AbstractA historic account is provided of the development of quantitative structure‒activity relationships (QSARs) for the toxicity of simple nonelectrolyte organic compounds. The aquatic toxicity of many such compounds has been shown to be consistent with a narcosis mechanism involving pseudo‒steady‒state partitioning into a lipoidlike biophase site of action. These data are well fitted to a linear QSAR model involving solely the logPparameter.The toxicity of such nonelectrolytes administered by inhalation yields a linear QSAR based on the oil/gas partition coefficient. In contrast, the toxicity of these substances produced by nonequilibrium routes of administration, such as rat oral LD50, yields a parabolic or bilinear relationship consistent with observations published by Cros in France in 1863. Electrophile toxicants capable of forming covalent adducts with biochemical target molecules are more toxic than predicted by the corresponding narcosis models. Proelectrophile toxicants, which require metabolic activation to electrophiles, are also more toxic than would be predicted by narcosis