Evaluation of PBK models using the OECD assessment framework taking PFAS as case study

Physiologically based kinetic (PBK) models are becoming increasingly important in chemical risk assessment, helping in linking external and internal exposure concentrations, thereby supporting the development of regulatory health-based limits for chemicals with exposure from environmental, occupational, and consumer sources. To increase confidence in PBK models for regulatory purposes, the OECD published a guidance document in 2021 outlining the characterization, validation and reporting of PBK models. However, its use remains limited in chemical toxicology as reflected by the few publications that have applied it during model development. The aim of this study was to evaluate several published PBK models for Per- and polyfluoroalkyl substances (PFASs) as proof of concept to assess their validity and credibility for regulatory purposes, based on the OECD guidance. Out of 28 published PFASs human PBK models considered, 11 were selected for evaluation. The assessment used the OECD guidance document, encompassing two main areas: i) documentation (context/implementation, documentation, software implementation, verification, and peer engagement) and ii) assessment of model validity (biological basis, theoretical basis of model equations, input parameter’s reliability, uncertainty and sensitivity analysis, goodness-of-fit and predictivity). To standardize this process, an online evaluation system based on the OECD guidance was developed and used for this model evaluation exercise. The collected data were analysed to assess the overall quality of published models and identify limitations in the current PFAS model landscape. Our analysis revealed opportunities for improvement in the biological representation within current PFAS models, particularly regarding the inclusion of diverse population groups. Currently, PFAS models primarily focus on only four compounds, highlighting an opportunity to extend coverage to other PFASs using read-across approaches for data-poor chemicals. Furthermore, our findings show that a harmonized approach for PBK model reporting is needed. To facilitate broader adoption of the OECD guidance, we developed and hosted an R Shiny template on our group’s web server (https://app.shiny.insilicohub.org/Evaluation_PBPK/). This template can act as valuable tool for researchers evaluating PBK models according to the OECD guidance.

GitHub: PBPK-OECD-EVALUATION.