In Vitro to In Vivo Extrapolation (IVIVE): Integrating Bioactivities into Safety Decision Making

The development of in silico and in vitro approaches is accelerating the movement away from animal studies in chemical safety testing. These technologies have the potential to increase confidence and throughput of chemical safety decision making. A critical component in redirecting toxicity testing towards high-throughput methodologies is the development of techniques for quantitatively comparing bioactivity levels seen in new approach methodologies (NAMs) and estimated human exposures. In vitro-to-in vivo extrapolation (IVIVE) provides a quantitative framework for converting bioactivity values derived from in vitro testing to an equivalent external exposure. This conversion allows direct comparison between chemical hazard levels and anticipated exposure scenarios, resulting in more relevant safety decision making.

IVIVE is an integral component in new approach methodologies (NAMs)-based risk assessment paradigms for rapidly translating large-scale in vitro toxicity assay results in the context of in vivo exposure. There is additional value for data submission to regulatory bodies where the weight of evidence will be used. Regulators who may require the use of animal studies use dosimetry to answer questions such as:

"To what extent the doses in an in-life (animal) study correspond to what humans would be exposed to under normal use or based on extraordinary circumstances such as occupational exposure?"

Models of dosimetry such as high-throughput IVIVE can be used to estimate the relationship between an in vitro concentration of interest—such as a benchmark dose estimate—and the whole-animal or human exposure that would lead to the equivalent target tissue concentration. An example of recently published HT-IVIVE work is the development and validation of a fit-for-purpose assay that predicts tissue-specific responses to estrogens (i.e., breast vs. uterine differences) and would also provide dose-response information sufficient to derive points of departure (PODs) for human risk assessment. Quantitative in vitro to in vivo extrapolation (Q-IVIVE) was performed to convert the in vitro concentrations from the assay to external human equivalent doses (HEDs). Its use is very valuable for prioritizing the health risk of chemicals.

For more complex scenarios, we use pharmacokinetic modeling or physiologically based pharmacokinetic (PBPK) modeling tools to convert chemical concentrations active in experimental in vitro systems equivalent exposure levels in vivo via reverse dosimetry.

ScitoVation provides pharmacokinetic modeling at various levels of complexity. Our PBPK/IVIVE modeling capabilities are tunable to meet your needs.