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Energy Deposition leads to Cataracts
Key Event Relationship Overview
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|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
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
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
Overall Weight of Evidence: High
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
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.
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).
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
|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|
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
Domain of Applicability
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.
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