The general objective of this proposal is to develop a toxicokinetic (TK) modelling framework for mammals and develop and integrate various data streams for mammalian bioaccumulation (B) assessment (Figure 1). The primary goal is to expand the development, evaluation, and application of the CEFIC-LRI funded Bioaccumulation Assessment Tool (BAT) and other B, TK, and risk assessment models for mammals. Many objectives and components listed in the ECO.44 RfP already exist in LRI-ARC.3 BAT project; therefore, our proposal objectives seek to enhance and advance the stated objectives in the RfP. A particular focus will be to address data gaps and uncertainty in biotransformation half-lives. To satisfy these general objectives, we will: 1) Assimilate critically evaluated data from various sources, including ~30 years of in vitro and in vivo TK data (rodents and humans), as well as field B data in mammals (TMF and BMF). Information from recently-completed and ongoing projects will be leveraged (Figure 2). Quantitative Structure-Activity Relationship (QSAR) model predictions will be included to compare and analyze various data streams. 2) Develop and test one-compartment TK (1-CoTK) and generic physiologically-based TK (G-PBTK) models for mammalian species. The models will be parameterized for laboratory test mammals (rats, mice), and evaluated along with in vitro-in vivo extrapolation (IVIVE) models to integrate TK data with collected in vivo and in vitro laboratory data. These evaluations will test different assumptions for blood protein binding, renal elimination, and chemical degradation in the gastro-intestinal tract (GIT) to characterize best scientific practices for applying B models for mammals. 3) Develop and test various QSAR models for predicting biotransformation half-lives and other endpoints relevant for TK and B model applications (e.g., hepatic clearance, degradation half-lives in the GIT, protein binding). 4) Refine the BAT for mammalian species (e.g., include a “lab rat”) and evaluate the BAT model predictions for mammals with field and laboratory data. 5) Synthesize the state of the science and available data streams to develop an integrated testing strategy (ITS) for additional ADME priority chemicals. This will inform future testing needs to address current measurement gaps and QSAR model uncertainties.
|Titolo:||LRI-ECO44: Integrating Bioaccumulation Assessment Tools for Mammals (iBAT-Mam)|
PAPA, ESTER (Corresponding)
|Data di pubblicazione:||2018|
|Appare nelle tipologie:||Coordinamento Proget. Ricerca Naz. ed Internaz.|