Evaluation of carcinogenic responses in the Eker rat following short-term exposure to selected nephrotoxins and carcinogens.

This study examined the response of the Eker rat to nephrotoxic compounds and to genotoxic nonrenal carcinogens. Groups of male Eker rats received either no treatment; a vehicle treatment; treatment with a noncarcinogenic nephrotoxin (aluminum nitrilotriacetate, 2 mg/kg/day of aluminum, intraperitoneally, 3 days per week or cyclosporine A, 30 mg/kg/day, orally by gavage, 7 days/week); or treatment with a genotoxic nonrenal carcinogen (furan, 8 mg/kg/day, orally by gavage, 5 days/week or 2,4-diaminotoluene, 6.5 mg/kg/day, orally by gavage, 7 days/week or 2-nitropropane, 89 mg/kg/day, orally by gavage, 3 days/week). Duration of treatment was 4 and/or 6 months. Tissues from the Eker rats were evaluated microscopically and numbers of proliferative renal lesions were counted. Administration of nephrotoxic compounds (Al-NTA and cyclosporine) significantly increased the number of preneoplastic and neoplastic renal lesions in the Eker rat compared to concurrent vehicle controls. The genotoxic nonrenal carcinogens had no consistent effect on numbers of preneoplastic or neoplastic renal lesions and did not produce neoplasms in the expected target organ (liver).

A 90-day oral gavage toxicity study of D-methylphenidate and D,L-methylphenidate in Sprague-Dawley rats.

D-methylphenidate is an enantiomer of D,L-methylphenidate and was developed as an improved treatment for attention deficit hyperactivity disorder in children. The current study was performed to determine and compare the toxicity of 2-50 mg/kg per day D-MPH and 100 mg/kg per day D,L-MPH for 90 days in rats with the top D-MPH dose being equimolar to 100 mg/kg D,L-MPH. The top D-MPH and D,L-MPH doses were at least 67 times that of the human dose and produced systemic exposures that were over 10 times higher than those typically achieved in children. During the course of the study, one male each from the 50 mg/kg per day and D,L-MPH groups and one female from the 50 mg/kg group died. Incidences of material around nose/eyes, scabbing, foot swelling, alopecia and abrasions were evident at 50 mg/kg per day D-MPH and 100 mg/kg per day D,L-MPH doses. Body weight and its changes decreased in a dose-dependent manner for D-MPH males. There were significant changes in some clinical chemistry measurements at the terminal bleed in the high dose groups of both sexes although most of these changes were resolved by the recovery bleed. Differences in absolute and relative body and certain organ weights for high dose D-MPH and D,L-MPH groups were seen at terminal necropsy with the differences no longer present after the recovery period. No abnormal or gross histopathological changes were associated with any of these organ weight changes reported for the terminal and recovery periods. Based on body weight changes, the no observed adverse effect level for D-MPH in rats was 20 mg/kg. Overall, the toxicity profile observed in rats with 50 mg/kg per day D-MPH was comparable to that of an equimolar dose of D,L-MPH (100 mg/kg per day) when given repeatedly for 90 days using a twice a day dosing regimen.