Background: Benzene is a ubiquitous chemical classified as a Group 1 carcinogen by the International Agency for Research on Cancer, primarily due to its established causal link to acute myeloid leukaemia. However, evidence linking occupational benzene exposure to lung cancer, the leading cause of cancer mortality globally, has been considered limited and inconsistent. Clarifying its pulmonary carcinogenic potential is critical for occupational health policy and primary cancer prevention.

Objectives: We aimed to comprehensively evaluate the association between occupational benzene exposure and lung cancer risk through two complementary approaches: (1) a multicentre pooled analysis of individual-level data to evaluate the association; and (2) a systematic review, quality assessment, and meta-analysis of published cohort and case-control studies to further investigate the association across the broader epidemiological literature.

Methods: For the multi-centre pooled analysis, we harmonised individual-level data from 14 lung cancer case-control studies across Europe and Canada, comprising 12,329 cases and 15,719 controls (SYNERGY project). Benzene exposure was assessed using a quantitative job-exposure matrix. Logistic regression models assessed risk, adjusting for smoking and five main occupational lung carcinogens; we further stratified analyses by smoking status and lung cancer subtypes. Following the pooled analysis, we conducted a systematic review of studies published up to August 2024, including the SYNERGY results, with detailed evaluation of study quality and risk of bias for the included studies. Pooled relative risks (RR) and associated confidence intervals were calculated using random-effects models, and a flexible exposure-response meta-regression was fitted to assess the shape of the association. Detailed subgroup analyses were conducted to explore the consistency and effect heterogeneity.

Results: In the pooled analysis, lung cancer odds ratios increased with cumulative benzene exposure, ranging from 1.12 (95% CI: 1.03-1.22) for the lowest exposure group to 1.32 (95% CI, 1.18-1.48) for the highest (P_trend=0.002). Increased lung cancer risk was also associated with longer exposure duration and more recent exposure cessation. Positive associations were present for the main lung cancer subtypes and among all smoking subgroups, including never-smokers. Subsequently, the meta-analysis, based on 13 eligible studies covering 366,975 participants, showed an elevated risk for ever-exposure to occupational benzene (pooled RR=1.14; 95% CI: 1.03-1.27). Larger pooled RRs were observed in studies with higher overall quality and better exposure assessments. No difference was found in pooled risk estimates based on studies that adjusted for smoking and those that did not. A positive linear trend was observed in the exposure-response meta-analysis.

Conclusions/Implications: This comprehensive synthesis provides robust and consistent evidence of an association between occupational benzene exposure and increased lung cancer risk, independent of smoking and other occupational carcinogens. These findings have important implications for occupational health policy, such as workers' compensation policies, to additionally recognise lung cancer attributable to benzene exposure. Furthermore, these findings highlight the need for stricter regulatory limits and enhanced controls, particularly in industries and regions where benzene exposure remains prevalent.