The Effects of Diet, ad Libitum Feeding, and Moderate and Severe Dietary Restriction on Body Weight, Survival, Clinical Pathology Parameters, and Cause of Death in Control Sprague-Dawley Rats
TOXICOLOGICAL SCIENCES
The Effects of Diet, ad Libitum Feeding, and Moderate and Severe Dietary Restriction on Body Weight, Survival, Clinical Pathology Parameters, and Cause of Death in Control Sprague-Dawley Rats
Marie-Francoise Hubert 1 2
Philippe Laroque 1 2
Jean-Pierre Gillet 1 2
Kevin P. Keenan 0 1
0 West Point , Pennsylvania 19486
1 Department of Safety Assessment , Merck Research Laboratories
2 63963 Clermont-Ferrand Cedex 9 , France
A 2-year study was conducted in Sprague-Dawley rats to compare the effects of ad libitum (AL) feeding and dietary restriction (DR) on body weight, survival, cause of death, and clinical pathology parameters. Three groups of 120 rats/sex each received the following daily rations of a maintenance rodent diet: ad libitum (AL group); 75% of adult AL food consumption (25% DR group); and 45% of adult AL food consumption (55% DR group). Among the 3 groups, there were generally no differences in relative (food intake per gram of body weight) food consumption. Compared to the AL group, decreased body weight gain occurred in DR groups and was associated with an increase in survival proportional to the DR rate. The main cause of death was pituitary adenomas in all groups. Decreases in total leukocyte, segmented neutrophil, lymphocyte, and platelet counts occurred in the 55% DR group. In serum biochemistry, there were decreases in total protein, albumin, total and HDL cholesterol, and total calcium, and increases in alkaline phosphatase activities and chloride in 55% DR females, as well as decreases in triglycerides in the 55% DR group and in 25% DR females. Results of urinalyses showed decreases in urine volume and protein, and increases in urinary pH in both DR groups. In conclusion, a DR rate of approximately 25% appears to be appropriate for Sprague-Dawley rats in toxicity and carcinogenicity assays to improve survival without impairing growth and routine clinical pathology parameters.
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In rat carcinogenicity studies, regulatory agencies generally
expect an overall, minimal survival of 50%, or 25 animals/sex/
group at the end of the 2-year study period. However, over the
past 3 decades, a decline in laboratory rat survival has been
seen in most rat strains, including Sprague-Dawley (SD),
Fischer 344, Wistar, and Long-Evans rats (for reviews see
Keenan et al., 1995a,b; Nohynek et al., 1993), very commonly
used strains in toxicity and carcinogenicity studies.
While both genetic and environmental factors are involved,
1 To whom correspondence should be addressed at Laboratoires Merck Sharp &
Dohme-Chibret, Route de Marsat-Riom, 63963 Clermont-Ferrand Cedex 9,
France. Fax: (33) 473 38 56 91. E-mail: .
rat survival can be improved by simple dietary restriction (DR)
(for reviews see Weindruch, 1996). Indeed, DR is the most
efficient and convenient means to intervene in aging and
disease outcomes (for reviews see Holehan and Merry, 1986;
Masoro et al., 1991a,b). In addition, DR appears to be one
logical solution, since the decrease in life span of laboratory
rats has coincided with a trend to obesity of the affected strains
(for reviews see Rao et al., 1990). However, moderate DR is
known to prevent or delay both spontaneous and
carcinogeninduced tumors (for review see Keenan et al., 1996).
Therefore, it seems necessary for each strain and stock of rats to
determine an appropriate rate of DR that will increase survival
and will not substantially modify other biological parameters.
With this objective in mind, a 2-year study was conducted in
SD rats from Charles River France, given either ad libitum
(AL) feeding or 2 different dietary-restricted regimens,
approximately 75% (25% DR) and 45% (55% DR) of adult AL food
consumption. This paper presents data showing the relation
between the rate of food intake and the increased survival rate
and decreased incidence of causes of death, as well as the
effects of food regimens on routine clinical pathology
parameters in this stock of SD rats.
MATERIALS AND METHODS
Three-hundred and sixty male and 360 female SD, Crl:CDt(SD)BR
(International Standard) rats were obtained from Charles River France
(Saint-Aubinle`s-Elbeuf, France). They were received and maintained throughout the study
under VAF (virus antibody free) pathogen status. The animals were 35 days
old at study initiation, with males weighing 104 195 grams and females
104 180 grams. The rats were housed based on a random allocation scheme,
in individual suspended stainless steel wire cages, in air conditioned rooms
with a temperature of approximately 22C, humidity between 30 and 70%, and
a 12-h light cycle; they had free access to tap water. The animals were
identified by tail tattoos and assigned to the 3 different regimen groups
described below in order to get similar initial mean body weights (BW) across
study groups.
Diet and Dietary Regimens
The experimental groups contained 120 rats/sex/group. All rats were given
certified UAR AO4C rodent diet from UAR (Villemoisson sur (...truncated)