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Understanding nanotechnology: an emerging challenge for the toxicologic pathologist.

Hubbs-AF; Sargent-LM; Sriram-K; Porter-DW; Rojanasakul-L; Fluharty-KL; Castranova-V; Mercer-RR
Cutting Edge Pathology: 2nd joint meeting of the European Congress of the ESTP, ESVP and ECVP, 32nd Meeting of the European Society of Veterinary Pathology, 12th Meeting of the European Society of Toxicologic Pathology, 25th Meeting of the European College of Veterinary Pathology, August 27-30, 2014, Berlin, Germany. 2014 Aug; :28-29
Nanotechnology is the technology which enables engineering in the nanoscale, a size range of less than approximately 100 nm. Nanotechnology products (NPs) have enormous and increasing economic impact. Importantly for toxicologic pathologists, NPs frequently have dimensions similar to subcellular structures. Since NPs are defined only by size, the number of potential products is virtually infinite (Hubbs et al., 2013). The variety of NPs means that the potential effects are necessarily diverse. However, some features of the nanoscale can influence toxicity relative to micron-sized products with the same chemical composition. Fundamentals of particle toxicology In general, for a given material, particle toxicity increases as particle size decreases. The exception is the toxicity of liquid and highly soluble particles which largely depends upon mass because the chemical components rapidly dissolve. For particles of moderate solubility, nanoscaling generally enhances the dissolution rate. If the chemical components of those particles are toxic, this increases exposure rate and, thus, toxicity. For poorly soluble particles, nanoscaling increases surface area per unit mass that interacts with biological structures, generally increasing toxicity (Hubbs et al., 2013). Particle biopersistence extends the duration of particle exposure, and, thus, enhances toxicity. Some inhalable fibers, such as asbestos, have well-established toxicity attributable to biopersistence combined with a high ratio of length to width, a feature known as high aspect ratio. Some new products of nanotechnology, such as the carbon nanotubes, combine biopersistence with a high aspect ratio and surface reactivity, suggesting that these nanoparticles may share toxicity features with asbestos (Donaldson and Poland, 2012). Finally, some particles contribute to altered immunologic and allergic responses by functioning as adjuvants or by enhancing the environmental dispersal of antigens (Beezhold et al., 2003; Granum et al., 2000). Recent studies suggest that it may be possible to intentionally manipulate the immune system using engineered particles to meet specific diagnostic and therapeutic needs (Moon et al., 2012). A thorough understanding of nanoparticle toxicology is a necessary foundation for designing therapeutic NP that are optimised for desired biological effects and avoid unintended toxicities. Intracellular and extracellular transport in the nanoscale Many intracellular and extracellular translocation pathways have specific size limitations. For example, endocytosis can selectively translocate macromolecules and NPs into cells but may exclude material exceeding 100 nm in diameter. Extracellular circulation is similarly size limited. For example, entry into the lymphatic circulation is generally restricted to particles transported within phagocytes or to some extracellular NPs (Hubbs et al., 2013). Importantly, the functional size of NPs in vivo is highly influenced by two factors 1) the agglomeration state, and 2) binding of biological material to the NP surface, creating a biomolecular corona. Two recent reviews summarise the current understanding of pathways which translocate NPs (Coppola and Caracciolo, 2014; Kettiger et al., 2013). Specific targeting of these intracellular and extracellular pathways will be a key factor in the development of nanomedicine. Lessons from the first generation products of nanotechnology Recent studies reveal some concerning observations which are consistent with the principles of particle toxicology and enhanced intracellular and extracellular transport in the nanoscale. Inhaled multi-walled carbon nanotubes caused time-dependent accumulation in multiple tissues, pleural and nuclear penetration, as well as strong tumour-promotion (Mercer et al., 2013; Sargent et al., 2014). Both multi-walled and single-walled carbon nanotubes also cause disruption of the mitotic spindle and aneuploidy in vitro at occupationally relevant doses. The mitotic spindle changes involved interaction between carbon nanotubes and the mitotic microtubules, chromatin and centrosomes (Sargent et al., 2014). This suggests that some NPs interact with diverse subcellular structures, including those which control the fidelity of genetic information. Human exposures to these first generation NPs were frequently occupational. In order to protect workers, there are now strategies for the safe development of nanotechnology (Schulte et al., 2014). A great deal can be learned from these criteria as strategies emerge for the safe development of nanopharmaceuticals which incorporate precise targeting of desired therapeutic effects while avoiding off-target toxicities.
Nanotechnology; Toxicology; Toxicopathology; Pathology
Ann F. Hubbs, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 1095 Willowdale Rd, Morgantown, WV 26505
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2nd joint meeting of the European Congress of the ESTP, ESVP and ECVP, 12th European Congress of Toxicologic Pathology, August 27-30, 2014, Berlin, Germany