Proportional response addition (Prop-RA), a model for predicting response from chemical mixture exposure, is demonstrated, and evaluated by statistically evaluating data on all possible binary combinations of the four regulated trihalomethanes. In the Prop-RA model, the contribution of each component to mixture toxicity is based on its proportion in the mixture as well as its response at the total mixture dose. To allow evaluation of Prop-RA, an experimental design was employed using a set of doses common to all components and mixtures, providing hepatotoxicity data on the four single trihalomethanes and the two combinations. The primary analysis conducted on these data consisted of 160 evaluations. Statistically significant departures from the outcome predicted under an assumption of Prop-RA additivity, were found for 7 evaluations, with 3 greater than and 4 less than the response predicted by the Prop-RA model. Interaction magnitudes (n-fold different response than the Prop-RA prediction) ranged from 1.3 to 1.4 for the greater than additive responses and 2.6 to 3.8 for the less than additive responses. The successful prediction of trihalomethane mixture response by Prop-RA lends support to the idea that the method works best with chemicals where the effective dose ranges overlap. As Prop-RA does not have the mechanistic assumptions of either dose or response addition, it may be best applied to mixtures where the same component chemicals affect the same organ/system but where knowledge of whether the components act via the same, converging or independent pathways is not known.

This dataset is associated with the following publication: Teuschler , L., R. Hertzberg , T. McDonald, Y. Sey, and J. Simmons. Evaluation of a Proportional Response Addition Approach to Mixtures Risk Assessment and Predictive Toxicology Using Data on Four Trihalomethanes. Toxics. MDPI, Basel, SWITZERLAND, 12(4): 240, (2024).