Search Results (59)

Allometric scaling provides a practical framework for predicting human pharmacokinetic (PK) parameters from animal data by relating physiological processes to body size through power-law equations. Despite its simplicity and widespread use in first-in-human (FIH) dose selection, its predictive performance is limited by species-specific differences in absorption, distribution, metabolism, and excretion (ADME). This review summarizes the mathematical foundations, workflows, and diagnostics of allometric scaling, while critically examining where the approach succeeds and where it fails. Core concepts, including clearance, volume of distribution, correction factors, and the rule of exponents, are discussed alongside complementary methods: in vitro–in vivo extrapolation (IVIVE), physiologically based pharmacokinetic (PBPK) modelling, and the Wajima normalized time-course method. Historical clinical failures, including fialuridine, TGN1412, BIA 10-2474, and rofecoxib, illustrate the limits of relying solely on allometry, while thalidomide and the fenfluramine combination exemplify toxicodynamic species-selection failures. Modern advances, including the Extended Clearance Classification System (ECCS), target-mediated drug disposition, FcRn recycling, and emerging artificial intelligence and machine-learning methods, are integrated within a framework. Overall, the review treats allometric scaling as a disciplined starting hypothesis that must be triangulated with mechanistic, experimental, and regulatory evidence to support safer and more reliable human translation. Full article

Metformin-associated lactic acidosis (MALA) involves mitochondrial Complex I inhibition, traditionally diagnosed via indirect markers. We present platelet high-resolution respirometry (HRR) as a novel “liquid biopsy” to directly quantify metformin-induced systemic bioenergetic lesions. A 65-year-old diabetic male presented with severe lactic acidosis, acute kidney injury, and profound hypoglycemia after intentionally overdosing on metformin (120 g), dapagliflozin (600 mg), and insulin glargine (300 U). While hemodialysis cleared plasma metformin and resolved the acidosis, refractory hypoglycemia required high-dose IV glucose for over six days. Day 2 platelet HRR revealed severe Complex I inhibition despite significantly decreased plasma metformin, indicating a profound “toxicodynamic lag.” Mitochondrial bioenergetics recovered by Day 7, reflecting natural platelet turnover. The protracted hypoglycemia was driven by a synergistic triad: metformin-inhibited gluconeogenesis, insulin glargine’s prolonged depot effect, and dapagliflozin-induced persistent renal glucose wasting. Platelet HRR has the potential to be a clinically applicable tool to reveal the “hidden” cellular phase of metformin toxicity missed by standard biomarkers. Furthermore, clinicians must anticipate severe, protracted hypoglycemia in mixed overdoses involving SGLT2 inhibitors. Full article

Heavy metals including mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) remain significant global toxins due to their environmental persistence, widespread anthropogenic release, and serious biological effects. This review consolidates current understanding of their natural and industrial sources, environmental cycling, human exposure routes, and population-level vulnerabilities. It covers their toxicokinetics and toxicodynamics, emphasizing species-specific absorption, distribution, and injury mechanisms, including oxidative stress, thiol binding, mitochondrial dysfunction, endocrine disruption, and cancer risk. Clinical signs range from subtle neurocognitive impairment and kidney damage to severe acute poisoning. The review evaluates evidence-based approaches to risk assessment and biomonitoring, such as blood, urine, hair, and speciation tests, noting issues, including unvalidated provoked testing. Treatment focuses on removing exposure, providing nutritional support, and offering supportive care, with chelation therapy reserved for specific cases. It explains the chemistry, pharmacology, and roles of chelating agents—ALA, DMSA, DMPS, Cys, GSH, and physiologic thiols, comparing their effectiveness, limitations, and costs for various metals. Emerging therapies, precision toxicology, and public health strategies are discussed within a prevention-focused context. Unlike prior reviews focused primarily on toxic mechanisms or isolated clinical management, this review integrates mechanistic toxicology, biomarker interpretation and speciation, evidence-based clinical care, and ethical, cost-conscious decision-making within a single translational framework. This narrative review synthesizes foundational and contemporary literature published through 2025, with particular emphasis on studies published since 2000 that inform toxicokinetics, biomarker interpretation, diagnostics, clinical management, and prevention. Full article

Photosensitization is a clinically significant dermatological and systemic disorder affecting grazing livestock worldwide. The condition arises following the ingestion or dermal exposure to photodynamic compounds that, upon activation by ultraviolet (UV) or visible light, induce tissue injury. Plant-associated photosensitization remains one of the most important aetiological categories in veterinary toxicology and may occur via primary (direct phototoxic) or secondary (hepatogenous) mechanisms. This review synthesizes current knowledge on the occurrence of photosensitizing compounds in plants, their biochemical and toxicodynamic properties, and their clinical relevance in livestock species. Emphasis is placed on major primary photosensitizing taxa, including Heracleum spp. and Hypericum perforatum, as well as hepatotoxic pyrrolizidine alkaloid-containing plants such as Senecio spp. Mechanistic pathways, plant metabolite ecology, and toxicopathological outcomes are discussed alongside illustrative case material. Plant-associated photosensitization also carries substantial economic consequences through decreased productivity, increased treatment costs and culling losses in affected herds and flocks. This condition represents a significant animal welfare concern in pasture-based production systems, where prolonged sunlight exposure, limited shade availability, and variable botanical composition of grazing areas can exacerbate both the incidence and severity of clinical manifestations. This review may provide a consolidated veterinary toxicology framework for understanding plant-associated photosensitization in grazing systems. Full article

“Vomiting disease” in ruminants is one of the most economically significant phytotoxicities in South Africa and is caused by chronic ingestion of sesquiterpene lactone compounds present in plants of the Geigeria genus. Affected livestock demonstrate mortality due to actin and myosin damage in the striated musculature; however, a validated parental-exposure laboratory animal model would be useful for further study of the toxicodynamics. We exposed Sprague–Dawley rats to ivalin in a sequential dosing procedure and evaluated clinical signs, mortality, histopathology and muscle ultrastructure. Three of the five exposed rats died acutely, and a maximum likelihood estimate method was used to calculate a Median Lethality (LD₅₀) of 135.4 mg/kg Body Weight (BW). Striated muscle in exposed rats showed only minimal and inconsistent histopathological and ultrastructural changes. Subcutaneous ivalin exposure causes acute mortality with minimal muscle pathology, contrasting with the more protracted muscular disease seen in ruminants after plant ingestion. This suggests toxicity by parenteral exposure is due to another mechanism, most likely mitochondrial energy pathway disturbances. Whilst subcutaneously exposed rats do not appear to provide a suitable model for oral sesquiterpene lactone exposure in ruminants, this study provides a starting dose for further investigation of plant extracts in both species. Full article

Objectives: One of the major trends in modern computational toxicology is the development of explainable predictive tools. However, the complex nature of the mechanistic representation of biological organisms and the lack of relevant data remain limiting factors. Methods: This work provides a publicly available dataset of 12,654 compounds with mouse intravenous ${\mathrm{LD}}_{50}$ values, as well as docking scores (Vina-GPU 2.0) against 44 toxicity-associated proteins. NIH and Brenk filters were applied to refine the chemical space. Results: Across the entire protein panel, the human ether-a-go-go–related gene channel (hERG/KCNH2), vasopressin receptor 1A (AVPR1A), the L-type voltage-gated calcium channel Cav1.2 (CACNA1C), the potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) and endothelin receptor A (EDNRA) showed the strongest association with acute toxicity. Statistically significant differences were found in the distribution of ${\mathrm{LD}}_{50}$ values for compounds that bind antitargets compared with non-binders. Using known bioactive molecules such as anisodamine, butaperazine, soman, and several cannabinoids as examples confirmed the effectiveness of inverse docking for elucidating mechanism of action. Conclusions: The dataset offers a resource to advance transparent, mechanism-aware toxicity modeling. The data is openly available. Full article

Amanita muscaria (L.) Lam., commonly known as fly agaric, remains an uncommon yet clinically important cause of acute mushroom intoxication. Although typically associated with mild to moderate neuropsychiatric disturbances, the mushroom’s toxic profile is highly variable and continues to attract scientific, toxicological, and public health interest. This work provides an integrative review of the biochemical composition, toxicodynamics, and clinical manifestations associated with A. muscaria exposure, with particular emphasis on the pharmacological actions of its principal constituents, ibotenic acid and muscimol. The review is complemented by two contemporaneous cases of severe intoxication in elderly individuals, illustrating the real-world clinical expression of the toxidrome and the challenges in diagnosis and management. Both cases presented with rapid-onset gastrointestinal symptoms, profound central nervous system depression, and cholinergic features, requiring intensive supportive therapy, atropine infusion, and continuous monitoring. Full recovery was achieved in both patients. These clinical observations contextualize the broader toxicological framework discussed in the review and underscore the need for increased clinical vigilance, improved public education, and strengthened diagnostic and therapeutic preparedness regarding psychoactive wild mushroom exposures. Full article

Environmental pollution, driven by industrialization, urbanization, and agricultural practices, has intensified global ecological degradation. Among the most concerning pollutants is PFOS, a synthetic compound known for its chemical stability, environmental persistence, and bioaccumulative potential. Widely utilised in industrial and consumer products, PFOS infiltrates ecosystems and food chains, posing substantial risks to human and animal health. Upon exposure, PFOS disrupts lipid metabolism, damages cellular membranes, and alters signaling pathways through partial metabolism by cytochrome P450 enzymes. Accumulating evidence links PFOS to oxidative stress, mitochondrial dysfunction, endocrine disruption, neurotoxicity, and immunotoxicity. Critically, PFOS contributes to the development and progression of prostate, breast, and ovarian cancers via mechanisms such as hormonal interference, chronic inflammation, and epigenetic modifications. Epidemiological studies further associate elevated PFOS serum levels with increased cancer risk, particularly in occupationally and environmentally exposed populations. This review brings together the latest knowledge on PFOS emissions, mechanistic toxicity, and cancer-causing potential, highlighting the urgent need for focused research and improved regulatory measures to safeguard public health. Full article

Honey is a valuable natural product prized for its nutritional and therapeutic properties, including antioxidant, antimicrobial, and anti-inflammatory effects. However, in addition to health-promoting compounds, honey may also contain plant-derived toxins, contaminants, and degradation products. Certain phytotoxins—such as pyrrolizidine alkaloids, grayanotoxins, triptolide, celastrol, gelsedine-type alkaloids, and tutin—can be transferred to honey from specific plant sources and pose health risks, particularly at high doses or with long-term exposure. Furthermore, compounds like 5-hydroxymethylfurfural, trace metals, pesticide residues, and Clostridium botulinum spores may present additional risks, especially to sensitive groups such as infants. Consumers often assume that natural products are inherently safe, which may lead to unintentional exposure to harmful substances. Adverse effects can range from chronic toxicity to, in extreme cases, death. Therefore, raising awareness among consumers and vendors is essential to reduce the intake of honey from unverified sources. Continuous monitoring of honey composition and further studies on the toxicodynamics of rare contaminants are crucial to ensuring safety while preserving the therapeutic benefits of this remarkable natural substance. Full article

The widespread production and poor management of plastic waste have led to the pervasive presence of microplastics (MPs) in environmental and biological systems. Among various polymers, polyethylene (PE) is the most widely produced plastic globally, primarily due to its use in single-use packaging. Its persistence in ecosystems and resistance to degradation processes result in the continuous formation of PE-derived MPs. These particles have been detected in human biological matrices, including blood, lungs, placenta, and even the brain, raising increasing concerns about their bioavailability and potential health effects. Once internalized, PE MPs can interact with cellular membranes, induce oxidative stress, inflammation, and apoptosis, and interfere with epigenetic regulatory pathways. In vitro studies on epithelial, immune, and neuronal cells reveal concentration-dependent cytotoxicity, mitochondrial dysfunction, membrane disruption, and activation of pro-inflammatory cytokines. Moreover, recent findings suggest that PE MPs can induce epithelial-to-mesenchymal transition (EMT), senescence, and epigenetic dysregulation, including altered expression of miRNAs and DNA methyltransferases. These cellular changes highlight the potential role of MPs in disease development, especially in cardiovascular, metabolic, and possibly cancer-related conditions. Despite growing evidence, no standardized method currently exists for quantifying MPs in human samples, complicating comparisons across studies. Further, MPs can carry harmful additives and environmental contaminants such as bisphenols, phthalates, dioxins, and heavy metals, which enhance their toxicity. Global estimates indicate that humans ingest and inhale tens of thousands of MPs particles each year, yet long-term human research remains limited. Given these findings, it is crucial to expand research on PE MP toxicodynamics and to establish regulatory policies to reduce their release. Promoting alternative biodegradable materials and improved waste management practices will be vital in decreasing human exposure to MPs and minimizing potential health risks. Full article

Povidone-iodine (PVP-I), a widely used aquaculture disinfectant, remains poorly understood in terms of sublethal toxicity and damage reversibility. This study employed Macrobrachium rosenbergii as the model organism to evaluate the acute toxicity and sublethal effects of PVP-I through a 4-day exposure experiment followed by a 7-day depuration period. Acute toxicity tests enabled the determination of 24–96 h median lethal concentrations (LC₅₀), with the 96 h LC₅₀ being 5.67 mg/L and the safe concentration (SC) being 1.37 mg/L. Based on this, three sublethal concentrations (1.14, 1.89, and 2.84 mg/L) were tested over a 4-day exposure followed by a 7-day depuration period. Investigated endpoints included gill ultrastructure, apoptosis, and antioxidant and immune-related gene expression. Subacute exposure at 1.89 and 2.84 mg/L induced mitochondrial vacuolization, upregulated apoptosis-related genes (Cyt-c, Caspase-3, Bok), and downregulated antioxidant gene expression (SOD, CAT, GSH-Px). The high-concentration group also showed sustained Toll-like receptor (Toll) gene overexpression and acid phosphatase (ACP) gene suppression. After depuration, antioxidant gene expression normalized; however, apoptotic markers in gill tissue remained impaired. Overall, high PVP-I concentrations cause irreversible gill damage via mitochondrial-mediated apoptosis, whereas lower concentrations (≤1.14 mg/L) allow for greater recovery. These results offer crucial toxicodynamic insights for safer PVP-I use and risk assessment in M. rosenbergii aquaculture. Full article

Background: Sirolimus (SRL, rapamycin) is a clinically important mTOR inhibitor used in immunosuppression, oncology, and cardiovascular drug-eluting devices. Despite its long-standing FDA approval, the human metabolic profile of SRL remains incompletely characterized. SRL is primarily metabolized by CYP3A enzymes in the liver and intestine, but the diversity, pharmacokinetics, and biological activity of its metabolites have been poorly explored due to the lack of structurally identified standards. Methods: To investigate SRL metabolism, we incubated SRL with pooled human liver microsomes (HLM) and isolated the resulting metabolites. Structural characterization was performed using high-resolution mass spectrometry (HRMS) and ion trap MSⁿ. We also applied Density Functional Theory (DFT) calculations to assess the energetic favorability of metabolic transformations and conducted molecular dynamics (MD) simulations to model metabolite interactions within the CYP3A4 active site. Results: We identified 21 unique SRL metabolites, classified into five major structural groups: O-demethylated, hydroxylated, didemethylated, di-hydroxylated, and mixed hydroxylated/demethylated derivatives. DFT analyses indicated that certain demethylation and hydroxylation reactions were energetically preferred, correlating with metabolite abundance. MD simulations further validated these findings by demonstrating the favorable orientation and accessibility of key sites within the CYP3A4 binding pocket. Conclusions: This study provides a comprehensive structural map of SRL metabolism, offering mechanistic insights into the formation of its metabolites. Our integrated approach of experimental and computational analyses lays the groundwork for future investigations into the pharmacodynamic and toxicodynamic effects of SRL metabolites on the mTOR pathway. Full article

Botanical insecticides derived from neem (Azadirachta indica A. Juss.) seeds have gained significant interest due to their sustainable characteristics and low environmental impact. However, their use in sericulture remains contentious due to the heightened sensitivity of domesticated silkworms to environmental stressors. This study systematically investigates the toxicodynamic effects of aqueous neem seed extract (ANSE) on fifth instar larvae of Thai multivoltine Bombyx mori L., focusing on larval mortality and carboxylesterase (CarE) enzyme activity in essential detoxification organs. Larvae were exposed to ANSE concentrations ranging from 5 to 50 mg L⁻¹ for up to 72 h. Key findings highlight a pronounced dose- and time-dependent increase in mortality, with an accurately determined LC₅₀ value of 17 mg L⁻¹ at the longest time exposure, accompanied by mortality rates reaching approximately 83% at the highest concentration tested, indicating considerable susceptibility. Additionally, notable and distinct organ-specific responses were observed, with significant inhibition of CarE activity in the midgut contrasting with elevated activities in the fat body and Malpighian tubules. These differential enzymatic responses reveal previously undocumented adaptive detoxification mechanisms. Consequently, the study advocates cautious and regulated application of neem-based insecticides in sericulture, recommending precise management of concentrations and exposure durations according to silkworm strain sensitivities to ensure optimal silk production. Full article

Objectives: There is growing concern over tyrosine kinase inhibitor (TKI)-induced cardiotoxicity, particularly regarding left ventricular dysfunction and heart failure in clinical treatment. These adverse effects often lead to treatment discontinuation, severely impacting patient outcomes. Therefore, there is an urgent need for more precise risk assessment methods. This study aimed to assess the cardiotoxicity of TKIs, refine in vitro to in vivo extrapolation (IVIVE) methodologies to improve predictive accuracy, and identify critical in vitro parameters for assessment. Methods: By leveraging high-throughput cardiotoxicity screening with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), a mechanism-based toxicodynamic (TD) model for TKIs was constructed. A QSP-PK-TD model was developed by integrating pharmacokinetic (PK) and quantitative systems pharmacology (QSP) models. This model incorporates critical drug exposure factors, such as plasma protein binding, tissue–plasma partitioning, and drug distribution heterogeneity to enhance extrapolation accuracy. Results: The QSP-PK-TD model validated the reliability of IVIVE and identified the area under the curve of drug effects on mitochondrial membrane potential (AEMMP) and cardiomyocyte contractility (AEAAC) as key in vitro parameters for assessing TKI-induced cardiotoxicity. Incorporating critical drug exposure factors obviously improved qualitative and quantitative extrapolation accuracy. Conclusions: This study established a framework for predicting in vivo cardiotoxicity from in vitro parameters, enabling efficient translation of preclinical data into clinical risk assessment. These findings provide valuable insights for drug development and regulatory decision-making, offering a powerful tool for evaluating TKI-induced cardiotoxicity. Full article

Mycotoxins are secondary metabolites of filamentous fungi and ubiquitous dietary contaminants. Aflatoxins, a group of mycotoxins with high prevalence and toxicity, have raised a high level of public health concern, the most prevalent and toxic being aflatoxin B1 (AFB1). Many aspects appertaining to AFB1 poisoning are not well understood. Yet this information is necessary to devise appropriate surveillance and mitigation strategies against human and animal aflatoxicosis. This review provides an in-depth update of work carried out on mycotoxin poisoning, particularly aflatoxicosis in humans and animals, to identify gaps in knowledge. Hypotheses explaining the functional significance of mycotoxins in fungal biology and their dietary epidemiological data are presented and briefly discussed. The toxicology of aflatoxins and the challenges of their mitigation are discussed in depth. It was concluded that the identification of potential mycotoxin-hazard-prone food items and quantification of the associated risk of cancer ailments in humans is a prime priority. There is a dearth of reliable sampling methodologies for estimating AFB1 in animal feed. Data update on AFB1 in animal feed and its implication in animal production, mitigation strategies, and elucidation of risk factors to this hazard is required. To reduce the burden of aflatoxins, surveillance employing predictive technology, and biocontrol strategies seem promising approaches. Full article