Lung Dosimetry and Extrapolation of Results from Animal Inhalation Studies to Man

Abstract

ABSTRACT

The dose in the respiratory tract which causes an effect depends critically on airway geometry, ventilatory parameters, particle characteristics and clearance and retention kinetics. Most often, effects of inhaled compounds are characterized by "exposure-response" relationships rather than by "dose-response" relationships. However, exposure is not equivalent to a dose. Knowledge of respiratory tract dosimetry is required to understand the relation between inhaled, deposited and retained doses and effects. Predictive models of particle deposition for specific regions in the lung or specific airway generations can be applied to estimate regional and local doses of an inhaled compound. In addition to applications in diagnostic and therapeutic aerosol delivery, lung dosimetry is of importance for extrapolation of results from animal studies to humans. Species specific deposition and retention of inhaled paniculate compounds, normalized for airway surface area or tissue weight, have to be considered to compare doses rather than exposures. However, the underlying assumption that equal doses in animals and man will lead to the same effects can be challenged. An additional problem is given by the need to extrapolate from high experimental to low environmental or occupational exposures. Examples from inhalation toxicology including cadmium, diesel exhaust and asbestos will be used to demonstrate principles of lung dosimetry. Future research needs include the incorporation of mechanistic data to develop mechanistically oriented dosimetric models for extrapolation modeling.