all that exists are atoms and the void..

Transcription

1 Andre Nel M.B.,Ch.B, PhD all that exists are atoms and the void.. Democritus of Abdera (ca. 470-ca. 380 BC)

2 University of California Los Angeles, Santa Barbara, Davis, Riverside; Columbia University, NY; University of Texas, University of New Mexico, Lawrence Livermore National Laboratory, Lawrence Berkeley National Laboratory University College Dublin, Nanyang Techonological University, Cardiff University Wales, Unversity of British Columbia, Universitat Rovira i Virgili, Foundation Institute for Materials Science

3 Objectives of the UC CEIN Develop a library of reference NMs Understand the impacts of different classes of NMs on cells, organisms and ecological systems Develop a predictive model of toxicology and environmental impacts of NMs Develop a computerized expert system for risk ranking Develop guidelines and decision tools for safe design and use of NMs

4 How do we approach the safety of a new technology on a scale commensurate with its rate of expansion? Do we do it the traditional way: one material at a time? Hazard Identification Example of the traditional approach: Chemical Industrial Toxicology Exposure Assessment Risk Characterization Risk Management 50,000 plus chemicals registered for commercial use in the US < 1,000 have undergone toxicity testing Overwhelming of resources: each test $2-$4 million (for in vivo studies) > 3 years to complete

5 US National Academy of Science (NAS) Report (2007): Toxicity Testing in the 21st Century: A Vision and a Strategy Descriptive single material tox testing in animals is time consuming and expensive Transformative approach is required that can provide broad coverage of panels of toxicants Use a robust scientific basis to perform safety testing Robust = array of predictive in vitro tests that utilize toxicity pathways and mechanisms High content or high throughput screening to facilitate testing of large batches of materials In vitro hazard needs to be predictive of in vivo

6 The Science at the Nano-bio interface Nanoparticle physicochemical properties Suspending Media modulating those properties Living matter Nanoparticle Influence zone Nano-bio interface

7 In vitro assays that could be useful for high content or HTS to build quantitative SAR s for nanomaterials Characteristics defining cell uptake and bioavailability Hydrophobicity Charge Protein coating Size Shape Dispersability Material Composition Cellular binding and uptake Characterization Screening Characteristics defining biocatalytic activity Oxidant injury Lysosomal injury Mitochondrial injury Apoptosis Membrane damage DNA damage etc

8 High Throughput Screening and Data Mining based on QSAR relationships that can be used to rank NM for risk and priority in vivo testing 100 s/year 1000 s/year 10,000 s/day 100,000 s/day Immediate Relevance High Throughput Bacterial, Cellular or Molecular Screening Prioritize in vivo testing at increasing trophic levels

9 Interdisciplinary Research Groups (IRGs) IRG #1 NM libraries & characterization IRG #3 IRG #3 Organism, population, community & ecosystem toxicology IRG s #5-7 Hi Thru put screening Computerized expert system, multimedia modeling, risk ranking Risk perception IRG #2 Cellular/tissue/systemic Molecular, cellular, & organ injury pathways IRG #4 Fate & Transport

10 IRG 1: Nanomaterial Synthesis and Physicochemical Characterization IRG Leader: Eric M.V. Hoek (UCLA) IRG participants: Hoek, Zink, Kaner, Wang, and Yaghi (UCLA) Stucky (UCSB) Walker, Yan, and Haddon (UCR) Mädler (Bremen) Boey, Loo, Jan, Yoong, and Yang (NTU) Somasundaran (Columbia Univ) Bertozzi (UCB/LBNL)

11 Standard Reference Material library acquisition and characterization Preliminary SRMs: Oxides: TiO 2, SiO 2, CeO 2, ZnO Carbonaceous: C 60, CNTs, carbon black Metals: gold and silver NPs, quantum dots Selection criteria: Large production volume of commercial analogs Expected applications leading to environmental exposure Synthesis/acquisition: Commercial samples CEIN synthesized analogs

12 Combinatorial Library Combinatorial library designed to provide the same material in different sizes, shapes, roughness, aspect ratios, states of dispersal, chemical composition etc NPs X Y Z Surface charge Hydrophilicity/phobicity Biomolecules Drug molecules Automated Nanocrystal Synthesis at The Molecular Foundry

13 IRGs 2: Interactions at Molecular, Cellular, Organ and Systemic Levels Klaine SJ et al Environmental Tox & Chemistry IRG 2 Team Patricia Holden (UCSB) Andre Nel (UCLA) Gary Cherr (UCD) Leonard Rome (UCLA) Joshua Schimel (UCSB) Roger Nisbet (UCSB) Hunter Lenihan (UCSB)

14 IRG2: Interactions at Molecular, Cellular, Organ and Systemic Levels Responses Cellular Organismal Population Population Growth / Respiration -NM NM DEB Modeling relates state of the environment to rates of growth, reproduction/division, respiration other fluxes Time

15 Xia et al ACS Nano Online Nel et al. Nature Materials. Accepted Particle Dissolution and release of toxic Metal ions Particle environment (vacuum, gas, water) Dissolution in suspending medium Cell MeO x - NP Me 2x - ion Bio-molecule Proton Additional cellular effects Lysosome Particles and ions crossing the cell membrane v-atpase Lysosome ph

16 Nel et al. Science, 311, , 2006 Particle-mediated Oxygen Radical production TiO 2 UV OH. H 2 O O 2. - h O 2 e - Electron hole pairs Excited state Electron-donor active groups Semiconductor properties e - O 2 O 2. - TiO 2 Fullerene Metal oxide ZnO Dissolution Release of ions Redox cycling and catalytic chemistry OH. Fe H 2 O 2 e - Q Q.- O 2. - O 2 Fenton chemistry Redox cycling organics Ambient UFP Metal NP Carbon NT

17 Nel et al. Nature Materials. Accepted Endosome Lysosome Cationic v-atpase polymer H CFTR Enzyme Cationic toxicity and the Proton Sponge Hypothesis Cl- H2O H2O Apoptosis

18 IRG 5: High Throughput Screening, Data Mining, and Quantitative Structure-Activity Relationships for NM Properties and Nanotoxicity Group Leader: Ken Bradley (UCLA) Participants: Damoiseaux Nel Hoek Keller Cherr Establish HTS methodologies Perform HTS Data Mining & QSAR profiling

19 Genotoxicity: Mutatox Cellular viability: Microtox ATP levels: ATPlite Luminescent reporter genes Mitochondrial damage, ROS generation, stress response, cellular apoptosis Luminescence Cells Bacteria Yeasts Organisms Nano Materials UV/Vis spectroscopy NADP (Mitoscan) Growth/viability/proliferation via culture optical density Fluorescence Spectroscopy Fluorescence microscopy Fluorescent Reporter Genes (GFP) Mitochondrial damage (Mitotox) ROS generation Cellular apoptosis

20 Nel, Wiesner et al. Nano Letters In vitro comparison of Nanoparticle toxicity based on the hierarchical oxidative stress paradigm Epithelial Endothelial Macrophage Kidney Liver Neuronal etc Abiotic Biotic Signaling JNK NF-kB [Ca 2 ] i Tier 2 Inflammation cytokines chemokines Particle 1 Tier 3 Mitochondria MMP ATP ROS [Ca 2 ] m Cell death caspase activation PI uptake MTS assay ROS Tier 1 Tier 2 Tier 3 Particle 2 Tier 1 Phase 2 anti-ox enzymes HO-1 GSH Particle 3 Particle 4 Particle 5 Particle 6

21 IRG3: Organismal, Population, Community, and Ecosystem Ecotoxicology Focus: Quantifying effects of NMs on the structure and function of food webs, bioaccumulation and biomagnification, and ecosystem-level processes IRG 3 Team Hunter Lenihan (UCSB) Joshua Schimel (UCSB) Gary Cherr (UCD) Roger Nisbet (UCSB) Bradley Cardinale (UCSB) Jorge Gardea-Torresday (UTEP)

22 IRG3: Three model ecological systems Terrestrial Freshwater Marine Micro arthropods Predatory fish Predatory invertebrate Protozoa Invertebrate grazers Invertebrate filter-feeders Bacteria Benthic algae Planktonic algae

23 IRG 4: Fate & Transport IRG Leader: Arturo Keller (UCSB) Participants P Somasundaran (Columbia U) S Walker (UCR) E Hoek (UCLA) A Keller (UCSB)

24 IRG 4 Objectives Develop methods for sampling and analyzing NP in aqueous media Develop relationships between NP characteristics and fate & transport parameters: NM interactions with different types of water in the absence or presence of NOM Transport phenomena Effect of NM on biogeochemical reactions

25 Detecting nanomaterials in the environment Develop protocols for quantitative measurement of NMs in aqueous samples Separation Gravitational FFF (Field-Flow Fractionation) Ultracentrifuge FFF Split FFF HPLC Ultracentrifuge w/o FFF

26 Detecting nanomaterials in the environment Analysis of nano-scale fractions Dynamic Light Scattering (size distribution) AA or ICP-MS (chemical composition) X-ray spectromicroscopy (chemical composition) Spectroscopic analysis (using IRG 1 signals) C-14 labeled particles (to test protocol)

27 IRG 6: Integrated Data Management, Integrated Multimedia Modeling and Computerized Expert System for Risk Ranking and NM Safe Design IRG 6 Team Yoram Cohen (UCLA) Ken Bradley (UCLA) E. M.V Hoek (UCLA) Barbara H. Harthorn (UCSB) NCEAS Ecoinformatics (UCSB) Arturo Keller (UCSB) Francesc Giralt (URV) Robert Rallo (URV)

28 Computerized Expert System Nanoparticle structural & physicochemical information Cell, organism, HTS Environmental Impact Exposure Risk Evaluation Scoring Ranking QRA QSARs Machine Learning/ Pattern Recognition/ Fuzzy ARTMAP Classification/ Cognitive NN AIR Soil Water Multimedia Analysis In vivo toxicity Fate & transport

29 8 3 Expert system for Nanomaterial Safe design 7 Zn Zn e Toxicological properties that could be modified to improve safety ROS 6 O 2 / H 2 O 1. Size, shape, aspect ratio 2. Hydrophobicity 3. Surface area, roughness & porosity 4. Solubility-release of toxic species 5. Surface species, contaminants, adsorption during synthesis/history 6. Capacity to produce ROS 7. Structure/composition 8. Surface charge 9. Dispersion/aggregation Nel et al. Nature Materials. Accepted

30 IRG 7: Environmental Risk Perception and Risk Communication IRG 7 Team Barbara H. Harthorn (UCSB) Terre Satterfield (UBC) William Freudenburg (UCSB) Nick Pidgeon (Cardiff) Paul Slovic (DR) Robin Gregory (DR)

31 Objectives of IRG 7 Quantify Risk Perception Factors Develop comprehensive program to identify factors driving emerging public perceptions of risks to the environment regarding NMs and their enabled products. Behavioral Implications Develop models of emergent knowledge about nanotechnology risks, identifying key potentials for stigmatization or attenuation Develop scoring methodology Identify risk scoring factors to account for risk concerns and risk perception Develop scoring factors Risk Communication Work with science journalists to develop socially sustainable environmental risk communication Study Cases Focus research on cases of water filtration, soil/food production, nano energy and air quality, and climate change

32 Education and Outreach Group Leader: Hilary Godwin (UCLA)

33 Program Objectives Train a diverse cohort of new scientists who are broadly trained to handle complex issues related to nanomaterials in the environment Train researchers to use appropriate safeguards when handling or disposing of nanomaterials Build a cohesive network of stakeholders with interests at the interface of nanoscience and the environment Accurately communicate to the public the implications of nanotechnology in the environment

34 Core Program Components Course on Nanotechnology and the Environment Capstone course on Nanotoxicology Training Course on Safe Handling of NMs Annual International Meetings Journalist Scientist Communication Program

35 Disasters of the First Industrial Revolution

36 Mesoporous Nanoparticles for delivery of guess molecules, imageging and targeting Drug Thread Luminescent Probe, gadolinium Targeting epitope Stopper Motorized Bifunctional valve Stimuli Light ph Enzymatic Temp Redox Paramagnetic FeO

37 Multifunctional Silica Mesoporous Nanoparticles designed for targeted delivery and imaging FeO nanocrystal Anticancer drug Phosphonate coating Targeting ligand Liong et al. ACS Nano. 2008