Chemoavailability of Organic Electrophiles: Impact of Hydrophobicity and Reactivity on Their Aquatic Excess Toxicity.
Organic electrophiles have been recognized as important components of the exposome that can be characterized as cumulative totality of exposure in the organism in response to environmental perturbation. For such compounds, chemical reactivity may contribute significantly to the toxicological profile through covalent attacks at nucleophilic sites of peptides such as glutathione (GSH), proteins, lipid components, and the DNA and RNA. Employing a Michael acceptor set of 58 α,β-unsaturated carbonyls with 15 ketones, 18 aldehydes, and 25 esters, the hydrophobicity and reactivity contributions to their toxicity enhancement Te over baseline narcosis with the ciliates Tetrahymena pyriformis is analyzed through a conceptual model, featuring toxicokinetic phase transfer steps and the reactive molecular initiating event (MIE) at endogenous target sites exposed to water-rich or water-poor compartments. To this end, hydrophobicity was quantified by the octanol/water partition coefficient, Kow, electrophilic reactivity through second-order rate constants of reaction with GSH in a kinetic chemoassay, kGSH, and Te as the ratio of narcosis-level vs experimental concentration yielding 50% growth inhibition of the ciliates within 48 h of exposure. The observed decrease of log Te with increasing log Kow can be traced back to a rate-determining impact of the toxicant transfer from the membrane to the intracellular cytosol. Moreover, the recently introduced concept of chemoavailability is shown to enable, from knowledge of log Kow and log kGSH alone, a screening-level discrimination between reactive and hydrophobic MIEs triggering predominantly alone or in parallel respective adverse outcome pathways (AOPs) including the diffusion-control limit of reactive MIE saturation. As such, chemoavailability may aid in evaluating prevalent MIEs expected for a given organic electrophile and in assessing its toxicological profile within AOP schemes addressing aquatic toxicity.
UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research , Permoserstr. 15, 04318 Leipzig, Germany.
Alexander
A
Böhme
UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research , Permoserstr. 15, 04318 Leipzig, Germany.|Institute for Organic Chemistry, Technical University Bergakademie Freiberg , Leipziger Str. 29, 09596 Freiberg, Germany.
Anja
A
Laqua
UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research , Permoserstr. 15, 04318 Leipzig, Germany.|Institute for Organic Chemistry, Technical University Bergakademie Freiberg , Leipziger Str. 29, 09596 Freiberg, Germany.
Gerrit
G
Schüürmann
D000447:Aldehydes / Q000737:chemistry* / Q000633:toxicity*; D004952:Esters / Q000737:chemistry* / Q000633:toxicity*; D057927:Hydrophobic and Hydrophilic Interactions; D007659:Ketones / Q000737:chemistry* / Q000633:toxicity*; D007700:Kinetics; D013769:Tetrahymena pyriformis; D014867:Water / Q000737:chemistry*
D000447:Aldehydes; D004952:Esters; D007659:Ketones; D014867:Water