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American Health Foundation Naylor Dana Institute fouDisease Prevenlion Valhalla, Nly, 10595 {

i. ., Response to Dr. Osdene's letter of Progress Report - April 6, 1981 On the Selective Reduction of Tobacco Specific N-Nitrosamines from Cigarette Smoke

AMERICAN HEALTH FOUNDATION NAYLOR DANA INSTITUTE FOR DISEASE PREVENTION Dana Road, Valhalla, New York 10595 Telephone: 914-592-2600 Amerlcan Health Foundation 320 East 43rd'Street. New York. New York 10017 rTetephone:212-953-1900 'OFFICERS AND BOARD OF TRUSTEES ' David J. Mahoney, Chairman Chairman and Chief Executive Officer Norton Simon„Inc. William J. Levitt, Pasf Chairman Founden-Chairmen Levitt 8 Sons, Inc. Ernst L. Wynder, M.D., President . John D. Twiname„Managing Dlrecfor Eric M. Javita. Secretary Senior Partner Javits & Javits TRUSTEES: John J. Burns, Ph.D. Vice Preaidentfor Research Hoffmann-La Roche. Inc. Thomas L. Chrystie ' Chairman ?: Merrill Lynch White Weld Capitai'Markets Group Theodore Cooper, M.D. Dean Cornell University Medical College Mrs. Charles A. Dana D. Ronald Daniel Msnaging Director, McKinsey & Company, Inc. Ralph Landau, Sc.D. Chairman & Chief Executive Officer Halcon International, Inc. Hildegarde E. Mahoney -.; Bruce S, Nevins . President Perrier, Great Waters of France, Inc. Joseph Robbie Managing Partner Miami Dolphins, Lid. Hon. Donaid H. Rumstefd' President & Chief Executive Officer G.D. Searle & Company John W. Simmons President & Chief Executive Officer Morton-Norwich Products,Inc. Mts. Jennifer Jones Simon '. Thomas A. Watson ADM. E. R. Zumwalt, Jr., USN (Ret;) President 6.ChiefExecuttve Officer American Medical Buildings, Inc. John H. Weisburger, Ph,D. Vice Presldentfor Research Naylor Dana Institute Charles e. Arnold, M.D., M:P.H. Vice President for Research Health Maintenance Institute Dr. T. Osdene Director of Research ~Philip Morris Research Center Main Complex Commerce Road ~Richmond, VA 23261 Dr. Osdene: Please find attached our response to ,youur letter of February 24th, 1981. : Dietri:ch Hoffmann, Ph.D. .Associate Director DH/cch Encls. cc: Dr. E.L. Wynder, President Mrs. I. Hoffmann, Res. Coordinator $ ~ © r w oo~p W ~

0 RESEARCH CENTER: P.O. BOX 26583, RICHMOND, VIRGINIA 23261 TELEPHONE (804) 271,2000 . As per our telephone conversation of today would you kindly . Dr. Dietrich Hoffman, Associate Director ;~Naylor Dana Institute `Dana Road ; Valhalla, N.Y. 10595 Dear Dietrich: supply the following information with regard to the Project "Q" study: ~ 1. In the hamster inhalation study (H-60) there was a 12-week comment regarding the significance or lack of it with regard to this 48 weeks). Can you supply historical control summary data regarding the survival of male and female Syrian Golden Hamsters with some -grou s(50% survival for males was 62 weeks and for females it was 1dilfference in survival for the two sexes in the untreated control surv:ival difference. : the biological activity of the two cigarettes was not different in the cigarettes respectively) having any influence on the determination that `hamsters treated with smoke from X6D8ALB and X6D7AKJ (test and control 2. Do you consider the survivali difference between male and female : hamster inhalatiion study H-60? 3'.' In the hamster study H-60.the survival for males treated with - .r._ ..: .June 20, 1979? ~.r .ri;; nificant difference in biological acti~vity for the two cigarettes. .4. Was Project "Q" conducted in accordance with the United States Food and Drug Administration's Good Laboratory Practices Regulations of vival difference have influenced in any way the determination of no sig- -;at 78 weeks. Is this survival difference significant? Could this sur- :smoke from X6D8ALB (test) and X6D7AKJ (control) was 13% and 29% respectively 3~2?4, 5. Would you please prepare a summary document which would include CD all aspects of Project "Q" at your Institute. I am not so much interested 0)

Dr. Dietrich Hoffmann -2- February 24, 1981 iin raw data as I am in a collection of summaries describing results of chemistry, short term in vitro and in vivo results and chronic in vivo results. I woul'd very rauch appreciate a prompt response since we are in the process of.making recommendations to our Management. Sincerely, T. S. Osdene, Ph.D. . Director of Research and Extramural Studies

Survival Rates of Ciqarette Smoke Ex to Controls. osed Hamsters Compared In our smoke inhalation studies with Syrian golden hamsters, exposure to tobacco smoke in,'the Hamburg II device appears to we have confirmed the observation of other investigators that the prolong the lifespan of the hamsters over those that are only ex- posed to air (sham-smoking). -In our setting, this was deduced from the higher survival rates of male and female hamsters in a smoke inhalation study which was terminated after 18 months (-80 weeks). Tables 1 and 2 summarize the survival data for male and •female Syrian golden hamsters exposed to smoke from 3 different cigarettes and those in their respective control groups (shammed and untreated). These tables do not list the mean survival time for each group, but these data can be readily extrapolated, if requested. Our observations are in line with other reports (1-3). sion, sion, the weights of the "smoked" hamsters remain below those of are lower. However, in the experimental setting under discus- ed hamsters could be related to the fact that their body weights . .. The phenomenon of an increased lifespan for the smoke expos- the "sham-smoked" animals only for the first 30 weeks. The path- ological reports suggest a delay in the onset of amyloidosis in the smoke exposed.hamsters and the survival data in our study tend.to support this conclusion, which is also made by Wehner et It R

2. Weight Differences Between Female and Male Hamsters. is a fact, that in Syrian golden hamsters (SGH), males ted, treated, sham smoked or exposed to diluted cigarette smoke (1-3).This was also confirmed in this study. During the last 11 have a longer average survival rate than females whether untrea- weeks of smoke exposure (weeks 67-78), the average survival rate smoke fr=cigarette A. However, there was no difference in sur- be slightly greater than that of male SGH exposed to diluted of male SGH exposed to diluted smoke from cigarette B appears to vival rates among the female SGH groups, and the difference ob- served among the males is not considered to be of significance. Activity. _. _ . .. . , . ~., _ _ .-,- .3. Survival Difference and Effect on the Relative Biological The biological activity of the diluted smoke from both cigarettes A and B in Syrian golden hamsters is so low that of the American Health Foundation exceed the requirements of the T survival rates is inconsequential. -slight difference in 4. The Research Animal Facility (RAF) ` The practices and inspection of the Research Animal Facility tions of June 20, 1979. The RAF is fully accredited by the Amer- ican Association for the Accreditation of Laboratory Animal Care (AAALA) and is inspected semi-annually by the U.S. Department of Food and Drug Administration's Good Laboratory Practices Regula- Agriculture and by the State of New York.

Our chemical laboratories are approved_by the Research Contract Safety Officer of the National Cancer Institute for studies and synthesis of carcinogenic chemicals. 0 N : 1rJ: W ~~r~:

SUMMARY AS CONTROL Both cigarettes were identical in all physical CHEMICAL ANALYSES AND BIOASSAYS OF THE SMOKE OF CIGARETTE A WITH AN ADDITIVE COMPARED TO CIGARETTE B parameters including filter tips, weights, burning rates any differences in the make-up of the cigarettes except for an additive in the tobacco of cigarette A kind of paper for both. Chemicalljr,we did not identify and draw resistance. The wrapper was also the same .which was detected during the nicotine analysis by gas .I. Chemical Analysis of Cigarette Smoke Both cigarettes A and B were low in smoke yields as reflected in the low values for "tar" (FTC-TPM 4.15 we determine routinely for all cigarettes tested at the American Health Foundation since 1975. Outstandina low and carbon monoxide (7.3.and 7.8 mg) and also shown by low values for all of those smoke constituents which and 4.45 mg/cigarette), nicotine (0.46 and 0.58.mg) values were hydrogen cyanide (61 and 69 ug), phenol (13.7 and 13.7 ug) and catechol ..'K._ C- (26 and 25 ug). Generally„ the smoke profiles for both cigarettes were comparable. Naphthalene itself appeared to be slightly increased in the smoke of the control cigarette, although profiles Z;

for the total naphthalenes are comparable. This may require reconfirmation. liver homogenate activation in tester strains TA98, TA100, and TA1538. The S-9 liver homogenate used for the metabolic activation was isolated from rats treated with phenobarbitol, 3-methylcholanthrene or Aroclor, II. Mutagenicity of Tars I and II in the Ames Test The whole "tars" of cigarettes A and B, as well as their neutral, weakly acidic, acidic and basic portions were assayed for mutagenic activity with and without S-9 respectively. The tars and their fractions were assayed for mutagenic activity at dose levels of 25,50,100,250, . 500, and 1,000 pg. Significant activity (i.e. at least twice the activity of negative controls) was ~ {} - -- - ~ - -- , ~ `found only for the whole "tar" and for the basic fraction differences in the degree of mutagenic activities of the fraction at all 6 dose levels. We did not detect any and was about the same for whole "tar" and for the basic after metabolic activation with S-9 liver homogenate, "tars" nor in those of the basic fractions deriving from cigarettes A and B. - 5--