Toxicological Review

Introduction. Modern industrial enterprises are noted for pollution of the workplace air with a multicomponent mixture of chemicals, the combined exposure to which can significantly differ from their isolated ones and have a different toxic effect. Experimental studies and mathematical modeling of combined effects of toxic metals on various systems and organs are the scientific basis for assessing both occupational and environmental risks.The purpose of the research was to study the combined toxicity of lead and copper in an in vitro experiment using mathematical modeling.Material and methods. Experimental studies were carried out on an in vitro model using the IMR-32 cell line. Cytotoxicity was established following exposure to soluble lead and copper salts by measuring dehydrogenase activity using the MTT assay.Results. We have demonstrated that, in terms of dehydrogenase activity, the type of the combined effect of lead and copper in IMR-32 neuroblastoma cells changes with the increase in concentrations of the toxicants. At low doses of copper and lead, the type of combined action is additive, but with increasing doses it becomes antagonistic.Limitations. To assess the effect of lead and copper on cell culture, estimates calculated from one measured parameter of the dehydrogenase activity were used.Conclusion. Our findings support the general theory of combined toxicity, postulating the ambiguousness of the type of effect exhibited by the same pair of agents.Compliance with ethical standards. The study does not require the submission of the conclusion of the biomedical ethics committee and other documents.Authors’ contribution: Minigalieva I.A., Sutunkova M.P. – concept and design of research, editing; Shabardina L.V. – collection of material, data processing, writing; Panov V.G. – data processing, statistical analysis; Bushueva T.V., Karpova E.P. – collection of material and data processing. All co-authors are responsible for approving the final version of the article and ensuring the integrity of all its parts.Conflict of interest. The authors declare no apparent and potential conflicts of interest in relation to the publication of this article.Funding. The study had no sponsorship.Received: March 3, 2025 / Revised: April 4, 2025 / Accepted: November 25, 2025 / Published: January 15, 2026

Introduction. Iodine deficiency disorders remain a relevant problem despite salt iodization programs. A promising direction is the  is the creation of organic forms of iodine with high biological availability, such as a complex with alpha-lactalbumin.The aim of this study was to evaluate the bioavailability and toxicokinetics of this complex in a subchronic experiment.Material and methods. During a 90-day experiment on mature male rats, the oral administration of the iodine-alpha-lactalbumin complex at a dose of 150 µg iodine/day was studied. The control group received a standard diet. Body weight, hematological and biochemical blood parameters, thyroid hormone levels (TSH, FT3, FT4), and total serum iodine content were assessed on days 45 and 90.Results. The use of the complex led to a significant (2.2–3.2 times) increase in serum iodine levels, indicating its high bioavailability. By day 90, the experimental group animals developed iodine-induced hypothyroidism, manifested by a characteristic triad: an increase in TSH against a background of decreased FT4 and FT3. This was accompanied by metabolic disorders – decreased concentrations of glucose, total protein, and albumin. A paradoxical result was an increase in hemoglobin levels.Limitations. The main limitation is the use of an animal model and a fixed iodine dosage, which does not allow full extrapolation of the obtained data to humans or assessment of dose-dependent effects.Conclusion. Subchronic intake of iodine in the form of a complex with alpha-lactalbumin at a dose of 150 µg/day induces the development of iodine-induced hypothyroidism in rats against a background of high systemic bioavailability. The identified metabolic changes are consistent with a hypothyroid state, while the unexpected hematological effect requires further study. A promising direction is the investigation of the dose-dependent effects of the complex.Compliance with ethical standards: The study was approved by the Bioethical Commission of the F.F. Erisman Federal Scientific Center of Hygiene (protocol from 09.04.24 No.1/24), and conducted in accordance with the European Convention for the Protection of Vertebrate Animals Used for Experiments or Other Scientific Purposes (ETS N 123), Directive 2010/63/EC of the European Parliament and of the Council of the European Union of 22.09.2010 on the protection of animals used for scientific purposes.Authors’ contribution: All the authors have made an equal contribution to the writing of the article.Conflict of interests. The authors declare no apparent and potential conflicts of interest in relation to the publication of this article.Funding. The study was sponsored by I2LIFE Co., Ltd.Received: Jule 14, 2025 / Revised: October 24, 2025 / Accepted: November 25, 2025 / Published: January 15, 2026

Introduction. Thioacetamide belongs to highly toxic compounds that cause significant pathological changes in organs and tissues. In the context of the widespread use of chemicals, the search for effective methods of protecting the body from their negative effects remains an urgent task. The most promising strategy is the development of methods to reduce toxic damage to the body as a result of exposure to chemicals.Material and methods. The study was performed on 56 outbred male rats in a chronic experiment lasting 100 days with an intermediate study of morphological parameters on the 50th day. The animals were divided into 4 groups (2 control and 2 experimental): rats of the second (positive control), third and fourth groups were administered thioacetamide intraperitoneally twice a week at a dose of 50 mg / kg of body weight. The first group of rats (negative control) was administered an equivalent volume of physiological solution in a similar way. One hour before the toxicant, the third experimental group was administered the comparison drug ademetionine at a dose of 25 mg / kg of body weight, the fourth – a complex compound of oxymethyluracil with acetylcysteine at a dose of 500 mg / kg of body weight. The effectiveness of the correction was assessed by pathomorphological changes in the kidneys of rats.Results. In the middle of the experiment, no pathological changes were found in the kidneys of rats of all the studied groups. By the end of the experiment, under the influence of thioacetamide, signs of damage to the renal parenchyma were observed in the form of granular dystrophy, swelling of the cytoplasm of epithelial cells, narrowing of the lumen of the tubules and the formation of protein inclusions. When corrected with a complex compound of oxymethyluracil with acetylcysteine, pathological changes in the kidneys were less pronounced. Morphometric analysis of the cross-sectional area of ​​the proximal tubules and the area of ​​the cell nuclei confirmed the results of histological studies by groups.Limitations. With long-term exposure to thioacetamide, the hepatoprotective efficacy of drugs was assessed primarily by morphological characteristics, but for a more comprehensive assessment of the correction of toxic effects, it is also necessary to take into account biochemical and functional indicators.Conclusion. Chronic administration of thioacetamide to rats at a dose of 50 mg/kg body weight has a nephrotoxic effect, which is reduced by prophylactic administration of ademetionine and a complex compound of oxymethyluracil with acetylcysteine ​​to animals. According to pathomorphological signs, the effectiveness of the nephroprotective effect of the complex compound of oxymethyluracil with acetylcysteine ​​is higher than that of ademetionine.Compliance with ethical standards. The study was approved by the bioethics committee of the Ufa Research Institute of Occupational Medicine and Human Ecology (protocol No. 01-02 dated 08.02.2024).Authors’ contribution: Khmel A.O. – collecting and processing material, writing text; Yakupova T.G., Muhammadieva G.F., Gizatullina A.A., Khusnutdinova N.Yu. – collecting and processing material; Ryabova Yu.V., Repina E.F. – editing; Karimov D.O. – research concept and design, statistical analysis. 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 apparent and potential conflicts of interest in relation to the publication of this article.Funding. The work was carried out as part of the state assignment for the industry research program of Rospotrebnadzor “Scientific justification of the national system for ensuring sanitary and epidemiological well-being, managing health risks and improving the quality of life of the population of Russia” for 2021-2025. clause 6.1.8, state no. registration 121062100058-8. Received: April 2, 2025 / Revised: May 5, 2025 / Accepted: November 25, 2025 / Published: January 15, 2026

Drug independence of the Russian Federation requires the presence of full-cycle enterprises of strategically important medicines and, consequently, the safety of workers, which is impossible without modern approaches to the hygienic regulation of pharmaceutical substances in the air of the working area.The purpose of the study was to identify prospective areas for updating the existing regulatory and methodological framework in the hygienic regulation of pharmaceutical substances in the air of the working area.The article presents an analysis of domestic and foreign literature containing information on international and national approaches to the regulation of pharmaceutical substances in the air of the working area.Modern approaches to hygienic regulation of pharmaceutical substances based on the use of NOAEL (no observed adverse effective level) and BMD (benchmark dose) as points of departure taking into account different safety factors, the use of pharmacokinetic modeling methods to extrapolate data from oral toxicity studies to inhalation, machine learning to predict the properties of chemicals, assessment of carcinogenic risk when rationing direct-acting genotoxicants, as well as on the establishment of standards for excipients of medicinal products and account for the biological activity of active substances that are analogues of endogenously synthesized substances.The regulatory and methodological framework for hygienic regulation of pharmaceutical substances in the air of the working area requires updating, taking into account new approaches. The most promising is the use of NOAEL and BMD as reference points in the justification of safe exposure levels, and pharmacokinetic modeling.Authors’ contribution: All co-authors have made an equal contribution to the research and preparation of the article for publication.Conflict of interests. The authors declare no apparent and potential conflicts of interest in relation to the publication of this article.Funding. The study is funded as part of the research project “Methodology development of the hygienic regulation of pharmaceutical substances in the air of the working area, the atmospheric air of populated areas and the water of water bodies” of the Rospotrebnadzor sector program “Hygiene”.Received: November 22, 2025 / Accepted: November 25, 2025 / Published: January 15, 2026

In the structure of reported cases of acute poisoning, a significant part is drug poisoning, among which a notable proportion is occupied by neuroleptics, particularly haloperidol and risperidone. The material for the analysis was the sources of literature reviewed in PubMed, Scopus, and RSCI bibliographic databases. The content analysis was conducted taking into account the peculiarities of the toxic effect and existing methods for the determination of neuroleptics in biological samples.It has been demonstrated that neuroleptic poisoning presents a serious medical and social issue due to its high prevalence and severity of intoxication. This study presents the current procedure for conducting chemical and toxicological, forensic and chemical examinations of neuroleptic poisonings, with blood, urine, and hair being used as biological samples. It has been established that the determination of neuroleptic substances in hair is the most informative method, as these substances are not metabolized and can be detected over a long period after taking the drug. Information is provided on the pharmacokinetics and pharmacodynamics of haloperidol and risperidone, the clinical picture of poisoning with these antipsychotics, and existing treatment approaches. The analysis of methods for isolating and detecting haloperidol and risperidone in biological samples, such as blood, urine, and hair, was conducted. It was found that solid-phase and liquid extraction are the most effective methods for isolating these drugs from biological materials. High-performance liquid chromatography with various detectors was identified as the preferred technique for detecting these drugs.Neuroleptic poisoning is a significant social and medical issue that necessitates the development of improved methods for isolating and identifying drugs in biological samples.Authors’ contribution: All co-authors made an equal contribution to the research and preparation of the article for publication.Conflict of interests. The authors declare that there are no conflicts of interest.Funding. The study had no sponsorship.Received: March 11, 2025 / Accepted: November 25, 2025 / Published: January 15, 2026

Introduction. To eliminate the difficulties encountered in classifying chemicals by specific and long-term effects in accordance with the GHS, the Scientific Information and Analytical Center “Russian Register of Potentially Hazardous Chemical and Biological Substances” has developed a decision-making algorithm based on the weight of evidence. It includes a systematic assessment of the full range of available data, both confirming and refuting the effect, taking into account their contribution (from 1 to 3 points) according to the criteria of reliability, consistency, biological plausibility, dose-effect relationship, comparability of the effect observed in animals with potential consequences for human health. Evidence is ranked by the sum of points, and evidence with the lowest number of points is given priority when assessing and classifying the hazard of a chemical according to the GHS. The algorithm is applicable to all types of effects, including carcinogenicity, mutagenicity, reprotoxicity, sensitization, and effects on the endocrine system.The purpose of the study was to demonstrate approaches to the evidence base formation for assessing and classifying the hazards of chemicals by specific and long-term effects, taking into account the characteristics of these types of exposure.Material and methods. The analysis of national and international approaches to the evidence base formation for the assessment and classification of the hazards of chemicals with specific and long-term effects is carried out.Results. The features of using a decision-making algorithm in assessing the mutagenic, carcinogenic, reprotoxic, sensitizing effects and effects of chemicals on the endocrine system are described, as well as the procedure for applying appropriate testing methods and interpreting the results.Limitations. The research is limited to the analysis of open literary sources, including databases Scopus, Web of Science, PubMed, ResearchGate, Cyberleninka, RSCI, eLibrary.Conclusion. Basic schemes for the formation of evidence bases for assessing and classifying chemical hazards based on specific and long-term effects were presented, taking into account the characteristics of these types of exposure, which contribute to the transparency and reliability of decision-making.Compliance with ethical standards. The study does not require an opinion from the Bioethics Commission.Authors’ contribution: Khamidulina Kh.Kh., Tarasova E.V. – concept and design of the study, editing, approval of the final version of the article, responsibility for the integrity of all parts of the article; Nazarenko A.K., Tverskaya A.S., Dorofeeva E.V., Zamkova I.V., Proskurina A.S., Rabikova D.N., Lastovetskiy M.L., Araslanov I.N., Aniskova Yu. Yu., Balashov P.E. – collecting and processing material, writing text, editing.Conflict of interests. The authors declare the absence of obvious and potential conflicts of interest in connection with the publication of this article.Funding. The study was carried out as part of the research project “Validation of alternative research methods in assessing the hazard and risk of exposure to chemicals on human health as a tool for regulating the safety of chemical factors” under the industry research program on hygiene for 2024–2025.Received: November 5, 2025 / Accepted: November 25, 2025 / Published: January 15, 2026

Introduction. The neuroactive insecticide imidacloprid, a member of the neonicotinoid class, is widely used worldwide to control various insect pests. Its high solubility leads to its entry into surface and groundwater, posing a significant risk to aquatic life.The aim of this study was to evaluate the acute and subchronic toxicity of imidacloprid on Danio rerio, including determining the LC50 and investigating the effects of varying insecticide concentrations on hematological parameters, genotoxicity, and histopathology of the gills, liver, trunk kidney, and middle intestine.Material and methods. The study used standard methods for determining the sublethal concentration in aquatic toxicology, as well as examining the leukocyte formula, genotoxicity, and histological preparations of D. rerio.Results. The 96-hour LC50 (LC5096) was determined to be 85.3 mg/L, with a 95% confidence interval (CI) of 76.16-96.98 mg/L. Hematological and histopathological changes were investigated for subchronic toxicity across a concentration range of 4 to 76 mg/L. Imidacloprid exposure resulted in a concentration-dependent decrease in erythrocyte counts, an increase in leukocyte counts, lymphopenia, and elevated numbers of monocytes, neutrophils, and basophils. An increased number of erythrocytes with nuclear abnormalities (deformed nuclei, 2.77‰; and fragmented nuclei, 2.85‰) was observed at concentrations of 38 and 76 mg/L. Histological changes were observed in the gills (basal epithelial atrophy and respiratory epithelial detachment), liver (sinusoidal capillary dilation and hepatocyte vacuolization), and kidneys (capillary dilation and tubular epithelial necrosis). The most prevalent histopathological finding was impaired circulation. In the middle intestine, an increased number of goblet cells and intraepithelial lymphocytes was observed.Limitations. The toxic effect of imidacloprid was assessed within the acute experiment. Additional experiments with longer duration and on other laboratory species would allow to reveal in more detail the mechanisms of toxic effect and related histopathological in disorders.Conclusion. The findings demonstrate the systemic toxicity of imidacloprid at concentrations exceeding 19 mg/L in Danio rerio organs and tissues.Compliance with ethical standards. The study was approved by the Commission on Bioethics of K.G. Razumovsky Moscow State University of Technology and Management, 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.Authors’ 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 apparent and potential conflicts of interest in relation to the publication of this article.Funding. This work was supported by the Russian Science Foundation (project No. 23-16-00123).Received: March 1, 2025 / Revised: April 30, 2025 / Accepted: November 25, 2025 / Published: January 15, 2026

Introduction. The growth in the production of antibacterial remedies, in particular clindamycin hydrochloride (CH), and the increase in the number of workers in contact with them have determined the relevance of experimental research to substantiate the maximum permissible concentration of CH in the air of the working area (MPC).Material and methods. Using a complex of physiological, behavioral, hematological, biochemical and histological methods, the severity of toxic manifestations in white rats was studied depending on 3 successively threefold decreasing concentrations of CH inhaled over 4 months.Results. Chronic inhalation exposure to CH at a concentration of 13.5 mg/m³ led to the development of significant shifts in a number of hematological (increase in the number of leukocytes due to a significant increase in the number of monocytes) and biochemical parameters of blood serum (increase in the levels of urea, total bilirubin and decrease in the concentration of direct bilirubin and cholesterol) and pronounced pathomorphological changes in the lung tissue, liver, kidneys, myocardium and spleen in the bodies of experimental animals. Exposure to CH at a concentration of 4.4 mg/m³ was accompanied by less pronounced and widespread toxic effects (an increase in total bilirubin and a decrease in the levels of direct bilirubin and cholesterol in the blood serum, mainly weak structural changes in the bronchi, lung parenchyma and spleen of experimental white rats). In experimental animals after chronic exposure to CH at a concentration of 1.6 mg/m³, the values of all studied morphofunctional parameters and histological characteristics of internal organs did not differ significantly from those in control ones.Limitations. The research is limited to studying the toxic effect of the pharmaceutical substance CH in a chronic experiment with inhalation exposure. The results of the study are applicable for the justification of MPC of the studied substance in the air of the working area.Conclusion. Based on the results of the inhalation experiment, the concentration of CH at the level of 4.4 mg/m³ was accepted as the threshold for chronic toxic effect, which was more than 3 times lower than the previously established threshold concentrations of subchronic specific dysbiotic and allergic effects, which determined the leading harmful general toxic effect on the body as a criterion for hygienic standardization of CH. Taking into account the calculated safety factor (11) to the threshold concentration of chronic toxic effects, MPC limit in the air of the working area for clindamycin hydrochloride aerosol was justified at the level of 0.4 mg/m³, hazard class II.Compliance with ethical standards. The studies were carried out in accordance with the principles of the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg, March 18, 1986), the Directive of the European Parliament and the European Union on the protection of animals used in experiments 2010/63/EU and approved by the Bioethics Commission of the Scientific Practical Centre of Hygiene, dated March 29, 2022, No. 2.Authors’ contribution: Zemtsova V.O. – collection and processing of the material, statistical analysis, writing a text; Bogdanov R.V. – concept and design of the study, editing; Rjabceva S.N. – collection and processing of the material, statistical analysis; Shevlyakov V.V. – writing a text, editing; Sychik S.I. – concept and design of the study, editing; Chernyshova E.V. – collection and processing of the material. All co-authors are responsible for approving the final version of the article and ensuring the integrity of all its parts.Conflict of interests. The authors declare no apparent and potential conflicts of interest in relation to the publication of this article.Funding. The work was carried out as part of the implementation of task 03.10 of the State Scientific and Technical Program “Scientific and Technical Support for the Quality and Availability of Medical Services” for 2021–2025 and was financed from the republican budget.Received: March 19, 2025 / Revised: June 6, 2025 / Accepted: November 25, 2025 / Published: January 15, 2026