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Occupational lung cancer and smoking: a review in the light of current theories of carcinogenesis Alan C. Chovil, ma, mb, b chir, mph, dab prey med This paper considers modern theories of carcinogenesis as they apply to the induction of lung cancer by tobacco smoking and occupational exposure to carcinogens. Some of the known and postulated factors affecting carcinogenesis are discussed, with particular reference to syncarcinogenesis and thresholds. Factors affecting the intensity of smoking exposure are reviewed, and the generally accepted occupational lung carcinogens are listed. Relative risks for the various carcinogens according to smoking status (where known) are presented. The carcinogens are considered individually, and known or postulated interactions with smoking are discussed. It is concluded that the effects of lung carcinogens can be explained on the basis of current theories that support a rational definition of priorities for the prevention of occupational lung cancer. Cette etude s'interesse aux theories modernes de la carcinogenese telles qu'elles s'appliquent a I'induction du cancer du poumon par le tabac et par les risques du metier relie aux carcinogenes. Quelques facteurs connus ou postules relatifs a la carcinogenese sont discutes, avec un interet particulier pour la syncarcinogenese et les seuils de tolerance. Les facteurs qui influencent I'intensite de I'exposition au tabac sont revus et on fait I'inventaire des carcinogenes pulmonaires relies au metier. On presente les risques relatifs (lorsqu'ils sont connus) des differents carcinogenes chez les fumeurs. Les carcinogenes sont consideres individuellement, et les interactions connues ou postulees avec I'usage du tabac sont discutees. On conclut que les effets des carcinogenes pulmonaires peuvent s'expliquer a partir des theories courantes qui soutiennent une definition rationnelle des priorites visant a prevenir le cancer professionnel du poumon. Most people now accept that smok ing plays a major part in the gen esis of lung cancer1 and that in the general population it is probably the most important factor. The evi dence is largely epidemiologic and, while strong, is still questioned.2 It is also generally accepted that sev eral types of industrial exposure are capable of causing lung cancer.8 The role that smoking plays in as sociation with industrial hazards is less clear. There is a tendency for some of those associated with in dustry to play down the occupa tional risks and emphasize smok ing.4 The tobacco industry and cigarette addicts tend to do the op posite. This paper will briefly re view the current theories of carci nogenesis and explore the possible mechanisms of interaction between smoking and occupational hazards. Reprint requests to: Dr. Alan C. Chovil, Industrial medicine consultant, Ontario Workmen's Compensation Board, 2 Bloor St. E, Toronto, Ont. M4W 3C3 Factors in carcinogenesis Genetic mutation Research has failed to show an association of viruses with most cancers that occur in humans. Cur rently the favourite theory is that most cancers arise as a result of genetic mutations, which may be induced by chemicals, ultraviolet or ionizing radiation, or the inter action of viral deoxyribonucleic acid (DNA) and cellular DNA, or may be congenital.5 Carcinogenic chemicals react with DNA because they are usually strongly electro philic or alkylating. A number of known carcinogens require conver sion to an active form in the or ganism. An example is benzo[a]pyrene, one of the earliest carcino gens to be isolated. This substance is converted by a complex enzyme, aryl hydrocarbon hydroxylase, which is present in various tissues.6 The active carcinogen is one of a number of products of the normal metabolic degradation of this type of polycyclic compound. Hereditary variations in the inducibility of aryl hydrocarbon hydroxylase may play some part in the cancer susceptibil ity of individuals. Experiments have shown that lung cancers in animals may occur from the absorp tion and systemic spread of in gested carcinogens that may be ac tivated in the lung or other tissues, such as liver, but in humans all the known causes of lung cancer are inhaled and appear to act lo cally.7 It is thought that several sequen tial mutations are required for malignant transformation. Some chemicals, while capable of induc ing the complete process alone, have a massively enhanced effect in animals if a promoter chemical is administered subsequently.8 The mechanisms of promotion are only partly understood, and the pro cesses involved in the often pro longed latent period between expo sure and tumour development re main obscure. Promotion may in volve enzyme induction, derepres sion of suppressed genetic traits, or simple chemical or physical facilita tion. Latency may be a function of host response, cumulated dose, age, carcinogenic potency or target tis sue type. Known and postulated variables Some of the known and postu lated variables are shown in sim plistic form in Table I. There is some confusion in terminology be tween authors, but it seems best to limit the use of the term syncar cinogenesis to the additive effect of two or more carcinogens independ ently acting on the same target tissue. Threshold concentrations There has been a vigorous debate on whether there are threshold con centrations of carcinogens below 548 CMA JOURNAL/SEPTEMBER 8, 1979/VOL. 121 which there is no risk of cancer among exposed persons. Most au thors seem to accept that there is no absolutely safe threshold con centration for a carcinogen and that, therefore, one must be con cerned with establishing practical levels. Kotin10 and Mantel and Schneiderman16 favoured establish ing "virtually safe levels", recog nizing that at low exposures effects may be delayed beyond the normal life-span. Flowers17 developed the concept of "radioequivalent level" -- the dose of a carcinogen that results in a cancer risk equal to that produced by normal back ground radiation -- and suggested this as a practical level. These au thors ignored the problems of co carcinogenesis and syncarcinogenesis. Preussman,18 Brown,19 Bingham, Niemeier and Reid,8 and Truhaut20 seem to have concluded that neither "safe" nor "virtually safe" levels are practical because of syncarcinogenesis. Nutrition There is evidence that vitamin A deficiency renders some epithelial tissues more prone to carcinogenic effects.14 There are suggestions that this may be reversible, and the use of vitamin A analogues in the pro phylaxis of lung cancer in high-risk groups is currently under investiga tion. Smoking The prevalence of smoking in in dustrial situations is very poorly do cumented, as often are the data on exposure to other carcinogens, par ticularly if exposure occurred many years previously. Some employers permit smoking at any time, some at "breaks" only and some never. Cigarette smoking is a powerful addiction and there is likely a self selection by addicts away from jobs where smoking is banned or re stricted. This may partly account for the low incidence of lung cancer in coal miners.21 Whether the re verse is true, with smokers tolerat ing fumes or smells better than non smokers and possibly being subject to higher risks, is a matter of spec ulation. It certainly cannot be as sumed that the prevalence of smok ing in any occupational subgroup reflects that of the general working population. Cigarette smoke contains a num ber of carcinogenic substances. The group of polycyclic aromatic hydro carbons, including benzo[a]pyrene, is usually thought of as prominently involved.22 Although their carcino genic potency is low, the intensity and duration of exposure produced by the inhalation of cigarette smoke are thought to account for their strong effect in humans. Cigarette smoking may enhance the effect of other carcinogens in at least two ways. First, cigarette smoke is di rectly toxic to ciliated epithelium.23 Smoking soon leads to a loss of ciliary function and resultant diffi culty in clearing sputum, which may contain a variety of inhaled carci nogens. Later, smoking induces metaplasia of the bronchoepithelium to a squamous type. It is also postulated that the particles in ci garette smoke are of such a size that they can adsorb other carci nogens and carry them to the epi thelium of the lower bronchial tree.24 Occupational carcinogens Table II lists the industrial ha zards for which there is substantial epidemiologic evidence of a causal relation to lung cancer. Only bron chogenic carcinoma will be con sidered, although several of the substances pose other risks to health. Tumour types vary consi derably, and there may be some relation between the degree of dif ferentiation of the cells in a tumour and the activity of the causal agent, but this is too indefinite to be of use in assigning responsibility to a given agent.25,26 The degree of occupational ha zard depends partly on exposure and partly on the carcinogenic po tency of the substance. A review of Table II--Occupational lung carcinogens Carcinogen Occupation Asbestos Mining, refining, in sulation work, man ufacturing and con struction Arsenic Mining, metal refining, work involving agri cultural chemicals Chlormethyl Work involving these ethers chemicals Chromates Refining and man ufacturing Coal tar distillates Coke oven operation, work with coal gas and tar Mustard gas Manufacturing Radiation Uranium mining and processing, fluor spar and hematite mining Nickel Refining CMA JOURNAL/SEPTEMBER 8, 1979/VOL. 121 549 the relative risks has been at tempted in Table III within the very marked limitations imposed by difficulties in relating the statistical conclusions of various studies to each other when they are based on different designs, have used dif ferent population controls and have involved large variations in the de gree of exposure. The conclusions of studies lacking smoking data in which the risk of cancer was low are particularly vulnerable to criti cism. Unfortunately, fairly solid relative risks for smokers and non smokers have been established only for asbestos workers and uranium miners. Not shown in Table III are the wide differences in latent periods and in the relative doses required to induce an effect. Mustard gas and the chlormethyl ethers are ap parently intensively reactive, with lung cancer occurring after a rela tively short latent period (8 to 16 years).41 The latent period asso ciated with radiation exposure in mines is similar.42 Asbestos,80 nickel,84 coal tar distillates3'37 and mustard gas88 all seem to involve latent periods of at least 20 years, while the latent period for arsenic may be 35 to 40 years.31 Asbestos The relative risks of broncho genic carcinoma for smokers and nonsmokers exposed to asbestos are well documented from a variety of sources.43 The evidence suggests that the risk for a nonsmoker is relatively low but that the risk for a smoker is high.30 Asbestos is non reactive in the Ames mutagenic testing system and therefore may not be a true carcinogen but in stead may act as a foreign body implanted in the vulnerable tissues, where it can adsorb and then slow ly release active carcinogens derived from the air, the diet or metabolic sources.44 There is some evidence of covalent binding of benzo[a]pyrene by the trace metals associated with asbestos. As well, exposure to as bestos may interfere with the im mune system and thereby increase the risk of cancer.45 Arsenic There has been much debate on whether arsenic is a carcinogen. The authors of the National Aca demy of Science report " `Arsenic' 1977" reviewed published and un published data and concluded that there was strong evidence of pul monary carcinogenesis with a doseresponse relation, particularly when exposure was associated with sul fur dioxide, and an astonishingly long latent period -- up to 40 years.46 They noted the absence of an animal model for the carcino genicity of arsenic. It is well known that orally administered arsenic produces skin changes that ulti mately progress to cancer in hu mans, but it is possible that arse nic's role is that of an initiator only and that this substance may be in active in the absence of some pro moter (or vice versa). Most of the reported cases of lung cancer asso ciated with exposure to arsenic have been in smelter workers, and the reports have lacked both smoking data and environmental analyses for polycyclic aromatic hydrocarbons, although one would expect signif icant levels of these compounds in the environment of such operations. There have been, however, a few cases of lung cancer reported in agricultural workers exposed to arsenical sprays or dusts. Chromates There have been several reports of an increased incidence of lung cancer in chromate workers, but none that considered the role of cigarette smoking.83 Nickel An unusually high incidence of lung and sinus cancer has been noted in workers in nickel refi neries in England, Canada and Norway.83 84 The specific carcinogen has never been identified with cer tainty, but the role of nickel and nickel compounds has been ques tioned; most authors accept nickel as a carcinogen for animals.47 The only paper in which smoking was considered lacked data to deter mine relative risks for smokers and nonsmokers.48 550 CMA JOURNAL/SEPTEMBER 8, 1979/VOL. 121 Chlormethyl ethers These chemicals have been shown to be very active carcinogens for animals, and the observed ex posure and latent period in humans with lung cancer induced by these substances have been relatively brief.35 The numbers of cases were small and the distribution of smok ers and nonsmokers was similar to that of the general work force. One paper, however, suggested that the irritant action of these substances was so great that it discouraged smoking, so that the greatest expo sure to chlormethyl ethers was re corded in nonsmokers.49 Coal tar distillates The active agents in coal tar dis tillates include polycyclic aromatic hydrocarbons. Industrial exposure is principally in coke oven and gas and coal tar workers.36,37 Unfor tunately, none of the published studies considered smoking his tories. The authors of the US En vironmental Protection Agency re port used a formula to derive a relative risk for nonsmoking steel workers to show that all the risk could not be attributed to smoking. It is probably reasonable to as- Occupational exposure to carcinogens can occur anywhere, from greenhouses to nuclear power plants. Exposure is reduced by the appropriate clothing. (Photographs from the National Film Board-Phototheque). CMA JOURNAL/SEPTEMBER 8, 1979/VOL. 121 553 sume that the carcinogens in tobac co tars and coal tars are similar and that there is a simple additive effect. Polycyclic aromatic hydrocar bons are widespread, occurring with almost all forms of combus tion.50 They have been detected in kitchens, barbecued steaks and, at low levels, ambient air. Exposure is universal and not limited to smokers or certain occupations, al though it is obviously greater in some occupations. cated that the prevalence and in tensity of smoking in the fluorspar miners was unusually high.40 The tumours were epidermoid rather than the oat-cell variety encount ered with uranium exposure in Co lorado. This epidemic occurred in a relatively isolated and possibly in bred community, so that one might suspect that genetic factors were involved. However, the exposureresponse relation was strong,53 and radiation exposure per se was prob ably the most important risk factor. thought could be given to restricting employment in possibly hazardous jobs to nonsmokers, although this might be considered discrimination by some and could be difficult to implement. Ultimately, in view of the large number of mutagens and potential carcinogens, both natural and man-made,54 techniques to im prove host defences may prove to be the most practical way to reduce the risk of lung cancer to negligible levels, but this is still only a distant possibility. Mustard gas Mustard gas is a highly reactive alkylating agent that is, one hopes, of historical interest only. Cases of lung cancer in humans resulted from its manufacture as "war gas" in Japan.38 Derivatives of this agent are used in the treatment of cancer and are suspected of being capable of causing cancer. Ionizing radiation Lung disease was described in the Schneeberg miners in Europe long before cigarettes were in vented, and was shown to be can cerous in 1879. As early as the 1920s this problem was attributed to radiation exposure in the mines. Uranium miners in Colorado and Ontario have been shown to have an excessive incidence of lung can cer.39,49 It is theorized that radon daughters can adsorb onto aerosol particulates, so that damage from a-radiation is localized to the areas of the respiratory tract where such particles tend to deposit.51 There is evidence from Colorado of only a slightly increased risk of lung can cer for miners who are nonsmokers. There smoking seems to have been permitted underground (it was banned in Ontario in 1973); hence, it is possible that the cigarette smoke aerosol was a factor and that a-emitters were deposited on already damaged bronchial epithe lium with reduced natural defences. A tragic epidemic of lung cancer in fluorspar miners in Newfound land has also been attributed to radiation exposure from radon daughters.40 The exposure was com parable to that in Colorado for which Archer and Lundin52 showed a relative risk of 7.9. A report of the Newfoundland tragedy indi Conclusions In cases in which smoking and occupational carcinogens interact, the combined effects may be accounted for by an additive mech anism of syncarcinogenesis that includes delayed clearance of car cinogens from mucosa already damaged by cigarette smoke. The result for smokers exposed to air borne asbestos or radiation is a greatly increased risk of lung can cer. Data are either absent or ex tremely scanty, however, for ex posure to all occupational carcino gens except asbestos and radiation, and the mechanism of carcinogen esis by asbestos is still obscure. As most cases of lung cancer asso ciated with exposure to arsenic, chromates and nickel have occurred in situations in which polycyclic aromatic hydrocarbons would have been present, one can speculate that the metals may have acted as pro moters rather than initiators. Care ful epidemiologic evaluation of smoking as a factor in these cases is desirable but may be impossible since conditions of poor industrial hygiene in these industries are now generally a thing of the past. Considering the dual role of smoking in the induction of lung cancer, one would expect smokers to be the first to show an increased incidence of lung cancer when ex posed to relatively weak additional lung carcinogens. As a corollary, while one must not ignore the known occupational carcinogens, the most effective immediate step to reduce the incidence of occupa tional lung cancer would be to con centrate on reducing smoking. It will probably be impossible to elim inate all respiratory carcinogens from the environment. Therefore, I thank the editorial reviewers for the Journal, whose constructive criti cism and advice proved most valuable. References 1. Smoking and Health. Report to the Surgeon General, US Dept of Health, Education, and Welfare, Public Health Service, Washington, 1964 2. Sterling TD: A critical reassess ment of the evidence bearing on smoking as the cause of lung can cer. Am J Public Health 65: 939, 1975 3. Key MM (ed): Occupational Dis eases: a Guide to Their Recognition, DHEW (NIOSH) publ 77-181, US Dept of Health, Education, and Wel fare, Public Health Service, Center for Disease Control, National In stitute for Occupational Safety and Health, Washington, 1977, p 443 4. Kotin P: quoted in Occup Health Saf Lett 7 (10): 7, 1977 5. 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Archer VE, Lundin FE: Radio genic lung cancer in man: exposureeffect relationships. Environ Res 1: 370, 1967 53. De Villiers AJ, Windish JP, Brent F de N, et al: Mortality experience of the community and of the fluor spar mining employees at St. Law rence, Newfoundland. Occup Health Rev 22: 1, 1971 54. Ames BN: Environmental chemicals causing cancer, birth defects: de veloping a strategy for minimizing human exposure. California Policy Seminars, Berkeley, Dec 1977 CMA JOURNAL/SEPTEMBER 8, 1979/VOL. 121 555