Protectiveness of NAM-based hazard assessment - which testing scope is required?

Fecha de publicación: 04/12/2023 Fecha Ahead of Print: 04/12/2023

Autores de IIS La Fe

José Vicente Castell Ripoll

Autor
Laia Tolosa Pardo

Autor

Participantes ajenos a IIS La Fe

Zobl, Walter
Bitsch, Annette
Blum, Jonathan
Boei, Jan J. W. A.
Capinha, Liliana
Carta, Giada
Davoli, Enrico
Drake, Christina
Fisher, Ciaran P.
Heldring, Muriel M.
Islam, Barira
Jennings, Paul
Leist, Marcel
Pellegrino-Coppola, Damiano
Schimming, Johannes P.
Snijders, Kirsten E.
van de Water, Bob
van Vugt-Lussenburg, Barbara M A
Walker, Paul
Wehr, Matthias M.
Wijaya, Lukas S.
Escher, Sylvia E.

Grupos

Hepatología experimental y Trasplante hepático

Investigador Principal

Laia Tolosa Pardo
Unidad Mixta de Investigación en Hepatología Experimental

Investigador Principal

Ramiro Jover Atienza

Abstract

Hazard assessment (HA) requires toxicity tests to allow deriving protective points of departure (PoDs) for risk assessment irrespective of a compound's mode of action (MoA). The scope of in vitro test batteries (ivTB) thereby necessitated for systemic toxicity is still unclear. We explored the protectiveness regarding systemic toxicity of an ivTB with a scope, which was guided by previous findings from rodent studies, where examining six main targets, including liver and kidney, was sufficient to predict the guideline scope-based PoD with high probability. The ivTB comprises human in vitro models representing liver, kidney, lung and the neuronal system covering transcriptome, mitochondrial dysfunction and neuronal outgrowth. Additionally, 32 CALUX- and 10 HepG2 BAC-GFP reporters cover a broad range of disturbance mechanisms. Eight compounds were chosen for causing adverse effects such as immunotoxicity or anemia in vivo, i.e., effects not directly covered by assays in the ivTB. PoDs derived from the ivTB and from oral repeated dose studies in rodents were extrapolated to maximum unbound plasma concentrations for comparison. The ivTB-based PoDs were one to five orders of magnitude lower than in vivo PoDs for six of eight compounds, implying that they were protective. The extent of in vitro response varied across test compounds. Especially for hematotoxic substances, the ivTB showed either no response or only cytotoxicity. Assays better capturing this type of hazard would be needed to complement the ivTB. This study highlights the potentially broad applicability of ivTBs for deriving protective PoDs of compounds with unknown MoA. Animal tests are used to determine which amount of a chemical is toxic (threshold of toxicity) and which organs are affected. In principle, the threshold can also be derived solely from tests with cultured cells. However, only a limited number of cell types can practically be tested, so one challenge is to determine how many and which types shall be tested. In animal studies, only few organs including liver and kidney are regularly among those most sensitively affected. We explored whether a cell-based test battery representing these sensitive organs and covering important mechanisms of toxicity can be used to derive protective human thresholds. To challenge this approach, eight chemicals were tested that primarily cause effects in organs not directly represented in our test battery. Results provided protective thresholds for most of the investigated compounds and gave indications how to further improve the approach towards a full-fledged replacement for animal tests.

Datos de la publicación

ISSN/ISSNe:: 1868-596X, 1868-8551
Tipo:: Article
Páginas:: 302-319
DOI:: 10.14573/altex.2309081
PubMed:: 38048429
Factor de Impacto:: 1,058 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

No hay documentos

Métricas

Filiaciones

Filiaciones no disponibles

Keywords

NAMs; benchmark dose modelling; qIVIVE; systemic toxicity; tiered hazard assessment

Proyectos y Estudios Clínicos

DESARROLLO DE UN MODELO HEPATOCELULAR HUMANO DIFERENCIADO PARA ESTUDIOS DE METABOLISMO Y POTENCIAL INDUCTOR DE NUEVOS FARMACOS

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

SAF2003-09353 . 2003

A-CUTE-TOX

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

LSHB-CT-2004-512051-ACUTE TOX . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2005

DESARROLLO DE NUEVAS ESTRATEGIAS DIAGNOSTICAS BASADAS EN EL ESTUDIO DE LA CAPACIDAD METABOLIZANTE DE LA PIEL Y DEL PAPEL DE LAS CELULAS DENDITRICAS EN LA INDUCCION DE LAS REACCIONES ALERGICAS FRENTE A FARMACOS

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

PARTIC PI05/2290 - FUND IMABIS . INSTITUTO DE SALUD CARLOS III; FUNDACION FIMABIS . 2007

DEVELOPMENT OF A HIGH THROUGHPUT GENOMICS-BASED TEST FOR ASSESSING GENOTOXIC AND CARCINOGENIC PROPERTIES OF CHEMICAL COMPOUNDS IN VITRO

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

CARCINOGENOMICS . COMISION EUROPEA . 2006

LINTOP

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

LSHB-CT-2006-037499 - LINTOP . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2005

MECANISMOS TRNACRIPCIONALES IMPLICADOS EN LA ETIOLOGIA DEL HIGADO GRASO NO ALCOHOLICO. ESTUDIOS EN UN MODELO CELULAR HUMANO DE ESTEATOSIS Y APLICACION AL TRANSPLANTE DE HEPATOCITOS EN TERAPIA CELULAR.

Investigador Principal: RAMIRO JOVER ATIENZA

PI07/0550 . INSTITUTO DE SALUD CARLOS III . 2007

TU HOSPITAL INVESTIGA PARA TI

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

CCT005-07-00936 . 2007

PROYECTO CAIBER

CAI08/01/0061 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2009

FORINVITOX

Investigador Principal: MARÍA JOSÉ GÓMEZ-LECHÓN MOLINER

FORINVITOX 1, START UP 2 . REMA; UNIVERSIDAD AUTONOMA BARCELONA; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2008

RED DE INNOVACION EN TECNOLOGIAS MEDICAS Y SANITARIAS - RED ITEMAS

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

RD09/0077/00156 . INSTITUTO DE SALUD CARLOS III . 2010

CREACION Y MEJORA DE INFRAESTRUCTURAS EN MEDICINA REGENERATIVA

Investigador Principal: FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA

PLE2009-0141 ACI-PLAN E . MINISTERIO DE CIENCIA E INNOVACION; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2009

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

INNOVALIV: INNOVATIVE STRATEGIES TO GENERATE HUMAN HEPATOCYTES FOR TREATMENT OF METABOLIC LIVER DISEASES: TOOLS FOR PERSONALIZED CELL THERAPY

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

278152_INNOVALIV_PE_CASTELL_FP7-HEALTH-2011-two-st . COMISION EUROPEA . 2011

PROGRAMA DE TECNICO DE APOYO. MODALIDAD EMPRESAS

Investigador Principal: FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA

PTA2012-8060-E . MINISTERIO DE ECONOMIA Y COMPETITIVIDAD . 2013

SOLICITUD DE CENTRO I+D RAMON Y CAJAL

Investigador Principal: MARÍA ÁNGELES TORMO MAS

RYC-2012-12246 . MINISTERIO DE ECONOMIA Y COMPETITIVIDAD; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2014