No 3 (2022)
- Year: 2022
- Published: 20.06.2022
- Articles: 9
- URL: https://rjsocmed.com/0869-7922/issue/view/9763
- DOI: https://doi.org/10.47470/0869-7922-2022-30-3
Articles
Research Institute of Hygiene, Occupational Pathology and Human Ecology of the Federal Medical-Biological Agency — history, present, perspectives. To the 60th anniversary of the founding
Abstract
Федеральное государственное унитарное предприятие «Научно-исследовательский институт гигиены, профпатологии и экологии человека» Федерального медико-биологического агентства (ФГУП «НИИ ГПЭЧ» ФМБА России) — многопрофильное предприятие, одна из ведущих организаций в области медико-гигиенического сопровождения химических производств, диагностики, профилактики и лечения профессионально обусловленных заболеваний, гигиены окружающей среды, гигиены труда, организации здравоохранения.
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Original articles
Low-resolution GC-MS in metabolic profiling of biological samples with the mass spectrometry. Updating of the method
Abstract
Introduction. The introduction of metabolomic approaches into the practice of toxicological studies, as well as the expansion of the methodological capabilities of the laboratory for the determination of low-molecular, metabolic biomarkers of the effect, makes it possible to more effectively detect and identify new biomarkers.
Material and methods. For metabolic profiling of blood plasma and urine samples, Shimadzu QP2010plus or Agilent 5975C gas chromatomass spectrometers were used. The results were processed using optimized databases of analytical characteristics of endogenous compounds and the AMDIS system; NIST/EPA/NIH 2017 was used to identify the detected compounds. Statistical processing was performed using Statistica.
Results. A two-stage procedure for preparing blood plasma and urine samples for analysis by GC-MS was developed, a mixture of internal standards was selected, a list of compounds — endogenous metabolites was determined, and the metrological characteristics of their determination were evaluated.
Limitations. The list of analytes suitable for determination by GC-MS is limited to volatile and conditionally volatile compounds.
Conclusion. Using an optimized database of sample metabolites prepared for analysis according to a standardized procedure allows filtering out analytes with low reproducibility. Small (up to 100) chromatospectral databases make it possible to increase the reliability of identification, eliminate the effect of retention time drift, and, as a result, increase the statistical power of the entire experiment without increasing the number of laboratory animals.
139-148
Experimental comparing of lipophilicity of opioid antagonists
Abstract
Introduction. The high lipophilicity of synthetic opioids determines their abnormally high toxicity in comparison with natural opiates. The need to develop medical treatment of poisoning with such substances validates the task to study experimentally the logP partition coefficients of narcotic analgesics and their antagonists in standardized conditions close to the conditions of a living organism.
Material and methods. The lipophilicity of pharmacological agents was determined in accordance with the principles of GOST 32474-2013. “Methods of testing chemical products that pose a threat to the environment. The determination of the n-octanol/water partition coefficient by high-performance liquid chromatography”, using the selected calibration dependence of the lipophilicity values on the logarithm of the retention factor of the substances studied.
Results. The HPLC method has been proposed to determine the logP value of opioid antagonists using selected reference pharmacological agents. The method has revealed a linear dependence of the logP of CNS-active pharmacological agents on the logarithm of their retention factor in the chromatographic column, which allowed to determine the logP value of a number of opioid receptor antagonists and a model representative of synthetic opioids in one experiment.
Limitations. The calibration dependence of the lipophilicity value on the logarithm of the retention factor of the studied substances has been obtained using reference logP values of a limited number of reference substances.
Conclusion. When conducting pharmacological studies, using the HPLC method for the definition of logP provides high reproducibility of measurement conditions close to the conditions of a living organism and allows to compare the results obtained. Thus, the correlation of the logP values, found by the HPLC method, has showed a ten times lower lipophilicity of naloxone relative to fentanyl. The largest value of logP, among the studied opioid receptor antagonists used in clinical practice, was found for nalmefene.
149-157
The role of cytochromes CYP1A and CYP3A in the genotoxic effect of benzo(a)pyrene
Abstract
Introduction. Benzo(a)pyrene metabolites are genotoxic compounds, the accumulation of which contributes to carcinogenesis. The main mechanism of metabolite formation is the benzo(a)pyrene oxidation by cytochromes P450 (CYP). Inhibitors of the main cytochromes can reduce the rate of metabolite formation and, as a result, to decrease the genotoxic effects of benzo(a)pyrene metabolites. In contrast, inducers of cytochromes contribute to the enhancement of genotoxicity.
Objective. The aim of the work was to develop a cell model based on the HepaRG cells to study the role of cytochromes activity in the genotoxic effect of benzo(a)pyrene.
Material and methods. To assess the effect of inhibitors of cytochromes CYP3A and CYP1A on the genotoxic effect of benzo(a)pyrene in HepaRG cells, the content of active forms of proteins of the DNA damage detection and repair system, phosphorylated forms of signaling cascade proteins was determined by immunoassay using Luminex xMAP technology. The cytotoxicity of benzo(a)pyrene was assessed by real-time cell analysis on xCelligence analyzer.
Results. Inhibitors of CYP3A and CYP1A cytochromes, ketoconazole and α-naphthoflavone demonstrate the ability to diminish the toxic effects of benz(a)pyrene, reduce the activation of the DNA repair system, and have a multidirectional effect on the different tyrosine kinases phosphorylation in signaling pathways.
Conclusion. HepaRG human hepatoma cells are a suitable cell model both to assess the contribution of cytochromes to the metabolism of xenobiotics and to study of the cell protection from the genotoxic effect of benzo (a) pyrene by cytochrome inhibitors.
Limitations. The study was performed on a cell culture. To extrapolate the data to the organism, it is necessary to take into account the data of toxicodynamics and toxicokinetics.
158-166
Study of the toxicity of combustion products of polymer materials using chromatomass spectrometry
Abstract
Introduction. Carrying out studies of the toxicity of combustion products (HCL50) of polymer materials: epoxy glue grade EK-5T and compound ELPLAST-180ID according to GOST with the additional use of gas chromatography with mass selective detection.
Objective. Experimental study of the toxicity of combustion products (HCL50) of polymer materials in various modes of thermal oxidative degradation: epoxy glue grade EK-5T and compound ELPLAST-180ID, as well as a survey mass spectrometric analysis of products of thermal oxidative degradation.
Material and methods. The studies were carried out in accordance with GOST 12.1.044-89. Equipment: “Toxicity” unit, “Infracar M2.01” gas analyzer, Focus GC chromato-mass-spectrometric instrumental complex with DSQ II mass spectrometer (Thermo Scientific, USA), Nova Medical Stat Profile automatic analyzer of blood gases, electrolytes and oximetry Model CCX (USA). Blood sampling was carried out in capillaries “Stat Profile Critical Care Express Capillary Tube 230 µL with Na Heparin” LOT 107669, СО2 chamber.
Results. In the course of studying the products of outgassing of polymer materials using an exposure chamber and a gas chromatomass spectrometer, a significant increase in toxicity (4.8 times) of a mixture of chemicals released from epoxy glue EK-5T during the transition from thermal-oxidative decomposition (smoldering) to flame combustion was established. The toxicity index of the combustion products of the ELPLAST-180ID compound under the same conditions increases by 1.8 times. A linear dependence of the percentage of lethality of laboratory animals on the integral indicator of the toxicity of combustion products has been established.
Limitations. Studies of the toxicity of combustion products were carried out on non-metallic materials: epoxy glue EK-5T, compound ELPLAST-180ID. These materials are planned to be used in hermetically sealed objects of the Navy.
Conclusion. The expediency of using gas chromatography-mass spectrometry for assessing the combined effect of combustion products is shown.
167-176
Experimental substantiation of the tentatively safe level of diethyl disulfide in the air of the working area and the atmospheric air of populated areas
Abstract
Introduction. Diethyl disulfide belongs to the group of dialkyl disulfides, is a part of disulfide oil and a mixture of dialkyl disulfides. As a result of industrial purification of hydrocarbon raw materials from mercaptans, tens of thousands of tons of dialkyldisulfides and their mixtures are accumulated annually, the toxicity and danger of which have not been fully studied. No hygiene standards have been developed for diethyl disulfide.
Material and methods. Studies of the effects of diethyl disulfide were carried out in non-linear animals (rats and mice). The toxic properties of diethyl disulfide were studied under the conditions of single and repeated exposure to the intragastric, intraperitoneal, inhalation and cutaneous routes of entry into the body.
Results. Based on the studies carried out, the toxicometric parameters of diethyl disulfide were established. Average lethal dose with intragastric administration LD50 = 1575 mg/kg, average lethal concentration CL50 = 18700 mg/m3, coefficient of possible inhalation poisoning CPIP = 1.3, limit of acute inhalation action (Limac) is set at 120 mg/m3, acute zone Zac = 156, cumulation coefficient was 3.2. Diethyl disulfide does not have a skin-resorptive toxic effect, but it has a moderately pronounced irritating effect on the mucous membrane of the eyes.
Limitations. The results of the diethyl disulfide exposure assessment are given for two animal species and four main routes of entry.
Conclusion. The data obtained indicate that diethyl disulfide is a moderately hazardous substance with a single intragastric, inhalation and cutaneous route of entry into the body. The cumulative properties of diethyl disulfide are moderately expressed. Based on the analysis of literature data, the results of experimental studies and mathematical forecasting, a value of 4.0 mg/m3 is recommended as an approximate safe level of exposure in the air of the working area, in the atmospheric air of urban and rural settlements — 0.04 mg/m3.
177-181
New biomarkers for 1,1-dimethylhydrazine
Abstract
Introduction. Despite the large-scale use of asymmetric dimethylhydrazine (UDMH) in the domestic rocket and space industry, its biomarkers of exposure in blood plasma and urine, as well as biomarkers of cardiotoxic effects, have not yet been described.
Material and methods. The study of blood and urine samples of rats after a single injection of 10 mg/kg UDMH (1/16 LD50) was carried out by HPLC-MS. The determination of the non-metabolized form of UDMH was also carried out using the method of gas chromatography with mass-selective detection with preliminary derivatization with 4-pyridinecarboxyaldehyde. The cardiotoxic effect of UDMH was assessed on a model of an isolated rat heart with subchronic intragastric administration for 28 days at doses of 0,02; 0,2; 2,0 mg/kg.
Results. It has been established that the main metabolites of UDMH are dimethylhydrazones of pyridoxal (vitamin B6) and pyruvic acid (pyruvate). The possibility of determining the non-metabolized form of UDMH in blood and urine by HPLC-MS was shown, concentrations reach 10–60 ng/ml of blood plasma and 200–2000 ng/ml. The use of UDMH leads to an increase in the mass coefficient of the heart at a dose of 2,0 mg/kg. In ex vivo experiments on the rat heart, the cardiotoxic effect of UDMH was shown at subchronic use at a dose of 0,2 mg/kg and above, expressed in significant dilatation of the coronary bloodstream and left ventricle, the development of pronounced negative inotropic and chronotropic effects, and a decrease in the maximum rate of contraction and relaxation of the left ventricle. ventricle, reflecting the inhibition of myocardial energy metabolism.
Limitations. In the work, biomarkers were detected after a single intragastric injection of NDMG, the toxicokinetic characteristics of biomarkers and their retrospectivity were not evaluated.
Conclusion. The main metabolites of UDMH with intravenous administration of 1/16 DL50 are dimethylhydrazones of pyridoxal (vitamin B6) and pyruvic acid (pyruvate). With subchronic administration, UDMH has cardiotoxicity at a dose of 0,02 mg/kg and above.
182-190
Contractile activity of isolated rat small intestine after chronic inhalation exposure to dioctyl terephthalate
Abstract
Introduction. Dioctyl terephthalate (DOTP) is an ester of 2-ethylhexanol and terephthalic acid. It is a new generation plasticizer that is used as a more environmentally friendly and safer substitute for dioctyl phthalate (DOP) and other phthalates. Despite the established low level of toxic effects on the human body, the expansion of industrial production of DOTP requires an in-depth assessment of its safety.
Material and methods. The effect of DOTP on the motility of isolated segments of the small intestine of rats was assessed under chronic inhalation exposure for 120 days at concentrations of 3.4 and 18.6 mg/m3.
Results. The course exposure to dioctyl terephthalate, regardless of the dose, reduces the spontaneous contractile activity and adrenoreactivity of the smooth muscle cells of the rat small intestine, and also increases their sensitivity to cholinergic effects.
Limitations. The study demonstrates a change in the spontaneous contractile activity isolated segments rat small intestine under the influence of the main mediators autonomic nervous system. Additional research is required for a detailed assessment possible mechanisms for the development of the identified changes.
Conclusion. As a result of the study, it was found that chronic inhalation of dioctyl terephthalate at concentrations of 3.4 and 18.6 mg/m3 equally cause a decrease in the tone and amplitude of contractions in isolated segments of the rat small intestine. Chronic exposure to DOTP leads to a change in the reactivity of small intestine myocytes to mediators of the autonomic nervous system. The results obtained indicate that DOTP, when administered by inhalation, is enterotropic.
191-196
Health status analysis of the population living in the zone of protective measures of a chemical weapons destruction facility, during the conversion period
Abstract
Introduction. One of the tasks to be solved in the framework of the of the “Destruction of chemical weapons stockpiles in the Russian Federation” Federal Targeted Program was the social and hygienic monitoring (control) over the health of the population living in the zones of protective measures (ZPMs) of chemical weapons destruction facilities (CWDFs) as an integral part of state policy in the field of ensuring citizens’ guarantees for a favorable living environment and preservation of life and health.
The purpose of the study is to determine the possible impact of the conversion of a chemical weapons destruction facility on the health of the population living in the zone of protective measures.
Material and methods. The article presents the results of the assessment, according to the statistical reporting forms, the health parameters of the population living in the zone of protective measures of the Maradykovsky CWDF located in the Kirov region.
Results. Analysis of the medical and demographic parameters of the Orichi and Kotelnich Districts, Kirov Region, located in the ZPM zone of the Marazykovsky CWDF, in 2018, a decrease in the population compared to the previous year by 0.7% and 2.1%, respectively, was revealed. The birth rate proved to be lower compared to the weighted average birth rates over the period of 2010−2015, and the overall mortality rate proved to be higher than the birth rate, which was explained by the aging of the population and the regressive type of age structure. The prevalence and primary morbidity rates among the adult population were statistically significantly lower than the levels in the control groups (p < 0.05), and the structure of prevalence and primary morbidity compared with the respective values for the control group. Comparison of the prevalence rates for certain classes of diseases between the populations living in the territory in focus and in other territories revealed no increase in the mass noninfectious morbidity threshold.
Limitations. When studying the health indicators of the population living in the zone of protective measures of the chemical weapons destruction facility “Maradykovsky”, located in the Kirov region, an assessment of the statistical reporting materials of the departments of the MIAC of the Kirov region, data from reporting forms No. 12 “Information on the number of diseases registered in patients living in the service area of the medical institution” of the Kirov region was carried out.
Conclusion. The study revealed no correlation the activities of the the Maradykovsky CWDF during the conversion period and the health status of the population living in the ZPM of the facility.
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Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 81728 от 11 декабря 2013.