Re-defining kinetic lung overload: Time for new paradigms

This paper compares two previously published 13-week inhalation studies with poorly soluble, low-toxicity particles (PSLTs) in rats to identify the unifying key metric of kinetic lung overload. The PSLTs compared are Multi-Walled Carbon Nanotubes (MWCNT) and black iron oxide (Fe3O4, magnetite). Their material densities and related displacement volumes differ approximately 30-fold. This offers an opportunity for analyzing the impact of the PSLT-density of agglomerates on endpoints currently conceived to be involved in kinetic lung overload. Corpuscular volumes and counts of cells retrieved by bronchoalveolar lavage (BAL) are analyzed to interrelate modeled cumulative lung burdens of solid aerosol to predict the no observed adverse effect concentration (NOAEC) and range of conditions causing various degrees of kinetic lung overload up to and beyond the maximum tolerated cumulative dose (MTD). Both descriptors are a reflection of accumulated lung burdens and, by design, bracket repeated exposure inhalation studies with PSLTs. This comparative analysis of high- and low-density PSLTs reveals that the leading adverse outcome pathway (AOP) is caused by a markedly increased pool-size of BAL-cells rather than any increased corpuscular volume of cells. The overload-related increased pool-size of BAL-cells is shown to be the dependent variable for the prorated increased elimination half-time of PSLTs. This interrelationship was used to predict the exposure concentrations for attaining a NOAEC and MTD of guideline-based repeated exposure inhalation studies with PSLTs. Earlier approaches suggesting a loss of the migratory capabilities of particle-laden, enlarged alveolar macrophages to be the cause for any increased elimination half-time of PSLTs could not be confirmed. In summary, kinetic modeling provides a versatile means to predict the cornerstones of repeated inhalation studies with PSLTs on rats. Such possibilities leverage adjustment of studies from different sources to identical degrees of kinetic overload. They also facilitate and foster AOP-facilitated read-across approaches. The course taken enables risk assessors to better differentiate lung pathologies caused by generic lung overload and substance-specific pathologies.