Development of human biotransformation QSARs and application for PBT assessment refinement. (February 2018)

• Record Type: Journal Article
• Authors: Papa, Ester; Sangion, Alessandro; Arnot, Jon A.; Gramatica, Paola
• Is Part Of: Food and chemical toxicology. Volume 112(2018)
• Page Start: 535
• Page End: 543
• Publication Date: 2018-02
• Subjects: In vivo biotransformation -- Biotransformation half-life -- QSAR -- Hazard assessment -- Refined PBT assessment; 1-CoPK one-compartment pharmacokinetic model -- AD Applicability Domain -- ADME Absorption, Distribution, Metabolism and Elimination -- B Bioaccumulation -- BCF Bioconcentration Factor -- CAS RN Chemical Abstract Service Registry Number -- CCC Concordance Correlation Coefficient -- CLINT intrinsic clearance -- E-State Electrotopological-State -- GA Genetic Algorithm -- h hour -- hi/i leverage value -- HLB whole-body primary biotransformation half-life -- HL half-life -- HLT whole body total elimination half-life -- I-State Intrinsic-State -- kB whole body primary biotransformation rate constant -- Km Michaelis constant -- kT whole body total elimination rate constant -- kx sum of rate constants for passive elimination -- MLR Multiple Linear Regression -- OLS Ordinary Least Square method -- PAH polycyclic aromatic hydrocarbon -- PBT Persistent Bioaccumulative and Toxic -- PC Principal Component -- PCA Principal Component Analysis -- PCB polychlorinated biphenyl -- PCDD polychlorinated dibenzodioxin -- PCDF polychlorinated dibenzofuran -- PPCP Pharmaceutical and Personal Care Product -- PT Persistent and Toxic -- Q2LMO Q2 Leave Many Out -- Q2LOO Q2 leave-one-out -- QSAR Quantitative Structure-Activity Relationships -- QUIK Q Under the Influence of K rule -- R2Yscr R2 Y-scrambling -- RMSE Residual Mean Squared Errors -- RMSEP Residual Mean Squared Errors Prediction -- RMSET Residual Mean Squared Errors Training -- SMILES Simplified Molecular Input Line Entry System -- US-EPA United State Environmental Protection Agency -- Vm maximum velocity of the reaction; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2017.04.016
• Languages: English
• ISSNs: 0278-6915

Abstract

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. Graphical abstract: Image 1 Highlights: New QSAR models for the prediction of in vivo human biotransformation rate data. Reliable predictions for over 1300 Pharmaceuticals and Personal Care Products. A new approach combines QSAR and multivariate analysis to refine PBT assessment.