There has been explosive growth in engineering disciplines based on nanomaterials, with over 350 nanotechnology consumer products presently in commerce. Their unique physical properties compared to larger microparticles both enable these novel engineering applications as well as raise questions related to their interaction with biological systems. There is a crucial need to define in vivo disposition of manufactured carbon nanomaterials (MNM) where environmental and/or occupational exposure can occur, as well as assess if in vitro assays and physicochemical properties predict in vivo disposition. It is clear that insufficient absorption, distribution, metabolism and elimination (ADME) data exists on well-characterized MNM to allow for a thorough understanding of the toxicological implications of environmental or occupational exposure. Due to the large number of MNM involved, first-principles linking physical chemical properties to biological behavior must be defined. Our studies are specifically designed to assess what physicochemical properties of commercially available, or environmentally and occupationally relevant, carbon MNM are needed to predict their in vivo behavior. The research will characterize the physicochemical interactions between MNM and biological systems by conducting in vivo ADME studies of fullerenes and single walled carbon nanotubes (SWNT) in rats and pigs, along with intensive physicochemical characterizations and in vitro cell assays. We will utilize a matrix of twelve fully characterized MNM, balanced to provide a range of sizes (0.7-180 nm), shapes (spheres, ultra-short and short SWNT), surface charge (-, 0, +), and other properties (conducting, hydroxylation, agglomerates) to define the relationship of these properties and physical chemical characterizations to in vitro biomarkers and in vivo ADME endpoints defined by pharmacokinetic parameters used in chemical and drug disposition studies. Knowledge of ADME data after intravenous, oral and dermal administration in both species creates a basis for making route-to-route extrapolations in risk assessment analyses. A novel physicochemical approach for assessing MNM biological active surface areas in biological environments will be developed. In addition, we will specifically probe the involvement of the lymphatic system in MNM absorption and translocation. Experiments will be conducted in two animal species (rats and pigs) that are accepted biomedical models for human applications as well as providing physiological differences that may be important in extrapolating nanoparticle disposition between laboratory animals and humans. These coordinated studies will provide data to link physical chemical characterizations to in vivo MNM disposition.
