Regulatory hazard and risk assessment of endocrine-active substances currently specifies four modes of action: interference with sex hormone (oestrogen, androgen) pathways, steroidogenesis, and thyroid hormone signalling. This does not encompass the full complexity of the endocrine system and its extended interfaces with environmental pollutants that can potentially disrupt the carefully maintained balance. Here we take the retinoid signalling pathway as a European case study for both, under- and unregulated endocrine pathways and outline the different levels of interference, discuss their adversity, and indicate crosstalk to other signalling pathways. Retinoid compounds already exist in drinking water sources, occur naturally in cyanobacterial blooms and/or enter surface waters via wastewater discharge, where they pose a potential hazard to the environment and human health - a situation that can be expected to worsen due to water shortages induced by climate-change and population growth. We briefly review relevant aspects of current endocrine disruptor (ED) testing for regulatory purposes and then expand upon the needs for inclusion of disruption of retinoid signalling in (ED) regulatory safety assessment contributing to adverse health outcomes that include cognitive function and neurological disease. An overview of developmental effects of retinoid signalling disruption across species highlights critical processes and potential crosstalk with other signalling pathways. A focused weight of evidence-based evaluation of the biologically plausible associations between neurological disorders and altered retinoid signalling highlights the evidence gaps. We show that monitoring only a limited number of anthropogenic priority chemicals in water is insufficient to address the environmental risks of retinoid signalling disruption. To comprehensively assess impacts on the endpoints, processes, and pathways of the endocrine system that are most vulnerable to chemical interference we need further investigation of the true mixture composition in environmental matrices. On a weight of evidence-basis this information can then be integrated into a reliable, inclusive, quantitative approach that ultimately accommodates all the critical pathways. By focusing on the retinoid signalling pathway, we intend to improve the scope and relevance of an integrated approach for the risk assessment of endocrine disruptors.

内分泌活性物质的法规危害和风险评估目前规定了四种作用方式：干扰性激素（雌激素，雄激素）途径，类固醇生成和甲状腺激素信号传导。这不包括内分泌系统的完全复杂性及其与环境污染物的扩展接口，而这些环境污染物可能会破坏精心维护的平衡。在这里，我们将类维生素A信号通路作为欧洲案例研究，用于对内分泌通路的调节不足和未调节，概述不同程度的干扰，讨论其逆境，并指出与其他信号通路的串扰。类维生素A化合物已经存在于饮用水中，天然存在于蓝藻水华中和/或通过废水排放进入地表水，它们对环境和人类健康构成潜在危害-由于气候变化和人口增长引起的水资源短缺，这种情况预计会恶化。我们简要回顾了当前内分泌干扰物（ED）测试的相关方面，以用于监管目的，然后扩展了在（ED）监管安全性评估中纳入类维生素A信号传导中断的需求，这有助于不良健康结果，包括认知功能和神经系统疾病。类维生素A信号跨物种破坏的发展影响概述突出了关键过程以及与其他信号途径的潜在串扰。对神经系统疾病和类维生素A信号转导之间生物学上合理联系的循证评估重点突出了证据空白。我们表明，仅监测水中有限数量的人为优先化学物质不足以解决类维生素A信号破坏的环境风险。为了全面评估对最容易受到化学干扰的内分泌系统的终点，过程和途径的影响，我们需要进一步研究环境基质中的真正混合物组成。基于大量证据，可以将这些信息集成到一个可靠的，包容的，定量的方法中，该方法最终可以容纳所有关键途径。通过专注于类维生素A信号通路，