Exposure to Nitrosamines, Carbon Black, Asbestos, and Talc and Mortality from Stomach, Lung, and Laryngeal Cancer in a Cohort of Rubber Workers

Kurt Straif, Ulrich Keil, Dirk Taeger, Dagmar Holthenrich, Yi Sun, Martina Bungers and Stephan K. Weiland

From the Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
There is sufficient evidence for an excess occurrence of stomach and lung cancer among rubber workers. However, evidence for causal associations with specific exposures is still limited. A cohort of 8,933 male German rubber workers was followed for mortality from January 1, 1981 through December 31, 1991. Work histories were reconstructed using routinely documented cost center codes. For each cost center code, calendar time- and plant-specific levels of exposure to nitrosamines, asbestos, talc (low, medium (m), and high (h)), and carbon black (two levels) were estimated by industrial hygienists. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models, with the lowest exposure level used as the reference category. Exposure was lagged 10 years to account for latency. Exposure-response relations between exposure to asbestos and lung cancer mortality (RRm = 1.3, 95% CI: 0.9, 1.9; RRh = 2.0, 95% CI: 0.9, 4.1) and between exposure to dust (talc and asbestos combined) and stomach cancer mortality (RRm = 1.8, 95% CI: 0.9, 3.8; RRh = 2.7, 95% CI: 1.0, 7.1) were observed. Exposure to nitrosamines was not associated with mortality from stomach or lung cancer. These results suggest that the increased mortality from lung and stomach cancer among rubber workers is associated with exposure to asbestos and dust, respectively. Am J Epidemiol 2000;152:297–306.

asbestos; carbon; laryngeal neoplasms; lung neoplasms; nitrosamines; occupational exposure; stomach neoplasms; talc

Abbreviations: PAHs, polycyclic aromatic hydrocarbons


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
There is a long history of epidemiologic investigation of carcinogenic risks in the rubber industry (1Go, 2Go). In 1982, a working group of the International Agency for Research on Cancer concluded that there was sufficient evidence for an excess occurrence of leukemia and cancers of the urinary bladder, stomach, and lung among rubber workers (3Go). However, evidence for causal associations between an excess occurrence of stomach and lung cancer and exposure to specific carcinogens was limited (3Go). A recent review of studies published after this monograph supported most of the findings of the initial evaluation (4Go). Furthermore, an excess occurrence of laryngeal cancer was found in most recent studies. However, because of the absence of detailed exposure assessment, no additional evidence for the causal role of specific carcinogens could be established (4Go).

Exposure conditions in the rubber industry are complex (3Go). The highest concentrations of nitrosamines in the human environment have been reported in the rubber industry (5GoGo–7Go). Furthermore, approximately 90 percent of the world's carbon black is used in the rubber industry (8Go). Nitrosamines have been classified as "probably carcinogenic to humans" (9Go), and carbon black has recently been listed as "possibly carcinogenic to humans" (8Go). Talc, potentially contaminated by asbestos, has been widely utilized as a filling material and detackifier, and asbestos was formerly handled in some departments of the rubber industry. Exposure to other known or suspected carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) or acrylonitrile, may have occurred in some rubber factories (3Go).

We conducted a retrospective cohort study in the German rubber industry (10GoGo–12Go). On the basis of our previous analyses by work area, we speculated that the excess of laryngeal and lung cancer may be related to exposure to asbestos (11Go) and that the excess of stomach cancer may be associated with exposure to dust or asbestos (12Go). In this paper, we report results for these three cancer sites based on an expert assessment of exposure to nitrosamines, carbon black, asbestos, and talc.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
Cohort definition and follow-up
The definition and follow-up of the cohort have previously been described in detail (10Go). Briefly, the cohort included all male German blue collar workers in five study plants who were hired during or after 1950 and who were alive and actively employed or retired on January 1, 1981. Follow-up of individual cohort members started on January 1, 1981, but not before completion of 1 year of employment, and ended at the age of 85 years, at death, or at the end of the follow-up period, December 31, 1991.

For all cohort members reported to have died, death certificates were requested from the respective community health departments. Death certificates were coded by professional nosologists from the State Institute of Statistics of North-Rhine-Westphalia according to the International Classification of Diseases, Ninth Revision.

Exposure classification
Individual work histories within the rubber companies were reconstructed using routinely documented and archived cost center codes ("Kostenstellen") (11Go). Complete individual work histories (date of hire, work history within the rubber industry, and date of termination) were available for 98.9 percent of the cohort members from the beginning of their employment.

Since environmental monitoring of nitrosamines and other compounds of interest was not performed before 1979, it was necessary to make retrospective semiquantitative estimates of exposure. In cooperation with industrial hygienists from the involved rubber plants and other experts, a scheme for exposure categorization was developed. Because of uncertainties with regard to changes in production processes and plant structures during World War II and soon thereafter, it was decided to limit exposure assessment to the period from 1950 onwards.

The categorization scheme for assessment of exposure to nitrosamines was based on evidence from a hazard survey conducted in the early 1980s that included some of the plants involved in this epidemiologic study (6Go). The highest nitrosamine concentrations were detected in curing and vulcanization: 1,060 µg/m3 for N-nitrosodimethylamine and 4,700 µg/m3 for N-nitrosomorpholine (6Go). While most of the nitrosamines detected in the air of rubber factories are formed during vulcanization, N-nitrosodiphenylamine was used as a retarder until early 1980 (13Go). N-nitrosodiphenyl-amine was found to serve as a potent transnitrosating agent (14Go), thereby increasing exposure to total nitrosamines by an order of magnitude (6Go). In addition, salt bath curing resulted in some of the highest concentrations of nitrosamines, except when peroxide accelerators were used instead of amine derivatives (6Go). We assessed exposure to total nitrosamines, because studies of exposure to low levels of different nitrosamines have indicated linear additive carcino-genicity (15Go) and because assessment of exposure to specific nitrosamines would not have been possible. The retrospective exposure assessment was based on judgements of the industrial hygienists. The following cutpoints served as orientation for classification of exposure to nitrosamines: For the high exposure category, we assumed nitrosamine concentrations of >15 µg/m3. The current technical limit value for nitrosamine exposure for specific operations in the German rubber industry (16Go), 2.5 µg/m3, was used as the upper bound for the low exposure category.

Asbestos was used in all five plants at least until the early 1980s. Tasks involving raw material storage and mixing and weighing were considered to entail high exposure when asbestos had been utilized as a filler material. Cleaning and repair of jute bags used for delivery of asbestos and sewing of asbestos-containing gloves were also classified as tasks with high exposure. The wearing of asbestos-containing heat-protective clothing–mostly only gloves–was categorized as medium exposure to asbestos. Maintenance workers were classified according to their specific job and workplace (e.g., working in separate workshops vs. trouble-shooting all over the plant). We are aware of only a few measurements of asbestos concentrations in the investigated plants before 1980. For example, in the main mixing area of one plant, an asbestos level of 0.13–0.26 mg/m3 (corresponding to ~5 fibers/cm3) was detected in 1976 (unpublished data).

Talc has been widely used in the rubber industry, and it may be contaminated by asbestos, depending on its origin. In the plants we studied, talc served as filling material, and some rubber compounds contained up to 50 percent talc. High exposure to talc also occurred in work areas for vulcanization of inner tire tubes, where talc was heavily used as a detackifier. Other work areas in which talc was used as a detackifier were coded as having high or medium exposure, depending on the specific production process. Wet application of talc or documentation of respirable dust concentrations of <6 mg/m3 was coded as low exposure to talc.

Exposure to carbon black occurred mainly in weighing and mixing, where carbon black was added to the rubber formulation, and among maintenance workers. Only a dichotomous classification of exposure to carbon black (exposed vs. nonexposed) was available for this analysis.

On the basis of this categorization scheme (table 1), industrial hygienists in the investigated plants estimated calendar time- and plant-specific exposures to nitrosamines, asbestos, talc, and carbon black for each cost center code, independently of individual cohort members.


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TABLE 1. Categories used for assessment of exposure to nitrosamines, asbestos, and talc among male German rubber workers, 1950–1991

 
Data analysis
All analyses were based on the cohort of 8,933 workers hired after January 1, 1950. Standardized mortality ratios were calculated using the male population of German nationality in western Germany as the reference group. For exposure-specific analyses, exposure categories were determined a priori. In exposure categorization 1, the high exposure category for each variable included workers who had been employed for at least 1 year in cost center code areas with high exposure levels, and the low exposure category included workers who had been employed for less than 1 year at medium or high exposure levels. Otherwise, workers were included in the medium exposure category. In exposure categorization 2, the cutpoints were 10 years for high exposure and one half year for low exposure. Exposure was treated as a time-dependent variable; i.e., a risk set was formed whenever a death from a cancer of interest occurred in the cohort, and an exposure category was assigned to the index case and the corresponding risk set according to the current exposure status. Exposure was further lagged 10 years to account for latency. Lagging was performed such that a worker's current person-year at risk was assigned to the exposure level achieved 10 years earlier (17Go).

Hazard rate ratios and 95 percent confidence intervals for exposure to specific compounds were calculated using the low exposure category for each compound as the reference group. The SAS procedure PROC PHREG 6.12 (SAS Institute, Cary, North Carolina) was used to calculate time-dependent and age-adjusted (time marker-adjusted) hazard rate ratios. All analyses were restricted to cohort members with complete information on all variables included in the respective model (18). In bivariate analyses, each exposure variable was investigated in separate models. In multivariate analyses, all exposures were assessed simultaneously.

A priori collapsing of exposure categories for asbestos and talc in multivariate models was based on the following rationales: 1) With regard to lung cancer, pure talc has not been shown to be carcinogenic. However, there is sufficient evidence that asbestos-containing talc is a human carcinogen (19Go), and therefore medium or high level exposure to talc potentially contaminated with asbestos was collapsed with medium level exposure to asbestos. 2) With regard to stomach cancer, the evidence for asbestos carcinogenicity is weak and is restricted to very high exposure conditions (20Go) not usually found in the rubber industry. However, there is some evidence that exposure to high levels of dust may be a risk factor for stomach cancer (21Go). Because measurements or direct exposure estimates for dust were not available, we used exposure to talc, the major component of dust exposure in the rubber industry, as an indicator for exposure to dust, and we also considered medium or high levels of exposure to asbestos medium exposure to dust.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
At the beginning of follow-up, the cohort (n = 8,933) included 6,875 actively employed workers and 2,058 retirees. Among the retirees, 1,156 (56 percent) workers had retired between 1975 and 1980 and 663 (32 percent) between 1970 and 1974. At retirement, 1,056 (51 percent) retirees were older than 60 years; and because of early retirement regulations, 759 were between 55 and 60 years old. Assessment of vital status and causes of death in this cohort was almost complete. A total of 1,521 (17.0 percent) cohort members died during follow-up, and 31 (0.3 percent) were left untraced. Among deceased cohort members, the cause of death could not be assessed for 42 (2.8 percent) deaths.

Complete exposure assessment was available for approximately 95 percent of the cohort members. Table 2 shows the distribution of cohort members by exposure category at death or at the end of follow-up. Approximately 27 percent of the cohort members were exposed to high levels of nitrosamines, and another 25 percent were exposed to medium levels of nitrosamines. Regarding talc and asbestos, 3.4 percent of the cohort members were exposed to high levels of asbestos and 13.2 percent to high levels of talc. Approximately one out of every three cohort members was exposed to medium or high levels of asbestos and talc, and almost 20 percent were exposed to carbon black.


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TABLE 2. Distribution of a cohort of male German rubber workers (n = 8,933) by categories of exposure to nitrosamines, asbestos, talc, and carbon black (exposure categorization 1),* 1981–1991

 
In comparison with the general population of western Germany, all-cause mortality and mortality from major nonmalignant causes were close to expected levels. Standardized mortality ratios for cancer of the stomach, larynx, and lung were slightly increased among the total cohort (table 3).


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TABLE 3. Observed numbers of deaths and standardized mortality ratios among male German rubber workers (n = 8,933), by cause of death, 1981–1991

 
In bivariate analyses, mortality from stomach cancer was increased among workers with exposures to asbestos, talc, and carbon black (table 4). Using exposure categorization 1, we observed an exposure-response relation for talc exposure and stomach cancer risk, with a more than twofold statistically significant risk in the high exposure category. When we used exposure categorization 2, the point estimates of these risks increased substantially, and they were statistically significant for the high exposure categories of talc and carbon black. In multivariate models (table 5), we collapsed the medium category for talc and the medium and high categories for asbestos in order to assess exposure to talc- and asbestos-containing dust. In these models, the adjusted rate ratios for carbon black were markedly reduced for both exposure categorizations. In both multivariate models, we observed increasing mortality from stomach cancer with higher exposure to talc- or asbestos-containing dust.


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TABLE 4. Hazard rate ratios for stomach cancer death (bivariate models) by categories of exposure to asbestos, talc, nitrosamines, and carbon black (lagged 10 years), Germany, 1981–1991

 

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TABLE 5. Hazard rate ratios for stomach cancer death (multivariate models) by categories of exposure to asbestos, talc, nitrosamines, and carbon black (lagged 10 years), Germany, 1981–1991

 
In bivariate analyses, the highest risk of lung cancer was observed in association with exposure to high levels of asbestos, and the observed risk was moderately higher when we used exposure categorization 2 (table 6). Increased mortality from lung cancer was also found in association with exposure to talc and carbon black. In the multivariate models (table 7), categories of medium and high levels of talc were combined with the category for medium exposure to asbestos. For this combined asbestos/talc exposure variable, an exposure-response relation with lung cancer was observed, while the adjusted risk estimate for carbon black was markedly reduced.


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TABLE 6. Hazard rate ratios for lung cancer death (bivariate models) by categories of exposure to asbestos, talc, nitrosamines, and carbon black (lagged 10 years), Germany, 1981–1991

 

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TABLE 7. Hazard rate ratios for lung cancer death (multivariate models) by categories of exposure to asbestos, talc, nitrosamines, and carbon black (lagged 10 years), Germany, 1981–1991

 
Exposure to nitrosamines was not associated with mortality from lung and stomach cancer in bivariate analyses. The effect estimates were not significantly altered after we adjusted the data for exposure to asbestos, talc, and carbon black or after we changed the cutpoints of the exposure categories.

In bivariate analysis, we observed increased hazard rate ratios for laryngeal cancer among workers who were exposed to asbestos, talc, or carbon black. However, because of few deaths in these exposure categories, only high exposure to talc and exposure to carbon black were statistically significantly associated with increased risk of laryngeal cancer (table 8). An inverse association was observed for exposure to nitrosamines and mortality from laryngeal cancer. In view of the small number of deaths and the correlated exposure variables, no further analyses were performed.


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TABLE 8. Hazard rate ratios for laryngeal cancer death by categories of exposure to asbestos, talc, nitrosamines, and carbon black (lagged 10 years), Germany, 1981–1991

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
There is sufficient evidence for an excess occurrence of lung, stomach, and laryngeal cancer among rubber workers but only limited evidence for a causal association with specific occupational exposures (3Go, 4Go). To our knowledge, this is the first study to have investigated the associations between exposure to specific carcinogens and risks of lung and laryngeal cancer among rubber workers. One previous study investigated exposure to specific compounds and the risk of stomach cancer among rubber workers (22Go).

Validity of findings
In assessing the validity of our findings, we must consider the potential for residual confounding due to smoking and other occupational exposures in the rubber industry which were not considered in the exposure assessment. Exposure to high levels of PAHs has been linked with an increased risk of lung cancer (23Go, 24Go). Exposure to PAHs may have occurred in the rubber industry via aromatic oils (25Go). However, we believe that exposure to PAHs among our cohort members was not a risk factor for lung cancer, because exposure to PAHs in the rubber industry is relatively low in comparison with other industries (7Go, 25Go). With regard to stomach cancer, the overall evidence for an association with exposure to PAHs is weaker (21Go); furthermore, the study of rubber workers conducted by Blum et al. (22Go) found no association of stomach cancer risk with exposure to PAHs.

On the basis of animal studies, acrylonitrile has been classified as "probably carcinogenic to humans" (19Go), and early epidemiologic studies (26Go, 27Go), including one of a subcohort of workers employed in the rubber industry (28Go), reported an increased risk of lung cancer among workers exposed to acrylonitrile. However, a recent review of updated cohort studies did not suggest that acrylonitrile is a human lung carcinogen (29Go). Furthermore, exposure to high levels of acrylonitrile among rubber workers occurred mainly during the production of specific synthetic rubber polymers, and substantially less in the manufacturing of tires and technical rubber goods.

Tobacco smoking is a risk factor for lung and laryngeal cancer. Currently, we have no data with which to directly assess potential confounding by smoking status. However, our results were based on internal controls, and we have no indication that the prevalence of smoking was related to job assignment or exposure to asbestos and talc. In addition, other smoking-related deaths, such as those due to bladder cancer, were not associated with exposure to asbestos or talc. Furthermore, two epidemiologic studies of rubber workers that had data on individual smoking habits investigated potential confounding of lung cancer risks by smoking (30Go, 31Go) and found no indication that increased lung cancer risks were confounded by differential smoking habits.

Lung cancer
Our findings support the hypothesis that increased lung cancer risk among rubber workers may be associated with exposure to asbestos and talc (11Go). To our knowledge, these are the first exposure-specific data on lung cancer risk among rubber workers. Several previous studies have reported lung cancer risks by work area. These studies observed increased risks in areas of preparation of materials (32GoGo–34Go) and vulcanization (31Go, 33Go, 35GoGo–37Go). On the basis of these work area-specific results, there was speculation that exposure to asbestos may have played an etiologic role in the increased lung cancer risk observed among rubber workers (11Go, 38Go). Furthermore, talc was discussed as a potential risk factor for lung cancer in two studies from China which found increased lung cancer risks in the production of tire tubes (31Go, 34Go). However, while pure talc has not been classified as a human carcinogen (19Go), it has been shown that Chinese talc may be heavily contaminated by asbestos. Therefore, asbestos may be the underlying cause of the increased lung cancer risks in those two studies. Additional evidence for substantial exposure to asbestos among rubber workers may be found in the increased mortality from asbestosis (39Go) and mesothelioma (11Go, 40Go, 41Go) among rubber workers.

On the basis of experimental studies, carbon black has been classified as possibly carcinogenic to humans (8Go). Historically, the highest exposures to carbon black have occurred in the carbon black manufacturing industry, but results from epidemiologic studies have been inconclusive (42Go, 43Go). Approximately 90 percent of the carbon black produced is utilized in the rubber industry, and exposure to carbon black in this industry is likely to be higher than in other industries that use carbon black. To date, no exposure-specific results for carbon black have been reported from the rubber industry. Our results indicate that the observed association between exposure to carbon black and lung cancer may be confounded by exposure to asbestos.

Nitrosamines are potent carcinogens, and experimental studies have indicated that the lung may be a target organ of nitrosamine-related carcinogenicity (9Go). Two case-control studies reported an association between lung cancer and intake of food contaminated with N-nitrosodimethylamine (44Go, 45Go). However, no increased risk of lung cancer was observed among automobile workers exposed to nitrosamines, especially to N-nitrosodiethanolamine via synthetic metalworking fluids (46Go), or in our cohort of highly exposed rubber workers.

Stomach cancer
Several reviews have suggested that there may be an association of dietary intake of nitrosamines with increased risk of stomach cancer (47GoGoGoGo–51Go). Knowledge about high exposure to nitrosamines in the rubber industry (52Go) and sufficient evidence for an increased occurrence of stomach cancer among rubber workers (3Go) seemed to further support this hypothesis (21Go). However, an increased risk of stomach cancer was mostly confined to workers in early production stages, where exposure to nitrosamines was relatively low (3Go, 53Go). Exposure-specific results of our study and one other study of rubber workers (22Go) do not support an association between exposure to nitrosamines and risk of stomach cancer. If positive results from nutritional epidemiologic studies and negative results from occupational epidemiologic studies both reflect true relations, the different major routes of exposure–inhalation among rubber workers and ingestion in nutritional epidemiology–might explain the differing findings.

Our results and those of Blum et al. (22Go) indicate an association between exposure to talc and risk of stomach cancer. In both investigations, relative risks among highly exposed workers were statistically significant, and exposure-response relations and latency were consistent with a causal association. One other study also reported an increased risk of stomach cancer among workers exposed to talc in diverse industries (54Go); however, no risk increase was found among highly exposed talc miners and millers (55Go, 56Go).

Results from our bivariate analyses seemed to suggest a role of asbestos exposure in an increased risk of stomach cancer; however, the observed risks were not statistically significant. Furthermore, the evidence from high risk cohorts for an association between asbestos exposure and stomach cancer risk has generated controversy (19GoGo–21Go, 57Go). It appears that if there is any increased risk of stomach cancer among workers exposed to asbestos, this risk is confined to workers exposed to high levels of asbestos (20Go), and it is not very likely that the rubber workers investigated in our cohort experienced such a high exposure to asbestos.

Our bivariate results also seemed to indicate an increased risk of stomach cancer among workers exposed to carbon black. Similar results were reported by Blum et al. (22Go). In our study, however, after adjustment for exposure to talc- and asbestos-containing dust, the observed risks were substantially reduced and no longer statistically significant. Blum et al. (22Go) did not present multivariate results. Furthermore, epidemiologic studies of workers in the carbon black production industry (42Go, 43Go, 58Go) and one population-based case-control study (59Go) did not find an association between carbon black exposure and stomach cancer.

The overall evidence seems to indicate that exposure to dust in general may be associated with an increased risk of stomach cancer (21Go, 60Go), whereas the evidence for any specific type of dust is weaker. Under this hypothesis of dust-induced stomach cancer, we collapsed our exposure variables and observed in our multivariate models increasing mortality from stomach cancer with higher exposure to talc- and asbestos-containing dust. Dust may irritate the gastric mucosa and cause superficial gastritis and increased cell proliferation, which in turn increases the probability of mutations. Furthermore, dust may act as a carrier of carcino-gens to the gastric mucosa (21Go).

Laryngeal cancer
An excess occurrence of laryngeal cancer has been found in most recent epidemiologic studies of the rubber industry (4Go). Our previous analyses based on work areas (11Go) and the findings of two other studies (32Go, 35Go) have suggested that the increased mortality from laryngeal cancer among rubber workers may be associated with employment in weighing and mixing areas and with exposure to dust. The current exposure-specific results tend to support an association between exposure to asbestos, talc, or carbon black and increased mortality from laryngeal cancer. Considering the current epidemiologic and toxicologic evidence with regard to these agents, asbestos seems to be the most likely candidate. However, because of the small number of observed deaths, our results preclude firm causal inferences.


    Conclusions
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
Our results support the possibility of associations between asbestos exposure and increased lung cancer mortality and between dust exposure and increased stomach cancer mortality among rubber workers. Increased relative risks for carbon black observed in bivariate models seemed to be confounded by exposure to asbestos and talc. We found no association between exposure to nitrosamines and mortality from stomach cancer or lung cancer. Findings for laryngeal cancer were consistent with the results for lung cancer; however, the small number of observed deaths precluded firm conclusions.


    ACKNOWLEDGMENTS
 
The study was funded by the Berufsgenossenschaft der Chemischen Industrie, Heidelberg.

The authors thank the participating companies, especially the industrial hygienists and occupational health physicians. They are particularly grateful to Drs. Bertold Spiegelhalder, Hans Kromhout, and Klaus Norpoth for their scientific advice regarding retrospective exposure assessment in the rubber industry. The authors also acknowledge the important contributions of the field-workers, programmers, and secretaries.


    NOTES
 
Correspondence to Dr. Kurt Straif, Institute of Epidemiology and Social Medicine, University of Münster, Domagkstrasse 3, D-48129 Münster, Germany (e-mail: straif{at}nwz.uni-muenster.de).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 

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Received for publication May 6, 1999. Accepted for publication November 29, 1999.