A quantitative weight-of-evidence method for confidence assessment of adverse outcome pathway networks: A case study on chemical-induced liver steatosis

Toxicology, Journal Year: 2024, Volume and Issue: 505, P. 153814 - 153814

Published: April 25, 2024

Language: Английский

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Next Generation Risk Assessment of Hair Dye HC Yellow No. 13: Ensuring Protection From Liver Steatogenic Effects

Regulatory Toxicology and Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 105794 - 105794

Published: Feb. 1, 2025

This study employs animal-free Next Generation Risk Assessment (NGRA) principles to evaluate the safety of repeated dermal exposure 2.5% (w/w) HC Yellow No. 13 (HCY13) hair dye. As multiple in silico tools consistently flagged hepatotoxic potential, likely due HCY13's trifluoromethyl group, which is known interfere with hepatic lipid metabolism, liver steatosis was chosen as primary mode action for evaluation. AOP-guided vitro tests were conducted, exposing human stem cell-derived cells varying HCY13 concentrations over 72 hours. The expression 11 metabolism-related marker genes (AHR, PPARA, LXRA, APOB, ACOX1, CPT1A, FASN, SCD1, DGAT2, CD36, and PPARG) triglyceride accumulation, a phenotypic hallmark steatosis, measured. PROAST software used calculate Points Departure (PoDNAM) each biomarker. Using GastroPlus 9.9, physiologically-based pharmacokinetic (PBPK) models estimated internal (Cmax liver) HCY13, ranging from 4 20 pM. All PoDNAM values significantly exceeded predicted Cmax liver, indicating that at unlikely induce under assumed conditions. research demonstrates utility NGRA, integrating AOP-based assays computational protect health support regulatory decision-making without animal testing.

Language: Английский

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E‐waste: mechanisms of toxicity and safety testing

FEBS Open Bio, Journal Year: 2024, Volume and Issue: 14(9), P. 1420 - 1440

Published: July 10, 2024

Currently, information on the toxicity profile of majority identified e‐waste chemicals, while extensive and growing, is admittedly fragmentary, particularly at cellular molecular levels. Furthermore, chemical mixtures likely to be encountered by humans during after informal recycling, as well their underlying mechanisms action, largely unknown. This review paper summarizes state‐of‐the‐art knowledge potential associated with exposures, a focus toxic responses connected specific organs, organ systems, overall effects organism. To overcome complexities assessing possible adverse outcomes from exposure growing number new approach methodologies have emerged in recent years, long‐term objective providing human‐based animal‐free system that scientifically superior animal testing, more effective, acceptable. encompasses variety techniques, typically regarded alternative approaches for determining chemical‐induced toxicities holds greater promise better understanding key events metabolic pathways mediate known health scenarios. crucial establishing accurate scientific mixed exposures shorter time frames efficacy, supporting need safe management hazardous chemicals. The present discusses important gaps shows promising directions mechanistically anchored effect‐based monitoring strategies will contribute advancement methods currently used characterizing e‐waste‐impacted ecosystems.

Language: Английский

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A tiered next-generation risk assessment framework integrating toxicokinetics and NAM-based toxicodynamics: “proof of concept” case study using pyrethroids

Archives of Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Language: Английский

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Unlocking the future of Environmental Safety: a Framework for Integrating New Approach Methodologies in Decision-Making

NAM journal., Journal Year: 2025, Volume and Issue: unknown, P. 100028 - 100028

Published: May 1, 2025

Language: Английский

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Data-Driven Characterization of Genetic Variability in Disease Pathways and Pesticide-Induced Nervous System Disease in the United States Population

Environmental Health Perspectives, Journal Year: 2024, Volume and Issue: 132(5)

Published: May 1, 2024

BACKGROUND: Genetic susceptibility to chemicals is incompletely characterized.However, nervous system disease development following pesticide exposure can vary in a population, implying some individuals may have higher genetic pesticide-induced disease.OBJECTIVES: We aimed build computational approach characterize single-nucleotide polymorphisms (SNPs) implicated chemically induced adverse outcomes and used this framework assess the link between differential population pesticides human disease.METHODS: integrated publicly available datasets of Chemical-Gene, Gene-Pathway, SNP-Disease associations Chemical-Pathway-Gene-SNP-Disease linkages for humans.As case study, we these with spatialized application data US from 1992 2018 rates 2018.Through this, characterized SNPs that be important states high occurrence based on there.RESULTS: found number SNP hits per positively correlated incidence prevalence Alzheimer's disease, Parkinson multiple sclerosis.We performed frequent itemset mining differentiate over time low only 19% sets overlapped 10 rates, more were pathways states.Through crossvalidation subsets five states, SNPs, genes, pathways, frequently states.DISCUSSION: Our findings support contribute developed priority lists pesticides, further study.This data-driven adapted other chemicals, diseases, locations chemical exposures.

Language: Английский

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Harnessing Computational Methods to Characterize Chemical Impacts on Biodiversity

Environmental Science & Technology Letters, Journal Year: 2024, Volume and Issue: 11(3), P. 185 - 194

Published: Feb. 15, 2024

Chemical pollution can threaten biodiversity at different levels, from genetically diverse populations (genetic diversity) to species (species and ecosystem traits/interactions (functional diversity). Most assessments of chemical impacts on levels depend wet lab field experiments, including sequencing large numbers organisms, environmental DNA approaches, single chemical–species–outcome toxicity tests, trait-based methods. However, it is impossible assess all chemicals, species, populations, ecosystems using these Therefore, we advocate that computational methods are necessary characterize, quantify, predict biodiversity. We briefly introduce the current state research into genetic diversity, functional diversity describe new opportunities for like data integration, machine learning, cross-species/cross-ecosystem extrapolation, adverse outcome pathways, Bayesian support in three areas. By harnessing currently our disposal preparing take advantage continuously emerging sets, approaches be paired with monitoring so biological organization serve as consecutive warning signs This will enable effective protection measures better developed implemented prevent loss pollution.

Language: Английский

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MAATrica: a Measure for Assessing Consistency and Methods in Medicinal and Nutraceutical Chemistry Papers

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 273, P. 116522 - 116522

Published: May 23, 2024

The growing number of scientific papers and document sources underscores the need for methods capable evaluating quality publications. Researchers who are looking relevant their studies ways to assess value these documents. One approach involves using semantic search engines that can automatically extract important knowledge from body text. In this study, we introduce a new metric called "MAATrica," which serves as foundation an innovative method designed evaluate research papers. MAATrica offers way analyze categorize text, focusing on consistency documents in life sciences, particularly fields medicinal nutraceutical chemistry. This utilizes descriptions cover silico experiments, well vitro vivo essays. Created aid evaluation processes like peer review, uses toolkits applications build proposed measure, identify entities, gather information. We have applied roughly 90,000 present our findings here.

Language: Английский

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Next generation risk assessment for occupational chemical safety – A real world example with sodium-2-hydroxyethane sulfonate

Toxicology, Journal Year: 2024, Volume and Issue: 506, P. 153835 - 153835

Published: June 8, 2024

Next Generation Risk Assessment (NGRA) is an exposure-led approach to safety assessment that uses New Approach Methodologies (NAMs). Application of NGRA has been largely restricted assessments consumer use cosmetics and not currently implemented in occupational assessments, e.g. under EU REACH. By contrast, a large proportion regulatory worker are underpinned by toxicological studies using experimental animals. Consequently, represents area would benefit from increasing application decision making. Here, workflow for conducting context was developed, which illustrated with case study chemical; sodium 2-hydroxyethane sulphonate (sodium isethionate or SI). Exposures were estimated standard exposure model following comprehensive life cycle SI considering factory-specific data. Outputs this then used estimate internal exposures Physiologically Based Kinetic (PBK) model, constructed specific Absorption, Distribution, Metabolism Excretion (ADME) PBK modelling indicated worst-case plasma maximum concentration (Cmax) 0.8 μM across the cycle. bioactivity assessed battery NAMs relevant systemic, reproductive, developmental toxicity; cell stress panel, high throughput transcriptomics three lines (HepG2, HepaRG MCF-7 cells), pharmacological profiling assays relating toxicity (Reprotracker devTOX quickPredict). Points Departure (PoDs) ranged 104 5044 µM. Cmax values obtained compared PoDs derive Bioactivity Exposure Ratios (BERs) demonstrated workers exposed current levels factory risk management. In summary, tiered iterative developed here opportunity integrating non animal approaches subset substances systemic required. Such could be followed ensure testing only conducted as "last resort"

Language: Английский

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Macrophage polarization as a novel endpoint for assessing combined risk of phthalate esters

Environment International, Journal Year: 2024, Volume and Issue: 190, P. 108835 - 108835

Published: June 19, 2024

Combined exposure to phthalate esters (PAEs) has garnered increasing attention due potential synergistic effects on human health. This study aimed develop an in vitro model using macrophages evaluate the combined toxicity of PAEs and explore underlying mechanisms. A high-throughput screening system was engineered by expressing a PPRE-eGFP reporter THP-1 monocytes monitor macrophage polarization upon exposure. Individual exhibited varied inhibitory M2 polarization, with mono(2-ethylhexyl) (MEHP) being most potent. Isobologram analysis revealed additive interactions when MEHP other PAEs, resulting more pronounced suppression markers compared individual compounds. Mechanistic studies suggested may exert modulating PPARγ activity inhibit polarization. Notably, equimolar mixture six showed inhibition markers. In vivo experiments corroborated hepatotoxic effects, mice exposed exhibiting reduced liver weight, dyslipidemia, decreased hepatic DEHP alone. Transcriptome highlighted disruptions PPAR signaling, distinct pathway alterations cholesterol metabolism group. Collectively, these findings underscore importance evaluating provide novel approach for hazard assessment implications environmental health risk assessment.

Language: Английский

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