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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

lf the . condensates, tars or derivatives have been preparul or stored under abnormal conditions, experimentation with them has no bear- ing on the practical evaluation of tobacco products in relation to health. The Scientific Advisory Board, with the help of scientists at the varous laboratories of the tobacco induslry itself, developed a detailed description of the best available smoking machines. This material will be published so that investigators anywhere can reproduce the smoking techniques and increase the significance, applicability and comparability of their work. Much more research needs to be carried out on the isolation, idcrtifi- cation and analysis of the great number of chemical substances dcr'ved from the fractionation of tobacco and cigarette paper products. Such research Is being encouraged among Independent scientists as well as in the tobs:cco industry's own laboratories. In planning research on substances In tobacco, the Board received valuable advice and aid from Dr. A. J. Haagen-Smit of the California lnsti- lute of Technology. Dr. Flaagen-Smit pointed out that isolation and chemical identification of tobacco fractions could proceed successfully, but he fore- saw a"botticncck" in the absence or inadequacy of methods for assaying In humans or animals the possible effects of substances so obtained. A considerable number of investigators In many laboratories will prob- ably continue to concern themselves with Isolation and identification of various tobacco fractions. Such efforts may he helpful, but until much more effective methods of assaying their effects on lung and other tissues are devised, their contributions to experimental analysis of the problem will be incomplete and inadcquate. One of the Board's efforts to dcal with the deficiency are discussed ttnder Section V dealing with tissue culture. I1. U.eo/CarGon- aa aTracer Element In Tobacco (l)tt. JACOBSON) Application of our recently acquired knowledge of using Induced radioactive isotopes as tracer elements has been given serious study. For conducting experiments on the analysis of tobacco, plants grown in a car- bon dioxide atmosphere containing C", one of the radioactive isotopes, are potentially valuable. The Board has surveyed existing facilities for growing such plants and has considered several steps to be taken should any extension or incrcase In such facilities become essential. ilccause of the technical difflcuities In "processing" tobacco so grown and bccause of Ihe small amount of material that would eventually lie nvail- nhle, any active prrrgrnm of Inereased production frns been prrstprrnul until the nccd bccomcs more cvidcnt. 16 I 111. PathologJoAnatonrlclte.eurch (Dns. ItetMAt rNCll, KOTIN) The Board early recognized a need for greatly increased knowledge o' the pathology of the human lung. Study of human lung tissues was dc- &ired to observe the kinds and extent of abnormal changes and their possible relation to occupation, place of rysidence, past ailments and t)te like. No one institution had sufficient data for a wide coverage of this ficld, nor did it seem probable that any one laboratory could alone obtain a sullicient mass of data. The Board, therefore, planned a cooperative study to include twelve clinical-pathological laboratories. It called together the following patholo- gists for a conference to discuss the feasibility of the plan, and, if approvcd, to put it into operation: DR. D. MURRAY ANOEVINE, University of Wisconsin Medical Sch^ .:, Madison. Wisconsin DR. E. M. B(JIT, Los An`eles County Ilospital and University of Southern C.lirornia School of Medicine, l.os Angeles, Califoroia DR. WII.LIAM I1. CARNES, Stanford Uolversi(y School of Mcdicine. San hrauclsco, ('alifurola I)R. RUSSt?I.L S. FISHER, OFBce of the Chief Medicat Esamincr, Stare of Maryland and University of Maryland School of Medicine, Buhi- more, Maryland DR. RUSSELL L. ItOLMAN, Louisiana State University School of Medl- ciue, New Orleam, Louisiana DR. KENNETH P. KNUDTSON, Veterans Administration Hospital and University of Washington Medkal Schoot, Seallle, Washington DR. MARVIN KUSCIINER. New York University-Beltevue Medical Cco- ter, New York, N. Y. DR.11. R. PRA1T-TIIOMAS, Medieal College of South Carolina, Charles- ton, South Carolina DR. WILLIAM O. RUSSELL, M.D. Anderson Hospital. The University of Tcsas Medical Cenler, IFouston, Texas DR. E. I). WARNER, State University of Iowa. College of Mcdicine, Iowa Cily, lowa DR. WILLIAM B. WARTMAN. Wesley Memorial Itospital and North- western University Medical School, Chicago, Illinois DR. Rl/SSELL W. WELLER, The FFahnemano Mcdical College and Ilus- pilal of Philadelphia. Pennsylvania (Now at I:phrata, 1'ennsylvania, (;ommunity Ilospitd) A preliminary conference enabled the Iloard to organize the project, and produced frank and free discussion of techniqucs and experience which proved to bc most fruitful and stimulating. Two other conferences of these pathologists have been held with practically 10(1`y, representation and with stcadiiy growing evidcnce Ih:rt lhe principles underlying such a cooperative vcnture nre sound and creative. "Ilris pathologic-anntomic sludy of human lungs was bcl;nn in l~ehru- ary, 1955, nnd rencwcd for a second year in Fcbruary, 1956. 117 3~~

The twi uticipants arc widely scattered geographically for the purpose of randomizing the effects of environment upon the subjects of study. Special attention is also being given to the nature and extent of lesions indicative of previous infection of the lung tissue. Statistical study of the possible history of previous infection Ln relation to lung cancer may be an important matter and may give interesting leeds for more extensive pathological investigations. To make the data derived from the different laboratories comparable and standardiied, a uniform system of recording was devised by Miss Mary L3urke, the Scientific Advisory Board's atatistical assistant, after consultation with Dr. E. B. Wilson, a member of the Board, and with the twelve cooperat- ing invcstigators. This will greatly facilitate statistical analysis of (be pooled data obtained and will thus augment the value of the effort. IV. Dlrect Applicotlon oJ Tobacco DerlvatIve. (1)as. RaIMAhN, L.tTTI.a, 1ACOeu)N) Animals of different genetic background not only produce different characteristic incidence of lung and other typea of cancer, but also react in different characteristic ways and degrees to challenging substances applied directly on the skin or elsewhere. The Board, therefore, agreed on the policy of advocating the use of experitnental animals of known genetic composition wherever possible. With this in mind, assistance is being given through a grant to the Roscoe B. Jackson Memorial Laboratory, Bar Lfarbor, Maine, to help stabilize and increase production of the desired strains and hybrids of mice, which arc the most widely used and best analyzed experimental animals. Recognizing also the great difference in response to chemical challenge as shown by dilIerent species of animals, the Board is interested in incrcas- ing knowledge of species susceptibility as well as strain ausceptibilities. In the same way, various sites at which the challenge is applied require careful study. The high degree of reactability of the skin of mice, rats and rabbits contrasts intcrestingly with the relative inertia of the skin of guinea pigs or of primates. Rclationships of this sort indicate the need for extrenle conservatism in extrapolating results oblaincd and conclusions drawn from one species to another, and even from the reactions of one tissue or organ system to anuthcr in the field of earcinogenesis. Only an extensive scrics of experimcnts with animals hl which sl+ccics, strnin, sex, age, drrsaPc antl other fnr'tors are contralled and evaluntctl can give Ihe sott uf e.uct inturrnadun otr whith reasonably aare cunctusittns c;tn be based. 1(t l. 11 oo (. -1 Another type of exposure is through inhalation. D, in has had loog experience in this field and is acting as a subcommittee of one tu review applications relating to inhalation experiments. Close contact is maintained by the Board within the whole field uf experimental exposure. Efforts are continually being made to evaluate both the positive and negative results which various investigators have reported and are obtaining at present. At best, work in animal exposure can produce only indirect evidence on the etiology of human luog cancer. However, there is real vnluc in animal work; it can and often does suggest problenls and pathways in clinical research. V. Ttaaue Culture Research (f)ks. 1ACOUSUN, L.YNCIS, (_'uMk(,e, REIMANN, LITTLE) Since it is difficult to observe or to experiment on tlre animal or human lung or on ttre cardiovascular system in s7tu, efforts are being made to dis- cover and (levclop techniques by which experimenters can obtain access to living lung tissue under conditions which allow direct observatirtn and manipulation. As was pointed out by Dr. LLaagen-Smil, the real problem involved in the functional study of the derivatives of tobacco is in finding better and more accurate ways of determining the effects of thcse chemical substances on living tissue. The Board, therefore, believes that among its major responsibilities is the development of new methods of bio-assay that will allow the direct observation of reactions of human and aninlal tissue of various agcs and origin. To survey the possibility of initiating and supporting research into 11•- maintenance and growth of lung tissue and of cardiovascular tissue irr virrtr, eleven of the leading American investigators in the field of tissrle cullure were invited by the Board to New York for an informal conference, exchange (+f views and discussion. "lhose in attendance were: DR. t.AWRENCC BI?RMAN. Pro/rimr u/ Atrdirinr, Wayne (/nivcnily Colteae of Medicine. Detroit, Michigan DR. )OtIN 1. BIPSI7.t?, l/rod, Crll Cruwrh Srui,on, Shl:m Ke(Icring Imli lute for ('.nccr Rerearcb, New Yurk, N. Y. DR. IIARRY ItA(31.1!, ('h/r/, F.tprrlrurnfut Thrruprurirr. N.uirtnA hlicm hluluCical Imtltule, NatlUnal IInllllltes uf 11r:Jth, Ilcthrsd.r, A1.uyl:,nd DR. WII'1ON k. FARI.H, lJruJ, 7Yrtur ('utrrrrr Srrti-rn, I:hmal-ny ut Nluloty, National ('unccr Iuwilulc, NutimWaI Imtltulr. u/ IIc..Ilh, netbrld., Maryland MRS. R1/111 (iPI(1Uk, Nrurupyihi.dric Ihtoilutc, tluivctaty uf Illm-u., Chicuau, Illinoiti ]9

hR. ( I! O. (1L'Y, A»bran! Pro/essor of Sur ery, lohm Ilopkin. ll.., dy School of Medicine, Baltimore. Mary~and DR. MAILGARET R. MURRAY. AuoelartYro/elsor of Anatomy. Colum- bia University College of Physicians and Surgeons. New York. N. Y. DR.C. M. POMERAT, 1•rofeiior of Cytology, 7ho Uoiveraity of 'I'esas, Medical Branch, Oalveston, Tesas DR. JOSEPIt 1. Q(JILLIOAN, la., Chief, Vlrus and Tltlut Culture l.ab- orarories, College of Medical Evanecllsu, l.oura Linda, Lo. Angcles, C:alilornla DR.CHARtIY WAl'MOUTN, Research Fellow. Roscoo B. Jackson Me- morial Laboratory, Bar Harbor, Maine DR. Pt111.IP R. Will If, Research Associate. Roscoe B. Jacksoa Memorial l..boratory, Bar flarbor, Maine The confcrence was most rewarding in its delineation of the present status of the art and science of cell culture, and encouraging with respect to its potential applications to the problems at hand. Following the conference, the Scientific Advisory Board recommended an appropriation be made to assist the summer training program of the Tissue Culture Association and to provide several fellowships for study of human lung tissucs In vitro. The appropriation was subsequently approved by the Tobacco Industry Re- search Coulnlittce. VI. Cardlorasculur and Coronary Reaearch (DRs. CATTel1., Col,qt08 ) Cheat Physiology (DR. RreNffoPP) Various relationships between nicotine, and perhaps other tobacco derivatives, and vascular and cardiac function have long been hypothesized and rumored. Examination of ttle literature reveals a distinct need for further research to take full advantage of newer experimental techniques and to fill very real gaps in our knowledge in this field. So evident is the need for careful and critical planning based on frank discussion of our present level of information that the Board hcld a con- ference in New York of research workers who are grantees of the Tobacco tndustry Research Cornmittce or who are associated with its program, together with a few guests. The following persons attended: Crantees anti Aaaoclatea DR. FRNI'S 1'O A'I'1 INGfiR, Bottnn ('ity Rospltal, Bostnn. Massachusctts I)R. kI('IIAkt) 1. IIIN(1, Medical College of Alah:ima, Nlrmingham, Alahnrna t1R. 1OIIN W. 1('KSI FIN, Mav.chusrlh Memorial Iluspluls, I1onton, MJs1.!(hulClts 20 I I I I i I 1)R. FRANK C. FERGl1SON, )rt., Albany MeJ~cal Colleg. any, New Yor k DR. VIN('F.NT 1. I'ONTANA, New York l)niversity-Bcllevue Medical Center. New York, N. Y. DR.IACK FRf?l1ND, Medical College of Virainia, Richmond, Virginia DR. CAR1. C. ORl)1121T, University of Pennsylvania. (iraduate School of Medicioe, Philadelphia, Pennsylvania DR. 1OSFPII It. HAFKENSCIIIEL,Tbe Lankenau tlospilal, Philadclphla. Pennsylvania DR. KELI.Y l'. McKEE, Medkal College of South Carollna, Charleslon, South Carolina DR. HU(iH MONTGOMFRY, University of Penmylvanla, Philadelphia, Pennsylvania DR.IIURLEY LP.E MO7l.EY, University of Southern Californla, 1.os Angeles, California DR. WALTER RFDISCII, Ooldwater Memorial Hospital. New York. N. Y. DR. SFYMOl1R It. RINZLER, Cornell University Medical College. New York. N. Y. DR. NANS ROTTENSTEIN, University of Pennsylvania, Philadelphia. Pennsylvania DR. MAURICE S. SP.OAL, Boston City Hospital. Boston, Massachusetts DR. IANI?f TRAVFI L, Cornell University Medical College. New York. N. Y. DR. RICIIARD WIiCI1SLF.R. Monleffore Hospital Institute of Rcsearch, Pittsburah, Pennsylvania DR. l. EDWIN WOOD, Maasachusetts Memorial Hospitals. Boston, Maasa- ehusetb C teab DR. FRANK DAVIS. Johns Itopkins Ilospital, Baltimore. Maryland DR. C.IIARLFS D. MARPI.P., American Ifeart Association, Ine., New York, N. Y. MR. FELIX F.. MOORE. National Ileart Instilute, Bethe.da, Maryland Three half-day sessions were held. One was devoted to the heart and coronary circulation, one to the peripheral circulation, and one to lung function and pulmonary circulation. Preliminary findings were conlpared and newer methodologies were discussed at some length. VII. Iluccal and Castrointeatina[ Research The Board wants further re<earch into tobacco in rclation to these body sites, and is reviewing the ficicf with the object of developing an orderly and crwxdinated prograrn, rather than to support scattered and dis- connected investil;ations that may Ix lacking in pertinency. AlthouFh priority has had to he givcn to olher areas of research, and the progranl rrf research on the buccnl anrt I;astroinlcstinnl sites is in its early stnges, a few Im+ic projects havc hccn sulrpnrletl and pr(rkress reported. More nttcntinn Irr these phnses rif resc:rrch is cnntemhlaled. 21 , , 00 0(1F: ".

V111. S g unGit,-Phy.rcnl enrl 1'.ycholoalcal Type. (bas. WtISON, I.tTTLP.) Another fascinating but little-known field for investigation is into the types of persons who rcact to the strain, stress and frustration of intense modern living by the formation of habits of excess. Common sense and everyday experience have proved that individuals differ from one another in their ease and degree of self-control and adjust- ment and in their tempo of living. The same individual may vary in type and extent of reaction at different ages and under different kinds and intensity of stress. These differences may reflect types and grades of physio-psychological interrelations and degrees of balance. Such factors would naturally affect the incidence of basic psychosomatic disturbances and diseases. They would thus be an important element in increasing the health risk and death rate of the individuals who present more critical phases of reaction to strain and stress. It is, of course, difficult to reduce problerns of this sort to exact scientific proportions and to devise sufftciently definite techniques of continued ob- scrvation and measurcrnent. There are, howevcr, several population groups with which studies have been progressing for some time under careful and wcll-trained investigators who have a kcen appreciation of the difficulties involvcd. The Board has made arrangements to assist and Implement certain of these studies so tFat smoking habits can and will be recorded and can later be correlated with various physiological and psychological types which arc idcntificd and defined. Since we already know that hormonal secretion may be influenced by emotional or psychological stress and that hormonal secretion also can influence the origin and development of certain types of cancer, investiga- tions in this field of "personality" may reveal Important evidence of eorrela- tions between "personality type" and "health risk" in which habits of excess are "reflections" rather than being "causes" of instability, disease or death. IX. Pe+Iloro.hJp ProRrnrn Rccognizing the widely admitted serious scarcity of young, well-trained research workers in the biological sciences, the Aoard recommended research fcllowships of $5(H) each for students in 52 rnedical schools In 1955. 'llrc Tobacco lndustry Research ('ommittee approved u.e nf funds for Ihis purpose. 'Iltis hrogram was rcccivcd with enthusiism and for 1956 the T.I R('., 22 I on recommendation of the Board, is making possible the aw 20 addi- tional fcllowships above the 1955 total. Students who receive these fellowships are chosen directly by the dcar or other administrative otticers of the schools and assigned tu research pruj- ects during summer or other olf-terms. 'lltcy may work on any problem sele.ctal by thern and approved by the dcans. The Cominittce keeps entirely out of contact with both students and schools until the selection has been made and the problems chosen. The Committee's only rcquest is that the school notify it of the name of the student, tlle subject of the research and that, at the end of the fellowship period, an informal report be made on the purpose and progress of the research. CONCLUSIONS 'f'his report is designed to describe the current status and extent of the research program developed by the Scientific Advisory t3oard to the'1'obacco Industry Research Committee. Clearly, any attempt to evaluate at this time the results of existing research projects would be extremely prcmaturc. Ilowever, these general observations, based on existing scientific litera- ture, may be made: I. 7'he very extent of the practice of smoking among our population is proof that it provides some kind of pleasure and satisfaction to those whoengage in the habit. lfow and why it does so are among the uncertainties that need exploring. Ilowcver, like any other human activity, the use of tobacco affects some individuals in different ways. The same may be said, of course, of almost anything else we come into contact with, including the food we eat. 2. Any possible role of smoking in the etiology of lung cancer remains an unresolved question. It cannot be said that smoking has been absolved from suspicion; neither have the charges that smoking has a role in lung cancer causation been proven. So ninny unknowns still obscure the whole field of cancer causation that it is not possible at this stage to say either "this is it" or "this is not it" about any single factor. 3. In the cardiovascular and coronary disease ficlds, the uncert:rintics regarding cause and even treatment remain innumerable. 'f'he hc:ut tttt:rck experienced last fall by President Eisenhower dramalically brought to pulr- lic attention how little we really know about the cause or prcvcntiun of hcwt ailments. Whether smoking hus any significant p:ut, and indtcd, whcdicr such a part rnay he positive or ncgativc, is only unc uf thc ntauy :ucas in cardiovascular invcstil;ation that should be explorcil. 4. Preliminary study iudic:rtcs Ihnt tltc physic:rl, emnti"nal ,`J rucntel characteristics of people who becorne snrnkers nt:ry Ire of nrnrc Nit;nitiianrc 23 ,t,i(•,c) !-, 33'

thnn has bu r rccogniccd. It is s fact that many smoking stuclics in- volving humaus ..dVC ignored or neglected personal information other than their smoking habits and one or two of the more obvious kinds of physi- ~ cal ailfuents. ~ The Tobacco Industry Research Committee's complete willingness to permit the Scientific Advisory Board to initiate and sponsor basic research into our health problems as well as to finance applied research into specific problems should prove a genuine and unselfish contribution to the gaining of new knowledge with a maximum of speed and efficiency. (T 2 t (J ~; ooszSf;

~ Z: ! i

REPORT o/ the SCIENTIFIC DIRECTOR CI.ARF:N(:R C(x)K t.1TTt.E, Sc.n. (auir.n.n, ScienliRe Ad.iwory Qo.rd 1956 '1'()ItA(:(:() INI)IISTRY RFSEARIaI (:()MM11'1'F1: 1S0 F:st.t 42nc1 Str.rt, New York 17. N. Y.

SC11•;NTIFIC ADVISORY It(1AIt11 to the Tobacco Inductry Research Committee (•I.ARI:N(•r-: COOK t.1TTLe, Sc.D., LL.D., Lrrr.D. Chnirmnn, Scientific Advi" Doard ,Crirnri/ic I)irrrtnr, Tobacco Industry Research Committee I'rr.vidrnt, Rnccnc R. lackson Mcmnrial Laboralnry flat Ilartror, Maine Mr K f f N CATT ELL, Pt+.D., M.D. I'rn/rttnr nJ I'hurnrarnlnRy ('nrnell Univcrsity Medical ColkRe New York, N. Y. JUL/l1S 11. CnMROfi, 1R., M.D. (Yrairmnn and rrn/rtrnr, nrparrmrnr of Phyrlololry and r'harmacwfoRy ( Iniversilr nt Penn%ylvania Graduale Sehonl of Medicine Philadclpfiii, I•cnnsylvania 1 .FON O. lA(`(111SON, M.A. Prn/rrlnr of MrAirinr. Univerai/) of (hicaRn I)irrrrnr, Argonne ('ancer Recearch llospilal ('hicaRo, Illinois PA11t, KOTIN. M.D. A c.nrinrr rrn/r..rnr of Pnr/rnlnttv I/nivcrsity of Southern California School of Medicine l.ot AnReles, California KI?NNIiTII MI?RRILL LYNCN, M.D.. Sc.D., 1.1..D. Prr.tlArnt, nran n/ Faru/ry ond Prn/rrrnr of Pnrhnlngy Medical ColleRe of South Carolina (Tarkann, South Carolina STAN1.fY P. RRIMANN, M.D., Sc.D. SrirntiFr lli.rr(nr, lnslitule (ot Cancer Research I)irrrrnr, I.ankenau Itn.pilal Research In.titule 1'hiladelphia, Pennsylvania WII.I.IAM F. RIF.NIInFF. 1R.. M.D. A...nrinr, Prn/rsr.x of SarRrry Jnhm Ilopkins llnivenity School of Medicine Ilallimtxe, Maryland I f)WIN It. WII SnN, Prt D. rrrv/ecrnr Emrrirra n/ Vlral SratirNrs I larvanl I lnivcr.ity ('amhridge, Mai.rchuaN. -o- ROItt7RT ('. 11(K'KfiTT, Ptr 1). Afr,-r Inrr Srlrntitir 1)irrrhor

'1' I ic Rcsca rch Pro gra rn Two years s6o, the Sckotifk Advisory Board to the Tobacco Indus- try Research Committee was tormally organized and undertook to ereate a program of research that would contribute eoosUuctivel2 to our search for answen to fundamental 6ealt6 probkms. Specibedly, the program w.a to develop facts reiative to the eReets of tobaeeo use. Today, well over $1.200.000 in T.I.R.C. funds have already been Rranted to more than 55 scientists who, with their eollea6ues, are partkipat- in6 in a carefutly -planned, we0-integrated scienti6e endeavor to help in the solving of important health questions. The Committee has appropriated 51,5()0,t)n0 for such grants and has pkdaed more funds as needed. The program is still developing and growing. 7119 report discusses the Sckotilk Advisory BoRrd'a approach to its assi6nment and the current status of the research program. At the outset, the ©ovd recwpixed that ackotifie knowledge eoocera- ing health aspects of tobacco tue was uncertain and spotty. Tobacco use, particularly cigarette trmoking, has become widespread throu6hout the world, especially In the more hishl2 developed eountrks. Recently, there have been charges that smoking is associated with certain buman ailments, among them cancer of the lung. The Board did not aet out to prove or di.prove anything. Its position was and is in agreement with the vast m.jority of experimental scientists who concur in the view that our knowledge of the tormidabk challenRen of human survival-such as cancer and heart disease-is far from conclu-tive or complete. The sole purpose, therefore, was to encoura6e and support quali- fied research scicntists in their eRorts to learn more about these complex proh'-ms, meanwhile refraioing from premature judgments. Thii approach has proved sound and correct. The need for further study is, if anythinR, mnrc compelling than it was two years ago. We have karned much in the past two years, but perhaps the mott important thing we have learned is how much more must be done before definitive an.wers can be given. 1`RtN:RF:S9 MAt1t: IN MAJOR AREA9 At this itiiRe, thcrefore, the accompHshments of the re.er,rch program ruptwntcd hr the '1 nhxco Industry Rescarch Cnmmlttce must he mea+urrd In terms of proprr-, rether than (n eoncluaive 6ndinR.. 5

IlavinR been given a completely free hand to cnnsider the whole field of the ute of tobacco in relation tir health, the Iloard assumed the fullowinR retponsihilities: (a) blocking nul majur subdivitions of this field which can and shnuld tx covered by scicntific research; (b) considering persnnncl and facilities availabie, or capable of development, to meet research needs in tluse subdivisioos; (c) recommending to the lobaceo lndustry Retearch ('ommittee the amount of financial support needed for each tyf,e of effort, and the personncl and institutions which should receive it; and (d) review- ing the progress of work thus supported to make it as eRcctive as possibk and to follow up new kads and probkms ari.inR from these effort.. Among the more sisnificant accomplishments that have come out of these efforL art: 1. The development of a program defining the range of research perti- nent to our major interestU, thus making pcmible the most efficient and cficctive u+e of teseart•h funtls. 1 hiq has helped In prevent a duplicatinn of eRort, htis mark prnsibk suppkmentatirrn of existinR work, and has enahled us to give proper emphasis to fundamental and praclical projcctt. 'ihe out- line of this program will he dixutaed more Fully in the brKly nf lhis rrptul. 2. 1?re initiatiim and supfxut of individual re.earch projects carried out by indcprndcnt. qualified acienli.ts in sc.me of the natinn's outstanding research and educational in,titutinm. While lhese are sep.rate and inde- pendent investiRetions, each fils into the cr.nrc7inated program of objectives dcvclcncd by the Scirntific Advialry Iltrard 3. In the three ficldq ttf aaJy Ji.cutattl t.rLlw, initiatinn <,f craq.era- tive endeavors amonR scicntistt woukrnR r.n lhc .arne or tnnilir prnhkm+ In order to coordinate their eRnrti and comparc prr.cedurrs '1 hii arl.ruach has proveo etttrcmely valuable in eliminating unnrrcettary tluplicatinn and in creating a large degree of unity and comparability in the woik of the individual investiRatori. The three arcas of intcrest covered were: . Nun.en 1'.unor Tl..r. Study. Patholol(ists 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 lun6s to learo more of the factors Involved in lung ailments. b. ll.art.nd Clrrrfetfon. Speciali,ts in cardiova+cul.r and coro- nsry research were brought together to explore what is knowu nd not koown about relalion.hips of tobacco use, particularly of nkntine intake, to vasculnr and cardiac functinn.. c. Tf..r.w (:u/ture R..r+rcA. t.cadina invcstiR.ton in the ficW of ti..ue culture conferred under the au.pkei of the Scirntific Atl- viatry Htl.rd to dNermine lhc txst wayt of tpcedinR rex.rclt into the cultivation and maintenance of lung tissue and cardio- vauular tissue under eonditions that would allow better observa- tion and control than is now possibk. 4. 1)evelopment of acceptable standards for governing work with tobacco derivatives to meet  ehalkngin6 need among Investigators. The problem was that many esperimenti with tobacco smoke constituents had been or were being conducted under eonditions bearin6 Gtek, if 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 esperiments to the expericnce of human smoking. Substantial propesa has been made In: a. Preparation of standard tobacco derivati.ea for labotatory use. b. Definition of standard operating conditiot,t for smoking ma- chines, including control of temperature ranaes In subjecting material to eombuation. c. Further development and production of genetically controlled laboratory animals, partkululy mice, with known character- istics, to be used in tobacco eaperimeots. 5. Inauguration of a modest pro6ram of research fellowships for medi- cal students. tincouraaertxnt of bask medical research is contidered a fundamenlal contribution to the efforts to karn more about how to attack the constitutional diseases. Despite its necessary limitations, this program has brought e.tremely gratifying response from the parlicipating medical colleRcs and the recipients of the fellowships. A(TIVE 1'ROIEC'i'9 It is, and will continue to be, the establisihcd policy of the Sckntific Advisory EToard to permit each investigtor to publish his findings Inde- pendently when he feels he is ready to report on his work. Although the great majority of grant tecipkota are still engaged In their research, a few are at the stage of making public teports of progress to sckntific groups or in scientific publications. Although grants are made on a one-year basL+, msny have been renewed. In the field of scientific eedeavor, It Is often impossible to put definite lime limitations on the period of study necessary for subslantial accomplishmcnt. True nicmists are naturally cautious. 71tey are awue of the great nd obvinus danger fur the lay public and for those In the ffeldi of science and medicine that may result fmm premature and con}eetural opinions. InvestiRatnri working under T.I.R.C. grants and the arcas of study undertaktn are +hrrwn In the following listint of grants now in force. For cnrrvenicnce, the list is alphabetical by the InvestiRatnr's name. T 6 T 1 ./ (J ,p

(:nAPl1f:F. ANI) IP(c1TTVT1()P( D. MI/RRAY ANnf'VINP. M.I), Pro- /r.rnr nf I'nrh,.lnrr. l/nlvertity of Wi.- cnn+in MedicI School. Madlson, W i.cnndn FRFf)1'RICK W. RARNPt, le, M D.. Ptt U, A rtncinrr Profrfrnr of A(rdl- clnr nnrf PhrnnlnRirof (:Aem(lrn.lnhnt llnplins Ilni.rrtily School of Medicine. Balllmnre 5. Mar)Lnd RICIIARD 1. RtNO, M.D., Prn/rrsor o/ [ tprnmrnrnl A1rdi.lnt .nd Clinic fi PAytiolnry, The Medkal Col/ege of Alah.m.- Rlrminghsm 1. Alafrarna (Now a W..hinRlnn llnlrersily School of Medicine. SI. Lnuis, Miriourl) IAMFS P. RONNfR, Pn D., Profrnnr of Siotory, ('.Bfnrni• IntliHule of lech nn1n.). P.vdrns. C.lifornla 1OSFF M. RROIf K. Prt 1), Arrncfarr Prolnrnr of Pher/nln~lr.l Ifrernr, I.hornlury nf rhyvnln1ic.) llrarne, (fmrrnlly nf Minne.nla Sch,u.l or Put- Ik Ilr.h'h, Minnr.p..lis 14. Minnr.ol• P. M. nlr)T, M 1), Pro/nrnr of PnrAnl- oRf, lJnirrrtlty of Snulhern ('.lifnrnla School of Medicine; ('A/r/ Porhnlnrht, Lrn AnRctc. (bunry 11mrilal, I.rn Ae- gelrs )1,('.lifnrni. WILI IAM /1. CARNI S, M D., Prn/rrrnr of P.rholnrl. Sl.nfnld l)nl.er.lll School of Medicine, S.n Fr.nti.eo, ('alifornla Ll[Oro1.D CFRfCr'[)O, Pn D., ProJrr ror of RlntArmbny, Iordbam llnlver- rlty, New York SII, N. Y. IIANS T. CLARKI: f) Sc.. Prn/r.mr of fllncArn.hrr~, ColumAl l/nlrer.lty ColleRe of Phy.icbns and Surgenns, New Yorl, N. Y. PIIIl.IP COOrFR, M h, Annclnar Pro- /rssor of Chni,nl sr• rry, Rminn l/nl- •erdll School of MrSicine. 1lnctnn tlt, M.fv.chusrtt.: CA/r/, .Surritel Srrrltr .nd fllrrcrnr, SurRlrel Rr.rnrcA faA- orotnry, Veleran. Adminidratlon Ilos- phst, Proridence II, Rhode Idand IIAN] I.. FAI K. rN n, Aufr(.n( Prn/rr- ror of Mrrthr.nhrn, Unlvenlty of Sobthrrn (llifornla School of Mrdl- clne, 1 rrr Angrlr. 11, ('.llfnrnl• R1/SC1'1 I 1 11(ft MAN, M f), r.n/rnnr I ,...,,..,, PR())F,(T T1T1E rNhnlnRk - An.lnmlc Study of Cellul.r ChanKt in Iluman Rroochl The Role of /lyrerplnl. In 7i(.ue Re- eponse In ('hrnnk 1)amqn The FRect of Smoking on the Coronary Blood I k,w .nd Certsln rha.ei of Myo- cardial Metaholhm In rairnls Wirh Arterlmclrrolk or /IypertenJre C.rdio- .ascul.r !)iuase Irncymalk StuAy of Methylatlon Re.o Rioes In Pl.nt Tissue A Quanlit.tlre Study of RMIn,kal ('har actrrFhlkf of Man As.otl.tr'1 wilh 1)If- ferenrrs In Ills Trndency In AArTI and M.inlaln ()iflerent Smollng It.brls Study of Tr.ce Metal Storsge of Pulmon- ery and l.iver Tlnue by Speelolraphk and Chemkal Methods Palhnlogk-Anaomlc Stud, of Cellular ('h.nRes In Ilum.n Rronttrl P.Ihntogic - Anatomic Studr of Cellular ChanJr. In Ituman Rronchl A Sludy of rarly Chrmlcal Ch.nRes In Ihe lunvbl lumnr-Rearina R.Ls and Mice Proteolylk Aclivitles of the White Rtond Cells of Man nnd the FRect on Whhe Rl.x+d Cell Aclivitirv of C.reinojen.- Nulrilinn and OIher Influenres A Study of the FRec1i of ('l/tarrtle Smnlt- ing on I erel+ of (:aslric Acid, Pep.in and Uroprpdn Fc.minalL.n of ('Iil.rette P.prr and C'Ig.. rrllt Srn.•le (ondrn+>tlr7 for Aromalle rrrlycyr ht Ilydrnt.rl.nn9 r.th.dntir . An.b.m/c Clo,fy .4 ('rllul.r / h.nRr. In /bu.r.n Ilr..u. hi H FRANK C. FPRC)l1SON, 1n. M.D., ( Anirmnw of f)•po rrmrnl of thnrme- r.dner, Albany Medical College. AI- h.ny 11, New Yortt R I/SS FLL S. F ISI I F R. M D, CAfe/ Mrd4 cet f..ornlnrr. Stale of Maryland; Pro- Jaror of L.rqol Mrdlcinr, l)ni.erslty of Maryland Medical Schoo, Ballhnort, M.ryl.nd R. L. FREFDL.ANDFR, M.D., Di'rector of Cencrr RrrrorrA, M1. 7ioe ltonphd, S.n Francisco IS, Califoraia ) ACK F R P UND, M D., f.cru.rr i'n PA.r- mnolnAniu,.nl In AfrNclnr, Mtdi- eal ('olle~e of Virslni.. Rkbrnoed if, Virginia A. CLARK QRIFFIN, Pr(D., Rt.I of RlorArmfrhy, DrperMren/, M D. Ander- .nn Ilotpital and Tumor loslhute, Unl- senit' of Teu. Medkal Center. Howu- toa 2S, Tctes CARL C. aRUI171T, Pn D.. M.D.. At- Iociorr /w PAytfolnp.nd PA.rw.ocolon, Unlreniy of Pennsylsanie praduale School o/ Mediclne. Phlladelphl. 4. Penafylrenla H. R. IIAAO. M D, Profrtrorof t1l.rwr.- eolnRy, Medical College of Vlrgisla. Richmoad 19. Virgisl• IOSPPIf W. 11AFKF.NSCHIP1_ M.D.. f)Irrrinr of Cordloprlmon.r) (/n/t, l..nlenau Ilmpit.l, PAlladelpbl. )1, Penn.ylvanla NPRBP.RT R. IIAWTl1ORNP M.D. ('Aelrmow of 1)rporlmrnl of Surrr), l)elrenity of Pennytranla pradual. School of Mediclee. Phlladelphla 4. Pennsylvanl. CI.ARK W. 11PA111, M D., PAytlcl.n, tlrp.rlmrnl of flyf/enr, Ilars.rd Uel- .cr.lly, C.mhrldge )0, Mavs.chuselts (NowAlre(Ird by Oana 1. r.rmworlh, M 1), Ilrnry A. (lh.rr Prnfrnnr o/ Ifytfrnr end Itbrrror of Unlrrrrllf f/rahA Slrrlrrr) PRecH of Tobacco Smn1e l/pnn the rune- Iinn of the Cardiov..cul.r Sy+lem In Animals and Man Pathnlogk - An.tomic SIuA' of Cellular ChanRes in Itr.man Rtonchl The FRect of Tobaecr+ Patr.cts on Ose Carcinogenic FRect of Methyknotae- 1Mene and of Ulua-Violet I Ighl; tbe fRnt of Tobacco F:clracls on C:arclno- genk ERect of Urethane-Induced Pu!- monary Adenornas In Strain A Mice: . the Use of Vetiors Sulphydryl Com- pounds es Neulralltlng or Cnunterac0- in. A~ents for the Possible Carclnogeok EAecI of Tobacco Falcacts la Mice Comlalkus of Multltechn/caf Procedurt. Pe(formed on Ihe Perlpherel Clrcula- llon of Normal Individuals In Recum- benl and Ereel Posillons and After Pa- erclse Before aed After Sharn aed Actual Smollnit T'be ERed nf P.posure In Cltarelte Srnole on the Induction of Caocer by (.bemkal Compounds Phermacololtk Study of Nicollne and Re- laled Alkaloids Pre~ rello. for Publication of a Book oe ,he Biolottle Aspectu of Tobacco aad Itu Srnote Measurement of Coronary Rttutd Flow Cardix Work and Cardr.c VcyRen aeJ C-arhohydeale Metahnliam In Norn.o- ten.lse Subrecls nefine and After Intra- tenous Nknline and Aller Smoking Standard Clg.rellen Atlempls to Induct Pulmonary Nenplasms In C.perlmental Animalr hf 1°.powre of the Tracheo Rronchial System In fo- bacto Smo1e Per.nn.llty and Smn1InR In Cn11rRr Orad aales: A 1 Ihrce Year I ulluw llp Sludr 9

P /IoMAt1ROP-R, M.D.. RrrrarrA Pro- Jrrrnr of Ahd/rlnr ena I)Irrrlor, ('enfrr RrsrerrA end Canrrr Cenlrnt f/nlr, lbftt I/nlvenitr Schonl of Mrdklne, Nrw PnRl.nd Mevlic.I Center. Aostnn II, M.vachuaor SrfrnN/{c Ar.orlarr• Rnsrnt A. l•c\.nn Memnrl•1 I..Mr•- lory• R.r Il.rha, M.Ine 1PRRY /IART IACOASnN, M D, I)f- rrrlnr of Flrrrrn A,rlnfn~, New Yor\ 1've •nd /'.r InRrm.ry, New Yd! ), N Y. ANCPL KF,YS- M D• Pro/r»n. o/ PA,r- Inlnffrel ll,flrnr enA f)frrcrnr. LiAnra- ror, of rhfrfnlotflrcl H,Pfrnr, Unl.erdt, nf Mlnne.nt• School of Puh- Ile Flydth, Mlnne.pnlls 11, Mlnne.nu 1OSPP/I A KIRSNFR. M D. rrn/rr«.r of MrAlrfnr, l)nl.enlt, of (Tkatp. Srhnnl of Medicine. (Tkaro, flllnolt KPNNPTN P. KNImTS()N. Mn. Ar- sfrrenr CA/r/. LiAnnarnry Srrvfce. Vet- tr.n. Adminlttr+tlnn lln.plt•I, 4.ttlt. Wa,hlnelnn: Irn/rrnnr of rerAnfnn. [lel.er.lt, of W.hln1roe MedIc.t School. Srahk, N•,hlnglos MARVIN KttSC/1NPR, M n. rrnhrrer of Per/lnlnrv. New Yn.\ lfnl.enlf, Cnl/ege of Medkine; L)frrrrnr n/ Ia- IAnfnp.. Arlk•ue 11n,rital, New YnlI /R, N. Y. T11f)MAC C I.AIPPI.Y, M n. A.r.rterr L'rnfrsrnr of PntAnlnr,, Nnrlhwraern Unl.er.ity Medical Sch.xd, (bk•R^. llllnols PAUL S. 1.ARSON, Pw D., Profrr.nr of PAarn.ecolnT,, Medical Colkge of Vlr- trInl•. Rkhmnnd 11, VIrr1nI• CPCT[ IP. I Pt1CIrTPNAPROPR, Prt [). Asmrierr rnolrr>M of Crrnlo,n, Wr+t- trw Rexr.e Usleerthy School of MeAt• clne, Ckvtl.nd R, Ohio KPl I Y T. McKPP, M 1), Anorlerr lro- /rrrnr of M.dl.lnr, Medkal (-olktte of ..wth Carolina. ( h.rlretnn, S.wth C•r- nlln• [)AVIf) P- MANN, I• , Pve D, A.rorfarr ~n L'.n/rrrn. o/ rAa.n.n.nl•.rf.Trmp I• nf Ph.rrnar,. Phit.- ~ drtp/.l. .n, Prnn.,l..nl. A Stud, of the Frterlt nf ('Iprrttr T•r. Upon the Reha.lor of Tr.n,plaul•hle lumnr• in R-trntt (:rnptn)ing • New lechniquenf tnhwterinr lumar 1r.n,I td.ntainn A Comp•r#.no of P.tnetrnretlnnp.p Af •t • Meam of P.du.NnR the FtTrct of Vbnonntlricl.x nruR• tll...n ('rrthral and Retinal ('fieutati..n With Other Trehnlqur" for TTI. f)rtermin.tirn. ('A.r.derltf" of Mrs• Including Sn+o\- Mg. Is Po{•ulatlort+ fNRrrinl In the In- cidence of Cnrr.n.ry /lr.rt hiv.,e The Plletl of Tn/.a-cn Smnllnif Ilp..n Aa.a1 O.,hk Secretion, In M.n P.thnlngkllnatornk ShoAT of Ctllul•r ('h.nges le Iluman Arc.nrhl P.thnlnilloAn.tmnk Stud/ of Cellul•r ('h.nRr. In Iluman Rrnnchl P.Ihnlntk AnatnnJc Stud, of Crllnl.r (-h.ngr. In Num.n Rronchl PnrTm•1k Tranforrn.llnnt of Nicotine (runllt•tiro An•1ysis of Nuckrnlnrqelm In Tl..ur. From Anlm•h Suh/rcted In Tnh•cco Smole hf Mk++nprct+..phnto- metrT•ndlntrrference Mkro.cnpy('nr- ret.ted with (',tolnric•1 •nA Ili,tnln1l- t.l Studies Stud, of I ong PunclLar In Srnnlrrt and Nnn Smolrr• Fnrc/ of Tnh.cr.. Smnle .n•I lnt.acrn Mrth,tthnl.n~hrrn. 1111r041r0 on Indured SIIn rv.ln•.•rnr,l. In %fi,e 10 li[fGll MONTGnMFRY, M.D., A»arf, arr rro/rrrnr of Mrdlrlnr, University of Prnn.ylveni. Medlc.l School, Philadel- rhi• ., Penn,,l.•nl. (1P(/RrP P. MOORP, Pn D, M.D., D1- rrrrnr, Ro.well P.rk Memorial Irntltutt, Aunaln ), New Yrn1 IIIIR/ rY I PP M(m.PY, M n., rre/r,- rnr, oof MrAlclne end btrrnnr, Candlo- Rr•PGrsfnry Lwhorarorjr, Ueltetsltj of Srwlhern (:.lifornl• Schnolo/ Medicine. I n. Angeln 11, California W111.tAM S. M[/RRAY, Se.D., ReNercA Arrrrcferr and AAn.fnlsrrarlon nhrrrnr, Rmcne R 1•cR.nn Mrmnri.l 1.•hor•- lnry, Par ll.rhor, Maine t 11 R PRATT-TIIOMAS•M D., lro/rtdor of PnrAnfnry, Medical Colktte of South ('•tolln•, Ch•rlnlnn, South C•rolin• V ICTpR R ICI I A R r)S, M D, Iro/rs.o. e/ Serrrr7, Fvrvrhr IIreA. OrPerlmrn( of SvrRrry. Stanford llnlvenil' Schml of Medicine. San Fr.ncixo I), C•tl- forni• R. [L RIGnf)N, M,n., P`ro/rs"r of Pa- IAnInA and Llirrnor. LilbrerorP nf Frperimrnral RneanrA, Uelvenltir of Ar.nch.~l•Leetna,le.n l eau. Medical NII.LIAM O. R[/CCPLL, M.D., IrAolo- gIrt In-cAfr/, M 1). Andenoe NorpR.d and lunvx In.dtute, llnl.ertlly of le.a. Medical Centcr, Ilnuaos 21. les•s PAI/I. 1) SAI7MAN, PwD, Anbrens Prn/rr.nr n/ Rln. Arn.hlrt, Unl.rnlt~ nf Snu/hrrn C.lih•rnl. School of Medl• elne. ( n. Angele. 1, Cafirownl• ItA AC S('llOI /R. 1) h t,/1r n.. n Sc.. me.rnfnA~ rrn/.r.n, nf fllrlnlnp, .nA IF and Ilran. Ilnlvrr,l1' of Illlnnls ('ol- te\e of hentHtrr. (ltk.n+ 12. Illinois leRuence nf Toh•cco Smo\Ing os the Alnod Flow of S\ie and of Muxlra of P.stremitks Is Symp.thectornlred and (ln..ymp•Iheetomis,ed Suh/eet. A. t..e.NPllos of !fw MPslobde.l PI- fecb of tNrecl Inh•l•t{on of Tob.cco Smo\e by [.•bontory Anlm•/s •sd tha StudTof the Alolotlad Retponxof tAb- oraor~ Anlm•h to Continuous In~es- tM. o( 1)ttt-Tobsooo Producy Mlsture. A Study of the PRecL of Smotlng on Pul- nuwr•ry Fenclion The lar.ducllnn of (kneUc.11y Controlled Anlm.ls and Temwn for Use In Psper1- ntenl•1 Rese•reb on Tobacco In Rtl•- tlon to llt•hh bry (e) the Pap•slon of Know. /nbred ocls and Gwrrcrs of Temoe SrroplP; (b) ths Produdlos of Sneb IIrMids or IleternrrRcwu T)pea .s Aewn.e Neet..a~ : and (e) the Ret•- Ilns of UM Material to SPeclfic P.sperl- Inental wort at Ihs 1.•bor.tory A pptkab. of s New SloAsy TechelQue ls P..ernin•tlnn of CI`erette Smo\e Condees•les for Pos.lhk C•rclnn~tr~. P•IhnloRk-An•Irwnle Study of Ctilut•r Ch•nges Is Ilum•u 1leonehl A Comp•ntive Stedt• of the P.Red• of Whole and Pr.cllnn•ted Patr•cu of CiR•rettt Smole •nd Tlro.e of Knnwn Carelnovem oxx (1) The CYtology and Nuclear DNA Content of Ppldermh Is Various Str•1nt of Mks and/or (2) Tlx CT(olon and Nuclear DNA Con- lent of l.ung •nd P thellum of the Aronchl•t Tree of M sod /1•m.lers StudP of the PRed of MethTkhol•nthrene on the T1..ues of the 1)uck with Prn- ph..h nw the Reectinn In the Trachea 1Mhew Comp. red With the S\In of ths Sodf .nd the Web of the Pont P.tholoRie-An•tnrnk Studr of Cellular Ch.nges le Ilum•n Aronchl The Pnr>rn•llc Mech•nhm fnr the 1).r\ F1.•tlnn of CR. by Toh.eco Ill.lnlnif/c Ch•n~r. In the (N.1. Ph.ryn- r.l .nd Na..' 11t,urt nf 1'.pr.Imrnl.l Aolm.l. Suh/tcted to loMcco Smn1e 11 t~~ ,

MAf1RI('P S SrOA1. Mb., Ci'Inlrel rrofrrrnr of M.Airi.r. Tuhs tlnl.er,ify School of Medkinr, nnHon, Me,v(hu- etl/.; lll,rrror, Ilrparrmrnr of Inheter/nn 7Arropr, Rr.,lun City F1o+pit.l, Ro,ton. Me„achu.etts ('/IARLPS P. SIIFRWOO1), M I)., Ar- aerren/ rrnfnrnr nf RnArornrt, llnlrer- silr of Rnrhedtr Schmi nf Medicine end Ihntistry, Roeheder, New Yotk DAVID L SIMON, M D., lnrerurior In Mrdlclnr and fenn, iw C.rdioraxu/er Rr.rerrA, Uel.eniry of Clecinnetl Col• kile of Mtdiclne end Cardl.c I ehore- tory, Clnclnn.tl Uraerel Ilo,pllel, C'Inclneetl 21, Ohio ZAM SOROP, Psn 1). Rrrrarrh As.orlrtr, lhe (nailule for C.nccr Re,eerch end l.nlen.u t/mp 11./ Rrse.rch Inslilure. MiLd<IpAle I I, Peemyt.aele FRPDPRICR 1. STARP PeD, Prolr.- u+r of NuMrinn, It.rrsrd Schonl of Publlc Fltatlh. llrsttro 15, Meuechu- Klls MARION fi. SI)1.ZRPR(1PR, M D., rro- frrior and CAoltn.on, !)rparmrnl of Drrm.loloq •nd SyplWnlnr.. New York llnlvenltr Ptnt Oradusle Medk.t School; Ulrrrrnr, Nr+ Yortt 31iw end Cenrrr (Jnir, New Yntk UeLenllr- Selle.ue Medk.l C'enler, New York 16. Nc. York CARO1 INP. RFbPI I. T7I[7MAS, M D.. Airorlen rrnfrrrnr of Mrdlc/nr. lnhns Hopklns lJel.enlty School of Medidne. Setllrnor. 3. Merylend 1 A N PT T)t A V P1.h M b. A ssorrnrr rr¢ frunr n( cnnrrel rncrm.rnrnry. c'nr• sell Unl•er,lty Medkal ('ollete. New Yolk 21. Ne. York P_ D WARNPR. M f), Imfnrnr of I•& rAo1n/ySlete tlnl•cr.lty of Inwe ('ol- lege of Medklne. lowe ('Ity, tnw. RICIIARf) f_ WP('IISI FR, M U, ('Ifnl. cer rArrlyd..elu, Mnnlrflore Ito.pltal Imlhule nf Rr"e.rh. Plll.hurah 1), Prnn.yl..ni. FRett, of Cip.retle SmoLInR on I nna 1 unt/ion in Norrnal Suhirtl, .nd 1'e- Iknt, With ('ertain Rr.riratary 1)iaea ('unditiun. in,eatlgellon Into the Nsturel Iti,tory of (',rcinorne of the 1.unt With Particuler Reference to Ihe RadiuRtephic Appear- eece of Such Prtre..es, the I arGe,t M.nlfeslelion of ('encer on ('he.t X- Rey Pboloarephs eod the 7 ehultlloe of the Reletiomhip of Smoking It.hits esd Occupelion With the Incidence of l.ung C.nccr The FReets nf ("hewina Tnhacco on the Cudb..aeuler Syalem of Man Cberntcel eed Physlcal Sludles of Ihe Tls- .ue Proteins In.nlred In ( hemic.l ('.r- tinnaent•ds Prpcrimeetel Studies of Canter UtTltrJnl a New lechoiQue to See if Verlous I en Pst..cled From Tohacto May Incife the Formellon of I ung Tumon tnreitlptbn nf the FRecti of Tohaeco ne the Ilum.n Va,culer Sy,lem In I.Ivlna Vnlunleers; .nd In Prticular of the Poaibilhr Ihei Cerlein lnhact•o FRrcts .re Sexd on Peculier Allergic Suu•epll- biltty of Specific Imhri,fual. R.ther iTan Upoe Ohti'atorily Tn.k Producta Ie tobecco Smole Tlx Slanlfkence of niflerrnt Individual Pstterns of (arculetory Reapon.e to Clgarette Smoking Plectroesrdlntrsphle PRec1s of Nlcotlne in Ihe Rahblt with Frrerimeotel Coru nerY Alhertnclero.t, P.IholoafcAnelomle Snrdy of (•elluler Chenses In ttum.n Ifrunchl PfTtci r.f (-Ig.retle Smollna r.n Cerehr.l Blood Flo.. (-rrchral Mrl.holl.rn, Rlnrd Oaw,, nh.r1 pll. Atlrrl.l 1'ulw Prr.Wre (~rrrr,, IIrtIr.K.rdlnp.m., end 1'Itttrurnccphdogr.rna 12 I ' RUSSPt 1. W. WF,1 I.PR, M.D., P.rAofn- firr, Memnri.l (I n+pirel, Wrst t'hester, renn,yl.enia; rnrAr.InRbr, Cornrnunity Iltnpilal, Fphreta, 1'enmyL.nle; Aaao- rintr rrnfrnrnr eJ ror6olnRf. N.hnt- menn Medicel ('otleRe, Philedelphie 2, reoe,rt..nie SIMt7N It. WPNT)FR, Pw.l)., Rrseerrfi Prnfnrnr of ('ArmJUr~, Unlvenhy of U1lahnme Reaeerch Insthule, Norman. 0ltahome 1. Pt)WTN WOpD, M.D., Inrrruttor fn Mrdlrlnr, Brnlon Unl.enlty School of Medklee and Robert Dew,nn Esas Memnrlel t)ep.rtrntn/ of ('tlnlcel Re- seerch end Pre.enllrt Medlclne, Meue- ehu.etls Mernor i.l I loapll.ls, Sosto. I S, M w.ebu.elte i Pethntnak•Analnmk Study of Cellular Chenaes In /lumen Rronchl A Qualltallve rrnd Quenlltdl.e Study of Ihe Indi.idual Pdrphenol Cnnten( of Cigarette Tobacco end of the Smoke and Tsri Resu11Mt from ('iaertltt Snq11nR, and Alw Sludy of the Fele of TAese C'ompounds Is the Anlmel RespketorylSrstem The Elfect of Prolowged Insalelloe of To- b.cco Smoke snd of Prolonaed Ab,lln- tnce fronsthe Use of loh.cco os the Periphersl V.sculer Rnpnme (n Acute lehetetlos of Tobacco Smoke Is Mae PRfNC1PLFS ANT) COPtDTi7OtY9 OF OPERATiON Before discnasing In detail Ihe resear(:h program. It will fint be wise to outline hriefly the conditions under which the Sckntific Advisnry Board operates. These involve the followin6 three relationships: 1. R.(ntlorr fo fhe Tn6~srro fndtsetry Rea.wrelS Cnmmlrtrw. When the Scientific Advimry Board waa or6ani>•ed and its participants accepted memherahip, it wan clearly atated by the Tobacco /nduary Research Com- mittee that the Roard would have complete freedom In all of Its activitks. The Committee must, of course, determine Ihe total amount of funtlt which will be made available for research activitka. The Board. how'ever, was not to be restrictcd or In any way Influenced In preparing or makinR its rccommenda- tions, either Renernl or detailed. These policks have been ob.erved and ell of the Iloard'q recommendations have been accepted by the T.I.R.C. i 2. Re/arfnn to Rrrlpl.nt. ./ S.ppori. in preparing guiding prln- ciplcs for Rrantees, the Scientific Advt>,ory Board and Tobacco Induatry Re- search Committee followed the most liberal etampks theyeould find recorded by other RrantlnR aRencki. A copy of "Sratement of Conditlons and Terms linder Which Project firant. Ate Made" (s given to all grant reciplents, as well as anytlne elu Intcreeted. ThH .tatement includef these points' "Re.rary h pnik'y and proRrarnminR re the rraf.ctnaihllity of the Scientific Adviutry Iloard... i,

"7?u Committee desires to have aciend,ts work with 'he Rrratesl freedom and without dnminatinn of any kind. It will make nro altemrt to direct the administralinn of the rroject once afarted. to influence its cnume nr to aintrol i1s results other than to he assured that the funds are properly e><f+en(kd for the purposes of the grant and that all findings are rs;+orted in accordancc with the hc,t sckntific practke... "Grantees are to furnish a rrprxt of activities semi•annually. These need nr,t be eatenslve hut should be suRcknlly in/orma- live to permit the Sckntifx Adv1.r" Roard to the Tobacco Indus- Iry Research Committee tn know what is being accomplished... "The Tobacco indu,lry Research Committee arr+roves the initial presenlation by the (nvesliRatnr of research results only in accepted medical and .ckntific jnurmis or before accepted medi- cnl nr sclrntific x.cktks. It has no ohjt+ctinn to disseminalion to the puhtic of any or all final ennclu,ions from rrn}rcl, In thfse ways...' 3. R.1stlnn of Sr/.ntffSr Adr4.nry Ifoerd M.n.hrrn to F.swh nther. The Rnard rrcnRnired that its ,ise must be kept small In insure the gttat but intangihle creative value of intima/e mntual fricnd~hip and understandinR between itl meml.ers Such a relatinnship p/arantees the hiRhest dep,ree of allendancr, interest, interchanRe of idea, and eonservation nf time and eRnrt. I/owever, a,mall board al~n requires free and unrestricted u+e nf cnn- sullanls, either Individually or In Rrnups, in order In have access tn all available information and to obtain much neeessarradvice in planning new lines of research. l.ater in the report it will be seen how helpful these cnrnullents have been and will continue to be. Another Important factor In the activitks of the Scientific Adviu,ry Bnard is the divi,ion nf labor according to the special intere,ta and aptitudes nf the individual memhers. Prcliminar7 review of applications for Rranh-in- aid, inter.kws with prospective Rrantees, and contacts with medical and Rcienlifie groups are etamples of the sort nf work aceomplished by itr`ard memherl between tmrtinRs. Recommendations based on such ennlacts are (fiscussed .nd acted ul+nn by the full Ronrd. In all ol Ihis review fnnctinn, the aervkes of 1)r. Rnt.ert C. /lnckell, Asxlciate Scknlific hirector of the Committee, have been invaluahk. The ftnard mainlains f+rr.nnal contact with each makx RrantcY, for nnli v by so doinR ean the Roard deveh.l+ nd maintain the type nf "front line" infnrrn.linn an neerssarT in sueh  c(implex and uncfiarted firl'l TIIF: RF.SF.AR(lli I'ROCRAM The first rcspnnsihirty of an advisory board is to take time to think ahnut all pha,es and asf,ecb of the rrsponltihility with which it is charged. The broad definition of "tobacco in relation to health" involved far more score than any one person or small board could hofx to cover in detail by espert knowledge. Out of discusanns by the Sckntific Advisory Board evolved a broad "macter plan" which included three main areas of investigation as follnws: I. The phyriral and chinrkal r»rnnn.drlon of tofrorro and accnmRany- inR prnducls, such as ciRarette papers and additivcs, and of their combustion ind pyrnlysis products. 2. Tirtvl rhonRfJ In hnman.r and In onlmoLr, In normal life and under laboratory cnnditirxls; subjexted to various "a, duration and intensity of exf+osure to various tnhaccnl and derivetivett, and other potential irritants. Tissues of sl+ecial inlerest .re those of the lunRs, cardiovascular ay,tem, mouth, throat, endocrine Rlands, and other or6ans In suhjects of various ages, sex and strains. 3. SmnA1nR nnrf nthrr rnha.rv+ hohlr.t, and the nnnrlnnnl nnrf phyrfrnl rnnllr-up n/ xnrnArrr, with rrsfrcet to estahlishment, duration and Intensity of tobacco use, and cnnelatinn of these data with metahnik. Rlandular and nervous tvT+es under varinus degrees of atress and challenge and of other environmental factnn. Rrnad and inclusive as this three-area program is, it defined the fleld nf general interest and, from this, the Roard could determine the pertinency of ~rant applkatinns and create the more definitive rescarch program that has since Ruided our eRorh. While the Rnard ol+erates on f+olicy matters and grant applicalinns as a whnle, each member has aeeepted special resprmsihilitks to help guide and devekqp the prornlm In one or more of the nine qpxcific fielrls nf tesenrrh intn ..hkh the S I,St10,11(10 so far appropriated by the T.1.R.t'. are now being channeled. A discussinn of these nine fields fnlbws: 1. Pr.lrwrnrlnn and Anaiy.fo of Tob.rrn I'1.rlrv.Nrti. (1)a. ('AT- Trl l, IArYN1SlN1 AHn KOTM) hefinitkin and estahliahment of etl+erirnental conditions whkh simu- late Ihnse under whkh tobacco Is normally amoked or otherwise used was needed since the prnducta of partial eombustinn and distillntinn of any nrgank material will vary In enmf+nsition with ennditlnns of the prfKCS, ilsclf. v 14 1; (.~ (J

If the cmoke condensates, tars or derivatives have been prepnred or stored under abnormal conditions, erperimentation with them has no hear- InR on the practical evaluation of tobacco prnducts in relation to health. The Scientific Advisory Board• with the help of scienticb at the various lahoratories of the tobacco industry itself, developed a detailed description of the best availabie amnkinR machines. This material will he published an that investlRaton anywhere can reprcxluce the smoking techniques and Increase the siRnificance, applicability and comparability of their work. Much more research needs to be earried out on the Isolatinn, identifi- cation ^nd analyqis of the great number of chemical substances derived from the fractionation of tobacco and cigarette paper products. Such research is being encouraged among independent cclentists as well as in the tobacco industry's own fabonfories. In planning researrh on auMtances In tobacco, the ftoard rrcelved valuable advke and ald from nr. A. J. ItaaRen-Smit of the California lnsti- tute of Technology. hr. 1faaRen-Smit pointed out that Isolatinn and chrmical Identiflcatinn of tobacco fractions could proceed succe«fully, but he fore- saw a"bottleneck" In the absence or inatkquacy of methods for atsayinR In humnn-i or animals the possible effects of suhsennces so obtained. A eontlderahie numher of inveqliRatnrq in many labnratories will prob- ably continue in concern themselveq with laolatinn and Identificalinn of various tobacco fractinnq. StKh elhrtq may he hrlpful, hut until much more effective methods of aiqayinp thrir rfTrcts on IunP anll other fietllrs are deviaed, their cnntrihutinm to etrrrimrnt,A .nalyqic of the rmhicm will IT incnmplete and inndequate. One of the Rnard's eRnrts in deal with the dr(icicncy are diuuaed under Section V dealing with tlisue culture. U. fl.e of f.arbonre as aTracrr Ffemrnl in Tobarro (Da.laconsoN) Applkatinn of our tecently acquired knowledge of using Induced radioactive Isotofxs as tracer eiemcnts has been given serious study. For conducting experiments on the annlyais of tobacco, plants grown in a car- bon dioxide atmosphere containing C", one of the radioactive lsotopes, are potentially valuable. The f)oard has surveyed eilttinR faciiitkt for growing such plants and has eonsidered eevenl rtept to he taken ahnuld any eatrmion or Increase in such facilitks become es+entlal. Reeause of the technical difticultks In "proces+InR" tobacco an trown and because of the small amount of ineterid that would evrntually be nvnil- .hlr, any active rrl.r.m of inrrraaerl prcwluctinn has hren Prrol+.rnrrt untll the nrfd t'rComrt more evident. in. Parho4,Rtc Anafon+k Rene•arch (DRs. Re1MANN, (.YNCtr, KoTnm) The Iloard early recognized a need for greatly increased knowledge of the pathology of the human lung. Study of human lung tissues was de- sired to observe the kinds and eatent of abnormal changes and their possible relation to occupation, place of residence, past aifinents and the like. No one institution had sufficieot data for a *idt coVera6e of this field, nor did it seem probable that any one laboratory could akne obtaln a autricknt mass of data. The Board, thereforr, planned a cooperative study to include twelve clinical-patholo6ical laboratories. It calkd to6ether the following patholo- Rists for a conference to discuss the feasibility of the plan, and, if approved, to put it into operation: DR. D. MURRAY ANOPViNI; Udeenlty of Wbcv.sl. Medk.l School, M.di,oa. Wivoo.,l. DR. P. M. 111517, I o. A^~tks Co.nlr flo.ph.l ord Unlvenlty of Snuthers C.tiforni. Sctxrol of Medklaq Lor AMK1M California DR. Wtt.l IAM It. CARNFS, Stuford Vnirenly School of Medklee, Sne Fr.nciscn• CaIlfor.la DR. RI1SSF11. S. FISIIER, OQlcw of the Chkt Medical P.aaminer, Stua of M.rrl.nd ad Uelvenity of Muyl.ad School of Medkine, Ifdt1- more, Maryland DR. RUSSFI.L L. IIOLMAN, louiriaea StNw Udeenhy School of Medl- elne, New (Hk.a+, l.ouWae. DR. KF.NNETII P. KNUOTSON• Ve(er.as Administnttoa {tospltd and Univenity of Washingloa Medical Schoot, Seattle. Washinpoe DR. MARVIN Kl1SC11NFR, New York U.lvershy-ficlkvue Medkd Cea- te-, New York, N. Y. OR. H. R. PRATT•TTtOMA3. Medkd Colkge of Sovts CYrolina• Chnks lon, South Carolina 1)R. WII I IAM O. RUSSP.t.L, MD. A.deryoa Horpltul, Tbe University of Teur Medical Ce.ter, Hoston. Teaas OR. if. D. WARNr?R, State UtdvenNy of lowa. Collegs of Medklne, lowe cur. Iowa DR. Wt1.t.tAM P. MARTMAN, Wesky Memori.l Itosphd and Norsb- we+tere University Medkd School, Chk.p, 111inob DR. Rt1SS17I L W. WI?t1F.R• The Il.hnemane Medical C.otlrre and I1.». pital of Phitnlelphl., Pesrurlwni. (Now at PpM.ta, Pennmrrv.ni., (:ommunity llospitd) A preliminary confereoce enabled the Board to organize the project. and produced frank and free discussion of techniques and experience which proved to be most fruitful and stimulating. Two other conferencea of these patholoRists have been held with practically Itl(Iq„ representation and with steadily growing evidence that the principles underlyinR such a eocquralive venture are sound and creative. T his pathnhyic-anatomk study of human lungs was fxRun In Feh-u- ary, 1955, and rrnewrd for a!tecond year in Februaty. 1956. (T 1~ 17 (•1

1hr twrlvc participants are widely scattered p,eographically for the I.urlr.cr of randumving the effects of envirunmrnt upon thr suhjrcts of stwtr. . Sl.rcial attrntion is also heing given to the nature and utent of lesions mJrcatrvc of prrvinua infection of the lung tissue. StatrltKal stuJy of the possihk history of previous infection in rclaticrn to Inng canccr may t.e an important matter and may give intcresting Icada hu murc cslcmrvc pathokogical investigations. 1 tr make the data derived from the different laboratorics comparable and trandar,lircd, a uniform systcm of reeording was di:vised by Mi+s Mary Itur-r, the S<irntihc Advisory lloud's atatislical assislant, nJter eorrsullation with I)r 1' 11 Wrlu.n, a mcmber of the ISoard, and with the twelve ctr.pcrat- inr m.c.tir..tltua I his will greatly facilitate statialical analyah of the perrled tLv.i •Mainrd and will thus augment the value of the effort IV. I7Lrrt Appllydbn o~ ToGsrro f)~r:oativra (U~s. IZrurANN, I It rt n, lAC<rev1N) Anrrnefs (d ddfrrcnt grnctic backRround out only prothrcc diflcrcnl tharat,rrltlK incidrnce of lung and other types of eatxer, but elut rcact in ddlcrcnt chunclrristic ways and degrees to challcnging suhrtanccs applicd tlirectly on the rk in or eLxwhere. 1)hc FlouJ, thrrcfore, agrecd on the policy of advocating the use of ctpctirnental animslt of known genetic composilioo wherever fxwarble. With thrs in mind, assistance is being given through is grant to the Roscoe D. )xkson Mcmur'ral Lahoratory, Ifru 1lubor, Maine, to help stabilize ^nd intteux prt.duction of the desucd strains and hybritb of mice, which are the mt.,t widcly uud and liest andyred crpcrimeotal animali. RcctrRnizing nl.u the great difference in tesponse to chemical challenge as shown by Jillerent species of animals, the tloard is interested in increas- inR knowledgc of sl+ccics susceptibility as well as strain tusccptibilitirs. In the tame way, varions sites at which the ehalknge is applied require careful study. T1,e high degree of reactability of the akin of mice, rats and nhbih c'ontrasts intcrestingly with the relative inertia of the skin of guinea pigs t•t of primatcs. Relationships of this r:ort indicate the need for estreme ct.nscrviriam in catrelx+lalinR results obtained and conclusions drawn from one tipct its to >.nunccr, and even from the reactions of one lissuc or organ syNrm to another in the field of carcint+r.rncsis. Only an rrfrmrve scries of erfarirnrMs with animds in whieth tprcies, alrAin, .t1, nRr. dt.tnRr and othcr fatttas •re conlrtdlcd and evaluntrtl can Rivr the rnl .J r.+r t infnrmatinn on whith rrra..nnhly tafr c.mt 6rti.u,s , nn IY t.nK.t Annthcr tyf.e of eaposwe is throngh inhalati<>o. Dr. Kotin has had long csl.erienee in this field and is acting as a subcommittee of one to review appiicatiuns relating to inhalation esperimcnts. ( luse contact is maintained by the doud within the wholc field of csfxrimcntal erpusurc. Efforts are continuafly being made to evaluate ht,th the positive and negative resulls which various investigators have refwirled and are obtaining at pretent. At hcat, work in animal exposure can produce only indirect evitknce on the clittluRy of human lung cancer. flowever, there is real valuc in animal work; it can and often dcres suggest probkmi and pathways in clinical rcacarch. V. Tiaaue Culture Rwaeoch (UeS. JaCUesuN, I.vNC tt, ('uMaur, f{YIMANN, f,tlllr:) Suuc it is drllicull to ohserve or to eraperitnent on the anirnal or humsn lung of on the cardiovascular cystem in situ, effo(ts are being made to dis- cover and develop techniques by which experimenters can obtain acce+s to living lung tivtue under conditions which allow direct observation and manipulation. As was LC,inled out by Dr. Ilaagen-Smit, the real problem involved in the functional ttudy of the derivatives of tobacco it in finding better and more arcurate ways of determining the effects of these chemical suhstances on living tigsue. The ftoard, thcrrfore, believes that aawng its maj'or responsihilities is the dcvclupmcnt of new methods of bio-assay that will allow the direct ohurvatiun of Icactions of human and animal lissue of various alrcs and origin. To survey the prnsibility of initiating and tupporting reseateh into the maintcnancc and growth of lung tiasuc and of catdiovascular ti%suc in vilr,., eleven of the Itarling American investigalora in the field of tisiuc culture were invited by the fltrard to New York for an informal urnfcrence, exchangc of views and diccu+eion. Those in attendance were: t)R I.AWRfNCt? RtiRMAN. Irofrunr of MrAlrlnr, Wayne tlnivrrtilr ('ntlrRe of Mrdicinr, tk,rott, Michlirras r)R 1OItN 1 RII:Cr l V. NroA. Crfl GrarrA S.rrtnn, Sru.n Krrrr,inig IrnN Iu1r fnr ('.nrrr Rrtrarth, New Yor\, N. Y. 1)R tURRV I:A(71t', (-Alr/, f r/vrbnrnra/ 74sreNur4r, N.li..nnt Ari.,o f.inl..ah.1 InMttutr, N.rlon.l In,tilulrr of tladrh, Rrlhnd., M.,r1anJ t/R Wit 10N R tARt 1', Ifro/, Thrrr ('..Irrr• Nl..l..av. N.rl..nd 1'.n«r Iotrnurr, N.N..ed ,n,,.rurr• .,f Ilr.nh, Rrrhr,d., MuyLnA MNC Rtrttr (111trff P. Nrnrnp.t.f.f.r.Ic tn.rn.H., Irnivr..ur ,f IJU.,.i... ( h.,.rn IOlm,t, 14) I Il

OR_ (:P(IRU1'. o. OfY, Anl,ran( Irofrr.nr of Suryrrrl. lohru Itot 1im Un~.en~tr $choul of Mrd.cinc, Ratomnre, Maryland DR Mi1RGnRf I R. Ml1RRA)', Ar..rc,arr PrnJr.rar o/ Anm..m.. (~nlnm Ina tlnr.rn,ty (i•llrge ul 1'hr,.cr.n. anA lurarnn., New Yoil, N. Y I)R. (: M POMIRA1, P.n/.n.,. of C)rolnrv, Ihe Vni.en,ty .d lr.._, Mrd.rd I1r.nch, (:.Ivr,tno• Ic.a DR 1rtS1 P11 1. Ollll l/OAN, 1., ('A/ef, Virus and Tbrur ('uhor• L,A ornra,r,e,. ('nllege of Medical Iiv.naeli,t., lA,.na lind•, I.r Anitrlr., ( aldmnia I)R. ( IInRI l Y WAYMOVtII, RrrrerrA Frtfe.r, Rnuoe R. l.ct.oe Me morul I atx)r.fory, Rar Ilarhor, Maine t)R. P1111 IP R. WIII I P. Rrr.arcA Aau,rlarr, Rmcne R. J.clu,n Mrm.nial ( at..ntnry. Bv 1/arBor, Maioe lhe cunfcrcnce was most rewarding in its delineation of the prescnt status of the art and scicnce of cell culture, and encouraging with respect to its Iwtrnual al+ptrrations to the problcros at hand Followtno thc crm(errncc, the ticrcnlrlrc AJvru+ry Huard tecornmcn(1cd an af+prnpriathr,n hc marlc to a«iat Ihr somrnrr training I,roRrarn of thc lissuc ('ulltue Ass.Kiatnro and to T,rr,villr ~rvrral Icllowslnl.s for sludy of hun,.n lung lissurs in vrn.,. ') he afq,trq.natrun was suhsrqurntly npproved by the Tobacco Indu%try Re- sc.u( h ( "ummittcc. VI. Cordiorn.culnr anJ Coroner7 Rcarnrrh (f)RS. ('A)irtt, (-oMlrpR ) (:h..r Phyalof.,Ry (f)a. Rlrr+lloPP) Va)ious retationships between nientine, nd f.erhrps other tnbaceo dcrivativcs, and vascular and cardiac function have lon6 been hY1w,thctircd and rumored. 1'xnrninatioa of the litcrature rcveals a distinct need for furthrr rcuarch to take full advantage of newer experimeotal techniques and to fill very real gaps in our knowledRe in this field. So evident i+ the need for careful and critical planning baird nn frank discuvion of our present kvcl o( information that the Board hcld a con- fetence in New York of research worken who are grantees of the Tobaeco Industry Reseenh Committee or who are ass(xiated with its program. IoRrthrr with a few gucsll. llte following pcrsont attrndrd: Crantr.s and ./.•nelnfca t1R 1'R11ICi (1 At~I1N(11 R, Rn•rnn ('Itr Ib..r•Ir.t. R.,,rnn. M.....hu.rn. 1)R RI/ IlnRtt I nINO, Mrdfic.d l'.,I/err af Al.h,m.. n1.b...,. OR Irtl)1+ N' I('KCI1lN• M.,_..ha,rn. Mrrno~/.l ILnpIr.I,, 1lnann, ~I....~. hu.rn. 20 i DR 1 RANK C. fPRGIKnN, 1., Athany, Medkat Co11rRe. Alh.nv, Ne. Yn.l' UR VINI IN1 I 1ONTANA, New Ynrk Uni.rrary.-Retlevue Mrdiul ( enrr., New Yorlt, N Y. DR IM'K fRfl/Nt)• Medic.l Cniklte of Virainia, Rich.nnnd, Vbainta 1)R ('ARI C (;RUI17fT, l/nivenit~ of Penn.ylv.ni.• l:r.du.te Schr.ol of Mrdu ine• /'hd.delphia• Prnn.)l..ni• 1)R 1/)CI P111t 11'AI'KPNSClalfl_ 7he t.anf<enao lin.pit.l, PhilaAetrhla, Prnn.ylv.ni• DR KI'11 Y I". MrKPF Medical Cotk/te of Sou1h Carolina. ('h.rte_Ino, $nurh Carnlina DR /11)(al MONTCOMfRY• tlni.rr.ity of Penn rlvanl., Phlt.drtphia, 1ron.rlvwnl DR t/tlRl PY I fF MOIt fY• t/nlvcnity, of Srwthern C.IIfornla, IM AnRAe., C.hb,rnla DR WAI If'R Rff)fC('/1 l:nld.aer Memmlal ll.npit.l, Nrw Ynrk.N Y 1)R tr'YMt)t/R 11 RIN71 PR• C.,rnell llnlvenitr Med/cd CotlrV, Nr.. Y,at• N. Y. DR IIANC Rt)ftl'NTIfIN, t)nl.enity of Penn.)L.n1., Phd.delphta, Prnn.ylv.nl. 1/R MAt/Rt(l' S SI'l)AI, R.nt.,n ('trr Rfmpltat• Rrntnn, M...arhn.rtt_ 1)R IANI t 7RAVt 11, (-ornelt tlniver.aty, Mrdkat (-rAlelrr• Ne.. Ynrl, N Y DR. RI( IIARr) WP(-NSLPR• MnnteRnre Henpitat In.ritufe of Re.e.rch• Pdr,hurRh• Prnrnflvant. DR. 1. 1'1)WIN WOn[), Mar..chwrtls Memort.t Ilo.ph.1., B,Mne, Mais.. (M,.rn• DR 1"RANK nAVIS. )ohm Itnplln, Iln+pl(d, Naldmrne, M.ryl.nd DR CIIARI1'S 1). MARPI.P., Anxrk.n Ileart A.u.cialMn, Inc. Ne. Y.nIt, N Y. MR fl I tX r MOnRP. Natinnal Ilesrt In.tltute, Rethe.d., M.r)l.nd Three half-day xaintls were held. One wu dcvoted to the heart nd coronary circulation, one tn the peripheral eirculation, and one to lung funclion and pnlmnnary eireulation. Preliminary findinRi were eompared and newcr methndnlnries were diccu.xd at x)me knglh V11. Re..rnl ancl ('...arrnlnf.atJnaf Ri.rarcll 71te Bnarrl wan1s (urther rrccarch Into tobacco in r('letion In th"c fxwly vtca, and ii reviewing the field with the nhjeet of dcvell.rinr nn ordetly and c(w,rdinatrd pmRram, rather than to itipport scsit/crtd and di+- eonnected investiPairrns that may l.e IackinR In pertinency Ahhnuph priority has had to hr riven In other .rres of resrarrh, and the (•mPrarn of rraen( /h nn the hul'ca „nr1 ila.troinlroinnl aites im In its early .tnPre, e few l,avc rrnjrctq have t,rrn IuMntrrl end f+rn/re-vs ref+c,rted Mnri• nltrntinn tn these phaars nf rriearch iq contemplated. 21

VIII..CmnRi„R 1lehir.-1'Ihr.ir..1 ond P.yclhnlnRinal Type. (1)pt. WItS(IN, T./T1It•) Amrthcr faccinalinp hut littlr-kmrwn hclrl fnr invr,tir.:rtirrn is intn the typcs of f.rranns who rcact tn the auain, ctress and fru,tritinn nf intense nxxkrn livinp by the fnrmatinn nf hahits of rscess. (-nmmnn srnse and everyday cxpcricncc have rrnvc,l that inrlividuals diflcr from one another in their case and degree of aclf<.rntrnl and adlusl- ment and in thrir Irmpo of IivinR. The same indivifiral may vary in type and cstrnt nf rcacti.ln at diffcrent agcs and under different kinrts and intcnsity of stress. Thrae diflercnccs may reflect tyf•es and gradrs of rhy.in-r~ychnlnRical interrrlatinnr and drRrces of hahncr. Such facrnrs wnuhl natvrally affect the incidence rrf haaic p.ychmnmMic rli.turhances and dnra,rs Thry wnuld Ihu. tre an imlw.rlant ekment in irxrra.inR the health ri.k ~nr1 drath falr of Ihe imliviOnak ..hn present mnrc cri/ical pha.cs nf rracti,m to strain an.t .Irr.. 11 i., nf cr-urcr, diRcull tn rrducc rrnhlcros of Ihis snrt tto exact scientific prnfwatinnt anrl to devise .uffcicntly definite rcchniqrrrs of cnntinurd nh- servatir.n and mrasurcment. 1}rrrr nrc, hnwcvcr, scvrral rirpnlarinn Rrrwpt with which studi<s have bccn prnrrrainR for some time unJrr carctul and well tr.inccl invcstiratnrq who have a kcrn spprccialinn of the difTicultica invnl.rrl 'Ihr ftnard has ma.k arranrcmrntc to asaid am1 implrmrnt ccrtain nf thccr atnifirs an that smnkinR habits ci.n And will he rrcnnlyd and can lmrr I~c c-nrrrlated with vrrinus phyvnlr.yrcal and psychnln`Kal tyT.cs which arr irTrntifirrt anrl <kfined. Since we alrredy know that hnrmnnitl srcrrtinn may fx influcncrd hy emr.tinnnl nr p~ychnMgical stress end that hnrmnnal sccrrtion alen can influence the nripin nd development of certein tyT.es nf cancer, inveelir,i- linns in Ihis firld of "persnnality° may reveal imprxtant evirtrncr nf cnnrta- tic.ns between "persnnality type" and "health riak" in which hahits of excea are "refleclinns' rather than hrinR "causes" of indahility, di,case or dealh TR. F.1r.+.r.hlp ProRren. Rmnrni?inf. the widely admitted serir,us «rarcity nf ynuny, well-traincd rrseatch wnrkrrs In the hink.gical aciences. the flnarrl rrcnmmrnrlr.l rrsrarch fcllnw.hirs nf SStx) each fnc etudents in 12 nxrlical schrwilq in 17SS 1he Tnha(cn Inrlnslry Rc.rarch ('nmmittre arprnvrr+ u- of fvn-ls fr.r Ihis prrrf.nr ')1u. Irr.Irr.1m w.14 frCrlvr,1 with rnthuei.am an,l for 1'tSG thr T I R(' , i on rccummcndatiun of the fioud, is makins possible the award of 21/ addi- tinnal fcllnwshr/rs above the 1955 total. Studcnts whu receive these felbwships are choscn dircctly by the dean or uthcr admrni,trative ulliccrs of the schools and assigocd to research proj- ccts during summcr or other oA-terms. '1hey may work on any problem selected by thcm and approved by the deans. lhe Committee keeps cntircly oul of contact with both students and schoob until the selection has been madc and the problems chosen. The Commiltee's only reyucst u that the school notify it of the name of the studcnt, thc subjcct of thc resrarch and that, at the cod of the fclluwship period, an informal report he made on the purpose and progress of the research. l:(rN(:Ll ISIONS '1 his rclhut is drsiRncd to dcscribe the currcnt slatus and estent uf the rescanlr farrgram rkvelulscd by the Scientific Advisury Hoard tu thc'1 obaccu Indu,try Rcac:uch ('nrnrnittce. Ckarly, any attempt to evaluatc at Ihis tinic the results of c.isting research projects would he e><trcntely prematurc. I lowever, these general observations, based on caislin6 scientific litcra- ture, may be made: 1. The very er<tcnt of the practice of smoking among our population is prrxof that it provi.ks some kind of plcasure and satisfactiun to those who engage in Ihe habit. f-low and why it does so are among the uncertainlics that need eaplvring. Ilowever, like any other human acUivity. Ihc use of tobacco aRects some individuals in different ways. The same may be said, of cuursc, of almost anything else we come into contact with, including Ihe food we cal. 2. Any poasibk role of smoking in the etiology of lung cancer remains an unresolvcd question. It cannot he said that smoking has t.cen aharlvcd front suepicinn; neither have the charges that smnking has a role in lung cancer causation been proven. So many unknowns still obu ure Ihe whole ficid of cancer causation that it is not possible at this s1aRc to say either "this is it" or "Ihis is not it" about any single factor. 3. In the cardiovascular and coronary disease fields, the unccrtainties regarding cause arn1 even treatment remain innumerabk. The heart attack eaperienced last fall by President fFisenhower dramatically brought to puh- lic attention how little we really know about the eause or preventiun of heart ailments. Whether smnkinR has ny significant part, nd indcerl, whether such a part may t.r Ixnilive oc negativc, is only one of the many arrta in cafAir.vascular invcviFarinn that should be esplorcd. 4 I'rcliminary .tmty InJicatcs that /he physical, rm.dinnnl nn4l mrntnl charactrridirs nl Lc.qplc whn become arnnkcri may trc nf mr.rr sipnfit an, r C7, ^Z 2.1 ~_• ,c.

r than hat been ao far rern6nized. It is a fact that many smoking studics in- volving bumans have ignored or neglccted peruinal information other than their smoking h.bit.i and one or two of the more obviowq kind+ of physi- cal ailmeots. 'ihe Tobaeco Induslry Rcsearch Committce's complete willingness to permit the Scienti6c Advisory Boud to initiate and sponxrr ba.ie rtseucb into our health problems as weH Ls to 6nance applied research intn speei5e problems should prove a Seouine and unset6sh contribution to the gaining of new knowledae with a maximum of speed and c(ficiency. r 11