Tobacco Documents Online

THE CIGARETTE'- LUNG CANCER ENIGMA Talk presented before small group in Boston January 4, 1960 by Edwin B. Wilson, Ph.D. Office of Naval Research and Harvard School of Public Health Boston, Mass. The subject announced is: The Cigarette - Lung Cancer Enigma. By the use of Enigma I mean that whatever relationship there may be has not been satisfactorily explained. The difference between finding statis- tical evidence of a relationship and the explanation of the relationship is great, and has been, in many human activities, observations and beliefs, medical and other. In the public health field~one need cite only malaria. If we go no further back than the Century Dictionary which ap- peared during the so-called "gay nineties,"'one finds this definition of malaria: "1. Air contaminated with some pathogenic substance from the soil; specifically, air impregnated with the poison producing intermittent and remittent fever. 2. The disease produced by the air thus poisoned... The disease is contracted by presence in the locality and not from the sick, nor do the latter seem to transplant it to the new places where they may go. The disease may apparently be introduced into the body through water that is drunk as well as through the air,"'etc. All these statements could be proved by statistics and had been jV ~ inferred from associations observed by scientists. In the past century N ~ Pettenkofer of Munich attributed the typhoid epidemics to bad air and proved ~ it to~his and others' satisfaction in a most effective way by cleaning up 0 most of the ill-smelling spots in Munich and thereby markedly reducing the (~ typhoid rate.

- 2' - When the d'efinition' in' the Century Dictionary was written the syxnptomatic differentiation' between mal.axia and typhoid was probab]1y lhaown but both had as their cause the iimpregrnation of the air with pathogenic material. When Renald Ross was trying to convince the British that mos- quitoes caused'the spread of malaria, an able statistically minded British army med'ical officer proved statistically that Rbss was al]i wrong and that the old malaria theory was right. I do not propose tonight to solve the enigma of the relation of lung cancer to cigarette smoking, or to tell you that you should or should not smoke cigarettes, but merely to try to give you some idea of why I think the problem of the explanation of the association which the statis- ticians find is still non-existent. To do this I must go back to my per- sonal professional contacts with' the sta.tistical and epidemiological work on' cancer in general. Across the summer of 1922 I transferred from M.I.T. to Harvard where a new School of Public Health was being organized. My task was to set up a Department of Vita1 Statistics for both instruction and research and for cooperation with the public health work of the State and the City of Boston. The school was set up to work in close contact with the Harvard Medical School with' many members of the two schools in common. Dr. Rosenau was professor of Preventi~ve Medicine in the Health School and professor of Epid'emiology in' the Health School. He had detailed to him by the U.S. Pub- lic Health' Service Dr. J. W. Schereschewsky, an: able and mature man, as- signed to study the rise in the cancer death rates i;n the ten original reg- istration States from 1900 to 1920 (28, 29). For technical statistical advice Dr. Rosenau sent him to me. The ana]1ysi;s of the change in time of any disease requires a good mature mind and a wide acquaintance not only

3 with the reported facts but with all sorts of possibilities for errors in the reports, for changes in the matter of diagnosis, for changes in man- ner of classification, etc. Such a mind and such an awareness Dr. Schereschewsky had; for there had'been much previous discussion of the ris- ing cancer rates in this country and abroad, and he knew the literature. On the general subject of the difficulty confronting a student of the history of the incid'ence of disease let me quote from a more recent paper by Major Greenwood'(12) as follows: "One should never believe that a disease is becoming more or less deadly until all other explanations have been excluded... Change of fashion in certification due to increasing know- ledge may affect comparability. For example, between 1861-70 and 1901-10 the rate of mortality from Acute and Chronic Nephritis increased; the in- dex number for males rose from 153 to 435. In 1911-20 it fell to 406 and in 1921-30 to 303. It would be rash to infer that the 'disease' increased and then diminished. A much more probable explanation is that after 1870 doc- tors increasingly spoke of nephritis and eschewed certifying a mere physi- cal sign -- dropsy -- which might be due to many diseases; and after 1910 they preferred to certify arteriosclerosis, thinking, no doubt rightly, that the change in the kidneys was secondary to changes in the vascular system."' Whether you believe Greenwood, who was a distinguished student of the history of medicine, or do not accept his interpretation of this parti- cular case and believe his general statement exaggerated, there remains a very great deal of truth in his position, particularly in periods when med- ical knowledge is rapidly increasing and conditions of life are changing a ~ good deal in the course of a human lifetime. Dr. Schereschewsky's study (~!1 0 came to the conclusion that something between 25% and~30;6 of the increase M on reported for cancer between 1900 and 1920 was real, but the rest was only ~ ~

3 with the reported facts but with all sorts of possibilities for errors in the reports, for changes in the matter of diagnosis, for changes in.man- ner of classification, etc. Such a mind and such an awareness Dr. Schereschewsky had; for there had been much previous discussionof the ris- ing cancer rates in this country and abroad, and'he knew the literature. On the general subject of the difficulty confronting a student of the history of the incidence of disease let me quote fr=a more recent paper by Major Greenwood (12)~ as follows: "One should never believe that a disease is becoming more or less deadly until all other explanations have been excluded... Change of fashion in certification due to increasing know- ledge may affect comparability. For example, between;1861-70~and 1901-10 the rate of mortality from Acute and~Chronic Nephritis increased; the in- dex number for males rose from 153 to 435. In~19]11-201it fell to 406 and in 1921-30 to 303. It would be rash to infer that the 'disease' increased!and thendiminished. A much more probable explanation is that after 1870 doc- tors increasingly spoke of nephritis and eschewed certifying a mere physi- cal sign -- dropsy -- which might be due to many diseases; and'after 1910 they preferred to certify arteriosclerosis, thinking, no doubt rightly, that the change in the kidneys was secondary to changes in the vascular system." Whether you believe Greenwood, who was a distinguished student of the history of medicine, or do not accept his interpretation of this parti- cular case and~believe his general statement exaggerated, there remains a very great deal of truth in his position, particularly in periods when med- ical knowledge is rapidly increasing,and conditions of life are changing a good d'ea1 in the course of a human lifetime. Dr. Schereschewsky's study came to the conclusion that something between 25% and 30% of the increase reported'for cancer between 1900 and 1920 was real, but the rest was only

4 apparent (28y 29). How good'his estimates were I have no id'ea, but I do know that in one of those 21 years there was a marked rise in breast cancer from what it had been previously or what it was afterwards. That there was really any such discontinuity across that one year was inconceivable. In- quiry at the Bureau of Mortality Statistics in Washingtomrevealed the fact that the Bureau had sent out a special inquiry to a large number of physi- cians who had returned death certificates which seemed to the classifiers at the Bureau~likely to have been deaths from breast cancer instead of from the cause certified, and it had been from the obligimg answers returned by the doctors that the excess deaths from that cause were reported for that year. It would have happened~the next year if the same inquiries had been sent out in the same circumstances. What may happen over a time period may be seen in Massachusetts in our figures for deaths from appendicitis. They were 242 in a population of 2,800,000 in 1902, making a death rate from this cause of 82 per 100,000; in 1912 the rate was 92; in 1922 it was 122, and in 1932 it reached 14Z. All this time the operative technique was probably improving and the cure rate should~certainly not have been decreasing. Did we have really a 30 year rise in the incidence of appendicitis? The rate is now down to about 1 per 100,000. In the early days of this century cancer of the lung was so little in the eye of physicians and registrars of deaths that it was not separately tabulated. In 1932 the rate was 4 per 100,000 in Massachusetts; by 1942 it was up to 9; doubling in ten years; by 1952 it had doubled again to 18', and in 1957 it was 232 per 100,000 in this State. These are rough crude death rates; for careful work one has to use variously ad~justed rates to insure comparability, but such details are not necessary for this talk. I should,

5 however, point out that the cure rates differ greatly for different dis- eases, even for different sites of cancer, so that if one desires to com- pare the liability to different diseases or sites of a disease, one must use incidence rates if the cure rates differ substantially. For cancer of the lung and of some other sites the cure rates are presently so low that the death rates can be taken as incidence rates. One has, however, always to bear in mind that both death rates and incidence rates are reported rates subject to the reservations inherent in the accuracy and'comparability of the reporting,in different places and at different times. If yow follow Greenwood quite literally in his somewhat d'ogmatic statement that "one should never believe that a:d!isease is becoming more or less deadly until all other explanations have been excluded," you will be a long time getting,around to attributing causes for the changes in reported figures. I have seen in recent years a number of studies by sincere people, who must be considered competent and honest, indicating,that various amounts from relatively little to a large proportion of the reported increase in lung cancer are not real (10, 11, 16, 20, 21, 23, 24, 25, 26, 27, 30. As a result we do not know how much~of the increase we have to explain and how much we have to explain away. This I take to be one of the Enigmas in this subject. Thirty-five years ago, soon after I went to the Harvard School of Public Health, a great stir was made about the poor facilities in the State of Massachusetts for the care of 3indirgent cancer patients, for the purchase of radium, and for the establishment of a State Cancer Hospital. There were a number of bills before the Legislature at different times, and final]1y one passed which directed the Departments of Public Health and of Public Welfare to make a joint study of the situation with special attention to inoperable

6 cases and'the number of beds available for them. The study was made and reported in House Document 1200, General Court of 1926. The field work for the study was made by Dr. Herbert L. Lombard, who retired last Thursday (December 31, 1959) after 35 years of distinguished service to this State in administrati=and research on cancer and its control. He has put the story together in mimeographed form in a 170-page document: "The Massachusetts Cancer Program." Dr. Lombard had been a student in the School who had shown great interest in statistics and, when he began his field work for the study of the cancer situation in the State, was naturally in close contact with me and with Dr. Doering who was a member of my department. One of the early studies which Dr. Lombard conducted with the aid of Dr. Doering was a dis- cussion of the data collectedfrom a small sample of 217 cancer patients and 217 controls, matched for sex and age, each containing 55 men and 162 women (18). Use of tobacco was one of the questions asked, because it had been suggested that the use of tobacco was related to cancer of certain~sites, namely, lip, jaw, cheek, and tongue, all other sites being supposed to be unrelated to tobacco. In those days women did not smoke or did not admit to i,t, so the study of any relation of tobacco to cancer had to be restricted to men, and the sample of 55 was too small to show anything by site. How- ever when cancer as a whole was considered, it did~appear that "heavy smoking has some relation to cancer in general." This conclusion has been corrobo- rated by much larger studies since then. In 1927 lung cancer was not consid'ered~as important; also ciga- rettes were very little smoked. Pipe smoking was the favored form of using tobacco, with cigars next, and chewing was more frequently reported than cigarettes -- at least in this sample of 55 male cancer patients and their

7 55 matched controls. In respect to the form in which tobacco is used there has been a great change over the years, and if the form in which i;t is used is of great importance in' the incidence of any type of disease we cannot accept Greenwood's generalization. Despite the smallness of the sample it is interesting to go back to the old tables of Lombard and Doeri~ng to note what are the statistical results by type of tobacco use. Pi;pe smoking was significantly assoeiated with cancer; cigarette smoking was not, though by any formula used to measure the amount of association it would show almost as much associationy the lack of significance being due to the small number of users of cigarettes; cigar smoking was negligibly associated with cancer, as it seems to be in recent studies; but chewing had a significant associa- tion of about the same magnitude as pipe smoking. Recent studies omit chew- ing, and they do not show the association with' pipe smoking which Drs. Lombard and Doering found (2,3,4,5,6,7,8,13,14-). Statistics, even when sig- nificant by the accepted tests, can be tricky, and conditions can change. It is not easy to be sure that what appears to be a control is in fact a good one. In another paper of about the same old time, more than 30 years ago (L7), Drs. Lombard and Doering showed that there was a great dif- ference in the reported rates for cancer among the native born of native parents (for whom the rate was 85), the native born of foreign parents (for whom' the rate at 160 was nearly twice as much)i, the native born of mixed parents (l1.l)', and the foreign born (137,)'. It can therefore be seen thaty both in samples and controls, ma.tching with respect to these variables would be desirable. Nobody ever can be sure that there is no unnoticed variable which has a large enough effect to make an appreciable bias be- tween the sample and its supposed control.

8 This difficulty I will not call an enigma of cigarettes and~lung cancer, or of smoking and cancer in general, but of statistics in general. And now how did the poor little cigarette get into this messy situation in which we find it? In 1933 Dr. Evarts Graham of St. Louis was operating on a fellow physician for lung cancer, expecting to have to take out only a part of a lung, but he found the condition so bad~that it was necessary to remove the whole lung -- and the patient lived:. That was the first successful removal in one stage of an entire lung. It was very suc- cessful, for the patient was still living and practicing his profession, as an obstetrician, twenty years later when he was good~enough~to come to Boston to help open our April cancer drive; he is still alive and active, at last reports. On March~ 4, 1957, DDr. Graham died' of lung cancer; he could not be saved because both lungs were involved. But in the intervening years he inferred from his clinical observations that persons with lung cancer had usually been unusually heavy cigarette smokers, and thus pointed the finger of suspicion at the cigarette as a possible causative agent in most cases. I say "in most cases" because there are cases of lung cancer where the pa- tient has never smoked cigarettes or anything else and there is no known agent of any kind on which one can lay the blame. Also there are old per- sons who have smoked cigarettes furiously for many years and seem to be in ~ •perfect]1y good health for their age. You can note the same of alcohol, or C underweight or overweight, and a great many other things that seem to be QQ ~ bad for some individuals. It has long been remarked in the proverb: One ~ man's meat is another man's poison. C Probably many medical generalizations and many generalizations in other fields have been made by observant practitioners of the arts and crafts and professions. One hears a nauseous amount of talk about how much more

9 important it is to do basic research than applied; if there had been no applied research there might have been no tools, or even ideas, with which to do basic research. But one thing seems certain; the basic research folks distrust the generalizations made by the practitioners quite as much as the practitioners distrust the wisd=of the theoreticians in practical matters. And so when Dr. Graham and his collaborators had pointed a finger at the cigarette as responsible for many of the cases of lung cancer, two studies were set up systemmatically to check the generalizationy one by Doll and Hill in Englandy one by Hammond and Horn working for the American Cancer Society. Dr. Doll and Professor Hill asked the physicians of Britain to let them know what and how much they smoked and~have been following them ever since, and I hope will long continue to follow them, for lengthening follow- up rapidly increases the total yield of this sort of study (2-7). Hammond and~Horn asked a large number of the volunteer workers of the Cancer Society to find out what and how much ten of their male acquaintances between 50 and 69 years of age smoked and further to keep them informed as to their being still alive or to have died (13, 14). The follow-up was good on nearly 200,000 men for about four years, when it was stopped; for one cannot expect to keep the interest of volunteers indefinitely. These two studies have shown that the rates of death from lung cancer among cigarette smokers have been much in excess of those of non- smokers or cigar or pipe smokers and that the rates of death have increased with the rate of cigarette consumption. They have done more than this; for they have shown that the rate of death from all causes is greater for ciga- rette smokers and~that the same is true for a considerable number of indi- vidual causes of deathy though not for all. There is a further study of

- 10 - the same sort by Harold Dorn of the National Institutes of Health (8) upon veterans who have Government insurance. This is a captive population and if the study can be }ept up long enough something valuable is sure to be learned, particularly if a few more questions can be asked the veterans. And we must not omit the long continued studies of Dr. Lombard in this State (19). There is one point of difference in Dr. Lombard's results from those of others. They plot death against rate of smoking as of a particu- lar time such as the time the study started; he plots against total life- time packs of cigarettes smoked. He then finds that there is little or no increase of lung cancer deaths until something like 9000 packs have been smoked. This indicates that there is a threshold, a substantial threshold so that one cou7ld smoke half a pack a day for 50 years before he reached it. There have been those who have maintained that there is no threshold, which seems to me unbiological. I shall use Dorn's figures (8) to give you some idea of the sort of results that are found. The general death rate of smokers of all kinds from all causes is about 22% greater than that of nonsmokers, meaning there- by those who never smoked. You may be surprised that there are veterans who never smoked, but nearly one fifth of the total experience of these veterans was in the never smoked class. The pipe and cigar smokers are up less than 10`/6and the figure is not too well established because the total experience is small. The regular cigarette smoker is up 58%. So much for the general death rate. When it comes to lung cancer the picture is very bad. Compared with those who never smoked, those who have used tobacco have six times as much lung cancer and the regular smoker of cigarettes alone has nine and a third times as much. It is only fair to point out that the total number of lung cancer deaths among nonsmokers was only 17 so that the ratio must have

a very large sampling error and could not be consid'ered as well established were there not other studies which give comparably large ratios. One of the interesting phenomena is that those who smoke cigarettes and something else have lower rates than those who smoke cigarettes alone. I have been told that this is so even for those who smoke as many cigarettes and some- thing else in addition'. Tb some this would seem a bit of an enigma and I cannot say how well established it is. I doubt if any explanation offered for it is we11 establiished. There are so few deaths from lung,cancer among cigar and pipe smokers that the ratio, though' above uni;ty, is not well established. This discussion could be pushed much further but it is not very interesting listening,to figures. So here is the great Enigma. Why does the mild little cigarette show up so badly when the big strong cigar and the stinking old pipe get off practically scot-free? Why is "up to 2 a pack" a day more harmful than 5 to 8'cigars or more than 20 pipes a day? (8), In the past decade I have read hundreds of pages of the literature (I somehow hate to call it science and I would not give the impression that it is elegant as literature) on the resolution of this enigma, and while there are suggestions of this or that for a possible answer, I do not find any decent proof of any. You might be interested to hear of some of the suggestions. Fiirst there is the paper. If you will disembowel a couple of cigarettes and burn the paper and the tobacco separately for comparison you will probably find ~I the burning paper the more acrid. There is very little paper in a ciga- Cf~ ® rette and probably most of its fomes goes off in the side-stream rather than ~ into the smoker's mouth'. Most chemists who have studied the matter think O there is not enough carcinogenic materi.al in the paper to do any damage. ~

- 12 - Then there is the tobacco itself. When burned' its smoke is a very complex mixture of chemicals, acid, alkaline and neutral, very labile and varying with the temperature of burning. There are undoubtedly in the mixture traces of a number of substances which would be carcinogenic if applied in suffi- cient concentration; but I recently heard~a very distinguished biochemist say that he had spent 5 years of his life and a good deal of somebody's money trying to find enough of any or all carcinogens in cigarette smoke to be carcinogenic to the lung in the concentrations to which it is exposed'y and he was through, was going to quit and do something else. Then there is the inhaling. It is believed that cigarette smokers inhale and other smokers do not. Dolll and Hill decided'(2, 3, 6) 7) on;the basis of some statistical trials that inhaling did not matter. There is a French study (1) which shows that i;nhalers have a little more lung cancer than non-inhalers, but the ad- dition is no more for the very heavy smokers than for the very light ones, which seems rather queer. When the association between cigarette smoking and~lung cancer was first revealed both in England and in this country we all felt that a first class prima facie case had been made for the smoking of cigarettes being,the cause of most of the lung cancer deaths, and it is doubtless true that, until somebody finds something else on which the blame can be as easily laid, the temptation to lay it on the cigarette will be practically irresist- ible. This much was certain 5 years ago when I attend'ed'the Glenburnie con- ference called'by the American Cancer Society to consider the situation. N Since then more statistical findings of much the same sort have come out ~ without adding much to the evidence. In the intervening five years millions 0 of dollars have been spent altogether by the American Cancer Society, by M the National Cancer Institute, by the Tobacco Industry Research Committee, ~ .41

- 13 - by the various tobacco companies in their own laboratories and by similar organizations in Britain a.nd France trying to find out what it can be about the mild little cigarette which gives it this bad statistical picture. Thus far nobody has found out; there have been claims but so far as I have learned they have not stood.the test of time. I presume that if we knew that something specific in the cigarette caused the trouble the very good industrial chemists of the industry could take it out -- unless it were the nicotine -- and give the public a "safe" cigarette which would be en- tirely acceptable; I doubt if a dsnicotinized product would be satisfactory, for I believe we want the nicotine. Denatured wine) coffee and other prod- ucts do not seem to be popular. I do not know why we want the nicotine. Most of us have un- pleasant experiences from our first contacts with tobacco and on the Pavlovian theory of conditioning should tend to be conditioned against it. Perhaps it is only that we see that those habituated to it seem to get so much pleasure or comfort or some sort of satisfaction from its use. I remember talking about this matter many years ago with the great food chemist and generally learned scientist Carl Alsberg as we were passing the time smoking on a trip across the continent. Alsberg remarked that, so #'sx as he knew; the human race sometime somewhere had tried to use in its diet every plant like tobacco which contained some poisonous alkaloid like nicotine or morphine or caffeine. Whea I suggested that sometime somewhere the human group may have been short enough of rations to try anything that was edible; he said that that was not what he had in mind but that for some unknown reason the human animal needed one or another of these poisonous alkaloids in moderation. In an introductory paragraph to a brief note in 1938 on tobacco smoking and longevity; Raymond Pearl (22) estiroe,ted that

- 14 - 90% of the world's adult population used one or another of some such prod- ucts, including alcohol, and~said that the purely hedonistic elements in behavior, present in the lower animals as well as in man, have real importance. I mentioned earlier that Lombard and Doering found'that native stock had less cancer than the foreign~born. The Registrar-General in Britain tabulates deaths by social class in some of his studies. Recently Herdan of the department of Public Health in the University of Bristol, England (15)1, has discussed lung cancer by social class on the basis of these figures of R.-G. (1958): Standardized Mortality Rates for ages 20-64 and Years 1949-53: Males Married Women Class I II III IV V I II III IV V Rate 81 82 107 91 118' 119 95 102 98 96 The correlation coefficient for males is 0.81 and for females - 0.69. I really cannot compare these figures withiours because we have not the same classification and I do not know how meaningful they are anyhow, for to cor- relate on the basis of 5 classes is not very satisfactory. I do it not to criticize Herdan (who does not do it) but to point out that if we take these correlations seriously, they mean that in England 66% of the variance of the death rate for men and 48y6 for women is accounted for by their social class, leaving only 34% and 52% respectively to be explained by the amount of smok- ing, except as that is correlated with social class and thus includ'ed~with it~ automatically in the figures. [jt In my concluding remarks I wishistrongly to emphasize this point. ~ The problemlof the explanation of the association of lung cancer andiciga- rette smoking, or of any two ve.riables, in a mulitivariate situation cannot

be solved'by considering just two of the variables of which one is assigned'the role of effect and the other the role of cause of that supposed effect. It is rare that the real cause of any cancer in anybody is known. Various types of cancer in a population are associated in~various degrees with a variety of variables, none of which may be a real cause any more than bad'air was the real cause of malaria or typhoid (or other diseases) which the Century Dictionary had mixed together in the definition I quoted at the start. Some of the variables known to be associated with the lung cancer d'eath rate in Britain are: social class, urbanizationy atmospheric pollution, sex, age, and smoking. It is probable that individual genetic constitution is also important, but very hard to specify in a species so heterozygous as man. In Britain there seems to be a very high~correllation between lung cancer, urban. izatiomand atmospheric pollution; in this country the impression seems to prevail that these correlations are lower; for neither country have I seen any satisfactory multivariate analysis of the problem. Although the statistical situation is far from satisfactory as an analysis of possible causation, and the chemical situation is enigmatical in its inability to find in the cigarette anything in sufficient quantity to~ cause lung cancer, the statistical association of lung cancer and cigarette smoking continues to keep alive the hypothesis that smoking cigarettes is somehow responsible for a good many of the cases of lung cancer, and there- fore leads to speculation that if nobody smoked cigarettes there possibly would be less lung cancer. Certainly, however, if nobody smoked cigarettes N there would be amarked decrease in one of those hed'onistic elements in our F~.l ~ living which Pearl seemed to feel so important humanly as often to overbear Q ~ both reason and'physiological]1y inhibiting influences. ~ ~ d

- 16 - If as the great British geneticist R'. A. Fisher* and the great American geneticist C. C. Little seem to feel, the individual constitu- tion is primarily the cause of an individual's susceptibility to lung can- cer, the whole matter must come d'own to the balancing by the individual of his willingness to take whatever risk there may be with the pleasure he has in smoking cigarettes. Sometime we may know more about the individ!ual, the cigarette and lung cancer in their mutual relationships. *Sir Ronald Fisher has recently published from the house of Oliver and Boyd a brochure of about 50 pages in which he has collected some of his essays under the title "Smoking: The Cancer Controversy: Some Attempts to Assess the Evidence." BIBLIOGRAPHY 1. DENOIX, P. F., SCHWARTZ, D. & ANGUERA, G., Bulletin de l'Association Francaise pour l'Etude du Cancer 45/1:1-37, Jan.-March 1958 2. DOLL, R. & HILL, A. B., British Medical Journal, Sept. 30, 1950:739-748 3. Ib id~. , De c. 13, 1952':1!271-1286 4. IbU., June 26, 1954:1451-14~55 5. Ibid., Nov. 10, 1956:1071-1081 6. DOLL, R'., Acta Unio~Intl. Contra Cancrum, 15/2:417-423, 1959 7. Ibid., 15/6:1283,1296, 1959 ~ O 8. DORN!, H. F'., Public Health Reports, 74/7:581-593, July 1959 0 9. GILLIAM, A. G., Military Medicine, 116/3!:163-174, March 1955 a) 10. GILLIAM, A. G., J. Nat. Cancer Institute, 15/5:1307-1312, April 1955 ~ 11. GILLIAM, A. G., Cancer, 8/6:1130-1136, Nov.-Dec. 1955 ~ 12. GREENWOOD, M., J. Royal Statistical Soc., Series A, Part III:230-234, ]1948 13'. HANASOND; E. C. & HORN, D., J. Am. Med. Assn., Aug. 7, 1954:1316-1328' 14. Ibid., March 8, 1958:1159-1172 and March 15, 1958:1294-1308' 15. HERDAN, G., Brit. J. of Cancer, 12/6:492-506, Dec. 1958 16. LEW, E. A., J. Intl. College of Surgeons, 24/1:12-27, July 1955

- 17 - 17. LO W H. L. & DOERING, C. R., Proc. Nat. Academy of Sciences, 13/10:728- 735, Oct. 1927 18. LONISARD, H. L. & DOERING, C. R., J. Am. Med. Assn., April 26, 1928: 481-487 19. LOMBARD, H. L. & SNEGIREFF, L. S., Cancer, 12/2:406-413, March-April 1959 20. MYERSON, M. C., California Medicine, 82/2:111-113, Feb. 1955 21. MYERSON, M. C., Annals of Oto. Rhino. Lar., 64/2:412-417, June 1955 22. PEARL, R., Science, March 4, 1938:216-217 23. RIGDON, R. H. & KIRCHOFF, H., Texas Rep. Biol. & Med., 10/1:76-91, Spring 1952 24. Ibid., 11f4:715-727, Winter, 1953 25. RIGDON, R. H., Southern Med. J., 50/4:524-532, April 1957 26. ROSENBLATT, M. B. & LISA, J. R., "Cancer of the Lung," Oxford U. Press, 1956 27. ROSENBLATT, M. B., J. Kentucky State Med. Assn., 56/2:131-136, Feb. 1958 28. SCHERESCHEFISKY, J. W., U.S. Public Health~Bulletin #155: "The Course of Cancer Mortality in the Ten Original Registration States for the 21- year Period 1900-1920 (with Statistical Appendix by Edwin B. Wilson.)" 29. SCHERESCHEWSKY, J. W., J. Am. Med. Assn., Oct. 17, 1925:1175-1180 30. WILKIl3S, E'. E. Jr. & SWEET, R. H., New Eng. J. of Med., Feb. 21, 1957: 346-351