Dataset Information

Evaluation and Optimization of Pharmacokinetic Models for in Vitro to in Vivo Extrapolation of Estrogenic Activity for Environmental Chemicals.

ABSTRACT: BACKGROUND:To effectively incorporate in vitro data into regulatory use, confidence must be established in the quantitative extrapolation of in vitro activity to relevant end points in animals or humans. OBJECTIVE:Our goal was to evaluate and optimize in vitro to in vivo extrapolation (IVIVE) approaches using in vitro estrogen receptor (ER) activity to predict estrogenic effects measured in rodent uterotrophic studies. METHODS:We evaluated three pharmacokinetic (PK) models with varying complexities to extrapolate in vitro to in vivo dosimetry for a group of 29 ER agonists, using data from validated in vitro [U.S. Environmental Protection Agency (U.S. EPA) ToxCast™ ER model] and in vivo (uterotrophic) methods. In vitro activity values were adjusted using mass-balance equations to estimate intracellular exposure via an enrichment factor (EF), and steady-state model calculations were adjusted using fraction of unbound chemical in the plasma ([Formula: see text]) to approximate bioavailability. Accuracy of each model-adjustment combination was assessed by comparing model predictions with lowest effect levels (LELs) from guideline uterotrophic studies. RESULTS:We found little difference in model predictive performance based on complexity or route-specific modifications. Simple adjustments, applied to account for in vitro intracellular exposure (EF) or chemical bioavailability ([Formula: see text]), resulted in significant improvements in the predictive performance of all models. CONCLUSION:Computational IVIVE approaches accurately estimate chemical exposure levels that elicit positive responses in the rodent uterotrophic bioassay. The simplest model had the best overall performance for predicting both oral (PPK_EF) and injection (PPK_[Formula: see text]) LELs from guideline uterotrophic studies, is freely available, and can be parameterized entirely using freely available in silico tools. https://doi.org/10.1289/EHP1655.

SUBMITTER: Casey WM

PROVIDER: S-EPMC6375436 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Evaluation and Optimization of Pharmacokinetic Models for <i>in Vitro</i> to <i>in Vivo</i> Extrapolation of Estrogenic Activity for Environmental Chemicals.

Casey Warren M WM Chang Xiaoqing X Allen David G DG Ceger Patricia C PC Choksi Neepa Y NY Hsieh Jui-Hua JH Wetmore Barbara A BA Ferguson Stephen S SS DeVito Michael J MJ Sprankle Catherine S CS Kleinstreuer Nicole C NC

Environmental health perspectives 20180901 9

<h4>Background</h4>To effectively incorporate <i>in vitro</i> data into regulatory use, confidence must be established in the quantitative extrapolation of <i>in vitro</i> activity to relevant end points in animals or humans.<h4>Objective</h4>Our goal was to evaluate and optimize <i>in vitro</i> to <i>in vivo</i> extrapolation (IVIVE) approaches using in vitro estrogen receptor (ER) activity to predict estrogenic effects measured in rodent uterotrophic studies.<h4>Methods</h4>We evaluated three ...[more]

PMID: 30192161

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Project description:In this review, we describe the absorption rates (Caco-2 cell permeability) and hepatic/plasma pharmacokinetics of 53 diverse chemicals estimated by modeling virtual oral administration in rats. To ensure that a broad range of chemical structures is present among the selected substances, the properties described by 196 chemical descriptors in a chemoinformatics tool were calculated for 50,000 randomly selected molecules in the original chemical space. To allow visualization, the resulting chemical space was projected onto a two-dimensional plane using generative topographic mapping. The calculated absorbance rates of the chemicals based on cell permeability studies were found to be inversely correlated to the no-observed-effect levels for hepatoxicity after oral administration, as obtained from the Hazard Evaluation Support System Integrated Platform in Japan (r = -0.88, p < 0.01, n = 27). The maximum plasma concentrations and the areas under the concentration-time curves (AUC) of a varied selection of chemicals were estimated using two different methods: simple one-compartment models (i.e., high-throughput toxicokinetic models) and simplified physiologically based pharmacokinetic (PBPK) modeling consisting of chemical receptor (gut), metabolizing (liver), and central (main) compartments. The results obtained from the two methods were consistent. Although the maximum concentrations and AUC values of the 53 chemicals roughly correlated in the liver and plasma, inconsistencies were apparent between empirically measured concentrations and the PBPK-modeled levels. The lowest-observed-effect levels and the virtual hepatic AUC values obtained using PBPK models were inversely correlated (r = -0.78, p < 0.05, n = 7). The present simplified PBPK models could estimate the relationships between hepatic/plasma concentrations and oral doses of general chemicals using both forward and reverse dosimetry. These methods are therefore valuable for estimating hepatotoxicity.

Project description:Hepatic in vitro biotransformation assays, in combination with in vitro-in vivo extrapolation (IVIVE) and bioaccumulation modeling, can be used to support regulatory bioaccumulation assessments. In most applications, however, these methods ignore the possibility of extrahepatic metabolism. Here we evaluated intestinal biotransformation in rainbow trout using S9 fractions prepared from the upper intestinal (GIT) epithelium. Measured levels of activity determined using standard substrates for phase I and phase II biotransformation enzymes were within 2-fold of activities measured in hepatic S9 fractions. In vitro intrinsic clearance rates for 2-ethylhexyl-4-methoxycinnamate (EHMC; an organic sunscreen agent) and two polycyclic aromatic hydrocarbons (pyrene [PYR] and benzo(a)pyrene [BAP]) were significantly higher in liver S9 fractions than in GIT S9 fractions. For octocrylene (OCT; a second sunscreen agent), however, in vitro intrinsic clearance rates were higher in GIT S9 fractions compared to liver S9 fractions. An existing 'liver only' IVIVE model was expanded to consider biotransformation in both the liver and GIT. Relevant IVIVE scaling factors were developed by morphological, histological, and biochemical evaluation of trout intestines. For chemicals biotransformed at higher rates by hepatic S9 fractions (i.e., BAP, PYR, EHMC), the 'liver & GIT' model yielded whole-body biotransformation rate constants (kMET) that were within 1.2 to 1.4-fold of those estimated using the 'liver only' model. In contrast to these findings, the mean kMET for OCT obtained using the 'liver & GIT' model was 3.3 times higher than the mean kMET derived using the 'liver only' model and was in good agreement with empirical kMET estimates determined previously for trout (<20 % difference). The results of this study suggest that current 'liver only' IVIVE approaches may underestimate in vivo biotransformation rates for chemicals that undergo substantial biotransformation in the GIT.

Dataset Information

Evaluation and Optimization of Pharmacokinetic Models for in Vitro to in Vivo Extrapolation of Estrogenic Activity for Environmental Chemicals.

Publications

Evaluation and Optimization of Pharmacokinetic Models for <i>in Vitro</i> to <i>in Vivo</i> Extrapolation of Estrogenic Activity for Environmental Chemicals.

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