September 17, 1973

Dr. Peter B. Hutt

General Counsel

Food, Drugs, and Product Safety Division
Department of Health, Education and Welfare
Rockville, Maryland 20852

Dear Peter,

The further review of cyclamate safety may give us a remmrkable
opportunity to apply some rational analysis to the evaluation of a
food additive. There is a good deal of motivation, from different angles,
to get at the root of the problem and therefore a basis for making
substantial research investments. And at least as my ow subjective
judgment, the burden of proof is this time properly located.

In view of the problems of extrapolating from findings on animals to
man I hope that something less than 100% of the effort is centered on
purely empirical studies on the carcinogenéaisy of cyclamate in animals.
Better than for most comparable situations we have a theoretical rationale
for the possible biological side-effects, namely the splitting of
cyclamate to cyclohexylamine and the further metabolism of this to hydroxyl
derivatives which are almost certainly the actual culprits. These metabolic
conversions may well not occur in the same degree in relatively short-term
experiments in animals compared to chronic life-time exposure of humans.
This is a matter of particular concern because of the likelihood that
adapted bacterial flora, occurring rather variably in the intestinal
contents of different individuals, may be responsible for the first step.

It would therefore seem reasonable forme that the problem be factared
into the following components: 1) carcinogenicity of cyclohexylamine and of its
hydroxylated derivatives in animals, on a quantitative basis. Since the compounds
are biologically active, with much higher probability and extent than the
original cyclamate, it should be much easter to collect statistically
useful data; 2) it may be unethical to do further experiments with
cyclamate in man and the historical data are probably sufficient. However,
if there are still populations still using cyclamate they should be scrutinized
further for the distribution of the capability of splitting this into
cyclohexylamine; 3) if in a variety of animals one could calibrate the relative
carcinogenicity of cyclohexylamine and beta-naphthylamine, we might have a
resonable basis to extrapolate the risks aseertained in animals to man.

In any event, given the certain knowledge that cyclohexylamine is
produced in at least some human consumers as a result of the ingestion of
cyclamate, it would seem reasonable to require that cyclohexylamine itself
be exonerated before the parent compound can be registered. Whatever complaint
there might be about the fussiness of a procedure that requires studies on
metabolites as well as the original compound, ought to be dissipated by
the prima facie case that already exists for the cyclohexylamine.
Dr. Peter Hutt -2- 9/17/73

Sincerely yours,

Joshua Lederberg
Professor of Genetics

JL/rr

P.S. I realize most people have already made up their minds on this
subject. However, I have the possibly vain hope that if Abbott
weuddto study cyclohexylamine and verify its carcinogenicity
they might even convince themselves about the hazard implicit
in the product.

Perhaps I have not been following the literature sufficiently
closely but I do not know of comparable biochemical information
on saccharine that would be helpful in guessing at the proximal
chemical hazard, if any.

t
® Aine 2 + Lek LNB >