LAUSR

Discussions are ongoing on which dose metric should be used for quantitative in vitro-to-in vivo extrapolation (QIVIVE) of in vitro bioassay data. The nominal concentration of the test chemicals is most commonly used and easily accessible, while the concentration freely dissolved in the assay medium is considered to better reflect the bioavailable concentration but is tedious to measure. The aim of this study was to elucidate how much QIVIVE results will differ when using either nominal or freely dissolved concentrations. QIVIVEnom and QIVIVEfree ratios, that is, the ratios of plasma concentrations divided by in vitro effect concentrations, were calculated for 10 pharmaceuticals using previously published nominal and freely dissolved effect concentrations for the activation of the peroxisome proliferator-activated receptor gamma (PPARγ) and the activation of oxidative stress response. The QIVIVEnom ratios were higher than QIVIVEfree ratios by up to a factor of 60. The risk of in vivo effects was classified as being high or low for four chemicals using the QIVIVEnom and for three chemicals using QIVIVEfree ratios. Unambiguous classification was possible for nine chemicals by combining the QIVIVEnom or QIVIVEfree ratios with the respective specificity ratios (SRnom or SRfree) of the in vitro effect data, which helps to identify whether the specific effect was influenced by cytotoxicity. QIVIVEfree models should be preferred as they account for differences in bioavailability between in vitro and in vivo, but QIVIVEnom may still be useful for screening the effects of large numbers of chemicals because it is generally more conservative. The use of SR of the in vitro effect data as a second classification factor is recommended for QIVIVEnom and QIVIVEfree models because a clearer picture can be obtained with respect to the likelihood that a biological effect will occur and that it is not caused by nonspecific cytotoxicity.