The underlying mechanisms of toluene-induced neurotoxicity in the human brain: physiological and cognitive perspectives

甲苯是一种众所周知的神经毒性有机溶剂，也是许多工业和商业产品的主要成分，如粘合剂，油漆稀释剂和汽油。许多工人在工作环境中经常接触甲苯，长期接触甲苯可能会导致患上与工作有关的疾病。为避免对健康造成不良影响，各国已设定了职业接触限值（OEL），范围为14- 300 ppm。这些安全限度范围广泛，部分原因是对人体潜在病理生理学效应的了解不足。我们最近已经证明了急性甲苯暴露通过非侵入性脑刺激技术在健康参与者的神经生理学的影响，并发现了重要的影响，神经可塑性和皮质兴奋性下的德国OEL允许的曝光。在本提案中，我们的目标是将有关甲苯作用的知识扩展到有或无临床症状的职业长期暴露人群。将招募三组受试者（无暴露的健康对照组、无症状的长期暴露组和有症状的长期暴露组），并将在认知和神经生理参数方面进行探索和比较。此外，将在两个无症状组中探索急性暴露于甲苯的影响。我们预期，在没有急性甲苯暴露的研究中，与健康的非暴露组相比，长期暴露组显示出认知和生理缺陷，并且这种影响在出现症状的组中更为突出。我们还预计，与非长期暴露的健康对照组相比，急性甲苯暴露对无临床症状的长期暴露组的这些参数有更显著的影响。该项目的结果将提供更深入的了解甲苯在人体内的作用机制和条件，特别是关于这种有机溶剂从急性到慢性神经毒性作用的过渡。

Toluene is a well-known neurotoxic organic solvent and a major component of many industrial and commercial products such as adhesives, paint thinners and gasoline. Many workers are regularly exposed to toluene in their working environment with the potential risk to develop work-related diseases due to long-term exposure. Occupational exposure limits (OELs) have been set, ranging from 14-300ppm across countries, to avoid adverse health effects. The wide range of these safety limits is partially due to poor understanding of the underlying pathophysiological effects in humans. We have recently demonstrated the neurophysiological impact of acute toluene exposure via non-invasive brain stimulation techniques in healthy participants, and found important effects on neuroplasticity, and cortical excitability under exposures permitted by the German OEL. In this proposal, we aim to extend the knowledge about the action of toluene to the population with occupational long-term exposure with or without clinical symptoms. Three groups of participants (healthy controls without exposure, chronically exposed without symptoms, and chronically exposed with symptoms) will be recruited, and will be explored and compared with respect to both, cognitive and neurophysiological parameters. Additionally, the effects of acute exposure to toluene will be explored in the two groups without symptoms. We are expecting that in the study without acute toluene-exposition, the chronically exposed groups show cognitive, and physiological deficits, as compared to the healthy non-exposed group, and that this effect is more prominent in the group which developed symptoms. We expect furthermore that acute toluene exposition has more prominent effects on these parameters in the chronically exposed group without clinical symptoms, as compared to the not chronical exposed healthy control group. The results of this project will provide more profound insight into the mechanisms, and conditions, of the action of toluene in humans especially with respect to the transition from acute to chronic neurotoxic effects of this organic solvent.