Interspecies modeling of inhaled particle deposition patterns

Abstract

To evaluate the potential toxic effects of ambient contaminants or therapeutic effects of airborne drugs, inhalation exposure experiments can be performed with surrogate laboratory animals. Herein, an interspecies particle deposition theory is presented for physiologically based pharmacokinetic modeling. It is derived to improve animal testing protocols. The computer code describes the behavior and fate of particles in the lungs of human subjects and a selected surrogate, the laboratory rat. In the simulations CO2 is integrated with exposure chamber atmospheres, and its concentrations regulated to produce rat breathing profiles corresponding to selected levels of human physical activity. The dosimetric model is used to calculate total, compartmental (i.e. tracheobronchial and pulmonary), and localized distribution patterns of inhaled particles in rats and humans for comparable ventilatory conditions. Perhaps most importantly regarding dose delivery, the computer program is used to determine distributions on an airway-by-airway basis throughout human and rat lungs. In this format, calculated particle deposition patterns are related to focal lesions observed experimentally. Likewise, topical fluid dynamics profiles (e.g. the laryngeal jet) are correlated with deposition hot spots and clinically observed sites of lung carcinomas. Implementation of the model will permit toxicologic and pharmacologic exposure tests to be conducted in a manner conducive for the accurate extrapolation of animal data to man. The model, therefore, is complementary to surrogate testing. Computational details are presented which stress the applications of the interspecies deposition model. Results indicate that physiologically comparable ventilatory levels do not necessarily yield similar dose distributions. For example, inhalation exposures with the resting rat may not simulate the resting human, depending upon specific particle sizes examined and the resolution of deposition patterns demanded by the investigator (i.e. whether total, compartmental or localized distributions are of most importance). However, it is demonstrated that the model can be used to predetermine the exposure conditions necessary to produce particle deposition efficiency patterns in rats that are equivalent to those in humans at prescribed physical activities. © 1992.