Review
Toxicology
Anna Itkonen, Jukka Hakkola, Jaana Rysa
Summary: Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia by activating pregnane X receptor (PXR). PXR activation disrupts lipid metabolism and promotes hypercholesterolemia through multiple mechanisms. This novel toxicity pathway is of great concern and requires further attention.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Toxicology
Kristina Pogrmic-Majkic, Dragana Samardzija Nenadov, Biljana Tesic, Svetlana Fa Nedeljkovic, Dunja Kokai, Bojana Stanic, Nebojsa Andric
Summary: This study utilized AOPs and AOP networks to understand the impact of chemicals on human health. It derived the HFRT-AOP network and mapped DEHP to this network, providing insights into the toxic mechanism of DEHP-induced human female reproductive toxicity.
ARCHIVES OF TOXICOLOGY
(2022)
Article
Toxicology
Terje Svingen, Daniel L. Villeneuve, Dries Knapen, Eleftheria Maria Panagiotou, Monica Kam Draskau, Pauliina Damdimopoulou, Jason M. O'Brien
Summary: The AOP framework organizes scientific knowledge to infer cause-effect relationships between stressor events and toxicity outcomes, supporting chemical safety assessment and regulatory toxicology. However, developing robust AOPs requires substantial work and time, leading to a proposed more pragmatic approach for AOP development.
TOXICOLOGICAL SCIENCES
(2021)
Review
Pharmacology & Pharmacy
Mathieu Vinken
Summary: Up to half of hospitalized COVID-19 patients may experience liver damage, which can be caused either by direct actions of the virus or pharmacological treatment. Research suggests that liver injury may result from direct viral binding and local actions in cholangiocytes, or indirectly from systemic hypoxia and inflammation in patients. URGENT further research is needed to fill knowledge gaps for future targeted development of vaccines and therapies.
Article
Environmental Sciences
Janani Ravichandran, Bagavathy Shanmugam Karthikeyan, Areejit Samal
Summary: An adverse outcome pathway (AOP) is a representation of mechanistic information on adverse effects caused by environmental exposure. This study focuses on the construction and analysis of an endocrine-relevant AOP (ED-AOP) network. The connectivity analysis and graph-theoretic analyses of the network revealed important events and system-level perturbations caused by endocrine disruption, providing insights for risk assessment and the development of new endpoints or assays.
SCIENCE OF THE TOTAL ENVIRONMENT
(2022)
Article
Toxicology
Wanyu He, Jiaqi Ding, Ning Gao, Lingyan Zhu, Lin Zhu, Jianfeng Feng
Summary: This study expands the understanding of the toxicity of organophosphate esters (OPEs) and systematically identifies the mechanism of OPEs toxicity under the framework of adverse outcome pathway (AOP). The results show that the toxicity mechanism of OPEs on aquatic organisms and mammals differ, primarily due to their different biological metabolic systems.
ARCHIVES OF TOXICOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Patrudu Makena, Tatiana Kikalova, Gaddamanugu L. L. Prasad, Sarah A. A. Baxter
Summary: Lung fibrosis is a progressive fatal disease caused by deregulated wound healing of lung epithelial cells. Chronic cigarette smoking and oxidative stress are major risk factors for lung fibrosis. This study aims to develop an adverse outcome pathway (AOP) to investigate the mechanisms of lung fibrosis due to lung injury caused by inhaled toxicants, including cigarette smoke. Cellular and tissue-level events lead to the development of lung fibrosis through proinflammatory and profibrotic mediators.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Toxicology
Jimmy Alarcan, Georges de Sousa, Efrosini S. Katsanou, Anastasia Spyropoulou, Petros Batakis, Kyriaki Machera, Roger Rahmani, Alfonso Lampen, Albert Braeuning, Dajana Lichtenstein
Summary: This study utilized an in vitro assay toolbox to investigate the combined effects of mixtures containing differently acting compounds and refine the molecular mechanisms underlying liver steatosis AOP. The results showed dose addition effects in the mixtures, suggesting the validity of the additivity assumption, and proposed further refinement of the AOP to better reflect the diversity of molecular mechanisms causing adverse outcomes.
ARCHIVES OF TOXICOLOGY
(2022)
Article
Engineering, Environmental
Yuan Jin, Guangshuai Qi, Yingqing Shou, Daochuan Li, Yuzhen Liu, Heyuan Guan, Qianqian Zhang, Shen Chen, Jiao Luo, Lin Xu, Chuanhai Li, Wanli Ma, Ningning Chen, Yuxin Zheng, Dianke Yu
Summary: This study developed a highly reliable AOP model concerning human health, validated and quantitatively evaluated it, and conducted targeted bioassays to further understand cellular responses. Through these research efforts, a comprehensive AOP network was established, providing valuable insights for risk assessment.
JOURNAL OF HAZARDOUS MATERIALS
(2022)
Review
Cell Biology
Helena T. Hogberg, Ann Lam, Elan Ohayon, Muhammad Ali Shahbaz, Laure-Alix Clerbaux, Anna Bal-Price, Sandra Coecke, Rachel Concha, Francesca De Bernardi, Eizleayne Edrosa, Alan J. Hargreaves, Katja M. Kanninen, Amalia Munoz, Francesca Pistollato, Surat Saravanan, Natalia Garcia-Reyero, Clemens Wittwehr, Magdalini Sachana
Summary: This review organizes available knowledge on the neurobiological mechanisms of COVID-19, identifies four AOPs leading to neurological adverse outcomes, and discusses factors influencing the impact of COVID-19 on neurological AOPs. The use of the AOP framework helps visualize core pathways and shared mechanisms.
Article
Pharmacology & Pharmacy
Elena Menegola, Christina H. J. Veltman, Maria Battistoni, Francesca Di Renzo, Angelo Moretto, Francesca Metruccio, Anna Beronius, Johanna Zilliacus, Katerina Kyriakopoulou, Anastasia Spyropoulou, Kyriaki Machera, Leo T. M. van der Ven, Mirjam Luijten
Summary: The study described a linear AOP for skeletal craniofacial defects with CYP26 inhibition as the MIE and conazoles as representative stressors. It showed high biological plausibility and moderate overall empirical evidence, with high essentiality assessment for the KEs.
Article
Engineering, Environmental
You Song, Keke Zheng, Dag Anders Brede, Tania Gomes, Li Xie, Yetneberk Kassaye, Brit Salbu, Knut Erik Tollefsen
Summary: This study used multiomics dose-response modeling to identify the hazards of low-dose ionizing radiation to Daphnia magna. It demonstrated the use of omics data to support the development of an adverse outcome pathway (AOP) network for ionizing radiation. The results showed that molecular pathways related to oxidative stress, DNA damage, mitochondrial dysfunction, protein degradation, and apoptosis were highly relevant to the effects of gamma radiation.
ENVIRONMENTAL SCIENCE & TECHNOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Yann Gueguen, Marie Frerejacques
Summary: An adverse outcome pathway (AOP) is a conceptual framework that describes the causally and sequentially linked events occurring during exposure to stressors, with relevance to risk assessment. This paper proposes a review of knowledge on uranium-induced kidney impairment and suggests a tentative AOP for this condition. The identified key events include mitochondrial dysfunction, DNA damage, and cellular stress responses, leading to tubular damage and kidney failure.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Toxicology
Lorna R. Jones, Stephanie J. Wright, Timothy W. Gant
Summary: This study conducted a literature review on the hazard assessment of microplastics and identified multiple knowledge gaps. The physical properties of microplastics may be altered by environmental exposure, and it is currently not possible to determine a single adverse outcome at the organ level. The study highlights the importance of understanding both external and internal exposure and developing hazard data for better risk assessment.
TOXICOLOGY LETTERS
(2023)
Article
Public, Environmental & Occupational Health
Qier Wu, Youcef Bagdad, Olivier Taboureau, Karine Audouze
Summary: The study shows that computational approaches based on network science can help us better understand the complexity of drug health effects, with the aim to support drug safety assessment.
FRONTIERS IN PUBLIC HEALTH
(2021)
Article
Public, Environmental & Occupational Health
Silke Gabbert, Miriam Mathea, Susanne N. Kolle, Robert Landsiedel
Summary: This article explores and compares different approaches to quantify the Borderline Range (BR) of experimental results, which represent ranges where the study result is ambiguous. The precision of the testing methods determines the size of their BRs, and consensus on a BR is needed to account for the limited precision of testing methods.
Review
Chemistry, Multidisciplinary
Wendel Wohlleben, Annette Mehling, Robert Landsiedel
Summary: Chemicals can be assessed for hazard in groups based on their similar structures and toxicological properties, similar to how elements are grouped in the periodic system. Strategies for chemical grouping have been used to support the evaluation of human health hazards, exposures, and risks, as shown in case studies. Structural similarity is commonly used as the basis for grouping, but it may not always be sufficient. Ten principles for grouping have been derived, including transparency, adequacy of methods, and consideration of toxicological properties, which can facilitate effective risk management.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Medicine, Legal
Susanne N. Kolle, Melanie Flach, Marcus Kleber, David A. Basketter, Britta Wareing, Annette Mehling, Lars Hareng, Nico Watzek, Steffen Bade, Dorothee Funk-Weyer, Robert Landsiedel
Summary: In the past decade, several non-animal methods have been adopted as OECD test guidelines to identify skin sensitization hazards. However, the predictive accuracy of these methods for substances beyond the chemical domains of individual validation studies remains largely untested. This study compares the skin sensitization test results from in vitro and in chemico methods to available in vivo data for plant extracts and polymeric materials.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2023)
Biographical-Item
Toxicology
Jan G. Hengstler, Hermann Bolt, Uwe Heinrich, Andrea Hartwig, Robert Landsiedel
ARCHIVES OF TOXICOLOGY
(2023)
Correction
Toxicology
Jan G. Hengstler, Hermann Bolt, Uwe Heinrich, Andrea Hartwig, Robert Landsiedel
ARCHIVES OF TOXICOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Dunja Dimitrijevic, Eric Fabian, Dorothee Funk-Weyer, Robert Landsiedel
Summary: In pharmacokinetics, plasma protein binding (PPB) is an important parameter affecting drug metabolism. The unbound fraction (fu) is considered the effective concentration at the target site. In vitro models, such as physiologically based toxicokinetic models (PBTK), are increasingly used in pharmacology and toxicology. This study compared three methods (rapid equilibrium dialysis, ultrafiltration, and ultracentrifugation) to quantify fu and found that the selection of the separation method should be based on the properties of the test substance. Rapid equilibrium dialysis was suitable for a broader range of substances, while ultrafiltration and ultracentrifugation were suitable for polar substances.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Cell Biology
Sabina Ramirez-Hincapie, Barbara Birk, Philipp Ternes, Varun Giri, Volker Haake, Michael Herold, Franziska Maria Zickgraf, Andreas Verlohner, Hans-Albrecht Huener, Hennicke Kamp, Peter Driemert, Robert Landsiedel, Elke Richling, Dorothee Funk-Weyer, Bennard van Ravenzwaay
Summary: Cell-based metabolomics provides multiparametric readouts for decision making in compound development. A LC-MS/MS-based metabolomics platform was developed for liver toxicity classification in HepG2 cells. The platform showed dose response and differentiation between liver toxicity modes of action, and identified specific metabolite patterns for each mode of action. This method offers a mechanistic-based, cost-effective screening for compound development pipelines.
CELL BIOLOGY AND TOXICOLOGY
(2023)
Article
Toxicology
Sabina Ramirez-Hincapie, Barbara Birk, Philipp Ternes, Varun Giri, Franziska Maria Zickgraf, Volker Haake, Michael Herold, Hennicke Kamp, Peter Driemert, Robert Landsiedel, Elke Richling, Dorothee Funk-Weyer, Bennard van Ravenzwaay
Summary: This study applied a high-throughput LC-MS/MS-based broad targeted metabolomics system to investigate the metabolic dynamics of nitrofurantoin over time and concentration and derived a mechanistic-anchored approach for point of departure (PoD) derivation. The results showed clear time and concentration effects on the metabolome of HepG2 cells. This approach allows for the derivation of PoD that can be mechanistically anchored to established key events and contribute to the development of new adverse outcome pathways.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Pia Wilhelmi, Varun Giri, Franziska Maria Zickgraf, Volker Haake, Stefan Henkes, Peter Driemert, Paul Michaelis, Wibke Busch, Stefan Scholz, Burkhard Flick, Marta Barenys, Barbara Birk, Hennicke Kamp, Robert Landsiedel, Dorothee Funk-Weyer
Summary: Through LC-MS/MS and GC-MS metabolomics, this study investigated the changes in endogenous metabolites in zebrafish embryos as indicators of developmental toxicity pathways. The results showed that exposure to the compound PTU led to morphological alterations and significant metabolic changes, which could be linked to the inhibition of thyroid peroxidase and potential neurodevelopmental impairments. This study demonstrated that metabolite changes in zebrafish embryos provide mechanistic information associated with the mode of action of PTU.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
Article
Medicine, Legal
Jens C. Otte, Heli Miriam Hollnagel, Christiane Nagel, Renata Friederike Gerhardt, Wendel Wohlleben, Nathalie Vallotton, Diederik Schowanek, Gordon Sanders, Joe M. Frasca, Tushar Mahale, Mark Pemberton, Bjoern Hidding, Robert Landsiedel
Summary: This study proposes a three-tiered regulatory approach for assessing polymers, which includes grouping the polymers based on their chemistry, physico-chemical properties, and hazard similarity. By reducing animal testing and providing sufficient data, this approach aims to achieve an adequate level of protection.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2023)
Article
Toxicology
Franziska M. Zickgraf, Aishwarya Murali, Robert Landsiedel
Summary: This article summarizes studies on the effects of engineered nanomaterials (ENM) on the gut microbiome, showing that ENM can affect the microbiome in various ways, although few studies demonstrate a link to adverse effects on the host. Based on these findings, future studies can assess the hazards and risks of ENM through changes in the microbiome.
CURRENT OPINION IN TOXICOLOGY
(2023)
Correction
Environmental Sciences
Johannes G. Keller, Michael Persson, Philipp Mueller, Lan Ma-Hock, Kai Werle, Josje Arts, Robert Landsiedel, Wendel Wohlleben
Meeting Abstract
Environmental Sciences
Naveed Honarvar, Astrid Zander, Eva Dony, Miyuki Shigano, Brandy Williamson Riffle, Markus Frericks, Tobias Seiser, Dorothee Funk-Weyer, Robert Landsiedel
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
(2022)
Article
Biochemistry & Molecular Biology
Annette Mehling, Susanne N. Kolle, Britta Wareing, Robert Landsiedel
Summary: Significant progress has been made in the past two decades in developing alternative methods to animal testing for regulatory and safety testing. In 2021, a breakthrough in regulatory testing was achieved with the acceptance of non-animal test methods for skin sensitization as OECD guideline 497. This achievement required the hard work and perseverance of many individuals.
Article
Toxicology
Kathryn Page, Walter Westerink, Kristie Sullivan, Thomas McDonald, Clive Roper
Summary: This study developed a new method to assess the skin irritation of antimicrobial cleaning products. The method utilized a more human-like model and demonstrated its effectiveness through comparison with in vivo rabbit skin irritation data.
TOXICOLOGY IN VITRO
(2024)
Article
Toxicology
Arupam Patra, Thirukumaran Kandasamy, Siddhartha Sankar Ghosh, Gurvinder Kaur Saini
Summary: This study successfully produced recombinant anisoplin and demonstrated its significant anti-cancer effect and ability to induce apoptosis in breast cancer cells. The activation of related signaling pathways may be the key to cell death.
TOXICOLOGY IN VITRO
(2024)
Article
Toxicology
Thomas Haller, Alexander Jesacher, Alberto Hidalgo, Christina Schmidt
Summary: This study used live cell imaging to observe the accumulation of amiodarone in primary rat alveolar type II cells, and found that it specifically accumulates in lamellar bodies. The uptake is rapid, while storage is persistent. The main mechanisms for intracellular bioaccumulation of amiodarone are proposed to be passive diffusion, ion-trapping, and lipophilic interactions.
TOXICOLOGY IN VITRO
(2024)
Article
Toxicology
Filiz Bakar-Ates, Erva Ozkan
Summary: This study investigated the ferroptotic effect of CuB in breast cancer cells and evaluated its combination with erastin, a ferroptosis inducer. The results showed that the combination treatment significantly activated the ferroptotic pathways and altered the expression of iron-related proteins in breast cancer cells.
TOXICOLOGY IN VITRO
(2024)
Article
Toxicology
Rachel Z. Bennie, Ian C. Shaw
Summary: Estrogen mimics are synthetic and naturally occurring compounds that can interact with estrogen receptors in animals. In vitro transactivation reporter gene assay and in silico molecular modelling can be used to predict the mimicry of these compounds, reducing reliance on animal studies.
TOXICOLOGY IN VITRO
(2024)
Article
Toxicology
Sevda Isik, Semra Cicek
Summary: This study found that high doses of riboflavin can cause cytotoxicity in rainbow trout gonad cells and affect the transcriptional expressions of antioxidant enzymes and growth and reproductive genes, potentially leading to DNA damage and cell death.
TOXICOLOGY IN VITRO
(2024)
Article
Toxicology
Ying Wang, Jie Wu, Mengqi Wan, Dou Yang, Fasheng Liu, Kehao Li, Manxin Hu, Yuanyuan Tang, Huiqiang Lu, Shouhua Zhang, Yuanzhen Xiong
Summary: m-Cresol is commonly used as an intermediate for pesticides and other industrial applications. This study investigated the hepatotoxicity of m-cresol using zebrafish larvae and explored its molecular mechanisms. The results suggest that m-cresol may induce liver damage in zebrafish larvae through oxidative stress and cell apoptosis pathways.
TOXICOLOGY IN VITRO
(2024)
Article
Toxicology
Vincent J. Manna, Shannon Dwyer, Vanessa Pizutelli, Salvatore J. Caradonna
Summary: The widespread use of electronic cigarettes and the emergence of a new illness have raised concerns about the effects of e-cigarette vapor on respiratory tissues. Researchers have developed a simple device to mimic the response of human airway tissue after long-term exposure to e-cigarette vapor, and have identified differences in the effects of different vapor compositions on airway tissue.
TOXICOLOGY IN VITRO
(2024)
