MEAN VALUE OF LET FOR ONCOGENIC EFFECTS OF RADON AND ITS PROGENY.

The topic of the article is to define the average value of linear energy transfer (LET) for carcinogenic effects of radon progeny. The microdosimetric model of boundary specific energy is used. It follows that the effect at high LET should decrease approximately with the third power of LET. This is verified by the analysis of the relationship between radiation effects ratio and LET in published experiments with oncogenic transformation of mammalian cells irradiated with the monoenergetic alpha particles. If these cells are exposed with the radon irradiator, our analysis leads us to conclude that the oncogenic effect of radon progeny is comparable to that of alpha particles with a LET of 75 keV/µm. It is about a quarter lower than the LET value, where the effect of the monoenergetic alpha particles reaches its maximum level. Some implications for lung cancer due to radon inhalation may also be carefully examined.

Use of threshold-specific energy model for the prediction of effects of smoking and radon exposure on the risk of lung cancer.

Lung cancer is the leading cause of cancer death in both men and women. Smoking causes 80-90% of cases of lung cancer. In this study, an attempt was made to assess the impact of cigarette smoking on the risk of lung cancer by the so-called threshold-specific energy model. This model allows to analyse the biological effects of radon daughter products on the lung tissue, and is based on the assumption that the biological effect (i.e. cell inactivation) will manifest itself after the threshold-specific energy z0 deposited in the sensitive volume of the cell is exceeded. Cigarette smoking causes, among others, an increase in the synthesis of the survivin protein that protects cells from apoptosis and thereby reduces their radiosensitivity. Based on these facts, an attempt was made to estimate the shape of the curves describing the increase in the oncological effect of radiation as a function of daily cigarette consumption.

Microdosimetric approach to the problem of lung cancer induced by radon progeny.

The increased risk of lung cancer arising from chronic exposure to radon progeny in Czech uranium mines was analyzed on the basis of specific energy distributions for basal and secretory cell nuclei. The distributions were calculated from published results of lung microdosimetry. Whereas classical concepts consider that cell nuclei are hit one or more times by alpha particle tracks, the microdosimetry is able to distinguish glancing (non-lethal, possibly carcinogenic) hits from alpha particle traversals near to nucleus center (which probably inactivate the cell). The simple microdosimetric model differentiates both cases by the quantity termed boundary specific energy. The importance of some confounding factors is examined. Particularly the continuous replacement of bronchial epithelium cells by the new ones is worth considering. Still, the lung cancer frequency seems to be related to the number of sensitive cells with glancing hits. This might be a relevant argument to the toxicity of radon progeny. The central idea of the model, the boundary specific energy, was tested on the basis of radiobiological experiments with isolated cell lines.

Effect of plutonium-239 on the mitotic activity of mouse bone marrow cells.

Mitotic index of the bone marrow cells was studied in femoral bone marrow of mice given 313 kBq 239Pu kg-1. The attention was turned to the femoral midshaft and the mitosis concentration, intensified by Colcemid stathmokinetic effect, was evaluated in a sampling field from endosteal surface to the central venous canal, throughout 68 weeks. It has been found that the plutonium effect in the sampling band is rather uniform except the points in subendosteal zone early after plutonium injection, where the mitotic index was reduced in such a way that the mitotic gradient, observed in controls, was affected. The mitotic activity in femoral diaphysis of plutonium injected mice was mobilized approximately till the 30th week of contamination. Later it deteriorated progressively. The results are discussed and should not be regarded as representative for the entire bone marrow hemopoiesis.

Long-term effects of low-level 239Pu contamination on murine bone-marrow stem cells and their progeny.

The effects of long-term internal contamination with 13.3 kBq kg-1 239Pu injected intravenously were studied in 10-week-old ICR (SPF) female mice. Radiosensitivity of spleen colony-forming units (CFU-S) and 125IUdR incorporating into proliferating cells of vertebral bone marrow and spleens were determined in plutonium-treated and control animals one year after nuclide injection. The CFU-S in 239Pu-treated mice were more sensitive to X-rays (D0 = 0.52 +/- 0.01 Gy) than in controls (D0 = 0.84 +/- 0.02 Gy). 125IUdR incorporation into bone marrow and spleen cells was reduced after plutonium contamination. At one year following plutonium injection, the occurrence of chromosome aberrations was evaluated in metaphase figures of femoral bone marrow cells. The frequency of aberrations increased early after plutonium treatment, at later intervals it tended to decrease but not below the control level. While the relative numbers of vertebral marrow CFU-S decreased significantly, but only to 86 per cent of normal, cellularity of vertebral bone marrow, peripheral blood counts and survival of 239Pu-treated mice did not differ from the control data.

Self-renewal capacity of murine hemopoietic stem cells under internal contamination with 239Pu and 241Am.

The self-renewal capacity of murine pluripotent hemopoietic stem cells (CFU-S) of vertebral bone marrow was studied under conditions of short-term and long-term internal contamination with 239Pu or 241Am in female mice. Measurement of the CFU-S self-renewal capacity was carried out using double transplantation assay. To evaluate the production of differentiated progeny of stem cells average erythroblast numbers/visible spleen colony and 59Fe-uptake/colony were computed. The marrow cellularity/vertebra and the number of CFU-S/vertebra were decreased and affected more by 239Pu than by 241Am. The production of erythroblasts per a single CFU-S and the 59Fe-uptake/colony were reduced, similarly the numbers of secondary spleen colonies and of secondary CFU-S in primary colonies. The above changes resulting from impaired functions of surviving CFU-S were more serious with 241Am than with 239Pu. The biological effects of plutonium and americium appeared independent of the phase of contamination.

Radiosensitivity of vertebral bone marrow CFU-S surviving in mice internally contaminated with 239Pu or 241Am.

The radiosensitivity of pluripotent hemopoietic stem cells was studied in ICR "Swiss" mice (28 g/mouse) given i.v. 198.6 kBq 239Pu/kg as citrate complex or 208.6 kBq 241 Am/kg as nitrate at the age of 10 weeks. The bone marrow cells were examined at the early and late phases of radionuclide contamination. To obtain data for survival curves and D0 of stem cells the CFU-S assay was used and the donor vertebral marrow cells were exposed to the complementary X-irradiation either early after injection to the heavily irradiated recipients or to the "in vitro" irradiation given before the transplantation. To determine the iron uptake in splenic erythroid progeny the recipients given marrow cells unexposed to the X-rays received 37 kBq 59Fe 6 h before they were killed and the relative activity per colony was calculated. The radiation effect of the used actinides on the bone marrow cells resulted in decreased cellularity and seriously altered both relative and absolute CFU-S numbers. The radiosensitivity of CFU-S increased in all intervals examined (D0 from 0.60 to 0.86 Gy, in controls 0.97 to 1.06 Gy) and was more expressed when the CFU-S were exposed to the X-rays immediately after the bone marrow cell transplantation to the heavily irradiated hosts. The stem cell pool appeared, especially at older age, to be affected also in its ability to produce erythrocytic progeny.

Biological effects of bone-seeking alpha emitters with respect to the risk of internal contamination in man.

Some results of long-term experiments performed in mice contaminated with 226Ra and 239Pu, especially the damage to the hemopoietic system and the incidence of osteosarcoma, are reported. Different degree of damage to the bone marrow hemopoiesis, depending on the arrangement of marrow cavities and the capability of stem cells to produce differentiated progeny are evaluated. This ability decreases with age and with duration of the contamination due to radionuclides. From the above aspects of radiation injury the ability of hemopoiesis to compensate the decreased production of differentiated peripheral cell forms is discussed. It is remarkable that myeloid leukemia occurred earlier and more frequently in 239Pu-contaminated animals than in controls. After the injection of plutonium-239, myeloid and lymphatic leukemias were diagnosed in most of the animals dying without osteosarcoma. These diseases represented a danger not lower than that of osteosarcoma which appeared in average later and the expected incidence of which was estimated to rise linearly with age. The findings are discussed from the aspect of their application in evaluating the risk resulting for man from the incorporated bone-seeking alpha emitters.