THE EFFECTS OF DIET, OVERFEEDING AND MODERATE DIETARY RESTRICTION ON SPRAGUE-DAWLEY RAT SURVIVAL, DISEASE AND TOXICOLOGY

Overfeeding by ad libitum (AL) food consumption is the most significan t, uncontrolled variable affecting the outcome of the current rodent b ioassay. The correlation of food consumption, the resultant adult body weight and the 2-y survival in Sprague-Dawley rats is highly signific ant. Feeding natural ingredient diets that varied in protein, fiber an d metabolizable energy content did not improve low 2-y survival if Spr ague-Dawley rats were allowed AL food consumption. Moderate dietary re striction (DR) of all diets tested significantly improved survival and delayed the onset of spontaneous degenerative disease (i.e., nephropa thy and cardiomyopathy) and diet-related tumors. By 2 y, moderate DR r esulted in an incidence of spontaneous tumors similar to that seen wit h AL consumption; however, the tumors were more likely to be incidenta l and did not result in early mortality. There was a decreased age-adj usted incidence in pituitary and mammary gland tumors, but tumor volum e and growth time were similar in the AL and DR groups, indicating a s imilar tumor progression with a delay in tumor onset. Moderate DR did not significantly alter drug-metabolizing enzyme activities or the tox icologic response to five pharmaceuticals tested at maximum tolerated doses (MTD). However, moderate DR did require higher doses of compound s to be given before classical MTD were produced with four pharmaceuti cal drug candidates. Toxicokinetic studies of two of these compounds d emonstrated steady-state systemic exposures that were equal or higher in moderate DR-fed rats. These and other data indicate that moderate D R is the most appropriate method of dietary control for rodent bioassa ys used to assess human safety of candidate pharmaceuticals.