Stakeholder Input Towards Further Refinement and Consolidation of the Alternative Safety Profiling Algorithm (ASPA) for Next Generation Risk Assessment (NGRA)

Next generation risk assessment (NGRA) aims to enable transparent, reproducible chemical safety assessments based on human-relevant, animal-free new approach methodologies (NAMs). The Alternative Safety Profiling Algorithm (ASPA) was developed within the ASPIS cluster to provide an algorithmic workflow that structures problem formulation, evidence integration, and decision-making across three main pillars – hazard, ADME (toxicokinetics), and exposure. A stakeholder workshop was organized to refine ASPA. Four breakout groups systematically reviewed corresponding workflow sections, identifying strengths, conceptual gaps, and opportunities for harmonization. Across groups, participants endorsed ASPA’s modular, technology-neutral nature and its focus on standardizing processes rather than prescribing specific test batteries. The hazard pillar discussions emphasized a sensitive, hypothesis-generating Tier 1, complemented by a specific, mechanistic Tier 2, capable of deriving points of departure (PoDs). ADME experts supported a physiologically based kinetic (PBK) modelling strategy, advancing from generic towards more complex models, using mechanistic information and experimental data. The exposure group proposed refinements for transparent, tiered exposure modelling, with emphasis on realistic worst-case scenarios and explicit uncertainty communication. Cross-pillar discussions highlighted the importance of feedback loops among all pillars, and the documentation of decision points to achieve consistency and defensibility. The workshop outcomes informed three parallel developments: (i) algorithmic refinement and re-design toward the next ASPA version, (ii) the creation of detailed guidance for each building block, and (iii) the establishment of practical case studies to demonstrate workflow implementation. This report already contains a first case study (developmental neurotoxicity assessment of desnitroimidacloprid). These advances increase the operability, transparency, and regulatory readiness of ASPA. Plain language summary Next generation risk assessment (NGRA) aims to make chemical safety testing more human-relevant without using animals. The Alternative Safety Profiling Algorithm (ASPA) offers a structured way to combine all required data. These include information on chemical hazards, predictions on how chemicals move through the body (ADME), and estimates of exposure levels. A stakeholder workshop reviewed and improved the ASPA workflow and the associated software platform. Participants stressed the importance of the tool to make NGRA transparent and reproducible between different groups of evaluators. They suggested refinements for each part, such as clearer exposure estimates that include assessment of uncertainty. They also stressed the need for feedback between the different main modules of ASPA. An example of an ASPA evaluation was prepared to illustrate all process steps.