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Even at low levels, exposure to ionising radiation can lead to eye damage. However, the underlying molecular mechanisms are not yet fully understood. We aimed to address this gap with a comprehensive in silico approach to the issue. For this purpose we relied on the Comparative Toxicogenomics Database (CTD), ToppGene Suite, Cytoscape, GeneMANIA, and Metascape to identify six key regulator genes associated with radiation-induced eye damage (ATM, CRYAB, SIRT1, TGFB1, TREX1, and YAP1), all of which have physical interactions. Some of the identified molecular functions revolve around DNA repair mechanisms, while others are involved in protein binding, enzymatic activities, metabolic processes, and post-translational protein modifications. The biological processes are mostly centred on response to DNA damage, the p53 signalling pathway in particular. We identified a significant role of several miRNAs, such as hsa-miR-183 and hsamiR-589, in the mechanisms behind ionising radiation-induced eye injuries. Our study offers a valuable method for gaining deeper insights into the adverse effects of radiation exposure.

COVID-19 can cause a range of complications, including cardiovascular, renal, and/or respiratory insufficiencies, yet little is known of its potential effects in persons exposed to toxic metals. The aim of this study was to answer this question with in silico toxicogenomic methods that can provide molecular insights into COVID-19 complications owed to exposure to arsenic, cadmium, lead, mercury, nickel, and chromium. For this purpose we relied on the Comparative Toxicogenomic Database (CTD), GeneMANIA, and ToppGene Suite portal and identified a set of five common genes (IL1B, CXCL8, IL6, IL10, TNF) for the six metals and COVID-19, all of which code for pro-inflammatory and anti-inflammatory cytokines. The list was expanded with additional 20 related genes. Physical interactions are the most common between the genes affected by the six metals (77.64 %), while the dominant interaction between the genes affected by each metal separately is co-expression (As 56.35 %, Cd 64.07 %, Pb 71.5 %, Hg 81.91 %, Ni 64.28 %, Cr 88.51 %). Biological processes, molecular functions, and pathways in which these 25 genes participate are closely related to cytokines and cytokine storm implicated in the development of COVID-19 complications. In other words, our findings confirm that exposure to toxic metals, alone or in combinations, might escalate COVID-19 severity.

This study aimed to assess the redox status and trace metal levels in 49 shoe industry workers (11 men and 38 women) occupationally exposed to a mixture of volatile organic compounds (VOCs), which includes aliphatic hydrocarbons, aromatic hydrocarbons, ketones, esters, ethers, and carboxylic acids. All measured VOCs were below the permitted occupational exposure limits. The control group included 50 unexposed participants (25 men and 25 women). The following plasma parameters were analysed: superoxide anion (O2•−), advanced oxidation protein products (AOPP), total oxidative status (TOS), prooxidant-antioxidant balance (PAB), oxidative stress index (OSI), superoxide dismutase (SOD) and paraoxonase-1 (PON1) enzyme activity, total SH group content (SHG), and total antioxidant status (TAS). Trace metal levels (copper, zinc, iron, magnesium, and manganese) were analysed in whole blood. All oxidative stress and antioxidative defence parameters were higher in the exposed workers than controls, except for PON1 activity. Higher Fe, Mg, and Zn, and lower Cu were observed in the exposed vs control men, while the exposed women had higher Fe and lower Mg, Zn, and Cu than their controls. Our findings confirm that combined exposure to a mixture of VOCs, even at permitted levels, may result in additive or synergistic adverse health effects and related disorders. This raises concern about current risk assessments, which mainly rely on the effects of individual chemicals, and calls for risk assessment approaches that can explain combined exposure to multiple chemicals.

The link between environmental pollution and obesity is of high importance, because understanding the relationship between the two can provide valuable insights into the complex factors contributing to the obesity epidemic. These chemicals, termed "obesogens," are believed to disrupt lipid metabolism processes, therefore promoting the development of obesity. Human activities such as industrialization, urbanization, agriculture, and transportation have significantly contributed to environmental pollution. Therefore, the main identified obesogens are BPA found in plastics, food packaging, and thermal paper receipts, phthalates, commonly used in plastics, personal care products, and food packaging, toxic metal(oid)s, determined in non-stick cookware, water-resistant fabrics, and food packaging, pesticides, used in agriculture, as well as other persistent organic pollutants (POPs), and pharmaceuticals (waste). Addressing environmental pollution not only has the potential to improve environmental quality, but also to promote public health and prevent obesity-related diseases. Addressing the causality between pollutants and obesity could be a new and challenging road map for health professionals.

This study aimed to investigate the effect of 150 mg/L sodium fluoride (NaF) on redox status parameters and essential metals [copper (Cu), iron (Fe), and zinc (Zn)] in the blood, liver, kidney, brain, and spleen of Wistar rats and to determine the protective potential of selenium (Se) against fluoride (F-) toxicity. Male Wistar rats were randomly distributed in groups of five (n=5) receiving tap water (control) or water with NaF 150 mg/L, NaF 150 mg/L + Se 1.5 mg/L, and Se 1.5 mg/L solutions ad libitum for 28 days. Fluorides caused an imbalance in the redox and biometal (Cu, Fe, and Zn) status, leading to high superoxide anion (O2 .-) and malondialdehyde (MDA) levels in the blood and brain and a drop in superoxide dismutase (SOD1) activity in the liver and its increase in the brain and kidneys. Se given with NaF improved MDA, SOD1, and O2 .- in the blood, brain, and kidneys, while alone it decreased SH group levels in the liver and kidney. Biometals both reduced and increased F- toxicity. Further research is needed before Se should be considered as a promising strategy for mitigating F- toxicity.

Considering that some researchers point to a possible influence of air pollution on COVID-19 transmission, severity, and death rate, the aim of our in silico study was to determine the relationship between the key air pollutants [sulphur dioxide (SO), carbon monoxide (CO), 2particulate matter (PMx), nitrogen dioxide (NO2), and ozone (O3)] and COVID-19 complications using the publicly available toxicogenomic analytical and prediction tools: (i) Comparative Toxicogenomic Database (CTD) to identify genes common to air pollutants and COVID-19 complications; (ii) GeneMANIA to construct a network of these common and related genes; (iii) ToppGene Suite to extract the most important biological processes and molecular pathways; and (iv) DisGeNET to search for the top gene-disease pairs. SO2, CO, PMx, NO2, and O3 interacted with 6, 6, 18, 9, and 12 COVID-19-related genes, respectively. Four of these are common for all pollutants (IL10, IL6, IL1B, and TNF) and participate in most (77.64 %) physical interactions. Further analysis pointed to cytokine binding and cytokine-mediated signalling pathway as the most important molecular function and biological process, respectively. Other molecular functions and biological processes are mostly related to cytokine activity and inflammation, which might be connected to the cytokine storm and resulting COVID-19 complications. The final step singled out the link between the CEBPA gene and acute myelocytic leukaemia and between TNFRSF1A and TNF receptor-associated periodic fever syndrome. This indicates possible complications in COVID-19 patients suffering from these diseases, especially those living in urban areas with poor air quality.

Crayons and colored pencils for children may contain toxic elements (TEs) exhibiting potential risk for children’s health including cognitive development, after their ingestion, through mouthing and chewing and eventually, their accumulation. The aim of this study was to determine total content of As, Pb, Cr, Cd, Ni and Sb and estimate their bioaccessibility conducting artificial saliva extraction. Sixty samples of colored pencils and crayons from 10 manufacturers were analyzed. Microwave acid assisted digestion followed by inductively coupled plasma optical spectroscopy (ICP-OES) was performed for determination of total content of TEs. Simulation of extraction by artificial saliva was applied to get more reliable data when bioavailability is concerned. The total concentrations of TEs were higher in colored pencils than in crayons and their maximum levels were: 5.78, 9.36, 9.97, 0.615, and 6.63 mg kg-1 for As, Pb, Cr, Cd and Ni, respectively. Concentration of Sb was below the detection limit for all investigated samples. This study showed that concentration of As and Pb in several samples did not comply with European Union regulative. Bioaccessibility study showed the high degree of leaching of Cr and As from pencils, but regardless of extracted portions, concentrations of selected investigated TEs were below allowed levels.

Mercury (Hg) is one of the most important environmental pollutants with endocrinedisrupting properties. There is little data from epidemiological studies describing the doseresponse relationship between toxic metal levels and hormone levels. The aim of this study was to use the nearest neighbor matching analysis to determine the difference in Hg concentration in healthy/sick subjects with thyroid disease and to use Benchmark modeling to determine the doseresponse relationship between Hg levels in the blood and thyroid-stimulating hormone (TSH) and thyroid hormones in serum. Blood samples were collected and used for Hg measurement using the ICP-MS method, and separated serum was used for hormone analysis. The study showed the existence of a statistically significant difference in Hg levels measured in healthy and sick subjects and the existence of a dose-response relationship between Hg and all measured hormones, with a narrow interval obtained for the Hg-TSH pair. The results of this research support the use of the Benchmark dose approach for the purpose of analyzing data from human studies, and our further research will be focused on examining the impact of low doses on animal models in order to determine more precise effects of low doses on the organism.

Background/Aim. Health professions education is facing emerging issues. A comprehensive situation analysis was performed among academic staff, healthcare practitioners, and healthcare science students to address and respond to new trends. The aim of the study was to investigate the attitude, perception, and the recognized needs towards experiential education (EE), interprofessional education (IPE), and teaching competencies development (TCD). The critical evaluation of the existing quality standards for further quality improvement in health professions education in Serbia was provided. Methods. The survey on EE, IPE, and TCD was conducted within the Reinforcement of the Framework for Experiential Education in Serbia (ReFEEHS) project, co-funded by the Erasmus+ program of the European Comission at four Serbian universities (the University of Belgrade, the University of Kragujevac, the University of Niš, and the University of Novi Sad). Four task groups were appointed to perform a desk review of the existing curricula, recommendations, and practices within each of the four health professions education (Medicine, Pharmacy, Dentistry, and Nursing) in Serbia and assess the level of compliance with relevant educational policies and practices in the European Union. Results. A total of 1,507 respondents completed the survey. A highly expressed positive attitude was found towards EE, IPE, and TCD among all the respondents. The majority of the respondents (> 70%) shared that EE should be organized in real-life practice and involve students’ work under the supervision of a qualified supervisor, as well as interactions with patients and healthcare professionals. About 90% of the respondents supported the inclusion of IPE teaching activities into EE, with 77% of students expressing high motivation to attend those classes, whereas 93% of academic staff was eager to deliver and teach joint IPE subjects. Only 20% of academic staff has already attended some TCD program, while 75% recognized the need for its organization. Moreover, 90% of healthcare practitioners have recognized that mentors/clinical supervisors also need additional skills for effective mentoring work within health science education. Based on the survey results, recommendations for improvement were given within three educational fields, healthcare science curricula, professional practice (traineeship), teaching staff, and regulations. Conclusion. The results derived from the survey served as a starting but also a vital point for higher education improvement in Serbia. All interested parties – academia, students, healthcare professionals, and regulatory bodies should collaborate on achieving improved, contemporary, and transformative health professions education.

While experimental animal investigation has historically been the most conventional approach conducted to assess drug safety and is currently considered the main method for determining drug toxicity, these studies are constricted by cost, time, and ethical approvals. Over the last 20 years, there have been significant advances in computational sciences and computer data processing, while knowledge of alternative techniques and their application has developed into a valuable skill in toxicology. Thus, the application of in silico methods in drug safety assessment is constantly increasing. They are very complex and are grounded on accumulated knowledge from toxicology, bioinformatics, biochemistry, statistics, mathematics, as well as molecular biology. This review will summarize current state-of-the-art scientific data on the use of in silico methods in toxicity testing, taking into account their shortcomings, and highlighting the strategies that should deliver consistent results, while covering the applications of in silico methods in preclinical trials and drug impurities toxicity testing.

Cadmium (Cd), one of the most abundant environmental pollutants, is considered to have endocrine disrupting properties. However, data on the dose-response relationship between Cd dose and levels of hormones have been insufficiently studied, especially in human data sets. Thus, the aim of this study was to determine the possibility of analyzing data obtained from a case-control study in female patients with benign/malignant breast tumors, using the Benchmark dose (BMD) concept. The collected data on Cd levels in breast tissue and estrogen serum levels were processed in PROAST software using different variables. The dose-response relationship between the internal dose of Cd and estradiol levels in the serum was investigated and BMD intervals were calculated. The dose-response relationship between the Cd concentration in breast tissue and the estradiol serum level was shown, indicating lower estradiol serum levels as a consequence of higher Cd concentrations in breast tissue. As one of the few studies analyzing human data using the BMD approach, these findings could have a pivotal role in dose response analysis of data collected from human studies.

Most Pb and Cd neurotoxicity studies investigate exposure to either of the toxic metals alone, while data on co-exposure are scarce. The aim of our study was to fill that gap by investigating acute combined effects of Pb and Cd on redox and essential metal status in the brain of Wistar rats. Animals were randomised in four groups of six to eight rats, which received 15 or 30 mg/kg of Cd, 150 mg/kg of Pb, or 150 mg/kg of Pb + 15 mg/kg of Cd by gavage. The fifth, control, group received distilled water only. Co-treatment with Pb and Cd induced significant increase in malondialdehyde (MDA) and thiobarbituric acid-reactive substances (TBARS) compared to control and groups receiving either metal alone. This is of special importance, as MDA presence in the brain has been implicated in many neurodegenerative disorders. The groups did not significantly differ in Zn, Cu, Mn, and Fe brain levels. Our findings highlight the importance of metal mixture studies. Neurotoxicity assessments of single chemicals do not provide a real insight into exposure to mixtures in real life. Further research should look into interactions between these metals to reveal complex molecular mechanisms of their neurotoxicity.

Immunochromatographic strips for urine drug screening tests (UDSTs) are common and very suitable for drug abuse monitoring, but are also highly susceptible to adulterants kept in the household, which can significantly alter test results. The aim of this study was to see how some of these common adulterants affect UDST results in practice and whether they can be detected by sample validity tests with pH and URIT 11G test strips. To this end we added household chemicals (acids, alkalis, oxidizing agents, surfactants, and miscellaneous substances) to urine samples positive for amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), tetrahydrocannabinol, heroin, cocaine, or benzodiazepines (diazepam or alprazolam) and tested them with one-component immunochromatographic UDST strips. The UDST for cocaine resisted adulteration the most, while the cannabis test produced the most false negative results. The most potent adulterant that barely changed the physiological properties of urine specimens and therefore escaped adulteration detection was vinegar. Besides lemon juice, it produced the most false negative test results. In conclusion, some urine adulterants, such as vinegar, could pass urine specimen validity test and remain undetected by laboratory testing. Our findings raise concern about this issue of preventing urine tampering and call for better control at sampling, privacy concerns notwithstanding, and better sample validity tests.

This paper aims to present the importance of the benchmark dose (BMD) as a point of departure (the lowest dose or concentration in the experiment that deviates from the response that differs from the normal response) in toxicological risk assessment, as well as to present commonly used software for its calculation (BMDS and PROAST). Benchmark dose is defined as a statistical lower confidence limit of a dose that results in a small change in effect (5-10%) in comparison with the control value. The BMD approach is considered a substitution for the NOAEL approach, which uses the highest observed no-effect level (NOAEL) to obtain the reference dose. The BMD approach is a methodically more forward-thinking technique than the NOAEL approach because it has statistical power and provides a wide range of dose-response relationships and allows the determination of their uncertainty and variability. Moreover, the BMD approach contributes to the reduction of experimental animals in toxicity studies. Therefore, the European Food Safety Authority (EFSA) recommends the use of BMDL10 values for quantal and BMDL05 for continuous data.

For over a century, one of the main toxicologists' goals was finding the relationship between the chemical structure and toxicity. The development of computer technologies has lead to the production of software models that could be applied for this purpose. However, use of in silico methodology in toxicology is very complex. Having in mind that toxic effect occurs through multiple mechanisms on different tissues and organs, creating software that can make reliable toxicity predictions is very complicated. In silico methods found the application in toxicity assessment of substances for which data obtained from traditional toxicity tests is lacking (metabolites, drug impurities, etc.). Also, in silico methods can be used in the process of chemical synthesis, with the aim of designing safer chemicals. Currently, in silico methods for toxicity predictions are most commonly used along with standard toxicological tests, with a tendency to replace in vitro and in vivo toxicity tests in the future. This paper will present the strengths and limitations of commonly used software in in silico toxicology (OECD QSAR Toolbox, Derek Nexus, ToxTree i MultiCASE).

Background/Aim. Fluoride has beneficial effect on dental caries prevention and enables high hardness of enamel. However, fluoride intake above optimal levels can have adverse effects on teeth and bones, especially in young children during the period of intense growth and teeth development. The aim of this study was to assess fluoride intake from water and toothpaste among 3-year-old children in Belgrade, Serbia, in the municipalities of Vračar and Novi Beograd. Methods. A questionnaire for the parents (n = 40) was used to provide information on the water consumption (tap and/or bottled water) and the brand of toothpaste used by children as well as the frequency of tooth brushing and the amount of toothpaste during brushing. Fluoride concentrations in water and toothpaste samples were determined electrochemically by using fluoride-selective electrode. Fluoride intake was estimated through a mathematical model commonly used by the U.S. Environmental Protection Agency. Results. The obtained results indicate no significant difference in daily fluoride intake through drinking water and toothpaste in 3-year-old children in Vračar (n = 19) compared to Novi Beograd (n = 21) (p > 0.05). However, all estimated fluoride levels (0.089–0.625 mg/day) are significantly lower than the optimal daily intake level for caries protection (0.7 mg/day for children up to 4 years, FNB-USA National Institute of Medicine) and two to six times lower than tolerable upper fluoride level for the children of same age (1.3 mg/day, FNB-USA National Institute of Medicine). Furthermore, calculated daily fluoride intake per kilogram body weight confirm very low fluoride intake by water and toothpaste in children of investigated municipalities in Belgrade, being significantly below the recommended an adequate intake (0.05 mg/kg/day, EFSA). Conclusion. This preliminary study has shown that daily fluoride intake in 3-year-olds is lower than tolerable upper fluoride level, even not sufficient for the prevention of dental caries. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III46009]

Bearing in mind that cosmetic products are applied throughout the lifetime and that they can contain potentially harmful and toxic substances, valid EU regulation in this area has set strict requirements regarding their safety. Manufacturers are required to provide a cosmetic product safety report containing a toxicological assessment made by experts. Toxicological assessment is based on existing in vivo toxicological data, and in particular in silico and in vitro, since EU regulations in the field of cosmetic products prohibit new animal studies. Although sporadic cases of serious poisoning after the application of cosmetic products have been recorded, adverse effects after normal and reasonably foreseeable use of cosmetic products are usually mild (allergic reactions and skin irritation) and completely reversible. EU regulations require mandatory reporting of serious adverse effects (functional incapacity, hospitalization, disability, etc.) in order to detect ingredients of cosmetic products that potentially endanger human health and prevent similar effects from recurred. The paper describes the procedure of toxicological risk assessment for cosmetic ingredients because the assessment of the safety of the cosmetic product is based on the assessment of the safety of its ingredients.

Cadmium (Cd) is today one of the most significant metal poisons, both in the area of professional as well as of eco toxicology. In the organism, cadmium has a harmful effect on the kidneys, liver, bones, testicles, etc., and, based on evidence in humans that it causes lung carcinoma, it has been placed in the first group of carcinogens. In spite of numerous data in literature on the harmful effects of cadmium, the interactions between cadmium and bioelements as a significant mechanism for cadmium toxicity have still not been sufficiently explained. Since the data so far point to a positive effect of supplementation with certain bioelements regarding toxicity and cadmium content in the organism, the objective of this work was to investigate the effect of increased simultaneous intake of magnesium, zinc and copper on urinary elimination of cadmium in rabbits exposed to cadmium. Rabbits were divided into two groups: Cd group - for a period of 28 days the animals received per os 10 mg Cd/kg b.m/day and Cd+(Mg+Zn+Cu) group - 10 mg Cd/kg b.m. + 40 mg Mg/kg b.m, 20 mg Zn/kg b.m. and 10 mg Cu/kg b.m/day. Daily urine was collected on days 0, 10, 15, 17, 19, 21, 23, 25, and 28 of the experiment. Following decomposition of urine samples with the help of concentrated HNO3 and HClO4 (4:1), the metal concentration was determined using the method of atomic absorption spectrophotometry. Supplementation with magnesium, zinc and copper did not result in significant changes in the elimination of cadmium through urine in animals poisoned with cadmium, in comparison with the animals that were administered only cadmium, while the concentration of all three applied bioelements in urine was significantly increased. It can be concluded that the simultaneous administration of increased doses of zinc, copper and magnesium does not have a positive effect on the elimination of cadmium in conditions when rabbits are poisoned with cadmium.

Background/Aim. The beneficial effects of medicinal plants are well-known from the ancient times. However, expansion of phytopharmacy and phytotherapy occured during the last decades. Medicinal plants can absorb environmental contaminants from the ground and consequently may cause harmful effects on human health. Quality control usually comprises standard methodology which includes macroscopic identification and examination of active ingredients. Additionaly, there is a permanent need to control the level of pollutants in herbs, with a particular attention to the level of toxic metals. In this study we estimated the level of contamination by determining the content of cadmium (Cd) in the herbs of Hypericum perforatum and Thymus serpyllum collected from the different localities of the mountains Rtanj and Ozren. Methods. Herbs of investigated plants were collected during July 2005 from various localities of Rtanj and Ozren mountains. After drying, homogenization and mineralization, Cd content was determined by atomic absorption spectrophotometry. Results. The obtained results show that Cd content varies significantly in Hypericum perforatum samples collected. The lowest Cd level was found in samples from the one of Rtanj localities (0.25 mg Cd/kg), while the highest was observed in Hypericum perforatum from Ozren locality (1.24 mg/kg). Levels of Cd in the three of four investigated localities were higher than pro posed by WHO (0.3 mg/kg dried herb material). In all investigated samples of Thymus serpyllum herbs Cd levels were below the limit of detection of analytical method (0.2 mg Cd/kg dried materials). Conclusion. This work contributes to the issue of Cd content in Hypericum perforatum and Thymus serpyllum grown in localities of Rtanj and Ozren, and implies the importance for systemic control of Cd content in Hypericum species in order to provide safety of their preparations. Furthermore, regarding Cd toxicity, maximal permissible level of Cd in plant material should be evaluated and established concerning national legislative frame.

This study aimed to explore the health impacts, mechanisms of toxicity, and key gene biomarkers of a mixture of the most prominent perfluoroalkyl/polyfluoroalkyl substances (PFAS) through in silico ADMET and toxicogenomic analysis. The following databases and tools were used: AdmetSAR (2.0), ADMETlab (2.0), Comparative Toxicogenomic Database, ToppGene Suite portal, Metascape (3.5), GeneMANIA server, and CytoHubba and CytoNCA Cytoscape (3.10.3) plug-ins. ADMET analysis showed that PFAS compounds pose risks of organ-specific toxicity, prolonged retention, and metabolic disruptions. Forty mutual genes were identified for all the tested PFAS. The mutual gene set was linked to disruption of lipid metabolism, particularly through nuclear receptors. The most important gene clusters identified were nuclear receptor signaling and PPAR signaling pathways, with kidney and liver diseases, diabetes, and obesity as the most significant related diseases. Phenotype data showed that PFAS compounds impact cell death, growth, inflammation, steroid biosynthesis, and thyroid hormone metabolism. Gene network analysis revealed that 52% of the 40 mutual genes showed co-expression, with co-localization as the next major interaction (18.23%). Eight key genes were extracted from the network: EHHADH, APOA2, MBL2, SULT2A1, FABP1, PPARA, PCK2, and PLIN2. These results highlight the need for further research to fully understand the health risks of PFAS mixtures. [ABSTRACT FROM AUTHOR]