Tobacco Documents Online

1962 RREPORT of the SCII;NTIFIC DIRI;CTOR C(.AliTaNCi: COOK LTTTLF., Sc.D.

TABLE OF CONTENTS ~ ('7 'N~1+ . M Page Tntroducticm . . . . . . . . . . . . . . . . . . 5 Research Findings and Studfes . . . . . . . . . . . . . 8 Abstracts of Reporta Stodies at the Cellaiar Level . . . . . . . . . . . 18 Pulmonnry Physiology and Anatotny. . . . . . . . . 22 Cardiovascutar Stadka . . . . . . . . . . . . . 23 Psycho-pbyatolo8ical Stadlea . . . . . . . . . . . 33 Tobacco Chemistry and Btocbemirery . . . . . . . . 36 PharmacoloSl . . . . . . . . . . . . . . . . 40 . Other Stndiea . . . . . . . . . . . . . . . . 41 Reriew . . . . . . . . . . . . . . . . . . 43 Recipients of Oranta . . . . . . . . . . . . . . . . 44

SCIENTIFIC ADVISORY BOARD to the Tobacco Industry Research Committee KENNE7H MERRILL LYNCH, M.D., Sc.D., LL.D., Chairman Chancellor and Professor of Pathology Medical College of South Carolina Charleston, South Carolina RICHARD J. BINO, M.D. Professor and ChaJrman. Department of Medicine Wayne State University College of Medicine Detroit, Michigan McKEEN CATTELL, Ptt.D., M.D. Professor Emtrirus of Pharmacology Cornell University Medical College New York, N. Y. LEON O. JACOBSON, M.D. Pr+vfessorand Chairman. Department of Medicine University of Chicago Director. Argonne Cancer Research Hospital Chicago, Illinois PAUL KOTIN, M.D. Chief. Catcinogenesis Studies Branch National Cancer Institute Bethesda, Maryland CLARENCE COOK LrITL E, Sc.D., LL.D., Ltrr.D. Scientific Director. Tobacco Industry Research Committee Director Emerfnrs, Roscoe B. Jackson Memorial Laboratory Bar Harbor, Maine STANLEY P. REIMANN, M.D., Sc.D. Director Emeritus, The Institute for Cancer Research Philadelphia, Pennsylvania WILLIAM F. RIENHOFF, Jtt., M.D. Profc.tror Emeritus of Swrgery Johns Hopkins Unirenity School of Medicine Baltimore, Maryland EDWIN B. WILSON, Ptt.D., LL.D. Profrtsor Emerldu of Vlral Statistics Harvard University Cambridge, Massachusetts Introduction During the past year the Tobacco Industqr Research Committee hpi continued and extended its support of researeh. The major direetion con tinues to be into some of the many dinial and experimental factors tha still need to be identified, investigated and evaluated In coroideratSon o' the origin of lung ancer, ardiovascnlar diseases, and other compka eonstitutionai ailments. While these research studies have ineteased our factual 'knowtedge. they have at the same time continued to make clear and to emphasite the great and critical gaps In that knowledge. They have oonfinned the sound- ness of the position held and exprtased by the T.I.R.C. This position is that there does not exist the essential experimental and clinical knowledge with which acience an evett define or identity the multiple factors or influences that may contribute to the origin and progress of these diseases. This statement holds good aa a genenlixation. It also apptins with even greater signiRance to judgmeets concerning the ama of these diseasea in any individual buman being. Ttutt have been and will continue to be speculations and opinions on the auses, bw lt Is a matter of sclenrlfic fact that, In our prcsart srare of knowttdae, no one knows the answer.r. Repetftiee Studfe. Iweowc+faufea Reported epidemiological findings, resulting from similar snrvM that use questionnaires and intetview:, inndicate eerfain "associations" between the incidence of these diseases and one or more environmental factors. Including tobacco use, especially when that particular factor Is singkd out for study. The methodology of such surveys and alio the interpretation of their reported findings have beett examined and criticined by competent statis- tlcians and epidemiologista. ~ ROBERT C. HOCKBTT, Ptt.D. J. MORRISON BRADY, M.D. ~ Asroefate Scientific Director A.troclare Scientific Director

It is not surprising that every time another survey of this type is con- ducted under eonditions that are broadly similar, the same general results are obtained. However, the repetition of an indirect or unsatisfactory scien- tific proceduie does not add to the reliability of the data collected by previoua efforts of the same type. Reviews and reports continue to appear, based mostly on statistically- oriented surveys. The unquestioning, unreserved endorsement, as conclusive, of each such repetitive report, which contains no new or original data but amounts to a statement of opinion, is a disservice to true scientific research. This places an obstacle in the path of accurate recognition and analysis of the problems that remain before us. As stated, great gaps exist in knowledge of the causes of cancer and of cardiovascular diseases. These result in a large degree from the lack of adequate and controlled methods of bioassay of suspected processes or aubstances, and from the absence of controlled clinical studies fully utilizing available biochemical tests of metabolic and hormonal changes and develop- ments under different physical, physiological, and mental environments. /n.proetn.ent of Re.eareh Sor61.t The T.1.R.C. is continuing its activities In supporting scientific studies and In conducting conferences of scientists In order to delineate methods of improving research in these directions. As ideaa and opportunities for the establishment of new research undertakings are deflned, studies will be initiated and continued for what- e.er period is necessary to solve the many complex problems that uni- versally are recognized as ying ahead. It is hoped that it may soon be possible for various interested organi- ntions, no.w conducting or snpporting research independently of one an- other, to cooperate In organizing programs of more sophisticated and ~ potentially more significant studies aimed at filling the gaps in our knowl- edge. edge' ~ Thia should lead to progress more intelligently than does exploiting . exclusively any one over-simpiitkd hypothesis of specific environmental 7• causation, or of aeloctire emphasis on any one factor statistically associated with certain causes of death. No Slmpte "JKagfe Bntfel" Eslata Tbe need for a broader, tnote mature and more diversified program of research waa evident In retttha of some investigations reported during 1962. During that year, scientific work contimted to support the view that the quest for a single, simple °magie bulkt^ to explain the auses or pro-. vide the cure for cancer and of heart dbea" ia unrealistic and probably futile. The interaction of many constitutional and environmental factors and influences, some of which still may be uadetected. is beooming increas- inglr evident. For this reason alone--tlte fad that research indieates a possible in- volvement for these many fadors and influentxs-it ia at present ackntifk- allr unwise and indeed may be harmful to atttibvte a simple, defiaithe, causative role to any one of them, or to attempt to assign them relative degrees of importance. The smoking of tobacco coutinoes to be one of the anbjects reqoi:itg study in the lung cancer problem, as do many other agents and Influences in modern living. Science does not yet know enough about any tnspeeted factors to judge whether they may operate alone, whether they may operate in conjunction with othert, or whether they may affect or be affected by factors of whose existence science is aot yet aware. Indeed, it is not known whether these factors actually are "cawatfve" In att7 real aeeae. 6 7

Research Findings and Studies During 1962 the Scientific Advisory Board to T.T.R.C. made grants for a number of new pn*cts and awarded grant renewals for continuing work in the broad areas of laboratory experimentation, clinical investiga- tlons, and epidemiology. Progress of the research is partly reflected in pspers published by recipients of grants. Since the 1961 Report, 60 addi- tional reports have been published, bringing the total to date to 282. Abstracts of the new papers appear elsewhere in this Report, and may be consulted for details on progress of research. Ail grants awarded by the Board are for studics that promise to ad- vance the Board's objective of stimulating rrsearch that will produce help- ful knowledge about what is involved in the problems of lung cancer, coronary disease, and other ailments. Viruses and Cancer World-wide scientific interest in the viral theory of carcinogenesis is obvious and growing. Considerable attention was given to this subject at the VIIIth International Cancer Congress held the summer of 1962. Some 50 papers related to the possibility of a viral etiology of cancer were prestnted, compared with only four papers on that topic at the Cancer Congress held only four years previousiy. This increased interest in and attention to virus-cancer research is indicative of the rapid changes that can take place in research concepts concerning cancer. Viruses have been shown to induce a variety of cancers in several animal species. In 1962 there were reports that human adenoviruses known to cause respiratory ailments such as colds, when injected into experi- mental animals, had resulted in the development of cancers in the animals. C) As with other agencies, the T.I.R.C.'s research grants in this field have "~ been incteasmg in recent years. '.~ One T.I.R.C.-supported study is seeking to determine whether -isjected .iral agents, either alone or in combination with various environ- mental factors, will tesult in measurable effects on the tracheobronchial tree and pulmonary tissues of laboratory animals. This work also will be extended to include tissues in organ culture. Anotlter study En ptojress involvea the question of any interrelated role that infiuenza virm infections, expotute to cigarette smoke and other factors may have in the developtnettt of pulmonary and bronchial lesions in mice. "This particular study 1s an extension of work that has been supported for Wseveral years into the correlated histology, cytology, and cytachemistry of 00 the tracheobronchial tree and lungs of experimental animals. 8 Also under way is a project imolvtng the use of chemical agents in virvs-free animals to see whether it is possible to elucidate the relationship, If any, between viral and chemical carzinogenesisL cea studies Of vital Importance to virtually a/l experitnental scientNfc endea.or is work Involving the ceil: For years the T.LR.C. has been aappoRtng basic cell research, aiming primarily at the training of more experienced workers and at the devetopment of more reliable and aonttate techniqties. While previous interest tended to otxkentrate upon the ntotphology of ce11s and morphological changes, the emphasis has now been shifted to the atea of the metabolism and behavior of cells in respotne to various tnestmettts. Studies now In progress aim at deacribiog basic diffettnces between normal and abnormal, or cancer, cells in vitr+o, te6ard(ess of how the celh may be affected by the challenge of some external agent. Of coatx, tn a sense a normal cell in a culture medium Is not exactly "normal" because it has been removed from the medium of ha natural host. In one laboratory scientists found that continuous ultraviolet irr.dta- tion of the nucleus of a living cell produoes damage to the nnekvs. S•imllar damage was found to occur with the use of certain chemical agents. One Important implication of this particular work Is the possibiIIty of developing and perfecting a ntore rapid and accutate bioassay metLod. A series of agents, among them polycydle hydrocarbons, are now being tested In the hope of developing a aemi-qutadtative bioassay for relative carcinogenic potential or activity of a mtuhltnde of subehttoes. On April 21, 1962, the Scientific Advisory Beard eponaored a oon- ference on cell differentiation it the Itttttitute for C6mcer Reaeatrb, Pttiia- delphia. Among the topics discansed at the Informal session were the fao- tors within cells kading to and geiding dMetetttlatlon, and the Influences on cells of various environmental factnrs. Cheetlcd zeooestltutloe of an- diRercntiated to differentiated alls reai.ed attentlon. Discussed wete celhs- lar and tis:ue potentials, infiuence of chrontoraoefes and genes, varfoas forms of "rtttttatlon," organiration of thsnea, and otbet tapks. In addition to staff inemben and members of the SAB, the followle= were present: DR. JOHN T. BONNBR, prbebt0e LfAl.atAr, Sineeton, N. J. DR. DON W. PAWCEIT, Natvind UnLetfity, C1ambridae, MaMr. DR. CLIFFORD W. OURNEY, Uah"ahr.of Chkato, q+icago, Itt. DR. ALPRED 8. MIRtlCY, Rot4efefler Intiditiil, New York. DR. JOHN RUNNSTROM, WemrerOreL 1tt'titnte, Stookholm, Stiwcden. DR. P. C. STEWARD, Cat+etl Uni.er.tty, Itlnca, N. Y. 9

From the Institute for Cancer Research: MARIE DI BERARDINO. Ph.D. JEROME J. FREED. Ph.D. THOMAS J. KINO. Ph.D. . A. LIMA-DE-FAINE, Fit. Dir., Research Fellow MARTIN J. NEMER, Ph.D. ROBERT P. PERRY, Ph.D. GEORGE RUDKiN, Ph.D. JACK SCHULTZ, Ph.D. TIMOTHY R. TALBOT, JR., M.D. Cardiovascular Studies Support of cardiovascular research continues to be an important part of the Advisory IIoard's research program. This is a complicated and com- piex field and eneompasses, of necessity, a variety of specific topics. Work continues on a T.I.R.C: supported project which is seeking to determine if environmental factors have any effect on the development of atherosclerosis as revealed by autopsy studies of accident victims. Trained interviewers are seeking to learn all they can about the victim's life-his diet, his smoking and other habits-to compare or connect this informa- tion if possible with the autopsy data. In the same general field, a T.I.R.C. grantee has reported finding that during smoking there was a rise in serum free fatty acids . (FFA) in 17 patients with healed myocardial iefarstion, aged 36-64. A lesser rise was found during smoking In 16 non-coronary patients, and the researcher suggested that the greater FFA response In the coronary patients resulted from a greater release of catecholamine after nicotine stimulation. This dif- fereece in response, if confirmed, may reflect a constitutional difference be- tween persons who are predisposed to coronary disease and those who are not. It is, of course, not known what the effects may be of repetitive rises in the blood levels of FFA, which actually are a vital body fuel. Post-mortem comparisons of the degree of atherosclerosis In the coronary arteries of smokers and nonsmokets have shown no significant differences. Animal experiments carried out under the T.I.R.C. program have also shown no clear differences In the degt+ce of atheroscktosis In cholesterol-fed animals of tuveral species as a conseqdence of chronic nicotine irritation. 9meldwa maf Bloed net. Of importance In the cardiovascular field Is a research project that sought to investigate the effect of tobacco smoking on skeletal muscle , blood flow. Tiiere has been conQicting evidence on this subject in the few studies existing in the medicallitetatate. Working under a T.LR.C. grant, two Boston in.estigators used the disappearance rate of a radiosetive Isotope from skeletal nmscle as a measure of its nutritive blood flow. Of 17 notatal subjects studied, 14 showed an increase in skeletal tm»ek mmithre blood flow as meattttred by the radioisotope disappearance rate during cigarette smoking despite small changes in total calf blood flow aed the tnaal deasases in skie tempera- ture. The mechanism of such an Increase still temains unknown. According to the seientists, this work reveals constancy of the Increase and suggests that inhalation is not a factor. The Investigators reported that evidently an intact nervotta supply to the limb Is unnecessary since three of four sympatheetomixed limbs also showed an increased disappearattoe nte durMg anaking. Assuming that skin blood ffow does not decrease In sTmpathectomixed Mtbs during smok- ing, they said, the incrrased disappearance rate does not represent a simple shift of blood from the vasoconstricted skin to the muscle. fVtroNne end Cerbo. Mon"lde The Scientific Advisory Board has aha auQarized a studT to fee whether determination of metabolites of nicotine or of earbon monoxide in the blood stream will give more aecurate iMormatiot: on the extent to which cigarette users Inhale the stnoke. Nicotine Is absorbed in aottte deo- gree in the buccal cavity and to a gteater degrtx foibwiaa deep Inhalation of smoke. Carbon monoxide, on the other band, Is reputed to be absorbed only on deep Inhalation. Perfection of enett etef6ods may petmit more accurate detetininatioa of true phy:ioloaleal amoke expoeoa from dgar- ettes, pipes and cigars than questionnaires on smoking habits and the depth of inhalation, and thus may ralse coerelatioe studies to a new kvel of reliability. The methods developed In thts itudy w1II bd at+ed by the Irt.eitlIatoa to help interpret resnlts of anothet project on the relationship between steroid levels In body fluids and .arioes forma of heart dfsease attd cerhin types of malignant tntnon. This lattet pro)oet Is to be supported by, a federal agency. An Investigation has been 1nlvlited IY1Qf tegard to earboe tnotf- oxide. The amounts of carbon monoxidd that Cae bti absorbed eaee thteugh very heavy smoking have been oht~l'n t0 liti well.below the toxlc level. Since the traces of carbon ntonouidb.Qttlent In dh*+etts smoke are relatively constant, this study wiil seek to at:termtttt whether blood levels of arboxr- hemoglobin, which can be dctermined very tk.~eeratety, will reflect the 10 !1'

differences between the amount of smoke contact with the alveoli involved in several different forms of smoking. Work also is being supported with the objective of learning some- thing about the effects of nicotine on the cerebral circuiation. A technique of angiography has been developed whereby it is possible to take what amounts to x-ray "movies" of the blood flow in the cranial vessals includ- ing the so-called "circle of Willis," the structural distribution system that monitors rtgional cerebral arterial llow. This technique has already shown its value In diagnosis of circulatory obstruction. This and other studies are supplementary to previous indications that nicotine may have stimulating or, in some ways, tranquilizing effects on the central nervous system. ConJern.ee on Cerr6ral Effecta of JYicotine A conferenee on the effects of nicotine on the central nervous system was held by the Scientific Advisory Board in New York on Sept. 28, 1962. Work under way in this area and specific topics in need of further research were discussed by grantees and others Investigating this particular field. In addition to members of the T.I.R.C. staff and of the Board, the following wete present: DR. A. K. ARMiTAOE, Kina s College Hospital Medical School. Lon- don. England. DR. EDWARD F. DOMINO. The Univenity of Michigan Medical School, Ann Arbor. DR. ESKIL HANSSON, University of California Medical Center. Los Angeles. DR. ERBE CURTIS IiOFF erro DR. CHARLES HOCKMAN. Medical College of Virginia. Richmond. DR. PAUL S. LARSON, Medical Collete of Virginia. Richmond. DR. EDWARD W. PELIK;AN, Boston Univenity School of Medicine. DR. H. C.•SABELLI, Chicago Medical School. Chicago. Itl. DR. CARL G SELTZER. Harvard University. Cambridge, Mass. DR. DUANE 0. WENZEL. University of Kansas. Lawrence. Stardlea In tAe Cireatlatery Area Ne.w atttdiea eow bdat supporttDd in the getteral circulatory area are eoneerned with vasettlar eeapottsa to tobaoco smoking in patients with .aacular draease, the relwe of atbcholaffiittea frtatt the Isolated heart. the effect of niootine and related substance on amine levels In the nervous .ystem, and the InAtxttce of drugs on arterial acid mucopolysacchsrides. i . A study was undertaken to Investigate the controversial quatton whether Buerger'a disease and general peripheral vascular disease are separate clinical entities. Research done under a T.I.R.C. grant led the authors to conclude that they are. The study itrnestigated the Bttetger syndrome in patients, most of whom were heavy smokers, in the Orient, where it was found to ocntr with relatively high frequency in J.pan and Korea among persons of 1ow to6o•economic elaaa, and in the United Statea. It was found that those already aflficted with the Butrget tyndtvtne were sensitive to tobacco, but there was no itnplicatiat that a sintilar arnsi- tivity occurs in persons with getteral peripheral vaxalar disease. Multiple factors of undetermined etiologr seem to be Imohed. Work in this particular field Is conthtuing with a study of Boergeei disease among various Jewish ethnic groopa In hrnel Some acientlats hare reported that, for some still unknown autson, the diaeaae appeara to astict male Jews more than those of afly other tace. Of intetest in coronary research are the fe.ctat stttdka that ha.e been previously reported on the relationship bttweeo the incidence of heart disease and stress. One survey covered 10,000 phydoiatta, dentista, and lawyers subdivided according to the relative atteasfuhtaa of their speetal- ties. Its author, a cardiovascular aptscialist, teported that entotional attesa appeared to be an Important accelerating factor in athenngeneata when the diet is relatively high in animal fat. Other ttaeasdtets htt.c tepattd flnditts an association betwtxn coronary diseaae and etttotioeal attess and strain. The investigator is about to undertake a similar study with stock market workers under a T.I.R.C. grant Snwlidng end Prelefw ilfetabettaea It has long been tnown that young tteintah exposed to tobaooo smoke or treated chronically with nicotitte, pin weigltt at a lower t:te than non-exposed controls. If protein aceea! Is adequate, attrniral of tlte animals is not impaired. Following reports from England that ratt so expoud eartete more nitrogen than controls during the duration of the eltposttre, att in.esdgatiott was begun to determine whether an analagottY effect can be observed In healthy, young human subjects. Cenetfe emd Payeho•Physfolejled Paeferl Of continuing interest to the Sctentiflc Ad.isoty Board and to others is the relatively unexplored probknn of the a1tft and ditTering eharaetet- istics of people-genetk, psychological and phy:fologkal-.nd the bearing of such differences on disease prcdispoaition. 12 13

It is now recognized from a number of studies here and abroad that there are measurable or detectable differences both among people who smoke in various ways and between those who do and those who do not smoke, subgesting that smoking practices may in part reflect constitu- tional factors that may influence different disease predilections. One study of male patients at chest clinics reported that the person- ality traits of lung cancer patients differed significantly from those of cancer-free persons. A T.I.R.Crsupported study of a biologically and culturally homo- geneous group of italian-American factory workers, almost al1 born In this country, found that the leaner individuals smoke significantly more than the stout or fat, but not museular, ones. Contrary to other previous reports, the smokers in this group were no kss masculine in physiqlre, no more active, and consumed no more alcohol than nonsmokers. Another eontinuing study is seeking to determine or define the pre- enrsors of hypertension and coronary artery disease in a group of medical school students. Reports already have indicated that a familial factor is involved. A prospectlve phase of this long-term project is the analysis of figure drawings obtained from the students. It is believed that these figure drawings may provide a simple, effective, psychological screening device for the pecromdity appraisal of normal subjects. Also continuing ia a study of the psychological, cultural and health ehar.deristica of aging smokers and nonsmokers. Another investigation just beginning will seek to examine the extent of and constitutional basis for differences In taste sensitivities, and their possible "correlation with any constitutional predisposition to pathologic conditions, with differences in smokirig practices and with food dislikes. Also getting under way is a study into psychological intluences upon the translation of motives into action with smoking behavior as an instance. C14eerl.by md Bloel,ee.bery The Scientific Ad.iaory Board awarded a grant to scientists at North Carolina State Colkge to measure the levels of arsenic absorption by tobacco plants In relatiott to soil content of the element and to estimate the residual levels of arsenie In the soils used for tobacco growing in various parts of the state. Tbe study fottnd tbat aistnie In sotls ranged from I to 5 parts per milltoe (ppm), with an airetare for all areas of the state of 2.8 ppm. This value is close to the 4 ppm reported by J. E. t3reaves In 1913 for a virgin aoil and thm suggests that thete has been no measurable increase from the pre.ioos use of atyenial inaeetiddes In the arsenic contents of soil In which tobacco Is grown. , The investigators reported arsenic in the cured leaf of tobacco grown in these soils was from 0.5 to 3.55 ppm, with an average for all leaf samples of 1.5 ppm. Also under T.I.R.CC support Is a study designed to see whether virious amounts of trace metals, including arsenic and nickel, when added to tobacco, will have any effect on the Incidence of pulmonary adenomas In Strain A mice that inhale the smoke from such tobacco. Control studies will administer the same metals by other routes. Another supported project will attempt•to identify individual poly- phenotic compounds In cigarette smoke and to estimate their amoonts. Where feasible, these compounds will be prepared for future or oonn+nent studies on their metabolism and possible effect on human beings. Epidem(ofoRice! .bre A study is now under way Into the Influence of certain environmental factors In the genesis of neoplastic disease In tuberculosis patients atd in children. The work Is being done by four California acientists who received a grant from T.I.R.C. to augment their current project of tesft the hypo- thesis that medical uses of radiation are associated with an iaerase In the Incidence of leukemia or other maNgnattcies. The T.I.R.C.aupported project will seek to study the Incidence of lung cancer or other cancer In tuberculosis patients with a design that would ascertain the relationship, if any, betweett lang ancer In such patients and three factors-tuberculosia, smoking habits, and radiation expoture. Also under way In Massachusetts is an epidemiologieal lung cancer study designed to check a previons investigation. The investigators found in earlier work that there appeared to be a statistial correlation between lung cancer and cigarette tmokinE, ttspiratoty illness, heavy consumption of alcohol, and outdoor occupatjott. They ttaid that while the statistial correlation between lung cancer and cigatette tefoking was stronEest, the data suggested that a threshold In oonsumptioA had to be passed before a linear relationship occnrted. The data furthtx showed, they reported, that the same level of cigarette use with eddltfart of pipe or eigas smoking dimin- ished the disease association, a result diffieult to interptet. Lana P14y.foloory ' Certain phases of the actual telctttiikii *Or1: of the human lung remain a mystery to science. One such p6.fe it pulmonaryclarance- exactly how does the lung retttove Inhaled particla. A stodj now under way In this subject deals with the phag.ocytea found in the palmottary alveoli. is 14

The work began with the concept of measuring the overall lung clear- ance capacity of healthy, Intaet rabbits. Radioactive silver iodide, 1-131, (which is also used by meteorologists to seed clouds for production of rain) was introduced into the lungs of the rabbits by a non-inhalation procedure. The movement of the radioactive element was then traced with aensitive measuring equipment. It was found that eventually all of the 1-131 was engulfed by the alveolar phagocytes and carried to the alimen- tary canal whence it was excreted. The current phase of the study encompasses the inhalation of whole cigarette smoke following Introduction of the 1-131 in order to determine the overall effect on clearance rates and the relative rates by alternative routes. Other animals are to be used in the project in addition to the rabbit, and drugs that affect the flow of mucous also are to be investigated, as well as the effects of other inhaled gases and aerosols. Alveoli Studled In P.lmonary Emplrrsema Recent discovery that a powerful surfactant substance lines the alveoli has gone far toward explaining the hitherto mysterious physical character- istia of these structures and their behavior during expansion and contrac- tion. Moreover, the effects of this agent and the consequences of its deficiency suggest that a biochemical approach to the investigation of the etiology of emphysema may now be within reach. A project has been sponsored in which lung tissues obtained at surgery and at autopsy are being studied. It will attempt to measure the relative activity of this sarfaetant recavered from lungs afflicted with carcinoma, emphysema, and bronehieetasis. Effort will be made to determine whether tobacco smoke inhalation affects the activity of this surfactant, and further study of Its chemistry will be undertaken. A report by a T.I.R.C. grantee in 1962 said that bronchial disturb- ances may produce an obstructive airway mechanism leading to air trap- ping as well as indirectly influence surface tension phenomena in the lung or impair clearance of entrapped pollutants. In this way, the report said, erosion of the alveolar membrane is initiated. Other Projeet+ Among t2te other pt»jects, which are under way In institutions throughout the cotmtry, are: A study of the nasal and pharyngeal bacterial flora of smokers, non- smokers and former aetoiters. W The classilieatbn, prognosis and possible etiologic facton in primary O lung tumots as determined from postmortem observations. A comparative study of the effects of 3-methyldtoianthrene and e9g- arette smoke condensate applied to the oral tissues of Swiss mice in which liver damage has been previously induced. The purification and structure determination of the chlorogenie acid Isomers. Mechanitms of the psychotropic effects of nicotine. Fello+oi6fp Progrom In 1962, as In every previrnts year since 1955, the T.I.R.C., upon recommendation of the SAB, provided funds for the granting of fellow- ships to the nation's accredited medieal and osteopathic schools. Nearly 600 young men and .ronteo have so far received fellowships. Deans of the schools choose the fellows, and the shtdents, working with their faculty advisors, determine the subjects they wish to atady dur- ing summer or other off-term time. The fellawship program seeks to stimu- late interest in basic research among medical school students and any subject of study may be selected by fellows, without regard to its rekvance to tobacco use or effects. Summary This narrative section seeks only to ittdiate briefly some of the more recent findings and trends. More complete details will be foitnd In previous Annual Reports and in the abstracts they contain. Work In many of these fields is continuing to receive svppott. In closing, it seems appropriate to reiterate the bask belief anderlying the Advisory Board's position, which was fully expressed In the Board's report two years ago. That report corrciuded with this paragraph: "As the tobacco industry continues Its sappott of the aearch for trvtb and knowledge, it must recognize, as is always the caae In true acJeatltlc research, there can be no promise of a quict answer. The important thing is to keep on adding to knowledge until the accumulative faets provide the basis for a sound conclusion." ~ 16 17

Abstracts of Reports Each recipient of a Tobacco Industry Research Committee grant-in- aid is responsible for the initial presentation or publication of the results of his research in scientific meetings or in appropriate scientific journals. Following are abstracts, approved by the authors, of research reports acknowledging support from the T.I.R.C. that have appeared in scientific journals since the 1961 Report of the Scientific Director. These abstracts have been grouped under the following headings: 1. Studies at the Cellular Level; 11. Pulmonary Physiology and Anatomy; III. Cardiovascular Studies; IV. Psycho-Physiological Studies; V. Tobacco Chemistry and Biochemistry; VI. Pharmacology; VII. Other Studies; VIII. Review. 1. Studies at the Cellular Level "INDUCTION OF CHANGES IN SURFACE ACTIVITY OF STRAIN L CELLS AT GAS-MEMBRANE INTERFACES." By Philip Cooper, Irene Goldring and Morris Klein, Departments of Surgery. Albert Einstein College of Medicine and Bronx Veterans Administration Hospital, New York. N. Y. Science. March 2, 1962, pages 725-726. (T.I.R.C. grantee: Cooper) During an investigation of the effects of various gaseous agents• on the growth of strain L and HeLa cells in cell culture, the immediate direct effect of the passage of particulate and non-particulate gases over the surface of these cells, in a Rose perfusion ehamber, was observed. The gaseous agents included smoke from the combustion of eiganettcs, of cigarette tobacco only, of cigarette paper, and of onionskin Paper, and non-smoke gases such as carbon monoxide, hydrogen sulfide, i luminating gas, oxygen, and helium. Immediately after the in)eetion of all gases tested there is a very rapid inerease of the surface area of the cell as well as increased granularity. Most evident, however, is "blebbing" of the surface of the cells, which is most marked near the center of the bubbks of gas and is not seen on the surfaces of neighboring cells. The "blebbing" persists as long as bubbles of gas remain In the per- fusion chamber. If the contaminated medium is replaced by fresh me ium within 10 to 15 minutes after eontamination, the ee11s are promptly restored to their original appearance. If "bkbbing" is allowed to continue for more extended periods, cellular aetivity gradually decreases and the cells die. "Bkbbing does not occur when cells in a chamber without medium are exposed to air or medium alone, under various degrees of increased pressure. It appan that the "blebbing" results from a disturbance of the sol-gel relations ~h'p d the cell surfaces and apparently can occur at a gas-membrane interface. "ALTERATIONS IN GROWTH OF STRAIN L CELLS EXPOSED TO SMOKE GASES." By Philip CooRer, Morris Klein and Irene P. Goldring, Albert Einstein Co of Medicine and Bronx Veterans Administration Hospital, New York. Y. Proceedings of the Society for Experimentol Biology end Medicine, Volume 110, pages 11-13, May 1962. The pn:sent series of stndies was undertaken to elucidate further the direct action of smoke on living cells maintained in a culture medium. The test substances included smoke from the combustion of cigarettes, cigarette tobacco, cigarette paper, onionskin paper, and tobaa:o-wra~ed cigarettes. Smoke was collected under sterile cottditions. The culture_Aasks were In- verted and the prescribed volume of smoke was introduced into each flask. The flasks were re-inverted, the fluid medium was a11ow2d to wash over the cells, and the flasks were gent]y agitated until all smoke was absorbed by the medium. Control cultures were treated In exactly the same matmer, except that they received similar doses of sterile air. The effect of non-smoke gases, In- cludin; illuminating gas and carbon monoxide, was studied uttder similar conditions. Under the conditions of this study it appears that there is a"toxic" effect of smoke gases on strain L cells in culture. This results both In mor- pholog~cai changes in the alls and in altetatlons in growtlt earres, as Indi- cated by the reduction of ceil popviations. The amoke from the combustion o[ either cigarette paper or onionstin papa ag to be more ~toxic" than that from the combuation ot whok eigarettes or tigarette tobaoop alorte. Smoke from papcr contained tnore particulate matter than smoke ftom cig- arette tobacco or the whok eigarette, suggestittg that the particnlar matter ptesent in smoke gases may be ot signitfance. "CULTiVATION OF NORMAL AND MALIGNANT HUMAN LUNG TISSUE. I. THE ESTABLISHMENT OF THREE ADENOCARCINOMA CELL S7RAINS." By Mary V. Reed, Ph.D., and Georgu O. Oey, M.D., Finney-Howell Cancer Reaeat+¢b Laboratory, DeFuttneat of Surgery, 7obm Hopkins Hospital, Baltimore, Md. Laboratory Inresdgarlon, Voi 11, pages 63$-652, August 1962. (T.I.R.C. Vanta: Oey) The ultimate goal of these tmtdk>t ia the etitabiishmettt of avtotosotts strains of normal and mallgnattt luntt epitbdkm for tvb.equettt compatatl.e studies with each other and with emtnyonic huts ce11s in regard eo cytologk and biochemical characterisNca and respoeses to vhuaa. Specimens from 41 human ases ptvvisiotnlly diaattaed as hnta at- cinomas and from I 1 humaa etnbyrdnIc Imp were cultured In roller tubes on collagen, in plasma clot, and on the glana tttMace with different cortcetl- tratlona of unsupplemented human sentm and of trctum fortiflled with thetk media: Normal bronchial epithellum pve early responsa with beat~ cilia survtving 2 to 3 n+onths. Human arcinoma cells 4a4t tlie tnetabolic advasibaga over their normal prvtotypes aa prefereatial tttmiva! and growth in oontittuons culture. Strtitntal damttttmea may mitigate agaimt such realfottses and often aocoants for failnra to obtain ekher normal or malignant cell growth In conthmoutt cuhute. , The three human tumorats epithellal oetl ttraMs described ie tMa paper are in the second, fourth attd tifth yetttf tespectlrely. Two wete ea.- tablished from poorly dil[entntiated adenoaxdeomas of the hmg, and one was a metastatic carcinoma of the breast to the lung. Each strain has dis- tinctly different cytologic and growth eharacteristb. Ig 19