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Med. Pr. 2003;54(4)

4-CHLORO-O-TOLUIDINE:AN ETIOLOGICAL AGENT IN THE INDUCTION OF URINARY BLADDER CANCER, HISTORY OF A DISCOVERY (p. 347-353)

4-CHLORO-O-TOLUIDYNA: ETIOLOGICZNY CZYNNIK INDUKCJI RAKA PĘCHERZA MOCZOWEGO, HISTORIA JEDNEGO ODKRYCIA (ss. 347-353)

Mirosław J. Stasik Z Institut für Arbeits, Sozial-und Umweltmedizin der Johannes Gutenberg Universität Mainz, Niemcy

Abstract

Despite a well established scientific thesis on the exclusive cancerogenic effect of polycyclic aromatic amines on urinary bladder of man, we succeeded to demonstrate in a cohort study that simple, monocyclic aromatic amin, 4-chloro-o-toluidine (4-COT) - an intermediate for the manufacture of dyestuffs, pigments and of chlordimeform, a pesticide - also induces urinary bladder cancer.
Our study revealed urothelial carcinomas in 8 of 116 4-COT exposed workers who formed a sub-cohort. All the eight workers had been employed in the 4-COT production plant before industrial hygiene improvements were introduced in 1970. This presumably higher level of 4-COT exposure lasted for 14 year (median). The latency period lasted for 27.5 years (median). The standardized incidence rate for urothelial carcinomas in the 4-COT sub-cohort was 72.7 times higher (95% CI: 31.4-143.3) than expected.
Until 2000, a sub-cohort incidence increased to 12 bladder cancers (12.3%).
4-COT becomes covalently bound to the DNA of mice and ratsś livers. Its genotoxic and carcinogenic effects in animals have been described earlier.
Hemorrhagic cystitis is a main finding of 4-COT acute poisoning,which can be considered as a precancerous state.
Based on our study results, the DFG and IARC experts classified 4-COT as carcinogenic to humans (1988) carcinogen and probably carcinogenic to human (1990), respectively. The commercial production of 4-COT discontinued in majority of countries (EPA, 1988).

Key words

urothelial carcinoma, monocyclic aromatic amine, covalent binding 4-COT-DNA, N-acetylation phenotypes, haemorrhagic cystitis