Document GmNQDo5gOg9voMGD8EkYbj74

ORIGINAL ARTICLES Scand J Work Environ Health 1994;20:243--50 Asbestos exposure and the risk of lung cancer in a general urban population by Antti Karjalainen, MD,1 Sisko Anttila, MD,1 Esa Vanhala, MSc,1 Harri Vainio, MD12 * KARJALAINEN A, ANTTILA S, VANHALA E, VAINIO H. Asbestos exposure and the risk of lung cancer in a general urban population. Scand J Work Environ Health 1994;20:243--50. Objectives -- The aim of the study was to investigate the asbestos-associated risk of lung cancer according to histological type of cancer, lobe of origin, pulmonary concentration, and type of amphibole fibers and also to estimate the etiologic fraction of asbestos for lung cancer. Methods -- The pulmonary concentration of asbestos fibers in 113 surgically treated male lung can cer patients and 297 autopsy cases among men serving as referents was determined by scanning elec tron microscopy. The age- and smoking-adjusted odds ratios of lung cancer were calculated accord ing to pulmonary fiber concentration for all lung cancer types, sqaumous-cell carcinoma, and adeno carcinoma and for the lower-lobe and the upper- and middle-lobe cancers. Results -- The risk of lung cancer was increased according to the pulmonary concentration of as bestos fibers (f) of 1.0 to 4.99 106 f g"' [odds ratio (OR) 1.7] and >5.0 - 106 f - g~' (OR 5.3). The odds ratios associated with fiber concentrations of > 1.0 106 f g_1 were higher for adenocarcinoma (OR 4.0) than for squamous-cell carcinoma (OR 1.6). The asbestos-associated risk was higher for lower lobe tumors than for upper lobe tumors. The risk estimates for anthophyllite and crocidolite-amosite fibers were similar, except for the risk of squamous-cell carcinoma. An etiologic fraction of 19% was calculated for asbestos among male surgical lung cancer patients in the greater Helsinki area. Conclusions -- Past exposure to asbestos is a significant factor in the etiology of lung cancer in south ern Finland. The asbestos-associated risk seems to be higher for pulmonary adenocarcinoma and low er-lobe tumors than for squamous-cell carcinoma and upper-lobe tumors. Key terms -- amosite, anthophyllite, autopsy, crocidolite, electron microscopy, Finland. Asbestos-related lung cancer is believed to be numer ically the most important occupational cancer in the world (1). The frequencies of histological lung can cer types have varied among asbestos-exposed work ers (2), but there is evidence that the asbestos-asso ciated risk would be especially high for lung adeno carcinoma (3, 4). Anthophyllite asbestos has been widely used in Finland due to its domestic production in 1918-- 1975. About 40% of all asbestos used in 1918--1988 consisted of anthophyllite (5). An increased risk of lung cancer has been reported among anthophyllite miners and millers (6, 7). The objective of the present study was to estimate the proportion of lung cancers attributable to past asbestos exposure in Finland and to investigate the asbestos-associated risk by histological type, lobe of origin, and amphibole fiber type. 1 Finnish Institute of Occupational Health, Helsinki, Fin land. 2 International Agency for Research on Cancer, Lyon, France. Reprint requests to: Dr A Karjalainen, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, FIN-00250 Helsinki, Finland. Subjects and methods Surgical lung cancer patients The study population consisted of 135 lung cancer patients who underwent surgical lobectomy or pulmectomy in the Department of Thoracic and Cardi ovascular Surgery at the Helsinki University Hospi tal between August 1988 and July 1993. Consecu tively diagnosed lung cancer cases from two of the three surgical units of the Department were includ ed. The mean age of the 113 men was 62.8 (range 35--81) years, and the mean age of the 22 women was 61.3 (range 41--75) years. In each lung cancer case the histological cell type of lung cancer and the lobe of origin was determined from the surgical lung specimen and classified ac cording to the 1981 classification of the World Health Organization. There were 67 squamous-cell carcinomas, 49 adenocarcinomas, 9 large-cell carci nomas, 9 small-cell carcinomas, and 1 adeno squamous carcinoma. There were 71 upper-lobe, 56 lower-lobe, and 6 middle-lobe cancers. In two cases the lobe of origin could not be defined due to the large size of the tumor. The presence of histological diffuse interstitial fi brosis compatible with asbestosis was determined from the surgical lung specimens. At least three tis sue sections per lobe were evaluated. 243 Scand J Work Environ Health 1994, vol 20, no 4 Referents A series of autopsy cases served as the male refer ents. Lung tissue samples were collected as a part of a large study on sudden deaths among men. This series comprised all sudden, unexpected deaths of men aged 35 to 69 years who had died in Helsinki and were autopsied between 15 January 1991 and 30 January 1992 at the Department of Forensic Medi cine, University of Helsinki. Cases in which the body was combusted or macerated were excluded. Two men aged 33 years were inadvertently included. The autopsy series comprised 30% of all deaths among men in this age group in Helsinki. The distribution of the causes of death among the referents is shown in table 1. About 60% of the deaths were due to a disease, including ischemic heart disease (85 cases), other cardiovascular dis eases (37 cases), respiratory diseases (13 cases), cerebrovascular diseases (10 cases), hepatic diseas es (8 cases), malignant neoplasms (5 cases), gas trointestinal diseases (6 cases), neurologic diseases (5 cases), deaths due to chronic alcoholism (4 cas es), metabolic disease (2 cases), and urologic dis ease (1 case). There were no deaths due to mesothe lioma or asbestosis. Two of the deaths were due to lung cancer, and in one additional case lung cancer was diagnosed but was not the primary cause of death. These lung cancer cases were excluded from the original series of 300 autopsy cases; the refer ence group thus consisted of 297 men. We per formed analyses both using all 297 referents and using only those 176 cases in which the death was due to a disease. As the results were similar, only the results for all 297 referents are presented. No reference group was available for the female lung cancer patients. Random lung cancer patients As the results of the study are based on the lung bur den analyses of the aforementioned surgical lung cancer series, they may not be generalizable to non- Table 1. Causes of death for 297 autopsy cases among Finn ish men. Cause of death Age (years) N Range Mean Disease Suicide Accident3 Alcohol intoxication Not defined6 All 176 36-69 54.7 52 33--69 48.7 41 35-65 48.3 21 36--62 47.7 7 37--69 46.6 297 33--69 52.1 a Includes 18 cases of accidental poisoning, 14 cases of ac cidental falling, 3 homicides, 2 cases of accidental suffoca tion, 2 traffic accidents, 1 case of accidental explosion, and 1 case of hypothermia. b Could not be defined whether the death was due to accident or suicide. surgical lung cancer patients. To estimate possible differences in the distribution of occupational expo sure to asbestos, we compared the occupational his tories of the surgical lung cancer patients with the occupational histories of a random lung cancer se ries. This series comprised 178 lung cancer patients diagnosed consecutively between June 1990 and May 1991 at three local pulmonary clinics of the Helsin ki University Hospital (Kiljava Hospital, Laakso Hospital, and Meltola Hospital). The mean age of the 148 men was 67.4 (range 46--82) years, and that of the 30 women 67.5 (range 47--87) years. Accord ing to data from the clinical patient records, there were 74 squamous-cell carcinomas, 37 small-cell carcinomas, 34 adenocarcinomas, 21 large-cell car cinomas, and 12 pulmonary malignancies without specified histology. This random lung cancer series contained 13 patients in common with the surgical lung cancer series. Electron microscopy The tissue pieces for the fiber analysis by electron microscopy were taken from the peripheral part of the lung, not including pleural or tumor tissue. The lung tissue samples of the referents were taken from the left upper lobe. The samples of the lung cancer patients, in cases of lobectomy, were taken from the lobe where the tumor was situated. In cases of bilobectomy or pulmectomy, the sample was taken from the lobe which appeared to be closest to nor mal (with the least amount of emphysema or pneu monia). A tissue piece of about 100 mg (wet weight) was taken for the fiber analysis. A low-temperature ash ing technique was used to remove organic tissue. Fib ers (f) were detected with a JEOL 100 CX-ASID4D electron microscope in the scanning mode (8). A length-to-width ratio of > 3 and roughly parallel sides were used as the fiber criteria. A magnification of 5000 x was used in the counting. Fibers longer than 1 pm could be detected. A minimum of 200 view ing fields were evaluated to find at least 4 to 30 fib ers per sample, depending on the density. With this procedure an analytical sensitivity (one fiber per sample) of about 0.07 - 106 f g dry tissue-1 could be reached. According to Poisson statistics, this value corresponds to a detection limit of <0.3 106 f - g-1 (four times the analytical sensitivity). An energy dispersive X-ray microanalyzer (Tracor TN 5500) was used to determine the fiber type by comparing peak ratios to standard spectra. Amosite and crocidolite have almost similar X-ray spectra and are distinguished poorly. Therefore their data have not been presented separately. In a study on Finnish lung cancer patients, crocidolite fibers accounted for the great majority of amosite-crocidolite fibers identified with transmission electron microscopy (9). Chrysotile fibers are poorly detected by scanning electron microscopy, and consequently 244 Scand J Work Environ Health 1994, vol 20, no 4 the results represent the concentration of amphibole fibers. Tremolite concentrations exceeding 0.3 106 f g-' were detected in nine samples. Chrysodle and tremolite fibers have been included in the number of total asbestos fibers, but their data have not been reported separately. The fiber analyses were carried out by a person who was unaware of the casereferent status of the samples. Occupational history The lung cancer patients were interviewed person ally about their complete, chronological occupational history, including past occupational, domestic, and environmental exposure to asbestos. The interview was carried out during their stay in the hospital. Spe cial attention was focused on the detailed descrip tion, occurrence, duration, and years of work and tasks with definite or probable exposure to asbestos or other occupational carcinogens. The surgical and random lung cancer patients were interviewed by the same interviewer. The probability of past occupational exposure to asbestos was evaluated by two occupational hygien ists by consensus and without any knowledge of the asbestos counts from the tissue samples. An expo sure time of one month was regarded as minimum. The exposure was classified into four categories ac cording to the following guidelines: Definite expo sure (group 1): employment in mining asbestos, man ufacturing asbestos products, insulating with asbes tos, or demolishing old buildings; probable exposure (group 2): employment in shipyards, the construc tion industry, or metal workshops; possible exposure (group 3): employment in various trades with expo sure to dust, such as mining, power plants, transpor tation, or the pulp and paper industry; unlikely or unknown exposure (group 4): employment in occu pations with no known exposure to asbestos. In ad dition, the frequency and duration of tasks with at least probable exposure to asbestos were considered in the classification. Smoking habits The information on the smoking habits of the lung cancer patients came from a personal interview. The smoking habits of the referents were recorded in an interview of one of the relatives. A relative suitable and willing for the interview was available for only 166 of the 297 referents. For 94% of these 166 cases the widow, a child, one of the parents, or one of the sisters or brothers was interviewed. Two of the male and two of the female lung cancer patients were non smokers; the rest were either current or ex-smokers. About 18% of the referents were nonsmokers. Statistical analyses The odds ratios (OR) and their confidence intervals (Cl) were calculated with logistic regression. Adjust ment for age (four classes) and smoking-years (five classes) were used. The etiologic fraction (popula tion attributable risk) was calculated by multiplying the proportion of exposed cases of all the cases by the term (RR-D/RR. The age-adjusted odds ratios were used as estimates of the risk ratio (RR). Results Table 2 shows the age-adjusted odds ratios of lung cancer according to asbestos exposure as estimated from the pulmonary fiber counts. The risk estimate was greater for high fiber counts (>5 106 f g"') than for intermediate fiber counts (1.0--4.99 106 f g-')- The risk estimates were similar for anthophyllite and crocidolite-amosite fibers. When the two exposed categories were combined, an age-adjusted odds ra tio of 2.3 (95% Cl 1.3--3.9, P = 0.004) was calcu lated for asbestos fiber counts of > 1.0 106 f g 1. This value gives an etiologic fraction of 19% for asbestos among male lung cancer patients. The risk estimates of table 2 give an etiologic fraction of 9.8% for 1--4.99 106 f g-1 and 9.3% for >5.0 106 f g-1 in lung tissue. Two of our patients had been previously diagnosed as suffering from asbestosis, and in seven addition al cases mild histological fibrosis compatible with asbestosis was detected in the surgical lung speci men. When the cases with clinical asbestosis or his tological indication of fibrosis compatible with as bestosis were excluded, an increased risk of lung can cer was still associated with asbestos fiber concen trations of >5.0 106 f g-' (age-adjusted OR 2.8, 95% Cl 0.9--8.7, P = 0.07) and asbestos fiber con centrations of 1.0--4.99 106 f g~' (OR 1.5, 95% Cl 0.8--2.9, P = 0.19). ' The risk was elevated for both adenocarcinoma and squamous-cell carcinoma, but the risk estimate was greater and statistically significant only for ade nocarcinoma (table 2). For the men with a pulmonary fiber concentration exceeding or equaling 1 106 f g"1, about 44% of the lung cancers were adenocarci nomas versus 27% of adenocarcinomas among those with less than 1 106 f g~` in lung tissue. Among the 22 female lung cancer patients the distribution pat tern was different. None of them showed an elevated pulmonary fiber concentration (>1 106 f g '); yet 55% of the lung cancers were adenocarcinomas (ta ble 3). The asbestos-associated odds ratios were high er for lower-lobe cancer than for cancers of the up per-middle lobe (table 4). Smoking habits were known for 166 of the refer ents. The smoking-adjusted risk estimates for asbes tos exposure (tables 2 and 4), acquired for only ref erents with known smoking habits, were similar to the smoking-unadjusted risk estimates. Lung tissue samples were not available for the ran dom lung cancer patients. Table 5 shows the distri bution into exposure categories according to the eval- 245 Scand J Work Environ Health 1994, vol 20, no 4 Table 2. Age-adjusted odds ratio (OR) for lung cancer according to pulmonary fiber type and fiber concentration in 113 male lung cancer patients and 297 referents. (95% Cl = 95% confidence interval) Cancer type Number Number of cases of referents Ageadjusted OR for the age-adjusted OR P-value All histological cancer types Total asbestos (106 f g-') <1.0 1.0 to 4.99 ^5.0 Anthophylliteb (106 f g-') <1.0 >1.0 Crocidolite-amosite1 (106 f g-1) <1.0 >1.0 Adenocarcinoma Total asbestos (106 f g-1) <1.0 >1.0 Anthophylliteb (106 f g-1) <1.0 >1.0 Crocidolite-amositec (106 f g_1) <1.0 >1.0 Squamous-cell carcinoma Total asbestos (106 f g_1) <1.0 2:1.0 Anthophylliteb (10s f g-1) <1.0 >1.0 Crocidolite-amosite0 (106 f g-1) <1.0 >1.0 74 246 1.0 Reference 26 44 1.7 0.9--3.2 0.08 13 7 5.3 1.9--14.8 0.001 89 272 1.0 Reference 24 25 2.0 1.0--4.0 0.05 96 274 1.0 Reference 0 CD 1 17 23 1.9 0.10 20 246 1.0 Reference 17 51 4.0 1.8-8.6 <0.001 25 272 1.0 Reference 12 25 3.7 1.4-9.3 0.007 27 274 1.0 Reference 10 23 3.1 1.1-8.2 0.03 43 246 1.0 Reference 18 51 1.6 0.8--3.3 0.17 50 272 1.0 Reference 11 25 1.8 0.7--4.2 0.20 56 274 1.0 Reference 5 23 0.9 0.3--2.9 0.91 a OR2 adjusted for age and smoking years with the use of 166 referents with known smoking habits. b Adjusted for age and pulmonary concentration of crocidolite-amosite fibers. c Adjusted for age and pulmonary concentration of anthophyllite fibers. OR2a 1.0 1.7 5.3 1.0 2.1 1.0 1.7 1.0 4.2 1.0 3.7 1.0 2.9 1.0 1.5 1.0 1.7 1.0 0.8 Table 3. Distribution of histological lung cancer types according to pulmonary concentration of asbestos fibers among 113 male and 22 female surgically treated lung cancer patients. Fiber concentration in lung tissue Histological cell type of lung cancer --------------------------------------------------------------------------------------------------------------------------------------- Squamous-cell Adeno- Large-cell Small-cell Adenosquamous carcinoma carcinoma carcinoma carcinoma carcinoma < 1.0 -106 f g-' Men Women a 1.0 106 f g-1 Men Women 43 20 6 12 18 17 uation of occupational histories in the surgical and random lung cancer series. The distribution was sim ilar in the two patient series. Among the surgical lung cancer patients concentrations of >1.0 106 f - g~' were detected in 79% of those with definite, 41% of those with probable, 25% of those with possible, and 7% of those with unlikely exposure (table 6). Among the 39 patients with a concentration of at least 1 106 f g_l there were one asbestos factory worker and four men who had done insulation work. The rest had 246 Scand J Work Environ Health 1994, vol 20, no 4 Table 4. Age-adjusted odds ratio (OR) for lung cancer according to lobe of origin of cancer and pulmonary concentration of asbestos fibers in 111 male lung cancer patients and 297 referents. (95% Cl = 95% confidence interval) Lobe of origin Number of cases Number Age-adjusted of referents OR 95% Cl of ,he age-adjusted OR P-value 3 ue OR/ Lower lobe <1.0 106 g-1 1.0 to 4.99 106 - g-1 >5.0 - 106 - g-1 Upper or middle lobe <1.0 106 g-1 1.0 to 4.99 106 g-1 >5.0 106 g-1 27 246 1.0 Reference 1.0 14 44 2.8 1.2-6.2 0.01 2.8 8 7 8.0 2.4--26.5 <0.001 7.7 45 246 1.0 Reference 1.0 12 44 1.2 0.6--2.6 0.61 1.0 5 7 3.2 0.9--11.3 0.07 3.9 a OR2 adjusted for age and smoking years with the use of 166 referents with known smoking habits. Table 5. Occupational exposure to asbestos among 135 surgical and 178 random Finnish lung cancer patients. Exposure group Definite exposure Probable exposure Possible exposure Unlikely exposure Surgical lung cancer series Men (N = 113) (%) Women (N = 22) <%) 12.4 0 32.7 0 31.9 18.2 23.0 81.8 Random lung cancer series Men (N = 148) (%) Women (N =30) (%) 13.5 0 33.1 0 31.8 30.0 21.6 70.0 been exposed in construction, shipyard, or mainte nance work. Table 6. Pulmonary concentration of asbestos fibers accord ing to probability of occupational exposure to asbestos among 135 Finnish surgical lung cancer patients. Discussion An elevated risk of lung cancer, with an indication of a dose-response, was associated with increased pulmonary fiber concentrations. The comparisons of smoking-adjusted and unadjusted risk estimates did not indicate that the results were biased by differ ences in the smoking habits between the exposed and unexposed subjects. The smoking habits were not known for all the referents, however, and a complete adjustment for smoking could thus not be done. Fur ther difficulties in the adjustment of the effect of to bacco smoking were caused by the small number (two cases) of nonsmokers among the male lung can cer patients. Hence, the lowest smoking category used in the analyses not only contained nonsmokers, but also smokers with less than 20 smoking-years. The accuracy of the information given by the rela tives of the referents on smoking-years may have also been less than that given by the lung cancer patients in their personal interview. Yet it is unlikely that these methodological inaccuracies would explain the risk estimates associated with past asbestos exposure. As estimated from the occupational histories, the past exposure to asbestos was similar between the surgical and random lung cancer patients. This find ing suggests that there were no major differences in Exposure category Definite Probable Possible Unlikely Number of patients 14 37 40 44 Pulmonary concentration of asbestos fibers (106 f g-1) Range Median >1.0 (%) 0.5--150 <0.3-13 <0.3--4.5 <0.3--1.9 5.6 0.6 0.3 <0.3 79 41 25 7 the exposure between the surgical and random lung cancer patients. Among the surgical lung cancer pa tients there was, however, an overlap in the pulmo nary fiber concentrations between the exposure cat egories, especially between groups of probable and possible exposure. This finding implies that the pul monary fiber concentration and the occupational his tory classification are not identical exposure indica tors. The differences in the distribution of histolog ical types between the two cancer series also indi cate that the results of the surgical lung cancer se ries may not be generalizable to apply to all lung can cers, especially in respect to small-cell cancer. In pre vious studies the etiologic fraction of asbestos in a random lung cancer series was 6% in Glasgow and the west of Scotland, 20% in Trieste, Italy, 23% in Telemark, Norway, and 16% in Goteborg, Sweden (10--13). It must be emphasized that, when the eti- 247 Scand J Work Environ Health 1994, vol 20, no 4 ologic fraction is equated with the expected change in disease load following the removal of a risk fac tor, it is supposed that the relationship between the factor and the disease is causal and not only statisti cal. In the case of asbestos and lung cancer a causal relationship is reasonably well established, and the etiologic fraction is a relevant measure when preven tion strategies are evaluated. When etiologic fractions are interpreted, it must, however, be emphasized that, due to the combined effect of smoking and occupa tional carcinogens, the sum of the epidemiological ly calculated etiologic fractions of different agents in a given population usually exceeds 100%. The use of the etiologic fraction also involves terminologi cal and conceptual problems and usually requires specific assumptions about exposure action and in teractions (14). In previous studies of several asbestos-exposed cohorts, the ratio of excess cases of lung cancer to mesothelioma cases has varied from 1:1 to 10:1 (1, 15). During the five-year period from 1987 to 1991, there were 34 cases of mesothelioma among men in Helsinki according to the statistics of the Finnish Cancer Registry. This value would corre spond to 34 to 340 excess cases of lung cancer, which is 3.9 to 39% of the 872 lung cancer cases among men during the same period of time in Hel sinki. Our estimate of 19% among male surgical lung cancer patients is within this range. The corre sponding proportion for other parts of Finland is probably lower, as the use of asbestos was more ex tensive and the number of exposed construction, shipyard, and industry workers was higher in Hel sinki and the surrounding area than in other parts of Finland. This result is reflected by the age-adjusted incidence rate of mesothelioma among men in 1987--1991, which, according to statistics of the Finnish Cancer Registry, was 9 per million men in Finland as compared with 23 per million men in Helsinki. If we assume that the regional differences in the diagnostics of mesothelioma are minor, these figures suggest that the asbestos-attributable fraction of all Finnish lung cancers among men may be less than half of our estimate for the greater Helsinki area. Most of the exposed lung cancer patients had been exposed in construction, shipyard, or maintenance work. Exposure during the use of asbestos products in construction and shipyard work and indirect ex posure during insulation work and asbestos spraying are thus not to be neglected when the health hazards of asbestos and their prevention are evaluated. In such cases it is often difficult to assess the intensity of past exposure on the basis of the work history and exposure interview, and crucial information of the individual exposure can be gained from a pulmonary fiber analysis. When pulmonary fiber analyses are used at the individual level, it may be preferable to use several samples from different parts of the lung to improve the analytical reliability. A wide varia tion in the fiber counts has been observed in inter laboratory comparisons, and laboratory-bound refer ence values should be used (16). Despite the obvi ous advantages of the pulmonary Fiber analysis, it should be stressed that a complete work history with special emphasis on jobs and tasks with probable or definite exposure to asbestos is the most important exposure indicator, and actually the only way to es timate latency. Chrysotile is cleared more rapidly from the lungs than amphiboles, and, even if transmission electron microscopy is used, the chrysotile content of lung tis sue is not an equally representative measure of past cumulative chrysotile exposures as is the amphibole content for amphibole exposures (17, 18). As about 40% of all asbestos used in Finland during 1918-- 1988 consisted of amphiboles (5) and a mixed ex posure to chrysotile and amphiboles took place in most of the industrial applications, the amphibole content in the lung tissue is probably a reasonably representative indicator of past exposure to asbestos in Finland. In cases with main exposure to chrysotile these methodological problems must, however, be recognized. The use of occupational history as an exposure indicator in the risk analyses would not suf fer from such problems. In our study the differenc es in the quality of occupational history data between the cases and the referents, however, did not allow us to do such analyses. In our study the sample site for the fiber analysis among the lung cancer cases depended on which lobe or lobes were resected, whereas the tissue samples of the referents were all taken from the upper lobe. We assume that these fiber concentrations are com parable and equally representative of cumulative ex posure to asbestos. In previous electron microscopy studies counting fibers of all sizes together, either no systematic differences or an indication of higher con centrations in the upper lobes than in the lower lobes has been found (8, 19--21). If the fiber concentra tion is higher in the upper lobes, our method would have underestimated the exposure of lower-lobe lung cancer cases and thus also the asbestos-associated risk estimates. The absence of elevated pulmonary fiber concen trations and exposure histories indicating probable or definite exposure to asbestos among the 22 female surgical and 30 random lung cancer patients suggests that the proportion of lung cancers attributable to as bestos is much lower among women than among men. This observation reflects the low proportion of female workers in the construction, shipyard, and asbestos industries. This result is also in accordance with the statistics of the Finnish Registry of Occu pational Diseases; in 1987--1991 129 and 4 cases of asbestos-related lung cancer were reported for the men and women, respectively. This ratio of men to women among the cases (about 32:1) is much high er than the about 4.5:1 ratio for men to women among all lung cancers in Finland during 1987-- 248 Scand J Work Environ Health 1994, vol 20, no 4 1991 (8601 men and 1905 women according to the statistics of the Finnish Cancer Registry). Our results indicate that the asbestos-associated risk of lung cancer is higher for adenocarcinoma than for squamous-cell carcinoma. Because of the small number of patients, we were unable to draw any con clusions about the association between asbestos and small-cell or large-cell carcinoma. The higher risk of adenocarcinoma, as compared with squamous-cell carcinoma, is in agreement with the findings of pre vious studies among Danish and Swedish asbestos cement workers (3, 4), but also opposite results or reports with no difference in the risk have been pub lished (2, 11, 22). Different selection criteria between exposed and reference lung cancer cases (surgery, autopsy, bronchoscopy) and variation between pathologists in the typing of lung tumors may have confounded some of these studies (23--25). It thus remains controversial whether the asbestos-associat ed risk of lung cancer is greater for some histologi cal cancer type or whether there are no differences in the risk. A difference in the risk between these cancer types would raise the question of a possible difference in the carcinogenic mechanisms. Both as bestos and smoking seem to be complex carcinogens which can affect more than one stage of lung car cinogenesis, and very limited information is availa ble on the interaction between asbestos and smok ing in causing specific histological types of lung can cer (26). It is interesting that in our study the pro portion of adenocarcinomas was especially high among the female lung cancer patients (all unexposed to asbestos). This finding probably indicates that women have a lower incidence of tobacco-associated squamous-cell carcinomas rather than that they would have a higher incidence of adenocarcinoma. The difference in the asbestos-associated risk be tween lower- and upper-lobe tumors is compatible with the findings of our previous report (9). There was an elevated risk of lung cancer associ ated with high pulmonary concentrations of asbes tos fibers even after cases with histological indica tions of mild asbestosis were excluded. These find ings support the view that asbestos increases the risk of lung cancer even in the absence of asbestosis. As for the cases with asbestosis, it is impossible to con clude whether the fibrosis and the lung cancer were independently caused by asbestos or whether the can cer was caused by the fibrosis. Most of the asbesto sis cases were mild and could be detected in the his tological examination only. It is doubtful whether such a mild case of fibrosis could have caused the cancer. Some of the exposed referents might have also had mild histological fibrosis compatible with asbestosis and should thus have been excluded from the aforementioned analysis. This exclusion would have increased the risk estimate. As the presence of histological fibrosis among the referents was not evaluated, no such exclusion could be done. It is noteworthy that six of the nine lung cancer patients with histological fibrosis (and heavy exposure) had an adenocarcinoma, two a squamous-cell carcinoma, and one a small-cell carcinoma. Because of the small number of nonsmokers among the male lung cancer patients, it was not pos sible to compare the asbestos-associated risk between the nonsmokers and smokers. The two male non smokers in the lung cancer series were both unex posed to asbestos and had adenocarcinoma. The use of pulmonary fiber concentrations as ex posure indicators resulted in similar lung cancer risk estimates for anthophyllite and crocidolite-amosite fibers. This finding is in agreement with the lung can cer risks observed in previous studies among antho phyllite and crocidolite miners (6, 27, 28). It is note worthy that there is a clear difference in the risk of mesothelioma between these cohorts of anthophyl lite and crocidolite miners. This difference could be due to the difference in the dimensional character istics between these fiber types. It has been conclud ed that mesothelioma is the most closely associated with numbers of fibers longer than 5 um and thin ner than 0.1 pm, whereas lung cancer is the most closely associated with numbers of fibers longer than 10 pm and thicker than 0.15 pm (29). In the present study the risk estimates of squamous-cell carcinoma were elevated for elevated anthophyllite concentra tions but not for elevated crocidolite-amosite concen trations. This observation was based on a small number of cases and was not statistically significant. The distributions of histological lung cancer types in the cohorts of anthophyllite or crocidolite miners have not been reported. Acknowledgments We thank L Heikkila, MD, P Karhunen, MD, K Lalu, MD, and A Penttila, MD, for their help with the col lection of the material. We also thank P Kyyronen, MSc, for his help with the statistical analyses, and A Tossavainen, DTech, and T Tuomi, DSc, for their help in classifying the occupational histories. We are grateful to E Pukkala, MSc, of the Finnish Cancer Registry and T Kauppinen, PhD, of the Finnish Reg istry of Occupational Diseases for the cancer statis tics and to T Kaustia, MA, who did the linguistic re vision of the manuscript. This work was supported by the Finnish Work Environment Fund and the Finnish Medical Society Duodecim. References 1. Doll R, Peto R. The causes of cancer: quantitative es timates of avoidable risks of cancer in the United States today. Oxford: Oxford University Press, 1981. 2. Churg A. Lung cancer cell type and asbestos exposure. JAMA 1985;253:2984-5. 3. Raffn E, Lynge E, Korsgaard B. 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