Evaluation of risk factors for lung tumour induction in rats exposed to either NpO(2) or PuO(2) aerosols.

PURPOSE: To compare the incidence of each lung tumour type after inhalation exposure of rats to either NpO(2) or industrial PuO(2) aerosols, which have a similar size. MATERIALS AND METHODS: Male Sprague-Dawley rats were exposed once and followed during their whole life span. At the end of their life, the whole lungs were fixed, embedded and cut into thin sections for histological analysis. The presence of tumours was evaluated on three distinct levels of the lobes for phenotype determination to establish dose-effect relationships. RESULTS: In the range of lung doses studied (0.05 to more than 50 Gy), the general trend was an increased frequency of all types of tumours after inhalation exposure to neptunium compared with plutonium. The linearity of the lower part of the dose-effect relationships for all malignant lung tumours leads to the conclusion that NpO(2) is 3.3-fold more carcinogenic than PuO(2). CONCLUSIONS: According to a linear extrapolation of the data on malignant lung tumour incidence collected among all studies reported on actinide oxide carcinogenesis, the risk of lung tumour appears to vary over a factor of about 10 depending on the nature and/or size of the aerosol. This variation has to be taken into account for a realistic assessment of tumour risk.

Ultrastructural apoptotic lesions induced in bone marrow after neptunium-237 contamination.

This study describes the ultrastructure of lesions induced by neptunium-237 (237Np), a by-product of uranium in nuclear reactors, in the bone marrow. A group of rats were given a single injection of 237Np-nitrate solution in order to observe the acute toxicity effects of this actinide. Electron microscopy was used to describe the different lesions. Observations included the swelling of the cell membrane, nuclear membrane lyses, abnormal chromatin condensation or nucleus convolution. These ultrastructural alterations of the nucleus and the cellular membrane appeared shortly after treatment. This study demonstrates the toxic effects of neptunium and its implication in the induction of apoptosis in bone marrow.

Ultrastructural lesions induced by neptunium-237: apoptosis or necrosis?

In this study, we are concerned with the 237 isotope of neptunium (237Np), which is a by-product of uranium in nuclear reactors. To study ultrastructural lesions induced by this element, a group of rats were injected with a solution of 237Np-nitrate once a day for 14 weeks. Lesions observed in liver and kidney are described using electron microscopy. Ultrastructural alterations of cellular membranes and intracellular organelles demonstrated the existence of neptunium toxicity. This toxicity was characterized by various lesions, such as cytoplasmic clarification, disappearance of mitochondrial cristae, swollen mitochondria, abnormal condensation of nuclear chromatin, and nuclear fragmentations. This study demonstrated the probable induction of apoptosis by neptunium both in liver and kidneys.

Survival, lung clearance, dosimetry and gross pathology of rats exposed to either NpO2 or PuO2 aerosols.

PURPOSE: To compare survival, lung dosimetry and gross pathology after inhalation exposure of rats to either NpO2 or industrial PuO2 aerosols with similar granulometric parameters. Because the specific alpha activity ratio Pu/Np is about 600, a much more homogeneous lung irradiation was expected for NpO2. MATERIALS AND METHODS: Male Sprague Dawley rats were exposed once and their lung burdens were measured by X-ray spectrometry at different times post-exposure up to death. The time-course of doses delivered to the lungs were estimated, taking into account individual lung clearance parameters and body and lung weights. Gross lung pathologies were scored at autopsy. RESULTS: In the range of initial lung deposits (ILD) studied (0.1-4 kBq), lung clearance impairment and reduced lifespan were only observed after exposure to NpO2. For similar ILD or doses, the highest incidences of lung lesions assumed to be tumours were observed for NpO2 with a saturation of lung tumour induction for doses larger than 8 Gy (ILD: 1.5kBq). Up to 22Gy (ILD: 3.5kBq), such saturation was not observed for PuO2. CONCLUSIONS: NpO2 appears much more toxic than PuO2. Before saturation, lung tumour incidence increased nearly linearly with dose, the slope of the curve for NpO2 being about twice as steep as that for PuO2.

Chemical toxicity of some actinides and lanthanides towards alveolar macrophages: an in vitro study.

PURPOSE: To compare the toxicity of lanthanides (cerium, gadolinium) with actinides (thorium, neptunium, uranium) added in soluble form to rat alveolar macrophage cultures. MATERIALS AND METHODS: The metals were added 1 day after seeding alveolar macrophages extracted by pulmonary lavage, and the metal toxicity was scored 3 days later. Cell death was measured after vital staining to distinguish between apoptosis and necrosis; relative cell density was also quantified. The physico-chemical form of the metals in the culture medium was characterized using filtration and radioactive measurements. RESULTS: Except for thorium, induction of cell death was observed for all the elements studied and the death mechanism involved was apoptosis. Graduated toxicity was observed from uranium to neptunium, cerium and gadolinium, in the range of concentration from 10(-3)-10(-6) M. From pilot experiments, it was hypothesized that soluble compounds were mainly involved in lanthanide toxicity, whereas insoluble forms were mainly involved in actinide toxicity. CONCLUSION: This study demonstrates that the toxicity of neptunium and uranium was concomitant with the presence of insoluble forms in the culture medium. Further studies are needed to characterize the cell death mechanisms involved and the potential synergistic effects of chemical toxicity and irradiation.

Lung carcinogenesis in rats after inhalation exposure to (237)NpO2.

The results of several studies of experimental carcinogenesis suggest that, after inhalation of alpha-particle emitters, lung tumor incidence varies depending on the exposure rate and dose distribution in the tissue. In the case of transuranics, the main influencing factor would be the specific alpha-particle activity of the inhaled actinide. To confirm these results, long-term studies were performed using male Sprague-Dawley rats exposed to (237)NpO(2) by inhalation. The initial lung burdens of the animals ranged from 0. 1 to about 7 kBq. The rats were followed during their life span and weighed regularly, and their lung burdens were determined in vivo and at death to estimate the lung dose. At death, the incidence of lung tumors and their malignancy and histological types were analyzed. The analysis revealed a typically linear-quadratic dose response for incidence of malignant lung neoplasm and a differential dose response for various types of tumors. Although these results confirm the influence of the activity of the inhaled actinide oxide, further experiments are needed to be able to compare a more homogeneous population of animals.

Dosimetry and pathology of 237Np in female rats.

Female Sprague-Dawley rats, 10-12-week old and weighing about 240 g, were injected intravenously with 237Np-nitrate. In the toxicological study 77 rats served as controls and 28 rats per group received single doses of 5.2 and 26 kBq, respectively, per kg body weight. In addition, 12 rats of each injection level, sacrificed at defined points in time, were used for dosimetric studies. During the whole life-span the body weight and 237Np whole body-content of each animal were recorded. After death a detailed pathological examination was made of each animal in the cronical study. One day after injection 48% of the injected activity was in the skeleton, 9.3% in the liver, 3% in the kidneys and 4.4% in the rest of the organs. Whereas in all organs the activity decreased very fast, the half-life in the skeleton was about 1400 days. The bodyweights were comparable in the three groups, but the life span decreased from 800 days (control group) to 644 days after injection (26 kBq kg-1 body weight group). The main lesions in the female rats were mammary tumors (73%) and pituitary gland tumors (52%). With increasing activity the incidence of pituary gland tumors decreased and that of osteosarcomas increased from 1.3% (control group) to 32% (26 kBq kg-1 body weight group), whereas the remaining lesions showed no influence on the activity.

Intranuclear sites of Np 237 in mammalian cells: a study using electron microscopy and electron probe microanalysis.

Two methods, electron microscopy and wavelength dispersive electron probe microanalysis, were used to determine the intracellular sites and chemical form of concentrations of neptunium nitrate 237 after chronic intoxication by the intraperitoneal route in two organs in the rat known to concentrate this element (kidney, liver). Abnormal intranuclear formations in the form of clusters of dense granules containing neptunium, phosphorus, sulphur, and calcium were found in the nuclei of kidney proximal tubule cells and hepatocytes. These formations had a maximum diameter of the order of 2 microns and were located in the central part of the nucleus, away from the nucleolus and peripheral chromatin. Serious nuclear and cytoplasmic ultrastructural lesions are often associated in cells containing neptunium inclusions. The absorbed doses in the kidney and the liver were very low. A relationship between these abnormal intranuclear structures and the carcinogenic effect of neptunium remains to be clarified. This effect is related more probably to the chemical toxicity of Np 237.

[Selective localization of neptunium-237 in nuclei of mammalian cells]. / Localisation sélective du neptunium-237 au sein des noyaux des cellules de mammifères.

After injection in the rat of soluble neptunium salt, the distribution of this element was studied at the subcellular level by electron microscopy and electron probe microanalysis. Abnormal structures have been observed by electron microscopy in the nuclei of hepatocytes, and the same structures have also been observed in the nuclei of the proximal tubules cells of the kidney. These structures are formed of clusters of very small and dense particles, several nanometers in diameter. The clusters are localized in the central part of the nuclei and they are separate from nucleoli and heterochromatin. Electron probe X-ray analysis of this cluster have shown that they contain neptunium associated with phosphorus. In the cell containing neptunium inclusions, other non specific lesions are also observed (nuclear pycnosis, mitochondrial depletion).

The biodistribution and toxicity of plutonium, americium and neptunium.

In the nuclear fuel cycle the transuranic radionuclides plutonium-239, americium-241 and neptunium-237 would probably present the most serious hazard to human health if released into the environment. Despite differences in their solution chemistry the three elements exhibit remarkable similarity in their biochemical behaviour, apparently sharing similar transport pathways in blood and cells. After entering the blood the elements deposit predominantly in liver and skeleton, where retention appears to be prolonged, with half-times of the order of years. The principal late effects of all three radionuclides are the induction of cancers of bone, lung or liver. For the latter tumours the induction risk per unit radiation dose appears similar for the three radionuclides. But in bone there are indications that, due to microscopic differences in the distribution of the alpha-particle radiation dose, the efficiency of bone cancer induction may increase in the order americium-241 less than plutonium-239 less than neptunium-237. No case of human cancer induced by these radionuclides is known.