Effect of Dietary Optimization on Growth, Survival, Tumor Incidences and Clinical Pathology Parameters in CD Sprague-Dawley and Fischer-344 Rats: A 104-Week Study

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Abstract
Controversy regarding the use of ad libitum feeding in chronic rodent toxicity studies will soon result in issue of a FDA Points to Consider document. Caloric intakes are now recognized to be important uncontrolled variables in bioassays because rodents chronically fed ad libitum become obese, reproductively senile and have increased incidences of age-related diseases, higher tumor burdens and decreased survival. The available literature suggests that ad libitum feeding neither optimizes the health and well-being of rodents nor provides the best model for use in evaluation of pharmacological and toxicological profiles. Use of an optimized diet, restricted in terms of caloric intakes, has been proposed for chronic toxicity and carcinogenicity studies in rodents. It is suggested that limiting caloric intakes to 50-80% of ad libitum consumption would result in lower body weights, decreased tumor incidences and prolonged survival in the controls. To evaluate the influence of diet on chronic toxicity and carcinogenicity studies in rats, two 104-week studies were conducted. These studies consisted of 280 CD Sprague-Dawley and 280 Fischer-344 rats fed ad libitum, and 140 CD Sprague-Dawley and 140 Fischer-344 rats fed a diet that was optimized by limiting caloric intakes by 15-35%. Both diets consisted of certified commercial diet in meal form. The optimized diet reduced weight gain approximately 50% after 100 weeks. Clinical chemistry and hematology parameters showed negligible effects of reduced diet, with the exception that serum triglycerides were lower in males and females in both strains at weeks 52 and 104. The ad libitum-fed animals had a higher incidence of pseudopregnancy, aggressiveness, foot sores and abscesses than the animals fed an optimized diet. These effects were more pronounced in the CD Sprague-Dawley rats than in the Fischer-344 rats. At the completion of the 104-week study, survival in the ad libitum fed CD Sprague-Dawley rats was approximately one-half that of the animals fed an optimized diet (39% versus 76%). The difference in survival between Fischer-344 rats fed ad libitum and those fed an optimized diet was less pronounced (78% versus 89%). A reduced incidence of palpable tissue masses in the ad libitum-fed CD Sprague-Dawley rats versus the animals fed an optimized diet reflected inability to detect small masses in the obese ad libitum-fed animals. In contrast, the leaner Fischer-344 ad libitum-fed animals had an increased incidence of palpable tissue masses. After 52 weeks, 40 animals from each strain and feeding regimen were killed and subjected to complete necropsy and histopathological examination; the remainder of the survivors was examined at the completion of the study (104 weeks). Use of an optimized diet substantially reduced the incidences of endocrine-mediated tumors in both rat strains and delayed the onset of leukemia in Fischer-344 rats. These results indicate the need to further investigate the relationship of increased caloric intakes and endocrine-mediated or strain specific tumors and support FDA's and others' positions that use of diet optimization in chronic toxicity and carcinogenicity rodent bioassays has the potential to remarkably improve the scientific quality and relevance of these studies. It also identified that the small increases in cost associated with diet optimization are far exceeded by the advantages of increased survival of animals, reduced intercurrent disease and rumor burdens, and increased ease of histopathological processing and evaluation.