Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Ionizing energy leading to lung cancer||MolecularInitiatingEvent|
|All life stages||High|
Key Event Description
Direct deposition of energy refers to events where subatomic particles or electromagnetic waves of sufficient energy cause ionization in the media through which they transverse (Beir, 1999). The resulting energy can cause the ejection of electrons from atoms and molecules, thereby breaking chemical bonds and ionizing atoms and molecules. 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. 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. Direct ionization is the principal path where charged particles interact with DNA to cause a biological damage. Photons, which are electromagenetic 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, 1999). There are no chemical mimetics or prototypes of energy deposition.
Given the fundamental nature of energy deposition by nuclei, nucleons or elementary particles in material, this process is universal to all biological contexts. It is a phenomena dictated by radioactive decay laws. As such chemical initiators are also not applicable to this MIE.
How It Is Measured or Detected
|Assay Name||References||Description||OECD Approved Assay|
|Monte Carlo Simulations (Geant4)||Douglass et al., 2013; Douglass et al. 2012||Monte Carlo simulations are based on a computational algorithm that mathematically models the deposition of energy into materials.||N/A|
|Fluorescent Nuclear Track Detector (FNTD)||
Sawakuchi, 2016; Niklas, 2013; Koaira et al., 2015
|FNTDs are biocompatible chips with crystals of aluminium oxide doped with carbon and magnesium; used in conjustion 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.||N/A|
Domain of Applicability
Energy can be deposited into any substrate, both living and non-living; it is independent of age, taxa, sex, or life-stage.
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
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, 2012b; 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. 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.
Alloni, AD. et al.(2014),” Modeling Dose Deposition and DNA Damage Due to Low-Energy β – Emitters.”, Radiation Research.182(3):322–330. doi:10.1667/RR13664.1.
Beir, V. et al. (1999), “ The Mechanistic Basis of Radon-Induced Lung Cancer.”, https://www.ncbi.nlm.nih.gov/books/NBK233261/.
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.”, Med Phys. 40(7), 071710. doi:10.1118/1.4808150.
Douglass, M. et al. (2012),” Development of a randomized 3D cell model for Monte Carlo microdosimetry simulations.”, Med Phys. 39(6):3509-3519, doi:10.1118/1.4719963.
Friedland, W. et al. (2017),” Comprehensive track-structure based evaluation of DNA damage by light ions from radiotherapy- relevant energies down to stopping.”, Nat Publ Gr.1–15. doi:10.1038/srep45161.
Hada, M. & Georgakilas, AG. (2008), “Formation of Clustered DNA Damage after High-LET Irradiation.” J Radiat Res. 49(3):203–210. doi:10.1269/jrr.07123.
Hunter, N. & Muirhead, CR. (2009).” Review of relative biological effectiveness dependence on linear energy transfer for low-LET radiations Review of relative biological effectiveness dependence.”, Journal of Radiological Protection. 29(1):5-21. doi:10.1088/0952-4746/29/1/R01.
Kodaira, S. & Konishi, T. (2015), “Co-visualization of DNA damage and ion traversals in live mammalian cells using a fluorescent nuclear track detector.” Journal of Radiation Research. 360–365. doi:10.1093/jrr/rru091.
Liamsuwan, T. (2014).” Microdosimetry of proton and carbon ions.”, Med Phys. 41(8):081721. doi: 10.1118/1.4888338.
Lorat, Y. (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.
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 Radical Research. 50(sup1):S64-S78.doi:10.1080/10715762.2016.1232484.
Niklas, M. et al. (2013), “Engineering cell-fluorescent ion track hybrid detectors.”, Radiation Oncology. 8:141. doi: 10.1186/1748-717X-8-141.
Okayasu, R. (2012a), “heavy ions — a mini review.”, Int J Cancer. 1000:991–1000. doi:10.1002/ijc.26445.
Okayasu, R. (2012b), “Repair of DNA damage induced by accelerated heavy ions-A mini review.”, Int J Cancer. 130(5):991–1000. doi:10.1002/ijc.26445.
Robertson, A. et al. (2013), “The Cellular and Molecular Carcinogenic Effects of Radon Exposure.”, Int J Mol Sci.14(7):14024-63. doi: 10.3390/ijms140714024.
Sawakuchi, GO. & Akselrod, MS. (2016), “Nanoscale measurements of proton tracks using fluorescent nuclear track detectors.”,Med Phys. 43(5):2485–2490. doi:10.1118/1.4947128.
Wyrobek, A. J. et al. (2005), “Relative susceptibilities of male germ cells to genetic defects induced by cancer chemotherapies.”, J Natl Cancer Inst Monogr.(34)” 31-35. doi:10.1093/jncimonographs/lgi001.