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to lung cancer in the mouse. Nature Genet. 14, 465–467(1996).

57. Wright, S. Genic and organismic selection. Evolution 34,825–843 (1980).

58. Kinzler, K. W. & Vogelstein, B. Gatekeepers andcaretakers. Nature 386, 761–763 (1997).

59. Albertson, D. G. et al. Quantitative mapping of ampliconstructure by array CGH identifies CYP24 as a candidateoncogene. Nature Genet. 25, 144–146 (2001).

60. Perou, C. M. et al. Molecular portraits of human breasttumours. Nature 406, 747–752 (2000).

61. Haab, B. B., Dunham, M. J. & Brown, P. O. Proteinmicroarrays for highly parallel detection and quantitationof specific proteins and antibodies in complex solutions.Genome Biol. 2, 1–13 (2001).

62. Gibbs, W. W. Cybernetic cells. Sci. Am. 285, 52–57 (2001).

AcknowledgementsWork in the author’s laboratory has been supported mainly by theCancer Research Campaign (UK) and by the National CancerInstitute (USA). I am grateful to colleagues and the anonymousreviewers for useful comments on the manuscript.

Online links

DATABASESThe following terms in this article are linked online to:CancerNet: http://cancernet.nci.nih.gov/index.html chronic myeloid leukaemiaLocusLink: www.ncbi.nlm.nih.gov/LocusLink/APC | BRCA1 | BRCA2 | HRAS | TP53 | Trp53 | RBOMIM: www.ncbi nlm.nih.gov/Omim/adenomatous polyposis coli | hereditary non-polyposiscolorectal cancer | xeroderma pigmentosum

FURTHER INFORMATION Boveri information web sites: www.biozentrum.uni-wuerzburg.de/about/boveri.html;http://zygote.swarthmore.edu/fert6b.htmlComputer models of cellular signalling:www.cellularsignaling.orgHuman Genome Sequence: http://www.ncbi.nlm.nih.gov/Mendel’s Genetics:http://anthro.palomar.edu/mendel/mendel_1.htmMendelWeb: www.netspace.org/MendelWeb/

Tobacco and the global lung cancer epidemicRobert N. Proctor

T I M E L I N E

Tobacco is the world’s single mostavoidable cause of death. The World HealthOrganization has calculated that the 5.6trillion cigarettes smoked per year at theclose of the twentieth century will causenearly 10 million fatalities per year by 2030.Lung cancer is the most common tobacco-related cause of cancer mortality, with onecase being produced for every 3 millioncigarettes smoked. How was the globallung cancer epidemic recognized, and whatcan we expect in the future?

The tobacco plant is native to the Americas;archaeological evidence indicates that Mayanswere smoking the leaf as early as the first cen-tury BC (FIG. 1). Columbus discovered theArawaks using dried tobacco leaves in severalcurious rituals, and was offered the plant as agift. Several of his men took up smoking, andthe habit was soon exported to Europe andthe rest of the world. Tobacco was used spo-radically throughout the seventeenth andeighteenth centuries, although objectionswere sufficiently strong in many places tohave bans enacted. A Chinese imperial edictof 1612 barred growing or smoking the leaf,and the city of Berlin banned smoking in17231. Smoking was illegal in 14 Americanstates as late as 1921, although none of thesebans would survive the decade.

Tobacco has been used in many differentforms. Native Americans ‘drank’ the smoke in

hand-rolled palm or maize leaves, whereasEuropean sailors tended to prefer chewing toavoid the hazards of fire. Cigarettes were notpopular until the nineteenth century; theFrench Revolution gave snuff an aristocraticodour and cleared a path for ‘little cigars’2.Health effects were limited in these early years,however, as the methods most commonlyused to cure the leaf made the smoke too

harsh to inhale. Cigarettes were also time-con-suming to manufacture: the women and girlswho hand-rolled cigarettes in the mid 1800scould usually roll only about 200 per day.

Cigarette production was given an enor-mous boost in 1880 with the invention of theBonsack cigarette-rolling machine (FIG. 2),which could churn out more than 100,000cigarettes per day. W. Duke, Sons andCompany of Durham, North Carolina,installed two such machines in 1884, allowingthem to produce an unprecedented 744 mil-lion cigarettes in a single year. When com-bined with mass marketing and the inventionof safety matches (in 1855), cigarettes quicklybecame a popular consumer item. Americanssmoked only about eight cigarettes per personper year in the 1880s; by the end of the century,this figure would more than quadruple.Cigarettes were included with the rations ofsoldiers in the First World War, and many ofthe young men who entered the war asabstainers returned home as addicts.Consumption was further increased by newmethods of advertising and governmentencouragement, following the recognitionthat tobacco could supply an impressivestreak of tax revenues. Tobacco taxes in theUnited States, for example, went from about$13 million in 1910 to nearly $5 billion (109)some 60 years later. Tobacco provided 8% ofGermany’s entire national tax income in the1930s , and China today earns an even higherpercentage (~ 10%). Dependence on tax rev-enues is one of the main reasons why govern-ments have been reluctant to challenge thetobacco juggernaut. One tobacco company

Figure 1 | The oldest existing illustration of a smoker — a Mayan god. (Image courtesy of ImperialTobacco.)

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caused by pathogenic microbes also fos-tered the impression that cancer, too, mightbe caused (exclusively) by some kind ofinfectious agent. The bacteriological revo-lution made it easier to diagnose lung can-cer, but it also diverted attention from whatwould turn out to be its primary cause.

In the second decade of the twentiethcentury, physicians began to notice anincreased incidence of the disease. IsaacAdler in 1912 noted that although lungmalignancies were “among the rarest forms”of cancer, the disease seemed to be showing“a decided increase”11. This was confirmed in1923, at the annual meeting of Germany’sPathology Association. German pathologywas known for its rigour — many Germancities required autopsies to identify the causeof death, and several boasted sophisticatedcancer registries. It was therefore increasinglydifficult to argue that the lung cancer epi-demic was purely an artefact of diagnosis.

has even argued that cigarettes can actuallysave a nation money by killing off the burden-some elderly, obviating the need to pay formedical care and costly pensions3.

The cancer connectionCancers caused by tobacco were among theearliest discovered environmental cancers (seeTIMELINE). John Hill in England in 1761warned that “an immoderate use of snuff ”could cause cancer of the nose, and Samuel T.von Soemmerring in Germany in 1795 cau-tioned that pipe smokers were excessivelyprone to cancer of the lip4,5. Such studies fitwith an increasing interest in environmentalcancer — Percival Pott’s 1775 demonstration,for example, that the ‘soot wart’ of chimneysweeps was an epithelial cancer of the scro-tum, and Bernardino Ramazzini’s earlier (andless sound) speculation that nuns sufferedfrom high rates of breast cancer as a result offailing to bear children6.

The nineteenth century saw further effortsto buttress a tobacco–cancer link, using ele-mentary statistics. In 1858, for example, aMontpellier surgeon by the name of Etienne-Frédéric Bouisson recorded that 63 of his 68patients who suffered from cancer of themouth were pipe smokers7. The famousGerman pathologist Rudolf Virchow corrob-orated the connection in the 1860s8, by whichtime the tobacco historian FriedrichTiedemann had reported several cancers ofthe tongue brought on by smoking9.

Tobacco cancers of the oral cavity andlip were among the first to be recognized,

primarily because they are easily visible,both to doctors and to the suffering patient.Links to cancers of the internal organs —notably bladder and lung — were not dis-covered until the twentieth century.Internal cancers were more difficult todiagnose, but there was also the alreadymentioned fact that tobacco smoke wasrarely inhaled until the invention of ‘flue-cured’ tobacco (also known as ‘bright’ or‘Virginia’ tobacco) in the nineteenth century.Charcoal-based fermentation at high tem-peratures (yielding a bright yellow, flue-cured leaf) allowed a milder, nicotine-richsmoke to be rapidly delivered to the lungs,which helped cigarettes replace cigars andpipes as the favoured form of smoking.Inhalation of cigarette smoke also allowed anew kind of tobacco-related cancer to cometo the fore.

Lung cancer was extraordinarily rarebefore the twentieth century. It was noteven described until the eighteenth century(by Giovanni Battista Morgagni), and formany years thereafter was notoriously diffi-cult to diagnose. Only 140 cases had beenreported in the world medical literature by189810, and only 374 were known to Adlerwhen he composed his 1912 review11. Aslate as 1919, physicians were still beingcalled in to observe a case, believing theymight never see another2. The invention ofX-ray photography in 1895 made it easierto distinguish pulmonary malignanciesfrom tuberculosis or influenza, althoughthe discovery that many diseases were

NATURE REVIEWS | CANCER VOLUME 1 | OCTOBER 2001 | 83

Figure 2 | The Bonsack cigarette-makingmachine. (Image courtesy of Imperial Tobacco.)

John Hill, a Londonphysician, identifiesthe use of snuff as acause of nasal polyps.

Friedrich Tiedemann inGermany reportstobacco-inducedcancers of the tongue.

Samuel T. von Soemmerring ofMainz, Germany, links cancerof the lip to pipe smoking.

Isaac Adler apologizes forwriting on lung cancer, giventhat it is so rare – fewer thana thousand known cases,globally.

Franz Hermann Müller ofCologne uses case-control epidemiologicalmethods to shore up thetobacco–lung-cancer link.

Fritz Lickint of Dresden presentsthe first ‘case-series’epidemiological study linking lungcancer and cigarette smoking.

(1950–1954) Studies by R. Doll, A. B. Hill, E.Wynder and others appear in the US and UK,tying the lung cancer epidemic to cigarette use.

The Royal College ofPhysicians concludesunequivocally that smokingis “a cause of lung cancerand bronchitis”.

E. C. Hammond launches a massiveprospective epidemiological studythat will further nail downtobacco–cancer links.

Etienne-Frédéric Bouissonin France characterizesmouth cancer as a‘cancer des fumeurs’(cancer of pipe smokers).

Tobacco dust – notsmoke – is linked to lungcancer among Germantobacco workers.

The German Pathological Congressdocuments the skyrocketing incidenceof lung cancer in central Europe.

Schairer and Schöniger inJena improve Müller’s case-control methods to establisha conclusive tobacco–lung-cancer link (p<10–7).

The US Surgeon Generalreports that cigarettesmoking is “causally relatedto lung cancer in men; themagnitude of the effect … faroutweighing all other factors”.

Oscar Auerbach produces early invasivesquamous cell carcinoma in laboratorybeagles that are forced to smoke.

US tobaccoindustry finallyadmits thatsmoking poses ahuman health risk.

1761 1795 1854 1858 1898 1912 1923 1929 1939 1943 1950 1959 1962 1964 1970 1981 1996 1997 1999

Timeline | Key events in the discovery of tobacco–cancer causation

G. Pfeifer shows thatbenzopyrene, a constituentof tobacco smoke, cancause mutations in thegene that encodes p53.

Richard Doll andRichard Peto attribute80–90% of all lungcancers to smoking.

World Health Organizationestimates that tobaccowill kill 10 million peopleper year by 2025.

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Vienna and the German expatriate, WilhelmHueper (although Hueper would laterprotest what he saw as the exaggeration ofthe relationship)6. In 1942, BertholdOstertag reported that the increased inci-dence in lung tumours among smokers was“well established and undisputed”18. AngelH. Roffo of Argentina had, by this time,induced cancers on the ears of rabbits byrubbing them with tobacco tars, and thoughsubsequent critics objected that he hadburnt his tobacco at unrealistically hightemperatures19, his work nonetheless helpedshift attention from nicotine to tar as thecarcinogenic agent in tobacco smoke.

After the Second World War, British andAmerican scholars further nailed down thelink, while German research was in disarray.Richard Doll, A. Bradford Hill, ErnstWynder and others published epidemiologi-cal studies showing more rigorously thanbefore that tobacco was the culprit behindthe modern rise of lung cancer20–24. Thesewere followed by Ernst Wynder’s animalexperimental work25 and the large prospec-tive study by E. Cuyler Hammond of theAmerican Cancer Society in the UnitedStates26, along with further studies by Doll,Hill and others, including cohort studies27,28.These new studies used much larger samplesizes and quantified the statistical signifi-cance of the results in new ways, enablingBritain’s Medical Research Council to assignformal blame to tobacco in 195729. London’sRoyal College of Physicians summarizedthese findings in 1962, concluding thatsmoking was a significant cause of cancerand that steps were needed “to curb the pre-sent rising consumption of tobacco”30. TheUnited States Surgeon General concluded 2years later that smoking was “causally relatedto lung cancer in men” and that the evidence“pointed in similar directions” for women31.

Despite well-funded attacks and denialsfrom scientists in the pay of the tobaccoindustry6, knowledge of the hazards eventuallyreached a broader public. Cigarette consump-tion in the wealthier parts of the world beganto decline in the 1980s, and tobacco compa-nies shifted their attention to previouslyuntapped markets in Asia, Africa, SouthAmerica and the new nations spawned by thebreak-up of the Soviet Union. The PhilipMorris company in its 1997 Annual Reportstated that global opportunities for cigarettesales were “larger than ever”32.

Lawsuits against the industry haveincreased in recent years, following the releaseof secret documents showing that the mainUnited States tobacco companies knew aboutthe smoking hazard long before they admitted

a bias towards occupational causes13. A num-ber of observers in the 1920s suggested atobacco–lung-cancer link, but the first quan-titative analysis to support this came fromFritz Lickint — a Dresden physician andardent tobacco opponent — who, in 1929,showed that lung cancer sufferers were morelikely to be smokers14. German interest inthis issue was given a boost by the rise ofNazism, which tended to frown on tobaccoas an unhealthy vice. In 1939, FranzHermann Müller, a Cologne physician, pro-duced the world’s first case-control epidemi-ological study on the relationship betweentobacco and lung cancer, concluding thatsmoking was the main cause of the epidemic.In 1943, Eberhard Schairer and ErnstSchöniger at the University of Jena publishedfurther work with even more careful con-trols, establishing (with “high probability”)15

that tobacco was the primary cause of thelung cancer epidemic12,16.

The same conclusion was also reached bya number of other scholars in the German-speaking world — Adam Syrek of Cracow,for example17, along with Franz Högler in

There was not yet agreement on what thecause might be: air pollution and trafficexhaust were blamed, as were the delayedeffects of the 1919 influenza epidemic, theincreasing use of X-rays, increased racialmixing, and exposures to poisonous gas inthe First World War12.

Discovery of the link to cigarettes wasmade difficult by the fact that lung cancerstypically have a time lag between exposure andthe onset of symptoms of more than 20 years.This was not yet a familiar phenomenon inmedicine, and not something to be expected ifcancer was caused by a quick-acting infectiousagent. As many other causes seemed possible,and as statisticians did not initially distinguishcancer type by site in the body, it is not sur-prising that it took some time for the truecause of the epidemic to be appreciated.

The lung cancer linkAdler in 1912 was apparently the first to sug-gest that cigarettes might be a cause of thelung cancer epidemic. Hermann Rottmannhad previously blamed exposure to tobacco-factory dust, an interesting early example of

Box 1 | The evolution of tobacco industry strategies

The tobacco industry has been creative in finding new ways to keep cigarettes on the market. Inthe 1950s, the industry developed the strategy of insinuating doubt about the hazards of tobacco.When epidemiological studies showed higher rates of cancer and heart disease, the industryresponded by saying that the hazard had not yet been proven in animals. When the hazard wasdemonstrated in animals, the industry responded that the link was “merely statistical”. Since the1950s, when the Tobacco Institute and Council for Tobacco Research were established, theindustry has spent hundreds of millions of dollars on basic tobacco biochemistry, directingattention away from the simple fact that stopping smoking can save lives.

It wasn’t until the late 1990s that the tobacco industry conceded, following the release of secretinternal documents33, that tobacco was a “risk factor” in the development of certain diseases.The concession was part of a larger legal strategy to argue that the risks of smoking have beenwell-known for decades, and that people therefore voluntarily assume such risks when they takeup the habit.

With the decline in smoking in developed nations, marketing targets have shifted to thedeveloping world and nations with weak anti-smoking movements. Some of the strategies nowbeing used to extend global cigarette use include:

• mass advertising, including billboards, television advertisements and film implants (includingpaying actors to smoke on camera)

• sponsorship of sporting and cultural events

• marketing in countries where health regulations are weak

• political lobbying to keep down cigarette tax rates and to counter tobacco legislation

• aggressive marketing to children and teenagers

• marketing using sexual and ‘adventure’ imagery

• encouragement of smuggling to circumvent taxation (e.g., in Canada)

• targeting of women to increase ‘gender equity’ in smoking.

Such efforts have been accompanied by continued attempts to challenge anti-smokingprogrammes; there have also been efforts to discredit the credentials of anti-smoking advocatesand to re-orient public debate from ‘health versus the tobacco industry’ to ‘smokers versus theanti-tobacco lobby.’

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what does this tell us about the future of globalcancer rates?

Max Parkin et al.42 have estimated a globalannual lung cancer toll of 1,240,000 newcases (incidence) and 1,100,000 deaths(mortality) for the year 2000. Assuming that85% of all lung-cancer deaths are caused bytobacco43, this gives a global toll of about935,000 lung-cancer deaths per annum. As anation’s lung cancer burden seems to be anexpression of smoking levels that were inexistence roughly 35 years previously (onaverage), this means that the 3 × 1012 ciga-rettes smoked per year in the mid-1960s gaverise to about 900,000 lung-cancer deaths, orabout one lung-cancer death for every 3 mil-lion cigarettes smoked. This is consistentwith the tobacco–cancer trajectory of manyindividual nations. In the United States, forexample, there were about 162,000 lung-cancer deaths in the year 200044. The 510 bil-lion cigarettes that were smoked in 1965yielded a harvest of 0.9 × 162,000 = 146,000tobacco lung-cancer deaths in the year 2000,assuming that 90% of all lung cancers weretobacco induced. (In ‘late-stage’ epidemiccountries such as the United States, we canassume that a slightly higher fraction of alllung cancers are due to tobacco, hence the90% figure.) That turns out to be about onelung-cancer death for every 3 million ciga-rettes. This is also consistent with what weknow about lifetime individual risks ofsmoking, as a person who smokes 10,000cigarettes per year for 50 years has a one in

it, and that they later tried to cover up thatknowledge33. The legal strategy of the tobaccocompanies shifted in the mid-1990s — fromdenying the health ‘risk’ flat-out, to arguingthat it has been known for centuries, and thatpeople therefore have only themselves toblame for taking up the habit (BOX 1).

Global cancer consequencesThe scientific case against tobacco was essen-tially closed by the 1950s, though subsequentwork would add new ways to prove the causallink, along with new insights into carcino-genic mechanisms. The pathologist OscarAuerbach in 1970 showed that several of thebeagles he had taught to smoke had devel-oped lung cancer34 and, in 1981, Doll andPeto published their conclusion that cigarettesmust be considered a cause “of all, or nearlyall, of the excess of lung cancers observedamong smokers”35. That same year, TakeshiHirayama, in Japan, showed that second-hand smoke could cause lung cancer36 and, in1996, Gerd Pfeifer et al.37 showed that tobaccosmoke caused mutations in one of the best-known tumour-suppressor genes, TP53,encoding the famous p53 protein. In recentyears, epidemiologists have begun to examinethe nature and extent of the global tobaccocatastrophe, also exploring approaches thatmight help slow the epidemic38.

The World Health Organization (WHO)has estimated that tobacco will cause about 10million deaths per annum by the year 2020 or2030 (REF. 39). That figure could prove to be a

slight overestimate, but only if tobacco con-sumption rates decline dramatically. Recentfigures indicate that total world consumptionpeaked in the mid 1990s, and has actuallybegun to fall (per capita consumption culmi-nated in 1990)40. Even if we see a decline fromthis point on, however, deaths from smoking-induced heart disease and cancer will continueto grow over the next two or three decades(because of the time lag), assuming no dra-matic breakthroughs in the treatment ofheart or lung disease. Roughly a quarter ofthese deaths will be from lung cancer, andmost will be in developing nations. TheWHO has estimated that more than 100 mil-lion people will die from tobacco-related dis-ease over the next 30 years — more than fromAIDS, tuberculosis, car accidents, homicideand suicide combined41.

One convenient way to think about thelung cancer epidemic is in terms of howmany cigarettes it takes to generate a givenkind of cancer. Cigarette smoke is unlikeradon, asbestos, aniline dye or most other car-cinogens in that the dosages delivered to thebody are remarkably uniform. Cigarettes arepretty much the same size and compositionthroughout the world, as are the routes bywhich the body is exposed. And as consump-tion rates are carefully recorded by govern-ments (primarily for taxation purposes), it isfairly easy to predict the long-term cancerconsequences of a given level of consump-tion. How many cigarettes does it take — onaverage — to produce a lung cancer? And

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Figure 3 | Global cigarette consumption (a) and lung cancer mortality (b), 1900–2030. Consumption peaked in the 1990s; lung cancer rates will not peakuntil 2020 or 2030. Consumption figures for the pre-1950 period are based on data from P. N. Lee46 and estimates of United States production and global marketshare. Consumption is assumed to be roughly equal to production in both cases. Production (= consumption) data for 1950–1998 are from the WorldwatchInstitute and the United States Department of Agriculture. Post-1950 figures are minimum values, as hand-rolled cigarettes are ignored. Pre-1990 lung cancerrates are calculated from the assumption that one lung cancer death is generated for every 3 million cigarettes smoked, with a 35-year time lag betweenconsumption and mortality. Non-tobacco-related lung cancers are those from ‘background’ sources such as naturally occurring radon, occupational exposuressuch as asbestos, petrochemical products, inhaled radioactive gases from mining, spontaneous tumours, and tumours from X-rays or unknown causes. Post-2000 projections assume no improvements in lung cancer treatment.

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19. Doll, R. Lung cancer and tobacco consumption. Int. J.Epidemiol. 30, 30–31 (2001).

20. Wynder, E. L. & Graham, E. A. Tobacco smoking as apossible etiologic factor in bronchiogenic carcinoma.JAMA 143, 329–336 (1950).

21. Doll, R. & Hill, A. B. Smoking and carcinoma of thelung. Preliminary report. Br. Med. J. 2, 739–748 (1950).

22. Schrek, R., Baker, L. A., Ballard, G. P. & Dolgoff, S.Tobacco smoking as an etiologic factor of disease.Cancer Res. 10, 49–58 (1950).

23. Levin, M. L., Goldstein, H. & Gerhardt, P. R. Cancer andtobacco smoking. A preliminary report. JAMA 143,336–338 (1950).

24. Mills, C. A. & Porter, M. M. Tobacco smoking habits andcancer of the mouth and respiratory system. Cancer Res.10, 539–542 (1950).

25. Wynder, E. L., Graham, E. A. & Croninger, A. B.Experimental production of carcinoma with cigarette tar.Cancer Res. 13, 855–864 (1953).

26. Hammond, E. C. & Horn, D. Smoking and death rates:report on forty-four months of follow-up of 187,783 men.JAMA 166, 1159–1172 (1958).

27. Doll, R. & Hill, A. B. Lung cancer and other causes ofdeath in relation to smoking. Br. Med. J. 2, 1071–1081(1956).

28. Doll, R., Peto, R., Wheatley, K., Gray, R. & Sutherland, I.Mortality in relation to smoking: 40 years’ observations onmale British doctors. Br. Med. J. 309, 901–911 (1994).

29. Medical Research Council. Tobacco, smoking andcancer of the lung. Br. Med. J. 1, 1523–1524 (1957).

30. Royal College of Physicians of London. Smoking andHealth (Pitman Medical, London, 1962).

31. USPHS. Smoking and Health: Report of the AdvisoryCommittee to the Surgeon General of the Public HealthService 31 (US Government Printing Office, WashingtonDC, 1964).

32. Philip Morris Company. Annual Report, 1997.33. Glantz, S., et al. The Cigarette Papers (Univ. California

Press, Berkeley, 1996).34. Auerbach, O., Hammond, E. D., Kirmian, D. & Garfinkel, L.

Effects of cigarette smoking on dogs II. Pulmonaryneoplasms. Arch. Environ. Health 21, 754–768 (1970).

35. Doll, R. & Peto, R. The Causes of Cancer 1220 (OxfordUniv. Press, Oxford, 1981).

36. Hirayama, T. Nonsmoking wives of heavy smokers have ahigher risk of lung cancer: a study from Japan. Br. Med. J.282, 183–185 (1981).

37. Denissenko, M. F., et al. Preferential formation ofbenzo[a]pyrene adduct at lung cancer mutation hotspotsin p53. Science 274, 430–432 (1996).

38. Peto, R. & Lopez, A. Mortality from Smoking inDeveloped Countries, 1950–2000 (Oxford Univ. Press,Oxford, 1994).

39. World Health Organization. Tobacco or Health: A GlobalStatus Report (World Health Organization, Geneva, 1999).

40. ‘World Kicking Cigarette Habit’. Worldwatch Issue Alert,May 9, 2000, http://www. worldwatch.org/chairmanissue/000509d. html.

41. World Health Organization. The Tobacco Epidemic: ACrisis of Startling Dimensions (World Health Organization,Geneva, 1998).

42. Ferlay, J., Bray, F., Pisani, P., & Parkin, D. M. GLOBOCAN2000: Cancer Incidence, Mortality and PrevalenceWorldwide Version 1.0. IARC CancerBase No. 5 (IARCPress, Lyon, 2001).

43. Liu, B.-Q., et al. Emerging tobacco hazards in China: 1.Retrospective proportional mortality study of one milliondeaths. Br. Med. J. 317, 1411–1422 (1998).

44. American Cancer Society. Cancer Facts and Figures 200011 (American Cancer Society, Atlanta, Georgia, 2000).

45. Proctor, R. The Nazi War on Cancer 246 (Princeton Univ.Press, Princeton, 1999).

46. Lee. P. N. Tobacco Consumption in Various Countries(London, Tobacco Research Council, 1975).

Online links

FURTHER INFORMATIONAction on Smoking and Health (ASH) Tobacco GlobalTrends:www.ash.org.uk/html/international/html/globaltrends.htmlAmerican Cancer Society: www.cancer.orgCenters for Disease Control and Prevention: www.cdc.govTobacco Control Archives from the UCSF Library:www.library.ucsf.edu/tobaccoTobacco Timeline:www.tobacco.org/History/Tobacco_History.html

A billion tobacco deaths?Tobacco caused the deaths of about 100million people in the twentieth century. Ifconsumption rates do not decline from present rates, there could be as many as 1billion deaths from tobacco in the twenty-first century, including 250 million fromlung and other cancers. Hopefully, this is anoverestimate. Even if everyone on the planetwere to quit tomorrow, however, the deathtoll from that point on would still be in thetens of millions. Much depends, of course,on what kinds of approaches are taken inChina, India, Japan and the nations onceruled by the Soviet Union — although itshould not be forgotten that US-based firmsare still the world’s leading exporters of fin-ished tobacco products. Until governmentstake the problem of global tobacco controlseriously38, the golden leaf of the Americaswill remain the world’s leading cause of pre-ventable death, and a black mark on ourability to turn knowledge into a force forhuman health and well-being.

Robert N. Proctor is in the Department of History,Pennsylvania State University, Weaver Building,

University Park, Pennsylvania 16802, USA.e-mail: rnp5@psu.edu

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7. Bouisson, E.-F. Tribut à la Chirurgie 1259–1303 (Baillière,Paris, 1858).

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10. Kaminsky, M. Ein Primäres Lungencarcinom mitVerhornten Plattenepithelien. Thesis, University ofGreifswald (1898).

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12. Proctor, R. N. The Nazi war on tobacco: ideology,evidence, and possible cancer consequences. Bull. Hist.Med. 71, 435–488 (1997).

13 . Rottmann, H. Über Primäre Lungencarcinome 29, 52Thesis, University of Würzberg (1898).

14. Lickint, F. Tabak und Tabakrauch als ätiologischer Factordes Carcinoms. Zeitschr. Krebsforsch. 30, 349–365(1929).

15. Schairer, E. & Schöniger, E. Lungenkrebs undTabakverbrauch. Zeitschr. Krebsforsch. 54, 261–269 (1943).

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six chance of dying from lung cancer. Again,this means that one lung cancer is producedfor every 3 million cigarettes smoked in agiven society (FIG. 3).

There are obviously a number of assump-tions built into such estimates: that cigarettesare pretty much the same throughout theworld (and over time), that most lung cancersare caused by tobacco, that lung cancer treat-ment contributes negligibly to survival rates,that dose-response curves are essentially lin-ear, and so on. Some variance might beexpected according to changing tar content,what kind of ingredients are mixed withtobacco and differences in national smokingpatterns, such as how much of a cigarette issmoked. In Germany after the Second WorldWar, for example, it seems that it took onlyabout 2 million cigarettes to generate a lungcancer, perhaps because of the practice ofgathering and smoking cigarette butts45. Suchestimates might err on the low side, however,if large numbers of cigarettes were beingsmoked ‘unofficially’ (for example, fromhome-grown tobacco). The number of ciga-rettes required to generate a lung cancermight also be expected to vary according tothe stage of the epidemic. In an early stage, forexample, a higher cigarette/lung cancer ratiomight be expected, if people were smokingfewer cigarettes per person and, therefore,taking longer to develop cancer (from a pop-ulation point of view). There is also the obvi-ous fact that the fraction of lung cancers dueto tobacco will be lower in the early stages ofan epidemic, as non-tobacco causes will exer-cise more of an influence.

In 1997, the World Health Organizationestimated that in the developed world, wherecigarette smoking has a longer history, lungcancers account for about 27% of all smok-ing-related deaths. In China, by contrast,lung cancer seems to account for only about15% of all smoking fatalities (and tobaccohas a more important role in causing dis-eases such as liver and stomach cancer)43.The percentage of lung cancer fatalities(among all tobacco-related fatalities) isexpected to grow, as global smoking historycomes to look more like that of the devel-oped nations. In countries such as India andChina, the tobacco epidemic seems to beunfolding much as it did in the United Statesand in Europe some 40 years previously.China’s per capita consumption of cigarettesmore than quadrupled from 1965 to 1995,for example. The world’s most populousnation now produces — and smokes — 1.7trillion cigarettes each year, about a quarterof the world’s supply.