THE EFFECTS OF DIET, AD-LIBITUM OVERFEEDING, AND MODERATE DIETARY RESTRICTION ON THE RODENT BIOASSAY - THE UNCONTROLLED VARIABLE IN SAFETY ASSESSMENT

Ad libitum (AL) overfeeding is the most significant, uncontrolled vari able affecting the outcome of the current rodent bioassay. There is a highly significant correlation between AL food consumption, the result ant obesity and body weight, and low 2-yr survival in rodents. AL feed ing of diets with lowered protein, metabolizable energy (ME), and incr eased fiber does nor improve survival. Only dietary restriction (DR) o f all diets tested significantly improves survival and delays the onse t of spontaneous degenerative disease (i.e., nephropathy and cardiomyo pathy) and diet-related tumors. Moderate DR results in an incidence of spontaneous tumors similar to AL-fed rats, but the tumors are found i ncidentally and do not cause early mortality. There is a decreased age -adjusted incidence of pituitary and mammary gland tumors in moderate DR-fed rats, but tumor growth time is similar between AL and DR rats w ith only a delay in tumor onset time seen in DR-fed groups. Moderate D R does not significantly alter drug-metabolizing enzyme activities nor the toxicologic response to 5 pharmaceuticals tested at maximum toler ated doses (MTDs). However, moderate DR-fed rats did require much high er doses of 4 additional pharmaceutical compounds before classical MTD s were produced. Toxicokinetic studies of 2 of these compounds demonst rated equal or higher steady-stare systemic exposures to parent drug a nd metabolites in moderate DR-fed rats. Markers of oxidative stress (l ipid peroxidation, protein oxidation) are decreased and cytoprotective anti-oxidant markers are preserved in moderate DR-fed rats. But moder ate DR does not delay reproductive senescence in female rats. Only mar ked DR delays reproductive senescence compared to AL and moderate DR-f ed female rats. These and other data indicate that moderate DR is the most appropriate method of dietary control for the rodent bioassay whe n used to assess pharmaceuticals for human safety and compounds for ri sk assessment.