Comparative pulmonary response to inhaled nanostructures: considerations on test design and endpoints

Recently there has been increased concern and focus on the toxicity of engineered nanoparticulates (NPs). The tendency of NPs to aggregate and agglomerate in a concentration- and/or matrix-dependent manner often provides a continuum of particulates, ranging from nanosized to micrometer-sized. Agglomerated arrangements of closely packed nanoparticles increase the void-space volume and increase the composite volume of phagocytized particles. Consequently, much less particle mass is needed to exceed the volumetric overload limit for the inhibition of macrophage-mediated clearance. A unifying, most appropriate metric of NPs conferring pulmonary biopersistence and toxicity has not been demonstrated yet. Hence, it is timely to analyze and to consider to what extent current testing paradigms need to be modified in order to identify the unique hazards potentially associated with engineered nanostructured materials. Before embarking on novel testing paradigms, toxicological testing of NPs should be carried out according to already existing test guidelines to allow for a judicious utilization of the wealth of information that has already been generated for micrometer-sized particles. From the studies analyzed it is apparent that repeated inhalation exposure protocols of at least 1 mo are better suited than single high-dose instillation or inhalation studies to reveal the inhalation hazards of poorly soluble NPs. Along with all poorly soluble particles, due to their long retention half-times and associated biopersistence in the lung, even short-term inhalation studies may require postexposure periods of at least 3 mo to reveal NP-specific dispositional and toxicological characteristics.