Tobacco Documents Online

R' Interactions between Smoking and Other Exposures: Occupation and Diet STEVEN D. STELLMAN American Cancer Society New York, New York 10001 INTRODUCTION There are two important reasons for investigating the relationship between tobacco smoking and other factors in the causation of illness. In the first place, smoking is causally related to a very large number of diseases, including those which cause the majority of deaths in our society. Many of these diseases, particularly cancers of the lung and other sites, also have environmental causes in addition to stnuking. Many of these environmental factors increase the qpantitatfive risk of diseases by amounts sintilar to or oftenJess than the risks associated1with smoking; yet many people exposed to these factors also smoke„so that it is often a nrajur methodb- logical problem in epidemiological studies to disentangle the effects due to smoking from those due to other exposures. The second reason for pursuing smoking-environment interactions is that samc substances, notably asbestos, increase the risk of smoking-related disease far above the amount' expected if smoking and asbestos excrtcd their effects indcpcndL•ntly. This effect„often called synergism, has profound implications for predicting future numbers of': cases of diseases (Selikoff 1981), as well' as for developing strategies for prevention. Most multiple-factor studies have centered~ around cigarette smoking and occu- pational exposures. The literature on this subject is now sufficiently abundant that the 1986 Surgeon-General's report on smoking and health is devoted exclusively to occupation. Among the topics treated at length in that report are general work- piace interactions, chronic lung disease, and cancer. Among the exposures con- sidrjred are petrochemicals, aromatic amines, pesticides„asbestos, radon daughters, and cotton dust. Rather than attempt to cover these topics which have already been reviewed in great depth in that report, in detail, this paper will be confined to presenting a superficial summary of the interaction problem, with~ some interesting illustrations from studies of both occupation and nutrition in relation to smoking and cancer. I will mention some of the problems encountered in trying to analyze these situa- tions epidemiologically and present some new American Cancer Society data which may help us as we proceed to investigate the interrelationships between smoking and other exposures. 377 Btrnbury Report 23: Mechanisms in Tobacco Carcinogenesis: Q Cold Spring HarborLahnratorv. 0-87969-223-5-8/86 $1.00 + .00

378 / S. D. StNlman The 1979 Surgeon-General's report lists six ways in which cigarette smoking can interact with the occupational environment to increase risk of illness or injury'(U.S. Dept. Health, Education, and Welfare 1979). (1) A working environment may facilitate body absorption of the toxic com- ponents of cigarcttc smoke. (2) Cigarette smoking can transform workplace chemicals into more toxic sub- stances. (3) A worker can be doubly exposed to the toxic constituents of tobacco smoke and to the same constituents in the workplace. (4) The health effects from environmental exposure can be concurrent with similar health effects from smoking. (5) The synergistic effects of all agents can posc a grave health problem to:workers. (6) Accidents canbc caused by smoking initho industrial cnvironment. During the past few years, an elaborate-and' sometimes controversial-mathe- maticai formalism has been developed for d'escribing and quantifying such inter• actions, particularly as they apply to measuring the contributionrto total risk of disease due to individual exposures (Walker and Rothman 1972; Rothman 1976, 1981; Saracci 1977, 1980; Rothman et al. 1978; Walter and Holford 1981). Formal definitions have been proposed for causal types of concepts, such as interaction and synergy. The main difficulty in this area has not been lack of good statistical ideas so much as lack of good data. As will be shown below, the basic environmental dosage measurements, which are hard enough to obtain reliably for a single ex- posure, become very tenuous when applied two at a time. Nevertheless, there are now available a number of useful examples to illustrate the wide range of inter- actions between these various exposures and smoking. To simplify the discussion and focus attention on ~ the factors themselves, I' willl present data from a number of multfiplc•factor studies in terms of two simple models: additive and multiplicative. The numericali aspects of these models are presented in Table I, in terms applicable to studies in whichieither relative risks or Table 1 Comparison of Additive and Multiplicative Models for Two Simultaneous Exposures Exposure Relative risk Rate Neither 1.0 lo Smoking s sio Additional factor a alo Both Additive modet' (s + a - [i) (s + a - 11) [o Multiplicative model sa sata

Smoking Ihteractions with Occupation and Dia / 379 absolute rates are available. If s is the relative risk conferred by smoking in the absence of the second exposure, and a is the relative risk due to the second' ex- posure in the absence of sluuking; tllen aciording to the :IdditJvl) IIIUdCI the felallve' risk among persons exposed to both shoul& be s+ a - I, whereas according to the multiplicative model it should be sa. Extension, to ntultiple levels of exposure is straightforward. The key to developing both models is that risks due to any combination of exposures must always be measured relative to a common reference point. SMOKING AND OCCUPATION Figure l shows the relative risk for lung cancer in relation to both smoking and shipyard work according to the data of Blot'and'Fraumeni(1981) combine&across four studies. Smoking apart, it is assumed that the excess lung cancer risk among shipyard workers is due mainly to exposure to asbestos, although other contribu- tory factors are certainly possible. Except' for former smokers, the relative risk (RR) among shipyard workers is higher at each level of smoking, compare&to the 24.0 22.0 20.0 1&0 i 1 16.0 14.0 ~ 12.0 10.0 8.0 6.0 4.0 ~ 2.0-i 0.0 LEGENO 9MYUIe WORK M 1:1 NO Y., MaoeliVn MoASI A.M.• ACdiHrr. M.M.:• MWfip/ieulivr 10.7 r1lK 2.2 1.0 6.0 8 6:2 .-.:Y.. 4.9 4 .-A:fa 3.7 F~~.F I ffl ,,.a rY.M 10_2 22.7 ~YY tf.x NON- Ex- 0.50.3-1.3 2+ SMOKERSMOKER PACK PAqCSPACKS CIGARETTE SMOKING STATUS Figure 1 Relative risk for lung eancen according to number of cigarettes smoked per day and'whether or nor subject worked in a shipyard. Data from four case-control studies combined. Data from, Blot and Fraumeni (1981):

380 1'S. D. Stellman RR among nonshipyard workers. At the level ofl 0.5 to 1.5 packs per day, the actual RR among shipyard workers is higher than the additive model predicts, but less than the multiplicative modcl, whereas among the heaviest smokers, it is nearly the same as the mtdtiplicative ntodel:. Tahlo2shows tthe lu.ngcancer death ratess determined by Hammond a al. (1979) among asbestos insulation workers ac- cording to whether or not they smoked and according to the source of information on cause of death (death eertificate versus bestevidence). In either case„the actual rate among those exposed to both asbestos and cigarette smoking is well above the additive model, and, in the case of death certificate ascertainment, is nearly multi- plicative (601.6 observed versus 633.6 predicted). Stellman and Garfinkel (1984) recently reported on the mortality experience of 10,322 men employed in woodworking industries and followed up for 12 years in an American Cancer Society study. Figure 2 shows the standerdized mortality ratio (SMR) for lung cancer„according to smoking habit and usual employment as nonwoodworker, woodworker, or in the carpenter-joiner subgroup. The mortality rates for woodworkers in general and for the carpenters among them were higher than in the nonwoodworkers only among smokers of 20 or more cigarettes per day. Figure 3 shows the analogous SMR pattern for bladder cancer„with similar findings. In the case of lung caneers the risks of smoking and woodworking seem to be additive, but with bladder cancer they are more nearly multiplicative. Whether or not exposure to ionizing radiation in the form of radon daughters, particularly through underground mining, increases lung cancer risk multiplicatively has yet to be resolved. Relative risks for lung cancer among smoking Swedish under- ground miners of iron ore, computed by Damber and Larsson (1985), shown in Table 3„agree well with those predicted with a multiplicative model. On the other i Table 2 i Comparison of Observed Cancer Death Rates with Predictions of Additive and Multiplicative Models Exposure Lung cancer dlath rate Best evidence Death~ certificate Neither 11.3 11.3 Smoking 122.6 122.6 Asbestos 80.2 58.4 Both Actual 693.8 601.6 Predicted Additive model 191.5 1!69.7 Multiplicative model 870.1 633.6 Basu:d on data from llammond et al. (1979)

Smoking intxactions with Occupation and lDi.t / 381 500 250 C NON-WOOOWORKER. E» mOOOMORKER t= CKMCBTRY AMO AOINERY F/ V. P" NEvER SY0KE0 REGUUARIn •A C!•8 ::i_.__ 11_i1 O 1-i9 20. 21-39 40.CURRENT C"RETTE SYOK[RS,AMT vER DAY Er- wvf OR R SNOKERS CiGA SNOKERS Figure 2 Standardized mortality ratios (SMR) t'ur lung cancer by occupation lwcxxiwurker or nut) and srnoking habits. All categories arc relative to nunwocKlworkcrs whn were current smokers uf 20 ciylrettos per day (= 100). Reprinted, with pcrmiticion„frnmiStelhnanand Garfinkel (d984)1 hand„several other studies (Edling 1982; Radford and St Clair Renard 1984) show risks that are additive. Hirayama (1981) has reported age•stand'ardized death rates from all cancer, lung caneen, and stomach cancer (Table 4)!among material metal workers, in the context of a very large prospective study of the general population in Japan. According to his data, the actual rates for all cancers and fon stomach~cancer are considerably above those predicted by either modbl, whereas the lung cancer rate is consistent witit an additive model. In a case-control study in an industrialized area of Mbrthern Italy,,Pastorino et al. (1984) computed relative risks for lung cancer in relation to smoking and em- ployment in occupations in which exposures to known carcinogens are likely. Such exposures included asbestos, polycyclic aromatic hydrocarbons, chromium, nickel, and arsenic compounds, bis-chloromethyl ether, chloromethyl methyl'ether, and vinyl chloride. Subjects were classified as not exposed (-), or as definitely or potentially exposed (+,?). Figure 4 shows the relative risks. For the heaviest smokers, the RR was 20, which is higher than that predicted by an additive model (112.5) but Ics.c'thana multiplicative nuxlcl ('_7.5):

382 / S. D. Stellman Exposure Relative risk for lung cancen Neither 1.0 Smoking 7.4: Underground mining 5.5 Both Actual 40.6 Predicted Additive model 11.9 Multiplicative model 40.7 Table 3 Comparison of Observed Cancer Death Rates with Predictions of Adtlitive and Multiplicative Models Based on data from Damber and'larsson (1:985) NEYER SNOKED REOUIA/lT 1-1e 20 21-3f 10• CURRENT CIWRETTE SYOKER3,4YT.7ER.DA7 Ex- M0E OR SYOKERS CIDA R. SYOKERS Figure 3 Standardized mortality ratios (SMR) for bladder cancer by occupation (woodworker on not) and smoking habits. All categories are relative to nonwoodworkers who were currenn smokers of 20 cigarettes per day (- 100). Reprinted, with permission, from Steilman and Garfinkel (1984)1

Smoking Interactions with Occupation and Di.t /, 383 Table 4 Comparison of Observed Cancer Death Rates with Predictions of Additive and Multiplicative Models Age-standardized death rate per 100,000 from: Exposure All cancers Lung cancer Stomach cancer Neither' 304.3 20.7 136.5 Daily smoking 495.9 85.5 200.7. Material metal' workers 305.1 62.5 180.8 Both Actual 851.7 142:1 400.3 Predicted Additive model 496.8' 127.3 244.3 Multiplicative model 497.5 258:2 264.9 aApproximated'by total ttudy population nonsmokers Based on data l'rum llirsyanta (1981) . 0 1-9 10-19 20-29 30 + ugarettas Figure 4 Relative risk for lung eancer, by definite (+) or possible (?) occupational exposure to industrial' carcinogens, according,to number of cigarettes smoked'per day. Reprinted, with permission, from Pastorino et al. (1i984);.

384 / S. D. Sta/tman SMOKING AND DIET In addition to interactions between smoking and occupation„the interactions with alcohol consumption have been studied extensively. The recent surge,of interest in nutritional aspects of' carcinogenesis has also led to a realization that the samee principles may also appiy: In studies of diet and lung' cancer, Ilur example, it iss essential to take smoking habits into account, so as not to mistakenly report an apparent diet-lung cancer effect that might actually be due to confounding byy smoking. Alcohol plays an etiologic role in cancers of the mouth, larynx, oral cavity, and esophagus (Wynder and Stellman 1977, 1979). It has been widely stated that alcohol is not: a carcinogen by itself but that it promotes titie carcinogenic effects of tobacco smoke. However, it has always been difficult to settle this point„because of the cultural nature of heavy drinking: ltis very'rare to find a heavy drinker who is not also a smoker. Consequently,, the error bounds for estimates of' RR in heavy drinkers in the absence of smoking are usually too large to permit drawing firim conclusions about the carcinogenicity of alcohol alone. Further difficulties im estimating the relative risks of alcohol accurately arise from uncertainties in assigning dosages. Some heavy drinkers consume similar quantities of alcohol each day, as with cigarette smoking; but others drink in binges, spaced by short or long periods of time. The epidbrniologist musY conse• quently make drastic assumptions about exposure in order to aggregate sufficient numbers of cases into a small enough number of categories for useful analysis. Figure 5 shows a reasonable way in which such categorization has been done (Mashberg et al. 1981). Here, drinking has been classified according to the number of "whisky equivalents" (we) ~ consumed per day, as a way of normalizing beer, wine, and spirit consumption, on the same scale. An interesting feature of this case- control study of oral squamous carcinoma is the use as a reference gruup of "minimal" smokers and. "minimal" drinkers, rather than nonsmoking nondrinkers. This distinctioniwas necessary because of the high prcvalence ofbuth smoking andi drinking in: the entire study population. Among "minimal" smokers, the RR ruse with the number of we per day. At each higher level of smoking, the RR among heavier drinkers was higher than among "minimal"drinkers, but the relationships are not consistent. Table 5 shows the interaction models at the highest levels of smoking anddruiking; The RR (104.7) is somewhat between, the additive (30?), and multiplicative ('185.6) models. An alternative classification scheme for aloohol' consumption was proposed by Olsen et al. (1985) in a case-control study of cancer of the larynx. Figure 6 shows smoking- and alcohol-specific RRs, at levels of 0-100. 101-?00, 201-300, an& 301+ g of alcohol per week. As in the preceding study, the reference levels of both alcohol and tobacco usage were not restricted to total abstainers. A number of investigators have recently begun to examine the interaction be- tween smoking and specific food item consumption: Table 6 shows the SMR for

Smokinp Interactions with Occupation and Diet /'385 < O 160 I 2 J cc 1 40 I ' +' < ~ .' J M 120 • ' IDO Cl N ip1M ~ W N / t •e I % 0 e: • % 0 so Y 40 `%• • ~ • ' Q 20 0~.. • ~ l{ p / ` 0. _ YYi.a_ WNIMML CIGAR 10-19 20-3f 40+ J W %PE 0: DALYpGARETTE SMOKING NIkBIT Figure 5 Relative risk for ural afuantous earcinuma. aceording to number uf cigyrottcs vnuked per day and number of "whisky equivalents" consumed per day. Reference group cunsists of "minonal" drinkers and smokers„radier than nondrinkers and nonsmokers. (we) Whisky equivslents. Data from Mashberg et al. (1981): Table 5 Comparison ofl Relative Risks with Predictions of Additive and Multiplicative , Models Exposure Relative risk for oral' squamous.carcinoma "Minimal"smoking andidrinking 1'.0 Smoking 40 or moru vigJrettes per day 8.0 Drinking 10 or more whisky equivalents per day 23.2' Both Actual 104.7 Predicted Additive model 30.2 Multiplicative model 185.6 IMs.d on data from Mashberg,et al. (1981)

388 1 S. 0. Stellm6n .,«.., 1.~....,. xoi-~oa ~ ~oi-zoc o-10 0 0-10 I I+20 21+ TOBACCO (g/doy) Figure 6 Age- and sex-adjusted~rclative risk for larynx cancer according to numberof cigarettes smoked porday and number uf g uf alcohol consumed per week. Data from Ul.cun cti•rll (1985). Table 6 Comparison of Observedi Cancer Death Rates with Predictions of Additive and Multiplicative Models Age-standardized deathirate per 100,000 from lung cancer E xposure Males F ern ales Neither 14.5 1!1.7 Daily smoking 66.3 1i9:0 Avoidance of green-yellow vegetables 32.4 1i6:7 Both Actual 79.5 33.9 Predicted Additive model 84.1 24.0 Multiplicative model 147.8 27.1 Based on data from Hirayama (1979)