A preliminary evaluation of the applicability of the <i>in vitro</i> to <i>in vivo</i> extrapolation approach to quantitative risk assessment

The applicability of the in vitro to in vivo extrapolation (IVIVE) approach for the quantitative risk assessment of chemicals was evaluated using the results of mouse uterotrophic bioassays conducted by the Japanese Ministry of Health, Labour and Welfare. Five chemicals were selected. In the uterotrophic bioassay, three chemicals exhibited positive estrogenic activity, whereas two exhibited negative activity. These chemicals were active in 16 in vitro assays that investigated the key events from estrogen receptor (ER) binding (initiating event) to ER-induced proliferation, enabling us to derive IVIVE conversion factors using a physiologically based kinetic model. The oral equivalent doses (OEDs) that were extrapolated from the activity concentrations at the half-maximal response (AC₅₀) and the cutoff point (ACC) were compared with those of other key events to determine the critical key event that plays the most important role in the occurrence of uterotrophic responses. For the three chemicals that exhibited positive estrogenic activity, the OEDs from the in vitro AC₅₀ values for the determined critical events were within a factor of 2 of the lowest observed effect levels in the uterotrophic bioassay. In addition, the OEDs from the ACC values for the critical key events of the two chemicals that exhibited negative activity were higher than the highest dose tested in the bioassay. Based on these findings, the IVIVE approach was largely valid. However, the critical key events that significantly affect in vivo responses need to be appropriately determined to apply the IVIVE approach for the quantitative risk assessment of chemicals.