Mixture toxicity and its modeling by quantitative structure-activity relationships

Abstract

Environmental contaminants are frequently encountered as mixtures, and the behavior of chemicals in a mixture may not correspond to that predicted from data on the pure compounds. This paper reviews current quantitative structure-activity relationship (QSAR) methodology for the analysis of mixture toxicity. Interactions of components in a mixture can cause complex and substantial changes in the apparent properties of its constituents, resulting in synergistic or antagonistic effects as opposed to the ideal reference case of additive behavior: concentration addition (CA) and independent action (IA) are two prominent reference models for the evaluation of joint activity, and both have mechanistic support from pharmacology. After discussing graphical tools for analyzing binary mixtures and joint effect indices suitable also for multicomponent mixtures, water solubility and hydrophobicity of mixtures are analyzed with respect to the property contributions of the individual components. With the former, small but significant deviations from ideal behavior are observed even for simple organics, whereas in the case of low concentrations, mixture hydrophobicity was found to agree approximately with the fractional contributions of the components. A variety of studies suggest that mixtures of compounds exerting only one (narcotic or specific) mode of action can be modeled satisfactorily by assuming CA, whereas the interaction of differently acting compounds tends to yield a less than CA joint activity. The QSARs have been used to predict concentrations of components in mixtures from joint effects and defined mixture ratios and have been developed to predict narcotic-type mixture toxicity from molecular descriptors that are calculated as composite properties according to the fractional concentrations of the mixture components. In the case of ionogenic compounds, initial results suggest that CA may serve as a first-order approximation for the joint effect of un-ionized and ionized compound portions.