The dose disrupts the pathway: application of Paracelsus principle to mechanistic toxicology

Toxicological Sciences, Год журнала: 2024, Номер 200(2), С. 228 - 234

Опубликована: Май 7, 2024

Abstract Arguably the most famous principle of toxicology is “The dose makes poison” formulated by Paracelsus in 16th century. Application Paracelsus’s to mechanistic may be challenging as one compound affect many molecular pathways at different doses with and often nonlinear dose-response relationships. As a result, studies environmental occupational compounds use high xenobiotics motivated need see clear signal indicating disruption particular pathway. This approach ignores possibility that same xenobiotic mechanism(s) much lower relevant human exposures. To amend simple concise guiding principle, I suggest recontextualization following its letter spirit: disrupts pathway”. Justification this statement includes observations broad range cascades, are sensitive chemical exposures, compound. become useful guidance educational tool toxicological applications, including experimental design, comparative analysis hypotheses, evaluation quality studies, risk assessment.

Язык: Английский

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Transcriptomic point of departure determination: a comparison of distribution-based and gene set-based approaches

Frontiers in Genetics, Год журнала: 2024, Номер 15

Опубликована: Май 9, 2024

A key step in assessing the potential human and environmental health risks of industrial agricultural chemicals is to determine toxicity point departure (POD), which highest dose level that causes no adverse effect. Transcriptomic POD (tPOD) values have been suggested accurately estimate values. One most common approach for tPOD determination involves mapping genes annotated gene sets, a process might lead substantial information loss particularly species with poor annotation. Alternatively, methods calculate directly from distribution individual omit this step. Using rat transcriptome data 79 molecules obtained Open TG-GATEs (Toxicogenomics Project Genomics Assisted Toxicity Evaluation System), hypothesis was tested based on all will give similar value via set-based method. Gene using four different set structures were compared five methods. Results revealed high concordance tested, especially at least 300 dose-responsive probesets: 90% those molecules, within 4-fold each other. In addition, random sets upon structure biological knowledge-derived produced median absolute fold change 1.3–1.4 when original counterparts, suggesting little used generation approach. These findings indicate distributions viable parsimonious alternative sets. Importantly, distribution-based do not require knowledge organization can be applied any including poorly

Язык: Английский

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Comparison on the mechanism and potency of hepatotoxicity among hemp extract and its four major constituent cannabinoids

Toxicology, Год журнала: 2024, Номер 506, С. 153885 - 153885

Опубликована: Июль 14, 2024

Cannabidiol (CBD) has been reported to induce hepatotoxicity in clinical trials and research studies; however, little is known about the safety of other nonintoxicating cannabinoids. New approach methodologies (NAMs) based on bioinformatic analysis high-throughput transcriptomic data are gaining increasing importance risk assessment regulatory decision-making data-poor chemicals. In current study, we conducted a concentration response hemp extract its four major constituent cannabinoids [CBD, cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN)] hepatocytes derived from human induced pluripotent stem cells (iPSCs). Each compound impacted distinctive combination biological functions pathways. However, all impaired liver metabolism caused oxidative stress cells. Benchmark (BMC) showed potencies transcriptional activity were order CBN > CBD CBC CBG, consistent with their cytotoxicity IC

Язык: Английский

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Applying genomics in regulatory toxicology: a report of the ECETOC workshop on omics threshold on non-adversity

Archives of Toxicology, Год журнала: 2023, Номер 97(8), С. 2291 - 2302

Опубликована: Июнь 9, 2023

In a joint effort involving scientists from academia, industry and regulatory agencies, ECETOC's activities in Omics have led to conceptual proposals for: (1) A framework that assures data quality for reporting inclusion of assessments; (2) an approach robustly quantify these data, prior interpretation use. continuation this workshop explored identified areas need facilitate robust such the context deriving points departure (POD) risk assessment determining adverse change normal variation. ECETOC was amongst first systematically explore application methods, now incorporated into group methods known as New Approach Methodologies (NAMs), toxicology. This support has been form both projects (primarily with CEFIC/LRI) workshops. Outputs included workplan Extended Advisory Group on Molecular Screening Toxicogenomics (EAGMST) Organisation Economic Co-operation Development (OECD) drafting OECD Guidance Documents reporting, potentially more follow transformation interpretation. The current last series technical development workshops, sub-focus derivation POD data. Workshop presentations demonstrated developed within frameworks scientific generation analysis can be used derive POD. issue noise discussed important consideration identifying changes Such variability or "noise" comprise biological variation dataset should clearly distinguished homeostatic responses. Adverse outcome pathways (AOPs) were considered useful which assemble number case examples presented illustration point. What is apparent high dimension will always subject varying processing pipelines hence interpretation, depending they are in. Yet, provide valuable input toxicology, pre-condition being collection together comprehensive description how interpreted, conclusions reached.

Язык: Английский

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Transcriptomics‐Based Points of Departure for Daphnia magna Exposed to 18 Per‐ and Polyfluoroalkyl Substances

Environmental Toxicology and Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Март 7, 2024

Per- and polyfluoroalkyl substances (PFAS) represent a large group of contaminants concern based on their widespread use, environmental persistence, potential toxicity. Many traditional models for estimating toxicity, bioaccumulation, other toxicological properties are not well suited PFAS. Consequently, there is need to generate hazard information PFAS in an efficient cost-effective manner. In the present study, Daphnia magna were exposed multiple concentrations 22 different 24 h 96-well plate format. Following exposure, whole-body RNA was extracted extracts, each representing five individuals, subjected sequencing. analytical measurements verify exposure quality control processed cDNA libraries sequencing, concentration-response modeling applied data sets 18 tested compounds, concentration at which concerted molecular response occurred (transcriptomic point departure; tPOD) calculated. The tPODs, measured PFAS, generally ranged from 0.03 0.58 µM (9.9-350 µg/L; interquartile range). most cases, these two orders magnitude lower than similarly calculated tPODs human cell lines They also apical effect reported seven some crustacean or invertebrate toxicity available, although few exceptions. Despite being available benchmarks, D. were, average, four greater maximum aqueous Great Lakes tributaries. Overall, this high-throughput transcriptomics assay with holds promise as component tiered evaluation strategy employing new approach methodologies. Environ Toxicol Chem 2024;00:1-16. © 2024 SETAC. This article has been contributed by U.S. Government employees work public domain USA.

Язык: Английский

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Empirical Characterization of False Discovery Rates of Differentially Expressed Genes and Transcriptomic Benchmark Concentrations in Zebrafish Embryos

Environmental Science & Technology, Год журнала: 2024, Номер 58(14), С. 6128 - 6137

Опубликована: Март 26, 2024

High-throughput transcriptomics (HTTr) is increasingly applied to zebrafish embryos survey the toxicological effects of environmental chemicals. Before adoption this approach in regulatory testing, it essential characterize background noise order guide experimental designs. We thus empirically quantified HTTr false discovery rate (FDR) across different embryo pool sizes, sample and concentration groups for toxicology studies. exposed 0.1% dimethyl sulfoxide (DMSO) 5 days. Pools 1, 5, 10, 20 were created (n = 24 samples each size). Samples sequenced on TempO-Seq platform then randomly assigned mock treatment before differentially expressed gene (DEG), pathway, benchmark (BMC) analyses. Given that all treated with DMSO, any significant DEGs, pathways, or BMCs are positives. As expected, we found decreasing FDRs DEG pathway analyses increasing sizes. Similarly, BMC decreased size groups, more stringent premodel filtering reducing FDRs. Our study provides foundational data determining appropriate experiment designs toxicity testing embryos.

Язык: Английский

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Comparing Transcriptomic Points of Departure to Apical Effect Concentrations For Larval Fathead Minnow Exposed to Chemicals with Four Different Modes Of Action

Archives of Environmental Contamination and Toxicology, Год журнала: 2024, Номер 86(4), С. 346 - 362

Опубликована: Май 1, 2024

Язык: Английский

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

Toxicology, Год журнала: 2024, Номер 506, С. 153835 - 153835

Опубликована: Июнь 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"

Язык: Английский

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Mining toxicogenomic data for dose-responsive pathways: implications in advancing next-generation risk assessment

Frontiers in Toxicology, Год журнала: 2023, Номер 5

Опубликована: Ноя. 17, 2023

Introduction: While targeted investigation of key toxicity pathways has been instrumental for biomarker discovery, unbiased and holistic analysis transcriptomic data provides a complementary systems-level perspective. However, in systematic context, this approach yet to receive comprehensive methodical implementation. Methods: Here, we took an integrated bioinformatic by re-analyzing publicly available MCF7 cell TempO-seq 44 ToxCast chemicals using alternative pipeline demonstrate the power approach. The original study focused on analyzing gene signature comparing them vitro biological pathway altering concentrations determined from HTS assays. Our workflow, comparison, involves sequential differential expression, set enrichment, benchmark dose modeling, identification commonly perturbed network visualization. Results: Using approach, identified dose-responsive molecular changes, pathways, points departure untargeted manner. Critically, modeling based recapitulated apical endpoints, while also revealing additional mechanisms missed single endpoint analyses. Discussion: This systems-toxicology multifaceted insights into complex effects chemical exposures. work highlights importance data-driven techniques, alongside methods, comprehensively evaluating initiating events, dose-response relationships, pathways. Overall, integrating omics assays with robust bioinformatics holds promise improving risk assessment advancing new methodologies (NAMs).

Язык: Английский

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Derivation of Transcriptomics‐Based Points of Departure for 20 Per‐ or Polyfluoroalkyl Substances Using a Larval Fathead Minnow (Pimephales promelas) Reduced Transcriptome Assay

Environmental Toxicology and Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Фев. 28, 2024

Abstract Traditional toxicity testing has been unable to keep pace with the introduction of new chemicals into commerce. Consequently, there are limited or no data for many which fish and wildlife may be exposed. Per‐ polyfluoroalkyl substances (PFAS) emblematic this issue in that ecological hazards most PFAS remain uncharacterized. The present study employed a high‐throughput assay identify concentration at 20 PFAS, diverse properties, elicited concerted gene expression response (termed transcriptomics‐based point departure [tPOD]) larval fathead minnows ( Pimephales promelas ; 5–6 days postfertilization) exposed 24 h. Based on reduced transcriptome approach measured whole‐body 1832 genes, median tPOD tested was 10 µM. Longer‐chain carboxylic acids (12–13 C–F); an eight‐C–F dialcohol, N ‐alkyl sulfonamide; telomer sulfonic acid were among potent eliciting responses concentrations <1 With few exceptions, minnow tPODs concordant those based whole‐transcriptome human cell lines. However, often greater than Daphnia magna same PFAS. overlapped other sublethal effects have reported (available PFAS). Nonetheless, orders magnitude higher aqueous detected tributaries North American Great Lakes, suggesting substantial margin safety. Overall, results broadly support use transcriptomics derive screening‐level potency estimates risk‐based prioritization. Environ Toxicol Chem 2024;00:1–16. © 2024 SETAC. This article contributed by U.S. Government employees their work is public domain USA.

Язык: Английский

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