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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
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Deposition of energy leading to cataracts
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.5

Graphical Representation

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Authors

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Emma Carrothers1, Meghan Appleby1, Vita Lai1, Tatiana Kozbenko1, Dalya Alomar1, Benjamin Smith1, 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), Komae, Tokyo, Japan

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

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

Environmental Research Group within the School of Public Health, Faculty of Medicine at Imperial College of Science, Technology and Medicine, London, UK.

Point of Contact

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Vinita Chauhan   (email point of contact)

Contributors

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  • Vinita Chauhan

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on March 08, 2024 11:38

Revision dates for related pages

Page Revision Date/Time
Increased Modified Proteins March 08, 2024 11:53
Deposition of Energy March 08, 2024 11:49
Increase, Oxidative damage to DNA March 08, 2024 11:58
Increase, DNA strand breaks March 08, 2024 12:05
Inadequate DNA repair March 08, 2024 12:15
Increase, Mutations May 15, 2023 08:47
Increase, Chromosomal aberrations March 08, 2024 12:20
Increase, Cell Proliferation March 08, 2024 12:25
Occurrence of Cataracts March 08, 2024 12:34
Oxidative Stress March 08, 2024 12:28
Energy Deposition leads to Increase, DNA strand breaks March 08, 2024 12:44
Energy Deposition leads to Increase, Oxidative DNA damage March 08, 2024 15:21
Energy Deposition leads to Oxidative Stress March 08, 2024 13:28
Energy Deposition leads to Increase, Mutations March 08, 2024 15:24
Energy Deposition leads to Modified Proteins March 08, 2024 14:16
Energy Deposition leads to Increase, Chromosomal aberrations March 08, 2024 15:26
Oxidative Stress leads to Increase, Oxidative DNA damage March 08, 2024 14:39
Energy Deposition leads to Increase, Cell Proliferation March 08, 2024 15:27
Oxidative Stress leads to Increase, DNA strand breaks March 08, 2024 14:44
Oxidative Stress leads to Modified Proteins March 30, 2023 09:45
Energy Deposition leads to Cataracts March 11, 2024 10:42
Inadequate DNA repair leads to Cataracts March 11, 2024 10:47
Increase, Oxidative DNA damage leads to Inadequate DNA repair March 08, 2024 14:48
Increase, DNA strand breaks leads to Inadequate DNA repair March 08, 2024 14:56
Oxidative Stress leads to Cataracts March 11, 2024 10:50
Inadequate DNA repair leads to Increase, Mutations March 08, 2024 15:00
Inadequate DNA repair leads to Increase, Chromosomal aberrations March 08, 2024 15:05
Increase, Mutations leads to Increase, Cell Proliferation March 08, 2024 15:10
Increase, Chromosomal aberrations leads to Increase, Cell Proliferation March 08, 2024 15:11
Modified Proteins leads to Cataracts March 08, 2024 15:13
Increase, Cell Proliferation leads to Cataracts March 08, 2024 15:19
Increase, Oxidative DNA damage leads to Increase, DNA strand breaks March 08, 2024 15:19
Ionizing Radiation May 07, 2019 12:12

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

An AOP was developed describing a simplified path from “deposition of energy” (MIE; KE#1686) to cataracts (AO; KE#2083). The AOP is initiated by deposition of energy resulting in oxidative stress (KE#1392) within cells from increased free radical generation. If this exceeds antioxidant defence mechanisms, the oxidative stress, in turn, can damage molecules, the most well-studied include DNA and proteins.  Within the lens of the eye modified proteins (KE#2081) can aggregate, such as crystalline, and if not eliminated, can accumulate resulting in lens opacity. Concurrently, unmanaged oxidative stress can increase oxidative DNA damage (KE#1634) leading to DNA strand breaks (KE#1635). If these lesions are inadequately repaired (KE#155), an increase mutation frequency (KE#185) in critical genes and chromosomal aberrations (KE#1636) can occur. Mutations in genes associated with cell cycling can lead to uncontrolled cell proliferation (KE#870) of lens epithelial cells and the eventual AO, cataracts. The overall assessment of this AOP indicates high biological plausibility of the KERs as they are well established and understood; moderate levels of evidence support the essentiality and the Bradford-Hill empirical evidence criteria; low weight of evidence was identified for quantitative understanding across adjacent relationships, with some uncertainties and inconsistencies in mechanisms. Broadly, the information presented in this AOP can be used to support the review of radiation effects classification and broadly 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 this AOP, a cataract is defined when over 5% of the lens is opacified. . Cataracts typically occur after the age of 50 in humans, as an age-related disease (Liu et al., 2017); however, progression of this disease can be initiated or accelerated after exposure to a variety of agents, one of which is radiation.  

For radiation induced cataracts, most research shows that the anatomical location is within the posterior sub capsular region of the eye with limited occurrence in the cortical and nuclear region. Available epidemiological evidence confirms a positive statistically significant association between radiation exposure and cataracts (Nakashima et al., 2006; Worgul et al., 2007; Chylack et al., 2012; Little et al., 2018). The data comes from Chernobyl workers, radiologic technologists, and patients exposed to radiation through medical procedures, with the most compelling evidence derived from atomic bomb survivors. Although there is concern for the role of long duration space flight missions in cataract formation, there is limited data from astronauts.  

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. 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. It is believed the progression of cataracts at high  doses and s higher dose-rates generally induce more damage than lower dose-rates (Brooks et al., 2016).

This AOP provides a summary of the relevant studies and endpoints that can inform future research designed to understand the role of radiation in causing cataracts. Assays and study designs spanning biological levels of organization across relevant models were identified, with the end goal to improve testing strategies and 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 three AOs of vascular remodeling, bone loss, and learning and memory impairment. 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 KEs and KERs 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 established for disease progression, routinely and robustly measurable 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). 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.  

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. Relevant references identified by SWIFT were then screened in Distiller SR (Evidence Partners) using the defined PEOE criteria. Human screeners additionally evaluated references for their suitability to meet the Bradford-Hill criteria. At the end of the process, screened-in studies were used for the WOE evaluation.  

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: 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 supported the response-response relationships. Human and animal studies were prioritized unless data was limited, and then in vitro studies were used to support the KERs. Due to the regulatory application, studies using relevant eye lens models were prioritized. 

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 High

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 High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
rhesus monkeys Macaca mulatta Moderate NCBI
rabbit Oryctolagus cuniculus Moderate NCBI
guinea pig Cavia porcellus Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Male High
Female High

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) and then branches to cataract formation either from modified proteins or through DNA damage processes. Ionization events from deposition of energy interact directly or indirectly with the DNA. Indirect damage can also occur when water molecules dissociate producing radicals such as reactive oxygen species (ROS) that induce DNA breaks (Ahmadi et al., 2022). Moreover, a cascade of ionization events can cause the formation of clustered damage (Joiner and van der Kogel, 2009). Many studies use ultraviolet radiation as a stressor, and it is important to note that ionizing and non-ionizing radiation interact through  different mechanisms when inducing cataracts. Ionizing radiation can remove tightly bound electrons from atoms to create charged particles,  but also excite molecules without ionization. The absorption of non-ionizing radiation results in heat generation from molecular vibrations (Alcócer et al., 2020).

Deposition of energy can also lead to high levels of ROS and reactive nitrogen species (RNS) (collectively RONS) (Tangvarasittichai & Tangvarasittichai, 2019). There are several pathways leading to ROS, but 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). Additionally, deposited energy can directly upregulate enzymes involved in reactive RONS production (de Jager et al., 2017). Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) within mitochondria can 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). 

Protein damage leading to cataracts 

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 phosphorylation, 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; Wang et al. 2020; Chandrasekher et al., 2004 ). 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, these modified proteins can lead directly to cataracts, the AO. Aggregated proteins cause improper lens epithelial cell (LEC) organization and increases light scattering, therefore resulting in 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).  

DNA damage leading to cataracts 

Oxidative stress is also directly connected to increased DNA strand breaks. Cells under oxidative stress have excessive levels of ROS, molecules that 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). Furthermore, these strand breaks and a combination of various DNA abnormalities occurring in close proximity can create complex lesions that are more difficult to repair (Nickoloff et al., 2020). The formation of SSBs induces base excision repair (BER), a DNA repair mechanism; however, cells are often unable to support multiple sites of repair in one area, leading to residual unrepaired SSBs that will increase the number of DSBs. It has been shown that radiation-generated ROS are more likely to produce clustered damage (Cannan & Pederson, 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). 

DNA strand breaks can lead to inadequate DNA repair. DSBs, the most detrimental form of this damage (Iliakis et al., 2015), are 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 an active pathway for DNA DSB repair in the G1 phase of the cell cycle, DSBs are repaired using this pathway, leading to decreased repair accuracy (Jeggo et al., 1998). Although NHEJ is predominantly the preferred repair mechanism throughout the cell cycle, homologous recombination (HR) and single-stranded annealing (SSA) are favored during the S and G2 phases in scenarios where the NHEJ repair pathway is inhibited. The absence of HR leading to an increase in SSA activity is still a matter to debate (Ceccaldi et al., 2016). Furthermore, clustered damage generated by high linear energy transfer 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). 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 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). 

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). Alternate models suggests that CAs occur when the enzymes responsible for binding DNA strands during the repair of enzyme-induced DNA breaks dysfunctions. 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. This presents 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- and incidence-concordance 

Overall evidence of time- and dose-concordance is moderate to low throughout the AOP. Certain relationships, particularly those directly connected with deposition of energy, are well supported with measurable changes in expression in a temporal and dose concordant manner. However, KEs at the cellular and organ level are generally supported by a weaker WOE with inconsistencies. The use of different models, time-points and radiation types across studies may be the reason for inconsistencies.  

Evidence of time concordance is demonstrated by the occurrence of upstream KEs at earlier timepoints than the downstream KEs. Time concordance involving deposition of energy is well supported by studies showing the deposition of energy followed by downstream changes later in a time course. Studies using in vitro and in vivo models have found downstream effects occurring within minutes to years of the MIE. For example, oxidative stress in human LECs can occur within an hour following 0.25 Gy γ-rays exposure (Ahmadi et al., 2022), while it may take months to years for cataract development under radiotherapy or space radiation exposure (Gragoudas et al., 1995; Cucinotta et al., 2001). However, cellular and organ level events are not well-studied to demonstrate consistent time concordance.  

Studies in the AOP provide evidence of upstream KEs observed at the same doses or lower doses as the downstream KEs. The KERs directly involving the deposition of energy contain  the most evidence for dose concordance. Downstream KERs have limited support for dose concordance in a lens model but are supported with evidence from other cell types.  

A few studies demonstrate greater changes produced by the upstream KE than the downstream KE following a stressor (incidence concordance). One KER showing incidence concordance is oxidative stress to DNA strand breaks. For example, there was a 5x increase of DNA strand breaks, while only a ~1.4-fold increase in oxidative stress marker in human LECs (Liu et al., 2013a).   

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

The present AOP encompasses several notable uncertainties.  

  1. 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.  

  1. Many studies do not directly measure cataracts, instead measuring indirect indicators, such as minor opacities, that do not always progress into cataracts.  

  1. Observation periods used in many studies may be too short to account for cataract development, leading to an apparent decrease in cataract prevalence.  

  1. 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.  

  1. KERs describing 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. 

  1.  The use of different assays to assess KEs can result in diverse quantitative interpretations of data.

Essentiality of the Key Events 

Essentiality of the Deposition of Energy (MIE#1686) 

  • Radiation exposure increases levels of DNA strand breaks (Reddy et al., 1998; Barnard et al., 2019; Barnard et al., 2021), 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/reducing the amount of radiation decreases the amount of damage to macromolecules found within the cell. 

Essentiality of Increased Oxidative Damage to DNA (KE#1634) 

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

Essentiality of Increased DNA Strand Breaks (KE#1635) 

  • It is difficult to demonstrate the essentiality of increased DNA strand breaks as there are no modulators that can alter the KE and show effects to inadequate repair. However, it has been indirectly demonstrated that knock-out of mechanism related to repair processes can lead to increased strand breaks.  

Essentiality of Inadequate DNA Repair (KE#155) 

  • 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 (KE#185) 

  • The essentiality of this KE has been assessed as part of other AOPs, as described in the overall assessment of AOP #272. However, there was no available data from eye lens models to demonstrate the essentiality of this KE and show the effects on downstream KEs. 

Essentiality of Increased Chromosomal Aberrations (KE#1636) 

  • The essentiality of this KE has been assessed as part of other AOPs, as described in the overall assessment of AOP #272. However, there was no available data from eye lens models to demonstrate the essentiality of this KE and show the effects on downstream KEs. 

Essentiality of Increased Cell Proliferation (KE#870) 

  • 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 Oxidative Stress (KE#1392) 

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

Essentiality of Modified Proteins (KE#2081) 

  • 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  

Moderate 

Low 

 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. 

MIE#1686→ KE#1635: 

Deposition of energy → Increase DNA strand breaks 

High 

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. 

MIE#1686→ KE#2081:  

Deposition of Energy → Modified Proteins 

High 

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. 

MIE#1686→ KE#1392: 

Deposition of Energy → Oxidative Stress 

High 

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. 

KE#1392→ KE#1634: Oxidative Stress →Increase Oxidative DNA Damage 

High 

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. 

KE#1392→ KE#1635:  

Oxidative Stress → Increase, DNA Strand Breaks  

High 

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 levels of ROS have also been linked to DNA strand fragmentation. Furthermore, decreased antioxidant levels have also been linked to increased DNA strand damage.  

KE#1392→ KE#2081: Oxidative Stress → Modified Proteins 

High 

There is high 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. 

KE#1634→ KE#155: Increase, Oxidative DNA Damage → Inadequate DNA Repair 

High

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. There are limited data from eye lens models to support this relationship. However, this KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #296. 

KE#1635→ KE#155: Increase DNA strand breaks → Inadequate DNA repair 

High

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.  

KE#155→ KE#185: Inadequate DNA Repair → Increase, Mutations 

High

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272.  However, there was no available data from eye lens models to support this relationship. 

KE#155→ KE#1636: Inadequate DNA Repair → Increase, Chromosomal Aberrations 

High

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.  

MIE#1686→ KE#1634: Deposition of energy → Increase oxidative DNA damage 

High 

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 such as  ultraviolet (UV), a form of electromagnetic radiation, this process occurs through the MAPK pathway.  

MIE#1686→ KE#1636: Deposition of energy → Increase chromosomal aberrations 

High

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.  

MIE#1686→ KE#870: Deposition of Energy → Increase, Cell Proliferation 

Moderate

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

MIE#1686→ KE#2083: Deposition of Energy → Cataracts 

High 

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.  

KE#2081→ KE#2083: Modified Proteins → Cataracts 

High 

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.  

KE#155→ KE#2083: Inadequate DNA Repair → Cataracts   

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.  

KE#1392→ KE#2083: Oxidative stress → Cataracts 

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.  

KE#870→ KE#2083:  

Increase, Cell Proliferation → Cataracts 

Moderate 

There is biological plausibility support for the relation between increased cell proliferation and cataracts. Since the lens is a closed system with little turnover, the increased proliferation of the metabolically active LECs can result in cataracts. Gradual lens opacification and eventual cataract development can result from the improperly differentiated and proliferating cells that are not removed from the system. 

KE#1634→ KE#1635: Increase, Oxidative DNA Damage → Increase, DNA Strand Breaks 

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  

Moderate 

Low 

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#1686: Deposition of energy 

High 

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 decreases the amount of damage to macromolecules found within the cell. 

KE#1634: Increase, oxidative damage to DNA  

Moderate 

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

KE#1635: Increase, DNA strand breaks 

Low 

The essentiality of increased DNA strand breaks is difficult to demonstrate as there are no modulators that can alter the KE and show effects to inadequate repair.  However, indirectly, it has been shown that knock-out of mechanism related to repair processes can lead to increased strand breaks.  

KE#155: Inadequate DNA repair 

High 

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. 

KE#870: 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. 

KE#1392: Oxidative stress 

Moderate 

Oxidative stress increases levels of DNA strand breaks above background levels. Inhibition of oxidative stress through the use of antioxidants reduces DNA strand breaks. 

KE#2081: Modified proteins 

Low 

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  

Moderate 

Low 

 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 

MIE#1686→ KE#1635: 

Deposition of energy → Increase DNA strand breaks  

High  

There is a high level of empirical evidence to support the relationship between energy deposition and increased DNA strand breaks. The evidence collected to support this relationship was gathered from various in vitro and in vivo studies. Various stressors were applied, including X-rays, gamma rays, protons and photons. The studies supported a dose and time concordance between the deposition of energy and DNA strand breaks. 

MIE#1686→ KE#2081:  

Deposition of Energy → Modified Proteins  

Low  

There are a number of studies to support a dose response between energy deposition and protein modification, but no time response data. Evidence suggests that in vitro and in vivo model exposure to higher (>2 Gy) doses and long UV exposures can initiate protein modification. 

MIE#1686→ KE#1392: 

Deposition of Energy → Oxidative Stress 

High 

There is a large body of evidence supporting a time and dose relationship from the deposition of energy to oxidative stress. Various studies using in vitro and in vivo rat, mice, rabbit, squirrel, bovine and human models provided evidence for this KER. A wide range of stressors were applied, including UV light (UV-B and UV-A) and ionizing radiation (gamma rays, X-rays, protons, photons, neutrons, and heavy ions). A dose-dependent increase in oxidative stress was observed in studies that examined a range of ionizing radiation doses (0-10 Gy). 

KE#1392→ KE#1634: Oxidative Stress →Increase Oxidative DNA Damage 

Low 

There is very limited evidence supporting time and dose concordance for this KER. In vivo rodent studies informed a dose concordance following O2 exposure as a stressor and a time concordance following 11 Gy X-rays. 

KE#1392→ KE#1635:  

Oxidative Stress → Increase, DNA Strand Breaks  

Moderate 

There is evidence supporting the dose and incidence concordance of this relationship. There is limited evidence to support a time concordance. A limited variety of stressors are used as evidence supporting this KER. Most studies informing this relationship come from in vitro human models. 

KE#1392→ KE#2081: Oxidative Stress → Modified Proteins 

Low 

Limited evidence supports dose and incidence concordance for this relationship. No evidence found supporting time concordance. Stressor types are limited to UVA radiation or H2O2 exposure. 

KE#1634→ KE#155: Increase, Oxidative DNA Damage → Inadequate DNA Repair 

Moderate 

There is limited available data from eye lens models to support this relationship This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #296.

KE#1635→ KE#155: Increase DNA strand breaks → Inadequate DNA repair 

Moderate  

There is limited available data from eye lens models to support this relationship This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272.

KE#155→ KE#185: Inadequate DNA Repair → Increase, Mutations 

Moderate 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272. However, there was no available data from eye lens models to support this relationship.

KE#155→ KE#1636: Inadequate DNA Repair → Increase, Chromosomal Aberrations 

Moderate 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #296.  However, there was no available data from eye lens models to support this relationship.

MIE#1686→ KE#1634: Deposition of energy → Increase oxidative DNA damage 

Low 

There is limited evidence to support this KER. No incidence concordance evidence is available. Low variety of stressors (X-rays and UVB) inform this relationship. In vitro human lens epithelial cells exposed to X-rays or UVB lead to a dose concordant increase in oxidative DNA damage. In vivo mice models exposed to X-rays showed a time concordant increase in oxidative DNA damage. 

MIE#1686→ KE#1636: Deposition of energy → Increase chromosomal aberrations 

High  

There is a high level of empirical evidence to support this KER. Various studies demonstrate dose and time concordance between the deposition of energy and increased frequency of chromosomal aberrations. The evidence collected to support this relationship was gathered from various in vitro and in vivo studies. Various stressors were applied, including X-rays, gamma rays, and heavy ions. Chromosomal aberrations were detected as early as 30 minutes post-irradiation.  

MIE#1686→ KE#870: Deposition of Energy → Increase, Cell Proliferation 

High 

There is high evidence to support dose and time concordance between energy deposition and cell proliferation, but no evidence for incidence concordance. Various in vivo and in vitro studies on rodents, rabbits, or human models inform this relationship. A variety of stressor types such as gamma rays, UV, or X-rays were used as evidence for this KER. 

MIE#1686→ KE#2083: Deposition of Energy → Cataracts 

High 

There is high evidence to support dose and time concordance between energy deposition and cataract development. Various in vivo and in vitro studies and a variety of stressor types inform this relationship.  

KE#2081→ KE#2083: Modified Proteins → Cataracts 

Low 

There is a small pool of evidence to support the time and incidence concordance between modified proteins and cataracts. Limited in vivo rodent studies and stressor types (gamma rays, X-rays) provide support for incidence and time concordance. 

KE#155→ KE#2083: Inadequate DNA Repair → Cataracts  

Low 

There is a low amount of empirical evidence to support the relationship. The only available studies involve mice genetically predisposed towards inadequate DNA repair. Time concordance is supported by the in vivo studies, but no evidence is available for dose and incidence concordance. Mice irradiated with X-rays show cataract development 1-3 weeks sooner than wild type animals. 

KE#1392→ KE#2083: Oxidative stress → Cataracts 

Low 

There is a limited amount of empirical support for this KER. No available studies support incidence concordance. Dose and time concordance are supported by a low amount of empirical evidence from in vitro and in vivo studies exposed to gamma rays or H2O2.  

KE#870→ KE#2083:  

Cell Proliferation → Cataracts 

Low 

There is no confident empirical evidence to accurately demonstrate a dependant relationship between the two events. Limited studies support time and dose concordance using relevant stressors and models. 

KE#1634→ KE#1635: Increase, Oxidative DNA Damage → Increase, DNA Strand Breaks  

Moderate 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #296.  However, there was no available data from eye lens models to support this relationship. 

KE#1636 → KE#870: Increase, chromosomal aberrations → Increase, Cell Proliferation 

Moderate 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272.  However, there was no available data from eye lens models to support this relationship. 

KE#185 → KE#870: Increase, Mutations → Increase, Cell Proliferation 

Moderate 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272.  However, there was no available data from eye lens models to support this relationship.

MIE#1686→ KE#185: Deposition of energy → Increase, Mutations 

High 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272.  However, there was no available data from eye lens models to support this relationship.

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 

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. 

Deposition of energy leading to modified proteins

Deposition of energy leading to oxidative stress

Oxidative stress leading to modified proteins

Deposition of energy leading to increase oxidative DNA damage

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. 

Deposition of energy leading to modified proteins

Deposition of energy leading to oxidative stress

Oxidative stress leading to increase DNA strand breaks

Deposition of energy leading to cataracts

Modified proteins leading to cataracts

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 a toxic environment, therefore reducing the risk of cataracts. 

Deposition of energy leading to oxidative stress

Increase DNA strand break leading to inadequate DNA repair

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. 

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 low. While certain KERs, such as MIE to AO, are well understood quantitatively with the literature, the understanding of other KERs is limited. For example, the quantitative understanding regarding the amount of DNA strand breaks and oxidative DNA lesions that would exceed cellular repair capacities to predict downstream effects require further investigation. Furthermore, studies often examined different endpoints at various time-points, using different stressors, doses, dose-rates, and models within each KER, causing difficulty in accurately comparing studies and deriving a quantitative understanding of the relationship, including precisely predicting 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. 

Review of the Quantitative Understanding for each KER 

Defining Question 

High 

Moderate 

Low 

To what extent can a change in KEdownstream be predicted from KEupstream? With what precision can the uncertainty in the prediction of KEdownstream be quantified? To what extent are the known modulating factors of feedback mechanisms accounted for? To what extent can the relationships described be reliably generalized across the applicability domain of the KER?   

Change in KEdownstream can be precisely predicted based on a relevant measure of KEupstream; uncertainty in the quantitative prediction can be precisely estimated from the variability in the relevant KEupstream measure. Known modulating factors and feedback/feedforward mechanisms are accounted for in the quantitative description. Evidence that the quantitative relationship between the KEs generalizes across the relevant applicability domain of the KER. 

Change in KEdownstream can be precisely predicted based on a relevant measure of KEupstream; uncertainty in the quantitative prediction is influenced by factors other than the variability in the relevant KEupstream measure. Quantitative description does not account for all known modulating factors and/or known feedback/feedforward mechanisms. The quantitative relationship has only been demonstrated for a subset of the overall applicability domain of the KER. 

Only a qualitative or semi-quantitative prediction of the change in KEdown can be determined from a measure of KEup. Known modulating factors and feedback/feedforward mechanisms are not accounted for. Quantitative relationship has only been demonstrated for a narrow subset of the overall applicability domain of the KER. 

MIE#1686→ KE#1635: 

Deposition of energy → Increase DNA strand breaks  

High  

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. 

MIE#1686→ KE#2081:  

Deposition of Energy → Modified Proteins  

Moderate  

There is a large amount of quantitative evidence supporting an increased amount of modified proteins following 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. 

MIE#1686→ KE#1392: 

Deposition of Energy → Oxidative Stress 

High 

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. Oxidative stress can be represented by several different endpoints, including catalase, glutathione (GSH), superoxide dismutase, glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and ROS levels. Measurements have also been made over a large range of doses and dose rates 

KE#1392→ KE#1634: Oxidative Stress →Increase Oxidative DNA Damage 

Low 

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

KE#1392→ KE#1635:  

Oxidative Stress → Increase, DNA Strand Breaks  

Low 

There is a considerable amount of evidence supporting dose concordance for 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.  

KE#1392→ KE#2081: Oxidative Stress → Modified Proteins 

Low 

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

KE#1634→ KE#155: Increase, Oxidative DNA Damage → Inadequate DNA Repair 

Low 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #296. However, there was no available data from eye lens models to support this relationship.

KE#1635→ KE#155: Increase DNA strand breaks → Inadequate DNA repair 

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. This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272.   

KE#155→ KE#185: Inadequate DNA Repair → Increase, Mutations 

Moderate 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272. However, there was no available data from eye lens models to support this relationship.

KE#155→ KE#1636: Inadequate DNA Repair → Increase, Chromosomal Aberrations 

Low 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #296.  However, there was no available data from eye lens models to support this relationship.

MIE#1686→ KE#1634: Deposition of energy → Increase oxidative DNA damage 

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. 

MIE#1686→ KE#1636: Deposition of energy → Increase chromosomal aberrations 

High 

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.  

MIE#1686→ KE#870: Deposition of Energy → Increase, Cell Proliferation 

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.  

MIE#1686→ KE#2083: Deposition of Energy → Cataracts 

High 

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.

KE#2081→ KE#2083: Modified Proteins → Cataracts 

Low 

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. 

KE#155→ KE#2083: Inadequate DNA Repair → Cataracts  

Low 

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. 

KE#1392→ KE#2083: Oxidative stress → Cataracts 

Low 

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. 

KE#870→ KE#2083:  

Cell Proliferation → Cataracts 

Low 

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

KE#1634→ KE#1635: Increase, Oxidative DNA Damage → Increase, DNA Strand Breaks 

Low 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #296. However, there was no available data from eye lens models to support this relationship.

KE#1636 → KE#870: Increase, chromosomal aberrations → Increase, Cell Proliferation 

Low 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272. However, there was no available data from eye lens models to support this relationship.

KE#185 → KE#870: Increase, Mutations → Increase, Cell Proliferation 

Low 

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272. However, there was no available data from eye lens models to support this relationship.

MIE#1686→ KE#185: Deposition of energy → Increase, Mutations 

High  

This KER has been assessed as part of other AOPs, as described in the overall assessment of AOP #272. However, there was no available data from eye lens models to support this relationship.

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

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