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

1973; Elsevier BV; Volume: 62; Issue: 1 Linguagem: Inglês

10.1002/jps.2600620103

1520-6017

Elwood O. Dillingham, Richard Mast, George E. Bass, John Autian,

Essential Oils and Antimicrobial Activity

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 ( E s ) parameters. A high correlation ( r = 0.98) was found between tissue culture toxicity (ID 50 , the concentration required to produce 50% inhibition of growth) and hemolytic activity (H 50 , the concentration required to produce 50% hemolysis in saline, 37°). The product of intrinsic toxicity ( T i , 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 (LD 50 , the single intraperitoneal dose required to kill 50% of the mice in 7 days). The T i /P to LD 50 ratio showed a fourfold variation as compared to a 164-fold variation for the T i /LD 50 ratio. This relationship supported the conclusions that T i 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 T i /P to LD 50 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 E s 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.