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A Four-Step Approach for Evaluation of Dose Additivity (Presentation)
Citation:
Hertzberg, R., Y. Pan, R. Li, L. T. Haber, R. Lyles, V. C. MOSER, D. W. HERR, AND J. E. SIMMONS. A Four-Step Approach for Evaluation of Dose Additivity (Presentation). Presented at Society of Toxicology (SOT) Annual Meeting, Washington, DC, March 06 - 10, 2010.
Impact/Purpose:
A four step approach was developed for evaluating toxicity data on a chemical mixture for consistency with dose addition.
Description:
A four step approach was developed for evaluating toxicity data on a chemical mixture for consistency with dose addition. Following the concepts in the U.S. EPA mixture guidance (EPA 2000), toxicologic interaction for a defined mixture (all components known) is departure from a clearly articulated definition of component additivity. The EPA guidance specifies two key characteristics of dose additivity: the mixture components have toxic potencies that are proportional to each other, and the mixture dose can be represented by a linear combination of the component doses. The component chemicals must then share a common dose-response model, where only the dose coefficients depend on the chemical; we call this the combined prediction model (CPM). Further, the mixture must be described by the same model type, with a distinct coefficient for the total mixture dose. Consequently, the mixture response can be predicted from the component dose-response curves by using the CPM with dose as the linear combination of component doses. The four steps are to evaluate: 1) toxic proportionality by determining how well the CPM fits the single chemical data sets; 2) fit of the mixture model (the model developed using just the mixture data) to the mixture data; 3) agreement between the mixture data and the CPM; and 4) consistency between the CPM and the mixture model. These four steps contribute different pieces of information about the consistency of the component chemical and mixture dose-response data with this two-part definition of dose additivity. Because there are four evaluations instead of one, there are more opportunities to reject dose addition, so statistical adjustment for multiple comparisons is necessary, and interpretation of the toxlcoloqic significance of the results is critical. This approach is demonstrated with neurotoxicity data on carbamate mixtures. (This abstract may not reflect EPA policy.)