Generalized concentration addition for ligands that bind to homodimers.

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.