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.

Animals↗

PubMedDate not supplied

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.

Aging↗

PubMedDate not supplied

Effects found in a one-year oral toxicity study in Sprague-Dawley rats of a novel 5-HT1A receptor partial agonist for the treatment of anxiety in humans.

A potent and selective serotonin (5-HT1A) partial agonist with potential as a human anxiolytic drug was given in oral doses of 0, 5, 15, or 50 mg/kg/day by gavage to Sprague-Dawley rats for 6 or 12 mo. Some animals were allowed 1 mo to recover after each treatment period. The 10-fold increase in dose resulted in a 20-fold increase in drug plasma concentration due to saturable first-pass metabolism. This resulted in disproportionately higher concentrations and greater bioavailability of the 15- and 50-mg/kg/day regimens. Drug exposure was associated with decreased spontaneous activity in the 15- and 50-mg/kg rats. The activity of these rats returned to normal during the recovery period. There were significant (p < 0.05) decreases in mean body weights during the study for 50-mg/kg males, with improvement during the recovery periods. No biologically significant effects were noted in clinical laboratory parameters. Based on organ weight increases and histopathological evaluation, drug-related effects after 6 and 12 mo of treatment were in the pituitary (both sexes) and all treated female reproductive organs. In general, these effects persisted into periods of recovery, except for pituitary hyperplasia, which was not apparent following recovery after treatment for 6 mo. After treatment for 12 mo and the following recovery, there were significant increases in adrenal weights in the 15- and 50-mg/kg/day males with no morphological correlate. There was increased pituitary hyperplasia that persisted through the recovery period in all treated groups in both sexes, but there was no increase in pituitary neoplasms. In treated females, there was also morphologic evidence of persistent diestrus (estrogenic effect) evidenced by endometrial squamous metaplasia, increased corpora lutea, vaginal mucification, and decreased uterine size. The clinical and pathological changes seen with these 2 regimens were considered exaggerated pharmacological effects of the drug on serotonin receptor-rich organs.

Animals↗

PubMedDate not supplied

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.

Animals↗

PubMedDate not supplied

Toxicity of aerosols of sodium reaction products.

Sodium is used as the heat transfer medium in several new energy technologies such as liquid-metal fast-breeder reactors and solar-thermal collection systems. Because sodium burns in air and reacts violently with water, the potential exists for an airborne release of sodium combustion products and subsequent human exposure. To help evaluate the potential short-term hazard from an accidental sodium fire, male juvenile or adult Wistar rats were exposed to sodium aerosols for 2 hours to determine the dose at which 50 percent of the animals were affected (ED50) for each age group. The estimated ED50 of 510 microgram/l for adults was not significantly different from the estimated ED50 of 489 microgram/l for juveniles. The incidence of acute laryngitis, attributed to exposure, was three times higher for juvenile rats than for adults, and the degree of severity of this lesion was significantly (P less than 0.05) higher for juveniles.

Aerosols↗