Schultz, T.W.; Netzeva, T.I.; Roberts, D.W.; Cronin, M.T.D. Structure-Toxicity Relationships for the Effects to Tetrahymena pyriformis of Aliphatic, Carbonyl-Containing, α,β-Unsaturated Chemicals. Chem. Res. Toxicol. 2005, 18, 2, 330–341.

Abstract

Toxicity data for 82 aliphatic chemicals with an alpha,beta-unsaturated substructure were compiled. Toxicity was assessed in the 2-day Tetrahymena pyriformis population growth impairment assay. Toxic potency [log(IGC50(-1))] for most of these chemicals was in excess of baseline narcosis as quantified by the 1-octanol/water partition coefficient (log K(ow)). The toxicity of the alpha,beta-unsaturated aldehydes was modeled well by log K(ow) in conjunction with the sum of partial charges on the vinylene carbon atoms (Q(C4) + Q(C3)) and the energy of the lowest unoccupied molecular orbital (E(lumo)). These electronic descriptors were also successful at modeling the toxicity of alpha,beta-unsaturated ketones. The toxicity of a range of acrylates was constant within about 0.2 of a log unit. Conversely, the toxicity of methacrylates and esters containing the vinylene group varied considerably and was explained by their hydrophobicity. The comparison of the quantitative structure-activity relationship (QSAR) for the methacrylates and esters with that for non-polar narcosis showed little significant difference and hence suggested that substitution on the carbon-carbon double bond in the methacrylates and vinylene unsaturated esters does not enhance toxicity over that of baseline. Substitution on the carbon-carbon double bond in the alpha,beta-unsaturated aldehydes resulted in toxicity that was similar to that for saturated derivatives. Although an excellent hydrophobicity-dependent QSAR was developed for the esters containing ethynylene group, these compounds are considered to act as Michael-type acceptors. Attempts to combine different groups of Michael-type acceptors into a single QSAR, based on mechanistically derived descriptors, were unsuccessful. Thus, the modeling of the toxicity of the alpha,beta-unsaturated carbonyl domain is currently limited to models for narrow subdomains.