Developing a Solution for Nasal and Olfactory Transport of Nanomaterials
Updated December 22, 2023
DECember 2023
NIOSH Dataset RD-1076-2023-0
Introduction
Nanotechnology is one of the most rapidly developing areas of the economy and involves the study and control of matter in the nanoscale. The nanoscale is the size range from 1 to 100 nm. Recently, some nanomaterials have demonstrated the ability to enter the brain through the olfactory pathway from the nose to the brain. This pathway can potentially enable inhaled nanomaterials to enter the brain. Inhalation exposures are technically difficult and expensive. Intranasal instillation is a potential screening tool for evaluating nose to brain transport. However, particles in aqueous media tend to agglomerate and agglomerated particles often act like larger particles in terms of surface area, toxicity, and size thresholds for transport pathways. For neuronal transport within the brain, the upper size limit is estimated to be approximately 100 nm. Therefore, nanomaterials must be adequately dispersed in the vehicle used for instillation in order to evaluate their potential for transport from the nose to the brain.
Because 100 nm is the upper size limit estimated for transport within the central nervous system, components of dispersion media may need to be different from dispersion media used to evaluate toxicity in other tissues. For example, albumin, a protein which is useful in dispersion media developed for the lung, can interact with nanomaterials and increase their size. In addition, neurons transport sodium out of the cell, suggesting that a dispersion medium to evaluate nose-to-brain transport should avoid high sodium concentrations. To overcome issues with the size of albumin and other proteins as well as the potential effects of sodium and phosphate, we hypothesized that free amino acids, a balanced electrolyte solution, and a mixture of phospholipids could produce a solution that both dispersed nanomaterials and was compatible with neuronal transport. This study describes and characterizes a solution for nasal and olfactory transport (SNOT) that can disperse nanomaterials and dyes with nanoscale dimensions, enabling intranasal instillation so that potential nose-to-brain transport can be evaluated.
- Confidence Intervals for Medians [XLS – 446 B]
- Data Dictionary [PDF – 92 KB]
- Dataset Overview [DOC – 21 KB]
- DLS Data MWCNT Size in NIOSH dispersion medium & diluted with SNOT [XLS – 75 KB]
- E607 Dispersion medium biocompatibility pathology report [PDF – 106 KB]
- E610 and E636 Dextran dye timecourse pathology report [PDF – 178 KB]
- Estimation of median diameter from HBN in SNOT DLS Data [XLS – 5 KB]
- Lung histopathology E613 with pathologist’s interpretative summary [PDF – 111 KB]
- Materials and Methods [PDF – 265 KB]
- NIR & GFP fluorescence in nose or olfactory bulb [XLS – 2 KB]
- Nose T2 Dextran Study Plastic Section Fluorescence [XLS – 801 B]
- Raw data SNOT preparation time course from DLS [XLS – 379 KB]
Methods Collection
- The SNOT is composed of 1 mg/mL DPPC (as 10 μL of a 1:10 dilution of DPPC in 200 proof ethanol), 0.25 mg/mL DMPC (as 25 μL of a 1:100 dilution of DPPC in 200 proof ethanol), 959 μL/mL LRS and 6 μL/mL TrophAmine®.
- DLS measurements (ZetaSizer Nano ZS, Model Zen3600, Malvern,) were used to determine particle hydrodynamic diameter (dH) of SNOT and hexagonal boron nitride nanoparticles (HBN) in SNOT after varying sonication procedures
- B6;129P2-Omptm3Mom/MomJ heterozygous (OMP-GFP) mice were obtained from Jackson Laboratory (Stock #006667)
- OMP-GFP mice display intense green fluorescence in olfactory neurons from the nose to their axonal terminus in glomeruli of the olfactory bulb
- Rhodamine dextran (tetramethylrhodamine 3000 MW anionic lysine fixable dextran) and anionic NIR dextran in SNOT (Alexa Fluor 680; 3,000 MW, Anionic) were used to track the movement of dextran in SNOT in the nasal cavity and olfactory bulb using stereomicroscopy and epifluorescence
- Plastic sections and fluorescence microscopy were used to demonstrate the presence of rhodamine dextran in the neuroepithelium of the nose
- Hematoxylin and eosin-stained sections of lung and nose were evaluated by a board-certified veterinary pathologist for potential morphologic alterations in those tissues
Attribution
N99 is a certification mark of the U.S. Department of Health and Human Services (HHS) registered in the United States. N95 and NIOSH Approved are certification marks of the U.S. Department of Health and Human Services (HHS) registered in the United States and several international jurisdictions.
Citation
O’Connell R C, Dodd TM, Clingerman SM, Kara L. Fluharty KL, Coyle J, Stueckle TA, Porter DW, Bowers L, Stefaniak AB, Knepp AK, Derk R, Wolfarth M, Mercer RR, Boots TE, Sriram K and Hubbs AF. Developing a Solution for Nasal and Olfactory Transport of Nanomaterials. Toxicol Pathol. 2022 Apr;50(3):329-343. doi: 10.1177/01926233221089209.
Acknowledgements
This project was funded by an intramural Nanotechnology Research Center
Project: Nanoparticle-induced Neuropathology 6939051B.
Authors
Ryan C. O’Connell rco0002@mix.wvu.edu
Tiana M. Dodd tdodd493@gmail.com
Sidney M. Clingerman okp5@cdc.gov
Kara L. Fluharty knk0@cdc.gov
Jayme Coyle jaymec2010@gmail.com
Todd A. Stueckle tstueckle@cdc.gov
Dale W. Porter dhp7@cdc.gov
Lauren Bowers mju3@cdc.gov
Aleksandr B. Stefaniak boq9@cdc.gov
Alycia K. Knepp ytd0@cdc.gov
Raymond Derk rhd8@cdc.gov
Michael Wolfarth mgz1@cdc.gov
Robert R. Mercer (retired)
Theresa E. Boots OPH6@cdc.gov
Krishnan Sriram kos4@cdc.gov
Ann F. Hubbs afh0@cdc.gov
Contact
For further information contact:
Pathology and Physiology Research Branch (PPRB), Health Effects Laboratory Division (HELD), National Institute for Occupational Safety and Health (NIOSH), Morgantown, WV