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Low-cost, high-throughput in vitro bioassays have potential as alternatives to animal models for toxicity testing. However, incorporating in vitro bioassays into chemical toxicity evaluations such as read-across requires significant data curation and analysis based on knowledge of relevant toxicity mechanisms, lowering the enthusiasm of using the massive amount of unstructured public data. We aimed to develop a computational method to automatically extract useful bioassay data from a public repository (i.e., PubChem) and assess its ability to predict animal toxicity using a novel bioprofile-based read-across approach. A training database containing 7,385 compounds with diverse rat acute oral toxicity data was searched against PubChem to establish in vitro bioprofiles. Using a novel subspace clustering algorithm, bioassay groups that may inform on relevant toxicity mechanisms underlying acute oral toxicity were identified. These bioassays groups were used to predict animal acute oral toxicity using read-across through a cross-validation process. Finally, an external test set of over 600 new compounds was used to validate the resulting model predictivity. Several bioassay clusters showed high predictivity for acute oral toxicity (positive prediction rates range from 62-100%) through cross-validation. After incorporating individual clusters into an ensemble model, chemical toxicants in the external test set were evaluated for putative acute toxicity (positive prediction rate equal to 76%). Additionally, chemical fragment -in vitro-in vivo relationships were identified to illustrate new animal toxicity mechanisms. The in vitro bioassay data-driven profiling strategy developed in this study meets the urgent needs of computational toxicology in the current big data era and can be extended to develop predictive models for other complex toxicity end points. https://doi.org/10.1289/EHP3614.

The idea of this study was the estimation of the theoretical acute toxicity (t-LD50, rat, oral dose) of organophosphorus-based chemical warfare agents from the G-series (n = 12) using different in silico methods. Initially identified in Germany, the G-type nerve agents include potent compounds such as tabun, sarin, and soman. Despite their historical significance, there is a noticeable gap in acute toxicity data for these agents. This study employs qualitative (STopTox and AdmetSAR) and quantitative (TEST; CATMoS; ProTox-II and QSAR Toolbox) in silico methods to predict LD50 values, offering an ethical alternative to animal testing. Additionally, we conducted quantitative extrapolation from animals, and the results of qualitative tests confirmed the acute toxicity potential of these substances and enabled the identification of toxicophoric groups. According to our estimations, the most lethal agents within this category were GV, soman (GD), sarin (GB), thiosarin (GBS), and chlorosarin (GC), with t-LD50 values (oral administration, extrapolated from rat to human) of 0.05 mg/kg bw, 0.08 mg/kg bw, 0.12 mg/kg bw, 0.15 mg/kg bw, and 0.17 mg/kg bw, respectively. On the contrary, compounds with a cycloalkane attached to the phospho-oxygen linkage, specifically methyl cyclosarin and cyclosarin, were found to be the least toxic, with values of 2.28 mg/kg bw and 3.03 mg/kg bw. The findings aim to fill the knowledge gap regarding the acute toxicity of these agents, highlighting the need for modern toxicological methods that align with ethical considerations, next-generation risk assessment (NGRA) and the 3Rs (replacement, reduction and refinement) principles.

Here, we fabricated two plasmonic 2D Ti C T -based nanocomposites (Au/MXene and Au/Fe O /MXene) with similarly high anti-cancer photothermal therapy (PTT) capabilities, but with less in vivo toxicity than a pure MXene. Au/MXene was synthesized by in situ reduction of tetrachloroauric acid using NaBH on Ti C T flakes. For targeted PTT, magnetic Au/Fe O /MXene was synthesized via a reaction between freshly prepared magnetite Fe O NPs and MXene solution, followed by in situ integration of gold nanoparticles (AuNPs). Morphological characterization by XRD, SEM, and TEM revealed the successful synthesis of Au/MXene and Au/Fe O /MXene. Both new composites exhibited a significant in vitro dose-dependent PTT effect against human breast cancer cells MCF7. Interestingly, in vivo acute toxicity assays using zebrafish embryos indicated that Au/MXene and Au/Fe O /MXene had less embryonic mortality (LC ≫ 1000 µg/mL) than pure MXene (LC =257.46 µg/mL). Our new Au/MXene and Au/Fe O /MXene nanocomposites could be safer and more suitable than the pure MXene for biomedical applications, especially when targeted PTT is warranted.

Abstract Toxicological studies are essential for developing novel medications in pharmaceutical industries including ayurvedic preparation. Hence, the present study is aimed to evaluate acute and 28-days repeated dose oral toxicity of anti-obesity polyherbal granules (PHG) in Sprague Dawley rats by OECD guidelines No 425 and 407, respectively. In an acute oral toxicity study, a single dose of 2 g/kg PHG was administered to rats and mortality, body weight, and clinical observations were noted for fourteen days. However, in the subacute oral toxicity study, the PHG was administered orally at doses of 0.3, 0.5 and 1 g/kg daily for 28 days to rats. Food intake and body weight were recorded weekly. On the 29th day, rats were sacrificed and subjected to haematological, biochemical, urine, necropsy, and histopathological analysis. In an acute oral toxicity study, no treatment-related, mortality, behavioral changes, and toxicity were found throughout fourteen days. Likewise, in the sub-acute toxicity study, no mortality and toxic effects were found in haematology, biochemical, urine, necropsy and histopathological analysis in rats for 28 days of treatment with PHG. Based on these results, the LD50 of PHG was found to be greater than 2 g/kg and the no-observed-adverse-effect level (NOAEL) of PHG for rats was found to be 0.5 g/kg/day. Thus, anti-obesity polyherbal granules showed a good safety profile in animal studies and can be considered an important agent for the clinical management of obesity. Resumo Estudos toxicológicos são essenciais para o desenvolvimento de novos medicamentos nas indústrias farmacêuticas, incluindo a preparação aiurvédica. Assim, o presente estudo tem como objetivo avaliar a toxicidade oral aguda e de dose repetida de 28 dias de grânulos de polierva (PHG) antiobesidade em ratos Sprague Dawley pelas diretrizes da OCDE nº 425 e 407, respectivamente. Em um estudo de toxicidade oral aguda, uma dose única de 2 g/kg de PHG foi administrada a ratos, e mortalidade, peso corporal e observações clínicas foram observadas por 14 dias. No entanto, no estudo de toxicidade oral subaguda, o PHG foi administrado oralmente em doses de 0,3, 0,5 e 1 g/kg diariamente por 28 dias em ratos. A ingestão alimentar e o peso corporal foram registrados semanalmente. No 29º dia, os ratos foram sacrificados e submetidos a análises hematológicas, bioquímicas, de urina, necropsia e histopatológica. Em um estudo de toxicidade oral aguda, nenhuma mortalidade, alterações comportamentais e toxicidade relacionadas ao tratamento foram encontradas ao longo de 14 dias. Da mesma forma, no estudo de toxicidade subaguda, não foram encontrados mortalidade e efeitos tóxicos em análises hematológicas, bioquímicas, de urina, necropsia e histopatológica em ratos durante 28 dias de tratamento com PHG. Com base nesses resultados, verificou-se que a DL50 de PHG era superior a 2 g/kg e o nível de efeitos adversos não observados (NOAEL) de PHG para ratos foi de 0,5 g/kg/dia. Assim, os grânulos poliervais antiobesidade apresentaram um bom perfil de segurança em estudos com animais e podem ser considerados um importante agente para o manejo clínico da obesidade.

Different chemovars produce diverse pharmacological and behavioral effects. With the widespread use of cannabis in Nigeria, detailed toxicological effects of Nigerian chemovars are lacking. This study aimed to identify phytocannabinoids and investigate the toxic effects of an indigenous . The plant samples were air-dried, powdered, extracted with ethanol, and characterized (phytochemical screening, Fourier Transformed Infrared Spectroscopy (FTIR), and Gas Chromatography-Mass Spectrometry (GC-MS)). Acute and subacute toxicity tests were done following Organisation for Economic Co-operation and Development (OECD) protocols. Screening showed appreciable levels of alkaloids, tannins, saponins, cardiac glycosides, and phenol. FTIR analysis indicated functional groups and chemical linkages like alcohols, fatty acids, alkynes, ketones, and esters, and 11 phytocannabinoids with delta-9-tetrahydrocannabinol in abundance (35.78%) reported by GC-MS. Acute toxicity test indicated an oral lethal dose (LD ) value of ˃5000 mg/kg, a no-observed-adverse-effect-level (NOAEL) dose of ≤300 mg/kg, and a significant ( 0.05) decrease in the weight of animals in the 2000 mg/kg treatment group. The sub-acute toxicity test showed significantly ( 0.05) decreased ALP and ALT levels at 25 mg/kg body weight, and significantly lower triglyceride ( 0.01) and LDL ( 0.05) levels. Urea and some haematological parameters were significantly ( 0.05) higher in the 250 mg/kg group. Also, we observed mild to moderate necrosis in the excised pancreas and liver, and mild tubular changes in the kidney. This suggests that our indigenous variety of may be considered safe following oral consumption.

We present a method for calculating the Acute Insecticide Toxicity Loading (AITL) on US agricultural lands and surrounding areas and an assessment of the changes in AITL from 1992 through 2014. The AITL method accounts for the total mass of insecticides used in the US, acute toxicity to insects using honey bee contact and oral LD50 as reference values for arthropod toxicity, and the environmental persistence of the pesticides. This screening analysis shows that the types of synthetic insecticides applied to agricultural lands have fundamentally shifted over the last two decades from predominantly organophosphorus and N-methyl carbamate pesticides to a mix dominated by neonicotinoids and pyrethroids. The neonicotinoids are generally applied to US agricultural land at lower application rates per acre; however, they are considerably more toxic to insects and generally persist longer in the environment. We found a 48- and 4-fold increase in AITL from 1992 to 2014 for oral and contact toxicity, respectively. Neonicotinoids are primarily responsible for this increase, representing between 61 to nearly 99 percent of the total toxicity loading in 2014. The crops most responsible for the increase in AITL are corn and soybeans, with particularly large increases in relative soybean contributions to AITL between 2010 and 2014. Oral exposures are of potentially greater concern because of the relatively higher toxicity (low LD50s) and greater likelihood of exposure from residues in pollen, nectar, guttation water, and other environmental media. Using AITL to assess oral toxicity by class of pesticide, the neonicotinoids accounted for nearly 92 percent of total AITL from 1992 to 2014. Chlorpyrifos, the fifth most widely used insecticide during this time contributed just 1.4 percent of total AITL based on oral LD50s. Although we use some simplifying assumptions, our screening analysis demonstrates an increase in pesticide toxicity loading over the past 26 years, which potentially threatens the health of honey bees and other pollinators and may contribute to declines in beneficial insect populations as well as insectivorous birds and other insect consumers.

Background Equisetum diffusum D. Don commonly known as ‘Himalayan horsetail’, has been traditionally used in the treatment of back pain, bone fracture and dislocation, and arthritis by various tribal communities of India. Our previous study confirmed the anti-inflammatory efficacy of the plant through in silico, in vitro , and in vivo model studies. Therefore, the current research is focused on safety dose evaluation for the first-time of the whole-plant methanol extract (EDME) of E. diffusum through appropriate in silico, in vitro, and in vivo approaches. Method The whole plant, along with its rhizomes, was collected, and the methanol extract was prepared. The in silico ADMET study was performed to predict the pharmacokinetics profile and toxicity of all the identified phyto-compounds of EDME previously screened by GC–MS study. In vitro cytotoxicity study of EDME was performed using two cell lines: kidney (HEK293) and liver (Huh7) cell lines. The in vivo toxicity study of EDME was validated by the acute toxicity (OECD 423, 2002) and sub-acute toxicity assays (OECD 407, 2008) in the Wistar Albino rat model. Results The in silico ADMET study of all 47 bioactives predicted good pharmacokinetic and low toxicity profiles. In vitro cytotoxicity showed higher IC 50 values of EDME viz., 672 ± 15.7 μg/mL and 1698 ± 6.54 μg/mL for both kidney (HEK293) and liver (Huh7) cell lines, respectively, which were considered as low-toxic. Based on acute oral toxicity, the LD 50 value of the extract was considered “non-toxic” up to a feeding range of 2000 mg/kg of body weight. The regular consumption of the extract for an extended period (28 days) was also qualified as safe based on the body and organ weight, hematological, biochemical, and histoarchitecture results in the sub-acute toxicity assay. Conclusion The detailed in silico , in vitro , in vivo (acute and sub-acute oral toxicity) studies gave us a new insight to the safety dose evaluation of Equisetum diffusum , which may serve as a reliable documentation for undertaking the experimental validation of the ethnobotanical uses of the plant which would help in the field of drug development for the treatment of inflammation related complications.

Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. models built using existing data facilitate rapid acute toxicity predictions without using animals. The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 ( value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [ ( )], and nontoxic chemicals ( ). An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with results. CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495.

Background This study aimed to investigate the potential toxic effects of Molybdenum disulfide nano-flowers (MoS 2 NF), which have been suggested as a chemotherapeutic agent, but lack previous toxicity studies. Methods Acute, sub-acute and developmental toxicity studies were conducted following OECD guidelines 425, 407 and 414, respectively. Results In the acute toxicity study, female Wistar rats received logarithmic doses (1.75–550 mg/kg) of MoS 2 NF over 14 days. Results indicated a decrease in oxidative stress markers (CAT, SOD and GSH) and increased MDA levels, along with significant decrease in organ weight compared to normal control. Alterations in liver enzymes, CBC profile and lipid profile and histopathological analysis were observed in MoS 2 NF groups. Sub-acute toxicity (28-day at 3 and 10 mg/kg in both male and female rats) resulted in increased levels of ALT and AST, decreased levels of CAT, SOD and GSH and increased MDA and urea levels. Sperm analysis in male group showed increased motility and concentration, with more defective morphology. In developmental toxicity studies, a 10 mg/kg dose for 21 days decreased all oxidative markers except MDA, which increased. Fetal crown-to-rump length increased, while uterine SOD, CAT and GSH levels decreased. Histopathology revealed organ damage in both sub-acute and developmental studies. Maternal weight remained unaffected, whereas fetal weight showed an increased. Conclusion MoS 2 NF exhibited mild-to-moderate toxicity, however, long-term and studies are recommended to assess the safety and therapeutic potential of MoS 2 NF.

The target of this novel work is to assess the immunosuppression, genotoxicity, histopathological alterations, and cumulative mortality induced by acute toxicity of magnetite nanogel (MNG) in Nile catfish. Furthermore, a subsequent 10-day depuration period is adopted to estimate the restoration of those disturbed indices. Nile catfish ( n  = 180) were allotted into four groups and exposed to different concentrations of MNG (0, 1/10, 1/8, and 1/5 96-h LC 50 ). The outcomes displayed a remarkable concentration-dependent decline in the immune indices level (LYZ, NO, and MPO). The gene expression of antioxidant (SOD) and apoptosis-regulatory genes (MAPK3 and JNK) was upregulated in MNG-exposed fish. Histopathological disruptions in the tissue architecture of gills and intestines were also evident in MNG-exposed groups. Interestingly, after a 10-day depuration period, marked improvement in the level of immune response mediators and gene expression of apoptotic genes was evident in all experimental groups, particularly at 1/10 of LC 50 . Overall, exposure to higher concentrations of MNG (1/5 and 1/8 of LC 50 ) exerts multiple adverse influences on the Nile catfish, which were less pronounced at 1/10 of LC 50 . Surprisingly, a subsequent 10-day recuperation time was adequate for alleviating those impairments, with the maximum improvement in the Nile catfish exposed to 1/10 of LC 50 .