Mixtures and interactions.

Drinking water can be considered as a complex mixture that consists of tens, hundreds or thousands of chemicals of which the composition is qualitatively and quantitatively not fully known. From a public health point of view it is most relevant to answer the question of whether chemicals in drinking water interact in a way that results in an increased overall response as compared to the sum of the responses to the individual chemicals in the mixture, or indeed in an effect that is simply a summation of the expected effects of the individual chemicals. Present methods for risk assessment of mixtures rely heavily on some form of additivity model, unless data are adequate for a direct risk assessment of the mixture of concern in its entirety. The "dose-addition" concept ("simple similar action") is the most common approach to risk assessment of mixtures and it is applicable over the whole range of exposure levels from low non-toxic to toxic levels when all chemicals in the mixture act in a similar way. However, in toxicity studies at environmentally relevant exposure scenarios the mixtures that meet such conditions are the exception rather than the rule. In that case the "effect addition" model has to be followed assuming "independent joint action". For these compounds now experimental data have indicated that the results at low exposure levels are probably difficult to predict based on response additivity found at higher dose levels. Thus, although the additivity models are mathematically simple, they require assumptions about the mechanisms of action and the high-to-low dose extrapolation. Therefore, theoretical considerations in risk assessment of chemical mixtures should be verified by simple case studies. Up till now, the number of environmentally relevant mixtures to which a direct risk assessment has been devoted is limited. Even if toxicity data on individual compounds are available, we are still facing the immense problem of extrapolation of findings obtained at relatively high exposure concentration in laboratory animals to man being exposed to (much) lower concentrations. Therefore the prioritization of compounds for further research and the extrapolation to low doses should be considered as key issues in the assessment of possible health risks from exposure to chemical mixtures such as drinking water.