Radiation Cataractogenesis Research Articles

Radiation cataract in Heterogeneous Stock mice after γ-ray or HZE ion exposure

Health effects of space radiation are a serious concern for astronauts on long-duration missions. The lens of the eye is one of the most radiosensitive tissues in the body and, therefore, ocular health risks for astronauts is a significant concern. Studies in humans and animals indicate that ionizing radiation exposure to the eye produces characteristic lens changes, termed “radiation cataract,” that can affect visual function. Animal models of radiation cataractogenesis have previously utilized inbred mouse or rat strains. These studies were essential for determining morphological changes and dose-response relationships between radiation exposure and cataract. However, the relevance of these studies to human radiosensitivity is limited by the narrow phenotypic range of genetically homogeneous animal models. To model radiation cataract in genetically diverse populations, longitudinal cataract phenotyping was nested within a lifetime carcinogenesis study in male and female heterogeneous stock (HS/Npt) mice exposed to 0.4 Gy HZE ions (n = 609) or 3.0 Gy γ-rays (n = 602) and in unirradiated controls (n = 603). Cataractous change was quantified in each eye for up to 2 years using Merriam-Focht grading criteria by dilated slit lamp examination. Virtual Optomotry™ measurement of visual acuity and contrast sensitivity was utilized to assess visual function in a subgroup of mice. Prevalence and severity of posterior lens opacifications were 2.6-fold higher in HZE ion and 2.3-fold higher in γ-ray irradiated mice compared to unirradiated controls. Male mice were at greater risk for spontaneous and radiation associated cataracts. Risk for cataractogenesis was associated with family structure, demonstrating that HS/Npt mice are well-suited to evaluate genetic determinants of ocular radiosensitivity. Last, mice were extensively evaluated for cataract and tumor formation, which revealed an overlap between individual susceptibility to both cancer and cataract.

Ionizing radiation reduces glutathione levels in the eye: A pilot study

In 2011, the International Commission on Radiological Protection recommended reducing the threshold dose and occupational equivalent dose limit for the lens of the eye. However, this recommendation was based on limited epidemiological evidence and a few assumptions. Additional epidemiological and biological studies are thus required to understand radiation cataracts and optimize radiation protection practices. Glutathione is present in large amounts in the lens and inhibits the onset and progression of cataracts. A few studies have reported changes in glutathione levels in laboratory animal lenses after irradiation, but evidence about dose rate and time dependence remains lacking. In this study, we analyzed dose rate- and time-dependent changes in whole-eye reduced glutathione (GSH) and oxidized glutathione (GSSG) levels after γ-irradiation. We found that both decreases in eye GSH levels and delays in eye GSH recovery depended on dose rate. Our results support the concept that changes in GSH levels influenced on radiation cataractogenesis, consistent with previous biological research. This study will contribute to the mechanistic understanding of radiation cataractogenesis.

A biologically based mathematical model for spontaneous and ionizing radiation cataractogenesis.

Cataracts have long been known, but a biomathematical model is still unavailable for cataratogenesis. There has been a renewed interest in ionizing radiation cataracts because the recent international recommendation of the reduced lens dose limit stimulated the discussion toward its regulatory implementation in various countries. Nevertheless, a relationship between radiation (dose and dose rate) and response (e.g., incidence, onset and progression) remains incompletely understood, raising the need for a risk-predictive mathematical model. We here report for the first time an in silico model for cataractogenesis. First, a simplified cell proliferation model was developed for human lens growth based on stem and progenitor cell proliferation as well as epithelial-fiber cell differentiation. Then, a model for spontaneous cataractogenesis was developed to reproduce the human data on a relationship between age and cataract incidence. Finally, a model for radiation cataractogenesis was developed that can reproduce the human data on a relationship between dose and cataract onset at various ages, which was further applied to estimate cataract incidence following chronic lifetime exposure. The model can serve as the foundation for further development of the risk-predictive model for cataractogenesis along with additional considerations of various biological mechanisms and epidemiological datasets.

Inverse dose-rate effect of ionising radiation on residual 53BP1 foci in the eye lens

The influence of dose rate on radiation cataractogenesis has yet to be extensively studied. One recent epidemiological investigation suggested that protracted radiation exposure increases radiation-induced cataract risk: cumulative doses of radiation mostly <100 mGy received by US radiologic technologists over 5 years were associated with an increased excess hazard ratio for cataract development. However, there are few mechanistic studies to support and explain such observations. Low-dose radiation-induced DNA damage in the epithelial cells of the eye lens (LECs) has been proposed as a possible contributor to cataract formation and thus visual impairment. Here, 53BP1 foci was used as a marker of DNA damage. Unexpectedly, the number of 53BP1 foci that persisted in the mouse lens samples after γ-radiation exposure increased with decreasing dose-rate at 4 and 24 h. The C57BL/6 mice were exposed to 0.5, 1 and 2 Gy ƴ-radiation at 0.063 and 0.3 Gy/min and also 0.5 Gy at 0.014 Gy/min. This contrasts the data we obtained for peripheral blood lymphocytes collected from the same animal groups, which showed the expected reduction of residual 53BP1 foci with reducing dose-rate. These findings highlight the likely importance of dose-rate in low-dose cataract formation and, furthermore, represent the first evidence that LECs process radiation damage differently to blood lymphocytes.

Editorial: ERCP-Related Radiation Cataractogenesis: Is It Time to Be Concerned?

With the growing number of fluoroscopic guided endoscopic procedures, radiation-related risk needs to be further assessed. Recent evidence indicates that radiation cataractogenesis occurs at a lower dose threshold than previously believed. While body aprons and thyroid shields are well-established standard protection during fluoroscopy, ocular safety and the use of protective eyewear are not as well defined. This prospective study answered two important questions: Does the standard body dosimeter provide an accurate ocular dosimetry? And what is the time of fluoroscopy needed to warrant using lens protection? It also raises the question whether current guidelines need to be updated.

Cataractogenesis following high-LET radiation exposure.

Biological effectiveness of ionizing radiation differs with its linear energy transfer (LET) such that high-LET radiation is more effective for various biological endpoints than low-LET radiation. Human exposure to high-LET radiation occurs in cancer patients, nuclear workers, aviators, astronauts and other space travellers. From the radiation protection viewpoint, the ocular lens is among the most radiosensitive tissues in the body, and cataract (a clouding of the normally transparent lens) is classified as tissue reactions (formerly called nonstochastic or deterministic effects) with a threshold below which no effect would occur. To prevent radiation cataracts, the International Commission on Radiological Protection (ICRP) has recommended an equivalent dose limit for the lens according to the threshold for vision-impairing cataracts. ICRP recommended the threshold of >8Gy in 1984 and an occupational dose limit of 150mSv/year in 1980. These remained unchanged until 2011, when ICRP recommended lowering the threshold to 0.5Gy and the dose limit to 20mSv/year (averaged over 5 years with no single year exceeding 50mSv). Although such reduction of the threshold was based on findings from low-LET radiation, the dose limit was recommended in Sv. Historically, the lens is the exceptional tissue for which ICRP had assigned a special factor in addition to a general radiation weighting factor, predicated on a belief that the lens is more vulnerable to high-LET radiation than other tissues. Considering such radiosensitive nature of the lens, a deeper understanding of a cataractogenic potential of high-LET radiation is indispensable. This review is thus designed to provide an update on the current knowledge as to high-LET radiation cataractogenesis. To this end, changes in ICRP recommendations on lenticular radiation protection, epidemiological and biological findings on high-LET cataractogenesis are reviewed, and future research needs are then discussed.

Role of carcinogenesis related mechanisms in cataractogenesis and its implications for ionizing radiation cataractogenesis

Ionizing radiation is a proven human carcinogen and cataractogen. The crystalline lens of the eye is among the most radiosensitive tissues in the body. A clouding of the normally transparent lens (i.e., cataract) is very common. Conversely, the lens continues to grow throughout life without developing tumors, suggesting that the lens possesses strong anti-carcinogenesis mechanisms. There is mounting evidence that mutations of oncogenes, tumor suppressor genes, DNA repair genes involved in base excision repair, nucleotide excision repair, and DNA double-strand break repair, and genes involved in intercellular interactions (e.g., via connexin gap junctions), and inflammation affect cataract development. Associations of these factors with cancer have long been recognized, highlighting that cataractogenesis shares some common mechanisms with carcinogenesis. This paper briefly overviews the current knowledge on the potential involvement of tumor related factors, DNA repair factors, intercellular interactions and inflammation in spontaneous cataractogenesis, and discusses its implications for cataractogenesis induced by targeted and nontargeted effects of ionizing irradiation.

Ionizing radiation-induced cataract in interventional cardiology staff.

Background:The use of ionizing radiation has led to advances in medical diagnosis and treatment.Objectives:The purpose of this study was to determine the risk of radiation cataractogenesis in the interventionists and staff performing various procedures in different interventional laboratories.Patients and Methods:This cohort study included 81 interventional cardiology staff. According to the working site, they were classified into 5 groups. The control group comprised 14 professional nurses who did not work in the interventional sites. Participants were assigned for lens assessment by two independent trained ophthalmologists blinded to the study.Results:The electrophysiology laboratory staff received higher doses of ionizing radiation (17.2 ± 11.9 mSv; P < 0.001). There was a significant positive correlation between the years of working experience and effective dose in the lens (P < 0.001). In general, our findings showed that the incidence of lens opacity was 79% (95% CI, 69.9-88.1) in participants with exposure (the case group) and our findings showed that the incidence of lenses opacity was 7.1% (95% CI:2.3-22.6) with the relative risk (RR) of 11.06 (P < 0.001).Conclusions:We believe that the risk of radiation-induced cataract in cardiology interventionists and staff depends on their work site. As the radiation dose increases, the prevalence of posterior eye changes increases.

The Role of Age, Sex and Steroid Sex Hormones in Radiation Cataractogenesis

It is critical to identify and gain a better understanding of the factors that enhance or reduce the risk of cataractogenesis, to minimize the possibility of occurrence after deliberate (e.g., radiation therapy, interplanetary travel) or unintentional exposure to ionizing radiation. Both gender and age at the time of exposure have been established as key determinants of cataractogenesis induced by sparsely ionizing (low-LET) and densely ionizing (high-LET) radiation. However, animal data from several older studies are often conflicting and somewhat difficult to interpret, in that the experiments suffered from small group sizes, limited dose ranges or short periods of observation, and human data are sparse or statistical significance is sometimes limited. Steroid sex hormones (SSH) may underlie age and gender-based differences in the progression and prevalence of cataracts that otherwise occur spontaneously in humans and animal models, and may also underlie age and sex-related differences in radiation cataractogenesis. Here, we review data that have aided in our understanding of the role of age, sex and steroid sex hormones in radiation cataractogenesis.

Ionizing Radiation as a Risk Factor for Cataract: What about Low-Dose Effects?

Lens opacities are potential serious consequences of eye exposure to ionizing radiation. Several studies have shown with certainty that radiation cataractogenesis has a much lower threshold than the old radiation protection guidelines of the International Commission on Radiological Protection (ICRP), specifically 2 Gy (Grays) for acute exposure and 5 Gy for fractioned exposure. In April 2011, the ICRP revised its eye dose threshold for cataract induction downwards from 2 Gy to 0.5 Gy, and the occupational annual dose limit from 150 mSv to 20 mSv/year. Moreover, based on previous studies the traditional view that posterior subcapsular opacities are the only signature form of radiation cataract may have to be broadened to cortical cataracts.We present the most recent results on lens opacities and early stages of cataract that were observed for ionizing radiation doses below 1 Gy and which have led the ICRP to decrease the eye lens dose threshold.

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

This paper presents the response of the Health Protection Agency (HPA) to the 2011 statement from the International Commission on Radiological Protection (ICRP) on tissue reactions and recommendation of a reduced dose limit for the lens of the eye. The response takes the form of a brief review of the most recent epidemiological and mechanistic evidence. This is presented together with a discussion of dose limits in the context of the related risk and the current status of eye dosimetry, which is relevant for implementation of the limits. It is concluded that although further work is desirable to quantify better the risk at low doses and following protracted exposures, along with research into the mechanistic basis for radiation cataractogenesis to inform selection of risk projection models, the HPA endorses the conclusion reached by the ICRP in their 2011 statement that the equivalent dose limit for the lens of the eye should be reduced from 150 to 20 mSv per year, averaged over a five year period, with no year’s dose exceeding 50 mSv.

Lenses from Brown‐Norway pigmented rats are more tolerant to in vitro ultraviolet irradiation than lenses from Fischer‐344 albino rats

To investigate if the previously shown difference in in vivo-induced ultraviolet B radiation (UVR-B) cataractogenesis between pigmented and albino rats can be seen also with in vitro irradiation. The shielding effect of the iris and UVR absorption in the anterior segment is nullified, and inherent differences in lenticular UVR-B sensitivity between the strains may be revealed. Lenses from albino (Fischer-344) and pigmented (Brown-Norway) rats were irradiated in vitro with 1.8 kJ/m(2) UVR-B. The lenses were cultured in standard environment in a culture incubator. Cataract was quantified daily by measuring the amount of lens forward light scattering over a period of 1 week. All lenses were photographed during the week. Two days after exposure, both strains developed significant cataract compared to control lenses, and the light scattering increased exponentially to the last day. From day 4, exposed Fischer lenses scattered more light than Brown-Norway lenses. This difference increased towards the end of the week. The type of cataract (anterior subcapsular, equatorial, and posterior cortical cataract) was similar in both strains. No anterior polar or nuclear cataract was observed. Lenses from albino Fischer rats are more sensitive to in vitro UVR-B than lenses from pigmented Brown-Norway rats. Ultraviolet B radiation cataract type induced in vitro differs from in vivo cataract in pigmented rats, but not from albino rats. In vitro UVR-B exposure induces more cataract than corresponding lenticular UVR-B in vivo exposures, for both albino and pigmented rat.

WE-B-202-01: IAEA Study of Cataract in Staff Working in Catheterization Laboratories

Staff working in catheterization laboratories, predominantly interventional cardiologists and nurses, are potentially exposed to relatively high levels of ionizing radiation and may be at risk of developing cataracts after several years of work if radiation protection rules are not followed. A number of studies in other radiation exposed populations, including astronauts, atomic bomb survivors, X-ray technologists and those exposed after the Chernobyl nuclear accident, have indicated an increased risk of radiation associated lenticular changes after low-dose exposures, raising concerns regarding interventional cardiology professionals. Recent studies indicate that the threshold for cataract development is lower than was previously estimated and that radiation cataractogenesis may in fact be more accurately described by a linear, no-threshold model and may thus need to be classified as stochastic effect. The higher workload that is typical now in many cath labs, a lack of training in radiation protection and non-availability or non-use of radiation protection devices can result in doses to the eye lens that are high enough to cause lens injuries. International Atomic Energy Agency (IAEA) had launched a project to test the eyes of interventional cardiologists and support staff. The prospective testing was associated with a retrospective dose assessment for the lens of the eye. The eye testing exercises have been done in 20008–2009 at Bogota, Columbia; Montevideo, Uruguay; Kuala Lumpur, Malaysia; Varna and Sofia in Bulgaria. The talk will review the basic information about radiation catactogenesis and results of recent studies that indicate the need for change. It will present the summary of results of yet to be published studies on interventional cardiologists and nurses that do indicate increased prevalence of dots that represent lens injuries which may lead to cataract after many years. Learning Objectives: 1. To understand the basic information about radiation cataractogenesis 2. To understand the studies that have been conducted in the last 15 years that show that cataract is seen at doses lower than the currently believed threshold 3. To become aware about the likely changes in current recommendation that may be brought up by international bodies such as ICRP.

Effect of Gender on Radiation-Induced Cataractogenesis

Radiation cataractogenesis is an important consideration for radiotherapy patients and for astronauts. Data in the literature suggest that gender and/or estrogen may play a role in the incidence of age-related cataracts. However, few data exist on the effect of gender on radiation-induced cataractogenesis. We compared the incidence and rate of progression of cataracts induced by ionizing radiation in male and female Sprague-Dawley rats. Male rats were implanted with either an empty silastic capsule or a capsule containing 17-beta-estradiol. Ovary-intact female rats were implanted with empty capsules. All rats received a single dose of 10 Gy (60Co gamma rays) to the right eye only. Lens opacification was measured at 2-4-week intervals with a slit lamp. The incidence of radiation-induced cataracts was significantly increased in male rats compared to female rats (P=0.034). There was no difference in the rate of cataract progression between the three groups. Our data suggest there is a gender-related difference in radiation-induced cataractogenesis, but the increased incidence of radiation cataractogenesis in male rats compared to female rats cannot be attributed to estrogen levels, since there was no difference in cataract incidence between male rats implanted with empty capsules and those implanted with capsules containing 17-beta-estradiol.

Radiation Cataractogenesis: A Review of Recent Studies

The lens of the eye is recognized as one of the most radiosensitive tissues in the human body, and it is known that cataracts can be induced by acute doses of less than 2 Gy of low-LET ionizing radiation and less than 5 Gy of protracted radiation. Although much work has been carried out in this area, the exact mechanisms of radiation cataractogenesis are still not fully understood. In particular, the question of the threshold dose for cataract development is not resolved. Cataracts have been classified as a deterministic effect of radiation exposure with a threshold of approximately 2 Gy. Here we review the combined results of recent mechanistic and human studies regarding induction of cataracts by ionizing radiation. These studies indicate that the threshold for cataract development is certainly less than was previously estimated, of the order of 0.5 Gy, or that radiation cataractogenesis may in fact be more accurately described by a linear, no-threshold model.

Estrogen Protects against Radiation-Induced Cataractogenesis

Cataractogenesis is a complication of radiotherapy when the eye is included in the treatment field. Low doses of densely ionizing space radiation may also result in an increased risk of cataracts in astronauts. We previously reported that estrogen (17-beta-estradiol), when administered to ovariectomized rats commencing 1 week before gamma irradiation of the eye and continuously thereafter, results in a significant increase in the rate and incidence of cataract formation and a decreased latent period compared to an ovariectomized control group. We therefore concluded that estrogen accelerates progression of radiation-induced opacification. We now show that estrogen, if administered continuously, but commencing after irradiation, protects against radiation cataractogenesis. Both the rate of progression and incidence of cataracts were greatly reduced in ovariectomized rats that received estrogen treatment after irradiation compared to ovariectomized rats. As in our previous study, estradiol administered 1 week prior to irradiation at the time of ovariectomy and throughout the period of observation produced an enhanced rate of cataract progression. Estrogen administered for only 1 week prior to irradiation had no effect on the rate of progression but resulted in a slight reduction in the incidence. We conclude that estrogen may enhance or protect against radiation cataractogenesis, depending on when it is administered relative to the time of irradiation, and may differentially modulate the initiation and progression phases of cataractogenesis. These data have important implications for astronauts and radiotherapy patients.

Mrad9 and Atm Haploinsufficiency Enhance Spontaneous and X-Ray-Induced Cataractogenesis in Mice

Rad9 and Atm regulate multiple cellular responses to DNA damage, including cell cycle checkpoints, DNA repair and apoptosis. However, the impact of dual heterozygosity for Atm and Rad9 is unknown. Using 50 cGy of X rays as an environmental insult and cataractogenesis as an end point, this study examined the effect of heterozygosity for one or both genes in mice. Posterior subcapsular cataracts, characteristic of radiation exposure, developed earlier in X-irradiated double heterozygotes than in single heterozygotes, which were more prone to cataractogenesis than wild-type controls. Cataract onset time and progression in single or double heterozygotes were accelerated even in unirradiated eyes. These findings indicate that the cataractogenic effect of combined heterozygosity is greater than for each gene alone and are the first to demonstrate the impact of multiple haploinsufficiency on radiation effects in an intact mammal. These observations may help explain observed interindividual differential radiosensitivity in human populations and have important implications for those undergoing radiotherapy or exposed to elevated levels of cosmic radiation, such as the astronaut corps. These findings demonstrate that Mrad9 and Atm are important determinants of lens opacification and, given the roles of Atm and Rad9 in maintaining genomic stability, are consistent with a genotoxic basis for radiation cataractogenesis.

Effect of Estrogen on Radiation-Induced Cataractogenesis

Cataractogenesis is a widely reported late effect that is observed in patients receiving total-body irradiation (TBI) prior to bone marrow transplantation or radiotherapy for ocular or head and neck cancers. Recent studies indicate that estrogens may protect against age-related and drug-induced cataracts. Moreover, other reports suggest that estrogen possesses antioxidant properties. Since the effect of estrogen on radiation cataractogenesis is unknown, we wished to determine whether estrogen modulates radiation-induced opacification of the lens. Intact or ovariectomized Sprague-Dawley rats were treated with either 17-beta-estradiol or an empty silastic capsule. The right orbit was then irradiated with either 10 or 15 Gy of (60)Co gamma rays using a Leksell Gamma Knife, and lenses were examined at various times postirradiation with a slit lamp or evaluated for light transmission. We found that for ovariectomized rats irradiated with 15 Gy, the lens opacity and the incidence of cataract formation in the estradiol-treated group were significantly increased compared to the control group at the end of the 25-week period of observation. Cataract incidence was also high in irradiated eyes of ovary-intact animals at 25 weeks postirradiation but was greatly reduced in the ovariectomized control group, with less than half of irradiated eyes showing evidence of cataractogenesis. Thus, after irradiation with 15 Gy of gamma rays, estrogen increased the incidence of cataract formation. We also observed that although the incidence of cataract formation in rats irradiated with 10 Gy and receiving continuous estrogen treatment was not altered compared to rats in the control group that did not receive estrogen, the latent period for posterior subcapsular cataract formation decreased and the severity of the anterior cataract increased. Taken together, our data suggest that estrogen accelerates progression of radiation-induced opacification.

Radiotherapy for age related macular degeneration causes transient lens transparency changes

AIMEvaluation of potential side effects of photon radiotherapy on the transparency of the lens.METHODSThe anterior segments of 14 phakic eyes from patients suffering from subfoveal neovascularisation as a result of...

The effect of verapamil in the prevention of radiation-induced cataract

Purpose: Cataract is an unavoidable complication when radiation therapy includes the lens, even in small doses. Alterations in the ion content of the lens were considered to play an essential role in cataract formation. In this experimental study, the effect of verapamil on ion concentrations within the irradiated lenses was investigated in rats. Methods and Materials: Forty female Wistar albino rats, each weighing 180–250 g, were divided into three groups: (a) radiation treated ( n = 10); (b) no treatment ( n = 10); (c) or a combination of radiation and verapamil ( n = 20). Both the radiation group and verapamil-treated group received 5 Gy radiation to the cranium in a single fraction, including the eyes, within the irradiation volume. All animals were sacrificed by bleeding, 7.5 weeks posttreatment. Calcium, sodium, and potassium levels were measured in blood and in lens homogenates. However, for technical reasons, magnesium levels could only be studied in lens homogenates. Results: Potassium and sodium concentrations in lens homogenates did not differ in the control and radiation groups, but both were significantly lower in the verapamil-treated group ( p = 0.001, p = 0.009, respectively). Calcium levels were higher in the radiation group and lower in the verapamil-treated group compared to the controls ( p < 0.0001); magnesium levels did not differ ( p = 0.37). Conclusion: Verapamil effectively decreased the lens calcium concentration, which is accepted as the key element in radiation cataractogenesis. It is therefore concluded that verapamil may reduce the risk of radiation-induced cataract formation.