Objectives Previous analyses of cataract in radiation-exposed populations have assessed relative risk; radiogenic excess additive risk (EAR), arguably of more public health importance, has not been estimated. Previous analysis of a large prospective cohort of US radiologic technologists (USRT) quantified excess relative risk of cataract in relation to occupational radiation dose. We aim to assess EARs of cataract.
Methods We estimated EARs of cataract/cataract surgery in the USRT cohort using generalised additive models in relation to occupational radiation exposure, and assessed risk modification by a priori-selected cataract risk factors (diabetes, body mass index, smoking, race, sex, birth-year, ultraviolet B (UVB) radiation exposure).
Results There were 11 345 cataract diagnoses and 5440 of cataract surgery during 832 462 and 888 402 person-years of follow-up, respectively. Cumulative occupational radiation exposure was associated with self-reported cataract, but not with cataract surgery, with EAR/104 person-year Gy=94 (95% CI: 47 to 143, p<0.001) and EAR/104 person-year Gy=13 (95% CI: <0 to 57, p=0.551), respectively. There was marked (p<0.001) variation of EAR by age and by diabetes status, with risk higher among persons ≥75 years and diabetics. There were indications of elevated risk among those with higher UVB radiation (p=0.045), whites (p=0.056) and among those with higher levels of cigarette smoking (p=0.062). Elevated additive risk was observed for estimated occupational radiation eye-lens doses <100 mGy (p=0.004) with no dose–response curvature (p=0.903).
Conclusions The elevated additive risks associated with low-dose radiation, if confirmed elsewhere, have important public health and clinical implications for radiation workers as well as regulatory measures.
- public health
- diabetes mellitus
- visual defects
- ionising radiation
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What is already known about this subject?
Previous analyses of cataract in radiation-exposed populations have assessed relative risk, with emerging evidence of risk at low doses (<100 mGy).
Radiogenic excess additive cataract risk may be of more importance than relative risk for assessing impact on public health.
What are the new findings?
We observed markedly elevated excess additive risks of cataract in relation to occupational radiation dose in the US radiologic technologists, with excess risk below 100 mGy; there was no elevation in risk of cataract surgery.
Risk was very much higher among persons aged ≥75 years and among patients with diabetes.
How might this impact on policy or clinical practice in the foreseeable future?
The elevated additive risks associated with low-dose radiation have important public health and clinical implications for radiation workers as well as worker protection and regulatory measures, also for those exposed to diagnostic medical exposures such as CT.
Those with diabetes and radiation exposed should be subject to increased surveillance for cataract.
Cataract is one of the major morbidities in the US population, with overall prevalence of ~24% above age 40 years but increasing to ~71% above age 75.1 High radiation doses of 1 Gy or more can induce cataract,2 and accumulating evidence from follow-up studies of the Japanese atomic bomb survivors3–5 and worker populations6–12 suggests that cataracts may be induced by cumulative lower doses, of the order of 100–250 mGy. A recent study of cataract in the US radiologic technologists (USRT) demonstrated cataract risk associated with cumulative ionising radiation exposure below 100 mGy.13 The use of diagnostic CT in the USA is substantial with about 18% of visits to the emergency room associated with use of CT.14 Among persons receiving one or more CTs, it is estimated that about 15% will receive cumulative effective radiation doses of 100 mGy or more.15
All previous studies including our studies have assessed radiogenic relative risk of cataract, and in particular in the only two studies that have examined potential modification of effect by known and suspected non-radiation risk factors (eg, the Japanese atomic bomb survivors and the USRT) have done so in relation to measures of excess relative risk (ERR).4 13 To the best of our knowledge, radiogenic excess additive risk (EAR) (ie, the number of cases per person-year and per unit of dose) has not previously been assessed for cataract, although additive risks have been assessed for radiation and cancer risks.16 The ERR is the proportional increase in risk in the exposed over the risk in the unexposed, whereas the EAR is the additional risk in the exposed above that among the unexposed. The EAR is potentially more important in assessing the impact of an exposure on public health than ERR, by providing an estimate of the number of cases that could potentially be prevented by reducing this exposure.
The objective of this study is to provide the first evaluation of estimated EAR of cataract in relation to highly fractionated low-dose and low-dose-rate radiation exposure. We assessed additive risks of self-reported questionnaire-derived history of cataracts or cataract surgery in the USRT cohort in relation to estimated cumulative absorbed dose to the eye lens from occupational radiation exposures. We examined the degree to which excess additive radiation risk was modified by a broad range of known and suspected risk factors for cataract. We report additive risk at various levels of estimated occupational radiation eye-lens dose.
Data and methods
Population and follow-up
The USRT study has been previously described.13 Four questionnaires (administered during 1983–2014) collected information on health outcomes, work history and other variables.13 Since data on cataract were only elicited in the second through fourth questionnaires, we only included responders to the second or third questionnaire and at least one subsequent questionnaire for follow-up of these ocular endpoints. Exclusions are as previously used so that we censored follow-up after a diagnosis of cancer (other than non-melanoma skin cancer) because of the potential for radiotherapy. After various exclusions (for history of radiotherapy on the first or second surveys, inconsistent questionnaire responses for cataract or cataract surgery, or reporting cataract or cataract surgery in the first questionnaire responded to), all as in the previous analysis13 (and also as detailed in online appendix A figures A1 and A2), there were a total of 67 246 technologists eligible for study of cataract and 67 709 eligible for study of cataract surgery13; a further 3894 technologists were excluded with trivial follow-up (ie, with date of exit from follow-up=date of entry to follow-up), resulting in an analysis cohort for cataract history of 63 352 persons. A similar process, but excluding also 3088 technologists with trivial follow-up resulted in a cohort of 64 621 persons informative for cataract surgery. Among these exclusions were 4502 persons with prevalent cataract history at baseline questionnaire, and 82 cataract surgeries at baseline questionnaire. Follow-up began at the first survey in which lack of cataract was reported, and ended at the earlier of the date the last questionnaire answered, or the date of the first assessed cataract. There was no information elicited on the questionnaires about type of cataract. Additional details are given in our earlier paper.13
Occupational ionising radiation dosimetry
A historical dose reconstruction was undertaken to estimate cumulative annual radiation absorbed doses to the eye lens from occupational exposure for each radiologic technologist13 17 up to 31 December 1997. Doses were lagged by 5 years. Additional details are given elsewhere.13
Ultraviolet cumulative radiant exposure
As discussed elsewhere,18 cataract is thought to result from oxidative stress in the eye lens,19 part of which is likely due to cumulative ultraviolet A (UVA) exposure.20 UVA and ultraviolet B (UVB) are highly correlated, so it is sufficient for our purposes, as an adjusting variable, to use UVB. A standard UVB exposure metric is cumulative UVB radiant exposure (in units of J m−2), which is proportional to cumulative solar UVB energy deposition on a surface over a period of time. This measure of cumulative ambient UVB exposure is recommended by the Commission Internationale de l’Eclairage (International Commission on Illumination).21 We estimated this measure from National Aeronautics Space Administration (NASA) Total Ozone Mapping Spectrometer (TOMS) satellite-based UVB data,22 linkage of which with the USRT we now describe.
On the third questionnaire in the USRT study cohort, city and state of longest residential location for five age periods (age <13, 13–19, 20–39, 40–64 and 64+ years) was collected. The TOMS database (http://toms.gsfc.nasa.gov) maintained by NASA provides a daily estimate of ambient UVB exposure, measured as the irradiance at 305 nm in mW m−2 nm−1,23 in a 1° longitude × 1° latitude grid. Using residential location for the five age periods, ambient UVB irradiance was calculated at each point over the lifetime. The scaling of this measure to provide cumulative UVB radiant exposure used the method previously described.18
A person-year table was generated for the dataset using the variables listed in online appendix table A1. Risks for cataract were assessed using a generalised additive model24 in which the expected number of cases in cell i with associated group (for some modifying variable) m of the tabulation is assumed to be Poisson distributed with mean:
where was the number of person-years of follow-up and was the mean time-varying cumulative 5-year lagged eye lens absorbed dose in Gy, were the lifestyle (eg, cigarette smoking history), environmental (eg, UVB) and medical risk factors (eg, diabetes, obesity), was the EAR coefficient per unit eye lens absorbed dose (Gy) for group m, and were coefficients adjusting for other risk factors. The term allowed for departures from linearity in the dose response. The baseline (zero-dose) group is the group without radiation exposure. The model was fitted via Poisson maximum likelihood,25 using Epicure.26 The baseline (zero-dose) models, given by the terms inside the first exp in expression (1) were chosen using the forward stepwise algorithm, using a p value for selection of p=0.05.25 For cataract surgery, this procedure was modified slightly, resulting in the indicated terms for body mass index (BMI)3, BMI4, BMI5 being dropped from the model because of instability in certain fits. Similar models were used to adjust for baseline risk in figures 1 and 2, using for figure 2 factor terms rather than continuous loglinear adjustments for age, and dropping the adjustment for year of birth, as this led to instability. Cumulative UVB radiant exposure was treated as time-varying, and lagged by 5 years, as previously.13 Because UVB radiation can only be estimated for the subset of persons who answered the third questionnaire, an indicator for UVB missing data was also included in the baseline risk model. The test of heterogeneity conditional on the marginal totals, used in online appendix A table A2, employed a generalisation of Fisher’s exact test, and was evaluated via 107 simulations using the algorithm of Patefield27 in R.28
There were 11 345 technologists with self-reported cataract among 63 352 eligible persons with 832 462 person-years of follow-up; for cataract surgery, there were 5440 cases among 64 621 persons with 888 402 person-years of follow-up (data not shown) (table 1). There were pronounced, and generally highly statistically significant (p<0.001) differences between the groups determined by whether or not they developed cataract or cataract surgery for a number of baseline characteristics (online appendix table A2); only for ethnic group was this heterogeneity not statistically significant. Online appendix table A2 demonstrates that those in each subcohort who had cataract surgery as well as a reported history of cataract were more likely to be male, older at start of follow-up, born earlier in time, had a history of diabetes, currently or formerly smoked cigarettes and had higher cumulative UVB than those who reported a history of cataract only but no cataract surgery. Occupational radiation exposure was strongly associated with self-reported cataract, with an EAR of 94.21/104 person-year Gy (95% CI: 46.67 to 142.9, p<0.001), although there was no such significant association for cataract surgery, with an EAR of 12.98/104 person-year Gy (95% CI: −26.82 to 56.91, p=0.551) (table 1, figure 1). We observed pronounced (p<0.001) variation of radiogenic EAR by attained age (table 1, figure 2), and by diabetes status (both p<0.001) (table 1), with risk higher among older persons (age ≥75 years) and among those with diabetes; there were similar variations of EAR of cataract surgery by attained age (p=0.007) and by diabetes status (p<0.001) (table 1). There was weaker evidence (p=0.045) of heterogeneity of radiation risk between groups characterised according to cumulative UVB radiant exposure, with additive radiation risk increasing among those with higher cumulative UVB, although there were weak indications of non-convergence. Table 1 also shows that there was weaker evidence of heterogeneity by racial group (p=0.056) and by levels of cigarette smoking (p=0.062) and by sex (p=0.080), with risk higher among whites, among those with higher levels of cigarette smoking and for males, but with the first two of these factors there were indications of non-convergence.
Table 2 demonstrates that there was elevated EAR for cumulative dose under 200 mGy with an EAR of 88.09/104 person-year Gy (95% CI: 39.12 to 138.1, p<0.001), and under 100 mGy with an EAR of 81.61/104 person-year Gy (95% CI: 25.10 to 139.2, p=0.004), although not under 50 mGy (p=0.157). Cataract surgery risks were non-significantly negative for all the restricted dose ranges considered (table 2). Table 3 reveals that there was no pronounced curvature in the dose response, either for cataract (p=0.903) or for cataract surgery (p=0.400).
We have documented pronounced EAR of cataract (but not of cataract surgery), with particularly marked excess risk among those with diabetes and in old age (age ≥75 years). Risks remain significantly elevated at dose under 100 mGy, the conventional level determining low-dose exposure.29 30 To the best of our knowledge, this is the first study to estimate EAR of cataract in relation to low-dose radiation exposure. Therefore, we are unable to directly compare our findings with those from other radiation-exposed populations. However, in the previous cataract analysis of the USRT cohort, ERRs were compatible with most other exposed groups.13
EAR is potentially more important in assessing the impact of an exposure on public health than relative risk, as it expresses the additive level of excess risk that a person may be subject to, and the degree of burden on society in relation to provision of health services. In particular, it expresses the excess additive radiation risk in relation to the medical and lifestyle risk factors that may modify risk. We have shown that persons who have diabetes, who therefore have an elevated baseline risk of cataract, are at even higher risk of a radiogenic cataract. Our study suggests that about five excess cases of cataract would be expected among 1000 persons receiving 50 mGy (close to the mean level of exposure of 56 mGy in this cohort13) and followed over 10 years (close to the mean 13.1-year follow-up (table 1)). This suggests that special protective measures may be warranted for persons with diabetes who undergo radiation exposure.
Table 1 and figure 2 demonstrate that the increase in radiogenic EAR with age is not generally at a higher rate than the increase in the underlying background (zero-dose) cataract risk with age. This explains therefore the strongly decreasing modification of radiogenic ERR with increasing age observed in the previous analysis.13 The findings in relation to diabetes are more striking. We previously reported a marked reduction in ERR among those with diabetes,13 whereas we report here a radiogenic EAR among those with diabetes that is markedly elevated, nearly 20 times that among those without this disease (table 1). This may be explained by the fact that the background (zero-dose) cataract risk is much higher among those with diabetes than those without.13
Strengths of the present study include the large population with low (mostly <100 mGy) cumulative protracted radiation doses and low dose rates (mostly < 5 mGy/h) and prospective cohort design. We utilised a comprehensive occupational dosimetry with estimated absorbed doses specific to the eye lens.13 Although a substantial proportion of the estimated cumulative occupational dose is derived from questionnaires,17 the dosimetry has been extensively validated, in particular via chromosome aberrations assayed via fluorescence in situ hybridisation.31 The large number of covariates evaluated was another strength, and the comprehensive work history, demographic, lifestyle and medical factors evaluated facilitated analysis of modifying effects of these variables on the radiation dose response.
Our study had several limitations, particularly the self-report and lack of clinical validation of cataracts. However, the population of radiologic technologists reported here is medically literate so that self-reports of cataract and other medical conditions such as diabetes should be reasonably reliable. All analyses adjust for age, which should largely eliminate the major risk factor for tendency to mis-recall diagnostic information. A related weakness is lack of information on cataract subtype. No information was collected on ocular trauma, which is a well-known risk factor for cataract,32 although relatively rare32 33 and thus unlikely to substantially confound the trend with occupational dose. As with many occupational studies, cohort members had to survive to answer the second questionnaire and be free of cataract at that point. Such selection will not necessarily bias our analysis, since everyone had to survive to answer a questionnaire, and all risk was assessed conditional on that. Follow-up was censored at the date of the last informative questionnaire answered; it is plausible that such censoring was non-informative for cataract.
Of some concern is the discrepancy between the findings for cataract history and cataract surgery, where risks for the latter were somewhat lower and generally not significant (table 1); treating these as independent samples (which they are not) the risks for cataract surgery were significantly lower (p=0.014) than the risks for cataract history (table 1, figure 1). This contrasts with the situation for excess relative risk considered in the previous analysis,13 where the difference in risks between cataract surgery and cataract (again treating them as independent samples, which they are not) was not significant (p=0.366). The rather lower background risks for cataract surgery (by about a factor of about 2 [=11 345/5440 (table 1)]) combined with the approximately twofold lower relative risks for this endpoint (=0.69/0.34)13 will mean that one would expect about fourfold lower additive risks, not far removed (especially if uncertainties are allowed for) from the sevenfold lower risks (table 1 [94.21/12.98]) that we observed. There are differences between those who reported a history of cataract surgery and a history of cataract versus those who reported a history of cataract but no surgery for a number of baseline characteristics; the former were more likely to be male, older at start of follow-up, born earlier in time, had a history of diabetes, currently or formerly smoked cigarettes and had higher cumulative UVB (online appendix table A2). However, we do not regard these as necessarily explaining the differences between the radiation risks for cataract and cataract surgery. Although the baseline characteristics may exhibit heterogeneity of this sort, nevertheless very similar variations in radiation risk by these baseline characteristics are seen for cataract and cataract surgery (table 1). As with the previous analysis of the present cohort using relative risk models,13 a very similar pattern of significant ERR for cataract and non-significant ERR for cataract surgery has also been reported in the Russian Mayak nuclear workers.9 34 Indeed among the various groups that have been studied for radiation-associated cataract, a significant ERR for cataract surgery has been reported only in the Japanese atomic bomb survivors,4 12 35 possibly a consequence of differences in exposure (dose rate) or mean follow-up period from the present cohort or the Mayak workers.35 While some of the USRT subjects may harbour vision impairing cataracts, it is likely that only a proportion of these will further receive cataract surgery, depending on various factors which may include not only the cataract size, severity and location within the eye but also socioeconomic, medical-cost and health consciousness, visual acuity in the opposite eye, the nature of the work or vocational activities affecting the need for visual acuity, and amount of ultraviolet exposure.35 36 Therefore, there is no reason to suppose that cataract surgery prevalence will be simply proportional to cataract prevalence. Even in developed countries not all vision impairing cataracts are treated with cataract surgery.37
In summary, we found a notable increase in EAR of cataract associated with low-dose and low-dose-rate occupational protracted radiation exposure (eg, eye-lens absorbed dose mostly <100 mGy at <5 mGy/h). There was a particularly large EAR among those with diabetes and among those ages≥75 years. The implications for those with diabetes who may experience radiation exposure may be clinically important to consider. The additive risks of cataract that we report have not been assessed in any other study, but the variation in relative risks previously reported13 are comparable with those in other populations evaluated for radiation exposure response. In particular, our findings, if confirmed, have important implications for clinical screening and public health along with consideration of radiation protection and regulatory measures, particularly for physicians performing fluoroscopically guided interventional procedures who have been shown to potentially receive eye-lens doses well over 100 mGy.38 39 Future studies should assess EAR of cataracts along with ERRs in other radiation-exposed occupational groups with clinically ascertained diagnosis of cataract by cataract type, medical record validation of cataract severity/opacity, well-validated dosimetry and high-quality data on relevant lifestyle, environmental and medical risk factors, to ascertain if our findings are confirmed that cataract is inducible by low doses of radiation (at <100 mGy).
The authors would like to thank the Associate Editor and the two referees for their detailed and helpful comments. The authors thank the radiologic technologists who participated in the study, Dr Jerry Reid of the American Registry of Radiologic Technologists for continued support, and Diane Kampa and Allison Iwan of the University of Minnesota for study management and data collection.
Contributors MPL, CMK, EKC, SLS and MSL conceived and designed the study, and produced an analytical plan. MSL and MPL were responsible for acquisition and processing of data (including questionnaire, mortality and cancer validation data). SLS, MSL and MPL were responsible for dose estimation and validation. MPL was responsible for data analysis. MPL, NH, MSL, CMK and EKC interpreted the results. MPL produced a first draft of the manuscript. All authors reviewed the manuscript and provided intellectual input. MPL, CMK, EKC and MSL are guarantors.
Funding This work was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. The views expressed herein by the authors are independent of all funding agencies.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study has been approved annually by the National Cancer Institute Special Studies Institutional Review Board and by the University of Minnesota Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon request.
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