Database of Families of Workers Chronically Exposed to Radiation: Data and Biospecimen Resources.

ABSTRACT: Animal experiment findings suggest that high doses of ionizing radiation exposure (>1.0 Gy) may cause genetic and epigenetic effects in offspring. However, epidemiological studies of offspring of radiation-exposed parents did not find increased risks of any health effects. Findings of cellular/experimental investigations and studies of human health effects are contradicting, and further investigations are needed to help resolve ambiguities using updated and/or improved data. This paper provides a detailed description of a database of families of workers of the first Russian nuclear facility, Mayak Production Association, located in the Southern Urals in the Chelyabinsk region close to Ozyorsk city, which started its operation in 1948 and today consists of reactors, radiochemical and plutonium production plants, and auxiliary facilities. The Mayak worker cohort includes 22,377 individuals (25% females) who were hired at one of the main Mayak PA facilities between 1948 and 1982 and were externally or internally exposed to ionizing radiation over prolonged periods. Advantages of the cohort include its large size, extensive follow-up period (70 y), individually measured doses from external and internal exposure and the wide range of these doses, heterogeneity by gender/age/ethnicity/initial health status, complete data on vital status and causes of death, available medical information on morbidity and reproduction, available data on non-radiation factors, and stored biological specimens donated by more than one-third of the cohort members. Based on medical and dosimetry database "Clinics" containing raw data on workers of the study cohort, the Mayak workers' family and offspring database was created. To date, it comprises 12,195 family couples (a husband and a wife) and 16,585 offspring. Biological specimens are available for more than 1,000 family triads (a husband, a wife, and their child). Stages of assembling the database and its descriptive characteristics are presented in this paper. Examples of potential applications of the database for investigations of non-targeted and transgenerational radiation effects in offspring of exposed parents are discussed.

The Russian Radiobiological Human Tissue Repository: characteristics of biological specimens donated by nuclear workers with lung cancer.

Purpose: Characteristics of biological specimens donated by nuclear workers with lung cancer.Materials and methods: Biological specimens were identified at the Radiobiological Human Tissue Repository (RHTR). It was established at the Southern Urals Biophysics Institute in Russia and has been developed and supported within the bilateral US-Russian Agreement on International Cooperation for Minimization of the Effects of Prolonged Radiation Exposure. Biological specimens were collected from workers of the Russian nuclear production facility Mayak PA who were exposed to gamma radiation and/or alpha particles. To determine a histologic type of lung cancer, immunohistochemistry was used.Results and conclusions: Today biological specimens donated by 343 registrants with lung cancer are available at the RHTR. Among them, 255 donors (74%) are Mayak PA workers hired at the main facilities (reactors, plutonium production, and radiochemical plants) in 1948-1982. These workers donated about 6024 specimens of lung tissues (tumor and tumor-free) stored mostly as formalin-fixed paraffin-embedded tissue blocks (31%) and histology slides (64%); in addition, they donated 1800 specimens of blood/blood components, buccal epithelium cells, and sputum. Among histologic types identified for these lung cancer cases, adenocarcinoma and small cell carcinoma were prevalent. Information about individual doses from external and internal radiation exposure, data on quantitative smoking characteristics and diseases are available for all workers with lung cancer. Complete information on radiation exposure, health status and non-radiation factors annotated to RHTR registrants and the high quality of the available biological specimens are a unique resource for studying biological mechanisms of radiation-induced lung cancer.

Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation.

Liver cancer is associated with genetic mutations caused by environmental exposures, including occupational exposure to alpha radiation emitted by plutonium. We used whole exome sequencing (WES) to characterize somatic mutations in 3 histologically distinct primary liver tumors (angiosarcoma of the liver (ASL), cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC)) from Mayak worker subjects occupationally exposed to ionizing radiation (IR) to investigate the contribution of IR to the mutational landscape of liver cancer. DNA sequence analysis revealed these tumors harbor an excess of deletions, with a deletions:substitutions ratio similar to that previously reported in radiation-associated tumors. These tumors were also enriched for clustered mutations, a signature of radiation exposure. Multiple tumors displayed similarities in abrogated gene pathways including actin cytoskeletal signaling and DNA double-strand break (DSB) repair. WES identified novel candidate driver genes in ASL involved in angiogenesis and PIK3CA/AKT/mTOR signaling. We confirmed known driver genes of CCA, and identified candidate driver genes involved in chromatin remodeling. In HCC tumors we validated known driver genes, and identified novel putative driver genes involved in Wnt/ß-catenin signaling, chromatin remodeling, PIK3CA/AKT/mTOR signaling, and angiogenesis. This pilot study identifies several novel candidate driver mutations that are likely to be caused by IR exposure, and provides the first data on the mutational landscape of liver cancer after IR exposure.

The Russian Human Radiobiological Tissue Repository: A Unique Resource for Studies of Plutonium-Exposed Workers.

The Russian Radiobiological Human Tissue Repository (RHTR) at the Southern Urals Biophysics Institute in Ozyorsk, Russia, was established to collect and store biospecimens supporting research on health consequences of chronic, low-dose radiation exposures. The purpose of this paper is to describe the RHTR resources and the availability of high-quality biological specimens. RHTR has enrolled two groups of subjects from 1951 to the present time: exposed workers at the Mayak Production Association facilities and residents of Ozyorsk who were never occupationally exposed to ionizing radiation (controls). Biospecimens are collected with informed consent of participants and are annotated with demographic, occupational, dosimetry and medical information. To date, 900 individuals have provided surgical tissues and 1000 have provided autopsy tissues. Blood samples are also collected and stored. Familial DNA is available from parent-offspring triads. Biospecimens and annotated data are available to interested scientists worldwide, via the RHTR website.

Decoupling of the nernst-planck and poisson equations. Application to a membrane system at overlimiting currents.

This paper deals with one-dimensional stationary Nernst-Planck and Poisson (NPP) equations describing ion electrodiffusion in multicomponent solution/electrode or ion-conductive membrane systems. A general method for resolving ordinary and singularly perturbed problems with these equations is developed. This method is based on the decoupling of NPP equations that results in deduction of an equation containing only the terms with different powers of the electrical field and its derivatives. Then, the solution of this equation, analytical in several cases or numerical, is substituted into the Nernst-Planck equations for calculating the concentration profile for each ion present in the system. Different ionic species are grouped in valency classes that allows one to reduce the dimension of the original set of equations and leads to a relatively easy treatment of multi-ion systems. When applying the method developed, the main attention is paid to ion transfer at limiting and overlimiting currents, where a significant deviation from local electroneutrality occurs. The boundary conditions and different approximations are examined: the local electroneutrality (LEN) assumption and the original assumption of quasi-uniform distribution of the space charge density (QCD). The relations between the ion fluxes at limiting and overlimiting currents are discussed. In particular, attention is paid to the "exaltation" of counterion transfer toward an ion-exchange membrane by co-ion flux leaking through the membrane or generated at the membrane/solution interface. The structure of the multi-ion concentration field in a depleted diffusion boundary layer (DBL) near an ion-exchange membrane at overlimiting currents is analyzed. The presence of salt ions and hydrogen and hydroxyl ions generated in the course of the water "splitting" reaction is considered. The thickness of the DBL and its different zones, as functions of applied current density, are found by fitting experimental current-voltage curves.