ral or pleural cavity (Hueper et al. 1952). Eleven of 33 rats with injection of uranium in the right femur developed sarcomas that surrounded or were in the immediate vicinity of uranium deposits. Six of the sarcomas produced metastases in the inguinal, abdominal, or mediastinal lymph nodes or the lungs. Sarcomas also developed at the site of intrapleural injections in two of 33 rats. The authors concluded that the results clearly established the carcinogenic nature of uranium; however, a definitive conclusion could not be reached regarding the role of the chemical vs radiologic properties of uranium in the cause of the sarcomas. The latent period and the histologic structure of the sarcomas that formed in response to the uranium injections were noted to be similar to those of sarcomas induced by injection of metallic nickel powder, and this suggested a similar chemical-based mechanism of action. Both nickel and uranium injections produced local necrotizing, hyalinizing, and fibrosing reactions, which were often associated with a local proliferation of periosteal and endosteal cancellous bone. However, the authors noted that the intensity of exposure to alpha radiation in tissue immediately adjacent to uranium deposits was much higher than the radiation intensity that occurs from uranium stored in bone after systemic exposure to soluble uranium. In addition, the latent period for the uranium-induced sarcomas in these experiments was similar to reported latent periods for sarcomas produced in rats by the radioactive elements radium and thorium. Thus, the basis of the powdered metallic uranium’s carcinogenic effects remained uncertain. Since the 1950s, when this study was conducted, research has suggested that local sarcomas forming around many types of embedded metals may be due to chronic local inflammation (IARC 1999); this mode of action should be considered in determining cancer risks associated with DU exposure.

Leach et al. (1970, 1973) conducted 5-y inhalation studies in monkeys, dogs, and rats with natural uranium dioxide dust about 1 μm in mass median diameter. Animals were exposed to uranium at 5 mg/m3 6 h/d 5 d/wk for up to 5 y. Evidence of neoplastic changes (pulmonary glandular neoplasms and atypical epithelial proliferation) was observed 2-6 y after exposure ceased and only in dogs. That finding was important because tumor incidence was 50-100 times higher than in controls. Evidence of pulmonary neoplasia was observed in six of 13 dogs followed for up to 6.5 y after exposure to uranium dioxide. In contrast, no pulmonary tumors or areas of atypical epithelial proliferation were observed in six monkeys followed for up to 7.5-y after exposure (Leach et al. 1973). One monkey had lymphoma that involved some tracheobronchial lymph nodes. The difference in cancer incidence between the dogs and the monkeys, the authors noted, might have been due to the different proportions of the life spans over which the dogs and monkeys were tested and observed. Leach et al. also noted that glandular neoplasms occur infrequently in humans, so quantitative extrapolation of the results of this study to humans would be difficult. The authors were concerned, however, that neoplasms developed in the dogs at radiation doses that were about 20-25% lower than those produced by 239Pu, leading them to propose that natural uranium might exert both chemical and radiologic effects.

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