Investigating open access new approach methods (NAM) to assess biological points of departure: A case study with 4 neurotoxic pesticides.
Curr Res Toxicol
; 6: 100156, 2024.
Article
en En
| MEDLINE
| ID: mdl-38404712
ABSTRACT
Open access new approach methods (NAM) in the US EPA ToxCast program and NTP Integrated Chemical Environment (ICE) were used to investigate activities of four neurotoxic pesticides endosulfan, fipronil, propyzamide and carbaryl. Concordance of in vivo regulatory points of departure (POD) adjusted for interspecies extrapolation (AdjPOD) to modelled human Administered Equivalent Dose (AEDHuman) was assessed using 3-compartment or Adult/Fetal PBTK in vitro to in vivo extrapolation. Model inputs were from Tier 1 (High throughput transcriptomics HTTr, high throughput phenotypic profiling HTPP) and Tier 2 (single target ToxCast) assays. HTTr identified gene expression signatures associated with potential neurotoxicity for endosulfan, propyzamide and carbaryl in non-neuronal MCF-7 and HepaRG cells. The HTPP assay in U-2 OS cells detected potent effects on DNA endpoints for endosulfan and carbaryl, and mitochondria with fipronil (propyzamide was inactive). The most potent ToxCast assays were concordant with specific components of each chemical mode of action (MOA). Predictive adult IVIVE models produced fold differences (FD) < 10 between the AEDHuman and the measured in vivo AdjPOD. The 3-compartment model was concordant (i.e., smallest FD) for endosulfan, fipronil and carbaryl, and PBTK was concordant for propyzamide. The most potent AEDHuman predictions for each chemical showed HTTr, HTPP and ToxCast were mainly concordant with in vivo AdjPODs but assays were less concordant with MOAs. This was likely due to the cell types used for testing and/or lack of metabolic capabilities and pathways available in vivo. The Fetal PBTK model had larger FDs than adult models and was less predictive overall.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Curr Res Toxicol
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Países Bajos