Proliferative bone lesions in rats fed a diet containing glucocorticoid for up to two years.

A glucocorticoid was fed in the diet to 50 Sprague-Dawley rats/sex at 0, 0.03, 0.06, 0.12, 0.25, 0.50, and 1.0 mg/kg/day for up to 2 yr. A total of 1,400 rats were examined. Bone neoplasms (5 osteosarcomas and 2 osteomas), involving the head, occurred in 7 males that were fed the test compound at the highest dose (0.25 mg/kg) with long-term survivors. One osteoma and 1 hyperostotic lesion were seen in 2 males receiving lower doses (0.06 mg/kg and 0.12 mg/kg, respectively); 1 female rat that received the highest dose (1 mg/kg) had an osteosarcoma. The results suggest, but do not confirm, a relationship between glucocorticoid exposure and bone proliferations in male Sprague-Dawley rats. Other proliferative bone lesions included hyperostosis in a 0.12-mg/kg male, osteoma in a 0.06-mg/kg male, and osteosarcoma in 1 female at 1.0 mg/kg. The purpose of this report is to characterize the incidence and morphology of primary bone proliferative lesions found in rats of 1-yr glucocorticoid toxicity and 2-yr carcinogenicity studies conducted in our laboratory.

Spontaneous vascular neoplasms in aged Sprague-Dawley rats.

Primary benign and malignant vascular neoplasms occurred spontaneously in 8 of 710 male (1.1%) and 4 of 710 female (0.6%) Crl:CD Br strain Sprague-Dawley rats employed in two 2-yr oncogenicity studies (1,400) and as controls in a 1-yr toxicity study (20). Four of 13 neoplasms were found in the spleen; skin and kidney each had 2 neoplasms. Single vascular neoplasms were in the liver, testicle, uterus, mesenteric lymph node, and vagina. Hemangioma was more common (5 males, 2 females) than hemangiosarcoma (3 males, 2 females). Vascular neoplasms were considered the cause of death in 2 females, both with hemangiosarcomas involving the spleen or kidney. One male had 2 primary hemangiomas in separate organs. Vascular neoplasms are infrequently reported [1/82 females (1.2%), 1961; 9/880 both sexes (1.0%), 1985] in this rat strain. The incidence of vascular neoplasms of this report was higher in males (9) than in females (4), in contrast to incidences reported in the literature.

Chronic effects of corticosteroid oral treatment in rats on blood glucose and serum insulin levels, pancreatic islet morphology, and immunostaining characteristics.

Corticosteroids have for many years proven beneficial in the necessary treatment of diseases and conditions that respond to their anti-inflammatory, immunosuppressive, or hormonal effects. Deflazacort is a derivative of prednisolone and is currently used in humans. Deflazacort was fed in the diet for 1 yr to Crl:CD BR rats at doses from 0.03 to 1.0 mg/kg/day to evaluate its toxic potential. Deflazacort-induced pancreatic islet cell hyperplasia in the 1-yr study was evaluated using subjective and objective methods on routine hematoxylin-and-eosin- or peroxidase-anti-peroxidase-stained preparations of pancreas (islets); the relationship of blood glucose and serum insulin levels to doses of deflazacort administered to rats was also examined. Diagnostic electron microscopy was conducted on similar proliferative islet lesions for a few high-dose males of a parallel carcinogenicity study. This study revealed that proliferative islet lesions were comprised mainly of beta cells (insulin producing) and that the islet area correlated well with hyperplasia grade and dose. However, there were no statistically significant relationships among reductions in blood glucose, serum insulin concentration, and proliferative islet alterations.

Spontaneous skin neoplasms in aged Sprague-Dawley rats.

A total of 93 tumors of the epidermis, its appendages, and dermis were observed in 1,433 (717 males, 716 females) rats employed in oncogenicity studies over a 2-yr period. Mammary gland neoplasms will be reported separately. Fifty-seven (61.3%) were epithelial with 49 in males and 8 in females. Keratoacanthoma was the most frequent epithelial neoplasm in males (22) followed by squamous cell carcinoma (11) and papilloma (5). Sebaceous gland neoplasms seen in males (5) included both adenomas (3) and carcinomas (2). In males, there were also 3 trichoepitheliomas, 1 pilomatricoma, 1 basal cell tumor, and 1 malignant melanoma. Of the 8 epithelial neoplasms in females, there were 3 squamous cell carcinomas, 2 keratoacanthomas, and 1 each basal cell tumor, malignant melanoma, and trichoepithelioma. There were 21 mesenchymal neoplasms in males and 15 in females. The most frequent neoplasm was fibroma (7 males, 8 females) followed by lipoma (7 males, 4 females) and fibrosarcoma (4 males, 3 females). One male had a liposarcoma and 2 males each had hemangioma. The total neoplasm incidence of 70/717 (9.8%) in males and 23/716 (3.2%) in females showed that skin neoplasms were 3 time more common in males than in females. Epithelial neoplasms of the skin were 6 times more common in males than in females. Males were more than twice as likely to have epithelial rather than mesenchymal skin neoplasms whereas the reverse was seen in females.

Spontaneous brain and spinal cord/nerve neoplasms in aged Sprague-Dawley rats.

Primary malignant neoplasms of the brain and spinal cord occurred in 20/718 male (2.8%) and in 13/717 female (1.8%) Crl:CD Br strain Sprague-Dawley rats. Of 33 neoplasms, 30 were found in brain while 3 were in the spinal cord. In males and females, the most common brain neoplasm was astrocytoma (13 males, 9 females). Other neoplasms, granular cell tumor (1 male), mixed glioma (2 males, 1 female), reticulosis (1 male, 2 females), and oligodendroglioma (2 males), were especially uncommon. Spinal cord neoplasms included 2 schwannomas (1 male, 1 female) and an astrocytoma (1 male). The overall brain neoplasm incidence was similar for males (2.8%) compared to data compiled for this strain, and there was a 2-fold increase for females (1.8% vs 0.9%) compared to available incidence data.

Naturally occurring intestinal epithelial neoplasms in aged Crl:CD BR rats.

Spontaneous primary epithelial neoplasms of the intestinal tract occurred in 6/682 (0.9%) male and 1/694 (0.1%) female Sprague-Dawley rats. Six of 7 neoplasms were adenocarcinomas, and 1 of 7 was an adenoma. Metastasis to the liver or lung occurred in 3 of the rats with adenocarcinoma. These findings are consistent with those reported for female Sprague-Dawley rats and for males and females of other strains over the past 25 years. The intestinal neoplasm incidence in males exceeded that reported for other Sprague-Dawley males with one exception, reported 30 years ago.

Spontaneous renal neoplasms in aged Crl:CDBR rats.

Primary neoplasms of the kidneys occurred in 11/682 male (1.6%) and 2/694 female (0.3%) Crl:CDBr strain Sprague-Dawley rats. Eight of 13 neoplasms were of mesenchymal origin and 5 of 13 were epithelial. Five neoplasms were lipoma (3) or liposarcoma (2). Three of 13 were either hemangioma (1) or mesenchymal tumors (2). The epithelial neoplasms were carcinomas. There was no microscopic evidence of metastasis among those neoplasms judged malignant on morphologic criteria. The overall natural incidence in males was nearly double that compiled for this strain while in females the incidence was similar to that reported for other females.