att- JUL 14 1969

THE UNIVERSITY OF CONNECTICUT Department of Laboratory Medicine

HEALTH CENTER June 9, 1969 a Za

Dr. Joshua Lederberg

Department of Genetics

Stanford University Medical Center
Stanford, California 94305

Dear Doctor Lederberg:

Thank you for your gracious note, and for the reprint of your essay
which was published in the Congressional Record. I concur wholeheartedly
with the views which you expressed regarding the carcinogenic hazards of
occupational and environmental exposures to nickel,

Our recent demonstration that Ni(CO), is a potent inhibitor of RNA
polymerase activity in mammalian systems furnishes a mechanism whereby
nickel can produce acute alterations in the expression of genetic infor-
mation, The possible relevance of this finding to the initiation of
nickel carcinogenesis is suggested by similarities between the inhibitory
effects of Ni(CO), upon RNA synthesis, and the effects of several other
chemical carcinogens, including aflatoxin, 4-nitroquinoline-N-oxide, and
actinomycin D,

As yet, no one has studied the effects of Ni(CO), upon nucleic acid
synthesis in bacterial or viral systems. The major deterent to such
studies has been the extreme toxicity of Ni(CO),, and hence the necessity
of safeguards and monitoring devices to protect the investigators who
employ Ni(CO),. To avoid this disadvantage, we have arranged to have
Ni(CO), ampouled in 0.5 vials which can be handled safely in an ordinary
fume hood. Perhaps you or your colleagues might consider employing Ni(CO)
in your studies of mutagenesis. 4

NaWI AANNS

In your letter, you emphasized the desirability of identifying the
chemical form in which Ni is emitted in gasoline exhaust. I believe that
this task can now be accomplished by use of our new gas chromatographic
method for detection and measurement of Ni(CO),.

Your attention is directed to the possibility of a co-carcinogenic
relationship between nickel and 3,4-benzpyrene. Both of these compounds
are known to be present in tobacco smoke, automobile exhaust, and polluted
urban atmospheres. We have shown that Ni(CO), blocks the induction of
benzpyrene hydroxylase, the principal detoxiftcation mechanism for polycyclic
aromatic hydrocarbons. Moreover, unpublished studies in our laboratory have
shown that exposures of rats to Ni(CO), prolong the retention of 3,4-benzpyrene
in the lungs and liver. These indications of carcinogenic synergism of nickel
and benzpyrene may be especially pertinent, since the Surgeon General's Report

McCOOK HOSPITAL
2 HOLCOMB STREET, HARTFORD, CONNECTICUT 06112
Dr. Joshua Lederberg
Page 2
June 9, 1969

on Smoking and Health emphasized that the carcinogenicity of cigarette
condensates is greater than the sum of the known carcinogenic constitu-
ents, ,

Enclosed are tables (from a paper in preparation) which list the
available data on nickel content of cigarettes, urban atmospheres and
asbestos fibers. In accordance with your request, I have also enclosed
reprints and preprints of our recent studies. Please let me know if
there is any way in which I can be helpful to you.

With best wishes, I am
Sincerely yours,

Katte Fi lism —

F. William Sunderman, Jr., M.D.
Professor and Head

FWS:nil
Enclosures