Schultz, T.W.; Sinks, G.D.; Cronin, M.T.D. Identification of Mechanisms of Toxic Action of Phenols to Tetrahymena pyriformis from Molecular Descriptors. In Quantitative Structure-Activity Relationships in Environmental Sciences; Chen, F.; Schüürmann, G., Eds.; SETAC Press; 1997.

Abstract

Toxicity data (log IGC50(-1)) for 198 phenols were obtained from the TETRATOX database. Based on·a series of 2-dimensional (2D) structural rules, mechanisms of toxic action (MOA) were assigned and a 3-dimensional (3D) toxic response surface evaluated. Log IGC50(-1) along with the distribution coefficient (log D) and the molecular orbital property, the lowest unoccupied molecular orbital energy (E(LUMO)), provide the axes for the toxic response surface. The toxicity of the weak acid respiratory uncouplers, soft electrophiles, pro-electrophiles, and pro- redox cyclers are all in excess of the toxicity of the polar narcotics. Based on E(LUMO), there was a separation of phenols according to MOA. The weak acid respiratory uncouplers were in 1 broad window of E(LUMO) values less than -1.0. The soft electrophiles were also observed in 1 broad window of E(LUMO) values ranging from -0.75 to -1.6. Moreover. they exhibited E(LUMO) values that overlapped those for the weak acid respiratory uncouplers. The pro-electrophiles were in 1 broad window with E(LUMO) values ranging from -0.25 to 0.6. The majority of these overlapped the E(LUMO) values of the least bioreactive polar narcotics. The polar narcotics had E(LUMO) values of -0.9 to 0.6. The polar narcotics separated into 3 narrower zones: > 0.1, -0.1 to 0.1, and -0.9 to -0.1. In conjunction with simple structural rules, this hydrophobicity/bioreactivity response surface is a useful method to assign MOA.