Convincing evidence suggests that poorly soluble low-toxicity particles (PSP) exert two unifying major modes of action (MoA), in which one appears to be deposition-related acute, whilst the other is retention-related and occurs with particle accumulation in the lung and associated persistent inflammation. Either MoA has its study- and cumulative dose-specific adverse outcome and metric. Modeling procedures were applied to better understand as to which extent protocol variables may predetermine any specific outcome of study. The results from modeled and empirical studies served as basis to derive OELs from modeled and empirically confirmed directions. This analysis demonstrates that the accumulated retained particle displacement volume was the most prominent unifying denominator linking the pulmonary retained volumetric particle dose to inflammogenicity and toxicity. However, conventional study design may not always be appropriate to unequivocally discriminate the surface thermodynamics-related acute adversity from the cumulative retention volume-related chronic adversity. Thus, in the absence of kinetically designed studies, it may become increasingly challenging to differentiate substance-specific deposition-related acute effects from the more chronic retained cumulative dose-related effects. It is concluded that the degree of dissolution of particles in the pulmonary environment seems to be generally underestimated with the possibility to attribute to toxicity due to decreased particle size and associated changes in thermodynamics and kinetics of dissolution. Accordingly, acute deposition-related outcomes become an important secondary variable within the pulmonary microenvironment. In turn, lung-overload related chronic adversities seem to be better described by the particle volume metric. This analysis supports the concept that ‘self-validating’, hypothesis-based computational study design delivers the highest level of unifying information required for the risk characterization of PSP. In demonstrating that the PSP under consideration is truly following the generic PSP-paradigm, this higher level of mechanistic information reduces the potential uncertainty involved with OEL derivation.

中文翻译：

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低毒性等距生物持久性颗粒的职业暴露水平（OELs）的推导：肺动态超负荷范式如何用于改进吸入毒性研究设计和OEL推导？

令人信服的证据表明，难溶性低毒性颗粒（PSP）发挥两种统一的主要作用方式（MoA），其中一种似乎是与沉积有关的急性反应，而另一种是与保留有关的，并且与肺中的颗粒堆积有关以及相关的持续性炎症。MoA都有其针对研究和累积剂量的不良结果和指标。应用建模程序可以更好地了解方案变量可以在多大程度上预先确定研究的任何特定结果。建模和实证研究的结果可作为从建模和实证确认的方向得出OEL的基础。该分析表明，累积的保留颗粒置换体积是将肺部保留体积颗粒剂量与致炎性和毒性联系起来的最突出的统一分母。但是，传统的研究设计可能并不总是总是恰当地将表面热力学相关的急性逆境与累积滞留量相关的慢性逆境区分开。因此，在缺乏动力学设计的研究的情况下，将物质特异性沉积相关的急性效应与更长期的累积累积剂量相关效应区分开来可能变得越来越具有挑战性。结论是，在肺环境中颗粒的溶解度似乎被低估了，归因于由于粒径减小以及溶解的热力学和动力学的相关变化而引起的毒性。因此，急性沉积相关的预后成为肺微环境中重要的次要变量。反过来，与肺超负荷相关的慢性逆境似乎可以通过颗粒量指标更好地描述。该分析支持以下概念：基于假设的“自我验证”计算研究设计可提供PSP风险表征所需的最高级别的统一信息。在表明所考虑的PSP确实遵循通用PSP范式时，