A goal within the Tox21 collaboration is to research, develop, validate, and translate innovative test methods that will better predict how chemicals may affect humans and the environment. Tox21 and ToxCast efforts have screened ~10,000 chemicals with limited biological information in hundreds of high-throughput screening (HTS) in vitro assays. Translating these HTS data into a common language among toxicologists, specifically risk assessors, is an important next step toward making the data useful. This website allows users to estimate doses at which chemical-biological interactions are "likely", "possible", and "possible w/10-fold safety factor" for humans in vivo.
This web-application is a companion to Sipes NS et. al., 2017
A goal within the Tox21 collaboration is to research, develop, validate, and translate innovative test methods that will better predict how chemicals may affect humans and the environment. Toward this effort, ~10,000 chemicals in hundreds of HTS assays have been screened to elucidate mechanisms of chemical-biological interactions as a majority of the chemicals previously had limited biological activity information. These data were processed into activity concentrations at half maximal efficacy (AC50), for hazard characterization. Translating these HTS AC50s into a common language among toxicologists, specifically risk assessors, is an important next step toward making the data useful.
In understanding chemical-biological interactions, risk assessors evaluate the dose-response relationship, often expressed in terms of external dose (i.e., mg/kg/day), between a chemical and the incidence of an adverse toxicological response, such as cancer or developmental defects. With a mechanistic or pathway approach, we use chemical concentrations and efficacies, often expressed in µM and percent or fold-change with respect to the positive control, respectively, to describe chemical-biological interactions above a noise threshold. In vitro to in vivo extrapolation (IVIVE) applications are available to take the chemical concentration from in vitro studies that are defined by an AC50 and estimate the dose given to the organism to achieve a blood concentration equal to the AC50.
Using the IVIVE method, we can predict daily dosing scenarios assuming the blood concentration to elicit a biological effect is equivalent to the Tox21/ToxCast HTS activity metric (i.e., AC50) for any chemical. Is this assumption correct? How much of it in the blood is needed to have an effect? To address this, we borrow an approach used by the FDA in translating in vitro assay results to clinical relevance for pharmaceutical research applications. For example, FDA guidance documents have been drafted to predict whether a chemical can interfere with in vitro metabolizing enzymes and transporters adequately to disrupt normal metabolic processes by calculating the ratio of peak plasma an efficacy cutoff, to minimize false positives (e.g., 40% of positive control response) and has proven to be a useful estimate of the potential for chemicals to elicit clinically relevant drug-drug concentrations (Cmax) of the chemical and dividing by the observed in vitro potency (Ki). (Draft Guidance for Industry 2006, link). The interaction is "likely" if the calculated ratio is >1 (blood concentrations equivalent or higher than in vitro half-maximal applied concentrations), "possible" if 0.1 < X < 1, or "possible w/10-fold safety factor" if the ratio is < 0.1 (blood concentrations more than 10-fold lower than requisite in vitro half-maximal applied concentrations).
The High-Throughput Toxicokinetics (HTTK) R-package (link) was used to perform in vitro to in vivo extrapolation of HTS data to daily human equivalent doses [Wambaugh J et. al., 2015; Pearce R et. al., 2017].
The analyses with the Tox21/ToxCast data in the IVIVE approach has been and is currently limited to ~500 chemicals with in vitro measured CLint & fup values and cannot be applied to the entire Tox21 chemical library, unless they are predicted.
This approach requires robust interactions, as we are evaluating HTS data and nuanced data should be avoided in a clear step. We reduced false-positive data by keeping only good quality Tox21/ToxCast data (i.e., ones with limited curve-fitting issues and efficacies > 40%). Specifically,
Data downloads correspond to: