Bladder cancer is a significant global health concern, ranking among the top ten most frequently diagnosed cancers. Occupational carcinogens contribute substantially to bladder cancer incidence, with estimates ranging from 5-25% in males and 8-11% in females. Several occupations involving solvent use, such as dry cleaning, rubber manufacturing, and painting, have been linked to increased bladder cancer risk. Workers in these occupations are exposed to various organic solvents, including benzene, toluene, and xylene (BTX), which are frequently found together in workplaces. Perchloroethylene, a dry-cleaning solvent, shows probable evidence of bladder carcinogenicity, but the role of other common organic solvents remains unclear. Prior research on the association between specific organic solvents and bladder cancer yielded inconsistent results, with some studies reporting positive associations and others showing no association. Methodological limitations in prior studies, such as reliance on job titles or assessment of diverse worker groups, hampered the ability to accurately assess exposure to specific solvents. Recent studies utilizing job-exposure matrices (JEMs) provided more quantitative exposure assessments, but further investigation is warranted. This study uses data from the New England Bladder Cancer Study (NEBCS), a large population-based case-control study with detailed occupational histories, to evaluate the association between occupational solvent exposure and bladder cancer risk, while accounting for confounders such as smoking.

The existing literature on the link between occupational solvent exposure and bladder cancer presents conflicting evidence. Some studies have shown positive associations between exposure to certain solvents, such as trichloroethane, trichloroethylene, toluene, and benzene, and an increased risk of bladder cancer. These studies, however, often had limitations, such as relying on job titles for exposure assessment rather than quantifying exposure levels or failing to control for confounding factors such as smoking, a major risk factor for bladder cancer. Other studies failed to demonstrate a clear relationship between solvent exposure and bladder cancer. The inconsistency across studies highlights the need for research employing more robust methodologies and detailed exposure assessments.

The study utilized data from the New England Bladder Cancer Study (NEBCS), a population-based case-control study including 1182 incident bladder cancer cases and 1408 controls from Maine, Vermont, and New Hampshire. Participants provided detailed lifetime occupational histories, including job titles, tasks, chemicals handled, and duration. Solvent exposure was assessed quantitatively using the Canadian Job-Exposure Matrix (CANJEM), which links jobs to exposure probabilities and frequency-weighted intensity (FWI) for various solvents. Because benzene, toluene, and xylene (BTX) are frequently co-exposed, two BTX exposure metrics were created: 1) CANJEM-based metrics and 2) hybrid metrics integrating CANJEM with participant-specific information from open-ended questions and exposure-oriented modules. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, smoking status, state, race, ethnicity, and non-solvent-exposed high-risk occupations. Cumulative exposure was calculated, and exposure-response relationships were examined using quartiles of cumulative exposure and regression splines, also considering lagged exposure to account for latency periods. Sensitivity analyses were conducted using different exposure probability thresholds.

Statistically significant increased risks of bladder cancer were observed for ever exposure to benzene (OR=1.63, 95% CI: 1.14–2.32), toluene (OR=1.60, 95% CI: 1.06–2.43), and xylene (OR=1.67, 95% CI: 1.13–2.48) individually. A significant exposure-response relationship was observed for cumulative BTX exposure, with a stronger association found using the hybrid BTX metrics compared to CANJEM-based metrics (p-trend=0.001 vs. p-trend=0.02 for 20-year lagged exposure). The hybrid approach, incorporating participant-specific details about tasks and chemicals, refined exposure assessments and enhanced the exposure-response relationship. No statistically significant increased risks were found for other solvents examined, except a non-significant decreased risk for perchloroethylene, but this was based on a small number of exposed cases. The strong correlation between benzene, toluene, and xylene exposures emphasized the importance of assessing BTX as a group, reflecting real-world occupational exposure scenarios.

This study provides strong evidence for an association between cumulative occupational exposure to BTX and bladder cancer risk. The findings are consistent with some previous research showing a positive association between exposure to benzene and toluene, and bladder cancer risk although this is not consistently demonstrated. The study's use of detailed occupational histories and the hybrid exposure assessment approach strengthens the findings. The stronger association observed using the hybrid metrics highlights the value of supplementing JEMs with participant-specific data to reduce exposure misclassification. This is a unique finding, as this is one of the few studies to demonstrate an association between BTX and bladder cancer risk and the use of a novel approach to assessment in a large population-based case-control study. Several plausible biological mechanisms could explain the observed association, including BTX's genotoxicity, oxidative stress induction, and effects on DNA repair and immune function. Benzene, a known human carcinogen, is a component of BTX and is excreted in urine, making it bioavailable to the bladder. The results of this study are pertinent given the co-occurrence of these solvents in many occupations.

This population-based case-control study demonstrates for the first time a statistically significant association between cumulative occupational BTX exposure and bladder cancer risk. The hybrid exposure assessment method enhanced the detection of this association, highlighting the importance of detailed occupational data in assessing environmental exposures and their impact on cancer risk. Further research is needed to confirm these findings and explore the specific mechanisms linking BTX exposure to bladder cancer development. Future studies should prioritize more precise exposure measurements and investigation into the individual and combined effects of the BTX components.

As a case-control study, recall bias is a potential limitation. Although it's unlikely participants were aware of the association between BTX exposure and bladder cancer, it remains a possibility. The study's reliance on CANJEM, which is based on Canadian data, for exposure assessment might introduce some variability when applied to a US population, although the proximity and similarities in occupational practices likely minimize this limitation. The strong correlation between BTX components limited the ability to isolate the individual effects of each solvent. The study's focus on BTX exposure and other solvents in a few categories might not be fully generalizable to all occupational settings.