Key messages

• The human relevance of testing strategies currently used, including toxicity studies in experimental animals and New Approach Methodologies (NAMs ↗), is usually uncertain.
• A pragmatic workflow for human relevance assessment of Adverse Outcome Pathways (AOPs ↗) and New Approach Methodologies (NAMs) would greatly help to overcome this challenge; such a workflow is being developed.
• By conducting realistic case studies we aim for substantial refinement of both the workflow itself and accompanying guidance and templates.

Overview

The project focuses on optimizing a harmonised workflow for assessing the human relevance of Adverse Outcome Pathways (AOPs) and related New Approach Methodologies (NAMs), focusing on key events (KEs) and key event relationships (KERs). At present, no standard method is available to determine whether the biological processes described in an AOP are relevant to humans. This limits the regulatory acceptance of NAMs and hinders their use in risk assessment.

The optimization aims to improve both qualitative and quantitative aspects of human relevance assessments. This includes integrating cross-species comparisons and aligning data across test systems, such as in vitro models with in vivo studies and human based data, helping to ensure that NAM-based evidence is scientifically robust and regulatory-ready. A key focus is also strengthening the weight of evidence evaluation by ensuring a structured integration of different data types and lines of evidence. The workflow will be designed to support transparent and consistent evaluations of AOPs and NAMs in regulatory contexts.

To ensure its practical use, the workflow will be applied to case studies selected together with ECHA ↗ and EFSA ↗. These case studies will demonstrate how the workflow can guide regulatory decision-making under frameworks such as REACH ↗ and the Chemicals Strategy for Sustainability (CSS) ↗.

This work supports PARC’s priority on developing NAMs to replace animal testing for hazard endpoints by improving trust in NAMs for human health assessment. It also addresses PARC’s priority on read-across and NAMs case studies by providing concrete examples of how NAMs can be applied in regulatory processes.

Achievements & Results

• Building on previous work, the project will deliver a refined version of the workflow for human relevance assessment of AOPs and NAMs, including updated guidance, structured templates, and a curated toolbox of supporting resources.
• The project will focus on improving the approach to weight-of-evidence assessment and semi-automation of data collection, to further support modern, non-animal testing strategies in human health risk assessment.
• The applicability of the workflow will be demonstrated through various case studies that are regulatory relevant.

Policy relevance

The project supports European-wide goals to better utilize human-relevant scientific knowledge in chemical safety assessments and to reduce the use of experimental animals for toxicity testing. Developed with input from EFSA and ECHA, the workflow is aligned with current and near future regulatory needs and next-generation risk assessment approaches.