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Event: 1686

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Direct Deposition of Energy

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help

Energy Deposition

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. More help

Organ term

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Ionizing energy leading to lung cancer	MolecularInitiatingEvent	Brendan Ferreri-Hanberry (send email)	Under development: Not open for comment. Do not cite	EAGMST Under Review

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Name
Ionizing Radiation

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	High	NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Life stage	Evidence
All life stages	High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Term	Evidence
Unspecific	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information. More help

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

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

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.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

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.