Exploring the Biotic-Abiotic Interface:
Implications for Nano Toxicity
December 16, 2013
National Capitol Area Chapter
Society of Toxicology
Christopher P. Weis, Ph.D., DABT.
National Institutes of Environmental health Science
Objectives
• What’s going on at the Biotic – Abiotic interface?
• Why is the Biotic-Abiotic interface important?
• What are the implications for Health Risks and Regulations?
Basic Respiratory Anatomy
Images developed under contract to the National Institutes of Health
Anatomy of the bronchiolar alveolus clusters
Bronchiole Alveolar Structure Maina & van Gils (2001) Comp. Biochem and Physiol. 130(4)781-798.
Gas exchange in the lung
The alveolar- capillary membrane is just 0.2 microns thick!
Blood volume in capillary space Is about 70 mL.
Blood flow through the lung is about 5L/min.
Water: the molecule of life
Solid – Liquid Interface
Nel et
al. (2
00
9)
Nat
. M
ater.
8:5
43
Qiao, R. et al. (2007) Nano Lett. 7(3):614
“C60 molecule can readily “jump” into the bilayer and translocate the membrane within a few milliseconds”
“The simulation results indicate that, although a pristine C60 molecule can readily “jump” into the bilayer and translocate the membrane within a few milliseconds, the C60(OH)20 molecule can barely penetrate the bilayer.”
Small chemical modifications Can have big Consequences
Qiao, R. et al. (2007) Nano Lett. 7(3):614
ENM – Biomolecule Interactions
Nel et al. (2009) Nat. Mater. 8:543
Nel et al. (2009) Nat. Mater. 8:543
Nanoparticle endocytosis at the cell membrane: The clathrin-coated vessicle
Clathrin coated vessicles transporting materials across the cell
membrane
Attribution: University of British Columbia Dept. of Zoology (Permission requested)
Objectives
• What’s going on at the Biotic – Abiotic interface?
• Why is the Biotic-Abiotic interface important?
• What are the implications for OELs?
Attribution: F.A. Murphy, Univ.Texas Medical Branch
Coronavirus on a Mouse epithelial cell ~40,000X mag.
Coronavirus
(~70 - 200nm)
Corona Virus on Cultured Cell Surface Attribution: Dr. Steve Patterson
Targeted Docetaxel Nanoparticle
Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile.
Hrkach et al. (2012) Sci. Trans. Med 4:128ra39
~90 nm
Docetaxel MW=807
Strain-specific differential response to TOPO-PMAT Cd-
Se/ZnS QDs
Oropharyngeal aspiration 10 nM solution, 8 h PE
BALF Neutrophils
Mouse Strains
Univ. Washington Nanotoxicology Center
Ceria nanowires introduced
shape-dependent toxicity
Inflammasome activation
N
pro-IL-1β IL-1β
lysosome
IL-1β NALP3
Macrophage AR 0= 1
Ф = 7 nm
AR 7>200
L = 1~2 μm
0
50
100
150
200
250
300
0 25 50 75 100 125
IL-1
β a
cti
vit
y (
pg
/mL
)
Concentration (µg/mL)
R0R1R2R3R4
AR 6
AR 0-5
AR7
THP-1 cells
AR7
Lysosomal Damage
AR7
SEM TEM
Frustrated endocytosis
AR: aspect ratio
IL-1β T
HP
-1 c
ell
s
TH
P-1
cell
s
Ceria nanowires introduced shape-dependent toxicity NIEHS-funded Center for Nanobiology and Predictive Toxicology
Objectives
• What’s going on at the Biotic – Abiotic interface?
• Why is the Biotic-Abiotic interface important?
• What are the implications for Risks and Regulations?
Att
ribut
ion:
CP
Weis
Nano-sized mineral fibrils from Western Montana A
ttribu
tion:
Phagocytosis of asbestos fibers
pulmonary alveolar macrophage cell attempting to engulf and ingest several long mineral fibers incomplete ingestion of bio-persistent fibers can lead to extensive ‘selective release’ of proteolytic enzymes and ROS from the ‘frustrated’ PAMs
Microscopic and macroscopic lung abnormalities caused by durable fibers
‘mineral bodies’
‘ferruginous bodies’
Radiograph of Pleural plaques
Anatomy of Pleural plaques
Attribution: Med. Digital Library. Univ. of Michigan
High Resolution Computed Tomography (HRCT) of a pleural plaque
HRCT scan of a 45 Y.O. female with secondary (take home) exposure to nano particle taconite dust in the Upper Peninsula of Michigan.
Harbut et al. (2009) Int J Occup Environ Health 15(3):269-
273.
“Fibres shorter than 5 mm have traditionally not been counted by methods used for regulatory standards for asbestos because these methods were developed to provide a reproducible index of fibre exposure. The findings from our analysis show that cumulative exposures to all fibre size indices, including fibres <5 mm in length, were highly statistically significant predictors of lung cancer or asbestosis mortality.”
Stayner et al. (2008) Occ. Env. Med 65(9):613
Size–based Risk Management: a good idea?
Summary
• Biophysical chemistry at the abiotic-biotic
interface is critical to understanding
toxicity of engineered nanomaterials;
• Characterization of nanomaterials
(especially effects on the A-B interface) is
key;
• Toxicity studies for nanomaterials must
include minimal physico-chemical
characterization.