Kainic acid (or kainate) is an agonist of glutamate, one excitatory neurotransmitter of the central nervous system. KA has neuroexcitotoxic and epileptogenic effects and has been developed as the gold standard neuroexcitatory amino acid for the induction of seizures and the study of neurodegenerative diseases in experimental animals

(Moloney, 2002 and see for review Vincent and Mulle, 2009). Its effect on neuronal activity and the mechanism of action have been well described both in vivo and in vitro ( Vincent and Mulle, 2009). Together with MUS it provides a good combination for a binary mixture where the two compounds exert opposite effects. With our set of data the prediction of the mixture’s toxicity can be made with comparable efficacy by both the CA and Autophagy activator IA additive models and the predicted IC50s are lower compared to the ones obtained with fitted experimental data. We employed two of the most widely used pesticides, PER and DEL, to model a mixture whose components act with the same mode of action. The primary target site of pyrethroid pesticides is the voltage-dependent sodium channel in excitable membranes. The interaction of pyrethroids with the sensitive fraction of the sodium channels results in a prolongation of the inward sodium current during excitation, buy Crizotinib which subsequently results in a pronounced repetitive activity, both in nerve fibers and

terminals. Besides repetitive firing, membrane depolarization results in enhanced neurotransmitter

release and eventually blocking of excitation (Vijverberg and van den Bercken, 1990) leading to paralysis and death. Concerning the mixtures with PER and DEL the results show that the IC50 obtained with the CA and IA models are quite similar when compared with the experimental variability, hence it is not possible to conclude that CA produces better results as one could expect for this kind of mixture. The same is also true for the other binary mixtures where one would expect better predictions using IA. A recent published work (Qin et al., 2011) proposes an PTK6 alternative approach where CA and IA are integrated through multiple linear regression (ICIM). By using two training sets of chemicals, the study demonstrates that, when the CA and IA models deviate from the concentration–response data of the mixtures, the ICIM approach has a better predictive power. It would be worth exploring the ICIM approach with the binary mixtures used in this work. Our combined approach has demonstrated that neurotoxicity of mixtures can be predicted by additivity at least for the binary mixtures analyzed and that MFR is a parameter which can be fitted with the CA and IA models. Neuronal activity is the primary functional output of the nervous system and deviations from its physiological level often result in adverse behavioral or physiological function. A compound is considered to be potentially neurotoxic when it affects an endpoint specific of neurons (i.e.