Can a tiered next generation risk assessment framework bridge human health and environmental risk assessment? Insights from pyrethroids in wild mammals

Pyrethroids are widely used insecticides with proven environmental presence and known toxicological effects on non-target organisms. However, current environmental risk assessment (ERA) approaches often fall short in capturing cumulative exposures, mechanistic effects, and population-level outcomes. This study adapts a previously developed human health Next Generation Risk Assessment (NGRA) framework (Fernandez-Agudo & Tarazona, 2025) to the environmental domain, with the aim of testing whether new approach methodologies (NAMs) and toxicokinetic (TK) modeling can be extended to mammalian ERA. The framework integrates in vitro bioactivity data with toxicokinetic (TK) modeling to simulate internal concentrations and derive margins of exposure (MoEs) at different levels of biological organization. Tier 1 and Tier 2 focused on screening and prioritization, comparing bioactivity thresholds and exploring target tissue relevance without formal risk quantification. Tiers 3 and 4 apply toxicokinetic modeling to link exposure scenarios with internal bioactivity thresholds, while Tier 5 explores combined margins of exposure as a screening step toward future population-level modeling. While early tiers demonstrated potential to identify internal risks, higher-tier analyses revealed limitations in the framework's ability to consistently identify key toxicants, such as l-cyhalothrin for brain tissue. Results showed good coherence with traditional in vivo endpoints for most compounds, although limitations emerged in TK parameterization and the lack of species-representative data. Overall, the study provides a proof of concept for extending NAM-based NGRA approaches from human health to wildlife ERA. While current applications remain protective rather than predictive, the findings highlight the potential of mechanistic, tiered strategies to reduce reliance on animal testing and improve the ecological relevance of chemical safety evaluations.