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STUDIES OF DBP INTERACTIONS
Impact/Purpose:
Investigations of interactions are being conducted to gain an improved understanding of the type(s) of interactions that might be expected from mixtures of DBPs. This research may be important rule when evaluating what assumptions to use for assessing complex mixtures (e.g., use an assumption of additivity for noncarcinogens, carcinogens, or some other assumption).
Description:
The trihalomethanes (THMs), chloroform, bromodichloromethane (BDCM), chlorodibromomethane and bromoform, were selected as the first class of chemicals for investigation. We examined in the male F-344 rat the assumption of additivity for acute exposure to mixtures of BDCM and chloroform under both dose additivity and effects additivity. This work used a number of dose levels, allowing for an examination of the effect of dose region on possible interactions. To increase environmental relevance, emphasis was placed on the lower end of the observable effect region. Currently, an effort to examine the 6 possible binary combinations of the 4 THMs is underway. This will allow us to develop an understanding of the nature of the interactions among the 4 THMs. In addition, these experiments have been designed to aid in development of efficient experimental designs for collection of mixtures data and to provide data for assessment and refinement of risk assessment methods for mixtures. The dose levels and mixing ratios were selected to be useful for 3 quantitative methods: testing for departure from dose additivity at low doses with a threshold model; estimation of mixtures toxicity from single chemical and binary data using an interaction-based hazard index; and, use of proportional response addition as a risk assessment method.
Another portion of the ongoing effort is examination of the additivity assumption. An efficient experimental design coupled with analysis by a threshold additivity model, in which the mixture response under additivity is simulated based on the dose-response curves of the individual chemicals, is being used. The response of the mixture is then determined experimentally and compared to the simulated or expected response under additivity. In addition to evaluation of the validity of an assumption of dose additivity, an objective is comparison of mixtures of DBPs for mixtures of the resulated trihalomethane and mixtures of the resulated laluacetic acid, representative of chlorination with mixtures representative of ozonation/post-chloramination. To facilitate an understanding of the possible relevance for human environmental exposure to those mixtures exhibiting nonadditive interactions in experimental animals, pharmacokinetic and pharmacodynamic experiments will be conducted to elucidate the underlying mechanism(s). Portions of this research are being conducted in collaboration with NCEA scientists; NCEA contact: Linda Teuschler.