Search Results (6,771)

Ionizing radiation induces reactive oxygen species (ROS) and inflammatory signaling that contribute to both therapeutic efficacy and normal tissue toxicity. While the effects of high-dose radiation are well characterized, responses to low-dose-rate radiation (LDRR) remain inconsistent and are not adequately explained by conventional linear dose–response models. To address this gap, we conducted a narrative review of recent experimental studies across multiple biological systems, including body fluids, joint microenvironments, and reproductive tissues, focusing on redox and immune-related responses under LDRR conditions (dose rates: 0.39–3.49 mGy/h). Literature was identified through PubMed/MEDLINE, Web of Science, and Google Scholar, with emphasis on studies published between 2015 and 2026. These studies demonstrate that LDRR elicits nonlinear, dose-dependent effects that vary across biological compartments and involve coordinated changes in oxidative stress, immune signaling, and metabolic regulation. Based on this synthesis, we propose a unifying framework of nonlinear redox–immune coupling, in which oxidative stress functions as a threshold-dependent regulator and immune responses follow a biphasic trajectory characterized by activation at lower dose rates and attenuation or adaptation at higher levels. These responses are strongly influenced by the local microenvironment, resulting in compartment-specific variability. This integrated perspective supports a shift from dose-centric to systems-level interpretations of radiation biology and provides a basis for improving biomarker development, risk assessment, and therapeutic strategies in chronic low-dose radiation exposure settings. Future research priorities include time-resolved mechanistic studies to define compartment-specific redox thresholds, validation of candidate biomarkers under identical multi-compartment experimental conditions (e.g., GSH/GSSG ratio, 8-OHdG, circulating cytokine panels including IL-10/TNF-α ratio), and integration of subject-specific biological variables (e.g., age, sex, and baseline redox capacity) into predictive models of LDRR response. Full article

Dental fluorosis (DF) remains a global public health challenge traditionally attributed to elevated water fluoride F⁻. However, the Halo Effect and environmental factors now complicate this dose–response relationship. Following PRISMA 2020 guidelines, this systematic review identified 20 observational studies (n = 21,780) via PubMed, Scopus, and Web of Science. Inclusion logic utilized the PICOS framework, specifically selecting human studies that reported quantitative water F⁻ levels alongside environmental or dietary confounders. Quality was assessed via the Newcastle–Ottawa Scale. Synthesis revealed that in optimal fluoridated areas (0.7 mg/L), mild DF prevalence reached 15–20% in cohorts with high “Halo Effect” exposure (infant formula, processed beverages) a twofold increase over historical benchmarks. High altitude (>2000 m) and arid climates further exacerbated toxicity by altering renal clearance. These factors sustain systemic fluoride levels that inhibit protease activity (MMP-20/KLK4) and induce endoplasmic reticulum stress during enamel maturation, causing hypomineralization. Current water-centric monitoring is insufficient for modern risk assessment. A transition toward Total Daily Intake (TDI) models and context-specific standards accounting for altitude and dietary diffusion is essential to balance caries prevention with systemic safety. Full article

Radiotherapy is central to the treatment of nasopharyngeal carcinoma and selected sinonasal malignancies, but sinonasal toxicity remains incompletely characterized. Radiation-induced rhinosinusitis (RIR) is increasingly recognized after head-and-neck radiotherapy, particularly in nasopharyngeal carcinoma, where the paranasal sinuses and drainage pathways may receive substantial incidental dose. Reported prevalence varies widely because studies use different endpoints, including radiologic mucosal thickening, endoscopic inflammation, and patient-reported symptoms. Across available nasopharyngeal carcinoma cohorts, imaging-defined sinonasal inflammatory changes are common, with reported rates generally ranging from approximately 30% to more than 70% depending on timing, radiation technique, and diagnostic criteria. This narrative review summarizes current evidence on the epidemiology, pathophysiology, dosimetric predictors, imaging findings, prevention, and management of RIR. Radiation-induced sinonasal injury appears to arise from epithelial damage, impaired mucociliary clearance, altered local defense, and chronic mucosal remodeling. Available data suggest that higher doses to the paranasal sinuses and drainage pathways, baseline sinus disease, and tumor extension into sinonasal structures increase risk, although validated dose constraints are not yet established. We propose a harmonized reporting framework that integrates symptoms, endoscopy, imaging, dosimetry, baseline sinonasal status, and oncologic context. Greater recognition of RIR as a clinically meaningful survivorship toxicity may support more consistent outcome reporting, prospective studies, and future radiation-planning strategies aimed at reducing sinonasal morbidity. Full article

Melittin (Mel) is a membrane-active peptide with potential anticancer activity, but its direct therapeutic application may be limited by nonspecific toxicity and delivery-related challenges. The study aimed to assess melittin-functionalized magnetic nanoparticles (MNPs-Mel) as a strategy to enhance antitumor activity in Caco-2 cells, with/without magnetic hyperthermia (MH) association. BJ fibroblasts were used as a normal human in vitro cellular model. The effects of free Mel (2.5 µg/mL), MNPs, and MNPs-Mel (50 µg/mL both) + MH (30 min at 355 kHz and 25 kA/m) were assessed using colorimetry (for viability), luminescence (ATP), and spectrophotometry (lactate) following different exposure conditions. The mechanism of apoptosis induction was evaluated by ELISA (caspase 8 and 9 levels). Transmission electron microscopy (TEM) was also used to evaluate nanoparticle morphology and treatment-associated cellular ultrastructural changes. Free Mel reduced viability in both cell lines, with Caco-2 cells showing greater sensitivity at lower concentrations. MNPs (with/without MH) produced limited and less consistent effects, whereas MNPs-Mel significantly reduced Caco-2 viability and ATP levels and increased LDH and caspase 9. MH further enhanced the effects of MNPs-Mel: reduced viability (57–58% of the control at 24 h and 72 h), decreased ATP levels (67% of the control at 24 h and 53% at 72 h), increased LDH levels (206% of the control at 24 h and 301% at 72 h), and induced the mitochondrial apoptotic pathway (caspase 9 increased with 2164% of the control at 72 h). TEM proved the internalization of both MNPs and MNPs-Mel and revealed extensive ultrastructural alterations concerning mitochondria and lysosomes produced by MNPs-Mel, particularly in the Caco-2 cells. These modifications were heavily increased by MNPs-Mel + MH exposure. Overall, these findings demonstrate that Mel functionalization increases the antitumor activity of Mel at lower doses and that MH further potentiates this effect in Caco-2 cells. Full article

Background/Objectives: The emergence of drug-resistant Plasmodium falciparum highlights the need for new antiplasmodial compounds with distinct mechanisms of action. Microbial secondary metabolites, particularly from Streptomyces species, remain important sources of bioactive molecules. This study aimed to evaluate antiplasmodial metabolites associated with a Mongolian Streptomyces isolate. Methods: Streptomyces sp. strain D10 was isolated from Mongolian soil samples and extracted with ethyl acetate. Bioassay-guided fractionation was performed, followed by LC–HRMS analysis and GNPS-based spectral dereplication. Antiplasmodial activity was evaluated against P. falciparum 3D7, K1, and Dd2 strains using a SYBR Green I assay. Cytotoxicity was assessed in HSF cells. Stage-specific susceptibility assays were conducted using synchronized 3D7 parasites. Comparative docking analyses against β-hematin and the chloroquine resistance transporter (PfCRT), together with target prediction and molecular docking analyses, were performed to explore potential mechanisms. In vivo efficacy was evaluated using a Plasmodium yoelii 17XNL mouse model. Results: Fractionation yielded an active fraction (C2), and LC–HRMS and GNPS-based dereplication suggested a bile acid-like metabolite, with ursodeoxycholic acid (UDCA) returned as a putative spectral library candidate associated with fraction C2. Fraction C2 and UDCA showed comparable antiplasmodial activity against P. falciparum 3D7 (IC₅₀ = 6.55 ± 3.00 and 4.68 ± 0. 65 µg/mL, respectively) without detectable cytotoxicity up to 200 µg/mL. Activity was retained against multidrug-resistant K1 and Dd2 strains. Stage-specific assays demonstrated inhibitory activity across ring, trophozoite, and schizont stages without significant stage-dependent differences. Comparative docking analyses suggested interaction profiles distinct from chloroquine in β-hematin and PfCRT models. Additional docking analyses identified PfGluPho, PfMAPK, and PfPFT-β as potential targets. In vivo, UDCA reduced parasitemia in a dose-dependent manner without significant toxicity. Conclusions: UDCA exhibited moderate antiplasmodial activity across in vitro, in silico, and in vivo evaluations with a favorable selectivity profile, supporting further investigation of bile acid-like metabolites as potential antimalarial scaffolds. Full article

Background: Treatment-resistant obsessive–compulsive disorder (TR-OCD) remains a major therapeutic challenge. Although current guidelines recommend optimized serotonin reuptake inhibitor (SRI) therapy, clomipramine switching, exposure and response prevention, and antipsychotic augmentation, a substantial proportion of patients continue to experience severe and disabling symptoms. In such cases, clinicians may consider pharmacological intensification strategies beyond guideline-endorsed algorithms. Methods: This study combines a structured narrative synthesis of pharmacological strategies for TR-OCD with a retrospective observational case series from a tertiary OCD referral clinic. Treatment resistance was defined as failure to achieve at least a 35% reduction in Yale–Brown Obsessive Compulsive Scale (Y-BOCS) score after at least two adequate SRI trials, including clomipramine, and optimized exposure and response prevention when available. Five patients treated with pharmacological intensification strategies were included. The primary outcome was percentage change in Y-BOCS score at 12 weeks. Results: The case series illustrates five strategies used in highly refractory OCD: supratherapeutic SSRI dosing, SSRI plus mirtazapine augmentation, dual SSRI therapy, serotonergic intensification in a clozapine-treated patient, and glutamatergic/GABAergic augmentation with topiramate. Baseline Y-BOCS scores ranged from 28 to 32. At 12 weeks, symptom reduction ranged from 23% to 36%. One patient met criteria for response, three showed near-response, and one demonstrated partial improvement. No cases of serotonin toxicity or clinically significant cardiac complications occurred. Conclusions: These cases suggest that carefully monitored pharmacological intensification may be feasible in selected specialist settings, but efficacy and safety require confirmation in prospective controlled studies. Recommendations: Pharmacological intensification should be reserved for highly refractory patients managed in specialist services, implemented with gradual titration, structured serotonin toxicity and electrocardiographic monitoring, and explicit individualized risk–benefit discussion; dual SSRI therapy should be regarded as the most experimental and highest-risk serotonergic option; and prospective controlled studies incorporating standardized functional outcomes are needed to refine patient-selection criteria and clarify which patients may benefit. Full article

Background/Objectives: Tordylium trachycarpum Boiss. (Apiaceae) is traditionally used in Kurdish ethnomedicine for the management of gastrointestinal disorders; however, its pharmacological efficacy and safety profile remain insufficiently investigated. This study evaluated, for the first time, the gastroprotective activity and associated antioxidant, inflammatory, and apoptotic responses of the methanolic extract of T. trachycarpum using an ethanol-induced gastric ulcer model in Sprague–Dawley rats. Methods: Preliminary phytochemical screening revealed the presence of phenolics, flavonoids, terpenoids, tannins, coumarins, and glycosides. Acute oral toxicity testing demonstrated no signs of toxicity at doses up to 5 g/kg. Gastric ulceration was induced by absolute ethanol, and animals were pretreated with the extract (250 and 500 mg/kg) or omeprazole (20 mg/kg). Results: The extract significantly decreased the gastric lesion area from 258.50 ± 6.38 mm² in the ulcer control group to 143.70 ± 0.76 mm² and 115.50 ± 0.76 mm², corresponding to ulcer inhibition rates of 44.41% and 55.31%. Additionally, the extract increased mucus production, maintained mucosal structure, and raised stomach pH. Biochemical analysis showed a significant increase in antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] and a reduction in malondialdehyde (MDA) levels, indicating attenuation of oxidative stress. In addition, the extract modulated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10). Blood-based ELISA analysis demonstrated increased expression of heat shock protein 70 (HSP70) and reduced Bax levels, suggesting anti-apoptotic activity. Conclusions: These findings indicate that T. trachycarpum exerts significant gastroprotective activity through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, supporting its traditional use and highlighting its potential as a natural therapeutic candidate for the management of gastric ulcers. Full article

Pediatric drug therapy remains fundamentally challenged by profound interindividual variability driven by dynamic development, genetic, and environmental factors. Although dosing strategies based on age, body weight, or body surface area remain important starting points in pediatric pharmacotherapy, they may not fully capture ontogeny-dependent variability in drug disposition and response. Consequently, clinically relevant differences in efficacy and toxicity may still occur among children receiving similar weight-adjusted doses. Pharmacogenomics offers a promising framework for individualized therapy; however, its clinical translation in pediatrics is limited by developmental variability in gene expression and enzyme activity. Emerging evidence highlights the pivotal role of epigenetic regulation, including DNA methylation, histone modifications, and microRNAs, in modulating pharmacogenetic expression across developmental stages, thereby reshaping drug response trajectories. Concurrently, advances in artificial intelligence and next-generation sequencing enable integration of multidimensional datasets, facilitating predictive modeling of drug efficacy and toxicity. This narrative review provides a comprehensive synthesis of developmental pharmacology, pharmacogenomics, and epigenetic mechanisms, while critically evaluating current translational gaps and implementation challenges. Importantly, it proposes an integrative precision framework that incorporates genetic, epigenetic, and computational insights to optimize pediatric pharmacotherapy. By bridging mechanistic biology with emerging digital health technologies, this work advances a paradigm shift from empirical prescribing toward predictive, adaptive, and individualized therapeutic strategies. The proposed approach holds significant potential to enhance clinical outcomes, minimize adverse effects, and accelerate the realization of precision medicine in pediatric populations. Full article

Characterizing the human health risk posed by constituents in drinking water is often challenging due to a lack of published toxicity values. The PIANO (Paraffin, Isoparaffin, Aromatic, Naphthene, and Olefin) analytical method measures nearly 300 compounds in JP-5 jet fuel, 43 of which have published oral reference doses (RfDs). The remaining compounds are typically assigned surrogate toxicity values. We predict RfDs for 290 PIANO compounds using Quantitative Structure–Activity Relationship (QSAR) models based on stepwise linear regression of 2-dimensional molecular descriptors (MDs) and published toxicity values. Five training groups, created by randomly selecting 80% of the non-PIANO compounds and 50% of the 43 PIANO compounds that have RfDs within a master dataset of 1113 compounds, were used to develop five QSAR models. We used the geometric means of four QSAR model results of sufficient quality to predict RfDs for compounds lacking toxicological information. For compounds with known RfDs, 884 (79%) were within 8-fold of published RfDs, well within the acknowledged uncertainty inherent in published RfDs. Our approach has applicability beyond PIANO compounds and represents a new alternative methodology (NAM) that may be used to reduce uncertainty in human health risk assessment and guide regulatory decisions. Full article

Background: Hexavalent chromium (Cr(VI)) is a widespread environmental toxic heavy metal with strong oxidative properties; however, its immunotoxicity and metabolic mechanisms in rabbit spleen remain largely unclear. Methods: In this study, New Zealand rabbits were exposed to 0, 12.5, 25, and 50 mg/L Cr(VI) (as potassium dichromate, K₂Cr₂O₇) via drinking water for four weeks to investigate splenic damage and the underlying molecular pathways. Spleen pathological injury was evaluated by hematoxylin and eosin (H&E) staining, and the distribution of T cells, B cells, and macrophages was assessed by immunohistochemistry. Antioxidant enzyme activities and antioxidant substance levels were determined using ELISA, and the relative mRNA expression of immune factor genes, antioxidant-related genes, and ferroptosis-related genes was quantified by quantitative real-time PCR (qRT-PCR). In addition, the distribution of iron in splenic tissue was detected by enhanced Prussian blue staining. Results: Our results demonstrate that high-dose Cr(VI) significantly inhibited body weight gain, induced lymphocyte atrophy, vacuolization, and widening of intercellular spaces in the splenic white pulp. Furthermore, Cr(VI) reduced T and B lymphocyte populations, promoted macrophage infiltration and inflammatory cytokine gene expression in a concentration-dependent manner, impaired total antioxidant capacity, and led to a decrease in glutathione (GSH) levels in the spleen. Additionally, Cr(VI) exposure increased iron accumulation, activated the ACSL4–NOX lipid peroxidation cascade, and downregulated GPX4 expression, ultimately triggering ferroptosis. Conclusions: These findings reveal that Cr(VI) causes splenic immune injury by disrupting oxidative homeostasis and inducing ferroptosis, providing novel insights for evaluating immunotoxicity and identifying metabolic targets under Cr(VI) pollution. Full article

Bone marrow (BM) is highly sensitive to ionizing radiation: high doses cause extensive cell death, BM failure, and immune suppression, whereas low doses may increase long-term cancer risk without acute toxicity. Radiation-induced BM effects are partly mediated by disrupted intercellular communication via extracellular vesicles (EVs), including alterations in their microRNA cargo. EV–microRNA packaging remains unclear, although RNA-binding proteins are thought to contribute. To address this, murine BM cells and EVs were isolated 24 h after total body irradiation (0, 0.1, or 3 Gy). MicroRNAs were analyzed using nCounter and validated by RT–qPCR, while RNA-binding proteins (hnRNP A2b1, hnRNP Q) were assessed by Western blotting and confocal microscopy. Protein–microRNA interactions were examined using motif analysis and immunoprecipitation, and functional associations were explored via KEGG pathway analysis. High-dose irradiation induced widespread microRNA changes, whereas low-dose irradiation had minimal effects. Distinct cellular and EV microRNA profiles indicated selective sorting, with specific microRNAs enriched in cells but depleted in EVs. hnRNP A2b1 emerged as a potential regulator, showing nuclear relocalization and reduced EV association after irradiation; these changes correlated with decreased export of motif-containing microRNAs, possibly linked to key BM pathways. Overall, radiation alters EV–microRNAs through dose-dependent, protein-mediated selective sorting, potentially affecting BM communication and homeostasis. Full article

Psilocybin, a psychedelic drug with reported anxiolytic and antidepressant potential, is rapidly metabolized to its active metabolite psilocin. However, a lack of adequate toxicity studies and tissue distribution studies currently restricts its development and application. This study combined behavioral assays in zebrafish with desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to systematically evaluate the acute neurotoxicity of psilocybin and characterize the in vivo spatial distribution of its active metabolite, psilocin. The novel tank test was used to evaluate zebrafish following a 4 h exposure to psilocybin at three different doses (20, 40, and 80 μM; n = 6 per group). Statistical analysis of the data was performed using ANOVA. Behavioral analyses revealed that exposure to psilocybin induced pronounced neurobehavioral alterations, including hyperactivity and disrupted swimming patterns, as evidenced by significant increases in the number of zone transitions and shuttle frequency. We established a DESI-MSI-based method for quantitative mapping and visualization of psilocin in zebrafish tissues. Methodological validation indicated that a linear relationship between ion intensity, spotted amount (R² = 0.9947), and reproducibility (RSD < 15%) is suitable for quantitative analysis of psilocin in zebrafish tissues. Spatial distribution maps showed that following continuous exposure for 4 h, psilocin was widely distributed across multiple tissues, such as the eye, brain, heart, liver, and kidney, with marked accumulation in the brain and the periportal regions of the liver. Relative psilocin signal intensity revealed a dose-dependent increase in tissue drug levels. The dose-dependent increase in both behavioral hyperactivity and brain psilocin levels points to a consistent relationship, in line with a central site of action. Collectively, these findings demonstrate that DESI-MSI provides a visual and efficient strategy for studying drug distribution in biological tissues from exposed animals. The neurobehavioral toxicity phenotypes and distinct tissue distribution patterns of psilocin uncovered in this study offer critical insights into the biological effects and potential risks of this psychoactive substance. Full article

Tobramycin is a highly hydrophilic aminoglycoside antibiotic with limited cellular permeability and negligible oral bioavailability, necessitating parenteral administration. This study aimed to develop drug delivery systems based on nano-sized colloidal assemblies (NCAs) incorporating tobramycin ion pairs to enhance its lipophilicity, potential for transition to the oral route, and antimicrobial activities. Tobramycin was ionically paired with oleic acid, lauric acid, and fluorescein and formulated into NCA preconcentrates (F1–F5) using combinations of Tween 80, DMSO, and propylene glycol. The resulting formulations formed stable nanodroplets upon dilution (9.50–16.30 nm) with narrow size distributions (polydispersity index; PDI < 0.3) and moderate negative zeta potentials (−4.99 to −11.13 mV). In vitro release studies indicated sustained drug release for ion-paired systems compared to the rapid release of free tobramycin. Cytotoxicity evaluation in Caco-2 cells demonstrated high biocompatibility at 1:10,000 and 2:10,000 dilutions, while concentration-dependent toxicity at higher doses suggested enhanced intracellular delivery. Cellular uptake studies revealed significantly higher tobramycin internalization (p < 0.001) from formulations F1–F3, with uptake values in the range of 81.76–96.14% compared to free drug, which showed zero or negligible uptake. Fluorescein-labeled formulations (F4 and F5) further confirmed enhanced uptake, demonstrating strong intracellular fluorescence. This was supported by visual observation, UV–Vis absorbance (70.5–84.8% relative to positive control), and confocal microscopy imaging. Antimicrobial activities against P. aeruginosa and S. aureus were comparable between formulations F1–F5 and free tobramycin (inhibition zones of 16–18 mm), utilizing the same tobramycin concentration in the diluting medium. These findings validate the effectiveness of the formulated NCAs in facilitating intracellular delivery of tobramycin while preserving biocompatibility and similar antimicrobial activities. Moreover, the uptake of fluorescein provides indirect evidence supporting the enhanced internalization of tobramycin in analogous ion-paired formulations. This strategy holds promise for overcoming intestinal barriers and improving oral bioavailability, potentially enabling the transition of tobramycin from parenteral to oral administration. Full article

Despite technological advances in radiation therapy (RT), improvements in locoregional control of locally advanced disease remain limited, indicating a plateau in RT effectiveness. It is becoming increasingly clear that RT occurs within a dynamic metabolic microenvironment that merges oncogenic activity with metabolic and immune interactions. This includes responses to oxidative stress, regulation of cell death and survival signals, energy metabolism, protein synthesis, autophagy of molecules and organelles, and ultimately, the anti-tumor immune response. Each tumor, regardless of its histology, maintains a unique molecular and microenvironmental identity that influences its response to RT. Furthermore, RT acts as a cellular stressor that activates responses in cancer and stromal cells, impacting clinical outcomes. The concept of Metabolism and Immunity Adaptive Radiotherapy (M.I.A.R) recognizes that RT success depends not only on radiation dose and distribution but mainly on key interventions that alter and influence the biological environment before, during, and after therapy. It highlights the importance of an initial diagnostic workup, which is achievable with current tools, to identify tumor-specific oncogenes, metabolic, and immune profiles. Within the context of M.I.A.R., effective RT requires tumor preconditioning combined with concurrent use of drugs, including metabolism-targeting agents, to increase tumor sensitivity to radiation. Post-RT metabolic and immune interventions are essential for complete tumor eradication. This involves combining existing oncogene-targeting therapies with available immune treatments, supported by low-toxicity modulating drugs/agents with demonstrated preclinical activity against specific molecular and microenvironmental features. Overall, while MIAR remains a theoretical approach, existing preclinical and recent clinical data, e.g., those exploiting tumor hypoxia and re-oxygenation status, or post-RT immunotherapy, strongly support further dedicated investigation. Full article

M8OI is a cytotoxic methylimidazolium ionic liquid solvent through its binding to the ubiquinone binding site on complex I of the mitochondrial electron transport chain. Given the overlap in terms of toxic mechanism of action with the pesticide rotenone, the potential neurotoxic effects of M8OI were examined. In vitro, cytotoxicity and mitochondrial function were assessed in SH-SY5Y cells by measuring MTT reduction and oxygen consumption/extracellular acidification using a Seahorse analyser. SH-SY5Y cells were sensitised to M8OI toxicity by replacing medium glucose with galactose. Glucose protected the cells from M8OI toxicity, whereas galactose showed no clear dose–response protection. M8OI induced a dose-dependent reduction in oxygen consumption rate with a compensatory increase in extracellular acidification rate, consistent with inhibition of mitochondrial oxidative phosphorylation and a shift toward glycolysis. In vivo, rats were orally exposed via drinking water for 20 weeks and assessed using behavioural tests. In addition, the concentrations of M8OI and its metabolites were quantified by LC–MS in rat brain and other tissues. In rats, M8OI concentrations were ~30-fold higher in kidney than brain, and brain levels were at least 100-fold lower than the concentrations that affected SH-SY5Y cell viability in vitro. However, based on open field tests, M8OI exposure suppressed motor activity without any anxious behaviours. The cytotoxicity of M8OI in SH-SY5Y neuroblastoma cells was associated with metabolic mitochondrial dysfunction. However, the neurobehavioural changes observed in orally exposed rats occurred at significantly lower brain concentrations than would be predicted to lead to neural cell death. Nevertheless, direct comparisons between acute in vitro exposures and chronic in vivo outcomes should be interpreted cautiously. Full article