Quantitative Structure-Activity Relationship (QSAR) Modeling of Toxicokinetics (TKs) for Health Risk Assessment. M. Béliveau and K. Krishnan, Université de Montréal, Canada
The use of tissue dose (TD) of chemicals enhances the scientific basis of health risk assessment because they can account for the toxic moiety, exposure scenario, and interspecies differences in TK. Since direct measurement of TD is not always possible, physiologically-based toxicokinetic (PBTK) models are used to simulate the TD of chemicals. Given the similarity in structural features among various volatile organic chemicals (VOCs), particular molecular structural fragments can be hypothesized to consistently contribute to the PBTK model parameter values, leading to the development of quantitative structure-property relationships (SPRs). In the present study, SPRs were developed for the various input parameters required by PBTK models (i.e., blood:air PC (Pb), tissue:air PCs (Pt), metabolism constants (Vmaxc and Km)) in rats and humans, and were incorporated within PBTK models to predict the TKs of VOCs simultaneously in both rats and humans. Experimental values of the input parameters for 21 structurally unrelated VOCs were taken from the literature, and each VOC was described as the composite of a basic structure (BS) and substituent (S) group(s). Structural features and parameter (Pi) values were regressed using a Free-Wilson additive model: Pi=BSi+åfsxCsi where BSi = contribution of the BS to Pi, fs = frequency of occurrence of each S, and Csi = contribution of each S to Pi. The average ± SD of the ratios of estimated/experimental values were: 1.08±0.16, 1.25±0.48, 1.64±0.46, 1.73±0.68, and 1.31±0.21 for rat Pb, human Pb, Pt, Vmaxc and Km, respectively. The ratio of the steady-state arterial blood concentrations simulated using the conventional PBTK model and QSAR-type PBTK model was 1.11±0.36. The QSAR-PBTK model developed in this study facilitates the evaluation of the influence of structural features of chemicals on an important determinant of risk, namely the tissue dose.
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