A four-step approach to evaluate mixtures for consistency with dose addition

摘要: Mixture risk assessment is often hampered by the lack of dose–response information on mixture being assessed, forcing reliance component formulas such as dose addition. We present a four-step approach for evaluating chemical data consistency with addition use in supporting based assessment. Following concepts U.S. EPA guidance (U.S. EPA, 2000a,b), toxicological interaction defined (all components known) departure from clearly articulated definition additivity. For common additivity, identifies three desirable characteristics, foremost which that chemicals are toxicologically similar. The other two characteristics empirical: have toxic potencies fixed proportions each (throughout range interest), and term additive prediction formula, we call combined model (CPM), can be represented linear combination doses. A consequent property proportional must share model, where only coefficients depend components. further consequence described same mathematical function (“mixture model”) components, but distinct coefficient total dose. response predicted curves using CPM then compared observed results. four steps to evaluate: (1) proportionality determining how well matches single models regarding mean variance; (2) fit data; (3) agreement between prediction; (4) model. Because there evaluations instead one, some involving many parameters or groups, more opportunities reject statistical hypotheses about addition, thus adjustment multiple comparisons necessary. These contribute different pieces empirical examine this it show support predictor an untested screening level decision whether apply should all those evidentiary understanding these include interpretations numerical issues arise during evaluation. This demonstrated neurotoxicity carbamate mixtures.