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A

Scientific Perspective . on the

. Cigarette

Controversy

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Note _ Certain of the quotations in this booklet arc from Government documents and arc in the public domain. AIl other quotations herein arc included by special permission of the authors and publications. No part of this document may be reproduced for any advertising or trade purpose.

TOBACCO INDUSTRY RESEARCH COMMITTEE 5400 Empire State Building

New York 1, N. Y.

TIMN 0140767

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Introduction

No activity in all the vast field of medical research is being carried on so intensively, In so many areas and at such cost as the effort to track down the causes and cure of cancer. With the whole world anxiously waiting for some word of success, any reported identification of a cause of cancer arouses immediate and wide public interest.

This has happened in the past year with the promotion of a theory by a number of research doctors that cigarette smoking may be in some way linked with lung cancer.

In papers read before scientific groups and published by medical journals, Doctors Ernest L. Wynder, Evarts A. Graham, and Alton Ochsner and others maintained that the sharp rise in lung cancer reported in this country was "compatible" with the greatly increased use of tobacco. A similar statistical association was suggested in England by Doctors Richard Doll and Bradford Hill.

In addition to this alleged statistical association, considerable attention was paid to reports of experiments in which Doctors Wynder and Graham had been able to induce skin cancer on mice by application of cigarette tars.

Some doctors have gone on record as accepting these views. But other distinguished medical authorities and research scientists have questioned the validity of the statistical methods and the conclusions drawn from laboratory experiments with mice. Among basic questions raised is how much of the apparent rise in lung cancer is real and how much is due to other reasons such as better diagnosis and the aging population.

These other a~~?ri~~s find no proof establishing that cigarette smoking is a cause of lung cancer. Especially significant is the stand taken by the National Cancer Institute of the United States Government. In a report published in April, 1953, the NCI says:

"Aside from the statistical significance and apparent realness of these associations there remains the question of whether smoking is etiologically related to lung cancer. Considerations are presented which

TIMN 0140768

lead to the conclusion that the etiological (etiology: the science of "1 causes of diseases) significance of these associations remains unestablished."

Because of the wide publicity given statements made about tobacco by Doctors Wynder, Graham and Ochsner, many laymen and even physicians are unaware of the extent to which these statements have been questioned by other authorities. It is in the interest of science and of the public that these

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other views be brought to public attention, and it is for that purpose that

this compendium is being published.

The following pages contain the statements of many qualified cancer experts and organizations in the United States and overseas.

The Tobacco Industry Research Committee does not suggest that these views represent the entire body of scientific opinion on the subject. Researchers the world over are studying dozens of theories in attempts to solve the mystery of cancer. At latest count there were more than 850 cancer research grants active in the United States alone, anyone of which might produce evidence to unlock the secrets of lung cancer.

As set forth in its public statement on January 4, 1954, the position of the group comprising the Tobacco Industry Research Committee is that they "accept an interest in people's health as a basic responsibility and paramount to every other consideration in their business."

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In that spirit, it is believed that no serious medical research, even

though its results -are incOnclusive, should be disregarded or lightly dismissed. The important thing is to recognize the urgent need to explore every scientific avenue which could lead to discovery of the cause of lung cancer.

The Tobacco Industry Research Committee has pledged its aid and assistance to the researcheffort into all phases of tobacco use and health. The joint effort, of course, will be in addition to that already being contributed by individual companies.

TOBACCO INDUSTRY RESEARCH COMMITTEE 5400 Empire State Building

New York 1, New York

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Comment on Current Theories

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Questions Role of Cigarette

Many Comparable Correlations

"None of Evidence Conclusive"

If excessive smoking plays a role in production of lung cancer, "it seems to be a minor one," according to Dr. W. C. Hueper, Chief of the Cancerigenic Studies Section, National Cancer Institute. Writing in a 1953 issue of the Bhode Island Medical Iournal, he says:

"It may be concluded that the existing evidence neither proves nor strongly indicates that tobacco smoking and especially cigarette smoking represent a major or even predominating causal factor in the production of cancers of the respiratory tract and are the main reason for the phenomenal increase of pulmonary tumors during recent decades. If excessive smoking actually plays a role in the production of lung cancer, it seems to be a minor one, if judged

from the evidence on hand,"! .

Prof. R. D. Passey, Director of Cancer Research at England's University of Leeds, cautions "let us be sure of our evidence." In a February, 1953, letter to the British Medical Iournal, he says:

"In view of the present interest in the relationship of smoking to lung cancer there is undoubtedly a large body of opinion, both professional and lay, which accepts, as though it had been proved, that smoking is the main cause of the recorded increase in lung cancer; and no doubt there is considerable distress in the community on this account. In the present state of our knOWledge, is this anxiety really justified? •••

"It is easy to call to mind other close statistical correlations. What catches the popular fancy is the way the rise in the habit of cigarette-smoking goes hand in hand with the rise in lung cancer mortality. But in the long history of our profession's attempts to elucidate the causes of cancer it has found many correlations of a comparable nature which have in the end proved false. • • •

"It may be that a proportion of lung cancers in man are induced by tobacco smoke; at the moment we do not know, but let us be sure of our evidence before we scare the public."!

A public statement November ·27, 1953, by the Damon Runyon Fund says that the evidence is not conclusive.

"It is recognized that lung cancer is now more common than it was one or two decades ago. Many suggestions as to the cause of this increase have been made; the possible relationship of air pollution, vehicle exhaust fumes, smoking and other factors have been widely mentioned. Some of these SUIID.ises are purely speculative, some are drawn from statistics, others derive from the experimental induction of cancer in animals of these materials. However, none of these factors has as yet induced in experimcntal animals lung cancer of the kind seen in man. None of this evidence is conclusive but does urge the need for carefully controlled research to secure the answer. Three questions arise which require solution: first, is there a causal relationship; second, if so, \ what factors are responsible; third, how can they be eliminated?"1

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TIMN 0140770

Unwarranted Conclusion

Facts and Fancies Need to be

Sorted

Dr. Max Cutler, internationally noted cancer surgeon of Chicago, says, "I feel strongly that the blanket statements and conclusions which appeared in the press that there is a direct and causative relation between smoking of cigarettes, and the number of cigarettes smoked, to cancer of the lung are absolutely unwarranted."

During the last 30 years Dr. Cutler has published two books and dozens of

medical papers on cancer. His unsolicited statement follows:

"1 feel strongly that the blanket statements and conclusions which have appeared in the press that there is a direct and causative relation between smoking of cigarettes, and the number of cigarettes smoked, to cancer of the lung are absolutely unwarranted.

"Medical literature has numerous examples of such fallacious conclusions which have been proved to be wrong in the light of subsequent experience. This whole question of cause and effect deducted on a statistical basis is subject to the greatest fallacies. One way 1 like to emphasize it is to say that simply because one finds bullfrogs after a rain does not mean that it rained bullfrogs."

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"To accept the conclusion that has been drawn of a direct causal relationship between ·smoking and cancer of the lung simply because there has been an increase in both, appears to me unscientific and hazardous.

"From all the available evidence, I think it is conceivable that in a very small, probably infinitesimal percentage of sensitive individuals smoking may ultimately prove to be one of numerous contributing factors in lung cancer.

"Under these circumstances, is it wise to scare the public and create widespread anxiety among millions of people on the flimsy evidence that has been presented?"

Need for a calm, objective appraisal of evidence is emphasized by Professor D. W. Smithers. Director of Radiotherapy at England's Royal Cancer Hospital.

In his report, entitled "Facts and Fancies About Cancer of the Lung," appearing in the June 6, 1953 British Medical Journal, he says, "the moment the word cancer is mentioned to the public (of which doctors are but a part)· emotion is aroused and any calm objective view of the value of evidence presented becomes most difficult."

Following _is_~mplete text of his conclusions:

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"The startling rise in the recorded death rate from lung cancer is in large part due to change in numbers and age of the population and to improved diagnosis. It is due in part to a real increase, but we are not yet in a .position to say how great that real increase is.

"The size and the difficulty of this problem are clear to us all. Although the five-year survival rate for the fortunate few who are operable when they first reach hospital has risen from nothing to between 20 and 30% in 20'years, and while much can be done with x-ray treatment to relieve suffering and sometimes prolong life for the less fortunate ones who are, nevertheless, still in fairly good general condition, there are still thousands of these patients each year for whom no real attempt at treatment is being made.

"Since we all have to die, since some 90,000 people are doing so each year with lung symptoms, and since this number is falling well, we should ask ourselves how far we are performing a useful service by helping to make a public issue oia comparatively smaIl Change within that group, which may be in large

• Professor Smithers' parenthetical statement;

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More Accurate Tests Needed

"Etiological Significance ••• U nestabUshed"

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part due to our own method of recording. We should not be too readily swayed by those who demand that the public be told 'the truth' while we are still attempting to sort the facts from the fancies for ourselves, especially since 'the truth' when told may not appear to them in at all the same light as it does to us. Anthony Hope once wrote that 'telling the truth to people who misunderstand you is generally promoting a falsehood.'

"The moment the word cancer is mentioned to the public (of which doctors are but a part) emotion is aroused and any calm objective view of the value of evidence presented becomes most difficult. It is important that the medical profession take note of this difficult problem of lung cancer and help to deal with it more efficiently, but it is also important that they do not make matters

t worse by merely joining in a cry and increasing the alarm.

"A sensible view of the relationship of smoking to this problem, for instance, should be and, after some wild comments in the lay and medical press, is now being presented to the general public; but no comparable effort seems to be going into an endeavour to persuade the authorities to cleanse the air of our industrial towns. As a profession which speaks so much and so rightly of the need to allay the cancer fear we should beware of putting extravagant accounts of rising cancer death rates and their causes before the public, especially when neither the magnitude of the one nor the degree or responsibility of the other has yet been fullyestablished."S

Internationally known in the field of cancer investigation, Dr. Clarence Cook Little, Director of the Roscoe B. Jackson Memorial Laboratory at Bar Harbor, Maine, believes "If smoke in the lungs were a sure-fire cause of cancer, we'd all have had it long ago. The cause is much more complicated than that." Dr. Little's laboratory is credited with breeding a million laboratory mice per year.

In connection with a recent New York Town Hall program, Dr. Little stated:

"In proving a cause-and-effect relationship between any substance and any specific type of cancer in man, it is essential that a logical and rational approach to the problem and to the interpretation of data be employed.

"From a laboratory point of view. I do not feel that a definite cause-andeffect relationship between cigarette smoking and human lung cancer has been established on a basis that meets the requirements of definiteness, extent and specificity of data which the seriousness and implications of the problem deserve. :Further. and more accurate experimental tests and methods of analysis of the many factors involved should be devised and utilized.

"Fo_!'_~ese reasons I would regret any undue alarm on the part of the public at this time."G-

. Statistical Associations

Three National Cancer Institute specialists, Dr. A. G. Gilliam, Chief of Epidemiology, and research associates J. Cornfield and D. A. Sadowsky, in a 1953 report of the Institute's Journal, have questioned the relationship of smoking to lung cancer. Their report contains the following observations:

" ... In this study an association of about the same degree as that observed with cancer of the lung has been shown between cancer of the larynx and cigarette smoking. A phenomenal increase in cancer of the larynx, such as that recorded for cancer of the lung, has Dot been observed in this country. If the association between cigarette smoking and lung cancer is of etiological signift-

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TIMN 0140772

Clinical Data Questioned

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Diagnostic Factor

cance, some explanation is needed as to why a corresponding increase in laryngeal cancer has not followed an increase in cigarette consumption, with which this disease is also associated.

"These data also provide no evidence that age at onset of disease is influenced by the quantities of cigarettes smoked. , ••

"In the same fashion these data provide no firm evidence that risk increases with increase in duration of smoking. When age was kept constant no clear-cut trend in this direction was apparent. , , ,

"It would therefore appear that though the association between cigarette smoking and lung cancer seems real, the significance of this association remains unestablished. •• ,

, "Aside from the statistical significance and apparent realness of these associations there remains the question of whether smoking is etiologically related to lung cancer. Considerations are presented which lead to the conclusion that the etiological significance of these associations remains unestablisbed."7

Experts at the University of Texas School of Medicine have studied the statistical associations employed in relating cancer to cigarette smoking. Dr. Paul Brindley, Chairman of the Department of Pathology, Dr. R. H. Rigdon, Director of the Laboratory of Experimental Pathology, and Mrs. Helen Kirchoff, Research Associate in Pathology, have reported on these studies.

Drs. Brindley and Rigdon, in a 1950 report in the Texas State Journal of Medicine have questioned whether there is an etiologic factor in lung cancer. They also question the basic data on frequency of lung cancer, citing ''variation in the clinical data and the difference in these data and those obtained from autopsies." Their observations :

"The distribution of the cases of cancer of the lung in the districts of Texas as reported to the State Health Department does not suggest to us any etiologic factor as playing a significant role in the production of pulmonary neoplasms. Furthermore, nothing significant as to the etiology is noted in our cases studied at autopsy."

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"From this study of primary carcinoma of the lung at autopsy there is insufficient evidence to prove that the frequency of this neoplasm in all malignancies has increased during the past twenty years. There is no evidence to indicate that cancer of the lung is increasing in the female within this period. One of the factors contributing to the confusion relative to the frequency of cancer of the lung is the variation in the clinical data and the difference in these data and those obtained from autopsies. A second factor contributing to this problem is the failure to separate data referable to these tumors ,in the white and Negro patient. In autopsy series the frequency of cancer of the lungs may be established more readily by determining the percentage of these tumors in all neoplasms rather than only their incidence in routine autopsies."8

In a 1952 paper, published in the Spring Texas Reports on Biology and Medicine, Dr. Rigdon and Mrs. Kirchoff question the theories advanced on the increase in lung cancer, and find that control of infectious diseases, increased aging of the population and other factors arc significant.

Quoting from this paper:

"There is such a wide variation in the significance of the theories advanced to account for the increase in the frequency of cancer of the lung that the data, in our opinion. do not justify the conclusion that cancer of the lung has actually increased as a result of anyone so far advanced. The statistical data presented

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by some investigators relative to cigarette smoking are impressive; however. there is such a wide variation in control samples that, in our opinion, additional sampling is needed to warrant their conclusions. There is no significant correlation between the amount of tobacco consumed and the death rate for cancer of the lung in the United States. There is, however. a significant correlation in the United States between the population to physician ratio and the population to bed ratio and the number of reported deaths from cancer of the lung. Better diagnoses, decrease in the number of deaths from infectious diseases by both prevention and therapy, and the increased aging of the population seem to be more significant factors than anyone or group of carcinogens to account for the apparent increase in the frequency of carcinoma of the lung.'~

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"Let's Review the Facts"

In a 1953 paper, published in the Winter Texas Reports on Biology and Medicine, Dr. Rigdon and Mrs. Kirchoff made a broad analysis of the statistical data that have been aimed at cigarette smoking.

Their paper, entitled "Smoking and Cancer of the Lung - Let's Review ~e

Facts," contains the following observations:

"Regardless of the fact that some of the groups have very few cases, we would like to emphasize that in each of these three studies the percentage of individuals who smoked less than 15 cigarettes a day and did not have cancer of the lung is much higher than that of the corresponding group who had bronchiogenic carcinoma. Furthermore, as far as we know the cases of cancer of the lung studied by Doll and Hill (1950) and Breslow (1951) were not proven by pathologic examination, while the study by McConnell and associates (1952) was based on proven cases of cancer of the lung. The latter investigators concluded that 'no significant difference was found in the incidence of smoking, or of the proportion of cigarette-smokers, in the two groups' ...

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",As you know, Dr. Ochsner has been interested in smoking and cancer of the lung for several years. However, from a review of his publications it would seem that his opinion has varied relative to this relationship. In 1941 he presented a graph showing the comparison of the death rate per 100,000 population from cancer of the lung with the production of tobacco and automobiles

_in the United States during the period 1920 to 1936. Of automobiles and cancer of the -liirig. Ochsner and associates concluded that there was no significant relationship. but they did find an obvious parallelism between the increased production of tobacco and cancer of the lung. In 1948 Ochsner and his group stated that 'although we previously were of the opinion that the chronic irritation resulting from excessive cigarette smoking was a factor, this cannot be proved. However, the fact that there is a parallelism between the number of cigarettes sold in the United States and the increased incidence of bronchiogenic carcinoma is interesting ..•. In our series we have not been able to show that there has been a higher incidence of smokers than in the average population of a whole.' Then in 1952 Ochsner said, 'For some time two of us have been convinced that there is a causal relationship between the increased incidence of bronchiogenic carcinoma and the increased use of cigarettes.' Ochsner (1951) said that Dr. Evarts Graham has said to him, 'Yes, there is a parallelism betwee~ the increased incidence of bronchiogenic carcinoma and the sale of cigarettes; bur also there is a parallelism between the increased incidence of bronchiogeniC carcinoma and the sale of nylon stockings'."

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"In summary it may be said that in our opinion the data available today do not justify the conclusions that the increase in the frequency of cancer of the lung is the result of cigarette smoking. The statement that carcinoma of the bronchus has actually increased in frequency is in our opinion open to question. Furthermore, adequate studies are not now available on the frequency of cigarette smoking in the population. These factors would be necessary in establishing a causal relationship between smoking and cancer of the lung."lO

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"Evidence Gave Equivocal Results"

ttHow Much 0/ the Rise Is Real"?

A Hospital Survey

Dr. W. C. Hueper, Cancerigenic Research Studies Section Chief at the Federal Government's Cancer Control Branch, National Institutes of Health, says the statistical relation is "in urgent need of supporting biologic evidence." In 1953 he reported in the Rhode Island Medical Journal:

"The apparent lack of uniformity in the human material analyzed by the different authorities is further demonstrated by the appreciable differences in the sex distribution of lung cancers reported at different times, from different regions and by different investigators. The male to female sex ratio fluctuates between 2:1 to 20:1 (Hueper). It is noteworthy. however. that the uniformly observed prevalence of lung cancer among males has in general become in recent years even more pronounced than in former decades. This observation strongly militates against a predominant causal role of cigarette smoking in the production of lung cancer, because all previous experience in the field of occupational cancer indicates that given the same type of carcinogenic exposure for both sexes and at the same time an increasing equalization of the intensity of exposure, there occurs a narrowing of the gap in incidence rates of the two sexes and not a widening, which actually exists. This interpretation of the diverging sex related frequency trends is not fundamentally affected by the statement that the interval between the start of tobacco smoking and the appearance of a lung cancer is between 20 to 40 years (Wynder and Graham; Ochsner, "DeCamp and DeBakey; Sehrek, Baker and Ballard). Even if women may not have indulged on a large scale in tobacco smoking some thirty years ago, there can be little doubt that the cigarette smoking habit has made during this period much greater strides among women than among men.

"The purely statistical approach leading to the assumption of the existence of causal relations between two coincidental events and trends is, thus, in urgent need of supporting biologic evidence in man, since the available experimental evidence gave equivocal results."ll

The Metropolitan Life Insurance Company during 1953 issued a statement saying the data were far from conclusive.

"In the present state of knowledge it is difficult to account for the recorded increase in the mortality and morbidity from respiratory cancer, or even to determine how much of the rise is real. Improved techniques for diagnosis and the greatly increased frequency of their use have resulted in many cases being detected and reported which, in the past, would have been overlooked. This applies especially to diagnostic x-rays in medical and hospital practice. Mention, too, should be made of the increase in the number of physicians with training and experience in this field. Contributing in a lesser way to the more frequent discovery of cancer of the respiratory tract is the increasing use of the bronchoscope and of cytological examination of lung secretions. . . . The role ofother_f~ct()rs,sllc_h as coal tar products, excessive tobacco smoking, and specific contaminants, is still far from conclusive. "12

A survey of lung cancer patients by Dr. E. D. Gagnon of the Chest Clinic at Montreal's Notre Dame Hospital revealed (as translated from the French):

"Since February, 1949, bronchopulmonary cancer was observed in 120 men and 5 women admitted to the thoracic clinic of the Notre-Dame Hospital in Montreal. Of the 125 patients, 97 were over 50 years; the oldest was 79 and the youngest 21. Fifty patients smoked more than 20 cigarettes daily and 10 did Dot smoke. Etiological factors discussed in (medical) literature are so numerous and so contradictory that it is impossible for us to be sure of one etiological factor. Many statistical analyses have tended to incriminate tobacco (esp. as cigarettes) but there are just as many analyses that negate such an etiology."13

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Much More Research Necessary

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Dr. Milton B. Rosenblatt, Associate Clinical Professor of Medicine, New York Medical College and visiting physician to the New York City Hospital, in a paper read at the New York Medical College, March 16, 1954, stated:

"The tremendous increase in the incidence of lung cancer for the past two decades has furnished a therapeutic challenge to the medical profession. Many explanations have been offered for the unusual increase in incidence but smoking at the moment occupies the prime position in the lay press. However, the public which is already so concerned about cancer should not be unduly alarmed without proper justification. A great deal of thought and experimental i'nvestigation is necessary before any definite conclusions can be reached.

"The increase in the incidence of lung cancer can be attributed to two main causes. The disease was clinically unrecognizable 25 years ago - bronchoscopy, the perfection of x-ray technique, cytological studies, etc., have been developed in recent years. At the Brompton Hospital in London (which specializes in chest diseases) there were only 29 bronchoscopies between 1926-29; at the present there are more than 800 done each year. The second factor for the tremendous increase has been the general awareness of the disease and the intensification of pathological studies. It has been commented philosophically that a sharp rise in incidence in certain institutions was coincident with the establishment of pathology departments. Much has been made of the increase in autopsy statistics in lung cancer on the assumption that autopsy statistics reflect the general trend in population.

"Necropsy records are subject to the same errors of distortion, lack of control and misinterpretation as clinical data. The widespread use of antibiotics has resulted in fewer hospital admissions and fewer deaths from infectious diseases, and proportionately, more from malignancy.

"Probably the most important consideration in the explanation for increase in incidence is the age distribution of patients with lung cancer which is a disease of older age groups. The span of life has steadily increased and with it has come a proportionate increase in the number of potential candidates for lung cancer. There are now four times as many people, age 65 or over in the U. S., as there were in 1900.

"The evidence pointing to smoking has been chiefly on a statistical basis. A statistical correlation does not signify that there is a cause and effect relationship. Analysis of numerous statistical studies shows that there is actually very little difference in the incidence of smoking between cancer patients and control patients, particularly if the statistics are evaluated with respect to age groups. In the report of Mills and Porter, the percentage of heavy smokers in the control group equalled or exceeded that of the cancer patients in the respective age groups. Ochsner stated that the carcinogenic effect of cigarette smoking does not become evident until approximately 20 years. Also that the death rate will increase steadily so that by 1970 it will be 29.4% per 100,000 of population. This is merely a form of extrapolation, or educated guessing, and is not to be interpreted as establishing a cause and effect relationship between lung cancer and smoking.

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"Pathologically lung cancer in mice resembles only remotely bronchogenic carcinoma in the human. The occurrence of lung tumors in mice in the course of experimental studies may be incidental inasmuch as lung cancer often occurs spontaneously in mature mice.

"A great deal more research must be done before one can establish the etiology of lung cancer or, as a matter of fact, all cancer. The recent ability to diagnose lung cancer plus the fact that it occurs only in older age groups, which have increased tremendously during the past two decades, seems sufficient to explain the increased incidence of the disease. Although the percentage of heavy smokers (20 years or longer) between 40 and 45 years of age is very large, the incidence of lung cancer in this group is negligible. "14

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Calls Mice Conclasions "Dangerous"

"Tissues Respond Differently"

British Experimental Studies

Tobacco PPRelatively Unimportant"

Dr. Jonathan L. Hartwell of the National Cancer Institute says it would be "dangerous to conclude that man is resistant or susceptible to a given carcinogen" merely on the basis of experiments with a single species of laboratory animal.

In the "Survey of Compounds Which Have Been Tested for Carcinogenic Activity," Second Edition, published by the Federal Security Agency, Public Health Service, Public Health Survey #149, page 2, Dr. Hartwell says:

"Another pitfall is the attempt to carry over, without reservation, to man, conclusions based on animal experiments. We do not know whether man is more or less susceptible than mice to particular carcinogens. Some animal species, such as the rat, rabbit and dog, are much more resistant to certain chemical carcinogens than is the mouse, and vice versa, while in the monkey none of the powerful carcinogens has been shown to produce tumors. It would, therefore, be dangerous to conclude that man is resistant or susceptible to a given carcinogen merely on the basis of experiments with a single species of laboratory animal ••• "15

Two other National Cancer Institute scientists, Dr. Murray J. Shear and Joseph Leiter, are quoted from the Ioumal of the National Cancer Institute, Vol. 2, 1941-42, page 254, as saying:

"" ••• there are pronounced differences in the response of different species 'to the action of compounds carcinogenic in the case of the mouse •.. Furthermore, in the mouse itself, it is now abundantly evident that different tissues respond differently to the same compound ..• The mode of administration may also influence the results markedly. The dose may be too high as well as too low ••• The solvent or vehicle may affect the results profoundly ••• Moreover, the sex of the animal is not without influence on the results ••. Diet, too, may be an important factor .••

" .•• the term 'carcinogenic potency' as used in these studies is not to be considered as an invariable property inherent in a compound but is merely a summary of the results of particular experiments and is valid only for animals of the species, strain, sex, age, diet, etc., of the particular animal employed, as well as for the dose, menstruum, mode and site of application, etc., of the compound in question. "16

In a 1923 edition of the British Medical Journal, the late Dr. Archibald Leitch, then Director of the Cancer Hospital Research Institute, London, had this to say about an attempt to induce skin cancer in mice with smoking tobacco fractions:

" .•. We applied these fractions to two series of mice for many months. They produced epilation of the areas to which they were applied, and they induced chronic ulcerations, but in no single case did any neoplastic reaction result. We have thus no evidence in support of the contention that tobacco smoke contains a cancer-producing property, though we may not therefore conclusively reject the idea that there is something connected with tobacco smoking which may be operative on the oral mucous membrane of human beings. But what is of more theoretical and practical interest is the fact that here we had a substance with a very marked irritative effect on the skin in that it produced chronic lesions and yet no tumour formation supervened. We might say that it is not a specific irritant of the tumour-producing class. "1'1

Reporting on studies of tobacco smoking and cancer in 1932, four British researchers at the University of Birmingham, Drs. F. W. Mason Lamb, E. Ashley Cooper, and Prof. E. L. Hirst, and associate Edgar Sanders, had this to say:

'The fact that only one tumour has been obtained in the course of subjecting a large number of mice to the action of tobacco tar, compared with the very high incidence of cancer in mice treated with coal tar, indicates that tobacco is relatively unimportant in the causation of cancer."II

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A 1932 American Experiment

"Is Remains to be Shown"

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"Evidence Not Convincing Enough"

Two American investigators, Dr. Emil Bogen, Director of Laboratories and Research at Olive View Sanitorium, Olive View, California, and his associate, Russell N. Loomis, reported in 1932 in the American Journal of Cancer on attempts to induce skin cancer in mice. Following quotes are from their report:

"In the mice treated with the tobacco tar, no marked changes in the skin were observed." • • •

"From these experiments we may conclude that the cutaneous application of a tar derived from the destructive distillation of tobacco did not possess the irritating and ephithelial-stimulating properties that lead to the production of neoplastic growths, as tested upon the skin of mice and rabbits."19

In a 1952 contribution to the British Empire Cancer Campaign's 30th Annual Report, the Campaign's Yorkshire Council observed that "it remains to be shown that smoking can give rise to lung cancer."

An extract from the Yorkshire Council's contribution to the report reads as follows:

"With the evidence available at the moment, it is not possible for anyone to say with certainty that lung cancer can be caused by smoking, or that it cannot.

"Nationally we are faced with a large rise in the numbers of reported cases of lung cancer: in the Registrar-General's Statistical Review, 1946 to 1947 (Text) there is the statement: - 'Comparing the rates in 1947 with the mean annual rates 1921 to 1930, men between 45 to 75 show a lO-fold increase.'

"At the same time there has been an increase in the habit of smoking cigarettes which is due, in some part, to a change-over in the national habit of pipe smoking to that of cigarette smoking. What is not so well known is that the increase in the total consumption of tobacco has, in that period, been less than is supposed.

"In 1900 the total consumption per annum of all tobacco goods in the United Kingdom was 7.2 Ibs, per adult male, in 1920 9.1 lbs. and in 1951 9.6 Ibs, Yet in 1871 the consumption of tobacco, mainly in the pipe, was some 5.7 lbs, per adult male. Thus, from these figures of the consumption of tobacco, smoking is nothing new, nor is the increase per male in recent years outstanding.

"If in their recent paper (1952) Doll and Bradford Hill are correct when they infer that the pipe is suspect as well as the cigarette, it must be admitted that the increase in tobacco consumption from 5.7 lbs. in 1871 to 9.6 lbs, in 1951 has little correlation with the great increase recorded by the RegistrarGeneral. If tobacco smoke can induce lung cancer, it has caused this condition since Sir Walter Raleigh introduced tobacco into England, but the condition has not been widely recognized until the recent diagnostic means were available. HOvvever, it remains to be shown that smoking can give rise to lung cancer.

"If, at some future date, it should be shown that some lung cancers are the result of smoking it would stiII remain to be established what proportion of the total cases are dependent on the habit. We are surely on firm ground when we state that a large proportion, how large we do not know, have nothing to do with smoking. For instance, Doll and Bradford Hill found 40 non-smokers out.of their 108 women with lung cancer.''20

Reports from Lay Media

Dr. Walter B. Martin, president-elect of the American Medical Association, in an ABC network television interview, December 16, 1953, said, "1 do not think the evidence is convincing enough to establish as a positive fact that cigarette smoking is necessarily the cause of cancer of the lung."

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Additional Factors Need Study

rtToo Much Talk"

Following is a verbatim excerpt of his remarks:

''We have known a long time about the tremendous increase in lung cancer. My first observation on that was in a scientific article that came out in 1922. It pointed out that cancer of the lung was on an increase at that time.

''It is true that we have been interested in the parallelism between the increase in cigarette smoking and the increase in cancer of the lung. But there are some other para1Iels such as the increased use of internal combustion engines,

although there is no positive proof that a connection exists. ,

"We are very much interested in the recent work that has been reported in connection with the relationship between cigarette smoking and lung cancer, 'but I would like to point out that this is an animal experimentation which does not indicate the definite part tobacco plays on humans. We think that the proper attitude is one of caution and we hope that further investigation will be made to establish positively whether it is a factor. • ••

" ••• On an individual basis we doctors advise a great many people not to smoke. At the present time I still think it is a matter between the individual physician and his patient as to what advice should be given.

"I do not think the evidence is convincing enough to establish as a positive fact that cigarette smoking is necessarily the cause of cancer of the lung."

-

When Dr; Martin was asked if he smoked, he replied:

"I've smoked long enough to have incurred all the possible dangers and don't think I will stop now."

The New York Times for April 30, 1953, reported that Dr. John R. Heller, Director of the National Cancer Institute, questioned the connection between smoking and cancer. Following are pertinent paragraphs from the Times' Washington dispatch:

"Dr. John R. Heller, director of the National Cancer Institute, says any connection between heavy smoking and lung cancer has not been definitely established 'to our satisfaction.'

•

•

•

"Dr. Heller said lung cancer has increased 'severalfold' among men in the past twenty-five to thirty years. But there has been no similar increase among women, he added, even among heavy smokers.

"He conceded that 'there is a very high correlation between heavy cigarette smoking and the occurrence of lung cancer.' But, he added 'our ••• scientists seem to feel that there are some additional factors which we have not yet discovered or studied sufficiently, which may have a bearing on this particular problem.'''

Dr. Anthony J. Lanza, Chairman, Institute of Industrial Medicine, Post Graduate Medical School, of New York University, says "more knowledge is needed before any conclusion can be reached," Following are pertinent paragraphs of a January 15, 1954, report from San Juan, Puerto Rico, as carried by the New York World Telegram and Sun:

"Dr. A. J. Lanza, Chairman of the Institute of Industrial Medicine, Post Graduate Medical School of New York University, says more knowledge is needed before any conclusion can be reached regarding a possible connection between cigaret smoking and lung cancer.

'''There is too much talk and too little action in relation to tobacco as a cancer cause,' Dr. Lanza said. 'Scientific investigation is in less than embryonic stage, and lung cancer statistics show little.

'''Sixty million Americans smoke, and the few hundred cases studied do not show much about' tobacco as a cancer cause.'''

12

Tn\1N 0140779

Comparison With Other Nations

j;

Baltimore Specialists Question Proof

• i

,

One of America's top experts, Dr. Harold Stewart of the National Cancer Institute, says that, percentage-wise, lung cancers are more prevalent in Austria, England and the Netherlands than in the United States. As quoted in the Chicago Daily Tribune, November 4, 1953:

"Dr, Harold Stewart, National Cancer Institute, Bethesda, Md. cited reports that lung cancer accounts for about 17 per cent of all cancers among men in Austria, England, and the Netherlands, 9lh per cent in the United States, 2 per cent in Japan, and half of 1 per cent in Thailand (Siam).

"Yet 1 understand that the smoking habits in Thailand are about the lame as in the United States,' he said. He added that mice exposed to heavy cigarette smoke 40 hours every week for eight months or more did not show any in-

crease in lung cancer." .

On the basis of experience with hundreds of cases of lung cancer, Dr. William F. Rienhoff, Jr., pioneer lung surgeon and assistant professor in surgery at JohnsHopkins University, Baltimore, has been quoted as saying "there is no proof whatsoever that cigarette smoking causes pulmonary disease."

Drs. Rienhoff and Lawrence M. Serra, both chest specialists, are quoted in a story which appeared in the Baltimore Sun, July 13, 1950. Following is the pertinent text of the newspaper report:

"Several Baltimore doctors, questioned yesterday, largely expressed disagreement with the recently published view of five investigators that 'excessive and prolonged' use of cigarettes 'seems to be an important factor' in cancer of the lung.

"In studies reported in the Journal of the American Medical Association, it was stated that of 605 male cancer patients interviewed in three St. Louis hospitals, only 1.3 per cent were nonsmokers, while 51.2 per cent had smoked the equivalent of more than twenty cigarettes a day over a period of many

ye~~r. William F. Rienhoff, re, Baltimore surgeon, said that 'I have reviewed more than 500 cases of lung cancer that were operated on and a large number that were inoperable, and I have found no relation whatsoever to smoking:

Feels There Is No Proof

"He declared that 'there is no proof whatsoever that cigarette smoking causes pulmonary disease. 1 feel very definite about this.'

"Dr. Rienhoff and Dr. Lawrence M. Serra, chest diagnostician, cited the vastly greater number of lung cancers that occur in men in comparison with women.

"The ra.no of persons developing this disease is about eight men to one woman, according to Dr. Rienhoff, 'yet,' he added, 'women axe almost as heavy smokers as men.'

Idell W lIS Advanced Be/Me

"Saying that 'I don't believe smoking plays much of a part at all' in lung cancer, Dr. Serra recalled that clinics in New Orleans a few years ago expressed the conclusion that smoking did play a big part in this disease, then he added, 'but most clinics have not borne this out at all.'

"A surgeon who asked to remain unnamed declared that 'what strikes one forcibly is that smoking is SO prevalent there would be a lot more lung cancer if this were the cause.'

"Dr. Rienhoff expressed the same view.

'The other doctor said that lung cancer 'is not as prevalent as you might think in comparison with many other diseases. Three doctors do practically all the operating for this disease in Baltimore.' "

• •

•

13

TIMN 0140780

Dr. RienhofJ's March, 1954, Position:

. I I

Yale Test Proves Negative

On March 8, 1954, Dr. Rienhoff, who is credited with being one of the first to remove successfully an entire lung, made the following statement:

"The highest concentration of tobacco smoke, whether it be from cigarettes, pipe, or cigars, is naturally in the mouth, the naso pharynx. the trachea or windpipe, and probably very slight penetration of smoke into the right and left primary or stem bronchi. Now, it would seem if tobacco smoke were the cause of a cancer of the primary bronchus, which has exactly the same mucosal lining or epithelial lining found in the main windpipe in the neck or trachea, that there would be an equal increase in carcinoma of the lining of the mouth, pharynx and main windpipe or trachea; and there certainly has not been a

• comparable increase in cancer of these regions of the upper respiratory tract.

•

•

•

"Most of the patients with cancer of the lung which we see do not have cancer of the primary bronchus or near the trachea but in the peripheral alveolar regions, that is, the small air sacs or cells far from the main bronchi.

:'At the present time women are smoking almost as much as men and there has not been a proportionate increase in cancer of the lung in women. Just as in cancer of other organs, there must be a sex tendency; for instance, cancer of the breast is very infrequent in men and more frequent, as everyone knows, in women.

. "If one were to chart the increase of cancer of the lung with the increase in the number of automobiles in the urban districts, from which most of our patients with cancer of the lung come, it seems to me a definite parallel between the automobiles and cancer of the lung would be evident. Incomplete combustion of gasoline and additives for supposed more power, together with tar from the roads, the smoke from diesel engines and pollution of the atmosphere in my opinion probably play a greater role in the production of lung cancer than tobacco.

"Other facts that vitiate a conclusion that tobacco causes cancer are that doctors are now aware and looking for cases of lung cancer and diagnosing it more frequently; and even patients are more aware of the symptoms and signs; more thorough postmorten examinations and operations revealing cancer of the lung all help to improve the statistics collected by the various health departments. Anti-biotics preserve more patients for the cancer age.

"Unproven correlations are dangerous. It is quite true that alcohol to excess will produce, in some sensitive individuals, cirrhosis of the liver, but because cirrhosis of the liver exists and can be connected with many diseases and nutritional disturbances other than the use of alcohol, it would certainly not be a very strong argument against the use of alcoholic beverages.

"Excesses in eating, drinking or smoking may have a harmful effect on the general body metabolism, but to say that cigarette smoking causes lung cancer would indeed be premature. There has to my knowledge, up to this time, March, 1954, been no factual proof whatever produced to support the loose, unscientific and irresponsible statements that are continuously appearing in newspapers and magazines."U

Results of an experiment conducted by Dr. Harry S. N. Greene, Yale University. are reported in the November B, 1953, New York Herald Tribune:

"Dr. Wynder set up a smoking machine, collected the smoke from cigarettes and distilled from this smoke a tar. The tar he painted on the backs of eighty-one mice, 44 per cent of whom developed cancers on the painted spots.

"But at the same meeting. conversely, Dr. Harry S. N. Greene, of Yale University, described an even more sensitive test for tobacco carcinogenicity. He took tobacco products and implanted them in the armpits of mice together with a bit of tissue from an unborn mouse. No cancers developed, even though most other known carcinogens. produce cancer under these circumstances."

14

TlMN 0140781

i .

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I J f

!

•

Vital Statistics

Results of Case-Finding Survey

The findings of a committee of Boston specialists who searched for cancers in the chest x-rays of 536,012 persons are quoted below for the light they throw on statistical conclusions about the increase in lung cancer. These are quoted from a report by Dr. James M. McNulty in the January 1954 New England lournal of Medicine:

'This paper presents the findings of a detailed follow-up study of the clinical records of 398 patients suspected of having lung tumor by a roentgenologic review board that interpreted the films of a total of 536,012 persons. It was prepared under the auspices of the medical subcommittee on nontuberculous diseases of the Boston Chest Survey and conducted with funds provided by the Massachusetts Divisioneof the American Cancer Society. This survey extended from September ,IS, 1949, to February I, 1950.

*

*

*

"Table I summarizes the results of the present follow-up study of all cases. It is noteworthy that there were 39 cases (9.8 per cent) of proved bronchogenic carcinomas among a total of 398 cases in which tumor was suspected. Thirtythree of the 39 patients were men, and 6 were women. There was 1 case in the fourth decade, 6 in the fifth, 14 in the sixth, 13 in the seventh, 4 in the eighth and 1 in the ninth.

"Follow-up Results in Cases Classified as Presumptive Tumor

Result of Study No. of Cases

Primary bronchogenic carcinoma-proved.................................... 39

Primary bronchogenic carcinoma-presumptive............................ 13

Metastatic pulmonary tumors........................................................ 19

Other types of cancer.................................................................... 1 Miscellaneous group...................................................................... 275 No follow-up report...................................................................... 51

---

398"22

Five Tables In any health study it is important to consider the incidence of a fatal disease in on Death relation to the death rate nom other causes. An examination of the latest issue of

Causes Vital Statistics of the United States, Volume Ill, 1950, brings into focus the relative standing of lung cancer as a cause of death. Note that in more than half the cases of deaths attributed to lung cancer the lungs are not specified as the starting point of the cancer.

Data in the following tables are taken from the official figures recently published by Secretary Oveta Culp Hobby of the Department of Health, Education and Welfare:

I-Deaths from All Causes-1950........................................................ 1,542,454.tl

n-Cancer vs. Major Death Causes-one in seven.

Diseases of circulatory system .

Neoplasm (cancer) .

Diseases of nervous system .

Accidents, poisoning, violence ..

Diseases of early infancy ~

Diseases of respiratory system .

Diseases of digestive system .

No. Deaths 588,323 216,107 170,256 116,376

60,989 60,539 54,699"

15

TIMN 0140782

Five Tables on Death Causes (Cont.)

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:1

'I. I

j

.,

i r

,

III-Lung Cancer vs. Non-Cancer Death Causes-one in eighty.Zi

No. Deaths Arteriosclerotic heart disease, coronary...................................... 321,003

Accidents 91,249

Hypertension with heart disease.................................................... 85,193

Pneumonia 40,523

Tuberculosis, all forms _........................ 33,959

Nephritis & nephrosis.................................................................. 28,147

Diabetes mellitus.......................................................................... 24,419

, Lung cancer, unspecified.............................................................. *10,695

Lung cancer ** 7,618

Larynx 1,852

·not specified as primary source of neoplasm ··specified as primary source of neoplasm

IV-Lung Cancer vs. Other Cancer Causes-one in twelve.26

No. Deaths

Genital Organs................................................................................ 34,742

Stomach 24,258

Intestine 23,000

Breast 18,973

'Prostate 11,339

Rectum 10,383

Urinary Organs 10,044

Pancreas 8,952

Leukemia & aleukemia.................................................................... 8,845

Lymphosarcoma 7,911

Lung Cancer, unspecified *10,695

Lung Cancer 7,618

Larynx :......................................................... 1,852

·not specified as primary source of neoplasm ··specified as primary source of neoplasm

(Following are the basic figures on respiratory cancer as they appear in Vol. III, Vital Statistics of the United States.I'1

V-Malignant Neoplasm 0/ Respiratory System.

Oflarynx .

Of trachea, and of bronchus and lung specified as primary .

Of lung and bronchus, unspecified as primary or secondary ..

Of other parts of respiratory system .

Total .

No. Deaths 1,852 7,618 10,695 1,054

21,219

16

TIMN 0140783

-";T;~~

_"-~~ - .. _,.r:-

Reference Index

1 Hueper, W. C., M.D.,"Air Pollution and Cancer of the Lung", Rhode Island Medical Journal, pp. 34-36, January, 1953.

% Passey, R. D., Prof., "Smoking and Lung Cancer", British Medical Journal, p. 399, February 14, 1953.

3 Damon Runyon Fund, Statement issued November 27, 1953, from the Fund's headquarters, Astor Hotel, New York, New York.

'Cutler, Max, M.D., Personal Communication dated March 3,1954.

(; Smithers, D. W., Prof., M.D., F.R.C.P., D.M.R., "Facts and Fancies About Cancer of the Lung", British Medical Journal, pp. 1235-1239, June 6, 1953.

6 Little, Clarence Cook, M.D., Personal Communication, March 18, 1954.

'1 Sadowsky, D. A., Gilliam, A. G., M.D., and Cornfield, J., 'The Statistical Association Between Smoking and Carcinoma of the Lung", Journal of the National Cancer Institute 13 (5), pp. 1237-1258, 1953.

8 Rigdon, R. H., M.D., and Brindley, Paul, M.D., "Primary Carcinoma of the Lung", Texas State Journal of Medicine 46, pp. 885-889, 1950.

9 Rigdon, R. H., M.D., and Kirchoff, Helen, "A Consideration of Some of the Theories Relative to the Etiology and Incidence of Lung Cancer", Texas Reports on Biology and Medicine 10 (1), pp. 76-91, Spring 1952.

10 Rigdon, R. H., M.D., and Kirchoff, Helen, "Smoking and Cancer of the Lung - Let's Review the Facts", Texas Reports on Biology and Medicine 11 (4), pp. 715-727, Winter 1953.

11 Hueper, W. C., M.D., "Air Pollution and Cancer of the Lung", Rhode Island Medical Journal 36, (1), pp. 24-30, 34, 36, 52, 1953.

12 Metropolitan Life Insurance Company, 1 Madison Avenue, New York, New York.

Statistical Bul., Vol. 34 No.2, p. 3, February, 1953.

13 Gagnon, E. D., M.D., ''Bronchopulmonary Cancer: Statistical Analysis of 125 Cases", Union Medicale du Canada, Montreal 82, p. 767 July, 1953. Abstract in Journal of the American Medical Association 153 (10), p. 986, 1953.

H Rosenblatt, Milton B., M.D., "Relationship of Smoking to Cancer of the Lung", a paper presented before The Society of the New York Medical College, March 16, 1954.

15 Hartwell, Jonathan L, M.D., "Survey of Compounds Which Have Been Tested for Carcinogenic Activity", Second Edition, Federal Security Agency, Public Health Service, Public Health Survey Publication #149, p. 2, 1951.

16 Shear, Murray J., M.D., and Leiter, Joseph, Journal 0/ the National Cancer Institute, Vol. 2, p. 254, 1941-1942-

17 Leitch, Archibald, M.D., "The Experimental Inquiry into the Cause of Cancer", British Medical Journal, Vol. 2, p. 3262, July 7, 1923.

1S Cooper, E. Ashley, M.D., D.F.C., F.Le.; Lamb, F. W. Mason, M.D.; Sanders, Edgar, M.Sc.; and Hirst, E. L, D.F.C., F.R.e.; 'The Role of Tobacco-Smoking in the Production of Cancer", Journal 0/ Hygiene, VoL XXXII, No.2. (From the University of Birmingham.) Undertaken at the request of the Birmingham Commission of the British Empire Cancer Campaign, April 1932 (British).

III Bogen, Emil, M.D., and Loomis, Russell N., M.S., "Tobacco Tar: An Experimental Investigation of its Alleged Carcinogenic Action", American Journal of Cancer 16, pp. 1515-21, 1932.

20 An extract from a contribution to the 30th Annual Report for 1952 of the British Empire Cancer Campaign by its Yorkshire Council. British Empire Cancer Campaign, 11 Grosvenor Crescent, London SWl, Captain F. B. Tours, OBE. RM (Ret.), Secretary General.

17 _

TIMN 0140784

i

, ~ ..

I

i

I

I "

I

- " _ __. ", ,_ .'. -~.

!1 Rienhoff, William F., M.D., Statement dictated March 8, 1954.

22 McNulty, James M., M.D., "Clinical Follow-up Study of 398 Patients Suspected of Having Lung Cancer Discovered in the Boston Chest X-ray Survey", New England Journal of Medicine, Vol. 250 (1), pp. 14-17, January, 1954.

U Vital Statistics of the United States, Volume m, U. S. Department of Health, Education and Welfare, p. 76, 1950.

U Ibid., pp. 76--ll8. ulbid., pp. 76--118 .

.

26 Ibid., pp. 84-90.

2'1 Ibid., p. 86.

List of Authorities

PAGE

Bogen, Emil, M.D _ 11

Brindley. Paul, M.p _ __ _... 6

Cooper, E. AshIey, D.F.C., F.I.C .10

Cornfield, J _. __ _ _ 5

Cutler, Max, M.D __ _ _ .. _ 4

Damon Runyon Fund 3

Gagnon, E. D., M.D __ 8

Gilliam, A. G., M.D., Dr. P.H.,

F.A.P.H.A. _ .. _._ 5

Graham, Evarts A, M.D., D.Se. 7

Greene, Harry S. N., M.D __ . __ .. 14

Hartwell, Jonathan L .10

Heller, John R., M.D __ .12

Hirst, E. L., Prot, D.F.C., F.R.S _10

Hueper, Wilhelm C., M.D _ .3, 8

Kirchoff, Helen _ __ ._ 6, 7

Lamb, F. W. Mason, M.D __ 10

Lanza, Anthony J., M.D _ ... _ _12

Leitch, Archibald, M.D _. __ 10

Leiter, Joseph _ _ .. __ . __ _ . .10

PAGE

Little, Clarence Cook, M.D 5

Loomis, Russell N., M.S 11

Martin, Walter B., M.D .11

McNulty, James M., M.D .15

Metropolitan Life Insurance

Company 8

National Office of Vital Statistics .lS. 16

Ochsner, Alton. M.D _ 7

Passey, R. D., Prof _..... 3

Rienhoff, William F •• M.D .13. 14

Rigdon. R. H., M.D _ 6. 7

Rosenblatt, Milton B., M.D _ 9

Sadowsky, D. A. _ 5

Sanders, Edgar, M.S.C. _ .. _ 10

Serra, Lawrence M., M.D .13

Shear, Murray J., Ph.D _ .10

Smithers, D. W., Prof _ 4

Stewart. Harold L., M.D 13

Yorkshire Council, British Empire

Cancer Campaign _ .. 11

18

TIMN 0140785