No 1 (2023)

Введение. Проведена экспериментальная оценка влияния ССL₄ и трансплантации клеток фетальной печени (КФП) на степень деградации и процессов репарации ДНК в клетках печени крыс, используя метод щелочного гель – электрофореза единичных клеток.

Материал и методы. Острое токсическое поражение печени крыс моделировали однократным внутрижелудочным введением крысам – самкам линии Вистар препарата CCl₄ в масляном растворе в дозе 3000 мг/кг. В качестве протекционного средства использовали суспензию КФП плодов крысы 19 ДР. Для количественной оценки, степени повреждения ядерной ДНК клеток печени, применяли метод щелочного электрофореза единичных клеток (ДНК-комет) на 1, 3, 5, 7 и 16 сутки эксперимента.

Результаты. Внутривенное введение КФП через 6 часов после воздействия тетрахлорметана активировало процессы репарации ДНК в гепатоцитах крыс на 5 – 7 сутки, что приводило к снижению интенсивности повреждения ядерной ДНК. Тенденция к уменьшению числа неповрежденных гепатоцитов сохранялась и на 16 сутки эксперимента, при этом усиление репаративных процессов после введения КФП реализовалось в достоверном сокращении количества гепатоцитов с высокой интенсивностью повреждения ядерной ДНК.

Заключение. Использованный в наших экспериментах метод щелочного гель – электрофореза единичных клеток (ДНК-комет) позволил количественно оценить степень повреждения генома и его репарацию. Выявленные позитивные результаты   свидетельствовали о протекторной роли КФП на структуру ДНК клеток печени крыс, после острого воздействия CCL₄.

The aim of the study. Obtaining new data on the pathogenesis of endotoxicosis (ET) in the rehabilitation period of acute poisoning by assessing the conjugacy of hemorheology (HR) disorders with the development of ET.

Material and methods. To obtain new information about the pathogenesis of acute poisoning in the rehabilitation period in 145 patients with severe acute poisoning with psychopharmacological agents (PFAp) due to the addition of pneumonia, neurotoxicants (NTp) with the development of toxic hypoxic encephalopathy and corrosive substances (CSp) with deep and widespread burns of the mucous membranes of the gastrointestinal tract, a pair correlation analysis of the block structure of the obtained correlation matrix was undertaken, establishing the relationship between the two indicators, as well as a canonical correlation analysis revealing the nature of the statistical relationship between groups of indicators, with the calculation of the canonical correlation coefficient. 

Results. As a result, statistically significant correlations were established between the indicators HR (viscometric, aggregation and indicators hemostasis) and ET (total and effective albumin concentration, the level of medium molecular weight peptides, the content of leukocytes, lymphocytes, neutrophils and circulating immune complexes detected in the blood, and his integral indicators) (–0.32–0.48 for PFAp, 0.29–0.35 for NTp and 0.28–(–0.51) for CSp), as well as statistically significant values canonical correlation coefficients, which indicated the development of ET due to disorders of HR. 

Limitations. The study was performed on laboratory data obtained during the examination of patients with acute poisoning, and therefore has no restrictions for the further use of this methodological approach in clinical trials.

Conclusion. The obtained data can serve to optimize the treatment of ET in this pathology by targeted therapeutic effects on parameters of HR (on viscosity and hemostasis in PFAp and NTp, and in CSp, in addition, on aggregation).

Compliance with ethical standards. The study does not require the submission of the opinion of the biomedical ethics committee or other documents.

Contribution of the authors:
Goldfarb Yu.S. — concept and design of the study, writing and editing of the text of the article, interpretation of the results of the study, coordination of the actions of the author’s team;
Elkov A.N. — mathematical processing of the material, interpretation of the results of the study;
Badalyan A.V. — examination of patients within the framework of the study design, participation in the writing and editing of the article;
Potshveriya M.M. — editing the text of the article, participation in the interpretation of the received data;
Bitkova E.E. — performing the laboratory part of the study within the framework of the study design, processing and interpretation of laboratory data.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Conflict of interests. The authors declare no conflict of interest.

Financing. The study had no sponsorship.

Received: May 05, 2023 / Accepted: 2022 / Published: February 28, 2023

Introduction. Heavy metals have a serious toxic effect on the human body. The availability of adequate models for the elimination of toxicants and the testing of enterosorbents based on them will improve the quality of poisoning therapy.

Material and methods. To assess the effectiveness of the sorbent, a formalized model based on data on the cumulative excretion of cadmium in urine and feces for 20 days was used. Intramuscular priming with cadmium acetate was carried out during the first three days of the experiment at a daily dose of 3 mg/ kg, the enterosorbent was administered orally at a dose of 100 mg/kg during the study. The cadmium content in the biological media was determined by methods of inversion voltammetry.

Results. During the experiment, no more than 3% of the injected toxicant was removed from the animals of both groups. The enterosorbent in the conditions of the experiment did not change the amount of cadmium excreted, but affected the redistribution between the renal and intestinal elimination streams. A significant effect of the enterosorbent on the cadmium content in the liver was noted.

Limitations. Evaluation of the effect of the drug on the elimination of the toxicant was carried out for a limited period of time. Additional experiments with longer observation periods and other metals and their dosages would allow to reveal in more detail the beneficial properties of the studied drug.

Conclusion. A significant effect of the enterosorbent on the cadmium content in the liver was noted. There may be a secondary intake of cadmium into the blood from the intestine and a negative effect of this process on kidneys.

Compliance with ethical standards. The study was carried out according to the principles of humanity set out in the Directive of the European Parliament and of the Council of the European Union (2010/63/EU).

Author contribution. All co-authors made an equal contribution to the research and preparation of the article for publication.

Conflict of interest. The authors declare no conflict of interest 

Acknowledgments. The study was carried out within the framework of the state task of Federal State budgetary institution «Scientific and Clinical Center of Toxicology named after Academician S. N. Golikov Federal Medical and Biological Agency».

Received: July 1, 2022 / Accepted: January 2023 / Published: February 28, 2023

Introduction. For the treatment of agricultural crops, an original herbicide of selective action was created — propisochlor, a derivative of chloroacetanilide. Its characteristics in an acute toxicological experiment didn’t reveal the features of the pathogenesis of intoxication. The identification of regularities in the manifestation of the toxic properties of propisochlor in various regimens with the oral route of exposure is necessary at the stage of production design. Moreover, it is necessary to substantiate a number of hygienic regulations for safe production and its further application in agriculture, which lies in the plane of solving the leading state tasks aimed at protecting human health and its environment, and meets the requirements of international legislation. A special role in the development of such methods and methods belongs to the sanitary-toxicological study of new xenobiotics and generic molecules, as a result of which threshold and subthreshold doses of pesticide preparations and their active substances are determined.

The aim of this study was to characterize propisochlor in a chronic oral toxicology study in rats. To achieve the goal, it was necessary to solve the following tasks: to study the chronic oral effect of the chloroacetanilide derivative on the rat organism; establish a dose that does not have a visible undesirable effect (NOELch); set the lowest dose at which no adverse effects are observed (LOAELch); calculate the allowable daily intake, or allowable daily exposure (ADD, or ADI, or PDE) for a person.

Material and methods. The object of testing in this work was a herbicide from the class of chloroacetanilide, propisochlor. The test system in the chronic experiment was white male rats, on which the influence of the test compound was evaluated in dynamics after 1, 3, 6 and 12 months according to the state of integral indicators.

Results. The parameters of the oral toxicity of the test compound were determined and the changes in the studied integral indicators were evaluated at various stages of the experiment in a chronic experiment.

Conclusion. Based on the comparative characterization of a new herbicide propisochlor in a chronic oral toxicology study in rats, a non-acting dose (NOEL), the lowest effective dose (LOAEL), and an acceptable daily dose for humans (ADI, or PDE) are justified.

Compliance with ethical standards. the study was approved by the Commission on Bioethics of F.F. Erisman Federal Scientific Center of Hygiene of Rospotrebnadzor, carried out in accordance with the European Convention for the Protection of Vertebrate Animals used for Experimental or other Scientific Purposes (ETS No. 123), Directive of the European Parliament and the Council of the European Union 2010/63/EU of September 22, 2010 on the protection of animals used for scientific purposes.

Author contribution. All co-authors made an equal contribution to the research and preparation of the article for publication.

Conflict of interests. The authors declare no conflict of interest.

Funding. The study was not sponsored.

Received: June 08, 2022 / Accepted: January 2023 / Published: February 28, 2023

Introduction. The testing for mitochondrial dysfunction has become routine assay for drug and cosmetics safety evaluation. Mitochondria are targets of many pharmaceutical and therapeutic agents that can damage them and lead to changes in morphology and function. Spermatozoa have one of the highest ratios of mitochondria to body size, they lack the cytoplasm between the mitochondria and the plasma membrane, which makes them a good potential model for a rapid test on mitochondrial toxicity.

The aim of our work — assessment of motility and mitochondrial membrane potential of bovine spermatozoa Bos taurus taurus in the presence of T-2-toxin and deltamethrin.

Material and methods. T-2-toxin and deltamethrin were used as toxins. The main parameters studied were the level of mitochondrial potential (using the MitoTracker™ Green FM dye), sperm motility and their relationship.

Results. We found a strong correlation between the motility of bovine spermatozoa and the mitochondrial potential of their mitochondria (R>0.87; p<0.05). The mitochondrial toxicity of deltamethrin has been confirmed, although to a much lesser extent than that of the T-2-toxin. In addition, certain patterns were found in the distribution of active zones of the mitochondrial potential in bull spermatozoa.

Conclusion. Using deltamethrin and T-2-toxin in this study, it was shown that the sperm cells of bulls and their mitochondrial potential can be used as an express test for mitochondrial toxicity.

Limitations. Determination of the mitochondrial potential of the studied spretamotozoa using the MitoTracker™ dye was rather of a qualitative nature, reflecting not so much the level of the mitochondrial potential but the number of spermatozoa that have the potential sufficient to initiate the luminescence of the dye.

Compliance with ethical standards. The study doesn’t require the submission of the opinion of the biomedical ethics committee or other documents.

Author contribution:
Valiullin L.R., Egorov V.I., Raginov I.S. — concept and design of the study, statistical analysis;
Zaripov F.R. — collection and processing of material;
Nabatov A.A. — concept and design of the study, writing the text;
Timerbulatova L.M. — collection and processing of material, editing.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Acknowledgment. Authors express gratitude to D.V. Samigullin for providing the necessary confocal microscopy facilities to carry out this work. 

Conflict of interest. Authors declare no conflict of interest.

Funding. The research was carried out with the financial support of the Federal State Budgetary Institution "Federal Research Center "Kazan Scientific Center of the Russian Academy of Sciences".

Received: September 02, 2022 / Accepted: January 2023 / Published: February 28, 2023

Introduction. Currently, the most popular in agricultural production are complex chlorine-free mineral fertilizers with trace elements. The inclusion of trace elements in fertilizers improves plant nutrition, optimizes the effect of fertilizers. At the same time, trace elements are added to the fertilizer in the form of salts, in ionic form, most often, sulfates belonging to substances of hazard class 1–2, which can affect the toxicity of fertilizers and the safety of their production and use. To prevent a possible negative impact on human health and the environment for production, sale and use, it is necessary to conduct toxicological studies included in the state registration procedure.

The aim of the study is to study the nature of the toxic effect on the body of laboratory animals (rats, rabbits, guinea pigs) of new complex chlorine-free mineral fertilizers with trace elements.

Material and methods. Samples of liquid agrochemicals (preparations No. 1, No. 4, No. 5) and solid (preparations No. 2, No. 3) with different nitrogen, phosphorus and potassium content and different composition of trace elements in the form of salts were taken for research. The experimental work was performed on 90 nonlinear, sexually mature white male rats weighing 200–220 g, 30 purebred male rabbits weighing 3000–3500 g and 90 male guinea pigs weighing 350–400 g. During the work, existing methodological approaches and recommendations were used, including generally accepted informative methods of toxicological and statistical studies.

Results. Based on the conducted studies, the parameters of acute oral and dermal toxicity, irritating effect on the skin and mucous membranes of the eyes, sensitizing effect of 5 samples of complex chlorine-free mineral fertilizers with trace elements were established. For all studied drugs, acute oral toxicity (LD₅₀) > 5000 mg/kg body weight, acute dermal toxicity (LD₅₀) > 2500 mg/kg body weight, mild irritating effect on the skin of rats (the average group-wide total score of the severity of the skin-irritating effect was 0.7 points for drugs No. 1, No. 4, No. 5 and 0.5 points for drugs No. 2 and No. 3), mild irritating effect on the mucous membranes rabbit eye shells (the average cumulative score of the severity of the irritating effect of samples of liquid fertilizers No. 1, No. 4, No. 5 was 1–3 points, solid fertilizers No. 2, No. 3 — 1–2 points), the absence of a sensitizing effect in guinea pigs within the standard research protocol (reactions of specific leukocyte lysis (RSLL) showed negative skin tests in guinea pigs of all experimental groups; the relative percentage of lysis did not exceed 10%).

Research limitation. The definition of the hazard class was revealed in the study of the acute toxic effect of new complex chlorine-free mineral fertilizers with trace elements on the body of laboratory animals.

Conclusion. Generalization of all the obtained results of experimental toxicological studies of complex chlorine-free nitrogen-phosphorus-potassium fertilizers with trace elements from the point of view of hygienic safety allows them to be classified as moderately dangerous substances (hazard class — 3).

Compliance with ethical standards. The study does not require the submission of the conclusion of the Biomedical ethics committee or other documents.

Author contribution:
Rusakov V.N. — research concept and design, text writing, editing;
Rumyantseva L.A. — material processing, editing;
Mikhailov I.G. — research concept and design, material processing, text writing, editing;
Vetrova O.V. — statistical analysis, editing;
Istomin A.V. — concept and design research, editing.

Conflict of interest. The authors declare the absence of obvious and potential conflicts of interest in connection with the publication of this article.

Funding. The study had no sponsorship.

Received: June 28, 2022 / Accepted: January 2023 / Published: February 30, 2023

45 сессия Комиссии Codex Alimentarius («Кодекс Алиментариус», CAC45) прошла в штаб-квартире ФАО (Продовольственная и сельскохозяйственная организация Объединённых Наций) в Риме (Италия) с 21 по 25 ноября 2022 года очно, с удалённым участием некоторых делегатов.

Введение. В настоящее время наиболее востребованными в сельскохозяйственном производстве являются комплексные бесхлорные минеральные удобрения с микроэлементами. Включение в удобрения микроэлементов улучшает питание растений, оптимизирует действие удобрений. Вместе с тем микроэлементы добавляются в удобрение в виде солей, в ионной форме чаще всего, сульфатов, относящихся к веществам 1-2 класса опасности, что может повлиять на токсичность удобрений и безопасность их производства и применения. Для предотвращения возможного негативного влия­ния на здоровье людей и среду обитания к производству, реализации и применению необходимо проведение токсикологических исследований, входящие в процедуру государственной регистрации.

Цель исследования - изучение характера токсического действия на организм лабораторных животных (крысы, кролики, морские свинки) новых комплексных бесхлорных минеральных удобрений с микроэлементами.

Материалы и методы. Для исследований были взяты образцы жидких агрохимикатов (препараты № 1, № 4, № 5) и твердых (препараты № 2, № 3) с различным содержанием азота, фосфора и калия и различным составом микроэлементов в виде солей. Экспериментальная работа выполена на 90 нелинейных, половозрелых белых крысах- самцах массой 200-220 г, 30 породистых кроликах-самцах массой 3000-3500 г и 90 морских свинках- самцах  массой 350-400 г. При проведении работы использовали существующие методические подходы и рекомендации, включающие в себя общепринятые информативные методы токсикологических и статистических исследований.

Результаты. На основании проведенных исследований установлены параметры острой пероральной и дермальной токсичности, раздражающее действие на кожу и слизистые оболочки глаз, сенсибилизирующее действие 5 образцов комплексных бесхлорных минеральных удобрений с микроэлементами.  Для всех изученных препаратов  острая пероральная токсичность   (DL₅₀)  > 5000 мг/кг массы тела.,  острая дермальная токсичность (DL₅₀)   > 2500 мг/кг массы тела, слабое раздражаюшее действие на кожу крыс (среднегрупповой общесум­марный балл выраженности кожно-раздражающего дей­ствия равнялся 0,7 баллов для препаратов №1, №4, №5 и 0,5 баллов для препаратов №2 и №3), слабое раздражающее действие на слизистые оболочки глаз кроликов (среднесуммарный балл выраженности раздражающего действия образцов жидких удобре­ний №1, №4, №5 равнялся 1-3 баллам, твердых удобрений  №2, №3 – 1-2 балла), отсутствие сенсибилизирующего эффекта  у морских свинок в рамках стандартного протокола исследований (реакции специфического лизиса лейкоцитов (РСЛЛ) показали отрицательные кожные пробы у морских свинок всех опытных групп; относительный процент лизиса не превышал 10%).

Заключение. Обобщение всех полученных резуль­татов экспериментальных токсикологических исследований комплексных бесхлорных азотно-фосфорно-калийных удобрений с микроэлементами  с точки зрения гигиенической безопасности позволяет  отнести их к веществам умеренно опасным (класс опасности – 3).

Ключевые слова: минеральное удобрение, токсичность, раздражающее действие, сенсибилизирующее действие, гигиеническая безопасность.

Соблюдение этических стандартов. Исследование  не требует представления заключение комитета по биомедицинской этике или иных документов.  

Для цитирования: Русаков Н.В, Румянцева Л,А., Михайлов И.Г., Ветрова О.В.,  Истомин А.В. К вопросу гигиенической безопасности новых комплексных минеральных удобрений с микроэлементами. Токсикологический вестник. 2022; …

Для корреспонденции: Русаков Владимир Николаевич, руководитель отдела здорового и безопасного питания ФБУН  «Федеральный научный центр гигиены им. Ф.Ф. Эрисмана», Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человека, 141014, Российская Федерация, Московская область, г. Мытищи,  E-mail:  rusakovvn@fferisman.ru.

Конфликт интересов: Авторы декларируют отсутствие явных и потенциальных конфликтов интересов  в связи с публикацией данной статьи.

Финансирование: Исследование не имело спонсорской поддержки.

Участие авторов: Русаков В.Н. – концепция и дизайн исследования, написание текста, редактирование; Румянцева Л.А. – обработка материала, редактирование; Михайлов И.Г. – концепция и дизайн исследования, обработка материала, написание текста, редактирование; Ветрова О.В. – статистический анализ, редактирование, Истомин А.В.- концепция и дизайн исследования, редактирование.

Указатель статей, опубликованных журнале в 2022 г.