Occupational risk factors for urothelial carcinoma: agent-specific results from a case-control study in Germany

Beate Pescha, Johannes Haertingb, Ulrich Ranfta, Andreas Klimpelc, Burkhard Oelschlägelb, Walter Schilld and the MURC Study Group,e

a Medical Institute for Environmental Hygiene at the Heinrich Heine University of Düsseldorf, Germany.
b Institute of Medical Epidemiology, Biometry and Medical Informatics at the Martin Luther University, Halle, Germany.
c Institute for Kidney and Hypertension Research, Berlin, Germany.
d Bremen Institute for Prevention Research and Social Medicine, Bremen, Germany.
e Collaborators of the Multicenter Urothelial and Renal Cancer Study (MURC Study Group): Wolfgang Barth, Uta Brettschneider, Elisabeth Bronder,

Reprint requests to: Beate Pesch, Unit of Environmental Epidemiology, Medical Institute for Environmental Hygiene, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany.


    Abstract
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
Background This multicentre population-based case-control study was conducted to estimate the urothelial cancer risk for occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons (PAH), and chlorinated hydrocarbons besides other suspected risk factors.

Methods In a population-based multicentre study, 1035 incident urothelial cancer cases and 4298 controls matched for region, sex, and age were interviewed between 1991 and 1995 for their occupational history and lifestyle habits. Exposure to the agents under study was self-assessed as well as expert-rated with two job-exposure matrices and a job task-exposure matrix. Conditional logistic regression was used to calculate smoking adjusted odds ratios (OR) and to control for study centre and age.

Results Urothelial cancer risk following exposure to aromatic amines was only slightly elevated. Among males, substantial exposures to PAH as well as to chlorinated solvents and their corresponding occupational settings were associated with significantly elevated risks after adjustment for smoking (PAH exposure, assessed with a job-exposure matrix: OR = 1.6, 95% CI : 1.1–2.3, exposure to chlorinated solvents, assessed with a job task-exposure matrix : OR = 1.8, 95% CI : 1.2–2.6). Metal degreasing showed an elevated urothelial cancer risk among males (OR = 2.3, 95% CI : 1.4–3.8). In females also, exposure to chlorinated solvents indicated a urothelial cancer risk. Because of small numbers the risk evaluation for females should be treated with caution.

Conclusions Occupational exposure to aromatic amines could not be shown to be as strong a risk factor for urothelial carcinomas as in the past. A possible explanation for this finding is the reduction in exposure over the last 50 years. Our results strengthen the evidence that PAH may have a carcinogenic potential for the urothelium. Furthermore, our results indicate a urothelial cancer risk for the use of chlorinated solvents.

Keywords Bladder cancer, urothelial cancer, case-control study, aromatic amines, polycyclic aromatic hydrocarbons (PAH), chlorinated solvents, job-exposure matrix

Accepted 29 September 1999


    Introduction
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
Histologically the urothelium comprises the urinary bladder, ureter, and renal pelvis. Urothelial cancer originates in the mucosa of the lower urinary tract, and most cases of urothelial cancer affect the urinary bladder. Urinary bladder cancer has been much studied and has long been considered an occupation-related tumour, especially in males.1–3 In spite of the fact that certain aromatic amines, which have been shown to be strong carcinogens for the urinary bladder, have been banned for decades, the age-adjusted incidence rates of bladder cancer are still high in Germany (about 30 in men and 6 in women per 100 000, European standard population).4

Since the 1980s there has been epidemiological evidence that occupation-related agents other than aromatic amines can be causally linked to urothelial cancer.5 Coal gasification, and steel and aluminium production as well as exposure to tar or pitch are occupational settings with exposure to polycyclic aromatic hydrocarbons (PAH), and these are associated with an elevated bladder cancer risk.6–8

The International Agency for Research on Cancer has recently concluded that tetrachloroethylene and trichloroethylene are probably carcinogenic to humans.9 A review of epidemiological studies5 and recently a French case-control study10 reported an excess risk for cancer of the urothelium from occupational exposure to chlorinated solvents.

This multicentre population-based case-control study was conducted to estimate the urothelial cancer risk for occupational exposure to aromatic amines, PAH, and chlorinated hydrocarbons besides other suspected risk factors. Details of the study design and further results are reported elsewhere.11


    Material and Methods
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
Cancer cases and controls
From 1991 to 1995, this population-based case-control study was conducted in five regions of Germany (West Berlin, Bremen, Leverkusen, Halle, Jena). Eligible were German nationals without age limit for both cases and controls. Two case series were enrolled simultaneously, 1035 urothelial cancer cases and 935 renal cell cancer cases. A case was eligible for inclusion in the study only if the diagnosis was histologically confirmed during the 6 months before recruitment. Histologically the urothelium comprises urinary bladder (90.2% among male cases and 84.3% among female cases), ureter, and renal pelvis. Participation of the large hospitals in the study areas assured a population-based enrolment of cases which was ascertained by an accompanying cancer incidence study.11

The controls were frequency-matched to cases by region, sex (Table 1Go), and age (5-year interval). The matching procedure was such that for the two case series a 1:2 matching for urothelial cancer and a 1:4 matching for renal cell cancer to controls was planned. During the recruitment, an increase in the incidence rates of renal cell cancer was observed. Therefore, the recruitment period of renal cell cancer cases was expanded to clarify possible causes. Due to this extension and because of differences in the age distribution of urothelial and renal cell cancer cases, a group of 4298 randomly selected population controls from local residency registries was finally enrolled. This control group was used in the statistical analysis of both cancer sites.


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Table 1 Distribution of cases and controls by study region and gender
 
In all, 704 male and 331 female incident cases of urothelial cancer were interviewed in hospitals within 6 months of first diagnosis, and 2650 male and 1648 female population controls were interviewed at home. Face-to-face interviews were conducted by centrally trained interviewers. A structured questionnaire was used to obtain lifestyle and occupational exposure information. Basic characteristics of the cases and controls with regard to interview duration, age, education and smoking behaviour are given in Table 2Go. The slight difference in the age distributions of cases and controls resulted from the sharing of the control group with younger renal cell cancer cases. The overall response rates were 84% for cases, and 71% for controls.


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Table 2 Selected characteristics of cases and controls
 
Exposure assessment
The assessment of exposure to occupational risk factors was based on the subject's occupational history (job titles) and supplementary information on job tasks with suspected exposure to the agents under study. For selected job tasks, and while being shown lists of the agents under study, the interviewee was also asked to self-assess exposure by estimating the average working hours per day of exposure. Every job title held at least for one year was classified according to the International Standard Classification of Occupations of the International Labour Office.12 The subject's lifetime exposure with respect to a specified job title was quantified as the duration (in years) working in this job. For job tasks, the quantification of exposure was the respective weighted sum of years, where the weights were the fractions of working time spent carrying out this task. Quantification of exposure to self-assessed agents was done in the same way. We referred to those exposure variables as ‘duration’.

So far, only the information provided by the interviewee was used for exposure assessment. For quantifying the exposure to specified agents, we additionally applied expert knowledge by means of job-exposure matrices (JEM) and a job task-exposure matrix (JTEM). For every job title and job task, respectively, the exposure matrix provided an expert rating in terms of the probability and the intensity of exposure to a specified agent using for both measures the categories ‘none’, ‘low or medium’, and ‘high’. For the job title-based assessment, we adapted two job-exposure matrices (the so-called British JEM;13 and the ‘German’ JEM14). Experts within our study group developed a corresponding job task-exposure matrix (JTEM) where regional differences between East and West Germany and temporal changes concerning occupational exposure were taken into account. To obtain an agent-specific measure of a subject's lifetime exposure, the products of duration, probability, and intensity were summarized over all jobs held or job tasks operated, respectively. For this quantification, the ordinal categories ‘none’, ‘low or medium’ and ‘high’ for both probability and intensity of exposure were transformed into the scores 0, 1, and 3. We referred to these exposure variables as ‘exposure indices’.

Statistical analysis
Conditional logistic regression models15 were applied for risk estimation using the SAS procedure PHREG,16 separately for males and females because of gender differences in the anatomy of the urogenital tract and in the metabolism of xenobiotics.17 According to the frequency matching of cases and controls, the risk estimation was conditional on 45 strata resulting from nine age groups (<40, 40–49, 50–54,...,75–79, 80+) and five study regions.

Considering possible highly non-linear associations between risk estimates and exposure measures, four exposure categories were defined for each exposure variable using the 30th, 60th and 90th percentiles of the distribution of the exposure variable among the exposed controls. Concerning exposure duration, we refer to these categories as ‘short’, ‘medium’, ‘long’ and ‘very long duration’ of exposure, and with respect to exposure indices, as ‘low’, ‘medium’, ‘high’ and ‘substantial exposure’. The reference groups comprised the unexposed subjects and the subjects with ‘short duration’ or ‘low exposure’.

Smoking was considered as a confounder because it is an established risk factor for urothelial cancer1 and has a higher prevalence among blue collar workers.18 Cumulative cigarette consumption was measured as log (packyears + 1). Additionally, quitting smoking (cutpoint 2 years before interview) and exclusive smoking of other tobacco products (yes/no; for males only) were included. Socioeconomic status (SES) was not used as a confounder for occupational risk analysis, since the definition of SES was based upon professional qualification and graduation at school.11 Table 3Go shows the risk estimates for tobacco smoking and SES.


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Table 3 Odds ratios (OR) of the conditional logistic regression for possible confounders
 
In the statistical analyses, we only adjusted for smoking and ignored mutual confounding by other agents or occupations. Mutual confounding by other occupations is not a relevant problem due to the low prevalence of people in high risk jobs. On the other hand, agent-specific exposures often go with complex exposure circumstances. For example, paints are mixtures of pigments and solvents. The ubiquitous correlation between agents like PAH and aromatic amines at the workplace can hardly be disentangled.


    Results
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
Occupations and job tasks
Table 4Go presents the regression results for occupations and job tasks selected as probably exposed to the agents under study. Due to small numbers of occupationally exposed women, fewer OR could be estimated for females than for men. Chemical workers did not show an elevated risk for urothelial cancer although there was a chemical industry in three of the study regions. Long duration of employment as a leather worker, printer, motor vehicle driver, or worker in the metal production were shown as high risk occupations. No excess risks could be found for barbers and hairdressers based on three male and three female cases ever employed (not shown in Table 4Go). Rubber production and textile manufacture were not represented as large industries in the study regions.


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Table 4 Odds ratios (OR) of the conditional logistic regression for selected occupations and job tasks by duration of occupational exposure
 
Among the job tasks, there was an excess risk for a very long duration of exposure in the production of tar, pitch and bitumen as well as in dyeing and finishing of leather or textiles, but with small numbers of observed cases. Job tasks with significantly elevated OR were metal degreasing and use of Stoddard solvents in occupational settings.

Products and substances
Table 5Go presents the regression results for the self-assessed and expert-rated exposure indices, adjusted for smoking. Occupation- related exposure to aromatic amines and to paints and pigments were not associated with urothelial cancer risk. But the production of paints, especially the use of benzene as a raw material and chlorophenols as intermediates of dyestuff production, may imply a possible cancer risk.


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Table 5 Odds ratios (OR) of the conditional logistic regression for occupational exposure to selected substances, self-assessed (duration) and expert-assessed (exposure index)
 
High and substantial exposure to PAH seemed to be a risk factor for urothelial cancer. Elevated risks could be found for tar and pitch exposed jobs based on the British JEM and on the JTEM approach. The elevated risks for exposure to heat may also indicate a possible cancer risk from pyrolytic gases.

Chlorinated solvents were assessed as a further independent risk factor for the urothelium, especially if the job task ‘metal degreasing’ is considered as an occupational setting with exposure to trichloroethylene.


    Discussion
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
Exposure information
Until now, many case-control studies on occupational risk factors for bladder or, respectively, urothelial cancer have been conducted, among them three studies in Germany.19–21 For the most part, epidemiological evidence has been derived from either job titles or self-assessed exposures to certain agents; only a few bladder cancer studies had an expert evaluation of exposure to occupationally related agents.7,10,22–24 The chemical knowledge of the study participants is considered insufficient for a valid recall of agent-specific worksite exposures. The small numbers of people reporting agent-specific exposures in comparison to the expert-based exposure assessments support the lower sensitivity which was documented in some validity studies.25–27

Whereas the job history does not seem to be vulnerable to differential recall, the agent-specific information derived from job titles is limited. Job tasks can have a higher specificity.28 The use of chlorinated solvents in the job task ‘metal cleaning’ is more likely than for the job title ‘tool maker’. On the other hand, data for selected job tasks can suffer from loss of sensitivity if interviewee knowledge about technological processes or materials is necessary to gain exposure information.29 The number of job tasks reported by retired people showed a decline with age, but the number of job titles did not.11

In bladder cancer epidemiology, the majority of case-control studies are hospital-based. This study was population-based, and a selection bias resulting from the lower response rate of the population controls cannot be excluded. On the other hand, the similar SES distribution of male controls and renal cell cancer cases, which were another independent outcome of this project, does not indicate a strong selection bias.11 Renal cell carcinoma is not considered to be an occupation-related cancer.

Exposure estimates based on duration of exposure only seemed not to be strongly affected by recall bias. Relatively high risks for a very long duration of exposure in specified occupational settings like metal cleaning or production of tar, pitch and bitumen could be identified. The low prevalence of subjects working for a very long time in some specified job tasks or occupations reduced the statistical power considerably. The next step towards an agent-specific exposure assessment by means of JEM and JTEM can introduce an additional misclassification of exposure or a loss in specificity and, hence, the corresponding risk estimates for exposure indices were for the most part closer to the null value. The evaluation of the probability and intensity of exposure for a large set of agents is only very crude and can differ considerably between experts due to subjective ratings and due to the outcome for which the exposure is rated. The German JEM was developed for a Morbis Parkinson study focused on the impact of solvents. Therefore, in the low dose range, more occupations were considered exposed than in the British JEM. Another misclassification of exposure can be introduced by unspecific exposure variables. The exposure variable ‘lead and its compounds’ does not differentiate between organic and inorganic lead compounds which have a different carcinogenicity.

Dose-response relations
One of the postulates for epidemiological evidence is to show a dose-response relation for the agents under study. Clear dose-response relations are difficult to demonstrate for occupational exposures in a population-based case-control study. Besides the methodological problem of exposure misclassification both from self- or expert-assessed exposure to a chemical agent, the misspecification of the exposure metric can also contribute to a smoothing of the dose-response relation towards the null value. For this study, cumulative exposure indices were developed according to the 1986 US EPA guidelines for carcinogenic risk assessment.30 The underlying assumption of toxicological equivalence of exposure time and concentration for cumulative exposure indices may not hold for many agents, like chlorinated solvents. The 1996 revised guidelines of the US EPA refer to the growing toxicological data on defence mechanisms.31 Furthermore, cumulative exposure indices do not take into account age at exposure. Recent studies showed that people exposed at different ages can differ in cancer risk.32,33

An increase of effect with increasing dose can more easily be observed for a potent carcinogen like tobacco smoke with a high exposure prevalence (Table 3Go). For occupation-related carcinogens, only a very small fraction of the general population is exposed to high workplace concentrations. Therefore, our emphasis was on the category of substantial exposure. As a trade-off, the small numbers in this category caused large confidence intervals in the risk estimates.

The reference group comprised unexposed as well as little-exposed people to compensate for a possible recall bias or confounding by social status. This inclusion of people with low exposure was supported by the assumption that a complex set of defence mechanisms can detoxify low or even medium doses of several xenobiotics34 e.g. trichloroethylene.35

Occupations and job tasks
Coal gasification, iron and steel founding, aluminium production, the rubber industry, magenta and auramine production, and shoe and leather manufacture were rated as occupational circumstances with sufficient carcinogenic potential for the human urinary bladder,6 and this is still reflected in the German bladder cancer mortality pattern in men.36 In our study, leather manufacturers and workers in steel and iron foundries showed an excess risk of urothelial cancer. Aluminium and rubber production were not among the large industries in the study regions.

Many studies found a bladder cancer risk among chemical workers,10,20,37–40 but negative findings have also been reported.21,41–44 We found no excess risk among the chemical workers in our study. ‘Chemical industry’ covers exposure to a wide range of chemical agents, and the job title ‘chemical worker’ is unspecific for the agents under study.

The elevated risk for motor vehicle drivers reported in many studies2,10,19,45–56 could be confirmed. Two other German case-control studies did not find an excess risk for drivers20 or for non-smoking drivers.21 Besides diesel exhaust,56 high concentrations of side stream components of tobacco smoke in the driver's cabin should also be taken into account as possible causal agents.

There is toxicological evidence that water-soluble azodyes can be metabolized into carcinogenic aromatic amines.57–59 Dyers, painters, printers, barbers, and hairdressers are expected to show an excess risk. We could demonstrate a significantly elevated risk only for male printers with a very long duration of employment. Other studies are not conclusive with respect to an association for the commercial use of paints, with the exception of textile and leather dyers.50–51,60–61

Metal degreasing, manufacture of tar, pitch and bitumen, and dyeing and finishing of leather exhibited high risks for a very long duration of exposure, but statistical significance could only be shown for metal degreasing.

Products and substances
Selected aromatic amines have been known to be strong carcinogens since the end of the last century.62–64 Both substitution and technological progress have reduced exposure in the German dyestuff production industry considerably. Our negative findings may reflect this reduction in exposure levels to aromatic amines. On the other hand, for benzene as a raw material and chlorophenols as intermediates in paint production, an excess risk for cancer of the urothelium cannot be excluded. This is also supported by the elevated bladder cancer mortality in German regions with a benzene processing industry.36,65

Hitherto, no consensus exists to acknowledge other agents as causally linked with bladder cancer. Reviews of epidemiological studies5,8 suggested increased risks with exposure to combustion gases, and more recent studies7,22,24 also found evidence for a bladder cancer risk from PAH. We could confirm the cancer risk for exposure to PAH as well as to tar and pitch. The elevated risks found for exposure to heat and for the use of asbestos for heat protection also support the possible cancer risk of combustion gases.

Epidemiological studies and long-term carcinogenicity studies in animals suggest that some chlorinated hydrocarbons are probably or possibly carcinogenic.6 Trichloroethylene is a vapour degreaser for the cold cleaning of metal parts, a chemical intermediate and a solvent for fats, rubber, inks, and paints. Tetrachloroethylene is also a standard solvent for dry cleaning. Rubber workers, dyers and printers may have contact with chlorinated solvents among many other agents. An excess bladder cancer risk for occupational exposure to chlorinated solvents was reported in a French study.10 Our data indicate an excess risk among substantially exposed males in occupational settings which are likely exposed to chlorinated solvents, especially in metal degreasing. For the majority of the corresponding exposure indices, elevated risks for highly or substantially exposed males could be shown and, with limited evidence, for some indices in females. There was a significant excess risk for substantially exposed males for both trichloroethylene and tetrachloroethylene (JTEM) and for highly exposed males to tetrachloroethylene (German JEM).


    Acknowledgments
 
Financial support from the Federal Ministry of Research and Technology (BMFT), grants no. 01HL 201, 211, 221, 231, 241, 251, 261, is gratefully acknowledged. We thank the interviewees, interviewers and clinical staff for their generous cooperation.


    Notes
 
Katrin Farker, Johannes Faßbinder, Rainer Frentzel-Beyme, Eberhard Greiser, Karin Greiser, Lothar Heinemann, Annemarie Hoffmann, Wolfgang Hoffmann, Werner Hofmann, Christine Lautenschläger, Ullrich Matz, Martin Molzahn, Wolfgang Pommer, Manfred Steinkohl.


    References
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 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
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