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Assessment of the predictability of mixture effects of estrogenic chemicals on vitellogenesis in fish

A freshwater fish species (fathead minnow), and a marine species (sea bass) were used to assess the predictability of the vitellogenin response to a mixture of environmental estrogens. Fish were exposed to chemicals using a flow-through system. Firstly, concentration-response curves were determined for each individual chemical. Mixture effects were predicted on the basis of the potency of each chemical using the model of concentration addition (CA).

Actual mixture effects were then determined by combining the chemicals according to their relative potencies. Fish were then exposed to various dilutions of the mixture using a fixed ratio design (based on the EC50 of each chemical). The level of agreement between the observed and predicted mixture effects was analysed using biometrical modelling techniques. A second mixture experiment using the fathead minnow was designed to investigate the potential for mixture effects at low doses of the individual mixture components. The doses tested were equivalent to one-fifth of the EC50 of each chemical. This dose was selected on the premise that it would not be sufficient to induce a significant effect when present individually, but that combined exposure to all five chemicals at this concentration would induce a 50% response.

The results obtained from the freshwater fish mixture studies demonstrated an excellent agreement between predicted and observed effects for the 5-component mixture. There was no statistical deviation between the best fit of the observed and predicted mixture effect, with the prediction lying within the 95% confidence limits along the full length of the curve. The results of the sea bass studies also demonstrated an excellent agreement between predicted and observed effects with both a 5- and a 3-component mixture. These findings provide evidence that estrogenic chemicals act together according to the principles of CA in fish.

The second phase of mixture studies involving the fathead minnow vitellogenin assay involved the evaluation of the response to the five-component mixture, where each individual chemical was present at a low effect concentration. This demonstrated that although each chemical on its own did not induce a significant response, the 5-component mixture was capable of significantly raising VTG concentrations (to between 50-60% of the maximum response) in the test organism. There was good agreement once more between the observed effect of the mixture and the prediction of CA, with the prediction falling within the confidence limits of the observed effects. This confirms that the combined effects of these chemicals do not deviate from additivity in the low-effect concentration range, and reinforces the theory that allowable limits calculated for environmental concentrations of such chemicals may be inadequate if they are based on low-effect concentrations of individual chemicals. It is clear that, as a result of data such as these, risk assessment procedures, which are currently based on single substance exposure studies, will require extensive review.

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