Taking Stock of the OSH Challenges of Nanotechnology: 2000 - 2015

Taking Stock of the Occupational Safety and Health
Challenges of Nanotechnology: 2000-2015
Schulte, PA, Hodson LL, Murashov V, Hoover MD,
Zumwalde RD, Castranova V, Kuempel ED, Geraci CL,
Roth GA, Stefaniak AB, Howard J
National Institute for Occupational Safety and Health, USA
Disclaimer: The findings and conclusions in this report are those of the author and do not
necessarily represent the views of the National Institute for Occupational Safety and
Health.

Presentation Objectives
 Describe nanotechnology
 Summarize the last 15 years of progress since the inception of
commercial nanotechnology
 Describe the efforts of the occupational safety and health
community
 Identify what still needs to be accomplished

A New Technology
 Illustrates the challenges to society of a new technology
 Beneficial properties
 Potential hazard
 What to do when information is lacking or uncertain

Workers
 Workers generally the first people in society exposed to a new
technology
 Nanotechnology is not an exception
 More than 1,000 nano-enabled products in commerce
 Workers make and use them

Transport
Commercial
Academic
Research Laboratories
Warehousing/Maintenance
Waste Handling
Start Up/Scale Up Operations
Transport
Manufacturing/Production
Transport
Waste Handling
Incorporation in Products
Maintenance of Products
Manipulation of Products
Application of Products - Medical Delivery
Disposal / End of Life
Recycling

Nanotechnology
 Development of materials at the atomic, molecular, or
macromolecular levels with at least one dimension in the range of
1-100 nanometers
 Creating and using structures, devices, and systems that have
novel properties and functions because of their small and/or
intermediate size
 Ability to control or manipulate matter on the atomic scale

How little is “nano?”
If the diameter of the Earth represented
1 meter…
…1 nanometer
would be the size of a dime.

Size of Nanoparticles Relative to
Microorganisms and Cells
Influenza virus
75-100 nm
Tuberculosis bacteria
2,000 nm
Red blood cells
8,000 nm

From Milli to
Nano…
“Nano” is less than 100 nm
Welding fume
1.4 nm
Single-walled carbon
nanotubes
1 nm 10 nm 1 µm 10 µm100 nm
Dust collected 5 miles from
Mt. St. Helens
100 µm 1 mm
Respirable crystalline silica
Human Hair
~70 µm

Nanoparticles: Some Old, Some New
Naturally occurring Man-made
by-product
Engineered
Nanomaterials (ENM)

Not only smaller, but different
• Lower melting point
• Useful as catalyst
• Different color
• Different conductivity
Same Properties
60 nm bar
New Properties
30 nm bar

New Properties of Matter
Based on Size and Surface
Area
¼m
1nm
1m
GOLD
Each side = 1 meter
Mass ≈ 43,000 lb
Surface Area (SA) = 6 m2
≈ 8 ft x 8 ft room
Each side = 1/4 meter
Mass ≈ 43,000 lb
SA = 24 m2
Each side = 1 nanometer
Mass ≈ 43,000 lb
SA = 6 billion m2 ≈ 2500 miles2
Area of Delaware = 2490 miles2
ScalingcomparisoncourtesyofKristenKulinowski, Ph.D.

Why are nanomaterials
potentially dangerous?
1 10 1,000 10,000100
Diameter (nm)
60
40
20
0
%SurfaceMolecules
Source:Kelly[2009]

What could a “nanoparticle” be?
Source:Dr.A. Maynard:WoodrowWilsonInternationalCenterfor Scholars

Nanoparticles: Many shapes, many chemistries
Not all nanoparticles are the same

Same Composition—Different Shape
Zinc oxide nanoparticles
Source:MaterialsTodayJune2004.ZhongLinWang,GeorgiaInstituteof Technology

Parameters That Could Affect Nanoparticle Toxicity
 Size
 Shape
 Composition
 Solubility
 Crystalline structure
 Charge
 Surface characteristic
 Agglomeration
 Impurities
 Attached functional groups

Nanomaterial Science: Opening the 3rd
Dimension of the Periodic Table
”Carbon just isn’t carbon anymore”

Why is nanotechnology of great interest?
 Imparts useful properties to materials
 Stronger
 Lighter
 More durable
 Different melting temperatures
 Enhanced electrical conductivity
 More transistors on integrated chip
 Enhanced chemical reactivity
All of these point to the possibility of creating new and very powerfulapplications.

Applications of Nanotechnology
Agriculture More efficient, targeted delivery of plant nutrients, pesticides
Automotive Lighter, stronger, self-healing materials
Biomedical Targeted therapeutics, enhanced detection, new structural
materials
Energy More efficient fuel cells, solar collectors
Environmental New pollution control and remediation tools, sensors
Food New safety sensors, food preservatives, nutrient additives
Materials Self-cleaning glass, stain resistant, stronger materials, body
armor
Water New purification approaches

Early Nano-Enabled Consumer Products are on
the Market Now [Gibbs 2006]
Eddie Bauer
Ruston Fit Nano-
Care khakis
Wilson Double
Core tennis balls
Kodak EasyShare
LS633 camera
Laufen Gallery washbasin
with Wondergliss
Smith & Nephew Acticoat 7
antimicrobial wound dressing
Samsung Nano
SilverSeal Refrigerator

Nanoparticulate fuel
additives = 10%
better fuel economy
Nanocomposite
body moldings =
20% lighter
Nanoscale catalysts
= 20% reduction in
emissions
Source:Gibbs[2006]

Picturesource:Burnham Institute
Nanotechnology: Turning Fiction to Reality
• Potential for:
– Disease sensing
– Diagnosis
– Targeted therapy
Cancer treatment
(nano.cancer.gov)

Potential Revolution in Manufacturing
• See and
manipulate one
atom at a time –
building molecular
tools
– Using 35 Xenon
atoms to spell out
a logo
• Copy nature –
mimic self
replication
Source:IBMResearch

$0.0
$3.0
$3.5
2000 2020 (estimate
TRILLIONSOFU.S.D.
World US
2008 2015 (estimate)
YEAR
Adapted from Savolainen et al. (2013)
$2.5
$2.0
$1.5
$1 Trillion
$1.0
$0.5
$3 Trillion
Market Incorporating Nanotechnology

Background for Concerns
 Ultrafines in air pollution epidemiology
 Health effects of diesel and welding fumes
 Metal fume fever
 Fumed silica—acute pulmonary inflammation
 Nanogold travel from nasal mucosa to brain (DeLorenzo 1970)
 Animal pulmonary studies of ultrafine zinc respiratory effects
(Amdur et al. 1988)

National Science Foundation Workshop
September 28-29, 2000
Futuristic safety concerns
were envisioned early:
“As currently envisioned,
nano-mechanisms are likely to
possess at least three properties
that will generate novel safety
and governance challenges:
invisibility, micro-locomotion,
and self-replication.”
Page 214

“Presumably nanoparticles must be handled with the same
care given to bio-organisms or radioactive substances.”
(p34) (Swiss Re, 2004)

The Royal Society & Royal Academy of Engineering
(2004)
“There are uncertainties about this risk of nanoparticulates currently
in production that need to be addressed immediately to
safeguard workers and consumers and support regulatory
decisions.”

(2004)
“The evidence that we have reviewed suggests that manufactured
nanoparticles and nanotubes are likely to be more toxic per unit
mass than particles of the same chemical at larger size and will
therefore present a greater hazard.”

(2004)
“Free particles in the nanometer size range do raise health,
environmental and safety concerns and their toxicology cannot be
inferred from that of particles of the same chemical at larger size.”
(p42)

Conceptual Timeline for Growth of Nanomaterial
Products and Workforce
NumberofProductsonEmerging
NanotechnologyInventoryasSurrogatesfor
VolumeofENMinCommerceandNumberof
Workers
1959
Feynman’s
Vision
1974
Taneguchi
“Nanotech-
nology”
1986
AFM
Invented
1990
First
Nanotech-
nology
Journal
2004
First
NanOEH
Conference
(Buxton)
2010 2015 2020
272
1300
(est.)
Initial calls for
precautions
1814 (est.)
Beginning of epidemiologic
surveillance and assessment of
precautionary guidance in use
More specific
precautionary
guidance
3400

Buxton
2004
Minneapolis
2005
Taipei
2007
Helsinki
2009
Boston
2011
Nagoya
2013
Limpopo
2015
NanOEH Conferences

Hazard Identification
“Is there reason to believe this
could be harmful?”
Risk Management
“Develop procedures to minimize
exposures.”
ExposureAssessment
“Will there be exposure in real-
world conditions?”
Risk Characterization
“Is substance hazardous and will
there be exposure?”
Key Elements
in Worker
Protection

Risk Management
exposures.”
ExposureAssessment
Hazard
Nanotoxicology
What do we know?
Are there “trends?”
Key Elements in
Worker
Protection

Othersites
(e.g.,muscle,placenta)
Injection Inhalation IngestionDeposition
Exposuremedia
Uptake
pathways
Translocation
&distribution
Excretory
pathways
CNS
PNS
Lymph
Bonemarrow Kidney Spleen Heart
GItract
Sweat/ exfoliation Urine Breastmilk Feces
Source: Oberdörster, et al. [2005]
Blood
(platelets,monocytes,
endothelialcells)
AirDrugdelivery Food,waterAir,water,clothes
Skin
Respiratorytract
Nasal Tracheo-
bronchial
Alveolar
Liver
Lymph
Confirmedroutes
Potentialroutes

0.001 0.01
6%
12%
18%
24%
Lungtumor
proportion
0.1 1
Particle surface area dose (m2
/g lung)
TiO
2
Carbon Black
Talc
Toner
Coal Dust
Diesel Eshaust particulate
30%
36%
Lung Tumor Response is Associated with Particle Surface AreaDose
of Fine Poorly Soluble Low Toxicity Particles (PSLT) or Ultrafine PSLT
NIOSH (2011)
Driscoll (1996)
Oberdörster and Yu(1990)

Nel et al. (2006)
Hierarchical Oxidative Stress Model

Nel et al. (2006)
Possible Mechanisms by which Nanomaterials
Interact with Biological Tissues

Toxicology
 Particle and fiber toxicity paradigms underpin the majority of
toxicological investigations of ENMS
 Confirmed that particle size is generally an important factor in
toxicity but other physico-chemical factors may play major roles
 Confirmed that nanoparticles could reach the alveoli and could
enter the interstitium and blood stream

Toxicology
 Pulmonary exposure to carbon nanotubes (CNTs) causes
alveolar interstitial fibrosis, which develops rapidly and is
persistent. Fibrotic potency appears related to the
physicochemical properties of the CNT
 Pulmonary exposure to nanoparticles can cause cardiovascular
effects (alteration of heart rate and blood pressure, and
microvascular dysfunction)

Toxicology
 Multi-walled carbon nanotubes (MWCNTs) (Mitsui-7) are a promoter of lung
cancer
 Nanoparticles deposited in the lung can translocate to distal sites
 Insoluble nanoparticles do not appear to rapidly cross intact skin or the GI
tract
 Nanoparticle penetration through intact skin is not likely but exposure to
sensitizers and irritants still a concern

A single MWCNT penetrating from the subpleural tissue through the visceral pleura intothe
pleural space of a mouse is shown in the FESEM image of 7 D (80 μg dose, 56 day post-
aspiration).
Mercer et al. Particle and Fibre Toxicology 2010 7:28 doi:10.1186/1743-8977-7-28

Two dividing control cells with normal
centrosome morphology Courtesy Linda Sargent

Tripolar mitosis following exposure to
.024 g/cm2 SWCNT

Four polar mitosis, nanotube association 24 hours
following exposure to .024 g/cm2 SWCNT

Mitotic Spindle Damage 24 Hours Following Exposure to .024-
24 g/cm2 SWCNT

Mitotic Spindle Aberrations
 Following acute and chronic exposure to carbon nanotubes
 SWCNT enter the nucleus, are integrated with microtubules and
centrosomes, are within the bridge separating dividing cells
• Fragment the centrosome
• Disrupt the mitotic spindle
• Induce aneuploidy
• Chemicals and fibers that induce centrosome damage, mitotic spindle damage and
aneuploidy increase risk of cancer
Linda Sargent, Ph.D.
Molecular Genetics Laboratory, NIOSH

H. F.Krttg
if@Md 001: 10.1(0l/a.rce,2014(•J;(i1
anosafety Research - A r c We on the Right Track ?
Hamid F.Krug

Physical Hazards
 Explosive potential
 Flammability

Risk Management
exposures.”
ExposureAssessment
Exposure
Can it be measured?
Where is it occurring?
Metric?
Key Elements in
Worker
Protection

Multiple Metrics Can Be Used to Assess Exposure
 Mass: Links to historical data; lacks sensitivity and specificity
 Size distribution: More information not always easy, not specific
 Number concentration: Fairly simple with monitors, not specific
to particles, recent correlation of number in ambient air to
biomarkers of coronary heart disease
 Surface area: Some relevance based on toxicology and
technology is available
“Each one may be right”

.eport of JJn.&.estigation
Reference Material® 8013
Gold Nanopa1ticles, Nominal 60 n1nDiameter
This Reference Material (RM) is intended primarily to evaluate and qualify methodology and/or instrument
performance related
biomedical research.
to the physical/dimensional characterization of nanoscale particles used in pre-clinical The RM
may also be useful in the development and evaluation of in vitro assays designed to
assess the biological response (e.g., cytotoxity, hemolysis) of nanomaterials, and for use in interlaborato 1y test
comparisons. RM 8013 consists of nominally 5 mL of citrate-stabilized Au nanopanicles in an aqueous suspension,
supplied in hermetical ly sealed pre-scored glass ampou les steri lized by gamma irradiation. A unit of RM8013 consists
of two 5 mL ampoules. The suspension contains primary particles (monomers) and a small percentage of clusters of
primary pa,ticlcs.
Expiration of Value Assignment: The reference values for RM 8013 are valid, Vithin the measurement uncenainty
specified, until 25 October 2018, provided the RM is handled and stored in accordance with the instructions given in
th is rcpori (sec "Notice and Warni ng to lJscrs"). This report is nul l ified if the R M is damaged, conlamfoaled, or
olherwise mod ified.
Maintenance of RM: NIST ,viii monitor this RM over the period of its validity. Ifsubstantive technical changes
occur thal affect lhe reference values before the expiration of this report, N lST will nolify lhe purchaser. Registration
(see attached sheet or register online) will facilitate notificatfon.

International Attention Needed to Resolve
 Consensus on prioritization of RM needs
 Harmonization of terminology
 Poorly defined or qualitative measurements and lack of metrological traceability
 Better understanding of measurement process
 When RMs are not available, clarify when test materials can be useful for hypothesis testing
Stefaniak et al.(2013)

Exposure Assessment
 Exposure to ENMs is:
 Occurring, often episodic or task-based
 Measurable
 Many ENM emissions form agglomerates
 Growing body of published exposure data
 Importance of measuring background
 International harmonization is occurring

Small Literature on Exposure
 Relative newness of exposure scenarios
 Uncertainties of what metric to use
 Difficult getting entrance to worksites
 Not a wide range of operations assessed
 Little information on downstream users

Nanoparticle Emission Assessment Technique
(NEAT) for the Identification and Measurement
of Potential Inhalation Exposure to Engineered
Nanomaterials — PartA
and
Part B: Results from 12 Field Studies
M. Methner, L. Hodson, C. Geraci
National Institute for Occupational Safety and
Health (NIOSH), Nanotechnology Research
Center, Cincinnati, Ohio
Recent Published Summary of
Field Exposure Assessments
JournalofOccupationaland
EnvironmentalHygieneMarch 2010

Graded Approach to Measurement
• Step 1
– Particle counters and simple size analyzers to
screen the area and process
• Step 2
– Filter based samples for electron microscopy
and elemental analysis, collected at Source
• Step 3
– Filter based samples for electron microscopy
and elemental analysis, collected at Personal
Breathing Zone
• Step 4
– Less portable aerosol sizing equipment

Am,.Oc.:"up. llJg.,2015, VoL59, No.6,70$-i23
doi:10.1093iannl,yu•l'v020
Adv;in<eAe<esspubl i tion7ApriJ 2015
•-.c(,,;r,')l"!Q(')(t x-c :o,
w..1,'CfhOO<lhFror-ccrhn
Carbon Nanotube and Nanofiber Exposure
Assessments:An Analysis of 14Site Visits
Matthew M. Dahm' Mary K. Schubauer-Berigan1,
DouglasE..Evans2, M. Eileen Birchi,Joseph E. Fernbackl and
JamesA.Deddens'
1. lndcn:rywid<' S:udiM6un<h.0.vu or. NSorv('t.llMl r<'.Hurd Ev.afo11ti(lr,.u1d Pi<'ldStUdi<'S. N.AtiClll lMtitutt fo•Om1r.1tlon.1J 1i;:1fi'1rand
Hc-..!tl.1; 1091)Tu'4"1"1.1A,,:, MS•R14,C111u111ut1,OH Sl:26,US.;
l.Chnnlr.aJ Exposu:'t'ar.d MC'oitoting 8r.anch1UM.5ionofApplioo Rt.5Nrch ilndT«hnolcgy, N.nio:Wttu1itlt(' fo, Occll(Mtional Safl'ly nd I
l<'.ulb, l090il1,culU1r1Axt:.Cincinn:11i,OJ I4116,t.:S1
't,',d]u,;IV wlmm c.u;rt':,pvr.Jt'nu::.l1uu J bt .:JJ1 sed.TI: +l·Sl3..fS8·7l36;(.u.: +151J·84J ·+t86;t:·rnll :1n,hhm(.llcdc.g,;,¥
Submlrrtd 3!it"ptcmbrr 2014;mi$00 23J.amury2015: t t ist'd v,milOnacc.-:p1td2.2Ftbru.uy201S,
AJISTIUC.T
Recent evidence l.l$ suggc...tedthepoten tial For widc·r,mging llcaJth effect th.it couJdrcsuh fromupo·
sure to crhon n:inotubcc; (CNT) and c:arbn nanc)6hcr (CNF). In rc poMe, the Nationa.l ln.tt1tutt
for Om,p•tio<1al S..fel)' and He-1th (NIOSH) ,et•recomm<n d,Jcrposurc Limit (REL) fO<CNTand
CNF: l 1;1,gm 'a$;i,n S·h limt weighted aver.1ge (TWA) ofclcmcntal carbon (EC) forrht spirable siu
fr1<tion. The purpose o( thjs study w;1s to conduct 1 l l indtrywide exposure .i.SS-essment among US
CNT and CNF manufacturs.md users. Fourteen toul sites "';ere viiited to 1sseu exposott-s toC. n
( D sites) ,nd CNF (I site). Person,!breathing ion• (POZ) ,r.d aruiamples wm, col!tcted for both
the inhd1ble ,nd r,spirable r.1ass concentrotion of EC, using NIOSH Method SO.JO. lnhabble P8Z
s:timplcs were collcctc<I u ninesi:cs while !lt the remaining five s i t both respirablc and inhJ1:able, l'HZ
samples were collected siJc b;·-:;idc. TraNmi.$sion electron microscvpy (TEA,() PBZ an<l area s.im·
pies were alsocollected at the inhakibk sh.c fraction and analyzed to quantify andsi1.c CNT an<l CNF
agglomcntc :md fibrous cxpo5urcs.Rc-spira.blc EC PSZ concentrations ranged from 0.02 lo 2 94 pg
m·>with agcomctnc mean (GM) of0.34 gm·)and an 8-h TV/A o(O.l6 pg m l. PBZ s.uuJ1lts ;a1thP
inhabblcs1zc fraction for EC ranged (rom0.01 to 79.!,7 F&m >witha G·lo( 111t•gm..J. PBZsarnpls
:amlr«d byTEM )hawed co11cc;:1trations ranging from 0.0001lo 1.613CNT or CNF structm'S 1-.er
cml with GM o(0.008 and an $-h TWA concentration of 0.003.The most comnum Ct-:T n1ct1.l.l'e
site$,re found tobe hrgcragglomcrates in the2-Slllll nngc ;iswdlas agslomcr.,tcs >S 1,m.Ast:.tisti·
c:illy signifkant correlation was ol>Krvcd bctwc"-n the lnh.a ablc samples for the ma s of EC an<lstru<·
turc cou:n,br TEM (Sporman p•0 . 3 , . f' <0.000 1).O,,crnU, EC PBZand area rv.:snmplC!ii w·.-e
bc:lowthe NIOSH REL {96% wen: -<J g m >at thercspirabl,c iit'e fraction), while 3 0 of the inhal,1ble
P.82ECsampJeswerefound to be >l pgm·l. Untilmore information is known abuut healthdT'.1.lS
.U50('i.m:d with larger agglomt"ratcs. 11seems prurlcnl to :.11s::,t';SSworker cxpo:.urc tomrborne CNT anJ
CNFmaterialsby monitoring £C:itboth th, rl'Spir.ible an(I mhafable sin fr.actions. Concurrent TF.M
sJmplcs should be,oJlcc-wd toconfirm the prcsen<e ofCNT .ind CNF.
l(EYWOROS : carbo1, 1ianofibc1-s;(.l1bon o..notub..-s;cxp(});mc a :.cs:,u1cnt;no1nu11,.1 1.i1!s

ISSN 0 0 0 3 -4S 7S (.:>Al"-T>
ISSN 147;;;-3162(ONLINE)
The Annals Of
.''.l JTCRN:TIONiL SCll'.:NTII'JC J>URNAL
01 IHI- C A U A I I O I AND CON IKOL O r
WORK-RE..ATED JLL-HE.'U,TH
Occupational Hygiene
Volume S+ Number 6 August 2010

Images from field air
samples. Complex
nanomaterial shapes
in a complex matrix.

Exposure Data
Conclusions/Challenges
 Exposure metrics and approaches need to be harmonized
 Mass is still the primary metric
 Mass and particle number might be a good association
 Direct-reading approaches have a place
 Agglomeration is a reality
 Confirmatory methods are needed

Risk Management
exposures.”
ExposureAssessment
Risk
Hazard x Exposure
Key Elements in
Worker
Protection

Quantitative Risk Assessment (QRA)
 The estimation of the severity and likelihood of adverse
responses associated with exposure to a hazardous agent
 Can be used to estimate the exposure concentrations that are
likely—or unlikely—to cause adverse health effects in workers
 Two sources for prediction
 Animal data
 Human (epidemiologic) data

Assume equal response to equivalent dose
Rat
Dose-response model
(particle surface area
dose in lungs)
Calculate lung tissue
benchmark dose
Working lifetime
exposure concentration*
Equivalent tissue dose
Estimated lung
deposition fraction
Recommended
exposure limit
Technical feasibility of
measurement and control
Extrapolate
(Adjust for species
differences in lung
surface area)
*Comparerat-basedriskestimateswithconfidenceintervalsfromhuman studies
Quantitative Risk Assessment in Developing
Recommended Exposure Limits for Nanoparticles
Human

www.cdc.gov/niosh/docs/2011-160

Risk Assessment: Ultrafine (Nano) TiO2
• NIOSH draft recommended exposure
limits (RELs)
– 2.4 mg/m3 fine TiO2
– 0.3 mg/m3 ultrafine TiO2
– Reflects greater inflammation & tumor risk of
ultrafine on mass basis
• Key message: The OEL for a material in
its “large” form may not be appropriate for
the nano form.

www.cdc.gov/niosh/docket/review/docket161A/pdfs/carbonNanotubeCIB_PublicReviewOfDraft.pdf

Risk Assessment: Carbon Nanotubes
• Use data from Ma-Hock (2009)
– Wistar rats exposed 0.1, 0.5, 2.5 mg/m3 multiwall carbon
nanotubes (6 hr/day, 5 days/wk, 15 wks)
• OEL for a risk of pulmonary fibrosis at less than 1/1000
over a working lifetime
• Likely to be less than the limit of quantitation for organic
carbon i.e., < 7 g/m3

Nadonal tnsdnoteforPublicHealth
and thennvironment
ltitusuyo{Hea1ck,Wel(arew,dSpon
Grouping
nanomaterials
Astrategytowards
groupingandread-across

Risk Management
exposures.”
ExposureAssessment
Recognize and
Manage Risk
What works?
What has been used?
What can be reapplied?
Key Elements in
Worker
Protection

Risk Management
 Follow hierarchy of controls
 Establish OELs
 Utilize Prevention through Design
 Institute medical surveillance
 Conduct epidemiological studies

Societal Level
 Ethical principles
 Workers have a right to safe and healthy
workplace and a right to know hazards
 Employers have responsibility to provide safe
and healthy workplaces
 Uncertainty and precaution

When hazard is uncertain,
precaution should be high
Schulte & Salamanca-Buentello [2007]
Hazard
Identification Risk
Assessment
and
Characterization
More Precautionary
Risk Communication
and Management
Less
Precautionary
Less
Certain
More Certain

Conventional controls should work
Exhaust Ventilation
Capture
Inertia
Dominants
Diffusion
Dominates
No
Capture
Air Stream
About
1 nm
Most
Fine
Dusts
Micro
Scale
200 to
300 nm

Controls have been applied in research
and pilot development work

Air
Air
Concentration
m air
concentration
Concentration "With" due to use ofLEV
"Without" LEV LEV ('Yo)*
Manganese (Mn) Reactor c1eanout 3619 150 96
Silver (Ag) Reactor cleanout 6667 L714 74
Iron (Fe) Reactor clcanoul 714 41 94
Background (Reactor area Prior to
cleanout) ND ND NIA

Manufacturing Containment
Courtesyof NanocompTechnologies, Inc.

Filtration Performance of an Example NIOSH Approved N95
Filtering Facepiece Respirator
n=5; error bars represent standard deviations
TSI 3160; Flow rate 85 L/min

Task
Duration
Quantity
milligrams
kilograms
15 minutes
8 hours
slurry/suspension highlydisperseagglomerated
Physical Form
Factors Influencing Control Selection
Engineered Local Exhaust
Ventilation
Closed
Systems
Occupational Health Hazard
mild /
reversible
severe /
irreversible
Courtesy Donna Heidel, formerly atNIOSH

Exposure Management
Control Banding—Concept
Low Dustiness Medium Dustiness High Dustiness
Hazard Group A
Small 1 1 1
Medium 1 1 2
Large 1 2 2
Hazard Group B
Small 1 1 1
Medium 1 2 2
Large 1 3 3
Hazard Group C
Small 1 1 2
Medium 2 3 3
Large 2 4 4
Hazard Group D
Small 2 2 3
Medium 3 4 4
Large 3 4 4
Hazard Group E
For all hazard group E substances, choose control approach 4
Parameters
Amount Used
Dustiness
Hazard Group (R-Phrase)
ilo.orgSource:T.J.Lentz, NIOSH
ControlApproach
1. General Ventilation
2. Engineering Control
3. Containment
4. SpecialistAdvice

•
. TI1i" AJli,/ f;,f.,( Hlrl,....""'t 11•ov,1 fot ; i •)'IVl"1)· ul1 f' "(t),fl<,,•fit': ll tt·, Fmn1).11 l': )elit'' tu
."'>l.11Jli:-·1,1 ·1·yi:-l,y ol 11.111:11n.it".i,1 .•:,,ul.,111i "J.clli•.k":-,f1'.'lk• l11111i•••:f11:11:-if'I• l,1l.1 i:. 11¥y( 11II:,,
1eedr!cl to imprc,w:hcwte.:fgecf 11 :t: s ::,r th m:1.rke:, wl"o is £k.?OS00 andY,'lat shot le 00
-gllatd.Member SUt&S lWlteme SL<:h i1wllteriei t.d h.!W- dE: c:ied thfr own ini:iat·1,·s
wh leatth,$Jmtlr"te.llort.hg he E1.1rQ"Pean Commi$$io,t.o $ter; in n the process. Att-it'r3
humnnio.atinn,,r t P. ratinnal iritiati>; c. -. ::.·ud,ol, fn, p1•)J;"!f r t 1 at.ion i:c; nP.t>.t.P.d :n"1<.L1e f!fnpP:r ptotP:ctir:, af hc.,riln !r:1
,y·,•i1f1Uffl"1·t.1I h,1.1ltl· ff"', 'l,11 .t<. H'.HI< lti,Ur> lr.,, I :'Ifti<.k.11Ul1,ljl't'111t
Introduction
"'·,d,:rJu:,t ,,rIll!' •11ll..::i'cl I'.<.·r.Ji1.-,.., ;1;,lu•.1·.·)a·,:lxY:1
·.1t·111, 1,i,1li:.l•J,1111. .lu. 11 J;'ly u c 1,y·••,11u111 f'.,.v;-...IJwiJ>.•
:'>C4.bh i1k1tif ::d.,.. h.i',Tl!J r<::Ju:.ll, l11Jl i,UH UCtl.t: n-il .,c:rnrJ ,;.1i.1I
.m;11,:i10:-rrn.mu d,:,1u·1·,;,;dc:l;,;1·,,;. :111I i1er.>sp1:e;e ea·c,nics .:1d
c,:;mputec1s;.ene.rg;· d en•, rc ·uren:; f o 3fl•1 a1:if :J'Jb..1re;
h)u.;ns; a d (C•l'lStfu;Ji<>n. me-Jial ind phan 1)e,... utkal, ;X:lt'lfal
(a:, a14flHJk .:.p<,n 30,1 d·:J
:,H .,11111.:r' pi:11111I, I.,.::,.f 1111, 11, ·:(,.,I $ol1111nJl;:1iJh ··1
.,' d;u!: r , ..;:.·i ;·:: t; ·;:
pr,i:;rtits Ike high s1, 1ac:e :1re:1, r,;<:lct i/1t .elem1;c,nd1,cti' it,
an1 }..1rtie-ent'9'1•,.•·,i.,13ft mc·eu5een,J l ti: ditlertnt fr.:),..l"'IC:
n1t:J, f.'.)f,.:: elf '.)(1 ;,-L-.r: 31TV:f r illf f 31.
Bui 'J:,.i..1..1.·)111. . u ' ,-thrnI h1-Ir...;•, J -tll•I fll•,'·,ihl I.,k, ,.f
n,11(lltlill!'I ,,15•lld h( ,-:k ol l:r CIWk'lh·• KJI lh('fll,:·111 toi !Nte
irrt,rm;nicl l } l :e d s(k,;ej 1<·:t prc Jel regul.:t<·
trame·;IOf',:.t.s':"t; it i JfCl arexa,jy' hown1,:1, 31:icleson t1e
,nukct ,:Muiu 11a1''.)1"3ttticl . r.-:·i1t'>t.arll'.-:':.JitoVIL::i<:n,v<,1lc:rs
ha·;.::, " I ·.iP.t'"'h."lr.fth!'.v a·hardlinr, n;;,"ll··utt-irak,,·'th.it
:,1i:uttit.,.,. arn1v. ,.1'IP.I , u 11,·,tt lf!v (lr+,..,. ; i ,bm'tf .T lP. ,1 ¥:ff!
:Jrlie.' ,-.111 •h;ri·lru !-".,r.·k fn1 11•..- >lt' 1w"'1ij h,i!: t•t'.:.O"l rel ing tc,r
1ip,,:1ii 1?,:r·de; 1t 5 ::in tb:' pol it :11;,erd• bi.=-:use s:ake10lder d
s<usi.:,rs·,:i!t the Jla:or1t·:><ies<-nthe )upl
;;f infarn-.a:ic1C"lr3fi:'o«31.Nial.;ar;:hafi:c l}'Ctac od:ec.
TheEU's E.6.11ul.:tic1 onthe feJist'9fon e;·9lua1ion. au1·)1iai<
l auJ rtM'k:un d du:-11ials.rr uir:s :1,1)st 1ft:·11. J, t.11C:i$JJ J
ii •1>.Cclf,l;J f('.'jbt,:1 I u".ir:J1l:fl1i(.J s d ,1.)ftO!:
. t , 11 u.t" .I.nIIK", hlll '.ll t .,..,J :...1rdy. -1.W; yL'I, lh;: c1,pbliv11
t.:>Il,·1:. r:> :,,v..:t.ifio. •,wi;iicu.,. :m r.Jnvu,h:·i,d. JrM. he
l:,n;:,:;cr, >Jr 1<1u,c11.,,_,..rull,;;1-.Hl l"IC ::11rm1:,11c:,1I.<;"'" Ud.e
ther,eed tor::.·.iewREAUItoen:.Jr: hilt'TE 'n}<ctl 1, ,c,nml:.ef
1,;r1d1llc li)Jl ·estont(::-ff:tti:dal C11r1.;:>e3·,.,:triar,en:..2C09).
·1u,:k.e, i')',111i·,U:.u:l.ll+: "''..vi ·:h1:1l 11.1w1111I.1:1.1do:lc·,
f1.m,·uk i:.t1:.if-:·cvr:tl..: fc r JIvii :1l..:1,I:,!> Ure n:cd fort1
rt:lllry c:I 11Jrl;rr :.l.:.;rtL l1x1.:11n 1·;1 prc•.lt..s. l t11; lu:.t, l;e,
:1uSEv,hilE rrMemte, 5'a s ltlt hv,urtd tuce.:011 ty i'.;:e·1s
br ra1,:,m3le'ial.s S'.>f'lle tc'rr1 <:t u::>r::Jinaticri is
:::'><.::1·ia b,;:-.Ju.' d, o::111ry' has:i,;:,·::li:>r<:'1 ii.<.:11,1a:>r,'a:J1
1'r.i tt·o;. ,r.-k1':o;. urr..-,,....t, 3fm:m :.af:m 1r·,"lf r.iffirult. 111·¢
1:,1·w·111,·.-i<: ",1·1!11vil'·•. ,.f lhP.·,i:,r•::,0.,11..11'1 lh<·,.i:-MP.ml'!f
etu1.

Establishment of OELs
 No officially promulgated OELs
 16 “unofficial” proposed OELs

Pauluhn
4
5
3
0
1
5
5000
MWCNT
2.5 µg/m3
CNT & CNF
7 µg/m3
MWCNT
30 µg/m3*
OELs for Carbon Nanotubes
OSHA Carbon black PEL
3500
Baytubes
MWCNT
50 µg/m3
OSHA Graphite PEL(respirable)
*Period-limited (15-yr)
Nanocyl NIOSH Japan
BSI—0.01 f/ml [benchmark exposure limit-BEL] high aspect ratio nanomaterials
–established at 1/10 asbestos OEL
OEL(µg/m3)

Anticipatory international consensus standards established at the
introductory stage of nanotechnology could potentially hinder the
“race to the bottom” where nations compete for jobs by lowering
national workplace safety standards.
Murashov et al. [2012]

Prevention through Design (PtD)
Design molecule
Nanotechnology
Design process

Parameters that could affect nanoparticle
toxicity
Size
Shape
Composition
Solubility
Crystalline structure
Charge
Surface characteristic
Agglomeration
Impurities
Attached functional groups

Occupational Health Surveillance
GROUP
Medical Surveillance
INDIVIDUAL
Medical Screening

Issues in Medical Surveillance for
Workers in Nanotechnology
NeedsAssessment
Is there a hazard?
Is there exposure?
What is the risk?
Decisions on Medical Surveillance
Medical Screening Systematic Data
Collection
Exposure
Registry
Hazard
Surveillance

Medical Surveillance
 Insufficient scientific and medical evidence to recommend the specific
medical screening of workers potentially exposed to engineered
nanoparticles
 If nanoparticles are composed of chemical or bulk material, for which
medical screening recommendations exist, these would apply to
nanomaterial workers
 Analysis of change in frequency of adverse effects in worker groups is
warranted
 Exposure registries may be useful in some situations

 Value of medical screening
 Lack of specific health end point
 Hazard surveillance
 Potential for exposure registry
Interim Guidance Issued by NIOSH

Medical Screening
Health Council of the Netherlands [2012]
 No screening programmes are currently available, anywhere in
the world, for individuals who work with nanoparticles

NIOSH Recommendations for Surveillance among
Nano-workers: Specific Cases
 Ultrafine titanium dioxide
 Current Intelligence Bulletin
(CIB) recommends following
general guidance for
nanomaterials (NIOSH 2009)
Difference based on toxicological hazard (pulmonary fibrosis for CNT) at occupationally relevant exposure levels
 Carbon nanotubes & nanofibers
 CIB recommends employers
consider implementing medical
monitoring for workers exposed
to CNT or CNF at levels above
the recommended exposure limit
 Baseline evaluation, spirometry,
chest x-rays, others

Epidemiology
 Few epidemiological studies have been conducted
 Difficult to identify workers exposed to specific nanomaterials
 Difficult to form cohorts
 Cross-sectional biomarkers studies have been initiated
 Most biomarkers have not be validated for their positive predictive
value

etc.
Sector:Food
Sector:Electronics
Sector:Medicine
Sector:Energy
Sector:Materials
Workplaces
NanomaterialType
Carbon
Nanotubes
Graphene
Metal
Oxides
Dendrimers Fullerenes
Metal Nanomaterials
Nanowires
Nanostructured Metals
Nanoporous Materials
Nanoscale Encapsulation
Laboratory
Research
Start up/Pilot
Manufacturing
Production
Disposal

RTI Contract Report [2014]
Flowchart of the uses of iron oxide nanoparticles
within key industries

First Wave of Epidemiological Studies of
Nanomaterials Workers
16 Studies Completed or Issued Abstracts
 11 cross-sectional
 5 longitudinal (panel studies)
 Generally used biomarkers as
dependent variables
 Generally had limited exposure
assessment
 Small sample size
 Exposures:
 Carbon nanotubes
 Nanosilver
 Titanium dioxide
 Iron oxide
 Calcium carbonate
 Nanogold
 Carbon black

?
?
?
?
Estimated number of workers actually
exposed to engineered nanoparticles
2000 2010 2015 2025
1000
10,000
100,000
1,000,000
10,000,000
NumberofWorkersExposed
Dilemmas in Identifying Workers Exposed to Engineered
Nanoparticles
1959
Feynman’s
vision
1990’s
Beginning of
commercialization Source: Schulte[2009]
Global employment estimated
USA employment estimated
[Roco & Bainbridge, 2005]

Conceptual Illustration of a
Nanomaterials Worker Health Study
Continued exposure assessment
• Register
workers
• Characterize
exposure
• Baseline health
assessment
• Epidemiologic
investigations
• Specimen
banking
Prospective studies of sub-cohorts
Biomarker
cross-sectional
(CS) studies
CS CS
Periodic medical monitoring
Timeline
Components

Registry of
NOAA exposure
CNT exposed workers cohort
Specific
TiO2 exposed workers cohort
Worker
inclusion
questionnaire
Prevalence & incidence morbidity
cross-sectional &
panelstudies
Mortality
data
Generalist CMR
job-exposure
matrices (JEM)
Generalist PM &
fibers JEM
(MatPUF, Ev@lutil)
Research & expertise
institutions: INRS, INERIS,
INSERM, CEA, …
Data on associated exposures
and potential confounders
data
Health care and
drug prescription
database
(SNIIRAM)
Hospital
discharge
summary (PMSI)
International
collaborative
studies
Perimeter of the integrated system for epi-surveillance and research on NOAA
InVS abilities in data gathering andabstracting Collaborative actions
Measurement
of ENM
exposure &
biomarker
studies
Epi-surveillance
& descriptive
statistics
General
prospective
follow-up
Causes of
death register
(CépiDC)
Declaration R-nano
Worker
follow-up
questionnaire
Guseva
Canu (2010)

Potential Objectives for Future Epidemiological
Research
 Legacy nanomaterials
 Carbon black
 Nano-titanium dioxide
 Harmonized global approach to epidemiologic studies of
engineered nanomaterials (ENMs)
 Prospective studies

J N:inopart Res (2014) 16:2302
DOI 10.1007/s11051-014-2302-9
REVlEV
Biomarkers of nanomaterial exposure and effect: current
status
Jvo lavicoli ·Veruscka Leso ·Mau1izio Manno ·
Pa.ul A. Schulte
Received: 30 July 201:3/Accepted: 27 January 2011 /Published online: 22 februa.ry 201'1
© Springer Science+Business fedia Dordreht 2014
Abstract Recent advances in nanoteclmology have
induced a widc:sprc.ad prnduction rutd application of
nanomaterials. As a consequem.:e, an increasing num
her of worker.s are expected to undergo exposure to
the&c xenobiotics, while the possible hazards to their
health remain nol being rnmpkldy understood. InLhis
context, hiological mon itoring may play a key rolenot
only to identify potential hazards from .:'Indto evaluate
but also
metallic content in blood or urine or other biological
materials, whereas spc:cific mole;culc.smay becarefully
evaluated in Lurgel tissues as possible biomarkers oi
hiologically effective dose. Oxiclat.ive stres.s hiomark
ers, such as 8-hydroxy-dc0xy-guruto&ine, gcnotoxicity
biomurkers, andinllmrumrlory responseindic.:alors may
also he useful, although not speci fic, as hiomarkers of
nanomaterial early adverse health effects. Finally,
polcnlial from

Source
----...__...........--..-......--
"E x p o s u r e ) Internal dose;>
. /
Amb ient
environment

Lung
Blood
MWCNT
Lung RXN
Blood
Produced
Complex
Signal
Minimal transport
of
MWCNT into blood
MWCNT act in lung and
induce “serome”
response.
MWCNT
Modest
Transport
Courtesy of Andrew Ottens, VCU; Matthew Campen, UNM; Aaron Erdely, NIOSH; Unpublished Findings

10ug
MWCN
T 40ug
MWCN
T
10ug
MWCNT
40ug
MWCNT
2,507 Responsive Factors, Kruskal-Wallis; FDR 5%
Factors
on/off
with
MWCNT
No dose
effect
Log(2)
Log(2)
Courtesy of Andrew Ottens, VCU; Matthew Campen, UNM; Aaron Erdely, NIOSH; Unpublished Findings

To what extent are nanomaterial
workers being protected?

Adherence to Precautionary Guidance

Examples of Government Guidance Documents
NIOSH
IRSST
BAuA
UK HSE
METI
JNIOSH
Safe Work
Australia
IRSST, Institut de Recherche Robert-Sauvé en Santé et en Sécuritédu
Travail
BAuA, (German) Federal Institute for Occupational Safety and Health
HSE, Health and Safety Executive
METI, Ministry of Economy, Trade and Industry (Japan)
JNIOSH, Japanese National Institute for Occupational Safety and
Health

Is risk management guidance being followed?
What is known? What is not known?
 Guidance has been followed in
some cases
 The extent of awareness and
adherence with exposure
controls and precautionary
guidance needs to be assessed
 The effectiveness of adherence
with guidance needs to be
assessed – what works and
what doesn’t work
 Additional targeting of guidance
may be needed for specific
workplaces and workforces
where adherence is low

Image source: United States Government Accountability Office, 2015.

Fused Filament Fabrication
Operation:
1. Thermoplastic heated in print head.
2. Print head scans platform, deposits plastic.
3. Thermoplastic cools and solidifies.
4. Platform lowers or print head raises.
Subsequent layers add height.
KeyAspects:
• Inexpensive (< $1,000)
• Poor resolution
• Thermoplastics only; additives (including
nanomaterials) are being explored
• Most common consumer 3D printing technology
Image source: Eva Wolf,2012.

Occupational Safety and Health Concerns
• Materials
– Nanomaterials (powders,
additives)
– Heavy metals
– Organic chemicals
(polymers/binders)
• Energy
– Thermal sources
– Lasers & electron beams
• Emissions
– Releases during operation
– Cleanliness of products
– Machine maintenance
• IH Practices
– Return of “cottage industry”
– New material testing

Generations of Nanomaterials
 1st generation
 2nd generation
 3rd generation
 4th generation
Passive nanomaterials
Active nanomaterials
Integrated system
Nano systems

The Long Run Trajectory in nanotechnology
Development
 Shift from passive to active nanostructures [Subramanian et al.
2010]
 An active nanostructure—“changes or evolves its state during
operation” [NSF 2006]
 Structure, state, and/or properties change during their use
 “…Build stuff that does stuff” [Smalley quoted in Maynard 2009]

http://python.rice.edu/~kolomeisky/nanocar
.htm
Molecular Car

5 Types of Active Nanomaterials
1. Remote actuated active nanostructure:
Nanotechnology whose active principle is remotely activated or
sensed.
2. Environmentally responsive active nanostructure:
Nanotechnology that is sensitive to stimuli like pH, temperature,
light, oxidation-reduction, certain chemicals etc.
3. Miniaturized active nanostructure: Nanotechnology which is a
conceptual scaling down of larger devices and technologies to
the nanoscale.

5 Types of Active Nanomaterials
(cont’d)
4. Hybrid active nanostructures:
Nanotechnology that involves uncommon combinations (biotic-
abiotic, organic-inorganic) of materials.
5. Transforming active nanostructures:
Nanotechnology that changes irreversibly during some stage of its
use or life.

Extrinsic Properties
 Beginning to create materials that are unique
 Have properties never before available to scientists

Extrinsic Properties (cont’d)
 Could have human health and environmental risks never before
encountered
 Functionality associated with carefully engineered collection of
chemicals and components (what it does)
 Becomes more than just the sum of its parts

Extrinsic Properties (cont’d)
 We are moving to a world where knowing what something is
made of is no guarantee of how to handle it safely
 When does engineering a substance at nanoscale lead to
deviation in its conventionally established risk profile?

Most regulations focus on the intrinsic properties of materials
instead of extrinsic

Increasingly Sophisticated Nanomaterials
 Since materials change during their use successive changes may
have unforeseen and unintended consequences
 Challenges to re-think exposure scenarios
 Could have unique risk profiles
 Could have the potential to stress and force change in existing
regulatory frameworks
 How do we anticipate the stresses?

leturnal of Oc.cupatiett!i.·ll ani E,i·.,•ironmen,.a,Hygie.ne,9: D12 D:22
ISSN: 1545-9624 print J1545-9632 onlioc
DOT: 10.1080il 545%24.2012.6ll2 l i
Commentary
Progression of Occupational Risk Management with
Advances in Nanomaterials
Vladimir Murashov, Paul Schulte, and John Howard
National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention,
Washington, D.C.
INTRODUCTION
anotedrnulogy h;1sbt',cm Louted as a lransfonualiv tt'.(;h
Nnology lhal wou ld encompass a broad rnngc of protlucls
am] applicalion are,as ancl improvt', urnny aspe,cls of human
life. As rnmolcdrnolugy urntures, lhc crnupkxiLy of iLs main
product. nano111aterials. increa!'-e. Four generations of nano
mat.erial!- have heen rletinecl by a Worlcl Technology Evalua
tion Center (WTEC) Report,('J namely, passive nanomaterials,
active nanomaterials. integrated nanosystems, and molecular
nanosystems. According to the Woodrow Wilson Nanotech
nology Consumer Product Inventory, V• there are over 1000
self-identified nano-enabled consumer products on the market.
Mosl of Lht'.se, proclui.;ls art bai:;e,tl on fi.ri:;l-gt',nt',ralion "passive'.
nanomaterials." Limited understanding of passive nanoma
krial ha.am.ls has challcng,xl trndilional occupalional heallh
ri:-k asscssrn(.111.arnl rnanagclllcnl. approaches. New approaches
including rmg,gest.ions for rhe development and adopt.ion of
proaeLiw approaches l.o nanolcchnology risk assesslllcnL and
control have heen propoerl(:;, I.Jnl ike reactive approache!-,
where risk control measures are applied to well characte1ized
hazards, proactive or anticipatory approaches aim at minimiz-
.'.'Ind nanosystems m.'ly present more compkx health risks th.·m
p;1ssivc nanomal,:rials,(10> risk asi:;,:ss1m:nt i:;tudies i:;pccifi.illy
directed at. these mater ials in the workplace need to he funded
anrlconducted.
ltwas recognized tlutnanotechnology and advanced nano
materia Jr; raise isr;uer; that are more compleir anrl far-reaching
than many other iimovations.'1 1
'•111erefore, approaches to the
overall risk governance of emerging tedmologies, which can
be defined as a comprehensive oversight framework encom
passing re.gulaLory and non-rt',gulalory approache,i:; lo rii:;k as
sessment and risk management, may need to be validated and
rnotlified as appropriaLe,.
Inlhis Cmmn..:nlary, soui..:of lhc compkx. issu,:spertaining
to the occupational safety anrl health risk i111plicat.io11sofactivc
nanomat.er ials anrl nanoyst.ems are explored.
NANOMATERIAL COMPLEXITY
Generations of Nanomaterials
Aclvancemc".nL of rnnoltdnmlogy can bt eharaclc".riL.e.cl by
a number of factors, such as the narnre of the manufacturing
proc,:sscs used Lopnx.lucc nanolilaLeriali:;, bn:.aclLhofnanoL,:ch-

Future Needs
• More standardized toxicological studies
with better particle characterization
• Develop refined metrological approaches
• More collection, collation, publication and
meta-analysis of exposure data
• More attention to toxicity and exposure to
advanced ENMs
• Further development of categorical
approaches for risk assessment and
management
• Refined medical surveillance guidance
• More epidemiologic studies
• Global assessment of compliance to risk
management guidance

Taking Stock of the OSH Challenges of Nanotechnology: 2000 - 2015

Recomendados

Mais conteúdo relacionado

Mais procurados

Mais procurados (14)

Destaque

Destaque (20)

Semelhante a Taking Stock of the OSH Challenges of Nanotechnology: 2000 - 2015

Semelhante a Taking Stock of the OSH Challenges of Nanotechnology: 2000 - 2015 (20)

Mais de The Windsdor Consulting Group, Inc.

Mais de The Windsdor Consulting Group, Inc. (20)

Último

Último (20)

Taking Stock of the OSH Challenges of Nanotechnology: 2000 - 2015