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Biologically-Based Lumping Methodology (BBLM) To Investigate Toxicological Interactions of Complex Chemical Mixtures
Citation:
LaFew, W. AND H. A. EL-MASRI. Biologically-Based Lumping Methodology (BBLM) To Investigate Toxicological Interactions of Complex Chemical Mixtures. Presented at Society of Toxicology (SOT) Annual Meeing, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
We have developed a novel mathematical method, biologically-based lumping methodology (BBLM), which reduces the complexity of a mixtures model and increases computational efficiency
Description:
Many cases of environmental contamination result in concurrent or sequential exposure to more than one chemical. Limitations of available resources prevent experimental toxicology from providing health risk information about all the possible mixtures to which humans or other species may be exposed. In order to increase the efficiency of risk assessment, toxicological predictions based on computational models can complement experimental efforts. We have developed a novel mathematical method, biologically-based lumping methodology (BBLM), which reduces the complexity of a mixtures model and increases computational efficiency. BBLM clusters chemicals according to similar biological properties, their metabolic rate, for instance. This method of clustering gives both a greater correlation to physical interactions and to mechanistic effects than previously utilized clustering criteria. BBLM also allows computation of error wnlch results from lumping. By calculating the error of different lumping configurations one can find an optimal lumping configuration in the tradeoff between simplification and accuracy for a given application. To demonstrate this method, lumped equations based on a typical inhalation physiologically based pharmacoklnetlc (PBPK) model with metabolic competitive inhibition were developed. Two mixtures of 100 chemicals with randomly generated parameters were simulated separately for different exposure conditions. The error, computed as the average difference of simulated venous blood concentrations between the non-lumped PBPK mixtures model and the BBLM generated lumps,was examined for a range of lumping configurations.Thisapplication of BBLM produced lumping configurations of up to 90 chemicals, and the error was less than 1% of the maximum attainable venous concentration determined by the non-lumped PBPK mixtures model.