Inhalation studies in laboratory animals - Current concepts and alternatives

Highly standardized and controlled inhalation studies are required for haza rd identification to make test results reproducible and comparable and to f ulfill general regulatory requirements for the registration of new drugs, p esticides, or chemicals. Despite significant efforts, the results of inhala tion studies have to be analyzed judiciously due to the great number of var iables. These variables may be related to technical issues or to the specif ic features of the animal model. Although inhalation exposure of animals mi mics human exposure best, ie. error-prone route-to-route extrapolations are not necessary, not all results obtained under such very rigorous test cond itions may necessarily also occur under real-life exposure conditions. Atte mpts are often made to duplicate as closely as possible these real-life exp osure conditions of humans in appropriate bioassays. However, this in turn might affect established baseline data, rendering the interpretation of new findings difficult. In addition, specific use patterns, eg, of inhalation pharmaceuticals or pesticide-containing consumer products, may impose test agent-specific constraints that challenge traditional approaches. Moreover, specific modes of action of the substance under investigation, the evaluat ion of specific endpoints, or the clarification of equivocal findings in co mmon rodent species may require exposure paradigms or the use of animal spe cies not commonly used in inhalation toxicology. However. particularly in i nhalation toxicology, the choice of animal models for inhalation toxicity t esting is usually based on guideline requirements and practical considerati ons, such as exposure technology, expediency, and previous experience rathe r than validity for use in human beings. Larger animal species, apart from the welfare aspects, may require larger inhalation chambers to accommodate the animals, but for technical reasons and the difficulty of generating hom ogenous exposure atmospheres in such inhalation chambers, this may jeopardi ze the outcome of the study. Some of the many variables and possible artifa cts likely to occur in animal inhalation studies are addressed in this pape r.