Comparative Analysis of Chemical Distribution Models for Quantitative In Vitro to In Vivo Extrapolation
Abstract
1. Introduction
2. Materials and Methods
2.1. Model Comparison and Performance Evaluation
2.1.1. Models Selected for Analysis
2.1.2. Data Used for Comparisons
- (1)
- Ratio of free to nominal concentration
- (2)
- Chemical amount in media and in cells
2.1.3. Model Parametrization
- (1)
- Chemical-related parameters
- (2)
- Cell-, media-, and labware-related parameters
2.1.4. Model Assumptions, Execution, and Evaluation
2.2. Sensitivity Analysis
2.3. Chemical Distribution Model Application: Assessing In Vitro–In Vivo Concordance of PODs
3. Results
3.1. Comparing Performance of Four In Vitro Mass Balance Models
3.2. Determining the Impact of Input Parameters on In Vitro Bioavailability Predictions
3.3. Model Application: Effects of In Vitro Bioavailability Adjustment on In Vitro–In Vivo Concordance of POD Estimations
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
QIVIVE | Quantitative In Vitro to In Vivo Extrapolation |
Tox21 | Toxicity Testing in the 21st Century |
HTS | High-Throughput Screening |
BED | Biologically Effective Dose |
PBK | Physiologically Based Kinetics |
iPSCs | Induced Pluripotent Stem Cells |
POD | Point of Departure |
IOC | Ionizable Organic Chemical |
PFAS | Per- and Polyfluoroalkyl Substances |
PBDEs | Polybrominated Diphenyl Ethers |
PRH | Primary Rat Hepatocyte |
PHH | Primary Human Hepatocyte |
RED | Rapid Equilibrium Dialysis |
FBS | Fetal Bovine Serum |
CERAPP | Collaborative Estrogen Receptor Activity Prediction Project |
PCA | Principal Component Analysis |
MAE | Mean Absolute Error |
ME | Mean Error |
MW | Molecular Weight |
MP | Melting Point |
OED | Oral Equivalent Dose |
iTTC | Internal Threshold of Toxicological Concern |
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Model Reference | Applicable In Vitro System | Applicable Chemicals | Model Type | Partitioning Included a | Other Factors/ Processes | |||
---|---|---|---|---|---|---|---|---|
Media | Cell | Lab-Ware | Head-Space | |||||
Fischer et al. [22] | Generic | Neutral/ionized; Non-volatile | Equilibrium partitioning model | √ | √ (protein and lipid) | |||
Armitage et al. [19] | Generic; culture media with serum and monolayer cell | Neutral/ionized; Non-volatile/volatile | Equilibrium partitioning model | √ | √ | √ | √ | Solubility |
Fisher et al. [16] | Generic | Neutral/ionized; Non-volatile/volatile | Time-dependent model | √ | √ (protein, lipid, lysosome and mitochondria) | √ | √ | Metabolism |
Zaldivar-Comenges et al. [23] | Generic | Neutral; Non-volatile/volatile | Time-dependent model | √ | √ (protein, lipid and mitochondria) | √ | √ | Evaporation; abiotic degradation; cell growth |
Parameters (Abbreviation) [Unit] | Model | |||
---|---|---|---|---|
Fischer et al. [22] | Armitage et al. [19] | Fisher et al. [16] | Zaldivar-Comenges et al. [23] | |
Molecular weight (MW) | √ | √ | √ | |
Melting point (MP) [°C] | √ | √ | ||
Octanol–water partition coefficient (log KOW) | √ a | √ | √ | √ |
Air–water partition coefficient (log KAW) | √ | √ | ||
Solubility (CSAT,W) [mg/L] | √ | |||
Salting-out constant (Ksalt) | √ b | |||
pKa | √ a | √ | √ | |
IOC type | √ | √ | ||
Henry’s constant at 37 °C (H37) [Pa × m3/mol] | √ | |||
Molecular volume (Vb) | √ | |||
Distribution ratio at pH 7.4 between bovine serum albumin (BSA) and water (log DBSA/w) | √ a | |||
Distribution ratio at pH 7.4 between phospho-lipid liposomes (lip) and water (log Dlip/w) | √ a |
Dataset | Chemical (s) a | Cell Type (s) b | Endpoint Measurement |
---|---|---|---|
Ratio of free to nominal concentration | |||
Huchthausen et al. [24] | Neutral and IOC (n = 12) | MCF7, HEK293H | Measured freely dissolved IC10 conc., then obtain ratio |
Tanneberger et al. [25] | Neutral and IOC (n = 27) | Fish RTgill-W1 | Ratio of conc. in medium at the end and beginning of experiments (C24h/C0h) |
Schug et al. [26] | Neutral organics (n = 9) | Fish RTgutGC | Ratio of conc. in medium at the end and beginning of experiments (C24h/C0h) |
Nicol et al. [27] | Neutral and IOC (n = 30) | No cell | Ratio of conc. in buffer and in total matrix. These measurements were performed using a Rapid Equilibrium Dialysis (RED) plate |
Valdiviezo et al. [28] | Pesticides (n = 20) | No cell | Ratio of response ratios measured from free media and initial exposure media |
Blanchette et al. [29] | Neutral and IOC (n = 30) | No cell | Ratio of response ratios measured from free media and initial exposure media |
This study | PFAS (n = 14) | No cell | Ratio of response ratios measured from free media and initial exposure media |
Amount of chemicals in media and/or cells | |||
Bellwon et al. [30] | Cyclosporine A (n = 1) | PRH, PHH, HepaRG | Measured chemical amount in cell lysate and media at multiple timepoint (≤24 h) |
Broeders et al. [31] | Chlorpromazine (n = 1) | Balb/c 3T3, Caco-2, HepaRG | Measured chemical distribution % in cells and medium at 48 h (Balb/c 3T3 and Caco-2 cells) or 72 h (HepaRG cells) |
Broeders et al. [32] | Chlorpromazine (n = 1) | PRH, PHH, HepaRG | Measured chemical amount in cell lysate and media at multiple timepoint (≤24 h) |
Kodavanti et al. [33] | PBDEs (n = 3) | Rat cerebellar granule cell | Measured chemical amount in cell lysate at multiple timepoint (≤24 h) |
Pomponio et al. [34] | Amiodarone (n = 1) | PHH, HepaRG | Measured chemical amount in cell lysate at multiple timepoint (≤24 h) |
Truisi et al. [35] | Ibuprofen (n = 1) | PRH, PHH, HepaRG | Measured chemical amount in cell lysate and media at multiple timepoint (≤24 h) |
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Lin, H.-C.; Ford, L.C.; Rusyn, I.; Chiu, W.A. Comparative Analysis of Chemical Distribution Models for Quantitative In Vitro to In Vivo Extrapolation. Toxics 2025, 13, 439. https://doi.org/10.3390/toxics13060439
Lin H-C, Ford LC, Rusyn I, Chiu WA. Comparative Analysis of Chemical Distribution Models for Quantitative In Vitro to In Vivo Extrapolation. Toxics. 2025; 13(6):439. https://doi.org/10.3390/toxics13060439
Chicago/Turabian StyleLin, Hsing-Chieh, Lucie C. Ford, Ivan Rusyn, and Weihsueh A. Chiu. 2025. "Comparative Analysis of Chemical Distribution Models for Quantitative In Vitro to In Vivo Extrapolation" Toxics 13, no. 6: 439. https://doi.org/10.3390/toxics13060439
APA StyleLin, H.-C., Ford, L. C., Rusyn, I., & Chiu, W. A. (2025). Comparative Analysis of Chemical Distribution Models for Quantitative In Vitro to In Vivo Extrapolation. Toxics, 13(6), 439. https://doi.org/10.3390/toxics13060439