1) A major problem with using Sprague-Dawley rats in risk assessment
assays is that they are an outbred stock. They are genetically
heterogeneous so that selection for "healthy", i.e. larger, animals
as breeding stock may account for the great increase in body weight
observed over the years. Inadvertent inbreeding in each breeder's
colony would differentiate that colony genetically from those of
other breeders. Therefore, the responses to xenobiotics could be
expected to differ in assays using SD rats from different colonies.
In my opinion, this is a serious consideration, more so than the body
weight increase, with regard to the use of genetically heterogeneous
rodents such as SD rats for risk assessment assays.
2) Most men and women are not likely to reduce their caloric intake
voluntarily by 25-40% over a lifetime. Therefore, the use of
calorically-restricted rodents for determining the carcinogenic
potential of suspect substances is not necessarily more valid than
the use of ad lib fed animals. Use of calorically-restricted
animals may underestimate the risk to humans, while ad lib fed
rodents may provide a more appropriate estimate of this risk because
of the prevalence of obesity in many human populations.
3) For carcinogenicity/toxicity risk assessment assays I have long
proposed using inbred or F1 hybrid genomes in which different
levels of susceptibility to neoplasia are provided by differential
expression of a single gene. The background strain genome can be
chosen for desired tissue-specific sensitivities, while the gene
enhances that sensitivity to different degrees in genetically
identical obese and lean phenotypes. The gene is dominant and has
a coat color marker so that it can be easily maintained by forced
heterozygosis in combination with a recessive allele. The latter has
no effect on the animal's responsiveness to carcinogens. Thus, a
genetically homogeneous assay system can include three easily
distinguishable phenotypes, each with a different degree of
response to the test agent, e.g. maximum, some, none. If anyone
is interested in further details. I would be pleased to provide such
as well as bibliographic references.
George L. Wolff
Tel: (501) 543-7522
FAX: (501) 543-7635/7662
NCTR HFT-140
3900 NCTR Road
Jefferson, AR 72079-9502
