httk: R Package for High-Throughput Toxicokinetics

Abstract

Thousands of chemicals have been profiled by high-throughput screening programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics. Toxicokinetic models aid in predicting tissue concentrations resulting from chemical exposure, and a “reverse dosimetry” approach can be used to predict exposure doses sufficient to cause tissue concentrations that have been identified as bioactive by high-throughput screening. We have created four toxicokinetic models within the R software package httk. These models are designed to be parameterized using high-throughput in vitro data (plasma protein binding and hepatic clearance), as well as structure-derived physicochemical properties and species-specific physiological data. The package contains tools for Monte Carlo sampling and reverse dosimetry along with functions for the analysis of concentration vs. time simulations. The package can currently use human in vitro data to make predictions for 553 chemicals in humans, rats, mice, dogs, and rabbits, including 94 pharmaceuticals and 415 ToxCast chemicals. For 67 of these chemicals, the package includes rat-specific in vitro data. This package is structured to be augmented with additional chemical data as they become available. Package httk enables the inclusion of toxicokinetics in the statistical analysis of chemicals undergoing high-throughput screening.

In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model

“…For pharmaceuticals, C max values were extracted for this comparison from the PharmaPendium database. For the remaining compounds, steady state blood concentrations were estimated by combining exposure estimates from the U.S. EPA CompTox Chemistry Dashboard (https://comptox.epa.gov/dashboard) and toxicokinetic model predictions (Pearce et al . 2017; Wetmore et al .…”

Hybridization promotes asexual reproduction in Caenorhabditis nematodes

“…Based on genotyping error rate estimates we further required a minimum of 70 SNP calls per scaffold and a minimum length of 1 kb, yielding 1337 non-redundant scaffold markers spanning 81.5 Mb. Six linkage groups were recovered over a wide range of minimum pairwise LOD scores, and within linkage group marker ordering was carried out by the minimum spanning tree method implemented in ASMap [71].…”

Screening for neurotoxic potential of 15 flame retardants using freshwater planarians

“…In addition to comparing with other toxicological models, comparing with human environmental exposure can contextualize the relevancy of observed toxicity in a given system. Therefore, we overlaid our regenerating planarian screening results to measured or estimated in vivo plasma concentrations using the HTTK R-package (Figure 5) (Alzualde et al, 2018; Pearce et al, 2017). The nominal water concentrations at which effects were seen in regenerating planarians are significantly greater (1-2 orders of magnitude) than the highest estimated concentrations based on reported human exposure levels.…”