Toxicity Studies Research Articles

Effects of New Btk-Based Formulations BLB1 and Lip on Aquatic Non-Target Organisms.

Integrated pest management based on the use of biopesticides is largely applied. Experimental bioassays are critical to assess biopesticide biosafety at the ecotoxicological level. In this study, we investigated the effects of the new Bacillus thuringiensis subsp. kurstaki (Btk)-formulated-based biopesticides BLB1 and Lip, efficiently tested in field assays (IPM-4-CITRUS EC project no. 734921) on two aquatic non-target organisms, precisely the water flea Daphnia magna and the bioluminescent bacteria Aliivibrio fischeri. Acute toxicity studies, carried out in a comparative manner with Delfin® as the reference bioproduct and the lactose-based Blank formulation, show that no significant toxicity was observed up to 1 g/L. Our results indicated that BLB1- and Lip-formulated new bioproducts are far less toxic than the Delfin® reference bioproduct.

Sweet lime peel biomass derived nano-cellulose for dye removal: Kinetics, thermodynamics, optimization and toxicity studies

Sweet lime peel biomass derived nano-cellulose for dye removal: Kinetics, thermodynamics, optimization and toxicity studies

Sustainable detergent-disinfectant agent based on whey mineralizate and silver nanoparticles for cleaner production in dairy industry

Detergents and disinfectants for dairy industry must meet a variety of characteristics, including low toxicity, high antibacterial activity, and excellent rinsing of pollutants from working surfaces. This work presents an innovative detergent-disinfectant agent based on whey mineralizate and silver nanoparticles (Ag NPs), which allows reducing production costs and ensuring high cleanliness of treated surfaces compared to analogues. For this purpose, a method for obtaining sols of Ag NPs stabilized with didecyldimethylammonium bromide (Ag NPs-DDAB) was developed and optimized using neural network algorithms. Characterization of Ag NPs-DDAB showed particles with a radius of 4.5 nm and 20 nm, stable in the pH range from 2 to 11. An acute toxicity study of Ag NPs in mice showed LD50 = 4230 μg/kg. Based on the degree of accumulation and inhalation toxicity, Ag NPs-DDAB are classified as low-hazard chemicals. The developed detergent-disinfectant had a washability of about 90%, high antimicrobial activity (0.005 mg/mL) against Penicillium roqueforti and a sanitary and hygienic effect on coliforms, general contamination and pathogenic microorganisms, a low-corrosive effect and low toxicity (315 mg/mL) to Danio rerio. It was concluded that the use of detergent-disinfectant agent will completely eliminate the consumption of water for the equipment cleaning process and can be used to clean an electrodialysis unit’s circuits, enabling the utilization of secondary waste from membrane milk processing and promoting resource efficiency and cleaner production in the dairy industry.

Evaluation of the chronic oral toxicity of the classical ancient prescription Kai-Xin-San

Ethnopharmacological relevanceThe Kai-Xin-San (KXS), as an ancient classic prescription, has been used for the treatment of amnesia for thousands of years. Modern clinical and non-clinical pharmacological studies have found that it has significant therapeutic effects on dementia and depression, but there are relatively few studies on its safety. Aim of the studySubacute and chronic toxicity studies were conducted to investigate the symptoms, severity, target organs, development and recovery of toxic reactions, as well as the toxic dose. These studies provide technical data for ensuring the safety of KXS. Materials and methodsIn the sub-acute toxicity study, rats were orally administered KXS at doses of 0.80, 1.61, 3.22, and 6.43 g/kg body weight for a duration of 4 weeks. In the chronic toxicity study, rats were orally administered KXS at doses of 0.27, 0.81, and 2.43 g/kg body weight for a duration of 26 weeks, and a withdrawal study was conducted for a period of 4 weeks after the treatment.The rats were observed daily for clinical signs and mortality. Changes in body weight, food consumption, and water consumption were periodically monitored. Additionally, urinalysis results, hematological and biochemical parameters, relative organ weights, and pathology were monitored at specific observation time points. ResultsIn the sub-acute toxicity study, necropsy of dead and moribund rats revealed evident distension and swelling of the gastrointestinal tract, as well as thinning of the intestinal wall. The main adverse reactions observed included flatulence, piloerection, abnormal breathing sounds, and emaciation. Doses of 1.61 g/kg and below did not cause animal death. The gastrointestinal system is the main target organ of toxicity. In the chronic toxicity study, the no-observed-adverse-effect-level (NOAEL) of KXS was 0.27 g/kg, and its toxic effects were primarily concentrated in the gastrointestinal system. This led to secondary pathological changes in the immune system, hematopoietic system, and heart, suggesting that relevant indicators should be monitored when large doses are used clinically for an extended period of time. ConclusionsDuring the rodent toxicity evaluation, severe gastrointestinal damage was observed when KXS, powdered with crude drugs, was administered. The NOAEL for rats was found to be 0.27 g/kg/day.

Potential of chitosan and silver nanoparticles as fungicides against chocolate spot of faba bean: physiological, ultrastructural and toxicity studies

Potential of chitosan and silver nanoparticles as fungicides against chocolate spot of faba bean: physiological, ultrastructural and toxicity studies

Experimental study of acute toxicity of the intramuscular form of a specific immunobiostimulator — transfer factor

Relevance. The article presents data on the toxicological assessment of the safety of the specific immunobiostimulant of antigen-directed action “Transfer Factor” in a form ready for intramuscular administration and obtained from the blood of hyperimmunized donors on laboratory animals in an acute experiment.Methods. The object of the study was the finished form of “Transfer Factor”, the acute toxicity of which was determined in models on laboratory animals (nonlinear mice, nonlinear rats).Results. It was found that after administration of the drug to mice intramuscularly (0.25 ml/head) and intraperitoneally (0.5 ml/head), to rats intramuscularly (2.5 ml/head) and intraperitoneally (2.5 ml/head), muscle tremor is observed, disappearing after 15–20 minutes. Intraperitoneal administration of the drug to mice and rats in dosages of 0.75 ml/head and 3.75 ml/head, respectively, determines the presence of tremor lasting 40 minutes. During the 14-day observation period, the body weight of mice and rats increases by 10.15-14.25 and 11.84-17.67%. Autopsy of animals does not reveal visible changes in the location of organs and fluid in the abdominal and pleural cavities. However, some pathological changes in color, consistency and size are found in the lungs, heart, spleen and liver with intramuscular administration of Transfer Factor to mice and rats at a dose of 0.25 ml/head and 2.5 ml/head, intraperitoneal administration to mice at a dose of 0.5 ml/head and 0.75 ml/head and to rats 2.5 ml/head and 3.75 ml/head. Based on the totality of changes in the vital signs of laboratory animals, body weight and macroscopic characteristics of internal organs according to GOST 12.1.007-76, the drug “Transfer Factor” can be classified as hazard class IV “Low-hazard substances”.

Toxicology profile of a novel GLP-1 receptor biased agonist-SAL0112 in nonhuman primates

Oral small-molecule GLP-1 receptor biased agonists exhibit promising treatment efficacy of type 2 diabetes and obesity. SAL0112 is a novel compound that has demonstrated remarkable efficacy in preclinical animal models. Herein, both in vitro and in vivo preclinical toxicity investigations were conducted to explore the safety profile of SAL0112. The HTRF assay and TR-FRET assay were utilized for cAMP detection. Patch clamp assay was employed for hERG potassium ion channel determination. Cynomolgus monkeys were used in a cardiovascular safety pharmacology study and a 13-week repeated dose toxicity study. The telemetry system was employed to detect cardiovascular indicators such as ECG, HR, and BP. During the repeated dose toxicity study, body weight, food intake, hematology, coagulation function test, serum biochemistry tests, and urine analysis were measured. Macroscopic and microscopic observations were conducted at the end of the study. TK studies were conducted on Day 1 and Day 91. SAL0112 exhibited a high degree of potency in activating the monkey GLP-1 receptor whereas had no effect on the rodent GLP-1 receptor. In contrast to Danuglipron, which demonstrated high potency on hERG with an IC50 value of 6.9 μM, the IC50 of SAL0112 on hERG was greater than 100 μM. Compared to the Vehicle Control group, no significant changes in cardiovascular indicators were observed in the cardiovascular safety pharmacology study after a single dose of SAL0112 up to 250 mg/kg (P > 0.05). A repeated dose toxicity study revealed moderate anorexigenic effects and a reduction in body weight, effects that were found to be reversible and not associated with any pathological changes. The NOAEL of SAL0112 is 150 mg/kg, providing an approximate safety margin of threefold. SAL0112 demonstrated a favorable safety profile in cynomolgus monkeys, with a substantial therapeutic window that supports the progression of this compound into clinical studies.

Evaluation of the in vitro toxicity and anti-inflammatory activity of the methanolic extract of the leaves of Pistacia lentiscus L. harvested from northwestern Algeria.

Medicinal and aromatic plants have been used for thousands of years for their therapeutic properties, to treat various ailments and maintain health. This study was carried out to test the in vitro toxicity and anti-inflammatory activity of the methanolic extract of the leaves of Pistacia lentiscus L., native to the north-western region of Algeria. Toxicity was studied in vitro by the hemolysis test and anti-hemolytic activity on human red blood cells, while anti-inflammatory activity was assessed in vitro by the protein denaturation method. The study of toxicity by hemolysis of red blood cells showed a high rate of hemolysis at a dose of 200 mg/mL, with a hemolytic percentage of around 88.64%, while a high rate of anti-hemolysis was observed at a dose of 25 mg/mL, with an inhibition percentage of around 83.17%. Evaluation of anti-inflammatory activity revealed a high percentage of inhibition of ovalbumin denaturation, reaching 63.53% at the 2000 ug/mL dose, while the lowest percentage was obtained at the 3500 ug\mL concentration with 10.16%. This extract has a toxic substance but does not exceed the toxicity threshold which achieves significant anti-inflammatory activity with depandant doses.

Ameliorative Effect of Curcuma longa Ethanolic Extract on the Histology, Hepatic Glycogen Content and Some Biochemical Parameters of the Liver in Streptozotocin-Induced Hyperglycemic Wistar Rats

Introduction: Diabetes mellitus is a life threatening disease that requires immediate medical treatment. Numerous medicinal plants have been known for their anti-diabetic effects and Curcuma longa (turmeric) is one of them. This attribute is possible due to the pharmacological properties of its bio-constituents. In this study, the ameliorative potential of ethanolic extract of Curcuma longa was investigated on the liver of hyperglycemic adult Wistar rats. The objectives were to determine its effects on liver histology, hepatic glycogen content and some liver biochemical parameters. Methods: Forty (40) rats weighing between 120-180g were used for the research. Sixteen (16) rats were used for its acute toxicity study, while twenty-four (24) rats were grouped into four. The groups were labelled A to D and contained six rats each. Group A (normal control) rats were given food pellets and distilled water only. Group B (diabetic control) rats were given 65mg/kg BW of streptozotocin IP. Group C served as the standard group and was given 65mg/kg of streptozotocin IP + 250mg/kg of metformin IP, while Group D (test group) rats were given 65mg/kg BW of streptozotocin IP + 500mg/kg of Curcuma longa extract. Curcuma longa extract was administered through the oral route with the aid of an oral gavage. The administration lasted for twenty-eight (28) days, after which the rats were made to fast overnight with access to only water. The rats were then anaesthetized and whole blood obtained through cardiac puncture for biochemical analysis. Liver tissue was obtained for histological and glycogen content analyses. Results: The results showed severe destruction of hepatocytes with widely spread cytoplasmic vacuolation, loss of hepatic lobules and hepatic inflammation in the diabetic group, whereas it showed prominent nuclei, hepatocytes and distinct sinusoidal spaces in the normal control group. The metformin group showed an intact architecture of the liver tissue with indicating regeneration in the liver, while the Curcuma longa extract group showed a preserved liver cytoarchitecture. There was a significant decrease (p<0.05) in the fasting blood glucose level and liver enzyme activities in the standard and test groups compared to the diabetic group (p<0.05). There was also improvement in glycogen content of the standard and test groups in comparison with the diabetic group (p<0.05). Conclusion: Curcuma longa possesses hepato-protective properties and a strong anti-diabetic potential, therefore it can be considered as an alternative drug in the management of diabetes mellitus and its complications.

In vivo immunomodulatory effect and safety of MSC-derived secretome

Background: Secretomes have been gaining interest in treating several diseases due to their pharmaceutical effects, such as the immunomodulatory effect. This study aimed to determine the immunomodulatory effect of secretomes derived from human umbilical cord mesenchymal stem cells (MSCs) and their safety. Methods: We conducted an in vivo immunomodulatory study using a carbon clearance assay. The safety of single-dose administration of secretome was done using fixed-dose methods of acute toxicity test. Results: The phagocytic index was higher in mice treated with secretome than in untreated mice. The acute toxicity study also showed that the administration of secretome derived from human umbilical cord MSCs did not change the mice’s body weight, physical examination results, organ weight, and gross anatomy examination. Conclusions: This study presents the potential of secretome derived from MSCs as a safe immunomodulatory agent.

EVALUATION OF ANTI-DIABETIC ACTIVITY OF METHANOLIC EXTRACT FROM THE FRUIT PEEL OF ATALANTIA MONOPHYLLA (LINN.) IN ALLOXAN INDUCED DIABETIC MICE

Objective: Atlantia monophylla is an indigenous medicinal plant, with a folk reputation as hypoglycemic agent throughout India. Considerable research has shown that plants rich in flavonoids content with anti-oxidant potential are known to be bioactive for the management of diabetes mellitus (DM). In the present investigation, hypoglycemic activity of aqueous fruit peel extract of A. monophylla was evaluated using alloxan-induced hyperglycemic mice. Methods: Aqueous extract of the fruit peel of A. monophylla (AEAM) was subjected to preliminary phytochemical screening and acute oral toxicity study as per Organization for Economic Cooperation and Development guidelines 425. AEAM was evaluated for hypoglycemic activity, Alloxan induced DM in mice, oral glucose tolerance test in fasted mice. In vitro α- amylase inhibitory in albino mice method was employed for evaluation of hypoglycemic activity. Results: All of the mice in each group had their blood glucose levels measured both before and after the treatments on fasting animals. The extract was given at doses of 200 mg/kg and 400 mg/kg body weight, or 100 mg/kg body weight of the conventional antidiabetic medication Metformin. A glucometer was used to measure the blood glucose level. After 1 h, 2 h, and 4 h, the extract-treated diabetic mice had a substantial (p≤0.05) drop in blood glucose levels. The hypoglycemic action was similar to that of the medication Metformin used as a benchmark. Conclusion: The results of this study indicate that AEAM has strong hypoglycemic properties. One such method might include the activation of insulin receptors and subsequent release of insulin once β cells are stimulated. The hypoglycemic effect of the plant could be achieved through increasing insulin release from the pancreas.

Phytochemical and pharmacological evaluation of bacopa monniera for anti – anxiety activity

Anxiety, a common emotional response to stress, involves numerous brain regions and neurotransmitters, including the amygdala, prefrontal cortex, and hippocampus, and is partially by genetic, environmental, and biological factors. This study evaluates Bacopa monnieri, a herb known in Ayurvedic medicine for its cognitive-enhancing and adaptogenic properties, as a potential anti-anxiety agent. The plant's ethanolic extract revealed a variety of phytochemicals, including alkaloids, flavonoids, and saponins. Acute toxicity studies indicated a high safety margin with an LD50 exceeding 2000 mg/kg body weight. The anti-anxiety effects were assessed using three established models. In the Elevated Plus-Maze Test, Bacopa monnieri significantly reduced anxiety levels in mice, comparable to the standard anxiolytic benzodiazepine. The Hole-Board Test showed increased head-dipping and rearing behaviors, while reducing immobility, suggesting anxiolytic activity. The Light-Dark Exploration Test demonstrated the herb's ability to decrease anxiety-related behaviors, including a reduction in rearing in dark compartments and increased exploration of light areas. These findings provide scientific validation for Bacopa monnieri's traditional use in treating anxiety and support its potential as an effective and safe anti-anxiety agent in managing central nervous system disorders.

Drug Delivery Systems for Infectious Eye Diseases: Advancements and Prospects

Infectious ocular diseases like keratitis, conjunctivitis, and endophthalmitis pose significant clinical challenges due to the complexities of delivering drugs to the eye. Recent advancements in drug delivery systems offer promising improvements for treating these conditions. Key strategies include targeted delivery through physicochemical modifications, magnetic nanoparticles, and ligand-receptor interactions. This review explores the safety and biocompatibility of ocular drug delivery systems through in vivo ocular toxicity studies, in vitro cytotoxicity assays, hemocompatibility studies, ocular tolerance tests, and genotoxicity assays. It also examines combination therapies and stimuli-responsive delivery systems for their potential to enhance therapeutic efficacy. Furthermore, we discuss tailored and optimized drug delivery approaches for infectious ocular diseases, outlining current challenges and future directions for developing effective ocular drug delivery systems.

Pesticides Risk Assessment Review: Status, Modeling Approaches, and Future Perspectives

Pesticide exposure poses significant environmental and human health concerns, particularly given its extensive use in agricultural activities. The assessment of pesticide risks is a multifaceted and resource-intensive process, often requiring time-consuming toxicity studies. In response to this challenge, advanced computational models, remote sensing, and GIS (geographic information systems) have emerged as efficient and precise tools for evaluating pesticide exposure risks. This comprehensive review aims to provide an in-depth examination of the latest research methodologies for assessing the risks associated with pesticide exposure and their practical applications. These methodologies encompass the assessment of pesticide exposure in air, soil, and water, offering a comprehensive understanding of potential environmental pathways. The paper also delves into the effective utilization of these tools for pesticide risk assessment and examines the potential implications of their findings. The approaches outlined in this review hold promise for a thorough and insightful assessment of pesticide risks and are positioned to equip researchers and policymakers with valuable knowledge to mitigate the impacts of pesticide exposure on human health and the environment.

A Comparison of European Union and Turkish Reports on the Statistics of Experimental Animal Use in Toxicity Testing.

The data on the number of animals used for experimental purposes, with a particular focus on regulatory toxicity studies, in Turkey and EU member states plus Norway (EU+), were compared for the period 2015 to 2020 (UK data after Brexit for 2020 were included too). The total number of listed vertebrates used for regulatory toxicity testing in the full 6-year reporting period in Turkey was 3.6% of that reported for the EU+. However, these numbers showed an increasing trend over the reporting period in Turkey, while the trend decreased in the EU+. In the top three most-used species for regulatory toxicology purposes in Turkey, 41% were fish (68,758 animals), followed by rats (29%; 49,975 animals), and then mice (20%; 33,292 animals). Turkey used low numbers of cats and dogs, while the corresponding number for the EU+ was more than 70-fold higher. Non-human primates were not used at all in Turkey, whereas about 34,000 were used in EU+ laboratories. The majority of toxicity tests (57%) performed in Turkey were categorised as 'Other' toxicity tests, and 27% were acute and sub-acute toxicity tests. Successful replacement alternatives (e.g. in vitro and in silico approaches) are already used in a wide range of research areas. However, although this new research and testing paradigm is underpinned by scientific evidence, the legislation and pace of acceptance of these new techniques in Turkey is considerably lagging behind other countries.

Non-clinical safety evaluation of Yongdamsagan-tang water extract: A 13-week subchronic oral toxicity study in Sprague Dawley rats.

Despite the continued clinical application of traditional herbal medicines, scientific evidence such as toxicological safety profile of Yongdamsagan-tang water extract (YSTW) has not yet been established. The purpose of this study was to investigate the potential toxicity profile of YSTW following a 13-week repeated oral administration at various concentrations to Sprague Dawley rats. YSTW was administered orally to rats once daily at doses of 0, 1000, 2000, and 5000 mg/kg bw/day for 13 weeks. During the experimental period, there were no significant toxicological changes related to YSTW treatment. These results indicate that the administration of YSTW for 13 weeks in the rat resulted in no signs of toxicity at up to 5000 mg/kg bw/day, which was considered the no-observed-adverse-effect level.

Phytochemical analysis, digestive enzymes inhibition, and toxicity study of Beta vulgaris

Phytochemical analysis, digestive enzymes inhibition, and toxicity study of Beta vulgaris

Acute and Sub-Acute Toxicity Studies of Soursop Starch in Swiss Mice and Wistar Rats

Acute and Sub-Acute Toxicity Studies of Soursop Starch in Swiss Mice and Wistar Rats

Statistical applications of virtual control groups to nonrodent animal toxicity studies: An initial evaluation

Utilization of data from historical control animals to form virtual control groups (VCGs) is an innovative approach to embody the 3Rs (reduce, refine, and replace use of control animals) principle in research. However, there is no available systematic comparison of statistical performance between concurrent control groups (CCGs) and VCGs in nonrodent safety assessment. The optimal selection criteria and combination of VCGs and CCGs also remain unclear. This study retrospectively evaluated VCGs’ statistical performance to detect test article effects on body weight and clinical pathology endpoints in dog and nonhuman primate (NHP) systemic toxicity studies. Body weight and six clinical pathology endpoints were analyzed against the reported study findings from a cohort of 22 previously reported nonrodent 1-month oral gavage toxicity using three different methods of generating VCGs. When the fold change from baseline was used, VCGs yielded a similar or higher statistical sensitivity to detect test article relatedness than CCGs. Compared to simple random sampling or using fixed criteria, the propensity score matching by BW, age, and year of study initiation yielded higher sensitivities. Our analysis supports the hypothesis that VCGs can be a viable instrument in nonrodent toxicity studies.

Chemical Characterization, Evaluation of Acute Oral Toxicity, and Anti-Diabetic Activity of Aloe sabaea Flowers Extract on Alloxan-Induced Diabetic Rats.

The study aimed to conduct chemical profiling, acute in-vivo toxicity evaluation, and the potential anti-diabetic effect of standardized Aloe sabaea flowers ethanolic extracts (ASFEE) on alloxan-induced diabetic rats. The chemical composition was analyzed using GC-MS and TLC techniques. The oral acute toxicity study was performed according to the WHO 2000 and the OECD 420 guidelines. Furthermore, anti-diabetic activity was investigated using two doses of ASFEE (0.2 and 0.5 g/kg/day BW, p.o.) compared with glibenclamide (5 mg/kg/day, p.o.). A molecular docking investigation of the identified components with the PTPN9 enzyme was performed to figure out the proposed anti-diabetic mechanism. GC-MS analysis displayed the existence of 18 compounds; mostof the compoundswere fatty acids and theiresters, and phytosterols. Total phenolic and flavonoid contents were 42.00±1.26 mg GAE/g DW and 22.21±1.55 mg QE/g DW, respectively. The results of the in-vivo toxicity study revealed the absence of noticeable signs of toxicity or mortality at various doses establishing the safety of the tested extract. The estimated LD50 value was higher than 10 g/kg. Antidiabetic action exhibited a noticeable decline in fasting blood glucose (FBG) levels comparable to glibenclamide with no inducing intense hypoglycemia and considerable excess weight.