Risk of bladder cancer in male Japanese workers exposed to ortho-toluidine and other aromatic amines

Int Arch Occup Environ Health. 2021 Aug;94(6):1427-1439. doi: 10.1007/s00420-021-01658-2. Epub 2021 Mar 2.


Purpose: Nine bladder cancer (BCa) cases were reported among aromatic amine-exposed male workers at a factory manufacturing organic dye/pigment intermediates in Japan. We aimed to evaluate the characteristics of aromatic amine-exposed workers by cross-sectional observation, and the risk of BCa by assessing the standardized incidence ratio (SIR).

Methods: In the cross-sectional study, our subjects were: 9 BCa patients, 36 aromatic amine-exposed non-patients, and 79 non-exposed workers from 3 factories. We evaluated the subjects' medical history, urinalysis, qualitative determination of nuclear matrix protein 22, and urinary cytology. For SIR assessment, 98 aromatic amine-exposed workers from 1 factory were included, and the Japanese general male population was used as a referent population. Since no direct aromatic amine-exposure data were available, we calculated surrogate exposure levels using information on job sites, exposure potency, and duration.

Results: Coexistent aromatic amines were ortho-toluidine (OT), aniline, para-toluidine, ortho-anisidine, 2,4-xylidine, and ortho-chloroaniline. The prevalence rates of cystitis and bladder lesion-related symptoms in both BCa patients and aromatic amine-exposed non-patient workers were significantly higher than those of non-exposed workers. Overall, the SIR for BCa in OT-exposed workers was 56.8 (95% CI 27.7-104.3) and apparent dose-response relationships were revealed between the SIR and the surrogate exposure level in the 0-10-year lagged analyses. Overall, SIRs in other aromatic amine-exposed workers were also significantly high but no or unclear dose-response relationships were observed.

Conclusions: We conclude that OT may be responsible for the increased risk of BCa. Regular monitoring of bladder lesion-related symptoms is essential for the early identification of BCa.

Keywords: 2,4-Xylidine; Aniline; Bladder cancer; Cross-sectional study; SIR; ortho-Toluidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amines / toxicity*
  • Carcinogens / toxicity*
  • Cystitis / epidemiology
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Incidence
  • Japan / epidemiology
  • Male
  • Middle Aged
  • Occupational Exposure / adverse effects*
  • Prevalence
  • Risk
  • Urinary Bladder Neoplasms / epidemiology*
  • Young Adult


  • Amines
  • Carcinogens