JVIR-D-16

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unfortunately do not routinely use personal dosimeters even when made ... Recently, studies have explored the use of electronic active dosimeters that provide.
Elsevier Editorial System(tm) for Journal of Vascular and Interventional Radiology Manuscript Draft Manuscript Number: JVIR-D-16-00029R2 Title: Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences. Article Type: Review Article Corresponding Author: Dr. Kieran J. Murphy, M.D. Corresponding Author's Institution: University of Toronto First Author: Danyal

Khan

Order of Authors: Danyal Khan; Marie-Constance Rizwana Khan, MD; Kieran J. Murphy, M.D.

Lacass, MD FRCPC;

Abstract: In the high volume and increasingly complex world of image guided therapy and medical imaging, awareness of the potential risks secondary to occupational radiation exposure in medical professionals needs greater focus. One of these risks are radiation-induced cataracts, a recently recognized entity, which may impact the physician's professional proficiency, quality of life and career span. This review article aims to explain the pathogenesis of radiation-induced cataracts, exploring emerging evidence on its development. It also explores the existing monitoring and protection measures available to protect against such radiation-induced pathologies.

Title Page - Include All Author Information

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Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences.

Danyal Zaman Khan 1 Marie Constance Lacasse MD 2 Rizwana Khan MD 1 Kieran PJ Murphy MD FRCPC FSIR 2

1 The Royal College of Surgeons, Dublin, Ireland 2 Toronto Western Hospital, University Health Network, University of Toronto

Corresponding author Kieran Murphy MB FRCPC FSIR Dept of Medical Imaging Toronto Western Hospital University Health Network [email protected]

*Response to Reviewers

MS JVIR-D-16-00029 MANUSCRIPT TITLE: Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences. Point by Point Response to Editor/Reviewers Dear Editors and Reviewers, Thank you very much for conditional acceptance of this article. Here are the point-by-point modifications we made to our manuscript (in red font) in order to address your recommendations. Due to further editing of the article in order to shorten it, some of the specific points mentioned by the reviewers might have been taken out of the article. We hope the new version of our manuscript will satisfy you. Regards,

REVIEWER #3 COMMENTS -There is a discrepancy between the title and some of the contents. -Amended to: Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences. -First line of an abstract: "Radiation-induced cataracts secondary to occupational exposure is a disease specific to the interventional radiology field". This pathology needs to be urgently recognized as one of the main occupational risk to the interventional radiologist, leading to early cataract surgery in middle-aged successful professionals. These statement are misleading and unacceptable*. -Amended to: In the rapidly evolving world of medical imaging, awareness about the potential risks secondary to occupational radiation exposure in medical professionals has to be emphasized. One of such risks are radiation-induced cataracts, a recently recognized entity, which may impact the physician’s professional proficiency, quality of life and career span. -All Fluoroscopy guided interventionalists are at risk and not IR's only. -Agreed, although IR's and radiation technologists represent a group of particular concern and hence are the focus of many of major studies in this field which is why our focus was directed towards them in the “Occupational radiation exposure studies: dose accumulation and cataract prevalence” section. -Moreover, it's not specific, there are various degrees of the problem, when the Cataract is the most advanced and irreversible one. -Mentioned at Pathogenesis section: “The principal proposed mechanism of PSCCs is radiation damage to germinative zone dividing cells [4], which induces a short period of mitotic inhibition at the basement membrane, followed by overcompensation with disorganized abnormal mitoses [8, 9]. This results in accumulation of aberrantly organized and shaped lens fiber cells with pyknotic nuclei that are theorized to produce the cloudy lentoid body at the PSC region [6]. This manifests histologically as small dots and vacuoles of opacification, which progressively coalesce overtime to form larger conglomerates, eventually causing visual impairment if left untreated [10].” -We talk about posterior subcapsular opacification of various degrees. -The Merriam-Focht system and LOCS III systems were both mentioned.

REVIEWER #4 COMMENTS -Addressing the 85% left sided distribution: The original article does not claim statistical significance of the findings; the known left-right dose distribution is about 65%-35% for cardiologists and essentially no gradient (50-50) for radiologists. -Amended statement to illustrate the suggestive but not statistical signifigant nature of the finding: ‘These specific tumors are known for their potential to be radiation-induced [22], with some case cohorts observing an 85% left-sided dominance, thought to possibly be secondary to the more direct radiation exposure to this area during interventional procedures [21].” -Addressing the technologists: The references do not provide dose related correlations; the possibility of other causes of the findings (beyond radiation) in the IR environment are not discussed. The assumption in the references and much of the other recent literature that all adverse findings are radiogenic is not supported. -Presuming this is refering to the 2008, Chodick et al. study, it states ”we found a significant association between history of three or more diagnostic x-rays to the face or neck and increased risk of cataract” which we used to in conjugation with other studies to simply imply a suggestion of a possible risk of cataractogenesis at low radiation doses and hence as a reason to be concerned. Thus, the paragraph was adjusted according to emphasize the possibility of increased risk suggested by this study as opposed a conclusive correlation.

-Turning to the aims of the paper: Data for cataracts are presented only as embedded text; there are no summary tables or figures. The paper does not critically compare the reported findings, something that one would expect in a review paper. Section 3 a) similarly presents a listing of radiation monitoring and protective devices without any substantial advice on their applicability. Table I is simply a non-critically reviewed listing of radiation management techniques. -Results: Results are presented as text in a disorganized manner. No tables of comparative findings are provided -Discussion: There is no critical discussion of the findings. Advice on radiation reduction methods are not critically reviewed or discussed -Tables: A review paper should synthesize the findings in tabular format. One is trying to understand the consistency of the literature in order to draw conclusions. -The hetrogenous nature of the methods of cataract classification systems, measering lens dosing and availabilities of protective equipment across centres & specialities served to greatly complicate the simplication of the data into tabular format. Hence, the text format was chosen to present the information in a logical order of paragraphs. Where possible and appropiate, we attempted to highlight areas of concern based on current literature: -“ In order to decrease chronic radiation exposure, there has to be strict adherence and appropriate use of the active (patient dose reduction techniques) and passive (room and personal protection devices) components of radiation protection” -“ Finally, to achieve the greatest reduction in dose exposure, room-shielding equipment must be combined with personal protective devices.” -“ Although current technology has the ability to provide major protective benefits to physicians, unnecessarily high dose protocols and poor compliance needs to be addressed in future guidelines.” -Materials and Methods: Cited literature seems to be a random selection rather than a comprehensive review. No description of systematic methods of literature review, comprehensive literature review, table of data that could be abstracted or reviewed by readers (esp compared with other review) -Added a Materials and Methods section with our search stragedy in Table 1

-Summary : My impression is that this manuscript is an uncritically reviewed dive into the literature. A good and critical review of this topic would be very timely. Can the authors increase the rigor of their reporting, by methods used to search for literature (eg PRISMA), provide a literature table, etc? These would be parts of all useful reviews for scholarly journals and would be important. -Added a Materials and Methods section with a search stragedy figure.

*Clean Revised Manuscript - No Author Information Click here to view linked References

COMPLETE MANUSCRIPT TITLE: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Radiation Cataractogenesis: The Progression of our Understanding and its Clinical Consequences.

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Manuscript Type: Review Article 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Word Count:4527

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BMI: Body mass index CI: Confidence interval DSA: Digital subtraction angiography ERCP: Endoscopic retrograde cholangiopancreatography EVAR: Endovascular aortic repair IAEA: International atomic energy agency ICRP: International commission on radiological protection LOCS: Lens opacities classifications system NCRP: National council on radiation protection and measurements OCCCGS: Oxford clinical cataract classification and grading system O’CLOC: Occupational cataracts and lens opacities in interventional cardiology OR: Odds ratio PSC: Posterior sub-capsular RELID: Retrospective evaluation of lens injuries and dose UNSCEAR: United Nations scientific committee on the effects of atomic radiation UVB: Ultraviolet B WHO: World health organization

Key words: cataractogenesis, radiation-induced cataracts, interventional radiology, radiation protection.

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ABSTRACT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

In the high volume and increasingly complex world of image guided therapy and medical imaging, awareness of the potential risks secondary to occupational radiation exposure in medical professionals needs greater focus. One of these risks are radiation-induced cataracts, a recently recognized entity, which may impact the physician’s professional proficiency, quality of life and career span. This review article aims to explain the pathogenesis of radiation-induced cataracts, exploring emerging evidence on its development. It also explores the existing monitoring and protection measures available to protect against such radiation-induced pathologies..

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INTRODUCTION Radiation-induced cataracts secondary to occupational exposure represent a recently recognized entity. In the rapidly expanding world of medical imaging and image guided therapy, awareness about the potential radiation risks to medical professionals has to be emphasized. Knowledge and constant reinforcement of the basic radiation protection principles needs to be implemented to decrease unnecessary radiation exposure. Thus, this article explores our development of understanding of the pathogenesis of radiation induced cataracts and its close link with radiation-induced oncogenesis. This is followed by discussion of existing monitoring and protection measures available to protect against such radiationinduced pathologies.

MATERIALS AND METHODS We obtained anatomic pathology specimens of human lens with posterior chamber catarcts (Figure 1,2,3,4). A systematic literature search was performed by the authors using the PubMed database (US National Library of Medicine, National Institutes of Health) and the following initial terms: “radiation-induced cataracts” and “lens occupational radiation monitoring and protection”. Any further searches were more specific to source information regarding radiation-induced oncologic pathologies of relevance to the scope of this paper. Inclusion criteria for initial literature searches were broad and as follows: full-text articles, publications in English, between the years 1950-2016 with the subject matter on radiation-induced cataracts pathogenesis, lens dose monitoring or radiation protection strategies. The exclusion criteria were formed from the converse of the inclusion criteria. By reading the titles or abstracts, the same authors excluded studies not fulfilling the parameters set by the inclusion and exclusion criteria. Each remaining article was reviewed and relevant information was extracted if in congruence with the scope of the paper. This information is presented as part of the paper’s results and discussion. This search strategy is presented in (Figure 5).

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RESULTS AND DISCUSSION 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

1.The Pathogenesis of Radiation-Induced Cataracts: Modern cataract surgery uses an emulscification process to minimize incision size no anatomic specimens are obtained. After extensive searching we found anatomic pathology of the human lens in a pathology museum. The unique structure of the lens is fundamental to its refraction capabilities, and is the basis for its high radiosensitivity and unique pathology, cataracts [1] (Figure 1). The development of cataracts results from the opacification of the lens [1]. It is the main cause of blindness worldwide, and second reason for visual impairment after uncorrected refractive errors [2]. Age-related "senile" cataracts are the most common type of cataracts [3].

Cataracts are the classified anatomically into nuclear, cortical and posterior subcapsular (PSC) subtypes [1]. Nuclear and cortical cataracts develop from pathological changes within the lens fiber cells, while PSC cataracts (PSCCs) are associated with abnormalities at the germinative zone of the lens [1, 4] (Figures 2-4). PSCCs are most commonly associated with ionizing radiation exposure(2), followed by cortical cataracts [5]. However, other contributive factors to PSC cataract development include lack of endogenous antioxidants and steroid use [6, 7].

Cataract pathogenesis is not fully understood and is most likely multifactorial, involving numerous genetic and environmental factors. The principal proposed mechanism of PSCCs is radiation damage to germinative zone dividing cells [4], which induces a short period of mitotic inhibition at the basement membrane, followed by overcompensation with disorganized abnormal mitoses [8, 9]. This results in accumulation of aberrantly organized and shaped lens fiber cells with pyknotic nuclei that are theorized to produce the cloudy lentoid body at the PSC region [6]. This manifests histologically as small dots and vacuoles of opacification, which progressively coalesce overtime to form larger conglomerates, eventually causing visual impairment if left untreated [10]. Relatively minor opacities to the posterior pole of the lens’ visual axis lead to significant visual impairment [10]. Interestingly, PSCCs have been viewed as the “cancer-like pathology” of the lens [4] 6

as the ionizing radiation also damages specific genes involved in DNA repair and cell 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

cycle control which are usually attributed to the process of carcinogenesis [4].

2. Emerging evidence and its consequences on the understanding:

a) Major influencing factors for radiation-induced cataractogenesis: Many factors have been shown to influence the development of radiation-induced cataractogenesis. Age is the single most important risk factor, with a 15% increased risk for each year of life [11, 12]. Other risk factors identified include female sex, marital status (single), low socioeconomic status, >15 packs/year smoking history, >25kg/ m2 body mass index (BMI), increased alcohol consumption, diabetes, hypertension, hypercholesterolemia as well as chronic use of systemic steroids [11, 12]. However, most of the previously stated risk factors also affect the incidence of non-radiation-induced cataracts, such as senile cataracts [3], which complicates the analysis of radiation-induced cataractogenesis prevalence.

Lately, there has been increased interest in identifying specific genetic variations influencing individual susceptibility to radiation-induced cataracts following radiation exposure [13]. These potential genetic factors complicate the elaboration of safety guidelines which currently assume relative homogeneity of radio-sensitivity within populations [7]. In animals, earlier appearance of radiation-induced cataractogenesis was found in mice nullizygous or heterozygous for the DNA repair genes ATM, RAD9 and BRCA 1 [14, 15]. Indeed, human ATM polymorphisms were found in atomic bomb survivors, and seemed to modify the risk of undergoing cataract surgery [16]. Interestingly, heterozygosity for the ATM gene has been estimated in 13% of the United States population [17]. BRCA 1 and 2 germ line mutations are found in 2% of the Ashkenazi Jewish population. If some interventionalists are more radiosensitive that others should consideration be given to genetic screening for those with deminished DNA repair ability?

b) Radiation-induced oncogenesis: In the last few years, it was hypothesized that radiation cataractogenesis may possibly function as a stochastic process [6, 18, 19]. Indeed, Hamada et al. 7

proposed that the lack of a dose rate effect may suggest there is only an initial 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

accumulation of damage from radiation needed within the lens tissue in order to trigger the stochastic process [6]. This stochastic relationship with radiation exposure is also evident in radiation-induced oncogenesis, which is emerging as an important group of pathologies to investigate when exploring radiation exposure to the head region,

A particularly concerning group of oncological entities in close proximity to the eye are brain neoplasms, however, current evidence for a direct causal relationship between brain tumors and chronic occupational radiation is suggestive but not conclusive, due to small sample sizes and lack of follow-up [20]. Nonetheless, when anecdotal reports of clustering are considered, the issues become quite concerning [20]. For example, a 2013 case study identified 31 cases of brain cancers in interventionalists including glioblastoma multiforme (17/31), meningioma (5/31) and astrocytoma (2/31) [21]. These specific tumors are known for their potential to be radiation-induced [22], with some case cohorts observing an 85% left-sided dominance, thought to possibly be secondary to the more direct radiation exposure to this area during interventional procedures [21]. Furthermore, a recent observational study performed on technologists working with radiation showed a twofold increased risk of brain cancer mortality, and mild elevations in the incidence of melanoma and breast cancer when compared to technologists never exposed to radiation [23].

Furthermore, although specific genes have not yet been conclusively identified, epidemiological studies, as mentioned earlier, have displayed variations in radiation sensitivity amongst particular sub-populations, which may important implications regarding radiation-induced oncogenesis of the head and reck [24].

c) Dosing of radiation: concepts and mechanisms understood: As mentioned earlier, there is still uncertainty about the exact pathogenesis of cataracts. The knowledge is also scarce on the relationship between cataract development, dose protraction and latency period, as well the stochastic versus deterministic nature of radiation-induced cataracts [4].

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In April 2011, following emerging evidence from numerous studies, the International 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Commission on Radiological Protection (ICRP) reviewed its previous 2007 guidelines concerning lens dose thresholds for radiation cataractogenesis [25, 26]. The eye lens absorbed dose threshold was established at 500mSv for lifetime exposure, and decreased from 150mSv to 20mSv per year for the annual occupational exposure limit [25, 26]. The annual occupational exposure limit now has to be averaged over 5 years, with no single year to exceed 50mSv [25]. The slim evidence for the risk lowering effect of dose protraction has suggested it did not significantly affect the threshold dose [18, 19]. Data on the latency period is also scarce and suggests an inverse relationship between dose and latency [27]. In order to better understand the decision of the ICRP to significantly decrease the radiation thresholds for professionals, knowledge of the studies that led to those changes is essential.

Field studies: investigations of dose thresholds and dose effects: In 2007, Neriishi et al. analyzed the radiation dose exposure and dose response of 3,761 atomic bomb survivors, including 479 postoperative cataract cases [28]. Neriishi et al. found an increased cataract prevalence with a dose of 1Gy at an odds ratio (OR) of 1.39 [28] . Within the 0- 1Gy range, a non-significant dose threshold of 0.1Gy was seen [28]. These results advocated for a far lower threshold than the 2007 ICRP recommendations, and also suggested the concept of a no threshold, dose-response relationship between radiation exposure and cataractogenesis [28]. Previous research also supported Neriishi et al.’s conclusions. At 1Gy exposure, a study by Hall et al. reported a 1.49 OR for PSC in infants treated with radiation therapy for skin hemangiomas [5] and Worghul et al. reported an OR of 1.42 for PSC cataracts [29] when examining 8,607 Chernobyl clean-up workers. These studies reporting an increased risk of cataracts with low doses of radiation supported the idea of a threshold as low as 0.5Gy, or no threshold at all [13, 18, 19].

Occupational radiation exposure studies: dose accumulation and cataract prevalence: Multiple epidemiological and clinical studies investigating occupational radiation exposure to healthcare professionals have confirmed the prevalence of radiation9

induced cataracts in the medical community. In 2008, Chodick et al. published 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

results of a 1983-2004 cohort study of 35,705 US radiology technologists (initially cataract free), aged 24–44 years, followed-up using two detailed questionnaires [11]. They reported 2,382 cataracts and 647 cataract extractions, with 25% of the cataracts occurring before 50 years of age [11]. Results showed a mean radiation dose to the lens of 28.1mGy in the entire cohort and after being adjusted for other known confounding factors, suggested a possible risk of cataractogenesis at low radiation doses [11]. Just three or more diagnostic head or neck x-rays were found to increase the risk of cataractogenesis [11]. The dose to risk of cataract relationship was strongest with subjects younger than 50 years old, with PSC cataracts being the most prevalent type of opacity found in this age group [11]. Furthermore, a study on Finnish physicians reported an OR for any lens opacities of 0.13 (95% CI -0.02-0.28) per 10mSv of whole body cumulative effective dose [12].

Organizations such as the ICRP, the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), the International Atomic Energy Agency (IAEA) and the National Council on Radiation Protection and Measurements (NRCP) have also attempted to raise awareness and evaluate the risk of cataracts from a chronic occupational radiation exposure by publishing annual reports and guidelines and initiating collaborative studies [25, 26, 30-32]. In the last few years, the steady increase in the number of medical procedures requiring radiation has led the UNSCEAR group to undertake a task force in order to analyse and record worldwide radiation exposures coming from the medical field [32]. In an epidemiological study by the O’CLOC group in 2013, Jacob et al. investigated the risk of cataract in French interventional cardiologists and electrophysiologists [10, 33]. The retrospective assessment showed a cumulative eye lens exposure ranging from 25 to over 1600mSv, as estimated by taking into account the number of procedures done, the average radiation dose per procedure, and the various radiation protection equipment utilized [33]. A mean exposure of 423mSv was found for a mean working time of 22 years , with an OR of 3.8 (1.3–11.4) for the development of PSC in exposed medical personnel compared to non-exposed controls [33]. This data suggested that approximately 25% of these professionals were over the revised ICRP threshold of 500mSv [33]. Furthermore, the new ICRP annual exposure limit of 20 mSv/year was surpassed a minimum of once by 60% of cardiologists during the 10

study period [33]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Indeed, interventional cardiologists have become the focus of many similar studies attempting to estimate occupational lens dose and cataract prevalence in this group. Ciraj-Bjelac et al.’s study found a lifetime cumulative dose to the lens of 3.7±7.5Gy (0.02-43Gy) over an average of 9 working years [34], while Vano et al. found a cumulative occupational lens dose of 6.0±6.6Sv (0.1-27Sv) over a mean working time of 14 years [35]. These results were, like the O’CLOC study, estimated from the numbers of procedures performed by the interventionalist, the baseline eye lens dose per procedure type, and the radiation protection conditions [33]. The doses were likely overestimated in these studies, since lens opacities were found in only 38% of participants in Vano et al. [35], less than what would be expected with medians of such high values [33]. The wide discrepancies between estimated levels of exposure and the PSCC incidence was hypothesized to be secondary to a lack of systematic monitoring, leading to inaccurate estimates of occupational exposure [33]. However, all these studies ultimately did show an increase in the crude relative risk of radiation cataractogenesis, which was still significant after being adjusted for confounding factors and compared with the control subject [33-35].

Another important source of discrepancies in studies reporting the prevalence of PSC cataracts comes from the use of different classification systems and grading schemes available. For example, the reported prevalence of PSC opacities in the O’CLOC, Vano et al., and Ciraj-Bjelac et al. studies were evaluated at 17%, 38% and 52% respectively [10, 34, 35]. Ciraj-Bjelac et al. and Vano et al. both used a modified Merriam-Focht system specifically designed for posterior lens opacities [36], while the O’CLOC study used the Lens Opacities Classification System III (LOCS III) [37], a system that evaluates and grades any type of cataract. With LOCS III, the ophthalmologist compares the morphology of the lens fiber in all regions of the lens (nuclear, cortical and PSC), and compares it to reference slides in order to determine the severity of the opacities in each region [37]. All these grading systems also differ in the methods used to assess the opacities, including dilated slit-lamp biomicroscopy, retro illumination and Scheimpflug imaging [6]. These factors constitute a major limiting factor when comparing studies, and further complicate pooled analysis [6]. Hence, for future studies, standardization of the cataract grading 11

systems and is critical for an effective analysis of prevalence [6]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

3. Protocol, clinical applications and their issues:

a) Monitoring and protection: Radiation dose monitoring devices are essential to assess the physician’s occupational risk. Because of the lack of a direct quantification method to measure eye lens dose, studies such as the O’CLOC, Vano et al., and Ciraj-Bjelac et al. studies have sought to use various formulae to estimate retrospective assessment of eye lens exposure [33-35]. These methods are not reliable or reproducible for the assessment of radiation dose, due to inherent differences in patients, physicians, procedures and protective equipment used [38, 39]. Furthermore, many physicians unfortunately do not routinely use personal dosimeters even when made available [40].

Hp(3) is the most accurate operational quantity for the eye lens dose [41]. However, the dosimeters provided to clinicians often only include effective dose/whole-body dosimeter Hp(10) and local skin dose/partial body dosimeter Hp(0.07), and calibration for Hp(3) is impossible[40, 41]. In this context, Hp(0.07) is used to provide the closest dose estimate to the lens [38, 40].

Recently, studies have explored the use of electronic active dosimeters that provide physicians with real-time maximum dose rates and total cumulative dose for a single procedure [42, 43]. Such devices could serve as an occupational dose education and awareness tool for physicians, while potentially increasing compliance to protective equipment and other dose reduction techniques [42, 43].

In order to decrease chronic radiation exposure, there has to be strict adherence and appropriate use of the active (patient dose reduction techniques) and passive (room and personal protection devices) components of radiation protection (Table 1).

Radiation to the eye in the fluoroscopy room mainly comes from scatter radiation from the patient [44, 45]. Central to any dose reduction strategy is first and foremost 12

to decide if the exam to be performed is clinically indicated, and if the use of the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

fluoroscopy guidance is essential. If the procedure is deemed appropriate, careful planning of the procedure to optimize the use of radiation is necessary [44]. Strategies to reduce radiation dose to the patient include shorter fluoroscopy time, decreased frame rate, use of collimation, avoidance of magnification, decreased digital subtraction angiography (DSA) sequences acquisitions, increased distance between the source and the patient, and decreased distance between the patient and the image receptor [44].

Passive strategies such as room shielding devices protect against the scatter radiation, and include ceiling-suspended shields and shielded drapes [44]. Ceilingsuspended shields, when used properly, were shown to reduce occupational exposure doses by up to 100-fold and therefore should always be used if interventionalist positioning is not compromised as a result [44]. Similarly, drapes placed around the image intensifier was shown to provide an approximate 90% dose exposure reduction to the endoscopist during endoscopic retrograde cholangiopancreatography (ERCP) [45]. Other measures to reduce scatter radiation include using protective disposable shielded drapes, which showed a 23% reduction in total radiation dose to the operators in a randomized controlled trial [46], and dose reduction to the hands and chest of interventionalists of 49% and 55% respectively during endovascular aortic repair (EVAR) procedures [47].

Finally, to achieve the greatest reduction in dose exposure, room-shielding equipment must be combined with personal protective devices. These include protective aprons, thyroid shields, gloves and eyewear for physicians [44]. The use of lead eyewear that is properly fitted and has lateral eye shielding can reduce eye lens dose by a factor of 2.1 for the tube side eye, and 0.8 for the non-tube side eye [48]. Unfortunately, evidence suggests poor compliance with only 25% of interventionalists and 36% of cardiologists wearing glasses during the procedures [41]. Although current technology has the ability to provide major protective benefits to physicians, ineffective protocols and poor compliance needs to be addressed in future guidelines.

b) Proficiency and treatment procedure: 13

Without comprehensive evidence-based guidelines, effective dose monitoring tools 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

and the use of appropriate protective equipment and dose-reducing strategies, physicians are at risk of pathological manifestations from their occupational radiation exposure. This might impact on the physician’s professional proficiency, quality of life and career span [6]. For example, because of their central position, PSCCs may cause significant visual impairment and decrease contrast sensitivity and present a specific surgical group of patients that is likely to be younger than the majority of "senile" cataract patients [49].

CONCLUSION Throughout this paper, the numerous potential risk factors of cataractogenesis were presented, and the pathogenesis of radiation-induced cataracts was reviewed. A brief parallel was made between radiation-induced cataractogenesis and oncogenesis, two process that share multiple similarities. The recent IRCP guidelines changes were described, and the studies which led to these changes were presented. Future areas of research include the study of specific genetic traits that could potentially affect an individual’s vulnerability to radiation, and more precise and homogeneous ophthalmologic diagnostic tools for the diagnosis of PSC cataracts. In the current interventional radiology field, there is an urgent need to recognize that there is no safe dose of radiation. Will we one day see Posterior Chamber Cataracts as the canary in the cold mine? In order to prevent the detrimental effects of occupational radiation on health workers, there must be a strict worldwide application of the recent lower radiation threshold guidelines, a more effective means of monitoring radiation exposure, and finally, the consistent use of appropriate radiation protection strategies.

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Von Sallmann, L., Experimental studies on early lens changes after roentgen irradiation. III. Effect of x-radiation on mitotic activity and nuclear fragmentation of lens epithelium in normal and cysteine-treated rabbits. AMA Arch Ophthalmol, 1952. 47(3): p. 305-20.

10.

Jacob, S., et al., Interventional cardiologists and risk of radiation-induced cataract: results of a French multicenter observational study. Int J Cardiol, 2013. 167(5): p. 1843-7.

11.

Chodick, G., et al., Risk of cataract after exposure to low doses of ionizing radiation: a 20-year prospective cohort study among US radiologic technologists. Am J Epidemiol, 2008. 168(6): p. 620-31.

12.

Mrena, S., et al., Lens opacities among physicians occupationally exposed to ionizing radiation--a pilot study in Finland. Scand J Work Environ Health, 2011. 37(3): p. 237-43.

13.

Hammer, G.P., et al., Occupational exposure to low doses of ionizing radiation and cataract development: a systematic literature review and perspectives on future studies. Radiat Environ Biophys, 2013. 52(3): p. 303-19.

15

14. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Worgul, B.V., et al., Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts. Proc Natl Acad Sci U S A, 2002. 99(15): p. 9836-9.

15.

Kleiman, N.J., et al., Mrad9 and atm haploinsufficiency enhance spontaneous and Xray-induced cataractogenesis in mice. Radiat Res, 2007. 168(5): p. 567-73.

16.

Neriishi, K., Hayashi, T., Nakashima, E., Imai, K., Nakachi, K., ATM haplotypes and radiosensitivity in A-bomb survivors – preliminary trial using existing data at RERF., in Abstract Book of Radiation Cataractogenesis Workshop 2009. 2009: Hiroshima, Japan, RERF.

17.

Swift, M., et al., Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med, 1987. 316(21): p. 1289-94.

18.

Ainsbury, E.A., et al., Radiation cataractogenesis: a review of recent studies. Radiat Res, 2009. 172(1): p. 1-9.

19.

Bouffler, S., et al., 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. J Radiol Prot, 2012. 32(4): p. 479-88.

20.

Picano, E., et al., Cancer and non-cancer brain and eye effects of chronic low-dose ionizing radiation exposure. BMC Cancer, 2012. 12: p. 157.

21.

Roguin, A., et al., Brain and neck tumors among physicians performing interventional procedures. Am J Cardiol, 2013. 111(9): p. 1368-72.

22.

Flint-Richter, P. and S. Sadetzki, Genetic predisposition for the development of radiation-associated meningioma: an epidemiological study. Lancet Oncol, 2007. 8(5): p. 403-10.

23.

Rajaraman, P., et al., JOURNAL CLUB: Cancer Risks in U.S. Radiologic Technologists Working With Fluoroscopically Guided Interventional Procedures, 1994. AJR Am J Roentgenol, 2016: p. 1-9.

24.

Hricak, H., et al., Managing radiation use in medical imaging: a multifaceted challenge. Radiology, 2011. 258(3): p. 889-905.

25.

ICRP, Statement on Tissue Reactions, in ref. 4825-3093-1464, ICRP, Editor. 2011. Available on http://www.icrp.org/docs/icrp statement on tissue reactions.pdf.

26.

ICRP, The 2007 Recommendations of the International Commission on Radiological Protection, in Publication 103, ICRP, Editor. 2007, Elsevier.

16

27. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Merriam, G.R., Jr. and B.V. Worgul, Experimental radiation cataract--its clinical relevance. Bull N Y Acad Med, 1983. 59(4): p. 372-92.

28.

Neriishi, K., et al., Postoperative cataract cases among atomic bomb survivors: radiation dose response and threshold. Radiat Res, 2007. 168(4): p. 404-8.

29.

Worgul, B.V., et al., Cataracts among Chernobyl clean-up workers: implications regarding permissible eye exposures. Radiat Res, 2007. 167(2): p. 233-43.

30.

IAEA, IAEA Annual Report 2012- Human Health. 2012. p. 41-44.

31.

NCRP, NCRP Annual Report 2011. 2011. p. 66.

32.

UNSCEAR, Sources and Effects of Ionizing Radiation Vol. 1. 2000. p. 1-203.

33.

Jacob, S., et al., Eye lens radiation exposure to interventional cardiologists: a retrospective assessment of cumulative doses. Radiat Prot Dosimetry, 2013. 153(3): p. 282-93.

34.

Ciraj-Bjelac, O., et al., Risk for radiation-induced cataract for staff in interventional cardiology: is there reason for concern? Catheter Cardiovasc Interv, 2010. 76(6): p. 826-34.

35.

Vano, E., et al., Radiation cataract risk in interventional cardiology personnel. Radiat Res, 2010. 174(4): p. 490-5.

36.

Merriam, G.R., Jr. and E.F. Focht, A clinical and experimental study of the effect of single and divided doses of radiation on cataract production. Trans Am Ophthalmol Soc, 1962. 60: p. 35-52.

37.

Chylack, L.T., Jr., et al., The Lens Opacities Classification System III. The Longitudinal Study of Cataract Study Group. Arch Ophthalmol, 1993. 111(6): p. 831-6.

38.

IAEA. Radiation and cataract : Staff protection. 2013 [cited 2015 July 17]; Available from: https://rpop.iaea.org/RPOP/RPoP/Content/InformationFor/HealthProfessional s/6_OtherClinicalSpecialities/radiation-cataract/Radiation-and_cataract.htm CAT_FAQ11.

39.

Ciraj-Bjelac, O. and M.M. Rehani, Eye dosimetry in interventional radiology and cardiology: current challenges and practical considerations. Radiat Prot Dosimetry, 2014. 162(3): p. 329-37.

40.

Duran, A., et al., Recommendations for occupational radiation protection in interventional cardiology. Catheter Cardiovasc Interv, 2013. 82(1): p. 29-42. 17

41. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Vanhaverea F., C.E., Domienikc J., Donadilled L., Ginjaumee M., Gualdrinif G., Koukoravab C., Krima S., Nikodemovag D., Ruiz-Lopezh N., Sans-Merceh M. and L. Struelensa, Measurements of eye lens doses in interventional radiology and cardiology: Final results of the ORAMED project. Radiation Measurements, November 2011. 46(11): p. p.1243-1247.

42.

Vano, E., et al., Occupational radiation doses in interventional cardiology: a 15year follow-up. Br J Radiol, 2006. 79(941): p. 383-8.

43.

Prlic, I., M. Suric Mihic, and Z. Vucic, Active electronic personal dosemeter in interventional radiology. Radiat Prot Dosimetry, 2008. 132(3): p. 308-12.

44.

Bartal, G., et al., Management of patient and staff radiation dose in interventional radiology: current concepts. Cardiovasc Intervent Radiol, 2014. 37(2): p. 289-98.

45.

Muniraj, T., et al., A double-blind, randomized, sham-controlled trial of the effect of a radiation-attenuating drape on radiation exposure to endoscopy staff during ERCP. Am J Gastroenterol, 2015. 110(5): p. 690-6.

46.

Politi, L., et al., Reduction of scatter radiation during transradial percutaneous coronary angiography: a randomized trial using a lead-free radiation shield. Catheter Cardiovasc Interv, 2012. 79(1): p. 97-102.

47.

Kloeze, C., et al., Editor's choice--Use of disposable radiation-absorbing surgical drapes results in significant dose reduction during EVAR procedures. Eur J Vasc Endovasc Surg, 2014. 47(3): p. 268-72.

48.

van Rooijen, B.D., et al., Efficacy of radiation safety glasses in interventional radiology. Cardiovasc Intervent Radiol, 2014. 37(5): p. 1149-55.

49.

Elliott, D.B. and P. Situ, Visual acuity versus letter contrast sensitivity in early cataract. Vision Res, 1998. 38(13): p. 2047-52.

18

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Figure Legends

Figure 1. Normal lens showing (1) lens capsule, (2) peripheral lens fiber, (3) nucleus with higher concentration of lens fibers, (4) iris, (5) cornea, (6) ciliary body, (7) artifact.

Figure 2. Posterior sub-capsular cataract showing (1) presence of a layer of epithelial cells under the posterior capsule which have migrated from the equatorial cells, (2) the lens fibers still maintain some normal appearance.

Figure 3. Posterior sub-capsular cataract with (1) epithelial cells under the posterior lens capsule that have migrated from the equator or lens bow cells, (2) artifacts.

Figure 4. Nuclear cataract showing (1) lens fibers have lost their concentric lamination giving rise to homogenous eosinophilic appearance, (2) separation of lens fibers during slide processing, (3) artifact.

Figure 5 Search strategy

19

*Revised Manuscript with Tracked Changes - No Author Information

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1

COMPLETE MANUSCRIPT TITLE:

2

Radiation Cataractogenesis: The Progression of our Understanding and its

3

Clinical Consequences.

4 5 6

1

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Manuscript Type: Review Article

8 9

Word Count:4257.

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10

Abbreviations:

11

BMI: Body mass index

12

CI: Confidence interval

13

DSA: Digital subtraction angiography

14

ERCP: Endoscopic retrograde cholangiopancreatography

15

EVAR: Endovascular aortic repair

16

IAEA: International atomic energy agency

17

ICRP: International commission on radiological protection

18

LOCS: Lens opacities classifications system

19

NCRP: National council on radiation protection and measurements

20

OCCCGS: Oxford clinical cataract classification and grading system

21

O’CLOC: Occupational cataracts and lens opacities in interventional cardiology

22

OR: Odds ratio

23

PSC: Posterior sub-capsular

24

RELID: Retrospective evaluation of lens injuries and dose

25

UNSCEAR: United Nations scientific committee on the effects of atomic radiation

26

UVB: Ultraviolet B

27

WHO: World health organization

28 29

Key words: cataractogenesis, radiation-induced cataracts, interventional radiology,

30

radiation protection.

31

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ABSTRACT

33 34

In the high volume and increasingly complex world of image guided therapy and

35

medical imaging, awareness of the potential risks secondary to occupational

36

radiation exposure in medical professionals needs greater focus. One of these risks

37

are radiation-induced cataracts, which may impact the physician’s professional

38

proficiency, quality of life and career span. This review article aims to explain the

39

pathogenesis of radiation-induced cataracts, exploring emerging evidence on its

40

developmenrt. It also explores the existing monitoring and protection measures

41

available to protect against such radiation-induced pathologies.It is important that

42

interventionalists realise that annual lens dose limits have been lowered to 1/7 of

43

previous levels. They also should be aware that the cataracts that occur in this

44

context are fundamentally different in pathogenesis and anatomic location to

45

common senile cataracts.

4

46 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

47

INTRODUCTION

48

Radiation-induced cataracts secondary to occupational exposure represent a

49

recently recognized entity. In the rapidly expanding world of medical imaging and

50

image guided therapy, awareness about the potential radiation risks to medical

51

professionals has to be emphasized. Knowledge and constant reinforcement of the

52

basic radiation protection principles needs to be implemented to decrease

53

unnecessary radiation exposure. Thus, this article explores our development of

54

understanding of the pathogenesis of radiation induced cataracts and its close link

55

with radiation-induced oncogenesis. This is followed by discussion of existing

56

monitoring and protection measures available to protect against such radiation-

57

induced pathologies.

58 59

MATERIALS AND METHODS

60

We obtained anatomic pathology specimens of human lens with posterior chamber

61

catarcts (Figure 1,2,3,4). A systematic literature search was performed by the

62

authors using the PubMed database (US National Library of Medicine, National

63

Institutes of Health) and the following initial terms: “radiation-induced cataracts” and

64

“lens occupational radiation monitoring and protection”. Any further searches were

65

more specific to source information regarding radiation-induced oncologic

66

pathologies of relevance to the scope of this paper. Inclusion criteria for initial

67

literature searches were broad and as follows: full-text articles, publications in

68

English, between the years 1950-2016 with the subject matter on radiation-induced

69

cataracts pathogenesis, lens dose monitoring or radiation protection strategies. The

70

exclusion criteria were formed from the converse of the inclusion criteria. By reading

71

the titles or abstracts, the same authors excluded studies not fulfilling the parameters

72

set by the inclusion and exclusion criteria. Each remaining article was reviewed and

73

relevant information was extracted if in congruence with the scope of the paper. This

74

information is presented as part of the paper’s results and discussion. This search

75

strategy is presented in (Table1Figure 5).

76 77

5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

78

RESULTS AND DISCUSSION

79

1.The Pathogenesis of Radiation-Induced Cataracts:

80

Modern cataract surgery uses an emulscification process to minimize incision size

81

no anatomic specimens are obtained. After extensive searching we found anatomic

82

pathology of the human lens in a pathology museum. The unique structure of the

83

lens is fundamental to its refraction capabilities, and is the basis for its high radio-

84

sensitivity and unique pathology, cataracts [1] (Figure 1). The development of

85

cataracts results from the opacification of the lens [1]. It is the main cause of

86

blindness worldwide, and second reason for visual impairment after uncorrected

87

refractive errors [2]. Age-related "senile" cataracts are the most common type of

88

cataracts [3].

89 90

Cataracts are the classified anatomically into nuclear, cortical and posterior sub-

91

capsular (PSC) subtypes [1]. Nuclear and cortical cataracts develop from

92

pathological changes within the lens fiber cells, while PSC cataracts (PSCCs) are

93

associated with abnormalities at the germinative zone of the lens [1, 4] (Figures 2-4).

94

PSCCs are most commonly associated with ionizing radiation exposure(2), followed

95

by cortical cataracts [5]. However, other contributive factors to PSC cataract

96

development include lack of endogenous antioxidants and steroid use [6, 7].

97 98

Cataract pathogenesis is not fully understood and is most likely multifactorial,

99

involving numerous genetic and environmental factors. The principal proposed

100

mechanism of PSCCs is radiation damage to germinative zone dividing cells [4],

101

which induces a short period of mitotic inhibition at the basement membrane,

102

followed by overcompensation with disorganized abnormal mitoses [8, 9]. This

103

results in accumulation of aberrantly organized and shaped lens fiber cells with

104

pyknotic nuclei that are theorized to produce the cloudy lentoid body at the PSC

105

region [6]. This manifests histologically as small dots and vacuoles of opacification,

106

which progressively coalesce overtime to form larger conglomerates, eventually

107

causing visual impairment if left untreated [10]. Relatively minor opacities to the

108

posterior pole of the lens’ visual axis lead to significant visual impairment [10].

109 110

Interestingly, PSCCs have been viewed as the “cancer-like pathology” of the lens [4] 6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

111

as the ionizing radiation also damages specific genes involved in DNA repair and cell

112

cycle control which are usually attributed to the process of carcinogenesis [4].

113 114

2. Emerging evidence and its consequences on the understanding:

115 116

a) Major influencing factors for radiation-induced cataractogenesis:

117

Many factors have been shown to influence the development of radiation-induced

118

cataractogenesis. Age is the single most important risk factor, with a 15% increased

119

risk for each year of life [11, 12]. Other risk factors identified include female sex,

120

marital status (single), low socioeconomic status, >15 packs/year smoking history,

121

>25kg/ m2 body mass index (BMI), increased alcohol consumption, diabetes,

122

hypertension, hypercholesterolemia as well as chronic use of systemic steroids [11,

123

12]. However, most of the previously stated risk factors also affect the incidence of

124

non-radiation-induced cataracts, such as senile cataracts [3], which complicates the

125

analysis of radiation-induced cataractogenesis prevalence.

126 127

Lately, there has been increased interest in identifying specific genetic variations

128

influencing individual susceptibility to radiation-induced cataracts following radiation

129

exposure [13]. These potential genetic factors complicate the elaboration of safety

130

guidelines which currently assume relative homogeneity of radio-sensitivity within

131

populations [7]. In animals, earlier appearance of radiation-induced cataractogenesis

132

was found in mice nullizygous or heterozygous for the DNA repair genes ATM,

133

RAD9 and BRCA 1 [14, 15]. Indeed, human ATM polymorphisms were found in

134

atomic bomb survivors, and seemed to modify the risk of undergoing cataract

135

surgery [16]. Interestingly, heterozygosity for the ATM gene has been estimated in 1-

136

3% of the United States population [17]. BRCA 1 and 2 germ line mutations are

137

found in 2% of the Ashkenazi Jewish population. If some interventionalists are more

138

radiosensitive that others should consideration be given to genetic screening for

139

those with deminished DNA repair ability?

140 141

b) Radiation-induced oncogenesis:

142

In the last few years, it was hypothesized that radiation cataractogenesis may

143

possibly function as a stochastic process [6, 18, 19]. Indeed, Hamada et al. 7

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

144

proposed that the lack of a dose rate effect may suggest there is only an initial

145

accumulation of damage from radiation needed within the lens tissue in order to

146

trigger the stochastic process [6]. This stochastic relationship with radiation exposure

147

is also evident in radiation-induced oncogenesis, which is emerging as an important

148

group of pathologies to investigate when exploring radiation exposure to the head

149

region,

150 151

A particularly concerning group of oncological entities in close proximity to the eye

152

are brain neoplasms, however, current evidence for a direct causal relationship

153

between brain tumors and chronic occupational radiation is suggestive but not

154

conclusive, due to small sample sizes and lack of follow-up [20]. Nonetheless, when

155

anecdotal reports of clustering are considered, the issues become quite concerning

156

[20]. For example, a 2013 case study identified 31 cases of brain cancers in

157

interventionalists including glioblastoma multiforme (17/31), meningioma (5/31) and

158

astrocytoma (2/31) [21]. These specific tumors are known for their potential to be

159

radiation-induced [22], with some case cohorts observing an 85% left-sided

160

dominance, thought to possibly be secondary to the more direct radiation exposure

161

to this area during interventional procedures [21]. Furthermore, a recent

162

observational study performed on technologists working with radiation showed a

163

twofold increased risk of brain cancer mortality, and mild elevations in the incidence

164

of melanoma and breast cancer when compared to technologists never exposed to

165

radiation [23].

166 167

Furthermore, although specific genes have not yet been conclusively identified,

168

epidemiological studies, as mentioned earlier, have displayed variations in radiation

169

sensitivity amongst particular sub-populations, which may important implications

170

regarding radiation-induced oncogenesis of the head and reck [24].

171 172

c) Dosing of radiation: concepts and mechanisms understood:

173

As mentioned earlier, there is still uncertainty about the exact pathogenesis of

174

cataracts. The knowledge is also scarce on the relationship between cataract

175

development, dose protraction and latency period, as well the stochastic versus

176

deterministic nature of radiation-induced cataracts [4].

177 8

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

178

In April 2011, following emerging evidence from numerous studies, the International

179

Commission on Radiological Protection (ICRP) reviewed its previous 2007

180

guidelines concerning lens dose thresholds for radiation cataractogenesis [25, 26].

181

The eye lens absorbed dose threshold was established at 500mSv for lifetime

182

exposure, and decreased from 150mSv to 20mSv per year for the annual

183

occupational exposure limit [25, 26]. The annual occupational exposure limit now has

184

to be averaged over 5 years, with no single year to exceed 50mSv [25]. The slim

185

evidence for the risk lowering effect of dose protraction has suggested it did not

186

significantly affect the threshold dose [18, 19]. Data on the latency period is also

187

scarce and suggests an inverse relationship between dose and latency [27]. In order

188

to better understand the decision of the ICRP to significantly decrease the radiation

189

thresholds for professionals, knowledge of the studies that led to those changes is

190

essential.

191 192

Field studies: investigations of dose thresholds and dose effects:

193

In 2007, Neriishi et al. analyzed the radiation dose exposure and dose response of

194

3,761 atomic bomb survivors, including 479 postoperative cataract cases [28].

195

Neriishi et al. found an increased cataract prevalence with a dose of 1Gy at an odds

196

ratio (OR) of 1.39 [28] . Within the 0- 1Gy range, a non-significant dose threshold of

197

0.1Gy was seen [28]. These results advocated for a far lower threshold than the

198

2007 ICRP recommendations, and also suggested the concept of a no threshold,

199

dose-response relationship between radiation exposure and cataractogenesis [28].

200 201

Previous research also supported Neriishi et al.’s conclusions. At 1Gy exposure, a

202

study by Hall et al. reported a 1.49 OR for PSC in infants treated with radiation

203

therapy for skin hemangiomas [5] and Worghul et al. reported an OR of 1.42 for PSC

204

cataracts [29] when examining 8,607 Chernobyl clean-up workers. These studies

205

reporting an increased risk of cataracts with low doses of radiation supported the

206

idea of a threshold as low as 0.5Gy, or no threshold at all [13, 18, 19].

207 208

Occupational radiation exposure studies: dose accumulation and cataract

209

prevalence:

210

Multiple epidemiological and clinical studies investigating occupational radiation

211

exposure to healthcare professionals have confirmed the prevalence of radiation9

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

212

induced cataracts in the medical community. In 2008, Chodick et al. published

213

results of a 1983-2004 cohort study of 35,705 US radiology technologists (initially

214

cataract free), aged 24–44 years, followed-up using two detailed questionnaires [11].

215

They reported 2,382 cataracts and 647 cataract extractions, with 25% of the

216

cataracts occurring before 50 years of age [11]. Results showed a mean radiation

217

dose to the lens of 28.1mGy in the entire cohort and after being adjusted for other

218

known confounding factors, suggested a possible risk of cataractogenesis at low

219

radiation doses [11]. Just three or more diagnostic head or neck x-rays were found to

220

increase the risk of cataractogenesis [11]. The dose to risk of cataract relationship

221

was strongest with subjects younger than 50 years old, with PSC cataracts being the

222

most prevalent type of opacity found in this age group [11]. Furthermore, a study on

223

Finnish physicians reported an OR for any lens opacities of 0.13 (95% CI -0.02-0.28)

224

per 10mSv of whole body cumulative effective dose [12].

225 226

Organizations such as the ICRP, the United Nations Scientific Committee on the

227

Effects of Atomic Radiation (UNSCEAR), the International Atomic Energy Agency

228

(IAEA) and the National Council on Radiation Protection and Measurements (NRCP)

229

have also attempted to raise awareness and evaluate the risk of cataracts from a

230

chronic occupational radiation exposure by publishing annual reports and guidelines

231

and initiating collaborative studies [25, 26, 30-32]. In the last few years, the steady

232

increase in the number of medical procedures requiring radiation has led the

233

UNSCEAR group to undertake a task force in order to analyse and record worldwide

234

radiation exposures coming from the medical field [32]. In an epidemiological study

235

by the O’CLOC group in 2013, Jacob et al. investigated the risk of cataract in French

236

interventional cardiologists and electrophysiologists [10, 33]. The retrospective

237

assessment showed a cumulative eye lens exposure ranging from 25 to over

238

1600mSv, as estimated by taking into account the number of procedures done, the

239

average radiation dose per procedure, and the various radiation protection

240

equipment utilized [33]. A mean exposure of 423mSv was found for a mean working

241

time of 22 years , with an OR of 3.8 (1.3–11.4) for the development of PSC in

242

exposed medical personnel compared to non-exposed controls [33]. This data

243

suggested that approximately 25% of these professionals were over the revised

244

ICRP threshold of 500mSv [33]. Furthermore, the new ICRP annual exposure limit of

245

20 mSv/year was surpassed a minimum of once by 60% of cardiologists during the 10

246 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

study period [33].

247 248

Indeed, interventional cardiologists have become the focus of many similar studies

249

attempting to estimate occupational lens dose and cataract prevalence in this group.

250

Ciraj-Bjelac et al.’s study found a lifetime cumulative dose to the lens of 3.7±7.5Gy

251

(0.02-43Gy) over an average of 9 working years [34], while Vano et al. found a

252

cumulative occupational lens dose of 6.0±6.6Sv (0.1-27Sv) over a mean working

253

time of 14 years [35]. These results were, like the O’CLOC study, estimated from the

254

numbers of procedures performed by the interventionalist, the baseline eye lens

255

dose per procedure type, and the radiation protection conditions [33]. The doses

256

were likely overestimated in these studies, since lens opacities were found in only

257

38% of participants in Vano et al. [35], less than what would be expected with

258

medians of such high values [33]. The wide discrepancies between estimated levels

259

of exposure and the PSCC incidence was hypothesized to be secondary to a lack of

260

systematic monitoring, leading to inaccurate estimates of occupational exposure

261

[33]. However, all these studies ultimately did show an increase in the crude relative

262

risk of radiation cataractogenesis, which was still significant after being adjusted for

263

confounding factors and compared with the control subject [33-35].

264 265

Another important source of discrepancies in studies reporting the prevalence of

266

PSC cataracts comes from the use of different classification systems and grading

267

schemes available. For example, the reported prevalence of PSC opacities in the

268

O’CLOC, Vano et al., and Ciraj-Bjelac et al. studies were evaluated at 17%, 38% and

269

52% respectively [10, 34, 35]. Ciraj-Bjelac et al. and Vano et al. both used a modified

270

Merriam-Focht system specifically designed for posterior lens opacities [36], while

271

the O’CLOC study used the Lens Opacities Classification System III (LOCS III) [37],

272

a system that evaluates and grades any type of cataract. With LOCS III, the

273

ophthalmologist compares the morphology of the lens fiber in all regions of the lens

274

(nuclear, cortical and PSC), and compares it to reference slides in order to determine

275

the severity of the opacities in each region [37]. All these grading systems also differ

276

in the methods used to assess the opacities, including dilated slit-lamp bio-

277

microscopy, retro illumination and Scheimpflug imaging [6]. These factors constitute

278

a major limiting factor when comparing studies, and further complicate pooled

279

analysis [6]. Hence, for future studies, standardization of the cataract grading 11

280 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

systems and is critical for an effective analysis of prevalence [6].

281 282

3. Protocol, clinical applications and their issues:

283 284

a) Monitoring and protection:

285

Radiation dose monitoring devices are essential to assess the physician’s

286

occupational risk. Because of the lack of a direct quantification method to measure

287

eye lens dose, studies such as the O’CLOC, Vano et al., and Ciraj-Bjelac et al.

288

studies have sought to use various formulae to estimate retrospective assessment of

289

eye lens exposure [33-35]. These methods are not reliable or reproducible for the

290

assessment of radiation dose, due to inherent differences in patients, physicians,

291

procedures and protective equipment used [38, 39]. Furthermore, many physicians

292

unfortunately do not routinely use personal dosimeters even when made available

293

[40].

294 295

Hp(3) is the most accurate operational quantity for the eye lens dose [41]. However,

296

the dosimeters provided to clinicians often only include effective dose/whole-body

297

dosimeter Hp(10) and local skin dose/partial body dosimeter Hp(0.07), and

298

calibration for Hp(3) is impossible[40, 41]. In this context, Hp(0.07) is used to provide

299

the closest dose estimate to the lens [38, 40].

300 301

Recently, studies have explored the use of electronic active dosimeters that provide

302

physicians with real-time maximum dose rates and total cumulative dose for a single

303

procedure [42, 43]. Such devices could serve as an occupational dose education

304

and awareness tool for physicians, while potentially increasing compliance to

305

protective equipment and other dose reduction techniques [42, 43].

306 307

In order to decrease chronic radiation exposure, there has to be strict adherence and

308

appropriate use of the active (patient dose reduction techniques) and passive (room

309

and personal protection devices) components of radiation protection (Table 12).

310 311

Radiation to the eye in the fluoroscopy room mainly comes from scatter radiation

312

from the patient [44, 45]. Central to any dose reduction strategy is first and foremost 12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

313

to decide if the exam to be performed is clinically indicated, and if the use of the

314

fluoroscopy guidance is essential. If the procedure is deemed appropriate, careful

315

planning of the procedure to optimize the use of radiation is necessary [44].

316

Strategies to reduce radiation dose to the patient include shorter fluoroscopy time,

317

decreased frame rate, use of collimation, avoidance of magnification, decreased

318

digital subtraction angiography (DSA) sequences acquisitions, increased distance

319

between the source and the patient, and decreased distance between the patient

320

and the image receptor [44].

321 322

Passive strategies such as room shielding devices protect against the scatter

323

radiation, and include ceiling-suspended shields and shielded drapes [44]. Ceiling-

324

suspended shields, when used properly, were shown to reduce occupational

325

exposure doses by up to 100-fold and therefore should always be used if

326

interventionalist positioning is not compromised as a result [44]. Similarly, drapes

327

placed around the image intensifier was shown to provide an approximate 90% dose

328

exposure reduction to the endoscopist during endoscopic retrograde cholangio-

329

pancreatography (ERCP) [45]. Other measures to reduce scatter radiation include

330

using protective disposable shielded drapes, which showed a 23% reduction in total

331

radiation dose to the operators in a randomized controlled trial [46], and dose

332

reduction to the hands and chest of interventionalists of 49% and 55% respectively

333

during endovascular aortic repair (EVAR) procedures [47].

334 335

Finally, to achieve the greatest reduction in dose exposure, room-shielding

336

equipment must be combined with personal protective devices. These include

337

protective aprons, thyroid shields, gloves and eyewear for physicians [44]. The use

338

of lead eyewear that is properly fitted and has lateral eye shielding can reduce eye

339

lens dose by a factor of 2.1 for the tube side eye, and 0.8 for the non-tube side eye

340

[48]. Unfortunately, evidence suggests poor compliance with only 25% of

341

interventionalists and 36% of cardiologists wearing glasses during the procedures

342

[41]. Although current technology has the ability to provide major protective benefits

343

to physicians, ineffective protocols and poor compliance needs to be addressed in

344

future guidelines.

345 346

b) Proficiency and treatment procedure: 13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

347

Without comprehensive evidence-based guidelines, effective dose monitoring tools

348

and the use of appropriate protective equipment and dose-reducing strategies,

349

physicians are at risk of pathological manifestations from their occupational radiation

350

exposure. This might impact on the physician’s professional proficiency, quality of life

351

and career span [6]. For example, because of their central position, PSCCs may

352

cause significant visual impairment and decrease contrast sensitivity and present a

353

specific surgical group of patients that is likely to be younger than the majority of

354

"senile" cataract patients [49].

355 356

CONCLUSION

357

Throughout this paper, the numerous potential risk factors of cataractogenesis were

358

presented, and the pathogenesis of radiation-induced cataracts was reviewed. A

359

brief parallel was made between radiation-induced cataractogenesis and

360

oncogenesis, two process that share multiple similarities. The recent IRCP

361

guidelines changes were described, and the studies which led to these changes

362

were presented. Future areas of research include the study of specific genetic traits

363

that could potentially affect an individual’s vulnerability to radiation, and more precise

364

and homogeneous ophthalmologic diagnostic tools for the diagnosis of PSC

365

cataracts. In the current interventional radiology field, there is an urgent need to

366

recognize that there is no safe dose of radiation. Will we one day see Posterior

367

Chamber Cataracts as the canary in the cold mine? In order to prevent the

368

detrimental effects of occupational radiation on health workers, there must be a strict

369

worldwide application of the recent lower radiation threshold guidelines, a more

370

effective means of monitoring radiation exposure, and finally, the consistent use of

371

appropriate radiation protection strategies.

14

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

372

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Kleiman, N.J., Radiation cataract. Ann ICRP, 2012. 41(3-4): p. 80-97.

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retrospective assessment of cumulative doses. Radiat Prot Dosimetry, 2013.

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Catheter Cardiovasc Interv, 2012. 79(1): p. 97-102.

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47.

Kloeze, C., et al., Editor's choice--Use of disposable radiation-absorbing surgical

486

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487

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48.

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van Rooijen, B.D., et al., Efficacy of radiation safety glasses in interventional radiology. Cardiovasc Intervent Radiol, 2014. 37(5): p. 1149-55.

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Elliott, D.B. and P. Situ, Visual acuity versus letter contrast sensitivity in early cataract. Vision Res, 1998. 38(13): p. 2047-52.

492 493 494 495 496 497 498 499 500 18

501 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

502 503 504 505 506 507 508 509 510 511

Table 1. Our search strategy for exploring the relevant literature.

512 513 514 515 516

Table 2. Protective measures to decrease radiation exposure in interventional

517

radiology.

518 Passive

Personal protection

Protective glasses Lead apron Lead gloves Thyroid shield

Room-specific protection

Suspended screens Suspended drapes Disposable shielded drapes

Active

Operator-specific

Decrease length of

strategies

fluoroscopy Decrease frame rate Use collimation Avoid magnification Decrease number of DSA acquisitions Increase distance between 19

patient and source 1 2 3 4 5 6 7 8 9 10 11 519 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Decrease distance between patient and image receptor Increase distance between operator and source if possible

20

520 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Figure Legends

521 522 523

Figure 1. Normal lens showing (1) lens capsule, (2) peripheral lens fiber, (3) nucleus

524

with higher concentration of lens fibers, (4) iris, (5) cornea, (6) ciliary body, (7)

525

artifact.

526 527

Figure 2. Posterior sub-capsular cataract showing (1) presence of a layer of

528

epithelial cells under the posterior capsule which have migrated from the equatorial

529

cells, (2) the lens fibers still maintain some normal appearance.

530 531

Figure 3. Posterior sub-capsular cataract with (1) epithelial cells under the posterior

532

lens capsule that have migrated from the equator or lens bow cells, (2) artifacts.

533 534

Figure 4. Nuclear cataract showing (1) lens fibers have lost their concentric

535

lamination giving rise to homogenous eosinophilic appearance, (2) separation of lens

536

fibers during slide processing, (3) artifact.

537 538

Figure 5. Search Strategy

21

Figure 1 Click here to download high resolution image

Figure 2 Click here to download high resolution image

Figure 3 Click here to download high resolution image

Figure 4 Click here to download high resolution image

Figure 5

Records identified through database search of keywords: (n=455)

Full text articles available: (n=297)

Articles excluded upon review of abstract: (n=99)

Exclusion due to non-English language: (n=10)

Exclusion due to publication prior to the years 1950-2016: (n=2)

Articles included upon review of abstract: (n=198)

Exclusion due to the lack of subject matter on radiationinduced cataracts pathogenesis, lens dose monitoring or radiation protection strategies: (n=87)

Full text articles assessed and included as part of review: (n=49)

Full text articles assessed and excluded due to the lack of subject matter on radiationinduced cataracts pathogenesis, lens dose monitoring or radiation protection strategies: (n=149)

Table1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Table 2. Protective measures to decrease radiation exposure in interventional radiology.

Passive

Personal protection

Protective glasses Lead apron Lead gloves Thyroid shield

Room-specific protection

Suspended screens Suspended drapes Disposable shielded drapes

Active

Operator-specific

Decrease length of

strategies

fluoroscopy Decrease frame rate Use collimation Avoid magnification Decrease number of DSA acquisitions Increase distance between patient and source Decrease distance between patient and image receptor Increase distance between operator and source if possible

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

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