Update and Evaluation of a High-Throughput In Vitro Mass Balance Distribution Model: IV-MBM EQP v2.0
This study demonstrates the utility of an updated mass balance model for predicting the distribution of organic chemicals in in vitro test systems (IV-MBM EQP v2.0) and evaluates its performance with empirical data. The IV-MBM EQP v2.0 tool was parameterized and applied to four independent data sets...
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| Autores principales: | , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/852c45b01bc74d2ca5b94e5992b1a138 |
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| Sumario: | This study demonstrates the utility of an updated mass balance model for predicting the distribution of organic chemicals in in vitro test systems (IV-MBM EQP v2.0) and evaluates its performance with empirical data. The IV-MBM EQP v2.0 tool was parameterized and applied to four independent data sets with measured ratios of bulk medium or freely-dissolved to initial nominal concentrations (e.g., C24/C0 where C24 is the measured concentration after 24 h of exposure and C0 is the initial nominal concentration). Model performance varied depending on the data set, chemical properties (e.g., “volatiles” vs. “non-volatiles”, neutral vs. ionizable organics), and model assumptions but overall is deemed acceptable. For example, the r<sup>2</sup> was greater than 0.8 and the mean absolute error (<i>MAE</i>) in the predictions was less than a factor of two for most neutral organics included. Model performance was not as good for the ionizable organic chemicals included but the r<sup>2</sup> was still greater than 0.7 and the <i>MAE</i> less than a factor of three. The IV-MBM EQP v2.0 model was subsequently applied to several hundred chemicals on Canada’s Domestic Substances List (DSL) with nominal effects data (<i>AC</i>50s) reported for two in vitro assays. We report the frequency of chemicals with <i>AC</i>50s corresponding to predicted cell membrane concentrations in the baseline toxicity range (i.e., >20–60 mM) and tabulate the number of chemicals with “volatility issues” (majority of chemical in headspace) and “solubility issues” (freely-dissolved concentration greater than water solubility after distribution). In addition, the predicted “equivalent EQP blood concentrations” (i.e., blood concentration at equilibrium with predicted cellular concentration) were compared to the <i>AC</i>50s as a function of hydrophobicity (log octanol-water partition or distribution ratio). The predicted equivalent EQP blood concentrations exceed the <i>AC</i>50 by up to a factor of 100 depending on hydrophobicity and assay conditions. The implications of using <i>AC</i>50s as direct surrogates for human blood concentrations when estimating the oral equivalent doses using a toxicokinetic model (i.e., reverse dosimetry) are then briefly discussed. |
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