In silico methods for physiologically based biokinetic models describing bioactivation and detoxification of coumarin and estragole: Implications for risk assessment

Abstract

In chemical safety assessment, information on adverse effects after chronic exposure to low levels of hazardous compounds is essential for estimating human risks. Results from in vitro studies are often not directly applicable to the in vivo situation, and in vivo animal studies often have to be performed at unrealistic high levels of exposure. Physiologically based biokinetic (PBBK) modeling can be used as a platform for integrating in vitro metabolic data to predict dose- and species-dependent in vivo effects on biokinetics, and can provide a method to obtain a better mechanistic basis for extrapolations of data obtained in experimental animal studies to the human situation. Recently, we have developed PBBK models for the bioactivation of the alkenylbenzene estragole to its DNA binding ultimate carcinogenic metabolite 1'-sulfooxyestragole in both rat and human, as well as rat and human PBBK models for the bioactivation of coumarin to its hepatotoxic o-hydroxyphenylacetaldehyde metabolite. This article presents an overview of the results obtained so far with these in silico methods for PBBK modeling, focusing on the possible implications for risk assessment, and some additional considerations and future perspectives.

Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

“…Figure 5A summarizes the reported correlations between scaled in vitro and in vivo measured clearances based on incubations with primary hepatocytes. The correlation coefficients (r 2 ) be- A B chemicals in transport activity as well as metabolic turnover to predict mixture effects (Rietjens et al, 2010;Rostami-Hodjegan and Tucker, 2007). PBPK models are generally evaluated on a case-by-case basis.…”

“…PBPK models are generally evaluated on a case-by-case basis. Those using input of in vitro kinetic data show adequate quantitative predictions of in vivo kinetics, including C max , AUC and bioavailability (Flanagan et al, 2016;Gobeau et al, 2016;Rietjens et al, 2010). An evaluation of the various risk evaluations (Fig.…”

“…Developed PBPK models often include kinetic parameters fitted to in vivo studies (Clewell and Clewell, 2008). The use of in vitro kinetic data (including e.g., Caco-2 absorption data and in vitro clearance measurements with primary hepatocytes or tissue fractions as described above) to build PBPK models has increased drastically over the last decades, thereby contributing to a reduction in animal testing (Rietjens et al, 2010;Rostami-Hodjegan and Tucker, 2007). PBPK models allow evaluation of dose-dependent effects in kinetics and can be developed for multiple species to evaluate species differences.…”

“…PBPK models simulate the ADME of chemicals in an organism, allowing the prediction of blood or tissue concentrations of a chemical or relevant metabolites (Clewell and Clewell, 2008;Rietjens et al, 2010). These simulations are made with ordinary differential equations that include chemical-specific kinetic parameters (e.g., absorption and metabolic conversion rates), as well as physiological parameters (e.g., cardiac output, tissue volumes, and tissue blood flows) and physicochemical parameters (e.g., tissue:blood partition coefficients).…”

“…(Q) SARs for kinetics aim at the use of chemical descriptors of a compound to predict kinetic parameters such as rate of absorption, metabolism or the type of metabolites that might be formed (Kiwamoto et al, 2015;Pirovano et al, 2014). PBPK models mathematically describe the absorption, distribution, metabolism, and excretion of a chemical in an organism based on a series of ordinary differential equations and are used to simulate the fate of chemicals in a body (Rietjens et al, 2010).…”