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rom the standpoint of ence available in the ission staff in support might, in fact, erode egan five years ago trying del for the pending bill, te consumption has continued ic basis for the proposed ation," he told the committee, ease has been established. L blished fact in this bill ""` gs of many eminent scientists.' en made aware of the so-called !s le are in a position to make r not k " " o smo e . a provision of the bill to carbon monoxide yields from rtising. ' tine levels have been e advertisement since 1970. ," he declared, "the ts provided to you will show igarette smoking is not a J 755 S T A T E M E N T 0 F R 0 B E R T C A S A D H 0 C K E T T I am Research Director of The Council for Tobacco Research -- U.S.A., Inc. I have been employed by the council and its predecessor, the Tobacco Industry Research Committee, since 1954, first as Associate Scientific Director, then Acting Scientific Director, and in my present capacity. My Curriculum Vitae is attached. In my opinion, the proposed amendment to the Federal Cigarette Labeling and Advertising Act will cause justifiable consternation among many earnest,and able investigators of can- cer, heart diseases and emphysema at the experimental and clini- cal levels. These scientists labor in the hope of clarifying the etiology and pathogenic steps and stages in the development of these disorders with a view to preventing or delaying their clinical appearance. Contrary to the "findings" in the bill, however, the cause or causes of these diseases have not been scientifically established, and much work remains to be done. Statistical Association The claims against smoking are based largely on epide- miologic studies. Positive statistical association, however, -- as epidemiologists are aware -- does not mean causation. Accordingly, these studies do not support the "findings" in the 0 W ~ 0 ~ N ~ GD I ®

756 proposed amendment. Students of logic have long recognized that a negative statistical association between an event and a putative cause may be conclusive. Th us when it was suggested that some hair dyes might produce cancers in women, a study of 5,000 beauti-a cians who had been exposed to such dyes for twenty years showed that these persons had not experienced any excess of cancer. This negative correlation appears q uite conclusive with respect to dyes that have long been in use. Similarly a concern regard- ing the SV-40 virus, which causes bladder cancer in monkeys and was found to be present in some polio vaccines, was considered resolved when no higher cancer rate was found in the vaccinated humans than in the unvaccinated ones. On the other hand, ap9sitive statistical association between an exposure and a disease condition is well known to be only evidence of some sort of a relationship, the nature a of, which remains to be discovered. For example, there is a statis-/ t tical association of severe overweight in women with higher uterine• and ovarian cancer rates and in men, of highe~ colon-rectum and prostatic cancer. In the same category is tbe~ positiv e correlation between early marriage (or sexual activity'~i, of women and eventual cancer of the cervix. Such positive associations only indicate a need for other kinds of investiga-r tion in order to elucidate the nature of the relationship. -2- f Still more striki finding that men and women ;ight have lower death rat ttiose getting either more t han f ive h ours h ad v ery h i !nurs or more per night had I have previously I •ijurs in bed of the short- :,,~r night, would be unlike] ''.,re likely the amount of "i "c.hieve is a reflection of -:av be the basis of the dif lterable. Studies show th ":seful and effective slee ":hers may have difficulty i :1.11y on account of psycho' ~s. Whether such persons siIns is a question many -tack. ' Surveys have s'howr .`^eling that smoking cigaret 1r2 drowsy but to relax the It these contradictory impre -lethods has been difficult, R'ams have claimed correlati *w es and psychological cha

ing recognized that a negative n event and a putative cause was suggested that some hair ien, a study of 5,000 beauti- h dyes for twenty years showed Aenced any excess of cancer. quite conclusive with r espect Similarly a concern regard- bladder cancer in monkeys and oolio vaccines, was considered .te was found in the vaccinated es. )sitive statistical association condition is well known to be rela tionship, the nature a of =or example, there is a statis- :rweight in women with higher tes and in men, of higher y marriage (or sexual activity) )f the cervix. Such positive I for other kinds of investiga- ture of the relationship. 757 Still more striking is the reported epidemiological finding that men and women who average seven hours of sleep per night have lower death rates from coronary heart disease than those getting either more or less sleep. Those getting less than five hours had very high death rates and those sleeping ten hours or more per night had higher than average rates. I have previously pointed out that merely changing the hours in bed of the short-term or long-term sleepers to seven per night, would be unlikely to change this picture radically. More likely the amount of "useful sleep" that an individual can achieve is a reflection of a psychophysiological diathesis that may be the basis of the diffeirence and which may or may not be alterable. Studies show that many persons are able to achieve "useful and effective sleep" in a relatively short period. Others may have difficulty in getting to sleep or sleeping rest- fully on account of psychological tensions or emotional prob- lems. Whether such persons can b e treated to reduce such ten- sions is a question many investigators are attempting. to attack. Surveys have shown that.many smokers testify to the feeling that smoking cigarettes helps to arouse them when they are drowsy but to relax them when they are tense. Confirmation of these contradictory impressions by objective pharmacological methods has been difficult, but studies of electro-encephalo- grams have claimed correlations between certain types of brain waves and psychological characteristics of the subject. Some -3-

I 758 subjects can learn to produce various types of brain waves (electro-encephalograms) at will. Others have difficulty in~ producing the types reputed to reflect inner repose. Smoking *r has been claimed to promote this kind of tranquility but the; evidence so far is widely regarded as "soft". The discovery off, ,°d centrally active small peptides (endorphins, encephalins and. related substances) may eventually provide an answer to these questions. .,.~a Lun Cancer Diagnosis . ~~ ;J In 1912, a book by Adler called attention to the occurrence of primary carcinoma in the lung and apparently created the impression that this disease was a new developmentx 1 whose cause must be sought. By coincidence this book appeared ~~ near the time when development of the blended cigarette in the United States was stimulating a vast expansion of cigarette use in this country, which was further stimulated by the social conditions brought about by World War I. Thus, a basis was laid ' for the claim promulgated a few years later that an "epidemic" . ys. of lung carcinoma had been engendered by cigarette smoking. a .:y} Meanwhile, however, the late Dr. Milton B. Rosenblatt ' had made a very intensive and extensive study of lung cancer as `~ described in the m edical literature, mostly European, of the :~ sst,•:: nineteenth century where the art and science of pathology was ` developed and practiced relatively early. The application of -4 - ~,,)st-mortem examinatio utinely in some cen came prevalent in o ~cognized, post mortem ssed altogether in cl -is missed clinically spitals where post mc ,;ularly, carcinoma o ;tal male cancers si: ~'ay. Yet in that era In retrospect, :-,sed in clinical di: ~~~~rce of bleeding fr •;•:oerally occurred in t -s not suspected. As better cli " ' as radiography, aploratory thoracotomy i1,1gnoses and post-mort :.radually o ver several "ventually played a r -Solved, exposing a cai In the United : 1ittle known. The do "I-tastatic so that the

758 :e various types of brain waves .11. Others have difficulty in o reflect inner repose. Smoking .his kind of tranquility but the .rded as "soft". The discovery of tes (endorphins, encephalins and Adler called attention to the ,ma in the lung and apparently iis disease was a new development 3y coincidence this book appeared : of the blended cigarette in the 3 vast expansion of cigarette use urther stimulated by the social id War I. Thus, a basis was laid ~-w years later that an "epidemic" idered by cigarette smoking. he late Dr. Milton B. Rosenblatt sxtensive study of lung cancer as arature, mostly European, of the :rt and science of pathology was -4 - 759 post-mortem examinations for cause of death was made quite routinely in some central European hospitals long before it became prevalent in other areas. Carcinoma of the lung was recognized, post mortem, in a great many cases where it had been missed altogether in clincial pre-mortem diagnoses. In fact, it was missed clinically as often as 90-95% of the time. In hospitals where post mortem histological diagnosis was practiced regularly, carcinoma of the lung constituted a proportion of total male cancers similar to or greater than that reported today. Yet in that era cigarettes were practically unknown. In retrospect, it is not strange that lung cancer was missed in clinical diagnosis. Tuberculosis was common as a source of bleeding from ; he lung and death from pneumoniay generally occurred in the lung carcinoma patient so that cancer was not suspected. As better clinical diagnostic methods came into use, such as radiography, bronchoscopy, exfoliative cytology, exploratory thoracotomy and others, the gap between clinical diagnoses and post-mortem discovery of lung cancer was closed gradually over several decades. The introduction of antibiotics eventually played a role also since a pneumonia might be resolved, exposing a carcinoma to discovery. In the United States, this European work was apparently little known. The dogma was that all lung cancer must be metastatic so that the primary lesion must be found if the -5- I 0

760 origin of_ the neoplasm was to be known. Moreover, post mortem examination was much less frequently made than in Europe. Although histological examination of cancer tissue by an experienced pathologist still provides th e most reliable " diagnosis available, the development of clinical methods that are quicker an d easier apparently discouraged th e application of painstaking post-mortem study in this country, and has promoted the general use of less reliable clinical methods. The lung is a frequent target for metastases from other organs. Dr. Shields Warren reported that about one-third of cancers arising in other regions of the body al l - eventually metastasize to the lung, often at a early stage. Dr. Rosenblatt , thought it very unlikely that such metastatic cancer present in ~ the lung but not originated there was "caused" by tobacco' smoke. He felt it logical to exclude metastatic cancer in the lung from any statistical study of correlation with smoking. But the distinction between primary and metastatic cancers in the lung is not always easy and a distinction is no longer required on death certificates or attempted in statisticaO records. While the distinction appears to be very important for3 5 the study of causative factors and etiology the necessary datay are not easily available. ST Nevertheless in a careful review of contemporary death certificates and hospital records in a few individual hospitals, t Rosenblatt found considerable clinical over-diagnosis of lung' -6- carcinoma in pati Similar findings h: Animal Experiments When the the association b o-rere described p investigators unde animals, including smoke inhalation. produced lung carc ~,,npire Cancer Camp t:p to a "striking r The first unproductive of re recalled that the destructive distil cancers when pai researchers began : of mice. Conden nechanically and p condensed into a not "tar" as defi close resemblance t It must belief, tobacco sm<

761 . Moreover, post mortem e than in Europe. ion of cancer tissue by ides the most reliable ~f clinical methods that iraged the application of ountry, and has promoted 1 methods. Eor metastases from other .t about one-third of all f the body eventually _y stage. Dr. Rosenblatt istatic cancer present in as "caused" by tobacco metastatic cancer in the )rrelation with smoking. id metastatic cancers in istinction is no longer ttempted in statistical to be very important for ology the necessary data iew of contemporary death 'ew individual hospitals, over-diagnosis of lung carcinoma in patients who were known to be cigarette smokers. Similar findings have been made by Feinstein. Animal Experiments When the first large-scale epidemiological studies of the association between cigarette smoking and lung carcinoma were described publicly in the mid-fifties, a number of investigators undertook to expose many different species of animals, including mice, rats, h amsters and hens, to cigarette smoke inhalation. None of these early inhalation studies produced lung carcinomas. The 1958 Annual Report of the British Empire Cancer Campaign referred to these experiments as adding up to a "striking negative result." . The first wave of smoke inhalation studies was so unproductive of results that other methods were sought. It was recalled that the black tar accumulated as a by-product from destructive distillation of coal had been shown to produce skin cancers when painted on mice and rabbits. Accordingly, researchers began applying tobacco smoke condensate on the backs of mice. Condensate was obtained by puffing cigarettes mechanically and passing the smoke into a cold trap where it was condensed into a dark-colored viscous liquid. Though this is not "tar" as defined in the dictionary and does not bear any close resenblance to coal tar, the term persists. It must be pointed out that, contrary to popular belief, tobacco smoke condensate -- or "tar" -- is not actually -7- I ® ®

-8- constitute the b -7ich influences ::•ie aerosol are '•,)wn, and otherwi :rap, the most re thick liquid but This sit -nosing animals d chenical prop ~:st we can do is ',^chanically unde `.,:nans and get it 1': monitored dosag These cor piinting of mice w ^:Jng material ir `rons tissue of th- To the b, -',:_ed the type of 5-,,)king by exposin ""ole smoke. The c "'Idings of twent ^ctreme brevity wi- w emphasizing st ~ 1 basic level ti ' ~ also to shor. trictive in the "*'-n77 0-82--49 762 a material to which h uman smokers are exposed. Many chemical studies have shown that there are qualitative, as well quantitative differences between laboratory condensate and frestl smoke to which humans are exposed. Nevertheless, researchers began painting such tobacco smoke condensate on the backs of mice, generally dissolved iA some solvent. After persistent treatment over a long perioi with enormous doses, neoplasms did appea r on th e skins of thes mice. This method of testing was seized upon by numerous othe #- investigators with many variations of technique, differen ;¢ species and strains of animals and varying results. Some o; • the tars and by the proliferating techniques nf rhromatnvraDhYJ,- component s ot~~ of reliabilityt identified literally thousands of chemical cigarette smoke condensate with a high degree Probably no other complex mixture in the human environment hiC ever been so thoroughly analyzed. I was critical of this development from the start! 'fi ,- <. "typical" human smoker draws a puff of air throug cigarette. This generates a cloud of smoke that enters mouth within a fraction of a second following formation, remaltii. in his oral cavity for another fraction of a second and then.., ~i~ ;=?YEP'" ~ . . drawn into the lung diluted with five to ten volumes of air. During this short interval, rapid physical and chenitsl changes are taking place. The tiny liquid droplets I tb~t

are exposed. Many chemical re qualitative, as well as iboratory condensate and fresh began painting such tobacco mice, generally dissolved in :reatment over a long period appear on th e skins of these seized upon by numerous other )ns of technique, different nd varying results. Some of icible. - Chemists fractionated ; techniques of chromatography of chemical components of high degree of reliability.' in the human environment has evelopment from the start. A puff of air through his ud of smoke that enters his d following formation, remains iction of a second and then is ve to ten volumes of air. 1, rapid physical and chenical tiny liquid droplets that go ¢i 763 constitute the blue cloud are growing in size by coalescence, which influences deposition in the lung. Numerous compounds in the aerosol are polymerizing, interacting, combining, breaking down, and otherwise changing. If such a mixture enters a cold trap, the most readily condensed substances wil be deposited as a thick liquid but other phases of the smoke escape into the air. This situation complicates the design of devices for exposing animals to inhalation of smoke comparable in physical and chenical properties to that inhaled by h uman smokers. The best we can do is to design devices that will produce the smoke mechanically under conditions approximating those attained by humans and get it to the animal's lung at a comparable age and in monitored dosages. • These considerations led me to characterize the skin- painting of mice with cigarette smoke condensate as applying the "wrong material in the wrong form, in the wrong dosage, to the wrong tissue of the wrong animal." I still hold the same view. To the best of my knowledge, to date no one has pro- duced the type of lung cancer that is associated with human smoking by exposing experimental animals to inhalation of fresh, whole smoke. The considerations, experiences, trials, tests and findings of twenty-eight years that have been described in extreme brevity will, I hope, make it clear why The Council is now emphasizing study of the "cc..:stitutional" diseases as such on a basic level with the help of new research tools. I have tried also to show why dogmatic positions are inappropriate and restrictive in the present state of knowledge. 95-077 0-82-49 I 8 I 0 I 0

764 ' CURRICULUM VITAE OF DR. ROBERT C. HOCKETT Relationships He Personalii Dr. Robert C. Hockett, Research Director of The Council for Tobacco Research - U.S.A., Inc., 110 East 59th Street, New York, New York 10022, was born in Fayette, Missouri on July 1, 1906. Chemist on the Institute staff from 1931 to 1935. Health, U.S. Public Health Service from 1929 to 1931 and then Associate Chemistry, he was a guest scientist at the National Institute of chemistry there in 1929. As a National Research Council Fellow in graduate study in the same institution and received the Ph.D. degree in A graduate of the Ohio State University, Dr. Hockett pursued In 1935 he joined the faculty of the Massachusetts Institute of Technology as Assistant Professor of Chemistry, becoming Associate Professor in 1941. In 1943 he was granted a leave of absence from M.I.T. to serve as scientitic uirector ot tne augar nesearcu rounaa «au, -« position he occupied until 1952. He has also been Visiting Professor at the Universities of Illinois and North Carolina. W From 1952 until 1954 he served as a consultant to industrial I ;i1 firms on problems relating to foods, nutri;ion, pharmaceuticals, fermentations and sponsored research. In 1954 he joined the present Council for Tobacco Research's predecessor organization - the Tobacco Industry Research Committee as an Associate Scientific director. _ Dr.-Hockett is a Fellow of the American Academy of Arts and Sciences, the New York Academy of Sciences, the American Public Health Association, the Royal Society of Arts, and the American Institute of Chemists. He holds membership in the American Chemical Society, in which he has served as an Alternate Councilor, member of the Nomen- clature Committee, Vice-Chairman of the Division of Carbohydrate Chemistry in 1944, Chairman in 1945 and 1946, and Secretary-Treasurer from 1956 to 1960. He also holds membership in the American Society of Biological Chemists, American Association for the advancement of Science, Friends of'the World Health Organization, Royal Society of Health, and the Phi Beta Kappa Associates. He has served as a Lecturer in Switzerland for the American- ~ Swiss Foundation for Scientific ExchanRe. member of the Food Industries! Advisory Committee to the Nutrition Foundation, Inc., Collaborator to the United States Department of Agriculture, member of the Advisory Committee for Advances in Carbohydrate Chemistry, as Associate to the State Department's Committee for Interamerican Scientific Publication and member of the Sugar Advisory Committee to the Administrator of the' Production and Marketing Act, U.S. Department of Agriculture. He is author of numerous research papers on the chemistry of carbohydrates, of articles and lectures on nutrition and public health, of many reviews and summaries on tobacco and health research and contributor to a book, Beet Sugar Economics. I am Charles D.'Spiel Center for Research t in Tampa. I obtaine< and have been a membc bilt University and : in ClinicaL Psycholo I was also employed ' in psychology. I am of Psychologists and Journals and on the have contributed to years, and have beer behavior for the pa` Due to a long-standi Personality Assessmt 4-9 official host fot I will be unable to to present the ressi and which I believe y•R. 4957. Z have, Subcommittee.