Toxicology letters最新文献

{"title":"CEC04-01 Evaluation of non guideline studies as important source of information","authors":"M. Batke","doi":"10.1016/j.toxlet.2025.07.025","DOIUrl":"10.1016/j.toxlet.2025.07.025","url":null,"abstract":"<div><div>The first guideline for toxicokinetic studies was adopted in 1984 by the OECD, and the current version of 2010 still refers to the need for further specification of the recommendations of the responsible agencies. This implies that older toxicokinetic studies are available, particularly for existing chemicals, and that differences in study design and outcome may depend on the existence or non-existence of regulatory recommendations. Furthermore, toxicokinetic studies published in peer-reviewed literature, especially those not conducted for regulatory purposes as well as academic research studies may not be guideline conform.</div><div>Non-guideline studies are an important source of information for a wide array of chemical substances. For the structured assessment of toxicity studies criteria checklists are well established and support evaluating the evidence of non-guideline studies.</div><div>Currently, the evaluation of toxicokinetic studies is performed as a narrative review which is not supported by a systematic approach to standardize the strength of the evidence obtained from non-guideline toxicokinetic studies for regulatory assessments. In particular, the impact of a single aspect such as purity of the test item, specifications of the analytical methods, or number of animals, to the final rating is important in evaluating the overall reliability of the study.</div><div>The transparent way of a systematic review of diverse, non-guidelines studies provides direct evidence of their importance for current risk assessment based on the 3R principles.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Pages S8-S9"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CEC02-01 Brief Session Introduction on DNT","authors":"E. Fritsche","doi":"10.1016/j.toxlet.2025.07.015","DOIUrl":"10.1016/j.toxlet.2025.07.015","url":null,"abstract":"<div><div>No abstract has been submitted.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S6"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CEC02-05 Bridging across cell-based assays/simple model organisms, rodent behavioral studies and human disease","authors":"P.J. Lein","doi":"10.1016/j.toxlet.2025.07.019","DOIUrl":"10.1016/j.toxlet.2025.07.019","url":null,"abstract":"<div><div>No abstract has been submitted.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S7"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CEC05-01 Basic concepts of Regulatory Toxicology (Theoretical lecture)","authors":"G. Kass","doi":"10.1016/j.toxlet.2025.07.030","DOIUrl":"10.1016/j.toxlet.2025.07.030","url":null,"abstract":"<div><div>While history books contain numerous descriptions of intoxications due to the consumption of mycotoxins and exposure to heavy metals, regulatory toxicology only emerged in the early 20th century, when industrialization and the use of chemicals in everyday products and food raised concerns about their potential risks. In 1905, France pioneered its Law on the Repression of Fraud, followed in 1906 by the creation of the U.S. Food and Drug Administration (FDA), marking the first major step toward regulating toxic substances. However, it was only in the 1940s and 1950s that toxicology gained more recognition as a specialized field with the growth of the chemical and pharmaceutical industries and, in Europe, the establishment of national agencies and the development of safety standards. The formation of the European Union (EU) brought about a harmonized approach to chemical regulation with the creation of European Medicines Agency (EMA) (1995), the European Food Safety Authority (EFSA) (2002) and the European Chemicals Agency (ECHA) (2007).</div><div>The objective of regulatory toxicology is to protect human health and the environment. This requires the establishing of safe exposure limits, supported by appropriate toxicity testing that follow accepted guidelines. The key activities falling within the remit of regulatory toxicology include the following.</div><div>Hazard identification and characterisation: to understand the toxicological properties of substances by performing laboratory studies to test for short-term to long-term toxicity, reproductive-developmental toxicity, adverse effects on the genetic material and for other potential adverse effects. Where thresholds (Points of Departure) can be identified, these can be used to derive health-based guidance values.</div><div>Risk Assessment: to determine the level of risk associated with exposure to a particular substance.</div><div>Risk Management: to establish appropriate safety standards, labelling requirements and restrictions on the use of harmful substances.</div><div>This first introductory presentation will set the scene for the CEC5 ‘Regulatory Toxicology in the context of the EU Legislations’</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S10"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S08-01 Advancing Cardiotoxicity Risk Assessment: Integrative Modeling with New Approach Methodologies","authors":"S. Krishna","doi":"10.1016/j.toxlet.2025.07.067","DOIUrl":"10.1016/j.toxlet.2025.07.067","url":null,"abstract":"<div><div>The cardiovascular system is vulnerable to pharmaceuticals and environmental chemicals, but risk assessment remains challenging due to data gaps and reliance on animal testing. New Approach Methodologies (NAMs) – comprising <em>in vitro</em>, in chemico, and <em>in silico</em> techniques – provide efficient, human-relevant strategies to enhance hazard and risk assessment.</div><div>We developed an integrative modeling workflow using physiologically based pharmacokinetic (PBPK) models to translate bioactive concentrations from over 300 high-throughput screening (HTS) assays targeting cardiovascular-relevant endpoints into human daily equivalent administered doses (EADs) for more than 800 substances. These chemicals span categories such as personal care products, flame retardants, herbicides, pesticides, pharmaceuticals, and industrial byproducts.</div><div>Human-relevant risk predictions were generated by comparing <em>in vitro</em>-derived EADs with human exposure estimates and <em>in vivo</em> points of departure (PODs) from toxicological studies. Additionally, geospatial analysis was applied to evaluate combined risks for various populations across different U.S. regions.</div><div>Our approach integrates HTS data, animal study-derived PODs, human exposure estimates, geospatial exposure data, and PBPK modeling to identify chemicals with potential cardiovascular toxicity at relevant exposure levels. Key targets of concern included endothelial cell signaling, nuclear hormone receptors, and other critical cardiovascular pathways.</div><div>This workflow advances human health risk assessment from molecular mechanisms to population-level insights. It identifies communities disproportionately affected by chemical exposures, enhancing predictive capabilities for regulatory decision-making and prioritizing chemicals for further testing.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S21"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S08-02 Current and emerging concepts of cardiotoxicity: applicability inrisk assessment for regulatory purposes","authors":"K. Tsarouhas","doi":"10.1016/j.toxlet.2025.07.068","DOIUrl":"10.1016/j.toxlet.2025.07.068","url":null,"abstract":"<div><div>Cardiomyopathy is a myocardial disorder. The heart muscle is structurally affected and/or functions abnormally, and in many cases, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease. Before clinicians conclude their diagnosis on idiopathic cardiomyopathy, toxic as well as viral and immune causes should also be considered.</div><div>For some medication, such as anticancer drugs, epidemiological studies point to cardiotoxic manifestations. Other implications related to specific cardiovascular drugs (e.g. calcium-channel blockers, beta-blockers) are mostly associated in overdose with acute heart failure <span><span>^[1]</span></span>.</div><div>Industrial chemicals can exert toxic action, directly or indirectly, on various components of the cardiovascular system. Cardiotoxins (e.g. plant glycosides from oleander, foxglove and lily) can alter the heart functionally or structurally depending on the dosage and exposure period. The main molecular targets of the toxins in the heart are sodium, potassium and calcium channels <span><span>^[2]</span></span>. Oxidative stress plays also a crucial role in cardiac toxicity caused by industrial chemicals, like mercury. Metals like platinum, cause direct injury on the myocytes, and cause mitochondrial ultrastructural abnormalities and platelet activation and aggregation. Cobalt-related cardiomyopathy probably results from interference with energy production and contractile mechanisms, but additional factors (nutrition, hypothyroidism) are often implicated. Nanoparticles are known to affect the heart through oxidative stress and inflammation, cellular apoptosis and decreased cell proliferation, decreased heart rate and down regulation of genes functioning in heart formation and development. The aetiology of ethanol-related cardiotoxicity is multifactorial, with individual susceptibility being important. The true prevalence of toxins/ chemicals related-dilated cardiomyopathy in the general population is not known.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S22"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S07-03 Impact of Glyphosate and its Mixture with 2,4-D and Dicamba on Gut Biochemical Function, Intestinal Barrier Integrity and Microbiome Composition in Adult Rats with Prenatal Commencement of Exposure","authors":"M.N. Antoniou ,&nbsp;R. Mesnage ,&nbsp;S. Ferguson ,&nbsp;P.M. Nechalioti ,&nbsp;L. Cercelaru ,&nbsp;A.O. Docea ,&nbsp;A. Tsatsakis ,&nbsp;D. Kouretas","doi":"10.1016/j.toxlet.2025.07.066","DOIUrl":"10.1016/j.toxlet.2025.07.066","url":null,"abstract":"<div><h3>Background:</h3><div>Large scale use of glyphosate herbicides in genetically modified (GM) glyphosate-tolerant cropping and non-GM cropping applications has resulted in the spread of many glyphosate-resistant weed species. As a result, the agricultural biotechnology industry has launched GM crops tolerant to glyphosate plus 2,4-D and to glyphosate plus dicamba. Consequently, people are increasingly exposed to a mixture of glyphosate, 2,4-D and dicamba.</div></div><div><h3>Objectives:</h3><div>Our objective was to investigate the effects of glyphosate alone and in combination with 2,4-D and dicamba, using regulatory relevant doses, on gut structure and function in rats.</div></div><div><h3>Methods:</h3><div>Pregnant Wistar rats were administered via drinking water from day-6 of gestation with glyphosate at the European Union (EU) no observed adverse effect level (NOAEL; 50 mg/kg bw/day) and acceptable daily intake (ADI; 0.5 mg/kg bw/day), and with a mixture of glyphosate, 2,4-D and dicamba, with each at the ADI (0.3 mg/kg bw/day dicamba; 0.02 mg/kg bw/day 2,4-D; 0.5 mg/kg bw/day glyphosate). Offspring continued on this regimen for 13 weeks post-weaning, at which point large and small intestinal tissues and gut content were isolated and analysed for inflammation, gut epithelial integrity, oxidative stress, microbiota composition and histopathology.</div></div><div><h3>Results:</h3><div>Treatment with theglyphosate, dicamba and 2,4-D mixture resulted in increased gut inflammation and permeability (leaky gut), which was associated with oxidative stress and alterations in microbial community composition. The glyphosate NOAEL dose gave similar though less prominent gut inflammation and integrity outcomes but was also associated with oxidative stress. Histological analysis confirmed structural alterations and inflammation in large and small intestine. Effects were more pronounced in the large intestine but no major, significant differences were observed between sexes.</div></div><div><h3>Discussion:</h3><div>Our results indicate that exposure to a mixture of glyphosate, 2,4-D and dicamba at their respective EU ADI constitutes a potential health hazard with respect to gut structure and function. Our data also suggests that safety (ADI) limits for pesticides should be based on mixtures and not individual “active substances” as currently practised. Outcomes seen from treatment with the EU glyphosate NOAEL dose add to evidence that this value may be incorrect and thus the ADI too high.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S21"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S03-01 An emerging toolbox for Botanical risk assessment","authors":"C. Mahony","doi":"10.1016/j.toxlet.2025.07.050","DOIUrl":"10.1016/j.toxlet.2025.07.050","url":null,"abstract":"<div><div>The HESI Developmental and Reproductive Toxicology (DART) Working Group of the Botanical Safety Consortium is dedicated to developing reliable screening strategies to identify botanicals with potential developmental or reproductive toxicity. Our mission encompasses the selection of <em>in silico</em> and <em>in vitro</em> tools capable of accommodating the complex mixtures inherent in botanicals, as well as the evaluation of candidate botanicals based on suspected DART endpoints. We have established a series of botanical case studies to assess the efficacy of a NAM toolbox based on functional as well mechanistic assays.</div><div>In our recent evaluations, we identified several botanicals that have been studied for DART effects. Blue cohosh (Caulophyllum thalictroides), traditionally used to induce labour, was associated with fetal bovine cardiac defects. Usnea Lichen affected estrous cycling in a 90-day rodent study, and usnic acid demonstrated teratogenic effects in rats and zebrafish. Conversely, ashwagandha, Asian ginseng, and milk thistle are not expected to cause DART effects.</div><div>Selected assays, such as Devtox Quick Predict and transcriptional profiling with Connectivity Mapping, were employed to explore their utility in identifying DART-relevant botanicals. Notably, the Devtox assay revealed significant changes in cystine and ornithine metabolism for blue cohosh and usnea lichen, indicating a high potential for developmental toxicity. Ginseng showed changes in cystine metabolism alone, and no response was detected with ashwagandha. Although milk thistle exhibited changes in both metabolites, these occurred at concentrations affecting cell viability. Connectivity Mapping (CMap) analysis linked blue cohosh to compounds like GABA receptor antagonists, acetylcholinesterase inhibitors, and mycophenolic acid, all of which are associated with adverse reproductive outcomes. Ginseng connections included ginsenosides and various agents with potential stimulating and hormonal effects.</div><div>The data generated from this research will be made publicly available via the NIEHS database. As we continue, we aim to refine our data analysis and expand our assays and botanical repertoire to enhance safety decision-making processes in botanical evaluation.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S16"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S06-03 Considerations for dose level selection for developmental and reproductive toxicity studies: Industry perspectives","authors":"M. Beekhuijzen","doi":"10.1016/j.toxlet.2025.07.063","DOIUrl":"10.1016/j.toxlet.2025.07.063","url":null,"abstract":"<div><div>During 2020, ECHA started an evaluation of the OECD Test Guideline 443: Extended One Generation Reproductive Toxicity Study (EOGRTS) with the aim to analyse specific aspects relating to the performance of the study with respect to design, conduct and toxicological findings. A significant outcome of this ECHA evaluation focused on adequate dose level selection and subsequently, in 2022, ECHA published their recommendations for developmental and reproductive toxicity (DART) studies. However, following these recommendations poses several challenges for industry and the laboratories conducting these studies. This presentation will cover the implications for, and impact on, study outcomes and interpretation for different chemicals and sectors, highlighting the challenges in balancing animal use and welfare with regulatory requirements and the need for continued dialogue on this topic.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S20"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S11-03 Lung surfactant interaction assay – a method to predict early signs of acute inhalation toxicity","authors":"J. S⊘rli","doi":"10.1016/j.toxlet.2025.07.077","DOIUrl":"10.1016/j.toxlet.2025.07.077","url":null,"abstract":"<div><div>Acute inhalation toxicity testing for regulatory purposes relies on the use of guideline studies in rodents. Apart from the ethical concerns of exposing animals to toxic chemicals, <em>in vivo</em> testing is expensive and time-consuming. The results from acute inhalation toxicity is systemic (lethal concentration for 50% of the exposed animals) and death obscures effects on the portal-of-entry, i.e. the lungs <span><span>^[1]</span></span>. Understanding the effect on the lungs, is essential for replacement of animals for acute inhalation testing. However, the lung is a complex organ, with different potential targets for toxicity <span><span>^[2]</span></span>. In this presentation, the reliability and relevance of a cell-free method based on the monitoring of lung surfactant biophysical function during exposure to a test chemical for predicting acute effects on the lungs will be discussed <span><span>^[3]</span></span>. The method addresses the molecular initiating event of the adverse outcome pathway AOP 302; “inhibition of lung surfactant function” that can lead to the adverse outcome “decreased lung function” <span><span>^[4]</span></span>. The main function of lung surfactant is to regulate the surface tension at the respiratory air-liquid interface to avoid alveolar collapse <em>in vivo,</em> starting a cascade that leads to decreased lung function. The effect of more than 150 different chemicals and products have been tested, covering consumer products, occupational exposures, inhaled pharmaceuticals and single chemicals. On this background the current applicability domain of the method will be explored, and how the results of this <em>in vitro</em> test relates to outcomes in guideline studies for acute inhalation toxicity <span><span>^[5]</span></span>. This cell-free method is a promising candidate for prioritization and screening of chemicals, and its inclusion in an integrated approach to testing and assessment will contribute to the reduction of the use of rodents for acute inhalation toxicity testing.</div><div><em>This work was partly supported by ‘FFIKA, Focused Research Effort on Chemicals in the Working Environment’ from the Danish Government.</em></div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"411 ","pages":"Page S25"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}