Utilization of quantitative structure-activity relationships (QSARs) in risk assessment: Alkylphenols

Abstract

Alkylphenols are a class of environmentally pervasive compounds, found both in natural (e.g., crude oils) and in anthropogenic (e.g., wood tar, coal gasification waste) materials. Despite the frequent environmental occurrence of these chemicals, there is a limited toxicity database on alkylphenols. We have therefore developed a “toxicity equivalence approach” for alkylphenols which is based on their ability to inhibit, in a specific manner, the enzyme cyclooxygenase. Enzymeinhibiting ability for individual alkylphenols can be estimated based on the quantitative structure-activity relationship developed by Dewhirst (1980) and is a function of the free hydroxyl group, electron-donating ring substituents, and hydrophobic aromatic ring substituents. We evaluated the toxicological significance of cyclooxygenase inhibition by comparison of the inhibitory capacity of alkylphenols with the inhibitory capacity of acetylsalicylic acid, or aspirin, a compound whose low-level effects are due to cyclooxygenase inhibition. Since nearly complete absorption for alkylphenols and aspirin is predicted, based on estimates of hydrophobicity and fraction of charged molecules at gastrointestinal pHs, risks from alkylphenols can be expressed directly in terms of “milligram aspirin equivalence,” without correction for absorption differences. We recommend this method for assessing risks of mixtures of alkylphenols, especially for those compounds with no chronic toxicity data.