The effects of overfeeding and moderate dietary restriction on Sprague-Dawley rat survival, pathology, carcinogenicity, and the toxicity of pharmaceutical agents

Abstract

Ad libitum (AL) overfeeding is the most significant uncontrolled variable effecting the rodent bioassay. There is a highly significant correlation between food consumption, the resultant body weight, and two-year survival in laboratory rats. We have studied the effects of AL overfeeding, moderate dietary restriction (DR) and several modified diets on Sprague-Dawley (SD) rat longevity, spontaneous disease, carcinogenesis and the toxicity of pharmaceuticals. AL feeding of diets varying in protein, fiber and metabolizable energy content did not significantly alter two-year rat survival. Moderate DR (within the range of reported AL food intake) of all diets tested significantly improved survival and delayed the onset of spontaneous degenerative disease and diet-related tumors compared to AL-fed rats. Moderate DR resulted in a similar incidence of spontaneous tumors by 2 years, however, the tumors were more likely to be incidental and not result in early mortality. There was a decreased, age-adjusted incidence of pituitary and mammary gland tumors, but tumor volume and growth time was similar between AL and DR groups indicating similar tumor progression with a delay in tumor onset. Moderate DR did not change Phase I and Phase II drug metabolizing enzyme levels and did not significantly alter the toxicological response to 5 pharmaceuticals tested at maximum tolerated doses (MTDs). Additional studies with 4 pharmaceutical candidates did demonstrate that moderate DR allowed higher doses of compounds to be given before classical MTDs were observed. However, toxicokinetic studies of two of these compounds demonstrated steady state systemic exposures that were either equal of higher in the moderate DR fed rats. These and other data indicate that the moderate DR fed SD rat is a more appropriately controlled rodent model for toxicity and carcinogenicity studies to assess human safety of candidate pharmaceuticals.