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Update and Evaluation of a High-Throughput In Vitro Mass Balance Distribution Model: IV-MBM EQP v2.0

AES Armitage Environmental Sciences, Inc., Ottawa, ON K1L 8C3, Canada
ARC Arnot Research and Consulting, Inc., Toronto, ON M4M 1W4, Canada
Department of Physical and Environmental Sciences, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
Author to whom correspondence should be addressed.
Academic Editors: Annie M. Jarabek, Alicia Paini and Peter P. Egeghy
Toxics 2021, 9(11), 315;
Received: 6 October 2021 / Revised: 15 November 2021 / Accepted: 17 November 2021 / Published: 20 November 2021
(This article belongs to the Special Issue Computational Toxicology: Expanding Frontiers in Risk Assessment)
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 r2 was greater than 0.8 and the mean absolute error (MAE) 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 r2 was still greater than 0.7 and the MAE 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 (AC50s) reported for two in vitro assays. We report the frequency of chemicals with AC50s 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 AC50s as a function of hydrophobicity (log octanol-water partition or distribution ratio). The predicted equivalent EQP blood concentrations exceed the AC50 by up to a factor of 100 depending on hydrophobicity and assay conditions. The implications of using AC50s 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. View Full-Text
Keywords: in vitro; bioactivity/toxicity; distribution; Q-IVIVE in vitro; bioactivity/toxicity; distribution; Q-IVIVE
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MDPI and ACS Style

Armitage, J.M.; Sangion, A.; Parmar, R.; Looky, A.B.; Arnot, J.A. Update and Evaluation of a High-Throughput In Vitro Mass Balance Distribution Model: IV-MBM EQP v2.0. Toxics 2021, 9, 315.

AMA Style

Armitage JM, Sangion A, Parmar R, Looky AB, Arnot JA. Update and Evaluation of a High-Throughput In Vitro Mass Balance Distribution Model: IV-MBM EQP v2.0. Toxics. 2021; 9(11):315.

Chicago/Turabian Style

Armitage, James M., Alessandro Sangion, Rohan Parmar, Alexandra B. Looky, and Jon A. Arnot. 2021. "Update and Evaluation of a High-Throughput In Vitro Mass Balance Distribution Model: IV-MBM EQP v2.0" Toxics 9, no. 11: 315.

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