All

21

22 3

Summary 1 1 3 1.1 4 1.2. 8

1.2.1 10 1.2.2 11 1.2.3 12 1.2.4 13 1.2.5 14 1.2.6 16 1.2.7 17 1.2.8 18 1.2.9 19 1.2.10 20 1.2.11 21 1.2.12 22 1.2.13 23 1.2.14 24 1.2.15 25 1.2.16 26 1.2.17 27 1.2.18 28 1.2.19 29 1.2.20 30 1.2.21 31 1.2.22 32 1.2.23 33

1.3 34 1.3.1 36 1.3.2 38 1.3.3 40 1.3.4 41 1.3.5 42

i

1.3.6 43 1.3.7 45 1.3.8 46 1.3.9 48

1.4 1 49 2 51 2.1 51 2.2 54 2.2.1 58 2.2.2 64 2.2.3 72 2.2.4 85 2.2.5 104 2.2.6 111 2.2.7 122

2.2.8 154 2.3 2 170 2.4 177 3 183 3.1 183

3.1.1 183 3.1.2 (EU) 187 3.1.3 190 3.1.4 190 3.1.5 192 3.1.6 193

3.2 197 3.2.1 197 3.2.2 (EU) 199 3.2.3 200 3.2.4 200 3.2.5 201

3.3 204 3.3.1 OECD 204 3.3.2 ISO 206 3.3.3 UN 207

ii

3.3.4 WHO 208 3.4 209

4 International Conference on the Environmental Effects of Nanoparticles and Nanomaterials (

3.4.1 thnano2009)

3.4.2 224 209

3.5 3 226 4

227

4.1 227 4.2 (EU) 231 4.3 234 4.4 235 4.5 239 4.6 240 4.7 OECD 243 4.8 246 4.9 247 4.10 4 254 5 255 7

iii

21

OECD

1. 2. 3. 4.

2008 10

IT

77 19 4 103 20 1 53 in vitro41 in vivo41 10in vitro in vivo ADME OECD-WPMN / in vitro in vivo EHS2009 /

I

EPAEU

OECD

ISO/TC229

EHS

2000

OECD ISO

EHS

II

Summary This report is the results of An Investigative Research on Consumers Safety in Utilizing Nanomaterials (2009) administrated by The Ministry of Health, Labour and Welfare, Japan. It aimed to promote the contribution of our country to Working Party on Manufactured Nanomaterials (WPMN), Organization of Economic Cooperation and Development (OECD), and to gather facts and figures needed in examining the safety precaution of nanaomaterials to which use to the consumers products was being expanded. The investigation items were executed, described below;

1. Investigation on the actual conditions for the use of nanomaterials in the country.

2. Research and analysis in the literatures concerning safety, especially in toxicology, of nanomaterials.

3. Research in the international trend concerning safety precaution of nanomaterials.

4. Analysis of reports concerning safety precaution of nanomaterials published by overseas administrative bodies and international organizations.

Item 1 was performed mainly by the interviews to each enterprise that manufactured or used the nanomaterials with referring to the results both document retrieval and internet search, and the result was brought together according to the each nanomaterial and the usage for nanomaterials, respectively. On the nanomaterials of the high rank of the manufacturing amount, for example carbon black, silica, nickel nanoparticle and titania, the industrial production decreased from 2008 to 2009, and it was figured out that the stock price crash in the USA of October, 2008 and the steep appreciation of the yen caused the stagnation of the industrial manufacturing of nanomaterials. About mounting the nanomaterials on the products, it was thought that the replacement with old goods mainly progressed steadily through the quality improvement and the technical improvement.

The investigation and the analysis of the document concerning the safety of the nanomaterials were executed for 77 articles in this report. As the entire tendency, it is understood that the number of articles concerning the safety of the nanomaterials increases year after year. In addition, it is thought that it is a feature of the survey that the number of articles that present information such as ADME in various form observation results and in vivo increases in in vitro in addition to the report of toxicity.

The situation of each country and the each international organization for the restriction was investigated centering on environment, health and safety (EHS) of the nanomaterials. About the safety action on nanomaterials, topics in this year were to

III

have strengthened the institution for preliminary notification on the nanomaterials in United States, Canada, and California State, USA. In the examination and the research strategy that offered the scientific basis of the restriction, US EPA and EU have begun the working scheme that clearly intended the environment of the engineered nanomaterials and the data collection concerning environment, health and safety. Moreover, it has started to shown the guideline of various test methodologies concerning the safety of the nanomaterials by OECD: WPMN and ISO/TC229. It is expected to improve the information on the environment, health and the safety of the nanomaterials through the improvement of sharing of the research results and the standardization of data interpretations.

As the feature of the overseas reports concerning the safety precaution of the nanomaterials collected in this investigation, it was begun to publish documents on the risk evaluation and the risk management of the nanomaterials.

It was expected that the ensuring safety of the nanomaterials including the action on the EHS problem would enter a new step in several years in the future.

IV

)

OECD 18 10 1 OECD OECD

19 11 OECD 14

OECD

1

OECD

1. 2. 3. 4.

4 7

- 2 -

1

2008 10

- 3 -

1.1 1.1.1. 100nm 1.1.2.

9

1.1.1

DDS

()

- 4 -

1.1.3. 23 1.1.2

1.1.2

C60 1

WS-C60 2

SWCNT 3

MWCNT 4

5 6 CB 7

8

9

10 11 12 13 PSt 14 15 16

CNF 17

18 19 20 21 22 23

- 5 -

1.1.4.

1.1.5.

1) 2) 3) 4) 5) 6) 2008 2009 7)

1.1.6.

ABA B

B

A

- 6 -

1.1.3

A

B

A

B

- 7 -

1.2 23

1) 2) 3) 2007 2008 2009 4) 5) 6)

1.2.1

19

2008 10

2008 1030%2009

- 8 -

1.2.1 2008 2009

1 1 1

2

100kg 100kg 3 SWCNT 500 400 4 MWCNT

5 5 5 300 300 6 81.4 18.5 57.7 8.9 7

800 700 8

150 150 9

700 500 10 30 30 11 400 400 12

5 2 4 2 13 15 15 14 5 5 15

200 200 16

80 80 17

750 750 18 350 400 19

1 1 20

100kg 100kg 21 kg kg 22 1,500 1,500 23

- 9 -

1.2.1 C60

1nm nm m

1nm

2007 1 2008 1

2009

1

CFRP EL

X PCBM([6,6]-Phenyl C61-butyric acid methyl aster)

fullerene198560C606070 7476 78 96 240

- 10 -

1.2.2.

1nm nm m

2007 2008

2009

- 11 -

1.2.3. SWCNT

0.82nm 1001,000m

SWCNT

/100kg 2007

/100kg 2008

/100kg

2009

SWCNT MWCNT

DDS

SWCNT HER2 HER2

1 0.34nm ()

- 12 -

1.2.4. MWCNT

20150nmm

/

2007 500 2008 500

400 2009 2008 20%

HDD CNT

MWCNT

EL

MWCNT

DNA

- 13 -

1.2.5.

210nm 50500nm

2000 500600 5 1% 2007 +

2008 5

5 2009

100nm

15nm100nm

ABSPC

- 14 -

- 15 -

1.2.6.

50nm x 100200nm 40200nm

20-40nm Fe2O3() Fe2O3()

100-300nm

1000 30% 300 2007

2008 300

300 2009

CNT

MRI

MRI

UHF

30300GHz

- 16 -

1.2.7.

10-80nm10500nm

30250nm m m 0.5

2mm

83.0 2007 14.9 81.4 2008 18.5

57.7 2009 8.9

20 tire soot 90%%

UV

nm 10500nm nm um 1mm

- 17 -

1.2.8.

5100nm 15nm100nm

1080nm /

20.3 100nm 800 2007 20.8 100nm 800 2008

17.3 100nm 700 2009

B UV-B

20

100nm

- 18 -

1.2.9.

15155nm 7200nm

3.8 100nm 150 2007 4.0 100nm 150 2008

3.7 100nm 150 2009

200

- 19 -

1.2.10.

15-50nm 50m100nm

0.610m60nm300nm

30 2000 700 2007

2008 700

2008 30% 500 2009

50nm

- 20 -

1.2.11.

10-100nm 0.62.5m

100200nm 80150nm

6,000 0.5m30 2007 30 2008

5,000 30 2009

SOFC

- 21 -

1.2.12.

19-120nm

3040nm2035nm

7.9 100nm 400 2007 7.7 100nm 400 2008

7.7 100nm 400 2009

ITO

100nm UV-A320400nmUV-B290320nm

- 22 -

1.2.13.

10-70nm 722nm715nm1m

20-50nm

5-50nm10-12nm 5-50nm

2007 6 2.5

2008 5 2

4 2009 2

20

ECC

- 23 -

1.2.14.

3-20m

100-200nm210m 10-1000nm

330 15 5% 2007

2008 15

15 2009

FRP

FRP

- 24 -

1.2.15.

15-50nm 20-40nm

100nm

50 510% 2007

2008 5

5 2009

DDS

- 25 -

1.2.16.

1nm1001000nm10m

1520m() 1nm100nm

4 70 200 2007 70 200 2008

60 200 2009

90

/ PET

- 26 -

1.2.17.

10100nm 120m

CNF 2 8 250t 80

2007

2008 80

80 2009

2007

- 27 -

1.2.18.

5200nm 10100m

3.5 0.5% 2% 150 600

2007

3.3 150 600 2008

3.0 150 600

2009

nm mm 2

- 28 -

1.2.19.

0.1 150 80-200nm m

4,000 100nm 400 10% 2007 3,500 100nm 350 10% 2008

4,000 100nm 400 10% 2009

()

- 29 -

1.2.20.

80300nm DDS100nm 60150nm

DDS1 2007 DDS1 2008

DDS1 2009

1988 5

50400nm

- 30 -

1.2.21.

250nm

25nm210nm

0.54%

5.0 100kg 2007 6.5 100kg 2008

5.0 100kg 2009

CO/NOx

- 31 -

1.2.22.

1.61.8nm 5.47.3nm

20nm x 5nm

320nm

kg 2007 kg 2008

kg 2009

1980 1998

2006

2008 2030nm/50nm

//

nm20nm 0 10 1

- 32 -

1.2.23.

30100nm 100500nm

1,200 2007 1,500 2008

1,500 2009

()

150200nm

- 33 -

1.3

9

A B A B

B 1.3.1

1 ,2

1 http://staff.aist.go.jp/kishimoto-atsuo/nano/index.htm2 Woodrow Wilson International Center for Scholars The Project on Emerging

Nanotechnologies (PEN), Consumer Products Inventory http://www.nanotechproject.org/inventories/consumer/

- 34 -

- 35 -

1.3.1

1

2

3 SWCNT 4 MWCNT 5 6

7

8

9

10

11

12 13 14 15 16

17

18 19 20

21

22 23

[]

1.3.1

A

B A

B 1) A

Drug Delivery SystemsDDSDDS

PEG19885

DDS100nm60150nm

MRI

SWCNT HER2 HER2

SWCNT /

DDS

- 36 -

40

2) B

HIV C

DDS DDS

- 37 -

1.3.2

A

B

1) A

30nm

Q10

E

nm 2) B

1-5nm H-

30nm CE

- 38 -

1)

2) 3)

- 39 -

1.3.3

A

B A

B

1) A

PET 3% PET

1-2nm 1000

2) B

PET

50-150nm

- 40 -

1.3.4

A

B

B

1) A

2050nm

300

50nm

100nm 2) B

- 41 -

1.3.5

A B

B

1) A

1.3.2

3 1) 2) 3)

2) B

UV

- 42 -

1.3.6

A

B

B

1) A

JIS Z 2801

SIAA 1900

: /

- 43 -

2) B

- 44 -

1.3.7

A

B

A B 1) A

1.3.6

2006 2008

2) B

- 45 -

1.3.8

+

A

A B 1) A

1) 2) 3) 4)

840nm

1) 2)

3)

- 46 -

4)

5)

JISISO2008 2) B

- 47 -

1.3.9

100nm

FRP

13nm

- 48 -

1.4 1

2008 10

IT

- 49 -

- 50 -

- 51 -

2

77 in vivo

ADME EHS 2.1

JDream II JSTPlus JMEDPlus

STN TOXICENTER MedLine 200811200910

JDream IISTN TOXICENTERMedLine

L1L2ADME L32.1(L1 and L2) or (L1 and L3) JSTPlus1761JMEDPlus133STN

339277

- 52 -

2.1

L1

++++++++++++(++++2 +++++)*(++"nm")

L2

++++++++++++++++++++

JDream II

L3

(++++++++++++++++++)#(/TI+/TI+/TI)

L1

nanomaterial OR Nanostructures+NT/CT OR Fullerenes OR Carbon (1W) tube OR carbon black OR dendrimer OR nanoclay OR (Silver OR 7440-22-4 OR Ag OR iron OR Fe OR 7439-89-6 OR titanium dioxide OR TiO2 OR 13463-67-7 OR 7440-32-6 OR Al2O3 OR aluminium oxide OR 11092-32-3 OR 1344-28-1 OR Ce2O3 OR CeO2 OR cerium oxide OR 1306-38-3 OR ZnO OR zinc oxide OR 1314-13-2 OR SiO2 OR silicon dioxide OR 7631-86-9 OR polystyrene) AND (nm OR nano OR nanosize OR nano size OR nanoscale)

L2

toxicity tests+NT/CT OR Toxicology OR toxicity OR toxic OR adverse event OR adverse effect OR risk+NT/CT OR assessment OR Hazard OR safety OR carcinogen##### OR mutagens OR DNA damage OR cytotoxicity OR Reactive Oxygen Species OR oxidative stress OR Macrophage OR inflammation OR granulocyte OR Body Burden OR bioaccumulat### OR accumulat###

STN (TOXICENTER)

L3

(pharmacokinetics OR Drug Administration Routes+NT/CT ORInhalation Exprosure OR intratracheal OR aspiration ORoral OR gavage OR Nutritional Support+NT/CT OR Cutaneous Administration/MeHS OR skin OR cardiovascular OR nervous OR neurological OR lung OR pulmonary OR reproductive OR deposition OR permeation OR bioaccumulat### OR accumulat###) NOT (Gene Delivery/TI OR drug delivery/TI OR DDS/TI)

- 53 -

2.1

L1

nanomaterial OR Nanocomposites OR Nanostructures+NT/CT OR quantum dot OR Fullerenes OR nanotubes OR Carbon (1W) tube OR carbon black OR dendrimer OR nanoclay OR (Silver OR 7440-22-4/RN OR Ag OR iron OR Fe OR 7439-89-6/RN OR titanium dioxide OR TiO2 OR 13463-67-7/RN OR 7440-32-6/RN OR Al2O3 OR aluminium oxide OR 11092-32-3/RN OR 1344-28-1/RN OR Ce2O3 OR CeO2 OR cerium oxide OR 1306-38-3/RN OR ZnO OR zinc oxide OR 1314-13-2/RN OR SiO2 OR silicon dioxide OR 7631-86-9/RN OR polystyrene) AND (nm OR nano OR nanosize OR nano size OR nanoscale)

L2

Toxicology OR toxicity OR toxic OR adverse event OR adverse (1W) effect OR risk OR assessment OR Hazard OR safety OR carcinogenicity OR mutagenicity OR genotoxicity OR cytotoxicity OR Reactive Oxygen Species OR Macrophage OR inflammation OR granulocyte Polymorphonuclear leukocyte OR Body Burden OR bioaccumulat### OR accumulat###

STN (MedLine)

L3

(ADME OR pharmacokinetics OR Inhalation OR intratracheal OR aspiration OR oral OR gavage OR drug delivery system (L) intragastric/AB OR dermal OR subcutaneous OR cutaneous OR skin OR cardiovascular OR nervous OR neurological OR lung OR pulmonary OR reproductive OR bioaccumulat### OR accumulat###) NOT (Gene Delivery/TI OR drug delivery/TI OR DDS/TI)

- 54 -

2.2

endpoint 77 endpointin vitroin vivo in vitroin vivo 2.4 2.2

- 55 -

2.2

ABB Air-blood barrier ACP Acid phosphatase ALT Alanine aminotransferase ANA anti-Nuclear antibodies ANCA anti-Neutorophil cytoplasmic antibody AO/EO assay

Acridine orange/ ethidium bromide assay /

APS Aerodynamic particle sizer

AST Aspartate aminotransferase BAL Bronchoalveolar lavage BALF Bronchoalveolar lavage fluid BEGM Bronchial epithelium growth media BET Brunauer, Emmett and Teller BUN Blood urea nitrogen C-ANCA Cytoplasmic anti-neutrophil antibody CBMN assay

Cytokinesis blocked micronucleus assay

CFU Colony Forming unit CFU-Eo Colony Forming unit-eosinophil CFU-G Colony-forming unit granulocyte CFU-GM Colony forming unit-granulocyte, macrophage CFU-M Colony-forming unit macrophage cNOS Constitutive nitric oxide synthase Cryo-TEM Cryo-Transmission Electron Microscopy CVD Chemical vaporization deposition DEP Diesel exhaust particle DLS Dynamic light scattering DSC Differential scanning calorimetry EC50 Half maximal (50%) effective concentration ED Embryonic day EDS Energy dispersive X-ray spectrometer X EDX Energy-dispersive X-ray spectroscopy X EELS Electron energy-loss spectroscopy ESCA Electron Spectroscopy for Chemical Analysis X ESR Electron Spin Resonance ETAAS Electro thermal atomic absorption spectroscopy Ex/Em Excitation/emission wavelengths / FE-SEM Field emission scanning electron microscopy FIB system Focused ion beam system

FPG Formamidopyrimidine-DNA glycosylase DNA

- 56 -

2.2

FSP Flame spray pyrolysis FTIR Fourier Transform Infrared spectroscopy GFAAS Eelectro thermal atomic absorption spectroscopy GO Gene Ontology GSD Geometric standard deviation GST Glutathione S-transferase S - HiPco the high pressure CO disproportionation process HiPco HO-1 Heme oxygenase-1 -1 HRSEM High Resolution Scanning Electron Microscope HRTEM High-resolution transmission electron microscopy HSP70 Heat shock protein 70 70 HUVEC Human Umbilical Vein Endothelial Cells

ICP-AES Inductively Coupled Plasma Atomic Emission Spectrometry

ICP-MS Inductively Coupled Plasma Mass Spectrometer

ICP-OES Inductively coupled plasmaoptical emission spectroscopy

JNK Jun N-terminal kinase Jun N LAL the Limulus amebocyte lysate LDH Lactate dehydrogenase value LGS Leaky gut Syndrome LSM Laser Scanning Microscopy MI Mitotic index MMAD Mass median aerodynamic diameter MN-PCE Micronucleated polychromatic erythrocyte MPO Myeloperoxidase mTOR Mammalian target of rapamycin NOAEL No Observed Adverse Effect Level Nrf-2 NF-E2-related factor 2 NF-E22 NRU assay Neutral red uptake assay PALS Phase analysis light scattering PALS(PALS) PBMC Peripheral Blood Mononuclear Cell PCE Polychromatic erythrocyte PCS Photon correlation spectroscopy PDI Polydispersity index PMA Phorbol myristate acetate PMNs Polymorphonuclear cell poly-APS polymeric Alkylpyridinium salts 3- RES Reticuloendothelial system ROS reactive oxygen species RT-PCR Reverse transcription-polymerase chain reaction sc-CO2 Supercritical CO2

- 57 -

2.2

SEM Scanning electron microscopy

SFRD Supercritical fluid reactive deposition

siRNA small interfering RNA RNA SPION Super Paramagnetic Iron-Oxide SPME Solid Phase Micro Extraction STEM Scanning transmission electron microscopy TBARS Thiobarbituric Acid Reactive Substances TEER (TER)

Transepithelial electrical resistance

TEM Transmission Electron Microscopy TGA Thermogravimetric analysis VSM Vibrating Sample Magnetometer XDC X-ray Disc Centrifugation (X ) XRD X-ray diffraction X

- 58 -

2.2.1 No. 47 S. Kato et al., Basic Clin. Pharm. Toxicol., 104(6), 483, 2009.

LF-SQ05000g/plate6S9 mix48hrsLF-SQ01000g/mL13UV50NRIC50UV PIF (photo-irradiation factor) 3Bronaughs diffusion chamber 3hrsLF-SQ24hrsLF-SQ2.2322.3223 ppm3x 17.7lHPLC

endpoint in vitro 1. (LF-SQ)

2. (Buckmister fullereneHPLC) 1. Vitamin C60 BioResearchhighly purified and organic solvent-free fullerenes 2. Sigma-AldrichBuckmister fullerene99.5%

1. C60 220-500 ppm Lipo Fullerene (LF-SQ) 100.1m

HPLC

1. Salmonella typhimurium (strains TA 98, TA 100, TA 1535, TA 1537) 2. Escherichia coli (WP2uvrA (pKM101)) 3. mouse fibroblast cell (Balb/3T3)

4. three Caucasoid women 1. histidine-demanding strains 2. tryptophan-demanding strain 3.

In vitro

4.

In vivo

UV IC50 LF-SQS9 mix C60

- 59 -

No. 15 P. Spohnet al., Environ. Pollut., 157, 1134, 2009.

MTT assayoxidative stress assay OECD 202MTT assaytotal DNAHoechst 33258MTT assay nC60THFnC60H2O060 mg/mL6wash13075% of total volume66 oxidative stress assayVoelkel (2003) ROSOECD 202110nC60THFnC60H2O61224g/mL0182448hrsEC50

endpoint in vitro C60 () Sigma-Aldrich>98%

nC60THFDeguchi (2001) C60 THFMilliQ 3 wash1wash2wash3 3 nC60H2OCheng (2004)Brant (2005) C60 MilliQ

UV-VISSEMPCSSPME

human lung epithelial cell line A549 (CCL-185) In vitro Daphnia magna ()24hrs

In vivo

nC60H2O nC60nC60THF nC60448.2 33.1 nm25%wash1wash2 total DNA MTT assay0%

nC60THF THF

- 60 -

No. 31 J. K. Folkmann et al., Environ. Health Perspect., 117(5), 2009.

0.0640.64 mg/kg b.w. in 200l84 24hrs DNA1) 8-oxodG2) 8-oxodG OGG1NEIL1MUTYHNUDT1HO1mRNADNA

endpoint 1.

2. SWCNT 1. Sigma-Aldrich0.7 nm99.9%

2. Thomas Swan0.9-1.7 nm

- 61 -

No. 43 H. Aoshima et al., J. Toxicolo. Sci., 34(5,) 555, 2009.

GLP Draize3HPFs 0.5 g in 0.3 ml PGDraize5HPFs 20 mg in 0.2 ml PG2Kay and Calendra (1962) 6HPFs 0.1 g (1989) 30 HPFs 50 mg (1989) 20 HPFs 50 mgMorikawa (1974) 10HPFs 7.5mgFinn Chamber (21) (24)HPFs 0.01 g

endpoint

Vitamin C60 BioResearchhighly purified fullerenes (HPFs)C60C70fulleritesublimed technical grade99.5%

In vitro

1. (Kbl:JW11) 2. (Hartley guinea pigs6) 3. (21) (24)22-56 1. dermalocular 2. dermal

In vivo

3. dermal

HPFs HPFsHPFs1hr24hrs

48hrs

- 62 -

No. 48 M. Naota et al., Toxicol. Pathol., .37, 456., 2009.

3051hr6hrs24hrs7136105min625g/0.05 ml1hr6hrs24hrs71000g/0.05 mlTEM

endpoint Material Technologies Research0.68 nm

PBSvortex

In vitro

(ICR101129-34 g)

In vivo intratracheal instillation

TEM ()

(ABB)

- 63 -

No. 58 J. Valant et al., J. Hazard. Mater., 171, 160, 2009.

AO/EB assay in vivoAO/EB assay16AO/EB 1/10 ( 3l)3 1000g/mL10

Cu2+poly-APSCu2+Cu(NO3)2 11000g/mL 4 0.000550200 mg/mLpoly-APS0.0221.12.2 mg/mL

endpoint 1. C60 () 2. TiO2 3. ZnO

4. bulk ZnO 1. Sigma-Aldrich 2. Sigma-Aldrich30 mg

In vivo oral (directly)

bulk ZnO

C60

- 64 -

2.2.2 No. 14 B. J. Panessa-Warren et al., Environ. Pollut., 157, 1140, 2009.

H2SO4/H2O2 7 SWCNT Panessa-Warren (2006, 2008) 10100 mg/L in 2l()/ (TEMFESEM)

endpoint in vitro 1. SWCNT (As-prepared Carbolex) 2. SWCNT (Air-oxidized Carbolex) 3. SWCNT (Acid/peroxide treated Carbolex Newly prepared in fresh water)Acid/peroxideH2SO4/H2O2

4. SWCNT (Aged in fresh water 7yr) 1. LexingtonCarbolex1.4-1.5 nm0.4-1m70-90%Ni 23.2 3.0%Y 4.8 1.5% 2. LexingtonCarbolexColomer (1999) Perk (2006) 2.1-2.3 nm0.18-0.4m70-90%Ni 5.9 1.4%Y 0.9 0.6% 3. LexingtonCarbolexLiu (1998) Panessa-Warren (2008) 1.4 nm0.0132-0.0338mNi 0%Y 0%disruptedeasily20-300 nm

4. LexingtonCarbolexLiu (1998) Panessa-Warren (2008) 7 Ni 0%Y 0%aggregates300-500 nm

MilliQPBSvortex

TEMFESEMUV-VISXFTIR

human lung epithelial cell monolayers (NCI-H292) In vitro

In vivo

SWCNT SWCNT FTIR SWCNTH2SO4/H2O2

SWCNT

SWCNT

- 65 -

No. 34 A. E. Porter et al., ACS Nano, 3(6), 1485, 2009.

Porter (2006) SWCNT 010g/ml 7 4 (HMMs) neutral red assay (NR assay)MTT assayTEM

endpoint in vitro 1. SWCNT (unpurified SWCNT)

2. SWCNT

1. Carbon Nanotechnologies chemical vaporization deposition (CVD) method SWCNT purified HiPco15 wt % ash content0.9-1.2nm 1. 10 Figure SE1

2. SWCNT1g/L10

high-resolution (HR) TEMEELS

human monocyte derived macrophage cells (HMMs) In vitro

In vivo

SWCNTNR assayMTT assaySWCNTNR assayMTT assay

SWCNTSWCNTcarbon wallTEM SWCNTSWCNT

- 66 -

No. 67 H. Yang et al., J. Appl. Toxicol., 29, 69, 2009.

0-100g/mL24hrs (MTT assayWST assayLDH)ROS oxidative stress assay (GSHSODMDA )comet assay in vitro

endpoint in vitro 1. CB 2.CNTs 3. SiO2

4. ZnO 1. Nano-Innovation12.3 4.1 nmSphere>99.4%2. COCC, Chinese Academy of Science8 nm99.9% 3. Runhe20.2 6.4 nmCrystal structure>99.0%

4. Nanuo19.6 5.8 nmCrystal structure>99.9%

4 hrs180 CFBSLam (2004)Leong (1998)

TEM

primary mouse embryo fibroblast cells (BALB/3T3) In vitro

In vivo

MTT assayWST assayZnOoxidative stress assayCNTsZnOcomet assay DNA

- 67 -

No. 56 A.R. Murray et al., Toxicology, 257, 161, 2009.

in vitro SWCNT SWCNT (PBS)AP-1NKFROS ()ROSESRSWCNT0.060.24 mg/mL24hrs SWCNT () SWCNT SWCNT75g/150l 18 hrs in vivoSWCNTSWCNT540160 g/mouse24hrsLAL assay LPSELISA MPO GSH ()

endpoint in vitro 1. SWCNT (unpurified SWCNT)

2. SWCNT 1. Carbon NanotechnologiesHiPcoSWCNT30% (wt) iron

- 68 -

in vivoSWCNTMPOPMNs

160 g

- 69 -

No. 17 A. Erdely et al., Nano Lett., 9(1), 36, 2009.

Rao (2003) 40g/mouse 4hrsBAL LDH TaqMan array real-time RT-PCRELISA

MWCNT7SWCNT5UFCB57 endpoint

1. MWCNT 2. SWCNT 3. ultrafine carbon black (UFCB) 1. MitsuiSWCNT>UFCBMWCNT5

- 70 -

No. 31 J. K. Folkmann et al., Environ. Health Perspect., .117,(5), 2009.

0.0640.64 mg/kg b.w. in 200l84 24hrs DNA1) 8-oxodG2) 8-oxodG OGG1NEIL1MUTYHNUDT1HO1mRNADNA

endpoint 1.

2. SWCNT 1. Sigma-Aldrich0.7 nm99.9%

2. Thomas Swan0.9-1.7 nm

- 71 -

No. 54 H. Tong et al., Toxicol. Appl. Pharmaco., 239(3), 224, 2009

Gilmour (2004) 1040g/mouse in 50lLPS 2g/mouse in 50l24hrsBAL

endpoint

1. SWCNT 2. SWCNTAF-SWCNT 3. ultrafine carbon black (UFCB)

4. UFCBAF- UFCB 1. Sigmacatalogue number636797 2. 1. SWCNTSaxena (2007) 3. Dr. Vickie Stone

4. 3. UFCBSaxena (2007)

AF-SWCNTAF- UFCBSaxena (2007)

thermo-optical methodICP-OESUS EPA Method 3050B (measured gravimetrically)TEMBET analysesZetasizer Nano ZS

In vitro

(CD-112-1630.8 0.7 g)

In vivo Inhalation (pharyngeal aspiration route)

AF-SWCNTUFCBAF-UFCB40g

AF-SWCNT40g

- 72 -

2.2.3 No. 10 X. WANG et al., J. Nanosci. Nanotech., 9(5), 3025, 2009.

MWCNT MWCNT 020g/mL 5 3hrs MTT assay6hrs TEM 12hrs 24hrs

endpoint in vitro 1. MWCNT

2. Quartz () Shenzhen Nanotech Port 10-20 nm1-5m>95%(MWNT10) Shenzhen Nanotech Port 40-60 nm1-5m>95%(MWNT40) Shenzhen Nanotech Port 60-100 nm1-5m>95%(MWNT60)

The National Institute for Occupational Health and Poison Control

- 73 -

No. 57 U. Wirnitzer et al., Toxicol. Lett., 186, 160, 2009.

MWCNT OECD TG 473471OECD TG 4731) MWCNT 010g/mL 4 S9 mix 4hrs 18hrs 2) MWCNT 10g/mLS9 mix 18hrs 30hrs 3) MWCNT 010g/mL4S9 mix 18hrs OECD TG 47105000g/plate S9 mix 48hrs

endpoint in vitro MWCNT Bayer MaterialScienceBaytubes>95%

10 mg/mL 30

1. OECD TG 473Chinese hamster lung fibroblasts V79 cell 2. OECD TG 471Salmonella typhimurium (strains TA 1535, TA 100, TA

1537, TA 98, TA 102) 1. OECD TG 473

In vitro

2. OECD TG 471

In vivo

OECD TG 473 OECD TG 471

- 74 -

No. 69 L. Tabet et al., J.Toxicol. Environ. Health. Part A;72, 60, 2009.

MWCNT0100g/mLCB nanoparticles100g/mL6244872hrs4872hrs

endpoint in vitro 1. MWCNT 2. () 3. ()

4. CB nanoparticles 1. ARKEMAGraphistrength C10012 nm0.1-13m 2. UICC20 nm 3. UICC80 nm

4. Degussa/EvonikFR10195 nm

MWCNT MWCNT (DPL)PBS CBPBSvortex

TEMICP-MSESCASEMBET analysesKnudsen flow reactor 1. A549

2. MeT5A 1.

In vitro

2. ()

In vivo

MWCNTA549MeT5APBS DPL 100g/mL

CB

- 75 -

No. 25 M. Chiaretti et al., J. Phys.: Condens. Matter, 20(474203),1, 2008.

in vitro3MWCNT 00.1 mg/ml2472hrs in vivoMWCNT 7Irwin test

1 35 102040 mg/kg b.w.15 mg/kg b.w.7

14 endpoint in vitro

MWCNT

Sigma-Aldrichproduct number659258110-170 nm5-9m>90%

in vitroin vivo90

2Tween-80 (5%)PEG 400 (5%)(MTC 0.5%) Tween-80 (2.5%)MTC (0.5%)

TEMSEM

1. Caco-2 2. hSMCs

In vitro

3. MCF-7 (CD1 Swiss27-32 g)

In vivo

in vitro Caco-2 hSMCs 72hrs MCF-7 in vivo

ANAanti-ENAanti-CLC-ANCAP-ANCA

- 76 -

No. 66 G. Bardi et al., Nanomedicine: Nanotech Biol. Medicine, 5(1), 96, 2009.

in vitroMTT assayPF1270.001%0.05%MWCNT0.5mg/mlin vivo PF127-MWCNT 0.1M PBS4%FIB system1lPF127 0.1%MWCNT35g/mL

endpoint in vitro MWCNT

Nanothinx10-30 nm2m97.06%metal particles2.94%amorphous carbon and other carbon impurities

- 77 -

No. 5 L. A. Mitchell et al., Nature Nanotech., 4, 451, 2009.

16hrs14MWCNT 00.31 mg/m317318hrsBALF ELISAEIAreal-time RT-PCRJerne-Nordin plaque assay

endpoint MWCNT

Shenzhen Nanotech Port 10-20 nm5-15m97%100 m2/g0.5% iron0.5% nickel

BET analysisTEMSEMLAL assay

In vitro

(C57Bl/68) (wild-type B6;129P2 (COX-2+/+)9)

(B6;129P2-PTGS2tm1Unc (referred to as COX-2 knockout or COX-2-/- mice)9)

In vivo

BALFMWCNT 1 mg/m330TB COX-2 PTGES2 COX-2TMWCNT

- 78 -

No. 9 G. Qu et al., Carbon, 47, 2060, 2009.

130 (15)5287142128 28 (ALTASTCRBUN)1728MWCNTCOOH 11 mg/mL in 100lMWCNTCOOH 21 mg/mL in 100lPBS100l ()PBS with 1% Tween 80100l ()

endpoint MWCNT

Chengdu Organic Chemicals chemical vaporization deposition (CVD) pristine MWCNT20-40 nm0.3-10m>95%

- 79 -

No. 12 J. G. Li et al., J. Nanosci. Nanotech, 9, 1384-, 2009.

2 32.61 mg/m36hrs19 30 15 60 30 3BALF

endpoint MWCNT Shenzhen Nanotech Port 50 nm10m>95% MWCNT SEM

In vitro

(Kunming30 g)

In vivo inhalation

30 15 60 30 BALFALPACPLDH MWCNT

- 80 -

No. 13 X. Deng et al., Carbon, 47, 1421, 2009.

RES16S-MWCNT60 mg/kg b.w.100 mg/kg b.w. 2 17153060 oxidative stress assay (GSHSODMDA)1715 carbon clearance

endpoint S-MWCNT

Shenzhen Nanoharbor chemical vaporization deposition (CVD) methodpristine MWCNTTEMTGAICP-MSDeng (2007) S-MWCNT12.63.2 nm269160 nm>95%

1.

TEMTGAICP-MS

In vitro

(Kunming522-25 g)

In vivo intravenous injection

RESoxidative stress assayS-MWCNTS-MWCNT

- 81 -

No. 17 A. Erdely et al., Nano Lett., 9(1), 36, 2009.




- 82 -

No. 19 Y. Sakamoto et al., J. Toxicol. Sci., 34(1), 65, 2009.

MWCNT (CMC) 52 MWCNT1 mg/kg b.w.72 mg/kg b.w.10 ()CMC2 ml/kg b.w.5 ()

endpoint 1. MWCNT 2. () 3. CMC () 1. MITSUI MWCNT-7 lot number060125-01k 2. UICC-grade, stocked at the Tokyo Metropolitan Institute of Public Health

3. Kanto Chemical 2% CMC

Takagi (2008a) MWCNT 5% Triton X-100 SEM ICP-MS 2% CMC

SEMTEMICP-MS

In vitro

(Fisher 344 DuCrlCrlj12235 g)

In vivo a single intrascrotal injection

MWCNT6/7 37-40 CMC

- 83 -

No. 26 A. Liu et al., J. Nanoparticle Res., 10, 1303, 2008.

Lam (2004) MWCNT 01357 mg/kg 173090 TEMin vivo time-effects nanotoxicitydose-effects nanotoxicity

endpoint MWCNT

Shenzhen Nanotech Port 40-60 nm0.5-500m95%agraphitic carbon

- 84 -

No. 76 D. Elgrabli et al., Toxicology, 253, 131, 2008.

Elgrabli(2007) 6h/daysMWCNTBSA 0110100g/rat in 150l16173090180whole-body plethysmographyBradford RT-qPCR luminex

endpoint

MWCNT Sigma-Aldrichproduct number63664920-50 nm0.5-2m

Elgrabli (2007) BSA MWCNTBSA 80%

- 85 -

2.2.4 No. 30 X. Hu et al., Sci. Total Environ.,40(7), 3070, 2009

(mg/L)CuO(25-200)ZnO(50-150)Al2O3 (600-1200)La2O3 (200-600)Fe2O3 ,SnO2 ,TiO2 (600-1200)2LD50La2O3(14C-)

endpoint LD50 (fatal to 50% of the bacterium E. coli) 1. ZnO 2. CuO 3. Al2O3 4. La2O3 5. Fe2O3 6. SnO2

7. TiO2 17. Sigma-Aldrich30-40 nm MilliQ20

E. coli(Migula) In vitro

In vivo

LD50(mg/L)CuO(64.5)ZnO(21.1)Al2O3 (326.1)La2O3 (456.9)Fe2O3 (638.3)SnO2(1045.6)TiO2 (1104.8)ZnOE. coliCuOE. coliSnO2Fe2O3 La2O3 Al2O3La2O314C-LD50

- 86 -

No. 32 B. C. Schanen et al., Am. Chem. Soc., 3(9), 2523, 2009

0-100M48ROSCD4+ TT

endpoint 1. (TiO2) 2. (TiO2) 3. (TiO2) 1. in-house product 7-10 nm 2. in-house product(8002X) 15-20 nm

3. in-house product(120-1502024) 10-15 nm70-150 nm

DPBS

XRDHRTEM

(HUVEC)(PBMC) In vitro

In vivo

HUVECPBMCTiO2

TiO2(>1m)TiO2 ROS TiO2 TiO2 15%CD4T

- 87 -

No. 44 Z. Pan et al., small, 5(4), 511, 2009

0-0.8 mg/mL0-0.5 mg/mL()TEMROS

endpoint 1. TiO2- 2. TiO2- 3. TiO2- 1. US Cosmetics15.03.5 nm3.92 2. US Cosmetics20013 nm

3. TiO2/

full-Dulbeccos Modified Eagle Medium(DMEM)

SEMTEMXRD

In vitro

()

In vivo

TiO2()(mobility)

ROS

- 88 -

No. 62 L. Bregoli et al., Toxicology, 262, 121 (2009)

7CFU()525100 ppm14 (CFU-G/CFU-M/CFU-GM/CFU-Eo)(BFU-E))Sb2O3 (K562, HL-60, CEM, CEM-R, Thp-1, Jurkat, and Molt-4)5 ppmPCRSTEM

endpoint 1. (Fe3O4) 2. (Fe2O3) 3. (Ag) 4. (Au) 5. (Sb2O3) 6. (Co)

7. (TiO2) 1. Nanoamor20-30 nm 2. Nanoamor55-65 nm 3. Nanoamor90-210 nm 4. Nanoamor50-100 nm 5. Nanoamor41-91 nm 6. Fluka Chemical50-200 nm

7. TAL Materials20-160 nm (18990)15

DLS

9CD34

(K562HL-60CEMCEM-RThp-1JurkatMolt-4)In vitro

In vivo

CFU Co Sb2O3 5ppm 5100ppm STEMSb2O3

5ppm Sb2O3

CFU7Sb2O3Thp-1 PMA

- 89 -

No. 64 H. L. Karlsson et al., Toxicol. Lett., 188 (2009) 112 DNA

4080g/mL1880g/mL(CuO10, 20, 30, 40g/mL)16(FPG)4080g/mL4

endpoint In vitro 1. () (Fe2O3 nano) 2. () (Fe2O3 micro)

- 90 -

CuO DNA Fe2O3 TiO2CuO DNA CuO Fe3O4

- 91 -

No. 75 T. Xia et al., ACS Nano, 2008, 2 (10), 2121

( 25gmL 116 6100g/mL16ZnO12.550g/mL ZnSO4(150600M) 6 ) H2O2(10g/mL)25gmL116ROS(H2O2O2-)1-3 Tiers(Tier 1HO-1Tier 2JNKTNF- IL-8Tier 3[Ca2+])CeO(CeO25gmL2425g/mL DEP 16 )()

endpoint 1. (TiO2) 2. (ZnO) 3. (CeO2) 1.()(97%)m- FSP 11 nm/=8020(nm)612()284(DMEM)493(BEGM)(mV)-8 ()-10 (DMEM)-9 (BEGM) 2.(Zn

- 92 -

BEAS-2B RAW 264.7 Zn2+ CeO2 BEAS-2B -1RAW 264.7(LAMP-1)ROS TiO2 CeO2 ZnO Zn2+ Zn2+

- 93 -

No. 21 H. W. Kim et al., J. Nanoparti. Res., 11,(1) , 55 (2009)

in vitro0520g/cm224MTS LDH DNA (252g/ cm2 24 )(200g/mL6)in vivo05 mg/kg/day52BAL

endpoint in vitro in vivo BAL 1. Micro-SiO2 (mSiO2) 2. Nano-SiO2 (nSiO2) 3. Micro-TiO2 (mTiO2)

4. Nano-TiO2 (nTiO2) 1. Sigma-Aldrich 15m5.1 m2/kg(BET)(q-quartz) 2. Sigma-Aldrich14 nm77.7 m2/kg(BET) 3. Sigma-Aldrich1m5.8 m2/kg(BET)

4. 30 nm35.7 m2/kg(BET)

in vitroDPBS2SFMin vivoDPBS

(RAW264.7) In vitro

(Balb/C619-24 g)

In vivo

in vitroLDHNano-SiO2Micro-SiO2Nano-SiO2LDHin vivoBALSiO2Nano-SiO2TiO2SiO2Micro-TiO2SiO2

- 94 -

No. 1 M. Yokohira et al., J. Toxicol. Pathol., 22, 71-, 2009

1-60.1% DHPN 2 4 0.5mg/0.2 mL1,72,8CuO micro3,9CuO nano4,10TiO2 micro5,11TiO2 nano(6DHPN12)30()

endpoint 1. (TiO2 micro) 2. (TiO2 nano) 3. (CuO micro) 4. (CuO nano)

5. (Quartz dustDQ-12) 1. ()< 5m(Lot. TCG4139) 2. ()80 nm(Lot. DPN0960) 3. Sigma-Aldrich< 5m 4. Sigma-Aldrich33 nm

5. Deutsche Montan Technologies< 7m

In vitro

(F344/DuCrlCrj4)

In vivo

DHPNCuOTiO2DHPNCuO TiO2DHPNCuOTiO2

- 95 -

No. 2 M. Shimizu et al., Particle and Fibre Toxicol., 6(20), 1, 2009,

1g/L TiO2100L616(ED 16)(GO)Medical Subject Headings (MeSH) DNA

endpoint (TiO2) Sigma-Aldrich25-70 nm, 20-25 m2/g,

0.05 %(v/v)Tween 801g/LTiO2

In vitro

(Pregnant ICR mice)

In vivo

GO terms

23 MeSH terms

- 96 -

No. 20 K. Takeda et al., J. Health Sci., 55(1), 95 (2009)

1mg/mL TiO2100L37101446TEMFE-SEM FE-SEM/EDS()

endpoint (TiO2)

Sigma-Aldrich25-70 nm20-25 m2/g

99.9% 0.05 % Tween 801mg/mLTiO2

FE-SEM

In vitro

(Pregnant ICR mice)

In vivo

TiO2

- 97 -

No. 35 D. Drobne et al., Environ. Pollut., 157, 1157, 2009

0-1000 ug TiO2/g dry food314()S-(microtiter plates)

endpoint S- 1. (TiO2)

2. (TiO2) 1. Sigma-Aldrich25 nm200-220 m2/g()BET10 nm145 m2/gTEM()10-20 nm(N)(S) DLS()750-950 nm400-460 nm

2. Sigma-Aldrich(5 wt%)50 nm(XRD), 75 nm(BET)()BET40 nm40 m2/gTEM()10-120 nm(N) DLS()100-200 nm

(pH 5.7)

BETTEMDLS

In vitro

P. scaber Latreille

In vivo

2314S- ()TiO2(

- 98 -

No. 39 G. Liang et al., J. Toxicol. Environ. Health, Part:A, 72, 740, (2009)

0-50 mg/kg1TP, ALB, ALT, AST, BUN, CR(SODGSH-PXMDA)

endpoint 1. (TiO2-S50)

2. (TiO2-S210) 1. Degussa Corporation21 nm(TEM)50 m2/g(BET)

2. Hongsheng Materials Technology Company Lid.5 nm(TEM)210 m2/g(BET)

0.15%(w/w)15-202-3

In vitro

(Sprague-Dawley180200 g)

In vivo

TiO2-S210TiO2-S50(AST, ALT)(BUN, CR)

TiO2-S210 SOD GSH-PX TiO2-S50MDA MDATiO2-S210

- 99 -

No. 51 J. Chen et al., J. Appl. Toxicol., 29: 330, 2009

0-2592 mg/kg714(ICP-MS)2448

endpoint

(TiO2)3.6 nm80-110 nm(100 nm)

-TiO2 -Ti(OC4H9)4

TEMXRD

In vitro

(ICR 4202 g)

In vivo

BUN ALTASTTiO2

TiO2 TiO2

- 100 -

No. 58 J. Valant et al., J. Hazardous Mater., 171, 160, 2009.

AO/EB assay in vivoAO/EB assay16AO/EB 1/10 ( 3l)3 1000g/mL 10min





bulk ZnO

C60

- 101 -

No. 65 N. Kobayashi et al., Toxicol., 264, 110 (2009)

35 mg/kg241 2 35 mg/kg2491 12 BAL ()

endpoint 1. (TiO2)(ST-01, ultrafine(UF)) 2. (TiO2)(ST-21, superfine(SF)) 3. (TiO2)(ST-41, fine(F)) 1. ST-01(1)UF4.9 nm316 m2/g19 nm(13.5-31.3) (2) 3UF1UF2UF3ST-01() 4.9 nm316 m2/g( ) UF1 18.0 nm(14.8-23.9) UF2 64.5nm(35.8-113.8)UF3299.2 nm(216.4-422.0) 2. ST-21 (1) SF23.4 nm66.0 m2/g28.4 nm(19.2-43.9)

3. ST-41 (1) F154.2 nm10.0 m2/g10.0 m2/g176.3 nm(109.9-311.9)

(DSP) (1)UFDSP(8000g, 1h)DSP 2 mg/mLSFDSP1mDSP 2 mg/mLFDSP1mDSP 1 mg/mL (2)UF1ST-01(16000g, 1h)DSP 2 mg/mLUF2ST-010.1-1mDSP 3.4 mg/mLUF3ST-011m(1000g, 1h)DSP 13 mg/mL

DSLTEMXRFpH

In vitro

(Crl: CD (SD)8279335 g)

In vivo

1UF>SF>F() 1TiO2 2

- 102 -

24 1TiO2

- 103 -

No. 77 J. Wang et al., Toxicology, 254, 82 (2008)

30 1 500g/(sub-brain)TiO2 ()(GSH-PxGSTSODGSHMDA)()TEM()()

endpoint 1. TiO280 nm

2. TiO2commercial fine)155 nm 1. Hangzhou Dayang Nanotechnology 80 nm(71.423.5 nm16.6 nm99%)

2. Zhonglian Chemical Medicine155 nm(155.033.0 nm16.7 nm

2 Milli-Q

ICP-MSX

In vitro

(CD-1)

In vivo

TiO230 TiO2 MDA 155 nm80 nm

155 nm TiO2TNF-IL-1

- 104 -

2.2.5 No. 23 W. Lin et al., J. Nanoparticle Res., 11, 25 (2009) DNA

025g/mL048101214g/mL24(ROSGSH)LDH014g/mLDNA()NAC(00.5 mM)Zn2+(ZnSO4)016g/mL

endpoint DNA 1. (ZnO)70 nm

2. (ZnO)420 nm 1. Sigma-Aldrich>99.98%701312.16 m2/g169.5 ppm

2. Sigma-Aldrich>99.98%4202698.61 m2/g56.6 ppm

5

TEMBETXRDICP-MSDLS

(A549) In vitro

In vivo

ZnO8-18g/mL70 nm420 nm ZnO ROS GSHLDHDNAZnONAC Zn2+ ZnOROS

- 105 -

No. 30 X. Hu et al., Sci. Total Environ., 407, 3070 (2009)





In vivo


- 106 -

No. 55 V. Sharma et al., Toxicol. Lett., 185, 211 (2009)

0.00820g/mL 362448 MTT NRU LDH 8g/mL624485g/mL2448A4310.0010.0080.080.85g/mL60.0010.0080.080.8g/mL24GSHSOD

endpoint DNA (ZnO)5070 nm(BET)

SigmaAldrich>99%165 nm30 nm(TEM)26 mV

Milli-Q 10 DMEM

DLS(PALS)TEM

(A431) In vitro

In vivo

MTTLDHMRUZnOZnO68g/mL

GSHSOD 24 0.008g/mLZnODNA

- 107 -



endpoint in vitro 1. CB 2. CNTs 3. SiO2




TEM


In vivo


- 108 -

No. 75 T. Xia et al., ACS Nano, 2 (10), 2121, 2008



- 109 -


- 110 -

No. 58 J. Valant et al., J. Hazardous Mater., 171, 160, 2009.

AO/EB assay in vivoAO/EB assay16AO/EB 1/10 ( 3l)3 1000g/mL 10min





bulk ZnO

C60

- 111 -

2.2.6 No. 24 K. O. Yu et al., J. Nanoparticle Res., 11, 15 (2009)

0200g/mL24TEMLDHMTTROS

endpoint 1. (SiO2 A) 2. (SiO2 B) 3. (SiO2 C)

4. (SiO2 D) 1. in-house product()30 nm(DLS) 2. in-house product()48 nm(DLS) 3. in-house product()118 nm(DLS )

4. in-house product()535 nm(DLS)

5

DLSTEM

(HEL-30) In vitro

In vivo

TEMDLS

LDH30 nm48 nm118 nm535 nmLDHMTT30 nm48 nm118 nm535 nmMTTGSH30 nm50g/mLGSHROS

- 112 -

No. 27 D.M. Souza et al., J. Non-Cryst. Sol., 354, 4894 (2008)

2.710-3g/mL2.110-4g/mL 2 MTT

SIRCOL endpoint

1. (MtSi)

2. 1. (FeCl3)(Mt)- Mt (TEOS)(MtSi)10 nm

2. TEOS

FTIRXRDpH

((Wistar1-5)) In vitro

In vivo

MtSi20%

- 113 -

No. 33 I. Stayton et al., Anal. Bioanaly. Chem., 394, 95 (2009)

5.0108/mL A549 032 210()(PI=10.7BSAPI=4.8PI=7.1)FBSLi

endpoint

1. (CdS-CdSe ) 2. (Plain amorphous silica) 1. in-house product(Wang)133.3 nm, 3 nm 2. Degussa15 nm

(FBS)15

TEMUV-vis

(A549) In vitro

In vivo

2153 28.56FBS3 24

- 114 -

No. 37 D. Napierska et al., , small, 5(7), 846, 2009

()( 12000g/mL 24 MTT LDH )( TC25224 LDH)(TC5024 )

endpoint 13. (ultrafine silica)(S-16S-19S-60) 45. (fine silica)(S-104S-335) 67. (silica nanoparticles)(L-14L-15) 13. Stber16.419.460.4 nm( )18314533 m2/g 45. Stber104.4335 nm( )287.7 m2/g

67. Sigma-AldrichLudox13.814.7 nm( )196179 m2/g

X-RaySEMTEMDLS

EAHY926 In vitro

In vivo

Stber Ludox

Stober Ludox LDH TC50

- 115 -

No. 38 F. Wang et al., Toxicol. in Vitro, 23, 808 (2009)

01000g/mL 24 0200g/mL1248MTTROSGSH(TBARS) 0100g/mL 24

endpoint 1. SiO2

2. SiO2 1. 20 nm

2. 30 nm

(HEK293) In vitro

In vivo

24LD5080.26.4g/mL(20nm)140.38.6g/mL(50 nm)

ROSGSHTBARS

G2/M sub-G1 population

- 116 -

No. 40 M. Fisichella et al., Toxicol. in Vitro, 23, 697 (2009) MTT

050g/mL 4 24 MTT WST-1LDH050g/mL 4MTT TEM

endpoint

MSN(MSN- NH2MSN-AMF)

(MSN)(MCM-41)(MSN-NH2)(MSN-AMF) MSN; 5 nm(TEM) 350cm2/g(NMR)

1. (HeLa cells)

In vitro

2.

In vivo

HeLa MSN-AMF MTT HeLa LDH WST-1 MTT MSN-AMF

MSN- NH2MSN-AMF

- 117 -







TEM

primary mouse embryo fibroblast cells In vitro BALB/3T3

In vivo


- 118 -

No. 21 H. W. Kim et al., J. Nanoparticle Res., 11,(1) , 55 (2009)

in vitro0520g/cm224MTS LDH DNA (252g/ cm2 24 )(200g/mL6)in vivo05 mg/kg/day52BAL

endpoint in vitro in vivo BAL 1. Micro-SiO2 (mSiO2) 2. Nano-SiO2 (nSiO2) 3. Micro-TiO2 (mTiO2)

4. Nano-TiO2 (nTiO2) 1. Sigma-Aldrich 15m5.1 m2/kg(BET)(q-quartz) 2. Sigma-Aldrich14 nm77.7 m2/kg(BET) 3. Sigma-Aldrich1m5.8 m2/kg(BET)

4. Degussa30 nm35.7 m2/kg(BET)

in vitroDPBS2SFMin vivoDPBS

In vitro (RAW264.7) (Balb/C619-24 g)

In vivo

in vitroLDHNano-SiO2Micro-SiO2Nano-SiO2LDHin vivoBALSiO2Nano-SiO2TiO2SiO2Micro-TiO2SiO2

- 119 -

No. 42 H. Nishimori et al., Eur. J. Pharmac. Biopharmac., 72, 626 (2009)

1030 mg/kg24(ALTBUN)(HYP)

endpoint (SP70)(70 nm) Micromod Partikeltechnologie55.7nm

In vitro

(BLAB/c8)

In vivo

SP70

1030 mg/kg ALT BUN

- 120 -

No. 46 H. Nishimori et al., Eur. J. Pharmac. Biopharmac., 72, 496 (2009)

10100 mg/kg(ALTBUN)ELISA (IL-6TNF-)CPA01030 mg/kg24(ALTBUN)(HYP) 1030 mg/kg24(ALT)

endpoint 1. (SP70)(70 nm) 2. (SP300)(300 nm) 3. (SP1000)(1000 nm) 1. Micromod Partikeltechnologie75.7 nm 2. Micromod Partikeltechnologie311 nm

3. Micromod Partikeltechnologie830 nm

5

In vitro

(BLAB/c8)

In vivo

SP70 IL-6TNF-ALT CPA SP70 ALT ALT BUN SP70ALT

- 121 -

No. 74 S. J. So et al., J. Nanosci. Nanotech.,8, 5367, 2008 ()

(1%)10(140 g/kg)H&E(Si)()( Balb/c)

endpoint 1.

2. 1. 0.530m>99.8%

2. 1.3090 nm

1%

In vitro

(Adult Balb/c2030g)(C57BL/6J8)

In vivo /

Balb/c C57BL/6J AST ALT Balb/cSiALTAST

- 122 -

2.2.7 a) No. 52 S. Arora et al., Toxicol. Appl. Pharmac., 236(3), 310, 2009

0500g/mL24hrs IC50 (XTT assay)1/2 IC502 1) TEM2) Bradford3) oxidative stress assay (GSHSOD)4) Caspase-3 colorimetric assayAO/EB assay

endpoint in vitro

World Patent application under PCT No. WO/2006/ 0010337-20 nm ( >90% particles in the size range)16.6 nm

TEM

1. primary dermal fibroblasts (Swiss albino mice1 day old)

2. primary liver cells (Swiss albino mice1 day old) 1. In vitro

2.

In vivo

IC5061g/mLIC50449g/mLTEM

GSHSOD GSH

1/321/40

- 123 -

No. 53 P. V. AshaRani et al., ACS Nano, 3(2), 279, 2009.

100g/mL48hrs TEM STEM25400g/mL5 244872hrsATP 25400g/mL 5 244872hrs 25400g/mL548hrsV/PIROS 25200g/mL 425hrsROS CBMN assay100200g/mL48hrsPoonepalli (2005) comet assay25400g/mL5DNAin vitro

endpoint in vitro

Sigma-Aldrich Raveendran (2003) 6-20 nm

TEMUV

(IMR-90)

In vitro

(U251))

In vivo

ATP G2/M CBMN assaycomet assayDNAU251 V/PI TEM

- 124 -

No. 62 L. Bregoli et al., Toxicology 262 (2009) 121





DLS

9CD34


In vivo


5ppm Sb2O3

CFU7Sb2O3Thp-1 PMA

- 125 -

No. 71 F. F. Larese et al., Toxicology, 255, 33, 2009. in vitro

Franz diffusion cell method41) 870g/cm21/1024hrs GFAAS receiving chamberTEM 2) Bronough (1985) 1) 3) 570g/cm21/10482024hrs ETAAS receiving chamber TEM 4) Bronough (1985) 3) 482024hrsETAAS receiving chamberTEM

endpoint in vitro

25 7.1 nm (25-75th percentiles 19.5-29.3min. 9.8 nmmax. 48.8 nm with 5% larger than 36.6 nm)

Graf (2003) PVP99%TEM

TEM

In vitro

In vivo

1) 2) 24hrs receiving chamber 0.46 ng/cm2 24hrs receiving chamber 2.32 ng/cm2 0.43 ng/cm211.6 ng/cm23) 4) receiving chamber receiving chamber

- 126 -

No. 49 J. H. Sung et al., J. Soc.Toxicol., 108(2), 452, 2009.

OECD TG 413 6hrs/day5days/week 13 (90 ) fresh-air 0.6106particle/cm349g/m31.4106particle/cm3133g/m33.0106particle/cm3515g/m31 10

90 21

Sung (2008) ()

endpoint

18-19 nm Ji(2007)Jung(2006) TEM

In vitro

(Slc:SD8253.2g ()162.6g ())

In vivo inhalation

- 127 -

b) No. 4 C. R. Keena et al., Environ. Sci. Technol., 43(12), 4555 (2009)

50250M(Fe)1LDHROS

endpoint 1. (nZVI; Fe0(s)) 2. (Fe[]) 3. weathered nZVI 1. 10100 nm33.5 m2/g 2. ()

3. nZVI 4 PBS

PBS

(Fe)UV-vis()DPD()HPLC

(16HBE14o) In vitro

In vivo

nZVI Fe[]weathered nZVIROS

- 128 -

No. 11 J. K. Hsiao et al., J. Nanosci.Nanotechnol., 9, 1388, 2009

0100g Fe/mL244872MRIELISA (IL-1TNF-)(NO)

endpoint (NMPs) (SPIOs)

In vitro (RAW264.7)

In vivo

NMPs100gFe/mL TNF- IL-1NO

No. 27 D.M. Souza et al., J. Non-Cryst. Sol., 354 (2008) 4894

2.710-3g/mL2.110-4g/mL 2 MTT

SIRCOL endpoint

1. (MtSi)

2. 1. (FeCl3)(Mt)- Mt (TEOS)(MtSi)10 nm

2. TEOS

FTIRXRDpH

In vitro ((Wistar1-5))

In vivo

MtSi20%

- 129 -

No. 30 X. Hu et al., Sci. Total Environ., 407, 3070 (2009)





In vivo


- 130 -

No. 45 M. Mahmoudi et al., J. Colloid and Interface Sci, 336 (2009) 510

MTT(2880 rpmPVASPION020 mM32448)(30800 mM)

endpoint

PVA(r=05)(SPION)12

PVAMw=30,000-40,000(Fe2+Fe3+=12)10,000gPVA/ r=05720-4320 rpm12

TEMSEMHRSEMXRDTGAVSM

(L929 ) In vitro

In vivo

PVA SPION r (PVA/)

SPION

- 131 -






DLS

9CD34


In vivo


5ppm Sb2O3

CFU7Sb2O3Thp-1 PMA

- 132 -

No. 64 H. L. Karlsson et al., Toxicol. Lett. 188 (2009) 112 DNA



- 133 -


- 134 -

No. 50 M.-T. Zhu et al., Toxicol. Sci., 107(2), 342 (2009)

in vitroRAW264.710g/mL142448U9370.2220g/mL624(ICP-MS) in vivo59Fe2O3 40L172150TEM(Fe2O3 40L)

endpoint Fe2O3

Nanjing Haitai Nanoaterial14436 nm(DLS)- Fe2O353.27 m2/g99.46%(Cu 4.98Cr 0.10Zn 0.20Mn 0.07)

Fe2O3 2 59Fe2O3100mg/mL()105in vitroFe2O3

TEMICP-AESXRDDLS

(RAW264.7)(U937) In vitro

(Sprague-Dawley25010 g)

In vivo

59Fe2O3

in vitro Fe2O3RAW264.7 U937 0.150.03%3.960.47%in vivo59Fe 10 22.8 3.06g/

59Fe2O3 59Fe 59Fe

- 135 -

No. 16 R. S. Slesinski and D. Turnbull, Intl J. Toxicol., 27, 427 (2008)

131525 mg/m36 / 5 /104 1416 mg/m36 /5 /

endpoint

5.1m45-50%(Fe3O4(CAS No. 1317-61-9))45-50%( 60)< 5%((CAS No.112945-52-5)(

- 136 -

No. 18 A. R. Jalilian et al., Radiochemica Acta, 97(1), 51 (2009) SPION

10Ci 67Ga-SPION0.1 mL124 Ga3(67Ga-GaCl3)

endpoint () 1. (SPION)

2. 67Ga(67Ga-SPION) 1. Fe3/Fe2=2 molar SPION 5 nm

2. 67Ga 96%(TLC)

SPION 67Ga

TEMHRSEMXRDFTIRTGADSCVSMTLC

In vitro

()(normal rat)

In vivo

SPION 67Ga-SPION96%(TLC)41Ga67Ga-SPION 2 67Ga-SPIONGa22-243524

- 137 -

No. 22 B. Wang et al., J. Nanoparticle Res., 11, 41 (2009)

2130g112721430GSH-PxTotal GSHGSSGGSH/GSSGCuZn-SODMn-SODTBARSTEM

endpoint 1. 21 nm -Fe2O3

2. 280 nm -Fe2O3 1. Nanjing Haitai Nanomaterial216 nm>99%()214 nm()

2. Chengdu Shi-Jia-Wei-Er28080 nm>99%() 44-102 nm(ca.10%)113-291 nm(ca. 90%)

0.1%SCMC5-7

TEMICP-AESXRD

In vitro

(CD-ICR420-22g)

In vivo

GSH-PxCu,Zn-SOD cNOSGSHGSH/GSSG

- 138 -

No. 61 J. Pauluhn, Toxicology, 259, 140 (2009)

0.496 mg/m3(0.4100 mg/m37) 6 /5 / 4 4 BAL6

endpoint 1. BoehmiteAlOOH-40(-AlO(OH))Pural 200 2. BoehmiteAlOOH-10 (-AlO(OH))Disperal 3. Magnetite (Fe3O4)FerroxideBlack 88P 1. Sasol43.9%105 m2/g(BET)2.9 g/cm30.51 g/cm340 nmMMAD(GSD) 0.6m(2.6) 2. Sasol39.4%182 m2/g(BET)2.9 g/cm30.46 g/cm310 nmMMAD(GSD) 1.7m(2.7)

3. Rockwood 69.5%10.5 m2/g(BET)4.6-4.8 g/cm30.6-0.8 g/cm3300-600 nmMMAD(GSD) 1.5m(2.1)

AlOOH-10 nm

BET

In vitro

(Wistar Bor:WISW)2230g)

In vivo

AlOOH-10Fe3O4AlOOH-40Fe3O4100 mg/m315%AlOOH28 mg/m3BALLDH

/()

- 139 -

c) No. 30 X. Hu et al., Sci. Total Environ.,407, 3070 (2009)





In vivo


- 140 -

No. 7 A. Balasubramanyam et al., Muta. Res., 676, 41 (2009)

50010002000 mg/kg bw3048 OECD 474 1824 (MI) OECD475(Al)(14)

endpoint MN-PCE 1. -(Al2O3-B) 2. -30 nm(Al2O3-30) 3. -40 nm(Al2O3-40) 1. 50-200 nm>90% 2. NovaCentrix39.8531.33 nm(TEM) 3. NovaCentrix47.3336.13 nm(TEM)

1% Tween 8010

TEM

In vitro

(albino Wistar4590100 g)

In vivo

Al2O3-30Al2O3-40 MN-PCE Al2O3-B Al2O3-30Al2O3-40()Al2O3-B Al3Al2O3AlAl2O3-30Al2O3-40AlAl2O3-BAl

- 141 -

No. 59 J. Pauluhn, Toxicol. Sci., 109(1) 152 (2009)

00.4328 mg/m3 6 /5 /4 BAL Al

endpoint 1. BoehmiteAlOOH-40 nm(-AlO(OH))Pural 200

2. BoehmiteAlOOH-10 nm (-AlO(OH))Disperal 1. Sasol43.9%105 m2/g(BET)2.85 g/cm30.51 g/cm340 nmMMAD( /APS)0.6m(2.6)/0.9m(1.6-2.1)min. 0.7 mL/g

2. Sasol39.4%182 m2/g(BET)2.85 g/cm30.46 g/cm310 nmMMAD(GSD) ( /APS) 1.7m(2.7)/2.3m(1.8)0.5 mL/g

AlOOH-10 nm400/10

SEM

In vitro

(Wistar Bor:WISW)2)

In vivo

BALLDH-NAG-GT 28 mg/m3AlOOH 28 mg/m3

Al AlOOH-40 nmAlOOH-10 nm

- 142 -

No. 61 J. Pauluhn, Toxicology 259 (2009) 140

0.496 mg/m3(0.4100 mg/m37) 6 /5 / 4 4 BAL6

endpoint 1. BoehmiteAlOOH-40(-AlO(OH))Pural 200 2. BoehmiteAlOOH-10 (-AlO(OH))Disperal 3. Magnetite (Fe3O4)FerroxideBlack 88P 1. Sasol43.9%105 m2/g(BET)2.9 g/cm30.51 g/cm340 nmMMAD(GSD) 0.6m(2.6) 2. Sasol39.4%182 m2/g(BET)2.9 g/cm30.46 g/cm310 nmMMAD(GSD) 1.7m(2.7)

3. Rockwood 69.5%10.5 m2/g(BET)4.6-4.8 g/cm30.6-0.8 g/cm3300-600 nmMMAD(GSD) 1.5m(2.1)

AlOOH-10 nm

BET

In vitro

(Wistar Bor:WISW)2230g)

In vivo

AlOOH-10Fe3O4AlOOH-40Fe3O4100 mg/m315%AlOOH28 mg/m3BALLDH

/()

- 143 -

d) No. 8 B. Rothen-Rutishauser et al., Environ. Sci. Technol., 2009, 43(7), 2634

241020300.0120.0190.024 mg/cm2TEERLDH(TEM)(LSM)

endpoint TJDNA (CeO2)

(2-)()( 21)5-20 nm

- 144 -

No. 75 T. Xia et al., ACS Nano, 2008, 2(10), 2121



- 145 -


- 146 -

e) / No. 41 J. Pelka et al., Chem. Res. Toxicol., 22, 649 (2009)

0.00011000 ng/cm23ROSNrf-2 324 GSHDNADNAFPG

endpoint ROSNrf-2GSHDNA 1. (Pt

- 147 -

f) No. 30 X. Hu et al., Sci. Total Environ., 407, 3070- (2009)





In vivo


- 148 -






DLS

9CD34


In vivo


5ppm Sb2O3

CFU7Sb2O3Thp-1 PMA

- 149 -

No. 64 H. L. Karlsson et al., Toxicol. Lett., 188 (2009) 112 DNA



- 150 -


- 151 -

No. 72 S. Bastian et al., Environ. Health Perspec., 117(4), 530, 2009

(CoCl2)(VI)(Na2WO42H2O) 10%v/v WC 7.51530g/mLWC-Co8.2516.533 (Co51M) g/mL13

endpoint 1. (WC)

2. (WC-Co) 1. 6.9 m2/g(BET)1455 nmPDI0.2-35 mV

2. Co10wt%6.6 m2/g(BET)1455 nmPDI0.2-50 mV

WC-CoGrahams salt()

BETDLSPCSICP-OES

(CaCo-2)(HaCaT)(A549)(OLN-93)(18(Wistar) ) In vitro

In vivo

WC WC-CoCaCo-2>OLN-93>HaCaT>A549>Co CoCl2WCCoCl2 CoCl2 100M CaCo-2HaCaTA549 WC-Co 51M CoCl2(50M)CoCl2(50M)+WC(15g/,L)WC-Co

OLN-93 42M(28%)

- 152 -

No. 1 M. Yokohira et al., J. Toxicol. Pathol.,;22: 71 (2009)

1-60.1% DHPN240.5mg/0.2 mL1,72,8CuO micro3,9CuO nano4,10TiO2 micro5,11TiO2 nano(6DHPN12)30()

endpoint 1. (TiO2 micro) 2. (TiO2 nano) 3. (CuO microCAS 1317-38-0) 4. (CuO nanoCAS 1317-38-0)



In vitro

(F344/DuCrlCrj4)

In vivo


- 153 -

No. 29

G. Sonavane et al., Colloids and Surfaces B: Biointerfaces, 66 (2008) 274-280

1 g/kg24(ICP-MS)

endpoint (15 nm) (50 nm) (100 nm)

(200 nm) ()(HAuCl44H2O)(Turkevich)152.30 nm0.440.05 505.65 nm0.420.08 1005.56 nm0.360.07

2007.56 nm0.320.06

0.5%(w/v) 0.22m Millipore2

(Zetasizer 3000HSAMalvern Instruments, Ltd.)SEMICP-MS

In vitro

(ddY682530 g)

In vivo

15 nm

50100 nm(100 nm)50100 nm15 nm200 nm

- 154 -

2.2.8 a) CB No. 67 H. Yang et al., J. Appl. Toxicol., 29, 69, 2009.






TEM


In vivo


- 155 -

No. 69 L. Tabet et al., J. Toxicol. Environ. Health. Part A, 72, 60, 2009.







2. MeT5A 1.

In vitro

2. ()

In vivo

MWCNTA549MeT5APBSDPL100g/mL

CB

- 156 -

No. 17 A. Erdely et al., Nano Letters, 9(1), 36, 2009.




- 157 -

No. 54 H. Tong et al., Toxicol. Appl. Pharmacol., 239(3), 224, 2009

Gilmour (2004) 1040g/mouse in 50lLPS 2g/mouse in 50l24hrsBAL

endpoint

1. SWCNT 2. SWCNTAF-SWCNT 3. ultrafine carbon black (UFCB)

4. UFCBAF- UFCB 1. Sigmacatalogue number636797 2. 1. SWCNTSaxena (2007) 3. Dr. Vickie Stone

4. 3. UFCBSaxena (2007)

AF-SWCNTAF- UFCBSaxena (2007)

thermo-optical methodICP-OESUS EPA Method 3050B (measured gravimetrically)TEMBET analysesZetasizer Nano ZS

In vitro

(CD-112-1630.8 0.7 g)

In vivo Inhalation (pharyngeal aspiration route)

AF-SWCNTUFCBAF-UFCB40g

AF-SWCNT40g

- 158 -

b) PSt No. 3 E. Frhlich et al., J. Toxicol. Sci., 34(4), 363 (2009)

(010%FBS ) 31.25500g/mL424 (ATP sulfo-B)

endpoint 1. ( carboxyl PS) 2. (carboxyl modified PS) 3. (Amidine PS) 4. (505/515)

5. (580/605) 1. 20406080100200nm2634628293160 nm 2. 20 nm24 nm) 3. 200 nm220 nm)4. FluoSpheres2040200 nm

5. FluoSpheres2040200 nm FBS010%DMEM

DLS

(EAhy926) In vitro

In vivo

FBS20 nmPS40 nmPS20 nm200 nm

- 159 -

No. 63 K. Sarlo et al., Toxicology, 263 (2009) 117

20 nm11014100 nm1.110131000 nm1.2101090 20 nm11014100 nm510121000 nm71099020 nm41014100 nm2.210131000 nm2.210910120 BALF

endpoint (755/715) 20 nm100 nm1000 nm(3) 15 DLSCryo-TEM

In vitro

(F344120130 g)

In vivo () ()

31001000 nm20 nm320 nm1001000 nm20 nm3 1720 nm

3 1000 nm 20100 nm

- 160 -

No. 68 K. Inoue et al., Toxicol. Appl. Pharmacol., 234 (2009) 68 LPSOVA

LPSLPS(75g/body)(125250g/body)vehicleLPSLPS+OVAvehicleOVAOVA+ OVA(1g/body)(50100g/body)1/6BAL

endpoint (micromer-blue F plain) Micromod2550100 nm 0.05% Tween 80PBS(pH 7.4)3

In vitro

(ICR62933 g)

In vivo

LPS

50 nm+LPS

(vWF)LPS

IgG1 IgE 50 nm

- 161 -

c) No. 70 C. Li et al., J. Molecul. Cell Biol., 1, 37 (2009),

in vitro100g/mL24-3(G3G5.5100g/mLG33MA(3-)10mM3mM24)13(LC3)(G3G5.530g/mL G33MA 10mM 24 )LC3-(100g/mL 4 )G3 100g/mL 24 siRNA ATG6 siRNA G5.5(100g/mL) G4(100g/mL) G5(20g/mL) G6(20g/mL) G7(20g/mL)G8(20g/mL) 4 LC3- 24 (3MA(3mM 1mM))G3 100g/mL 24mTORS6LC3TSC2Akt in vivo50 mg/kgG5.5G34/

(endpoint /

PAMAM (Polyamidoamine dendrimer)18(G1G2G3G3.5G4G4.5G5G5.5G6G7G7.5G8) Sigma-AldrichPAMAM 24PBS

(A549) In vitro

(Balb/c610)

In vivo

PAMAMA549PAMAM (G3G4G5G6G7G8) PAMAM PAMAM G3ATG6(1) 3MA siRNA PAMAM G3PAMAM G3 Akt-TSC2-mTOR PAMAM G3

3MA

- 162 -

d) Quontum DotQD No. 36 B. A. Koeneman et al., Toxicol. in Vitro, 23, 955, 2009.

Caco-2QDsCa2+/Mg2+-free PBS0.011000 mg/L14Caco-2 24hrs 0.011000 mg/L) mass concentration analysisWater (1998) QDs ICP-AES Koeneman (2004) 41 HBSS41HBSSAlexa 488 cells grown on inserts for TEER measurementsCaco-2 14TEERCaco-2 Koeneman (2004)

endpoint in vitro (Water soluble quantum dots (QDs)) American Dye Source

QDsstock suspension0.25 wt%pH 1011Ca2+ Mg2+-Ca2+/Mg2+-free PBS

Caco-2 In vitro

In vivo

TEER QDs 1mg/LQDs0.1mg/L1mg/LQDs (10 mg/L1000 mg/L)

- 163 -

No. 73 C.-H. Lin et al., Nanotechnol., 20, 215101, 2009.

16QD705QD-ORG40 pmol (41g)100l/mouse 1day12416weeks

TaqMan array RT-PCRICP-MS Cd/Te MT-1/2 RAG in vitroMT-1 QD705 Cd/Te 69:1 QD705

1) 2) QD705

endpoint 1. Quantum Dot 705(QD705)

2. Quantum Dot 705-organic QD-ORG) 1. Invitrogen Cd/Se/Te ZnS shell methoxy-PEG-500020 nmCd/Se/Te 56.16 8.54 % Cd5.80 3.60 % Se0.92 0.20 % Te 2. InvitrogenCd/Se/Te methoxy-PEG-500020 nmCd/Se/Te 56.16 8.54 % Cd5.80 3.60 % Se0.92 0.20 % Te

In vitro (ICR8 )

In vivo single intravenous dose (injected via tail vein)

4 QD705 QD705 >>>>QD70516

42QD705Cd/Tein vivoMT-1MT-1 mRNA

- 164 -

No. 28 P. Lin et al., Environ. Sci. Technol., 42(16), 6264, 2008.

16QD70540 pmol100l/mouse 1hr4hrs24hrs371428days6

TEMMass balanceQD705 24hrs28days6 QD705QD705ICP-MS (Cd111)

endpoint

Quantum Dot 705QD705)

Quantum Dot CorporationCdSeTe core (with approximately 46% Cd10% Se1% Te) ZnS shellmethoxy-PEG-500018.5 nm1.5 106 g/mol

Giepmans (2005)

In vitro

(ICR832.9-38.7 g)

In vivo single intravenous dose (injected via tail vein)

QD705286QD705QD705 28

QD705QD705286

- 165 -

e) No. 6 J. Sun and, T. Ding, IEEE Trans. Nanobiosci., 8(1), 78, 2009 DNA

10200g/mL 4 24 RT-PCR P53P21Gadd45HSP70 endpoint P53P21Gadd45HSP70

1. (HAP)

2. (TCP) 1. 3080 nm

2. 3080 nm

1010%RPMI-1640

(SD 6%) In vitro

In vivo

P53HAPTCP10g/mL P53 P21100g/mL200g/mL Gadd45 HAP TCP 20g/mL Gadd45 HAP HSP70 P53 TCP 20g/mL

- 166 -

No. 10 X. Wang et al., J. Nanosci. Nanotechnol., 9(5), 3025, 2009.

MWCNT MWCNT 020g/mL 5 3hrs MTT assay6hrs TEM 12hrs 24hrs

endpoint in vitro 1. MWCNT

2. Quartz () Shenzhen Nanotech Port 10-20 nm1-5m>95%(MWNT10) Shenzhen Nanotech Port 40-60 nm1-5m>95%(MWNT40) Shenzhen Nanotech Port 60-100 nm1-5m>95%(MWNT60)

The National Institute for Occupational Health and Poison Control

- 167 -

No. 69 L. Tabet et al., J. Toxicol. Environ. Health. Part A, 72, 60, 2009.







2. MeT5A 1.

In vitro

2. ()

In vivo

MWCNTA549MeT5APBSDPL100g/mL

CB

- 168 -

No. 1 M. Yokohira et al., J. Toxicol. Pathol., 22: 71, 2009

1-60.1% DHPN240.5mg/0.2 mL1,72,8CuO micro3,9CuO nano4,10TiO2 micro5,11TiO2 nano(6DHPN12)30()

endpoint 1. (TiO2 micro) 2. (TiO2 nano) 3. (CuO microCAS 1317-38-0) 4. (CuO nanoCAS 1317-38-0)



In vitro

(F344/DuCrlCrj4)

In vivo


- 169 -

No. 19 Y. Sakamoto et al., J. Toxicol. Sci., 34(1), 65, 2009.

MWCNT (CMC) 52 MWCNT1 mg/kg b.w.72 mg/kg b.w.10 ()CMC2 ml/kg b.w.5 ()

endpoint 1. MWCNT 2. () 3. CMC () 1. MITSUI MWCNT-7 lot number060125-01k 2. UICC-grade, stocked at the Tokyo Metropolitan Institute of Public Health

3. Kanto Chemical 2% CMC

Takagi (2008a) MWCNT 5% Triton X-100 SEM ICP-MS 2% CMC

SEMTEMICP-MS

In vitro

(Fisher 344 DuCrlCrlj12235 g)

In vivo a single intrascrotal injection

MWCNT6/7 37-40 CMC

- 170 -

2.3 2 2.1 77 19 4 103 20 1 53 in vitro41 in vivo41 10

in vitro in vivo ADME 45 / 111 2.3

10 OECD-WPMN / in vitro in vivo 3 EHS

in vivo a) in vitro / b)

- 171 -

c)

d)

/

e)

/ in vitro DNA

f)

g)

in vitro DNA

- 172 -

h)

MWCNT

- 173 -

2.3.

No.in vitro in vivo

15 31 43 47 48

1

58 14 17 31 34 54 56

3

67 5 9 10 12 13 17 19 25 26 57 66 69

4

76 62 49 52 53

5

71 []in vitroin vivoADME

- 174 -

2.3.

No.in vitro in vivo

4 11 27 30 45 62 64 50 16 18 22

6

61 17 54 67

7

69 30 32 44 62 64 75 21 1 2 20 35 39 51 58 65

8

77 30 7 59

10

61 8 11 75

[]in vitroin vivoADME

- 175 -

2.3

No.in vitro in vivo

23 30 55 58 67

12

75 24 27 33 37 38 40 21 42 46 67

13

74 3 63 14 68

15 70 21 / 41

28 36 22 73

[]in vitroin vivoADME

- 176 -

2.3

No.in vitro in vivo

1 30 64

Quartz 10 69 19 30 30 62 62 62 72 72

29 6 6

24

1 []in vitroin vivoADME

177

2.4 No.2.2

No. 1. Masanao Yokohira, Nozomi Hashimoto, Keiko Yamakawa, Satoshi Suzuki, Kousuke Saoo, Toshiya Kuno,

and Katsumi Imaida, Lung Carcinogenic Bioassay of CuO and TiO2 Nanoparticles with Intratracheal Instillation Using F344 Male Rats, J Toxicol Pathol 2009; 22: 71-78

2. Midori Shimizu, Hitoshi Tainaka, Taro Oba, Keisuke Mizuo, Masakazu Umezawa and Ken Takeda, Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse, Particle and Fibre Toxicology 2009, 6:20, 1-8 (2009)

3. Eleonore Froehlich, Claudia Samberger, Tatjana Kueznik, Markus Absenger, Thomas R Pieber, Cytotoxicity of nanoparticles independent from oxidative stress, J Toxicol Sci., 34(4), 363-375 (2009)

4. Christina R. Keenan, Regine Goth-Goldstein, Donald Lucas, David L. Sedlak, Oxidative Stress Induced by Zero-Valent Iron Nanoparticles and Fe() in Human Bronchial Epithelial Cells, ENVIRONMENTAL SCIENCE & TECHNOLOGY, 43, (12), 45554560, (2009)

5. L. A. Mitchell, F. T. Lauer, S. W. Burchiel, J. D. McDonald, Mechanisms for how inhaled multiwalled carbon nanotubes suppress systemic immune function in mice., Nature Nanotechnology, 4, 451-456, 2009

6. Jiao Sun, Tingting Ding, Differences in DNA Damage Pathways Induced by Two Ceramic Nanoparticles, IEEE TRANSACTIONS ON NANOBIOSCIENCE, 8 (1), 78-82, 2009

7. A. Balasubramanyan, N. Sailaja, M. Mahboob, M.f. Rahman, S. Misra, Paramjit Grover, Saber M. Hussain, Evaluation of genotoxic effects of oral exposure to Aluminum oxide nanomaterials in rat bone marrow, Mutat Res/Genetic Toxicol. Environ. Mutagenesis, 676, 41-47 (2009)

8. B. Rothen-Rutishauser,.Blank, C. Mhlfeld, C. Brandenberger, D. O. Raemy, P. Gehr, R. N. Grass, L. K. Limbach, W. J. Stark, Direct Combination of Nanoparticle Fabrication and Exposure to Lung Cell Cultures in a Closed Setup as a Method To Simulate Accidental Nanoparticle Exposure of Humans, Environ Sci Technol, 43(7), 2634-2640 (2009)

9. Qu Guangbo, Bai Yuhong, Zhang Yi, Yan Bing , Jia Qing, Zhang Weidong, The effect of multiwalled carbon nanotube agglomeration on their accumulation in and damage to organs in mice., Carbon 47, 2060-2069, 2009

10. Wang X., Jia G., Wang H., Nie H., Yan L., Wang S. , Deng X. Y., Diameter Effects on Cytotoxicity of Multi-Walled Carbon Nanotubes., Journal of Nanoscience and Nanotechnology, 9, 3025-3033, 2009

11. J. K. Hsiao1, T. I. Weng, M. F. Tai, Y. F. Chen, Y. H. Wang, C. Y. Yang, J. L. Wang, H. M. Liu, Cellular Behavior Change of Macrophage After Exposure to Nanoparticles, Journal of Nanoscience and Nanotechnology, 9, 13881393, 2009

12. Li J.G., Li Q.N., Xu J.Y., Cai X.Q., Liu R.L., LiY.J., Ma J.F., Li W.X., The Pulmonary Toxicity of Multi-Wall Carbon Nanotubes in Mice 30 and 60 Days After Inhalation Exposure., Journal of Nanoscience and Nanotechnology, 9, 1384-1387, 2009

13. Deng Xiaoyong, Wu Fei, Liu Zhen, Luo Man, Li Ling, Ni Qingshun, Jiao Zheng, Wu Minghong, Liu Yuanfang, The splenic toxicity of water soluble multi-walled carbon nanotubes in mice., Carbon 47, 1421-1428, 2009

14. Barbara J. Panessa-Warren, Mathew M. Maye, John B. Warren, Kenya M. Crosson, Single walled carbon nanotube reactivity and cytotoxicity following extended aqueous exposure., Environmental Pollution, 157, 1140-1151, 2009.

178

15. P. Spohn, C. Hirsch, F. Hasler, A. Bruinink, H.F. Krug, P. Wick, C60 fullerene: A powerful antioxidant or a damaging agent? The importance of an in-depth material characterization prior to toxicity assays, Environmental Pollution, 157, 1134-1139, 2009.

16. Ronald S. Slesinski, Duncan Turnbull, Chronic Inhalation Exposure of Rats for up to 104 Weeks to a Non-Carbon-Based Magnetite Photocopying Toner, International Journal of Toxicology, 27, 427-439, (2008)

17. A. Erdely, T. Hulderman, R. Salmen, A. Liston, P. C. Zeidler-Erdely, D. Schwegler-Berry, V. Castranova, S. Koyama, Y.-A. Kim, M. Endo, P. P. Simeonova, Cross-Talk between Lung and Systemic Circulation during Carbon Nanotube Respiratory Exposure. Potential Biomarkers., Nano Letters, 9(1), 36-43, 2009

18. A. R. Jalilian, A. Panahifar, M. Mahmoudi, M. Akhlaghi, A. Simchi, Preparation and biological evaluation of [67Ga]-labeled-superparamagnetic nanoparticles in normal rats, Radiochemica Acta, 97,(1), 51-56 (2009)

19. Yoshimitsu Sakamoto, Dai Nakae, Nobutaka Fukumori, Kuniaki Tayama, Norio Ohashi, Akio Ogata, Akihiko Maekawa , Induction of mesothelioma by a single intrascrotal administration of multi-wall carbon nanotube in intact male Fischer 344 rats., The Journal of Toxicological Sciences, 34,(1), 65-76, 2009

20. K. Takeda, K. Suzuki, A. Ishihara, M. Kubo-Irie, R. Fujimoto, M. Tabata, S. Oshio, Y. Nihei, T. Ihara, and M. Sugamata, Nanoparticles Transferred from Pregnant Mice to Their Offspring Can Damage the Genital and Cranial Nerve Systems, Journal of Health Science, 55 (1), 95-102 (2009)

21. Hye Won Kim, Eun-Kyung Ahn, Bo Keun Jee, Hyoung-Kyu Yoon, Kweon Haeng Lee, Young Lim, Nanoparticulate-induced toxicity and related mechanism in vitro and in vivo, Journal of Nanoparticle Research, 1,(1) , 55-65 (2009)

22. B. Wang, W. Feng, M. Zhu, Y. Wang, M. Wang, Y. Gu, H. Ouyang, H. Wang, M. Li, Y. Zhao, Z. Chai, H. Wang, Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice, Journal of Nanoparticle Research, 11, 41-53, (2009)

23. Weisheng Lin, Yi Xu, Chuan-Chin Huang, Yinfa Ma, Katie B. Shannon, Da-Ren Chen, Yue-Wern Huang, Toxicity of nano- and micro-sized ZnO particles in human lung epithelial cells, Journal of Nanoparticle Research, 11, 2539, (2009)

24. Kyung O. Yu, Christin M. Grabinski, Amanda M. Schrand, Richard C. Murdock, Wei Wang, Baohua Gu, John J. Schlager, Saber M. Hussain, Toxicity of amorphous silica nanoparticles in mouse keratinocytes, Journal of Nanoparticle Research, 11, 1524 (2009)

25. M. Chiaretti, G. Mazzanti, S. Bosco, S. Bellucci, A. Cucina, F. Le Foche, G. A. Carru, S. Mastrangelo, A. Di Sotto, R. Masciangelo, A. M. Chiaretti, C. Balasubramanian, G. De. Bellis, F. Micciulla, N. Porta, G. Deriu, A. Tiberia, Carbon nanotubes toxicology and effects on metabolism and immunological modification in vitro and in vivo., J. Phys.: Condens. Matter, 20, 474203, 1-10, 2008

26. Liu Aihong, Sun Kangning , Yang Jiafeng, Zhao Dongmei, Toxicological effects of multi-wall carbon nanotubes in rats., J. Nanoparticle Res., 10, 1303-1307, 2008

27. D. M. Souza, A. L. Andrade, J. D. Fabris, P. Valrio, A. M. Ges, M. F. Leite, R.Z . Domingues, Synthesis and in vitro evaluation of toxicity of silica-coated magnetite nanoparticles, Journal of Non-Crystalline Solids, 354 (2008) 4894-4897

28. P. Lin, J.-W. Chen, L. W. Chang, J.-P. Wu, L. Redding, H. Chang, T.-K. Yeh, C. S. Yang, M.-H. Tsai, H.-J. Wang, Y.-C. Kuo, R. S. H. Yang, Computational and Ultrastructural Toxicology of a Nanoparticle, Quantum Dot 705, in Mice., Environmental Science & Technology, 42(16), 6264-6270, 2008

29. Ganeshchandra Sonavane, Keishiro Tomoda, Kimiko Makino, Biodistribution of colloidal gold nanoparticles after intravenous administration: Effect of particle size, Colloids Surf B, 66(2), 274-280 (2008)

30. Xiaoke Hu, Sean Cook, Peng Wang, Huey-min Hwang, In vitro evaluation of cytotoxicity of engineered metal oxide nanoparticles, Science of the Total Environment 407 (2009) 3070-3072

179

31. Janne K. Folkmann, Lotte Risom, Nicklas R. Jacobsen, Hkan Wallin, Steffen Loft, Peter Mller, Oxidatively Damaged DNA in Rats Exposed by Oral Gavage to C60 Fullerenes and Single-Walled Carbon Nanotubes., Environmental Health Perspectives, 117(5), 2009.

32. Brian C. Schanen, Ajay S. Karakoti, Sudipta Seal, Donald R. Drake III, William L. Warren, and William T. Self, Exposure to Titanium Dioxide Nanomaterials Provokes Inflammation of an in Vitro Human Immune Construct, (Article) American Chemical Society, 3 (9), 2523-2532 (2009)

33. Isaac Stayton, Jeffrey Winiarz, Katie Shannon, Yinfa Ma, Study of uptake and loss of silica nanoparticles in living human lung epithelial cells at single cell level, Analytical and Bioanalytical Chemistry (2009) 394, 951608

34. Alexandra E. Porter, Mhairi Gass, James S. Bendall, Karin Muller, Angela Goode, Jeremy N. Skepper, Paul A. Midgley, Mark Welland, Uptake of Noncytotoxic Acid-Treated Single-Walled Carbon Nanotubes into the Cytoplasm of Human Macrophage Cells., ACS Nano, 3(6), 1485-1492, 2009

35. Damjana Drobne, Anita Jemec, Ziva Pipan Tkalec, In vivo screening to determine hazards of nanoparticles : Nanosized TiO2, environmental Pollution, 157, (2009) 1157-1164

36. Brian A. Koeneman, Yang Zhang, Kiril Hristovski, Paul Westerhoff, Yongsheng Chen,John C. Crittenden, David G. Capco, Experimental approach for an in vitro toxicity assay with non-aggregated quantum dots., Toxicology in Vitro, 23, 955962, 2009

37. Dorota Napierska, Leen C. J. Thomassen, Virginie Rabolli, Dominique Lison, Laetitia Gonzalez, Micheline Kirsch-Volders, Johan A. Martens, Peter H. Hoet, Size-Dependent Cytotoxicity of Monodisperse Silica Nanoparticles in Human Endothelial Cells, small 2009, 5, (7), 846853

38. Fen Wang, Feng Ga, Minbo Lan, Huihui Yuan, Yongping Huang, Jianwen Liu, Oxidative stress contributes to silica nanoparticle-induced cytotoxicity in human embryonic kidney cells, Toxicology in Vitro 23 (2009) 808815

39. Geyu Liang, Yuepu Pu, Lihong Yin, Ran Liu, Bing Ye, Yaoyao Su, and Yanfen Li, Influence of Different Sizes of Titanium Dioxide Nanoparticles on Hepatic and Renal Functions in Rats with Correlation to Oxidative Stress, Journal of Toxicology and Environmental Health, Part A, 72, 740-745, (2009)

40. Matthieu Fisichella, Hinda Dabboue, Sanjib Bhattacharyya, Marie-Louise Saboungi, Jean-Paul Salvetat, Tobias Hevor, Martine Guerin, Mesoporous silica nanoparticles enhance MTT formazan exocytosis in HeLa cells and astrocytes, Toxicology in Vitro 23 (2009) 697703

41. P. Joanna, G. Helge, E. Melanie, T. Michael, C. Marlene, B. Stefan, M. Thierry, B. Holger, S. Winfried, Z. Volker, B. Patrice, S. Reinhard, G. Dagmar, M. Doris, Cellular uptake of platinum nanoparticles in human colon carcinoma cells and their impact on cellular redox systems and DNA integrity., Chem. Res. Toxicol., 22(4), 649-59 (2009)

42. Hikaru Nishimori, Masuo Kondoh, Katsuhiro Isoda, Shin-ichi Tsunoda Yasuo Tsutsumi, Kiyohito Yagi, Histological analysis of 70-nm silica particles-induced chronic toxicity in mice, European Journal of Pharmaceutics and Biopharmaceutics 72 (2009) 626629

43. Hisae Aoshima, Yasukazu Saitoh, Shinobu Ito, Shuichi Yamana, Nobuhiko Miwa, Safety evaluation of highly purified fullerenes (HPFs): based on screening of eye and skin damage. The Journal of Toxicological Sciences, 34(5), 555-562, 2009.

44. Zhi Pan, Wilson Lee, Lenny Slutsky, Richard A. F. Clark, Nadine Pernodet, and Miriam H. Rafailovich, Adverse Effects of Titanium Dioxide Nanoparticles on Human Dermal Fibroblasts and How to Protect Cells, small 2009, 5(4), 511520

45. M. Mahmoudi, A. Simchi, A.S. Milani, P. Stroeve, Cell toxicity of superparamagnetic iron oxide nanoparticles, Journal of Colloid and Interface Science, 336 (2009) 510518

180

46. Hikaru Nishimori, Masuo Kondoh, Katsuhiro Isoda, Shin-ichi Tsunoda, Yasuo Tsutsumi, Kiyohito Yagi, Silica nanoparticles as hepatotoxicants, European Journal of Pharmaceutics and Biopharmaceutics 72 (2009) 496501

47. Shinya Kato, Hisae Aoshima, Yasukazu Saitoh, Nobuhiko Miwa, Biological Safety of LipoFullerene composed of Squalane and Fullerene-C60 upon Mutagenesis, Photocytotoxicity, and Permeability into the Human Skin Tissue., Basic & Clinical Pharmacology & Toxicology, 104(6), 483-487, 2009.

48. M. Naota, A. Shimada, T. Morita, K. Inoue, H. Takano, Translocation Pathway of the Intratracheally Instilled C60 Fullerene from the Lung into the Blood Circulation in the Mouse:Possible Association of Diffusion and Caveolae-mediated Pinocytosis., Toxicologic Pathology, 37, 456-462, 2009.

49. J. H. Sung, J. H. Ji, J. D. Park, J. U. Yoon, D. S. Kim, K. S. Jeon, M. Y. Song, J. Jeong, B. S. Han, J. H. Han, Y. H. Chung, H. K. Chang, J. H. Lee, M. H. Cho, B. J. Kelman, I. J. Yu, Subchronic Inhalation Toxicity of Silver Nanoparticles., Toxicological Sciences, 108(2), 452-461, 2009.

50. M.-T. Zhu, W.-Y. Feng, Y. Wang, B. Wang, M. Wang, H. Ouyang, Y.-L. Zhao, Z.-F. Chai, Particokinetics and Extrapulmonary Translocation of Intratracheally Instilled Ferric Oxide Nanoparticles in Rats and the Potential Health Risk Assessment, Toxicological Sciences, 107(2), 342-351 (2009)

51. Jinyuan Chen, Xia Dong, Jing Zhaoa and Guping Tang, In vivo acute toxicity of titanium d

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