Extrapolation steps in quantitative in vitro to in vivo extrapolation to advance in vitro-based chemical risk assessment for human health

Abstract

The transition towards Next Generation Risk Assessment (NGRA) aims at increasing human relevance and efficiency of chemical risk assessment, by using human-based in vitro and in silico methods. Quantitative in vitro to in vivo Extrapolation (QIVIVE) is central to this approach and enables the derivation of health-based guidance values (HBGV) from in vitro data. However, consensus on the required extrapolation steps within QIVIVE is missing. To find out which extrapolation steps are necessary when executing a QIVIVE analysis, this review identified and analyzed potential key extrapolation steps across 212 research articles and regulatory documents. Six key extrapolation steps were identified: 1. Extrapolations based on choice of in vitro cell model 2. Extrapolation from nominal concentration to target concentration in vitro, 3. In vitro target concentration to in vivo target compartment concentration (dose metric alignment), 4. In vivo target compartment concentration to external dose, 5. Effect extrapolation, and 6. Extrapolation of exposure duration. Furthermore, uncertainties and variations within the steps should be considered. Although extrapolation steps 2 to 4 are increasingly standardized, challenges are more prominent regarding the execution of in vitro model choice, effect and exposure duration extrapolation. To advance the field of NGRA and gain trust in QIVIVE, further QIVIVE case studies and in vitro studies are needed that report results systematically on the different extrapolation steps.