Animal Models in Toxicology/JBudny post 17Feb96
George L. Wolff
GWOLFF at NCTR.FDA.GOV
Wed Feb 21 10:56:01 EST 1996
The point I tried to make in my previous post, obviously
unsuccessfully, was that specific animal models are valid as human
substitutes ONLY if the biochemical/physiological patterns which give
rise to/result in the phenotypic endpoint of interest are either
identical (most unlikely) or closely similar in both species.
Inborn errors due to similar single gene mutations in humans and
animals would appear to be straightforward candidates for
investigation in animal models; however, since the background strain
genomes are different, the phenotypic expression of the inborn error
may differ at the organismic level in the two species. Thus, even
here, caution is necessary in extrapolating from animal model to Homo
Dose response types of toxic responses in animal models are,
similarly, subject to the expression of gene patterns in the
background strain genome which may differ between the animal model
and humans. In fact, even within genetically homogeneous animal
populations, there is demonstrable phenotypic variation with respect
to tumor formation in response to the same dose level of test agent.
I discuss this in extenso in the February issue of Fundamental &
Applied Toxicology 29:176, 1996 under "Variability in gene
expression and tumor formation within genetically homogeneous animal
populations in bioassays."
Homo sapiens is genetically relatively heterogeneous in
comparison with the genetically homogeneous F1 hybrid and inbred
animal populations used in toxicological bioassays. Therefore, the
obvious question is always to WHICH subgroup of men/women can the
animal test data be extrapolated with any sort of validity?
Since toxic agents cannot, ethically, be tested in a variety of
human populations, what is the alternative to the use of test animals?
In vitro tests cannot provide information on the toxic response of
the intact organism although the toxic response of particular cell
types can be elucidated in such systems. However, the organismic
extracellular microenvironment - which plays a major role in the
toxic response of cells - is absent and thus extrapolation to the
whole organism is still fraught with doubt.
The validity of using animal models and which are the "best"
models to use for particular investigations has been discussed for
decades without satisfactory resolution. Hopefully, by continuing
this discussion over a prolonged period of time with input from
toxicologists and others with diverse viewpoints, it should be
possible, eventually, to arrive at a rational solution to this
serious dilemma. At least, it should be fun trying!
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