Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older bio-kinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.

Ultrafine particles (UFP, particles 50% of inhaled UFP can be depositing in the nasopharyngeal region during nasal breathing. Preliminary estimates from the present results show that approximately 20% of the UFP deposited on the olfactory mucosa of the rat can be translocated to the olfactory bulb. Such neuronal translocation constitutes an additional not generally recognized clearance pathway for inhaled solid UFP, whose significance for humans, however, still needs to be established. It could provide a portal of entry into the CNS for solid UFP, circumventing the tight blood-brain barrier. Whether this translocation of inhaled UFP can cause CNS effects needs to be determined in future studies.

The rapid proliferation of many different engineered nanomaterials (defined as materials designed and produced to have structural features with at least one dimension of 100 nanometers or less) presents a dilemma to regulators regarding hazard identification. The International Life Sciences Institute Research Foundation/Risk Science Institute convened an expert working group to develop a screening strategy for the hazard identification of engineered nanomaterials. The working group report presents theelementsof a screening strategy rather than a detailed testing protocol. Based on an evaluation of the limited data currently available, the report presents a broad data gathering strategy applicable to this early stage in the development of a risk assessment process for nanomaterials. Oral, dermal, inhalation, and injection routes of exposure are included recognizing that, depending on use patterns, exposure to nanomaterials may occur by any of these routes. The three key elements of the toxicity screening strategy are: Physicochemical Characteristics,In VitroAssays (cellular and non-cellular), andIn VivoAssays.There is a strong likelihood that biological activity of nanoparticles will depend on physicochemical parameters not routinely considered in toxicity screening studies. Physicochemical properties that may be important in understanding the toxic effects of test materials include particle size and size distribution, agglomeration state, shape, crystal structure, chemical composition, surface area, surface chemistry, surface charge, and porosity.In vitrotechniques allow specific biological and mechanistic pathways to be isolated and tested under controlled conditions, in ways that are not feasible inin vivotests. Tests are suggested for portal-of-entry toxicity for lungs, skin, and the mucosal membranes, and target organ toxicity for endothelium, blood, spleen, liver, nervous system, heart, and kidney. Non-cellular assessment of nanoparticle durability, protein interactions, complement activation, and pro-oxidant activity is also considered.Tier 1in vivoassays are proposed for pulmonary, oral, skin and injection exposures, and Tier 2 evaluations for pulmonary exposures are also proposed. Tier 1 evaluations include markers of inflammation, oxidant stress, and cell proliferation in portal-of-entry and selected remote organs and tissues. Tier 2 evaluations for pulmonary exposures could include deposition, translocation, and toxicokinetics and biopersistence studies; effects of multiple exposures; potential effects on the reproductive system, placenta, and fetus; alternative animal models; and mechanistic studies.

Studies with intravenously injected ultrafine particles have shown that the liver is the major organ of their uptake from the blood circulation. Measuring translocation of inhaled ultrafine particles to extrapulmonary organs via the blood compartment is hampered by methodological difficulties (i.e., label may come off, partial solubilization) and analytical limitations (measurement of very small amounts). The objective of our pilot study was to determine whether ultrafine elemental carbon particles translocate to the liver and other extrapulmonary organs following inhalation as singlet particles by rats. We generated ultrafine 13 C particles as an aerosol with count median diameters (CMDs) of 20-29 nm (GSD 1.7) using electric spark discharge of 13 C graphite electrodes in argon. Nine Fischer 344 rats were exposed to these particles for 6 h. in whole-body inhalation chambers at concentrations of 180 and 80 w g/m 3 ; 3 animals each were killed at 0.5, 18, and 24 h postexposure. Six unexposed rats served as controls. Lung lobes, liver, heart, brain, olfactory bulb, and kidney were excised, homogenized, and freeze-dried for analysis of the added 13 C by isotope ratio mass spectrometry. Organic 13 C was not detected in the 13 C particles. The 13 C retained in the lung at 0.5 h postexposure was about 70% less than predicted by rat deposition models for ultrafine particles, and did not change significantly during the 24-h postexposure period. Normalized to exposure concentration, the added 13 C per gram of lung on average in the postexposure period was ~9 ng/g organ/ w g/m 3 . Significant amounts of 13 C had accumulated in the liver by 0.5 h postinhalation only at the high exposure concentration, whereas by 18 and 24 h postexposure the 13 C amount of the livers of all exposed rats was about fivefold greater than the 13 C burden retained in the lung. No significant increase in 13 C was detected in the other organs which were examined. These results demonstrate effective translocation of ultrafine elemental carbon particles to the liver by 1 d after inhalation exposure. Translocation pathways include direct input into the blood compartment from ultrafine carbon particles deposited throughout the respiratory tract. However, since predictive particle deposition models indicate that respiratory tract deposits alone may not fully account for the hepatic 13 C burden, input from ultrafine particles present in the GI tract needs to be considered as well. Such translocation to blood and extrapulmonary tissues may well be different between ultrafine carbon and other insoluble (metal) ultrafine particles.