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THE SECOND REPORT TO THE AD HOC' ADVISORY COMMITTEE OF'THE HARUARD IJP!1 I VE RS I'IY TOBACCO' AND' HEALTH RESEARCH PROGRAM! December 15, 1'978' GarX L. Huber, M. D. Principal Investigator

TOBACCO ANDHEALTH RESEARCH PROGRAM AD HOC ADVISORY COMMITTEE Jere Mead,, M.D., Chairman. Clifford A,, Barger, M. D. Kurt J. Bloch, M.D. Joseph,D. Brain, S'c.,D., Kenneth C'. Hayes, M.D. 5dward H. Kass, M. D'. , Ph, D'., Lynne M. Reid,, M.D. . I

TABLE 0F' COINiTENTS I NTRODUCT ION Ad'visory Committee Charge ADMINISTRATIVE REPORT Program Developments History and Background Harvard University-Tobacco Ind!ustry Support Continued!Posiition of TobaccolIndustry Support Potential Termination ofthe Tobacco:and Health Research Program Harvard Medicaii Sehool~ Support Potential Solutions to Facilities Development Current Status of Relevant Decisions Program FaciSities - Present Research Facilities - Will!iam B. Castle Laboratory - Chariesgate Animal Inhalation Laboratory - Facilities andlProgram Management SCIENTIFIC REPORT The Research Programi - Personnel and Organization - Personnel Changes, Animal InhalationlProgram - Smoking Machines - Tobacco Smoke Chemistry and Physics - - - Pigeon Inhalation Bioassay Nicotine Analyses Smoke Particulate Delivery - Particle Size Measurements - - - Response to Advisory Committee Anticipated Research Speciali Problems Metabolism and Function: - Alveolar Macrophage Function - Metabolic and Enzymatic S'tudies C - Alveolar Macrophage Subpopulations Tobacco Investi ations - Other h'on j g - Ln - Catalase Activity and Alveolar Macrophages O - Response to Advisory Committee - Anticipated Research W' - Special Problems

Maerophage Morphology Alveolar Macrophage Structure Localization of Catalase inittie Alveolar Macrophage Tobacco Smoke and Catallasomes In situ Versus Lavage-Recovered Alveolar Macrophages Alveolar Macrophages Recovered at Different Lavaging,Temperatures Response to the Advisory Committee Anticipated Research Special Problems Airway Mprphology Airway Morphologic Studies Rodent Pulmonary Infections M'arij'uanaland Airway M'orphologic Studies TobaccoiSmoke and the:Larynx Response to the Advisory Committee Anticipated Research Special' Problems. Parenchymal Morphology - Tobacco Smoke andlEmphy:sema. - Response to the Advisory Committee - Anticipatedi Research - Special Problems Cardiovascular Effects of'Cigarette Smoke - Direct Effect of Tobacco Smoke on Cardiac Muscle - Experimental Atherogenesis - Infection inithe Pigeon Quarters - Research,on the Pathogenesis of Athexosclerosis - Cigarette Smoking and Cardiovascular Function:in Man~ Response to the Advisory Committee - Anticipated Research - Sp cial Problems Human Smoking Behavior - Physiologic Studies on Human Smokers - Nicotine Titration (Accommod'ation)' in - Response to the Advisory Committee - Anticipated Research - Special Problems. Biostatistics - Biostatisti!cians - Human Epid'emiologic Studies - Morphometric Modeling - Response to the Advisory Committee - AnticipatedlResearch - Special Problems Human Smokers

OTHER CONSIDERATIONS~ - Federal Support. - Budget Pro j ect iions and Expenditures - Publications Additional Perspectives

1. INTRODUCTION

2. TOBACCO AND HEALTH RESEARCH1 PROGRAM Advisory Committee Charge: The Principal Investigator and Associate Investigators in the Harvard University Tobacco and Health Research Program have requested'that an ad hoc Advisory Committee,, formed of University faculty members who are not directly associatediwith our research efforts or with the:Departments in which our research is conducted,, evaluate on aniongoing basis the research endeavors of the Program. The:charge of this Advisory Committee will' continue to be to appraise our past accomplishments, our current research activities, andd the direction of our anticipatedresearch, and on the basis of that assessment to make recommendations directly to the administration of Harvard Medicall School and to the participants of the Program in a manner that will help to improve the~overall contribution of their efforts. It is our understanding that the scope of the review will be confinedito the scientific and technical aspects of o~urresearch„ i~ncludi'ng an evaluation of research~facillities andiadminis- tration,, in accordance with the specific agreements and guiidelines signed betweeniH'arvard Medical School and'the sponsoring organizations. In the:context of those guid'elznes, the Principal Investigator and participating scientists of the Tobacco and Health Research Program continue openly to welcome and encourage criticism, suggestions and advice on program development and direetion., It is anticipated that written recommendations will be made directly to the Principal~ Investigator, as welll a~s to the associate investigators„ and to that part of the Harvard University administration directl~yrespons~iblefor the Program. I!tishoped that the Adv:isory Committee will review periodically:the response of'the research group to those recommendations., Our First Report on the Tobacco and Health Research Program was preparedion January 30, 1978'. The ad hoc Advisory Committee first met with the Investigators in the Program oniFebruary 1'.4, 1978 andl then again on March 13, 19:78 for an on- si'te review of'the research facilities. The First Report of the ad hoc Advisory Committee of the Harvard University Tobacco and Health Research Program was submitted oniApri1 6, 1978. This Communication represents the Second Report of the Investigators in the Program to the:Advisory Committee. We have three goals for this Report. First, we have attemptedito review the rather remarkable series of events andladmini:strative decisions that have occurred since our last meeting with the!Advisory Committee, as they pertain both to our research progress since that time and the current status of our research endeavors. Second, we have included the rel'evant materialls that have been compiled to reflect the development of a solution to the research, admin- © istrative, and facIlities needs of the Tobacco and Health Research Program. ~ Third, we again have reviewed specific research progress by individual areas of %P scientific discipline, and in so doing have.incllud'ed both a summary of progress t-11 made on the recommendations developed by the Advisory Committee and anioutline of' anticipated researchifor each section in the comi:ng months. We have al'so tri'ed to identify any special problems inherent to each scientific Section of ~ the Harvardl University Tobacco and Health Research Program. We aill especially look forward to the time when the efforts spent in future Reports to the Advisory Committee will emphasize the third of these stated goals, hopefull'y:at the nearr exclusion of the first two. That is not the calse,, however„ at this time.

The interim between the last meeting with the Advisory Committee and the present has been a character building experience for the investigators,, to say the least. In additionito the problems with laboratory and animali facilities and research supporting resources,, we have hadito live from, week-to-week, and then from month-to-month with indecision regazrding the future of'the Program. This has resulted in functionall impairment to the anticipated progression of academic careers during,what should be some of the most investigativelly creative and productive years of the research team. The effect of the present situation onithe personal lives of our staff has not beeniinsignificant. Adjustment to these stresses and uncertainties is within the realm of our human capacity for adaptation, and we as investi- gators have been able to grow in many ways with some of these experiences. The loss of the most important commod'ity we have, time, is much more d'i'ffi~;cul'tt to reconcile, however., Considerable energies have been expended in an"attempt to find an acceptable solution'for the Harvar&University Tobacco and Health Research, Programi. The report by the Advisory Committee to the Program has been crucially important and hellpful in the search for these solutions. The administration of Harvard Medical School and the investigators in the Program have tried to be responsive to the:guidance given1by the Advisory Committee. We hope that continued assistance in this direction will be provided and that the Committee wi1l be cogpisant of the response of the Program to its input. Our presentation of this Report to the Aduisory Committee is somewhat arbitrarily divided into~twomajor sections: an ADMINISTRATIVE REPORT and a! SCIENTIFIiC REPORT. Some thought and discussion were given to condensingg the administrative section~„ or to including the detailed information contained'; thereinias an appendage. Inithat the facilities and administrationio£ any investigative program reflect its research potentiali, however,, and in that the-conditions under which we have had to conduct our research effort over the past year or more are not acceptable by any reasonable considerations,, we have concl~uded that it is imp'ortant to identifyr and review again compre- hensively our facilities and administrative need&. It has taken much longer than anyone could have imagined to develop options for continuation of'this Program. The potential solutions now identified, although far fromiideali„ are acceptable. It is our hope that the Advisory Committee will review the proposed solutions for providing, adequate facilities to the Tobacco and Health Research Program with,the same priority given to our research activities. All parties concerned will welcome the!input of the Advisory Committee members in reaching final recommendations to the granting,agencies.

4. C , ADMINISTRATIVE REPORT ~

5. C , P'ROGRAINi' DEVELOPMENTS History and Background:Th~ehi'story and'.background of the:Harvard,Uni~versity Tobacco andiHlealth Research Program were reviewed at length in the First Report to the Advisory Committee., In summary, the:Program is supported'by a consortium~ of'cigarette manufacturing companies and tobacco growers and warehousemen, and by indzvidual research grants and contracts from the Federal government., At present, with all awarded funding implemented',, approximately 65% of the program support is derivedifromindustrial sources andi 35a' from the National' Institutes of' Health.If all of' our currently-approved grant and contract requests to~ the Federa~l government could be implemented, the Program would'be supportedapproxi- mately equally by NIH and1by tobacco industry sources., Harvard'U'niversity-Tobacco Industry Agreements: The initial and the renewal agreements between the tobacco industry and HarvardlUniversity, as well a~s all related important correspondence„ were submitted to the Advisory Committee~ as supplemental material to the First Report. It is a requirement of those agreements that the Principal Investigator must provide the grantors with a yearly report affirming that the agreements are being honored. Over the past year,; we could not provide the grantors with those assurances, especially in regardlto the entry in the Extension Agreement, implemented'lon July:1, 1977, requiring the provision or arrangement by Harvard Medical School for adequate housing,,services, and the like:for the Program., On that basis, as well as on the basis of other problems identified in the First Report to the Advisory Committee, the tobacco industry grantors withheld the semi-annual installment,, in the amount of $311,A'07',, due Harvard University onJanuary 1, 1978, as well as the semi-annual installment, in the amount of $'322,,075, due on July 1', 1978. Thus,, the Program is currently approximately $'600,,000 in deficit spending, which has been borne in total by HarvardlMedical School. Because of these events, as well as the yet undetermined future of our Program, we have in addition not been able to accept or implement significant new research support competitively awardedlto our Program by the National Cancerr Institute. Continued Position of Tobacco ZndustrySu.port: We have beeniin regular communication1with our liaison to and the representatives of the tobaccoo companies,, and they have consistently expressed their desire to continue support for our research~program if acceptable facilities can be developed in which,to house and to implement a scientifically objective research programirelatiye to smoking,and health with,the goal' of providing major contributions toward the solutionlof'some of the questions regarding cigarette smoking., A smalli com- mittee:of industry-representatives was formed to evaluate the situation of the Program at Harvard Uni:versity:. This committee consi'sted of Mr. Hi.C. Roemer, Vice-President and GeneraL Counsel of R.J. Reynolds Industries, Inc., Arthur J. Stevens,, V'ice-President and General Counsel of' Loril'.lard, a Di:visi'on of Loews Theatres,„ Inc.,, William W. Shinn andiLeeE., Stanford, both, of' Sho~ok„ Hardy and Bacon, the law office in Kansas Ci'ty that has served to consolidate~and com- municate the tobacco industtry"s interests in the Harvard University Tobacco and Health Research,Progr=., 0301s05,e0 Following our request of'December 25, 1977, to the tobacco industry grantors to provid'e supplementary suupport to improve our animal inhalation facilities, which in our judgement are not of acceptable quality to perform the research, for which weweTefunded, the industry committeescheduled' a visit to Boston on~