Barton H A, Andersen M E
ICF Kaiser, Research Triangle Park, North Carolina 27709, USA.
Regul Toxicol Pharmacol. 1997 Jun;25(3):292-305. doi: 10.1006/rtph.1997.1106.
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.
危害识别为化合物在接触人群中产生影响的可能性提供了证据。剂量反应评估确定了与最小不良反应风险相关的暴露条件范围。对于内分泌活性化合物（EAC），目前绝大多数资源都用于危害识别。过去，剂量反应评估是基于对这些关系的实证分析。这些模型的实证基础不允许对动物研究结果进行低剂量和种间外推得出结论。基于作用模式（药效学）和剂量学（药代动力学）知识的基于生物学的剂量反应评估有望为这些EAC开发广泛适用的定量剂量反应评估策略。这些方法将关注体内正常的生理内分泌信号传导过程、其相关的控制机制以及不同内部信号通路之间的相互作用。信号传导的一个关键要素是信号化合物浓度的调节，例如甾体性激素。作为信号但逃避信号化合物浓度正常稳态控制的外源性化合物代表了一类EAC。这些信号系统的其他分子成分包括受体、第二信使和DNA辅助/转录蛋白复合物；EAC可能会干扰这些成分中的任何一种的功能。毒理学和风险评估行业面临的挑战是将监管策略建立在这些EAC与调节全身反应的基本控制机制的相互作用基础上，并确定这些相互作用在活体动物中产生特定剂量反应行为的程度。
