Animal Models in Toxicology

Paul Whitehead p.whitehead at dial.pipex.com
Wed Feb 7 12:24:15 EST 1996


drjackbud at aol.com (DrJackBud) wrote:

>In article <4f5ci8$7eb at soap.news.pipex.net>, p.whitehead at dial.pipex.com
>(Paul Whitehead) writes:

>>Therefore, an animal model as used in toxicology research is not
>>necessarily a good alternative to a human model. 

>I presume when you say "human model" you mean HUMANS. 

Well, yes and no.   In a sense we assess toxicity in small groups of
humans and extrapolate to populations.  In this sense a human can be
regarded as a model for the whole population.  Alternatively, the
animal is the model for humans.

>outside of epimediology, I can't think of any prospective way we can test
>toxicity in humans.  Any ideas or can you shed any light of how we might 
>do this?

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.

Chemicals can be tested in humans for skin irritation and
sensitisation for example, but again animal studies in relevant models
are required first for ethical reasons.

I agree with you that I cannot see stand-alone human toxicity studies
conducted under ethical conditions replacing animal studies.

As yet, we have not considered in vitro studies using human tissue.
These can provide  useful models for clarification or delineation of
toxicity/pharmacology.

>>The philosophy now is to demonstrate toxicity in the
>>requisite number of species, then prove it can't happen in man :-)

>What if humans are the only outlier and all of the animal species behave
>one way and humans behave differently?

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.

My original comment was a little 'tongue in cheek', but the whole
purpose of animal toxicity studies is to determine target organ
toxicity and the threshold (or NOEL).  There is little guarantee that
the animal target organ is necessarily the target in man, and each
time the relevance is dismissed, another nail is put in the coffin of
the animal model.

>It has been my sad experience that when I set out to "prove" something by
>emperical investigations, I end up, at best, building a circumstantial
>case.  Furthermore, testing in a number of species, then testing in man is
>a "responsible", "ethical"  or "competent" thing to do; BUT are the
>animals "models" or are they merely security checks or tests????  Have the
>animals told you anything about humans?  If not, then the only reason to
>do anything in animals is for the above stated reasons.  However, if the
>animals told you anything about humans, I'm at a loss to identify exactly
>what the work in animals told.

I think you've neatly summed up the paradox.  Cynically, most
toxicology studies are conducted because the regulatory authority
demands them, not because they are necessarily relevant.

>>Another well known species specific example is  alpha 2 mu globulin
>>nephrocarcinogenicity in male rats. 

>This good example you cite, related to gasoline renal carcinogenicity is
>getting close to the issues at hand about animal models.  You would likely
>say that the rat would not be a good animal model for gasolone
>carcinogenicity in humans.  Why???  Well, you'd probably say because the
>observation in rats is not seen in humans.  Therin lies the question of a
>generic nature "Why?"

Trimethyl pentane is not my concern re gasoline.  I'm more worried
about the benzene content!  I don't think that this particular
carcinogenic response says the rat is not an acceptable model in the
*first instance* for the prediction of gasoline tumorigenicity.  With
most chemicals we will never know whether tumours in animals have
their counterpart in man (cf IARC classifications re possible,
probable, inadequate evidence, etc., which to a certain extent fudge
the issue), unless they are clearly of species-specific non-genotoxic
origin.

>>structural or metabolic differences exist between animal models and man. 

>What other differences do you feel are important?
> e.g., one sees the sam endpoint in animals
>and man?  When should the line be drawn in "differences"??????

This would not be predictive toxicology, but retrospective
confirmation of human observations.  The serious problem comes in
predicting whether the same target organ(s) will be affected in both
species. 

However, the same endpoint toxicity by different routes would  be
equally as important to define mechanistically since risk management
(by treatment dose, monitoring, etc.) is likely to  be completely
different.

I think at this stage we should agree a definition of the word
'model'.  The Oxford Concise does not appear to have one relevant to
this thread.







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




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