Tobacco Documents Online

CTR. I 255 CTR MN 001202

1961 R1•;('OR'I' of IIlc S C I I; n''[' r F1 C 1) 1 it f; C'I' 0 it cOOt; r.rr-rr,r:, 5,.n.

TABLE OF CONTENI'S Page Preface by Dr. C. C. Little . . . . . . . . . . . . . 5 Progress of Research Cancer Research . . . . . . . . . . . . . . g Human Lung Studies . . . . . . . . . . . . . 16 Cardiovascular Studies . . . . . . . . . . . . . 17 Psycho-physiological Stud}es . . . . . . . . . . . 22 Tobacco Chemistry and Biochemistry . . . . . . . . 22 Other Studies . . . . . . . . . . . . . . . 23 Abstracts of Published Reports Cancer Research . . . . . . . . . . . . _ . 24 Human Lung Studies . . . . . . . . . . . . . 32 Cardiovascular Studies . . . . . . . . . . . . . 34 Psycho-physiological Studies . . . . . . . . . . . 49 Tobacco t;hemistry and Biochemistry . . . . . . . . SO Other Studies . . . . . . . . . . . . . . . 55 Recipients of Grants . . . . . . . . . . . . . . . . 60

S(aF,Ni'IF1C ADVISORY B()ARn to the Tobacco Industry Research Committee KENNi'ili MERRILL 1.YNC11, M.D., Sc.D., Li..l)., ('hnirmon Chancellor and Profrssnr of Pathofngy Medical College of South Carolina Charleston, South Carolina RICHARD J. B1Nt3, M.D. Pro%ssor and Chairman, Department of Medicine Wayne State University College of Medicine Detroit, Michigan McKEEN CATTELL, Ptt.D., M.D. Professor Fmerftus of PharmacoloRy Cornell University Medical College New York, N. Y. LEON O. JACOBSON, M.D. Professor and Chairrrtan. Department of Medicine. University of Chicago Directo., Argonne Cancer Research Hospital Chicago, Illinois PAUL KOTIN, M.D. Paul Peirce Professor of Pathology University of Southern California, School of Medicine Los Angeles, California CLARENCE COOK LIT71E, Sc.D., LL.D., Lrrr.D. Scitnti(rc Director. Tobacco Industry Research Committee Director Emeritus, Roscoe B. lackson Memorial i.aborauxy Bar Harbor, Maine STANLEY P. REIMANN, M.D., Sc.D. Director Emeritus, The Institute for Cancer Research Philadelphia, Pennsylvania WILLIAM F. RIENHOFF, ht., M.D. Professor Emrrltw of Srrrgery Johns Hopkins University School of Medicine Baltimore, Maryland EDWIN B. WILSON, Ptt. D., LLD. Pro/esso• Emeritus of Vital Statistics Harvard University Cambridge, Masaschusetts ROBERT C. HOCKETT. PH.D. J. MORRISON BRADY. M.D. Assoefate Scientific Director Associate Scientific Director i I Preface A monograph on eancer morbidityo, {ssued by the United States Public Ilealth Service, commented on statistical and epidemiological data as follows: "In the stud~ of cancer, a dh~ease tbat apparently can be induced by a muit'rplicity, of etiolo~ical agenta, one cannot realy istically expect to do more than Identify factors that appear to be frequently assoeiated with ancer. The propf of an etiological relationship must then be aought through rnore intensive clinical or experimental studies." This is substantially the position adopted In 1954 by the Scientitk Advisory Board to the Tobacco Industry Resarrh Committee. It waa reaffirmed in 1960 and remains unchanged at the present tirne. It is a position that also is held by many others, including statisticians and researchers. F.etdtnoe o/ Vorrora Poulble Paetora During this period signiflant evidence of various possible eontribntorr causal factors in lung cancer has been accumulating from both statistical and experimental reseanch. Previous lung infectitxn, air pollutants, genetic factors, stress, hor- monal influences, viruses, diet, and other possible influences are being investigated further and, as they are, a more accurate perspective of the whole picture of lung cancer causation is emerging. These factors are not cited either to answer or to evade the question as to what role, if any, tobacco may have M the origin of lung cancer. They do not and will not deter the Tobacco Indestry Research Committee from continuing to support Independent ttaemh which is trying to answer this question. Luwg Cancer OriRfn fi Contrplea rts.d Obaesr* The present situation emphasira the truth of what we and others have said repeatedly. The origin of hmg caeeen Is complex and still obscure. There probably are many oonWbutMg fadots. However, development of researeh Into vatian aspects of the lung cancer program has had to be carried on in an unusual and sometimes dif• Rcvlt psychological climate. This came about because there are those who would insist on accepting as a proved fact the hypothesis that cigarette smoking represents a primary causative faetor in lung canoer. This group •'MorbWtty from eaneer in the Unhed StNerr,' Pnb/k Nealth Monoaraph No. 36, t1. 3. Department of Hntth, t'4ucation and Wetf.re, 1939. Wa.hlnaton, D. C. f•aae 4. S

makcs one of the most definite and blunt designati<ms or a spccific causc 111.11 has been advanccd for any major type of canccr, and they do so at a timc when scicncc is .till trying to determine the basic origins of this diseasc. Those who most actively promote this hypothesis have consistcntly ignored or, at bcst, have minimized the fact that numerous directly relevant experimcnts either have failed to support the hypothesis or havc providcd only weak or uncertain data. This situation has tcnded to obscure the real nature of the problem and also the significance of research findings that are not cdnsistent with pre- conceived attitudes toward tobacco . Since its inception in 1954, the T.1.R.C. has advocated development of an accurate and objective perspective. This policy is reflected in the quality or the scicntists who have been given research Rrants by the Sci- entific Advisory f3oard, in the kind of work they are doinF, and in the scores of research reports they have published in the literature. The complex nature of cancer origin is itself a delaying factor and no amount of enthusiasm for any one theory can either hastcn or prevent the eventual detection and analysis of the various components and clements that are involved. Trnnnrn ernd ran.°rr Another factor of importance in the general psychological climate that surrounds the lung cancer problem is the ovcr-cmphasis of the role attributed to irritation in the carcinogenic pmcess. The matter is of rreat interest to the clinician. The obvious trauma caused by x-ray burns or that resulting from the application of certain chemicals to the skin or laboratory animals is a striking phenomenon and quite naturally attracts the attention of the re- search worker or clinician. It is well to remcmber, however, that any kind of obvious irritation per se is not necessarily or even usually a precursor to the essential intra- cellular change or changes that constitute what is called malignancy. If it wcrc. it is pmhahle that humnn beings would long ago have been wiped out by cancer. In any trauma or area of irritation there are concentric rings or hands of tissue composed of the following types of ce11s: (a) At the central point of the trauma, cells arr killcd and broken down. They cannot form cancer. » (b) Outside of these are damaged cells with impaired function and t,JT reduced power of cell division. Thcse are not precursors of CD cancer. (c) Surrounding the whole nffected area arc normal cells entirely unaffected. (d) I/ r.nrcer .xrnr.r, It i.r formed In the arra Whkh lit,r betM•enr (b) and (c•). Nrre intact and vi.ribly unharmed cells mav he released /ronr ctnnoliZed crnrnol and actually may divide m.>.t rapidly than do the normal ones. In the process of uncontrolled and, up to now, uncontrollable growth that charactcrizcs cancer formation, there may be observed changes in the number and morphology of the chromosomes. From time to time such changes have been considered to be of etiological significance. Such changes are probably of little or no actual significance in cancer causation. There are many recorded observations of highly malignant tumors with the normal number of chromosomes. There are also many types of non-tumorous cells with striking abnormalities in number and/or conformation of the chromosomes. Science must look inside the cell's most minute and delicate structures and must analyze and explain its finest and most intricate functions before the diffcrcnces between the normal and malignant cell are understood. F;pld.nrlotoRfrnl Studiea Not F,wosRh It is small wonder, thercforr, that the data derived solely from epi- dcmiological studies leave much to be desired as a foundation on which to base sweeping and dogmatic hypotheses of cancer causation. Scicntists, physicians, and the public are recognizing that fact in ever itxreasing num- hcrs, and are admitting the need of far more knowiedgc than we now rnsscss before this complex problem is fully understood and the answers to its many challenges can be expected. While the answers we seek are still not within our gnsp, we now have a far better understanding of the questions. Ckatlr, progress is being made. The findings of the past year, as reported by acientists throughout the country, indicate real hope for eventual solutions to the challenges of cancer, heart disease and other constitutional ailments. I wish to express aincere thanks to my associates on the SeientiAc Advisory f3oard, and to the as.sociate scientific directors of the T.I.R.C.. Dr. Robert C. Hockett and Dr. !. Morrison Brady. Dr. HockNt, who has been closely associated with the Soard's tesearch proEram for eight yean, has made many valuable tontrihutiens to the review of research on the pages following. While this review illustratcs the scope and complexities of prob- Icros being investigatcd, It is essentially optimistic and descriptive of genuine progress. C. C. Uttie srirntf/k nrrrrtor 6 7

The Progress of Research Progress of the Tobacco Industry Research Committee program, as developed and carried out by the Scientific Advisory Board, is reflected only in part by the increasing number of papers published by recipients of grants. Since the 1960 Report. 60 new published papers have appeared. bringing the total to 222. Abstracts of the new published works are in- cluded in another section of this Report. Mere numbers of papen, however, do not measure the significance of research progress. A review of completed and continuing research gives reason to believe that some of the year i developments open more direct paths toward discoveries that may be expected to contribute practical mea- sures for coping with certain forms of cancer and cardiovascular diseases. This review essays to estimate the state of progrtss in several fields, to assess the impact of certain findings, and to define the nature of some un- solved problems. The discussion is divided into these sections: 1. Cancer Research. It. Human Lung Studies. Ill. Cardiovascular Studies. IV. Psycho-Physio- logical. V. Tobacco Chemistry and Biochemistry. VI. Other Studies. 1. Cancer Reaearch In planning cancer research it is helpful to distinguish two different levels of attack. A full and final solution of the cancer problem may he expected to come only when we understand the basic biological mech% anisms of cell differentiation and of the regulation of metabolic and cell division processes. The most fundamental investigations of the day ane at this level, and more effective participation in such long-range and basic Cilresearch is definitely one goal of the T.I.R.C.'s program. -4 At the same tirne, research at a' kss basic level can be expected to ~produce useful information and sometimes to yield immediately applicable e uI+~asures for partial control or delay of cancer in the human population. ~tany such measures have Indeed been developed in the past. Well-designed experiments at this level may be successful in apprais- ing the relative effects of many controilabk extrinsic, as well as intrinsic. factors upon the level or h+cidenee of particular forms of cancer in animals. Perhaps the best hope of developing control measures for some forms of malignancy in the relatively near future lies in studies of this type. Scientific Z,:~istory provides many qxs rrhere such tesearch not only solved immediate C7roblems but also produced scientific by-products of even greater ultimate j value. Pasteur's discovery of induced immunity may be traced to his origi- rial attack upon the practical problems of the beer and wine industries. The Scientific Advisory Board, along with other scientists, has con- sistently held that pathogerxsis of bronchosenic carcinoma must be a complex phenomenon and that real prostess toward solution must be ex- pected through discovery and relative evaluation of a whole series of con- tributory factors. This position has sometimes been miscorutrued as Im- plying that no progress in the oontrol of lung canctt could be expected until the whole cancer problem could be finafly and fully solved at the basic level of biological discovery. This is far from the true meaning of this position. TNE EXPERIMENTAL APPROACN The several reports of statistial associatiorn between cigarette smoking and lung cancer incidence made it logical to develop res~earch to see If smoking could play a direct, primary rok in the etiology of the disease. To be sure, statisticians worthy of respectful attention did point out many anomalies and inconsistencies in the atatistical pktnte. Some even questioned seriously whether biases of several kinds might trot Invalidate the reported relationships. These legitimate questions about the statistia could, however, be left for eventual resolution by quali}kd experts In the field of epidemi- ology and statistics. The testing of the question cancerning tobacco as a possible causative factor calkd for extensive experimentat research in the laboratory and clinic. Stert.rteef Aisotietfor. Gnmet Proee Gnaettew The point reQtriring re-emphasii la this: Evee If a statistical associa- tion is assumed to be completely valid, it does not and cannot demonstrate that smoking is actually a factor in the etiology of human broncfiogenic carcinoma. It has been sho..n, for example, that there la an excellent correlation between sociosconomk class leveh and the incidence of "chronic bron- ehitis" In Britain. No clinician or statistician would suggeat for a moment that the amount of monry a man recehres per am„nn could of Itself cause any diseaal, unless he •hre actualfy infeeled by microbes from coins or paper money. We automatically ptoeeed to eotltSdetation of such mat- ters as dietary adequacy, homina eonditiom, kind of clothing worn, nature of emphoyment, level of ntedkal are, atnoont of rest or exercise, nature of recreation, exposure to the elementa and other factors which may be o0rcreQ by income and which In turn may inftuence incidence of the disease. O 8 9

The existence of a statistical association does not disclose the number of intermediate variables that may lie between the end result (diuace) and the environmental factor orginally taken into account. The useful function of finding such a correlation thus lies in the clues and hints turned up which may be further and separately validated. "Fallncy o/ Mi.plncrd Concrrtentar" Tn the particulsr illustration just given, the impossibility of a direct causal relationship is surTrciently obvious to prevent investigators from mak- ing premature or false inferences. In the case of the reported association between smoking and lung cancer, the statistical evidence is actually no dif- ferent from that of the income-bronchitis situation and does not, of itself, permit any mote reliable conclusion with respect to direct causation. Dr. Aerkson has called this seizure upon the opparently obvious ac an example of the "fallacy of misplaced conertteness" A surmise that smoking could be a prime causative factor in lung cancer could be used only as a working hypothesis but not as a proved fact. Nevertheless, the habit of using this hypothesis from day to day as a gener- ator of experimental designs seems to have induced some scicnticts to forget its wholly tentative status. Even as an hypothesis, it actually contained a very serious limitation: Only a very small proportion of even the heaviest smokers ever devciops this disease and it also occurs among nonsmokers. This is actually strong evidence that the etiology of the disease is complex and that a number of Influences must act in concert in its genesis. The implication is strong that there must be factors determining the degree of susceptibility or resistance in individuals. It would appear to be a promising enterprise to determine what these (') factors are, with the view of utilizing them In control of cancer. Yet this "~ possibility has been largely ignored In practice. The relatively low inci- ~ dence of lung cancer in heavy smokers as well as in the general population 0 has been attributed rather pretmptorily to "natural differences in sus- ceptibility." as if these were unimportant or inaccessible to study. Cilliam's recent observation of the diminishing rate of increase in lung cancer in- cidenee suggests the gradual disappearance of a particularly susceptible population. . Animnl Inhnlntlon Tpet. ConsLttntfr 1Yewee One way used to study the hypothesis that cigarette smoke might be a, prime causative factor in the genesis of lung cancer was animal experiments- tion. The most directly pertinent of these experiments were the numerous studies in which animals of several species were made to inhale fresh, whole cigarette smoke at frequent intervals over long periods of time, often during the whole natural span of life after weaning. These experiments consistently failed to produce squamous cell carcinomas of the type that are most prev- alent in humans. These failures, in view of the number, extent and duration of the tests by many able and experienced investigators, militated against the sur- mise that tobacco smoke could be a primary factor in the Induction of such cancers. liowever, the problem of species differences in susceptibility could be raised, and general ignorance of the effects even of strong carcinogenic agents on the lung tissues left the reasons for negative results uncertain. Further work has helped clear up the uncertainties. Tt was logical to extend these studies to inveitigations in which ani- mals were made to inhale aerosols or fumes of potcnt, known earcinogens, including methyicholanthrene and 3,4-benzyprene. Such experiments on rats by Kuschner were also negative. Again, ahe results could he interpreted in several ways. The efflcient Iuns cleansing mechanisms (includinx mucus flow, phagocytic activity, and absorption, metabolism and excretion) of the healthy animal might not permit a contact time, or eRective dosage, adequate for carcinogenie action. ne problem of species differences In ausceptibtlity could perhaps still be raised, though Andervont had long before shown that squamorn long carcinomas could he induced In C-57 black mice by tnnsflxing threads Im- pregnated with 1,2,S,6-dibenzanthracene through the lung. 77ris had dem- onstrated that mouse lung cells are btobgkally capable of transformaticm into malignant tissue of this histological type. Rigdon and Shubik have shown that large dosea of carcinogemic hy- drocarbons introduced into the tracheas of ducks and hamsters respectively in oil solutions will produce cancers of various typea. Similar experiments using tobacco smoke condensates have failed to produce cancer. These experiments have, however, further confirmed the fact that lunes of sev- eral animal speeies are biologically susceptible to malignant ehange when dosages of known carcinogens are sufficicnt and contact time is long enough. 10 11

I 1 i Trnama end RrRwnrrntfon Po.albly Involved Andervont's studies and their extension by Kuschner using thread transfixion introduced the additional factor of trauma along with increased contact time and interference with normal cleansing mechanisms. The relatively high incidence of squamous cell carcinomas in these experiments drew attention to the possible role of trauma and perhaps of attempted regeneration in susceptibility of the lung to carcinogcnesis. Subsequently, a series of studies showed that a number of radioactive and potent chemical substances can induce epidermoid lung cancers in rats and mice. These studies are not directly illuminating with respect to the etiology of epidermoid lung cancer in man, because they were carried out on animals and they employed very powerful agents not widely en- countered by human beings in ordinary life. The studies do. however, dispel any doubts about lack of species susceptibility. Meanwhile, clinical and epidemiological studies of human subjects by a number of investigators pointed toward the possibility that damage to the lung, followed by regeneration, might be a predisposing factor in human lung cancer, whether the damage was due to tuberculosis lesions, infarction, or mechanical injury. Winternitz long ago pointed out the frequent occurrence of severe metaplasias in the lungf of persons who died following in/1uem.a in the 191II-19 epidemic and had called attention to their "precancerous appear- ance." Several investigators had attempted to produce lung cancers in animala by repeated influenza infections but, though metaplastic changes were produced, no truly invasive tumon developed. Cnncer Experlw.enw dN4 Yinues By combining repeated influena infections with inhalation of syn- thetie smog. Wiseky, Kotin. Fowler and Trividi have obtained invasive and metastatic squamotts cell carcinomas in the lungs of C-57 black mice at a substantial level of incidence. Almost at the same time, Manin and his collaborators showed a synergistic action between several viruses and a spe- cific chemical arcinoltett by obtaining tumors when combined small doses of virus and chemicals were given. Given separately, at the same levels, these agents faikd to induce cancer. Stanton also has teported the hnduction of ,quamous cell lung car- cinomas by chemial ateinogena administered Intravenously Into rats in whjch areas of lung infarction had been produced. ( These recent eventa are cited to illustrate the rapid development of methods for study of squamous cell carcinoma in animal lungs. 12 . These methods provide a basia for evaluating the relative effects of many other extrinsic and intrinsic faetors on the rate and level of incidence of bronchogenic carcinoma in animals. Hy suitable design, it should become possible to evaluate the effects of age, sex, nutritional atatus, excess or defl- dency of hormones, stimulation or depression of the reticuloendothelial system, cancer promoting agents, v.rious types of trauma, irritants, mucus composition and abundance, activity of cilia, eHieiency of detoxifiation mechanisms and many other factors. Te.ts ConNnre ow Tobaere Smoke Tests of tobacco smoke In this experimenhl biological system have not yet been completed. So far, the indications ftvnt these and many other tests of the activity of tobacco smoke, ate that the smoke is much too feeble to play a role In the etiology of lung cancer aa a direct contact arcinogen. This does not necessarily exclude tobacco from having any role at ail, nor is any such role established. More ittveatigations are neceaaary on the sug- gestions of possible indireet, contributory rolea for tobacco. As the experimental systems described gradually permit the relative evaluation of all the possible external and Internal inAuences listed above, it should become possible to determine whether and to what extent tobacco smoke can contribute, whether as kritant, promoter, modifier of ciiiary activity, influencer of nutrition or by any other means. 1t ia a task of con- siderable magnitude, but the means now seem to be at hand. The fortunate aspect Is that• as the oo6tribntiott: of the various suspect factors are evaluated, methods of nullifying or blocking some of them may become apparent. Of course, the problems of speeks differettees and rele- vance to man will remain to be resolved. Hopefully, effective methods of reducing the toll of human lung cancer may beeome evident from this type of work. • CURRENT CONTRIBUTIONS FROM T.I,R.C. PROGRAM The program of anoer raearch attppotted by T.1.R.C. grants pro- duced several significant developments during the year. The suggestion that some tram+mhnlbk agent Is prdduced by certain tumors has ootne from further study of tite h+ereased concentrations of deoxyribonuckie acid (DNA) In tamoc bearMa tata In tiasues distant from the actual tumor. Extr.ctt of hnta, kidney, liver and spleen of rats bearing the Walker 256 areinoma and the 1en.en s.roonia have been found to In- corporate thymidine-Hl more rapidly than those from normal rats, indiat- ing a possible influenee from the tumors. 13

In three diQerent laboratories, exposure of cultured cclls to smoke and non-smoke gases was studied with description of morphological changes, alterations in growth rates, and modification of modal valucs of chromosome numbers. Effects of irradiating human amn'nm cells have been similarily de- scribed. Since morphological changes and ploidy of chromosome constitu- tion are not simply or directly diagnostic of malignant modification, it is expected that future studies at the cell and tiswe culture levels under T.f.R.C. support will place increasing cmphasis on changcs in the dynamics of the living cell. Further quantitative eytochemical studies on the rcl,tion of DNA to various pathological conditions also point toward the conclusion that deviations from normal in amount and distribution of DNA are not specifically diagnostic of malignant transformation, hut rather of growth or regeneration regardless of eause, or of DNA virus infection. No l.unR CeneYra in Mfee Fxpo.ed to Srnoke A new summary reviewed the histological, cytological and cytochemi- eal study of the traeheobronehial tree and lungs of mice exposed to cioa- rette smoke. It confirmed the previously reported variability of response, ranging from absence of significant histological change, through mild bronchitis with swollen epithelium and mild hyperplasia, to severe bron- chitis with a typical basal cell hyperplasia, squamous cell metaptasia and occasional dysplasia or "carcinoma-in-situ." Invasive carcinoma was nor found. The extreme variability of response, regardless of dose and duration of exposure, pointed to contributing factors, such as latent virus infections, characteristic of the individual animal. Long-continued studies with the white Pekin duck have culminated in production of non-metastatic neoplasms of varied type in the lungs of birds given methykholanthtene in polysorbate 90 by intratrachcal infusion. To- bacco smoke condensates similarly infused have not produced tumors. BlOASSAY MBTKODS Numerous studiet have been supported by grants in the effort to obtain a more exact quantitative method of testing for relative over-all "carcinogenic potencks" of various substances and mixtnres, including tobacco smoke and condensates. On a strictly theoretical basis, "carcinogenic potency" is not an in- hercnt property of a chemical substance. Rather it is the result of an interaction of some kind between an agent and a dynamic living entity - i . the host. "Relative potency," then:fore, implies comparison of activity within some fixed or standardized biological system. Each such system will produce its own scale, since there are wide variations in reaction both • among and within species. If several scales based on different biological phenomena, other than actual tumor production, art: set up, there is no guarantee that any parallclism will exist between them in the relative positions assumed by the various agents tested. lf a degree of parallelism should occur among several such scales, it might encourage confidence in their significance, especially if one at least is based on actual tumor production. Obviously a method more rapid and controllable than mouse skin painting, and requiring only very small quantities of test substance, would be of great practical value in speeding research. In the T. I. R. C. grant program over the past half dozen yean, a score of methods have been tried out in the attempt to test for the relative "carcinogenic potency" of tobacco smoke and other substances. Such in- formation would, it was thought, help assess the hypothesis that such smoke contributes to human cancer as a contact carcinogen and help determine where emphasis In research Rhould be directed. None of these earlier attcmpts proved to be satisfactory for relative quantitative evaluation. Most, but not all, gave completely negative results. But even though not wholly satisfactory, these many studies produced an overall impression that tobacco smoke of normal character, in Its tenuous state, is too weak a carcinogen, if it is one at all for humans, to act in this capacity as a generator of human lung cancer. F,nronrnRinR Rran/b in Three Arrrra Now the benefits of this work art coming to fruition. The research for more satisfactory bioasssy methods has entered a new phase which appcan encouraging along three lines: - 1. A method based on the activity of "careinogenk agents" In enhancing growth of transplanted tumor and normal skin grafts has been shown capable of quantitation, and an "activity seale" for a large series of highly purified polycyclic hydrocarbons is in construction. 2. Further standardh>stion !s in progreta for a protozoan assay for carcinogenic hydrocarbons, based on the response of Parornecfnm rnndornm to ultraviolet and related radiation follow- ing cxposure to the hydroarbons in high dilution. A second potency scale is also to be constructed by this method, with use of the same samples of highly purified hydrocarbons. r'n% . 14 15

3. A third projeeted scale is to be based upon animal skin tumor production by an accelerated method, if plans materiati7ie. The relative evaluation of various "unknown" substances on these scales is contemplated in due course, when background informa- tion becomes adequate. Conference on l3loossey end CaretnoRenes/s Many of the matters outlined above were d'ncussed in a round table conference Un May 25, 1961, in the offices of the Committee. Besides members of the Scientific Advisory Board and staft. the following guest scientists participated: DR. T. D. DAY. University of Leeds School of Medicine. Leeds. England DR. WALTER E. RESTON. National Cancer Institute. Bethesda, Md. DR. FREDDY HOMBURGER, A'ro-Rexarch Inititute. Inc.. Cam- txidRe. Mau. DR. RORERT W. HUI.t., Northwestern Univenity, Evanston, fll. DR. CHARLES J. KENSLER. Arthur D. Little. Inc.. Cambridge. Mass. DR. WILLIAM E. POEL, University of Pittsburgh. Pittsburah, Pa. DR. MURRAY J. SHEAR. National Cancer Institute, Bethesda. Md. DR. CONSTANTINE S. STEPHANO. Stephano Brothers. Inc.. Phitadelphia, Pa. DR. HAROLD STEWART, N.tional Institutes of Health, Bethesda. Md. MR. O. F. TODD. Tobacco Manufadureri Standing Committee, London. England. fl. Human Lung Studtea Among studies on pulmonary function and physiology was a signifi- cant contribution in the rneasurement of "airway resistance" by the method of body pkthysmognphyV Inhalation of cigarette smoke both by normal persons and patienN with various lung diseases, whether habitual smokers or nonsmokers, produced a mild bronchoconstriction lasting from 10 to R0 minutes in most individuals. The effect did not appear to mediate through nicotine or other volatile substances and could be prevented by isoproterenol. Data were inadequate to warrant relating of this effect causally to initiation or aEgraration of chronic pulmonary disease. A review has appeared describing experience in the cooperative study of pathatOBical anatomy of the human bronchial tree and hmgs which the Scientific Advisnry Board initiated in 1954. About 3.000 cases were in- vestigatcd, yielding R.S90 slides from males and 3,661 from females. Participating were 12 pathologists in different locations around the country. The review reports. chiefly on problems of diagnosis and classification. The study is now being extended under auspices of the United States Public Health Service. A more detailed report by one of the participartts In the eooperative study has indicated that only 48 percent of the cases could be considered normal and fewer of these occurred among smokers than among non- smokers. Results of such studies indicate the many problems in defining pathological changes and interpreting their signifiance. iif. Cnrdlotrcucular Studlea Several of the cardiovascular diseases have been reported by investi- gators in epidemiology to he associated with the use of tobacco, especially cigarettes. As in the case of the other association, these reports have given impetus to additional studies on the epidemiological level as well as to many of a clinical or experimental nature. The objeet has been to determine whether the associations are truly meaningful and whether they reflect any contribution by smoking to the etiology of these diseases, or whether the link with smoking is only fortuitous or indirect, through intermediate com- mon factors. 7Keny Orher Fnrtors Also fl.lt.F $hdtrd, Among other factors under investigation in studies of cardiovascular disease development are heredity, emotional eonatitution, stress and the individual manner of reacting to stresa, physical activity in relation to caloric intake, relative body weiltht, metabolie characteristics, thyroid activity and dietary habits, especially with respect to the amount and kinds of fat consumed. Sex and ethnic origin are ahto Involved. Recent progress in several centers suggests that a dhtinction may need to be drawn between those Influences that affect the rate of progres- sion of chronic vascular degenerative proceases such as atherosclerosis, and those that may help precipitate acute episodes such as myocardial infarc- tion, the mechanisms of which still elude full elucidation. Evidence emerging from the Tobacco Industry Research Committee program and elsewhere suggests that the prrvnient types of chronic vascular degeneration are not significantly (nfluenced In rate or degree by the periodic administration of nicotine in smalt amounts over a k+nR p.•rirxt or by the modcratc practice of smoking by average penon.. Still obscure are 16 17