Pulmonary Retention and Clearance of Inhaled Biopersistent Aerosol Particles: Data-Reducing Interpolation Models and Models of Physiologically Based Systems: - A Review of Recent Progress and Remaining Problems

Abstract

During the last 40 years, most models of long-term clearance and retention of biopersistent particles in the pulmonary region of the lung were phenomenologically oriented and accounted for only a small portion of the growing insight into lung dynamics by pulmologists, histologists, and biochemists. In this review, theoretical developments of modeling pulmonary dynamics for biopersistent particles during or after inhalation exposure are discussed. Several characteristic examples are given of the present state of the art. Most of the models presently in use are pragmatical compartmental models with a single compartment for the pulmonary region. They relate to observed data and facilitate an interpolation within the range covered by observation. Occasionally, these models are unjustifiably used for extrapolations in efforts to derive hypothetical risk assessments. Modeling efforts aiming at models of physiologically based pulmonary systems with a potential for extrapolations are not common and were published only during the last decade. Of this kind of approach, the review covers four examples. Promising progress has been made, but scarcity of supporting experimental data slows validation and extension. The two most recent model developments are based on a hypothesis by P.E. Morrow⁷². According to Morrow, alveolar clearance is accomplished by mobile alveolar macrophages after phagocytosis of particles on the alveolar surface. The macrophage mobility, however, and thus the efficiency of the transport to the mucociliary escalator of the tracheobronchial tract will eventually decline towards total loss of mobility after the particle burden of the macrophages exceeds a critical value. The POCK model⁸³ has been evaluated for a variety of chronic and subchronic rat exposure studies with noncytotoxic aerosols and gave good simulation results. The model by Tran et al.⁸⁷ appears to be still in the developing stage of facilitating simulations for cytotoxic aerosols, but the combination of both model approaches seems to be a sound route of future efforts.

Key Words:

• insoluble particles
• biopersistent particles
• multicompartmental pulmonary modeling
• extrapolation bias
• rat lung
• overload carcinogenesis