NP are…

Transcription

NP are…

NANOTECHNOLOGY IN
COSMETICS AND
SUNSCREENS: IS THERE A
HEALTH RISK?
Gerhard J. Nohynek, Ph.D., D.A.B.T. and Eric Dufour, D.V.M., M.Sc.
L’OREAL R&D, WORLDWIDE SAFETY EVALUATION
[email protected]
October 21, 2008
1
How does the bot do it? Using
nanotech, of course…
2
G Nohynek – Congrès de la SFT, 20-21 octobre 2008, Paris – Copyright © SFT – Tous droits réservés
WHY AFRAID OF NANO?
3
GREY GOO THEORY
Eric Drexler (1986):
End-of-the-world diaster nanotechnology
scenario
Self-replicating nanobots consume all living
matter on earth, while constructing more of
themselves
Idea taken up in Michael Crichton’s tale
Prey on runaway, rioting nanobots (2003)
Grey Goo reference (?) by Prince Charles
started nanotechnology debate / fear:
Royal Nanoangst
Review of the safety of nanotechnology
by the Royal Society of Engineers, UK
(2004)
4
GJN – 5/2007
THE CHALLENGE OF UNDERSTANDING
NANOSCALE IS SIZE…
« Nanomaterials »: generic term for materials that
have at least one dimension at >1 and <100 nm
1 dimension: layers (films, coatings)
2 dimensions: nanotubes, nanowires
3 dimensions: nanoparticles (NPs)
Football (30 cm)
100 m
10-1 m
Flea (1 mm)
10-2 m
(1 m)
hair (80 µm)
10-3 m
(1 mm)
TiO2 nanoparticles
(40 to 200 nm)
10-4 m
RBC (7 µm)
10-5 m
10-6 m
(1 µm)
Fullerene, C60,
Buckyball (0.7 nm)
Herpes virus (100 nm)
10-7 m
(100 nm)
10-8 m
10-9 m
10-10 m
(1 nm)
Salicylic acid
(1 nm)
5
GJN – 5/2007
Definition of nanoparticles (NP)
SCCP (12 June, 2007, draft opinion): NP defined as a particle
with at least one dimension at <100 nm (?)
Is a membrane of a size of a newspaper but at <100 nm
thickness a nanoparticle?
MORE PRACTICAL:
Particle at three dimensions at the nanoscale (EU SCENIHR)
NP have 1 to 100 nm in diameter (US EPA, 2005)
NP are particles smaller than 100 nm (IKU, Germany, 2005)
NP are… ultra-fine particles with lengths in 2 or 3 dimensions
greater than 1 nm and smaller than 100 nm (ASTM, E56-03, under
evaluation by ISO)
6
NANOTECHNOLOGY /
NANOPARTICLES - NEW
TECHNOLOGIES?
7
GJN – 5/2007
FIRST COMMERCIAL APPLICATION OF NP QUANTUM
EFFECTS: « RUBY GLASS » (GOLD NPs) – 17th
CENTURY
Solution of Gold NPs
Ruby Glass
Johannes Kunckel,
Alchimist, 1630-1703
macro
G Nohynek – Congrès de la SFT, 20-21 octobre 2008, Paris –Gold,
Copyright
© SFT – Tous droits réservés
8
GJN – 5/2007
Commercial Nanoparticles, 1949
Rheology
Color
G Nohynek – Congrès de la SFT, 20-21 octobre 2008, Paris – Copyright © SFT – Tous droits
réservés
9
GJN – 5/2007
TWO PRINCIPAL FEATURES MAY AFFECT PHYSICAL
PROPERTIES OF NANO- OR MICROPARTICLES
Quantum effects
Important at the low end of nanoscale
May produce changes in physical
(optical, magnetic, thermal or
conductivity) properties
No evidence for change in chemical
properties (chem. reactions take place
at the molecular level)
Chemical properties: major parameter in
toxicity
Increased surface area per unit
mass
NASA SILICA AEROGEL:
<0.05 g/cm3
1 mL of nanoparticles (2.5 nm; 5 g/cm3)
(the world’s lightest solid material)
has a surface of >300 m²
Surface may affect dissolution kinetics /
bioavailability and biological effects
associated with surface activity
10
GJN – 5/2007
NANOTOXICOLOGY?
NPs systemically available after inhalation or oral exposure: UNCERTAIN
Surface of NPs affects toxicity: ↑ or ↓
NPs remain longer suspended in air and water, increasing exposure:
IMPROBABLE
NP produce new toxicities: NONE FOUND
SWCNTs* produce asbestos-like toxicity: NORMAL, THEY ARE µ-SIZED
FIBRES
Relative particle surface: mm-particles << microparticles << nanoparticles
<< solutions or vapours (individual molecules)
* singlesingle-wall carbon nano tubes
11
NANO-SIZED VESICLE DRUG CARRIERS *
SOLUTION
LIQUID
LIPOSOME
LIPID SHELL
NANOCAPSULE
SEMI-SOLID SHELL
SOLID LIPID
NP
LIPID SHELL
*** **
*
****
** * *
**
**** **** ** *
**
***** ** *** *
**
** * *
DRUG
MOLECULARLY
DISSOLVED
POLAR CORE
LIPID CORE
DRUG OR
DRUG-ENRICHED
CORE
* Müller et al., 2000
12
Do nano-sized vesicle materials penetrate
into through human skin? THEY DO NOT
Liposomes or nanosomes do not penetrate through the intact human
stratum corneum
>50 articles published on percutaneous penetration of liposomes or
similar formulations using 14C-labelled vesicle membranes
Intact capsules -hard or soft- were only found on the surface of the SC
Lipids from soft capsules may penetrate into the deep layers of the SC,
but were absent in the living skin.
13
NANO-EMULSIONS AND EXPOSURE: Izquierdo
(2007)
100 nm
100 nm
14
Do nano-sized formulations enhance skin penetration of
ingredients: 25 Years of Transdermal Drug delivery (TDD)
Research
Molecules with an intrinsic capacity to penetrate
through human skin penetrate better when in
solution
Passive delivery systems (occlusive patches)
used for such drug substances
Vesicle-type formulations may moderately
enhance or reduce (2- to 5-fold) skin absorption
of less-penetrating molecules, when compared to
traditional formulations (creams, gels, solutions)
15
GJN – 5/2007
NPs PENETRATE HUMAN SKIN? - EXPERIENCE FROM 20
YEARS OF TRANSDERMAL DRUG DELIVERY (TDD)
RESEARCH
Passive TTD (occlusive patch) only possible, if drug substance
combines 4 aspects:
Solubility and high pharmacological activity
MW <500 Daltons (size ≅ 1 nm)
MP: <200 °C
LogPo/w: 1 to 3
Molecules not meeting these criteria: skin penetration only by
active TDD methods (abrasion, suction blisters, electrical,
mechanical or other energy-related techniques)
16
GJN – 5/2007
DRUG SUBSTANCES USED IN PASSIVE TDD PRODUCTS
(OCCLUSIVE PATCHES)
DRUG
SUBSTANCE
MOL.
SIZE a
(nm)
MOL.
WEIGHT
THERAPEUTIC
USE
1.13
303.36
Motion sickness
0.75
227.09
Angina
0.89
230.10
Hypertension
1.23
272.39
Postmenopausal symptoms
1.17
288.43
Male hypogonadism
N
0.81
162.23
Smoking cessation
N
1.17
234.34
Postherpetic neuralgia
1.63
336.47
Pain management
1.57
357.49
Urinary incontinence
STRUCTURE
Scopolamine
OH
N
O
O
O
O
+
Nitroglycerin
N
O
O
+
N
O
O
O
+
N
O
O
O
Cl
H
N
Clonidine
N
NH
Cl
OH
H
Estradiol
H
H
H
HO
OH
H
Testosterone
H
H
H
O
N
Nicotine
H
N
Lidocaine
O
Fentanyl
O
N
N
Oxybutynin
O
O
OH
N
17
Distance in angstroms (1 nm = 10 A) between the two farthest atoms of the molecule calculated with the molecular modelling
software SYBYL 7.1 (Tripos Inc., 1699 South Hanley Rd., St. Louis, Missouri, 63144, USA
GJN – 5/2007
Are nano-sized vesicles « nanoparticles »?
(EU SCENIHR / SCCP: unlikely)
Vesicles and emulsions are liquid/liquid
dispersions that are intrinsically instable
Trivialisation of the term « nanoparticle »: milk
(containing oil / casein nano-vesicles), cell
components, membranes ?
Questionable, whether the term « nanoparticle »
should be applied to vesicles
Risk assessment for such formulations should be
similar to that of solutions
18
RISK ASSESSMENT OF HUMAN DERMAL
EXPOSURE TO INSOLUBLE NPs: SUNSCREENS
Exposure: NPs used in sunscreens
consist of ZnO or TiO2
Systemic exposure: penetration
of NPs into / through the skin,
systemic exposure?
Hazard: does nano-size increase
the reactivity / toxicity of cosmetic
NPs, such as ZnO or TiO2?
Risk management: can a
potential chemical / photo-chemical
/ biological activity of ZnO or TiO2
be modified (coating)?
19
GJN – 5/2007
INSOLUBLE NANOPARTICLES IN SUNSCREENS
Titanium dioxide is a broad-spectrum UV filter composed of micronsized aggregates. The aggregates themselves are composed of NP
grains, which are often coated
Zinc Oxide is a broad spectrum (UVA – UVB) UV filter, available as
coated/uncoated, pigment grade /micronised NP
TiO2 (15 nm)
TiO2 (35 nm)
Pigmentary TiO2 (180 nm)
20
G Nohynek – Congrès de la SFT, 20-21 octobre 2008, Paris – Copyright © SFT – Tous droits réservésGJN – JAN 2007
Why use nanoparticles as sunscreens? Nano-sized, but
not micro-sized particles are effective UV filters
All products diluted in Cyclopentasiloxane (0.001% TiO2)
Spectrophotometer Hitachi U-3310 - Integrating Sphere
(Slide made available by KOBO, www.koboproducts.com)
21
GJN – 5/2007
Why use nanoparticles as sunscreens?
Transparency of TiO2 nanoparticle dispersions
195
60
35
15
10 nm
195
195
60
35
15
10 nm
195
60
60
35
15
10 nm
35
15
10 nm
10nm TiO2 produces transparent dispersions for all skin types.
(Slide made available by KOBO, www.koboproducts.com)
22
GJN – 5/2007
INSOLUBLE NANOPARTICLES IN
SUNSCREENS
Titanium dioxide (TiO2) is a broad-spectrum UV filter composed of
micrometer-sized aggregates. The aggregates themselves are composed
of NP grains, which are often coated
Nano titanium
dioxide clusters
23
Do insoluble nanoparticles penetrate into living or through
human skin – previous studies
Tan et al., 1996 (TiO2)
Lademann, 1999 (TiO2)
Pflücker et al., 2001 (TiO2)
Schulz et al., 2002 (TiO2)
Alvarez Roman et al., 2004 (polystyrenen NP)
EU Nanoderm project, T. Butz ,2005: TiO2
Gamer et al., 2006 (ZnO, TiO2)
Cross et al., 2007 (ZnO, TiO2)
Mavon et al., 2007 (TiO2)
THEY DO NOT!
24
Recently published studies on dermal
absorption of TiO2 NPs: NO PENETRATION
STUDY
MATERIAL
RESULTS
Lekki et al., 2007 (EU
NANODERM project)
TiO2 (20 nm) in sunscreen
formulations (ion microscopy
and autoradiography)
- No penetration into living skin (human and
porcine skin in vitro)
TiO2 NPs in sunscreen
formulations (nuclear
microscopy)
- No penetration into living skin, using human
intact or psoriatic skin in vivo
Japan Cosmetic Industry
Association (2007)
TiO2 (10-20 nm) NPs in
Water/D5 emulsions
No evidence of skin penetration of TiO2 NPs
beyond first layers of the SC (see pictures
next slide), pig skin in vitro
Filipe et al (2008), EU
NANODERM project
Commercial sunscreens
containing nano TiO2
No evidence of skin penetration beyond SC of
TiO2 NPs; human intact or psoriatic skin in
vivo, realistic conditions; tape-stripped skin
with occlusive patch
Kiss et al (2008)
Commercial sunscreens
containing nano TiO2
No penetration of TiO2 into living skin:
human skin xenografts implanted onto mice
Pinheiro et al. (2007)
- Presence of NPs in 3-5 first layers of SC and
in follicles only (mechanical movement, no
« diffusion » pathway)
- TiO2 permeation profile similar in healthy
and psoriatic skin: NPs retained in first layers
of SC
⇒ NO EVIDENCE THAT TOPICALLY APPLIED TiO2 NPs PENETRATE
(NORMAL
ORParis
PSORIATIC)
GINTO
NohynekLIVING
– Congrès deSKIN
la SFT, 20-21
octobre 2008,
– Copyright © SFT – Tous droits réservés
25
Nanoparticle Sunscreens
TiO2 does not penetrate the stratum corneum
Particle Induced X-Ray Emission
(PIXE)
High resolution electron microscopy
(HRTEM)
NANODERM Quality of Skin as a Barrier to ultra-fine Particles
QLK4-CT-2002-02678 Final Report 2007
26
Titanium dioxide and Zinc oxide in a
topical sunscreen*
Dussert et al Int J Cosm Sci 19: 19-129 (1997)
27
GJN – 5/2007
SKIN PENETRATION OF SMALL MOLECULES IN
SOLUTION vs. INSOLUBLE NPs
?
?
?
?
Insoluble NPS: NO MECHANISM TO
Chemical in Solution: DRIVING FORCE
DRIVE PENETRATION INTO THE SKIN
= CHEMICAL CONCENTRATION
GRADIENT
NPs move by mechanical force: why
Diffusion of molecules into the skin
28 ?
should a rock move only in one direction
PSEUDO-PENETRATION:
ARTEFACTS OF IN VITRO PERCUTANEOUS
PENETRATION STUDIES ON SMALL,
INSOLUBLE PARTICLES
29
GJN – 5/2007
Example: ZnO nanoparticles *
Electron micrographs of human skin
show ZnO nanoparticle mineral
components present on the surface of
the skin & around desquaming
corneocytes
No penetration into the underlying
intact stratum corneum was observed
Multiphoton images also showed zinc
oxide & 10nm Cerium Oxide was
retained in follicle openings & around
desquamating corneocytes
Stretching or flexing the skin did not
affect particle distribution
*Cross et al., Skin Pharmacol. Physiol., 2007
30
GJN – 5/2007
Pseudo-penetration: nanoparticles (and other insoluble
subtances/particles) in the ostium interpreted as
penetration into the epidermis/skin*
TAPE STRIPPING
(S.C.)
SECTIONING
OF
EPIDERMIS
OR ANALYSIS
OF EPIDERMIS
+ DERMIS
* Lademann et al., 1999; Mavon et al., 2007
31
GJN – 5/2007
How efficient is tape-stripping?
Current evaluation of in vitro skin penetration studies is based on the principle that
tape stripping removes all material on/in the stratum corneum
Remaining materials is presumed to be in the epidermis/dermis compartment, i.e.
systemically available → « Systemic Exposure Dose »
Human skin in vitro after 92 tape strips (Lademann et al., 2005)
32
G Nohynek – Congrès de la SFT, 20-21 octobre 2008, Paris – Copyright © SFT – Tous droits réservésGJN, 12/2007
IN VITRO ARTEFACTS: DO NPs PENETRATE INTO
CELLS – OR DO CELLS GOBBLE UP NPs?
ENDOCYTOSIS / PHAGOCYTOSIS
Elie Metchnikoff (1845-1916): Cells may ingest insoluble
materials by endocytosis. Gradually, the cell membrane
extends around the particle until it is completely enclosed. The
membrane enclosing the p article then breaks away from the
edge and moves to its destination within the cell - often the
lysosomes, the cell’s garbage disposal units.
GJN – 5/2007
Phagocytosis of
bacteria, viruses,
insoluble particles
by mammalian cells
Mammalian cells in culture tend to phacocytose small insoluble particles
Release of peroxide and lysomal enzymes reactive oxygen species lipid peroxidation cell damage cytoxicity genotoxic effects
Normal physiological reaction of cells exposed to an excess of insoluble
particles, well-known from hip and knee joint implants (wear debris)
Micro-particles generally more toxic than NP (critical size 0.2 to 0.8 µ)
Relevance of in vitro studies on describing such effects?
* Görög et al. Artherosclerosis, 1988
34
G Nohynek – Congrès de la SFT, 2008, Paris – Copyright © SFT – Tous droits réservés
ICH Genotoxicity Guidelines: don’t treat
cells with particles!
DESERT DUST:
A GENOTOXIC RISK?
IN VITRO TESTS ARE
UNSUITABLE TO
IDENTIFY HAZARDS OF
NPs!
(US NIEHS / NTP Expert Group,
2004)
35
GJN – 5/2007
Are nanoparticles more toxic
than microparticles?
Do nanoparticles roam around
the organism once absorbed?
36
GJN – 5/2007
LESSONS FROM WEAR DEBRIS PARTICLE RESEARCH
ARTIFICIAL HIP JOINT
WEAR DEBRIS PARTICLES
Wear debris particles (50 – 5000 nm) may be cytotoxic:
up to 8.5 x 108 to 5.7 x 1013 particles/g of peripheral
tissue
⇒ osteolysis
37
Toxicity studies on wear debris and other
particles
MATERIAL
PARTICLE SIZE
(nm)
TEST
SYSTEM *
TOXICITY
REFERENCE
POLYSTYRENE
Al2O3
450 / 3500
430 / 2800
HFB
HMP
3500nm > 450 nm
2800 > 430 nm
(Olivier et al.,
2003)
TiO2
ZrO2
Al2O3
Si3N4
SiC
90/130/1600
530
590
700
180
HFB
1600 / 700 / 590 nm
more toxic than
90 / 130 / 180 nm
particles
Yamamoto et al.,
2004
CdO
Ag
MoO3
Fe3O4
Al
MnO2
W
1000
15/100
30/150
30/47
103
200
27000
HEP
Toxicity correlated
with test material,
but not particle size
(CdO, Ag most toxic)
Hussain et al.,
2005
Al2O3
ZrO2
600/4500
600/4500
HFB
4500 nm > 600 nm
Catelas et al.,
1999
* HFP = human fibroblasts; MP = human macrophages; HEP = rat hepatocytes
CONCLUSION: TOXICITY UNRELATED TO PARTICLE SIZE (CRITICAL SIZE: µm-range)
38
TiO2 NPs TOXICITY DEPENDS ON CHEMICAL
CHARACTERISTICS, NOT PARTICLE SIZE
Recent results published by Warheit (2007a, 2007b) on pulmonary
toxicity of TiO2 and quartz NPs (intra-tracheal instillation, rats)
Toxicity of TiO2 (and quartz) NPs depends on
Cristalline form
Surface characteristics of particles
Inherent pH of particles
INHALATION TOXICITY OF NPs BETTER CORRELATE WITH
SURFACE CHARACTERISTICS THAN WITH PARTICLE
SIZE/SURFACE AREA
39
Once absorbed, do NPs freely
roam around the organism? *
Intravenous particles are phagocytosed in
the blood (monocytes), liver (Kupffer cells,
macrophage-like) or spleen (macrophages):
« phagocytic barrier »
Highly efficient barrier filtering and clearing
small particles: major obstacle to
intravenous NP- or vesicle-containing drug
formulations
Major research efforts to camouflage NPs
against detection by immune system:
« stealth particles »
Today, a single intravenous NP-based drug
formulations on the market
* Moghimi et al., Pharmacol. Rev. 53, 283-318, 2001
GJN – NOV 2006
40
GJN – 5/2007
Stealth NP for Intravenous Administration
of Drugs
Surface-coated by
molecules to
escape the immune
system (PEGs)
Important for iv
drug formulations,
e.g. insoluble,
lipophilic anticancer drugs
Coating avoids
detection by the
« phagocytic
barrier »
A single drug on
the market
(doxorubicin, 2006)
NB: 20 years of research attempting to overcome the phagocytic
41
barrier…. Yet, NP freely roam around the organism?
GJN – 5/2007
TOXICITY, GENOTOXICITY,
PHOTO-GENOTOXICITY OF TiO2
AND ZnO NANOPARTICLES
42
GJN – 5/2007
NANO-PIGMENTS USED IN SUNSCREENS: TOXIC?
Recent results on TiO2 NPs confirm
their very low intrinsic toxic
potential, similarly to micrometersized TiO2 (Warheit, 2007c)
Low potential to produce lung tissue
inflammation (inhalation route)
No skin irritant or sensitising potential
No genotoxic potential
No toxic potential by the oral route
No photo-genotoxic potential
(Theogaraj, 2007)
43
BASE SET TOXICITY DATA ON TiO2: LOW HAZARD POTENTIAL FOR
MICRO- AND NANO-SIZED PARTICLES *
MATERIAL / TEST
µf-A
(136 nm)
µf-B
(149 nm)
Fine
(380 nm)
COMMENT
Pulmonary toxicity
+
+
++
Quartz
(0.2– 2.0 µm): +++
Dermal irritation,
rabbit
nonirritant
nonirritant
nonirritant
Sensitisation
(LLNA)
nonsensitising
nonsensitising
nonsensitising
Acute oral toxicity,
rats
Nontoxic at 5000
mg/kg
Nontoxic at 5000
mg/kg
Nontoxic at 5000
mg/kg
Ocular irritation,
rabbit
nonirritant
nonirritant
nonirritant
Ames test
negative
negative
negative
CA, CHO cells
negative
negative
negative
96h tox., rainbow
trout
LC50 > 100 mg/L
LC50 > 100 mg/L
LC50 > 100 mg/L
48h tox., Daphnia
LC50 > 100 mg/L
LC50 > 100 mg/L
LC50 > 100 mg/L
72h tox. , algae
EC50 (growth rate):
87 mg/L
EC50 (growth rate):
87 mg/L
EC50 (growth rate):
61 mg/L
* Warheit et al., Tox. Lett.171, 2007
-
-
-
-
-
-
-
44
CASE STUDY: FATE OF SC INJECTED TiO2
NPs
Umbreit et al (2007 SOT poster)
SC-injected mice with 5600 mg/kg (total dose, 4 injections) TiO2 NPs (4.7
nm)
IV-injected mice with 560 mg/kg (total dose, 2 injections) TiO2 NPs (4.7
nm)
SC-injected mice: most of the injected material remained at injection
site as a solid aggregate
SC-injected mice: very few or no macrophages with TiO2 in the liver,
spleen and lungs
IV-injected mice: TiO2 aggregates inside macrophages in the liver,
spleen and lungs (phagocytic barrier)
NB: in the meantime, 2 more studies on iv toxicity of TiO2-NP
in rodents: non-toxic *
CONCLUSION: TiO2 NPs, even if could penetrate through the skin,
would not roam around the organism, nontoxic after iv admionistration
* Fabian et al, 2008; Sugibayashi et al., 2008
45
GENO- AND PHOTO-GENOTOXICITY OF TiO2
PARTICLES (AMES TEST, CHO CELLS)
NAME
CRYSTALLI
NE FORM
MEAN
PARTICLE
SIZE (nm)
COATING
Ames / PhotoAmes
CHO /
PhotoCHO
1
Rutile
14
Al2O3/Dimethicone
negative
negative
2
Anatase
60
Al2O3/SiO2
negative
negative
3
Anatase
60
Uncoated
negative
negative
4
Anatase
200.000
Uncoated
negative
negative
5
Rutile
20
Al2O3/Dimethicone
negative
negative
6
Rutile
17
Al2O3/Stearic acid
negative
negative
7
Rutile
20
Uncoated
negative
negative
8
Rutile
15
Al2O3/Stearic acid
negative
negative
9
Rutile
15
Uncoated
negative
negative
10
Rutile
11-28
Al2O3/SiO2
negative
negative
46
GJN – 5/2007
HAZARDS OF NP IN PERSPECTIVE
Principal potential human health hazard from NP:
inhalation exposure
Indoor emissions represent 50-80% of human
exposure to NP (10.000 to 240.000 NP/mL air)
Polluted city air: 10.000 to 50.000 NP/mL air
EMISSION SOURCES
Burning natural gas
Candles, toasters
Oven roasts, pan frying
Man has lived with NP since the invention of fire
Many initial inhalation findings (systemic
exposure to NP, toxicity of NP > µP) were not
confirmed by recent studies
47
GJN – 5/2007
PRINCIPAL HUMAN EXPOSURE TO NANOPARTICLES IS
NOT DUE TO CHEMICALS / POLLUTION: OVEN COOKING
AND WAX CANDLES *
* Abt et al., EHP 2000; Afshari et al., 2005
48
Nanoparticles and Neanderthals *
a) carbon nanotube from an
ice core sample, 700 m depth,
>10.000 years old
b) Typical carbon nanotube in
contemporary air
(natural gas combustion)
* Photos from LE Murr et al., Water Res. 38, 4282-4296, 2004
49
CONCLUSION
No hard data on a human health risk of NPs by inhalation, oral or
dermal exposure: hypothetical risk
EU / US has a >1 million new annual cases of largely UV-induced
skin cancers per year: genuine risk
Excellent evidence that NP-containing sunscreens reduce UV
exposure and UV-induced skin cancers: an available and useful
tool for risk reduction
Should we be more concerned by genuine or hypothetical
risks?
Conclusion:
no hazard + no exposure = no risk!
50
HAIR JACKS
51
BARBER SAUCERS…
52
RECENT PUBLICATIONS
53
MERCI
54
SKIN PENETRATION OF QUANTUM DOTS
(QDs) THROUGH SUNBURT SKIN in Mice
Recently, Mortensen et al. (2008) reported “qualitatively
higher” (sic) levels of percutaneous penetration of
Quantum Dots (QDs) in UV-irradiated mice
These results are not relevant for the safety evaluation of
ZnO/TiO2 in Humans
Less stringent skin barrier properties of mouse skin vs
humans
QDs have little in common with nao ZnO/TiO2 (size, chemical
composition, surface properties, shape….)
QDs used have been reported to penetrate to some extent
through normal skin (Ryman-Rasmussen, 2006; present
study)
No quantitative analysis performed (only 2 pictures shown,
see next slide)
skin penetration is reported to be « minute » both through
normal and sunburnt mouse skin
Preferential collection of QDs in folds of Stratum corneum
55
Dosimetry – a genuine or false problem?
Dosimetry, i.e. particle size, shape and number that are actually
administered in toxicology studies has been described to be a major
uncertainty factor in NP toxicology studies
Nanoparticles may agglomerate in oral, dermal or ecotoxicology
(solutions/suspensions) or inhalation (aerosols, dusts) toxicity studies
However, nanoparticles would also agglomerate in a real world (air,
occupational environment, water)
Attempts to create dispersed NPs in solutions (in vitro tests) has created
artefactual data secondary to impact of surfactants
Therefore, toxicity studies on NPs should be performed under realistic
exposure conditions: changes in dosimetry is a part of realistic test
conditions
56
Are current toxicological methods suitable for
investigation of the hazard profile of nanomaterials?
Current toxicological protocols (OECD, US EPA, EU, ICH) are
adapted to investigate the hazard of liquids, solids, suspensions,
dusts, aerosols, gases and vapours
Dusts and aerosols contain particles that are larger than NPs
Gases, vapours and liquids contain particles smaller than NPs (free
molecules or molecules in solution)
Given that these protocols are suitable for hazard investigation of
particles larger and smaller than NPs, they should also be suited for
nanomaterials
57
Hair Follicles
Left: Three element map of a hair follicle which shows TiO2
nanoparticles within follicle.
Right: Same image, with enhanced Ti-signal and reduced S- and Psignal.
58
SKIN PENETRATION OF QUANTUM DOTS (QDs)
THROUGH SUNBURT SKIN in Mice
(A) Overview (20× magnification) of the 8 h Ctrl (i) and 24 h Ctrl (ii). Perinuclear localization
highlighted by magnified inset. Minimal presence of QD can be seen even in the lower stratum
corneum layers. (B) Example slices of the 24 h UVR exposed mouse skin with high penetration
areas in the dermis highlighted by magnified insets.
59
Nano TiO2 associated with organic UV filters:
Synergistic effects of on sun protection
Organic UV filters
UV Filter A
8,5%
UV Filter B
3%
UV Filter C
0,9%
TiO2
Nano TiO2
3%
Organic UV filters + TiO2
UV Filter A
8,5%
UV Filter B
3%
UV Filter C
0,9%
Nano TiO2
3%
SPF vitro = 23
SPF vitro = 4
SPF vitro = 39
60
SIZE… molecular size of a drug substance
used in passive TDD (nicotine) vs. TiO2 NP
N
N
NICOTIN MOLECULE (0.81 nm):
ABOUT 50% PENETRATION
UNDER PATCH
TITANIUM DIOXIDE NANOPARTICLE (50 nm,
insoluble, high melting point, MW = >200000D):
PENETRATES THE SKIN??
61
GJN – 5/2007
COMMON PARTICLES SIZES IN
TOXICITY STUDIES
Football (30 cm)
100 m
10-1 m
(1 m)
Flea (1 mm)
10-2 m
hair (80 µm)
10-3 m
10-4 m
(1 mm)
SOLIDS
COARSE
RBC (7 µm)
10-5 m
10-6 m
(1 µm)
FINE
Fullerene, C60,
Buckyball (0.7 nm)
TiO2 NPs (50 nm)
10-7 m
10-8 m
(100 nm)
ULTRAFINE
10-9 m
Water
(0.1 nm)
10-10 m
(1 nm)
NANO MOLECULAR
POWDERS / SUSPENSIONS / AEROSOLS
VAPOURS
GASES
SOLUTIONS
62
Why use nanoparticles as sunscreens? Nano-sized, but
not micro-sized particles are effective UV filters
63

NP are…

Transcription

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