Advances in mass spectrometry imaging for toxicological analysis and safety evaluation of pharmaceuticals.

Safety issues caused by pharmaceuticals have frequently occurred worldwide, posing a tremendous threat to human health. As an essential part of drug development, the toxicological analysis and safety evaluation is of great significance. In addition, the risk of pharmaceuticals accumulation in the environment and the monitoring of the toxicity from natural medicines have also received ongoing concerns. Due to a lack of spatial distribution information provided by common analytical methods, analyses that provide spatial dimensions could serve as complementary safety evaluation methods for better prediction and evaluation of drug toxicity. With advances in technical solutions and software algorithms, mass spectrometry imaging (MSI) has received increasing attention as a popular analytical tool that enables the simultaneous implementation of qualitative, quantitative, and localization without complex sample pretreatment and labeling steps. In recent years, MSI has become more attractive, powerful, and sensitive and has been applied in several scientific fields that can meet the safety assessment requirements. This review aims to cover a detailed summary of the various MSI technologies utilized in the biomedical and pharmaceutical area, including technical principles, advantages, current status, and future trends. Representative applications and developments in the safety-related issues of different pharmaceuticals and natural medicines are also described to provide a reference for pharmaceutical research, improve rational clinical medicine use, and ensure public safety.

Safety evaluation and effects of dietary phlorotannins on the growth, health, and intestinal microbiota of Litopenaeus vannamei.

Phlorotannins are phenolic compounds with diverse biological activities, yet their efficacy in aquatic animals currently remains unclear. This investigation scrutinized the influence of phlorotannins on the growth, immunity, antioxidant capacity, and intestinal microbiota in Litopenaeus vannamei, concurrently evaluating the potential adverse effects of phlorotannins on L. vannamei. A base diet without phlorotannins supplementation was used as a control, and 4 groups of diets with different concentrations (0, 0.5, 1.0, 2.0 g kg-1) of phlorotannins were formulated and fed to juvenile shrimp (0.25 ± 0.01 g) for 60 days followed by a 24-h challenge with Vibrio parahaemolyticus with triplicate in each group. Compared with the control, dietary 2.0 g kg-1 phlorotannins significantly improved the growth of the shrimp. The activities of enzymes related to cellular immunity, humoral immunity, and antioxidants, along with a notable upregulation in the expression of related genes, significantly increased. After V. parahaemolyticus challenge, the cumulative survival rates of the shrimp demonstrated a positive correlation with elevated concentrations of phlorotannins. In addition, the abundance of Bacteroidetes and functional genes associated with metabolism increased in phlorotannins supplementation groups. Phlorotannins did not elicit any detrimental effects on the biological macromolecules or histological integrity of the hepatopancreas or intestines. Simultaneously, it led to a significant reduction in malondialdehyde content. All results indicated that phlorotannins at concentrations of 2.0 g kg-1 can be used as safe feed additives to promote the growth, stimulate the immune response, improve the antioxidant capacity and intestinal health of L. vannamei, and an protect shrimp from damage caused by oxidative stress.

Risk assessment of broflanilide for human and non-target terrestrial organisms in cauliflower production.

Broflanilide is a newly-developed meta-diamide insecticide, proposed for the control of a wide variety of chewing pests on many crops. In view of the proposed use of broflanilide and its environmental fate, it may be exposed to consumers and non-target organisms, which adversely affect human and the environment. In this paper, a rapid, sensitive and valid UPLC-MS/MS method was established for simultaneous analysis of broflanilide and its two major metabolites, DM-8007 and S (PFP-OH)-8007, in cauliflower. Then, the dissipation behaviors and final residues of broflanilide and its two major metabolites in cauliflower from eight sites with different climatic conditions in China were studied via the described analytical method. In addition, the acute toxicity test of 9.5 % suspension concentrate of broflanilide, broflanilide standard, DM-8007 and S (PFP-OH)-8007 were conducted to non-target terrestrial organisms. Risk assessment for human and non-target terrestrial organisms in cauliflower production was evaluated based on the maximum annual application rates and intervals. The results showed that the highest residue of broflanilide detected in cauliflower samples was all lower than the corresponding MRLs (2 mg/kg) in Japan. Chronic food dietary risk estimates for broflanilide do not exceed 50 % for all the Chinese population groups. Moreover, broflanilide is of low acute toxicity to birds and earthworm, while broflanilide and its metabolites is classified as highly toxic to adult honeybees. Acute risks of broflanilide to birds and earthworms were deemed to be acceptable in a realistic worst-case scenario, while its risk to adult honeybees and ladybug was unacceptable. A protection statement for honeybees and ladybug is required to recognize the high toxicity of broflanilide on related product labels. The study will be conducive to provide guidance for the rational application of broflanilide in cauliflower production.

Insecticidal potential and risk assessment of diamide pesticides against Spodoptera frugiperda in maize crops.

The effectiveness, tolerance, and safety of pesticides must be established before their scientific or rational. This study evaluates the field control efficacy of broflanilide, tetraniliprole, and chlorantraniliprole in combating Spodoptera frugiperda in maize crops, as well as the resistance of S. frugiperda to these three diamide pesticides after exposure. By assessing field control efficiency, toxicity, effects on development and reproduction, and detoxification enzyme activity of these diamide pesticides on S. frugiperda, highlights broflanilide's significant insecticidal potential. A highly sensitive and efficient method using QuEChERS/HPLCMS/MS was developed to simultaneously detect residues of these three pesticides on maize. Initial concentrations of broflanilide, tetraniliprole, and chlorantraniliprole ranged from 2.13 to 4.02 mg/kg, with their respective half-lives varying between 1.23 and 1.51 days. Following foliar application, by the time of harvest, the terminal residue concentrations of these pesticides were all under 0.01 mg/kg. Chronic dietary intake risk assessments and cumulative chronic dietary exposure for three pesticides indicated that the general population's terminal residue concentration was within acceptable limits. Not only does this research provide valuable insights into field control efficiency, insecticidal effects, resistance, residues, and risk assessment results of broflanilide, tetraniliprole, and chlorantraniliprole on maize, but additionally, it also paves the way for setting suitable Maximum Residue Limits (MRLs) values based on pre-harvest interval values, rational dosage, and application frequency.

Safety evaluation of single-sperm cryopreservation technique applied in intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) is a technique that directly injects a single sperm into the cytoplasm of mature oocytes. Here, we explored the safety of single-sperm cryopreservation applied in ICSI. This retrospective study enrolled 186 couples undergoing ICSI-assisted pregnancy. Subjects were allocated to the fresh sperm (group A)/single-sperm cryopreservation (group B) groups based on sperm type, with their clinical baseline/pathological data documented. We used ICSI-compliant sperm for subsequent in vitro fertilization and followed up on all subjects. The recovery rate/cryosurvival rate/sperm motility of both groups, the pregnancy/outcome of women receiving embryo transfer, and the delivery mode/neonatal-related information of women with successful deliveries were recorded. The clinical pregnancy rate, cumulative clinical pregnancy rate, abortion rate, ectopic pregnancy rate, premature delivery rate, live birth delivery rate, neonatal birth defect rate, and average birth weight were analyzed. The two groups showed no significant differences in age, body mass index, ovulation induction regimen, sex hormone [anti-Müllerian hormone (AMH)/follicle-stimulating hormone (FSH)/luteinizing hormone (LH)] levels, or oocyte retrieval cycles. The sperm recovery rate (51.72%-100.00%) and resuscitation rate (62.09% ± 16.67%) in group B were higher; the sperm motility in the two groups demonstrated no significant difference and met the ICSI requirements. Group B exhibited an increased fertilization rate, decreased abortion rate, and increased safety versus group A. Compared with fresh sperm, the application of single-sperm cryopreservation in ICSI sensibly improved the fertilization rate and reduced the abortion rate, showing higher safety.

Hepatitis A Virus Infection in Cynomolgus Monkeys Confounds the Safety Evaluation of a Drug Candidate.

In a 3-month toxicity study in cynomolgus monkeys at a European contract laboratory, animals were infected with HAV, initially resulting in hepatic injury being incorrectly attributed to the test compound. Elevated serum ALT/AST/GLDH (5- to 10-fold) were noted in individual animals from all groups including controls, with no apparent dose, exposure, or time-related relationship. Liver histopathology revealed minimal to slight inflammatory cell accumulation in periportal zones of most animals, and minimal to slight hepatocyte degeneration/necrosis in 10/42 animals from all groups. As these findings were more pronounced in 6 drug-treated animals, including 2/6 in the low dose group, the draft report concluded: "treatment-related hepatotoxicity at all dose levels precluded determination of a NOAEL." However, the unusual pattern of hepatotoxicity suggested a factor other than drug exposure might have caused the hepatic effects. Therefore, snap-frozen liver samples were tested for hepatitis viruses using a PCR method. Tests for hepatitis B, C, and E virus were negative; however, 20/42 samples were positive for hepatitis A virus (HAV). Infection was strongly associated with increased serum ALT/GLDH, and/or hepatocyte degeneration/necrosis. Re-evaluation of the study in light of these data concluded that the hepatic injury was not drug-related. A subsequent 6-month toxicology study in HAV-vaccinated cynomolgus monkeys confirmed the absence of hepatotoxicity. Identification of HAV infection supported progression of the drug candidate into later clinical trials. Although rarely investigated, subclinical HAV infection has occasionally been reported in laboratory primates, including those used for toxicology studies and it may be more prevalent than the literature indicates.

Safety Evaluation for Fabricated Small Box Girder Bridges Based on Fuzzy Analytic Hierarchy Process and Monitoring Data.

During the operation of fabricated small box girder bridges, which face safety issues such as structural degradation and failure, there is an urgent need to propose a safety evaluation method to cope with the possible risks. This article quantitatively evaluates the safety state of a fabricated small box girder bridge in Wuhan City based on Fuzzy Analytic Hierarchy Process (FAHP) and structural health monitoring (SHM) data. Firstly, the FAHP model is established, and stress, deformation, and temperature are selected as evaluation factors. The safety thresholds of stress and deformation are determined by combining the industry specifications and the historical statistical patterns of the massive SHM data. The temperature field of the bridge is simulated and analyzed by combining ANSYS, HYPERMESH, and TAITHREM, and the most unfavorable temperature gradient is determined as a threshold for the safety evaluation. Finally, the scores of indexes of the bridge are determined based on the measured SHM data, which in turn provides a quantitative description of the safety state. The results show that the thresholds determined by the joint industry specifications and the massive SHM data are reasonable; the temperature field simulation model established in this article is consistent with the measured results, and can accurately determine the temperature gradient of the bridge. The safety evaluation result from the FAHP model is the same as the field test results, which verifies the effectiveness and applicability of the proposed method to actual bridge projects.

Design and Implementation of a Two-Wheeled Vehicle Safe Driving Evaluation System.

The delivery market in Republic of Korea has experienced significant growth, leading to a surge in motorcycle-related accidents. However, there is a lack of comprehensive data collection systems for motorcycle safety management. This study focused on designing and implementing a foundational data collection system to monitor and evaluate motorcycle driving behavior. To achieve this, eleven risky behaviors were defined, identified using image-based, GIS-based, and inertial-sensor-based methods. A motorcycle-mounted sensing device was installed to assess driving, with drivers reviewing their patterns through an app and all data monitored via a web interface. The system was applied and tested using a testbed. This study is significant as it successfully conducted foundational data collection for motorcycle safety management and designed and implemented a system for monitoring and evaluation.

The Accomplishments of KoCVAM in the Development and Implementation of Alternative Methods in Korea.

The Korean Center for the Validation of Alternative Methods (KoCVAM), which promotes the Three Rs principles and the use of alternative methods in Korea, has been operating within the Toxicological Screening and Testing Division of the Ministry of Food and Drug Safety (MFDS) since 2009. KoCVAM has exchanged opinions and information on the development and validation of non-animal alternative test methods as part of the International Cooperation on Alternative Test Methods (ICATM), and provided input into draft OECD Test Guidelines (TGs). Several Korean laws (e.g. the Cosmetics Act) encourage the use of alternative test methods for chemical testing and assessment. To promote and support the use of alternative test methods in the country, KoCVAM has published information and provided training on the national guidelines, which are based on the OECD TGs. In addition, KoCVAM has held annual training workshops on alternative test methods, to help Korean research institutions (including GLP test facilities) to implement them. In addition, by helping to develop and validate alternative test methods that were adopted in OECD TG 442B, TG 492 and TG 439, KoCVAM has contributed to the enhanced competitiveness of Korean industry on the worldwide stage.

Advancing Adverse Drug Reaction Prediction with Deep Chemical Language Model for Drug Safety Evaluation.

The accurate prediction of adverse drug reactions (ADRs) is essential for comprehensive drug safety evaluation. Pre-trained deep chemical language models have emerged as powerful tools capable of automatically learning molecular structural features from large-scale datasets, showing promising capabilities for the downstream prediction of molecular properties. However, the performance of pre-trained chemical language models in predicting ADRs, especially idiosyncratic ADRs induced by marketed drugs, remains largely unexplored. In this study, we propose MoLFormer-XL, a pre-trained model for encoding molecular features from canonical SMILES, in conjunction with a CNN-based model to predict drug-induced QT interval prolongation (DIQT), drug-induced teratogenicity (DIT), and drug-induced rhabdomyolysis (DIR). Our results demonstrate that the proposed model outperforms conventional models applied in previous studies for predicting DIQT, DIT, and DIR. Notably, an analysis of the learned linear attention maps highlights amines, alcohol, ethers, and aromatic halogen compounds as strongly associated with the three types of ADRs. These findings hold promise for enhancing drug discovery pipelines and reducing the drug attrition rate due to safety concerns.

In Silico Safety Assessment of Bacillus Isolated from Polish Bee Pollen and Bee Bread as Novel Probiotic Candidates.

Bacillus species isolated from Polish bee pollen (BP) and bee bread (BB) were characterized for in silico probiotic and safety attributes. A probiogenomics approach was used, and in-depth genomic analysis was performed using a wide array of bioinformatics tools to investigate the presence of virulence and antibiotic resistance properties, mobile genetic elements, and secondary metabolites. Functional annotation and Carbohydrate-Active enZYmes (CAZYme) profiling revealed the presence of genes and a repertoire of probiotics properties promoting enzymes. The isolates BB10.1, BP20.15 (isolated from bee bread), and PY2.3 (isolated from bee pollen) genome mining revealed the presence of several genes encoding acid, heat, cold, and other stress tolerance mechanisms, adhesion proteins required to survive and colonize harsh gastrointestinal environments, enzymes involved in the metabolism of dietary molecules, antioxidant activity, and genes associated with the synthesis of vitamins. In addition, genes responsible for the production of biogenic amines (BAs) and D-/L-lactate, hemolytic activity, and other toxic compounds were also analyzed. Pan-genome analyses were performed with 180 Bacillus subtilis and 204 Bacillus velezensis genomes to mine for any novel genes present in the genomes of our isolates. Moreover, all three isolates also consisted of gene clusters encoding secondary metabolites.

Removal of ochratoxin A in wine by Cryptococcus albidus and safety assessment of degradation products.

BACKGROUND: Ochratoxin A (OTA) is a mycotoxin that contaminates grape-based products and is extremely harmful to the health of the host. It is effectively removed by yeast during the fermentation of wine, whereas the removal mechanism of OTA remains unclear. Therefore, the present study aimed to investigate the removal mechanism of ochratoxin A by yeast and to evaluate the safety of its degradation products. RESULTS: Cryptococcus albidus (20-G) with better effect on ochratoxin A (OTA) was screened out in the main fermentation stage of wine. The results showed that 20-G removed OTA through biosorption and biodegradation. Intracellular enzymes played the main role (18.44%) and yeast cell walls adsorbed a small amount of OTA (8.44%). Furthermore, the identification of proteins in 20-G revealed that the decrease in OTA content was mainly a result of the action of peroxidase, and validation tests were carried out. By analyzing the degradation products of OTA, OTα and phenylalanine with lower toxicity were obtained. Animal experiments showed that the intervention of yeast 20-G reduced the damage and adverse effects caused by OTA toxicity to the mice. CONCLUSION: The present study demonstrates the mechanism of OTA removal by 20-G and the toxicity of OTA was reduced by peroxidase in 20-G. © 2023 Society of Chemical Industry.

Recent advances in biosynthesis of mycotoxin-degrading enzymes and their applications in food and feed.

Mycotoxins are secondary metabolites produced by fungi in food and feed, which can cause serious health problems. Bioenzymatic degradation is gaining increasing popularity due to its high specificity, gentle degradation conditions, and environmental friendliness. We reviewed recently reported biosynthetic mycotoxin-degrading enzymes, traditional and novel expression systems, enzyme optimization strategies, food and feed applications, safety evaluation of both degrading enzymes and degradation products, and commercialization potentials. Special emphasis is given to the novel expression systems, advanced optimization strategies, and safety considerations for industrial use. Over ten types of recombinases such as oxidoreductase and hydrolase have been studied in the enzymatic hydrolysis of mycotoxins. Besides traditional expression system of Escherichia coli and yeasts, these enzymes can also be expressed in novel systems such as Bacillus subtilis and lactic acid bacteria. To meet the requirements of industrial applications in terms of degradation efficacy and stability, genetic engineering and computational tools are used to optimize enzymatic expression. Currently, registration and technical difficulties have restricted commercial application of mycotoxin-degrading enzymes. To overcome these obstacles, systematic safety evaluation of both biosynthetic enzymes and their degradation products, in-depth understanding of degradation mechanisms and a comprehensive evaluation of their impact on food and feed quality are urgently needed.

Recent progress in health effects and biosynthesis of lacto-N-tetraose, the most dominant core structure of human milk oligosaccharide.

Human milk oligosaccharides (HMOs), which are a group of complex carbohydrates highly abundant in human milk, have been recognized as critical functional biomolecules for infant health. Lacto-N-tetraose (LNT) is one of the most abundant HMO members and the most dominant core structure of HMO. The promising physiological effects of LNT have been well documented, including prebiotic property, antiadhesive antimicrobial activity, and antiviral effect. Its safety has been evaluated and it has been commercially added to infant formula as a functional ingredient. Because of great commercial importance of LNT, increasing attention has been paid to its highly efficient biological production. In particular, microbial synthesis based on metabolic engineering displays obvious advantages in large-scale production of LNT. This review contains important information about the recent progress in physiological effects, safety evaluation, and biosynthesis of LNT.

Assessing adverse events in clinical trials during the era of the COVID-19 pandemic.

Interpretation of safety data for clinical trials that were ongoing at the onset of the COVID-19 pandemic or were started subsequent to the beginning of the pandemic may be affected in a variety of ways. Pandemic-related issues can influence the extent of study participation and introduce data collection gaps. A SARS-CoV-2 infection among study subjects as a post-randomization event may introduce a number of confounding factors that can alter the frequency of adverse events, in some cases appearing as an increase in the frequency of an adverse event associated with a study drug relative to a comparator. The authors discuss clinical challenges and statistical concerns, specifically the estimand framework, including examples for consideration, to address these challenges in safety evaluation wrought by the COVID-19 pandemic. Our aim is to shed light on the importance of starting an early dialogue among the drug development team on the evaluation of safety, critical for benefit-risk evaluation throughout the drug development process.

From worst-case to reality - Case studies illustrating tiered refinement of consumer exposure to cosmetic ingredients.

Consumer exposure to cosmetic ingredients is estimated in a tiered manner. Simple Tier1 deterministic aggregate exposure modelling generates a worst case estimate of exposure. Tier1 assumes that a consumer uses all cosmetic products concomitantly daily, at maximum frequency, and products always contain the ingredient at the maximum allowed % w/w concentration. Refining exposure assessment from worst case to more realistic estimates uses evidence from surveys of actual use levels of ingredients and Tier2 probabilistic models, where distributions of consumer use data can be applied. In Tier2+ modelling, occurrence data provides evidence of products on the market actually containing the ingredient. Three case studies are presented using this tiered approach to illustrate progressive refinement. The scale of refinements from Tier1 to Tier2+ modelling for the ingredients, propyl paraben, benzoic acid and DMDM hydantoin were: 0.492 to 0.026; 1.93 to 0.042 and 1.61 to 0.027 mg/kg/day exposure dose. For propyl paraben, moving from Tier1 to Tier2+ represents a refinement from 49-fold to 3-fold overestimate of exposure when compared to a maximum estimate of 0.01 mg/kg/day exposure seen in human studies. Such refinements from worst case to realistic levels of exposure estimation can be critical in the demonstration of consumer safety.

Nonclinical safety evaluation of two vaccine candidates for herpes simplex virus type 2 to support combined administration in humans.

Herpes simplex virus type 2 (HSV-2) is the most common cause of genital disease worldwide. The development of an effective HSV-2 vaccine would significantly impact global health based on the psychological distress caused by genital herpes for some individuals, the risk transmitting the infection from mother to infant, and the elevated risk of acquiring HIV-1. Five nonclinical safety studies were conducted with the replication defective HSV529 vaccine, alone or adjuvanted with GLA-SE, and the G103 subunit vaccine containing GLA-SE. A biodistribution study was conducted in guinea pigs to evaluate distribution, persistence, and shedding of HSV529. A preliminary immunogenicity study was conducted in rabbits to demonstrate HSV529-specific humoral response and its enhancement by GLA-SE. Three repeated-dose toxicity studies, one in guinea pigs and two in rabbits, were conducted to assess systemic toxicity and local tolerance of HSV529, alone or adjuvanted with GLA-SE, or G103 containing GLA-SE. Data from these studies show that both vaccines are safe and well tolerated and support the ongoing HSV-2 clinical trial in which the two vaccine candidates will be given either sequentially or concomitantly to explore their potential synergistic and incremental effects.

Impacts of ovarian preservation on the prognosis of neuroendocrine cervical carcinoma: a retrospective analysis based on machine learning.

BACKGROUND: Neuroendocrine cervical carcinoma (NECC) is a rare but aggressive malignancy with younger patients compared to other common histology types. This study aimed to evaluate the impacts of ovarian preservation (OP) on the prognosis of NECC through machine learning. METHODS: Between 2013 and 2021, 116 NECC patients with a median age of 46 years received OP or bilateral salpingo-oophorectomy (BSO) and were enrolled in a retrospective analysis with a median follow-up of 41 months. The prognosis was estimated using Kaplan-Meier analysis. Random forest, LASSO, stepwise, and optimum subset prognostic models were constructed in training cohort (randomly selected 70 patients) and tested in 46 patients through receiver operator curves. Risk factors for ovarian metastasis were identified through univariate and multivariate regression analyses. All data processing was carried out in R 4.2.0 software. RESULTS: Among 116 patients, 30 (25.9%) received OP and showed no significantly different OS compared with BSO group (p = 0.072) and got better DFS (p = 0.038). After construction of machine learning models, the safety of OP was validated in lower prognostic risk group (p > 0.05). In patients ≤ 46 years, no impacts of OP were shown for DFS (p = 0.58) or OS (p = 0.67), and OP had no impact on DFS in different relapse risk population (p > 0.05). In BSO group, regression analyses showed that later stage, para-aortic LNM, and parametrial involvement were associated with ovarian metastasis (p < 0.05). CONCLUSIONS: Preserving ovaries had no significant impact on prognosis in patients with NECC. OP should be considered cautiously in patients with ovarian metastasis risk factors.

Dissipation and dietary exposure risk assessment of spinosad, thiocyclam, and its metabolite nereistoxin in cucumber and groundwater for different population groups.

A QuEChERS (quick, easy, cheap, effective, rugged, and safe) technique using ultrahigh-performance liquid chromatography with tandem mass spectrometry for the analysis of spinosad (spinosyn A + spinosyn D), thiocyclam, and nereistoxin in cucumber was developed with mean recoveries of 93-104%, relative standard deviations of ≤9%, and limits of quantification of 0.01 mg/kg. Field trials of spinosad and thiocyclam were performed in 12 representative cultivating areas in China. Field trial results indicate that spinosyn A and spinosyn D easily dissipated in cucumber with half-lives of 2.48-6.24 and <3 days, respectively. Nereistoxin was produced after thiocyclam application and was more persistent than its parent. The terminal residues of spinosad were all below the maximum residue limits (0.2 mg/kg) in China, whereas the terminal concentration of nereistoxin (calculated as the stoichiometric equivalent of thiocyclam), which was much higher than that of thiocyclam, was far beyond the maximum residue limits of thiocyclam in cucumber (0.01 mg/kg) established by the European Union. The predicted no-effect concentrations of spinosyn A, spinosyn D, thiocyclam, and nereistoxin leaching into groundwater were estimated using China-PEARL (Pesticide Emission Assessment at Regional and Local scales) models after application. However, the dietary (food and water) exposure risk quotient for different populations was below 1 with a preharvest interval set at 5 days after the last application, indicating that the application of spinosad and thiocyclam in cucumber was unlikely to pose unacceptable risk for human health. This study provides data for the safe use of spinosad and thiocyclam in cucumber ecosystem.

Biochemical and histopathological analysis after sub-chronic administration of oxyresveratrol in Wistar rats.

Oxyresveratrol (OXY) is a naturally occurring phenolic compound; however, there are no toxicity studies reported on its long term use. The aim of our work was to demonstrate the evaluation of acute and sub-chronic toxicity of oxyresveratrol in rats to assess its safety profile. To evaluate the LD50 value, 2000 mg/kg of oxyresveratrol was administered to Wistar rats by oral gavage. For sub-chronic toxicity assessment, 80 Wistar rats were randomly divided into four groups (10 animal/sex/group) and oxyresveratrol administered at a dose of 50, 100, 150 mg/kg/day by oral gavage. Bodyweight, food, and water consumption were monitored every week. At the end of the experiments, biochemical and hematological parameters were analyzed. Gross and microscopic organ analyses were also carried out. LD50 of oxyresveratrol was greater than 2000 mg/kg sub-chronic administration of oxyresveratrol did not influence any mortality. Doses of 50 and 100 mg/kg of oxyresveratrol did not produce any sign of toxicity. However, the 150 mg/kg oxyresveratrol group depicted changes in multiple biochemical and hematological parameters with changes in the pathology of cardiac, hepatic, and renal tissues when compared with control. Therefore, no observed adverse effect level (NOAEL) of oxyresveratrol was observed to be 100 mg/kg per day for both male and female rats.