Applied Pharmacology and Toxicology, Inc. and CEHT, Univ. FL College of Vet. Med., Gainesville, FL, USA.
University of Mississippi School of Pharmacy, University, MS, USA.
Arch Toxicol. 2018 May;92(5):1685-1702. doi: 10.1007/s00204-018-2186-z. Epub 2018 Apr 9.
The European Commission has recently proposed draft criteria for the identification of endocrine disrupting chemicals (EDCs) that pose a significant hazard to humans or the environment. Identifying and characterizing toxic hazards based on the manner by which adverse effects are produced rather than on the nature of those adverse effects departs from traditional practice and requires a proper interpretation of the evidence regarding the chemical's ability to produce physiological effect(s) via a specific mode of action (MoA). The ability of any chemical to produce a physiological effect depends on its pharmacokinetics and the potency by which it acts via the various MoAs that can lead to the particular effect. A chemical's potency for a specific MoA-its mechanistic potency-is determined by two properties: (1) its affinity for the functional components that comprise the MoA, i.e., its specific receptors, enzymes, transporters, transcriptional elements, etc., and (2) its ability to alter the functional state of those components (activity). Using the agonist MoA via estrogen receptor alpha, we illustrate an empirical method for determining a human-relevant potency threshold (HRPT), defined as the minimum level of mechanistic potency necessary for a chemical to be able to act via a particular MoA in humans. One important use for an HRPT is to distinguish between chemicals that may be capable of, versus those likely to be incapable of, producing adverse effects in humans via the specified MoA. The method involves comparing chemicals that have different ERα agonist potencies with the ability of those chemicals to produce ERα-mediated agonist responses in human clinical trials. Based on this approach, we propose an HRPT for ERα agonism of 1E-04 relative to the potency of the endogenous estrogenic hormone 17β-estradiol or the pharmaceutical estrogen, 17α-ethinylestradiol. This approach provides a practical way to address Hazard Identification according to the draft criteria for identification of EDCs recently proposed by the European Commission.
欧盟委员会最近提出了内分泌干扰物（EDCs）的鉴定标准草案，这些物质对人类或环境构成重大危害。根据产生不良影响的方式而不是不良影响的性质来识别和描述毒性危害，这偏离了传统做法，需要对化学物质通过特定作用模式（MoA）产生生理效应的能力的证据进行适当解释。任何化学物质产生生理效应的能力取决于其药代动力学和通过各种可能导致特定效应的 MoA 发挥作用的效力。化学物质对特定 MoA 的效力（其机制效力）取决于两个特性：（1）其与构成 MoA 的功能成分的亲和力，即其特定的受体、酶、转运蛋白、转录因子等，以及（2）其改变这些成分的功能状态的能力（活性）。我们使用雌激素受体 alpha 的激动剂 MoA 来说明确定人类相关效力阈值（HRPT）的经验方法，该阈值定义为化学物质通过特定 MoA 在人类体内发挥作用所需的最低机制效力水平。HRPT 的一个重要用途是区分那些可能有能力，而不是那些可能没有能力，通过指定的 MoA 在人类中产生不良影响的化学物质。该方法涉及比较具有不同 ERα 激动剂效力的化学物质与这些化学物质在人类临床试验中产生 ERα 介导的激动剂反应的能力。基于这种方法，我们提出了 ERα 激动作用的 HRPT 为 1E-04，相对于内源性雌激素 17β-雌二醇或药物雌激素 17α-乙炔雌二醇的效力。这种方法为根据欧盟委员会最近提出的 EDC 鉴定标准草案进行危害识别提供了一种实用方法。
