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

Our plain-English summary of Risk of Lung Cancer in Workers Exposed to Benzidine and/or Beta-Naphthylamine: A Systematic Review and Meta-Analysis, by K. Tomioka, K. Saeki, K. Obayashi, et al (Journal of Epidemiology, 2016).

The study

• Authors: K. Tomioka, K. Saeki, K. Obayashi, N. Kurumatani
• Journal: Journal of Epidemiology
• Published: 2016;26(9):447-58
• Type of article: Meta-analysis, Systematic review
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This was a systematic review and meta-analysis. The authors searched for studies of workers exposed on the job to benzidine and/or beta-naphthylamine and pooled their lung cancer results. They found 23 retrospective cohort studies from Europe, the United States and Asia, covering 1745 lung cancer cases among dye, chemical manufacturing, leather tanning and rubber workers. Across all studies, lung cancer risk was raised (pooled estimate 1.28; 95% CI 1.14–1.43), but results varied considerably between studies. Estimates were higher for direct exposure in dye and manufacturing work (1.58; 95% CI 1.31–1.89) and in six highly exposed groups (2.33; 95% CI 1.31–4.14). Asbestos was not the exposure studied here. It appeared among possible co-exposures in some cohorts, along with chromium, arsenic and bis(chloromethyl) ether, and studies with these co-exposures gave estimates similar to studies without them (1.37; 95% CI 1.11–1.68, versus 1.24; 95% CI 1.07–1.44). Only one study adjusted lung cancer risk for smoking, and the authors noted this could overstate the link. They concluded that lung cancer after such exposure may need to be considered a potential occupational disease.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Systematic review and meta-analysis of retrospective cohort studies, pooled with random-effects models. No prospective cohort or case-control studies were found.
• Who was studied: 23 retrospective cohort studies, published 1976 to 2015, from Europe, the United States and Asia, covering 1745 lung cancer cases. Industries: dye production (9 studies), leather tanning (5), rubber (5) and benzidine/beta-naphthylamine manufacturing (4). Most subjects were male. The databases searched were MEDLINE, EMBASE and CINAHL, up to March 19, 2015.
• Exposure: Occupational exposure to benzidine and/or beta-naphthylamine. This included dyestuff and manufacturing workers, leather tannery workers using benzidine-based dyes, and rubber workers exposed to beta-naphthylamine or benzidine as a contaminant in antioxidants. Some cohorts were potentially also exposed to chromium, asbestos, arsenic and bis(chloromethyl) ether.
• Main results:
  • All 23 studies combined: pooled lung cancer risk estimate 1.28 (95% CI, 1.14–1.43), with significant heterogeneity among studies (I2 = 64.1%, P less than 0.001). Individual study estimates ranged from 0.49 to 3.73.
  • Direct exposure (dye and manufacturing, 13 studies): pooled estimate 1.58 (95% CI, 1.31–1.89). Indirect exposure (tannery and rubber, 10 studies): 1.12 (95% CI, 0.97–1.29).
  • By industry, pooled estimates were raised for dyestuff workers (1.60; 95% CI, 1.29–1.99) and for workers at benzidine/beta-naphthylamine manufacturing plants (1.51; 95% CI, 1.07–2.14). They were not raised for leather tanning workers (1.07; 95% CI, 0.85–1.36) or rubber industry workers (1.15; 95% CI, 0.95–1.38).
  • Cohorts reporting a bladder cancer SMR/SIR of 4.7 or higher: pooled lung cancer estimate 1.68 (95% CI, 1.35–2.09). Other cohorts: 1.15 (95% CI, 1.02–1.31).
  • Pooled estimates were similar for workers with occupational exposure to other lung carcinogens (chrome, asbestos, arsenic, bis(chloromethyl) ether; 7 studies), at 1.37 (95% CI, 1.11–1.68), and for workers without such exposure (16 studies), at 1.24 (95% CI, 1.07–1.44).
  • Combining the highest-exposure groups from 6 studies gave a pooled lung cancer estimate of 2.33 (95% CI, 1.31–4.14), with significant heterogeneity (I2 = 67.2%).
  • No difference in risk was found between cohorts with high and low national prevalence of male smoking.
  • Dropping each study in turn gave pooled estimates from 1.24 to 1.31, all statistically significant. The Egger test did not show significant funnel plot asymmetry.
• The authors' conclusion: The authors concluded that occupational exposure to benzidine and/or beta-naphthylamine is associated with an increased lung cancer risk. In their view, a lung cancer diagnosis after such exposure may need to be considered a potential occupational disease, although confounding by smoking cannot be completely ruled out.
• Limitations the authors state:
  • The analysis could not account for smoking. Only one study presented a smoking-adjusted lung cancer estimate, and lack of adjustment might overestimate the association.
  • A high bladder cancer risk, used as a marker of higher exposure, may also indicate greater confounding by smoking.
  • There was statistically significant heterogeneity between studies, which study characteristics and quality did little to explain.
  • Concurrent occupational exposures to other chemicals were not taken into consideration, so the results might be biased.
  • No included study reported exposure as workplace measurements.
  • No case-control studies were identified.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Systematic Review, Meta-Analysis, standardized mortality ratio (SMR), Standardized Incidence Ratio (SIR), Occupational Exposure, Confounding, Occupational Disease.

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