Dosimetric principles for extrapolating results of rat inhalation studies to humans, using an inhaled Ni compound as an example.
Dose-effect relationships of inhaled substances are complicated by the interrelationship between inhaled dose, deposited dose, and retained dose. Deposited and retained doses are most important for evaluating dose-effect relations; however, inhaled dose and exposure concentration that are not representative of the actual dose to target sites are widely used for this purpose. For extrapolating results of animal inhalation studies to humans, several factors have to be considered for calculating a human equivalent dose to the respiratory tract and for estimating a human equivalent exposure concentration. Among these factors are separate deposition in nasopharyngeal, tracheobronchial, and alveolar regions, both total regional deposition and deposited dose per unit surface area. Predictive particle deposition models for the respiratory tract can be used for calculating these. The retained dose is another factor that takes into account respiratory tract retention and determines the long-term dose to the respiratory tract. A rat inhalation study using Ni3S2 exposure (concentration, 970 micrograms m-3; duration, 78 wk; exposure, 6 h d-1, 5 d wk-1) resulted in bronchogenic and alveologenic tumors. Extrapolation modeling of rat data was performed based on dose factors discussed above, and assuming different conditions of pulmonary retention for Ni3S2 with half-times of 36 d for rats and 103 d for humans. Model calculations showed that deposited surface area dose was greater for the tracheobronchial than for the pulmonary region in both rat and man. The retained dose per gram of lung was greater in rat than in man under resting conditions. An equivalent exposure concentration would be lower in humans than in the rat if it is based on the retained dose expressed per square centimeter of alveolar surface area. However, inhaled equivalent concentration in man can be considerably higher when the tracheobronchial surface area dose is considered. The most sensitive region of the respiratory tract--for example, with regard to tumor induction--should be selected for estimating human equivalent exposure.