You are using an outdated browser. For a faster, safer browsing experience, upgrade for free today.


Lalimenko O. S.


State Institution "V.Y. Danilevsky Institute of Endocrine Pathology Problems of the National Academy of Medical Sciences of Ukraine", Kharkiv

Full article (PDF), RUS

Introduction. In recent time in order to detect cause-effect relations between exposure to chemical factors and development of occupational diseases the biological monitoring is used.

Purpose of the study. Identification and substantiation of biomarkers of exposure and effect, as criteria of biological monitoring of an antidiabetic agent, a derivative of succinic acid.

Materials and methods. Experiments were conducted on 85 male rats. Peculiarities of toxicokinetics were studied in a single intragastric administration of the aqueous emulsion of the antidiabetic agent to rats in the dose of 100 mg. The subchronic exposure was studied in condition of intragastric (30-fold in the dose of 100 mg) and intranasal (20-fold in the dose of 6,7 and 1,0 mg/ml) administrations of the antidiabetic agent to experimental animals. The doses for intranasal administration were recalculated, according to the threshold of acute and chronic inhalation effects of the compound. The state of lipid peroxidation, antioxidant protection and nitric oxide metabolism was investigated. The chromatographic determination of the antidiabetic agent and its metabolites in blood plasma of experimental animals was conducted using a HPLC method.

Results. The toxicokinetic parameters in conditions of the single intragastric administration of the antidiabetic agent have been established. The antidiabetic agent quickly enters the blood and circulates there for a long time. We established that processes of biotransformation of the agent prevailed over its excretion. The concentration of the agent or its metabolites (2-HPhSA, β-PhESA) in blood plasma is biomarkers of exposure of this antidiabetic agent. The biomarkers of effect in the intragastric administration are: increase of lipid hydroperoxide levels in the blood serum, the decrease of levels of NO2-/NO3- in the blood plasma, glutathione peroxidase in the red blood cell hemolysate and c-NOS in the liver tissue. Biomarkers of the effect in intranasal administrations: increase of lipid hydroperoxide levels in the liver tissue, decrease of levels of NO2-/NO3- in blood plasma, glutathione peroxidase and c-NOS in blood red cell hemolysate.

Conclusion. The detected biomarkers of exposure (concentration of the antidiabetic agent and its metabolites in blood plasma and biomarkers of effect are limiting criteria of the effect of this compound on the body. These criteria should be taken into account for hygienic regulation of antidiabetic agents in the working zone air for improving the accuracy of risk assessment of the effect of the tested compounds on workers’ health.

Key words: biomonitoring, biomarkers of exposure and effect, antidiabetic agent


  1. Kundiev, J. I., Nagornaja, A. M. 2007, "Occupational health in Ukraine. Epidemiological analysis", Avicenna, 396 p. (in Russian).
  2. Burov, Yu. V., Rozhnov, G. I. 1995, "Actual ecological­hygienic problems in chemical­pharmaceutical and biotechnological industry", Gigiena and sanitariya, no. 4, рр. 21–25 (in Russian).
  3. Kundiev, J. I. Trakhtenberg, I. M. 2004, "Chemical hazard in Ukraine and measures for its prevention", Journal of Academy of medical sciences of Ukraine, v. 10, no. 2, рр. 259–267 (in Russian).
  4. Shevchenko, O. L. 2002, "The development of phar­maceutical in Ukraine: tendencies and perspectives", Marketing in Ukraine, no. 3, рр. 20–24 (in Ukraine).
  5. WHO 1999, "Biomarkers and risk assessment concepts and principles", World Health Organization, 96 р. (in English).
  6. National Academies Press 2006, "Human Biomonitoring for Environmental Chemicals", Committee on Human Biomonitoring for Environmental Toxicants, 291 р.
  7. ACGIH 1999, "TLVs and BEIs. Based on the Documentations for Threshold Limit Values for chemical substances and Physical Agents Biological Exposure Indices", American Conference of Governmental Industrial Hygienists, 184 p.
  8. ACGIH 2005, "Based on the Documentations of the Threshold Limit Values for chemical substances and physical agents and Biological Exposure Indices", American Conference of Governmental Industrial Hygienists, 64 p.
  9. DFG 2005, "MAK­ and BAT­Values. Commission for the investigation of health hazards of chemical compounds in the work area", Deutsche Forschungsgemeinschaft, 165 р. (in German).
  10. Scientific Committee on Occupational Exposure Limits 2013, "Methodology for the Derivation of Occupational Exposure Limits", European commission, 38 р.
  11. WHO 2005, "Biological Monitoring of Chemical exposure in the workplace guidelines", World Health Organization, 89 р.
  12. Onishchenko, G. G., Zaitseva, N. V., Zemlyanova, M. A. 2011, "Identification of health effects, caused by environmental chemical exposure", Perm, 532 p. (in Russian).
  13. Scott, A. J. 2003, "Occupational health in the pharmaceutical industry: an overview", Occup Med (Lond), v. 53, no. 6, рр. 354–356.
  14. Piotrowski, E. 1976, "The application of metabolic and excretion kinetics to problems of industrial toxicology", Department of health, 194 р. (in Russian).
  15. Gorbenko, N. I. 2004, Pathogenic basis of succinic acid derivative – phensuccinal efficacy in therapy of diabetes mellitus and its complications (experimental study): Autoref. of Thesis … Doctor of Biol. Sciences : 14.01.14., V. Danilevsky Institute of Endocrine Pathology Problems at AMS of Ukraine, 36 p. (in Ukrainian).
  16. Kudrya, M. Ya. 2005, "Рarticularities of functional and metabolic parameters in rats under the influence of inhaled antidiabetic agent fensuktsynal", Problems of endocrine pathology, no. 3, рр. 63–71 (in Ukrainian).
  17. General ethical principles of experiments on animals, 2003, Endocrynology, v. 8, no. 1, рр. 142–145 (in Ukrainian).
  18. Мethodical instructions 1.1.5­121­2005, "Guidelines on grounding maximum permissible concentrations of drugs in the air of the working area and the air of settlements", Ministry of Health of Ukraine; State Sanitary Epidemiological Service, 30 р. (in Ukrainian).
  19. Platzer, Z., Vydlakova, М., Kupila, L. 1970, "Defenition of dienic conjugates and general hydroperoxides in biological samples", Czechoslovak. Med. Survey, v. 16, no. 1, рр. 30–34 (in Russian).
  20. Asakawa, T., Matsushite, T. 1980, "Colorings conditions of thiobarbituric acid test for detecting lipid hydroperoxides", Lipids, no. 15, рр. 137–140 (in Russian).
  21. Stalnaya, I. D., Garishvili, T. G. 1977, "A method of definition of Malonic Aldehyd with the help of the thiobarbituric acid", Methods in Biochemistry, (Ed. V. N. Orekhovich): Meditsina, no.1, рр. 66–68 (in Russian).
  22. Arutyunyan, A. V., Dubinina, E. E., Zybina, N. N. 2000, Methods on estimating the free­radical oxidation and anti­oxidant system of the body, Method. recomm. Russ. Acad. Med. Sci. 104 р. (in Russian).
  23. Misheneva, V. S., Goryukhina, T. A. 1968, "Pre­sence of Glutathione in the normal and tumor tissues in humans and animals", Voprosy onkologii, v. 14, no. 10, рр. 46–49 (in Russian).
  24. Korolyuk, M. A., Ivanova, L. I., Tokarev, V. E. 1988, "Method of definition of the Catalase activity", Lab. delo, no. 1, рр. 16–19 (in Russian).
  25. A photometric method of determination of nitrites and nitrates in biological liquids (Instructions on application). 2001, Appr. by Мinistry of Health of Belarus Rep.,Vitebsk: [w/o publ.], 9 p. (in Russian).
  26. Sumbayev, V. V., Yasinskaya, I. M. 2000, "Effect of DDT on the activity of oxide synthase in rat liver, lungs and brain", Sovremen. Probl. Toks., no. 3, рр. 3–7 (in Russian).
  27. Gasparov, V. S., Gegtyar, V. G. 1994, "Definition of protein by its linkage to Kumassi Diamond light­blue G­250 dye", Biokhimiya, v. 59, no. 6, рр. 763–775 (in Russian).
  28. Software package for statistical analyses Statistic 10 (in Ukrainian).