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

The paper reports on findings of the study of mortality from diseases of circulatory system (DCS) in Russian nuclear workers of the Mayak Production Association (22,377 individuals with 25.4% of females) who were hired at the facility in 1948–1982 and followed up until end-2018. Using the AMFIT module of EPICURE software, relative risks and excess relative risks 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) gray) for males and 0.37 (0.56) Gy for females. The mean cumulative liver absorbed alpha dose from internal exposure to incorporated plutonium was 0.18 (0.65) Gy for males and 0.40 (1.92) Gy for females. By the end of the follow-up, 6019 deaths from DCS as the main cause of death were registered among Mayak PA 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, ischemic heart disease (IHD) and cerebrovascular disease (CeVD) with gamma-ray exposure dose in the entire cohort, the resident subcohort and the migrant subcohort (either in males or females). For the subcohort of residents, a significant association with gamma dose was observed for mortality from ischemic stroke in males 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 males no significant associations of mortality from any of the DCS with liver absorbed alpha dose were observed, but for females positive associations were found for DCS (the entire cohort and the resident subcohort) and IHD (the entire cohort) mortality. No significant associations of mortality from various types of DCS with neutron dose were observed either in males or females, although neutron absorbed doses were recorded only in 18% of the workers.

Use of Physiologically-Based Kinetics Modelling to Reliably Predict Internal Concentrations of the UV Filter, Homosalate, After Repeated Oral and Topical Application

Ethical and legal considerations have led to increased use of non-animal methods to evaluate the safety of chemicals for human use. We describe the development and qualification of a physiologically-based kinetics (PBK) model for the cosmetic UV filter ingredient, homosalate, to support its safety without the need of generating further animal data. The intravenous (IV) rat PBK model, using PK-Sim®, was developed and validated using legacy in vivo data generated prior to the 2013 EU animal-testing ban. Input data included literature or predicted physicochemical and pharmacokinetic properties. The refined IV rat PBK model was subject to sensitivity analysis to identify homosalate-specific sensitive parameters impacting the prediction of Cmax (more sensitive than AUC(0-∞)). These were then considered, together with population modeling, to calculate the confidence interval (CI) 95% Cmax and AUC(0-∞). Final model parameters were established by visual inspection of the simulations and biological plausibility. The IV rat model was extrapolated to oral administration, and used to estimate internal exposures to doses tested in an oral repeated dose toxicity study. Next, a human PBK dermal model was developed using measured human in vitro ADME data and a module to represent the dermal route. Model performance was confirmed by comparing predicted and measured values from a US-FDA clinical trial (Identifier: NCT03582215, https://clinicaltrials.gov/). Final exposure estimations were obtained in a virtual population and considering the in vitro and input parameter uncertainty. This model was then used to estimate the Cmax and AUC(0–24 h) of homosalate according to consumer use in a sunscreen. The developed rat and human PBK models had a good biological basis and reproduced in vivo legacy rat and human clinical kinetics data. They also complied with the most recent WHO and OECD recommendations for assessing the confidence level. In conclusion, we have developed a PBK model which predicted reasonably well the internal exposure of homosalate according to different exposure scenarios with a medium to high level of confidence. In the absence of in vivo data, such human PBK models will be the heart of future completely non-animal risk assessments; therefore, valid approaches will be key in gaining their regulatory acceptance.Clinical Trial Registration: https://clinicaltrials.gov/, identifier, NCT03582215

241Am and 137Сs in the Khoiniki district of Belarus: updated radiological assessment of the local existing exposure situation

The results covered in this paper relate to the “Khoiniki” research sub-unit of a larger-scale sequence of studies focused on the local assessments of the present-day 241Am and 137Cs concentrations in the soils and locally produced foods, with the estimation of the public internal radiation doses in the residential areas of the Gomel region of the Republic of Belarus most closely adjacent to the ChNPP resettlement zone. The objective was to make a conservative estimate of a committed annual dose of internal exposure from 241Am and 137Сs received by the villagers of 96 farmsteads in 30 settlements of the private sector of Khoiniki countryside through both, inhalation and consumption of local foodstuffs. The results obtained in this study include an update of the existing contamination levels of 241Am and 137Сs present in the local soils and foods grown or produced in private backyards and households. 241Am in food samples was determined by alpha-spectroscopy radiochemical analysis with the use of selective extraction-chromatographic resins. Gamma-spectrometry techniques were used to measure 241Am in soil samples and 137Сs in soil and food samples. Based on our findings, the present-day deposition density of 241Am in the soils does not exceed 4 kBq/m2 , while the values of 137Cs contamination are by one to two orders of magnitude higher than that of 241Am and vary between 30 and 500 kBq/m2 . Generally, the values of activity concentration of 241Am detected in local soils are well within 10 Bq/kg in the majority of inspected villages, with the exception of three sites where higher levels of 241Am contamination is soils were detected ranging from 14 to 16 Bq/kg. The ambient dose rates in the countryside range from 0.05 to 0.38 μSv/hour, with the average of 0.15 μSv/hour. No cases of 137Сs contamination above the established reference levels of 80, 100 and 90 Bq/ kg have been found in the local food samples of, respectively, potatoes, vegetables (incl. roots and tubers) and grains. The content of 241Am in the staple foods produced in the area varies from single digits to tenths of mBq/ kg, which is less by three orders of magnitude than 137Сs activities concentrationd found in the same staples. Of the two pathways contributing to the local committed internal exposure from 241Am, the dominant one is through inhalation (0.006–0.038 mSv/year) prevailing over the consumption pathway of this same radioisotope by at least one order of magnitude. At the time of gardening and other household field works, the existing levels of 241Am contamination in soils are estimated to produce from 85 to 98% of the internal radiation dose received by individuals from inhaling the total of 241Am and 137Сs. The maximum committed annual doses of internal exposure from 137Сs are estimated to be above 1 mSv/year in 6 out of 30 villages engaged in our study. At the same time, the estimated internal radiation dose due to 241Am does not surpass 0.04 mSv/year. The 137Сs major contribution to the internal exposure of villages in the Khoiniki countryside is through food consumption.

Factors Influencing the Formation of Chemical–Hemoglobin Adducts

Hemoglobin (Hb) adducts have been used as biomarkers for the internal exposure to chemicals. Simultaneous exposure to chemicals that bond with the N-terminal valine of Hb to form adducts, such as glycidol, acrylamide, and glucose, may affect the formation of the individual Hb adducts. In this study, various factors influencing the formation of chemical–Hb adducts were analyzed using in vitro and in vivo systems. In the in vitro assays, the formation of glycidol– and acrylamide–Hb adducts was altered in the presence of glucose, serum albumin, and other chemicals. In contrast, in the in vivo experiments, glycidol– and acrylamide–Hb adduct formation was unchanged in mice exposed to glycidol and acrylamide. The interaction between glycidol and acrylamide with residues other than the N-terminal valine of Hb was analyzed using the protein thermal shift assay. Glycidol and acrylamide also interacted with amino acid residues other than the N-terminal valine of Hb. The presence of other blood components, such as amino acids, may affect the formation of chemical–Hb adducts. Further research is expected to elucidate the remaining unknown factors that affect the formation of chemical–Hb adducts.

Analysis of Relation Between Lifetime Rates and Incorporation of Plutonium-239 in Atomic Production Workers Regarding Tumor and Non-Tumor Causes of Death

Purpose: The objective of the study was in quantitative assessment of the effect of internal exposure to lifetime in Mayak PA workers based on analyzing dependence of certain lifetime rates on incorporation of plutonium-239 regarding tumor and non-tumor causes of death. Material and methods: The cohort of deceased Mayak PA workers employed in1948–1958 with known Pu-239 body burden comprising 2343 individuals, of them 1739 males and 604 females, was investigated. Using regression analysis we have assessed dependence of general lifetime and lifetime after start of work as well as of proportion of individuals who did not survive until standard age in general and after start of work from incorporated Pu-239 separately for workers of different age regarding tumor and non-tumor causes of death. Statistical values were defined using Statistica software. Results: It was stated that in case of increase of plutonium-239 body burden in males and females reliably increased shortening of lifetime and lifetime after start of work was observed as well as increased proportion of individuals who did not survive until standard lifetime rate and until standard lifetime after start of work. Reliable regression equations for dependence of the studied lifetime values from radionuclide incorporation rate were obtained based on regression analysis. Generally, changes in the studied characteristics of lifetime after start of work were more evident than in general lifetime characteristics. Conclusion: Reliable dependence of shortening of lifetime and lifetime after start of work, of increased proportion of individuals who did not survive until standard lifetime and lifetime after start of work among Mayak PA workers of different gender from incorporation of plutonium-239 regarding tumor and non-tumor causes of death was stated. Dependence of lifetime after start of work on incorporated plutonium-239 was higher than of general lifetime that could be probably due to direct contact of workers with radionuclide after start of work. The results obtained indicate feasibility of using not only general lifetime but also lifetime after start of work in assessment of lifetime among workers who are in contact with production hazardous factors.

Isolation and radiochemical purification of samarium isotopes using ion exchange resins АВ 17×8 AND KU-2

The relevance of the research is caused by the need to develop a methodological base for determining 151Sm content in the soil cover of radioactively contaminated territories of Kazakhstan. The developed method for the determining of 151Sm will make it possible to assess the levels of soil contamination with this radionuclide, to determine the character of its spatial distribution, to allow estimating the internal exposure doses for the personnel and the population. The aim of the research is to carry out the isolation and radiochemical purification of samarium isotopes from acid solutions via using ion-exchange resins AV 17×8 and KU-2. Objects: salt solutions based on nitric and hydrochloric acid containing the stable isotopes of some natural, artificial β-emitters and isotopes of U and Th. The concentrations of nitric and hydrochloric acids were equal to the concentrations of the same acids used in the routine analysis of Pu and Am. Concentrations of chemical elements were determined using the Agilent 7700x quadrupole mass spectrometer and the iCAP 6300 Duo atomic emission spectrometer. The results of the experiments on the isolation and radiochemical purification of samarium isotopes from acidic solutions using anion-exchange resin AV 17×8 and cation-exchange resin KU-2 have been presented. It has been shown that the Sm-fraction can be purified from alkaline elements, Tl and U isotopes using the KU-2 cation-exchange resin. In turn, the isotopes U, Fe and Co can be removed using an anion exchange resin in 9M HCl media.

HBM4EU Occupational Biomonitoring Study on e-Waste—Study Protocol

Workers involved in the processing of electronic waste (e-waste) are potentially exposed to toxic chemicals. If exposure occurs, this may result in uptake and potential adverse health effects. Thus, exposure surveillance is an important requirement for health risk management and prevention of occupational disease. Human biomonitoring by measurement of specific biomarkers in body fluids is considered as an effective method of exposure surveillance. The aim of this study is to investigate the internal exposure of workers processing e-waste using a human biomonitoring approach, which will stimulate improved work practices and contribute to raising awareness of potential hazards. This exploratory study in occupational exposures in e-waste processing is part of the European Human Biomonitoring Initiative (HBM4EU). Here we present a study protocol using a cross sectional survey design to study worker’s exposures and compare these to the exposure of subjects preferably employed in the same company but with no known exposure to industrial recycling of e-waste. The present study protocol will be applied in six to eight European countries to ensure standardised data collection. The target population size is 300 exposed and 150 controls. Biomarkers of exposure for the following chemicals will be used: chromium, cadmium and lead in blood and urine; brominated flame retardants and polychlorobiphenyls in blood; mercury, organophosphate flame retardants and phthalates in urine, and chromium, cadmium, lead and mercury in hair. In addition, the following effect biomarkers will be studied: micronuclei, epigenetic, oxidative stress, inflammatory markers and telomere length in blood and metabolomics in urine. Occupational hygiene sampling methods (airborne and settled dust, silicon wristbands and handwipes) and contextual information will be collected to facilitate the interpretation of the biomarker results and discuss exposure mitigating interventions to further reduce exposures if needed. This study protocol can be adapted to future European-wide occupational studies.

Non-Hodgkin lymphomas and ionizing radiation: case report and review of the literature

Non-Hodgkin lymphoma (NHL) increased continuously since the last century in developed countries. While they are considered as disease in elder ages, a remarkable increasing incidence is also observed in German children and juveniles. The higher rates are interpreted by the changes in classification because diseases such as chronic lymphocytic leukaemia were also identified as NHL. Considerable rates of NHL were found in nuclear workers and liquidators of Chernobyl, i.e. in cases of low-dose chronical exposures. In Germany, we noticed three workers who developed NHL after decontamination of nuclear facilities. The bone marrow is generally considered as target organ for ionizing radiation, but NHL is obviously induced in the whole pool of lymphocytes. Therefore, the dosimetry in cases of typical occupational external and internal exposure must be revised. A high radiation sensitivity for NHL is a possible suspect and likely reason which may partly explain the continuous rise of the diseases in populations underlying the current increases of medical diagnostic exposure. NHL is also induced in children and juveniles with a history of diagnostic X-rays.

PIG-A gene mutation as a genotoxicity biomaker in polycyclic aromatic hydrocarbon-exposed barbecue workers

Background The PIG-A gene mutation assay is a valuable tool for measuring in vivo gene mutations in blood cells. The human PIG-A assay, used as a potential genotoxicity biomarker, is minimally invasive, sensitive, and cost-efficient; however, the relationship between carcinogen exposure and PIG-A mutations is not well understood. Methods We investigated the genotoxic effect of red blood cells using PIG-A assay and lymphocyte cytokinesis-block micronucleus test in barbecue restaurant workers (N = 70) exposed to polycyclic aromatic hydrocarbons (PAHs) and self-identified healthy control subjects (N = 56). Urinary PAH metabolites were measured to evaluate internal exposure levels. Results Multivariate Poisson regression showed that the PAH-exposed workers exhibited significantly higher PIG-A mutant frequency (MF) (8.04 ± 6.81 × 10− 6) than did the controls (5.56 ± 5.26 × 10− 6) (RR = 0.707, 95% CI: 0.615–0.812, P < 0.001). These results indicate that PAH exposure is a risk factor for elevated PIG-A MF. The frequencies of micronuclei (MN) and nuclear buds (NBUD) in the PAH-exposed workers (MN: 3.06 ± 2.07 ‰, NBUD: 1.38 ± 1.02 ‰) were also significantly higher than in the controls (MN: 1.46 ± 0.64 ‰, P < 0.001; NBUD: 0.70 ± 0.60 ‰, P < 0.001). Additionally, PIG-A MFs showed better associations with several urinary hydroxylated PAH metabolites (P2-OH-Flu = 0.032, r2-OH-Flu = 0. 268; P2-OH-Phe = 0.022, r2-OH-Phe = 0.286; P3-OH-Phe = 0.0312, r3-OH-Phe = 0.270; P4-OH-Phe = 0.018, r4-OH-Phe = 0.296), while the increase in MN, NPB, and NBUD frequencies was not associated with any OH-PAH metabolites; and high-PAH-exposed workers showed the highest PIG-A MFs. Furthermore, there was a significant association between PIG-A MF and PAH exposure levels (Chi-square test for trend, P = 0.006). Conclusions Our results indicate that an increase in PIG-A MF in barbecue workers could reflect the response to PAH exposure, providing evidence of its potential as a genotoxicity biomarker in human risk assessment.