Comparative study on Tp53 gene mutations in lung tumors from rats exposed to 239Pu, 237Np and 222Rn.

The tumor suppressor gene Tp53 was analyzed by polymerase chain reaction-amplification of genomic DNA extracted from paraffin-embedded tissue sections of rat lung tumors to compare mutations that occurred after inhalation exposures to plutonium dioxide, neptunium dioxide, or radon and radon progenies. Exons 5 to 8 of the gene were amplified in 16 plutonium-, 23 neptunium- and 15 radon-induced lung tumors, and their polymerase chain reaction products were examined for mutations by single strand conformational polymorphism analysis and direct sequencing method. Two point mutations were detected in the plutonium-induced tumors, i.e., a guanine to adenine transition at codon 219 of exon 6 and a cytosine to thymine transition at codon 266 of exon 8. Although only one point mutation was found at codon 175 of exon 5 (cytosine to thymine transition) from neptunium-induced tumors, no mutations were detectable from radon-induced tumors. These results indicate that the abnormalities of the Tp53 gene might not be so critical for the pulmonary carcinogenesis after the inhalation of different alpha emitters, even though the presence and frequencies of the Tp53 gene mutations were different.

Influence of exposure rate on radon-induced lung cancer in rats.

A new series of experiments was carried out to investigate specifically the influence of exposure rate on lung cancer induction in rats at relatively low cumulative exposures of about 100 WLM, and at potential alpha energy concentrations (PAECs) ranging from 13 to 150 WL. The results indicate that at relatively low cumulative exposures comparable to lifetime exposures in high-radon houses or current underground mining exposures, the risk of lung cancer in rats decreases with decreasing PAECs, i.e. exposure rates. They confirm the results of previous experiments conducted at lower cumulative exposure, showing that for a similar cumulative exposure of 25 WLM, the risk of lung cancer decreases with decreasing exposure rates. These data suggest that the induction of lung cancer results from a complex interplay between cumulative exposure and exposure rate, with an optimal combination of these two parameters, i.e. a combination of cumulative dose and dose rate that results in a maximum risk of lung tumour induction. They support the hypothesis that, at low doses, the risk of lung cancer is governed by the rate at which the dose is delivered, and not by the total cumulative dose alone. These data are also consistent with that of underground uranium miners showing an inverse dose-rate effect at high cumulative exposures, but a diminution of this effect at cumulative exposures lower than 50 WLM.