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Relationship: 2815
Title
Energy Deposition leads to Cataracts
Upstream event
Downstream event
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 | Under Review |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Female | High |
Male | High |
Life Stage Applicability
Term | Evidence |
---|---|
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, if this occurs in the lens of the eye, it can lead to the formation of lens opacification, leading to the formation of 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. Cataracts 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.
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
Biological Plausibility
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; Little et al., 2021).
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 LEC 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 LEC 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 LECs becomes too high, they become incapable of differentiating 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 a stochastic effect, 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).
Empirical Evidence
Dose Concordance
There is strong evidence in the literature to support a dose-response for the development of cataracts following the deposition of energy. Several studies by NASA and others have investigated the exposure of flight personnel and astronauts to cosmic radiation and cataract development. Chylack et al. (2009) found that there was an exponential radiation dose-response in cataract prevalence in astronauts following their space travels. The prevalence of cataracts was more than twice as high in astronauts exposed to higher doses of ionizing and UV radiation than those exposed to relatively lower doses (Chylack et al., 2009; Chylack et al., 2012). The development of cataracts can be observed from space radiation doses as low as 8 mSv (Cucinotta et al., 2001). Commercial pilots with career radiation doses up to 21 mSv were also at risk of developing cataracts (Rafnsson et al., 2005), although the risk was not as high as that typically seen in astronauts (Jones et al., 2007).
There was an exponential dose-response in prevalence of cataract development in individuals following the exposure to radiation released from the atomic bomb dropped on Hiroshima (Minamoto et al., 2004; Nakashima et al., 2006; Otake and Schull, 1990). The odds ratio remained ~1 when exposed to 1 Sv of radiation, but the odds ratio increased to 4 when exposed to up to 4 Sv (Minamoto et al., 2004; Nakashima et al., 2006). Cataract development can be detected as low as 0.01 Gy in 1% of individuals (Otake and Schull, 1990). Exposed at a higher dose of 2 Gy, the prevalence increased to ~7%, but this prevalence further increased to 42% when exposed to 6 Gy (Otake and Schull 1990; Nefzger et al., 1969; Choshi et al., 1983). Individuals exposed to nuclear radiation at Chernobyl in the Worgul et al. (2007) study showed a similar result where <600 mGy exposure resulted in an odds ratio of ~1 and increased to ~1.7 when the exposure increased to 1 Gy. It has been reported there is a significantly increased risk of cataracts below 100 mGy (but not below 50 mGy) in occupational technologists exposed to radiation (Little et al., 2018; Little et al., 2020). Patients with head and neck cancer showed a rise in the percentage of lens opacity three and six months following radiotherapy (Arefpour et al., 2021).
Several animal studies have investigated the low dose effect of high energy particles on cataract development. These particles include fast neutrons, 56Fe, 40Ar, 20Ne, 12C, protons and 4He. There was a linear dose-response in cataract prevalence resulting from exposure to the following radiation: 0.5-4 Gy 4He and 0.03-0.5 Gy 12C (Fedorenko et al., 1995), and 0.01-0.3 Gy fast neutrons (Bateman et al., 1963). The rate of cataract formation increased linearly with dose when exposed to 56Fe (Brenner et al., 1993; Worgul et al., 1993). Cataract severity plateaus after 0.6 Gy X-rays, but not after exposure to the same dose of 40Ar, 20Ne or 12C (Cox et al., 1983; Ainsworth et al., 1981). Within each of the studies, dose-responses were more profound when observed at later, rather than earlier, post-irradiation time points. The dose-response for cataract development also depends on the type of radiation and its energy level or linear energy transfer (LET). When exposed to the same dose ranges, 40Ar (LET of 100 keV/μm) resulted in more severe cataract formations compared to that of radiation with lower LET, such as 20Ne (LET of 30 keV/μm) and 12C (LET of 10 keV/μm) (Cox et al., 1983; Ainsworth et al., 1981). When examined 40 weeks post-irradiation, lenses exposed to a range of 1-4 Gy of 645 MeV protons showed an apparent linear dose-response, compared the dose-response to 9 GeV protons over the same dose range that was linear until 2 Gy and then reached a plateau (Fedorenko et al., 1995). Additionally, it was observed that cataracts were more prevalent in lenses exposed to 9 GeV protons than in lenses exposed to 645 MeV protons. In another study, various mouse species exposed to 6060Co γ- irradiation atmultiple doses (0.5, 1 and 2 Gy) using two dose rates (0.063 and 0.3 Gy min-1) revealed that the average lens density rose was elevated with dose and dose rate when Ercc2 and Ptch1 mutations were present (McCarron et al., 2022).
Time-Concordance
High support exists for a time-response relationship between the deposition of energy and cataracts. There is an exponential time-response in cataract development to space radiation exposure. The shape of the exponential time-response curve was greatly influenced by radiation dose. Astronauts exposed to <8 mSv had a similarly shaped time-response curve for cataract prevalence, although at a lower prevalence level, compared to astronauts exposed to >8 mSv (Cucinotta et al., 2001). Large opacifications were not detected in the astronauts exposed to <8 mSv until 25 years after their first space travel. This observation greatly differs from astronauts exposed to >8 mSv, where opacification was detected in <5 years.
Epidemiological studies in humans investigating the time-response of cataract development from low doses of high energy particles is limited. High doses of high energy particles are used commonly in radiation therapy for uveal melanoma patients. Gragoudas et al. (1995), Meecham et al. (1994), and Char et al. (1998) showed that there was an increase cataract prevalence with time after exposure to radiation used in therapies. The change in cataract prevalence over time was greatly influenced by radiation dose and percent of the lens exposed. Thirty-six months after proton beam therapy with doses up to 70 cobalt Gy-equivalents (GyE), cataract prevalence ranged from 20~75%, depending on the risk group (based on the dose that the lens received and tumor height) (Gragoudas et al., 1995). Twelve years after helium ion therapy using a dose range of 48 to 80 GyE, cataracts were found in 20~100 % of those treated, depending on the proportional area of the lens that was irradiated (Meecham et al., 1994). In a similar helium ion therapy, Char et al. (1998) found that 20~90% of patients developed cataracts ten years after treatments using a dose range of 50~80 GyE. Reports from radiotherapy patients and cancer survivors also serve as evidence for radiation induced cataracts. In a study by Chodick et al. (2016) 3.5% of subjects experienceds a case of cataracts during the first 5 years after cancer diagnosis, with prevalence increasing as the dose of radiotherapy increased.
Several authors have investigated the time-response of cataract development in animal models exposed to low dose radiation released from high energy particles. The majority of the studies showed a linear time-response in cataract development to radiation exposures. The results were similar across different animal species. A time-response was evident for cataract severity by exposing animals to 90-180 reps (ca 0.9–1.8 Gy) cyclotron (Upton et al., 1956), 45-180 reps (ca 0.45-1.8 Gy) fission neutrons (Upton et al., 1956), 1.3-37.3 reps (ca 0.013-0.373 Gy) PO-B neutrons (Upton et al., 1956), 1-200 cGy 56Fe (Riley et al., 1991; Wu et al., 1994; Worgul et al., 1993; Worgul et al., 1995), 0.01-1 Gy 40Ar (Merriam et al., 1984) and 0.25-1.25 Gy protons (Cox et al., 1992; Cleary et al., 1972). The steepness of the linear response curve was greatly influenced by dose. Exposure to higher doses was likely to result in an immediate linear time-response in cataract prevalence, while an initial lag phase was present prior to entering the linear phase after exposures to relative low doses (Worgul et al., 1996; Worgul et al., 1993; Medvedovsky et al., 1994; Brenner et al., 1993). It is uncertain whether the results of some of these studies using low dose exposures would continue their linear increase to the 100% maximum over time, or if they would reach a plateau without attaining the 100% maximum. A longer post-irradiation time of observation would be required to determine this. A sigmoidal time-response curve for cataract severity was observed after radiation exposures within a range of 0.05-2 Gy 56Fe (Lett et al., 1986) and 0.25-1.00 Gy protons (Cleary et al., 1972). Merriam et al. (1984) demonstrated exposure to 0.01-0.25 Gy did not produce a significant effect on cataract severity until >40 week post-irradiation, while a significant effect appeared relatively earlier (at 10 week post-irradiation) after an exposure of 1 Gy 40Ar. McCarron et al. exposed different mouse species to 60Co γ-irradiation at doses of 0.5, 1, and 2 Gy, employing two dose rates (0.063 and 0.3 Gy min-1). Lens opacity was evaluated from 0-18 months post irradiation. The results indicate that with the passage of time, there is a gradual rise in lens opacity (McCarron et al., 2022).
Essentiality
Radiation exposure has been found to increase cataracts above background levels, studies using various radiation types demonstrate this relationship (Bateman et al., 1963; Cleary et al., 1972; Cox et l., 1983; Lett et al., 1986; Orake & Schull, 1990; Riley et al., 1991; Worgul et al., 1993; Jones et al., 2007; Kocer et al., 2007).
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.
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).
Stochastic vs. Deterministic Effects
The overall consensus is that cataract risk increases with radiation dose as a stochastic effect due to the linkage of cataracts to genotoxic effects (Seals et al., 2016). This is reinforced through cataract occurrence in animals with genetic mutations relating to DNA repair and cell division; the stochasticity is apparent because damage to singular cells is transmitted to successive cells, resulting in cataract formation (Seals et al., 2016). However, there is also controversy on whether there is a threshold dose below which tissue reactions (deterministic effects) do not occur (Thome et al., 2018; Hamada, 2023).
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 |
Quantitative Understanding of the Linkage
The following tables provide representative examples of the relationship, unless otherwise indicated, all data is significantly significant.
Dose Concordance
Reference |
Experiment Description |
Result |
Chylack et al., 2009 |
In vivo, mixed sex humans exposed to median dose 12.9 mSv from UVF and space travel with LOCSIII grading of lens opacities. |
Astronauts exposed to various doses of radiation from 0 to ~200 mSv showed a general trend of exposure to higher doses leading to the largest posterior subcapsular opacity. The odds ratio for increased risk of high opacity was 2.23 for astronauts exposed to higher space radiation doses. |
Chylack et al., 2012 |
In vivo, mixed sex humans exposed to median dose of 12.9 mSv from space travel with % opaque area measuring opacity severity. |
In astronauts exposed to doses from ~10-275 mSv, the progression rate of cortical opacification was estimated to be (0.25 ± 0.13) % lens area/Sv/year. |
Rafnsson et al., 2005 |
In vivo, male humans exposed to 1-48 mSv from space travel with the World Health Organization simplified grading system to measure cataracts. |
Humans exposed to radiation from 1-48 mSv showed a greater risk of cataracts at higher doses. Compared to the unexposed group, the odds ratio of nuclear cataract risk was 2.48-2.82 for pilots exposed to cosmic radiation of 1-21 mSv. Those who had the most exposure (22-48 mSv) had the highest odds ratio of 4.19. |
Cucinotta et al., 2001 |
In vivo, mixed sex humans exposed to 0.2-91 mSv radiation from space travel with slit lamp microscopy to grade lens opacification. |
Astronauts exposed to radiation from 0.2-91 mSv showed that the probability of developing any type of cataracts in astronauts exposed to high dose radiation (>8 mSv) was up to ~2.5-fold higher than those exposed to low dose radiation (<8 mSv). In comparison, the same study showed the probability of developing non-trace cataracts (loss of vision) can increase up to 3-fold due to space radiation. |
Jones et al., 2007 |
In vivo, male humans exposed to space with slit lamp microscopy to grade opacity severity. |
At the age of 70, the prevalence of cataracts in astronauts exposed to high doses was 1.2-fold higher than that seen in astronauts exposed to low doses, 2.8-fold higher than that seen in commercial pilots, and 8.5-fold higher than that seen in healthy US males. |
Minamoto et al., 2004 |
In vivo, mixed sex humans exposed to atomic bomb irradiation at doses of 0.005-3 Sv with slit lamp and LOCSII grading of opacification. |
Humans exposed to doses of 0.005-3 Sv after an atomic bomb showed a gradual increase in the odds ratio for posterior subcapsular opacities (indicative of cataract risk) with the maximum dose displaying a 3x increase compared to control. |
Nakashima et al., 2006 |
In vivo, mixed sex humans exposed to 0.005-4 Gy of radiation from an atomic bomb with LOCSII grading of opacities. |
Atomic bomb survivors exposed to doses of 0.005-4 Gy showed an increased risk of cataracts at higher doses. The odds ratio for cataract development increased from 1 to 3-4 with increasing radiation doses up to 4 Gy. |
Nefzger et al., 1969 |
In vivo, mixed sex humans exposed to 0-2 Gy of irradiation from an atomic bomb with slit lamp examination to determine level of opacification. |
Atomic bomb survivors exposed to doses of 0-2 Gy showed an increased risk of cataracts at higher doses. Individuals exposed to higher dose (>0.2 Gy) and lower dose (<0.2 Gy) radiation had ~28% and ~7% increases in cataract incidence, respectively, compared to those not exposed. |
Choshi et al., 1983 |
In vivo, mixed sex humans exposed to 0-1.00+ Gy irradiation from an atomic bomb with slit lamp examination for lens opacities. |
Atomic bomb survivors exposed to doses of 0 to over 1 Gy showed an increased risk of cataracts at higher doses. The prevalence of cataracts was increased by ~5-10 percentage points for individuals exposed to >1.00 Gy, compared to those exposed to 0.01-0.99 Gy. |
Otake & Schull, 1990 |
In vivo, humans exposed to up to 6 Gy of irradiation from an atomic bomb with slit lamp biomicroscopy observation of opacities. |
Atomic bomb survivors exposed to doses of <0.01-6 Gy showed an increased risk of cataracts at higher doses. One percent of individuals developed cataracts after exposure to <0.01 Gy. This prevalence increased to 42.3% for individuals exposed to 4-5.99 Gy. |
Worgul et al., 2007 |
In vivo, mixed sex humans exposed to up to 1000 mGy of radiation from Chernobyl with modified Merriam-Focht opacity grading. |
Humans exposed to Chernobyl radiation from <100-1000 mGy showed increased cataracts risk at increasing doses, increasing from 1 with low doses (<100 mGy) to 1.77 when exposed to greater than 800 mGy. |
Little et al., 2018 |
In vivo, 67,246 mixed sex US radiologic technologists who held a certification during at least two years from 1926 to 1982 completed four questionnaires over the course of 31 years to determine information on their cataract history as well as potential modulating factors. |
Radiologic technologists occupationally exposed to <10.0 - 499.9 mGy showed a gradual increase in hazard ratios for cataract risk, eventually increasing to 1.76x control at the maximum dose. |
Hall et al., 1999 |
In vivo, mixed sex human children were exposed to β, γ or X-rays with a mean dose of 0.4 Gy with a range of 0 – 8.4 Gy, and an average dose rate of 0.13 Gy/h, given over an average of 2.1 treatments. Cataracts were measured using LOCS I. |
Children who received a dose to the lens of 1 Gy were 35% more likely to develop a cortical opacity (95% confidence interval (CI) 1.07-1.69, LOCS ≥ 1.0), and 50% more likely to develop a posterior subcapsular opacity than unexposed children (95% CI 1.10-2.05, LOCS ≥ 1.0). |
Neriishi et al., 2012 |
In vivo, Japanese atomic bomb survivors that were exposed to a mean dose of 0.50 Gy with a range of 0.0 – 5.14 Gy, the mean age at exposure was 20.4 years. Cataracts were measured based on surgical removal. |
Atomic bomb survivors demonstrated that the incidence of cataracts increased as the dose increased. The estimated excess cases were 33 per 10,000 people/year/Gy. |
Chodick et al., 2016 |
In vivo, mixed sex childhood cancer survivors were exposed to a mean dose of 2.2 Gy with a range of 0 – 66 Gy during radiotherapy. After an average of 21.4 years post-exposure, their cataract history was measured via questionnaire. |
In childhood cancer survivors exposed to 0-66 Gy radiation there was a linear dose-response relationship between lens dose and cataracts (excess odds ratio per Gy = 0.92; 95% CI 0.65-1.20). Furthermore, doses greater than 0.5 Gy had an increased odds ratio (OR) compared to doses less than 0.5 Gy (OR = 2.2; 95% CI 1.3-3.7). |
Su et al., 2020 |
In vivo, mixed sex humans ≥45 years that were exposed to a cumulative lens dose of 189.5 ± 36.5 mGy and range of 0.0221 – 0.3104 Gy, after residing in a high natural background radiation area in Yangjian City, had the presence of cataracts determined using the LOCS III system. |
In humans exposed to high background radiation, the estimated dose threshold for cortical opacities was 140 mGy (90% CI 110-160 mGy). Furthermore, the odds ratios for cortical, nuclear, and posterior subcapsular opacities at 100 mGy were 1.26 (95% CI 1.00-1.60), 0.81 (95 CI 0.64-1.01), and 1.73 (95% CI 1.05-285). |
Yamada et al. 2004 |
In vivo, mixed sex atomic bomb survivors exposed to 0-3+ Sv of radiation with cataractogenesis determined by biennial health examinations. |
In atomic bomb survivors, there was a positive linear dose-response relationship (risk ratio of 1.06 at 1 Sv, P=0.026) between radiation dose and cataracts. However, there was only a significant relationship between the two KEs for those under 60 years of age (risk ratio of 1.16 at 1 Sv, P=0.009). |
Jacobson, 2005 |
In vivo, mixed sex retired radiation workers (median age of 76) with transuranic body burdens from three DOE-supported installations received a lifetime occupational exposure to actinide (0-600 mSv) with ophthalmologist-reported diagnoses of cataracts. |
The authors predicted an increase in the odds ratio for posterior subcapsular cataracts in radiation workers exposed to 0-600 mSv of 40.5% per additional 100 mSv (logistic regression coefficient of 0.0034 ± 0.0016 mSv-1. Furthermore, workers with lifetime doses over 201 mSv were significantly more likely to develop posterior subcapsular cataract compared to those with lifetime doses under 201 mSv. |
Bateman et al., 1963 |
In vivo, female mice received partial-body exposure to 0.01-0.30 Gy of neutrons (0.43 Mev, no dose rate available) or 0.5-9.75 Gy of X-rays with opacification graded based on % of area covered. |
In mice, lens opacification increased as the dose of neutron irradiation increased. For example, after 26 weeks post-irradiation with 1.8 MeV neutrons, 0.01 Gy resulted in a 2x increase to lens opacity, while 0.3 Gy resulted in an 11x increase to lens opacity. Identical trends were observed using 0.43 MeV neutrons (0.01-0.3 Gy) and 250 kVp X-rays (0.5-3.5 Gy). |
Worgul et al., 1993 |
In vivo, rats received head-only exposure to 1-50 cGy iron ions with Merriam-Focht scoring of opacities. |
In rats exposed to 56Fe at 450 MeV/amu, the cumulative cataract rate increased ~2-fold when the dose increased from 2 to 5 cGy. The rate further increased 4-fold following an exposure to 25 cGy. |
Brenner et al., 1993 |
In vivo, rats received head-only exposure to 0.01, 0.02, 0.05, 0.25, 0.5 Gy of iron ions with slit lamp and Merriam-Focht scoring of cataracts. |
In rats exposed to 56Fe at 450 MeV/amu, the cumulative cataract rate increased 3x in a log-log plot when the dose increased from 0.01 to 0.02 Gy. A similar increase was observed between 0.02 and 0.04 Gy. The 56Fe had LET of 192 keV/um. |
Cox et al., 1983; Ainsworth et al., 1981 |
In vivo, mice received whole-body exposure to 0.05-0.9 Gy heavy ions with opacification grading based on % of area affected. The dose rate was 0.5-2 Gy/min. 40Ar with 570 MeV/amu had a LET of 100 keV/um. 20Ne with 425 MeV/amu had a LET of 30 keV/um. 12C with 400 MeV/amu had a LET of 10 keV/um. |
Cox et al. (1983) showed that in mice exposed to 0.05-0.9 Gy of 40Ar, 20Ne, and 12C, higher doses resulted in relatively more severe cataracts, with a maximum opacity score of ~2.6 at 0.9 Gy. The opacity score in the control was ~0. There was a relatively larger difference in severity between 0.05 and 0.9 Gy for the 40Ar exposure than for the 20Ne, with less still for 12C. Ainsworth et al. (1981) conducted similar experiments showing similar data but using 20Ne with 470 MeV/amu. |
Fedorenko et al., 1995 |
In vivo, mixed sex mice received either head-only or whole-body exposure to 0.03-4 Gy of heavy ions and 1-6 Gy of protons with electrophtalmoscope and opacification grading. The 4He with 5 GeV/nucleon had a LET of 0.82 keV/um, and was administered at a dose rate of 1.5 cGy/sec. The 12C with 300 MeV/nucleon had an LET of 12 keV/um, and was administered at a dose rate of 0.004 cGy/sec. The protons with 645 MeV were administered at a dose rate of 6.3 cGy/sec and had an LET of 0.25 keV/um. The protons with 9 GeV were administered at a dose rate of 2 cGy/sec and had a LET of 0.23 keV/um. |
Mice exposed to 0.5 Gy vs. 2 Gy of 4He showed a nearly 60% increase in cataract prevalence. Prevalence also increased with increased post-irradiation time. Exposure to 0.5 Gy of 12C resulted in an ~50% increase in cataract prevalence compared to exposure to 0.03 Gy. Mice exposed to 1 Gy vs 4 Gy of 9 GeV protons showed a 30% increase in cataract prevalence, while mice exposed to the same doses of 645 MeV protons showed a 65% increase in cataract prevalence. |
Rastegar et al., 2002 |
In vivo, human lenses exposed to 2-373 days in space with digital Scheimpflug imaging to determine opacification. |
Aged from 40 to 70 years old, cataract severity increased ~4-fold for astronauts compared to ~1.3-fold for the non-astronaut reference group of the same age range who received negligible doses of radiation. |
Riley et al., 1991 |
In vivo, male rats received head-only exposure to 0, 0.1, 0.5, 1, 2 Gy of 56Fe with subjective opacification grading. The 56Fe had an energy of 600 MeV/A and an LET of 190 keV/µm. |
In rats exposed to 0.1-2 Gy of 56Fe, the cataracts severity increased with increasing doses, with 2 Gy resulting in stage 3.5 cataracts while lower doses resulting in stage 3 or less. |
Wu et al., 1994 |
In vivo, rat lenses exposed to 25-50 cGy of 56Fe with Merriam-Focht scoring of opacification. The 56Fe had an energy of 450 keV/amu. |
In rats irradiated immediately with 25 and 50 cGy from 56Fe, cataracts had reached stage 2 and 2.5, respectively. |
Lett et al., 1986; Cox et al., 1992 |
In vivo, rabbit lenses exposed to 0.05, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4 Gy of 56Fe with slit lamp microscopy and opacification grading. The 56Fe had an LET of 223 keV/µm. |
In rabbits irradiated with 0.5~2 Gy 56Fe, 2 Gy resulted in stage 1 cataracts, while lower doses resulted in stage <1. The study was continued by Cox et al. (1992). Six years post-irradiation, these authors found the rabbits that had been exposed to 1 Gy showed a slight increase to stage >1 cataract severity, while rabbits exposed to 0.5 Gy remained at stage <1. |
Merriam et al., 1984 |
In vivo, rats received head-only exposure to 0.01, 0.05, 0.25, 1, 3.5 Gy of argon (570 MeV/amu). Merriam-Focht grading following slit lamp examination. |
In rats irradiated with 40Ar, 1 Gy resulted in stage 3-3.5 cataracts, while the results of lower doses were cataracts of stage <2.5. |
Cleary et al., 1972 |
In vivo, rabbit lenses were locally exposed to 0.25-10 Gy of protons (100 MeV) with slit lamp observation and opacity grading. |
In rabbits irradiated with 25-100 rad of protons, cataracts severity reached stage 5, 3.5, and 2 after exposure to 100, 50, and 25 rad, respectively. |
Arefpour et al., 2021 | Humans (both sexes) with head and neck cancer were exposed to radiation therapy ranging from 0-22 Gy) for treatment. Lens opacity was measured in 3 and 6 months after radiation therapy. | the analysis of the data derived from radiotherapy patients exposed to doses of radiation using a linear accelerator ranging from 0-22 Gy showed an exponential dose response relationship with maximum lens opacity observed after 3 months post-exposure. |
McCarron et al., 2022 |
In vivo, mixed sex mouse models of lenses were exposed to 0.5, 1, 2 Gy of 60Co γ-irradiation with a dose-rate of 0.063 and 0.3 Gy min-1 and the maximum opacification were measured 1-18 months post-irradiation. | Mice irradiated to 0.5, 1, 2 Gy 60Co γ-rays at a dose-rate of 0.063 and 0.3 Gy min-1 resulted in an increased incidence of lens opacity in a dose response manner. |
Time Concordance
Reference |
Experiment Description |
Result |
Cucinotta et al., 2001 |
In vivo, mixed sex human lenses exposed to averages of 45 mGy or 3.6-4.7 mGy of radiation from space travel with slit lamp microscopy to grade opacity severity. |
In astronauts immediately occupationally exposed to space radiation (average lens dose of 3.6 mSv) cataract probability slowly increased with time since exposure, with a particularly large increase to 25% 16 years after the average exposure. |
Gragoudas et al., 1995 |
In vivo, mixed sex lenses of uveal melanoma patients that had undergone fractionated radiotherapy exposed to 70 cobalt gray equivalent (CGE) of protons with subjective cataract grading based on opacity and lens changes. |
In humans exposed immediately to 70 CGE of protons, cataracts were detected ~2 months post-irradiation. By 36 months post-irradiation, there was a 20% increase in cataract prevalence detected in patients with <50% area of lens exposed to radiation. In patients with >50% area of lens exposed, there was an 80% prevalence of cataracts. |
Meecham et al., 1994 |
In vivo, lenses of uveal melanoma patients that had undergone fractionated radiotherapy exposed to 48-80 GyE of helium ions with subjective lens grading. |
In humans exposed immediately 48-80 GyE, cataracts were detected <2 years post-irradiation. By 4 years post-irradiation, nearly 100% of the patients with 76~100% irradiated lens area had cataracts. In comparison, the prevalence was ~10% for the patients with 0~25% irradiated lens area. This prevalence increased to ~20% by 14 years post-irradiation. |
Char et al., 1998 |
In vivo, mixed sex lenses of uveal melanoma patients that had undergone fractionated radiotherapy exposed to 50-80 GyE of helium ions with subjective lens grading. |
In humans exposed immediately 50-80 GyE, cataracts were detected <2 years post-irradiation. By 4 years post-irradiation, 90% of the patients with 75~100% irradiated lens area had cataracts. In comparison, the prevalence was ~10% for the patients with 0~24% irradiated lens area. This prevalence increased to ~70% by 16 years post-irradiation. |
Upton et al., 1956 |
In vivo, mixed sex mice, rats, and guinea pigs exposed to various doses of neutrons with opacity grading system. The cyclotron fast neutrons had dose rate of 60-125 rep/min. Fast neutrons from a Po-B source had energies of 2-3 MeV and a dose rate of 1-4 rep/h. |
In mice, rats, and guinea pigs that were immediately administered 90-180 reps (equivalent dose to 0.837-1.674 Gy) of cyclotron fast neutrons, cataracts were detected in <5 months post-irradiation. Rats irradiated with 180 reps reached the highest severity of cataracts in <20 months, but not so for guinea pigs exposed to the same dosage. In mice irradiated with either 0.45 or 1.8 Gy of fission neutrons or 1.3-37.3 reps Po-B neutrons, cataracts were detected in <5 months. |
Worgul et al., 1996 |
In vivo, mixed sex rat eyes exposed to 2-250 mGy of neutrons with modified Merriam-Focht opacity grading. The irradiating neutrons had an energy of 440 keV and a dose rate of 8 mGy/min. |
In rats immediately irradiated with 2-250 mGy neutrons, cataracts were detected (0.5 grade) within 20 weeks. Rats exposed to 2 mGy showed a maximum cataract severity within 60 weeks, while rats exposed to 250 mGy showed a maximum cataract severity within 20 weeks. |
Riley et al., 1991 |
In vivo, male rats received head-only exposure to 0, 0.1, 0.5, 1, 2 Gy of 56Fe with subjective opacification grading. The 56Fe had an energy of 600 MeV/A and an LET of 190 keV/µm. |
In rats treated immediately with 0.1-2 Gy 56Fe, cataracts were detected within 20 weeks. Rats exposed to 2 Gy had stage 3.5 cataracts at 80 weeks post-irradiation. |
Wu et al., 1994 |
In vivo, rat lenses exposed to 25-50 cGy of 56Fe with Merriam-Focht scoring of opacification. The 56Fe had an energy of 450 keV/amu. |
In rats irradiated immediately with 25 and 50 cGy from 56Fe, cataracts were detected within 10 weeks. By 40 weeks post-irradiation, the cataracts had reached stage 2 and stage 2.5, respectively, from the two different doses. |
Worgul et al., 1993; Worgul et al., 1995 |
In vivo, rats received head-only exposure to 1, 2, 5, 25, and 50 cGy of 56Fe with an energy of 450 keV/amu and an LET of 190 keV/µm. Merriam-Focht scoring was used to quantify opacities. |
In rats exposed immediately to 10-50 cGy 56Fe, cataracts were detected within 10 weeks. By 110 weeks post-irradiation, cataracts reached stage 3 or higher from exposure to 50 cGy. |
Lett et al., 1986; Cox et al., 1992 |
In vivo, rabbit lenses exposed to 0.05, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4 Gy of 56Fe with slit lamp microscopy and opacification grading. The 56Fe had an LET of 223 keV/µm. |
In rabbits irradiated immediately with 0.5-2 Gy 56Fe, stage 1 cataracts were detected at ~150 days post-irradiation (Lett et al., 1986) Severity remained steady at 150~600 days post-irradiation. The study was continued by Cox et al. (1992), who observed cataracts greater than stage 1 in the rabbits six years post-irradiation. |
Medvedovsky et al., 1994 |
In vivo, male mice exposed to 5, 10, 20, 40, 150, 360, 504 cGy of 56Fe with modified Merriam-Focht grading. The 56Fe had energy of 600 MeV/amu and an LET of 175 keV/µm. |
Mice immediately irradiated with 5-40 cGy 56Fe showed cataract formation in ~40 weeks. Mice treated with all doses reached 100% cataract prevalence prior to 120 weeks post-irradiation. |
Brenner et al., 1993 |
In vivo, rats received head-only exposure to 0.01, 0.02, 0.05, 0.25, 0.5 Gy of 56Fe with slit lamp examination and Merriam-Focht grading. |
Rats were immediately exposed to 0.01-0.5 Gy 56Fe. Cataracts were detected at ~10 weeks post-irradiation for doses of 0.05-0.5 Gy and ~50 weeks for doses of 0.01 Gy. All doses reached 100% cataract prevalence prior to 80 weeks post-irradiation. |
Merriam et al., 1984 |
In vivo, rats received head-only exposure to 0.01, 0.05, 0.25, 1, 3.5 Gy of argon (570 MeV/amu). Merriam-Focht grading following slit lamp examination. |
In rats immediately irradiated with 40Ar, mild stage cataracts were detected ~10 weeks post-irradiation for all doses. Cataracts were observed up to stage 3.5 by ~50 weeks post-irradiation. |
Cox et al., 1992 |
In vivo, monkeys were exposed to 1.25, 2.5, 5, 7.5 Gy of protons (55 MeV) with slit lamp examination and subjective opacification grading. |
In rhesus monkeys immediately exposed to proton doses of 1.25 Gy, cataracts were detected 20-22 years post-irradiation, and the severity increased slightly to stage ~1 after 25 years. |
Cleary et al., 1972 |
In vivo, rabbit lenses were locally exposed to 0.25-10 Gy of protons (100 MeV) with slit lamp observation and opacity grading. |
In rabbits immediately irradiated with 25-100 rad of protons, cataracts were detected <0.5 years post-irradiation. By 1 year post-irradiation, severity increased to stage 5 at the highest. At 1.5 years post-irradiation, cataract severity remained constant. |
McCarron et al., 2022 |
In vivo. Female and male 8–12-week-old Ptch1+/-/CD1 and CD1 mice received whole-body exposure to 60Co γ-rays with doses of 05, 1, and 2 Gy, and dose rates of 0.063 and 0.3 Gy/min. Lens opacification was measured via Scheimpflug imaging. |
In mice immediately exposed to 1 Gy, the two largest maximum opacification values were 35 and 27%, detected in female Ptch1+/-/CD1 mice 15 and 16 months after exposure. Generally, the maximum opacification increased as time post-irradiation increased. |
Arefpour et al., 2021 | Humans (both sexes) with head and neck cancer were exposed to radiation therapy ranging from 0-22 Gy) for treatment. Lens opacity was measured in 3 and 6 months after radiation therapy. | The analysis of the data derived from radiotherapy patients exposed to doses of radiation using a linear accelerator ranging from 0-22 Gy showed a time response relationship with maximum lens opacity observed after 3 months post-exposure. |
Response-response Relationship
Time-scale
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
N/A
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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