Neurotoxicology of Nanomaterials.

The remarkable advances coming about through nanotechnology promise to revolutionize many aspects of modern life; however, these advances come with a responsibility for due diligence to ensure that they are not accompanied by adverse consequences for human health or the environment. Many novel nanomaterials (having at least one dimension <100 nm) could be highly mobile if released into the environment and are also very reactive, which has raised concerns for potential adverse impacts including, among others, the potential for neurotoxicity. Several lines of evidence led to concerns for neurotoxicity, but perhaps none more than observations that inhaled nanoparticles impinging on the mucosal surface of the nasal epithelium could be internalized into olfactory receptor neurons and transported by axoplasmic transport into the olfactory bulbs without crossing the blood-brain barrier. From the olfactory bulb, there is concern that nanomaterials may be transported deeper into the brain and affect other brain structures. Of course, people will not be exposed to only engineered nanomaterials, but rather such exposures will occur in a complex mixture of environmental materials, some of which are incidentally generated particles of a similar inhalable size range to engineered nanomaterials. To date, most experimental studies of potential neurotoxicity of nanomaterials have not considered the potential exposure sources and pathways that could lead to exposure, and most studies of nanomaterial exposure have not considered potential neurotoxicity. Here, we present a review of potential sources of exposures to nanoparticles, along with a review of the literature on potential neurotoxicity of nanomaterials. We employ the linked concepts of an aggregate exposure pathway (AEP) and an adverse outcome pathway (AOP) to organize and present the material. The AEP includes a sequence of key events progressing from material sources, release to environmental media, external exposure, internal exposure, and distribution to the target site. The AOP begins with toxicant at the target site causing a molecular initiating event and, like the AEP, progress sequentially to actions at the level of the cell, organ, individual, and population. Reports of nanomaterial actions are described at every key event along the AEP and AOP, except for changes in exposed populations that have not yet been observed. At this last stage, however, there is ample evidence of population level effects from exposure to ambient air particles that may act similarly to engineered nanomaterials. The data give an overall impression that current exposure levels may be considerably lower than those reported experimentally to be neurotoxic. This impression, however, is tempered by the absence of long-term exposure studies with realistic routes and levels of exposure to address concerns for chronic accumulation of materials or damage. Further, missing across the board are "key event relationships", which are quantitative expressions linking the key events of either the AEP or the AOP, making it impossible to quantitatively project the likelihood of adverse neurotoxic effects from exposure to nanomaterials or to estimate margins of exposure for such relationships.