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1.
Arch Toxicol ; 98(4): 1111-1123, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38368582

RESUMO

While grouping/read-across is widely used to fill data gaps, chemical registration dossiers are often rejected due to weak category justifications based on structural similarity only. Metabolomics provides a route to robust chemical categories via evidence of shared molecular effects across source and target substances. To gain international acceptance, this approach must demonstrate high reliability, and best-practice guidance is required. The MetAbolomics ring Trial for CHemical groupING (MATCHING), comprising six industrial, government and academic ring-trial partners, evaluated inter-laboratory reproducibility and worked towards best-practice. An independent team selected eight substances (WY-14643, 4-chloro-3-nitroaniline, 17α-methyl-testosterone, trenbolone, aniline, dichlorprop-p, 2-chloroaniline, fenofibrate); ring-trial partners were blinded to their identities and modes-of-action. Plasma samples were derived from 28-day rat tests (two doses per substance), aliquoted, and distributed to partners. Each partner applied their preferred liquid chromatography-mass spectrometry (LC-MS) metabolomics workflows to acquire, process, quality assess, statistically analyze and report their grouping results to the European Chemicals Agency, to ensure the blinding conditions of the ring trial. Five of six partners, whose metabolomics datasets passed quality control, correctly identified the grouping of eight test substances into three categories, for both male and female rats. Strikingly, this was achieved even though a range of metabolomics approaches were used. Through assessing intrastudy quality-control samples, the sixth partner observed high technical variation and was unable to group the substances. By comparing workflows, we conclude that some heterogeneity in metabolomics methods is not detrimental to consistent grouping, and that assessing data quality prior to grouping is essential. We recommend development of international guidance for quality-control acceptance criteria. This study demonstrates the reliability of metabolomics for chemical grouping and works towards best-practice.


Assuntos
Espectrometria de Massa com Cromatografia Líquida , Metabolômica , Ratos , Masculino , Feminino , Animais , Reprodutibilidade dos Testes , Metabolômica/métodos , Fluxo de Trabalho
2.
Toxicol Lett ; 382: 13-21, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37164126

RESUMO

In long term rodent studies administering Cyclobutrifluram (TYMIRIUM® Technology), a new agrochemical, there was a slight elevation of incidence of hepatocellular carcinomas in male CD-1 mice that was within the historical control range but appeared to be dose responsive. Cyclobutrifluram's ability to activate mouse constitutive androstane receptor (CAR) mediated gene transcription was confirmed in vitro, therefore a 28-day dietary toxicity study was conducted in vivo in male CD-1 mice to assess the CAR activation mode of action hypothesis of Cyclobutrifluram along with phenobarbital, a known CAR activator. In addition to other end points comprehensive (polar and lipidomic) hybrid metabolomics analyses were performed on terminal plasma and liver samples following 2-, 7- and 28-days dietary exposure to cyclobutrifluram and phenobarbital. The data generation and quality assessments were performed in line with the principles of the MEtabolomics standaRds Initiative in Toxicology (MERIT).First the full annotated feature set was used to compare the metabolomic changes induced by the administration of the two test substances using Shared and Unique Structures plots. This gave a comprehensive overview of the similarity of the two effect profiles showing good correlation and demonstrated that no other, alternative effect signatures were detected. Then the phenobarbital induced differentially abundant metabolites were selected, compared to the literature and their direction of change was assessed in cyclobutrifluram profiles, finding good agreement. Both approaches concluded that the metabolomics data supports the CAR activation hypothesis. Comparison of the metabolomic effect profiles can be a line of evidence in mode of action hypothesis testing in the chemical risk assessment process.


Assuntos
Segurança Química , Neoplasias Hepáticas , Masculino , Camundongos , Animais , Fígado/metabolismo , Hepatócitos , Receptores Citoplasmáticos e Nucleares/metabolismo , Fenobarbital/toxicidade , Fenobarbital/metabolismo , Neoplasias Hepáticas/patologia , Metabolômica
3.
Nature ; 233(5319): 406-7, 1971 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-16063403
4.
Science ; 157(3790): 799-800, 1967 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-17842780

RESUMO

Numerous grains of gibbsite surrounded by zones of chlorite were found in six samples of sediment taken from Waimea Bay off the coast of Kauai, Hawaii. The chlorite has formed from the gibbsite, and growth bands in the chlorite either are parallel to chlorite-gibbsite interfaces or are concentric around small remnants of gibbsite. Aggregates were found that appeared to be composed of two or more gibbsite grains surrounded by chlorite bands that have grown together. The index of refraction of the chlorite ranged from 1.58 to 1.60 and the chlorite displayed anomalous blue interference colors. The gibbsite was formed on land under conditions of strong weathering and strong leaching. When transported to the sea, the gibbsite was deposited in a solution containing silicic acid, magnesium, potassium, and hydrogen ions, in which it is unstable. Chlorite, a stable mineral in this solution, replaced the gibbsite.

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