Risk of Lung Cancer in Workers Exposed to Benzidine and/or Beta-Naphthylamine: A Systematic Review and Meta-Analysis

Benzidine (BZ) and beta-naphthylamine (BNA) have been classified as definite human carcinogens for bladder cancer by the International Agency for Research on Cancer. However, the epidemiological evidence for an association between exposure to BZ and/or BNA and lung cancer has been inconclusive. We conducted a systematic review and meta-analysis to determine the risk for lung cancer among workers exposed to BZ/BNA. A systematic literature search was conducted to identify studies that had reported occupational BZ/BNA exposure and the outcome of interest (lung cancer death and/or incidence). Meta-analyses were performed using random effects models to combine standardized mortality ratios (SMRs) or standardized incidence ratios (SIRs). We identified 23 retrospective cohort studies including 1745 cases of lung cancer; only one study reported smoking-adjusted lung cancer risk. A significantly increased lung cancer risk (pooled SMR/SIR 1.28; 95% CI, 1.14-1.43) was observed by combining all studies, with significant heterogeneity among studies (I(2) = 64.1%, P < 0.001). Effect estimates were higher for studies with direct BZ/BNA exposure (ie, dyestuff and manufacturing industries) (pooled SMR/SIR 1.58; 95% CI, 1.31-1.89), and studies that identified BZ/BNA-associated bladder cancer with SMR/SIR ≥4.7 (pooled SMR/SIR 1.68; 95% CI, 1.35-2.09). Effect estimates were similar for studies with and without concomitant occupational exposure to chromium, asbestos, arsenic, or bis(chloromethyl) ether. The cumulative meta-analysis showed that the evidence of association between occupational BZ/BNA exposure and lung cancer has been stable since 1995. Although the results of this meta-analysis have the potential for confounding by smoking and heterogeneity, our findings suggest that a finding of lung cancer following occupational BZ/BNA exposure should be considered to be a potential occupational disease.