B-72

M. G. Robl¹ , P. L. Wiesenfeld¹ , L. H. Garthoff¹ , T. J. Sobotka¹ , J. K. Suagee² , ¹OARSA, CFSAN, FDA, Laurel, MD, ²University, of Maryland, College Park, MD

Background: Acute oral toxicity of COL, gender differences and pre-exposure to LPS in rats was investigated (details in Wiesenfeld et al. poster). Histopathology examination of selected tissues was performed to facilitate understanding the gender related toxicity and lethality of COL and interaction with LPS.

Methods: Following a gross necropsy evaluation of most of the rats, tissues were saved and fixed in formalin. Selected tissues from the high dose (30 mg/kg COL of BW) group were processed into H and E stained slides and light microscopic evaluation performed.

Results:Even though more females than males died in rats dosed with 30 mg/kg of BW COL during the first 5 days post dosing (PD), necrosis of bone marrow cells, hepatocytes and lymphocytes was observed in both sexes. The tissues were near normal in surviving rats at 10 days PD. Necrosis of gastrointestinal epithelial cells and/or blunting of the mucosal tissue were found in several rats that died within PD-5. Necrosis of seminiferous tubular epithelium occurred in a few male rats.

The combination of COL (30 mg/kg of BW) and LPS (83 µg/kg of BW) was lethal to most rats. Moderate to severe necrosis of bone marrow cells, hepatocytes and lymphocytes were observed in both sexes. The lesions were minimal and tissues near normal in the few surviving animals at PD-10.

Conclusion: Rats of both sexes that died within 5 days of a single oral dose of 30 mg/kg of BW COL had necrosis of bone marrow cells, lymphocytes and hepatocytes. Necrosis of gastrointestinal and seminiferous tubular epithelial cells also occurred in a few rats. Most of the lesions were similar but more severe when COL and LPS were co-administered. Minimal abnormalities were observed in surviving animals at PD-10.  In order to further evaluate COL and LPS gender related differences in lethality, future work may include examination of tissues saved from mid and low dose COL treated rats.