Can mode of action predict mixture toxicity for risk assessment?

Recent regulatory guidance for mixture risk assessments and for regulating pesticide chemicals recommends using information about the "mode" or "mechanism" of action of individual chemicals to predict dose response characteristics of mixtures. Dose addition is assumed for mixtures of chemicals that have similar mechanisms and response addition for those with dissimilar mechanisms. Three different sets of criteria have been formulated to guide the selection of an appropriate data set for characterizing a chemical's mode of action, but the sufficiency of those criteria to predict dose addition for a mixture has not been validated experimentally. Several examples from the pharmacological and toxicological literature challenge the premise that dose response characteristics of a mixture can be predicted from the modes of action of its components. Detoxification pathways may need to be understood before dose addition in the observable effect range can be extrapolated to mixture concentrations below the no observable effect levels of the mixture components. Because elucidating discreet mechanisms of action may be possible only for chemicals that exhibit a high degree of biological specificity and dose sensitivity, practical limitations on the approach must be defined. To reduce the large uncertainties inherent in the recommended approach, future research should be focused on defining the mechanistic features that predict dose additive toxicity in mixtures. A detailed characterization of pharmacodynamics, pharmacokinetics, and slope of dose response curves may be necessary to evaluate whether the toxicity of a mixture can be predicted by the mode of action of its component chemicals.