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MODELING THE INTERACTION THRESHOLD: THE BREAK-POINT BETWEEN ADDITIVITY AND NON-ADDITIVITY
Citation:
EL-MASRI, H. A. MODELING THE INTERACTION THRESHOLD: THE BREAK-POINT BETWEEN ADDITIVITY AND NON-ADDITIVITY. Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.
Description:
Dose-dependent changes in toxicity mechanisms of single chemicals may take place along the full dose-response spectrum. At high doses, the possibility exists for some steps in the principle mechanism of toxicity to shift to other mechanisms. The possibility of mechanism shifts for single chemicals can also be observed for interaction mechanism of chemical mixtures. For instance, interactions (synergism or antagonism) taking place at high individual doses of a mixture, may not be significant at low levels. One of the early experiments indicating a change of the mechanism of interaction with dose was conducted using chloral hydrate and ethanol. The boundary that separates the dose space into regions of interaction and additivity is called the interaction threshold boundary. The interest in defining this region is important because it signifies the need to include or exclude interactive effects in the calculations of health risks of the mixtures, specifically at low environmentally relevant doses. The interaction threshold boundary may take a variety of different shapes, and the shape of this boundary is not likely to be known. Hamm et al. (2005) developed a general procedure to accommodate various potential shapes for this boundary. Predictive modeling (such as PBPK/PD models) along with experiments provides an efficient methodology for the identification of interaction thresholds. For example, the presence of an interaction threshold between binary chemicals was investigated using PBPK models for two different sets of chemicals; volatiles (TCE and 1,1-DCE), and pesticides (chlorpyrifos and parathion). (This abstract does not necessarily reflect EPA policy.)