Structure-toxicity relationships for the effects to Tetrahymena pyriformis of aliphatic, carbonyl-containing, alpha,beta-unsaturated chemicals.

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.

• Authors: T Wayne Schultz, Tatiana I Netzeva, David W Roberts, Mark T D Cronin
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 18 Issue 2 Pg. 330-41 (Feb 2005) ISSN: 0893-228X [Print] United States
• PMID: 15720140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Organic Chemicals
• Carbon

Topics

• Animals
• Carbon (chemistry)
• Organic Chemicals (chemistry, toxicity)
• Regression Analysis
• Structure-Activity Relationship
• Tetrahymena pyriformis (drug effects, growth & development)
• Toxicity Tests