Where mixtures are made up of chemicals thought to have dissimilar modes-of-action, mixture toxicology theory predicts that the mixture will be without effect provided that all its constituents can be shown to have no effect individually.
Drugs with different modes-of-action, potencies, and potential for off-target effects may have dissimilar effects on gene expression under these reported experimental conditions.
Two basic concepts have been established for predicting additive joint effects based on the known toxicity of the individual mixture components: the concept of concentration addition (CA) for mixtures of substances with similar modes of actions and the concept of independent action (IA, also called response addition) for mixtures of substances with dissimilar modes of action [7, 10, 11].
The classification of similar and dissimilar modes of action as applied in the present study relates to the pesticidal mode of action of the a.s., hence to the specific toxicity towards the target organisms based on the known molecular target and the development of cross-resistances in target organisms.
Is the same true for mixtures composed of chemicals with dissimilar modes of action?
In these cases, independent action has been generally assumed for substances believed to cause toxicity through dissimilar modes of action (ATSDR, 2001a, b; USEPA, 2000).
A probabilistic method to evaluate multiple simultaneous exposures to chemicals acting by similar and dissimilar modes of action has been developed (NRC, 2004).
From the results, we conclude that differences in response of physiological variables to two anesthetics of dissimilar modes of action, one inhalant and one injectable, do not account for differences of radioligand binding to neuroreceptors in the central nervous system.
Similarly, The European Food Safety Authority Panel on Plant Protection Products and their Residues (PPR Panel) produced a scientific opinion on the relevance of dissimilar modes of action and their relevance for cumulative risk assessment of pesticides residues in food (482).
The PPR Panel found good evidence that combination effects can arise from co-exposure to chemicals that produce common (adverse) outcomes through entirely different modes of action and recommended cumulative risk assessment methods to evaluate mixtures of pesticides in foods that have dissimilar modes of action (396).
