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Abstract
Objectives We investigated the association between low-dose external occupational radiation exposure and circulatory disease morbidity among diagnostic medical radiation workers.
Methods A cohort of 11 500 diagnostic medical radiation workers was linked with the National Dosimetry Registry data and the National Health Insurance Service data. Relative risks (RRs) were calculated to explore the association between occupational factors and circulatory disease morbidity, and excess relative risks per 100 milligray (ERR/100 mGy) were estimated to quantify the radiation dose-response relationship.
Results Overall, there were 2270 cases of circulatory diseases during 93 696 person-years of observation (average follow-up=8.1 years). RRs for hypertension were significantly increased for individuals who started working before 2000 compared with those who started in 2005 and later. ERR/100 mGy for all circulatory diseases was 0.14 (95% CI −0.57 to 0.99). Radiation risks of cerebrovascular diseases and ischaemic heart disease were non-significantly increased with estimates of individual cumulative doses to the heart (ERR/100 mGy=3.10 (−0.75 to 11.59) and 1.22 (−0.71 to 4.73), respectively). However, ERR estimates were generally more strongly positive for female versus male workers and for younger workers versus more than 50-year-old workers.
Conclusions This study provides little evidence in support of a positive association between occupational radiation exposure and the overall risk of circulatory disease over a short follow-up period among medical radiation workers in South Korea. However, significantly increased RR with earlier year first worked, elevated ERR in female workers and young workers should be further followed up.
- radiation
- epidemiology
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Key messages
What is already known about this subject?
High dose of radiation exposure has been known as a risk factor for circulatory disease.
However, evidence of low-dose radiation effects on circulatory disease is unclear.
The number of medical radiation workers is rapidly increasing worldwide.
What are the new findings?
Little evidence in support of a positive association between the overall risk of circulatory disease and exposure to low-dose radiation was observed among the diagnostic medical radiation workers.
The excess relative risk of morbidity due to circulatory diseases was significantly higher in female than male workers and for cerebrovascular diseases than for other subtypes of circulatory disease.
The findings were not significantly affected by adjustment for non-radiation lifestyle risk factors.
How might this impact on policy or clinical practice in the foreseeable future?
Our findings provide evidence of the radiation risks for morbidity according to the types of circulatory disease.
Careful monitoring for radiation protection is warranted to protect medical radiation workers from potential health risks.
Introduction
Diseases of the circulatory system are leading causes of morbidity and mortality among adults worldwide, representing one third of all global deaths in 2016 (https://www.who.int/data/gho/). As a risk factor for circulatory diseases (CDs), it has been determined that high-dose radiation could cause damage to the heart and the coronary and other large arteries, both in patients receiving radiotherapy and in experimental animals.1 Therapeutic doses of ionising radiation to the heart and large arteries have been shown to be associated with all CDs, cardiovascular disease and stroke in patients treated with radiotherapy for peptic ulcer,2 breast cancer3 and childhood cancer.4
The association between lower doses and CD remains, however, controversial. Studies of atomic bomb survivors showed dose-related increases for heart disease and stroke,5–8 and studies of patients who received diagnostic X-ray fluoroscopic exposures also provided evidence of increased radiation-associated risks of death from all CDs and ischaemic heart diseases (IHD).9 10 However, there is no direct evidence on the effects of radiation at doses less than 0.5 Sv.5 6
Studies of cohorts with occupational exposure to radiation have not provided clear evidence for or against radiation-associated increase in CDs.11 In 2010, a review reported a small, but statistically significant excess relative risk per Gy (ERR/Gy) of 0.09 for CD at the occupational and environmental dose level.12 A study of nuclear workers in 15 countries provided little evidence for CD risk,13 while studies of Mayak nuclear workers and the INWORKS study have reported significant associations between occupational radiation and CD.14 15 Although there are few studies of medical workers exposed to X-ray radiation and the risk of CD, US radiologic technologists reported an increased risk of CD.16 17 A study of workers at Italian interventional cardiology laboratories suggested increased risks of hypertension and hypercholesterolemia in the radiation exposed group,18 whereas mortality rates for CDs among British radiologists were significantly lower than expected for medical practitioners.19
A study on diagnostic medical workers in South Korea was initiated in 2012 to examine associations between low-dose X-ray occupational radiation exposure and the risk of cancer and other chronic diseases.20 Medical radiation workers have a higher proportion of female workers than nuclear energy workers and they are exposed to varying radiation exposure conditions that are more relevant to the general public. Here, we present the results of dose-response analyses for CD morbidity due to low-dose radiation exposure to X-ray radiation in medical radiation workers after accounting for the effects of non-radiation risk factors.
Methods
Study population
The study design of the Korean diagnostic medical workers’ study has been previously described.21 Briefly, we conducted the self-administered questionnaire survey via postal methods (43.2%), internet (27.6%), on-site visit (16.9%) and fax (12.3%) and merged them with the National Dosimetry Registry (NDR) data in cooperation with related professional societies and the Korean Center for Disease Control and Prevention. A total of 12 387 out of the 19 560 diagnostic radiologic technologists (63.3%) in service in 2012 responded to the questionnaire, while only small proportions of other diagnostic medical workers responded to the survey. We applied deterministic linkage methods by using name, birth year, month and day. In South Korea, a 13-digit resident registration number (RRN) is issued to all residents. The RRN included in the NDR database was used to link with the National Health Insurance Service (NHIS) data and the national cancer registry. Cases with CD were ascertained using International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes from healthcare utilisation records in NHIS data.
The study population comprised 12 902 diagnostic radiation workers who were linked with both the dosimetry data and the health data. Further, those with any CD prior to enrolment of the cohort (n=749) and diagnosed with CD in 2006 (n=455) were excluded to rule out prevalent cases. We also excluded workers diagnosed with cancer (n=140) based on the national cancer registry data follow-up until 2013, because they may include cases arising from cardiotoxicity due to medical treatment and additional medical radiation for cancer. We also excluded those with incorrect year first worked (n=58); thus, 11 500 workers were included in the final cohort for analysis.
The majority of the cohort comprised radiologic technologists (n=10 147, 88.2%) and others included radiologists, dentists, dental hygienists, nurses, physicians and other medical assistants. The present study was reviewed and approved by the Korea University Institutional Review Board (KU-IRB-12–12-A-1). Signed informed consent was voluntarily obtained from all individual study participants prior to enrolment.
Dosimetry
The Korean Center for Disease Control and Prevention maintains the NDR system for all diagnostic radiation medical workers since 1996. For the evaluation of personal occupational radiation dose, historical dose reconstruction was performed for workers who began working with radiation before 1996, using an annual dose model that described doses as a log-linear function of calendar year and age at the year of exposure.22 Organ-specific doses were estimated as the product of the individual badge doses, and two conversion coefficients were provided by the International Commission on Radiological Protection (ICRP): organ-absorbed dose per unit of air kerma free-in-air23 and personal dose equivalent per unit of air kerma free-in-air.24 We estimated heart doses by considering relevant uncertainty factors such as apron usage, badge location and dominant energy of the diagnostic radiation fields.22 More details of dose reconstruction and organ dose estimation are presented in the online supplementary materials.
Supplemental material
CDs and non-radiation risk factors
CD and non-radiation risk factors were ascertained by the NHIS data from 2006 to 2016. NHIS data are stored in a public database on healthcare utilisation and health screening for the entire population of South Korea, created by the NHIS.25 The healthcare utilisation database includes information on records of inpatient and outpatient usage and contains primary and secondary diagnostic codes according to the ICD-10. CDs were defined as those having the primary diagnostic code for the entire group of diseases of the circulatory system (ICD-10 coded as I00–I99), excluding haemorrhoids (I84). The disease was categorised as CD excluding cerebrovascular disease (CeVD) and others (I00–I52), CeVD (I60–I69) or others (I70–I99, except I84). CD excluding CeVD and others was classified as hypertension (I10–I15) and IHD (I20–I25). The initial episode of hospital admission or visit during the 1 January 2007 to 31 December 2016 study period was treated as one incident case of CD.
Non-radiation risk factors for CD were obtained from the NHIS general health screening database. The NHIS conducts an annual general health screening programme for the insured self-employed, insured employees and their dependents. The record of general health screening at baseline during the 2006–2016 study period was used in the study. Health screening items included blood pressure (BP), cholesterol level, blood glucose level and consultation information such as past medical history, smoking, alcohol intake and family medical history. We categorised each variable for analyses, as follows: smoking (never, former, current), alcohol intake (0–1 day per week, 2 days per week, ≥3 days per week), body mass index (BMI; <18.5 kg/m2, 18.5–24.9, 25.0–29.9, ≥30.0 kg/m2), BP (<120 mm Hg of systolic BP and <80 mm Hg of diastolic BP, 120≤systolic BP<140 or 80≤diastolic BP<90, ≥140 mm Hg of systolic BP or ≥90 mm Hg of diastolic BP), total cholesterol (<200 mg/dL, 200–239 mg/dL, ≥240 mg/dL), low-density lipoprotein cholesterol (<100 mg/dL, 100–129 mg/dL, 130–159 mg/dL, ≥160 mg/dL), high-density lipoprotein cholesterol (<40 mg/dL, 40–59 mg/dL, ≥60 mg/dL) and blood glucose (<110 mg/dL, 110–125 mg/dL, ≥126 mg/dL).
Statistical analysis
Each individual contributed person-years at risk from 1 January 2007 or from the year of start of work based on the NDR, whichever occurred later, up to the exit date of 31 December 2016, or the date of diagnosis of CDs or death, whichever occurred earlier. The person-years at risk were classified by sex, attained age (<30, 30 s, 40 s, ≥50 years), calendar time (2006–2010, 2011–2016), year of birth (<1960, 1960–1969, 1970–1979, ≥1980), year first worked (<1995, 1995–1999, 2000–2004, ≥2005), duration of employment and cumulative heart dose. Person-year-weighted mean cumulative doses and duration of employment were treated as time-dependent variables in each cross-classified cell in the regression analyses. To examine the impact of the possible confounding factors on radiation risk estimates, further stratification was made for risk factor variables such as smoking, alcohol intake, BMI, BP, cholesterol level, blood glucose level and family history of CD.
Relative risks (RRs) were calculated to explore the relationship between occupational characteristics and the morbidity of CD after adjusting for potential risk factors including smoking, alcohol drinking, family history of CD, BP, BMI, cholesterol and blood glucose. To analyse the relationship between cumulative heart dose and CD morbidity, we used a linear ERR model. The primary ERR models used here are as follows: 
, where s, a, b and d denote sex, attained age, birth year and occupational radiation dose, respectively. 
is the disease rate at dose d, 
is the background rate depending on sex, attained age and year of birth. We used continuous variables for attained age and birth year. The variables were selected based on the deviance and Akaike Information Criterion of each model.
δ
was an estimate of the ERR per 100 mGy of heart dose (ERR/100 mGy). To examine the impact of possible confounding factors on radiation risk estimates, lifestyle factors (smoking and alcohol intake), family history of CD and physical examination data such as BMI, BP, total cholesterol level and blood glucose level were additionally included in the models. The primary model used to evaluate the dose-response assumes a linear dose-response relationship, but we also evaluated a linear-quadratic model for dose. In addition, analyses were performed by subgroups (sex, attained age, year of birth, year of starting work and total years worked) and heterogeneity of risk estimates was tested using likelihood ratio tests. Sensitivity analyses were conducted by excluding workers who were employed for less than 1 year, by restricting to radiologic technologists, and by using cumulative brain dose. The doses were lagged by 10 years, similar to several studies on radiation exposure and CD risk;10 13 additional analyses were conducted using a latent period of 5 years and without a latent period. Regression parameters and 95% CIs were obtained using the maximum likelihood method with the AMFIT module in Epicure software (Risk Sciences International, V.2.0, Ottawa, Canada).
Results
Among the 11 500 Korean diagnostic radiation workers, there were 93 696 person-years accumulated with an average of 8.1 follow-up years (table 1). Most of the workers were men, born in 1970 or later, and first worked in 2000 or later. A total of 2270 cases of CD (1678 for men, 592 for women) were identified during follow-up (2007–2016). Most CD cases began working before 2000 (57%) and worked for 10 or more years (63%). The proportions of men, smokers, heavy alcohol drinkers, obese individuals and individuals with high BP, blood cholesterol and blood glucose were significantly higher among all CD cases. The mean cumulative heart dose of all CD cases was significantly higher (7.9 mGy) than that of non-cases (5.7 mGy). Average cumulative heart dose was 6.2 mGy, which ranged from 0.002 to 72.9 mGy, with male workers (7.7 mGy) receiving a significantly higher dose than female workers (2.7 mGy).
Number and percentage of selected characteristics of Korean medical radiation workers by type of circulatory disease
RRs for hypertension and IHD were significantly higher for men than among women, and the risks were higher for those born before 1980 and those first worked before 2000 adjusting for sex, attained age and birth year, particularly for hypertension (table 2). All major risk factors for CD such as alcohol intake, family history of CD and high BMI, BP, cholesterol and blood glucose were also significantly positively associated with CD, adjusting for sex, attained age and birth year. The results changed little after additional adjustments for smoking, alcohol intake and family history of CD (online supplementary table S1).
Supplemental material
RRs* and 95% CIs for types of circulatory disease associated with selected characteristics and non-radiation risk factors
A linear dose-response model provided no evidence of radiation dose response with an estimated linear ERR per 100 mGy for all CD (table 3). There was significant evidence of differences in ERR/100 mGy estimates for all CDs and CD except CeVD and others between men and women, with women having a higher ERR/100 mGy than men, although the uncertainty on their estimate was large. For all CDs, CD except CeVD and others, and hypertension, ERR estimates were generally more strongly positive for younger workers than for more than 50-year-old workers, for those born later than 1970 versus those born before 1970, for those who first worked after 2000 versus those who worked before 2000 and for those with less than 10 years of employment versus those with more than 10 years of employment.
ERRs per 100 mGy of cumulative heart dose by types of circulatory disease and selected characteristics
Non-radiation risk factors for CD such as alcohol intake, family history of CD, obesity, cholesterol level, BP and diabetes showed virtually no confounding with dose of radiation (table 4). Estimates tended to increase with increasing lag assumptions, except hypertension. The associations between radiation dose and CeVD or IHD were better described by a linear model than by a linear-quadratic model; however, the pattern for hypertension and all CDs was better described by the linear-quadratic model than by the linear model (online supplementary table S2). In the analyses excluding workers who were employed for less than 1 year or restricted to radiologic technologists, similar patterns were observed with the main results for each outcome and lag years (online supplementary table S3). In the sensitivity analyses using brain dose, the overall pattern of non-significant results was similar to that seen using heart doses (online supplementary table S4).
Effects of potential confounding factors on radiation risk estimates for types of circulatory disease morbidity (n=11 343 participants)
Discussion
The current study provides little evidence in support of a positive association between risk of CD and occupational radiation exposure among the diagnostic medical radiation workers in South Korea. However, some tendency of higher ERRs for CeVD, among female workers and younger workers, were observed. Our results were derived from the morbidity data with adjustment for important non-radiation risk factors of CD. This study may contribute to expand the evidence on the effect of radiation on CD at low-dose level among medical radiation workers.
The observed high, but non-significant, ERRs in the study may be the result of low-dose levels and a narrow range of distribution. Generally, quantification of the relationship between exposure and health effects requires the use of exposure estimates that show a range of exposure levels in the population under study.26 In studies of radiation workers exposed to low doses, the estimation of ERRs was hindered by the scarcity of high doses.27 In our study, individual cumulative radiation exposures were considerably lower with a mean heart dose of 6.2 mGy and badge dose of 13.0 mSv, and most workers were skewed to low levels of radiation with 9685 (84%) workers receiving less than 10 mGy and only 0.4% of the population exposed to more than 50 mGy. On the contrary, the average doses in other occupational studies were 20.7 mSv in the 15-Country study,13 25.2 mSv in INWORKS study15 and 540 mGy for men and 440 mGy for women in a Mayak worker cohort.14 Doses for workers at the Mayak nuclear facility also ranged widely; 17% of workers were exposed to doses above 1.0 Gy and 35% below 0.1 Gy.14 The relatively low radiation doses in this study could be because most workers started work during, or after, the 1990s and some workers were involved with procedures delivering low doses of radiation.28
Another feature of our study which may explain the results is that study finding was based on disease morbidity. In a meta-analysis and a study of the Mayak worker cohort, the risk obtained in the morbidity studies was slightly greater than that in the mortality studies.29 30 The longer latency for mortality than for incidence might not allow for detection of the excess in the mortality risk analyses.31 The difference of ERR in incidence and mortality may reflect the specific pathogenesis of radiation-induced CDs.32 In addition, there is a potential for including prevalent cases, although the cases diagnosed in 2006 (ie, initial year of follow-up) were excluded from this study. Including prevalent cases may inflate the rate of disease and may lead to relatively higher excess estimates.
Heterogeneity in ERR estimates between subtypes of CD was shown although our findings were generally statistically not significant. Some diversity in dose-response effects between stroke and heart disease29 and by different heart disease subtype8 or stroke7 has been reported in previous studies. Meta-analysis studies reported that stroke and CeVD may have a substantially larger risk than diseases specifically of the heart,29 33 and the ERR/Sv estimates for CeVD were larger in the lower dose range in the INWORKS study,15 which may be comparable to the current findings. Larger risks of stroke and CeVD than other subtypes of heart disease were also found in studies of US radiologic technologists.17 34 On the other hand, in the cohort of atomic bomb survivors, stronger and significant dose-response associations for heart diseases or hypertension than those for stroke were obtained, and inconsistent findings of IHD were reported.6 35 36 A similar nonlinearity of the dose response for hypertension risk was observed from the incidence data of atomic bomb survivors.36 However, considering the uncertainty about the shape of the dose-response curve in the low dose range, the non-linear pattern for hypertension needs to be further investigated with a longer follow-up period.
Our findings were not significantly affected by inclusion of additional adjustments for the non-radiation risk factors for CD. Although there are few studies that have investigated information on potential confounders, some studies among Mayak workers14 37 and atomic bomb survivors6 showed that adjustment of the data for other potential risk factors for CD had almost no impact on the associations with radiation. To control healthy worker survivor effect causing a negative confounding, duration of employment was considered to be adjusted in occupational cohort studies.13 15 However, the confounding effect was not significantly observed in this cohort because all workers were currently working at the time of the survey from 2012 to 2013. The ERRs additionally adjusted for duration of employment are shown in online supplementary table S5.
Consistent with the findings of previous studies, the estimates of ERR/100 mGy were generally more strongly positive for female versus male workers and for younger versus more than 50-year-old workers in our study. Although average cumulative dose among women was very low, they had a higher ERR/Sv than men for both IHD and CeVD in the INWORKS study.15 Risk of incident stroke was also significantly elevated in women, but not men, in a US radiologic technologists study.17 A review shows that radiation effects are sex-specific, and radiosensitivity in women is higher than that in men who receive a comparable dose of radiation.38 Young attained age was reported to be an important modifier of radiation risk for incidence of CeVD and stroke in the Mayak worker cohort.32 37 Significant dose-response associations were also observed for CD among younger workers in the 15-Country study.13 However, our participants are much younger (mean age 39 years at the time of end of follow-up) than other occupational cohorts; thus, time dependence of the ERR from exposure to low doses should be confirmed with extended follow-up.
Although there are some limitations for interpreting the results by different lag periods due to the short follow-up with an average of 8.1 years, the current study shows some evidence of late-onset CD from radiation exposure. This pattern was marked in CeVD, which suggests that doses received many years previously may play a more important role in CeVD than in other types of CD. This result is consistent with the INWORKS study, where an increasing tendency of estimates with increasing lag assumptions was more pronounced for CeVD than for IHD.15 Similarly, radiation-related effects were not seen until at least 10 years after exposure in the 15-Country study13 and higher dose studies.39 40
Our study has limitations that reduce the power to detect radiation effects on CD risks. First, there are some possibilities of underestimation of doses, although studies on reconstruction of badge dose were conducted to estimate dose before 1996.22 Second, at low doses, the disease risk attributable to radiation may be so small that it may be undistinguishable from the risk of lifestyle and socioeconomic factors. Finally, the relatively young cohort and short follow-up are likely to have limited our ability to detect radiation-induced cases.
Our study has the strength of having information on the important confounders such as BMI, BP, cholesterol level, blood glucose, smoking, alcohol intake and family history of CD. Our study participants, diagnostic radiation medical workers, could also expand the evidence on the effect of radiation on CD because occupational studies have been mainly conducted for nuclear workers. We also presented the results on dose-response relationship using individual dose estimates, which significantly improved compared with previous studies16 17 of medical radiation workers that were limited by the lack of individual dosimetry data. In addition, the results in the present study were derived from morbidity, while most studies assessed the risk of CD mortality.
In summary, we found little evidence in support of a positive relationship between external X-ray radiation exposure and CD among diagnostic radiation workers followed up for an average of 8.1 years. However, significantly elevated ERRs from occupational radiation exposure in female workers and young workers should be further followed up, with respect to the risk of CD from exposure to low doses. Continued careful monitoring of occupational radiation exposure and the implementation of protective measures are warranted to minimise the potential health risks to medical radiation workers.
References
Footnotes
Contributors WJL and ESC conceptualised the research. ESC performed the data analyses and wrote the first draft of the manuscript. LBZ, YJB and WJL provided advice on analysis of data and critically revised the manuscript. All authors contributed to the draft revision and approved the final manuscript.
Funding This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C1008891).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available.