A quantitative framework for animal-to-human extrapolation of inhaled aerosols using species-specific respiratory dosimetry.

Quantitative extrapolation of inhalation toxicity data from experimental animals to humans remains challenging because identical external aerosol exposures do not necessarily produce equivalent internal respiratory doses across species. This study aimed to establish a quantitative computational framework for animal-to-human extrapolation by integrating species-specific respiratory dosimetry using the Multiple-Path Particle Dosimetry (MPPD) model. Species-specific respiratory dosimetry models were developed for mice, rats, and adult humans using MPPD v3.04 under identical aerosol exposure conditions. Regional respiratory deposition was compared across species, while the effects of aerosol particle size (mass median aerodynamic diameter, MMAD) and human breathing scenarios were systematically evaluated. Regional deposition outputs were further integrated to derive quantitative dosimetry indices, human equivalent concentrations (HECs), and species correction factors (SCFs) for animal-to-human extrapolation. Marked interspecies differences were observed in regional respiratory deposition despite identical aerosol exposure conditions. Rodents exhibited predominant deposition within the extrathoracic region, whereas humans demonstrated substantially greater pulmonary deposition. Species-specific deposition differences became more pronounced with increasing MMAD, and pulmonary delivery in humans was strongly influenced by breathing scenario. Quantitative dosimetry analysis demonstrated that pulmonary deposition in humans was approximately three-fold greater than in rodents under the reference exposure condition, resulting in substantially different regional respiratory deposition metric despite equivalent external exposures. The proposed HEC and SCF metrics enabled quantitative comparison and translation of animal and human exposure conditions using MPPD-derived regional deposition metrics rather than external aerosol concentration alone. This study presents a species-specific respiratory dosimetry framework for quantitative animal-to-human extrapolation of inhaled aerosols. By integrating regional respiratory deposition with HEC and SCF analyses, the proposed framework provides a mechanistically informed strategy for inhalation dosimetry, human equivalent exposure estimation, and future integration with physiologically based pharmacokinetic modeling and inhalation risk assessment.