IA is the appropriate conceptual assumption for predicting the joint toxicity of mixtures composed of substances with dissimilar modes of toxic action [8, 20], while the CA prediction will often overestimate the toxicity for such mixtures [4, 9, 21, 22].
Such feature is highlighted by the interactions of TTR with diclofenac, a compound with high affinity for TTR, in two dissimilar modes, as evidenced by crystal structure of the complex.
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.
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].
If IA is considered due to dissimilar modes or mechanisms of action of the ingredients, it should be checked prior to any experimental work whether the actual mixture ratio allows for the possibility that IA might indeed lead to a different regulatory outcome of the assessment, see discussion by Backhaus and Faust,[22].
Is the same true for mixtures composed of chemicals with dissimilar modes of action?
Experimental results also indicated that integration of pathway structure information with gene differential expression analysis can identify dissimilar modes of gene reactions between chemosensitivity and chemoresistance.
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).
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.
