Development of human biotransformation QSARs and application for PBT assessment refinement

Abstract

Toxicokinetics heavily influence chemical toxicity as the result of Absorption, Distribution, Metabolism (Biotransformation) and Elimination (ADME) processes. Biotransformation (metabolism) reactions can lead to detoxification or, in some cases, bioactivation of parent compounds to more toxic chemicals. Moreover, biotransformation has been recognized as a key process determining chemical half-life in an organism and is thus a key determinant for bioaccumulation assessment for many chemicals. This study addresses the development of QSAR models for the prediction of in vivo whole body human biotransformation (metabolism) half-lives measured or empirically-derived for over 1000 chemicals, mainly represented by pharmaceuticals. Models presented in this study meet regulatory standards for fitting, validation and applicability domain. These QSARs were used, in combination with literature models for the prediction of biotransformation half-lives in fish, to refine the screening of the potential PBT behaviour of over 1300 Pharmaceuticals and Personal Care Products (PPCPs). The refinement of the PBT screening allowed, among others, for the identification of PPCPs, which were predicted as PBTs on the basis of their chemical structure, but may be easily biotransformed. These compounds are of lower concern in comparison to potential PBTs characterized by large predicted biotransformation half-lives.