ANIMAL-MODELS OF BERYLLIUM-INDUCED LUNG-DISEASE

The Inhalation Toxicology Research Institute (ITRI) is conducting rese arch to improve the understanding of chronic beryllium disease (CBD) a nd beryllium-induced lung cancer. Initial animal studies examined beag le dogs that inhaled BeO calcined at either 500 or 1000 degrees C. At similar lung burdens, the 500 degrees C BeO induced more severe and ex tensive granulomatous pneumonia, lymphocytic infiltration into the lun g, and positive Be-specific lymphocyte proliferative responses in vitr o than the 1000 degrees C BeO. However, the progressive nature of huma n CBD was not duplicated. More recently, Strains A/J and C3H/HeJ mice were exposed to Be metal by inhalation. This produced a marked granulo matous pneumonia, diffuse infiltrates, and multifocal aggregates of in terstitial lymphocytes with a pronounced T helper component and pulmon ary in situ lymphocyte proliferation. With respect to lung cancer, at a mean lung burden as low as 17 mu g Be/g lung, inhaled Be metal induc ed benign and/or malignant lung tumors in over 50% of male and female F344 rats surviving greater than or equal to 1 year on study. Substant ial tumor multiplicity was found, but K-ras and p53 gene mutations wer e virtually absent. In mice, however, a lung burden of approximately 6 0 mu g (similar to 300 mu g Be/g lung) caused only a slight increase i n crude lung tumor incidence and multiplicity over controls in strain A/J mice and no elevated incidence in strain C3H mice. Taken together, this research program constitutes a coordinated effort to understand beryllium-induced lung disease in experimental animal models.