Tobacco Documents Online

ANNUAL REPORT of trre SCIT;ITIPIC I)IItECTOTi Ci;Attl;nCT; COOK LITTLE, Sc:1>.

SCIENTIFIC ADVISORY ItOARD to The Council for Tobacco Research - U.S.A. KENNETH MERRILL LYNCH, M.D., Sc.D., LL.D., Chairman Chancellor and Professor Emeritus of Pathology Medical College of South Carolina, Charleston, South Carolina •HOWARD B. ANDERVONT, Sc.D. Scientific Ediror, The Journal of the National Cancer Institute Bethesda, Maryland RICHARD M. BING, M.D. Director of Cardiology and Intrnmarnf MtdJdnt Huntington Memorial Hospital, Pasadena, Califotnia Professor of Medicine University of Southern California School of Medicine Los Angeles, CaGfornia McKEEN CATTELL, PttD., M.D. Prof essor Emeritus of Pharnacoiov Cornell University Medical College, New Yodr, New York ROBERT J. HUEBNER, M.D. Chief, Viral Carcinogeneaia Branch National Cancer Institute Bethesda, Maryland LEON O. JACOBSON, M.D. Dean of the Divislon of Bioloafcn! Scltncw Regenstein Professor of Bioloslca! Sdencts University of Chicago, Illinois CLAYTON G. LOOSLI, Px.D., M.D. Nasrinas Professor of Medicine and Pathotoay University of Southern California School of Medicine Los Angeles, California CLARENCE COOK LITTLB, Sc.D., LLD., Lrrr.D. Scientific Dirccto., The Council for Tobacoo Research - U.S.A. Director Emerltrrs, Rosooe B. Jacbon Memorial Laboratory Bar Harbor, Maine WILLIAM F. RIENHOFF. Jr;., M.D. Prof tssor Enxrttut of SwYery Johns Hopkins University School of Medclne, BaltSmore, Maqiasd SHELDON C. SOMMERS, M.D. Research Director. The Council for Tobweo Reiewh - US.A. Director of Laboratories, Lenox Hill Hospital Professor of Pathology Columbia University College of Physiciam and Surgeons New York, New York ' ROBERT C. HOCKETT, Pn.D. Associate Scientific Director J. MORRISON BRADY, M.D. JOHN H. KREISHER, P1t.D. Associate Scientific Director Atsiocrore Scientific Director VINCENT F. LISANTI, D.M.D. Scientific Associate •RNf.rd

CoN'PF.IVTS Introduction . . . . . . . . . . . . . . . . . . . 5 Status of Current Research . . . . . . . . . . . . . . 6 Multivariate Analysis . . . . . . . . . . . 6 Cancer . . . . . . . . . . . . . . . . . . 8 ~ Cardiovascular Diseases . . . . 12 Nicotine: Psycho-Pharmacologicil and Behivioral Effects . . 14 Chronic Respiratory Diseases . . . . . . . . . . . 15 Abstracts of Reports . . . . . . . . . . . . . . . . 18 Psyr.ho-Physiolobical Studies . . . . . . . . . . . 18 CarciooSenesis Studies . . . . . . . . . . . . 22 Cardjv.a_.wlar System . . . . . . . . . . . . . 3 2 Respiratory System . . . . . . . . . . . . . . 45 Neurophysiology . . . . . . . . . . . . . . . 55 Studies at the Cellular L.erel . . . . . . . . . . . 58 Cd1 and Tissue Cuiture . . . . . . . . . . . . . 62 EP4demWoaJ' . . . . . . . . . . . . . . . . 67 Pharmacology and Psycho-Pharmaooio8y . . . . . . . 69 Metaboi"ic Studies . . . . . . . . . . . . . . 77 Cxrnistrr and Biochemistry . . . . . . . . . . . 81 Other Studiea . . . . . . . . . . . . . . . . 84 Re.iews . . . . . . . . . . . . . . . . . 86 Recipients of Active Pro;ects . . . . . . . . . . . . . 94 Reeipicnts of Compkted Projects . . . . . . . . . . . 106 Introduction The Council for Tobacco Researd+-US.AA aas established in 1954 for the purpose of providing 5nancial support for ttsnrch by independent scientists into all phases of tobacco use and heahb. From the beg3nning, full authority and responsibility for policy, de- velopment and direction of the raeatth effort were Stan to a Scientific Advisory Board to The Council. T1us Board eanzently consists of 10 physicians and scientists who tet.ain their afNiatioos with their respectire institutions. With their oombined experience and knowledae, and with the advice of other experts from the scientific community, the members of the Advisory Board have worked toward one aoal--to develop a research program to provide significant data about lung cancer, heart disease, chronic respiratory ailments, and other diseases. Through the years The ConncH has pro.ided the funding to enable the Scientific Advisory Board to develop and expand the raarth program. From 1954 through June 1969, the Board awarded over 400 original gants, and many more renewals, to 239 rc3enthts in 196 hospitals, medical schools and research institutSona. In the sante petiod, these research workers published 728 scientific papers on their stndies, supported in whole or in part by The Councit, in the profesaional literatute. Studies from the Advisory Board's program and from other proEran» have produced much valuable data In the paat 13 yeat:. They show, however, that we are not dealing with simple diseases and that we cannot expect simple answers. But the toeatbt~ of the Board and of other scientific organizatkns are optimistic tbat aaswes will be found. Investigators are constantly reporting resulta that will some day be pieced together to help solve the pnalo of these tomplex dbeases. It is apparent from the great amount of reaea:eb teported so far ttut a variety of genetic and environmental taet+xu may be invoired. The Council for Tobacco Research will continue to suppott scientific imestip- t;on and to work toward a better undtxstandFaa of the many unanswered questions that remain. The response from physiciana and scientists in leadins institutioes to The Council's oRer of research support is nwst gratifying and enoouraaea The Council to adhere to the demands of a realistic and ackntille appraoach.. 5

r . Status of Current Research Certain epidemiological studies have associated cigarette smoking with total mortality and morbidity rates and with mortality from lung cancer, cardiovascular diseases, chronic pulmonary ailments, and various other diseases. These associatiott: have been widely interpreted as signifying a causal role for smoking. However, it is an accepted fact that a statistical assodation is not necessarily one of causation. The information obtained from epidemiological studies may be helpful to investigators in framing necessary experimental studies. Underlying most present interpretations of these epidemiological studies is an assumption that cigarette smokers and nonsmokers are sufficiently similar in other respeets so that it is legitimate to compare their morbidity and mortality experience and to attribute observed differ- ences to a sole factor, Ymoking. The restricted monofactorial interpretation of smoking as a causal factor in total mortality or in relation to certain diseases ignores the validity of a vast amonnt of reaearch relating to the possible influence of many other factors or combination of factors. Multivariate Analysis ~ Three questions abotrt epidemidogial studks reported on tobacco ~ are: (1) Is cigarette smoking really a cause of incteased mortality, either -~ in general or from certain diseases? (2) How and to what extent do ® smokers and nonsmokers differ in genetie traits or genetically-inftuenced habits and patterns of IiviaS7 (3) Are these genetic traits or genctically- irdlnenced habits and paftrts of living themselves, singly or in groups. Influential with regard to death ateaT Stathticiana generally agree that it is Important to weight all known or possible factors, individually and In groups, as mathematical predictors of. any event (sach as mortality) preliminary to selecting those worthy of tArelative priority. This is a very laborious task because numerous factors are 00 ~ 00 6 involved, and most of the large data collections that might bear on the predictors for longer or shorter life have not been so analyzed. Any meaningful analysis, of course, requires that adequate and accurate data on such factors have been gathered inithlly. Of equal im- portance is the need for developing new, reliable and faster eompttter methods capable of handling these complex data. Aware of this problem, The Council for Tobacco Research is engaged in the study of the development of such methods. Pilot Study of Longevity A pilot study of longevity has been done in a group of S00 recently deceased veterans in the Boston ares. A large body of information has been collected on these subjects as part of a Cotmcil-tupported project. The ne+w methods of multivariate analysis were applled to see which factors would have served as the best predictors of longer or shorter life, if they had been so employed at the outset. Many factors, it was found, tended to "cluster" with cigarette smoking statistically so that good predictioen of longevity (in these data) could be made by t»e of a"proHk" of such other factors with smoking itself oeritted as a predictor. The resnlt was substantially the same as when smoking alone was used. In other words, the finding showed that smoking (and afso alcohol tm) appeared to "summarize" and.to be associated with other groups of charaderistkY. There was a significant by-prodnct of this new approach. it..as found that certain statistical asssociations between cigarette smoking and length of life can be explained by the secularity effeet-that is, the general change in prevalence and level of cigarette smoking with time. Secularity is de- scritxd in the words of the in.estigaton: a consequence of rapid social change and the prolonged human life span. Thtts, the younger decedents were part of a "selected" population hating, perhaps inddentally, a different cigarette smoking pattern than did the population tepresented by the older decedents. It is expected that these prelimit>:q applications of tmthivariate . analysis will be carried out on data ootlected In several other Conncil- sponsotrd projects on subjects not necessarily related to longevity but to methods of diagnosis, etc. Differences Between Smokers end Nonsmokers Other Council-sopported projects have shown statistically aignifiant differences between smokers and ttonsmoken. These are indications for pos- sible use in the multivariate te-analysis of existing data collections. It has 7

been shown, for example, that there is a prevailing difference in the dis- tn'bu6oo of body build types. Investigators have found personality diRer- ences. One researcher has reported observations on a number of factors that differ la smokers and nonsmokers and may be predictors of early heart and artery diseaae. Still another researcher has found a significant dGlfererxr in basic brain wave patteras of smokers and oonsmoken. Cancer Lwrg Cancer Sneoke Iwhel.tion Espertraents Previous Anmr.t Reports have specified the exacting criteria for con- ducting realistic experiments involving smoke inhalation. It is important to restate these criteria which have beee derived from the results of exten- sive research and from consultations with experts in many disciplines. First and forernoat, meaningful data can be obtained only if the whole smoke delivered to the various parts of the respiratoty tract of the animal is In the saase physical and chemial state as that which reaches similar anatomical areas of the human during normal cigarette smoking. To accomplish this, it is necessary to have a mechanical device-a amoking awchine-4hat simulates human smoking as closely as possible. 711s device should be able to deliver pulsed amounts of smoke in a quan- titative and reproducible manner. The machine should be so designed and coostruct+ed diat it will be possible to measure accurately the time between two soooessFve puffs, the time of the puff, the volume of the puff, the e=tent of dilution with air, and the number of puffs per cigarette. Care mant be taken so that the temperature of the burning tip does not exceed -hat reached when a haman smokea a cigarette, nor should the cigarette be ,~ll smoked" beyond a minimqm butt length. ~ 'Il+e macfiise sbocld have a port to permit sampling of the smoke a stream for chemical or gtu chromatographic analysis, if desired. For frac- ® tionating the whole smoke and to permit the bio.:say of the gaseous phase, the smoking machints should be designed so that a Cambridge filter can be attached. For comparison between laboratories, It Is desirable that a refer- ence type cigarette be used. (The University of Kentucky is now producing a referenoe efguttte.) The animai r+eoetvthe aeiote should be placed so that only its breathina apparatus i. In the t~tream of the smoke and no farther than ~+. E 00 ~ the distance of the human nose to the main branching of the airways In human lungs. The animal used should be fully described as to age, genetic background, weight, nutritional state, physical condition, virus oomponents, extent of surgical tnuma, and the degree of strets to which it is subjected. Appropriate numbers of both sham-smoked and pgo-held animals should serve as controls. The end points sought should Include more than morphological tltera- tions and the presence or abeence of tumors. For proper Interpretation they also should include appropriate biochemical ttKasarements and their analy- sis. Multivariate analysis should then be applied to the data obtained from the systematic observations of the controlled parameters relative to the smoking machine, the animal model, and the biological and biochemicxl measurements. By these means, it may be possible to develop bioasaay teehniques related to cigarette smoke. Past experiments, where the sole objective was the attempt to induce tumors, must be carefully and cautiously Interpreted in light of today's knowledge. Suitable Animal Modeli Needtd There is a gneat need for suitable animal models for inhalation ttndks related both to lung cancer and chronic respiratory ailments. Pending development of such models, tests have been designed under Council support to provide a careful, quantitative, deaeriptire picture of any and all observable morphological changes in the lungs of mice exposed to whole cigarette smoke or the gas-vapor phase. These experiments will be analot- ous in design to those now being completed with oxides of nitrogen, ora+e, and carbon monoxide. As regards lung cancer, it wonld be very helpful to have a positive animal model of the human disease. If sqnamous cell lung amcer---the type reported to be most common In humans-eould be produced by ttome t simple and acceptable procedure and at a repodtscibk level, it could be possible to plan systematic experiments to determine what added factors might induce it earlier or delay its appearance. Any such factors found to contribute to susceptibility or resistance In the animal model could then be checked in humans. The goal is to obtain clues to the possibiq contributory influence of many internal and external factors In the animal model and then see if these are related to the human experirnce In any way. In addition to sntoking, a great many other factors need to be eva?o- ated in this way. One is the effect of vitamin deDdeneiea, especially vitamM A. Another is liver damage, which has already been shown by Council- 9

supported studies to predispose to cancer of the oral cavity. Another is disturbance of the hormone balance. Another is air pollution. There are many more. Development o/.(pparatss and Techniques The Council has long supported research to develop apparatus and control methods for smoke inhalation experiments and also to find satis- factory teehniques of ineasuring lung surface dosages, especially of the particulate phase of the smoke. Considerabk progress has been made in development of improved mechanical equipment for such studies, and several new devices are now undergoing exacting tests. Feasibility studies have been conducted and it is expected that there shortly will be initiation of new, long-term inhalation work combining the use of improved equipment and also of better stand- ardmed animal substrates. Certain animals, for example, have long been considered inappropriate for meaningful inhalation experiments. With the use of presently available and partially improved smoke exposure devices, scientists working under a grant from The Council have exposed guinea pigs to short-term, chronic inhalation of whole smoke in order to observe whether changes would develop in the oxidative enzyme activity of isolated lung mitochondria. The stress effects of handling and machine exposure without smoke Inhalation have been assessed in control animals. These studies are now being extended to longer term exposures and to inhalation of gas-vaporphase without particulate matter or nicotine. Motase Skin Paintbsa.nd Lung Cancer The induction of skin cancer on mice painted with cigarette smoke eondensate ("tar") has been, and still is in some circles, accepted as evidence that smoking can contribute to human lung cancer. However, 0 smoke condensate is not whole smoke, the skin Is not like the lung, and studies supported by The Council have shown that various tissues in the ~ nme animal respond very diffetently to a single chemical carcinogen. The a• oral cavity tissues of mice, for example, are much more resistant to 0 benzo(a)pyrene than their skins. It must be emphastsed that there is no reliable evidence that the condensate fraction can produce tumors in the lunga of experimental animals. Many experiments supported by The Council and by pthers have failed completely to produce lung tumors when solutions or emulsions of cigarette smoke condensate were instilled directly into the lungs of ducks, hamsters and mice. Injectbn of smoke condensate emulsions into the I bloodstream of mice and of lung-damaged rats failed to produce lung tumors, though benzo(a)pyrene emutsions did so under the same tech- niques. Therefore, there is no reliable evidence that the "tar" fraction of cigarette smoke acts as a lung earcinogen even in experimental animals. Yiruses and Canar A growing field of researih is coocerned with the role of viral factors in human cancer. It has been known for a long time that viruses are directly involved in a number of animal cancers. The Council has sponsored a number of studies which touched In one way or another upon the possible role of varioas virus Infeetions in the genesis of cancer. Recent developments In the study of virus-eaneer inter- relationships, sponsored by other agencies, have produced much evidenee to support a unifying hypothesis which combines genetk concepts with con- temporary knowledge of the nature and aetion of virnses. 7liese developments concerning viruses tend to place new and In- creased emphasis on the condition of thb host In carcinogenesis experiments and introduce new dimensions and controls into animal test models- 7Tie Council has undertaken to support research connected with the testing and development of some phases of this virus-cancer theory. At the same time, it is helping to develop new and better-controlled cell culture and whole animal models for measuring the Interaction of susceptibility factors with external stimuli in tumor produetion. Such models, it Is hoped, will be useful as assay systems for testing the effects of whole, fresh, normal cigarette smoke or its fractions (particularly the gas-vapor phtae) or components more realistically than Is possible with cruder methods. Bladder Cancer Data relating to bladder anotx In humans are sparse other than those concerned with occupational factors, where there ia a much clearer picture. Though several epidemiologipf studies have teported a statistical associa- tion between cigarette smoking and eaneer of the bladder In human maks, the question of whether there is a eaasal relatlonrhip remains open. Tbe findings for females were contradictory, and there were Inconsistent results of animal experiments with cigarette smoke oondeneate. Vital statistics for the past 15 years do not show a signifiant rise In reported ear+es of bladder cancer. Hence, the reported statktical association has lacked rational ex- planation. IA~ ~ 10 11 O

~ ~ rV ~ ~ ...~. ® ~ .+... 0 0 ~ 1i~s .~.1 In 1965, a hypothesis was advanced to the effect that nicotine might so disturb the metabofiam of tr7Ptophan as to result in abnormal accumula- tion of certain normal intermediates related chemically to substances which, when implanted as pellets in the bladden of mice, were found to produce cancers in that species. A basic postulate of this th>•ory was that bladder cancer patients generany show a disturbance of tryptophan metabolism akie to that claimed to occur in smokers. This hypothesis has been investigated in three different centers as part of a broad bladder eanaer study that included clinical, pathological, bio- chemical and experimental aspects. Contrary to the hypothesis, four out of five bladder cancer patients were found to excrete tryptophan metab- olites in a normal pattern even after tryptophan loading tests. In mice, the liberal feeding of vitamin C prevented production of bladder cancers by Implanted pellets of 3-hydroxyanthraniiic acid, a normal tryptophan metabolite. The comparative excretion patterns of nine tryptophan metabolites by smoking and nonsmoking subjects have also been under investigation and reports are scheduled for early publication. As part of its sponsorship o( studies in this field, The Council con- tributed to the support of a symposium on "The Epidemiology and Etiology of Human Bladder Caneer," )ointly sponsored by the Cancer Research Institute of the New England Deaconess Hospital, and the Department of Pathology, Boston University School of Medicine. The symposium was held June 6 and 7, 196g, in Boston, and most of the papers presented were published in the Jotrrnal of The Norional Cancer Institute, 43, 217 (1969). Cardiovascular Diseases Cardiovaacular diseases account for more deaths among U.S. males than any other disease dtegory. The cardiovascular system itself is subject to a variety of disorders. The reost common of these is arterioeclerosis, the result of unknown pathological processes that lead to progressive loss of resiliency of the arterial vesad wall accompanied by increased rigidity and narrowing of the himen. A common sequel is abrupt occlusion by thrombosis, and the effects include a faulty supply of blood to a tissue or own, inadoqwte to meet Its needs. Frequent consequences are common forms of heart attacks, brain stroke, gangrene of a leg, rupture of the aorta, and certain kinds of high blood pressure. T'here are a number of suggested factors in arteriosclerotic diseases 12 including lipid metabolism, vascular connective tksue damage, endocrine dysfunction, and 6brin depoaits on the re=sel walls. Diet, hypertension, obesity, lack of exercise, psychological factors (sttess and tension), and smoking have been mentioned as possible contributors. Some autopsy studies have reported no association bet..eert smoking and arteriosclerosis. Others have reported that heavy cigarette smokers have more extensive lesions of the coror+ary arteries than do light or nonsmokers. Theae data are limited in quantity. The lesions reported also require further study to determine it they differ In quality or pathogenesis between smokers and nonsmokers, t+ince smoking has not been demon- strated to have an etiologic significance. Dietary cholesterol has been cited by many as perhaps the maior factor in heart disease. Hypertension appean to run second in impottance, according to some investigators. There have been reports claiming a rela- tionship between smoking and hypertension but, paradoxically, it has been found that men who are heavy cigarette smokers generally have lower blood pressures than nonsmokers. It is obvious that the situation, in general, Is complex and obscure. Twin Studies in 1lemn Disease Twin studies conducted both In this country ad abroad under other auspices have cast doubt on smoking as a cause of heart disease. These studies help to emphasize (by their control of factors which would other- wise vary between smokers and nonsmokers) the Importance of not only continued work with twins but of multivarlate analysis. If smoking twins have no higher mortality than nonsmoking twins (as Indicated by pre- liminary liminary reports), such a finding emphaaizes the need for caution in evaluating uncontrolled statbtical studies. With support from The Council for Tobacco Research, two ocientists undertook a study of the effects of environmental factors on the develop- ment of atherosclerosis as reveakd by autopsy of accident victims. Their work, with support from other sources, was later extended to be included in the International Atherosclerosis Projcct. These investigators found fatty sttraks In almost all the aortas of boys and girls aged 10-14 and similar streaks In the coronary arteries of most persons aged 20-29. The streaks are dinically harmless and poten- tially reversible, they noted. However, they said atherosclerotic lesions may appear in the coronary arteries before the age of 20 and that the conversion of fatty streaks to 6brous plaques occurs at an earlier age In populations with high coronary heart disease morbidity and mortality. 13

Nicotine: Psycho-Pharmacological and Behavioral Effects Soerc of the bases for human use of tobacco are certainly to be found in social or psyehological needs. However, on the assumption that others might also be found in the realm of psycho-pharmacology, that is, in the effects of smoking and/or nicotine on the central nervous system, The Council has supported a number of studies in this field. several of which have been summarized in previous Reports. The volume of this work reached a level deemed to justify a public symposium on "The Effects of Nicotine and Smoking on the Central Ner- vous System" which was sponsored jointly by The Council and the New York Academy of Sciences on April 7-9. 1966, and published by the Academy in March 1967. Crantees of The Council participated in the sessiort as did a considerable number of other independent investigators from the United States and abroad. Work reported at the symposium established that nicotine does defi- nitely pass the blood brain barrier and affects brain activity as shown by ekdroencephabgaphic ttscings both in animals and in man. Because of the rapWrty of these brain wave changes, it was postulated that smoke may also stimulate nerv e endittµ in the lungs to send signals to the brain. The effects of nicotine on the brain are not always the same. Depend- ing on the state of the eervous system and on the dosage, an "arousaP" or "S.ako-up" effect may ooaa which Is reflected both in brain waves and in behavior. This effect k aceotnpiished by a dilation of the pupila and a slight rise In blood pressure. Confirmation that this was due to nicotine came from experiments involving direct instillation of the alkaloid into the brains of animals. n In larger doses or In a diRerent state of the nervous system, a peculiar ~ steady state of longer daration is produced which may be described as .~'U intermedtate betwoen alertness and sleep. This has been described as a S "tranqnilizer effect" These f3ndings eonffrnt the subjective reports of cigarette smokers. Extension of the eki.troencephalographic studies to human subjects has produced some observatious that appear relevant to the question why sontre persons need or want to smoke while others do not. lt was found that the prevailing encephdographic patterns of nonsmokers differ mark- edly from those of smokers or persons who had never been smokers, even ~ long atter discontinuance of the habit. A marked difference in the ability to produce the "alpha" pattern by consdous effort also existed between these groups• Since long discontinuance of smoking by former heavy amokets did not alter these relationships, it was postulated that the difference in prevailing brain wave patterns has a congenital basis aod may explain the function of smoking to modify or "normalize" central nervous system activity. If this finding is confirmed, it will itdisxte that smokers and noe- smokers may have important basic eatstitational differences which also may produce differences In their predisposition to the development of cer- tain diseases, especially those of a"paychosomatic" nature. Since predis- position to cardiovascular disease has been attributed to difterences In psychological or personality type, it becomes Important to investigate poss;ble correlations between types as defined by a psychological test and as distinguished by encephalography. Besides these effects, it was reported at the symposiam that small doses of nicotine have a favorable effect on the learning process in both rats and some other animals when they are made to petform certain actions to receive a reward or to avoid a discomforting experience such as electric shock. Several ramifications of this basic finding have been putstsed further and certain pharmacolosical mechanisms were elucidated In some cases. Chronic Respiratory Diseases The Scientific Advisory Board has long been aware of the need tor research into chronic respiratory dfseaaes am has awarded many graets in this field. There is a reported inerease in ttoch d'nea~es as eames of illness and death but whether there has been any comparable true tnctesae remains questionable. 'I'here is reason to believe, in any ereat, on the basis of t+eseasch findings, that one important factor in any reported Increase Is the te:<ne, particularly with the use of antibiotics, of many persons from death due to severe lung infectioru. They then live on with damaged lungs to develop chronic respiratory ailments later In life. The possible influence of cigarette smohing on the causation or ex- accrbation of chronic respiratory diseases is dit19cu1t to assess. One of the difficulties is the inability to distinguish adequately between chronic bron- chitis and emphysema. Both eonditions are often found to co-exist in many patients. The aozurate classification and recognition of emphysema by the t,0 iS 14

medical pr ~an have really not advanced very far. For e:ample, de- trompensation in chronic pulmonary disease and cardiac abnormalities are not yet .eevrately distingunhabk. Stmederdi.sed Techniqacos Needed Fmther, standardized techniques are needed to compare the prevalence of emphysema in different societies or different eountries, an approach that is long overdue. Suitable morpho#ogk criteria for properly classifying, quantitating and evaluating emphysema have barely begun to emerge in the past five years. The necessary techniques are now used only in a few institutiorn. Even fixation of lungs ia the expanded state, the essential first step in establishing the presence, type and degroe o( emphysemi, is rarely pr2cliced. Death reported from emphysema eattnot.praently be defined with any accuracy as to what actual pathologic conditions may be present. No tmdormly applied, scienti8eally sound clinical methods are now in general use whereby emphysema can be identified and quantitated. The basic knowkdae and even the definition of chronic bronchitis are still lacking despite some recent notable contributions. Beyond the need to standardize, and even more to find better dinical and pathologic diagnostic criteria for chronic bronchitis, there are also problems of its possible rela- tion to repeated viral and bacterial infectioro over a lifetime, particulate and nortpartievlate irritattts, aEjna, changes in the bronchial mucosa, and hyperseraitivity diseases. The Council has supported pioneering studies to describe anatomic emphysema more quantitatively and to dilfersntiate among the several dis- tingtsishable types. ft has also spoesored  number of clinical studies of pulmotfary faection, for description of short-term effects of inhaled agents. h+e1 a Ent tobacco smok0. In subjects of various aaes and in various condi- tions. These have been described from time to time in earlier Annual RePaft More receady, The ConnciJ provided support for a study of the siblings of dxoeic rapirNory patleata. The siblings and the patients were the test goup and their spouses served aa a control group. This investiga- tbn revealed the eatistence of a familial tendency to functional impairment d the ha+sa. Otha imestigatfotn tsave'oootfttrted to the present impressive evi- deoce that certain genetic tatzytnts deflchncies (alpha; antitrypsin) strongly pred'rspoae to empi+ysema W honfaxytotea carrying this gene and that even a7E~a may show in enhanced degree of preedisposition. In-Depth Cfiniea! Stndlea Under lt'ay The Council has recently provided svpptxt for major long-term, In- depth clinical studies of chronic respiratory dbatse entities ih two geo- graphically separated urban oenters. A third cihsic that spedalisa ht lunt function tncasurements of youna ehildree has more recently been added to the projeet. The hope is that long-term repetitive esaminatlom of patients txr+ provide comprehensive information oe personal eMracteri:ties, family his- tory, manner of 1ife, envinonmeMal exposures (Including tobacco smoking), contributory infections, tespone to treatment and eoane of the disease. The extensive clinical and laboratory data oompiled by the inrestigattors may produce better definitions d the various clinical entities and motr reliable methods of differential diagnotis. It seems obvious that such de9nitions and diagnosis are absolute prerequisites to any real progress in the study of the etiology of chronic puimonary diseases in terms of the interplay of intrinsic and extrinsic factors. 16 17

Abstracts of Reports Each recipient of a grant-in-aid from The Council for Tobacco Re- search -U.S.A. is responsible for the initial presentation or publication of the rcsults of his resear+ch at scientific meetings or in appropnate scientific journals. Following are abatracts, approved by the authora, of reports on new ~ptt'+~+t~ ~h acktw..fea$mg support from The Council that have appeared in seientifie journals sincepu blicatioo of the 1966-67 Report of the Scientific Director. The name of the grantee is in italics. 71>he abstncts have been grouped under these hcadin&i: 1. Psycho- Physiological Studies, 11. CGreinogtnesis Studies, Ill. Cardiovascular Sys- tem. IV. Respiratory System, V. Neurophytiology, VI. Studies at the Cellular Level, VII. Cell and Tasue Culture, Vlll. Epidemiology, IX. Pharmacology and Psycho-Pharmacology, X. Metaboiic Studies, Xl. Chemistry and Bio- chemistry, XII. Other Studies, and XIII. Reviews. I. Ptycho-Phyitologioat Studiea ALTERATIONS IN THE BEHAVIORAL AND BIOCIfEMICAL FfFECTS OF ELECTROGbNVULSIVE SHOCK WITH NICOTINE Electrocon right after coodtt' i~ooed-reapoc e triini producest a~ retrograde amnesic e$eCL In experiments wrhere mice were pretreated with nicotine sulfate, this amnesic rtsponre to sbocY was aigni&antly blocked by the drug. The attenuation of the tetrogtade amnesia was particularly spparent when drug treatment was giren 45 to 60 minutes prior to training. The high incidence of conditioned respoese r tentbn In drug-truted mice was paralleled by a reversal of the predicted effect of ECS upon brain serotonin levels. While the celatiooehi~ betweea EGS-induced elevation in whole brain serotonin level and ECS-itdueed tetrogtade amnesia is not necesaanlq causal, the niootine-indaced reversal In both asns of the cvstomary ECS effects sug- ~possibie eacallaqr of the drug-induced facilitation of memory con- Fssntan, W. B., Steinbert, M. L. and Golod, M. 1. Pt7chononrkScknce 12(3):1U7-10g, 1968. OrM+r Rrw.torr Natlonal Institutes of Hcalth. From the Department of "oSy, Queens College of the City University of New York, Fluahing, N Y. TASTE THRESHOLDS IN TWINS AND SIBLINGS Taste thresholds for hydrochlork acM, quinine, and 6-n-propylthiours- cil (PROP) were detennMed in pain of tnonozygotic (MZ) twins, dizygotic (DZ) twins, and siblings (SiB). The numbets of pain Involved were 75 MZ, 70 DZ, and 78 SIB, for the latter two compounds; 26, 45, and 45, respectively, for the acid. Significant differenas in intrapair variance were found (1) between the MZ and the saroe-aex DZ pairs In thresholds for bitter-tasting PROP, and (2) between the male MZ pain and the male DZ or male SIB pairs for hydrochloric acid. The digtxenee in intrapair thres- hold variance was not significant for bitter-tastin= quinine. Intrapair differ- ences observed in the MZ twins indicate that nottgenetk factors also inffn- ence taste thresholds. Drugs, smoking, and the met>sttoat cycle are atttong the environmental factors that may affect taste thresholds. Other obserra- tions showed that, with all three compottnds, repeated taste tests on the same subjects yielded high numbers of results sind ar,within a single thresh- old range. Also, in 308 subjects, correlations between thresholds for the dilferent substances were positive and significant Koplan, A. R., Fisher, R., Karras, A.. Oriffin, F., Powell, W., Marsters, R. W. and Glanville, E. V. Acre Geneficnt Mrdicoe tr Ctmeffoloaioe 16(3 ):229-244, 1967. Other Rrantorr National Institutes of Htxltlt. From the Department of Genetim Cleveland Psychtatrie Institute, Cle.c- tand. PHYSIOLOGICAL AND PATHOLOGICAL CORRELATES OF DIFFERENCES IN TASTE ACUITY The effects of various parameters (geeetica, dietiry prcfermcese ase, sex, smoking, biological acuity, personallty, menstruation, duodend ulcers. and gastric ulcers) upon taste acvit7 are surveyed in this report When monozygotic (MZ) twins, diry t..ins (DZ), and non-twin sibling (SIB) pairs were tested for intrapair differences o( taste thresholds, it was seen that the intrapair differences in the MZ pairs wett aigni8eantly 1as than In either the DZ or SIB n. In other atudiea, sensitive tasters of quinine and 6-n-propylthiouracil (PROP) reported relatively larp numbers of food dislikes and a preference tor ndld-tsstin= foods, compared to Imetssltire tasters. The sensitive tasters Included a relativellr~h~ proportloo o[ non- smokera, compared to the insensitive tasters, who itxtoded a relativelr high proportion of heavy smokers. Taste threshold was not found to be related to age or sex when smoking habits were exptximentally controlltd, but heavy smokers were observed to manifest decttased taste sensitidty with increascd age. Phases of the menstrualcytk were aolrntimes associated with significant changes In taste thresholds. Ap}arentty, high taste sensitivity for both quinine and PROP may be assodatod with high feneral systetnic re- activity, and vice versa. There tdaosppears to be a possible association with personality differences. Individual differences In htte acuity patterns, re- lated to both genetic and noegenetic variables, have also been associated with significant differences in peptic uleer pathology. Duodenal uFcerpa- tients, as a group, were signiflcantly more sensitive to the taste of PROP. but not of quinine or hydrochloric atid, than cther gastric ulcer patients or nonpatient controls. I8 19