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Science-based grouping of nanoparticles for
industrial application of safe-by-design
Katarzyna Odziomek, Tomas Puzyn, Piotr Urbaszek, Andrea
Haase, Christian Riebeling, Agnieszka Gajewicz, Muhammed A.
Irfan, Robert Landsiedel, Meike van der Zande, and Hans
Bouwmeester
“To bridge the Mode of Action based computational modelling to the demands of grouping and safe by design of nanoparticles,
and make it applicable for industry”.
Objective
2
Are there (any) principles for grouping of NM?
..not every chemical needs to be tested for every endpoint...overall
data for that category should prove adequate to support a hazard
assessment... (OECD, 2014)
Grouping should take into account all aspects of NM life cycle.. (Arts
et al., 2014)
Structure and material properties, exposure, uptake and kinetics,
initiating cellular effects or apical effects.. (ECETOC 2014)
Oomen et al 2014 3
Establishing science-based criteria for grouping
4
Adapted from Agnes Oomen et al. 2014 In „Safety of nanomaterials along their life-cycle“ pp 358 – 379 ISBN 978-1-46-656786-3, 2014
ECETOC Grouping Strategy
5 Arts et al., 2015, A decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping). Regul Toxicol Pharmacol. 2015 Mar 15;71(2 Suppl):S1-27. doi: 10.1016/j.yrtph.2015.03.007.
Grouping Concepts
6
No single property groups all materials
– Need a multi-perspective grouping & testing strategy
Multi-perspective grouping
Refinement of grouping criteria
Tiered Testing
7
Panel of nanoparticles
8
Name Size SizeDLSw SSA Zeta XPSC XPSNa
BaSO4.NM220 32.00 350.00 41.00 -39.00 17.00 0.00
CeO2 200.00 N/A 33.00 6.00 9.00 0.00
CeO2.Al 81.00 N/A 46.00 18.00 9.00 0.00
CeO2.NM211 12.00 N/A 33.00 16.00 28.70 0.00
CeO2.NM212 40.00 N/A 27.00 42.00 79.90 0.00
SiO2.NH3 15.00 42.00 200.00 0.00 73.10 0.00
SiO2.PEG 15.00 50.00 200.00 -26.00 73.60 0.00
SiO2.PO3 15.00 40.00 200.00 42.90 77.10 0.00
SiO2.UNMOD 15.00 40.00 200.00 -39.00 0.00 0.00
TiO2.NM105 50.00 478.00 51.00 -17.00 0.00 0.00
TiO2.TLSF 50.00 N/A 100.00 -3.00 5.00 0.50
ZrO2 42.50 N/A 24.90 -12.00 4.00 1.00
ZrO2.ACR 9.00 9.00 117.00 -39.00 9.00 0.50
ZrO2.NH3 10.00 315.00 105.00 -3.90 9.00 0.00
ZrO2.PEG 9.00 27.00 117.00 -7.80 19.00 0.00
ZrO2.TOD 9.00 9.00 117.00 -6.50 19.00 0.00
DPP.BULK 200.00 N/A 42.00 -11.40 0.00 0.00
DPP.NANO 400.00 N/A 64.00 -12.30 0.00 0.00
DPP.RED 43.00 N/A 30.00 -16.00 11.00 0.00
With variations in surface modifications
9
10
DPP
Orange 1 (bulk)
DPP
Orange 2 (nano)
Pigment
Red 254-2 (nano)
MWNT
NM400
Graphen
e
Graphen
e nano-platelets
Carbon
black
SiO2-
naked SiO2 PEG
SiO2
Amino
SiO2
Phosphate
SiO2 FITC CeO2
NM212
CeO2
NM211 CeO2
Al-doped
CeO2
BaSO4
NM220
ZnO
NM111
ZnO
NM110
TiO2
NM105
TiO2 (T-
Lite SF)
ZrO2.Acr
ylate
ZrO2.PE
G
ZrO2.Am
ino
ZrO2.TO
Dacid AG50
AG50.mo
no
AG200.m
ono
AG50.citr
ate
Ag.Braak
uis
Ag.Braak
uis
Ag.Braak
uis
Ag.Braak
uis ZrO2 CuO
Materia
l Prop
ertie
s
Particle size
DistributionTE
M/SEM:
Primary
Particle Diameter
0.3-3 µm x
70-200 nm
(TEM)
30-400 nm
x 10-50 nm
(TEM)
43 nm 15 nm
Fiber
Up to10 µm
Flakes
Up to 30 µm
Flakes
50-100 nm
Globular 15 nm 15 nm 15 nm 15 nm 25 nm 40 nm 4-15 nm
Up to 200
nm
Globular
2-160 nm
Globular 32nm
80 nm
Globular 80 15x50 nm
50x10 nm
Fiber 9 nm 9 nm 10 nm 9 nm 7 nm 97 nm 134 nm 20 nm 18 nm 34 nm 60 nm 134 nm 25-60 nm 10 nm
Surface
Area (BET/Hg
intrusion)
42 m²/g 64 m²/g 30 m²/g 161 m2/mg 131 m2/mg 74 m2/mg 32 m2/mg 200 m2/g 200 m2/g 200 m2/g 200 m2/g 178 m2/g
30 m²/g
(Hg)
27 m²/g
(BET)
33 m2/g 33 m2/g 46 m2/g 41 m2/g 12 m2/g 12 m2/g 51 m2/g 100 m2/g 117 m2/g 117 m2/g 105 m2/g 117 m2/g 86 m2/g 6.2 m2/g 4.5 m2/g 30 m2/g 32 m2/g 17 m2/g 9 m2/g 1 m2/g 24.9 m2/g N/A
Surface
Chemistry
(XPS
element %)
C 73.1
Cl 9
N 9.5
O 8.4
C 73.6
Cl 8.8
N 8.7
O 8.8
C 77.1
O 10.9
N 5.9
Cl 6.1
C 99
O1
C 84.1
O 8.8
S 5.4
Na 0.6
Si 0.4 Cl 0.6
C 84.3
O 9.0
S 1.7
Na 3.0
Ca 1.5 Si 0.6
C 98
O 1
S 1
Cl <1
O 66
Si 29
C 4
Na 1
PEG
identified
(SIMS)
Amino
identified
(SIMS)
O 66
Si 29
C 5
Na 0,5
PO2,PO3 fragments
N/A
C 79.9
O 17.7
Ce 2.4
Ce 28.7
O 57.2
C 14.1
Ce 16
O 61
C 9
Al 9
Zr 5
Ce 21
Al 9
O 56
C 9
Zr 4 N 1
O 52
Ba 13
C 17
S 11
Cl, P 3 N 1
O 38
Zn 35
C 20
Cl 3
Na 3
O 38
Zn 35
C 30
Cl 3
Na 3
Ti 16
O 63
C 9
Al 7
Si 5 Na <1
Ti 16
O 63
C 9
Al 7
Si5 Na <1
d imethicone
/ methicone
copolymer
as coating
Zr 23
O 58
C 19
SIMS:
expected acrylic acid
PEG
identified
(SIMS)
Amino
identified
(SIMS)
Zr 24
O 63
C 11
N 0.7
S 0.2 SIMS:
expected
trioxadecan
oic acid
C 63
O 24
Ag 14
C 59
O 18
Ag 16
Na 8
C 77
O 10
Ag 12
Na 1
N 1
C 21
O 24
Ag 62
Na 2
N/A N/A N/A N/A
Zr 24
O 53
C 19 (C-C,
C-O, O-C =
O) N 3
Al 1
N/A
Zeta Potential
(pH 7.4) -11.4 mV -12.3 mV -16 mV N/A N/A N/A N/A -39 mV -26 mV 0 mV -42,9 mV N/A 42 mV 16 mV 6 mV 18 mV -39 mV N/A 20 mv -17 mV -3 mV -39 mV -7.8 mV -3.9 mV -6.5 mV -20 mV -7 mV -7 mV -45 mV -45 mV -45 mV -45 mV -45 mV -12 mV N/A
Dustiness
(Rotating drum
mg/kg)
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Inhalable
2845
Respirable
66
N/A N/A N/A
Inhalable
450
Respirable
80
Inhalable
1546
Respirable
70.6
N/A
Inhalable
1020±20
Respirable
28±10
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Bio
-Ph
ysic
al
In
teractio
n
Surface
Reactivity
(Electron Spin
Resonance
ESR)
N/A N/A N/A N/A N/A N/A N/A CPH 4
DMPO 11
CPH 1
DMPO 11
CPH 1
DMPO 21
CPH 2.2
DMPO 19 N/A N/A N/A N/A N/A
CPH 2
DMPO 2 N/A
CPH 22
DMPO 12
CPH 0,82
DMPO 3 N/A
CPH 1
DMPO 3.6
CPH 1,5
DMPO 1.7
CPH 1
DMPO 3.5
CPH 0.54
DMPO 0.94
CPH 8
DMPO 0.50
CPH 45
DMPO 0.4
CPH 72
DMPO 0.48 N/A N/A N/A N/A N/A N/A N/A
Dissolution/
Biopersistence N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
(Water)
0.002 wt%
(DMEM/FCS
)
<0.001 wt% (PSF)
<0.001 wt%
(PBS)
<0.001 wt%
(FassiF) <0.001 wt%
(0.1n HCl)
0.02 wt%
(Water)
<0.001 wt%
(DMEM/FCS
)
<0.001 wt% (PSF)
<0.001 wt%
N/A N/A
(PSF)
0.07 wt%
(PBS)
0.12 wt%
(FassiF) 0.1 wt%
(0.1n HCl)
1.02 wt%
N/A N/A
(PSF)
0.15 wt%
(PBS)
0 wt%
(FassiF) 0 wt%
(0.1n HCl)
0 wt%
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Solubility
(ions) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Ce <0.1
ppm
Ce <0.1
ppm
Ce, Al <0.1
ppm Ba 6 ppm
Soluble at
pH<6
Soluble at
pH 4.5 Ti <0.1 ppm
Soluble at
pH <6 N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Zr <0.1
ppm N/A
Dispersib ility
(D50): N/A N/A
(PSF) 9.5
µm
(PBS) 7.8
µm
(0.1M HCl) 16 µm
very stable
even in PSF
(Water)
Agglomerate
<0.01 wt%
below 100
nm
(DMEM/FCS
)
77000 nm
Water)
Agglomerate
<0.01 wt%
below 100
nm
(DMEM)
N/A
(Water)
Agglomerate
<0.01 wt%
below 100
nm
(DMEM)
N/A
(Water)
Agglomerate
1920 nm
<0.1 wt%
below 100 nm
(DMEM/FCS
)
67µm
N/A N/A N/A N/A N/A (Water)
432 nm
(Water)
2839 nm N/A N/A
(Water)
116 nm
(DMEM/FCS
) 285 nm
(Water)
Agglomerate
<0.01 wt%
below 100
nm
(DMEM/FCS
)
550 nm
N/A
(Water)
2700 nm
<0.1 wt%
below 100
nm
(DMEM/FCS
)
>>2 µm
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Lip id Affin ity
(DPPG/DOPG/
DPPG)
N/A N/A N/A N/A N/A N/A N/A 0.95 0.90 1.05 0.90 N/A N/A N/A N/A N/A N/A N/A N/A N/A 0.01 6.1 35.7 28.5 0.01 0.05 0.06 0.09 0.09 0.09 0.09 0.09 N/A N/A
Cytochrome C
Assay N/A N/A
Bio
kin
etic
s
Dermal
Penetration N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
No dermal
penetration
No
significant
dermal
penetration
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Lung
Deposition (%
of
concentration)
N/A N/A N/A N/A N/A N/A N/A 2 6 8 5 N/A 8 15 15 8 6 N/A N/A 3 N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Translocation N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Liver
Lung
Spleen
Kidneys
Testes Epididymis
Brain
Lungs
Bone
Cecum
Intestines
Spleen Stomach
Kidneys
Plasma
Heart
Brain RBC
Skeletal
Liver
Skin
Testes
N/A N/A
Liver
Spleen
Lung
Kidneys
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Clearance (%
after 21 days
recovery)
N/A N/A N/A N/A N/A N/A N/A 39 49 42 39 N/A N/A 5 5 7 77 N/A 16 N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Early
Bio
log
ical
Effect
Vector Model
(x fold
increase)
N/A N/A N/A N/A N/A N/A N/A 18.34 6.26 14.37 7.47 N/A N/A N/A N/A N/A 4.19 N/A 15.22 5.92 N/A 8.93 7.93 5.50 6.08 16.77 12.08 5.24 10.51 N/A N/A N/A N/A N/A N/A
Cytotoxicity: N/A N/A N/A N/A N/A N/A
Decreased
metabolic
activity LDH
release ROS
Decreased g lutathion
HO-1
Expression
increased
COX-2 Expression
increased
Secretion of
Il-8
increased
N/A N/A N/A N/A N/A
LDH release
Glutathion
decreased
HO-1
expression increased
COX-2
expression
increased
Secretion of IL-8
N/A N/A N/A
Decreased
metabolic
activity
Decreased
metabolic
activity LDH
release ROS
Glutathion decreased
Secretion of
IL-8
increased
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Genotoxicity N/A N/A N/A N/A N/A N/A N/A No No No
Comet
assay 50
µg/cm2
N/A N/A N/A N/A N/A No No
Comet
assay 10
µg/cm2
ATP assay
50 µg/cm3 N/A No
ATP assay
50 µg/cm3 No
Comet
assay 50
µg/cm2
No No No
Comet
assay 50
µg/cm2
N/A N/A N/A N/A N/A N/A
Ap
ical b
iolo
gic
al
Effect
Concentrations
Tested STIS
(mg/m3)
3
10
30
1
3
10
30
30
0.15 ± 0.05
0.57 ± 0.10
2.86 ± 0.82
0.54 ± 0.04
3.05 ± 1.05
10.1 ± 4.5
0.46 ± 0.11
2.08 ± 0.33
10.27 ±
1.44
0.5 ± 0.1
2.5 ± 0.2
10.9 ± 1.5
2
10
50
2.05
10.0
54.1
2.9
10.0
51.5
2.1
10.2
50.4
N/A
0.5 ± 2
5.3 ± 0.9
25.9 ± 6.0
0.48 ± 0
25.6 ± 6.0
0.5
2.5
10.0
0.5
2.5
10.0
0.5 ± 0.1
13.1 ± 0.7
53.4 ± 9.7
0.5 ± 0.1
2.4 ± 0.1
10.4 ± 1.3
N/A
2
10
50
0.5
2.0
10.0
1.9 ± 0.1
10.1 ± 1.0
50.5 ± 4.7
N/A N/A
2.0 ± 0.1
10.6 ± 0.3
52.2 ± 1.1
N/A N/A N/A N/A N/A N/A N/A N/A N/A
0
0.6
2.4
3.3
6.3 13.2
NOAEC
(mg/m3) 10 30 >30 <0.5 <2.5 <2.5 >10 2.5 >50 >50 >50 N/A <0.5 <0.5 <0.5 <0.5 >50 0.5 N/A <2 0.5 >50 N/A N/A >50 N/A N/A N/A N/A N/A N/A N/A N/A >10 0.6
Findings in
BALF
30 mg/m3:
increased
PMN,
marg inally
increased total cell
count,
increased
MCP-1 and
osteopontin level
No adverse
effect
No adverse
effect 0.5 mg/m3: 2.5 mg/m3: 10 mg/m3:
No adverse
effect
Slightly
increased
PMN
neutrophils
and lymphocytes
No adverse
effect
No adverse
effect
No adverse
effect N/A
0.5 mg/m3:
neutrophil
counts and
cytokine-
induced neutrophil
chemoattrac
tant-1
(CINC-1)
increased 5 mg/m3:
majority of
BALF
parameters
increased (ALP, MCP1,
CINC-1, M-
CSF)
25 mg/m3:
all parameters
increased
(ALP, NAG,
MCP1,
CINC-1, M-CSF)
0.5 mg/m3:
MCP-1 and
M-CSF
increased
5 mg/m3: majority of
BALF
parameters
increased
(ALP, MCP1, CINC-1, M-
CSF)
25 mg/m3:
all
parameters increased
(ALP, NAG,
MCP1,
CINC-1, M-
CSF)
Changes of
all
cytolog ical
and
b iochemical parameters
in BALF;
increased
levels of
Changes of CINC-1,
IFNγ, IL-1α,
MCP-1,
MCSF,
in BALF and lung tissue
Changes of
all
cytolog ical
and
b iochemical parameters
in BALF,
increased
MCP-1 and
CINC-1 in BALF,
increased
IL1-α in
lung tissue
No adverse
effect
Increased
total cell
counts and
N/A No adverse
effect
10 mg/m3:
Increased
PMN and
GGT
50 mg/m3: Increase in
total protein
and all
enzymes
examined (GGT, LDH,
ALP and
NAG)
No adverse
effect N/A N/A
No adverse
effect N/A N/A N/A N/A N/A N/A N/A N/A
No adverse
effect
A dose-
dependent
lung
inflammatio
n observed
Path/Histopath
-ology
30 mg/m3:
decreased
absolute
and relative
thymus weight
No adverse
effect
Lung:
Minimal
hypertrophy
/
hyperplasia: ep ithelial, in
bronchioles,
terminal
bronchioles
and alveolar ducts
0.5 mg/m3
Lung weight
increased at
also at 2.5
mg/m3 2.5 mg/m3:
Intraseptally
located
Microgranul
o-mas composed
of alveolar
macrophage
s
Small
aggregates
of alveolar
macrophage
s observed accumulatio
n was
concentratio
n dependent
Microgranulo-mas were
characterize
d by small
particle-
loaded aggregates
of
macrophage
s
the lungs of
one animal
exposed to
10 mg/m3
showed few intra-
alveolar
located
multifocal
aggregates of alveolar
macrophage
s
No adverse
effect
Slightly
increased
neutrophil
counts in
b lood after the end of
exposure.
Macrophage
aggregates
No adverse
effect
No adverse
effect
No adverse
effect N/A
Increased
macrophage
sand
alveolar
histiocytosis and
granuloma-
tous
inflammatio
n
Lung:
Part icles in
macrophage
s (recovery
group: add it ionally
mild
h ist iocytosis
)
Lung:
Particles in
macrophage
s (recovery
group: addit ionally
mild
histiocytosis
)
Lung: single
or
aggregated
particle-
loaded macrophage
s
No adverse
effect
Nasal
cavity:
moderate
multifocal
necrosis of olfactory
epithelia
Lung:
histiocytosis
, granulocytic
infiltration.
Mediastinal
lymph
nodes. lympho-
reticulo-
cellu lar
hyperplasia
N/A No adverse
effect
50 mg/m3:
Minimal
to mild
d iffuse
alveolar infiltration
with
histiocytes,
which are
considered to be
alveolar
macrophage
s minimal to
mild increase of
ep ithelium
thickness
which was
interpreted as
hypertrophy
/hyperplasia
No adverse
effect N/A N/A
No adverse
effect N/A N/A N/A N/A N/A N/A N/A N/A
No adverse
effect
2.4 mg/m3
Alveolit is,
bronchiolit is
,
vacuolation of
respiratory
epithelium
and
emphysema in the lung
Reversib le
Effects? Yes - Yes No No N/A - Partial - - - N/A
Partial
above 5
mg/m3
Partial
above 5
mg/m3
Partial Partial - Moderate N/A Yes Partial N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Long-term
effects N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Solubility of
nanoparticles in
realistic
environments
Biological matrix Water, Lung, Intestine
Nanomaterial
Ultrafiltration (UF) – ICP-MS • Accessible, (easy to use), cheap
methods based on ICP-MS, elementary detection
11
Results
% Dissolved Concentration
12
Approach failed in this project!
13
Detection (at low concentrations) is challenging:
● polyatomic interference, ● relatively low analytical recovery,
● Complex matrix is very difficult, interactions with the matrix or filter
“Lessons learned”: ● SP-ICP-MS: promising technique, but the size detection limit may be
limiting: thus not used here. ● Very interesting developments in AF4 or HDC-SP-ICP-hrMS method
development outside of this project!
7 Materials • NanoGem Silica 15 nm • NanoGem Silica (amino) 15 nm • NanoGem Silica (phosphate) 15 nm • NM-202 (Silica) • NM-203 (Silica) • NM-104 (TiO2) • NM-105 (TiO2)
Missing data to be addressed:
Cytochrome c assay for surface reactivity
● Cytochrome c is oxidised by NP surface
14
N
P
Ranking obtained from these results is in agreement with that from FRAS/FRAP assays CuO>Mn2O3>TiO2>CeO2>BaSO4
Classification tree for a short-term inhalation
study on rats
15
Descriptors selected: LUMO_C, Size, XPSNa
NOAEC
Class NOAEC [mg/m3]
TOX (1) ≤ 10
NTOX (2) > 10
NP LUMO_C Size XPSNa Split [S0]
NOAEC [original value]
NOAEC class [a priori]
NOAEC class [predicted]
Correct prediction
BaSO4.NM220 0.128 32 0 T 50.00 2 2 TRUE
SiO2.NH3 -1.031 15 0 T 50.00 2 2 TRUE
SiO2.PEG -1.031 15 0 V 50.00 2 2 TRUE
SiO2.PO3 -1.031 15 0.5 T 50.00 2 2 TRUE
ZrO2.ACR -0.191 9 0 T 50.00 2 2 TRUE
ZrO2.TOD -0.191 9 0 V 50.00 2 2 TRUE
DPP.NANO -1.742 400 0 T 30.00 2 2 TRUE
DPP.RED -1.879 43 0 T 30.00 2 2 TRUE
ZrO2 -0.191 42.5 0 V 10.00 1 2 FALSE
DPP.BULK -1.742 3000 0 T 10.00 1 1 TRUE
SiO2.UNMOD -1.031 15 1 T 2.50 1 1 TRUE
TiO2.NM105 -3.319 50 0.5 V 1.00 1 1 TRUE
TiO2.TLSF -3.319 50 0 T 0.50 1 1 TRUE
CeO2 -20.582 200 0 T 0.25 1 1 TRUE
CeO2.Al -20.582 81 0 V 0.25 1 1 TRUE
CeO2.NM211 -20.582 12 0 T 0.25 1 1 TRUE
CeO2.NM212 -20.582 40 0 T 0.25 1 1 TRUE
ZrO2.NH3 -0.191 10 0 P 2
ZrO2.PEG -0.191 9 0 P 2
T 1 2
1 6 0
2 0 6
T
Accuracy 1.00
Error 0.00
Sensitivity 1.00
Specificity 1.00
V0 1 2
1 2 1
2 0 2
V0
Accuracy 0.80
Error 0.20
Sensitivity 1.00
Specificity 0.67
16
NOAEC – multiple external validations
NP LUMO_C Size XPSNa NOAEC
[original value]
NOAEC class [a priori]
S0 S1 S2 S3 S4
BaSO4.NM220 0.128 32 0 50 2 T T T V T SiO2.NH3 -1.031 15 0 50 2 T T T T V SiO2.PEG -1.031 15 0 50 2 V T T T T SiO2.PO3 -1.031 15 0.5 50 2 T V T T T ZrO2.ACR -0.191 9 0 50 2 T T V T T ZrO2.TOD -0.191 9 0 50 2 V T T V T
DPP.NANO -1.742 400 0 30 2 T V T T V DPP.RED -1.879 43 0 30 2 T T V T T
ZrO2 -0.191 42.5 0 10 1 V T T V T DPP.BULK -1.742 3000 0 10 1 T V T T V
SiO2.UNMOD -1.031 15 1 2.5 1 T T V T T TiO2.NM105 -3.319 50 0.5 1 1 V T T V T
TiO2.TLSF -3.319 50 0 0.5 1 T V T T V CeO2 -20.582 200 0 0.25 1 T T V T T
CeO2.Al -20.582 81 0 0.25 1 V T T V T CeO2.NM211 -20.582 12 0 0.25 1 T V T T V CeO2.NM212 -20.582 40 0 0.25 1 T T V T T
ZrO2.NH3 -0.191 10 0 P P P P P ZrO2.PEG -0.191 9 0 P P P P P
Accuracy 80% 100% 100% 80% 100% Error 20% 0% 0% 20% 0%
Sensitivity 100% 100% 100% 100% 100% Specificity 70% 100% 100% 70% 100%
17
Towards Integrated Testing Strategies
18
Nanomaterial Protein carbonylation FRAS NOAEC
BaSO4.NM220 I A I
SiO2.NH3 A I I
SiO2.PEG I I* I
SiO2.PO3 A I I
ZrO2.ACR I I* I
ZrO2.TOD I I* I
DPP.NANO I* A I
DPP.RED I* A* I
ZrO2 I* A* A
DPP.BULK I* A A
SiO2.UNMOD A I A
TiO2.NM105 A A A
TiO2.TLSF I* A* A
CeO2 I* A* A
CeO2.Al I* A* A
CeO2.NM211 I* I A
CeO2.NM212 I* A A
ZrO2.NH3 I I* I*
ZrO2.PEG I I* I*
Conclusions
Optimization of analytical methods for determination of solubility in complex matrices needed!
Decision trees can be used for refining descriptor selection and
setting specific numerical thresholds of structural features related to
the change in biological properties
The identified key NP features (descriptors) can help in the design of
new nanomaterials, as they are the most relevant their safety
A predictive model is now proposed, can be applied in decision-
making framework for the grouping and testing of nanomaterials
(DF4nanoGrouping)
● Larger datasets on nanomaterials are needed: but now focus
on specific endpoints!
● Consistent data and data quality remain important issues
19
