Macrophage depletion of mouse lung following inhalation of 239PuO2

Changes in the free-cell population of the lungs of two strains of mice (SAS/4 and CBA/H) were studied up to 4 months after inhalation exposure to a sized fraction of 239PuO2 particles (1.5 micron AMAD) to give initial alveolar depositions (IADs) ranging from 17 to 810 Bq. A sample of the free-cell population of the lung was recovered by bronchoalveolar lavage, and a radiometric method was used to estimate the total number of pulmonary alveolar macrophages (PAM) in the lung. The response of the lung to 239PuO2 was characterized by an initial, dose-dependent depression in the total number of PAM following an IAD as low as 50 Bq. At IADs greater than 150 Bq, the initial depression continued for longer, merging into a chronic phase in which the PAM were larger and were accompanied by a minor infiltration of leukocytes. These findings were confirmed by histology, which also revealed focal accumulations of Type II pneumocytes. The results indicate that inhaled alpha-emitting particles are effective at producing a depletion in the alveolar macrophage population at relatively low IADs and that chronic effects on the cells can be produced by higher concentrations.     

Preliminary studies of the interaction between 239PuO2 and cigarette smoke in the mouse lung

Our current experiments were designed to show whether 12 months' exposure to cigarette smoke enhances the incidence of lung tumours in mice that had previously inhaled 239PuO2. These periods of smoke exposure are almost complete. After death their lungs will be cleared and any nodules found will be sectioned for histopathology. This paper reports the results of two preliminary experiments conducted earlier. The first study showed that mice could tolerate the proposed smoking regime for 3 months, with no sign of ill health in any animal throughout. The major difference found was a reduced growth rate in both smoke- and sham-exposed mice relative to that of cage controls. After 3 months of treatment, histopathology and morphometry of lung sections found only slight smoke-induced changes. These included a reduced proportion of alveolar space and an increased number of pulmonary alveolar macrophages (PAM) per unit area. Bronchopulmonary lavage showed that the PAM from smoke-exposed mice were larger than those from sham-exposed or control mice and that an increased proportion of cells were binucleate. All mice in the second study were initially exposed to 239PuO2, then subsequently divided into three treatment groups as above. Cigarette smoke exposure was shown to inhibit the removal of 239Pu from the lung whilst sham exposure had no effect. Smoke exposure also produced an increase and sham exposure a decrease in lung weights relative to those of cage controls. The latter was probably as a result of their lower growth rate. In our current experiments it is likely that the group receiving 239PuO2, then smoke, will receive a higher radiation dose to lung than those receiving 239PuO2 only. Any increased tumour incidence found will be considered in conjunction with this evidence.     

Activation of alveolar macrophages after plutonium oxide inhalation in rats: involvement in the early inflammatory response

Alveolar macrophages play an important role in the distribution, clearance and inflammatory reactions after particle inhalation, which may influence long-term events such as fibrosis and tumorigenesis. The objectives of the present study were to investigate the early inflammatory events after plutonium oxide inhalation in rats and involvement of alveolar macrophages. Lung changes were studied from 3 days to 3 months after inhalation of PuO2 of different isotopic compositions (70% or 97% 239Pu) and initial lung deposits (range 2.1 to 43.4 kBq/rat). Analyses of bronchoalveolar lavages showed early increases in the numbers of granulocytes, lymphocytes and multinucleated macrophages. The activation of macrophages was evaluated ex vivo by measurement of inflammatory mediator levels in culture supernatants. TNF-alpha and chemokine MCP-1, MIP-2 and CINC-1 production was elevated from 7 days after inhalation and remained so up to 3 months. In contrast, IL-1beta, IL-6 and IL-10 production was unchanged. At 6 weeks, pulmonary macrophage numbers and activation state were increased as observed from an immunohistochemistry study of lung sections with anti-ED1. Similarly, histological analyses of lung sections also showed evidence of inflammatory responses. In conclusion, our results indicate early inflammatory changes in the lungs of PuO2-contaminated animals and the involvement of macrophages in this process. A dose-effect relationship was observed between the amount of radionuclide inhaled or retained at the time of analysis and inflammatory mediator production by alveolar macrophages 14 days after exposure. For similar initial lung deposits, the inflammatory manifestation appears higher for 97% 239Pu than for 70% 239Pu.     

Chelation therapy of incorporated plutonium-238 and americium-241: comparison of LICAM(C), DTPA and DFOA in rats, hamsters and mice

The carboxylated catechoylamide 3,4,3-LICAM(C) was tested for removal of 238Pu and 241Am from small laboratory rodents. The effectiveness of treatment was compared with that of two ligand preparations approved for clinical use: calcium-trisodium diethylenetriaminepentaacetate (DTPA) and desferrioxamine (DFOA). With early treatment and at the dosage used clinically for the decorporation of actinides with DTPA (30 mumol/kg body weight) LICAM(C) was superior to DFOA but when compared with DTPA, the effect of LICAM(C) on 238Pu was greater only in bone; as little as 1 mumol LICAM(C)/kg was as effective as 30 mumol DTPA/kg. However, in all animals treated with LICAM(C) there was a large increase in the 238Pu content of the kidney. With 241Am the effect of DTPA was always superior to that of LICAM(C). The best overall results early (1 day) after injection of 238Pu and 241Am were achieved by a combination of a single injection of LICAM(C) and DTPA with subsequent continuous administration of DTPA in drinking water. LICAM(C) affected the retention of 238Pu even if given orally; the data suggested that about 3 per cent of ingested LICAM(C) was absorbed. When the beginning of treatment was delayed, LICAM(C) became equally effective or less effective than DTPA even as far as 238Pu retention in bone was concerned, but it still increased the accumulation of 238Pu in the kidneys.     

Plutonium,241Am,90sr,and137cs concentrations in some antarctic matrices

A radioecological survey in Antarctica shows that the^239+240Pu,²³⁸Pu,²⁴¹Am,⁹⁰Sr, and¹³⁷Cs activities were detectable in nearly all the samples. The activity level of^239+240Pu,²⁴¹Am, and¹³⁷Cs in antarctic sediments was about 5–20 times lower than in the northern Adriatic Sea sediments, but the²³⁸Pu activities were relatively high. It was interesting to note that the⁹⁰Sr concentrations in all the sediments tended to be low, which could be the result of the easier exchangeable behavior of⁹⁰Sr in water. High concentrations were detected in mosses and lichens and their activity levels were comparable to those in central Italy. The radionuclide ratio analyses show that the major part of^239+240Pu,²⁴¹Am,⁹⁰Sr, and¹³⁷Cs was a result of nuclear weapon tests. The higher²⁴¹Am/^239+240Pu ratio was observed and it could perhaps be the result of fallout of nuclear weapon tests prior to 1962. The²³⁸Pu/^239+240Pu ratio in the antarctic matrices was about seven times higher than in the Northern hemisphere and it could be inferred that the major part of²³⁸Pu was originating from the SNAP-9A satellite accident.     

Estimation of rate constant for dissolution of radioactive fuel particles

Some theoretical of the experimental investigation of solubility of radioactive aerosols were examined. Filters, which were exposed during October-November 1987 in Pripyat town, were studied. Measurements on 22 November 1987 showed that an activity in the air was 12.1-20.8 mBq/m3 for 137Cs, 34.9-89.3 mBq/m-3 for 144Ce, 24.3-30.5 mBq/m-3 for 106Ru. Disperse structure of aerosol hot particles and the number of hot particles on each filter fragment was estimated by radiography. To determine a dissolution rate constant a static system with two 0.14 micron pore size membrane MFE filters (Dubna, Russia) enclosing fragments of Petryanov filters was selected. The composition was held in Gamble's solution lung fluid anf then in 0.1 mol/l HCl as dastic juice simulation. The activity of 90Sr, 238Pu, 239 + 240Pu, 241Am and 244Cm in aerosol filters and solutions was measured by radiochemical methods. It was shown that leaching of radionuclides from aerosol hot particles in lung fluid simulation decreases in line 137Cs > 90Sr > 239 + 240Pu > or = 241Am, depending om particle diameter and time. Dissolution constants were presented. Dissolution of aerosol particles in 0.1 mol/l HCl is also shown (dissolution time was 3 days). A radionuclide transition to HCl solution decreases in line 90Am 241Am > 137Cs > 239 + 240Pu. A transition degree reached 21% for 90Sr and extraction of 241Am was 3-17%.     

Long-term development of the radionuclide exposure of murine rodent populations in Belarus after the Chernobyl accident

As a determinant of the associated health risks, the behavior of radionuclides in natural ecosystems needs to be better understood. Therefore, the activity concentration of various long-lived radionuclides released due to the Chernobyl accident, and the corresponding contributions to the whole-body dose rate, was studied as a function of time in mammalian indicator species inhabiting the natural forest ecosystems of Belarus, the bank vole (Clethrionomys glareolus) and the yellow-necked mouse (Apodemus flavicollus). The activity concentrations of ¹³⁷Cs, ¹³⁴Cs, ⁹⁰Sr, ²³⁸Pu, ^239,240Pu, ²⁴¹Pu and ²⁴¹Am in soil and in animals were measured at five monitoring sites with different ground deposition of radionuclides at different distances from the destroyed reactor. The observed temporal pattern of the radionuclide activity concentration in the studied animal populations reflects the changes in biological availability of these isotopes for biota, mostly due to fuel particle destruction and appearance of dissolved and exchangeable forms of radionuclides. The time course of ^134+137Cs activity concentrations in animal populations appeared as a sequence of increase, peak and decrease. Maximal levels of radiocesium occurred 1–2 years after deposition, followed by an exponential decrease. Concentrations of incorporated ⁹⁰Sr increased up to the tenth year after deposition. The activity concentrations of transuranic elements (²³⁸Pu, ^239,240Pu, ²⁴¹Pu and ²⁴¹Am) were much lower than those of the other radionuclides, in the studied animals. A considerable activity of ²⁴¹Am in animals from areas with high levels of contamination was firstly detected 5 years after deposition, it increased up to the tenth year and is expected to increase further in the future. Maximal values of the whole-body absorbed dose rates occurred during the year of deposition, followed by a decrease in the subsequent period. Generally, this decrease was monotonic, mainly determined by the decrease of the external γ-ray dose rate, but there were exceptions due to the delayed maximum of internal exposure. The inter-individual distributions of radionuclide concentrations and lifetime whole-body absorbed doses were asymmetric and close to log-normal, including concentrations and doses considerably higher than the population mean values.     

State of cellular immunity effectors of the lung after inhalation of 239Pu polymer nitrate]

Wistar rats, who inhaled 239Pu (IV) at a dose that did not reduce the average life expectancy (the initial level in the lung was 0.77 kBq) did not exhibit any essential changes in the quality and functional activity of the alveolar macrophages. Revealed were the injuries to cells of bifurcation lymph nodes, the severity of which was a function of dose absorbed in the lung.     

The induction of liver tumors by 239Pu citrate or 239PuO2 particles in the Chinese hamster

The influence of radiation dose distribution on the frequency of 239Pu-induced liver tumors was evaluated in the Chinese hamster. Different concentrations of 239Pu citrate 239PuO2 particles of known sizes were injected intravenously via the jugular vein. About 60% of the injected 239Pu citrate was deposited in the liver and 40% in the bone. The 239Pu citrate was rather uniformly distributed throughout the liver parenchyma. Injected plutonium oxide particles were taken up by the reticuloendothelial system with 90% of the body burden deposited in the liver. The 239PuO2 particles were localized in the Kupffer cells and produced nonuniform dose distributions that were dependent on particle size. There was an activity- and dose-dependent increase in the incidence of total liver parenchymal cell tumors following injection with either plutonium particles or citrate. For animals that received 14.0-, 2.7-, 0.3-, and 0.04-Gy dose to liver from 239Pu citrate the cumulative tumor incidence was 39, 32, 5, and 0%, respectively. Animals that were injected with the 0.24 micron 239PuO2 particles had doses of 42.0, 7.2, and 0.8 Gy to the liver and tumor incidences of 34, 26, and 5%, respectively. Plutonium citrate also produced hemangiosarcomas of the liver and tumors in bone and bone marrow. The latent period for liver tumor appearance in animals exposed to 239Pu citrate or 239PuO2 particles increased as the injected activity decreased. For animals injected with a similar total activity (7.4 Bq/g), the lifetime cumulative liver tumor incidence was similar for animals exposed to either 239Pu citrate (32%) or 239PuO2 (26%). There was little effect of particle size on liver tumor incidence. These data indicate that, in Chinese hamster liver, local radiation dose distribution is less important in altering tumor incidence than injected activity or average dose. However, the more uniform irradiation from 239Pu citrate administration was more effective in cancer production than the nonuniform irradiation from 239PuO2 particles.     

Role of granulocyte/macrophage colony-stimulating factor in the regulation of murine alveolar macrophage proliferation and differentiation

Granulocyte/macrophage (GM)-CSF is one of the hemopoietic growth factors that stimulates neutrophilic granulocyte and macrophage production by bone marrow progenitor cells. In this study, the effect of GM-CSF on the growth and differentiation of murine pulmonary alveolar macrophages (PAM) was investigated. In the presence of GM-CSF, normal murine PAM were induced to proliferate and develop into macrophage colonies with a dose-response curve similar to that of bone marrow GM colony-forming cells. PAM also responded to CSF-1, a lineage-restricted growth factor, but required much higher doses of CSF-1 and a longer incubation time for optimal colony formation. The proliferative response of PAM to CSF-1, however, was greatly enhanced by the concurrent addition of low doses of GM-CSF. In contrast, low doses of CSF-1 failed to potentiate the proliferative response of PAM to GM-CSF. Macrophages derived from GM-CSF cultures were rounder and less stretched and possessed less FcR-mediated phagocytic activity than cells produced in CSF-1 cultures. A study with hydrocortisone-induced monocytopenia showed that nearly one half of lung macrophages may be sustained by local proliferation of PAM without the continuous migration of blood monocytes. This study suggests that GM-CSF may play a major role in the production of PAM by two modes of action, 1) direct stimulation of cell proliferation and 2) enhancement of their responsiveness to CSF-1, thereby producing more mature and functionally competent macrophages.     

Degradation of pulmonary surfactant disaturated phosphatidylcholines by alveolar macrophages

Experiments were performed to determine whether rat pulmonary surfactant disaturated phosphatidylcholines (DSPC) are degraded by alveolar macrophages in vitro. When [3H]choline-labeled surfactant materials are incubated with unlabeled alveolar macrophages, approximately 40% of the labeled DSPC is broken down in 6 h. There is just a slight decrease in the specific activity of DSPC, which suggests that most products of degradation are not reincorporated into DSPC, at least during the 6-h incubation period. There is a time- and temperature-dependent association of surfactant DSPC with alveolar macrophages, and some of the cell-associated materials are released from the cell fragments after sonication. Association of surfactant with the cells precedes degradation. The breakdown of surfactant DSPC by intact alveolar macrophages lags behind that produced by sonicated cell preparations with disrupted cell membranes. These data and other information suggest that the surfactant materials are internalized by the cells, before the breakdown. The products of degradation probably include free choline and fatty acids, most of which appear in the extracellular fluid. The breakdown processes do not seem to depend on the physical form of the surfactant or on the presence of surfactant apoproteins. Incubation of the cells alone also results in disappearance of intracellular DSPC, some of which may be surfactant phospholipid taken up by the cells in vivo. These results indicate that alveolar macrophages can degrade surfactant DSPC and suggest that these cells may be involved in catabolism of pulmonary surfactant materials.     

Rabbit alveolar macrophage-mediated mutagenesis of polycyclic aromatic hydrocarbons in V79 Chinese hamster cells

Rabbit pulmonary alveolar macrophages (PAM) were used as a metabolizing device in combination with V79 Chinese hamster cells as a mutational indicator system. The capacity for metabolic activation of benzo[a]pyrene (B[a]P), its 7,8-diol and 2-aminoanthracene by PAM was investigated. Because of the high variation between different PAM preparations, a statistically significant effect of the 3 compounds could only be demonstrated in a series of 4 or 5 experiments. When the ability of PAM to metabolize B[a]P and the 7,8-diol to mutagenic products was compared with that of primary embryonic fibroblasts from Syrian hamsters, PAM were found to be one-tenth as efficient. Experiments were performed to find out how the phagocytic process could affect the metabolic activation of polycyclic aromatic hydrocarbons. The results showed that PAM-mediated mutagenesis of the 7,8-diol was enhanced 5-10-fold if PAM were fed with opsonized particles. The mechanism by which the phagocytosis of PAM enhanced the mutagenicity of 7,8-diol, as detected in co-cultivated V79 cells, can so far only be a matter for speculation.     

Quantitative nitric oxide production by rat, bovine and porcine macrophages

The aim of this work was to compare in vitro nitric oxide (NO) production by rat, bovine and porcine macrophages. NO production was induced by lipopolysaccharide (LPS) or by phorbol 12-myristate 13-acetate (PMA) with ionomycin or recombinant interferon gamma (rIFN-γ) and was assessed by Griess reaction. NO synthase type II (NOS II) expression was quantified by immunocytochemistry, Western blot and real-time polymerase chain reaction (RT-PCR). There were differences in NO production by pulmonary alveolar macrophages (PAM) in all species tested. The largest amounts of NO were produced by rat PAM. Less NO was produced by bovine PAM. Moreover, PAM in rats and cows differed in their abilities to respond to various stimulators. Neither porcine PAM nor Kupffer cells produced NO. Stimulation of porcine PAM with alternative concentrations of LPS did not lead to inducing NO production. Stimulation of porcine PAM with rIFN-γ together with LPS led to a significant increase in the expression of NOS II mRNA, albeit without detectable NO production or NOS II expression on the protein level.     

Organic forms of artificial radionuclide compounds in soil solutions from natural biogeocenosis

The date on the distribution of the main radiologicaly important polutants of biosphera (90Sr, 137Cs, 239 + 240Pu, 238Pu, 241Am) over the molecular mass fractions of organic matter in the soil solutions of natural environments are presented. Molecular mass constitution and radionuclide content in the fractions are dependent on radionuclide nature and type of soil and change along the soil profile. The major portion of 238Pu, 239 + 240Pu and 241Am (72-98%) was bound with organic matter in the soil solutions. In the case of organic horizons, these radionuclides were selectively connected with the fractions of high molecular masses (MMw > or = 2000). Radiostrontium is present principally in the fraction of inorganic compounds (19-100%) and in the low molecular mass fraction of organic matter (MMw = 350-500). A selective interaction of 137Cs with organic matter of definite molecular masses was not observed. The radionuclide was found in the "organic" fractions of a wide range of molecular masses (MMw from 350-500 to > or = 18,000) (34-97%) as well as in the fraction of inorganic compounds. The data obtained can provide the theoretical basis for explanation of higher mobility of 90Sr in soil profiles compared to other radionuclides.     

The distribution of the radionuclides in the main components of lake ecosystems within the Chernobyl NPP exclusion zone

The results of the studies devoted to the distribution of radionuclides 90Sr, 137Cs, 238Pu, 239 + 240Pu and 241Am in 1998-2003 in main components of Glubokoe Lake and Dalekoe-1 Lake located within Krasnensky flood lands of the Pripyat River (inner exclusion zone of the Chernobyl NPP) were analysed. The data about the radionuclide content in bottom sediments, in water, in seston, in macrozoobenthos (including bivalvia molluscs), in gasteropods molluscs, in higher aquatic plants and in fish are presented.     

90Sr, 137Cs, 238Pu, 239+240Pu,and 241Am radionuclides in macrophytes within the Krasnensky flood plain: species specificity of concentration and distribution in phytocenosis components

The analysis of the content of radionuclides 90Sr, 137Cs, 238Pu, 239 + 240Pu and 241Am in water vegetation of flood plain reservoirs has allowed studing features of radionuclide accumulation by various species of macrophytes and revealing bioindicators of radionuclide contamination. Thus species-specificity of radionuclide accumulation can essentially change the contribution of different species to a percentage ratio of the radionuclide content in phytomass of reservoirs in comparison with fund of higher aquatic plants.     

Influence of clay mineral type and organic matter content on the uptake of239Pu and241Am by plants

Summary The uptake of²³⁹Pu and²⁴¹Am from different clay mineral-organic matter-sand mixtures simulating contrasting soil types was examined in growth chamber experiments. The mixtures represented various combinations of organic matter (0, 5 and 10%), kaolinite (11 type) and montomorillonite (21 type) clay minerals, each at the levels of 5, 10 and 25%, and purified quartz sand (as filler).Results indicated a marked reduction in uptake of both²³⁹Pu and²⁴¹Am with increase in organic matter as well as clay content of the mixtures. The Pu Concentration Ratios (CRs) ranged from (2.5–7.0)×10^–3 in the case of kaolinite-organic matter mixtures, and from (0.9–5.5)×10^–3 in the case of montmorillonite-organic matter mixtures. The corresponding values of Am Concentration Ratios (CRs) obtained were (1.9–725.4)×10^–3 in the case of kaolinite-organic matter mixtures, and between (0.7–3.5)×10^–3 for the montmorillonite-organic matter mixtures.Reduction in the uptake of²⁴¹Am with increasing clay content was more pronounced in the montmorillonite clay-organic matter mixtures as compared to that in the case of kaolinite-organic matter mixtures. While similar qualitative reduction in²³⁹Pu CRs with increasing clay content was observed, the reduction was less marked than in the case of²⁴¹Am. The values for Am CRs were higher than the corresponding Pu CRs in kaolinite based mixtures whereas in the case of montmorillonite-organic matter mixtures Pu CRs exceeded the Am CRs.Increasing organic matter content and its interaction with both kaolinite and montmorillonite clay minerals were found to be equally effective in reducing the uptake of²³⁹Pu as well as²⁴¹Am by plants.     

In vitro cytotoxicity of chrysotile asbestos to human pulmonary alveolar macrophages is decreased by organosilane coating and surfactant

Human pulmonary alveolar macrophages were used to quantitate the cytotoxic effect of surface-altered chrysotile asbestos. Little difference was observed in mortality between chrysotile asbestos that was surface-treated to a 42% extent by a hydrophobic organosilane or untreated chrysotile. Little or no effect on mortality was observed when human pulmonary alveolar macrophages were cultured with untreated chrysotile or acid-leached asbestos in the presence of 10 mM dipalmitoyl lecithin. However, when human pulmonary alveolar macrophages were cultured with a hydrophobically-treated (to a 42% or 95% extent) chrysotile asbestos in the presence of 10 mM dipalmitoyl lecithin, a statistically significant decrease in mortality was observed compared to untreated chrysotile. No mutagenic activity was observed when V79 cells were cultured with acid-leached, or 42% hydrophobically-treated chrysotile asbestos, even when human pulmonary alveolar macrophages were included as an activation source. The 95% hydrophobically-treated and acid-leached chrysotile also exhibited decreased binding of benzo[a]pyrene compared to untreated chrysotile asbestos.Abbreviations AHH aryl hydrocarbon hydroxylase - B(a)P benzo[a]pyrene - CA chrysotile asbestos - CHO Chinese hamster ovary - DL dipalmitoyl lecithin - DMEM Dulbecco's Modified Eagle's Medium - FBS fetal bovine serum - O^r resistance to ouabain - PAH polycyclic aromatic hydrocarbon - PAM pulmonary alveolar macrophage - SCE sister chromatid exchange Deceased.     

Effect of Drinking Zn-DTPA on 238-Pu and 241-Am in rat bones

Conclusion Substantial fractions of²³⁸Pu and²⁴¹Am deposits were removed from the bones of growing rats by addition of Zn-DTPA to drinking water. The effect of treatment in various parts of long bones was different, obviously due to differences in the bone growth and remodelling.     

Pathogenetic process of lung tumors induced by inhalation exposures of rats to plutonium dioxide aerosols

Sequential examinations were done on the pulmonary cytokinetics and pulmonary lesions in rats after inhalation exposure to (239)PuO(2) aerosols to investigate the pathogenesis of lung tumors. Total cell yields of lavaged bronchoalveolar cells as well as the estimated numbers of pulmonary alveolar macrophages were significantly reduced from 1 to 3 months after exposure but recovered thereafter to the control levels. The proportions of multinucleated or micronucleated pulmonary alveolar macrophages increased significantly in lavaged cells from 1 month, and the increase was sustained up to 18 months after exposure. Both tumor necrosis factor and nitric oxide were shown to be differentially released from stimulated cultures of pulmonary alveolar macrophages during the period from 6 to 18 months after exposure. The labeling indices of alveolar and bronchiolar epithelial cells treated with 5-bromo-2'-deoxyuridine increased significantly in lungs from 3 months and were sustained up to 18 months after exposure. Histopathological examinations revealed that after the early inflammation, hyperplasia and metaplasia of the lining of the bronchioloalveolar epithelium were predominant from 3 to 6 months, while adenomatous or adenocarcinomatous lesions appeared and developed from 12 months after exposure. The appearance of primary lung tumors, almost all of which were adenomas and adenocarcinomas, was found in the dose range of 1 to 2 Gy from 12 months after exposures. These results indicate that the pathogenetic process initiated by early cellular damage and alterations associated with inflammation is followed by the proliferative and metaplastic lesions of pulmonary epithelium, leading to the appearance and development of pulmonary neoplasms from 1 year after the inhalation exposures in rats that received a minimum lung dose of more than 1 Gy.