Evaluation of the Interaction-Based Hazard Index Formula Using Data on Four Trihalomethanes from U.S. EPA's...

The interaction-based hazard index (HI_INT), a mixtures approach to characterizing toxicologic interactions, is demonstrated and evaluated by statistically analyzing data on four regulated trihalomethanes (THMs). These THMs were the subject of a multipurpose toxicology study specifically designed to evaluate the HI_INT formula. This HI_INT evaluation uses single, binary and quaternary mixture THM data. While this research is considered preliminary, the results provide insights on the application of HI_INT when toxicology mixture data are available and on improvements to the method. The results for relative liver weight show the HI_INT was generally not conservative but did adjust the additive hazard index (HI) in the correct direction, predicting greater than dose-additivity, as seen in the mixture data. For the liver serum enzyme endpoint alanine aminotransferase, the results were mixed, with some indices giving an estimated effective dose lower than the observed mixture effective dose and others higher; in general, the HI_INT adjusted the HI in the correct direction, predicting less than dose-additivity. In addition, a methodological improvement was made in the calculation of maximum interaction magnitude. Suggested refinements to the HI_INT included mixture-specific replacements for default parameter values and approaches for supplementing the usual qualitative discussions of uncertainty with numerical descriptions.