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Cited by 34Animal testing and alternativesCarcinogens and Genotoxicity AssessmentComputational Drug Discovery Methods

Toward Realistic Dosimetry In Vitro: Determining Effective Concentrations of Test Substances in Cell Culture and Their Prediction by an In Silico Mass Balance Model

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Dimitrijevic, Dunja, Fabian, Eric, Nicol, Beate, Funk-Weyer, Dorothee, Landsiedel, Robert·2022·Chemical Research in Toxicology
DOI 10.1021/acs.chemrestox.2c00128PMC PMC9682521
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Abstract

Nominal concentrations (C Nom ) in cell culture media are routinely used to define concentration-effect relationships in the in vitro toxicology.The actual concentration in the medium (C Medium ) can be affected by adsorption processes, evaporation, or degradation of chemicals.Therefore, we measured the total and free concentration of 12 chemicals, covering a wide range of lipophilicity (log K OW -0.07-6.84), in the culture medium (C Medium ) and cells (C Cell ) after incubation with Balb/c 3T3 cells for up to 48 h.Measured values were compared to predictions using an as yet unpublished in silico mass balance model that combined relevant equations from similar models published by others.The total C Medium for all chemicals except tamoxifen (TAM) were similar to the C Nom .This was attributed to the cellular uptake of TAM and accumulation into lysosomes.The free (i.e., unbound) C Medium for the low/no protein binding chemicals were similar to the C Nom , whereas values of all moderately to highly protein-bound chemicals were less than 30% of the C Nom .Of the 12 chemicals, the two most hydrophilic chemicals, acetaminophen (APAP) and caffeine (CAF), were the only ones for which the C Cell was the same as the C Nom .The C Cell for all other chemicals tended to increase over time and were all 2-to 274-fold higher than C Nom .Measurements of C Cytosol , using a digitonin method to release cytosol, compared well with C Cell (using a freezethaw method) for four chemicals (CAF, APAP, FLU, and KET), indicating that both methods could be used.The mass balance model predicted the total C Medium within 30% of the measured values for 11 chemicals.The free C Medium of all 12 chemicals were predicted within 3-fold of the measured values.There was a poorer prediction of C Cell values, with a median overprediction of 3-to 4-fold.In conclusion, while the number of chemicals in the study is limited, it demonstrates the large differences between C Nom and total and free C Medium and C Cell , which were also relatively well predicted by the mass balance model.

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Cited by

Sorted by citations

Authors
Dimitrijevic, D., Fabian, E., Nicol, B., Funk-Weyer, D., & Landsiedel, R.
Affiliations
  • Freie Universität Berlin (DE)
  • BASF (Germany) (DE)
  • Unilever (United Kingdom) (GB)
Corresponding author
Landsiedel, Robert
ORCID
Venue
Chemical Research in Toxicology
Publisher
American Chemical Society (ACS)
Published
2022-10-20
Volume
35
Issue
11
Pages
1962-1973
ISSN
  • 0893-228X (ISSN-L)
  • 1520-5010
DOI
10.1021/acs.chemrestox.2c00128
PMC
PMC9682521
OpenAlex
W4306897087
Cited by
34
References
0
Citations by year
2026: 15 · 2025: 9 · 2024: 5 · 2023: 5
FWCI
5.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Chemical Research in Toxicology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by-nc-nd)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver
Funders
BASF
Topics
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords
in vitro dosimetry, effective concentration, cell culture, mass balance model, in silico prediction, chemical toxicity testing
MeSH terms
Acetaminophen, Animals, Protein Binding, Cell Culture Techniques, Mice, Hydrophobic and Hydrophilic Interactions

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