plutonium-dioxide and Adenoma

Radiation-induced pulmonary carcinogenesis was compared in female Wistar rats following either inhalation exposure to alpha-emitting (239)PuO(2) aerosols, whole-body or thoracic X-ray irradiation. Dose-dependent survival reduction was correlated with increased malignant lung tumors at doses over 0.45 Gy, reaching the maximum incidence of 90% at 6.6-8.5 Gy in (239)Pu-exposed rats. While the differential dose responses for each histopathological type of tumors were noted, almost 70-80% were carcinomas among all of the primary tumors from (239)Pu-exposed rats. As the dose response curves for lung carcinomas were compared, the slope of the fit linear equation and the calculated relative effectiveness for 50% incidence of lung carcinomas were approximately 11-times as high in (239)Pu-exposure as those of thoracic X-irradiation. The numbers of tumor lesions distributed in the lung per tumor-bearing animal were about 2-fold more in (239)Pu-exposed rats, while the proportions of their histopathological types were similar between (239)Pu-exposure and X-irradiation. These results indicate that the magnitudes of the relative effectiveness or risk for pulmonary carcinogenesis are greater in (239)Pu-exposure than X-irradiation, and that radiation-induced lung tumors appear to originate mostly from the same target epithelial cells.

Topics: Adenoma; Animals; Carcinoma; Computer Simulation; Dose-Response Relationship, Radiation; Female; Inhalation Exposure; Lung Neoplasms; Models, Biological; Neoplasms, Radiation-Induced; Plutonium; Radiation Dosage; Radiometry; Rats; Survival Rate; Whole-Body Irradiation; X-Rays

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.

Topics: Adenocarcinoma; Adenoma; Administration, Inhalation; Aerosols; Animals; Bronchoalveolar Lavage Fluid; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; DNA Replication; Epithelial Cells; Female; Hyperplasia; Inflammation; Lung; Lung Neoplasms; Macrophages, Alveolar; Metaplasia; Neoplasms, Radiation-Induced; Nitric Oxide; Plutonium; Radiation Injuries, Experimental; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Female Wistar strain rats were exposed to a single inhalation of a submicron-size aerosol of high-fired 239PuO2 to investigate pulmonary carcinogenesis during lifespan periods. The absorbed lung doses of the exposed animals ranged from 0.6 to 12 Gy and were well correlated with the initial lung deposition (ILD) of 0.1 to 2.3 kBq. Survival and induction of primary lung tumors in 116 exposed rats were compared with those in 56 untreated control rats in respect to lung doses received. Mean survival time was greatly reduced, and the cumulative incidence of total lung tumors was markedly increased to 90-100% in rats that received more than 4 Gy, whereas of the controls only one animal (1.8%) died of primary lung tumors. Primary but benign adenomas were present in exposed animals given 1.0 Gy or less, and the incidence of adenomas was 22-25% at 4-5 Gy, but decreased sharply to 3-5% at 6-8 Gy. In contrast, no malignant carcinomas, including adenocarcinomas, adenosquamous carcinomas and squamous cell carcinomas, developed at a dose of less than 1.0 Gy, whereas they were present in 75% or more of the rats given 4-10 Gy, but only in 55% at 12 Gy. Although there were no clear differences in the dose and time required for induction among the carcinoma types, all tended to develop in earlier periods after inhalation than adenomas. Despite the limited number of exposed animals that received lower doses, results suggest that malignant lung carcinomas are highly and early induced and have a different dose-effect relationship than benign adenomas at doses of more than 1 Gy after inhalation exposure to 239PuO2.

Topics: Adenocarcinoma; Adenoma; Administration, Inhalation; Aerosols; Animals; Female; Incidence; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Rats; Rats, Wistar

Female, young adult, Wistar rats were given a single inhalation exposure to a submicron sized aerosol of high-fired 239PuO2 and observed during their lifespan for primary lung tumours. Rats were distributed among sham-control (n = 1052) and exposed (n = 2105) groups. Survival was significantly reduced only in rats with lung doses > 30 Gy. A total of 99 primary lung tumours were found, of which 92% were malignant and 80% were carcinomas. Of malignant lung tumours, 49 were squamous cell carcinoma, 23 adenocarcinoma, nine hemangiosarcoma, seven adenosquamous carcinoma, and three fibrosarcoma. One adenocarcinoma was found in controls and only four adenomas were seen in the exposed rat at lung doses < 1.5 Gy. The lowest doses at which lung tumours appeared in exposed rats were 1.5 Gy for squamous cell carcinoma, 3.1 Gy for adenocarcinoma. 4.1 Gy for hemangiosarcoma, and about 9 Gy for adenosquamous carcinoma and fibrosarcoma. Pulmonary squamous metaplasia was not seen in controls and was first seen in exposed rats only at lung doses > 1 Gy. Primary lung tumours were the presumed cause of death (fatal) in 60% of rats with malignant lung tumours; causes of death were equally distributed among all tumour types and doses. The incidence of all lung tumours was 0.095% in control rats, 0.21% in 1877 rats with lung doses < 1 Gy, and 41% in 228 rats with doses > 1 Gy. Lung tumour incidence increased in a linear manner from 6.9% at 2.3 Gy to an incidence of 64-88% at 16-44 Gy. Absolute malignant lung tumour risk averaged 270 lung tumours per 10(4) rat-Gy above a lung dose of 1 Gy. All types of malignant lung tumours induced by inhaled 239PuO2 exhibited a threshold at a lung dose > 1 Gy.

Topics: Adenocarcinoma; Adenoma; Administration, Inhalation; Aerosols; Animals; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Female; Fibrosarcoma; Hemangiosarcoma; Lung Neoplasms; Neoplasms, Radiation-Induced; Plutonium; Radiation Injuries, Experimental; Rats; Rats, Wistar; Survival Analysis