Can next generation ecological risk assessment decisions be made today?-A case study of regulatory risk assessment in the United States.

We examined the need for new in vivo avian toxicity testing for three common industrial chemicals (1,2 dichloropropane, 1,1,2-trichloroethane and triphenyl phosphate) based on estimated avian exposures using fugacity and multimedia fate models for current conditions of use compared to hazard information including existing in vivo test data for the chemicals and analogs, interspecies correlation estimates and results from hundreds of acute avian dietary toxicity studies. The data indicated that acute avian toxicity is not likely to be observed below 10 ppm in the diet for any chemical with the exception of those with a specific mode of toxic action. Modeling indicated low exposure potential for terrestrial birds to any of the three chemicals, with estimated dietary concentration of less than 0.001 ppm. Despite uncertainty associated with the underlying data sources, the four order of magnitude gap between potential exposure and a minimum hazard threshold suggests that additional avian in vivo testing would not generate valuable data. However, a weight of evidence approach for integrating data is necessary to engender greater confidence among government decision-makers in cases where data from a particular in vivo study is not expected to improve risk decision-making and an existing data gap can remain unfilled.

Bio distribution and acute toxicity profiling of Pluronic F127 coated Titanium dioxide nanotubes in adult Wistar rats.

Metal and metal oxide nanoparticles are gaining immense attention among researchers owing to their admirable application potentials in various therapeutic events. Titanium dioxide (TiO2) has been recognized as one of the leading candidates in this category and holds wide interest within the scientific community. Among the various morphological nanoforms of TiO2, nanotube is grabbing remarkable attention as they have succeeded as an active vehicle in various medical procedures like intravascular stenting, drug delivery, as biosensors etc. This ultimately demands toxicity profiling of nanotubes in various aspects. Present study elaborates a concept through which acute toxicity profiling of TiO2 nanotubes in adult Wistar rats is presented. TNTs were synthesized via solvo-thermal approach and surface coated with a biocompatible polymer; Pluronic-F127 (P-F127). This step assists in ameliorating the troubles associated with the nanomaterial dispersion stability. The experimental rats were intraperitoneally administered with TNT-P (10 mg/kg) and sacrificed on different time periods (3rd, 7th and 14th days). Biodistribution of the material was tracked in major tissues including brain, liver, spleen and kidneys. A set of acute toxicity studies was performed which comprises hematology evaluation, biochemical studies, antioxidant detection, analysis of urine parameters, immune modulation study and histopathology evaluation. Many of the experiments revealed an unaltered physiological response in rats; except for some biochemical and hematology parameters. Overall study suggests that, TNT-P do not result into a negative response in Wistar rats over 14 days.

The Safety Assessment of Mutagenicity, Acute and Chronic Toxicity of the Litsea martabanica (Kurz) Hook.f. Water Leaf Extract.

Litsea martabanica (Kurz) Hook.f. has traditionally been used as an anti-insecticidal agent and as a medication due to its hepatoprotective properties by highland communities in Thailand. This study examined the mutagenicity, as well as the acute and chronic toxicity, of the L. martabanica water leaf extract in Sprague-Dawley rats. The pharmacognostic evaluation of L. martabanica was performed in this study to ensure its authenticity and purity. Then, the sample was extracted using decoction with water to obtain the crude water extract. The assessment of acute toxicity involved a single oral administration of 5000 mg/kg, whereas the chronic toxicity assessment comprised daily oral doses of 250, 750, and 2250 mg/kg over 270 days. Various physiological and behavioral parameters, as well as body and organ weights, were systematically monitored. The endpoint assessments involved hematological and biochemical analyses plus gross and histopathological assessments of the internal organs. Our results exhibited no mutagenic activation by the L. martabanica water leaf extract in the Ames test, and no acute toxicity was observed. In the chronic toxicity tests, no abnormalities were found in rats receiving the L. martabanica water leaf extract across multiple measures, comprising behavioral, physiological, and hematological indices. Crucially, the histopathological assessment corroborated previous studies, reporting an absence of any tissue abnormalities. The results revealed that the L. martabanica water leaf extract had no adverse effects on rats over 270 days of oral administration. This demonstrates its safety and crucial scientific evidence for informing public policy and enabling its potential future commercial use in both highland and lowland communities.

Comparison of perioperative and subacute postoperative complications between LDR and HDR monotherapy brachytherapy for prostate cancer.

PURPOSE: We aim to investigate perioperative and subacute postoperative complications in patients undergoing LDR or HDR monotherapy for prostate cancer. We hypothesize a low rate of complications, and a favorable toxicity profile in patients treated with HDR compared to LDR. MATERIALS AND METHODS: A prospectively collected institutional database was queried for patients treated with HDR or LDR prostate monotherapy between 1998 and 2021. Toxicities were determined per CTCAE. Claims based billing codes were obtained to identify additional events. Events occurring within 4 months of treatment were defined as perioperative or subacute postoperative complications. RESULTS: 759 patients were identified, 446 received LDR with 125I, and 313 received HDR with 192Ir. HDR patients had higher risk features: 75.7% with Gleason score 7+ versus 2.4% of LDR, and 16% with initial PSA 10+ ng/mL versus 2.7% of LDR. Toxicities were mild with the most common being grade 1 GU frequency and nocturia at ∼50%. HDR patients had significantly less grade 2 dysuria (2.6% vs. 9.0%), frequency (4.8% vs. 9.4%), hematuria (1.0% vs. 5.2%), nocturia (3.8% vs. 9.4%), and urinary obstructive symptoms (7.3% vs. 11.2%), all statistically significant. 11 (1.4%) patients had infection requiring antibiotics: 8 (1.8%) from the LDR group and 3 (1%) from the HDR group. Cardiopulmonary events were low at <2% overall, without difference between HDR and LDR. CONCLUSIONS: Overall toxicity rates support the safety of prostate brachytherapy. HDR monotherapy is associated with significantly less perioperative and subacute postoperative GU events when compared to LDR monotherapy. Cardiopulmonary events were equally rare in both groups.

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.

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.

HT_PREDICT: a machine learning-based computational open-source tool for screening HDAC6 inhibitors.

Histone deacetylase 6 (HDAC6) is a promising drug target for the treatment of human diseases such as cancer, neurodegenerative diseases (in particular, Alzheimer's disease), and multiple sclerosis. Considerable attention is paid to the development of selective non-toxic HDAC6 inhibitors. To this end, we successfully form a set of 3854 compounds and proposed adequate regression QSAR models for HDAC6 inhibitors. The models have been developed using the PubChem, Klekota-Roth, 2D atom pair fingerprints, and RDkit descriptors and the gradient boosting, support vector machines, neural network, and k-nearest neighbours methods. The models are integrated into the developed HT_PREDICT application, which is freely available at https://htpredict.streamlit.app/. In vitro studies have confirmed the predictive ability of the proposed QSAR models integrated into the HT_PREDICT web application. In addition, the virtual screening performed with the HT_PREDICT web application allowed us to propose two promising inhibitors for further investigations.

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.

E-peroxone with a novel GDE decorated with hydrophobic membrane for the degradation of pyridine: Stability, byproducts and toxicity.

E-peroxone process is an emerging electrochemical oxidation process, based on ozone and the in-situ cathodic generation of H2O2, but the stability of cathode is one of the key restraining factors. In this study, we designed a multilayer gas diffusion electrode (GDE) decorated with a commercial hydrophobic membrane for the degradation of pyridine. It was found that a proper control of membrane pore sizes and hot-pressing temperature can significantly promote the GDE stability. Subsequently, key operational parameters of the constructed E-peroxone system were investigated, including the ozone concentration, current density, pH value, electrolyte type and initial concentration of pyridine. The degradation pathways were proposed according to six identified transformation products. The toxicity variation along the degradation progress was evaluated with microbial respiration tests and Toxicity Estimation Software Tool (T.E.S.T.) calculation and an efficient detoxification capacity of E-peroxone was observed. This research provides a theoretical basis and technical support for the development of highly efficient and stable E-peroxone system for the elimination of toxic organic contaminants.

Acute toxicity profiling of medicinal herb Ardisia elliptica leaf extract by conventional evaluations and proton nuclear magnetic resonance (NMR) metabolomics.

Background and aim: Interest in the safety of herbal medicine is growing rapidly regarding knowledge and challenges in natural products. Hence, this study aimed to reveal the toxicological profile of Ardisia elliptica, a traditional medicinal plant used in the treatment of various illnesses. Experimental procedure: Acute toxicity study was performed on female and male Sprague Dawley rats with a single oral administration of 2000 mg/kg BW of 70% ethanolic A. elliptica leaf extract, using a combination of conventional investigations and 1H-NMR-based metabolomics approaches. Results: Physical, hematological, biochemical, and histopathological assessments demonstrated the usual rat profile, with no mortality and delayed toxicity 14 days after administration. 1H NMR serum metabolomics depicted similar metabolites between normal and treated groups. Nevertheless, 1H NMR of urinary metabolomics revealed perturbation in carbohydrate, amino acid, and energy metabolism within 24h after extract administration, while no accumulation of toxic biomarkers in the collected biological fluids on Day 14. A minor gender-based difference revealed the influence of sex hormones and different energy expenditure on response to extract treatment. Conclusion: This study suggested that 2000 mg/kg BW of 70% ethanolic A. elliptica leaf extract is considered as safe for consumption and offered a comprehensive overview of the response of physiological and metabolic aspects applicable to food and herbal product development.

Pharmacological evaluation of anti-inflammatory, antipyretic, analgesic, and antioxidant activities of Castanopsis costata leaf fractions (water, ethyl acetate, and n-hexane fractions): the potential medicinal plants from North Sumatra, Indonesia.

Background and purpose: Inflammation, fever, and pain can be associated with several diseases, and the synthetic drugs used in the treatment of these conditions often have severe side effects. As a result, there is a need for effective, economical, and safe alternative drugs, such as those derived from medicinal plants. Therefore, this study aimed to evaluate the anti-inflammatory, antipyretic, analgesic, and antioxidant activities of Castanopsis costata leaf fractions (CcLF), as well as its acute toxicity. Experimental approach: For anti-inflammatory, antipyretic, and analgesic tests, rats were given CcLF (WFCC, EAFcC, and n-HFCC) at 50 and 100 mg/kg, diclofenac sodium (10 mg/kg), paracetamol (150 mg/kg), aspirin (100 mg/kg), and tramadol (20 mg/kg). For the antioxidant activity test, various concentrations of CcLF were used ranging from 25 to 200 µg/mL. This study also looked into whether there could be any acute toxicity and histopathology of the liver, stomach, and kidneys in experimental animals. Findings/Results: The administration of CcLF significantly inhibited the increase in foot edema volume, and CcLF (EAFCC at 100 mg/kg) considerably decreased rectal temperature and was proportional to the standard drug paracetamol, and significantly inhibited pain sensation in various models. Additionally, CcLF showed strong antioxidant activity, and its administration at a dose limit of 5000 mg/kg/day did not show any toxic effects or death in test animals. Conclusions and implications: The results of the current confirmed that CcLF has demonstrated anti-inflammatory, antipyretic, analgesic, and antioxidant properties in experimental models, and is practically non-toxic.

Acute and Chronic Oral Toxicity of Hydroethanolic Extract of Sclerocarya birrea (Anacardiaceae) in Wistar Rats.

Background: Sclerocarya birrea (A. Rich). Hochst, popularly known as Morula, is a plant in the Anacardiaceae family. The bark, fruits, and leaves have traditionally been used to manage a variety of health conditions, most especially diabetes. Unfortunately, there is a scarcity of data and publications on the toxicity and safety of this plant. Purpose: The current study was designed to assess the acute and chronic toxicity of a hydro-ethanolic extract of Sclerocarya birrea in albino rats. Materials and Methods: Sclerocarya birrea was extracted using an 80-20% hydro-ethanolic solution. For the acute toxicity study, female Wistar albino rats were treated with hydro-ethanolic leaf extract at a dose of 5000 mg/kg body weight and followed-up for 14 days. In the chronic toxicity study, 40 healthy Wistar albino rats were divided in 4 groups. The three treatment groups were administered the leaf hydro-ethanolic extract orally at dosages of 30, 150, and 1000 mg/kg once day for 90 days and the fourth group was a control group. Body and organs weights, haematological, serum biochemical, and histopathological parameters were measured at the end of the experiment. Results: Single-dose oral administration of hydro-ethanolic leaf extract of Sclerocarya birrea at 5000 mg/kg produced no mortality indicating the LD50 is greater than 5000 mg/kg body weight. Following 90 days of administration of a hydro-ethanolic extract of Sclerocarya birrea leaves, there was no significant change in body and organs weights. Furthermore, biochemical, haematological and histopathological parameters did not vary significantly. Conclusion: This data indicates neither acute or chronic toxicity in rats and is consistent with the widespread and long-term usage of Sclerocarya birrea in African traditional medicine.

Non-clinical Safety Evaluation of Camelina Oil: Acute and 12-Week Oral Toxicities.

This study assessed the acute and sub-chronic toxicity of Camelina oil, a well-known oil rich in polyunsaturated fatty acids that enhance cellular immunity and human health, in Wistar rats. Wistar rats, 5 per sex per group, were randomly assigned to three groups for acute (14 days) toxicity studies and five groups for sub-chronic (90 days) toxicity studies. In the acute study, Camelina sativa oil was administered orally at a single dose of 5000 mg/kg of body weight (BW). The positive control group received a single dose of 5 000 mg/kg BW Canola oil by gavage. In the sub-chronic study, Groups III-V received 250, 500, and 1 000 mg/kg BW of Camelina oil, while Groups I and II received ultra-pure water and Canola oil at a dose of 500 mg/kg BW, respectively. Throughout the experiment, clinical signs, mortality, and body weight were monitored. At the end of the sub-chronic study, hematological, biochemical, and histopathological investigations were conducted. Administration of Camelina oil and Canola had no significant effect on daily weight gain (P > 0.05) of the test rats. Serum calcium levels decreased while phosphorous levels increased in male rats treated with Camelina oil. Other hematological and biochemical parameters showed no significant differences or dose-response effects between control and seed oil groups in both sexes (P < 0.05). Moreover, in animal necropsy, there were no apparent lesions in the liver, heart, and kidney organs in any of the doses administered. In conclusion, the results suggest that oral administration of Camelina oil is unlikely to be toxic. Therefore, the possibility for the development of future human nutrition should be considered.

JWH-182: a safe and effective synthetic cannabinoid for chemotherapy-induced neuropathic pain in preclinical models.

Chemotherapy-induced neuropathic pain (CINP), a condition with unmet treatment needs, affects over half of cancer patients treated with chemotherapeutics. Researchers have recently focused on the endocannabinoid system because of its critical role in regulating our bodies' most important functions, including pain. We used in vitro and in vivo methods to determine the toxicity profile of a synthetic cannabinoid, JWH-182, and whether it could be potentially effective for CINP alleviation. In vitro, we evaluated JWH-182 general toxicity, measuring fibroblast viability treated with various concentrations of compound, and its neuroprotection on dorsal root ganglion neurons treated with paclitaxel. In vivo, we performed an evaluation of acute and 28-day repeated dose toxicity in mice, with monitoring of health status and a complete histopathological examination. Finally, we evaluated the efficacy of JWH-182 on a CINP model in mice using specific pain assessment tests. JWH-182 has an acceptable toxicity profile, in both, in vitro and in vivo studies and it was able to significantly reduce pain perception in a CINP model in mice. However, the translation of these results to the clinic needs further investigation.

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.

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.

Differential Toxicity of Arsenic in Daphnia pulex Under Phosphorus and Food Limitation.

The on-going anthropogenic degradation of freshwater habitats has drastically altered the environmental supply of both nutrients and common pollutants. Most organisms living in these altered habitats experience interactive effects of various stressors that can initiate adjustments at multiple levels impacting their fitness. Hence, studies measuring response to a single environmental parameter fail to capture the complexities of the status quo. We tested both the individual and the interactive effect of arsenic (As) exposure, food quantity, and dietary phosphorus (P)-supply on six life-history traits (Juvenile Growth Rate; Adult Growth Rate; Age and Size at Maturity, Lifespan, and Fecundity) as surrogates for organismal fitness in the keystone aquatic grazer Daphnia pulex. We also tested the effect of food quantity and P-supply on somatic As accumulation in Daphnia. Our results indicated an influence of P-supply on neonatal growth and an influence of As and food quantity on growth and maintenance later in life. Maturation was strongly influenced by all three variables, with no reproduction observed in the presence of two or more environmental stressors. We found a strong interaction between As and dietary P, with increased P-supply intensifing the toxicity effect of As. No such effects were seen between As and food quantity, indicating a differential role of quantity versus quality on As toxicity. We found a nominal effect of diet on somatic As accumulation. The results from the present study emphasize the importance of considering such interactions between co-occurring environmental stressors and the dietary status of organisms, to better predict and manage impacts and risks associated with common environmental toxicants in highly vulnerable ecosystems. Environ Toxicol Chem 2024;43:1807-1819. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Multi-task aquatic toxicity prediction model based on multi-level features fusion.

INTRODUCTION: With the escalating menace of organic compounds in environmental pollution imperiling the survival of aquatic organisms, the investigation of organic compound toxicity across diverse aquatic species assumes paramount significance for environmental protection. Understanding how different species respond to these compounds helps assess the potential ecological impact of pollution on aquatic ecosystems as a whole. Compared with traditional experimental methods, deep learning methods have higher accuracy in predicting aquatic toxicity, faster data processing speed and better generalization ability. OBJECTIVES: This article presents ATFPGT-multi, an advanced multi-task deep neural network prediction model for organic toxicity. METHODS: The model integrates molecular fingerprints and molecule graphs to characterize molecules, enabling the simultaneous prediction of acute toxicity for the same organic compound across four distinct fish species. Furthermore, to validate the advantages of multi-task learning, we independently construct prediction models, named ATFPGT-single, for each fish species. We employ cross-validation in our experiments to assess the performance and generalization ability of ATFPGT-multi. RESULTS: The experimental results indicate, first, that ATFPGT-multi outperforms ATFPGT-single on four fish datasets with AUC improvements of 9.8%, 4%, 4.8%, and 8.2%, respectively, demonstrating the superiority of multi-task learning over single-task learning. Furthermore, in comparison with previous algorithms, ATFPGT-multi outperforms comparative methods, emphasizing that our approach exhibits higher accuracy and reliability in predicting aquatic toxicity. Moreover, ATFPGT-multi utilizes attention scores to identify molecular fragments associated with fish toxicity in organic molecules, as demonstrated by two organic molecule examples in the main text, demonstrating the interpretability of ATFPGT-multi. CONCLUSION: In summary, ATFPGT-multi provides important support and reference for the further development of aquatic toxicity assessment. All of codes and datasets are freely available online at https://github.com/zhaoqi106/ATFPGT-multi.