Animal Models in Toxicology

Paul Whitehead p.whitehead at dial.pipex.com
Tue Feb 13 12:13:54 EST 1996

drjackbud at aol.com (DrJackBud) wrote:

>One does toxicity studies, albeit preliminary i.e., non-mechanistic
>studies in animals in order to do controlled pharmacology and toxicology
>studies in humans.  (While this may be true for therapeutic agents, its
>not necessarily the case with other chemicals.).  But how does one know if
>the animals in which the preliminary toxicity studies are conducted in
>anyway represents a model for humans?  (Sounds as if we may have a
>chicken-egg problem).

Well, really you don't.  We are generally limited to rats and
dogs/primates.  Pharmacology studies will give some indication of a
likely therapeutic dose, and provided a NOAEL in the subacute toxicity
studies is a reasonable margin above this, then an ascending dose
human study is legitimate.  The animal target organ(s) at the higher
doses provide guidance on the human monitoring.  However, within the
limited choice of species, one can use judgement, eg a primate would
be preferable to a dog for non steroidal anti-inflammatories, not
because the dog is not a representative model, but because of its
undue sensitivity to ulcerogenesis.

>But what about the rejection of a material for the Phase 1 studies in
>humans because of adverse preliminary responses in the initial animal
>toxicity studies ( those studies conducted to give some assurances that
>the Phase 1 studies in humans are reasonable)?  It is difficult to find
>examples of materials that, in spite of adverse preliminary or initial
>toxicity studies, were used in Phase 1 studies.  (Perhaps the examples lie
>in chemotherapeutic agents for the treatment of cancer.)

I think the answer above covers this also.  On the other hand, even if
there was a reasonable therapeutic margin, would you give a novel NSAI
to humans if you found testicular pathology, toxicity as far as I am
aware not normally found with this class?  I would believe that the
mechanisms would need to be identified first to see if they are
relevant to man.

>While Whitehead and I await for specific examples for cybertoxland, allow
>me to suggest dioxin as a modified hypothetical example.  IF dioxin had
>some therapeutic value, it would not have been developed based on
>preliminary toxicity studies, principally the LD50's in animals.  Yet, the
>acute toxicities, and some would argue the animal toxicity in general for
>dioxin, is not seen in humans.  Conversely, I'm not aware of anyone's
>ability to produce chloracne in animals.  Whitehead says:

I believe chloracne (ie acne from chlrinated organics) can be
demonstrated in primates, and the rabbit ear ;-)


Paul Whitehead BSc CBiol MIBiol DABT
United Kingdom
e-mail p.whitehead at dial.pipex.com

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