Effects of confounding and effect-modifying lifestyle, environmental and medical factors on risk of radiation-associated cardiovascular disease.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide. It has been known for some considerable time that radiation is associated with excess risk of CVD. A recent systematic review of radiation and CVD highlighted substantial inter-study heterogeneity in effect, possibly a result of confounding or modifications of radiation effect by non-radiation factors, in particular by the major lifestyle/environmental/medical risk factors and latent period. METHODS: We assessed effects of confounding by lifestyle/environmental/medical risk factors on radiation-associated CVD and investigated evidence for modifying effects of these variables on CVD radiation dose-response, using data assembled for a recent systematic review. RESULTS: There are 43 epidemiologic studies which are informative on effects of adjustment for confounding or risk modifying factors on radiation-associated CVD. Of these 22 were studies of groups exposed to substantial doses of medical radiation for therapy or diagnosis. The remaining 21 studies were of groups exposed at much lower levels of dose and/or dose rate. Only four studies suggest substantial effects of adjustment for lifestyle/environmental/medical risk factors on radiation risk of CVD; however, there were also substantial uncertainties in the estimates in all of these studies. There are fewer suggestions of effects that modify the radiation dose response; only two studies, both at lower levels of dose, report the most serious level of modifying effect. CONCLUSIONS: There are still large uncertainties about confounding factors or lifestyle/environmental/medical variables that may influence radiation-associated CVD, although indications are that there are not many studies in which there are substantial confounding effects of these risk factors.

Immunohistochemical Analysis of Lung Adenocarcinoma in Russian Mayak Nuclear Workers.

Specimens of lung adenocarcinoma (AdCa) from Russian nuclear workers (n = 54) exposed to alpha particles and gamma rays and from individuals non-exposed to radiation (n = 21) were examined using immunohistochemistry. Estimated significant associations with alpha dose were negative for Ki-67 and collagen IV in AdCa. Associations with gamma-ray dose were negative for tissue inhibitor of matrix metalloproteinase 2 and caspase 3 and positive for matrix metalloproteinase 2 and leukemia inhibiting factor in AdCa. The findings provide some evidence supporting alterations in apoptosis, cell proliferation and extracellular matrix in lung tissues affected by chronic radiation exposure that can contribute to radiogenic cancerogenesis.

Incidence risks for subtypes of heart diseases in a Russian cohort of Mayak Production Association nuclear workers.

Heart diseases are one of the main causes of death. The incidence risks were assessed for various types of heart diseases (HDs) in a cohort of Russian nuclear workers of the Mayak Production Association (PA) who had been chronically occupationally exposed to external gamma and/ or internal alpha radiation. The study cohort included all workers (22,377 individuals) who had been hired at the Mayak PA during 1948-1982 and followed up until 31 December 2018. The mean gamma-absorbed dose to the liver (standard deviation) was 0.43 (0.63) Gy, and the mean alpha-absorbed dose to the liver was 0.25 (1.19) Gy. Excess relative risk (ERR) per unit liver-absorbed dose (Gy) was calculated based on maximum likelihood. At the end of the follow-up, 559 chronic rheumatic heart disease (CRHD), 7722 ischemic heart disease (IHD) [including 2185 acute myocardial infarction (AMI) and 3976 angina pectoris (AP)], 4939 heart failure (HF), and 3689 cardiac arrhythmia and conduction disorder (CACD) cases were verified in the study cohort. Linear model fits of the gamma dose response for HDs were best once adjustments for non-radiation factors (sex, attained age, calendar period, smoking status and alcohol consumption) and alpha dose were included. ERR/Gy in males and females was 0.17 (95% confidence intervals: 0.10, 0.26) and 0.23 (0.09, 0.38) for IHD; 0.18 (0.09, 0.29) and 0.26 (0.08, 0.49) for AP; - 0.01 (n/a, 0.1) and - 0.01 (n/a, 0.27) for AMI; 0.27 (0.16, 0.40) and 0.27 (0.10, 0.49) for HF; 0.32 (0.19, 0.46) and 0.05 (- 0.09, 0.22) for CACD; 0.73 (- 0.02, 2.40) and - 0.12 (- 0.50, 0.69) for CRHD, respectively. Sensitivity analyses demonstrated the persistence of a significant dose-response regardless of exclusion/inclusion of adjustments for known potential non-radiation confounders (smoking, alcohol consumption, body mass index, hypertension, diabetes mellitus), and it was only the magnitude of the risk estimate that varied. The risks of HD incidence were not modified with sex (except for the CACD risk). This study provides evidence for a significant association of certain types of HDs with cumulative dose of occupational chronic external exposure to gamma radiation.

Incidence risks for cerebrovascular diseases and types of stroke in a cohort of Mayak PA workers.

Incidence risks for cerebrovascular diseases (CeVD) and some types of stroke in a cohort of 22,377 Russian Mayak nuclear workers chronically exposed to ionising radiation and followed up until the end of 2018 are reported. Among total 9469 cases of CeVD, 2078 cases were strokes that included 262 hemorrhagic strokes (HS) and 1611 ischemic strokes (IS). Data evaluation was performed with categorical and dose-response analyses estimating the relative risk (RR) and excess relative risk (ERR) per unit cumulative liver absorbed dose of external gamma-ray or internal alpha-particle exposure based on a linear model utilizing the AMFIT module of the EPICURE software. CeVD incidence was found to be significantly associated with cumulative radiation dose: ERR/Gy was 0.37 (95% confidence interval (CI) 0.27, 0.47) in males and 0.47 (95% CI 0.31, 0.66) in females for external exposure, and 0.31 (95% CI 0.11, 0.59) in males and 0.32 (95% CI 0.11, 0.61) in females for internal exposure. When the model for the analysis of external radiation effect did not include an adjustment for alpha radiation dose (and vice versa), the radiogenic risk estimate increased notably both for males and for females. In contrast, exclusion from or inclusion in the model of additional adjustments for non-radiation factors did not notably change the risk estimates. ERR/Gy of external gamma dose for CeVD incidence significantly decreased with increasing attained age (males and females) and duration of employment (females). No significant associations of either stroke or its types with cumulative gamma-ray dose of external exposure or alpha-particle dose of internal exposure were found.

Mortality from various diseases of the circulatory system in the Russian Mayak nuclear worker cohort: 1948-2018.

This paper reports on the findings from the study of mortality from diseases of the circulatory system (DCS) in Russian nuclear workers of the Mayak Production Association (22 377 individuals, 25.4% female) who were hired at the facility between 1948 and 1982 and followed up until the end of 2018. Using the AMFIT module of the EPICURE software, relative risks (RRs) and excess RRs per unit absorbed dose (ERR/Gy) for the entire Mayak cohort, the subcohort of workers who were residents of the dormitory town of Ozyorsk and the subcohort of migrants from Ozyorsk were calculated based on maximum likelihood. The mean cumulative liver absorbed gamma-ray dose from external exposure was 0.45 (0.65) Gy (mean (standard deviation)) for men and 0.37 (0.56) Gy for women. The mean cumulative liver absorbed alpha dose from internal exposure to incorporated plutonium was 0.18 (0.65) Gy for men and 0.40 (1.92) Gy for women. By the end of the follow-up, 6019 deaths with DCS as the main cause of death were registered among Mayak Production Association workers (including 3828 deaths in the subcohort of residents and 2191 deaths in the subcohort of migrants) over 890 132 (622 199/267 933) person-years of follow-up. The linear model that took into account non-radiation factors (sex, attained age, calendar period, smoking status and alcohol drinking status) and alpha radiation dose (via adjusting) did not demonstrate significant associations of mortality from DCS, ischaemic heart disease (IHD) and cerebrovascular disease with gamma-ray exposure dose in the entire cohort, the resident subcohort or the migrant subcohort (either in men or women). For the subcohort of residents, a significant association with gamma dose was observed for mortality from ischaemic stroke in men with ERR/Gy = 0.43 (95% CI 0.08; 0.99); there were no significant associations with liver absorbed gamma dose for any other considered outcomes. As for internal exposure, for men no significant associations of mortality from any DCS with liver absorbed alpha dose were observed, but for women positive associations were found for mortality from DCS (the entire cohort and the resident subcohort) and IHD (the entire cohort). No significant associations of mortality from various types of DCS with neutron dose were observed either in men or women, although neutron absorbed doses were recorded in only 18% of the workers.

Radiation detriment calculation methodology: summary of ICRP Publication 152.

Radiation detriment is a concept to quantify the burden of stochastic effects from exposure of the human population to low-dose and/or low-dose-rate ionising radiation. As part of a thorough review of the system of radiological protection, the International Commission on Radiological Protection (ICRP) has compiled a report on radiation detriment calculation methodology as Publication 152. It provides a historical review of the detriment calculation with details of the procedure used in ICRP Publication 103. A selected sensitivity analysis was conducted to identify the parameters and calculation conditions that can be major sources of variation and uncertainty. It has demonstrated that sex, age at exposure, dose and dose-rate effectiveness factor, dose assumption in the lifetime risk calculation, and lethality fraction have a substantial impact on the calculated values of radiation detriment. Discussions are also made on the issues to be addressed and possible ways for improvement toward the revision of general recommendations. These include update of the reference population data and cancer severity parameters, revision of cancer risk models, and better handling of the variation with sex and age. Finally, emphasis is placed on transparency and traceability of the calculation, along with the need to improve the way of expressing and communicating the detriment.

Evaluation of the lifetime brain/central nervous system cancer risk associated with childhood head CT scanning in Japan.

The use of computed tomography (CT) scanning has increased worldwide over the decades, and Japan is one of the leading countries in annual frequency of diagnostic CT. Although benefits of CT scan are undisputable, concerns have been raised about potential health effects of ionizing radiation exposure from CT, particularly among children who are likely more susceptible to radiation than adults. Our study aims to evaluate the cumulated lifetime risk of the brain/central nervous system (CNS) cancer due to head CT examinations performed on Japanese children at age 0 to 10 years in 2012, 2015 and 2018. The frequency and dose distribution of head CT examinations were estimated based on information from recent national statistics and nationwide surveys. The lifetime risk attributable to exposure was calculated by applying risk models based on the study of Japanese atomic-bomb survivors. In contrast to the overall increasing trend, the frequency of childhood CT, especially at age < 5, was decreasing, reflecting a growing awareness for efforts to reduce childhood CT exposure over the past decade. In 2018, 138 532 head CT examinations were performed at age 0 to 10, which would consequently induce a lifetime excess of 22 cases (1 per 6300 scans) of brain/CNS cancers, accounting for 5% of the total cases. More excess cases were estimated among men than among women, and excess cases could emerge at relatively young ages. These results would have useful implications as scientific basis for future large-scale epidemiological studies and also as quantitative evidence to justify the benefits of CT vs risks in Japan.

Occupational radiation exposure and excess additive risk of cataract incidence in a cohort of US radiologic technologists.

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.

Report of IRPA task group on issues and actions taken in response to the change in eye lens dose limit.

In 2018, the International Radiation Protection Association (IRPA) established its third task group (TG) on the implementation of the eye lens dose limit. To contribute to sharing experience and raising awareness within the radiation protection community about protection of workers in exposure of the lens of the eye, the TG conducted a questionnaire survey and analysed the responses. This paper provides an overview of the results of the questionnaire.

Risk of cataract removal surgery in Mayak PA workers occupationally exposed to ionizing radiation over prolonged periods.

In this study, the risk of cataract removal surgery was assessed in a cohort of workers occupationally exposed to ionizing radiation over a prolonged period. The study cohort includes 22,377 workers of the Mayak Production Association (about 25% of whom are females) first employed at one of the main facilities in 1948-1982, who were followed up to the end of 2008. Dose estimates used in the study are provided by the Mayak Worker Dosimetry System 2008. The mean cumulative dose from external γ-rays [personal dose equivalent Hp(10)] is 0.54 ± 0.76 Sv for males and 0.44 ± 0.65 Sv for females. The mean cumulative doses from neutrons (personal dose equivalent Hp(10)n) were 0.034 ± 0.080 Sv for males and 0.033 ± 0.092 Sv for females. Relative risks and excess relative risks per unit dose were calculated based on maximum likelihood. Among 4,177 workers diagnosed with a verified diagnosis of senile cataract, 701 lens removal surgeries (16.7%) were performed by the end of the follow-up period. The risk of cataract removal surgery was shown to be significantly associated with non-radiation factors such as sex, attained age, smoking, an ocular comorbidity (e.g., glaucoma), and a somatic comorbidity (e.g., diabetes mellitus). There was no significant association of cataract removal surgery with external γ-dose regardless of inclusion of the neutron dose adjustment with either linear or non-linear models. It is concluded that cataract removal surgery rate may not be a highly sensitive and specific indicator that could serve as a surrogate for radiation-related cataracts.

History of radiation detriment and its calculation methodology used in ICRP Publication 103.

Over the past decades, the International Commission on Radiological Protection (ICRP) has used radiation detriment, which is a multidimensional concept to quantify the overall harm to health from stochastic effects of low-level radiation exposure of different parts of the body. Each tissue-specific detriment is determined from the nominal tissue-specific risk coefficient, weighted by the severity of the disease in terms of lethality, impact on quality of life and years of life lost. Total detriment is the sum of the detriments for separate tissues and organs. Tissue weighting factors for the calculation of effective dose are based on relative contributions of each tissue to the total detriment. Calculating radiation detriment is a complex process that requires information from various sources and judgements on how to achieve calculations. As such, it is important to document its calculation methodology. To improve the traceability of calculations and form a solid basis for future recommendations, the ICRP Task Group 102 on detriment calculation methodology was established in 2016. As part of its mission, the history of radiation detriment was reviewed, and the process of detriment calculation was detailed. This article summarises that work, aiming to clarify the methodology of detriment calculation currently used by ICRP.

Risk of various types of cataracts in a cohort of Mayak workers following chronic occupational exposure to ionizing radiation.

This study is the first to report cataract type specific risks in a cohort of Russian Mayak Production Association workers following chronic occupational exposure to ionizing radiation. In this retrospective cohort study, 22,377 workers (females 25.4%) first employed in 1948-1982 were followed up till the end of 2008. All cataract subtypes were significantly dependent on sex, attained age, diabetes mellitus, myopia and glaucoma. For each of posterior subcapsular (PSC), cortical and nuclear cataracts, the risk of cataract incidence significantly linearly increased with increasing radiation dose. Excess relative risk per unit effective dose (ERR/Sv) from external γ-rays based on the linear model was 0.91 [95% confidence intervals (CIs) 0.67, 1.20] for PSC, 0.63 (95% CIs 0.49, 0.76) for cortical, and 0.47 (95% CIs 0.35, 0.60) for nuclear cataracts. For all three types of cataracts, exclusion of an adjustment for neutron dose as well as inclusion of additional adjustments for body mass index and smoking index decreased ERR/Sv of external γ-rays. Inclusion of an additional adjustment for glaucoma, however, modestly increased incidence risks for cortical and nuclear cataracts, but not PSC cataracts. Inclusion of an adjustment for diabetes mellitus decreased ERR/Sv of external γ-rays only for PSC incidence. Both males and females had increased risks for all three types of cataracts, but ERR/Sv was significantly higher in females than in males (p < 0.001), particularly for PSC cataracts. The results suggest that chronic occupational radiation exposure significantly increases risks of PSC, cortical and nuclear cataracts, and that such risks are higher in females than in males.

Occupational radiation exposure and risk of cataract incidence in a cohort of US radiologic technologists.

It has long been known that relatively high-dose ionising radiation exposure (> 1 Gy) can induce cataract, but there has been no evidence that this occurs at low doses (< 100 mGy). To assess low-dose risk, participants from the US Radiologic Technologists Study, a large, prospective cohort, were followed from date of mailed questionnaire survey completed during 1994-1998 to the earliest of self-reported diagnosis of cataract/cataract surgery, cancer other than non-melanoma skin, or date of last survey (up to end 2014). Cox proportional hazards models with age as timescale were used, adjusted for a priori selected cataract risk factors (diabetes, body mass index, smoking history, race, sex, birth year, cumulative UVB radiant exposure). 12,336 out of 67,246 eligible technologists reported a history of diagnosis of cataract during 832,479 person years of follow-up, and 5509 from 67,709 eligible technologists reported undergoing cataract surgery with 888,420 person years of follow-up. The mean cumulative estimated 5-year lagged eye-lens absorbed dose from occupational radiation exposures was 55.7 mGy (interquartile range 23.6-69.0 mGy). Five-year lagged occupational radiation exposure was strongly associated with self-reported cataract, with an excess hazard ratio/mGy of 0.69 × 10-3 (95% CI 0.27 × 10-3 to 1.16 × 10-3, p < 0.001). Cataract risk remained statistically significant (p = 0.030) when analysis was restricted to < 100 mGy cumulative occupational radiation exposure to the eye lens. A non-significantly increased excess hazard ratio/mGy of 0.34 × 10-3 (95% CI - 0.19 × 10-3 to 0.97 × 10-3, p = 0.221) was observed for cataract surgery. Our results suggest that there is excess risk for cataract associated with radiation exposure from low-dose and low dose-rate occupational exposures.

Basic amino acids in the N-terminal half of the PB2 subunit of influenza virus RNA polymerase are involved in both transcription and replication.

The PB2 subunit of influenza virus RNA polymerase is known to be involved in the initiation of transcription of the virus genome via cap binding. However, other specific roles of PB2 for viral RNA synthesis are not well understood. Here, we demonstrate that basic residues, 124R, 142R, 143R, 268R and 331K/332R, in the N-terminal half of PB2 are important for the polymerase activity. Notably, R124A mutation remarkably reduced the synthesis of mRNA, cRNA and vRNA in vivo, which was in good agreement with the data obtained in vitro. Cross-linking studies suggested that a reduction of the polymerase activity in the R124A mutant was due to a significant decrease in binding to the viral RNA promoter. In the three-dimensional structure of the polymerase, 124R is visible through the NTP tunnel and is located close to the polymerase active site. We propose that 124R plays a key role in promoter binding during RNA synthesis.

Metastasis of breast cancer cells to the bone, lung, and lymph nodes promotes resistance to ionizing radiation.

BACKGROUND: Metastasis represents the leading cause of breast cancer deaths, necessitating strategies for its treatment. Although radiotherapy is employed for both primary and metastatic breast cancers, the difference in their ionizing radiation response remains incompletely understood. This study is the first to compare the radioresponse of a breast cancer cell line with its metastatic variants and report that such metastatic variants are more radioresistant. MATERIALS AND METHODS: A luciferase expressing cell line was established from human basal-like breast adenocarcinoma MDA-MB-231 and underwent in vivo selections, whereby a cycle of inoculations into the left cardiac ventricle or the mammary fat pad of athymic nude mice, isolation of metastases to the bone, lung and lymph nodes visualized with bioluminescence imaging, and expansion of obtained cells was repeated twice or three times. The established metastatic cell lines were assessed for cell proliferation, wound healing, invasion, clonogenic survival, and apoptosis. RESULTS: The established metastatic cell lines possessed an increased proliferative potential in vivo and were more chemotactic, invasive, and resistant to X­ray-induced clonogenic inactivation and apoptosis in vitro. CONCLUSION: Breast cancer metastasis to the bone, lung, and lymph nodes promotes radioresistance.

Current situations and discussions in Japan in relation to the new occupational equivalent dose limit for the lens of the eye.

Since the International Commission on Radiological Protection recommended reducing the occupational equivalent dose limit for the lens of the eye in 2011, there have been extensive discussions in various countries. This paper reviews the current situation in radiation protection of the ocular lens and the discussions on the potential impact of the new lens dose limit in Japan. Topics include historical changes to the lens dose limit, the current situation with occupational lens exposures (e.g., in medical workers, nuclear workers, and Fukushima nuclear power plant workers) and measurements, and the current status of biological studies and epidemiological studies on radiation cataracts. Our focus is on the situation in Japan, but we believe such information sharing will be useful in many other countries.

A study on the effect of the internal exposure to (210)Po on the excretion of urinary proteins in rats.

This study was designed to assess the feasibility of a noninvasive urine specimen for the detection of proteins as indicators of internal exposure to ionizing radiation. Three groups of rats (five in each group) were intravenously injected with 1601 ± 376, 10,846 ± 591 and 48,467 ± 2812 Bq of (210)Po in citrate form. A sham-exposed control group of five rats was intravenously injected with sterile physiological saline. Daily urine samples were collected over 4 days following injection. Purification and pre-concentration of urinary proteins were carried out by ultrafiltration using a 3000 Da molecular weight cutoff membrane filter. The concentration of common urinary proteins, namely albumin, alpha-1-acid glycoprotein, immunoglobulins IgA and IgG, was measured by an enzyme-linked immunosorbent assay. Urinary excretion of albumin decreased dose-dependently (p < 0.05) 96 h post-injection relative to the control group. In contrast, no statistically significant effects were observed for other proteins tested. The dose-dependent decrease in urinary excretion of albumin observed in this study underscores the need for further research, which may lead to the discovery of new biomarkers that would reflect the changes in the primary target organs for deposition of (210)Po.