Frontiers in toxicology最新文献

[This corrects the article DOI: 10.3389/ftox.2025.1646075.].

With growing interest in new protein sources, driven by market trends and European Union (EU) food policy priorities, novel proteins are entering the market. These novel foods (NFs) might have the potential of introducing new allergens into the diet. In the EU, the European Food Safety Authority (EFSA) is tasked with assessing the safety of NFs and has recently updated its scientific guidance to reflect advancements in food science and built-up experience in NF risk assessment (RA). EFSA's allergenicity RA strategy follows a weight-of-evidence approach. Data requirements depend on whether the NF is produced from or with materials containing protein, derived from known allergenic foods (whether subject to mandatory labelling or not), or has unknown allergenic potential. For the latter, a tiered approach focused on assessing the cross-allergenicity potential is applied to single proteins, protein mixtures and whole foods. However, allergenicity RA continues to face challenges including the availability of reference standard materials and the lack of agreement on the interpretation of in silico and in vitro results, as well as lack of validated and internationally recognized methods meeting regulatory requirements. These limitations underscore the need for further research to deliver robust and fit-for-purpose RA tools to support safe food systems. This review highlights key aspects of the allergenicity RA approach presented in the updated EFSA NF scientific guidance and provides a critical overview of existing uncertainties and emerging approaches aiming at encouraging international cooperation and research to further enhance allergenicity RA.

Background: Oral tobacco-derived nicotine (OTDN) pouches are tobacco-free products and are considered potential reduced-risk alternatives to traditional tobacco products within the tobacco harm reduction framework. Despite their growing popularity, the local oral toxicity profiles of OTDNs remain poorly characterized. Although in vitro toxicity studies have been conducted, the lack of standardized testing protocols, including solvent vehicle selection, limits data comparability across laboratories. To address this, we evaluated and compared the biological effects of artificial saliva (AS) and complete artificial saliva (CAS) across four in vitro oral models to identify an appropriate solvent vehicle for mechanistic testing.

Methods: Extraction efficiency was first assessed using the Swedish-style reference snus pouch CRP1.1 extracted in AS and CAS from 10% to 30% w/v concentrations. Nicotine and tobacco-specific nitrosamines (TSNAs) were quantified for extraction efficiency. The biological effects of AS and CAS, including cytotoxicity, oxidative stress, and inflammatory responses, were evaluated across four in vitro oral models, including monolayer normal human gingival fibroblasts (NHGFs) and oral epithelial cells (NHOEs), as well as 3D organotypic models (EpiOral™ and EpiOral™ Full Thickness).

Results: The results showed comparable nicotine extraction efficiency between AS and CAS, with no significant impact from pouch cutting size or extraction duration. However, AS demonstrated higher efficiency in extracting TSNAs compared to CAS at 10% and 20% w/v, with the extraction efficiency decreasing as extract concentrations increased.Neither AS nor CAS induced cytotoxicity in any of the oral models. CAS triggered oxidative stress at the highest concentration in ORL-300-FT. Both AS and CAS elicited concentration-dependent pro-inflammatory responses in NHGFs and NHOEs. Specifically, AS increased both IL-6 and IL-8 secretion in NHOEs, while CAS elevated IL-8 release in both NHGFs and NHOEs but exhibited opposing effects on IL-6 secretion in NHOEs. In the organotypic tissue models, both AS and CAS reduced IL-6 secretion without significantly affecting IL-8 levels.

Conclusion: These findings emphasize the importance of evaluating additional biological responses alongside cytotoxicity in vehicle control studies. CAS and ORL-300-FT were chosen for future testing due to their minimal vehicle effects and greater biological relevance, providing a robust platform for assessing oral tobacco product toxicity.

Turmeric (Curcuma longa) and Indian gooseberry (Phyllanthus emblica) are widely used for their ethnopharmacological properties, particularly in ASEAN countries. Recently, our group has formulated Thai rice instant granules containing turmeric extract and P. emblica fruit pulp (TR instant granules); however, their toxicity profile has not been evaluated. This study investigated the long-term safety of TR instant granules in rats and assessed their effect on hepatic antioxidant status. Oral administration at doses of 200, 600, and 2,000 mg/kg body weight for 180 days resulted in no toxic effects, behavioral changes, mortality, or alterations in organ weights or hematological parameters. Significant changes were observed in biochemical markers, but there were no histopathological abnormalities. TR instant granules significantly upregulated hepatic antioxidant genes (Nrf2, GPx, CAT, GR, SOD, and HO-1). Phytochemical analysis identified chlorogenic acid and curcumin as major constituents. In silico molecular docking demonstrated that these compounds strongly bind multiple antioxidant enzymes and the Nrf2-Keap1 complex, supporting their potential as effective modulators of cellular antioxidant defenses. Overall, long-term administration of TR instant granules is safe and may enhance antioxidant mechanisms in rats. These findings support the potential development of TR instant granules as a safe functional food or nutraceutical with antioxidant benefits.

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) causes disabling cognitive-behavioral symptoms. While cortical atrophy is recognized as a correlate of long-term outcome, links between intracortical microstructural dynamics and clinical presentation remain largely unexplored. We followed a 51-year-old man with new-onset DEACMP for 5 months, using serial MRI combining cortical thickness with T1-weighted/T2-weighted (T1w/T2w) mapping as a proxy for intracortical microstructure. Despite progressive cortical thinning, T1w/T2w signals showed heterogeneous, region-specific trajectories. In the frontal networks, increases within premotor and dorsolateral prefrontal cortices aligned with improvements in executive function, whereas limited change in orbitofrontal/ventrolateral cortices was consistent with behavioral disinhibition. Overall, the clinical picture tracked more closely with intracortical signals than with morphometric atrophy. By combining T1w/T2w mapping with morphometry, this case provides the first longitudinal evidence of divergent cortical trajectories in subacute DEACMP-progressive thinning versus early intracortical improvement; confirmation in larger cohorts is warranted.

The use of Heated Tobacco Products (HTPs) is expected to have a reduced-risk potential for cardiovascular disease, including atherosclerosis, compared with combustible cigarettes (CCs) Because of the complex relationship between atherosclerosis and lifestyle factors, such as diet, physical activity, and smoking, focusing on the pathogenesis of atherosclerosis will help deepen our understanding of the reduced risk potential of HTPs. Organ-on-a-chip platforms are widely used to mimic human pathophysiology when studying such pathologic manifestations. In this study, a Vascular-on-a-Chip (VoC) model was used to mimic the characteristic physiology of the human vasculature and to establish an assessment model to measure three endpoints: endothelial barrier impairment, monocyte adhesion, and monocyte migration through vascular endothelial cells (VECs) which are the important initial key events in atherosclerosis. Macrophages were exposed to test cigarette smoke (CS) and HTP aerosol extracts, and conditioned medium was collected. VECs cultured on VoC were exposed to these conditioned media to mimic the effects on the vascular system caused by inflammatory responses elicited by inhaled substances. The HTP aerosol-exposed group had significantly reduced endothelial barrier impairment, monocyte adhesion, and monocyte migration compared with the CS-exposed group, and there was no significant difference with the solvent control. In summary, our model provided valuable insights into the reduced risk potential of an HTP compared with a CC by evaluating a series of endpoints in the early stage of atherosclerosis.

The Beibu Gulf, a representative semi-enclosed bay in the South China Sea, experiences microplastic transport and dispersion governed by a complex interplay of monsoons, ocean circulation, and extreme weather events, warranting systematic investigation. We developed a numerical modeling framework by coupling a three-dimensional hydrodynamic model with a Lagrangian particle-tracking module, and validated it against in observations. The model quantitatively demonstrates high accuracy, with maximum spatial deviations below 6 km and relative standard deviations within 7%, confirming its suitability for simulating microplastic transport. The simulation results indicate that the transport of microplastics in the Beibu Gulf is primarily controlled by the oceanic hydrodynamic environment, while also being indirectly affected by the monsoon. During winter and autumn, the northeast monsoon dominates, whereas in spring and summer, the southwest monsoon prevails, with the overall circulation exhibiting a counterclockwise coastal current pattern. In spring, microplastics can disperse up to 205 km, while in summer, southwest monsoon conditions lead to the formation of nearshore high-concentration zones (∼20 μg/m³). Vertical transport significantly modulates plume structure, with summer pollution coverage expanding by over 70% compared to scenarios excluding vertical motion.Storm surge events further intensify hydrodynamic conditions. As a case study, Typhoon Yagi induced significant alterations in the hydrodynamic conditions of the Beibu Gulf: prior to the storm, tidal forces governed periodic flow variations; during and after the storm, intense circulations generated prominent counterclockwise vortices, with velocities reaching 2.8 m/s, substantially enhancing long-range microplastic transport and extending their spatial distribution. This study reveals the key characteristics of microplastic transport in the Beibu Gulf under varying seasonal and hydrodynamic conditions, providing a rigorous theoretical foundation for understanding regional microplastic dispersal patterns.

Introduction: Despite the availability of control animal data sets from toxicological studies, the influence of external factors, such as age of animals, test site and study conditions, on clinical laboratory parameters in rats is only sparsely characterized.

Objective: In order to analyze the covariates of study design, we leveraged the largest available curated collection of control animal data from toxicological studies, sourced from five European pharmaceutical companies. We investigated the influence of external factors on commonly measured clinical chemistry, enzyme activity and hematology parameters in Han Wistar rats of both sexes.

Materials and methods: 457,605 control group clinical laboratory data points from 1,288 legacy toxicity studies on Han Wistar rats were curated and analyzed by ANOVA and partial eta squared to discern their effect sizes.

Results: Our analysis revealed that bodyweight, used as a surrogate for age in rats, significantly influences some parameters, while demonstrating stability in others. Descriptive statistics and tolerance intervals are provided for 20-g body weight class intervals. The effect size of these body weight classes, as calculated by partial eta squared, is large for parameters that change during development (e.g., phosphate or alkaline phosphatase) but was negligible for more stable parameters (e.g., calcium and alanine aminotransferase). For parameters which are less dependent on body weight class, the relative influence of other factors, namely, the company providing the study data, as well as study year is more prominent. These factors likely act as summary factors for various influences such as changes in analytical protocols, diet or housing conditions.

Conclusion: This analysis provides a comprehensive overview of parameter variability and offers critical guidance for parameters which need to be controlled when utilizing historical control data to establish reference intervals or generate virtual control groups.

The advancement of human pluripotent stem cell (hPSC) culture systems has revolutionized the landscape of preclinical drug discovery and toxicological evaluation. Progressing innovations from feeder-dependent and xenogeneic matrices to chemically defined, xeno-free, and fully synthetic platforms have addressed long-standing challenges in reproducibility, safety, and clinical translation. Developments in recombinant extracellular matrix proteins, synthetic peptide substrates, and polymer-based coatings have enabled the generation of Good Manufacturing Practice (GMP)-compliant, scalable hPSC cultures while minimizing biological variability and immunogenic risks. Integration of automation, artificial intelligence (AI), and three-dimensional (3D) bioprocessing technologies aims at further enhancement of standardization, quality control, and throughput. In the context of pharmaceutical research, hPSC-derived cellular models now underpin high-throughput drug screening and mechanistic toxicological assays, offering superior human relevance compared to traditional animal models. Despite these advances, barriers such as cellular immaturity, inter-batch variability, and limited regulatory acceptance persist, underscoring the need for further protocol standardization and technological refinement. This review provides a comprehensive analysis of current animal-free hPSC culture platforms, critically examines their strengths and limitations, and discusses future directions for advancing their application in drug discovery and predictive toxicology. The ongoing evolution of hPSC technologies promises to accelerate the development of safer, more effective therapeutic agents and to reshape the future of human disease modeling and pharmacological research.