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.
Tel: (501) 543-7522
FAX: (501) 543-7635/7662
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3900 NCTR Road
Jefferson, AR 72079-9502
