August 8, 1973

Mr. Fred H. Holt
Animal Health Institute
1030 15th Street, N.W.
Washington, D.C. 20005

Dear Mr. Holt,
Thank you for your interesting communication of August lst.

As you may already know from some of my public statements,
I am fully sympathetic with your scientific criticisms of the
Delaney Amendment. In practice I am not sure that it has been applied
as blindly as the letter of the law would allow for. In fact,
Mr. Peter Hut, Chief Counsel for the FDA, has pointed out that
almost all of the regulatory actions that have been popularly
associated with the "Delaney Clause” have in fact been promogated
under the mandate of the general safety requirement.

This is not to sweep away the problem of potential abuse and
public loss from an undiscriminating application of the Delaney Clause.

However, I cannot agree with some of the basic philosophy of
your report, as it would seem to me still éneumbent on the introducer
of a new product to verify its safety, not in absolute terms necessarily.
but at least to a level which is commensurate with the estimated risk.
The very first recommendationssuggest that "jydgement withheld until
the data are confirmed"; but the problem is then what is the appropriate
public policy action during a period of suspended judgement? ‘

For these reasons I have argued against the direct extension of
the principles of the Delaney Clause to situations like mutagenesis
and teratology. Instead I am inclined to support Senator Nelson's
version which would allow prima facie evidence of public harm to bhe
overridden by a judgement by the secretary that the probable public
benefit emceeds the public risk. I would also be prepared to support
the extension of such language to cancer risk as well, for I agree with
you that there are inherent paradoxes in the strict application of the
Delaney language. I do not believe that such decisions about the broader
values of permission versus restriction should be allowed te occur by
default, even in the absence of the information that one would like to
have to make a secure scientific judgement.

I must take very specific exception to the concluding remarks
on page 11 which attack the principle of the use of exaggerated doses.
Of course, I accept the possibility, even the likelihood, that the use
of such levels of dose may sometimes distort the appropriate model of
drug metabolism in the human exposed at typical levels. I would agree
Mr. Fred H. Holt -~2- 8/8/73

that conclusions that have been reached by the use of exaggerated
doses should be rebuttable by explicit evidence that warrants the
influence that they have distorted the experimental finding. But to
abolish the use of exaggerated doses in chronic toxicity experiments
would create more problems than it solves, for in many situations

it will be simply impractical to study a sufficiently large population
to make precise estimates of low-level risks. Where very large numbers
are exposed in commercial practice -- as is often true for food additives --
risks at levels like 10-4 or 1075 which are almost inaccessible to
laboratory examination, would nevertheless loom very large in public
policy determinations. Furthermore, exaggerated doses may give a
methodology which is invaluable in exploring the possibilities of
anomalous response to lower levels of a drug in isolated members of
the population. We already know that there are considerable variations
within the human population in the very capacity for metabolic drug
detoxication which is the foundation of the threshhold argument.

I am surprised that your discuskéon does not give more emphasis
to the estimation of benefit, the level of which should certainly
temper one's judgement about the level of risk-taking that might
condoned.

As this is a general area of public policy comment which is
unlikely to be conclusively settled in the near future, and with which
I predictably may continue to be engaged, I appreciate the opportunity
to discuss these matters with you and I hope you might keep me on your
mailing list for further communications. If you have a copy of the
federal register for July 19th conveniently accessible, I wonder if you
could send me the reference you quoted in your letter.

a

Sincerely yours,

Joshua Lederberg
Professor of Genetics

P.S. I would be interested to have more information about the AHI
generally and its activities and membership. Conversely I will
not complain at all if you wish to send copies of my response
to the members of the Toxicology Task Force.