Summary of the 2021 ICRP workshop on the future of radiological protection.

The International Commission on Radiological Protection (ICRP) has embarked on a process to review and revise the current System of Radiological Protection ('the System'). To stimulate discussion, the ICRP published two open-access articles: one on aspects of the System that might require review, and another on research that might improve the scientific foundation of the System. Building on these articles, the ICRP organized a Workshop on the Future of Radiological Protection as an opportunity to engage in the review and revision of the System. This digital workshop took place from 14 October-3 November 2021 and included 20 live-streamed and 43 on-demand presentations. Approximately 1500 individuals from 100 countries participated. Based on the subjects covered by the presentations, this summary is organized into four broad areas: the scientific basis, concepts and application of the System; and the role of the ICRP. Some of the key topics that emerged included the following: classification of radiation-induced effects; adverse outcome pathway methodologies; better understanding of the dose-response relationship; holistic and reasonable approaches to optimization of protection; radiological protection of the environment; ethical basis of the System; clarity, consistency and communication of the System; application of the System in medicine and application of the principles of justification and optimization of protection.

Methods of massive parallel reporter assays for investigation of enhancers.

The correct deployment of genetic programs for development and differentiation relies on finely coordinated regulation of specific gene sets. Genomic regulatory elements play an exceptional role in this process. There are few types of gene regulatory elements, including promoters, enhancers, insulators and silencers. Alterations of gene regulatory elements may cause various pathologies, including cancer, congenital disorders and autoimmune diseases. The development of high-throughput genomic assays has made it possible to significantly accelerate the accumulation of information about the characteristic epigenetic properties of regulatory elements. In combination with high-throughput studies focused on the genome-wide distribution of epigenetic marks, regulatory proteins and the spatial structure of chromatin, this significantly expands the understanding of the principles of epigenetic regulation of genes and allows potential regulatory elements to be searched for in silico. However, common experimental approaches used to study the local characteristics of chromatin have a number of technical limitations that may reduce the reliability of computational identification of genomic regulatory sequences. Taking into account the variability of the functions of epigenetic determinants and complex multicomponent regulation of genomic elements activity, their functional verification is often required. A plethora of methods have been developed to study the functional role of regulatory elements on the genome scale. Common experimental approaches for in silico identification of regulatory elements and their inherent technical limitations will be described. The present review is focused on original high-throughput methods of enhancer activity reporter analysis that are currently used to validate predicted regulatory elements and to perform de novo searches. The methods described allow assessing the functional role of the nucleotide sequence of a regulatory element, to determine its exact boundaries and to assess the influence of the local state of chromatin on the activity of enhancers and gene expression. These approaches have contributed substantially to the understanding of the fundamental principles of gene regulation.

Keeping the ICRP recommendations fit for purpose.

The International Commission on Radiological Protection (ICRP) has embarked on a review and revision of the system of Radiological Protection that will update the 2007 general recommendations in ICRPPublication 103. This is the beginning of a process that will take several years, involving open and transparent engagement with organisations and individuals around the world. While the system is robust and has performed well, it must adapt to address changes in science and society to remain fit for purpose. The aim of this paper is to encourage discussions on which areas of the system might gain the greatest benefit from review, and to initiate collaborative efforts. Increased clarity and consistency are high priorities. The better the system is understood, the more effectively it can be applied, resulting in improved protection and increased harmonisation. Many areas are identified for potential review including: classification of effects, with particular focus on tissue reactions; reformulation of detriment, potentially including non-cancer diseases; re-evaluation of the relationship between detriment and effective dose, and the possibility of defining detriments for males and females of different ages; individual variation in the response to radiation exposure; heritable effects; and effects and risks in non-human biota and ecosystems. Some of the basic concepts are also being considered, including the framework for bringing together protection of people and the environment, incremental improvements to the fundamental principles of justification and optimisation, a broader approach to protection of individuals, and clarification of the exposure situations introduced in 2007. In addition, ICRP is considering identifying where explicit incorporation of the ethical basis of the system would be beneficial, how to better reflect the importance of communications and stakeholder involvement, and further advice on education and training. ICRP invites responses on these and other areas relating to the review of the System of Radiological Protection.

The radiological environment at the Mayak PA site and radiation doses to individuals involved in emergency and remediation operations after the 'Kyshtym Accident' in 1957.

This article assesses the radiological environment at the nuclear site of the Mayak PA, Russian Federation, during and after the accident in 1957, the so-called 'Kyshtym Accident', and the radiation doses to those who participated in the eradication of its consequences. Based on numerous archival documents, this paper presents the radiation data for 1957-1960, including individual dosimetry monitoring data and estimated doses to the Mayak workers, as well as the to personnel in supporting organisations and the military involved in the remediation operations. From 1957-1959 some 38 500 individuals took part in the clean-up actions and remediation of contaminated areas of the Mayak PA industrial site after the accident, including individuals exposed at the time of the accident: Mayak PA employees, militarypersonnel, and civil construction workers. External equivalent doses to 10 500 individuals were estimated in the range of 220 to 265 mSv, while there were cases of doses up to 950 mSv and higher. The collective dose received during the accident and its aftermath was in the region of 7300 person-Sv. By October-December 1957, the collective dose was about 4500 person-Sv. Collective doses recorded in 1958 and 1959 amounted to 2250 person-Sv and 480 person-Sv, respectively.

Plutonium production and particles incorporation into the human body.

Plutonium is one of the most toxic radioactive substances known. The isotope 239Pu gained attention when it had become known as a potential explosive material for atomic bombs. This paper describes the main problems encountered during the early years of operation of the first plutonium production plant in the former Soviet Union, the Mayak Production Association (Mayak PA). Mayak PA caused severe radioactive contamination of the environment and exposure personnel and population living in the vicinity areas to high radiation doses. The authors focus on key findings of large-scale studies on the internal dosimetry of workers for use in assessment of radiological risks from exposure to plutonium. This work presents an overview of the important issues for inhalation dose assessments such as generation of plutonium particles, plutonium intake, dissolution of plutonium particles, distribution of plutonium in humans, related exposures and health effects. Understanding the relationship between health effects, radiation dose and route of exposure helps quantify the health risks associated with occupational exposure in the nuclear industry and validate the radiation protection standards used in the Russian Federation and worldwide.

External dose reconstruction for the former village of Metlino (Techa River, Russia) based on environmental surveys, luminescence measurements, and radiation transport modelling.

In the first years of its operation, the Mayak Production Association, a facility part of the Soviet nuclear weapons program in the Southern Urals, Russia, discharged large amounts of radioactively contaminated effluent into the nearby Techa River, thus exposing the people living at this river to external and internal radiations. The Techa River Cohort is a cohort intensely studied in epidemiology to investigate the correlation between low-dose radiation and health effects on humans. For the individuals in the cohort, the Techa River Dosimetry System describes the accumulated dose in human organs and tissues. In particular, organ doses from external exposure are derived from estimates of dose rate in air on the Techa River banks which were estimated from measurements and Monte Carlo modelling. Individual doses are calculated in accordance with historical records of individuals' residence histories, observational data of typical lifestyles for different age groups, and age-dependent conversion factors from air kerma to organ dose. The work here describes an experimentally independent assessment of the key input parameter of the dosimetry system, the integral air kerma, for the former village of Metlino, upper Techa River region. The aim of this work was thus to validate the Techa River Dosimetry System for the location of Metlino in an independent approach. Dose reconstruction based on dose measurements in bricks from a church tower and Monte Carlo calculations was used to model the historic air kerma accumulated in the time from 1949 to 1956 at the shoreline of the Techa River in Metlino. Main issues are caused by a change in the landscape after the evacuation of the village in 1956. Based on measurements and published information and data, two separate models for the historic pre-evacuation geometry and for the current geometry of Metlino were created. Using both models, a value for the air kerma was reconstructed, which agrees with that obtained in the Techa River Dosimetry System within a factor of two.

Small molecule inhibition of cAMP response element binding protein in human acute myeloid leukemia cells.

The transcription factor CREB (cAMP Response-Element Binding Protein) is overexpressed in the majority of acute myeloid leukemia (AML) patients, and this is associated with a worse prognosis. Previous work revealed that CREB overexpression augmented AML cell growth, while CREB knockdown disrupted key AML cell functions in vitro. In contrast, CREB knockdown had no effect on long-term hematopoietic stem cell activity in mouse transduction/transplantation assays. Together, these studies position CREB as a promising drug target for AML. To test this concept, a small molecule inhibitor of CREB, XX-650-23, was developed. This molecule blocks a critical interaction between CREB and its required co-activator CBP (CREB Binding Protein), leading to disruption of CREB-driven gene expression. Inhibition of CBP-CREB interaction induced apoptosis and cell-cycle arrest in AML cells, and prolonged survival in vivo in mice injected with human AML cells. XX-650-23 had little toxicity on normal human hematopoietic cells and tissues in mice. To understand the mechanism of XX-650-23, we performed RNA-seq, ChIP-seq and Cytometry Time of Flight with human AML cells. Our results demonstrate that small molecule inhibition of CBP-CREB interaction mostly affects apoptotic, cell-cycle and survival pathways, which may represent a novel approach for AML therapy.

A computer simulation study of soft tissue characterization using low-frequency ultrasonic tomography.

We investigate the potential of using ultrasonic diffraction tomography technique for characterization of biological tissues. Unlike most of other studies where ultrasonic tomography operates at frequencies higher than 1 MHz, low-frequency tomography uses lower frequencies on the order of 0.3-0.5 MHz. Such a choice is due to low attenuation at these frequencies, resulting in higher precision of input data. In this paper we explore transmission and reflection schemes for both 2D (layer-by-layer) and 3D tomography. We treat inverse tomography problems as coefficient inverse problems for the wave equation. The time-domain algorithms employed for solving the inverse problem of low-frequency tomography focus on the use of GPU clusters. The results obtained show that a spatial resolution of about 2-3mm can be achieved when operating at the wavelength of about 5mm even using a stationary 3D scheme with a few fixed sources and no rotating elements. The study primarily focuses on determining the performance limits of ultrasonic tomography devices currently designed for breast cancer diagnosis.

[Radiobiological Human Tissue repository: progress and perspectives for solving the problems of radiation safety and health protection of personnel and population].

Radiobiological Human Tissue repository was established in order to obtain and store biological material from Mayak PA workers occupationally exposed to ionizing (α- and/or γ-) radiation in a wide dose range, from the residents exposed to long term radiation due to radiation accidents and transfer of the samples to scientists for the purpose of studying the effects of radiation for people and their offspring. The accumulated biomaterial is the informational and research potential that form the basis for the work of the scientists in different spheres of biology and medicine. The repository comprises 5 sections: tumor and non-tumor tissues obtained in the course of autopsies, biopsies, surgeries, samples of blood and its components, of DNA, induced sputum, saliva, and other from people exposed or unexposed (control) to radiation. The biomaterial is stored in formalin, in paraffin blocks, slides, as well as in the freezers under low temperatures. All the information on the samples and the registrants (medical, dosimetry, demographic, and occupational data) was obtained and entered into the electronic database. A constantly updated website of the repository was developed in order to provide a possibility to get acquainted with the material and proceed with application for biosamples for scientists from Russia and abroad. Some data obtained in the course of scientific research works on the basis of the biomaterial from the Repository are briefly introduced in the review.

[The prevention of the acute urine retention and lower urinary tract infection after rectum surgery].

The possibilities of the prevention of the acute urine retention in patients with the prostatic enlargement after the rectum surgery. The method was successfully used in 106 patients.

Plutonium worker dosimetry.

Epidemiological studies of the relationship between risk and internal exposure to plutonium are clearly reliant on the dose estimates used. The International Commission on Radiological Protection (ICRP) is currently reviewing the latest scientific information available on biokinetic models and dosimetry, and it is likely that a number of changes to the existing models will be recommended. The effect of certain changes, particularly to the ICRP model of the respiratory tract, has been investigated for inhaled forms of (239)Pu and uncertainties have also been assessed. Notable effects of possible changes to respiratory tract model assumptions are (1) a reduction in the absorbed dose to target cells in the airways, if changes under consideration are made to the slow clearing fraction and (2) a doubling of absorbed dose to the alveolar region for insoluble forms, if evidence of longer retention times is taken into account. An important factor influencing doses for moderately soluble forms of (239)Pu is the extent of binding of dissolved plutonium to lung tissues and assumptions regarding the extent of binding in the airways. Uncertainty analyses have been performed with prior distributions chosen for application in epidemiological studies. The resulting distributions for dose per unit intake were lognormal with geometric standard deviations of 2.3 and 2.6 for nitrates and oxides, respectively. The wide ranges were due largely to consideration of results for a range of experimental data for the solubility of different forms of nitrate and oxides. The medians of these distributions were a factor of three times higher than calculated using current default ICRP parameter values. For nitrates, this was due to the assumption of a bound fraction, and for oxides due mainly to the assumption of slower alveolar clearance. This study highlights areas where more research is needed to reduce biokinetic uncertainties, including more accurate determination of particle transport rates and long-term dissolution for plutonium compounds, a re-evaluation of long-term binding of dissolved plutonium, and further consideration of modeling for plutonium absorbed to blood from the lungs.

[Quantitative plutonium microdistribution in bone tissue of vertebra from occupationally exposed worker].

The purpose of this work is the receiving of quantitative data on Pu microdistribution in different structural elements of human bone tissue for local dose assessment and dosimetric models validation. Thoracic vertebra sample was taken for the study from former Mayak worker with rather high Pu burden, including information on occupational and exposure history, medical information and data on Pu content in organs. Lexan film autodiagrams were obtained using method of neutron-induced autoradiography from bone tissue sections. Quantitative analysis of randomly selected vision fields on one of autoradiograms was performed: fission fragment tracks Pu in different bone tissue areas were calculated, surface of bone tissue areas were defined. Quantitative information on Pu microdistribution in human bone tissue was obtained for the first time. On the basis of obtained data quantitative relation of Pu decays in bone volume to decays on bone surface in cortical and trabecular fractions were defined as 2.0 and 0.4, correspondingly. Actual quantitative relation of decays in bone volume to decays on bone surface is significantly different from recommended by ICRP for cortical fraction. Biokinetic model parameters of extrapulmonary ICRP compartment might need to be adjusted after expansion of data set on quantitative Pu microdistribution in other bone types in human that will involve new cases with different exposure pattern of radionuclide.

Uncertainties in internal doses calculated for Mayak workers--a study of 63 cases.

This study makes use of 63 cases of Mayak workers exposed to Pu-239 with autopsy data and some late-time urine bioassay data. In addition, air-concentration data--used to construct monthly average values--are available for each case, which provide the time dependence and potential magnitudes of normal inhalation intakes for each case. The purpose of the study is to develop and test Bayesian methods of dose calculation for the Mayak workers. The first part of the study was to quantitatively characterise the uncertainties of the bioassay data. Then, starting with three different published biokinetic models, the data are fit by varying intake and model perturbation parameters, e.g., parameters influencing the lung, thoracic lymph nodes, liver and bone retention. Statistical self-consistency arguments are used to check the measurement uncertainty parameters within the Poisson-lognormal model. The second part of the study is to set up and test Bayesian dose calculations, which use the point determinations of biokinetic parameters from the study cases within a discrete, empirical Bayes approximation. The main conclusion of the study is that these methods are now ready to be applied to the entire Mayak worker population.

Comparison of dose estimation from occupational exposure to 239Pu using different modelling approaches.

Several approaches are available for bioassay interpretation when assigning Pu doses to Mayak workers. First, a conventional approach is to apply ICRP models per se. An alternative method involves individualised fitting of bioassay data using Bayesian statistical methods. A third approach is to develop an independent dosimetry system for Mayak workers by adapting ICRP models using a dataset of available bioassay measurements for this population. Thus, a dataset of 42 former Mayak workers, who died of non-radiation effects, with both urine bioassay and post-mortem tissue data was used to test these three approaches. All three approaches proved to be adequate for bioassay and tissue interpretation, and thus for Pu dose reconstruction purposes. However, large discrepancies are observed in the resulting quantitative dose estimates. These discrepancies can, in large part, be explained by differences in the interpretation of Pu behaviour in the lungs in the context of ICRP lung model. Thus, a careful validation of Pu lung dosimetry model is needed in Mayak worker dosimetry systems.

In vitro dissolution study of plutonium in aerosol particles from the Mayak PA: a tool for individualised dose estimates.

Chronic inhalation of Pu particles during Mayak processing is a potential concern for workers. Of the many particle properties that affect individualised dose estimates, particle solubility in lung fluids can be most important. This study compares in vitro dissolution rates of several plutonium industrial compounds present at different stages of the Mayak processing cycle using three different solvents. The results are then used to develop values of absorption parameters for individual dose assessments. In this study, the dissolution rates of nitrate, oxide and mixed plutonium aerosols were determined using a serum ultrafiltrate stimulant (SUF), phagolysosomal simulant fluid and Ringer's solution, all using a static system. According to the results obtained with SUF, Pu nitrate is absorbed into the blood to a larger extent than predicted using model parameters currently applied for Mayak workers. Absorption into the blood of 21.5 vs. 3% of deposited nuclide as current model predicts results in underestimation of systemic burden and overestimation of the lung dose. These data are being used to provide improved retrospective dose assessments for inhaled plutonium aerosols.

Lung cancer in Mayak workers: interaction of smoking and plutonium exposure.

Lung cancer mortality among 5,058 male workers of the Mayak Production Association has been analyzed with emphasis on the interaction of smoking and radiation exposure by using the two-step clonal expansion (TSCE) model of carcinogenesis. The cohort consists of all Mayak workers with known smoking status, who were employed in the period 1948-1972, and who either had the plutonium concentration in urine measured or who worked in the reactors, where plutonium exposure was negligible. Those who died during the first two years after the first urine sampling were excluded. The follow-up extended until the end of 1998. During this time, 2,176 workers died, including 244 lung cancer cases. Mayak workers were exposed to external (gamma and neutron) radiation, and in the radiochemical and plutonium plants to plutonium. In the preferred TSCE model, internal radiation and smoking act on the clonal expansion of pre-carcinogenic clones. Assuming a plutonium radiation weighting factor of 20, the excess relative risk per lung dose was estimated to be 0.11 (95% CI: 0.08; 0.17) Sv(-1). Most of the lung cancer deaths are found to be due to smoking. The second main factor is the interaction of smoking and internal radiation. The model is sub-multiplicative in relative risks due to smoking and radiation. In a multiplicative version of the TSCE model, internal radiation acts on initiation and transformation rates. This model version agrees with conventional epidemiological risk models, because it also suggests a higher risk estimate than the preferred TSCE model. However, it fits the data less well than the preferred model.

Adaptation of the ICRP publication 66 respiratory tract model to data on plutonium biokinetics for Mayak workers.

The biokinetics of inhaled plutonium were analyzed using compartment models representing their behavior within the respiratory tract, the gastrointestinal tract, and in systemic tissues. The processes of aerosol deposition, particle transport, absorption, and formation of a fixed deposit in the respiratory tract were formulated in the framework of the Human Respiratory Tract Model described in ICRP Publication 66. The values of parameters governing absorption and formation of the fixed deposit were established by fitting the model to the observations in 530 autopsy cases. The influence of smoking on mechanical clearance of deposited plutonium activity was considered. The dependence of absorption on the aerosol transportability, as estimated by in vitro methods (dialysis), was demonstrated. The results of this study were compared to those obtained from an earlier model of plutonium behavior in the respiratory tract, which was based on the same set of autopsy data. That model did not address the early phases of respiratory clearance and hence underestimated the committed lung dose by about 25% for plutonium oxides. Little difference in lung dose was found for nitrate forms.

Lung cancer in Mayak workers.

The cohort of nuclear workers at the Mayak Production Association, located in the Russian Federation, is a unique resource for providing information on the health effects of exposure to plutonium as well as the effects of protracted external dose. Lung cancer mortality risks were evaluated in 21,790 Mayak workers, a much larger group than included in previous evaluations of lung cancer risks in this cohort. These analyses, which included 655 lung cancer deaths occurring in the period 1955-2000, were the first to evaluate both excess relative risk (ERR) and excess absolute risk (EAR) models and to give detailed attention to the modifying effects of gender, attained age and age at hire. Lung cancer risks were found to be significantly related to both internal dose to the lung from plutonium and external dose, and risks were described adequately by linear functions. For internal dose, the ERR per gray for females was about four times higher than that for males, whereas the EAR for females was less than half that for males; the ERR showed a strong decline with attained age, whereas the EAR increased with attained age until about age 65 and then decreased. Parallel analyses of lung cancer mortality risks in Mayak workers and Japanese A-bomb survivors were also conducted. Efforts currently under way to improve both internal and external dose estimates, and to develop data on smoking, should result in more accurate risk estimates in the future.

Plutonium microdistribution in the lungs of Mayak workers.

The degree of nonuniform distribution of plutonium in the human lung has not been determined; thus current dosimetric models do not account for nonuniform irradiation. A better scientific basis is needed for assessing the risk of developing radiation-induced disease from inhaled alpha-particle-emitting radionuclides. We measured the distribution of plutonium activity in the lung by autoradiography and related the activity to specific compartments of the lung. The study materials were lung specimens from deceased workers employed by the Mayak Production Association. The approach to analyzing these lung samples used contemporary stereological sampling and analysis techniques together with quantitative alpha-particle autoradiography. For the first time, plutonium distribution has been quantified in the human lung. The distribution of long-term retained plutonium is nonuniform, and a significant portion of plutonium was retained in pulmonary scars. In addition, a large fraction of plutonium was present in the parenchyma, where it was retained much longer than was estimated previously. The sequestration of plutonium particles in scars would greatly reduce the radiation exposure of the critical target cells and tissues for lung cancer. Thus the prolonged retention of plutonium in lung scars may not increase the dose or risk for lung cancer.

Distribution of plutonium particles in the lungs of Mayak workers.

Lung tissues from workers at the Mayak Production Association were examined to determine the distribution of plutonium (Pu) activity in various lung compartments. Stereological sampling methods and autoradiography were used. Pu particles were identified by microscopic examination of autoradiographs and localised in one of six normal anatomic sites and two sites of fibrosis (parenchymal, non-parenchymal). Particle activity was determined by counting the number of tracks emanating from the particles. Over 50% of the Pu activity was localised in sites of fibrosis, which had significantly higher than average activity for the lung. Over 40% of the activity was in lung parenchyma. Activity in the bronchovascular interstitium was significantly lower than average. These results support the hypothesis that Pu activity is not uniformly distributed in the lung, with long-term retained particles concentrated in scars of the lung. The results may significantly affect estimates of dose from inhaled Pu.