Aop: 478

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Deposition of energy leading to occurrence of cataracts

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Deposition of energy leading to cataracts

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
W1siziisijiwmjivmtivmjavotgwnwlpnzfucl81ll9bt1bfumvwb3j0x0zpz3vyzxnfmv8uanbnil0swyjwiiwidgh1bwiilci1mdb4ntawil1d?sha=4cca675819152fc0

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Emma Carrothers1, Meghan Appleby1, Vita Lai1, Tatiana Kozbenko1, Robyn Hocking3, Carole Yauk2, Ruth Wilkins1, Vinita Chauhan

(1) Consumer and Clinical Radiation Protection Bureau, Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario  

(2) Department of Biology, University of Ottawa, Ottawa, Ontario  

(3) Learning and Knowledge and Library Services, Health Canada, Ottawa, Ontario, Canada 

Consultants

Nobuyuki Hamada1, Patricia Hinton2, Elizabeth A. Ainsbury3

(1) Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), Tokyo, Japan

(2) Canadian Forces Environmental Medicine Establishment, Toronto, Ontario, Canada  

(3) Chemical, Radiation and Environmental Hazards, UK Health Security Agency, United Kingdom 

 

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Vinita Chauhan   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Vinita Chauhan

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on December 23, 2022 15:49

Revision dates for related pages

Page Revision Date/Time
Increased Modified Proteins December 20, 2022 11:56
Deposition of Energy January 10, 2023 18:54
Increase, Oxidative damage to DNA January 09, 2023 20:30
Increase, DNA strand breaks January 09, 2023 20:47
Inadequate DNA repair January 09, 2023 20:45
Increase, Mutations January 10, 2023 19:00
Increase, Chromosomal aberrations January 09, 2023 20:54
Increase, Cell Proliferation December 19, 2022 09:35
Occurrence of Cataracts December 20, 2022 11:57
Oxidative Stress December 23, 2022 15:46
Energy Deposition leads to Increase, DNA strand breaks January 10, 2023 19:08
Energy Deposition leads to Increase, Oxidative DNA damage December 18, 2022 11:13
Energy Deposition leads to Modified Proteins December 19, 2022 09:46
Energy Deposition leads to Increase, Mutations January 10, 2023 19:20
Oxidative Stress leads to Increase, Oxidative DNA damage December 19, 2022 09:49
Energy Deposition leads to Increase, Chromosomal aberrations January 10, 2023 19:23
Oxidative Stress leads to Increase, DNA strand breaks December 19, 2022 09:50
Energy Deposition leads to Increase, Cell Proliferation December 18, 2022 13:04
Oxidative Stress leads to Modified Proteins December 19, 2022 09:51
Energy Deposition leads to Cataracts December 18, 2022 13:46
Inadequate DNA repair leads to Cataracts December 18, 2022 13:59
Increase, Oxidative DNA damage leads to Inadequate DNA repair January 09, 2023 20:55
Oxidative Stress leads to Cataracts December 18, 2022 14:28
Increase, DNA strand breaks leads to Inadequate DNA repair January 09, 2023 20:59
Inadequate DNA repair leads to Increase, Mutations January 10, 2023 19:12
Inadequate DNA repair leads to Increase, Chromosomal aberrations January 09, 2023 21:01
Increase, Mutations leads to Increase, Cell Proliferation January 10, 2023 19:15
Increase, Chromosomal aberrations leads to Increase, Cell Proliferation January 10, 2023 19:17
Modified Proteins leads to Cataracts December 18, 2022 13:52
Increase, Cell Proliferation leads to Cataracts December 18, 2022 14:35
Increase, Oxidative DNA damage leads to Increase, DNA strand breaks January 09, 2023 21:03

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

New recommendations to the dose limits for the lens of the eye from radiation exposure have triggered further interest in understanding the mechanisms to cataract formation particularly from varied doses and dose-rates. To this end, an adverse outcome pathway (AOP) was developed for a modular path to cataracts from a molecular initiating event (MIE) of deposition of energy. The AOP is part of a larger network, comprised of four other non-cancer outcomes that include: bone loss, vascular remodeling, and impaired learning and memory. Deposition of energy serves as the MIE and is relevant to a multitude of radiation stressors. Deposition of energy within cells can break water molecules leading to increased free radical generation and, if this exceeds the defence mechanism, oxidative stress can ensue that can, in turn, lead to modified proteins. Aggregated proteins such as crystalline can accumulate within the lens of the eye resulting in lens opacity. Concurrently, unmanaged oxidative stress can increase oxidative DNA damage leading to DNA strand breaks that can also be directly formed from the MIE If these lesions are inadequately repaired, it may increase mutation frequency in critical genes and cause chromosomal aberrations. Mutations in genes associated with cell cycling can lead to uncontrolled cell proliferation of lens epithelial cells and the eventual adverse outcome (AO), cataracts. The overall assessment of this AOP identifies the biological plausibility of the KERs to be strong as they are well established and understood; moderate for the evidence streams of essentiality and empirical evidence; low for quantitative understanding across direct relationships, with the presentation of some uncertainties and inconsistencies in mechanisms. Broadly, the information presented in this AOP can be used to support the review of classification of radiation effects and the system of radiological protection.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Cataracts, one of the leading causes of blindness, are a progressive condition in which the lens of the eye develops opacities and becomes cloudy, resulting in blurred vision as well as glare and haloes around lights (National Eye Institute, 2022). For the purposes of this AOP, they are defined as over 5% of cells in the lens exhibiting opacities. Cataracts typically occur after the age of 50 in humans, as an age-related disease (Liu et al., 2017), however progression of disease can be initiated or accelerated after exposure to a variety of agents, one of which being radiation. For radiation induced cataracts, most research shows that the anatomical location is within the posterior sub capsular region of the eye. Cataracts can also be found in the cortical and nuclear region within the lens of the eye. Available epidemiological evidence from Chernobyl workers, radiologic technologists, and patients exposed to radiation through medical procedures, with the most compelling evidence coming from atomic bomb survivors, confirm a positive statistically significant association (Nakashima et al., 2006; Worgul et al., 2007; Chylack et al., 2012; Little et al., 2018). There is limited data from astronauts, however there is concern for long duration space flight missions.  

In 2012, the International Commission on Radiological Protection (ICRP) recommended lowering the occupational eye lens dose limit from 150 mSv per year to an average of 20 mSv with no single year exceeding 50 mSv. This revision was based on new evidence from both radiobiological studies and relevant epidemiological data. The assessment of the literature indicated a threshold dose for radiation induced cataracts of about 0.5 Gy (ICRP, 2012). This change in exposure limit has led to a need to further understand radiation-induced effects at lower doses and dose-rates. This AOP, provides a summary of the relevant studies and endpoints that can inform future research designed across biological levels of organization using relevant models, with the end goal to improve the understanding in risk from low dose low dose-rate exposures. 

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

The present AOP is a component of a broader network that links the deposition of energy with four AOs: vascular remodeling, bone loss, learning and memory impairment, and cataract formation. The network is intended to demonstrate the interconnectivity in mechanisms of diseases. The strategy for developing this network began with the creation of a hypothesized set of key events and relationship identified through narrative review of key literature as well as extensive subject matter expert consultation. 

Many KEs were proposed for the preliminary network, however attention was focused on those deemed most essential for disease progression and which had greatest biological plausibility for connectivity to the rest of the pathway. The preliminary network served as the basis for the next stage of development in which a scoping review methodology was used to collect a weight of evidence (WOE) and refine KEs and KERs. Details of the methodology are described by Kozbenko et al. and are summarized below (Kozbenko et al., 2022).  

In short, literature collection consisted of structured database searches, followed by prioritization and screening stages. Focused searches were completed for each of the KERs in the pathway using combinations of key words related to involved KEs, as well as an overarching search, collecting all references broadly related to the MIE and AO. Following the literature searches, the results were processed in two stages to determine their inclusion in the pathway’s WOE. Both stages determined reference relevance according to inclusion and exclusion criteria that had been outlined prior to screening in a PEOE (Population, Exposure, Outcome, and Endpoint) statement. For articles to be included in the WOE, they had to include a population, exposure (i.e., stressor) and endpoint or outcome of interest.  

In the first phase, search results were prioritized using the SWIFT-Review software (Sciome, Durham NC, https://www.sciome.com/swift-review/). This software was used to identify the references most closely related to the PEOE statement as determined by the software created tags. The most relevant references identified by SWIFT were then screened by human screeners using screening forms created in Distiller SR (Evidence Partners). Screening in Distiller was split into title and abstract, full text and data extraction levels and human screeners were instructed to include references according to the same PEOE criteria. Human screeners additionally evaluated references for their demonstration of Bradford-Hill criteria. At the end of the process, screened in studies were used for the WOE.  

The present cataract AOP was continually refined throughout the screening process based on evidence extracted from the literature. The final pathway includes several KEs previously existing in the AOP Wiki, these include the deposition of energy (KE #1686), increased oxidative stress (KE #1392), increased DNA strand breaks (KE #1635), increased oxidative damage to DNA (KE #1634), inadequate repair (KE #155), increased mutations (KE #185), increased chromosomal aberrations (KE #1636), and increased cell proliferation (KE #870). Newly created KEs for this pathway include modified proteins (KE #2081) and cataracts (KE #2083). It should be noted that the WOE supporting this AOP is predominantly from space exposures, unless there was no available evidence, in which case other types of radiation stressors were used. Priority was also given to experiments using relevant eye lens models. Human and animal studies were prioritized unless data was limited, and then in vitro studies were used to support the KERs. 

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1686 Deposition of Energy Energy Deposition
KE 2081 Increased Modified Proteins Modified Proteins
KE 1634 Increase, Oxidative damage to DNA Increase, Oxidative DNA damage
KE 1635 Increase, DNA strand breaks Increase, DNA strand breaks
KE 155 Inadequate DNA repair Inadequate DNA repair
KE 185 Increase, Mutations Increase, Mutations
KE 1636 Increase, Chromosomal aberrations Increase, Chromosomal aberrations
KE 870 Increase, Cell Proliferation Increase, Cell Proliferation
KE 1392 Oxidative Stress Oxidative Stress
AO 2083 Occurrence of Cataracts Cataracts

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
Title Adjacency Evidence Quantitative Understanding

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.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. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Moderate NCBI
rabbit Oryctolagus cuniculus Low NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific Moderate

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Summary of evidence (KE & KER relationships and evidence) 

This assessment provides an overview of the pathway. Further details and references can be found in the individual KEs and KERs and within the AOP report. 

Biological Plausibility 

This AOP begins with an MIE (deposition of energy) that is directly linked to increased DNA strand breaks, increased oxidative stress, and modified proteins. The current understanding is that energy deposited onto biomolecules from stressors of radiation can potentially cause direct and indirect molecular-level damage. This is particularly likely to the sugar moiety of DNA. Direct damage occurs when ionization events from deposition of energy interact directly with the DNA, while indirect damage can occur when water molecules dissociate producing radicals such as reactive oxygen species (ROS) that induce DNA breaks (Ahmadi et al., 2021). Moreover, deposition of energy can also induce a cascade of ionization events and the formation of clustered damage (Joiner, 2009). 

Deposition of energy can also lead to high levels of ROS and reactive nitrogen species (RNS) (Tangvarasittichai & Tangvarasittichai, 2019). There are several pathways leading to ROS, radiolysis is the most prominent. Free radicals can combine to produce hydrogen peroxide, hydroxide, superoxide, and hydroxyl (Tian et al., 2017; Venkatesulu et al., 2018). Interactions with NO can also lead to RNS (Wang et al., 2019). Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), within mitochondria can also generate more ROS (Soloviev & Kizub, 2019). Energy absorption by an unstable molecule, such as the chromophore NADPH (Jurja et al., 2014) is another route for radical production. Overwhelming amounts of free radicals can decrease antioxidant levels, causing oxidative stress (Wang et al., 2019). 

Alongside DNA as a target to energy deposition, other macromolecules can be damaged. In terms of cataracts, there is much evidence to show that protein modifications such as deamidation, oxidation, disulfide bonds (Hanson et al., 2000), increased cross-linking, altered water-solubility, and increased protein aggregation are critical to disease progression (Fochler & Durchschlag, 1997; Reisz et al., 2014). ROS can also cause many alterations including conformational changes, protein cross-link formation, oxidation of amino acid side chains (Uwineza et al., 2019), and protein aggregation (Moreau et al., 2012). For example, alpha crystallin aggregation can be induced by free radicals oxidizing the thiol groups (Cabrera & Chihuailaf, 2011; Moreau & King 2012; Stohs, 1995). Finally, modified proteins can lead to cataracts, the AO. For example, protein aggregation leads to improper lens epithelial cell (LEC) organization and increases light scattering, therefore increasing lens opacity (Hamada et al., 2014). Additionally, modifications to connexin protein can lead to improper LEC layering, which has been linked to cataracts in humans (NCRP, 2016). Increased oxidative stress can also lead to increased oxidative DNA damage. In this case, ROS can induce DNA lesions, such as oxidized nucleotides or DNA breaks (Collins, 2014).  

Oxidative stress is also directly connected to increased DNA strand breaks. Cells under oxidative stress have excessive levels of ROS, molecules which can oxidize and remove nitrogenous bases, producing nicks in the DNA strand known as single strand breaks (SSB). Under circumstances when multiple SSBs are in close proximity, they may combine to form double strand breaks (DSB). The formation of SSBs induces base excision repair (BER), a DNA repair mechanism however, cells are often unable to support multiple repairs in one area, leading to residual unrepaired SSBs that will lead to an increase of DSBs. This is particularly likely as a result of radiation exposure, as radiation-generated ROS are more likely to produce clustered damage (Cannan & Pederson, 2016).  

Increases in DNA strand breaks can lead to inadequate DNA repair. DSBs, the most detrimental form of this damage (Iliakis et al., 2015), are most often formed in the G1 phase of the cell cycle. Cells utilize various systems to repair DNA damage, the most error-prone pathway being non-homologous end-joining (NHEJ). Since NHEJ is the most active pathway for DNA DSB repair in the G1 phase of the cell cycle, DSBs are most often repair using this pathway, leading to decreased repair accuracy (Jeggo et al., 1995). Furthermore, clustered damage, often generated by high-LET radiation (Nikitaki et al., 2016), overwhelms the repair systems, leading to increased probability of inadequate repair (Tsao, 2007). 

Similarly, increased oxidative damage to DNA can also lead to inadequate repair. Repair systems are unable to deal with increased levels of lesions within a small area, resulting in decreased repair ability and therefore inadequate repair (Georgakilas et al., 2013). Moreover, unrepaired oxidative lesions may be incorrectly bypassed during DNA replication, leading to the insertion of incorrect bases opposite unrepaired lesions (Shah et al., 2018). Furthermore, imbalances between the level of oxidative DNA lesions and cellular repair capacity can also lead to inadequate repair (Brenerman et al., 2014). Non-DSB oxidative DNA damage can also alter nuclease or glycosylase activity, resulting in decreased local DNA repair ability (Georgakilas et al., 2013). 

One of the possible outcomes of inadequate repair is increased mutations. DNA repair mechanisms, such as NHEJ (Sishc & Davis, 2017), break-induced replication (BIR), and microhomology-mediated break-induced replication (MMBIR) can be error-prone, leading to increased mutagenesis and genomic instability (Kramara et al., 2018). 

Similarly, inadequate repair can also lead to increased chromosomal aberrations (CA). The best-known model for this KER holds that unrepaired DSBs eventually lead to CAs (Schipler & Iliakis, 2013). The other model suggests that CAs occur when the enzymes responsible for binding DNA strands during the repair of enzyme-induced DNA breaks fail. Failure of different binding enzymes would lead to different forms of CAs (Bignold, 2009). Increased mutations and increased CAs are both linked to increased cell proliferation however, as no lens-specific data was found, the existing relationships in the Wiki (KER: 1978 and 1979) have not been altered however, this could present a possible focus for future research. 

Finally, increased cell proliferation of the metabolically active LECs can lead to cataracts. The lens is composed of several zones, with the germinative zone (GZ) being the only one that is mitotically active. In healthy lenses, cells in the GZ replicate and differentiate into lens fiber cells (LFCs). The LFCs are organelle-free, allowing light to pass through the lens. However, in cases of increased proliferation, cells are forced out of the GZ before forming fully differentiated LFCs. These improperly differentiated cells have not lost all of their organelles, resulting in reduced lens transparency (Ainsbury et al., 2016; Hamada, 2017; McCarron et al., 2022). As the lens is a closed system with little turnover, these cells are not removed, and their accumulation contributes to the cataractogenic load, a gradual lens opacification throughout life, which can eventually lead to cataracts (Ainsbury et al., 2016; Uwineza et al., 2019).  

Time- and dose-response concordance:  

The overall time- and dose-response concordance is moderate to low throughout the AOP. Certain relationships, particularly ones involving the deposition of energy, are well supported with consistent data. Studies using in vitro and in vivo models have found similar results, with downstream KEs occurring within minutes to days of the MIE. However, KEs at the cellular and organ level are generally supported by a weaker WOE with increased inconsistencies. Time- or dose-response concordance is only supported by one study in several KERs (increased oxidative stress to increased oxidative DNA damage, increased oxidative stress to increased DNA strand breaks, increased oxidative stress to modified proteins, modified proteins to cataracts, and increased oxidative stress to cataracts) and is not always consistent. Similarly, adjacent (directly linked) KERs are generally supported by a weaker evidence base.  

Uncertainties, Inconsistencies, and Data Gaps 

The present AOP encompasses several notable uncertainties. Firstly, there is no objective, universally acknowledged, definition for cataracts. A large variety of cataract scoring systems are used, with the major ones being the Lens Opacities Classification System I, II, and III (LOC I, II, and III), and the Merriam-Focht Cataract Scoring System. However, they are all subjective, relying partly on the examiner’s judgement. Furthermore, many studies do not directly measure cataracts, instead measuring indirect indicators, such as minor opacities, that do not always progress into cataracts. Similarly, observation periods used in many studies may be too short to account for cataract development, leading to an apparent decrease in cataract prevalence. Moreover, certain KERs, such as increased oxidative stress to increased oxidative DNA damage, increased oxidative stress to increased DNA strand breaks, increased oxidative stress to modified proteins, modified proteins to cataracts, inadequate DNA repair to cataracts, increased oxidative stress to cataracts, and deposition of energy to increased cell proliferation are only weakly supported by empirical evidence. Similarly, KERs increased oxidative DNA damage to inadequate DNA repair, inadequate DNA repair to increased mutations, inadequate DNA repair to increased chromosomal aberrations, and increased oxidative DNA damage to increased DNA strand breaks, while supported by non-lens evidence, are not supported by lens-based studies. 

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Overall, this AOP is applicable to all organisms with DNA that require a clear lens for vision. Of these, Homo sapiens (humans), Mus musculus (mice), and Rattus norvegicus (rats) had a moderate level of support, and Oryctolagus cuniculus (rabbits) had a low level of support throughout most of the pathway. However, portions of the pathway were also supported in Bos taurus (bovine), Sus scrofa (pigs), Cavia porcellus (guinea pigs), Sciurus linnaeus (squirrels), Macaca mulatta (monkeys) and Anura (frogs).  

This AOP is also applicable to all life stages, with a moderate level of support. However, it should also be noted that cataracts are primarily an age-related disease, generally occurring in humans after the age of 50 (Liu et al., 2017). As such, older organisms are at a higher risk of radiation-induced cataracts, as a gradual opacification of the lens may have already begun. 

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Essentiality of the Deposition of Energy (MIE) 

  • Radiation exposure has been found to increase levels of DNA strand breaks (Reddy et al., 1998; Barnard et al., 2019; Barnard et al., 2022), modified proteins (Zigman et al., 1975; Abdelkawi et al., 2008; Anbaraki et al., 2016), oxidative stress (Zigman et al., 1995; Zigman et al., 2000; Kubo et al., 2010; Ahmadi et al., 2022), oxidative DNA damage (Pendergrass et al., 2010; Bahia et al., 2018), chromosomal aberrations (Dalke et al., 2018; Bains et al., 2019; Udroiu et al., 2020), cell proliferation (Pirie & Drance, 1959; Markiewicz et al., 2015; Bahia et al., 2018), and cataracts (Worgul et al., 1993; Jones et al., 2007; Kocer et al., 2007) above background levels. Removing the amount of radiation can decrease the amount of damage to macromolecules found within the cell. 

Essentiality of Increased Oxidative Damage to DNA (KE1) 

  • Depletion of antioxidant removing enzymes can reduce oxidative DNA damage and initiate adequate repair mechanisms (Mesa & Bassnett, 2013) and increased DNA breaks (Domijan et al., 2006). 

Essentiality of Increased DNA Strand Breaks (KE2) 

  • Increased DNA strand breaks are essential for inducing inadequate repair as assessed using inhibitors and knock-out studies. For example, a human cell line with increased levels of DSBs and lacking DNA ligase IV, a DNA repair protein, had DSBs that had not been repaired as measured 240 – 340 h post-irradiated (McMahon et al., 2016). 

Essentiality of Inadequate Repair (KE3) 

  • The essentiality of inadequate DNA repair can be assessed through knock-out studies examining the effect of altering important repair genes on downstream KEs. In this way, inadequate DNA repair has been found to be essential in increasing mutations (Perera et al., 2016), chromosomal aberrations (Wilhelm et al., 2014), and cataracts (Kleiman et al., 2007) above background levels. For example, cataracts are up to 90% more common in ATM mutant mice, which have decreased DNA repair, compared to wild type mice (Worgul et al., 2002). 

Essentiality of Increased Mutations (KE4) 

  • No lens-specific information was retrieved to support the essentiality of this KE, however data from other cell types support the essentiality of this KE and are detailed in the overall assessment of AOP #272. 

Essentiality of Increased Chromosomal Aberrations (KE5) 

  • No lens-specific information was retrieved to support the essentiality of this KE, however data from other cell types support the essentiality of this KE and are detailed in the overall assessment of AOP #272. 

Essentiality of Increased Cell Proliferation (KE6) 

  • There is a moderate level of evidence supporting the essentiality of increased cell proliferation. Mice with decreased cell proliferation (Ptch1) have lower lens opacity compared to wild-type mice (McCarron et al., 2021) and vice versa (De Stefano et al., 2021). 

Essentiality of Increased Oxidative Stress (KE9) 

  • Oxidative stress has been found to increase levels of DNA strand breaks (Li et al., 1998; Liu et al., 2013; Cencer et al., 2018; Ahmadi et al., 2022) and cataract indicators (Karslioǧlu et al., 2005; Varma et al., 2011; Liu et al., 2013; Smith et al., 2015; Qin et al., 2019) above background levels. Additionally, inhibition of oxidative stress has led to a reduction in DNA strand breaks (Spector et al., 1997; Liu et al., 2013) and cataract risk (Van Kuijk, 1991; Spector, 1995; Smith et al., 2016; Qin et al., 2019). 

Essentiality of Modified Proteins (KE14) 

  • There is a low level of evidence supporting the essentiality of radiation in promoting modified proteins above a normal level. One study found that return of the lens protein solubility ratio to near control levels resulted in decreased lens opacity (Menard et al., 1986). 

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

1. Support for Biological Plausibility  

Defining Question 

High (Strong) 

Moderate 

Low (Weak) 

 Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge? 

 Extensive understanding of the KER based on extensive previous documentation and broad acceptance. 

 KER is plausible based on analogy to accepted biological relationships, but scientific understanding is incomplete 

 Empirical support for association between 

KEs, but the structural or functional relationship between them is not understood. 

Deposition of Energy (MIE) → Increase DNA strand breaks (KE2) 

Strong 

It is well established that deposition of energy can cause various types of DNA damage including SSBs and DSBs. Structural damage from the deposited energy can induce chemical modifications in the form of breaks to the phosphodiester backbone of both strands of the DNA. DSBs are also often formed by indirect interactions with radiation through water radiolysis and subsequent reactive oxygen species generation that can then damage the DNA. 

Deposition of Energy (MIE) → Modified Proteins (KE14)  

Strong 

It is well established that the deposition of energy leads to protein modifications. Energy deposited into cells, results in proteins undergoing post-translational modifications. These modifications culminate into larger protein changes such as high molecular weight aggregates and water-insolubility. 

Increase Deposition of Energy (MIE) → Increase, Oxidative Stress (KE9)  

Strong 

When deposited energy reaches a cell it reacts with water and organic materials to produce free radicals such as ROS. If the ROS cannot be eliminated quickly and efficiently enough by the cell’s defense system, oxidative stress ensues. 

Increase Oxidative Stress (KE9) →Increase Oxidative DNA Damage (KE1)  

Strong 

There is a large amount of evidence supporting the mechanistic relationship between increased oxidative stress and increased oxidative DNA damage. ROS react with DNA, causing changes such as DNA-protein cross-links, inter and intra-strand links, tandem base lesions, single and double strand breaks, abasic sites, and oxidized bases. The most common and best-studied lesion is 8-oxodG. 

Increase, Oxidative Stress (KE9) → Increase, DNA Strand Breaks (KE2)  

Strong 

There is a strong understanding of the mechanistic relationship between increased oxidative stress leading to increased DNA strand breaks. ROS oxidize bases on the DNA strand, triggering base excision repair, which removes the altered bases. These altered bases are usually adenine and guanine, as they have the lowest oxidation potentials. When multiple bases in close proximity are removed, the repair efforts cause strain which can lead to strand breaks. Increased ROS have also been linked to DNA strand fragmentation. Furthermore, decreased antioxidant levels have also been linked to increased DNA strand damage.  

Increase, Oxidative Stress (KE9) → Modified Proteins (KE14)  

Strong 

There is strong evidence to support increased oxidative stress leading to modified proteins. Studies show that following increases in ROS, proteins undergo cross-linking, thiol group oxidation, increased disulfide bonds, and amino acid oxidation and carbonylation. The increased amount of inter-protein linkages leads to aggregation, insolubility, and reduced chaperone action. 

Increase, Oxidative DNA Damage (KE1) → Inadequate DNA Repair (KE3) 

Weak 

 There is a risk of increased genomic instability and mutation potential associated with repairing the lesions. The high-risk area can become resistant to repair when non-DSB oxidative DNA damage results in altered nuclease or glycosylase activity.  

Increase DNA strand breaks (KE2) → Inadequate DNA repair (KE3) 

Strong 

It is well recognized that almost all types of DNA lesions will result in recruitment of repair enzymes and factors to the site of damage, and the pathway involved in the repair of DSBs has been well-documented in a number of reviews, many of which also discuss the error-prone nature of DNA repair. Error-prone repair processes are particularly important when DSBs are biologically induced and repaired during V(D)J recombination of developing lymphocytes and during meiotic divisions to generate gametes.  

Inadequate DNA Repair (KE3) → Increase, Mutations (KE4)  

Weak 

No available lens data supporting the biological plausibility of this relationship. However, there is available data from other cell types, as described in the overall assessment of AOP #164. 

Inadequate DNA Repair (KE3) → Increase, Chromosomal Aberrations (KE5) 

Moderate 

There is low support for the biological plausibility of this relationship in lens cells, however the relationship is well supported in other cell types. One of the repair mechanisms most commonly used for DSBs is NHEJ, which is error-prone and can lead to CAs.  

Deposition of energy (MIE) → Increase oxidative DNA damage (KE1) 

Strong 

A large body of evidence supports the biological plausibility of this KER. The deposition of energy produces ROS, which then overwhelms the cell’s defense mechanisms and induces a state of oxidative stress, leading to increases in oxidative DNA damage. For energy in the form of UV, this process occurs through the MAPK pathway.  

Deposition of energy (MIE) → Increase chromosomal aberrations (KE5) 

Strong 

Extensive and diverse data from human, animal and in vitro-based studies show ionizing radiation induces a rich variety of chromosomal aberrations The mechanism leading from deposition of energy to chromosomal aberrations has been described in several reviews. Other evidence is derived from studies examining the mechanism of copy number variant formation and induction of radiation-induced chromothripsis.  

Deposition of Energy (MIE) → Increase, Cell Proliferation (KE6)  

Moderate  

There is moderate available information to support the mechanistic relationship between energy deposition to increase cell proliferation, however empirical support is high, energy deposited onto cells causes increased cell proliferation via the combined efforts of oncogene activation, tumor suppressor deactivation, and upregulated signaling pathways.  

Deposition of Energy (MIE) → Cataracts (AO)  

Strong 

It is well understood that the deposition of radiation energy leads to cataract development. It has been clearly shown that radiation affects lenses structurally. These structural changes can be characterized by the measurement of lens opacification. Opacification may be the result of uncontrolled cell proliferation due to overwhelming DNA damages and conformational alteration in lens crystallin proteins. However, the effect of radiation on the functionality of lenses is uncertain, since adverse effects of opacification on vision are largely dependent on the proportion and location of the opacification. Whether minor opacification progress into vision-impairing cataracts is also uncertain.  

Modified Proteins (KE14) → Cataracts (AO)  

Strong 

It is well understood that the alteration of proteins leads to the development of cataracts/increased lens opacity. Changes in protein confirmation leads to aggregation, altering the ability of light to pass to the lens and leading to opaque regions within the eye. Protein alterations also result in the loss of protein functionality, which prevents repair and causes structural disorganization of lens proteins and loss of transparency and eventual cataracts.  

Inadequate DNA Repair (KE3) → Cataracts (AO)  

Moderate  

There is moderate evidence to support inadequate DNA repair leading to the development of cataracts. Poor DNA repair leads to aberrant lens fiber cell differentiation, contributing to light scattering and cataracts.  

Increase oxidative stress (KE9) → Cataracts (AO) 

High  

There is a large amount of evidence for the biological plausibility of increases in oxidative stress leading to cataracts. This includes various different pathways such as protein oxidation, lipid peroxidation, increased calcium levels, DNA damage, apoptosis, and gap junction damage. The best-studied pathway, through increased protein oxidation, results in increased protein cross-linking, leading to decreased protein solubility, increased protein aggregation, increased light scattering, and therefore increased lens opacity and cataract occurrence.  

Deposition of Energy (MIE) → Cell proliferation 

Moderate  

There is a moderate amount of evidence for the biological plausibility of this KER. Deposited energy can disrupt cell cycling mechanisms by causing mutations or chromosomal aberrations, which can inactivate tumor suppressor genes and activate oncogenes, leading to increased cell proliferation. 

Increase, Oxidative DNA Damage (KE1) → Increase, DNA Strand Breaks (KE2)  

Moderate  

There is moderate support for the biological plausibility of this relationship, the mechanism is generally understood. Findings include guanine and adenine being the most likely bases to be damaged, and clustered oxidized bases raise the risk of strand breaks.  

2. Support for Essentiality of KEs 

Defining Question 

High (Strong) 

Moderate 

Low (Weak) 

Are downstream KEs and/or the AO prevented if an upstream KE is blocked? 

Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs 

Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE 

No or contradictory experimental evidence of the essentiality of any of the KEs. 

MIE: Deposition of energy 

Strong 

Radiation exposure has been found to increase levels of DNA strand breaks, modified proteins, oxidative stress, oxidative DNA damage, chromosomal aberrations, cell proliferation, and cataracts above background levels. Removing the amount of radiation can decrease the amount of damage to macromolecules found within the cell. 

KE1: Increase oxidative DNA damage 

Moderate 

Depletion of antioxidant removing enzymes can reduce oxidative DNA damage and initiate adequate repair mechanisms and increased DNA breaks. 

KE2: Increase DNA strand breaks 

Strong 

The essentiality of increased DNA strand breaks was measured using inhibitors and knock-out studies. Increased DNA strand breaks are essential for inducing inadequate repair. 

KE3: Inadequate repair 

Strong 

The essentiality of inadequate DNA repair can be assessed through knock-out studies examining the effect of altering important repair genes on downstream KEs. In this way, inadequate DNA repair has been found to be essential in increasing mutations, chromosomal aberrations, and cataracts above background levels. 

KE6: Increase cell proliferation 

Moderate 

There is a moderate level of evidence supporting the essentiality of increased cell proliferation leading to cataracts.  Under homeostatic conditions, cells duplicate at a rate set by the speed of the cell cycle. Any disruption in regulators of the cell cycle can result in cellular transformation. Cell proliferation rates can be altered via deposited energy-induced genetic alterations, signaling pathway activation, and increased production of growth factors. 

KE9: Increase oxidative stress 

Moderate 

Oxidative stress has been found to increase levels of DNA strand breaks above background levels. Additionally, inhibition of oxidative stress has led to a reduction in DNA strand breaks. 

KE14: Modified proteins 

Weak 

There is a low level of evidence supporting the essentiality of radiation in promoting modified proteins above a normal level. 

3. Empirical Support for KERs 

Defining Question 

High (Strong) 

Moderate 

Low (Weak) 

 Does empirical evidence support that a change in KEup leads to an appropriate change in KEdown? 

  

Does KEup occur at lower doses and earlier time points than KE down and is the incidence of KEup> than that for KEdown? 

  

Inconsistencies? 

 Multiple studies showing dependent change in both events following exposure to a wide range of specific stressors. 

  

No or few critical data gaps or conflicting data 

 Demonstrated dependent change in both events following exposure to a small number of stressors. 

  

Some inconsistencies with expected pattern that can be explained by various factors. 

 Limited or no studies reporting dependent change in both events following exposure to a specific stressor; and/or significant inconsistencies in empirical support across taxa and species that don’t align with hypothesized AOP 

Deposition of energy (MIE) → Increase DNA strand breaks (KE2) 

Strong  

The vast majority of studies examining energy deposition and incidence of DSBs suggest a positive, linear relationship between these two events. Predicting the exact number of DSBs from the deposition of energy, however, appears to be highly dependent on the biological model, the type of radiation and the radiation dose range, as evidenced by the differing calculated DSB rates across studies. 

Deposition of Energy (MIE) → Modified Proteins (KE14)  

Moderate  

There is a large amount of quantitative evidence supporting an increased amount of modified proteins following from the deposition of energy, however no trend emerged that could reliably predict the changes. There is a large variety of protein alterations that are possible, and measurable. This makes finding connections between studies difficult, especially due to the wide range of doses used with inconsistencies as to the minimum dose needed to see effect 

Increase Deposition of Energy (MIE) → Increase, Oxidative Stress (KE9) 

Strong 

There is a large body of evidence supporting a quantitative understanding of the change in the deposition of energy needed to produce a change in the level of elements of oxidative stress. Several different endpoints representing oxidative stress have been used, including catalase, glutathione (GSH), superoxide dismutase, glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and ROS concentrations. Measurements have also been made over a large range of doses and dose rates. The majority of the evidence uses UVB, but there are also studies using UVA, neutrons, and 60-Co gamma rays. 

Increase Oxidative Stress (KE9) →Increase Oxidative DNA Damage (KE1) 

Weak 

There are a small number of studies that provide quantitative evidence for this KER. 

Increase, Oxidative Stress (KE9) → Increase, DNA Strand Breaks (KE2)  

Weak 

There is a significant amount of quantitative evidence supporting an increased amount of DNA strand breaks following exposure to increased oxidative stress, however no trend has emerged that could reliably predict the changes. Measurements of oxidative stress are quite varied across studies. There is a clear association between the two events, positive changes in oxidative stress indicators increase DSB however not reliably in relation to each other. 

Increase, Oxidative Stress (KE9) → Modified Proteins (KE14)  

Weak 

There is a moderate amount of quantitative evidence supporting an increased amount of modified proteins following exposure to increased oxidative stress; however, no trend has emerged that could reliably predict the changes.  

Increase, Oxidative DNA Damage (KE1) → Inadequate DNA Repair (KE3) 

Weak 

 There is no available lens data supporting the biological plausibility of this relationship. However, there is available data from other cell types, as described in the overall assessment of AOP #1909 

Increase DNA strand breaks (KE2) → Inadequate DNA repair (KE3) 

Moderate  

According to studies examining DSBs and DNA repair after exposure to radiation, a positive linear relationship between DSBs and radiation dose has been observed, and a linear-quadratic relationship between the number of misrejoined DSBs and radiation dose which varied according to LET and dose-rate of the radiation. Overall, 1 Gy of radiation may induce between 35 and 70 DSBs, with 10 - 15% being misrepaired at 10 Gy and 50 - 60% being misrepaired at 80 Gy. 

Inadequate DNA Repair (KE3) → Increase, Mutations (KE4) 

Weak 

There is no available eye lens data supporting a quantitative understanding between inadequate DNA repair and increased mutations. However, there is available data from other cell types, as described in the overall assessment of AOP #164.  

Inadequate DNA Repair (KE3) → Increase, Chromosomal Aberrations (KE5)  

Weak 

There is no available eye lens data supporting a quantitative understanding between inadequate DNA repair and increased chromosomal aberrations. However, there is available data from other cell types, as described in the overall assessment of AOP #1912. 

Deposition of energy (MIE) → Increase oxidative DNA damage (KE1) 

Moderate  

There is a moderate amount of quantitative understanding for this KER. The majority of the data investigates different indicators of oxidative DNA damage, namely 8-OH-DG, 8-OH G, cyclobutane pyrimidine dimers, and multiple chromophores such as NADH. 

Deposition of energy (MIE) → Increase chromosomal aberrations (KE5) 

Strong 

Most studies indicate a positive, linear-quadratic relationship between the deposition of energy by ionizing radiation and the frequency of chromosomal aberrations. Equations describing this relationship were provided in a number of studies. In terms of time scale predictions, this may still be difficult owing to the often-lengthy cell cultures required to assess chromosomal aberrations post-irradiation, as well as the potential inapplicability of long-term cultures in predicting events in vivo.  

Deposition of Energy (MIE) → Increase, Cell Proliferation (KE6) 

Moderate  

There is a large amount of quantitative evidence supporting an increased amount of cell proliferation following the deposition of energy, however no trend can reliably predict the changes.  

Deposition of Energy (MIE) → Cataracts (AO) 

Strong 

The levels of cataract prevalence and severity generally can be predicted quantitatively from the level of radiation exposure. Many studies show that cataract development is dose dependent. The prediction of cataract development can be made more reliably with higher-dose exposures than with lower-dose exposures. Low-dose exposures typically show long lag periods for the onset of cataractogenesis, that coupled with the short observation periods frequently used make the prediction of cataract severity or prevalence less reliable. There are many known modulating factors that influence cataract development such as quality and dose of the radiation, gender, age at exposure, and genetic predispositions. These factors all affect the onset timing, prevalence, and severity of cataract development. Radiation-induced cataracts have been observed consistently across several mammalian species. 

Modified Proteins (KE14) → Cataracts (AO) 

Weak 

There is limited quantitative understanding of increased lens opacity/cataracts from protein alteration.  Age is a known modulator of this relationship; protein aggregation increases naturally as the individual ages. 

Inadequate DNA Repair (KE3) → Cataracts (AO)  

Weak 

There is limited quantitative evidence supporting the development of cataracts following inadequate DNA repair, and as such, there is not enough information to observe a trend that could reliably predict the changes. 

Increase oxidative stress (KE9) → Cataracts (AO) 

Weak 

There is limited quantitative understanding for this KER. Most of the data has been obtained using H2O2 to induce oxidative stress, and cataracts are assessed indirectly. 

Cell Proliferation (KE6) → Cataracts (AO) 

Weak 

The quantitative understanding of this KER is weak. There is no confident empirical evidence to accurately demonstrate a dependant relationship between the two events. 

Increase, Oxidative DNA Damage (KE1) → Increase, DNA Strand Breaks (KE2) 

Weak 

No available eye lens data supporting a quantitative understanding between increased oxidative DNA damage and increased DNA strand breaks. However, there is available data from other cell types, as described in the overall assessment of AOP #1913. 

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved
Antioxidant levels  Adding or withholding antioxidants will decrease or increase the level of oxidative stress respectively. Increased oxidative stress leads to a higher likelihood of cataracts and the reverse is true for lower oxidative stress levels. 

KER: 2 – Deposition of energy leading to modified proteins 

KER: 3 – Deposition of energy leading to increase oxidative stress 

KER: 9 – Increase oxidative stress leading to modified proteins 

KER: 41 – Deposition of energy leading to increase oxidative DNA damage 

KER: 63 – Increase oxidative stress leading to cataracts 

Age  As the age of an organism increases, antioxidant levels are lower and show a greater decrease after radiation, resulting in a compromised radiation defense system. Increased age can also lead to increased chromosomal aberrations. Cataracts are due to an accumulation of small opacities in the lens, therefore as an organism ages the various opacities begin to add up. Younger lenses also show better recovery after oxidative stress, possibly due to higher levels of thioltransferase and thioredoxin and increased ability to upregulate appropriate gene expression. These factors combine to cause an increased risk of cataracts. Conversely, younger organisms display increased sensitivity to radiation and therefore increased risk of cataracts compared to adults between the ages of 20 and 50. Therefore, both younger and older organisms can be at a greater risk of cataracts compared to adults.

KER: 2 – Deposition of energy leading to modified proteins 

KER: 3 - Deposition of energy leading to increase oxidative stress 

KER: 8 – Increase oxidative stress leading to increase DNA strand breaks 

KER: 47 – Deposition of energy leading to cataracts 

KER 59: Modified proteins leading to cataracts 

KER: 63 – Increase oxidative stress leading to cataracts 

Oxygen concentration  Higher oxygen concentrations increase sensitivity to ROS and therefore, increase the likelihood of cataracts. Similarly, cells in an anoxic environment will rejoin DNA breaks more quickly than those in an oxic environment, therefore reducing the risk of cataracts. 

KER: 3 – Deposition of energy leading to increase oxidative stress 

KER: 22 – Increase DNA strand break leading to inadequate DNA repair 

KER: 63 – Increase oxidative stress leading to cataracts 

Increased LET  As the LET of the stressor increases, the amount of misrepaired and unrejoined DSBs also increases. One possible explanation is that, due to the clustered damage, DSB free ends are closer together with higher LET radiation, making it easier for misrepair to occur. Furthermore, higher LET stressors produce more complex, clustered breaks which increases repair difficulty. At very high LET values (over 10 000 keV/um), no significant DNA repair is detected, which can lead to an increased risk of cataracts.  KER: 22 – Increase DNA strand break leading to inadequate DNA repair 

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Quantitative understanding of the KERs in this AOP was rated as moderate. While certain KERs, such as MIE to AO, were well represented in the literature, others, such as increased cell proliferation to cataracts, were only covered by a limited number of relevant studies. Furthermore, studies often examined different endpoints at various time-points, using different stressors, doses, dose-rates, and models within each KER, causing difficulty to accurately compare studies and derive a quantitative understanding of the relationship, and precisely predict the downstream KEs from the upstream KEs. As such, the areas with low quantitative understanding could be the focus of future experimental work using a more co-ordinated approach to experimental design, data collection and analysis. This would allow for more informative quantitative data that could be combined to understand the quantitative concordance of direct relationships and better support risk modeling and understanding of minimal risk dose estimates. 

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

As the International Commission on Radiological Protection works to review literature on health effects from radiation exposure, the collected knowledge presented in this AOP will provide a structured approach to guide future recommendations. With better designed experiments that cross biological levels of organization, more informative quantitative data will be generated that can then inform risk assessment strategies. A stronger evidence base can provide better justification to support guidelines and standards for future space missions and settings related to occupational, environmental, and medical exposures, where cataracts are of concern. 

References

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

Abdelkawi, S., M. Abo-Elmagd and H. Soliman. (2008), “Development of cataract and corneal opacity in mice due to radon exposure”, Radiation Effects and Defects in Solids, Vol.163/7, Taylor & Francis, Oxfordshire, https://doi.org/10.1080/10420150701249603.  

Ahmadi, M. et al. (2022), “Early responses to low-dose ionizing radiation in cellular lens epithelial models”, Radiation Research, Vol. 197/1, Radiation Research Society, United States, https://doi.org/10.1667/RADE-20-00284.1    

Ainsbury, E. A. et al. (2016), “Ionizing radiation induced cataracts: recent biological and mechanistic developments and perspectives for future research”, Mutation research. Reviews in mutation research, Vol. 770, Elsevier B.V., https://doi.org/10.1016/j.mrrev.2016.07.010   

Anbaraki, A. et al. (2016), “Preventive role of lens antioxidant defense mechanism against riboflavin-mediated sunlight damaging of lens crystallin”, International Journal of Biological Macromolecules, Vol.91, Elsevier, Amsterdam, https://doi.org/10.1016/j.ijbiomac.2016.06.047.  

Bahia, S. et al. (2018), “Oxidative and nitrative stress-related changes in human lens epithelial cells following exposure to X-rays”, International journal of radiation biology, Vol. 94/4, England, https://doi.org/10.1080/09553002.2018.1439194   

Bains, S. K. et al. (2019), “Effects of ionizing radiation on telomere length and telomerase activity in cultured human lens epithelium cells”, International journal of radiation biology, Vol. 95/1, Taylor & Francis, Abingdon, https://doi.org/10.1080/09553002.2018.1466066  

Barnard, S. et al. (2022), “Lens epithelial cell proliferation in response to ionizing radiation”, Radiation Research, Vol. 197/1, Radiation Research Society, https://doi.org/10.1667/RADE-20-00294.1   

Barnard, S. G. R. et al. (2019), “Inverse dose-rate effect of ionising radiation on residual 53BP1 foci in the eye lens”, Scientific Reports, Vol. 9/1, Nature Publishing Group, England, https://doi.org/10.1038/s41598-019-46893-3  

Bignold, L.P. (2009), "Mechanisms of clastogen-induced chromosomal aberrations : A critical review and description of a model based on failures of tethering of DNA strand ends to strand-breaking enzymes.", Mutat. Res. 681:271–298. doi:10.1016/j.mrrev.2008.11.004.   

Brenerman, B., J. Illuzzi, and D. Wilson III (2014), “Base excision repair capacity in informing healthspan”, Carcinogenesis, 35:2643-2652.   

Cabrera, M. and R. Chihuailaf. (2011), “Antioxidants and the integrity of ocular tissues”, Veterinary Medicine International, Vol.2011, Hindawi Limited, London, https://doi.org/10.4061/2011/905153.   

Cannan, W. and D. Pederson. (2016), “Mechanisms and consequences of double-strand DNA break formation in chromatin”, Journal of Cell Physiology, Vol.231/1, Wiley, Hoboken, https://doi.org/10.1002/jcp.25048.   

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.   

Chylack, L.T. Jr et al. (2012), “NASCA Report 2: Longitudinal Study of Relationship of Exposure to Space Radiation and Risk of Lens Opacity”, Radiation Research, Vol.178/1, Radiation Research Society, Indianapolis, htps://doi.org/10.1667/RR2876.1.   

Collins, A. R. (2014), “Measuring oxidative damage to DNA and its repair with the comet assay”, Biochimica et biophysica acta. General subjects, Vol. 1840/2, Elsevier B.V., https://doi.org/10.1016/j.bbagen.2013.04.022   

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  

De Stefano, I. et al. (2021), “Contribution of genetic background to the radiation risk for cancer and non-cancer diseases in Ptch1+/- mice”, Radiation Research, Vol. 197/1, Radiation Research Society, https://doi.org/10.1667/RADE-20-00247.1  

Domijan, A., Zeljezic, D., Kopjar, D., Peraica, M. (2006), Standard and Fpg-modified comet assay in kidney cells of ochratoxin A- and fumonisin B(1)-treated rats, Toxciol, 222:53-59.  

Fochler, C. and H. Durchschlag. (1997), “Investigation of irradiated eye-lens proteins by analytical ultracentrifugation and other techniques”, Progress in Colloid and Polymer Science, Vol.107, Springer, Berlin, https://doi.org/10.1007/BFb0118020.   

Georgakilas, A. G et al. (2013), “Induction and repair of clustered DNA lesions: what do we know so far?”, Radiation Research, Vol. 180/1, The Radiation Research Society, United States, https://doi.org/10.1667/RR3041.1   

Hamada, N. (2014), “What Are the Intracellular Targets and Intratissue Target Cells for Radiation Effects?”, Radiation Research, Vol.181/1, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR13505.1.   

Hamada, N. (2017), “Ionizing radiation sensitivity of the ocular lens and its dose rate dependence”, International journal of radiation biology, Vol. 93/10, Taylor & Francis, England, https://doi.org/10.1080/09553002.2016.1266407   

Hanson, S. et al. (2000), “The major in vivo modifications of the human water-insoluble lens crystallins are disulfide bonds, deamidation, methionine oxidation and backbone cleavage”, Experimental Eye Research, Vol.71/2, Academic Press Inc, Cambridge, https://doi.org/10.1006/EXER.2000.0868.   

ICRP (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, Amsterdam, https://doi.org/10.1016/j.icrp.2012.02.001.   

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.   

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.   

Jones, J.A. et al. (2007), “Cataract Formation Mechanisms and Risk in Aviation and Space Crews”, Aviation, Space and Environmental Medicine, Vol.78/4 Suppl, Aerospace Medical Association, A56-66.    

Jurja, S. et al. (2014), “Ocular cells and light: harmony or conflict?”, Romanian Journal of Morphology & Embryology, Vol. 55/2, Romanian Academy Publishing House, Bucharest, pp. 257–261.   

Karslioǧlu, I. et al. (2005), “Radioprotective effects of melatonin on radiation-induced cataract”, Journal of radiation research, Vol. 46/2, The Japan Radiation Research Society, England, https://doi.org/10.1269/jrr.46.277  

Kleiman, N. J. et al. (2007), “Mrad9 and Atm haplinsufficiency enhance spontaneous and X-ray-induced cataractogenesis in mice”, Radiation research, Vol. 168/5, Radiation Research Society, United States, https://doi.org/10.1667/rr1122.1  

Kocer, I. et al. (2007), “The effect of L-carnitine in the prevention of ionizing radiation-induced cataracts: A rat model”, Graefe’s Archive for Clinical and Experimental Ophthalmology, Vol. 245/4, Springer, Germany, https://doi.org/10.1007/s00417-005-0097-1  

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  

Kramara, J., B. Osia, and A. Malkova (2018), "Break-Induced Replication: The Where, The Why, and The How", Trends Genet, 34:518-531. Doi: 10.1016/j.tig.2018.04.002.   

Kubo, E. et al. (2010), “Protein expression profiling of lens epithelial cells from Prdx6-depleted mice and their vulnerability to UV radiation exposure”, American Journal of Physiology, Vol. 298/2, American Physiological Society, Rockville, https://doi.org/10.1152/ajpcell.00336.2009.   

Li, Y. et al. (1998), “Response of lens epithelial cells to hydrogen peroxide stress and the protective effect of caloric restriction”, Experimental Cell Research, Vol.239/2, Elsevier, Amsterdam, https://doi.org/10.1006/excr.1997.3870.   

Little, M. P. et al. (2018), “Occupational radiation exposure and risk of cataract incidence in a cohort of US radiologic technologists”, European Journal of Epidemiology, Vol. 33/12, Springer, https://doi.org/10.1007/s10654-018-0435-3.   

Liu B. et al. (2013). “Computational methods for detecting copy number variations in cancer genome using next generation sequencing: principles and challenges”, Oncotarget. 4(11):1868-81. Doi: 10.18632/oncotarget.1537.   

Liu, Y. et al. (2017), “Cataracts”, The Lancet (British edition), Vol. 390/10094, Elsevier Ltd, England, https://doi.org/10.1016/S0140-6736(17)30544-5   

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.   

McCarron, R. et al. (2022), “Radiation-Induced Lens Opacity and Cataractogenesis: A Lifetime Study Using Mice of Varying Genetic Backgrounds”, Radiation Research, Vol.196, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RADE-20-00266.1.   

McMahon, S.J. et al. (2016), "Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage.", Nat. Publ. Gr.(April):1–14. doi:10.1038/srep33290.   

Menard, T. et al. (1986), “Radioprotection against cataract formation by WR-77913 in gamma-irradiated rats”, International Journal of Radiation Oncology Biology Physics, Vol.12, Elsevier, Amsterdam, https://doi.org/10.1016/0360-3016(86)90199-9.   

Mesa, R. and S. Bassnett (2013), “UV-B induced DNA damage and repair in the mouse lens”, Investigative ophthalmology & visual science, Vol. 54/10, the Association for Research in Vision and Ophthalmology, United States, https://doi.org/10.1167/iovs.13-12644   

Moreau, K. and J. King. (2012), “Protein misfolding and aggregation in cataract disease and prospects for prevention”, Trends in Molecular Medicine, Vol.18/5, Elsevier Ltd, London, https://doi.org/10.1016/j.molmed.2012.03.005.   

Nakashima, E., K. Neriishi and A. Minamoto. (2006), “A Reanalysis of Atomic-Bomb Cataract Data, 2000-2002: A Threshold Analysis”, Health Physics, Vol.90/2, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1097/01.HP.0000175442.03596.63.   

National Eye Institute (2022), Cataracts, https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/cataracts (accessed November 29, 2022).  

NCRP (2016), “Guidance on radiation dose limits for the lens of the eye”, NCRP Commentary, Vol.26, National Council on Radiation Protection and Measurements Publications, Bethesda.   

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.   

Pendergrass, W. et al. (2010), “X-ray induced cataract is preceded by LEC loss, and coincident with accumulation of cortical DNA, and ROS; similarities with age-related cataracts”, Molecular Vision, Vol. 16, Emory University, Atlanta, pp. 1496-513.    

Perera, D. et al. (2016), "Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes.", Nature 532, 259-263.  

Pirie, A. and S. M. Drance (1959), “Modification of X-ray damage to the lens by partial shielding”, International Journal of Radiation Biology and Related Studies in Physics, Chemistry and Medicine, Vol. 1/3, Taylor & Francis, England, https://doi.org/10.1080/09553005914550391  

Qin, Z. et al. (2019), “Opacification of lentoid bodies derived from human induced pluripotent stem cells is accelerated by hydrogen peroxide and involves protein aggregation”, Journal of cellular physiology, Vol. 234/12, Wiley Subscriptions, United States, https://doi.org/10.1002/jcp.28943  

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  

Reisz, J. et al. (2014), “Effects of ionizing radiation on biological molecules - mechanisms of damage and emerging methods of detection”, Antioxidants and Redox Signaling, Vol.21(2), Mary Ann Liebert Inc, Larchmont, https://doi.org/10.1089/ars.2013.5489.    

Schipler, A. & G. Iliakis (2013), "DNA double-strand – break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice.", Nucleic Acids Res., 41(16):7589–7605. doi:10.1093/nar/gkt556.   

Shah, A. et al. (2018), “Defective Base Excision Repair of Oxidative DNA Damage in Vascular Smooth Muscle Cells Promotes Atherosclerosis”, Circulation, 138:1446-1462.   

Sishc, B.J. & A.J. Davis (2017), "The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer.", Cancers (Basel), 9(7) pii E81, doi:10.3390/cancers9070081.   

Soloviev, A. I. and I.V. Kizub (2019), “Mechanisms of vascular dysfunction evoked by ionizing radiation and possible targets for its pharmacological correction”, Biochemical pharmacology, Vol. 159, Elsevier, Amsterdam, https://doi.org/10.1016/j.bcp.2018.11.019.    

Spector, A. et al. (1997), “Microperoxidases catalytically degrade reactive oxygen species and may be anti-cataract agents”, Experimental Eye Research, Vol.65/4, Academic Press Inc, Cambridge, https://doi.org/10.1006/exer.1997.0336.   

Stohs, S. (1995), “The role of free radicals in toxicity and disease”, Journal of Basic and Clinical Physiology and Pharmacology, Vol. 6/3-4, Walter de Gruyter GmbH, Berlin, pp. 205-228.    

Tangvarasittichai, O and S. Tangvarasittichai (2019), “Oxidative stress, ocular disease, and diabetes retinopathy”, Current Pharmaceutical Design, Vol. 24/40, Bentham Science Publishers, https://doi.org/10.2174/1381612825666190115121531   

Tian, Y. et al. (2017), “The Impact of Oxidative Stress on the Bone System in Response to the Space Special Environment”, International Journal of Molecular Sciences, Vol. 18/10, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms18102132.    

Tsao, D. et al. (2007), “Induction and processing of oxidative clustered DNA lesions in 56Fe-ion-irradiated human monocytes”, Radiation Research, Vol.168/1, United States, https://doi.org/10.1667/RR0865.1   

Udroiu, I. et al. (2020), “DNA damage in lens epithelial cells exposed to occupationally-relevant X-ray doses and role in cataract formation”, Scientific reports, Vol. 10/1, Nature Research, Berlin, https://doi.org/10.1038/s41598-020-78383-2  

Uwineza, A. et al. (2019), “Cataractogenic load – A concept to study the contribution of ionizing radiation to accelerated aging in the eye lens”, Mutation Research - Reviews in Mutation Research, Vol.779, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrrev.2019.02.004.   

van Kuijk, F. J. (1991), “Effects of ultraviolet light on the eye: role of protective glasses”, Environmental health perspectives, Vol. 96,  National Institute of Environmental Health Sciences, Unites States, https://doi.org/10.1289/ehp.9196177  

Varma, S. D., S. Kovtun and K. R. Hegde (2011), “Role of ultraviolet irradiation and oxidative stress in cataract formation – medical prevention by nutritional antioxidants and metabolic agonists”, Eye & contact lens, Vol. 37/4, Lippincott Willians & Wilkins Inc, United States, https://doi.org/10.1097/ICL.0b013e31821ec4f2  

Venkatesulu, B. P. et al. (2018), “Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms”, JACC: Basic to Translational Science, Vol. 3/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.jacbts.2018.01.014.    

Wang, H. et al. (2019), “Radiation-induced heart disease: a review of classification, mechanism and prevention”, International Journal of Biological Sciences, Vol. 15/10, Ivyspring International Publisher, Sydney, https://doi.org/10.7150/ijbs.35460    

Wilhelm, T. et al. (2014), "Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells.", Proc. Natl. Acad. Sci. 111(2):763-768. doi:10.1073/pnas.1311520111.  

Worgul, B. V et al. (2002), “Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts,”  Proceedings of the National Academy of Sciences, Vol. 99/15, National Academy of Sciences, https://doi.org/10.1073/pnas.162349699  

Worgul, B. V. et al. (1993), “Accelerated heavy particles and the lens VII: The cataractogenic potential of 450 MeV/amu iron ions”, Investigative Ophthalmology and Visual Science, Vol. 34/1, pp. 184–193  

Worgul, B. V. et al. (2007), “Cataracts among Chernobyl Clean-up Workers: Implications Regarding Permissible Eye Exposures”, Radiation Research, Vol.167/2, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR0298.1.   

Zigman, S. et al. (1975), “The response of mouse ocular tissues to continuous near-UV light exposure”, Investigative Ophthalmology, Vol.14/September, Association for Research in Vision and Ophthalmology, Rockville, pp.710-713.  

Zigman, S. et al. (1995), “Damage to cultured lens epithelial cells of squirrels and rabbits by UV-A (99.9%) plus UV-B (0.1%) radiation and alpha tocopherol protection”, Molecular and cellular biochemistry, Vol. 143, Springer, London, https://doi.org/10.1007/BF00925924.   

Zigman, S. et al. (2000), “Effects of intermittent UVA exposure on cultured lens epithelial cells”, Current Eye Research, Vol. 20/2, Informa UK Limited, London, https://doi.org/10.1076/0271-3683(200002)2021-DFT095.