Occupational exposure to organic solvents and risk of bladder cancer

Bladder cancer is a common malignancy globally and in the United States. A substantial fraction of cases is attributable to occupational carcinogens. Occupations with solvent exposures, such as dry cleaning, rubber manufacturing, and painting, have been linked to elevated risks. While perchloroethylene used in dry cleaning has probable evidence for bladder carcinogenicity, the roles of other organic solvents remain unclear. Prior studies of specific solvents report inconsistent associations, often relying on job titles or broad industry classifications. Using the New England Bladder Cancer Study (NEBCS), a population-based case-control study with detailed lifetime occupational histories and comprehensive smoking data, the authors investigated whether occupational exposure to organic solvents—particularly benzene, toluene, and xylene (BTX), which frequently co-occur—is associated with bladder cancer risk and whether increasing cumulative exposure relates to higher risk.

Earlier investigations showed mixed evidence linking organic solvents to bladder cancer. Some reported positive associations, while others found no link. Two recent studies used job-exposure matrices (JEMs) to quantify solvent-specific exposures. A pooled Italian case-control analysis found a positive association for trichloroethane without clear exposure-response. A large Nordic cohort (14.9 million individuals) reported increased bladder cancer risk with heavy exposure to trichloroethylene (HR 1.23), toluene (HR 1.20), and benzene (HR 1.16), but did not adjust for smoking. Evidence has been limited for xylene and equivocal for toluene, and benzene’s established carcinogenicity is based on leukemia, with insufficient evidence for bladder cancer. Given the frequent co-exposure to benzene, toluene, and xylene, separating individual effects is challenging; assessing BTX jointly may better reflect real-world exposure scenarios.

Design and population: The NEBCS is a population-based case-control study conducted in Maine, Vermont, and New Hampshire (2001–2004). Cases were ages 30–79 with newly diagnosed, histologically confirmed urothelial bladder cancer. Controls were randomly selected via state DMV (ages 30–64) and CMS (ages 65–79), frequency-matched to cases by state, sex, and 5-year age group. Participation rates were 65% for cases and controls. After excluding those without complete occupational histories, 1182 cases and 1408 controls remained. All participants provided informed consent; protocols were approved by relevant IRBs. Occupational history and exposure assessment: Participants reported all paid jobs held ≥6 months after age 16, excluding unpaid work and absentee ownership. For each job, open-ended details were collected on duration, hours/week, industry, tasks, tools/equipment, and chemicals/materials. Based on responses, participants completed job- and industry-specific exposure-oriented modules. Jobs were coded using SOC 2010. Solvent exposure was assessed by linking jobs to CANJEM, obtaining probability of exposure and frequency-weighted intensity (FWI) for 20 solvents/solvent groups. CANJEM was applied with SOC2010 and time periods (1920–1970, 1971–1980, 1981–1990, 1991–2005); jobs spanning periods were split. FWI categories (low/medium/high) were converted to numeric weights 1, 5, and 25 to construct dimensionless quantitative scores. Hierarchical assignment used the most specific SOC-time estimates available (6-digit; otherwise 1920–2005, or broader 5- or 3-digit codes). Exposure classification: Participants were considered ever exposed if any job had probability ≥50%; uncertain if any job had 0–<50%; unexposed if all jobs had 0%. Cumulative exposure was computed by summing over jobs: FWI weight × job duration (years), assigning zero to jobs below the probability threshold. Sensitivity analyses varied the probability threshold to 25% or 80%. BTX metrics: Because benzene, toluene, and xylene commonly co-occur and were highly correlated, the authors created two BTX metrics. (1) CANJEM-based BTX: probability was the maximum of the individual agents; FWI was the highest FWI among agents with probability ≥50%. (2) Hybrid BTX: experts, blinded to case-control status, reviewed CANJEM assignments along with participant-specific free-text and module information on tasks, tools, and chemicals to upgrade or downgrade probabilities and refine intensities using participant-level frequency data when available, capturing within-job heterogeneity. Statistical analysis: Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for ever exposure and for cumulative exposure categories (quartiles among exposed, based on control distributions). To account for latency, lagged exposure metrics were considered, with a 20-year lag selected by AIC. Categories included unexposed, uncertain, and exposed quartiles; trends were tested using Wald tests applied to category midpoints among exposed controls, excluding the uncertain group. Five-knot regression splines examined non-linearity. Models adjusted for age at diagnosis/interview, smoking status (never, former, current), state, race, ethnicity (Hispanic), and non-solvent high-risk occupations for bladder cancer. Correlations among benzene, toluene, and xylene cumulative exposures were evaluated with Spearman’s rho among controls overall and among solvent-exposed controls.

- Study sample: 1182 cases; 1408 controls. Cases had higher current smoking prevalence (31.9% vs 14.6%). - Ever exposure (CANJEM, probability ≥50%): • Mononuclear aromatic hydrocarbons: OR 1.84 (95% CI: 1.16–2.91). • Benzene: OR 1.63 (95% CI: 1.14–2.32). • Toluene: OR 1.60 (95% CI: 1.06–2.43). • Xylene: OR 1.67 (95% CI: 1.13–2.48). • Styrene: OR 0.94 (95% CI: 0.57–1.55) – null. • Alkanes C5–C17: OR 1.66 (95% CI: 0.99–2.79) – not statistically significant. • Perchloroethylene: OR 0.36 (95% CI: 0.13–0.96), based on 6 cases and 19 controls. No exposure observed for chloroform, 1,1,1-trichloroethane, or trichloroethylene. - Cumulative exposure by quartiles (CANJEM agents, unlagged and 20-year lag): Some elevated ORs in specific quartiles for benzene, toluene, and xylene, but no consistent monotonic exposure-response trends. Example (20-year lag): benzene Q3 vs none OR 2.07 (95% CI: 1.22–3.53); toluene Q2 vs none OR 2.91 (95% CI: 1.57–5.39); xylene Q2 vs none OR 2.37 (95% CI: 1.30–4.31); p-trends not significant. - Correlations among solvents (controls ever exposed to solvents): benzene–toluene rho 0.62; benzene–xylene rho 0.65; toluene–xylene rho 0.94 (strong co-occurrence). - BTX combined metrics: • Reclassification: ~15% of participants with uncertain CANJEM-based BTX exposure reclassified using hybrid metrics; high-probability BTX exposure identified in 13% (CANJEM-based) vs 24% (hybrid). Agreement: probability kappa 0.62; cumulative exposure Spearman 0.61. • CANJEM-based BTX cumulative exposure (20-year lag): ORs vs unexposed—Q1 1.54 (0.90–2.63), Q2 1.66 (0.95–2.90), Q3 1.94 (1.14–3.30), Q4 2.03 (1.16–3.57); p-trend = 0.02. • Hybrid BTX cumulative exposure (20-year lag): ORs vs unexposed—Q1 1.26 (0.83–1.90), Q2 1.52 (1.00–2.31), Q3 1.88 (1.24–2.85), Q4 2.23 (1.35–3.69); p-trend = 0.001. • Spline analyses supported quartile results, with stronger exposure-response for the hybrid BTX metric at higher cumulative exposures. - Overall: Statistically significant association between increasing cumulative BTX exposure and bladder cancer risk, robust to latency considerations and model adjustments.

The study demonstrates that occupational exposure to benzene, toluene, and xylene is associated with increased bladder cancer risk, and that considering BTX jointly better captures real-world co-exposure patterns than evaluating single solvents. The hybrid BTX metric, which integrates CANJEM with respondent-specific task and chemical information, yielded a clearer exposure-response relationship than the CANJEM-based metric alone, highlighting the value of reducing exposure misclassification. These findings align with large Nordic registry data showing increased bladder cancer risks with heavy benzene and toluene exposure, and with evidence from highly exposed worker cohorts, while addressing key limitations of prior studies by adjusting for smoking and evaluating latency. Biological plausibility is supported by evidence that benzene and its metabolites are excreted in urine and can reach the bladder, and that BTX exposures are associated with genotoxicity, oxidative stress, immune alterations, and chromosomal abnormalities. Together, the results suggest that cumulative BTX exposure may play a role in bladder carcinogenesis and underscore the need to assess concurrent exposures in occupational epidemiology.

This population-based case-control study found that cumulative exposure to BTX (benzene, toluene, xylene) is associated with an increased risk of bladder cancer, with a significant exposure-response, particularly when using a hybrid exposure assessment that incorporates participant-specific details. The results highlight BTX as an underrecognized occupational risk for bladder cancer. Future research should evaluate the carcinogenicity of BTX and other solvents in diverse populations, refine exposure assessment with measurement data, disentangle individual and joint effects of correlated solvents, and consider concurrent exposures and long latency.

- Case-control design with potential for recall bias; however, awareness of BTX-bladder cancer associations among participants was unlikely, reducing differential misclassification. - Application of CANJEM (developed from Canadian data) to a U.S. population may introduce exposure misclassification due to geographic or process differences; the hybrid metric partially mitigates this by incorporating subject-specific details. - High correlation and co-occurrence of benzene, toluene, and xylene limit the ability to isolate effects of individual solvents. - Limited numbers for certain chlorinated solvents (e.g., perchloroethylene, trichloroethylene) precluded robust evaluation. - Use of semi-quantitative FWI weights (1–5–25) as dimensionless exposure surrogates; direct exposure measurements would be preferable. - NEBCS was not specifically designed for solvent exposure assessment, limiting depth of exposure detail for some agents.