Structure−Toxicity Relationships for Benzenes Evaluated with Tetrahymena pyriformis

Abstract

Toxicity data for 200 substituted benzenes tested in the two-day Tetrahymena pyriformis population growth impairment assay representing the neutral narcosis, polar narcosis, respiratory uncoupling, and weak and strong electrophilic mechanisms of toxic action were evaluated. A quantitative structure−toxicity model correlating toxic potency [log(IGC₅₀^-1)] with hydrophobicity quantified by the 1-octanol/water partition coefficient (log K_ow) and electrophilic reactivity quantified by the molecular orbital parameter, maximum superdelocalizability (S_max), was developed. This model [log(IGC₅₀^-1) = 0.50(log K_ow) + 9.85(S_max) − 3.47; n = 197, r² = 0.816, s = 0.34, F = 429, Pr > F = 0.0001] allows for the prediction of acute potency without the a priori identification of the mechanism of action. The examination of residuals reveals that neutral narcotics with high volatility (e.g., methyl- and chloro-substituted benzenes) and highly reactive fluoro- and nitro-containing derivatives are fitted poorly. A comparison of observed (obs) and predicted (pred) toxicities on the additional set of derivatives [log(obs IGC₅₀^-1) = 1.05[log(pred IGC₅₀^-1)] + 0.02; n = 20, r² = 0.979, s = 0.13, F = 825, Pr > F = 0.0001] validated the model as a good predictor of toxicity regardless of the mechanism of toxic action.