Structure‐activity relationships for Pimephales and Tetrahymena: A mechanism of action approach

Abstract

AbstractThe toxicity data of 74 chemicals tested in both the 96‐h fathead minnow (Pimephales promelas) mortality assay and the 2‐d Tetrahymena pyriformis (a protozoan) growth inhibition assay were evaluated using quantitative structure‐activity relationships (QSARs). Each chemical was a priori assigned a mechanism of acute toxic action from either nonpolar narcosis, polar narcosis, weak acid respiratory uncoupling, soft electrophilicity, or proelectrophilicity. The polar narcotics were further split into a phenol group and an aniline group. The relationship between bioreactivity and the importance of penetration to the site of action in both systems was studied. Bioreactivity showed a trend to be inversely proportional to the value of the hydrophobicity term. The data were examined to investigate how different molecular descriptors modeled the mechanisms of action. Models were produced for nonpolar narcotics and anilines for both species with the 1‐octanol/water partition coefficient (log Kow) alone. Soft electrophiles were best predicted by the average acceptor superdelocalizability (Snav), whereas proelectrophiles were modeled by log Kow and Snav. The weak acid uncouplers modeled with either log Kow or log Kow plus the ionization constant (pKa) for Pimephales and Tetrahymena, respectively. Phenols yielded predictive models using a either a combination of log Kow with Snav or lowest unoccupied molecular orbital, for fathead minnow and protozoan, respectively.