Lung Cancer, Chronic Disease Epidemiology, and Medicine ...Lung Cancer, Chronic Disease Epidemiology, and Medicine, 1948–1964 Talley, Colin Lee, 1963-Kushner, Howard I. Sterk, Claire

Lung Cancer, Chronic Disease Epidemiology, and Medicine, 1948–1964

Talley, Colin Lee, 1963-Kushner, Howard I.Sterk, Claire E., 1957-

Journal of the History of Medicine and Allied Sciences, Volume59, Number 3, July 2004, pp. 329-374 (Article)

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JOURNAL OF THE HISTORY OF MEDICINE AND ALLIED SCIENCES, Volume , Number © Oxford University Press ; all rights reserved. DOI: ./jhmas/jrh

Lung Cancer, Chronic Disease Epidemiology, and Medicine, –

COLIN TALLEY, HOWARD I. KUSHNER, and CLAIRE E. STERK

ABSTRACT. Beginning in the early s, a series of epidemiological,biochemical, pathological, and animal studies demonstrated a link betweencigarette smoking and lung cancer. A number of reputable scientists chal-lenged these findings, but for a variety of reasons, including the behaviorof the tobacco industry, historians have assumed that these objections wereinsubstantial and disingenuous. Viewing these objections in scientific andmedical perspective, however, suggests that there was a legitimate andreasonable scientific controversy over cigarette smoking and lung cancer inthe s and early s. That controversy had important consequences.A new chronic disease epidemiology emerged, transforming the role andimportance of epidemiology to medical research. This new epidemiologysupplemented Koch’s postulates, establishing a statistical method thatallowed for linking environmental factors to the etiology of chronicdiseases. The report to the surgeon general, Smoking and Health, rep-resented the denouement and codification of these developments. Thisreexamination of the scientific controversy over smoking in the s andearly s provides an important context for understanding the subsequentpublic relations battles between the tobacco industry and public healthafter . KEYWORDS: chronic disease, cigarette smoking, epidemiology,

The research and writing for this project was funded entirely by the Rollins School ofPublic Health of Emory University. Colin Talley consulted as a part-time researcher for theWashington, D.C., law firm of Johnson, Tyler, and Purvis from August to September. The firm specializes in recruiting and developing expert witnesses for the defense intobacco industry lawsuits. Howard Kushner consulted with the firm as a potential expertwitness from August to October . Kushner could not come to an agreement withthe lawyers about the nature and extent of his testimony and ceased professional contactswith the firm and its clients in October . Neither Talley nor Kushner plan to work intobacco litigation in the future. Claire Sterk had no professional association with Johnson,Tyler, and Purvis or any party involved in litigation prior to and including the time thispaper was researched, written, and submitted. The contents and arguments of this papercontradict the primary historical defense made by tobacco industry expert witnesses and inno way are intended to support industry defense claims.

jrh088.fm Page 329 Tuesday, May 25, 2004 3:44 PM

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Journal of the History of Medicine : Vol. , July

epistemology, etiology, lung cancer, medical profession, scientific contro-versy, tobacco.

PIDEMIOLOGIST J. P. Vandenbroucke wrote inhis article in the American Journal of Epidemio-logy that “in the opinion of many present-dayepidemiologists, the reputations of some of thegreatest methodologists in biology and the life-sciences have been tarnished because they chose

the ‘wrong’ side in the great smoking lung cancer controversy of thes.” He reread “the seminal controversial papers of those greatscientists who were proven to be so wrong” and much to his sur-prise found “extremely well-written and cogent papers that mighthave become textbook classics for their impeccable logic and clearexposition of data and argument if only the authors had been on theright side.” Vandenbroucke concluded that “the arguments used andthe way of phrasing them are still used nowadays by epidemiologiststo criticize one another’s studies in newer areas of research.”1

Research on the association between cigarette smoking and lungcancer reveals a scientific controversy in which scientists who con-tested the association have been labeled as “wrong.” Along withVandenbroucke, we wondered whether these scientists’ objectionsto the association between smoking and lung cancer had any legit-imacy when placed in the historical context of scientific methodo-logy and practice prior to the report to the Surgeon Generalentitled Smoking and Health. Previous writers, including RichardKluger in his Ashes to Ashes: America’s Hundred-Year Cigarette War,the Public Health, and the Unabashed Triumph of Philip Morris (),and Stanton A. Glantz, John Slade, Lisa A. Bero, Peter Hanauer,and Deborah E. Barnes in The Cigarette Papers (), have not

. J. P. Vandebroucke, “Those Who Were Wrong,” Am. J. Epi., , , /, pp. –.Paul D. Stolley disagrees with Vandebroucke’s interpretation of Ronald Fisher’s skepticism.“My reading . . . revealed almost precisely the opposite of Vandenbroucke’s evaluation:incomplete and highly selected data (or no data but much speculation), with scant attemptsto weigh the evidence or reveal the obvious deficiencies in his data.” Paul D. Stolley,“When Genius Errs: R. A. Fisher and the Lung Cancer Controversy,” Am. J. Epi., , ,–, p. . To some extent, Stolley’s misinterprets Fisher by not placing his reactionsin historical context. It is ahistorical and unfair to judge scientists in the past by the standardsof the present.

E


Talley, Kushner, and Sterk : Lung Cancer

interpreted the controversies of the s in an appropriate historicalcontext.2 To be fair, none of these authors set out to conduct ahistorical investigation. For example, Richard Kluger wrote a jour-nalistic account on the story of tobacco, health, and science. Glantzand his colleagues, as public health activists, emphasize tobaccoindustry perfidy and mendacity, especially concerning the oncogenicand addictive properties of cigarettes based on previously secretindustry documents. We do not dispute their findings, nor do wecondone the duplicitous, self-serving, and manipulative behavior ofthe tobacco industry. But their account of the scientific controversyin the s is ahistorical. For example, in discussing the TobaccoIndustry Research Committee (renamed the Council for TobaccoResearch in ), no clear distinction is made between researchconducted prior to and after . Glantz and colleagues mainlyfocused on projects funded after and conducted outside of thescientific advisory board of the CTR, thereby creating a cloud ofsuspicion and corruption over those scientists and physicians whoagreed with the industry’s position in the s.

As historians of medicine it is our responsibility to place thestory in an accurate historical context. Mark Parascandola in “Cig-arettes and the US Public Health Service in the s” () hasilluminated the importance of understanding the context of theinstitutional culture of the Public Health Service in the s. Hepoints out that Kluger fails to adequately discuss National CancerInstitute scientists Harold Stewart, director of Pathology, andWilhelm Hueper, chief of the Environmental Cancer Section, andothers’ skepticism of the epidemiological data implicating smokingin lung cancer in the s. These scientists were not tobaccoindustry “hired guns.” Parascandola’s essay is concerned mainlywith why the Public Health Service was so slow to act on theproblem of smoking, even after two statements by the SurgeonGeneral. He explains how Hueper’s battles with polluting industriesmight have affected his position on smoking, and he importantly

. Stanton A. Glantz, John Slade, Lisa A. Bero, Peter Hanauer, and Deborah E. Barnes,The Cigarette Papers (Berkeley: University of California Press, ); Richard Kluger,Ashes to Ashes: America’s Hundred-Year Cigarette War, the Public Health, and the UnabashedTriumph of Philip Morris (New York: Vintage Books, Random House, ). See alsoKaren Miller, Smoking Up a Storm: Public Relations and Advertising in the Construction of theCigarette Problem, – (Columbia, S.C.: Association for Education in Journalism andMass Communication, 1992).



points out that the leaders of the Public Health Service did notbelieve it was their job to launch health crusades. He does notdelve into the details of the scientific controversy, which is under-standable, because his main goal is to understand the institutionalculture of the PHS.3

Allan Brandt, in a series of three articles (–), has pointedout that the scientific work on the health consequences of smokingled to a profound rethinking of the epistemological foundations ofbiomedicine by .4 His main interest is in explaining changes inthe larger American cultural context of the meaning of cigarettesmoking, notions of risk and individual responsibility, and loss ofindividual autonomy. He argues that the report to the SurgeonGeneral was necessary because there was “no authoritative ‘reading’of the mounting evidence.”5 Brandt mainly points to tobacco indus-try political and economic influence as creating this interpretivequandary. But if, as he also argues, the report represented aprofound rethinking of the foundations of biomedical epistemology,there must have been something else going on before thansimply the corrupting influence of the tobacco industry.

Indeed, by focusing on industry malfeasance, the work to date hasironically tended to obscure the remarkable achievement of publichealth scientists in creating this powerful new epistemology. Thiswas a fundamental turning point in the history of the science of dis-ease. It is only by delving into the details of the scientific issuesabout smoking and lung cancer facing biomedical scientists in thes that one can truly appreciate the difficulty and complexity ofthe puzzle these health scientists solved.

Our investigation reveals that there were grounds for legitimatescientific criticism of the evidence indicting smoking as a cause oflung cancer prior to . Moreover, close analysis of the scientificdisputes reveals two intertwined developments. One consequence of

. Mark Parascandola, “Cigarettes and the US Public Health Service in the s,” Am.J. Pub. Health, , , –.

. Allan M. Brandt, “The Cigarette, Risk, and American Culture,” Daedalus, , ,–; “ ‘Just Say No’: Risk, Behavior, and Disease in Twentieth-Century America,” inScientific Authority and Twentieth-Century America, ed. Ronald G. Walters (Baltimore: TheJohns Hopkins University Press, ), pp. –; Allan M. Brandt, “Blow Some My Way:Passive Smoking, Risk, and American Culture,” in Ashes to Ashes: The History of Smokingand Health, ed. Stephen Lock, Lois Reynolds, and E. M. Tansey (Amsterdam-Atlanta, Ga:Rodopi, ), pp. –.

. Brandt, “The Cigarette, Risk, and American Culture,” p. .



the problem of chronic disease as presented by lung cancer was thatepidemiology as a profession was transformed. Having to deal with achronic disease with often long latency periods and with manypossible etiologies created new problems to solve for a disciplineformerly focused on infectious conditions with a clear microbialbiogenesis. Besides focusing on problems of infectious disease, intothe s, epidemiology relied on the cross-sectional field survey asits most important tool. The cross-sectional field survey was a tool usedto create descriptive data thought to be representative of a population.It was a study design intended to describe, for example, the distrib-ution of diseases in morbidity surveys, community surveys of mentalhealth, and symptom inventories. The National Health Survey,which began in under the auspices of the Public Health Service’sCommission on Chronic Disease, is an example. The survey collectedrepeated samples of self-reported illnesses, medical examinations ofsmaller samples of defined age groups, and data from medical carefacilities. From the s to the s the cross-sectional field surveystudy design became more sophisticated with advances in samplingtheory and interviewing techniques and an increased understandingof intra- and inter-observer error, the misclassification of patients,and the lack of reliability of diagnostic observations. Epidemiologistsalso improved measures of sensitivity, specificity, predictive value, andlead-time bias.6

Nevertheless, these techniques were found inadequate for invest-igations of chronic diseases, mainly because of the lack of the abilityto address causation effectively.7 It was in the studies on lung cancerfrom to that many of the innovative techniques weredeveloped that allowed epidemiologists to design studies that movedbeyond the descriptive and answer questions of cause and effect indisease. The lung cancer studies were particularly important in movingforward the design of case-control studies and cohort studies. Thework of Doll and Hill () especially influenced epidemiologistsand moved forward the design of case-control studies. Elements ofthe study design innovation included advances in the precision ofcomparability of cases and controls with regard to place of inter-view, age, and gender, selective recruitment and attrition, ways to

. Mervyn Susser, “Epidemiology in the United States after World War II: The Evolu-tion of Technique,” Epi. Rev., , , –.

. Brandt, “The Cigarette, Risk, and American Culture,” p. .



deal with confounding factors, and measures to establish statisticalsignificance.8 They also advanced understanding of measures of thevalidity of outcome variables and ways of refining them. These variablesincluded measures of the reliability of the history of exposure, inter-viewer and response bias, measures of hypothetical causal variables,and dose relationships.

Prospective studies conducted by Hammond and Horn ()and Doll and Hill (), respectively sponsored by the AmericanCancer Society and the Medical Research Council, advanced thedesign of longitudinal cohort studies deployed to discover the multi-ple and unknown outcomes of a given exposure.9 Elements of theadvances in study design stimulated by the smoking and health stud-ies included more advanced study rationales, structured hypotheses,and estimates of sample sizes to ensure adequate statistical power. Inaddition, advances were made in modes of recruitment of subjects,identification of criteria of eligibility, measures of reliability, validity,and modes of analysis.

The other historical development involved the attitude andacceptance of epidemiology by members of the medical profession.There was resistance, if not hostility, among many physicians andbiomedical scientists to the claims made about disease causation inthe innovative studies on smoking and health in the s. Beforethe s, epidemiology was generally considered an ancillary“handmaiden” of medicine. After the smoking and health studiesand the controversy they provoked, epidemiology gained strengthand legitimacy as an independent health science. The landmark report to the Surgeon General, Smoking and Health, represented thedenouement of these closely related historical developments. Smok-ing and Health accepted the controversy as a legitimate disputeamong scientists but came down firmly on the side of a robust asso-ciation between cigarette smoking and lung cancer. It did so by

. Susser, “Epidemiology in the United States after World War II”; Richard Doll,“Uncovering the Effects of Smoking: Historical Perspective,” Stat. Meth. Med. Res., ,, –; Ernest Wynder, “Tobacco as a Cause of Lung Cancer: Some Reflections,” Am.J. Epi., , , –; C. White, “Research on Smoking and Lung Cancer: A Land-mark in the History of Chronic Disease Epidemiology,” Yale J. Biol. Med., , , –.

. Richard Doll, and A. Bradford Hill, “The Mortality of Doctors in Relation to theirSmoking Habits: A Preliminary Report,” Brit. Med. J., , , -; E. CuylerHammond and Daniel Horn, “The Relationship between Human Smoking Habits andDeath Rates,” J. Am. Med. Assoc., , , -.



endorsing and articulating a new epistemology of chronic diseaseepidemiology that the medical profession as a whole could accept asorthodox health science.10 Recognizing this context provides animportant historical framework for understanding the public relationsbattles that would take place after the publication of Smoking andHealth ().

THE RISE OF LUNG CANCER

In the s, reports about alarming increases in lung cancer ratesemerged in many parts of the world, including Britain, the UnitedStates, Canada, Australia, Denmark, Switzerland, Turkey, and Japan.For example, the lung cancer–related annual morbidity incidence inEngland and Wales rose from to , between and ,representing a fifteen-fold increase.11 A study conducted by theAmerican Cancer Society (ACS) revealed a “striking” increase inthe prevalence of cancer of the respiratory system between and.12 In their efforts to explain the increase, scientists suspected airpollution from car exhaust fumes, gas works, industrial plants, coalfires, road tars, and heredity as possible culprits.13 Others attributedthe increase to a delayed reaction to the great influenza epidemic of– or to the decline of tuberculosis.14 Again, others viewedcigarette smoking as a possible cause.15 Surgeons Alton Ochsner and

. Historian John C. Burnham found that “the so-called new epidemiology was pio-neered in the lung cancer studies.” John C. Burnham, “American Physicians and TobaccoUse: Two Surgeons General, and ,” Bull. Hist. Med., , , –, p. ; Smok-ing and Health: Report of the Advisory Committee to the Surgeon General of the Public HealthService (Washington, D.C.: Dept. of Health, Education, and Welfare, ), pp. –.

. Richard Doll and A. Bradford Hill, “Smoking and Carcinoma of the Lung,” Brit.Med. J., , , –, p. .

. Statistical Research Section, Medical and Scientific Department, American CancerSociety, Statistics on Cancer (New York: American Cancer Society, June ), pp. , .

. Burnham, “American Physicians and Tobacco Use: Two Surgeons General, and ,” p. . C. O. S. Blyth Brooke; “The Incidence of Cancer of the Lung –,”Brit. J. Cancer, , , –, p. .

. James T. Patterson, Dread Disease: Cancer and Modern American Culture (Cambridge,Mass.: Harvard University Press, ), p. . Smoking and Health: Summary and Report ofthe Royal College of Physicians of London on Smoking in Relation to Cancer of the Lung (NewYork, Toronto, London: Pitman Publishing Company, ), p. S; G. Herdan, “TheIncrease in the Mortality Due to Cancer of the Lung in the Light of the Distribution of theDisease Among the Different Social Classes and Occupations,” Brit. J. Cancer, , ,–, p. .

. Hammond and Horn, “Human Smoking Habits and Death Rates,” p. . A Massachusetts State Health Department study of , men over forty who had visited acancer clinic showed an association between lung cancer and cigarette smoking. Ibid.



Michael Debakey pointed out in that anecdotal clinical evidencesupported the view that the increase in lung cancer rates paralleledthe increase in cigarette smoking rates.16

The possible link between cigarette smoking and lung cancerbecame the focus of several studies. In , Morton L. Levin, assis-tant director of the Division of Cancer Control, New York StateDepartment of Health, began interviewing patients concerning theirtobacco use at Roswell Park Memorial Institute in Buffalo, NewYork. In Ernest Wynder, then a medical student, initiated astudy based on interviews with lung cancer patients. His preliminarydata indicated an association between smoking and lung cancer. Thefollowing year Wynder met with Charles Cameron, the Medicaland Scientific Director of the American Cancer Society who agreedto fund a study by Wynder and Evarts A. Graham, a professor ofsurgery at Washington University in St. Louis.17 Simultaneously,A. Bradford Hill, a professor of medical statistics at the LondonSchool of Hygiene and Tropical Medicine, and Richard Doll, amember of the Statistical Research Unit of the Medical ResearchCouncil, began studying lung cancer patients at London hospitals.18

All of these studies showed a positive correlation between ciga-rette smoking and lung cancer and called for more research.19 Thisresearch, conducted over the next fourteen years, was based on acombination of epidemiological studies, animal experiments, patho-logical research, and biochemical analyses. Scientists intensely exam-ined and debated the significance of this emerging body of evidencethroughout the s.

Reexamining the research on a possible link between lung cancerand cigarette smoking in the context of its time reminds us of thescientific resistance that had to be overcome for scientists to accept

. Doll and Hill, “Smoking and Carcinoma of the Lung,” p. . . Interview with Ernest Wynder, New York City, April , Box , Folder ,

Richard Kluger Papers, Manuscripts and Archives, Yale University Library, New Haven,Conn. (Hereafter Kluger papers). American Cancer Society, Annual Report, p. ;Richard Doll, “The First Reports on Smoking and Lung Cancer,” in Ashes to Ashes: TheHistory of Smoking and Health, ed. Stephen Lock, Lois A. Reynolds, E. M. Tansey (Amsterdamand Atlanta, Ga.: Rodopi, ), –, p. . The ACS awarded Graham, Wynder, andCroniger $, between and . The National Cancer Institute awarded theteam $, between March and September . C. Barber Mueller, Evarts A.Graham: The Life, Lives, and Times of the Surgical Spirit of St. Louis (Hamilton, Ont: B.C.Decker, Inc., ), p. .

. Doll and Hill, “Smoking and Carcinoma of the Lung,” p. . . Smoking and Health, p. v.



a new kind of evidentiary claim by chronic disease epidemiology. Inessence, the struggle was over under what conditions and accordingto which rules a cause and effect relationship could be persuasivelyestablished based on statistical analyses. The post- history of cig-arette smoking and its health consequences has obscured the nuancesof the scientific debate. It is hardly news that scientists frequentlydisagree with one another at the frontiers of knowledge. Given thecurrent climate of opinion about smoking and the tobacco industry,many observers have assumed that there could not have been anyreasonable doubts about the then new epidemiological, animal,pathological, and biochemical investigations. However, a reexam-ination of scientific reaction to these studies suggests that, prior to, there was a substantive debate among reputable scientistsabout the link between cigarette smoking and lung cancer.20

MAKING THE CASE

One of the earliest epidemiological investigations of lung cancer wasinitiated in the late s by Wynder and Graham.21 Their retro-spective study included four groups of respondents. The first con-sisted of male hospitalized patients diagnosed with epidermoid,undifferentiated and unclassified carcinomas. The second groupincluded hospitalized male lung cancer patients and patientsdiagnosed with a chest disease. The third group involved ,patients, without lung cancer, recruited from St. Louis hospitals.The final group consisted of eighty-three hospitalized patients whowere interviewed by physicians in New York, Boston, and Hines,Illinois.

Data were collected using standardized format interviews aboutsmoking behaviors.22 On completion of the interview, when avail-able, the site of lesion, microscopic diagnosis, and Papanicolaou andetiological class were recorded. Respondents were clustered into six

. Brandt, “The Cigarette, Risk, and American Culture”; Richard Doll, “The FirstReports on Smoking and Lung Cancer.”

. Ernest L. Wynder and Evarts A. Graham, “Tobacco Smoking as a Possible EtiologicFactor in Bronchiogenic Carcinoma: a Study of Six Hundred and Eighty-Four ProvedCases,” J. Am. Med. Assoc., , , –.

. Topics included, ever having had a lung disease and if so, when, for how long andsite of disease; lifetime smoking; if smoker, initial smoking age; average amount of tobacco(cigarettes, cigars, and pipe) used per day during the past twenty years; name of cigarettebrands smoked exclusively for more than five consecutive years; smoking prior to having



categories: nonsmokers, light smokers (one to nine cigarettes per dayfor more than twenty years), moderately heavy smokers (ten to fif-teen cigarettes per day for more than twenty years), heavy smokers(sixteen to twenty cigarettes per day for more than twenty years),excessive smokers (twenty-one to twenty-four cigarettes per day formore than twenty years), and chain smokers (thirty-five cigarettes ormore per day for more than twenty years).

Among the men in the first group, all of whom had been diag-nosed with lung cancer, . percent had no smoking history while. percent were either heavy (. percent), excessive (. per-cent), or chain (. percent) smokers. In the second group, all ofthe lung cancer patients were smokers; percent were excessivesmokers, percent were chain smokers.23 In the third group, menwithout cancer in the general hospital population, the percentage ofnonsmokers was . percent higher than among the first twogroups, but . percent were either heavy (. percent), excessive(. percent) or chain (. percent) smokers. Of the eighty-threepatients with lung cancer in group four, . percent were eitherheavy, excessive, or chain smokers.

Wynder and Graham believed they had demonstrated a definiteassociation between smoking and the risk of lung cancer, whichindicated that age was not as important a variable as smoking. Theyconcluded that excessive and prolonged cigarette smoking seemedto be an important factor in the induction of lung cancer, and thatlung cancer in nonsmokers was rare.24

In the late s the New York State Department of Health’sBureau of Cancer Control in Albany and its Roswell Park MemorialInstitute in Buffalo collaborated on an investigation of the causes of lungcancer. This study, published in by Morton L. Levin, HymanGoldstein, and Paul R. Gerhardt, also supported a link between smokingand cancer. Since , researchers at Roswell Park (a public

breakfast; presence of physical signs, such as chronic (morning) coughing; if former smoker,quitting age; professional history and exposure to fumes at work; exposure to irritative dustsor fumes outside of work, including the excessive use of insecticide spray; average dailyamount of alcohol consumption; date of birth and residence locations; and parental andsibling(s) cause of death.

. . percent patients without lung cancer were excessive smokers, and . percent ofpatients without lung cancer were chain smokers.

. Wynder and Graham, “Tobacco Smoking as a Possible Etiologic Factor inBronchiogenic Carcinoma.”



hospital specializing in cancer) had routinely recorded the smokinghabits of patients admitted to the hospital before their diagnoseswere known. The study was based on histories taken of , malepatients with lung, lip, pharynx, esophagus, colon, or rectum cancerand a few patients with cancer at different sites. Levin, et al., chose different male non-cancer patients for comparison because theyhad signs referable to the same sites, but that later proved not to becancer. The data showed that . percent of the cancer patientssmoked cigarettes, pipes, or cigars; but . percent of noncancerpatients smoked similarly. When adjusted for age, the investigatorsfound that cigarette smokers who smoked for twenty-five years hadtwice as many cases of lung cancer than pipe smokers, cigar smokers,or nonsmokers.25 They also showed that lip cancer was increasedamong pipe smokers and cigar smokers, but not cigarette smokers.Unlike Wynder and Graham, Levin and his colleagues did notreport the relationship between amount smoked and the risk of lungcancer. Also, they did not describe how the case histories were takenor whether a standardized form was used. Moreover, Levin admittedthat “the reliability of the quantitative aspects of smoking obtainedby a history is of course highly variable.”26

Contemporaneously, Hill and Doll initiated a study amongpatients admitted to the hospital for lung, stomach, colon, or rectumcancer. Eligible patients were identified by admitting clerks, house-physicians, the cancer registrar, and staff from radiotherapy depart-ments. Those who were eligible and interested were interviewedusing a questionnaire on their smoking habits. In addition, hospitalpatients without cancer, matched in terms of age and gender, wereenrolled as controls. Between April and October , ,cases were identified and a final sample consisting of , cases wasselected. Data collection involved face-to-face interviews on topicssuch as life-time smoking habits, ages started or stopped smoking,the amount smoked prior to admission, changes in their smokinghistory, most intense smoking habit, varying proportions of pipesand cigarettes smoked, and inhalation behavior. To classify as asmoker the subject must have smoked at least one cigarette a day fora year.

. M. L. Levin, H. Goldstein, and P. R. Gerhardt, “Cancer and Tobacco Smoking: APreliminary Report,” J. Am. Med. Assoc., , , –.

. Ibid., p. .



The control group consisted of general medical and surgicalpatients, matched except that they differed slightly with regard to theirresidence. Non-smokers were significantly (p<.) less representedamong the cancer cases than the controls, with non-smokers in bothgroups over-represented among women. When examining the amountsmoked, cases reported significant higher levels of smoking thancontrols (p<.). Specifically, heavy smokers were overrepresentedamong the cases.

Further analyses showed no association between cigarette smok-ing and cancer at sites other than the lung. Doll and Hill concludedthat there was a “real association between carcinoma of the lung andsmoking.” It is important to note that they did not claim proof ofcause and effect; instead they concluded that this association meantthat smoking was an important factor in the production of lungcancer.27

Whereas the association became accepted, its meaning remainedcontested. Moreover, the research was challenged on methodologicalgrounds.28 Of main concern was the retrospective nature of self-reported data. Concerns also were raised about the extent to whichrespondents provided socially desirable answers. Others noted thepotential sampling bias created by hospital recruitment.29 ACSepidemiologist E. Cuyler Hammond and Surgeon General LeonardScheele were dismissive of Wynder and Graham’s retrospectivestudy.30 Graham recalled that “Hammond told me that if he had any-thing to do with it, we would not get our grant from the AmericanCancer Society renewed. He went on to say also that he had noconfidence in your results or in the answers to the questionnaire thatMiss Croninger [Wynder and Graham’s research assistant] was getting.”Graham decided that he did not want to have any further dealingswith the American Cancer Society. “I think the attitude of Hammond,which was supported by Cameron [Medical and Scientific Directorof the ACS], was inexcusable and I feel somewhat sour on the whole

. Doll and Hill, “Smoking and Carcinoma of the Lung,” pp. –. . Leroy E. Burney, “Smoking and Lung Cancer: A Statement of the Public Health

Service,” J. Am. Med. Assoc., , , –, p. . . Doll, “The First Reports on Smoking and Lung Cancer,” pp. –. . Evarts A. Graham to Ernest L. Wynder, August , Box , Folder , Evarts

A. Graham papers, Becker Memorial Library, Washington University School of Medicine,St. Louis, Mo. [Hereafter Graham papers). Ernest L. Wynder to Evarts A. Graham, June, Box , Folder , Graham papers.



bunch.”31 Wynder called Surgeon General Leonard Scheele to findout the reasons for the grant denial and asked him whether he hadread Wynder and Graham’s JAMA article.32 Wynder reportedScheele’s reaction: “This article had not proved [sic] anything. Hesaid the same correlation could be drawn to the intake of milk.”Scheele added that “no kind of interviewing could get satisfactoryresults from patients.” Moreover, he concluded: “since nothing hadbeen proved [sic] there exists no reason why experimental workshould be conducted along this line.”33

Negative reactions to Wynder’s data collection methods camefrom other cancer researchers. For instance, Dr. James W. Ellis, ofthe Bureau of Disease Control, State of California Department ofPublic Health, wrote to Graham “that if your conclusions are basedupon statistics complied [sic] by Dr. Ernest Wynder, we very [sic]skeptical of their validity.” According to Ellis, Wynder’s investiga-tions in the Bay Area and in Los Angeles was observed by “the lead-ing men in those areas” and for a few days he was accompanied byone of Ellis’s investigators. “The concensus [sic] of opinion,” Ellisclaimed, “was that Dr. Wynder was extremely biased in hisapproach, asked leading questions regarding smoking habits, andreceived directed answers. He was uninterested in other possible fac-tors and ignored them. He impressed us as one who was trying tobolster a theory rather than make an objective survey.”34

Despite these concerns, or because of them, other studies wereinitiated, some by Wynder’s and Graham’s critics. In order to over-come the methodological problems associated with retrospectivestudies, Doll and Hill in Britain and Hammond and Horn in theU.S. began conducting prospective studies in the early s. AsDoll and Hill wrote: “Further retrospective studies of that same kindwould seem to us unlikely to advance our knowledge materially orto throw any new light upon the nature of the association. If, too,

. Evarts A. Graham to Ernest L. Wynder, August , Box , Folder ,Graham papers.

. This was an incredible phone call considering that Wynder had just finished hismedical degree from Washington University and was an intern at Georgetown UniversityHospital. Scheele was Surgeon General!

. Ernest L. Wynder to Evarts A. Graham, June , Box , Folder , Grahampapers.

. James W. Ellis to Evarts A. Graham, November , Box , Folder , Grahampapers. Wynder used his standard questionnaire for the interviews.



there were any undetected flaw in the evidence that such studieshave produced, it would be exposed only by some entirely newapproach.” Doll suggested that the next “approach we consideredshould be ‘prospective.’ It should determine the frequency withwhich the disease appeared, in the future, among groups of personwhose smoking habits were already known.”35

In summer and fall of , Hammond and Daniel Horn of theACS designed a standardized questionnaire to be used in a prospec-tive study. Four pages long, it covered areas such as demographiccharacteristics and smoking history.36 To conduct the interviewsHammond and Horn recruited and trained approximately ,volunteers from counties in nine states to collect the data. Eachtrained volunteer received a packet containing eleven questionnairesand was asked to recruit five to ten white men between fifty andsixty-nine years of age whom they could track for several years. Ini-tial enrollment began in January , and the follow-up began on November . Death certificates from the state health depart-ments were checked if a subject could not be reached. If cancer wasindicated as a cause of death, efforts were made to gather furtherdetails from the physician listed on the death certificate and from thehospital, tumor clinic, or cancer registry records when available. Thesecond follow-up began on November and included ,men, , (. percent) of whom had died.37

For purposes of analysis, the sample was divided into three cate-gories: never smoked, occasionally only, and regular smokers. Within

. Doll and Hill, “Mortality of Doctors.” . Questions asked included: Have you ever smoked at least as many as five to ten packs

of cigarettes? Have you ever smoked at least as many as fifty to seventy-five cigars? Haveyou ever smoked at least as many as three to five packages of pipe tobacco? If the respon-dent answered yes to any of these queries, the interviewer proceeded to the next set ofquestions, which began by asking how much cigarette smoking the respondent wasengaged in. The questions continued: If you do not smoke cigarettes now, how long has itbeen since you last smoked them? How old were you when you first smoked cigarettes?How many years altogether have you or did you smoke cigarettes? Thinking back over theyears you smoked, for how many of those years did you smoke cigarettes occasionally, butnot every day? For how many of those years did you regularly smoke cigarettes, but lessthan a pack a day? For how many of those years did you regularly smoke one pack ofcigarettes a day? For how many of those years did you regularly smoke more than one packbut less than two packs of cigarettes a day? For how many of those years did you regularlysmoke two or more packs of cigarettes a day? The questions for pipe and cigar smoking areomitted here for the sake of brevity.

. Annual follow-ups were conducted beginning November of , , , and.



each of the categories, age groups were constructed. The findingsshowed that regular smokers had a significantly higher mortality ratethan men who never smoked across all age groups (p<.). Whenexploring the number of cigarettes smoked, across all age groups, themortality rate of those who smoked ten or more cigarettes per daywas significantly higher than among those who smoked fewer ciga-rettes per day. Based on a percent confidence level, the estimatedlung cancer mortality rate was three to nine times higher amongregular smokers as compared to nonsmokers.

Hammond and Horn were persuaded that these results provedthat an association existed between regular cigarette smoking andcancer (not exclusively of the lung). The association appeared caus-ative when other evidence was included; for instance the earlier sta-tistical studies by Lombard and Doering (), Pearl (), and theMassachusetts State Health Department (), all of which also founda statistically significant association between smoking and lungcancer. They pointed to trends in cigarette use in the United States.In the rate of consumption was per person fifteen years ofage or older. By it had risen to , per person.38 The cumu-lative meaning of all this evidence, concluded Hammond and Horn,was that the relationship between cigarette smoking and cancer wascause and effect.39

A British Medical Research Council sponsored study, conductedby Doll and Hill, arrived at similar conclusions. In October ,Doll and Hill sent a questionnaire to , physicians on the BritishMedical Register about their smoking habits. The doctors wereasked to classify themselves into one of three groups: presentlysmoking, had smoked in the past but not at present, never regularlysmoked. Smoking was defined as at least one cigarette per day forone year. They also inquired about age of smoking initiation, theamount presently smoking, and present method of consumption.They obtained information about the cause of death of doctors theyhad enrolled from the Registrars-General of the United Kingdom

. They discussed more statistical studies. For the sake of brevity, these have been omit-ted because they all come to the same conclusion and are based on the “historic” method.

. Hammond and Horn, “Human Smoking Habits and Death Rates”; Walter S. Ross,Crusade: The Official History of the American Cancer Society (New York: Arbor House, );American Cancer Society, Annual Report. Horn was trained as a psychologist at Harvard.Kluger, Ashes to Ashes, p. .



and followed up on eighty-eight cases of reported lung cancer bycontacting the doctor who certified the death and the hospital orconsultant to whom the patient had been referred. Doll and Hillobtained radiology, laboratory, and microscopy reports to verify thatthe death was actually due to lung cancer. On this basis they con-cluded that seventy-nine physicians had died from lung cancer.40

Hammond and Horn continued their study, eventually following, men for an average of forty-four months. Based on compar-ison of expected deaths adjusted for age, Hammond and Hornshowed that the death rate for regular cigarette smokers was per-cent higher than for nonsmokers (p<.).41 Doll and Hill contin-ued to follow their physician subjects and published an update oftheir study in that confirmed their original findings.42

Even before Hammond and Horn announced the results of theirstudy, Wynder and Graham published a study using an animal modelto demonstrate the health consequences of smoking. They showedthat the skin of mice developed cancer when painted with a distillateof tobacco smoke.43 Complementing the statistical studies and themice skin-painting experiments, evidence indicting cigarette smok-ing as a cause of lung cancer emerged from pathology and biochem-istry in and . Based on smoker’s autopsies, Veterans

. A total of , physicians had responded. Doll and Hill eliminated men underthirty-five and all females from the study (because of the lower rate of lung cancer forfemales), resulting in an overall sample size of ,. This left . percent nonsmokers,. percent doctors who smoked one to fourteen cigarettes per day, . percent doctorswho smoked fifteen to twenty-four cigarettes per day, and . percent men who smokedtwenty-five or more cigarettes a day. After standardizing for age, the results showed thelung cancer mortality rate increased steadily from per , in nonsmokers to . per, in those smoking twenty-five or more cigarettes a day. The difference betweenobserved and expected deaths was statistically significant (x = ., n = , P = .), and thedose relationship was especially important. Doll and Hill, “Mortality of Doctors.”

. E. Cuyler Hammond and Daniel Horn, “Smoking and Death Rates—Report onForty-Four Months of Follow-Up of , Men,” J. Am. Med. Assoc., , , –,–.

. R. Doll and A. Bradford Hill, “Lung Cancer and Other Causes of Death in Relationto Smoking—A Second Report on the Mortality of British Doctors,” Brit. Med. J., , ,–. Two years later, Harold F. Dorn of the Veterans Administration released an anal-ysis revealing mortality rates among , veterans were significantly higher amongsmokers than among non-smokers. Harold F. Dorn, “Smoking—Mortality Rate AmongVeterans,” Pub. Health Rep., , , .

. Ernest L. Wynder, Evarts A. Graham, and Adele Croniger, “Experimental Produc-tion of Carcinoma with Cigarette Tar,” Cancer Res., , , –. Wynder and Corn-field released a retrospective study in based on the medical histories of physicians.Ernest L. Wynder and Jerome Cornfield, “Cancer of the Lung in Physicians,” New Eng. J.Med., , , –.



Administration pathologist Oscar Auerbach and colleagues published“Changes in the Bronchial Epithelium in Relation to Smokingand Cancer of the Lung” in . They found hyperplasia andmetaplasia in the cells of smokers who had died but did not havelung cancer: these changes were considered early stages in the devel-opment of tumors.44 In terms of biochemical evidence, BenjaminL. Van Duuren’s study demonstrated the presence of twelvepolynuclear aromatic hydrocarbons compounds in cigarette-smokecondensate in addition to the seven previously identified. His workwas a continuing effort to account for the known carcinogenicactivity of cigarette tar on mouse skin. Van Duuren wrote that “thecarcinogenic hydrocarbons found so far do not by themselves appearto be present in sufficient concentrations to account for the observedactivity.”45

By the late s, the combination of prospective epidemiologicalstudies, animal experiments, pathology studies, and biochemical evi-dence convinced most public health scientists that cigarette smokingwas a cause of lung cancer. This view was reflected in Surgeon Gen-eral Leroy Burney’s televised news conference statement of July (reprinted in Public Health Reports) that the “evidence was increas-ingly pointing in one direction” that excessive and prolonged ciga-rette smoking was one of the causative factors in lung cancer.46 Twoyears later, Burney expanded and strengthened his conclusions aboutthe dangers of smoking. In an article published in JAMA, he summa-rized the USPHS views:

. The weight of evidence at present implicates smoking as the principaletiological factor in the increased incidence of lung cancer. . Cigarettesmoking particularly is associated with an increased chance of developinglung cancer. . Stopping cigarette smoking even after long exposure is

. Oscar Auerbach, J. Brewster Gere, Jerome B. Forman, Thomas G. Petric, HaroldJ. Smolin, Gerald E. Muehsam, Digran Y. Kassouny, and Arthur Purdy Stout, “Changes inthe Bronchial Epithelium in Relation to Smoking and Lung Cancer,” New Eng. J. Med.,, , –. New York State Department of Health, Bureau of Cancer Control, Cig-arette Smoking and Lung Cancer (Albany: New York State Department of Health, ).

. Benjamin L. Van Duuren, “The Polynuclear Aromatic Hydrocarbons in Cigarette-Smoke Condensate,” J. Nat. Cancer Inst., , , –, p. .

. Leroy E. Burney, “Excessive Cigarette Smoking,” Pub. Health Rep., , , ,and “Policy over Politics: The First Statement on Smoking and Health by the SurgeonGeneral of the United States Public Health Service,” N. Y. St. J. Med, , , –;Luther L. Terry, “The Surgeon General’s First Report on Smoking and Health: A Chal-lenge to the Medical Profession,” N. Y. St. J. Med, , , –.



beneficial. . No method of treating tobacco or filtering the smoke hasbeen demonstrated to be effective in materially reducing or eliminating thehazard of lung cancer. . The nonsmoker has a lower incidence of lungcancer than the smoker in all controlled studies, whether analyzed in termsof rural areas, urban regions, industrial occupations, or sex. . Persons who

TABLE

Higher Aromatic Hydrocarbons in Cigarette-Smoke Condensate

Source: Benjamin L. Van Duuren, “The Polynuclear Aromatic Hydrocarbons in Cigarette-Smoke Condensate,” J. Nat. Cancer Inst., , , , by permission of Oxford UniversityPress.

Compound Concentration (γ/ cigarettes) Carcinogenicity

Pyrene . Negative . -Methylpyrene . Negative Fluoranthene . Negative -Methylfluoranthene — Unknown Alkylfluoranthene — Unknown Chrysene . Weak Alkylchrysene . Unknown Benzo[a]pyrene . Strong (,-Benzpyrene) . Benzo[e]pyrene . Weak

(,-Benzpyrene) Perylene — Negative Benzo[ghi]perylene — Negative

(,-Benzperylene) Benzo[mno]fluoranthene . Unknown Benzo[j]fluoranthene — Unknown

(,-Benzfluoranthene) Benzo[k]fluoranthene — Unknown

(,-Benzfluoranthene) ,-Benzfluorene — Unknown Debenz[a,h]anthracene . Strong

(,,,-Dibenzanthracene) Benzo[c]phenanthrene — Weak



have never smoked at all (cigarettes, cigars, or pipe) have the best chanceof escaping lung cancer. . Unless the use of tobacco can be made safe, theindividual person’s risk of lung cancer can be reduced by the eliminationof smoking.47

Burney’s statement reflected the opinion of the New York StateDepartment of Health () that there was “irrefutable scientificevidence that the long-range effects of cigarette smoking are harmfulfor many people.”48 The California State Department of PublicHealth followed suit in , by warning of the health risks associ-ated with smoking.49

Despite Burney’s statements and the announcements of twomajor state health departments, many reputable scientists, includingsome from the NIH, challenged the available scientific evidence.50

In addition, a number of the smoking and health researchers dis-cussed above disagreed with the conclusions of their colleagues’studies questioning others’ methodology, data, or the interpretationof the data.51 Dr. Lewis Robbins, Chief of Cancer Control Program,USPHS, wrote in , that “from the first hint of a relationshipbetween smoking and cancer there was controversy, and the contro-versy continues.”52 He claimed that “most practitioners have seemedreluctant to take a position against cigarette smoking in the face ofapparent contradictions in the evidence.”53 Summarizing the objec-tions to these studies, Robbins argued that “no one agent had yet beenisolated as the cause of lung cancer in man; no one agent had beenshown, under controlled conditions, to result in cancer, and, in itsabsence, not result in cancer of the lung. Nor has this been shown today[].” According to Robbins “some scientists believe that it maynever be possible to demonstrate conclusively that specific ingredients

. Burney, “Smoking and Lung Cancer,” pp. –. . New York State Department of Health, “State Health Department’s Position on

Smoking and Health,” Weekly Bulletin, September , , . . Malcolm H. Merrill, “Cigarette Smoking and Lung Cancer,” Cal. Health, June

, , –. . Interview with Leroy E. Burney, November , Box , Folder , Richard

Kluger papers; Parascandola, “Cigarettes and the US Public Health Service in the s,”pp. –.

. Doll, “The First Reports on Smoking and Lung Cancer,” pp. –; Brandt, “TheCigarette, Risk, and American Culture,” pp. –; and Kluger, Ashes to Ashes.

. Lewis C. Robbins, “Medical Practice and Lung Cancer,” Minn. Med., , , –, p. .

. Ibid., p. .



of cigarette smoke ‘cause’ lung cancer. Their belief is based on twomain contentions: first, the ‘incubation’ period of lung cancer maybe as long as to years; and second, it appears impossible tocarry out a controlled study, using human beings, which would per-mit the elimination of unessential variables.” Thus, Robbins con-cluded that, “lacking definite proof, as that term may be understoodin the biological sciences, there can be no wonder that there are manydifferent beliefs about the relationship of smoking to lung cancer.”54

CONTESTED EPIDEMIOLOGICAL EVIDENCE

One of the principal sources of the skepticism about the link betweensmoking and lung cancer was that in the s laboratory evidencewas the accepted standard by which cause and effect could be dem-onstrated in medical science. Statistical reasoning could not satisfyKoch’s postulates, which had guided medical scientists since thes.55 Koch’s postulates created evidentiary rules for claiming cau-sation in disease.56 First, the organism suspected of disease must beshown to be constantly present in characteristic form and arrangementin diseased tissue. Second, the suspected organism must be isolatedand grown in pure culture. Third, the pure culture must be provento induce the disease experimentally.57 And fourth, the disease couldnot exist in the absence of the pathogen. Not until the s didAmerican medicine resolve disputes about causal claims based onstatistical evidence.58 Mervyn Susser wrote that “some of the matu-rational lag of epidemiology can be attributed to the enormous suc-cesses of the germ theory.”59 The orthodox view in the s wasthat cause and effect relationships in medicine had to be established

. Ibid., p. . . Richard Doll, “Proof of Causality: Deduction from Epidemiological Observation,”

Persp. Biol. Med., , , –, p. ; Susser, “Epidemiology in the United Statesafter World War II,” pp. –. See also Mervyn Susser, “Choosing Future for Epidemi-ology: I. Eras and Paradigms,” Am. J. Pub. Health, , , –.

. Brandt, “ ‘Just Say No’: Risk, Behavior, and Disease in Twentieth-Century America,”pp. –.

. W. F. Bynum, Science and the Practice of Medicine in the Nineteenth Century (New York:Cambridge University Press, ), pp. –.

. Brandt, “The Cigarette, Risk, and American Culture,” and Brandt, “ ‘Just Say No’ ”;Risk, Behavior, and Disease in Twentieth-Century America;” Doll, “The First Reports onSmoking and Lung Cancer,” p. ; Harry M. Marks, The Progress of Experiment: Science andTherapeutic Reform in the United States, – (New York: Cambridge University Press,).

. Susser, “Epidemiology in the United States after World War II,” p. .



through “painstaking investigations into the pathology of the diseaseon a laboratory basis, through animal or human experimentation orthe isolation of the cause—bacterial or other.”60 Looking back tomedical profession resistance to acknowledging the link betweensmoking and cancer, Morton Levin, a pioneer cancer epidemiologistin smoking and health studies, noted that while the professionadhered to the Koch model of disease causation, epidemiology was“alien to most practitioners, who were used to dealing with individ-ual patients and their problems.”61 Koch’s postulates had proven tobe a powerful and effective tool against infectious disease. To aban-don such a successful paradigm would not be something conserva-tive doctors would do precipitously.62

By the s, infectious conditions were in retreat and chronicmaladies came to dominate the disease landscape. This posed parti-cular problems for the discipline of epidemiology.63 Epidemiologists,following the lead of the laboratory, had mainly examined diseasesthat emerged shortly after exposure to a pathogen.64 In contrast,lung cancer appeared decades after initial exposure. During thes, epidemiologists needed to develop new tools that wouldallow them to make scientific claims about chronic diseases withlong incubation or quiescent periods.65 Smoking and Health ()formalized and institutionalized new methods for chronic diseaseepidemiology. Paul Kotin, an environmental cancer specialist whohad initially opposed the smoking and lung cancer hypothesis,agreed in a interview that a major feature of Smoking and Health() was its modification of Koch’s Postulates and its endorsementof chronic disease epidemiology.66 Prior to scientists argued inprivate, in public, and in print over whether new rules for establish-ment of causation should be adopted, and these arguments were

. Herbert Arkin, “Relationship Between Human Smoking Habits and Death Rates: AnAnalysis of the American Cancer Society Survey,” Current Med. Digest, April , , –.

. Interview with Morton L. Levin, June , Box , Folder , Kluger papers. . Ibid. . Elizabeth Fee, “Adapting to Specialization: The Founding, Growth, and Transfor-

mation of the American Journal of Hygiene,” Am. J. Epidemiol., , , –; ElizabethFee and Barbara Rosenkrantz, “Professional Education for Public Health in the UnitedStates,” in A History of Education in Public Health: Health that Mocks the Doctors’ Rules, ed.Elizabeth Fee and Roy Acheson (New York: Oxford University Press, ), pp. –.

. Susser, “Epidemiology in the United States after World War II,” pp. –. . Ibid., p. . . Interview with Paul Kotin, Box , Folder , , Kluger papers.



placed in the context of the methods and conclusions of the smok-ing and lung cancer studies.

For example, some scientists questioned whether there was anincrease in lung cancer in the s.67 The apparent increase couldhave simply reflected improved diagnostic tools such as radiography,bronchoscopy, cytological and biopsy studies, and the emergence ofspecialized chest clinics and thoracic surgery.68

D. W. Smithers, Professor and Director of Radiotherapy at England’sRoyal Cancer Hospital, wondered whether statistical data showing anincrease in lung cancer rates reflected an actual increase or were a sta-tistical artifact reflecting an increased recognition of lung cancer.69

R. A. Willis wrote that in his experience “doctors frequently madediagnostic errors in cases of lung cancer. Having surveyed my ownexperience of the diagnostic errors made in this disease, my ownopinion is that it is not possible either to affirm or deny that there hasbeen a real increase.”70 Joseph Berkson, Head of the Division of Bio-metrics and Medical Statistics, Mayo Clinic, echoed concerns abouthow the changed ecology of disease and increased life expectancymight vitiate the supposed increase in lung cancer rates.71

. R. A. Willis to Harold L. Stewart, Box , Folder Dorn, H. F. , Harold L. Stewartpapers, MSC , National Library of Medicine, Bethesda, Md. (Hereafter Stewart papers).Tobacco Industry Research Committee, ed., A Scientific Perspective on the Cigarette Controversy(New York: TIRC, April ), pp. –. One of the first tasks of the TIRC was to compilequotes from scientists opposed to the idea that cigarettes caused lung cancer. This effort waspart of an elaborate public relations effort by the advertising firm Hill and Knowlton to allaypublic concerns during the first health scare over smoking and cigarettes. See Glantz, Slade,Bero, Hanauer, and Barnes, The Cigarette Papers, pp. –; Kluger, Ashes to Ashes, pp. –;and Miller, Smoking Up a Storm. National Cancer Institute Director John R. Heller gave hispermission to the TIRC to use a quote from him in the book. John W. Hill to Paul M.Hahn, February , Box , Folder , John. W. Hill papers, Archives Division, StateHistorical Society of Wisconsin, Madison, Wisc. (Hereafter Hill papers).

. R. A. Willis, “The Incidence and Histological Types of Pulmonary Carcinoma, withComments on Some fallacies and Uncertainties,” Med. J. Aust., , , –. Willisaccepted the proposition that smoking was a cause of lung cancer. But he believed that lungcancer was not uncommon in the past and was not convinced there had been any great risein the malady. His argument attenuated the importance of smoking as a cause of lung cancer.Others, such as W. C. Hueper, Harold Stewart, and Joseph Berkson used Willis’s work asfurther evidence against the cigarette/lung cancer hypothesis. See also Milton Rosenblattquoted in Tobacco Industry Research Committee, ed., A Scientific Perspective on the CigaretteControversy, p. .

. D. W. Smithers, quoted in A Scientific Perspective on the Cigarette Controversy, ed.TIRC (New York: TIRC, ), p. .

. R. A. Willis to Harold L. Stewart, Box , Folder Dorn, H.F. , Stewart papers. . Joseph Berkson, J. Am. Stat. Assoc., , , –; Joseph Berkson, in interview,

from “Transcript of Edward R. Murrow’s First TV Show on ‘Cigarettes and LungCancer,’ ” May , Box , Folder , Hill papers.



Berkson, considered the dean of American medical statistics, wasskeptical of Hammond’s and Horn’s data that associated smokingwith such a wide variety of cancers and with heart disease. No onehad ever theorized that heart disease and cancer had the same etiol-ogy. It sounded preposterous to him.72 Herbert Arkin, Professor ofStatistics at City College of New York, argued that their data wasnot representative because it was not a random sample. Inexperi-enced enumerators were told to question friends and relatives withwhom they would be in contact for several years; their data couldnot then be said to be representative of the population at large.Kotin agreed, remembering in that some considered that theHammond/Horn sample was biased socioeconomically, geographi-cally, and because the data were collected by amateurs.73 Arkin’sanalysis of the death rates reported by Hammond and Horn showeddiscrepancies in comparison with government published death ratesfor the population and the age groups studied. Moreover, Arkinbelieved that Hammond and Horn had not exercised caution inorder to avoid respondent bias. Arkin believed the questionnaireasked leading questions and distorted the responses. He added thatHammond and Horn had not secured adequate information aboutthe respondents’ physical, social, or occupational characteristics. Thismay have occluded other possible associations indicating possiblecauses of lung cancer. Therefore, for Arkin, Hammond and Hornhad committed the “common statistical fallacy of ascribing cause andeffect relationship to an association.”74

Doll’s and Hill’s work was criticized by the eminent epidemiolo-gist Sir Ronald Fisher. A editorial in the British Medical Journalhad urged that it was time to accept that cigarette smoking was acause of lung cancer. Fisher raised four major objections to thisclaim in publications in , , and . First, it was logicallypossible that lung cancer could cause smoking; that smoking couldrelieve irritation in pre-cancerous or malignant mucosa. Second,there might be a factor that caused a person’s smoking habit and hislung cancer, perhaps genetic; for example, pairs of monozygoustwins displayed more similar smoking habits than dizygous pairs.

. Berkson, “Smoking and Lung Cancer: Some Observations on Two RecentReports,” pp. –.

. Interview with Paul Kotin, , Box , Folder , Kluger papers. . Arkin, “Relationship Between Human Smoking Habits and Death Rates,” pp. –.



Third, he thought Doll and Hill’s finding that smokers with lungcancer inhaled less than smokers without lung cancer argued againstcausation. Finally, he thought that the association between smokinghabits and the increase in lung cancer was suspect because in the pre-vious fifty years the increase in female smoking was great, while formen the increase was small; lung cancer had dramatically risen in men.75

Like their counterparts in Britain, some American scientists werecritical of the evidence linking smoking to lung cancer. WilhelmHueper, Chief of the Environmental Cancer Section, National CancerInstitute, questioned the evidence publicly in a national broadcast ofthe Edward R. Murrow show, See It Now, on May . “Themere fact that two phenomena run parallel is no proof that theyhave any cause-and-effect relationship.” According to Hueper therewere “certain definite defects and inconsistencies in the medicalevidence advanced in support of the cigarette theory.”76 Indeed, JohnR. Heller, Director of the National Cancer Institute, reported onthe second part of the show broadcast on June that “at theNational Cancer Institute . . . in this problem of the relationship ofthe possible causation of lung cancer by cigarette smoking, our sci-entists are pretty well divided.”77

Focusing on the epistemological question of causation, David D.Rustein, Harvard University Professor of Preventive Medicine,observed that “epidemiologically . . . the case is clear. There is a linkbetween smoking and lung cancer. Nevertheless, we do not knowthe cause of cancer of the lung anymore than Jenner knew the causeof smallpox.”78 Because of questions concerning the etiology of lungcancer, Surgeon General Leroy Burney, qualified his publicindictment of smoking, writing that “since carcinoma of the lung isa disease that also occurs in nonsmokers, it is evident that factorsother than tobacco contribute to its etiology.”79

. Doll, “Proof of Causality,” p. ; Stolley, “When Genius Errs: R. A. Fisher and theLung Cancer Controversy,” pp. –.

. W. C. Hueper, in interview, from “Transcript of Edward R. Murrow’s First TVShow on ‘Cigarettes and Lung Cancer,’ ” May , Box , Folder , Hill papers.

. John R. Heller, “Transcript of Edward R. Murrow’s Second TV Show on ‘Ciga-rettes and Lung Cancer,’ ” June , Box , Folder , Hill papers.

. Robert K. Plumb, “Panel Asks Study of Dirty City Air,” New York Times, May, L, p. .

. Burney, “Smoking and Lung Cancer,” pp. –.



In response to the technical question of whether the statistical evi-dence adduced thus far provided proof of a direct link between smok-ing and lung cancer, even Doll and Hill answered negatively in. They observed that “in scientific work it is never possible toexclude entirely an alternative explanation of the observations.”80

Nevertheless, they did believe that the accumulated evidence denoteda cause-and-effect relationship and that there was not another viablealternative theory.81

Part of the reason scientists were divided was that it seemed tosome that the cigarette theory was overly simplistic. They assumedthat, as with other cancers, the etiology of lung cancer was multi-factoral. Hueper articulated the potential complexity of the problem.In a article in Public Health Reports, he pointed out that knownenvironmental carcinogens—such as dusts and fumes of nickel, chro-mium compounds, arsenicals, asbestos, coal tar, soot vapors or mistsof isopropyl oil, certain petroleum derivates, and radioactive oresand gases—remained suspects in the lung cancer. Some of these car-cinogens were found in the exhaust of gasoline and diesel enginesand in asphalted roads. Hueper argued that industry-related factorshad played a significant causal role in the increase in lung cancer inthe twentieth century.

As evidence for this he discussed epidemiological data that sug-gested lung cancer was more common in urban areas than in ruralareas. Lung cancer rates among manufacturing, mining, and trans-portation workers were higher than the general population. Therewere remarkable variations in the male–female sex ratio of lungcancer cases in different places and in different demographic groups.The rise in the lung cancer death rate more closely paralleled the risein the production and consumption rates of motor fuel, coal tar,petroleum products, and several carcinogenic metals and mineralsthan that of cigarettes. In addition, he argued that experimental evi-dence had demonstrated that these industrial and environmentalagents were carcinogenic. There was no definitive proof (in )that a known carcinogen was in cigarette smoke in sufficient quanti-ties to cause lung cancer. For Hueper it was more logical to hypothe-size that numerous atmospheric pollutants were responsible for the

. Anon., “Lung Cancer and Tobacco: The B.M.J.’s Questions Answered by ProfessorA. Bradford Hill and R. Doll,” Brit. Med. J., May , , –, p. .

. Ibid., p. .



observed increase in lung cancer.82 The possible consequences of thehabit of cigarette smoking seemed to pale in comparison to the vastconsequences of the industrial revolution on the human environ-ment of the previous seventy-five years.

Kotin, as a professor of pathology who specialized in environ-mental cancer research, emphasized the possible role of atmosphericpollution as an etiological factor in lung cancer.83 Kotin pointed tostrong evidence that air pollution might play a role in lung cancer.Scientists had been successful at using extracts of atmospheric sootsand pollutant source materials to induce skin cancers in C mice, aspecies resistant to spontaneous tumors. Moreover, short chain ali-phatic compounds had been isolated from the atmosphere and beensuccessfully used to produce skin tumors in mice. This experimentalevidence was supported by epidemiological data. Lung cancer rateshad risen, adjusting for the latency period, as these industrial pollutantswere introduced into the environment on a large scale. And, theseobservations, according to Kotin, could explain why there were fewercases of lung cancer in rural areas compared to urban environments.The tumor-dose exposure of rural residents was considerably lowerthan that for urbanites.84 In the s Kotin was persuaded thatpulmonary cancer “in common with all neoplasms” was initiatedand promoted by various factors. He thought atmospheric pollutioncontributed the dominant etiologic agents in lung cancer, and headded that the excessive use of tobacco only played a secondary role,if any, in the production of lung cancer.85

Because of the complexity of the problem and because there wasserious scientific debate about the role of tobacco in lung cancer,even the august American Medical Association (AMA) took no offi-cial position on the smoking and health question until . In, Dr. Ian G. MacDonald, Chairman of the AMA’s subcommit-tee on cancer, testified before the House Government Operations

. W. C. Hueper, “Environmental Causes of Lung Cancer,” Pub. Health Rep., January, , –.

. From to he held various posts at the N.I.H., ending as Director of theNational Institute of Environmental Health Sciences.

. Paul Kotin and W. C. Hueper, “Relationship of Industrial Carcinogens to Cancer inthe General Population,” Pub. Health Rep., , , –.

. Paul Kotin, “The Role of Atmospheric Pollution in the Pathogenesis of PulmonaryCancer: A Review,” Cancer Res., , , –, pp. –. Kotin was persuaded bySmoking and Health () that smoking caused lung cancer. Interview with Paul Kotin,, Box , Folder , Kluger papers.



Subcommittee saying that smog, nutrition, and sex might be moreproductive of lung cancer than cigarettes. Moreover, he complainedthat “virtually the entire basis of which this belief rests [that smokingcauses lung cancer] is statistical.”86 Two weeks after Burney releasedhis statement about smoking and health in JAMA, the editorsdisputed his conclusions, writing:

A number of authorities who have examined the same evidence cited byDr. Burney do not agree with his conclusions. Although the studies reveala relationship between cigarette smoking and cancer that seems more thancoincidental, they do not explain why, even when smoking patterns arethe same, case rates are higher among men than among women and amongurban than among rural populations. Neither the proponents nor theopponents of the smoking theory have sufficient evidence to warrant theassumption of an all-or-none authoritative position.87

Burney was “shocked” by the JAMA editorial.88 By , onlythe Medical Societies of California, Florida, New York, Maine,Pennsylvania, and North Dakota had unambiguously declared thatsmoking was a health hazard, despite two statements by the SurgeonGeneral, and clear positions taken by the American Cancer Society,the National Tuberculosis Association [American Lung Association],the American Heart Association, and the American Public HealthAssociation. In a interview, Emerson Foote, former advertisingexecutive and President of the National Interagency Council onSmoking and Health, recalled the AMA’s reluctance to join theanti-cigarette crusade, commenting that the AMA “dragged its feetvery badly.”89

Even after the release of Smoking and Health (), an officialAMA publication continued to raise questions about the robustnessof the link between cigarette smoking and lung cancer. Today’sHealth, the AMA’s publication for lay audiences found in doctors’officers, raised a number of questions that its authors felt remainedunanswered about the health hazards of smoking. Why did some

. Don Shannon, “Smog May Produce More Cancer than Cigarettes, SC ProfessorSays,” LA Times, July , , .

. Editorial, J. Am. Med. Assoc., , , . . Interview of Leroy E. Burney, November , Box , Folder , Kluger

papers. . Interview with Emerson Foote, November , Box , Folder , Kluger

papers.



people tolerate tobacco smoke better than others? With regard tolung cancer, one article noted that “the chemical causes of % ofthe biological activity are still unknown.” Today’s Health reportedthat “scientists still do not know the precise manner in which thechemicals in tobacco smoke can start the growth of cancer cells, ifthis is actually what happens.”90 As late as , Today’s Health toldits readers that “a smoker’s own genetic makeup may help deter-mine how cigarette smoking affects his health. Preliminary interpre-tations of a recent study indicate that heredity may influence whethera smoker develops heart and respiratory disease symptoms.”91

ANIMAL STUDIES

The animal studies indicting cigarette smoking also received signi-ficant criticism. Detractors claimed that the studies often were notreplicable, had questionable applicability to humans, and that cofactorstended to confound the evidence. Beyond this there were problemswith the experimental methodology and results were equivocal,leading researchers to qualify their findings.

The key study was Graham, Wynder, and Croninger’s “Experi-mental Production of Carcinoma with Cigarette Tar” (). Forthe experiment, machines smoked cigarettes in order to extract tar.The smoke precipitate was dissolved in acetone. The solution wasthen painted on the skin of mice. Of those mice painted with thesolution, . percent developed skin cancer. There was no canceron the control sample. The team successfully transplanted thetumors to the skin of healthy mice. Their finding was that cigarettesmoking contains something that is carcinogenic to the skin of mice.92

Graham himself qualified the meaning of the study in a lecturedelivered to the American College of Chest Physicians in San Fran-cisco on June . He pointed out that the data from the miceskin painting study did not mirror epidemiological data. “In view ofthe much greater frequency of bronchiogenic carcinoma in thehuman male it was of special interest that among the tarred mice

. Kenneth N. Anderson, “Research Report: Tobacco and Health,” Today’s Health,November , , –, pp. –.

. American Medical Association, “Genes May Influence Smoking Health Hazards,”Today’s Health, January , , .

. Ernest L. Wynder, Evarts A. Graham, and Adele Croninger, “Experimental Produc-tion of Carcinoma with Cigarette Tar,” Cancer Research, , , –.



of the cancers appeared in females and only in males.” While hemaintained that their study proved beyond reasonable doubt thatcigarette smoked contained something carcinogenic to the skin ofmice, there was “no absolute proof . . . that there is any etiologic rela-tionship between cigaret [sic] smoking and cancer of the lung” inhumans.93

Harry S. Greene, Head of Pathology at Yale Medical School,questioned the results and importance of Graham and Wynder’smice skin painting studies. Greene reported that he had been unableto replicate the studies in his laboratory. Because of this, he alsoquestioned the validity of the retrospective and prospective epide-miological studies: “I do not attach any fundamental significance tothe statistics linking cigarette smoking to human lung cancer. In fact,any statistics that purport to show a cause-and-effect relationshipshould be taken with a grain of salt.”94

British scientist R. D. Passey, who was sympathetic to Wynderand Graham’s experimental mice studies, was unable, after twoyears of trying, to induce malignant tumors on the backs of micepainted with tar from English cigarettes.95 Passey had first visitedGraham and Croniger in November to consult with themon their methods. Passey speculated that his failure might be con-nected with the lower temperature at which his machine smokedcigarettes.96 A year later, Passey wrote Graham indicating that“Dr. Woodhouse of Birmingham” had also failed to inducetumors in mice.97 Graham speculated that Passey’s failure was theresult of not having clipped the hair on the back of the mice asGraham had done.98 Wynder responded by stating that the failure

. Evarts A. Graham, “Bronchiogenic Carcinoma, A Brief Discussion of the Etiology,”First Jacob J. Singer Lecture Delivered Under the Auspices of the American College ofChest Physicians, San Francisco, Calif., June , Box , Folder BronchiogenicCarcinoma, A Brief Discussion of the Etiology, Graham papers.

. Harry S. Greene, “Transcript of Edward R. Murrow’s Second TV Show on ‘Ciga-rettes and Lung Cancer,’ ” June , Box , Folder , Hill papers. Although Greenewas later hired by the tobacco industry, there is no evidence that at this time he was influ-enced by anything other than his scientific views.

. R. D. Passey to Evarts A. Graham, March , Box , Folder , Graham papers. . R. D. Passey to Evarts A. Graham, January , Box , Folder , Graham papers. . R. D. Passey to Evarts A. Graham, March , Box , Folder , Graham papers. . R. D. Passey to Evarts A. Graham, March , Box Folder, , Graham papers;

Evarts A. Graham to Ernest L. Wynder, November , Box , Folder , Grahampapers.



to replicate the results might be due to insufficient painting of themice with tar.99

R. D. Passey continued his mice skin painting experiments usingthe same white Swiss mice as Wynder and Graham. In contrast tohis previous studies on five different strains of laboratory mice wherehe had negative results, in he reported that he obtained twoepitheliomata and three papillomata from English tar and three epi-theliomata, one subcutaneous sarcoma, and six papillomata fromAmerican tar. Passey questioned his own findings though, noting:“It is difficult, however, to know how to interpret these results inthat the mice . . . in this laboratory suffered from frequent extensivespontaneous ulceration.” He concluded that the carcinogenic actionof cigarette tar on the skin of mice was a weak one.100

Wynder and Graham also had difficulty replicating their studies.Wynder wrote to Graham in June that “I now believe that thedifferences in results between the CAF, Swiss, and C mice is oneof strain differences. The short-term tests seem to indicate quitestrongly that the Swiss mouse, for instance, does not react so quicklyto the carcinogen as the CAF mouse. We are planning to run a fewadditional tests with a known potent carcinogen on these strains.”101

Four days later he wrote that it “seems to me that the differences intumor formation in the various strains we used are primarily a resultof strain differences.”102

By Graham had been painting the bronchus of severaldogs through a bronchial fistula created surgically. But he had notbeen able to produce a papilloma in any of the dogs. He specu-lated that it would take a few more years for this to happen.103

Passey had also conducted experiments in which he attempted toinduce lung cancer in animals exposed to various concentrationsof cigarette smoke. Over a five-year period he obtained negative

. Ernest L. Wynder to C. P. Rhoads, October , Box , Folder , Grahampapers; Ernest L. Wynder to Evarts A. Graham, September , Box , Folder ,Graham papers.

. R. D. Passey, “Carcinogenicity of Cigarette Tars,” British Empire Cancer Campaignth Annual Report Part II, p. .

. Ernest L. Wynder to Evarts A. Graham, June , Box , Folder ,Graham papers.

. Ernest L. Wynder to Evarts A. Graham, June , Box , Folder , Grahampapers.

. Evarts A. Graham to Richard Doll, December , Box , Folder ,Graham papers.



results on experiments with mice, rats, and hamsters. He also paintedthe trachea of hamsters with English tar, and he injected rats sub-cutaneously with English tar with negative results in both cases.104

This problem of genetic diversity as a confounding cofactor in thebiogenesis of tumors in mice was considered a serious one. J. R. Heller,Director National Cancer Institute, in a letter to SurgeonGeneral Scheele wrote that studies have demonstrated that a numberof genetic predispositions have been tied to cancers of the lung. Forinstance, Heller noted, “an extensive program in the genetics of therelation to various types of cancer includes a substantial amount ofwork being done on the pulmonary tumors that occur spontane-ously or are induced by a variety of chemical agents in mice.” Otherstudies indicated “that genetically controlled obesity increases therisk in mice of pulmonary tumors, which is in keeping with findingsof certain insurance companies that their policy holders who arethought to be overweight have a higher frequency of cancers ingeneral than do those of average or sub-average weight.” Moreover,Heller pointed out, “preliminary results suggest that the lung itself isthe most important site because lung tissue transplanted from strainssusceptible to action of carcinogenic agents retains its susceptibilityeven when it resides in tissues of mice that resist the carcinogenicaction.”105 All of these studies reinforced Heller’s concern that scien-tists had been unable to induce tumors in the lungs of animalsthrough exposure to tobacco smoke.106

Indeed, Wynder and Graham had their own concern, which theydid not share with others, that their use of degraded tar presented aproblem for interpreting their data. Wynder wrote to Graham inDecember :

I have just been talking with Miss Croninger and Miss Crow. They havebeen anxious to get all of the smoking of the cigars and cigarettes which

. R. D. Passey, E. Boyland, B. M. G. Pratt, and I. Hieger, “Cigarette Smoking andLung Cancer,” British Empire Cancer Campaign th Annual Report , pp. –; R. D. Passey,“Carcinogenicity of Cigarette Tars,” British Empire Cancer Campaign th Annual Report Part II, pp. –; and “Cigarette Smoke and Cancer of the Lung,” British Empire CancerCampaign th Annual Report , pp. –.

. J. R. Heller to Leonard Scheele, March , Folder Intramural Research --A,Cigarette Smoking/Tobacco, –, NIH, Office of the Director (OD) Central Files,Accession , Manuscripts Collection, National Library of Medicine, History of MedicineDivision, Bethesda, Md.

. Ibid.



we have on hand finished as soon as possible. I am very doubtful about thewisdom of that myself because it means that the tars which have beencollected will be stored away for many months and some even for as longas a year. Nobody has any idea what may happen to the tar under suchconditions. Although it is true that the bottles are well stoppered and keptin a refrigerator and that there is some acetone with the tar. There maynevertheless be some chemical changes which take place about which weknow nothing. For example, I told Miss Croninger that if I were the Presi-dent of a Tobacco Company and was aware of the fact that some of the tarwhich had been used in our experiments was somewhere from six monthsto a year old I would say ‘Well! The conditions of the experimentationwere nothing at all like actual smoking because, of course, the tar whichthe smoker receives in his lung is fresh.’ In other words there is a possibil-ity that a carcinogenic substance may form from changes which take placewith long standing, or, on the other hand it may be that we loose [sic]some of the carcinogenic factor by the long standing.107

Graham reported to Wynder that Dr. Wright had shown that“changes...occur when cigaret [sic] tar stands for a long time in acetonesolution. I think these considerations are quite important, and are,I believe, responsible for the lowered rate of tumor formation in oursecond experiment.”108 Wynder responded that “it would of coursebe impossible to do the experiment with only fresh tar.”109

Hueper, Chief of the Environmental Cancer Section, NCI, wasconvinced that no adequate animal model had been identified. “Themajority of investigators,” wrote Hueper, in fact, either did not pro-duce any cancers of the skin in mice or rabbits, or produced only afew. Only two investigators succeeded in producing cancers of theskin in an appreciable number of animals.” For Hueper this meantthat “the evidence produced by animals can only be taken with verygreat reservations . . .mice are not men,” Hueper insisted, “and adirect application of any experimental animal to the human problemis not permissible.110

. Evarts A. Graham to Earnest L. Wynder, December , Box , Folder ,Graham papers.

. Evarts A. Graham to Ernest L. Wynder, December , Box , Folder ,Graham papers.

. Ernest L. Wynder to Evarts A. Graham, December , Box , Folder ,Graham papers.

. W. C. Hueper, “Transcript of Edward R. Murrow’s First TV Show on ‘Cigarettesand Lung Cancer,’ ” May , Box , Folder , Hill papers.



Harold Stewart, Chief of the Laboratory of Pathology at NationalCancer Institute, remained agnostic. In he wrote that “my atti-tude toward the question of cigarette smoking and lung cancer isjust where it has been for some years. I haven’t seen any new datathat has swayed me one way or the other.”111 Particularly troublingfor Stewart was the lack of an adequate animal model.112 He wrotethat “cancer of the lung has not been induced in experimental ani-mals exposed to the inhalation of cigarette smoke.” Nor had it beeninduced by the instillation of tobacco condensates into the tracheo-bronchial tree.113 As late as Gio Gori, Director of the Smokingand Health Program at National Cancer Institute, wrote that there isan “uncertain relationship of mouse skin painting to human lungcancer.”114

PATHOLOGICAL EVIDENCE

Pathological studies linking lung cancer with smoking were criticizedbecause of the uncertainty in distinguishing the types of carcinomafound in diagnosed patients. In a paper presented at the NationalCancer Conference in Memphis in February , Wynder andGraham reported the most prevalent type of lung cancer they hadfound in their retrospective study was of the epidermoid or squa-mous type and its variant, the undifferentiated carcinoma. Never-theless, they reported difficulties “in the histological classificationbecause of the variation in terms employed by the pathologists in thedifferent hospitals who examined the specimens.” Thus, they notedthat “what some pathologists would classify as an adenocarcinomaothers would classify as an undifferentiated carcinoma.” Moreover,they found that “in some cases the terms ‘oat cell’ and ‘round cell’

. Harold L. Stewart to Joseph Berkson, September , Box , Folder Berkson, J.–, Stewart papers.

. Ibid. Joseph Berkson, “Comments on Manuscript by Harold Stewart & C. Herrold,”, Box , Folder Berkson, J. –, Stewart papers.

. Harold L. Stewart and Katherine M. Herrold, “A Critique of Experiments onAttempts to Induce Cancer with Tobacco Derivatives,” Box , Folder “A Critique ofExperiments on Attempts to Induce Cancer with Tobacco Derivatives,” unpublishedmanuscript, Stewart papers.

. Gio B. Gori, “Foreword,” in Toward Less Hazardous Cigarettes: The Second Set ofExperimental Cigarettes, ed. Gio Gori (Washington, D.C.: HEW, ), p. iii, and “Fore-word,” in Toward Less Hazardous Cigarettes: The Third Set of Experimental Cigarettes, ed. GioGori (Washington, D.C.: HEW, ), p. v.



carcinoma were used, designations which are not recognized bysome pathologists.”115

Graham was pessimistic that a universal system of classificationcould be accepted by pathologists. One problem was the practice ofclassifying tumors by their morphological characteristics without ref-erence to their cause. According to Graham current practices were“about as far behind in our concepts of the classification of cancer asour ancestors were years ago in their concepts of the fevers.”116

The diversity of nomenclature posed a barrier to understandingthe factors that gave rise to particular cancers, according to R. A. Willis.The intellectual categories of bronchial carcinoma, adenocarcinoma,squamous-cell carcinoma, and oat cell carcinoma, Willis explained,did not refer to distinct entities. Moreover, a distinct pleomorphismwas possible in one tumor. In a study that Willis had conducted atthe Alfred Hospital, Melbourne, Australia, he found that one quarterof the tumors displayed a heterogeneous structure. Complicating thematter, the assignation of a tumor to a subdivision by pathologistsremained an interpretive exercise with somewhat arbitrary results asevidenced by conflicting reports. “Worse still, the compulsion to placea tumour of heterogeneous structure in one or another category meansthat the same pathologist will classify the same tumour differentlyaccording to the piece he chances to examine.”117

Similar concerns led Harold Stewart to question the significanceof pathology reports claiming pre-cancerous growths were predic-tive of lung cancer, and whether or not certain growths were evencancerous. “In my opinion,” wrote Stewart, “the word cancer in situis used too indiscriminately. From my limited knowledge of thework of Dr. Auerbach, I am not convinced that these lesionsprogress to cancer. It is unfortunate that the term cancer in situ withthe implication that it progresses to cancer was ever coined.”118 In aletter to Berkson in , Stewart asked, “Have you seen the papers

. Ernest L. Wynder and Evarts A. Graham, “Some Possible Etiological Factors ofBronchiogenic Carcinoma,” unpublished paper presented at National Cancer Conference,Memphis, Tenn., February , Box , Folder , Graham papers.

. Evarts A. Graham to Ernest L. Wynder, August , Box , Folder , Gra-ham papers.

. Willis, “The Incidence and Histological Types of Pulmonary Carcinoma, withComments on Some Fallacies and Uncertainties,” p. .

. Harold L. Stewart to Joseph Berkson, March , Box , Folder Berkson, J.–, Stewart papers.



by Rock, one in Cancer and the other in the AMA, both on thesame subject ‘Tobacco tar painting of the bronchus of dogs.’ Didyou read the information about the dog that he claims he inducedbronchial cancer in? If that’s a cancer, that’s about the fastest cancerthat ever developed.”119

BIOCHEMICAL EVIDENCE

Another set of objections in the early and middle s had to dowith the lack of biochemical evidence of the carcinogenicity oftobacco smoke. In D. V. Lefemine claimed to have identified acancer-producing chemical, benzpyrene, in cigarette paper smoke.He cited other studies claiming benzpyrene produced cancer in ani-mals. Lefemine admitted he had no evidence linking benzpyrene tohuman cancer. With regard to this, Wynder privately wrote Grahamthat “our preliminary data . . . indicate that there are minimal amountsof benzpyrene in tobacco smoke. . . . I am very doubtful that thisamount of benzpyrene will affect human tumor developmentbecause in this concentration it would not even cause skin tumors inmice”120 Graham agreed that the concentrations of benzpyrene incigarette smoke were probably too small to be significant.121

Benjamin Van Duuren who, as we discussed earlier, had demon-strated the presence of carcinogenic polynuclear aromatic hydrocar-bons in cigarette smoke, wrote that “the carcinogenic hydrocarbonsfound so far do not by themselves appear to be present in sufficientconcentrations to account for the observed activity.”122 Even in the Advisory Committee to the Surgeon General admitted thisconundrum writing:

Assays of tobacco smoke tars for carcinogenicity are done by applying adilute solution of tar in an organic solvent with a camel’s hair brush to thebacks of mice beginning when the animals are about six weeks old. Appli-cation is repeated three times a week for a period of a year or more. Theresults of a number of such assays present a puzzling anomaly: the total tar

. Harold L. Stewart to Joseph Berkson, January , Box , Folder Berkson, J.–, Stewart papers.

. Ernest L. Wynder to Evarts A. Graham, December , Box , Folder ,Graham papers.

. Evarts A. Graham to Ernest L. Wynder, December , Box , Folder ,Graham papers.

. Van Duuren, “The Polynuclear Aromatic Hydrocarbons in Cigarette-SmokeCondensate,” p. .



from cigarettes has about times the carcinogenic potency of thebenzo(a)pyrene present in the tar. The other carcinogens known to bepresent in tobacco smoke are, with the exception of dibenzo(a,i)pyrene,much less potent than benzo(a)pyrene and they are present in smalleramounts. Apparently, therefore, the whole is greater than the sum of theknown parts . . .One possible or partial explanation of the discrepancy isthat the tar contains compounds which, although not themselves carcino-genic, can enhance the cancer-producing properties of the carcinogens.123

The committee concluded that “assessment of all conceivable synergisticeffects presents a gigantic problem for exploration” (see Table ).124

J. R. Heller (Director NCI) linked the problem of weakconcentrations of known carcinogens in tobacco smoke with theproblem of creating an adequate animal model. He cited “an ear-lier study in which mice were exposed to atmospheres heavilycontaminated with tobacco smoke failed to reveal any evidence ofcarcinogenicity of the smoke under the particular experimentalconditions which really reproduced the smoke-filled room moreclosely than actual smoking.” Although Heller believed that “studieswith intratracheal administration” should be continued, “it mustbe readily apparent that we are up against a serious problem inmethodology.”125

. Smoking and Health, pp. –. . Ibid., p. . . Heller to Scheele, March .

TABLE

Polycyclic Hydrocarbons Isolated from Tobacco Smoke

Note: µg per g of tobacco consumed.Source: Smoking and Health: Report of the Advisory Committee to the Surgeon General of the

Public Health Service (Washington, D.C.: Dept. of Health, Education, and Welfare, ),chapter , p. , Table .

Hydrocarbon Cigarettes Cigars Pipes

Benzo[a]pyrene

Acenaphthylene

Anthracene ,

Pyrene



THE BIOMEDICAL CONTEXT

Aside from the merit the specific issues raised about the linksbetween smoking and lung cancer, similar scientific controversieswere normative during the s and s.126 They reflected thereluctance of the biomedical community to rely on statistics to iden-tify disease causation in general. Instead, they relied on the episte-mology provided by Koch’s postulates.

Clinical researchers rarely used statistical analyses in the s, andwhen they did so it was, according to Harry Marks, often in “a ritu-alistic and uncomprehending way.”127 After the Second World Warclinical research was characterized by individual inspiration, individ-ual control, and individual evaluation. Statistical studies, whichreported on population health, seemed to ignore the uniqueness ofeach patient and the advantage that intimate knowledge of a patient’smedical history conferred on the clinician. As Marks notes, therewas a widely held belief in the medical establishment that the clini-cian was in the best position to decide the efficacy of a treatmentbased on a practitioner’s scientific knowledge and experience with apatient.128 This led, writes David Rothman, to a “confusion ofexperimentation with therapy.”129

The idea that clinical trials should be separated from standardtherapy awaited the emergence of the standardization of the ran-domized clinical trial in the s. This innovation was one of studydesign, which included more sophisticated statistical analyses. Therewere no regulations requiring that drugs be proven efficacious inorder to be marketed until . Not until did the F.D.A.implement regulations based on the new law.130 The medical mentalitéwas different in the s; “few would have imagined,” then, writesMarks, “the central place statistics now holds in medicine.”131

. Marks, The Progress of Experiment, pp. –. “By the middle of the decade, debatesamong the scientific authorities were hot news. Exchanges of opinion took place as oftenin the pages of Time and Newsweek as in the abstruse abstracts reported in Circulation,”ibid., p. .

. Ibid., p. . . Marks, The Progress of Experiment, pp. –, , , , . . David J. Rothman, Strangers at the Bedside: A History of How Law and Bioethics Trans-

formed Medical Decision Making (New York: Basic Books, ), p. . . John P. Swann, “FDA and the Practice of Pharmacy: Prescription Drug Regulation

before the Durham-Humphrey Amendment of ,” Pharm. Hist., , , –;Marks, The Progress of Experiment, p. .

. Marks, The Progress of Experiment, p. .



Orthodox scientific medical research took place in the laboratoryin the s and the cancer research establishment was the perhapsthe most powerful laboratory-based biomedical research communityin the United States.132 Between and the NCI was thelargest and most powerful component of the NIH, distributing $million to extramural researchers.133 The dominant emphases in can-cer research focused on cellular processes, changes, and imperfec-tions that might lead to cancer. Environmental factors might beimportant in triggering malignant cellular changes, but these wereconsidered of secondary importance to fundamental patho-physiology.Leading cancer researchers were persuaded that individual suscepti-bility was the root cause of cancer. Thus, laboratory research intocellular behavior was accorded much more prestige and money thancancer control efforts or environmental investigations.134 Moreover,leading scientists considered environmental theories of cancer gene-sis to be merely conjectural because they were based mainly on ani-mal evidence. It was unclear whether humans reacted in the sameway to carcinogens as dogs or mice. In addition, cancer tended tomanifest in older people, after long latency periods, therefore, mostresearchers assumed that cancers were a combination of host factors(genetics) and environmental exposures. But because many peopleexposed to the same environmental exposures did not develop can-cer, the researchers believed the most important question was thenature of individual susceptibility. James Patterson has written thatcancer researchers “continued to believe that cancer stemmedmainly from inherent imperfections of cells. It followed that labora-tory research into cellular behavior, not strategies of prevention andcontrol, must be the front line of defense against the disease.”135

Because of the complexity of the patho-physiology and etiology ofcancer, most cancer researchers believed that laboratory researchoffered the most promising method to unravel these mysteries.136

The cancer research establishment was a vast enterprise comparedto chronic disease epidemiology, which Marks characterized as a“novel and fragile science” in the s. Mervyn Susser has found

. Patterson, Dread Disease, pp. –. . Ibid., pp. –. . Ibid., p. . . Ibid. . Ibid., p. .



that contemporary discoveries like the role of rubella in congenitalanomalies, of smoking in lung cancer, and sex hormones in breastcancer “arise from and are encompassed by a theoretic viewpointsharply different” from the views held in early years of the twentiethcentury.137 As Susser reminds us, after the decline in infectious dis-eases brought about by wide use of antibiotics in the two decadesfollowing the Second World War, epidemiology struggled to rees-tablish itself as a respected, needed, and independent discipline. Inthe process it created new methods and techniques that enabled it toshift from reporting and prediction of acute outbreaks to the studyof chronic conditions. The institutionalization of this new chronicepidemiological “paradigm,” as Susser labels it, was made possible bythe unprecedented increase in funding of epidemiological projectsand by the growth of the Centers for Disease Control. The intellec-tual force of the new paradigm was established by the success of twoareas: the smoking and lung cancer studies and the Framinghamcohort study of heart disease.138

Ultimately the Framingham study’s concern with multiple riskfactors became one of the main “intellectual levers” for advances inideas about risk factors in general.139 In our view, the lung cancerstudies were even more important because they came to strongerconclusions earlier, generated more public controversy, required, inthe case of the United States, federal intervention, and directly led tothe general acceptance of medicine as a whole of a new epistemol-ogy of causation. In contemporary epidemiology, writes Susser, the“search for causes is now the nub of the discipline.”140 Prior to thelung cancer and smoking controversy of the s, epidemiology

. Susser, “Epidemiology in the United States after World War II,” p. . . Ibid., p. . The Framingham study on cardiovascular disease, begun in , was

controversial. Research had produced a consensus among pathologists that atherosclerosiswas a disease and not an inevitable consequence of aging. Citing evidence of high choles-terol levels in heart attack patients, a number of researchers had concluded that a low-calorieand/or low fat diet might ameliorate atherosclerosis. This research was widely criticized asscientifically suspect because critics argued that mortality statistics from foreign sourcescould not be trusted. These critics derided data derived from questionnaires. They con-tested data on fat consumption, citing other laboratory and clinical studies that indicateddietary fat was only one of many possible cofactors in the pathogenesis of atherosclerosis(Marks, The Progress of Experiment, pp. –).

. Susser, “Epidemiology in the United States after World War II,” pp. , . . He goes on, “it is precisely the manifest weaknesses of the survey method in causal

research that engendered much of the thinking and methods today found in the kit of theepidemiologist” (Susser, “Epidemiology in the United States after World War II,” p. ).



largely relied on the descriptive cross-sectional field survey that didnot try to answer causal questions. After the lung cancer studies,epidemiology emphasized studies designed to answer questions ofcausation in an ecology of diseases dominated by chronic conditionswith often unknown or multiple environmental causes. It’s not thatcontemporary epidemiology became only chronic disease epidemi-ology, but that the discipline became more powerful with advancesin study design that allowed it to tackle causal questions. These wereprompted by the problems that arose with chronic diseases and theinadequacy of the cross-sectional survey to handle those puzzles. Asit turns out, lung cancer became a synecdoche for the larger, andthen new, landscape of diseases dominated by chronic maladies andthe problems they presented.

THE PUBLIC RELATIONS CONTROVERSY

The scientific controversy spilled, or perhaps washed like a tidalwave, into the public arena. The tobacco industry and the publichealth community, led by the ACS, fought an increasingly bitterbattle for the hearts, minds, and lungs of the American people. Thepublicity surrounding the studies linking smoking to lung cancerhad, by , led to a health scare about the hazards of smoking.Public reaction resulted in a percent decline in cigarette sales in and a percent decline the following year. In an attempt tocounter this trend, the tobacco industry hired the public relationsfirm of Hill and Knowlton.141 Hill and Knowlton recommendedthe formation of a Tobacco Industry Research Committee (TIRC),which would present a unified response in the media to publichealth claims about the risks associated with smoking. The TIRCwould also fund studies through its Scientific Advisory Board thatcould cast doubt on public health studies and challenge the emerg-ing public health consensus about the hazards of cigarette smoking.The true purpose of the TIRC, according to Glantz and colleagues(), was to serve as an elaborate public relations effort, not anobjective scientific enterprise. Renamed the Council on Tobacco

. Kluger, Ashes to Ashes, pp. –; “Cigarette Sales Fell percent in ,” NewYork Times, March , p. ; Miller, Smoking Up a Storm; “Surveillance for SelectedTobacco-Use Behaviors—United States –,” MMWR, November , (SS-), ; and Alexander R. Hammer, “Cigarette Sales Stage Comeback,” New YorkTimes, October , III, p. .



Research in , the TIRC also generated research that could beused by lawyers to defend the tobacco industry in court.142

In its first public effort, the TIRC released its now infamous“Frank Statement to Cigarette Smokers” on January . Pub-lished in newspapers across the country, the Frank Statementportrayed the health of its customers as the industry’s paramountconcern. The Statement attacked the claim that cigarette smokingcaused lung cancer, pointing out that many causes of lung cancerhad been posited, that there was no consensus among scientists, andno “proof” that smoking was the cause of lung cancer. “Statisticspurporting to link cigarette smoking with the disease,” the statementclaimed, “could apply with equal force to any one of many otheraspects of modern life. Indeed the validity of the statistics themselvesis questioned by numerous scientists.”

In early , the TIRC had discussions with Harold Stewart,Chief of Pathology at the NCI, about becoming the director of theTIRC’s scientific advisory board.143 Stewart declined, and the TIRCaccepted the fourth candidate, Clarence Cook Little, a respectedgeneticist and former executive director of the ACS. In one of itsfirst substantive tasks, in early , the TIRC scoured the medicalliterature for articles and public statements by scientists that could beused to cast doubt on the suggested link between smoking and can-cer. In April , the TIRC published A Scientific Perspective on theCigarette Controversy.144 They printed , copies, which theysent to , doctors, general practitioners, specialists, and thedeans of medical and dental colleges. They also sent the booklet andpress release to , journalists, including editors of daily andweekly newspapers, consumer magazines, veterans magazines, medi-cal and dental journals, news syndicate managers, business editors,editorial writers, science writers, radio and television commentators,news columnists and members of Congress. Through their massiveadvertising budgets and the diligence of the TIRC and, after the Tobacco Institute, the industry was successful in publicizingtheir point of view. They acknowledged that there appeared to be a

. Glantz, Slade, Bero, Hanauer, and Barnes, The Cigarette Papers, pp. –; Kluger,Ashes to Ashes, pp. –.

. A. Grant Clarke and Irwin Tucker to Paul Hahn, January , Box , Folder ,Hill papers; Letter to Timothy V. Hartnett, February , Box , Folder , Hill papers.

. This book was mainly a collection of quotes and citations that could be used torefute the studies condemning smoking.



statistical association identified in the smoking and health studies,but they claimed that this did not prove a relationship of causation.145

On the other side, the ACS carried out a concerted public healtheducation effort warning of the risks of smoking. Beginning in through the ACS relied on regular media channels to warnAmericans about the risks of smoking.146 Beginning in theACS began issuing and distributing pamphlets pointing out the risksof smoking. Where We Stand Today on Cigarettes and Lung Cancer() was the first of a series of pamphlets on the association ofsmoking with lung cancer. The next edition of the pamphlet, ToSmoke or Not to Smoke, was prepared in . By the end of ,. million copies had been distributed. To Smoke or Not to Smokewas the most widely requested ACS education pamphlet ever up tothat time.

In late , ACS initiated a national activist campaign to per-suade teenagers not to begin smoking.147 Even though it wasdirected mainly at students, the ACS expected that the educationcampaign would reach a large number of adults.148 By , theACS had distributed about , copies of its filmstrip kit, To Smokeor Not to Smoke? to , secondary schools in the United States,representing about one-half of all U.S. secondary schools.149 By the ACS had distributed over . million copies of the pamphletassociated with the filmstrip To Smoke or Not to Smoke?150 By ,the ACS had distributed seventeen million copies of two of its anti-smoking pamphlets and , copies of the filmstrip To Smoke orNot to Smoke? to schools across America.151 Over ten million copiesof the new ACS pamphlet, Shall I Smoke? were distributed by .152

. Hill and Knowlten, Inc. to Tobacco Industry Research Committee, May ,Box , Folder , TIRC-Scientific Advisory Board, Hill papers.

. Irving I. Rimer, “Panel: The Role of Broadcasting,” in The Second World Conferenceon Smoking and Health, ed. Robert C. Richardson (London: Health Education Council,), pp. –.

. ACS conducted a high school education pilot study in Portland, Oregon, in .American Cancer Society Annual Report. American Cancer Society, California Divi-sion, “Teen-Agers Get Smoking Facts in School,” The ACS Volunteer: the Bulletin of theAmerican Cancer Society, California Division, October , , ; “Cancer Group Sets Anti-Smoking Drive,” New York Times, June , p. ; Ross, Crusade.

. ACS, Annual Report. . ACS, Annual Report. . American Cancer Society, “Cigarette Smoking and Cancer,” , –, p. . . ACS, Annual Report. . ACS Cancer News, Fall , , .



A few state health departments joined in the effort. For example,in the New York State Department of Health (NYSDH)implemented an effort targeting health workers and citizens.153 By, the NYSDH distributed , copies of its pamphlet Memo toAdults About Cigarette Smoking.154 A pamphlet, Smoking-It’s Upto You, had a circulation of , copies.155

In terms of scientific research, the ACS spent $ million between to on basic lung cancer research; during the same periodthe TIRC, through its scientific advisory board, spent $. millionon basic scientific research related to lung cancer and smoking.156 Interms of the public relations campaign battle, the ACS always char-acterized it as a David and Goliath struggle because of the tobaccoindustry’s massive advertising budgets. What effect did the ACS’scampaign and the tobacco industry’s counterattacks have on theAmerican people? A January Gallup Survey found that only percent of Americans believed smoking caused lung cancer. Afterthe Hammond/Horn report was released in June , a Gallup pollfound that percent believed smoking caused cancer.157 By ,the last year Gallup took a poll before Smoking and Health, only percent of Americans accepted the link between smoking and lungcancer. Thus, the effect of the public health education campaign wasto persuade about half of Americans that smoking caused lung can-cer. Other data indicating the impact of the public health educationeffort comes from consumption patterns. The per capita consumptionof cigarettes was , in , the highest point in American history.158

. New York State Department of Health, “Cigarette Smoking-Lung Cancer BookletPublished by Department,” Weekly Bulletin, November , , ; New York StateDepartment of Health, Annual Report New York’s Health; New York State Departmentof Health, Annual Report New York’s Health; New York State Department of Health,“Long Time Studies Confirm Lung Cancer-Cigarette Tie,” Weekly Bulletin, January, , –.

. New York State Department of Health, New York’s Health Annual Report. . New York State Department of Health, New York’s Health Annual Report. . American Cancer Society, Answering the Most Often-Asked Questions about Cigarette

Smoking and Lung Cancer (New York: American Cancer Society, ). . American Lung Association, Epidemiology and Statistics Unit, “Trends in Tobacco

Use,” February , http://www.lungusa.org/data/smoke/smoke.pdf; “CigaretteSmoking in the United States, ,” MMWR, September , , –.

. American Lung Association, Epidemiology and Statistics Unit, “Trends in TobaccoUse.” In , Gallup took two additional polls. During the June/July poll, % believedsmoking caused cancer, while % believed this to be the case in the November/Decemberpoll. The poll revealed that only % of Americans believed smoking caused cancer.



By smoking prevalence rates had not been reduced and, in fact,would continue to rise until .159

By bringing together the evidence that had been accumulatingsince and by legitimating the epistemology of chronic diseaseepidemiology, Smoking and Health () ended the scientific con-troversy over the connection between smoking and lung cancer.A paradigmatic shift had to occur so the evidence could be given apersuasive, consensual meaning. After , only the tobacco indus-try continued to insist that scientists disagreed. To keep this “debate”alive, the industry recruited and subsidized those few scientists whostill harbored doubts and widely disseminated their claims. If thelegitimate scientific debate was over, the war between the publichealth community and the tobacco industry had just begun, and inthis arena, a specious controversy would continue for decades.

CONCLUSION

There is nothing unique or surprising that a number of reputablescientists resisted and interrogated the methods and conclusions ofthose who linked lung cancer to smoking in the s. Scientists aretaught to be skeptical about bold new claims, especially when theyare made by relying on novel methodologies. Historian Allan Brandthas argued that one of the functions of Smoking and Health was tosettle the epistemological questions raised by the smoking and healthstudies. The committee conducted no new research but reviewed andanalyzed previous studies. The main task of the committee was to cre-ate new meaning, not new data. They explicitly weighed in on thestatistical questions, among others, laid out the objections to the data,and answered those objections in detail.160 The main purpose of thecommittee was to adjudicate the scientific controversy. In their words:

Following the publication of several notable retrospective studies in theyears –, the medical evidence tending to link cigarette smokingto cancer of the lung received particularly widespread attention. At thistime, also, the critical counterattack upon retrospective studies and upon

. American Lung Association, Epidemiology and Statistics Unit, “Trends in TobaccoUse”; “Cigarette Smoking in the United States, .”

. Smoking and Health, pp. –; Brandt, “The Cigarette, Risk, and AmericanCulture.” The parallel British report, Smoking and Health: Summary and Report of the RoyalCollege of Physicians of London on Smoking in Relation to Cancer of the Lung (New York,Toronto, London: Pitman Publishing Company, ), also specifically dealt with the scien-tific controversy. The American report was more comprehensive, detailed, and theoretical.



conclusions drawn from them was launched by unconvinced individualsand groups. The same types of criticism and skepticism have been, and are,marshaled against the methods, findings, and conclusions of the later pro-spective studies.161

Lester Breslow (UCLA epidemiologist, former Director of CaliforniaState Department of Public Health, and a key figure in cancer con-trol efforts), remembered in a interview that in Smoking andHealth () “by far the most important thing was the presentationof criteria for causality in the association of smoking and health.”162

The authors of Smoking and Health () argued that because it wasnot practical to conduct experiments on humans to test the causalnature of the relationship between cigarette smoking and lung can-cer, “the judgment of causality must be made on other grounds.”163

The committees decided:

To judge or evaluate the causal significance of the association between cig-arette smoking and lung cancer a number of criteria must be utilized, noone of which by itself is pathognomonic or a sine qua non for judgment.These criteria include: (a) The consistency of the association (b) The strengthof the association (c) The specificity of the association (d) The temporalrelationship of the association (e) The coherence of the association.164

Further articulating the principles created in Smoking and Health(), Hill wrote that for causality to be established based onobserved associations, specific criteria or tests of the data must beemployed: strength of the association; consistency of the observationin different persons, places, circumstances, and times; dose-responserelationship or biological gradient; the temporal relationship of theassociation must make sense; biological plausibility; specificity ofthe association; coherence of evidence in that the cause-and-effectrelationship does not conflict with the generally known facts ofthe natural history and biology of the disease; experimental orsemi-experimental evidence bolsters the causal claim; and analogywith other diseases.165

. Smoking and Health, p. . . Interview with Lester Breslow, June , Box , Folder , Richard Kluger

papers. . Smoking and Health, p. . . Ibid., p. . . Austin Bradford Hill, “The Environment and Disease: Association or Causation?” Pro-

ceedings of the Royal Society of Medicine, May , , –; Doll, “Proof of Causality,” p. .



The scientific controversy ultimately stimulated the advisorycommittee to the Surgeon General and Hill to grapple in elaboratedetail with the contested evidence.166 In doing so, they created anew way to think about causality in medicine. After thetobacco industry tried to keep this controversy alive, basically con-tinuing the effort they had begun in with the TIRC. Becauseof this, many writers now assume that the original controversyamong scientists was fabricated. However, prior to , the scien-tific controversy was reasonable and perhaps necessary to advancethe science of chronic disease epidemiology.

. Brandt, “The Cigarette, Risk, and American Culture.”


Documents

Lung Cancer, Chronic Disease Epidemiology, and Medicine ...Lung Cancer, Chronic Disease Epidemiology, and Medicine, 1948–1964 Talley, Colin Lee, 1963-Kushner, Howard I. Sterk, Claire