Results

Table 1 shows the distribution of the cumulative probability of exposure to each of the four carcinogens in the case and the subcohort group (table 1). The percentage of exposed people to paint components, PAHs, and diesel exhaust were roughly equal between cases and subcohort members. However, there were relatively more cases than subcohort members in the highest exposure tertiles. Cases were also more often exposed to aromatic amines than subcohort members (table1).

The distribution of potential confounders for bladder cancer according to occupational exposure to paint components, PAHs, diesel exhaust, and aromatic amines is presented in table 2. The confounders were equally distributed among never and ever exposed subcohort members for all investigated carcinogenic exposures. Exposure to paint components was correlated with exposure to PAHs and diesel exhaust. Diesel exhaust was furthermore correlated with PAHs and aromatic amines (table 2).

Table 3 shows the associations of occupational exposure to risk of bladder cancer. The incidence rate ratio for bladder cancer adjusted for age and cigarette smoking was 1.29 (95% CI 0.71 to 2.33) comparing the highest tertile of exposure to paint components with no occupational exposure (p value for trend 0.08). After additional adjustment for other occupational exposures, the RR changed to 1.31 (95% CI 0.72 to 2.40, p value for trend 0.09). Men with a higher exposure to aromatic amines were also found to be at increased risk of bladder cancer, but the estimates were based on small numbers (adjusted for age and smoking RR 1.32, 95% CI 0.41 to 4.23). The corresponding RR was 1.36 (95% CI 0.42 to 4.35) after adjustment for age, smoking, and occupation. Exposure to PAHs or diesel exhaust did not substantially increase the risk of bladder cancer (p value for trend 0.80 and 0.50, respectively). Men in the highest exposure categories of PAHs had non-significantly higher risks of bladder cancer than men with no occupational exposure to PAHs (adjusted for age and smoking RR 1.24, 95% CI 0.68 to 2.27) and diesel exhaust (adjusted for age and smoking RR 1.21, 95% CI 0.78 to 1.88). After adjustment for other occupational exposures and cigarette smoking the RRs changed to 1.18 (95% CI 0.62 to 2.24) and 1.17 (95% CI 0.74 to 1.84), respectively (table 3). Additional correction for total fluid, alcohol, coffee, tea, vegetables, and fruit consumption did not essentially change the risk estimates for the carcinogenic exposures (data not shown).

The associations between cumulative probability of exposure to paint components and PAHs, and risk of bladder cancer were more explicit for current smokers than for never or former smokers (table 4). It was not possible to stratify exposure to aromatic amines on characteristics of cigarette smoking, because of sparcity of data. Among the former smokers it seemed that men who smoked more than 15 cigarettes a day had lower RRs for exposure to paint components and PAHs compared with men who had smoked less than 15 cigarettes daily, whereas among current smokers the opposite was found. The positive association between paint components, PAHs, and risk of bladder cancer increased by increasing number of cigarettes smoked among current smokers. Exposure to diesel exhaust was positively associated with risk of bladder cancer among current smokers and among men who smoked more than 15 cigarettes a day, irrespective of smoking habit (table 4).

The positive association between cumulative probability of exposure to paint components and transitional cell carcinoma of the bladder was similar for papillary and non-papillary (invasive) tumours. A positive association between exposure to PAHs and risk of bladder cancer was most pronounced in non-papillary invasive transitional cell carcinomas of the urinary bladder. The positive association between cumulative probability of exposure to diesel exhaust and risk of bladder cancer was most pronounced among men with non-papillary non-invasive tumours (table 5). Subgroup analyses for exposure to aromatic amines and tumour invasiveness and morphology were not possible because too few cases were exposed to aromatic amines.

Discussion

In this study we examined the association between four occupational exposures and the incidence of bladder cancer. The results suggest a possible positive association between cumulative exposure to paint components, PAHs, and aromatic amines and the incidence of bladder cancer, although significance was not reached. The broad 95% CIs might reflect the relatively few exposed cases in this study or random error in exposure assessment. Only very limited support, if any, was found for an association between diesel exhaust and the risk of bladder cancer. If there is an association between diesel exhaust and bladder cancer at all, the results indicate that it may be limited to non-papillary, non-invasive bladder cancer. Statistical adjustment for the effect of other potential risk factors tended rather to increase the RRs than to decrease the estimates.

Many studies on occupational risk factors for bladder cancer have been conducted.30 For the most part, epidemiological evidence has been derived from either job titles (obtained through a job exposure matrix (JEM)) or self assessed exposures to certain agents. In only a few studies a case by case expert evaluation of exposure to occupationally related agents was performed.8 31-34 The quality of the exposure assessment strongly affects the outcome of the risk estimate35 and ideally includes both intensity and duration of the occupational exposure for each specific study subject. However, in large population based studies it is almost impossible to obtain this quantitative information. Moreover, in this type of study the range of jobs with potential exposures is large and within given jobs there is a large variation in exposures. This makes it even more difficult to identify a clear link between jobs and exposures compared with industry based studies.36 37 Self assessment of occupational exposures is considered inadequate as the chemical knowledge of the study participants in general is not sufficient for a valid recall of agent specific, time specific worksite exposures.25 In our study only the occupational history of the study subjects was available, which does not allow an estimation of the actual exposure concentrations that were experienced in the past. The highest achievable was a retrospective exposure assessment of probability of exposure.21 In general this can be obtained through a JEM or a case by case expert assessment. Both techniques have been used in studies on occupational risk factors for bladder cancer.30 In this study a case by case expert assessment was used.21 The main advantage of this method, compared with the use of a JEM, is that all the available information (job title, type of the company, products, and period) is used for the exposure assessment36 37 whereas the agent specific and time specific information derived from a JEM is limited.30 36 Also the case by case expert assessment provides the option to use information on the name of the company where the study subject worked to further specify the exposure assessment. For example, a maintenance worker in a metal processing company would be classified by a JEM as not exposed to PAHs. However, if it is known that the person worked for ALDEL, an aluminum smelter, it is clear that the maintenance worker has probably been exposed to PAHs, as aluminum smelters contain pot rooms. Therefore, a JEM may produce more non-differential misclassification than exposure assessments by experts.36 37 However, with a case by case expert assessment in general there are no explicit definitions of the criteria, which are used for the assessment of exposure,37and that assessment is affected by the degree of learning of the experts. Therefore, a case by case expert assessment may be less reproducible than a JEM, which will produce the same exposure information for identical basic data. To improve reliability, we used a two stage exposure assessment in which two experts independently assessed the exposure. Disagreements were solved through consensus meetings.

The database available for the analysis provided us with the opportunity to test the possible effect of other risk factors, in particular cigarette smoking, on the observed associations. We modelled cigarette smoking habits so that they best explained bladder cancer.26 This resulted in a model including number of years smoked and habitual number of cigarettes smoked each day, both as continuous variables. We therefore think that the associations found were not entirely due to residual confounding by smoking, although we cannot exclude some effect. We were not able to explain our results on the basis of confounding of other factors as well as cigarette smoking, as the results were essentially unchanged after incorporating into the analyses known or suspected risk factors for bladder cancer, including total consumption of fluid, alcohol, coffee, tea, vegetables, and fruit.

After stratifying the study population into non-smokers, former smokers, and current smokers a pattern emerged indicating that the effects of the occupational exposures were confined to the current smokers. The RR of cumulative probability of exposure to paint components for bladder cancer in former smokers was 0.65, by contrast with an RR of 2.22 for current smokers. This was significant. A further breakdown of these groups into light smokers and heavy smokers showed a pattern consistent with a stronger association in current smokers who smoked more than 15 cigarettes a day compared with those who smoked less often. The interaction found might represent some form of biological synergy between cigarette smoking and exposure to aromatic amines and PAHs in bladder cacinogenesis, as some types of these compounds (naphthylamine and benzo[a]pyrene, respectively) are formed when tobacco is smoked. These results also show that current rather than former smoking might play a part in occupational carcinogenesis of bladder cancer. This effect was particularly clear for exposure to paint components and to a lesser extent for exposure to PAHs. Therefore, workers exposed to paint components even only in the past might be advised to refrain from smoking cigarettes. However it must be pointed out that as the information on amount of cigarette smoking was not always complete, the stratified estimates might possibly be overestimated especially among the current smokers. Also, despite the substantial size of this cohort study the number of cases limited the possibilities for further breakdowns and stratifications that are involved in subgroup analyses.

Several other researchers have reported possible interactions between smoking and the association between occupational exposures and risk of bladder cancer. Schumacher et al 38 reported an interaction between exposure to aromatic amines and bladder cancer with smoking. The odds ratio for never smokers exposed to aromatic amines for 10 or more years was 1.65, for non-exposed current smokers 3.57 and for current smokers exposed to aromatic amines 6.74. From further modelling the researchers concluded that the study gave support for some deviation from the additive model. Several other studies investigated the risks of bladder cancer from occupational exposures and cigarette smoking, but no analyses were done to test interaction between smoking and occupational exposures.39 40

In conclusion, our study provides only marginal evidence for an association between occupational exposure to paint components, PAHs, aromatic amines, and risk of bladder cancer. It further shows, despite the small proportion of exposed subjects in the study, that there might be a potentially important interactive effect from cigarette smoking, specifically for paint components, suggesting that the carcinogenic effect might decrease after stopping smoking.