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