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Heriot-Watt University Edinburgh, Scotland
Vicki Stone 1991
1994 1995
1996
January 2010
Dusty work
Particles you may know
Asbestos
Crystalline quartz
Nuisance dust
200nm PB (COOH)
Clift et al. 2008 TAAP 232; 418-427.
Particle uptake by macrophages
Macrophages – defence system
Clearing particles from the lungs
alveloar space
blood capillary
Epithelial cells
mucus airways
lymphatic vessel
CLEARANCE VIA LYMPHATICS
CLEARANCE VIA MUCOCILIARY
ESCALATOR
particle
macrophage
Stone 2008 J.Lead Book
Particle induced lung inflammation
. . .
Inflammatory cell
activation
Epithelial cell
damage Type I
epithelial cell
Type II
epithelial cell
Cytokines
+ ROS ALVEOLUS
RESPIRATORY
BRONCHIOLE
. . . . . . . . .
. .
INFLAMMATION
Inflammation and oxidative stress
Description An increased number of
immune cells accumulate
in one place
Purpose To deliver all of the cells and
molecules to a site of
infection or foreign particle
deposition to aid and promote
clearance
Friend Prevents infection
progression and therefore
death
Foe Will worsen disease
symptoms or even trigger new diseases
Oxidants Antioxidants
Key message
•The body possesses efficient mechanisms for
removing non-self particles
•But these defences can malfunction
•Some particles have the ability to kick-start this
malfunction via inflammation and oxidative stress
•Which particles cause problems and why?
London Fog episode of 1952
Daily
Deaths Smoke
SO2
1000
750
500
250 1000
2000
3000
4000
December 1952 5 10 15 1
Fog period
from Beaver 1952
(mg/m3)
Key message
•Pollutions smogs increase the death rate
•Causes include high exposure dose
•Causes include differences in susceptibility
between people
500nm
Increases in PM10 levels :
•reduce lung function
•asthma attacks
•hospital admissions
•deaths
•cancer
Particulate Air Pollution (PM10)
Bronchial epithelium
. .
10mm 1 mm 0.1mm
0.1mm
1.0 mm
Cilia 0.25mm diameter
Ultrafine particles
•Diameter less than 100 nm
•Induce more toxicity and
inflammation than larger
respirable particles
Size dependent lung inflammation
Ferin et al 1992 Am.J.Respir.Cell.Mol.Biol. 6: 535-542
0
20
40
60
80
100
0 10 20 30 40 50 60 70 Time from start of exposure (weeks)
Neutrophils in bronchoalveolar
lavage fluid X 105
21 nm TiO2
250 nmTiO2
Inflammation
Nanotechnology
•The manipulation of materials at the nanoscale.
•Many products of nanotechnology are nanoparticles
•BSI 2001 Terminology for nanomaterials
•Nanoscale 1-100nm
•Nano object at least 1 dimension 1-100nm
•Nanoparticle all 3 dimensions 1-100nm
•Nanoparticles are exploited in a wide variety of applications
due to unique properties that are exhibited at the nanoscale:
•E.g. Improved electrical conductance, surface reactivity, colour,
weight, strength....
Printed circuit board
Hair
1 ? 1 nm 1 1 mm 10 cm
MEMS
Ant Red cell
Atoms
DNA
Watch
1 ? 1 nm 1 mm 1 mm 10 cm Bigger Smaller
Nanotubes Integrated circuits
Atoms
Artificial structures
Animals
Natural structures
How small is nano?
C60 Fullerenes
Coating
Core
Shell
Quantum Dots Nanoparticle gold Carbon nanotubes
Nanomaterials
ZnO nano flowers
•Food and food packaging
•PET bottles (alcoholic beverages)
•Suntan lotion clear formulations
•Medicines / diagnostics
•Vitamins
•Childrens cups/bottles
•Cosmetics
•Paints/inks
•Stain resistant clothing
•Socks, tights, stockings
•Underwear and sports clothing
•Electronic gadgets
•Sports equipment
Uses and benefits of nanomaterials
Exposure to Nanomaterials
Human Exposure
Incidental Purposeful
Environmental Exposure
Incidental Purposeful
Understanding hazard Understanding exposure
Understanding risk
Manage risk
Manage exposure Manage hazard
Maximise potential of nanotechnology with minimum risk
Minimizing risk to maximise potential
Physicochemical characteristics
NANOPARTICLE Physicochemical characteristics
SIZE/ SA
SHAPE
COMPOSITION
CHARGE
CRYSTAL STRUCTURE
SOLUBLITY
STRENGTH
ELECTRICAL CONDUCTANCE
E.g. fibre shape effects clearance
Entry route and efficiency
Translocation
Electrochemical gradients
Membrane potential
Durability
Biopersistence
Clearance
Inherent toxicity E.g. low TiO2
High Cd
Molecular interactions
E.g. crystalline silica vs amorphous silica
Biopersistence Clearance
Release of toxic components
ENPRA – Structure activity relationship
Biological effects P
hys
ico
chem
ical
ch
arac
teri
stic
s
Oxidative
stress
Inflammation Granuloma
Size
Surface
area
High aspect
ratio
Particles uptake and impacts on distal organs
Inhaled particles
Lungs
Ingested particles
Gut
Cardiovascular system
Liver Brain Kidney Spleen Foetus
Martini. Fundamentals of Anatomy and Physiology,
7th edition, 2006.
Inhalation – occupational route of
exposure
Size and uptake in macrophages
20nm PB
200nm PB
30 minutes 60 minutes 120 minutes
Clift et al. 2008 TAAP 232; 418-427.
Surface area and surface atoms
Diameter 100 mm 10 nm Surface area 0.03 m2/g 286 m2/g % atoms at surface 0.001 % 10.5 %
Stone and Kinloch Nanotoxicology (book), 2007, Ed Monteiro and Tran.
Surface area and inflammation
0
5
10
0 200 400 600 800 1000 Surface Area instilled (cm2)
Lung inflammation
Bronchoalveolar
lavage neutrophils (millions)
Relatively low toxicity particles
For relatively low toxicity particles (TiO2 etc) there is a straight line relationship between surface area and lung inflammation.
Duffin et al. 2002 Ann Occup Hyg 46 [suppl 1]; 242-245.
Quartz
Highly pathogenic particles with a highly reactive surface (eg quartz), are more inflammogenic in this model.
Reactive oxygen species
Wilson et al. 2002 TAP 184: 172-179.
50
100
150
0 0.5 1.0 1.5 2.0 2.5
Particle dose (mg/ml)
DC
F Fl
uo
resc
ence
In
ten
sity
260 nm CB
14 nm CB
***
***
**
Key messages
•Nanomaterials are about the same size as
protein molecules found in the body
•Smaller particles may exhibit different properties
to larger particles that can make them interesting
but also potentially hazardous
Key messages
• Smaller particles have a larger surface area
per unit mass over which to interact and react
with their environment
• A range of physical and chemical
characteristics can influence particle toxicity
• Not all nanoparticles are the same, they vary
in their risk
Shape - Fibres and nanotubes
WHO fibre definition:
Aspect ratio > 3:1 Length > 5mm Width < 3mm
Long fibre amosite
MWCNT
Characteristics of NT:
Aspect ratio > 3:1 Length nm - cm Width < 3mm
Matthew Boyles
Frustrated phagocytosis
Asbestos uptake by macrophage
Carbon nanotube uptake by
macrophages
Vehicle
NP CB
SFA
NT tangled1
NT tangled2
LFA
NT long1
NT long2
Poland et al. 2008 Nature Nanotech 3, 423-428.
MWCNT induced pathology
Key messages
•Long fibres (10mm) are difficult to clear from the
body by macrophages
•Long fibres become trapped in the drainage
(lymphatic) system of the pleural (around lung)
cavity
•Lack of fibre clearance leads to their
biopersistance, enhanced inflammation which
leads to tissue damage and disease
•High aspect ratio nanomaterials which are
durable seem to mimic such effects in animal
models and in cells
Summary
Physicochemical properties of particles determine their biological
reactivity
-Size, surface area, shape, charge, composition.....
The human body protects itself from particles (e.g. Macrophages)
Biological consequences of ultrafine or nanomaterial exposure
include
-No effect, oxidative stress, inflammation, genotoxicity.....
If in doubt – get help
Questions?
Does anyone here work in a company handling particles of any type?
What is known about the hazards of these particles?
How do you manage the risks provided by hazardous materials?
Does anyone here work in a company handling nanomaterials?
How do you think you might manage the risks posed by
nanomaterials?
Would you treat all nanomaterials the same?
Who do you go to for help?
Help? - Free
Health and Safety Executive (HSE)
http://www.hse.gov.uk/pubns/books/hsg
272.pdf
NIOSH (USA)
http://www.cdc.gov/niosh/topics/nanotec
h/
European commission
http://ec.europa.eu/environment/chemic
als/nanotech/index_en.htm
Nanotechnologies Industries Association
http://www.nanotechia.org/services/occu
pational-health-safety
Help? - Services/collaborations
Prof Vicki Stone
Dr Steve Hankin
