Annals of Oncology 11: 909-914. 2000.

Editorial The regulation of tobacco and tobacco smoke Apparently the first epidemiological associations between tobacco smoking and lung cancer came in the first half of the (last) century from the UK [1], Austria [2], the US [3] and Germany [4, 5]. Following the publication of five epidemiological studies in the early 1950s [6-10] this association was progressively accepted by the medicalscientific community [11]. In 1962 the Royal College of Physicians in Great Britain produced their first landmark report [12]. It is reasonable to conclude that we have known with some certainty that cigarette smoking caused lung cancer for between 40 and 50 years at least [13], have understood the reality that it causes the large majority of lung cancer for 30-40 years, and that it has been one of the world's most consequential, avoidable causes of death for at least 20-30 years. Further we now know that smoking causes a number of other types of cancer [14, 15], and is a major avoidable factor involved in causation of heart disease and many other fatal and non-fatal conditions [16-18]. Unsurprisingly, given the strength and complexity of the mixture, the adverse effects of second-hand smoke have been progressively demonstrated over the past 15 years [19].

Watershed

Recent years have been a time of tumult for the tobacco industry, leading, in the US at least, to expensive settlements of state based lawsuits and vulnerability to class actions. Further, denials have turned to acceptance that cigarettes cause lung cancer, certain other diseases and that nicotine is addictive [20]. Although the industry lacks credibility, it still has profits, power, and is far from penitent. However, the forthcoming European Directive (of 2000) contains the beginnings of regulation of tar, nicotine, additives and further advertising restrictions and other countries are looking at these issues. Serious disclosure by law is under way in Massachusetts and British Columbia, which can be seen as a precursor to regulation. So examination of the ways in which tobacco smoke should be regulated is timely. The size of the problem

The actual size of the global tobacco problem is increasing at a startling rate. There are several reasons for this. One is the development of new markets and new generations of smokers, not by accident but by design

for which the industry is responsible. The second is the predictable effect of long duration smoking in such countries as China and central and eastern Europe where the smoking of past decades is still to wreak its full havoc. The third is the maturation of the tobacco epidemic among women. The most important determinant of lung cancer risk is the duration of smoking: long-term smokers have a 20-30-fold increased risk compared to non-smokers [21]. Risk varies also with other aspects of daily exposure including number of cigarettes smoked, depth of inhalation and smoke composition (tar components and nicotine). Lung cancer is the major tobacco related site and is the leading cause of cancer death in men in almost all developed countries. Annual incidence rates are between 80-100 per 100,000 in the highest incidence rate groups such as Afro-Americans [22] and rates exceeding 200 per 100,000 have been recorded among middle aged (35-64) men in cities of central and eastern Europe [23]. Lung cancer being frequently and rapidly fatal, mortality rates are high and, consequently, the social costs are high. Smoking among women in some developed countries has had the same effect as in men, with lung cancer now exceeding breast cancer as the most common cause of cancer death in the US, Canada, Denmark, Scotland and in many other countries the gap between the two is decreasing rapidly. Indeed, in Glasgow in Scotland, the incidence of lung cancer in women now exceeds the incidence of breast cancer [24]. Cigarette smoking kills half of all those who adopt and persist with this addictive habit with half of these deaths occurring in middle age and each losing over 20 years of non smokers life expectancy [17]. Tobacco smoking kills effectively in twenty-four different ways [17]. It can be estimated that, whereas it will cause 3,000,000 deaths per annum in the last half of this decade, by 2025 it will cause 10,000,000 deaths annually [18]. This global epidemic can only be ameliorated, and only to a limited degree, by controlling the tobacco industry's commitment to market expansion and by regulating the cigarette itself. Policies to reduce sales and consumption of cigarettes have been established for decades [25]. They include abolition of tobacco advertising both direct and indirect, increased taxation, education programs, smoking cessation programs and limits on tar and nicotine yields. Public Health policy has not hitherto included detailed control of tobacco or the additives which go into modern cigarettes. This is remarkable. It now seems only a matter of time before these items are regulated.

910 seen in smokers was demonstrated by Russell in 1980 and many others [37-43]. In the absence of systematic on-going analysis of Regulation of the content and yield of cigarettes will be complex. The complexity arises only partly from the what has been going into smokers lungs, we are left mixture of compounds in cigarette smoke. Difficulties with biological outcomes as an index of what has been arise from the need to consider and regulate nicotine in happening. There are three potentially important obserthe context of addiction en masse, and as a second issue, vations in this regard. First of all, it is very difficult to imagine that the large the need to reduce the disease causing potential of the fall in the tar content of cigarettes sold in the UK over mixture. Regulation may reasonably be expected to render the the last fifty years [44] has not directly influenced the cigarette less disastrous, it cannot be expected that lung cancer death rate which has been falling for two modifying the products of combustion of tobacco can decades in men in that country. ever produce an even moderately safe cigarette. Secondly, and somewhat paradoxically, mortality from Historically the tobacco industry in the US has lung cancer in men increased between the first (CPS-I) largely escaped regulation, although pressure has been and second (CPS-II) Cancer Prevention Studies of the applied to what is a global industry via voluntary agree- American Cancer Society [45, 46]: these studies recruited ments in the UK and Canada requiring reduced yields men from birth cohorts approximately 30 years apart. of tar, nicotine and carbon monoxide. The European At first glance, the decrease in mortality promised by Community (EC) currently mandates an upper limit for the yield reductions of the 1950s and 1960s has not been tar of 12 mg [26]. In the US, however, the industry has substantiated over the 1970s and 1980s. However, this been free to make its own decisions, and the results are may be too simple an interpretation. Information of the number of cigarettes smoked at apparent both in the marketplace and in the mortality rates among smokers. Although sales weighted tar is time of enrolment to both studies may not mirror the below 12 mg [27] the range of tar is up to 27 mg [28, 29]. lifelong patterns of smoking that cause lung cancer [47]: However, the means of achieving reduced yields of data on smoking in early life, which critically determines tar, nicotine and carbon monoxide to the Federal duration of smoking, are sparse in both studies. CigaTrade Commission (FTC) machine have not necessarily rette consumption during adolescence and early adultdelivered lower yields of carcinogens to the smokers. The hood was probably heavier among smokers in CPS-II FTC machine produces measures of tar and nicotine for several reasons. Manufactured cigarettes were more abstracted from a cigarette using a machine taking fixed readily available in the 1940s and 1950s than in the 1930s 'puffs' and fixed intervals of time. Since there are funda- and 1940s, eras when smoking was likely to be initiated mental differences between smokers in the frequency in the CPS-II and CPS-I cohort, respectively. and strength of puffs, this technology can only provide an Birth cohort analyses show that the prevalence of index. Furthermore, the addition of ventilated filters can smoking among white men increased with each succesfurther lead to reducing observed tar and nicotine levels. sive birth cohort born from 1900-1929 and decreased While the FTC method is quantitatively misleading, thereafter [48]. Age-specific lung cancer death rates have there have been qualitative changes too. Hoffmann and decreased in those born after 1930 [49, 50]. Hoffmann [28] have shown that the smoke of a leading The increases in lung cancer death rates from CPS-I US non filter brand shows a decrease in benzo(a)pyrene to CPS-II probably reflect unmeasured heavier smoking (BaP) by 60% between the mid sixties and late seventies, among CPS-II during the 1940s and 1950s as well as the while the tobacco specific carcinogen 4-(methylnitrosa- measured increase in daily consumption and duration mino)-l-(3-pyridyl)-l-butanone (NNK) has increased of smoking. In addition, CPS-II may include a more addicted 'hard-core' smokers, who find it virtually by 50% between the late seventies and the nineties. One must pause to ask whether, if cigarettes were impossible to quit smoking, and CPS-II smokers, partly regulated like pharmaceuticals or foodstuffs, any regu- to compensate for lower nicotine content of modern lator would have condoned such an increase in a known cigarettes, may inhale more deeply, take more puffs per cigarette and retain smoke larger in the lungs than carcinogen. The early concept that simply reducing tar and nico- did smokers in the past. The impact of lower tar and tine would reduce cancer risk was well founded on nicotine cigarettes is difficult to elucidate with all these epidemiological studies, which showed a reduction in other changes in effect. lung cancer risk, but not cardiovascular disease, of Thirdly, and what is clear, is that there has been a real between twenty and fifty percent in association with the swing towards higher rates of adenocarcinoma of the move to filter cigarettes which occurred over the fifties lung both in the US and elsewhere [51-60] which is and sixties [30-36]. It was therefore logical that public consistent with the hypothesis that qualitative changes health authorities should press for further reductions. in cigarette smoke have led to a change in the observed However the reductions which appeared in the yields as pattern of lung cancer but not to a substantial decrease measured by the FTC system do not reflect, in a quanti- in mortality. Clearly cigarettes are different but still seriously tative way, what passes into the lungs of smokers. That more intensive ('compensatory') smoking patterns are harmful after decades of self-regulation. The regulation of tobacco smoke

911 The carcinogenic component

itself. Such a proposal does not have to, and should not, provide carte blanche immunity for past actions but must enable publication and discussion of existing and future research. In this era of new-openness, the time may be ripe for the establishment of the tobacco-equivalent of the 'Justice and Truth' Commission employed in South Africa.

It is possible to conceive a system for regulation of carcinogens and other toxins in cigarette smoke which could follow the precedents set by the regulation of the automobile industry. The Environmental Protection Authorities around the world did not allow the automobile industry to set standards. Dialogue occurred and standards were set, initially as targets and ultimately as standards. The result has been a progressive reduction Nicotine regulation in air pollution achieved with the active assistance of the automobile industry's research facilities, and can be To consider regulating nicotine means considering seen as a public health triumph. Regulation has been addiction. Benowitz and Henningfield [63] have proposed common-sense. Lead could only be reduced by removing a gradual diminution in the weight of nicotine permitted it from petrol. Other emissions depended on engine in the actual cigarette. The idea has the merit of simplicity design and the manufacturers were set targets and and practicability and is analogous to limiting the lead standards which they could, and have, met. in petrol. If watched over by a competent regulatory With regard to the many components which make up agency, it would constitute a practical ongoing experitar, we should look to the EPA model with targets to be ment which (duly monitored) should in due course followed by standards. Analysis of the top twenty brands reveal whether a non addictive, or less addictive, cigafor the major toxins /carcinogens would show the upper rette can be manufactured, whether it is saleable, and and lower limits of the present market. As a starting how customers react to it, not merely in terms of sales, point it would show what is practical now. Setting target but in patterns of use. This is not prohibition by stealth, levels in the middle ranges would be a beginning and it is a reasonable approach to making the cigarette less research over time would show which targets could be addictive. met, and converted to industry standards, and which The alternative approach, which might be to allow could not [61]. This may mean telling the manufacturers nicotine content to be unregulated so that the smoker is of specific brands that they must, over time, bring levels nicotine satisfied, rather than encouraged to suck harder of, say, polyaromatic hydrocarbons or nitrosamines, and thereby inhale more carcinogens, is not a long-term down to those of other brands on the market, or vice solution to the problem of tobacco addiction. versa. It may also require sharing of manufacturing There are three important points. secrets. The first point is simple. The index of nicotine delivery This approach is compatible with that described as by the cigarette ought not to be the amount yielded to a the 'Selective Reduction of specific toxic constituents' machine running under one set of fixed conditions. pursued by RJ Reynolds in the development of their Ideally, it ought to be a better reflection of what goes recent 'heated tobacco' cigarette (Eclipse/Premier) [62]. into the arterial blood of the smoker and will surely This product delivers lower levels of some 37 'biolog- involve a series of tests conducted under a range of ically active' compounds thought by the industry to be smoking conditions. Failing this a simpler and more worthy of testing. Review of the material presented in practical index could be the actual weight per cigarette favour of 'Eclipse' establishes that the industry has the [63]. In addition it is necessary to reduce nicotine bioskills and knowledge to work in this way, although only availability so control of pH needs to be considered. a few outside the industry would have the detailed Since some additives both facilitate nicotine bioavailknowledge possessed by it. ability and themselves lead, when burnt, to carcinogen Such regulation is practical and in accord with estab- formation [64], they need to be either abolished or lished drug control and air quality control precedents. subject to the same safety testing (in burnt and unburnt Drugs with carcinogenic activity are already regulated. form) as nicotine replacement products are. In this case the whole process must be seen for what it is, The second point is difficult. How to deal with coma huge human experiment. The authorities must have the pensatory smoking? This phenomenon has been known right to allow what seems to be best practice on the basis since the early work of Russell in the seventies. The of existing knowledge. They must also be immune from tobacco industry has discovered a way to deal with this litigation over their efforts. Ongoing monitoring by ani- - delude the smoker into thinking the amount printed mal tests, laboratory tests and some cohort studies will on the packet means something (light?) and make the be needed. The changes required will probably be more nicotine more bioavailable by a variety of clever engioften based on what comes out of the cigarette than neering techniques [64]. The knowledge that reducing what goes into it. The manufacturers will have to use nicotine to low levels drives deeper inhalation is the their substantial research skills under regulatory scrutiny justification for the experimental approach proposed. instead of in secret. This latter point may require some The solution to the controversy surrounding the effects legal protection which will allow the industry to tell what of addiction and compensation has to be an ongoing it knows, at least for the future, without incriminating epidemiological analysis of smoker behaviour in relation

912 to nicotine content, as the nicotine content of cigarettes is progressively reduced en masse. Only in such a way can we develop a clear long term approach to the reduction of tobacco addiction. The fact that this is a population based, experimental approach should not be surprising. No ethical alternative is possible as the present cigarette is too dangerous to be allowed to remain on the market unchanged. Nearly all the important data we already have come from analysis of a massive (uncontrolled) human experiment, conducted, initially unwittingly, by an industry. Mass weaning of populations will not occur, on present experience, with the present cigarette. It may be, and probably is, possible. It will not happen while the tobacco industry is responsible for deciding what will be delivered by the cigarette. Neither will it happen unless there is a co-ordinated legislative program, preferably global, aimed at the progressive reduction of the addictive (and carcinogenic) properties of cigarettes. The third point arises here. There is a strong case for regulating all forms of Nicotine, both nicotine coming from tobacco smoking ('dirty') and that from nonsmoking sources ('clean'). The pharmaceutical industry is experienced in collaborative regulation, but the tobacco industry is not. However, the drug needs to be considered at a societal level. So regulation of nicotine in cigarettes needs to be considered together with the existing regulation of alternative nicotine delivery systems, and by the same agency. While cigarette regulation needs to progressively tighten, the regulation of 'clean' nicotine could usefully be substantially loosened. The time is right to consider whether more efficiently absorbed forms of clean nicotine are needed and should be allowed to compete freely with tobacco derived nicotine. The issues canvassed here are topical. There is now an opportunity to assert regulation over cigarettes in Europe, and indirectly to influence what happens elsewhere. While the concept of the Global Cigarette [65] in terms of maximum allowable limits of 12 mgms tar and 1 mgm nicotine has immediate validity for the developing countries where historical yields have been extremely high, a more sophisticated system is needed for developed, and eventually all, countries and this needs to become global as it evolves. With the global industry under pressure and the power to regulate incipient, Public Health Authorities and Governments which let slip the present opportunity to inhibit the epidemic will be judged harshly by history. What can the oncological community do today? Oncologists see daily the unforeseen consequences of cigarette smoking in their clinical practice. They are in a strong position to have an influential role in Tobacco Control although, surprisingly, they have never as a group exerted this potential. It is important that oncologists set an example: it defies logic that oncologists continue to smoke knowing

what they know, and see, about the long-term adverse effects of cigarettes. Oncological meetings should be completely non-smoking, smoking cessation advice and education should be available at these meetings and through learned societies, and oncologists should be trained in the methods of smoking cessation. However, smoking cessation is difficult and special efforts should be aimed at this professional group to increase the number of smokers who want to stop smoking and increase the probability that a quit attempt will be successful. Oncologists have the potential to be a large and important group of activists. Currently there is a new Tobacco Directive being discussed in the European Parliament which proposes, among others, to further reduce tar ceilings and to introduce ceilings on nicotine and carbon monoxide; to obtain disclosure of the type and nature of tobacco additives to cigarettes; and to eliminate the use of adjectives such as 'low', 'mild', and 'ultra mild' which could be construed by the general public as implying a safer product. This Directive deserves the active support of European oncologists who should leave their elected representatives in no doubt about the importance and value of such legislation to public health. Acknowledgements This work was conducted within the framework of support from the Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research). N. Gray l 2 & P.Boyle1 'Division of Epidemiology and Biostatistics European Institute of Oncology Milan, Italy 2 Past President, UICC Geneva, Switzerland

References 1. Tylecote FE. Cancer of the Lung. Lancet 1927: 2: 256-7. 2. Fleckseder R. Ueber den Bronchialkrebs und einge seiner Entstehungsbedingungen. Munch Med Wochenschr Nr 1936; 36: 1585-93. 3. Arkin A, Wagner DH. Primary carcinoma of the lung. J Am Med Assoc 1936; 135: 321-7. 4. Muller FH. Tabaksmisbrauch und Lungenkarzinom. Z f Krebsforsch 1940; 49: 57-85. 5. Schairer E, Schoniger E. Lungenkrebs und Tabaksverbrauch. Z f Krebsforsch 1943: 54; 261-9. 6. Schrek R, Baker LA, Ballard GP, DolgofTS. Tobacco smoking as an etiologic factor in disease. Cancer Res 1950; 10: 49-58. 7. Levin ML, Goldstein H, Gerhardt PR. Cancer and tobacco smoking. J Am Med Assoc 1950; 143: 336-8. 8. Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogemc carcinoma. J Am Med Assoc 1950; 143. 329-36. 9. Mills CA, Porter MM. Tobacco smoking habits and cancer of the mouth and respiratory system. Cancer Res 1950; 10: 539—42.

913 10. Doll R. Hill AB. Smoking and carcinoma of the lung. BMJ 1950; 2: 739-48. 11. US Public Health Service. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. DHEW Publication No. 1103. US Department of Health, Education and Welfare. Public Health Service. Centre for Disease Control 1964. 12. UK College of Physicians Report. Smoking and health. Summary and Report of the Royal College of Physicians of London on Smoking in Relation to Cancer of the Lung and Other Diseases. New York: Pitman Publishing 1962; 70. 13. Boyle P. Cancer, cigarette smoking and premature death in Europe. A review including the recommendations of European cancer experts consensus meeting, Helsinki, October 1996. Lung Cancer 1997; 17: 1-60. 14 Doll R, Peto R. Wheatley K et al. Mortality in relation to smoking: Forty years' observations on male British doctors. BMJ 1994; 309(6959): 901-11. 15 Doll R. Cancers weakly related to smoking. B M Bull 1996; 52: 35-49. 16. Wald NJ, Hackshaw AK. Cigarette smoking: An epidemiological overview. B M Bull 1996; 52: 3-11. 17. Peto R, Lopez AD. Boreham J et al. Mortality from tobacco in developed countries: Indirect estimation from national vital statistics Lancet 1992; 39; 1268-78. 18. Peto R, Lopez AD, Boreham J et al. Mortality from smoking world-wide. B M Bull 1996; 52: 12-21. 19. EPA (US Environmental Protection Agency). Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders. Washington, DC. US Environmental Protection Agency 1992. 20. Szymanczyk M. President and CEO of Philip Morris, deposition May 10, 2000, reported Associated Press May 20, 2000. 21. Peto R. Influence of dose and duration of smoking on lung cancer rates. In Zaridze DG, Peto R (eds): Smoking: An Internationl Problem. Lyon: I ARC 1986. 22. Parkin DM, Muir CS, Whelan S et al. (eds). Cancer Incidence in Five Continents, Vol VI (IARC Scientific Publication No. 120) Lyon: International Agency for Research on Cancer 1992. 23. Boyle P, Gandini S, Plesko I et al. Lung cancer incidence in cities of central and eastern Europe. The Lancet (submitted). 24. Gillis CR, Hole DJ, Lamont DW et al. The incidence of lung cancer and breast cancer in women in Glasgow. BMJ 1992; 305: 1331. 25. Gray N (ed). Lung Cancer Prevention; Guidelines for Smoking Control. Geneva: Union Internationale Contre le Cancer 1977. 26. Directive 90/239/EEC. Commission of European Communities, May 1990. 27. Hoffmann D, Hoffmann I. Tobacco Consumption and Lung Cancer. In H. H. Hansen (ed): Boston: Kluwer Academic Publishers 1994; 1 42. 28. Hoffman D, Djordjevik MV, Brunnemann KD. Changes in cigarette design and composition over time and how they influence the yields of smoke consituents. J Smoking-Rel Disorders 1995; 6: 9-23. 29. Federal Trade Commission. Tar, nicotine and carbon monoxide of the smoke of 1107 varieties of domestic cigarettes. Washington, DC: US Federal Trade Commission 1995. 30. Bross IDJ, Gibson R. Risk of lung cancer in smokers who switch to filter cigarettes. Am J Public Health 1968; 58: 1396-403. 31. Dean G, Lee PN, Todd GF, Wicken AJ. Report on a Second Retrosepective Study in Northeast England. Part 1. Factors Related to Mortality from Lung Cancer, Bronchitis, Heart Disease, and Stroke in Cleveland County with Particular Emphasis on the Relative Risks Associated with Smoking Filter and Plain Cigarettes (Research Paper 14). London: Tobacco Research Council 1977. 32. Hawthorne VM, Fry JS. Smoking and health. The association between smoking behaviour, total mortality and cardiorespiratory disease in West Scotland. J Epidemiol Commun Health 1978; 32: 260-6.

33. Lubin LH. Modifying risk of developing lung cancer by changing habits of cigarette smoking. BMJ 1984; 289: 1953-6. 34. Rimington J. The effects of filters on the incidence of lung cancer in cigarette smokers. Environ Res 1981: 24: 162-6. 35. Wynder EL, Mabuchi K. Beattie EJ Jr. The epidemiology of lung cancer: Recent Trends. J Am Med Assoc 1970; 213: 2221-8. 36. Wynder EL. Stellman SD. The impact of long-term filter usage on lung and larynx cancer risk: A case control study. J Natl Cancer Inst 1979:62:471-7. 37. Russell MAH. The case for medium-nicotine, low tar, low carbon monoxide cigarettes. Banbury Rep 1980; 3: 297-310. 38. US Surgeon General. The Health Consequences of Smoking. NIH Publ No. 86-7874. Bethesda, Maryland: United States Department of Health and Human Services 1986: 1-639. 39. Herning Rl. Jones RT. Bachman J, Mines AH. Puff volume increases when low nicotine cigarettes are smoked. BMJ Clin Res 1981; 283: 187-9. 40. Kozlowski LT, Rickert WS. Pope MA et al Estimating the yields to smokers of tar. nicotine, and carbon monoxide from the lowest yield ventilated filter cigarettes. Br J Addict 1982; 77: 159-65. 41. Fagerstrom K.O. Effects of a nicotine-enriched cigarette on nicotine titration, daily cigarette consumption, and the levels of carbon monoxide, cotinine and nicotine. Psychopharmacology 1982; 77: 164-7. 42. Haley NJ, Sepkovic DW, Hoffmann D, Wynder EL. Cigarette smoking as a risk factor for cardiovascular disease VI. Compensation with nicotine availability as a single variable. Clin Paharmacol Ther 1985; 338: 164-70. 43. Puustinen P, Olkkonen H, Kolonen S, Tuvmisto J. Micro-computer aided measurement of puff paramenters during smoking of low- and medium-tar cigarettes. Scand J Clin Invest 1987; 47: 655-60. 44. Wald N, Doll R, Copeland G. Trends in tar. nicotine and carbon monoxide yields of UK cigarettes manufactured since 1934. BMJ 1981; 282 (6266). 763-5. 45. Thun MJ, Heath CW Jr. Changes in mortality from smoking in two American Cancer Society prospective studies since 1959. Prevent Med 1997; 26 (4): 422-6. 46. United States Public Health Service. Reducing the Health Consequences of Smoking. A Report of the Surgeon General. DHSS Publication no. (CDC) 89-8411 US Department of Health, and Human Services. Public Health Service, Centre for Disease Control 1989; 143. 47. Thun MJ, Day-Lally C, Myers DG et al. Trends in tobacco smoking and mortality from cigarette use in cancer prevention studies I (1959 through 1965) and II (1982 through 1988). In Changes in Cigarette-Related Disease Risks and Their Implication for Prevention and Control. Bethesda, Maryland: National Cancer Institute 1977; Chapter 4 (NCI Monograph No. 8). 48. Burns DM. Tobacco Smoking, pp 15-49. In Somct JM (cd): Epidemiology of Lung Cancer New York: Marcel Dekker 1994. 49. Devesa SS, Blot WJ, Fraumeni JF. Decliing lung cancer rates among young men and women in the United States: A cohort analysis. J Natl Cancer Inst 1989; 81: 1568-71. 50. Gilliland FD, Somet JM. Lung Cancer. In Doll R, Fraumeni JF, Muir CS (eds): Trends in Cancer Incidence and Mortality. Plainview, New York: Cold Spring Harbor Laboratory Press 1994; 175-95. 51. Wynder EL, Muscat JE. The changing epidemiology of smoking and lung cancer histology. Environmental Health Perspectives. 1995; 103 (Suppl 8): 143-6. 52. Cox JD, Resner RA. Adenocarcinoma of the lung: Recent results from the Veterans Administration lung group. Am Rev Resp Dis 1979; 120: 1025-9. 53. Vincent RG. Pickren JW. Lane WW et al. The changing histopathology of lung cancer. Cancer (Phila.) 1977; 39: 1647-55. 54. El-Torkey M, El-Zeky F, Hall JC. Significant changes in the distribution of histological types of lung cancer. A review of 4928 cases. Cancer (Phila.) 1990; 65: 2361-7. 55. Johnson WW. Histologic and cytologic patterns of lung cancer in

914

56.

57. 58.

59.

2580 men and women over a 15-year period Acta Cytol 1988; 32: 163-8. Beard MC, Anneges JF,Woolner LB, Kurland LT. Bronchiogenic carcinoma in Olmsted County, 1635-1979. Cancer (Phila.) 1985; 55: 2026-30. Cutler SJ, Young JL. Third national cancer survey: Incidence data. J Natl Cancer Inst Monogr 1975; 41: 1-454. Young JL, Percy CL. Asire AJ (eds). Cancer incidence and mortality in the United States, 1973-1977. Natl Cancer Inst Monogr 1981; 57: 1-1082. Devesa SS, Shaw GL, Blot WJ. Changing patterns of cancer incidence by histologic type. Cancer Epidemiol Biomarkers Prev 1991; 1:29-34.

60. Wu AH, Henderson BE, Thomas DC, Mack TM. Secular trends in histologic type of lung cancer. J Natl Cancer Inst 1986; 77: 53-6. 61 Gray N, Boyle P, Zatonzki W. Tar concentrations in cigarettes and carcinogen content. Lancet 1998; 352: 787-8. 62. Townsend DE, in Report of Canada's expert committee on cigarette modifications. Health Canada 1996; 35. 63. Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction. N Engl J Med 1994: 331: 123-4. 64. Bates C, Connelly GN, Jarvis M (eds). Tobacco additives cigarette engineering and nicotine addiction. London: Action on Smoking and Health 1999; 1-15. 65. Gray NJ. The global cigarette. BMJ 1996; 313: 1348.