56. Sequential Study on Pathogenesis of Lung Tumors in Rats Following Inhalation Exposures to Plutonium Dioxide Aerosols

Yoichi Oghiso, Yutaka Yamada and Kumiko Fukutsu

Keywords: cytokinetics, dose, time, lung tumors, rats, ²³⁹PuO₂

Sequential examinations were done on the cytokinetics of pulmonary alveolar macrophages(PAM) and lining epithelial cells, proliferative and neoplastic lesions in the lungs of female Wistar strain rats following the inhalation exposures to submicron-size, polydispersed and high-fired ²³⁹PuO₂ aerosols to analyse the pathogenetic processes of pulmonary carcinogenesis as well as the estimation of absorbed lung doses and times required for the development of lung tumors. The early appearance of multinucleated and micronucleated PAM was noted from the period of 1 to 3 months after exposures, when both nitric oxide(NO) and tumor necrosis factor(TNF) activities released from PAM stimulated in vitro with lipopolysaccharides and interferon-g were also significantly increased. The numbers of BrdU-labelled bronchiolar or alveolar epithelial cells significantly increased from 3 months and sustained up to 18 months after exposures. As correlated with these cytokinetic changes occurred in the initial to the late stages after exposures, histopathological findings showed that the early inflammatory lesions associated with exudation of blood leukocytes and alterations of respiratory tract epithelium were reduced, and then both pulmonary fibrosis and hyperplastic metaplasias increased from 3 months, while adenomatous or adenocarcinomatous lesions developed from 6 to 12 months after exposures. The appearance of primary lung tumors, almost all of which were benign adenomas and malignant adenocarcinomas, was observed in the dose range of 1 to 2 Gy from 12 months after exposures. These results indicate that the pathogenetic processes initiated by inflammation and cellular damage, are followed by the increase of proliferative and metaplastic lesions of the lining epithelium leading to the appearance and development of neoplasias at least from 1 year or later when the absorbed lung doses should be estimated to be 1 to 2 Gy after inhalation exposures to ²³⁹PuO₂.

Publications:
Oghiso,Y., Yamada,Y. and Fukutsu,K.: Abstracts for 11th ICRR, edt. M.Moriarty, C.Mothersill, C.Seymour, Radiat.Res., 279, 1999.