September 25, 2022
Case Study On The Use Of Quantitative In Vitro To In Vivo Extrapolation (QIVIVE) To Prioritize Estrogen-Active Compounds In An In Vitro Human Uterotrophic Assay
Estrogenic compounds operate as endocrine disruptors which affect the endocrine system. In fact, there are concerns about these chemicals producing adverse developmental, reproductive and neurological effects in humans. The American Chemistry Council (ACC) questioned the relevance of using new approach methodologies (NAMs) to address these concerns. In response, ScitoVation successfully used NAMs to efficiently and effectively prioritize a list of estrogenic compounds for risk assessment.
- ScitoVation developed and validated a fit-for-purpose assay that predicts tissue-specific responses to estrogens (i.e., breast vs. uterine differences) and provides 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).
- This calculated daily exposure can be compared to high-throughput exposure estimates to produce an activity exposure relationship (AER). Calculation of an AER between a POD and daily exposure in the population is an effective way to indicate the potential hazard of chemicals. Its use is valuable for the health risk prioritization of chemicals. If the AER is large, there is a low level of human health concern. However, if the AER is small, there is an increased chance of health risk, indicating that a more in-depth investigation is necessary.
Results from our Work
- For substances active both in vitro and in vivo, the assay-derived HEDs were lower or equivalent to in vivo PODs for 83% of the compounds. Based on the AER, the fit-for-purpose assay was as or more protective of human health than the rodent uterotrophic assay for all assay-positive compounds.
- This means that the process of selecting, refining, and applying principles for fit-for-purpose assays, use of QIVIVE, and integration of bioactivity with exposure can provide a rapid, risk-based prioritization approach.
- These results suggest QIVIVE would be a useful tool for risk assessment prioritization in future efforts developing similar assays in different cell lines and for other Modes of Action (MOA).