Animal Models in Toxicology

DrJackBud drjackbud at aol.com
Mon Feb 12 01:06:10 EST 1996


This is the second post of mine addressing some of the thoughtful issues
raised in the 
Whitehead post dated 07Feb96.  In my first response I proposed that we
limit our use of the term "model" to trans-species comparisons.  When
using a limited number of the same species to draw conclusions about the
entire species, I suggested the use of the term "segment"  The
former("model") deals with inter-species comparisons, while the latter
("segment") deals with intra-species comparisons.

In this second post of mine, I would like to address the dilemma raised by
Whitehead in:

>If we consider pharmaceutical development, then phase 1 clinical
>trials are concerned with evaluation of pharmacological and
>toxicological responses in human volunteers.  Clearly these are
>preceded by animal studies, but at this stage there is unlikely to be
>great emphasis on mechanistic studies to clarify toxic responses in
>animals.  Therefore, humans will be exposed to carefully chosen dose
>levels, below the animal NOAEL.  Subsequent drug development continues
>to monitor toxicity in humans as well as clinical efficacy, subsequent
>to the relevant animal studies, in  a step-wise fashion.

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).

Whitehead would likely respond:

"Off the top of my head I cannot recall an example of a unique human
toxicant that cannot in some way be shown to be toxic under some
conditions in animals.  The most likely  scenario is that the toxicity
is missed at the first pass due either to the inadequacy of the animal
model or the narrow requirements of regulatory authorities, eg
thalidomide teratology in rabbits, benoxyprofen toxicity in geriatrics
due to pharmacokinetic differences, etc."

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.)

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:

"Off the top of my head I cannot recall an example of a unique human
toxicant that cannot in some way be shown to be toxic under some
conditions in animals."

I think the criteria for an animal "model" has to be more specific than
the nebulous "...in some way..." because all toxicities are not created
equal.  But as I challenge Whitehead, I also sympathesize with him (and
myself as well) because of the chicken-egg problem:  Test in animals,
uncertain of their ability to serve as models, so we will be able to
administer the material to humans so that we can begin to establish an
animal model.  In addition to being circular, it seems a little like
uncoupled oxidative phosphorlation: there is activity (electron flow) but
questionable results (no ATP generated).

Whitehead appears to throw up his hands in despair:

"Cynically, most toxicology studies are conducted 



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