Absence of phagolysosomal activation and high clearance efficiency define the low pulmonary toxicity of short asbestos fibers

The physicochemical properties of fibers critically determine asbestos pathogenicity, driving inflammation, fibrosis, and lung cancer. The prevailing paradigm in fiber toxicology posits that long and biopersistent fibers pose a greater health risk than short fibers. However, this assumption is debated due to limited studies specifically assessing the pathogenicity of short fibers. In this study, we compared the lung proinflammatory and profibrogenic effects of two amosite fiber types, long pristine amosite (pAmo, L > 5 µm) and short milled amosite (mAmo, L < 5 µm). In instilled C57BL/6 mice, long pAmo were significantly more inflammogenic and fibrogenic than short mAmo, which only induced limited acute pulmonary toxicity. Radical production under acidic phagolysosomal conditions occurred with long pAmo but not mAmo, explaining the pronounced pulmonary responses to pAmo. ICP-MS analysis revealed that long pAmo persisted in lung tissue, whereas short mAmo was completely cleared within four months. Nevertheless, a substantial fraction of short mAmo was biodistributed to extrapulmonary organs, including liver, spleen, and mediastinal lymph nodes in comparison to long pAmo. In conclusion, these findings establish fiber length as a critical determinant of asbestos-induced pulmonary pathogenicity and demonstrate that the limited pulmonary toxicity of short amosite fibers results from their low reactivity and rapid lung clearance. Moreover, the significant extrapulmonary translocation of short amosite observed in our study underscores the importance of considering the potential systemic effects of small fibers.