Research on ambient UFPs has laid the foundation for the emerging field of nanotoxicology, with the goal of studying the biokinetics and the potential of engineered nanomaterials (particles, tubes, shells, quantum dots, etc.) to cause adverse effects. Major differences between ambient UFPs and NPs are the polydisperse nature of the former versus the monodisperse size of the latter, and particle morphology, oftentimes a branched structure from combustion particles versus spherical form of NPs, although other shapes (tubes, wires, rings, planes) are also manufactured. In addition, combustion-derived volatile organic compounds and inorganic constituents (e.g., metals, nitrates, sulfates) of different solubilities on UFPs predict differences in the toxicologic profile between UFPs and NPs. However, as far as the insoluble particle is concerned, concepts of NSPs kinetics, including cell interactions, will most likely be the same for UFPs and NPs ().
Figure 16 Biokinetics of NSPs. PNS, peripheral nervous system. Although many uptake and translocation routes have been demonstrated, others still are hypothetical and need to be investigated. Translocation rates are largely unknown, as are accumulation and retention (more ...)
The introduction of nanostructured materials for biomedical and electronics applications opens tremendous opportunities for biomedical applications as therapeutic and diagnostic tools as well as in the fields of engineering, electronics, optics, consumer products, alternative energy, soil/water remediation, and others. However, very little is yet known about their potential to cause adverse effects or humoral immune responses once they are introduced into the organism—unintentionally or intentionally. Nanomedicine products will be well tested before introduction into the marketplace. However, for the manufacturers of most current nanotechnology products, regulations requiring nanomaterial-specific data on toxicity before introduction into the marketplace are an evolving area and presently under discussion (Bergeson and Auerbach 2004
; Foresight and Governance Project 2003
). During a product’s life cycle (manufacture, use, disposal), it is probable that nanomaterials will enter the environment, and currently there is no unified plan to examine ecotoxicologic effects of NPs. In addition, the stability of coatings and covalent surface modifications need to be determined both in ecologic settings and in vivo
. [Supplemental Material available online (http://ehp.niehs.nih.gov/members/2005/7339/supplemental.pdf
Results of older biokinetic studies and some new toxicology studies with NSPs (mostly ambient UFPs) can be viewed as the basis for the expanding field of nanotoxicology. These studies showed that the greater surface area per mass renders NSPs more active biologically than larger-sized particles of the same chemistry, and that particle surface area and number appear to be better predictors for NSPs-induced inflammatory and oxidative stress responses. The following emerging concepts of nanotoxicology can be identified from these studies:
The biokinetics of NSPs are different from larger particles. When inhaled, they are efficiently deposited in all regions of the respiratory tract; they evade specific defense mechanisms; and they can translocate out of the respiratory tract via different pathways and mechanisms (endocytosis and transcytosis). When in contact with skin, there is evidence of penetration to the dermis followed by translocation via lymph to regional lymph nodes. A possible uptake into sensory nerves needs to be investigated. When ingested, systemic uptake via lymph into the organism can occur, but most are excreted via feces. When in blood circulation, they can distribute throughout the organism, and they are taken up into liver, spleen, bone marrow, heart, and other organs. In general, translocation rates are largely unknown; they are probably very low but are likely to change in a compromised/diseased state.
The biologic activity and biokinetics are dependent on many parameters: size, shape, chemistry, crystallinity, surface properties (area, porosity, charge, surface modifications, weathering of coating), agglomeration state, biopersistence, and dose. These parameters are likely to modify responses and cell interactions, such as a greater inflammatory potential than larger particles per given mass, translocation across epithelia from portal of entry to other organs, translocation along axons and dendrites of neurons, induction of oxidative stress, pro-oxidant and antioxidant activity of NSPs in environmentally relevant species, binding to proteins and receptors, and localization in mitochondria.
The principles of cellular and organismal interactions discussed in this article should be applicable for both ambient UFPs and NPs, even if the latter are coated with a bio-compatible material. Knowledge about the bio-persistence of this coating is as essential as is knowledge about the bioavailability of the core material that could have intrinsic toxic properties, for example, semiconductor metal compounds in sub-10-nm quantum dots consisting of cadmium and lead compounds. The very small size of these materials makes them available to the same translocation processes described here for polydisperse NSPs, possibly even in a more efficient way because of their uniform size. When studying biologic/toxicologic effects, new processes of interactions with subcellular structures (e.g., microtubuli, mitochondria) will likely be discovered. The diversity of engineered nanomaterials and of the potential effects represents major challenges and research needs for nanotoxicology, including also the need for assessing human exposure during manufacture and use. The goal to exploit positive aspects of engineered nanomaterials and avoid potential toxic effects can best be achieved through a multidisciplinary team effort involving researchers in toxicology, materials science, medicine, molecular biology, bioinformatics, and their subspecialties.