Formation of Categories from Structure−Activity Relationships To Allow Read-Across for Risk Assessment: Toxicity of α,β-Unsaturated Carbonyl Compounds

Abstract

alpha,beta-Unsaturated carbonyl compounds are common environmental pollutants that are able to interact with proteins, enzymes, and DNA through various mechanisms. As such, they are able to stimulate a range of environmental toxicities and adverse health effects. In this study, a "category" of alpha,beta-unsaturated carbonyl compounds (aldehydes and ketones), assumed to act by a common mechanism of action (Michael type addition), was formed. This toxicologically and mechanistically important category was formed on the premise of structure-activity relationships. The acute aquatic toxicities to Tetrahymena pyriformis of compounds within the category were obtained in an effort to develop approaches for (qualitative) read-across. In addition, Salmonella typhimurium (strain TA100) mutagenicity data were analyzed to establish the structural differences between mutagenic and nonmutagenic compounds. These structural differences were compared with the structural characteristics of molecules associated with acute aquatic toxicity in excess of narcosis as well as other end points, for example, skin sensitization. The results indicate that a category can be formed that allows structural information and boundaries to be elucidated. This knowledge will guide future toxicity prediction within this category and assist in the development of category formation.

QSAR modeling of toxicity of diverse organic chemicals to Daphnia magna using 2D and 3D descriptors

“…The goal of any ecotoxicological QSAR is to determine the efficiency of the developed QSAR model for the toxicity of chemicals which cover a large structural diversity spanning a variety of mechanisms of toxic action, including narcoses and electrophilic mechanisms. These chemicals are capable of causing a wide range of adverse effects including general toxicity, allergenic reactions, mutagenicity, and carcinogenicity [8]. Dermal, oral, or respiratory exposures include gastrointestinal, neurological, and reproductive disorders; liver cirrhosis; hepatitis; cataracts; respiratory and skin irritation; nephrotoxicity; and hematological defects [9][10][11].…”

The Tunable Functionality of α,β‐Unsaturated Carbonyl Compounds Enables Their Differential Application in Biological Systems

“…In general, electrophilicity at the b-position is influenced by the different substituents of the a,b-unsaturated carbonyl unit. High carbonyl activities, as found in aldehydes and esters, translate into high Michael acceptor reactivities often leading to mutagenicity, skin sensitization and acute aquatic toxicity, [11] or toxicity, for example to liver cells.…”

Predicting Toxicities of Diverse Chemical Pesticides in Multiple Avian Species Using Tree-Based QSAR Approaches for Regulatory Purposes

“…In addition to the carbon in the carbonylic functionality, the β-carbon is positively polarized because of conjugation with the carbonyl group and becomes the preferred site of nucleophilic attack. 66 The unsaturated carbonyl compounds can undergo different interactions with DNA, which lead to different genotoxic and mutagenic responses. Aromatic amines have the ability to induce mutation and cancer.…”