Archives Of Toxicology[JOURNAL]
Sun
200 papers
PFAS and One Health: integrating human, animal, and environmental perspectives.
Souza MCO, Barbosa F, Domingo JL
Arch Toxicol · 2026 May · PMID 41699312 · Full text
Per- and polyfluoroalkyl substances (PFAS)-ubiquitous, persistent, and bioaccumulative-pose a cross-cutting threat to human, animal, and environmental health. Their resistance to degradation and global dissemination dema...
Per- and polyfluoroalkyl substances (PFAS)-ubiquitous, persistent, and bioaccumulative-pose a cross-cutting threat to human, animal, and environmental health. Their resistance to degradation and global dissemination demand an integrated One Health framework to address their complex, interdependent risks across ecosystems, wildlife, and public health. This review synthesizes current knowledge on PFAS, highlighting their anthropogenic origins, environmental persistence, and global dispersion. Common exposure pathways, such as dietary intake, contaminated drinking water, and maternal transfer, lead to convergent toxicological outcomes across species, including immunotoxicity, reproductive and developmental impairments, and carcinogenicity, validating the use of cross-species data in risk assessment and reinforcing the need for integrated protective strategies. Vulnerable human populations and wildlife face disproportionate risks, with the latter acting as both sentinels and exposure sources. Despite regulatory efforts, the ongoing use and development of replacement compounds sustain PFAS as a global concern. Effectively addressing this challenge requires a coordinated, cross-sectoral strategy that integrates environmental monitoring, transdisciplinary research, and harmonized regulatory frameworks. The One Health paradigm provides the essential model for developing these collaborative solutions.
Rat and human primary proximal tubule epithelial cells allow for cross-species comparisons of drug-induced nephrotoxicity in vitro.
Zuidervaart SA, Abraham BG, Fitzpatrick PA … +2 more , Sjögren AK, Bell CC
Arch Toxicol · 2026 May · PMID 41699311 · Full text
Translating nephrotoxicity risks from rat to human is hampered by species differences in kidney physiology. An in vitro rat kidney platform focused on proximal tubules, the primary site of drug-induced injury, could enab...
Translating nephrotoxicity risks from rat to human is hampered by species differences in kidney physiology. An in vitro rat kidney platform focused on proximal tubules, the primary site of drug-induced injury, could enable mechanistic, cross-species assessments. Here, we characterized rat primary proximal tubule epithelial cells (rPPTEC) and evaluated their use for nephrotoxicity studies in vitro. rPPTEC were characterized by gene and protein expression, and drug transporter functionality. Next, rPPTEC were exposed to 7 validation compounds (4 nephrotoxicants, 3 non-nephrotoxicants), after which cell viability was assessed with ATP and LDH assays, and high-content imaging. Finally, the toxicity response to compounds known to be more toxic in rat than in human (rat-enhanced nephrotoxicants) was compared in rPPTEC and human renal proximal tubule epithelial cells (HRPTEC). rPPTEC expressed proximal tubule markers (Aqp1, Ggt1), and functionally active drug transporters (P-gp, Oct2, Lrp2/Cubn), but lacked Oat1. The nephrotoxicants cisplatin, puromycin and cyclosporin A, but not tenofovir, induced dose-dependent decreases in ATP, increases in LDH, and alterations in imaging-based parameters. None of the non-nephrotoxicants were associated with major alterations in cell viability nor high-content imaging parameters. rPPTEC were more sensitive to the rat-enhanced nephrotoxicants zoledronate and ibandronic acid, but also to cisplatin and cyclosporin A. Notably, 45% of rPPTEC stained positive for Ki-67, compared to 0.7% of HRPTEC. rPPTEC exhibited a proximal tubular phenotype and correctly identified 6 out of 7 validation compounds. Parallel exposures in rPPTEC and HRPTEC revealed greater sensitivity of rPPTEC towards nephrotoxicants, potentially explained by the greater proliferative capacity of rPPTEC.
The double-edged sword of ion channel-targeting pesticides: a paradigm shift from health risks to precision intervention.
Wang J, Wang D, Chen Y … +3 more , Wu T, Yang W, Yu P
Arch Toxicol · 2026 Apr · PMID 41699310 · Publisher ↗
Amidst the dual challenges of global food security and ecological security, the development of highly effective and low-risk green pesticides has become a critical pathway for promoting sustainable agricultural developme...
Amidst the dual challenges of global food security and ecological security, the development of highly effective and low-risk green pesticides has become a critical pathway for promoting sustainable agricultural development. This review systematically summarizes the dual characteristics of novel pesticides targeting ion channels in precise pest control and ecological risk management. Research indicates that due to the high evolutionary conservation of ion channels in insects and mammals, pesticides exhibit cross-species similarity in their actions. This characteristic is key to understanding the broad toxicity of pesticides and also provides molecular targets for designing universal detoxification intervention strategies. By reviewing the regulatory mechanisms of typical pesticides such as pyrethroids and diamides on key ion channels like voltage-gated sodium channels and ryanodine receptors, we revealed their double-edged sword effect of "high efficacy coexisting with potential risks": while achieving precise insecticide action, they may induce neurotoxicity or endocrine disruption in non-target organisms due to the structural conservation of channels. Based on mechanistic toxicological analysis, this review further proposes novel intervention strategies centered on "reversible toxicity", including the use of computational toxicology for early risk warning, structure-guided molecular design to reduce cross-reactivity with mammalian channels, and the development of channel-specific antagonists and allosteric modulators as precise detoxification methods, thereby constructing a toxicity-blocking system covering the entire chain from "molecular recognition to clinical intervention". Through the multidimensional integration of intelligent delivery systems, comprehensive resistance management, and full life-cycle risk management, these strategies are expected to promote the formation of a new generation of pesticide research and development paradigm characterized by "efficacy-toxicity separation," providing theoretical support for harmonizing agricultural pest control and public health protection.
Extending a liver-based model to lung and intestine: a comparative study of CYP1A1 and CYP1A2 induction by cigarette smoke in human in vitro models.
Lenich AK, Kishimoto W, Nakase H … +3 more , Inui T, Mizuguchi H, Ruez S
Arch Toxicol · 2026 May · PMID 41699309 · Publisher ↗
Cigarette smoke contains over 5000 compounds, including polycyclic aromatic hydrocarbons, which induce cytochrome P450 (CYP) enzymes, particularly CYP1A1 and CYP1A2. Therefore, smoking significantly alters drug metabolis...
Cigarette smoke contains over 5000 compounds, including polycyclic aromatic hydrocarbons, which induce cytochrome P450 (CYP) enzymes, particularly CYP1A1 and CYP1A2. Therefore, smoking significantly alters drug metabolism and can reduce therapeutic efficacy. To investigate tissue-specific CYP enzyme induction by cigarette smoke extract (CSE), a previously established hepatic in vitro smoke induction model was expanded to include human intestinal organoids and lung cell models. CYP1A1, CYP1A2, and CYP3A4 mRNA expression and CYP1A1 and CYP1A enzyme activity were quantified following CSE exposure. CYP1A1 mRNA expression and enzyme activity were robustly induced in all tissues and donors (up to 77-fold and 212-fold respectively). CYP1A2 mRNA and CYP1A enzyme activity were induced in liver and intestine (up to 13-fold) but were only weakly detectable in lung. CYP3A4 induction was exclusively observed in liver (up to 16-fold). Comparison of F- and E-values of concentration-dependent induction across all models revealed that intestinal cells showed significantly lower values of CYP1A1 induction than liver cells. Other comparisons were non-significant. Inter-donor variability was visible across all cell models, CYP enzymes and tissue types (57-82% CV). This reflects physiological inter-individual variability, supporting the conclusion that these single-cell models capture donor-specific differences. Conclusively, it was shown that extrahepatic metabolism is altered by CSE and that considering tissue-specific CYP enzyme induction may be beneficial in clinical pharmacology to optimize drug efficacy and safety in smoking populations.
Variability and uncertainty of data from genotoxicity test guidelines: what we know and why it matters.
Raitano G, Pronk TE, Battistelli CL … +9 more , Bossa C, Hatzi V, Nikolopoulou D, Chaideftou E, Tcheremenskaia O, Adam-Guillermin C, Audebert M, Mertens B, Paparella M
Arch Toxicol · 2026 May · PMID 41699308 · Full text
This review comprehensively examines the variability and uncertainty associated with test guideline (TG)-conform genotoxicity data and explores the respective implications for the integration of non-animal-methods (NAMs)...
This review comprehensively examines the variability and uncertainty associated with test guideline (TG)-conform genotoxicity data and explores the respective implications for the integration of non-animal-methods (NAMs) into regulatory frameworks. Historical amendments to OECD TGs are mapped to reveal the method's evolution that improves the scientific quality of the data but also explains data heterogeneity within available databases. An analysis of the major genotoxicity databases ECVAM, ISSMIC, and OASIS demonstrates substantial variability in genotoxicity calls. Using the EFSA genotoxicity database, which currently harbours the best-curated (meta-) data, we estimate that 22-77% of compounds exhibit similarity of replicate results below 85%, depending on the assay. The potentially most important variables statistically explaining variability and sensitivity were analysed. The practical limitations to identify them with high reliability and to define their optimum needs to be accepted as a qualitative baseline uncertainty. These findings underscore the necessity of contextualizing NAM performance evaluations within the intrinsic variability and uncertainty of animal and in vitro reference data. We propose that this variability is explicitly considered in the development and validation of NAM-based Integrated Approaches for Testing and Assessment. This review provides a critical foundation for regulators and scientists aiming to enhance the acceptance and utility of NAMs in genotoxicity assessment.
Extrapolation of in vitro effect concentrations to in vivo bioavailable concentrations using PBK modelling in humans for two classes of persistent and mobile compounds: triazoles and triazines.
Ravi Shankar AL, Irwan J, Spaenig M … +9 more , Carlier M, Hansen T, Zumbülte N, Islam B, Lundquist P, Svensson R, Gouin T, Hamers T, Escher SE
Arch Toxicol · 2026 May · PMID 41699307 · Full text
Bottom-up in vitro ADME parameterized PBK models play a vital role in Next Generation Risk Assessment (NGRA), which evaluates the toxicological hazards of compounds through New Approach Methods (NAMs). The ZeroPM project...
Bottom-up in vitro ADME parameterized PBK models play a vital role in Next Generation Risk Assessment (NGRA), which evaluates the toxicological hazards of compounds through New Approach Methods (NAMs). The ZeroPM project, funded by the EU under Horizon 2020, develops strategies to prioritize persistent (P) and mobile (M) compounds for regulatory measures based on exposure levels and toxicological properties. This study developed a quantitative in vitro to in vivo extrapolation (QIVIVE) approach for two classes of PM compounds - 9 triazines and 16 triazoles. The virtual in vitro distribution model (VIVD) derived free medium benchmark concentration values (EC20 and IR1.5 (mol/L)) from a previously published NAMs testing battery. The VIVD model accounted for partitioning and ionization of PM compounds, while a bottom-up PBK model using in vitro ADME data accurately predicted rat plasma concentrations for tebuconazole and cyromazine. The same assumptions were translated to a human oral-route PBK model. Most triazines/triazoles had in vitro ADME data, where the data gaps were filled using read-across approach. The human PBK model employed forward dosimetry to estimate plasma concentrations from preclinical lowest observed adverse effect levels (LOAELs) or hypothetical exposure data, using surface- and groundwater concentrations as worst-case scenarios. Comparison to QIVIVE data indicates that NAMs-derived values are protective and can serve as basis for human risk assessment or risk-based prioritization.
Integration of in vitro and in silico approaches enables prediction of drug-induced liver injury.
Geci R, Sayin AZ, Schaller S … +1 more , Kuepfer L
Arch Toxicol · 2026 May · PMID 41699306 · Full text
Drug-induced liver injury (DILI) is a major cause of drug attrition and poses a significant threat to patient safety. However, current preclinical prediction methods, including heuristic screening rules, in vitro assays,...
Drug-induced liver injury (DILI) is a major cause of drug attrition and poses a significant threat to patient safety. However, current preclinical prediction methods, including heuristic screening rules, in vitro assays, machine learning models and animal testing, have serious limitations. Here, we demonstrate that combining in vitro toxicity data (cytotoxicity, mitochondrial toxicity, bile salt export pump (BSEP) inhibition) with pharmacokinetic information enables high DILI predictivity. In a retrospective analysis of 241 drugs, we show that the ratio of their in vivo maximum plasma concentration (Cmax) to their lowest in vitro toxicity strongly correlates with clinical DILI risks, with ROC AUC up to 96%. Then, we show that comparable predictivity (ROC AUC up to 91%) is achievable prospectively when Cmax values are predicted in silico by high-throughput physiologically based kinetic modelling. Dynamic simulations of bile acid perturbations further identify drugs potentially causing DILI specifically through BSEP inhibition, providing additional mechanistic insights. This integrative, mechanistic approach shows enhanced DILI predictivity and interpretability, offering an animal-free alternative for early drug development.
Autophagy in cancer nanomedicine: an implication of nanomaterials' impact on the evolutionarily conservative catabolic processes in human tumors.
Wiktorowski K, Szwed M
Arch Toxicol · 2026 May · PMID 41699305 · Publisher ↗
Autophagy is one of the best-characterized "pro-survival" pathways, which, paradoxically, in its extreme activation, can lead to cell death. Under conditions of moderate physiological disturbances, autophagy plays a cruc...
Autophagy is one of the best-characterized "pro-survival" pathways, which, paradoxically, in its extreme activation, can lead to cell death. Under conditions of moderate physiological disturbances, autophagy plays a crucial role in maintaining homeostasis within the human organism. Currently, in the context of treating cancer, researchers are exploring novel methods to modulate autophagic processes. Nanomedicine, which leverages nanoparticles (NPs) for targeted therapies, has become a prominent focus in numerous scientific studies. It has been observed that NPs can be employed to either stimulate or inhibit autophagic processes. Due to their diverse physicochemical properties, nanomaterials can influence cellular compartments directly involved in autophagy. This review examines the multifaceted effects of nanoparticle exposure on autophagy, with a focus on mechanisms that deviate from the classical autophagic flux. By dissecting the molecular crosstalk between nanomaterials and autophagy-related signaling networks, we aim to elucidate how NPs reshape cellular behavior and contribute to therapeutic outcomes in malignancy. Particular attention has been directed toward significant challenges in determining whether autophagy activation exerts protective or deleterious effects on cancer cells. A comprehensive understanding of the effects of nanotechnology-driven autophagy on biological systems could yield groundbreaking discoveries for advanced strategies in combating cancer and other proliferative diseases.
Reviewing the thoroughness of human safety testing for succinate dehydrogenase inhibitors: fluopyram as a case study.
Travis KZ, Bars R, Tinwell H
Arch Toxicol · 2026 May · PMID 41688829 · Full text
It has been suggested that fungicides which are succinate dehydrogenase inhibitors also inhibit this enzyme in humans, with potentially serious health consequences. It has also been suggested that regulatory studies cond...
It has been suggested that fungicides which are succinate dehydrogenase inhibitors also inhibit this enzyme in humans, with potentially serious health consequences. It has also been suggested that regulatory studies conducted on these fungicides have missed succinate dehydrogenase inhibition and its effects. Using fluopyram as a case study, this paper addresses these suggestions by critically examining all the studies related to human safety. The mechanism causing each toxicity is considered, including the possibility that inhibition of succinate dehydrogenase might be the root cause. If fluopyram were to inhibit succinate dehydrogenase, then the consequent effects and their likelihood of detection are evaluated. Many fluopyram toxicity studies are completely untargeted, with a huge number of endpoints examined, any one of which might reveal an important toxic effect. Rat and mouse studies from a single dose to near lifetime exposure are included, whilst dog studies add biological coverage. The consistent pattern seen is that the primary toxicities caused by fluopyram are effects on the liver and thyroid, plus a kidney effect in ageing male rats. The mechanisms causing these effects have been proven in bespoke mechanistic studies-they are not relevant to humans and do not involve the inhibition of succinate dehydrogenase. If fluopyram were to inhibit succinate dehydrogenase then this would be apparent, as the tissues most likely to be affected-the nervous system, heart and muscle-were examined microscopically in numerous studies with no effects seen. The low affinity of fluopyram for mammalian succinate dehydrogenase and its rapid metabolism explain the results.
Protein covalent modification and hepatic cytotoxicity of atorvastatin resulting from its metabolic activation.
Guan C, Zhang M, Li Y … +5 more , Li H, Li W, Hu Z, Peng Y, Zheng J
Arch Toxicol · 2026 May · PMID 41677906 · Publisher ↗
Atorvastatin calcium (ATV) is a statin drug that reduces low-density lipoprotein cholesterol and is widely used for the prevention and treatment of hyperlipidemia and cardiovascular and cerebrovascular diseases. However,...
Atorvastatin calcium (ATV) is a statin drug that reduces low-density lipoprotein cholesterol and is widely used for the prevention and treatment of hyperlipidemia and cardiovascular and cerebrovascular diseases. However, its liver injury reported in patients has brought attention to the risk of hepatic adverse effects. This study is the first to elucidate the association between ATV-induced hepatotoxicity and its P450-mediated metabolic activation. In an NADPH-supplemented incubation system, two phase I metabolites (M1 and M2) were detected. Using nucleophilic small molecules glutathione (GSH) and cysteine (Cys) as trapping agents, two GSH conjugates (M3 and M4) and two Cys conjugates (M5 and M6) were detected by LC-MS/MS. The observation of M3-M6 indicates the generation electrophilic quinone-imine intermediates. Furthermore, following intragastric administration of ATV (16.4 mg/kg) to mice, the corresponding GSH conjugation and protein adduction were observed in vivo. Following exposure to ATV, GSH conjugation and protein adduction were also detected in mouse primary hepatocytes. CYP3A was the enzyme predominantly responsible for the metabolic activation of ATV. Pre-treatment with CYP3A inhibitor ketoconazole (KTC) significantly reduced both ATV-derived protein adduction and hepatocyte susceptibility to ATV cytotoxicity. The findings facilitate the understanding of the mechanisms involved in ATV's idiosyncratic toxicity through systematic characterization of a CYP3A-mediated bioactivation process.
Correction to: Toxicological profiling of venoms from ten major chinese snakes: a mass spectrometry-based proteomic and multiroute assessment.
Zhao J, Wang L, Shi X … +2 more , Yang Y, Huang C
Arch Toxicol · 2026 Mar · PMID 41654651 · Publisher ↗
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Dietary phosphate exposure-strategies to protect vulnerable population groups.
Lampen A, Lachenmeier DW, Diel P … +9 more , Ensenauer R, Frommherz L, Guth S, Humpf HU, Kulling SE, Villar-Fernández MA, Wätjen W, Mally A, Steinberg P
Arch Toxicol · 2026 May · PMID 41654650 · Full text
Phosphorus is commonly part of the diets in developed countries, both as a natural component of protein-rich foods and as a food additive. Consumption of food containing high amounts of phosphate as a food additive has c...
Phosphorus is commonly part of the diets in developed countries, both as a natural component of protein-rich foods and as a food additive. Consumption of food containing high amounts of phosphate as a food additive has continued to rise over time, resulting in increasing dietary exposure to phosphate. In 2019, an evaluation of phosphoric acid and phosphates conducted by the European Food Safety Authority (EFSA) identified young populations as groups with exposures exceeding the Acceptable Daily Intake (ADI), and also raised concern that the current ADI may not be sufficiently protective for individuals with an impaired renal function, which may account for 10% of the general population. The Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) critically reviewed the safety of dietary phosphate, with a particular focus on the kidney as the primary target organ, taking into account the occurrence and content of phosphate in food, the most recent exposure estimates, the bioavailability of phosphate from different sources, the evidence linking excessive phosphate intake to kidney damage in animal models and humans as well as the exceedance of the current ADI in children. Moreover, the SKLM identified data gaps and research needs that should be addressed to improve the risk assessment of phosphate, with a special focus on vulnerable population groups. Based on the presented evidence, the Commission concludes that excessive dietary phosphate intake warrants further attention regarding possible health effects in vulnerable population groups or at exposure levels exceeding the ADI. Finally, the SKLM suggests a battery of risk management measures to reduce dietary exposure to phosphate, particularly in infants, toddlers and children, and to protect patients with chronic renal diseases.
Developmental neurotoxicity of thyroid hormone system-disrupting chemicals: a systems-level exploration using multi-omics approach.
Clavel Rolland N, Dagnino S, Vaysse PM … +4 more , Gangadharan B, Schorsch F, Pourcher T, Blanck O
Arch Toxicol · 2026 May · PMID 41654649 · Full text
There is increasing concern that thyroid hormone system-disrupting chemicals (THSDCs) may affect brain development during gestation and lactation. THSDCs comprise a wide range of natural and synthetic xenobiotics that ac...
There is increasing concern that thyroid hormone system-disrupting chemicals (THSDCs) may affect brain development during gestation and lactation. THSDCs comprise a wide range of natural and synthetic xenobiotics that activate diverse biological pathways. However, how disruption of specific molecular targets alters maternal thyroid hormone homeostasis and brain development in the offspring warrants further investigation. To address this question, this study investigates the effects of two THSDCs administered to pregnant rats from gestational day 6 through postnatal day 21: 5-propyl-2-thiouracil (PTU, 2.4 mg/kg/day), inhibitor of thyroid hormone synthesis, and pregnenolone-16α-carbonitrile (PCN, 300 mg/kg/day), inducer of hepatic enzymes involved in thyroid hormone metabolism. Circulating and brain thyroid hormone levels, enzymatic activities, and histopathology were assessed in dams and offspring. To further elucidate underlying mechanisms, multi-omics analyses combining proteomics, metabolomics, and spatial transcriptomics were performed on target organs including the thyroid gland, liver, and brain. Exposure to PTU resulted in severe thyroid hormone depletion in both serum and brain, accompanied by structural brain abnormalities, whereas PCN primarily induced hepatic enzyme activity with minimal effect on circulating thyroid hormone levels. Despite these distinct modes of action, multi-omics integration revealed convergent perturbations across molecular layers in the brain, particularly affecting energy metabolism and cytoskeletal organization with more pronounced effects observed following PTU exposure. Overall, multi-omics profiling enabled robust and highly sensitive identification of molecular signatures reflective of PCN exposure, without significant evidence of associated adverse toxicological effects. This approach highlights the value of multi-omics for mechanistic characterization and predictive assessment of THSDC-induced neurodevelopmental toxicity.
Single versus mixed perfluorinated compound exposures and cardiovascular disease risk: mechanistic insights from cross-sectional data and molecular interactions.
Liu XB, Zhou JX, Zheng ZY … +1 more , Ni HG
Arch Toxicol · 2026 May · PMID 41654648 · Publisher ↗
This study utilized National Health and Nutrition Examination Survey (NHANES) data to examine associations between perfluoroalkyl substances (PFAS) exposure and cardiovascular disease (CVD) risk, addressing controversial...
This study utilized National Health and Nutrition Examination Survey (NHANES) data to examine associations between perfluoroalkyl substances (PFAS) exposure and cardiovascular disease (CVD) risk, addressing controversial evidence on their mixed effects. Serum concentrations of PFNA, PFOA, and PFOS were analyzed using an integrated multi-model approach combining restricted cubic splines (RCS), weighted quantile sum regression (WQS), and Bayesian kernel machine regression (BKMR). While individual analysis replicated the debated pattern showing PFOS negatively correlated with CVD risk (PFNA/PFOA nonsignificant), mixture analyses revealed novel insights: both WQS and BKMR demonstrated significantly negative associations between combined PFAS exposure and CVD risk score, with PFOS identified as the primary driver. Age was a key confounder, likely reflecting cumulative exposure. Molecular docking/dynamics simulations confirmed angiotensin II receptor type 1 (AGTR1) as a specific cardiovascular target of PFOS, suggesting potential disruption of angiotensin II signaling. The critical discrepancy—null effects of individual PFNA/PFOA versus significant negative mixture effects predominantly driven by PFOS—resolves the initial controversy and underscores the complexity of co-exposure interactions. These findings highlight that traditional single-substance assessments mask mixture-driven health effects, necessitating focused epidemiological and toxicological research on PFAS mixtures.
Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury.
Korkut Celikates B, Ilgin S, Yilmaz MU … +1 more , Atli Eklioglu O
Arch Toxicol · 2026 May · PMID 41654647 · Full text
Gentamicin (GEN), an aminoglycoside antibiotic, induces nephrotoxicity primarily via mitochondrial dysfunction. This review summarizes mechanisms including reactive oxygen species (ROS) overproduction, mitochondrial DNA...
Gentamicin (GEN), an aminoglycoside antibiotic, induces nephrotoxicity primarily via mitochondrial dysfunction. This review summarizes mechanisms including reactive oxygen species (ROS) overproduction, mitochondrial DNA (mtDNA) damage, impairment of oxidative phosphorylation, and mitochondrial permeability transition pore (mPTP) activation. These mitochondrial alterations lead to adenosine triphosphate (ATP) depletion, apoptosis, and renal injury. In addition to apoptotic pathways, necrotic cell death can also be triggered, further aggravating kidney damage. Furthermore, GEN has been reported to directly interfere with mitochondrial ribosomes and gene expression, highlighting mitochondria as both targets and amplifiers of cellular toxicity. Therapeutic approaches targeting mitochondrial integrity, including antioxidants and mitochondrial transplantation, demonstrate potential nephroprotection. Additional strategies such as mPTP, stimulation of mitochondrial biogenesis, and pharmacological modulators of mitochondrial respiration have also shown promise in experimental studies. Understanding mitochondrial mechanisms underlying gentamicin-induced renal injury is crucial for developing targeted therapeutic strategies. A more comprehensive knowledge of mitochondrial regulation, organelle crosstalk, and early biomarkers of dysfunction will facilitate translation into clinical practice. Overall, preserving mitochondrial function represents a promising avenue for reducing nephrotoxicity while maintaining the antibacterial efficacy of GEN.
Regulation of chemicals demands assessment of risks rather than identification of hazards only.
Marx-Stoelting P, Ritz V, Herzler M … +20 more , Kneuer C, Aiello-Holden K, Brescia S, Escher SE, Feustel S, Fritsche E, Gebel J, Kenny EF, Landsiedel R, Sanders P, Schwarz M, Streitz M, Testai E, van Ravenzwaay B, Waetjen W, Wend K, Wilks M, Luch A, Tralau T, Hensel A
Arch Toxicol · 2026 Mar · PMID 41654646 · Full text
This position paper was collaboratively written during the international expert symposium "EU Chemicals Assessment - Risk- or Hazard-based?" that was organised by the German Federal Institute for Risk Assessment (BfR) in...
This position paper was collaboratively written during the international expert symposium "EU Chemicals Assessment - Risk- or Hazard-based?" that was organised by the German Federal Institute for Risk Assessment (BfR) in Berlin on November 27th and 28th 2025. Twenty experts from several institutions and European countries considered the scientific merits of both hazard-based and risk-based approaches to chemical safety assessment. While hazard information is essential, it does not reflect real-world exposure conditions that determine the likelihood of harm. On balance, we support a risk-based approach because it enables more proportionate, transparent and scientifically grounded regulatory decisions.
The use of new approach methodologies (high-throughput transcriptomics) to study nanoagrochemicals: mechanisms of toxicity of a commercial copper oxychloride to soil model invertebrates (Enchytraeus crypticus).
Gomes SIL, Scott-Fordsmand JJ, Amorim MJB
Arch Toxicol · 2026 May · PMID 41654645 · Full text
Nanoagrochemicals aim to increase safety and sustainability, representing an alternative to conventional agrochemicals. Given the infancy of this field, the risk-benefit analysis for nano-enabled agrochemicals remains un...
Nanoagrochemicals aim to increase safety and sustainability, representing an alternative to conventional agrochemicals. Given the infancy of this field, the risk-benefit analysis for nano-enabled agrochemicals remains unresolved. New Approach Methodologies (NAMs), such as omics, are high on the agenda to move beyond standard hazards, as the investigation of the mechanisms of toxicity deliver valuable information to understand the risks. NUCOP-M, a Cu-based commercial formulation containing nano-features, was previously assessed in Enchytraeus crypticus (Oligochaeta), impacting survival and reproduction based on the standard OECD Enchytraeid Reproduction Test (28 days) and its extension (56 days). The aim of the present study was to understand the mechanisms of toxicity of NUCOP-M at sublethal concentrations (100 and 500 mg Cu/kg soil of NUCOP-M) in short and longer exposure (2, 21 days) using a high-throughput gene expression microarray (NAMs) containing probles for 44,000 genes (a 4 × 44 K microarray). Results showed high transcriptomic response after 21 days exposure, although after 2 days there was an indication of increase in intracellular transport. At 21 days, the gene expression profile was compatible with effects on embryo development, which could be linked to reproductive effects observed at 28- and 56-days of exposure. Several of the genes found up-regulated points towards mitochondrial stress and activation of mechanisms to cope with oxidative stress. This study provides important insights into the mechanisms of toxicity of nanoagrochemicals in non-target species, filling a significant knowledge gap.
Tributyltin induces conjugation of ATG8s to single membranes via the V-ATPase-ATG16L1 axis, leading to transcription factor EB activation in human cell lines.
Hatamiya S, Miyara M, Takahashi N … +2 more , Oguro A, Kotake Y
Arch Toxicol · 2026 May · PMID 41654644 · Full text
Tributyltin (TBT) is an environmental contaminant that induces diverse toxic effects in mammals, but the cellular mechanisms underlying adaptation to TBT stress remain poorly understood. Conjugation of ATG8s to single me...
Tributyltin (TBT) is an environmental contaminant that induces diverse toxic effects in mammals, but the cellular mechanisms underlying adaptation to TBT stress remain poorly understood. Conjugation of ATG8s to single membranes (CASM) is a noncanonical LC3‑lipidation pathway activated by various stressors, distinct from canonical autophagy. We previously showed that TBT reduces lysosomal acidity and inhibits autophagy in SH-SY5Y cells. Furthermore, we observed TBT-induced LC3-II accumulation, which was reduced by bafilomycin A, and tubular LC3-positive structures as hallmarks of CASM. In this study, we investigated whether TBT activates CASM. TBT (700 nM) induced LC3-II accumulation, which was completely blocked by bafilomycin A in SH-SY5Y and HeLa cells. Unlike autophagy, TBT induced LC3-II accumulation even under class III PI3K inhibition by wortmannin and in FIP200-knockout cells. Salmonella effector protein SopF, which inhibits V-ATPase-ATG16L1 association required for CASM, inhibited TBT-induced LC3-II accumulation. In FIP200-knockout cells, TBT induced LC3 accumulation on lysosomes, the primary CASM target. TBT also promoted nuclear translocation of transcription factor EB (TFEB) in a SopF-sensitive manner. Together, these results identify CASM as a lysosomal stress response to TBT, induced via the V-ATPase-ATG16L1 axis, leading to TFEB activation. This mechanism provides a toxicological framework for understanding xenobiotic-induced lysosomal adaptations.
Keratin adducts in human hair prove exposure to sulfur mustard in a real case of poisoning and indicate exposure to sesquimustard and O-lost in vitro.
John H, Schmeißer W, Dentzel M … +3 more , Steinritz D, Sezigen S, Worek F
Arch Toxicol · 2026 May · PMID 41654643 · Full text
We herein present the development and application of a forensic mass spectrometry-based procedure simultaneously targeting hard keratins from human hair adducted with sulfur mustard (SM) and its structural analogues sesq...
We herein present the development and application of a forensic mass spectrometry-based procedure simultaneously targeting hard keratins from human hair adducted with sulfur mustard (SM) and its structural analogues sesquimustard (Q) and O-lost (T). These alkylating chemicals represent blister agents banned by the Chemical Weapons Convention (CWC). The procedure was applied to an authentic hair sample of an SM-poisoned patient and thus allowed for the first time the proof of exposure to SM based on keratin adducts in a real case of poisoning. Whereas adducts of SM were detected, those of Q and T were not found. Contact of SM, Q and T with hair induced the alkylation of side chains of glutamic acid (E*) residues in diverse hard keratins (adduct formation). For analysis hair proteins were subjected to lysis to make them soluble and subsequently to proteolysis with pepsin to generate adducted peptides. Micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (µLC-ESI MS/HR MS) allowed the detection of the three biomarker peptides AE*IRSDL, FKTIE*EL and LE*TKLQF. The characteristic alkyl-chain hydroxyethylthioethyl (HETE) was attached by SM, hydroxyethylthioethylthioethyl (HETETE) derived from Q and the hydroxyethylthioethyloxyethylthioethyl (HETEOETE)-moiety originated from exposure to T. Accordingly, we herein present an extended and improved forensic method for the biomedical verification of hair exposure to blister agents. Due to the currently growing threat by chemical warfare agents we also included some general toxicological and bioanalytical remarks of SM poisoning helpful not only for physicians and toxicologists.
Pyrazinamide-induced hepatotoxicity mediated by aldehyde oxidase and xanthine oxidase.
Zhang M, Guan C, Sheng G … +7 more , Ding Z, Zhao Y, Zhao G, Li W, Hu Z, Peng Y, Zheng J
Arch Toxicol · 2026 May · PMID 41653207 · Publisher ↗
Pyrazinamide (PZA) has been approved for the treatment of tuberculosis in clinical practice. However, its adverse effects, particularly hepatotoxicity, have raised concerns. The present study aimed at exploring the poten...
Pyrazinamide (PZA) has been approved for the treatment of tuberculosis in clinical practice. However, its adverse effects, particularly hepatotoxicity, have raised concerns. The present study aimed at exploring the potential relationship between PZA-induced hepatotoxicity and its metabolites resulting from metabolic activation. Glutathione (GSH) conjugates with confirmed structures were detected in mouse cytosol incubations containing PZA or pyrazinoic acid (POA, a major metabolite of PZA) supplemented with glutathione (GSH). Such GSH metabolites were also observed in both liver homogenates from mice administered with PZA and mouse primary hepatocytes exposed to PZA. Aldehyde oxidase (AO) and xanthine oxidase (XOD) were identified as key enzymes in the metabolic activation of PZA and POA. Both vitamin C (VC) and N-acetylcysteine (NAC) were found to reduce the generation of GSH conjugates derived from PZA and POA in incubation systems. Additionally, VC alleviated the susceptibility of hepatocytes to PZA-induced cytotoxicity. Consecutive administration of PZA for 7 days resulted in a marked elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice, and PZA-derived hepatic protein adduction was detected. Allopurinol administration attenuated the elevated serum ALT and AST in company with a reduction in the formation of GSH conjugates. This work provides solid evidence for the correlation between the metabolic activation of PZA and PZA-induced hepatotoxicity, enhancing the understanding of the underlying mechanisms of PZA toxicity in terms of molecular chemical structure.
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