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A Novel Approach for Evaluating Carbamate Mixtures for Dose Additivity
Citation:
Li, R., Y. Pan, R. Hertzberg, R. Lyles, V. C. MOSER, D. W. HERR, AND J. E. SIMMONS. A Novel Approach for Evaluating Carbamate Mixtures for Dose Additivity. Presented at Society of Toxicology Annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
Two mathematical approaches were used to test the hypothesis ofdose-addition for a binary and a seven-chemical mixture ofN-methyl carbamates, toxicologically similar chemicals that inhibit cholinesterase (ChE).
Description:
Two mathematical approaches were used to test the hypothesis ofdose-addition for a binary and a seven-chemical mixture ofN-methyl carbamates, toxicologically similar chemicals that inhibit cholinesterase (ChE). In the more novel approach, mixture data were not included in the analysis. One dose-response model formula (e.g., exponential, logistic) was identified that best fit each single chemical data set. The single chemical data were combined into a composite data set, and a combined prediction model (CPM) developed by fitting the dose-additive version of the selected model to the composite data. The CPM was evaluated for how well it described the composite data. This approach evaluates proportionality across the component chemicals, such as expressed by relative potency factors, and is necessary but not sufficient for consistency with dose-additivity. In the second approach, the mixture model (MM) (a dose-response model ofthe same mathematical form as the CPM), was fit to the actual mixture data along a fixed ratio ray (component proportions are fixed), and evaluated for model fit. Finally, the MM was statistically compared with the CPM, based on a null hypothesis of dose additivity. Comparison of models provides more information than simply evaluating whether the CPM matches the mixture data, by allowing an overall evaluation ofconsistency (rather than a dose by dose evaluation). This process identifies parameters where there is disagreement, suggesting biological processes to investigate for an interaction. Applying these approaches yielded mixed results. For example, the CPM agreed with the single chemical models for RBC and brain ChE inhibition for the binary mixture, but some parameters (primarily slope for brain ChE and plateau for RBC ChE) differed between the CPM and MM. Results consistent with additivity and potential reasons for uncertain results and/or lack of consistency with additivity are explored. (This abstract does not reflect EPA policy.)