Toxicological profiling of methanolic seed extract of Abutilon indicum (L.) Sweet: in-vitro and in-vivo analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Abutilon indicum, a shrub of the Malvaceae family, is found abundantly in tropical countries like India. A. indicum is widely used for its high medicinal properties. Traditionally, A. indicum seed powder is consumed to treat piles, constipation, chronic cystitis, gonorrhea, gleet, and pregnancy-related problems. Despite having numerous medicinal properties and widespread traditional use of A. indicum seeds, scientific validation, and toxicity studies have yet to be documented. AIMS OF THE STUDY: The primary objective of this study is to conduct a comprehensive study on phytochemical profiling, in-vitro cytotoxicity, mutagenicity, and in-vivo acute and sub-acute toxicity, and genotoxicity on animal models of methanolic extract of A. indicum seed (MAS). MATERIALS AND METHODS: The qualitative analysis of MAS was explored through FTIR and HR LC-MS. For in-vitro cytotoxicity, the HEK-293 cell line was used, and the TA100 (Staphylococcus typhimurium) bacterial strain was used for the Ames mutagenicity test. A single oral dose of 250, 500, 1000, or 2000 mg/kg body weight of MAS was given to each male and female rat for acute toxicity study and observed for 14 days for any toxicity signs. In the sub-acute toxicity study, 250, 500, or 1000 mg/kg body weight of MAS was administered orally to each rat for 28 days. The experimental animals were weighed weekly, and general behavior was monitored regularly. After 28 days of the experiment, the rats were sacrificed, and different serum biochemical, hematological, and histological analyses were performed. The blood samples of different doses of MAS were used for genotoxicity study through comet assay. RESULTS: FTIR analysis found different functional groups, which indicated the presence of phenolics, flavonoids, and alkaloids. HR LC-MS analysis depicts several components with different biological functions. The cell cytotoxicity and Ames mutagenicity results showed minimal toxicity and mutagenicity up to a certain dose. The acute toxicity study conducted in Wistar albino rats demonstrated zero mortality among the animals, and the LD50 value for seed extract was determined to be 2000 mg/kg body weight. Sub-acute toxicity assessments indicated that the administration of seed extract resulted in no adverse effects at dosages of 250 and 500 mg/kg body weight. However, at higher doses, specifically 1000 mg/kg body weight, the liver of the experimental rats exhibited some toxic effects. In the genotoxicity study, minimal DNA damage was found in 250 and 500 mg/kg doses, respectively, but slightly greater DNA damage was found in 1000 mg/kg doses in both male and female rats. CONCLUSIONS: The consumption of A. indicum seed powder is deemed safe; however, doses exceeding 500 mg/kg body weight may raise concerns regarding use. These findings pave the path for the creation of innovative medicines with improved efficacy and safety profiles.

(-)-Carvone Inhibits Oxytocin-induced Writhing Via Uterine Relaxation in Rodents.

(-)-Carvone, a ketone monoterpene, is the main component of essential oils from several medicinal plants and has been reported to have anti-arthriric, anticonvulsive, antidiabetic, anti-inflammatory, anticancer, and immunomodulatory effects. Therefore, this study aimed to investigate the spasmolytic activity of (-)-carvone in rodent models. The isolated virgin rat uterus was mounted in an organ bath apparatus, and the relaxing effect of ( -)-carvone and its mechanism of action were evaluated in tonic contractions induced by carbachol, KCl, PGF2α, or oxytocin. The animal model of primary dysmenorrhea was replicated with the injection of estradiol benzoate in female mice for three consecutive days, followed by intraperitoneal administration of oxytocin. Non-clinical acute toxicity evaluation was also performed. (-)-Carvone potency and effectiveness were larger in carbachol (pEC50 = 5.41 ± 0.14 and Emax = 92.63 ± 1.90% at 10-3 M) or oxytocin (pEC50 = 4.29 ± 0.17 and Emax = 86.69 ± 1.56% at 10-3 M) contractions. The effect of ( -)-carvone was altered in the presence of 4-aminopyridine, glibenclamide, L-NAME, or methylene blue. Mice pre-treated with (-)-carvone at a dose of 100 mg/kg showed a significant reduction in the number of writhing after oxytocin administration. No toxicity was observed after oral administration of 1 g/kg ( -)-carvone. Taken together, we showed that (-)-carvone reduced writhing by a spasmolytic effect, probably through the participation of KV and KATP channels and the nitric oxide pathway.

Chronic pain and accidental acute toxicity deaths in Canada, 2016-2017. / Recherche quantitative originale La douleur chronique et les décès par intoxication aiguë accidentelle au Canada, 2016-2017.

INTRODUCTION: Multiple Canadian jurisdictions have reported a pattern of chronic pain among people who died from substance-related acute toxicity. This study examined the prevalence and characteristics of those with chronic pain using data from a national study of people who died of accidental acute toxicity. METHODS: A cross-sectional analysis of accidental substance-related acute toxicity deaths that occurred in Canada between 1 January 2016 and 31 December 2017 was conducted. The prevalence of pain and pain-related conditions were summarized as counts and percentages of the overall sample. Subgroups of people with and without a documented history of chronic pain were compared across sociodemographic characteristics, health history, contextual factors and substances involved. RESULTS: From the overall sample (n = 7902), 1056 (13%) people had a history of chronic pain while 6366 (81%) had no documented history. Those with chronic pain tended to be older (40 years and older), unemployed, retired and/or receiving disability supports around the time of death. History of mental health conditions, trauma and surgery or injury was significantly more prevalent among people with chronic pain. Of the substances that most frequently contributed to death, opioids typically prescribed for pain (hydromorphone and oxycodone) were detected in toxicology more often among those with chronic pain than those without. CONCLUSION: Findings underscore the cross-cutting role of multiple comorbidities and unmanaged pain, which could compound the risk of acute toxicity death. Continued prioritization of harm reduction and regular patient engagement to assess ongoing needs are among the various opportunities for intervention.

A comparison of the characteristics of accidental substance-related acute toxicity deaths in Canada across life stages, 2016-2017. / Comparaison des caractéristiques des décès accidentels attribuables à une intoxication aiguë due à une substance au Canada aux différents stades de la vie, 2016-2017.

The acute toxicity (sometimes called "overdose" or "poisoning") crisis has affected Canadians across all stages of life, including youth, adults and older adults. Our biological risks and exposures to substances change as we age. Based on a national chart review study of coroner and medical examiner data on acute toxicity deaths in 2016 and 2017, this analysis compares the burden of deaths and circumstances of death, locations of acute toxicity event and death, health history and substances contributing to death of people, by sex and life stage.

This analysis reveals key differences in the characteristics of acute toxicity deaths by sex and life stage, and suggests potential intervention points for each group. Many people across demographics were alone while using substances before the acute toxicity event, and many were alone when they died. Youth, particularly female youth, more often died in circumstances where someone might have been available to help by calling 911 or administering first aid and naloxone. For the people who were in contact with health care prior to their death, about one-quarter (24%­28%) of adults and older adults sought assistance for reasons related to pain. Youth more often sought assistance for a nonfatal acute toxicity event (13%­14%) or for mental health (particularly female youth, 21%) than people in other life stages. Multiple substances contributed to most deaths, and both pharmaceutical and nonpharmaceutical substances were common causes of death for all life stages and sexes. There are demographic differences in the specific substances contributing to death.

Cette analyse présente les différences clés des caractéristiques des décès attribuables à une intoxication aiguë par sexe et stade de la vie, et propose des interventions possibles pour chaque groupe. Dans toutes les catégories démographiques, plusieurs personnes étaient seules au moment de consommer des substances avant l'intoxication aiguë, et plusieurs d'entre elles étaient seules au moment du décès. Les jeunes, et en particulier les jeunes femmes, sont décédées le plus souvent dans des circonstances où quelqu'un aurait pu être disponible pour aider en appelant le 911 ou en administrant les premiers soins et la naloxone. Parmi les personnes qui étaient en contact avec le système de santé avant leur décès, environ le quart (24 % à 28 %) des adultes et des aînés ont sollicité de l'aide pour des raisons liées à la douleur. Les jeunes ont plus souvent sollicité de l'aide pour une intoxication aiguë non mortelle (13 % à 14 %) ou pour des raisons liées à la santé mentale (en particulier les jeunes femmes, 21 %) que les personnes à d'autres stades de la vie. La polyconsommation de substances était en cause pour la plupart des décès, et les substances pharmaceutiques et non pharmaceutiques étaient toutes deux des causes courantes de décès pour tous les stades de la vie et les sexes. Il existe des différences démographiques en lien avec les substances spécifiques ayant contribué aux décès.

Safety evaluation of Indocalamus Iatifolius McClure leaves based on acute toxicity, harmful metals, and 9 organochlorine residue determination.

To investigate the safety of Indocalamu Iatifolius McClur leaves sold in the market, a study was conducted using Indocalamu Iatifolius McClur leaves randomly collected from an online store and a large supermarket. Acute toxicity experiments were performed on mice, and their body weight was monitored for 14 days after administration. After the observation period, blood samples were collected for biochemical analysis, and organ pathology was examined. Then, the content of copper (Cu), lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), and the residues of nine organochlorine pesticides in Indocalamu Iatifolius McClur leaves were measured according to the National Food Safety Standard (GB/T5009-2003) and the pesticide residue determination methods in the 2020 edition of the Chinese Pharmacopoeia. The results showed that the mice in the Indocalamu Iatifolius McClur leaves (online store) group experienced mortality and severe liver and lung damage. The levels of lead, cadmium, mercury, arsenic, and the nine organochlorine pesticides met the relevant standards and regulations. However, the copper content in the Indocalamu Iatifolius McClur leaves (online store) group was nearly 80 times higher than that in the supermarket group. Mice in the Indocalamu Iatifolius McClur leaves (supermarket) group remained healthy without any abnormalities, and the levels of harmful metals and organochlorine pesticides complied with the standards and regulations. The study suggests the need for regulatory policies and safety standards for the sale of Indocalamu Iatifolius McClur leaves.

Comparative Acute Toxicity Studies of Chlorpyrifos Technical Grade with its Emulsifiable Concentrate (20% EC) on Labeo rohita, a Freshwater Major Carp, and Mystus vittatus, a Freshwater Catfish.

Chlorpyrifos is widely used across the world as an organophosphate insecticide and frequently contaminates freshwater bodies through runoff from agricultural fields. In the laboratory, static bioassays were undertaken to examine differences in acute toxicity caused by exposure to the technical grade (94% a.i.) and an emulsifiable concentrate (20% EC) of chlorpyrifos to two species of freshwater fish, Labeo rohita and Mystus vittatus. The recovery of actual chlorpyrifos concentrations varied from 83% (technical grade, T) to 89% (emulsifiable concentrate, F) after two hours in water. The susceptibilities of the two fish species to the two types of chlorpyrifos varied. The 96-h LC50 values for T and F chlorpyrifos in L. rohita were 68 and 36 µg/L, respectively, and 120 and 62 µg/L in M. vittatus, respectively. As the exposure period was extended, the LC50 values gradually decreased. LC50 values between the technical grade and formulation were compared following the criteria of Mayer et al. (1986), Schmuck et al. (1994), APHA (1995), and Demetrio et al. (2014). It was concluded from the study that the emulsifiable concentrate (20% EC) of chlorpyrifos was more toxic than technical-grade chlorpyrifos.

Synthesis of glucosamine-selenium compound and evaluation of its oral toxicity and in vitro anti-hepatitis B virus activity.

Selenium supplements are beneficial to human health, however, concerns regarding the toxicity of inorganic selenium have stimulated research on safer organic compounds. The main objective of this study was to develop a novel glucosamine-selenium compound (Se-GlcN), clarify its structure, and subsequently investigate its oral toxicity and in vitro anti-hepatitis B virus (HBV) activity. Electron microscopy, infrared, ultraviolet spectroscopy, nuclear magnetic resonance and thermogravimetric analyses revealed a unique binding mode of Se-GlcN, with the introduction of the Se-O bond at the C6 position, resulting in the formation of two carboxyl groups. In acute toxicity studies, the median lethal dose (LD50) of Se-GlcN in ICR mice was 92.31 mg/kg body weight (BW), with a 95 % confidence interval of 81.88-104.07 mg/kg BW. A 30-day subchronic toxicity study showed that 46.16 mg/kg BW Se-GlcN caused livers and kidneys damage in mice, whereas doses of 9.23 mg/kg BW and lower were safe for the livers and kidneys. In vitro studies, Se-GlcN at 1.25 µg/mL exhibited good anti-HBV activity, significantly reducing HBsAg, HBeAg, 3.5 kb HBV RNA and total HBV RNA by 45 %, 54 %, 84 %, 87 %, respectively. In conclusion, the Se-GlcN synthesized in this study provides potential possibilities and theoretical references for its use as an organic selenium supplement.

Acute toxicity of Deoxynivalenol and Bioremediation of a highly effective Deoxynivalenol degrading Achromobacter spanius P-9 on Zebrafish Embryos and Adults.

Deoxynivalenol (DON) is one of the mostly concerned mycotoxins and several microbes showed bioremediation effects on DON toxic effects. In this study, the acute toxicity of a new DON degrading strain Achromobacter spanius P-9 with DON on zebrafish embryos and adults were firstly performed. For zebrafish embryos, bacterial concentrations of 2.5×107 CFU/mL and 5.0×107 CFU/mL had no significant effects on growth and development. However, at 7.5×107 CFU/mL, some effects were observed, and at 10.0×107 CFU/mL, the embryo survival rate decreased to 70%, with 3.3% teratogenicity. Higher bacterial concentrations correlated with faster heart rates. DON (100 µg/mL) significantly reduced embryo survival to 36.7% in 96 hours. Bacterial solutions at 7.5×107 CFU/mL and 10.0×107 CFU/mL expanded the zebrafish intestinal tissue wall, while DON at 100 µg/mL negatively impacted intestinal morphology. Liver tissue in zebrafish exposed to Achromobacter spanius P-9 showed no significant differences from the control group. However, exposure to DON solution increased liver fluorescence intensity and caused liver cell changes, including edema, vacuolization, and blurred boundaries. For adult zebrafish, the ROS and 8-OHdG contents in the exposure group increased with the increase of bacterial solution concentration, the SOD enzyme activity, CAT enzyme activity, GST enzyme activity and MDA was not significantly different with the control group. Compared with the control group, the content of ROS, GST enzyme activity, MDA and 8-OHdG after DON treatment showed an upward trend, SOD and CAT enzyme activities showed a decreasing trend. Achromobacter spanius P-9 has no obvious inhibitory effect on the growth and development of zebrafish embryos and has no obvious death and toxicity during the growth of adult fish, providing data support for the future application of this strain in the biodegradation of DON.

Safety evaluation of aqueous extract from Valeriana officinalis L. roots: Genotoxicity, acute, subchronic and teratology toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Valeriana officinalis L., commonly known as "valerian", is a traditional herbal medicine distributed in the north temperate zones of America, Europe and Asia. In traditional Chinese medicine, valerian and its roots were used for the treatment of restlessness of the heart and mind, palpitation and insomnia caused by internal depression of emotions and moods. However, safety evaluation of valerian remains deeply unclear. AIM OF THE STUDY: This study aimed to evaluate the genotoxicity, 14-days acute oral toxicity test, 90-day subchronic oral toxicity test and teratogenicity test of aqueous extract of valerian root (AEVR). MATERIALS AND METHODS: The genotoxicity of AEVR was evaluated with bacterial reverse mutation, mouse erythrocyte micronucleus test and in vitro mammalian cell chromosome aberration test. In the 14-days acute toxicity study, Kunming mice were administered at a dosage of 96 g/kg body weigh by gavage. In the 90-day subchronic toxicity study, Sprague-Dawley rats received oral doses of 0, 3.5, 7 and 14 g/kg body weight of AEVR. In the teratogenicity study, pregnant Sprague-Dawley rats received a dose of 0, 3.5, 7 and 14 g/kg body weight of AEVR. RESULTS: AEVR did not show any genotoxicity based on the bacterial reverse mutation, mouse erythrocyte micronucleus test and in vitro mammalian cell chromosome aberration test. In the acute toxicity study, AEVR at a dose of 96 g/kg body weight did not cause death or abnormal behavior in male or female mice. In the subchronic toxicity study, at the doses of 0, 3.5, 7, 14 g/kg body weight, no dose-related effects on clinical observation, body weight, organ weight, hematology, serum biochemistry and urinalysis of AEVR were detected in male or female rats. Teratogenicity test shown that there were no significant toxicologically changes in embryonic formation, body weight of pregnant rats, external, skeletal and visceral examination observed in pregnant and fetal rats at the dosage of 0, 3.5, 7, 14 g/kg body weight. CONCLUSION: In vivo or in vitro assays demonstrated that AEVR does not exhibit genotoxicity. The LD50 of AEVR was greater than 96 g/kg body weight in both sex of mice according to acute oral toxicity study. Subchronic toxicity and teratogenicity tests showed that the no observed adverse effect level (NOAEL) of AEVR was no less than 14 g/kg body weight. This study established a non-toxic dose of AEVR, providing a foundation for the use of valerian as a new resource food in some countries and regions.

Study on the acute and subchronic oral toxicity of Calculus Bovis Sativus in rats.

This study aims to assess the acute and subchronic toxicity of Calculus Bovis Sativus (CBS), which is an ideal substitute for natural Calculus Bovis. After conducting a test of acute toxicity with KM mice of both sexes, it was determined that oral CBS had a lethal dosage (LD50) of greater than 9.26 g/kg BW. For ninety days, Wistar rats were fed on CBS orally at dosages of 0, 167, 501, and 1503 mg/kg BW/day, respectively, as part of the subchronic investigation. A comparison of the controls with the 1503 mg/kg and 501 mg/kg dosage groups revealed significant differences in the hematological and serum biochemical parameters, such as RBC, HGB, MONO%, PLT, LYMPH% and GLU, TP, ALB, and Ca2+, were observed. However, values of the above parameters fell within our laboratory's normal range. In terms of body weight, food intake, urinalysis, clinical chemistry, and pathology, no other adverse effects were observed. After 90 days of exposure, the no observed adverse effect level (NOAEL) of CBS in rats was determined to be 1503 mg/kg BW/day.

Flusilazole induced developmental toxicity, neurotoxicity, and cardiovascular toxicity via apoptosis and oxidative stress in zebrafish.

Flusilazole is a well-known triazole fungicide applied to various crops and fruits worldwide. Flusilazole residues are frequently detected in the environment, and many researchers have reported the hazardous effects of flusilazole on non-target organisms; however, the developmental toxicity of flusilazole has not been fully elucidated. In this study, we investigated flusilazole-induced developmental defects in zebrafish, which are used in toxicology studies to assess the toxic effects of chemicals on aquatic species or vertebrates. We confirmed that flusilazole exposure affected the viability and hatching rate of zebrafish larvae, and resulted in morphological defects, reduced body length, diminished eye and head sizes, and inflated pericardial edema. Apoptosis, oxidative stress, and inflammation were also observed. These factors interrupted the normal organ formation during early developmental stages, and transgenic models were used to identify organ defects. We confirmed the effects of flusilazole on the nervous system using olig2:dsRed transgenic zebrafish, and on the cardiovascular system using cmlc2:dsRed and fli1:eGFP transgenic zebrafish. Our results demonstrate the developmental toxicity of flusilazole and its mechanisms in zebrafish as well as the detrimental effects of flusilazole.

Acute exposure to environmentally relevant concentrations of pharmaceutical pollutants induces neurobehavioral toxicity in zebrafish (Danio rerio).

Pharmaceutical waste from point and non-point sources enters, persists, or disseminates in the environment and is known as environmentally persistent pharmaceutical pollutants. Understanding the impacts of pharmaceutical pollutants on the environment and health is essential. This study investigates the behavioral impacts of pharmaceutical pollutants on aquatic organisms and delineates the possible nexus of oxidative stress. The male zebrafish were exposed to four major representative pharmaceutical pollutants, viz., acetaminophen, carbamazepine, metformin, and trimethoprim at environmentally relevant concentrations individually as well as in a mixture for seven days. Substantial alterations in social interaction, aggressive nature, novel tank exploration, and light and dark zone preferences were recorded and the degree varied to different pharmaceutical pollutants. The activity of oxidative stress markers, superoxide dismutase, glutathione-S-transferase, and catalase, was found to be suppressed to 66-20%, 42-25%, and 59-20% respectively with the elevated malondialdehyde generation (180-260%) compared to control. The activity level of acetylcholine esterase was found to be increased to 200-500% across all treatment groups. Despite the synergistic impacts of pharmaceutical pollutants on the whole system that could not be ascertained, this comprehensive study highlights their toxicity nature to induce neurobehavioral toxicity in zebrafish through oxidative stress mechanisms and altered cholinergic systems.

Ecotoxicity Assessment of α-Amino Acid-Derived Polyamidoamines Using Zebrafish as a Vertebrate Model.

The aquatic ecotoxicity of three α-amino acid-derived polyamidoamines (PAAs) was studied using zebrafish embryos as a viable vertebrate model organism. The PAAs examined were water-soluble amphoteric polyelectrolytes with a primarily negative charge, which were efficient flame retardants for cotton. The fish embryo acute toxicity test performed with PAA water solutions using 1.5-500 mg L-1 concentrations showed that toxicity did not statistically differ from the control. The survival rates were indeed >90%, even at the highest concentration; the hatching rates were >80%; and the numbers of morphological defects were comparable to those of the control. Tests using transgenic zebrafish lines indicated that the numbers of microscopic vascular and musculoskeletal defects were comparable to the control, with one random concentration showing doubled alterations. Sensory-motor tests in response to visual and tactile stimuli were also performed. In the presence of PAAs, embryos exposed to alternating light/dark cycles showed an insignificant mobility reduction during the dark phase. Touch-evoked response tests revealed a mild effect of PAAs on the neuromotor system at concentrations > 10 mg L-1. The cystine/glycine copolymer at 100 mg L-1 exhibited the greatest effect. Overall, the studied PAAs showed a minimal impact on aquatic systems and should be further considered as promising ecofriendly materials.

Development, Characterization, and Evaluation of Potential Systemic Toxicity of a Novel Oral Melatonin Formulation.

The need to create safe materials for biomedical and pharmaceutical applications has become a significant driving force for the development of new systems. Therefore, a chitosan-coated copolymer of itaconic acid, acrylic acid, and N-vinyl caprolactam (IT-AA-NVC) was prepared by radical polymerization and subsequent coating via nanoprecipitation to give a system capable of sustained delivery of melatonin. Although melatonin brings undoubted benefits to the human body, aspects of the optimal dose, route, and time of administration for the obtaining of suitable treatment outcomes remain under discussion. The entrapment of melatonin in biocompatible polymeric systems can prevent its oxidation, decrease its toxicity, and provide an increased half-life, resulting in an enhanced pharmacokinetic profile with improved patient compliance. The structures of the biopolymer and conjugate were proven by FTIR, thermal properties were tested by DSC, and the morphologies were followed by SEM. The loading efficiency and in vitro release profile were studied by means of HPLC, and a delayed release profile with an initial burst was obtained. The potential systemic toxicity of the formulation was studied in vivo; a mild hepatotoxicity was observed following administration of the melatonin-loaded formulation to mice, both by histopathology and blood clinical biochemistry. Histopathology showed a mild nephrotoxicity as well; however, kidney clinical biochemistry did not support this.

Size- and shape-dependent ingestion and acute toxicity of fragmented and spherical microplastics in the absence and presence of prey on two marine zooplankton.

As microplastics (MPs) are particulate pollutants, their size and shape, and the presence of prey in the media can affect their toxicity. However, the size- and shape-dependent toxicities of MPs and their prey-dependent ingestion patterns in marine zooplankton are not well understood. Thus, we investigated the ingestion and egestion patterns, and toxicity of different shapes and sizes of MPs on two marine zooplankton, Brachionus koreanus and Diaphanosoma celebensis, under different prey conditions. The ingestion assay showed that smaller MPs were ingested more frequently, regardless of their shape. However, fragmented MPs showed higher toxicity than spherical MPs of comparable size. Prey in the media reduced the uptake and toxicity of MPs in both species depending on the taxa's feeding strategy. Our findings demonstrate that the size and shape of MPs are important factors in determining toxicity and that the presence of prey should also be considered when assessing MP toxicity.

Ecotoxicity and environmental safety assessment of two-dimensional niobium carbides (MXenes).

Two-dimensional (2D) MXenes have gained great interest in water treatment, biomedical, and environmental applications. The antimicrobial activity and cell toxicity of several MXenes including Nb4C3Tx and Nb2CTx have already been explored. However, potential side effects related to Nb-MXene toxicity, especially on aquatic pneuma, have rarely been studied. Using zebrafish embryos, we investigated and compared the potential acute toxicity between two forms of Nb-MXene: the multilayer (ML-Nb4C3Tx, ML-Nb2CTx) and the delaminated (DL-Nb2CTx, and DL-Nb4C3Tx) Nb-MXene. The LC50 of ML-Nb4C3Tx, ML-Nb2CTx, DL-Nb2CTx, and DL-Nb4C3Tx were estimated to be 220, 215, 225, and 128 mg/L, respectively. Although DL-Nb2CTx, and DL-Nb4C3Tx derivatives have similar sizes, DL-Nb4C3Tx not only shows the higher mortality (LC50 = 128 mg/L Vs 225 mg/L), but also the highest teratogenic effect (NOEC = 100 mg/L Vs 200 mg/L). LDH release assay suggested more cell membrane damage and a higher superoxide anion production in DL-Nb4C3Tx than DL-Nb2CTx,. Interestingly, both DL-Nb-MXene nanosheets showed insignificant cardiac, hepatic, or behavioral toxic effects compared to the negative control. Embryos treated with the NOEC of DL-Nb2CTx presented hyperlocomotion, while embryos treated with the NOEC of DL-Nb4C3Tx presented hyperlocomotion, suggesting developmental neurotoxic effect and muscle impairment induced by both DL-Nb-MXene. According to the Fish and Wildlife Service (FSW) Acute Toxicity Rating Scale, all tested Nb-MXene nanosheets were classified as "Practically not toxic". However, DL-Nb4C3Tx should be treated with caution as it might cause a neurotoxic effect on fauna when it ends up in wastewater in high concentrations.

Spread-out Bragg peak FLASH: quantifying normal tissue toxicity in a murine model.

Objective: A favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model. Material/Methods: Radiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment. Results: Comparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4). Conclusion: Full dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development.

Bioaccumulation mediated by water solubility leads to differences in the acute toxicity of organophosphorus insecticides to zebrafish (Danio rerio).

The use of some organophosphate insecticides is restricted or even banned in paddy fields due to their high toxicity to aquatic organisms. The aim of this study is to elucidate the main pathways and target organs of organophosphate insecticide toxicity to fish exposed via different routes by integrating histopathological and biochemical techniques. Using malathion as the model drug, when the dosage is 20-60 mg/L, the toxicity of whole body and head immersion drugs to zebrafish is much higher than that of trunk immersion drugs. A dose of 21.06-190.44 mg/kg of malathion feed was fed to adult zebrafish. Although the dosage was already high, no obvious toxicity was observed. Therefore, we believe that the drug mainly enters the fish body through the gills. When exposed to a drug solution of 20 mg/L and 60 mg/L, the fish showed significant neurological behavioral abnormalities, and the pathological damage to key organs and brain tissue was the most severe, showing obvious vacuolization and the highest residual amount (8.72-47.78 mg/L). The activity of acetylcholinesterase was the most inhibited (54.69-74.68%). Therefore, brain tissue is the key toxic target organ of malathion in fish. In addition, we compared the bioaccumulation effects of different water-soluble organophosphorus insecticides in fish and their toxic effects. We found that the higher the water solubility of organophosphorus insecticides, the lower their toxicity to fish.

Novel herbicide flusulfinam: absolute configuration, enantioseparation, enantioselective bioactivity, toxicity and degradation in paddy soils.

BACKGROUND: Flusulfinam, a novel chiral herbicide, effectively controls Echinochloa crusgalli and Digitaria sanguinalis in paddy fields, indicating significant potential for practical agricultural applications. However, limited information is available on flusulfinam from a chiral perspective. A comprehensive evaluation of the enantiomeric levels of flusulfinam was performed. RESULTS: Two enantiomers, R-(+)- and S-(-)-flusulfinam, were separately eluted using a Chiralcel OX-RH column. The bioactivity of R-flusulfinam against the two was 1.4-3.1 fold that of Rac-flusulfinam against two weed species. R-flusulfinam toxicity to Danio rerio larvae and Selenastrum capricornutumwere was 0.8- and 3.0-fold higher than Rac-flusulfinam, respectively. Degradation experiments were conducted using soil samples from four Chinese provinces. The findings indicated that S-flusulfinam (half-life T1/2 = 40.8 days) exhibits preferential degradation than R-flusulfinam (T1/2 = 46.2-57.8 days) in the soils of three provinces. Under anaerobic conditions, soil from Anhui exhibited preferential degradation of R-flusulfinam (T1/2 = 46.2 days) over S-flusulfinam (T1/2 = 63 days). Furthermore, two hydrolysis products of flusulfinam (M299 and M100) are proposed for the first time. CONCLUSION: The enantioselective bioactivity, toxicity and degradation of flusulfinam were investigated. Our findings indicate that R-flusulfinam is an extremely effective and low-toxicity enantiomer for the tested species. The soil degradation test indicated that the degradation of flusulfinam was accelerated by higher organic matter content and lower soil pH. Furthermore, microbial communities may play a crucial role in driving the enantioselective degradation processes. This study lays the groundwork for the systematic evaluation of flusulfinam from an enantiomeric perspective. © 2024 Society of Chemical Industry.

The Agonistic Activity of the Human Epidermal Growth Factor is Reduced by the D46G Substitution.

BACKGROUND: Resistance to anti-tumor agents targeting the epidermal growth factor receptor (EGFR) reduces treatment response and requires the development of novel EGFR antagonists. Mutant epidermal growth factor (EGF) forms with reduced agonistic activity could be promising agents in cancer treatment. METHODS: EGF D46G affinity to EGFR domain III was assessed with affinity chromatography. EGF D46G acute toxicity in Af albino mice at 320 and 3200 µg/kg subcutaneous doses was evaluated. EGF D46G activity in human epidermoid carcinoma cells at 10 ng/mL concentration in serum-free medium and in subcutaneous Ehrlich ascites carcinoma mice model at 320 µg/kg dose was studied. RESULTS: The D46G substitution decreases the thermal stability of EGF complexes with EGFR domain III by decreasing the ability of the C-terminus to be released from the intermolecular ß- sheet. However, with remaining binding sites for EGFR domain I, EGF D46G effectively competes with other EGF-like growth factors for binding to EGFR and does not demonstrate toxic effects in mice. EGF D46G inhibits the proliferation of human epidermoid carcinoma cells compared to native EGF. A single subcutaneous administration of EGF D46G along with Ehrlich carcinoma cells injection inhibits the proliferation of these cells and delays tumor formation for up to seven days. CONCLUSION: EGF D46G can be defined as a partial EGFR agonist as this mutant form demonstrates reduced agonistic activity compared to native EGF. The study emphasizes the role of the EGF C-terminus in establishing interactions with EGFR domain III, which are necessary for EGFR activation and subsequent proliferation of cells.