Citation:

Hilal, S H., S W. Karickhoff, AND L. A. Carreira. PREDICTION OF THE SOLUBILITY, ACTIVITY COEFFICIENT AND LIQUID/LIQUID PARTITION COEFFICIENT OF ORGANIC COMPOUNDS. QSAR & COMBINATORIAL SCIENCE 23(9):709-720, (2004).

Impact/Purpose:

This task is divided into four major research areas: (1) Development of computational tools and databases for screening-level modeling of the environmental fate of organic chemicals; (2) Metabolism of xenobiotics: Enhancing the development of a metabolic simulator; (3) Metabonomics: The use of advanced analytical tools to identify toxicity pathways; and (4) Software infrastructure to support development and application of transformation/metabolic simulators.

For many chemicals, multiple transformation/metabolic pathways can exist. Consequently, transformation/metabolic simulators must utilize transformation rate data for prioritization of competing pathways. The prioritization process thus requires the integration of reliable rate data. When this data is absent, it is necessary to generate a database with metabolic and transformation rate constants based on: (1) experimentally measured values, including those requiring the use of advanced analytical techniques for measuring metabolic rate constants in vivo and in vitro; (2) rate constants derived from SPARC and mechanistic-based QSAR models; and (3) data mined from the literature and Program Office CBI. A long-term goal of this project is to build this database. This information will be used to enhance the predictive capabilities of the transformation/metabolic simulators. As indicated previously, exposure genomics, which provide early signs of chemical exposure based on changes in gene expression, will be used to guide chemical fate and metabolism studies. The incorporation of exposure genomics into fate studies will provide information concerning (1) the minimal concentrations at which biological events occur; and (2) the identification of biologically relevant chemicals(s) in mixtures.

The capability of categorizing chemicals and their metabolites based on toxicity pathway is imperative to the success of the CompTox Research Program. Metabonomics, which is the multi-parametric measurement of metabolites in living systems due to physiological stimuli and/or genetic modification, provides such a capability. The application of metabonomics to toxicity testing involves the elucidation of changes in metabolic patterns associated with chemical toxicity based on the measurement of component profiles in biofluids, and enables the generation of spectral profiles for a wide range of endogenous metabolites. Metabolic profiles can provide a measure of the real outcome of potential changes as the result of xenobiotic exposure.

Description:

Solvation models, based on fundamental chemical structure theory, were developed in the SPARC mechanistic tool box to predict a large array of physical properties of organic compounds in water and in non-aqueous solvents strictly from molecular structure. The SPARC self-interaction solvation models that describe the intermolecular interaction between like molecules (solute-solute or solvent-solvent) were extended to quantify solute-solvent interaction energy in order to estimate the activity coefficient in almost any solvent. Solvation models that include dispersion, induction, dipole-dipole and hydrogen bonding interactions are used to describe the intermolecular interaction upon placing an organic solute molecule in any single or mixed solvent system. In addition to estimation of the activity coefficient for 2604 organic compounds, these solvation models were validated on solubility and liquid/liquid distribution coefficient in more than 163 solvents including water. The RMS deviations of the calculated versus observed activity coefficients, solubilities and liquid/liquid distribution coefficients were 0.272 log mole fraction, 0.487 log mole fraction and 0.44 log units, respectively.

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