Carcinogenesis in laboratory mice after low doses of ionizing radiation

Experimental data on the incidence of solid tumors from various long-term mouse studies performed at the Casaccia laboratories over several years were reconsidered, limiting the analysis to the results available for doses equal to or less than 17 cGy of neutrons and 32 cGy of X rays since these dose limits are reasonably close to the generally accepted low-dose levels for high- and low-LET radiation (i.e. D(high-LET) < 5 cGy and D(low-LET) < 20 cGy, respectively). The following long-term experiments with BC3F1 mice were reviewed: (a) females treated with single doses of 1.5 MeV neutrons or 250 kVp X rays, (b) males treated with fractionated doses of fission neutrons, and (c) mice of both sexes irradiated in utero 17.5 days post coitus with single doses of fission neutrons or X rays. An experiment with CBA mice of both sexes treated with single doses of fission neutrons was also included in this study. Analysis was done on animals at risk; thus all incidences of tumor-bearing animals were expressed as the percentage excess incidence with respect to the controls. Ovarian tumors and other solid neoplasms were considered. The percentage frequencies and mean survival times of tumor-free mice were also recalculated. The results indicate the existence of a region at low doses where the final incidence of solid neoplasms is indistinguishable from the background incidence. These data reinforce the idea that at low doses the effectiveness of ionizing radiation in inducing solid neoplasms in laboratory mice is very low.     

Reduced oxygen enhancement ratio at low doses of ionizing radiation

A decreased oxygen enhancement ratio (OER) at lower radiation doses has been previously reported (B. Palcic, J. W. Brosing, and L. D. Skarsgard, Br. J. Cancer 46, 980-984 (1984]. The question remained whether or not this effect is due to a possible oxygen contamination at low doses, which was not the case at high doses. To ensure a sufficient degree of hypoxia prior to the start of irradiation, Chinese hamster cells (CHO) were made hypoxic by gas exchange combined with metabolic consumption of oxygen at 37 degrees C. At the same time oxygen levels in cell suspension were measured using a Clark electrode. It was found that under experimental conditions used in this laboratory for hypoxic irradiations, the oxygen levels before the start of irradiation are always below the levels which could give any significant enhancement to radiation inactivation by X rays. Full survival curves were determined in the dose range 0-30 Gy using the conventional survival assay and in the dose range 0-3 Gy using the low dose survival assay. The results confirmed the earlier finding that the OER decreases at low doses. It is therefore believed that the dose-dependent OER is a true radiobiological phenomenon and not an artifact of the experimental method used in the low dose survival assay.     

Rapid dicentric assay of human blood lymphocytes after exposure to low doses of ionizing radiation

The probability of losses of different chromosome aberrations during the dicentric chromosome assay of metaphase cells with incomplete sets of chromosome centromeres was estimated using a mathematical model for low doses of ionizing radiation. A dicentric assay of human blood lymphocytes without determination of the total amount of chromosome centromeres in cells without chromosome aberrations (rapid dicentric assay) has been proposed. The rapid dicentric analysis allows to register chromosome aberrations in full compliance with the conventional classification. The experimental data have shown no statistically significant difference between the frequencies of dicentric chromosomes detected by rapid and classical dicentric chromosome assays of human lymphocytes exposed to 0.5 Gy of 60Co gamma-rays. The rate of the rapid dicentric assay was almost twice as high as that of the classical dicentric assay.     

Mathematical analysis of genetic effects of low doses of ionizing radiation

The comparative study of effects of low doses of radiation on peripheral blood lymphocytes of persons occupationally exposed to radiation and non-exposed ones was carried out. The main attention was paid to radio-adaptive response forming under consistent exposure to low (0.05 Gy) and damaging (2 Gy) doses of gamma-irradiation. Noticeable heterogeneity in capacity for adaptive response forming in occupational group was revealed. The mathematical model adequate to experimental material was constructed using Kohonen neuronets.     

Response of hippocampal pacemaker-like neurons to low doses of ionizing radiation

Spontaneous discharges of hippocampal pacemaker-like neurons are induced by X- and gamma-rays doses lower than 0.8 cGy. The effect is direct and connected with the activation of an endogenous mechanism of unit activity generation.     

Cytogenetic effects in children exposed to low doses of ionizing radiation

The obtained data indicate that frequencies of different types of cytogenetic anomalies in investigated children groups living in radionuclide contaminated territories and children irradiated in utero have complicated patterns. The frequency of chromosomal anomalies in the investigated groups of children exceeds the average population level. At the same time, no statistically significant differences in frequencies of various types aberrations between groups of children were revealed.     

Non-monotonous dose-response relationship in the region of low doses of ionizing radiation

The statement about nonmonotony of dose-effect curves as a result of nonmonotony of the time-effect relationship including the field of low doses is discussed. The living cells possess a fundamental property to response to action of different stress agents by oscillatory--nonmonotonous--hanges of metabolism. The systems keeping up homeostasis by direct and feed-back regulation return metabolism to norm. In the fixed temporary point a dose-effect dependence may take the nonmonotonous character e.g. reverse dose-response relationship. The changes of the oscillation parameters suggested the inclusion of the different pathway for homeostasis keeping. Radiation hormesis does not focused on the metabolic and functional nonmonotonous response. Radiation stimulation is considered as consequence of the peculiarity of the homeostasis maintenance pathways in the certain interval of the low doses of ionizing radiation.     

Genetic efficacy of low doses of ionizing radiation in chronically-irradiated small mammals

Earlier we have established the genetic effects of low dose chronic irradiation in bank vole (somatic and germ cells, embryos), in pond carp (fertilized eggs, embryos, fry) and in laboratory mice (somatic and germ cells) in the range of doses from near-background to 10 cGy. These low dose effects observed in mammals and fish are not expected from extrapolation of high dose experiments. For understanding reasons this discrepancy the comparative analysis of genetic efficiency of low dose chronic irradiation and the higher doses of acute irradiation was carried out with natural populations of bank vole which inhabited the two sites differing in ground of radionuclide deposition. For comparing efficiency the linear regression model of dose-effect curve was used. Dose-effect equations were obtained for animals from two chronically irradiated bank vole populations. The mean population absorbed doses were in the range 0.04-0.68 cGy, the main part of absorbed doses consisted of external radiation of animals exposed to 137Cs gamma-rays. Dose-effect equations for acute irradiation to 137Cs gamma-rays (10-100 cGy) were determined for the same populations. Comparison of genetic efficiency was made by extrapolation, using regression coefficient beta and doubling dose estimation. For chronic exposure the doubling doses calculated from low-dose experiments are 0.1-2 cGy and the doubling doses determined from high-dose experiments are in the range of 5-20 cGy. Our hypothesis that the doubling dose estimate is calculated in higher-dose ionizing radiation experiments should be much higher than the deduced from the low dose line regression equation was verified. The doubling dose estimates for somatic cells of bank vole and those for germ cells of laboratory mice are in close agreement. The radiosensitivity of bank vole chromosomes were shown is practically the same as that for human lymphocytes since doubling dose estimates for acute irradiation close to each other. For low LET radiation a higher genetic efficiency of chronic low doses in comparison with the higher doses of acute gamma-irradiation (137Cs source) was proved by three methods.     

Influence of low doses of ionizing radiation on tenascin expression in hybridoma cell systems

One of the achievements of the modern radiation ecology is the preparation and application of stable eukariotic cell lines to solve various problems occurring under exposure to ionizing radiation, especially to low doses. The detection of onco-fetal protein--tenascin in different embryonic and tumor cells of humans and animals supposes the probability of appropriate gene expression in lymphoid cells, including hybridomal cells. Using the immunochemical method, the study of tenascin expression in two mouse hybridomal lines was carried out. Tenascin was revealed in hybridomal lines MLC-1 and K-48. Further hybridomal cell lines were exposed to X-ray radiation (120 KV) with doses 2.10,15 cGy. The obtained results demonstrated the sensitivity of tenascin expression to low doses of ionizing radiation, that may be used as a convenient model of studying of genotoxic effects of various damaging ionizing agents on a cell level.     

The effects of low doses of low-intensity ionizing radiation on DNA structure and function

Chronic effects of low doses of low-intensity ionizing radiation (IR) on biological objects have gained great social significance. This has given a considerable impetus to research into the biological effects and mechanisms of such exposures, both in Russia and abroad. In this paper, an overview of the physicochemical and molecular basis of IR influence at low doses is provided. Means of cell protection from radiation damage are studied and an analysis of the typical features and differences in the radiation effects at low and high doses is carried out. We considered DNA radiation damage, both in cell cultures and in vivo, as well as the processes and results of their repair. Particular attention is paid to changes in the basic paradigms of biological radiation effects at low doses.     

Effect of low doses of low-intensity ionizing radiation on the DNA structure and functions

Chronic effects of low doses of low intensity ionizing radiation (IR) on biological objects have now become of great social significance. This has given a considerable impetus to research into biological effects and mechanisms of such exposures both in Russia and abroad. This paper provides an overview of physicochemical and molecular bases of the IR influence at small doses and the ways of cell protection from the radiation damage, as well as the analysis of characteristic features and differences in the effects of radiation at small and high doses. We consider the DNA radiation damage both in cell cultures and in vivo, as well as processes and results of their repair. Particular attention is paid to the changes in the basic paradigms of radiation biological effects of small doses.     

Late consequences of action of low doses of ionizing radiation on human enzymatic antioxidant system

Age-related changes in the activity of superoxide dismutase and glutathione peroxidase in the blood of participants of the Chernobyl accident liquidation were studied. According to our findings the people under 30 years old are the most sensitive to irratiation.     

Early effects of low doses of ionizing radiation on the fetal cerebral cortex in rats

Pregnant rats were exposed to gamma radiation from a 137Cs irradiator on gestational Day 15. Fetuses that received 0.25, 0.5, 0.75, or 1.0 Gy were examined 24 h after irradiation for changes in the cells of the cerebral mantle of the developing brain. The extent of changes following 0.5 Gy was studied at 3, 6, 12, or 24 h after exposure. Cortical thickness of the cerebral mantle was not significantly altered. The number of pyknotic cells, number of macrophages, nuclear area, and number of mitotic cells were altered in a dose-related way. The number of pyknotic cells was significantly increased at all doses. A positive correlation between the number of pyknotic cells and the number of macrophages developed with time. At 3 h after irradiation about 60% of pyknotic cells were found in the subventricular zone and about 25% in the intermediate zone and cortical plate. The number of such cells in the upper layers of the cortex steadily increased up to 24 h, at which time about 70% of pyknotic cells were in these two layers. The relationship of the movement of pyknotic cells to migration of postmitotic neuroblasts is discussed.     

Modeling radioprotective mechanisms in the dose effect relation at low doses and low dose rates of ionizing radiation

A new model (Random Coincidence Model--Radiation Adapted (RCM-RA)) is proposed which explains a possible pseudo threshold for stochastic radiation effects. It describes the formation of cancer in the case of multistep fixation of lesions in the critical regions of tumor associated genes such as proto-oncogenes or tumor-suppressor genes. The RCM-RA contains two different possibilities of DNA damage to complementary nucleotides. The damage may be caused either by radiation or by natural processes such as cellular radicals or thermal damage or by chemical cytotoxins. The model is based on the premise that radiation initially is bionegative, damaging organisms at their different levels of organization. The radiation, however, also induces various cellular radioprotective mechanisms which decrease the damage by natural processes. Considering both effects together, the theory explains apparent thresholds in the dose-response relation for radiation carcinogenesis without contradiction to the classical assumption that radiation is predominantly bionegative at doses typically found in occupational exposures.