The study was aimed to assess hypertension incidence risk in a cohort of workers occupationally exposed to ionizing radiation. The cohort included workers of Russian Mayak nuclear enterprise who were employed in 1948 to 1982 and followed up until December 31, 2013 (22 377 workers). All workers were occupationally exposed to external γ-rays and some (76.03%) also to α-particles from internally deposited plutonium. Mean cumulative absorbed liver doses from external γ-rays (mean±SD) were 0.45±0.65 Gy in male and 0.37±0.56 Gy in female, whereas doses from internal α-particles were 0.23±0.65 and 0.44±1.93 Gy in males and females, respectively. An excess relative risk per unit dose was calculated based on Poisson regression analysis and was described as linear and nonlinear trends with radiation dose including adjustments for nonradiation factors via stratifications. As of the end of the follow-up period, 8425 hypertension cases (38% of workers) were verified in the cohort (5745 cases in males [36%] and 2680 cases in females [49%]). Hypertension incidence was found to be significantly linearly associated with cumulative liver absorbed dose from external γ-rays: excess relative risk/Gy=0.14 (95% CI, 0.09–0.20). No significant association of hypertension incidence with cumulative liver absorbed dose from internal α-particles was found: excess relative risk/Gy=−0.01 (95% CI, non-available–0.05). Hypertension incidence risk in the study cohort was higher than that in the Japanese cohort of atomic bomb survivors (AHS [Adult Health Study]) but lower than a corresponding estimate for Chernobyl clean-up workers.

Introduction

See Editorial Commentary, pp 1170–1171

Circulatory diseases (CDs, International Classification of Diseases, Ninth Revision [ICD-9] VII class of diseases) are the leading cause of death worldwide. Class of CDs includes rheumatic diseases, increased blood pressure (BP; hypertension), ischemic heart disease, cerebrovascular diseases, arterial diseases, and others.1 During recent decades, there is increasing evidence that CD mortality, as well as to incidence and mortality from certain subtypes of CDs, is associated with radiation exposure.2–11 Meanwhile, data on hypertension incidence and mortality are sparse. Moreover, information on hypertension risks in human cohorts after occupational radiation exposed over prolonged periods are lacking, so the issue of the impact of low dose rate ionizing radiation on hypertension incidence and mortality is still unclear. Thus, the present study was aimed to assess the hypertension incidence risk (401–404 ICD-9 codes) in the cohort of Russian workers occupationally exposed to ionizing radiation at low dose rates at the Mayak nuclear enterprise over prolonged periods.

Materials and Methods

Data are from the Southern Urals Biophysics Institute (SUBI, Russia). Because the data contain identifying and sensitive worker information, they may not be publically available because of privacy reasons. These restrictions on data availability are imposed by Federal Act No. 323 of 21 November 2011 on the basics of health care for Russian citizens and Federal Act No. 152 of 27 July 2014 on personal data. To request the data used in the presented analyses, please, contact T. Azizova, the head of the clinical department of the SUBI. Any access to the Mayak Workers Cohort must be approved by SUBI’s Institutional Review Board (Valentina Rybkina, MD, leading researcher of SUBI, Institutional Advisory Board member, [email protected]).

The study was reviewed and approved by SUBI Institutional Advisory Board, which confirmed that no signed consents were needed from members of the study cohort.

Study Cohort

The present study is a retrospective cohort study. The study cohort includes workers of the Mayak Production Association (PA)—the first Russian large-scale nuclear enterprise located in the Southern Urals close to the city of Ozyorsk.12 Based on Mayak worker dosimetry system 2008 (MWDS-2008) containing identification information (family name, first name, patronymic, sex, date of birth), and data on occupational history, 22 377 individuals (25.4% of females) were identified as workers first employed at one of the main facilities (reactors, radiochemical, and plutonium production plants) from 1948 to 1982 regardless of sex, age, education, nationality, occupation, duration of employment, or other parameters.

The following groups of individuals were excluded from the study cohort: (1) workers acutely exposed to external γ- or γ-neutron radiation due to radiation accidents (absorbed doses ranging from 0.2 to 131.3 gray [Gy] with dose rates from 0.3×10-4 to 1.1 Gy s-1; 43 individuals)13; (2) workers diagnosed with hypertension during a preemployment medical examination before Mayak PA employment were excluded from the study (62 individuals); and (3) workers with missing medical records (694 individuals accounting for 3.1%).

The cohort follow-up period was defined as starting from the date of the first employment at one of the main facilities and continued until the earliest of the following events: date of hypertension diagnosis, date of death, 31 December of 2013 for workers known to be alive at that time, date of the last medical information for workers with unknown vital status and migrants (workers who had left Ozyorsk for another place of residence).

All workers of the cohort were subjected to comprehensive health checkups which included examinations by medical specialists (a therapist, a neurologist, a surgeon, a dermatologist, an ophthalmologist, an otolaryngologist, an endocrinologist, and other physicians in accordance with medical reasons), complete blood counts, clinical urinalysis, biochemical blood tests, imaging examinations (fluorography or X-ray, electrocardiography, or ultrasound imaging and others in accordance with medical reasons). First, a preemployment medical examination was performed for every person hired at the Mayak PA, and then, health checkups were performed every 3 months during 1948 to 1953, every 6 months during 1951 to 1960, and later they were performed annually throughout the whole follow-up period. Moreover, every 5 years advanced medical health examinations were performed for every Mayak worker in a special hospital regardless of radiation dose and health status of a worker.

Data on incidence and nonradiation factors for migrants was not available once these workers left the city.

During routine health checkups, a qualified nurse took measurements of BP in the outpatient setting. BP levels were measured in a sitting individual twice (with an interval between the 2 measurements at both arms not <1 minute) by a standard auscultation method using a mercury sphygmomanometer.

Table 1 summarizes detailed characteristics of the cohort members. The majority of the cohort workers (above 80%) were first employed at the enterprise at the age below 30 years. As of the end of the follow-up period, age of most of the workers (58%) was below 50 years. The duration of employment of the cohort workers ranged from 1 month up to 60 years with an average duration of 18.04±14.28 (mean±SD) years. Approximately, half of the study cohort workers (47%) were employed at the Mayak PA for more than 10 years. Only 6.70% of workers were employed at one of the main Mayak PA facilities <1 year.

Table 1. Mayak Worker Cohort Characteristics Distribution of Workers by Age at First Employment at the Mayak PA Age at first employment, y Males Females Both N % N % N % <20 5854 36.33 895 16.38 6749 31.28 20–24 5502 34.14 1911 34.97 7413 34.35 25–29 2217 13.76 966 17.68 3183 14.75 30–34 1007 6.25 605 11.07 1612 7.47 35–39 748 4.64 590 10.80 1338 6.20 ≥40 786 4.88 497 9.10 1283 5.95 Total 16 114 100.00 5464 100.00 21 578 100.00 Distribution of workers by attained age as of the end of the follow-up Attained age as of exit of the study, y Males Females Both N % N % N % <40 7553 46.87 1698 31.08 9251 42.87 40–49 2471 15.33 829 15.17 3300 15.29 50–59 2968 18.42 1174 21.49 4142 19.20 60–69 2110 13.09 1046 19.14 3156 14.63 ≥70 1012 6.28 717 13.12 1729 8.01 Total 16 114 100.00 5464 100.00 21 578 100.00 Distribution of workers by duration of employment at one of the main facilities Duration of employment, y Males Females Both N % N % N % <1 1145 7.11 300 5.49 1445 6.70 1–10 7451 46.24 2483 45.44 9934 46.04 >10 7518 46.66 2681 49.07 10 199 47.27 Total 16 114 100.00 5464 100.00 21 578 100.00 Distribution of workers diagnosed with hypertension by age at diagnosis Attained age, y Males Females Both N % N % N % <40 1579 27.49 241 9.00 1820 21.60 40–49 1434 24.96 565 21.08 1999 23.73 50–59 1356 23.60 763 28.47 2119 25.15 60–69 1002 17.44 739 27.57 1741 20.67 ≥70 374 6.51 372 13.88 746 8.85 Total 5745 100.00 2680 100.00 8425 100.00

By the end of the follow-up, vital status was known for 95% of cohort members of whom 62% had died, and 38% were alive. The mean age at death was 61.52±13.63 years for males and 70.48±12.44 years for females, whereas the mean age of alive cohort members as of the end of the follow-up was 68.50±10.40 years in males and 76.59±9.75 years in females.

Archive and current medical records and patients’ hospital charts were used as sources of clinical information on disease incidence. To collect death-related information, autopsy and forensic medical examination reports were used. as well as medical death certificates. Workers whose medical records had been lost (3.1%) did not differ significantly from the whole cohort members in those characteristics which were available for them, that is, calendar period and age at first employment at the Mayak PA, facility type, duration of employment, mean dose from external γ-rays, vital status, etc.

For the study, an increase of systolic BP ≥140 mm Hg or diastolic BP ≥ 90 mm Hg or increases in both BP indicators were defined as hypertension. Hypertension cases in the cohort workers were identified using the medical and dosimetry database Clinic.14 We performed a retrospective expert review and verification of 100% of identified hypertension diagnoses using criteria recommended by the European Society of Hypertension and European Society of Cardiologists.15 All workers with registered diagnosis of hypertension which was verified and confirmed, regardless of whether they were taking antihypertensive medications or not, were included in the data set for the analysis as hypertensive individuals. It is important to point out that hypertension cases defined as secondary hypertensions (405 ICD-9 code or I15 ICD-10 code) were excluded from the analysis as they were induced by a certain and potentially reversible/irreversible cause of BP increase. The present record-based epidemiological study did not require any contact with cohort members.

Dosimetry

Mayak PA main facility workers were occupationally exposed to ionizing radiation over prolonged periods: reactor workers were exposed only to external radiation (γ-rays and neutrons) and radiochemical and plutonium production plant workers were exposed to combined external (γ-rays and neutrons) and internal α-particles of incorporated plutonium. Since the first days of Mayak PA operation, external γ-doses were measured with individual film badges for all workers, and organ absorbed doses from external γ-rays were calculated using dosimetry models.16 Starting from 1970s, α-activity of internally deposited radionuclides was measured in bioassay (mainly, urine samples), and organ absorbed doses from internal α-radiation were calculated based on these measurements using biokinetics and dosimetry models.17 For the study, individual doses of external and internal exposure were provided by the recent improved Mayak worker dosimetry systems developed in the framework of Russian-American collaboration.18

MWDS-2008 provides doses from external γ-rays and neutrons for every member of the cohort.16 For the study, liver absorbed doses from external γ-rays, and internal α-particles were used in the analyses as doses absorbed in blood vessels, heart, or brain, that is, circulatory system organs, are not available in MWDS-2008.

The majority of the cohort workers were exposed to combined radiation (external γ and internal α). Pearson test for correlation between external and internal doses accumulated by workers with estimated doses from both radiation types was 0.22; P<0.05. For the study, doses from internally deposited α-particles estimated within Mayak worker dosimetry system 2013 (MWDS-2013) were used.17 Following MWDS-2013, plutonium α-activity was measured in 8010 workers (35.8% of the entire cohort or 47.1% of those workers who could be potentially exposed to α-particles).

In addition to dose estimates for occupational exposure, MWDS-2008 provides estimates for medical diagnostic X-ray exposure for 85% of workers over their period of residence in Ozyorsk including fluoroscopy. The most relevant to hypertension development diagnostic external X-ray dose was judged to be that to the liver and lung; however, these doses were found to be several orders of magnitude lower than the occupational external γ dose in the cohort (the mean total lung dose from external diagnostic exposure was 0.05±0.05 Gy [95% percentile 0.14] for males and 0.05±0.04 Gy [95% percentile 0.12] for females for the whole follow-up period, and the corresponding doses to the liver were 0.01±0.01 Gy [95% percentile 0.03] for males and 0.01±0.01 Gy [95% percentile 0.04] for females); therefore, it was decided not to consider this information for the analysis.

A routine individual neutron radiation dose monitoring was carried out for Mayak PA workers from 1983. To reconstruct neutron doses for the period before 1983, a special technique was introduced within a framework of Russian and American collaborative research.19

We should note that considerable neutron fluxes were registered only in central reactor halls and in some areas of radiochemical and plutonium plants. The mean effective energy of neutron spectrum was estimated to range between 300 and 500 keV in central reactor halls and between 100 and 300 keV in some areas of radiochemical and plutonium plants. Four thousand seven hundred and forty-nine workers (21.22 %) of the cohort were exposed to neutron radiation.20

Some workers were exposed to other radioactive materials that included short-lived fission products and other α emitters, such as americium-241. But the major contribution to the dose from internal radiation in the cohort of Mayak workers was owing to incorporated plutonium (>90%).20

Statistical Analysis

Data used for the analyses were restricted to a period during which a worker was living in Ozyorsk because there was no available information on diseases and nonradiation factors for migrants. Comparisons were performed within the cohort of Mayak PA workers. To perform the analysis, the data were compiled as a multidimensional table (Table S1 in the online-only Data Supplement).

At the first stage, hypertension incidence was analyzed in relation to nonradiation factors. At the second stage, a radiogenic risk was investigated.

The main analysis of the radiogenic risk calculated relative risks (RRs) for the whole cohort and for male and female subcohorts for separate categories of cumulative liver absorbed doses from external γ-rays (<0.05; 0.05–0.10; 0.10–0.15; 0.15–0.20; 0.20–0.35; 0.35–0.50; 0.50–0.75; 0.75–1.00; 1.00–1.25; 1.25–1.50; 1.50–2.00; 2.00–3.00; 3.00–4.00. ≥4.00 Gy) and of cumulative liver absorbed doses from internally deposited α-particles (<0.01; 0.01–0.025; 0.025–0.05; 0.05–0.10; 0.10–0.15; 0.15–0.25; 0.25–0.50; 0.50–1.00; ≥1.00 Gy) relative to a reference category (<0.05 and <0.01 Gy, respectively). Additionally, we calculated RRs for the whole cohort for separate categories of cumulative liver absorbed doses from neutrons (<0.00025, 0.00025–0.001, 0.001–0.0025, 0.0025–0.005, 0.005–0.01, ≥0.01 Gy) in relation to a reference category (<0.00025 Gy) and combined γ-neutron doses (cumulative absorbed γ doses with added cumulative absorbed neutron doses weighted by a factor of 10).

Dose-response models were used to investigate linear and nonlinear trends of hypertension incidence parameters with external and internal radiation. These analyses provided estimates of excess RRs (ERR) per unit dose (Gy or sievert [Sv]).

RR and ERR per unit dose estimates were calculated using Poisson regression in AMFIT module of Epicure software.21 Ninety-five percentage CI and P values testing statistical significance were obtained using maximum likelihood methods. All significance tests were 2-sided. If P<0.05, differences were considered statistically significant.

In both RR and ERR analyses adjustments by stratification were made for the following nonradiation factors: sex, attained age (<20, 20–25, …, 80–85, >85), calendar period (1948–1950, 1951–1955, 1956–1960, …, 2011–2013), smoking status (never smoker, ever smoker, unknown), and alcohol consumption (occasional drinker, moderate drinker, heavy drinker, unknown). Thus, the Poisson regression models were as

where λ denoted a hypertension incidence rate; λ0 denoted a background hypertension incidence rate; s denoted sex; aa denoted attained age; ct denoted calendar period; smok denoted smoking status; alc denoted alcohol consumption; β denoted ERR per unit dose; Dγ denoted a cumulative liver absorbed dose from external γ-rays (Gy); Dα denoted a cumulative liver absorbed dose from internally deposited α-particles (Gy); Dγn denoted a cumulative combined γ-neutron dose (Sv).

Statistical analysis is described in details in the online-only Data Supplement.

Results

As of 31 December 2013, 8425 hypertension cases (37.65% of the whole cohort) were registered in the worker cohort over the follow-up of 429 707 person-years.

The distribution of hypertension cases by sex (35.65% of the male workers and 49.05% of the female workers) and attained age in the cohort are presented in Table 1 and Table S2.

The distribution of workers by total liver absorbed doses from external γ-rays, neutrons, and internally deposited α-particles, as well as mean annual doses, are presented in Figure 1.

Figure 1. Distribution of the cohort workers by cumulative and mean annual liver absorbed doses. (A)(D) external gamma-ray exposure; (B)(E) internal alpha-particle exposure; (C)(F) neutron exposure.

The mean cumulative liver absorbed dose from external γ-rays was 0.45±0.65 (mean±SD) Gy in males and 0.37±0.56 Gy in females. The mean cumulative liver absorbed neutron dose was 0.001±0.004 Gy (95% percentile 0.003) in male workers and 0.001±0.005 Gy (95% percentile 0.006) in female workers. The mean cumulative liver absorbed dose from internal α-particles was 0.23±0.65 Gy in males and 0.44±1.93 Gy in females. Mean annual doses were the highest in early years of Mayak PA operation (Figure 1). For example, in 1951, the mean annual γ dose was 0.30 Gy per year, but it decreased sharply over the next decade to 0.05 Gy per year by 1960. The doses continued to fall at a lower rate until 1980 when the annual doses from external γ-rays reached about 0.01 Gy per year and remained stable at this level from that time onwards (Figure 1).

It should be noted that 69.44% (237.727 per 10 000 person-years) of hypertension in males and 75.82% (245.507 per 10 000 person-years) in females were found in workers exposed to radiation at cumulative γ-doses <0.50 Gy (Tables S4 and S5). Workers exposed to neutrons at doses <0.0025 Gy accounted for 92.16% (211.806 per 10 000 person-years) of hypertension in males and 92.28% (218.873 per 10 000 person-years) in females.

About a half of hypertension cases (54.73% 187.075 per 10 000 person-years) were identified in workers exposed to internal α-particles at cumulative liver absorbed doses <0.025 Gy, whereas around one-third of all hypertension was registered in males (28.27% 296.844 per 10 000 person-years) and females (34.21% 351.869 per 10 000 person-years) exposed to internal α-particles at cumulative liver absorbed doses 0.05–1.00 Gy (Table 2, and Tables S4–S5).

Table 2. Hypertension Incidence RR in Various Groups of Cumulative Liver Absorbed Doses From Radiation Exposure Dose Range, Gy Mean Dose, Gy Person-Years No. of Cases RR* (95% CI) RRadj1† (95% CI) RRadj2‡ (95% CI) External γ-rays§ 0.00–0.05 0.02 116 398 1864 1 1 1 0.05–0.10 0.07 54 892 1122 1.28 (1.18–1.37) 1.08 (1.00–1.16) 1.08 (1.00–1.17) 0.10–0.15 0.12 33 502 711 1.32 (1.22–1.44) 1.12 (1.02–1.22) 1.13 (1.03–1.24) 0.15–0.20 0.17 24 463 523 1.34 (1.21–1.47) 1.16 (1.05–1.28) 1.17 (1.05–1.30) 0.20–0.35 0.27 49 458 1006 1.27 (1.18–1.37) 1.08 (1.00–1.18) 1.08 (1.00–1.17) 0.35–0.50 0.42 28 613 656 1.43 (1.31–1.56) 1.20 (1.09–1.31) 1.17 (1.06–1.29) 0.50–0.75 0.62 30 819 659 1.34 (1.22–1.46) 1.14 (1.04–1.26) 1.14 (1.03–1.26) 0.75–1.0 0.87 20 977 452 1.35 (1.21–1.49) 1.16 (1.04–1.30) 1.12 (1.00–1.25) 1.00–1.25 1.12 15 367 350 1.42 (1.27–1.59) 1.23 (1.09–1.39) 1.20 (1.06–1.37) 1.25–1.50 1.37 10 910 251 1.44 (1.26–1.64) 1.31 (1.14–1.50) 1.30 (1.12–1.51) 1.50–2.00 1.73 15 037 336 1.40 (1.24–1.56) 1.26 (1.11–1.42) 1.24 (1.08–1.42) 2.00–3.00 2.32 9939 252 1.58 (1.38–1.80) 1.44 (1.25–1.65) 1.42 (1.21–1.66) 3.00–4.00 3.34 1550 41 1.65 (1.19–2.22) 1.65 (1.18–2.23) 1.78 (1.25–2.47) >4.00 4.39 509 7 0.86 (0.37–1.66) 0.73 (0.31–1.42) 0.68 (0.26–1.41) Total 0.00–5.82 0.44 412 434 8230 … – – Internal α-particles‖ 0.00–0.01 0.003 101 958 1686 1 1 1 0.01–0.025 0.016 33 389 846 1.53 (1.41–1.66) 1.06 (0.97–1.16) 1.05 (0.95–1.16) 0.025–0.05 0.036 22 226 592 1.61 (1.47–1.77) 1.01 (0.91–1.12) 1.00 (0.89–1.12) 0.05–0.10 0.071 17 754 491 1.67 (1.51–1.85) 1.05 (0.94–1.18) 1.00 (0.87–1.13) 0.10–0.15 0.122 8361 263 1.90 (1.67–2.16) 1.16 (1.01–1.33) 1.10 (0.93–1.29) 0.15–0.25 0.193 8194 275 2.03 (1.78–2.30) 1.14 (1.00–1.31) 1.05 (0.89–1.24) 0.25–0.50 0.348 6650 244 2.22 (1.94–2.53) 1.23 (1.06–1.42) 1.10 (0.92–1.31) 0.50–1.00 0.695 3416 130 2.30 (1.92–2.74) 1.33 (1.09––1.60) 1.15 (0.91–1.44) >1.00 3.187 3336 99 1.80 (1.43–2.19) 1.08 (0.87–1.34) 0.92 (0.71–1.18) Total 0.00–38.05 0.25 205 284 4626 … … …

The analysis demonstrated that hypertension in the cohort workers was significantly associated with nonradiation factors, such as attained age, calendar period, and age at first employment at the enterprise, calendar period of the diagnosis, duration of employment, body mass index and smoking status (Table S2).

The RR of hypertension incidence in females was slightly lower (but nonsignificantly) than that in males. In both males and females, the RR of hypertension incidence increased with increasing attained age; however, in females, the risk observed in age categories up to 50 years was significantly lower than the corresponding risk for males being consistent with results of other studies that hypertension is diagnosed twice as often in men than in women before menopause.22,23 Hypertension incidence among males first employed at the Mayak PA after 1959 was significantly decreased compared with males hired in 1948 to 1953, and it was decreased in females first employed after 1973 compared with those hired in 1948 to 1953.

Hypertension incidence risk was dependent on calendar period of diagnosis. The observed increase in hypertension incidence in 1948 to 1955 was, apparently, due to exposing hypertensions which were missed during preemployment medical health examinations and to recording of in fact accumulated incidence during routine thorough medical surveillance of the workers. The increase of hypertension incidence from 1996 to 2000 potentially could be caused by complex social and economic situation induced by the breakup of the Soviet Union.

Hypertension incidence was not found to be associated with the type of facility. But it was decreased in males first employed at the age above 30 and in females first employed at the age above 40 while comparing to those first employed at the Mayak PA at the age before 20 (P<0.05). The RR of hypertension incidence was higher in workers employed at the facility during >10 years compared with those employed during 5 to 10 years. No similar association was found for female.

As expected, the hypertension risk incidence was higher in workers with increased BP levels (systolic BP above 140 mm Hg or diastolic BP above 90 mm Hg) registered during a preemployment medical health examination. No significant effect of smoking status on hypertension incidence was observed in the cohort. Both males and females with excessive body weight (with body mass index [BMI] above normal) demonstrated the significantly increased hypertension incidence risk; this agrees well with literature data.24,25

Categorical analysis results summarized in Table 2 revealed a significantly increased risk of hypertension incidence for all dose categories compared with the reference category which included workers exposed to external γ-rays at cumulative liver absorbed doses <0.05 Gy. It should be mentioned that hypertension incidence risk increased with increasing cumulative dose from external γ-rays (from 1.08 [95% CI, 1.00–1.16] for dose category of 0.05 to 0.10 Gy to 1.65 [95% CI, 1.18–2.23] for dose category 3.0–4.0 Gy but not for the highest dose category [>4 Gy], likely, due to a low number of cases among members of this dose group [n=7]; Table 2).

Analyses results for hypertension incidence association with neutron and γ-neutron exposure are presented in Table S3 and Table 3. The analysis demonstrated that the hypertension incidence risk was increased in almost all neutron dose categories except for 2 categories, but the risk estimates were nonsignificant. Similarly, the hypertension incidence risks were increased in almost all total γ-neutron dose categories except for 3 categories (0.05–0.1 Sv, 0.2–0.35 Sv, 4.0+ Sv); the RR increased with increasing dose categories, but significant risks were found only for workers exposed at 1.25–4.0 Sv doses.

Table 3. Hypertension Incidence Risks by Doses From Occupational Radiation Exposure Analysis No. of Cases ERR Per Unit Dose (95% CI) Incidence risk associated with dose from external γ-ray, ERR/Gy* Main analysis (0 y lag)† 8230 0.14 (0.09–0.20) Main analysis with first x years after start of work with ionizing radiation assigned to zero dose category with x-year dose lag 5 y lag 8230 0.15 (0.09–0.21) 10 y lag 8230 0.17 (0.11–0.24) 15 y lag 8230 0.19 (0.12–0.26) Main analyses without an adjustment for smoking and alcohol consumption, 0 y lag 8230 0.13 (0.08–0.19) Main analysis with additional stratification (0 y lag): For body mass index 8230 0.17 (0.12–0.24) For duration of employment 8230 0.16 (0.10–0.22) For smoking index 8230 0.14 (0.08–0.20) For baseline blood pressure 8230 0.12 (0.07–0.18) For dose from internal α particles 8230 0.14 (0.09–0.20) For neutron dose 8230 0.14 (0.08–0.20) For neutron dose and dose from internal α particles 8230 0.09 (0.03–0.16) Main analysis (0 y lag) restricted by workers employed at The reactor plant 1977 0.19 (0.04–0.37) The radiochemical plant 3515 0.18 (0.10–0.27) The plutonium production plant 2738 0.18 (0.04–0.34) P 1 ‡=0.39 Duration of employment, y <1 y 250 0.17 (non-available–0.96) 1–5 1251 0.21 (0.08–0.36) 5–10 1215 0.12 (0.02–0.26) 10–20 2188 0.12 (0.02–0.25) 20–30 1903 0.25 (0.11–0.42) 30 + 1423 0.13 (0.01–0.30) P 2 §=0.16 Males 5612 0.15 (0.09–0.22) Females 2618 0.14 (0.05–0.24) P 3 ‖> 0.50 Attained age of the workers, y <40 1712 0.06 (non-available–0.18) 40–49 1929 0.11 (0.01–0.24) 50–59 2104 0.14 (0.04–0.25) 60–69 1739 0.26 (0.14–0.41) 70+ 746 0.16 (0.02–0.34) P 4 ¶=0.22 P 5 #=0.28 Incidence risk associated with neutron dose, ERR/Gy Main analysis (0 y lag)** 1638 8.40 (−8.23–37.44) Incidence risk associated with γ-neutron dose, ERR/Sv Main analysis (0 y lag)* 8230 0.13 (0.08–0.19) Incidence risk associated with dose from internal α-radiation, ERR/Gy Main analysis (0 y lag)* 4626 −0.01 (non-available–0.05)

Another categorical analysis (Table 2) demonstrated that hypertension incidence was significantly higher in workers exposed to internal α-radiation at cumulative absorbed liver doses 0.10–0.15, 0.15–0.25, 0.25–0.5 and 0.5–1.00 Gy than that in workers exposed at corresponding doses <0.01 Gy (P<0.05). Moreover, the risk increased with increasing cumulative dose from internal α radiation. For workers who had been exposed internally at doses >1.00 Gy, the risk was increased but nonsignificantly because of a small number of cases in workers of this group (n=99; Table 2).

Analysis results providing estimates of the RR for various external and internal dose categories for males and females separately are summarized in Tables S4 and S5.

Hypertension incidence was found to be significantly linearly associated with the cumulative liver absorbed dose from external γ-rays with ERR/Gy of 0.14 (95% CI, 0.09–0.20; Table 3 and Figure 2).

Figure 2 Hypertension incidence by cumulative liver absorbed doses from external γ-rays. ERR indicates excess relative risk.

The hypertension risk estimates increased with increasing lag-period but decreased after exclusion of adjustments for smoking status and alcohol consumption and inclusion of an adjustment for the baseline BP level. The hypertension incidence risk was revealed to increase with inclusion into stratification of adjustments for additional nonradiation factors (body mass index and duration of employment), but the smoking index adjustment did not modify the risk estimate. An additional adjustment for internal α-dose or external neutron dose did not modify the hypertension incident risk in the study cohort (ERR/Gy=0.14 [95% CI, 0.09–0.20] and ERR/Gy=0.14 [95% CI, 0.08–0.20], respectively). However, the simultaneous inclusion of these 2 adjustments results in the risk modification (ERR/Gy=0.09; 95% CI, 0.03–0.16).

ERR/Gy for hypertension incidence due to external γ-radiation was approximately the same for males and females in the cohort (P>0.05). Roughly the same risk estimates were obtained for all facility types with no significant differences among them (P=0.39). No association of the risk with duration of employment was found (P=0.16). Despite the increase of ERR/Gy with increasing attained age, no significant association was revealed in risk with attained age (P=0.28). ERR/Gy of external γ-dose for hypertension incidence in the workers who had never migrated from Ozyorsk was approximately the same as that in the whole cohort while both adjusted for neutron and α-doses and unadjusted (Table S6).

The test for nonlinearity demonstrated that linear-quadratic and linear-exponential models provided a significantly better statistical fit for the data compared with the linear model (P=0.03 and P=0.048). The quadratic model fit the data worse than the linear one, and the difference between the models was also significant (ΔAkaike Information Criteria=14.072; Table S8). However, Figure 2 demonstrates that the curvature could likely occur due to the last point estimate (dose category >4.0 Gy). Once these workers were excluded from the analysis dataset, the best fit was observed when the linear model was used (Table S8).

The analysis of hypertension risk in relation to cumulative liver absorbed dose from internal α-particles did not find a significant association while the linear model was used (Table S5). The main analysis considering the whole dose range provided ERR/Gy of α-radiation for hypertension incidence of −0.01 (95% CI, non-available–0.05; Table 3). Testing of the effect of lagging was impossible because of nonapplicable result for the lower bound of 95% CI. The obtained result was modified neither by exclusion of adjustments for smoking status and alcohol consumption nor by inclusion of adjustments for additional nonradiation factors (BMI, duration of employment, smoking index, baseline BP level) and doses from external γ-rays and neutrons. No significant differences were found in risk estimates for different sexes, facility types, attained ages, and duration of employment (P=0.09, P=0.18, P>0.5, P=>0.5). ERR/Gy of internal α-dose for hypertension incidence in workers who had never migrated from Ozyorsk was approximately the same as that in the whole cohort while both adjusted for external γ- and neutron doses and unadjusted (Table S6).

Discussion

The results of the study provide evidence for an association of hypertension incidence in workers exposed to ionizing radiation at low γ-dose rates over prolonged periods with attained age, age and calendar period of first employment, calendar period of diagnosis, duration of employment, BMI, as well as demonstrating that hypertension incidence was not dependent on type of facility and smoking status. The expected hypertension incidence increased with increasing attained age and BMI agreed well with findings of other epidemiological and clinical studies.26–30 Hypertension and smoking are known to be comorbid cardiovascular risk factors that interact to increase the risk of atherosclerotic vascular diseases. So, the RR of stroke among hypertensive smokers is 5× that among normotensive smokers, but 20× that of normotensive nonsmokers.31 Some epidemiological studies found that smokers have a lower clinic BP compared with nonsmokers.32 Both male and female workers with excessive body weight (with BMI above normal) demonstrated the significantly increased hypertension incidence risk; this agrees well with literature data.24,25

The categorical analysis demonstrated the increased risk of hypertension incidence in all cumulative external γ-dose groups above 0.05 Gy compared with the reference category (<0.05 Gy). The risk estimate increased with increasing cumulative dose from external γ-rays, and the highest RR was observed in workers exposed at doses 3.0–4.0 Gy (1.78 95% CI, 1.25–2.47), but decreased to <1.0 at doses above 4.0 Gy. In addition, the increased risk of hypertension incidence was significant in workers exposed to external γ-neutron radiation at total doses 1.25–4.0 Sv when compared with the reference category <0.05 Sv but was reduced at cumulative doses above 4.0 Sv. The analysis of hypertension incidence with neutron dose did not demonstrate significant risks in any of the dose categories. Nonsignificantly increased risk estimates were also observed in workers exposed to α-particles at cumulative liver absorbed doses above 0 Gy as compared to the reference category (<0.01 Gy) except at doses above 1.0 Gy.

It should be emphasized that the significant risk estimates for hypertension incidence observed in the range of low doses from external γ-rays should be interpreted cautiously as they could be attributed to considerable dose uncertainties inherent to categories of low doses.

The dose-response analysis revealed the significant linear association of hypertension incidence with cumulative liver absorbed dose from external γ-rays with ERR/Gy of 0.14 (95% CI, 0.09–0.20) both including and not including the adjustment for internal α-dose, as well as with the total γ-neutron dose with ERR/Sv=0.13 (95% CI, 0.08–0.19). The test for nonlinearity demonstrated that the linear-quadratic and linear-exponential models provided significantly better data fit compared with the linear model. However, the additional analysis showed that the nonlinearity was mostly driven by a group of workers exposed at doses above 4.0 Gy (38 workers [0.17% of the total staff], with 4 females among them, contributing 509 person-years of the follow-up). Once this group of workers was excluded from the analysis, the linear model provided the best data fit. This is likely to be attributed to the heterogeneity of the data and the ratio of males to females for this group of workers. Analyses based on nonlinear models for male workers demonstrate that the linear model provided the best data fit with both inclusion and exclusion of workers exposed at doses above 4.0 Gy.

It was challenging to compare the obtained results with other studies because dose-response studies of hypertension incidence are sparse, and hypertension subtypes and their combinations investigated as study outcomes were inconsistent among researchers. For the first time, the increased risk of hypertension was shown in atomic bomb survivors (Japanese LSS [Life Span Study] cohort).33 The increased mortality ERR/Sv of 0.21 (90% CI, 0.00–0.45) was found in the cohort of 85 600 individuals followed up during 1950–1990. After the follow-up of this cohort was extended up to 2003, a significant dose-response was shown for mortality from hypertension (ICD-9 codes: 402, 404) with ERR/Gy of 0.37 (95% CI, 0.08–0.72)8; and after the extension up to 2008, the ERR/Gy became 0.36 (95% CI, 0.10–0.68).7 The AHS (Adult Health Study) of a subcohort of Japanese atomic survivors demonstrated a significant quadratic relationship between hypertension incidence (ICD-9 code: 401 or ICD-10 code: I10) and radiation dose; ERR 1Sv was 1.03 (95% CI, 1.01–1.06).34

Results of the Chernobyl clean-up worker study including 61 017 individuals followed up during 1986–2000 gave evidence to a significantly increased risk of hypertension incidence (ICD-9 code: 401 or ICD-10 code: I10); ERR/Gy was 0.36 (95% CI, 0.005–0.71).35 After extension of the follow-up period up to 2012, a significantly increased ERR/Gy of external γ-rays was shown for hypertension incidence in a subcohort of workers (N=53 704) who started clean-up operations in an area of the accident between April 26, 1986 and April 25, 1987; ERR/Gy was 0.26 (95% CI, 0.12–0.41).9

Overall, it may be pointed out that the hypertension risk estimate for Mayak PA workers exposed to external γ-rays over prolonged periods was higher than the corresponding estimate for the atomic bomb survivor subcohort (AHS) but lower than that for Chernobyl clean-up workers (Table 4). This might be explained with several reasons and first of all with variations in exposure scenarios: members of the Japanese cohort experienced acute single exposure at high dose rates; Chernobyl cohort members experienced short-term (days and months) radiation exposure, whereas Mayak workers were chronically exposed to radiation at low dose rates over many years.

Table 4. Comparison of the Observed Results With Results of Other Studies* Study Reference No. of Individuals Follow-Up Period Mean Dose and Dose Range, Sv Study Outcome (ICD-9 Codes) No. of Outcomes ERR/Unit Dose (Linear Model) RR 1Sv (Quadratic Model) LSS (mortality) Shimizu et al33 86 572 1950–1990 0.1 (0–4) Hypertensive disease (401–405) 1199 0.21 (0.00 to 0.45) P=0.003 Shimizu et al8 86 611 1950–2003 0.1 (0–4) Hypertensive heart disease and hypertensive heart and chronic kidney disease (402, 404) 922 0.37 (0.08 to 0.72) P=0.009 Essential hypertension, hypertensive chronic kidney disease, secondary hypertension (401, 403, 405) 411 0.07 (−0.22 to 0.55) P > 0.5 I. Takahashi et al7 86 600 1950–2008 0.1 (0–4) Hypertensive heart and chronic kidney disease (402–404) 1122 0.36 (0.10 to 0.68) P=0.004 Hypertensive heart disease (402) 879 0.37 (0.07 to 0.73) Hypertensive chronic kidney disease (403) 174 0.39 (−0.15 to 1.30) Hypertensive heart and chronic kidney disease (404) 69 0.26 (−0.79 to 1.31) AHS (incidence); estimates in brackets are unadjusted for smoking and alcohol consumption Yamada et al34 10 339 1958–1998 0.1(0–4) Essential hypertension (401)–linear model 5035 0.05 (−0.01 to 0.10) P=0.08; (0.04 (−0.01 to 0.09) P=0.14) (1958–1960; 1996–1998) Essential hypertension (401)–quadratic model 5035 1.03 (1.01 to 1.06) P=0.01; (1.03 (1.0 to 1.06) P=0.028) Hypertensive heart disease and hypertensive heart and chronic kidney disease (402, 404)—linear model 1886 −0.01 (−0.09 to 0.09) P=0.87; 0.01 (−0.08 to 0.10) P=0.86) Chernobyl accident participants and clean−up workers (incidence) Ivanov et al35 61 017 1986–2000 0.109 (0–>0.5) Hypertensive disease (401–405) 15 484 0.26 (−0.04 to 0.56) P=0.08 Essential hypertension (401) 11 910 0.36 (0.005 to 0.71) P=0.04 Hypertensive heart disease (402) 7680 0.04 (−0.36 to 0.44) P=0.85 Ivanov et al9 53 704 (cohort А) 1986–2012 0.161 Hypertensive disease (401–405) 29 695 0.26 (0.12 to 0.41) P<0.001 Mayak PA workers first employed in 1948–1982 (incidence) The present study 22 377 1948–2013 0.45±0.65 Gy (male) 0.37±0.56 Gy (female) Hypertensive disease (401–404)—linear model 8425 0.14 (0.09 to 0.20) P<0.001

The results of the present study demonstrate the lack of a significant association of hypertension incidence with internal α-particle doses based on both the linear (Table S6) and nonlinear models (Table S9). They should be interpreted cautiously because the dose-response analysis for internal α-radiation exposure of the study cohort workers has a lower statistical power than that of the external γ-radiation association analysis because internal α-doses are available for only one-third of the total cohort members. In addition, it should also be noted that considerable uncertainties are intrinsic in absorbed doses from internally deposited α-particles, especially in organs which build up the systemic model. Regarding the effect of internal radiation exposure due to incorporated plutonium on hypertension incidence, there are no reports on this association in available scientific literature.

The present study has a number of advantages, among which are the big size of the cohort (22 377 individuals), an extended follow-up period (1948–2013), cohort heterogeneity by sex and age, individually measured doses from radiation exposure and sufficient statistical power of the study. One of the main strengths of the cohort is the fact that all workers, regardless of occupation, site, and radiation dose, were subjected to mandatory annual medical health examinations which included checks performed by medical specialists, imaging, and laboratory examinations, etc. Moreover, the health examinations also included BP, height, and weight measuring, as well as interviewing about social habits—first, smoking and alcohol consumption, and this important data are available for the majority of the study cohort workers. Meanwhile, it should be highlighted that all workers, regardless of sex, age, working site, occupation, radiation type, and dose, etc were mandatorily subjected to health examinations following a standard unified protocol what excludes the possibility for self-selection (eg, due to ill health) and dose-selection biases. Neither doctors who performed medical health examinations nor workers knew anything about radiation doses accumulated by each certain worker what rules out a chance for dose-dependent selection of individuals for health examinations.

The main limitation of the present study is the lack of heart, brain, vessel doses, that is, doses absorbed in circulatory system organs, in the MWDS-2008, but in future, detailed occupation exposure routes, individual doses from external γ-rays measured with personal film badges, detailed radiation exposure scenarios, as well as occupation data will enable circulatory organ dose reconstruction and reanalysis of risk for the Mayak worker cohort based on an extended follow-up period and taking into account various types of hypertension.

Meanwhile, mechanisms of CD development in humans exposed to moderate and low radiation doses at low dose rates remain unclear.2 It should be noted that the class of CDs encompasses various groups of diseases of different cause and pathogenesis, and it is critical to gain an advanced understanding of their mechanisms rather than just to assess risks for each of these groups. Another limitation of the study was restriction of analyzed data with a period of residence of workers in Ozyorsk as information on disease incidence and nonradiation factors was unavailable for migrants.

Within the current study, we did not analyse mortality from hypertension as the main cause of death because of the small number of such outcomes among the study cohort members (101 deaths). To investigate mortality from hypertension, we lack statistical power to date. However, we plan to continue accumulating data on mortality following up the cohort. In future, we will certainly carry out an analysis of mortality caused by hypertension.

As the next stage of the study, we are going to assess incidence and mortality risks of separate hypertension subtypes extending the cohort follow-up period and, hence, increasing the statistical power of the study, as well as making use of updated, improved radiation dose estimates provided by a new Mayak worker dosimetry system MWDS-2016.

Conclusions

The study demonstrated that hypertension incidence in the Mayak PA worker cohort exposed to low dose rate radiation over prolonged periods was associated with attained age, age and calendar period of first employment at the enterprise, calendar period of diagnosis, duration of employment, smoking status, BMI, and was not associated with a facility type. We observed the significant linear association of hypertension incidence with cumulative liver absorbed dose from external γ-rays; ERR/Gy=0.14 (95% CI, 0.09–0.20). No significant association was observed for hypertension incidence with cumulative liver absorbed dose from incorporated α-particles; ERR/Gy=-0.01 (95% CI, non-available–0.05). The hypertension risk estimated for the study cohort was higher than the corresponding risk estimated for the Japanese AHS cohort but lower than that for Chernobyl clean-up worker cohort.

Perspectives

Findings of this study might be of importance for radiological protection perspective contributing to deep understanding of the concept of human health detriment because of effects from exposure to low levels of ionizing radiation.

Sources of Funding None.

Disclosures None.

Footnotes