Archives Of Toxicology[JOURNAL]
Sun
200 papers
ToxiGuard: an AOP-guided mechanistically interpretable framework for multi-organ toxicity prediction.
Zhao C, Wang J, Bo X … +1 more , He S
Arch Toxicol · 2026 May · PMID 42159741 · Publisher ↗
Accurate prediction of organ-specific toxicity with mechanistic interpretability remains a central challenge in chemical safety assessment and translational toxicology. Although animal-based assays provide biologically r...
Accurate prediction of organ-specific toxicity with mechanistic interpretability remains a central challenge in chemical safety assessment and translational toxicology. Although animal-based assays provide biologically relevant information, they are low throughput and increasingly constrained by ethical and regulatory considerations. In parallel, data-driven computational approaches-particularly deep learning-have achieved strong predictive performance but often lack transparency, limiting their utility for mechanistic interpretation and regulatory decision-making. Here, we present ToxiGuard, a mechanistically informed deep learning framework that embeds organ-specific Adverse Outcome Pathway (AOP) structures directly into the model architecture. By explicitly encoding Molecular Initiating Event-Key Event-Adverse Outcome (MIE-KE-AO) connectivity, ToxiGuard constrains representation learning to biologically plausible causal pathways rather than relying solely on post hoc explanation. The framework integrates molecular descriptors, functional-class fingerprints, and curated AOP networks to enable complementary interpretability at both chemical and biological levels. Across four organ toxicity endpoints-hepatotoxicity, cardiotoxicity, nephrotoxicity, and respiratory toxicity-ToxiGuard demonstrates robust and consistent predictive performance, outperforming traditional machine learning models and AOP-agnostic neural network baselines. SHAP-based analyses reveal concentrated contributions from specific physicochemical properties, molecular substructures, and mechanistic AOP components, including CAR/PXR-associated pathways in hepatotoxicity and hERG-related mechanisms in cardiotoxicity. These findings are consistent with established toxicological knowledge and support the biological plausibility of model predictions. Overall, this study demonstrates that embedding mechanistic toxicological structure into deep learning architectures can enhance both predictive reliability and interpretability. ToxiGuard provides a transparent, AOP-anchored computational approach that complements existing experimental and in silico methods for early-stage organ toxicity assessment and chemical safety evaluation.
Translating human biomonitoring data into quantitative exposure and risk estimates for chloromethylisothiazolinone and methylisothiazolinone using a population pharmacokinetic model.
Jang JH, Lee CH, Park YJ … +4 more , Chung KH, Lee B, Baek YW, Jeong SH
Arch Toxicol · 2026 May · PMID 42159740 · Publisher ↗
Human biomonitoring provides direct measures of internal exposure to environmental chemicals, but translating biomarker concentrations into quantitative external exposure and risk estimates remains challenging. Chloromet...
Human biomonitoring provides direct measures of internal exposure to environmental chemicals, but translating biomarker concentrations into quantitative external exposure and risk estimates remains challenging. Chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) are widely used biocides, and population exposure is typically assessed via urinary biomarkers. However, a quantitative framework connecting biomonitoring data to external dose and health risk is currently lacking. This study aims to quantitatively reconstruct external CMIT/MIT exposures from human urinary biomonitoring data using a population pharmacokinetic (PopPK) model and to assess human health risk via integrating reverse dosimetry with an internal dose-based reference dose (RfD). A human-scale PopPK model capable of quantitatively describing urinary excretion of N-methylmalonamic acid and the mercapturic acid metabolite M-12 following oral CMIT/MIT exposure was developed. Model parameters were estimated using nonlinear mixed-effects modeling and evaluated via bootstrap analysis, visual predictive checks, goodness-of-fit diagnostics, and normalized prediction distribution error analysis. The validated model was then applied to adult biomonitoring data from the German Environmental Sample Bank and to pediatric and adolescent survey data. External exposure doses were reconstructed via reverse dosimetry, accounting for inter-individual PK variability. Human health risk was quantified using the margin of exposure (MOE) approach, referencing an internal dose-derived oral RfD of 0.02 mg/kg/day. The final PopPK model reliably captured urinary biomarker excretion dynamics at population and individual levels. Parameter estimates were robust, with bootstrap medians closely aligned with the final model values. Reconstructed external exposures exhibited no consistent long-term increasing or decreasing trend in adults and no systematic age- or sex-related pattern in pediatric and adolescents. Most exposure scenarios yielded MOE values > 10, while only extreme upper-bound conditions yielded MOEs of approximately 2-5. Even under conservative assumptions, all MOE values remained above 1. This study demonstrates that human biomonitoring data can be quantitatively translated into external exposure and risk metrics using a PopPK-based reverse dosimetry framework. The findings indicate that current CMIT/MIT exposure levels in the general population are unlikely to pose health concerns under typical environmental conditions. The integrated biomonitoring-modeling approach offers a regulatory-relevant framework for linking internal biomarkers to external exposure and health risk assessment.
Unpacking amphotericin B toxicity: a critical review of amphotericin B aggregation and its link to toxicity and antifungal activity.
Chavali CH, Deplazes E
Arch Toxicol · 2026 May · PMID 42159739 · Publisher ↗
Amphotericin B (AmB) is a polyene antifungal that, despite its severe dose-limiting toxicity, is the most effective drug to treating invasive fungal infections. The drug's toxicity arises from its poor selectivity for er...
Amphotericin B (AmB) is a polyene antifungal that, despite its severe dose-limiting toxicity, is the most effective drug to treating invasive fungal infections. The drug's toxicity arises from its poor selectivity for ergosterol over cholesterol and its tendency to aggregate. Understanding the relationship between toxicity and aggregation is challenging due to the drug's complex mechanism of action, yet imperative to improve the safety profiles of existing and new polyene-based antifungal drugs. In this review, we critically examine and summarise studies that investigate the aggregation of AmB and its relationship to toxicity. As the aggregation behaviour of AmB is highly sensitive to environmental conditions, we provide an in-depth analysis of sample preparation, characterisation of aggregates and control experiments. While data from haemolysis, animal, and cell-based studies consistently show that oligomeric AmB is more toxic than larger aggregates, findings on the toxicity of monomeric AmB inconsistent. Our collated data underscores the need for careful consideration of sample preparation and proper use of vehicle controls when studying the complex relationship between the supramolecular organisation of AmB and its biological effects.
In vitro formation kinetics of two 2,5-dimethylfuran phase-I metabolites: cis-3-hexene-2,5-dione and 5-methylfurfuryl alcohol.
Appel J, Kulosa C, Becker N … +3 more , Stegmüller S, Sadzik S, Richling E
Arch Toxicol · 2026 May · PMID 42159738 · Publisher ↗
2,5-Dimethylfuran (DMF) is a heat-induced contaminant found in various thermally processed foods. Due to its structural similarity to furan, a well-known hepatotoxin and potential human carcinogen, the presence of DMF in...
2,5-Dimethylfuran (DMF) is a heat-induced contaminant found in various thermally processed foods. Due to its structural similarity to furan, a well-known hepatotoxin and potential human carcinogen, the presence of DMF in food poses a potential risk to consumers. DMF undergoes cytochrome P450 (CYP)-mediated biotransformation leading to the formation of two primary phase-I metabolites: the reactive cis-3-hexene-2,5-dione (HDO), which can react with cellular nucleophiles, and the primary alcohol 5-methylfurfuryl alcohol (MFA), formed after hydroxylation of the alkyl moiety. To deduce the in vitro formation kinetics of these two phase-I metabolites, we utilised a newly developed HPLC-ESI-MS/MS method to quantify HDO after scavenging with glutathione and monitored the formation of MFA by GC-MS in parallel. Metabolic activation and the formation of HDO was the predominant biotransformation pathway in human liver microsomes, whereas the parallel formation of MFA was significantly less efficient. In line with data on the metabolic activation of furan, CYP2E1 was the most active human CYP-isoform in the potential metabolic activation of DMF. However, CYP3A4 and CYP2D6 also contributed to the HDO formation in vitro. Hydroxylation of DMF and formation of MFA were exclusively catalysed by CYP2E1. Despite the formation of MFA as an alternative metabolic pathway, our kinetic data indicate that DMF is primarily metabolised by CYP2E1 to the reactive cis-enedial intermediate HDO, particularly at physiologically relevant concentrations. Therefore, exposure to DMF may contribute to the overall risk associated with dietary exposure to furans.
Global emergence and γ-aminobutyric acid type A (GABA) receptor activity of the new designer benzodiazepine ethylbromazolam.
Norman C, Acreman D, Bissram M … +10 more , Curtis B, Hamer S, Westphal F, Putz M, Stefan C, Delaney SR, Lines R, McLeod MD, McDonald K, Green H
Arch Toxicol · 2026 May · PMID 42159737 · Publisher ↗
Designer benzodiazepines (DBZDs) are a class of new psychoactive substances (NPS) designed as legal alternatives to prescription BZDs. Bromazolam has been the most prevalent DBZD detected on the recreational market aroun...
Designer benzodiazepines (DBZDs) are a class of new psychoactive substances (NPS) designed as legal alternatives to prescription BZDs. Bromazolam has been the most prevalent DBZD detected on the recreational market around the world; however, a new DBZD, ethylbromazolam (8-bromo-1-ethyl-6-phenyl-4 H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; also known as bromoethylazolam) has recently emerged. In this study, the emergence of ethylbromazolam in Canada, the UK, and Australia is reported based on analysis of samples from drug checking services and in Germany based on analysis of samples seized by customs and mail services. Since November 2024, ethylbromazolam has been increasingly detected with a concurrent decrease in bromazolam detections, suggesting that its emergence is likely in response to the international control of bromazolam on 3rd December 2024. Additionally, increased detections of other DBZDs, including desalkylgidazepam (bromonordiazepam) and clobromazolam (phenazolam) have been recently observed. The in vitro αβγ GABA receptor activity of ethylbromazolam was determined using an automated patch clamp assay. Ethylbromazolam was found to have similar in vitro GABA receptor activity as bromazolam (EC of 10.1 nM and 15.2 nM, respectively), indicating comparable pharmacological activity and potential for harm. The market should continue to be monitored closely as it continues to evolve in response to the control of bromazolam.
Micro- and nanoplastics in human biological materials: a systematic review of detection methods and methodological challenges.
Dmitrowicz A, Sacharczuk M, Skiba D
Arch Toxicol · 2026 May · PMID 42149209 · Publisher ↗
Micro- and nanoplastics are an increasing focus in biomedical research, yet their definition, classification, and detection methods remain largely unstandardised. The lack of consistent nomenclature, agreed size criteria...
Micro- and nanoplastics are an increasing focus in biomedical research, yet their definition, classification, and detection methods remain largely unstandardised. The lack of consistent nomenclature, agreed size criteria, and uniform reporting methods significantly hinders comparison of available data. Therefore, a systematic review of studies on analytical methods for detecting micro- and nanoplastics ex vivo in human biological samples was conducted. Most included studies (63.89%) were published between 2024 and 2025, highlighting the topicality of this research area. Study populations varied widely in age and health status, and sample sizes were often small. The most frequently analysed samples included placenta, kidneys, liver, lungs, heart, and urine, while other tissues were reported sporadically. Detection methods primarily involved microscopic techniques, chromatographic approaches, and Raman and FTIR spectroscopy. Considerable variability was observed in sample preparation procedures, including storage, digestion, and filtration, which may affect analytical sensitivity and specificity. Differences were also noted in quality control strategies and contamination minimisation approaches. Reported particle sizes and concentration units varied substantially, and many studies did not distinguish between microplastics and nanoplastics, treating them as a single category. This further hinders data comparison and the accurate assessment of human exposure.
Transforming animal study toxicology reports into structured, harmonized data using large language models.
Doktorova TY, Chernov IS, Formaggio A … +13 more , Zheng X, Serra A, Mohan PLB, Duchateau-Nguyen G, Draganov DI, Hayes M, Hasselgren C, Siramshetty VB, Gaudio S, Tecilla M, Maliver P, Musvasva E, Anger LT
Arch Toxicol · 2026 May · PMID 42133063 · Publisher ↗
Preclinical toxicology study reports contain the expert interpretations required to distinguish test article-related effects from incidental findings, yet these conclusions often remain embedded in unstructured text form...
Preclinical toxicology study reports contain the expert interpretations required to distinguish test article-related effects from incidental findings, yet these conclusions often remain embedded in unstructured text form that limit systematic reuse and integration with computational safety approaches. To address this gap, we developed a Large Language Model (LLM) - supported pipeline that converts toxicology reports into structured, machine-readable datasets harmonized with SEND terminology. The pipeline combines automated document preprocessing, section identification, schema-constrained information extraction, and semantic harmonization, complemented by targeted human curation. We evaluated the system performance using 200 Roche toxicology study reports, encompassing clinical pathology, histopathology, organ weights, exposure data, and study-level conclusions. Across domains, extraction performance was strong, characterized by consistently high sensitivity and precision for most parameters. Histopathology, organ weight, and NOAEL-related endpoints demonstrated the greatest robustness, with sensitivity typically above 95% and precision frequently exceeding 97%. Lower performance for parameters such as route of administration and substance identifiers reflected heterogeneous reporting practices rather than LLM-based method limitations. The structured datasets generated by this pipeline enable cross-study querying, identification of compounds with defined toxicological liabilities, integration with raw SEND data, and development of high-quality labels for predictive toxicology models. Practical utility has been demonstrated through representative use cases. These results demonstrate that LLM-assisted extraction can reliably capture expert toxicological interpretations at scale and provide a foundation for data-centric safety assessment, strategic decisions, reverse and forward translational toxicology research.
Analysis of transcriptomic alterations induced by 33 different per- and polyfluoroalkyl substances (PFAS) in differentiated HepaRG cells.
Sprenger H, Alker W, Rocchi A … +6 more , Leo C, Giglio R, Immobile Molaro G, Dondero F, Braeuning A, Buhrke T
Arch Toxicol · 2026 May · PMID 42128928 · Publisher ↗
Due to their high persistence and adverse health effects in humans the use of a number of per- and polyfluoroalkyl substances (PFAS) has been restricted. As a consequence, novel PFAS are increasingly being introduced for...
Due to their high persistence and adverse health effects in humans the use of a number of per- and polyfluoroalkyl substances (PFAS) has been restricted. As a consequence, novel PFAS are increasingly being introduced for industrial applications, although toxicological data are still limited or lacking for many of these compounds. This study examined the molecular mechanisms of action of novel PFAS with a focus on mono- and polyether PFAS with linear or branched structures and either carboxylic acid or sulfonic acid functional groups. Differentiated HepaRG cells, a model of human hepatocytes, were exposed for 24 h to different PFAS congeners at three non-cytotoxic concentrations each. Total RNA was isolated and subjected to whole transcriptome analysis. The study provides transcriptomic data for in total 33 PFAS congeners, for 13 of them for the first time. For most PFAS, the number of differentially expressed genes (DEG) increased in a concentration-dependent manner, whereas five PFAS induced only minor transcriptional changes even at the highest test concentration. Ingenuity Pathway Analysis (IPA) revealed broadly comparable transcriptional responses across all 33 PFAS, indicating convergent molecular effects in HepaRG cells despite marked structural differences among the PFAS congeners. The tested PFAS consistently activated canonical pathways related to fatty acid and lipid metabolism, mainly regulated by the nuclear receptor PPARα, and also affected pathways related to xenobiotic metabolism, partially linked to PXR and CAR signaling. In addition, several PFAS inhibited cholesterol and bile acid biosynthesis pathways. IPA further predicted effects on hepatocyte-relevant upstream regulators such as HNF4A, HNF1A, and FOXA2. Finally, IPA tox-function analysis indicated associations between PFAS-induced transcriptional changes and liver diseases related to cholestasis.
From animal models to NAMs: a paradigm shift in developmental immunotoxicity testing.
Iulini M, de Bruijn V, Hurem S … +6 more , Nygaard UC, Kerdine-Römer S, Spruck C, Tigges J, Vandebriel R, Corsini E
Arch Toxicol · 2026 May · PMID 42128927 · Publisher ↗
Developmental immunotoxicology (DIT) is emerging as a critical area in regulatory toxicology, driven by the recognition that the developing immune system is particularly vulnerable to xenobiotic exposure. Disruptions occ...
Developmental immunotoxicology (DIT) is emerging as a critical area in regulatory toxicology, driven by the recognition that the developing immune system is particularly vulnerable to xenobiotic exposure. Disruptions occurring during fetal or early postnatal life may result in long-lasting alterations in immune competence, tolerance, and disease susceptibility. This review provides a comprehensive overview of immune system development, highlighting key developmental stages from embryogenesis to postnatal maturation and identifying windows of heightened immune system sensitivity to toxicants. By integrating mechanistic insights and methodological advances, this review aims to support the improvement and extension of DIT testing frameworks and the development of predictive tools for regulatory and research applications. Recent advances in New Approach Methodologies offer promising alternatives for modeling human immune ontogeny, while highlighting the challenge of ensuring adequate coverage of critical developmental mechanisms and windows of susceptibility relevant to immunotoxicity. The integration of physiological maps and multi-omics technologies enhances mechanistic understanding, while epidemiological associations between exposures and functional endpoints underscore the real-world relevance of DIT and can identify biomarkers to guide the further development of relevant and sensitive models. Despite these advances, challenges remain, including the scarcity of human reference data, the lack of standardized protocols, and the need for validated test batteries covering diverse mechanisms once the tests have been refined. Addressing these gaps is essential to support the regulatory uptake of DIT data and to advance predictive, mechanistically anchored, and ethically sound strategies for DIT testing.
The landscape of cocaine cytotoxicity and the role of sigma-1 receptor modulation and adulterant synergism.
Steinmetz A, Moro CF, Freese L … +4 more , de Abreu MS, Braum RL, Barros HMT, Moura DJ
Arch Toxicol · 2026 May · PMID 42128926 · Publisher ↗
Cocaine remains one of the most widely consumed illicit drugs globally, representing a significant public health challenge. While its acute reinforcing effects are mediated by the facilitation of dopaminergic and seroton...
Cocaine remains one of the most widely consumed illicit drugs globally, representing a significant public health challenge. While its acute reinforcing effects are mediated by the facilitation of dopaminergic and serotonergic neurotransmission, chronic exposure leads to pervasive neurobiological adaptations and systemic toxicity. Beyond its psychoactive properties, cocaine exerts multifaceted cytotoxic effects across several organ systems, including the brain, heart, and liver, primarily through the induction of oxidative stress, mitochondrial dysfunction, and the activation of apoptotic pathways. This review provides a comprehensive analysis of these cellular and molecular mechanisms and introduces novel evidence regarding the toxicological impact of seized cocaine. Original in vitro data demonstrate that the association of cocaine with common adulterants, levamisole, phenacetin, and caffeine, markedly exacerbates cytotoxicity through synergistic interactions. Furthermore, this review examines the pivotal role of the sigma-1 receptor (σ1R) in cocaine-induced toxicity, supported by molecular docking analyses that characterize specific interactions between the cocaine, adulterants, and conserved receptor residues. This receptor-mediated framework suggests a central mechanism contributing to the drug's combined toxic and reinforcing properties. Collectively, these findings integrate experimental, computational, and literature-based evidence to offer a broader mechanistic understanding of cocaine-induced toxicity and its modulation by adulterants, providing compelling evidence for the role of σ1R in these cytotoxic processes.
Contribution of dermal ethanol absorption during laboratory-controlled high-frequency use of alcohol-based hand rubs followed by glove use.
Scheepers PTJ, Lassing K, Graumans MHF … +14 more , Driessen SHP, Gkintsev A, Konstantinou I, Leermakers V, Onstek H, Sülter M, van den Oord L, van Dolder C, Jansen HJ, Hardy EM, Duca RC, Ragas A, Russel FGM, Rustemeyer T
Arch Toxicol · 2026 May · PMID 42128925 · Publisher ↗
The safety of using ethanol-based products for hygienic hand disinfection in healthcare workers is controlled by restricting air levels. This raises the question of whether these workers are sufficiently protected agains...
The safety of using ethanol-based products for hygienic hand disinfection in healthcare workers is controlled by restricting air levels. This raises the question of whether these workers are sufficiently protected against potential dermal absorption. The study aim was to determine the contribution of the dermal route to the total uptake of ethanol. A laboratory-controlled study of 25 sequential alcohol-based-hand-rubs (ABHRs) with subsequent intermediate glove use was conducted in seven healthcare workers. Two exposure conditions were compared: hands and forearms placed inside a laboratory fume hood preventing inhalation (skin-only condition) and the same procedure but outside the fume hood to allow inhalation (native condition). The hand hygiene product contained 84% ethanol and 1% ethanol-d6 added to verify exogenous origin. Inhalation exposure was measured by personal air sampling. Blood was collected at baseline, during exposure and a post-exposure wash-out period and analysed for ethanol and ethanol-d6 by HS-GC-MS. The contribution of dermal uptake was assessed by comparing the area-under-curve (AUC) of blood ethanol concentrations in the skin-only condition with that in the native condition within each study participant. Inhalation exposure in the breathing zone was (mean ± sd): 5.3 ± 3.6 mg/m in the skin-only condition and 120 ± 7 mg/m in the native condition. The corresponding AUCs for blood ethanol concentrations were 1400 ± 1100 and 3300 ± 2300 (mg/L)*min (p = 0.014), respectively, indicating a contribution from dermal absorption of 43 ± 28% (N = 7). For ethanol-d6 these values were 17 ± 4 and 48 ± 17 (mg/L)*min (p = 0.064), respectively, with a contribution of dermal uptake of 40 ± 16% (N = 3). In conclusion, high-frequency ABHRs lead to significant dermal absorption of ethanol.
A multi-species lipidomic analysis of viperid snake venoms from the Americas.
Olalla-Tacuri K, Ochoa-Ocampo M, Garzón T … +3 more , Hernández-Altamirano JA, Mogollón NGS, Almeida JR
Arch Toxicol · 2026 May · PMID 42128924 · Publisher ↗
Snake venoms are multilayered and chemically diverse mixtures with important ecological and medical relevance, particularly in many regions of the Americas. Although venom research has largely focused on proteinaceous to...
Snake venoms are multilayered and chemically diverse mixtures with important ecological and medical relevance, particularly in many regions of the Americas. Although venom research has largely focused on proteinaceous toxins, venoms also contain low-molecular-weight components that remain poorly characterized. Among these, the lipidome represents one of the least explored layers of venom composition, and comparative information across species is limited. In this study, we applied an untargeted high-resolution mass spectrometry-based lipidomics approach to characterize and compare lipid signatures across nine viperid venoms representing eight American snake species from the genera Crotalus, Lachesis, and Bothrops. This multi-species analysis enabled the identification of both shared and divergent lipid features. Across all venoms, sphingolipids constituted a conserved and dominant lipid class, forming a common lipidomic core, while glycerophospholipids, glycerolipids, and fatty acid-derived lipids exhibited genus- and species-specific quantitative variation. Multivariate analyses revealed moderate but consistent lipidomic structuring associated with taxonomic grouping, with Bothrops and most Crotalus species clustering more closely, whereas Lachesis venoms displayed distinct lipidomic profiles. Supervised discrimination highlighted a restricted set of lipid species driving group separation, primarily through relative abundance differences rather than unique presence or absence. Notably, intra-genus variability was observed within Crotalus and between geographically distinct Lachesis muta populations. Together, these findings demonstrate that viperid venoms possess structured yet variable lipidomic landscapes that complement known proteomic diversity. This study expands the comparative framework of venom lipidomics and supports its integration with other omics approaches to achieve a more comprehensive understanding of venom composition and diversity.
From biomarkers to the risk index: a novel integrated model using multidimensional urinary biomarkers to quantify e-cigarette exposure.
Cui L, Han S, Yu P … +13 more , Miao R, Cun X, Zhang Y, Ren P, Feng P, Song L, Fu Y, Wang H, Tian Y, Li X, Song Z, Chen H, Hou H
Arch Toxicol · 2026 May · PMID 42128923 · Publisher ↗
E-cigarette use is a common form of tobacco consumption; however, just like secondhand smoke, its long-term health effects remain uncertain. At present, risk assessment indicators for e-cigarettes and second-hand smoke a...
E-cigarette use is a common form of tobacco consumption; however, just like secondhand smoke, its long-term health effects remain uncertain. At present, risk assessment indicators for e-cigarettes and second-hand smoke are not sufficiently comprehensive, and robust technical methods for holistic exposure evaluation are lacking. In this study, a questionnaire survey was conducted and urine samples from 100 non-smokers and 301 e-cigarette users were collected. Urinary metabolites of nicotine, volatile organic compounds, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, 1,2-propylene glycol, and glycerol were systematically analyzed, making this study the most comprehensive investigation to date of risk assessment indicators for e-cigarettes. The results showed significant differences in multiple urinary biomarkers between non-smokers and e-cigarette users, including total nicotine equivalents, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, 2-amino-1,3,4-thiadiazole-5-carboxylic acid, S-phenylmercapturic acid, N-acetyl-S-(2-cyanoethyl)-L-cysteine, 2-hydroxypropyl mercapturic acid, 3-hydroxypropyl mercapturic acid, and total hydroxylated naphthalenes. Using integrated biomarker response (IBR) calculations, a risk assessment model was established for e-cigarette exposure. The scientific validity of this model was evaluated using the cigarette consumption test for dependence and the Fagerström test for nicotine dependence scales, and it indicates that the higher the degree of addiction to tobacco products, the higher the risk of exposure. The biomarkers and IBR-based assessment model developed in this study may provide valuable tools for clinical evaluation of the health risk status of tobacco product users and second-hand smoke.
Rosiglitazone hepatotoxicity resulting from hepatic protein covalent binding derived from its aldehyde metabolite.
Zhao Y, Yang Y, Ding Z … +7 more , Sun Y, Zhang M, Li W, Liu T, Hu Z, Peng Y, Zheng J
Arch Toxicol · 2026 May · PMID 42128922 · Publisher ↗
Rosiglitazone (RGZ), a thiazolidinedione insulin sensitizer, is widely used in the treatment of type 2 diabetes mellitus. However, concerns regarding its dose-dependent hepatotoxicity have emerged, and the mechanisms of...
Rosiglitazone (RGZ), a thiazolidinedione insulin sensitizer, is widely used in the treatment of type 2 diabetes mellitus. However, concerns regarding its dose-dependent hepatotoxicity have emerged, and the mechanisms of the toxic action remain elusive. This study aimed to investigate the mechanism by which an aldehyde metabolite generated through metabolic activation of RGZ forms covalent adduction with protein lysine residues and its contribution to hepatotoxicity. Using in vitro liver microsomal incubations coupled with LC-MS/MS, the reactive aldehyde metabolite and its corresponding lysine adduct were identified. It was verified that RGZ was primarily metabolized by CYP3A and CYP2E1 into an electrophilic aldehyde metabolite which subsequently underwent covalent bonding with the ε-amino group of lysine residues. The formation of the protein adduction was found to be associated with the hepatotoxicity of RGZ.
Timing of exposure impacts how organophosphorus pesticides affect the developing brain in the planarian Dugesia japonica.
Somach RT, Ireland D, Tran HP … +2 more , Allotey G, Collins ES
Arch Toxicol · 2026 May · PMID 42128921 · Publisher ↗
Exposure to organophosphorus pesticides (OPs) during pregnancy has been suggested to cause adverse outcomes on neural development of the fetus but the mechanisms underlying developmental neurotoxicity of OPs remain uncle...
Exposure to organophosphorus pesticides (OPs) during pregnancy has been suggested to cause adverse outcomes on neural development of the fetus but the mechanisms underlying developmental neurotoxicity of OPs remain unclear. While OPs share acetylcholinesterase (AChE) as the primary molecular target, different OPs have been shown to induce different effects in laboratory studies. Previously, we found that OPs differentially affect regenerating planarians when applied on the first day of regeneration. To determine if the timing of OP exposure affects adverse outcomes, here, we performed a comparative study of 5 OPs-chlorpyrifos (17.8 μM), diazinon (16.2 μM), dichlorvos (1 μM), profenofos (10 μM), and malathion (56.2 μM)-in the planarian Dugesia japonica. We evaluated how effects on behavior and nervous system morphology changed with OP exposure starting on different days of regeneration/development. We found that some toxic effects were dependent on the developmental stage during exposure. For example, profenofos impaired brain development when exposure started on day 1 of development but caused lethality when exposure started during later stages. Inhibition of the enzymatic activity of AChE on day 12 of exposure was not affected by the different exposure paradigms, suggesting that the differential effects were either due to effects on the non-enzymatic functions of AChE or on other targets during neurodevelopment. This work provides insight into which neurodevelopmental key events are affected by OP exposure, enabling future mechanistic work to identify the targets underlying OP developmental neurotoxicity.
A PFAS mixture at environmental relevant concentration induces DNA damage and compromises the in vitro maturation of mouse oocytes.
Tatarczuch A, Kotarska K, Polański Z … +1 more , Ptak A
Arch Toxicol · 2026 May · PMID 42128920 · Publisher ↗
Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants that can accumulate in the human body, including follicular fluid (FF), potentially affecting the function of reproductive cells. We used...
Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants that can accumulate in the human body, including follicular fluid (FF), potentially affecting the function of reproductive cells. We used the mixture of these chemicals at concentrations previously reported in human FF to assess their effects on in vitro maturation, DNA integrity, and mitochondrial function of mouse oocytes. Exposure to PFAS led to meiotic abnormalities, manifested by an increase in the percentage of oocytes arrested at the germinal vesicle breakdown (GVBD) stage and a decrease in the number of oocytes reaching the metaphase II (MII) stage. We demonstrated that arrest at GVBD is associated with Spindle Assembly Checkpoint (SAC) activation as experimental inhibition of SAC restores normal maturation to MII. In addition, we observed increased DNA damage and changes in oxidative balance, including an increase in reduced glutathione (GSH) and a decrease in reactive oxygen species (ROS) levels. However, we found an increase in mitochondrial activity, basal oxygen consumption (OCR), and mitochondrial respiration intensity in immature GV stage oocytes, indicating disturbances in bioenergetic homeostasis. These findings show for the first time that PFAS mixtures, at concentrations relevant to human exposure, interfere with oocyte maturation, genome integrity, and mitochondrial function. The data obtained highlight the need for further research on the toxicity of PFAS mixtures, especially at doses mirroring their environmental presence, and their potential impact on female fertility.
Schizantherin B alleviates cisplatin-induced ototoxicity and does not interfere cisplatin-based chemotherapy in a breast cancer model.
Zhao Z, Han L, Xu Z … +10 more , Nan B, Tang H, Dong D, Zen Z, Gao Z, Ye C, Huang X, Zhang J, Li GL, Shu Y
Arch Toxicol · 2026 May · PMID 42128919 · Publisher ↗
Schizantherin B (SNB), a key bioactive ingredient of the Chinese traditional medicine Schisandra chinensis, possesses anti-inflammatory and antioxidant properties. Cisplatin (CDDP) is typically used to treat various mali...
Schizantherin B (SNB), a key bioactive ingredient of the Chinese traditional medicine Schisandra chinensis, possesses anti-inflammatory and antioxidant properties. Cisplatin (CDDP) is typically used to treat various malignant tumors, however, its clinical utility is often limited by significant off-target toxicities, most notably irreversible hearing loss. Various strategies have been explored to mitigate this side effect. In this study, we investigated the protective effects of SNB against cisplatin-induced hearing loss(CIHL) as a potential preclinical therapeutic strategy.Firstly, in the ex-vivo basilar membrane, we found that SNB alleviated CDDP-induced loss of hair cells, cochlear spiral ganglion cells, and ribbon synapses. Secondly, in vivo experiments showed that SNB protected animals against CHL, returning their response close to normal level. Thirdly, in multiple tumor cell lines, we found SNB did not interfere with CDDP's anti-tumor effects. Consistently, in a mouse model for breast cancer, we found that SNB did not obtrude CDDP's effects in reducing tumor mass. Finally, in examining the molecular mechanisms, we found that SNB reduced both oxidative stress and cell apoptosis in the auditory cell line of HEI-OC1 during CDDP treatment, likely through the Bcl-2/Bax/cleaved-Caspase-3 signal pathways. Collectively, our study demonstrated that SNB mitigates CIHL without interfering with its therapeutic effects in treating cancer, suggesting that SNB is a potential drug candidate for preventing CIHL in cancer patients.
Detection of paralytic shellfish toxins and tetrodotoxins in shellfish using a single-cell biosensor based on patch clamp technology.
Reverté J, Turner AD, Dhanji-Rapkova M … +7 more , Klijnstra MD, Gerssen A, Lage S, Tudó À, Diogène J, Sureda FX, Campàs M
Arch Toxicol · 2026 May · PMID 42128918 · Publisher ↗
Paralytic shellfish toxins (PSTs) are a well-known group of potent neurotoxins that may accumulate in shellfish, posing a significant risk to food safety and public health. To protect consumers, shellfish production area...
Paralytic shellfish toxins (PSTs) are a well-known group of potent neurotoxins that may accumulate in shellfish, posing a significant risk to food safety and public health. To protect consumers, shellfish production areas are subject to regulatory monitoring programs targeting PST contamination. However, tetrodotoxins (TTXs), another group of potent neurotoxins that may also accumulate in shellfish and co-occur with PSTs, are not currently included in regulations and routine monitoring schemes in most EU countries. This is of particular concern because PSTs and TTXs share the same biological target and mechanism of action and therefore pose a comparable neurotoxic risk. In this work, we present an automated patch clamp (APC) single-cell biosensing device as a toxicological bioanalytical solution addressing the need for tools capable of simultaneously detecting these two hazardous toxin groups. The biosensor was able to detect not only saxitoxin (STX) and TTX, but also their toxic analogues. The method achieved a limit of detection of 37 µg STX equivalents (equiv.) kg⁻¹, well below the current regulatory limit of 800 µg STX equiv. kg⁻¹. After the analysis of more than 70 samples exhibiting diverse toxin profiles, the results and correlations with reference methods demonstrate that APC single-cell biosensing provides a robust and integrative tool for the simultaneous monitoring of PSTs and TTXs.
o-Toluidine and its metabolites induce oxidative and nitrative DNA damage in human urinary bladder epithelial cells.
Chen HJ, Ahmed S, Cui ZG … +3 more , Kimura E, Ma N, Hiraku Y
Arch Toxicol · 2026 May · PMID 42128917 · Publisher ↗
o-Toluidine has been used for multiple industrial purposes, but causes bladder carcinogenesis in exposed workers. However, its underlying mechanism is still unclear. In this study, we examined oxidative and nitrative DNA...
o-Toluidine has been used for multiple industrial purposes, but causes bladder carcinogenesis in exposed workers. However, its underlying mechanism is still unclear. In this study, we examined oxidative and nitrative DNA damage caused by o-toluidine and its metabolites, 2-amino-m-cresol, 4-amino-m-cresol (4AC) and N-(4-hydroxy-2-methylphenyl) acetamide, using T24 human bladder epithelial cells. MTT assay showed that 4AC induced the most potent cytotoxicity among o-toluidine and its metabolites. In flow cytometry, 4AC showed the strongest ability of generating reactive oxygen species (ROS) and nitric oxide (NO) in exposed cells. Fluorescence immunocytochemistry revealed that 4AC significantly increased the staining intensities of an oxidative DNA lesion, 8-oxo-2'-deoxyguanosine, and a nitrative DNA lesion, 8-nitroguanine, at 5 nM. Their staining intensities were stronger than the other compounds. The comet assay showed that o-toluidine and its metabolites significantly increased the olive tail moment after the treatment with formamidopyrimidine DNA glycosylase. DNA damage was significantly reduced by transfection with small interfering RNA and antibodies against high-mobility group box-1 (HMGB1), receptor for advanced glycation end-products (RAGE) and Toll-like receptor (TLR) 9. These findings indicate that o-toluidine and its metabolites induce the release of HMGB1, which forms a complex with CpG DNA to bind to RAGE on neighboring cells and then is recognized by TLR9 in lysosomes, leading to ROS and NO production and DNA damage. In o-toluidine-induced carcinogenesis, TLR9-mediated inflammatory response and DNA damage induced by its metabolites, especially 4AC, may play a substantial role.
Free Fatty acid-induced disruption of hepatic vitamin D metabolism impairs bone homeostasis in an in vitro 3D human liver-bone model.
Hammour MM, Herzberger L, Xin Y … +10 more , Chen G, Tombaz M, Ehnert S, Springer F, Damm G, Vosough M, Hengstler JG, Müller-Vieira U, Nüssler AK, Aspera-Werz RH
Arch Toxicol · 2026 May · PMID 42126543 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic condition associated with compromised bone integrity. Emerging evidence suggests that disturbances in hepatic vitamin D metabolism may contri...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic condition associated with compromised bone integrity. Emerging evidence suggests that disturbances in hepatic vitamin D metabolism may contribute to these skeletal impairments. However, the hepatic mechanisms driving bone deterioration remain poorly defined. This study aimed to establish a human 3D in vitro model of MASLD and demonstrate that hepatic vitamin D dysregulation adversely affects bone homeostasis. Liver spheroids composed of HepaRG cells, LX-2 stellate cells, and HUVECs were stimulated with 600 µM free fatty acids (2:1 oleic: palmitic acid) to induce MASLD-like features, validated by BODIPY staining and gene expression. MASLD model induction led to downregulation of hepatic genes regulating lipid and vitamin D metabolism. ELISA confirmed significantly reduced 25-hydroxyvitamin D levels, aligning with downregulation of CYP2R1 and CYP27A1. Transcriptomic profiling of human MASLD liver biopsies validated these molecular changes. To evaluate MASLD's systemic impact on bone, THP-1-derived macrophages and SCP-1 mesenchymal stem cells were seeded onto bone scaffolds and co-cultured with spheroids. Bone scaffolds co-cultured with MASLD spheroids showed impaired mineralization and elevated expression of bone resorption markers. These findings mirror skeletal dysfunction observed in MASLD patients and suggest a mechanistic link between hepatic vitamin D dysregulation and bone pathology. This study introduces a pioneering 3D human liver-bone co-culture model that reveals MASLD-driven disruption of hepatic vitamin D metabolism as a direct contributor to bone deterioration. This 3D model develops a powerful translational platform for decoding systemic disease mechanisms and targeting the liver-bone axis therapeutically.
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