Effects of Diet and Overfeeding On Body Weight and Survival in the Rodent Bioassay: the Impact On Pharmaceutical Safety Assessment

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Abstract
Uncontrolled body weight due to ad libitum (AL) overfeeding is the most significant variable affecting the rodent bioassay. The correlation between AL food consumption, the resultant excessive adult body weight, and the low 2-yr survival in Sprague-Dawley (SD) rats was highly significant. However, initial body weight does not correlate with adult body weight or survival. AL feeding of diets that varied in protein, fiber, and energy content did not improve low 2-yr survival. Only moderate dietary restriction (DR) of all diets tested significantly improved survival and delayed the onset or severity of spontaneous degenerative diseases and tumors. Moderate DR-fed rats had a similar incidence of tumors as AL-fed rats by 2 yr; however, the tumors were more likely to be incidental and not fatal. There was a decreased age-adjusted incidence of pituitary and mammary-gland tumors, but tumor volume and growth time were similar between AL and moderate DR groups. These data indicate a similar tumor progression, but only a delay in tumor onset. Moderate DR did not significantly alter drug-metabolizing enzyme activities nor the toxicologic response to five pharmaceuticals tested at maximum tolerated doses (MTDs). However, moderate DR did require higher doses of compounds to be given before classical MTDs were produced with four drug candidates. Toxicokinetic studies of two of these compounds demonstrated steady-state systemic exposures that were equal or higher in moderate DR-fed rats. Biochemical markers of oxidative stress (lipid peroxidation, protein oxidation) were decreased and cytoprotective markers were increased by moderate DR. These and other data indicate that moderate DR is the most appropriate method of body weight control when used to assess pharmaceuticals for human safety.