The toxicology of NMP
(What adverse effects might we expect from exposure to NMP)
Professor Ken Donaldson
ELEGI Colt Laboratory
Centre for Inflammation Research,
Edinburgh University, Medical School,
Edinburgh , Scotland
ken.donaldson@ed.ac.uk
What diseases do particle cause or worsen?
Site
Airways
Parenchyma
Setting
Occ/Env
Occ
Occ
Occ/Env
Env
Occ
Occ
Occ
Occ
Pleura, peritoneum
Cardiovascular system
Occ
Env
Disease
Bronchitis
Small airways disease
Sensitisation/asthma
Lung cancer
Exacerbations of airways disease
– COPD and asthma
Emphysema
Silicosis (pneumoconiosis)nodular fibrosis
Asbestosis (pneumoconiosis)interstitial fibrosis
Progressive massive fibrosis
Silicosis (pneumoconiosis)nodular fibrosis
Mesothelioma
Atherothrombosis
Exemplar particles
Coalmine dust, organic dust, PM10
Coalmine dust, quartz
Metals, organic dusts
Quartz, metals, asbestos, PM10
PM2.5
Coalmine dust, quartz
Quartz, coalmine dust
Fibres
coalmine dust
Fibres
PM2.5
Airways – white bronchial tubes
Parenchyma – pink alveoli
Pleura – outside surface lung
surface and chest wall surface
Cardiovascular system –
blood vessels and heart
ken.donaldson@ed.ac.uk
If NMP have effects based on the occupational paradigm?
Exposure –
High (mg/m3 analogous to workplace) –peaks during
shifts , zero at other times
Typical particles - Silica, asbestos, welding fume, nuisance dusts
Exposed population -
Typical responses -
Predominantly healthy males <65 years old – no
susceptibles due to healthy worker effect
Pneumoconiosis, COPD, cancer, asthma
ken.donaldson@ed.ac.uk
If NMP had effects based on the environmental (PM10) paradigm?
Exposure -
Low (tens of ug/m3 as per urban environment) constant
with peaks
Exposure to -
urban PM10 containing combustion-derived nanoparticles
Exposed population - Everyone but acute effects are only seen in
susceptible and aged, ill populations with pre-existing oxidative stress and
inflammation = susceptibility
Typical responses – In susceptible populations - Exacerbations of
COPD/asthma, exacerbations of cardiovascular disease, cancer
In normals – very little except likely contribution to chronic disease
ken.donaldson@ed.ac.uk
Factors contributing to toxic response to particles in the lungs
Generally low for NMP but
exceptions e.g. quartz, metals
Intrinsic toxicity of the
material i.e. hazard
Variable but low for
NMP??
Exposure
concentration
Length of
exposure
For NMP could be
chronic or brief
Contribute to dose
ken.donaldson@ed.ac.uk
General scheme for what happens when harmful particles deposit in the lungs
Clearance
Muco-ciliary and
macrophage clearance
Exposure
Total
deposited
dose
Biologically
effective dose
That fraction of the
total dose that actually
delivers toxicity
Macrophage
clearance
Normal tissue
Tissue stress
Disease
Tissue
injury
Inflammation
oxidative damage
genotoxicity etc
Defences induced
Threshold
exceeded
Threshold not
exceeded
ken.donaldson@ed.ac.uk
We are not good at measuring the BED in our metrics
Particle
Biologically effective dose
Current metric
Quartz
Area of reactive (unblocked or
unpassivated) surface
Respirable mass
Asbestos
Biopersistent fibres longer than
~ 20mm
Fibres longer then 5mm, >3mm
diameter and Aspect Ratio>3
PM10
Organics/metals/surfaces
Mass by PM10 convention
Welding fume
(NP)
Diesel soot
Soluble transition metals
Respirable mass
Organics/metals/surfaces
Contained in PM10
Carbon black
(NP)
Surface area
Nuisance dust standard of
respirable mass
ken.donaldson@ed.ac.uk
The central hypothetical role of inflammation in the occupational paradigm
Occupational particles
Inflammation
Airways inflammation
COPD,
Stimulation of Oxidative adducts of
DNA
fibroblast growth and
ECM secretion
Pneumoconiosis,
Cancer
Airways inflammation/
adjuvant effect
Asthma
ken.donaldson@ed.ac.uk
The central hypothetical role of inflammation in the environmental paradigm
PM10
Inflammation
Superimposed on Airways
inflammation of Asthma, COPD
Exacerbation
Hospitalisation
Death (COPD)
Atheromatous plaque formation is an
inflammatory process
Endothelial
dysfunction
Pro-thrombotic
state
Increased inflammatory
activity in plaques
Plaque rupture
thrombosis
Myocardial infarction
Mortality
ken.donaldson@ed.ac.uk
The ubiquitous role of oxidative stress in particle effects
ken.donaldson@ed.ac.uk
Toxicology testing approaches
Approach depends on aim - screening, mechanisms, regulatory
NMP studies will be screening and mechanisms
1)
Characterising the physico-chemistry – surface area, size etc, metals –
aiming towards a structure:activity paradigm?
2)
In vitro cell-free – e,g detecting free radical –generation, complement
activation etc
3)
In vitro cells – huge number of endpoints but should be
pathophysiologically-relevant i.e. tells us about something we already
understand as having a role in disease e.g. ability to cause a proinflammatory effect
4)
In vivo- particle are instilled into or inhaled by rodents - lungs are then
examined for effects (huge number of potential endpoints)
ken.donaldson@ed.ac.uk
Example of an inhalation study with a NMP – Montserrat ash
The importance of using controls to contextualise the response
125
PMN (x106)
PMN (millions)
25
20
15
Ash
10
5
0
20
40
75
50
coalmine dusts L and A
volcanic ash
TiO2
25
TiO2
0
quartz
100
60
Lung burden (mg)
Rats inhaled ash along with a control dust TiO2
that is low in toxicity – at the same mass burden
the ash was more inflammogenic as shown by
more PMN in the lavage
0
0
10
20
30
40
50
Mass burden (mg)
However, when plotted alongside
particles of known toxicity, the ash was
less than coalmine dust and quartz (see
vertical axes).
ken.donaldson@ed.ac.uk
Summing up- toxicology of NMP
Site
Airways
Parenchyma
Setting
Occ/Env
Occ
Occ
Occ/Env
Env
Occ
Occ
Occ
Occ
Pleura, peritoneum
Cardiovascular system
Occ
Env
Disease
Bronchitis
Small airways disease
Sensitisation/asthma
Lung cancer
Exacerbations of airways disease
– COPD and asthma
Emphysema
Silicosis (pneumoconiosis)nodular fibrosis
Asbestosis (pneumoconiosis)interstitial fibrosis
Progressive massive fibrosis
Silicosis (pneumoconiosis)nodular fibrosis
Mesothelioma
Atherothrombosis
Exemplar particles
Coalmine dust, organic dust, PM10
Coalmine dust, quartz
Metals, organic dusts
Quartz, metals, asbestos, PM10
PM2.5
Coalmine dust, quartz
Quartz, coalmine dust
•Particle toxicology is a mature science- we know
what to do …but…
Fibres
coalmine dust
Fibres
PM2.5
•Does NMP as a grouping make sense?
•Coalmine dust, quartz and asbestos are NMP but
they are looked on as occupational diseases
•Do we have a disease from environmental exposures
to NMP?
•How many people are at risk – in UK?, in Europe? In
the world?
•What is the documented burden of ill-health due to
environmental exposures to NMP?
•Only if there is a recognition that environmental
exposures to NMP constitute a substantial health risk
will funding be diverted from other known substantial
heath risks
…….Discuss
ken.donaldson@ed.ac.uk