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Relationship: 2815

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Energy Deposition leads to Cataracts

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Deposition of energy leading to occurrence of cataracts non-adjacent High High Vinita Chauhan (send email) Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  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

An indication of the the relevant sex for this KER. More help
Sex Evidence
Female High
Male High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Energy can be deposited onto biomolecules stochastically from various forms of radiation (both ionizing and non-ionizing). As radiation passes through an organism, it loses energy; in the process it can potentially cause direct and indirect molecular-level damage. The extent of damage occurs at various levels depending on ionization and non-ionization events (excitation of molecules). The resulting particle-radiation interactions produce a cascade of negative biological consequences that lead to the formation of opacification in the eye lens, namely cataracts. This multistep process is initiated by the deposition of radiation energy onto the DNA molecules or crystallin proteins within lens cells. As a result, DNA damage is incurred, frequently as double-strand breaks of the DNA helix. Inadequate repair of DNA damage can lead to mutations and chromosomal aberrations. Accumulation of such genetic damage in critical genes involved in cell-cycle checkpoints can promote uncontrolled cellular proliferation (Hamada 2017; Hamada et al., 2020). An abnormally high rate of cell proliferation ultimately disrupts normal lens development, which is dependent on precise spatiotemporal regulation to maintain lens transparency. The lens is a closed system and has a limited turnover of macromolecule components (Uwineza et al., 2019), therefore the buildup of damaged components, including lens crystallin proteins, contributes to opacification of the lens known as cataracts. 

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall Weight of Evidence: High 

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

There is strong biological plausibility for the association between direct deposition of energy by ionizing radiation and cataract incidence. It is a well established relationship that has been described by many reviews and research articles (Ainsbury et al., 2021; NCRP, 2016; Hamada and Sato, 2016; Uwineza et al., 2019; Kleiman, 2012; Shore et al., 2010; ICRP, 2012).  

Cataracts are an eye condition in which the clear lens of the eye becomes opaque, resulting in reduced vision. Although cataracts are typically associated with aging, exposure of the lens to ionizing radiation is a known risk factor for the acceleration/induction of opacification within human lenses (Ainsbury et al., 2021; Dauer 2018). The majority of evidence supporting radiation-induced cataracts is drawn from primary research using experimental animals that have been exposed to varying qualities of radiation and from epidemiological investigations of health care professionals, flight personnel, astronauts, the Chernobyl cleanup workers, and atomic bomb survivors (NCRP, 2016; Bouffler et al., 2012; Hamada 2017; ICRP, 2012; Hamada & Sato, 2016).  

Ionizing radiation can be in the form of high energy particles (such as alpha particles, beta particles or heavy ions) or high energy waves (such as γ-rays or X-rays). Due to a thin layering of tissue covering the lens, radiation particles can reach sensitive areas in the lens and target cellular components that are biologically active (Ainsbury et al., 2021; Hamada, 2017). Primary targets of radiation in the lens are DNA molecules, crystallin proteins, and lens epithelial cells (LECs) in the germinative zone (Hamada et al., 2014; Ainsbury et al., 2016; ICRP, 2012). Crystallin proteins comprise 90% of the total protein content in lens fiber cells (Moreau and King, 2012), which form the bulk of the eye lens, making them a frequent target of radiation energy. Lens tissue is normally kept in a relatively low oxygen environment; hence it is prone to oxidative stress (Truscott, 2005). Radiation exposure can induce oxidative stress through interaction with surrounding molecules, such as water, to generate reactive oxygen species. Such reactive molecules distribute throughout the lens to initiate early destructive molecular events (Blakely et al., 2012). As well, deposition of energy can directly upregulate enzymes involved in reactive oxygen and nitrogen species (RONS) production (de Jager, Cockrell and Du Plessis, 2017).

Cataracts can result from two main mechanisms: an abnormal increase in lens epithelial cell proliferation, and changes in crystallin protein conformation. The uncontrolled cell proliferation is possibly the consequence of overwhelming genetic and chromosomal instability incurred in critical genes that regulate cell cycle checkpoints (Uwineza et al., 2019; Hamada et al., 2020). Radiation-stimulated lens epithelial cell proliferation has been reported in in vitro human lens cells (Bahia et al., 2018.), in vitro animal lens cells (von Sallmann, 1951) and in vivo experimental animals (Worgul et al., 1986; Richards, 1966; Markiewicz et al., 2015; Riley et al., 1989; Ramsell and Berry, 1966; Barnard et al., 2022). When the rate of division in mitotically-active lens epithelial cells becomes too high, they become incapable of transforming into typical elongated, organelle-free lens fiber cells (Wride 2011; Ainsbury et al., 2016). When there are changes in the structural properties of the highly soluble lens crystallin proteins, they denature and become insoluble, and thus tend to aggregate (Uwineza et al., 2019; Moreau and King, 2012). Radiation-stimulated lens crystallin protein alterations have been reported by many authors (Abdelkawi, 2012; Bahia et al., 2018; Kim et al., 2015; Shang et al., 1994). Both of these mechanisms produce opaqueness in the lens, reducing the ability of the lens to focus light onto the retina and produce sharp vision.  

The literature contains large amounts of epidemiological data, focused primarily on atomic bomb survivors, cancer survivors, and radiation workers. The overall consensus is that cataract risk increases with radiation dose, as measured based on various forms of cataracts, cataract surgery, or general opacities (Hall et al. 1999; Neriishi et al. 2012; Chodick et al. 2016; Su et al. 2020; Yamada et al. 2004; Jacobson, 2005).  

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Definition of cataracts and measurement methodology 

Cataracts are synonymously associated with lens opacification, yet there was no consistency in how cataracts were defined between studies. Such inconsistency was also apparent in the use of different methodologies to measure cataracts across different studies (Hammer et al., 2013; NCRP, 2016). Many of the scoring systems used to measure opacification were subjective, making it difficult to compare the risks observed between different studies (Jacob et al., 2011; Hamada et al., 2014). Although opacification is a direct measurement for cataracts, visual impairment was suggested to be the ultimate endpoint for radiation-induced cataracts, namely vision-impairing cataracts (VIC) (NCRP, 2016). Studies using visual acuity to measure cataracts pose challenges as the test is not specific for cataracts, even though the measurement is an indicative test for the ultimate function of the lens.  

Latency effect 

The time lapse for detection of cataracts varies roughly inversely with dose. The risk for cataracts caused by low doses of high energy particles may be underestimated in many studies due to length of the observation period used. More cataract development might have been seen with longer periods of observation. The extended latency period for cataract development posed challenges in the determination of causality, given the additional and complex confounding factors associated with aging (Ainsbury et al., 2021; Sakashita et al, 2019; Dauer et al., 2017). Whether opacification remains constant or progresses depends (in part, at least) on the level of radiation dose received; whether minor opacifications will transition to major visual impairments is also not entirely certain (Hamada et al., 2014; Shore et al., 2016; Hamada 2017; Hamada et al., 2020; Ainsbury et al., 2021). 

Partial lens irradiation 

There is evidence that non-irradiated sections of a lens can develop opacities following the irradiated sections receiving a dose of 10 or 50 mGy of X-rays. The irradiated section of the lens has a reduced number of opacities compared to lenses that were fully irradiated by the same dose, indicating a protective effect by the non-irradiated section (Worgul et al. 2005b). A second study found that opacities of partially irradiated lens are not long lasting and do not worsen over time into cataracts (Leinfelder & Riley, 1956). This suggests that some radiation-induced opacities are unable to manifest into cataracts, despite the deposition of energy initiating the relationship (Hamada & Fujimichi, 2015).  

Challenged study 

A study by Lehmann et al., 2016, showed cataracts in approximately 70% of voles from within contaminated Chernobyl zones. The study identified a positive relationship between cataracts and radiation doses of 20 – 80,000 µSv. However, the work is disputed as these cataracts detected may be due to the conditions under which the voles were preserved rather than radiation exposure (Smith et al., 2020; Laskowski et al., 2022). Furthermore, other studies did not find higher cataract rates when compared to non-exposed voles captured in the same geographical area as those in the Lehmann study (Williams, 2019).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)
Exposure regime   Fractionated dose exposures of high charge and low LET radiation types   Fractionated exposures of high charge particles were either effective at causing cataracts or made no difference compared with acute exposures. Results were demonstrated using 40Ar, 12C, neutrons, and 56Fe. These results were found to be in contrast to those produced with low-LET radiation, where fractionation exposures produced a tissue-sparing effect in cataract development.  Worgul et al., 1989; Ainsworth 1986; Worgul et al., 1996; Bateman et al., 1963; Worgul et al., 1993; Medvedovsky et al., 1994; Abdelkawi, 2012; Hamada, 2017 
Sex  Females and estrogen treated rats  Females among the atomic bomb survivors had a higher odds ratio of developing cataracts than males. Investigation following the radiation exposure from the Chernobyl nuclear plant also found a positive dose-response in female voles. Upon estrogen treatment, 56Fe-exposed rats had a higher and earlier onset cataract incidence than untreated animals of both sexes. 56Fe-exposed rats treated with estrogen also had a higher and earlier onset cataract incidence than ovariectomized females without the treatment under the same exposure.  Choshi et al., 1983; Dynlacht et al., 2006; Nakashima et al., 2006; Chodick et al., 2008; Bigsby et al., 2009; Garrett et al., 2020; Henderson et al., 2010; Dynlacht et al., 2011; Azizova et al., 2018; Little et al., 2018; Azizova et al., 2019 
Sex  Males  Contrary to the row above, males have also been found to have increased cataract incidence compared to females.  Henderson et al., 2009; Pawliczek et al., 2021 
Age  People below 20 (& 70) years of age  Exposure to radiation at a younger age appeared to increase the risk of developing cataracts, compared to similar exposures in older individuals. Epidemiological studies showed that the risk of developing cataracts was highly significant for those younger than 70 years of age, particularly those under 20 years of age, following exposure to the radiation released from an atomic bomb. Adults over 20 years old are less sensitive to radiation. The estimated latency period for the onset radiation-induced cataracts at five years. However, the onset time became smaller and less dose-dependent as age at exposure increased. The incidence of age-related cataracts increased at age over 50 years and became indistinguishable from radiation-induced cataracts. Results in an animal study were consistent with the results from human trials.   Choshi et al., 1983; Nakashima et al., 2006; Neriishi et al., 2012; Sakashita et al., 2019; Cox et al., 1983 
Genetics  Genes ATM, BRCA1, Ptch1, p53, Ercc2 and RAD9  Individuals who are sensitive to radiation exposure are likely to have mutations in genes associated with DNA repair. Several studies have observed early onset radiation-induced cataracts in Atm-deficient animals. See Hamada & Fujimichi (2015) for a more in-depth list of genotypes potentially increasing the risk of cataracts.  Worgul et al., 2002; Worgul et al., 2005a; Hall et al., 2006. Kleiman et al., 2007; Blakely et al., 2010; De Stefano et al., 2014; De Stefano et al., 2016; McCarron et al., 2021; Worgul et al., 2002; Hamada & Fujimichi, 2015; Barnard & Hamada, 2022; McCarron et al., 2022; Tanno et al., 2022 
Body Mass  BMI > or < “normal” range of 18.5-24.9 kg/m2  The BMI group most at risk to cataracts following irradiation is those with a BMI above or equal to 30 kg/m2 (Hazard ratio (HR) of 1.26 compared to “normal” BMI of 18.5-24.9 kg/m2). Other BMI cohorts also have elevated risk compared to the “normal” group; 0-18.4 kg/m2 people have an HR of 1.10 and 25-29.9 kg/m2 have an HR of 1.08.  Little et al., 2018 
Pre-existing Conditions  Diabetes  Individuals with diabetes are 2.18x more likely to develop cataracts following occupational radiation exposure than those without the condition.  Little et al., 2018 
Substance Use  History of cigarette use  People with a history of cigarette use have a higher risk of developing cataracts following occupational radiation exposure than people who have never smoked. Former smokers have an HR of 1.04 compared to non-smokers, which is still less than current smokers’ HR of 1.18.  Little et al., 2018 
Race  White People  White people have an elevated risk of developing radiation-induced cataracts (HR of 1) compared to Black or Other racial groups (HRs of 0.82 and 0.74).  Little et al., 2018 
Chemical modulators  Nigella sativa oil (NSO), zinc, L-carnitine, thymoquinone (TG), WR-77913, and propolis  Supplementation with antioxidants, particularly NSO, has led to decreased cataract formation following radiation-exposure. Other radioprotective agents, such as WR-77913, have led to similar results.  Menard et al., 1986; Taysi et al., 2022 
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The lag time of cataract development is inversely related to radiation dose in humans. At high doses, lens opacities or cataracts can develop within months of radiation administration (Hamada, 2017). Based on an acute exposure of ~0.5 Gy, it takes >20 years to develop cataracts that impairs vision (ICRP, 2012). Mathematical modelling by Sakashita et al. (2019) estimated a latency period of 5 years to produce cataracts.  

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

N/A

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

This KER is supported by a large body of literature and is plausible in all life stages, sexes, and organisms that have a clear lens for vision. Due to the large volume of studies, only in vivo studies were examined. The majority of the evidence supports adult humans, mice, and rats, and is not sex specific however, there is evidence supporting all ages, and sexes, as well as rabbits, voles, monkeys, guinea pigs, and rainbow trout. 

References

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

Abdelkawi, S. (2012), “Lens crystallin response to whole body irradiation with single and fractionated doses of gamma radiation”, International Journal of Radiation Biology, Vol.88/8, Informa UK Ltd, London, https://doi.org/10.3109/09553002.2012.695097.  

Ainsbury, E. et al. (2021), “Radiation-induced lens opacities: Epidemiological, clinical and experimental evidence, methodological issues, research gaps and strategy”, Environment International, Vol.146, Elsevier Ltd, London, https://doi.org/10.1016/j.envint.2020.106213.  

Ainsbury, E. 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, Amsterdam, https//doi.org/10.1016/j.mrrev.2016.07.010.  

Ainsworth, E. J. (1986), “Early and Late Mammalian Responses to Heavy Charged Particles”, Advances in Space Research, Vol.6/11, Elsevier, Amsterdam, https://doi.org/10.1016/0273-1177(86)90288-7. 

Ainsworth, E. J. et al. (1981), “Cataract Production in Mice by Heavy Charged Particles”, US Department of Energy, Berkeley, https//doi.org/10.2172/6395022. 

Azizova, T. V. et al. (2018), “Risk of various types of cataracts in a cohort of Mayak workers following chronic occupational exposure to ionizing radiation”, European Journal of Epidemiology, Vol. 33/12, Springer, https://doi.org/10.1007/s10654-018-0450-4 

Azizova, T. V. et al. (2019), “Risk of cataract removal surgery in Mayak PA workers occupationally exposed to ionizing radiation over prolonged periods”, Radiation and Environmental Biophysics, Vol. 58, Springer, Germany, https://doi.org/10.1007/s00411-019-00787-0 

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, Informa, London, https://doi.org/10.1080/09553002.2018.1439194.  

Barnard, S. et al. (2022), “Lens Epithelial Cell Proliferation in Response to Ionizing Radiation”, Radiation Research, Vol.197, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RADE-20-00294.1. 

Bateman, J.L., V.P. Bond, and H.H. Rossi. (1963), “Lens Opacification in Mice Exposed to Monoenergetic Fast Neutrons”, US Department of Energy, Upton, https://doi.org/10.2172/4163234. 

Bigsby, R. M. et al. (2009), “Ovarian hormone modulation of radiation-induced cataractogenesis: dose-response studies”, Investigative Ophthalmological Visual Sciences, Vol. 50/7, https://doi.org/10.1167/iovs.08-3262 

Blakely, E. (2012), “Lauriston S. Taylor lecture on radiation protection and measurements: What makes particle radiation so effective?”, Health Physics, Vol.103/5, Lippincott, Williams and Wilkins Ltd, Philadelphia, https://doi.org/10.1097/HP.0b013e31826a5b85.  

Blakely, E. A. et al. (2010), “Radiation cataractogenesis: epidemiology and biology”, Radiation Research, Vol. 173/5, The Radiation Research Society, United States, https://doi.org/10.1667/RRXX19.1 

Bouffler, S. et al. (2012), “Radiation-Induced Cataracts: The Health Protection Agency’s Response to the ICRP Statement on Tissue Reactions and Recommendation on the Dose Limit for the Eye Lens”, Journal of radiological protection : official journal of the Society for Radiological Protection, Vol.32/4, IOP Publishing, Bristol, https://doi.org/10.1088/0952-4746/32/4/479

Brenner, D.J. et al. (1993), “Accelerated Heavy Particles and the Lens. VIII. Comparisons between the Effects of Acute Low Doses of Iron Ions (190 KeV/Microns) and Argon Ions (88 KeV/Microns)”, Radiation Research, Vol.133/2, Radiation Research Society, Indianapolis, https://doi.org/10.2307/3578357. 

Char, D.H., S.M. Kroll, and J. Castro. (1998), “Ten-Year Follow-Up of Helium Ion Therapy for Uveal Melanoma”, American Journal of Ophthalmology, Vol.125/1, Elsevier, Amsterdam, https://doi.org/10.1016/S0002-9394(99)80238-4. 

Chodick, G. et al. (2016), “The risk of cataract among survivors of childhood and adolescent cancer: a report from the childhood cancer survivor study”, Radiation Research, Vol. 185/4, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR14276.1. 

Chodick, G. et al. (2008), “Risk of cataract after exposure to low doses of ionizing radiation: a 20-year prospective cohort study among US radiologic technologists”, American Journal of Epidemiology, Vol. 168/6, Oxford University Press, https://doi.org/10.1093/aje/kwn171 

Choshi, K. et al. (1983), “Ophthalmologic Changes Related to Radiation Exposure and Age in Adult Health Study Sample, Hiroshima and Nagasaki”, Radiation Research, Vol.96/3, Radiation Research Society, Indianapolis, https://doi.org/10.2307/3576122

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. 

Chylack, L.T. Jr et al. (2009), “NASA Study of Cataract in Astronauts (NASCA). Report 1: Cross-Sectional Study of the Relationship of Exposure to Space Radiation and Risk of Lens Opacity”, Radiation Research, Vol.172/1, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR1580.1. 

Cleary, S.F. et al. (1972), “X-Ray and Proton Induced Lens Changes in the Rabbit”, Health Physics, Vol.23/4, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1097/00004032-197210000-00001. 

Cox, A.B. et al. (1992), “Late Cataractogenesis in Primates and Lagomorphs after Exposure to Particulate Radiations”, Advances in Space Research, Vol.12/2–3, Elsevier, Amsterdam, https://doi.org/10.1016/0273-1177(92)90133-I.  

Cox, A.B. et al. (1983), “Cataractogenesis from High-LET Radiation and the Casarett Model”, Advances in Space Research, Vol.3/8, Elsevier, Amsterdam, https://doi.org/10.1016/0273-1177(83)90191-6. 

Cucinotta, F.A. et al. (2001), “Space Radiation and Cataracts in Astronauts”, Radiation Research, Vol.156/5 Pt 1, Radiation Research Society, Indianapolis, https://doi.org/10.1667/0033-7587(2001)156[0460:SRACIA]2.0.CO;2. 

Dauer, L.T. (2018), “Seeing through a glass darkly and taking the next right  steps”, European Journal of Epidemiology, Vol.33/12, Springer Science + Business Media, Berlin, https://doi.org/10.1007/s10654-018-0458-9.  

Dauer, L.T. et al. (2017), “Guidance on Radiation Dose Limits for the Lens of the Eye: Overview of the Recommendations in NCRP Commentary No. 26”, International Journal of Radiation Biology, Vol.93/10, Informa, London, https://doi.org/10.1080/09553002.2017.1304669. 

de Jager, T.L., Cockrell, A.E., Du Plessis, S.S. (2017), “Ultraviolet Light Induced Generation of Reactive Oxygen Species”, in Ultraviolet Light in Human Health, Diseases and Environment. Advances in Experimental Medicine and Biology, Springer, Cham, https://doi.org/10.1007/978-3-319-56017-5_2

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 

De Stefano, I. et al. (2016), “Nonlinear radiation-induced cataract using the radiosensitive Ptch1+/- mouse model”, Radiation Research, Vol. 186/3, The Radiation Research Society, United States, https://doi.org/10.1667/RR14440.1 

De Stefano, I. et al. (2014), “The patched 1 tumor-suppressor gene protects the mouse lens from spontaneous and radiation-induced cataract”, The American Journal of Pathology, Vol. 185/1, American Society for Investigative Pathology, https://doi.org/10.1016/j.ajpath.2014.09.019 

Dynlacht, J. R. et al. (2006), “Effect of estrogen on radiation-induced cataractogenesis”, Radiation Research, Vol. 165/1, United States, https://doi.org/10.1667/RR3481.1 

Dynlacht, J.R. et al. (2011), “Age and Hormonal Status as Determinants of Cataractogenesis Induced by Ionizing Radiation. I. Densely Ionizing (High-LET) Radiation”, Radiation Research, Vol.175/1, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR2319.1

Fedorenko, B.S., A.N. Abrosimova and O.A. Smirnova. (1995), “The Effect of High-Energy Accelerated Particles on the Crystalline Lens of Laboratory Animals”, Nutrition Reviews, Vol.26/5, Pleiades Publishing, Warrensburg, pp.573–88. 

Garrett, J. et al. (2020), “The Protective Effect of Estrogen Against Radiation Cataractogenesis Is Dependent Upon the Type of Radiation”, Radiation Research, Vol.194/5, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RADE-20-00015.1. 

Gragoudas, E.S. et al. (1995), “Lens Changes after Proton Beam Irradiation for Uveal Melanoma”, American Journal of Ophthalmology, Vol.119/2, Elsevier, Amsterdam, https://doi.org/10.1016/S0002-9394(14)73868-1. 

Hall, E. et al. (2006), “The relative biological effectiveness of densely ionizing heavy-ion radiation for inducing ocular cataracts in wild type versus mice heterozygous for the ATM gene”, Radiation and Environmental Biophysics, Vol.45/2, Springer, New York, https://doi.org/10.1007/S00411-006-0052-5.  

Hall, P. et al. (1999), “Lenticular opacities in individuals exposed to ionizing radiation in infancy”, Radiation Research, Vol. 152/2, Radiation Research Society, Oak Brook, https://doi.org/10.2307/3580093. 

Hamada, N., T.V. Azizova and M.P. Little. (2020), “An Update on Effects of Ionizing Radiation Exposure on the Eye”, British Institute of Radiobiology, Vol.93/1115, British Institute of Radiology, London, https://doi.org/ 10.1259/bjr.20190829. 

Hamada, N. (2017), “Ionizing radiation sensitivity of the ocular lens and its dose rate dependence”, International Journal of Radiation Biology, Vol.93/10, Informa, London, https://doi.org/10.1080/09553002.2016.1266407.  

Hamada, N. and T. Sato. (2016), “Cataractogenesis following high-LET radiation exposure”, Mutation Research - Reviews in Mutation Research, Vol.770/Pt B, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrrev.2016.08.005. 

Hamada, N. and Y. Fujimichi. (2015), “Role of carcinogenesis related mechanisms in cataractogenesis and its implications for ionizing radiation cataractogenesis”, Cancer Letters, Vol.368/2, Elsevier, Amsterdam, https://doi.org/10.1016/j.canlet.2015.02.017.  

Hamada, N. et al. (2014), “Emerging issues in radiogenic cataracts and cardiovascular disease”, Journal of Radiation Research, Vol.55/5, Oxford University Press, Oxford, https://doi.org/10.1093/jrr/rru036.  

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. & Y. Fujimichi (2015), “Role of carcinogenesis related mechanisms in cataractogenesis and its implications for ionizing radiation cataractogenesis”, Cancer Letters, Vol. 368/2, Elsevier, Ireland, https://doi.org/10.1016/j.canlet.2015.02.017 

Hammer, G.P. et al. (2013), “Occupational Exposure to Low Doses of Ionizing Radiation and Cataract Development: A Systematic Literature Review and Perspectives on Future Studies”, Radiation and Environmental Biophysics, Vol.52/3, Springer, Berlin, https://doi.org/10.1007/s00411-013-0477-6. 

Henderson, M.A. et al. (2010), “Effects of Estrogen and Gender on Cataractogenesis Induced by High-LET Radiation”, Radiation Research, Vol.173/2, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR1917.1. 

Henderson, M. A. et al. (2009), “Effect of gender on radiation-induced cataractogenesis”, Radiation Research, Viol. 172/1, Radiation Research Society, pp. 129-133 

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.  

Jacob, S. et al. (2011), “Ionizing Radiation as a Risk Factor for Cataract: What about Low-Dose Effects?” Journal of Clinical & Experimental Ophthalmology, Suppl.1/005, OMICS International, Hyderabad, https://doi.org/10.4172/2155-9570.S1-005. 

Jacobson, B.S. (2005), “Cataracts in retired actinide-exposed radiation  workers”, Radiation Protection Dosimetry, Vol.113, Oxford University Press, Oxford, https://doi.org/10.1093/RPD/NCH427.  

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.  

Kim, I. et al. (2015), “Site specific oxidation of amino acid residues in rat lens γ-crystallin induced by low-dose γ-irradiation”, Biochemical and Biophysical Research Communications, Vol.466/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.bbrc.2015.09.075.  

Kleiman, N.J. (2012), “Radiation cataract”, Annals of the ICRP, Vol.41/3-4, Elsevier, Amsterdam, https:/doi.org/10.1016/j.icrp.2012.06.018.  

Kleiman, N.J. et al. (2007), “Mrad9 and Atm Haploinsufficiency Enhance Spontaneous and X-Ray-Induced Cataractogenesis in Mice”, Radiation Research, Vol.168/5, Radiation Research Society, Indianapolis, https://doi.org/10.1667/rr1122.1. Leinfelder, P.J. and E.F. Riley. (1956), “Further studies of effects of X-radiation on partially shielded lens of rabbit”, Archives of Ophthalmology, Vol.55/1, American Medical Association, Chicago, https://doi.org/10.1001/ARCHOPHT.1956.00930030086012. 

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 

Laskowski, L. et al. (2022), “Environmental and industrial developments in radiation cataractogenesis”, International Journal of Radiation Biology, Vol. 98/6, Taylor & Francis, England, https://doi.org/10.1080/09553002.2020.1767820 

Lehmann, P. et al. (2016), “Fitness costs of increased cataract frequency and cumulative radiation dose in natural mammalian populations from Chernobyl”, Scientific Reports, Vol. 6/1, Nature Publishing Group, England, https://doi.org/10.1038/srep19974 

Lett, J.T., A.B. Cox and A.C. Lee. (1986), “Cataractogenic Potential of Ionizing Radiations in Animal Models That Simulate Man”, Advances in Space Research, Vol.6/11, Nature, Berlin, https://doi.org/ 10.1016/0273-1177(86)90305-4. 

Little, M. P. et al. (2021), “Low- and moderate-dose non-cancer effects of ionizing radiation in directly exposed individuals, especially circulatory and ocular diseases: a review of the epidemiology”, International Journal of Radiation Biology, Vol. 97/6, Taylor & Francis, England, https://doi.org/10.1080/09553002.2021.1876955. 

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. 

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. (2021), “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.  

Medvedovsky, C. et al. (1994), “The Influence of Dose, Dose-Rate and Particle Fragmentation on Cataract Induction by Energetic Iron Ions”, Advances in Space Research, Vol.14/10, Elsevier, Amsterdam, https://doi.org/10.1016/0273-1177(94)90502-9.  

Meecham, W.J. et al. (1994), “Anterior Segment Complications After Helium Ion Radiation Therapy for Uveal Melanoma”, Archives of Ophthalmology, Vol.112/2, American Medical Association, Chicago, https://doi.org/10.1001/ARCHOPHT.1994.01090140073026. 

Menard, T. W. et al. (1986), “Radioprotection against cataract formation by WR-77913 in γ-irradiated rats”, International Journal of Radiation Oncology, Vol. 12/8, Astro, https://doi.org/10.1016/0360-3016(86)90199-9 

Merriam, G.R. Jr et al. (1984), “Accelerated Heavy Particles and the Lens: I. Cataractogenic Potential”, Radiation Research, Vol.98/1, Radiation Research Society, Indianapolis, https://doi.org/10.2307/3576057

Minamoto, A. et al. (2004), “Cataract in Atomic Bomb Survivors”, International Journal of Radiation Biology, Vol.80/5, Informa, London, https://doi.org/10.1080/09553000410001680332. 

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. 

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.  

Nefzger, M.D., R. J. Miller and T. Fujino. (1969), “Eye Findings in Atomic Bomb Survivors of Hiroshima and Nagasaki: 1963-1964”, American Journal of Epidemiology, Vol.89/2, Oxford University Press, Oxford, https://doi.org/10.1093/OXFORDJOURNALS.AJE.A120922. 

Neriishi, K. et al. (2012), “Radiation dose and cataract surgery incidence in atomic bomb survivors, 1986-2005”, Radiology, Vol. 265/1, Radiological Society of North America, Oak Brook, https://doi.org/10.1148/radiol.12111947. 

Otake, M. and W. J. Schull. (1990), “Radiation-Related Posterior Lenticular Opacities in Hiroshima and Nagasaki Atomic Bomb Survivors Based on the DS86 Dosimetry System”, Radiation Research, Vol.121/1, Radiation Research Society, Indianapolis, https://doi.org/10.2307/3577557. 

Pawliczek, D. et al. (2021), “On the nature of murine radiation-induced subcapsular cataracts: optical coherence tomography-based fine classification, in vivo dynamics and impact on visual acuity”, Radiation Research, Vol. 197/1, Radiation Research Society, United States, https://doi.org/10.1667/RADE-20-00163.1 

Rafnsson, V. et al. (2005), “Cosmic Radiation Increases the Risk of Nuclear Cataract in Airline Pilots: A Population-Based Case-Control Study”, Archives of Ophthalmology, Vol.123/8, American Medical Association, Chicago, https://doi.org/10.1001/ARCHOPHT.123.8.1102

Ramsell, T. and R. Berry. (1966), “Recovery from x-ray damage to the lens. The effects of fractionated x-ray doses observed in rabbit lens epithelium irradiated in vivo”, The British Journal of Radiology, Vol.39/467, British Institute of Radiology, London, https://doi.org/10.1259/0007-1285-39-467-853.  

Rastegar, N., P. Eckart, M. Mertz (2002), “Radiation-induced cataract in astronauts and cosmonauts”, Graefe’s Archive for Clinical and Experimental Ophthalmology, Vol. 240/7, Springer, Germany, https://doi.org/10.1007/s00417-002-0489-4 

Richards, R. (1966), “Changes in lens epithelium after x-ray or neutron irradiation (mouse and rabbit)”, Transactions of the American Ophthalmological Society, Vol.64, American Ophthalmological Society, Rochester, pp.700-34.  

Riley, E. et al. (1991), “Relative Cataractogenic Effects of X Rays, Fission-Spectrum Neutrons, and 56Fe Particles: A Comparison with Mitotic Effects”, Radiation Research, Vol.125/3, Radiation Research Society, Indianapolis, https://doi.org/10.2307/3578114. 

Riley, E. et al. (1989), “Comparison of Recovery from Potential Mitotic Abnormality in Mitotically Quiescent Lens Cells after X, Neutron, and 56Fe Irradiations”, Radiation Research, Vol.119/2, Radiation Research Society, Indianapolis, https://doi.org/10.2307/3577616.  

Sakashita, T., T. Sato and N. Hamada (2019), “A Biologically Based Mathematical Model for Spontaneous and Ionizing Radiation Cataractogenesis”, PLoS ONE, Vol.14/8, PLoS, San Francisco, https://doi.org/10.1371/journal.pone.0221579. 

Shang, F., L. Huang and A. Taylor. (1994), “Degradation of Native and Oxidized Beta-and Gamma-Crystallin Using Bovine Lens Epithelial Cell and Rabbit Reticulocyte Extracts”, Current Eye Research, Vol.13/6, Taylor & Francis, Oxfordshire, https://doi.org/10.3109/02713689408999870. 

Shore, R.E. (2016), “Radiation and Cataract Risk: Impact of Recent Epidemiologic Studies on ICRP Judgments”, Mutation Research - Reviews in Mutation Research, Vol.770, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrrev.2016.06.006. 

Shore, R.E., K. Neriishi and E. Nakashima. (2010), “Epidemiological Studies of Cataract Risk at Low to Moderate Radiation Doses: (Not) Seeing Is Believing”, Radiation Research, Vol.174/6 B, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR1884.1. 

Smith, J. (2020), “Field evidence of significant effects of radiation on wildlife at chronic low dose rates is weak and often misleading. A comment on ‘Is non-human species radiosensitivity in the lab a good indicator of that in the field? Making the comparison more robust’ by Beaugelin-Seiller et al. “, Journal of Environmental Radioactivity, Vol. 211, Elsevier, England, https://doi.org/10.1016/j.jenvrad.2019.01.007 

Su, Yinping et al. (2021), “Lens opacity prevalence among the residents in high natural background radiation area in Yangjiang, China”, Journal of Radiation Research, Vol. 62/1, Oxford University Press, England, https://doi.org/10.1093/jrr/rraa073. 

Tanno, B. et al. (2021), “miRNA-signature of irradiated Ptch1+/- mouse lens is dependent on genetic background”, Radiation Research, Vol. 197/1, Radiation Research Society, United States, https://doi.org/10.1667/RADE-20-00245.1 

Truscott, R. (2005), “Age-related nuclear cataract - Oxidation is the key”, Experimental Eye Research, Vol.80/5, Academic Press Inc, Cambridge, https://doi.org/10.1016/j.exer.2004.12.007.  

Upton, A.C. et al. (1956), “The Relative Biological Effectiveness of Neutrons, x-Rays, and Gamma Rays for the Production of Lens Opacities: Observations on Mice, Rats, Guinea-Pigs, and Rabbits”, Radiology, Vol.67/5, Radiological Society of North America, Oak Brook, https://doi.org/10.1148/67.5.686. 

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.  

von Sallmann, L. (1952), “Experimental studies on early lens changes after roentgen irradiation III. Effect of X-radiation on mitotic activity and nuclear fragmentation of lens epithelium in normal and cysteine-treated rabbits”, Transactions of the American Ophthalmological Society, Vol.8, American Ophthalmological Society, Rochester, https://doi.org/10.1001/archopht.1952.01700030313005.  

Williams, D. (2019), “Do rodents in radioactive areas around Chernobyl Ukraine have high prevalence of cataracts?”, BSAVA Congress Proceedings, BSAVA Library, pp. 458 

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. 

Worgul, B. et al. (2005a), “Mice heterozygous for the ATM gene are more sensitive to both X-ray and heavy ion exposure than are wildtypes”, Advances in Space Research, Vol.35/2, Elsevier Ltd, London, https://doi.org/10.1016/J.ASR.2005.01.030.  

Worgul, B.V., N.J. Kleiman and J. David. (2005b), “A positive and negative bystander effect influences cataract outcome in the irradiated lens”, Investigative Ophthalmology & Visual Science, Vol.46/13, Association for Research in Vision and Ophthalmology, Rockville, pp.832 

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

Worgul, B.V., C. Medvedovsky and B. Wu. (1995), “Use of Non-Subjective Analysis of Lens Transparency in Experimental Radiation Cataract Research”, Ophthalmic Research, Vol.27/Suppl 1, Karger Publishers, Basel, https://doi.org/10.1159/000267855.  

Worgul, B.V. et al. (1996), “Quantitative Assessment of the Cataractogenic Potential of Very Low Doses of Neutrons”, Radiation Research, Vol.145/3, Radiation Research Society, Indianapolis, https://doi.org/10.2307/3578991.  

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, Association for Research in Vision and Ophthalmology, Rockville, pp.184–93.  

Worgul, B.V. et al. (1989), “Accelerated Heavy Particles and the Lens : III. Cataract Enhancement by Dose Fractionation”, Radiation Research, Vol.118/1, Radiation Research Society, Indianapolis, https://doi.org/10.2307/3577425. 

Worgul, B., G. Merriam and C. Medvedovsky. (1986), “Accelerated heavy particles and the lens II. Cytopathological changes”, Investigative Ophthalmology and Visual Science, Vol.27/1, Association for Research in Vision and Ophthalmology, Rockville, pp.108-114.  

Wride, M.A. (2011), “Lens Fibre Cell Differentiation and Organelle Loss: Many Paths Lead to Clarity”, Philosophical Transactions of the Royal Society B: Biological Sciences, Vol.366/1568, Royal Society, London, https://doi.org/10.1098/rstb.2010.0324. 

Wu, B., C. Medvedovsky and B.V. Worgul. (1994), “Non-Subjective Cataract Analysis and Its Application in Space Radiation Risk Assessment”, Advances in Space Research, Vol.14/10, Elsevier, Amsterdam, https://doi.org/10.1016/0273-1177(94)90504-5. 

Yamada, M. et al. (2004), “Noncancer disease incidence in atomic bomb survivors, 1958–1998”, Radiation Research, Vol.161, Radiation Research Society, Indianapolis, https://doi.org/10.1667/RR3183.