Mechanistic Middle-Out Physiologically Based Toxicokinetic Modeling of Transporter-Dependent Disposition of Perfluorooctanoic Acid in Humans.
Environ Sci Technol
; 57(17): 6825-6834, 2023 05 02.
Article
en En
| MEDLINE
| ID: mdl-37072124
Perfluorooctanoic acid (PFOA) is an environmental toxicant exhibiting a years-long biological half-life (t1/2) in humans and is linked with adverse health effects. However, limited understanding of its toxicokinetics (TK) has obstructed the necessary risk assessment. Here, we constructed the first middle-out physiologically based toxicokinetic (PBTK) model to mechanistically explain the persistence of PFOA in humans. In vitro transporter kinetics were thoroughly characterized and scaled up to in vivo clearances using quantitative proteomics-based in vitro-to-in vivo extrapolation. These data and physicochemical parameters of PFOA were used to parameterize our model. We uncovered a novel uptake transporter for PFOA, highly likely to be monocarboxylate transporter 1 which is ubiquitously expressed in body tissues and may mediate broad tissue penetration. Our model was able to recapitulate clinical data from a phase I dose-escalation trial and divergent half-lives from clinical trial and biomonitoring studies. Simulations and sensitivity analyses confirmed the importance of renal transporters in driving extensive PFOA reabsorption, reducing its clearance and augmenting its t1/2. Crucially, the inclusion of a hypothetical, saturable renal basolateral efflux transporter provided the first unified explanation for the divergent t1/2 of PFOA reported in clinical (116 days) versus biomonitoring studies (1.3-3.9 years). Efforts are underway to build PBTK models for other perfluoroalkyl substances using similar workflows to assess their TK profiles and facilitate risk assessments.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Caprilatos
/
Fluorocarburos
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Environ Sci Technol
Año:
2023
Tipo del documento:
Article
Pais de publicación:
Estados Unidos