Main content area

Rapid experimental measurements of physicochemical properties to inform models and testing

Nicolas, Chantel I., Mansouri, Kamel, Phillips, Katherine A., Grulke, Christopher M., Richard, Ann M., Williams, Antony J., Rabinowitz, James, Isaacs, Kristin K., Yau, Alice, Wambaugh, John F.
The Science of the total environment 2018 v.636 pp. 901-909
United States Environmental Protection Agency, databases, dissociation, exposure models, pharmacokinetics, prediction, quantitative structure-activity relationships, rapid methods, risk, toxicity, vapor pressure, water solubility
The structures and physicochemical properties of chemicals are important for determining their potential toxicological effects, toxicokinetics, and route(s) of exposure. These data are needed to prioritize the risk for thousands of environmental chemicals, but experimental values are often lacking. In an attempt to efficiently fill data gaps in physicochemical property information, we generated new data for 200 structurally diverse compounds, which were rigorously selected from the USEPA ToxCast chemical library, and whose structures are available within the Distributed Structure-Searchable Toxicity Database (DSSTox). This pilot study evaluated rapid experimental methods to determine five physicochemical properties, including the log of the octanol:water partition coefficient (known as log(Kow) or logP), vapor pressure, water solubility, Henry's law constant, and the acid dissociation constant (pKa). For most compounds, experiments were successful for at least one property; log(Kow) yielded the largest return (176 values). It was determined that 77 ToxPrint structural features were enriched in chemicals with at least one measurement failure, indicating which features may have played a role in rapid method failures. To gauge consistency with traditional measurement methods, the new measurements were compared with previous measurements (where available). Since quantitative structure-activity/property relationship (QSAR/QSPR) models are used to fill gaps in physicochemical property information, 5 suites of QSPRs were evaluated for their predictive ability and chemical coverage or applicability domain of new experimental measurements. The ability to have accurate measurements of these properties will facilitate better exposure predictions in two ways: 1) direct input of these experimental measurements into exposure models; and 2) construction of QSPRs with a wider applicability domain, as their predicted physicochemical values can be used to parameterize exposure models in the absence of experimental data.