Archives Of Toxicology[JOURNAL]
Sun
200 papers
Developmental exposure to a human-relevant PCB mixture: impacts on PCB congeners, metabolites, and drug-metabolizing enzymes in the bladder of post-weaning mice.
Wang H, Goskowicz A, Spiegelhoff A … +5 more , Kennedy CL, Ridlon MM, Marek RF, Lehmler HJ, Keil Stietz KP
Arch Toxicol · 2026 Jul · PMID 42400643 · Publisher ↗
Many women suffer from symptoms associated with dysfunction of the lower urinary tract, including incontinence and overactive bladder, especially during pregnancy. While causes are likely multifactorial, environmental fa...
Many women suffer from symptoms associated with dysfunction of the lower urinary tract, including incontinence and overactive bladder, especially during pregnancy. While causes are likely multifactorial, environmental factors, such as exposure to polychlorinated biphenyls (PCBs), have been shown to alter voiding in adult female mice. However, the distribution of PCBs and their metabolites to the bladder and urine, as well as their effects on bladder drug-metabolizing enzyme expression after dosing with PCB mixtures, remains largely unexplored. Female C57BL/6J mice were exposed to MARBLES PCB mixture (0, 0.1, 1, and 6 mg/kg/d) through gestation and lactation, and post-weaning bladder, urine, blood, adipose, and liver were collected for measurement of PCBs and OH-PCBs, and for abundance of cytochrome P450 (Cyp) transcripts in liver and bladder. PCBs and OH-PCBs were detected in all tissues in a dose-dependent manner. Bladder, adipose, and liver retained parent PCBs while OH-PCBs were predominant in urine and blood. Cyp1a2 mRNA abundance was elevated in the liver of the high dose PCB group versus the vehicle, and the same trend was observed in the bladder. These results define the signatures of PCBs and OH-PCBs in the bladders and urine of post-weaning dams exposed to the MARBLES mixture of PCBs and provide a reference for comparison with accumulation in more commonly studied tissues. Our results also provide new insights into the regulation of Cyp1a2 in the liver and bladder, changes that may play a role in how environmental exposures in adulthood alter voiding function.
Network toxicology deciphers micro- and nanoplastics-mediated mixture hazard, predictive risk assessment, and regulatory translation.
Wu W, Wāng Y
Arch Toxicol · 2026 Jul · PMID 42397579 · Publisher ↗
Micro- and nanoplastics (MNPs) are pervasive environmental contaminants and efficient carriers of coexisting pollutants, including heavy metals, organic chemicals, and antibiotics. Their capacity to adsorb, transport, an...
Micro- and nanoplastics (MNPs) are pervasive environmental contaminants and efficient carriers of coexisting pollutants, including heavy metals, organic chemicals, and antibiotics. Their capacity to adsorb, transport, and release contaminants has raised growing concern over mixture toxicity under realistic exposure scenarios. This review systematically examines the mechanistic basis of MNPs-mediated combined toxicity and evaluates the emerging role of network toxicology as a systems-based tool for hazard assessment. MNPs alter the bioavailability, environmental fate, tissue distribution, and intracellular delivery of associated pollutants through hydrophobic, electrostatic, and other intermolecular interactions. Carrier-mediated uptake, particularly the "Trojan horse" effect, appears to be a major driver of non-additive toxicity in co-exposure systems. We then outline the core workflow of network toxicology, encompassing target identification, network construction, pathway enrichment, and experimental validation, and discuss its application in decoding mixture toxicity. Oxidative stress, inflammatory signaling, metabolic disturbance, barrier dysfunction, and programmed cell death emerge as conserved and interconnected pathways underlying synergistic multi-organ injury. These findings indicate that toxicity in complex exposure systems is governed not only by the intrinsic properties of particles or chemicals, but also by their dynamic physicochemical and biological interactions. We further assess current advances and limitations in network toxicology and propose a next-generation risk assessment (NGRA)-oriented framework to support mechanism-based risk assessment and regulatory decision-making. Although current evidence is dominated by binary, high-dose laboratory studies, network toxicology offers strong potential as a new approach methodology (NAM) for predictive evaluation of environmentally relevant mixtures. Future priorities include standardized multi-omics integration, dose-time-response modeling, human-relevant validation, and regulatory translation.
Scientific approach to derive occupational exposure limits for formaldehyde releasers.
Michaelsen S, Laube B, Bartsch R … +12 more , Baumgärtel S, Breuer D, Grebenstein R, Leibold E, Lohmann R, Merk H, Schleh C, Fartasch M, Bader M, Drexler H, Blömeke B, Hartwig A
Arch Toxicol · 2026 Jul · PMID 42397578 · Publisher ↗
Formaldehyde is highly reactive, causing irritation and acute and chronic toxicity in target tissues (the eyes, respiratory tract, and skin) following inhalation and/or skin contact. Moreover, formaldehyde is a local car...
Formaldehyde is highly reactive, causing irritation and acute and chronic toxicity in target tissues (the eyes, respiratory tract, and skin) following inhalation and/or skin contact. Moreover, formaldehyde is a local carcinogen after inhalation exposure. It induces nasal squamous cell carcinoma in laboratory animals and nasopharyngeal carcinoma in humans, albeit less convincingly. While formaldehyde has been evaluated and classified by different organizations and committees in recent years, the question has arisen of how to deal with substances that release formaldehyde. These releasers decompose in aqueous media and are frequently used as biocides in water-miscible metalworking fluids, adhesives, paints, disinfectants, and cosmetics. In this context, the MAK Commission has developed a concept for differential evaluation regarding carcinogen classification and MAK value derivation. This approach is based on hydrolysis rates as a function of pH, temperature, and concentration under physiological conditions. Furthermore, vapor pressure is considered to determine whether the formaldehyde releaser will be present as a vapor or aerosol upon inhalation. This concept is demonstrated using four examples that lead to different carcinogen classifications and MAK value derivations. Additionally, the releasers were evaluated for percutaneous absorption and sensitization.
Molecular dosimetry of hemoglobin adducts in mice exposed to ethylene oxide.
Liu CW, Feng J, Peng J … +7 more , Zhao H, Wang X, Gollapudi BB, Li AA, Bus JS, Kirman C, Lu K
Arch Toxicol · 2026 Jul · PMID 42384196 · Publisher ↗
Ethylene oxide (EtO) is a widely used industrial compound with known carcinogenic potential in humans. Due to its high reactivity and short biological half-life, occupational exposure assessments (> 1 ppm) rely on the de...
Ethylene oxide (EtO) is a widely used industrial compound with known carcinogenic potential in humans. Due to its high reactivity and short biological half-life, occupational exposure assessments (> 1 ppm) rely on the detection of stable biomarkers, such as N-(2-hydroxyethyl)-L-valine (HE-V), formed as hemoglobin adducts in blood. Existing analytical methods for HE-V detection often require large volumes of blood and purified hemoglobin due to limited sensitivity, restricting their application in characterizing the dose-response relationship between EtO exposure and HE-V accumulation-particularly at low environmental exposure levels relevant to assessing potential general population health risks. In this study, we aimed to characterize the molecular dosimetry of HE-V formation in B6C3F1 mice exposed by whole body inhalation to a broad range of concentrations of EtO: 0, 0.05, 0.1, 0.5, 1, 50, 100, and 200 ppm, 7 days/week for 4 weeks. To achieve this, we developed a sensitive LC-MS-based workflow for HE-V quantification, incorporating hemoglobin purification, HE-V release plus enrichment, and targeted mass spectrometric detection from as little as 10 μL of blood and 50 μg of extracted hemoglobin. A clear, dose-dependent increase in HE-V levels was observed following EtO exposure, with statistically significant elevations detected even at 0.05 ppm compared to endogenous background levels. At lower concentrations (0.5 to 1 ppm), HE-V levels increased linearly with dose, while higher concentrations (50 to 200 ppm) exhibited an upward-bending (increasing slope) dose response. No sex-specific differences were observed. Taken together, these findings indicate EtO exhibits linear systemic toxicokinetics at lower exposures that transition to nonlinear toxicokinetics in the range of higher exposures (likely due to saturation of glutathione-mediated detoxification), thus providing new quantitative insights to support improved risk assessments and toxicological evaluations of EtO exposure.
From data mining to mechanistic prediction: a study on drug-induced lung injury integrating FAERS, machine learning, and network toxicology.
Zhao Y, Yan J, Zhou Y
Arch Toxicol · 2026 Jun · PMID 42371091 · Publisher ↗
Drug-induced lung injury (DLI) is a serious and potentially fatal adverse drug reaction that remains difficult to detect early and continues to challenge both drug development and clinical safety. Because current diagnos...
Drug-induced lung injury (DLI) is a serious and potentially fatal adverse drug reaction that remains difficult to detect early and continues to challenge both drug development and clinical safety. Because current diagnosis relies largely on exclusion and lacks specific early warning biomarkers, there is an urgent need for an integrated strategy that enables both risk prediction and mechanistic interpretation. To address this unmet need, we for the first time develop and validate a comprehensive integrated research strategy that combines FAERS database mining, XGBoost-based machine learning, and network toxicology, and is specifically designed for early DLI risk assessment and in-depth exploration of the underlying mechanisms. DLI-related adverse event reports were systematically extracted and standardized from FAERS to construct a curated small-molecule drug dataset. An optimized XGBoost model was then built using structural, physicochemical, and target-based features to predict DLI risk. In parallel, network toxicology was applied to construct drug-target-pathway networks for high-risk compounds and to identify key toxicological mechanisms. Our results highlighted MMP9 and ERBB2 as core targets associated with the pulmonary toxicity of Sunvozertinib and Zongertinib, and subsequent molecular docking and molecular dynamics simulations further suggested stable binding between the compounds and the above targets. This integrated framework enables efficient early prediction of DLI risk while providing mechanistic insights into drug-induced pulmonary toxicity. Overall, our study offers a practical and reproducible computational strategy for DLI risk assessment in drug development and supports safer clinical medication and rational drug design.
Copper oxide nanoparticles: from EU-regulatory landscape and mechanistic toxicity towards a cuproptosis-linked adverse outcome pathway.
Scholz S, Prinz J, Sevenants L … +8 more , Holzwarth A, Mertens B, Pieper R, Ritz V, Schulz K, Sieg H, Mangerich A, Böhmert L
Arch Toxicol · 2026 Jun · PMID 42365112 · Publisher ↗
Copper is an essential trace element, yet concerns regarding its toxic potential have gained increasing attention, particularly with regard to nanoparticulate forms of copper oxides. Both CuO and CuO are currently author...
Copper is an essential trace element, yet concerns regarding its toxic potential have gained increasing attention, particularly with regard to nanoparticulate forms of copper oxides. Both CuO and CuO are currently authorised in the EU for use in agriculture, biocides, and animal nutrition, but regulatory clarity regarding their nanoforms remains limited. This comprehensive review-combining narrative, bibliometric, and systematic approaches-addressed three key questions: (i) whether CuO and CuO nanoparticles are sufficiently considered within EU regulations to prevent unintentional oral exposure via the food and feed chain, (ii) whether these nanoparticles can cross the intestinal barrier as intact particles and accumulate in tissues, and (iii) whether they elicit distinct biological responses, including regulated cell death pathways such as cuproptosis. With respect to question (i), a detailed analysis of EU legal frameworks revealed a heterogeneous regulatory landscape and a lack of binding provisions that would preclude unintended presence of copper oxide nanoforms in regulated materials. Although some nano-specific data requirements exist, empirical information on nanoparticulate fractions in commercial products is still lacking. With respect to questions (ii) and (iii), our systematic literature analysis supports consistent intracellular uptake of CuO and CuO nanoparticles, yet direct evidence for transport of intact particles across the intestinal barrier is scarce. Mechanistic evidence supports cuproptosis as a key pathway for CuO nanoparticle toxicity, while the extent to which these effects differ quantitatively from ionic copper remains unclear due to insufficient data using appropriate experimental controls. Notably, a pronounced data gap was identified for CuO nanoparticles across all evaluated domains. Finally, to organise and integrate the mechanistic evidence presented, we developed an adverse outcome pathway (AOP), registered as AOP 590 in the AOP Wiki, describing how increased intracellular copper can induce cuproptosis via disruption of energy metabolism. Collectively, these findings highlight the need for coordinated analytical, mechanistic, and regulatory research to support evidence-based risk assessment of CuO and CuO nanoparticles in the food and feed context.
Causality analysis of toxicological mechanisms in networked systems such as adverse outcome pathway networks.
Hartung T, Kopańska K, Maertens A … +2 more , Whaley P, Hoffmann S
Arch Toxicol · 2026 Jun · PMID 42365111 · Publisher ↗
This paper examines why robust causality assessment is central to toxicology yet increasingly difficult in networked biological systems, including Adverse Outcome Pathway (AOP) networks and multi-omics datasets. Classica...
This paper examines why robust causality assessment is central to toxicology yet increasingly difficult in networked biological systems, including Adverse Outcome Pathway (AOP) networks and multi-omics datasets. Classical causal frameworks (e.g., Koch/Dale reasoning and Bradford Hill-type considerations) remain useful for scoping, but they offer limited operational guidance for multifactorial, nonlinear, and feedback-dominated mechanisms. We therefore synthesize a modern toolbox for causality analysis in toxicology spanning directed acyclic graphs for explicit causal assumptions, quantitative and probabilistic approaches for integrating evidence across key events, and network/dynamical methods that help identify influential hubs and points of vulnerability in AOP networks. Building on evidence-based toxicology, we propose an operational workflow that links (i) structured scoping and model specification, (ii) protocolized evidence retrieval across in vivo, in vitro, in silico and human data streams, (iii) risk-of-bias appraisal and quantitative synthesis of effect sizes and dose-response, (iv) mechanistic integration and targeted perturbation assays, and (v) translation via dual-strand certainty rating (mechanistic vs difference-making evidence) and Evidence-to-Decision tables. We discuss how explainable AI can support scalable integration and transparency. A worked developmental neurotoxicity example illustrates how this pipeline can support regulatory recommendations while explicitly documenting uncertainty.
Thyroxin displacement from single and combined thyroid hormone binding proteins by various test substances.
Brandt J, Fabian E, Aktalay-Hippchen A … +2 more , Jedermann L, Landsiedel R
Arch Toxicol · 2026 Jun · PMID 42365110 · Publisher ↗
The thyroid hormone system regulates physiological processes that are crucial for growth and metabolism. The homeostasis of thyroid hormones can be affected by test substances via multiple molecular interactions, one of...
The thyroid hormone system regulates physiological processes that are crucial for growth and metabolism. The homeostasis of thyroid hormones can be affected by test substances via multiple molecular interactions, one of them being the displacement of thyroid hormones from their binding proteins. The main thyroid hormone in the human bloodstream is L-thyroxine (T4), ≥ 99.5% of which is transported bound to three proteins: thyroxine binding globulin (TBG), transthyretin (TTR) and human serum albumin (HSA). To investigate the interactions of xenobiotics with the binding of T4 to these proteins, an in vitro thyroid hormone protein binding assay (THPB-assay) was developed. Samples containing 100 nM T4 were incubated with a T4-binding protein and increasing concentrations of a test compound, followed by removal of the unbound T4 via size exclusion chromatography and analysis of protein-bound T4. This assay allows for multiple adjustable parameters, including the choice of binding protein and the detection method for protein-bound T4, which can be extracted and measured via LC-MS or, when using I-T4, by a gamma counting. Eight test substances were tested for the displacement of T4 from TTR and TBG respectively. For interference with T4-TTR binding, Tetrabromobisphenol A was established as a positive control with an average measured IC of 287 nM. Displacement of T4 was observed for five more test substances, which displaced T4 from TTR with IC ranging from 101 nM for Tetrac and 121 nM for 2,4,6-tribromophenol (TBP) to 1056 nM for Genistein. 6-propylthiouracil and L-DOPA did not displace T4 from TTR. LC-MS analysis and gamma counting of I-T4 yielded similar results for each test substance. The five test substances which displaced T4 from TTR were additionally tested for displacement of T4 from TBG. Tetrac and Benziodarone displaced T4 with IC values of 3 µM and 22 µM, respectively, whereas the remaining compounds did not. Finally, a mix of TTR, TBG and HSA, in concentrations of 536 nM, 26.5 nM and 65.35 µM respectively, was tested with the potent T4 displacer Tetrac. Tetrac displaced T4 from this protein mix with an IC of 154 µM. Using the radioligand detection method, the T4 displacement of compounds from human and rat serum was tested to elucidate their effect in a physiological environment and identify potential species differences. Tetrac displaced T4 from human and rat serum at 10% serum concentration in samples, with IC values of 38 µM and 242 µM respectively. TBP displaced T4 from 10% rat serum with an IC of 1.3 mM. No displacement was observed in 10% human serum. At higher serum concentrations, no test substance was measured to displace T4 regardless of the species. While further research is essential, the insights regarding the absence of displacement at physiological serum concentrations challenge current risk assessment frameworks, which define changes in serum T4 levels as a key event in adverse outcome pathways related to the displacement of T4 from TTR.
Species, cell proliferation state and oxygen partial pressure are major factors in the in vitro toxicity of repurposed potential ADPKD drugs in human and murine renal proximal tubule cells.
Sotiropoulou P, Gerdemann A, Jovanovic S … +3 more , Humpf HU, Bürkle A, Dietrich DR
Arch Toxicol · 2026 Jun · PMID 42363980 · Publisher ↗
Unexpected nephrotoxicity during clinical stages of drug development, due to undetected toxicity in in vitro and in vivo settings, can lead to drug attrition and jeopardize drug development. The latter highlights the imp...
Unexpected nephrotoxicity during clinical stages of drug development, due to undetected toxicity in in vitro and in vivo settings, can lead to drug attrition and jeopardize drug development. The latter highlights the importance of in vitro renal toxicity testing that can safely be translated to humans. Two factors commonly overlooked in the latter are the continuous cell proliferation that occurs in regeneration processes after renal insult and the physiological O tension in the kidney. Autosomal Dominant Polycystic Kidney Disease is a genetic disorder characterized by the development of renal cysts and cellular changes, i.e. abnormal proliferation in conjunction with the Warburg effect. There is only one drug approved for the disease, tolvaptan, which, however, presents with liver toxicity and polyuria. In a quest for potential alternatives to tolvaptan, we compared the nephrotoxic and metabolic effects of four repurposed drugs, salicylic acid (up to 10 mM), birinapant (up to 100 µM), bardoxolone methyl (up to 1000 nM), and rapamycin (up to 160 nM) to tolvaptan (up to 100 µM) on human differentiated and proliferating (RPTEC/TERT1) and mouse proliferating (mProx24) renal proximal tubular epithelial cells at atmospheric (21%) and physiological (10%) O tensions. The focus was on improved interpretation of in vitro test results for the detection of potential adverse effects. We found that cell proliferation and O tension are major factors that determine the susceptibility of cells to compounds, while the drug effects on the metabolism and mitochondrial function provided further insight into the mechanisms underlying the observed in vitro toxicity.
PBK modelling of phthalates and their metabolites and the application in next generation risk assessment.
Shi M, Punt A, Pawar G … +4 more , Yang S, Yang H, Jia X, Tang D
Arch Toxicol · 2026 Jun · PMID 42363979 · Publisher ↗
Next generation risk assessment (NGRA) has substantially contributed to development of animal-free chemical risk assessment by integrating new approach methodologies. The present study aimed to further expand the applica...
Next generation risk assessment (NGRA) has substantially contributed to development of animal-free chemical risk assessment by integrating new approach methodologies. The present study aimed to further expand the applicability of NGRA to compounds with bioactive metabolites, using dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) as case studies. Physiologically based kinetic (PBK) models were developed for DBP, DEHP and their primary metabolites mono-butyl phthalate and mono-(2-ethylhexyl) phthalate by using in silico and in vitro-derived parameters, including measured metabolic clearance obtained by performing in vitro liver microsomal incubations. Models were evaluated against observed kinetic data and used to predict plasma maximum concentrations (C) from external exposure scenarios, which were further compared with ToxCast-derived points of departure (PoDs) to calculate bioactivity-exposure ratios (BERs) for risk classification. Results showed that the in silico-in vitro based PBK models accurately predicted plasma kinetics for the metabolites within 2-fold difference. Predicted C values for parent compounds across all exposure scenarios were much lower than minimal PoDs, resulting in BERs higher than 20,000. When metabolites were considered, BERs decreased markedly with the lowest value of 8.1, highlighting the importance of accounting for metabolites for phthalates. Our study provides a proof-of-principle for incorporating metabolites into PBK modelling and corresponding NGRA, enhancing its applicability to chemicals with bioactive metabolites.
Correction: The potent human CAR activator CITCO is a non-genotoxic hepatic tumour-promoting agent in humanised constitutive androstane receptor mice but not in wild-type animals.
Henderson CJ, McLaren AW, MacLeod AK … +10 more , Lin D, Cameron AR, Chatham LR, Moggs J, Inesta-Vaquera F, Thomson JP, Meehan RR, Chakravarty P, Schwarz M, Roland Wolf C
Arch Toxicol · 2026 Jun · PMID 42362751 · Publisher ↗
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Ferroptosis in e-cigarette aerosol-associated respiratory injury.
Sailis AB
Arch Toxicol · 2026 Jun · PMID 42362750 · Publisher ↗
E-cigarette use has increased substantially, particularly among adolescents and young adults, yet its long-term respiratory effects remain incompletely understood. E-cigarette aerosol contains biologically active constit...
E-cigarette use has increased substantially, particularly among adolescents and young adults, yet its long-term respiratory effects remain incompletely understood. E-cigarette aerosol contains biologically active constituents, including nicotine, propylene glycol, vegetable glycerin, flavoring chemicals, aldehydes, metals, particles, and reactive oxygen species, which may disrupt respiratory epithelial homeostasis. This review synthesizes experimental, preclinical, and human-relevant evidence linking e-cigarette aerosol exposure to respiratory epithelial injury, with emphasis on ferroptosis-related mechanisms. Available evidence indicates that e-cigarette aerosol can impair epithelial barrier integrity, alter mucociliary defense, increase MUC5AC expression, induce oxidative stress, and promote inflammatory signaling. Emerging preclinical data suggest that electronic nicotine delivery system exposure may induce ferroptosis-associated lung injury through increased CD71/TFR1 and ACSL4 expression, reduced GPX4, altered lipid profiles, BODIPY-C11-positive lipid peroxidation, epithelial cell death, inflammation, mucus accumulation, emphysema-like pathology, and fibrosis. Mechanistically, e-cigarette aerosol may create a ferroptosis-permissive epithelial environment by promoting redox imbalance, GPX4/GSH/SLC7A11 antioxidant defense impairment, altered iron handling, ACSL4-mediated PUFA-phospholipid remodeling, NRF2/ARE stress responses, mitochondrial dysfunction, and lipid peroxide accumulation. Ferroptotic epithelial injury may further amplify airway inflammation and remodeling through DAMP release, macrophage recruitment, cytokine production, barrier disruption, mucus dysregulation, and extracellular matrix deposition. However, direct human evidence remains limited, and many mechanistic links are extrapolated from cigarette smoke, particulate matter, and broader lung injury models. Future studies should use standardized exposure systems, human-relevant airway and alveolar models, comprehensive ferroptosis markers, and ferroptosis-specific rescue experiments to determine whether ferroptosis is a driver, amplifier, or downstream marker of e-cigarette-associated respiratory injury.
Structure-activity relationship of synthetic cathinones: integrated in silico, in vitro, and in vivo studies of α-PiHP analogues.
Pazos MD, García-Díez G, Pubill D … +6 more , Berzosa X, Estrada-Tejedor R, Camarasa J, Escubedo E, López-Arnau R, Nadal-Gratacós N
Arch Toxicol · 2026 Jun · PMID 42362749 · Publisher ↗
Synthetic cathinones represent the main group of emerging psychostimulants consumed worldwide. Structural modifications of these compounds have led to pyrovalerones, potent dopamine transporter (DAT) inhibitors associate...
Synthetic cathinones represent the main group of emerging psychostimulants consumed worldwide. Structural modifications of these compounds have led to pyrovalerones, potent dopamine transporter (DAT) inhibitors associated with high abuse liability. Among them, α-pyrrolidinoisohexanophenone (α-PiHP) became the most seized pyrovalerone in the European Union in 2023. Novel analogues have rapidly appeared, yet their neuropharmacological and toxicological properties remain unknown. This study aimed to characterize α-PiHP and five structurally related derivatives (3-Me-α-PiHP, 4-Me-α-PiHP, 3-F-α-PiHP, 4-F-α-PiHP, and MDPiHP). Monoamine transporter activity was evaluated using HEK293 cells expressing human norepinephrine (hNET), hDAT, or serotonin (hSERT) transporters through uptake inhibition and binding assays. Molecular docking was performed to model interactions at hDAT. Psychostimulant, thigmotactic, and rewarding effects were evaluated in male Swiss CD-1 mice using horizontal locomotor activity, open field, and conditioned place preference paradigms. Lethality after drug administration was also assessed. All compounds potently inhibited hDAT and hNET, while displaying limited activity at hSERT. This resulted in high hDAT/hSERT ratios indicative of a stimulant-like profile and elevated abuse liability, confirmed in vivo by pronounced psychostimulant and rewarding effects. All molecules interacted with the orthosteric binding site at hDAT and displayed higher binding affinity than cocaine in in vitro and in silico studies. Meta-substituted analogues showed greater hDAT affinity and behavioural responses than para-isomers. Notably, MDPiHP exhibited the highest potency and affinity, strongest psychostimulant effects and significant lethality. These findings demonstrate that minor structural modifications markedly influence pharmacological activity of pyrovalerone derivatives, highlighting the high abuse potential and health risks associated with emerging α-PiHP analogues.
Chemical components of tattoo inks and their potential role in carcinogenesis and their side effects.
Czaczkowska L, Jabłońska E, Bury J … +2 more , Szurant N, Ratajczak-Wrona W
Arch Toxicol · 2026 Jun · PMID 42362748 · Publisher ↗
Tattooing is an invasive procedure that has gained popularity, particularly among individuals. Growing attention has been directed toward the safety of tattoo ink ingredients, which are complex mixtures of synthesis prec...
Tattooing is an invasive procedure that has gained popularity, particularly among individuals. Growing attention has been directed toward the safety of tattoo ink ingredients, which are complex mixtures of synthesis precursors and byproducts. These inks may contain classified carcinogens, heavy metals, polycyclic aromatic hydrocarbons (PAHs), and phthalates, often at concentrations exceeding permissible limits. Tattooing involves the insertion of needles 1-3 mm into the dermis. While part of the pigment is eliminated with epidermal turnover, approximately 25% is transported to lymph nodes and subsequently into the bloodstream. The remaining pigment is engulfed by phagocytic cells involved in innate immunity. Repeated needle punctures trigger local inflammation, recruitment of immune cells, and release of inflammatory mediators, followed by tissue regeneration and remodelling driven by keratinocytes, fibroblasts, and endothelial cells. Cases of malignant melanoma, squamous cell carcinoma, keratoacanthoma, and lymphoma have been reported in individuals with tattoos. However, the relationship between tattooing and cancer is not fully understood. It is suspected that the cause may be the transfer of toxic substances to lymph nodes and then to organs. The possible carcinogenic effects of tattoo ink ingredients will be discussed based on available scientific reports.
Human internal exposures to alternariol and its monomethyl ether are predicted below thresholds of in vitro toxicity by physiologically based kinetic modeling.
Borsos E, Descamps B, Hetzschold N … +3 more , Varga E, Marko D, Aichinger G
Arch Toxicol · 2026 Jun · PMID 42362747 · Publisher ↗
The foodborne mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) have been associated with several adverse effects, including cytotoxicity, genotoxicity, endocrine disruption, and immunomodulation. As th...
The foodborne mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) have been associated with several adverse effects, including cytotoxicity, genotoxicity, endocrine disruption, and immunomodulation. As these endpoints are typically observed in vitro at micromolar concentrations, the question arises whether such levels are attainable in exposed humans. To address this data gap in chemical risk assessment, a physiologically based kinetic (PBK) model was developed to predict internal exposure doses to AOH and AME in humans. As input parameters, kinetic constants for hepatic glucuronidation were obtained in vitro by incubating Sprague Dawley rat and human liver S9 fractions with 0.5-50 µM AOH and 0.5-20 µM AME, demonstrating rapid biotransformation in both species. Intestinal absorption of AME and physicochemical parameters were estimated using quantitative structure-activity relationship (QSAR) models. Sensitivity analysis identified parameters describing hepatic glucuronidation and gastrointestinal uptake as among the most influential, confirming the importance of their reliable estimation. The PBK model was evaluated against available rodent toxicokinetic data and subsequently extrapolated to humans. Ultimately, the currently available exposure estimates published by EFSA in 2016 were applied to predict target tissue concentrations, which were compared to points of departure (PoDs) for relevant toxicological endpoints. Even in the most susceptible group of male toddlers, predicted internal concentrations (10⁻ µM range) were approximately four orders of magnitude below the respective PoDs. Consequently, under the applied exposure assumptions and considering the compounds as isolated chemicals, AOH and AME are not expected to reach systemic or tissue concentrations associated with the investigated effects.
Deficient arsenic methylation and global proteomic reprogramming in human keratinocytes during arsenic-induced skin carcinogenesis.
Nail AN, Banerjee M, Xu M … +8 more , Reynolds CH, Stýblo M, Cable PH, Wilkey DW, Merchant ML, Ferragut Cardoso AP, Thomas SD, States JC
Arch Toxicol · 2026 Jun · PMID 42362746 · Publisher ↗
Chronic inorganic arsenic (iAs) exposure affects > 220 million people worldwide and skin cancer is a hallmark of long-term iAs exposure. Limited information exists regarding arsenic methylation by human keratinocytes and...
Chronic inorganic arsenic (iAs) exposure affects > 220 million people worldwide and skin cancer is a hallmark of long-term iAs exposure. Limited information exists regarding arsenic methylation by human keratinocytes and how methylation influences skin carcinogenesis. Inorganic arsenite (iAs) and its methylated metabolites disrupt diverse zinc finger proteins, leading to differential toxicity patterns. We examined arsenic methylation capacity in non-malignant human keratinocytes and interrogated proteomic remodeling across three stages of iAs induced malignant transformation using the well-established preclinical HaCaT model. Arsenic methylation was assessed by hydride generation cryotrapping inductively coupled-mass spectrometry and global proteomic changes were analyzed by tandem-mass tagging liquid chromatography-tandem mass spectrometry. Primary, hTERT-immortalized and HaCaT human keratinocytes exhibited negligible arsenic methylation, with iAs comprising at least 98.5% of total intracellular arsenic, attributable to minimal expression of arsenite methyltransferase. Proteomic profiling identified over 275 differentially expressed proteins at each stage of transformation, including multiple zinc finger proteins implicated in cell cycle control, RNA metabolism, and genome stability. Ingenuity® Pathway Analysis revealed progressive, coordinated disruption of cancer-associated pathways and regulatory networks over the transformation timeline, including zinc-coordinating upstream regulators that may explain widespread pathway dysregulation. Collectively, our findings suggest that iAs promotes skin carcinogenesis by disrupting C3H1- and C4-type zinc finger protein-centered regulatory networks that coordinate cancer-associated signaling and metabolic pathways in human keratinocytes, highlighting key candidates for future mechanistic studies.
Transcriptomic responses to repeated exposure of human C3A liver spheroids to polystyrene nanoplastics.
Xiftou K, Jiang J, Caiment F … +4 more , de Kok TM, Vinken M, Sanz-Serrano J, Tabernilla A
Arch Toxicol · 2026 Jun · PMID 42362745 · Publisher ↗
Increasing evidence of nanoplastics (NPs) accumulation in the human liver has raised concerns regarding their potential hepatotoxicity. However, current knowledge is largely derived from animal studies or simplistic in v...
Increasing evidence of nanoplastics (NPs) accumulation in the human liver has raised concerns regarding their potential hepatotoxicity. However, current knowledge is largely derived from animal studies or simplistic in vitro models, often with unrealistic exposure scenarios, thereby constraining their relevance to human health. Human liver spheroids have emerged as relevant tools for long-term mechanistic toxicological studies, yet their application to the hepatotoxicity assessment of NPs remains limited. This study aimed to establish and characterize a human liver C3A spheroid model to explore the effects of repeated exposure to polystyrene (PS) NPs for up to 21 days at concentrations informed by real-life human intake and internal exposure estimates, namely 0.0068, 0.068, and 1.6 µg/mL. Throughout the 21-day culture period, the human liver spheroids preserved stable morphology, overall viability, low levels of cell death, and stable expression of hepatic-associated genes. PS NPs accumulated within the human liver spheroids in a concentration-dependent and spatially heterogeneous manner, but did not induce detectable changes in spheroid size, viability, or cell death across all concentrations and time points measured. Transcriptomic profiling revealed subtle, concentration-dependent gene expression changes, which were most pronounced at day 3 and attenuated over time. Although limited in magnitude, these changes involved genes and pathways related to liver lipid and bile acid homeostasis, stress signaling, and detoxification. Collectively, these findings indicate that human-relevant concentrations of PS NPs do not induce overt hepatotoxic effects, while potentially modulating molecular pathways implicated in cellular processes essential for normal liver function.
Revealing DNA damage levels in rat testicular germ cells in vivo using an adapted version of the alkaline comet assay.
Olsen AH, Ma X, Zheng C … +4 more , Dirven Y, Eide DM, Brunborg G, Sharma AK
Arch Toxicol · 2026 Jun · PMID 42362744 · Publisher ↗
Heritable mutations in male germ cells pose a critical risk to human health and future generations, however standardized methods for assessing germ cell genotoxicity remain limited. We refined the in vivo alkaline comet...
Heritable mutations in male germ cells pose a critical risk to human health and future generations, however standardized methods for assessing germ cell genotoxicity remain limited. We refined the in vivo alkaline comet assay (proof-of-concept (Dirven et al. 2023); protocol (Olsen et al. 2024)) to detect DNA damage in testicular germ cells, with selective addressment of haploid spermatids and primary spermatocytes. Measurements of DNA damage (% Tail DNA) and DNA content (total fluorescence intensity) in individual comets were combined with visual comet identification to distinguish testicular comet populations based on differences in DNA content and appearance. To verify the method's functionality and reliability, DNA damage was assessed in rats exposed to the direct-acting, well-characterized genotoxicants X-rays and ethyl methanesulfonate across distinct testicular cell populations, alongside liver and blood. To minimize experimental variation, the protocol included stringent standardization of animal handling, tissue processing, and comet assay procedures. Both X-rays and EMS induced significant DNA damage in testicular germ cells, with comparable responses across testicular cell types and similar (X-rays) or higher levels observed in somatic tissues. The low inter-animal variability observed supports the robustness of the method. Importantly, inclusion of testicular germ cells in OECD test guideline 489 would provide a valuable tool for hazard identification and mutagenicity classification of chemicals under the Globally Harmonized System of Classification and Labelling of Chemicals. This versatile, sensitive, and resource-efficient assay enhances the assessment of male-mediated genetic risks and supports regulatory efforts to protect reproductive health and safeguard the genetic integrity of future generations through the use of safer chemicals.
Prenatal developmental toxicity of nitrous oxide: results of a GLP-compliant OECD TG 414 study in rats and implications for hazard classification.
Colnot T, Dekant W
Arch Toxicol · 2026 Jun · PMID 42362743 · Publisher ↗
Nitrous oxide (NO) is classified as a reproductive toxicant (Repr. 1B, H360D) under the EU CLP Regulation based on developmental toxicity findings in non-guideline rat studies conducted in the 1970s and 1980s. Those stud...
Nitrous oxide (NO) is classified as a reproductive toxicant (Repr. 1B, H360D) under the EU CLP Regulation based on developmental toxicity findings in non-guideline rat studies conducted in the 1970s and 1980s. Those studies reported malformations and embryolethality after continuous 24-h exposures to high and anesthetic concentrations of N2O, but provided limited data on maternal toxicity and may have been confounded by hypoxia. A new prenatal developmental toxicity study was conducted in Wistar rats according to OECD Test Guideline 414 and following Good Laboratory Practice (GLP). Mated females (21-24 per group) were exposed nose-only to target concentrations of 0 (air control), 150,000; 380,000; or 750,000 ppm NO for 6 h/day from gestation day (GD) 6 to GD 19. All test atmospheres contained ≥ 25% oxygen and blood oxygen saturation was monitored to preclude hypoxia. No maternal mortality or clinical signs were observed. Body weight gain in dams was reduced at 750,000 ppm (- 15%); however, terminal body weights and gravid uterus-corrected body weight gains remained comparable to controls. Reproductive parameters were unaffected. No treatment-related malformations were detected at external, visceral or skeletal examinations in any group. Fetal body weight was reduced (- 8%) and the incidence of unossified sternebrae, a skeletal variation, increased only at the high dose, consistent with maternal toxicity and growth retardation. These results show that NO does not induce selective developmental toxicity in rats when tested under current OECD guideline conditions.
The crucible of resilience: hormesis as the unifying principle of evolution, genetics, and epigenetics.
Calabrese EJ, Agathokleous E
Arch Toxicol · 2026 Jun · PMID 42360462 · Publisher ↗
The traditional linear no-threshold model of toxicity and stress fails to capture the complex, adaptive nature of biological systems. Hormesis-a biphasic dose-response phenomenon where low-dose stress induces beneficial,...
The traditional linear no-threshold model of toxicity and stress fails to capture the complex, adaptive nature of biological systems. Hormesis-a biphasic dose-response phenomenon where low-dose stress induces beneficial, adaptive responses while high doses cause harm-offers a more comprehensive paradigm. This article asserts that hormesis is a major, unifying explanatory principle of life that efficiently integrates evolutionary theory, genetics, and epigenetics. From an evolutionary perspective, hormesis is an energy-efficient strategy of adaptive homeostasis, permitting organisms to build biological capital during mild hardships/stresses to survive subsequent acute or chronic environmentally and/or age-related life-threatening challenges. Mechanistically, this survival strategy is hardwired into the genome via highly conserved stress-response networks (e.g., Nrf2, FOXO, Sirtuins) that upregulate cytoprotective pathways upon the detection of mild stressors. Furthermore, epigenetics provides the temporal bridge, recording these stress events via chromatin remodeling to create a lasting 'memory' of resilience, which may even be transmitted transgenerationally to prime/adapt offspring for future adversity. Ultimately, synthesizing these three biological domains through the lens of hormesis redefines biomedically based understandings of health, aging, and disease, demonstrating that biological resilience is actively maintained through manageable environmental and age-related challenges rather than the absence of stress.
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