03584nas a2200565   4500000000100000000000100001008004100002260001500043653002000058653002800078653003100106653003600137653003100173653002600204100002500230700001900255700002200274700002200296700002100318700001600339700002400355700001900379700002200398700001900420700001900439700002100458700002200479700002400501700001700525700001900542700002600561700001700587700002700604700001800631700001700649700001600666700001900682700002200701700002500723700001900748700002100767700001700788700001700805245009200822856007200914300001100986490000800997520199901005022001403004       2023                            d  c2023-08-0110aChemical safety10aHuman health protection10anew approach methodologies10aNext generation risk assessment10aRegulatory risk assessment10aRegulatory toxicology1 aSebastian Schmeisser1 aAndrea Miccoli1 aMartin von Bergen1 aElisabet Berggren1 aAlbert Braeuning1 aWibke Busch1 aChristian Desaintes1 aAnne Gourmelon1 aRoland Grafström1 aJoshua Harrill1 aThomas Hartung1 aMatthias Herzler1 aGeorge E. N. Kass1 aNicole Kleinstreuer1 aMarcel Leist1 aMirjam Luijten1 aPhilip Marx-Stoelting1 aOliver Poetz1 aBennard van Ravenzwaay1 aRob Roggeband1 aVera Rogiers1 aAdrian Roth1 aPascal Sanders1 aRussell S. Thomas1 aAnne Marie Vinggaard1 aMathieu Vinken1 aBob van de Water1 aAndreas Luch1 aTewes Tralau00aNew approach methodologies in human regulatory toxicology – Not if, but how and when!  uhttps://www.sciencedirect.com/science/article/pii/S0160412023003550  a1080820 v1783 aThe predominantly animal-centric approach of chemical safety assessment has increasingly come under pressure. Society is questioning overall performance, sustainability, continued relevance for human health risk assessment and ethics of this system, demanding a change of paradigm. At the same time, the scientific toolbox used for risk assessment is continuously enriched by the development of “New Approach Methodologies” (NAMs). While this term does not define the age or the state of readiness of the innovation, it covers a wide range of methods, including quantitative structure–activity relationship (QSAR) predictions, high-throughput screening (HTS) bioassays, omics applications, cell cultures, organoids, microphysiological systems (MPS), machine learning models and artificial intelligence (AI). In addition to promising faster and more efficient toxicity testing, NAMs have the potential to fundamentally transform today’s regulatory work by allowing more human-relevant decision-making in terms of both hazard and exposure assessment. Yet, several obstacles hamper a broader application of NAMs in current regulatory risk assessment. Constraints in addressing repeated-dose toxicity, with particular reference to the chronic toxicity, and hesitance from relevant stakeholders, are major challenges for the implementation of NAMs in a broader context. Moreover, issues regarding predictivity, reproducibility and quantification need to be addressed and regulatory and legislative frameworks need to be adapted to NAMs. The conceptual perspective presented here has its focus on hazard assessment and is grounded on the main findings and conclusions from a symposium and workshop held in Berlin in November 2021. It intends to provide further insights into how NAMs can be gradually integrated into chemical risk assessment aimed at protection of human health, until eventually the current paradigm is replaced by an animal-free “Next Generation Risk Assessment” (NGRA).  a0160-4120