Development of test methods and database for the risk assessment of manufactured nanomaterials (I) K.H.Choi, J.H.Yoon, S.H.Lee, C.W.Lee, S.J.Kim, J.S.

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1 Development of test methods and database for the risk assessment of manufactured nanomaterials (I) 2007

2 Development of test methods and database for the risk assessment of manufactured nanomaterials (I) K.H.Choi, J.H.Yoon, S.H.Lee, C.W.Lee, S.J.Kim, J.S.Ryu, E.R.Park, H.Y.Ro, J.H ong, H.J.Kim Environmental Exposure Assessment Division Chemicals Assessment Department National Institute of Environmental Research 2007

3 1. (I) 2..,, OECD D/B ) 2) 3) 4) OECD

4 3.. DB 1) OECD, ISO (US EPA), (SETAC) 2) / / Woodrow Wilson Center( DB DB. 1) OECD 1 2) OECD ISO,

5 in vitro. 1) : : : (,, ) GSH : ppm, 48 :,, 100 mg Bradford assay GSH : kit (Total Glutathione Quantification Kit, Dojindo Laboratories, ) 415nm 2-nitrobenzoic acid GSH. 2) : (Sprague Dawley, SPF) : : : 4 / 1 14, 4 : 50.0±10 μg/m 3, 200.0±40 μg/m 3, 700.0±140 μg/m 3, :,,

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11 Abstract Nanotechnology has been emerging as one of the promising ares for the leading growth of national revenue, resulting in that human and environment have a greater exposure probability to nanomaterials. However, the information on the hazardous properties of manufactured nanomaterials is not enough. The concerns has been raised since it has been reported that smaller particles have larger surface areas suggesting possible higher bio-reactivity. OECD also recognised this concern and organized the working party for manufactured nanomaterials (OECD, WPMN) under the chemical committee in Republic of Korea is actively participating the WPMN activities. NIER (National Institute of Environmental Research) initiated researches on the sound management of nanotoxicity, including (a) development of the database providing information on the research activities on physicochemical properties and the environment, safety, and health effects of manufactured nanomaterials (b) collection of the information on target materials, test methods internationally agreed, (c) toxicity test of nanomaterials as a preliminary study. The lists of nanomaterials and end points, required to be investigated, are endorsed by the third OECD WPMN meeting in In addition, the aquatic toxicity and acute inhalation toxicity to fishes and rats of silver nanoparticles were respectively investigated as a preliminary study resulting from the consideration of those lists. The results suggested that 48-hr exposure to sliver nanoparticles could induce the changes in the glutathione (GSH) level in fish and the GSH level could be a good indicator to study the toxicity of nanomaterials. The 4-hr exposure via inhalation route did not cause death or severe

12 changes in rats. Therefore, further study would be required to clarify the effects of silver nanoparticles. Moreover, the investigation on GSH level in the organs of rats would be a valuable approach to find the effects of nanomaterials.

13 i Abstract ix x xiv xv xvi I. 1 II DB

14 OECD OECD Sponsorship programme III DB

15 4. OECD OECD IV. 41 V

16 DB , Glutathione (GSH)

17 OECD DB OECD

18 (Abbreviation Lists) CNT : Carbon Nano Tubes ( ) DEP : Diesel Exhausted Particles( ) DTNB : 5,5-Dithiobis (2-nitrobenzoic acid) EPA NNI : Environmental Protection Agency National Nanotechnology Initiative ( ) ER : Estrogen Receptor ( ) GSH : Glutathione ( ) HEK : Human keratinocytes ( ) ILSI : International Life Sciences Institute ( ) ISO : International Organization for Standardization ( ) KISTI : Korea Institute of Science and Technology Information ( ) LC 50 : 50% Lethal Concentration ( ) LDH : Lactate dehydrogenase ( ) MWCNT : Multi-Walled Carbon Nanotube( ) NHBE : Normal Human Bronchial Epithelial ( ) OECD : Organization for Economic Cooperation and Development ( ) RNA : Ribonucleic acid ( ) SETAC : The Society of Environmental Toxicology and Chemistry ( )

19 SPF : Specific Pathogen-Free ( ) SSA : 5-sulfosalicylic acid (5- ) SWCNT : Single-Walled Carbon Nanotube( )

20 I. EPA National Nanotechnology Initiative 1~100nm (Deanna Lekas. 2006)., OECD (Manufactured Nanomaterials) 100nm (OECD, 2006). nm.. (KISTI, 2006).. (Nanotoxicology) (particle toxicology).,...

21 ,. 2,, (DEP : Diesel Exhausted Particles).,.,,, (Bryan, 2007). OECD (OECD, 2006).. OECD DB,,.,,

22 ., OECD.

23 II. 1. DB,,, OECD.,,.. OECD, ISO OECD. (US EPA), ILSI, ( , Woodrow Wilson, ),, 2007 (SETAC),, PubMed.. / /, 47

24 . OECD. OECD (1), (2). 1, 2.. MS ACCESS 2003, DB 2. DB OECD Woodrow Wilson Center ( DB. 2.. OECD 1,.. OECD ISO,. in vitro,

25 ,, 3. 1) (CAS No , Sigma chemical Corp., USA), 100 mg/l 1,000 mg/l. 0.5, 1.0 mg/l.,. 2) 6 10L 48

26 . 24±1, 16 h/day. 3),, 100 mg. 5% 5-sulfosalicylic acid (SSA) 0.7 ml. 8,000 g 10 Bradford assay. 4) kit (Total Glutathione Quantification Kit, Dojindo Laboratories, ) 415nm. Ellman's DTNB (5,5-Dithiobis(2-nitrobenzoic acid)) GSH(Glutathione) GSH glutathione disulfide, DTNB 2-nitrobenzoic acid. 415nm 2-nitrobenzoic acid, GSH..,,.

27 1) Sprague-Dawley (SD) (SPF). 2), 4 / , (a:, b: ) 3),.

28 45±20% L/min, 8±20% L/min, 7±20% L/min AC 95±10% V. 22, 45%. differential mobility analyzer (nano-dma, 4220, HCT Co., Ltd. Korea) ultra-condensation particle counter (UCPC, 4312, HCT Co., Ltd. Korea) Group G1 (Control) G2 (Low) G3 (Medium) G4 (High) Target dose (particles/cm 3 ) Surface area (nm 2 /cm 2 ) Mass (μg/m 3 ) ±20% ±20% 50.0±20% ±20% ±20% 200.0±20% ±20% ±20% 700.0±20% Gender N M 5 F 5 M 5 F 5 M 5 F 5 M 5 F 5 4) 2,.

29 2. 1 / 1 / 1 1, 3, 7, , 3, 7, 14 ( ) NA 4. OECD,,,,. OECD.. OECD, (ISO).. OECD OECD

30 (SG3).,.. (SG4) 4 OECD., ISO,,,. Sponsorship programme OECD SG3 14 Sponsorship. (T/F).

31 . (SG8) (SG5) OECD,.

32 III. 1. DB. 2., 2. (Fullurene),, carbon black, (CNT, Carbon Nano Tubes) titanium dioxide, alumina, zinc oxide,,. (Fullurene) 60 (C60) 1985, 70 (C70), 84 (C84).

33 3. ( : (A) USEPA, (B)~(C) Argonne National Laboratory, (D) Dendritic Nano Technologies, Inc., (E) Lawrence Berkeley National Laboratory) Fullerene(C60) (oxidative stress),, (Zhen Hu et al., 2007). in vitro (TiO 2 ) Syrian Hamster Embryo Fibroblasts (apoptosis),,.

34 ( ),. in vivo.,, 3. 1),.. ),,.,,,,.,,.,.

4. (Life cycle - exposure). 2 5 nm (TiO 2 ) 0.9 10.

35 4. (Life cycle - exposure). 2 5 nm (TiO 2 ) /m 3 (4 ) (3 ),,, LDH(Lactate dehydrogenase) (inflammatory cytokine), (Grassian et al., 2006).,.

36 7. (Chronic pulmonary inflammation) (Hyperplasia of macrophages and epithelial cells) (Altered pulmonary clearance) (Large pulmonary burdens of particles) (Increased interstitialization of doposited particles) interstital lung disease (production of lung tumers).,,. ).,,.,.., (Kennedy P and Chaudhuri A, 2002)., in vitro (Wyenberg et al., 2007).

37 . 2),,,,,,.,, (SETAC) (CeO 2 ) C60 fullerene Daphnia magna Moina macrocopa (SETAC 2007). Hyallela azteca C60 fullerene, (ceriodaphnia). (nanocopper) (silver nano), (nano-tio 2 ) Zebra fish (sub-lethal concentration) 24, 48 (SETAC 2007).

38 5. (Oberdorster G., et al, 2005) 3),.,.,, (deformability), (stability)..,

39 (transcriptomics) (proteonmics)., (high-throughput screening).,,,, DNA., (end-points).,,. DNA (MWCNT, 1-20 /L) (nanosilver) (0.1-5 /L) Zebra fish in vivo., (SWCNT, Single-Walled Carbon Nanotube) in vitro (Mary Jane Cunningham et al., 2007). HEK (human keratinocytes) NHBE (normal human bronchial epithelial cell) SWCNT SiO 2 CI (carbonyl iron) 24, RNA 2.

40 . in vitro, LU175(20 ), LU205(250 ) (SETAC 2007).,,,. (Surface-treated Non-treated TiO 2 ),,,.. C60 SiO 2 DNA Comet assay. MWCNT (ER) ( SETAC 2007)....,,

41 .. OECD OECD DB DB Principal Investigator Information Additional Investigators Information 1. Last Name free text 2. First Name free text 3. Title free text 4. Institution free text 5. Address free text 6. Address free text 7. Country (of Designated Contact Point) Dropdown list 1. Last Name free text 2. First Name: free text 3. Title free text 4. Institution free text 5. Address free text 6. Address free text 7. Country Dropdown list

42 Project DB Information 1. Title free text 2. Start year Dropdown list 3. End year Dropdown list 4. Total funding ($US) 5. Funding source (organization (s)) 6. 'Status' of the project range and absolute values in local currency free text Dropdown list (planned, current, complete) 7. Project Summary/expected free text outcomes 8. Project web link free text (official website) 9. Web link to the relevant free text website 1. Main categories of the select any relevant research themes research themes from the (from SG2 s list of list or select Others if not Research themes) find relevant theme 2. Subcategories within the select any relevant research themes research themes from the (from SG2 s list of list. or select Others if Research themes) not find relevant theme Categorisation select any relevant 3. Chemical nanomaterials from the characterisation list provided by SG3 or (chemical name)s enter text for other nanomaterials select relevant test methods from the list of 4. Test method OECD TGs or enter text for 'other' test methods Overall Outcomes + Outputs free text, web link, and attachment

43 DB OECD MS ACCESS , 2 DB. 6. DB OECD DB 4 24,. 48 ( ), 11 23%.,.

44 ., 16, 1 2, 5 ~1 5, 5 3.,,,,., 6, 2, 2.. OECD DB, DB. DB OECD,. DB.

45 nm,,,,.,, OECD Silver nanoparticles 2 Single-walled carbon nanotubes (SWCNTs) 3 Multi-walled carbon nanotubes (MWCNTs) 4 Fullerenes (C60) 5 iron nanoparticles 6 carbon black 7 titanium dioxide 8 aluminium oxide 9 cerium oxide 10 zinc oxide 11 silicon dioxide 12 polystyrene 13 dendrimers 14 nanoclays

46 Woodrow Wilson Center 7 80%, 9%. 34%, 30%, 17%, 9%, 9% ( : Woodrow Wilson International Center for Scholars, 2006) (KISTI)

8 79 40 (50.5%), 39 (49.5%). 27 (67%), 24 (60%), 3 (7.

47 (50.5%), 39 (49.5%). 27 (67%), 24 (60%), 3 (7.5%) (KISTI, 2006).,..,. 8., ( : KISTI, 2006)

48 .,,, 100 ISO OECD,., in vitro. (endpoint) OECD. OECD,,, 5 9, 16, 13, 5 3 ( 5 ), 3 ( ). 5. OECD Group Nanomaterial Information/ Identification End point Nanomaterial name (from list) CAS Number Structural formula/molecular structure Composition of nanomaterial being tested (including degree of purity, known impurities or additives) Basic morphology Description of surface chemistry (e.g., coating or modification) Major commercial uses

49 Group End point Known catalytic activity Method of production (e.g., precipitation, gas phase) Agglomeration/aggregation Water solubility Crystalline phase Dustiness Crystallite size Representative TEM picture(s) Physical-Chemic al Properties and Material Characterization Particle size distribution Specific surface area Zeta potential (surface charge) Surface chemistry (where appropriate) Photocatalytic activity Pour density Porosity Octanol-water partition coefficient, where relevant Redox potential Radical formation potential Other relevant information (where available) Dispersion stability in water Biotic degradability Ready biodegradability Environmental Fate Simulation testing on ultimate degradation in surface water Soil simulation testing Sediment simulation testing Sewage treatment simulation testing Identification of degradation product(s)

50 Group End point Further testing of degradation product(s) as required Abiotic degradability and fate Hydrolysis, for surface modified nanomaterials Adsorption- desorption Adsorption to soil or sediment Bioaccumulation potential Other relevant information (when available) Effects on pelagic species (short term/long term) Effects on sediment species (short term/long term) Environmental Toxicology Effects on soil species (short term/long term) Effects on terrestrial species Effects on microorganisms Other relevant information (when available) Pharmacokinetics (ADME) Acute toxicity Repeated dose toxicity Mammalian Toxicology If available: Chronic toxicity Reproductive toxicity Developmental toxicity Genetic toxicity Experience with human exposure Other relevant test data Where available: Material Safety Flammability Explosivity Incompatibility

51 3.. Glutathione(GSH),. GSH GSH. 48,, GSH, 9 GSH., GSH,.. GSH (Eva, 2004)., GSH. GSH GSH., GSH.

52 대조군 Ag(0.5 ppm) Ag(1 ppm) 아가미 간 뇌 Glutathione (GSH) , 43%.

53 6. G1 (Control) G2 (Low) G3 (Medium) G4 (High) ( ) 22.96± ± ± ±0.51 (%) 43.00± ± ± ±0.25 (mmh 2 O) -5.00± ± ± ±0.60 (m/sec) 4.00± ± ± ±1.00 (nm, GM(GSD)) (0.35) 17.90(0.35) 20.35(0.69) 0.94x x x10 - (particles/cm 3 ) ±0.09x10 5 ±0.15x10 5 ±0.64x x x x10 - (nm 2 /cm 3 ) ±0.44x10 8 ±0.75x10 8 ±0.26x10 9 (μg/m 3 ) ± ± ± x10 6 ±0.09x10 5, 1.64x10 6 ±0.15x10 5, 3.08x10 6 ±0.64x10 5 particles/cm 3, ±3.25, ±5.99, ±35.62 μg/m 3.

54 10. 1,,, 14.,, 1, 3, 7, 14. 1, 3, 7, 14,,,,,,.,,., LC μg/m 3.

55 28 (Ji JH et al, 2007)., (ACGIH) 100 μg/m OECD OECD (WPMN), (SG),,,,, ( 07.4 ). ( 07.4, ).. OECD (ISO) (SG3) 2 OECD

56 .. OECD OECD OECD DB,, (SG2), (SG3) (SG4) OECD.. (SG3)...,

57 OECD (SG4) 4 OECD.,, ISO,.,.. Sponsorship programme OECD (SG 3) 3 OECD 14 Sponsorship,.,,,, OECD (SIDS; Screening Information Data Set ). OECD

58 . OECD. OECD Sponsorship Programme. (SG8) (SG5) OECD... (TNO).

59 11. OECD 8

60 IV. 1.,. 2. DB OECD, DB OECD MS ACCESS 3. OECD ,. 5. GSH. 6..

61 V J. Environ. Toxicol., 20(4): 259~ Beck-Speier I, Dayal N, Karg E, Maier KL, C, Ziesenis A and Heyder J Agglomerates of ultrafine particles of elemental carbon and TiO2 induce generation of lipid mediators in alveolar macrophages. Environ Health Perspec 109(4): Bernd Nowack and Thomas D. Bucheli Occurrence, behavior and effects of nanopaticles in the environment. Environmental Pollution, 150: 5~22 Bryan C. Daniels MU Researchers Examine the Environmental Effects of Silver Nanoparticles. Cunningham MJ, Shah M, Leme C, Magnuson S, Falduto C, Balzano L and Resasco D An OMICs approach for assessing the safety of single-walled carbon nanotubes in human skin and lung cells. The nanotechnology conference and trade show, May, 2007, Santa Clara, Deanna Lekas Nanotechnology Startup Concern, Information Needs, and Opperunities to Proactively Address Environmental, Health, and Social Issues. Woodrow Wilson International

62 Center for Scholars, Eva Oberdörster Manufactured Nanomaterials(Fullerenes, C 60 ) induce Oxidative Stress in the Brain of Juvenile Largemouth Bass. Environmental Health Perspectives, 112(10): 1058~1062 Federici G, Shaw BJ and Handy RD Toxicity of titanium dioxide nanoparticles to rainbow trout (Oncorhynchus mykiss): Gill injury, oxidative stress, and other physiological effects. Aquatic Toxicology 84(4): Grassian VH, O'Shaughnessy PT, Adamcakova-Dodd A, Pettibone JM and Thorne PS Inhalation Exposure Study of Titanium Dioxide Nanoparticles with a Primary Particles Size of 2 to 5 nm. Environ. Health Perspect. 115: Zhen Hu, Wenchao Guan, Wei Wang, Lizhen Huang, Haiping Xing and Zhou Zhu Synthesis of β-alanine C60 derivative and its protective effect on hydrogen peroxide-induced apoptosis in rat pheochromocytoma cells. Cell Biology International 31(8): ICON. International Council On Nanotechnology : A partnership for nanotechnology stewardship and sustainability Ji JH, Jung JH, Kim SS, Yoon JU, Park JD, Choi BS, Chung YH, Kwon IH, Jeong J, Han BS, Shin JH, Sung JH, Song KS and Yu IJ Twenty-eight-day inhalation toxicity study of silver

63 nanoparticles in Sprague-Dawley rats. Inhalation toxicology. Aug 19(10): Kim MS, Choi KH, Kim YH and Yi JH, 2007, Risk assessment for health and environmental hazards of nanomaterials, Clean Technology, 13(3): KISTI, NanoWeekly, 210 Mary Jane Cunningham and Mrinal Shah, 2007, Chapter 3.1, Toxicogenomics in "Handbook of Pharmaceutical Biotechnology". John Weily & Sons, Inc. Günter Oberdörster, Eva Oberdörster and Jan Oberdörster, 2005, Nanotoxicology : An Emerging Discipline Evolving from Studies of Ultrafine Particles, Environ. Health Perspect. 113: OECD Development of an OECD nanosafety database : potential project. ENV/CHEM/NANO/M(2006)5 OECD Draft summary record of the 1st working party on manufactured nanomaterials. ENV/CHEM/NANO/M(2006)1 OECD manifactured nanomaterials : Work Programme ENV/JM(2006)49/REV1 OECD Draft summary record of the 2nd working party on manufactured nanomaterials. ENV/CHEM/NANO/M(2007)1 Rojo I Toxicogenomic study of nanomaterials on the model

64 organism zebrafish. The nanotechnology conference and trade show, May, 2007, Santa Clarqa, Sabine A. Blaser, Martin Scheringer, Matthew MacLeod, Konrad Hungerbühler Estimation of cumaulative aquatic exposure and risk due to silver: Contribution of nano-functionalized plastics and textiles. Science of the Total Environment, 390: 396~409 Samanth D Modern methods and modelsystems for nanotoxicology. SETAC (2007) SETAC North America 28th annual meeting abstract book, Nov, Milwaukee, USA Sharon M. Friedman and Brenda P. Egolf Nanotechnology: Risks and the Media. IEEE Technology and Society Magazine, 2005 winter:: 5~11

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