Animal models and their limitations: On the problem of high-to-low dose extrapolations following inhalation exposures

Inhalation of complex mixtures such as combustion aerosols constitutes a parallel and simultaneous exposure of two distinctively different barriers to the body; the alveolar type I cells and the rest of the airway air/blood barrier, mainly the epithelium of the conducting airways. Exposure of the type I epithelium to most solutes leads to a rapid passage into the systemic circulation, and activation/deactivation of toxicants will take place mostly in the liver. Because of the huge metabolizing capacity of the liver, the dose-response of this component of an inhalation exposure is likely to be close to linear over larger exposure intervals. In contrast, exposures of the epithelium in the conducting airways lead to a slower passage, and in the case of semi-volatile solutes of high lipophilicities, a much slower passage into the systemic circulation. The result is a highly elevated concentration in the epithelium of the conducting airways during absorption, which may either lead directly to a localized toxicity, or, provide substrate for activating enzymes present in the airway mucosa. However, because of a limited capacity of the airway epithelium in this region both to dissolve sparingly soluble inhalants and to metabolize such solutes, the local dose-response is likely to saturate at rather low exposure levels. One important consequence of local saturation in the epithelium of the conducting airways, is that inhalation exposures of laboratory animals conducted at elevated concentrations and limited time spans, may underestimate the risk in humans chronically exposed at relatively low concentrations. The phenomenon could be relevant in the etiology of lung cancer as well as inflammatory airway disease, where semi-volatile organic toxicants are suspected to contribute significantly.