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

The interaction-based hazard index (HIINT), 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 HIINT formula. This HIINT evaluation uses single, binary and quaternary mixture THM data. While this research is considered preliminary, the results provide insights on the application of HIINT when toxicology mixture data are available and on improvements to the method. The results for relative liver weight show the HIINT 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 HIINT 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 HIINT included mixture-specific replacements for default parameter values and approaches for supplementing the usual qualitative discussions of uncertainty with numerical descriptions.

Evaluation of a Proportional Response Addition Approach to Mixture Risk Assessment and Predictive Toxicology Using Data on Four Trihalomethanes from the U.S. EPA's Multiple-Purpose Design Study.

In this study, proportional response addition (Prop-RA), a model for predicting response from chemical mixture exposure, is demonstrated and evaluated by statistically analyzing data on all possible binary combinations of the four regulated trihalomethanes (THMs). These THMs were the subject of a multipurpose toxicology study specifically designed to evaluate Prop-RA. The experimental design used a set of doses common to all components and mixtures, providing hepatotoxicity data on the four single THMs and the binary combinations. In Prop-RA, the contribution of each component to mixture toxicity is proportional to its fraction in the mixture based on its response at the total mixture dose. The primary analysis consisted of 160 evaluations. Statistically significant departures from the Prop-RA prediction were found for seven evaluations, with three predications that were greater than and four that were less than the predicted response; interaction magnitudes (n-fold difference in response vs. prediction) ranged from 1.3 to 1.4 for the former and 2.6 to 3.8 for the latter. These predictions support the idea that Prop-RA works best with chemicals where the effective dose ranges overlap. Prop-RA does not assume the similarity of toxic action or independence, but it can be applied to a mixture of components that affect the same organ/system, with perhaps unknown toxic modes of action.