The Role of Hydrophobicity in Toxicity Prediction

Mark   T.   D. Cronin

Abstract

The influence of hydrophobicity on toxic potency has been known for over a century. This paper summarises some of the key areas where hydrophobicity, in the form of the logarithm of the octanol-water partition coefficient (log P), is incorporated into quantitative structure-activity relationships (QSARs) for toxicity. Log P is frequently seen in QSARs for acute aquatic toxicity, especially for chemicals acting by non-reactive (i.e. in the absence of covalent binding) mechanisms of action.Within the narcoticmode of acute toxicity, a number of QSARs based on log P have been derived for different mechanisms such as non-polar and polar narcoses. For reactive chemicals, hydrophobicity is important for transport and distribution, such that hydrophobicity based QSARs may be derived for covalently binding chemicals with “constant” reactivity. Due to its contribution to pharmacokinetics, log P is also found in models for other mammalian toxicities such carcinogenicity and skin sensitisation.

Keywords: Toxicity, hydrophobicity, lipophilicity, quantitative structure-activity relationship, QSAR, n-octanol-water partition coefficient, narcosis, environmental effects, reactive toxicity, skin sensitisation