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:1 .l~ M9 i 4. I <<4 z 9 I • .t aLVuw: a .; t .! i . t' 1956 RREPORT of thc SCI ENTI hIC DI RECTOR CLAHFN(:E COOK LITTLE, Sc.D. C6.irm.n, ScitntiGc Advisory Board '1'(/itA(:C(1 INI)IIS'1'liY III:~I.AII(:11 (:Ot11t111'1°I'1:1: ()(162'73

I REPORT 011146 SCIENTIFIC DIRECTOR CLARENCE COOK LITI'LE, Sc.D. Ch.irnun, Scieoti6e Advisory F1o.rJ 1956 TnItACCO INI)l)STHY ItESH;ARCII Cl)MMI'I"fPa: 150 I:ntit 42nJ Street, New York 17, N. Y. O(1E;2'74

SCIENTIFIC ADVISORY It()Altt,. to the Tobacco Industry Research Commitlec CLARI:NCE COOK I.1'I"TL[?, Sc.D., LL.D.. Lrrr.D. Chairman, Scientific Advisory Board Scientific Direcror, Tobacco Industry Research ('ummiltec President, Roscoe 11. Jackson Memorial Laboratory 1lar Harbor, Maine McKEIiN CA'I"I'I?LL, Pu.D., M.D. Professor of 1'harmacology Cornell University Medical College New York, N. Y. JULIUS I-1. COMROF,IR., M.D. Chairman and ProJessor, 1)epartmtnt of 1'hysiology and Pharmacoloby University of Pennsylvania Graduate School of Medicine Philadelphia, Pennsylvania LEON O. JACOHSON, M.[). Professor of Afediilnr, lJniveraity of ('hicago 1Nrector, Argonne Canccr Research I lospilal Chicago, Illinois PAUL KOTIN, M.D. Associate Professor of 1'athology University of Southern California School of Medicine Los Angeles, California K[:NNETH MERRILL LYNCH, M.D., Sc.[)., LL.D. President, Dean of Faculty and Professor of 1'atholugy Medical College of South Carolina Charkston, South Carolina STANLEY P. RFIMANN, M.D., Sc.D. Scientific Dlrccror, Institute for Cancer Research Director. Lankenau 1[ospital Research Institute Philadelphia, Pennsylvania WII.LIAM F. RII?NIIOFF, Jra., M.D. Associate Professor of Surgery Johns Hopkins University School of Medicine [3altimore, Maryland [?I)WIN 13. WII.SON, PiO). 1'roftssor F.rrntrihts of Vital Starisrirs Ilarvard University ('amhridge, M:+ssachusclts -o- ROItFR [' ('. IIO('K1:'1'1', 1'hl 1). Asnwiatr SritnrifiC 1)ir[ctor • 'l~~lfll.~~

'I'lic Research Progr<<tn Two years ago, the Scientific Advisory Board to the Tobacco Indus- try Research Committee was formally organized and undertook to create a program of research that would contribute coostructivcly to our search for answers to fundamental health problems. Specifically, the program was to develop facts relative to the effects of tobacco use. Today, well over $1,200,000 in T.I.R.C. funds have already been granted to more than 55 scientists who, with their colleagues, are participat- ing in a carefully-planned, well-integrated scientific endeavor to help in the solving of important health questions. The Committee has appropriated $1,5(J0,000 for such grants and has pledged more funds as needed. The program is still developing and growing. This report discusses the Scientific Advisory Board's approach to its assignment and the current status of the research program. At the outset, the Board recognized that scientific knowledge concern- ing health aspects of tobacco use was uncertain and spotty. Tobacco use, particularly cigarette amoking, has become widespread throughout the world, especially in the more highly developed countries. Recently, there have been charges that smoking is associated with certain human ailments, among them cancer of the lung. The Board did not set out to prove or disprove anythiog. Its position was and is in agreement with the vast majority of experimental scientists who concur tn the view that our knowledge of the formidable challengers of human turvival-such as cancer and heart disease-is far from conclusive or complete. The sole purpose, therefore, was to encourage and support quali- fied research ecientists in their efforts to learn more about these complex problems, meanwhile refraining from premature judgments. 'Ihis approach has proved sound and correct. The need for further study is, i( anything, more compelling than it was two years ago. We have learned much in the past two years, but perhaps the most important thing we have learned is how much more must be done before dcGnitive answers can be given. PROGRESS l+tAUB IN MAJOR ARI.AS At this staFe, therefore, the accomplishments (rf the research program suppexled by Ihc 'frrhaccn Indusary Itesearch ('umrrmiUce nnrst hc mcasured in terms of pre,gress, rathcr than in conclusivc finrlings. 5 0(lEi27fi

}laving ;iven a cornpletciy frce hand to consider the whole field of the use ol .. __.co in relation to health, the Board assumed the followpig responsibilities: (a) blocking out major subdivisions of this field which can and should be covered by scientific research; (b) considering personnel and facilities available, or capable of development, to meet research necds in these subdivisions; (c) recommending to the Tobacco Industry Rcsearch Committee the amount of financial support needed for each type of effort, and the personnel and institutions which should receive it; and (d) review- ing the progress of work thus supported to make it as effective as possible and to follow up new leads and problems arising from these efforts. Among the more significant accomplishments that have come out of these efforts are: 1. The development of a program de6ning the range of research perti- nent to our major interests, thus making possible the most efficient and effective use of research funds. This has helped to prevent a duplication of efiort, has made possible supplementation of existing work, and has enabled us to give proper emphasis to fundamental and practical projects. The out- line of this program will be discussed more fully In the body of this report. 2. The initiation and support of individual research projects carried out by independent, qualified scientists in some of the nation's outstanding research and educational institutions. While these are separate and inde- pendent investigations, each fits into the coordinated program of objcctives developed by the Scientific Advisory Board. 3. In the three fields of study discussed below, initiation of coopera- tive endeavors among scientists working on the same or similar problems in order to coordinate their cQorts and compare procedures. This approach has proven extremely valuable in eliminating unnecessary duplication and in creating a large degree of unity and comparability in the work of the individual investigators. The three areas of interest covered were: a. /luman Lung Tissue Study. Pathologists from various parts of the country have met several times under the sponsorship of the Scientific Advisory Board to develop and coordinate clinical studies of human lungs to learn more of the factors involved in lung ailments. b. lleart and Clrcufatlon. Specialists in cardiovascular and coro- nary research were brought together to explore what is known and not known about relationships of tobacco use, particularly of nicotine intake, to vascular and cardiac functions. c. Tissue (:rrlrure Research. Leading investigators in the field of tissue culture confured under the ausfrices of the Scientific Arl- viwry lfrraril to rlctcrmine the best ways of speeding rucarch into the cultivation and maintenance of lung tissue ,nli<r vascular tissue under conditions that would allow better observa- tion and control than is now possible. 4. Development of acceptable standards for governing work with tobacco derivatives to meet a challenging need among investigators. The problem was that many experiments with tobacco smoke constituents had been or were being conducted under conditions bearing little, it any, relation to human use of tobacco. A defined range of methods and conditions was needed to give a greater degree of pertinency of the experiments to Ure experience of human smoking. Substantial progress has been made in: a. Preparation of standard tobacco derivatives for laboratory use. b. Definition of standard operating conditions for smoking ma- chioes, including control of temperature ranges in subjecting material to combustion. c. Further development and production of genetically controlled laboratory animals, particularly mice, with known character- istics, to be used in tobacco experiments. 5. Inauguration of a modest program of research fellowships fur medi- cal students. Encouragement of basic medical research is considered a fundamental contribution to the efforts to learn more about how to attack the constitutional diseases. Despite its necessary limitations, this program has brought extremely gratifying response from the participating medical colleges and the recipients of the feUowships. ACTIVE PROJECTS It is, and will continue to be, the established policy of the Scientific Advisory Board to permit each investigator to publish his findings inde- pendently when he feels he is ready to report on his work. Although the great majority of grant recipients are still engaged in their research, a few are at the stage of making public reports of progress to scientific groups or in scientific publications. Although grants are made on a one-year basis, many have been renewed. In the field of scientific endeavor, it is often impossible to put definite time limitations on the period of study necessary for substantial accomplishment. True scientists are naturally cautious. 71uy are aware of the grcat and obvious danger for the lay public and for thrrse in the fields of science and medicine th:rt may result from premature and conjectural opiniuns. Invcstigators working under '1'.1.R.C. grants and the areas of stmly undertaken are ahnwn in the following listing of grants now in force. Fur convenicnce, thc list is alphabetical by thc investigator's name, 7 6

CItANTE:E INSTITl1T1ON I). MURRAY ANGEVINE, M.D.. Pro- lessor of 1'nlholoyy. Universily of Wis- eonslo Medical School. Madison. Wisconsin FREDERICK W. BARNFS, 1.., M.D.. Pu D., ./ s,oclorr Professor of Mrdi- clne and 1'hy,lolotlcal Chemhrry,lohns Hopkins lJniversity School of Medicine. Baltimore 5. Maryland RICIIARD 1. RINn, M.D., Pro)essor o/ Eiprrlrnrnad Alediclne nrrd Clinlc /a Physiolocy. The Medical Colleto of Alabama. Rirmingham 3. Alabama (Now at Washin ton University School of Medicine, St. IFouis, Mlssourl) JAMES F. BONNER. Pit D., Professor of Biology. California Institute of Tech- nology, Pasadena, California IOSEF M. RRO7F1:, Prt f)., A,>oclare Professor o/ Phy,lologirnl Ilytlrne, Latx>ratory of Physiological FlyRIcncy llnivcrsity of Minnesota Sch(wd o( 1'ub- lic licalth, Aflnneapolls 1,, Minnesota N. M. n(T(T, M.1).. Pro/rrror of Parhof- oty. Univershy of Southern California School of Medicine; Ch/rJ Patholorisr, Los Angeles County Hmpital, Los An- geles J ), California WILLIAM If. CARNES. M.D.. Professor of Pathology, Stanford University School of Medicine. Sao Fraoclsco, California LEOPOLD CERECEDO. Prr D., ProJei- ror o/ Biochemistry. Fordbam Unlver- slty, New York 58, N. Y. HANS T. CLARKE, D.Sc., Professor of Biochemistry. Columbia University Collc`e of Physicl.ns and Surgcoos, New York, N. Y. PHII.IP COOPER. M.D, A,roclate Pro- /r„or of Clinical Surgery. Boston l)ni- verslty School of Medicine, Boston 18. Massachusetts; Chief. Surgical Service and D/rrctor, Surgical Research 1.a6- orarory, Veterans Administration Lios- pital, Providence 8. Rhode Island IUNS L. F-ALK, Prt I) , Arrhtanr ProJrr- tor of Hlrrchrrni>rry, University of Southern C.lifornia Schnol of Medl- einc, I In Angeles )1, ('ullfornla RI)SG l I. L.. 1101 MAN, M 1), Pro/r,rnr and Ilrad . ) I)rp.rrlorrnr o) l'uthululy, 1 nuisiana Statc l/nivrr.ily Sih<r>I nf Mcdicine, Ncw (hlc:rns 12.1 ouisiana F'ILOJECi' TIT7E Pathologle-Anatomle Study of Cellular Changes io Human BroocAl The Role of Ilyperplasla lo Tissue Re- apoose to Chronic Damage Tfie Effect of Smoking on the Cosooary Blood Flow and Cerlaio Phases of Myo- eardial Metabolism in Patients Wilh Arteriosclerotic or Hypertensive Cardlo- vaseular Disease Entymatk Study of Methylatlon Reae- lions In Plant Tiisue A Quantitative Study of Biological Char- acterlstlca of Mao Associated with Dif- fereoces In f 11. Tendency to Adopt and Maintain DlBcrcol Smoking Ilab,ta Study of Trace Metal Storage of Pulmoo- ary and Liver TI>sue by Spcctograpbk and Chemical Melhods Patbologie-Anatomie Study of Cellular Changes In Humao Bronchi Pathologic - Anatomic Studr of Cellular Chaoges In Iluman Broacbi A Study of Parly Chemical Chaoga In the Lungs of Tumor-Bearing Rats and Mke Proteolytk Activities of the White Blood Cells of Man and the Effect on Wbite Blood Cell Activities of Carcinogens. Nutrition and Other loflueoces A Study of the L?ficcls of Cigarette Smok- Ing on l.evcls of Gastric Acid, Pepsin and Uropepsin f:xaminaHnn of ('i`arette 1'apcr and Clga- rctte Smote Condensates for Aromatic 1'olycyclic Ilyd(ocarlxrom Palhologlc - Anatomlc Slwly of Cellular ('hanges in Iluman Itnmchl 8 PRANK C. PL?ROUSON, 1.., M.D.. Chairman of Department of Pharma- cofoiy, Albany Medical College. Al- bany a, New York RUSSEI.L S. FISI IER, M.D., Ch/eJ Medl- cat Examiner. State of Maryland; Pro- fessor of Legal Medicine. University of Maryland Medical Scboo:, Baltimore. Maryland B. L_ FREEDL.ANDER, M.D.. Dbector of Cancer Research. Mt. Zion Hospital, San Francisco 15. California JACK FREUND. M.D., Lecturer In Phar- mocolo`y, Assl,rant In Mrdlcine, Medi- cal College of Virglnia. Rkhmood 19, Vlrginla A. CLARK ORIPFIN, Pu.D., llead oJ Biochemistry Deportment. M.D. Aoder- aon Hospital and Tumor Inslilule, Unl- versily of Tesas Medical Ceater, Moua- too 23. Tesaa CARL C. ORUHZIT, PN.D.. M.D., Ar- aoclate fn Physiology and Pharmacofoty. University of Pennsylvania Graduate School of Mcdiciae. Philadelphia 4. Pennsylvania If. B. HAAd, M.D., Professor of Pharmo- cofoty, Medical Col ege of Vlrgiola. Richmond 19. Virglnla IOSEPH H. ffAFKENSCIIIEL, M.D.. Director of Cardlopulmonarr Unlf, Lankenau Hospital, Philadclp6la 71, Pennsylvania NERBERT R. IIAWTffORNP„ M.D.. Chairman of Urpartmrnt of Surgery. University of Pennsylvania Graduate School of Medicine. Philadelphia I, Pennsylvania CLARK W. l(1'.ATI1, M,D.. Phyrlclan, 1)epartmenr of llytlene, Ilarvard Ilni- verslly, Cambridgc )ft, Mauachuselts (Now directed by 1)ana 1.. harnswortb, M.D., l/rnry K. (>l(ver Pro)rrsor o/ lfyllrne and (>lrrctor of Unlvenlty flealrh Servlcrr) L•Recls of Tobacco Srn m thc Func- tion of the Cardiov_ r System in Animals and Mao Pathologic - Anatomic Study of Cellular Changes in Iluman Ilroachl The Effect of Tobacco Fseracts on Ihe Careinogenic F.ilcct of Mc:itiylchulao- threne and of Ultra-Viulet i.ish(; !be Effect of Tobaceo Extracts oa Car~' - genic Effect of Urethane-:-iduced Pul- monary Adenomas in Streir. A Mice; Ihe Use of Various Sulpaycry:. Cunr pounds as Neulralirin or Counleract- in~ Agcnls for the Poss~ble Carcinogenic Effeel of Tobacco Extracts in Mice Correlation of Multileehnical Procedures Pcrfurmed on the Peripheral Circula- tion of Normal Individuals In Recurn- benl and Erect Positions and Afler Ea- ercise Before and Afler Sbans and Actual Smoking The Effect of Eaposure toCigarette Srnolo on the Induction of Cancer by Chc,nlcal Compouods Pharmacologic Study of Nicotine and Re- lated Alkaloids Preparation for Publication of a Book on the Biologic Aspects of Tobacco aod /ts Smoke Measuremenl of Coronary Blood Flow, Cardinc Work and Cardrac Oxygen and Carbohydrsdc Metabolism in Normo- lensive Subjects Before and After Intra- venous Nicotine and After Smoking Standard Cigarettes Attemras to Induce Pulmonary Neoplasms In Laperimcntal Aninwls by I:aposu,e of Ihc T'rachco-Itronchial Syste,n to To- bacco Smoke Personality and Srnnking In College (7rad- uales: A Filtecn Year Fulluw-ltp Study 9 ,0()62'7(3

r. 11011,1111111 M.1), Research Pra /ruor of A. .r and Dlreetor, Can- cer Research and Cancer Control f/nlt, Tufts University School of Medicine, New Pogland Medical Center. Boston 11, Mauachusctls; Scientific A»ociart, Roscoe B. Jackson Memorial l.abora- tory, Bar Ilartx+r, Maine JFRRY IIART JACOBSON. M.D., D/- rector o/ Electuophysloloty. New York E?ye aed Par Inflrmary, New York 3. N. Y. ANCEL KEYS. PH D., Pro/rssor of Phys- lofo=Ical Ilyt/enr and Director, L.abor.- tory of Physiological Hytlrnr, l)nivenity of Mionesota School of Pub- Ik Healtb, MIooeapolis 14, Minnesota A Study of the 111ects of Cltarctte Tars Upon the Bchavior of Transplantable Tumors in Rodcnta Enploying a New Technique o( IntrauterineTumorTrans- plantatioe A Comparison of P.kctrorctinogr.phy as a Mean. of Evaluating the Effect of Vasoeooatriclor Drugs l)pon Cerebral and Retieal Circulation With Other TechoiQues for This Determination Characteri.tin of Men, Includint Sinok- lo~. ia PopuIatlons DiQerlog In the In- eideoee of Coronary Eleart Dlseue 11110111 MONfGOMPRY, M.D., Asrocl- atr ProJrssor of Mrdirinr, University of Pennsylvania Medical School, Philadel- phia l, Peoosylvaola OF?OROE E. MOORE, Prt.D., M.D.. DI- rrctor, Roawell Park Memorial Instltule, Buffalo l, New York NURLEY I.P.P. MOTI.CY, M.D., Pro/rs- sor of Medicine and Dlrector, Cardlo- Resp(ratory (aboratory, University of Southern California School of Medkioe, Loe Angeles 17, California Wll.l-IAM S. MURRAY, Sc.D., Research Associate and Adminlstrotion Dirrctor, Roscoe B. Jacksoo Memorial Labora- tory Bar ffarbor Malne IOSPPII B. KIRSNP.R, M.D., Pro/rssor TTe Effect of Tobacco Smoking Upon , , of Mrd/clne. University of Chicago Basal Oarlrie Secretlons In Man School of Medicine, Chlcato, Illlnoir KF.NNfTEII P. KNI1(YfSON. M D, Ar- Patholoilk-Ana(omk Study of Ccltular sbtant Chief. l.abnratory Servlcr. Vet- Changes In Human Bronchl crans Adminlstratlon flospital, Seattle. Washington: Profrsror of Pathofotry, It. R. PRATTTIIOMAS, M.D., Professor llnlversily of Wasblotton Medical i of Patholoty, Medical Colkge of South School. Sealtle, Washlngton Carolina, Cbarlestoa, South Carolina MARVIN Kl1SCFINPR, M D, ProJruor of PatholoRy, New York E/nlver.hy College of Medlclne; Dlrertor of Pa- tholoty, Bcltcvue Hospllal, New York 16, N. Y. Palholodc-Aoatomk Study of Cellular Ch.nges In Humao Bronchi VICTOR RICIfARDS, M.D., Professor of Surtery, Executive !lrad, Department of Surtrry, Stanford Univenity School of Mediclae, San Francisco IS, Cali- forni THOMAS C. LAIPPI.Y, M D, Asrocfarr Pro/rsror of Pathrifoty. N.rthwestern University Medical School, Chlcato, Illiools PAElI. S. LARSON, Pw.D., Profrs.ror of Pharmacoloty, Medical College of Vlr- ginla. Richmond 19, Vsrginla CPCILIP. LEl1CIfTP.NBPROPR, PttD., Asroclatr Profrssor of Cytoloty, West- ern Reserve Unlveraltr School of Medl- cine, Clevelnnd 6. Ohlo KF.I LY r. McKEI?, M 1), Associate Pro- frssor of Mrdlrlne, Medical College of South Carolina. Charles,nn, South Car- ollna DAVID IL MANN, la„ Pro I) , Asuutatr Prn/ruor o/ Pharmar.+loty. Tem le linlvcnity Sch r+l of Pharn.acy. PhFla- dclphla 40, Pennsylvaola PatholoQlc-Anatomlc Study of Cellular Chanka In Human Bronchi Entymatlc Transformalions of Nicotine Quaotitallve Analysis of Nucleoprolelns in Tlssuee From Animals Subjected to Tobacco Smoke by Microspectropholo- mNry and Inlerference Microaeopy Cor- rclNed with Cytological and Elistoloill- cal Studies Sludy of l.untt Puoctlon In Smokcn and Non Srnoken ERect of Tobacco Smoke and Tobacco Rcsidues on Melhylchulanthrcne- Induced Skin (-arcinogentrli In Mlco 10 R. 1t. RIODON, M.D., Professor of Pa- rholoty and Dfrector. Laboratory of Experimental Rrsearch, Uolversll7 of Teaas Medical Branch, Oalveston,l csas WILLIAM O. RUSSP1.l., M.D., Parhoto- tlss-In-chlel, M.D. Anderson Hospital aod Tumor Institule, University of Te:aa Medical Ccnter, Ilous/oo 23, Texas PA111. 1). SAI.TMAN, Prt D., Asslstant Professor of Rlochembtry. Uolversily of Southern Califnrnia School of Medl- cine, Loe Angeles 7, California ISAAC SCIIOIIR. D 1) S., Pro 1)., D Sc., Professor of Iltstoluty, and fimbryoloty and Dran, llnlvcrsilr of Illinois ('oI- lege of Dentislry. Chicago 12, Illinois Influence of Tohac+ Aing oo the Blood Flow of Skin ~.. of Museles of latremities (n Sympathcctomized and Unsympalbectomized Subjects An Investigation of the Physlological Ef- fecls of Direct Inhalation of Tobacco Smoke by l.aboratory Animals and the Study of the Biological Response of l.ab- oratory Aolmals to Continuous InSes- tion of Diel-Tobaeeo Product Mixtures A Study of the P_ffects of SmokIng on PuI- monary Function The Production of Genetically Controlled Animals and Tumors for Use io Papert- meatal Research on Tobacco In Rela- tioa to Healt6 by (a the Eapansion of Known Inbred Stoe~s and Sources of Tumor Sup ly; (b) the Production of Sucb I(ybriSs or IlelerozyRous Types as Become Neeeuary ; and (c) the Rela- tloo of this Materid to Specif/e Eapcri- mental Work at the Laboralory Application of a New Bio-AuayTechnlque In Examination of Cigarette Smoke Coedensales for Possible Cardnotens Pathologic-Aoatomk Study of Cellular Changes in Human Bronchi A Comparative Study of lhe PRects of Whole and Fractionated Pstracts of Cigarette Smoke and Those of Known Carcinogens on (1) The Cyloloty and Nuclear DNA Content of I.plde- ;, ro Various Strains of Mlce nd/or (2) The Cytology and Nuclear DNA Con- lent of l.ung and EpIthellum of the Bronchial Tree of Mke and Hamsters Study of the Effect of Methylcholanlhrene on the Tissues of the Duck with I'm- C sis on the Reaction In Ihe Trachea en Compared With the Skin of the Body and the Web of the f'ool Pathologic-Anatomic Study of Cellular Changes Io Iluman Bronchi The Pnzymallc Mechanlsm for the Ihrk Fiulion of CO- by'1'ubacco IIIsloloRic i'han~tes In the Onl, Pharyn acal aod Nual l'Irsucr of 1'.pcrlmtnt.l Animals SubJected lo'fohacco Snwke I I „]nn r,'~- 1 Ofl llf)?-1n

MAURICP 1I., M I)., Clinical Pro/cssor o, ..r....rlnc, Tufts University School of Medicine, Itostoa, Massacbu- aettt; U/rector, !)epartrnrnt o( )nhala- tlon Therapy. Boston City Ilospital, Bostoo. Massachuscltb CIIARI.FS F. SIIERW(X)I), M.D., Aa- rlttanr Professor oJ Radioi'o` y, Unlver- sity of Rochester School of Medicioe and Dentistry, Rochester, New York DAVID L SIMON. Instructor In Alediclne and Fellow In Cardlovascufar Refearch, University of Cincinnati Col- lege of Medicine and Cardiac Labor.- toty, Cincinnati General tlospltal, Cinclnnatl 29, Ohio SAM SOROP. Per.D., Research Arsaelat., The Institute for Cancer Research and Lankcnau llospiul Research Institute. Philadelphla 11, Pennsylvaala PREf)ERICK 1. STARP. PnD., ProJci- ror oJ Nunlrlon, Itarvard School of Public Ifeallh, Boston 15, Massacbu- actts MARION B. SUI78PRC)ER, M.D., Pro- fessor and Chabman. Drpartment of Dtrmarolopy and Syphilology. New York University Post-(iraduate Medical School; Director. New Yor4 S1/n and Cancer Unir, New York Univenity- Bellevue Medical Center, New York 16. New York CAROI 1NP BP.I)FLt. TIIOMAS, M.D.. Associate Pro/efror of Afrd/cine, lohns HopUnm [)niversity School of Medlclne. Baltimore 5. Maryland IANET TRAVPLt., M f) , Associate Pro- lusor o/ Chnlcal Phormacoloty, Cor- nell Ilnlverslty Medical College. New York 21. New York F.. I). WARNiiR. M I)., Professor of Pa- tholory. State [)niverslty of Iowa C.ol- Icte of Medicine. Iowa City, lowa RICftARI) I.. WI•CIItiI 1'R, M 1),('f/n/- tal 1'AycloLrrlrr, Mitntcfl"rc Ilotpltal Insllhrte of Rcurth, 1'itt.hurth 1). Pennrylvaola t!ftecls of Cigarette Smoking on I unit Function in Normal Subjects and Pa- tienta With Certain Respiratory [)isease Conditions lavestl4atlon Into the Natural Ilistory of Carcmoma of the Lung With Particular Reference to the Radiographic Appear- aoce of Such Proceucs, the Parlicst Manifestation of Cancer on Chest X- Ray Photographs and the Tabulation of the Relationship of Smoklng IlaJits aad Occupation With the Incidence of Lung Cancer Tbe Effects of Chewrng Tobacco on the Cardiovascular System of Mao Chemkal and Physical Studles of the Tis- sue Proteins Involved In Chcndul ('ar- canottenaia Eaperimental Sludlea of Cancer Utllirlng a New Technique to See it Various Tan Extracted From Tobacco May Incite the Formation of Lung Tumors lnvestlsatlon of the EQects of Tobacco on the [fuman Vascular System In Living Voluntcen; and in Particular of the Possibility that Certain Tobaeeo Efleeta are Based on Peculiar Allergic Susceptl- bllily of Specific Individuals Ralher Thao Upon Obll{atorily'Coslc Prodxts In Tobacco Smoto The SiAnificance of Different Individual Patterns of Circulatory Response to Cigarette Smoking F.lectroeardlographle Pffects of Nicotine in the Rabbit with Fsperlmcotal Coro- nary Atherosclerosis Pnthologlc-Analornic Study of ('cllular Changes In Iltunan BrontlJ 1!11ect uf Citlarclle SmaklnR on ('crehral lllood Flow, ('crebra) Mctabnllsru, BIunJ Oascs, Itb-kl pll, Ar,cri.l I'ulsc 1'rrssuro Curvcs, l•Icclrucardin`ranu, anJ Elcclrocecephalojrams 12 1 I RUSSEI.1. W. WI'1.1.1!R, M.D., Parhola- tiit, Memorial Ilospital, West Chesler, Pennsylvania; Pathologist. Communlty Itospital, Ephrata. Pennsylvania; Atao- clate Pro/ersor of Patholofy, Ifahne- mann Medical College. Philadelphia 2. Pennsylvania , SIMON It. WFNDER, Ptr.r)., Research Professor of Chrmistry, University of Oklahoma Research Institute, Norman, Oklahoma 1. EDWIN WOOD, M.D., lrorructor In Mcdlclne, Boston University School of Medicine and Robert Dawson Evans Memorial Department of Cliniul Re- search and Preventive Medicine, Massa- ehusetts Memorial llospitals, Boatoo tit, Maaachuaetta Palholugic-An:dumlc of l'cllular Changes In Iturnan ttr.,..,hi A Qualitative and Quantitative Study of the Individual 1'olypbenol Content of CiCarette Tubacco and of the Snwkc and 'Tari Resulting trom Cigarette SnsokinC, and Also Study of Ihe Fate of Thcse Compounds in Ihc Animal Respiratory System The Etfect of Prolonged Inhalation of To- bacco Smoke and of Prolonged Abstin- ence frorn the Use of Tobacco on the Peripherat Vascular Response to Acute Inhalation of Tobacco Smoke in Man PRINCIPLES ANl) CONUITIONS OF OPERATION Before discussing In detail the research program, it will first be wise to outline briefly the conditions under which the Scientific Advisory Board operates.'Iltese involve the following three relationships: I 1. Relation to the Tobacco /nduatry Reaearch Committee. When the Scientific Advisory 13oard was organized and its participants accepted membership, it was clearly stated by the Tobacco Industry Research Com- mittee that lfte Board would have complete freedom in all of its activities. Tlte Committee must, of course, determine the total amount of funds which will be made available for research activities. The Board, however, was not 1o be restricted or In any way influeneed In preparing or making its reconunenda- tions, either general or detailed. These policies have been Ohserved and all of the Board's recommendations have been acceptcd by the T.I.R.C. 2. Relation to Reclplentb o/ Sripport. In pre(saring guiding prin- ciples for grantees, the Scientific Advisory I3oard and'1'obacco Industry Re- iearch Committee followed the most liberal examples they could find recordat by other granting agencies. A copy of "Statement of C'onditions and '1'erms l Inder Whieh Project (irnnts Ate Mnde" Is i;ivcn to all grant reciitienls, aI well tts nnyttnc rhe Intcrestcd. 'I his statcmcnt includcs thcse prtints: "Research prrllcy and pretl;rornnsinl; nre the re.trnn,ilrility of the Scicntific Advisory Board... 13 (Inf;28n 1 6io r~, t:, "I

" onnnittce desires to have scientists work with the 'i'l1E ItESF"ARCIf 1'ItOGItAM greatest trecdorn and without domination of any kind. It will make no attempt to direct the administration of the project once started, In influence its course or to control its results other than to be assured that the funds are properly expended for the purposes of the grant and that all findings are reported In accordance with the bcst scientific practice... "Grantees arc to furnish a report of activities semi-annually. These need not be extensive but should be sufficiently informa- tive to permit the Scientific Advisory Board to the Tobacco Indus- try Research Committee to know what is being accomplished... "The Tobacco Industry Research Committee approves the initial presentation by the investigator of research results only in accepted medical and seientific journals or before accepted medi- cal or scientific societies. It has no objection to dissemination to the public of any or all final conclusions from projects in these ways..." 3. Relation of Srlerrt!/'rc Adol.ory IToard lllembers to Each Other. The (loard rerngnized that its size must be kept small to insure the great but intangible creative value of intimate mutual friendship and understanding between Its members. Such a relationship guarantees the highest degree of attendance, intcrest, interchange of ideas and conservation of time and effort. Ifowever, a small board also requires free and unrestricted use of con- sultants, either individually or in groups, in order to have access to all avaiiable information and to obtain much necessary advice in planning new lines of research. l.ater in the report it will be seen how helpful these consultants have been and will continue to be. Another important factor in the activities of the Scientific Advisory Board is the division of labor according to the special interests and aptitudes of the individual members. Preliminary review of applications for grants-in- aid, interviews with prospective grantees, and contacts with medical and scicntific groups arc examples of the sort of work accomplished by Board mcrnbcrs between meetings. Recomtnendations based on such contacts are discussed and acted upon by the full Board. In all of this review function, the services of f)r. Itobert C. flockeU, Associate Scientific I)ireetor of the Committee, have txen invaluable. 71re ikrard maintains personat contact with each rnnjor grantce, for only by so doing can the Board develop and maintain the type of "fromt linc" informntion sei necessary in such a compicx and unchnrted ficlii. lt t r 'I he first responsibility of an advisory board is to take timc to think about all phases and aspects of the responsibility with which it is charged. The broad definition of "tobacco in relation to health" involved far more scope than any one person or small board could hope to cover in dclail by expert knowledge. Out of discussions by the Scientific Advisory Board evolved a broad "master plan" which included three main areas of investigation as follows: 1. The physical and chemical composition of tobacco and accompany- ing products, such as cigarette papers and additives, and of their combustit+n and pyrolysis products. 2. Tlrsrrt changes In humans and In animals, in normal life and under laboratory conditions; subjected to various types, duration and intensity of exposure to various tobaccos and derivatives, and other potential irritants. Tissues of special interest are those of the lungs, cardiovascuiar system, mouth, throat, endocrine glands, and other organs in suhjects of various ages, sex and strains. 3. Smok/ng arud other tobacco hahlts, and fhe emotional and physical make-up of smokers, with respect to establishment, duration and intensity of tobacco use, and correlation of these data with metatxilic, glandular and nervous types under various degrees of stress anti challenge nntf of other environmental factors. Broad and inclusive as this three-area program is, i( defincd the field of general interest ond, from this, the Board could determine the pertinency of grant applications and create the more definitive research progratn that has since guided our efforts. While the Board operates on policy matters and grant applicatirms as a whole, each member has accepted special responsibilities to help gtthle and develop the program in one or more of the nine specific fields of research into which the $1.500.000 so far appropriated by the T.1.R.C. are now being channeled. A discussion of these nine fields follows: I. Preparation and Analyd, ol Tobacco I)rrlrnrirea (f)as. ('A1- TP.t t., )ACOHSr)N ANb KOTIN) 1)cfinition and establishment of experimental conditions which sintu- L•tte those undcr which tobacco Is normally smoked or rrtherwise uticrl w:rs needed since the Ixorlucts of partial comhustion and rti.tilhrtiun of any org.+nic ntatcri;rl will vary in crrmlrnsithrn wilh crrnititirtn. rrf thr frriKC.s itself. Is