Inhalation toxicology: Methodological and regulatory challenges

Highly standardized and controlled inhalation studies are required for hazard identification to make test results reproducible and comparable and also to fulfill general regulatory requirements for the registration of new drugs, pesticides, or notification of chemicals. Inhalation studies have numerous experimental variables; these are related to substance-specific physical factors such as particle size and phase and that a specific “exposure dose” can be achieved by two variables, viz. exposure concentration and duration. Variables related to the exposure or dosing regimen may become important, especially for short-acting substances. In addition, specific use or product patterns, e.g. specialized configurations designed for inhalation drug delivery or end-user products emitting aerosols may challenge traditional approaches. The testing of innocuous, poorly soluble particulates in the fine and ultrafine size range is a demanding exercise because the toxic manifestation of particle-induced effects often requires long postexposure periods. The difference in toxic potency of such particles may emerge from differences related to particle clearance, rate of dissolution within lung tissue, liberation of redox-active, free metal ions or the initiation of a somewhat self-amplifying and self-perpetuating pulmonary inflammation. Due to the heterogeneity of deposition of inhaled materials within the respiratory tract, each specific site of the tract may be exposed differently. Ensuing toxic responses may either be related to the solubility or insolubility of the inhaled material. The many facets of inhalation exposure and consequent occurrence of toxic effects caused by systemic and/or localized direct biochemical or secondary physiological effects appear to be a methodological challenge for alternative test approaches. Accordingly, it is experimentally challenging to articulate a unifying denominator of dose at critical cellular targets in both in vivo and in vitro test systems due to the complex dependence on test material-specific characteristics.