Quantitative -to- Extrapolation: Nominal versus Freely Dissolved Concentration.

Discussions are ongoing on which dose metric should be used for quantitative -to- extrapolation (QIVIVE) of 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. QIVIVE and QIVIVE ratios, that is, the ratios of plasma concentrations divided by 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 QIVIVE ratios were higher than QIVIVE ratios by up to a factor of 60. The risk of effects was classified as being high or low for four chemicals using the QIVIVE and for three chemicals using QIVIVE ratios. Unambiguous classification was possible for nine chemicals by combining the QIVIVE or QIVIVE ratios with the respective specificity ratios (SR or SR) of the effect data, which helps to identify whether the specific effect was influenced by cytotoxicity. QIVIVE models should be preferred as they account for differences in bioavailability between and , but QIVIVE 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 effect data as a second classification factor is recommended for QIVIVE and QIVIVE 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.