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r '. S BIO -lRESEARCH CONSULTANTS, INC. -~ CON!SUiLT'ATION . RESEARCH • DEVELOPMENT F. HOMBURGER, M, D: 9' COMMERCIAL AVENUE P. BERNFELD; Ph.D. CAMBRIDGE 41;, MASSACHUSETTS UNiversity 4-8735 June 26, 1964 Dr. H. B. Parmele, Vice President Director of Research P. Lorillard~ Company 200 East 42nd Street New York, New York 0017 Dear Dr. Parmele: This is to confirm our recent telephone conversation and to congratulate you and your associates on your discovery that one of the subfractions of fraction B contains 1, 1 dichlioro 2, 2 bis (p- chlorophenyl) ethane (otherwise known as tetrachlorodiphenylethane, (TDE), dichlorodiphenyl dichloroethane, (DDD); pp-TDE, rhotane C14H10C14 (mp 109 to 110 degrees). We note that this material is present in a concentration of 0.003°jo of the total tar. Since the first tumors in mouse sltin carcinogen studies appear after some 40 weeks of painting of 35 mg of tar per week per mouse, 45y of' DDD would have been applied during the latent period. We suggest that this be the basic dose chosen as the lowest level to be studied for possible co-carcinogenic activity. The quickest way to obtain an indication of the co-carcinogenic effect of this material is to conduct the experiment which you have authorized and which willi be started as soon as we shall receive the DDD which has been ordered. This material will be recrystalized prior to use and you will receive samples of the purified material such as we shall inject into mice.

BIO-RESEARCH - 1/64 - 6/64 O~tq~~2-- C-t

1 Page 2 Dr. Parmele June 26, 1964 Five hundred C57 B/6 male mice will be used, kept ten per cage in air-conditioned rooms and given purina chow and water ad lib. They will be divided into five groups of 100 each and will receive the following subcutaneous injections in 0. 5 ml of peanut oil,: Group 1 500Y of 3, 4, 9, 10 dibenzpyrene Group 2 500y of 3, 4, 9, 1'10 dibenzpyrene + 50Y DDD Group 3 500Y of 3, 4, 9, 110 dibenzpyrene + 500Y DDD Group 4 500y of 3, 4, 9, 110 dibenzpyrene + 5 mg of DDD Gr oup 5 5 mg of DDD The animals will be examined at frequent intervals by palpation, and the appearance of palpable tumors of 1 cm diameter will be noted. Some of these tumors in each group will be sectioned for histopathological study to ascertain the malignant nature of the tissue reaction. In the event that DDD itself alone should cause tumors, they would be transplanted to ascertain their malignant nature by bio-assay. In thousands of tumors which we have induced by 3, 4, 9, 1'0 dibenzpyrene (see attached reprints) none of the induced neoplasms appeared before the eight'h week, and their rate of appearance i~s extremely constant and reproducible. The addYtion of 3°jo cholesterol to 3, 4, 9, 10 dibenzpyrene, for example, has significantly increased the slope of this tumor appearance curve and revealed the co-carcinogenic nature of cholesterol after about nine weeks of' study. If DDD is co-carcinogenic, we may expect to detect this within eight to twelve weeks in, the present experiment. If it is a carcinogen this will also become apparent, alt'hough: perhaps not until twenty weeks after the start of the study. We realize your desire to obtain an indication soon of the co- carcinogenic or carcinogenic potency of DDD and are expediting this work as much as possible. Dr. Bogdonoff made a literature search yesterday which, failed to show any data on carcinogenesis and inforrnation only on the interesting pharmacological properties of DDD which do not concern us here.

l Page 3 Dr. Parmele June 26, 1964 You will, pay us for-this study as follows: $1, 000. per month for the first three months, and $500. per month, for the fourth, fifth and sixth month. The experiment will be terminated after a total of six months (24 weeks). We shall bill you monthly in advance beginning now, since we have already spent some professional and technical! time on this project. In view of the urgent nature of these studies, we shall~ report to you by telephone whenever the results appear interesting, and we shall report in the form of tumor incidence graphs at frequent intervals as soon as a significant number of tumors will appear. Dr. Kelley is enclosing a report to you on some of the polonium s tudie s . Yours sincerely, F,reddy Hoinburger, M, D. President and Director FH:er