A systematic review of human evidence for the intergenerational effects of exposure to ionizing radiation.

PURPOSE: To provide a synthesis of the published evidence pertaining to the intergenerational health effects of parental preconceptional exposure to ionizing radiation in humans. METHODS: The study populations are the descendants of those who were exposed to ionizing radiation prior to conception. A Boolean search identified publications for review in accordance with Office of Health Assessment and Translation guidelines. Initially, a risk of bias assessment was conducted for each published study and relevant data extracted. Information was organized into adverse health outcome groups and exposure situations. To make an assessment from the body of evidence within each group, an initial confidence rating was assigned, before factors including inconsistencies between studies, magnitude of effect, dose response and confounders were considered. From this, 'an effect', 'no effect' or whether the evidence remained 'inadequate' to determine either effect or no effect, was ascertained. This assessment was based primarily upon the author's conclusions within that evidence-base and, by binomial probability testing of the direction of effect reported. RESULTS: 2441 publications were identified for review which after screening was reduced to 127. For the majority of the adverse health groups, we find there to be inadequate evidence from which to determine whether the health effect was, or was not, associated with parental preconceptional radiation exposure. This was largely due to heterogeneity between individual study's findings and conclusions within each group and, the limited number of studies within each group. We did observe one health grouping (congenital abnormalities) in occupationally exposed populations, where an increase in effect relative to their controls or large magnitude of effects, were reported, although it is noted that the authors of these studies interpreted their findings as most likely not to be associated with parental radiation exposure. CONCLUSIONS: We find there to be a lack of evidence to enable the formal assessment of radiation-related adverse effects in offspring of exposed humans. This is not the same as there being no clear evidence that effects may occur but does infer that if adverse health effects do arise in children of exposed parents, then these effects are small and difficult to reproducibly measure. Inconsistencies in designing studies are unavoidable, however we highlight the need for an element of standardization and, more sharing of primary datasets as part of open access initiatives, in order for future reviews to make reasonable conclusions. Overall, there is a need for future work to ensure comparable measures between studies where possible.

M-FISH evaluation of chromosome aberrations to examine for historical exposure to ionising radiation due to participation at British nuclear test sites.

Veterans of the British nuclear testing programme represent a population of ex-military personnel who had the potential to be exposed to ionising radiation through their participation at nuclear testing sites in the 1950s and 1960s. In the intervening years, members of this population have raised concerns about the status of their health and that of their descendants, as a consequence. Radiation dose estimates based on film badge measurements of external dose recorded at the time of the tests suggest any exposure to be limited for the majority of personnel, however, only ∼20% of personnel were monitored and no measurement for internalised exposure are on record. Here, to in-part address families concerns, we assay for chromosomal evidence of historical radiation exposure in a group of aged nuclear test (NT) veterans, using multiplexin situhybridisation (M-FISH), for comparison with a matched group of veterans who were not present at NT sites. In total, we analysed 9379 and 7698 metaphase cells using M-FISH (24-colour karyotyping) from 48 NT and 38 control veteran samples, representing veteran servicemen from the army, Royal Airforce and Royal Navy. We observed stable and unstable simple- and complex-type chromosome aberrations in both NT and control veterans' samples, however find no significant difference in yield of any chromosome aberration type between the two cohorts. We do observe higher average frequencies of complex chromosome aberrations in a very small subset of veterans previously identified as having a higher potential for radiation exposure, which may be indicative of internalised contamination to long-lived radionuclides from radiation fallout. By utilising recently published whole genome sequence analysis data of a sub-set of the same family groups, we examined for but found no relationship between paternal chromosome aberration burden, germline mutation frequency and self-reported concerns of adverse health in family members, suggesting that the previously reported health issues by participants in this study are unlikely to be associated with historical radiation exposure. We did observe a small number of families, representing both control and NT cohorts, showing a relationship between paternal chromosome aberrations and germline mutation sub-types which should be explored in future studies. In conclusion, we find no cytogenetic evidence of historical radiation exposure in the cohort of nuclear veterans sampled here, offering reassurance that attendance at NTs sites by the veterans sampled here, was not associated with significant levels of exposure to radiation.

No evidence of increased mutations in the germline of a group of British nuclear test veterans.

The potential germline effects of radiation exposure to military veterans present at British nuclear tests in Australia and the South Pacific is of considerable interest. We analyzed germline mutations in 60 families of UK military personnel comprising 30 control and 30 nuclear test veterans (NTV). Using whole-genome sequencing we studied the frequency and spectra of de novo mutations to investigate the transgenerational effect of veterans' (potential) exposure to radiation at nuclear bomb test sites. We find no elevation in total de novo single nucleotide variants, small insertion-deletions, structural variants or clustered mutations among the offspring of nuclear test veterans compared to those of control personnel. We did observe an elevated occurrence of single base substitution mutations within mutation signature SBS16, due to a subset of NTV offspring. The relevance of this elevation to potential exposure of veteran fathers and, future health risks, require further investigation. Overall, we find no evidence of increased mutations in the germline of a group of British nuclear test veterans. ISRCTN Registry 17461668.

British nuclear test veteran family trios for the study of genetic risk.

The risk of radiation effects in children of individuals exposed to ionising radiation remains an ongoing concern for aged veterans of the British nuclear testing programme. The genetic and cytogenetic family trio (GCFT) study is the first study to obtain blood samples from a group of British nuclear test veterans and their families for the purposes of identifying genetic alterations in offspring as a consequence of historical paternal exposure to ionising radiation. In this report, we describe the processes for recruitment and sampling, and provide a general description of the study population recruited. In total, blood samples were received from 91 (49 test and 42 control) families representing veteran servicemen from the army, Royal Air Force and Royal Navy. This translated to an overall response rate of 14% (49/353) for test veterans and 4% (42/992) for control veterans (excluding responders known to be ineligible). Due to the lack of dose information available, test veterans were allocated to a three-point exposure rank. Thirty (61%) test veterans were ranked in the lower group. Nineteen (39%) of the 49 test veterans were classified in the mid (5 veterans; 10%)/high (14 veterans; 29%) exposure ranks and included 12 veterans previously identified as belonging to the special groups or listed in health physics documents. An increased number of test veteran families (20%), compared with control families (5%), self-reported offspring with congenital abnormalities (p= 0.03). Whether this observation in this small group is reflective of the entire UK test veteran cohort or whether it is selection bias requires further work. The cohort described here represent an important and unique family trio grouping whose participation is enabling genetic studies, as part of the GCFT study, to be carried out. The outcomes of these studies will be published elsewhere. ISRCTN Registry: 17461668.

Dose estimation after a mixed field exposure: Radium-223 and intensity modulated radiotherapy.

INTRODUCTION: Radium-223 dichloride ([223Ra]RaCl2), a radiopharmaceutical that delivers α-particles to regions of bone metastatic disease, has been proven to improve overall survival of men with metastatic castration resistant prostate cancer (mCRPC). mCRPC patients enrolled on the ADRRAD clinical trial are treated with a mixed field exposure comprising radium-223 (223Ra) and intensity modulated radiotherapy (IMRT). While absorbed dose estimation is an important step in the characterisation of wider systemic radiation risks in nuclear medicine, uncertainties remain for novel radiopharmaceuticals such as 223Ra. METHODS: 24-Colour karyotyping was used to quantify the spectrum of chromosome aberrations in peripheral blood lymphocytes of ADRRAD patients at incremental times during their treatment. Dicentric equivalent frequencies were used in standard models for estimation of absorbed blood dose. To account for the mixed field nature of the treatment, existing models were used to determine the ratio of the component radiation types. Additionally, a new approach (M-FISHLET), based on the ratio of cells containing damage consistent with high-LET exposure (complex chromosomal exchanges) and low-LET exposure (simple exchanges), was used as a pseudo ratio for 223Ra:IMRT dose. RESULTS: Total IMRT estimated doses delivered to the blood after completion of mixed radiotherapy (after 37 IMRT fractions and two [223Ra]RaCl2 injections) were in the range of 1.167 ± 0.092 and 2.148 ± 0.096 Gy (dose range across all models applied). By the last treatment cycle analysed in this study (four [223Ra]RaCl2 injections), the total absorbed 223Ra dose to the blood was estimated to be between 0.024 ± 0.027 and 0.665 ± 0.080 Gy, depending on the model used. Differences between the models were observed, with the observed dose variance coming from inter-model as opposed to inter-patient differences. The M-FISHLET model potentially overestimates the 223Ra absorbed blood dose by accounting for further PBL exposure in the vicinity of metastatic sites. CONCLUSIONS: The models presented provide initial estimations of cumulative dose received during incremental IMRT fractions and [223Ra]RaCl2 injections, which will enable improved understanding of the doses received by individual patients. While the M-FISHLET method builds on a well-established technique for external exposures, further consideration is needed to evaluate this method and its use in assessing non-targeted exposure by 223Ra after its localization at bone metastatic sites.

Exposure Worry: The Psychological Impact of Perceived Ionizing Radiation Exposure in British Nuclear Test Veterans.

Potential psychological issues faced by British nuclear test veterans have been under-researched. This study assessed the prevalence of clinically relevant anxiety in British nuclear test veterans and aimed to explore experiences of worry and the broader psychological impact of the British nuclear weapons testing programme. The Geriatric Anxiety Inventory (Short-Form) was completed by 89 British nuclear test veterans (33.7% met the criteria for clinically relevant anxiety). Nineteen veterans then participated in semi-structured interviews. Thematic analysis of the data generated three themes. The first theme highlighted how worry was relevant only in a few cases (four) generally regarding their grandchildren's health, but the guilt in those who perceive responsibility for family health conditions also appeared to be a pertinent issue. The second theme highlighted the anger towards authorities resulting from perceived negligence and deception. The third theme highlighted the relevance of how certain life events across the life course influence the potential psychological impact. This study suggests that guilt must be considered in (potentially) exposed individuals whose family members experience health conditions, which may exacerbate distress. It also suggests the importance that authorities ensure transparency when dealing with any radiological exposure scenario to reduce the potential for anger.

The psychological consequences of (perceived) ionizing radiation exposure: a review on its role in radiation-induced cognitive dysfunction.

PURPOSE: Exposure to ionizing radiation following environmental contamination (e.g., the Chernobyl and Fukushima nuclear accidents), radiotherapy and diagnostics, occupational roles and space travel has been identified as a possible risk-factor for cognitive dysfunction. The deleterious effects of high doses (≥1.0 Gy) on cognitive functioning are fairly well-understood, while the consequences of low (≤0.1 Gy) and moderate doses (0.1-1.0 Gy) have been receiving more research interest over the past decade. In addition to any impact of actual exposure on cognitive functioning, the persistent psychological stress arising from perceived exposure, particularly following nuclear accidents, may itself impact cognitive functioning. In this review we offer a novel interdisciplinary stance on the cognitive impact of radiation exposure, considering psychological and epidemiological observations of different exposure scenarios such as atomic bombings, nuclear accidents, occupational and medical exposures while accounting for differences in dose, rate of exposure and exposure type. The purpose is to address the question that perceived radiation exposure - even where the actual absorbed dose is 0.0 Gy above background dose - can result in psychological stress, which could in turn lead to cognitive dysfunction. In addition, we highlight the interplay between the mechanisms of perceived exposure (i.e., stress) and actual exposure (i.e., radiation-induced cellular damage), in the generation of radiation-induced cognitive dysfunction. In all, we offer a comprehensive and objective review addressing the potential for cognitive defects in the context of low- and moderate-dose IR exposures. CONCLUSIONS: Overall the evidence shows prenatal exposure to low and moderate doses to be detrimental to brain development and subsequent cognitive functioning, however the evidence for adolescent and adult low- and moderate-dose exposure remains uncertain. The persistent psychological stress following accidental exposure to low-doses in adulthood may pose a greater threat to our cognitive functioning. Indeed, the psychological implications for instructed cohorts (e.g., astronauts and radiotherapy patients) is less clear and warrants further investigation. Nonetheless, the psychosocial consequences of low- and moderate-dose exposure must be carefully considered when evaluating radiation effects on cognitive functioning, and to avoid unnecessary harm when planning public health response strategies.

Meeting report on ICRR2019, the 16th International Congress on Radiation Research.

The 16th International Congress of Radiation Research (ICRR2019) was held in Manchester, UK, in August 2019. The Congress, which is held every four years, covered a wide spectrum of topics relevant for all aspects of radiation research including basic mechanisms, translational research, radiotherapy and health effects, and ecology. Here, we provide a report of the plenary and keynote talks presented at the meeting.

DNA Damage Processing is Perturbed in Both Proliferative and Non-Proliferative Cells of Increased Chronological Cellular Age.

p53BP1 forms discrete foci within minutes of radiation exposure, at sites of DNA double-strand breaks, which ordinarily decay to background levels within 24 h of induction. Longer lived, persisting 53BP1 foci are thought to mark unrepaired or misrepaired damage and potentially, to be associated with genomic instability. It is known that repair of DNA damage is impaired in senescent (permanently arrested) and aged cells. We examined this further by measuring the induction and persistence of 53BP1 foci in proliferating and non-proliferating mid-passage (non-aged) and late-passage (in vitro aged) normal human bronchial epithelial cells. Our results showed background levels of 53BP1 foci to be elevated in in vitro aged cultures as expected and induction of 53BP1 foci after radiation exposure to be independent of culture age or proliferative status. In terms of 53BP1 decay, more cells with persisting foci were seen in in vitro aged cultures compared to non-aged populations; furthermore, this was observed in both non-cycling (nominally senescent) cells, as well as in actively proliferating cells. In conclusion, perturbation in radiation-induced damage processing is a function of increasing chronological cellular age per se and should be considered when extrapolating experimental data for radiation risk modeling.

Telomere elongation through hTERT immortalization leads to chromosome repositioning in control cells and genomic instability in Hutchinson-Gilford progeria syndrome fibroblasts, expressing a novel SUN1 isoform.

Immortalizing primary cells with human telomerase reverse transcriptase (hTERT) has been common practice to enable primary cells to be of extended use in the laboratory because they avoid replicative senescence. Studying exogenously expressed hTERT in cells also affords scientists models of early carcinogenesis and telomere behavior. Control and the premature ageing disease-Hutchinson-Gilford progeria syndrome (HGPS) primary dermal fibroblasts, with and without the classical G608G mutation have been immortalized with exogenous hTERT. However, hTERT immortalization surprisingly elicits genome reorganization not only in disease cells but also in the normal control cells, such that whole chromosome territories normally located at the nuclear periphery in proliferating fibroblasts become mislocalized in the nuclear interior. This includes chromosome 18 in the control fibroblasts and both chromosomes 18 and X in HGPS cells, which physically express an isoform of the LINC complex protein SUN1 that has previously only been theoretical. Additionally, this HGPS cell line has also become genomically unstable and has a tetraploid karyotype, which could be due to the novel SUN1 isoform. Long-term treatment with the hTERT inhibitor BIBR1532 enabled the reduction of telomere length in the immortalized cells and resulted that these mislocalized internal chromosomes to be located at the nuclear periphery, as assessed in actively proliferating cells. Taken together, these findings reveal that elongated telomeres lead to dramatic chromosome mislocalization, which can be restored with a drug treatment that results in telomere reshortening and that a novel SUN1 isoform combined with elongated telomeres leads to genomic instability. Thus, care should be taken when interpreting data from genomic studies in hTERT-immortalized cell lines.

TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription.

DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. Here, we show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation 'hotspot', MLL. Moreover, we find that TDP2 suppresses chromosome rearrangements induced by TOP2 and reduces TOP2-induced chromosome translocations that arise during gene transcription. Interestingly, however, we implicate TDP2-dependent NHEJ in the formation of a rare subclass of translocations associated previously with therapy-related leukemia and characterized by junction sequences with 4-bp of perfect homology. Collectively, these data highlight the threat posed by TOP2-induced DSBs during transcription and demonstrate the importance of TDP2-dependent non-homologous end-joining in protecting both gene transcription and genome stability.DNA double-strand breaks (DSBs) induced by topoisomerase II (TOP2) are rejoined by TDP2-dependent non-homologous end-joining (NHEJ) but whether this promotes or suppresses translocations is not clear. Here the authors show that TDP2 suppresses chromosome translocations from DSBs introduced during gene transcription.

Alpha-Particle-Induced Complex Chromosome Exchanges Transmitted through Extra-Thymic Lymphopoiesis In Vitro Show Evidence of Emerging Genomic Instability.

Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.

Relative proximity of chromosome territories influences chromosome exchange partners in radiation-induced chromosome rearrangements in primary human bronchial epithelial cells.

It is well established that chromosomes exist in discrete territories (CTs) in interphase and are positioned in a cell-type specific probabilistic manner. The relative localisation of individual CTs within cell nuclei remains poorly understood, yet many cancers are associated with specific chromosome rearrangements and there is good evidence that relative territorial position influences their frequency of exchange. To examine this further, we characterised the complexity of radiation-induced chromosome exchanges in normal human bronchial epithelial (NHBE) cells by M-FISH analysis of PCC spreads and correlated the exchanges induced with their preferred interphase position, as determined by 1/2-colour 2D-FISH analysis, at the time of irradiation. We found that the frequency and complexity of aberrations induced were reduced in ellipsoid NHBE cells in comparison to previous observations in spherical cells, consistent with aberration complexity being dependent upon the number and proximity of damaged CTs, i.e. lesion proximity. To ask if particular chromosome neighbourhoods could be identified we analysed all radiation-induced pair-wise exchanges using SCHIP (statistics for chromosome interphase positioning) and found that exchanges between chromosomes (1;13), (9;17), (9;18), (12;18) and (16;21) all occurred more often than expected assuming randomness. All of these pairs were also found to be either sharing similar preferred positions in interphase and/or sharing neighbouring territory boundaries. We also analysed a human small cell lung cancer cell line, DMS53, by M-FISH observing the genome to be highly rearranged, yet possessing rearrangements also involving chromosomes (1;13) and (9;17). Our findings show evidence for the occurrence of non-random exchanges that may reflect the territorial organisation of chromosomes in interphase at time of damage and highlight the importance of cellular geometry for the induction of aberrations of varying complexity after exposure to both low and high-LET radiation.

Reduced chromosome aberration complexity in normal human bronchial epithelial cells exposed to low-LET γ-rays and high-LET α-particles.

PURPOSE: Cells of the lung are at risk from exposure to low and moderate doses of ionizing radiation from a range of environmental and medical sources. To help assess human health risks from such exposures, a better understanding of the frequency and types of chromosome aberration initially-induced in human lung cell types is required to link initial DNA damage and rearrangements with transmission potential and, to assess how this varies with radiation quality. MATERIALS AND METHODS: We exposed normal human bronchial lung epithelial (NHBE) cells in vitro to 0.5 and 1 Gy low-linear energy transfer (LET) γ-rays and a low fluence of high-LET α-particles and assayed for chromosome aberrations in premature chromosome condensation (PCC) spreads by 24-color multiplex-fluorescence in situ hybridization (M-FISH). RESULTS: Both simple and complex aberrations were induced in a LET and dose-dependent manner; however, the frequency and complexity observed were reduced in comparison to that previously reported in spherical cell types after exposure to comparable doses or fluence of radiation. Approximately 1-2% of all exposed cells were categorized as being capable of transmitting radiation-induced chromosomal damage to future NHBE cell generations, irrespective of dose. CONCLUSION: One possible mechanistic explanation for this reduced complexity is the differing geometric organization of chromosome territories within ellipsoid nuclei compared to spherical nuclei. This study highlights the need to better understand the role of nuclear organization in the formation of exchange aberrations and, the influence three-dimensional (3D) tissue architecture may have on this in vivo.

DNMTs are required for delayed genome instability caused by radiation.

The ability of ionizing radiation to initiate genomic instability has been harnessed in the clinic where the localized delivery of controlled doses of radiation is used to induce cell death in tumor cells. Though very effective as a therapy, tumor relapse can occur in vivo and its appearance has been attributed to the radio-resistance of cells with stem cell-like features. The molecular mechanisms underlying these phenomena are unclear but there is evidence suggesting an inverse correlation between radiation-induced genomic instability and global hypomethylation. To further investigate the relationship between DNA hypomethylation, radiosensitivity and genomic stability in stem-like cells we have studied mouse embryonic stem cells containing differing levels of DNA methylation due to the presence or absence of DNA methyltransferases. Unexpectedly, we found that global levels of methylation do not determine radiosensitivity. In particular, radiation-induced delayed genomic instability was observed at the Hprt gene locus only in wild-type cells. Furthermore, absence of Dnmt1 resulted in a 10-fold increase in de novo Hprt mutation rate, which was unaltered by radiation. Our data indicate that functional DNMTs are required for radiation-induced genomic instability, and that individual DNMTs play distinct roles in genome stability. We propose that DNMTS may contribute to the acquirement of radio-resistance in stem-like cells.

Development and validation of 'AutoRIF': software for the automated analysis of radiation-induced foci.

BACKGROUND: The quantification of radiation-induced foci (RIF) to investigate the induction and subsequent repair of DNA double strands breaks is now commonplace. Over the last decade systems specific for the automatic quantification of RIF have been developed for this purpose, however to ask more mechanistic questions on the spatio-temporal aspects of RIF, an automated RIF analysis platform that also quantifies RIF size/volume and relative three-dimensional (3D) distribution of RIF within individual nuclei, is required. RESULTS: A java-based image analysis system has been developed (AutoRIF) that quantifies the number, size/volume and relative nuclear locations of RIF within 3D nuclear volumes. Our approach identifies nuclei using the dynamic Otsu threshold and RIF by enhanced Laplacian filtering and maximum entropy thresholding steps and, has an application 'batch optimisation' process to ensure reproducible quantification of RIF. AutoRIF was validated by comparing output against manual quantification of the same 2D and 3D image stacks with results showing excellent concordance over a whole range of sample time points (and therefore range of total RIF/nucleus) after low-LET radiation exposure. CONCLUSIONS: This high-throughput automated RIF analysis system generates data with greater depth of information and reproducibility than that which can be achieved manually and may contribute toward the standardisation of RIF analysis. In particular, AutoRIF is a powerful tool for studying spatio-temporal relationships of RIF using a range of DNA damage response markers and can be run independently of other software, enabling most personal computers to perform image analysis. Future considerations for AutoRIF will likely include more complex algorithms that enable multiplex analysis for increasing combinations of cellular markers.

Cellular Senescence - its role in cancer and the response to ionizing radiation.

Cellular senescence is a normal biological process that is initiated in response to a range of intrinsic and extrinsic factors that functions to remove irreparable damage and therefore potentially harmful cells, from the proliferative pool. Senescence can therefore be thought of in beneficial terms as a tumour suppressor. In contrast to this, there is a growing body of evidence suggesting that senescence is also associated with the disruption of the tissue microenvironment and development of a pro-oncogenic environment, principally via the secretion of senescence-associated pro-inflammatory factors. The fraction of cells in a senescent state is known to increase with cellular age and from exposure to various stressors including ionising radiation therefore, the implications of the detrimental effects of the senescent phenotype are important to understand within the context of the increasing human exposure to ionising radiation. This review will discuss what is currently understood about senescence, highlighting possible associations between senescence and cancer and, how exposure to ionising radiation may modify this.

High frequency of simple and complex chromosome aberrations detected in the Tokai-mura survivor four and five years after the 1999 criticality accident.

In September 1999 a criticality accident occurred in a uranium processing plant in Tokai-mura, Japan. During the accident, three workers (A, B and C) were exposed to high acute doses of neutrons and γ-rays: workers A and B fatally and worker C to an estimated whole body absorbed dose of 0.81 Gy neutrons and 1.3 Gy γ-rays. We obtained fixed peripheral blood lymphocytes (PBL) preparations from worker C approximately four and five years after the accident and assayed by 24 colour karyotyping (M-FISH) to determine the frequency and complexity of chromosome aberrations present. We observed a high frequency of simple reciprocal translocations, which we used to provide a rough estimation of dose and, in addition, for the assessment of the emergence of any clinically-relevant clonal exchanges. We did not observe any evidence of clonality but did find some evidence suggesting chromosome 1 as being preferentially involved in exchanges in stable cells. We also detected a relatively high frequency of damaged cells containing complex chromosome aberrations, of both the stable and unstable types. Qualitatively these complex aberrations were consistent with those observed to be induced after exposure to low doses of high-LET radiation or moderate doses of low-LET radiation, supporting the suggestion that heavily damaged cells can be quite long-lived in vivo.