Toxicity of Methyl- and Halogen-Substituted Alcohols in Tissue Culture Relative to Structure–Activity Models and Acute Toxicity in Mice

Abstract

The relationship of in vitro and in vivo toxicity of a series of methyl- and halogen-substituted alcohols was examined with respect to their octanol-water partition coefficients (P), charge (Q), and steric (Es) parameters. A high correlation (r = 0.98) was found between tissue culture toxicity (ID50, the concentration required to produce 50% inhibition of growth) and hemolytic activity (H50, the concentration required to produce 50% hemolysis in saline, 37°). The product of intrinsic toxicity (Ti, the slope of the dose-response curve in tissue culture) and 1/P for aliphatic alcohols was found to have a uniform relationship to acute in vivo toxicity (LD50, the single intraperitoneal dose required to kill 50% of the mice in 7 days). The Ti/P to LD50 ratio showed a fourfold variation as compared to a 164-fold variation for the Ti/LD50 ratio. This relationship supported the conclusions that Ti from tissue culture was a valid, time-independent estimate of the toxicant-receptor interaction and that 1/P was directly related to the effective aqueous concentration of the toxicants in vivo. The Ti/P to LD50 ratio was higher for the halogenated than for the aliphatic alcohols, which suggested a difference in mechanism of the toxicant-receptor interaction. Hansch analysis showed both Q and Es parameters to be important to the differential intrinsic toxicities of the two groups. Both Free-Wilson and Hansch-Fujita analyses supported the conclusion that the tissue culture system conforms closely to the Higuchi-Davis equilibrium model. The usefulness of the tissue culture assay in conjunction with P for the analysis and prediction of in vivo toxicity was demonstrated.