Metabolic dephenylation of the rubber antioxidant N-phenyl-2-naphthylamine to carcinogenic 2-naphthylamine in rats
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- 作者：Tobias Weiss (1)
Hermann M. Bolt (2)
Gerhard Schlüter (1)
Stephan Koslitz (1)
Dirk Taeger (1)
Peter Welge (1)
Thomas Brüning (1) - 关键词：2 ; Naphthylamine ; N ; phenyl ; 2 ; naphthylamine ; Haemoglobin adducts ; Urine ; Metabolism ; Bladder cancer
- 刊名：Archives of Toxicology
- 出版年：2013
- 出版时间：July 2013
- 年：2013
- 卷：87
- 期：7
- 页码：1265-1272
- 全文大小：334KB
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Hermann M. Bolt (2)
Gerhard Schlüter (1)
Stephan Koslitz (1)
Dirk Taeger (1)
Peter Welge (1)
Thomas Brüning (1)
1. Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universit?t Bochum (IPA), Buerkle-de-la-Camp-Platz 1, 44789, Bochum, Germany
2. Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystra?e 67, 44139, Dortmund, Germany - ISSN：1432-0738
文摘
N-Phenyl-2-naphthylamine (P2NA) was widely used as oxidation inhibitor, particularly in rubber manufacturing. Technical-grade P2NA was contaminated with carcinogenic 2-naphthylamine (2NA), and bladder cancer risk in exposed workers was attributed to this impurity. Investigations in humans and mammalian species revealed that small amounts of 2NA are excreted into urine after exposure to P2NA. However, since 2NA per se is not carcinogenic and main downstream metabolites of 2NA have not been found in urine so far, it remained uncertain if 2NA derived from P2NA dephenylation is further activated to carcinogenic downstream metabolites. An experimental animal study was therefore designed to indicate if, and if yes to which extent, 2NA from P2NA dephenylation is accessible to the metabolic pathway that is held responsible for the carcinogenicity of 2NA. Groups of 5 male and female CD rats were dosed with P2NA (2-50?mg/kg b.w.) and 2NA (0.075-5?mg/kg b.w.); 2NA-haemoglobin adducts and urinary 2NA excretion were determined applying GC–MS/MS. 2NA haemoglobin adducts originated dose-dependently after 2NA and P2NA dosing. To induce identical adduct concentrations, an approximately 100-00-fold higher dose of P2NA was necessary compared to 2NA. Since haemoglobin adducts are formed by the same pathway (N-hydroxylation) as the ultimate carcinogens from 2NA, the comparison of adduct concentrations after 2NA and P2NA dosage permits a quantitative estimate of the carcinogenicity of P2NA. The results show that 2NA derived from dephenylation of P2NA enters the carcinogenic downstream pathway of 2NA in rats. Hence, the bladder cancer risk after human exposures to P2NA must be re-evaluated.