Using effect biomarker thresholds in regulatory risk assessment: an OECD-based framework for assessing cumulative...

The international initiative titled: "Using Adverse Outcome Pathways (AOP) to address combined exposures to chemicals with relevant effect-biomarkers", was coordinated by the OECD's Working Parties on Exposure Assessment (WPEA) and Hazard Assessment (WPHA). It brought together over 90 experts from 25 countries to advance the regulatory and scientific use of effect biomarkers for assessing exposures to chemical mixtures and their associated biological and health-relevant effects. Effect biomarkers provide biologically integrated information that can complement traditional single-substance approaches by supporting the interpretation of combined chemical exposures and associated biological responses. While the official OECD Guidance targets primarily regulatory audiences, this article communicates the project's rationale and methodology to academic, industrial, and regulatory communities. Assessing chemical mixture exposures through effect biomarkers overcomes the limitations of traditional single-substance approaches that have guided regulatory frameworks for decades. Effect biomarkers, anchored in AOPs, offer biologically integrated assessments resulting from both known and unknown exposures integrating all exposure routes. Effect biomarkers are powerful in identifying biologically relevant responses, enabling targeted health assessments of vulnerable populations within human biomonitoring programs. This OECD project has produced a harmonised framework for deriving effect-based mixture threshold levels, applicable to both Occupational Biomonitoring Effect Levels (OBELs) for human health and Effect-Based Trigger values (EBTs) for environmental assessments. The framework establishes biologically anchored trigger values that help identify risks from exposures to complex chemical mixtures and can guide appropriate risk management measures. The derivation was guided by four core selection criteria and additional quality principles, ensuring biological relevance to regulatory-defined adversity, quantifiability, robustness, sensitivity, and interpretability for risk assessment. A four-tiered system (Tiers 0-3) reflects increasing toxicological and methodological certainty and relevance, with thresholds informing risk management decisions based on observed changes in biomarkers. Seven case studies demonstrate the framework's applicability across key hazard classes (genotoxicity/carcinogenicity, endocrine disruption, neurotoxicity, and reproductive toxicity), thus supporting harmonised group- and individual-level assessments and broader integration of effect biomarkers into occupational and environmental health assessments.