Nanotoxicology Program - cdc.gov

1 Nanotoxicology ProgramJenny R. Roberts, Toxicology and Internal Dose Critical Area CoordinatorNational Institute for Occupational Safety and HealthMorgantown, WVDefinitions Nanoparticle: A particle having one dimension less than 100 Nanotube (1 nanometer) x 100,000 = Strand of Hair (100 microns) Engineered Nanoparticle: Created for a purpose with tightly controlled size, shape, surface features and chemistry. Incidental Nanoparticle: Created as an inadvertent side product of a of Nanotoxicology as a Field of StudyScopus: Nanoparticles and ToxicityTimeline and Images: Number0500100015002000250030001980'sDisc overy ofNanocrystals and Fullerenes1990's Emergence of Nanotech CompaniesEarly 1990'sCarbon Nanotubes2000 NationalNanotechnology Innitiative20041st NTRC Science MeetingNTRCT oxicology & Internal DoseRiskAssessmentMeasurement MethodsEpidemiology &SurveillanceFire & Explosion SafetyExposureAssessmentGlobal CollaborationsControls & PPER ecommendations & GuidanceInformatics &ApplicationsNTRC: 10 Critical AreasNIOSH ProgramNanotechnology Research Center (NTRC) 2016 Nanotoxicology Projects: 11 HELD, 13 NTRC> 40 Extramural Collaborations Academia, Government, Industrial1.

2 Increase understanding of new hazards and related health risks to nanomaterial workers. Strategic Plan Goals Pertaining to ToxicologyConduct research to contribute to the understanding of the toxicology and internal dose of emerging whether nanomaterial toxicity can be categorized on the basis of physicochemical properties and mode of Expand understanding of the initial hazard findings of engineered whether human biomarkers of nanomaterial exposure and/or response can be the relevance of in vitro and in vivo screening tests to worker response to inhalation of of materials of interest for investigation through directives and/or partnerships with other agencies/organizations (military, CPSC, EPA, FDA, NIST, NTP, OECD, ISO, WHO) through partnership with Industry availability of materials that address NIOSH research questions (life cycle, prevention through design, structure function relationships, etc.)

3 , pairing of field studies and toxicological evaluation (occupationally relevant materials and exposures) highly produced/utilized materials global concern or globally identified as high priority nanomaterials that allow us to answer a specific research question - identify physical chemical properties and related mechanisms of action, address prevention through designNanomaterials Investigated at NIOSHMWCNT Mitsui 7 DWCNT double walled CNTMWCNT amine and carboxyl functionalizedMWCNT Doped (Nitrogen, Aluminum)MWCNT Heat TreatedVapor-grown Carbon nanofibers (CNF)CNT and CNF 10 US Facilities in Epidemiology StudySWCNT single-walled CNTC arbon NanodotsGraphite Nanoplateletsor NanoplatesGrapheneGraphene OxideNanocelluloseNanomaterialsNatural and OrganomodifiedMontmorillonite NanoclayLayered Reduced Graphene Oxide MWCNT- Mitsui 7 Courtesy of Bob MercerStacked Plates of Nanoclay courtesy of Todd StueckleNanomaterials Investigated at NIOSHB oron Nitride NanotubesBoron Nitride NanopowderSilicon nanowiresElemental nano-silverCerium Dioxide LanthiumOxideCobalt OxidesNickel OxideIron Oxides SiO2 coated and uncoatedZinc Oxide Spheres and NanowiresElemental ZnTitanium Dioxide Nanorods, nanowires, nanobeltsSiO2 amorphous and crystallineTungstate (particles and rods) CaWO4, SrWO4, BaWO4 Tungsten carbide-cobaltTungstate (particles and rods)

4 CaWO4 SrWO4 BaWO4 Copper OxideQuantum Dots ZnS/CdSeSi nanowires: Roberts et al., 2012 TiO2 nanospheres: courtesy of Dale PorterTiO2 nanobelts: courtesy of Dale PorterFunctionally Modified Nanoparticles Prevention through Design: Carboxylatedand HumicsAcid Titanium Nanobelts Nitrogen-doped MWCNT CarboxylatedMWCNT Amine Functionalized MWCNT Heat-Treated MWCNT Amorphous silica coated Iron Oxide and Cerium Oxide Gadolidium-doped and SiO2 coated cerium oxideNanomaterials Investigated at NIOSHG asset al., 2013 +Gd3+Courtesy of Stephen LeonardNanomaterials Investigated at NIOSHE xposure with Nanoparticle Components NanoRelease/Life Cycle: Crushed Preparation MWCNT CNT Polymer Composites Construction operations Sanding/SawingPrinter-Emitted Particles Toners and Inks (CPSC and Harvard University)Three Dimensional Printing Emissions (CPSC and West Virginia university)Copper-Treated Wood Dust from Construction Operations (CPSC)SuncreenSpray ZnOnanoparticles (FDA)Disinfectant Sprays ZnOor Silver NanoparticlesWood Sealant/Stain Aerosol Spraying Operations ZnONanoparticles (CPWR)Stain-Treated Wood Dust Construction Operations ZnONanoparticles (CPWR)Welding Fume Exposure mixture on metal nanoparticlesCNT in Composite Courtesy of A.

5 ErdelyZnOparticles on paint droplets Courtesy of CPWR, B. LippyNanotoxicology Program Highlights Generating Occupationally Relevant Aerosols for In Vivo Studies CNT A Model Toxicity Assessment Into the future with a life cycle approachInhalation Exposure SystemsDry Dust Acoustical GeneratorAnimal Exposure ChamberMonitoring Equipment: Feedback to computer regulated control of environmental conditionsDry Dust ChamberSpeaker SubwooferTSIM odel 3076 AtomizersSample ports use for:Real time mass con. reading, Real time count con. reading,Gravimetric filter analysis,APS samples,MOUDI samples,SEM Imaging samplesChamber Exhaust AirExposure air inputFlow straiten tubeStainless steel cage rack can hold 12 ratsCage support beams with individual exhaust ports located at the center of each Exposure Chamber Cube 150 Temperature & %RH probeChamber Pressure probeTo house VacuumHEPA(0-50 L/min) Flow ControllerUsed to maintain zero chamber pressureDrain linesFeed line35 PSI clean dry Air inputsFlow Controllers (10 L/min) eachInhalation Exposure Systems: Wet AerosolsProcessing and Characterizing Aerosols from Nano-Enabled MaterialsSampling LinesBoat for Particle CollectionSanding BeltNanocomposite SampleConstant-Force FeederInternal ViewFilter SamplerRespirable CycloneFilterCourtesy of A.

6 Erdely, L. Cena and A. AfshariCNT A Model Toxicity Assessment Initial Hazard Identification Studies SWCNT and MWCNT (Mitsui-7) Dose-response time course studies in mice aspiration of single bolus dose- Rapid Onset of Fibrosis- Extrapulmonary Effects: effects in cardiovascular, immune, and nervous system Inhalation Studies (Mitsui-7) - 1stStudies Conducted 5 mg/m3 Rapid development of pulmonary fibrosis (Porter et al., 2013) Pleural penetration and translocation to other organ systems (Mercer et al., 2013) Lung adenocarcinoma tumor promotion (Sargent et al., 2014) Basis for IARC ruling on Mitsui-7 and other CNTSWCNT Collagen Shvedova et al. 2003 - SWCNTM ercer et al., 2010-MWCNTM ercer et al., 2010-MWCNTS argent et al., 2014-MWCNTS iegrist et al., 2014-MWCNTCNT A Model Toxicity Assessment Integration of Exposure Assessment, Epidemiology, and Toxicology US Facilities Study Dosimetry Study (Mitsui-7) Aspiration vs Inhalation and Workplace Exposure Assessment Erdely et al.

7 , 2013 Comparative Toxicity Study: CNT and CNF from those US Facilities Biomarkers of Exposure and Disease - ~100 workers cross sectional study plasma, serum, sputum Marker were chosen from in vivo and other cohort studies Correlating these markers to ongoing exposure assessment Validates the in vivo biomarker studiesEstimates based on a worker exposed to aninhalable elemental carbon concentration of g/m3for 8 h/d for 250 d/y5 mg/m3 5 hr/d 19 d = 40 ugdepositedMouse modelWorker Exposure~76 mg/m3 5 hr/d 19 d = ugdeposited~ mg/m3 hr/d 19 d = ugdeposited~ yearsPulmonary ToxicityDeposition Pattern and TranslocationCardiovascular EffectsNeurological EffectsGenotoxicityFuture DirectionsMaterial ProcessingDistributionProduct Use and ConsumptionRecycleProduction of Primary ENMD isposalOtherMixingCoatingCompositingSoni cating/DispersingCutting, Sanding, Grinding, Heating.

8 Sonicating/DispersingDegradation/Leachin g Affected by Environment and WeatheringDry PowderWet ChemistryImages courtesy of Matthew Dahm, Doug Evans, Mary Schubauer-Berigan, NIOSHR esource ExtractionOccupational Material LifecycleJames AntoniniMin DingAaron ErdelyPatti ErdelyJeff FedanAnn HubbsRobert MercerDale Porter Yong QianJenny RobertsLiying RojanasakulKristen RussLinda SargentTabatha SettleAnna ShvedovaKrishnan SriramTodd StueckleNaveena YanamalaPius JosephHong KanElena KisinVamsi KodaliStephen LeonardQiang MaNTRC Critical Area Coordinators: Bean Chen, Kevin H. Dunn, Kevin L. Dunn, Doug Evans, Mark Hoover, Eileen Kuemple, Vladimir Murashov, Mary Schubauer-Berigan, AleksStefaniak, Doug Trout, Leonid TurkevichEngineers and Aerosol ScientistsDave Frazer, Walter McKinney, Travis Goldsmith, Ali Afshari, Bean Chen, Lorenzo CenaCharles GeraciLaura HodsonPaul SchulteAleksStefaniakVincent Castranova toxicology and internal dose critical area coordinator 2004-2014 Don BeezholdPaul SiegelJeff FedanMartin HarperRobert LanciottiJohn NotiSteven ReynoldsAcknowledgementsQuestions and Challenges:NTRC and Nanotoxicology version the second decade of researchWhat is the next emerging material for investigation?

9 Who is using nanotechnology, nano-enabled materials and how are they being used? Advanced manufacturing and additive manufacturingEntrenched in Omics Compiling all the data for use in predictive modeling (in vitro to in vivo, and mode of action) -Determining the Low Effect and No Effect Dose Level