The effects of simple mixtures of chemicals, with similar mechanisms of action, can be predicted using the concentration addition model (CA). The ability of this model to predict the estrogenic effects of more complex mixtures such as effluent discharges, however, has yet to be established. Effluents from 43 U.K. wastewater treatment works were analyzed for the presence of the principal estrogenic chemical contaminants, estradiol, estrone, ethinylestradiol, and nonylphenol. The measured concentrations were used to predict the estrogenic activity of each effluent, employing the model of CA, based on the relative potencies of the individual chemicals in an in vitro recombinant yeast estrogen screen (rYES) and a short-term (14-day) in vivo rainbow trout vitellogenin induction assay. Based on the measured concentrations of the four chemicals in the effluents and their relative potencies in each assay, the calculated in vitro and in vivo responses compared well and ranged between 3.5 and 87 ng/L of estradiol equivalents (E2 EQ) for the different effluents. In the rYES, however, the measured E2 EQ concentrations in the effluents ranged between 0.65 and 43 ng E2 EQ/L, and they varied against those predicted by the CA model. Deviations in the estimation of the estrogenic potency of the effluents by the CA model, compared with the measured responses in the rYES, are likely to have resulted from inaccuracies associated with the measurement of the chemicals in the extracts derived from the complex effluents. Such deviations could also result as a consequence of interactions between chemicals present in the extracts that disrupted the activation of the estrogen response elements in the rYES. E2 EQ concentrations derived from the vitellogenic response in fathead minnows exposed to a series of effluent dilutions were highly comparable with the E2 EQ concentrations derived from assessments of the estrogenic potency of these dilutions in the rYES. Together these data support the use of bioassays for determining the estrogenic potency of WwTW effluents, and they highlight the associated problems for modeling approaches that are reliant on measured concentrations of estrogenic chemicals.

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There has been a substantial proliferation in the number of studies reporting endocrine effects as an endpoint. The vast majority have focused on oestrogenicity in vitro but, with recent recommendations by the USEPA Endocrine Disrupter Screening and Testing Advisory Committee, tests are now being developed for (anti)-androgenicity and effects on the thyroid, largely because of the potential for altering reproduction or development via these mechanisms. Despite being a vital organ and involved in reproduction and development, there is currently no provision for assessing adrenocortical function. Similarly, the entire process of steroidogenesis poses multiple molecular targets for toxic disruption that are not included in current test strategies and at present there is no clear position on the significance of the data being generated. This review provides a framework for approaching endocrine data: that all the glands, tissues, receptors, transporter proteins and enzymes that comprise the endocrine system are targets for toxicity. They should be considered in much the same way as other target organs, with appropriate provision for the special cases of carcinogenesis and teratogenesis, and a pragmatic weight of evidence approach should be adopted considering all available data and recognizing its limitations. In this approach, structure-activity relationships and in vitro and targeted in vivo screens provide useful data but repeat-dose regulatory studies with defined endpoints provide the most powerful tools for hazard assessment. Pragmatic consideration should be given to exposure issues (which may highlight the practical irrelevance, for example, of very low potency oestrogens) and subsequently whether endocrine disruption is the critical or most sensitive endpoint for a compound. Finally, endocrine disruption may be considered a mechanism and, as with other toxic endpoints, knowledge of effect and no-observable-effect levels and reversibility is as important as identifying the target tissue or any inherent hormone-like property.

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