Модифицирующий эффект триадимефона на развитие предопухолевых состояний и опухолей в мультиорганном канцерогенезе у крыс

Abstract

Throughout life, the human body is exposed to multiple environmental carcinogens that may stimulate carcinogenesis in different organs. Critical place among these carcinogens belongs to nitroso compounds. Triadimefon belongs to the chemical class of triazoles that are widely used as fungicides in pesticides and medicinal products. Objective is to investigate the effect of triadimefon on the development of preneoplastic lesions of the tissues and tumours in carcinogenesis induced in different organs by nitroso compounds. Materials and Methods. Experiments were performed in male Wistar Han rats in which nitroso compounds - N-nitrosodiethylamine, N-methylnitrosourea, N-nitrosobis(2-hydroxypropyl) amine induced multi-organ carcinogenesis according to the N.Ito. protocol. Triadimefon at the doses: 16.0 and 80.0 mg/kg body weight that corresponded to the no-observed-effect and observed effect level by carcinogenic effect were administered intragastrically on a daily basis for 20 weeks. Clinical studies were conducted throughout the experiment. The general condition of animals, their body weight and body weight gain were assessed. After necropsy, gross examination, including aberrant multiple crypts of the colonic mucosa, and histological examinations were conducted. Nodules positive for γ-glutamyl transpeptidase (γ-GTP) were determined by histochemistry in the hepatic tissue. Results. No clinical signs of toxic action of triadimefon in rat body induced by nitroso compounds to carcinogenesis were established. No specific organotrophic action of triadimefon was found by changes in the internal organ weight, except for liver. High dose resulted in the increase of liver weight, as well as in the number and size of γ-GTP positive nodules suggesting an increase in the pool of transformed hepatocytes. Histological examination of internal organs allowed detecting proliferative processes that are criterial markers of carcinogenicity of chemical substances upon their study in multi-organ model. The tendency to the increase in the rate of dose-dependent thyroid adenoma has been established. Increase in the rate of epithelium hyperplasia of oesophagus and forestomach, prostatic gland, as well as the total rate of benign tumours in different organs of animals on the tumour-inducing dose of triadimefon was found. The rate of malignancies in these animals do not differ from the control. Conclusion. The tumour-inducing dose of triadimefon shows weak promotor effect on the development of preneoplastic lesions of tissues of the thyroid gland, liver, oesophagus and forestomach, prostatic gland, as well as on the development of benign tumours in rats induced by carcinogenic nitroso compounds. No-observed-effect level of triadimefon by oncogenic effect established in chronic experiments ensures its safety upon exposure in the body of rats initiated by carcinogenic nitroso compounds. Regulations developed on this parameters ensure oncological safety of its use in human.