Response-Surface Analyses for Toxicity to Tetrahymena pyriformis:  Reactive Carbonyl-Containing Aliphatic Chemicals

Abstract

A response-plane has been developed with Tetrahymena pyriformis population growth impairment toxicity data [log 1/50% growth inhibitory concentration (IGC50)], the 1-octanol/water partition coefficient (log Kow), and the energy of the lowest unoccupied molecular orbital (Elumo). A statistically robust plane [log 1/IGC50 = 0.530 (log Kow) -0.890 (Elumo) -0.271, n = 50, s = 0.295, r2 = 0.855, F = 145] was found for reactive carbonyl-containing aliphatic chemicals. These compounds had a variety of electrophilic mechanisms of action and included aldehydes acting as Schiff-base formers, alpha,beta-unsaturated aldehydes and alpha,beta-unsaturated ketones acting as Michael-type acceptors, and selected alpha-diones acting as selective binders to arganine residues; gamma-diones acting as selective binders to tubulin; and beta-diones with unknown mechanisms of action. Outliers to this model broadly fell into two groups: small reactive molecules (e.g., acrolein) that were more toxic than predicted and molecules in which the reactive center was sterically hindered by an alkyl group (e.g., 2,4-dimethyl-2,6-heptadienal) that were less toxic than predicted.

Interpretation of QSAR Models: Mining Structural Patterns Taking into Account Molecular Context

“…Modeling of acute aquatic toxicological endpoints has a long history and is based on the premise that toxicity is governed by the ability of a chemical to reach the active site (e. g. the cellular membrane) and its ability to interact there . In this context transport has usually been quantified by descriptors for hydrophobicity and interaction by descriptors for electrophilicity or more specific interaction such as receptor binding . Many QSAR models for acute aquatic toxicity have been developed on a mechanistic basis, currently more commonly referred to through Adverse Outcome Pathways …”

“…In this context transport has usually been quantified by descriptors for hydrophobicity and interaction by descriptors for electrophilicity or more specific interaction such as receptor binding . Many QSAR models for acute aquatic toxicity have been developed on a mechanistic basis, currently more commonly referred to through Adverse Outcome Pathways …”

Consensus QSAR Related to Global or MOA Models: Application to Acute Toxicity for Fish

“…Among them, α , β ‐unsaturated aldehydes such as chemical 5 (acrolein or prop‐2‐en‐1‐al) are systematic outliers in several QSAR studies 43. 44 The toxic potency of acrolein, mediated by a Michael addition toward nucleophiles, is very high and often underestimated. Chemical 4 , crotonaldehyde (but‐2‐en‐1‐al), have the same kind of reactivity than acrolein.…”

Structure-activity relationships for aquatic toxicity toTetrahymena: Halogen-substituted aliphatic esters

“…alkanitriles Akers et al, 1999 suggested that haloesters have the potential to exhibit toxicity in excess of base-Ž . line narcosis Schultz and Cronin, 1999 .…”