Reactivity and aquatic toxicity of aromatic compounds transformable to quinone-type Michael acceptors

Abstract

Reactive toxicity encompasses important endpoints such as skin and respiratory sensitization, hepatotoxicity and elevated acute aquatic toxicity. These adverse effects are initiated by, among others, electrophilic chemicals and those transformed into electrophiles; i.e. non-reactive chemicals activated into reactive electrophilic species by either a biotransformation (pro-electrophiles) or abiotic mechanism (pre-electrophiles). The presence of pro- and pre-electrophiles is important when developing quantitative structure–activity relationships (QSARs). In this study, the reactivity of potential pre-electrophile polyphenolics was investigated using an in chemico assay based on glutathione (GSH) depletion; in addition, the toxicity to Tetrahymena pyriformis was determined. For pre-electrophiles, no direct relationship between toxic potency and reactivity to GSH was obtained. The structural determinants for the pre-electrophile domain were characterized qualitatively by assessing structure–activity relationships (SARs). From this analysis, structural alerts for the pre-Michael acceptor domain (i.e. non-reactive chemicals activated into Michael acceptors) were extracted from the in chemico GSH data. A series of 10 structural alerts corresponding to 1,2- and 1,4-hydroxy and amino-substituted aromatics was developed. The relevance of the alerts was assessed by investigating the aquatic toxicity of these compounds. The structural alerts should help to identify and group pre-Michael acceptors and thus potent reactive toxicants.

Keywords:

• in chemico
• in silico
• structural alerts
• pre-electrophiles
• pre-Michael acceptors
• toxicity

Acknowledgements

This project was sponsored by Defra through the Sustainable Arable Link Programme. Gratitude is expressed to Frank T. Metelka and Cassie L. Sprafkin for their assistance in conducting the reactivity and toxicity experiments.