Health risk assessment of chemical mixtures from a research perspective

Human exposures to chemicals in the environment and workplace typically involve chemical mixtures. One of the key risk assessment issues for mixtures is that of extrapolation from high to low dose. Observation of an interaction among chemicals in a mixture at high concentrations in animals does not necessarily mean that the same effect, in type or magnitude, will be significant in humans exposed to lower concentrations of the mixture. Physiologically based toxicokinetic (PBTK) models can be used to assist in the extrapolation from high to low dose. Mechanisms observed in animals such as competitive inhibition of xenobiotic metabolism (e.g., butadiene and styrene or benzene and toluene) can be incorporated into PBTK models. The models can then be used to predict the magnitude of the interactive effects at high and low exposure concentrations. The most relevant predictions can then be tested using selected experiments. A research strategy involving hypothesis generation through quantitative modeling and testing through laboratory-based experiments may be the most effective strategy for addressing the complex issue of human health risks from exposures to chemical mixtures.