GorD BEKZ, 4

THE ROCKEFELLER UNIVERSITY

1230 YORK AVENUE NEW YORK, NY 10021

 

February 5, 1980

JOSHUA LEDERBERG

PRESIDENT

Dr. Leon Goldberg

President

Chemical Industry Institute of Toxicology

P. O. Box 12137

Research Triangle Park, North Carolina 27709

Dear Dr. Goldberg:

Thank you for sending me the January 16th statement
on the formaldehyde study. As you know there is little
doubt that formaldehyde is a bacterial mutagen and in fact
I had some small interest in this question myself around
1951. It occurred to me at that time that the important
variable governing the chronic toxicity of formaldehyde in
animals would probably be the body distribution of active
material given the variety of reactions that it would be
likely to undergo in transit, especially the formation of
Schiff bases and methylol derivatives.

In that connection I was particularly intrigued by the
possible difference in species response of rats versus mice.
I wonder if this might not be an excellent test case to pur-
sue mechanistic analyses of species differences (which I
hardly need persuade you are an essential part of the ra-
tionale for extrapolation to human risk!) I am not aware
of any premonitory information; but one in this case might
look for differences in the chemical activity of nasal se-
cretions as between the two species that might account for
the difference in response. (Of course there could be one
at the cellular level which would be much more difficult to
determine). Since there would be a fairly ready bioassay
for genotoxic activity it would probably not be too diffi-
cult to do at least a preliminary study on the complexes
found in rat versus mouse tissue. Of course one also has
to take into account the irritant and inductive effects of
the formaldehyde itself in eliciting these hypothetically
different secretions.
Dr. Leon Goldberg
February 5, 1980

-2-

Probably less likely to be relevant in the present
circumstance is the remarkable synergism between aldehydes
and peroxides that was observed by Dickey et al in 1949.
There is a hint there also of a spontaneous reaction be-
tween formaldehyde and molecular oxygen: I know this can
go to formate at some measurable rate but I just do not
know of any studies on the accumulation of peroxide in-
termediates. It is unlikely that the occurrence of peroxide
is going to be a species differential; but of course the
much larger question of enzymatic catalysis of the conver-
sion of formaldehyde to still more active reagents is, I
have to presume, both open and plausible.

I hope the more detailed footnotes do not obscure the
primary challenge that is presented by the species differ-
ence in response.

Yours sinc ly,

Geke .

Joshua aA
per CLIT

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