Abstract
BackgroundConvincing 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.ResultsThis 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.ConclusionIt 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.
Highlights
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
This paper focuses on the minimal prerequisites for deriving an occupational exposure limit value (OEL) of materials subsumed under the hypernym “poorly soluble low-toxicity granular particles (PSP)” at early stages of product development with yet limited human exposure data
OELs have to be derived on the basis of regulatory-driven toxicity studies in general and repeated inhalation toxicity studies in particular
Summary
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. This paper focuses on the minimal prerequisites for deriving an occupational exposure limit value (OEL) of materials subsumed under the hypernym “poorly soluble low-toxicity granular particles (PSP)” at early stages of product development with yet limited human exposure data At this stage, OELs have to be derived on the basis of regulatory-driven toxicity studies in general and repeated inhalation toxicity studies in particular. Direct extrapolation of the effect levels from animals to humans, that is to use a cumulative assessment factor (AF) of 1, has been suggested [4,7] In this regulatory context, harmonized OECD testing guidelines [8,9,10] should be observed to design and execute the regulatory set of studies to fulfill the substances’ requirement for Registration, Evaluation, Authorisation of Chemicals (REACH) and Globally Harmonised System (GHS) of Classification and Labeling [2,3,7,11]. It is beyond the scope of this concise paper to reproduce the specific terminology and background detailed in these guidelines or those related to the concepts to calculate the human equivalent concentration (HEC) [12] which served as basis for the translation of data from rat inhalation studies to humans
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
