Tobacco Documents Online

1 REDACTED COPY IN THE CIRCUIT COURT FOR THE SECOND JUDICIAL DISTRICT OF JONES COUNTY, MISSISSIPPI ESTATE OF EARL BUTLER, gi Civil Action No. 94-S-53 ) Plaintiffs, ) THIS VERSION IS SUBMITTED ) EX PARTE AND 2j CAMERA v. ) BECAUSE IT CONTAINS ) PRIVILEGED MATERIAL. A PHILIP MORRIS, INC., REDACTED VERSION IS ) BEING SERVED ON Defendants. ) PLAINTIFFS. ) AFFIDAVIT OF DR. VINCENT F. LISANTI STATE OF NEW YORK ) ) ss.: COUNTY OF NEW YORK ) REDAC T ED COPY VINCENT F. LISANTI, having been duly sworn, hereby declares as follows: 1. 1 was affiliated with The Council for Tobacco Research -- U.S.A., Inc. and The Council for Tobacco Research -- U.S.A. (together, "CTR") for 30 years, from 1964 until 1994. I make this affidavit in response to plaintiffs' contention that CTR participated in an alleged fraud. Personal Backg or und 2. I was born in Rochester, New York on June 23, 1918, and I am 78 years old. I reside in New Jersey.

3. After attending the University of Rochester, I received a degree in Dental Medicine (D.M.D.) from Tufts University in 1942. I served in the United States Army from 1942 to 1946 and attained the rank of Captain. Following World War II, I held a number of teaching positions in the fields of oral medicine and oral cavity research. From 1954 to 1960, I was an Associate Professor of Dental Research at Tufts University and taught Ph.D. candidates at Tufts as well as at Boston University and the Massachusetts Institute of Technology ("MIT"). Beginning in 1958 1 was a Director and Member of the Institute of Somatological Research in Cambridge, Massachusetts, which was a division of the Science Resources Foundation ("SRF") in Brookline, Massachusetts, a granting and research foundation. I remained affiliated with SRF until 1986. In addition, I have served as a research consultant to the Office of Naval Research, Warner-Lambert Pharmaceutical Company, Aero-Medical Center of the United States Air Force, the Veteran's Administration, and a number of other pharmaceutical companies and medical institutions. 4. 1 have published accounts of my research in journals such as 31M Archives of Oral Biology, The Annals of the New York Academy of Sciences, Science, The Journal of Bacteriology, Proceedings of the Society of Experimental Biology and Lancet. I have been a member of a number of professional organizations, including the American Association for the Advancement of Science, International Association for Dental Research, New York Academy of Sciences, American Society of Cell Biology 2 20343071.02

and the Massachusetts Public Health Association. A copy of my curriculum vitae from CTR's files is attached as Exhibit 1. Affiliation with CTR 5. In about 1963, 1 was invited to apply for a job at CTR by Dr. Robert Hockett, who was the Associate Scientific Director of CTR. I knew Dr. Hockett from his work at the Sugar Research Foundation, where he had been employed before going to CTR. I declined Dr. Hockett's invitation. In June 1964, Dr. Clarence Cook Little called me, saying I had been recommended to him for a position at CTR by Dr. E.B. Wilson, a member of CTR's Scientific Advisory Board ("SAB") of CTR. 6. I met with Dr. Little and was extremely impressed with him on a personal and professional level. We discussed scientific research generally, including the relative merits of directed contract research as compared to undirected grant research. As described below, this was a frequently discussed topic at CTR through much of my tenure there. After meeting again with Dr. Little, and talking to Dr. Hockett, Mr. Tom Hoyt (a non-scientist administrator at CTR) and Mr. Timothy Hartnett (a non-scientist who was the Chairman of CTR), I was offered a full-time position. I declined the full-time position but accepted a part-time position in 1964. No one told me, and I did not believe, that there was any requirement that I hold a particular opinion about smoking and health in order to be hired by CTR. 3 20343071.02

7. -Iri 1964, my title at CTR was Scientific Associate. My principal function was to monitor the activities of some CTR grantees (and later contract researchers) and report back to CTR as to how its grant-in-aid (and later contract) funds were being spent. I was not concerned with the scientists' research findings, but rather their qualifications, techniques, and procedures. It was not my function to interfere with their research, and I made every effort not to do so. 8. My time commitment to CTR steadily increased over the years, until I was working there virtually full-time in 1967. My title wass changed to Research Associate in 1973. In 1975, I become a full-time employee of CTR and my title was changed to Associate Research Director, which it remained until I retired in 1994. 9. Throughout the 30 years in which I was associated with CTR, its principal function was to award research grants-in-aid to independent scientists around the country and abroad. These awards were made after review and evaluation by the SAB, whose meetings I usually attended. CTR itself did not conduct any scientific research. Structure of CTR 10. When I first came to work for CTR it was an unincorporated association consisting of a committee of representatives of all the sponsor companies. The sponsor companies were most of the major participants in the U.S. tobacco industry. The chief executive officer of the association was the Chairman of the 4 zo3a9o71. oz

Council. From 1964 to 1969, the Chairman was Timothy Hartnett, formerly of the Brown & Williamson Tobacco Co. The scientific work of CTR was run by the Scientific Director, Dr. Little. Dr. Little's principal assistant was Dr. Hockett, formerly with MIT and the Sugar Research Foundation, an industry research organization. 11. In 1971, CTR changed from an unincorporated association to a non- profit corporation. A Board of Directors (consisting of representatives of the sponsor companies) was created, as well as a President and other corporate officers. 12. The Scientific Directors of CTR were distinguished scientists with no affiliation to the tobacco industry other than their work at CTR. The Scientific Directors whom I worked under were Dr. Clarence Cook Little (until 1971), Dr. William Gardner (1973-1981), Dr. Sheldon C. Sommers (1981-1987), Dr. James F. Glenn (1988-1991), and Dr. Harmon McAllister (1991). In addition, Dr. Hockett, who was the Associate Scientific Director from 1955 to 1972, was Acting Scientific Director from 1972 to 1973. Their curricula vitae are attached as Exhibit 2. Each of the Scientific Directors considered it one of his principal duties to foster and preserve the scientific integrity of the CTR. 13. 1 understand that Dr. McAllister and Dr. Glenn are submitting affidavits to this Court. Dr. Little, CTR's first Scientific Director at the time I joined CTR, was then one of the greatest living contributors to the science of cancer. He was 5 20343071.02

a Fellow of the gational Academy of Sciences, founder of the Roscoe B. Jackson Memorial Laboratory in Bar Harbor, Maine, and a former managing director of the organization that became the American Cancer Society. The Scientific Director after him, Dr. Gardner, had been a Professor at Yale University Medical School and was a past President of the International Union Against Cancer. Dr. Sommers, a graduate of Harvard College and Harvard Medical School, had been a Professor of Pathology at the Columbia University College of Physicians and Surgeons and Director of Laboratories at Lenox Hill Hospital. 14. CTR also had the Scientific Advisory Board ("SAB"), an Executive Committee of the SAB (consisting of several SAB members and the Scientific Director) and an Executive Committee of the Board of Directors. To the best of my knowledge CTR never had a "Committee of Counsel," a "Research Review Committee," an "Ad Hoc Committee" or a "Research Liaison Committee." 15. CTR has no relationship with the Tobacco Institute other than, I believe, an overlap in membership. To the best of my knowledge, the Tobacco [nstitute's employees have not been involved in CTR's activities during my 30 years at CTR. The Scientific Advisory Board 16. During my affiliation with CTR, the SAB met at least twice, and early on as many as four times, each year to review applications for research grants-in- 6 20343071.02

aid. These applications were received from independent scientists who sought grants from CTR. Each application was assigned to a subcommittee of two to four SAB members with expertise in that scientific field (augmented by outside consultants where necessary). Those members reviewed and prepared written critiques of the application. These reviews were distributed to the full SAB, which would discuss each application at its meetings. The SAB would decide which applications were approved or disapproved for funding. Beginning in about 1973, each approved application was given a score of 1 to 5 by each SAB member, and SAB members' scores for each application were averaged to arrive at a composite score for the application. (In the early 1990s, the SAB adopted a procedure whereby the SAB rated all acceptable applications, but designated others as "non-rated" rather than "disapproved. ") 17. The final decision-making as to funding was entrusted to CTR's Scientific Director, with the understanding that those decisions would adhere closely to the SAB's evaluation. The Scientific Director reported his funding decisions to the SAB at its next meeting. By reviewing and evaluating grant applications in this way, the SAB functioned much like a peer review board of the National Institutes of Health, the American Cancer Society or the American Heart Association. Once the amounts approved by the SAB began to regularly exceed CTR's budget (in the early 1970's), the Scientific Director was unable to fund all grants approved by the SAB. This is reflected in the SAB minutes for March 14-16, 1973, paragraph 4(2) at page 4, a copy 7 20343071.02

of which is attaclied as Exhibit 3. To the best of my knowledge, the Scientific Director did not fund any grant or contract that had not been approved by the SAB. 18. I attended over 90 SAB meetings from 1964 to 1994. These sessions were extremely educational. They were filled with lively and thoughtful debates about the grant-in-aid applications and research contracts, as well as about scientific issues generally. I also attended about 35 SAB Executive Committee meetings. 19. In evaluating grant-in-aid applications, the SAB's primary considerations were the scientific merit of the applications and their relevance to smoking and health. In the 90-plus SAB meetings that I attended, I do not believe that the SAB ever rejected a grant application because it proposed research the results of which might be detrimental to the tobacco industry. The SAB members cared about promoting science and making a contribution to scientific knowledge, not about the potential impact of any scientific research on the interests of the tobacco companies. 20. SAB meetings were attended by SAB members and by the administrative officers and scientific staff of CTR. Only the SAB members and the Scientific Director ever voted on grant applications. On occasion, guest scientists were present. Most SAB meetings were attended by a representative of the Industry Technical Committee ("ITC"), which consisted of tobacco company scientists. The sole function of the ITC with regard to CTR was to provide information to the SAB, 8 20343071.02

upon request, about technical aspects of proposed research that related to cigarette composition and tobacco smoke chemistry. No other industry representatives generally attended SAB meetings. 21. Leonard Zahn, a consultant to CTR whose principal functions were to attend and report on medical meetings and to prepare CTR's Annual Report and press releases, also attended SAB meetings. Mr. Zahn had no influence over the SAB's deliberations and evaluations. 22. One SAB meeting that I attended, in April 1978, was attended by CTR's attorney, Edwin Jacob. Other than that, I do not ever recall a lawyer attending an SAB meeting during my tenure. (During my affiliation with CTR, three officers of CTR were lawyers: Henry Ramm, Addison Yeaman, and Robert Gertenbach. They attended SAB meetings in their role as CTR officers.) 23. During my 30 years with CTR, I knew all but four of the 43 scientists who have served as SAB members during CTR's history. The names of all 43 and their affiliations are presented on the list of SAB members that is attached as Exhibit 4. I never met Dr. Julius Comroe, and have not met Dr. Carlo M. Croce, Dr. David Sabatini, or Dr. Hugh O' Neil McDevitt, because they did not serve during my tenure at CTR. The SAB was an extremely impressive group of scientists. The scientists on the SAB were prominent leaders in their fields, with a national or international reputation. 9 20343071.02

24. Four SAB members I knew were employees of the National Cancer Institute ("NCI"), which is part of the federal government: Dr. Paul Kotin (an SAB member from 1954 to 1965 who was with NCI beginning in about 1962), Dr. Harry Andervont (an SAB member from 1964 to 1966 and from 1970 to 1974), Dr. Robert Huebner (an SAB member from 1968 to 1981), and Dr. Peter Howley (an SAB member from 1982 to 1986). Thus, for almost 24 years from 1962 to 1986, there was an NCI employee on the SAB. Independence of the SAB 25. The members of the SAB were scientists and persons of great integrity. The SAB members were interested in helping to fund research that would further scientific truth and contribute to scientific progress -- not in advancing the interests of the tobacco companies. There was no uniformity of views about smoking and health on the SAB. The members of the SAB felt strongly about their independence from control by the tobacco companies. Any statement or suggestion that the evaluations and recommendations of the SAB were controlled or influenced by the tobacco companies is simply false. 26. I have reviewed a handwritten note, dated March 28, 1973, that apparently was sent from Dr. Helmut Wakeham of Philip Morris to Dr. Hockett of CTR. A copy of this note is attached as Exhibit 5. That note appears to contain Dr. Wakeham's "rating" of CTR grant applications that were considered by the SAB during 10 20343071.02

an SAB meeting Dr. Wakeham attended on March 14-16, 1973. The minutes of that meeting are attached as Exhibit 3. 27. 1 personally knew Dr. Wakeham and heard him express his views on the "relevance" of CTR research many times during the 1970s. Dr. Wakeham and his colleague at Philip Morris, Dr. Thomas Osdene, repeatedly expressed the opinion that CTR-funded research work was not sufficiently relevant to tobacco, based on their view that research which did not involve experiments using tobacco smoke was not "relevant" to CTR's mission. The CTR staff and SAB disagreed with, and never adopted, the view of Drs. Wakeham and Osdene. Based on my familiarity with Dr. Wakeham and his views about scientific "relevance," I believe that Dr. Wakeham's rating of " 1" meant he considered the research to be most relevant to tobacco Rg_r sg and that his rating of "5" meant he considered the research to be least relevant. I do not believe that he meant to give a grant application a low score based on its potential for research findings connecting smoking with disease causation. 28. At the time of Dr. Wakeham's memorandum, the SAB had already voted on the applications at issue. Therefore his comments could not have affected the SAB's vote. Exhibit 3 records both the SAB's recommendations and the actions taken by Dr. Hockett, who was then the Acting Scientific Director. Although some of the applications that were not funded had received low ratings from Dr. Wakeham, others that were not funded received high or medium ratings from him. Four of the grant 11 20343071.02

proposals that were funded by CTR received a "5" (the lowest rating) from Dr. Wakeham. Thus, it seems clear that Dr. Wakeham's comments had minimal, if any, influence on the actions of Dr. Hockett. In any case, Dr. Hockett's actions were reported to the SAB at the next meeting in October 1973, by which time Dr. Gardner had replaced Dr. Hockett as Scientific Director. The SAB and Dr. Gardner could have reversed Dr. Hockett's decisions at that time if they disagreed with them. 29. Until I was asked about Dr. Wakeham's note in 1995, 1 knew nothing about it, and I am not aware of any similar communications from tobacco company representatives to anyone at CTR. CTR Grant-in-Aid Research 30. Throughout my affiliation with CTR, recipients of CTR grants-in- aid were encouraged to submit their research findings to scientific journals for publications. Each year, CTR prepared an Annual Report listing the publications during the previous year, as well as current and active grantees. These Annual Reports form the basic record of CTR contributions to scientific research. In my 30 years of work for CTR, I am not aware of any instance in which a grantee was prevented from publishing research results or had his or her research suppressed, undermined or interfered with by CTR. 31. During my 30 years with CTR, the nature of the research funded by CTR evolved significantly. Because CTR administered a grant-in-aid program, the 12 2o3a3o71.02

projects that it funded were selected from applications submitted by researchers and therefore tended to reflect the general trends in the scientific community. Thus, as the methods of basic medical research became more sophisticated, so did the projects funded by CTR. I witnessed a general trend in CTR-funded research from whole- animal studies in the 1950s and 1960s, to cellular-level studies in the 1970s and 1980s, to genetic and molecular-level studies in the 1980s and 1990s. 32. CTR's mission, as I understood it, was to advance scientific knowledge about the causation of diseases that may be associated with smoking. As stated in the minutes of the SAB meeting on December 3-4, 1966, CTR funded projects having a "direct or clearly pertinent bearing on the general field of tobacco use and health." A copy of these minutes is attached as Exhibit 6. In my view, virtually all the research funded as part of CTR's grant-in-aid program was highly relevant to that effort. 33. Throughout the 1970s, CTR funded some research through contracts rather than through grants-in-aid. These research contracts were considered and approved by the SAB. CTR entered into research contracts as a supplement to grants- in-aid in cases where it was not feasible to accomplish certain types of research through grants-in-aid. For example, CTR was interested in developing standard experimental techniques, "smoking machines," animals and materials for animal inhalation experiments. A researcher would not be likely to submit a grant application for that 13 2o3a3a71. 02

type of work because it might not be useful to the researcher in the absence of funding for follow-on experiments using the materials or techniques developed. In addition, a grantee would be unlikely to undertake a large-scale, long-term inhalation experiment because of the large capital investment and overhead required. Early consideration by the SAB of contract type research is reflected in the minutes of the SAB meetings of September 23-24, 1967, at page 4, and March 2-4, 1968, at page 4. Copies of these minutes are attached as Exhibits 7 and 8. 34. CTR entered into contracts with commercial research laboratories to get this type of work done. Among the commercial laboratories used for these purposes were Dr. Freddy Homburger's Bio-Research Consultants, Inc., the Mason Research Institute, and Microbiological Associates, Inc. 35. Research contracts differ from research grants-in-aid in several significant ways. A grant-in-aid, in effect, is an award to the researcher, and the grantee is free to follow new research directions as they arise. A grantee's research findings, and the reports of those findings, belong solely to the grantee. By contrast, a contract researcher is legally obligated to follow the research directions set by the funding party in the contract. The research findings and reports of those findings legally "belong" to the funding entity. Accordingly, research contracts typically provide that the researcher can publish only with the consent of the funding entity. CTR's research contracts so provided. 14 20343071.02

-CTR's Relationship to the Tobacco Companies 36. I am aware that some people claim that CTR held itself out as totally independent of the tobacco companies, and I find that claim to be odd. [ believe that the scientific community and the government (and anyone else who knew anything about CTR) were well aware at all times that the CTR consisted of and was owned by its member tobacco companies. Thus, it could never be completely independent from its members, and it-would be impossible for CTR to pretend that it was. 37. The ultimate ownership of CTR by its member companies was open and obvious. From the time I started with CTR in 1964 until 1990, the Chairman of CTR was a former tobacco company executive. From the time I joined CTR until 1969, the Chairman was Timothy Hartnett, formerly of Brown & Williamson. From 1969 to 1975, the Chairman was Henry Ramm, formerly of R. J. Reynolds. From 1975 to 1980, the Chairman was Mr. Yeaman, formerly of Brown & Williamson. From 1981 until 1991, the Chairman was William Hobbs, formerly of R. J. Reynolds. 38. Nonetheless, CTR operated throughout my tenure a grant-in-aid program that was not dominated or controlled by the tobacco industry. This was possible because CTR was set up with an SAB and a Scientific Director who did not come from the tobacco industry and who followed their own scientific prerogatives. Because of the SAB and Scientific Director, CTR charted its own course with regard to grants-in aid and contracts. 15 20343071.02

39 I was aware during my tenure at CTR that some tobacco company personnel (a) criticized CTR for funding research that was not "relevant" to smoking and health, (h) complained that CTR-funded research was not sufficiently helpful to them and in some instances was harmful to them, and (g) proposed changes in CTR that would have given the tobacco companies impact into CTR's research program. I have recently reviewed a number of documents reflecting those criticisms. 40. Some of these criticisms are explained by the fact that most tobacco company scientists are chemists, and in many instances they lacked sufficient familiarity with the biomedical research being funded by CTR to understand its relevance. And it is true that much CTR-funded research, by focusing on fundamental questions of disease causation, was not likely to provide any findings that would be useful to the tobacco companies in the short-term. It is also true that much CTR- funded research could and did lead to findings implicating tobacco in disease causation. I am not surprised that tobacco company employees may have proposed that the companies take control of CTR's grant-in-aid program. I view those proposals as confirmation of CTR's independence. Notwithstanding these industry criticisms, I am not aware of any industry control over the SAB's research program during my 30 years of affiliation with CTR. 41. One issue on which tobacco company executives frequently expressed their views during the 1960s and 1970s was "directed" research. This issue 16 20343071.02

was also debated by the CTR Staff and the SAB. In the 1960s and 1970s, some of CTR's sponsors expressed the view that CTR should have a more "directed" research program. I understood this to mean a more product-oriented research program conducted primarily through contracts. The term "directed" research referred to scientific research that was more narrowly focused on predetermined topics, not to research whose outcome was predetermined. 42. The members of the SAB, Drs. Little and Gardner (the Scientific Directors in the 1960s and 1970s) and other members of CTR's scientific staff expressed varying views about the value of directed research. However, there was at all times a unanimous (or nearly unanimous) point of view among the SAB and the scientific staff that research did not have to directly involve tobacco to be relevant to smoking and health. The CTR staff and the SAB believed that research into the etiology of diseases associated with smoking was necessary in order to discover the nature of tobacco's relationship with those diseases. Such research did not directly involve tobacco products, but it was, and is, absolutely essential to understanding disease causation. I strongly shared that view, and still do today. 43. Furthermore, the prevailing view among members of the SAB (as well as among the scientific staff of CTR) was that CTR should remain principally a granting organization, with contracts used for research where appropriate. A granting organization can fund only research projects for which it receives applications. Thus, 17 20343071.02

the grant-in-aid process, by its very nature, limited to the ability of CTR to "direct" research or even its research program. 44. Nevertheless, until the late 1970s some members of the SAB were interested in trying to provide more focus to CTR's research program. Most of them were interested in funding research focused on the effects of tobacco smoke inhalation on laboratory animals, as part of a research program in which basic research through grants-in-aid predominated. This initiative was referred to as "planned" or "directed" research, as shown in the minutes of the SAB meeting of May 16-18, 1969, at page 5. A copy of these minutes is attached as Exhibit 9. As shown there, such research was to be "planned" or "directed" by the SAB, not by the tobacco industry. As part of this effort, the SAB formed a Planning Committee, whose task was to map out areas of research on which the CTR should focus its funding. This activity is reflected in the minutes of the SAB meeting of September 12-14, 1969, a copy of which is attached as Exhibit 10. 45. As part of the directed research effort CTR entered into a number of contracts, most of which related to the study of smoke inhalation by laboratory animals. These contracts culminated in a mouse inhalation study under contracts with Microbiological Associates, Inc. ("MAI") from the 1970s until about 1981. Ultimately, however, CTR did not alter its basic non-directed research approach. It remained in essence a grant-making organization, which awarded grants to applicants 18 20343071.02

and tried to interest high-quality investigators in submitting grant applications. It has not funded any contract research since the MAI project was concluded. 46. The issue of "directed" research was often discussed by employees of the tobacco industry. Some tobacco company representives expressed concern that such "directed" research, executed through contracts, would somehow compromise the independence of CTR's SAB-directed research program. However, as I have indicated, contracts were firmly within the jurisdiction of the SAB and "directed" research was "directed" by CTR and independent researchers, not the industry. These discussions are reflected in the following documents which I have reviewed and which are attached to this affidavit: (a) notes which appear to reflect a meeting of the Executive Committee of CTR in November 30, 1970, attached as Exhibit 11; (b) a December 6, 1977 letter from Mr. Heimann of American to Mr. Yeaman, then Chairman of CTR, attached as Exhibit 12; (c) Mr. Yeaman's December 9, 1977 response to Mr. Heimann, attached as Exhibit 13. 47. I believe these documents accurately reflect the attitude about CTR that I frequently heard expressed by people in the tobacco industry: that it was vital that CTR's SAB-guided research program be independent of control by the companies. These statements also confirm my distinct recollection that in the late 1960s and the 1970s tobacco industry executives differed among themselves as to what CTR could and should do while maintaining the independence of its research program. 19 20343071.02

48. The text for a speech given by Mr. Yeaman, then CTR's President and Chairman, at the December 10, 1975 meeting of the CTR Board of Directors, accords with my recollection of Mr. Yeaman's attitudes about CTR's relationship with the tobacco industry. A copy of this speech is attached as Exhibit 14. According to page 3 of Exhibit 14, Mr. Yeaman stated: "Give us your policy directions and we'll follow them within the limits of scientific integrity.... But don't look over our scientific shoulder." Based on my numerous conversations with Mr. Yeaman, I believe Mr. Yeaman meant that the CTR sponsor companies were free to propose general guidelines about matters like means of funding research CTR should use (such as contracts vs. grants) or what general subject-matter areas CTR should try to fund research in (such as animal inhalation, cancer, or heart disease), but that the SAB and the Scientific Director must be left alone to make funding decisions and would not do anything that was misguided or lacking in scientific integrity. 49. A memorandum dated October 12, 1967 from Dr. Osdene to Dr. Wakeham (both of Philip Morris) describes a meeting at CTR on September 25, 1967. A copy of that memorandum is attached as Exhibit 15. Although I had not seen this document until recently, I participated in the activities to which I believe Dr. Osdene refers. When Dr. Osdene quoted Dr. Hockett (on page 1) as stating that "CTR is moving into an era of active collaboration with the industry," I believe he was referring to CTR's efforts to collaborate with the Industry Technical Committee to develop 20 20343071.02

standard cigarettes and smoking machines for animal inhalation experiments. As reflected in the SAB meeting minutes from December 3-4, 1966 (at page 5), March 2- 4, 1968 (at page 5), and May 25-26, 1968 (at page 6), animal inhalation experiments required both standard cigarettes and standard smoking machines. As shown in the SAB minutes, CTR was assisted by members of the Industry Technical Committee with both projects. Copies of these minutes are attached as Exhibits 6, 8 and 16. 50. To the best of my knowledge, these efforts were the only "active collaboration" with the industry to which Exhibit 15 could refer. Although members of the ITC expressed opinions, based on their technical expertise, about smoking inhalation experiments to CTR's staff, it was not the role of the ITC to control those experiments. There was certainly no "collaboration" with respect to the selection of the research to be funded in CTR's grant-in-aid program. Exhibit 15 (at pages 3-4) accurately reflects the role of the Industry Technical Committee by quoting Dr. Little as saying that joint efforts by the ITC and CTR staff "in no way should be interpreted that the technical committee is making decisions in the approval or denial of grant application[s] which is the sole responsibility of the SAB." 51. I have also reviewed the following documents: (a) a November 13, 1978 memorandum by Dr. Osdene to the "File" relating to "Recommendations for Long-Term Plans for CTR," a copy of which is attached as Exhibit 17; (12) a document titled "Preliminary Draft" which purports to be the recommendations of industry 21 zos4so71.oz

research scientists about CTR, a copy of which is attached as Exhibit 18; (Q) a memo- randum dated March 7, 1968 from Helmut Wakeham to C.G. Goldsmith, regarding a Hilton Head meeting of industry research directors February 14-16, 1968, a copy of which is attached as Exhibit 19; (~) a letter and attachment dated March 31, 1980 from Bob Seligman at Philip Morris to Alex Spears at Lorillard, a copy of which is attached as Exhibit 20; and (.e,) a Philip Morris memorandum from Dr. Wakeham to Mr. Joe Cullman, III, dated December 8, 1970, titled "Best Program for CTR," attached as Exhibit 21. 1 have never seen any of these documents before. So far as I know, they were not circulated at CTR, and the recommendations set forth in them for changing CTR were not considered by anyone at CTR. To my knowledge, none of these recommendations were implemented. Dr. Hombut:ger 52. CTR provided research funding to Dr. Freddy Homburger and his for-profit company, Bio-Research Consultants, Inc. in Cambridge, Massachusetts, for a number of years. I have personal knowledge of Dr. Homburger's work for CTR because I was CTR's scientific liaison with Dr. Homburger. I visited his laboratory in Cambridge, Massachusetts on several occasions. 53. As shown in a May 15, 1970 CTR document entitled "The Cancer Program," a copy of which is attached as Exhibit 22, CTR funded research by Dr. Homburger as part of its animal inhalation program. In funding those studies, CTR 22 20343071.02

was hoping that Or: Homburger would be able to develop an animal model for lung cancer by exposing Syrian golden hamsters to cigarette smoke. CTR funded this research primarily through contracts. After three years, Dr. Homburger failed to produce a useful animal model because he failed to induce lung cancers in hamsters. 54. As stated in the February 13, 1974 letter to Dr. Homburger from Dr. Gardner, CTR's Scientific Director, a copy of which is attached as Exhibit 23, the SAB's decision not to enter into a further contract with Dr. Homburger was based on his failure to induce lung cancers in hamsters. As indicated in Exhibit 23, in 1973 CTR decided to use mice rather than hamsters in the extensive animal inhalation experiments that it later undertook through contracts with MAI. 55. In 1972, Dr. Homburger reported to CTR that he had induced laryngeal cancers (not lung cancers) in some hamsters by exposing them to cigarette smoke. I recall visiting Dr. Homburger's laboratory with Dr. Sommers. Dr. Sommers, an eminent pathologist who was then the Chairman of the SAB, examined Dr. Homburger's slides, in my presence, but did not agree with Dr. Homburger's interpretation. He did not think the lesions at issue were even pre- cancerous. 56. I am aware that Dr. Homburger has claimed that CTR tried to prevent the publication of his research findings in 1973 and 1974. I was a principal liaison to Dr. Homburger on his contract, and I do not agree with that claim. Dr. 23 20343071.02

Homburger did publish his research findings. Under Dr. Homburger's contract with CTR, his right to publish was conditioned on CTR's approval. As I stated above, CTR did not agree with the conclusions drawn by Dr. Homburger from his research. CTR was concerned that these incorrect conclusions would be ascribed to CTR by the scientific community because, as the contracting party, CTR "owned" the research. Eventually this concern was alleviated by having Dr. Homburger publish his articles with the notation: "Supported by a contract from the Council for Tobacco Research-- U.S.A. The views expressed are those of the authors and do not necessarily reflect the opinion of the Council for Tobacco Research." This notation appeared in Dr. Homburger's publication of his results in the Journal Qf lilt National Cancer Institute, a copy of which is attached as Exhibit 24. MAI Inhalation Study 57. Most of the research contracts entered into by CTR related to the massive study of the effects of smoke inhalation on mice that was conducted by MAI under contracts spanning from the 1970s until 1981, in which more than 10,000 mice were exposed to cigarette smoke. CTR spent approximately $13 million under these contracts (and related contracts). MAI was a commercial research facility that did work for the National Institutes of Health, among others. MAI had been recommended for the mouse inhalation research by Dr. Heubner, an SAB member who was employed by the National Cancer Institute. Although I have knowledge about MAI's contracts 24 20343071.02

from discussions aniong CTR staff and at SAB meetings, my own direct experience with MAI is limited to the period beginning in 1980, when I had a direct liaison role with MAI. 58. MAI's research contracts reflected a concerted, good-faith attempt by the CTR to find an "animal model" for human lung cancer -- i.t., to induce lung cancer in laboratory animals, in order to provide a basis for further study of the causation of human lung cancer. Any suggestion that the MAI inhalation study was planned or structured by CTR in order = to produce lung cancer in the exposed mice is absolutely false. 59. In 1980, MAI's long-term inhalation study had been nearly completed. MAI was seeking additional funding from CTR to repeat its inhalation tests. I attended meetings with SAB members where this proposal was discussed. From those meetings, I believe there was a consensus among the SAB members and CTR scientific staff (including myself) that the proposal, which essentially was to replicate what had already been done, was not worth the substantial funds that would be required. Also by that time the SAB had resolved to conduct research through grants rather than contracts wherever possible, because the SAB concluded from its experiences in the 1970s that grant work was more efficient and generally more productive. 25 2osa3o71.02

60. At the SAB Executive Committee meeting on June 20, 1980, two MAI researchers, Dr. Kouri and Dr. Henry, personally presented their proposal for additional funding. The SAB Executive Committee unanimously decided at that meeting to let the final MAI contract expire at year-end and to phase out MAI's contract research in 1981 (plus whatever time might be required for "writing up and publishing the results of the study"). A copy of the minutes of that meeting is attached as Exhibit 25. The full SAB approved that decision at its meeting on October 8-10, 1980, which I attended. A copy of the minutes of that meeting is attached as Exhibit 26. I believe that the SAB's decision in 1980 with respect to MAI was prudent and appropriate and that decision was made by the SAB in the exercise of its scientific judgment. 61. To the best of my knowledge, no one prevented MAI from reporting the results of any of the research that it conducted under contracts with CTR. No one from MAI ever complained to me about not having freedom to publish research findings. Indeed, CTR had to prod MAI repeatedly to get it to prepare and submit its final report. As shown in a CTR memorandum of October 31, 1983 and a letter from MAI to CTR dated November 16, 1983, MAI did not promptly complete its final report on the inhalation research and prepare a manuscript for publication, despite CTR's requests that it do so. Copies of these letters are attached as Exhibits 27 and 28. 26 20343071.02

62. Because CTR had invested so much time and so much money in the MAI contracts and had made the scientific community aware of this ongoing research, the SAB decided that CTR itself should arrange for publication of MAI's final report. In 1984, CTR published that final report in book form, intending to reproduce the report exactly as it had been received from MAI. (CTR did not even attempt to make typographical or grammatical corrections. ) 63. In addition, the MAI researchers published numerous articles in scientific journals. The MAI researchers stated in an August 12, 1981 letter to CTR that they had published 45 articles based on MAI's contracts with CTR. A copy of this letter is attached as Exhibit 29. MAI's final report lists 63 book chapters, abstracts and manuscripts from this research. After the publication of the final MAI report in 1984, Dr. Henry and Dr. Kouri published an article in the July 1986 Journal of the National Cancer Institute discussing their findings from their CTR contract research. A copy of that article is attached as Exhibit 30. CNS Research 64. During my tenure, CTR funded research into the effects of nicotine, including its effects on the central nervous system ("CNS"). In 1977, CTR had awarded grants-in-aid to several top-notch investigators in that field and was looking forward to funding additional research. On November 22, 1977, an informational meeting was held in which Dr. Donald Ford of CTR gave a presentation on plans for 27 20843071.02

CTR-funded CNS cesearch, and there was a presentation by a prominent CNS researcher, Dr. Leo Abood (who later joined the SAB). A copy of Dr. Ford's presentation paper is attached as Exhibit 31. This meeting was attended by CTR staff (including myself), industry researchers and lawyers for CTR and member companies. l ] THE BRACKETED PORTION OF THIS PARAGRAPH IS BEING SUBMITTED EX PARTE AND HAS BEEN REDACTED FROM THE VERSION OF THIS AFFIDAVIT SERVED ON PLAINTIFFS, ON GROUNDS OF ATTORNEY-CLIENT PRIVILEGE. 65. Mr. Jacob attended the SAB's regular meeting in April 1978. That was the only time CTR's lawyer attended an SAB meeting during my 30-year tenure. REDa CTED ED ~~ i ~~ ~ 28 R r.~, - ~-:- n c~tu 20343071.02

~'~.~; RED~~ 1 During the April 1978 SAB meeting, I was concerned that some SAB members might resign over this issue. However, the SAB remained in place and continued to function as before. THE BRACKETED PORTION OF THIS PARAGRAPH IS BEING SUBMITTED EX PARTE AND HAS BEEN REDACTED FROM THE VERSION OF THIS AFFIDAVIT SERVED ON PLAINTIFFS, ON GROUNDS OF ATTORNEY-CLIENT PRIVILEGE. 66. As to CNS research, CTR continued to fund excellent research in this area, even during. the period when applications were subject to attorney review, and was continuing to do so (without attorney review) when I retired from CTR in 1994. Conclusion 67. 1 am proud to have been associated with CTR. Throughout my 30- year association with it, CTR and the SAB were dedicated to furthering science and contributed significantly to the advance of scientific knowledge about the diseases associated with smoking. I did not ever seek, and to the best of my knowledge no one else at CTR ever sought, to mislead or deceive anyone. Any statements that CTR was merely a "front" are mistaken. The charge that CTR acted fraudulently or with 29 2osa3o71. 02

improper motives is completely false, and unfairly impugns the personal and scientific integrity of the many fine people who served on the SAB and on the staff of CTR over the years. VINCENT F. LISANTI Sworn to before me this ,~~day of February, 1997 Notary Public LORRAINE M. CALI Notary Public, State of New York No. 30-5062045 Qualified In Nassau County Certificate Filed in New York County Commission Expires April 30. 199-L 30 2o3a3071.02

... . . . .. ....... . . ... ..,,..._.. . .,.. ..._.. r ... . . .. .+~..,ywe~., . '.. , -....•v ..~.,..-~._...w...y„~ati ~ . . , .. _ ...,.........

,~)cv.6 .(1-0 ~ .~.1. .~..~.:...~ _ . VJ.L'\1~...LJ.. `/0 Dr. Vin cent .. Lis^:ai, Scientific Associate of l:e Co'r.:cii fcr ;~ocaccc 633 ~far~1 AVen ae, Yor.{, i\ew York 10017, was Cc:"n in Roches ter, ,';ew York, o n 3u:.e 23, 1518. the :i nive.s~~y of Roc::este=, Dr. Li°.ni ti reeeiVe~c a_"ofe55=:..::l Ger "ee in De n-.__ .....--Ci ne :ro' 11fts Uni.ver 53ty i n iCJ*2. -::e per_o4 :ro.:. 1942-i94o, he served ir. the tinited States A,ry Chtai=- ~ z: e rank of Car tain. ~O_~O'»_ :, his wF."t.L c Se: V_Cc, . . Li52: ~= Sc_ VeG in a i:,::— c= of tCG =" a nG r esearc.^. yo5itio.^.5 -L -,he ~ `e1Gs of oral :: ec.iCi ne a:,ii Grc_ cav~ -.y re5e: :,._:. _ . Cm 1951" z C 1G_~SC he was : .: As5ociat e . _ ..=e: Sor of . : ;-v a_ ::cSe:.rc : CC::c=ren:. ', :e £c'"'veG as a E.._ r.: C= J- thc o= : -_.,.~Cloo=...:._ =.::sC;:..... -.. -n teres-~ -.. oral cc'? ncer, ~~ . L1sG.^.ti 's areas of s ieCia_ reseG_ cP. have -::c_tIGeG s;1cA s;:;ject5 as hiStoCae.:.istry of o.c_ tiSs::e.5, e.^.Cj -_es anG c-i_.ical ~n ~~oa~1GnS of V21 iOLiS G15e25eS. Dr. Lisant_ .~-s h' isi-.ec accounts of his research extensively in jo•r: s.i.s s;:C: as: r^2 :?"C.^.ives of Oral .^,io1o--,,"Y, The Annals of the 'i.ew Yori: AC:.Ce:..,J of Sciences, Scie::ce, The Jc•=:a1 of ;acterioloeyr, ?roceedir.os of the Society of Si -_e=i=e nta; Biology a nc Yeiicir.e a na Lancet. _.e has also served as a research cons;:lta .t to the Office o; :.ava1 'eSea: C: , ;;~r P'rs.~`:aceutical Cor.pa ny, United States Air Force, Aero-.:'ecical Ce nte:, Veterars ' A4r.lnistration BnCd to a nLL:.Ger of other p:'.::."r..ace::tiCc~ and Dr. ?isa:.ti is a neWoer cr the foliowin~ :ro'essionzl societies: Fe=1o,: of A: _can :zssJc-Gzlo n for the Advar.ceme n-. of .ScienCe, Inter'.a-~G:1LL ASSOC_at~G : f Or L-.-al Coec~ Ch ,Si"r. 1{i, L...icron !\.°.J: a Ucs_lon, :;ew York eacaGC:y;` of Sciences, P_ e„i=Gr. Dental Association, : istocher.ical Society, 3osto:l C1~ ,_= e--. :._. ~_=ty c° Ce'_l __olo_-Zr, ~~ erica_^. Society o° . icro: io_o ,ists, :aso3C :',aet-_S .....-~c Le'alth Association a n... : o:._ey..y fGr ~.'ryobioloaj l~ J:~

-1-1-1--l -111--,.

QtT00051i0 CI~i~JIiJM 4ITAE OF DR. CIA8= COOS I= Dr. C3areaoe Cook Little, Scientific Director of Me Conacil for TobaOao Serearah - iJ.S.A., 633 MLIft Aveau., Dler York, 31er York, 10017, aad Ditrato,r Bo:ritns, Ro.oos B.' Jaeks= Idesooriat L.botstor?, Bar Narbar, Yhiae, was boza in Broouiae, Nsseaclmsetts, on October 6, 1888. A 6saduate of 84r.ard University, trhere be .araed A.B., B.St., sad D.Bc. de6eees, Dr. Little hnLde hoaorarF degrees lroa the UaiversitY ot ]Lr Brpahite, Albian Co3lege, tbe Uaiversity or Nev Nkodeo, Calt? Ca11.ge, the University ot llaioe, the University of Cbie,.p, Boetoa Uaiversi.Ly, Diatiaeon College eud lyasietta College. IIe Yas President of the University of Mdiae (1922-25) =d of the Uainrsityr of Jaehipan (1925-z 9). Be is tosaer Presidaot of tbe American Associatian for Cancer Bes.areh. Iatesaatioeally baotin ia the !ield of cancer ia.rstigatioa, Dr. Little vas a Aeseareb Fellor ia Gmetiu at Barvard, 1913-17; a Research AWOCiat. ia CoomparatiTe Pat6dagyr, Nar..ard Nsdiaal scboot, 1917-38i a Be.easoh Associate at Harvard Medical So6oo1, 1919-21, and Assistant Direotor of the Station Sor SYpertamtal Btrolutiffi, CarnW e Iartitntion of ia.bioatao, 1931-=. Bir c.raer iaeLtdes service as an Officer in the AnW ia fiorld ilar I; limaglag Director of the American Society tor Comtrol of Caoaer, 19Z9-45 (mr the American Cancer Society); mrober of the &ogenies Cammittse of the United St..t..e since 198Z; Director of the Iltrricsa Birth Control ?aWe sinee 190, President, 1g3ti-38; sneber ot ffi. Elaoatiiye Camdttes of the first ibrLd ftpulation Coot:.r.ce, Gm.va, 1M; President of the Aeee Hettezueati Comsress, 190-89; $earetarY Qeoaal aad CW.isesn of the Ca®oil of the Sixth Iatsnatioaal Congress os Gesetias, Ithaca, 1932; a.b.aot the Satioae.l Aeivisoa7 canno1 i. 1937-39i and President (1931-33 ) at the Nouot Desert IsLad Blo3ogieaL baborstosy. A FeliAr of the Ratioaal Ac.desr of 8cieaees, th. A.ariOaan Aademy of Arts esd Soieacee, the H.M York Acad.qr of itadicia., the 8ollwwood AcadeAr of Itesieia., the Arriaeo Association for the Ad.aao.eat of Science, and the Aati+aoal Institata ot 8oeial Science, he holds m.bmw.hip in the American 8oeietUr of Qatoralists, the American 9ociets of toologista, the Society ot BverSssOEal BScLoay and k.diMne, the Eosenie Aeeeasch Assoriatioo, the American Publie Sealth Association, the Ibpolation AssoOiat.ion of A.erica, tfu American Begeaica 8ocietr, the A.Qiean Assoeiation of Aaatomists, the American Society of Minmelogists, and the American Social Wgien. Apociatiao. - Dr. Little is the antbor of maerons books ead articles ca Q.m.tics, cancer research, and eddeati0nal aod social problev.. 5/26/62

rcer Research VOLUnnE 37 • NO.6 CNREA8 • PP 1099•135 June 197: 0

Qaemec Cook Liitfo tSU-i97t i35s CAACER RE

(GNCER RESLaRCR 32.1]l4-1336. Juae t97tl OBITUARY Clarence Cook Little Clarence Cook Little died of a heart attack Dtcemcer _3. 1971. in Ellsworth. Maitu. His wife of 41 years. Beatrice Johnson. twu diugttters. two sons. and niae grandchildren survive him. They and many friends throughout the +orld. whose lives have been profotmdly touched by his life. moutn the Ioss of this greu humaniarian. Dr. Little wu bom in Brookline. Massachusetts. October 6, 1853, the son of James Lovell and Mary Robbins Revere Little. a direct descendant of -ihe American patriot, Paul Revere. Dr. I4ttle's boyhood home was on a large estate. •~~here his family had many animals which ied to his interest in purebred livestock and pets. Later in his research he established the principle of using =eneually uniforrn animals in laboratory expenments. At the present time. Jackson Laboratory animals go to almost every country in the wurid-desired because of thtnr ksiown. controlled e_axtic makeup. Dr. Little was educated at Harvard Uttiretaty. receiving his A.B. in 1910, MS. in 1912, and D.Sc. la 1914 in todop, with special intaeat in the tu+r tciettee of 6etatia. For seeeral yeata he had ruiotn positions at Harvard Uttirersity- seeteary to President Lowl1, assisant dean of the colle fe, aetlnS ttqtshall, and partAime researcher at the Harvard Medical School. With the entrance of the United States into war in 1917. Dr. Little enlisted in the U.S. Army; trained at Plattsbunsh, N. Y.; and was subsequently assisned to the Signal Corps in Washington for administntive duty in what laur became the US. Air force. He was discharsed with the rank of Major at the end of the war in late 1918. During his tuilitary service. Dr. l.tede made sure that his beeedin6 stoclcs of tttioe were sustained in the laboratory at Harvard Medical School . in 1919, Dr. Little accepted a position as research associate .nd ssistant direetor of the Statton for Eupetttnenta! Evolution. Carnegie Institution. Cold Spring Harbor, Y. Y. Aftcr serving in this position for 3 years he became Peaideat of the University of Mains at Orono. After 3 years in Malae. ' he went on to Ann Arbor to become President of the ~ University of }!lchigan. At age 36 he was the youngest man cvcr to hold that position. In 1929. Dr. Little decided that his real interest was Grtaly • rooted in tnarnmalian ;eesetics and cancer. He had hoped to find the cause of anoer.llvids the financial baetmts of saeral prominent cititens of Dettoit he wenc back to btaine attd. at Bar Harbor on his beloved Mt. Desert lsland and on the very land where he and his students froat Maine had had a summer school and studied the migration of carrtoa beetles and other ~ ccuiogical phencrttens. he built the Roscoe B. Jackson Memorial Laboratory. Mr. Roscoe B. Jackson. President of the ~ Hudson Motor Corapany, Mr. and Mrs. Edsel Ford. and the • Meurs. Oscar and Richard Webber were the sponsors. [: nfortunately, before the labontary W as finished. Nr. Jackson died of a heart attack while vacationing abro3d. There was no endowment and the United States u•as having a Zepression, which meant that Dr. Little practically had to beeorne a mendicant friar begging for :anetnued support of his "Advennue in Faith " u he called it. The projea burgeoned and today not only is the laboratory widely known for its scientific program. but the inbred mice are tttudt in demand. millions being soid each ycar to help support the continuing research invenigatiotu. It •ras aiso in 1929 that Dr. Little atreed to sm haif=t(nte with the American Cancer Society as its Mutaft Dlreetor. a pasition he held unt11 1945. He ittsatnted a program throughout the United States of visitinE doetoa,vhoss mission was to tadt local physidaas better taetltods of ezaatinin= patients in search of early cancer. He obtaloed the capable cooperation of the Federatioa of woeaen's C]tsOs in launching the Wottssti s Field Army Against Cancer. Dr. Little's belief was that women thasnselves were in the best posftbn to detect eaeiy signs of unusual growths or differetsoes in their own physiological behavior. fltus. an intetw eduadomi caatpaipt we= undertakert. Its suoossa was pitenotasresl. Dr. Ltde eoatinned throttglt the ysats aa Olseepor of the Jaeiaon Laboratorry.nirh mnty other collatet~l at~tasats. la 1954 he beame Sd.ntifle Director of tlte Tabeeso Itttluttey Research Cot>=sdotx 2 yar: later he rttdnd m Dicector Esteritus of the Jaeksoa Laboratory and he aod Mts. Little mored jttst off the Wand to establish their htune. F.tate Ha.en. oeeeloofdns Gooae Cov.: an inlet of Freswhore's Bay. Bot tbe life of this man extended far beyond this bio6eaphieat eoee. He had active membership in the National Academy of Scienu, the Ataeripn Aadaay of Arts and Letteam aad many othet scisatiGc orpoasations and prominent social elubs. He was awarded haaaeary doctorates frCdt AIIN colleefa and uAlRrs>tifi. T!n wateriaa Assodulon for Caaur Retlarch oo es tntatt to or. Litde. He sawd as President of the Aatooiatiort in 1931 uand again in 1940, when he steered the teiosebees through the ianwl meeting at Pittsburgh to reorpnise tbe Assodation and establish CANCER RESEARCH as its oftidal orgm. Alcbou;h ths awdoas *nt+e stormy, at the end he fek great personal satlsfaetioa that the Asaoeiation was ttor orpnized ss c.hr members wanted it. Dr. Little waa an impressive tnm He was 1111. sqttare.shouldered, and athletie, with a closely elipped black trtastache and hyh forehead. He lived fife to the fuilest. leadiaf others along .rith him. Dr. W. E. Castle has rala:eJ thu. wheu he wat teaching pstetia at Hanat+d sotnesune before 1910, this tall eaptaitt of tM tradt telds omte over and sigaed up for his 6atetles coune. Aher a fe+r sesdons thc whole track teaet had si6ued up. Only in a personal way can one write abottt thi= man. In the university he vas a very popular president •ith the students. who called him •'hesty,' a name by w" he Ms affectionately known by all members of his seientuu stati as weU, although his eady 8ostottian and Harvard friends calleJ him "Pete." He nerer falted to inspire the young scientist. Oae going into Dr. Littte's room to disaus a research prucrim would come out feeling that he was doing sortuthine verv important and that he must get on with it. Later. 4hec th.e work would be presented at a meetin;, the tmster was alyr 1 JUvE 1972 ' I,;ss

Obituary there to offer a few worus in C1sc:aslon at r.ide even ehe rnedtocre papcr somethtna st`tuncsn:. rhere -ss a mutual :ffectton t:ctween ntm and his swf f taat :=:t:d be iclt best at rhe re¢ular i;.buratory parties that eyevor.e fircm d;:aer to dtrector. tn=iudin[ spouses and c:sisren. un tnose cold wmtcr :ventttgs Wuh :ouai interest ar.d .°cci:ag of stmii,catee. In iuauner this couid be a picnic inciudin; a tobstcr icast. aames. vr a foocrzce. Fie iiways wun even at an age when rnast Iu~e quit such phystcai antics. In ;tving the .cnnual report to the Board of Truscces he ::uid never ~r.ention his staff without choktng up with tears in his cyes and pausing z moment before aotng on. His vtable mterest in itudenu conttnued. and sctentitie • careen Were born in ntany higtt•schoul neophytea broue,ht into hu laboratory in a unique .urnrrnr program to work sida by ssde with the scientist. Dr. Litzle •+as a mn of great faith-futh in his Creator and faith in his leilowman. Oniy his closest friends were aware of the depth of his spirituality. He ».s an Eptscopaiian and on numerous Sundays he spotce from the puipus ot this Church. The Jackson Laboratory was buslt on his faith in his felio-nun. and this same faith carried the laboratory through the depression of the 1930's when the staff planted gardens to gtow their food and fished from the sea. His faith also brought the Iaboatory through the terttbie forest fire of 1947. Standing on the chuted ruias with the suuounditts tnes burned away. he said prophetscally, "Vow We can see the sea:' in a short time the horizons of the Jackson Laboratory had extended around the worid with a weflsqutpped new budding and a s:ieneitic program reaching far beyond the ortynol one. of tenctics of cut:er to include immunology, biochemistry. ccll culture. nroiogy, and behavior. Dr. Little ioved the outdoors. He said it entlched one's life when he heard the song of a bird through the woods to know what b:rd was stnyttt and to be able to visualize it. He knew where the fish were bitina. aad on the hunting team he always csme uut with the most points even though he had the kast titne to get out. Dr. Little lived far ahead of his time and thus at penods was controversiai. but even those who disaareed with htm admired his :omttutment to whst he saw as truch. pae of the faaoa in his leavtn4 the Universtty of Michigan in 1929 was that he advocated birth control. something that tn those days erert his faculty could not accept. But out ahead is where duat•eria :re n,ade. By 1920 he was already eonstdertns that X•nys could probably cause genetic cvnge. and he and his collaborators soon were publishing about heritable abnor- nuiities among descendents of their X-rayed mice. Mullcr's york wich Drosop/u7e, which eventually won for hirn the Vobel Prize in this area. came a number of years later. As chuact:ristic of Dr. Little's ever•proban; mntd• one day in 1938. %tiiti, a patr of forceps, he dtoped newborn mice into a solution of bcnzpyrene, because he fett t!tat these aninuls would be more susespttbie to the tcductton of cancer since their :mmune mechanisms would zct be zs highly developed as chose in older r.t:ce. More t'tan 20 yeus later the newbont uumal became the sensitive test 3rarnai of choice for musy potential carcinogens. including nrsses. Cancer ressuch owes much to his dedication artd untuirtf Xort for the tinanetai support of biomedical researels. He acccpted t::e presidency at the C'nivcrsity of Michigan only ifter he was asst{red that :3 reseuch progrun also M•••uld be pven .dcquace financial support. He approached the Amencan public by organutng the Women's Fisid Acnty, who rang doorbeiis to collect dollars for the support of catscer research: this Later developed into the grant program of the Aatencan Cancer Society. He then visualized the FederalGoretntitent as a ootencial source of extensive support for medial resesrch and ame to Washington to help wnte the Natiotui Cancer Instttute Act and to defend it before the Congressional heannss. He was arguing for the establishment of the National Cancer Institute with the unheard.of budget ot one million dollus a year to support not only intrnttual research but also a gtant pro;ram, and he did this in the face of certain proauuent men in cancer who thought thst the Federal Government had no business in medicsi research. (.atu he viewed prirate lndttuty as the last pounmi saters of almost uniintited funds to be tapped for medical tarardt and. a!tltough he ttny hsre told relatirely few p.ople, ft was the primary ttwtiratfni foree for his becoming assoeiaced with :he tobaceo industry. The published record of his contributions to science and ltzanwnd consists of approximately 200 arneies and books. in line with his t3rm foundation in ban sdeace is the ubserfuiun tbat his firstpa per pubtished in 1909 wa oa "The Peeuliar lnheritawa of Pink Eyes among Colored Kioe" sad the laa published 60 years iater was on "Reproduett.+e Exfectt.eness in Cros:es between Fsre Inbred Strains of Mice." Sem Pasp of the antazint breadth of the man is obtained itnttt a scanning of the atles in bet•reea. A paper on coat coior in ttriee is followed by one on facsors iatltuncitt; human sex ratio. The nest is on usheritana of coat color in Great Dmes. aad the next on inheritana in daws and tanaries. Later thete is one on how to educate worttea to reeoptize breast turaors, oae on white rus and deafnes:. and one on uterine catuer in Jm and Gentiles. Outstanding is his book. Rs*sanar Apow Ceneer. He led in lalrini the fottttdasion fot the science of ti:sw enttnpianation. He and his snff discovered the fint vieat to be readily accepted as a caaeer virt#s, but his Futac saeatifcc contnbution was the inbred strains of mice aod& iadireetly, of rats. This detison ehu genetiea}lY controlled setairts would be needed to answer questions in diseae. and partlatluiy c2nar. ante while he was stdl an underjraduate. He started to inbreed sttain DBA in 1909. Added to the printed word were the msnr itetures he gave. tt mtght be a college presidential inaugural address or a stuatP speech on tlte to.rn green. planned or estrsntpotatteous. but tt was al•rays delivered bewtifullY and with a{test command of the English !an=nage. Of ewn peater vAuewee+e the intitrtau con•ersatioen in whfehL with words of adriee at+d enc,ouraW ment. he gave so much to so many. Who can assess the contributions of this gisnt ideaiist? Who .an measure the breadth of a life that has inQuenced so auny other lives? Clarettce Cook Little was the greatest aun I ever knew. Walter E. Heston ,YSeaQrml Carree• lnrritt+te Ntdond Irrstintres of Xealri. Bediesds. MoY(mrd 2 001 -6 1356 CAYCER RESEARCIi VOL 3;

william U(llman) Gardner Born-Kinbrae, Minnesota (U.S.A.) Nov. 11, 1907 Parents James A. Gardner & Josephine L'llman Gardner Wife Katherine Homsley, July 15, 1934 Degrees. South Dakota State College. 3.S. 1930 University of Missouri MA 1931 University of Missouri Ph.D. 1933 Yale University (honorary) `1A 1943 South Dakota State College (honorary) D.Sc. 1960 University of Perugia (honorary) Dr. of Medicine & Surgery (Italy) - Academic Appointments National Research Council Fellow (Dept. Anatomy, Yale University) 1933-35 Research Assistant (instructor) " " 1935-37 Research Assistant (ass. professor) " " 1937-38 Research Associate (assoc. professor) I , 1938-1941 11 1 1 Associate Professor 1941-43 Professor and Chm. Dept. Anat. I I I I 1943-67 7. K. Hunt Professor of Anatomy I I I I 1958- Advisorv Functions and Committees Sec. and Treas. -Am. Assoc. Cancer Research 1942-45 ?resident " " " " 1946-47 Vice president, =nternationai Union .gainst Cancer (::ICC) 1949-50 C:ai-can, Com.mittee on Fellowships (UICC) 1960-66 Chairman, Committee on Fellowships & Personnel Eschange (UiCC) 1966-70 President-elect (UICC) 1968-70

President UICC 1970-7= President Am. Association Anatomists. 1972--.' Member, Committee on Fellowship, National Research Counsel (:vRC) 1945-1z1 " " on Naval Medical Research (NRC) 1962-1966 Member Board Scientific Advisors Jane Coffin Childs Memorial Fund 1953- Scientific Advisor Anna Fuller Fund 1953 Chairman. Teaching Institute, Anatomy and Anthropology, Assoc. American Med. Colleges 1954-36 Member. National Advisorv Cancer Counsel. USPHS 1948-5-,* " Board of Scientific Counselors Nat. Cancer Inst. 1962-6+ " Board of Governors, Zleanor Roosevelt Cancer Foundation 1962-66 Member. Committee, Sci. Personnel for Research. American Cancer Society 1962-68 Member. Committee on Anatomy, National Board of Medical E:caminer (1958-62) Associate Editor Cancer Research, 1931-1959 Anatomical Record 1940-1968 Excerota Medica - Cancer 1946 Anatomy Anthropology & Histology 1946- Membershios American Association of :A,zatomists. Am. %ssociation for Cancer Research. Society of Experimental Biology and Medicine. The Endocrine Society. Society for :he Study of Deve.iooment and Growth. New York Academv of Science.

Bibliography W. U. Gardner 1. Turner, C. W., and Gardner, W. U. 1931. The relation of the anterior pituitary hormones to the development and secretion of the mammary gland. Mo. Agr. Exper. Sta. Res. Bull., 158. 2. Turner, C. W., Frank, A. H., Gardner, W. U., Schultz, A. B., and Gomez, E. T. 1932. The effect of theelin and theelol on the growth of the mammary gland. Anat. Rec., 53: 227-234. 3. Turner, C. W., Gardner, W. U., and Schultz, A. B. 1932. The relation of the anterior pituitary to lactation. Report of Amer. Soc. of Animal Production, Jan. 4. Gardner, W. U., and Turner, C. W. 1933. Functional development of the mammary gland. Abst. 26th Annual Meeting of Amer. Dairy Soc. Acco., Urbana, June. 5. Gardner, W. U., and Turner, C. W. 1933. The function, assay and prepara- tion of galactin, a lactation stimulating hormone of the anterior pituitary and an investigation of the factors respon- sible for the control of normal lactation. Mo. Agr. Exaer. Station, Res. Bull., 196. 6. Allen, E., Gardner, W. U., and Diddle, A. W. 1934. Experiments with theelin and galactin in monkeys. Anat. Rec., 58: =+5. 7. Gardner, :.. U., Diddle, A. W., Allen, E., and Strong, L. C. 1934. The effect of theelin on the mammary rudiments of male mice differing in susceptibility to tumor development. Anat. Rec., 00: '57-475. S. `ardner, ::. i:., ..llen, r., Strong, L. C., and Diddle, A. W. 1934. .Theelin induced growth in mammary rudiments of male mice from normal and imbred cancer strains. Proc. Amer. Assoc. Anat., Anat. Rec., 58: 65 (Abst.). - 9. :.ilen, 5.., Gardner, W. U., and Diddle, A. W. 1935. Experiments with theelin and galactin on growth and function of the mammary ;iands of the monkey. -Endocrinology, 19: 305-313. 10. (Sardner, '.:. L'., and Hill, R. T. 1935. ?ersistance of pituitary grafts in the testis of the mouse. Proc. Soc. Exper. Biol. and Med., 32: 1382-i384. 5ardner, Y,. U., Gomez, ... T., and Turner, C. W. 1935. =urtaer scudies = the effects of the estrogenic and galactonoietia zcrmones upon the mammary glands of the rabbit. Am. J. ?hvsici., _12: 673-683.

-1) - 12. Gardner, W. U., and Strong, L. C. 1935. The normal development of the mammary gland of virgin female mice of ten strains varying in susceptibility to spontaneous neoplasms. 1m. J. Cancer, 25: 282-290. 13. Allen, E., Diddle, A. W., Strong, L. C., Burford, T. H., and Gardner, W. U. 1935. The oestrous cycles of mice during growth of spontane- ous mammary tumors and the effects of ovarian follicular and anterior pituitary hormones. Am. J. Cancer, 25: 291-300. 14. Gardner, W. U. 1935. The effect of ovarian hormones and ovarian grafts upon the mammary glands of male mice. Endocrinology, 29: 656-667. 15. Gardner, W. U. 1935. Pelvic changes occurring in male mice receiving large amounts of folliculin benzoate. Proc. Soc. Zxper. Biol. and Med., 33: 104-105. 16. Gardner, W. U., Smith, G. H., and Strong, L. C. 1935. The stimulation of abnormal mammary growth by large amounts of estrogenic hormone. Proc. Soc. Exner. Biol. and Med., 33: 148-150. 17. Gardner, W. U. 1935. The effect of estrogenic hormones-on the pelvis of the mouse. Anat. Rec., 64: 54. (Abst.). 18. Gardner, W. U., Smith, G. H., Allen, E., and Strong, L. C. 1936. Cancer of the mammary glands in male mice receiving estrogenic hormone. Arch. Path., 21: 265-272. 19. Gardner, W. U., Strong, L. C., and Smith, G. M. 1936. An observation of primary tumors of the pituitary, ovaries and mammary glands in one mouse. Am. J. Cancer, 26: 341-346. .,, Gardner, ... U., Smith, G. ".., Strong, ... C., and :_len, -. 1936. DDevelop- ment of sarcoma in male mice receiving estrogenic hormones. Arch. Path., 21: 504-508. Hill, R. T., and Gardner, W. U. 1936. Function of p_;.uitary grafts. Proc. Soc. Exper. Biol. and Med., 3~: 78-79. Gardner, „. U., Allen, E., and Strong, L. C. 1936. Atypical uterine and •:aQinal changes in mice receiving large amounts of estrogenic hormone. Anat. Rec., 64: 17 (Abst.). 23. 3i11, R. _., and Gardner, W. 1936. The maintenance c_' accessory organs b?- ovarian grafts in castrate male mice. -~nat. Rec., 64: 21. (Abst. Gardner, ~;. U. 1936. SSexual dimorphism of the pelvis of the mouse, the effect = estrogenic hormones upon the pelvis and upon tze development of scrotal narnias. Am. J. Anat., 39: 459-483.

-3- '3. Strong, L. C., Smith, G. `i. , and Gardner, W. U. 1936. Apparition anormale d'un eoitheiioma de 1' anus chez une souris du race pure (souche :). Bull. a. Cancer (France) ?3: 1-9. 26. Gardner, W. U., and I?ill, R. T. 1936. Effect of progestin upon the mammary glands of the mouse. Proc. Soc. Exper. Biol. and Med., 34: 718-720. 27. Gardner, w. U., Smith, G. M., Strong, L. C., and Allen, E. 1936. Experimental production of malignant growths in mice by estrogenic chemicals. J.A.`I.A., 107: 656-657. 28. :.llen, E., Diddle, A. W., Burford, T. H., and Gardner, W. U. 1936. Ovarian normone threshold for experimental menstruation in monkeys. Am. J. ?hysiol., 117: 381-392. 29. Gardner, W. U. 1936. Interstitial cell hypertrophv in the testes of mice receiving estrogenic hormones. Anat. Rec., 67: 49 (Abst.). 30. Allen, E., Smith, G. a., and Gardner, W. U. 1936. Accentuation of the growth effect of theelin on genital tissues by arrest of mitosis with colchicine. Anat. Rec., 67: 49 (Abst.). 31. Allen, Smith, G. :•I., and Gardner, W. U. 1937. Accentuation of the zrowth effect of theelin on genital tissues by arrest of nitosis with colchicine. Amer. J. Anat., 61: 321-341. 3Z. Strong, :.. C., Gardner, W. U., and Hill, R. T. 1937. ?roduction of estrogenic hormone by a transplantable ovarian carcinoma Endocrinology, 21: 268-272. 33. S., Smit:, G. and Gardner, a. i;. _937. A short test for ovarian follicuiar hormone and other estrogens. 7-ndocirn- oiogy, 21: =.1?-y13. 34. 3ardner, ::. U. 1937. =zfluence of estrogenic hormones on abnormal _zrowtzs. "Some fundamental aspects of c-::e cancer oroblem." Jcc. = uDl. e~SII. Assoc. Adv. Scl. , 4: 67-75. 35. 3omez, E. T., Turner, C. W., Gardner, W. U., and Hill, R. T. 1937. Oestroeenic treatment of 'r.ypophvsecter.:ized male mice. Proc. Soc. Etiner. Bioi. and :3ed., 36: 287-290. 36. ~;ardner, :Y. U. 193i. Hypertropny of interstitial cells in the testes cf -ice receiving estrogenic horWones. Anat. Rec., 68: 339-347. 37. .._len. `.. , Smit n, G. ... , and Gardner, K. y. 1937. ~ccent'1atio.^. ..= t1e E_rowtl effect of theelin on 2enital tissues of the ovariec- :omixed mouse Dt• arrest oL .^:Sitosi5 witn colcaiciae. :m. Anat., 61: 321-341.

-y- 38. Gardner, W. U., and Allen, E. 1937. Some effects of estrogens on :he uterus of the mouse. Endocrinology, -^1: 721-730. 39. Weinstein, L., Gardner, W. U., and Allen, E. 1937. Bacteriology of the uterus with special reference .to estrogenic hormones the problem of pycmetra. Proc. Soc. Exper. Biol. and and Med., 37: 391-393. 40. Hamilton, .:. B., and Gardner, W. U. 1937. Effects in female v_ oung of pregnant rats injected with androgen. Proc. Soc. born Exper. Biol. and Med., 37: 570-572. 41. Allen, E., Smith, G. M., and Gardner, W. U. 1937. Growth of tae ovaries and genital tract in response to normones as studied bv_ the colchicine technique. Anat. Rec., 67: 223 (Abst.). 42. Gardner, W. L'., and Pfeiffer, C. A. 1938. Skeletal changes in mice receiving estrogens. Proc. Soc. E.Yper. Biol. and Med., 37: 678-679. 43. Gardner, W. U., and van Wagenen, G. 1938. Experimental deveiooment of the mammary gland of the monicey. Endocrinology, 22: 164-172. 44. Strong, L. C., Smith, G. M., and Gardner, W. U. 1938. Inducticrn cf tumors by 3:4:5:6-dibenzcaroazoie in male mice of the CBA strain, which developes spontaneous hepatoma. Yale J. Biol. and Med.. i0: 335-346. 5. Gardner, w.-U., and van Wagenen, G. 1938. The influence of estrocens upoa the mammary glands oi monkeys. Anat. Rec., 70: "9 (Abst.). 6. tiirscabaum, y., Lits, F. J., Strong, L. C.. and Gardner, W. U. =938. Studies on the _%}monocvtes of normal and ieuicemic m;ce. Anat. Rec., 70: 46 (Abst.). :.eblond. C. P., and Gardner, W. U. 1938. Comparison de la zone X et des autres parties de 1a surrenaie de la souris, a 1'aide du nitrate d'argent. Compt. rend. Soc. de Biol., 127: 48. Gardner, ~. U., Allen, E., Smith, G. M., and Strong, L. C. 1938. Carcinoma : the cervix of mice receivine estrogens. 1'_0: :182-1183. -~ 9. Garcner, :;. i:.. and Pfeiffer, C. A. 1938. =nhibitiorn of estrceenic ef'ects :n tne siceiPton by testosterone injections. ?roc. *-:'oc. Exper. 3io1. and Med., 38: 399-602. 50. Lawrence, .;. ::., and Gardner, w. ti. 1938. ~ transmissible leuicemia in the "A" strain of mice. Am. ... Cancer, 33: 112-119. ~1. :ebiond, C. P., and Gardner, W. U. 1938. Distribution of vitamin C in the adrenal gland of the mouse with reference tc the nature cf the X zone. Anat. Rec., 72: 119-129.

-5- 32. Pfeiffer, C. A., and Gardner, W. U. 1938. Skeletal changes and blood serum calcium level in pigeons receiving estrogens. Endocrinology, 23: 435-491. 53. Strong, i. C., Hill, R. T., Pfeiffer, C. A., and Gardner, .y. ;:. 1938. Genetic and endocrine studies on a transplantable carcinoma of the ovary. Genetics, 23: 585-595. 54. Pfeiffer, C. A., and Gardner, W. U. 1938. Effects of estrogen and estrogern plus ar.'_:-.jgen_ t:a :eF•tes and gonaducts of adult male pigeons. Anat. Rec., 72: 59 (Abst.). 55. Smith, P. K., and Gardner, W. U. 1939. A note on the lack of carcinoeenic action of some cardiac glucosides and saponins. Yale J. Biol. and Med., 11: 187-188. 56. Gardner, W. U. 1939. Estrogens in carcinogenesis. Arch. Path., 27: 138-170. 57. Allen, E., Hisaw, F. L., and Gardner, W. U. 1939. The endocrine functions of the ovaries. Chap. VIII in Sex and Internal Secretions (edited by ?,llen. Danforth and Doisv) williams and Wilkins, Baltimore. 58. Gardner, and Pfeiffer, C. n. 1939. Sex hormones and bone changes in mice. Anat. Rec., -13: 21 (Abst.). 59. i.andauer, W., Pfeiffer, C. A., Gardner, W. U., and `San, E. 3. 1939 Hyoercalcification, - calcemia and - lipemia in chickens following administration of estrogeas. Proc. Soc. :.xoer. 3io1. and Med., 41: 80-82. 60. van Heuverswv_ n, .: ., Folley, S. J. . and Gardner. ~~. :.. 1939. `iammary growth in maie mice receiving androgens, estrogens and desoxvcortico- sterone. Proc. Soc. Exper. Biol. and 'Sed., =1: 389-392. 61. van Heuversc:vn, .:. , Collins, .. J. ,Williams, w. L., and Gardner, ... U. 1939. The progesterone-like activitv of desoxvcorticosterone. Proc. Soc. Exoer. Biol. and Med., 41: 552-534. 62. Gardner. ... U., and Allen, -. Uterine reactions to long-continued normone injections. ?roc. =hird 7 nternational Cancer Congress, 63. .._rscabau , :. p. 158 (Abst. ) . , ?feiffer. C. y. , van Heuverswvn, V., and Gardner, •.. 1939. Studies osceous changes cn irn gonad-nvpopn•:seal relationshi: anc _•c'-i.c tne Engiisn sparrow, Passer dc-iestic•.:s. :. anat. Rec., -5: -49-263. 6•. Cardner, ::. U., and Allen E. 1939. :ialignant and non-maiignant uterine and vaginal lesions in mice receiving estrogens and estrogens and androgens simultaneously. Yale J. Biol. and `Ied., 12: 1-13-234.

-6- 65. ?Gardner, W. U., Strong, L. C., and Smith, G. M. 1939. The mammary glands of mature female mice of strains varying in suscepti- bility to spontaneous tumor development. Am. J. Cancer, 37: 510-517. 66. Wentworth, J. H., Smith, P. K., and Gardner, W. U. 1940. The composition of bones of mice receiving estrogens and androgens. Endocrinology, 26: 61-67. 67. Gardner, W. U., Kirschbaum, A. and Strong, L. C. 1940. Lymphoid tumors in mice receiving estrogens. Arch. Path., 29: 1-7. 68. Gardner, W. U. 1940. Modifications of bones of animals receiving sex hormones. Aaat. Rec., 76: 22-23 (Abst.). 69. Gardner, W. U., and van Heuverswyn, J. 1940. Inhibition of pelvic changes occuring during pregnancy in mice by testosterone propionate. Endocrinology, 26: 833-836. 70. Kirschbaum, A., Gardner, W. U., Nahigian, R., and Strong, L. C. 1940. Differentiation between sarcomatous and leukemic lymphocytes in mice. Yale J. Biol. and Med., 12: 473-482. 71. Pfeiffer, C. A., Emmel, V. M., and Gardner, W. U. 1940. Renal hypertrophy in mice receiving estrogens and androgens. Yale J. Biol. and Med., 12: 493-501. 72. Gardner, W. U., and Strong, L. C. 1940. Strain-limited development of tumors of the pituitary gland in mice receiving estrogens. 73. Yale J. Biol. and Med. , 12: 543-548. Hooker, C. W., Gardner, W. U., and Pfeiffer, C. A. 1940. Testicular tumors in mice receiving estrogens. .,. Amer. Med. assoc., 115: 443-445. 74. Gardner, W. U. 1940. The breaking strength of femurs of mice receiving estrogens. Proc. Soc. Exper. Biol. and Med., 45: 230-232. %D. Kirschbaum, a., Strong, L. C., and Gardner, W. U. 1940. Influence of methylchoianthr.ene on age incidence of leukemia in several strains of mice. Proc. Soc. Exper. Biol. and Med., 45: 387-389. -6. ?feiffer, C. A., Kirschbaum, a., and Gardner, W. C. 1940. Relation of estrogen to ossification and the levels of serum calcium and lipoid in the English sparrow, Passer domesticus. Yale J. Biol. and Med. , 13: 279-284. Gardner, W. U., and DeVita, J. 1940. Inhibition of hair growth in does receiving estrogens. Yale J. Biol. and Ked., 13: ='_3-213. 78. Gardner, W. U. 1940. Growth of the mammary glands in hypopnysectomized mice. Proc. Soc. Exper. Biol. and Med., 45: 835-837.

-;- 79. Gardner, W. U. :941. Inhibition of mammary growth by large amounts of estrogen. Endocrinology, 28: 53-61. 30. Gardner, W. U., and Chamberlin, T. L. 1941. Local action of estrone on :zammary glands of mice. Yale .i. Biol. and Ked., 13: 461-~65. 81. Landauer, W., Pfeiffer, C. A., Gardner, W. U., and Shaw, J. C. 1941. 31ood serum and skeletal changes in two breeds of ducks receiving estrogens. Endocrinology, 28: 458-464. 82. Gardner, W. U., *~llen, E., and Smith, G. M. 1941. Hyperplasia and hyper- trophy of the mucosa of larger biliary ducts in mice receiv- ing estrogens. Proc. Soc. Bxper. Biol. and Med., 46: 311-513. 83. 3laisdell, J. S., Gardner, W. U., and Strong, L. C. 1941. Adrenal glands of mice from strains with different susceptibilities to rammary carcinoma. Cancer Reseazch, i: 283-289. 84. ;,hamberlin, T. :.. , Gardner, W. U., and Allen, Z. 1941. Local responses of the 'sexual skin' and mammary glands of monkeys to cutaneons applications of estrogen. Endocrinology, 28: 753-757. 85. Gardner, i 50. __len, U. 7-941. The effect of estrogen on the incidence of mammary and pituitary tumors in hybrid mice. Cancer Research 1: 345-358. and Gardner. U. U. i941. Cancer of the cerviti of the uterus in hvbrid mice following long-continued administration of estrogen. Cancer Research 1: 359-366. 67. sardner, U. U. 1941. Estrogenic effects of adrenal tumors of ovariectom- ized mice. Cancer Researcz 1: 633-637. 38. Gardner, U. C. 1_941. Cxperiments on maL.marv growt: in nvropnvseccomized -iaie mice. Anat. Rec., 79: 23-24 (Abst.). 89. Carciner, w. .,., and 'Wnite, A. 1941. :Sammarv srowtn in avoophysectomized -aie mice receiving estrogen and prolacc_n. Proc. Soc. 7xper. °ioi. and Med., w8: 590-592. 90. Gardner, W. U., and Alien, E. 1942. Effects of nvpophvsectomv at :^id- Pregnancv in the mouse. Anat. Rec., 33: 15-97. Cardner, U. C. 1942. Persistence and growth of spontaneous :,a=ar: tumors and hvperplascic nodules in hv_pophvsectomized r.:ice. Cancer Researc:: 2: 476-488. Gardner, W. ~.. and '.,._te, A. 1_942. `:ammarv growt:: in n,!pophv sec:omized maie -:ice. inac. 3ec., 82: 2' (Abst.). 9Lardner, W. „ . 1942. ':ammarv tumors in mice receiving g se% nor nones . Cancer Research 2: ; 25 (Abst. ) .

-8- 94. Gardner, W. U. 1942. Lymphoid tumors in astrogen-treated aice. Cancer Research 2: 7?5 (Abst.). 95. Gardner, W. U. 1942. `-iammary growth in male mice fed desiccated thyroid. Endocrinology 31: 124-127. 96. Collins, V. J., Gardner, W. U., and Strong, L. C. 1943. Experimental gastric tumors in mice. Cancer Research 3: 29-35. 97. Gardner, W. U. 1943. Testicular tumors in mice of several strains receiving triphenylethylens. Cancer Research 3: 92-99. 98. Gardner, W. U. 1943. Influence of sex and sex hormones on the breaking strength of bones of mice. Endocrinology 32: 1j9-160. 99. deG Treadwell, A., Gardner, W. U., and Lawrence, J. H. 1943. =i=ect of combining estrogen with lethal doses of roentQen-rav in Swiss mice. Endocrinology 32: 161-164. 100. Gardner, W. U., and Pfeiffer, C. A. 1943. Influence oi estrogens and androgens on :he skeletal system. Phvsiol. Rev., Z3: 139-165. 101. ;;einstein, L., Gardner, W. U., and Allen, -7. 1943. The effect o= estro- oenic hormones on the bacterial content of the uterus. Yale J. Biol. and Med., 15: 43-51. 10'. -Dougherty, T. F., Williams, ::. L., and Gardner, Sti. U. 1943. C:zanges in the mveloid and lymphoid tumors of estrogen-treated cogs. Anat. Rec., 85; 19 (Abst.). 103. ~-ardner, 1943. Spontaneous testicular tumors in -:ice. Research 3: -57-761. Cancer _0~+. ~ardner, , Uou2hert7, T. -. , and !dilliams, :%'. L. 1944. 1-.-mphoid tumors in mice receiving steroid hormones. Cancer Research -.. 73-87. '-0:. ~ardner, h ~., and Doughert-.,.: . H. 1944. :;le circulatinz 1zu:cccL tes o_' suceciing and non-sucicling lactating mice. Anat. Rec., 88: 17 (Abst.). 106. O-ortman, R. -. and Gardner, :. C. 1944. _!etaboiisw o-; tze sterc:c :zormones. ='he excretion of estrogenic material b-: ovariec- tomized -ice bearine adrenal tumors. =ndocrinoloe•- 34: 421-4=3. Oardner, :~. :.. '_94,. Tumors in experi:aental animals receivin= steroid :-icr.aones. Surter., 16: 3-32. _08. :ardner, 1944. ReDOLt at 6t^ meeting of Conference on :•letabciic Aspects oi Convalescence Inciuding Bone and Wound Healing. Josiah _•lacv, 3r. Pubi., 84-88.

-9- 109. Gardner, W. U., and Dougherty, T. F. 1944. The leukemogenic action c: estrogens in hybrid mice. Yale J. Biol. and Med., 1'. 'S-90, 110. Gardner, W. U., and Clouet, D. H. 1944. Osseous proliferation in estrogen- treated hypophvsectomized mice. Anat. Rec., 88: 433 (Abst.). 111. Gardner, W. U., and Clouet, D. H. 1945. Influence of estrogens upon the bones of young and old mice and of thyroid deficient Anat. Rec., 91: 275 (Abst.). 112. Gardner, 'ti. U. 1945. Hormonal factors in the growth of transplanced testicular tumors in mice. Cancer Research 5: 590 (Abst.). 113. Gardner, W. U. 1945. Some influences of hormones on the orowti and persistence of transplanted testicular tumors. Cancer Research 5: 497-505. 114. Gardner, W. U. 1945. Influences of sex aormones on bone. ~ale Si,._. :•Sae., 20: 7-8, 24-26. 113. Gardner, W. U. 1946. Howell's Saunders Reproduction in the Female. Chap. 54, pp. 1182-1212. Textbook of Physiology, J. F. Fulton, ed., '.;. B. Company, Philadelphia. 116. Gardner, , and Mahan, M. L. 1946. Osseous changes in estrogen- treated hypothyroid and 1ow-protein-fed mice. Anat. Rec., 94: 18 (Abst.). 117. Reed, C. I., Reed, B. P., and Gardner, W. U. 1946. The influence of estrogens on the crystal structure of bone as revealed by X-ray diffraction studies on the fe:nora of mice. ~ndocrin= oiogy, 38: 239-244. Cardner, +. ~. 1946. Humoral _actors in esperimental carcinoeenesis. Trans. and Studies Coll. ci ?zv. of Phila., 14: 13-17. __9. ;~illiazs, :~. i.. , Gardner, ::. i , and DeV_:a, J. '_9L6. ..ocal inhiDition of hair orowtn in dogs b•a percutaneous application of estrone. Endocrinology 38: 368-375. _10. L i, `.. c:. , and Gardner, ~1. U. 1947. Tumors in intrasplenic plants in castrated r.:ice. Science 105: 13- 13. Research 7: 38-39 (Abst.). ovarian trans- Cancer Gardner, :A'. U. 1947. Studies on steroid hormones in exoeri-:enta'_ carciac- senesis. Proc. =aurentian Ccnference 1; '17-259. , ?'eiffer, C. A.. and Gardner, :~. ,:. _947. :ntraspienic trans- ?iantation of testes in castrated zice. ?roc. Soc. 3io1. and Med., 64: 319-323. 123. .. ,... .. , and Gardner, ':. U. 1947. Granuiosa cell tumors in intra- pancreatic ovarian grafts in castrated mice. Science 106: 270.

-10- 124. Halvorsen, D., and Gardner, W. U. 1947. Influences of steroid hormones on muscular and osseous changes of denervated extremities. Hacy Report - 14th Meeting, 82. 125. Gardner, W. L. 1947. Endocrinology of Neoplastic Diseases. Chap. II. Tumors in experimental animals receiving steroid hormones. pp. 11-44. Oxford University Press. N. Y. 126. Gardner, W. U., and Li, M. H. 1947. Studies on the germinal epithelium in ovarian transplants in mice. Anat. Rec., 97: 336 (abst.). 127. Gardner, W. U., and Allen, E. 1940. Malignant and non-malignant uterine and vaginal lesions in mice receiving sex hormones. Unio Internalis Contra Cancrum. III Congres International Contre le Cancer, Atlantic City, New Jersey, 1939, 5: 106- 108. 128. Li, M. H., Gardner, W. U., and Kaplan, H. S. 1947. Effects of X-ray irradiation on the development of ovarian tumors in intra- spienic grafts in castrated mice. Jour. \atl. Cancer Inst., 8: 91-98. 129. li, M. H., and Gardner, W. U. 1947. Experimental studies on the patho- genesis and histogenesis oi ovarian tumors in mice. Cancer Research, 7: 549-566. 130. Gardner, W. C., and Pan, S. C. 1948. Malignant tumors of the uterus and vagina in untreated mice of tne P*: stock. Cancer Research, 8: 241-256. 131. ?an, S. C., and Gardner, W. U. 1948. Carcinomas of the uterine cervix and vagina in estrogen and androgen-treated hybrid mice. Cancer Research, g: 337-345 . Cardner, :;. U. 1948. Hormonal imbalances in tumorigenesis. Cancer Research 8: 397-411. '_33. Cardner, ::. ~. 1948. Hormones and Experimental Carc'_nogenesis. Acta. de L' ~nion Internationale Contre ie Cancer, 61: 124-133. '34. ~ ?an, S. C., and Gardner, W. U. 1948. Induction of malignant tumors by Tethvicholanthrene in transplanted uterine cornua and cervices of mice. Cancer Research S. 613-621. .A and Gardner, W. U. 1949. Further studies on the pataogenesis of ovarian tumors i.^n mice. Cancer Research 9: '_:-41. '35. -S-ita, _. W., ar.d Gardner, W. U. 1949. Thyroid secretion rate in ~_:=erent stocks of mice. Anat. Rec., 103: 506-507 ;Abst.). Gardner, ... ~., and Li, M. H. 1949. influence of age of host and of cvaries on tumorigenesis in intrasplenic ovarian grafts. Cancer Research, 9: 595-596 (Abst.).

138. Gardner, W. U. 1949.- Physiology of Reproduction, Section XII, pp. 1160- _188. Howell's Textbook of Pnysioiogy, J. :. Fulton, ed., ~. B. Saunders Company, Philadelphia. 139. Smith, F. W., Gardner, W. 0., Li, M. H., and Kaplan. H. 1949. Adrenal modullary tumors (pheochromocytomas) in mice. Cancer Researcn 9: 193-198. 140. Li, M. H., and Gardner, w. U. 1950. Influence of age of host and ovaries on tumorigenesis in intrasplenic and intrapancreatic ovarian grafts. Cancer Research 10: 162-165. 141. Gardner, W. U. 1950. Effect of estradiol benzoate and testosterone propionate on X-ray induced leukemia in mice. Cancer Research 10; 219 (Abst.). 142. Wolstenholme, C. T., and Gardner, W. U. 1950. Sinusoidal dilatation occurring in iivers of mice with a transplanted testicular tumor. Proc. Soc. Exper. Biol and Med., 74: 659-661. 143. Smith, F. W., and Gardner, ::. U. 1950. 3iologicai assay of mouse pituitary gonadotrophin. Anat. Rec., 106.: 248 (Abst.). 144. van Wagenen, G., and Gardner, W . L. 1950. Functional intrasplenic ovarian transplants in monkeys. -Endocrinoiogy, 46: 265-272. 145. Gardner, w. ~. 1950. Ovarian and lymphoid tumors in female mice subse- quent to roent2en-ray irradiation and hormone treatment. Proc. Soc. Exper. Biol. and Med., 75: 434-436. 146. Gardner, W. L'., and Boddaert, 3. 1950. Testicular interstitial cell tumors in hybrid mice given tri-p-anisv_1 cnioroethv_iene. Arch. Path., 50: 150-764. ~~.7. Gardner, ti. Z:. 1950. Hormonal imbalances in relation to ovarian tumors. International and Fourtn Amer. Cong. on Obst. and Gvnec. Abst. ~48. Gardner, W. _. 1951. Hormonal factors in experimental ovarian tumori- genesis. im. :. Obst. and 3%rnec., 61A; 83-87. 1.~9. Gardner, ::. C. 1952. Furtner observations on ovarian tumcri:enesis in :ransplanced ovaries. Cancer Res., 12: 264 (Abst.). 7:encin, ~. ~ JeVita, J., and Gardner, ~. U. 1952. EEffect of moderate coses o: estrosen and progesterone on mamma r: grctwth and zair growtn dogs. Anat. Rec., 1=3: 163-1i,. .:Qnew, L. R. C., and Gardner, ;;. Z;. 1952. =he iacidence ci sDontaneous :-eoatomas in CiH (low milk factor), and CBA mice and tne effect of estrogen and androgen on tne occurrence of tnese tumors in CiH mice. Cancer Research 12: 75%-%61.

-12- 152. Gardner, W. U. 1952. Report of cancer research and programs i.n tae Un ited S tates during 1950-1931. Unio Internat contra Ca ncrum. III: 214-222. 153. Gardner, w. U. 1953. Hormonal aspects of experimental t::morigenesisi Advances in Cancer Researcn, pp. 173-232. Academic Press. 154. van Wagenen, G., and Gardner, w. U. 1953. Absence of heaatic inactiva- tion of estrogen in tne monkey. Yale J. Biol. and _:!ed., 25: 477-483. 155. Gardner, :v. U., Pfeiffer, C. A., Trentin, .:. J., and Wolstennoime, ,;. T. 1953. Hormonal factors in experimental carcinogenesis. Chapter 12, pp. 225-297, ?hysionatnology of Cancer, ?aul B. Hoeber, Inc., New York. 156. Gardner, W. U., and Rygaard, .;. 1954. Further studies on the incidence of lympnomas in mice exposed to X-rays and given sex normones. Cancer Research 14; 205-209. 157. Xiller, 0. ,;., and Gardner, k. U. 1954. The role of thyroid function and food intake in experimental ovarian rumorigenesis irn mice. h 14 C R 220-226 : ancer esearc . 158. Gardner, :;. C. 1954. Role of steroids in cervical cancer. Proc. 2ad Nat1. Cancer Conference, 1952. 159. Gardner, w. ~. 1954. Induction and regulation of tumors in non-endocrine tissues by steroids. Proc. 2nd \atl. Cancer Cznference, 1952. 160. :;ardner, :.. ::. 1954. Studies on ovarian and pituitarv_ tumori2enesis. J. Nat. Can. Inst., 15; 693-709. 15i. Gardner, 1955. Oeveiopment and gro:;ta of tumors i:: cvaries transplanted into tne spleen. Cancer Research 115: 109-117. 162. Cardner, :~. ;.. 1955. Further studies on estrogens, =estosterone propionate, and roentgen irradiation orn ieuice^:ogenesis in BC mice. Proc. Amer. Assoc. Cancer Res., 2: 1S (:1bst.). 163. :,ardner, and Franicer_nuis, B. 1955. Uterine cervical and vaoinal cancer i.. -ice =ollowing intravaginal applicaticn cf estrogens. ?roc. ?..-ner. Assoc. Cancer Res., 2: 18-19 (Abst.). 16µ. lardner, ".ti. ::. 1955. Localization of strain differences in vaei:.ai sensitivi-. _.~ estrogens. Anat. Zec., 121: 297-29S (Abst.). :~:. -; orn, ,; , , and Gardner, W. ~. 1956. _nguinal hernias in :e-aie -iice treated --ndrogens or bearing grafts of :estes. Endocrinology 59: y8-54.

-13- 166. Gardner, W. U., and Ferrigno, `:. 1956. Unusual neoplastic lesions of the uterine horns of estrogen-treated mice. J. Nati. :.an. Inst., 17: 601-603. 167. Gardner, W. U. 1956. Introduction, Report of Teaching Institute of Anatomy and Anthropology in Medical Education. J. . Med. Education 31: 1-6. 168. Gardner, W. U. 1956. Instruction and Learning in Anatomy. J. Med. Education, 31: 45-66. 169'. Gardner, W. U. 1957. Hormones and Carcinogenesis. Canadian Cancer Conference, Vol. 2, 207-241. 170. Gardner, W. U., and Argyris, B. F. 1957. Differences in vaginal sensi- tivity of mice of inbred strains; localization in the vagina. Endocrinology 60: 532-546. 171. Gardner, W. U. 1957. Summary of informal discussion of first day. Cancer Research 17: 481-489. 172. Gardner, i1. U. 1957. Steroids in Experimental Carcinogenesis. Cancer 10: 725-730. 173. Trentin, J. J., and Gardner, ::. U. 1958. Site of gene action in suscepti- bility to estrogen-induced testicular interstitial-cell tumors of mice. Cancer Res., 18: 110-112. 174. Gardner, W. U. 1958. Further studies on experimental ovarian tumorigenesis. Proc. Am. Assoc. Cancer Research 2; 300 (Abst.). ~75. Gardner, :%. U. 1958. Large, biologically active pneocnromacvtcmas in -iice. ?roc. Am. Assoc. Cancer Researc:: 2: 300-301 (Abst. ) . 176. Gardner, :~. ' . '_958. Some studies on ovarian t.:morigenesis. Ciba :ound. Colloquia on Endocrinology 12: 133-169. Gardner, ;:. U. 1958. ~esticuiar tumorigenesis. Ciba :ound. Colloauia cn s.ndocrinology 12: 239-'_5w. '_78. Gardner, ::. U. 1958. Genetic aspects of hormonal influences on cancer. Annals N. Y. Acad. Sci., 71: _092-1099. :-9. Gardner, ::. :. Obituaries. =rancisco Ouran-Revnais. 1399-1958. :ancer Researcz 18: 1352-1353, 1958. _00. :"_ndle, :~. ..., Cardner, ::. _. 1958. :The =esponse c: avpc- and ^~_•~ertzyroid imsnature :emaie mice to gonadotropnin (FSH). 'iale J. Biol. and :Ied., 31: 130-143. _a:. Gardner, ... ~. _959. Experimentai induction of uterine cervicai and vaginal cancer in mice. Cancer Research 19: 170-176.

-14- 182. Gardner, W. U., Pfeiffer, C. a., and Trentin, J. .:. 1959. Hormonal Factors in Experimental Carcinogenesis. From Treatment of Cancer and Allied Diseases, 2nd ed. Paul B. Hoeber, Inc. 183. Gardner, W. U. 1959. Carcinoma of the uterine cervix and upper vagina: Induction under experimental conditions in mice. Ann. N. Y. Acad. Sci., 75; 543-564. 184. Gardner, W. U. 1959. Sensitivity of the vagina to estrogen: Genetic and transmitted differences. Ann. N. Y. Acad. Sci., 83; 145-159. 185. Gardner, W. I;. 1960. Tumors in transplanted pituitary glands in mice. Proc. Am. Assoc. Cancer Res., 3. 113 (Abst.). 186. iiazary, S., and Gardner, W. U. 1960. Influence of sex hormones on abnormal musculature and the formation of inQuinal and scrotal hernias in mice. Anat. Rec., 136: 437-443. 187. van wagenen, G., and Gardner, W. U. 1960. X-irradiation of the ovarv in the monkey (Macaca mulatta). Fert. and Ster., 11: 291-302. 188. Huxtable, K. A., and Gardner, W. U. 1960. `Iodification of growth and tunction of a transplanted ovarian granulosa-cell tumor. Jour. `:atl. Can. Inst., 25: 201-216. 189. Dj ima, a., and Gardner, id. U. 1961. Testicular interstitial cell tumors of mice: Hormone Production, Dependency and Cytology. ?roc. _1.mer. :ssoc. Can. Res. , 3: 255 (Abst. ) . 190. Hoshino, K. and Gardner, ~~. U. 1961. Growth potentialities of the ncrmal aammarr tissue in mice. Anat. Rec., 139: 240 (Abst.). 1 oi '"'.cntemurro, D. G., and Gardner, a. U. 1961. The e:fect cf subcutaneous *_ranspiants of hvpothalamus and pi:uitary ziand on the estrous c:cie of t7e mouse. Fed. ?roc., 20: 188 (Abst.). 192. Garcner, '.:. ~.:. 1961. Tumorigenesis in transplanted i:-:adiatea and non- irradiated ovaries. ~. Nati. Can. 26. 329-853. 193. Gardner, W. U. i961. ::terine cervical and vaginal cancers in experi- mental animals. :zcta 17: 905-909. 194. :-!ehta, 2., and Garcner, ~~. `~'. 1961. A study of lumbrical muscles in tae human hand. mer. .'. dnat., 109. ='-71-238. 195 . :arcner, ~.;. U. 1962. Some stscies on experimental tumorigenesis: ::smors transplanted ,-t.._tary glands. :n Cancer and Hor..:ones 39-106. 196. ~;arcner, a. :,. 1962. Endocrine deDendence in experimental testicular tumorieenesis and tumor growth. ?:enr}- Ford Hospital lnter- national Svmposium. Biological lnteractions in Normal and `eopiastic Growth. 391-411, little Brown and Comoanv.

-15- L97. `iontemurro, Donald G. and W. U. Gardner. 1963. Effect of subcutaneous transplants oi pituitary gland and hypothalamus on the estrous cycle of the mouse. Endocrinology 73: 174-184. 198. Gardner, W. U. 1964. Host-tumor relationships in testicular interstitial cell tumors. Acta Union Internatl. Contre le Cancer 20: 1439-1442. 199. Hoshino, K., W. _. Gardner, and R. A. Pawlikowski. 1965. The Incidence of Cancer in Quantitatively Transplanted Mammary Glands and its Relation to Age and Milk Agent of the Donor and Host Mice. Cancer Research 25, 1792-1803. Hoshino, K., W. U. Gardner. 1967. Transplantability and Life Span of `~lammary Gland during Serial Transplantation in Mice. Nature, -13, No. 5072, pp. 193-194. 201. ?ourreau-Schneider, Natalie, R. J. Stephens and W. U. Gardner. 1968. Viral Levdig Inclusions and other Cytopiasmic Components in a Cell Murine Tumor: An Electron Microscopic Study. .n:. J. Cancer: 3, 135-162. =02. ~cephens, R. J., N. ?ourreau-Schneider and W. U. Gardner. 1968. Cytological Morphoiogy of a Virus-Containing Mouse Testicular Interstitial Cell Tumor. J. Ultrastructure Research. 22, 494-507. '03. =isenield, A. J., :y. C. Gardner and G. van (•:agenen. 1971. Radioactive Estradiol Accumulation in Endometriosis of the Rhesus Monkey. American Journai oi Obstetrics and Gvnecology. 109, 124-130'.

204. Bollengier, W.E., Eisenield, a.J., and Gardner, W.U., Accumulation of -~H-Estradiol in Testes and Pituitary Glands of Mice of S trains Differing in Susceptibility to Testicular Interstitial Cell and Pituitary Tumors after Prolonged Estrogen Treatment. J. Natl. Cancer Inst 49:847-852, 1972 205. Petrea, I. and Gardner, W.U., Fine Structure o*f Pituitary Tumors and TransDlants in Mice: Effects on the Prostate. Int. J. Cancer: 11, 40-57 (1973) 206. ollengier, W.E., Eisenfeld, e~..J., Gardner, W.U., Accumulation of iH-Estradiol in Transplanted Interstitial Cell Tumors in Mice. J. Natl. Cancer Inst. 50: 195-200, 1973

Biographical data on WILLIAM U. GARDP!ER 'di 11 iam U. Gardner, Ebenczer K. Ilunt frofcs-:or of Anatomy at zre Yale School of f•tedicine, is a recognized authority in the physicicc_.` or' reeroauct i on and the ro i e of hormoncs i n the s t i rn: l a t i un c a::- normal growths and cancer. Dr. Gardner, a former chairman of the Department of Anatomy at Yale, has written extensively in the field of his soecialization, and is the author of more than 150 scientific articles, sections c•= books and books. ?orrn i n Ki nbrae, Fii nnesotW, on iJavemhPr 11, 1907, the son : of Ja'7cs and Josenhine Gardncr, Ur. Gardner r,ac,ivFd nct, c+eelree of ilc,chclor of Seicnee from South Dakota Sl.itL! C,r,IlIuN: in lf)-_'7. Dr. Gardner subseGuent ly recei ved the dodrecs ot i•1.A. ,nd P;i.D. in 1930 fro,n the University of HisSouri. He remained iZ thc University of Missouri as a Fellow ir, 193U-ij32 end Grecor\y- Fellow from 1932 to i933. "rom 1933 tc 19;5 Dr. Gardner held a I:ational ?esearch Fel io.:- s:30 in v.natomy at Yale. !',~ :•la_ :ippointed Lc th~: fr,cuity of the Yale School of Medicine 'r '11-135 'as aResClarcl-, la5ii stani in arnalr,roy. In i937 he-:•tas pro- r- 1 o the r,f t• ruft-ti ~or n,ri i n 1938 he becam;: o `aarch As.ociate ::i;h so::ir.te Prcressc:r 'rank. ?n 1941 :-. Gardner became Associate Professor of Anatomy and i-, 19!;3 he was namtd Professor of Anatomy and Chai rman of the De- pa-ment af :',nato^r, :... Gardner has received hunurary degrees of Doctor of Scienc= frc-. South Dakota Sta:e College in 196U, and of Doctor of Medicine ar.d Surgery fron ;^e Instituto di Anatomia e Istolocia Patcslccio u: tne L'niver_ i ty of Peruqia in 1969. Cr. Gorener nas e_enn a member of and aovisPr ta manv professic^a: 65soc;atio% _.c ortlenlzations, incluJinq tr,c rmuricd~ F.>SOCi3ti-_- (:` natomi;ts, ~Cour,c i i. 194?-j2), A,ni.1 it:Ln ?,s5ocit,tic:r, rc•r l.3nC" _=_2rcil, (rresidEttL. 1547) , the Nutic.nal kesearcrl lC .^.CI1, :e- c- Gro~•:th, 1`L-8-r?., ,,nd others. : rc- 1953 tc 1.965 Dr. Gardner was a rnemuer cf the Soara of C:.nsultenrs rtf the Ilational Cancer In;_1.jte, an; =ror^ '' .o 1969 '-:z was chairran or the Amcric3n Can_,ar Society 's Cc-- -. #or the u::ve iccr,.ent of Scient i f i c Per;onnel . --s vear Or. Gardner wiil beyin a four year term a5 President c= :`_ L'nicn Internationatc Contre l.c Cancer. iale, Dr. Gardncr nas been a :cll?nti l1: idviscr :U twU Cri- res_c'rcil fcLnd;,:ti!:n5 sinc:: 19~3; they arC C~le ~nna Ful ler Fu1d ~ ~.`e Jane Coffin Cai ids hemorial ,Fund. Gardner is married trithe former Katherine Hur;sley and they in ;lranae, Connecticut. ------------------------------ T-.e article attacned, from the Winter, 1969 issue of "Yale r±ea- ic*-," the ilurnni mac:zine of the Yale Schooi of N2dicine, will rro•:ioe more detail on tr.e research interests of Dr. Gardner.

c,sc,-~rs vr-.a, c c Sheldon C. Sc=ess, M.D. Boza: July 7, 1916, TY.4ia*y=p'lis, Indiana Maaied: tyovenfle_- 9, 1943, Edith Briggs, no children Harvard Cbllege. 1937, cua laude M.D., Harvard Medica.l a~ool, 1941, asa laude Isitern: thivrrsity of Chicage Cliaics, (Billings fiospital ), Ciicago, 1941-42 Assistant Ansident and Aesidesit in Pathology, New F1qiand D°uc'uss; Iiospital, Bcs,.::., 19:= A:.siszant Aesi3rsnt in Pathology, Free Hospital for W=Ien, Brookline, .Ass., 1948 Assistant Aesidesit in Pathology, Boston Lyirq-In Sospital, Boston, 1948-49 Aesidesit in Pathology, Henry Fbz'3 HosPital. Detroit, 1949-50 AIIerican Board Cr.r..ificate in Pathelogy (Clinical Pattnlcxgy & Pathcloqir Anat=iy), 1950 Associate Pathologist, New Ehgland Deaooness Iiospital, Bos=. 1950-53 Assistant Partrioloqist, F3a a Cances C=snissioa, Boston, 1950-53 Pathologist, Massach---,etts M&aarial Hos?itals, Boston, 1953-61 New Btigland Sxiety of Pathologists: Presidazt, 1959-60 Patbelogist, S=ipgs irletnrial Iiosoital, La Jolla, Califorrrnia, 1961-63 Associate Director of Laboratories, Francis Delafieid Flospital, New York, 1963-67; Director, 1967-68 Director of Laboratories, Ler= aill Bospital, New Yoaic, 1968-8i _ Assistant in Pathology, Harvard Medical School, 1948-49; Znstructar in Fa,holoc JAss oc iarry, 1950-:f: ociarr in Pathology, 1952-53; Lectures in Pathology, 1954-61 Associate Pzvfessor of Pathology, Boston University School of l4edicine, Boston, 1953-61 Qanical Professor of Pathology, University of Southern Califoszsia S~col of Mad,; c:z:e, Los Angeles, 1962 - Associate Professor of Pathology, Col=bia Uaiveisity, College of Physicians i A.-geors, 1963-65: Pzofessnr of Pathology, 1965-68; Clinical Pzflfessor of Pathology, 1968 - Lieutenant, 1942-43, Captain, Medical Corps, United States Atmyy, 1943-46 Silver Star, Bronze Star, C=ix de Gaer--e and k~tsidential Usit Gitatian New York Cbuuity Medical Society, New York Amesiean Association of Pathologists College of 14metican Pathologists Anpr:can 5ociety of Clinical Pathologists New asgland Cancer Sxiety International Acadesay of Pathology Federated Societies for Dcperimesita1 Biology and Medic.ine New York Acadesny of Mer3icine New York Acadaay of Sciem New York Pathological Society: Secetary 1969-72; President 1977-79 rditor, Pathology Aran:al, 1966-75, Cbeditor, 1976- ; Pathology Lecuuu.als, 1975; Dia7ostic Gyrecology and Cbstetzi.cs, 1979-82 Editorial Boards: American Journal of Suxgical Pat2-.jlogy, fLanaa-Pithology, C:ir_iral Nephrology, Ultrastr.ictzsral Pathology, Zn,f ertil_+ --y Scientific Advi.snry Board: Council for 2hbacco Pesearch, 1967- ; Research Di:ect=r, 1969-72; Scientific Director, 1981- !ental F3ygiPne Mec'.ical Review Poasd, New York State, Chai_-m3n, 1976-85 Arthur Purdy Stout Society of Surgical Pathologists; President, 1983-85

i PUBLISHm ARTICLFS Shaldon C. Sonmers, M.D. 1. Jacobs JL, Satmers SC: The specificity of fornnlized protei.*is. J 7Mainol, 36: 531-541, 1937 2. Menkin V, Kadish MA, Sanners SC: Leukocytosis-prc¢mting factor in inflammatory exudates of man. Arch Path, 33: 188-192, 1942 3. LeCozrate PM, Soineers SC, Lathrop FD: Ztamr of carotid body type arising in the middle ear. Arch Path, 44: 78-81, 1947 4. Warren S, Scn¢rers SC: Cicatrizing enteritis (regional ileitis) as a pathologic entity. Am J Path, 24: 475-501, 1948 5. Warren S, Sasmers SC: Giant-cell inclusions in cicatrizing enteritis. Proc Soc Dcpes Biol & Med, 8: 461-463, 1948 6. Warren S, Somrers SC: Pathogenesis of ulcerative colitis. Am J Path, 25: 657-659, 1949 7. Hertig AT, Samners SC: Genesis of endcnetrial carcinoma. I, Study of prior biopsies. Cancer, 2: 946-956, 1949 8. Sortmers SC, Hertig AT, Bengloff H: Genesis of encianetrial carcinoma. II. Cases 19 to 35 years old. Cancer, 2: 957-963, 1949 9. He_*-tig AT, Soamers SC, Bengloff H: Genesis of endcnetrial carcinoma. III. Carcinoma in situ. Cancer, 2: 964-971, 1949 10. S=ne_-s SC, Lawley TB, Hertig AT: A study of the placenta in preg- nancy treated by stilbestrol. Am J Cbst G, 58: 1010, 1949 11 Warren S, SomTers SC: P-roteolysis in intestinal disease. Gastroentv, 14: 522-526, 1950 12. Wyatt JP, Sommers SC: C-'-sonic marrow failure, myelosclerosis and ex- I trarreduilary her.atopoiesis. Blood, 5: 329-347, 1950 ~

2 13. Meissner WA, Srscar-Ts SC: Postpar+`zaa erdometrial hvp---plasi.a in diabetics treated with stilbest.-o1 and progestarone. J Clisi 5",C, 10: 603-609, 1950 14. S=mrs SC, Jchrsson JM: Cw%ger:ital tricu.,pid at--asia. Am Sea.r: J, 41: 130-143, 1951 I 15. S=ers SC, Wi3.son JC, HaTtsmen FW: Lyaphoi.d lesions in pot :=y.t ; ris, J EQ Med, 93: 505-512, 1951 ,' 16. Warren S, Bolt W, Satmers SC: Same early nuclear effects of i="' *+g radi.atiaa. Proc Soc D= Biol & Med, 77: 288-291, 1951 17. Holt irSw, S=Vers SC, Warren S: Preparation of tissue sections for quantitative h:stoc.emical stuZi.es. Anat Pec, 112: 177-186, 1952 18. Saiue--s SC, Z+eloh H: Ovarian sttamal hyperplasi a in hreast cancer. Arrh Path, 53: 160-166, 1952 19. Warren 5, Fiolt M, Scnmers SC: Some cytologic and histochaaicaZ studies of radiation reaction. Am J Clisi Path, 22: 411-417, 1952 20. M=ManLs RG, Samners SC: Breast cancer pzognosis and ovarian cort,i.cal str=&l hypezplasi.a. N Fhg J Med, 246: 890-892, 1952 21. Samrness SC, Young ZZ: Cacyphil parathy=oid ade*=ms. Am J Path, 28: 673-689, 1952 22. Ftdards JL, Sc..nrers 5C: Radiation reacti.ons in parabiotic rats. J La Cl Med, 40: 342-354, 1952 23. azute Fa1, Sam*s SC: Iisnolytic disease and polycyttemia in para- biosis inr.auicat,:on. Hlood, 7: 1005-1016, 1952 24. Fiollance.- A, Somers SC: Lepromatms leprosy. N Ezg J Med, 247: 634, 1952 25. L-:istensen WR, Scnmers SC, Spaulding CC: M!fect of soft roantcen rays on the ra:: it sfcln. Am J ibentg , 63: 801-808, 1952 10

' 26. 26A. .. r 26B. 27. 28. 29. c 30. r 31. 32. 33. c 34. 35. 3 Somme:s SC, Cu :e Fa7, WarM-Z S: Heta.-ct..-ansplantaricrn of hL-man cancer. Z. L--:adiar_ed rats. Cancer Ras, 12: 909-911, 1952 Cssr.e FN, Sarr--s Sr-. warrrss 5: bet.erotran.~~lantaticn of hi.'aaa cancer. II. Paaster chedc poc:c'i. Caacer Rrs, 12: 912-14, 1952 Somsrrs Sr. Sullivan BA, Warrert S: •:.ori of htaesan cancer. =. Gx~rioallarztoic m=ta*+es of eatzsyarsated eggs. Cancer Res, 12: 915-917, 1952 • Browa FII, Winstca R, Saraers SC: Mem6ranais staphyloc.ocr.a1 ente---..tis aftes an•::iotic t5esapy. Reaort of two cases. Am J Digest Dis, 20: 73-75, 1953 Sccsr--s SC, McWns RG: Msltigle arseai.cal cancers of skin and ta.-rsa.l organs. Cancer, 6: 347-359, 1953 Scaae--s SC, Anderson ZM. Warresi 5: Ba_~~nt mem+ra*+es in c.u-oaic uttestiaal disea se ~ . Lab Inv, 2: 223-226,. 1953 i4Wkef ieid M, Scnc:ers SC: Fata1 aembranous staahyloooc-..al enteri rs in surgical patients. Ana Sutr„ 138: 249-252, 1953 MC4anLs RG, Sass:pars SI-: Sicsrs:=:ranee of gastric polyps acc----.anying cancs. Am J G:n Path, 23: 746-757, 1953 Scnr.ers SC: Ovarian rate cysts. Aza J Path, 29 : 853-859, 1953 Sc-:n-r--s SC: Endccri-:e changes after hPlsaadrer:alect-cizy azid total body ir_ad_•:a tion in parabiotic rats. J lab C1i.-i Med, 24: 396-407, 1953 Bolt MW, Saiare.rs SC, 4zarren S: Lztranuclear changes resulting `m exposure to icn; z::.g radi.arioa as detected in frozen-dr:.ed prep.'_ a- t,icrLs. Lab Snv, 2: 408-418, 1953 Sr.cnrers SC, Geyer B5, C:ute FV: Autorad.iocraphic arse.tic in adult and er=-yonic epit`zeliua and con.zecti.ve tissue. Proc Soc D~ Bicl b:Led, 84: 234-239, 1953 Il

4 36. 37. r 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. Soimers SC, Z1P.lah F3A, Goldaan G: Chrarian influence tq= survival in breast cancer, prch Surg, 67: 916-919, 1953 Sarmers SC, Iarrbard CM: Cancer associated with avarian st..-omal hypesplasia. Arch Path, 56: 462-465, 1953 Garren S, ScQmr.rs SC: Pathalogy cf reqiarlal ileitis and ulcerat :ve colitis. ,7M, 154: 189-193, 1954 Ada=on NE Jr, Sam*= SC: E~danetrial ossificatiOn. Am J Cbsc G, 67: 187-190, 1954 Qiute PRN, Kenton FB, Saimers SC: A].aboratory epid_Mnic of hsaan-~.~e tr.be=c.ilosis in haiasters. Am J C.lin Path, 24: 223-226, 1954 Marcial-Rojas RA, Soumers SC: Differentiated mycoeoide=id tumcrs of salivary glands. Arch Otolar, 59: 135-140, 1954 Sollander A. Sosmers SC, GriaaAade AE: Histochemical and ult.aviolet ati.croscopic studies of chrQnic demmtoses and the coritsa memcrane. J Inves Der, 22: 335-348, 1954 Strande A, Saaasrs sC: Petrak M: Reqional enterxolitis in cocker sPa^.=el dogs. Arch Path, 57: 357-362, 1954 Sanw-rs SC, Meissnar WA: Baseaent membrane c.'zanges in chronic thyroiditis and =her thyroid diseases. Acn J Clia Path, 24: 434-440, 1954 Wood JS Jr, Holycke FID, Clason WPC, Satmers SC, Warren 5: An ex- perime.ntal study of the relationship between t== size and rnammer of ltmq mefaases. Cancer, 7: 437-443, 1954 Goddard JW, Scurm_-s SC: Methr:d for thyroid cell maMir.; Zab Irnrn, 3: 197-210, 1954 Col_=k BP, Sarmrs SC: Prognosis in Paget's disease of the breast. Su='g Cli.z NA, 34: 773-733, 1954 3u.-r AS, Land-In.: BH Sc~rs SJ.: A..hol.-hi1 tuaars of the hypcrhysis incuced i.-~c~ce by Z"' . Cancer Res, 14: 497-502, 1954 ,I

5 49. saaners SC, Meissner 5Q,: Cntisval carc?^^*as of the pancreas. Arch Path, 58: 101-111, 1954 50. Scsrmers SC, FAards JL, G`:ute Rv: I:rrease in hypersensitivity lesiors of parabiosis intaxicatiion aftar ~dres:al_d-*=Y. J La CI Med, 44: 531-543, 1954 51. Socmers SC, Ctozier R, Whrzrs: S: Ultraviclet adcrnscopy of qlcmerui a- diseases. Am J Path, 30: 919-939, 1954 52. ZLinPS ID, Scamers SC: Medical iatelliqe~e. N IIm J Med, 251: 744-745 1954 53 Patt Cnite lai Saane rs SC M s48 l i f h . , erson , , ra,a.,~ : antat cn o tvan into ccrtsone-treated hamstets. Cancar Fbes, 14: 656-659, 1954 54. Goddard JW, Socup-rs SC: Thyroid ;m,1ation in diabetes aallitus. Diabetes, 3: 383-388, 1954 55. Sommars SC, b3uphy SA, Warrm 5: Pancreatic duct hyperplasia and carlcer. . Gast-aes:ty, 27: 629-640, 1954 56. Rohman M, 9atsers SC: A double prizary carcir=ia of the urirary blaccer. J Urol, 72: 1174-1177, 1954 57, 5=rrp-•s SC: Same applicatians of ultraviolet micrQscoQy to pathology. 52. Boston Med Qtay, 5: 105-108, 1954 . Zeltcn &M, Satar,ers SC: Clinicopathologi.c conference. Am J C1Ln Path, 24: 1402-1407, 1954 59. Sanners SC. Csozier R,Warren S: A stucy of the •:.'traviolet mic=scoPy 60. of renal vascul.ar diseases. Circulation, 11: 31 .e3, 1955 i,t=d JS Jr, Fielycke ID, SamTess SC, warrez 5: Zn.`lues:ce of pituita,=y qza.rt-h hor•r Dne on growth and metastasis fermati.on rif a t_assplantable ll Johns Hc kins Iios 96 B 3 p u mouse sarcrsna. p, : 9 -100, 1955 6i. xz;re~s 5,;,, war_-en S: Ulce:ative crlitis lesions i:n i.ac::at_~ rats. Am J Diaest Dis, 22: 111, 1955

62. 63. 64. 63. 66. 67. 68. c 69. 70. ~ 71. 72. ( 73. 7;. S=m--s SC: fZ:docize abnnajalities in kae:en wit-s-. breast cance;. Iab Inv, 4: 160-174, 1955 Pialey FII., Dews Gi, Sactt:ers SC: A histochemical c;rpariscn of pr=ry thyroid hyperplasia ar:C adez=atous goite.:, Arch Path, 59: 635-640, 1955 I Iteefer C5, S=me..-s SC: Clinicopathalogic canferersce. Am J C1in Path, 25: 1053-1057, 1955 Srsimc*z SC, Gates 0, C,oo~cf LT: Iaate xecurrerice ttacars. Cbstet Gyn, 6: 395-398, 1955 of grarsulosa ce11 SoRr.ers SC: Development of research at Massachusetts Me=rial Hcs- pitals. Boston Med Qtrly, 6: 113-115, 1955 Barr:ler AH, Davis S, S==P-rs SC: Heterotranwlantation experiarsits with human cancers. Cancer ges, 16: 32-36, -1956 Pazker 2G, Satrners SC: Adrenal autical hyperplasi.a accaTW.ying cancer. Arch 51ug, 72: 495-499, 1956 Sotzme--s SC: Testic.aar spe...-atogenic cell hypprt.-ophy acs.-osmanying prostatic hy.p.----:...hy and carcer. Am J Path, 32: 185-199, 1956 S=mess SC, Haley Ki: Similarity of glcuexuir ultraviolet absorrtions in diabetes mellit:u and after c^ -isc:.e therapy. P-oc Soc Dc_p Bifll & Me3, 91: 262-265, 1956 xcm-p--s SC, Chute RN: Carc:.argenesis a:vd altered host reacticns i. parabiotic rats. Arch Path, 61: 295-304, 1956 Sac4rars SC: Introduction to pathology of neoplastic d_seases. J S=,dent RMA, 21-25, April, 1956 S'zak.rsashs T, Scmne_'s SC: Czrnic rensuual endcmetriur.i. Cbstat Gv-;, 8: 112-115, 1956 Scnne_-s 5.:: Baseman=~^'=rz^es , cr-rvnc: substances ar : 1y=:^.xytic ac~regates ._. ac_•-:; crcar.s. J C--cntol, 11: 251-260, 1956

7 75. 8ri-: M, Satmers SC.: A"bliqr'.tec:" ascitu tZ+ar=laat Bull, 3: 102-103, 1956 76. Sanaers SC, Wadman R7: Pathoger:esis of polycysric ovaries. Atn J Cbst G, 72: 160-169, I956 77. Bo=ghton GA, Sarcmss SC: Ars:a1 changes in stYxk treated with levarterrsacl (ZevwFshed). Am J Cli,n Path, 27: 29-34, 1957 78. Etiatr F3d, Sataers SC: Orssssoal causes of death after cardiac sus^:;ery. Am Heart J, 53: 232-239, 1957 79. Mar-rel A, Sane--s SC: Ezdecri^.e ccr=elations in momarv adeno- fibrsis and chronic cystic m3sziti;s. Ana Surg, 145: 3Z6-333, 1957 80. Scmme_''s SC: F`^d^=,::.e changes with grostatic carcir:ata. Cancer, 10: 345-358, 1957 81. Zabie AT, Burrows BA, Scmmers SC: C13nic.satholoqic Canfereslce. Pefractory arenia, agan=naalobuliaeaii..a, and mediast:.aa1 tL=r. Am J Clin Path, 27: 444-452, 1957 82. t.~hil.ty JR, Sonmers SC: Keratoacanthama as a surgical pat~~=Jogic entity. SL=q Gyn Cb, 104: 663-668, 1957 ., 83. Janes FC, Samers SC: G1cavrular alte_.•ations in kid:.eys of rats treated with desoxycertic^.sterone. Arc': Path, 64: 58-62, 1957 84. Saltz M, Samters SC. 9nit':wick, RH: Cliniccpatt^.ologic cor=e].atio.zs of renal bicpsies f=cn esseatial hype+^te-isive paties:ts. Cic.ilaticn, 16: 207-212, 1957 • 85. tyse.iam ,7C Jr, .., -s SC, I~ y periCUCtal hyalin iz d:.zbetic wamen. Lab Inv 6: 412-420, 19,' 86. Meissner S4A, Scnmezs Sr, gseae3n j: 'Rnetrial hyperplasia, endo- me•_:al carci.^-Cna, and encrsnetriesis produced experi,~r,e.z..iLy by est^x,e.z. Cac".ce-•, 10: 500-509, 1957

- 8 - 87. Scasts---s SC, Meissner YA: Aost relationshias i.z empier:..zta: enc?o- met..-:,.al c3rcjrrsna. Cancer, 10: 510-515, 1957 88. Scmmess SC, Meissnrr Wl: Eidocine abnozualities accompanying h=a.^. P1]dCiCeTS3 a 1 cancer. Cai1CpS, 10: 516-SZl. 1957 I / t C 89. Souttrs L, Sommers SC, Palmaa AS, F2serson CP: P=flblws in t'1e Sur;:ca.1 marsagement of thymic tuaors Arui -Sitq, 146: 424-438, 1957 90. Barr An1, Sauers 5C: IIndocrine alb^^*=al; ties a~panyir.g heca`,.ic cir--'=sis and hegat=a. J Clin End, 17: 1017-1029, 1957 91. Ullrick WC, Leanti,.i Ek. Scamers SC: Dccitab 'zIi_y arr3 cr:tractaity of gost=rr..ea ht..san heart muscie. lab Zav, 6: 528-535, 1957 92. Somness SC: Host fac-'..ors in fatal hsman lunq cancer. Arch Path, 65: 104-=, 1958 93. "&''^"MJC, : anp--s SC, S'ttithwick RH: Clinic..,pathologic cbr:-elati.orLS of zrsial biopsies in hypert.ension with cyelonegnriti.s. Citcv.laticn,- 17: 243-248, 1958 94. Reefer ID, Swinton NW, Atkinson RP, Sasaaers SC: Panel discussion on chronic u1c=.'ative colitis. Am J r'j sr•t*-nty . 29 : 359-373, 1958 95. Azar HA, Socssrers SC: fetroperitor.ea1 ectopic se:~~ inal vesicle c~atu.z.i- cati:.g with a cont..alateral solitary kie-rsey. Report of a case. J tlrcl, 79: 94-998, 1958 96. Soame=s SC, Relman AS, snittiwick, RH: Histologic studies of kidney biopsy specimezs f_-t:a Patients wit': hypertension. Am J Path, 34: 685-715, 1958 97. _q=mers Sc: Corstir..itional aspects of gastric carcinana. Armh Path 66: 487-493, 1958 98. U1L-ick, WC, Lenti:.i A. Scrmers SD: mcyeen consL=ticn of posr.crtem h:.masi heazt mi:scle. Prx Soc Ecr 3io1 & Med, 99: 246-247, 1958 99. 3':a=a AH. C,'x'-da--'d -'T^', -`CMM--s SC: A stuc'~J of `^.e ac:er.al stat•,:s in hypert ~-- -•sicr.. J C=-n Dis, 8: 587-595, 1958

-9- 100. ~ 101. r 102. r 103. 104. 105. 106 ~ 107. 108. 109. 110. f 111. 112. SSlva ZF, Sa,r ers St: Re'-nal biapsy c`sanges with phex Am J Med Sc, 236: 700-704, 1958 Xeffler R, lanson N, Sarmers SC: Carcin= arising in a:irinr salivarv gland ducts of the lower lip. AID J 3urg, 97: 79-82, 1959 ~ Strong Sri, Samnera SC: Branchiagenic carcisrsa. .1rch Otalar, 68 : 764- 7 6 1958 Wilkins RW, S=rp--s SC: Clir' .a. atlogiic Conferer:ce. Fhtax~,zt cf the hearr, cardiac failure and loose, dry scaly skui. Am j Cls.n ?ath, 31: 66-72, 1959 Scsmers SC: Pi=ita=y cell relations to bcdy states. Lab Znv, 8: 588-621, 1959 Coff-san JD, Sr.nMrs SC: Fa*d 7;m t psetxA cOCanthrsia elastic:an and valvtt.a.x heart disease. CirCUlatian, 19: 242-250, 1959. S=rL---'s SC: Patholocy of the kidney and adrer+al gland in relaticnship tc hype_-tension. In ~ty_o~rtension (ed JFI i~byes) WB Saurid~ers Cc, 23, 1958 Andr rsakis GD, Somners SC: Criteria of thyntic cancer and cli-iical caaelations of t.':yntic ttusnrs. J Thor Svrg, 37: 273-290, 1959 Arse-rrutsopoulos N1, Sccnners SC: Post::encaausal enc3awtriosss. Cbstet Gyn, 14: 245-248, 1959 Ull--iclc wC, Lant-'si FA, Scnmers SC: SLacmation and tetarus in post- mor~..en hunai hear' :cuscle. JAM1 Physiol, 14: 567-568, 1959 Aollander A, Scnmpss SC: Clirrent case of leprattatczis leprosy, acid- fast bacilli ir _pidean.is. Conn Med, *23: 650-654, 1959 Thayer G„ xnme:s SC: Host factors in carcir:ana of the uterir.e cervix. Am J Cbst G, 78: 386-392, 1959 Hloodti.c.--`: w:°.. San-rers 5C: "Ci-: :otic g:aTerulcsclz*osis" . A re^.a? lesicrn ass,oc-at°r wit-h henatic cixrr^.osis. Iab Inv, 8: 962-978, 1959

113. ffl:l,ler Csi, Scicmers SC: The thyroid status irn re.lation to ar.erio- sclemtic disease. Boston Med Qtly, 10: 1-2, 1959 114. Sanche: GC, Sacmers SC: Peptic u3.cer diathesis with a aLixed ade.,=- carcizxxna of the pancrpas: Case report. GasttDenty, 38: 467-470 1460. 115. Sasners SC: Finna1l and adrenal pathology in hypertension. Ccr.a M®d, 24: 240-244, 1960 - 116. ReI1y JFM, Parsons L, Friedrll C~i, Sonmers SC: A pathologic study in 55 autopsies after radical surgery for cancer of the cervix. SUrg GYn Ob, 110: 423-432, 1960 117. Fiollander A, Scnmers SC: A h3stochetaical study of aucapolysaccharicss of leprosy of the skin. Act Dar-Ven, lltti Znterrjat Cangr Desmat, 3: 407-411, 1957...1960 118. Huckingham 5, 5=nrnrs SC: Pularanaiy hyaline memhranrs. J Dis Qzi1d, 99: 216-227, 1960 119. Patton FB, Sanners SC: The histopat'ZOlogy of infarct.ion and otlzer ulcerative diseases of the esophagus. Am J Clin Path, 33: 516-524, 1960 120. Fiollander A, SaiaP-•s SC: Histoctuenical casparison of Boeck's sarcoiZ with other es.aneous granulomas. Arch Deanat, 81: 944-946, 1960 121. Friedell Ci, Shwrman JD, SaTrprs SC: Spleen and liver in the anemia of the tu:er-bearing hamster. Arch Path 70: 863-871, 1960 122. Grassi JE. Sa:arers SC: A case of carcir.cma of the breast in a you-.g wanan with hamartomatous hypotha].ami,c malfozasation. Am J Surg, 100: 606-617, 1960 - 123. e',elori.a X-, Frie~'..ell Gd, Sasrn.rs SC: Faynaud's disease and primazy pulaana..-y hypestension. Circulation, 22: 1055-1059, 1960 124. T,:.-_eon C, Scc:mers SC: Juxt.agl=ezula,.- cell c::u.Zts and h-~r. hvee-~e•~s__-. Am J Pat~j, 38: 227-241, 1961

11 125 I 126. 127. 128. 129. 130. r 131. i 132. 133. 134. C 135. 136. 137. 5amp--s SC, Ts7_eon C: Mn7holog~:c studi.es on relatior.ship of pyelorseph==s -to hyoertPunsion. In Biology of Pyelonephr tis, (eds E:. Cuinn, M Kass) Little Brown Z Co, Boston, 1960 McAuley FL, 5aomess SC: Mast ae1Ls in non..pecific uleeratiVe co].i-.=s. Am J Digeat Dis, 6: 233-236, 1961 Satmers SC, Verern'.ia JB: An a;pra; sat of labarato=y o'e}•-;n:ti.cns of est,-ogrsLs. Am J Clin Path, 35: 319-327, 1961 Yin, P-S, ,acuners SC: Sane pathologic cnrrelations of ovarian st+-am31 tcyoP..rpiasia. J C:in Ezd, 21: 472-477, 1961 Patalano VJ, Sasme=s SC: Biopsy diagnosis of pesia**e^ tis nodosa. Arch Path, 72: 1-7, 1961 ''_~'~sch i'~schi LG, S=vers SC: Cacytalan fibers :rrc`t DeTmat, 84: 128-130, 1961 -scleivsirx; hemu%gi.cm s. 9ocumrs SC: Saae pathologi.c conditions assaciated with renal and adrenal hypereasi: n. .]AM, 178: 715-717, 1961 Fri.edell GH, She=az JD, Sotrmers SC: Croanc c-,3rves of h=ar: cance; transt.lants duri:ng expp.ritental c''A=tt.erapy. Cancer, 14 : 1117,1121, 1961 Sherwin RP, Grassi JE, Scnmers SC: Hatn3z-,.=atous malfo_^sation of the posterolateral hypoLha~. Iab Inv, 11: 89-97, 1962 William MJ, SaMrs, SC: L-Id=i:.e and certain other c.Langes in sren with carcirxMa of the ltrsq. Caz:cer, 15: 109-117, 1962 L-1,en K, Friec'.ell GrI, Sctres,-"s SC: A stucy of ovarian t~.ecccatosis. &->lir ~Sed, 96: 254-256, 1962 Te&schi LG, Socrmrs SC: Ccsrtalan fibers - deana1 fibrcras and q:ant- cell tenccn sheat.`: -.:--:ars. Arch Dersat, 85: 527-529, 1962 Soe--cel fC-?, Sc.-mers SC: T.,.e alveolar epit~e1.i31 lesion of icio:.at'zic pul:=.ary aencsidiercsis. Acn Rev Resp Dis, 85: 540-552, 1962

138. Scpurge1. FQn, Samne-rs SC: Zdi.opathic Fulaas:ary hrsnosicex~sis and related sync,r=ms. Am J Mad, 32: 499-511, 1962 139. Soame-'s SC, Mctauq.'zlin PJ, i~4uley RL: Pat2sology of Ciast.olic hy=e: _er as a gerseralized vasc.il.ar disease. Am' J Card, 653-658 , May, 1962 140. Reeves G, Sasmrs sc: F2ud=ettia1 heQnsi dwrir, a,e w; 3Pr.ce. of met=nahagia. tbstet Gyn, 19: 790-792, 1962 141. Reynelds CT, 3aithwids RH, 5a:mrrs 9C: Dccision of ad*+n>> ade..raa and svcrPathectaay in the desapy of n. Am J 51uzq, 103: 696-701, 1962 142. Mire ffiK Sairmrs SC: Status of the myocasdial artericles in angira pectoris. Am Hea-"':: J, 64: 323-333, 1962 143. Reynolas C: , SoArt:ers SC: Synpathect=ty for glarerulone~ah.^ltis with hy?estensicr:. Arch SLtrg, 85: 390-393, 1962 _ 144. Sonmers SC, Rohbins CM, Babin D6, Itnaack CT: Chronic pyel.oneohritis, renal tut:ulaT atrophy and hyperr.Pxsion. Arch Iat Med, 110: 505-510, 1962 145. Wisenand JM, ICos`..as D, S=Irrrs SC: 5ca:e host factors in the c'.evelce- mesit of re.^a1. cell carci.~asa. west J R:rq Cristet Gyn, 70: 284-285, 1962 .1 146. Bouc.`ctrn R14, Sann--_-s SC: A new concept of renal hypertension. J Urrl, 89: 113-136, 1963 147. Peeves G, Lcz.ersstein L, So=ers SC: A suggested mechanisa of eryt,wrQ- pciatic ccn:-ol of juxtaqlcmeRu?aT cells. Am J Med Sc, 245: 134-187, 1963 148. Haric B, SacmPSs SC: IIu'.at+et-"..a1 a:..rttage in diagnosis and tuLerar.r.y. Cbstet Gyn, 21: 636-638, 1963 149. S=rrars SC, Weber tM, Ra'=ves 1:: A hemagglutinati„on re.:.tion of mot,'jers and irnfants of different ABO and Rh groups. Am J Clin Path, 39: 482-48;, 1963

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- 24 - 281. SaRmPrs SC: Ia patoloci.a de- la rolitis ulce_-vsa y granulomatosa. sd+la*+Tcs en Gast---ow*:terologia, (eds Z.c3 Fer.-.aru:ez, AGF Depaula) Az'qenti':a, pp 235-250, 1979 282. Scorp.:s S`: Triall by andi.a. Am J Diag G~m C*~qtet, 1: 3, 1979 , 283. Bell-Th=ipson J, Missier P, Sawiers SC: Zur:q carci,aana arisss:g in 283a. brts=hop+?aanary secgzstration. Camer,44: 334-9, 1979 9oamess SC: Carci-':cma in situ of the endoarrrit*^ . Am J Clin Path, 72: 284. 130, (letter to editor) 1979 Potte_-t'.am HZ, SanTers SC: IgG lyrrphcclasmacytic ir.t_sti.rsal lyaphcsaa: 285. A case zenor . H Ford Hosp Med J, 27: 218-22, 1979 Sazmers SC: Polycystic ovaries revisited. In Progress in Surr,ical Pathology 1: (eds C~S Fencglio. M Wolff) Massan Publ Co. NY, 221-232. 1980 286. Maier HC, Socnners SC: Media~in.As lynph rrx38 hypesplasia, hypeir,saglc..'-t:.: 287. emia, and a^e'*+" . JThor 5~, 79: 860-863, 1980 Fcmrey SL, Scmrars SC: Neoplastic Growth. In Fmmry SL. Gray MT. Little 288. A8, Merrill JA, 4uilliqan ES, Stander F3d: Gynecology arsd Cbstetrics. McCratirHi,ll, New York, Chap 12, pp 263-293, 1980 Satmers SC, Carter M, Palner E: Beginning of the New York State Menta1 289. F3ygie.*se Medical Review Board 1976-1980. Am J Forer.,1: 361-364, 1980 SoRmers SC: Premalignant lesions of the endcmettizan. In Goldsmitli's Practice of Surgery, (ed © Williams), Harper & Acw, Hagerstown, pp 1-10 1980 290. Sc=p-rs SC• Dr. Shislds Warren - an obituary. Ultra Path, 1: 589 1980 ( 291. Koss LG, C.-aap-r D, Fereaczy A, Gurside E, Reagan JW, Si.iteri PK, s=rp--s SC: Fece::t advances in endormtria1 neoclasia. Acr,a CYt.ologica, 24: 478-493, 1980

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CURRICULUM VITAE James Francis Glenn, B.A., M.D. Personal History Born: Lexington, Kentucky, 10 May 1928 Social Security Number: 405-28-4010 Home Address: Glenninish Farm 2600 Basin Springs Road Winchester, Kentucky 40391 Telephone (606) 744-1599 Medical Office: Department of Surgery University of Kentucky Medical Center Lexington, Kentucky 40536 Telephone (606) 233-6677 FAX (606) 258-1944 New York Apartment: Hampshire House 311 150 Central Park South New York, New York 10019 Telephone (212) 333-6078 New York Office: Council for Tobacco Research-U.S.A., Inc. 900 Third Avenue New York, New York 10022 Telephone (212) 421-8885 FAX (212) 421-8898 Married: Gale Brooke Morrison, Bolivar, New York, 29 December 1948 Children: Cambridge Francis Glenn 11 (12-5-49), Sara Brooke Glenn (5-22-53), Nancy Carrick Glenn (12-10-56), James M. W. Glenn (5-29-58) Education University School, Lexington, Kentucky, 1946 Yale Regional Scholar Bausch and Lomb Science Award University of Rochester, Rochester, New York, 1946-1949 Bausch and Lomb National Science Scholar Delta Kappa Epsilon Bachelor of Arts in General Science Duke University School of Medicine, Durham, North Carolina, 1949-1952 Alpha Omega Alpha Honor Medical Society Phi Chi Doctor of Medicine with Honors Postaraduate Trainine Peter Bent Brigham Hospital, Boston, Massachusetts, 1952-1954 Surgical House Offieer Duke University Medical Center, Durham, North Carolina, 1956-1959 Assistant Resident and Chief Resident in Urology

Academic Anoointments Instructor in Urology, Duke University School of Medicine, 1958-1959 Assistant Professor of Urology, Yale University School of Medicine, 1959-1961 Associate Professor of Urology, Bowman Gray School of Medicine, 1961-1963 Professor of Urology, Duke University School of Medicine, 1963-1980 Professor of Surgery, Emory University School of Medicine, 1980-1983 Professor of Urology, Mount Sinai School of Medicine, 1983-1987 Professor of Surgery, University of Kentucky College of Medicine, 1987- Administrative Aooointments Chief of Urology, Duke University Medical Center, 1963-1980 Dean, Emory University School of Medicine, 1980-1983 Acting Dean, Mount Sinai School of Medicine, 1983-1984 President, The Mount Sinai Medical Center, Mount Sinai School of Medicine, and Mount Sinai Hospital, 1983-1987 Council for Tobacco Research - U.S.A., Inc., 1987- Assistant Scientific Director, 1987-1988 Scientific Director, 1988-1991 Chairman of the Board and Chief Executive Officer, 1991- Executive Director, Markey Cancer Center, University of Kentucky, 1989- Hospital Apoointments Associate in Surgery, Yale-New Haven Hospital, 1959-1961 Attending Urologist, Veterans Administration Hospital, West Haven, Connecticut, 1959-1961 Consulting Urologist, Connecticut State Hospital, 1960-1961 Attending Urologist, North Carolina Baptist Hospital, 1961-1963 Attending Urologist, Duke University Medical Center, 1963-1980 Consulting Urologist, Veterans Administration Medical Center, Durham, North Carolina, 1963-1980 Consulting Urologist, Lincoln Hospital, The Babies Hospital, Watts Hospital and Durham County General Hospital, 1963-1980 Consulting Urologist, Womack Army Hospital, Fort Bragg, North Carolina, 1967-1980 Consulting Urologist, Veterans Administration Medical Center, Oteen, North Carolina, 1969-1980 Visiting Professor, Great Ormond Street Hospital for Sick Children and the Institute of Child Health, University of London, 1972-1973 Consultant, Agency for International Development, Vietnam Medical School Project under the American Medical Association, 1967-1971 Consultant to the Surgeon General, United States Air Force, 1975-1980 Attending Surgeon, Emory University Hospital, Grady Memorial Hospital, Crawford W. Long Hospital, and Henrietta Egleston Childrens Hospital, all in Atlanta, Georgia, 1980-1983 Consulting Urologist, Veterans Administration Medical Center, Atlanta, Georgia, 1980-1983

Attending Urologist, Mount Sinai Hospital, New York, New York, 1983-1987 Consulting Urologist, Veterans Administration Medical Center, Bronx, New York, 1983-1987 Attending Surgeon, University of Kentucky Hospital, 1987- Consulting Urologist, Commission for Handicapped Children, Commonwealth of Kentucky, 1987- Consulting Urologist, Veterans Administration Medical Center, Lexington, Kentucky, 1987- Consulting Urologist, Shriners' Hospital for Crippled Children, Lexington, Kentucky, 1988- Medical Licensure and Certification Diplomate, National Board of Medical Examiners, 1954 Certified, American Board of Urology, 1962 Licensed in Kentucky #11905 (1955), Connecticut (1959), South Carolina (1961), North Carolina (1962), Georgia (1980), and New York # 154036 (1983) Military Service Captain and Flight Surgeon, United States Air Force, 1954-1956 Hospital Commander, 3308th USAF Hospital, Stallings AFB, NC Honors and Awards Alpha Omega Alpha Honor Medical Society, 1953 Society of Sigma Xi, 1961 Robert V. Day Memorial Lecturer, Western Section, American Urological Association, 1969 Urologist of the Year, Buffalo Urological Society, 1972 Hugh Hampton Young Oration, Mid-Atlantic Section, American Urological Association, 1977 William T. Belfield Lecturer, Chicago Urological Society, 1977 Hugh Hampton Young Award, American Urological Association, 1982 Annual Distinguished Oration, New York Academy of Medicine, 1985 Honorary Fellow, Royal College of Surgeons of England, 1987 Editorial Award, "AUA Today," American Urological Association, 1990. Professional Or¢anizations American Academy of Pediatrics, 1972 American Association of Clinical Urologists, 1975 American Association of Genitourinary Surgeons, 1965 Councillor, 1990-1991 Vice-President, 1991-1992 President, 1992-1993 American College of Surgeons, 1963 American Federation for Clinical Research, 1964 American Joint Committee on Cancer, 1976-1983 American Medical Association, 1960 American Society of Nephrology, 1966 American Surgical Society, 1976

American Urologicai Association, 1963 Mid-Atlantic Section, 1977 (Honorary Member) New England Section, 1960 New York Section, 1983, 1990 (Honorary Member) South Central Section, 1985 (Honorary Member) Southeastern Section, 1962, 1984 (Honorary Member) Western Section, 1977 (Honorary Member)) Association of American Medical Colleges, 1966 British Association of Urologic Surgeons, 1975 Canadian Urological Association, 1972, 1983 (Honorary Member) Carolina Urological Society, 1962 Clinical Society of Genito-Urinary Surgeons, 1969 Vice-President, 1989-1990 President, 1990-1991 Colombian Urological Society, 1979 (Honorary Member)) Davison Club, 1974 DYSURIA, 1966 Engel Society, 1966 German Urological Association, 1972 Japanese Urological Association, 1992 (Honorary Member) Kentucky Medical Association, 1987 New York Academy of Medicine, 1983 New York Academy of Sciences, 1967 Pan American Medical Association, 1964 Royal College of Surgeons, 1987 (Honorary Fellow) Royal Society of Medicine, 1972 Societe Internationale de Chirurgie, 1977 Societe Internationale d'Urologie, 1964 Vice-President, 1985-1991 President, 1991-1994 Society for Pediatric Urology, 1963 President, 1972-1973 Society of Pelvic Surgeons, 1963 President, 1979-1980 Society of University Surgeons, 1968 Society of University Urologists, 1966 Secretary,l966-1970 President, 1972-1973 The Australasian Urological Society. 1974 (honorary) Urologic Investigators Forum, 1965 Miscellaneous Resoonsibilities Editorial Board, Medical Asoects of Human Sexuality " " Medical Tribune " " Monographs in the SurQical Sciences " " Urologv Diaest " " Urological Survey " " The Journal of Clinical SurAerv " " The Mount Sinai Journal of Medicine Principal Investigator, Cancer Chemotherapy Program, NIH, 1961-1963 Principal Investigator, Adjuvant Bladder Cancer Study, NIH, 1964-1970 Scientific Advisory Board, National Kidney Foundation, 1963-1968 Founding Member, American Society of Nephrology, 1966

Section Council on Urology, American Medical Association, 1968-1978 Assistant Secretary, 1968-1972 Secretary, 1972-1974 Vice-Chairman, 1974-1976 Chairman, 1976-1978 American Urological Association, Inc. Member, Committee on Graduate Instruction, 1967-1968 Chairman, Committee on Graduate Instruction, 1968-1969 Chairman, Committee on Continuing Education, 1969-1974 Member, Visual Education Committee, 1964-1966 Member, Committee on National Legislation, 1968-1969 Member, Review and Long Range Planning Committee, 1975-1979 Chairman, Review and Long Range Planning Committee, 1979-1980 Member, Public Relations Committee, 1985-1988 Consultant, Public Relations Committee, 1988- Chairman, Press Relations Committee, 1986 Representative to Commission on Cancer, 1988- American College of Surgeons Member, Graduate Education Committee, 1975-1981 Advisory Council for Urology, 1971-1975 Governor, 1978-1984 Commission on Cancer, 1988- American Joint Commission on Cancer, 1989- Southeastern Section, American Urological Association, Inc. Chairman, Commission of Constitution and ByLaws, 1968-1969 Chairman, Committee on Education and Science, 1970-1975 President-Elect, 1975-1976 President, 1976-1977 The Society for Pediatric Urology Vice-President, 1976-1977 President, 1977-1978 Residency Review Committee for Urology, AMA-AAMC Member, 1975-1981 Chairman, 1980-1981 Member, Urologic Task Force, American Joint Committee on Cancer, 1975-1978 National Academy of Sciences-National Research Council Consultant, Division of Medical Sciences, 1967-1968 Member, Committee on the Genito-Urinary System, 1968-1971 The Society of University Urologists Founding Member, 1966 Secretary, 1966-1969 Councillor, 1969-1970 President-Elect, 1970-1971 President, 1971-1972 Alpha Omega Alpha Honor Medical Society Councillor, Duke Chapter, 1968-1976 National Committee on Visiting Professorships, 1969-1971 Councillor Member, National Board of Directors, 1972-1978 Director, 1980-1986 President, 1984-1986 Association of American Medical Colleges Council of Academic Societies, 1977-1979 and 1987- Council of Deans, 1980-1985 The American Board of Urology, Inc. Trustee, 1976-1982 Vice-President, 1981-1982

The Society of Pelvic Surgeons Vice-President, 1978-1979 President, 1979-1980 The Greater New York Hospital Association Executive Committee, 1984-1987 Assistant Treasurer, 1985-1986 Treasurer, 1986-1987 Business and Other Exnerience President, Hilton Inn of Durham, North Carolina, 1973-1980 Member, E. R. Squibb Medical Advisory Board, 1976-1979 Board of Directors, First Union National Bank of Durham, North Carolina, 1970-1980 General Partner, Brookewood Apartments, Ltd., Durham, North Carolina, 1980- Partner, Glenn Brothers (auto dealerships), Lexington, Kentucky, 1980- Board of Directors, ValleyLab, Inc., Boulder, Colorado, 1980-1983 Consultant on Urologic Equipment, 1989- Board of Trustees, Transylvania University, Lexington, Kentucky, 1982- Trustee, The Kentuckians of New York, 1984- Vice-President, 1990- Director, Critical Care America, Inc., Westborough, Massachusetts, 1986- Kentucky Council for Science and Technology, 1986- Board of Directors, Cardinal Hill Hospital, Lexington, Kentucky, 1987- Investment Committee, 1988-1989 Patient Services/PubIic Relations Committee, 1989- Chairman, Quality Assurance/Review Committee, 1989- Secretary, 1989-1991 Chairman Elect, 1991- Board of Directors, Sanders-Brown Center for the Study of Aging, University of Kentucky, Lexington, Kentucky, 1988- Vice-Chairman, 1989-1991 Director, Meritech, Inc., Englewood, Colorado, 1988- Governor's Breast Cancer Advisory Committee, Commonwealth of Kentucky, 1990- Director, CommerceNational Bank, Lexington, Kentucky, 1990- Membershios Hope Valley Country Club, Durham, North Carolina, 1963-1980 Yacht and Racquet Club, Boca Raton, Florida, 1974- Pinehurst Country Club, Pinehurst, North Carolina, 1975-1981 The Lafayette Club, Lexington, Kentucky, 1975- The Yale Club, New York, New York, 1976- Capitol City Club, Atlanta, Georgia, 1981-1983 Westchester Country Club, Rye, New York, 1983-1988 The Century Club, New York, New York, 1984-1990 The Iroquois Hunt Club, Grimes Mill, Kentucky, 1987- Idle Hour Country Club, Lexington, Kentucky, 1988- Thoroughbred Club of America, Lexington, Kentucky, 1989- Thoroughbred Owners and Breeders Association, Lexington, Kentucky, 1990- The Keeneland Association, Lexington, Kentucky, 1990- University of Kentucky Faculty Club, Lexington, Kentucky, 1990-

Resume HARh1ON C. titcALLISTER. JR. Research Director The Council for Tobacco Research - USA, Inc. 900 Third Avenue New York, NY 10022 (212) 421-8885 Career Historv Born: Durham, NC April 5, 1936 1986- Research Director, The Council for Tobacco Research - USA, Inc. In addition to continuing duties as Associate Research Director (see below), the following are among those undertaken as Director. • Development and maintenance of the office's computing and word processing capabilities, including automation of most of CTR's routine office procedures. This has allowed the processing of 200% more grant applications with no increase in support staff. • Evaluation and standardization of all preliminary inquiries (cases) concerning research support prior to transmittal to the Executive Committee of the Scientific Advisory Board. • Serving when needed as part of the annual sponsor tour; and always as a supplier of background data. • Providing written evaluations of grant applications as part of the semi-annual review process. 1983-1986 Associate Research Director, The Council for Tobacco Research - USA, Inc. Responsibilities involved assisting in coordination of the entire grant application process and serving as monitor for CTR grantees. Duties in this latter area involved making site visits for evaluation of progress, facilities and the general working environment at the recipient's laboratory and the host institution. With other members of the Scientific Staff, advised the Scientific Director on the progress of renewal applicants prior to each SAB meeting and provided input on the distribution of award funds following each meeting. In support of the members of CTR's SAB, responded to general or specific questions and offered advice concerning specific grantees' projects. Other duties included attending relevant scientific conferences to identify emerging directions of research in areas of interest to CTR. 1976-1983 Director, Office for Institutional Research, Wayne State University, Detroit, Mich. Complete responsibility for admistrative unit of six professionals plus support staff with an annual operating budget of = S 1/4 million plus computing charges. Principal functions of the office included securing, verifying and analyzing data in support of policy and general planning decisions as well as fiscal, academic, space and operations management for the University. Ongoing duties inluded development and maintenance of extensive data bases, using both large mainframes and microcomputers. Supervised coordination of Federal, State, local and intramural data and information reporting functions, affirmative action monitoring, liaison with University faculty and staff, as well as with various governmental, proprietary and other external publics.

Resume (cont.) Harmon C. MkAllister, Jr. page 2 Career Historv (continued) 1973-1976 Coordinator of Curriculum Studies and Research Associate, Office of Academic Programs and Planning, Wayne State University. This position involved progressively increasing responsibilities in the areas of program analysis and planning, budget ananysis, and institutional budget request preparation. Directed extensive research projects for academic planning. 1972-1976 Consultant, Michigan Cancer Foundation, Detroit, Michigan Primarily worked on collaborative biomedical research projects with scientific staff at the Foundation. During one academic term, worked as a full-time research scientist in those laboratories. 1967-1973 Assistant Professor of Chemistry, Wayne State University. Performed the traditional duties of a University faculty member in a heavily research-oriented department. Primary areas of research: mechanisms of protein synthesis and control of gene expression. Research funded by competetive awards from National Science Foundation, National Institutes of Health, and National Heart Association. 1963-1967 Postdoctoral Research Fellow, Universities of Michigan and Kentucky Medical Schools (see below). 1958-1963 Graduate Assistant, University of North Carolina, including reasearch assistant- ships, NIH student traineeship , all involving teaching of graduate and medical students. 1955-1958 Undergraduate Research Assistant in Biochemistry, University of North Carolina. Education 1965-1967 Postdoctoral Fellow of the National Heart Institute. Studies on function of the active ribosome complex, with Professor Richard S. Schweet, Department of Cell Biology, University of Kentucky Medical Center, Lexington, Kentucky. 1963-1965 Postdoctoral Fellow of the Muscular Dystrophy Associations of America, Inc. Studies on the mechanism of biotin incorporation into carboxylase enzymes, with Professor Minor J. Coon, Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan. 1963 Ph.D. in Biochemistry, minors in Microbiology and Physiology, University of North Carolina Medical School, Chapel Hill, North Carolina. Dissertation: "Polyacrylamide Gel Electrophoresis of Histones and Histone Fractions and a Preliminary Metabolic Study". Dissertation director: Professor J. Logan Irvin. 1958 B.S. in Chemistry, University of North Carolina, Chapel Hill, North Carolina.

t Summarv Resume HARMON C: titcALLISTER, JR. Research Director The Council for Tobacco Research - USA, Inc. 900 Third Avenue New York, NY 10022 (313) 644-0560 Career Historv 1986- 1983-1986 1976-1983 1973-1976 1972-1976 1967-1973 1963-1967 1958-1963 1955-1958 Educstion Born: Durham, NC April 5, 1936 Research Director, The Council for Tobacco Research - USA, Inc. Associate Research Director, The Council for Tobacco Research - USA, Inc. Director, Office for Institutional Research, Wayne State University, Detroit, Michigan. Coordinator of Curriculum Studies and Research Associate, Office of Academic Programs and Planning, Wayne State University. Consultant, Michigan Cancer Foundation, Detroit, Michigan. Assistant Professor of Chemistry, Wayne State University. Postdoctoral Research Fellow, Universities of Michigan and Kentucky Medical Schools (see below). Graduate Assistant, University of North Carolina, Chapel Hill, North Carolina. Undergraduate Research Assistant in Biochemistry, University of North Carolina. Postdoctoral Fellow of the U.S.P.H.S. (National Heart Institute). Department of Cell Biology, University of Kentucky Medical Center, Lexington, Kentucky. Postdoctoral Fellow of the Muscular Dystrophy Associations of America, Inc. Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan. Ph.D. In Biochemistry, minors in Microbiology and Physiology, University of North Carolina Medical School, Chapel Hill, North Carolina. B.S. in Chemistry, University of North Carolina, Chapel Hill, North Carolina.

CURRICULUM VITAE OF DR. ROBERT C. HOCNETT Dr. Robert C. Hockett, Research Director of The Council for Tobacco Research - U.S.A., Inc., 110 East 59th Street, New York, New York 10022, vas born in Fayette, Hissouri on July 1, 1906. A graduate of the Ohio State University, Dr. Hockett pursued graduate study in the same institution.and received the Ph.D. degree in chemistry tbtre in 1929. As a National Research Council Fellow in Chemistry, he was a guest scient:sc at the National Institute of Health, U.S. Public Health Service from 1929 to 1931 and then Associate Chemist on the Institute staff from 1931 to 1935. In 1935 he joined the faculty of the Massachusetts Institute of Technology as Assistant Professor of Chemistry, becoming Associate . Professor in 1941. In 1943 he was granted a leave of absence from M.I.T. to serve as Scientific Director of the Sugar Research Foundation, Inc., which position he occupied until 1952. He has also been Visiting Professor at the Universities of Illinois and North Carolina. From 1952 until 1954 he served as a consultant to industrial firms on problems relating to foods, nutrition, pharmaceuticals, fermentations and sponsored research. In 1954 he joined the present Counril for Tobacco Research's predecessor organization - the Tobacco Industry Research Committee ae an Associate Scientific director. Dr.-Hockett is a rellow of the American Academy of Arts and Sciences, the New York Academy of Sci'ences, the American Public Health Association, the Royal Society of Arts, and the American Institute of Chemists. He holds membership in the American Chemical Society, in which he has served as an Alternate Councilor, member of the Nomen- clature Committee, Vice-Chairman of the Division of Carbohydrate Chemistry in 1944, Chairman in 1945 and 1946, and Secretary-Treasurer from 1956 to 1960. He also holds membership in the American Society of Biological Chemiats, American Association for the advancement of Science, Friends of the World Health Organization, Royal Society of Health, and the Phi Beta Kappa Associates. He has served as a Lecturer in Switzerland for the American- Swiss Foundation for Scientific Exchange, member of the Food Industries' 2 HH®378021

Adviaory Committee tz the 3utricion Foundation, Inc., Collaborator to the United States De-artmt-c of Agriculture, member of the Advisnry Committee for Advancas in :arbohydrate Chemistry, as Associate to the State Department's Czmmittsa for Interamerican Scientific Publication and member of the Susar Airiaory Committee to the Administrator of the Production and Marke-'ng e•c, U.S. Department of Agriculture. He is .uthor o' numa:ous research papers on the chemistry of carbohydrates, of ar-=clss and lectures on nutrition and public health, of many reviews and s=mmar-es on tobacco and health research and contributor to a booc, Bee: Sugar Economics. e:X NKd378022

~-" C01:2KCIL FOR TOBACCO I"CESEARCId-I:.S- 4.. I.VC. i t.. . CC[dF'ID%--%17-IAi R_r'i OR^ SCIE4:IFIC ?.DVISORY BOARD !~T'-22CG NEW YORK, REW YORK K.ARCH 14-15-16, 1973 Dr. Sheldon C. Somers, Chairman Dr. Howard B.;Andervont Dr. Richard J. Bing Dr. MeKeen Cattell Dr. Willia= U. Gardner Dr. Robert J. Huebner Dr. Leon C. Jacobson Dr. Clayton G. Loosli Dr. Hans Meier Dr. Jo ::: F. Wyatt Dr. Mu:ray Senkus Dr. He1mLt R. R. i-akehar.. rr:. H. H H. Ra..=_ r_-. W. T. Hoyt Dr. Robert C. Hockett Dr. J. Morrison Brady Dr. Jo`sn H. Kreisher Dr. Frederic W. Nordsiek Dr. Vincer:t F. Lisar.ti Cr. Arthur Furst t+_ . Leonard S. Za.':n Scientific Consulta_-st, CTR Chairman, ZTC Chairman Elect, Z:-, President, CTR Executive Vice President, CTR Act:ng Scientific Director. CTR Associate Scientific Director, C':R Associate Scientific Director, C:R Associate Scientific Director, CTR Scientific Associate. CTR Research Consultant, CI'R Consultant, C.'R 1. The repcr: of the SeFte=~:er 1972 a.eetinc of the Scientific Advisory Board was aprsoved. 2. The repcrt, actions and recomezdatio.zs of the December 8, 1972 seeting of the Planninc Cor:ittee were approved, incluLing the following: $100,000.00 for reference ciqarettes S 62,500.00 to cover cost of rebuild.ing Walton Horizontal Saoke Exposure mac`.ines CTR ~ ~ ~-SAB 0~}0~~~

2 3. The following administrative actions were approved: 467-B Thomas C. Westfall, Ph.D. Permission was granted to extend this grant from December 31. 1972 to March 31. 1973 without additional funds. 519-B5 Louis A. Soloff. M.D. A supplementary grant vas approved in the amount $5,000.00 to provide additional funds for purchase of coassanable ' supplies and certain permanent equipment vital to the current project 547-C Joseph J. Guarneri, Ph.D. Permission was ,cranted to carry forward the unexpended balance of $549.59 to 547-CR1. 548-A S. N. Pradhan, M.D., Ph.D. Permission was granted to extend this grant for a second time from December 31, 1972 to September 30, 1973 with z additional funds. 623-Bsl Walter B. Essman, Ph.D. Permission was granted (1) to use unexpended funds in the approximate amount of $4,190.77, and (2) to extend the project from January 31, 1973 to March 31. 1973. 646-AR1 Robert C. Rosan, M.D. Permission was granted to transfer $4,900.00 irz Salaries to Equipment for the purchase of an electrophoresis scanner_ 646-F An uncommitted balance of $3,256.97 was returner and deposited. 702R2 Albert H. Niden, M.D. An unexpended balance of $204.51 was received an deposited. 704 Lucile Smith, Ph.D. An unexpended balance of 51.321.50 was received an deposited. 734R2 Carroll E. Cross, M.D. Permission was granted to transfer $1.200.00 from Salaries to Supplies, and $1,800.00 from Salaries to Equipment. Since overhead is not allowed for Equipment, a check for $270.00 (representing 15% of $1,800.00) was returned by the University authorities and deposited. The grant, therefore, has been reduced fron: $23,175.00 to $22,905.00. 764R1 Charles G. Cochraoe, M.D. Permission was granted to carry forward the unexpended balance of $644.30, thus reducing 764R2 from $31,269.00 to $30,624.70. S08 Allen B. Cohen, M.D. An unexpended balance of $327.50 was returned and deposited. 814 Una Smith, Ph.D. The September minutes reported a time extension withai additional funds from September 30, 1972 to January 31. 1973. This has been amended from September 30 to December 31. 1972. The renewal grant (814R1) therefore became effective on January 1, 1973. 826 Thomas R. Dawber, M.D. Permission was granted to carry forward the unexpended balance of $11,324.64 to the current grant 826R1. 833 A. Stanley Fleltaian, Ph.D. An unexpended balance of $3.665.71 was received and deposited. CTR H I il-.JAr~.~ 000400

3 839 Edwin R. Fisher, M.D. Permission was granted to carry forward the unexpended balance of $6,246.00 to the current grant 839R1. 844 Duane G. Wenzel, Ph.D. Permission was granted to extend this grant from June 30, 1973 to June 30, 1974 without additional funds. 854 Miss Eleanor J. Macdonald. Permission was granted to carry forward the unexpended balance of $794.31 for the pusposes of the project. 864 T. A. Slotkin, Ph.D. The September minutes reported the amount approved as $12,109.00. The correct amount approved was $12,110.00. 869 Ronald P. Rubin, Ph.D. Permission was granted to reallocate $2,425.00 from Equipment to Salaries. 891 Dr. Georg 8. Neurath. The December 1972 Planning Coamzittee seeting minutes reported the amount approved as $41,007.50. The correct amount aroroved was $41,000.00. Contract 1-C Mason Research Institute. The December 1971 minutes approved an appropriation in the amount of $7,000.00 and in the March 1972 minutes $15,000.00 to defray the salary and expenses of Dr. Charles W. Nystrom of R. J. Reynolds Tobacco Cosapany. These totaled 513,437.19, and the balance remaining of $8.562.81 is cancelled. - _ 2-D Microbiological Associates, Inc. An extension from February 1 to March 31, 1973 was approved on a pro rata basis not to exceed a total of $25,000.00 during that period. 3-B ZIT Research Institute. The following per diem and expenses were paid to Dr. G. P. Brierly for consultation and work on the contract: Per Diem 5240.00 and Expenses $165.00, totaling $405.00. March 31, 1973. This contract was cancelled as of 6-E I:T Research Institute. This contract was cancelled as of March 31, 1973. 9-B University of San Francisco. Expenses and per diesn in the amount of $442.50 for the period July 1 to September 30, 1972 were approved for Dr. Robert K. xovatch, and $624.50 for the period October 1 to December 31, 1972. Expenses and per diem in the amount of $417.15 for Dr. Jay A. Levy were approved. 4. The followinc changes in operating procedure as described by Dr. Soam+ers and Mr. Ra..:.. were approved: (1) An Executive Comr.ittee of the Advisory Board will replace the Planning Cor.^.:ttee which had been formed as a stopgap operation when Dr. Little became less active. Since the Board now meets twice a year. the Executive Coar:uttee wiil convene as needed during the intervals between meetir.cs, and planning work will be a function of the scientific staff ~TR HISIN-5R6 000401

- 4 - of The Council. The Executive Comaittee was confirmed composed of Dr. Somaners, Chairman, Dr. Jacobson, Dr. Bing, Dr. Loosli, Dr. Wyatt and Dr. Gardner, ex officio. Any three members constitute a quorum and are authorized to take actions on behalf of the Board as needed. (2) The 1973 budget is earmarked to a large extent for specific projects which are planned, rather than unsolicited ones. In order to pursue planned projects and to cull out and integrate desirable application into The Council's program from the increasing nteber of xmsolicited applications, all projects in future will be evaluated by the Scientific Advisory Board or, in its stead, by the Executive Coammittee. After such evaluation, the Scientific Director, or the Acting Scientific Director, will decide which projects shall be funded and at what rate. 5. The folloving renewal applications were recessoended for approval, subject to the determination by the Acting Scientific Director as to priority and the amount to be fundec: 24R17 Paul S. Larson, Ph.D. 49,795.00 310R12 Richard J. Bing, M.D. 38,893.00 519-BRl Louis A. Soloff, M.D. 85,000.00 547-CR2 Joseph J. Guarneri, Ph.D. 22,944.00 573-BR2 Clayton G. Loosli, M.D., Ph.D. 181,944.00 $84,000.00 was recoamenc for nine additional months. This figure was based on a pro rata of $112,000.00 per year. 623-BR2 Walter B. Essman, M.D., Ph.D. V 758-BRl Hans Meier, D.V.M. 763-AR2 John W. Parker, M.D. 786R2 H. Hugh Fudenberg, M.D. 802R2 Attallah Kappas, M.D. 808R2 Allen B. Cohen, M.D., Ph.D. 826R2 Thomas R. Dawber, M.D. 838Et1..: Baruj Benacerraf, M.D. 844R1 Duane G. Wenzel, Ph.D. 8a7R1 Wayne L. Ryan, Ph.D. 857R:. Jerone I. Kleine:-mar., M.D. 662R1 James Travis, Ph.D. 21,579.00 Terminal 23,310.00 37,950.00 Terminal 61,737.00 Terminal 49,925.00 Terminal 12,487.00 Terminal 54,625.00 Terminal 62,110.00 12,264.00 Terminal 55,261.00 Terminal 16,414.00 Terminal 22,237.00 ~~~ MTN-SAB 000402

- 5 - 6. The following renewal aaplication was rated-for disapproval: 486-BMFcl Anthony A. Albanese, Ph.D. 16,606.00 7. The following contract proposals were recaanended for approval subject to the determination by the Acting Scientific Director as to priority and the amount to be funded: - Contract 9-C University of San Francisco 139,139.00 14 Microbiological Associates Incorporated 350,000.00 15 0ak Ridge National Laboratory 208,500.00 8. The following new applications were recoaQnended for approval subject to the detera.:natiorn by the Acting Scientific Director as to priority and the aaour.: to be funded: 455-B Benjamin Bell, M.D. 64,000.00 586-D B. Bhagat, Ph.D. 36,805.00 599-: Domingo M. Aviado, M.D. 39,984.00 629-D Carlton K. Erickson, Ph.D. 16,735.00 642-B Leonide Goldstein, D.Sc. 28,579.00 725-CN Jack Chalon, M.D. 18,110.00 741-A Joseph M. Lauweryns, M.D., Ph.D. 38,806.00 764-B Charles G. Cochrane, M.D. 37,892.00 766-F. Richard A. Lerner, M.D. 64,385.00 767-A Gary D. Friedman, M.D. 101,100.00 870 H. J. Eysenck, Ph.D., Sc.D. 21,562.00 879 H. David Mosier Jr., M.D. 29,513.00 883 Ronald R. Hutchinson. Ph.D. 14,030.00 897 Robert C. Rosan, M.D. 54,615.00 896 Norman W. Heimstra, Ph.D. 12,592.00 24° Martha Greenwood, M.D. 24,035.00 CTR MIN -'-RRW 000403

- 6 - a The folloving new applications were deferred pending receipt of additional information: 88E T. J. Yang, Ph.D. 901 George Weinbau:r, Ph.D. 43,692.00 45,332.00 10. The following new applications were rated for disapproval: 776-A Elliot S. Vesell, M.D. 34,730.00 880 Kurt Amplatz, M.D. 51,449.00 881 Victor Milstein, Ph.D. 6,843.00 882 R. Robinson Baker, M.D. 69,411.00 884 Albert Castro, Ph.D. 48,545.00 886 . Harold J. Sobel, M.D. 31,050.00 887 Alvin H. Sacks, M.D. 42,197.00 890 Frederick L. Schaffer, Ph.D. 32,727.00 893 F. W. Grant, Ph.D. 29,125.00 894 Laigi Valzelli, M.D. 21,748.00 89-,- Joel Warren, Ph.D. 22.994.00 90 _~" Vict-cr J. Schenker, Ph.D. 35,410.00 902 Morton Galdston, M.D. 43,492.00 903 Jose:z Mendicino, Ph.D. 31.Z30.00' Case 164 Paola S. Timiras, M.D., Ph.D. 11. It was recoamended that the follo++ing contracts be closed out as soon as practicable: Contract 4 Bio-Research Institute, Incorporated 5 Bio-Researeh Consultants, Inc. 12. The next meeting of the Scientific Advisory Board was scheduled to be held on October 10-11-12, 1973. C I T R ;~ I W. -5) RP- 000404

- 7 - 13. The Chairman expressed the gratitude of the Board to Dr. Murray Settilcus for his efforts and cooperation with the Board during his term as Chairman of the Indust Technical Coao::ttee. The Chairman welcomed Dr. Helmut R. R. Wakeham as the incoming Chairman of the Industry Technical Committee for a term of two years. 14. Subsequent to the meeting, of the renewal applications recemeAded for approval and referred to in paragraph 5f the Acting Scientific Director determined that the following s hould be funded in the respective amo unts indica ted: ' 24R17 Paul S. Larson, Ph.D. 49,795.00 310R12 Richard J. Bing, M.D. 38,893.00 519-BP.1 Louis A. Soloff. M.D. 62,500.00 547-CR2 Jose_nh J. Guarneri, Ph.D. 22,944.00 No assurance of furthe: support. 573-BR2 Clayton G. Loosli, M.D., Ph.D. 84,000.00 for nine months, Oct. : '73 to June 30, '74. 623-BR2 Walter B. Essman, ~.D., Ph.D. 21,579.00 Terminal 758-BR1 Hans Meier, D.V.N. 23,310.00 786A2 H. Hugh Fudenberg, M.D. 61,737.00 No assurance of furthe: support. 80BF.2 Allen B. Cohen, M.D., Ph.D. 12,487.00 No assurance of further support. 826R2 Thomas R. Dawber, M.D. 54,625.00 No assurance of further support. 838ic1 . Ba=Lj Benacerraf, I'..D. 50,000.00 No assurance of further support. 857R1 Jerome I. Kleinerman, M.D. 16,414.00 Terminal 862R1 James Travis, Ph.D. 22,237.00 ~Tf'% MTN-'-AB 00040";

- 8 - 15. Subsequent to the meeting, of the contract proposals recoemiended for approval and referred to in paragraph 7 above, and•those recoemmended to be closed out in parag shoul raph 11 a d be fund bove, t ed in t he Acting Scientific Director determined that he respective amounts indicated: the following Contract 4 Bio-Research Institute, Incorporated 31,800.00 5 Bio-Research Consultants, Inc. 26,872.00 9-C University of San Francisco 114,856.00 14 Microbiological Associates Incorporated 350,000.00 15 Oak Ridge National Laboratory 208,500.00 16. Subsequent to the meeting, of the new applications recoameended for approval and referred to in paragraph 8 above, the Acting Scientific Director determined that the following should be funded in the respective amounts indicated: 455-B Benjamin Bell. M.D. 64,000.00 599-C Domingo M. Aviado, M.D. 25,000.00 642-B Leonide Goldstein, D.Sc. 28,580.00 725-0~ 741-A Jack Chalon, M.D. Josevh M. Lauweryns, M.D., Ph.D. 18,110.00 21,090.00 764-B Charles G. Cochrane, M.D. 11.000.00 766-A Richard A. Lerner, M.D. 47,385.00 787-A Gary D. Friedman, M.D. 101.100.00 870 h. :. Eysenck, Ph.D., Sc.D. 21,000.00 897 Robert C. Rosan, M.D. 2.175.OC 838 Norrsr. W. fieimstra 12,592.00 No assurance of further support. $14,290.00 c this amount had previc been comnzitted at the Dec. 8, '72 meeting of the Planning Committee paragraph 2 above. No assurance of further support. No assurance of further support. 510.546.00 0: this amount had previo: been coem+itted at the Dec. 8, '72 meeting of the Planning Coes.ittee paragraph 2 above. Terminal $25,275.00 of this amour• had previously been onamitted at the Dec. 8 '72 meeting of the Planning CoAaaittee in paragraph 2 above. in U.S. dollars. Terminal. CTR H.-I.N-5PRE 000406

27. Subsequent to the meeting, the Acting Scientific Director determined that the recoaaaendations for approval by the Planning Camanittee, referred to in paragraph 2, should be funded in the respective amounts indicated: $100,000.00 for reference cigarettes. $ 62,500.00 to cover cost of rebuilding Walton Horizontal 8aake Exposure Machines. Ir'TQ MTN-rOIAR M0dn'f

September 3, 1996 THE COUNCIL FOR TOBACCO RESEARCH-U.S.A., INC. SCIENTIFIC ADVISORY BOARD MEMBERS (1954 - Present) McKeen Cattell, M.D. (dec.) 1954 - 1973 Professor of Pharmacology Cornell University Medical College New York, NY Julius H. Comroe, Jr., M.D. (dec. ) 954 1960 Chairman and Professor Department of Physiology and Pharmacology University of Pennsylvania Graduate School of Medicine Philadelphia, Pennsylvania Director Cardiovascular Research Institute University of California Medical Center San Francisco, California Leon O. Jacobson, M.D. (dec.) 1954 - 1991 (Chairman 1981 - 1989) Professor and Chairman of Medicine Dean and Regenstein Professor of Biological Sciences University of Chicago Director Argonne Cancer Research Hospital (later named The Franklin McLean Memorial Research Institute) Chicago, Illinois 20229740.01

Scientific Advisory Board Members (1954-Present) Paul Kotin, M.D. 1954 - 1965 Professor of Pathology University of Southern California School of Medicine Los Angeles, California Chief, Carcinogenesis Studies Branch National Cancer Institute Bethesda, Maryland Clarence Cook Little, D.Sc. (dec.) 954 1971 (Chairman 1954 - 1957) President Roscoe B. Jackson Memorial Laboratory Bar Harbor, Maine Kenneth M. Lynch, M.D. (dec.) 954 1974 (Chairman 1958 - 1969) Chancellor and President Dean of Faculty and Professor of Pathology Medical College of South Carolina Charleston, South Carolina Stanley P. Reimann, M.D. (dec. ) 954 1968 Scientific Director Institute for Cancer Research Philadelphia, Pennsylvania Director Lankenau Hospital Research Institute Philadelphia, Pennsylvania William F. Rienhoff, Jr., M.D. (dec. ) 954 1972 Professor of Surgery Johns Hopkins University School of Medicine Baltimore, Maryland 2 20229740.01

Scientific Advisory Board Members (1954-Present) Edwin B. Wilson, Ph.D. (dec.) 1954 - 1964 Professor Emeritus of Vital Statistics Harvard University Cambridge, Massachusetts Richard J. Bing, M.D. 1958 - 1991 Director and Professor of Medicine Washington University Medical Service, V.A. Hospital St. Louis, Missouri Professor and Chairman, Department of Medicine Wayne State University College of Medicine Detroit, Michigan Director of Cardiology and Intramural Medicine, and Director of Experimental Cardiology & Scientific Development Huntington Memorial Hospital Pasadena, California Professor of Medicine University of Southern California School of Medicine Los Angeles, California Visiting Associate California Institute of Technology Pasadena, California Howard B. Andervont, Sc.D. (dec.) 1964 - 1966, 1970 - 1974 Scientific Editor The Journal of the National Cancer Institute Bethesda, Maryland Clayton G. Loosli, M.D. (dec.) 1966 - 1973 Hastings Professor of Medicine and Pathology University of Southern California School of Medicine Los Angeles, California 3 20229740.01

Scientific Advisory Board Members (1954-Present) Sheldon C. Sommers, M.D. 1966 - 1989 (Chairman 1970 - 1980) Clinical Professor of Pathology Columbia University College of Physicians & Surgeons New York, NY Director of Laboratories Lenox Hill Hospital New York, NY Robert J. Huebner, M.D. 1968 - 1981 Chief, Viral Carcinogenesis Branch Chief, Laboratory of RNA Tumor Viruses Chief, Laboratory of Cellular & Molecular Biology National Cancer Institute Bethesda, Maryland William U. Gardner, Ph.D. (dec.) 1971 - 1985 E.K. Hunt Professor of Anatomy Yale University School of Medicine New Haven, Connecticut Hans Meier, D.V.M. (dec.) 971 1981 Senior Staff Scientist The Jackson Laboratory Bar Harbor, Maine 4 20229740.01

Scientific Advisory Board Members (1954-Present) John P. Wyatt, M.D. (dec.) 1972 - 1980 Professor and Head Department of Pathology University of Manitoba Faculty of Medicine Winnipeg, Canada Director Tobacco and Health Research Institute University of Kentucky Lexington, Kentucky Averill A. Liebow, M.D. (dec.) 73 977 Professor and Chairman Department of Pathology University of California School of Medicine San Diego, California Henry T. Lynch, M.D. 973 - Professor and Chairman Department of Preventative Medicine and Public Health Creighton University School of Medicine Omaha, Nebraska President and Professor of Medicine Hereditary Cancer Institute Creighton University Omaha, Nebraska 5 20229740.01

Sci ntific Advisory Board Members (1954-Present) Joseph D. Feldman, M.D. (dec.) 1974 - 1995 (Chairman 1990 - 1994) Department Head Department of Immunopathology Scripps Clinic and Research Foundation La Jolla, California Member Research Institute of Scripps Clinic Scripps Clinic and Research Foundation La Jolla, California Editor Journal of Immunology San Diego, California Lee W. Wattenberg, M.D. 1975 - 1979 Professor of Pathology Department of Laboratory Medicine and Pathology University of Minnesota Medical School Minneapolis, Minnesota John E. Craighead, M.D. 1976 - 1977 Professor and Chairman Department of Pathology University of Vermont College of Medicine and Medical Center Burlington, Vermont Roswell K. Boutwell, Ph.D. 1980 - 1984, 1986 - 1990 Professor of Oncology McArdle Laboratory for Cancer Research University of Wisconsin Madison, Wisconsin 6 20229740.01

Scientific Advisory Board Members (1954-Present) Gordon H. Sato, Ph.D. 1980 - 1994 Professor of Biology University of California, San Diego La Jolla, California Director W. Alton Jones Cell Science Center Lake Placid, New York Michael J. Brennan, M.D. 981 - President and Medical Director Michigan Cancer Foundation Detroit, Michigan Professor of Medicine Wayne State University School of Medicine Detroit, Michigan Director Familial Cancer Prevention Clinic Harper Hospital Detroit, Michigan Drummond H. Bowden, M.D. 81 - Faculty of Medicine, Professor and Head Department of Pathology University of Manitoba Health Sciences Center Winnipeg, Canada G. Barry Pierce, Jr., M.D. 1982 - (Chairman 1995 - ) Distinguished Centennial Professor of Pathology University of Colorado Health Sciences Center Denver, Colorado 7 20229740.01

Scientific Advisory Board Members (1954-Present) Peter M. Howley, M.D. 1982 - 1986 Chief Laboratory of Tumor Virus Biology National Cancer Institute Bethesda, Maryland Manfred L. Karnovsky, Ph.D. 985 1995 Harold T. White Professor of Biological Chemistry and Molecular Pharmacology Harvard Medical School Boston, Massachusetts Alfred G. Knudson, Jr., M.D., Ph.D. 1986 - 1994 Fox Chase Cancer Center Institute for Cancer Research Philadelphia, Pennsylvania Jeffrey R. Idle, Ph.D. 986 1991 Reader in Pharmacogenetics and Welicome Trust Senior Lecturer Department of Pharmacology St. Mary's Hospital Medical School London, England Professor of Pharmacogenetics Department of Pharmacological Sciences The Medical School, University of Newcastle upon Tyne Newcastle upon Tyne, England James F. Glenn, M.D. 1987 - 1990 Professor of Surgery University of Kentucky Lexington, Kentucky 8 20229740.01

Scientific Advisory Board Members (1954-Present) Peter K. Vogt, Ph.D. 1987 - Chairman Department of Microbiology University of Southern California School of Medicine Los Angeles, California Member The Scripps Research Institute La Jolla, California Wolfgang K. Joklik, D.Phil. 1990 - Chairman Department of Microbiology and Immunology Duke University Medical Center Durham, North Carolina - Harmon C. McAllister, Ph.D. 1991 Scientific Director Council for Tobacco Research-USA, Inc. New York, New York Gordon N. Gill, M.D. 991 Chief, Division of Endocrinology/Metabolism Associate Chairman for Scientific Affairs, Department of Medicine Chairman, Faculty of Basic Biomedical Sciences University of California, San Diego School of Medicine La Jolla, California Barry G. W. Arnason, M.D. 1992 - Professor and Chairman Department of Neurology Director Brain Research Institute University of Chicago Chicago, Illinois 9 20229740.01

Scientific Advisory Board Members (1954-Present) Leo G. Abood, Ph.D. 1992 - Professor of Pharmacology and Biochemistry Department of Pharmacology University of Rochester Medical Center Rochester, New York - Raymond L. Erikson, Ph.D. 1992 American Cancer Society Professor of Cellular and Developmental Biology Biological Laboratories Harvard University Cambridge, Massachusetts Judith L. Swain, M.D. 993 Herbert C. Rorer Professor of Medical Sciences and Chief, Cardiovascular Division University of Pennsylvania Medical Center Philadelphia, Pennsylvania - Carlo M. Croce, M.D. 1994 Director Jefferson Cancer Institute and Cancer Center Philadelphia, Pennsylvania David D. Sabatini, M.D., Ph.D. 995 The Frederick L. Ehrman Professor and Chairman Department of Cell Biology New York University Medical Center New York, New York 10 20229740.01

Scientific Advisory Board Members (1954-Present) Hugh O'Neill McDevitt, M.D. 1996 Professor of Microbiology & Immunology, Stanford University School of Medicine Stanford, CA 11 20229740.01

LO

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Cc)*;NCIL FOR TOB.ICCO SSEARCFI-IT.S.,1. • , . COl'FIDEI4TIAL REPORT SC=TIFIC ADVISORY BOARD MSrTING New York, New York December 3-k, 1966 Attendance Dr. Kenneth M. Lynch, Chairman Dr. C. C. Little Dr. Richard J. Bing Dr. McKeen Cattell Dr. Leon 0. Jacobson Dr. Clayton G. Loosli Dr. Stanley P. Reimann Dr. William F. Rienhoff Jr. Dr. Sheldon C. Scaorers Mr. W. T. Hoyt Dr. Robert C. Hockett Dr. J. Morrison Brady Dr. John H. Kreisher Dr. Vincent F. Lisanti Guest Dr. E. S. Harlov Scientific Director, CTR Executive Director, CTR Associate Scientific Director, CTB Associate Scientific Director, CTR Associate Scientific Director, CTR Scientific Associate, CTR • The American Tobacco Company 1. The report of actions taken at the September Weeting was approved by the Board. 2. In view of the two new merbers of the Board being present for the first time, Dr.. Lynch requested that Dr. Little give a descriptiorn of the origin of The Council, its policies -- both scientific and lay -- and a definition of the proEtram of the Scientific Advisory Board. This Dr. Little did and, in conclusion, stated: "These policies are not advanced with amy claim for permanency or for exemption fr= exception should the occasion arise. They are, as stated, for guidance only. "(1) Approval of 3rants-in-aid should depend on their having direct or clearly pertinent bearing on the general field of tobacco use and health. " This condition is reail,y not restrictive since the opportunities and problems ^:1fi11i:s this requirement will undoubtedly be numerous enough to require the funds now available. Should we encounter more problems which meet this requirement than existing funds will cover, the fact that they do so will form the best Yossible erglaent for requesting additional funds to meet the needs. "(2) Effcrts shculd constantly be made to define suitable research programs to fill existi:.e gaps in our knowledge of effects of tobacco use on health especially in the fields of cancer of the lung, oral cavity, bladder and prastate, in coronary disease and in chronic respiratory diseases. io'~. T ~i ;~ ; a , :~~ ~ ~ ~,;-::~p' Zo GG~~;~G

"(3) Conferences either individu,al or group to discuss these categories of needed research should be freely used by the S.A.B. as in the past. "(4) Once a need for new research can be defined, iammediate end continuing search should be made for the personnel best trained and fitted to initiate and conduct a program of investigation approved by the S.A.B. "(5) Should the importance and probable duration of a research program justify it, the training of personnel to aid in the project shots3d be supported by The Council Frovided no personnel already trained is available. "(6) 2tirect controversy or destructive criticis:m should, as in the past, be avoided or kept at a minimum. Constrnctive planning and continued support of creative investigation should be our objectives. "(7) Where projects suggested by applicants for grants show prc®ise in the fields of cancer, coronary disease or chronic respiratory disease but have no evident relationship to tobacco use and health, the applicants should be guided by us tosrard one or more grantir,3 agencies whose programs might include their interests." 3. Adsainistrat_ve Actions #278R5 R. C. Reynolds, M.D. The grantee was given permission to use approxdmately $900.00 rer^,~.=*:rg at the termination of the grant for the purposes of the project. _ #290R2 William S. Murray, Sc.D. Permission was granted to use the uAexpended balance of $209.67 SYom his terminated grant for the purposes of the project. #408R1 Benjamin R. Burrows, M.D. Unexpended funds in the amount of $408.0l have been returned by the grantee. #k51R1 Martin S. Protzel, D.D.S. Permission was granted to spend $1,251.90 of unexpended funds :or equipment. #455 Charles L. Rose Permission was granted to re-allocate the br.cAet according to the needs of the project. #483MS F:ermaa V. Boenig, Ph.D. The supplerental request for $11,070.00, vhic` was reported at the Septe=ber 17-18, 1966 meeting, was denied. #+9215 Walter M. Booker, Ph.D. A supplement in the amount of $500.00 was approved to defray the costs of extra travel expenses. r ~t ~~w~t J ~r Li a

3 k. Stmnlementar7 Apalications #455S Charles L. Rose The Board aptrroved a supplement of up to $800.00, the final amount to be set at the discretion of the staff, for a pilo, study of smoking in relation to varying blood pressures. #k77MR1S Mares N. Carroll Jr., Ph.D. The Board agoroved a supplement of up to $2,000.00 covering technicians' salaries, to be negotiated by the staff . #513S $= Engelberg, M.D. The Board ap~arov_ed a supplemental request for $1,885.00 covering salary increases for the ten-month period beginnia September 4, 1966. I• Deferred A4nlications #553M George L. Wied, M.D. $20,670.00 Denied without prejudice. The staff rras requested to vrite hizi iaging hia to seek fknds elsewhere due to the ].imited applicability of the application to The Council's aims. Should this be impossible, the Board will reconsider the application at a later date. #56k Jorgen U. Schlegel, M.D., Ph.D. $k5,861.00 The Board ayproved approximatel,yr $23,000.00, subject to negotiation of final budget and clarification of potential ultiszate outcome. #565 Lie Sha Tsai, Ph.D. $59,081•00 The Board awroved for one year, subject to negotiation of budget in the range ~15,000-20,000. #576 Joseph H. Rogers, M.D. $48,875.00 The Board a oved, subject to negotiation of final budget, for approxfmately 45,000.00 covering an 18-month period with the proviso that the grant be administered throu the Holy Name of Jesus Hospital. 6. Renewal Art1,ca..ons # 80R12 1967 ?elloWship Program $56,000.00 A=roved. #338R4 F. F.czrburger, M.D. $59,096.00 Amroved for a fifth and final year. #k13R2 Cecile Leuchtenberger, Ph.D. $55,150.00 Approved for one year, with an anticipated two additional years at 7,150.00 annually. #k51R2 Martin S. Protzel, D.D.S. $31,353.00 Approved as final year of presen- plan. #486R1 Anthory A. Albanese, Ph.D. $13,869.00 A roved. #510R1 Donald Massaro, M.D. $9,315.00 Apzroved as final year in project plan #516R1 Donald M. Pace, Ph.D. $14,927.00 Approved for the finel year of a ts.ro year plan. ~~-- t~G02'7 ~ 1 1 1 A ~\ J 1~.r~~ 1^ i~

O #517R1 Albert Damon, Ph.D., M.D. $13,282.50 A roved, to complete two-year plan. #519R1 Louis A. Soloff, M.D. $33,600.00 Approved. 7. ftew ATrolications #458M Baiss H. Zinsser, M.D. $23,712.00 Denied. #578 Harry S. Bernton, M.D. $17,025.00 Denied in present Yo=m. It vas suggested that Dr. Bernton be invited to participate in a future immunological conference. #579 Haiter M. Chopra, Ph.D. $23,955.00 Deferred pending inquiry into other programs supported by industry and govesnmment (U.S. Dept. of Agriculture). #580 FTed K. HaWaven, M.D. $26,517.00 Denied. #581 E. Richolas Sargent, M.D. $10,786.00 Denied. #582 Arthur L. McDonald, Ph.D. $13,205.00 Deferred. The Board suggested that the protocol be changed to measure the more predictive par=metc of audiogenic and neuromuscular variations of mice. The Boar,iwishe encourage this approach. #583 $yman J. Roberts, M.D. $13,685.00 Denied.` #584 Silvio Garattini, Ph.D. $17,825.00 Deferred. The Board felt that t: project had Werit, but that it would be funded more appropriately b; supplement to his AMA-FRF grant. The staff was requested to invest: #585 George W. Smetters, M.D. (Thamas C. Laipply, M.D.) Request for consolidation of grants #363, 450A and 450-B with no additional :1mc The Board terminated all grants, requesting a financial accounting. Residual funds are to be applied at the grantee's discretion and expenditures reported. #586 #587 #588 #589 #590 Vincent Groupe, Ph.D. $76,989.00 Denied. Martin Irwin Gold, M.D. $12,650.00 Denied. B. Bhagat, Fh.D. $9,695.C0 Approved. Josel S upsenvol, M.D. $9,085.00 Denied. Robert A. Kuhn, M.D. $30,100.00 Denied.

Z * ' U #591 Paul S. Larson, Ph.D. $40,186.10 The Board a aved the publication of the second edition of 'Tobacco," but requested that negotiations t the staff be undertaken to reduce the cost as presented if possible. #592 Donald J. Massaro, M.D. $7,820.00 Deferred pending site visit by Dr. Sommers. #593 Ira Gore, M.D. $26,220.00 Denied. 8. The staff was requested to hold a conference on allergy and immunolo®r, S. It was suggested that a conference be held on the topic of food sad dietarr relationships to carcinogenesis (vitamin A effects, etc.). 10. Broda 0. Barnes, M.D. (#554) The question of the pathological records xhich e2dat - in Graz, Austria under the supervision of Dr. Ratzenhofer xas discussed. It xas the concensus that any future work on these should be done directl,jr rrith Dr. Ratzenhofe rather than through Dr. Barnes. Before another grant is made it was agreed that the at would consult with Dr. Robert Loeb at the World Pr:ealth Organization, and that Drs. Reimann, Sammers and Brady would maise a site visit during the first part of 1967 to determine the value of the hospital records at Graz. u. Dr. Sockett discussed the anticipated need on the part of grantees for smoldag ! machines. He explained that the smoki:.g machine developed by Mr. Walton in connection with the Fkdburger grant (#k56Rl) vould be ideal for that purpose, and requested that the staff be authorized to order approximately seven machines at a total cost not to exceed $10,000.00. Paya:ent for these machines would ultimately be made as their cost is added to new or renewal grants for which they will be needed. The saving per machine by this method is expected to be approximate]y $500.00. The Board avp~rov_ec the request aa presented. 12. The Board decided to meet with selected grantees and other investigators one day prior to the next meeting for an open discussion of their progress. ~. The Board vill hold a conference on tissue culture and its application on the day following the next meeting, and will suggest discussants to be included. 14. The next meeting of the Board will be held on March ~+-5, 1967. The meeting with - grantees and other investigators will take place on March 3rd, and the tissue cult conference will be held on March 6th. The location will be La Jolla, California (first choice) or Pasadena (second). , ~'~ T~'~-SR~ (~00~ r'~~ V'~ , , I. , .~.

TFTF CUIT~CIL FOR 'rof3.CC ~ZFSEAI2CFI-.S,c~, ZT r 1~ ~~I •' • t ,,j ! CORFZDEPITIAL REPORT SCgRTIFIC AWISORY BOARD MEETING September 23-24, 1967 Dr. Kenneth M. Lynch, Chairman Dr. C. C. Little Scientific Director, CTR Dr. McKeen Cattell Dr. Leon 0. Jacobson Dr. Clayton G. Loosli Dr. William F. Rienhoff Jr. Dr. Sheldon C. Sommers Dr. Helmut R. R. Wakeham Philip Morris, Inc. . . ,, ~. v I J Mr. W. T. Hoyt Executive Director, CTR Dr. Robert C. Hockett Associate Scientific Director, CTR Dr. J. Morrison Brady Associate Scientific Director, CTR Dr. John H. Kreisher Associate Scientific Director, CTR Dr. Vincent F. Lisanti Scientific Associate. CTR . The report of actions taken at the May meeting was approved by the Board. 2. Administrative Actions #385R2 William F. McNary Jr., Ph.D. Refund of $3,107.27 received and deposited. #409R2 Frederik B. Bang, M.D. Permission given to carry over balance of $5,181+.67 to the current year. #415R1 Duane G. Wenzel, Ph.D. A time extension was authorized for one year, without additional funds, to May 31, 1968. #448R1 John S. Waugh, Ph.D. A time extension to June 30, 1968 and use of uncommitted b alance of $11,495.42 was authorized for the purposes of the project. #4555 Charles L. Rose, A.M. A supplement in the amount of $3,300.00 was approved. #477MR2 Marcus N. Carroll Jr., Ph.D. Word has been received from the institutional authorities that Dr. Carroll's salary has been guaranteed until June 30, 1968. His grant has therefore been activated in the amount of $19,620.00, effective July 1, 1967. #489 E. T. Angelakos, M.D., Ph.D. A refund of $247.84 received and deposited.

2 C !! ^ ~ i #492R2 Walter M. Booker, Ph.D. The May minutes record the sum appr-644 is`~ $17,205.00 whereas the correct amount is $17,705.00. #k93M Barbara K. Watson, Ph.D. Reallocation of the grant budget was authorized to cover travel expenses in the amount of $229.00. #493trfftl Permission was granted to carry over balance of $5,072.88 from the previous grant. #495 Walter Redisch, M.D. Permission was granted to extend the grant from June 30 to September 30, 1967, and to use the uncommitted funds for the purposes of the project during that interval. A financial report was requested. #506 Roger K. Larson, M.D. A refund of $486.57 was received and deposited. #510R1 Donald J. Massaro, M.D. A refund of $4,105.83 was received from Georgetown University and deposited. A new check in this amount has been issued to Duke University for continuation of the grant. #516 D. M. Pace, Ph.D. The grantee has requested that an estimated balance of $1,000+ be transferred from the University of Nebraskaa to the University of the Pacific to be used for additional personnel and equipment. A letter has been sent to the University of Nebraska requesting a financial statement and return of the excess funds. #534R1 Paul Goldhaber, D.D.S. The final sum approved for the renewal grant is $22,938•75 which, with an unexpended balance of $458.00 from the previou grant totals $23,396•75, the amount originally requested. #559R.1 Sheldon C. Sommers, M.D. Permission was granted to carry over the balance of $1,359.29 from the previous grant. #573 Clayton G. Loosli, Ph.D., M.D. Permission was granted to transfer $5,600.00 from the personnel to the equipment category for purchase of a microtome. #585 George W. Smetters, M.D. The balance of $13,879.67 (grants #363, 450A anc 450B) was returned as requested and deposited. #591 Paul S. Larson, Ph.D. The final sum approved for the cost of publication of "Tobacco" is $36,586.77. #599 Domingo M. Aviado, M.D. Permission was granted to reallocate the budget to provide $750.00 for travel expenses. #614 Maurice S. Segal, M.D. The final sum approved is $34,500•00, representing $30,000.00 plus 15% overhead in the amount of $4,500.00. ~. Modified Application #613M R. Ernest Clark, Ph.D. $23,328.80 Withdrawn.

3 J ~I Supplemental Applications #456R2S Freddy Homburger, M.D. $6,000.00 Approved, representing consultant fee for Mr. Richard Walton. The staff is to ascertain how long this will be required. #13 67R2S Thomas C. Westfall, Ph.D. $7,500.00 Approved. #5505 John E. Craighead, M.D. $2,572.00 Approved. ~. Renewal Applications #223R8 Herbert McKennis Jr., Ph.D. $46,205.00 Approved without commitment beyond the current year. Any uncommitted funds remaining are to apply against this award. A conference with the staff will be held to discuss the future, other classes of compounds, and to determine which specific the Board is most interested in. #361R4 George 0. Gey, M.D. $58,400.00 Approved, to terminate June 30, 1968. Financial arrangements are to be agreed upon in conference with the staff. The starting date will be October 1, 1967. There will be no consideration of extension until the matter comes up at the June 1968 meeting. #409R3 Frederik B. Bang, M.D. $30,609.00 Approved for the fourth year of the original five-year plan. An extension for a sixth year was not approvec #455R1 Charles L. Rose, A.M. $18,500.00 Approved for one year. Consideration will be given to further support only after an accounting and a formal application are received at the end of the year. #523R1 Oswald R. Jones, M.D. $32,428.00 Approved in the amount of $10,000.00. Dr. Loosli will make a site visit in October. #558MR1 Gilbert H. Friedell, M.D. $31,050.00 Approved for a terminal year. #561R1 Geoffrey L. Brinkman, M.D. $12,109.00 Approved for the second year of a three-year program. #566R1 Kenneth M. Lynch, M.D. and Forde A. Mclver, M.D. $32,570.00 Approved for the final year of an original two-year request. #567R1 Lucio Severi, M.D. $15,000.00 Approved for the second year of a three- year program. Dr. Loosli will make a site visit in February or March 1968. #569R1 Kenneth M. Moser, M.D. $15,980.00 Approved for the second year of a two-year plan. #573R1 Clayton G. hoosli, Ph.D., M.D. $51,576.00 Approved for the second year of a two-year program. The balance remaining from the first year is to be subtracted from the above figure.

4 6. New Applications i -t #338A Freddy Homburger, M.D. $55,617.00 Deferred. Drs. Sommers and Kreisher will make a site visit. #611 John R. Rowlands $116,058.00 Deferred, pending review by industry scientists. Dr. Wakeham will take charge of this matter. #622 Irving Geller, Ph.D. $29,442.00 Deferred, pending definition of AMA-ERF relationship. #623 Walter B. Essman, Ph.D. Cattell. $13,570.00 Deferred, pending site visit by Dr. #624 John E. Noakes, Ph.D. $30,900.00 Deferred. Dr. Wakeham will review with the Industry Technical Committee and will arrange a site visit. #625 Harry Darrow Brown, Ph.D. $12,548.00 Denied without prejudice. #626 Walter Redisch, M.D. $16,795.00 Denied. #627 Fritz K. Beller, M.D. $26,391.00 Denied. #628 Theodore N. Finley, M.D. $26,105.00 Approved for the first year of a three-year program following clarification of any proposed animal studies with staff. #629 Carlton K. Erickson, Ph.D. $9,350.00 Approved for one year. #630 Mary Stearns Parshley, Ph.D. $20,169.50 Approved for one year subject to re-assessment of program. A conference with the staff concerning ezperimental methods is planned. #631 Edward F. Domino, M.D. $28,565.00 Approved for the first year of a three-year program. #632 Jack P. Strong, M.D. $20,516.00 Deferred, pending a conference with staff and Mr. Enslein. #633 Saul Boyarsky, M.D. $61,950.00 Denied. 7. Following discussion of the Leuchtenberger project and other experimental results, the Board approved in principle the need for an enlarged smoking inhalation progrec including smoking machine development, testing and animal experiments. The staff was authorized to investigate laboratories where such experiments might be carried out. Specific experiments now underway at the Mason Research Institute and the University of Southern California will be assessed in the light of current needs. 8. A two-day conference on the fundamentals and applications of tissue culture was suggested. It should include discussion of in vitro changes in tissue cultures an their applicability to in vivo situations.

- 5 A conference on macrophages and the involvement of the reticuloendothelial system in relationship with smoking and health was suggested. .2. The next meeting of the Board will take place in New York City on December 9-10, 1967. ~

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~ ~ .,J;.1 CONFIDENTIAL REPORT SCIENTIFIC ADVISORY BOARD MEETING La Jolla, California March 2-3-4, 1968 th M. Lynch, Chairman Little ].don C. Sommers on G. Loosli 0. Jacobson J. Bing n-Cattell Industry Technical Committee T. Hoyt C. Hockett rrison Brady H. Kreisher nt F. Lisanti d would be desirable at some mutually convenient date. was resolved that a meeting between Council members and the Scientific Advisory essing sympathy and deep regrets at the passing of Dr. Reimann. 1esolution was passed by the Board to be sent to Mrs. Stanley P. Reimann, one year. : Irynch was re-elected Chairman of the Scientific Advisory Board for a period Scientific Director, CTR Executive Director, CTR Associate Scientific Director, CTR Associate Scientific Director, CTR Associate Scientific Director, CTR Scientific Associate, CTR - _ Enslein (3/2/68) report of actions taken at the December meeting was approved by the Board. &dministrative Actions 23M2R2S B. Eichel, D.D.S. A supplement in the amount of $10,500.00 was granted to carry on the work through the grant period. 519R2 Louis A. Soloff, M.D. The final sum agreed upon was $33,600.00. 4572R1 T. Timothy Crocker, M.D. Permission was granted to transfer $2,900.00 from personnel funds to the equipment category. Samuel Bellet, M.D. Permission was granted to use $600.00 of the grant funds toward the expense of attending the Interamerican Congress of Cardiology and the Interamerican Congress of Atherosclerosis.

-2- O~.,~~ , . Deferred Applications #451-A Martin S. Protzel, D.D.S. $32,976.65 Continuation of support was #609R1 authorized on a month-to-month basis at a rate to be negotiated by the staff with consideration of carryover funds available and the requirements of experiments not yet completed. Such support was not to continue beyond July 1, 1968, and it was understood that following conferences with staff and/or Board members a new proposal would be submitted for action by the Board not later than the May meeting. Arthur Furst, Ph.D. $33,314•00 Continuation of support was authorized on a month-to-month basis until June 1, 1968 at a rate to be negotiated by the staff, for rounding out experiments actually under way and nearing completion. It was understood that conferences with Dr. Loosli on lung pathology and with staff on smoking machines would be held with the expectation that a new proposal will be submitted for consideration not later than the May meeting of the Board. Donald B. Louria, M.D. $28,975•00 A proved as a six-month terminal grant from July 1 to December 31, 1, in the amount of $14,487.50. John R. Rowlands, Ph.D. $46,058.00 Approved for one year at an amount to be negotiated by the staff but not to exceed $20,000.00. Norman W. Heimstra, Ph.D. $5,116.50 Approved for a one-year program. At the request of the grantee, the starting date was changed to June 1, 1968. ~J_- Supplementary Applications #614S Sanford Chodosh, M.D. (Maurice S. Segal, M.D.) $12,375•00 Approved for the purpose of preparing data in the proper form for Mr. Enslein's computer program. Renewal Applications # 24R12 Paul S. Larson, Ph.D. $25,745.00 Approved for one year. #310R7 Richard J. Bing, M.D. $11,478.00 Approved for one year. #413R3 Cecile Leuchtenberger, Ph.D. $55,405.00 Approved for continuation on a monthly pro rata basis ($4,617.00) until appropriate reports are received assuring satisfactory progress and until conferences are held with staff and Drs. Loosli, Huebner and Sommers concerning future plans. A revised proposal is to be considered at the May meeting. #493MR2 Barbara K. Watson, Ph.D. $20,845.00 Approved for the third year of a three-year plan. #528R2 Sue Buckingham, M.D. $62,766.00 Approved at $31,624.00 for the third year of a three-year project, plus Dr. Buckingham's salary at $13,000. and additional fringe benefits of $2,600, for a total of $47,224.00 plus an appropriate adjustment for overhead.

- J - American Dental Association Fellowship Program. $37,000.00 Approved for one year. Donald J. Massaro, M.D. $9,278.00 Approved. Terminal. Ulrich Schaeppi, M.D. $10,160.00 Approved for the second year of a three-year proposal. #608R1 William F. McNary Jr., Ph.D. $15,927.00 Approved for the second year of a three-year proposal. #618R1 Edmond A. Murphy, M.D., Sc.D. $8,625.00 A proved. Terminal. #620R1 Willis H. Riesen, Ph.D. $50,609.00 Approved at $40,036.00 for one year. Dr. Sommers will investigate the feasibility of adding a histological study at a modest additional cost. New Applications #477-A Marcus N. Carroll Jr., Ph.D. $44,471.00 Deferred until the May meeting. It was suggested that in the interi.m he continue his old work accordin4 to the original proposal, and work out the details of conditions for controlled smoking, define his objectives more clearly and reduce the amount of money requested. #F91-A J. P. Long, Ph.D. $14,432.00 Approved for one year of a proposed three- year plan. #513-A Hyman Engelberg, M.D. $31,300.00 Denied. #517-AM #543-A Albert Damon, Ph.D., M.D. $11,270.00 Denied. Ulrich Schaeppi, M.D. $17,260.00 A roved for one year. #607-A Samuel Bellet, M.D. $17,870.00 Approved for one year. #64b Robert C. Rosan, M.D. $21,406.00 Approved for the first year of a threc year proposal. Daniel H. Wiseman, M.D. $41,330.00 Approved for the first year of a three-year propos al. #648 Melpar, Inc. $65,6 37,00 Denied. #649 Melpar, Inc. $28,7 80.00 Denied. #650 E. T. Angelakos, M.D., Ph.D. $12,075.00 Denied. #651 Norman D. Tabachnick, M.D. $4,780.00 Denied. #652 Maximo Dysine, M.D. $31,457.00 Denied. #653 Richard Ehrlich, Ph.D. $29,188.00 Deferred, pending site visit by Dr. Loosli.

#655 #656 #657 #658 I Herry Darrow Brown, Ph.D. $25,145.00 Denied. Sheldon B. Sparber, Ph.D. $23,597.00 Deferred, pending staff inquiry into psychological criterion and lethal dose response information. Michael Duffell, M.D. $11,245.00 Denied. Charles P. Larson, M.D. $47,490.00 Denied. , The Board approved the expenditure of $5,000.00 for travel expenses of speakers to a Bladder Cancer Conference to be held at the Statler Hotel in Boston on June 6-7. ,fbis program was organized by Dr. Gilbert H. Friedell of New England Deaconess Hospital. It-was felt that useful information arising from this conference should be made available in a published form and that the staff should investigate this possibility. A: George W. Smetters, M.D. (Thomas C. Laipply, M.D.) (#585M) The balance of $9,047.44 will be requested to be returned to The Council. If new studies are to be undertaken, a grant should be applied for in the customary manner. Dr. Lisanti presented an outline of animal inhalation studies proposed by the Mason Research Institute of Worcester, Massachusetts at an approximate cost of $350,000.00 per year for four years. It was explained that the proposal was still tentative, and the Board felt that it would have to be firmed up in considerable det ail before any final action could be taken on it. The Board requested Drs. Loosli, Sommers and Jacobson to make a site visit to Worcester and report back to the Board at its May meeting. The Board went on record as follows: "The Board favors the pursuit of a program for research work such as Mason Research Institute proposes, dealing with inhalation of whole smoke or fractions thereof, either at the Mason Research Institute or elsewhere, such a program to be funded from other than the Board's present budget. In view of the present Mason proposal and to attempt to develop it, it will be necessary for The Council to provide Mason with $15,000.00 a month for three months to continue feasibility studies and to do such other work as may be needed. Any program from Mason would have to conform. to satisfying the Scientific Advisory Board." Whatever total cost is indicated for the proposed Mason program should include whatever Mr. Enslein's participation would be. Also, any budget for work of this sort would necessarily have to be flexible. 12. Mr. Kurt Enslein presented a slamary of the applications of multivariant analysis. He explained that in his interest in the search for meaning of results he required various facilities. He related his technique and methods, as well as their applicabilit to the SAB program, by explaining work which he had done with the Rose, Thomas and Chodosh data. The Board thought highly of this application of multivariant ana],ysis and in discussing the methods of financing it, felt that Mr. Enslein should serve as a consultant to the staff. The Board also felt that, in instances where an investigator wished to use Mr. Enslein and the computer technology availab le to him, a supplement to the investigator's grant should be requested by each grantee which would be added to the basic grant approval.

-5- S: , Somers reviewed the situation in Graz, Austria, and defined what would be tion and present it to the staff. provide a written semzmary of what would be necessary to conduct such an ied to undertake this project. Dr. Sommers estimates that such a study would miaianym of five years and would probably cost between $500,000 and $1,000,000. deAce. He knows of a pathologist, Dr. Klaus Schreiber, who would be willing and have to be prospective and would require a good, full-time pathologist in reQui.red to conduct a significant study capitalizing on the material there. It ^The Board discussed informally a project in which Dr. Carl Seltzer proposes to t:tollow up the medical histories of 100,000 U.S. Army men who were somatotyped by etarting in 1942. The medical history of these individuals and the causes of 'ath among the decedents would be determined in order to relate body build and other ical characteristics to medical history. The Board felt that this study has entific merit but not in the form of one of its grants-in-aid. Dr. Griffith discussed the tobacco-related programs at the University of Kentucky. He reported on the standards recommended by the Industry Technical Committee for reference cigarette. Such a cigarette could be available by May 1968. The anticipate s of The Council grantees with regard to numbers of cigarettes was to be determined the staff. It is contemplated that the reference cigarettes would be produced every, ix months by a manufacturer selected on a bid basis. These reference cigarettes would .available at an estimated 50% of market cost to tax exempt institutions and would be ,ed through the University of Kentucky under the supervision of Dr. G. W. Stokes. 17. The Board requested Dr. Griffith to have the Industry Technical Committee submit suggestions for new ideas or developments which might lead to increased effectiveness of smoking devices. 18. Dr. Donald J. Massaro of the George Washington University School of Medicine will be invited to attend the next Board meeting. His curriculum vitae will be mailed out in advance to Board members. . The next meeting of the Board will be held in New York City on May 25-26, 1968.

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I TRE CUC\CIL FOR TOn.-,CC, 2ESEARCTr-L.$.A, r I . ~ . - . V i .. ~ C014FIDERTIAL ?RPQRT SCZEHTIFIC ADVISORY 30ARD MEETIRG Aev York, New York May 16-18, :.969 Dr. Kenneth M. Lynch, Chairman Dr. C. C. Little Dr. Howard B. Andervont Dr. McKeen Cattell Dr. Robert J. Huebner Dr. Clayton G. Loosli Dr. WilLiam F. Rienhoff Jr. Dr. Sheldon C. Sommers Dr. A. W. Spears MOr. . Heary H. Ramat Mr. W. T. Hoyt Dr. Robert C. Hoclcett Dr. J. Morrison Brady Dr. John H. Kreisher Dr. Vincent F. Lisanti Dr. Arthis Furst Smoking Machine Subcommittee, ITC - 5/16/69 Dr. Robert B. Griffith Dr. Thomas S. Osdene Dr. S. A. Ridlon Dr. Robert Spivey "J,.' G. . Scientific Director, CTR Research Director, CTR Vice Chaizman, ITC Cbaizman, Pro Tem. Execntive Director, CTR Associate-Scientific Director, CTft Associate Scientific Director, CZR Associate Scientific Director, CM Scientific Associate, C2R Research Consultant, CZR University of lCentucly Philip Morris, Inc. R. J. Reynolds Tobacco Compamr Brown & Williamson Tobacco Corporatic 1. The report of actions taken at the March meeting was approved by the Board vith the addition of $56,000.00 ann~ved for the Summer FelLowship Program. 2. The appointments of Dr. Sheldon C. Sommers to the position of Research Director and Dr. Arthts Furst as Research Consultant were announced. I• Administrative Actions F. Hcmburger, M.D. $13,000.00 A three-month extension to June 30, 19E was approved to continue animaL experimenta under way in the project. Cecile Leuchtenberger, Ph.D. $200.00 A supplement for travel expense; vas a roved for JacqueL'ae Blanchard. Rose Marie Pangborn. A six-month extension to December 31, 1969 was authorized without additional funds. #L93Mft2 Barbara K. Watson, Ph.D. Permission was granted to use unexpended ltin, to phase out and publish the results of her studies. A financial report has been requested.

f I - 2 - `\ r % A _/ , ; . .. .. i #528R2 Sue Buckingham, M.D. (deceased) Dr. Sheldon C. Sa®aers and Dr. Edward Curnen Jr. have undertaken the responsibility for liquidating the project as of June 30, 1969. Experiments in progress will be complet by Mildred Rothenberg, Te=hnician, and a final report and two papers for publication are being pre;.ared. The staff authorized budgetary transfer of approximatel;r S6,CCO.CO for purchase of equipment needed to improve alkaline phosphatase deter=lnations involved in the concluding phases of :.:«: study. 'a-hen liquidation is completed, a bslance from the grant -rill be refunded. #548R2 S. N. Pradhan, M.D., Ph.D. Follovir.g a staff visit, a reallocation of budget vas authorized froet the salary category as follows: Equipment $1,500 Travel 500 Laboratory alterations 2,000 #555-A Gene M. Smith, Ph.D. A reallocation of budget was authorized to cover travel expenses of $1,048.10. #561R1 Geoffrey L. Brinhan, M.D. A check for $207.42 was received and depos_ An unexpended balance of $2,000.00 was carried over to the current project (#561R2). #604R1 Richard H. Earle, M.D. A reallocation of budget was authorized :n the amount of $2,270.00 to psachase a carrier preamplifier and display oscilloscope and camera. - A09R1 Donald B. Louria, M.D. The Board approved the transfer of $9,091.26 f: the 1967-68 budget (#609) into the current year, and the continuatio: the grant through June 30, 1969 using the $11,551.81 on hand without further funding. The staff will aake arraagements with regard to thc budgetary breakdown and the activities to be carried out under the g: #618R1 Edmond A. Murphy, M.D., Sc.D. A reallocation of budget was authorized the amount of $750.00 from computer cost to medical student assistan- #629 Carlton K. Erickson, Ph.D. An uaexpended balance of $688.79 was recei• and deposited. #&+6R1Id Robert C. Rosan, M.D. Permission was granted to carry over the unexpe balance of $3,350.17 to the present grant. #647R1 Daniel Wiseman, M.D. The Board approved the requested transfer of $3,252.65 from the salary to the equipment category for the purchase a portable tape recorder and exhibit demonstrating computer techniaL: for blood gas ana]ysis, a nitrogen anal,yzer and a peak flow meter fo pulmonary function studies. The Board also approved the purchase of such office equipment and supply items replacing inefficient equipme now being used in conjunction with the project. #661R.1 Bruce Cameron, M.D., Ph.D. Permission was granted to transfer the prc from the New England Institute to the University of Miami School of Medicine effective June 15, 1969. The Board approved the transfer c $3,300•00 from salaries to permanent equipment, specifically to repl equipment within the statistical and chromatographic anal,ysis requir under the project. '"68 Stephen M. Ayres, M.D. A reallocation of budget was authorized to transfer a4,000.00 from consimmable supplies to personnel.

3 - ... J 4. Supplesnentsry Applications #519-AS Louis A. Soloff, M.D. $k,CC0.00 Agproved as follows: Salary increases $2,500 2 senior technicians, $1,000 each 1 Junior techn±cian, 500 Fringe benefits at 10.84 270 Supplies and materials 1,230 #572-AS T. Timotkw Crocker, M.D. $23,261.00 Approved subject to staff decis: #588-AS based on information conceraing support by other granting organizat: B. Bhagat, M.D. $12,025.00 Deferred until the September meeting vher the renewal application vill be considered. #603S2 Shirley L. ICauffman, M.D. $300.00 Approved to cover overhead on #60' #64083 David M. Goldenberg, M.D. $14,418.00 Approved to cover a six-month extension beginaing October 1, 1969 through March 31, 1970. A site visit vill be scheduled to check on faci3.ities to determine if the project is being carried out as plaaaed. S• Deferred Applications #611-A John R. Rovlands, Ph.D. $48,880.00 Approved for one year of a propo #69L+ three-year program, subject to possible modification in the event c duplication of support by the AMA. If interim support is necessary duaing negotiations, pro rata ertension of last year's $20,000.00 g xas authorized. . William A. Carter, M.D. $25,214•00 Approved for one year of a propo two-year program. A report on progress will be requested at the en aine months so that consideration can be given for a second year. #709 Lucio Severi, M.D. $15,000-00 Approved for one year without lurther coemitment. Dr. Huebner vill nalce a site visit. #713 Lars Friberg, M.D. $20,000.Oi` Denied. Staff conferences with inter experts vill be undertaken as a guide to possible further considere 6. Applications for Continuation #546-A Iaes Mandl, Ph.D. $33,875.00 Approved for one year of a proposed tt year program. #54?-B Joseph J. Guarneri, Ph.D. $14,882.00 Approved for one year of a prc two-year project. J548-A S. N. Pradhan, M.D., Ph.D. $11,490.00 Deferred pending consideratic the SAB Planning Ccmmit'„ee and until the opinions of Drs. Bing and Jacobson ca•n be made available.

O -4 J ; 7. Renewal A4olications #467-AR1 T^aomas C. Westfall, Ph.D. $27,913.60 Approved for the second year of an origina]ly-proposed three-year project. #631R2 Edward F. Damino, M.D. $30,'G21.C0 ADvr` oed for the third and terminal year of an origir.al three-year plan. :he staff was requested to investigate The Uai•rersit-I of blichigan statement regarding hiffiaa subjects for experinental research. #668R1 Stephen M. Ayres, M.D. $30,382.00 Approved for the second year of an origima 1 1 proposed three-year program. 8. Posttoned Atmlications #701 Carroll E. Cross, M.D. $23,425.00 Denied. #702 Albert H. Niden, M.D. $17,415.00 Ap_oroved for one year of a proposed three-year project. #703 #706 #707 #708 #710 #711 #712 Edward Leete, Ph.D. $30,101.00 Denied. John V. Weil, M.D. $29,304•00 A d for one year of a proposed tvo• year project. Robert Llamaa, M.D. $29,092.00 Denied. Aormaa W. Heimatra, Ph.D. $9,890.00 Delerred. I. Gordon Fela, Ph.D. $30,581.00 Denied. Patrick R. Atkins, Fh.D. $11,352.00 Denied. Ulrich Schaeppi, M.D. $17,140.00 A d for one year ssbfect to rert at the end of that period. Q. New Atelicatioas #715 William Regelson, M.D. $19,851.00 Approved for one year of a proposed three-year program. #716 Herschel Sidransipr, M.D. $27,961.00 Denied. #717 P. 1C. Kadaba, Ph.D. $19,426.25 Denied. P18 Irving Goodman, Ph.D. $44,182.00 Denied.

10. The Board discussed the ongoing analysis under Mr. Kurt Enslein. The program vill l - reviewed by-knavledgeable statisticians, and by Urs. Sommers and Furst, who vill reI back on its status and relevance to the overalr C-_j program. This will continue to be funded at the current level ($10,000.00 per month) until the September meeting. 11. Dr. Homburger's investigation (#338-A), including skin painting of smoke condensate: - from old and new cigarettes on mice backs, direct smoke applica,_Vn, as well as :ut, proposed inhalation experiments will be reviewed by Drs. S-rs and Furst before the September =eeting. Funding wi11 continue untir' that meeting at a rate not to exceed $13,000,00 a quar~,.er when overall program interrelationships wi11 be defined. The methoc used in defining histological change must be i=proved, and the question of the type of mc used and the methods of appraising lung irritation clarified. 12. Dr. Sommers was elected Chairman of the Planning Cooa4ittee of the Board, and also oi the Subcommittee of the Joint Committee on Tobacco and Health replacing Dr. Loosli. Multiple maitings for the Planniag Committee vill be handled by Mr. Hoyt acting as Secretary. 13. The Board discussed the matter of greater emphasis on planaed and directed programs as well as the rules to be applied thereto. These .+onld include initiation and decision-makiag procedures for solicited grants and provisioa for staff monitoring. It v:s mo+Fed that the Board instruct i2rs. Sommers and Furst to obtain specific information c all proposals before they are presented to the SAB, and to advise concerning the relevanc priority and scientific merit of such progosals. The Board also requested that Drs. Sommers and F1ast recosmmend priorities in the SAB program with regard to scientific disciplines and consider the grants and contracts.in relationship to one another vithin the overall program. 14. Smoking Machine Development Representatives of the ITC Smdcing Mark4*+~ Subco®ittee reported to the Board on their progress. a) Dr. S. Ridlon of R. J. Reynolds Tobacco Ccmpany reported that their machine, previously demonstrated for a subcommittee of the Board, has been in operation since January 1969 with no unforeseen mechanical difficulties. Up to 40 rat3 or mice can be smoked per hour, and the criteria set forth had been met. The cost, in groups of five machines, would be $5,000-5,500 with delivery in approximately 90 days. b) Dr. Thomas Osdene of Philip Morris, Inc. reported on their smoking machine, incorporating the Venturi principle, which has been operative for over one ye_ Deposition accounts for 15% of the particulate. Up to 30 rats or 100 mice can be smoked at one time. Cost would be between $5,000-10,000 including a CO monitoring system, with 3-4 months for delivery. c) Dr. Robert Spivey of Brovn & Williamson Tobacco Corporation reported on their prototype smoicing machine, developed in coordination with Scientific Associate Inc., a commercial subsidiary of Battelle Memorial Institute, Columbus, Ohio. Various features were pointed out including an automatic loading syatem, duel cerrousela holding 15 cigarettes each, and the possibility for infinite variation in smoke dilution. The development of animal-holding equipment is under va,y. Costa were estimated at $8,000-10,000 in quantity but do not inch animsl exposure chambers.

It xas moved that the Board express, through Dr. Spears, its appreciation of the expeditious hAndlI^g of the charge given to the ITC, i.e., to develop smoking machines fulfilling predetermined specifications. The Board expressed the wish to have several of each of the machines made available at designated laboratories as soon as possible for biological testing. '*he procedures and criteria for this testing will be determined by Drs. Sosmters and Furst. 15. The Board discussed the document prepared by Drs. Sommers, Loosli and Jacobson for the Joint Subcormittee on Smoking and Health. Dr. Soasners explained that the Subccemtiittees of :aX-AMA-CTTt expected to get together shortly to decide which points the; could agree upon and these, in turn, would be presented to the Joint Cammittee at the tiz of the AMA meeting in July. The Board felt that the latest version of the document prepared by the Subco®mittee comprising Drs. S-rs, Loosli and Jacobson could be (a) the basis for ongoing tobacco and health programs; 'b) used in the Scientific Director's Annual Report; and (c) used ii defiaing priorities in plarsaed research, i.ncluding proposals for reZerence nicotine cigarettes and smnkin$ machines, etc. 16. Dr. Robert Grifath discussed the nev Tobacco and Health Institute developing at thc - University of Kentucky of which he wi11 be the Director. This Institute. seeks state USDA, IV= and CZ'R ftmding, and its mission xi].L be to investigate ttather such areas as reference cigarettes, smoking machj*+es (incl"~~ biological-testing), and other medical and technological aspects of the tobacco and health relationship. The Institute, while F distinct entity, would utilize and coordinate the lUll spectrs~ of the University and Medical School faculties. 17. Viral Etiologr of Cancer The Board discussed the preliminary proposal trom Microbiological Associates, Inc., Bethesda, Maryland. This matter was referred to Drs. Sommers and Furst who vill make a site visit. 1$. Dr. Sommers outlined the following proposals which are not yet in the form of applications. He and Dr. Furst will consider and have each one worked up: (a) Dr. Russell Sherwin (University of California) has proposed, in conjunction with the Rand Corporation, a feasibility study using punch-card data to defiae criteria for the diagaosis of emphysema. This approach would use his point-counting photometric scanner as a basis for pathologic diagnosis. (b) Dr. Atan G. Foraker (Jacksonville, Florida) would like to contribute to a regional study of lung disease possibly coordinated with Dr. Thurlbeck (Montreal), Dr. David Spain (#678, New York) and another iuvestigator, possibly in California. The staff will talk with him and investigate his interest further. (c) Dr. Chalon, a cytologist, is interested in a sputzmm cytological diagnosis technique or possibly a program smaller but similar to that of Dr. Csodosh (#614R1).

0 -7- J . - - 12. Dr. Robert Griffith presented proposals for (a) further development of a smoking machine, and (b) development of cigarettes with varying amounts of nicotine at the University of Kentuclpr Tobacco and Health Institute. These were discussed but no action was taken since the proposals were not in the form of tormal applications and the Board felt it needed more information of a detailed nature on both. 20. The next meeting of the Board vill be held in Hev York City on September 12-13-1b, 1969.

TFiE COUICIL FOR TOA.%.CCG :ESEARCR-U.S..A- -.. C024FIDmr'."t'.'T..AL ?.E?:.'RT SCIENTZ T_,^. ADVISORY BOARD MEETI:IC New Yort, New Yrrk Septe=ber 1-14, 1969 Dr. Kenneth M. Lynch, Chair-...an Dr. C. C. Little Dr. Howard B. Andervont Dr. Richard J. Bing Dr. McK,een Catteil Dr. Robert J. Huebner Dr. Leon 0. Jacobson Dr. Clayton G. Loosli Dr. William F. Rienhoff Jr. Dr. Sheldon C. Sommers Scientific Director, C--R Research Director, CTS Dr. Alex W. Spears Mr. Henry H. Ramm Mr. W. T. Hoyt Dr. Robert C. Hockett Dr. J. Morrison Brady Dr. John H. Kreisher Dr. Vincent F. Lisanti Dr. Arthcr Furst Mr. Leonard S. Zahn Dr. Edward H. Ahrens Jr. (9/12/69) Chairman, ITC Chairman, Pro Tem., CZq Executive Director, C":.R Associate Scientific Diz-ector, CTR Associate Scientific Director, CZQ Associate Scientific Director, CTR Scientific Associate, C-:.R Research Consultant, C':R Consultant, CZR Professor, Rockefeller University 1. The report of actions taicen at the u.ay .:.eeting was approved by the Board. 2. The appointment of Mr. Leonard S. Zahn to the position of Public Relations Consultant was announced. ~. Administrative Acticns #223R9 Herbert McKerais Jr., Ph.D. Permission was granted to allov the balance of $17,389.62 remaining as of the termination date, June 30, 1a69, to be used to complete the project. #310R8 Richard J. Bir.g, M.D. ?ers<ission vas granted to transfer the project from Wayne State University to the University of Southern Csllforn;a effective October 1, 1969.

, #338-AS2 #415-A #566-A F. Homburger, M.D. 213,000.00 A three-month September 30, 1969 was n roved. extension lo ` ~ Duane G. aenzel, ?h.D. A five-month extension to Febraarf 1, 1970 vas authorized :rithout additional funds. Kenneth X. I;f::ch, M.D. A one-year extension to Septe=ber 30, 1970 was authorized wi:hout additional funds in order to complete the project. O11,.5 John R. Rowlands, Ph.D. A.*our-month extension to Sertenber 30, 1969 was apprved :n the amount of $6,667.00, representing a pro rata payment oi ::e original authorization of $20,CCO.CO. #630 Mary Stearns Parsii'_ey, Ph.D. A second three-month exzension was authorized to September 30, 1969 without additional funds. #681S Shoji Shibata, M.D., Ph.D. $440.42 Supplement was a-_.roroved to provide an `-r.c.:ease of 8% on all salaries and wages as of Julq l, 1969. #702 Albert H. Niden, M.D. A reallocation of budget of $2,000.00 ($800.00 from service contract and $1,200.00 from rersonnel) was authorized to biy a pcotomicroscope. Since this represents•a shift to permanent equipment for which no overhead is authorized, the grant has been reduced by $300.00 #714 Murra,y B. Gard:er, M.D. A reallocation of budget was authorized in the amount of s6,C00.00 to include the use (60% of the time) of a data processing irogrammer. #715 Willisa Riegelson, M.D. Permission was granted to transfer $3,000.00 frx :`.:=is for mouse purchase to the per=anent equipment category toward the purchase of a gamma counter. 4. Suonlementary A=licaticns #310R8S Richard J. 3irg, M.D. $12,500.00 Approved for the gurchase of isotopes in the.ieriod up to June 30, 1970. B. Bhagat, ?2:.D. S3,800.C0 At_%roved to complete the program defined in his approved application. #647R1S Daniel H. Wise=an, M.D. $10,C00.00 Approved in principle for the hiring of a?ublic Health nurse for patient follow-up. The exact amount f--r the balance of the current year is to be negotiated. #588-AS

3 5. Deferred Avolications #548-A S. N. Pradhan, M.D., ?a.D. $11,490.00 Anpr` _ed for one year without #611-A ftather c-:'rent. John R. Rowlands, Ph.D. $48,880.00 Approved for one year of a proposed t!:ree-year project. #708 Horman W. HeL-stra, :'h.D. $9,890.00 AlZaroved for a one-year project. 6. Applications for Ccntinua::cn #409-A Prederik B. Bang, M.D. $33,c42.00 Denied. #492-B Walter M. Booicer, Ph.D. $18,773.00 Denied. #550-A John E. Craigcead, M.D. $28,819.00 Denied in preseRt form. Dr. Andervont L:~-: discuss the project and determine ir it can provide more me aai:.~..`•. : ob j ective s. #573-A Clayton G. Icosli, M.D., Ph.D. $77,894.00 Alm=oved for one year. A committee composed of Drs. Hockett, Flrst and Lisanti will maioe a site visit and discuss additional tunding. Their findings xill be reported to the Plaaaing Committee for ftather action. #630-A Mary S. Parsh=ey, Ph.D. $34,812.00 Aimraved as presented to the Piana:ng C-ittee for one year of a proposed three-year project. A formal c::.iversity-approved application vi11 be requested to support the inforral inquiry. 7. Renexaal Amlicatior.s #381-ARl Barbara Brown, Ph.D. $29,160.00 Approved in the amount of $18,7C0.C0 for the second year of a proposed three-year project. #413-AR1 Cecile iJeuchtenberger, Ph.D. $38,180.00 Agnroved for the second year of a proposed three-year project. The request to allov $6,000.00 to be carried over into the new grant year to pay for a smoking machine was denied. The normal $2,000.00 carryover viil be alLoved: #k72Rk James E. P. 'aan, Ph.D. $20,020.00 Approved for the fifth and term.inal year of an original five-year project. #614R2 Sanford Chodosh, M.D. $88,307.00 Approved for the third and terminal year of an original three-year project. #628R2 Aaron J. Ladnan. F'a.L. $26,795.00 Approved for the third and termina: year of an original three-year project. #645R2 Donald J. Massaro, M.D. $27,107.00 A oved for the third and termin year of an original three-year project.

-k- #651+R1 C J 1'1 Bertram Eichel, D.D.S. $60,703.00 Denied in present form. The staff was requested to determine if his expertise can be used in coordination with Dr. Chodosh' project (#614R2), and report to an ad hoc ct=ittee comprising Drs. Sommers and Jacobson (Furst and Hockett) with power to iapie.:.ent a grant up to ;30,000.00 for year LT. #669R1 Oscar J. Balch=, M.D. $105,880..C0 Arn~ d for the second year of an originaUy proposed five-year project. #688R1 Sheldon C. S=ers, M.D. $35,402.00 A=roved for the second year of an originaUy proposed three-year project. 8. New A=lications #719 Donald H. York, Ph.D. $26,700.00 Deferred until possible AMA-ERF funding is iavestigated. #720 Donald E. Johnson, Ph.D. $24,993.00 Denied. #721 Sidney Cassin, Ph.D. $16,942.00 Denied. #722 Ra,ymond N. Hiramoto, Ph.D. $21,070.00 Denied. #723 Archie F. Wilson, M.D. $24,753.00 Denied. #724 Joseph R. Bianchine, M.D., Ph.D. $18,5{4.00 Denied. #725 Jack Chalon, M.D. $14,046.25 A=d for one year without furthcr comait.:.ent. #726 Dorot-ty T. Hcf+:an, Ph.D. $32,754.00 Denied. #727 James J. McGrath, Ph.D. $11,985.00 Denied. #728 Duane G. Wenzel, Ph.D. $17,247.OC Denied. #729 Nathan B. Friedman, M.D. $19,41o.00 Denied. #730 Norman D. Weiner, Ph.D. $20,445.00 Denied. #731 Richard A. Ahrens, Ph.D. $24,032.00 Denied. #732 Harold R. Henry, Ph.D. $56,360.00 Denied. #733 Peter K. Vogt, Ph.D. $81,093.00 Deferred. Pro rata funding is to be provided at a negotiated rate until the December meeting. Staff and Board :.:presentatives will make a site visit. S, Viral Etiology of Cancer, Microbiological Associates, Bethesda, Md. $250,000•CO The Board avv r oved S125,CC0.00 for a six-month contract to initiate research into the most sensit:ve in vivo or in vitro system to measure viral carcinogenesis. Detai'__ are to be worked out with a wra plaa, etc., by Dr. Furst, Mr. Hoyt and an ad hoc cccoittee from the Board.

5 . ,- .F~: 10. The Board a=roved in principle $8,000.00 to support a fellow in cardiovascular - disease under Dr. :.duard H. Ahrens Jr. at Rockefeller Universitf. Dr. Ahrens expects that he will bring other candidates to the Board for review and support. The staff is to develop a plan for the administration of such a program. 11. The Board aparoved Y-o rata support of $13,750.00 per quarter for Freddy Homburger, M.D. ff338-:.) lu,yil the Planning C:,mmittee can decide what contribution this group could maise. ~. St:L= of Dr. Hcmburger's staff will be asked to discuss the oncogenesis studies in hamsters with Dr. Huebner. 12. The Board anproved $30,0C0.00 for September, October and November to support Mr. Kurt Enslein in his ongoing ana.i,ysis of various CTft research programs. He will be invited to the next Board meeting to discuss the findings to date. 13. The Pleaning Comrsittee, cemprising Drs. Furst, Jacobson, Loosli and Sommers, reported on their progress to date in detenaiaing the relative emphasis to be given the various areas of interest in the CTR program. They discussed the isportance associated with the fields of cardiovascular disease, cancer and chronic pulmonary disease, aad how the C',".°. objectives might moat expeditious.L,y be attained in each field. The various research programs already nnderwa,y or proposed were discussed with relevance to their contributions toward attaiaing the goal of understanding the possible implication of smokistg aad health. 14. The Board discussed procedure on research initiation projects (R.I.P.) and resolved that: a. The Plannirg C-ittee investigate new areas of research and potential investigators. A subcommittee appointed by the Board should then pl R.I.P. with qualified iavestigators. b. The R.I.P. should be approved by the Plnnning Committee and then passed on to the Board. c. If the R.I.P. is approved by the Board the amount, term and conditions of the award shall be determined by an ad hoc subcommittee appointed for the project. - 15. The Planniag Cecmittee was authorized to proceed to let a contract of $50,000.00 - to test the four saoicing machines which are now available. If unforeseen problems arise in connection with the tests, an additional $25,000.00 is to be made available. i6. Dr. Edward H. Ahrt--s Jr. of Rockefeller University discussed the advances in - the understanding and management of cardiovascular disease. He covered the epidemiological apprcac::es, including collection and handling of the data obtained from "passive-prospective" (Frsmingham) and "active-prospective" (government research on effect of drugs or diet on cardiovascular disease) studies. The large expense of undertakirg such studies limits them to government sponsorship.

-6- Dr. Ahrens discussed the new chromatograpaic tools and analytical techniques vhich permit the refined study of the three vascular ccmponents associated with cardiovascular disease -- i.e., the vessel or arterial wa.LL involved, the fluid passing by and the metabolic discrders leading to a change in the liquid or vall. He noted the failure to date of the classical ;.athological approaches in attempting to obtain an animal model analcgaus to aaa, and the morphological studies. The beta-lipoprotein and fibrin now deronstrated in human athercmas, and the possible dissolution of the protein moietf leavi.:; the :-Ipid plaque, thus initiating the atherosclerotic process was discussed. The lack of information as to the turnover rates and cosaposition of lipids in various tissues was noted. The possible metabolic changes which might alter these =zovzr rates such as hormonal effects, porphyria, etc., are areas for research. :".uch remains to be learned about the composition of membrane lipids and subceL'ular 'pids. The Board reemphasized its desire to make a contribution to understanding in this area. 17. The next Board meeting will be preceded by a two-day vurkshop and seminar concerning "Advances in Tissue Cultuxe aad Their Possible Contribution to the C3R Program. 18. The next meeting of the Board vi]1 be held in Bev York City on December 12-1h, _ 1969. 19. Tentative plans were to be instigated to hold a semiaar on "Inhalation Techniques" in March and on "Cardiovascul2z Disease" in May.

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~~;. . . ._ ._ /.S O.. &V(N.6:C. S.4VV WQY. tiLM O...Ct O/ tMo C-.....0 s. T..4 @O&MO ..e e.... a.oyr.......es• December 6, 1977 Mr. Addison Y. YearJ.a,n Chair:aan and President The Council f'or :bbacco ltescarch-Q.S.A., Inc. 110 East 59th Street ' New York, New York 10022 Dear Mr. Yeasaan: Following our discussion of December 5, I should like to su..^m:arize our Company's position with re- spect to The Council For Tobacco Research. For many years after the T.I.R.C. was established in 1954 we were able to say that "all grants are made upon reco:rrcndation of an advisory board of inde- penden t doctors, scientists and educators. Recipients of grants are assured complete scientific freedom in conducting their investigations." Zadeed, this point was made a part of our pledge to the public in full- page advertisements headlined 'A Frank Statement to Cigarette Smokers• and "Nine Important-Facts about Smoking and Your Health.s-Thc latter ad specifically said: "A Scientific Advisory Board of outstanding doctors, scientists and educators has complete and f ree rein in directing the research program and awarding the money for grants." This we can no longer say since what is called 'directed" or "cantract" research has been brought into t.he picture. As I remarked at the September 1976 meeting, .re original concept of T.I.R.C. did not embrace t'~e idea of contract research but en- visioned industry support of research on a pro bono publico, arm's-length basis. I believe t_':e current movement toward contract research is a violation of our advertised pledges to the public and I also be- lieve industry support of objective and independent 6743 I 11752

scientific research is of'cardinal importancF in r:aintaining a statesmanlike stance. I do not think it would be an exaggeration to say that'the curr!nt- shif.t to contract researrh bastardizes a fine concept of objectivity which asany good people in past years ' worked long and hard to establish. Quite apart from the departure from first principles represented by contract research, this new develop- ment seems to have led to internal inconsistencies as well. For exaaple,, at 'the September 1976 Directors Meeting your Research Director made the point that • mouse resdarcch in the area of smoking and health in- volved the wrong animal, the wrong tissue and the wrong material. Zt seems to me that the contract research labeled MA-22, among other projects, a,mounts to precisely that type of misguided research and that no amount of talk about 'animal models' and the like can gainsay the now-obvious nontransferability of animal results to man. A11 of us are witness to the scientific reductios ad absurdurc resulting from the FDA's litera adherence to the Delaney Amendment, which makes it possible to label almost any substance carcinogenic. In any event, there appears to me to be a distinct contra- diction between the Research Director's position and the Scientific Director's enthusiasm for contract re- search of this particular kind, analogous perhaps to the contrast between the CTR's emphasis on fundamental and_objective scientific research during its first two decades and its current swing towards contract research. An Interesting sidelight to the above cbmments on con- tract research and on animal research as such is the experience of the U.X. tobacco industry which conducted its own animal research on a very large scale at its own Harrogate laboratory for many years at a cost of millions of pounds. A few years ago this massive effort evaporated when the sponsors simply turned their backs on it as being fruitless. Another side result of our new•'direction is that we seem to be combining in one person a Scientific Director and a quasi-grantee, a comhination which is hardly compatible with the administration of an 11753

objective and independent grant progra:a. Kithout entering in any way into a personality questicn.. it seems to sne that no single individual can properly dischnrge both functions at tttc same time. _~ By you.r own defiaition you are the 'i.nterface' - _ between the indust..-y sponsors and the scientists of CTR. Equally important in our view is the interface between our industry and the public generally. It is ironic that we decided some years ago ta rename T. I. R. C. "'i'he Council For 2bbacco Research" because "Ztiobacco industry Research Con=f.ttee' sounded too much like industry-directed, as distinct from ia- • • dependent, research. We think it is a pity that the current CTR lacks the restraint and discipline to live up to the newer name. f 4(4~e Robert R. aeimann Chairman and Chief Executive Officer cc: Mr. V. B. Lougee, III Miss Janet Brown Mr. Richard E. Stinnette Mr. Joseph F. Cullman, III Mr. Joseph E. Edens Mr. Clifford B. Goldsmith Mr. William D. Hobbs Mr. Curtis 8. Judge Mr. Calin Stokes bcc: Arnold I3eneon 11754

a 13

T111: COUNCIL I' OR TOI3ACC0 RCSRARCH-U.S.A., IrC. 110 EAST 39rx STRLET N*EW TORK. N. T. 10022 December 9, 1977 Hr. Robert K. Heimann Chairman and Chief Executive Offirer :,.:.erican 8rands, Inc. 245 Park Avenue ::ew York, ":ew York 10017 near Mr. Heirsann: The thrust of your letter to -e of December 6, 1977, as I .:aderstand it, is that because certain o: the research projects carried on by :he Council are performed under contract rather than as a grant, the original purposes and principles of the :obacco Industry Researc:z Com-+ittee (?ater The Council for Tobacco Research - U.S.A., Inc.) have in cor.siderab'-e degree been subverted or violated. :f that is the opinion entertained by you thzn I can only say that I belie•:e you to be corpletely mistaken. The fact is that every ccntract entered into, just as any crant made, by The Council is consistent with the programs developed and a?groved by the Scientific Advisory 3oard, of which of course the Scienti°_ic Director is a member. Every such ccntract is subject to the same consultation, scrutiny, discussion, modification and ultimate vote on approval or disap=roval as is every grant. The fact that a project is carried on under contract is in no way and to no degree at the sacrifice of "objective and independent scientific research" (your letter). :".orsover, there is an unusual review orocess to which contracts are sub;ecte_s a subcocsmlittee of the Advisory 3card clus ad hoc consultants review the contract programs and progress once or twice each year in addition to the a.nnual overal; review by the entire ?,dvisory 3oard. There is no "contrast be tween the CTR's emphasis on fundamental and objective scientific research during its first two decades and its ct:rren= swing toward contract research" (your letter). Contracts are used because irr each instance it has been found ir..:racticable or impossible to carry out the work through the medium of a grant-in-aid to an individual researc;er. The emphasis is still on "fundamental and cbjective scientific research" (your letter). R:search under contract :o The Council is as purely "pro bono p::blico" as is research carried on under grants.

Fo~u'1'ui:,kCC;c~ I.c. Hr. Robert K. Heimann - 2 - December 9, 1977 I have made no effort to reply to your letter in detail because to do so would, I think, simply lead to disputation. You will understand, however, that I would welcome t.*.e opoortsnity to discuss your letter in greater depth. Ve-ry~~rul yours. . ~ Addison Ye President AY:ek cc: Mr. V. B. Lougee III Miss Janet Brown Mr. Richard H. Stin^ette Mr. Joseph F. Cull:nan III Mr. Joseph E. Edens Mr. Clifford H. Goldsmith ' Mr. William D. Hobbs Mr. Curtis H. Judge Mr. Colin Stokes

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~ D~81,:000;) Gmtlmmm~ml z baas iaelnd.d ia the Aqseda a saport aos the Psridsat baaalss I thiafc that artss taa amtlss ia tae job Ws isasbast an an to tsu yon what I tiad the ptssset stats of tzft to b., ths way rwouLd hops tn aiqht iunetiaa io the ist~s sad@ llariaq oat of tsat# a bsoad statsmset ot vbat I wald look tar ia sr sooosstos. Lsssbsso vbsa I was appeosah.d t+s tNcs tds job sad Ms.n I ayssad to oas. ia. it ws aa the clear vodssstsadiaq aq tisat psiositr woaLd ba to tiad saroes to ssplaa sr oa what is bopsd woala ba a•eazsas basis.' It ar Ksw an dittsset lsaa Vow ois,+.. I a..d to lmor it imor b.tasa I yo issrebs. i I•a yolaq to a.m eba litst pssoe pseasm to aweid asW iapliaatsoas ~ tsat sbat I say tKlsets any bot sp otia t•iws ad agial ees. I'a sot goiaq to I pe.=sos ..os~/ statsrst nitb e1i sr vpisioai' iOSt bass ii miOd tbat Z as f sm9zpsiaP opiaLamse aad q wa opisioos at tbat. Ls Jers aesd Jalp. vti.n IWws ..playad as a eoassltsat. I triad to ' tariliariss s4salf with the dq-br-daY opsatioa ot tbe asr ltos! ottio.. %at , vsrs the adslaistrative activities aad Aow wrr they paslesa.d7 SsmsdlY. I ewatsd to Ist ta bar @. Carmar Mw was a dstoal stsamqss to se. oe. aoak.tt Z atw kmra asa appr.eiatsd for years. tl5o v.es tde sta:f seisatiats# what did they do. aad bor did tbsr do it. .te.. ste. UsontY lA.w was tot,ally opsm sad balptnl md ar. Cas+Qe~.: s4t ba" q:osnad at s7 i.4ositioas an b!a tias. Tam ort haa Doaa atlaolntall la.alaabie to sr. i lwov tbe sintr atd bolts prsttY ' L auqwt I bsaw Psasids.t and boqau sr .doeatioo ia the qot Qosstioe - Aer dbs CTi as an satitt s.e its twpoasisi23tiss aod bon do.. it yo aboot dissbasQirp tSasal I Aave bsss nM losemfats in sssioq, ovs four santlu, tbs ln11 oaant of CT1e's aoti.iti.s aed Uov Oar. Casdoss osqaoisas thsa. 10002219

-:- D4Q1400!U Z bs.. sat tliroaqh a ao-aaY oosf.rswen of very distioqaisbod sei.otists as a scisotific problam so sotaric that this LWas dids't midsatwd a word of it. fnt vbat I did mdasst.o8 ws that it was a disamioa totslly 4~ to oat i psoblar, oes&uet.d by hi" Qaalifi.d p.wls ia aa air of oosplLts sasP.at for tbsir dost, tta CTi. I haw sat throoph the staff sssioos p:sWaratotW to the s.aiaq oi the sel.atific Ad.isorr loard. thx dqs of aBosrd =Nttaq. aed tha staft sssian to es4soiss aad ooosidar ths amtia qiv.a bt the iilf. I hase sat ia am tlfa AstsaaLoatsoas of 4satit and oontraet psiositia. IPartidaatsd ia the p3aonie~q of tto soiattific bodq.t oonsidaed Lara. I Law pattieipatsd ia tbs litorsaZ pe.s.Otatsoa of badqat r.oan.ndstioss to the isaiTldual a..b.e oo.p.aiaf. =a aheaet. in too: ao.tf. I'w s..m the rm3. 9ost of Rs's aoti.itiss. ='a roak 0011 to Yrlb tte speQi=SCttiOOe Ibw the fteli6aol. fttt 3s or s+0it s.d it..dlats orasr of ba.iass. !st I om't do that until I kaor riat Yos waat the CM to bs. Uwt !s tb. C'= aw? It isn't the tM I 1- - rv rbss I ratftad lsoa iP at the aed of ' 72. aad ?vo Aaw saart ]m mad Dt. Qardnsr te tLa.k tor that. Ad tbaok tesa Toa sheof e. Or. 0asdesr ha. as.a.rd. aca soti..ly disabarqssf the tsspaasibi3iqr of plaeniap the spsdfic dirsctloro os: r.saatdi sLon1Q tales. !as rrspmsisility for avalnatlaq .ppiicationn for qrsats is tmm et tb.ir soisvamoa to ttosa dirsetims ia Us. !!n shposribilttY fos p1ase4 oootr.ct yroiasts to m..t otsr rsaseft saqulr...ots is his. ras rsspoeuibi2ity for osdsrino the Prioritias of grants appro+rod bp the W is hL. Aad the k1teh.n dos.a't sw a bit too hot for dis. I anr of Yoo have acoss to Itialfar AisthoritY I soq4at yoa iacloA. Or. Cardr.r ia yonr prar.rs. !s. sdstific h4.isory soasd is uar +sactlr vhat its aar. i.plisst it is adK.ozy. I's eot going to boss poti with a stata.rit of how it doss its work, bat work it doos aad with a d.dleation that has bssa a i7wiatim to as. Include tb.a in Yowr prq.rs. i I 10002220

I R 3 OFi61'3UU 1 I . L th. CTa pesiiscti Of oouss it isn't aad it aswes rill bs* bsiaq a Msen crqanisatim. Sat %bsss doss it lall slastt !ss lrs.s of tafsz*aos fra. +rhioh ons loob at a psoblsm adoas a tsss~.adoa. diflas.oos. tm.a z lookad at = fsou the stauftoist of a s+.ab.r = ws a w:r 41lb eritio. As a lsaxtioniaQ past of tZ7t i as s,ot so qlib. Nt thrr+s ass araas ia rhicb Z bops CZft's psrfesreos oss be i.Qsowd. tdat is tas ps.s.ot stata of taovladqs aboat cancse, ssvlljssr. earaLo+rasoalas disaedsss. is raLtioa to tabsooot Msfbs w on¢bt to talos tias off aad ts:• to spsll oot ohat ve taor. Zf ns du tbat* sYbs vs aoaM =ocos oue rssoasm plamist .ora shasplr. Itaybs sioe t the gsablass of elasass as+s so seRSex, ss sdtL• so aiil=a that aqbs ve cso't aoearataly spsll eat sbat we lma. ia tass of ss3asoos to ost ptablss,. attC i ttlalc we o.qM to tsT. tsat ars the rslatioas of Csa to its o.bssship aad to the othss adjoACts of tt" tobsooo ia&uatrrt Y to tbs a..bfrsa ao susst. Civs s yoat poliQ dilscti00s aed rs'11 tollor tbsn vittia the 1laits of sdsatifio intsqritr. 1o oaoblsa tbsrs. Ict bsiaQ bosorabls asd dso.st sis ooescioss of Yess wa sospossibilitisc. iat aea't 3ook o~.r sae sdsntittc aboalasst lst ts dlsdusqa the gespoosiallttiss Toar po.lidss lq as ss. Ay.ia. as swat. 1br tor a tssrsl obsarntios. The 'l'ibaooo mdENtrt IhssarCk Cassittss ws fossN to ssot a pabiic rslatim. assa aM it v.e a*R ysstsa. Zt bown, ta Yvur wisdos, the isst=vsetality tor ttn discbuy: of Yous t+rpossibilitf to liaor all yes osald kbev a6ode the patt tobacoo ssY plar ia be.s dissas.. it ia ar sob.r jadq..at that !S't. is it aor opssstsuf is the grsatsst psJblic rsLtioas asset you sa.o ia tb& psobir of tobacoo aad bsalth. snt the so.est tTR bscass , or tA* attaqt is si.ds to wo it, as a palio 'rslations iastzoa.ntality. yoar ass.t vill loss its valw bpnso it vili Dar. lost its actantific iat.qritr. trA of ssraroa. 10002221

OW81nG012 int lbss's aootbtr si0ft to !he ooda. In a 7aq tallt vitd naw 1as*. ii11 feim a.d Dan lb.l z pmehd tUt s.moa as4 tlfta - Daeaw I bsli... it - that all esa sssoator.o ail the Imarl.aq.. alI the Mip tmWts'V a.n giv.* abeade ba avai7abla te the lswss, to rm 'lbbaooo mttitnlss d to sW ot6sr of the t:'o0pa !s th. tiald. Dnl. IsR sa sr bst. ir saiA. 71at t oa s.aa ia. QX sboold be lnd.p.adast bat air.rr aneaste3a .ed wailrbL.• sW@ with aalT e!s!s a8ditias -'iad.p.oe.et dmia tlre poliel~r sat da+a by tbs si.b.dtiP.' . S bslisw tbw ee.atlon ef the Ymm.atsh Liai.aa Gbaitw !s a wnt sLlal atop torasd aoosdLaatiaQ sd..tMs .lmaet asa vili bs3p CM be .we toes aaataib"eti.O. 1 0002222

15

PKiliP "C-?iS iNCC;:CRATED INT-? OFFf:- C:xi_SOE%t ._ . s~I,•ct: • D:. H. Wakeaan o.c.: Oct:ber 12, 195; T. S. Osde:.e Meeting held in New York City or. Sepcember 25, 1967 at the Council for Tobacco Resear:h The following people were present at the CTR matting: 1 T. vayt ~ R. C. Hockec: , J. Rreisaer CTR J. M. 3rady ' C. C. Latle V. Lisanci .. Miss Janet 3rown W. W. Saces - Liggett and Myers E. S. Harlow - American Tobacco Co. .Z: Z z< R. 3. Gri:f:th - 3rown and Williamson -~• - a. M. :_rke - uerican Tobacco Co. Senkus - Reynolds Tobacco Co. Nielsen - Reynolds Tobacco Co. Sa nfor= - 3ro:-1 and Will:a.:son s ~-t= ===i A. W. S:ears - P. L^rillard Co. s = _ SLeI rn - Laras & 3rother Co. .-% T. S. Osdane - Philip aorris Inc. T > Dr. Hockett stated that C:R is Woving into an era of active ~ collaboration with -^e in=_s::y and -t:ey wish to make the tect:r.ical cc.^i t:ee eore e::ective by including biologists. He briefly reviewed t::e biological tests sys:ets now in use and stated that the working principle of the SAS is to sec up studiis and pin down the effec:s of cercain co~onenca, e.g., ac•u flow and skin painting in He feels t::ac C7.1 has had reservation on lung cancer in the hu.:a:: and correlation with skin painting controversy, and is not interes:rd in skin per se. Ihus, =o' exa,ale, -ae differences in suscepti=i:i:y in various species are well rcnown and these will have co be solved before the human picture can be studied. He ce::tioned the work ~y che Leuchtanbergers but felt that this was not t~se answer to the `u.:an problem. One of the r_i:ical questions is how much swoke gets into the lung and when this is answered, dose response curves t-.:st be obtained. Three different snoking :.achines have been designed and put into operation by Dr. Art Furs:, San Francisco, Dr. Freddy Hor..burger of 3io-Resear:'.^l in 3cston, and the Leuchcenbergers i^~ Swi:zerland for the pur=ose of defini-g soecifications for this type of work. :he Leuc^tenbergers have also been studying viral :a_ec:icns ~WU' bU931S

L J thac a Steering Ccrit:ee =ay be fy:med to supervise the Mason Institute project but it _as laterdecided that the first or:er _ things was to hear and see -Le :Zson I nsciate resula whic:: •.-_ '=e --==_ given at a fcr~--a1 p:esenta:::n. Z=: Z ~_- SoWe new carbon c:o-oxide cs:e~i: a:i^ nethods, based on the carbcxp which could be synergistic :-i: h s=oke. Thay have worked with ieicwn infections such as influenza w:.ich is active in the lung. The question has come up whet:er these are pure viruses, and that they will try to find out which vir:ses are prasent. Recently, the Leuchtenbergers have found tr:ors in the lungs of their anirils. The three smoking .ac.+iines are being checked out side-by-side at the Mason Institute. They are being checked for puff duration, puff intervals, and any possibia bugs. Certain acute experiments on mica are also being condLctad in which Millerton Swiss mice are being exposed to saoke ar.d seeing how long before they die of nicoti:ie poison. It is the intenti = of CTR to send the technical cocmit:ee to :Sason Instituce to see and evaluate the machines after they have been proven out mechanically. At that tiae an evaluation will be rade o = all the observations. T'.as should take place within the next 60 days. ~' In the acute exposures, an anti-nicocine agent is being explored and = r= the animal deaths are delayed somewhat. Death occurs later, presubly due co carbon monoxide poisc-..i..-g. There is a possibility, however, =:'y that the drug may potentiate t.`e effect of carbon monoxide. It was ~ z~c ascertained that a u.iforr cigarette is being used. It was suggested henoglcbin content, have been - rnis:.ed to Lench and Hoaburger. ::e question arose as c: how nicotine should be determ,ined in the iLng (R. J. C. Harris has done sc=e of this work previously). Homburger's work with ca:bon-14• has s`_rs --nat tagged smoke was evenly dist=ibuted between gas phase and T?`:. :x:er:=encs using Cambridge filters di~ noc work out. Nielsen described some of :;e work done at Batelle Northwest by Bair (work for AEC) and was very :aaressad by their cor.sp ecence. :ork was largely done in dogs and rsny of the early AEC prablems were ^- unlike tobacco ones. They have s:udied inhalation of various radio- acciva materials in dogs and have also st'.oked t-h ese dogs to see i= this would aggravate the pr=ble_. ~sey have scudied lung clearaace using radioactive iron and fz== no alteration in the lung clearance mechanism. Batelle has now ta;cez over the running of the facili:•: which is located in 3ichland near '.?anford, Washington. Under this regine new contracts are a::c:red :or work on projects outside of :=e AEC. They have their own s:rai:: cf beagles which, after rar.y generations. are new clean c' :arasices and appear tz be an excel:es:: experi=ental aniral. They have c:evelo:-ed a system of smoking by w;-_c= a csask is used and a.::be is -::serced ....:o the mouth of che dcg. '::e,v Qf°JU16U9317 >

-3- have had to condition the dogs so as to become less sensitive co nicocine and at this tiae ct:ey no longer loose dogs due to nicotine poisoning, although they do get sick sometimes. They have undertaken a group inhalation study in which dogs smake 5-6 cigaretces daily on a 5-day smoking basis. It is hoped that they vill go to 7-day smoking per week. Some of the dogs have apparently developed a liking for smoke. Their monitoring syscems for radioactivity are highly sophisticated. They use Neucron acti•ration cechniques mostly following the mineral constituents of tobacco and particularly following bro ::ne. They then scan the whole dog in this equipment so as to get the location of various cotsponencs. In additicn, they also monitor aany of the physiological responses. Nielsen feels that the Batelle• studies are excellent and cor.siders t»:ch of the rodent data to be poor and feels quite sceptical about ic. -There was a general opinio: :hac in tiae one may have to shi:: rany ot the tests over to larbez animals. Hockett expressed the opinicn that C:'3 would lika co set up bio- chemical monitoring syscers ~ r chronic exposures to smoke such as enzyme activicies, rineral-values, ecc. These could be examined later to see i! they have diagnos::c values. He may ask-Mason Institute to line up some of these invest:gations. Other possibil: aes are to reasure how many repeti::•:e dcses o: smoke an animal can .olerate and ccr.pare this W:_` :.`.e h~n situation. The big ques:i:ns are: (1) How to measure ex:cs::=e :e::er--peraaps with zandoaly tagged carbon-14 tobacco? (2) HcW .-_c^ s-oke gecs into the lung? As an a:cempt cc answer -hese ques:_-ns,: was recognized by the SA3 that the program sssst be expanded and t: ey have asked the staff of C:3 to prepare plans. Prograas :+:11 :e developed in which Hockec: wishes to use the industry cecsnical co: _ ttee pe:ple to give advice wh:c.h will go into the devel:pme^.t o= plans for submission to the SAB. C. C. Little would like to meec W:_h :::is comaittee either before or after the SF.B meeting. He feels that this would be an oppor=.:nity t; build a creative future and :::a: C:7 would move with more speed. At this point Bates expressed a feeling of f:astration over the previous attempts co do this. :'_ss Janet 3rown raised the possible legal i~lication if grants are disclcied to the industry tec== ical coamsittee. Little expressed the a:shes cc cooperate cc the :.:llest extent with the industry cech: ical co-_ictee. Hoyt feels t::ac the ct:airsan of the cechnical gro::p could possibly attend the S.1B meec:n3s and report back to che cec.h_-ical group. Harlow would like to see cantinunity of the attending me=ber. :h.is would serve two purpcses, (1) cc allow the techr.:cal c-- ~==ee co understand how the Sa5 operates and also (2) to se:ve in an advisory function by wh:c'.^. ;roblems can be discussed bef:re ::ey are submitted to che SA3. ~Uu11s09319

-4- Little felt that the jcint of the C?R staff and the tec._.:cal co^rittee wou?d be most usef•_1 in ,:a~cing technical recomWe::dations to the SA9, but this in no way shoul: be interpreted that the technical cosomittee is making decisions in the approval or denial of grant application which is the sele responsibility of the SAB. Janet Brown made another legal disccurse. The quescion was asked of Miss Brown whether this cc: _::ee caa go to Mason Institute? She felt that this was probably okay. A decision as to who will go to Mason will be left up to the individual research directors. Lisanti will obtain speci::u tior.s on the three smoking machi:us as soon as possible so as to make t:.em available cc the commit:ee_ s was requested by Alex Spears. Spears also asked ttu t C'IR provide topics for f•ature aeetings. 3ockea reqc:ested cF.at if we had any ideas on how to measure dosage of s=ke we should chink aoout it and submit it to him (this per:a:ns co -ice). It was decided chat the com i t:ee will meet again at the of::ces of C7R on Friday, Dece.:aer 8, 1967 at 2:00 p.=. \ ! \ i "I ~.- \. _. v C.: L

PNuI/1N 111 IN 011111 hN V. 1711I IM hIIINNIS. F I A1. U11%1:NINAININ 11 /•IU/11111111 b U% 1•N/llia 11VI: . I/MIILM I NI / NI I/ 111 1111 I 1/11N 1 49011;09320 W z~ ~ ./r \ 1 -- f ' = la r o. Q:

C7UNCIL FOR TOBACCO E 3EARCH•TJ.S.A. C02FIDERTIAL REPORT SCIZtiTIFIC ADVISORY BCIARD lEETI2PG 3ev York, Iiev York riay 25-26, 1968 , Dr. Kenneth M. Lynch, Ck+*•** Dr. C. C. Little Dr. Richard J. Bing Dr. McKeen Cattell Dr. Robert J. Huebner Dr. Leon 0. Jacobson Dr. Clayton G. Loosli Dr. Willia% F. Rienhoff, Jr. Dr. S :eldon C. Soamers Dr. R. B. Griffith Mr. W. T. Hoyt Dr. Robert C. Hockett Dr. J: Morrison Brady Dr. John H. Kreisher Dr. Vincent F. Lisanti Guest Dr. Done.ld J. Massaro (5/25) Scientific Director, CIR Iadustry Technical Committee bcecutive Director, CTt Associate Scientific Director, C= Associate Scientific Director, CTR Associate Scientific Director, CTR Beientific Associate, CTR 1. The report of actions taken at the March meeting vas approved by the Board. 2. Admi-istrati)M Actions #3CR12 1967 Fellowship Pr ograe:. A ba.lance of $4,450.00 vas retsaaed to the general fimd. The amount of money expended dtaing^1967 is therefore $5,1,550.00. #:173 #527 #52&R2 #537 Cecile Ireuchtenberger, Ph.D. Pending Board action at the September 1968 meetizg, this grant is extended to September 30, 1968. An t~_~^ded balance of apgroxirsately $28,991.00 remains, which vill take care of the g3antee's needs dtiaing this period. Nox=a W. Fieiastra, Ph.D. A balanee ef $197.C7 vas asttherised to be carried over to grant #641. Sue Buckinghaa, M.D. The final fi,gta•e vith an sgustsent far over- head is 445,617. Hans G. Keitl, M.D. A grant in the amount of $500.00 was authorized but never used. Thts aoney has therefore been returned to the general f.::.3. cTR H I %W. -57J A 6 0 0 02292 11066062

-2- Lucio 6e.eri, }t.D. A sup^,lement to the gzsnt in the smouat of $767.57 is reqsusted to co*er bill•s that She Coimcll paid whL le Dr. Sevrri aad his psrtq vtre in ths Llnited Ststas. (Qaaerst ?umd checks 0+975,>C26, 50Z7 aad 3074.) #599R1S Daztngo M. ATWo, !(.D. O00.00. A_r_a.ed to Dtpr adattioaal eqttfpsent. #606S Arthsa lhast, Ph.D. $5,743.00. Ap woved to eontiaue the pro- Jeet through June 30, 1968 mmtil a as+r applicatim can be jreseated. #610 Csroliae B. Zhomas, M.D. A ene-tfoath estension authorized to June 30, 1968. #iS2CR1 Willis R. Riesen, Ph.D. The grantee accepted in the amoisat of j40,036.00, s.nd a revised budget has been received. #592 & 6+5 Doaa,ld J. 1ia*saro, M.D. A ehsek for $9,k72.80 vss received from Duke University, deposited, and another in & sir.ilar amount vas sent to George Yashiagton UniRSsity School of liedicine. 3. Defer_ed Annlieations A77-AM liarcus N. Carroll, Ph.D. $27,759.50. Denied. #606-::?: Arthia lurst, Ph.D. #19,612.00. Denied. #653 Richard E:.rlich, Ph.D. $29,1.88.C+0. Denied. #656 Sheldor.. B. Sps.rbe:, Ph.D. $23,591.00. Denled. k. Suvclcenta••-y Applications A23W2S Dertram Fichel, D.D.S. $ 8,$02.00. A .,ed to cover pro rata ssoathl,y suFpc=t at the current rate ssntil Septssber 30, 1968, plus cost of living inereases. #451R2S )fart.n S. Protzel, D.D.S. $8,L00.00 A d to sQgp2aent the Qant szfltil October 1968 rhen the project tcmisates. if-4=S Walter M. Booker, Ph.D. $4,322.50. A o.eQ to cover pro rata stigport for three nonths until Septmber 30, 1968. #528R25 Sue Buc}cingh=, M.D. $5,000.00. Denied. Peamission sras aranted to use the greseat year's funds, begiaaina July 1, 1968 to cover outstanding bills relating to the project. CTR MrN-~R~ 000,- 9 3 11066063

•3- #553W #57-ms ahelaan C. Sa.uers, M.D. $5,730.45. A a.ed. Clayton G. Ioosli, Ph.D., X.D. $69,745.00. A d for the parchase cif an eleetron nicrosccpe, sab3ect to aQjatt,ent for duty it it oan be admitted dctT tree. 579S ftiter H. Chopra, Ph.D. $L,963•76. A a.ea to co.er pro rata sUppart for tosa aonths to October 31, 1968 tntil eonsidera- tion far renewal graat can be taicen s;p at the Beptsber aeettng. #614S 8aatord Chodosh, li.D. $8,625.00 . A, d to cen+rr pro rata support imtil Sept~ber 30, 1968. 5. Renexal A=licatioas #223R9 Berbert t3cKenais Jr., Ph.D. Au=oaed for a term+n•> >rear at $46,205.00. The Board stipulated that ao Sta ther funds vvuld be applied to continue this tpeeitic warY. Me Scientitic Advisory Board requested a szmatiae nt the results to date, containing ans.lytical nethods to d.texntna the smouat ot smoke Sahalation in experimental an•z•l. #"12M2 Rose Marie Pangbarn. $14,699.00. Aunro.ed for a terminal tear to conclude a three-year proposal. #521R2 C.sare Biancitiore, M.D. $10,355•~. A~ d for a te=r1na.Z - Tear to cnnclssde an original three-year project. * J''j34R2 Paul CelGhs.ber, D.D.S. $23,396•75. Aroroved for a t•rm<nl 7esr to conclude a three-year project. #546R2 Ines Mfandl, Ph.D. $28,557.00. Appro"d for a tesmi*l yess to conclude a three-year project. ' #54$it2 8. t. Pradhaa, K.D., Ph.D. $9,928.00. Ap r~ for a trssinal 7ear to conclnde a three-year pra3ect. ' 6%03&1 Shirley L. Kauftmaa, M.D. # 21,588.00. Arored jor a*,e*+inLI year to conclude the oriai ut two-year plan. #bd+Rl Richard H. Larle, M.D. $.14,746.C0. A o.ed tar a seeond 7ear ot a three-Tear project. #61CR1 Caroline B. Thomas, M.D. $29,865.00. A a.ed tor one l ear rith no cacmitnent beyond that point. #614R1 gaator3 Chodo:h, M.D. $85,650.00. Deferred nntil the September seeting. ~637.R1 ZdYard !. Domino, M.D. $29,738.00. Agproved for the second Tear oS a three-year Fropo.al. CTR M I N-SRS 000294 11066064

-h- 6. AF4lications for Continuation Dnane d. Wenzel, Ph.D. $12,498.00. Ao.ed far .the flrst year of a tw-yesr ISOposal.. ftasss C. Westfzll, Ph.D. $19,937.00. Av~ for the first year of a three-YesS pSoposal. Walter X. 8ooker, Ph.D. $1,8,460.00. Deferred =ti1 the Septem- Der aeetiag. Oustate A. 2asaenzi, ht.D. 411,722.00. Arvroed for a aneyesr Plan - 7. Rev Arnlications #555-A Qene K. saith, Ph.D. $9,60Q.00. Deferred tmtil the Beptember meeting. #65k Bertrsm Eichel, D.D.S. tessber meeting. $137,583.00. Deferred nntil the Bep- #659 P. E. s. Palmer, x.B. $85,000.00. Deaied. #66o Isrry Fdths.nson, M.D. $31,141.00. Denied. #66.1 Brace Came-on, M.D., Ph.D. $22,k92.o0. A=C"d for the first year of a two-year progrs,m. #662 Kenneth B1=, Ph.D. $16,054.00. Deferred. #663 Eudolt Rob1e, M.D., Ph.D. $12,075.00. Daa,fed. i66k Jay D. Ca.:ftan, Ph.D. #6,6k6.C0. Ar=oved for a one-y+ear progrsm. #665 Dairid Y. Weiss, Ph.D. $30,750.00. Denied. #666 Barry Sorcn'f, M.D. $116,417.00. Sel.d a.+er for Srpteaber meeting. #667 A. Z. Andersoa Jr., X. D. $9,685.00. Denied. ^68 Stephen K. Ayres, x.D. $27,281.00. Amwa.ed for the first year of a three-year grogram. #66 9 Oscar J. Balehssa, K.D., Ph.D. $63,325.00. Be1d over for Srptem- ber meeting. #670 Riehsrd J. Rickey, Ph.D. $56,859.00. Reld a.er for September sreeting. ~~"~c ~ I~~-S(~B 000295 11066065

#671 George Q. Rich, ld.D. $+7,195.Q0. Denied. 0672 Joseph Y. Iey, Ph.D. t3.8,000.00. Denied. 0673 tccrt ffirschhora, x.D. $34,805.00. Detesred for staff ransmlta- tien concerning teasibility study at lesser budget. #674 =dvia R. Risher, x.D. #20,419.00. Denied. #675 David Staoe, Ph.D. $b1,450.00. Denied. 8. #338-A Freddy Kssbnager, x.D. $35,617.00. The Boesd dtscnssed Dr. Scmbwger's reqnest that its approval be made on the basis of one grant rather than three grojects vith three budgets. The Board decided that a percentage is to be obtained, indicatir$ the pnrt of the total represented by each project, as continuation was voted based upoa svah a hrealydovn. The Board sgreed to provide the total smount tar the grant as one item !er this fiscal year but rlll reqiiire progress reports on each of the three projects. Any renewal vil1 depend npoa a breakdown into three applications with an indiTidml budget on each. 9. The lfason Research Institute prcposal vas discussed at s®e length. A2thongh the Board expressed its intention to continue the derelogient of an inhalation grogram, it did not tee]f that- the proposal by the Nuon Research Institute as submitted vas acceptable and it vas therefore aot agyrorsd. 10. #413R3 - Dr. Levahtenberger's letter to the Execsrtive Director vas read to the Board. In it she eraressed a desire to have the Board take positive action on the graat even thasgh that positive aatioa be denisl 3n order to determine bar ltittzae personnel requirements. The iiai" nevertheless felt that it needed siare time to make a final decision oa continuation of the present progras until groblems associated vith smokir.g nachines, viral iaglicatioas In earciaogeas and other points were clarified before long-term ezperisentation ean be 3vstitied. The decision thereSore was to extend the present vork to January 1, 1968 as a terminal date. This should permit plenty of tine to conclude her gresent activities. The Board indicated a villitfgness to consider vorY other than the present project if she vished to advise of a specific project of interest to both Dr. Leuchtenberger and the Board. It Yas the consensus that she shoold be encouraged to cooperate with Dr. Rubner in such msaner as be maT advise in order to determine the virus bsaden of the affimals she bas been usi,a6 In bes recent experiments. 11. Dr. Huebner suggested that rating sheets be grepsred for all applications to be considered at Suttia e meetings, such rating sheets to be sent to the Board -bers vith the agenda books tvo veeYs prior to each metisg. !Se rating sheets could then be ssrked by each Board sember and retsaned to the staff for comgilation grior to the actual meeting. CTR MIN-SR6 0002196 11066066

. . ;, • ~ . .: ... -6- 12. The Board nade a request through Dr. Qrif.*ith to the Industry Zlechnical Com- mittee to assist as rapidlyy as possible (a) in the de.elopient ot a satisSac- tory smoking machine for inhslation resesrch, snd (b) in the sMestion of proced•,aes for determining the estent of smoka exposias. U..Zhe next meeting of the Board vill be beld in Xev Yark City on Slgtesber 14-15. It xas the coasensus that time for a specisl session fcr discnssion of plsaaed prograas should be grovided. 7.f the agenda af regular bluinsss g~ises to be heavy, the staff is to notify the ak-izza^ as early as possible so that extra meeting time can be scheduled if necessary aad possible. AuCtst 1968 CTR E EItZ-SR ~ 0VQc~.,77 11066067

pERSONAL & CONFIOENTIAL PHILIP MORRIS U. S. A. INTEt-OFFICE CORRE3P ONOENCE 1199111019. V1letelA File 0~ ~6v s.a: November 13, 1978 T. S. Osden44~•' Q s..i«:: . 3rco"endations for Lon:-Term Plans for CTR Aftez some tventy.-five years of existence, CTR as ori inally' strs+ctured at:y luvs outlivad its usefulness, especial~y in the arena o:f P.B.. As a consequence, it is recommended that the followimA restruct::rin; be uadertaken: 1. Future plans and programs should be relevant to the needs of the industry. 2. CTR should be controlled both legally and scientifically by representatives of the industry. Implicit in the above, the SAS should be constituted with a majority of industry members. Several outside members (but not a majority) should be nominated to the SAB. These members should not have access to CTR funding. 3. CTR should fund work largely by means of contracts, thus reserving the right to control publications which miaht be detrimental to the industry. 4. The CTR staff should be more responsive to industry needs and should report frequently to the new SAB. S. The long-term scientific program should be carefully planned such that the results obtained should not be able to harm the industry. Recommendations for scientific program will be given later. 6. Consideration should be given to whether CTR should establish its own labs. 7. There should be a=reater participation by industry scientists in contracts and/or grants given by CTR. This should include site visits, interim monitoring of results as well as disposition of final results. In addition there should be more complete feedback M+ to the industry sponsors. ^ 0 C CG~ G1 O O 00

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1 A ( PRODUCFI) I N pUTI.ER V. PNi1.IP M(1RRIf1. P.T w_.. IrI!:!:F:HINIITI(NJ IS 1'N()IIIIIIIIa) IIY PIt/r1F.l"tIVF. URDER I:NI'I:Ithlr hY 'flll: ('OIIRT Y f I, C) . V d 4 (~(i(!(1~'.,`i i ii1 Pj

l C0 4~p NS a- ?R_L ::.1IyA RY-ORAF- At t.':eir .:.eecirzs or June 2 and j.ay'7'.he research di.ec:crs ,.,: various c;garet compantes cock cogn:zance of the latest (1968-1y69) Annual Report of T::e Councii for T obacco Research (U. S.A. ) and of the announcement t7ac Dr. C'.are.^.ce C. Little is retirtng as Scientif ic Director of C.T.R. It was ;.':e consensus of the group that this might t>e an approprtate point in ctr.:e co express their views on C.T. R. and on now, in tneir opinion. C.T. R. might become more effective as an instrument for t.he good of the cooacco industry. In the words of me Annual Repcr:, me announced aim of C.T. R. is "to develop a researcn progr arn co provide s ignificanc data about lung cancer, heart d:sease, chronic respiracory ailments, and other diseases." (Page 5) ?resumaoiy, .c is :ne ncpe :-at cnts searcn otner causes :han cigare: smoking will ce ir.:?iicaced `.or :ne diseases in euestion. ;`.:e researcr dir ectCr s recognize nac t:::s cefe.^.s ive approach may have -:er;c °r .,- legal and puciic r eiacions viewpo uncs . On = e ocher nand, after i o;rears tais defensive posture does not a;,pear to have relieved any of the r-ess_:e on c:garecs as a causative fac:cr in the smoking and nealth controversy. It is t^e oointon of cae r esearc:: dir eccors mat the C. T. R. effort oe directed at me cotal effects of smoking - not only at me implied medical nazard, but also at me undouoced benefits of smoking. More crcadly, tnen, t.ne aims of tne C."-. R. rrogram might be stated as: '.J ~ ... 1. To define me effects of cigaret smoke on me human system. ~ 2. To define motivational mechanisms of smoking, using laxratcry animal models as well as zuraan populations. ., ve vZ .T :.i r

.. 3. To conceptualtze and explore ocher hypotheses relattve to A? me smoking and heaitn question by epidemiological and s other approprtate methods. A cursory analysts of the e:tsting C.T. R. program indicates major ~ ernphasis on the first of cnese oojecaves (92%) with practically none on points Z(6~p_) and 3129). This distrtDCUfon is not surpristng in view of the fact tnat to date the C.T. R. program nas oeen decided oy - tne tnedtcally oriented Scientific Advisory Board. In effect tnis Board =_ s44 has set me objectives of the program. The researcn directors are of cne vtew mat tnese objectives might better be set by cne industry itself '~ -t e -. ratner man by part-time medical consultants wnose maaor interests are o=~ tneir own research progra.a. It is clear czat che pursuit of a -roader C.T. R. r ograrn as indicated above will requir e some r e-oriez:acion and exte^s ion of :::e existing format. i'te researcn d'sectors feel cnat to acnieve c.^.is kind of a re- scruc:uring of C.T.R. the new scie.^.tific director must x a very broad, very strong, aggressive scientist and leader. He must x given wide latitude and auL7ortty as well as responsibility for :.7e prnram. '`:e research directors oCez c.heir usistance botn individualiy and collectively in finding the best qualtfted scientist and researca administrator for :hts position. 7hey aLso strongiy recommend that in order to oroaden --he C.T. R. program defintte responsi.otltcies be given to competent and separate assistant scientific directors in eacn of the following areas of activtty. ~ ^ . .. ~ 1. Medical research grants. nis activity would provide tne staff O services to the current granting program of the Scientific Advisory Board. G G1 C.i irZ

,l :)RAF- - 3 - ive in pursuing the program objectives. 2. ?ioto¢ical resear c" c- rac:s. : ae contracting program should be cieariy and indepen:e::::v ad.-:inistered by an assistar.t direc:or without involve^:ent of -"e _.' . 9. 3. Smoker Behavioral Studies. -'.:is program should employ in-house, grants, or contract research, whichever appears to be most efrec:- 4. 5:atistical and Epidemioiogical Studies. Again, both in-house and contract research might be used. F Enallv, :::e researchdi: ectors feel t5at a strong, well coordinated and well ac.:.inister ed r esear c^ rrogram in one institution is prefer able to :::e invoIvement of several or3anizaaons. Certainly, the single researc:: or- ganiza:,cn will reduce ccrf::sion •Xith respect :o cotr.munications, jurs- dic:ienai _",oundaries and resDOrsi`i:i:ies. 'une

19

. ~{!• . . . .J ...~.: _ CU;~:~IUEN T i,^-' : - V Mr. C. H. Goldsmitlt March 7, 1963 r H. Waktham . . , . . <. .. .. _ . . • . _ . y, --T-•~--- `. Hilton Head Meeting of the Cigaret Cocnpany Research Directors • : ~....,. ='_= February 14-16, 1968, or Some Thoughts on Cooperative Research `~. . in the Tobacco Industry ~.~ . ~ .. . . . . .. . . .. . . When the smoking and health questton became crittcal In the 1950's, the . tobacco industry took two steps to meet the situation. First, it adopted , the "vigorous denial•• approach: "the statistlcal evidence is biased," • "not.ying is proven," "animal experiments don't tell us what happens in : humans." At the same time, the Industry set up the Tobacco Industry Research Cotnmittee to sponsor medical research on cancer. The in- dustry hoped In this way to demonstrate ita concern for the cancer ~. problem and to discover by research, lf possibie, the truth about • = smoking and health. No efforts were spared to make TIRC a completely objective, independent agency whose results would be believed by the public and the scientific cotnmunity to be free of blas. • ; ., These actions were no doubt effective, at least as ftrst, In assuring the • public (as well as the Industry people themselves) that the industry was :: coping with the problem; but they failed to deal effectively with the basic -.scientific aspects of the problem. At the same time the constant activity of the anti-ctgaret people ln the form of newspaper publicity, magazine ., o=:: _-; - articles, governmental actions, and lately the Surgeon General'a Commit- - :.~;;:3 tee Report and the "warning label" have built up out of all sensible propor- tion t' e health risk of ctgaret smoking. Certainly it would be hard to find ~-= `a Pe T raon in the Lnited States today who would say that cigaret smoking is '''341- .' • - : healthful. To the contrary, most everyone believes that smoking involves 'more or less serious risk to hea2th albeit a risk most smokers are willin , g to tare for the pleasurea of amoking. ~.~ -to_.:.: .i. . . _.. ,,.. .. . . _ ~ ~ . d• ` . • , ~ .r.s-.v • ..i ~ • . : . . . . :C'.2, . .. ri. _ _ .. . •. . . •4.! ... . _ .. .. . •r . • . . : j i- 'vieanwhlle the industry, continuing its policy of "vigorous dental," finds Itself In the role of the "bad boy" in opposition to the forces ostensibly ~== dedicated to the welfare oi the people: Federal agencies like F.T.C., ' M ;I; N. I. H. , P. H. S. , and U. S. O. A. ; cancer research institutes like Sloan- • Kettering and Roswell Park; public supported he•alth organizations like American Cancer Society, American Heart Association, etc. This image ~V: ~'' k bll it h l d i li i ' r~ :'- ots an y see ers (po pu c encourabes t e antl•c garet zea t cians e=c ) ~ ,. ". to use the ciSaret Industry as a convenient whlFPln8 boy, which onl y makes . the lmage If anything worse In the mind of the public. To this the industry A , , has essentially replied merely by repeating the vigorous deniaL• "experimental y~ ; .-- ..• ' prooi Is still lacking," "the statistics are poorly obtained and tn any event• ' not to be trusted," "no one lanow• the cause of cancer so how cin lt be cigarets, ' . i A-A- :e.' .~ •i. { •;~. :!Iv1~ i •.~..~..•~ 0 a

,` . . . . . . Mr. Goldam ith • Z. March 7, 1968 + ~.. ..;: _. . . _ . . . • = . . . . ~ ; ! . . . L . ~. "the cLims against cigaret smoking are grossly esaggereted." and anyway - why pick on us when there are so many other more frequent causes of death T~~' .• than lung cancer? Of this the public can only say like Hamlet's Queen•Mother, • • "fie lady dot11 proteu too much." '. . . ...;,., .. .. ~ ti,.-... .. ;; -~ •. . . .--.. . . : 1: The lou3 cries od the antl•ctgaret zealots have nov.•convinced so many of the uninformed masses that ctgarets are harmful that the vvice of the moderates : ls stilled throughout the Inad. The situation has gotten to the poia that the moderates, most physicians, and other scientific professionals will not spealr ' oia on,tt,e subject even In behali of scientific truth because they are fearful of , public criticism and professional ostracism. We have it on good authority, ''.. for example, that many scientists and physiciana believe that Dr. Carl C. Selzer committed prQfeastonal sulcide in his courag'eoua attack in 1. A. M. A. on the antl-cigaset "estahliahment" and tts alLgattons that smoking coronary heart diaease. Dr. Joseph Berkion and Proiessor K. Ale:a' Broamlee and others who formerly spoke up In behalf of scientific objectivity : have been strangely silent during the past few years. ... .. Fortunately, despite this loss of credibiltty on the part of industry, smoking goes on essensially unabated, although the inereasing popularlty of-flltera and ~" acceptability of low delivery branda indicate people are worrying abovt the : problern. The popular and stock market reaction to Strickman clearly deanon- f~ l atrates pub ic concern, ard one may expect per capita parttclpattoa In smoking . , to decrease as the current anti-smoking propaganda campaign begins to take '' - effect. . ; . _ What steps has the lndustry taken to combat this dsterioration of Its image * ~ over the past fifteen years? It established the Tobacco Industry Research :~ Committee (now The Council for Tobacco Research - U.S.A.) which, although it may initially have had a public relations beaefit, hae, in this writer's " " ' opinion, given litile positive support to the vtgorous denlal approach nor -"----• -' - -`--- ~ ~~. pr uced few !f any objective and newsworthy findtnge to controvert the . :•~:, ~; has lt ven respectability to the tndua gi try's poaure of objectivity. It has _ auegsclons tz Lne aral•Glgares zealou. 1An saale negaLive conclusion might :~ - oe maoe aa Lne A. M. A. I oaacco ann tteaua resea2'cn program, although it u too eariy to evaluate us reauue In any cepttt. ..;' .; 1nn S10fin 16 obiectivity In the minds of knowing people. Sotnewhere between no resefrch must lie an area ia which the industry can flnd an image of credibility and Somewhere between the "vigorous dental" and the open adrnission of allegations• ~ : and a massive ettort to find the cause of carrcer there must be an area of.' ' scientittc endeavor which will gtve the lndustry a solld basta ot; which to stand. '- :_ , Somehow or ocher it must be possible to establish a group of lndustry supported ~~ scientists, respected by their peers even in the anti•cigaret scientific community, who can raise a voice In favor of scientific truth that will be heard. - :71 R,e S+'+':: ,/Y•.. r ..ir.+' m

y ... . w . ~ Mr. Goldsmith 11• ~ ~ . Masrh 7, 19" • might be called the Ctgaret Research Institute. Its membership would be open to all cigaret manufacturers. Its puzpoae and oblectives would be to asaemble. tn a cigzret lridustry cooperative researcli organtzation. Such an or=anization ' The writer believes that the basis for this kind of a scientific endeavor Ites pected that tbe Cigaret Reseirch Institute would carry out a broad enough and sound enough program to establish the scientific fact needed to put the smoking and health problem Into proper perspeaive. further use as the mesabers may deem appropriate: In time it might be es- to make such ircformatton available to the member companies and for sucts • generate, and evaluate scientific Information about tobacco, cigarese, cigaret components, srtiold ng behavior, etc. of common intereat to the members and There follows a list ot lnduatry-wide research problams to which the Cigaret Industry Institute could addreu itself hnrnediately: - 1. What is the smoHng behavior ad the cigaret consuming public, arsd how is this related to the actual smoke expoeure of the smoking publlc (as opposed to the potential exposure based on a F.T.C. tar test method)? 2. Development d irdormation oc the relation oI smoke com• ,.. ~ position to the conditions and/or method of smoke generatioa leading to the improved definition of smoking conditions and/ - or machines which simulate human smoking. >' 3. Determir,ation of the precursors of compounds In smoke, - parttcularly of those which might be deemed hazardous to . : health. procedures of common lntezeat. - _ 4. Lbvelopmetrt of improved and accepted standard aaaIyttcst . .. . ~~ , ~ .~..:.~ S. Compilatton ot data on tobacco composition as related to ;~. _~.~~~ other characteristics and conditions of growth beyond that . V r,x : now betng done in the cooperative crop development prog,rata tn the esperimental stations. ~ _~ 6. Determinatton of itr;orrnation relative to agricultursl residues in tobacco and amoke. , ' . . . tobacco industry may some day wish to initiate: -T~.$ . 4'.~~t . .,, "I1hese studies will provide a background for two other broad studies which the , •. r~` A. A review of eadesr•iological evidence relating human ailments - to environmental and behavioral faetors with the aim' of re- `:; . vealtng oc:~er areas which can be lnvesttgated to find to what~~ ~ i-t••~.i~~i•i, ;! i. T; -C ~ '

Mr. Goldsmith March 7, 1968 •.. -: :. . '. ;.: . t .'~ - , 't• . '•.:1 . . • . . . .. ~ ~y. • . ,~• .. B. A camplete quantificatioa od physiologic and morphologic ..::. =• 1. Our major technical problems are common to a11 ctgaret companies and are of such a magnitude and complexity that the large effort a` required is beyond the research resources of any single company. o ~ Under these circurnstances, a concerted action is better and-more effective than indSvidual aaion. It overcomes the disadvantage of effecu cd whole szaoka, sraoke iracttons, and/or srr:oke components on various arlmal systetas. • . ... ..,..,..... . •.:_. . ... :. _:: ~ There are probabiy other areas in which a cooperative program would be ' btneitcial, but the above listing will suffice for the moment. Let us review some advantages of the propose+d Ctgaret Research Institute. o= C -~ > o •• duplicattan, and Increases greatly the over-aIl quantity of lntor• matton available to all compantes. Furthermore, the strength '~'*=. =< J In n=Dess working on common objeaives Is more effective in - . desling arith our scienttfic crittcs. > _ - . . . . . _ _ . _. . . , . ,..,:::: ~+ . . . , . . . . . . . • aaent human atlmencs are really due to smoking and what are due to other causes. An outgrowth of this study might be an atterrtpt to define tn some manner those elements of - the population who, like asbestos industry workers, are "more likely to encocmter serious risk by smoking and who, theretore, should be discouraged from tndulgin,g the habit. Nothing could give gzeater credibi2ity to ttu;ood will of the cigaret lnouscry than this iclna at a move. ~ •. . r.~a 2. An tndustry research. tnstitute would provide a basts for technical -_--- ---- ------ -o------- ----- -- w----------~• -------- ..`... , foundations, puhitc suI-,~orted associations, etc., which would ;.- ~;;4- '= find it awkward to deal with one si - ngle company as a repteaerscattve of the industry. ReIartons of this type in the legal, polttical, and tublic relations field are being handled by T1ne Tobacco Institute. z - etc., but no such mechanism ts available for technical liaison and 7 • communication. . `_ . . . . , r-.-' . The Research Institute could have an apparatus which .rould antt• 4. ganda blasts of a scientiAc nature. . . . ,. ... . . .. . ... . ., ... ctpate and prepare information for countering saci•cigaret propa• - ri 15Z The Research Instttute would provide a mechanism for caztying' : tnventors. Of course, it would have to be recognized that the ;: : i the entire industry which are brought in by outside agencies ard _-~-,1~` ti .~ ;:z WO out contract research and for investigating areas oi lnterest to -• " :« v . Institute management would have to guard against needless diversion., of the effort due to outside idea tnvestigation snd attempts by others ~

± ,•'. to use the institvte for propaganda or public relations purpoaes. 7he Institute ahould limit itselt to basic technologiea applicable to broad tndustry prograrns. In its organization the Institute would require a capable director, famtliar .!..: _ with the proble=s of the tndustry and yet of suifictent scientific stature to cocntr.and the respect of the non-tobacco scientific profession. It would require an efficient cmtral research facility. Soane of the work of the Instituu could be done by parceling out cooperative activities to the various c rripany research laboratories In those Instances where the cotnpany laboratories are uniquely qualtfied, both In terms oi manpower and equipment, to carry on cestain types of work. Other areas oi investisation could be contracted out to suitable research ttutitutes, universities, and similar "' organtzations. It Is na-vtsualized that the Institute would make grants for academic type research, and ln this respect It should be emphas/zed that the Institute program should be considered as uxnplemeatary to rather than equal to or replacing existing programa in other tobacco tndustry supported agencies. A most ditftcult aspecx of the Instltutewould be the control of itiforrnatton generated by the Institute. One approach tatght be that all of the Information obtatned by it should be restricted to the research depara•nerrs of the member = companies, on whota would then be placed the responstbtltty tor the proper use of the information. Since the company research groupa are generally under the corapany managements, they would be expected to be sutitciently : sensitive to the Fropriety of releasing information which would undermine and posstbly destroy the benefits of the CISaret Research Institute to the industry as a whole. •. •. ... . _. . .,. . '~ •• . Ftnally, Iet tt be said that this proposal l.t In essence the more effective or;amlzation of activities already underway on an ad hoc basis. The research directors of the several ci;azet companies now meet to discuss and solve ' Mr. Goldsmith - S• March 7, 1968 ' f- - com-non problems. Examples are the formation of the Tobacco Institute :;: rt -W Testing Laborasory, the tnvestigation of Chemosol, the evaluation ol smoking .~~~ machine prototypas for The Council of Tobacco Research, the study of smoking *..: pattcrns for selection of a standard butt lenit8, ete, All of tl:ese auivtties have been cooperatively carried out, itiltzing both tnternal and external resources, and under the supervision of one or another V of the company research directors. To a greater or lesser extent these V.it activities have lnterfered with the cornpan3' dtrected goals of the respective research depastments. It Is time an effective industrywide technical or• gantzation be considered to handle these and other Important technical mattera. :~ To be sure there would be problems in this as In any other organtzatlon, but ••=%r ; none whtch could nac be solved by capable leadership. .:- .. :~ : •. t. ,1005106319

.,,...s:. The cigaret Industry casunoc help•but benefit ln theloag run frotn the executton and publicatloa of properly designed and perforaned researches which lead to the reveLzlon oi tru;h, whatever It may be. Our present situation stems from lack of knowle+dge rather tham from sn overabundance. u we bad avatlable better or mor+e certain krcwledge cf any existing or potenttal health hazard rom ciaaret smoki i nq, we Mould have a greaser likelihood of modlfying cissrets "-' '~ in a manner to reduce the hazard and to preserve the benetlts of smoking and ,,,, ..,., .. our bustness. If, on the other hand, good researches reveal eew truths, negating prevtous coaclustons regarding the hazards of cigaret smoking, =;.: eventuaSly these trnxhs will silence our crittca and again benefit the lndustsy. : . : : . ,,,: :: :: 'I1u one way in which we can in the long run do ourselves the greatest harra , _. ta to fail to learn al1 we can about our produas and our business, to fail to •:..T. :' do the researches necessary to meet the technical challenge the Industry now faces. .. ~r:._'• ..::. <: . . . , Y. .....•. . I . A • / l, - ..: :•. . .iz~~• r.' .. ~ ~ ~ . ~ , • .. ..... ~ . . . .~...~. . . c V T 7 = t ^ sy ~ r C ~ -9 Aj ~ = T n L ~ Z s e T K Y+ ti > T

*N.-. C. F. Colds.:.ic:: (v:ch acuc:.rears) " tL-. W. S:. HcDovel: (crich accactL.eacs) PHILIP MO=S U. 3. A. R[3LAaai. Ctnt[n, QICNrOwO, VISairIa •O8[at •. scUOr.w, 0%. O. .+.~ ...r~..• ..~a.... r. rHa...r.. 1 Marc L 31, 1980 t Dr. Alex Spears p. Lori.lZara C4NFDENTIAL- .2525 r'arkec Sc_ee: Greeasbo_o, Nor:!i CarQl:,:.a 27420 Dear Alex: X.r. . C. 3ov1?:.g of our Nesr York Off~ce asked c:at I send you our reco=eadaciocs for iadusury- research which we prepared Iast yeas. To crac e::d, you _-iII F::.d accacked a List eacicZed,"?ocescial Long-Ier.^ Sc:eaci.:c Studies" which Dr. Osdeae aad I geae_aced early Last year. Addicioaally, I have added a Lis= of c::ree s::bjects uhic!: I feel s4ou1d be avoided. If you have any quesc:ons, please Iec ce 4co:+. Very c-__y ycu_s, f NM GEN-278 r.=Cac--...._.: _ Pi.A1NTiFr='S c ~: 5L .-. S. C~'e^eS ECHIB(T ;t •_•..- - -- -

Rn-u T a i r nrrr•-T-=++ c r CxtTT C T r' c-1rn r ee CONF7DEM' r 1• Validation of new short-ter= bicassays versus Iong_te= skin painti:,g and inhalation. Z.• Correiat_oa between skin painting and izItalat?on. The efrect of enviro=eatal and other faczors in skia painting and/or i.ahalatioa. Ca) 53c:.:. pait:ag in ger, = free anicals (b) tf=ect o_' diet on tes ts Cc) -ffec=s o= inducers i-2 diet on test. _. Cd) Yiral eavi-rca„^.e5t/i~~ologieal corr.peteae:. . 4• I:=xects o: st=a" variation in skin pain::ag. ~. e^e=- s1-c_es respor-se to - saoke aad/or cc:c_-sats . 6- Rele•ranea c= :oag•terr tests to can in bioche=:ca1 t:r»s c %. In•res:ibate t::eshold or carc:nogens in varicus spec-.;es v speeific cher..: cals . - 8- I:.vestigat_ end points of bioassays, especiaZly i- i:zhalztlca (expericental an:rals) , 9. Scoke related ef=ects i,z respiratory systec csiag single o. ault-ple sno~Ce cotroaents. 10. Metaholie fate of micz.-:.•~ e u-..g:"..g labeled .r,.ctine _c a : - _~. Iaterac-- : on c t aie- ,,e uith cr-,;gs (b:ce::e~car c-T • , -Yi Pasit-ve e___cts of sr.okin g (e= n ~ ' . ,, sccc _::; . AdCress cc:est_eZ 1_ d: e-` i s•: a:' i ni:a a._-.. .,,,_colcsr. - -- "7.`.e r.i::a_e 5k" i- _ = pa~ •. y Hocr dces cr ._ g ve-s:a .. _ ~ - ~ .;;age `e t-acc c::l • ..v N 7-• 5'aya=_-~~Sy- .._:C._..- C: :a_'Je :°7S::S '_%. IZ. 12. 13. 1..

f et1nJ"75 TO pF AV,~OTT)OD Z. Deveiopiag aex tests fo,r eareiaogeaicirj. Z. AL~e--;r Zo relzte hu=a d.isezse to stcakiag. 3. CondLcr ez;er:.aeats tirhicS: require large doses of carc~.:agea to shos+ additive effeet of saok:.: g. CONFIDF.NTIAl-`

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Y . -a TO: FROM: SL; BJECT: Mr. J. F. Cu11rr,an Ilt December S. 1970 K. wakehara "Sest" 2rogr In retrospect of the November 30 meeting of the CTR Executive Cor:imtttee, it .ratght be appropriste to comment on the quescton "What kind of CTR program is best for the lndustry?" At the meeting'it was apparent this question is troubling many elements of the Industry to the extent people are reluctant to discuss the subject openly because of the dlverstty of views. To some eutent this uniettled r state also exists within Phillp Morris. In the hopes of clarifying, at least par- ttally. the matter I offer the followittg summary, hastlly adding that these state• ~ ments embody Ideas from many places. • .s• 1. Scated Objective or Purpose of CTR "To aid and assist research into tobacco use and health. and to maSce available co the public factual Inforrnatton on this. subject". This. is a very broad statement which has been interpreted more narrowly to "providing ftnanctal support for research by independent scientists. ..» "to provide significant data about lung cancer. heart disease, chronic respiratory ailments, and other diseases." (1968-69 Report of the Scientific Oirector, C.T. R. -U. S. A. ) • A broader CTR program involving the mechanisms of contracts as -well as ra and areas of research pertinent to health. other than scrtciy eiomedlc=1. is not excluded by the statement of puz2ose. The narrower tnterprecaclon indicated above must stern etther from inds:scry policy guidance or from the strong medical orien- cation of the Scientific Advisory Board. In any case, •thts statement of puz%pose does not reveal the objective need of the industry in supporting the C,'TR program. 2. It has been stated that CTR is a program to find out "the truth about smoking and heasth." What is truth to one is false to another. C; R and the (ndustry have ;.ubitcly and frequently denied what others find as "truth." Let's face it. We are tnceresced In evidence which we believe denies the allegation that cigaret smoxtng causes dlsease. If the CTR ;=gram is aimed In this direttion, it Is in effect crying to prove the negattve, that cigaret smoking does not cause disease. Both lawyers and sctenttsts will agree that this task is extremely dlfficult. if not tr.t- poss ib le . 3. What then are the alcarnativeil Somehow all caveats and platttudes as lde, we must assurne that CTR exists for the good of the Induutry. How could this benefit be achieved? Ooc~ A. 1001609570 Aim the program at contrtbuttng co the searc:t for the causes of dtseases, especially ,hose diseases alleged to be caued by smolcing. Rationai 1 orrroono vubllco: trattcu:tc::al public relations • the industry is interested In ~ Aq , j

' N_-,c- ° ae :.5 3 Am EDISOH •+ALTMaLL. MUttL btla 's-e oov.. F. Cullmaa tII December 8, 1970 human Weifare and alleviation of hsr:.arn suf:ertng: therefore, the public should love and respect us and buy our rrod_c:s. Rational 2 ~ctR more research there ta a good chance the smokrr-reiated diseases will be . found to result from causes otrier than smolcin,g, and the Induscry is "off the hook." Problem I n a cocal nacional health research effort of 1.000 million dollars. what impact will ourcontribution have? Is it even worth PR value? Problem 2 Asurs e we ca.rget projects related to specii[cs, like lung cancer. Will our 2 to3 million dollars have any effect? Probably noc. The national cancer research effort today totals over 200 millioa dollars. Besides, how do you judge high- return. worthy, viable fields of work for support? Too many investigators have selfish interests for us to cake their judgments at face value. No matter what or how we select, prospects for a positive benefit are small. Option B. Use the CTR prograrrt as a means of establishing expert scientific witnesses who will testify on behalf of the Industry In legislative hallt, in littgations. at seienttfic raeectngs, and before the press and the public. if this obiective is the purpose of CTR. then a very limited. selective grand program should be adequate to do the job. There would be litxle need for research contracts or an cxtensive sta& in headquarters. One might also question how long it would take for the witnesses to acquire the "taint" of Industry money. I cannot 3udge the lictgacive value of this approach, but I am impressed by the legts- lattve cescir.:ony we are able to nus:er at Congressional hearings. On the other hand, my contacts with sciencists outside the [ndustry do not reveal an extensive awarer.ess of, or appreciation for, the GTA program. It would be interesting to try to measure such awareness by the public, the med[cal profession. or by scientists at large. I1 after 16 yesss and 20 million dollars such a study comes up with a blank. as I think tt would. then we can only conclude chat CTR as presently organized and operated ts not convtncing tre public that we are objectively seekir.g the "truth" or "establlshing good fatch in the scientific coasmuntty." ~ Cton C. Alm CTR resesrch at the discovery of tnforr.sation of use and value to the ctgaret . i ndus try. Rattonal OU1609571 • tiere are many unresolved quesciors ralacing cigaret smoking to the smoker. Research on these problems would help us to understand better our produc:- and our consumer. The results of such research applied to our business would undoubtedly help us overcome some of the criticisms we are facing. These topics are not new. - „ 1. 8iomedical studies on the efYects of smoke on the smoker and on how to " amelicrate ur.desirable effects by changing our produc:9. ~__:

Mr. 1. F. Cullman III - 3 - - December 8. 1970 2. Psychosoctal scudies on the positive benefits of smoktng as revealed by smoker behavior pazerns. 3. Ea tderztologtca1 and derr.ogr:phtc studies so we can give scholarly replies to the erroneous allegattons of our critics. The way to earn the approval and respect of the sctenttfic corrmmunity La to carry out and publish good research. I don't thinlc we get much credit for this by gtving gruus. CONCLUSION It would seem appropriate to explore in some depitt durinQ the ne= year or two how CTR is or might be serving the needs of the cigaret tndustry. The disparity of opinion on this subject within the tadustry indicates that the answer to the questton is not ocvtous. tf we (members of the Industry) cannot convince ourselves of a defia::= answer to the question "HOW", then we might very well decide it is wasted effort. if so, CTR should be terminated. cc: Mr. R. R. MI112siser Mr. C. H. Goldsmtth .titr. A. Holtznun Mr. P. D. Srnith Mr. H. Culltaan Mr. J. C. Bowling Dr. R. Fagan Dr._T. S. Osdene I

22

May 15, 1970 V6lSYr " ^ '~'~ ._Jil:] The Csacer Pre.-av HN1087105G At the present moaent there a.: tve_ty active projects and one cor.traet research relatir,g to cancer, w"t-e Zvo other eontracto for planned or directed researches are •3nde- nepptiation. Six of these studie+ are qaite directly rela:ed to -.'&e nea "vires theory of eancer" as set forl0f by Dr. Hober: :. 3acbnc and ais colleagues. Viruscs and Ce-neer The new theory holds that cancer is ae of several possible `espreasions" of a"letent C-Z/pc R11A viral ; enme" found in all eclls of all artimals but noaslly represse:. A cooplex interplay of Internal and externsl factors detcrzzcs +ivtmAer, when and hov "ex- prtasion" will occur. The contract study at'ficro`:o'_o•'t:r: Associate: In Be:besdn, M.A. is 6eveloping test systemi at tSree levY..- vhieh staaid 1 shoi- t2te differe:nets in result when the seae agt.-: is applied to two similar test systems, one of tihieh is sus:ept-ble r:.:le the othcr is na: and (2) permit identifieatien of eubstaace: or :rae::ons, for eample in cigarctte smokc, that are a=tive in a respssSve sys•.ert. The three kinds of systean cxntioned mr,V ult~a:ely ir.e:ude (a) cells in culture (b) whole aairal skin paintina and (c) r.1o1e aAimal inLalation. The long-term objective of the basic "v:rus' s:'zzy is to learn ho:• •a prevent derepressicn of this latc-.t Ee:--= -_`st ca.i produce cancer. Noaruhile it nay be possible to le:ra :~rom t better controlled and aorc realistic assry syr:ea than y y new in ase, .bethcr cigarette snokc does have aib.tifioant activity and, if so, -a determir.c what substanr.es are most active In a highly s•ucc;:ale tes: systea. Several other current C.T.R. greit s:udies are einrd at tS:ling gaps and roundlnQ out. t.he ba+ie tiirus-csnce-- hl'othesic but without direct involversent of saokc: John E. Craivh^ed. N.J. et the 7aive-:it,r o!' Vennon: is scudyiag epitheliol cell transforns::on a.zd :s:einwa indnctien by "L•" type R11A viruses. Peter K. Vort, Ph.D. of t.:e Universiw of JaahSnstor School of Nedicino, Seattle is study:ag t1: bC'.avior of avian tsmror viruses in nm-alie.n tost:. pans Ilcier, D.V.K. of The Jackson L`orator•jr, Bu• Harbor, Ftc. is aLUdyin~ one~renesl.s in the riob+t: ccnetie -tnserrtiL:lity, vertic:l trnnsmission of virus and eYiro:aev.al influcnct:. ".he eonecpt that cancer mmy 9c brsic-lly a•rirus disease 1.qs stil.ulated net+ interest in iturfyirZ t9c :edi1± rochir.ery th:t eon: Its viruses, in order to learn rhether saa!-t:_n of sueh protee:fve sechnn?a+s will help prevrnt ce.lce-. S.ver_ studSes arc foci' rd on these problesic.:

HK0OS 710j'? ti,'illiarr A. Carter. N..D. The Jct.= ;io;:<ins University, is stud-Arsg the setion of int:rfe:on iz the body, as one type of virus-repressin,r, subssr.cc. tT.:a approach is now re- gnrded by the Board as less prcasinr than sooe others and it swy therefore be taperei off at ---e end of the year.) Willian Rerelson, k!.D. of The Y.edica: College of Virginia, is studying the funetion of the :eti:ao-cndothelial systea as it ms,y be related to tusor sd==on ard growth. Wilton E. yannier, M.D. of the University of Southern California is exploring the poss:ble effees :S tobec,!o smoke on the issnunological systes in aan, (v=ich system is involved in combating viruses). John W. Parker M.D. also of :he University of sosthern C ifornia, is studying hew ear.inoianie hydrocarbons nUr suppress ecllular ismanolegiei, nec'rsnir-.:, in preparation for direct studies of the possible ef'e::s of tobacco smoY.e or its constituents. -- Tobacco Sroke Studies Besides 'cancer-virus° et.dies, scsfe of .+bieh includu direct observations of tobacco effects, there are several other eancer" oriented studies involving direct esposure of vbole aniaals to amoke. In all such studies, it is noti a part of the plan to standardize snd control the virus content of the saiaals used so that this factor cen be taken into account. b1-eddy HombnrROr, H.D. at the 31o-Aesenreh Institnte of Cambridte, Mass. is carrying out a long-tera s:ady of the effects of blowing a concentrated stream of 'vhole, fresh, norml' cigarette sooke directly on the skins of his ex-c_eriseatal mice of the same strain that were used in his skin-paina»D experiments with "tars". In this procedta e al. coaponeats cf the smoke isspinLe upon the skin and ssargy of the constitucnts e^_zder.se upon the surface. :ne treatssent is being carried out toth vith and without acetone, which has Eener" been ased as a solvent for "tars" In skin• painting e,cperisenu, and in or.e group a"pronating sgent' !s being used to intensiiy any carcinogenie effects. This t eatment has now been carried out for G:re than a year. So far skin ttmors have not developed. wbile Uis experimental plan still uses the 'wrong tissue of the wrong animal" it does employ smoke in the condition encounte:ei in nors:l huisan sna::ing and should provide further insicht into the siZificance or non-significanec of the widely prevalent souse-skio -air •inC vith stale "ters" in a solver.t, as a bioassay systen. A proposed contract arre_n-csnent .it_•. !fr: Homburrcr for eontirmation and repctition of this work en c la:~er scole is under negotirtion. Also ane:.her separate eeitract .::nr.rarent is under negotiction for a study viLh h:_-isters, w!,ich terc cr-tain ad^mteres over micc for inhalation studico. Thcy, have :ar;er lxwrs and are much more

-3- HKBOS7io58 reaistant to nicotine. The p:an io•i:: include a repetition of the so-called Saffiotti metbod of prY--:cine squsrsous-ecli er_ einona of the lung in these animals by lodg::.g a mixture of ironaxiAc and benspyrer.e in the lung. This prr_edure has given erratic results in the past. By selett:M :i right strain of animal and eontrollin , the content and eond:a:r= of the viruses, it ssa.y be possible to develop this procedure a l+ositive humsn-type) lung cancer model for study:n, ae ?:ssible effects of sutLy factors, inoluding saoke inhalnt:oa, s, sleving dowr or speeding up the developexnt of esnce:s. Cecile Leuchtenber6er, ph.D. at the Ss+iss Institute of fi5cperimental Cancer Research in Lausanne, 3.rttze::a:.d, is continuing long-term chronic smoke inhalation ezperir.ents, •rith Cvo strains of mice, ard witb use of itep:oved eqvipsxnt that delivers "vhole, fresh, normel" cigarette smke to :.tie lung stafaces. She ead ber husband, Rudolph Leuehtenberger, M.D. have s.'%7rn that mice exposed to such inhalation of vholc smoke, or of gas-phase, develop ~ the types of lung tumors, adenom.s (non-ralig•m..-t) and adenocareinomas (mildly malignant) that develop in these sam mice vithoat any treatment. The only difference is the tazmrs develop earlier and at a bigher level when gas-phase or whole smoke is inhaled over a long period. Eo tumors of the prevalent bz.an type (squamous carcinoma) have ever been found in any of :be very namerous mice that have now been studied and minutely exrained. They believe that smoke may stimulate rovth of the tvanrs thst arise spontaneously (or are produced by an unleashing of the _atent virus present) but that smoke does not transform normal cells .nto sialipmnt ooes. The gas-phase is more active than wnole saoice in this effect, and is also sore active in producing the in.=aarnatory effects sometimes seen. The Leuchtenbrrgers are also o'_ins several types of cell and organ cultures in smoke exposure studies i= an effort to develop "shcrt- cut" methods that s+ay accsi ately predfcs the long-term results in whole animals. By cooperation vi:k::r. Huebner's group, the inpli- cations of the cancer-viras theory are being applied to this work. Cl11vton G. Lflnali. ?:.D, of the U.-iiversay of Southern California has bcen conductiaa a minute stud,y of :he effects of chronic inhalation of several pure ,tsses and _xtstres of such on the lunEs of stice. Using a superb :eehaiqcc far inflatina, fixing, and differentially staining the lung :isrses, be bas describcd the effects of inhslin6 oxides of ni:rogen, ozone, carbon monoxide and sulfur dioxide at various dosages ar.d over various periods. The effects of these expasures on rosistznce or surceptibility to bacterial and virus infecti_ns have also been observed. This work is relevant both to ca.-tcer snd chronic respiratory diseases. It is relevrl+t both t:, air poliution problens and to tobacco =+oke since oxides of ni:roEc-% and carbon monoxide occur in smnke. In general thc effects of n.tro;,cn oxides hove bocn surprisinCly snall and er,u:::rc :^pc_ s actnally to increase resistance to viruses.

- 4 - HifQ0S71059 It is expected that these teehaiTaes v:ll te applied to a study of the eLronie effects of vr.ele-::.e;:e and gas-phase ir5alation as soon as sooking nachines caa be it_-atahed. His techniques should aske the distincticn betveen sdenoms end adanocercinosu nuch more clear and reliable than heretofare. Timothy T. C:•ocker, t{.D. of the thsiver:ity of California is eontin- uing organ ana tis:ue calture s:adies ained at deteraining whether tobacco amoke can transfo.-3 no.-Pal c:as into aaliGnant ones. Virus controls are nov being irelude:. M Stearns Porshlew Ph.D. of =clm~ia University, is undertakin5 to eoapare the biocheaic and histoaZieal behavior, in cultures, of lung cells fron uatreated Zice and from nice that have been exposed to cigarette awke inhalation in vivo. Other Cancer'Studies Sheldon C. Scaners, K.D. o: Lcrs 1:3': Hospital and Columbia University: is continuing his studies cS hat fu :ors, especially abnormalities of the endocrine system, as t.`.ey s: e rc:ated to oar.eer of the luag in nan. Gilbert A. }~'iedel, lG.D_. nav at St. Vincent Hospital of Worcester, M.ss. is finishing off s study o= bladdcr esneor in aon. He shovcd that, coatrary to reports, there is not c pu allelisn between disturbances in tryptophanc sx•.abolisa in bladder cancer patients and reputed effects of nicctine on tbe same metabolic function. Kenneth H. Lvr.ch, H.D, of the 4edic~ ~allege of South Carolina, is viodins up a iong-term stucy of asbestos inhalation alone or with other factors, by dogs. It vss aiaed at deterroning whether lung cancers voald be produced. :bouah t8ere is nuch indirect evidcnce that asbestos dust may be ca:cirrgenie in man, these particular dog , experiments have been negative in reralt. David M. Goldenbert, M.D. a: the University of Pittsburgh, is ctm- pleting a study of the tsmwth ef hsean csncers, including lung cancers, when transplanted into hamsters. It was thought that this teehniqne sd5ht provide a uselttl method of studying human tissues. It has been found, houever, that the humisn tissue becomes hybridited vith hastster cells and that the picture is too:plicated by viruses, so that the original objects will probably not be attained. Shirley L. Xaufflasn. M.D. of the Downstate !•tcdieal Center, State University of IJev York, is con::nu:ng a ainute study of the ncchea:sns by which carcinogenic sCents affect the development of cells In the alveoli (air-sacs) of mice to g:ve rise to the adenomas that occur in this species. This bas:c work should op^_n the way for studies o: possible snokc eff-cts on these cells and the hope is that it eay converge upon Dr. LcuchtenberRer's fi:xiiaGa. Romeo A. Vidone, M.D. cf tho Yale University School of Medicine, is continuing stuay of the mucins yroducrd by lung eanccrs of vr;lous types in comparison with those of norn_1 lunC_. One object i: to deterstine whether the type of sucin prodneed vill prcdict the clinical

_ 5_ H K®OS i t 0ti(1 course of the disease. Luo7o Sevcri. A1.D. of the Uaiver:ity of Perugia, Italy has been studying the effects of isoniasa, a ts4g used in the trcatment of hvan tuberculosis, in 'prIdoMr.g' edenocarcinoma in nice. This drug and a nwaber of cheaically ~elated substances have been shown to be active in :his mainer. UsinP lung tumor pro- duction by such drugs os a bioassay s7sten, he has studied tT:c effects of hornwne additions or delet:ons on the tusnr incidence. In view of the developoent of the virs concept of cancer, this study will probably be phased ozt um:ees it can be modified to inclnde strict virus eantrols. Murrqy B. Cardner, M.D. of :be Univessay of Southern CaliSornia is coapleting an epidemiological study aisud at discoverine whether there is any relationshap betveen h•asen caneer and the presence of cert&in viruses in hoimebsld pets. (None was foundJ. This vas one part of an extensive Cover ment.sponr.ored field and laboratory research. -

-5- Carllovasealar Sr3dies NKOos71os1 Ybo key problems are noe regerded as remaining in this field: 1. Since arterlosolerosis (inclsding atherosclerosis) is regarded as underlying aost of the eardioras~lar diseases that are the leading causes of deatC, such as besr."attaas and strokes, the question of preventing or delaying (or re.ers:g) the process is parmonnt. In the tobacco fie_d, a pr3e question is vbether snosing and/or nicotine has an** effect L= ryeed:ng the development of erterio- sclerosis. In spite of sM ssdies, tzelndir.g several that throw considerable doubt upon the concept that sao's:ing supr speed this procers, there is still no clear-cut proof that it does not. A really satisfactory anisal model for reproducing the htaan disease, and which might therefore be used for obtaining a reliable assver is M1l lacking. Such a aodel is being sought actively. 2. Onee arteriosclerosis er a-herosclerosis has been estsblisDed, particularly at an advanced stage, the qaestion is vhat influences suy "trigger" an acute event such as a bear: attack or a stroke. Here too, the maia question relating a,obaeco is rhether nieotine or saaking - could itsrnish such a trigger. Basic differences betyeen :be kinds of people rbo like or need to smohe and those who do aot are espesially is~ortant here because the "diathesis" that predisposes to these diseses mq also be related to their need for tobacco, and thus conflsse the issues, especially in epideaiological studies. The twin ssudles tend to bear this out. Riebard J. Bin3, M.D. now of the Huatington Me.orial Hospital in Pasadena, s1'ter coepletsfg aamr other relevant researehes, is now aahing a new approach to the atberoselerosis problesr. Ra is studring bumaa arteries in tissue culture by perfusion sethods. Re hopes to show vbetber nicotine affects deposition of fatty materials in the artery rall :ra. serua or plasea when conditions are set up to resemble the situation in life - with respect to pressnre on %he .essel valls, and the concen- tratioos of albssta, cholesterol, free fatty acids etc. He is also studying blood !lov in the aierocirenlLtion of the heart to determine whether it is affected by nicotine. Seauel Bellet, M.D. of Philsdelphia General Hospital is coa- tinuins a lon8-tere series of stndies. His speelal interest no+r is in drterainina rhether ssnking or nicotine vill lover the "fibrillation taresbhold" in dogs with seriously ispaired coronary artery flow. (librillation is the irregular, chaotic contraction rtCrt.ha :hat soaetises leads to sudden death.) Be is also attespting to isq>roee nethods for determinisg nicotine in the blood.strese ae one necessary step in getting better coteparisons betveen cigar, pipe snd cigarette esfotiag with respect to nicotine absorption. Louis A. Soloff, M.D. of t.1e Teaple University Health Sciences Center, Philadelp'~ia, a locg.ters grantee, is now particularly interested in the influeare *f the blood-suaar level on the effects of nicotine. Meas:uesents of the effects of nicotine

-7- H tl®087106': on such things M serim free fatty acids, eholesterol levels, stroke volume, cardiac output etc., have generally been carried out in the "basal state" vhen the patient has been deprived of food for soae ti'a. Be finds quite different effects under normal conditions of feeding and ar_ivitr and is therefore conducting nev stndies of ssoking effects under such conditions. Stephen M. Ayres, M.D. of St. Vincents 8ospital in IIev York is another loag-tera grantee vbo aade studies of ehroaic puLmoaary disease. He is nor interested in the effects of carbon monoxide. Baving shown that saa1.1 anonats of carbon nnmside coaDined with the besoglobin of :he blood, have acae influence o-i the t7aasport of oxygen than .ouli be predictkd fr® the percentage of bemglotin so tied up,lds nov engaged in investigating the systemic and *vcardial (heart suscle) responses to relatively sms.11 concen- trations of earbaxyhesog].obia in normal parsons and in heart patients. He has developed a quick and accurate method for measuring carbon aqnoxide in blood by gss chromatography. Bruce F. ~emeren, Pb.D. nov at the University of Miaai School of Medicine ia riisml, Plorida is a sioeAenist interested in be>toglnbir. and especially in abnarsal variations in this red oxprgen.carrying substance in the blood- Se is developing better spectroplwtametrie sethods for deteeting esrboa saanmtide and ni+.ric oxide combinations vitb normal and abnaraal he.a+globin. Such methods should help identify persons vi:b abnormalities in their peaoglobin vbo might incnr a special risk by saoklag, and also in aonitoriag the effects of chronic asroke inhalation in animal experiments. Bnfte. Bhs~[st. M.D. nor of St. Louis Uaiversity Medical School is studying tura.over rates of bioasaic amines in the braia". Wiy effects of nicotine on the brain are akin to thoae produced by nor-epinephrine, a borsase that bas stisulatory properties. While lt had been known that aieotiae can trigger release of norepinephrtne from body storage depots, yet, following nieotine adstinistration, the levels of the boreaoe in the braia were not found to be inereasei. Dr. Ba6ac solved the aDrstery by shorin6, with tagged acrepineptirine, that the turnover of the hormone is increased by nicotine - aore is released and anre u.ed up - while the coneentratic , at any 9oeent reaains unchanged. He feels that the eonseqnences of :his effect are responsib:e for sme of the benefits of seokiAg. It may also explaia hahituatioo to mokirag. Dr. Bhagat is also engaged in sasir other related and colla:era: studies. (Note: '1Tis project could also be classed urter newrt.• pharaeeo ioa). Richard L. Yaeye, M.D. of Pennsylvania State Un/v.r+4.v iie,.i,ey neatcau center has recently andertaken a quantitative nprpho]oRic po.t-snrtss study of the blood vessels of the tunp,e of Atmasi saokerc and non-sswkers to determine whether there is a Etreater "flbrous thickening In the walls of arterioles and small artewfes of ssokers. Me ha. e.v.1 ....A ••--

-8- yKaos7ios3 type of examsination. 8rogrese reports indieate no significant differenee betveen smokers and non-®okers in the cases studied. Lnane G. uenzel. Ph.). of the University of Ranaas in Lawrence, is completing a stncq aised at determining whether intermittent adsinistration of niootine to produce oarked fluctuations in blood pressure Yill altimately lead to pathological changes in the heart s:uscle (of rats). Dr. wensel has done several previous studies on other suUjects ttader Council grants. Carolyn Bedell :^hoaas, M.D. ot the Johns Sopkina Unlversity sebool of Medicine is con•.iaulag her long-term study of the Johns Hopkins medical students rhich is aiaed at finding out what characteristics, measured at an early age, will turn out to be predictors of early cardiovascular disease. The real ansver can be found only when a substantial mmber of he- subjects actually develop such disease. This is to be expected within the next five years. Meanwhile she has enSaged in studying what patterns of aeasurable characteristics describe sainkers as conpared to non-saokers and what characteristics are correlated .ri h a femSly history of cardiovascular disease. In the present year she is eossparing the profiles of former smokers vith those of eontinLing smokers and of aon-anokers. This is potentially .aportant since if smokers who quit are constitutionally different froa taose who do not, the finding mp substantially affcet the interpretstion of epidesiological studies which ha-c; generally usumed that differences in health or longevity of stopped smokers and conti •m :zg smokers nust necessarily be due tc smoking, par se_ Sbo,11 Shibata, 'h.^% at the University of Ravaii has undertaken a new study to discover %,hethes ehanges in calcitm ion mobility induced by nicotine, p:a,y a role in addition to that of catecholamines, in bringing about the short-term changes of the cardiovaseular function that follon ssrokins. Erik Ski j, M.D. of the Bispeb3erg Hospital in Copenhagen, Denmark has just undertaken a ser stttd,r of the short-term effects of smoking upon regional blood flow in the brain. Habitual smokers aad non- ssokers are to be coapared. The relative reactivity of the cerebral blood vessels to other physiological stimuli are to be compared in habitual smokers and in non-smokers. Dr. SRinbbj is reputed to be the outstanding expert in this field. Jack A Begaa. M.D. of Jse University of California at Los Angeles School of Medicine, a year ago, undertook a sosewhat intricat- study aimed at distinguishisg between the direct effect of nieo tine in lnitiating constriction of certain blood vessels and a po;entiatlnR effect through eysrpathetie nerve activity. This study is being discontinued by the Co•a~eil beeanse it is supported adequately by ete American Medical AssoeiatioA 6dueation and Research Fbundation. (dote: This project could be classed under Nicotine Pharmacology.)

-9- Chron:e ?esairato:/ Diseases HK008710G4 The besic problem in studying tlfese diseases, and especially in determining their canses, Ss caai:al distinction betveen the various condiaons that can produce breathing difficulties - especislly eaphysema, bronchitis, ast.hsa and eertain heart eonditions. Poor definition and distinction has coafased efforts at epideoiological studies of causation or aggravation. Diagnostic uncertainties and changes in popularity of sncD teres as "emphysesa" have produced a fictitious appearance of inc-esses in prevalence. Multifactorial Clinical Stu_ies The Council has been ssr"ort2ng three "demoutration stndies" in pulmonary disease cliaics aisad at distinguishing these disease entities in terms of cmprehensive and repetitive observations on maety patients over a long period, follovsd up by post-mortea examination. Oscar J. Balchum. M.D.. ?s.D. of the University of Southern California is coerSuct:u3 one such study of 'Determinants of the Course of lbpaysena - Bronchitis" while Sanford Chodosh, M_D. of the :hf'.s Cs2versity Lung Station is Boston is en- gaged in another 1t the opposite and of the coustry. T4ere is ceesnmication brcweea the two and same of their methods are being sude uniform. Such studies should provide the coatest in vhicb smohin; effects can be appraised. TIIe ia- flueace of a congenital deficiency of the essyme alphal- anti•.rypsin in suseeptAility to espqysena is being investi- gated, snona sany o•..her factors. Another clinical study by Daniel E. Yisessau. M.D. at the University of Southern :aliforaia involves study of young children with the object of determining vhstber severe infections in early life aq produce lasting isq+airasnt or ps.e the ..vy for elsoaic lung diseases such as tapbTsema, in later life. Other Human Stadies of I.uae Cisease and Lunp Funetion David M. aia M.D. of Hrookdals Hospital Ceotez, Brooklyn 11. . is stuQyrisg the incidence of setaplasia (eell changes~ in the broncdial epitbelim of healthy adults r0o died suddenly vitbout long illnesses. They all lived in urban areae noted for air pollution. About fifty peroest of all adults in the 500 studied shored se*.aplasia, vomen aboat half as tnueb as men. :t increased from ZOL in sea wder 30 to 80R in mer of 50 and declined after age sizty. Smslters shor eetaplasia aase often than non-snokers but the hig3s incideace in non- smokers has been the striking obaer.ation. The auallty of changes was indistinsuishable in saohers and s.on-smokers. Jack Chalon, N.D. of Albert Einstein College of Medicine, Bronx, s s observiag the cyclic ehargee in structure of lung cells of young woeen, recovered by vessings, that correlate with the menstrual cycle. Since seo have no such cyele, this study may ttv on sone liptt on the sex differenee in susceptibility to lang diseases.

H KQOS7106a John V. Weil. M.D. of the University of Colorado Medical Center is s:u4fing the ef:ects ot a lack of oxygen on the "respiratory drive" or mechanical fUnation of the lmu. Ae haa evidence :hat chronic obstrnction of the ai.rvays will decreaee this drive and thns create a vicious circle vith still furt`.er Mgen deficiency. He is endeavoring to fiad out wbetber nitotane ebeorption affeets thii drtve, either acutely or as a chronic ef'ect. Beruam Eichel. 9.D.S. of the Science Resources Toundation in Boston ie present},y cooperating vith Dr. Sanford Chodoah in studying the bioeDeeieal activities of sputum cells from patients with varioos :7pes of ch.ronie lung disease. The hope is that d2ffesenees in nub oella suy assist in defining and diatiaeuishing these conditio.~ss. Any differences between the sputtim cells of smokess and noo-smokers will be observed. Earlier, 9r. 3.ehe1 s-Adied the vbite scavenger cells that occur in vast smbers in the mouth aa•a defensive aechaaism. Be found that smote erposuaa rlll immobilize and inactivate these cella (thoogh new millions are rapidly seereted to succeed t5em). As a test systm, however, these oral lencocytes made it possible to shor that the active ingredients of the amoke are in the gas-vapor phase and that acrolein alnae, in very small concentrations, will duplicate the effect. Ines Mandl, Ph.D. of Coltabia University is studying the role of earyae defleiencies - alphal-antitrypsin and of bereditsry elastase inhibitor - as fae0ors in the etiolomr of euph7senu. She is also eamparing the ebenioal structure of the elastic saterial from aasal and esPb9seastovs knmao laogs and of rat lungs made ea"4lsematoos by experimental treatmeat. A good saimal sodel :br reproduein6 hsman-type eapbysma should faeilitate mup studies of eaasal factors and of preventive methods. Aaron J. Lsdasn. Ph.D. of the t7nSversity of Rer Mexico School of )iedicine is endeavoring to discover vhether the lnag cells and other products that can be recovered by washing (lavage) will differ as bet~eeea noraal smoRera and normal non-ssmokere. So tar he finds the lipid (fatty material) analysis of alve:olar lining vaterial and of ma¢ropbages to be the sme in both. Ro.ever the distribution shows some differences. Dr. Ladsan collaborates with 2. A. ?inley, M.D. of Mount Zion Hospital in San Francisco. Animal Lung S.udies Donald Mstsaro, M.D. of 2he George Washington Medical School in the District of Coltmbia is studying the synthesis of protein and glycoprotein by the surface %:ella of the tracbea and bronchus. The expectation is that study of the normal process should .ielp in understanding changes that ocror in disease. He proposes later to study effects of ci5arette smoke exposure on such protein synthesis.

fiK8087106b Albert H. Viden, K.D. of Tesple University School of Medicine ?Ailadelphia, 7a. is stuGying under the ultrsatcroscope, the fine structural changes that occur in certain bronchiolar cells (Clara cels) after heir aeite and chronic exposure to abnorsaily high or lar concentrations of earbon dioxide snd oxygen and to various 6ases sa,i drugs. He is preparing to compsre the effecta of cigasette ®eYe exposure. He rrill also studj ehanges in metabolism of these cells folloving such exposurea. Dominto M. Av:a1o. !+.D. of the Uni%ersity of Pennsylvaafia School of Medicine, ?hiladelphin is continuing a long series of studies e)n :be effects of cigarette snoke inhalation on lung funetion, esrecia;•:7 pulmonerP resistance, in several species of aniaals. Re finds short-term effects that differ smoaig species and that a feaale sex hormone, pro6esterone, reduces or blocks thes. Ia chronic smoke inhslation experi- ments be has found so pernanent changes of the kinds that occur in euph.7lsema. :n experinentally imdueed empqysem, be found no evidence of a coatribotion by the kinds of ehamges that smoke inhalation ean produce. Robert C. Rosan, M.D. nov of St. Louis University Medical School is continaisg a three year study aiaed at isolatir$ funetioning ribosones frm the lvn6s of e:perisientsl animels, observing the speed of their forsation and relating this to the metaplastie and dysplastic lesions produced in an1.".la by a system of high-wpgen exposure .hieb is Imorn to caase such lesions in husanis. His thesis is that abnorsalities of lung cells are in part an expression of such ribosomal activity and t`at :his is affected by excess ooprgen exposure. Josrsh J. Guarneri. Ph.D. of 3t. Vincent Hospital in Worcester, Mass. is :ootinuisg and ertending the studies initiated under Dr. Gustave A. i.aurearl, M.D. These concern the effects of saote esposure on the palaonary saeropha6es (scavenger cells that help clear the lung of debris sad destroy mdero-organisms). This includes their mbilisation and activity, their capacity to destroy baeteria and their mKtaholie setivity. While smoke exposure appears to etiaulate sacropba;e mobilisation, it diminishes sose of the activities of the cells. This is not necessarily hsrmtlsl since the capacity for mscrophage production is very great. Ho.e.er, it auy be possible to identify the agents in ssmte that produce the effect and to eliminate or dimiDish thes if desiroble. Carroll E. Cross M.D. of the University of California at Dav s, School of Medlcine has just launched upon a nev study to elarify the relations between lueK lymphocytes and pulmonary nscrophages both of vhich are parts of the imaune systea. By use of a"eell marker" he hopes to arrive at a precise definition of the oriR!ns and functions of these two important lung eell types and eventusl:y to study effeets of smoke upon them.

_12 HKO0871067 Josepb M. Lawer.ns, m.3., Pd.D. of the Univesslty of Loaraia in Helgium is begluai:g a stuQ)r of the lympbatiea of the 1ung, tbeir structuae and rcle in fluid transport aad in oleerance of sirporne partie7]s:e aatter from the 1ung, ihis is a basic study that does not imeciatelT ssrolve toDasco snote Dut mq do so later.

-3 - .re,:rapharnaeolo,d and Peycholo,a NK©057106N Most of the pbarveacolo6ieal studies of the Couecil are oov directed tovard the effec:s of sieotiae and/or smohiag on the central nervous systm (the brain) v2-h the olyect of learning anre about r1p people like, vant or need to saake. Sueh studies, hopefull,y,oay, derine the "benefits" of sao'sin;. F:res more isportaatly they should help reveal the basic differences betwees smokess and non-mokers. This is inportaot because of the videspread sssmption, in epidesaiologieal studies, that the differences be:weea saxers and mo-saokers, as in disease incidence or leng-.h of life, are due sisrply to the practice of noking er se. We class eight eisrent studies as belonging primarily within this group. others overlap in.o this a:ea. Effects of 8icotine on the Brtin and fer.om Svstm Barbara B. Brovn, Ph.?. of the Veterans' Adettnistratim Hospital In ScInUveda, Califoraia is continuing her studies of the effects of nicotine or ssot].a; m tbe brain waves of human sutjects. Conputer sethods of analyz::a these 'eleetroencephalograsu' sahe their interpretation arh aore obiective asw rellable than foraerly. Moreover the aeaaing of the rsve patterns in teras of "deep sleep", 'a:onsal', "svake bot in repose" etc., are nar lmorn. ase "aroasal effect" of nicotine is now veil recognized. Dr. Brown's most significant observation is that beavy smokers haee a different basic pre.atling brain wave pattern fioa those of non-snokers. She believes that this pattern is congenital and that it antedates and influences the adoption of tobaeeo use. This finding is obTiousljr vcrf isportant if verified and s:vtained. A conference is d be Celd on June 1 to lay plans for independent studies by other experts to test her hypotheses. Edward T. Doaiso, M.?. at the thiversity of MSehiRan in Asa ArLor is continuing his pro47ss ia =s are+t, Vinich dates back to 1959. He called attention to the arousal effect of nicotine in aaiaals, actually tracing out the braio areas vbere action occ+as, and pioneered in showing bow tL•s arousal alYects beherior. He also ound a brief, non-cusilati+e effect of nicotine in relaxing the mselea in htman subjects. It has been suggested that aental arousal or alertnesa~ e~oabtned with suscle relanstion, way be an iaportant basis for toDaceo ase. Ulrich R. Sehaeppi, 4.D. noe of the Mason Researeh Institute in Worcester, Mass. is emtinning related research into the effeets of nicotine applied directly to various areas of the brain in eats, and ia now follo+dnE >p the bu ie studies by observing spontaneous behavioral effe^_u of such nicotine application to several brain areas. Leonide Goldstein 9c.D" of The Den Jersey Mearopsychiatric nstitute ia continulag a relatively new study aised at r.hoving hov chronic nicotine adain:stration alYeets the elect:ical activity of the various brain centers and their responses to other "psycho-trapic" irugs (stiailaats, tranquilizers, sedatives etc.) He feels that he has found a pharmaeolosical basis for benefieial

NK®OS71063 effects of nicotine. Effects of Nicotine on Behavior (Animals)* Walter 3. Essnan, Ph.9. of Queens CoL'eae, City Onivasity of Ner Yors in Flushina, is eonpletins a study of the effects of nicotine uroa nmorr coosolidation in rats. Several techniques for studying the learning process in rats bave becoae standard. It had been found that an elec' ic shock at the crucial s~ent vill prevent rats fros °consolidatind' or reaembering vhat they have learned. ?sssian bas shovs that nicotine sdainistered in advsnee will offset the effects of such an electric shock. Sa explains this by the observaaon that n:cotine affects the metabolism of serotiain in various regions of the brain. Carlton E. Eriekson. ?h.DR of the University of Kansas in 7.avrence, is completiag a stma of the euehanism of learning facilitation by nicotine. ais hypothesis is that learains- facilitation, which he regards as estsblished, is due not merely to the arousal effect but is the result of increased "cholinergic" activity in the brain (i.e. through aoetyl choline). Sachiodra N. Pradhan Ph.D. of Norard University in Washington, P. C. is continuing amtCer stadf of the effects of nicotine on several schedules o' learning behsvior in rats. Nieotine effects are skin to those of asphetaaines, stis:ul.ating spontaneous activity and, depending on dose, also stiaolatin` the response rate in learning schedules with food rerard or electric shod[ a.oidence. • The policy of the Board Ss to liait the extent of work in this field to establishment of significant effects. They do not plan to follow the numeroue ranificatlons of acadesaic ir.;.erest indefinitely. Peychology Only one project can be classed as being in the field of humn poythology. Nornen W. Neisstra, Ph.D. of the University of South Dakota, io Veraillion, vho has cospleted several pre.ioua and productive studies, is nox engaged in a study ataed at findinQ out rEether a substantial ehanse in sood, produced by a mtion pictnre with strona motional effects, will change the spontaneous smoking behavior of a group of hsmsn subJects. This is frankly a loLg- shot effort, at oodest cost, to .ee whether the 6eneral ispressioa that peo,ile often axoke to relieve Motional stress can be eon- firmed in a controlled experiaent.

Ceneral .fieo tine PSarmacology HK0CSi107U in its earlier years the Cauncil supported manyr stadies of general nicotine pharoucoloay on the assmeption that more detailed descriptions of this a].taloid's sa.~ short-tera effects at various gsnglia and "chemo-receptcs'$vith thei.- acaow and canater actions, mtght produce some explans:ioo ss to hor nicotine might contribute to the development of dizease, espeeiallr cardiovascular disease or pnlsonary disease. This is a fertile field for aesdeaic research. After a period of *ers a reviev of this research suggested that rhile a great deal of 7 ocentiaLl,y useful intormation ha+d been stock.pilet, it had not aGiad sp to up explanation or suggestion of a contribution by nicotine to :ausation of snch diseaae. Subsequently the enpbuis vaa therefore :h`.g;ed a the search for aa,r possible chronic effects of nicotine and mc?e especiall, a effects on the central nervous system that might explain vq so suny people, and particularly yhat types of people, find ®ok:u yleanasble or beneficial. M)reover, the A.M.A.3.3.T. tmdertook a nmber of projecta in the field of general aieot= pbarmeology vhich suggested that the Conncil aigfst ilather d'.mWsh emphssis in this area and increase attention to others, especally cancer and the developing concept of the latter'as a "virus" expression. At present, the Coscil has three remaining projects in the field of general nicotine ?harsacolau: J. P. Lcnft. Ph.D. of the lhiversitr of Iova has bad a series of grants since 1961. liis ewreat stwly is entitled "8yepatho- sisetic Action of li_otine', that is t!e action of nicotine on the branch of the se.-+ass s7ste eallsd the syslpatbstic systes. At the aoaeot he is especia7.1P interested in a drug ealled DMAB which is a potent aitinieotiaie agent. In other rords, it inhibits the cardiasseular and respiratory stimulating actions of nicotine. Jaees E. P. lbmea. ?h.D. of The Laicago Medical School Das had a series of graau siaee 1~P62. He describes his project as 'part of a loog-ce-a and broad p.rogrm in neurophassaoology, aised at the aaaljsis of the central qn.ptic actions of drugs and their correlation rith effects upon behavioral parameters. The central effects af nicotine are studisd in ccaparison to and in interaction rith relevant eholinergie, serotoaergic and adrenergic agents in an effcrt to stud, separately the ebolino- siaetio and catechalssine releasing setiona of the drng". 81s group has published a/arge mmber of papers describing intricate ac:ions and reae•:ons, and relations betreen effects of nicotine and those of other lrvgs. It is difficult for a non-specialist to suzzasrize in cosa:n larVsge what this stock-pile of inform- ation about nieotiw sdds u-, to. I rould ea11 thia a basic desQiptive study :>Sat is not targeted tovard asLy specific question ahout nie2tine in relatioo to disease or benefit.

16_ HK00871071 Triomss C. uesttall °S.D. of the Uai7ersity of Virginia Scbool o Medieine has Deen s grsatee since 1965. His qtesat topie is the "Infiuence o' ]icotiae and Related D.-ugs on the Uptake, Storage, Release and :lsrnv+er of Ca•,.eeholsmines in Ces:ral and Peripheral Tissues'. This vork is a'sia to that of Dr. Bhagat.

-17- E,videsiclov~r NKQ0S7107; Only one projee: la .rhios the Coune1l is involved ie placed ander this cle.ssificatica. Tha is the Aorsave I~ing Study ceatered at the Veterans' Adminittratioa Ootpatient Clinic ia Boston under the general direction of B:a!amin Bell, N.D. vitk: Charles Aose. PS.D. as coordinator. '-'his atudy has received its main support, at a bigh level, fro' the Veterans' Admisstratioo. '.Le atm of the stud7 is to teake numerous periodic exassinations of a large group of sule vetersns, vith a hlah initial level of bealth, in arder to deseribe the changes that occur in nornal aging. Me excdnations inc_ude sedieal sad dental evaluation, nesauremeats of body build asd flmetion, biochemieal tests, bebav'ioral tests, tests of perceptloa and collectiea of iafbrmation about life babits. Since snoking is included, the saterial collected promises to provide importsn: irSoraation shout the di'fereaces betvaen smokers and nom-snokers. (This can be a sho.-t-tera product of the etnd.y). Over the years soae of these sub~4eets riil develop diseases and die. It is hoped that the great s:oek-pile :f descriptive information rill make it possible, through anitivesiate snalysis, to deterriine .+hether there are clusters of factors that can predict disease suseeptibility, losgewity or relatively short life span. In the context of this extensive information, it should be possible to get better perspective on the role of asoldng, if azw, in laflwncing life span or bisease developnent. (This kind of result can be obtainsd only after r. ssbstantisl elspse of tiae). The Council bas assisted this stcdy 'r., 'urnishing a part of the statistical sertice for eeapnter analysis c' t--e eomple: data. So far this has been chiefly through Mr. burt Ens.. c_a. ;he Coimcil also fiaaaeed a prelialaarf subsidisrr project to stssd,r a ssaller group of five huDdred recent deeedents, largely tc test out new methods of mttltivesi r.e analysis' project. Dr. Carl Seltser snO Dr. Albert Dernc are consultants to tbic (Dr. Caroliae eedell 1Z+ames' stucLQ could be elassea under epid. es.iology).

- 13 Other S:•adies of Smoke Effects W0871073 Willis R. Rieseo. Ph.D. of the Illinois Instittrte of iecbooloU in Chicago is studying oertain biocaesdcal effects of chrooic ssoke inhalation by golnea pigs. Using a Halton-Aombuager-Morrissey machine (which has fSmetioned very well for txo years) he aas isolated the mitochondria ?om exposed lungs and studied the oxygen traasport systen in these small cell coaponents that are the seat of soe of the cell's most inportant finetions. Hecaose the experience of the aaimal in the saoking machine is quite stress.'hl, especially if the oose is sealed to rote snnth breathing Coapulsory, control ani-als exposed to all the hasdling and trestments exeert for the actnal smoke SnLalation were used for campsrison. :be result found vas that the nitochond-ia of the stressed animals, without smoke, shoved a very s:.gs.tficaat impairseat of the oxprgen transport sJstea vhieh .as traced to nro specific sites of the chain. The inhnlation of whole smoke largely pre.ented this stress effect. So also did the gas-vapor phue of snaoke vithovt partiev lates. Simoo S, Vender, Ph.D. of the Uaive:sity of Oklaboaa Das bad a series of grants, espeeially for analytical stud,y of poyphenols present in tobacco aad in saoke. Ctirrently he is eoncluding an imrestigatioo of the effects of exposing aniaal cell eultnres, both norMl aad naligaaat, to knorn chemical careinogens aad to tobacco sssol[e rlth special reference to the production of free proline. A near relative of this smiao acid is a constituent of eonnective tissue. 1hSle effects have been reporled, inter• pretatioa of their sesning is unclear. At present the continuation of thi: project is not ooatessplated.

( _ 19 - H K©0571074 Miseellaneous Studies Paul S. :arson. Ph.D. of the Medicsl College of Virgiala ia Ricl®onC, continues vith Eerbert Silvette, Ph.D. the collection. abstraeting and analysis of the tiorld literatuae on tobaeeo, esperi- mental and clinical studies. A second supplement to their n+oaograpb on this sub3ect is due to be published by U1111sou snd Yil7dns this year. 2iaiter M. Chaora. Y~.D. of the A~iecUtnral and Tecbnical College of Dortb Carolina in Greess0oro is eosipletins a three-7ear study of the degradation of DDT, T9b snd dieldrin (insecticides used on tobacco) during the burning, under mraa2 standardized conditions, of cigarettes coatsining various smowts of these substance.. The object is to find out rhat breakdown products appear in minstireo and sidestrese smtec. John R. Rarlsnds, Ph.D. of the Soathwest Research Institute i.i San Antonio, Tws, is attasptin6 to discover hon free rsdiCats, part:• cularly osides of nitrogea, =reseat in fteshl7 generated tobseoe ssol[e interact vitE living aniaal tisaoes or blood. Sleetron syin resoasnee spectroseopy is the aaln tool for this vorY. The Institote bas saes unique equipment of this kind.

f'M N

Februa_ry 13, 1974 Preddy Homburger, t1.D. President Bio-Research Consultants, Inc. 9 Commercial Avenue Cambridqe. Maasachusetts 02141 Dear Tredd, y: Our last letters aooarea *.!7 =ossed in the mail. I was aware of the paper by Doutenwili an= associates; in fact, I had known of its contents for same time. That was ono re3oa why we wanted you to get your definitive paper on your results with smoke e:oosere of hamsters in so that it might be published. I have cone over yo•_ detai:ed final renort and it certainly sesms that the work reported there merits reoorting. Photc,ranhs of the lesions were not available ho•aeier. a:5ea we qet a manuscript and illustra-•.iors so that the results can be evaluated by us and our consultants we will be in a better position to disc•ass definiti•re publication with you. ::e desire to e.r-,:edite early definitive publication of your work. As Dr. Hockett and others of us :^.ave told you, 'soroe-ter, we- cannot agree to fraqsentary or isareciso nublieatio.-is, which may be nisinterpretcd. "_^.-ere=ore, we must insist on vour cbservinc your contract obli?ationss not to publish wit.'tout our rporoval. _:. l:ockett kas ta4er. ur with you sacse of the points that we and our eatholcrv cor.eu;ta.Rts : ad nenticr.e.; in relation to your wrk and abstracts c° naocrs to be _nresentea at meeti:ns. AR;in illustrations were not avaLlable. If msterial ie to be presented repeatedl7 at meetings it should, at leastre in procenq of de_'in:ti,o nualication. As to your previoL-3 letter and attached chronoloqyy, no useful guroose would .`.e served hy flotailec rc?erence to the mistt7crs ar,! distortions contained in them. However, a_ew gcneraa o-servationa thnt have ecen :aade to you aeveral tises deserve repetition. A::•ou know, and as I learnd.9 c:rlien ' became affiliated with The Council, the contract vith 3i_-Research Crns::ltant.;, ...... was for suopert of a feasibility study for the exposure of hsrster, as lehorntorv anima=s to fresh smoke. Your experiences indicated that the ha..-atcr vss the spec?es you considered most desirable. ':".te Council and its Fcientific A•ivi4ory 9oa_rd were desirous of qettin3 an animal model that right give cancer of the lunqs sL-nilar to those arising in can and associated statistically xith exposure to caarette smoke over long perieds of time. The haaster did not do this in either your nor Dontenwill'a investicatior.s. As we have told you several tLses, it was for this az well as other reasons - ranging from a choice of the mouse over the hartster as the animal to be exoosed to consideration of available facilities for various aspects of the work -- that we decided not to support further hamster inhalation work at your CTR EQNTRRCTS Qa5507Y

i Preddy Scsburqer. M.D. - 2 - Febsvary 13. 1974 laboratory. As you krur., our decision has zt been to saspend or terminate inhalation exposure work bat rather to c^ fr-:varZ with ezpanded support of correlated researah. I understand that you have saat cogies of your previous letter referring to this subject to several of the tobacco comoanies. I am therefore eendinq them copies of this letter. Sinearely. F+: ek Sfi231a.i 0. Gazdner. Ph.D. Scien =fic Director bcc: Messrs. Y.eimann (Fletsco, Leake:. ':a~ ;3rfta. Hu!rhesl, Tisch [Stevens, spears ) , CaL'man (Ahrensfel=. Wz:ei.t=;. a^.i.th (Paemer, Senkua). Bantle [Bennett] , Causbell, Sloat (=aas: ,.=nzzob, HarZy and Rryxs. CTR caNTRRCTS 005506

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ttKm00~~~I~''~ 1144 aLRMiatD. NO4aUlGLR. AMO RtKVE1D Fsposve a ciRamue smokc reduced body weiehs ol both inbred stuains by about 10 g during the first 2 oaks of treatment. Subsequendy. weilthts increased again. bot sornewhar rnore slowly in 810 15.16 tFun 81O 87.T0 animals. Because of the low tinal weiRht of eage•held 81O 1S.16hamsten, d+e weight difference between the eontrds aad amoke-ex hamssen was nsrch less in drc 81O 15. 16 Mae in the B10 87.20 line. Sham smoking produced body tveighu intermediase between thame of the age•beld eontrols and the tmoke<apared animals in lint 810 15.16; it had +o eRert on body weight in line S1U 87.20. It thus appean that the long-term response to smoke mnalanor4 i.c., the failure of the smoke• ergoev animab a gain weighq was due largely io dirset e6ees of smoke inhalation rather than to nosnpeciFe svsw e.ae. srwt«.wt.t uwor Saxine le%vlc of earbmryhemoRiobin ransed from about 0.1 to 03t,. Immediately afur exposure of hamsters not previously inhaling smoke to a sequence of 40-paB ey:Jes, earbost7henmglobin lexls sose 20-40%. Within 4 houa atter eaporne. these high leveh kll to 4-10 ;. A second eapoeute on the same day agam raised the I-rl to 911`W;_ After two •7 -~ ""...........r--J. .. . S I /- .r..a.w.+ r ....•. ,... M..wmR.. . , .. .. . - o ~ .«.. ...«: TTet-na+.r 7.-d..re ia aseee kdr .rrt' R d arO /5.16 aarnsten eurmt eapvRRe m rsoenr R+wae aed Uwe d e..ueh .... . n... ~ 7Yanww.Rr 1.-CinMa n e.wtye tode .dtMa sf S!O 67 20 hanNas duny ta/rre v, tipamte an.t.e aod th.r ./ conwY 20t}•;r ranonue~ se ciSareue smoke within 4 S hoara on the sarr~ eay, and then 18-19 houn of rest dsrioe the nm"t. the earboayhemoglobin re• turoed to r..ar presrotmeRt k.rls in all instanres. fr.sm these rew{s uo animak not included in the ehsus.e iniulnioa study, espaure of hamxen to eiyarene smchr for much shoner time periods, i.e . to 8•poH cydes wice aday as us the eh:ons snhalauon eapcrinea. may vatm be avmned to cause no laainq acet mrl.uia of carbon rnonoaide in the blood This was confirmnJ in Y kamaten after 19-45 weeks in the chronic lnhalacian acudy. Blood earborylrcnsoglobin mcawred on a f:rsday nmorwsg before the first esposure to enokc ivsalation of the week ranged from 0.2 to 2.0:,. with a mean of Ob3 ;. Canys M Wnw iryyeMU tawla Ses ten trstycercc kvels, deYrmirsed in ten and conud annaaih at .wdt 45 of the experirnent, ranged fiom Ia5 to 272 mR. l00 atk with standard deviadoas feom :3 to 4: mS1K0 ml. Because of tfseae latite itr ditsd•aal suedasd ek dations, the ditfereners were far fsom sgra5cant. T:na aeisher arnoke caWsure nor sham anoking ptsdtr:d ehanga irs aernm eri6lycsride. Vtn. Iwfbn Th,: viruf profiks rere determined at 45 wee]u in 6 animals lsva earh esperimtstal group and in 6 youoR. uets•eated aaimak of earh suain that eorre- aporded in .eight ard age to the teu hamuen at the besunug d tne eapetYnent. The dau dearly rhowed that the view prafde was not eh.ngad by emohe exr pewrc. sham ar.olers. or psplsnSed eagitsg under the eondi:i6ns d the esper.oent. IIS11Mnr1 at SaMe Eauwo M OqM MNghd Because d train dderenees in 6ody ria (table 1) and the wei.at thanges prodtset:d by the experinsmul pn.cedves, atsdute organ weighs in these asomals were diRscuk to iatcpret. 7heeeforo. ocsly relative orRan weiRhs were a6alyaed (tables 2-4). Wdghu were taaulaud ooly fa the anima6 killed. ooc for those dwmtg apoa/ancouiy. This ..u done became changes in the respiratx" tract were of the greatest iotwt rdacve a a~+ie eapaaure, and inclt.ion of the hstg weishts 6t sponsaneoiWy dead hamsten would have nwod.mi a variable and unkoown amount of asanal pakssonary rongestion and pul- maoary edesa toto the averages. Rdati.t we+8hs af ergarn (Ii.eT, apleeR, kidneys. adtatals, bear. or loop) did aot differ aignifsantly beereen aoimab of nce 2 iobnd saaias at any of the age asudied. as fotad by eomparirm with data for cagtheid co.tsoie Relative osgr we*hta tetsdcd to issus.c with advantiag age in estpcritnensd aod control greups. 71ey also beome more t•arsable, as evidennd by hi;her taandand de+riatiana in the older anunalL The aEasdated inneare in relative weight was particubriy marksd a the kidneys of both inbred nrauss and war rano by oid depositiors. Renal amybdom was a Ha, theading cause of death

T.ar. 7. Rrlar'rc rpMto uviyAr.. rf A.n,teq Mldd f.e AmaGl"r .Irdve Lenpb of 8/w11•uenl wIImlAc.nce d d111rrrncc. het.ccn amera Inbred Rrlatlvr epiren w1• 4 h.n•k.. (m61 mwn. n/ 2 payr ..1 .nnr• Ll,red ti.e ld b. r liee • er/ .t I I ; .p mrn m. e f/•.n ~K.I w 3L. ~m~kM rn dll4~n rslol emniete .. u lrol Cn oMld c.rnlrol u d ,{ p v po p m p e n f n po (.k) . leepd. Oroup) 1)rnup (nwnol I) (oonlrnl 2) Rqal Rreap IieplL pnup Gmlrol I v+. %r. tonbd I %w. ton~r~J 2 cwnlr•.1 2 6e/e) BCln/A1n/61 el 60-6n 1i 1e 7e 7(19 2tu l7f6) (2 04) . . . sl aa ITO. 0196. 1Ve1 -1-:' 1 Q 26-90 17i.2(a/.61/2,) Iln 9171 '1/171 114 eM 96f11' >oo Ifl. 6(6t.71/261 IJS. 016Q 26/6) 117. 4141, 2J/12) ~ 60-60 e7.40 6l 0(f16.4a/6) 62 0144.30/7 6] 7116.0o/a1 - 2.911 11.1111) ~ ~ 61-7a A,SYI),. 00/91 92 11J2. 2A/I ) IBi. 11107.91/111 7.7n 2P/ n-en e6. 1/19. 32/271 09. 111 31. r1/6) Ih6. S(tA na/1/) 2 87 >90 10e_O({I. 1a/201 //P. e116 1151111 11Y. pl2R 76/7) i •.uwt...e61w. ~uOM.f IneLN W 6.dr ..yfu p./1...1Y/11N M N6 6Y...Jae. ls por.Wln' wMe. N Weda ~ Nwvl.d.rrA0osr4 N Ktotl4ns Mn111'SenIL alrar...t.eb pt Y NMM/a+In4t.41ya16u.vw..o~dF.a Irr.l celf I>•<6n1.1rlre r bwlw• 1• d••w..www.r...nwuwrdlr IturM•a.w. i S Y Tn.e t]. - Re4/i-. A•.•t r nr64 ,J A 31.Ilsdr.l M/tm6r.nre .a dlRcrrnee. brln, ~ f limu un Inbnd R+IwI{rr brurl wt• oJ hnmwlrrn /u~el nr•wn• .J 1 p..np• ..1 -lw Inl. •1 1uv ~ r.p.dn..olwl Awrnrl.r Iln. .. . . .- '---- --------' ---- u..rlw.l condu Wro 11/111) &nn4..rpnaed /troup Illunl•wmn6rd rn6tlul r.AI Lep/l. 91.01.1 pnnp let.nrr.d 1) (1o~c•in4d renlrnl enwp (oou•e.•1 2) Fap•I anap v. r~~oln.l 1 ---- G.pd. u..np .w wnh~.l 7 - Cnn, rnl I... r..~l~,•1 : t ~ IO 407.8 176 07fe` sl1.c(16.0 IS 6fs) /06.o1i61 4 n7 330 6 1 as ~ t 61-7a ia41. 6( i7K $it~) ,le. (i,~lin6) l 76•MI ` 917. 0(7Q 6WI/10' - - x • 676.01172.s/76) f6+.6(62.M/e/ .f2.e(s3q/72) 2.69 3.21 I:L7 .n -6o 67 20 .07.6 (6f. 9sfe) aa0.9(21. Oh/91 2fe. 3 24. 3nf6r 9. e7 3 17 O r I -1s .77.1/76 lonl .16..(1e.61/11) a77.1 a1A66/I1) C) " 76-90 477.4 (W A7/22) 460.2(16 w6) ,42.6 64./17/la) - - ,.9o ,62. 7 (6t,s3/70) ,f1.7(ei 0//121 J61.7127.0!•1) :T •.eael•.~r.d.ar y1M.NW Ly .rJDU On tl. adeyYd M IOL M.. ealra 1. prnrs ~Ry..f W..4 ~ /7urWddpl9erab aKo.M...lnatt'f../..wl...wlrM~Ml.prownnMr.ww..{wlm.aw or. w.MwYwIWrIr16161.w6MM1•rMwl•I...,,NSw.+lrrrlnewo•dN ~•~ dpr6o.c IIW~.IOtdN. • M

b~ o ~1 ~~g~~~~~°~~~ IIIi'iII jI1iuJoRijii Oi V O _ l~ ~ i1jIHtiH ~-ir_~y~~ .~ ~. ~~~'F~~iC$3tr~F n B7g~p~ u~~ st g.5 ...5 M V ~ i O z " 1w+u) IdA ~ '4wM/.'MU...wnrwulul'aw.w•N'wt\rsanpr pr'PwVP.~a/1/Clh..:./y°.'WMapl'(APw r ." tw/YWI N PaM ~'IMaP~ M1/pY- . ~ (yt )a x c - (t/~:•:z)A erol rn/~titclt'ICtI laeuA Ai/u te~l : A,.. 1 (91/Y BMCqILSi1 19f1'1LNL'CILI (ti/~'Wtl!''fYtil p8yt (/S II 9Y1)1't.8 I/1/L SLI~UIf.ll (0/0'YOL)t'IVZI YL-19 (LLi) St'C (9/Y'LAa)981r9 U/C'Wt1U'0[A (9/8'18/)L'0L01 0d,'L9 _ AV'L ct't liI/q MI)t'Npl lA//;4 t0) 0'tC01 LLh yLl'19 L011 a~! _ - - Ulno%tL~i •@9ZI (YU; oAt)Z'6SL) I8L/A V.wA'A911 ~ 9G-9t Ity'Z) - ` ) -' IO/0'Uo)L'IOLI . 9L-/9 (16 L) - IU/ta'Iellt'LiY IL/W'ii10'EL91 (9/91 ZOIS'BLE 91'41 09-46 • Z Wwoa Z Ialwa W. '+w 1 p4voJ dn" 'ild., Jno>>l pday (Z lYtluea) (I µu)u°a) dnmf (dneA -(,d.al I(..rf.lYn/) dn,a)I ru/una PIa4•a)lr,) (uuluca paqoawwvAC dn00 patnd.a•afemg aYn paLqvl a1W. N odnntll t )n.Y.,w lt.~) .~.yvav ^I II N11 Uaarlaq .p.atsa/p p aau..pluta pallyn/6 1~~ me. w I t1I~) (/)t91 nwllryvoa .ull aapm.Q mU.u~µada,a ptiqat uU wu11 N Va1va•t .nyqa ..MM/wt Ml IM'1 .•')n.q /r .ryhtw Aae) .a).)~1-' f 77. vy

NK8005 r, n ''':' aa.cterrtc sstoz-1 trwaunal O araatn M•Yrrats ouriear dysplasia. The basal layer remained intact and fairly strauht (fi(ts 1-9) Thn change wa+ seen in 40r; of the Gv)ittcs of smate-eapo,ed 81O 1S lo hawcn and in 51 ; of the 610 87.20 line, but in aone of the conwi animaN. (tablea S. 6). Qaaf tNf AffinreNVg was defined b prollferaaon of Ilu sqwmotu epitbdium in whtnc cells 6rew down inro the dermis, often in a rniculu pattern. \uclrar dytpiasia and miwtic activity tended to be more intense than in simJlle hyperptaua (fg 4). This qpe of change was more frequrm m B1O 1S.16 (40%) than in the BIO 87.20 (19%) anirtals, and 'u was absent in the conaels in roany cases of this lype of change, the basement membnne of epidermis :ppeand to be intact (fiss. S, 6) It somrsimes hrome rery irre6ular, with apparently isolatad cell clumps in the dermis, a few ul)t(ealin; 1)tic+phalir inwlon (6gs. 7-10). In advanced suees, basal all hyperactiriq• was difficult to di/fetemisle rrom earlc mvasirr eamnoma; however, no dtNaat mewtates weee found in any animal. The advanced +tages elaaifed as ••srve+e basal cell hyperaanity In tables S and 6, and often ndislimuuiuble fron micro- iovasive cancer. occurred in 19 % of the smokeaspaed smmils in the B1O 1S.16line6 but in only 1~r of Ihose of the 810 87.20 line: thev wcre absent io the coerro4. Small squamous ppiNe.rr similar to thou occun nae in the tnchea and bronchi were found in t.tie 1147 l.ryneeal epinheLam of 2S:r of smokeKaposcd ham- sters aed e+ IS^ 1 the 210 15.16 animnls. Occa- sirwuy ttere was dow.gowth of cells at the base of Papiilemn lhts. fa. 121. A le. tarynse of smeke•esposed hannten also sho~.ad eheonc infaaunausn and/or sqwmous meu• platia of srximts Ea.ds (fK. 13). CSuanic inAamma• do. n a kw einaoY was asuciated wnh slight epithclial OrcYalmr bus ne.er with true hypespissmaia. pse.doeptr.diomawow change. or papolorna for- tiod 8harn-naisd and ca8e-hdd conuols did not diBer s18mGcaody, n Jw respect. >-" Hisalepc san.ntian of 90% of the lungs from BIO t5.16 hamslW. and all of those (rom the BIO 87.20 strain reveakd elurcat slnin diElerenen and ssmficanm effects d)ma:e e:posurc (tables 7, 8). Q..yeT .,/ aan...es. Pulmwnary maeeophages is bo~ araan d harss+ers forened small clumps within the ahed,. This tedency was much gnater in the B1O 87.10 dtan in -ne 1130 15.16 straia, as sean Gom a c9reparison of ae ease•hdd control 8loups (44r. vs. 6;). It was accent.alcd by tmoke apasure in hocE srains 02. s S3r',,, snpt:rtivrly)- In neitner su-ao was the iRideoce of maatophaee /lumpoe afkrted by snam saot:l8. There were quiilauve an neL as auantiuwe diBQatos in ooac.aoiusje ctumpin6 among the vari- TanLC i-Nrbb4ir )F.Uys i. rAr lerO.M.f B/O /a.1t L.rwN Lenph of Kun- Nu.. 1karKnt 8rwp tmr uw raprn- ler u( Oat d N PG/ nvntd eondr unmM Iar.nns t1041Pk) aa0(H stumrd VuswOw d aFOds wItY Hry.r. 7Ltal lHno• Pap1{. Chrwie 8yvs- p.w. BCH: ln.r Iossn io8.M- motn /IR mlli mela- OO~r pla- (i) (8) (wl (i.) (v) (a) lvih (.uil ful1 (f) (ail SnMe.apowd..... 40o-60.......... 7 S - '............ (il-7a.......... 17 7 1 .......... 76-00.......... 31 16 1 ............ >1n........... 251 20 - .............. Sobto/nl...... LH e6157J 2(!) aI-r ......... s . ....... 7a-00.......... 21 ............ >60............ to ~ „ .... 8ubtn1nl...... 42 301801 Gr.M4.......... 4aa6... ...... f S ............ 61-75.......... 4 4 .............. 76-00 ......... 1: II ............. >tW........... 13 7 a 1 - - - - 7 3 1 2 2 4 1 2 4 3 9 e 6 4 1 3 19;10/ 19(e0) /1(10) 7(1S) 7(15) 8(17) S 7 ls s 010) T7f7S) 3 7 a(o) EU 1 0 s 3 •(2s) 3 2 4 " _..... RdwMa1...... 40 251U1 17(6R1 0(0) q01 0101 0(01 8(721 0(0) TtnaltwTSnam...... ... 166 1®1a6) 46(t21 IAU7) t^1171 9114 7(0) 24(221 8(7) 'IJlwl. rwwr..w.r. wwlt, .Lnw w.nN Wa~rW. M rw.wl r~.rw r r..M r.J M...wYl. aryo b prr.Mnr. wo /~rw~e..erwl'llr/IrswWa. N s~.n.rr.w..rawwr~:.o l. uw~au.~re r...n ~1r.r a..Nt.w..q.a.rr sm tssr ni. taarw~e rr.a• ta~t.rl N..w.nr. I

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C16ARLTTI: 7MOK[ INNALATIOy L% INat(D MAa16Lt T.av R-Rirtalqfe fluliye O. /ar b.r a/ 8J0 87 Nl w+rea• 1149 .`Wnbrr d aMi.ri• with lenpll of Oo+c Nunber [iumMr 7TeuRrot 6Taup nn e.pmrmntsl ut e/luy Oaaiqed Bnn- Ir. A(els- eoodttqtn O.rl anana)• wten1es NPD enaoe- eddar Enuple 6aaa stnie autp~. n.d.~d Pa.F't ~: baee matqn tumcr II) (iil Ui) ed iN 110 (.1 (n) (efi) twiil (n) Ie) Bsotr.apnud......... 40-60.............. 8 B - S 2 - - - ~. .... 61-7s..... ------- 2' 23 3 19 4 - - I ................. 76-lO.............. 3s :3 1 25 la 6 - t .. ... > 90............... 31 31 - 30 T2 4 2 - ................. Subtetal....... m 1711oDI 4f 3 6D!!1 46(n.t1 10111) I/I) I(') snrfa+oled.......... 40-60.............. 7 1 6 - l - - - ft 4 - ................. 61-76 .............. 19 19 6 7 4 4 2 ................. 76-60 .............. 6 6 - 3 3 2 - 1 ................. >90............... II 12 - tn 3 5 1 •................ SuMotal.......... 44 441 16D I 12(r) 2!(iS/ 13(30) 11(Zl) 317) 3(71 Ca6e•beSd............ 40-60.... .......... 7 7 3 3 - I I - '.. ............ 61-73........._.... 0 13 2 7 6 9 - 1 " ............... 76-l0.............. 20 20 4 6 11 7 2 - ............... ?90.......... ..... 6 6 1 i 6 3 1 3 ................. SbD.ntal.........- 46 46(1001 10(2tt l1t44) 1tS(46) 20(42) a(1) 4(8) Total perstntin...................... 179 1791 h10) 26(1S) 121(6z) 61(4S1 41(23) 9(!) 9(5) •YY4MS•aMI.IW.L ow groups. In hematosylin and eosinetainct+ slides of Df O 15.16 hantster lung from all groups aod H(O 87.20 harrwer luns fmm the control 6roupsm the dutaps eonsiued of cumparativeiy few, small, loosdy puked maetopha(tes cwluinie(e dark.becwn n b/ark pt6meot (fig. 14). in lung of smoke•mepmed 110 87.$0 hamsters, the elurllps were larger, mon abun- dantd and eomposed or.•ery large eells eonutnmg Wle 8aid pi6mcnt- Tlwe cells wtre frequently miad with polyrnarpYonuclearleukacytes (hR. l5). Rarc anoke- raposed 81O 87.20 hamsan not havi~g~auch clumped macrophasea in their lungs were usually those found dead of soate iosmeurrent d'sease. Uaclophasea of both .tranq both isolaud c28L and dmse occurring in rJumpu, eharaetensueallv gave A positive prussian-blue reaction kr iron. 71su was imense in the sma)I macropha8s of all 510 15.16 atumals Bad BIO 87.20 controls. 1t was weak in the Ia1Ne m.cmpha8es of uoohe-e:posed 810 87.20 hatn- ctes: ther tells alsn appeared lo contain ydiownh irrn-ne7auve pigment. Occasbnal `tanules of black, irarneEauve pigment cantislent with carbon wcrr found in a few maelopha8es. Brnr4idar nwrapfean was drfined as mnaplaia of 8at al.eolar epithulium inmo columnar epithdium o( the btwtchelar type (6R. 16). The sirsin dtficrence was highly signifinn•: Afetaplasia occurred in near)y hail of all B10 87.20 hannrrn, but in less than 5r~ o( the 310 15.16 strain. In both sswins, the appearancr of bronehiolar metapl.nia was aEte telated but was nm wpnificsntly .lfected by wnoke eapostar. EneJv F... /.nnaim• Pulrnonarr parenehylna in both nralns eontalned sawU foci of ecsopc btane nuw assoeiateb with alamnution or other obvious r•,LSeax oraces I7xse fori otcurred in 18^. of the ease- hek) 1110 IS.1E and 42-r of the D1O 8720 aoimala. lncldence was not tsf(cnad by eaperimcntal prou• dures ia tYe 810 15.16 hatttstcrs. It was reduced by both ta.o(cs and sbaet snwkin` in tne 8710's. A k+r kalgs in both strains ahewed atute or chronir parummte or contained menstasic wmon of sotae snet, uwJy adnrnal earemomw. lymphoma, or )eu- kcmie smiltrax. No difterencn in thee parameten could be aacribed to strain or to smote exposure. naase SK sraw Absoraailities of the air passages were rare in 311 groups. A'rw snall patcErs of squ:npus metapiaua were sees in S-IOrr of HLO 15.16 hamuers, in whxh the innd_roce.ras not apliflcasdv affected by smake ecposule In tae ca6e•bdd 510 87.20 ammak, aquarants netap>tasia wa nm aeea ia the traehea and in only /~~ af the bronchus spacimes ln smoke- e.oosed 310 8720 animN; thesr fsfn/ro incseased to 26 and 21:,, tapectively (68s. 17. 18). No ttewrs of :he air paswes were found in tontsvl amA.h of either strain. tree betuso squanae papillonos in the trachea weee kwtnd in smoke espostd 810 IS 16 hanrten Four benign squamws papsilontis wele fou.d in smoketxposcd B70 87.20 humsns 2 oaurinpt in dle (rarhea and 2 in the main brcethm (ft;s: 19, 20). Naqtrpr. Crrarwctioln werr taken of the wopharYnx and .diarent .ruet.res• of the head in all groups of

i 1150 rdRMrLiD. nO4al/RGLJI. \rto nl'+i/1EID hamstr.s. Approaimatdy half contained only normal tieae. The remainder showed .ariou• path"rc pevrases uscluding 6inEi.itis denta/ carut ocular mAamnution with phthsus bulbi. and thromboses of orbtyl vefns Nooe of these phenomena could be rebted to unoke exposure. Gldy 2 tumors wele found in the navpharyns, both r.currinF in B1O 15.16 animah exposed to sawke 60-75 weelu. One was an adenoid cystic tumor believed io have oriSinated frotn mucous glands (fig. 21) The other was a hbrosarcoma Ihat bad pm- dtced numerous small pnltnonary metasutes (hgs. 2Z. 231. Mean The heart itself was not secunned routineh in thb expcnment. Ho..e.er, it was included with the lungs of 20-25, of the animals. Of the cage•held control BJO 1516 heans, 251;; showed myocardial deEenera- tioe ts compared with 17 , of the 810 87 20 hearts Tha comrted of myolysn with (in the 010 15.16 arnmals only) an abundant infiltration dh•nQhocyta. Smoke exposure appeared to inereasr m>vcatdiaf de- generarron in both ura ns, especially in the BIO 15.16 animals. However, the number of animab exaP,ined was too snull to permit deCnitive conelu- eam (data not statistiwlly signifwant). !•(ural ih-ombi were seen in apprmcimauh• on.• iJth of tne hearts of both atrains. Ineidence waa not aftectd by the experimental procedures. lAn 7he nwft frequent abnormaliry in the 1'wen of thee hat.uers was estit hyperplaia of the bile duca, in rate i/wances.etEins on cholangibcarcinoma. Thit rhange oceurred after el:e 60th week of the esperiment and was more frequeat in the BIO 87.20 (60 ,) than in the 810 15.16 (17 ~-,) animals. Other abrormalirfes noted were not !train related and tsnsiued of sporadic infiltration with amyloid and kukemie material, atiy metamorphosis• local irdlammation. and foeal oeeraas. Ocr primary hematsiosarcoma of the liver was found in a ca%v-hdd 810 15.16 conttd. Notse of thae chanses could be related io smoke exposure. SPUe. Apprvsimately three-quaners of the spkms es- amned in both strains were hitdogieally normaL Leaons in the remainder tncfuded hemanaioooas. ymphorturous or leukermc in6ltratls. and amyloid. Nane of thae eonditia, was related to strait or in sraofte exposwe. K/nnrye Some renal atnyloidasis was tten in 861, of tie B1O 15.16 and 69!'; of the 310 8720 hamners. In nnther urain was it affected by smote inhalat on. 7Ste on(v odtcr renal pathdo;y consisted of rare. minute faci of ealrifsratioo in a few hamuers -if each strain_ A*n.ab Tne mon irequrv chante nbsrnYd in the adreaals ol botk euan. .w profderanon of cipwlar cells. Ti,is wat re;orted peviously in hamuers (d) and in mit:. where n wa A)led' A-B ceU hy'paplasia" (9). 'Ihu pmirfration, not affected by smokr exposure, w-,n xen ir. 41!e of pl0 15.16 and in 2001 of BIO 87D tam-rn. Of he 8IO 15.16 hamaers, li"i had adrenai admome a.d 1;, carcinomas. as compared with 11 ~, wti adr.ornas and See with tatcinomas in th.. B10 B;20 :n.nals. Rarely earcinomas meras- +a%2ed to +r~ iunei The occurrence of adtenal tumors w:s rot « Laxd to sroke exposure. Of the animals in both susaa. f 10r, exhibited adrenal artryioidatis. axu>otora T:.e ntotl srstess usrd by us diBee from that repated bf Oonts..ill et al (1) and Uoaunwill (10) in snrnl imqoetam reprcu ul addition to our use of inbred haraam. Tae composition of the IRI ICen- tuchT sefrrace esarettes was different than that of DontenwiQ's cigar.+es In Dontenwill's ttudy, ham- strrs' bod'e+ were eraosed in a tube and thus severely stretsta: in 3un tber we,r no:. Smhke exposure wn cosortuous a DooaawilPs machine, intermntent in ours. Cotcertratior. of inhaled smoke was abau 6.7 % in tse Gernan rnasel and 20 ; in ouss, and amahe was adtniattxred br different dosa¢e schcduka. Notseurcies. both modd aysterro permit the same tmjQ coataasioos: C2uonie eaposure to eigarette smoke pne:en r•ere hyperplastie and neoplauic ehaqe in me sqe,mouaepsthdium of the hamster larynx and s assoc~sed with decreavd body weight. ln ne+ther rratem cid smoke exposure tncrease pro- liferative chanse auttade the rtspiratory caet or IrlrTr!•e the tlna.aRiplastle rJegeneeal/Ye changes charactennr of aga hamatetc (Our obsen•atioas on possibkr smosc-rd:cd ehanges in the heart are prrr emh eqursaaf; fv:her evestigation is desirable.) Qronfr snroke e:oaaue signi6candy reduced sur- . ival time ;a the Dontenwill model; nn such effea was seen in wrs. This dtHerenee may be attributed to the twidd hiEeer carbon monoxide concentntioo inhaled be ]ontea.iB's hmnuers than by ours. In fact. prt+mus obaer.atiom of Dmtenwill (10) showed a susuined 'ecsease s blood earbosyheoaglobin in his tstadelL whr'raa ouo produced only c•tnsient ioereases. Both ststeem nrodared no ehange in blood triglyeer- ides. I. addition. re sbowed no change in virus profi4e. The polm of zTattu practical importance to croregr 4om our wart is the atrikag diHeretsces among , ariwn linea of hausten with reapeet to susceptibility to acute toae eRece of ntmhe and to hyperplauic reap.tnar of tlse lamatt to atswke (3). Animals of the i nbnd 910 .3. 16 1irr have both the highest raiatance tosuciror=counetoairit) and thegreatest sar}Tgeal susrepibili"ua.iues ueath• increasiryt the srn.- t,.it% of the r.adel. funher studies with latper num- ben of anie.zlt wi8 be aetessary• in attrrtain the si(miiicmre ±f thr laryqe.l tdtaafta in ditferent straint

N h®0055G:11 C1GAtaT1i tYOEE INMALATION Il ,lelalD ilwltlMi No tumoe of the lunE paeenehyma after smoke ripowre were obeerved either by Domem.ill or by ub We :.u not coaflrm the alightly signifxant incrcax in .n~omaloid larom obxrved by Donicnwill. !n both utodel rystemt so-called "tmoke eellr" utexaxd in the alveoli after Smoie eapaure. The obaenralion that yellow imn-nc;ative aod also blaelt parneks occur in the oucrophages wggetts that the partiedate phare of aanoke reached the alreolar wall lo be taken up by the olaevphaga. L'se of tke 2 inbred linn in out experirnene permmed the eanelusion that these cella ale na direcJy related to hyperplauic changea in the respiratory tnct They werr much morr abun• dast in the 810 C).20 harlnten, which h•id the lower iocidmce of hyperplarir lesioro. The tracheal and hronehial papillonut and the ossopharyngeai rumon (one with eleartut mesas- tasn) ohservcd to our mwke-aapoled hacuters reem- bk nanon ioduced by othen..ith niuwamines (1!) ard i.ggoc the presencc of thi+daa of s.brance in the rnolee fmm our nfenence ci;aeettes Thr only nitrawmine to fai ~leterted in eisarette mohe con- dcasates, however, 's dimnnylninvaamine (!?). 1EFEwEMC6 (!7 Oowrarwai W. de.r.u H•J, Hru. H•P. et J: 1.- vaetieelae.e Yr dceo de/uws cia.re~ieneole iw eala.ae r frrian~.iden Mowae.l Ma0 C.ncu tn.e S1:17ti1• 1l32. 1977 (2) Wtoaa fL Horrrrx D. Eeper+oeaal rolaero ur einq- !. Ai.aner is Ctincr Rre.e6/Haoda. A. Wd.6- S, ede ), .d 8. Ne- Yal, Ac.deaic /re. Ine . IVA, pp 7/0.751 (3) gavnu P, Muweeao F Hilh nlco~inr tokrance ot Srr.r pJbn hr.wa.. To.itol Appi Phum.ea/ 72:'3[. 1972 (4) Horr.r D W..~e EL: Chanie. deWqwun. and anm/d.pneon.l. lnhalaaoa Cernnaaeaerie / Menne Ri0 Ir. Ne.We"e P, Gil6en JR. ade.l. AEC Symp Sa+a "Ia !i 1971 pp 173-1a9 (5) Atoe.a WO: Ihad,a:ti.n of cunpk qoetd far aber[e aae aealYr reaeaah. ToLaeco aoC Me.14 Cad Rex Me. t, 1970, p 98 (A) Ceeeme ar. L.vnaa PJ A eeritive mnhad br ehe sa~ua d jl...A.ewwebb:~ :~ a Rn~a prict re~ledblaA lr tod>•1edM:139-143. 961 U) Ltesae C. Leoeee. H: Fho'wnaric mea~uaeeni .f tnpaeda /e Awowuebm ie Anatrar+l CAe Teeerca Swnpra t96S (Sketp LT, rd ~ Ne~r Yo11 Ftei.4 IsL. p xl-3.! (F) Ho.uoae F. R..usan ASt: An Inhrd Ibe af Syriaa lu~ees +.i 6qre9 cp~ adeaa/ ewa., C.nea ne. D:DY7015, 1970 (r) w.maa. GW. Tusae e( eae adRnal eenee !c Gba Fusaer.e i,iWreerisolyy. 12. Harnose Pmdl• tie+ u iwew Trrurs 'Wdwewhe GE. O'Cwaor AL eerl Dsul, L1nk !ww t Go.. 1968, pp 122-176 (PJ) Doeren.aa W: htoeiam.W ioealtlgaeauoe Jeefact r( a4reue rrie inbdao.a en .r.all la6erarrf r~r. 1. feM/aton Cueioa~eaew /H.nnh hIG Jr. VauoMrn P. C76vn JR, eds.4 AEC Syre SairP Vo. /a, 1971p? 3f9-i11 (II) Heasaea K!d: l.d.a.oe of oUseeeef eeveeKadial a.e, e Srnae Wmeme by dte0wiaae.mne. Caec ee 17. i 1 F121. 1964 t l)f HeCa nea A!4aauox MJ. Dw.u. MAl et J: Nies ~ .~rem emake sao0ot.au. Newee ITkw 1]q 1973

.4 .- • .- ~•~es. ..` ~ . s... ~ .. ,. . ' ,?,,, eri •._ti'° It. dp ~ • v -~ ~ ~ ~~ ~ T~ '%A W dt' pro ~a~ ~~ +1A~N'~ ~cTa a ~~ N , . ~ ;•~ '' N d~.CE s r =c- . I1-Y, v iN, . 1 I ..-- •.7 i` ~y~ y~1., T.,w cow• - - - _ ~ • .~~~ . .^ ' ' eu" . Fwtne 1.-Lanu nf mak 610 15 1, lumrrr r.paPo le citartlle swete for 71 +eek. Epilheln•m .hsv. itimccianW ItuY-.am, N.r pevwiu~l. nlniv la.v e/ Wul crlb Hnna-r and ee.. (H a E1 X 400 Fwe•.e 2-Hypr*p/atia in lanu of mde 810 6710 hatn+v nvsN t..watr (. tD tcb Xw i.mrtaelT lhctmed epidernd.w wraWlr .NpK+I .unei. •nd u.Wl b<w! /arc. H d1 6 X BOJ Fqwe 7-Faai hrvnpWf.le larrnd a1 male )10 Il.Ib bawne apmd r amie /er 73 .ee1..Yw nurtedle ayp.ol oucki md ~eucl be..l /anr. H 4 E. X 60. Fou.a d-Euiv barl eell h.qn.rv.rr M lanma ef m.k !Ul 1.116 hrn npsN lormete /o. I60 web Nd.lhiet ealtehu/n .nW nuew eone d npvbrn~ tvaur.al~.+. De.nEr..J d b...l M...~b ~.i~.~. ru.w. anJ wnrc nuckar ai7p.: ha.e.v, .anH arkmanon a reu% lurle etll inamuuea H k L X40l Fev.e S.-Eaeh• buW cell hyneneln.q• so lu,wx a/ male 810 117:01,arrr opavl 1e.nmdr br 66 wert. B..J Laycu ao.c,ew,lul stqulv buaW/ lnuaLNwatypnr nuck, uqabnmuW terawvarweda.peellalnpll. H i! X MI Feua. 6.-Alarbrd ba•.1 reli h.onx~.:n m lar.n. d..Jr 610 1S.K b.w.v. ..pe.d r.uri. fur 1: .nb Ce.e.- t,q- tentuu and uanlbsn wiih nurka, arvpia. parueuJulr t. lte baul wlma..t•r nprlr pAxu~.en d taul ce1L.a deep all nele H k E. X 250 1152 6ElucrcLO. Hollw.au, wwo avcccICLo

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0000 / FoR Tos cco R x- L S A IVc L C T ^ ~ L w E6EAR .. •. • • H C1 f F. OLI : REPCIFC SCZENI03;'ZC AWLSQ'Zl' BOAM Af..'°T= M3+1 YCRK, NEW YM 1980 Attaxiance Dr. Sbeldon C. Sarrers, Qzaitzcan Dr. Rid=d J. Bing Dr. Joseph D. Feldxaan Dr. Fcbe_^t J. Htae-hne= Dr. Iam O. Jaoabsw Dr. Haas Meier Dr. Herity T. Lynch Dr. Gaztlan H. Sato Dr. Prestr,n H. 7- ke Mr. Dr. Jack Frankel (10/8/80) Dr. Stuart Wolf (10/9/80) Dr. David Stcne Mr. Addi•sC ci Yearan i-L-. W. T. Hoyt Mr. RGtert F. Gertertbac17 Dr. Fbbert. C. Horkett Dr. DonaLd H. Ford Dr. Vis:ce*it F. Lisazti Lexar3 S. Zahn Chaisrsan, Z.T.C. t2niv+ersity of Sa=th Flarida Taiple Univ+ezsity President, CTR DcecZtLive Vioe Presi3erzt, CTR Viae Presideat, CTR Fesearch Directar, C'IM Associate Ftaseexrh Directar, CiR Associ.ate Fpsearch Director, CTFt Associate Rr3eardh Disecta2, C3'R Iawa.rd Za?m and Associates, Inc. 1. T:* report of the meecti.-cs cf the Scianti=ic Advisoxy Bonrd, held ai Apsil 9-10-11, 1980, wras appr~ve3. 2. " l:e report of the Exwu'•.ive Ca:r.,It :ee nmeetisr3, held on Jtia:e 20, 1980, was appsoved. 3. T.-* followisg ad~ninistrative a_ticrs were app=^wed: 1160RR Leslie Baer, M.D. An cr:expended balanae of $56.40 s.Es rec:eiverd a-~c,' dexsiter. 1:71R1 Ba:bara J. van de. Berc, M.D. An unexpended ttilaa=e of $22.00 was reaeived arri ceposited. ,~c M~~~-~g~ 00~a~:'€ 11066346

r , 2 764-F 6 764=F5 tharles G. Cochzane, M.D. An tawgmmded balarxe of $461.17 was received and tleposited. 1066 F, David W. Crutpac3cer, Ph.D. An urmqpended balance of $6,080.66 was reoeiv®d and dePosited. 1088R2 I+lxchael C. Gaoisas, M.D., Ph.D. was received a,nd deposited. An wmcpwxW ba3~¢~oe of $65.22 1253 Fiira L. Gtitrtco, D.V.M., Ph.D. was received and deposited. An taexpwrled balanoe of $213.86 1164 t Caroline B. Hall, M.D. An tamoqxrded ba]•anae of $1,199.48 was 116 4 A1 zemived and deposited. 1143R: Aaran Janoff, Ph.D. An iamc_.ended balance of $118.27 was received V - asyd dePosits3. 1095-Astl D3ward L. K3a«T, M.D. An tiamQerdei balance of $2,940.32 was received ar,d deposite3. 1190 Jerare Kleinesman, M.D. An UrAmqended balarsoe of $1,180.90 was received and depositsd. 1267 Bevrsly Paic_en, Ph.D. An une)qmided baiance-of $1,446.73 was received and deposited. 1080R? Kenneth Paiven, Ph.D. An tt*iexpanded bataaoe o_ $143.17 was received arld de~osite3. 949 AR2 B. V. Fama Sastry, D.Sc., P*: n, was received a,nd deposited. An tamcpended balanoe of $86.25 1058. Ja.knb Scrrr.idt, M.D., Ph.D. received and de=osit.ed. An uwycpended balance of $668.50 was 1165 Nathan H. Sloane, Ph.D. An tanexpende3 balance c: $57.80 was received and deposi•..ed. 1031R2 Lee W. Wnttrr,be.rg, Ph.D. An tmmqxrided balance of $257.02 was received and deposited. 1163*f-A Rcna].d W. Gillette, Ph.D. Authorization was given to oetend this grant fran July 1 to AcCIUSt 31, 1980, and to uti]ize the urAmpanr.'ed funds of apprcxima•..ely $2,650.00. 1130-B Margit Iiasosh, Ph.D. Authnrization was givas to ext+es3 this grant fran Octeber 1, 1980 to 5egtesber 30, 1981 with nc additicrsa]l fLr*e-s. 945-3 Harry L. Ioachim, M.D. Autharization was giv+an ta extend this grant fran July I to Dem-~:er 31, 1980, and to utilize the =%sxnt balance of $9,326.00. ~~R €~ ~ N -a~AW. 0 0 0 5 11066347

3 1242 l=-t= c-a1ds+r*+, M.D. Authorization was givesi to transfer $4,666.00 fram. Persamel to £q,iigment f or the purchase of (1) a pH stat m-_ar, and (2) a Becl¢ran Centri.f,re. This amosnt will be aztbtraat,ed f-=. grant 2242R1's tsudget. 1174R1 Reresa Gesaner, Ph.D. Authorization was given to traasfer $257.00 fran a pmjected ia02qMWsi+ed h+uar~ce of $800.00 frM Persa=l to 4rave1, and the balarce to S'upplies. ~ 1226 ARL Lirnla M. Hall, Ph.D. Authorization vas given to transfer $1,250.00- fztitn S1polies to Peanermt EqtYipmeit for use toward the purchase of a saisztillati.ai oountrs. 1808R2 1Cermeth Paigen, Ph.D. Authorization was given to utilize the m q mi 4ed balance of $2,025.63 by trmsferring $411.84 for misoellarA=s itans arrl $1,613.79 for Persamel. 1201R1 Iarsis A. Soloff, M.D. Authorization was given to transfer $800.00 with.in the budget for Travel. 1135R2 James Travis, Ph.D. Authorization was given to transfer $3,500.00 fra:~ Persarml to Eq*Ta++e+i (52,500.00) ard Supplies ($1,000.00). 1263 David L. B1 ee, Ph.D. Autharizaticn was givers to carry foQward apprcxisnately $7,000.00 in irccpxnded itncis to grant 1263R1. 1244 Pcbert Echt, Ph.D. Authorization was given to carry fn=ward to grant 1244 A$2,000.00 with the stipulation that the reme.issis,g taiexperded ta2anae of $4,602.41 he rets3m3 for deposit. 1174R? Teresa Gessner. Ph.D. Authorization was given to carry faxwexd to to grant 1174R2 an uaseqmrled balanee of $1,721.18. 2235 Wayne P. fbss, Ph.D. Authorization was eiven to carry fcsn.ard $516.22 in La~e~c_.~.ded funds to grant 1235R1. 1267 Severly Paigen, Ph.D. Authorazatim was given to carry forward to grant 1267R1 $6,218.00 with the stipulatian that the rana.ir.,ing ta~oc; ~, r3ed balance be ret=yad for deposit (see page 2) . 1127 A Herbert Y. Fdeymlds, IM.D. Authorization was given to carty foxward $4,275.00 in trwcpended fux3s to grant 1127-M. Contract 30S. MiQobiological Associ.ares. Rn taiomtnitted L•+alarroe of $71,000.00 renalTl 7 cn the boeYcs is earxxlled. 1216 e Jack W. Frankel, Ph.D. A~ Momxnded balance of $2,757.68 was ret=ned 1216S by the CLZiversity of Sa.-th Florida, dePnsitad, and a dhecc was drawn to the Veterans Ad-:.^istration for that a;r=t for use by Dr. Ftarskel. ~', ~ ;~ j~~-~R~ C~005: ~ 11066348

4 t 1259 S h,aran Jancff, Ph.D. An extezsian of six manths was granted to 1259S Decenber 31, 1980, and a aupQlement,al grant of $2,000.00 was roved far the assistance of the studies of Dr. Philippe iaurent. 1011-AR2 & Jay A. Levy, M.D. A ttsee-arnth ectaLsian to Septanbez 30, 1980 1011-B was autlYrixed for a fina.l aaa;untirq of grant 1011-M. - As for grant 2011-8, shich was aut2raf.zed in the a+ount of $50,00o.oo for a twel.ve-nmth paricd begitrAM July 1. 1980, authorizaticn was given to ahcrtm the t3u= peri,od to six mwrths t3zroagh Deoa1 bes 31, 1980. 941-AR2 Haixy T. hyrjch, M.D. An tarAocPended balat~ce of $8,877.11 vas carried vwer to grant 1297M, and the budget for the riew grant was therefore redtr_red fran $93,426.00 to $84,548.89. 1169A1S Gerald '..hk.Iar, D.D.S. A 4-rnrith pro rata extensicr.*was oved sn the amAalt of $16,000.00 for the period Septarber 1 th.rough DecBrber 31, 1980. 1287 B--sce A. wcda, M.D. A crroval was givsn•for the transfer of this grant to the City of Hope Atati=a). Mec:ica.I Caitrr ahd to in0rea,se the award fran $61,465.00 to $64,305.00 4. ZY,e folloyriryc rezewal applicati,ons for grants saere rated -for app=vval subject to the detezrini.•saticsz by the Scieatific Director as to griarity and the ssr=t to be ftr-ded: 1162 RRl Frnncis C. Chao, M.D., Ph.D. $47,248.00 Teaminal. 1203"= Aaror~ E. Freentian, Ph.D. $85,593.00 Te=irsal. 1221tt2 , {je11 P1ace, M.D. $67,356.00 Teami.r:al. 1088-ARI. Michael C. Geokas, M.D., Ph.D. $87,400.00 1081 AR2 I3oassan W. Heir.s-..ra, Ph.D. $46,057.00 41ezr.zizsal. 1.24LZ2 Carol J. Henxy, Ph.D. $45,400.00 Te*z+i*y+l. 1143-ARI Aaran Janoff, Ph.D. $21,193.00 1217R2 David A. JohrLscn, Ph.D. $36,791.00 Zemiml. 1234 AR1 Abel Iajtha, Ph.D. $32,430.00 1187MR2 Paul D. Lewis, M.D. $24,418.00 Teattir3al. 1290rZ'~. Hans Meier, D.V.M. $51,472.00 1230R2 Donald I3elstnz, Ph.D. $18,975.00 fiezmirusl. 1245R1 Eileen Rsnold-O'Dwzne11, Ph.D. $33,991.00 CTR MIN-SAE 0005;'9 11066349

5 r 116.*'".r~2 Gerald Shy.lar, D.D.S. $70,504.00 T'esiainal. 1030-AR2 Fl-.i1 R. thsari:ie, M.D. $64,579.00 T'e~ d.~. 5. At the reqoest of the Bnard, Dr. Jadc Fran}cel gave a rep=t of his ptogress tmder ramwa2 graat 1216R1. Priar to the close of the meeting, Ltr. Frankel Provided an es,:imste of the cost to aarplete the Fseatsit phaee of his wnrk thrau5h June 30, 1981. He indicated that the cost wvuld rioC aocae3 $54,000.00, and the 8oaxd aPPrvaed an ''tsae mt to es~ci that ammt througts Jiam 30, 1981. 6. The follawirg sA+ and oantirsuatian aPQlications were rated for apgrvval svEjeR to the determi,aatian of the Scientific Direetar as to griarity and the ww=t to be furxded: 1349 Bernard M. Babior, M.D., Ph.D. $30,429.00 1160-A Leslie Baer, M.D. $89,600.00 1171-A Barbara J. van den Berg, M.D. $76,935.00 1340 Jtaze L. Biadler, Ph.D. $54,625.00 1339 Rebecca Btyson, Ph.D. $76,175.00 1352 Wflliat: A. Carter, M.D. $97,750.00 1208-B Carltan K. Erickscn, Ph.D. $37,784.00 1337 iA..=ray B. Cardrier, M.D. $77,689.00 1354 Gabriel C. Godman, M.D. $76,900.00 1164-A Caroline B. Hall, M.D. $69,628.00 1346 Robert M. IiofhTw, Ph.D. $64,192.00 1235-A Ftayrye Hoss, Ph.D. $63,667.00 1343 Rebrst W. Kreil.ick, Ph.D. $46 - 560. 00 1344 Dm Lspwias, M.D. $51,411.00 1215 A E. Clinton Iawrence, M.D. $53,000.00 1357 Fabian J. Licmetti, Ph.D. $48,530.00 Z55 A J. Wister Meigs, X.D. $32,843.00 1351 J. A. Mitchell, Ph.D. $50,387.00 1350 Dem-Lis J. 0'CaLaghan, Ph.D. $42,238.00 CTR HIN-SHI-Or"t 0005-J60 11066350

- 6 - 0 1097-C Fra= Oesch, Ph.D. $64,285.00 1322.*2 John E. Repine, M.D. $89,461.00 814-C Lna S. P.yan, Ph.D. $65,568.00 1359 Dwriis M. Saith, Ph.D. $50,204.00 1325t: S3z3ara A. thxda:-wocr3, Ph.D. $63,347.00 1338 Arit=ia Ver*+adakis, Ph.D. $91,610.00 1341 Stanfor3 Wnssler, M.D. $58,452.00 7. The fcLowirg new ard aantsszuaticsz applicaticxzs were disaporoyed: 1342 Drna1d R. Rdans, Ph.D. $34,740.00 1347 Lyle J. Arnold Jr., Ph.D. $122,438.00 1336 ,7ack L7salczi, M.D. $32,781.00 1355 Nonrbibi K. Day, Ph.D. $66,026.00 1356 H. F*red Downey, Ph.D. $37,480.00 1345 £acene F. Geppert, M.D. $62,417.00 1360 h,ichael D. Goldz-zn, M.D. $100,746.00 1225-A Je=Yr.e L. Hojnacki, Ph.D. $41,584.00 1333 Allan E. Klein, Ph.:). $43,528.00 10:1-C Jay A. Leay, M.D. $45,831.00 1346 Sandra Pane-, Ph.D. $57,787.00 1334 GiusepPe G. Pietrra, M.D. $46,895.00 1161-A Arritew M. ZVmets}co, Ph.D. $45,625.00 8. =he folla,titi7 new anc cnnti.z,iatiai aPplica.tiaLs were defetzIi: 1358 Patil Fianosh, M.D. $54,910.00 1353 H,PSUy Aothschild, M.D., Ph.D. $119,307.00 1335 Lynn M. Taussig, M.D. $10,925.00 CT! MT 4'''~,-~r~.~ 000t ~ 11066351

7 0 9. 10. 27,e a-jaizican armaaiced that the first cticioe of dates for the next seniarmual meetinc of the Scientifie Advisaxy Boaxd was Jpril 8-10, 1981. -Sz: the evmt these dates grove Lasaocec.rtable, the nect chcice would be Agril 22-24, 1981. 11. At the resjest of the Soard, Dr. Stuart Wo2f prvsriried a repart on sare of - work in the cazdiotirascalar field. 12. SLtseque.Zt to the :setirg, of the xerewa1 apQlioat.ions reoa;r:m ,ded for aPgroval ard refe_zed to in paragraph 4, the Sciernific Director dtteanirr,e3 that the fol1aring st»uld be f-.axled in the re.~~ecr :ve a==ts indicated: 1162-ARl F`rasics.s C. Qhao, M.D., Ph.D. $47,248.00 'v=d*+al. 1203.'--nt2 paron E. Preemaz, Ph.D. $75,000.00 R1m=%irsa.t. 1223R2 Kjell Fvxe, M.D. $67,356.00 Z'e_'rai.aa2. 2088-AR1 Mir.hael C. Geokas, M.D., Ph.D. $87,400.00 1081-AR2 t3oanar: W. Heir.zst.-a, Ph.D. $46,057.00 TetzZi-sal. 124L'U Ca_•vl J. Henry, Ph.D. $45,400.00 Z1a=++i*+al. 1143-AR1 Aaroa Jarroff,. Ph.D. $24,193.00 1217R2 Qivir3 A. Jotusson, Ph.D. $36,791.00 Tssminal. 1234 ARI Abel Iajtha, Ph.D. $3 2,430:00 1187MR2 Paul D. Is,*is, M.D. $ 24,418.00 Te_.ni*al. 1290R1 F3atLs l4eier, D.V.M. $5 1,472.00 1230R2 rk=Ald Nelsor,, Ph.D. $18,975.00 Za=Lirsa2. 1245R1 Eileen Aarn13-0'mnnel l, Ph.D. $33,991.00 1169M2 Ge.rald Shk1a_-, D.D.S. $50,378.00 ZexmLsal. 1C3G-1,n2 Lmi1 R. t]-ianue, Y.D. $60,000.00 't`P*mi*+al. Dr. Lisaati reviewed the detail.s of tezmLnating the agzawgmt with Microbiologic,z:: Associ.ates, after which the following oa::racts were rated for approra1: 30-C Microbiological Aaszciates. $861,300.00 throogh terr:irjatian an De~s 31, 1981. In additicn, tesminat,iai aoets not to exceed $69, 700.00 were a.2so appsov+ari. 15-G Cnk Ridge 2datiasal Iaboratozy. $78,600.00 Ltaough t=mitsaticn on Jta1e 30, 2981. 27S Prooess & Irsstrumts C2mzporatian. $20, 000 . 00 throu;h ts+*am mAt,ion ' on JjrA 30, 1981. ~T; ~ T1 ~-73 ~~ `? 11066352

f 13. sutsec_uent to the meetisig, the re3uest for a supplsnent reoanwded for aPPrvval and referred to in paragraph 5, The Sciernific Directcr dete=n,i,-:ed that the fol2arisr3 strould be f-=Arad ir. the anaunt irx-licated: 1216R?5 Jac3c Frankel, Ph.D. $53,750.00 14. Sahsequent to the aeetti.ng, of the new ar:d c=*=tati.aa a=licatiorLS referred to in Iara9raph 6, the Scies:ti.fic DiTec.'tOr dat•*+*; *Ad that the folloaring atrou2ri snt be ft4:ded: 1340 June L. Biedler, M.D. $54,625.00 1354 GaDr:,el C. C=tmn, M.D. $76,900.00 1343 Anb= t W. Rxti.lic3c, Ph.D. $46,560.00 -1350 Dersn.is J. D'Ca11a#ian, Ph.D. $42,238.00 1325:? BatDara A. L34erwrod, Ph.D. $63,347.00 1338 At:tania Vezradatiis, Ph.D. $91,610.00 1341 Stanfor.3 Wessler, M.D. $58,452.00 15. Subsasmt to the mee--irg, the Scierstific Directoz detexmis,ed that the foila.ing shauld be deferred iasti1 the Scientific Advisory Board meeti-ic in April 1981: 1337 t4-a:• B. G3rdrser, M.D. $77,689.00 . 16. Subse:-ue_*st to the mee~i-:a, of the rsea and continuation applications recu=.wided for aW=.rdl ar:d refe_-re~ to in paragraph 6, the Seientific Directar dete=iec: that the foll.orzng should be ft-nded in thee respec-tive am=ts indi-ca*_ed: 1349 B+sr,ard M. Babior, M.D., Ph.D. $30,429.00 1160-A Leslie Baer, M.D. $89,600.00 1171 A 8arbara J. van de:: Besg, M.D. $76,935.00 1339 Pabeoca szyr,on, Ph.D. $76,175.00 1352 Wi11imr. A. Lax'te.z, M.D. $97,750.00 1208-B CarltCn R. Eric3cs,cm, Ph.D. $37,784.00 1164 A Caznli.r* B. F3a11, M.D. $69,628.00 1348 Pcbp-,,+: M. Hofftran, Ph.D. $64,192.00 1235-A Way;* fioss, Ph.D. $63,667.00 ~~~ ~ ~ ~`~-~RB 000~S~ 11066353

4• t 9 1344 Dan Sapen3s, M.D. $42,253.00 1215-A E. Clintan 2a+irem=, M.D. $53,144.00 1357 Fabian J. Lionetti, Ph.D. $48,530.00 1255-A J. Wist+ci Meigs, M.D. $32,843.00 1351 J. A. MitdveL1, Ph.D. $50,387.00 1097-C Franz pesch, Ph.D. $64,285.00 1322m Jchn E. Aepine, M.D. $62,500.00 814-C Una S. Ryan, Ph.D. $65,568.00 1359 Desnis M. Ph.D. $40,000.00 17. Subss+cJUer:t to the reetirrg, of the nsa and aontiauing applicati,aZS that were deferred and referred to in peragra.Ph 8, the Scientific Dirnctar detexsj--ed that the followiss7 shoul3 be ftianded in the respectiva aiotatts irYiicated: 1358 Paul Pia=sh, M.D. $48,000.00 1335 Lyna M. Taussig, M.D. $5,500.00 18. Suhsecrjent to the meetisr, of the ndr and oositiauir,r3 a~^+.Qlicatims that were deferr•a and refe_-red to in paraaraph 8, the Scientific Directrr detesM.L-ed that the followiirg should not be f•.a7ded: 1353 Henry Rothsc3iild, l:.D., Ph.D. $119,307.'00 19. Sxbsequent to the meet' ng, c: the carttsact proposals refe_-rsi to in paragraph 9, the Scienr_:fic Director detea-ina3 that the followinq acntracrs shovld be f=mded irl t'3e re.~rpectiv+e acmirts indicated: ~-. 30-C Micrcbiological Associates. $861,300 th=agh *am+*+ati,vn on Deoe , er 31, *19 81. In addition, taanu:aticn oosts not to eaaceed 15-G $69,700.00 were also aPgrvv+ed. Oak Ridge Natio:•al Liboratnsy. $78,600.00 t=mjgh trsmissation on June 30, 1981. 27S Prooess & 7s:strutents Oorporation. $20,000.00 tYtrvugh tranirsatioa on Jtm 30, 1981. .T c NYIN-JAPU 000584 11066354

-,r»y.~•

TFiE COUNCIL FOR TOBACCO RESEARCIi-U.S.A., Itir. October 31, 1983 ME9fJRAMiYr1 ZD FIIs S William D. Hobbs, Max Crohn (Jacob & Medizger) ,'Iince Lisanti, Ttm Hoyt met with Dr. Jacl: Parker, President, Microbic:.:r-:cal Associates on October 31, 1983. Hobbs coened the discussion by e-r.pla-^.ing that CTR had put saae 12 million dollars into the contracts with MA e-r.~osir.q thousands of mice to cigarette smdce over.the span of their lives. :-.is aontract was concluded over a year and a half ago but to date we have aot had a final report or a published manuscr_pt. Now menbers of CTa's Sci_-;.if:c Advisory Board who approved this eapenc:i =:re are asking 'ahy" ar.d %iien °. Crohn reviewed the teums of the cnn=-acts and pertinent eozrespondence establishing that CTR was enti:l_:.' to a final report on findings as well as a manuscript for publicaticn ineozporating the negative results indicated in the poster MA presented at mze 13th International Cancer Congress. Parker said he had reviewed the __'-es re the contract and did not wish to get :.-lto an interpretation of the of the contract teaas. He said that a manuscz"-pt was half completed on rethodol.ogy of the work and that any final repor_ would require the =nple-- n of that manuscript and preparr- tion cf another one dealir.g with the pat-holocfir.^ings. He stated that the principal problen is that Drs. Kouri and -Henr.• a_-a actively engaged in other work which makes the availability of their t:..-ie =..:_Ffi;..11t. He agreed that the results of the ~,;ork tur~er the contract should be .:oc,-ented and prani.se3 to contact us within the .^.ext week to 10 days regard_'ng a time schedule as to ctien papers could be canple*_ed with an estimate of the cost. W.T.H. ~JJ ~_

ti

/ /'MICROBIOLOGiCAL ~ ASSOCIATES Mr. Tom Hoyt The Council for Tobacco Research - U.S.A., Inc. 110 East 59th Street New York, New York 10022 Dear Mr. Hoyt: Weroo.oiopKai Assocutes A Unit of •Nnntaaer eoroorauon 5221 Nwer RoaO 9etnesoa, maryuna 20816 !7011 654•St00 TeNa No 90-6793 November 16, 1983 Thank you for your letter of November 10 with its comments on MA's proposal and schedule for meeting our mutual objectives as we discussed on October 31. :n order to provide the information to Mr. Hobbs in a timely fashion, we will make a best effort to submit the following by December ;: a) Technical recorendations for publication of the Chronic S:ucy; b) Financial recc-r..endations, including estimated costs for pathclocy ano statistical evaluation; and c) Estimatec date for submission of drafts of manuscripts describir.c :^e C^ronic Study. As you know, we have teen and continue to be interested in publication of the work '•'icrooieiogical Associates performed for The Council; however, puolica_icn dates can never be targeted accurately because the in-depth ana:vsis required often raises questions which may require indefinite peric:--s `:.,r -esolution. The Chronic Study is a state-of-the-art stucy .:^e ::s _,ublication will provide a benchmark for future years; there`:)re, 1 am certain you will agree that toaether we must represent CTR ano "A with a high quality scientific publication that will be held in niah reeard by our scientific peers. If consultations t,ith oatheiooists and statisticians are reouired, the persons selected -ust be mutually acceptable to MA and CTR.

1 Tom Hoyt November 16, 1923 Page 2 Although the nistooatholoqy observed in the Chronic Study was not specifically rentioneo in the working outline provided with my letter of November "-, we Dlan to include a description and analysis of these data in the final reoort. The above should clarify the questions raised in your letter, and we look forward to-proceeding with the project as outlined. Sincerely,~, c~> a-~y John C. Parker, Ph.D. President

rn ~ N

"FQ2cUU03 Microbiological Associates 5221 RIVER ROAD • 3ETHESDA, MARYLAND 20016 TELE?~-CNE: !3011 55a•3Q00 au yus : :2, :?2: Dr. William U. Gardner The Council for 'aoacco Research-U.S.A., :nc. 110 East :9th Street New York, ?lY 1CC22 Dear Bi11, Some time aco v'.nc=_ reaues:ec a list o' :ur .•:3lic3:':)ns wnic!1 have been suooor:=c in part oy contrac:s -..,, C-?. Enclosed is a list of '1 sucn :uolications. : be `eve i: is complete, but please :o not hesi:ate to call 4f :-e.*e is a question. 51nce'o;y !ours, Caro'. :. yenrv, ~~._. Direc: r, Cecar:mer= - Excer'-enta: 'jH/ph _nclOsure , , ..c. Mr. '. Hoyt Dr. :'. Lisan:* ~ c, Vls lC v 0.~f~izittaker ~

Sf~~LCruG`F u PUBLICATI:NS FROM MICROBIOLOGICAL ASSCC.I 'E; SUPPORTED BY CTR AS CF AUG;:ST 12, 1981 1) Whitmi:e, C.E., Salerno, R.A., Rabs-.5., Huebner, ~.,;. and Turner, H.C. RNA Tumor-Virss An_~-_e^: Expression in Chemica-ly Induced Tumors. 'Ji:ss-•Se^cme-Speci:ied Common Antigens Detected by Complement Fixa::on in Mouse Tumors Induced by 3-Methylcholanthrene. J. aat:. Cancer Inst. 47: 1255, 1971. 2) whitmi:e, C.E. and Hueoner, , n..:. _....._. _ion oi Chemica: Ca:- _.nogenes_s by Viral Vacc_nes. Sc:e:::e :_ 60, 1972. 3) whit:ni:e, C.C. and Salerno, R.a. =yA ...mcr Virus Antigen and Tumor Induction by Various :oses o: 2-metZylcholant:zrene iz Various Strains of Mice '":ea:ed as '.++e=nlincs. Cancer Res. 1:Z9, 1972. 4) iCouri, R.E., Ratr:e, H. and ,.._. Evidence :or Genetio Relationsnin yetween Suscecti..____. to 3-Met7y:- ..nolan:Zrene :nduced Suocutaneeus .,.m„:s and o: arv: Hydrocarbon Hydroxylase. ,;. Vat'_. Cancer :zst. 19", 1973. 5) *Kouri, <.C., Salerno, R.A. and Wh i=..,_:e, C.... Relaticnshirs Between Aryl Hydrocarbon aydroxylase :,dLCibility and Sens:- t'_vit: :-- Chemicallv-Induced S~.;Dc;:taneous Sarcomas in Vari- ..;:s S-.:a'_ns o: vat1. :.ancer :zst., 50: 363, ;?7=.

r~ (~ 5 PUBLICATIONS FROM MICROBIOLOG:CA;. ASSOCIATES SUPPORTED BYJCTA ?60 Rhim, J.S. and Huebner, R..:. :n 'titzo Transformation Assay of Major Fractions of C:caret:e SmoKe Condensate (C33C) in Mammalian Cell Lines. Proc. Soc. Ex2 t:. Biol. d Med. :4I: 1003, 1973. 7 Salerno, R.A., Ramm-, G.K. and Whitmire, C.E. Chemical :nduc- tion of Subcutaneous Tumo:s in 3aL8/c and Swiss Mice In:ect- ed with Wild Type CRNA '.'!.uses :)ervied from BALB/c .issc;es. Cancer Res. 33: 69, :97-1. o) Whitmire, C.E. Virus-C,hem:=a: Carc:noaenesis: A Possiz:e viral Immunologic I::=luence on ?-Methylc:nolantzrene Sarco-:a Induction. :. Natl. Cance: _-st. 473, 1973. 9) Whitmire, C.E. and Sa:e.., ,:..,;. :n:luence of rre:..:ect.on of C57HL/6 Mice wit^ :,euKemia Virus on ant:::ene-induced Suocutaneous ~a:coma. Proc. Am. Soc. Experimental Biol. s Ne:. _, 5%4-079, .973. .J) Demoise, C.F., Kouri, S.E. and Whit:nire, C.E. Cei-Mediated Immunity After :ntra::acnea: zxposure to 3-Metnylcnola,^.- threne and its Relationsn:= to Tumor Transplant Growt:i in C3H/f Mai Mice. In: -r. Ka:ce and ,,.F. Park (eds.), Exper.- mental Lung Cancer, -...-=er-Ve::ac, New York, pp. 72-60, 1974.

PUBLICATIONS FROM MICROBIOLOGICAL ASSOC:A:ES SUPPORTED BY CTR ,, u ~26000 ~ Kouri, R.E., Demoise, C.F. and Whitmire, C.E. The Signifi- cance of the Aryl Hydrocarbon Hydroxf:ase 7nzyme Systems in the Selection of Model Systems for Respiratory Carcinogene- sis. In: E. Karbe and J.F. Park (eds.), Experimental Lung Cancer, Springer-Verlag, New York, r;.. 48-61, 1974. 12) Kouri, R.E., Ratiie, H. and Whitmire, C.=. Genetic Control of Susceptibi:ity to Cancers :nduced :.y :-Methyicholan- threne. Proc. XI Int. Cancer Congress, _. 77, 1974. 13) Kouri, R.E., Ratrie, H. and Whitmi:e, C.=. Genetic Control of Susceptibi:ity to 3-Methylcholantarene-Induced Subcutane- ous Sarcomas. :nt. J. Cancer, :3: ":4, :974. 14) 'rihit:ni:e, C.=., Demoise, C.F. and Kou:i, R.E. The Role of the Host in tne Development o: :n yivo :~odels for Car- cinogenesis S:scies. :n: _.Karoe and J.:. Park (eds.), Experinenta: :.ung Cancer, Sprinae:-veriac, New :orK, p.. :3- 47, 1974. :5? Kouri, R.E., '++h:t-:ire, C.E. and 3enedic:, W.F. :n Vivo and In yi:ro Ef°ec:s of Cigarette S::oke Condensate Frac- tions. ?roc. Am. Assoc. Cancer Res., 16: 173, 1975. 16) Kouri, R.E., Rude, T.H., ':homas, ?.~. and Whitmire, C.Z. Studies on Puimonary Ary: Hydrocar_-on Wvdroxylase Ac:ivitv 3

PUBL:CATIONS FROM MICROBIOLOCICAL ASSOCIATES SUPPORTED BY CTR in Inbred Strains of Mice. Chem. Biol. Interactions, :3: 317, 1976. 17) Levy, R.L., Barrington, M.H., Lerner, R.A., Griffin, G.F. and Whitmire, C.E. Immunosuppressive Effects of 3-Metzyl- cnolanthrene Given Intratracaeally in Various Strains of Mice. Cancer Res. 37: 3392, :977. :3) Nayar, K.T., Kouri, R.E. and ;.evy, ,;.A. Xenotropic Expression and Susce2tibi::ty to Chemicaliy Induced Cance:. Proc. Am. Soc. Microbio:. p. 272, 1978. 9) whitmire, C.E. and :,opez, A. ;,~mparison of the r-::eca _: 5eesr+ax:Trioctanoin and :':ioc:anion Vehicies on 3-Me:-y:- cnolant:::ene, 8enzo(a)ry:e::e, and 7,12-Oimet::ylcent,a,a::=na- cene Subcutaneous Carcinogenesis in Three Strains of M:=e and One Hybrid. :. Nat_. Cancer Inst. _ _1C% 197 . . ~ Z0) 3remner, T., Reddy, P., yaya:, K.T. and•Xou:i, R.E. Nuc:ec- side Phosphorylase (NP-Z, of Mice. Biocnem. Genet. _ :143, 1979. 21) :ienry, C.J, Lopez, A., whi_...:e, C.., , Caton, J.E, Hencer- son, G.M. and Kouri, R.I. Jeposition and Jistributiorn c: %ta1 Particulate !!atte: ("P!!) in BC3F1 Mice After Ex;os;.:e to Cigarette SmoKe. :'ox:col. b appl. Pha::nacol. 49: ?,5, 4

^j Fv2 PUBLICATIONS FROM MICROBIOLOGICAL ASSOCIATES SUPPORTED BY CTR Levy, J.A., Joyner, J., Nayar, K.T. and Kouri, A.E. Genetics of Xenotropic Virus :xpression in Mice: :. Ev:dence for a Single Locus Regulating Spontaneous Productiorn of Infectious Virus in Crosses Involving NZS/BINJ and :Z9/;. Strains. Virology 30: 754, 1979. J . 23) Kouri, R.E., Rude, '".a., Curren, R.D., B:andt, K.R., Sosnoa- Z. ski, R.G., Schecztman, L.M., Benedict, ii.F. and 'rien:y, :..,. Biological Activity of Tocacco SmoKe and :'ooacco SmoRe- Related Chemicals. =:zvi:on. Healt.ft PersF.ectives, 29: 1979. C~. 24) Curren, R.D., Kouri, R._- and ScSecntmar., ...M. 3_::cies on Metabolic Activation of Chemicals for Mamma:ian Ce:: :'rans- formation and Mutagenesis. in: N. Misr.:a, V. :unxei and M. Mehlman (eds.), Advances in Modern Envi:=zmen:a. '"zxico:ac•: Vol. 1, Mammalian Cell Transformation zy Che:,-,:ca: Carcinogen, Senate Press :nc., Princeton 319-353, 1980. Junc..on, ".;, zo. 25) DinowitZ, M., yims, R., 9hooshan, 3., Kouri, ;.E. anc Fienry, C.J. Induction of C:nit.ftine Decarboxylase (OCC) by :2-0- Tetradecanoylphorbol-l3-acetate (TPA) in Pulmonary Tissue: A Model System :o: Tumor Promotion iz Mouse Lungs. Assoc. Cancer Res. =': 31, 1980. Proc. Am. 5

S FC26C-C° PUBLICATIONS FROM MICROBIOLOGICAL ASSCCIATFa SUPPORTED 8Y CTR Henry, C.J., Avery, M.D., Dansie, L.R., :.Opez, A., Breth, L.A., Billups, L.H. and Kouri, R.Z. The ==fect of Exposure to Whole Cigarette Smoke on ?-Methylc-o:anthrene (MCA) In- duced Lung Tumors in BC3F1/Cu:a Mice. P::=. Am. Assoc. cer Res. 21: 126, 1980. Can- 27) Henry, C.J., Billups, L.H., Dinowi_z, M., Rasmussen, R.E., Avery, M.D., Dansie, D.R.. Lopez, A., _.A., Mull _nax, H.D. and Rouri, R.E. The C::ect of =xpcs_:e :o Whole Ciga- rette Smoke on Pulmonary Mixed cur,ctio:: =xidase, orn:taine Decarboxylase, DNA Repair Capaci:y and ~r 3-Methylc::olan- threne (MCA) Induced Lung Tumors in 3C-F:/Cum Mice. Sympo- sium on Co-Carcinogenesis and 3:..:og::a: =::ects of '"umc: Promoters, Castle of Elmau, K:a:s/3avaria, Fede:a: Republic of Cermany, r. 56, :98G. 23) Henry, C.J., :vhi:-:ire, C.C., _cpe:, A., Cans:e, ..R., Avery, M.D., Caton, ..... , Storcely, ...n., ;..w., Gseri^, M.R. and Kouri, R.E. The Dos:met , and _:st:_tution of Who:e Cigarette SmoKe Particulates in =zorec :::aizs of Mice: Comparison of a Large S:noxe-Expos::re Ma:nine (SEM) witz a Sma11-Capacity Smoke Exposure Machine (walton). In: Sanders, Sanders, F.T. Cross, G.--. Dagie and :.A. Mahafley (eds.), Pulzsonary Toxicology of Resp:rable Pa:::=1es. Technical :nformation Center, U.S. Depart.ment .._ =nergy, NTIS. ,:=. 177-132, 1980. 6

PUk3LICATIQNS FROM MICROBIOLOGICAi. ASSOCIATES SUPPORTED BY CTR S F02bC0i~ ~ Kouri, R.E., Billups, L.H., Rude, T.H., Whitmire, C.E., Sass, B. and Henry, C.J. Correlation of Inducibility of Aryl Hydrocarbon Hydroxylase with Susceptibility to 3-htethyl- cholanthrene-Induced Lung Cancer. Cancer Letters 9: 277, 1980. 30) Nayar, K.T., Levy, J.A., 0'yei::, 3. and Kouri, R.E. Xeno- tropic virus Expression and ="sceptibility to Chemical:y- Izduced Cancer. Cance: Res. `: 4364, 1960. 3:) Nayar, K.T., 0'Neill, B. and {ouri, R.Z. :nneritance .._ :-'..- dogenous RNA Viruses. :n: Genetic Dif:erences in Chemica: Carcinogenesis. R.Z. Kou:i (ed.), CRC Press, West Pa1- 8each, Florida, pp. 93-::3, 1960. 32) Schechtman, L.M., Henry, _.,,. and Xouri, R.E. Lx2 osu:e, take and Dist:ibution of C::emical Carcinogens. In: R.E. Kouri (ed.), Genetic --i=:erences in Chemical Carcinocenes.s, CRC Press, Boca Raton, ':or.=a, Yp. 1-20, 1980. 33) :ienry, C.J., Billups, ...:'.., Avery, M.D., Rude, T.H., Dansie, D.R., ..opez, A., Sass, B., Whi:mire, C.E. and Kouri, ::._. A Lung Cancer Model System Using Inbred Strains of Mice. Can- cer Res. (In press), :9e-.

~FU26UO-i PUBLICATIONS FROM MICROBIOLOGICAL ASSOCIATES SUPPORTED BY CTR Henry, C.J., Breth, L.A., Gerhart, J.M., :,anise, D.R., Mul- linax, H.D. Whitmire, C.E. and Kouri, R.=. Carboxyhemoglobin Levels as a Measure of Cigarette Smoke -Exposure in Mice. (In preparation), 1981. Henry, C.J., Caton, .:.E., Stokely, J.R., Guerin, M.R., Lopez, A., Avery, M.:.., Dansie, D.R., Hencerson, G.M., Gayle, T., Whitmire, C.E. and i(ouri, R.E. Deposition and Distribution of t:ze :'otal Particulate Mat:er of Cigaret=e Smoke in Mice Using a Large Capacity Smoxe Exposure System. - Toxicol. & Appl. Phar;nacol. 58: 399, 1981. -'+) Henry, C.J.r M.R., Hall, W.C., ?-.;t.'l.an, :r., :.ubet, R.A., Dansie, :.n., Avery, M.D., McKinney, C.M. and icouri, R.E. Effects of Sendai Virus and Vaccine on Sho:_-Term Toxi- cological and :mmunc:ogical Markers in St:ain A/J Mice. Proc. of Am. Cmllece Vet. Pata. (In press;, 198:. 37) Henry, C.J., Gelharc, ...C., Gosneil, S., tinlpsc:ler, R.C., Lopez, A., Dansie, D.R., Si::ups, L.H. Ha::, 'w'.C. and Kouri, R.E. Pulmonary Loca:i:.ation of a Particulate Constituent of Cigarette Smoxe in Mice. (Submitted), 198:. 39) Henry, C.J., :.ooez, .a., Oansie, D.R., Ave:y, K.~., Whitmire, C.D, Caton, .,.E , =toKe:v, J.R., Guerin, m.R., Cur:en, R.D. and Kouri, R.---. :)ist:ibution and Clearance of TSree Ciga- 8

SFQ2;-~ .,ri ~ PUBLICATIONS FROM MICROBIOLOGICAL ASSOCIATES SUPPORTED BY CTR rette Smoke Constituents, Dotriacontane !DTC), Nicotine (NIC) and Benzo(a)pyrene (BP), after ExF.csure of Mice to Whole Cigarette Smoke. The Toxicologist _: 139, 1981. 39) Hwang, X.-K., Bhooshan, B., Kouri, R.-S. and Henry, C.J. Synthesis of Tritium Labelled Catechc:. J. of Labelled Com- pounds and Radiopharmaceuticals (In press), 1981. 40) Hwang, {.-K., Sonko, 0., Dansie, ~.n.. Jaqusick, M., riou::, R.=. and Henry, C.J. Urinary Metabolism :n Mice of Catecnc_ in Whole Cigarette Smoke (In prepara:icn;, 1981. 41) Hwang, {.-K., Sonko, 0., Dans:e, .,.R., Xouri, R.:,. anc Henry, C.J. Studies on the Depcsiticn and Distribution .,_ Catechol :rom Whole Cigarette S-noRe :n 3C3F1/Cum Mice. (Submitted), 1981. 42) Kouri, ~... , McKinney, C.:.. and Henr,•, '.J. Geneti: o: Breast Cancer Susceptibi:ity in A;,iaa'.s. :n: Henry T. Lynch (=d. ), Genetics in 3 reast Cancer, Van Nostrand- Reinhold, New York, NY, pp. :4-48, 1?81. 43) Kouri, R.S., McKinney, C.E., Slomiany, :.J., Snodgrass, D.R., Wray, N.P. and McLemore, T.L. ?ositive Correlat:or. Between High Aryl Hydrocarbon 'r.ydroxylase Activity and Pr:ma;y Lung Cancer - Analysis in C:yo:reserved Lymono- cytes. (Submitted), 1981. 9

~FvL~JJ~ PUBLICATIONS FROM MICR08IOLOGICAL ASSOCIATES SUPPORTED 8Y CTR Kouri, R.E., Oberdorf, J., Slomiany, D.J. and McKinney, C.M. A Method for Detectinc Aryi Hydrocarcon Hydroxf:ase Activities in Cryospreserved Human Lymphocytes. Cancer Letters (In press), 1981.ress), 1981. 45) Rasmussen, R.E., 9oyd, C.H., -~'ansie, D.R., Kouri, R.~. anc Henry, C.J. DNA Replication and Unscneduled DNA Syntnes:s in Lungs of Mice Exposed to C:=are::e Smoke. Cancer Res. ;_: 2583, 1981. 10

30

Chronic Inhalation Studies in Mice. II. Effects of Long-Term Exposure to 2R1 Cigarette Smoke on (C57BL/Cum X C3H/AnfCum)F, Mice'23 Carol J. Henry'-s and Richard E. Kouri 4•6•r ABSTRACT-Standnrdized exposurs conditions with Kentucky reference 2H1 cigarettes were used to expos.2,053 (C57BVCutn X C3WAnfCum)Ft female mice (nose only) to fresh, whole cigarene smoke. in addiUon, 1.014 mice were sham-exposed, and 449 miea were heW as shelf controks. The protocol entaiMd expos- ing mice to smoke (or sham-exposure) on a daily basis. S days/ week, for 110 wa.ks and observing remaining mice until death. A large number of anlmals was used so that the amoke generation and anirra6holding systems could be tested and evaluated and yet provide significant numbers of animals for exposure to cigarette smoke for a major portion of their lifetime. Deposition of smoke particulates was estimated to be about 125-200 yg total paRieufate matterAung/day. The only lung txncers observed were diagnosed as aiveolar adenocarcinomas (AAC). A total of 19 of 978 smoke- exposed mice and 7 of 651 shatn-exposed mice wara observed with AAC. The difference between the smoke- and shatn-exposed groups was not statistically significant at P5.05, but the data sug- gested that the tumors occurred with a shorter latency in the smoke-exposed group (P=.10). The data were analyzed by vanoua methods• including analysis of subsets of the population of ani- mals. A significant increase in the incidence of lung cancer was observed in one subset however, this difference was not tound in the population as a whole or as a result of any other anafysei Under these exposure conditions. 2q1 cigarette smoke would seem to nave weak carcinogenic activity In mouse ktng tiasue- Other changes associated with smoke expostre were incrcasad incidance of pigmented alveolar macrophage aceuntulation• ot'rtis media, and head and neck f[brosareomas. However, the incidence of nephritis• hematopoietic cancers (e.g., leukemias, fympftoear- cemas, and reticulum cell sarcomas), and pulmonary congestion was sigr.ificanty higher in the aham-exposed animals.-JtVCI 1986: 77 203-21 2. assom~ated with smoke exposure and 2) quantitation of lonr--erm effects of model chemimis on nrdnogenesis of t_e respiratory tract (*-6). The experimental condi- tiom in this chronic smoke inhalation study were desi;ned to maximize the responses known to be in- voned from the short-term effects and to observe the rest:ts of long-term exposure to cigarette smoke. MEce were chosen as the animal model for these stud- ies a_nd• in particular, (C57BL1Cum X C3H/AnfCum)FI mi-_ This choice was based on several factors: a) avail- abi1=7 of large numbers of animals; b) susceptibility to the :nduction of lung tancer (squamous cell nrdnoraa, AA-C. poorly differentiated tareinotna, etc.) by model cacid mrdnogeru (t, 6). which was linked to generi- aIfv dete:atined differences in hydrocarbon metabolism capaaty (7); c) availability of animals that were free of co>r.:-on advenatiotu agents, in particvlar, Sendai virus and pneumonia virus of mice•, d) ease and cost effective- ness of handling and manipulating on a daily basis: e) con^^erable background known on longevity and spon- tanntu expression of disease (4); f) smoke particulate depcsition characterized with nose-only exposure equip- m- (5); 3) certain characterized short-term effects such as _dttcdon of aryl hydrocarbon hydroxylase (7), induc- tion of sister ehromatid exchange (8, 9), increase in per- Aastr+ta-na%s rsso: AACi at.eolar aderoeardnotna(s): ACY=stve- ouu ziatptessing ncdutes ANCN=alveolar noncompressing nodules: COz =-Arboxyftetnoglobin: PAMA=pigtnented al.eolar meophaee *==uLa Licini(sG '-?St- total particulate matter. The experimental design of studies to evaluate the long-term effects of exposure to cigarette smoke in an animal model system must attempt to simulate human exposures. The aiteria used to design such studies should be based on those reported to be important in cigarette smoke-associated human diseases. Those fac• tors inciude high exposure to fresh mainstream cigarette smoke on a daily basis for a major portion of the life- time of the individual (2, 3). Even under these condi- tions. however, resultant smoke-associated diseases have been observed in oniy a small fraction of the exposed individuals. Our laboratories have been involved in tae development of animal model systems and inhalation equipment to assess the biological effects of acute and chronic inhalation of cigarette smoke. In the develop- ment of the mouse model systcm, two approaches t.•ere taken: 1) quantitation of short-term effects known to Se •;L-tived Augssst 19, 1985: revised January 27. 1986; accepted F:Jzsv 2i. 1986. -.Yponed by mnuact CPR-0OSO with The Council for Tobacca Aesz-~-C'.S_~.Inc- . s?!,^ented in part at the Thirteenth International CGncer Congerss. Seacr. WA. September 8-15, 1982 (I). The interpretations anl opi :a,-os are those of the authors and not neeesncily those of The Cotaa for Tobarm Researed +4aobiologioi Auoaiates Ine, 5221 River Rtl. Bethesda. StD 2osi? 'As.aerr reprint requests to Dr. Henry at her present sddreu: 1G= Inmr-ooterL Internatiatal Square. 1850 KSt., ?LW.• Wathington. DC ?ooCr_ s~'-_snt addresr International Biotechnoingies, tne. "-75 Wincheater Ax_ . \ew Haven. CT 06511. t%e thank Dr. Leonard Billups and Dr. William Hall (or p.ahoing.- sitpp%r Nts- DeniseAvery, Mr. David Dansie, and Mr. H. Duvie Jfu:- lin-s :ar technical support: Mr. Robert Kranko for computer prt, gra..vingt and ?1L Cynthia Whitfieid for typing the nsanusatpt. 203 JNq• VOL 77. YO. 1. JULY 19r6 CTR CGNTRRCT5 025007

204 Henry and Kouri centage of cells undergoing DNA synthesis (10, 11), and inhibition of lung DNA repair capacity (12); and h) similarity to the mouse strain used by the National Toxi- cology Program for the Chemical Bioassay Program. The susceptibility of these mice to the long-term effects of cigarette smoke was not known. However, the average life-span of the animals was approximately 124 weeks, and diseases that 'could interfere with interpretation of the effects of cigarette smoke (i.e., lung cancer) were known to occur very late in life (mean time of 112 wk of age) and at low frequency (<7%) (4). The smoke generation and exposure equipment used in these studies has been described in detail elsewhere (5, 13). This equipment was designed for standardized, documented inhalation exposures of large numbers of mice to fresh, whole cigarette smoke. Dosimetry studies demonstrated that 80-90% of the smoke particulates that were deposited onto smoke-exposed mice were found in the respiratory tract and that animal-to-animal variation was less than 20% (5). In this study, standardized exposure conditions with Kentucky reference 2RI cigarettes (high tar and high nicotine) were used to expose 2,053 (C57BL/Cum X C3H/AnfCum)FI female mice to whole cigarette smoke, 1,014 mice were sham-exposed, and 449 mice were held as shelf controls. In addition, 710 mice were included for co-treatment with benzo[a]pyrene by intratracheal inoc- ulation, followed by smoke exposure or sham-exposure. The results from these latter studies will be reported sep- arately (Henry CJ, Kouri RE: Submitted for publication). MATERIALS AND METHODS Data collection.-An Experiment Information Man- agement System on a Hewlett Packard 3000 computer provided means for recording and collating the observa- tions and data for each animal over the course of this 3-year study. Animals were randomized, given individ- ual identification ear tags (National Band and Tag, Knoxville, TN), and assigned to a specific experimental group and treatment schedule. This information was entered into the experimental data base, interpreted by an edit program, and added to the existing data base via an update program. As the experiment proceeded, ob- servations, inventories, monthly body weights, and the levels of TPM generated each day were obtained and added to the data base. An automatic-tare Sartorius bal- ance was interfaced with a Hewlett Packard 2644 com- puter terminal to collect and record animal weights. At the time of the animals' death or sacrifice, autopsy forms were prepared to describe any gross pathological obser- vations and to assign specific histopathology numbers to each animal. The computer system supported the diagnoses using the Systematized Nomenclature of Pathology codes for the interpretation and reporting of the microscopic results. Animals.-Mice were purchased from Cumberland View Farms (Clinton, TN) at 4-6 weeks of age. Females from the first filial hybrid generation from C57BL/Cum X C3H/AnfCum mice (i.e., BC3Fi/Cum) were used. Females were chosen because they were not aggressive with their cage mates during long-term experiments and because their smaller body size reduced the need for neck restraints of different sizes. These neck restraints were used for smoke exposure and for sham-exposure. Upon arrival, mice were tested serologically for adven- titious agenu. inoculated ip with 0.1 ml Sendai virus vaccine [M.A. Bioproducts, Walkersville, MD; (4, 14)], and quarantined for a minimum of 3 weeks prior to treatmenL The serological testing and animal husbandry procedures have been described previously (4, 13). Smoke generation and monitoring.-Cigarette smoke was generated on the SEM II, a large-capacity, dynamic, intermittent smoke exposure system in which the smoke is routed to the animal containment system as a contin- uously flowing stream for nose-only exposure of mice (5,13,15). Mice were restrained in stocklike holders, and up to 480 mice were exposed nose only to the same smoke-exposure regimen (13). Two SEM II machines were required for the large numbers of animals in these studies. A separate sham-exposure machine was also used (13). Three animal containment racks were used, one for each smoking machine and one for the sham- exposure machine. Mice were loaded into the neck- restraint holders and transported on specially designed carts for loading onto the exposure modules. The animal-holding system was described elsewhere (13). The mice were restrained approximately 2.5 hours/day. A standardized smoke-exposure regimen was used. The cigarette was puffed once per minute, generating an average 35-m1 puff during a 2-second period. For these studies, a nominal 10% percent (vol/vol) smoke aerosol was produced. The exposure cycle alternated 20 seconds of smoke with 40 seconds of air/minute for 6-8 consecu- tive minutes (6-8 puffs/cigarette). Preliminary studies showed that these numbers of puffs approached a maxi- mum tolerated dose for this cigarette: however, this regi- men also resulted in smoking about the first one-half of the cigarette and resulted in delivery of approximately one-third of the potential TPM of the 2R1 cigarette. After an 8-minute rest during which air was provided, the smoke exposure cycle was repeated. Five such expo- sure cycles (cigarette equivalents) with an air rest be- tween each cycle were given each day. To acclimate the mice to this exposure regimen, the length of exposure was gradually increased over the 1st month of the study. Smoke- and airflow-monitoring devices were devel- oped to provide documentation of smoke particulate exposure levels and to provide safety systems for acci- dental toxic exposures or machine malfunctions (13). The on-line smoke monitor provided daily puff-by-puff documentation of the smoke particulate levels (13). Flow sensors were added to the exposure equipment during the Ist year of the study and were designed to provide auxiliary air to the exposure modules if neces- sary. Details of the design and use have been given else- where (13). University of Kentucky 2R1 cigarettes were used for all exposures. These cigarettes are standard 85-mm non- Jlh(1. VOL 77. NO. 1. JULY 1986 rTP rf?WTPorTq n?qnAfi

1 Chronic Cigarette Smoke Inhalation Studies 205 filtered experimental reference cigarettes and have been characterized under standard Federal Trade Commission procedures at Oak Ridge National Laboratories, Oak Ridge, TN. Under these conditions, the 2R1 cigarette delivered approximately 4-1 mg TPM. 2.4 mg nicotine. and 21 ml of carbon monoxide (16). Cigarettes were removed from frozen storage and conditioned at 70-75°F and 60% relative humidity for at least 18 hours before use. Animal weights.-All mice were weighed at monthly intervals at approximately the same time of day, 2 days after cages were changed. Smoke- and sham-exposed animals were weighed at least 2 hours after exposure. Data were recorded for each animal, and the mean and standard deviation were calculated for each group at monthly intervals. TPM deposition and COHb leuels -As determined from parallel radioactive dosimetry experiments, smoke particulate deposition was determined to be between approximately 125 and 200 µg TPM/day/mouse lung for this exposure regimen using 6-8 puffs/cigarette. [See Henry et al. (5) for a description of the methods and results.] COHb levels were determined at monthly intervals. Blood from the retro-orbital sinus was collected from 3-5 -mice/group. Natelson blood-collecting tubes (175 µi;'Shen.•ood Medical Industries, Inc., St. Louis, MO) were prepared shortly before use by rinsing the tubes with a drop of sodium heparin (10,000 U/ml; Abbott Laboratories, Baltimore, t1D). After blood collection, the tubes were sealed s.•ith Critocaps, stored on ice, and analyzed within 30 minutes using an IL-CO-Oximeter (IL-282; Instrumentation Laboratory, Inc., Lexington, MA). Necropsy.-Mice were observed twice daily for evi- dence of illness or respiratory distress. Dates and circum- stances of death were recorded for all mice. Nonauto- lyzed tissues from mice found dead and those killed when moribund were examined microscopically. Lungs were fixed in situ with approximately 1.5 ml of 10% buf- fered Formalin by infusion via the trachea. Lungs were ligated at the trachea. and the thoracic viscera were removed as a single unit and examined grossly. Lung, trachea, esophagus, and thoracic lymph nodes were sec- tioned (6 µm) as a unit at 3 levels, using a frontal plane of section. During the Ist year, respiratory tissues (lungs, larynx, trachea, nasal cavity, and middle ear) and abnormal tissues were examined microscopically from a random sampling of 13 0 of the animals that died. Dur- ing the 2d and 3d years, respiratory tissues and any abnormal tissues from all animals were fixed and stained. Respiratory tract tissues from 96% of the ani- mals were examined microscopically. In addition. 16 other tissues from major organs were examined micro- scopicalh- from a random sampling of 10% of the ani- mals. These tissues included salivary glands, cervical lymph nodes, spleen, liver, kidneys, adrenal glands, uri- nary bladder, ovaries, uterus, heart, stomach, large and small intestines, pancreas, and thymus. Tissues were examined microscopically from a total of 987, 659, and 369 mice in the smoke-exposed, sham-exposed. and shelf-control animals, respectively. Morphological criteria.-A brief description of the lesions observed in these studies is presented below. AAC occurred as discrete grayish-white, firm masses, located in the peripheral portions of the lung, and were often multiple. Some tumors occasionally showed pleu- ral invasion and metastasis. Adenomas are not included in this category. Pulmonary adenomas were scored in two categories: ACN and ANCN. This classification scheme was devised as part of other on-going studies to determine the possi- ble progressive nature of adenomatous lesions to carci- nomas. Details of the chemical inducibility, time course, and transplantability of the ACN and ANCN will be reported elsewhere: however, ACN, as well as AAC, grew into tumors after transplantation into newborn BC3Fi/- Cum mice in about 30% of the cases (Henry CJ, Billups LH, Hall WC, et al.: Manuscript in preparation). Histo- logically, ACN and ANCN were differentiated on the basis of size and extent of compression of the surround- ing lung parenchyma. ACN were rounded masses of hyperplastic alveolo- genic cells, about 2-3 mm in diameter, that did com- press the surrounding parenchyma. Nodules located in the most peripheral portions of the lung tended to invade the pleura. ANCN were similar to ACN, but they did not compress the surrounding parenchyma. These nodules were barely visible grossly. Mitoses were ob- served occasionally. Congestion in the lung was.observed as dilated pul- monary veins and capillaries, which were engorged with blood. The congestion could have been the result of an active process resulting in lung irritation, a passive pro- cess resulting in reduced flow of blood from the lung, or an inadvertent.delay in neaopsy after death. Head and neck fibrosarcomas were malignant neo- plasms of fibrous tissues. They were unencapsulated and often showed scattered yellow areas of necrosis or red- dish foci of hemorrhage. Many of these observed in this study were highly aggressive. metastatic tumors, com- posed of cells with large spindle-shaped nuclei and scant cytoplasm. Once established, these tumors grew rapidly, invaded veins, and metastasized to other tissues, includ- ing the lung. Hematopoietic cancers were grouped together as can- cers of the hemic and lymphatic systems. They included lymphosarcomas, reticulum cell sarcomas, and lympho- cytic leukemias. Nephritis included all inflammatory lesions of the kidney, glomeruli, and renal pelvis. The inflammatory lesion can be caused by adventitious agents, foreign materials, or other processes. Otitis externa is an inflammation of the external ear. It is usually considered an incidental finding in the mouse. Otitis media is an inflammation of the middle ear and was relatively severe. Usually of bacterial origin, it can be due to ascending infections along the eustachian tube. The eustachian tube, lined by ciliated epitheliutn, JNQ, VOL 77. NO. I. JULY 1986 [''TP rnWTpof''Tct r171;r1n4

W 206 Henry and Kouri can be a portal of entry for inhaled material. Extension of this lesion into the brain mn result in death of the mottsp- P.aNA was observed as clusters of alveolar foam cells or pulmonary macophages in the alveolar spaces. The cells contained brown pigment and were often large and vacuolated. Data analysis.-An attempt was made to determine the cause of death of each animal. The major reasons fcr death were either conditions that randomly removed the animals from the study (i.e., smoke-related or sham- exposure-related, holder-related, or documented airflow or smoke flow factors) or diseases that likely led to the death of the animal. This tabulation allowed us to ana- lyrr the data by two methods (4, 17, 18). Tne Frrst method assumed that the lesion caused the death of the animal, and thus an "actuarial" table was constructed that compared the numbers of animals that died carrying that specific lesion to the total number of animals alive at the beginning of that interval. For the actuarial analysis, the total numbers of animals at risk either were those that were strictly defined to have died as a result of their lesions or were those generally defined as the total number of animals that had histo- pathological examinations. The second method assumed that the lesion did not lead to the death of the animal. In this way, the "inci- dence" of a particular lesion at a given interval was al- culated by determining the number of animals fotmd with a specific lesion compared to the total numbers of animals that died during that interval. The numbers of animals in this interval were either those animals that were strictly defined to have been taken off test nn- domlv or the total number of animals that died during that interval. Statistical analyses were determined according to the method of Mantel and Haenszel (19) and Kaolan and Meier i ;20). The procedure is briefly stated as follows. For 2 groups to be compared, the number of animals with a given lesion and the number of anirrals that were at risk for that lesion for each interval were used to rnn- struct 2X2 contingency tables. The nulnbs of lesions expeaed and the variance of this nur.:be: could then be de:-~ ined for each interval. The sum of the expected va;:jes ..as treated as an approximately normal random .ariaae with known mean and variance. The chi-squar! aatis3c. corrected or uncorrected for continuity, was uen `ised to determine the level of significance of the di:f=ence between the expected number of lesions and the :bsetved number of lesions for 2 experimental grot:; t over any given interval. RESULTS Smoite Generation and Monitoring Data from the on-line smoke monitor showed that an ava'age of 0.62 g TPM/day was delivered to the mice. Thus an animal that survived for the complete exposure time ':Pf 110 weeks was exposed to approximately 339 g TP'.L Data from previously reported dosimetry studies U) s:owed that following exposure to 6-8 puffs of 2RI agar-tte smoke. about 125-200 Fcg TPM would be de- ;.ositad in the respiratory tract of these mice during one -xpnsiue session. Multiplying the daily amount depos- ited ie the total exposure time suggested that up to :00 =g TPM could have been deposited per mouse lung ove the course of this study. COHb levels were also determined at montbly inter- vals. The mean COHb levels weie 17.15 = 42 (SD), !•4+ = 0.4 (SD), and 1.8% t 0.4 (SD) for ccle smoke- ezposed. shamtsposed. and shelf-control mice, respec- LIve1T. Toxicity of Treatment S-rival.-A large number of animals were used in these studies so that this smoke generation and animal- holding system could be tested and evaluated and still alievr :or signifiant numbers of animals to be exposed to c3uette smoke for a significant percentage of their 1ifed=e. Table I summarizes the disposition of mice duri: g this S-year study. During the 1st year, almost 50'. of t!ie smoke-exposed and 30% of the sham-exposed mice diea of exposure-equipment-related problems. One majar problem was an inability to monitor •when or i_' air was flowing through the modules. At the attd of the :st .3r, flow sensors (see "Materials and Nfe:hods" for descption) were added, and these safety systeas resultec in tzzaneed survival of mice in both the smoke- and sba=-exposed groups. TenLS 1.-Disporrtian o/ aaimaL .iYrinp e~-Prie tualatioa ol =RI oiqarettt smokaa `a. of animals Treat^ent No. of Year L Year 2 Year 3 l i h T animals tested Microscopic evaluation No neeropsy or evaluaticn \iicrostropie evalua:dsn No neeropsy r= evalaation Microscopic evaluation No necropsy or evaluation ota w t =Slcroscople tvaluation 2R1 tr^oke 2.053 154 97S 4Y' 27 406 7 9S7 Sham 1.014 74 325 31: 10 2746 5 659 Shel! 449 3 19` 129 40° 237 21` 369 ' C;,: ditions for smokeex posure of 10%2R1 ciearettesmoke. wit}t 20 sec ci s-oke alternatin¢ with 40 seeof air for a period o: E-3 min. Five sucii ez;rsures were given each day. Sham-.xposure was the same wa:out sr.oke. "Irc6u.ies Y, animals that died in the 4th yr. Ir.oWses animals removed from test for collabontive studies. Jy('}. t'QL 77. NO. 1. JULY 1986 CTR cohtTRACTS 025010

. The surviving fraction of mice as a function of time on test is presented in text-figure l. These curves were corrected for those animals that were determined to be randomly removed from the study (i.e., they died of exposure-equipmento-related factors). The survival curves of the smoke- and sham-exposed groups decreased more rapidly than those of the shelf-control animals, indicat- ing that the daily smoke exposure or sham-exposure caused a detectable level of morbidity and mortality. After 80 weeks on test, however, the shelf-control group was observed to die at a more rapid rate than the smoke- or sham-exposed mice. This was also the time when the shelf-control animals were losing body weight (ree next section and text-fig. 2). Body weights.-Body weight analyses of the smoke- exposed. sham-exposed, and untreated shelf-control ani- mals are presented in text-figure 2. The shelf-control mice gained weight until 50-60 weeks and then gradu- ally declined in weight during old ag-- The rate of weight gain of the shelf-control animals was signifi- cantly greater (P<.05) than that of the smoke- and sham- exposed mice. At about 80 weeks on test, the shelf- control mice had an average weight of 50 g. No differ- ence between the mean body weights of the smoke- and sham-exposed mice was found over the course of the study. Smoke- and sham-exposed mice gained weight slowly until about 60 weeks on test, after which their weight gradually declined. The average maximum weight of BC3F1/Qim mice in the smoke- or sham- exposed groups was 32 g, which was seen at about 60 weeks on test. - WEEKS ON TEST Chronic Cigarette Smoke Inhalation Studies 207 Clinical signs.-Mice were observed during and im- medi.ately after daily exposure to smoke and sham- treatment. For the smoke-exposed animals, while a cer- tain amount of adaptation occurred, the animals never accepted smoke exposure without some agitation or struggling in the holder. They ocasionally demonstrated some shallow breathing or gasping during exposure. Immediately after exposure, mice in the smoke-exposed groups were often lethargic, ataxic. and hypothermic The sham-exposed animals also demonstrattd agitation and struggling while restrained in the holders, but generally they appeared normal afta exposure. After 20-30 weeks of exposure, certain artimals were observed to have reddened skin and worn-away hair around the neck area that fits into the stoddike holder. In 30-40% of the cases, these irritated areas progressed to open sores as exposures continued. Periodically, during the 2d year of the study the mice were rested and not exposed. Such rests enabled the neck cuts to heal. The length of the rests varied liom I day to 1 week. Polycar- bonate inserts for the stocklike restraints were found to cushion the nerJt slot and could be effective in limiting such neck abrasions. It is recommended that such inseru be used for any long-term studies where animals of dif- ferent ages and/or sizes may be used. Nistopathologic Observatlona The shelf-control mice died mrrying a similar spec- truat of diseases to that reported previously for this hybrid strain of mice (4); i.e., about 60% died of neoplas- SMOKE EXPOSURE STOPPti.U Tt.`tTnecat l.-Survivuag iracuun oi mice presemed as a funaion of time on tesL Mice included in this analysu were eho,e that died or were killed when moribund (nonrandom dealhs: iee tese for definit:un/. JNCL VOL r7. YO. l. JULY 190 CTR CC1NTRRCT5 025011

208 Henry and Kouri S0 1 40 ~ 30 ^ jll IlI( 11:j1~ I III~I Y 1 ~ ~ i 11 40i 10 -1 20 m m 80 100 WEEKS ON TEST TE Sbelf Sham Smoke 0 140 TENrr•navtti 2.-Me-aa body weights of B©FI/Cum mice in the smoke-esposed s5am ccpoeed and shdf.aenuol6.oups as a function of time o0 iac One ssandard devia¢on of the mean is indiorcd by the ben. tic diseases and 40A died of nonneoplastic causes. The major neoplastic diseases observed were hematopoietic tumors (31%), sarcomas (5%), fibrosarcomas (9R), lung adenocaranomas (4 e:•. liver carcinomas (490), and mam- rnary carcinomas (9 :). The major nonneoplastic dis- eases observed were congestion-pneumonia (8%), neph- ritis-cystitis (31), and conditions where no major disease was found (13 a). In geneml, the same spectrum of diseases was observed in the smoke- and sham-exposed mice. The distribution of lesions and the latency of uccurrenee, however, seemed to be influenced by smoke exposure or sham- exposure. Table 2 summarizes the histologic lesions observed in the smos-exposed and sham-exposed mice. In addition, it presents the number of mice observed with a lesion, the total number of mice whose tissues were evaluated for that lesion, the highest level of signifi- cance (i.e.. "P"-value) observed between the smoke- exposed and sham-e..posed groups, and the time during the studr when this difference occurred. The only lung catscers observed were diagnosed as AAC-no squamous cell carcinomas or poorly differen- tiated czreinotnas were found. A total of 19 of 978 smoke-cxposed mice and 7 of 551 sham-exposed mice J\CL VOL 77. YO. I, JULY 15116 were observed with AAC. The difference between the smo'co- and sham-exposed groups was not statistimilv signirmnt at P<-.05, but there were suggestions that the turnots occurrec with a shorter latency in the snuske- exp,.ud group. At 81.8 days following initiation of the stud-. the nurabers of AAC in smoke-ex:~osed animal~ were greater than those in sham-exposed -tice at P=.l0. Atte--pts were made to analyze these data in different wavx Fi.zt, the number of animals that were found with aiveciogenic adenomatous lesions. ehought to be precur- sors of AAC, was dessoted. These adenomatous lesions w'ere termed "..k-VChi" and "ACV" (see "Materials and Methods"). Analysis of the incidence of these lesions. both individually and grouped itt various ways (see "Waterials anc Methods" and table 2). indicated that at no :ime was the incidence in smoke-exposed mice higl:c than that in the sham-exposed animals at a level of P<05. Aga.in, there was the suggestion of a shor:er latency for expression of either A.AC or AC V by 813 davs of a-.tnent (P=.09). Another method of analysis took advantage of the fact that Curing tl:e conduct of the study an attempt was made to detenninc the cause of death of each animal (ser CTR CQNTRRCTS 025012

• Chronic Cigarette Smoke Inhalation Studies 209 TwatE 2-Summary o/ ineidenee o/ lesiona in BCJF,/CaK mies asinq lonq tsnn e:posaee to 2RI eiqarette tmoFe No. of aoim s.a Lesion Smoke-exposed 3haaextmsed Highest level of sianifieance• Present Total Praunt Total Respiratory tract' AAC 19 978 7 651 Smoke > sham• P=.10 at 813 days AI1C + ACN 49 918 28 651 Smoke > shams P=.OD u 813 days ANCN + ACN 38 978 21 651 Smoke > sham: P=.39 at 757 days AAC + ACN + Ali C\ 69 978 38 651 Sttake > sham: P=.18 at 813 days PA1[A 158 978 1 661 Smeke» sham Congestion 183 978 158 651 Sham > smoke; PSOS at 412 days Rhinitis 14 502 8 319 Smoke > sham; P=.32 at 869 days Cditis media 66 579 U 371 Smoke > sham: P5.05 at 421 days Otitfs exteraa 140 679 73 371 Smoke > sham P=.14 u 661 days Nonrespiratory tract VepbnGs 27 179 ?6 110 Sham > smoke; P=.16 at 953 days Head-neck (btrosar- 29 987 ii 669 Smoke> sham: P5.05 a:841 days comaa Hematopoietic cancers 125 987 136 659 Sham > smoke; P5.05 at 729 days • The highest level of significance for the difference between tie atmka- anc sham-exposed groups and the time at which the difference oceurred are given. These data were determined from ehi-square aaalysa of esn of the lesionsor groups of lesions at1-wk intervals over tae course of the study (up to 1.120 days on test). • Respiratory tract tiuua included lung. larynx traehea, nasal eavity, aac aiddle ear (see'Materials and Metheds"). "Macerials and Methods"). Thus the total numbers of animals that died could be divided into those that died of factors unrelated to their lesions (i.e., random factors) and those that likely died as a result of their lesions (ie., nontandom factors). Assttming that the animals died as a result of these tumors yields the analysis shown in table 3. In this actuarial analysis, the total number of animals at risk was 504 and 379 in the smoke- and sham- exposed groups, respectively. Analysis of this subset of the population showed that there was no difference in the incidence or latency of AAC between the smoke- and sham-exposed mice. Table 4 presents the results of the analysis of another subset of the population, where only those animals taat were determined to be randomly taken off the test were studied. In this case the numbers of animals found car- rying lung tumors were compared to the numbers of animals that were observed not carrying the tumor. In this analysis, a total of 7 animals were found with a.aC. and all were in smoke-exposed animals. The final ir.d- dence of 7 Ar1C of 474 smoke-exposed animals is s:gnifi- cantly higher than 0 AAC of 272 sham-exposed animais (chi-square statistic = 4.18; P=.04). The m0nth-bv- month cumulative probability, however, never reached a level of significance of P:S05 (see table 4). Similar analyses were done on all the lesions Listed in table 2. The respiratory tract lesions found to be signiii- cantly higher in smoke-exposed mice were PAMA and otitis media. PAMA was found only in the smoke- exposed animals. and approximately 35% of all :nice that died during the last 4 months of smoke cxposi:e had this lesion. For some unknown reason. I+nlmonarv congestion was found to be higher in the sham-cxposcd animals than in the smoke-exposed animals. Certain other nonrespiratory tract lesions were also anaivzed by the methods descTibcd above. Table 2 shcws that the incidence of head-neck fibrosarcotnas was sig- nifiandy higher in the smoke-exposed animals than in the saam-exposed animals. Analysis by actuarial mettods also showed significant differences (data not shown). However, the incidence of nephritis and hema- topoiedc cancers (i.e., leukemias, lymphosarcomas, and reticulum cell sarcomas) was significantly higher in the sham-'tposed animals than in the smoke-exposed mice. This lauer observation would seem to be an example oi competing risks, when the ocnurenee of a specific lesion Mas aaered by the simultaneous expression of anothe- disease process that removed the anitrtal from the study. DISCUSSION T::_ results of this !tudy suggest that 2R1 cigarette smoke has weak carcinegenic activity in mouse lung tissz:e. No bronehogev;c squamous cell carcinomas were :)bse-:ed in any of thc;e animals. .>v.aC, as well as other 3leeologenic lesions, were observed in smoke-exposed animals, and the incidence was higher in :he smoke- exposec animals than in the sham-exposed animals. The cifference in incidence of these A.aC and othc aiveo::)genic lesions, however, never reached the level o: signiiance of P<05. The data suggested that the la- !enL- :or the occurrence of these tumors is shorter in the smoke-exposed animals (P=.10: ree table 2). Va-:otu methods of analyses were performed on these aata. including incorporation of other aiveologer.ic lesions with the lung cancers and analysis ni suhsets o; the population of animals that were cztegorized as to _ause 3f death (i.e., random vs. nonrandomi. In genera:. these analyses yielded no significant differences between the smoke- and sham-exposed groups. However, the analysis of one subset of the population, thase animals cak`n off test randomly, did yield an interesting observa- JNCt. VOt- 77. \O. I, 11t1.Y 1hti. CTR coNTRACTS 025013

. 210 Henry and Kouri TaBLC 3.-Actaarial analysie of BC3Ft/Cum +nics dyinq o/fvnp cancer darinp loep-fem ezpoeure to rRt ciqarette anoke• No. of animals Days on test Smoka-exposed Sham-erpesed P-value• w~t At risk' D/W At risk 1-28 0, 504 0 379 1.0 28-66 0 503 0 377 1.0 57-84 0 502 0 377 1.0 85-112 0 501 0 377 1.0 113-140 0 501 0 377 1.0 141-168 0 501 0 377 1.0 169-196 0 501 0 377 1.0 197-224 0 500 0 377 1.0 225-252 0 499 0 377 1.0 253-280 0 499 0 37T 1.0 281-308 0 499 0 377 1.0 309-336 0 498 0 377 1.0 337-364 0 495 0 377 1.0 365-392 0 493 0 376 1.0 393-420 0 490 0 375 1A 421-448 0 483 0 370 1.0 449-476 0 479 1 369 90 (.26) 477-604 0 476 0 365 .90 (.26) 505-532 0 470 0 361 .90 (.26) 533-560 0 465 0 355 .90(26) 561-588 1 454 0 3J6 1.0 (B6) 589-616 0 445 0 339 1.0 (.86) 617-644 0 427 0 327 1.0 (.86) 645-672 0 404 0 306 1.0 (.86) 673-700 0 394 0 291 1.0 (.86) 701-728 1 365 1 277 1.0 (.79) 729-766 0 343 0 257 1.0 (.79) 757-784 1 313 0 233 1.0 (99) 785-812 1 294 0 204 .96 (.65) 813-840 3 264 1 179 .67 (.45) 841-868 0 229 2 156 1.0 (.99) 869-896 0 190 0 124 1.0 (.99) 897-924 0 161 0 98 1.0 (.99) 925-952 1 128 1 71 1.0 (F8) 958-980 2 94 0 52 1.0 (.84) 981-1.008 1 66 0 39 .89C 70) 1.009-1.036 0 43 0 17 .991.70) 1.037-1.064 1 17 0 .79 (.61) 1.065-1.092 0 8 0 5 .79 (.G1) 1.093-1.120 0 3 1 2 97 09) 12 7 ° Mice in this analysis were onlv :hose whose dos/bs were assumed to be related to tbeir lesions. i.e. 1cn-ando,r» All lung cancers were AAC. I No. of animals found dead with tumor. ' No. of animals at risk in a subset of the gopulation that was alive at the beginning of the interval. See ict for definition of the population subset • Level of significance for the differences between the expected and observed No. of tumors was determined trom the chi-square statistic corrected for continuity. The ehiaquare statistic uncor- rected for continuity is given in parrr.Neses the animals were taken off test. In our opinion, the fact that the two tests did not agree tends to lessen the impact of the condtuion that smoke-exposed animals in the subset population had a sigrtifinntly higher ina- dence of lung tumors than the sham-exposed animals. Exposure to 2Rl cigarette smoke resulted in signifi- ontly increased incidence and decreased latency of PA3rIA and otitis media. PA.rIA were observed at a rela- tively low incidence, with the first ocatrrence after 309 days on test. During the last 4 months of smoke expo- sure, the incidence of PAMA reached 35%, suggesting that macrophage accumulation was in response to a T.tEt.E 4.-peeurrenee o/htap eanen nr BCJF!/Cuot atice ratedomly taken o// test durinp lorp-tern° erposure to !Rt ei.qarette enteke° No. of animals Smoke-expoaed Sham-extyxed Days on test P-valco Tumor- t~~F Tumor- ~ bearine besting bear'na bearin; 1-28 0 8 0 3 1.0 29-56 0 16 0 7' 1.0 57-94 0 7 0 3 1.0 85-112 0 16 0 0 1.0 113-140 0 6 0 2 1.0 141-168 0 7 0 3 1.0 169-196 0 10 0 2 1.0 197-224 0 14 0 2 1.0 2215--262 0 10 0 5 1.0 253-280 0 13 0 5 1.0 281-308 0 4 0 4 1.0 309-336 0 5 0 7 1.0 337-364 0 22 0 23 1.0 365-392 0 26 0 28 1.0 393-420 0 21 0 19 1.0 421-448 1 19 0 13 1.0 (.42) 449-476 0 20 0 21 1.0 (.42) 477-504 0 16 0 18 1.0 (.42) 506-632 0 23 0 16 1.0 (.42) 533-560 0 26 0 12 1.0 (.42) 561-588 0 19 0 12 1.4 (.42) 589-616 1 11 0 I8 .48(.16) 617-644 0 11 0 7 .48 (.16) 645-672 2 23 0 15 20 (.08) 873-700 1 30 0 6 .18 (.07) 701-728 0 20 0 4 .18 (.D') 729-756 2 31 0 2 .17 (.07) 757-784 D 20 0 4 .17 (.07) 7e5-812 0 1 0 0 .17 (.07) 813-840 0 0 0 0 .17 (.07) 841-868 0 0 0 0 .17 (.07) 869-896 0 0 0 0 .17 (.07) 897-924 0 0 0 0 .17 (.07) 925-952 0 0 0 0 .17 (.07) 953-980 0 0 0 0 .17 (.07) 981-1.008 0 0 0 0 .17 (.07) 1.009-1.036 0 12 0 6 .17 (.07) tion. Zhe final incidence of 7 lung cancen (all AAC) in 474 smoke-exposed mice compared to 0 lung cancers in 272 sham-exposed mice was significantlv different (rre table 3). In contrast. cumulative chi-square analysis at 4-week intervals was not st_¢nificatulv Liifferent. The most likely reason for disagreement between the two sta- tistical tests concerns the population d-ntamics of how JNCI, VOL 77. NO. l. JDLY 1988 7 467 0 272 ° Mice in this analysis were only :hose whose deaths were assumed to be unrelated to their lesions. i.e.. random. All lung cancers were AAC. ~ Level of significance for the differences between the expected and observed No. of tumors was determined from the chi-square statistic corrected for continuity. The chi-square statistic uncor- rected for continuity is given in parentl~s. CTR CLINTRRCTS 025014

. Chronic Cigarette Srnoke Inhalation Studies 211 cumulative dose of smoke. These data regarding PAMA give biological evidence that the smoke particulates reached the alveolar regions of the lung. Further evi- dence that the smoke particulates reached other areas of the respiratory tract can be seen from the increased incidence and decreased latency of otitis media The cu- stachian tube with its ciliated epithelium was likely a portal of entry for these inhaled materials and would seem to have been impacted by smoke exposure. Exposure to 2RI cigarette smoke also resulted in significantly incezsed incidence and decreased latency of head and neck fibrosarcorms. The mechanism by which these tumors develop is unclear. Whether such factors as localized deposition of smoke particulates in this area and/or the relative severity of neck cuts or abrasions caused by chronic restraint played a role in the formation of these tumors is not known at this time. In rats, chronic exposure to cigarette smoke has been asso- ciated with increased incidence of tumors of the forelegs (21). In these studies the rats were exposed to smoke in whole-body tubes. It was suggested that these tumors resulted from the combination of smoke particulate deposition on the forelegs and the presence of abrasions on the forelegs caused by the method of restraint. The dose of cigarette smoke given in this study was limited by the inherent toxicity of this particular cigarette smoke for this stain of mice. Following expo- sure to 6-8 puffs of 2R1 cigarette smoke, the dose was estimated to be 125-200 µg TP.11/lung/day. Previous studies with another cigarette type (high tar and low nicotine) have shown thac up to 1 mg TPM/lung/day was given (5). Additionally, the exposure regimen ud- lized about the first one-half of the 2R1 cigarette It is not known whether the first one-half of the cigarette has different biological activity compared to that of the other one-half. Thus the smoke exposure conditions used in this study (low dose and first one-half of the cigarette) may not have been optimal to detect signifi- cant biological or carcinogenic activity. In drawing conclusions from this study, several alter- natives are possible. The first is that the mouse may not be a good tnodel for long-term human cigarette smoke inhalation studies. Mice are obligate nose breathers, have a turbinate structure different from that of humans, ~ have a shorter life-span. do not actively inhale smoke as do humans, and ar- more sensicive to certain smoke- assodated chemicals (e.g., nicotine) that limit the dose of smoke that cut be given. All of these factors tend to mitigate against rodents as an implicit model for human inhalation studies. On the other hand, the mouse appears to be a good model for the study of the effects of smoke inhalation as noted by the following: Lung and kidney aryl hydrocarbon hydroxYlases are increased in smoke-ea:posed mice (6, :, 10); the number of sister chromaud exchanges in bone marrow cells is increased in smoke-exposed mice (5, 9); PAMA is increased in smoke-ecposed mice: DNA repair capacity of lung tissue from smoke-exposed mice is approximately 50% inhib- ited (1Z); DNA synthesis in lung tissue from smoke- exposed mice is increased up to twentyfold (10); and squamous cell carcinoma can be produced in these mice at high incidence with known chemical carcinogens (4, 6;. A further alternative to this latter observation is that poly-7dic aromatic hydrocarbons are poor model chemi- als to use for biologic activity of cigarette smoke. In gertenl, rodents have not been observed to develop high inaristces of lung cancer following exposure to cigarette stnoie (see reviews (22, 23)]. Notable among these many studies is that bronchogenic squamous cell carcinoma has been observed only in 1 rat (F344) after exposure to cigareue smoke (21). In this case. 10 respiratory tna tumors were observed in 7 of 80 animals (9%), with the difference between smoke-exposed and sham-exposed rats :--ported to be significant at P<05. The tumors wese :eported to be I adenocarcinoma and 1 squamous cell carcinoma of the nasal cavity and 5 adenomas, 2 al:mlogenic carcinomas, and 1 squamous cell carci- noma of the lung (21). Exttttsive studies by Dontenwill et aL (24, 25) using randombred Syrian golden hamsters have indicated sig- n'tf'innt changes in laryngeal tissues after smoke expo- sure- including laryngeal carcinoma, with little or no changes reported in the lung. Using inbred Syrian golden hamsters, Bemfeld et al. (26, 27) have reported neoplastic changes in the larynx of hamsters exposed to smoke, with few changes reported in the lung. Broncho- genic squamous cell carcinomas have not been reported in e:tser mice or hamsters after exposure to cigarette smoke, although the incidence of AAC has been reported increased in mice (28, Z9). A second alternative conclusion to this study is that the smoke exposure conditions did not reflect the "true" biologinl potential of this 2R1 cigarette smoke. Ap- proximately the first one-half of the cigarette was used, and :Satfvely low levels of TPM were deposited, znainly because the high nicotine content of the cigarette limited the dose. Additional studies with other cigarette types -nill have to be done to test this alternative. A third alternative is that cigarette smoke alone has fairlv o.eak biologic activity and that the data in rodents reflec this activity. The high biological activity and response observed in human smokers (23, 30) may be a result of a combination of factors, which so far have failed to be duplicated in the laboratory setting. REFERENCES (1) H*_qty CJ. B:Y.Lurs LH. H.ttt WC et al. The effect of lifetime e:posure to whole eisarette uaoke in BC3FI/Cum mice. In: ?roeseding oF the Thirteenth Inu:mauonal Cancer CanSress. Seattk. WA. Gmera: intmutional Union Against Cancer. t98L (2) Pt¢ MC. Hr.votarat BE Epidemiology of polycTdic h.Jro- arboas: Quantifying the nncc risk trom cigarette stooking and air pollution effeeu. In: Gelboin H. ed. Polycyciic h.dro- ntbons ana oncer. New York: Aadanic Press. 1981:317-331. (3) Doti R Ptru R The causes of ancer. Quantiuti.e estimues of avoidable tisks of cancer in the United States today. JNCI 1G81: 5&119I-Ifdt (+) Hr•wtY CJ• tio.tttn t.Fi, Avaar MD, et aL Lung cancer model s.stem using S•medtykholanthrme in inbred strains ni miee. Csnrs Aes 1961: 41:50'D-sos2. JNCt. VOL fl. NO. l, JULY 1986 CTR CaNTRRCTS 025015

L 212 Henry and Kouri (5) HLN1Y CJ, Carow JE. STOCaLY JR. et al. Deposition and disa's- budon of the sonl pasticuiate matter of cigarette sowie in miu using a largeopadsv smoke exposure system. Toxicol Appl P harvsaenl 1981: W99-103. (6) Kousu RE, Btstun LH. RunL TH. et aL Correlation of induo- bility of uyl hydrocarbon hydroaylase with susoeptibility of 3-methyk:holanthreno-induced lung oneers. Canca Len l9go- 9277-284. (7) Roust RE, Runt TH. Cuwuw RD, et aL Biologiol activity of usbaoeo smoke and tobacco smoke-related ehemids EaYUeo Health Petspeet 1979: P9:83-69. (8) BmmCT WF, BaNentc[ A. Lu:aenutwast B1C, et aL Itsonsed sister chtoaaatid exchange in mia exposed tn wbole dptate ssnoke. Mutat Rm 1984: 13b:73-80. (9) Pvyxa.v DL D.tvtn RdS, MetHosx JM. et aL Sism duomadd eschange induction in bone manow cefls of mice exposed nosronly to whole dgareue smoke. Mutu Res 19E5: 15& 1e1-186. (10) Kt>Aa.LtNO,w BX. Run SM. Dvoa DR es aL Autoradiv graphic anallais of DNA syntbesis in pulmonary tissues of mice exposed to whole cigarette smoke. TheTossicoiogist aB1+2 24S (11) HEn'stY CJ, HvaNe SK. L.uv.GAt-wws Y1CL et a1 Remu de.d• optssents in inbalation soaicaiogy: Eraluation of sekssed short- tam endpoitus following "nosaonlj" exposun- of rodents. In: Homburger F. ed. Safety evaluation and regulation al New Yotk: Rarger, 1983a33-242 (12) Rw9cussm RE, BoYn CH, DANSa DR et al. DNA rapfindon and unscheduled DNA syntheis in lunp of miee e:posed to dgoene smoke. Cancer Res 1981; 41:2583-2588. (13) HoctY CJ, GAY1E T. Piotitscr L, ec al. ( tuatuc in_ -la,s.... studies in miea L Facilities and equipment for nose-ealy exposure to eigareue smoke. Beisr Tabak[oesch Iat 19tS: 1i•l7-S4. (14) HAt1. WC. LusaT RA, HsxeY CJ. et a1 Sendai .inu-ditase processes and resateh eompliorions: In: Hamm T. ed_ Coso- pliotions of .iral and snycoplasmal ittfeaioas in sodsat toxicology research and testing. SVashitsgton, DC Hetnispbee Publiotions. In preu (12) MosnynuN JH, Szocr.t.Y JR. Ft.otuxr L Process and Instso- meau Corporation Automatic Smoke Exposure Machine- SF-%t II. In: Guein MR. Stokely JR. Higgins CE- eds. DOE report ORNL-5424. Oak Ridge National Laboratory. Spting- fidd. VA: Nad Techniol Information Service. U.S. Dept Comsoeree. 1979:19-33. tl6) JL~Km RA, WHrR SIC. GasssT WIi. et al. Cbemio.i dsaraaerisa. uon al the smokes of selected L'S. msomocial cigre(ses: Tar. nicotine, carbon monoude. oxides of nitroSen, hydrogen cyanide, and aesolein. DOE seport OR.YLlIN.8749. Osk Ridge National Laboratory. Springfield, VA: Yad TecMiol Issfort.ation Serviee. U.S. Dept Cotsaaae:. 19g3. (17) International Agency for Research on CanQt L,eng-tazm and shaet-asnss sonendsg assays for otoinogau: A aitid appraisal. IARC Motsogt 1960; suppl Z1-i26. Ut) Mrrpau. TJ. TuswstsLL BW. Lwsg-lintar models in the analy- sis of disease prevalence data from susviraVaeifice aperi. maws. Biosssevia 1979; 35:l21-Y2L t19) 3+Ltrrtt N. HAtnaiL W. Stasistiol aspects of the analysis of 1959, 2)=719-T4E.pective studies of diseu. J Nad CanoQ tnst 120) Wf.tst EL- Muu P. Nonparameeic estimadon from incom- pkm abset.ationt J Am Stat Assoe 1953, 53:457-4l1. '21) Dat.a[Y WE, Ns7TnNros P. GasWust R, a aL CSronic inhala. uoss of dgarette smoke by F344 sats JNCI :9dP. il38}-390. '22) Ptnt.io W. Experimental respiratory ardnoSmeis in stnall aniaaala Environ Res 1984; 33:144-188. (Z!) iamnatioml Agency for Reseuch on Cancer. Toban~o smokiny IARC Monogr E.al (Srdnog Risk Chem Hum. :n ptess (21') Do-ut W, CsaV.uia. HJ, HAass AP, et a1 Sadia on the effeets of chronic dgatetse smoke inbakscon in Syrian golden hatnssers and the imponanoe of ainmin A on morphobgiel alteations after smoke exposure. Z SteLstorsdt 1977; !9: 153-1go. (25) Do.vrztttatL W. Cfttrau[u HJ. FLttcz HP. ee aL 4wesdptioeu on the effeets of chronic dgamse-ssnoke inhaFaoon in Syran =oldn hamstes. J Nau Caocer Inst 1975; 51:I i8i-IBlL (26) B[sNaita P. Hoawultoae F, RL3«s n AB. Stsain difleseeas in the respanse of inbred Syrian hamssas to ai;arate smoke i++halatioa. J Natl Csnoa Inu 1974; 53:114:-I15'. (27) BLtLNazLD P, Hosrsuaa[s F. Soio E. et aL Cigarette smoke inhalation uudin in inbred Syrian golden vmsoerz JNCt 1979; 63d673-W. (2d) H.utets RJ. NuaoNt G. Produaion of lung arcnomas in C57BL mice esposed to a cigarette smoke and au miuure. Br Med J 1967: 4:637-b41. (2!) H.uass RJ, Nceaoto G. Luno:wrs S. ec aL The incdenceof lung «sttsas in C57BL mioneaposed to cigarette smoke Air mi:onta Eor prolonged paiods. Int J Caneer 1974:14::30.13E (V) Lo[n LA. Estrtm¢ VI., W.uc.~uc I:E, et aL Smoking and lung anaer An oeerview. Canar Ra 1994: 445940-5938. JNCI. VOL 77. NO. 1. JULY 1986 CTR CQNTRRCTS 025016

31 ~ ,~

'iHE, Coc`ctr. F on ToL.tcco Iac. RESEARCH IIvFOR•IATIO2T. R.nIIES•I NOVE'rlBz'R 22, 1977 Onening Cor-mments. Ftr. Addison 7ea.:.an Some Ne•.oer Central Nervous System Studies. Dr. Donald H. Ford Nicotine ana Related Substances and the Cantrz], tlervous S:•stem. Dr. Leo G. Abood, Professor of E_oche_:sstrr...and Brain Rese_rch, L'niversity of Rochester ::edical Cezte.. Rochester, New Yor}c. Aryl Hydrocar1;on Hydro::ylase: Status in ".an and i!osse. Dr. John if. Kreis:ler Ge neti.. Fac_.,_s i*.. .asconse to T'ic. .._..e. Dr. Sheldon C. So:rners Some Otier Cou.^.ci1-SuoDorted Researc_^.es of Interest. Dr. tdilliam U. Gard-.er - COP~Y

G f'~7 . i C _1-7 ~ &N . J J'A PROSPECTIVES FOR CTR IN RELATION TO CPIS STUDIES COpy Several investigators in recent years have been inter.ested.in the effects of smoking or nicotine on the CN5 (See review, Annals<of the New York Academy of Sciences, vol. 142, art. 1, 1967; Smoking Behaviour: Motives & Incentives, Ed W.C. Dunn, 1973; See Also Tobacco Supp1. ITI, Larson & Silvette, 1975). Regional localization of nicotine, effects of brainstem neurons, effects on arousal, EEG and evoked responses and behavioural responses were described, amongst other effects. Despite the considerable efforts of these investigators and others, the results remain preliminary. Basic questions concerning mechanisms of action in relationships between neurons, neurons and supporting cells as well as intracellular~functions remain unresolved. Ten years since the 1r,-67 conference, with.more information accumulated (See Tobacco, Suppl. III, Larson & Silvette, 1975), the situation remains much the same although it now seems evident_tha.t nicotine like narcotics, influences the CNS in multiple ways involving eft`ec.ts related to most of the knmn neurotransmitters. (Chemical mediators of neurone activity). Further, the dependence which develops to tobacco in humans (+ withdrawal symptoms during cessation of smoking) and the degree of tolerance to nicotine which occurs in certain animal•paradigms , strongly suggest that nicotine is an habituating agent. l~ ,~ G p 0 Z5 4 883 While numerous avenues exist whereby the eff ectsof smoking, nicotine (and rnetabalites or nicotine derivatives), nitrosamines, benzo(a) pyrene and C0 on the CNS may°be determined, the results could be diffuse if some attempt were not first made to define which particular areas of study might be most profitable. The following represents some degree of consolidation into five major research fields which might be approached simultaneously. Then, as progress is made on one or the other front, an emphasis might then be made in that field which seems

most likely to provide the answers on the basic mechanisms of action. However, while one may speak of limiting approaches to five major types of investigation, the technological methods available in each area are sufficiently diverse to produce an appearance of uncoordinated programing. Cppy Primary Catagories of Investigation 1. Receptors and sites of nicotine action: Identification and localization of nicotine receptors within the CPIS. Are they all cholinergic (associated with acetylcholine, a neurotransmitter), or is there a novel non-cholinergic nicotine receptor, as suggested by Abood? Are the receptors all at synapses (interneuronal:.junctions) or are there also "acceptor" molecules for nicotine in neurons or glia (supporting cells) which relate to non-connectivity functions? Arc <t'.1e synaptic receptors all post synaptic: What is the degree of ste_reospeciFicity of nicotine? Does nicotine receptor localization mimic that of opiate narcotics in the limbic syste3 (that part of brain associated with pain perception, pleasure and various emotional responses) and can specific receptors be identified whose role is associated with the dependency co,zponent of smoking? Are there effects on non-nicotinic receptors, modulating their activity. To what degree can nicotine act to modulate the effects of any of the neurotransmitte_Ts? Current technological advances in receptor chemistry should facilitate studies in this area. II. Basic Neurochemical Studies: 4C00254884 WWhile it might be of interest to consider pursuing all or several of ~ the various neurochemical lines of study (protein, carbohydrate, lipid, RI;A, DNA, ions, amines, etc.) available, it seems more profitable to cazcentrate on protein (as an end product already known to be influenced by nicotine) and then work backyrards to RrIA and DNA as progress is made. This is also because co7:sider- able advances have been made in the isola tion and characterization•of many brain

COP,~Y specific proteins. (5-100, 14-3-2, Tubulin, Synaptin, Neuractin + t•tyosin contractile proteins, Neurophysin, Glial acetic protein, etc.). Antisera to the S-100 and synaptic membrane proteins have produced difficulties in learning paridigr.xs in experimental animals; the 14-3-2 neuron specific protein has been shcran to consist of 3 isoz3znes of enolase, (a cellular respiratory enzyme) Tubulin (fresn fleurotubules) appears as an important structural protein as well as playing a significant role in axonal transport. This may relate specifically to transport from the cell body of a nicotine receptor protein to the synapse. Further, a protein has been isolated fran the neurons of the electric eel which migrates down the axon (prest.~.-~aably associated with the: rsicrotubules ). This protein has been demonstrated to have ir-nunoiogical identity with the nicotine acetylc:oline receptor of the electric organ. Considerable advances have also been made in defini:.g the properties of neuropa;; sin, the protein associated with the neural hormon_s, vasopressin and.;oxcytocin of the posterior pituitary which regulate blood pressure and sodiuz clearance. Another pair of neuronal proteins are neuractin and neuroxyosin. These t•ao contractile proteins have chemical properties similar to those of 'the actin and myosin of muscle, yet they are not completely identical. They,are believed to play a role in the release of 4 transmitter at the synapse. FinaL,;•, there are a n'L=ber of proteins associated with glia (glial acidic proteins) which are believed to be important in normal glial function and which increase markedly in amount in diseases involving glia. These could be important in normal nerve function in as much as glia are essential for neuronal viability. . 9~`i002J'r488J'r It:is oelieved by neurochemists that a major disruption of these proteins by any dr.ug°at the level of synthesis (RPU1 transcription, etc.) or degradation may have profound effects on CP:S function. A more mild disruption could lead to a variety of behavioural disorders or perhaps only to changes which could only be monitored objectively by neurochemical procedures. An initial phase in the

4,. synthetic-deo adative turnover pathway which might be altered by a drug ., (i.e. nicotine or its metabolites) is the mechanism of amino acid transport, either fron blood to brain or within the compartments within the CNS. (Currently being investigated by CTR grantce A. Lajtha). III. F.ffects on Development and Differentiations: Piumerous reports relate heavy smoking among pregnant women to premature birth of their offspring which tend to also be smalll for date. These observations raise serious o_uestions about the developwent of organ systems in the offspring, despite the fact that there have been many uncontrolled variables in these studies (Consumption of alcohol, environmental pol.lutants,"nutritional state of the mother) which make it difficult to interpret the resul.ts. Hudson et al demonstrated a dos e related response of nicotine on the grcr.•rz:r :(d epress ed ) of off spring of nicotine-treated pregnant rats. Further, ~icotine influenced the level of the electroshock tk-seshold (EST) in the offsp^incr. (It was first elevated and then depressed in relation to controls at a-;-dose level of 3.0 mg of nicotine/day throughout preg na:,c;; ). ::icotine and CO effects on the uterus have also been reported which may influence fetal,.,-rowth by irpairir.g the supply of nutrients. Further, studies by Matalka demor.::=rate a perceptual deficit in offspring of pregnant rats treated w'zah.nicotine throughout pregnancy. P1umerous morphological, bioche-nical and physiological studies might be planned on the basis of these observations of def ective perception, providing that adequate nutritional or st ress controls are established. Development of enz•,,•me systems could be exa.mined by both histo and neurocnemical procedures, levels of transnitters and their turnover could be evaluated, growth of neuronal and glial populations determined, nerve cell . gro:•rth and , synaptogenesis measured, etc. One might also determine i f there are dcla;{s in maturation (morphological or bioche.-aical) in which there is a°catching up". If so, to what degree does the distir.bance in the time table of maturation alter function. Finally, are there behavioural changes? ~C00254986 COPY

5. N. Ptueroendocrinology: If decra~:ents in developmer.t and differentiation occur, they may be associated with disorders of neuroendocrine function, which can themselves readily lead to behavioural problems. Such effects might be mediatcd by an altered degree of binding of various hormones to their specific receptors in neuronal nuclei, or as in the case of corticosterone, an interference with..hormone association with some protein factor in the cell body prior~to nuclear binding to a receptor. This could disruot the r.orzal activity of the hormone at the level of the nuclear material in the chro:aosczes. As is well knc:•m, the diffe-re::tiation of' various re-ions of the hypothalp-mus (part of tne brain controi, ing,pituithr3•, te_^:peratse, reproduction, feeding, etc.) is particularly sensitive to inapsrcpriately high or lo-,: levels of male sex_ hor::ones in both sexes: 'r:_;;:^_ levels r-asculinize females and low levels lead to feminization in males. T:.:,-roid deficiency inte.rferes with normal neuronal growth and delays di z^:`e_ Antiation. Adrenal cortical horr.:ones mai_^_tai_n ^cr^.,I rates of ne_^ ve cell di ; si on .r.t::i., gi : e n periods...diffi- , ciencies lead to shortening of the cell division perioc?, hormone in excess prolongs cell division. 2iorma7ly some sort of bal~zce seems to exist between thyroid and adrenal corticoids in regulating pe_-~iods of cell division vs. maturat;. Could smoking and the chem.ical.s associated ur_th smoking alter this balance or $ in any way alter the other delicate effects hormones have in the hypothalamus? O O Since nicotine is kzoym to stimulate vasopressin release (action at the N supraoptic nucleus) and depresses the preovulatory su_~ge of LH (influences L1 ovulation) in adults as well as the release of prolactin (associated c-:ith ~ milk formation) in suckled mothers, it does not seem unreasonable to e.tipect that there may be other effects caused by exposure of the hypothalamus to nicotine during the period of differentiation or cell division when the neurons are more sensitive to external influences. COP_y

6. V. Behaviour: Certainly the most difficult data to put into its proper perspective is that obtained from behavioural studies. This is perhaps due to co..unication di~ iculties between psychologists and the uninitiated or to an.inherent resistence to accepting bar pressing and maze data as relevent to "learning" and '4nenory" or "emotional behaviour" in prinates. On the other hand, acti.-ity studies, state dependent and discrininative stimulus studies in relation to certain drugs do appear to have some relevance if the drugs used are not toxic or do not in and of the-mselves produce effects (paralysis, seizures, etc.)'which would interfere with a behavioural study. Thus, many such studies, do provide useful clues as to what may happern in -nan with the same or similar dr~:.~.;s. The ability of drug A to preve*:t or facilitate a rat from di:c:iminatizg between saline and a very low dose of drug B (a narcotic) at doses<belo;r the threshold for pharmacological responses may be meaningful in ter^s of definir.o the response of the CI S to either A or B.. This is particularly true where both drugs are :cnotm -to have an effect in man. Lesion or elect*bde stimulating stu=ies in cor.junction with applications of agents which<influence transmitter release, re-uptake or degradation may further refine ttie results in relation to understanding the pharnacologic action of the drug. Ultimately, however, one must seek for answers at the molecular level. Tae:behaviour which one observes is only an expression of what occurs at synapses, or in the synthesis and degradation of transmitters, or in the levels of interactions between neurons. In human terms, one arrives at the following in relation to behaviou_r as associated with..saoking. (These are sel•~° evident and appear almost as a quote from Dunn): 1. Why do people start smoking initially? or curiosity? COPY Is it simply peer pressure ~000254888

7. 2. Why do people continue to smoke when there is so much evidence that it may be harmful to their health? Is the habituation that over.rhel:.ing? 3. To what degree do people become physiologically and (or) psychologically dependent on smoking and nicotine? What is the basis of in- dividual differences in this respect? Is genetics the sole and only answer? 4. Why does it appear more difficult for women to give up smo!cing than men? Is it simply because they are afraid of gaiitin; weight or are there more complex psycholooical issues which aa;r be dependent or reinforced by the cyclic endocrine status of females with fluctuations of estro~ens and progesterone (and metabolites) as co=4red to the more static endocrine status of males ? COpy

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