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Reevaluating the carcinogenicity of ortho-toluidine: A new conclusion and its implications

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Abstract

The aromatic amine ortho-toluidine has been recognized by IARC as an animal carcinogen for the past decade. Three recent epidemiological studies of worker populations have now implicated this chemical as a human bladder carcinogen. In a study by E. Ward, A. Carpenter, S. Markowitz, D. Roberts, and W. Halperin ((1991), J. Natl. Cancer Inst. 83, 501–506), workers definitely exposed to ortho-toluidine for at least 10 years experienced a Standardized Incidence Ratio (SIR) of 27.2 (90% CI = 11.8–53.7). The other major exposure was to aniline, which significant epidemiological studies have failed to confirm as a human carcinogen. In retrospect, studies by G. F. Rubino, G. Scansetti, G. Piolatto ((1982) Environ. Res. 27, 241–254) and M. J. Stasik ((1988) Int. Arch. Occup. Environ. Health 60, 21–24) also support the hypothesis that ortho-toluidine is a human bladder carcinogen. Animal studies of both ortho-toluidine and its possible confounders in these epidemiological investigations further confirm this hypothesis. When evaluated in a suitably comprehensive way, according to the traditional standards for assessing causality outlined by A. B. Hill ((1977) A Short Textbook of Medical Statistics, pp. 288–294, Lippincott, Philadelphia) the evidence that ortho-toluidine causes human bladder cancer has become much more conclusive. In this case, animal tests have proven a good predictor of human carcinogenicity.

References (52)

  • M. Batiste-Alentorn et al.

    Genotoxicity studies with the unstable Zeste-White (UZ) system of Drosophila melanogaster: Results with ten carcinogenic compounds

    Environ. Mol. Mutagen.

    (1991)
  • R.A.M. Case et al.

    Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. II. Further consideration of the role of aniline and of the manufacture of auramine and magenta (fuchsine) as possible causative agents

    Br. J. Ind. Med.

    (1954)
  • R.A.M. Case et al.

    Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. I. The role of aniline, benzidine, Alpha-naphthylamine, and Beta-naphtylamine

    Br. J. Ind. Med.

    (1954)
  • W.B. Deichmann
  • E. I. du Pont de Nemours and Company, Inc

    Toxicity Data and Literature Survey on Ortho-Toluidine, 1981

  • B. Ekman et al.

    Demonstration of tumorigenic decomposition products of 2,3-azotoluene

    Acta Physiol. Scand.

    (1947)
  • B. Ekman et al.

    The effect of some split products of 2,3′-azotoluene on the urinary bladder in the rat and their excretion on various diets

    Acta Pathol. Microbiol. Scand.

    (1949)
  • A. Feinstein

    Scientific standards in epidemiologic studies of the menace of daily life

    Science

    (1988)
  • M. Fernandez et al.

    Use of newt larvae for in vivo genotoxicity testing of water: Results on 19 compounds evaluated by the micronucleus test

    Mutagenesis

    (1989)
  • D. Gropp

    Zur Atiologie des sogenannten Anilin-Blasenkrebses

  • A.B. Hill
  • J. Hradec et al.

    The initiator tRNA acceptance assay as a short-term test for carcinogens. 2. Results with ten compounds selected by the International Programme on Chemical Safety for the evaluation of short-term tests for carcinogens

    Carcinogenesis

    (1988)
  • International Agency for Research on Cancer (IARC)

    4-Aminobiphenl

  • International Agency for Research on Cancer (IARC)

    Ortho-toluidine (Hydrochloride)

  • International Agency for Research on Cancer (IARC)

    Ortho-toluidine and ortho-toluidine hydrochloride

  • International Agency for Research on Cancer (IARC)

    Aniline and aniline hydrochloride

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    Research supported in part by NIEHS Training Grant 5 T35 ES07269 and by NIEHS Center Grant 5P30 ES00928.

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