Towards reproducible structure-based chemical categories for PFAS to inform and evaluate toxicity and toxicokinetic testing

Per- and Polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals that are in widespread use and present concerns for persistence, bioaccumulation and toxicity. Whilst a handful of PFAS have been characterised for their hazard profiles, the vast majority of PFAS have not been studied. The US Environmental Protection Agency (EPA) undertook a research project to screen ∼150 PFAS through an array of different in vitro high throughput toxicity and toxicokinetic tests in order to inform chemical category and read-across approaches. A previous publication described the rationale behind the selection of an initial set of 75 PFAS, whereas herein, we describe how various category approaches were applied and extended to inform the selection of a second set of 75 PFAS from our library of approximately 430 commercially procured PFAS. In particular, we focus on the challenges in grouping PFAS for prospective analysis and how we have sought to develop and apply objective structure-based categories to profile the testing library and other PFAS inventories. We additionally illustrate how these categories can be enriched with other information to facilitate read-across inferences once experimental data become available. The availability of flexible, objective, reproducible and chemically intuitive categories to explore PFAS constitutes an important step forward in prioritising PFAS for further testing and assessment.