determined using a statistical sampling design) over a time interval (at time t = 0 and again at time t = 1), and the total number of organisms within each unit are counted. The numbers recorded are assumed to be representative for the habitat overall, and can be used to estimate the population growth rate within the entire habitat over the time interval. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● For species that are mobile throughout a large range, a strategy such as using a mark-recapture method may be employed (i.e. tags, bands, transmitters) to determine a count over a time interval (at time = 0 and again at time =1). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Population growth rate can also be estimated using mathematical model constructs (for example, ranging from simple differential equations to complex age or stage structured matrix projection models and individual based modeling approaches), and may assume a linear or nonlinear population increase over time (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). The AOP framework can be used to support the translation of pathway-specific mechanistic data into responses relevant to population models and output from the population models, such as changing (declining) population growth rate, can be used to assess and manage risks of chemicals (Kramer et al. 2011). As such, this translational capability can increase the capacity and efficiency of safety assessments both for single chemicals and chemical mixtures (Kramer et al. 2011). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Some examples of modeling constructs used to investigate population growth rate:</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A modeling construct could be based upon laboratory toxicity tests to determine effect(s) that are then linked to the population model and used to estimate decline in population growth rate. Miller et al. (2007) used concentration–response data from short term reproductive assays with fathead minnow (<em>Pimephales promelas</em>) exposed to endocrine disrupting chemicals in combination with a population model to examine projected alterations in population growth rate. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A model construct could be based upon a combination of effects-based monitoring at field sites (informed by an AOP) and a population model. Miller et al. (2015) applied a population model informed by an AOP to project declines in population growth rate for white suckers (Catostomus commersoni) using observed changes in sex steroid synthesis in fish exposed to a complex pulp and paper mill effluent in Jackfish Bay, Ontario, Canada. Furthermore, a model construct could be comprised of a series of quantitative models using KERs that culminates in the estimation of change (decline) in population growth rate. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A quantitative adverse outcome pathway (qAOP) has been defined as a mathematical construct that models the dose–response or response–response relationships of all KERs described in an AOP (Conolly et al. 2017, Perkins et al. 2019). Conolly et al. (2017) developed a qAOP using data generated with the aromatase inhibitor fadrozole as a stressor and then used it to predict potential population‐level impacts (including decline in population growth rate). The qAOP modeled aromatase inhibition (the molecular initiating event) leading to reproductive dysfunction in fathead minnow (Pimephales promelas) using 3 computational models: a hypothalamus–pituitary–gonadal axis model (based on ordinary differential equations) of aromatase inhibition leading to decreased vitellogenin production (Cheng et al. 2016), a stochastic model of oocyte growth dynamics relating vitellogenin levels to clutch size and spawning intervals (Watanabe et al. 2016), and a population model (Miller et al. 2007).</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● Dynamic energy budget (DEB) models offer a methodology that reverse engineers stressor effects on growth, reproduction, and/or survival into modular characterizations related to the acquisition and processing of energy resources (Nisbet et al. 2000, Nisbet et al. 2011). Murphy et al. (2018) developed a conceptual model to link DEB and AOP models by interpreting AOP key events as measures of damage-inducing processes affecting DEB variables and rates.</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● Endogenous Lifecycle Models (ELMs), capture the endogenous lifecycle processes of growth, development, survival, and reproduction and integrate these to estimate and predict expected fitness (Etterson and Ankley, 2021). AOPs can be used to inform ELMs of effects of chemical stressors on the vital rates that determine fitness, and to decide what hierarchical models of endogenous systems should be included within an ELM (Etterson and Ankley, 2021).</span></span></span></span></p>
<p> </p>
<p>Consideration of population size and changes in population size over time is potentially relevant to all living organisms.</p>
Not SpecifiedUnspecificNot SpecifiedAll life stagesHigh<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MD, Hartig PC, Gray LE. 2003. Effects of the androgenic growth promoter 17b-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ. Toxicol. Chem. 22: 1350–1360.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Bookhout TA. 1994. Research and management techniques for wildlife and habitats. The Wildlife Society, Bethesda, Maryland. 740 pp.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Caswell H. 2001. Matrix Population Models. Sinauer Associates, Inc., Sunderland, MA, USA</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Cheng WY, Zhang Q, Schroeder A, Villeneuve DL, Ankley GT, Conolly R. 2016. Computational modeling of plasma vitellogenin alterations in response to aromatase inhibition in fathead minnows. Toxicol Sci 154: 78–89.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Conolly RB, Ankley GT, Cheng W-Y, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. 2017. Quantitative adverse outcome pathways and their application to predictive toxicology. Environ. Sci. Technol. 51: 4661-4672.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Etterson MA, Ankley GT. 2021. Endogenous Lifecycle Models for Chemical Risk Assessment. Environ. Sci. Technol. 55: 15596-15608. </span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Gotelli NJ, 2008. A Primer of Ecology. Sinauer Associates, Inc., Sunderland, MA, USA.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Holbech H, Kinnberg KL, Brande-Lavridsen N, Bjerregaard P, Petersen GI, Norrgren L, Orn S, Braunbeck T, Baumann L, Bomke C, Dorgerloh M, Bruns E, Ruehl-Fehlert C, Green JW, Springer TA, Gourmelon A. 2012 Comparison of zebrafish (<em>Danio rerio</em>) and fathead minnow <em>(Pimephales promelas</em>) as test species in the Fish Sexual Development Test (FSDT). Comp. Biochem. Physiol. C Toxicol. Pharmacol. 155: 407–415.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Kramer VJ, Etterson MA, Hecker M, Murphy CA, Roesijadi G, Spade DJ, Stromberg JA, Wang M, Ankley GT. </span><span style="color:black">2011. Adverse outcome pathways and risk assessment: Bridging to population level effects. Environ. Toxicol. Chem. 30, 64-76.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">McComb B, Zuckerberg B, Vesely D, Jordan C. 2021. Monitoring Animal Populations and their Habitats: A Practitioner's Guide. Pressbooks, Oregon State University, Corvallis, OR Version 1.13, 296 pp. </span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Miller DH, Villeneuve DL, Santana Rodriguez KJ, Ankley GT. 2022. A multidimensional matrix model for predicting the effect of male biased sex ratios on fish populations. Environmental Toxicology and Chemistry 41(4): 1066-1077.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Miller DH, Tietge JE, McMaster ME, Munkittrick KR, Xia X, Griesmer DA, Ankley GT. 2015. </span><span style="color:black">Linking mechanistic toxicology to population models in forecasting recovery from chemical stress: A case study from Jackfish Bay, Ontario, Canada. Environmental Toxicology and Chemistry 34(7): 1623-1633.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Miller DH, Jensen KM, Villeneuve DE, Kahl MD, Makynen EA, Durhan EJ, Ankley GT. 2007. </span><span style="color:black">Linkage of biochemical responses to population-level effects: A case study with vitellogenin in the fathead minnow (<em>Pimephales promelas</em>). Environ Toxicol Chem 26: 521–527.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Miller DH, Ankley GT. 2004. Modeling impacts on populations: Fathead minnow (<em>Pimephales promelas</em>) exposure to the endocrine disruptor 17b-trenbolone as a case study. Ecotox Environ Saf 59: 1–9.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Murphy CA, Nisbet RM, Antczak P, Garcia-Reyero N, Gergs A, Lika K, Mathews T, Muller EB, Nacci D, Peace A, Remien CH, Schultz IR, Stevenson LM, Watanabe KH. 2018. Incorporating suborganismal processes into dynamic energy budget models for ecological risk assessment. Integrated Environmental Assessment and Management 14(5): 615–624.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Murray DL, Sandercock BK (editors). 2020. Population ecology in practice. Wiley-Blackwell, Oxford UK, 448 pp.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Nisbet RM, Jusup M, Klanjscek T, Pecquerie L. 2011. Integrating dynamic energy budget (DEB) theory with traditional bioenergetic models. The Journal of Experimental Biology 215: 892-902.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Nisbet RM, Muller EB, Lika K, Kooijman SALM. 2000. </span><span style="color:black">From molecules to ecosystems through dynamic energy budgets. J Anim Ecol 69: 913–926.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Perkins EJ, Ashauer R, Burgoon L, Conolly R, Landesmann B,, Mackay C, Murphy CA, Pollesch N, Wheeler JR, Zupanic A, Scholzk S. 2019. Building and applying quantitative adverse outcome pathway models for chemical hazard and risk assessment. Environmental Toxicology and Chemistry 38(9): 1850–1865. </span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Vandermeer JH, Goldberg DE. 2003. Population ecology: first principles. Princeton University Press, Princeton NJ, 304 pp.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, LaLone CA, Landesmann B, Lattieri T, Munn S, Nepelska M, Ottinger MA, Vergauwen L, Whelan M. Adverse outcome pathway (AOP) development 1: Strategies and principles. Toxicol Sci. 2014: 142:312–320</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Watanabe KH, Mayo M, Jensen KM, Villeneuve DL, Ankley GT, Perkins EJ. 2016. Predicting fecundity of fathead minnows (<em>Pimephales promelas</em>) exposed to endocrine‐disrupting chemicals using a MATLAB(R)‐based model of oocyte growth dynamics. PLoS One 11: e0146594.</span></span></span></li>
</ul>
2016-11-29T18:41:242023-01-03T09:09:06a04f2bdb-2fe9-4bd1-b3f5-2b4125b8a595c2bac1e0-e4a7-4c94-bdab-f6c7e55a6517<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Direct deposition of ionizing energy refers to imparted energy interacting directly with the DNA double helix and producing randomized damage. <span style="color:#e74c3c">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).</span> <span style="color:#e74c3c">Among these,</span> 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). <span style="color:#e74c3c">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).</span> 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 particle<span style="color:#e74c3c">s, heavy ion particles, and neutrons</span> can deposit larger quantities of energy within a single track than low LET radiation, such as <span style="color:#e74c3c">γ-rays, X-rays, electrons, and protons</span> (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). Thus, 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.</span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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).</span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Overall Weight of Evidence for this KER: High</span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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; <span style="color:#e74c3c">Lipman, 1988; Hightower, 1995</span>; Terato & Ide, 2005; Goodhead, 2006; <span style="color:#e74c3c">Kim & Lee, 2007</span>; Asaithamby et al., 2008; Hada & Georgakilas, 2008; Jeggo, 2009; Clement, 2012; Okayasu, 2012b; <span style="color:#e74c3c">Stewart, 2012</span>; M. E. Lomax et al., 2013; <span style="color:#e74c3c">EPRI, 2014; Hamada, 2014</span>; Moore et al., 2014; Desouky et al., 2015; <span style="color:#e74c3c">Ainsbury, 2016; Foray et al., 2016; Hamada & Sato, 2016; Hamada, 2017a;</span> Sage & Shikazono, 2017; Chadwick, 2017; <span style="color:#e74c3c">Wang et al., 2021; Nagane et al., 2021; Sylvester et al., 2018; Baselet et al., 2019</span>). 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.</span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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<sup>-18</sup> s and 10<sup>-14</sup> 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).</span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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).</span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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).</span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Empirical data strongly supports this KER. The evidence presented below is summarized in table 1. The types of DNA damage produced by ionizing radiation and the associated mechanisms, including the induction of DSBs, are reviewed by Lomax et al. (2013) and documents produced by international radiation governing frameworks (Valentin, 1998; UNSCEAR, 2000). Other reviews also highlight the relationship between the deposition of energy by radiation and DSB induction, and discuss the various methods available to detect these DSBs (Terato & Ide, 2005; Rothkamm et al., 2015; Sage & Shikazono, 2017). A visual representation of the time frames and dose ranges probed by the dedicated studies discussed here is shown in Figures 1 & 2 below.</span></span></p>
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<p> </p>
<p><img alt="" src="https://aopwiki.org/system/dragonfly/production/2022/10/12/4zw4nw353c_ke1_mie_dsb_dose_v2.png" style="height:734px; width:1000px" /></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Figure 1: Plot of example studies (y-axis) against equivalent dose (Sv) used to determine the empirical link between direct deposition of energy and DSBs. The z-axis denotes the equivalent dose rate used in each study. The y-axis is ordered from low LET to high LET from top to bottom. </span></span></p>
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<p> </p>
<p><img alt="" src="https://aopwiki.org/system/dragonfly/production/2022/10/12/a85jspx5_ke1_mie_dsb_time_v2.png" style="height:706px; width:1000px" /></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Figure 2: Plot of example studies (y-axis) against time scales used to determine the empirical link between direct deposition of energy and DSBs. The z-axis denotes the equivalent dose rate used in each study. The y-axis is ordered from low LET to high LET from top to bottom. </span></span></p>
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<p><u><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Dose Concordance</span></span></u></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">There is evidence in the literature suggesting a dose concordance between the direct deposition of energy by ionizing radiation and the incidence (Grudzenski et al., 2010) of DNA DSBs. Results from in vitro (<span style="color:#e74c3c">Aufderheide et al., 1987; Sidjanin, 1993; Bucolo, 1994;</span> Frankenberg et al., 1999; Rogakou et al., 1999; Belli et al., 2000; Sutherland et al., 2000; Lara et al., 2001; Rydberg et al., 2002;<span style="color:#e74c3c"> Baumstark-Kham et al., 2003</span>; Rothkamm and Lo, 2003; <span style="color:#e74c3c">Long, 2004;</span> Kuhne et al., 2005; Sudprasert et al., 2006; Beels et al., 2009; Grudzenski et al., 2010; Liao, 2011; Franken et al., 2012; <span style="color:#e74c3c">Bannik et al., 2013;</span> Shelke & Das, 2015; Antonelli et al., 2015; <span style="color:#e74c3c">Markiewicz et al., 2015; Allen, 2018; Dalke, 2018; Bains, 2019; Ahmadi et al., 2021; Sabirzhanov et al., 2020; Ungvari et al., 2013; Rombouts et al., 2013; Baselet et al., 2017</span></span></span><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">), in vivo (<span style="color:#e74c3c">Reddy, 1998</span>; Sutherland et al., 2000; Rube et al., 2008; Beels et al., 2009; Grudzenski et al., 2010; <span style="color:#e74c3c">Markiewicz et al., 2015; Barnard, 2018; Barnard, 2019; Barnard, 2022; Schmal et al., 2019; Barazzuol et al., 2017; Geisel et al., 2012</span></span></span><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">), ex vivo (Rube et al., 2008; Flegal et al., 2015) and simulation studies (Charlton et al., 1989) suggest that there is a <span style="color:#e74c3c">positive, linear</span>, dose-dependent increase in DSBs with increasing deposition of energy across a wide range of radiation types (iron ions, X-rays, ultrasoft X-rays, gamma-rays, photons, UV light, and alpha particles) and radiation doses (1 mGy - 100 Gy) (<span style="color:#e74c3c">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; </span>Rube et al., 2008<span style="color:#e74c3c">; Grudzenski et al., 2010; Bannik et al., 2013; Shelke & Das, 2015; Antonelli et al., 2015; Dalke, 2018; Barazzuol et al., 2017; Ungvari et al., 2013; Rombouts et al., 2013; Baselet et al., 2017; Geisel et al., 2012</span></span></span><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">). DSBs have been predicted to occur at energy deposition levels as low as 75 eV (Charlton et al., 1989). </span></span></p>
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<p><u><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Time Concordance</span></span></u></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">There is evidence suggesting a time concordance between the direct deposition of energy and the incidence of DSBs. A number of different models and experiments have provided evidence of <span style="color:#e74c3c">ionizing radiation-induced foci (IRIF), which can be used to infer DSB formation </span>seconds (Mosconi et al., 2011) or minutes after radiation exposure (Rogakou et al., 1999; Rothkamm and Lo, 2003; Rube et al., 2008; Beels et al., 2009; Kuefner et al., 2009; Grudzenski et al., 2010; Antonelli et al., 2015<span style="color:#e74c3c">; Acharya et al., 2010; Sabirzhanov et al., 2020; Rombouts et al., 2013; Nübel et al., 2006; Baselet et al., 2017; Zhang et al., 2017</span></span></span><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">). </span></span></p>
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<p><u><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Essentiality</span></span></u></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Deposition of energy is essential for DNA strand breaks. They can also be caused through other routes, such as oxidative stress (Cadet et al., 2012), but under normal physiological conditions deposition of energy is necessary. This was tested through many studies using various indicators such as 53BP1 foci/cell, γH2AX foci/cell, DNA migration, and the amount of DNA in tails for the comet assay. Various organisms such as humans, mice, rabbits, guinea pigs, and cattle were used. They showed that without the deposition of energy, there was only a negligible amount of DNA strand breaks (Aufderheide et al., 1987; Sidjanin, 1993; Bucolo, 1994; Reddy, 1998; Rogers, 2004; Bannik et al., 2013; Dalke, 2018; Bains, 2019; Barnard, 2019; Barnard, 2021). </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Uncertainties and inconsistencies in this KER are as follows:</span></span></p>
<ul>
<li><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></li>
<li><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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; <span style="color:#e74c3c">Dalke, 2018</span>). 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).</span></span></li>
<li><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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).</span></span></li>
</ul>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Quantitative understanding of this linkage suggests that DSBs can be predicted upon exposure to ionizing radiation. This is dependent on the biological model, the type of radiation and the radiation dose. In general, 1 Gy of radiation is thought to result in 3000 damaged bases (Maier et al., 2016), 1000 single-strand breaks, and 40 DSBs (Ward, 1988; </span></span></span><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Foray et al., 2016; </span></span></span><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Maier et al., 2016) . The table below provides representative examples of the calculated DNA damage rates across different model systems, most of which are examining DNA DSBs.</span></span></span></p>
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<p><span style="color:#0000ff"><strong><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Dose Concordance </span></span></strong></span></p>
<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">The following tables provide representative examples of the relationship, unless otherwise indicated, all data is significantly significant. </span></span></span></p>
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<p><span style="color:#0000ff"><strong><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Reference </span></span></strong></span></p>
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<p><span style="color:#0000ff"><strong><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Experiment Description </span></span></strong></span></p>
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<p><span style="color:#0000ff"><strong><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Result </span></span></strong></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ward, 1988 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Cells containing approximately 6 pg of DNA were exposed to 1 Gy. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Under the assumption of 6 pg of DNA per cell. 60 eV of energy deposited per event over a total of 1 Gy. Deoxyribose (2.3 pg/cell): 14,000 eV deposited, 235 events. Bases (2.4 pg/cell): 14.7 keV deposited, 245 events. Phosphate (1.2 pg/cell): 7,300 eV deposited, 120 events. Bound water (3.1 pg/cell): 19 keV deposited, 315 events. Inner hydration shell (4.2 pg/cell): 25,000 eV deposited 415 events. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Charlton, 1989 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In-silico. A computer simulation/model was used to test various types of radiation with doses from 0 to 400 eV (energy deposited) on the amount of DNA damage produced. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Simulated dose-concordance prediction of increase in number of DSBs/54 nucleotide pairs as direct deposition of energy increases in the range 75-400 eV. In the range 100 - 150 eV: 0.38 DSBs/54 nucleotide pairs and at 400 eV: ~0.80 DSBs per 64 nucleotide pairs. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sutherland, 2000 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Human cells were exposed to <sup>137</sup>Cs γ-rays (0 – 100 Gy, 0.16 – 1.6 Gy/min). The frequency of DSBs was determined using gel electrophoresis. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Using isolated bacteriophage T7 DNA and 0-100 Gy of γ radiations, observed a response of 2.4 DSBs per megabase pair per Gy. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rogakou et al., 1999 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Normal human fibroblasts (IMR90) and human breast cancer cells (MCF7 were exposed to 0.6 and 2 Gy <sup>137</sup>Cs γ-rays delivered at 15.7 Gy/min. The number of DSBs were determined by immunoblotting for γ-H2AX. </span></span></span></p>
<p> </p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Radiation doses of 0.6 Gy & 2 Gy to normal human fibroblasts (IMR90) and MCF7 cells resulted in 10.1 & 12.2 DSBs per nucleus on average (0.6 Gy), respectively; increasing to 24 & 27.1 DSBs per nucleus (2 Gy). </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kuhne et al., 2005 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Primary human skin fibroblasts (HSF2) were exposed to 0 – 70 Gy <sup>60</sup>Co γ-rays (0.33 Gy/min), X-rays (29 kVp, 1.13 Gy/min), and CKX-rays (0.14 Gy/min). The number of DSBs were determined with pulsed-field gel electrophoresis. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">γ-ray and X-ray irradiation of primary human skin fibroblasts (HSF2) at 0 - 70 Gy. γ-rays: (6.1 ± 0.2) x 10-9 DSBs per base pair per Gy, X-rays: (7.0 ± 0.2) x 10-9 DSBs per base pair per Gy. CKX -rays: (12.1 ± 1.9) x 10-9 DSBs per base pair per Gy. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rothkamm, 2003 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Primary human fibroblast cell lines MRC-5 (lung), HSF1 and HSF2 (skin), and180BR (deficient in DNA ligase IV) were exposed to 1 mGy – 100 Gy X-rays (90 kV). Low doses were delivered at 6 – 60 mGy/min and high doses were delivered at 2 Gy/min. The number of DSBs were determined with pulsed-field gel electrophoresis. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">X-ray irradiation of primary human fibroblasts (MRC-5) in the range 1 mGy - 100 Gy, 35 DSBs per cell per Gy. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Grudzenski et al, 2010 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Primary human fibroblasts (HSF1) and C57BL/6NCrl adult mice were exposed to X-rays (2.5 – 200 mGy, 70 mGy/min), and photons (10 mGy – 1 Gy, 2 Gy/min (100 mGy and 1 Gy), and 0.35 Gy/min (10 mGy)). γ-H2AX immunofluorescence was observed to determine DSBs. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">X-rays irradiating primary human fibroblasts (HSF1) in the range 2.5 - 100 mGy yielded a response of 21 foci per Gy. When irradiating adult C57BL/6NCrl mice with photons a response of 0.07 foci per cell at 10 mGy was found. At 100 mGy the response was 0.6 foci per cell and finally, at 1 Gy; 8 foci per cell. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">de Lara, 2001 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Chinese hamster cells (V79-4) were exposed to 0 – 20 Gy of<sup> 60</sup>Co γ-rays (2 Gy/min), and ultrasoft X-rays (0.7 – 35 Gy/min): carbon-K shell (0.28 keV), copper L-shell (0.96 keV), aluminum K-shell (1.49 keV), and titanium K-shell (4.55 keV). The number of DSBs were determined with pulsed-field gel electrophoresis. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">V79-4 cells irradiated with γ-rays and ultrasoft X-rays (carbon K-shell, copper L-shell, aluminium K-shell and titanum K-shell) in the range 0 - 20 Gy. Response (DSBs per Gy per cell): γ-rays: 41, carbon K-shell: 112, copper L-shell: 94, aluminum K-shell: 77, titanium K-shell: 56. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rübe et al., 2008 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vivo. Brain, lung, heart and small intestine tissue from adult SCID, A-T, BALB/c and C57BL/6NCrl mice; Whole blood and isolated lymphocytes from BALB/c and C57BL/6NCrl mice were exposed to 0.1 – 2 Gy of photons (whole body irradiation, 6 MV, 2 Gy/min) and X-rays (whole body irradiation, 90 kV, 2 Gy/min). γ-H2AX foci were determined with immunochemistry to measure DSBs. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Linear dose-dependent increase in DSBs in the brain, small intestine, lung and heart of C57BL/6CNrl mice after whole-body irradiation with 0.1 - 1.0 Gy of radiation. 0.8 foci per cell (0.1 Gy) and 8 foci per cell (1 Gy). </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Antonelli et al., 2015 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Primary human foreskin fibroblasts (AG01522) were exposed to 0 – 1 Gy of <sup>136</sup>Cs γ-rays (1 Gy/min), protons (0.84 MeV, 28.5 keV/um), carbon ions (58 MeV/u, 39.4 keV/um), and alpha particles (americium-241, 0.75 MeV/u, 0.08 Gy/min, 125.2 keV/um). γ-H2AX foci were determined with immunochemistry to measure DSBs. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Linear dose-dependent increase in the number of DSBs from 0 - 1 Gy for γ-rays and alpha particles as follows: γ-rays: 24.1 foci per Gy per cell nucleus, alpha particles: 8.8 foci per Gy per cell nucleus. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Barnard et al., 2019 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vivo. 10-week-old female C57BL/6 mice were whole-body exposed to 0.5, 1, and 2 Gy of 60Co γ-rays at 0.3, 0.063, and 0.014 Gy/min. p53 binding protein 1 (53BP1) foci were determined via immunofluorescence. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Central LECs showed a linear increase in mean 53BP1 foci/cell with the maximum dose and dose-rate displaying a 78x increase compared to control. Peripheral LECs and lower dose rates displayed similar results, with slightly fewer foci. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ahmadi et al., 2021 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Human LEC cells were exposed to 137Cs γ-rays at doses of 0, 0.1, 0.25, and 0.5 Gy and dose rates of 0.065 and 0.3 Gy/min. DNA strand breaks were measured using the comet assay. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Human LECs showed a gradual increase in the tail from the comet assay with the maximum dose and dose-rate displaying a 3.7x increase compared to control. Lower dose-rates followed a similar pattern with a lower amount of strand breaks. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hamada et al., 2006 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Primary normal human diploid fibroblast (HE49) cells were exposed to 0.1, 0.5, and 4 Gy X-rays at 240 kV with a dose rate of 0.5 Gy/min. The number of H2AX foci/cell, which represented DNA strand breaks, was determined 6 – 7 minutes after irradiation through fluorescence microscopy. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Cells displayed a linear increase in the number of H2AX foci/cell, with the maximum dose displaying a 125x increase compared to control. </span></span></span></p>
<p> </p>
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<td><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Dubrova & Plumb, 2002</span></span></span></td>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">At 1 Gy observe 70 DSBs, 1000 single-strange breaks and 2000 damaged DNA bases per cell per Gy.</span></span></span></p>
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<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sabirzhanov et al., 2020</span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Rat cortical neurons were exposed to 2, 8 or 32 Gy of X rays (320 kV) at a dose rate of 1.25 Gy/min. Western blot was used to measure γ-H2AX, p-ataxia telangiectasia mutated (ATM) and p- ATM/RAD3-related (ATR) levels. </span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In rat cortical neurons, p-ATM increased at 2, 8, and 32 Gy, with a 15-fold increase at 8 and 32 Gy. γ-H2AX levels increased at 8 and 32 Gy. </span></span></span></td>
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<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Geisel et al., 2012 </span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vivo. Patients with suspected coronary artery disease receiving X-rays from computed tomography or conventional coronary angiography had levels of DSBs assessed in blood lymphocytes by γ-H2AX fluorescence. </span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">There was a correlation between effective dose (in mSv) and DSBs. For both conventional coronary angiography and computed tomography, a dose of 10 mSv produced about 2-fold more DNA DSBs than a dose of 5 mSv. </span></span></span></td>
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<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ungvari et al., 2013 </span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Rat cerebromicrovascular endothelial cells and hippocampal neurons were irradiated with 2-10 Gy of <sup>137</sup>Cs gamma rays. DNA strand breaks were assessed with the comet assay. </span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">DNA damage increased at all doses (2-10 Gy). In the control, less than 5% of DNA was in the tail, while by 6 Gy, 35% of the DNA was in the tail in cerebromicrovascular endothelial cells and 25% was in the tail in neurons. </span></span></span></td>
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<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rombouts et al., 2013 </span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. EA.hy926 cells and human umbilical vein endothelial cells were irradiated with various doses of X-rays (0.25 Gy/min). γ-H2AX foci were assessed with immunofluorescence. </span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">More γ-H2AX foci were observed at higher doses in both cell types. In human umbilical vein endothelial cells, few foci/nucleus were observed at 0.05 Gy, with about 23 at 2 Gy. In EA.hy926 cells, few foci/nucleus were observed at 0.05 Gy, with about 37 at 2 Gy. </span></span></span></td>
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<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Baselet et al., 2017 </span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Human telomerase-immortalized coronary artery endothelial cells were irradiated with various doses of X-rays (0.5 Gy/min). Immunocytochemical staining was performed for γ-H2AX and 53BP1 foci. </span></span></span></td>
<td><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Doses of 0.05 and 0.1 Gy did not increase the number of γ-H2AX foci, but 0.5 Gy increased foci number by 5-fold and 2 Gy by 15-fold. A dose of 0.05 Gy did not increase the number of 53BP1 foci, but 0.1 Gy, 0.5 Gy and 2 Gy increased levels by 3-fold, 7-fold and 8-fold, respectively.</span></span></span> </td>
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<p> </p>
<p><strong><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Time Concordance </span></span></span></strong></p>
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<p><strong><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Reference </span></span></span></strong></p>
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<p><strong><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Experiment Description </span></span></span></strong></p>
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<p><strong><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Result </span></span></span></strong></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rogakou et al., 1999 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Normal human fibroblasts (IMR90), human breast cancer cells (MCF7), human astrocytoma cells (SF268), Indian muntjac Muntiacus muntjak normal skin fibroblasts, Xenopus laevisA6 normal kidney cells, Drosophila melanogaster epithelial cells, and Saccharomyces cerevisiae were exposed to 0.6, 2, 20, 22, 100, and 200 Gy 137Cs γ-rays. Doses below 20 Gy were delivered at 15.7 Gy/min and other doses were delivered in 1 minute. DNA breaks were visualized using γ-H2AX antibodies and microscopy. </span></span></span></p>
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<p><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">DSBs </span></span></span><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">were </span></span></span><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">present at 3 min </span></span></span><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">and </span></span></span><span style="color:#0000ff"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">persisted from 15 - 60 min. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hamada & Woloschak, 2017 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. human LECs were exposed to 0.025 Gy X-rays at 0.42 – 0.45 Gy/min. 53BP1 foci were measured via indirect immunofluorescence. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In cells immediately exposed to 0.025 Gy, the level of 53BP1 foci/cell increased to 3.3x relative to control 0.5 h post-irradiation. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hamada et al., 2006 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Primary normal human diploid fibroblast (HE49) cells were exposed to 0.1, 0.5, and 4 Gy (deposition of energy) at 240 kV with a dose rate of 0.5 Gy/min. The number of H2AX foci/cell, which represented DNA strand breaks, was determined through fluorescence microscopy. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In cells immediately exposed to 0.5 Gy, 11% of cells had 18 foci six min post-irradiation, compared to 90% of controls having 0 foci. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Acharya et al., 2010 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Human neural stem cells were exposed to 1, 2 and 5 Gy of γ-rays at a dose rate of 2.2 Gy/min. The levels of γ-H2AX phosphorylation post irradiation were assessed by immunocytochemistry, fluorescence-activated cell sorting (FACS) analysis and γ-H2AX foci enumeration. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">The number of cells positive for nuclear γ-H2AX foci peaked at 20 min post-irradiation. After 1h, this level quickly declined. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Schmal et al., 2019 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vivo. Juvenile and adult C57BL/6 mice were exposed to whole body 6-MV photons at 2 Gy/min. Irradiations were done in 5x, 10x, 15x and 20x fractions of 0.1 Gy. Double staining for NeuN and 53BP1 was used to quantify DNA damage foci and the possible accumulation in the hippocampal dentate gyrus. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">To assess possible accumulation of persisting 53BP1-foci during fractionated radiation, juvenile and adult mice were examined 72 h after exposure to 5×, 10×, 15×, or 20× fractions of 0.1 Gy, compared to controls. The number of persisting 53BP1-foci increased significantly in both juvenile and adult mice during fractionated irradiation (maximum at 1 m post-IR). </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Dong et al., 2015 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vivo. C57BL/6J mice were exposed to 2 Gy of X-rays at 2 Gy/min using a 6 MV source. γ-H2AX foci were assessed with immunofluorescence in the brain. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">At 0.5 h, about 14 γ-H2AX foci/cell were present. This decreased linearly to about 2 foci/cell at 24 h, with no foci/cell from 48 h to 6 weeks. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Barazzuol et al., 2017 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vivo. C57BL/6 mice were exposed to 0.1 or 2 Gy of X-rays (250 kV) at a rate of 0.5 Gy/min. 53BP1 foci were quantified with immunofluorescence in neural stem cells and neuron progenitors in the lateral ventricle. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">At both 0.5 and 6 h post-irradiation, increased 53BP1 foci were observed, with the highest level at 0.5 h. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sabirzhanov et al., 2020 </span></span></span></p>
<p> </p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Rat cortical neurons were exposed to 2, 8 or 32 Gy of X rays (320 kV) at a dose rate of 1.25 Gy/min. Western blot was used to measure γ-H2AX, p-ATM and p-ATR levels. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In rat cortical neurons, γ-H2AX, p-ATM and p-ATR all increased at 30 minutes post-irradiation, with a sustained increase until 6 h. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Zhang et al., 2017 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. HT22 hippocampal neuronal cellsT were irradiated with X-rays (320 kVp) at 8 or 12 Gy at a dose rate of 4 Gy/min. The comet assay was preformed to assess the DNA double strand breaks in HT22 cells. Western blot was used to measure γ-H2AX and p-ATM. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">At 8 Gy, the comet assay showed an increased tail moment at both 30 minutes and 24 h post-irradiation. At 12 Gy, p-ATM was increased over 4-fold at both 30 minutes and 1 h post-irradiation. γ-H2AX was increased over 3-fold at 30 minutes post-irradiation and almost 2-fold at 1 and 24 h. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Geisel et al., 2012 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vivo. Patients with suspected coronary artery disease receiving X-rays from computed tomography or conventional coronary angiography had levels of DSBs assessed in blood lymphocytes by γ-H2AX fluorescence. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">DSBs were increased at 1 h post-irradiation and returned to pre-irradiation levels by 24 h. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Park et al., 2022 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Human aortic endothelial cells were irradiated with 137Cs gamma rays at 4 Gy (3.5 Gy/min). γ-H2AX was measured with western blot. p-ATM and 53BP1 were determined with immunofluorescence. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">γ-H2AX, p-ATM, and 53BP1 were shown increased at 1 h post-irradiation and slightly decreased for the rest of the 6 h but remained elevated above the control. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kim et al., 2014 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Human umbilical vein endothelial cells were irradiated with 4 Gy of 137Cs gamma rays. γ-H2AX levels were determined with immunofluorescence. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">γ-H2AX foci greatly increased at 1 and 6 h post-irradiation, with the greatest increase at 1 h. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Dong et al., 2014 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Human umbilical vein endothelial cells were irradiated with 2 Gy of 137Cs gamma rays. γ-H2AX levels were determined with immunofluorescence. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">γ-H2AX foci increased 8-fold at 3 h, 7-fold at 6 h, and 2-fold at 12 and 24 h post-irradiation. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rombouts et al., 2013 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. EA.hy926 cells and human umbilical vein endothelial cells were irradiated with X-rays (0.25 Gy/min). γ-H2AX foci were assessed with immunofluorescence. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">The greatest increase in γ-H2AX foci was observed 30 minutes post-irradiation, while levels were still slightly elevated at 24 h. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Nübel et al., 2006 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Human umbilical vein endothelial cells were irradiated with gamma rays at 20 Gy. DNA strand breaks were assessed with the comet assay and western blot for γ-H2AX. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">The olive tail moment increased 5-fold immediately after irradiation and returned to control levels by 4 h. A large increase in γ-H2AX was observed at 0.5 h post-irradiation, with lower levels at 4 h but still above the control. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Baselet et al., 2017 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vitro. Human telomerase-immortalized coronary artery endothelial cells were irradiated with various doses of X-rays (0.5 Gy/min). Immunocytochemical staining was performed for γ-H2AX and 53BP1 foci. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Increased γ-H2AX and 53BP1 foci were observed at 0.5 h post-irradiation, remaining elevated at 4 h but returning to control levels at 24 h. </span></span></span></p>
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</tr>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Gionchiglia et al., 2021 </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In vivo. Male CD1 and B6/129 mice were irradiated with X-rays at 10 Gy. Brain sections were single or double-stained with antibodies against γ-H2AX and p53BP1. </span></span></span></p>
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<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">In the forebrain, cerebral cortex, hippocampus and subventricular zone (SVZ)/ rostral migratory stream (RMS)/ olfactory bulb (OB), γH2AX and p53BP1 positive cells increased at both 15 and 30 minutes post-irradiation, with the greatest increase at 30 minutes. </span></span></span></p>
</td>
</tr>
</tbody>
</table>
<p> </p>
<p> </p>
HighUnspecificHighAll life stagesHighHighHighLowLowLow<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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.</span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ahmadi, M. et al. (2021), “Early responses to low-dose ionizing radiation in cellular lens epithelial models”, Radiation research, Vol.197/1, <em>Radiation Research Society</em>, United States, https://doi.org/10.1667/RADE-20-00284.1 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ainsbury, E. A. et al. (2016), “Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research”, <em>Mutation research. Reviews in mutation research</em>, Vol. 770, Elsevier B.V., Amsterdam, https://doi.org/10.1016/j.mrrev.2016.07.010 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Alexander, J. L. and Orr-Weaver, T. L. (2016), “Replication fork instability and the consequences of fork collisions from replication”, <em>Genes & Development</em>, Vol. 30/20, Cold Spring Harbor Laboratory Press, https://doi.org/ 10.1101/gad.288142.116 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Allen, C. H. et al. (2018), “Raman micro-spectroscopy analysis of human lens epithelial cells exposed to a low-dose-range of ionizing radiation”, <em>Physics in medicine & biology</em>, Vol. 63/2, IOP Publishing, Bristol, https://doi.org/10.1088/1361-6560/aaa176 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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.</span></span></p>
<p><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">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. </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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.</span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Aufderheide, E. et al. (1987), “Heavy ion effects on cellular DNA: Strand break induction and repair in cultured diploid lens epithelial cells”, <em>International journal of radiation biology and related studies in physics, chemistry and medicin</em>e, Vol. 51/5, Taylor & Francis, London, https://doi.org/10.1080/09553008714551071 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Bannik, K. et al. (2013), “Are mouse lens epithelial cells more sensitive to γ-irradiation than lymphocytes?”, <em>Radiation and environmental biophysics</em>, Vol. 52/2, Springer-Verlag, Berlin/Heidelberg, https://doi.org/10.1007/s00411-012-0451-8 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Bains, S. K. et al. (2019), “Effects of ionizing radiation on telomere length and telomerase activity in cultured human lens epithelium cells”, I<em>nternational journal of radiation biology</em>, Vol. 95/1, Taylor & Francis, Abingdon, https://doi.org/10.1080/09553002.2018.1466066 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><span style="color:#e74c3c">Barazzuol, L et al. (2017), “A coordinated DNA damage response promotes adult quiescent neural stem cell activation. PLOS Biology, 15(5). </span><a href="https://doi.org/10.1371/journal.pbio.2001264" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1371/journal.pbio.2001264</span></a><span style="color:#e74c3c"> </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Barnard, S. G. R. et al. (2018), “Dotting the eyes: mouse strain dependency of the lens epithelium to low dose radiation-induced DNA damage”, <em>International journal of radiation biology</em>, Vol. 94/12, Taylor & Francis, Abingdon, https://doi.org/10.1080/09553002.2018.1532609 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Barnard, S. G. R. et al. (2019), “Inverse dose-rate effect of ionising radiation on residual 53BP1 foci in the eye lens”, <em>Scientific Reports</em>, Vol. 9/1, Nature Publishing Group, England, https://doi.org/10.1038/s41598-019-46893-3 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Barnard, S. G. R. et al. (2022), “Radiation-induced DNA damage and repair in lens epithelial cells of both Ptch1 (+/-) and Ercc2 (+/-) mutated mice”, <em>Radiation Research</em>, Vol. 197/1, Radiation Research Society, United States, https://doi.org/10.1667/RADE-20-00264.1 </span></span></span></p>
<p> </p>
<p><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Baselet, B. et al. (2019), “Pathological effects of ionizing radiation: endothelial activation and dysfunction”, Cellular and molecular life sciences, Vol. 76/4, Springer Nature, https://doi.org/10.1007/s00018-018-2956-z </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">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, https://doi.org/10.3389/fphar.2017.00213 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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”, <em>Advances in space research</em>, Vol. 31/6, Elsevier Ltd, England, https://doi.org/10.1016/S0273-1177(03)00095-4 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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.</span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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.</span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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.</span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Bucolo, C. et al. (1994), “The effect of ganglioside on oxidation-induced permeability changes in lens and in epithelial cells of lens and retina”, <em>Experimental eye research,</em> Vol. 58/6, Elsevier Ltd, London, https://doi.org/10.1006/exer.1994.1067 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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 </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Cadet, J. et al. (2012), “Oxidatively generated complex DNA damage: tandem and clustered lesions”, Cancer letters, Vol. 327/1, Elsevier Ireland Ltd, Ireland. https://doi.org/10.1016/j.canlet.2012.04.005 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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, https://doi.org/10.1111/php.12814 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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 </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Citrin, D.E. & J.B. Mitchel (2014), "Public Access NIH Public Access.", 71(2):233–236. doi:10.1038/mp.2011.182.doi. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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, https://doi.org/10.1007/s00411-017-0728-z </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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, https://doi.org/10.1186/1476-4598-5-20 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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, https://doi.org/10.1016/0891-5849(92)90142-4 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p> </p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif"><span style="color:#e74c3c">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. </span><a href="https://doi.org/10.3109/09553002.2014.988895" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.3109/09553002.2014.988895</span></a><span style="color:#e74c3c"> </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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, https://doi.org/10.1667/RR13682.1 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">EPRI (2014), Epidemiology and mechanistic effects of radiation on the lens of the eye: Review and scientific appraisal of the literature, EPRI, California </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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, https://doi.org/10.1016/j.mrrev.2016.09.001 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p> </p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px"><span style="color:#e74c3c">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, </span><a href="https://doi.org/10.1007/s00330-012-2426-1" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1007/s00330-012-2426-1</span></a><span style="color:#e74c3c"> </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">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. </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">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, https://doi.org/10.1667/RR3577.1 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hamada, N. (2014), “What are the intracellular targets and intratissue target cells for radiation effects?”, Radiation research, Vol. 181/1, The Radiation Research Society, Lawrence, https://doi.org/10.1667/RR13505.1 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hamada, N. and T. Sato (2016), “Cataractogenesis following high-LET radiation exposure”, Mutation Research. Reviews in mutation research, Vol. 770, Elsevier B.V., Amsterdam, https://doi.org/10.1016/j.mrrev.2016.08.005 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hamada, N. (2017a), “Ionizing radiation sensitivity of the ocular lens and its dose rate dependence”, International journal of radiation biology, Vol. 93/10, Taylor & Francis, Abingdon, https://doi.org/10.1080/09553002.2016.1266407 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hamada, N. and G. E. Woloschak (2017), “Ionizing radiation response of primary normal human lens epithelial cells”, PloS ONE, Vol. 12/7, Public Library Science, San Francisco, https://doi.org/10.1371/journal.pone.0181530 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Havas, M. (2017), “When theory and observation collide: Can non-ionizing radiation cause cancer?”, Environmental pollution, Vol. 221, Elsevier Ltd, England. https://doi.org/10.1016/j.envpol.2016.10.018 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hightower, K. R. (1995), “The role of the lens epithelium in development of UV cataract”, Current eye research, Vol. 14/1, Informal UK Ltd, Philadelphia, https://doi.org/10.3109/02713689508999916 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Iliakis, G., T. Murmann & A. Soni (2015), "Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations.", Mutat. Res. - Genet. Toxicol. Environ. Mutagen. 793:166–175. doi:10.1016/j.mrgentox.2015.07.001. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Joiner, M. (2009), "Basic Clinical Radiobiology", Edited by. [1] P.J. Sadler, Next-Generation Met Anticancer Complexes Multitargeting via Redox Modul Inorg Chem 52 21.:375. doi:10.1201/b13224. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Jorge, S.-G. et al. (2012), "Evidence of DNA double strand breaks formation in Escherichia coli bacteria exposed to alpha particles of different LET assessed by the SOS response.", Appl. Radiat. Isot. 71(SUPPL.):66–70. doi:10.1016/j.apradiso.2012.05.007. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kadhim, M.A., M.A. Hill & S.R. Moore, (2006), "Genomic instability and the role of radiation quality.", Radiat. Prot. Dosimetry. 122(1–4):221–227. doi:10.1093/rpd/ncl445. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Khanna, K.K. & S.P. Jackson (2001), "DNA double-strand breaks: signaling, repair and the cancer connection.", Nature Genetics. 27(3):247-54. doi:10.1038/85798. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kim, K. S. et al. (2014), “Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells”, International Journal of Radiation Biology, Vol. 90/1, Informa, London, https://doi.org/10.3109/09553002.2014.859763 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kim, J. N. and B. M. Lee (2007), “Risk factors, health risks, and risk management for aircraft personnel and frequent flyers”, Journal of toxicology and environmental health. Part B, Critical reviews, Vol. 10/3, Taylor & Francis Group, Philadelphia, https://doi.org/10.1080/10937400600882103 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kleiman, N. J., R. Wang and A. Spector (1990), “Ultraviolet light induced DNA damage and repair in bovine lens epithelial cells”, Current eye research, Vol. 9/12, Informa UK Ltd, Oxford, https://doi.org/10.3109/02713689009003475 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, 1–12. https://doi.org/10.1080/09553002.2022.2110306 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kuefner, M.A. et al. (2009), "DNA Double-Strand Breaks and Their Repair in Blood Lymphocytes of Patients Undergoing Angiographic Procedures.", Investigative radiology. 44(8):440-6. doi:10.1097/RLI.0b013e3181a654a5. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kuefner, M.A. et al. (2015), "Chemoprevention of Radiation-Induced DNA Double-Strand Breaks with Antioxidants.", Curr Radiol Rep (2015) 3: 81. https://doi.org/10.1007/s40134-014-0081-9 </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Kuhne, M., G. Urban & M. Lo, (2005), "DNA Double-Strand Break Misrejoining after Exposure of Primary Human Fibroblasts to CK Characteristic X Rays, 29 kVp X Rays and Co γ-Rays.", Radiation Research. 164(5):669-676. doi:10.1667/RR3461.1. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">de Lara, C.M. et al. (2001), "Dependence of the Yield of DNA Double-Strand Breaks in Chinese Hamster V79-4 Cells on the Photon Energy of Ultrasoft X Rays.", Radiation Research. 155(3):440-8. doi:10.1667/0033-7587(2001)155[0440:DOTYOD]2.0.CO;2. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Liao, J. et al. (2011), “Anti-UVC irradiation and metal chelation properties of 6-benzoyl-5,7-dihydroxy-4-phenyl-chromen-2-one: An implications for anti-cataract agent”, International journal of molecular sciences, Vol. 12/10, MDPI, Basel. https://doi.org/10.3390/ijms12107059 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Lipman, R. M., B. J. Tripathi, R. C. Tripathi (1998), “Cataracts induced by microwave and ionizing radiation”, Survey of ophthalmology, Vol. 33/3, Elsevier Inc, United States, https://doi.org/10.1016/0039-6257(88)90088-4 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Lomax, M.E., L.K. Folkes & P.O. Neill (2013). "Biological Consequences of Radiation-induced DNA Damage: Relevance to Radiotherapy", Statement of Search Strategies Used and Sources of Information Why Radiation Damage is More Effective than Endogenous Damage at Killing Cells Ionising Radiation-induced Do. 25:578–585. doi:10.1016/j.clon.2013.06.007. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Long, A. C., C. M. H. Colitz, and J. A. Bomser (2001), “Apoptotic and necrotic mechanisms of stress-induced human lens epithelial cell death”, Experimental biology and medicine, SAGE Publications, London, https://doi.org/10.1177/153537020422901012 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Lorat, Y. et al. (2015), "Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy – The heavy burden to repair.", DNA Repair (Amst). 28:93–106. doi:10.1016/j.dnarep.2015.01.007. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Maier, P. et al. (2016), "Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization.", Int. J. Mol. Sci., 14;17(1), pii:E102, doi:10.3390/ijms17010102. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Markiewicz, E. et al. (2015), “Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin D1 expression and lens shape”, Open biology, Vol. 5/4, Royal society, London, https://doi.org/10.1098/rsob.150011 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Milligan, J. R. et al. (1995), « DNA repair by thiols in air shows two radicals make a double-strand break”, Radiation Research, Vol 143/3, pp. 273-280 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Moore, S., F.K.T. Stanley & A.A. Goodarzi (2014), "The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation – No simple task.", DNA repair (Amst), 17:64–73. doi: 10.1016/j.dnarep.2014.01.014. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Mosconi, M., U. Giesen & F. Langner (2011), "53BP1 and MDC1 foci formation in HT-1080 cells for low- and high-LET microbeam irradiations.", Radiat. Envrion. Biophys. 50(3):345–352. doi:10.1007/s00411-011-0366-9. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Nagane, M. et al. (2021), “DNA damage response in vascular endothelial senescence: Implication for radiation-induced cardiovascular disease”, Journal of Radiation Research, Vol. 62/4, https://doi.org/10.1093/jrr/rrab032 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Nenoi, M., B. Wang & G. Vares (2015), "In vivo radioadaptive response: A review of studies relevant to radiation-induced cancer risk.", Hum. Exp. Toxicol. 34(3):272–283. doi:10.1177/0960327114537537. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Nikitaki, Z. et al. (2016), "Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET).", Free Radiac. Res. 50(sup1):S64-S78, doi:10.1080/10715762.2016.1232484. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Nikjoo, H. et al. (2001), "Computational approach for determining the spectrum of DNA damage induced by ionizing radiation.", Radiat. Res. 156(5 Pt 2):577–83.</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px"><span style="color:#e74c3c">Nübel, T. et al. (2006), “Lovastatin protects human endothelial cells from killing by ionizing radiation without impairing induction and repair of DNA double-strand breaks”, Clinical Cancer Research, Vol. 12/3, American Association for Cancer Research, https://doi.org/10.1158/1078-0432.CCR-05-1903 </span></span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px"><span style="color:#e74c3c">Ojima, M., N. Ban, and M. Kai (2008), “DNA double-strand breaks induced by very low X-ray doses are largely due to bystander effects”, Radiation Research, Vol. 170/3, Radiation Research Society, United States, https://doi.org/10.1667/RR1255.1 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Okayasu, R. (2012a), "Repair of DNA damage induced by accelerated heavy ions-A mini review.", Int. J. Cancer. 130(5):991–1000. doi:10.1002/ijc.26445. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Okayasu, R. (2012b), "Heavy ions — a mini review.", 1000:991–1000. doi:10.1002/ijc.26445. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Park, J. W. et al. (2022), “Metformin alleviates ionizing radiation-induced senescence by restoring BARD1-mediated DNA repair in human aortic endothelial cells”, Experimental Gerontology, Vol. 160, Elsevier, Amsterdam, https://doi.org/10.1016/j.exger.2022.111706 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Parris, C.N. et al. (2015), "Enhanced γ-H2AX DNA damage foci detection using multimagnification and extended depth of field in imaging flow cytometry.", Cytom. Part A. 87(8):717–723. doi:10.1002/cyto.a.22697. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Radulescu I., K. Elmroth & B. Stenerlöw (2006), "Chromatin Organization Contributes to Non-randomly Distributed Double-Strand Breaks after Exposure to High-LET Radiation.", Radiat. Res. 161(1):1–8. doi:10.1667/rr3094. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rastogi, R. P. et al. (2010), “Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair”, Journal of nucleic acids, Hindawi Ltd, United States. https://doi.org/10.4061/2010/592980 </span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Reddy, V. N. et al. (1998), “The effect of aqueous humor ascorbate on ultraviolet-B-induced DNA damage in lens epithelium”, Investigative ophthalmology & visual science, Vol. 39/2, Arvo, pp. 344-350 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rogakou, E.P. et al. (1999), "Megabase Chromatin Domains Involved in DNA Double-Strand Breaks In Vivo.", J. Cell Biol, 146(5):905-16. doi: 10.1083/jcb.146.5.905. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Rogers, C. S. et al. (2004), “The effects of sub-solar levels of UV-A and UV-B on rabbit corneal and lens epithelial cells”, Experimental eye research, Vol. 78/5, Elsevier Ltd, London, https://doi.org/10.1016/j.exer.2003.12.011</span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Rombouts, C. et al. (2013), “Differential response to acute low dose radiation in primary and immortalized endothelial cells”, International Journal of Radiation Biology, Vol. 89/10, Informa, London, https://doi.org/10.3109/09553002.2013.806831 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rothkamm, K. et al. (2015), "Review DNA Damage Foci: Meaning and Significance.", Environ. Mol. Mutagen., 56(6):491-504, doi: 10.1002/em.21944. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rothkamm, K. & M. Lo (2003), "Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.", PNAS, 100(9):5057-62. doi:10.1073/pnas.0830918100. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rübe, C.E. et al. (2008), "Cancer Therapy: Preclinical DNA Double-Strand Break Repair of Blood Lymphocytes and Normal Tissues Analysed in a Preclinical Mouse Model: Implications for Radiosensitivity Testing.", Clin. Cancer Res., 14(20):6546–6556. doi:10.1158/1078-0432.CCR-07-5147. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Russo, A. et al. (2015), "Review Article Genomic Instability: Crossing Pathways at the Origin of Structural and Numerical Chromosome Changes.", Envrion. Mol. Mutagen. 56(7):563-580. doi:10.1002/em. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Rydberg B, Heilbronn L, Holley WR, Lobrich M, Zeitlin C et al. 2002. Spatial Distribution and Yield of DNA Double-Strand Breaks Induced by 3-7 MeV Helium Ions in Human Fibroblasts. Radiat Res. 158(1):32-42.</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px"><span style="color:#e74c3c">Sabirzhanov, et al. (2020), “Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways.”, Int J Mol Sci. 21(15):5239. doi: 10.3390/ijms21155239.</span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sage, E. & N. Shikazono (2017), "Free Radical Biology and Medicine Radiation-induced clustered DNA lesions: Repair and mutagenesis.", Free Radic. Biol. Med. 107(December 2016):125–135. doi:10.1016/j.freeradbiomed.2016.12.008. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sasaki, H. et al. (1998), “TEMPOL protects against lens DNA strand breaks and cataract in the x-rayed rabbit”, Investigative ophthalmology & visual sciences, Vol. 39/3, Arvo, Rockville, pp. 544-552</span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Schmal, Z. et al. (2019), “DNA damage accumulation during fractionated low-dose radiation compromises hippocampal neurogenesis”, Radiotherapy and Oncology. 137:45-54. doi:10.1016/j.radonc.2019.04.021.</span></span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sears, C. R. and J. J. Turchi (2012), “Complex cisplatin-double strand break (DSB) lesions directly impair cellular non-homologous end-joining (NHEJ) independent of downstream damage response (DDR) pathways”, Journal of biological chemistry, Vol 287/29, The American Society for Biochemistry and Molecular Biology, Inc, USA, https://doi.org/ 10.1074/jbc.M112.344911 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Shah, D.J., R.K. Sachs & D.J. Wilson (2012), "Radiation-induced cancer: A modern view." Br. J. Radiol. 85(1020):1166–1173. doi:10.1259/bjr/25026140. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Shelke, S. & B. Das (2015), "Dose response and adaptive response of non- homologous end joining repair genes and proteins in resting human peripheral blood mononuclear cells exposed to γ radiation.", (December 2014):365–379. doi:10.1093/mutage/geu081. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sidjanin, D., S. Zigman and J. Reddan (1993), “DNA damage and repair in rabbitlens epithelial cells following UVA radiation”, Current eye research, Vol. 12/9, Informa UK Ltd, Oxford, https://doi.org/10.3109/02713689309020382 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Smith, J. et al. (2003), "Impact of DNA ligase IV on the delity of end joining in human cells.", Nucleic Acids Research. 31(8):2157-2167.doi:10.1093/nar/gkg317. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Smith, T.A. et al. (2017), "Radioprotective agents to prevent cellular damage due to ionizing radiation." Journal of Translational Medicine.15(1).doi:10.1186/s12967-017-1338-x. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Stewart, F. A. et al. (2012), “ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs – threshold doses for tissue reactions in a radiation protection context”, Annals of the ICRP, Vol, 41/1-2, Elsevier Ltd, London, https://doi.org/10.1016/j.icrp.2012.02.001 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sudprasert, W., P. Navasumrit & M. Ruchirawat (2006), "Effects of low-dose γ radiation on DNA damage, chromosomal aberration and expression of repair genes in human blood cells.", Int. J. Hyg. Envrion. Health, 209:503–511. doi:10.1016/j.ijheh.2006.06.004. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sutherland, B.M. et al. (2000), "Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation.", J. of Rad. Res. 43 Suppl(S):S149-52. doi: 10.1269/jrr.43.S149</span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Sylvester, C. B. et al. (2018), “Radiation-Induced Cardiovascular Disease: Mechanisms and Importance of Linear Energy Transfer”, Frontiers in cardiovascular medicine, Vol. 5, Frontiers, https://doi.org/10.3389/fcvm.2018.00005 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Terato, H. & H. Ide (2005), "Clustered DNA damage induced by heavy ion particles.", Biol. Sci. Sp. 18(4):206–215. doi:10.2187/bss.18.206.</span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ungvari, Z. et al. (2013), “Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity”, The journals of gerontology. Series A, Biological sciences and medical sciences, Vol. 68/12, Oxford University Press, Oxford, https://doi.org/10.1093/gerona/glt057 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Valentin, J.D.J (1998), "Chapter 1. Ann ICRP.", 28(4):5–7. doi:10.1016/S0146-6453(00)00002-6. http://www.ncbi.nlm.nih.gov/pubmed/10882804. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Venkatesh, P. et al. (2016), "Effect of chromatin structure on the extent and distribution of DNA double strand breaks produced by ionizing radiation; comparative study of hESC and differentiated cells lines.", Int J. Mol. Sci. 17(1). doi:10.3390/ijms17010058. </span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px"><span style="color:#e74c3c">Wang, et al. (2021), “Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms.”, Cells. 10(12):3570. doi: 10.3390/cells10123570 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ward, J. F. (1988), "DNA Damage Produced by Ionizing Radiation in Mammalian Cells: Identities, Mechanisms of Formation, and Reparability.", Prog. Nucleic Acid Res. Mol. Biol. 35(C):95–125. doi:10.1016/S0079-6603(08)60611-X. </span></span></p>
<p><span style="color:#e74c3c"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Wolf, N. et al. (2008), “Radiation cataracts: Mechanisms involved in their long delayed occurrence but then rapid progression”, Molecular vision, Vol. 14/34-35, Molecular Vision, Atlanta, pp. 274-285 </span></span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Wu, L.J. et al. (1999), "Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells.", Proc. Natl. Acad. Sci. 96(9):4959–4964. doi:10.1073/pnas.96.9.4959. </span></span></p>
<p><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Yamaguchi, H. et al. (2005), "Estimation of Yields of OH Radicals in Water Irradiated by Ionizing Radiation.", J. of Rad. Res. 46(3):333-41. doi: 10.1269/jrr.46.333.</span></span></p>
<p><span style="color:#e74c3c"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">Zhang, L. et al. (2017), “The inhibitory effect of minocycline on radiation-induced neuronal apoptosis via AMPKα1 signaling-mediated autophagy.”, Sci Rep.7(1):16373. doi: 10.1038/s41598-017-16693-8. </span></span></span></p>
2019-08-26T12:00:062023-03-22T09:29:33c2bac1e0-e4a7-4c94-bdab-f6c7e55a6517272e3cfa-feed-4c62-8f38-05ea4e59ceff2022-03-01T15:58:492022-03-01T15:58:49272e3cfa-feed-4c62-8f38-05ea4e59ceff15e299b2-92d0-4946-b2ac-68f707797cc12020-04-30T16:44:142020-04-30T16:44:1415e299b2-92d0-4946-b2ac-68f707797cc1bbcfd6ef-9864-4450-b251-d4d6d312fbd32022-03-01T12:49:102022-03-01T12:49:10bbcfd6ef-9864-4450-b251-d4d6d312fbd3c4d26bd2-a76f-4155-8de3-0c949ceb8f90<p>SEE BIOLOGICAL PLAUSIBILITY BELOW</p>
<p>Updated 03/20/2017</p>
<p>Using a relatively simple density-dependent population model and assuming constant young of year survival with no immigration/emigration, reductions in cumulative fecundity have been predicted to yield declines in population size over time (Miller and Ankley 2004). Under real-world environmental conditions, outcomes may vary depending on how well conditions conform with model assumptions. Nonetheless, cumulative fecundity can be considered one vital rate that contributes to overall population trajectories (Kramer et al. 2011).</p>
<ul>
<li>Using a relatively simple density-dependent population model and assuming constant young of year survival with no immigration/emigration, reductions in cumulative fecundity have been predicted to yield declines in population size over time (Miller and Ankley 2004). However, it should be noted that the model was constructed in such a way that predicted population size is dependent on cumulative fecundity, therefore this is a fairly weak form of empirical support.</li>
<li>In a study in which an entire lake was treated with 17alpha-ethynyl estradiol, Kidd et al. (2007) declines in fathead minnow population size were associated with signs of reduced fecundity.</li>
</ul>
<ul>
<li>Wester et al. (2003) and references cited therein suggest that although egg production is an endpoint of demographic significance, incomplete reductions of egg production may not translate in a simple manner to population reductions. Compensatory effects of reduced predation and reduced competition for limited food and/or habitat resources may offset the effects of incomplete reductions in egg production.</li>
<li>Fish and other egg laying animals employ a diverse range of reproductive strategies and life histories. The nature of the relationship between reduced spawning frequency and cumulative fecundity and overall population trajectories will depend heavily on the life history and reproductive strategy of the species in question. Relationships developed for one species will not necessarily hold for other species, particularly those with differing life histories.</li>
</ul>
<ul>
<li>Cumulative fecundity is one example of a vital rate that can influence population size over time. A variety of population model constructs can be adapted to utilize measurements or estimates of cumulative fecundity as a predictor of population trends over time (e.g., (Miller and Ankley 2004; Miller et al. 2013).</li>
<li>The model of Miller et al. 20014 uses a relatively simple density-dependent population model and assuming constant young of year survival with no immigration/emigration, use measures of cumulative fecundity to predict relative change in in population size over time (Miller and Ankley 2004).</li>
</ul>
Not SpecifiedUnspecificNot SpecifiedAll life stagesModerate<p>Spawning generally refers to the release of eggs and/or sperm into water, generally by aquatic or semi-aquatic organisms. Consequently, by definition, this KER is likely applicable only to organisms that spend a portion of their life-cycle in or near aquatic environments.</p>
<ul>
<li>Kidd KA, Blanchfield KH, Palace VP, Evans RE, Lazorchak JM, Flick RW. 2007. Collapse of a fish population after exposure to a synthetic estrogen. PNAS 104:8897-8901.</li>
<li>Kramer VJ, Etterson MA, Hecker M, Murphy CA, Roesijadi G, Spade DJ, Spromberg JA, Wang M, Ankley GT. Adverse outcome pathways and ecological risk assessment: bridging to population-level effects. Environ Toxicol Chem. 2011 Jan;30(1):64-76. doi: 10.1002/etc.375. PubMed PMID: 20963853</li>
<li>Miller DH, Ankley GT. 2004. Modeling impacts on populations: fathead minnow (Pimephales promelas) exposure to the endocrine disruptor 17b-trenbolone as a case study. Ecotoxicology and Environmental Safety 59: 1-9.</li>
<li>Miller DH, Tietge JE, McMaster ME, Munkittrick KR, Xia X, Ankley GT. 2013. Assessment of Status of White Sucker (Catostomus Commersoni) Populations Exposed to Bleached Kraft Pulp Mill Effluent. Environmental toxicology and chemistry / SETAC (in press).</li>
<li>Wester P, van den Brandhof E, Vos J, van der Ven L. 2003. Identification of endocrine disruptive effects in the aquatic environment - a partial life cycle assay with zebrafish. (RIVM Report). Bilthoven, the Netherlands: Joint Dutch Environment Ministry.</li>
</ul>
2016-11-29T18:41:332017-03-20T13:49:05Deposition of energy leading to population decline via DNA strand breaks and oocyte apoptosisDeposition of energy leading to population decline via DSB and apoptosis<p>You Song<sup>1</sup>, Knut Erik Tollefsen<sup>1,2,3</sup></p>
<p><sup>1</sup>Norwegian Institute for Water Research (NIVA), Økernveien 94, 0579 Oslo, Norway</p>
<p><sup>2</sup>Centre for Environmental Radioactivity (CERAD), Norwegian University of Life Sciences (NMBU), Post box 5003, N-1432 Ås, Norway</p>
<p><sup>3</sup>Norwegian University of Life Sciences (NMBU), Faculty of Environmental Sciences and Natural Resource Management (MINA), Post box 5003, N-1432 Ås, Norway </p>
Under development: Not open for comment. Do not cite<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">It is well documented that ionizing radiation( (eg. X-rays, gamma, photons, alpha, beta, neutrons, heavy ions) leads to energy deposition on the atoms and molecules of the substrate. Many studies, have demonstrated that the type of radiation and distance from source has an impact on the pattern of energy deposition (Alloni, et al. 2014). High linear energy transfer (LET) radiation has been associated with higher-energy deposits (Liamsuwan et al., 2014) that are more densely-packed and cause more complex effects within the particle track (Hada and Georgakilas, 2008; Okayasu, 2012ab; Lorat et al., 2015; Nikitaki et al., 2016) in comparison to low LET radiation. Parameters such as mean lineal energy, dose mean lineal energy, frequency mean specific energy and dose mean specific energy can impact track structure of the traversed energy into a medium (Friedland et al., 2017)</span></span><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:12px">. The detection of energy deposition by ionizing radiation can be demonstrated with the use of fluorescent nuclear track detectors (FNTDs). FNTDs used in conjunction with fluorescent microscopy, are able to visualize radiation tracks produced by ionizing radiation (Niklas et al., 2013; Kodaira et al., 2015; Sawakuchi and Akselrod, 2016). In addition, these FNTD chips can quantify the LET of primary and secondary radiation tracks up to 0.47 keV/um (Sawakuchi and Akselrod, 2016). This co-visualization of the radiation tracks and the cell markers enable the mapping of the radiation trajectory to specific cellular compartments, and the identification of accrued damage (Niklas et al., 2013; Kodaira et al., 2015). There are no known chemical initiators or prototypes that can mimic the MIE.</span></span></p>
<p>Cumulative fecundity is the most apical endpoint considered in the OECD 229 Fish Short Term Reproduction Assay. The OECD 229 assay serves as screening assay for endocrine disruption and associated reproductive impairment (<a href="http://www.oecd-ilibrary.org/environment/test-no-229-fish-short-term-reproduction-assay_9789264185265-en">OECD 2012</a>). Fecundity is also an important apical endpoint in the Medaka Extended One Generation Reproduction Test (MEOGRT; <a href="http://www.oecd-ilibrary.org/environment/test-no-240-medaka-extended-one-generation-reproduction-test-meogrt_9789264242258-en">OECD Test Guideline 240</a>; OECD 2015).</p>
<p>A variety of fish life cycle tests also include cumulative fecundity as an endpoint (<a href="http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2008)22&doclanguage=en">OECD 2008</a>).</p>
<p> </p>
<p>Maintenance of sustainable fish and wildlife populations (i.e., adequate to ensure long-term delivery of valued ecosystem services) is a widely accepted regulatory goal upon which risk assessments and risk management decisions are based.</p>
adjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedHighFemaleHighAdult, reproductively matureHighNot SpecifiedHighHigh2017-06-29T08:00:092023-04-29T13:02:15