Bridging the life-course exposome approach with a life-cycle perspective in safe and sustainable by design (SSbD) for chemical risk

: Safe and Sustainable by Design (SSbD) and life‑course exposome science share a primary‑prevention goal: reducing harmful exposures by intervening early in the chemical and product life cycle. Here we propose an integrated, replacement‑first decision workflow that links life‑course exposure considerations to SSbD stage‑gates using New Approach Methodologies (NAMs). The framework combines: (i) problem formulation informed by susceptible windows and populations; (ii) AOP‑guided selection and curation of mechanistic in vitro bioactivity evidence (e.g., ToxCast/Tox21, transcriptomics); (iii) physiologically based pharmacokinetic (PBPK) modelling with quantitative in vitro‑to‑in vivo extrapolation to translate in vitro potency into internal dose anchors; and (iv) transparent multi‑criteria synthesis to support early design trade‑offs. We illustrate this approach with an endocrine‑relevant substitution scenario comparing bisphenol A (BPA) with a structurally similar alternative (BPAP) and a bio‑based monomer candidate (isosorbide). Estrogen receptor (ER) bioactivity anchors derived from curated HTS assays are contrasted with PBPK‑predicted internal concentration ranges to generate an internal margin for stage‑gate decisions. The example shows how candidates with weak or absent pathway‑relevant bioactivity can be advanced, while structurally similar alternatives with ER potency approaching predicted internal concentrations can be deprioritised or redesigned pending improved exposure controls. By explicitly mapping NAM outputs to AOP key events and life‑course windows, the workflow operationalises the 3Rs by replacing broad exploratory animal testing with targeted, human‑relevant evidence and reducing unnecessary in vivo studies through early prioritisation.