PREVENTIVE

MEDICINE

5,245

- 261 (1976)

Smoking DIETRICH Naylor

and Occupational HOFFMANN

AND

ERNST

Dana Institute for Disease Prevention, American New York I0595

Cancers’ L. WYNDER Health

Foundation,

Valhalla,

The relative importance of tobacco smoking as a cofactor in occupational cancers is discussed. Where epidemiological evidence is available, relative effects for both agents, occupational carcinogens and tobacco smoke, can be evaluated; where it is not available, mechanistic considerations derived from animal studies are presented in an attempt to assess the relative roles. A review of the literature shows a lack of epidemiological data for the joint action of occupational carcinogens and tobacco smoke. This applies particularly to nickel carcinogenesis, coke oven and gas workers, and for workers in the chemical industries related to halo ethers and vinyl chloride and certain urinary carcinogens. Synergistic and/or additive effects of occupational carcinogens and tobacco smoke may be regarded as epidemiologitally established in the areas of exposure to radon daughters and to some types of asbestos. Experiments designed to support evidence of syncarcinogenic and/or cocarcinogenic effects of totiacco smoke and occupational carcinogens are needed in the areas of carcinogenesis of nickel, chromium, arsenic&, vinyl chloride, and halo ethers. The latter, however, are very potent respiratory carcinogens by themselves. Similarly, the aromatic amines as potent industrial bladder carcinogens may be studied for cocarcinogenic mechanisms with tobacco smoke constituents. It is emphasized that epidemiological studies in occupational cancer must include the smoking histories in order to gain knowledge of the relative contribution of causative factors. Furthermore, it is the heavy cigarette smoker who is most likely to be the tirst affected by traces of carcinogens and will therefore give us the first clue as to the occurrence of new cancer hazards.

INTRODUCTION

A study of the mortality of various cancers in occupational groups underscores the importance of lifestyles apart from the occupational setting, and particularly the importance of cigarette smoking. This observation parallels a common occurrence in carcinogenesis. Often, the cumulative action of two agents contributes more to the development of a cancer than would the agents separately. Therefore, when reporting on a given occupational group, the determination of such habits as tobacco smoking is necessary in order to ascertain whether the increased risk is due to the occupational exposure itself, or the greater smoking habit of individuals in the group compared with controls, or to the combined effect of smoking and exposure to occupational carcinogens. In this communication we shall review the extent of available epidemiological evidence indicating an added effect of tobacco usage to that of occupational carcinogens. It is apparent from our review of the literature that in most of the epidemiological studies dealing with occupational carcinogenesis, information relative to other background data for the individual, particularly regarding tobacco usage, is not available. In addition, we are I Research support is acknowledged

from American Cancer Society Grants. No. BC-56 and CI-I 15. 245

Copyright All rights

0 1976 by Academic Press. Inc. of reproduction in any form reserved.

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presenting experimental studies which have attempted to examine the possible interrelationship between tobacco smoke and specific occupational carcinogens. RESPIRATORY

CANCER

Cancer of the respiratory tract has been causally associated with exposure to industrial agents such as radiation, vapors, and dusts. The list of the major industrial respiratory carcinogens includes uranium and iron ores, asbestos, arsenicals, nickel, vinyl chloride, halo ethers, nitrogen and sulfur mustards, and aerosols from coke ovens. This communication will be limited to those industrial carcinogens for which data are available for smokers and non-smokers. Even independent of such human data, it must be stressed that all workers who smoke face a higher risk for cancer of the respiratory tract than the corresponding non-smoking workers. a. Uranium Mining Epidemiology. As early as the middle ages, miners of uranium-bearing ores in the Erzgebirge near Schneeberg (Saxony) and near Joachimsthal (Bohemia) were known to die from pulmonary diseases called “Bergsucht” (1). In 1879, “Bergsucht” was shown to include cancer, subsequently diagnosed as squamous cell cancer (37,72). The first statistical evaluation found the lung cancer mortality of the Schneeberg miners to be 35-45 times higher than that of the male population of Vienna, Austria (68). The causative agents in the atmosphere of the mines were a-particles resulting from the decay of the short-lived radon daughters (26). The reports on European miners have been supplemented by studies on North American non-uranium miners (26,101,102) and on workers in U.S. mining industries. Wagoner et al. found a highly significant increase for cancer of the lung among 3,415 white underground U.S. uranium miners for the period 1950 through 1963 and, even after adjustment for smoking, a suggestive close response between cumulative exposure estimate (less than 120 to 3,720 working level months = WLM) and incidence rates for cancer of the lung (77,101). A mortality study of 3,414 white uranium underground miners in relation to radiation exposure, hard rock mining and cigarette smoking for the years 1950 through 1%7 revealed a significantly excessive death rate (398 vs 251) for U.S. males (54). One major factor for the excessive death rate was the high incidence of malignant neoplasms of the respiratory tract (62 vs 10 expected). Even after adjustment for the smoking habit, a high excess of lung cancer remained (62 vs 16). The authors estimated that non-smoking uranium miners experienced 1.7 excess respiratory cancer deaths per 10,000 persons per year of observation while the excess for cigarette smoking miners was 17/10,000 persons per year. Among the 761 nonwhite underground miners, only two lung cancers were observed; one lung cancer death was a smoker, Since the majority of the nonwhite, primarily Indian, underground miners were nonsmokers or only light cigarette smokers, it appeared surprising that the authors did not discuss the possibility that in respect to lung cancer, radiation and smoking may be more than just additive. The same group of white U.S. underground uranium miners was the subject of a very detailed study by Saccomanno (76), who reported that 78% of the miners

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were cigarette smokers and that among the 62 lung cancer cases there were only two nonsmokers. Saccomanno calculated an annual lung cancer incidence of 700/ 100,000for cigarette smoking uranium miners and 95,230, and 265 per 100,000for nonuranium-mining smokers of half a pack, l-2 packs, and more than two packs per day of cigarettes, respectively. The author concluded that there is a very potent synergistic effect in cigarette smoking and radon daughter exposure. Saccomanno suggests that in view of this finding and considering the very short life of radon daughters (less than two hours), prohibition of smoking during mining would be an effective preventive measure in that it reduces the synergistic effects significantly. In a later publication, data for the above study were further extended and corrected and included 3,366 white and 761 nonwhite miners (4). The follow-up was extended to September 1968 and included only uranium miners employed prior to 1964. In the case of white miners, 70 lung cancer deaths were reported vs 12 expected cases. The authors present smoking histories of the lung cancer cases, their calculated radiation exposure, and histological data for 115 underground uranium miners (1950-1971). Of these, two were non-smokers, 100 cigarette smokers, and 13 ex-smokers (for at least 10 years). Ninety-nine cases had Kreyberg type I lung cancer (30 epidermoid and 69 oat cell cases), eight had Kreyberg type II (adenocarcinoma plus undifferentiated carcinomas), three cases had both types of lung cancer and five cases were not diagnosed histologically. The distribution between Kreyberg lung cancer type I and II is comparable with the findings for lung cancer cases among male cigarette smokers (46,104). For Kreyberg type I, however, the uranium miners had a higher prevalence for oat cell carcinoma as compared to squamous carcinoma. The authors concur with earlier conclusions as to the risk for lung cancer in U.S. uranium miners; however, they stress that cigarette smoking appears to be even more harmful to uranium miners than to smokers in general because of the combined effect of tobacco smoke and radon daughter exposure. Experimental. Are high lung cancer incidence rates for cigarette-smoking uranium miners caused by additive or synergistic action of the two pulmonary carcinogens? Several experimental studies have been concerned with this problem. During 12-24 months, Chaumeand et al. induced lung cancer in rats after exposure to between 500 and 14,000 Working Level Months (WLM) of a-particles from radon daughters. Exposure of 500 to 9,600 WLM indicated a dose response for all histological types of lung tumors. Experiments with rats involving radon radiation and tobacco smoke as cofactors have not been completed as yet (16). Filipy et al. induced pulmonary lesions in dogs after exposure to 600 WLM of radon daughters with uranium dust (29). After 4% years, only preneoplastic lesions were observed in the alveolar regions. The lungs of dogs exposed to low doses of cigarette smoke via masks and, in addition, to 600 WLM of radon daughters and uranium dust, also showed only preneoplastic changes. We need to consider that only minute amounts of smoke particulates will reach the lungs of dogs when smoke masks are used. Cigarette smoke action can be shown only when the smoke is introduced into the lungs of dogs via a tracheotomy as developed by Battista et al. (6).

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Thus, there is no direct experimental evidence at this time that the carcinogenic effect of radon radiation or uranium dust in inhalation studies can be potentiated by additional exposure to cigarette smoke. Until such data become available, we must extrapolate from model studies showing the synergistic effect of a-radiation (210Po)and a chemical carcinogen (benzo(a)pyrene) after tracheal installation in hamsters (58). Since tobacco smoke is known to contain benzo(a)pyrene (BaP) and other carcinogenic aromatic hydrocarbons, this study is germane to the problem. McGandy et al. instilled into the trachea of male Syrian golden hamsters 15 weekly doses of 2.5 pCi of 210Poon ferric oxide (I), or 15 weekly doses of 0.3 mg of BaP on ferric oxide (II), or 15 weekly doses of both (III). After 10 weeks, the lung tumor yields were: for group I, 12.2% (lo/82 hamsters); group II, 7.6% (5166); and for group III, 34.2% (25/73). All tumors were combined adenocarcinomaepidermoid carcinoma type and arose in the peripheral region of the lung. This result suggests a synergistic action between a-radiation and a chemical carcinogen. In summary, epidemiological data have demonstrated a significantly higher risk in developing cancer for uranium miners who smoke than for non-smoking miners. It appears possible that the effects of the two carcinogens, cigarette smoke and a-radiation, are not only additive but also synergistic. At present we lack experimental data for the effects of simultaneous exposure of animals to a-radiation and cigarette smoke. However, the yield of pulmonary tumors in hamsters which were simultaneously exposed to a-radiation from 210Poand the chemical carcinogen BaP support the possibility of a synergistic effect in the lung also for a-radiation and tobacco smoke. b. Asbestos Epidemiology. Occupational and environmental exposure to asbestos dust and the development of asbestotic reactions in the lung have been known for centuries (18). The first cases of asbestosis complicated by pulmonary carcinomas were described in 1933 (32). Since then, and especially during the last two to three decades, epidemiological studies have shown that with the enormous increase in the production and industrial use of asbestos, the rate of carcinoma of the lung and mesothelioma of the pleura and peritoneum has sharply risen in asbestos workers. Hueper, in his monograph on “Occupational Respiratory Cancer” (1966), listed carcinomas of the lung in 240 confirmed cases from eight Western countries (43). Since then the number has further increased as is well documented by studies from South Africa, England, and the United States (20,81,103). In 1972, the National Registry of South Africa reported 360 cases of mesothelioma of the pleura, 205 of which were found in workers with known exposure to asbestos, as well as 28 cases of bronchiogenic carcinomas in a group of 784 asbestos miners (103). In 1960and 1964, the first discussion appeared in the literature on the possible existence of a syncarcinogenic effect of asbestos and cigarette smoke with regard to the induction of bronchiogenic cancer in asbestos workers (13,81). Selikoff et al. traced the medical records of 632 men who had been employed as asbestos insulation workers in the New York City area and who were on union rolls between 1943 and 1962 (82). The 370 workers who were still living at the end of 1962 were interviewed, examined, and followed up for 52

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months. In this group, 10 died of pleural and peritoneal mesothelioma (none expected), and 24 died of cancer of the lung, bronchus, and trachea (all cigarette smokers) with 2.3 expected cases without adjustment and 2.98 expected with adjustment for smoking habits. With non-asbestos workers who never smoked (0.26 cases expected) as a basis, the authors calculated that the combined carcinogenic risk of smoking and asbestos exposure for bronchiogenic carcinoma has been increased 92 times. The data also suggest that the risk for bronchiogenic cancer in asbestos workers increases not only for cigarette smokers compared to nonsmokers, but that there is a clear dose related increase with the number of cigarettes smoked. It is also significant that none of the nonsmokers (48) nor the pipe and cigar smokers developed bronchiogenic carcinoma, and of the 10 cases with pleural and peritoneal mesothelioma, eight were cigarette smokers and only one case each was recorded with peritoneal mesothelioma for a nonsmoker, and for a pipe and cigar smoker. Hammond and Selikoff subsequently studied the death rates among 17,800 U.S. and Canadian asbestos workers between 1967 and 1971 (36). They recorded 213 cases of lung cancer2, 26 cases of pleural mesothelioma, and 51 cases of peritoneal mesothelioma. From the 2,066 nonsmokers or cigar and/or pipe smokers, two developed bronchiogenic carcinoma (5.98 expected) and 134 of the 9,590 cigarette smokers (25.09 expected). Again, a large excess of lung cancer was observed for the cigarette smoking asbestos workers and, in fact, the ratio of observed to expected cases may have been even larger if the smoking habits had been known for the remaining 6,144 insulation workers with 77 bronchiogenic carcinomas. The authors did not draw a conclusion as to the importance of cigarette smoking on the induction of pleural mesothelioma in asbestos workers. Of the 26 cases, 17 were cigarette smokers, one a cigar smoker, one a nonsmoker, and of seven cases the smoking habits were unknown. The experiences of 51 cases with peritoneal mesothelioma (nine nonsmokers, 29 cigarette smokers, 13 workers with unknown smoking history) suggested to the authors that for this type of tumor, smoking does not increase the risk among asbestos workers. Berry er a/. studied the smoking habits of 1,325 male and 482 female asbestos workers of a London factory and followed their mortality from lung cancer over a lo-year period (8,64,65). Among the male workers they observed a total of 35 bronchiogenic carcinomas, two in ex-smokers and 33 in cigarette smokers, as well as seven pleural mesotheliomas. Among female workers, there were a total of 15 bronchiogenic carcinomas, one in a nonsmoker and 14 in cigarette smokers, as well as five pleural mesotheliomas. After adjustment for smoking habits the observed lung cancer rate for smokers with severe asbestos exposure was 25.5 compared to the expected number of 9.9; the figures for female smokers with severe asbestos exposure were, observed 15.5, expected 1.4. The authors examined the data for smoking workers with heavy asbestos exposure and lung cancer and concluded that the effect of the two carcinogens, asbestos dust and cigarette smoke, may be not only additive but may be even multiplicative, a hypothesis in line with the observations by Hammond and Selikoff (65). * (Origin

and type

of cancer

were

not presented).

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In recent years, several investigators have been concerned with the exposure of the general population to asbestos dust from construction sites, brake linings, and from polluted air close to asbestos factories. Langer and Selikoff identified chrysotile in the lungs of New York City residents without occupational exposure (50). Bohlig and Hain reported 38 cases of mesothelioma between 1950and 1968in residents of suburban Hamburg, Germany, proximal to an asbestos factory (12). These observations make it possible to theorize that the inhalation of asbestos particles with polluted air may increase even further the lung cancer risk of cigarette smokers per se. We conclude from the epidemiological findings that asbestos induces mesothelioma of the pleura and peritoneum, but not by itself of the bronchus, that cigarette smoke and asbestos dust combined are carcinogenic to the bronchial epithelium, and that their combined effect induces a higher incidence rate of bronchiogenic carcinomas than cigarette smoke alone (75,94). The mechanistic effect, however, could be best evaluated by animal experiments.These studies will also enable us to define the relative carcinogenic potential of the five commercially used asbestos minerals; amosite, anthrophyllite, chrysotile, crocidolite and tremolite, and their various subforms (60). Experimentai. Upon intrapleural injections of various naturally occurring asbestos fibers, several groups were able to induce mesotheliomas in rats (71,86,88,99) and to demonstrate that the particle size is an important factor for the carcinogenic activity of the asbestos fiber (87). The induction of mesothelioma in rats upon intrapleural application was found to be independent of the natural oils and waxes which are often present with the asbestos materials (38). These oils and waxes are known to contain carcinogenic hydrocarbons and appear, therefore, not to have an additive or cocarcinogenic effect in respect to the induction of mesotheliomas. Smith and Hubert also induced mesotheliomas in Syrian hamsters upon intrapleural injection and, in addition, obtained data which indicate a dose response for chrysotile, amosite, and crocidolite (85). Pylev and Shabad instilled intratracheally into hamsters chrysotile washed free of BaP (I), chrysotile containing BaP in the oil (II), chrysotile plus synthetic BaP (III), and BaP alone (IV) (69). They found no tumors in the lungs of groups I and IV, but they observed significant numbers of bronchiogenic tumors in groups II and III. These results suggest a cocarcinogenic or additive effect of the two respiratory carcinogens. Inhalation is the most realistic way of exposing animals to various types of dusts and cigarette smoke as it most closely parallels the human situation. Using asbestos directly from an industrial dust collection apparatus, Wagner, in his earlier work, was unable to induce bronchiogenic tumors or mesotheliomas in rats upon long-term exposure (98). In more recent experiments on rats with respirable dust of five types of asbestos samples, Wagner and Berry reported a few mesotheliomas and peritoneal tumors and even a squamous cell carcinoma in one instance after relatively short-term exposure. The data were supplemented and confirmed by results from long-term exposure. The authors stressed that the methodology of asbestos inhalation had to be refined and standardized in order to yield results of value (99,100).

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Gross et al. used hammer milled chrysotile which yields asbestos dust of ultramicroscopic dimensions and exposed rats 30 hours per week to this asbestos aerosol for 62 weeks (33). Of 61 rats, 10 developed lung tumors including three squamous cell carcinomas, six adenocarcinomas, and three fibrosarcomas. Despite its various shortcomings, this method is of value, in principle, for studying the effect of the simultaneous exposure of rats to cigarette smoke and asbestos dust. So far, only one study has been reported on the effects of asbestos and cigarette smoke on animals (27). Five hundred pg of asbestos were instilled intratracheally into hamsters, and subsequently, the animals were exposed to diluted cigarette smoke 10 times weekly for 18 months. Since only 1% of the smoke particulates reached the hamster lung, the smoke dose was far too low to be expected to induce tumors in the lower respiratory tract or to potentiate the subthreshold dose of the carcinogenic asbestos. Therefore, experimental data which can explain the carcinogenic activity of asbestos together with cigarette smoke are still lacking. Nevertheless, one would consider the strong absorptive powers of asbestos to be a key for its own carcinogenic activity and its ability to increase significantly the carcinogenicity of tobacco smoke. Upon deposition of the asbestos fiber in the respiratory tract, it may gradually release some of its carcinogenic metals and/or its carcinogenic organic compounds. This will lead to a constant diffusion of these carcinogens into the bronchial epithelium. The increase of the carcinogenic effect of cigarette smoke might be explained by the “extraction” of the tumorigenic agents from the smoke particulates by asbestos and subsequently the gradual release of the smoke carcinogens and their absorption by the lung tissue. Although this concept of the “absorptive power” is a unifying concept for the carcinogenic potentials of asbestos, it remains a hypothesis at present. c.

Nickel

Epidemiology. In 1933, the first 10 cases of cancer of the nose and paranasal sinuses were reported from a nickel refinery in Wales (14). Plant workers were exposed to the volatile nickel carbonyl which occurs during the Mond process in the relinery. Seven additional cases of nasal cancer and 19 cases of lung cancer were reported for employees from the same factory (5). Morgan and Doll wrote the last reports on nasal and lung cancer in nickel refineries in Wales, in all, 131 and 62 cases, respectively (21,61). Subsequent findings of a few cases of lung and nasal cancer in workers exposed to vapors of metallic nickel or other nickel compounds supported the conclusion that the hazard was not specifically due to Ni(CO), (53,92). Recently, Sunderman listed all documented cases of respiratory cancer which occurred among workers exposed to nickel compound inhalation (90). The reports originated from four West European countries, Canada, USA, USSR, and Japan-totalling 327 lung cancer cases and 115 cases of nasal cancer. Doll et al. studied in great detail the cancer mortality of workers in a nickel refinery in South Wales (24). Among 845 men, who were employed before 1944 and worked at least tive years at the factory, all but 27 were traced until death or until 1967. Of these workers, 113 died from lung cancer and 39 from nasal cancer. Whereas men employed before 1925 had a lung cancer risk of five to 10 times

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higher than expected and 100to 900 times the risk for nasal cancer, only eight men employed after 1925 had lung cancer, expected 6.2, and none had nasal cancer. It appears likely that respiratory cancer had decreased with improved working conditions in the factory. However, the difference in the decrease of lung and nasal cancer suggests that at least one additional factor played a role in lung cancer risk but that nasal cancer appeared to be correlated with the exposure to nickel vapors alone. In contrast to the epidemiology of the uranium miners and asbestos related cancers, the data on nickel workers contain no mention of tobacco smoking except the suggestion by Doll et al. that cigarette smoking accounts as a second factor for the increased risk for lung cancer. It is unlikely that a detailed study on the added effect of cigarette smoking on the risk of respiratory cancer in nickel workers will ever be undertaken since the Mond process is now rarely used and hygienic conditions in factories have reached high standards. We must, therefore, conclude that cigarette smoking was only a minor factor for the earlier increased risk of lung cancer in nickel workers. Experimental. The Sundermans showed that nickel carbonyl is capable of inducing epidermoid and adenocarcinomas of the lungs in rats (89,91). In addition, a variety of other nickel compounds, especially metallic nickel and nickel sulfide (N&Z&), have also been found carcinogenic, upon injections, in the experimental animal (90). While the exact biochemical mechanism(s) for the carcinogenicity of nickel compounds remains unknown, there are indications that the activity is correlated with the effect on intracellular RNA synthesis. Since a modification of the RNA will subsequently be transcribed into the nuclear DNA, and since several of the carcinogenic tobacco smoke constituents, especially PAH, are thought to have an effect on DNA synthesis, one may consider such concept as a basis for the combined carcinogenic effect of nickel compounds and tobacco smoke. This possible mechanism remains a hypothesis, although it could explain why nickel compounds in tobacco smoke may play a role in tobacco carcinogenesis. d. Arsenicals Epidemiology. Inorganic arsenicals have long been suspected to act as carcinogens in the respiratory tract following their introduction into occupational environments, and their use as drugs, in food, and in drinking water (15,43). In most cases where arsenicals are the suspected lung carcinogens, the workers had also been exposed to radioactive materials or dust from gold, nickel, cobalt, or other metals, and we can assume that many of them were cigarette smokers. The fact that some of the materials that occur together with the arsenicals could by themselves be considered carcinogens in certain occupational settings has motivated Doll, as well as Shubik, to place arsenicals in the group of “suspected carcinogens” (22,84). This classification is somewhat supported by inconclusive data from bioassays for carcinogenicity of arsenicals (93). We, nevertheless, consider arsenic to be an established lung and skin carcinogen. Several points suggest this more cautious conclusion. First, the studies by Doll, Shubik, and others were not a priori intended to disqualify arsenicals as possible carcinogens in man, but rather to point to the unresolved problems related to the carcinogenic effect of materials containing arsenic. Secondly, in addi-

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tion to lung cancer, arsenic workers often have primary cancers in other organs, especially the skin-an observation absent from the records of metal workers with lung cancer. Thirdly, excess deaths have been reported from lung cancer in German vineyard workers who used arsenicals as pesticides (45,73,74). Roth studied 27 deaths among workers in the Moselle region who developed chronic arsenic poisoning after being exposed to arsenic insecticides over a 12 to 14 year period. From these 27 deaths 12 were cases of lung cancer (73,74). Studies in the United States of America also support the concept that arsenic is an occupational respiratory carcinogen (IO). Although smoking histories of these workers were not recorded, we cannot but accept that the arsenic pesticide was a likely causative agent for the lung cancer in most of these cases. It is hoped that in future, case histories of workers who were exposed to materials containing arsenicals and who develop lung cancer will also contain data on their smoking habits. A recent study from a small city in Japan showed that from 19 men who died with lung cancer between 1%7-1969 (four times the mortality rate of Japanese men), 11 had been employed as copper smelters with heavy exposure to arsenic (47). Of these 11 smelters, 10 were light to moderate cigarette smokers (less than 30 cigarettes per day). Since comparisons were not made with the smoking habits of the general city population, no conclusion can be drawn as to the effect of smoking in the smelters. Blot and Fraumeni found that the average mortality rate from lung cancer for white males and females in the U.S.A. (1950- 1969)was increased in counties with copper, lead, or zinc smelting and refining industries, but this was not observed in counties where other nonferrous ores are processed (10). After adjusting for various other factors and assuming no significant differences in smoking habits, an increased mortality rate remained and, for one type of county, was suggested by the authors to be related to community air pollution from industrial emissions containing inorganic arsenic. In the case of arsenic, and smoking and respiratory tract cancer, no experimental studies have been reported (10). e. Chromate In the past 60 years, a steady increase has occurred in the production and use of chromate ores, chromium metal, chromium alloys, and chromium compounds. Since the tist reports from Germany in 1936 (2,3), several retrospective studies confirmed a steady increase of lung cancer among chromium workers in Europe and the U.S.A. Hueper summarized all reports in 1966and listed among chromate workers 180 cases of cancer of the lung, five cancers of the nasal sinuses, and one cancer each of larynx and nose (43). About 80% of the reported lung cancers were squamous cell carcinomas, and the remainder were adenocarcinomas. Most of the epidemiological studies on cancer of the respiratory tract in chromate workers did not record the smoking history. Fisher and Reikert studied this aspect and found in a group of 38 chromate workers with lung cancer two nonsmokers, three who smoked pipes only and/or cigars, three smoked less than one pack per day, 19 smoked 1% packs per day, and five smoked two packs (30). In a group of 24 workers who worked three or more years in a small chromate

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factory, Langard and Norseth found that one developed nasal cancer and three developed bronchiogenic carcinoma (two of the three were cigarette smokers) (49). Gafafer et al. recorded in 1953that 81.1% of the chromate workers with lung cancer were smokers, a rather high percentage compared to the percentage of smokers in the general U.S. population, which never exceeded 55% of the adult male population (31). From presently available epidemiological data we can only suspect that cigarette smoking increases the risk of lung cancer for workers exposed to chromate dust. In the experimental setting, various chromium compounds have been shown to be carcinogenic. Compounds yielding significant results include: chromium oxide and certain chromates, particularly calcium chromate, introduced intrapleurally or intramuscularly (67). The most convincing experimental data in support of the human findings derive from studies in which pellets containing several forms of chromates and chromic oxides were implanted. Calcium chromate induced six squamous cell carcinomas and two adenocarcinomas in a group of 100 rats. The observed tumors were histologically comparable to tumors found in the lungs of chromate workers. So far no experiments have been reported in which laboratory animals were concurrently exposed to chromate and cigarette smoke. f.

Chloromethyl

Ethers

In 1973, Figueroa et al. reported 14 cases of lung cancer in a group of 125 workers employed from 0- 17 years in a chloromethyl methyl ether plant (28). The respiratory environment of the work place was found to contain the powerful animal carcinogen bis(chloromethy1) ether (51,93,95). Eleven of the 14 cases were cigarette smokers, two nonsmokers (ages 37-44), and one a pipe smoker only (age 43).This observation, and the fact that 12 of the 14 cases had confirmed oat cell carcinoma and that four were younger than 40 years and none older than 53 years, demonstrated clearly that these workers were exposed to a powerful respiratory carcinogen. In addition, Laskin et al. have shown that bis-(chloromethyl) ether in concentrations as low as 0.1 ppm induces bronchiogenic carcinomas and esthesioneuroepitheliomas in rats (51). These facts leave no doubt that technical chloromethyl ether is a human respiratory carcinogen as already indicated by six cases of lung cancer in a chloromethyl ether plant in California (62). Although a detailed study is underway on the lung cancer incidence among chloromethyl ether workers, the closing of these plants (63), effectively curtailing them, makes it unlikely that we will ever know the actual contribution of cigarette smoking on the incidence rate of this type of occupational lung cancer. g.

Other Occupational Carcinogens Vinyl Chloride (VC) was reported in 1966 to induce acroosteolysis in VC work-

ers (83). This observation led to long term inhalation studies. Concentrations from 10,000ppm down to 50 ppm of VC induced tumors of the skin, bones, and lungs of rats (55,56,97), lung adenomas, mammary carcinomas, and lymphomas in mice (44,55,56), and melanomas and lymphomas in hamsters (55,56). In addition, all three types of animals developed vascular tumors including angiosarcomas of the liver, a tumor rarely seen in laboratory animals. This observation among animals becomes of special significance since between I964 and 1974 six VC workers

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from one U.S. plant developed angiosarcomas of the liver (9,83). Since thenuntil the fall of 1975-a total of 30 cases of this rare tumor have been seen in VC workers in nine countries (56); it is expected that the number of cases will continue to rise. Retrospective studies on VC workers have also shown that they face an increased risk for tumors of the brain and tumors of the lung (50-60%) (56,59). Although smoking data were not presented for the diseased VC workers, it appears reasonable to consider the possibility of a syncarcinogenic action of VC and cigarette smoke. Since VC had been used in the past as a propellant for household and cosmetic products (34), is formed during the combustion of vinyl chloride plastics (1 l), and is also present in trace amounts in cigarette smoke (lo-30 pg/cig) @IO),it appears theoretically possible that VC plays a role in cancer of the lung in smokers. The high lung cancer risk of cigarette smokers makes it unlikely that the importance of VC in lung carcinogenesis can be properly evaluated in the general population. Clues of syncarcinogenic activity of VC will have to come from retrospective studies of cigarette smoking VC workers. Fumes from coke ovens and from coal carbonizing processes represent two aerosols from coal which are proven respiratory carcinogens in man (52). Redmond et al. reported in 1972 an increased lung cancer risk for coke oven workers with five or more years of experience (70). The overall risk for these workers was 3.5 times that expected. An especially high risk with 6.9 times that expected was found for the loaders on top sides of coke ovens. Smoking histories of these workers were not collected. In fact, they were not even discussed. This information, however, would have been of special interest since aerosols from coke ovens, especially during loading, are very rich in carcinogenic polynuclear aromatic hydrocarbons (PAH) (79) and since according to experimental studies, cigarette smoke is a strong cocarcinogen for PAH (41,104). Gas workers engaged in coal carbonization also face a higher risk for lung cancer. The first report came from Japan in 1936, a time in which lung cancer was rare in that country (48,80). Doll et al. studied 2,449 gas workers for 12 years in England and Wales (25). They found 99 cases of lung cancer and calculated from that number that these workers faced a 3.82 times higher lung cancer risk than expected. Since the authors only had smoking histories for a 10% random sample of the gas workers, they were not able to determine whether smoking and occupational hazard in gas workers interacted. URINARY

CANCER

Hueper, in his monograph on cancer of the urinary tract for the years 1934 to 1967, listed 1364 cases of bladder cancer in dye workers (42). Listed as known industrial bladder carcinogens were P-naphthylamine, benzidine, and 4-aminobiphenyl. Of the 1364 cases, 543 were associated with the production of p-naphthylamine and an additional 42 cases with technical cr-naphthylamine. The latter is known to contain 4-6% of p-naphthylamine as an impurity (78). Although most European countries and some states in the U.S.A. have prohibited the production of P-naphthylamine, certain workers are still exposed to trace amounts of this amine while being exposedto combustion products. Combustion of protein is known to lead to the direct formation of p-naphthylamine as well as other

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aromatic amines with possible carcinogenic activity (57). Tobacco smoke is known to contain such amines (66) and, per cigarette, 28 ng of a-naphthylamine and 22 ng of /3-naphthylamine (39). In addition, tobacco smoke may contain N-nitrosamines which are metabolically activated to bladder carcinogens. In 1972, Doll et al. reported that gas workers in England and in Wales face a significantly higher bladder cancer risk (20/100,000 per year) than one-pack-a-day cigarette smokers (7/100,000) and than nonsmokers (4/100,000) (23,25,35). Chemical analytical studies have shown that inside the retort houses, gas workers inhaled /3-naphthylamine and other aromatic amines as air contaminants (7). Since most of the gas workers are cigarette smokers, their exposure to bladder carcinogens occurs concurrently from two sources. Several studies have shown that as little as two years of employment in a hazardous industrial environment is sufficient to raise man’s risk for bladder cancer. Furthermore, Cole has suggested that the risk does not increase with continued exposure beyond two years but that extended duration of exposure is associated with reduced latent periods (17). This concept may explain why the estimated contribution of cigarette smoking and hazardous occupations to bladder cancer in man decreases with advancing age (17). Certainly many more data are needed before we can assume that cigarette smoking increases the bladder cancer risk of workers exposed to a heavy load of aromatic amines in combustion products. Nevertheless, it is most timely to combine our knowledge from industrial workers with the knowledge emerging from studies on smokers and evaluate these data in respect to cancer of the lower urinary tract. CONCLUSION

AND OUTLOOK

Occupational Considerations. From an epidemiological point of view, it is important that we understand whether a given occupation can increase the risk of a given cancer by itself or whether it enhances the effect of another agent such as cigarette smoke. Such information is essential for management, for the workforce, and for public health officials. The answer to this question is often twofold. Clearly, there are some instances, as in the relationship between asbestos and bronchiogenic cancer, where the occupational exposure acts primarily as an enhancer of the effect of the tobacco smoke. There are other situations, for instance, relating to asbestos and peritoneal mesothelioma and chloromethyl ethers, where an agent can induce cancer in the absence of cigarette smoke. A reduction of risks therefore involves not only improved industrial hygiene conditions but also a change in lifestyle. It is hoped that future studies in occupational carcinogenesis will include detailed data on all other factors that could affect the risk for a given cancer. There is another point of epidemiological interest that should be discussed. In some occupations (e.g. policemen, miners), it is unlikely that persons would smoke while at work, and therefore they may be expected to have a lower rate of lung cancer on the basis of their smoking habits; while in other occupations such as taxi cab drivers who smoke more than the average population, there may be an increased risk of lung cancer independent of any occupational exposure. The lung cancer rates in these groups as compared to the general population must be

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evaluated in terms of smoking habits. For a number of reasons, therefore, a careful smoking history should be included in the evaluation of those occupations that affect sites, that can possibly also be affected by tobacco usage. Epidemiology must be an integral part of any study of occupational carcinogenesis. Preventive Zmpfica?ions. During the last few decades we witnessed a significant reduction of the cancers caused by industrial agents. Despite the fact that even in developing nations occupational cancers account for merely a few percent of all environmental cancers, we must consider their occurrence as a neglect of society. We require a fresh approach of scientists toward the elimination of occupational cancer. We should investigate all volatile chemicals which serve as monomers for inexpensive and large volume production of polymers. Part of our present and future plastic wrappers and containers will be disposed of by burning. Are the workers at the incinerators exposed to new volatile carcinogens? These and many other questions demand a new look at out present and future industrial products, their make-up and their mode of disposal. Such demands become even more urgent when we realize that many people in out society choose to smoke cigarettes and will continue to do so. It will be the smoker who is likely to be the first affected by traces of industrial and environmental carcinogens. The medical records of workers should contain their smoking history in addition to their industrial experiences. In fact, special attention should be given to the cancer incidence t-ate of smokers in industrial occupations. We wonder whether society is willing to add voluntarily a description of the working conditions and smoking habits of individual members to union registers and lists of professional organizations. Often the heavy cigarette smokers are the first affected by new industrial and environmental carcinogens. From their medical histories we are likely to observe the first clues for possible new cancer hazards. It is apparent that the risk of developing many of the occupationally induced respiratory tract and bladder cancers is significantly enhanced by variables such as tobacco usage. It behooves all who are concerned with industry-related cancer to pay attention not only to the working environment but also to the lifestyle of the affected population. To be effective, preventive measures demand a consideration of man’s total environment both within and outside his immediate control. REFERENCES 1. Agricola, G. De re metallica, Base1 (1957), cited in “Occupational and Environmental Cancers of the Respiratory System” (W. C. Hueper, Ed.) p. 127. Springer Verlag, New York, 1966. 2. Alwens, W., Banke, E. E. and Jonas, W. AutTallende Hautigkeit des Bronchialkrebs bei Arbeitem der Chemischen Industrie. Muench. Med. Wochschr. 83, 485-487 (1936). 3. Alwens, W. and Jonas, W. Der Chromat-Lungenkrebs. Acta Unio Intern. Contra Cancrum 3, 103- 114 (1938). 4. Archer, V. E., Wagoner, J. K. and Lundin, F. E. Lung cancer among uranium miners in the United States. Health Whys. 25, 351-371 (1973). 5. Bader, E. W. Berufskrebs. Neuere Ergebnisse auf dem Gebiete der Krebskrankheiten. (C. Adam and D. Auler, eds.) pp. 116- 117, S. Hirzel Verlag, Leipzig, Germany, 1937. 6. Battista, S. P., Guerin, M. R., Gori, G. B. and Kensler, C. J. A new system for quantitatively exposing laboratory animals by direct inhalation delivery of cigarette smoke. Arch. Environ. Health 27, 376-382 (1973). 7. Battye, R. Bladder carcinogens occurring during the production of town gas by coal carbonisation.

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