Dose–Response Assessment Strategies for Endocrine-Active Compounds

Abstract

Hazard identification provides evidence for the potential of compounds to cause effects in exposed people. Dose-response assessments define the range of exposure conditions associated with minimal risks of adverse effects. With endocrine-active compounds (EACs), the vast majority of resources are presently being applied to hazard identification. In the past, dose-response assessments have been based on empirical analysis of these relationships. The empirical underpinnings of these models do not permit conclusions about the low-dose and interspecies extrapolation of the animal study results. Biologically based dose-response assessments relying on knowledge of mode-of-action (pharmacodynamics) and dosimetry (pharmacokinetics) offer promise to develop broadly applicable strategies for quantitative dose-response assessments with these EACs. These approaches would focus on normal physiological endocrine signaling processes in the body, their associated control mechanisms, and the interaction among different internal signaling pathways. A critical element of signaling is regulation of the concentration of the signaling compound, e.g., steroid sex hormone. Exogenous compounds that act as signals but evade the normal homeostatic control of signaling compound concentrations represent one class of EACs. Other molecular components of these signaling systems include receptors, second messengers, and DNA-accessory/transcriptional protein complexes; EACs may interfere with the functions of any of these components. The challenge facing the toxicology and risk assessment professions is to base regulatory strategies on the interaction of these EACs with the fundamental control mechanisms which regulate responses throughout the body and to determine the extent to which these interactions create specific dose-response behaviors in the living animals.