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  3. A read-across case study on chronic toxicity of branched carboxylic acids (1): Integration of mechanistic evidence from new approach methodologies (NAMs) to explore a common mode of action.

A read-across case study on chronic toxicity of branched carboxylic acids (1): Integration of mechanistic evidence from new approach methodologies (NAMs) to explore a common mode of action.

Fecha de publicación: Fecha Ahead of Print:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Escher, Sylvia E.
  • Aguayo-Orozco, Alejandro
  • Benfenati, Emilio
  • Bitsch, Annette
  • Braunbeck, Thomas
  • Brotzmann, Katharina
  • Bois, Frederic
  • van der Burg, Bart
  • Castel, Jose
  • Exner, Thomas
  • Gadaleta, Domenico
  • Gardner, Iain
  • Goldmann, Daria
  • Hatley, Oliver
  • Golbamaki, Nazanin
  • Graepel, Rabea
  • Jennings, Paul
  • Limonciel, Alice
  • Long, Anthony
  • Maclennan, Richard
  • Mombelli, Enrico
  • Norinder, Ulf
  • Jain, Sankalp
  • Capinha, Liliana Santos
  • Taboureau, Olivier T.
  • Vrijenhoek, Nanette G.
  • van Vugt-Lussenburg BMA
  • Walker, Paul
  • van de Water, Bob
  • Wehr, Matthias
  • White, Andrew
  • Zdrazil, Barbara
  • Fisher, Ciaran

Grupos

Abstract

This read-across case study characterises thirteen, structurally similar carboxylic acids demonstrating the application of in vitro and in silico human-based new approach methods, to determine biological similarity. Based on data from in vivo animal studies, the read-across hypothesis is that all analogues are steatotic and so should be considered hazardous. Transcriptomic analysis to determine differentially expressed genes (DEGs) in hepatocytes served as first tier testing to confirm a common mode-of-action and identify differences in the potency of the analogues. An adverse outcome pathway (AOP) network for hepatic steatosis, informed the design of an in vitro testing battery, targeting AOP relevant MIEs and KEs, and Dempster-Shafer decision theory was used to systematically quantify uncertainty and to define the minimal testing scope. The case study shows that the read-across hypothesis is the critical core to designing a robust, NAM-based testing strategy. By summarising the current mechanistic understanding, an AOP enables the selection of NAMs covering MIEs, early KEs, and late KEs. Experimental coverage of the AOP in this way is vital since MIEs and early KEs alone are not confirmatory of progression to the AO. This strategy exemplifies the workflow previously published by the EUTOXRISK project driving a paradigm shift towards NAM-based NGRA.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Datos de la publicación

ISSN/ISSNe:
0887-2333, 1879-3177

TOXICOLOGY IN VITRO  Elsevier BV

Tipo:
Art Exhibit Review
Páginas:
105269-105269
Factor de Impacto:
0,692 SCImago ℠
Cuartil:
Q2 SCImago ℠

Citas Recibidas en Web of Science: 17

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Keywords

  • AOP-network, Liver steatosis, Mechanistic hazard assessment, NAM, Read-across

Proyectos asociados

MECANISMOS TRANSCRIPCIONALES IMPLICADOS EN EL HIGADO GRASO NO ALCOHOLICO DE ORIGEN METABOLICO E IATROGENICO: INFLUENCIA DE LA RESISTENCIA A LA INSULINA

Investigador Principal: RAMIRO JOVER ATIENZA

PI10/00194 . INSTITUTO DE SALUD CARLOS III . 2010

METABONOMICA Y CITOMICA COMO NUEVOS PARADIGMAS Y ESTRATEGIAS EXPERIMENTALES PARA EL ESTUDIO DE LOS MECANISMOS DE HEPATOTOXICIDAD DE FARMACOS, PREDICCION DE SU POTENCIAL HEPATOTOXICO Y LA TRANSICION DE HEPATITIS I ATROGENICA A AUTOINMUNE.

Investigador Principal: MARÍA TERESA DONATO MARTÍN

PI10/00923 . INSTITUTO DE SALUD CARLOS III . 2010

APROXIMACIONES METABONÓMICAS PARA EL ESTUDIO DE LA HEPATOTOXICIDAD IDIOSINCRÁSICA CON BASE METABÓLICA Y LA IDENTIFICACIÓN DEL AGENTE CAUSAL.

Investigador Principal: MARÍA TERESA DONATO MARTÍN

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Desarrollo de modelos celulares personalizados para el estudio in vitro de la hepatotoxicidad idiosincrásica.

Investigador Principal: MARÍA TERESA DONATO MARTÍN

ACIF/2018/257 . CONSELLERIA DE EDUCACION . 2018

EUTOXRISK21. AN INTEGRATED EUROPEAN ‘FLAGSHIP’ PROGRAM DRIVING MECHANISM-BASED.

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

681002_EUTOXRISK_CASTELL_H2020-PHC-33-2015 . COMISION EUROPEA . 2016

Evaluación preclínica de nuevas fuentes celulares y biomateriales en terapia celular para el tratamiento metabolopatías congénitas y fallo hepático.

Investigador Principal: LAIA TOLOSA PARDO

PI18/00993 . INSTITUTO DE SALUD CARLOS III . 2019

Tu hospital investiga RRI.

Investigador Principal: ANA ISABEL JUAN ROCH

FCT-18-14018 . FUNDACION ESPAÑOLA PARA LA CIENCIA Y LA TECNOLOGIA . 2019

IMPROVING FEASIBILITY OF LIVER CELL THERAPY: NEW CELL SOURCES AND STRATEGIES TO IMPROVE THE CLINICAL OUTCOME. (PROYECTO)

Investigador Principal: LAIA TOLOSA PARDO

CP16/00097 . INSTITUTO DE SALUD CARLOS III . 2017

ESTANCIA DE PERSONAL INVESTIGADOR DOCTOR EN CENTROS DE INVESTIGACION RADICADOS FUERA DE LA COMUNIDAD VALENCIANA. Laia Tolosa Pardo

Investigador Principal: LAIA TOLOSA PARDO

BEST2020/144 . CONSELLERIA DE EDUCACION . 2020

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