Irradiated Populations Research Articles

Frequency of acute myeloid leukaemia-associated mouse chromosome 2 deletions in X-ray exposed immature haematopoietic progenitors and stem cells

Exposure to ionising radiation can lead to an increased risk of cancer, particularly leukaemia. In radiation-induced acute myeloid leukaemia (rAML), a partial hemizygous deletion of mouse chromosome 2 is a common feature in several susceptible strains. The deletion is an early event detectable 24h after exposure in bone marrow cells using cytogenetic techniques. Expanding clones of bone marrow cells with chromosome 2 deletions can be detected less than a year after exposure to ionising radiation in around half of the irradiated mice. Ultimately, 15–25% of exposed animals develop AML. It is generally assumed that leukaemia originates in an early progenitor cell or haematopoietic stem cell, but it is unknown whether the original chromosome damage occurs at a similar frequency in committed progenitors and stem cells. In this study, we monitored the frequency of chromosome 2 deletions in immature bone marrow cells (Lin−) and haematopoietic stem cells/multipotent progenitor cells (LSK) by several techniques, fluorescent in situ hybridisation (FISH) and through use of a reporter gene model, flow cytometry and colony forming units in spleen (CFU-S) following ex vivo or in vivo exposure. We showed that partial chromosome 2 deletions are present in the LSK subpopulation, but cannot be detected in Lin− cells and CFU-S12 cells. Furthermore, we transplanted irradiated Lin− or LSK cells into host animals to determine whether specific irradiated cell populations acquire an increased proliferative advantage compared to unirradiated cells. Interestingly, the irradiated LSK subpopulation containing cells carrying chromosome 2 deletions does not appear to repopulate as well as the unirradiated population, suggesting that the chromosomal deletion does not provide an advantage for growth and in vivo repopulation, at least at early stages following occurrence.

Abstract 5233: Modeling ionizing radiation exposure in vitro and in vivo using the Virtual Tumour.

Abstract Ionizing radiation exposure induces DNA double strand breaks in mammalian cells. In response, cells activate repair mechanisms which involve cell cycle arrest at discrete transition points of the cell cycle. The results in an accumulation of cells in S and G2 phase in an irradiated cell population over a period of time following exposure. Using the Virtual Tumour, a cell population simulator of cancer cells and tissue, we have built a model of irradiation of tumour cell culture in vitro as well as tumour tissue in vivo for various cancer cell types. We show how cell cycle timings and radiosensitivity can accurately reproduce both in vivo and in vitro response to irradiation-induced DNA damage. We also study how the radiosensitization effect of gemcitabine is time-dependent. This demonstrates how the Virtual Tumour can help maximise therapeutic efficacy of combinations involving irradiation. Citation Format: Eric Fernandez, David Orrell, Frances Brightman, David Fell, Christophe Chassagnole. Modeling ionizing radiation exposure in vitro and in vivo using the Virtual Tumour. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5233. doi:10.1158/1538-7445.AM2013-5233

Predicting the effect of ionising radiation on biological populations: testing of a non-linear Leslie model applied to a small mammal population

The present work describes the application of a non-linear Leslie model for predicting the effects of ionising radiation on wild populations. The model assumes that, for protracted chronic irradiation, the effect-dose relationship is linear. In particular, the effects of radiation are modelled by relating the increase in the mortality rates of the individuals to the dose rates through a proportionality factor C. The model was tested using independent data and information from a series of experiments that were aimed at assessing the response to radiation of wild populations of meadow voles and whose results were described in the international literature. The comparison of the model results with the data selected from the above mentioned experiments showed that the model overestimated the detrimental effects of radiation on the size of irradiated populations when the values of C were within the range derived from the median lethal dose (L50) for small mammals. The described non-linear model suggests that the non-expressed biotic potential of the species whose growth is limited by processes of environmental resistance, such as the competition among the individuals of the same or of different species for the exploitation of the available resources, can be a factor that determines a more effective response of population to the radiation effects.

Low-Dose Gamma Irradiation Enhances Superoxide Anion Production by Nonirradiated Cells Through TGF-β1-Dependent Bystander Signaling

We show here that low-dose gamma irradiation substantially increase in extracellular superoxide anion production in oncogenically transformed cells and tumor cells but not by nontransformed cells. The transfer of only a few cells from an irradiated culture to nonirradiated control cells was sufficient for the transmission of a signal to induce superoxide anion production in the nonirradiated cells. The number of irradiated cells that was necessary for the successful induction of superoxide anion production in the nonirradiated cells depended on radiation dose. When irradiated cells were allowed to incubate for 1 h before transmission to the nonirradiated cultures, nearly all of the cells from the irradiated cell population were able to communicate the inducing signal to nonirradiated cells. siRNA-dependent knockdown and reconstitution experiments showed that TGF-β1 was sufficient to mediate the bystander effect triggered by low-dose radiation in this experimental system. A kinetic analysis demonstrated that the enhanced superoxide anion production was substantially reduced before the release of the bystander signal by activated TGF-β.

Dose Response of Soft X-Ray-Induced Bystander Cell Killing Affected byp53Status

A radiation-induced bystander response, which is generally defined as a cellular response that is induced in nonirradiated cells that received bystander signals from directly irradiated cells within an irradiated cell population. In our earlier X-ray microbeam studies, bystander cell killing in normal human fibroblasts had a parabolic relationship to the irradiation dose. To elucidate the role of p53 in the bystander cell killing, the effects were assessed using human non-small cell lung cancer cells expressing wild-type or temperature-sensitive mutated p53. The surviving fraction of bystander wild-type p53 cells showed a parabolic relationship to the irradiation dose; survival was steeply reduced up to 0.45 Gy, recovered toward to 2 Gy, and remained at control levels up to 5 Gy. In contrast, in the mutated p53 cells at a nonpermissive temperature, the surviving fraction was steeply reduced up to 1 Gy and remained at the reduced level up to 5 Gy. When the mutated p53 cells were incubated at a permissive temperature, the decrease in the surviving fraction at 2 Gy was suppressed. The wild-type p53 cells were not only restrained in releasing bystander signals at 2 Gy, but were also resistant to the signals released by the mutated p53 cells. These results suggest that the X-ray-induced bystander cell killing depends on both the irradiation dose and the p53 status of the targeted cells and the bystander cells.

Gamma Ray Induced Radio Sensitivity in Three Different Mulberry (<i>Morus</i>) Genotypes

Mulberry genotypes M5, S54 and Kosen were procured from mulberry germplasm bank, Department of Sericulture, Bangalore University. Juvenile twigs of mulberry genotypes were used for cuttings preparation. Newly prepared juvenile cuttings were irradiated with different doses of gamma rays (1 kR - 10 kR) from Co60 gamma unit. Propagation parameters like sprouting, rooting, survivability, plant height, number of branches, internodal distance and leaf area were recorded. Results revealed decline in growth parameters with the increase in gamma ray dosage (1 kR - 10 kR). Moderate dosages (4 kR - 7 kR) are the most competent range and height of the irradiated population significantly reduced with the increase in gamma rays dosage. Higher doses of gamma rays (8 kR - 10 kR) drastically reduced the number of branches. M5 and S54 showed marked improvement in plant height at 4 kR (155.14 cm) and 7 kR (147.86 cms) respectively compared to control. Morphologically, leaf mutants like enlarged (4 kR), curled (8 kR), mosaic (8kR) and biforked (9 kR) leaves were observed in gamma irradiated M5 genotype. Kosen exhibited small, crumpled, biforked and chlorophyll deficient leaves (8 kR - 10 kR). S54 exhibited boat shaped leaves with wrinkled texture (8 kR).

Cancer risks from diagnostic radiology: the impact of new epidemiological data

Cancer risks from diagnostic radiology: the impact of new epidemiological data

Abstract 19696: Hypertension and Elevated hs-CRP Predict Occult Cardiovascular Disease in Asymptomatic Survivors of Hodgkin's Lymphoma Treated with Chest Radiation

Background: Cardiovascular disease (CVD) is the leading cause of mortality in Hodgkin’s lymphoma (HL) survivors treated with chest radiation therapy (RT). The contribution of traditional cardiovascular risk factors (CRFs) to CVD development in this irradiated population is unclear since most studies are retrospective. Methods: Two hundred and ten asymptomatic HL survivors treated with RT at 3 Harvard hospitals were recruited and assessed for treatment- and patient-related CRFs. Each patient underwent an outpatient cardiology visit and laboratory testing. Blood pressure (BP) measurement, electrocardiogram, and resting and stress echocardiography were performed. CVD detected on screening was correlated with patient-related CRFs. Results: One hundred eighty-two HL survivors (59% female, mean age 44.1 ± 8.7 years, follow-up time 15.1 ± 7.2years) completed cardiac screening and formed the cohort. 81% of patients had ≥ 1 modifiable CRF. 26% (47) of patients (53% female, mean age 45.3 ± 9.0 years, follow-up time 16.9 ± 8.3 years) had occult coronary artery disease (CAD), at least moderate valve disease, or left ventricular systolic dysfunction (LVSD). Hypertension (OR=4.9, p=0.0003), elevated high-sensitivity C-reactive protein (hs-CRP) (OR=2.9, p=0.01), and older age (OR= 1.1, p=0.006) were correlated with CAD/valve disease. LVSD was not correlated with patient CRFs. For every 5mmHg decrease in systolic BP or in diastolic BP, the odds of CAD/valve disease decrease 22% or 26% respectively. Conclusions: This is one of the most comprehensive prospective assessments of CRFs in HL survivors. Hypertension and hs-CRP are common and sensitive markers of CAD/valve disease in asymptomatic survivors treated with chest RT, and may allow better identification of those with occult CVD treated with chest radiation.

In-vitro investigation of out-of-field cell survival following the delivery of conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans

The aim of this work is to determine the out-of-field survival of cells irradiated with either the primary field or scattered radiation in the presence and absence of intercellular communication following delivery of conformal, IMRT and VMAT treatment plans. Single beam, conformal, IMRT and VMAT plans were created to deliver 3 Gy to half the area of a T80 flask containing either DU-145 or AGO-1522 cells allowing intercellular communication between the in- and out-of-field cell populations. The same plans were delivered to a similar custom made phantom used to hold two T25 culture flasks, one flask in-field and one out-of-field to allow comparison of cell survival responses when intercellular communication is physically inhibited. Plans were created for the delivery of 8 Gy to the more radio-resistant DU-145 cells only in the presence and absence of intercellular communication. Cell survival was determined by clonogenic assay. In both cell lines, the out-of-field survival was not statistically different between delivery techniques for either cell line or dose. There was however, a statistically significant difference between survival out-of-field when intercellular communication was intact (single T80 culture flask) or inhibited (multiple T25 culture flasks) to in-field for all plans. No statistically significant difference was observed in-field with or without cellular communication to out-of-field for all plans. These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields when cellular communication between differentially irradiated cell populations is present. This data is further evidence that refinement of existing radiobiological models to include indirect cell killing effects is required.

No influence of serotonin levels in foetal bovine sera on radiation-induced bystander effects and genomic instability

Purpose: The aim of this study was to contribute to an inter-laboratory investigation within the Non-Targeted Effects of Ionising Radiation Integrated project (NOTE) (2006–2010) to investigate the role of serum serotonin concentration on radiation-induced bystander effects using our successful experimental design. Two sera of high and low serotonin levels were tested alongside standard serum used in our laboratory.Materials and methods: Primary Human Fibroblast 19 (HF19) cells were sham/irradiated with 0.5 Gy alpha-particles, in medium supplemented with serum of different levels of serotonin. Filtered medium was transferred to unirradiated HF19 bystander cells. Cells from irradiated and bystander populations were harvested for chromosomal analysis at early and delayed times post-irradiation/media transfer to assess initial damaging effects and induction of delayed chromosomal instability respectively.Results: Chromosomal damage was elevated to significant levels (p = ≤ 0.005) above respective controls in both cell populations in all groups. Induction of delayed chromosomal instability was significantly observed in all groups at delayed time post irradiation/medium transfer. Furthermore, induction of bystander effects at early and delayed times was not significantly different between groups.Conclusions: No effect of serotonin on the induction of either bystander effects of genomic instability was observed using this experimental system.

Effects of Very Low Fluences of High-Energy Protons or Iron Ions on Irradiated and Bystander Cells

In space, astronauts are exposed to radiation fields consisting of energetic protons and high atomic number, high-energy (HZE) particles at very low dose rates or fluences. Under these conditions, it is likely that, in addition to cells in an astronaut's body being traversed by ionizing radiation particles, unirradiated cells can also receive intercellular bystander signals from irradiated cells. Thus this study was designed to determine the dependence of DNA damage induction on dose at very low fluences of charged particles. Novel techniques to quantify particle fluence have been developed at the NASA Space Radiation Biology Laboratory (NSRL) at Brookhaven National Laboratory (BNL). The approach uses a large ionization chamber to visualize the radiation beam coupled with a scintillation counter to measure fluence. This development has allowed us to irradiate cells with 1 GeV/nucleon protons and iron ions at particle fluences as low as 200 particles/cm(2) and quantify biological responses. Our results show an increased fraction of cells with DNA damage in both the irradiated population and bystander cells sharing medium with irradiated cells after low fluences. The fraction of cells with damage, manifest as micronucleus formation and 53BP1 focus induction, is about 2-fold higher than background at doses as low as ∼0.47 mGy iron ions (∼0.02 iron ions/cell) or ∼70 μGy protons (∼2 protons/cell). In the irradiated population, irrespective of radiation type, the fraction of damaged cells is constant from the lowest damaging fluence to about 1 cGy, above which the fraction of damaged cells increases with dose. In the bystander population, the level of damage is the same as in the irradiated population up to 1 cGy, but it does not increase above that plateau level with increasing dose. The data suggest that at fluences of high-energy protons or iron ions less than about 5 cGy, the response in irradiated cell populations may be dominated by the bystander response.

Mutation rates in Scots pine (Pinus sylvestris L.) from the Chernobyl exclusion zone evaluated with amplified fragment-length polymorphisms (AFLPs) and microsatellite markers

Ionizing radiation is a strong mutagenic factor and, accordingly, elevated mutation rates would be expected in plants exposed to high chronic or acute radiation after the Chernobyl accident in 1986. Somatic mutations were analyzed in pines (Pinus sylvestris L.) planted before and after the Chernobyl accident and in control material of the same origin planted in sites with natural radiation. Microsatellites (SSRs) and amplified fragment-length polymorphisms (AFLPs) were investigated. The mutation rates for microsatellites were estimated as 2.8×10−4–7.1×10−4 per locus for different irradiated tree populations; no mutations were detected in the controls. In the case of AFLPs, the observed mutation rates were 3.74×10−3–3.99×10−3 and 1.06×10−3 per locus for contaminated and control areas, respectively. Thus a statistically highly significant three-fold increase in number of mutations was found by the use of AFLP markers, indicating that ionizing radiation causes strong DNA damage across the entire genome and that AFLPs may be the appropriate marker system for this kind of analysis.

Detection of Chromosomal Instability in Bystander Cells after Si490-Ion Irradiation

There is increasing evidence that two of the biological effects associated with low-dose ionizing radiation, genomic instability and bystander responses, may be linked. To verify and validate the link between the two phenomena, the ability of Si490 ions (high-energy particles associated with radiation risk in space) to induce bystander responses and chromosomal instability in human bronchial epithelial (HBEC-3kt) cells was investigated. These studies were conducted at both the population and single cell level in irradiated and nonirradiated bystander cells receiving medium from the irradiated cultures. At the general population level, transfer of medium from silicon-ion (Si490)-irradiated cultures (at doses of 0.073Gy, 1.2Gy and 2Gy) to nonirradiated bystander cells resulted in small increases in the levels of chromosomal aberrations at the first division. Subsequently, single cell clones isolated from irradiated and bystander populations were analyzed for the appearance of de novo chromosome-type aberrations after ∼50 population doublings using mFISH. Both irradiated and bystander clones demonstrated chromosomal instability (as seen by the de novo appearance of translocations and chromosomal fragments), albeit to different degrees, whereas sham-treated controls showed relatively stable chromosomal patterns. The results presented here highlight the importance of nontargeted effects of radiation on chromosomal instability in human epithelial cells and their potential relevance to human health.

Radiation-Induced Bystander Effects: What Are They, and How Relevant Are They to Human Radiation Exposures?

The term radiation-induced bystander effect is used to describe radiation-induced biological changes that manifest in unirradiated cells remaining within an irradiated cell population. Despite their failure to fit into the framework of classical radiobiology, radiation-induced bystander effects have entered the mainstream and have become established in the radiobiology vocabulary as a bona fide radiation response. However, there is still no consensus on a precise definition of radiation-induced bystander effects, which currently encompasses a number of distinct signal-mediated effects. These effects are classified here into three classes: bystander effects, abscopal effects and cohort effects. In this review, the data have been evaluated to define, where possible, various features specific to radiation-induced bystander effects, including their timing, range, potency and dependence on dose, dose rate, radiation quality and cell type. The weight of evidence supporting these defining features is discussed in the context of bystander experimental systems that closely replicate realistic human exposure scenarios. Whether the manifestation of bystander effects in vivo is intrinsically limited to particular radiation exposure scenarios is considered. The conditions under which radiation-induced bystander effects are induced in vivo will ultimately determine their impact on radiation-induced carcinogenic risk.

Out-of-Field Cell Survival Following Exposure to Intensity-Modulated Radiation Fields

To determine the in-field and out-of-field cell survival of cells irradiated with either primary field or scattered radiation in the presence and absence of intercellular communication. Cell survival was determined by clonogenic assay in human prostate cancer (DU145) and primary fibroblast (AGO1552) cells following exposure to different field configurations delivered using a 6-MV photon beam produced with a Varian linear accelerator. Nonuniform dose distributions were delivered using a multileaf collimator (MLC) in which half of the cell population was shielded. Clonogenic survival in the shielded region was significantly lower than that predicted from the linear quadratic model. In both cell lines, the out-of-field responses appeared to saturate at 40%-50% survival at a scattered dose of 0.70 Gy in DU-145 cells and 0.24 Gy in AGO1522 cells. There was an approximately eightfold difference in the initial slopes of the out-of-field response compared with the α-component of the uniform field response. In contrast, cells in the exposed part of the field showed increased survival. These observations were abrogated by direct physical inhibition of cellular communication and by the addition of the inducible nitric oxide synthase inhibitor aminoguanidine known to inhibit intercellular bystander effects. Additional studies showed the proportion of cells irradiated and dose delivered to the shielded and exposed regions of the field to impact on response. These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields with cellular communication between differentially irradiated cell populations playing an important role. Validation of these observations in additional cell models may facilitate the refinement of existing radiobiological models and the observations considered important determinants of cell survival.

A Centrosome-autonomous Signal That Involves Centriole Disengagement Permits Centrosome Duplication in G2 Phase after DNA Damage

DNA damage can induce centrosome overduplication in a manner that requires G2-to-M checkpoint function, suggesting that genotoxic stress can decouple the centrosome and chromosome cycles. How this happens is unclear. Using live-cell imaging of cells that express fluorescently tagged NEDD1/GCP-WD and proliferating cell nuclear antigen, we found that ionizing radiation (IR)-induced centrosome amplification can occur outside S phase. Analysis of synchronized populations showed that significantly more centrosome amplification occurred after irradiation of G2-enriched populations compared with G1-enriched or asynchronous cells, consistent with G2 phase centrosome amplification. Irradiated and control populations of G2 cells were then fused to test whether centrosome overduplication is allowed through a diffusible stimulatory signal, or the loss of a duplication-inhibiting signal. Irradiated G2/irradiated G2 cell fusions showed significantly higher centrosome amplification levels than irradiated G2/unirradiated G2 fusions. Chicken-human cell fusions demonstrated that centrosome amplification was limited to the irradiated partner. Our finding that only the irradiated centrosome can duplicate supports a model where a centrosome-autonomous inhibitory signal is lost upon irradiation of G2 cells. We observed centriole disengagement after irradiation. Although overexpression of dominant-negative securin did not affect IR-induced centrosome amplification, Plk1 inhibition reduced radiation-induced amplification. Together, our data support centriole disengagement as a licensing signal for DNA damage-induced centrosome amplification.

Gold Nanoparticles as Radiation Sensitizers in Cancer Therapy

Among other nanoparticle systems, gold nanoparticles have been explored as radiosensitizers. While most of the research in this area has focused on either gold nanoparticles with diameters of less than 2 nm or particles with micrometer dimensions, it has been shown that nanoparticles 50 nm in diameter have the highest cellular uptake. We present the results of in vitro studies that focus on the radiosensitization properties of nanoparticles in the size range from 14-74 nm. Radiosensitization was dependent on the number of gold nanoparticles internalized within the cells. Gold nanoparticles 50-nm in diameter showed the highest radiosensitization enhancement factor (REF) (1.43 at 220 kVp) compared to gold nanoparticles of 14 and 74 nm (1.20 and 1.26, respectively). Using 50-nm gold nanoparticles, the REF for lower- (105 kVp) and higher- (6 MVp) energy photons was 1.66 and 1.17, respectively. DNA double-strand breaks were quantified using radiation-induced foci of gamma-H2AX and 53BP1, and a modest increase in the number of foci per nucleus was observed in irradiated cell populations with internalized gold nanoparticles. The outcome of this research will enable the optimization of gold nanoparticle-based sensitizers for use in therapy.

Tracking genomic instability within irradiated and bystander populations

Over the past two decades, our understanding of radiation biology has undergone a fundamental shift in paradigms away from deterministic 'hit-effect' relationships and towards complex ongoing 'cellular responses'. These responses include now familiar, but still poorly understood, phenomena associated with radiation exposure such as genomic instability and bystander effects. Although these responses share some common features (e.g. they occur at high frequency following very low doses, are heterogeneous in their induction and are observed at time points far removed from the initial radiation exposure), the precise relationship between genomic instability and bystander effects remains to be elucidated. This review will provide a synthesis of the known, and proposed, interrelationships among irradiated and bystander cellular responses to radiation. It also discusses our current experimental approach for gaining a clearer understanding of the relationship between damage induction and long-term effects in both irradiated and bystander cells.

Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies

IntroductionMost human mammary epithelial cells (HMEC) cultured from histologically normal breast tissues enter a senescent state termed stasis after 5 to 20 population doublings. These senescent cells display increased size, contain senescence associated β-galactosidase activity, and express cyclin-dependent kinase inhibitor, p16INK4A (CDKN2A; p16). However, HMEC grown in a serum-free medium, spontaneously yield, at low frequency, variant (v) HMEC that are capable of long-term growth and are susceptible to genomic instability. We investigated whether ionizing radiation, which increases breast cancer risk in women, affects the rate of vHMEC outgrowth.MethodsPre-stasis HMEC cultures were exposed to 5 to 200 cGy of sparsely (X- or γ-rays) or densely (1 GeV/amu 56Fe) ionizing radiation. Proliferation (bromodeoxyuridine incorporation), senescence (senescence-associated β-galactosidase activity), and p16 expression were assayed in subcultured irradiated or unirradiated populations four to six weeks following radiation exposure, when patches of vHMEC became apparent. Long-term growth potential and p16 promoter methylation in subsequent passages were also monitored. Agent-based modeling, incorporating a simple set of rules and underlying assumptions, was used to simulate vHMEC outgrowth and evaluate mechanistic hypotheses.ResultsCultures derived from irradiated cells contained significantly more vHMEC, lacking senescence associated β-galactosidase or p16 expression, than cultures derived from unirradiated cells. As expected, post-stasis vHMEC cultures derived from both unirradiated and irradiated cells exhibited more extensive methylation of the p16 gene than pre-stasis HMEC cultures. However, the extent of methylation of individual CpG sites in vHMEC samples did not correlate with passage number or treatment. Exposure to sparsely or densely ionizing radiation elicited similar increases in the numbers of vHMEC compared to unirradiated controls. Agent-based modeling indicated that radiation-induced premature senescence of normal HMEC most likely accelerated vHMEC outgrowth through alleviation of spatial constraints. Subsequent experiments using defined co-cultures of vHMEC and senescent cells supported this mechanism.ConclusionsOur studies indicate that ionizing radiation can promote the outgrowth of epigenetically altered cells with pre-malignant potential.

Clastogenic plasma factors: a short overview

A large number of studies have revealed that irradiated subjects produce soluble factors found in their blood plasma which, when transferred into cell cultures from non-irradiated individuals, show clastogenic (chromosome breaking) activity. Increased yields of chromatid-type aberrations have been characteristic in most of these studies. Exposed cohorts of various origins have revealed to possess this feature: from A-bomb survivors to patients treated with radiotherapy. It is apparent that the plasma factors are sustainable for long time periods. On the other hand, they seem to be produced very fast after exposure. Considerable variation in the effect has been found between individuals with similar radiation exposure. Further, the phenomenon is not restricted to irradiated populations. Clastogenic plasma has also been observed in patients with inflammatory diseases or congenital chromosome breakage syndromes as well in subjects exposed to other agents than ionizing radiation. Chromosomal aberration inducing substances have been detected not only in vivo, but also in vitro. A common feature to all the conditions is that they are associated with oxidative stress. Studies on the biochemical nature of the clastogenic factor(s) have been conducted, and tumor necrosis factor alpha and lipid peroxidation products, among others, have been suggested as good candidates. The relevance of the plasma factors to health effects remains open. The aim of the paper is to give a short overview on the phenomenon of clastogenic factors--their occurrence and formation as well as possible effectors.