Animal Models in Toxicology

George L. Wolff GWOLFF at NCTR.FDA.GOV
Thu Feb 22 14:36:13 EST 1996


    Instead of determining toxicity of xenobiotics in test animals 
by using the "dose response" approach, I would like to bring up the 
concept of "response to dose" for discussion. This concept proposes 
that an array of genotypes, conferring different degrees of 
susceptibility of the animals to the toxic endpoint of interest, be 
exposed to the same dose level of the test agent. This dose level (or 
levels) might be calculated to be equivalent to the maximum dose to 
which any human population might be exposed multiplied by a safety 
factor. This would be an improvement over the MTD which, in many if 
not most cases, overwhelms the normal defensive processing mechanisms 
in both humans and test animals - and would make extrapolation to 
human populations exposed to far lower dose levels more meaningful.
    To implement this approach Michael Festing has repeatedly proposed 
the use of multiple inbred strains - without increasing the total 
number of animals in the bioassay - to mimic some of the diversity 
of genotypes and sensitivities to induction of toxic endpoints within 
human populations.
    In a slightly different mode I have used carefully chosen F1 
hybrids in which a dominant gene mutation with a distinguishing coat 
color segregates. This mutation enhances response to carcinogens 
as well as the rate of tumor growth. One parent strain is chosen for 
its high tissue-specific susceptibility to neoplasia. The other 
parent strain provides the dominant mutation. Thus, two different 
genotypes/phenotypes with identical background genomes are produced -
differing by only a single allele - with very different 
susceptibilities to induction of specific tumor endpoints. In this 
particular system there is a third phenotype with tumor 
susceptibility intermediate between the two genotypes. This third 
phenotype is the result of DNA methylation of the promoter of an 
intracisternal A particle (IAP) which induced the mutation by 
insertion into the mouse gene. The different degrees of tumor 
susceptibility are correlated with different concentrations of agouti 
protein.









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