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Generalized concentration addition for ligands that bind to homodimers.

Authors
  • Webster, Thomas F1
  • Schlezinger, Jennifer J2
  • 1 Department of Environmental Health, Boston University School of Public Health, 715 Albany Street, Boston, MA 02118, USA. Electronic address: [email protected]
  • 2 Department of Environmental Health, Boston University School of Public Health, 715 Albany Street, Boston, MA 02118, USA.
Type
Published Article
Journal
Mathematical biosciences
Publication Date
Oct 01, 2019
Volume
316
Pages
108214–108214
Identifiers
DOI: 10.1016/j.mbs.2019.108214
PMID: 31201847
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Concentration addition/dose addition (CA) has proved to be a powerful tool for estimating the combined effect of mixtures that act by similar mechanisms. We earlier proposed generalized concentration addition (GCA) to deal with the inability of CA to estimate effects of mixtures above the level of the least efficacious component. GCA requires specifying mathematical concentration response functions for each mixture component that must be invertible, yielding real numbers. We construct concentration response functions using pharmacodynamic models of ligand-receptor interaction, an important molecular initiating event for adverse outcome pathways. Here, we extend our earlier work in two novel ways. First, we show how composite functions can be used to extend these predictions to downstream events. Second, we show that GCA can accommodate not only receptors with single binding sites but also receptors that bind ligand at each monomer and then dimerize. The derived concentration response functions for receptors that homodimerize meet the requirements for using GCA. Copyright © 2019 Elsevier Inc. All rights reserved.

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