1 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
2 International Epidemiology Institute, Rockville, MD.
3 Department of Medicine, Vanderbilt University Medical School, Vanderbilt-Ingram Cancer Center, Nashville, TN.
4 Department of Occupational Medicine, Aarhus University Hospital, Aarhus, Denmark.
5 National Institute for Occupational Health, Copenhagen, Denmark.
Received for publication March 24, 2003; accepted for publication June 24, 2003.
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ABSTRACT |
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adenocarcinoma; biliary tract neoplasms; esophageal neoplasms; kidney neoplasms; liver neoplasms; lymphoma, non-Hodgkin; occupations; trichloroethylene
Abbreviations: Abbreviation: CI, confidence interval.
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INTRODUCTION |
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Previously, we reported a significantly increased risk of non-Hodgkins lymphoma and esophageal adenocarcinoma among men and cervical cancer among women, nonsignificantly increased risk for cancer of the liver and biliary tract, but no increased risk for kidney cancer in a relatively small cohort of Danish workers with confirmed individual exposure to trichloroethylene (10). In the present study, we report on the cancer morbidity of a much larger cohort of workers employed at 347 Danish trichloroethylene-using companies.
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MATERIALS AND METHODS |
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Only a relatively small proportion of workers employed at these companies were likely to be exposed to trichloroethylene. On the basis of information collected at 93 trichloroethylene-using companies, we observed an inverse relation between the number of employees at a company and the proportion of trichloroethylene-exposed workers; in companies with 150, 51100, 101200, and more than 200 employees, the proportions of exposed workers were, respectively, 48, 30, 11, and 2 percent (12). Therefore, to increase the likelihood of trichloroethylene exposure in the present study, we excluded 110 companies with more than 200 employees.
The main industries represented by the remaining 347 and the excluded 110 companies, respectively, were iron and metal (48 and 48 percent), electronics (11 and 12 percent), painting (11 and 0 percent), printing (8 and 3 percent), chemical (5 and 6 percent), dry cleaning (5 and 2 percent), and other industries (13 and 30 percent).
Employees at the companies
By use of the unique company number, each of the 347 companies was linked to the computerized records of the national Supplementary Pension Fund, which includes information on the type of industry of the company and the identity and employment history of all employees (15). Membership in the Pension Fund has been mandatory for all employees in Denmark since its establishment in 1964. Altogether, 152,726 workers at these companies were identified by the unique 10-digit personal identification number assigned to each resident in Denmark since the Central Population Registry began on April 1, 1968. Thus, all workers who were employed by the companies since this date were identified. By use of the personal identification number, these employees were linked to the files of the Central Population Registry, which provides information on job title and dates of death, emigration, or disappearance. By use of the job title, each employee was characterized as a blue-collar worker, white-collar worker, or unknown. The Central Population Registry shows only the most recently reported job title for each individual; although the relevance of this job title to periods of employment in trichloroethylene-using companies is uncertain, the classification using blue collar versus white collar would be expected to be very stable over time in Denmark.
We excluded four workers with a personal identification number that could not be verified by the Central Population Registry. In addition, to increase the proportion of trichloroethylene-exposed workers in the cohort, we excluded 39,074 presumably unexposed white-collar workers and 56,970 workers for whom blue- or white-collar status was unknown. Among the remaining 56,678 blue-collar workers, we excluded 16,629 workers with a duration of employment of less than 3 months. Thus, our study cohort consisted of 40,049 blue-collar workers who were followed for cancer incidence.
Exposure assessment
We previously addressed trichloroethylene exposure patterns of Danish workers (11, 12). On the basis of these studies and the characteristics of the cohort of this study, three variables seem most reliable as predictors of trichloroethylene exposure, namely, duration of employment, year of first employment at a trichloroethylene-using company, and number of employees in the company.
Duration of employment is often a useful surrogate for cumulative exposure to occupational agents. Measurements of trichloroacetic acid (a metabolite of trichloroethylene) in the urine of Danish workers showed arithmetic mean concentrations of 58 mg/liter for measurements taken between 1960 and 1964 and 14 mg/liter for measurements taken between 1980 and 1985 (11). Similarly, the arithmetic mean concentration of trichloroethylene in Danish work environments was 318 mg/m3 for measurements taken in the 1960s and 75 mg/m3 for measurements taken in the 1980s (12). Thus, calendar year is a strong predictor of trichloroethylene exposure of Danish workers, and we would expect 45 times higher exposures in the 1960s than in the 1980s.
In each of the three strata of company size, 59 percent were blue-collar and 41 percent were white-collar workers (calculated using the 63 percent of workers for whom status was known). The exclusion of white-collar workers, who were assumed to be unexposed, would increase the proportion of trichloroethylene-exposed workers from 48, 30, and 11 percent among all workers to 81, 51, and 19 percent among the remaining blue-collar workers in companies with 150, 51100, and 101200 employees, respectively. Thus, the proportion of exposed workers is expected to be about four times higher in smaller than in larger companies, and 41 percent of the entire cohort would be expected to be exposed to trichloroethylene. Trichloroethylene exposure levels were also found to increase as the company size decreased (12).
Follow-up for cancer
Each person in the cohort was linked to the files of the nationwide Danish Cancer Registry by use of the personal identification number (16). Data on the type of cancer and the date of diagnosis were retrieved for all recorded cancers among cohort members. Tumors were classified according to a Danish modified version of the International Classification of Diseases, Seventh Revision (17), which allowed us to subdivide kidney cancers into renal cell carcinomas and renal pelvis/ureter cancers (18) and to identify esophageal adenocarcinomas. The period of follow-up for cancer occurrence began on April 1, 1968, or the date of first employment at a trichloroethylene-using company, whichever occurred later. Follow-up ended on the date of death, emigration, disappearance, or December 31, 1997, whichever occurred first. We calculated the expected numbers of cancers based on Danish national incidence rates of site-specific cancers by sex, 5-year age group, and calendar year.
Analyses
We calculated standardized incidence ratios, the ratios of observed-to-expected cancers, and 95 percent confidence intervals, assuming that the observed number of cancers followed a Poisson distribution (19). We allowed for latency by calculating standardized incidence ratios after inclusion of a lag period from the date of first employment to the start of follow-up for cancer. Moreover, standardized incidence ratios were calculated within different strata of duration of employment (<1 year, 14.9 years, 5 years), first year of employment (before 1970, 19701979, 1980 and later), and number of employees in the company or companies where the worker had been employed (<50, 5099.9, 100200). The latter variable was calculated as a time-weighted average over the actual follow-up period of each worker.
For non-Hodgkins lymphoma, renal cell carcinoma, and esophageal adenocarcinoma, standardized incidence ratios were further explored in a subcohort with presumably higher exposure levels, including only workers with first employment before 1980 and with employment for at least 1 year. In addition, we calculated standardized incidence ratios for those workers employed for at least 3 months in the trichloroethylene-using companies who were excluded from the blue-collar cohort (i.e., white-collar workers and workers with unknown blue- or white-collar status). We would expect the lowest trichloroethylene exposure among white-collar workers, intermediate trichloroethylene exposure among those with unknown status, and highest trichloroethylene exposure among the blue-collar workers.
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RESULTS |
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DISCUSSION |
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In this study, follow-up was virtually complete, and reliable nationwide registries provided information on the employment history, cancer morbidity, and vital status of cohort members. The expected numbers of cancers were calculated on the basis of cancer rates for the Danish population, but lower social classes were probably overrepresented in the cohort of blue-collar workers; this would lead to underestimation of standardized incidence ratios for cancers associated with higher social classes and overestimation of standardized incidence ratios for cancers associated with lower social classes. Such selection bias may partly explain the general pattern of slightly elevated standardized incidence ratios for the majority of cancer sites, particularly those associated with cigarette smoking and alcohol consumption. Selection bias may also arise because of the healthy worker effect, which would tend to produce underestimated standardized incidence ratios, but this effect is likely small in cancer studies (20).
Employment as a blue-collar worker at trichloroethylene-using companies was used as a marker of exposure, but only an estimated 41 percent of workers in the cohort had likely exposure to trichloroethylene, defined as working in the same room where trichloroethylene was used (12). An unknown proportion of workers in the cohort who were not considered to have likely trichloroethylene exposure may have been exposed to trichloroethylene at levels 3050 percent of the exposure levels of actual trichloroethylene workers (11). Some of the workers in the cohort, however, probably received little or no trichloroethylene exposure, which would introduce a nondifferential misclassification likely to bias standardized incidence ratios toward the null value and decrease somewhat the statistical power of this large study.
We included lag time and evaluated risk patterns according to three exposure-related variables (i.e., duration of employment, year of first employment, and number of employees in the company) to help assess whether the observed associations were likely to be causal. Because the Pension Fund provided information on employment only from 1964, earlier employment was not included when duration of employment was calculated. For workers with employment in a trichloroethylene-using company earlier than 1964, this could lead to misclassification of cohort members from higher to lower categories of duration of employment (e.g., if they left employment prior to 1969). Such misclassification of duration could lead to attenuation of an apparent dose-response relation. No other studies have examined the relation between trichloroethylene exposure potential and company size. The inverse relation between the number of employees in the company and the proportion of exposed workers was established from data collected in 1989 and 1998, and the degree to which the finding can be generalized to preceding decades is uncertain (12). Our previous study also indicated that exposure levels between 1964 and 1989 were higher in small companies, although we would expect the differences in exposure levels among the categories of company size to be much less than exposure differences among the categories of calendar time and duration of employment (12).
As in previous trichloroethylene and cancer studies, confounding by exposure to chemicals other than trichloroethylene cannot be excluded, although no such chemical is apparent. Since many of the standardized incidence ratios were only slightly elevated (table 2), even weak confounding by factors possibly relating to the socioeconomic status of the cohort (e.g., diet, smoking, alcohol consumption, and sexual behavior) is a concern. Cigarette smoking is a possible confounding factor, since smoking prevalence tends to be higher in the least educated groups in Denmark (21, 22) and therefore probably also among blue-collar workers. Indeed, among women, standardized incidence ratios for tobacco-related cancers were substantially elevated, whereas among men, standardized incidence ratios for lung and laryngeal cancers were only slightly elevated, and standardized incidence ratios for bladder cancer and squamous cell carcinoma of esophagus were not elevated (table 2).
The finding of increased risk of non-Hodgkins lymphoma in this study is unlikely to be explained by the lower social class of the cohort, because non-Hodgkins lymphoma risk appears to increase somewhat with increasing social class (23, 24). Because the etiology of non-Hodgkins lymphoma is largely unknown (24), confounding cannot be ruled out. We found, in both sexes, elevated standardized incidence ratios for variables related to exposure. Three Nordic cohort studies of workers monitored for a urinary metabolite of trichloroethylene because of occupational exposure to trichloroethylene all reported elevated standardized incidence ratios for non-Hodgkins lymphoma; the combined standardized incidence ratio from all three studies is 2.1 (95 percent CI: 1.3, 3.1; number of cases (n) = 21) (10, 25, 26). Three other cohort studies with individual assessment of trichloroethylene exposure found a standardized mortality ratio of 1.2 (n = 14) with indication of an exposure-response pattern (5), a rate ratio of 2.0 (n = 28) and no indication of exposure response (27), and a standardized mortality ratio of 1.0 (n = 3) (28). A number of case-control studies have provided mixed results (2934). The association between trichloroethylene exposure and non-Hodgkins lymphoma found in this study is consistent with the results of the most reliable cohort studies, and it can be considered as independent of the similar finding of our previous study (10) because the overlap between cases was negligible; only two non-Hodgkins lymphoma cases were included in both studies.
The present study indicated an association between trichloroethylene exposure and renal cell carcinoma, which is unlikely to be explained by the lower socioeconomic status of the cohort (23, 3542). The results for lung and other smoking-related cancers indicate that smoking was more prevalent in the cohort than in the background population and may have contributed to the elevated standardized incidence ratio for renal cell carcinoma. However, since current smokers tend to have only about a 40 percent increased risk of renal cell carcinoma (43), the percentage of smokers would have to be extraordinarily high among cohort members to account for the 20 percent and 40 percent excesses observed in the cohort and subcohort, respectively (table 2 and 4). Such a high smoking rate would be expected to generate a much higher excess risk of lung cancer than was observed in this study (standardized incidence ratio = 1.4, 95 percent CI: 1.3, 1.6). Most previous cohort and case-control studies have found little or no relation between trichloroethylene and renal cell carcinoma (39). For the three Nordic cohort studies of workers monitored for trichloroethylene exposure, the combined standardized incidence ratio for kidney cancer is 1.0 (95 percent CI: 0.6, 1.6; n = 16) (10, 25, 26). The three cohort studies assessing trichloroethylene exposure at the individual level found a standardized mortality ratio for kidney cancer of 1.0 (n = 7) and no indication of a dose-response pattern (5), a rate ratio of 1.6 (n = 15) with indication of an inverse dose-response relation (27), and a standardized mortality ratio of 1.3 (n = 8) (28). Other cohort studies where trichloroethylene was only one of many potential exposures (4448) and most but not all of the case-control studies of renal cell carcinoma and kidney cancer reported relative risk estimates close to unity (31, 34, 41, 49, 50). An odds ratio of 11 found in another case-control study (51) strikingly contrasts with other findings, and the study methods have been criticized (5254). Two cluster-motivated studies reported substantially elevated relative risks for renal cell carcinoma associated with trichloroethylene exposure (55, 56), but confirmation of such clusters is suitable for generatingnot testinghypotheses. Thus, although research into the metabolism and toxicology of trichloroethylene has identified a possible nephrocarcinogenic mechanism (57), the most reliable cohort studies provide no support for a causal link between exposure to trichloroethylene and renal cell carcinoma. The previously reported higher relative risk of renal cell carcinoma for women than for men exposed to trichloroethylene (50) was not apparent in the present study.
We observed an elevated standardized incidence ratio for esophageal adenocarcinoma, one of the most rapidly rising cancers in Europe and the United States (58). The result for esophageal adenocarcinoma represents an independent confirmation of our earlier finding (10), because only two esophageal adenocarcinoma cases were included in both studies, and yet the highest standardized incidence ratios were observed for esophageal adenocarcinoma in both investigations. The other two Nordic studies of workers monitored for trichloroethylene exposure did not report on esophageal cancer (25, 26). Risk factors for esophageal adenocarcinoma include gastroesophageal reflux disease, obesity, and, to a lesser extent, cigarette smoking (58). The association with smoking is much weaker than that between smoking and esophageal squamous cell carcinomas (59, 60). Just as was the case for renal cell carcinoma, the association between smoking and esophageal adenocarcinoma would be expected to account for little of the increased standardized incidence ratio for esophageal adenocarcinoma in our cohort. Except for our previous study, we are aware of no epidemiologic reports on occupational hazards for esophageal adenocarcinoma, although metal dust has been reported to increase the risk of tumors of the lower third of the esophagus where adenocarcinomas usually occur (61), and perchloroethylene exposure has been associated with esophageal cancer (although primarily with squamous cell carcinoma) among dry cleaners (62).
We challenged our findings for non-Hodgkins lymphoma, renal cell carcinoma, and esophageal adenocarcinoma in different ways. If the cases clustered mainly among workers in a single or a few companies, which were not the same for the three types of cancer, then it would be less likely that trichloroethylene was the common causal factor. No such clustering was observed. Similarly, if the distribution of industries where cases had worked differed markedly for non-Hodgkins lymphoma, renal cell carcinoma, and esophageal adenocarcinoma, it would be less likely that trichloroethylene was the common causal factor; we detected no significant difference in the distribution of industries for non-Hodgkins lymphoma, renal cell carcinoma, and esophageal adenocarcinoma cases.
We found substantially elevated standardized incidence ratios for cancer of the liver and gallbladder/biliary passages among women but not among men. Evidence of elevated risk of cancer of the liver and biliary tract played an important role in the classification of trichloroethylene by the International Agency for Research on Cancer as a probable human carcinogen (2). For the three Nordic studies of workers monitored for trichloroethylene exposure, the standardized incidence ratio for cancer of the liver or biliary tract is 1.8 (95% CI: 1.1, 2.9; n = 18) (10, 25, 26). The three other cohort studies with trichloroethylene exposure assessment reported standardized mortality ratios of 0.5, 1.2, and 1.0 for liver cancer (5, 27, 28). In the current cohort study, the lower standardized incidence ratios when including lag time and the inverse relation of standardized incidence ratios with duration of employment and first year of employment argue against a causal relation between trichloroethylene exposure and cancer of the liver and gallbladder/biliary passages. Alcohol is a major risk factor for primary liver cancer in Denmark (63), and standardized incidence ratios for other alcohol-related cancers (i.e., laryngeal, esophageal squamous cell, and buccal cavity and pharyngeal cancer) were also found in the current study for women but not for men. However, despite a stronger association with alcohol for these cancers (63), the standardized incidence ratios were less increased than those for liver and biliary tract cancer and moreover, in general, Danish women from lower social classes have a lower alcohol intake (64). Thus, neither trichloroethylene exposure nor alcohol consumption alone provides a likely explanation for our finding.
The results of this study showed an increased risk of cervical cancer, which was also found in some (10, 25, 27) but not all (5, 28) previous studies of trichloroethylene-exposed cohorts. Two Nordic studies reported a twofold increased risk of cervical cancer among women of lower social classes (23, 65), and confounding by social class is, therefore, the likely explanation for the increased risk of cervical cancer in our study. Moreover, the lower risk when including lag time and in association with long duration of employment argues against trichloroethylene as the causal agent for cervical cancer.
Finally, the lower risk for skin melanoma in the cohort is probably caused by the social selection, as two Nordic studies have consistently shown a similar decreased risk among the lower social classes (23, 65).
In conclusion, the results of our cohort study provide support for an association between trichloroethylene exposure and non-Hodgkins lymphoma, which is consistent with several earlier studies. The study also found evidence for an association with renal cell carcinoma, which, however, is less consistent with the epidemiologic evidence. Our increased standardized incidence ratio for liver and biliary tract cancer in women did not follow a dose-response pattern; however, in view of past findings the possibility of an association between trichloroethylene and liver/biliary passage cancer cannot be excluded. We confirmed our previous observation of an increased standardized incidence ratio for esophageal adenocarcinoma among Danish workers exposed to trichloroethylene; such an association has not been reported by others but warrants further research, given the rapid increase in esophageal adenocarcinoma incidence rates in industrial countries.
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ACKNOWLEDGMENTS |
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The authors thank Andrea Meersohn and Visti Birk Larsen for data processing.
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NOTES |
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REFERENCES |
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