Adverse Endpoints

During the last 5-10 years, research has shown that signaling is the predominant mechanism for toxic effects rather than a direct role of reactive chemicals. As a result of this shift, subtle biological effects like altered biological signals versus direct effects like mutations have attracted greater attention [28]. In that light the U.S. EPA considers endocrine disruption as a step that could possibly cause toxic effects, and encourages studies to define dose-response relationships across multiple endpoints, describe mechanisms of action, and determine the complete organism's response to an environmental exposure [29]. The minimal system needed to study alterations in endocrine pathways is displayed in Fig. 3, where a xenoestrogen or phytoestrogen is able to interfere at any level.

The bioavailability of EACs, their effect on endogenous hormone metabolism, their interaction with hormone receptors and the interaction with cell-signaling pathways, each have a distinct outcome. Whether this outcome, e.g., increased transcription of a particular gene, is considered as an (adverse) effect or not requires a more defined description of variability in unexposed populations [28] partially resulting from different sensitivities to agents at different ages. Secondly, besides intensity, frequency and duration of the exposure, timing of the exposure should also be taken into account. Third, both primary and secondary interference can disturb endocrine function [29]. Consideration of all of the above will allow discrimination between a genuine (adverse) effect, as a result of the compound's impact, and the boundaries of normal homeostatic endocrine functioning. Furthermore, the outcomes can function as precursors, individually or combined, for intermediate and long-term endpoints. This poses a second, more philosophical question of which marker best describes an adverse (health) effect. In the long term there are only two actual adverse effects; increased incidence or earlier onset of illness and/or death. See Fig. 4 for an overview of (adverse) effects of endocrine disruption.

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