animal models for toxicology

Charles A. Montgomery cmontgom at ix.netcom.com
Thu Feb 8 19:36:08 EST 1996

I think John has a great idea for  a discussion group.  I have spent
28 years in Comparative Pathology and Comparative Medicine and have
seen the definitions change many times woth advances in scientific
research.  In the early years there were great workshops seminars,
etc. sponsored by ILAR,NIH, and the  Registry of Comparative Pathology
at AFIP, on this subject.  Whole books have been written on animal
models for cardiovascular disease, genetic disease, cancer, and the
list goes on.  Today with the massive explosion in molecular biology,
and the development of  transgenic animals, the whole definition of
animal  models changes each day, as we discover new methods, and
applications. When one defines animal model it really does't  make any
difference whether it is a mammal or invertebrate.  The key thing is 
reproducibility.  A case report of a genetic defect or type of cancer
in a cat is not an animal model unless you can reproduce the disease
and fullfill Koch's Postulates.  The same thing holds true in
toxicology.  Spontaneous and induced diseases in rodents vary alot
between species and strains of rodents.  There is even genetic drift
in the same strain over time.  The basic definition of "Animal Model"
is a disease or syndrome in animals that is similar to a human disease
therefore has merit in  investigating the pathogenesis of that disease
in humans using animals.  In the early years of Comparative Medicine,
it was simple.  We studied diabetes mellitus in animals  that a high
incidence of the disease.  Then we learned more about mouse genetics,
and developed inbred strains that got the disease faster and mimicked
the human disease more.  This allowed specialists to focus on diabetic
lesions in the kidney, vasculature etc.  Later came the rat models
that you could induce diabetes by chemically destroying the Beta cells
in the Islets of the pancreas,  then came transgenic animal models..
Why do we use animal models in toxicology?  This has been argued ad
nauseam.  There have been many attempts to replace animals in
toxicology testing over the years, but we still use these animals to
define the chemicals we fear.  Why is that?  The Ames Test answers
some of the mutagenicity  questions we have about specific chemicals
of concern, but it is not a panacea.  Ray Tennents work at the
National Toxicology program has shown  that for years.  The bottom
line is there is no way to replace an animal if you are trying to
assess systemic effects of xenobiotic insult. Until we can study
renal, hepatic, or cardiovascular function in Salmonella sp.  we are
stuck with animal models higher up the phylogenetic scale.  I have
seen some excellent computer models that can screen chemical classes
and predict with accuracy the chances of compound X   being a
carcinogen, however computers can't metabolize that compound, and do
not appreciate dose related injury, or accumalative effect over time.
Animals do.  If you want to get into an interesting discussion, ask
the powers to be, why they are using the strain of animal they are
using in industry vs. government      Chuck Montgomery.  

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