Subject: Summary:QSAR and Gov. approval

From: Beverly Bendiksen <[email-masked]>
Date: Thu, 15 Aug 96 13:57:52 -0000

This serves as a summary of replies that I received on this topic.

My original post:
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I'm in search of experiences, both published and unpublished, successes 
or failures, of the use of QSAR to model data for new compounds that are 
being proposed for FDA approval.  For example, in my company we are 
seeking to reduce the time it takes to run extraction studies for paper 
processing chemicals for food-contact paper.  The FDA requires estimates 
of how much of the chemicals used to make paper might wind up in human 
tissue.  The extraction studies can take several weeks, yet alternative 
of mathematical estimates of worst case (all the compound leaches from 
paper to food to humans) are usually much too high, and overestimate 
potential toxic effects.  The use of FDA databases and QSAR molecular 
modeling poses a unique possibility, providing that the US government 
would be willing to accept a modeled result of this type.  Certainly, the 
model would need some verification, but this would still reduce 
experimental time.  

From:        William Welsh, [email-masked]

Predict the chromatographic retention of  a family of polycyclic aromatic 
hydrocarbons (PAHs) based on their chemical structures:
E. R. Collantes, W. Tong, W. J. Welsh, and W. L. Zielinski, Anal. Chem., 
68,
2038 (1996).

Predict the chemotherapeutic activity of anti-Alzheimer's Disease drugs 
based on their chemical structures:  
W. Tong, E. R. Collantes, Y. Chen, and W. J. Welsh, J. Medicinal Chem., 
39, 380
(1996).
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From:        Soaring Bear, [email-masked]

	Your scenario of trying QSAR for paper toxins is interesting.
I applaud your interest in using new tools for old methods.  As 
a QSAR scientist, I would be the first to admit its limits.   It
should only be used as an indicator for directing further research
and it would never be accepted as a sole method.   
	Keep in mind that it is just a statistical method to make 
a linear regression based on certain physical properties of the 
compounds.   There are often outliers which are hard to explain
and the presence of those exceptions will keep governmental
agencies from accepting QSAR on its own.
	I do encourage you to use QSAR to help you concentrate
your research efforts, but don't expect it to replace experimental
verification.
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From:        Phil Howard, [email-masked]

        I am not aware of any uses of QSARs that have been accepted by 
FDA.
We have discussed with FDA a lot of estimation methods that we have
developed with EPA (see http://esc.syrres.com/~ESC/estsoft.htm) which have
been used for new chemicals under the Toxic Substances Control Act (TSCA).
The response I have gotten was that they don't rely on estimated values -
they test.  I will be interested to hear other peoples experience.
_____________________________________________________________________

From:        David Livingstone, [email-masked]

There is quite a bit of literature on PBPK (Physiologically Based 
PharmacoKinetic) modelling.  This is (it seems to me) a better 
approach than the "traditional" method of mathematical modelling of 
chemical distribution in Man (and animals).  In your "worst case" 
modelling the amount that gets into Man is less important than what 
happens to it when it gets there.  There is a report of an EC funded 
workshop on the replacement of animals in experiments which contains 
quite a lot of references to QSAR studies of toxicity and PBPK models:

The Integrated Use of Alternative Approaches for Predicting Toxic
Hazard" M.D. Barratt, J.M. Castell, M. Chamberlain, R.D. Combes, J.C.
dearden, J.H. Fentem, I. Gerner, A. Giuliani, T.J.B. Gray, D.J.
Livingstone, W. McL. Provan, A.J.J.L. Rutten, H.J.M. Verhaar and P.
Zbinden. ATLA, 23, 410-29 (1995).

There are also stacks of papers on QSAR models of various kinds of 
toxicity - I expect someone will send you a reference to a recent 
review.

I believe that the FDA uses TopKat to draw up priority lists for 
testing - try speaking to the people at Health Design (now owned by 
Oxford Molecular).  There are also various other programs around 
which attempt to predict hazards and metabolic fate (you can't really 
have one without the other).  There is a chapter in my book which 
briefly discusses some of these systems if you are not very familiar 
with them:

"Data Analysis for Chemists: Application to QSAR and Chemical Product 
Design", D.J. Livingstone, Oxford University Press, 1995, ISBN 
0-19-855728-0.
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Many thanks to all who replied!
bev

Beverly Bendiksen
[email-masked]
Pittsburgh, PA