Cargando...
Fecha
2025-05-07
Editor/a
Director/a
Tutor/a
Coordinador/a
Prologuista
Revisor/a
Ilustrador/a
Derechos de acceso
info:eu-repo/semantics/openAccess
Título de la revista
ISSN de la revista
Título del volumen
Editor
Springer
Citas
0 citas en 
0 citas en 
Resumen
New Approach Methodologies (NAMs) in Next-Generation Risk Assessment (NGRA), integrating toxicokinetics (TK) with toxicodynamics (TD), provides an accurate evaluation of combined chemical exposures. This study assesses pyrethroids, which pose regulatory challenges due to their widespread use and cumulative exposure risks. A tiered NGRA framework was compared with conventional risk assessment (RA) to evaluate regulatory applicability. In Tier 1, ToxCast data established gene and tissue bioactivity indicators, facilitating hypothesis-driven hazard identification. Tier 2 examined combined risk assessments, rejecting the hypothesis of the same mode of action and highlighting inconsistencies in in vitro data and NOAEL/ADI correlations. Tier 3 applied Margin of Exposure (MoE) analysis and TK modeling to realistic exposure estimations for risk assessment screening based on internal doses, identifying tissue-specific pathways as critical risk drivers. Tier 4 refined bioactivity indicators using TK approaches to improve the NAM-based effect assessment, including an in vitro vs. in vivo comparison, with coherent results based on interstitial concentrations, though intracellular estimations remained uncertain. Tier 5 confirmed that dietary exposure in healthy adults is close to but below levels of concern, with bioactivity MoE values remaining below concern thresholds, and in vivo MoEs within the standard safety factors. Nevertheless, the MoEs are insufficient for addressing the additional non-dietary exposure expected from other pyrethroid uses such as biocides or pharmaceuticals. Results demonstrate that NGRA with TK-NAM-based TD offers a nuanced, regulatory-relevant framework for risk assessment. The proposed approach integrates the information on individual pyrethroids using bioactivity indicators; and the re-assessment of regulatory toxicity studies to select organ-relevant NOAELs allowed an improved in vitro-in vivo comparison, demonstrating the capacity of bioactivity-based MoEs for combined exposure assessments. This tiered approach provides key insights for regulatory decision-making, establishing a robust model for evaluating pyrethroids and similar chemical classes.
Descripción
The registered version of this article, first published in “Archives of Toxicology (2025)", is available online at the publisher's website: Springer, https://doi.org/10.1007/s00204-025-04045-9
La versión registrada de este artículo, publicado por primera vez en “Archives of Toxicology (2025)", está disponible en línea en el sitio web del editor: Springer, https://doi.org/10.1007/s00204-025-04045-9
Categorías UNESCO
Palabras clave
Next-generation risk assessment (NGRA), New Alternative Methods (NAMs), toxicokinetics, toxicodynamics, pyrethroids
Citación
Fernandez-Agudo, A., Tarazona, J.V. A tiered next-generation risk assessment framework integrating toxicokinetics and NAM-based toxicodynamics: “proof of concept” case study using pyrethroids. Arch Toxicol (2025). https://doi.org/10.1007/s00204-025-04045-9
Centro
Facultad de Ciencias
Departamento
Ciencias y Técnicas Fisicoquímicas