A tiered next-generation risk assessment framework integrating toxicokinetics and NAM-based toxicodynamics: “proof of concept” case study using pyrethroids

Fernandez Agudo, Ana; Tarazona, Jose

Publicación:
A tiered next-generation risk assessment framework integrating toxicokinetics and NAM-based toxicodynamics: “proof of concept” case study using pyrethroids

dc.contributor.author	Fernandez Agudo, Ana
dc.contributor.author	Tarazona, Jose
dc.date.accessioned	2025-05-20T10:59:37Z
dc.date.available	2025-05-20T10:59:37Z
dc.date.issued	2025-05-07
dc.description	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
dc.description.abstract	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.	en
dc.description.version	versión final
dc.identifier.citation	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
dc.identifier.doi	https://doi.org/10.1007/s00204-025-04045-9
dc.identifier.issn	1432-0738 \| 0340-5761
dc.identifier.uri	https://hdl.handle.net/20.500.14468/26565
dc.journal.title	Archives of Toxicology
dc.language.iso	en
dc.publisher	Springer
dc.relation.center	Facultad de Ciencias
dc.relation.department	Ciencias y Técnicas Fisicoquímicas
dc.rights	info:eu-repo/semantics/openAccess
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/deed.es
dc.subject	24 Ciencias de la Vida
dc.subject.keywords	Next-generation risk assessment (NGRA)	en
dc.subject.keywords	New Alternative Methods (NAMs)	en
dc.subject.keywords	toxicokinetics	en
dc.subject.keywords	toxicodynamics	en
dc.subject.keywords	pyrethroids	en
dc.title	A tiered next-generation risk assessment framework integrating toxicokinetics and NAM-based toxicodynamics: “proof of concept” case study using pyrethroids	en
dc.type	artículo	es
dc.type	journal article	en
dspace.entity.type	Publication