EFFECT OF DIETARY OPTIMIZATION ON GROWTH, SURVIVAL, TUMOR INCIDENCES AND CLINICAL PATHOLOGY PARAMETERS IN CD SPRAGUE-DAWLEY AND FISCHER-344RATS - A 104-WEEK STUDY

Citation
Ms. Christian et al., EFFECT OF DIETARY OPTIMIZATION ON GROWTH, SURVIVAL, TUMOR INCIDENCES AND CLINICAL PATHOLOGY PARAMETERS IN CD SPRAGUE-DAWLEY AND FISCHER-344RATS - A 104-WEEK STUDY, Drug and chemical toxicology, 21(1), 1998, pp. 97-117
Citations number
30
Categorie Soggetti
Toxicology,"Pharmacology & Pharmacy
ISSN journal
01480545
Volume
21
Issue
1
Year of publication
1998
Pages
97 - 117
Database
ISI
SICI code
0148-0545(1998)21:1<97:EODOOG>2.0.ZU;2-9
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 uncontro lled 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 optimiz es the health and well-being of rodents nor provides the best model fo r use in evaluation of pharmacological and toxicological profiles. Use of an optimized diet, restricted in terms of caloric intakes, has bee n proposed for chronic toxicity and carcinogenicity studies in rodents . It is suggested that limiting caloric intakes to 50-80% of ad libitu m consumption would result in lower body weights, decreased tumor inci dences and prolonged survival in the controls. To evaluate the influen ce of diet on chronic toxicity and carcinogenicity studies in rats, tw o 104-week studies were conducted. These studies consisted of 280 CD S prague-Dawley and 280 Fischer-344 rats fed ad libitum, and 140 CD Spra gue-Dawley and 140 Fischer-344 rats fed a diet that was optimized by l imiting caloric intakes by 15-35%. Both diets consisted of certified c ommercial diet in meal form. The optimized diet reduced weight gain ap proximately 50% after 100 weeks. Clinical chemistry and hematology par ameters showed negligible effects of reduced diet, with the exception that serum triglycerides were lower in males and females in both strai ns at weeks 52 and 104. The ad libitum-fed animals had a higher incide nce of pseudopregnancy, aggressiveness, foot sores and abscesses than the animals fed an optimized diet. These effects were more pronounced in the CD Sprague-Dawley vats than in the Fischer-344 rats. At the com pletion of the 104-week study, survival in the ad libitum fed CD Sprag ue-Dawley rats was approximately one-half that of the animals fed an o ptimized diet (39% versus 76%). The difference in survival between Fis cher-344 rats fed ad libitum and those fed an optimized diet was less pronounced (78% versus 89%). A reduced incidence of palpable tissue ma sses in the ad libitum-fed CD Sprague-Dawley rats versus the animals f ed 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 mass es, After 52 weeks 40 animals from each strain and feeding regimen wer e killed and subjected to complete necropsy and histopathological exam ination; the remainder of the survivors was examined at the completion of the study (104 weeks). Use of an optimized diet substantially redu ced the incidences of endocrine-mediated tumors in both rat strains an d delayed the onset of leukemia in Fischer-344 rats, These results ind icate the need to further investigate the relationship of increased ca loric intakes and endocrine-mediated or strain specific tumors and sup port FDA's and others' positions that use of diet optimization in chro nic toxicity and carcinogenicity rodent bioassays has the potential to remarkably improve the scientific quality and relevance of these stud ies. It also identified that the small increases in cost associated wi th diet optimization are far exceeded by the advantages of increased s urvival of animals, reduced intercurrent disease and rumor burdens, an d increased ease of histopathological processing and evaluation.