The Pneumoconiosis Renaissance: Revisiting the Pulmonary Pathology of Poorly Soluble Low Toxicity Particles: Insights from Rodent Inhalation Studies on Titanium Dioxide Nanoparticles

Historically, the toxicological evaluation of poorly soluble low toxicity particles (PSLTs), such as titanium dioxide nanoparticles (TiO2 NPs), has focused on carcinogenicity and lung overload, leaving their pathological function in development of pneumoconiosis undefined. In this study, we initiate a "Pneumoconiosis Renaissance", redefining the human "Gold Standard" of pneumoconiosis pathology as a primarily interstitial "Dust Macule (DM) to Mixed Dust Fibrosis (MDF) axis." In contrast, rats develop a species-specific "Airspace-Dominant Phenotype" (Pulmonary Dust Foci) driven by airspace stagnation. Integrating recent continuous inhalation exposure and recovery after inhalation exposure studies, we demonstrate that this overwhelming alveolar pathology in rats acts as a "Biological Mask," physically superimposing upon and obscuring human-relevant interstitial sequestration. Crucially, however, extended recovery periods can unmask these interstitial events, revealing the true underlying pathology. We propose that future risk assessments and Adverse Outcome Pathways (AOPs) must incorporate spatial resolution. By rigorously segregating sensitive rat-specific airspace events from human-relevant interstitial remodeling, we can accurately bridge the interspecies gap. This review argues that rather than discarding the rat model, we must learn to decode it—using spatial distinctions to filter the airspace mask and evaluate the true interstitial risk of inhaled biodurable particles.