The Mayak Worker Dosimetry System (MWDS 2013): Soluble Plutonium Retention in the Lungs of An Occupationally Exposed USTUR Case.

For the first time, plutonium retention in human upper airways was investigated based on the dosimetric structure of the human respiratory tract proposed by the International Commission on Radiological Protection (ICRP). This paper describes analytical work methodology, case selection criteria, and summarizes findings on soluble (ICRP 68 Type M material) plutonium distribution in the lungs of a former nuclear worker occupationally exposed to plutonium nitrate [239Pu(NO3)4]. Thirty-eight years post-intake, plutonium was found to be uniformly distributed between bronchial (BB), bronchiolar (bb) and alveolar-interstitial (AI) dosimetric compartments as well as between the left and right lungs. 239+240Pu and 238Pu total body activity was estimated to be 2333 ± 23 and 42.1 ± 0.7 Bq, respectively. The results of this work provide key information on the extent of plutonium binding in the upper airways of the human respiratory tract.

Overview of ICRP Committee 1: radiation effects.

This paper does not necessarily reflect the views of the International Commission on Radiological Protection. The author passed away on 13 November 2015.Committee 1 of the International Commission on Radiological Protection (ICRP) addresses issues pertinent to tissue reactions, risks of cancer and heritable diseases, radiation dose responses, effects of dose rate, and radiation quality. In addition, it reviews data on the effects of radiation on the embryo/fetus, genetic factors in radiation response, and uncertainties in providing judgements on radiation-induced health effects. Committee 1 advises the Main Commission on the biological basis of radiation-induced health effects, and how epidemiological, experimental, and theoretical data can be combined to make quantitative judgements on health risks to humans. The emphasis is on low radiation doses, in the form of detriment-adjusted nominal risk coefficients, where there are considerable uncertainties in terms of the biology and the epidemiology. Furthermore, Committee 1 reviews data from radiation epidemiology studies and publications on the molecular and cellular effects of ionising radiation relevant to updating the basis of the 2007 Recommendations published in ICRP Publication 103 This paper will provide an overview of the activities of Committee 1, the updated work of the Task Groups and Working Parties, and the future activities being pursued.

International Commission on Radiological Protection Committee 1: current status and future directions.

Commission 1 of the International Commission on Radiological Protection considers the risk of induction of cancer and heritable disease (stochastic effects) together with the underlying mechanisms of radiation action. Committee 1 also considers the risks, severity, and mechanisms of induction of tissue/organ damage and developmental defects (deterministic effects). The Committee was significantly revamped in 2013 and last met in Abu Dhabi in October 2013. Committee 1 evaluated progress on two ongoing task groups: Task Group 64 'Cancer Risk from Alpha Emitters' and Task Group 75 'Stem Cell Radiobiology'. Following approval from the Main Commission, Committee 1 established two new task groups: Task Group 91 'Radiation Risk Inference at Low Dose and Low Dose Rate Exposure for Radiological Protection Purposes' and Task Group 92 'Terminology and Definitions'. This article presents a synopsis of the current status of Committee 1 and outlines the tasks that Committee 1 may undertake in the future.

No evidence for a low linear energy transfer adaptive response in irradiated RKO cells.

It has become increasingly evident from reports in the literature that there are many confounding factors capable of modulating radiation-induced non-targeted responses, such as the bystander effect and the adaptive response. In this paper, we examine recent data which suggest that the observation of non-targeted responses may not be universally observable for differing radiation qualities. We have conducted a study of the adaptive response following low-linear energy transfer exposures for human colon carcinoma cells and failed to observe adaption for the endpoints of clonogenic survival or micronucleus formation.

Profiling mitochondrial proteins in radiation-induced genome-unstable cell lines with persistent oxidative stress by mass spectrometry.

Previous work by Morgan and coworkers on radiation-induced genome instability in Chinese hamster ovary (CHO) cell lines showed that unstable LS-12 cells had persistently elevated levels of reactive oxygen species (ROS) that were likely due to dysfunctional mitochondria. To further investigate the correlation between radiation-induced genome instability and dysfunctional mitochondria, we performed quantitative high-throughput mass spectrometry on samples enriched in mitochondrial proteins from three chromosomally unstable CHO cell lines and their stable unirradiated GM10115 parental cell line. Out of several hundred identified proteins, sufficient data were collected on 74 mitochondrial proteins to test for statistically significant differences in their abundance between unstable and stable cell lines. The LS-12 cell line, which exhibited the highest level of ROS among the three unstable cell lines, was characterized by eight significantly down-regulated mitochondrial proteins, all associated with the TCA (tricarboxylic acid). Elevated levels of ROS relative to the unirradiated parental control were also statistically significant for the CS-9 cell line. The protein profile of CS-9 revealed five significantly up-regulated mitochondrial proteins, three of which are involved in oxidative phosphorylation. Elevation of ROS in the unstable 115 cell line was nearly as large as that seen in CS-9 cells but was not statistically significant. The mitochondrial protein profile of 115 cells showed significant down-regulation of acetyl-CoA-acetyltransferase, which was also down-regulated in LS-12, and two other proteins with abundances that were significantly different from control levels but were not directly related to either the TCA or oxidative phosphorylation. These results provide further evidence that elevated ROS and mitochondrial dysfunction are associated with radiation-induced genome instability; however, additional work is required to establish a firm mechanistic relationship between these end points.

Environmental Mutagen Society symposium on 'Risks of low dose, low dose rate exposures of ionizing radiation to humans'.

The Symposium, held in Vancouver, Canada, on 17 - 21 September 2006, was organized by the Environmental Mutagen Society, and it was their 37th Annual Meeting. Sessions were chaired by Drs W. F. Morgan and J. L. Schwartz, and papers were presented by Drs R.C. von Borstel, D. J. Brenner, J. L. Redpath, B. E. Erickson and A.L. Brooks.

Comparison of effects of GnRH and prostaglandin in combination, and prostaglandin on conception rates and time to conception in dairy cows.

OBJECTIVE: To assess the effectiveness of a gonadotrophin-releasing hormone (GnRH) / prostaglandin program (GnRH-PG-GnRH, Ovsynch) on conception rates and time to conception of lactating dairy cows compared with a PG program (double prostaglandin injection). DESIGN: A randomised multi-centre cohort study was conducted with 778 cows from nine dairy herds. Cows at different stages of lactation were randomly assigned, after matching for days open at the time of treatment, to either the PG or Ovsynch program. PROCEDURE: Cows on the PG program received two intramuscular injections of prostaglandin (2 mL, Prosolvin) 11 days apart. The Ovsynch program consisted of two intramuscular injections of GnRH (1 mL, Fertagyl) 9 days apart, separated by one injection of prostaglandin 40 h before the second GnRH injection. Milk samples were taken at the time of artificial insemination and assayed for progesterone by radioimmunoassay. RESULTS: The Ovsynch program was not significantly different to PG in achieving conception, with overall conception rates of 37.6% and 41.4%, respectively, for each program. There was, however, a significant interaction between the effects of parity and treatment (P = 0.03), because conception rates were higher in older cows (parity 5 or more) on the PG program than for older cows on the Ovsynch program. There was no significant effect of treatment (P > 0.5) on time to conception after treatment, but older cows were slower to conceive (P < 0.0001). Conception rates differed (P < 0.0001) among herds. CONCLUSION: The median days to conception for both groups was 22 and mean days from treatment to conception were 36.3 +/- 3.3 and 31.6 +/- 2.7 for the Ovsynch and PG programs respectively, indicating that reproductive performance of cows was not significantly different with Ovsynch program or PG program. There appears to be a need to evaluate causes of reproductive failure in older cows.

Attenuation of radiation-induced genomic instability by free radical scavengers and cellular proliferation.

To investigate the mechanisms of radiation-induced chromosomal instability, cells were irradiated in the presence of the free radical scavengers DMSO, glycerol, or cysteamine, in the presence of DMSO while frozen, or held in confluence arrest post-irradiation to permit cells to repair potentially lethal DNA damage. Clones derived from single progenitor cells surviving each treatment were then analyzed for the subsequent development of chromosomal instability. The presence of scavengers (+/- freezing) during irradiation, and the recovery from potentially lethal damage after irradiation led to an increase in cell survival that was accompanied by a decrease in the initial yield of chromosomal rearrangements. Furthermore, analysis of over 400 clones and 80,000 metaphases indicates that these same treatments reduced the incidence of instability at equitoxic doses when compared to controls irradiated in the absence of scavengers at ambient temperature. Results suggest that preventing reactive species from damaging DNA, promoting chemical repair of ionized DNA intermediates, or allowing enzymatic removal of genetic lesions, represent measures that reduce the total burden of DNA damage and reduce the subsequent onset of radiation-induced genomic instability.

A role for chromosomal instability in the development of and selection for radioresistant cell variants.

Chromosome instability is a common occurrence in tumour cells. We examined the hypothesis that the elevated rate of mutation formation in unstable cells can lead to the development of clones of cells that are resistant to the cancer therapy. To test this hypothesis, we compared chromosome instability to radiation sensitivity in 30 independently isolated clones of GM10115 human-hamster hybrid cells. There was a broader distribution of radiosensitivity and a higher mean SF(2)in chromosomally unstable clones. Cytogenetic and DNA double-strand break rejoining assays suggest that sensitivity was a function of DNA repair efficiency. In the unstable population, the more radioresistant clones also had significantly lower plating efficiencies. These observations suggest that chromosome instability in GM10115 cells can lead to the development of cell variants that are more resistant to radiation. In addition, these results suggest that the process of chromosome breakage and recombination that accompanies chromosome instability might provide some selective pressure for more radioresistant variants.

Compliance of Victorian dairy farmers with current calf rearing recommendations for control of Johne's disease.

Questionnaires were posted to 800 randomly selected registered Victorian dairy farmers in 1996. Five hundred and thirty-four responses were received and analysed. Johne's disease (JD) had been diagnosed on the farm of 13.2% of respondents in the last 5 years. JD was rated second only to neonatal diarrhoea in importance as a disease of calves, even though other diseases occurred more frequently. However, there was a low level of compliance with JD control recommendations by the respondents. There was no significant difference in the number of JD control recommendations adopted by farmers between the three major Victorian regions. There was a significant difference in compliance between farms having had a diagnosed case of JD and those that had not. Although there is awareness among dairy farmers of the importance of JD, there appears to be a poor implementation of measures by farmers to prevent the spread of the disease. Current JD control recommendations and the method of information transfer to Victorian dairy farms should be reassessed to ensure that dairy heifers are reared with minimal risk of transmission of JD.

Polymerase eta deficiency in the xeroderma pigmentosum variant uncovers an overlap between the S phase checkpoint and double-strand break repair.

The xeroderma pigmentosum variant (XPV) is a genetic disease involving high levels of solar-induced cancer that has normal excision repair but shows defective DNA replication after UV irradiation because of mutations in the damage-specific polymerase hRAD30. We previously found that the induction of sister chromatid exchanges by UV irradiation was greatly enhanced in transformed XPV cells, indicating the activation of a recombination pathway. We now have identified that XPV cells make use of a homologous recombination pathway involving the hMre11/hRad50/Nbs1 protein complex, but not the Rad51 recombination pathway. The hMre11 complexes form at arrested replication forks, in association with proliferating cell nuclear antigen. In x-ray-damaged cells, in contrast, there is no association between hMre11 and proliferating cell nuclear antigen. This recombination pathway assumes greater importance in transformed XPV cells that lack a functional p53 pathway and can be detected at lower frequencies in excision-defective XPA fibroblasts and normal cells. DNA replication arrest after UV damage, and the associated S phase checkpoint, is therefore a complex process that can recruit a recombination pathway that has a primary role in repair of double-strand breaks from x-rays. The symptoms of elevated solar carcinogenesis in XPV patients therefore may be associated with increased genomic rearrangements that result from double-strand breakage and rejoining in cells of the skin in which p53 is inactivated by UV-induced mutations.

Chromosomal instability induced by heavy ion irradiation.

PURPOSE: To establish the dose-response relationship for the induction of chromosomal instability in GM10115 cells exposed to high-energy iron ions (1 GeV/nucleon, mean LET 146 keV/microm) and gold ions (11 GeV/nucleon, mean LET 1450 keV/microm). Past work has established that sparsely ionizing X-rays can induce a long-lived destabilization of chromosomes in a dose-dependent manner at an incidence of approximately 3% per gray. The present investigation assesses the capacity of High-Z and High-energy (HZE) particles to elicit this same endpoint. MATERIALS AND METHODS: Clonal populations derived from single progenitor cells surviving heavy-ion irradiation were analyzed cytogenetically to identify those clones showing a persistent destablization of chromosomes. RESULTS: Dose-response data, with a particular emphasis at low dose (< 1.0 Gy), indicate a frequency of approximately 4% per gray for the induction of chromosomal instability in clones derived from single progenitor cells surviving exposure to iron ions. The induction of chromosomal instability by gold ions was, however, less responsive to applied dose, as the observed incidence of this phenotype varied from 0 to 10% over 1-8 Gy. Both iron and gold ions gave dose-dependent increases in the yield of chromosomal aberrations (both chromosome- and chromatid-type) measured at the first mitosis following irradiation, as well as shoulderless survival curves having D0=0.87 and 1.1 Gy respectively. CONCLUSIONS: Based on the present dose-response data, the relative biological effectiveness of iron ions is 1.3 for the induction of chromosomal instability, and this indicates that heavy ions are only slightly more efficient than X-rays at eliciting this delayed phenotype.

Genomic instability induced by high and low LET ionizing radiation.

Genomic instability is the increased rate of acquisition of alterations in the mammalian genome, and includes such diverse biological endpoints as chromosomal destabilization, aneuploidy, micronucleus formation, sister chromatid exchange, gene mutation and amplification, variations in colony size, reduced plating efficiency, and cellular transformation. Because these multiple endpoints persist long after initial radiation exposure, genomic instability has been proposed to operate as a driving force contributing to genetic plasticity and carcinogenic potential. Many of these radiation-induced endpoints depend qualitatively and quantitatively on genetic background, dose and LET. Differences in the frequency and temporal expression of chromosomal instability depend on all three of the foregoing factors. On the other hand, many of these endpoints appear independent of dose and show bystander effects, implicating non-nuclear targets and epigenetic regulatory mechanisms. The present work will survey results concerning the LET dependence of genomic instability and the role of epigenetic mechanisms, with a particular emphasis on the endpoint of chromosomal instability.

Genomic instability in Gadd45a-deficient mice.

Gadd45a-null mice generated by gene targeting exhibited several of the phenotypes characteristic of p53-deficient mice, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a -/- cell lineages and may contribute to the aneuploidy. Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability.

Critical target and dose and dose-rate responses for the induction of chromosomal instability by ionizing radiation.

To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (<1.0 Gy); at higher doses (>1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.

The Impact of Biology on Risk Assessment--workshop of the National Research Council's Board on Radiation Effects Research. July 21-22, 1997, National Academy of Sciences, Washington, DC.

The linear no-threshold extrapolation from a dose-response relationship for ionizing radiation derived at higher doses to doses for which regulatory standards are proposed is being challenged by some scientists and defended by others. It appears that the risks associated with exposures to doses of interest are below the risks that can be measured with epidemiological studies. Therefore, many have looked to biology to provide information relevant to risk assessment. The workshop reported here, "The Impact of Biology on Risk Assessment", was planned to address the need for additional information by bringing together scientists who have been working in key fields of biology and others who have been contemplating the issues associated specifically with this question. The goals of the workshop were to summarize and review the status of the relevant biology, to determine how the reported biological data might influence risk assessment, and to identify subjects on which more data are needed.

The nucleus is the target for radiation-induced chromosomal instability.

We have previously described chromosomal instability in cells of a human-hamster hybrid cell line after exposure to X rays. Chromosomal instability in these cells is characterized by the appearance of novel chromosomal rearrangements multiple generations after exposure to ionizing radiation. To identify the cellular target(s) for radiation-induced chromosomal instability, cells were treated with 125I-labeled compounds and frozen. Radioactive decays from 125I cause damage to the cell primarily at the site of their decay, and freezing the cells allows damage to accumulate in the absence of other cellular processes. We found that the decay of 125I-iododeoxyuridine, which is incorporated into the DNA, caused chromosomal instability. While cell killing and first-division chromosomal rearrangements increased with increasing numbers of 125I decays, the frequency of chromosomal instability was independent of dose. Chromosomal instability could also be induced from incorporation of 125I-iododeoxyuridine without freezing the cells for accumulation of decays. This indicates that DNA double-strand breaks in frozen cells resulting from 125I decays failed to lead to instability. Incorporation of an 125I-labeled protein (125I-succinyl-concanavalin A), which was internalized into the cell and/or bound to the plasma membrane, neither caused chromosomal instability nor potentiated chromosomal instability induced by 125I-iododeoxyuridine. These results show that the target for radiation-induced chromosomal instability in these cells is the nucleus.

DNA double-strand breaks, chromosomal rearrangements, and genomic instability.

DNA double-strand breaks can lead to chromosomal rearrangements at the first mitosis after exposure to the DNA strand-breaking agent. The evidence suggests a number of different pathways for DNA double-strand break rejoining in mammalian cells, but it is unclear what factors determine the fate of the induced break and whether or not it will lead to chromosomal rearrangement. If a cell does survive and proliferate after DNA cleavage, delayed chromosomal instability can be observed in the clonal descendants of the exposed cell. Most, but not all DNA double-strand breaking agents are effective at inducing this delayed chromosomal instability. In this paper, we review the evidence for the role of the DNA double-strand break in directly induced and delayed chromosomal rearrangements.