Mechanisms of action for general and polar narcosis: A difference in dimension



There are currently two schools of thought surrounding the existence of polar and non-polar narcosis mechanisms in aquatic toxicity. Some authors argue that there is a real distinction between the two modes of action but recently support has grown for the suggestion that there may be no real difference and that the apparent distinction disappears when membrane/water partition ceofficients Kmw are used, and has arisen purely because the octanol/water partition coefficient P is in fact an inadequate descriptor of partitioning into a lipid membrane. In this paper the evidence is analysed and it is concluded that although practically useful QSARs covering both general and polar narcotics can be developed based on log Kmw, there is nevertheless a real mechanistic difference between general and polar narcosis, which manifests itself by: significantly different QSARs, even when based on log Kmw, for general and polar narcotics treated separately; differences in FATS; non-additivity between general narcotics and polar narcotics in mixture toxicity studies. We propose that this difference is based on a difference in physical chemistry, general narcotics acting via 3-D partition (able to move in all directions in the hydrocarbon-like interior of the membrane) and polar narcotics acting via 2-D partition (involving binding between a functional group on the narcotic and the polar phosphatidyl choline head groups at the membrane surface). Based on this hypothesis a mathematical model is derived which can explain: why log P based QSARs covering diverse general narcotics are of statistically better quality than log P based QSARs covering diverse polar narcotics; why the slopes of log P based QSARs are larger for general narcosis than for polar narcosis: why the intercepts of log P based QSARs are larger for polar narcotics than for general narcotics; why some chemicals show additive toxicity both with general and polar narcotics.