Genotoxicity assessment: opportunities, challenges and perspectives for quantitative evaluations of dose–response data

Archives of Toxicology, Год журнала: 2023, Номер 97(9), С. 2303 - 2328

Опубликована: Июль 5, 2023

Abstract Genotoxicity data are mainly interpreted in a qualitative way, which typically results binary classification of chemical entities. For more than decade, there has been discussion about the need for paradigm shift this regard. Here, we review current opportunities, challenges and perspectives quantitative approach to genotoxicity assessment. Currently discussed opportunities include determination reference point (e.g., benchmark dose) from genetic toxicity dose–response data, followed by calculation margin exposure (MOE) or derivation health-based guidance value (HBGV). In addition new major emerge with interpretation data. These rooted limited capability standard vivo testing methods detect different types damage multiple target tissues unknown relationships between measurable genotoxic effects probability experiencing an adverse health outcome. addition, respect DNA-reactive mutagens, question arises whether widely accepted assumption non-threshold relationship is at all compatible HBGV. Therefore, present, any assessment remains be evaluated case-by-case. The prioritization purposes, e.g., connection MOE approach, could seen as promising opportunity routine application. However, additional research needed assess it possible define genotoxicity-derived that can considered indicative low level concern. To further advance assessment, priority should given development experimental provide deeper mechanistic understanding comprehensive basis analysis relationships.

Язык: Английский

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Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators

Cell Metabolism, Год журнала: 2024, Номер 36(5), С. 1126 - 1143.e5

Опубликована: Апрель 10, 2024

Язык: Английский

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Progress in toxicogenomics to protect human health

Nature Reviews Genetics, Год журнала: 2024, Номер unknown

Опубликована: Сен. 2, 2024

Язык: Английский

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A Systematic Genotoxicity Assessment of a Suite of Metal Oxide Nanoparticles Reveals Their DNA Damaging and Clastogenic Potential

Nanomaterials, Год журнала: 2024, Номер 14(9), С. 743 - 743

Опубликована: Апрель 24, 2024

Metal oxide nanoparticles (MONP/s) induce DNA damage, which is influenced by their physicochemical properties. In this study, the high-throughput CometChip and micronucleus (MicroFlow) assays were used to investigate chromosomal damage in mouse lung epithelial cells induced nano bulk sizes of zinc oxide, copper manganese nickel aluminum cerium titanium dioxide, iron oxide. Ionic forms MONPs also included. The study evaluated impact solubility, surface coating, particle size on response. Correlation analysis showed that solubility cell culture medium was positively associated with response both assays, form showing same or higher than larger particles. A subtle reduction observed post-exposure some surface-coated MONPs. difference genotoxicity highlighted mechanistic differences MONP-induced response, possibly stability chemical composition. results highlight combinations properties influence alone, while playing an important role, not enough explain toxicity. have implications potential application read-across strategies support human health risk assessment

Язык: Английский

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Consensus findings of an International Workshops on Genotoxicity Testing workshop on using transcriptomic biomarkers to predict genotoxicity

Environmental and Molecular Mutagenesis, Год журнала: 2025, Номер unknown

Опубликована: Янв. 5, 2025

Abstract Gene expression biomarkers have the potential to identify genotoxic and non‐genotoxic carcinogens, providing opportunities for integrated testing reducing animal use. In August 2022, an International Workshops on Genotoxicity Testing (IWGT) workshop was held critically review current methods genotoxicants using transcriptomic profiling. Here, we summarize findings of workgroup state science regarding use chemicals in vitro vivo. A total 1341 papers were examined that show most promise identifying genotoxicants. This analysis revealed two independently derived vivo three that, when used conjunction with standard computational techniques, can (rat or mouse liver) human cells culture different gene profiling platforms, predictive accuracies ≥92%. These been validated differing degrees but typically high reproducibility across platforms model systems. They offer several advantages applications contexts genotoxicity including: early signal detection, moderate‐to‐high‐throughput screening capacity, adaptability cell types tissues, insights mechanistic information DNA‐damage response. Workshop participants agreed consensus statements advance regulatory adoption genotoxicity. The be other test strategies short‐term rodent exposures may cause cancer heritable genetic effects. Following are from workgroup. Transcriptomic Weight Evidence (WoE) evaluation to: determine mechanisms hazards; misleading positives assays; serve as new approach methodologies (NAMs) into battery tests. Several developed sufficiently robust training data sets, external demonstrated performance multiple laboratories. following established study designs models designated through existing validation exercises WoE evaluation. Bridging studies a selection needed deviate protocols confirm biomarker is being applied other: models, platforms. Top dose time critical should during development. conditions only ones suited unless additional bridging pharmacokinetic conducted. Temporal effects operate via distinct considered interpretation. Fixed sets analytical processes do not need rederived validation. Validation focus set sets. Robust ensure minimum spanning modes action. Genes known mechanistically involved responses. Existing frameworks described NAMs could biomarkers. Reproducibility bioinformatic application bioinformatics expert creating reproducible qualification each biomarker.

Язык: Английский

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Unlocking the Power of Transcriptomic Biomarkers in Qualitative and Quantitative Genotoxicity Assessment of Chemicals

Chemical Research in Toxicology, Год журнала: 2024, Номер 37(3), С. 465 - 475

Опубликована: Фев. 26, 2024

To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose-response data are needed. Two transcriptomic biomarkers, GENOMARK TGx-DDI, have shown a high classification accuracy for genotoxicity. As these biomarkers were extracted from different training sets, we investigated whether combining the two in human-derived metabolically competent cell line (i.e., HepaRG) provides complementary information of genotoxic hazard identification potency ranking. First, applicability to TempO-Seq, high-throughput technology, was evaluated. HepaRG cells exposed 72 h increasing concentrations 10 chemicals eight known

Язык: 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, Год журнала: 2025, Номер unknown, С. 105794 - 105794

Опубликована: Фев. 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.

Язык: Английский

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Visualization strategies to aid interpretation of high‐dimensional genotoxicity data

Environmental and Molecular Mutagenesis, Год журнала: 2024, Номер 65(5), С. 156 - 178

Опубликована: Май 17, 2024

Abstract This article describes a range of high‐dimensional data visualization strategies that we have explored for their ability to complement machine learning algorithm predictions derived from MultiFlow® assay results. For this exercise, focused on seven biomarker responses resulting the exposure TK6 cells each 126 diverse chemicals over concentrations. Obviously, challenges associated with visualizing were further complicated whenever there was desire represent entire chemical set as opposed results single chemical. Scatter plots, spider parallel coordinate hierarchical clustering, principal component analysis, toxicological prioritization index, multidimensional scaling, t‐distributed stochastic neighbor embedding, and uniform manifold approximation projection are considered in turn. Our report provides comparative analysis these techniques. In an era where multiplexed assays algorithms becoming norm, stakeholders should find some useful efficiently effectively interpreting data.

Язык: Английский

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The Use of Effect Biomarkers in Chemical Mixtures Risk Assessment – are they Still Important?

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Год журнала: 2024, Номер 896, С. 503768 - 503768

Опубликована: Май 1, 2024

Human epidemiological studies with biomarkers of effect play an invaluable role in identifying health effects chemical exposures and disease prevention. Effect that measure genetic damage are potent tools to address the carcinogenic and/or mutagenic potential exposures, increasing confidence regulatory risk assessment decision-making processes. The micronucleus (MN) test is recognized as one most successful reliable assays assess genotoxic events, which associated may cause cancer. To move towards next generation crucial establish bridges between standard approaches, new approach methodologies (NAMs) for increase mechanistically-based biological plausibility human studies, such adverse outcome pathways (AOPs) framework. This paper aims highlight still active MN biomarker evolution applicability methods approaches assessment, positive consequence, provide a deeper knowledge biology these endpoints.

Язык: Английский

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Role of Flow Cytometry in the Rapid Assessment of Organ-Specific Toxicity

Опубликована: Янв. 1, 2025

Язык: Английский

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