Development of a Multi-Component Damage Assessment Model (MDAM) for Time-Dependent Mixture Toxicity with Toxicokinetic Interactions

A new mixture toxicity model was developed to predict the time-dependent toxicity of a mixture with toxicokinetic interactions directed specifically toward addressing biotransformation. The Damage Assessment Model (DAM), a toxicokinetic-toxicodynamic model that describes and predicts the time-dependent toxicity of a single compound, was extended to a multicomponent model for mixture toxicity. The model assumes that cumulative damage from the parent compound, metabolites, and/or a biotransformation inhibitor are additive, and the sum of the cumulative damage determines mixture toxicity. Since incorporation of the damage addition hypothesis into the DAM was equivalent to an independent action model for mixture toxicity, it was applied to describe the combined effect of mixture components with potentially dissimilar modes of action. From the multicomponent DAM, a time-dependent toxic unit model was derived and applied to determine the toxic units of mixture components. This model suggests a series of experimental designs required to assess the role of biotransformation in the toxicity of metabolized organic compounds and a data analysis method to separately estimate toxicodynamic parameters forthe parent compound and metabolites.