Wageningen University, Sub-department of Toxicology, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
Toxicol In Vitro. 2013 Jun;27(4):1320-46. doi: 10.1016/j.tiv.2013.02.012. Epub 2013 Feb 27.
The thyroid hormone (TH) system is involved in several important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo-regulation, and axis of regulation of other endocrine systems, sexual behaviour and fertility and cardiovascular function. Therefore, concern about TH disruption (THD) has resulted in strategies being developed to identify THD chemicals (THDCs). Information on potential of chemicals causing THD is typically derived from animal studies. For the majority of chemicals, however, this information is either limited or unavailable. It is also unlikely that animal experiments will be performed for all THD relevant chemicals in the near future for ethical, financial and practical reasons. In addition, typical animal experiments often do not provide information on the mechanism of action of THDC, making it harder to extrapolate results across species. Relevant effects may not be identified in animal studies when the effects are delayed, life stage specific, not assessed by the experimental paradigm (e.g., behaviour) or only occur when an organism has to adapt to environmental factors by modulating TH levels. Therefore, in vitro and in silico alternatives to identify THDC and quantify their potency are needed. THDC have many potential mechanisms of action, including altered hormone production, transport, metabolism, receptor activation and disruption of several feed-back mechanisms. In vitro assays are available for many of these endpoints, and the application of modern '-omics' technologies, applicable for in vivo studies can help to reveal relevant and possibly new endpoints for inclusion in a targeted THDC in vitro test battery. Within the framework of the ASAT initiative (Assuring Safety without Animal Testing), an international group consisting of experts in the areas of thyroid endocrinology, toxicology of endocrine disruption, neurotoxicology, high-throughput screening, computational biology, and regulatory affairs has reviewed the state of science for (1) known mechanisms for THD plus examples of THDC; (2) in vitro THD tests currently available or under development related to these mechanisms; and (3) in silico methods for estimating the blood levels of THDC. Based on this scientific review, the panel has recommended a battery of test methods to be able to classify chemicals as of less or high concern for further hazard and risk assessment for THD. In addition, research gaps and needs are identified to be able to optimize and validate the targeted THD in vitro test battery for a mechanism-based strategy for a decision to opt out or to proceed with further testing for THD.
甲状腺激素（TH）系统参与许多重要的生理过程，包括调节能量代谢、生长和分化、大脑功能的发育和维持、体温调节、渗透调节以及其他内分泌系统的调节轴、性行为和生育以及心血管功能。因此，对甲状腺激素破坏（THD）的关注导致了制定策略以识别 THD 化学品（THDCs）。关于潜在引起 THD 的化学品的信息通常来自动物研究。然而，对于大多数化学品，这种信息要么有限，要么无法获得。出于伦理、财务和实际原因，也不太可能在不久的将来对所有与 THD 相关的化学品进行动物实验。此外，典型的动物实验通常不能提供关于 THDC 作用机制的信息，这使得更难将结果推断到不同物种。当影响是延迟的、特定于生命阶段的、实验范式（例如行为）未评估的或者仅当生物体必须通过调节 TH 水平来适应环境因素时，相关影响可能不会在动物研究中被识别。因此，需要体外和计算替代品来识别 THDC 并量化其效力。THDC 具有许多潜在的作用机制，包括改变激素的产生、运输、代谢、受体激活和破坏几种反馈机制。许多这些终点都有可用的体外检测方法，并且现代“组学”技术的应用，适用于体内研究，可以帮助揭示相关的、可能的新终点，以纳入针对 THDC 的体外测试组合。在 ASAT 倡议（无动物测试保障安全）的框架内，一个由甲状腺内分泌学、内分泌干扰毒理学、神经毒理学、高通量筛选、计算生物学和监管事务领域的专家组成的国际小组审查了（1）已知的 THD 机制加上 THDC 的例子；（2）目前可用于或正在开发的与这些机制相关的体外 THD 测试；（3）用于估计 THDC 血液水平的计算方法。基于这项科学综述，该小组建议使用一系列测试方法，以便能够将化学品分类为低或高关注程度，以进一步进行 THD 的危害和风险评估。此外，还确定了研究差距和需求，以便能够优化和验证针对 THD 的基于机制的策略的体外 THD 测试组合，以选择退出或继续进行进一步的 THD 测试。
