International Journal of Toxicology最新文献

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Polyhydroxystearic Acid, Poly(3-Hydroxyoctanoic Acid), and Polylactic Acid as used in cosmetic formulations. These ingredients are reported to function in cosmetics as a non-surfactant dispersing agent, a skin-conditioning agent, and an abrasive agent, respectively. The Panel reviewed the available data to determine the safety of these ingredients and concluded that these ingredients are safe in cosmetics in the present practices of use and concentrations described in this safety assessment.

The FDA has recently approved a medical device which determines a glomerular filtration rate assessment at the point-of-care by transdermal detection of the fluorescent tracer agent relmapirazin. Previous in vitro and in vivo studies on this agent yielded negligible safety/toxicology concern resulting in advancement to phase I, II, and III human clinical studies. Now that clinical use is occurring, herein we investigated possible interference this agent may induce with typical clinical diagnostic assays given to incoming and hospitalized patients. The testing methodology followed the CLSI EP07-A3 Interference Testing in Clinical Chemistry guideline for determination of interference. No interference from relmapirazin was detected in the suite of metabolic and cardiac assays evaluated.

Artificial intelligence (AI) and machine learning are increasingly used in toxicological risk assessment to predict chemical toxicity, identify hazardous compounds, and support regulatory decision-making. However, the widespread adoption of these models is limited by their "black-box" nature, which reduces interpretability, transparency, and regulatory confidence. Explainable artificial intelligence (XAI) has emerged as a promising approach to address these challenges by revealing how input features, including chemical structures, exposure levels, and biological pathways, contribute to toxicity predictions. Techniques such as SHAP (SHapley Additive exPlanations) and LIME (Local Interpretable Model-agnostic Explanations) provide interpretable insights into model decision-making and enhance trustworthiness, accountability, and mechanistic understanding. Despite these advances, most XAI applications in toxicology remain at the computational or preclinical stage, with limited clinical and regulatory translation. This review summarizes current AI-based approaches for toxicity prediction, examines the interpretability challenges that hinder their practical implementation, and highlights the emerging role of XAI in bridging the gap between computational prediction and clinical application. Greater standardization, integration of human data, and collaboration among academia, industry, and regulatory agencies will be essential for advancing transparent and clinically actionable toxicology models.

Benzothiazoles are widely used rubber additives and common contaminants in urban runoff, yet their toxicity across human tissues remains poorly characterized. We evaluated the cytotoxicity of six benzothiazole derivatives, benzothiazole (BTH), 2-hydroxybenzothiazole (OH-BTH), 2-aminobenzothiazole (NH₂-BTH), 2-methylbenzothiazole (Me-BTH), 2-mercaptobenzothiazole (SH-BTH), and methyl-thiobenzothiazole (Me-S-BTH), across nine human cell lines representing intestinal, skin, lung, kidney, brain, endothelial, muscle, epithelial, and hepatic tissues. EC₅₀ values spanned more than nine orders of magnitude (1.5 × 10^-9 M to >1 M), revealing strong compound- and cell-type-specific variability. SH-BTH was the most potent derivative, with EC₅₀ values of 1.5 × 10^-9 M in Caco-2 (intestinal cells), 1.1 × 10^-8 M in HMC-3 (brain microglia cells), 3.9 × 10^-5 M in MRC-5 (lung fibroblasts), 6.6 × 10^-4 M in HMEC-1 (microvascular endothelial cells), and 1.3 × 10^-3 M in HepaRG (hepatocytes). Me-S-BTH showed similarly high potency in HMC-3 (2.0 × 10^-8 M) and moderate toxicity in endothelial and hepatic cells (2.3 × 10^-3 M and 1.1 × 10^-3 M, respectively). In contrast, BTH and Me-BTH exhibited low cytotoxicity, with EC₅₀ values typically ≥10^-3 M and no measurable toxicity (>1 M) in several models, including HepaRG. OH-BTH and NH₂-BTH showed intermediate effects, with micromolar activity in selected cell lines but minimal toxicity in hepatic cells. Caco-2 and HMC-3 cells were the most sensitive models, whereas HepaRG, RMS13 (skeletal muscle), and skin HEK001 (skin keratinocytes) were the least responsive. Overall, toxicity was strongly structure-dependent, with sulfur-containing derivatives showing the highest potency.

Novel Psychoactive Substances (NPSs) and other psychoactive or misuse-relevant compounds present a persistent global public health threat, underscoring the critical need for real-time crawling and monitoring tools to investigate and provide valuable information assisting in the management and preparedness against that dynamic and evolving threat. This study utilized the NPSfinder^® web crawler to analyze NPS trends during the post-pandemic period, with data collected from selected highly trafficked psychonaut websites continuously monitored between January and September 2023. Following a comprehensive filtering process of screening, assessment, and evaluation, the dataset provided insights into the availability and characteristics of recently reported NPSs. Three hundred and sixty-eight molecules were analyzed, of which 158 were newly captured NPSs, suitable for inclusion in the NPSfinder^® database. Those substances were classified based on their chemical structure, pharmacological mechanism of action, therapeutic indication, if any, and abuse liability. The main NPS classes identified were natural origin/herbal substances (25; 16%), cannabinoids (23; 15%), prescribed medications (23; 15%), synthetic opioids (20; 13%), phenethylamines (14; 9%), cathinones (11; 7%), and anabolic substances (8; 5%). The findings highlight ongoing diversification in substances identified across selected online sources during the post-pandemic period. The study benefits from a timely focus, a substantial and systematically curated dataset, and the application of a continuous web-crawling methodology enabling near real-time detection of emerging substances. The integration of pharmacological and chemical classification further enhances the interpretability and potential clinical relevance of the findings. However, results should be interpreted cautiously. The reliance on predominantly English-language, open-web sources may introduce selection bias and limit geographic generalizability, and the descriptive design does not allow inference regarding prevalence, user behavior, or causal trends. Within these constraints, web-crawling approaches may serve as valuable complementary tools to established early warning systems, supporting early signal detection and informing future toxicological and public health responses.

Today, toxicologists have a diverse role in drug development and function in multidisciplinary teams with unique expertise. This article summarizes presentations from a continuing education (CE) course at the 2024 Annual Meeting of the American College of Toxicology (ACT), discussing different case studies with regulatory input. The six case studies from the CE course on regulatory toxicology in pharmaceutical drug development span small molecules, biologics, and gene therapy and illustrate key nonclinical challenges encountered across the development continuum, including formulation changes, impurities and degradants, route-specific toxicology, local tissue risk assessment, and interpretation of unexpected toxicity findings. Additional topics include evaluation of residual solvents, application of weight-of-evidence approaches, and integration of nonclinical and clinical data to support regulatory decision making. The case studies reflect real-world regulatory and scientific considerations across multiple stakeholder perspectives, including industry, contract research organizations, and regulatory agencies. Collectively, they demonstrate how toxicologists must integrate data from chemistry, manufacturing and controls (CMC), nonclinical studies, and clinical pharmacology to support risk assessment and clinical development strategies. Across the cases, common themes emerge, including increasing reliance on exposure-based assessments, application of integrated weight-of-evidence frameworks, adaptation of study designs to novel therapeutic modalities, and the importance of early and proactive regulatory engagement. These examples further highlight the need for toxicologists to manage uncertainty, interpret incomplete datasets, and provide scientifically justified recommendations within compressed development timelines. Overall, these case studies illustrate the evolving role of the toxicologist responsible for translating multidisciplinary data into regulatory strategies that enable safe and efficient drug development.

Short-chain fatty acids (SCFAs) support intestinal homeostasis and have been explored for applications in functional foods. SCFA 455 is an SCFA-enriched culture filtrate powder produced from Clostridium butyricum S-45-5. This study evaluated the subchronic oral toxicity and genotoxic potential of SCFA 455 in OECD guideline-compliant studies. Acute oral toxicity up to a dose level of 2000 mg/kg (OECD TG 423), and repeat dose oral toxicity for 90 days with a 4-week recovery period (OECD TG 408) at the dose levels of 0, 1000, 2000, and 4000 mg/kg bw/day, were assessed in Sprague-Dawley rats. No mortality or treatment-related clinical signs were observed. Minor changes in urinalysis, hematology, serum biochemistry, and organ weights were sporadic or lacked a consistent adverse pattern and were not supported by histopathology; therefore, these findings were considered non-adverse. The no-observed-adverse-effect level (NOAEL) was 4000 mg/kg bw/day, the highest dose evaluated under the study conditions. Genotoxicity was assessed using a bacterial reverse mutation test (OECD TG 471), an in vitro chromosomal aberration test (OECD TG 473), and an in vivo micronucleus test in male ICR mice (OECD TG 474). SCFA 455 did not induce gene mutations or chromosomal aberrations in vitro, nor did it induce micronuclei in male ICR mice. Overall, SCFA 455 showed low systemic toxicity and no evidence of genotoxicity, supporting further development of SCFA 455 as a postbiotic candidate and potential functional food ingredient.

We identified an assay-dependent, artifactual prolongation of activated partial thromboplastin time (aPTT) during nonclinical safety studies of an enzyme biologic conjugated with a next-generation polyethylene glycol (PEG)-like stealth polymer, poly(oligoethylene glycol) methyl ether methacrylate (POEGMA), in cynomolgus monkeys. Two repeat-dose studies (8 and 13 weeks) with twice-weekly subcutaneous dosing evaluated pharmacokinetic/toxicokinetic (PK/TK) and pharmacodynamic (PD) assessments, clinical pathology, and gross/histopathology. The 8-week study used a single silica-based aPTT assay; the 13-week study used both silica-based and kaolin-based assays. In the 8-week study, the silica-based assay showed time- and dose-dependent aPTT prolongation at Weeks 4 and 8. PK/PD effects were most evident in Weeks 1-2, decreased thereafter, likely due to immunogenicity, and did not correlate with aPTT changes. Other coagulation parameters (eg, prothrombin time and fibrinogen) were unremarkable, and histopathology showed no bleeding or coagulopathy. In the 13-week study, aPTT prolongation again occurred only with the silica-based assay, whereas the kaolin-based assay showed no effect. Ex vivo aPTT testing used naïve monkey plasma spiked with either the biologic or POEGMA alone; neither component prolonged aPTT with either assay, indicating no direct interference. Collectively, these data indicate that the observed aPTT changes were assay-dependent artifacts related to the silica activator, rather than true pharmacologic or toxicologic effects. In contrast, such artifactual aPTT prolongation was not induced by the same enzyme biologic when conjugated with conventional 20-kDa PEG, indicating a POEGMA-conjugate-specific artifact.

Diosgenin, derived from Dioscorea alata, is a well-known traditional medicinal compound with therapeutic potential against various conditions, including cancer and cardiovascular diseases. This study aimed to synthesize diosgenin polyethylene glycol succinate (DPGS) from diosgenin and evaluate its acute and chronic toxicity in rats. DPGS was designed as a novel amphiphilic excipient for universal solubilization, improving drug delivery and therapeutic performance. The acute toxicity assessment involved administering DPGS to female Albino-Wistar rats, while the chronic toxicity study was conducted over 90 days in both male and female Albino-Wistar rats at doses of 0 (control), 500, 1000, and 2000 mg/kg body weight/day. Additionally, recovery groups from the control and high-dose categories were observed for another 28 days. In the acute toxicity study, no clinical toxicity or mortality was observed at the highest dose of 2000 mg/kg body weight/day. Similarly, in the 90-day chronic study, no mortality or significant treatment-related effects were detected across all dose groups in either sex, based on histopathological, hematological, and clinical chemistry evaluations. These findings suggest that the oral no-observed-adverse-effect level (NOAEL) of DPGS in Albino-Wistar rats is greater than 2000 mg/kg body weight/day. The results support the safety profile of DPGS and its potential application as an excipient in drug formulation and delivery systems.