Background. We investigated mortality in workers of the world’s largest chrysotile mine and enrichment factories located in the town of Asbest, Russian Federation.

Methods. This historical cohort study included all workers employed for at least 1 year between 1975 and 2010 and follow-up until the end of 2015. Cumulative exposure to dust was estimated based on workers’ complete occupational history linked to dust measurements systematically collected from the 1950s. Exposure to chrysotile fibers was estimated using dust-to-fiber conversion factors. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated as mortality rate ratios in Poisson regression models.

Results. A total of 30 445 (32% women) workers accumulated 721 312 person-years at risk and 11 110 (36%) died. Of the workers, 54% had more than 30 years since their first exposure. We found an exposure-response between cumulative dust and lung cancer mortality in men. No clear association with dust exposure but a modest increase in the highest category of fiber exposure was seen for lung cancer in women. Mesothelioma mortality was increased (RR=7.64, 95% CI=1.18 to 49.5, to at least 80 fibers per cm³ years and RR=4.56, 95% CI=0.94 to 22.1, to at least 150 mg/m³ years [dust]), based on 13 deaths. For colorectal and stomach cancer, there were inconsistent associations. No associations were seen for laryngeal or ovarian cancer.

Conclusion. In this large-scale epidemiological study in the world’s largest active asbestos mine, we confirmed an increased risk of mesothelioma with high fiber exposure and an increasing mortality for lung cancer in men with increasing dust exposure. Less clear-cut increased lung cancer mortality was seen in the women. Continued mortality follow-up is warranted.

Primary source. The original article in English was published on January 22, 2024, in the Journal of the National Cancer Institute (USA), license number for publication of the Russian version is 5722671193983.

For citation (primary source): Schüz J., Kovalevskiy E., Olsson A., Moissonnier M., Ostroumova E., Ferro G., Feletto E., Schonfeld S.J., Byrnes G., Tskhomariia I., Straif K., Morozova T., Kromhout H., Bukhtiyarov I. Cancer mortality in chrysotile miners and millers, Russian Federation: main results (Asbest Chrysotile Cohort-Study). Journal of the National Cancer Institute. 2024; 00(0): 1–10. https://doi.org/10.1093/jnci/djad262

Author contributions:
Joachim Schüz — conceptualization, formal analysis, investigation, methodology, project administration, resources, supervision, writing — original draft, writing — review & editing;
Evgeny Kovalevskiy — conceptualization, data curation, funding acquisition, investigation, methodology, project administration, resources, supervision, writing — original draft, writing — review & editing;
Ann Olsson — data curation, investigation, methodology, project administration, supervision, writing — original draft, writing — review & editing;
Monika Moissonnier — data curation, formal analysis, methodology, software, validation, visualization, writing — review & editing;
Evgenia Ostroumova — data curation, investigation, methodology, supervision, validation, writing — review & editing;
Gilles Ferro — data curation, formal analysis, methodology, software, validation, visualization, writing — review & editing;
Eleonora Feletto — data curation, formal analysis, methodology, visualization, writing — review & editing;
Sara J. Schonfeld — conceptualization, data curation, investigation, methodology, project administration, writing — review & editing;
Graham Byrnes — formal analysis, methodology, writing — review & editing;
Iraklii Tskhomariia  — data curation, investigation, project administration, writing — review & editing;
Kurt Straif — conceptualization, methodology, writing — review & editing;
Tatiana Morozova — investigation, project administration, resources, validation, writing — review & editing;
Hans Kromhout — conceptualization, data curation, formal analysis, investigation, methodology, supervision, validation, writing — original draft, writing — review & editing;
Igor Bukhtiyarov — conceptualization, funding acquisition, investigation, project administration, resources, supervision, validation, writing — original draft, writing — review & editing.

Funding. The work was supported by the Ministry of Health of the Russian Federation in the framework of the Federal target programme, National System of Chemical and Biological Safety of the Russian Federation of 2009–2014 and of 2015–2020 under a general framework of action between the Federal State Budgetary Scientific Institution, Izmerov Research Institute of Occupational Health (IRIOH) and the International Agency for Research on Cancer–World Health Organization (IARC‑WHO) (2015–2023). The work by Dr Schonfeld on this manuscript was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Conflicts of interest. Dr Kovalevskiy reported receiving, on behalf of his institute and personally through consulting firms, payments from companies to evaluate exposure to asbestos and risk of asbestos-related disease in those workplaces. All other authors have no competing interests to declare.

For full transparency, Dr Kovalevskiy reported participation as an occupational and environmental health expert as part of the delegation of the Russian Ministry of Health at multiple World Health Assembly meetings as well as at the Conference of the Parties to the Basel and Rotterdam Conventions. Dr Kovalevskiy reported attending meetings organized by the International Chrysotile Association and reported that all expenses for attendance were paid by his institute.

Dr Schüz, who is a JNCI Associate Editor and co-author on this paper, was not involved in the editorial review or decision to publish the manuscript.

Acknowledgements. The study team mourns the loss of their dear colleague Dr Sergey Kashanskiy (SK) from the Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers, Yekaterinburg, Russian Federation, who was instrumental in the conduct of the study but passed away on February 9, 2023, before the draft of this manuscript was completed.

We also acknowledge the work conducted by the extended study team. The late Dr Nikolai Izmerov, director (1971–2012) and scientific supervisor (2012–2016) of the Federal State Budgetary Scientific Institution, Scientific Research Institute of Occupational Health, made a large contribution to the organization and implementation of the study at its initial stages. The data entry team in Asbest town rigorously entered written information into electronic format: the late Isolina Smirnova, Zoya Lapuhina, and Yulia Nurdinova. Dr Valerie McCormack of the International Agency for Research on Cancer — World Health Organization (IARC-WHO) helped tremendously in setting up the study and writing the study protocol. Dr Madar Talibov and Dr Dana Kristjansson supported specific activities of the study during their stay at IARC-WHO. Dr Veronika Fedirko, while at IARC-WHO, was involved in pilot activities preparing for the full-scale study, and Dr Paolo Boffetta was IARC-WHO section head when the initial contact about the study was made. Ms Christine Bassier and Ms Catherine Chassin, IARC-WHO secretaries, were involved in organizing study-related travels and meetings. Dr Kirsten Frederiksen, a senior statistician at the Danish Cancer Institute, Copenhagen, Denmark, conducted selected independent analyses of the data as an additional quality assurance measure.

The study is monitored by an independent scientific advisory board, which oversees the progress of the study. The scientific advisory board members are Professor Franco Merletti (chair), Professor Mads Melbye (until 2017), Professor Julian Peto, Professor Martin Röösli (from 2017), and Dr Antti Tossavainen. Scientific advisory board members provided their reviews of this manuscript, but the integration of their comments remained at the discretion of the authors. The authors like to express their gratitude to the scientific advisory board for many years of advice and their helpful comments on the manuscript.

Where authors are identified as personnel of the IARC-WHO, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the IARC-WHO. The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; or the writing of the manuscript.

Received: 06.12.2023 / Accepted: 12.02.2024 / Published: 15.03.2024

Introduction. Maintaining labor efficiency, working under conditions of stress and uncertainty, high level of requirements to the functional state of workers in various professions actualize the occupational health study of work performance. Methodological applications of predictive medicine and psychogenetics make it possible to identify specific hereditary (biological) predispositions of individuals, to carry out professional orientation of a person, to provide humanistic recommendations on occupation of a certain type of professional activity.

The study aims to identify a correlation between ACE genotypes and work performance capability in individuals from a professional leadership community.

Materials and methods. Individuals from a professional leadership community, after dividing into two cohorts consisting of entrepreneurs and non-entrepreneurs, were interviewed and genotyped for evidence of genotype-by-insertion/deletion (I/D) polymorphism associations of the angiotensin I converting enzyme (ACE) gene and health status. Answers to 4 questions characterized the state of work performance and memory, and another 4 questions characterized the cardiovascular system. The mean age was 37±1.7 years for entrepreneurs and 34.23±0.66 years for non-entrepreneurs. There were 44 females and 129 males among them.

Results. Analysis of genotyping of 173 people (25 entrepreneurs and 148 non-entrepreneurs) revealed a significant deviation of actual frequencies of I and D alleles from theoretically expected values in the whole group of managers and between non-entrepreneurs (p=0.95, χ²>3.8). In all groups, there was a marked increase in the frequency of the I/I genotype at the expense of a decrease in the frequency of the D/D genotype compared to the literature data. A significant difference between D/D and I/D genotypes in work performance was found in entrepreneurs (p=0.9817), which coincides with a significant difference between their representatives by age (p>0.99). Contrary to expectations, representatives of the D/D genotype, at least entrepreneurs, demonstrated the most optimal level of functioning of the autonomic nervous system. No associations were found between the genotype for the ACE gene (rs4646994) and work performance and memory.

Conclusion. In the total sample of leaders and among the subgroup of non-entrepreneurs, a strong and reliable change in the frequencies of alleles I and D was found compared to the theoretically expected (frequencies). There was a significant increase in the frequency of I/I genotype in all groups. The significant difference in the rates between the D/D and I/D groups coincides with a significant difference between their representatives in terms of age. According to the results of test answers, representatives of entrepreneurs of D/D genotype had the most optimal level of vegetative nervous system functioning.

Financing. The study was performed with the support of the 20.35 Univ., and DDT.

Conflict of interest. The authors state that there is no conflict of interest.

Received: 20.11.2023 / Accepted: 28.02.2024 / Published: 15.03.2024

Introduction. Ambroxol hydrochloride is a biologically active substance used as a pharmaceutical substance in the manufacture of medicines for secretolytic therapy in the case of acute and chronic bronchopulmonary diseases. To date, there is no hygienic standard for the safe content of substances in the air of the working area in the republic.

The study aims to substantiate and develop the maximum permissible concentrations and hazard class of the pharmaceutical substance ambroxol hydrochloride in the air of the working area.

Materials and methods. The authors have conducted experimental toxicological studies of the pharmaceutical substance on animals (rats, mice, rabbits) in accordance with the requirements of technical regulatory legal acts and recommendations of methodological documents regulating the justification of hygienic standards.

Results. Scientists have found that the pharmaceutical substance ambroxol hydrochloride, when injected into the stomach and inhaled, is classified as a low-hazard substance at an average lethal dose/concentration (according to GOST 12.1.007-76), has a mild irritant effect on the skin and moderate on the mucous membranes of the eyes, does not exhibit a skin-resorptive effect, is characterized by a weak cumulative effect and does not it has sensitizing activity. Under the conditions of inhalation of the substance into the body of laboratory animals (rats), the threshold values of acute and chronic harmful effects of this pharmaceutical substance were at the level of 90 mg/m³ (in terms of the effect on the functional state of the nervous activity of rats) and 30 mg/m³, respectively (in terms of changes in behavioral indicators, weight and mass coefficient spleen, blood glucose, alanine aminotransferases and urea) accordingly.

Conclusion. Based on the experimental results of the toxicological assessment, the authors have justified the standard of permissible content of the pharmaceutical substance ambroxol hydrochloride in the air of the working area at the level of 4.0 mg/m³, they also have established the hazard class of the substance according to GOST 12.1.007-76 (class 3, medium-hazard substances).

Ethics. The Bioethics Commission of the State Enterprise "SPCH” has approved the use of laboratory animals for experimental purposes (Protocol No. 1 dated 03/04/2020). The treatment of animals was in accordance with the provisions of Directive 2010/63/EU of the European Parliament and of the Council of the European Union of September 22, 2010 on the protection of animals used for scientific purposes.

Contribution:
Vasilkevich V.M. — the concept and design of the study, the execution of the experiment, writing the text of the article;
Bogdanov R.V. — research concept, article editing;
Evtereva A.A. — experiment execution, data collection and processing;
Sychik S.I. — the concept of research, editing of the article.

Funding. The authors have conducted the study as part of the implementation of the State scientific and technical program "Development of pharmaceutical substances, medicines and regulatory support for the pharmaceutical industry", task 2.12 (action 1087 SP).

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

Received 17.11.2023 / Accepted: 05.02.2024 / Published: 15.03.2024

Introduction. Toxic pulmonary edema is an acute syndrome characterized by the accumulation of fluid in the extravascular spaces of the lungs, impaired gas exchange, the formation of tissue hypoxia and acidosis, which can occur in acute inhalation poisoning with pulmonary toxicants at work. Existing methods of drug and respiratory therapy are ineffective in the development of alveolar pulmonary edema (end-stage acute respiratory distress syndrome; ARDS). In this regard, the search for new approaches to the treatment of this condition, which is characterized by almost 100 % mortality, is of great practical importance. One of such approaches is the use of perfluorocarbon (PFC) fluids, which, due to their unique physical and chemical properties, are able not only to ensure the evacuation of edematous fluid from the alveoli and respiratory tract, but also to restore gas exchange in the parts of the lungs filled with them. This article will present an experimental evaluation of the use of PFC fluids in a model of the alveolar stage of toxic pulmonary edema.

The goal of the study is to determine the effect of bronchoalveolar lavage (BAL) using perfluorocarbons on the indicators of acute respiratory failure and the outcome of the alveolar stage of toxic pulmonary edema.

Materials and methods. The study was carried out on male Wistar rats aged 4 months, weighing 180–230 g. Toxic pulmonary edema was initiated by endotracheal injection of 0.1 M HCl solution. Anesthetized rats were intubated with a cannula, then intratracheally injected with 0.1 M HCl solution at a dose of 2 ml/kg and connected to a ventilator. After that, the animals were randomized by weight into groups of 6 individuals each. Animals of the experimental group with a decrease in saturation below 80%, 2–6 procedures of bronchoalveolar lavage (BAL) with PFC-oxygenated liquid in a single dose of 2.0 ml/kg were performed. Heart rate, oxygen saturation, duration of survival, and overall survival by group were recorded.

The results. In all rats, there was a decrease in oxygen saturation (SpO₂) and heart rate (HR) after HCl administration, which was restored to the lower limits of normal within 5 minutes. However, after 25 to 30 minutes, the animals experienced a rapid decrease in SpO₂, an increase in heart rate, the appearance of wet wheezing in the lungs, and the discharge of foamy fluid from the catheter. Against this background, there was a rapid death of animals, At the same time, the average duration of survival was 30.6±3.3 min. In turn, in the animals of the experimental group, after each BAL procedure, an increase in saturation was noted, it was possible to evacuate a total of 9.1±0.8 ml/kg of edematous fluid from the lungs. It was also noted that the average duration of survival of rats in the experimental group was 1.69 times and amounted to 51.6±3.8 minutes.

Conclusions. The use of BAL with PFC fluids in the alveolar stage of toxic pulmonary edema makes it possible to evacuate a significant amount of edematous fluid from the lower parts of the lungs due to its displacement by a perfluorocarbon with a higher density; to short-term reduce the severity of manifestations of acute respiratory failure after instillation of oxygenated PFC liquid; to increase the duration of survival of animals by ensuring gas exchange in previously uninvolved parts of the lungs.

Ethics. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. The Clinical Study Protocol was reviewed at a meeting of the local Ethics Committee FSBSI IRIOH. Protocol No. 4 of May 25, 2022.

Contribution:
Isabekov N.R. — concept and design of the study, data collection and processing, text writing, editing;
Tonshin A.A. — concept and design of the study, text writing;
Bonitenko E.Yu. — concept and design of the study, editing.

Funding. The work was carried out within the framework of the state assignment, code the number FGFE-2024-0003.

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

Received: 18.01.2024 / Accepted: 06.02.2024 / Published: 15.03.2024

The significant prevalence of industrial aerosols with unintentional nanoparticles and the increasing use of engineering nanoparticles in modern production determine the relevance of research on the patterns of interaction with the human bronchopulmonary system. Unintentional nanoparticles are formed during various production processes: melting and welding of metals, combustion, crushing, grinding of minerals, plasma processing of materials. Engineering nanoparticles are released into the air of the work area during their production or use in any technological processes.

The respiratory system, as a barrier organ, is most vulnerable to the effects of adverse environmental factors. At the same time, nanoparticles are the least studied component of industrial aerosols. In order to systematize data on the role of nanoparticles in the development of occupational bronchopulmonary pathology, the authors conducted a literature review.

The size determines the features of the physical, chemical and biological properties of nanoparticles. They have high values of the ratio of surface area to volume, total surface area, which leads to an increase in reactogenicity and penetrating power. The pathogenic properties of nanoparticles depend on the chemical composition, shape, curvature of the surface, structure, charge, mass concentration, total surface area of the particles, and exposure time.

The multidimensionality of hygienic characteristics determines the complexity of hygienic rationing and monitoring of nanoparticles. To date, safe exposure levels have not been established. When interacting with cells of the respiratory tract, nanoparticles induce the following cellular and molecular mechanisms: oxidative stress, inflammation, violation of the epithelial barrier, autophagy and dysfunction of lysosomes, stress of the endoplasmic reticulum, apoptosis, senescence, fibrosis, endothelial dysfunction, DNA damage. This leads to the development of interstitial pneumonitis, pulmonary fibrosis and obstructive disorders, and an increase in the activity of allergic inflammation. All these mechanisms are present in the pathogenesis of occupational lung diseases. Under the influence of nanoparticles of various chemical compositions, separate phenotypes of occupational chronic obstructive pulmonary disease are formed. There is a lack of epidemiological studies of the possible etiological role of nanoparticles. Nanoparticles of industrial aerosols are a significant factor in the development of occupational diseases of the bronchopulmonary system and have a significant impact on the formation
of phenotypes.

Contribution:
Shpagina L.A. — the concept and design of the review, collection, analysis and interpretation of data (literary sources), writing the text;
Zenkova M.A. — the concept and design of the review, collection, analysis and interpretation of data (literary sources);
Saprykin A.I.— the concept and design of the review, collection, analysis and interpretation of data (literary sources);
Logashenko E.B. — the concept and design of the review, collection, analysis and interpretation of data (literary sources), writing the text;
Shpagin I.S. — the concept and design of the review, collection, analysis and interpretation of data (literary sources), writing the text;
Kotova O.S. — the concept and design of the review, collection, analysis and interpretation of data (literary sources), writing the text;
Tsygankova A.R.— collection, analysis and interpretation of data (literary sources);
Kuznetsova G.V.— collection, analysis and interpretation of data (literary sources);
Anikina E.V. — the concept and design of the review, collection, analysis and interpretation of data (literary sources), writing the text;
Kamneva N.V.— collection, analysis and interpretation of data (literary sources);
Surovenko T.N.  — writing the text

Funding. The research was carried out at the expense of a grant from the Russian Science Foundation (project No. 19-74-30011).

Conflict of interests. The author declares no conflict of interests.

Received: 23.01.2024 / Accepted: 15.02.2024 / Published: 15.03.2024

Nanoparticles are the main product of artificial technologies, and also accompany production processes in various industries. The main routes of exposure to nanoparticles are through the respiratory tract, skin and orally; therefore, most toxicological studies have focused on the lungs, liver and skin. Nanoscale particles easily penetrate the alveolar-capillary barrier and enter the bloodstream of the body. Thus, they can reach various organs, accumulate, cause toxicity, and the heart is one of the target organs.

The study aims to search and systematize the literature data on the mechanisms of cardiotoxic action of nanoparticles of various chemical nature (elemental, elementoxide).

The researchers conducted a literature review as part of a study of the cardiotoxic effect of nanoparticles on the body. The review is based on modern original research. When searching for literary sources, the authors used the following information databases: PubMed, Google Scholar, CyberLeninka Scientific Electronic Library, Russian Scientific Electronic Library eLibrary.Ru. In total, there were 37 original articles in the review, including 35 foreign ones, and 15 — no older than 5 years. The development of oxidative stress and an inflammatory reaction leads to the formation of cardiotoxicity of nanomaterials, which subsequently leads to necrosis and apoptosis of cells.

Indicators of oxidative damage to lipids and DNA molecules indicate that the tissues of the heart and lungs suffer from oxidative stress not only as a result of an increase in the formation of reactive oxygen species, but also due to a malfunction of antioxidant mechanisms caused by exposure to nanoparticles.

Studies using endothelial cells have shown that exposure to metal and metal oxide nanoparticles can promote the release of cytokines, the expression of adhesion molecules and monocyte adhesion, which are key events associated with the development of cardiovascular diseases.

These results, combined with other in vitro data, suggest that direct contact of the cardiovascular system with metal-based nanoparticles may cause cardiovascular toxicity associated with inflammatory reactions, oxidative stress, autophagy dysfunction and endoplasmic reticulum stress. Oxidative stress induced by nanoparticles leads to apoptosis and inflammatory reactions in cardiomyocytes, as well as disrupts the integrity of mitochondrial membranes and cell organelles, leading to various heart pathologies. One of the main mechanisms of toxicity of nanoparticles of different chemical nature is oxidative stress.

Contribution:
Klinova S.V. — literature review, preparation of the manuscript of the article;
Minigalieva I.A. — concept and design of the study;
Sutunkova M.P. — concept and design of the study;
Nikogosyan K.M. — literature review, preparation of the manuscript of the article.

Funding. The study had no funding.

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

Received: 29.11.2023 / Accepted: 21.12.2023 / Published: 15.03.2024

Exposure to harmful chemical factors of production can contribute to the development of metabolic disorders in workers in the petrochemical industry. Oil production conditions are associated with exposure to endocrine disruptors, such as aromatic hydrocarbons, whose effects are associated, among other things, with disorders of immuno-endocrine regulation.

The aim of the study was to analyze the features of the immune and genetic status of workers in the oil-producing segment of the petrochemical industry with metabolic syndrome contaminated with benzene.

142 operators of the oil production enterprise with pathology with metabolic syndrome were examined. The observation group included workers (n=94) characterized by contamination of the biological medium with benzene. The comparison group consisted of 48 people who were not contaminated with benzene. The state of cellular immunity was assessed by flow cytometry (CD3⁺CD8⁺, CD3⁺CD95⁺, CD3⁺), cytokine profile by enzyme immunoassay (IL‑6). Gene polymorphism was studied by real-time PCR.

In workers with metabolic syndrome contaminated with benzene, the features of the clinical course of the metabolic syndrome, accompanied by functional and laboratory signs of atherosclerotic vascular changes, as well as an imbalance of the immune profile, whose phenotypes were: an increase in the absolute and relative content of CD3⁺CD8⁺ lymphocytes (1.3–1.6 times, respectively) (p<0.05), CD3⁺ lymphocytes (1.2–1.3 times) (p<0.05) relative to the comparison group, CD95⁺ cluster deficiency in relation to the reference interval and the indicators of the comparison group (1.4–1.9 times; p<0.05), IL-6 hyperproduction (1.6 times; p<0.05) relative to the values of the corresponding indicators of the group of workers where benzene contamination was absent. The genetic profile of workers (SNP) contaminated with benzene allowed us to establish a 1.4-fold increased prevalence of the C-allele of the FADS2 gene (OR=2.13; 95% CI: 1.05–4.29, p<0.05); 2.3 times the G-allele (OR=3.30; 95% CI: 1.46–7.33, p<0.05) of the TP53 gene.

Established in operators of the oil-producing segment of the petrochemical industry with metabolic syndrome contaminated with benzene, features of the immune status: an increase in the expression of CD3⁺ and CD8⁺ lymphocyte clusters, IL-6 cytokine, and a decrease in CD95⁺ lymphocyte reception (p<0.05) were accompanied by polymorphisms of candidate genes FADS2 (rs174583) and TP53 (rs 1042522) associated with obesity and apoptosis.

Ethics. The study was approved by the ethics committee of the Federal Scientific Center for Medical and Preventive Health Risk Management Technologies. All patients were informed about the purpose of the study, and voluntary informed consent was obtained.

Contribution:
Otavina E.A. — the collection and processing of material, statistical processing, writing the text;
Dolgikh O.V. — concept, study design, editing, responsibility for the integrity of all parts of the article;
Alekseev V.B. — the concept and design of the study, writing a text, editing;
All authors — are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.

Funding. The study had no funding.

Cоnflict оf interests. The authors declare no conflict of interests.

Received: 26.12.2023 / Accepted: 20.01.2024 / Published: 15.03.2024