Informatics for toxicokinetics.

Toxicokinetic and pharmacokinetic (PK) summary parameters, such as C_max (peak concentration), AUC (time-integrated area under the plasma concentration curve), and t_1/2 (elimination half-life from the body), are important information for understanding chemical safety in both pharmaceuticals and commercial industry. Although standardized tools exist for PK analysis of individual chemicals, new workflows can enhance chemoinformatic trend analysis. The Concentration versus Time Database (CvTdb) is a public repository of PK data at the U.S. Environmental Protection Agency (EPA). The CvTdb contains manually curated, standardized toxicokinetic data from hundreds of publications. Experimental time-course data of chemical concentrations in body fluids and tissues are extracted along with descriptive metadata. The advantage of standardized data is that it can be analyzed systematically. For example, we observe that 88.6% of replicate measurements of blood or plasma concentrations of chemicals after intravenous or oral dosing are within two-fold of the mean concentration. Although most experimental data have final timepoints within three days, some experiments extend up to a year, usually for long-lived chemicals. Here we have estimated PK parameters of CvTdb data using a custom R package, invivoPKfit. Standardized 1- and 2- compartmental PK model parameters were estimated using all data associated with a particular compound, including data that spans multiple references. We used invivoPKfit to estimate PK parameters such as volume of distribution (V_d) and t_1/2. The parameter values estimated with invivoPKfit are distributed similar to estimates made in the literature by a variety of methods. Overall, CvTdb serves as a standardized set of open data and for calibrating and evaluating PK models, while invivoPKfit allows for batch processing of this data type in a transparent and scalable manner. In addition to scientific insights, chemical risk assessment may be better informed by transparent, reproducible, and open-source workflows for PK informatics.