Kinetics and biological effects of neutron-activated uranium dioxide particles

Hot particles are defined as highly radioactive particles made up of radionuclides from fission or activation reactions and/or actinides. Hot particles have been found in the nuclear power plant environment, and in the fallout of nuclear weapon tests and nuclear reactor accidents. The Chernobyl fallout in 1986 contained all non-volatile fission products, including the β-emitters 95Zr, 95Nb, 103Ru, 106Ru, 141Ce and 144Ce attached to uranium matrix. The so-called 'hot particle hypothesis' is based on the assumption that a non-uniformly distributed radiation dose is more carcinogenic than an equal radiation dose delivered uniformly to the same organ or tissue. This hypothesis has repeatedly been refuted by many theoretical and experimental studies. This study was performed to investigate the kinetics and biological effects of neutron-activated UO2 particles, i.e. hot particles, in laboratory animals in vivo, and to study the mechanisms of in vitro transformation. The primary aims of the study were to estimate the health risk of an important environmental pollutant in the nuclear power industry and to study the molecular mechanisms involved in hot particle-induced carcinogenesis. Uranium fission products 144Ce, 141Ce, 103Ru, 95Zr and 95Nb are almost metabolically inert in the fused particulate form in uranium matrix. In the gastrointestinal tract these radionuclides are not absorbed in the particulate form, and from the lungs they are not translocated to the other organs or tissues at the same rate as is characteristic for their elementary form. The current metabolic models probably overestimate the health risk associated with the ingestion of radionuclides, whereas the models may underestimate the effects of the radionuclides on the lungs following inhalation. Neutron-activated UO2 particles are more effective in producing malignant cell transformation in vitro in C3H 10T1/2 cell culture and in the mouse skin in vivo than the conventional non-threshold stochastic models of radiation-induced cancer would predict. The conventional theoretical dose risk assesment models used in radiation protection are not appropriate when predicting biological effects of this unique radiation source and mode of exposure. The apparent carcinogenesis-related molecular changes occur frequently in the hot particle-exposed mouse skin before the development of a distinct tumour, and even before premalignant changes can be detected by conventional histopathological analysis. Overexpression of the tumour suppressor gene p53 appear to be a common change at early stages in radiation-induced carcinogenesis in the mouse skin and this change is regularly associated with overexpression of two 'critical' (nuclear and cytoplasmic) oncoproteins p62c-fos and p21N-ras. Overexpression of p53 protein is probably a common molecular effect also in radiation-induced malignant lung tumours in the rat. In addition, ionizing radiation appears to cause 'radiation-specific' point mutations in the p53 gene. C:G to T:A transition in the CG dinucleotide may be a common change induced by low-LET ionizing radiation. In view of the basically non-specific action of ionizing radiation on DNA, the observed regularity in the cancer-related molecular changes in the mouse skin and rat lung is surprising. (author)