uc cein - ucla.edu

University of California

Center for Environmental Implications of Nanotechnology (UC CEIN)

NSF: DBI‐0830117 DBI‐1266377

Annual Report Year 7

April 1, 2014 ‐ March 31, 2015

UC Center for Environmental Implications of Nanotechnology Year 7 Progress Report

TABLE OF CONTENTS

1. NSF Cover . Table of Contents 1 3. Project Summary 2 4. List of Center Participants, Advisory Boards, Participating Institutions 4 5. Quantifiable Outputs (NSF Table 1) 15 6. Mission and Broader Impacts 16 7. Highlights 23 8. Strategic Research Plan 43 9. Research Program, Accomplishments, and Plans 45

Theme 1: Compositional and Combinatorial ENM Libraries for Property-Activity Analysis 46 Theme 2: Molecular, Cellular, and Organism HTS Screening for Hazard Assessment 53 Theme 3: Fate, Transport, Exposure and Life Cycle Assessment 60 Theme 4: Terrestrial Ecosystems Impact and Hazard Assessment 65 Theme 5: Marine and Freshwater Ecosystems Impact and Toxicology 71 Theme 6: Environmental Decision Analysis for Nanoparticles 78 Theme 7: Using UC CEIN Knowledge Generation to Engage and Impact Stakeholders 85

NSF Table 2 – NSEC Program Support 91 10. Center Diversity – Progress and Plans 92 11. Education 94

NSF Table 3a – Education Program Participants – All 106 NSF Table 3b – Education Program Participants – US Citizen/PR 107

12. Outreach and Knowledge Transfer 108 13. Shared and Experimental Facilities 119 14. Personnel 124

NSF Table 4A – NSEC Personnel – All 129 NSF Table 4B – NSEC Personnel – US Citizen/PR 130

15. Publications and Patents 131 16. Biographical Information 137 17. Honors and Awards 139 18. Fiscal Section 139

a. Statement of Unobligated Funds 139 b. Budget 140

19. Cost Sharing 162 20. Leverage 162

Table 5 – Other Support 163 Table 6 – Partnering Institutions 164

21. Current and Pending Support – PIs and Thrust Leaders 165

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3. Project Summary The University of California Center for Environmental Implications of Nanotechnology (UC CEIN) was established in September 2008 with a long-term vision of developing a multidisciplinary and quantitative framework for assessing the potential environmental impact, hazard and exposure to ENMs, in both their primary as well as commercial nano-enabled formulations. The Center also provides feedback and guidance for the safer implementation of nanotechnology, including risk reduction and safer design strategies. The multidisciplinary approach of the Center involves materials science, environmental chemistry and engineering, toxicology, ecology, social science, computer science and modeling, statistics, public health, law and policy formulation. Collectively, these fields of expertise are necessary to address the complexity of the ENM physicochemical properties involved in hazard generation, establishment of structure-activity relationships (SARs), and use of exposure assessment to evaluate ecosystems impact. The UC CEIN’s vision is to generate predictive tools for environmental hazard and exposure assessment as well as to develop strategies to ensure the safe implementation of nanotechnology to the benefit of society, the environment and the economy. These tools and knowledge are disseminated through vibrant and impactful educational and outreach programs.

The Center makes use of well-characterized compositional and combinatorial ENM libraries to study their fate and transport in parallel with the materials' bioavailability and potential to engage toxicological pathways in organisms and environmental life forms. Where possible, this exploration involves high throughput screening (HTS) to develop structure-activity relationships (SARs) that can be used to predict the impact of primary ENMs' on organisms in freshwater, seawater, and terrestrial environments. In silico data transformation and decision-making tools are involved in data processing to provide hazard ranking, exposure modeling, risk profiling, and construction of nano-SARs. These research activities are combined with educational programs that inform the public, students, federal and state agencies, as well as industrial stakeholders of the impact of CEIN’s research on the safe implementation of nanotechnology in the environment. Collectively, these activities contribute to evidence-based nanotechnology environmental health and safety (nano EHS) for society. Through the pursuit of interdisciplinary, predictive and high throughput approaches, the UC CEIN has made, and will continue to make, a transformative impact on nano EHS assessment. The cornerstone of this impact is our ability to use an interdisciplinary approach for acquisition and synthesis of ENM libraries, which are assessed by high throughput and facilitative test strategies that inform about nanomaterial hazard and potential impact across a broad range of nano/bio interfaces, from cells to ecosystems. Coupled with our computational analysis tools and fate and transport modeling, this allows environmental impact analysis of broad material categories, including the use of this information for safety assessment, safer design and regulatory decision-making. A major goal of the UC CEIN is to educate the next generation of nano-scale scientists, engineers, and policy makers to anticipate and mitigate potential future environmental hazards associated with nanotechnology. Our educational programs are developed to broaden the knowledge base of the environmental implications through academic coursework, research, and training courses for industrial practitioners, public outreach, and a journalist/scientist communication program. Through the activities of our education team (Theme 8), we have had a profound impact on the quality and quantity of educational materials available both nationally and internationally in the area of Environmental Nanotechnology. In partnership with Science Buddies, we developed a science fair project aimed at students based on research generated in the Center. The first project, Tiny Titans: Can Silver Nanoparticles Neutralize E. coli Bacteria, was made publicly available through the Science Buddies website in June 2013 and has been accessed over 11,000 times. The Center has also greatly enhanced

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the professional development opportunities for graduate students and postdoctoral researchers within our Center, as we build a cohesive and interdisciplinary environment for science and education. We regularly engaged the public in settings such as science museums and public libraries to inform them of our work. We have made concerted efforts to involve minority institutions, including the recruitment of minority faculty and students. Additionally, we are proud to have four Hispanic serving institutions (UTEP, UNM, UCR, and UCSB) as core partners in our Center and are working to incorporate strategies for promoting diversity and inclusion and underrepresented minorities into all of our educational activities. UC CEIN has become one of the most preeminent NanoEHS centers in the world. We have impacted national and international understanding and decision-making in the areas of NanoEHS research, protocol development, knowledge dissemination, and contributions to the regulatory agencies. In the coming year, we will continue our predictive scientific investigation and modeling of a progressively wider range of ENMs and their impact on the environment. We will continue to play a leading role in national and international Nano EHS forums and continue to develop informal science education tools for the public as well as expand our interaction with State and Federal agencies and industrial stakeholders.

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4. Center Participants, Advisory Boards, and Participating Institutions Center Participants Participants Receiving Center Support Faculty: Kenneth Bradley UCLA Associate Professor, Microbiology Jeffrey Brinker University of New Mexico/Sandia Professor, Chemical/Nuclear Engineering Bradley Cardinale UC Santa Barbara Assistant Professor, Ecology Evolution, Marine Biology Gary Cherr UC Davis Professor, Environmental Toxicology/Nutrition Chi-On Chui UCLA Associate Professor, Electrical Engineering Yoram Cohen UCLA Professor, Chemical Engineering J.R. DeShazo UCLA Associate Professor, Public Policy Curtis Eckhert UCLA Professor, Environmental Health Sciences William Freudenberg UC Santa Barbara Professor, Environmental Studies and Sociology Jorge Gardea-Torresdey University of Texas, El Paso Professor, Chemistry Hilary Godwin UCLA Professor, Environmental Health Sciences Robert Haddon UC Riverside Professor, Chemistry Barbara Herr Harthorn UC Santa Barbara Professor, Women’s Studies/Anthropology Mark Hersam Northwestern University Professor, Materials Science & Engineering Eric Hoek UCLA Professor, Civil & Environmental Engineering Patricia Holden UC Santa Barbara Professor, Environmental Microbiology Milind Kandlikar University of British Colombia Associate Professor, Institute for Global Issues Arturo Keller UC Santa Barbara Professor, Environmental Biogeochemistry Hunter Lenihan UC Santa Barbara Professor, Marine Biology Alex Levine UCLA Professor, Chemistry and BioChemistry Shuo Lin UCLA Professor, Molecular, Cell, & Developmental Biology Lutz Madler University of Bremen Professor, Materials Science Timothy Malloy UCLA Professor, Law Edward McCauley UC Santa Barbara Professor, Ecology, Evolution, Marine Biology Jay Means UC Santa Barbara Adjunct Professor, Environmental Toxicology Huan Meng UCLA Assistant Adjunct Professor, Nanomedicine Nirav Merchant University of Arizona Director, Biotechnology Computing, iPlant Andre Nel UCLA Professor, Medicine; Chief, Division of NanoMedicine Roger Nisbet UC Santa Barbara Professor, Ecology, Evolution, Marine Biology Robert Rallo Universitat Roriv i Virgili/UCLA Professor, Chemical Engineering Theresa Satterfield University of British Colombia Professor, Institute of Resources Joshua Schimel UC Santa Barbara Professor, Ecology, Evolution, Marine Biology Ponisseril Somasundaran Columbia University Professor, Materials Science Galen Stucky UC Santa Barbara Professor, Chemistry and Biochemistry Sangwon Suh UC Santa Barbara Associate Professor, Environmental Sci & Mgmt Donatello Telesca UCLA Assistant Professor, Biostatistics Sharon Walker UC Riverside Professor, Chemical and Environmental Eng. Korin Wheeler Santa Clara University Assistant Professor, Chemistry Tian Xia UCLA Assistant Adjunct Professor, Nanomedicine Jeffrey Zink UCLA Professor, Chemistry and Biochemistry Research Staff: Jacob Agola University of New Mexico Fnu Aoergele UCLA Dennis Bacsafra UCLA Berenice Barajas UCLA Raven Bier UC Santa Barbara Eric Carnes Sandia National Laboratory

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Robbie Castillo University of New Mexico Chong Hyun Chang UCLA Irina Chernyshova Columbia University Lauren Copeland UC Santa Barbara Robert Damoiseaux UCLA Anna Davison UC Santa Barbara Helen Dickson UC Santa Barbara Corinne Dorais UC Santa Barbara Darren Dunphy University of New Mexico Bryan France UCLA Kendra Garner UC Santa Barbara Jennifer Gowan UC Santa Barbara Fred Griffin UC Davis Taimur Hassan UCLA Sean Hecht UCLA J.A. Hernandez-Viezcas University of Texas, El Paso Susan Jackson UC Davis Zhaoxia Ivy Ji UCLA Xingmao Jiang Sandia National Labs Sambamurthy Khadrika Columbia University Frederick Klaessig Pennsylvania NanoBio Systems Ning Li UCLA Yu-Pie Liao UCLA Ya-Hsuan Liou UC Santa Barbara Yu-Shen Lin University of New Mexico Huiyu Liu UCLA Marianne Maggini UC Santa Barbara Huan Meng UCLA Robert Miller UC Santa Barbara Delia Milliron Lawrence Berkeley National Laboratory Taleb Mokari Lawrence Berkeley National Laboratory Erik Muller UC Sana Barbara Laure Pecquerie UC Santa Barbara Jose Peralta-Videa University of Texas, El Paso John Priester UC Santa Barbara Dad Roux-Michollet UC Santa Barbara David Schoenfeld UCLA Jo Anne Shatkin Virio Advisors Yiming Su UC Santa Barbara Matthew Tallone UC Santa Barbara Laurie Van De Werfhorst UC Santa Barbara Carol Vines UC Davis Hongtuo Wang UC Santa Barbara Meiying Wang UCLA Xiang Wang UCLA William Wooten UCLA Maria Yepez UC Santa Barbara Haiyuan Zhang UCLA Postdoctoral Researchers: Carlee Ashley Sandia National Laboratory Mafalda Baptista UC Santa Barbara Christian Beaudrie University of British Columbia

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Elizabeth Beryt UCLA Muhammad Bilal UCLA Rafaella Buonsanti UCLA/Lawrence Berkeley National Laboratory Bryan Cole UC Davis Shelly Cole-Moritz UC Santa Barbara Mary Collins UC Santa Barbara Gwen D’Arcangelis UC Santa Barbara Guadalupe De La Rosa University of Texas, El Paso Cristina Duarte-Torres UC Davis Cassandra Engeman UC Santa Barbara Elise Fairbairn UC Davis Xiaohua Fang Columbia University Yaqin Fu University of New Mexico Yuan Ge UC Santa Barbara Saji George UCLA Nalinkanth Ghone UCLA Debraj Ghosh UCLA Shannon Hanna UC Santa Barbara Yongsuk Hong UC Santa Barbara Allison Horst UC Santa Barbara Chia-Hung Hou UC Santa Barbara Angela Ivask UCLA Wendy Jiang UCLA Xue Jin UCLA Mikael Johansson UC Santa Barbara Sanaz Kabehie UCLA Irina Kalinina UC Riverside Moshen Kayal UC Santa Barbara Myungman Kim UCLA Nichola Kinsinger UC Riverside Hiroaki Kiyoto UC Santa Barbara Tin Klanjscek UC Santa Barbara Chris Knoll UC Santa Barbara Konrad Kulacki UC Santa Barbara Jae-Hyeok Lee Northwestern University Juon Lee UC Santa Barbara Minghua Li UCLA Ruibin Li UCLA Sijie Lin UCLA Yu-Shen Lin University of New Mexico Rong Liu UCLA Xiangsheng Liu UCLA Martha Lopez University of Texas, El Paso Cecile Low-Kam UCLA Nature McGinn UC Davis Milka Montes UC Santa Barbara Monika Mortimer UC Santa Barbara Sumitra Nair UCLA Sandip Niyogi UC Riverside Manuel Orosco UCLA Olivia Osborne UCLA Partha Patra Columbia Anton Pitts University of British Columbia

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Suman Pokhrel University of Bremen Philippe Saint-Cricq-Riviere UCLA Aditi Singhal UC Santa Barbara Elizabeth Suarez UCLA Yiming Su UC Santa Barbara Bingbing Sun UCLA Won Suh UC Santa Barbara Paul Teehan UC Santa Barbara Reginald Thio UC Santa Barbara Jason Townson University of New Mexico Jessica Trujillo University of Texas, El Paso Raja Vukanti UC Santa Barbara Xiang Wang UCLA Bing Wu UC Davis Bing Hui Wu UC Santa Barbara Haiyuan Zhang UCLA Lijuan Zhao University of Texas, El Paso Lijuan Zhao UC Santa Barbara Yang Zhao UCLA Graduate Students: Khadeeja Abdullah UCLA Adeyemi Adeleye UC Santa Barbara John Albino Columbia Hayley Anderson UCLA Suzanne Apodaca University of Texas, El Paso Barbora Bakajova UC Santa Barbara Susmita Bandyopadhyay University of Texas, El Paso Ana Barrios University of Texas, El Paso Lynn Baumgartner UC Santa Barbara Samuel Bennett UC Santa Barbara David Boren UCLA Terisse Brocoto University of New Mexico Olivier Brun UC Santa Barbara Benjamin Carr UC Santa Barbara Savanna Carson UCLA Chen Chen UC Riverside Eunshil Choi UCLA Kabir Chopra UCLA Indranil Chowdhury UC Riverside Kristin Clark UC Santa Barbara Jon Conway UC Santa Barbara Alyssa de la Rosa University of Texas, El Paso Laura De Vries University of British Columbia Juyao Dong UCLA Matthew Duch Northwestern University Paul Durfee University of New Mexico Daniel Ferris UCLA Janelle Feige UCLA Marina Feraud UC Santa Barbara Allison Fish UC Santa Barbara Emma Freeman UC Santa Barbara Kendra Garner UC Santa Barbara

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Sheetal Gavankar UC Santa Barbara Thomas Glaspy UCLA Linda Guiney Northwestern University Maria Isabel Hernandez University of Texas, El Paso Jose Hernandez-Viezcas University of Texas, El Paso Ryan Honda UC Riverside Jie Hong University of Texas, El Paso Carlin Hsueh UCLA Daniel Huang UC Santa Barbara Yuxiong Huang UC Santa Barbara Angela Hwang UCLA Annikka Jensen University of New Mexico Chitrada Kaweeteerawat UCLA Jun-Yeol Kim UC Santa Barbara Jacob Lanphere UC Riverside Anastasiya Lazareva UC Santa Barbara Kathryn Leonard UCLA Zongxi Li UCLA Zu Lu Li UCLA Monty Liong UCLA Dayu Liu UC Santa Barbara Haoyang Haven Liu UCLA Sanhamitra Majumdar University of Texas, El Paso Nikhita Mansukhani Northwestern University Catalina Marambio-Jones UCLA Tyronne Martin UC Santa Barbara Yufei Mao UCLA Suzanne McFerran UC Santa Barbara David McGrath UCLA Ilya Medina University of Texas, El Paso John Meyerhofer UC Santa Barbara Randy Mielke UC Santa Barbara Erving Morelius University of Texas, El Paso Arnab Mukherjee University of Texas, El Paso Loren Ochoa University of Texas, El Paso Abigail Padilla University of Texas, El Paso David Padilla University of New Mexico Julio Padilla University of Texas, El Paso Sudhir Paladugu UC Santa Barbara Trina Patel UCLA Satish Ponnurangam Columbia University Venkata Pullagurala Reddy University of Texas, El Paso Swati Rawat University of Texas, El Paso Cyren Rico University of Texas, El Paso April Ridlon UC Santa Barbara Michelle Romero-Franco UCLA April Sawvell UC Santa Barbara Corrinne Schmidger UC Santa Barbara Alia Servin University of Texas, El Paso Bion Sheldon University of New Mexico Sharona Sokolow UCLA Louise Stevenson UC Santa Barbara S. Drew Story UC Riverside

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Sirikarn Surawanvijit UCLA Carlos Tamez University of Texas, El Paso Wenjuan Tan University of Texas, El Paso Mengya Tao UC Santa Barbara Derrick Tarn UCLA Alicia Taylor UC Riverside Courtney Thomas UCLA Michael Tsang UCLA Jessica Twining UC Santa Barbara Laura Urbisci UC Santa Barbara Kari Varin UCLA Bill Vosti UC Santa Barbara Pria Vytla UC Santa Barbara Travis Waller UC Riverside Zoe Welch UC Santa Barbara Rebecca Werlin UC Santa Barbara Tristan Winneker UC Santa Barbara Kimberly Worsley UC Riverside Sijing Xiong Nanyang Technological University Min Xue UCLA Kristin Yamada UCLA Yafeng Zhang UCLA Yichi Zhang UC Santa Barbara Dongxu Zhou UC Santa Barbara Akanitoro Zuverza-Mena University of Texas, El Paso Undergraduate Students: Richard Abraham University of New Mexico Carola Acuro UC Riverside Nicolai Archuleta UC Santa Barbara Raul Armendariz University of Texas, El Paso Cindy Au UC Santa Barbara Yasmin Awad University of New Mexico Ana Cecilia Barrios University of Texas, El Paso Arielle Beaulieu UC Santa Barbara Nicole Beaulieu UC Santa Barbara Alex Besser UC Santa Barbara Daniel Bischoff University of Bremen Alexandra Bowers UC Santa Barbara Rebecca Britt Armenta University of Texas, El Paso Cameron Burgard University of New Mexico Lillian Burns UC Santa Barbara Cody Burr UC Davis Robert Burt UC Santa Barbara Alex Burton UC Riverside Lauren Bustamante University of New Mexico Ryan Capps UC Santa Barbara Kelly Carpenter UC Santa Barbara Bernice Chan UCLA Wai-Yin (Rhyn) Cheung UCLA Tim Chow UC Riverside Gwen Christiansen UC Santa Barbara Maia Colyar UC Santa Barbara

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Aaron Coyoca UC Riverside Stephen Crawford UC Santa Barbara Brian Cruz UC Riverside Jacob Dabrowski UC Santa Barbara Israel Del Toro University of Texas, El Paso Hao Diu UCLA Vivian Do UCLA Corrinne Dorias UC Santa Barbara Daniel Dunham UC Santa Barbara Kathlynne Duong UCLA Sahar El Abbadi UC Santa Barbara Tyler Eline UCLA Katharine Epler University of New Mexico Janel Feige UCLA Garth Fisher Santa Rose Junior College Austin Fullencamp UC Santa Barbara Aaron Fulton UC Santa Barbara Ryo Furukawa UCLA Charles Futoran UC Santa Barbara Fred Garcia University of New Mexico Jason Gehrke UC Santa Barbara Colton Gits Northwestern University Daniel Gold UC Santa Barbara Arjan Gower UC Santa Barbara Joseph Gramespacher UC Santa Barbara Briana Gray UC Santa Barbara Risa Guysi UC Riverside Edward Hadeler UC Santa Barbara Brittany Hall UC Santa Barbara Natalie Hambalek Sonoma State University Anthony Hearst UC Santa Barbara Trevin Heisey University of New Mexico Kai Henry UC Santa Barbara Rudolf Hergesheimer UC Santa Barbara Cecilia Herrera-Vega UCLA Elizabeth Horstman UC Riverside Rebecca Howard UC Santa Barbara Andy Hseuh UC Santa Barbara Edward Hu UC Santa Barbara Kevin Humphrey University of New Mexico Kevin Huniu UC Santa Barbara Avery Hunker UC Santa Barbara Emily Hurd UC Santa Barbara Sarah Hutton UC Davis Aaron Ibarra University of Texas, El Paso Igor Irianto UC Riverside Kenta Ishii UC Santa Barbara Matthew Jackson University of New Mexico Otto Janek University of Bremen Young Jeon UC Santa Barbara Natalie Johannes University of New Mexico Erica Johnson UC Santa Barbara Grace Kao UC Santa Barbara

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Rachel Ker UC Santa Barbara James Kim UC Riverside Peter Kim Northwestern University Soomin Kim UC Santa Barbara Kathryn Kleckner UC Santa Barbara Katherine Krattenmaker UC Santa Barbara Justine Ku UCLA Adeel Lakhani UC Santa Barbara Casey Leavitt UC Santa Barbara Andrew Lee UCLA Anson Lee UCLA Annabelle Lee UC Santa Barbara Claire LeMaitre UCLA Guan Hao Li UC Santa Barbara Joseph Liao UC Santa Barbara Leuh Yang Liao UCLA Erica Linard UC Santa Barbara Angela Liu UCLA Malina Loeher UC Davis Amanda Lokke University of New Mexico Corey Luth UC Riverside Wilson Mai UCLA Michael Maidaa UC Santa Barbara Ruben Martinez University of New Mexico Kristin Matulich UC Santa Barbara Ariel Miller UC Santa Barbara Brianna Miner UC Santa Barbara Josh Minster University of New Mexico Alex Moreland UC Santa Barbara Fabiola Moreno University of Texas, El Paso Ayse Muniz University of New Mexico Berenice Munos-Herrera University of Texas, El Paso Kaysha Nelson UC Santa Barbara Diego Noeva UC Riverside Ashley Noriega UC Santa Barbara Scott Obana UC Santa Barbara Michelle Oishi UCLA Ekene Oranu UC Santa Barbara Kathleen Pacpaco UC Santa Barbara Karmina Padgett Columbia University Leanne Paragas UCLA Calvin Parshad UCLA Scott Pease UC Santa Barbara David Pereira UC Santa Barbara Aaron Perez UC Santa Barbara Thomas Perez UC Santa Barbara Christopher Perry UC Santa Barbara Minhham Pham UCLA Nanetta Pon UCLA Kellie Pribble UC Santa Barbara Scott Pritchett UC Santa Barbara Alexander Prossnitz University of New Mexico Ingmar Prokop UC Santa Barbara

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Clarisse Rangel UC Riverside Sarah Rathbone UC Santa Barbara Alden Reviere University of New Mexico Raquel Ribeiro UCLA Niki Rinaldi UC Santa Barbara Brandon Rogers UC Riverside Gabriel Rubio UC Santa Barbara Paige Rutten UC Santa Barbara Jenna Rydz UC Santa Barbara Michael Salazar University of New Mexico Cynthia Sanchez UC Santa Barbara Katherine Santizo UC Santa Barbara Patricia Schultz University of Bremen Jacqueline Sheng UCLA Esther Shin UC Davis Christianna Sim UC Santa Barbara Allen Situ UCLA Kristine Sommer UC Santa Barbara Helaine St. Amant Santa Rosa Jr. College Amy Stuyvesant UC Santa Barbara Allen Taing UCLA Alejandro Tafoya University of Texas, El Paso Tiffany Takade UC Santa Barbara Tony Tharakan Columbia University/GWU Ryan Tjan UC Santa Barbara Stephen Tjan UC Santa Barbara Christine Troung UCLA Nancy Tseng UC Santa Barbara William Ueng UCLA Ryan Utz UC Santa Barbara Jesus Valdez UCLA Jose Valle UC Riverside Danielle Vallone UC Santa Barbara Colin Van Zandt UC Santa Barbara Peter Voong UC Santa Barbara Ashley Watchell UC Santa Barbara William Wellman UC Riverside Daniel White UC Riverside Brian Wilkinson University of New Mexico Dan Wilkinson University of New Mexico Christina Wong UCLA Bobby Wu UCLA Edward Wyckoff University of New Mexico Maria Yepez UC Santa Barbara Kevin Young UC Santa Barbara Xuechen Yu UCLA Melanie Zecca UC Riverside High School Students (Interns): Sherya Banerjee UC Santa Barbara Akanitoro Brown Columbia University Jose Clement University of New Mexico Anirudh Dayal UC Santa Barbara

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Christina Gerges UC Riverside Sean Hagerty University of Texas, El Paso Jeremy Hutton UC Santa Barbara Jessica Nelson University of New Mexico Courtney Kwan UC Santa Barbara Ashley Wachtell UC Santa Barbara Staff/Administration: David Avery UCLA Colleen Callahan UCLA John Chae UCLA Mariae Choi UCLA Anna Davison UC Santa Barbara Julie Dillemuth UC Santa Barbara Kristin Duckett UC Santa Barbara Meghan Horan UCLA Vi Tuong Huynh UCLA Catherine Nameth UCLA Elina Nasser UCLA Nancy Neymark UCLA Jeri O'Mahoney UC Santa Barbara Stacy Rebich-Hespana UC Santa Barbara Leslie Sanchez UC Santa Barbara Kathleen Scheidemen UC Santa Barbara Benjamin Trieu UCLA Cristina Wilson UC Santa Barbara Affiliated Participants, Not Receiving Center Support Faculty: Carolyn Bertozzi UC Berkeley/Lawrence Berkeley Lab Professor, Chemistry, Molecular/Cell Biology Gretchen Bielmyer Valdosta State University Associate Professor, Ecotoxicology Freddy Boey Nanyang Technological University Professor, Materials Science Engineering Kenneth Dawson University College Dublin Professor, Physical Chemistry Francesc Giralt Universitat Rovira I Virgili Professor, Chemical Engineering Jordi Grifoll Universitat Rovira I Virgili Associate Professor, Chemical Engineering Joachim Loo Nanyang Technological University Associate Professor, Materials Engineering Nick Pidgeon Cardiff University Professor, Applied Psychology Graduate Students: Xinxin Zhao Nanyang Technological University External Science Advisory Committee Pedro Alvarez Rice University Professor, Engineering Ahmed Busnaina Northeastern University Professor, Engineering; Director, HRNM Sharon Dunwoody University of Wisconsin-Madison Professor, Journalism/Mass Communication Menachem Elimelech Yale University Professor, Chemical Engineering C. Michael Garner Garner Nanotechnology Solutions Nanotechnology Consultant James Hutchison University of Oregon Professor, Assoc. VP, Research Agnes Kane Brown University Professor, Pathology & Laboratory Medicine Fred Klaessig Pennsylvania Bio Nano Systems Marc Lafranconi Tox Horizons Consultant and CEO Terry Medley DuPont Global Director, Corporate Global Affairs Julia Moore Woodrow Wilson International Center Deputy Director, PEN

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Kent Pinkerton UC Davis Director, Center for Health/Environment Rick Pleus Intertox Managing Director/Toxicologist David Rejeski Woodrow Wilson International Center Director, PEN Omowunmi Sadik SUNY Binghamton Professor, Chemistry Ron Turco Purdue University Professor, Agronomy Isiah Warner Louisiana State University Professor, Environmental Chemistry Jeff Wong Department of Toxic Substances Control Retired, Deputy Director, Science Paul Zimmerman Intel Program Manager, External Programs Academic Participating Institutions Cardiff University Centro de Investigacion y de Estudios Avanzados del Instituto Politechnico Nacional (CINVESTAV) Columbia University Instituto Nacional de Salud Publica (INSP) Nanyang Technological University Northwestern University Universitat Rovira I Virgili Santa Clara University University of Arizona University of Birmingham University of Bremen University of British Colombia University of California, Los Angeles University of California, Santa Barbara University of California, Davis University of California, Riverside University College Dublin University of New Mexico University of Texas, El Paso Non Academic Participating Institutions California Science Center Environmental Protection Agency, Computational Toxicology Program Lawrence Berkeley National Laboratory Lawrence Livermore National Laboratory National Institute of Occupational Safety and Health (NIOSH) National Institute of Standards and Technology (NIST) Sandia National Laboratory Santa Monica Public Library

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Table 1: Quantifiable Outputs

Outputs

Reporting Year -4 Reporting Year -3 Reporting Year -2 Reporting Year -1 Reporting Year

Total

Publications that acknowledge NSF NSEC Support

48 45 72 71 74 310

2 0 2 1 2 7

2 0 0 1 0 3

50 45 74 73 76 318

Multiple Authors: Co-Authored with NSEC Faculty 50 45 74 73 76 318

Publications that do not acknowledge NSF NSEC Support

In Peer-Reviewed Technical Journals 0 0 0 0 0 0

NSEC Technology Transfer

0 0 0 0 0 0

0 0 0 0 1 1

0 0 0 0 0 0

0 0 0 0 0 0

0 0 0 0 0 0

0 0 0 0 0 0Degrees to NSEC Students

3 4 0 2 4 13

1 3 4 1 2 11

2 1 13 3 5 24

NSEC Graduates Hired by

1 0 3 4 3 11

NSEC Participating Firms 0 0 0 0 0 0

Other U.S. Firms 1 0 3 4 3 11

1 2 3 0 2 8

0 3 8 5 1 17

0 0 0 0 0 0

0 0 0 0 1 1

NSEC Influence on Curriculum (if applicable)

2 1 1 0 0 4

3 3 7 14 21 48

0 0 0 0 0 0

18 13 0 0 1 32

0 0 0 0 0 0

0 0 0 0 0 0

0 0 0 0 0 0Information Dissemination/Educational Outreach

1 0 3 1 1 6

2 1 0 1 4 8

185 198 212 222 138 955

2 1 2 0 0 5

Software Licensed

Master's Degrees Granted

Workshops, Short Courses to Others

New Courses Based on NSEC Research

Doctoral Degrees Granted

Industry

Government

Academic Institutions

Other

Bachelor's Degrees Granted

Seminars, Colloquia, etc.World Wide Web courses

Courses Modified to Include NSEC Research

New Textbooks Based on NSEC Research

Free-Standing Course Modules or Instructional CDs

New Full Degree Programs

New Degree Minors or Minor Emphases

New Certificate

Workshops, Short Courses to Industry

In Peer-Reviewed Technical Journals

In Peer-Reviewed Conference Proceedings

In Trade Journals

Unknown

With Multiple Authors

Inventions Disclosed

Patents Filed

Patents Awarded

Patents Licensed

Spin-off Companies Started (if applicable)

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6. Mission, Significant Advances, and Broader Impacts The mission of the University of California Center for Environmental Implications of Nanotechnology (UC CEIN) is to use a multidisciplinary approach to conduct research, knowledge acquisition, education and outreach to ensure the responsible use and safe implementation of nanotechnology in the environment. This will enable the USA and International communities to leverage the advantages of nanotechnology to the benefit of the global economy, society and the environment. This mission is being accomplished by the development of environmental decision making tools that consider the importance of engineered nanomaterial (ENM) physicochemical properties in determining environmental fate, transport, exposure, and hazard generation across a wide spectrum of nano/bio interfaces in cells, bacteria, organisms, communities and ecosystems. The Center makes use of well-characterized compositional and combinatorial ENM libraries to study their fate and transport in parallel with the materials' bioavailability and potential to engage toxicological pathways in organisms and environmental life forms. Where possible, this exploration involves high throughput screening (HTS) to explore structure-activity relationships (SARs) that can be used for prediction making of primary ENMs' impact on organisms in freshwater, seawater, and terrestrial environments. In silico data transformation and decision-making tools are involved in data integration to provide hazard ranking, exposure modeling, risk profiling, and construction of nano-SARs. These research activities are combined with educational and outreach programs that inform the public, students, federal and state agencies, as well as industrial stakeholders of the impact of CEIN’s research on the safe implementation of nanotechnology in the environment. The research of the UC CEIN is carried out by 29 distinct but interactive research projects (supported by 4 service cores) across seven interdisciplinary research themes and our education/outreach program:

• Theme 1: Compositional and Combinatorial ENM Libraries for Property-Activity Analysis • Theme 2: Molecular, Cellular, and Organism High-Throughput Screening for Hazard Assessment • Theme 3: Fate, Transport, Exposure, and Life Cycle Assessment • Theme 4: Terrestrial Ecosystems Impact and Hazard Assessment • Theme 5: Marine and Freshwater Ecosystems Impact and Toxicology • Theme 6: Environmental Decision Analysis for ENMs • Theme 7: Using UC CEIN Knowledge Generation to Engage and Impact Multiple Stakeholders • Theme 8: Education, Career Development, Knowledge Dissemination, and Interactive Efforts

Through the pursuit of interdisciplinary, predictive and high throughput approaches, the UC CEIN has made, and will continue to make, a transformative impact on nano EHS assessment. The cornerstone of this impact is our ability to acquire and synthesize ENM libraries, which are assessed in an interdisciplinary approach by high throughput and facilitative test strategies that inform about nanomaterial exposure and hazard across a broad range of nano/bio interfaces, from cells to ecosystems. Coupled with our computational analysis tools and fate and transport modeling, this allows environmental impact analysis of broad material categories, including the use of this information for safety assessment, safer design and regulatory decision-making. Over the past year, key Center highlights include: The synthesis, design, and acquisition of compositional and combinatorial ENM libraries as well as nano-enabled commercial products by Theme 1 is continuing to expand CEIN’s list of materials to understand the role of the physicochemical properties of ENMs in hazard generation and exposure, also with a view to use the SARs for safer design. Major progress over the last 12 months has been:

• Improved understanding of the role of the electronic structure of ENMs in hazard generation, as defined by the band gap and Fermi energy levels of metal oxide nanoparticles, which was demonstrated by the creation of heterojunctions through Pd-doping and being able to demonstrate

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that band gap bending and the catalysis of cellular redox reactions can induce Biological oxidative stress, which also translates into pro-inflammatory responses in vivo.

• We are interested in the role of metal oxide dissolution in hazard generation by a specific group of highly soluble materials, such as CuO, which forms the basis of one of the Center’s cross-disciplinary working groups (Cu Working Group). We introduced a library of CuO nanoparticles that were doped with Fe ions to change the dissolution characteristics, and therefore helpful for comparative analysis with commercial nano-Cu used as a pesticide for studying the impact on zebrafish embryos, as reported in Project 2.

• Acquisition of ionic, nano and micron scale III-V materials to launch studies clarifying the potential environmental impact of the slurries generated during the chemical-mechanical planarization process for the synthesis of industrial semiconductor materials. We have performed physicochemical characterization, and will soon commence biological testing.

• New variants of highly pure and dispersible nanoparticles were provided across themes to allow for detailed studies to understand the effect of crystal structures (polymorphs of Fe2O3), unpaired electrons (Pd and PdO) and nanocopper (Cu and CuO) on biological responses.

• To further understand the role of electronic and crystal structure effects on ZnO, a library of Al doped ZnO was synthesized: electron-hole interactions at defect sites were more important than dissolution in decreasing toxicity. Additionally, internal defects and ring structures within materials are also important.

• Synthesis of a doped fumed silica library to determine whether Al and Ti doping can decrease the siloxane ring structure and surface display of toxic soluble groups that can lead to biological membrane disruption and the generation of pro-oxidative and pro-inflammatory responses. We have shown that doping decreases the surface reactivity and prooxidative effects of the newly designed fumed silica nanoparticles.

Theme 2 is continuing the development of predictive toxicological paradigms that are related to a constellation of ENMs physicochemical properties, allowing the materials to engage cellular, bacterial and zebra fish adverse outcome pathways (AOP) that leads to biological injury, in which the AOP could be involved in the pathogenesis of disease, thereby allowing hazard ranking and tiered risk assessment analysis. Major progress over the last 12 months has been:

• Utilizing PdO doping of Co3O4, we were able to generate Heterojunctions leading to the band gap bending and tuning of Fermi levels that lead to abiotic generation of oxygen radicals as well as quantifiable changes in cellular redox potential to develop a predictive toxicological paradigm for oxidative stress. We demonstrated that the specific adjustment of bandgap and Fermi energy levels by the p-type semiconductor nanoparticles play a role in the generation of biological oxidative stress and acute inflammation in the murine lung. This study complements the previous research on 24 metal oxide nanoparticles, which demonstrate that the bandgap profiling of specific materials can be used to predict toxicological potential.

• The data generated with 24 MOx’s in mammalian cells could be duplicated in E. coli gown in minimal tropic media. The growth inhibition in key MOx materials correlated with assays assessing bacterial membrane damage and conduction band energy levels with biological outcome, indicating the mechanisms of MOx toxicity are consistent across taxonomic domains.

• We have previously demonstrated that long aspect ratio ENMs that induce lysosomal injury and activation of the NRLP3 inflammasome pose biological hazard by inducing chronic inflammation. Over the last year, we have demonstrated that the ability of rare earth oxide or rare earth doped upconversion nanoparticles to complex with structural and functional biological phosphate groups, also trigger lysosome damage and inflammasome activation, and demonstrated that surface

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passivation of these particles through interaction with phosphate residues under neutral pH may constitute a safer by design approach.

• The use of zebrafish embryos for high content screening has allowed the UC CEIN to study the speciation of pristine and commercial Cu and CuO nanoparticles in a simulated septic tank system in collaboration with Project 3. We demonstrated that the dissolution and complexation of Cu by natural organic material decreases the bioavailability of Cu ions to the zebrafish hatching enzyme, resulting in the new commercialization of the hatching inhibition effect of these materials. This model to approach using the zebrafish embryo as a screening tool, has allowed us to be able to make predictions about the possible impact of nano-Cu on aquatic toxicity without the need for direct particle imaging. This novel use of zebrafish screening procedures will be extended to Theme 5 where zebrafish embryo HTS will be used to study the impact of semiconductor slurries containing potentially toxic III-V ionic and particulate materials.

• We have developed nanowire field-effect transistors for lab-on-a-chip detection of cytokines and cellular biomolecules which can be implemented for the development of highly sensitive screening assays.

Theme 3 is providing information about ENM fate and transport, releases to air, soil and water, Life Cycle Assessment (LCA) and estimation of environmental exposure concentrations on which to base the experimental design of studies in Themes 2, 4 and 5:

• Detailed LCA allows for the prediction of annual mass release of ENMs to various environmental compartments (air, water, soils) to assist prediction of environmental concentrations at the regional and local level. As one example, the predictions about spread of nano-Cu to waste water treatment plants have led to the design of the septic tank modeling system and experiments on zebrafish described above. LCA is also assisting the Carbonaceous Working Group in their selection of most relevant C-based ENMs for experimental studies, based on production volumes and intended applications. The material flow analysis model has been incorporated into the web-based open access framework developed by Theme 6.

• The fate and transport of three types of Cu ENMs in aquatic (rivers, estuaries, coastal waters) and terrestrial (soils) is strongly influenced by the presence of natural organic matter, as demonstrated in the zebrafish study, as well as the production of exopolymeric substances by phytoplankton, which affects Cu nanoparticle aggregation and dissolution rates in the estuarine mesocosms.

• Cu ENMs and graphene oxide sheets were found to be strongly retained in soils, making them less bioavailable and mobile, which helps to design plant exposure experiments.

• In wastewater treatment experiments, most Cu ENMs had minor effects on the treatment process, and in collaboration with Theme 2 Cu particles that were treated through the wastewater system were found to have no toxicity to zebrafish upon exposure.

Theme 4 is delivering a new understanding of MNM hazards in the terrestrial environment, including how to assess and predict impacts to microbes, how food production and food quality are susceptible to MNMs, and how to mitigate agricultural impacts. The major impacts of Theme 4 research over the last twelve months are:

• Using an assay system that we previously developed for screening NM toxicity to environmentally relevant bacteria, we discovered that slow-dissolving cysteine-capped Ag nanoparticles inhibited bacterial growth from Ag+ ion-mediated ROS accumulation causing membrane damage. A related collaborative Theme 2-led study screened impacts of 24 MOx NPs to E. coli, discovering that growth inhibition scaled with band-gap and hydration energies, mirroring effects and mechanisms discovered previously in the UC CEIN (Theme 2) for mammalian cells.

18


• We discovered that Ag+ ions (from dissolving Ag NMs), but not TiO2 NMs, inhibited polyhydroxybutyrate accumulation by wastewater treatment plant (WWTP) activated sludge bacteria involved in biological P removal.

• We demonstrated nCeO2, following either uptake through cucumber leaves or roots and translocation throughout the plant, caused root and leaf oxidative stress. nCeO2 exposure also changed plant nutritional quality, as it did for corn, wheat, and soybean . Overall, a broad range of food plants (including radish, and bush bean) were shown to be sensitive to nano-ceria according to plant yield and food quality, with effects varying by plant and NP dose. Additionally nCeO2 was trophically transferred from soil-grown zuchinni through insect herbivores to insect predators in a terrestrial food web. We discovered that growth, chlorophyll content, and antioxidant activity were reduced in green peas grown with nano-ZnO, but that Fe-doping nano-ZnO decreased such impacts as well as Zn uptake into plants. We discovered that Cu-NPs exerted similar effects as Cu-salts when evaluating growth but accumulation of some nutrients was species driven in alfalfa and lettuce.

• We discovered that, likely via plant-mediated effects on belowground carbon allocation, soybean plants reduced the effects of ZnO MNMs, but increased the impacts of CeO2, on soil microbial communities; this reinforces that NM ecosystem impacts likely derive from complex biophysical interactions.

• A new Dynamic Energy Budget (DEB) model was developed to predict time-course ROS generation, by NMs and through normal metabolism, and to include feedbacks from cellular repair processes that scavenge ROS yet are in turn subject to damage. This model will have broad utility across the CEIN. An additional conceptual model for DEB parameterization was developed for predicting bacterial and symbiotic N2 fixation under the influence of NM-enhanced reactive oxygen and nitrogen species (RONs).

• Carbonaceous NMs (MWCNTs, carbon black, graphene) were characterized and used in soil, bacterial, and protozoan exposures, revealing differential impacts for foundations in designing trophic transfer and mesocosm studies in the next period.

• Theme 4 (with Theme 7) critically evaluated “environmental relevance” in nanotoxicology by extracting exposure concentrations for < 600 published hazard assessments, and juxtaposing against those predicted or measured to conclude recommended future exposure regimes.

Theme 5 examines the impacts of ENMs on aquatic ecosystems using sentinel organisms in novel HCS platforms, microcosms, and mesocosms. Over the past year, research highlights include:

• Phytoplankton HCS assessment of numerous cytological effects caused by high volume nano-metals in the CEIN library showed that ROS damage of phytoplankton mitochondrial membrane function was linked to reduced photosynthetic efficiency and reduced population growth. Toxicity of metal and metal oxide ENMs (e.g., ZnO, CuO, CeO2, nano-Ag) was closely related to dissolution rates. Phytoplankton HCS protocols are now being expanded into a routine assessment tool.

• ENM rankings from phytoplankton HCS were used to predict impacts at higher levels of biological organization, such as phytoplankton population growth.

• HCS platform based on hemocytes (primary immune cells for invertebrates that protect against pathogens) of mollusks was developed. Results indicated that ZnO, CuO, nano-Ag, and single-walled Carbon nanotubes damaged hemocytes, and thus impaired mussel and oyster immune system functioning through reduced phagocytosis. However, impacts were observed only at relatively very high concentrations (1-5 ppm in seawater).

• Established impacts of graphene and metal oxide nanomaterials on multidrug resistance transporters in both marine embryos (herring and sea urchins) and mammalian cells.

19


• During early development in sea urchins, the fertilization envelope protects the developing embryo from particulate metal oxide nanomaterials but not dissolved ions.

• Metal ions inhibit the freshwater zebrafish hatching enzyme, but no effect on hatching was observed for marine fish (Pacific herring) or sea urchin embryos, suggesting differences in responses between aquatic environments.

• Designed and constructed a mesocosm system at the UC Davis Bodega Marine Laboratory (BML) that will be used to test impacts of a subset of the CEIN ENM library on sentinel estuarine organisms.

• Long-term (complete life cycle) experiments on the effects on the model organism Daphnia of simultaneous food stress and exposure to Ag nanoparticles – critical data for DEB model of freshwater plankton communities.

• Developed a new DEB-based model of zebrafish hatching. • Demonstrated the effect of exposure to TiO2 on the sinking rate of phytoplankton cells and on

marine snow, important processes for marine carbon cycling. • Estimated leaching rates of six types of marine nano-based antifouling paint in the laboratory to

predict effects in a field experiment designed to test effects of nano-paints on marine ecosystems and inform California regulatory agencies.

Theme 6 is engaged in the development of an advanced modeling platform for environmental impact assessment (EIA) of nanomaterials and case studies to elucidate these potential impacts. Theme 6 utilizes machine learning and statistical methods to analyze large quantities of ENM toxicity data to develop hazard ranking. Key accomplishments over the last year include:

• A methodology was developed for nano-(Q)SAR development that makes use of a support vector machine (SVM) technique along with a sequential forward floating selection (SFFS) to identify the relevant QSAR descriptors and applicability domain. The above approach was applied to arrive at new and highly accurate toxicity QSARs for surface-modified iron-oxide NPs and gold NPs with various surface ligands. In addition, a highly accurate QSAR was developed for bacterial toxicity of metal oxide, in collaboration with Theme 2, demonstrating significant correlation of toxicity with metal ion hydration enthalpy and NP conduction band energy.

• A meta-analysis approach was developed (with Theme 2) based on random forest machine learning technique and utilized to arrive at a comprehensive evaluation of the body of evidence (integrating categorical and quantitative data) regarding the toxicity of quantum dots, based on 1,741 QD toxicity data samples extracted from over 300 published studies. This study revealed that QD toxicity closely correlated with the NP properties (including shell, ligand, and surface modifications), diameter, assay type, and exposure time.

• A visual data analytics approach was developed in collaboration with Theme 4 and applied to explore the impact of ZnO and TiO2 NPs on soil bacterial communities. Significant compositional changes in soil bacterial communities, due to exposure to high doses of ZnO and TiO2 NPs, was readily identified. Direct visualization enabled rapid identification of the interrelationships between exposure to NPs and response of bacterial taxa, with the family level being particularly suitable level for NP impact assessment.

• A web-based model of the environmental multimedia distribution of nanomaterials (MendNano) has been completed, validated and utilized to assess both the potential environmental ENMs exposure concentrations and as a teaching tool in undergraduate/graduate course on environmental impact assessment. The utility of this tool has led to quantification of potential exposure levels for various nanomaterials in different regions. Such information is directly relevant to guiding experimental toxicity studies (with respect to establishing relevant exposure levels) and as a support tool for environmental impact assessment.

20


• A LCA for the Release of Nanomaterials (LearNano) was developed (in collaboration with Theme 3) as both a stand-alone web-based model and as part of an integrated platform with MendNano to rapidly estimate the potential release and environmental distribution of nanomaterials (RedNano) and thus estimate potential ENMs exposure concentrations. With the above modeling tool the potential releases of ENMs was evaluated for a range of materials and regions for a wider range of scenarios, thereby providing direct input to MendNano to assess the multimedia distribution and exposure associated with ENMs.

• The collection of computational tools for analysis of NPs toxicity data, fate and transport analysis and decision analysis support tools were integrated as part of a new nanoinformatics web-portal (www.nanoinfo.org).

Over the past year, the UC CEIN continued to expand its science translation and outreach efforts to multi-stakeholder communities (Theme 7). The knowledge and approaches generated in the UC CEIN are being used to engage national and international thought leaders in the areas of nano EHS policy, governance, and anticipatory decision making. In May 2014, we convened a two-day roundtable workshop entitled Categorization Strategies for Engineered Nanomaterials in a Regulatory Context at the Woodrow Wilson Center in Washington, DC, bringing together 42 national and international leaders from government, industry, academia, and NGOs to discuss ENM categorization, grouping, ranking, and read-across strategies for testing, evaluation, decision, analysis, risk guidance, and regulation. The workshop resulted in an ACS Nano Perspectives article on the use of categorization to facilitate regulatory decision making. Theme 7 also conducts research on new or existing policy models, providing critical feedback on how regulatory agencies can respond to new and emerging data on ENMs. As the result of a visit to legislative representatives in December 2013, on their request an analysis of the Chemical Safety Improvement Act was prepared for legislators suggesting how to better incorporated Alternative Test Strategies (ATS) into the regulatory framework. A manuscript has been submitted analyzing TSCA tracking the historical use of ATS in TSCA decision making and highlight potential opportunities for ATS incorporation. UC CEIN has had markedly increased their efforts for translating the scientific discovery and methodologies in the Center into practical tools and outputs that can be used by industry and the regulatory community. Industry representatives have actively participated in open discussions about the utility of ATS approaches for hazard assessment, and several companies will participate in our ongoing study to validate the use of ATS to predict the in vivo hazard of CNTs, with a view to using this tool for material categorization and assistance of regulatory decision-making. Our faculty continues to participate in high profile international scientific and policy forums to disseminate our research advances to a broad audience. A major goal of the UC CEIN Education Program (Theme 8) is to train the next generation of nano-scale scientists, engineers, and policy makers and to develop a comprehensive workforce to assist in the safe implementation of nanotechnology for the benefits of society, the environment and our economy. Our programs are developed to ensure the science performed and the discoveries made within the Center are levered to serve broader societal needs. The activities of our education and outreach team has had a a considerable impact on knowledge development and dissemination in the area of Environmental Nanotechnology, designing programs that foster collaborative interdisciplinary science, advance discovery and understanding while promoting teaching training and learning, mentor students and postdocs. This includes the participation of underrepresented groups in the sciences. In partnership with Science Buddies, we develop science fair projects for middle school students based on research generated in the Center. The first project, Tiny Titans: Can Silver Nanoparticles Neutralize E. coli Bacteria, was made publicly available and has been accessed over 11,000 times. A second science fair project based exploring the effects of nanosilver on the life stages of Daphnia (based on research in Theme 5) is currently under development. Additionally, the Center is currently designing and implementing a research-based laboratory module for undergraduate chemistry classes based upon the high throughput screening assays used within the CEIN.

21


The module, piloted at Santa Clara University, will be made publicly available upon evaluation and presentation at this year’s High Impact Technology Exchange Conference. The Center has greatly enhanced the professional development opportunities for graduate students and postdoctoral researchers within our Center, as we build a cohesive and interdisciplinary environment for science and education. We regularly engaged the public in settings such as science museums and public libraries to inform them of our work. We make concerted efforts to involve minority institutions, including the recruitment of minority faculty and students. We have four Hispanic serving institutions as core partners in our Center, and are working to incorporate strategies for promoting diversity and inclusion and underrepresented minorities into all of our educational activities.

22

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etal

. 201

4. E

S&

T

NSF

: DBI‐1

2663

77


32

NSF

: DBI‐1

2663

77

Interaction of M

NMswith

Plan

ts: Effects on

yield and

nu

trition

al qua

lity


33

NSF

: DBI‐1

2663

77

Cytotoxic effects in High Co

nten

t Screen

ing pred

ict p

opulation

impa

cts for m

arine ph

ytop

lankton

Objectiv

e:Li

nk c

ellu

lar t

oxic

ity o

f en

gine

ered

nan

omat

eria

ls(E

NM

s) in

Hig

h Co

nten

t Sc

reen

ing

(HCS

) ass

ays t

o ec

olog

ical e

ffect

s at t

he

popu

latio

n le

vel (

in m

esoc

osm

s)

Find

ings:

•M

etal a

nd m

etal o

xide

EN

Ms i

nduc

e m

ultip

le

cyto

toxi

c in

jurie

s at 0

.1‐1

0 m

g L‐

1 (p

pm)

conc

entr

atio

ns;

•Cy

toto

xic

inju

ries p

redi

cted

po

pula

tion

grow

th e

ffect

s;•

Cyto

toxi

c m

echa

nism

s di

ffer f

or d

iffer

ent E

NM

s;•

HCS

scre

ens e

ffect

ive

in

first 2

4 hr

s;•

Agin

g of E

NM

s red

uced

cy

toto

xici

ty, i

ndic

atin

g re

duce

d to

xici

ty p

oten

tial

in n

atur

e;•

HCS‐

to‐p

opul

atio

n st

udie

s w

ith p

hyto

plan

kton

refle

ct

bact

eria w

ork

in T

hem

e 4

Robert M

iller, B

ryan

Cole, H

unte

r Len

ihan

, & G

ary

Che

rr, U

CS

B &

UC

Dav

is


34

NSF

: DBI‐1

2663

77

Develop

men

tal toxicity

of

nano

‐CuO

in se

a urchin

(Lytechinu

s pictus) embryos

Cristina Torres Dua

rte & Gary Ch

err,UC Da

vis

Objectiv

e:Te

st e

ffect

s of n

ano‐

CuO

expo

sure o

n em

bryo

nic

deve

lopm

ent i

n se

a ur

chin

s in

96 h

rmic

roco

sm e

xper

imen

ts

Find

ings:

•To

xic

resp

onse to

Cu

met

als

obse

rved

as d

isrup

tion

of th

e de

velo

pmen

tal a

xis;

•Cu

ions fr

om m

icro‐c

onta

min

ant

CuSO

4 m

ore

toxi

c th

an n

ano‐

CuO

form

s, d

ue to

hig

h di

ssol

utio

n ra

te;

•Pu

rifie

d na

no‐C

uOha

s a h

ighe

r di

ssol

utio

n ra

te, h

ighe

r sur

face

area

, and

a h

ighe

r zet

a po

tent

ial

than

com

mer

cial n

ano‐

CuO

, fac

tors

that c

an c

ontr

ibut

e to h

ighe

r to

xici

ty;.

•Cu

acc

umul

atio

nin e

mbr

yos a

nd

oxid

ativ

e da

mag

e (t

otal a

ntio

xida

nt

capa

city

) cau

sed

by n

ano‐

CuO

not

expl

aine

d by

am

ount o

f sol

ubili

zed

Cu;

•Hy

poth

esis: C

u N

Ps a

re in

tern

alize

d,

and

once in

side

the

embr

yos,

diss

olve c

reat

ing

copp

er “

hot‐

spot

s” th

at c

ause si

gnifi

cant

oxid

ativ

e da

mag

e.


35

NSF

: DBI‐1

2663

77

Mesocosm

expo

sure to

Nan

o‐Cu

Oinjures k

illifish and

impa

irs

osmoregulation

Jeffe

ry M

iller, A

ndrew W

hitehead

, & Gary Ch

err, UC Da

vis

Objectiv

e:Te

st e

ffect

s of C

uOen

gine

ered

nan

omat

eria

ls(E

NM

s) o

n os

mor

egul

atio

n in k

illifi

sh u

sing

estu

arin

e m

esoc

osm

syst

em w

ith

vary

ing

salin

ity

Find

ings:

•Ex

posu

re to

CuO

ENM

s ca

uses g

ill ti

ssue

da

mag

e an

d in

flam

mat

ion, a

nd

redu

ces e

nzym

atic

activ

ity (N

a/K

ATPa

se);

•Im

pact

s of C

uOEN

Ms

due

to n

anop

artic

le

effe

cts

not i

onic e

ffect

;•

Gill im

pairm

ent

com

prise

s ab

ility to

ad

apt t

o sa

linity

ch

ange

s;•

Salin

ity c

halle

nged

fish

expo

sed

to n

ano‐

CuO

NPs lo

ose

plas

ma

chlo

ride

hom

eost

asis


36

NSF

: DBI‐1

2663

77

Expo

sure to

nan

o‐Silver

enha

nces pop

ulation im

pacts o

f food

scarcity

in Dap

hnia

Louise Stevenson

& Rog

er Nisb

et, U

C Santa Ba

rbara

Objectiv

e:Te

st in

tera

ctiv

e ef

fect

s of

expo

sure to

nan

o‐Si

lver a

nd fo

od

limita

tion

on th

e re

prod

uctio

n of

Daph

nia

in a

quat

ic m

esoc

osm

s

Find

ings:

•Da

phnia

repr

oduc

tion

high

ly

sens

itive to

phy

topl

ankt

on

avai

labi

lity;

•Ex

posu

re to

nan

o‐Ag

at o

nly

low p

arts p

er b

illio

n co

ncen

trat

ions su

bsta

ntia

lly

enha

nced

effe

cts o

f foo

d lim

itatio

n;•

Effe

cts

on Dap

hnia o

bser

ved

as in

crea

sing

varia

bilit

y in

repr

oduc

tion

thro

ugh

time

(0‐4

0 da

ys);

•Da

phnia

usua

lly li

ves o

n th

e ed

ge in

term

s of r

esou

rce

avai

labi

lity, so

exp

osur

e to

smal

l am

ount

s of E

NM

s ca

n ha

ve la

rge

effe

cts;

•Ef

fect

s no

w b

eing

mod

eled

w

ith D

EB m

odel

s.


37

A Web

‐Based

Platform fo

r EN

Ms Environm

ental Impa

ct

Assessmen

t (EIA)

NSF

: DBI‐1

2663

77

http

://w

ww

.nan

oinf

o.or

g


38

Envi

ronm

enta

l Im

pact

Asse

ssm

ent

Data M

inin

g

CEIN Nan

oDatab

ank, Data

Analytics a

nd Nan

oEHS

Decision Supp

ort Too

ls

Phys

icoc

hem

ical

char

acte

rizat

ion,

toxi

city d

ata

HTS

ENM

s ex

perim

enta

l da

ta

Lite

ratu

re m

ined

to

xici

ty d

ata

Biol

ogic

al

Resp

onse

Data st

orag

e, R

etrie

val

Inpu

t raw

Dat

a, c

ondu

ct d

etai

led

anal

ysis, sh

are

findi

ngs

(usin

g di

ffere

nt se

ttin

gs) u

sing

Cent

raliz

ed N

anod

atab

ank

ENM u

sers

Man

ufac

ture

rs

Regu

lato

rs

Rese

arch

ers

NSF

: DBI‐1

2663

77

http

://w

ww

.nan

oinf

o.or

g


39

Stakeh

olde

r Engagem

ent:

ENM Categorization

Engagemen

t of A

cade

mia, Ind

ustry, and

NGOs in Two

Day W

orksho

p on

ENM Categorization (M

ay 201

4)

Disc

ussio

non

how

data

from

alte

rnat

ive

test

ing

stra

tegi

es(A

TS)

can

beus

edto

faci

litat

eEN

Mca

tego

rizat

ion

toris

kpo

tent

ial

and

how

such

anap

proa

chco

uld

faci

litat

ere

gula

tory

deci

sion‐

mak

ing

inth

efu

ture

.

Cate

goriz

atio

nst

rate

gies

are

need

edto

allo

wre

gula

tors

and

indu

stry

topr

edic

tEN

Mris

kan

dto

prio

ritize

the

leve

lof

test

ing

(haz

ard,

expo

sure

,ph

ysic

oche

mic

al)

need

edto

estim

ate

pote

ntia

lris

kw

hile

min

imizi

ngtim

e‐co

nsum

ing

and

cost

lyin

vivo

stud

iest

hatc

hara

cter

izetr

aditi

onal

risk

asse

ssm

ent

Insights on Cu

rren

t Utility

of C

ategorization of ENMs :

•Ph

ysic

oche

mic

alpr

oper

ties

notc

urre

ntly

suffi

cien

tfor

ENM

cate

goriz

atio

nfo

rreg

ulat

ory

purp

oses

•Ca

tego

rizat

ion

met

hods

for

regu

lato

rypu

rpos

essh

ould

incl

ude

indi

cato

rsof

haza

rdan

dex

posu

repo

tent

ial

•AT

Sm

aypr

ovid

eus

eful

mea

nsfo

rex

pedi

ted

haza

rdsc

reen

ings

forE

NM

s•

Deci

sion‐

tree

appr

oach

esfo

rcat

egor

izin

gCN

Tsac

cord

ing

toris

kpo

tent

ial

post‐m

anuf

actu

ring

coul

dfa

cilit

ate

deci

sion

mak

ing

inth

eEP

A’s

New

Chem

ical

sPr

ogra

man

din

othe

rfr

amew

orks

•Ta

rget

edcr

oss‐

com

paris

onof

ATS

with

stan

dard

assa

ysm

aybe

need

edfo

rAT

Sto

bein

corp

orat

edas

anac

cept

edco

mpo

nent

ofca

tego

rizat

ion

stra

tegi

esin

som

ere

gula

tory

cont

exts

NSF

: DBI‐1

2663

77

God

win e

t al,

ACS

Nan

o 20

15


40

Pu

blis

hed

Pro

ject

11,0

00+

pag

e vi

ews

sinc

e Ju

ne 2

013

Top

ic:

How

do

nano

-bas

ed a

ntib

acte

rial p

rodu

cts

wor

k?

Au

die

nce

: 8th

grad

e+

Sel

ect

Vo

cab

ula

ry:

•A

ntib

acte

rial;

Ant

imic

robi

al•

Esc

heric

hia

coli

(E. c

oli)

•K

irby-

Bau

er a

ntib

iotic

test

ing

met

hod

•N

anos

cale

, Nan

opar

ticle

s, N

anom

eter

•P

arts

per

mill

ion

(PP

M)

•Z

one

of in

hibi

tion

Fu

nd

amen

tal S

cien

ce C

on

cep

ts In

clu

de:

-S

elec

t & u

se a

ppro

pria

te to

ols

& te

chno

logy

to p

erfo

rm te

sts,

co

llect

dat

a, a

naly

ze r

elat

ions

hips

, dis

play

dat

a

-D

istin

guis

h be

twee

n va

riabl

e &

con

trol

led

para

met

ers

in a

test

-F

orm

ulat

e ex

plan

atio

ns b

y us

ing

logi

c an

d ev

iden

ceNSF

: DBI‐1

2663

77

Inform

al Scien

ce Edu

catio

n:

Develop

ing Mod

ules Based

on

CEIN Research


41

An

IRB

-app

rove

d cu

rric

ulum

dev

elop

men

t pro

ject

Inco

rpor

atin

g C

EIN

-dev

elop

ed H

TS

ass

ays

into

an

unde

rgra

duat

e ch

emis

try

curr

icul

um to

pro

vide

stu

dent

s w

ith a

n au

then

tic, i

nter

disc

iplin

ary

rese

arch

exp

erie

nce

with

rea

l-wor

ld a

pplic

atio

ns

Cu

rric

ulu

m

Wee

k 1:

Nan

opar

ticle

syn

thes

is

& c

hara

cter

izat

ion

Wee

k 2:

Nan

opar

ticle

ec

otox

icity

assa

y

Wee

k 3:

Res

earc

h ev

alua

tion

and

(re)

desi

gn

Stu

den

ts

Und

ergr

adua

tes e

nrol

led

in

CHEM

12H

at a

prim

arily

unde

rgra

duat

e un

iver

sity

Pre

sen

tati

on

s &

P

ub

licat

ion

s

Pre

sent

atio

n ac

cept

ed:

Pre

sent

atio

n su

bmitt

ed t

o M

ST

EM

201

5:

ww

w.m

ater

ials

inst

em.o

rg

Jour

nal a

rtic

le(s

) in

pro

gres

s

Cat

herin

e N

amet

h (U

CLA

) &

Kor

in W

heel

er (

San

ta C

lara

Uni

vers

ity)

NSF

: DBI‐1

2663

77

Ed

uca

tio

n S

eed

Pro

ject

: S

ust

ain

able

nan

oM

Ate

rial

sL

abo

rato

ry (

SM

AL

)


42


8. Strategic Plan The emergence and rapid expansion of nanotechnology, now reaching a large number of consumers in products such as personal care products, food additives, pharmaceuticals, electronics, energy harvesting, coatings, and paints, has generated considerable concern about the environmental health and safety (EHS) of engineered nanomaterials (ENMs). In response to this concern, the University of California Center for Environmental Implications of Nanotechnology (UC CEIN) was established in October 2008 with a long-term vision of developing a multidisciplinary and quantitative framework for assessing the potential environmental impact, hazard and exposure to nanomaterials, in both their primary as well as consumer product formulations. The Center also provides feedback and guidance for the safer implementation of nanotechnology, including risk reduction and safer design strategies. The multidisciplinary approach involves materials science, environmental chemistry and engineering, toxicology, ecology, social science, computer science and modeling, statistics, public health and policy formulation. Collectively, these fields of expertise are necessary to address the complexity of the ENM physicochemical properties involved in hazard generation, establishment of structure-activity relationships (SARs), and use of exposure assessment to evaluate ecosystems impact. The CEIN’s vision is to generate predictive tools for environmental hazard and exposure assessment as well as to develop strategies to ensure the safe implementation of nanotechnology to the benefit of society, the environment and the economy. These tools and knowledge are being disseminated through vibrant and impactful educational and outreach programs. This vision is clearly aligned with the National Nanotechnology Initiative’s (NNI) and national research needs, as echoed by the 2012 PCAST report.

Towards continuing the implementation of this vision over the next five years, our strategic plan includes the use of a multidisciplinary approach to achieve four overarching goals, namely:

i. To develop hazard ranking and structure-activity relationships (SARs) that relate the physicochemical properties of compositional and combinatorial ENM libraries to toxicological responses in cells, bacteria and multi-cellular organisms, with a goal to develop predictive toxicological paradigms to understand the environmental impact of nanotechnology;

ii. To estimate environmentally relevant exposure concentrations of high-volume and potentially high-impact ENMs (primary nanoparticles as well as commercial nano-enabled products) using life cycle assessment (LCA) and fate and transport modeling to obtain quantitative information about the uptake, bioaccumulation, and hazard of nanoparticles in terrestrial and estuarine ecosystems;

iii. To determine the potential of ENMs, selected through high throughput screening (HTS), SAR analysis, LCA and multimedia modeling, to impact ecosystem services in model ecosystems. These include terrestrial mesocosms with food crop plans and bacterial populations that control nutrient cycles, and estuarine mesocosms comprised of a representative natural food web;

iv. To use UC CEIN knowledge acquisition and environmental impact assessment tools to educate the next generation of nano EHS scientists as well as to inform and engage academic, government, industrial and societal stakeholders involved in risk perception, regulatory decision-making, policy development, risk management and safe implementation of nanotechnology.

The multidisciplinary UC CEIN team addresses these overarching goals through four major thrusts, which include eight research themes. The first thrust (Structure-Activity Relationships) involves nanomaterial acquisition and characterization with a view to perform high-content screening (HTS) of ENM libraries to

43


understand structure-activity relationships at the nano/bio interface. This task is carried out by material scientists and chemists who acquire and synthesize compositional and combinatorial ENM libraries that are used to assess the physicochemical properties that could contribute to hazard generation in cells, bacteria, yeast, zebrafish embryos, terrestrial and aquatic life forms. Where possible, the hazard assessment is carried out by automated high throughput screening (HTS) in the Molecular Shared Screening Resource (MSSR) in the California NanoSystems Institute (CNSI). The rich data sets emerging from the HTS are deposited into the UC CEIN data repository, enabling computer scientists and engineers to develop a computational framework for assessing the environmental impact of ENMs through the use of knowledge extraction and machine learning

methods for data visualization (e.g., heat maps and Self-Organizing Maps), hazard ranking and establishment of quantitative structure-activity relationships (SARs). The second major thrust (Ecosystems Impacts) looks at the impacts of selected materials, identified through hazard ranking and exposure modeling, on terrestrial and aquatic ecosystems. The terrestrial theme emphasizes the ENM impact on microbes and plants, while the aquatic theme looks at estuarine species that are chosen based on the likelihood of suspension (pelagic organisms) or sedimentation (benthic organisms) exposures. Both environmental themes are focused on ENM impacts on ecosystem services (e.g., nutrient cycling, food webs, and biodiversity) and ecological processes (e.g., growth, primary production, and trophic transfer). The ecosystems studies also include development of dynamic energy budget (DEB) models that quantify and integrate the ecosystem impacts across scales and life stages. The third major thrust examines Environmental modeling through the lens of environmental fate and transport lifecycle analyses. In combination with multimedia modeling tools developed by Theme 6, this research is used for ENM environmental decision analysis and modeling of the environmental exposure scenarios. The fourth thrust (Societal Outputs) is engaged in societal implications, education and outreach activities that generate new knowledge about societal contexts for ENM risk and also translates our research, knowledge acquisition and decision-making to students, experts, the public and industry stakeholders.

UC CEIN Research IntegrationStructure/Activity

RelationshipsTheme 1:

ENM Physical/Chemical

Characteristics

Theme 2:HTS and Predictive

Toxicology

Environmental Modeling

Theme 3:Environmental Fate

& Transport; Life Cycle Modeling

Theme 6:Exposure Modeling;

and QSARs

Ecosystems Impacts

Theme 4:Terrestrial Impacts

(Food supply)

Theme 5:Estuarine Impacts

(Benthic and Pelagic Organisms)

Societal OutputsTheme 7:

Stakeholder Engagement and Translational Activities

Theme 8:Educational Programs and Workforce

Development

Integrated UC CEIN research thrusts and themes: Thrust 1 includes Theme 1, which is responsible for the synthesis, acquisition and characterization of ENM libraries and commercial ENMs. These materials are used for high content and HTS in cells, bacteria, yeasts, and zebrafish embryos by Theme 2. The rich data content is used for hazard ranking and development of QSARs by the computational modeling efforts in Theme 6. Theme 6, in collaboration with the fate and transport in LCA studies in Theme 3, is responsible for environmental modeling in the second thrust, thereby assisting the planning and execution of terrestrial and estuarine ecosystems impact studies being conducted in the Ecosystems Impacts thrust in Themes 4 and 5, respectively. The Thrust for Societal Outputs is responsible for stakeholder outreach, engagement and translational activities (Theme 7) while Theme 8 is responsible for educational programs and the development of a future nano EHS workforce.

44


9. Research Program, Accomplishments, and Plans The Center makes use of well-characterized compositional and combinatorial ENM libraries to study their fate and transport in parallel with the materials' bioavailability and potential to engage toxicological pathways in organisms and environmental life forms. Where possible, this exploration involves high throughput screening (HTS) to develop structure-activity relationships (SARs) that can be used to predict the impact of primary ENMs' on organisms in freshwater, seawater, and terrestrial environments. In silico data transformation and decision-making tools are involved in data processing to provide hazard ranking, exposure modeling, risk profiling, and construction of nano-SARs. These research activities are combined with educational programs that inform the public, students, federal and state agencies, as well as industrial stakeholders of the impact of CEIN’s research on the safe implementation of nanotechnology in the environment. Collectively, these activities contribute to evidence-based nanotechnology environmental health and safety (nano EHS) for society. The research of the UC CEIN is carried out by 29 distinct but interactive research projects (supported by 4 service cores) across seven interdisciplinary research themes and our education/outreach program:

• Theme 1: Compositional and Combinatorial ENM Libraries for Property-Activity Analysis • Theme 2: Molecular, Cellular, and Organism High-Throughput Screening for Hazard Assessment • Theme 3: Fate, Transport, Exposure, and Life Cycle Assessment • Theme 4: Terrestrial Ecosystems Impact and Hazard Assessment • Theme 5: Marine and Freshwater Ecosystems Impact and Toxicology • Theme 6: Environmental Decision Analysis for ENMs • Theme 7: Using UC CEIN Knowledge Generation to Engage and Impact Multiple Stakeholders • Theme 8: Education, Career Development, Knowledge Dissemination, and Interactive Efforts

Details of the key accomplishments and research plans for each of the Center’s research themes are summarized on the following pages. For more information about the Center’s support cores, please refer to Section 14: Personnel.

45


Theme 1: Synthesis of ENM Libraries For Property-Activity Analysis Faculty Investigator List: Jeffrey I. Zink, UCLA, Professor of Chemistry and Biochemistry – Theme leader C. Jeffrey Brinker, University of New Mexico and Sandia National Laboratory, Professor of Chemical

Engineering and Sandia Fellow Mark Hersam, Northwestern University, Professor of Chemistry Lutz Mädler, University of Bremen (Germany), Professor of Production Engineering Galen Stucky, UC Santa Barbara, Professor of Chemistry Graduate Students: 7; Undergraduate Students: 14; Postdoctoral Researchers: 7 Short Summary of Theme 1: The primary goals of Theme 1 are to synthesize, purify, characterize and disperse, in relevant media, libraries of nanomaterials that are chosen to develop property-activity relationships that reflect fundamental physical/chemical properties of nanoparticles and the relationships to biological responses in cells and organisms. An important subsidiary goal is to identify and test new materials that are being developed for commercial applications before they are in widespread production in order to pre-empt environmental danger. Fundamental understanding will lead to practical applications such as the ability to predict whether a nanomaterial will have deleterious environmental impacts and the ability to design nanomaterials with a desired function but greater safety than existing materials.

Theme 1 Projects: There are four projects in Theme 1 as listed below. Multiple faculty investigators contributed to the projects; the names of the investigators who made significant contributions are given in the summaries of the major accomplishments discussed in the next section.

• ENM1: Relationships between ENM Electronic Structure and Biological Outcomes (Zink, Stucky, Madler, Brinker)

• ENM2: Relationships between ENM Shape/Size and Biological Outcomes (Hersam, Brinker, Zink) • ENM3: Relationships between ENM Surface Structure/Chemistry and Biological Outcomes

(Zink, Hersam, Brinker, Madler) • ENM4: Relationships between Novel ENM Properties and Environmental Outcomes

(Zink, Hersam)

Major Accomplishments since March 2014: ENM1: Relationships between ENM Electronic Structure and Biological Outcomes In light of CEIN’s recent demonstration of the importance of semiconductor properties and dissolution of industrially important ENMs that could have biological and environmental impact, the members of Theme 1 contributed 5 classes of new nanoparticles for detailed and quantitative understanding of the biological responses to the conduction band energy and the dissolution rate. In addition, some of the new nanoparticles were synthesized to demonstrate how these properties could be tuned to study their structure-activity relationships (SARs) and safer design. Another attempt was to provide highly dispersed, high purity nanoparticles to perform comparative analysis against commercial products that exhibit more complex behaviors (e.g., aggregation, and impurities). The ENMs used for studying the role of electronic structure in biological outcome included:

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The Mädler laboratory synthesized a homologous library of (1-10%) Fe doped CuO in order to test the hypothesis that crystal structure changes caused by iron doping have an impact on cellular toxicity. This library was collectively chosen by the Cu-working group in CEIN. The primary particle sizes were in the range of 10-12 nm. The Fe content in CuO after flame spray was 1.2, 2.2, 4.5, 6.3, 8.5, and 9%, demonstrating an efficient composition control during Flame Spray Pyrolysis (FSP) preparation. Zebrafish embryos were exposed to these particles for hatching response. The results showed hatching interference for CuO NPs exposure but 6 and 10 % Fe/CuO showed reduced interference. Higher Fe loading significantly lowered the hatching interference that is probably linked to the iron-induced variation in crystal structure. The data will be used by the Cu-working group to study the role of dissolution and bioavailability of these materials in various environmental settings. The Zink group synthesized copper nanoparticles using a solution-based hydrothermal method in a basic arginine medium. Copper nanoparticles are difficult to make and have a short shelf life because of rapid oxidation. Well dispersed, truly nanocrystalline copper oxide is now available for biological testing. In the new synthetic procedure, arginine was chosen as the base because of its ability to act as a buffer in aqueous solution, maintaining the pH of the solution constant during the entire reaction, and because the presence of amine functions help to stabilize both the copper precursor and the newly formed particles. We also achieved size tuning of these particles. The copper oxide nanoparticles were synthesized at room temperature using a similar approach. Biological effects of dispersable individual nanocrystals of high purity Cu and CuO can now be compared to those obtained from studies using highly aggregated commercial samples. The Mädler laboratory also synthesized a new Al-doped ZnO library for cellular cytotoxicity screening both in presence of light and in the dark for prediction of the protective levels of doped ZnO based libraries (Al or Fe doped ZnO) in environmental conditions. Al (1-10%) was doped in ZnO with sizes in the range of 12-18 nm. The elemental maps of pure and doped NPs showed homogeneous distribution of Al in ZnO. The band gap energy of the Al doped ZnO (3.5 eV) and Fe-doped ZnO (3.2 eV) was derived using UV-visible spectroscopy. Comparing the reduction of ZnO cytotoxicity achieved by Fe-doped and/or Al-doped ZnO NPs, the latter had more enhanced protective effect in terms of cellular oxidative stress. In the presence of light, the hydroxyl radical generation through 1% Al doping was about 5 times less than those observed for 1% Fe doping. The same experiment was repeated in the presence of RAW 264.7 cells and the oxidative stress response induced by 10% Fe doped ZnO was almost 6 times more than those induced by 10% Al-ZnO. To verify these observations in a different organism (fish cell line, RT gills W1), Al doped ZnO NP was exposed both in the presence of light and dark conditions followed by measuring mitochondrial superoxide generation. Little or no cytotoxicity was found under dark conditions. However, in presence of light the superoxide generation decreased systematically with increasing Al in ZnO (possibly due to e-/h+ recombination in the defect sites). The cellular responses involve both decreased dissolution and the combination of defects and light. The data will be used for additional demonstration of a safer design methodology for ZnO in the aquatic and terrestrial settings. To study the effects of tuning the conduction band energies of metal oxides, the Zink group synthesized specific crystalline polymorphs of iron oxide. The purpose was to change the band gap but to keep the chemical composition constant. To make nanocrystals, the iron oxides were grown in a mesoporous template and were annealed. At annealing temperatures of 380 °C and 430 °C, only γ-Fe2O3 was formed. However, α-Fe2O3 was observed as dominant iron oxide at the annealing temperature of 500 °C. The new nanoparticles now make it possible to study in detail the relationship between crystal structure, band gap and biological outcomes.

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Impregnation of a mesoporous silica template followed by thermal annealing was used to synthesize supported Pd and PdO nanocrystals. These nanocrystals attached to metal oxides were hypothesized to generate p-n junctions and thus could induce oxidative stress. Pure Pd and PdO nanocrystals were not available. To synthesize them, a silica support was impregnated with H2PdCl4 and annealed under vacuum (to produce metallic Pd nanocrystals) or in air (to produce PdO nanocrystals). Surprisingly the particles are ferromagnetic. Magnetic properties from the unpaired electrons are probably a result of surface and internal defects. Distinctive twin boundaries were observed in supported Pd NPs. The biological effects of pure nanocrystals both free and on an inert oxide matrix can now be compared to those of palladium compounds on metal oxides described in Theme 2 and will lead to further understanding of the effects of electron transfer on toxicity. As a further extrapolation of our work on semiconductor materials, a novel library of pure and Ge doped (1%, 4%, 8% and 10%) Ga2O3-based NPs (5-5.5 nm) was synthesized by the Mädler group, because these particles have a strong potential for adhesion on any solid surface through dipole-dipole interactions. It was hypothesized that the strong Ga2O3-cellular membrane interaction could give rise to increased cellular toxicity. However, doping Ga2O3 with Ge may alter the adhesion onto the cell membrane giving rise to a different injury response. The UV-Vis measurements showed a slight decrease in the band gap with Ge doping (GeO2 = 4.4, Ga2O3 = 5.04; 1%Ge/Ga2O3 = 5.10; 4%Ge/Ga2O3= 5.01; 8%Ge/ Ga2O3= 4.94 and 10%Ge/ Ga2O3= 4.87 eV). This library will be available for biological testing in the near future.

ENM2: Relationships between ENM Shape/Size and Biological Outcomes We have previously reported the construction of a long aspect ratio (LAR) CeO2 nanoparticle library, which was used successfully in tissue culture cells to show that there is a critical LAR beyond which there is generation of pro-inflammatory effects and cytotoxicity in tissue culture cells such as macrophages and epithelial cells. During the last reporting period, this library has been implemented in zebrafish and pulmonary installation studies in rodents, which have demonstrated the critical role of aspect ratio in determining toxicity in the gastrointestinal tract of zebrafish larvae and pulmonary fibrosis in mice (see Project HTS-1 in the Theme 2 report). An additional important advance over the last year has been the recognition of the unique ability of two-dimensional (2D) materials, such as graphene and molybdenum disulfide, to participate in interactions at the nano/bio interface, which differ but also overlap with the hazard potential of 1D material such as CNTs. This aspect will be addressed in ENM4. ENM 3: Relationships between ENM Surface Structure/Chemistry and Biological Outcomes. We have previously demonstrated that fumed silica, produced under high temperature flame spray conditions, exhibit unexpected high toxicity potential at cellular level (membrane disruption and activation of pro-inflammatory responses) due to their siloxane ring structure and display of highly reactive surface silanols groups. During this reporting period, Drs. Brinker and Madler undertook careful synthesis of additional libraries of fumed silica nanoparticles to understand the effects of surface silanol groups and siloxane ring structures on toxicity. In-house as well as commercial fumed silica were modified to vary the surface display of the reactive silanols groups, including through aluminum and titanium doping as well as changing the chemical precursors. The Madler group synthesized an OH- functionalized fumed silica nanoparticle library using flame spray pyrolysis for cellular assessment based on red blood cell hemolysis and for comparison with the results obtained from particles prepared by base-catalyzed hydrolysis of tetraethylorthosilicate (from the Brinker group). During synthesis, one independent flame was used for Si-precursor combustion while a second jet was used for controlling the water vapor pressure. Red cell hemolysis showed a strong correlation to the normalized OH-display on the particle surfaces. In the second stage of the

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experiments, the fumed silica surface was doped with Al and/or Ti (1-10%). The cellular toxicity assessment using MTS assay showed fumed silica induced toxic effects in THP-1 cells. However, with Al and/or Ti doping, the toxicity was significantly decreased. Assessment of the pro-inflammatory effects by studying NLRP3 inflammasome assembly and IL-1β production, demonstrated a progressive reduction in IL-1β release in THP-1 cells with incremental Al and/or Ti doping. We are now in the process of testing the in vivo significance of the cellular results in animal models. The Brinker group monitored the reaction of commercial fumed silica in deionized water and found that strained three membered rings (3MRs) (previously correlated with toxicological activity) are present in three populations: surface (with rapid hydrolysis upon exposure to water), internal (slow reaction), and defect centers that are initially invisible to Raman due to broken symmetry but contribute to the overall 3MR concentration after addition of water. Annealing of fumed silica at 650° for 12 hours removes most 3MRs, with no detectable defect centers. The luminescent background of fumed silica, significant in as-received material, disappears rapidly upon exposure to water, consistent with removal of defect centers. Studies of fumed silica (pure silica and Ti-doped) synthesized by the Mädler group show a different luminescence behavior, appearing at a slightly different energy and taking longer to decay once added to water. Addition of Al lowers the 3MR increase, consistent with reduced toxicity through fewer defects trapped in the silica framework during the material synthesis. Hemolysis assays also showed that addition of as little as 1% Ti or Al significantly reduces hemolytic activity in human RBCs. This work is of potential importance to the production and marketing of fumed silica as one of the most highly produced ENMs globally. Themes 2-4 often need fluorescent tags so that particles can be tracked. The surfaces of metal oxide nanoparticles of different composition, morphology and shapes were successfully derivatized by the Zink group and modified by attaching fluorescence imaging markers, using a general coupling synthetic method. The nanoparticles include fumed silica, lanthanide oxide and aluminum oxyhydroxide. The luminescent dyes, such as fluorescein and rhodamine make it possible to track and image the particles in biological settings. The particles were used by Theme 2 for toxicity characterization and for optical detection of the particles in in vitro and in vivo. The amount of fluorescence labeling of silica can also be used as an indication of hydroxyl group concentrations on particle surfaces. ENM 4: Relationships between Novel (2D and upconversion) ENM Properties and Environmental

Outcomes. The new materials introduced over the last 2 years were selected because of their rising importance in applications such as electronics, photonics and imaging. These include materials that display unique 2D properties such as graphene and molybdenum disulfide (MoS2), as well as upconverting nanocrystals that are increasingly being used for imaging purposes. Early attempts to address the hazard potential of these new nanomaterials, including their environmental impact, are of considerable importance due to the pace of commercialization. During this reporting period graphene oxide, graphene ink, forms of MoS2, upconverting lanthanide fluoride nanocrystals and lanthanide oxides in porous nanosilica were synthesized and studied. The Hersam laboratory has introduced graphene and graphene oxides as an important class of new 2D materials that have been extensively characterized and used for comparison against CNTs, as outlined in Theme 2. Dr. Hersam’s group also continued their collaboration with the United States EPA on the environmental fate and transport of graphene oxide in the aquatic environment. Since different commercial applications for graphene oxide require different oxidation levels, the objective in this work is to determine the role of graphene oxidation level on environmental fate and transport. To this end, a

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spectrum of graphene oxide samples have been prepared, ranging from graphene oxide to highly reduced graphene oxide. The effects of these differences in oxidation on the stability and aggregation kinetics of the nanomaterials within the aquatic environment are currently being investigated. This set of graphene oxide samples has also been included in the CEIN library, where they will subsequently be used for in vitro and in vivo toxicity testing. The Hersam Laboratory also developed a graphene ink based on a graphene/ethyl cellulose powder, the production of which has been scaled to gram quantities using shear mixing in place of ultrasonication. These large-scale quantities of well-characterized graphene nanomaterials will facilitate emerging ecological studies of this nanomaterial. In particular, a collaborative effort is being established with the Holden’s laboratory at UCSB to assess the bioavailability and transport of graphene in mesocosm studies, which will lead to a better understanding of the persistence and toxicity of graphene nanomaterials. Two-dimensional transition metal dichalogenides (e.g., MoS2) have emerged as a leading successor to graphene due to their desirable electronic and optical properties. In particular, their visible fluorescence holds promise for light-emitting diodes, photovoltaics, and biomedical imaging. Due to this commercial potential, it is important to assess the hazard potential of nanoscale, two-dimensional MoS2. In addition to bulk MoS2, two exfoliated dispersions of this material were prepared by the Hersam laboratory. The first dispersion, lithiated MoS2, was prepared via a lithium intercalation process. The second dispersion, Pluronic-dispersed MoS2, was prepared by ultrasonicating bulk MoS2 in an aqueous solution containing Pluronic F87, a biocompatible triblock copolymer. These three MoS2 samples were provided to Theme 2 for cellular toxicity studies and developing a predictive toxicological paradigm in the lung, upon inhalation or instillation. The preliminary data indicate that while bulk MoS2 induced a pro-inflammatory response in tissue culture cells and acute lung inflammation in a rodent model, the exfoliated materials do not generate the same level of inflammation and do not cause chronic pulmonary effects. These results suggest that the toxicity of MoS2 can be mitigated by nanoscale dispersion, thus facilitating the use of two-dimensional MoS2 in industrial and biomedical applications. Dr. Hersam also studied the environmental fate and transport of lithiated and Pluronic F87-coated materials in collaboration with Sharon Walker’s laboratory at UC Riverside. The results of this study show that lithiated MoS2 has the potential for long-term transport and has a higher tendency to be remobilized in the environment, whereas Pluronic-dispersed MoS2 is significantly less mobile and irreversibly binds to quartz surfaces, limiting remobilization in the environment. A major discovery in the previous reporting period was the demonstration that the rare earth metal oxide nanoparticles can induce a unique form of cellular and organ toxicity due to surface binding of cellular phosphates to the particle surfaces, leading to lysosomal damage and pro-inflammatory effects. We have since demonstrated that upconversion nanoparticles, which are doped with rare earth elements, also exhibit the same hazard potential, and have developed a library of lanthanide-doped UCNPs that are being used to attempt safer design as described in Project 4 in Theme 2. This is done by phosphonate coating that passivates the particle surfaces. By using a stepwise phase transfer method, NaY1-nLnF4 (where L = Yb3+, Er3+ Tm3+ ) upconverting nanocrystals and a superparamagnetic Fe3O4 nanocrystal were encapsulated by the Zink laboratory in mesoporous silica nanoparticles MSN that provides rigid structure support. The construction is designed to enable both magnetic manipulation and spectroscopic monitoring of the particles. These additions to the library of fljuorescent magnetic nanoparticles are ready for use for tracing, collecting and recovering nanoparticles from microcosms, mesocosms and the environment.

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Using porous SiO2/La2O3 particles synthesized by the Brinker group using evaporation-induced self-assembly, it was shown that the presence of La3+ does not appreciably impact E. coli growth, but does result in an enhancement of 1-N-phenylnapthylamaine uptake. To examine the relationship between REO NP composition, structure, and bacterial interaction, the release rates of La3+ from several types of ‘La2O3’ and SiO2/’La2O3’ NPs were measured. Imaging of E. coli exposed to these various types of NPs showed that high release rate is correlated with the formation of extensive LaPO4 clusters external to the E. coli cells, while low release rate produces LaPO4 primarily at the surface of cell membranes. Impacts on the Overall Goals of the Center: The results of the synthetic research programs in Theme 1 continue to expand CEIN’s nanoparticle libraries with new compounds designed to enlarge our knowledge of the factors that contribute to toxicity and the designs that can be used to increase safety. A major component of our current understanding of biological responses to metal oxide materials is the electronic structure of the particles, specifically the energies of the conduction bands and the Fermi levels. In this reporting period we modified the crystal structures and band gaps of CuO by doping with Fe ions. Zebrafish studies in Theme 2 showed that increased iron doping decreased hatching interference. These data are being used by the Cu-working group to study the role of dissolution and bioavailability in various environmental settings. A new library of Ge doped Ga2O3 was synthesized and will be used to extend the studies of the effects of semiconductor materials on toxicity in theme 2. We also contributed samples of highly pure and dispersable nanoparticles for detailed understanding of the effect of crystal structures (polymorphs of Fe2O3), unpaired electrons (Pd and PdO) and nanocopper (Cu and CuO) on biological responses. In addition to the electronic and crystal structural effects, dissolution of ions plays a key role in materials such as ZnO. To compare the relative importance of these two properties, a library of Al doped ZnO was synthesized; Theme 2 found that electron-hole interactions at defect sites were more important than dissolution in decreasing toxicity. Surface properties of nanomaterials have an enormous effect on biological outcomes. A library of SiO2 with varying amounts of –OH groups on the surface was synthesized. Hemolysis induced by the particles increased with increasing –OH concentration. Internal defects and ring structures also play an important role. Doping of toxic fumed silica with 1% Al and Ti ions significantly reduces hemolysis by reducing the defect concentration in the silica, suggesting that fumed silica can be made safer by doping with metals. New materials selected for addition to the library were chosen because of their increasing importance in applications such as electronics, light-emitting diodes and imaging. New two-dimensional layered materials such as graphene and MoS2 (bulk and exfoliated) were prepared and then studied by Theme 2; bulk materials induced a pro-inflammatory response whereas exfoliated materials elicited a reduced response suggesting that toxicity can be mitigated by nanoscale dispersion. The synthetic efforts by the members of Theme 1 continued to contribute not only libraries of new chemical compositions, but also libraries of particles with specifically designed structural, electronic and morphological properties that in collaboration with Theme 2 is leading to a more detailed understanding of dangerous characteristics and of strategies to make them safer.

Major Planned Activities for the Next Reporting Period: We will continue to synthesize new libraries of nanoparticles to assist in the development of predictive models of toxicity. The libraries related to electronic structure will include not only doping of materials to fine tune their conduction band energies and Fermi levels, but also synthesis of polymorphs for fine tuning the energies and for exploring crystal structural effects on toxicity. Detailed studies by tuning band energies using libraries of mixed metal oxides, p and n doping of metal oxides, p-n junctions between different metal oxides and metal nanoparticles and metal oxides, and by comparing catalytic

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activities of metal oxide nanoparticles with biological outcomes will be carried out. The prior history of nanoparticles, including the temperature at which they were synthesized, calcined or annealed, changes their effects on cells and organisms. Libraries of metal oxide nanoparticles made by flame-spray pyrolysis, hydrothermal methods and sol-gel or aerosol methods will be synthesized. The synthesis methods affect the surface structure, and safe by design nanomaterials will be synthesizable by changing the synthesis temperature. We will continue to work closely with Theme 2 and the zebrafish studies in Theme 5 to design and synthesize specialized nanoparticles to test and develop new hypotheses about toxicity. All of the above new data will be used for modeling in Theme 6. A continuing focus will be to develop safer materials that can be used commercially.

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Theme 2: Molecular, Cellular and Organism High Throughput Screening for Hazard Assessment Faculty Investigators: André Nel, UCLA – Professor, Medicine; Chief, Division of NanoMedicine- Theme leader Kenneth Bradley, UCLA – Associate Professor, Microbiology Hilary Godwin, UCLA – Professor, Environmental Health Sciences Patricia Holden, UC Santa Barbara – Professor, Environmental Microbiology Shuo Lin, UCLA – Professor, Molecular, Cellular, and Developmental Biology Tian Xia, UCLA- Assistant Adjunct Professor, Medicine, Division of NanoMedicine Huan Meng, UCLA- Assistant Adjunct Professor, Medicine, Division of NanoMedicine Graduate Students: 2; Undergraduate Students: 85; Postdoctoral Researchers: 6 Short summary of Theme 2: The main goal of Theme 2 is to use high content screening (HCS) and high throughput screening (HTS) for Engineered Nanomaterials (ENMs) at cellular and organismal (zebrafish) levels to develop predictive toxicological paradigms, hazard ranking and SARs to guide nano EHS decision-making and ecological research (Themes 4 and 5). HTS of industrially important metal, metal oxide, rare earth oxides (REOs) and upconversion ENMs as well as in-house synthesized doped ENMs (Theme 1) were used since February 2014 for cellular, bacterial, and zebrafish screening. HTS was also used to assist center-wide copper case studies. In addition to continuing to develop mechanistic toxicological assays that are predictive of in vivo toxicological outcomes, we also introduced new approaches, including: (i) more sensitive luminescence-based assays to replace fluorescence-based methods for assessing oxidative stress, organelle dysfunction, and cytotoxicity; (ii) a predictive paradigm for REO toxicity premised on disruption of lysosomal integrity due to high affinity binding of structural phosphate groups; (iii) HTS of semiconductor metal oxide ENMs based on bacterial oxidative stress pathways; and (iv) developing assessment of sub-chronic toxicity in adult zebrafish. We have also implemented the site visit recommendation to develop more cost-effective HTS analysis by initiating work on lab-on-a chip technologies.

Theme 2 Projects:

• HTS-1: Zebrafish HTS and Sub-chronic Toxicity Studies in developing larvae- (Lin, Nel) • HTS-2: Use of multi-parametric oxidative stress screening to compare the toxicological effects

of metal, metal oxide and semiconductor nanoparticles in mammalian cells – (Xia) • HTS-3: High Throughput Screening to Determine the Mechanistic Toxicology of Engineered

Nanomaterials in Bacteria – (Godwin, Holden) • HTS-4: Assessment of the toxicological potential of rare earth oxide nanoparticles with a view

to develop safer design strategies– (Xia) • HTS-5: Developing of Lab-on-a-Chip Technology for rapid and cost-effective assessment of

ENM-induced cytokine responses in cells – (Meng, Chui) • HTS-6 Effects of MWCNT nanocomposite degradation particles on zebrafish larvae (Seed

Funding) – (Lin) Major Accomplishments since March 2014: Theme 2 conducted 6 productive projects, resulting in 4 UC CEIN funded publications, 4 leveraged publications and 7 papers that have been submitted or are being drafted. The progress reported in these projects is as follows:

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HTS-1: Zebrafish HTS and Sub-chronic Toxicity Studies in developing larvae The goals of this project are: (1) to use zebrafish embryo high throughput screening (HTS) in the Center’s Copper Working Group to gain a mechanistic understanding of the hazard potential of fungicidal Cu ENMs after entering a wastewater treatment process; 2) to develop a subchronic toxicity model in adult zebrafish that can be used to study the hazard potential of citrate- and PVP-coated 20 and 110 nm Ag nanoparticles. Aim 1 of the 1st goal is to use zebrafish HTS to compare the hatching interference of the pristine nano Cu, fungicidal CuPRO, and micro Cu particles with the transformed particle products recovered from effluents generated in a simulated septic tank system established in Prof. Sharon Walker’s laboratory in Theme 3 (FT-4). While pristine nano Cu and CuPRO particles interfered in embryo hatching at ≥ 0.5 ppm, no hatching interference was seen with any of the effluents generated from the septic tank system. In order to obtain a mechanistic understanding of the decreased toxicity, we investigated the transformation and speciation of Cu in the effluent samples (Aim 2). Through the use of X-ray diffraction analysis, ICP-OES and Visual MINTEQ modeling (Theme 1), it was determined that all Cu in the septic tank effluent underwent transformation to insoluble inorganic Cu species, such as Cu(H2PO2)2, or non-diffusible organic-bound Cu, regardless of the original composition and particle size. These forms of Cu are not bioavailable and failed to interfere in embryo hatching. This study, which was recently published in ACS Nano24, demonstrates the utility of zebrafish HTS in studying the transformation of nanoparticles in a simulated environmental exposure model. This work is currently being extended to a library of CuO ENMs, doped with 1 %, 2%, 4%, 6%, 8% and 10% Fe (Dr. Suman Pokhrel and Prof. Lutz Mädler, Theme 1), to study the hypothesis that the reduced Cu dissolution as a result of the doping will lead to decreased environmental hazard potential. Towards goal 2, we have previously established a pulse-exposure method to study the importance of ENM aspect ratio on zebrafish larvae. Aim 1 of the new study is to adapt our approach to assess the hazard potential in adult zebrafish of Ag ENMs with different primary particle sizes and surface coatings. Our hypothesis is that ionic Ag that is shed from Ag ENMs during sub-chronic exposure may gain access to tissues such as the brain, gill, intestine, liver, gonads or fins, leading to the generation of organ-specific toxicity. In order to develop an adult zebrafish exposure model that is logistically feasible, we used 2 liter tanks and mating boxes to carry out the ENM exposure (instead of the Petri dish, used for larvae). The exposure was conducted for 3 to 6 month old zebrafish over a 4 day period. Post exposure, one half of the adult fish population was sacrificed and dissected to harvest organs of interest for further analysis. Moreover, the remaining fish were depurated for 4 days before sacrifice and organ harvesting. We are developing a suite of assays to perform hazard ranking as well as evaluation of mechanisms of toxicity in various tissues (Aim 2). This study opens up the possibility to use adult zebrafish for sub-chronic studies and to perform comparative analysis between the zebrafish and other aquatic organisms used in Themes 3, 4 and 5. In the next year we also propose to use this methodology to explore the toxicokinetics of Ag ENMs, with intention to assess adsorption, distribution, metabolism and excretion. HTS-2: Use of multi-parametric oxidative stress screening to compare the toxicological effects of

metal, metal oxide and semiconductor nanoparticles in mammalian cells The goals of this project are to use multi-parametric HTS to investigate: (1) the toxicity of metal oxide and semiconductor ENMs to understand the role of material bandgap and oxidative stress, and (2) delineation of the basis of Ag ENM responsiveness or resistance in mammalian cell lines, using luminescence-based instead of fluorescence-based assays. Aim 1 is to investigate the toxicological effects of doped p-type metal oxide nanoparticles to understand the role of bandgap changes and Fermi levels in cellular redox stress. This extends previous work showing the importance of conduction band energy in the generation of cellular oxidative stress as the basis for semiconductor nanoparticle toxicity. Use of these paradigms allowed us to make predictions about the acute toxicological potential of

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transition metal oxides (TMOs) in the mouse lung. Because most of the TMOs exhibiting acute lung toxicity are p-type semiconductors, we hypothesized that the Fermi level of the materials are important, and proposed that doping of Co3O4 ENMs with PdO should be able to generate more “holes” that will allow small adjustments to the bandgap. A library of PdO-doped Co3O4 NPs was synthesized by Theme 1, (Lutz Madler and Suman Pokhrel) using flame spray pyrolysis. Detailed characterization demonstrated a gradual decrease in Fermi energies with incremental PdO doping. The accompanying tuning of the bandgap and increased generation of holes at the particle surface initiated abiotic hydroxyl radical generation. This was accompanied by increased ROS generation and glutathione (GSH) depletion at the cellular level, leading to heme oxygenase (HO-1) expression, IL-8 & TNF-α generation as well as cytotoxicity in BEAS-2B and RAW 264.7 cells. These data demonstrate the importance of the Fermi level in the toxicity of p-type semiconductors. The findings were published in JACS42. In the next year of study, we will explore the toxicological potential of III-V semiconductor materials, including GaN, GaP, GaAs, GaSb, InP, InAs, GaInAs, and InAlAs nanoparticles, based on the hypothesis that their electronic properties and ionic dissolution will generate cellular oxidative stress, and toxicological effects in organs and the environment. This study is relevant from the perspective of the semiconductor industry, and the generation of III-V material slurries during the polishing of wafers. Aim 2 is to develop luminescence-based methods to replace the use of fluorescence in our HTS assays. We are using new reagents developed by Promega to study cellular oxidative stress, including the use of CellTiter-FluorTM, ROS-GloTM, CytoTox-FluorTM and GSH-GloTM. As a demonstration of the utility of these assays, we are studying the impact of silver nanoparticles (Ag NPs), which have previously been demonstrated to yield absent or no toxicity in “Ag-resistant” cell lines (Caco-2 and NHBE), while inducing high toxicity in “Ag-sensitive” cell lines (BEAS-2B, RLE-6TN, RAW 264.7 and THP-1). Use of the GSH-Glo assay, to date, has demonstrated that all the resistant cell lines maintain a high level of GSH expression after Ag ENM exposure, while all the susceptible cell lines showed significant decreases. These results suggest that Caco-2 and NHBE cells exhibit strong antioxidant defense. Overall, luminescence-based assays are more sensitive than fluorescence assays, which are also associated with less background from nanoparticle surface interactions with fluorescent dyes. A manuscript describing these findings is being drafted. HTS-3: High Throughput Screening to Determine the Mechanistic Toxicology of Engineered

Nanomaterials in Bacteria This goal of this project is to demonstrate that HTS of ENMs in bacteria can be used to assess and predict the hazard that different ENMs pose in environmental systems. Because bacteria form one of the biological foundations for ecosystems and because specific bacteria may be critical sentinel species, demonstration of effective use of HTS for nanotoxicology in bacterial systems is a high priority for the UC CEIN. Aim 1 is to determine how the formulation of Cu antimicrobials impacts the magnitude and mechanism of their toxicity in bacteria and whether this varies depending on the taxa of the bacteria. Since February 2014, we have completed studies on how Cu NPs impact two species of enteric bacteria (Escherichia coli and Lactobacillus brevis) using a growth inhibition assay and a series of sublethal assays. These studies are significant in that they demonstrate that the mechanisms of toxicity exhibited by nano-sized Cu particles are different than those exhibited by micron-sized particles or ionic Cu2+. These studies also demonstrate that different bacterial species can respond differently to Cu ENMs, both qualitatively and quantitatively, and suggest that studying effects across diverse taxa is important and that Cu ENMs may alter bacterial population structures in waste treatment systems. We have validated the use of an in vitro DNA-damage assay with ENMs and have applied this assay to a series of Cu, particulates, and ionic Cu2+. We have also performed 3D TEM studies on nano-Cu in E. coli, which confirmed that this EMN enters the cells. Combined with the results from the in vitro DNA damage assay, these data demonstrate an important difference in the impact of nano-Cu on bacteria compared to other copper species that were studied. Aim 2 is to determine which physicochemical properties of

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metal oxide (MOx) ENMs correlate with their toxicity in bacteria and use this analysis to develop a predictive paradigm for the toxicity of MOx ENMs in bacteria. We completed a study in which we used a suite of sublethal assays to investigate 24 MOx ENMs, previously used for toxicological profiling of mammalian cells, and demonstrated that the toxicity of MOx ENMs correlates with their hydration energy and conduction band energy. These data suggest that, although MOx ENMs as a class are not highly toxic to E. coli, the growth inhibitions observed in E. coli parallel those found in mammalian cells.19 In the next year, we will use our in vitro DNA-damage assays using to investigate the toxicity and uptake of the Cu library in L. brevis. We are also planning to perform elemental analysis by energy dispersive X-ray spectroscopy (EDX) on E. coli cells that have been exposed to nano-Cu to study subcellular Cu localization. Further, we are coordinating with the Holden and Walker groups to ascertain how our results compare to those they have seen in other bacteria and in the model septic system. The Graduate Student working on this project (Kaweeteerawat) plans to graduate in Spring 2015, and as a result she is in the process of writing up all of her work in the UC CEIN and we will be submitting multiple manuscripts describing these results over the coming months. HTS-4: Assessment of the toxicological potential of rare earth oxide nanoparticles with a view to

develop safer design strategies The goal of this project is to develop safe implementation and safer design of rare earth (RE) based ENMs, which are increasingly being used for applications such as magnets, catalysis, electronics, biomedicine etc. These materials have become of great strategic and economic significance since China has implemented a moratorium on the export of RE minerals. Because of increased mining activity for RE materials in the US and a history of occupational lung disease, we have previously demonstrated that RE nanoparticles pose a particular hazard due to the ability to disrupt cellular phosphate homeostasis and lysosome function in pulmonary macrophages. Over the last year, we have extended this research by focusing on a new line of RE doped ENMs that are being commercialized for biological applications, including imaging. These are also known as upconversion nanoparticles (UCNPs), which can absorb multiple low energy photons and emit higher energy anti-stokes luminescence. Since conventional RE ENMs are unstable in the presence of phosphates in the acidifying lysosomal compartment in macrophages,i it is possible that similar complexation of phosphates could negatively impact the imaging qualities and biosafety of UCNPs. We have noticed that that prior interaction of RE surfaces with phosphate groups at neutral or physiological pH, leads to the formation of the surface coating that prevents further interaction with bystander phosphates under acidic lysosomal conditions. This led to our hypothesis that phosphonate coating could be used for the safer design of UCNPs. To test this hypothesis, we first prepared two UCNPs, including in-house synthesized La(OH)3 doped with Er & Yb, as well as NaYF4 : Er, Yb NaYF4 : Er, Yb and La(OH)3 : Er, Yb, which is commercially available. These ENMs were thoroughly characterized in Theme 1 to determine size, zeta potential and hydrodynamic size in water and cell culture media. Aim 1 investigated the transformation of UCNPs under acidic biological conditions. We observed that both particle types undergo transformation to mesh-like or urchin-shaped structures in phagolysosomal simulated fluid (PSF) as well as in the lysosomal compartment of THP 1 cells. This transformation represents dissolution of RE from the particle surface and complexation to REPO4. The phosphates are scavenged from the lysosomal compartment, which leads to organelle damage, cathepsin B release and IL-1β production. In addition to the generation of cytoxicity, the transformation of UCNPs also leads to fluorescence quenching, as demonstrated by a decrease of the emission peak intensity under acidic conditions. Aim 2 was to develop a safer phosphonate coating for UCNPs. We experimented with a series of phosphonate molecules to determine which phosphonates bind to UCNP surfaces with high affinity. We found that ethylenediaminetetra (methylenephosphonic acid) (EDTMP) provides optimal and stable coating, which prevents acidic intracellular transformation as well as quenching of fluorescence intensity. Moreover, the phosphonate treated particles also had

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lesser proinflammatory effects in vitro and in vivo. In summary, phosphonate coating represents a safer design method for a broad range of RE-enabled nanoproducts. This work is being written up for publication (R. Li et al., in preparation). HTS-5: Developing of Lab-on-a-Chip Technology for rapid and cost-effective assessment of ENM-

induced cytokine responses in cells Significant effort has gone into developing in vitro toxicological analysis of ENMs. This includes the development of multi-parameter HTS assays, which frequently require the use of an automated HTS facility. HTS facilities are costly and not widely available. The assessment of pro-inflammatory and pro-fibrogenic cellular responses was used in the development of predictive toxicological paradigms for the redox-active metal oxides and long aspect ratio (LAR) ENMs. Their toxicities are being studied by using protein biomarkers (e.g. cytokine, chemokine, growth factor) that are routinely analyzed by labor-intensive ELISA assays. Compared to ELISA, a semiconductor electronic protein assay (SEPA) that is carried out by nanowire field-effect transistors (nwFETs) offers superior detection sensitivity. This measurement is further facilitated by the use of a novel T-shape signal amplification design. There are additional advantages such as the rapid turnaround time, multiplexing, and low-cost integration to perform rapid throughput analysis. The goal of this project is to design a lab-on-a-chip system capable of rapid and quantitative determination of pro-inflammatory and pro-fibrogenic cellular responses by LAR and metal oxide ENMs. Our hypothesis is that the nwFET platform could be used as a powerful lab-on-a-chip discovery tool that allows ultrasensitive and multiple parallel measurements of ENM-induced protein biomarkers, which can be used for hazard ranking. Aim 1 is to fabricate and test the performance characteristics (sensitivity and selectivity) of the nwFET biosensors in the detection of a representative biomarker, IL-1β, diluted in PBS. We have fabricated approximately 20 nwFET devices that included the T-shaped p-type Si nanowires in our clean room. The nanowires were decorated by the immobilized human IL-1β antibody. To avoid readout interference by fabrication defects, we have calibrated each device before use and developed a portable chip-with-wire connection that could be used in the lab. Our data show a 10-fold increase in sensitivity and selectivity with nwFET compared to ELISA. Aim 2 is to use the nwFET platform to quantify ENM-induced IL-1β production in THP-1 cells exposed for a range of LAR materials such as CeO2 nanorods and MWCNTs. The parallel analysis for IL-1β measurement using nwFET and ELISA has led to highly consistent results, which were further confirmed by cellular studies to determine IL-1β production. We are preparing a manuscript that describes the IL-1β analysis data (Mao et al, in preparation). This will serve as the proof-of-principle evidence in using nwFET for cytokine quantification. Over the next year, we will expand the use of nwFET to assess additional cytokine levels, i.e. fish cell culture and mussel hemocytes. HTS-6: Effects of MWCNT Nanocomposite Degradation Particles on Zebrafish Larvae This seed project was initiated in response to the CEIN renewal goal of incorporating more commercial nanomaterials, including nanocomposites from which hybrid materials are released through sanding, grinding, weathering, etc. In collaboration with BASF, we have since identified two representative MWCNT nano composites, i.e. MWCNT-POM (polyoxymethylene) and MWCNT-cement. The goal is to investigate the environmental hazard potential of the nanocomposite degradation particles in zebrafish. The rationale is that the degradation particles could be released into the air, soil and water, thereby leading to environmental exposure. Aim 1 studied the release of MWCNT nanocomposites under two degradation conditions, namely: (i) short time sonication of the nanocomposite to mimic intense mechanical abrasion; (ii) immersion of the nanocomposites in zebrafish growth medium, followed by agitation in an orbital shaker for a week. To date, we have demonstrated that both degradation processes result in the generation of MWCNT degradation particles (DPs). Based on TEM analysis, we ranked the extent of the degradation as MWCNT-cement (probe) > MWCNT-POM (probe) > MWCNT-

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cement (shaker) > MWCNT-POM (shaker). The presence of MWNCTs in all DPs was confirmed by confocal Raman microscopy. Aim 2 used our previously developed pulse-exposure method to study the hazard potential of the DPs in the gastrointestinal tract (GIT) of developing zebrafish larvae (1). No significant growth retardation was found in the larvae exposed to either of the DP sources. Although the confocal Raman confirmed the presence of MWCNTs in the GIT, we did not observe any impact on digestive function, similar to what was seen with CeO2 nanorods.25 Since CNTs can exert adverse effects on fish gills, we are continuing the study in adult zebrafish. This pilot project serves as an early demonstration of our approach of studying industrial nanomaterials, including released fragments and ions. In Theme 5, we will study the impact of ionic and particulate slurries releases from semiconductor wafers in zebrafish. Impacts on the Overall Goals of the Center: The work in Theme 2 is continuing our high impact approach of developing predictive toxicological paradigms that utilize adverse outcome pathways (AOP) in cells to make predictions about the likelihood of in vivo toxicological injury premised on the promotion of disease pathogenesis by the same AOP. In the current period, this was demonstrated by accomplishing predictive toxicological paradigms for MOx as well as the RE containing ENMs. In the case of MOx ENMs, we have previously shown that overlap of the conduction band energy with the biological redox potential of select materials predict the MOx’s that can generate cellular oxidative stress, leading to triggering of pro-inflammatory pathways in cells and in the lung. The research in HTS-2 has further extended the bandgap concept by demonstrating that the valence band and Fermi energy levels of p-type semiconductors also play a role in the generation of oxidative stress and acute inflammation. PdO doping of Co3O4 ENMs (Theme 1) has allowed us to create a particle library of homogeneous size, but progressive tuning of band gap and Fermi energy levels that are capable of generating incremental levels of oxidative stress and inflammation at the cellular level. The cellular responses, in turn, showed good correlation to the generation of oxidative stress and inflammation in the murine lung. Gratifyingly, the data generated with 24 MOx’s in mammalian cells could also be duplicated in E. coli grown in minimal trophic media. Thus, of the 24 materials studied, ZnO, CuO, CoO, Mn2O3, Co3O4, Ni2O3 and Cr2O3 were found to exert significant growth inhibitory effects; this growth inhibition correlated with assays assessing bacterial membrane damage and oxidative stress responses. Overall, there is good correlation of MOx hydration energy and conduction band energy levels with biological outcome. The similarity of the response in mammalian cells, demonstrates that the mechanisms of MOx toxicity are consistent across different taxonomic domains. Similarly, the generation of lysosomal injury and inflammasome activation as a result of the surface interactions of RE oxide or RE-doped UCNPs with cellular phosphate residues, has allowed us to develop a predictive toxicological paradigm that links inflammasome activation to the generation of chronic inflammation and pulmonary fibrosis. The SAR linked to phosphate complexation and precipitation of REPO4 on the particle surfaces, also allowed us to develop a safer-by-design strategy, using phosphonates to passivate particle surfaces. In addition to using our existing in vitro screening methods, including the use of fluorescence-based methodology for HTS, the transition to luminescence-based methods allows the introduction of even more sensitive screening assays, which are less susceptible to signal quenching than fluorescence-based methods. Moreover, the introduction of nanowire field-effect transistors for lab-on-a-chip detection of cytokines and cellular biomolecules holds the promise of further refining our screening assays. Altogether, the development of so-called alternative test strategies (ATS) that reduces or replaces animal testing, has allowed CEIN to play a prominent role nationally in discussing with government and industry stakeholders new scientific approaches to assist regulatory decision-making, thereby speeding up nanomaterial commercialization. These accomplishments are discussed in Theme 7.

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Our studies using the zebrafish embryo and larvae for HCS have allowed CEIN to engage in creative environmental research, which allows broad categories of materials to be investigated in a novel way. One example is the ability to perform environmental risk assessment of Cu-based fungicides by using zebrafish embryo screening of the effluent obtained from a model wastewater treatment system. This research has demonstrated the importance of changing the bioavailability of Cu as a result of its organic speciation, thereby allowing us to track the transformation of these materials in a complex exposure environment without the need for direct particle imaging. The novel use of zebrafish screening procedures will be extended to Theme 5, in which zebrafish embryo HTS will be used to study the impact of semiconductor slurries, as well as helping to prioritize the materials that will be used in environmental microcosm and mesocosm studies. We are also using the zebrafish to study the impact of LAR nanomaterials for potential GIT injury, as demonstrated with CeO2 nanorods. We are currently using this screening procedure to investigate hybrid MWCNT materials released from composites. Major Planned Activities for the next period: We will continue the development of predictive toxicological paradigms to perform safety testing, ranking and development of tiered decision analysis for commercial and synthesized ENM libraries. We will expand the use of commercial ENMs in order to be in alignment with the 2014 PCAST recommendations for nano EHS, which advocates the “development of a multidisciplinary nanotechnology environmental, health, and safety ecosystem that promotes non-animal based (alternative) test strategies for safety assessment and multi-stakeholder participation in regulatory decision making and safe implementation to facilitate market access of nanomaterials and nanotechnology-enabled products”. The specific exploration in each project is highlighted in each section discussed above. In addition to addressing commercial ENMs, CEIN will also use zebrafish studies in Theme 5 to leverage the success of this organism for high content screening, with the ability to prioritize studies on aquatic and estuarine species in theme 5. We will work closely with the investigators in Themes 4, 5 and 7 to develop predictive ecotoxicological approaches that will have the same impact as achieved in mammalian systems. It will also be necessary to continue performing mechanistic studies on new ENMs libraries to develop the SARs that can be used for Theme 6 modeling. as well as implementation of safer design approaches.

i Li R., Ji Z., Chang C.H., Dunphy D., Cai X., Meng H., Zhang H. Sun B., Wang X., Dong J., Lin S., Wang M., Liao Y., Brinker C.J., Nel A.E., Xia T. (2014) Surface interactions with compartmentalized cellular phosphates explains rare earth oxide nanoparticle hazard and provides opportunities for safer design. ACS Nano, 8(2):1771-1783. Doi: 10.1021/nn406166n

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Theme 3: Fate, transport, exposure and life cycle assessment Faculty Investigator List: Arturo Keller (UCSB) - Theme leader & Professor, Bren School of Environ. Science & Mgmt. Sharon Walker (UC Riverside) – Associate Dean and Professor, Chemical Engineering Sangwon Suh (UCSB) – Associate Professor, Bren School of Environ. Science & Mgmt. Ponisseril Somasundaran (Columbia University) – Professor, Earth & Environ. Engineering Graduate Students: 12; Undergraduate Students: 23; Postdoctoral Researchers: 2 Short summary of Theme 3: Theme 3 provides the UC CEIN with quantitative information on the fate and transport of the nanoparticles (NPs), the life cycle implications of engineered nanomaterials (ENMs), and experimental methods to measure and estimate likely NP exposure concentrations in different environmental media (e.g. freshwater, estuaries, coastal, terrestrial). Theme 3 Projects:

• FT-1: Life Cycle Impacts Assessment of Engineered Nanomaterials (Suh, Keller) • FT-2: Exposure Assessment in Aquatic Environments (Keller) • FT-3: Exposure Assessment in Terrestrial Environments (Keller) • FT-4: Transformation of nanoparticles in wastewater treatment (Walker) • FT-5: Determining Aquatic Exposure (Somasundaran)

Major Accomplishments since March 2014: FT-1: Life Cycle Impacts Assessment of Engineered Nanomaterials The goal of this project is to perform screening Life Cycle Assessments (LCA) of different engineered nanomaterials (ENMs), including metals, metal oxides, and carbon nanotubes, to predict the annual mass of ENMs released to various environmental compartments (air, water, soils). This information provides predicted environmental concentrations (PECs) of ENMs for use in the dosimetry of toxicological studies in CEIN themes. In 2014, we developed a method to allocate the worldwide release estimates for the top ENMs (generated in 2013i) to eight major regions of the world, and then for the USAii. This approach allowed us to predict ENM concentrations at the local level. For example, we estimate ENM concentrations for the San Francisco Bay area wastewater treatment plant effluent (0.1-50 µg/L) and biosolids (0.5-1000 mg/kg), which cover the range of observed concentrations in these systems. We also published estimates for New York City, London and Shanghai, to illustrate how differences in local production, use and disposal lead to significant differences in release concentrations.23 Since “personal care products” is the most important use category for environmental release of ENMs, we performed an in-depth analysis of the production and use of ENMs for this application.20 Zinc oxide and titanium dioxide were by far the most common ENMs in personal care products, resulting in high release amounts to the environment, either in treated waste water plant effluent or biosolids applied to agriculture. Recent interest in the environmental fate and effects of manufactured nanoceria stem from its expanded use for a variety of applications including fuel additives, catalytic converters, chemical and mechanical planarization media, and other uses. Increasing material flows of nanoceria in many applications will probably result in increasing releases to air, water and soils. We determined that although the release concentrations are increasing they are at present below most toxicity thresholds.5

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The findings from this project have helped guide the selection of case studies for the Copper Working Group (e.g. release and exposure from marine paints and pesticide application) and the Carbonaceous Working Group (e.g. selection of most relevant C-based ENMs based on production volumes and intended applications). The material flow analysis model developed by Theme 3 has now been incorporated into the web-based, open access framework developed by Theme 6. The release and exposure estimates are also being used by Themes 6 and 7 in the development of case studies on Risk Assessment and Alternatives Analysis. FT-2: Exposure Assessment in Aquatic Environments This project seeks to determine the behavior of ENMs in complex aquatic environments such as estuaries, with dynamic salinity, sediment and biota. We recently concluded a case study of the speciation, dissolution, aggregation and sedimentation of copper ENMs in different waters, with and without extracellular polymeric substances (EPS) produced by phytoplankton1, in a 90 day exposure. This allows us to better predict the behavior of these ENMs in Theme 5 estuarine mesocosms where phytoplankton are present. Phytoplankton EPS improved the stability of commercial copper-based nanoparticles in most conditions, in addition to influencing their dissolution. Dissolution rate was pH 4 >> pH 7 > pH 11. The presence of EPS correlated with higher dissolved Cu at pH 7 and 11, and lower dissolved Cu at pH 4. More dissolution was observed at higher IS due to complexation with Cl-. Nano-Cu and Cu(OH)2 were observed to aggregate rapidly to >103 nm while the aggregate size of nano-CuO averaged between 250-400 nm and showed a strong positive correlation with salinity. Aggregate size did not correlate well with sedimentation rate, suggesting sedimentation was primarily influenced by other factors. Nano-CuO was stabilized by the presence of phosphate, which was shown to reverse surface charge polarity at concentrations as low as 0.1 mg L-1 PO4. These results highlight some of the key factors such as EPS, IS, phosphate, carbonate, and ENM oxidation state in determining Cu ENM behavior in natural waters.6 We also conducted collaborative projects on the effect of humic substances45 and coagulants41 on the stability of TiO2 ENMs, with a focus on removing them in water treatment plants. These results are being used to design the estuarine mesocosms in Theme 5, and for the copper ENM risk (Theme 6) and alternatives assessment (Theme 7) case studies. We are planning work with Fe-doped Cu from Theme 1. Until a few years ago, little was known about the fate and toxicity of ENMs in the environment, but recent studies suggest important emerging patterns.10 We found that in general ENMs are more stable in freshwater and stormwater than in seawater or groundwater, which indicates that both transport and exposure risk might be higher in freshwater than in seawater. ENMs in saline waters will sediment out rapidly (hours to days), with a potential for increasing ENM concentrations in sediments over time. Dissolution is significant for specific ENMs (e.g. Ag, ZnO, copper ENMs, nano zero valent iron), which can result in their disappearance over time, but release metal ions that may be more toxic than the ENM. We combined these findings with regards to ENM fate, transport, and exposure with emerging information on nano-ecotoxicity to determine that hazard risk is low for most ENMs at current predicted environmental concentrations. FT-3: Exposure Assessment in Terrestrial Environments The goal of this project is to identify and quantify the physicochemical interactions between ENMs and biological systems that lead to bioaccumulation, trophic transfer, and physiological. In particular we aim to quantitatively determine the uptake, bioaccumulation, biotransformation and transport of different ENMs in CEIN Terrestrial Theme 4 studies. We are investigating the interactions between soils, nutrients, ENMs and terrestrial plants. This three-part project looks at how ENM fate and transport in the terrestrial environment through soil may affect plant uptake of the ENMs, how ENMs interact with

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important nutrients in soil and water, and how plants are affected by the presence of nanomaterials during their life cycle. In transport studies all three ENMs (TiO2, CeO2 and Cu(OH)2) were seen to be mostly retained in the upper 3 cm of a soil column and showed increased transport when coated with Suwannee River humic acid. For the fraction that did transport below 3 cm, it was mobilized well below the root zone of the crop plants. TiO2 and CeO2 at 100 mg ENM kg-1 soil were shown to significantly increase the bioavailability of phosphorous in potting soil and farm soil, respectively, and TiO2 was also seen to increase the water extractable fraction of P in potting soil. No effects on P were seen in grassland soil, possibly due to its low natural concentration of P. We have found that the photoactive ENMs TiO2 and CeO2 reduce the photosynthesis rates of plants grown in fertilized potting soil, while non-photoactive Cu(OH)2 does not. Together, these results suggest that photo-induced ROS production by the two photoactive ENMs interfere with the photosynthetic mechanisms of the plants. Lastly, radishes and wheat were grown in farm and grassland soils, under high and low light conditions and exposed to the three ENMs. Initial results suggest TiO2 and CeO2 reduced water use efficiency in wheat but increased radish biomass. In summary, this project is looking at the nano-bio interface in terrestrial ecosystems by investigating uptake and nutrient interactions with plants and the behavior of ENMs in soils. In a separate study conducted at UCR, groundwater transport of two-dimensional graphene oxide and molybdenum disulfide sheets was evaluated. We found that the hydrodynamic diameter of graphene oxide was stable and unchanging at lower ionic strength (soft groundwater), after which it became unstable in harder waters (ionic strength ≥ 10–1.5 M). Furthermore, graphene oxide was found to be very mobile at low ionic strength (≤ 10–2 M KCl) with only 5% retention in the soils, but had very low mobility at higher ionic strength with >99% of graphene oxide sheets retained in soil. These projects address questions regarding actual environmental exposure levels in Theme 4 studies, as well as the bioavailability of ENMs and nutrients needed for plant growth. The information will also be useful for enhancing the Multimedia Environmental Fate & Transport model developed by Theme 6 to predict exposure in terrestrial systems. FT-4: Transformation and Effects of Nanomaterials in Model Wastewater Systems This study investigates the effects of three copper particles (micron- and nano-scale Cu particles, and a nano-scale Cu(OH)2-based fungicide) on the function and operation of a model septic tank. Septic system analyses included water quality evaluation and microbial community characterization to detect changes in and relationships between the septic tank function and microbial community phenotype/genotype. Each Cu particle elicited a different response within the septic system. During exposure to nano-scale Cu, biochemical oxygen demand (BOD) was reduced by at least 63%, which is in the typical expected range of BOD reduction. A 30-50% reduction is anticipated for BOD in real world septic tanks from the influent to the effluent conditions; this indicates the nano Cu did not cause a disruption in BOD function. Also, pH decreased to ~6.4, outside the optimum anaerobic fermentation range (pH 6.7-7.6) during the micro Cu exposure, indicating that the organic waste may have undergone incomplete degradation due to methanogenesis inhibition. The copper fungicide, Cu(OH)2, caused an increase in total organic carbon (highest recorded value 208 mg/L, average range recorded 54 mg/L), which corresponded to increased BOD (267 mg/L was recorded, typical range between 35-200 mg/L) during the majority of the Cu(OH)2 exposure. However, the septic system was able to recover to typical operating conditions after 3 weeks post-exposure. This suggests that during periods of Cu introduction, there are likely pulses of improper waste treatment and incomplete organic breakdown. Furthermore, high throughput screening (in collaboration with Theme 2 Project HTS-2) using zebrafish demonstrated that “aged” copper complexes with organic and inorganic constituents in the effluent are non-toxic.

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FT-5: Determining Exposure in Terrestrial & Estuarine Mesocosms Accurate assessment of the actual amounts of ENMs in different natural locations presents a very challenging analytical problem. To solve this problem, we have proposed two novel detection methods for ENMs in natural matrices (in natural waters). One method is optical (UV-Vis absorption or fluorescence) spectrophotometry combined with a colorimetric ligand sensitive to a particular metal nanoparticles. However, this method is not sensitive for detecting nanoparticles at low concentration <1% (by wt). Thus, the main goal of this project is to enrich ENMs from soil matrices and then quantify them using spectrophotometry. This novel approach is based on the combination of selective flotation of ENMs followed by spectrophotometric quantification. Using selective flotation by an octyl hydroxamate surfactant, we were able to successfully concentrate TiO2 nanoparticles from a model soil matrix 2-3 times so that we can perform an analysis of ENM concentration and composition. We are also exploring an electrochemical detection method for nanoparticle aggregates in water. This method has advantages of being able to discern the characteristic signal from the nanoparticles, makes it easier to measure the material concentrations, and is portable. The detection of metal oxide nanoparticles is realized by measuring current due to nanoparticle collisions with the surface of a microelectrode. We have successfully validated the use of this method by measuring aggregate size of anatase nanoparticles in water by electrochemical as well as dynamic light scattering methods (~150 nm). These results show a promising start for this in situ electrochemical method that uniquely quantifies each ENM type in aqueous suspension and can be potentially developed for natural waters with complex matrices such as the estuarine mesocosms in Theme 5. Impacts on the Overall Goals of the Center: Theme 3 generated estimates of ENM releases to air, soil and water, and ENM release concentrations, to develop realistic exposure concentrations for Themes 2, 4 and 5. The fate & transport of three types of Cu ENMs in aquatic (e.g. rivers, estuaries, coastal waters) and terrestrial (i.e. soils) was shown to be a strong factor of natural organic matter, and in particular exopolymeric substances, which affects their aggregation and dissolution rates in the estuarine mesocosms, as well as HTS and other toxicity testing. We also determined that in many instances Cu ENMs and graphene oxide sheets will be strongly retained in soils, making them less bioavailable and mobile, which helps to design plant exposure experiments. Cu(OH)2 ENMs were shown to reduce the performance of wastewater treatment plants in terms of BOD removal, but the systems can recover after about 3 weeks post-exposure. Other Cu ENMs had minor effect on wastewater treatment. The aged Cu particles were shown, in collaborating with Theme 2, to have no toxicity to zebrafish embryos. Selective flotation was shown to be a promising approach for concentrating TiO2 particles, separating them from other soil particles, for ENM identification from water or soils, for example for samples from terrestrial (plants) or estuarine mesocosms. Major Planned Activities for Next Reporting Period: Project FT-1 will develop quantitative life-cycle material flows for ENMs in food products. Project FT-2 is working closely with Theme 5 on the fate and transport of Cu ENMs in estuarine mesocosms. Project FT-3 will study the transfer of ENMs from biosolids to soils, in support of Theme 4 terrestrial plant experiments. Project FT-4 will begin evaluating other ENMs in their septic system, including additional metal oxides and carbonaceous ENMs. Project FT-5 will continue to improve the recovery of ENMs and their detection from realistic samples.

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i Keller A.A., McFerran S., Lazareva A. and Suh S. (2013) Global life-cycle emissions of engineered nanomaterials. J. Nanoparticle Research, (15), 1692. Doi: 10.1007/s11051-013-1692-4 ii Keller A.A. and Lazareva A. (2014) Predicted releases of engineered nanomaterials: from global to regional to local. Environ. Sci. Tech. Letters, 1, 65−70. Doi: 10.1021/ez400106t.

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Theme 4: Terrestrial Ecosystems Impact and Hazard Assessment Faculty Investigators: Patricia Holden, UC Santa Barbara – Professor, Environmental Microbiology – Theme Leader Jorge Gardea-Torresdey, University of Texas, El Paso – Professor, Environmental Chemistry Roger Nisbet, UC Santa Barbara – Professor, Theoretical Ecology Joshua Schimel, UC Santa Barbara – Professor, Ecosystem Ecology Graduate Students: 15; Undergraduate Students: 6; Postdoctoral Researchers: 3 Short Summary of Theme 4: The main goals of Theme 4 are to develop approaches to study, and to determine the impacts of, selected manufactured nanomaterials (MNMs) as related to terrestrial processes involving soils, microbes, and plants, and then to model the processes to predict hazards at population, community and ecosystem scales. Nano-TiO2, ZnO, CeO2, Ag-based, Cu-based, multiwalled carbon nanotubes (MWCNTs), graphene, and carbon black (CB) are focal MNMs on the basis of either their high production volumes as per Theme 1, their hazards as per high throughput screening (HTS) in Theme 2, or their propensity to migrate into terrestrial environments as per material flow analyses (Theme 3) and transport simulations (Theme 6). Major progress over the last year has been in modeling and measuring multiple MNM variants (e.g. MOx, MWCNTs, Ag- and Cu-based) for their impacts on microbial and plant populations, microbial communities and trophic transfer, and plant-microbe interactions. Since 2014, we have focused on assessing MNM impacts on environmental bacteria, and broadening the understanding of MNM effects on plant health and quality and on soil microbial communities that support plant growth. A key element of our work has been expanding dynamic energy budget (DEB) formulations towards predicting MNM effects on environmentally-relevant bacterial populations and plant-microbe interactions for soil-grown soybean. Theme 4’s overall impact derives from emphasizing hazard assessment of food crops, using a transferable ecological nanotoxicology system that begins with screening MNM hazards using environmentally-relevant bacteria and hydroponic plants, mechanistically predicting hazards across terrestrial exposures, and judiciously examining bioavailability and trophic interactions using terrestrial mesocosms. Theme 4 Projects:

• TER-1: Interactions of metal, metal oxide, and carbonaceous MNMs with environmentally-relevant microorganisms (Schimel, Holden)

• TER-2: Toxicity and uptake of nanoparticles by terrestrial plant species (Gardea-Torresdey) • TER-3: Metal oxide and carbonaceous MNM effects and fates in terrestrial soil systems (Holden) • TER-4: DEB bacterial population and plant growth modeling (Nisbet)

Major Accomplishments Since March 2014: TER-1: Interactions of metal, metal oxide, and carbonaceous MNMs with environmentally-relevant microorganisms The goals of this project are to develop approaches for determining the impacts of metal, metal oxide, and carbonaceous MNMs on environmentally-relevant microorganisms, and to apply the approaches to understand hazards to microbial populations, communities, and ecosystem-level microbial processes. Using an assay system with multiple measurements targeting membranes (integrity, polarity, the function of electron transfer, and free radical generation measured abiotically, or biotically with live cells), we showed that slowly-dissolving cysteine-capped Ag NPs (from Theme 1, Stucky) reduced

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population growth of Escherchia coli and Pseudomonas aeruginosa in environmentally-relevant (minimal) media due to Ag ions and high cellular reactive oxygen species (ROS)36. A study with Theme 2 (Godwin) showed that E. coli single-gene deletion mutants were similarly more susceptible to Ag ions than Ag MNMs, but that toxicity mechanisms varied with MNM cap chargei. By using high throughput screening (HTS) across 24 MOx MNMs, we collaboratively (with Theme 2) showed that band gaps and hydration energies explained reactive oxygen species (ROS)-mediated bacterial membrane damage and inhibition of E. coli population growth20. Similar low throughput approaches are underway for the environmentally-relevant N2-fixing strain Bradyrhizobium japonicum USDA 110, using culture media developed to support DEB modeling of bacterial population growth as a function of MNM exposure (TER-4). Results show dose-dependency of Cu-based MNM toxicity to B. japonicum growth up to 2 ppm (total Cu basis), implying that the agriculturally-important function of symbiotic N2 fixation could be impaired by Cu-based MNMs. For activated sludge microbial communities (sampled from an anoxic selector at an operating municipal wastewater treatment plant or WWTP), Ag MNMs, but not nano-TiO2, decreased polyhydroxybutyrate (PHB) production by PHB-accumulating bacterial communities involved in phosphorous (P) removal. The impacts were from Ag MNMs dissolving and releasing Ag ions, demonstrating the importance of controlling Ag MNMs in sewage to avoid compromising P removal, an essential process for preventing coastal eutrophication37. Within the Theme 4-led Carbonaceous NM Working Group (CWG, including cross-CEIN, US EPA, NIST and LLNL participants), model carbonaceous MNMs—available in sufficient quantities—were selected for ecological hazard assessments; CB, a historically high production industrial NM, was defined as a negative control material. Recent hazard assessment research for selected carbonaceous MNMs (MWCNTs and graphene, vs. CB) focuses on microbial populations and microbial food chains, toxicity assay performance analysis, and developing environmental HTS using N2-fixing bacteria. Results from studying population level effects of MWCNTs on membrane integrity, membrane potential, and electron transport chain activity of P. aeruginosa (prey) and Tetrahymena thermophila (predator) populations in low-nutrient conditions showed dose-dependent effects above 10 mg/l MWCNTs, with 1 mg/l being subtoxic, as needed for studying trophic transfer of 14C-labeled MWCNTs. With Theme 7, Theme 4 evaluated over 600 peer-reviewed nanotoxicology studies to compare MNM exposure concentrations to those predicted or measured, concluding that microbial studies should improve relevancy by routinely using low-dose exposures and that nanotoxicology broadly must define “environmentally relevant” exposure conditions for future research17. TER-2: Toxicity and uptake of nanoparticles by terrestrial plant species The overall goal of this project is to determine the biological/physiological impacts80 of CEIN-selected MNMs on crop plant species (large scale production and garden grown crops), including MNM trophic transfer and transformation in plants9. We continued studying the effects of nCeO2 in bush bean (Phaseolus vulgaris), radish (Raphanus sativus), tomato (Solanum lycopersicum), wheat (Triticum aestivum), and rice (Oryza sativa); TiO2 in zucchini (Cucurbita pepo); iron doped nZnO (Fe@ZnO) in green peas (Pisum sativum); and Cu NPs/compounds in cilantro (Coriandrum sativum). These studies were mainly focused on determining the effects of the MNMs on the nutritional quality of the plants; as in the previous period we studied MNM effects on plant physiological and agronomical parameters. We also started studying the effects of core–shell Fe/Fe3O4 and Cu/CuO MNMs in lettuce (Lactuca sativa), Cu MNMs/compounds in sugarcane (Saccharum officinarum), carbonaceous materials in green peas, and coated and uncoated TiO2 in basil (Ocimum basilicum). These plants and material reflect the concern of the UC CEIN to study the effects of MNMs likely to achieve environmentally relevant concentrations on plants that are consumed. Hydroponic cucumber exposed aerially to nCeO2 as either powder (0.98 and 2.94 g/m3) or suspension (20, 40, 80, 160, and 320 mg/L) showed uptake through leaves and translocation into the plant; effects included increased root catalase and leave ascorbate

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peroxidase activities18. Both nCeO2 and ZnO MNMs changed the nutritional quality of cucumber fruit, with differing effects on carbohydrates, proteins, antioxidants, and micronutrients45. In corn, the presence of alginate in soil significantly changed CeO2 MNM impacts on seedlings by increasing effects on micro- and macronutrients, chlorophyll, and expression of a heat shock protein44. In wheat, nCeO2 at 500 mg/kg improved plant growth, shoot biomass, and grain yield by 9.0, 12.7, and 36.6%, respectively. There was a lack of Ce transport to the aboveground tissues across the nCeO2 treatments. However, nCeO2 modified sulfur and manganese storage in grains. At low concentration (62.5 mg/kg), nCeO2 also modified the amino acid content, and increased the linolenic acid (an 18:3 fatty acid) content by up to 6.17% but decreased the linoleic acid (an 18:2 fatty acid) by up to 1.63%, compared to the other treatments39. ZnO and CeO2 MNMs altered the micro- and macro-nutrient contents of soil-grown soybean34, and infrared spectroscopy suggests that CeO2 MNMs cause differential effects across rice, wheat, and barley. In radish, nCeO2 at 500 mg/kg significantly retarded seed germination but did not reduce the number of germinated seeds. At 250 mg nCeO2/kg increased the tubers’ antioxidant capacity, expressed as FRAP, ABTS•− and DPPH, by 30%, 32%, and 85%, respectively. Cerium accumulation in tubers of plants treated with 250 and 500 mg/kg reached 72 and 142 mg/kg (dry weight), respectively. In bush bean, nCeO2 was found to reach the root vascular tissues and translocate to aerial parts with time. Upon prolonged exposure to 500 mg nCeO2/L, the root antioxidant enzyme activities were significantly reduced, simultaneously increasing the root soluble protein by 204%, and increasing the leaf guaiacol peroxidase activity29. Fe@ZnO MNMs increased Zn bioaccumulation in roots (200%) and stems (31-48%) but Fe absorption was not affected. At 500 mg/kg Fe@ZnO MNMs treatment decreased chlorophyll content (27%) and H2O2 production (~50%). Toxicity of doped ZnO MNMs was less than that of bare ZnO MNMs as per zinc uptake, chlorophyll content, and ROS (H2O2) accumulation.33 Green peas grown in up to 500 mg/kg ZnO MNM-amended soils had elongated roots, less leaf chlorophyll, lower antioxidant (CAT and APOX) activities, and elevated ROS and leaf lipid peroxidation32. In studies performed as part of the Center’s Cu Working Group, we found that nano-Cu/CuO increased Cu in roots compared to CuSO4 treatment; in roots, all Cu treatments increased CAT activity but decreased APX activity. Nano-Cu/CuO increased Cu, Al and S but reduced Mn, P, Ca,and Mg in lettuce leaves41. Also, hydroponic alfalfa and lettuce exposed to nCu, bulk Cu, nCuO, bulk CuO, Cu(OH)2 (CuPRO 2005, Kocide 3000), and CuCl2 (0, 5, 10, and 20 mg/L) showed that all Cu NPs/compounds reduced root length by 49% in both plant species. All Cu NPs/compounds increased Cu, P, and S (>100%, >50%, and >20%, respectively) in alfalfa shoots and decreased P and Fe in lettuce shoot (>50% and >50%, respectively, excluding Fe in the CuCl2 treatment)19. In zucchini, nTiO₂ induced genotoxicity as reflected by shifts in DNA band intensity as well as both loss and appearance of new bands; this corroborates previous work31. In a novel study of effects on the food chain, zucchini was grown in soil amended with either bulk or nCeO2; leaf tissue was fed to crickets (Acheta domesticus) that were then fed to wolf spiders (family Lycosidae). More ceria accumulated in plant tissue with nCeO2 than with bulk CeO2 and Ce from nCeO2 was transferred up the food chain to a greater extent [23]. Taken together, this research shows the widespread potential for MNMs to be accumulated into crop plants and to degrade the food quality and plant health9. TER-3 Metal oxide and carbonaceous MNM effects and fates in terrestrial soil systems The goals of this project are to assess the impacts of metal oxide and carbonaceous MNMs on terrestrial ecosystems through hazard assessment of microbial communities and plant-microbe interactions, and to develop the capacity to predict MNM effects on terrestrial ecosystems. In this period, we re-evaluated prior microbial community data from MNM-treated soil microcosms to understand sources of data variation, therein showing the importance of batching DNA sequencing efforts to control analytical errors12. We then used two phylogenetic approaches to assess the interactive effects of soybean plants on soil microbial communities exposed to ZnO or CeO2 MNMs, finding that plants reduced the effects of

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ZnO MNMs on soil microbial communities, but increased the impact of CeO2. In ZnO MNM-amended mesocosms, plant root exudates reduced bioavailability or toxicity of Zn ions to soil microbes. However, plant responses to CeO2 MNMs altered the below ground carbon allocation for a low CeO2 concentration such that plants preferentially allocated C to N2-fixing root nodule symbioses. These patterns resulted in concomitant soil microbial community changes11 and reinforce the importance of studying plants and microbial communities simultaneously. In this period, methods were adapted for laboratory cultivation and population synchronization of Caenorhabditis elegans, a model soil nematode, to study its susceptibility to MWCNTs and CB. Also, soils exposed for one year to a series of condensed carbonaceous materials (biochar, CB, three types of MWCNTs, and graphene) were extracted for phylogenetic analysis of soil microbial communities. Additional experiments were performed to determine the cause of initial CO2 release upon amending these carbonaceous materials to grassland soil. Through comparative analysis across this material spectrum, we aim to determine the relative hazard of carbonaceous MNMs that are engineered (e.g. graphene or MWCNTs) versus industrial CB or biochar, for benchmarking terrestrial environmental hazards. TER-4 DEB bacterial population and plant growth modeling The overarching goal of this project is to extend DEB bacterial population modeling and plant hazard assessment into a model of the effects of MNMs in the soil on planted agricultural crop growth. This involves formulating and analyzing new bacterial and plant models that predict hazard effects on selected food crops, using results of mesocosm studies. During this period we developed new, general, modular, “systems” models of ROS dynamics for interpreting UC CEIN data on ROS and other measures of cellular and organismal damage48. These models are poised to have broad impact, because they improve upon current representations of ROS dynamics in DEB models based on previous CEIN studies (e.g. Theme 4 modeling of effects of CdSe quantum dots on bacteria) which were sound but lacked broad applicability30. In the new models, we have confronted limitations such as (i) the common lack of information on the relationships between model variables and proxy measurements used to quantify ROS; and (ii) the diversity of metrics used to characterize cellular damage. The new model framework describes ROS that is created by either metabolism or by toxicant (MNM) action, and describes change over time of both ROS and of cellular damage. ROS and cellular damage dynamics are modeled with both positive and negative feedbacks: ROS production is accelerated by MNM exposure and by damage but ROS is removed though antioxidant enzymes, while damage production is accelerated in response to ROS but mitigated through cellular repair processes. During this period, we found that the model : (i) predicted the time course of co-variation in ROS and damage in response to nanoparticle exposure history; (ii) predicted “tipping points” if either enzymatic control of ROS decreases or cell damage increases; and (iii) provided a mechanistic basis for interpreting observed “no-effect” levels of exposure. Tests of detailed model predictions require time-resolved data, and on-going CEIN experimental work (e.g. mesocosm studies of soybean plants exposed to carbonaceous MNMs) has been designed taking into account the data requirements for the new model. In preparation for this work, during this period we developed a prototype DEB model describing plant bioaccumulation, growth and reproduction, and this work is continuing. We also advanced the development of a modeling framework motivated by the discovery (TER-3) that CeO2 MNMs could shut down nitrogen fixation in soybean nodules. The overall goal to develop a DEB model of N2-fixing bacteria – both free-living and in symbiotic relationship with plants—was advanced in this period by the development of a prototype model structure for N2 fixation in Rhizobia. The impact of the new model is that it incorporates considerable detail including energy requirements for N2-fixation, effects of oxygen tension, production of reactive O and N species (RONS), and inhibition of N2-fixation by RONS. A proof-of-concept study for a model of plant-Rhizobium symbiosis was completed that is being used to support design and interpretation of experimental studies of free-living N2-fixers (TER-1).

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Impacts on the Overall Goals of the Center: Theme 4 is delivering a new understanding of MNM hazards in the terrestrial environment, including how to assess and predict impacts to microbes, how food production and food quality are susceptible to MNMs, and how to mitigate agricultural impacts. The major impacts of Theme 4 research over the last twelve months are:

• Using an assay system that we previously developed for screening NM toxicity to environmentally relevant bacteria, we discovered that slow-dissolving cysteine-capped Ag nanoparticles inhibited bacterial growth from Ag+ ion-mediated ROS accumulation causing membrane damage. A related collaborative Theme 2-led study screened impacts of 24 MOx NPs to E. coli, discovering that growth inhibition scaled with band-gap and hydration energies, mirroring effects and mechanisms discovered previously in the UC CEIN (Theme 2) for mammalian cells

• We discovered that Ag+ ions (from dissolving Ag NMs), but not TiO2 NMs, inhibited polyhydroxybutyrate accumulation by wastewater treatment plant (WWTP) activated sludge bacteria involved in biological P removal.

• We demonstrated nCeO2, following either uptake through cucumber leaves or roots and translocation throughout the plant, caused root and leaf oxidative stress. nCeO2 exposure also changed plant nutritional quality, as it did for corn, wheat, and soybean . Overall, a broad range of food plants (including radish, and bush bean) were shown to be sensitive to nano-ceria according to plant yield and food quality, with effects varying by plant and NP dose. Additionally nCeO2 was trophically transferred from soil-grown zuchinni through insect herbivores to insect predators in a terrestrial food web.

• We discovered that growth, chlorophyll content, and antioxidant activity were reduced in green peas grown with nano-ZnO, but that Fe-doping nano-ZnO decreased such impacts as well as Zn uptake into plants.

• We discovered that Cu-NPs exerted similar effects as Cu-salts when evaluating growth but accumulation of some nutrients was species driven in alfalfa and lettuce.

• We discovered that, likely via plant-mediated effects on belowground carbon allocation, soybean plants reduced the effects of ZnO MNMs, but increased the impacts of CeO2, on soil microbial communities; this reinforces that NM ecosystem impacts likely derive from complex biophysical interactions.

• A new Dynamic Energy Budget (DEB) model was developed to predict time-course ROS generation, by NMs and through normal metabolism, and to include feedbacks from cellular repair processes that scavenge ROS yet are in turn subject to damage. This model will have broad utility across the CEIN.

• An additional conceptual model for DEB parameterization was developed for predicting bacterial and symbiotic N2 fixation under the influence of NM-enhanced reactive oxygen and nitrogen species (RONs).

• Carbonaceous NMs (MWCNTs, carbon black, graphene) were characterized and used in soil, bacterial, and protozoan exposures, revealing differential impacts for foundations in designing trophic transfer and mesocosm studies in the next period.

• Theme 4 (with Theme 7) critically evaluated “environmental relevance” in nanotoxicology by extracting exposure concentrations for < 600 published hazard assessments, and juxtaposing against those predicted or measured to conclude recommended future exposure regimes.

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Major Planned Activities for the Next Report Period: Consistent with Center goals, Theme 4 will conduct research across its four projects over the next 12 months. Final manuscripts are to be completed from a prior collaborative soybean mesocosm study, i.e. regarding plant physiology and N stable isotope analysis. A study regarding stability of various carbonaceous nanomaterials and their effects on soil microbial community will be completed. Trophic transfer and biodegradation of MWCNTs will be assessed in microbial food webs. A study of bacterial biofilm susceptibility to MWCNTs vs. CB will be completed for bacteria grown in sand cultures. New soil-grown soybean mesocosms will be established to test the impacts of MWCNTs and graphene relative to CB on plant growth, using soil type (e.g. C content) as an additional variable. N2-fixing bacterial growth with nano-Cu, -CeO2, MWCNTs, graphene, and CB will be studied, and physiological impacts will be parameterized for DEB modeling. The effects of various coatings and caps will continue as an emphasis for determining how to limit bioavailability of MNMs to soil-grown and hydroponic plants. Also, the range of food crop plants will continue to expand, as will the MNM core chemistries and characteristics, so that the mechanistic understanding of MNM effects on plants can be increased. In addition to the N2-fixing bacteria model, DEB modeling will work to more effectively integrate plant and microbial effects of MNMs on soil-grown crops.

i Ivask A, ElBadawy A, Kaweeteerawat C, Boren D, Fischer H, Ji ZX, Chang CH, Liu R, Tolaymat T, Telesca D, et al.: Toxicity mechanisms in Escherichia coli vary for silver nanoparticles and differ from ionic silver. ACS Nano 2014, 8:374-386.

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Theme 5: Marine and freshwater ecosystems impacts and toxicology Faculty Investigator List Hunter Lenihan (UCSB) – Theme co-leader & Professor, Marine Ecology Gary Cherr (UC Davis) – Theme co-leader & Professor, Ecotoxicology Roger Nisbet (UCSB) – Professor, Ecology Robert Miller (UCSB) – Research Biologist, Marine Ecology Andre Nel (UCLA) – Professor, Medicine (NanoMedicine and Nanosafety) Sijie Lin (UCLA) – Research Scientist, Ecotoxicology Graduate Students: 3; Undergraduate Students: 9; Postdoctoral Researchers: 4. Short summary of Theme 5: Theme 5 addresses biological impacts of engineered nanomaterials (ENMs) in estuarine ecosystems, the ultimate destination for ENMs discharged into watersheds. Estuaries provide important ecosystem services, act as possible sinks for anthropogenic pollutants, and are characterized by distinct spatial gradients in abiotic conditions that influence ENM fate, transport, bioavailability, and toxicity. We examine the impacts of ENMs on sentinel aquatic (estuarine, marine, and freshwater) organisms: (i) single-celled phytoplankton, the major primary producers in aquatic ecosystems that provide a framework for the testing of hypotheses linking ENM physiochemical characteristics to cytological injuries, and then to population-level responses; (ii) Pacific herring and sea urchins, that provide relevant estuarine/marine models for testing mechanistic hypotheses on hatching success and embryonic development; (iii) oysters and mussels, with which we examine immune system and individual performance responses (growth, survival, and reproduction), as well as trophic transfer via phytoplankton; and (iv) zebrafish embryos that provide a High-Throughput-Screening (HTS) platform to test hazards of nano-enabled industrial materials. HTS with zebrafish, and other model organisms used in CEIN, generate or inform hypotheses about fundamental biological impacts of ENMs on the aquatic environment. These hypotheses are then tested in the sentinel aquatic organisms using High-Content-Screening (HCS) combined with model, targeted in vitro and in vivo studies, with the goal of predicting the toxic effects and mechanisms of injury that can be related to ENM physicochemical properties in aquatic environments. Key predictions from these studies are then tested in mesocosm experiments designed to mimic natural estuarine conditions. Theme 5 Projects:

• MFW-1: High Content Screening with Marine and Estuarine Organisms (Cherr, Lenihan, Lin, Miller)

• MFW-2: Estuarine Microcosm and Mesocosm Experiments of ENM Environmental Toxicity (Cherr, Lenihan, Miller)

• MFW-3: Predictive DEB models of toxic effects on an estuarine ecosystem (Nisbet) • MFW-4: Effects of Nanoparticle-based Antifouling Coatings on Marine Biodiversity

(Lenihan, Miller) (Seed Project) Major Accomplishments since March 2014: High Content Screening (HCS) of Phytoplankton and High Throughput Screening (HTS) of Zebrafish (MFW-1, 2, and 3): The goal of this project is to develop and use rapid and HCS approaches in phytoplankton and estuarine bivalves, and HTS with zebrafish to compare batches of ENMs (e.g., metal oxides, CNTs, semiconductor materials) that may cause damage to estuarine and other aquatic environments. HCS was developed for

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single celled phytoplankton based on the great success of zerbrafish HTS. As the major primary producers in estuaries, phytoplankton provide the biomass that fuels estuarine food webs, thus representing sentinel organisms that reflect estuarine ecosystem health. The HTS-to-HCS approach is required because it is not logistically feasible to test various types and categories of ENMs in more complicated mesocosms individually, and we can use the hazard ranking by HCS to prioritize which ENMs we test in mesocosms. HCS can also be used to test how a large numbers of variables in an estuarine environment, such as changes in salinity, pH, natural organic matter, and sediment grain size, influence ENM toxicity in a rapid and integrative manner. Toxicological effects of ENMs can also vary across taxa from different ecosystems, thus our tests help generate information for CEIN to compare responses in terrestrial and aquatic organisms. HCS also provides the predictive capability for linking cytological (subcellular and cellular) injuries caused by ENMs to population-level responses (phytoplankton population growth rate) tested in microcosms, and community processes (trophic transfer between phytoplankton and oysters) tested in mesocosms. During this reporting period, MFW-1 developed phytoplankton HCS to assess numerous cytological effects of high volume nano-metals in the CEIN library. Results from fluorescence-based HCS found that ROS damage of phytoplankton mitochondrial membrane function was linked to reduced photosynthetic efficiency and reduced population growth3,8. HCS results a l s o revealed that toxicity of these ENMs are closely related to the dissolution rate of metal ions, information generated by Theme 3. As predicted, ZnO, the EMN with the highest dissolution rates in seawater, was toxic at lower concentrations than CuO, Ag, and CeO 2 , causing elevated levels of ROS and mitochondria membrane damage at 225 ppb. CuO caused ROS generation and cytological membrane damage at 1 ppm, but increased photosynthetic efficiency at >250 ppb, thus indicating it acted as limiting trace element. Ag generated elevated ROS at 2.5 ppm but caused no cell membrane damage at <10 ppm. Thus, nano-Ag appeared to have low toxicity in seawater. Ce0 2 caused a decrease in photosynthetic efficiency at 5 ppm, but no sublethal cytotoxic effects or reduction in population growth were measured. These HCS results were used to establish a ranking of ENM toxicity that was, in turn, used to predict the impacts at a higher level of biological organization, specifically the population growth of phytoplanktoni. Cytological-focused HCS with phytoplankton was done in collaboration with project MFW-2, which conducted experiments on photosynthesis efficiency and population growth rate on the same organisms. The four metal ENMs that exhibited the highest levels of toxicity in the HCS experiments displayed the same ranking of toxicity to phytoplankton growth rates, with a toxicity ranking of ZnO (>250 ppb) >CuO (>500 ppb) >Ag (>1 ppm) >CeO2 (>2.5 ppm). Overall, photosynthetic efficiency (“PAM”) was a poor predictor of ENM population growth rates, and thus the HCS ranking, because for ZnO and CuO PAM increased while population growth rate declined. A likely reason is that Zn and Cu ions were limiting trace elements for photosynthesis. There was no relationship between PAM and population growth rates under exposure to Ag and CeO2. The most robust cellular endpoint was ROS generation, which predicted population declines for all metals, for the two species of phytoplankton that were examined. Inhibition of the multidrug resistance efflux pumps (ABC transporters) and mitochondrial membrane potential were moderately good predictors of population growth rate changed, and may have promise along with ROS in the further development of phytoplankton HCS, a priority of Theme 5. DEB modeling by MFW-3 provided estimates of EC50 from our phytoplankton HCS data and were used to predict impacts on population growth rates. This work was presented at the 2014 ACS meeting. Additional experiments conducted by MFW-2 compared toxicity of nano-CuO, ZnO, and AgO with Cu, Zn, and Ag micro-sized metal salts (ZnSO4, CuCl2, and AgCl2) to test the hypothesis that the degree to which phytoplankton population growth is reduced by nano vs. micro metals is related to the relative amount

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of metal ions that enter the cell vs. those that attach to the outer cell wall3. This study was motivated by previous CEIN results (Miller et al. 2010, 2011, and Jarvis et al. 2013) suggesting that nano-metals attach to phytoplankton cells and act as time-release agents for ion exposure. As predicted, micro-sized metals were more toxic than nano-metals in each case because cellular uptake of metal ions in cells was higher for metal salts, which dissolved more rapidly than nano-metals14. In summary, the assessment of phytoplankton responses provides a toxicity ranking of large batches of ENMs that link impacts of subcellular responses to phytoplankton responses. The focus of Theme 5 research moving forward is to develop phytoplankton as a robust HCS platform for screening the CEIN library of 24 metal oxide ENMS, testing toxicity predictions of dissolution and the role of aspect ratio of nanoceria, and using the CEIN zebrafish embryo HTS platform to generate predictions to be tested in HCS and population-level assays. In a recently initiated project, which aims to promote collaboration between Theme 2 and 5, we will (i) use the zebrafish embryo HTS platform to assess the hazard potential of nano-enabled industrial products, as well as nanomaterials used in manufacturing processes that might generate potential hazardous waste to the environment; (2) to feed the HTS data into dynamic energy budget (DEB) modeling (MFW-3) with the aim of delineating threshold concentrations at which the nano-enabled products exert adverse effects at the ecosystem level, and to use these data to assist the prioritization of HCS in marine and estuarine organisms and micro/mesocosm studies (MFW-2). In AIM 1 of this work, a library of semiconductor III-V materials was assembled which is comprised of nano-sized GaAS, GaP, InAs, and InP, as well as the micron-sized counterparts, as a study example of nano-enabled industrial products. In AIM 2, we propose to perform zebrafish embryo HTS to understand the kinetics and abundance of III-V sorption to Chemical Mechanical Planarization (CMP) nanoparticle surfaces. These will be modeled using a DEB-based representation recently formulated and tested for CoO nanoparticles. In AIM 3, a library of magnetized silica nanoparticles (MSN) will be established (in collaboration with Dr. Jeff Zink) to study the sorption characteristics of III-V materials in relation to the physicochemical properties of silica nanoparticles, e.g., particle size, surface area, and surface change etc. Following Aim 3, AIM 4 will assess the hazard potential of sorbed III-V materials on silica nanoparticles through comparisons to III-V materials alone and the non-sorbed MSNs. Overall, this integration of zebrafish HTS into MFW-1 will provide hazard assessment data and ranking of III-V materials and CMP nanoparticles to allow DEB modeling and prioritization of studies on marine and estuarine organisms as well as micro/mesocosms48.

High Content Screening with mussel and oyster hemocytes (MFW-1): Hemocytes are the primary immune cells of invertebrate animals (e.g., mollusks) that carry out phagocytosis, a critical immune mechanism that protects against pathogens. Dysfunction of hemocytes through reduced cell viability, mitochondrial membrane permeability results in decreased individual health and population abundance of mollusks, which provide seafood and ecosystem services such as maintaining water quality. We developed the first ENM HCS platform for estuarine and marine invertebrate organisms, which are major biological components of estuarine and marine ecosystems, to test whether predictions of ENM toxicity generated by zebrafish HTS and phytoplankton HCS are valid for these organisms. The novel assay was made possible by developing a new 96-well HCS tool based on Hoechst 33342 stains. In the preliminary test, CuO NMs decreased phagocytosis at 1 ppm and cell viability at 5 ppm. However, soluble CuSO4, used as a positive control, was significantly more toxic than the nano-Cu form. Soluble ZnSO4, another positive control, and nano-ZnO were very similar in their toxicities (toxic at >5 ppm), which was expected based on ZnO’s rapid dissolution in seawater. Ag ions (effects at 1 ppm) were more toxic than nano-Ag (effects at 5 ppm), which was probably a result of limited dissolution of nano-Ag over the short assay period (2 hrs). SWCNTs decreased cell viability

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starting at 2.5 ppm, but stimulated hemocyte phagocytosis only in the presence of a natural stimulant, Zymosan (yeast) that is routinely used in immunoassays. Tests are underway to screen all 24 CEIN nano-metals in the library with mussel or oyster hemocytes and to generate predictions of ENMs impacts in mesocosm exposures. Overall, molluscan hemocyctes promise to be a robust HCS tool for aquatic organisms. Impacts of ENMs on marine and estuarine embryos (MFW-1): The goal of this research was to assess the effects of ENMs on normal development of sea urchin and herring embryos, which represent a widely-used marine model system for assessing stage-specific impacts of environmental contaminants. The work during this period focused on nano-ZnO and nano-CuO, a model ENM examined by the Cu working group. Two different CuO NMs were studied, one a highly purified NM from Univ. Bremen with relatively low solubility, and a commercial NM from Sigma with very low solubility. Both were compared to soluble micro-sized Cu2+ (CuSO4). Oxidative stress responses were determined for all three copper compounds, as was intracellular copper levels. A new nuclear staining approach was developed for cell viability and quantitation for normalizing all probe responses. We also tested sea urchin embryos to determine whether non-toxic levels of CuO NMs can act as chemosensitizers (making other toxic chemicals even more toxic) through inhibition of efflux transporters. Results showed that nano-CuO and nano-ZnO produced inhibition of ABC transporters at different developmental stages of sea urchin embryos based on metal solubility differences. After the first 30 min post-fertilization, crosslinking of the fertilization envelope reduced the inhibition of ABC transporters by nano-CuO. At >30 min post-fertilization, ABC inhibition by nano-ZnO occurred due to the metal oxide undergoing rapid dissolution. This indicates that the crosslinked fertilization envelope (>30 min post-insemination) protects embryos from exposure to NMs, but not soluble metals ions. Nano-CuO and nano-ZnO, at non-toxic concentrations (500 ppb), significantly increased another chemical’s (e.g., vinblastine) toxicity, indicating that they act as chemosensitizers in sea urchin embryos, and therefore can make organisms more susceptible to other contaminants that are substrates of efflux pumps. This is a potential new source of indirect NM toxicity. Work was also initiated with Pacific herring (Clupea pallasii) embryos comparing CuO ENMs and bottom paint with nano-CuO ENMs. Herring, an important commercial fish, represent a highly relevant estuarine-marine analogue for zebrafish, allowing us to test hypotheses generated in our zerbrafish HTS experiments but under estuarine conditions. No toxic impacts of commercial CuO NMs were observed in herring embryos, but significant embryo toxicity (but not hatching inhibition) with soluble CuSO4 was observed. Similar impacts on sea urchin embryos have been observed for nano-CuO and Cu2+ (no effect on hatching but severe developmental abnormalities). A paper is being prepared that will report these results.

Effects of Ti02 ENMs on phytoplankton sinking and the marine Carbon cycle (MFW-2): A goal of Theme 5 is to develop novel approaches to explore the potential global-scale environmental implications of ENMs. One such global-scale process involves the marine-atmosphere carbon cycle, in which phytoplankton play a major role by taking up carbon, in the form of CO2, during photosynthesis, thus providing a critical environmental sink for atmospheric carbon that enters ocean surface waters across the seawater-atmosphere interface. The uptake of CO2 by phytoplankton, and subsequent phytoplankton growth, death, and sinking/depositing into deep water constitutes the world’s most important natural “pumping” system for removing and sequestering anthropogenic CO2 emissions. We developed microcosm experiments with phytoplankton to test the hypothesis that exposure of nano-Ti02 increases the sinking rates of coastal phytoplankton cells and phytoplankton-produced bio-products (i.e., marine snow), and thus increases the rate at which carbon is removed from surface waters and

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sequestered in deep ocean sediments30. This study system was designed based on our prior work that showed substantial aggregation of nano-Ti on phytoplankton cells (Miller et al. 2011). Preliminary results indicated that exposure to TiO2 concentrations of 0.25-1 ppm increased the sinking rate of phytoplankton cells and marine snow, mainly because the ENMs were sequestered in cell metabolites. The results in terms of potential ocean carbon sinking rates are being modeled. Estuarine mesocosm design, construction, and experiments (MFW-1, 2, and Theme 3): Another goal of Theme 5 is to test whether paradigms of ENM toxicity generated from HTS and HCS hold true under varying and complex environmental conditions, with a focus on the physically very dynamic estuarine environment, which acts as a major sink from anthropogenic contaminants. To test predictions of ENM toxicity in estuaries, we designed and built a multiparameter mesocosm at the UC Davis Bodega Marine Laboratory (BML) that will be used to test impacts of a subset of the CEIN ENM library on sentinel estuarine organisms, especially phytoplankton, mussels and oysters that feed on phytoplankton, benthic invertebrates living in estuarine sediments (where we expect ENMs to concentrate), and killifish which eat benthic invertebrates. The mesocosm system enables manipulations of salinity, temperature, organic content of water and sediment, and sediment grain size. We conducted an initial fate and transport experiments with nano-CuO in collaboration with Theme 3, and also tested the impacts of CuO on oyster hemocytes in changing salinity. CuO ENMs are the first case study for mesocosms experiments, along with a control micro-Cu compound, CuCl2. Results of the preliminary experiment are currently being analyzed. The first experiment exposing Pacific oysters to CuO in the mesocosm was completed and stress responses, including assessment of induced thermotolerance and HSP70 expression, were measured and the results are being processes. Preliminary tests of killifish exposures to CuO were conducted in November 2014 and results are also being analyzed. The next steps for mesocosm experiments are to conduct additional runs with Theme 3 testing hypotheses about the influence of changing salinity on the fate and transport of nano-Cu and other EMNs; to expose phytoplankton to nano-Cu and Zn under varying salinities to compare phytoplankton growth rates with prior results from microcosms (Miller et al. 2010); and to expose Pacific oysters to nano-Cu and Zn contaminated phytoplankton as a means to assess trophic transfer under varying salinities. Experiments with other ENMs will also be conducted based on results from HCS experiments. Future work testing HCS-based predictions of CNT impacts in marine organisms will utilize isotopic methods developed for tracking CNTs that we reported during this period15.

DEB models to support continuing experiments on freshwater plankton (MFW-3): Population level predictions using DEB models are rarely tested, yet testing is essential if data from HTS/HCS are to be used as components of predictions for populations30,48. The need for empirical evidence of DEB performance motivates continuing long-term (2-3 month) DEB-guided chemostat experiments relating suborganismal, individual, and population properties of freshwater zooplankton exposed to Ag NPs (Stevenson et al. 2013 cited in last report). These will be the first rigorous tests ever conducted on individual-to-population dynamic connections for animals exposed to ENMs. In view of experimental evidence that phytoplankton in the freshwater systems were experiencing dual nutrient limitation (N and P), we tested a “standard” DEB model. This was inconsistent with data. New DEB-based models are in development; having a model that fits both batch and continuous (chemostat) culture data is an essential prerequisite for modeling the effects of Ag NPs used in the studies. We completed a series of experiments on Daphnia performance (growth, survival, reproduction) when experiencing simultaneous low food availability and exposure to Ag NPs. DEB models were formulated to interpret these data. DEB models were also used successfully to measure the impact of metal-oxide ENMs on phytoplankton population growth responses, and have been integrated into HTS studies with zebrafish.

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Effects of nanoparticle-based antifouling coatings on marine biodiversity (MFW-4, Seed Project): “Biofouling” by organisms that grow on manmade surfaces in the ocean increases drag, weakens structures, and transports invasive species, and millions of dollars are spent addressing it and preventing it using antifouling coatings. Most antifouling coatings at present are Cu-based paints, and some include nano-scale Cu. This project tests the impact and efficacy of nano-Cu and Zn based antifouling paints compared with traditional coatings at three locations across the California coast. Fouling plates that mimic boat bottoms are painted with traditional Cu-based, nano-based copper, traditional zinc-based, and nano-based zinc and deployed for 8 months. Organisms on all plates are identified and counted producing data to detect effects on both species diversity and the abundance of single species. Detection of metal leaching from each treatment coating is conducted with diffusive gradient in thin films (DGT), and the collection of filter-feeding organisms at varying distance from the treatment plates (10 cm, 50 cm, 1m) to evaluate whether metals leaching from the coatings are taken up by nearby organisms. Lab experiments quantify leaching of metals from nano vs. conventional coatings. To date, fouling plates have been fabricated and prepared for deployment in the field. Laboratory experiments have been completed for two types of non-nano Cu-based paints and are underway for nano-Cu and four zinc-based paints, including one employing nano ZnO. Both Cu paints showed considerable release (leaching) of dissolved copper. Impacts on the Overall Goals of the Center: Theme 5 contributes to the overarching goals of the Center, namely to develop hazard ranking and structure-activity relationships (SARs) that relate the physicochemical properties of ENM libraries, including semiconductor III-V materials (e.g., nanoparticles used in chemical mechanical planarization), those with varying aspect ratios, and band gap energy, to toxicological responses in aquatic organisms, with a goal to develop predictive toxicological paradigms. Such paradigms are vital for determining the extent to which hazard ranking and SARs developed through HTS and HCS assays relate to impacts at higher biological levels, specifically marine and estuarine populations and communities, which are the major foci in environmental science for assessing and detecting environmental harm and injury in aquatic ecosystems. Theme 5 tests impacts of nanomaterials on estuarine, marine, and freshwater organisms that are important in providing human society with ecological good and services, such as nutrient cycling, seafood, and habitats that support biodiversity. Our work is contributing significantly to our understanding of how the environmental implications of nanomaterials vary across taxa and with dynamic environmental (i.e., abiotic and biotic) conditions. Specific achievements in the reporting period that contribute to these goals include:

• Phytoplankton HCS assessment of numerous cytological effects caused by high volume nano-metals in the CEIN library showed that ROS damage of phytoplankton mitochondrial membrane function was linked to reduced photosynthetic efficiency and reduced population growth. Toxicity of metal and metal oxide ENMs (e.g., ZnO, CuO, CeO2, nano-Ag) was closely related to dissolution rates. Phytoplankton HCS protocols are now being expanded into a routine assessment tool.

• ENM rankings from phytoplankton HCS were used to predict impacts at higher levels of biological organization, such as phytoplankton population growth.

• HCS platform based on hemocytes (primary immune cells for invertebrates that protect against pathogens) of mollusks was developed. Results indicated that ZnO, CuO, nano-Ag, and single-walled Carbon nanotubes damaged hemocytes, and thus impaired mussel and oyster immune system functioning through reduced phagocytosis. However, impacts were observed only at relatively very high concentrations (1-5 ppm in seawater).

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• Established impacts of graphene and metal oxide nanomaterials on multidrug resistance transporters in both marine embryos (herring and sea urchins) and mammalian cells.

• During early development in sea urchins, the fertilization envelope protects the developing embryo from particulate metal oxide nanomaterials but not dissolved ions.

• Metal ions inhibit the freshwater zebrafish hatching enzyme, but no effect on hatching was observed for marine fish (Pacific herring) or sea urchin embryos, suggesting differences in responses between aquatic environments.

• Designed and constructed a mesocosm system at the UC Davis Bodega Marine Laboratory (BML) that will be used to test impacts of a subset of the CEIN ENM library on sentinel estuarine organisms.

• Long-term (complete life cycle) experiments on the effects on the model organism Daphnia of simultaneous food stress and exposure to Ag nanoparticles – critical data for DEB model of freshwater plankton communities.

• Developed a new DEB-based model of zebrafish hatching. • Demonstrated the effect of exposure to TiO2 on the sinking rate of phytoplankton cells and on

marine snow, important processes for marine carbon cycling. • Estimated leaching rates of six types of marine nano-based antifouling paint in the laboratory to

predict effects in a field experiment designed to test effects of nano-paints on marine ecosystems and inform California regulatory agencies.

Major Planned Activities for the Next Reporting Period: Focus in the next 6-12 months will be on further developing robust HCS platforms and DEB models based on phytoplankton and molluscan hemoctytes that can be used to screen CEIN library materials, especially the 24 metal oxides and CNTs, with a special emphasis on testing hypotheses developed in HTS with zebrafish concerning dissolution, aspect ratio, cell membrane lysis, and fibrogenesis. HTS with zebrafish, coupled to DEB-based models, will forge ahead by screening the semiconductor III-V materials library comprised of nano-sized GaAs, GaP, InAs, and InP, as well as the micron-sized counterparts. The study will determine zebrafish embryo hatching rates, survival, and morphological abnormalities. We will also perform HCS of ionic materials sorbed to surfaces of silica nanomaterials to estimate the environmental hazards of industrial slurries. These slurries can be introduced to estuarine and terrestrial media from which particles can be retrieved for HCS and population level assays. We will complete freshwater plankton coupled population dynamic experiments, as well as mesocosm exposures of phytoplankton, oysters, and killifish, and field experiments with NM boat bottom paints.

i Muller, E.B., S.K. Hanna, S.K., R.J. Miller, H.S. Lenihan, and R.M. Nisbet. 2014. Impact of engineered Zinc Oxide nanoparticles on the energy budgets of Mytilus galloprovincialis. Journal of Sea Research 94: 29-36.

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Theme 6: Environmental Decision Analysis for Nanomaterials Faculty Investigator List Yoram Cohen, UCLA – Professor, Chemical and Biomolecular Engineering – Theme Leader Donatello Telesca, UCLA – Assistant Professor, Department of Biostatistics Rong Liu, UCLA – Assistant researcher, Institute of the Environment and Sustainability Robert Rallo, URV – Associate Professor, Departament d’Enginyeria Informatica i Matematiques Sharon Walker, UCR – Associate Professor, Chemical and Environmental Engineering Andre Nel, UCLA – Professor, Medicine; Chief, Division of NanoMedicine Arturo Keller, UC Santa Barbara – Professor, School of Environmental Science and Management Hilary Godwin, UCLA – Professor, Environmental Health Sciences Graduate Students: 2; Postdoctoral Researchers: 2 Short summary of Theme 6: Theme 6 research focuses on the development of rigorous approaches to identify and rank ENMS of potential environmental concern. This goal is pursued through integration of knowledge derived from high content data generated via HTS (Themes 2 and 4) and other toxicity studies (Themes 4 and 5), assessment of the environmental distribution of ENMs based on multimedia fate and transport (F&T) analysis and experimental mesocosm studies of Themes 3- 5. The premise of the approach is that environmental impacts are governed by toxicity of and exposures to ENMs. Therefore, environmental impact assessment (EIA) requires estimates of potential ENMs exposure concentrations, dose, toxicity information and analysis platform to support decision making regarding safe design and use of ENMs. Accordingly, Theme 6 over the past year has engaged in developing: (a) an advanced modeling platform (implemented for cloud-based computing) for EIA of nanomaterials (NanoEIA), and (b) case studies to elucidate the potential environmental impact of ENMs. As an integral component of the above effort, Theme 6 is exploring (via machine learning and statistical methods) voluminous ENM toxicity data (Themes 2, 4 and 5) to develop hazard ranking. Theme 6 is also integrating Theme 3 approaches for ENMs emission estimates with multimedia F&T modeling to assess various potential exposure scenarios, and for integration within the NanoEIA framework. Theme 6 Projects:

• EDA-1: Computational models of Nanomaterial Toxicity (Cohen, Telesca, Rallo) • EDA-2: Multimedia Analysis of the Environmental Distribution of Nanomaterials (Cohen, Rallo,

Keller) • EDA-3: Environmental impact analysis for nanomaterials (Cohen, Godwin) • EDA-4: Development of in-vitro Dosimetry Model to Improve ENM toxicity Analysis (Seed Fund)

(Liu, Xia) Major Accomplishments since March 2014: In pursuing its objectives Theme 6 has accomplished the following: i. A methodology was developed for nano-(Q)SAR development that makes use of support vector

machine (SVM) technique along with a sequential forward floating selection (SFFS) to identify the relevant QSAR descriptors and applicability domain. The above approach was applied to arrive at new and highly accurate toxicity QSARs for surface-modified iron-oxide NPs and gold NPs with various surface ligands. In addition, a highly accurate QSAR was developed for bacterial toxicity of metal oxide, in collaboration with Theme 2, demonstrating significant correlation of toxicity with metal ion hydration enthalpy and NP conduction band energy;

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ii. A meta-analysis approach was developed (with Theme 2) based on random forest machine learning technique and utilized to arrive at a comprehensive evaluation of the body of evidence regarding the toxicity of quantum dots, based on 1,741 QD toxicity data samples extracted from over 300 published studies;

iii. A visual data analytics approach was developed in collaboration with Theme 4 and applied to explore the impact of ZnO and TiO2 NPs on soil bacterial communities;

iv. A web-based model of the environmental multimedia distribution of nanomaterials (MendNano) has been completed, validated and utilized to assess both the potential environmental ENMs exposure concentrations and as a teaching tool in undergraduate/graduate course on environmental impact assessment;

v. A Lifecycle Environmental Assessment for the Release of Nanomaterials (LearNano) was developed (in collaboration with Theme 3) as both a standalone web-based model and as part of an integrated platform with MendNano to rapidly estimate the potential release and environmental distribution of nanomaterials (RedNano) and thus estimate potential ENMs exposure concentrations;

vi. An improved computational model of the agglomeration of nanoparticles (in collaboration with Theme 3) was advanced that considers hydration repulsion energy in addition to van der Waals attraction and electrostatic repulsion energies;

vii. A computational model was developed to estimate ENM sedimentation (i.e., delivered dose) accounting for particle Brownian diffusion with the considerations of the full particle size distribution (PSD), the fractal structure of ENMs agglomerates, and agglomerate porosity;

viii. A comprehensive review was completed of environmental impact assessment (EIA) approaches that are potentially applicable to ENMs and an EIA approach for ENMS was formulated. Subsequently, a first generation decision support tool, which can provide an assessment of the suitability of available information for EIA, was implemented using a decision-tree and Bayesian network techniques.; and

ix. The collection of computational tools for analysis of NPs toxicity data, fate and transport analysis and decision analysis support tools were integrated as part of a new nanoinformatics web-portal (www.nanoinfo.org).

Additional details of the above accomplishments and ongoing efforts are addressed in the following Theme 6 projects: EDA-1: Quantitative Structure-Activity Relationships (QSARs) of Nanomaterials Toxicity and Physicochemical Properties. An improved workflow for nano-(Q)SAR development was designed for exploring both linear and non-linear (based on epsilon support vector regression (ε-SVR)) relationships between ENM properties and their induced cellular responses. The workflow included sequential forward floating selection (SFFS) for identification of suitable nano-(Q)SAR descriptors. QSAR prediction accuracy was estimated via a bootstrapping validation approach, which has proven particularly suitable when confronted with limited number of training samples (e.g., ENMs). A multiple-round random permutation approach was also introduced to assess both QSAR robustness and descriptor significance. In addition, a new applicability domain analysis method was developed for non-linear QSARs using average kernel similarity instead of the conventional leverage that is only suitable for linear QSARs. Based on the above methodology, QSARs were developed for cellular uptake of NPs of the same iron oxide core but with different surface-modifying organic molecules. The majority of the identified linear and ε-SVR nano-QSARs were related to lipophilicity and van der Waals surface areas, while atomic partial charges, atom and bond counts, and molecular size were also found to be significant in correlating NP uptake. A linear QSAR provided high prediction accuracy of R2=0.751 (coefficient of determination) using 11 descriptors selected from an initial pool of 184 descriptors calculated for the NP surface-modifying molecules, while a ε-SVR

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based QSAR with only 6 descriptors improved prediction accuracy to R2=0.806. The linear and ε-SVR based QSARs both demonstrated good robustness and well spanned applicability domains and outperformed previously reported nano-QSARs developed based on the above dataset. In biological fluids proteins adsorption on the NP surface form a “protein corona”, thereby impacting cellular bioactivity. In order to identify the specific proteins that are relevant to NPs cellular association, Theme 6 expanded its collaboration with Professor Warren Chan’s group (University of Toronto) and explored an extensive gold NPs protein corona dataset71. The study relied on the utilization of QSARs to explore the relationships between NPs cell association and protein corona fingerprints (PCFs) as well as NP physicochemical properties. It was shown that a non-linear ε-SVR model with only 6 serum proteins and zeta potential had higher accuracy (R2=0.895) relative to the linear model (R2=0.850) with 11 PCFs. Considering the initial pool of 148 descriptors, the APOB, A1AT, ANT3, and PLMN serum proteins along with NP zeta potential were identified as the most significant in correlating cell association with gold NPs. Consistent with previous Theme 6 work on cytotoxicity QSARs, a collaborative effort with Theme 2 demonstrated the significant correlation of bacterial toxicity with the NP conduction band energy and the metal ion hydration enthalpy E. coli.20. A classification nano-(Q)SAR based on support vector machine (SVM) demonstrated prediction accuracy as high as 91.5% (per 0.632 estimator). A nano-(Q)SAR utilizing the redox potential instead of conduction band energy was of lower classification accuracy (74%), suggesting that the conduction band energy is a more significant correlating parameter for bacterial toxicity. The above developed nano-QSARs provide quantitative information to guide the control and manipulation of NP physicochemical properties, surface modifications, and protein binding support the planning and interpretation of NP toxicity studies and guide the design of NPs for various applications. In order to arrive at a comprehensive understanding of the significance of various factors that could impact NP toxicity, a meta-analysis approach was developed in collaboration with Dr. Medintz’s group (U.S. Naval Research Laboratory) for assembly and generalization of published engineered nanomaterial cellular toxicity data. The methodology was demonstrated for semiconductor quantum dots (QDs) data mined from 307 publications, generating 1,741 QD toxicity data samples, each with 24 qualitative/quantitative attributes describing QD properties and experimental conditions. Random forest (RF) modeling was then utilized to assess the adequacy, consistency and generalizability of literature QD toxicity. RF based predictive models demonstrated performance of R2=0.67 for cell viability as a toxicity metric, with good performance (typically acceptable for data-driven models) of R2=0.75 for the IC50 model. In addition, a similarity network was established based on the proximity obtained during RF model development for QD cell viability, indicating not only the high heterogeneity in QD literature data but also the existence of different QD attribute-cell viability correlations. Data analysis via predictive RF models demonstrated that toxicity closely correlated with QD surface properties (including shell, ligand, and surface modifications), diameter, assay type, and exposure time. This approach, integrating quantitative and categorical data, provides a roadmap for interrogating compiled ENM toxicity evidence to identify key correlating attributes and suggests that meta-analysis can support ongoing efforts to develop predictive nanotoxicology. In collaboration with Theme 4, a new approach to visual data exploration was developed aimed at evaluating the impact of ZnO and TiO2 nanoparticles (NPs) on soil bacterial communities79. Data on the impact of ZnO (~20-30 nm) and TiO2 (~15-20nm) NPs on soil bacterial communities (exposure times of

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up to 60 day and NP dose range of 0.05-2.0 mg/g (soil). Interrelationships between NP and responses of bacterial taxa were illustrated by bipartite graphs, allowing fast identification of important soil bacterial taxa that are susceptible to NPs. Hierarchical clustering and nonmetric multi-dimensional scaling (NMDS) of the dataset demonstrated that, high dose of ZnO and TiO2 NPs caused significant compositional changes in soil bacterial communities. The suitability of family level for NP impact assessment was demonstrated by the simplified NMDSs and the distance correlation between NP impacts summarized at different taxonomic levels. In support of Theme 2, statistical analysis based on strictly standard mean difference (SSMD) was carried out for toxicity data of human bronchial epithelial (BEAS-2B) and mouse macrophages (RAW 264.7) exposed to a library of PdO doped Co3O4 NPs39. The analysis confirmed that the generation of cellular oxidative stress is indeed due to the conduction band energy when it is within the range of the biological redox potential (-4.12 to -4.84 eV). EDA-2: Multimedia Analysis of the Environmental Distribution of Nanomaterials The design of a modeling platform for Lifecycle Environmental Assessment for the Release of Nanomaterials (LearNano) and its web-based implementation was completed, in collaboration with Theme 3. LearNano tracks the mass release rates of ENMs from their production, through use in various applications (e.g., coating, cosmetic, composite), to disposal and release to the environment. LearNano enables exploration of ENMs release rates associated with various ENM applications to different regions. LearNano was also integrated with MendNano to directly enable estimation of release rates within the MendNano simulator user interface.78

Using the integrated simulator (i.e., LearNano/MendNano) for estimating the release and environmental distribution of nanomaterials (RedNano) simulations were carried out to investigate the effect of intermedia transport processes (i.e., dry deposition, rain scavenging, wind dilution) on the environmental concentration of ENMs78. Simulation results revealed that over the range of typically expected meteorological conditions, wind dilution, rain scavenging, and dry deposition removes 90% of ENMs from atmosphere airshed within ~0.5 – 2 days, ~2 – 6 hrs, and ~100 – 230 days, respectively. Since rain events are episodic, annually averaged ENM removal rate by rain is expected to be significantly higher than that for dry deposition, even for areas of low rainfall. In order to develop an expanded library of potential NPs multimedia exposure concentrations (and mass distributions) various scenarios were simulated for a range of NPs (TiO2 and CeO2) in 12 selected countries, whereby release rates were estimated using LearNano78. Uncertainty in release estimates (as quantified by the relative difference between high and low release estimates) is a factor of 1.36 – 12.3. The difference in release rates between countries with highest and lowest total release rates is a factor 130 – 257. Simulation results revealed that expected regional average exposure concentrations are in the range of 0.0003 - 30 ng/m3 (air), 0.0058 - 150 ng/L (water), 0.0095 - 40 μg/kg (soil), and 0.0054 - 100 mg/kg (sediment). As expected, ranking of total release rates and based on environmental concentrations for the 12 countries are attributed to differences in regional geography and thus release rates per unit area. Another set of simulations was carried out for TiO2, SiO2, and CNT to assess the impact of environmental releases associated with various ENM use applications78. The results demonstrated that coating, paints, pigments and cosmetics contribute most significantly to the release of TiO2 (combined 80% - 98%). Energy and environmental application contributes significantly to the release of SiO2 and CNT to air and soil (20% - 46%), while ENM releases associated with coating, paints, and pigments are the largest contributors to SiO2 and CNT releases to water. ENM used in Composite is also a major release source for CNT to air.

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Agglomeration of NPs affects their transport and thus, the CEIN NP agglomeration model was extended to include the effect of hydration repulsion (HR) energy27. HR parameters were tuned based on experimental measurements of PSD performed in collaboration with (Theme 3), as well as measurements obtained from published studies for TiO2, CeO2, SiO2 and α-Fe2O3 (hematite). Simulation results showed that the classical DLVO theory (without account for HR interaction energy) significantly underestimates the total repulsion energy in suspensions of high IS or low ζ-potential (by up to a factor of ~9). In contrast, in suspensions of low IS and high absolute ζ-potential, the impact of accounting for the contribution of HR energy to the total interaction energy on the prediction accuracy may be negligible. Therefore, simulations based on only classical DLVO theory may overpredict agglomerate size by up to a factor of X for the above ENMs over IS range of 1-600 mM and ζ-potential range of 5-50 mV, where the degree of overprediction is most significant in NP suspensions of high IS and low ζ-potential. EDA-3: Environmental Impact Analysis of Nanomaterials A web-based nanoinformatics platform (www.nanoinfo.org) was developed to provide the necessary support tools for comprehensive assessment of environmental impact analysis (EIA) for ENMs. The nanoinformatics platform currently incorporates the following tools: (a) Lifecycle assessment for the release of nanomaterials (LearNano), (b) Multimedia environmental distribution of nanomaterials (MendNano), (c) High throughput/content data analysis tools (HDAT), (d) Database of nanomaterials properties (NanoDatabank), and (e) Environmental impact assessment for nanomaterials (NanoEIA). As a first tier in EIA, an environmental impact screening (EIS) was developed based on a comprehensive literature review of environmental risk assessment approaches. The EIS is intended to guide the EIA analyst by providing a preliminary assessment of the adequacy of the available data for conducting quantitative EIA. The EIS approach was refined and it is now functional as an online tool for several different ENM types and their applications. A hierarchical tree based approach (i.e., Dempster Shafer evidential reasoning) was adopted for the EIS tool which provides aggregation of an overall probabilistic score for quantitative analysis. The above EIS approach enables aggregation of uncertainties of lower level attributes to arrive at a “global” uncertainty for the overall assessment and thus the level of confidence for subsequent quantitative EIA. In further support of EIA, a new meta-analysis approach (based on Bayesian Networks) was developed for assessing the body of evidence with respect to published literature regarding the toxicity of nanomaterials.

EDA-4: Development of in-vitro Dosimetry Model to Improve ENM toxicity Analysis (Seed Funding) in order to expand the dosimetry analysis, a computational model was developed to estimate ENM sedimentation (i.e., delivered dose) accounting for particle Brownian diffusion and settling considering the full particle size distribution (PSD), the fractal structure of ENMs agglomerates and agglomerate porosity. Model results demonstrated that when considering the full PSD there is reasonable agreement of model predictions with measured sedimentation fraction for the evaluated NPs (i.e., CuO, Co3O4, CoO, Cr2O3, Mn2O3, Ni2O3, and ZnO). Sedimentation data were obtained based on analysis of hydrodynamic size distribution by dynamic light scattering (DLS) in BEGM and DMEM tissue culture media, in addition to elemental analysis (via ICP). The developed sedimentation model was implemented as a web-application in order to enable rapid evaluation of the relevance of delivered versus administered dose in high throughput screening (HTS) demonstrated the same dose-response slopes (i.e., unchanged toxicity ranking in terms of potency), irrespective of whether delivered or administered dose metrics (on the basis of total mass in the plate well) were used. It is also noted that for NP systems that exhibited complete sedimentation (i.e., Cr2O3, Mn2O3, CoO, and Ni2O3), within the experimental exposure period, relative toxicity ranking based on EC50 remained unchanged irrespective of the dose metric (i.e., administered or delivered). However, for Co3O4, CuO, and ZnO NPs the fraction

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of sedimented NPs (over the 24 hour exposure period) was estimated to be in the range of ~30-50% and their assay-specific (i.e., ATP, LDH, and MTS) EC50 values were reduced by ~20-60%. Current effort is ongoing to finalize validation of the sedimentation (delivered dose) model, with both CEIN and available literature sedimentation data, and further refine the evaluation of toxicity ranking based on the two different dose metrics. Impacts on the Overall Goals of the Center: The activities of Theme 6 has impacted the CEIN main goals through the following activities: (i) Supporting development of hazard ranking through quantitative structure-activity-relations (QSARs) and other modeling approaches to predict and/or correlate ENMs toxicity; (ii) Supporting Themes 2, 3, 4 and 5 efforts to develop predictive toxicological paradigms via data mining and exploration using advanced computational machine learning tools and algorithms, as well as advanced visualization techniques; (iii) Providing quantitative information on the impact of NP physicochemical properties, surface modifications and protein binding on NP cell association and thus implications for design and interpretation of toxicity studies; (iv) Developing a meta-analysis approach to evaluate and assemble literature data for ENMs (e.g., QDs) to arrive at a comprehensive understanding of the significance of various factors that could impact ENM toxicity; (v) Developing an advanced model for estimating the delivered ENMs dose in support of Theme 2 work on ranking of ENM toxicity based on different dose metrics; (vi) Development of a comprehensive multimedia fate and transport (F&T) model (MendNano) to predict the environmental distribution of nanomaterials. This model served to confirm the range of potential exposure concentrations pertinent to evaluating the impact of ENMs on soil bacteria (Theme 4) and in aquatic systems (Theme 5); (vii) Collaborating with Theme 3 to cast the LCA approach of estimating the release of ENMs to the environment as a computational web-based application (LearNano). This useful research tool has also been integrated into LearNano and will be demonstrated in the upcoming 2015 Nanoinformatics meeting. It is also noted that the integrated LearNano/MendNano modeling platform is now serving for student training to conduct “real-world” environmental impact assessment for ENMs; (viii) Providing Theme 7 with a comprehensive evaluation of modeling/software approaches (via the development of illustrative test case) for alternative analysis (AA) of potential environmental impacts of ENMs; (ix) Continued collaboration regarding NanoEHS projects with Government Agencies (USEPA, US Naval Research Laboratory) and research organizations (EU European Cooperation in Science and Technology; nanoinformatics CaBig Initiative and the National Nano-SAR working group and Health Canada) and non-CEIN affiliated academic institutions (e.g., NSF iPLant Collaborative, Oregon State University, and University of Toronto). For example, Y. Cohen is serving as a US-COR Chair of the EHS computational modeling effort and has given webinars to the CaBig Nano working Group; (x) Organization of the successful nanoinformatics workshop held in conjunction with IEEE International Conference on Bioinformatics and Biomedicine (Belfast, UK, Nov. 1-5, 2014). This workshop provided a major forum for leading scientists and engineers in the growing field of nanoinformatics to exchange ideas and discuss the latest research developments across broad aspects of nanomedicine and environmental health impact assessment of nanomaterials; and (xi) Participation in the education/outreach activities organized by CEIN, to support the dissemination of information regarding the applications and safety of ENMs. Among specific tasks, Theme 6 members participated in an education program with the California Science Center giving a talk to young middle school kids about ENMs and the importance research activities within the center. Major Planned Activities for the Next Reporting Period: Over the next reporting period we expect to complete the analysis and model development (EDA-1) for the toxicity data of rare earth NPs and CNTs generate by Theme 2 to arrive at suitable QSARs for use in the development of the EIA model (EDA-3). We also expect to further extend the joint Theme 6/Theme

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2 meta-analysis work to enable a probabilistic inference of the uncertainty in the reported literature ENM toxicity data. Together with Themes 3 and 5 we will continue in expanding the use of MendNano to explore the range of expected exposure concentrations in aquatic and soil systems (EDA-2). In Project EDA-3 we expect to complete the development of an ENM environmental impact assessment framework (NanoEIA) using Bayesian Networks (BNs). Such a BN based framework will include a wide range of relevant parameter nodes including, but not limited to, ENMs physicochemical and transport properties, toxicity information, environmental transport parameters, as well as production/release information (e.g., production levels, emissions to various media). The developed BN based framework will provide: 1) EIA structure that will allows one to identify stressors, receptors, and endpoints as variables (i.e., nodes)) of various probability distributions and reflects causal pathways, 2) uncertainty quantification, 3) integration of both domain knowledge and experimental or modeling data. Case studies for the BN based EIA will be developed based on ENMs being currently studied at the CEIN (e.g., Cu/CuO and CNT NPs), whereby toxicity and exposure data will be acquired from both published resources and from various CEIN projects including those coordinated through the CEIN Cu Workgroup). Once data gathering and weight of evidence analysis are completed, we will construct a series of case studies with relevant ENMs (Nano CuO, Nano CeO2, Nano TiO2, CNTs and QDs) and will integrate the above case studies into a nanoinformatics web portal.

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Theme 7: Using UC CEIN Knowledge Generation to Engage and Impact Multiple Stakeholders Faculty Investigators: Hilary Godwin, UCLA - Professor, Environmental Health Sciences - Theme Co-Leader André Nel, UCLA – Professor, Medicine; Chief, Division of Nanomedicine – Theme Co-Leader J. R. DeShazo, UCLA – Associate Professor of Public Policy Barbara Herr Harthorn, UC Santa Barbara –Professor, Anthropology Timothy Malloy, UCLA - Professor, Law and Environmental Health Postdoctoral Researchers: 1 Short summary of Theme 7: The overarching goal of Theme 7 is to integrate and translate the research of the UC CEIN for discussion and use by multiple stakeholder groups to assist the development of new policy approaches, safety assessment, and safe implementation approaches for engineered nanomaterials (ENMs). This is being accomplished by utilizing the UC CEIN’s body of knowledge to inform multiple stakeholder communities about the potential adverse impacts of nanotechnology in the environment; working to integrate salient scientific results into existing and developing nanotechnology decision frameworks; and elevating the UC CEIN as a key thought leader of how predictive toxicological paradigms can assist nano Environmental Health and Safety (EHS) policy and decision making. To achieve this goal, our focus has been on enhancing relationships across stakeholder groups as well as recognizing the sensitivities facing industry (e.g., confidential business information and changing established rules of engagement) with respect to participating in open dialogue. In addition, by partnering with experts in academia, law, policy, industry, and civil society organizations in a series of workshops, we have identified key priority areas for engagement and science translation. Theme 7 Projects:

• KNO-1: Stakeholder Engagement for Improved Science Utilization for Nano EHS Policy and Decision-Making (Nel, Godwin, Malloy, Harthorn)

• KNO-2: Developing or Transforming Nano Regulatory Approaches (Malloy, DeShazo) Major Accomplishments since March 2014: Over the past year, the UC CEIN has continued to expand its science translation and outreach efforts. The knowledge and approaches generated in the UC CEIN are being used to engage national and international thought leaders in the areas of nano EHS policy, governance, and anticipatory decision-making in part through conferences and workshops. Major accomplishments of KNO-1 include: the hiring of a new Outreach Coordinator, Meghan Steele Horan (July 2014); completion of the ENM Categorization Workshop (May 2014) leading to a Perspectives piece (submitted to ACS Nano); preparation of a multi-stakeholder carbon nanotube (CNT) validation study on pulmonary toxicity, which stemmed from the ENM Categorization Workshop in May 2014; and the planning of an Environmental Exposure of ENMs Workshop (March 2015) in which industry, government, and academia will participate. Additionally, CEIN Director André Nel served on the President’s Council for Science and Technology review panel for the National Nanotechnology Initiative, which provided key recommendations for research priorities over the next two years. Major accomplishments of KNO-2 include preparation of an analysis on the proposed “Chemical Safety Improvement Act,” which was sent to Congressional staff as a follow up of the UC CEIN’s legislative visit to Capitol Hill in December 2013; and preparation of a manuscript for publication that analyzes the Toxic Substances Control Act (TSCA) with the intent of identifying gaps, limitations, and opportunities for the use of emerging science and

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policy approaches. We have also hosted an Alternatives Analysis (AA) workshop in collaboration with Professor Tim Malloy that brought those in the fields of AA, toxicology, engineering, and decision-making together to build the knowledge and networks necessary for developing effective AA tools and methods. This will result in several additional white papers and communications. KNO-1: Stakeholder Engagement for Improved Science Utilization for Nano EHS Policy and Decision-Making The goal of KNO-1 is to engage industry, NGOs, and regulatory agencies to develop opportunities for intellectual exchanges between diverse stakeholders across sectors working within the field of nano EHS. As a leader in this area, the UC CEIN is well positioned to facilitate discussions about how emerging scientific discoveries in this field can be made more useful and accessible to assist regulatory decision-making. These discussions assess the adequacy of data for regulatory decision making related to ENMs with the goal of understanding varied stakeholder perspectives, building capacity to utilize the UC CEIN’s science, and, in turn, influence the regulatory processes for ENMs in a balanced approach. To continue our success in KNO-1, the UC CEIN hired a new Outreach Coordinator, Meghan Steele Horan (July 2014), to take over from Elina Nasser, so that continuity in staff support of this function is maintained. Engagement of multi-stakeholders by the UC CEIN is noted below. The UC CEIN convened a two-day roundtable workshop entitled Categorization Strategies for Engineered Nanomaterials in a Regulatory Context (May 2014) at the Woodrow Wilson Center in Washington, D.C. as follow up to the January 2013 Alternative Test Strategies (ATS) Workshop and the May 2013 Nano EHS Workshop. This meeting brought together 42 national and international leaders from government, industry, academia, and NGOs to discuss ENM categorization, grouping, ranking and read across strategies for testing, evaluation, decision analysis, risk guidance, and regulation. During this workshop, CNTs served as a model for how to use categorization for risk analysis and regulatory purposes. It was determined that, at this stage, it is challenging to develop a single categorization strategy that will work for all classes of ENMs and in all regulatory paradigms. Developing a general categorization approach that can be customized and elaborated for specific classes of ENMs and for specific regulatory contexts. The workshop led to the publication of an ACS Nano Perspectives article13. The paper discusses essential characteristics of successful strategies for the categorization of ENMs for regulatory purposes and how ATS and a decision-tree approach could be used to facilitate ENM regulatory decision-making. CNTs served as example ENMs in a proposal for how ATS data could be incorporated into a decision-tree approach for categorizing CNTs according to their risk potential. ATS could play a key role in a tiered testing approach in which in vitro testing (Tier 1) could be used to promote short-term bolus installation (Tier 2) and long-term aerosolized inhalation (Tier 3) test strategies. As a direct result of the ENM Categorization workshop, the UC CEIN is in the early stages of a multi-stakeholder CNT validation study. Participants of the workshop viewed ATS worthy of consideration for categorization and regulatory decision making. The UC CEIN presented an example of a validation effort that participants perceived could be helpful, but we decided that it was important to have participation from academics and researchers across the U.S. federal agencies, Europe and Asia to contribute to the effort of selecting a set of CNTs from various sources (including historical examples), to be studied by commonly and individually preferred ATS protocols. In this study, participants will test a series of CNT materials, both historically studied and newly available, by mechanistic in vitro assays across a series of laboratories. Further decisions about testing in vitro ranking of animals by a tiered approach can be made once the data are analyzed. If confirmed that in vitro tests can predict the in vivo outcomes, then in vitro tests may gain acceptance as a first pass screening tool to reduce the reliance on expensive animal testing. This could be done by prioritizing and conducting in vivo tests only on those materials

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which show an in vitro toxicity potential. Preparation thus far includes creating a finalized list of nominated CNT materials that are available for use, a list of in vitro assays that can be performed, and participants in the study. It is important to understand that this is a voluntary effort that does not amount to an official validation exercise as required by the Organisation for Economic Co-operation and Development (OECD). This past year, the UC CEIN also co-hosted the Advanced Materials Partnering Conference in conjunction with the UCLA Office of Intellectual Property and Industry Sponsored Research (OIP-SIR). The meeting showcased the nanosafety research of the UC CEIN as a key example of how to bridge academia and industry interests on new technology development. Speakers included representatives from the U.S. EPA and Cal EPA discussing regulatory considerations for commercialization. The UC CEIN Director, Dr. André Nel, presented on Advances in Materials Safety Testing to attendees, which included UCLA researchers, investors, and industry executives. The conference provided an opportunity for participants to network and establish new relationships for furthering innovation. Some industry and investment representatives included BASF Ventures, Dow Chemical, Phoenix Venture Partners, Samsung Ventures, and Schlumberger. The conference featured industry panels and showcased recent developments from some of Southern California’s leading research institutions. Planning of our next stakeholder workshop entitled Implementing Environmentally-Relevant Exposures for Improved Interpretation of Laboratory Toxicology Studies of Manufactured and Engineered Nanomaterials (M&ENMs) is currently underway. The need for this workshop is to develop a predictive toxicological approach for ecotoxicology based on expected environmental exposures of nanomaterials. The workshop is taking place at UCLA on March 19-20, 2015 with over 40 national and international ecotoxicology researchers, exposure modelers, material manufacturers, and government agencies. The planning committee includes representatives from the U.S. EPA, Fraunhofer IME, Purdue University, and the UC CEIN. Discussions will focus on the state of knowledge regarding ENM environmental exposure conditions, what exposure conditions are used in assessing ENM ecological hazard potential, what conditions should be simulated in ecological nanotoxicological research to best inform risk management and mechanistic understanding, and how concepts such as environmental (or laboratory) concentration, exposure speciation, dose and body burden can be utilized in interpreting biological and computational findings. The basis for discussion at this workshop is premised on the ideas presented in a review publication by Holden et al. “Evaluation of Exposure Concentrations Used in Assessing Manufactured Nanomaterial Environmental Hazards: Are They Relevant?” (ES&T, 2014). The focus of this paper was on illustrating ENM concentrations administered in environmental hazard research and juxtaposing against those measured and modeled, asking what ENM concentrations have been used in hazard assessments, and are they “environmentally relevant?” An overarching objective of this workshop is to produce and disseminate a consensus statement that addresses the motivating questions and provides guidance to future studies. The UC CEIN website (www.cein.ucla.edu) continues to provide a broad and impactful overview of the scientific and educational accomplishments of the UC CEIN. The UC CEIN continues to share researcher spotlights. These spotlights provide key information about the societal benefits of the UC CEIN research while educating the public on what the science means. Currently, one spotlight is featured per month on the UC CEIN website and social media sites, highlighting the diverse members and the work of the UC CEIN. As new students and staff join the UC CEIN, future spotlights will be created to share new areas of research. Other social media outlets continue to disseminate information about the UC CEIN progress and key developments in Nano EH&S. The UC CEIN Twitter (231 followers) and Facebook Page (169 likes) reach international communities of researchers as well as the general public.

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http://www.cein.ucla.edu/

KNO-2: Developing or Transforming Nano Regulatory Approaches The research focus of KNO-2, research on new or existing policy models, provides critical feedback to allow regulatory agencies to respond to new and emerging data on ENMs. DeShazo and Malloy are exploring how regulatory approaches (including soft law, adaptive regulation, and prevention-based approaches) leverage the range of predictive toxicological methods, management protocols and decision-analysis tools under development at the UC CEIN. The specific regulatory framework determines whether a specific test can be applied for screening purposes, risk assessment purposes, or comparison purposes to assist regulatory agencies in making decisions. Therefore, projects take a regulatory decision-centric approach and include an analysis of the limitations and opportunities in the use of emerging science and policy approaches in existing regulatory frameworks. They also take into account the interest of other stakeholders such as industry and NGOs. KNO-2 also focuses on how predictive toxicology methods could be used in regulatory alternatives analysis (AA), to improve prevention based approaches in the regulation of chemicals. Those within KNO-2 work closely with other themes within the UC CEIN to provide insight on the potential translation of developments from the UC CEIN into the regulatory and industry setting. In addition, KNO-2 is concerned about improving regulatory approaches. Analysis of potential policy reforms involves policy adaptations (incremental changes to existing statutes and procedures) as well as more transformational visions of regulations and treaties. As a follow up to the legislative visit in December 2013, Malloy and Beryt prepared an analysis of the proposed “Chemical Safety Improvement Act,” which was sent to congressional staff. Suggestions focused on ways to better incorporate AA test strategies. KNO-2 also prepared a manuscript pending publication on the analysis of TSCA, which tracks the historical use of ATS in TSCA decision-making and highlights the potential opportunities and limitations of near term adoption of ATS. While there is hesitation by certain stakeholders to support regulatory adoption of ATS, there is significant opportunity for integration of these strategies into TSCA regulation of new and existing chemicals based on agency practices, judicial standards, and recent scientific developments. In particular, the use of basic forms of ATS in past agency action can inform the future adoption and use of more advanced forms of ATS for screening purposes, comparative assessment, and risk management. This analysis also identified how work in the UC CEIN might address identified gaps, limitations, and opportunities in the use of emerging science and policy approaches. Currently, Malloy continues to provide regulatory background for the Copper (Cu) Working Group in the UC CEIN about various Cu products (e.g., Kocide, CuPro) that are being studied. Presentations on the Cu products help to keep UC CEIN scientists educated and up to date on regulatory issues surrounding these products, which allow UC CEIN science and regulatory policies and frameworks to be better intertwined. For each of the relevant Cu products, Malloy and Beryt identified and summarized the regulatory programs implicated, any regulatory actions taken, and available information generated by those programs, including information submitted by the manufacturers. This work allows Theme 7 to work closely with the other themes in the UC CEIN. In regards to alternative analysis, the UC CEIN planned and hosted, with UCLA’s Sustainable Technology and Policy Program, a two day conference, Advancing Alternatives Analysis (A3)- Working Conference (October 2014) at UCLA. AA or alternatives assessment is a method that assists in determining the viability of safer substitutes for existing products that use hazardous substances. AA allows for the comparison of ENMs to conventional chemicals. With the identification of safer alternatives, replacements can be made with less hazardous materials. This meeting (referred to as the AA

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Workshop) brought together over 50 leaders in the fields of AA, toxicology, engineering, and decision making to build the knowledge and networks necessary to develop effective AA tools and methods. During this conference, participants used a case study involving commercially available alternatives to copper-based marine anti-fouling paint as background, providing context for the discussion of AA. As a result of the conference, a proceedings publication is being produced which highlights the salient points discussed at the conference. The conference proceedings will discuss the promise and limitation of integrating predictive toxicology and decision analysis tools into AA, and the recommended next steps to accomplish this goal. The conference proceedings will also encourage further collaboration and capacity building, and serve as a foundation for future actions to blend the disciplines of predictive toxicology, decision analysis, and AA. As part of the UC CEIN’s outreach activities, the conference proceedings publication will be useful in facilitating future projects and networks between the UC CEIN and members of the regulatory AA community. KNO-2 will complete the aforementioned AA case study in which a regulatory AA methodology for evaluating nano products and their alternatives will be developed. The project will identify potential opportunities, as well as methodological gaps and further research required for integration of UC CEIN methods and models into emerging frameworks for regulatory AA. The case study will address two particularly challenging aspects of regulatory AA: pervasive data gaps regarding toxicity of existing and new materials, and the complex nature of decision-making involved in AA. Conventional animal testing and ecological studies intended to fill data gaps are typically expensive and time consuming, delaying or even preventing the evaluation of new alternatives. Emerging predictive toxicity methods could avoid these problems by using mechanistic screening approaches, and cutting edge computational methods in lieu of animal testing. Impacts on the Overall Goals of the Center: In the two years since the focus of Theme 7 has shifted to the translation of the UC CEIN research for multiple stakeholder groups, the UC CEIN has made significant progress in becoming recognized as one of the leading think tanks for knowledge and advice regarding the safety assessment and safe implementation of nanomaterials in the environment. As a direct result of targeted outreach to industry, regulatory groups, policy makers, and academia, the UC CEIN faculty has had markedly increased interactions revolving on how to translate the scientific methodologies into practical advances within industry and the regulatory community. For example, over the past twelve months, a number of key industry representatives have approached the UC CEIN for advice on how to conduct safety assessment of potential new nanomaterial products prior to commercialization. Industry representatives have actively participated in open discussions about the utility of UC CEIN ATS approaches for hazard assessment, and several companies volunteered to actively participate in a study to confirm the use of ATS to predict in vivo outcomes. The UC CEIN faculty continues to participate in high profile international scientific and policy forums to disseminate the advances we have made to a broad audience. UC CEIN Director André Nel was invited to serve on the President’s Council for Science and Technology’s review of the National Nanotechnology Initiative, highlighting the key role that the UC CEIN occupies in the national discussion on Nano EHS. Through strengthened interactions with the Environmental Protection Agency’s Office of Research and Development (the research branch of the EPA) and the Office of Pollution Prevention and Toxics (the division tasked with regulatory authority over the new chemicals program), the U.S. EPA has not only worked to adjust their internal research mission to capture some of the research being carried out by the UC CEIN, but has also given consideration to predictive toxicology screening during the pre-manufacturing review process. Over the coming year, we will continue to strengthen these interactions as we conduct the in vitro predictive toxicological screening of CNTs, conduct a workshop focused on environmentally relevant exposures and

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in laboratory toxicology studies of ENMS, and disseminate UC CEIN science to the various stakeholder communities we are involved with. Major Planned Activities for the Next Reporting Period: In the coming year, Theme 7 will continue to focus on the integration and translation of UC CEIN research for use by multiple stakeholders to assist the development of new policy approaches, safety, assessment, and safe implementation of ENMs.

1. Stemming from the May 2014 workshop on ENM categorization is the planning of a CNT validation study involving international stakeholders (as described in KNO-1). The UC CEIN Outreach Coordinator will serve as project coordinator for this effort.

2. Conducting a workshop entitled Implementing Environmentally-Relevant Exposures for Improved Interpretation of Laboratory Toxicology Studies of Manufactured and Engineered Nanomaterials (M&ENMs) (March 2015). We foresee that the workshop will allow us to develop a consensus of how to move forward in addressing the motivating questions that will form the basis of the discussion, and a consensus direction for the research community.

3. KNO-2 will work on a proceedings publication based on the AA workshop, which will serve to facilitate future projects and networks between UC CEIN and members of the AA community.

4. Establish a low-cost, low-entry fee discussion industry forum series where the UC CEIN engages a limited number of industry partners in discussions about UC CEIN research advances and how these can be utilized by industry to foster safer design, rapid implementation, and responsible commercialization of nanomaterials.

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10. Center Diversity The UC CEIN is committed to ensuring the cultural, gender, racial, and ethnic diversity of the UC CEIN at all levels, particularly courting involvement of women and underrepresented minorities as UC CEIN participants. We seek to ensure the broadest diversity possible by:

• From the inception of the Center, we have strived to place female and minority faculty in positions of leadership within the Center, where they can serve as positive role models for young scientists. Our Center leadership currently has 3 senior female faculty who interact with students and postdocs across the Center on a regular basis.

• Strategically engaging minority-serving institutions as full research partners in the Center. Our partners include 4 Hispanic-Serving Institutions (HSIs): University of Texas, El Paso (UTEP), University of New Mexico (UNM), UC Riverside (UCR), and UC Santa Barbara (UCSB). Students and postdocs from UTEP, UNM, UCR, and UCSB participate in our Center's leadership workshops, annual meetings, and working groups.

• UTEP, UNM, UCR, and UCSB participate in undergraduate mentoring programs- during Year 7, CEIN-affiliated faculty at these four campuses mentored a total of 44 undergraduates. Additionally, two of these undergraduates were on a summer REU program at UNM, and all of these campuses provide laboratory research experience underrepresented minorities (URMs). These programs encourage students to seek advanced educational opportunities in the sciences.

• Seeking partnerships with faculty at community and technical colleges to integrate CEIN-authored curriculum (Sustainable nanoMAterials Laboratory/SMAL) into current nanoscience programming.

• Encouraging our members to participate in public outreach events and to contribute to organizations that encourage K-12 interest in STEM, such as Science Buddies, public and independent schools, and local science museums, nature centers, and public libraries.

• Recruiting a diverse postdoctoral researcher pool. All open positions within the Center (including postdoctoral researchers) are advertised widely, and efforts are made to recruit a diverse applicant pool for consideration.

• The Center incorporates job skills and mentoring training into our Student and Postdoctoral Leadership workshops, which will encourage successful application of our diverse students and postdoctoral fellows into careers in academia and industry.

Progress in the past year period: As our Center matures, we have increased engagement from a diverse range of faculty, research staff, postdoctoral scholars, graduate students, and undergraduates in our research and education/outreach activities. We have successfully engaged a high percentage of female researchers amongst our research staff (44%), graduate students (54%), postdocs (35%), and undergraduates (53%), which is notable given the traditionally low numbers of females in the fields of science and engineering. Additionally, 53% of our graduate students and 84% of our undergraduate participants were US citizens in the current reporting year. While the Center does not have influence over the recruitment of new female and/or minority faculty at our member institutions, we are proud of the strong female representation in our Center leadership, with 3 area leads serving on our Executive Committee and an additional 2 female faculty active in the

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Center’s research and educational development activities. We feel this strong representation of female faculty leadership sets a strong example to up-and-coming scientists. Plans for the next reporting period: Over the next year, we will continue to strengthen our education and outreach partnerships, particularly those with the California Science Center, the Santa Monica Public Library, and Science Buddies. Our partnership with Science Buddies is notable for many reasons, including diversity and reaching diverse audiences: In 2013, the Science Buddies website was visited by more than 11 million unique users (students, parents, teachers), including underrepresented minorities, and 56% of these visitors were female. Since June 2013, the date our science fair project was published on Science Buddies’ website, over 11,000 unique users have viewed our science fair project, approximately 59% of whom are female. In addition to these longstanding partnerships, we are working on expanding community-based partnerships at the California Science Center (Los Angeles) and Gourmet au Bay (Bodega Bay, CA) in the coming year. We will continue to participate in UCLA and UCSB outreach events, such as NISE Net’s NanoDays, geared towards public and K-12 audiences. The Center remains committed to our partnerships with UTEP, UNM, UCR, and UCSB and will explore avenues through existing and new programs to strengthen the path to higher education opportunities for minorities and women in the field of environmental nanotechnology. We have recruited a diverse External Science Advisory Committee who will provide us valuable input on the Center's outreach and diversity goals.

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UC Center for Environmental Implications of Nanotechnology Year 7 Annual Report

11. Education, Career Development, Knowledge Dissemination, and Integrative Efforts Faculty Investigators: Hilary Godwin, UCLA – Professor, Environmental Health Sciences – Theme Leader Andre Nel, UCLA – Medicine; Chief, Division of NanoMedicine Arturo Keller, UC Santa Barbara – Professor, Bren School of Env. Science & Management Korin Wheeler, Santa Clara University – Assistant Professor, Chemistry Short Summary of Education Program The overarching goal of UC CEIN Education is to ensure that the science performed and the discoveries made within the Center are leveraged to serve broader societal needs; to this end, UC CEIN Education fosters cross-Theme and cross-campus dialogue and interaction by designing programs that foster collaborative interdisciplinary science, advance discovery and understanding while promoting teaching, training, and learning, mentor students and postdocs, and include the participation of underrepresented groups in the sciences. Following is an Education Summary Report for Year 7 (April 1, 2014-present), based on UC CEIN member self-reporting. Education programming occurs at all UC-CEIN sites; to capture information on this important programming and its participants, Center members report on it via an online reporting mechanism, http://www.surveymonkey.com/s/CEINEducationOutreachReport. Since April 2014, UC CEIN education, presentation, and dissemination highlights include: 122 Talks

2 Webinars

14 Posters

2 high-school and 59 undergraduate students in 13 UC-CEIN labs

CEIN research in teaching: 21 courses on 7 campuses

Informal Science Education and Public Outreach

• 2 radio interviews • Lab tours for 100+ high school students and teachers at Bodega Marine Lab • Programming at K-12 schools & summer camps for more than 550 K-12 students • Campus-affiliated events at 5 campuses in 2 states reached 1,000+ people

Congressional testimony: Mark Hersam testified before the U.S. House of Representatives

Committee on Science, Space, and Technology’s Subcommittee on Research and Technology, Nanotechnology: From laboratories to commercial products, on May 20, 2014.

Organization and Integration of Education Projects CEIN Education consists of four project areas and one seed project. Project abstracts follow, while the aggregate quantitative impacts of CEIN Education were summarized on the previous page of this report.

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http://www.surveymonkey.com/s/CEINEducationOutreachReport


Project 1: Student/Postdoctoral Mentoring and Professional Development The primary goal of the UC CEIN’s student/postdoctoral mentoring and professional development program is to improve participants’ workforce preparation and professional skills by offering mentoring activities and targeted professional development workshops. To help the Center’s students and postdocs develop effective, professional communication skills for presenting their research, the Center offers participant-centered activities and workshops throughout the year. Individual workshops focus on spoken presentation skills or on written communication, and participants receive targeted feedback on their skills and suggestions for areas for substantive and presentation skills improvement during each workshop. The Center’s yearly Leadership Workshop offers students and postdocs a chance to network with each other, engage in cross-thematic group and cross-campus interactions, and to improve on their own mentoring and leadership skills. Project 2: Course Development, Workshops, and Learning Tools The goal of this project is to develop and disseminate educational outputs related to nanoscience and the environment. Educational outputs include lectures, workshops, and online learning modules related to Center research. Additionally, CEIN has partnered with Science Buddies by providing a validated, step-by-step science fair project idea, “Tiny Titans: Can Silver Nanoparticles Neutralize E.coli bacteria?” which has been viewed by over 11,000 people since its publication in June 2013. The Center’s educational outputs contribute to stakeholder understanding of concepts related to nanoscale science and engineering, fill gaps in the stakeholder knowledge base, and provide a springboard from which the Center can build future collaborations and partnerships. Project 3: Informal Science Education (ISE) and Public Outreach The goal of our public outreach projects is to provide formal and informal opportunities for dialogue between the Center and its stakeholders, and to expand the knowledge base on research, societal implications, and risk perception related to the environmental implications of nanotechnology. The Center engages in public outreach by hosting academic conferences, seminars, and symposia, and by participating in public events. Yearly public events include NISENet’s NanoDays (Los Angeles and Santa Barbara), a public lecture and discussion at the Santa Monica Public Library, and UCLA’s “Exploring Your Universe” event. Additionally, the Center works with CNSI’s ArtSci program every summer to introduce “nanoscience and the environment” concepts to high school students, and Education partners with the California Science Center for NanoDays in Los Angeles and with The Center for Nanotechnology and Society and the Santa Barbara Museum of Natural History for NanoDays in Santa Barbara with the aim of reaching underserved audiences. Each year, over 1,000 children and adults learn about nanoscience and the environment at CEIN-affiliated public events. In addition to the above Center-organized ISE and public outreach activities, Center members not located at UCLA or UCSB participate in similar activities in their local areas. Project 4: Synergistic/Integrative Center Activities To promote collaboration, cross-fertilization, and interdisciplinary partnerships across the UC-CEIN and with other research partners, the Education group helps to develop and deliver mechanisms to support face-to-face and web-based meetings, such as monthly working group meetings, seminar speakers, and the Center’s annual meeting. Currently, working group meetings include the Copper Oxide Working Group and the Carbonaceous Working Group, both of which are cross-Theme and cross-campus. Project 5: Sustainable nanoMAterials Laboratory (SMAL) (Seed Project) Catherine Nameth (UCLA) and Korin Wheeler (Santa Clara University)

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http://nisenet.org/

http://smpl.org/

http://www.astro.ucla.edu/%7Eoutreach/eyu2013.html

http://www.astro.ucla.edu/%7Eoutreach/eyu2013.html

http://artsci.ucla.edu/

http://www.californiasciencecenter.org/


This is a curriculum development project funded by the Center from June 2014-May 2015. This project aims to translate the cutting-edge research of the UC CEIN to an undergraduate population by collaboratively designing and developing a research-based laboratory module for the undergraduate chemistry classroom. In the Sustainable nanoMAterials Lab (SMAL) module, students will evaluate the role of common biological macromolecules in nanotoxicity; this module will be based upon the high throughput screening (HTS) assays already established at UC CEIN. By bringing scientific research to the classroom, undergraduates will engage in a learning-by-doing approach, thereby providing students with an authentic, interdisciplinary research experience with real-world applications. Specifically, students will be exposed to issues considered in the evaluation of chemical toxicity (in human health and the environment) and techniques involved in sterile cell growth and safe handling of laboratory chemicals. Many students traditionally underrepresented in the sciences do not seek out science majors and research experiences in particular. By introducing undergraduates to research at an introductory level, we extend the reach of the traditional research model and engage these students in the scholarly community early in their career. Integration of Education Projects CEIN Education Coordinator Catherine Nameth serves as the day-to-day point-person for the planning, implementation, and evaluation of CEIN’s education projects. Nameth works in partnership with UCSB-based Coordinator Leslie Sanchez, CEIN Assistant Christine Truong, and CEIN Outreach Coordinator Meghan Horan on the planning and implementation of cross-Theme projects related to the translation and dissemination of the Center’s research as well as the Center’s website and social networking sites (Facebook and Twitter). Education Project 1 includes CEIN students and postdocs from all thematic groups and locations. Education Project 2 includes the development of learning tools that communicate concepts from Center research to K-12, undergraduate, and researcher audiences. Education Project 3 consists of public education programs with partner museums and other research centers in California. Intra-Center integrative activities comprise the thrust of Project 4 and promote interdisciplinary synergism through working group meetings (Copper Oxide Working Group; Carbonaceous Working Group); additionally, Nameth has been working with Bacsafra (CEIN Web and Data Specialist, Theme 6) to integrate educational reporting and impacts into the Center’s data management system. Major Planned Activities for the Next Reporting Period Project 1: Student/Postdoctoral Mentoring and Professional Development: In the coming months, the Center’s students and postdocs will be working with their faculty as well as Sanchez and Nameth on public speaking and poster preparation for the Center’s NSF/EPA site visit. Brown bag webinars and in-person workshops are being planned. In the coming year, UC-CEIN students and postdocs have requested workshops on career development, and Sanchez and Nameth will be working together to plan these workshops for 2015. Additionally, Sanchez will continue to organize and facilitate CEIN-UCSB’s monthly meetings, wherein students and postdocs often present their research and receive feedback from the group. Project 2: Course Development, Workshops, and Learning Tools: In the coming six months, UC-CEIN’s second project with Science Buddies, The effects of nanosilver on the life stages of Daphnia, which was inspired by research in the Nisbet lab at UCSB, will be completed and published on the Science Buddies website. Graduate student Louise Stevenson and CEIN Assistant Christine Truong are co-authors. Project 3: Informal Science Education (ISE) and Public Outreach: The Center will continue to partner with the California Science Center (Los Angeles, CA) and the Santa Monica Public Library, it will continue to provide support (education, training, funding) for Center members to participate in ISE activities in

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their local areas. Sanchez/UCSB will partner with the Center for Nanotechnology in Society and the Santa Barbara Natural History Museum for education events, such as NanoDays 2015. Project 4: Synergistic/Integrative Center Activities: CEIN Education will continue to facilitate cross-thematic and cross-disciplinary discussion and interaction by providing webinar support for the Copper and Carbon Working Group meetings. There will continue to be consistent coordination between Nameth/Education and Sanchez/UCSB/Copper Working Group as well as Horan/Theme 7/Carbon Working Group for seminars, webinars, and other integrative activities. Project 5- Seed Project- Sustainable nanoMAterials Laboratory (SMAL): Nameth and Wheeler (Santa Clara University) have been meeting their benchmarks for each of the aims of this project. They have co-written the lab manual as well as pre- and post-lab assignments, and they received IRB approval to conduct a research study focused on how undergraduate student feedback informs curriculum design. In February 2015, 20 undergraduates at Santa Clara University pilot tested the module and many of these students participated in Nameth & Wheeler’s research study. Nameth & Wheeler are writing up their research findings, editing the module, and networking with community/technical colleges to include this module into their curriculum. To this end, Nameth & Wheeler have been in contact with faculty at both De Anza Community College (Cupertino, CA) and Florida Polytechnic University (Lakeland, FL), and they will present the module at the High Impact Technology Exchange Conference (HI TEC), a conference for educators and researchers at community colleges and undergraduate-serving institutions, in Portland, Oregon, in July 2015. By June 2015, Nameth and Wheeler will submit their research findings as well as the module for publication to peer-reviewed science education journals. Planned CEIN Education Outputs, 2015-2016

Project Area Outputs

1. Student/Postdoc Mentoring & Professional Development

Monthly group conference calls; Site visit preparation (Poster Preparation & Presentation skills); Fall 2015 career development workshop; Winter 2016 writing workshop

2. ISE & Public Outreach

Publications Nameth- Guest blog post for American Evaluation Association on internal evaluation at a federally-funded research center; Article- A rubric for direct observation in informal learning environments- for peer-reviewed journal Presentations (Nameth, with Bishop from NIMBioS) It’s just me: Navigating the waters as the sole internal evaluator and (Nameth) Pause-Commit-Engage: A rubric for direct observation in informal learning environments submitted to American Evaluation Association’s 2015 Annual Meeting Events Exploring Your Universe 2015; NanoDays 2016 Website: Mini lectures (“Snapshots”) of Center research

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3. Courses, Workshops, and Learning Tools

Science Buddies’ Daphnia project Publication (Nameth, Truong, Stevenson, Science Buddies staff) for Science Buddies’ website- Tips for translating scientific research to a science-fair project for the middle-school audience

4. Synergistic/Integrative

Evaluation: Internal evaluations of programs; Annual Center-wide survey; Collaborate with Bacsafra (Theme 6) on capturing education impact data as part of Center’s data management system

5. Seed Project (SMAL)

Publication (Nameth& Wheeler): Using undergraduate student feedback to inform curriculum design- in science education journal Presentations (Nameth & Wheeler): Sustainable nanoMAterials Lab-HI-TEC 2015 and MSTEM 2015

Nameth tracks CEIN student and postdoc alumni. The number of alumni in non-profit, consulting, industry, government, and academia are as follows:

• 1 in non-profit • 3 in consulting • 7 in industry • 8 in government • 21 in academia (11 faculty/tenure-track, 1 lecturer)

Impacts on the Overall Goals of the Center CEIN Education reaches across all themes and cores of the Center and thus influences every Center member. Graduate students and postdocs help determine the leadership activities of the Center. Materials from all areas of CEIN research are drawn upon for the development of academic coursework and the synthesis of information for the Center’s public education programs. We recruit participants from all levels of the Center (undergraduate, graduate student, postdoc, research staff, and faculty) to participate in the full range of Education activities, which are coordinated on a volunteer basis. An annual Center-wide survey asks each member to report on their experience in an interdisciplinary research center, which includes their participation in interdisciplinary working groups. Postdoctoral Mentoring Plan The UC CEIN is committed to educating and training the next generation of interdisciplinary scientists and engineers needed to advance the field of nanotechnology and who can also anticipate and mitigate any potential future environmental hazards associated with this important technology. To enhance the professional development of our Center trainees, the UC CEIN Education program conducts a coherent and effective series of annual leadership and mentoring activities within the Center designed to further the professional development of all Center trainees (undergraduate and graduate students as well as postdocs). UC CEIN conducts participant-centered professional development workshops and provides one-on-one professional development/job skills support for Center students and postdocs to improve their skills in the areas of public speaking, professional presentations, and writing. Topics for the

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workshops and individual mentoring are determined by input from the Center's students and postdocs as well as priority areas identified by Center faculty. We are committed to providing leadership development opportunities to postdoctoral researchers at all Center partner institutions, and funds are available in the Education budget to fund travel for out-of-state participants. Additional development opportunities include our cross-campus trainee (students and postdocs) seminar series. Trainees from the Center are supported to travel to a partner campus to present a seminar and lead a discussion on their ongoing research projects. This program fertilizes cross-disciplinary discussions at the trainee level and has been extremely popular. In the first round of funding, UCLA and UC Santa Barbara hosted "visiting researcher" graduate students and postdoctoral scholars, and we will expand these opportunities in years 6-10. This is critical to our students and postdocs being able to form substantive interactions with their counterparts at distant institutions within the Center. The UC CEIN Education Coordinator conducts both formal and informal internal evaluations of the Student/Postdoctoral Mentoring and Professional Development Program. The Coordinator also offers year-round in person and online sessions on presentation skills and report writing. The Coordinator is available to all postdoctoral researchers for one-on-one consultation for writing skills, presentation skills, and career development advice. In addition to Center-wide mentoring and leadership activities, all postdoctoral researchers across the Center develop a written training plan for their research and undergo an annual performance evaluation with their mentor. The UC CEIN conducts evaluations of all Center mentoring activities, results of which are summarized in our Center's annual reports and are used to inform program development. Informal Science Education and Public Outreach During Year 7, 23 CEIN members (faculty, staff, research staff, graduate students, postdocs) reported on a range of informal science and public outreach activities. An additional four people- two CNSI graduate students (Hwang & McCormick), one UCLA staff (Oishi), and one CEIN alumni (Thomas)- helped the public understand key concepts about nanoscience and the environment. Together, these 27 people participated in science education programming and collectively reached over 2,500 people through radio interviews, community organizations, museums, K-12 schools, campus-affiliated events, lab tours, and outreach targeted towards undergraduates. Additionally, in March 2015, an educational activity developed by CEIN (Truong & Nameth)- Oil Spill Clean Up Simulation- was selected to be a NISENet Linked Product and can be accessed at http://www.nisenet.org/catalog/oil-spill-clean-simulation. Location/Partner/Program CEIN Member(s) Radio interviews KCSB (91.9 FM) Adeleye KPCC (89.3 FM) Lanphere In the community First Presbyterian Church (Santa Barbara, CA) Stevenson Gourmet Au Bay Wine Bar (Bodega Bay, CA) Fairbairn (Author & Organizer)

Sandia National Laboratory (NM) Brinker # reached= 350

At museums California Science Center (NanoDays) Godwin, Hwang, S. Lin, Nameth, B. Sun, Truong

Riverside Nature Center (CA) Taylor

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http://nisenet.org/

http://www.nisenet.org/catalog/oil-spill-clean-simulation


Santa Barbara Museum of Natural History (NanoDays) Stevenson

# reached= 400 With K-12 Albuquerque Public Schools (NM) Brocato Bethune Elementary (Riverside, CA) Taylor

California Science Center’s Curator Kids’ Club (Los Angeles, CA)

Hwang, S. Lin, Nameth, Osborne, Romero, B. Sun, Thomas, Truong

La Cuesta High School (Santa Barbara, CA) Stevenson Magnolia Elementary (Riverside, CA) Taylor Riverside STEM Academy (Riverside, CA) Taylor & Walker

St. Catherine of Alexandria (Riverside, CA) Taylor

Tomales High School (Bodega Bay, CA) Fairbairn

300

Campus-affiliated UCLA CNSI’s ArtSci Avery, S. Lin, Osborne, Truong

UCLA CNSI’s Summer Nanoscience Program S. Lin, B. Sun

UCLA’s Exploring Your Universe! Hwang, Kaweeteerat, S. Lin, McCormick, Nameth, Oishi, Osborne, Taylor, Truong

UCLA’s EmpowerHER STEM Day Nameth, Romero, Truong

UCSB’s Cooke Bridges Program Holden

UCD Bodega Marine Lab Fairbairn, Torres UCR Science Ambassadors Taylor

UTEP’s Graduate Research Expo Gardea-Torresdey 1000

Lab Tours UCD Bodega Marine Lab Fairbairn UCLA’s Nel Lab Wang UNM Lab Brinker

200 To undergraduates North Dakota State University (Webcast) Holden

Santa Clara University Fairbairn, Mansukhani, Nameth, Osborne, Torres

UC Riverside- California Alliance for Minority Participation (CAMP) Walker

UCSB Summer Start Stevenson UTEP Freshman Orientation Gardea-Torresdey, Majumdar

350 Academic Courses Incorporating CEIN-related Content

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Since April 2014, 15 CEIN members- faculty, postdocs, and graduate students- reported incorporating Center-related content into their existing courses. Through these 21 courses on seven campuses, over 400 students (292 undergraduates and 141 graduate students) have an awareness of current research related to nanoscience and the environment.

21 Courses 15 CEIN Members 7 Campuses 400+ Students

E4160 Somasundaran Columbia 40 Undergraduate & Graduate

E6252 Somasundaran Columbia 7 G

AEROSOL Madler U Bremen 24 G

INTRO Pokhrel U Bremen 12 U

NANO Pokhrel U Bremen 10 G

PARTICLE TECH Madler U Bremen 33 U

ETX 127 Cherr & Fairbairn UC Davis 29 U

ETX 240 Fairbairn UC Davis 10 G

C218 Romero UCLA 15 G

M1B Romero UCLA 20 U

HPNG 150 Walker UC Riverside 100 U

ANTH 104 Harthorn UCSB 17 U

ANTH 157L Harthorn UCSB 25 U

EEMB 508 Nisbet UCSB 20 G

ENV NANO Stevenson UCSB 30 U

ESM 214 Holden UCSB 14 G

ESM 222 Keller & Adeleye UCSB 18 G

ESM595PH Holden UCSB 7 G

ESM595SS Holden UCSB 17 G

SOC 591 Harthorn UCSB 8 G

NSMS 518 Brinker UNM 16 G

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Graduate students & Postdocs

• Adeyemi Adeleye, UC Santa Barbara: ESM 222 Fate & Transport of Pollutants in the Environment • Ellie Fairbairn, UC Davis Bodega Marine Laboratory: ETX 240 Ecotoxicology • Suman Pokhrel, U Bremen: Introduction to Combustion and Energy Applications;

Nanotechnology • Michelle Romero, UC Los Angeles: C218 Multimedia Environmental Assessment; M1B

Environment and Sustainability • Louise Stevenson, UC Santa Barbara: ES120 Toxics in the Environment

Faculty

• C.J. Brinker, University of New Mexico: NSMS 518 Synthesis of Nanostructures • Gary Cherr and Ellie Fairbairn (Postdoc), UC Davis Bodega Marine Laboratory: ETX 127 Aquatic

Tox • Barbara Herr Harthorn, UC Santa Barbara: ANTH 104 Risk and Inequality; ANTH 157L Medical

Anthropology; SOC 591 Workshop in Social Research • Patricia Holden, UC Santa Barbara: ESM214 Biological Waste Treatment; ESM595PH Seminar in

Environmental Microbiology and Microbial Ecology; ESM595SS PhD Seminar • Arturo Keller, UC Santa Barbara: ESM 222 Fate & Transport of Pollutants in the Environment • Lutz Madler, U Bremen: Particle Technology; Aerosol and Nanotechnology • Roger Nisbet, UC Santa Barbara: EEMB 508 Ecology & Evolution • Ponisseril Somasundaran, Columbia: E4160 Solid & Hazardous Waste Management; E6252

Applied Surface and Colloid Chemistry • Sharon L. Walker, UC Riverside : HPNG 150 Introduction to Research Across Disciplines

Professional Development Activities

• The UC CEIN’s 2014 Student/Postdoc Leadership Workshop was held September 4 & 5 in Santa Monica, California, thereby preceding the Center’s annual retreat. The seventeen student/posdoc attendees chose the topic for this year’s workshop- Communicating Research Science to Non-Scientists- and Malloy led a workshop on this topic, while Nameth and UCSB Coordinator Sanchez planned and organized teambuilding activities.

• In response to student/postdoc requests for more cross-campus interaction, since January 2015 there have been monthly- rather than biannual- student/postdoc conference calls. Led by Nameth, the January meeting focused on the challenges and opportunities in interdisciplinary research, while the February meeting focused on data visualization tips for students/postdocs. Meetings for March, April, and May will also focus on presentation skills, which along with in-person poster and presentation skills workshops, will help students/postdocs prepare for the site visit and prepare for other future professional presentations.

• In the past six months, the CEIN data management repository has been migrated from Sharepoint (CDM) to the NanoDatabank. It is imperative that all CEIN members, including students and postdocs, are able to understand the NanoDatabank and use it effectively. In the coming months, Data Manager Bacsafra will hold in-person hands-on trainings at UCSB, UC Riverside, and UCLA and will be available to offer customized assistance to CEIN members at all locations. In addition to those training sessions, Bacsafra has coordinated with Nameth to recruit and hold a half-day training for select students/postdocs from UCLA, UCSB, UC Riverside, UC Davis Bodega Marine Lab, and Northwestern University in Los Angeles in June.

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Mentoring High School and Undergraduate Students Theme 1 (13 undergraduates)

• Brinker Lab (Brinker) o Richard Abraham, Cellular replication in silica and titania o Yasmine Awad, Silification of single-cell and multicellular organisms o Cameron A. Burgard, Amplification of CRISPR plasmids & transfection of plasmids into in

vitro models o Lauren Bustamante, Synthesis and characterization of controlled porosity silica

materials for fundamental studies of biodegradability and biocompatibility o Kevin Humphrey, Nanoparticle drug-loading efficiency and release characterization &

optimizing lipid:particle conditions for ideal fusion method o Amanda Lokke- Synthesis & modification of mesoporous silica nanoparticles for nucleic

acid delivery o Ayse J. Muniz- Evaluation of nanoparticle impact on transfection efficiency using

plasmids, mRNA, siRNA, and minicricle plasmids o Alexander Prossnitz- Assessment of bacterial membrane permeabilization using cationic

nanoparticles o Alden Reviere- Interactions of liposomes with silica surfaces as model systems o Michael Salazar- Measuring release rates of metal ions from nanoparticles o Edward Francis Wycoff- Fluorescence imaging of various in vivo nanoparticle samples &

preparation of samples for SEM via silicon substrate to better understand biodistribution

• Hersam Lab (Hersam, Mansukhani) o Peter Kim- Aqueous dispersions of transition metal dichalcogenides

• Stucky Lab o Kevin Young- Electrochemical probing on the nanotoxicity of metal oxides

Theme 2 (10 undergraduates)

• Nel Lab (Nel, Chang, S. Lin, Meng, Xia) o Jusine Ku- Physical-chemical properties of nanomaterials affecting inflammazone

activation o Anson Lee- UCLA Grand Challenges Project o Nanetta Pon- Nanoparticle characterization o Raquel Ribeiro- Developing HTS using wild type and transgenic zebrafish strains o Allen Situ- Use of mesoporous silica nanoparticles o Allen Taing- Physical-chemical properties of nanomaterials affecting inflammazone

activation o William Ueng- Zebrafish high-throughput screening o Jesus Valdez- High throughput screening o Bobby Wu- Use of mesoporous silica nanoparticles o Xuechen Bella Yu- Using zebrafish HTS to understand the hazard potential of III-V

materials

Theme 3 (1 high-school student,* 19 undergraduates) • Keller Lab (Keller, Adeleye, Conway)

o Arielle Beaulieu- Transport and effects of metal oxide ENMs on terrestrial plants and soil o Nicole Beaulieu- Transport and effects of metal oxide ENMs on terrestrial plants and

soils

103


o Aaron Fulton- Life Cycle Assessments of Engineered Nanomaterials o Daniel Gold- Life Cycle Assessments of Engineered Nanomaterials o Edward Hadeler- Aggregation Kinetics of surface-coated TiO2 nanoparticles o Ekene Oranu- Aggregation Kinetics of surface-coated TiO2 nanoparticles o Thomas Perez- Dissolution and speciation of copper-based nanoparticles o Paige Rutten- Surface characterization of copper-based nanoparticles in the presence of

EPS and Suwannee River NOM o Cynthia Sanchez- Release of consumer products into natural waters

• Somasundaran Lab o Akan Brown*– Selective flotation to concentrate engineered nanomaterials from natural

matrices o Karmina Padgett- Surface and interfacial techniques o Tony Tharakan- Surface and interfacial techniques

• Walker Lab (Walker, Lanphere, Story, Taylor, Waller) o Carola Acurio- Metal nanoparticles impacting bacteria in anaerobic environments o Alex Burton- Model colon/septic system o Aaron Coyoca- Model colon/septic system o Risa Guysi- ICP-MS for septic tank/zebrafish study o Igor Irianto- Model colon/septic system o Corey Luth- Fate and Transport of Molybdenum Disulfide Experiments o Diego Noeva- Metal nanoparticles impacting bacteria in anaerobic environments o Daniel White- Model colon/septic system

Theme 4 (1 high-school student,* 9 undergraduates)

• Holden Lab (Holden) o Corinne Dorais- Fate and effects of condensed carbon nanomateirals in soil o Kathleen Pacpaco- Inventorying exposure data in nanotoxicology o Niki Rinaldi- Impacts of carbonaceous nanomaterials on agricultural crops

• Nisbet Lab (Nisbet, Stevenson) o Alexandra Bowers- Effect of low food levels on growth and reproduction of Daphnia

pulicaria o Andy Hseuh- Lab maintenance to support UC-CEIN projects o Erica Johnson- Growth and reproduction of Daphnia pulicaria o Katherine Krattenmaker- Combined effects of low food and citrate-coated silver

nanoparticles on the growth and reproduction of Daphnia pulicaria o Ally Mintze*- The effect of parking lot runoff on Daphnia magna

• Gardea-Torresdey Lab o Raul Armendariz- Effects of Cu NPs/compounds on jalapeno peppers o Fabiola Moreno Olivias - DNA sequencing of zucchini exposed to TiO2 nanoparticles

Theme 5 (7 undergraduates)

• Cherr Lab (Cherr, Fairbairn) o Cody Burr- Development of sea urchin embryos in relation to effects of antibiotics

(nanosilver and penicillin/streptomycin) on bacteria flora o Sara Hutton- The combined effects of nano-CuO and ocean acidification on purple sea

urchin embryonic development

104


o Malina Loeher- Phototoxicity of titanium dioxide nanoparticles in the starlet anemone Nematostella vectensis

• Lenihan Lab (Lenihan, Miller) o Rebecca Howard- Impacts of ENMs on marine systems o Ashley Noriega- Impacts of ENMs on marine systems o Amy Stuyvesant- Impacts of ENMs on marine systems o Ashley Watchell- Impacts of ENMs on marine systems

Theme 7 (1 undergraduate)

• Harthorn research group (Harthorn) o Maria Yepez (UCSB- Harthorn)- Public deliberation of new technologies: Emergent risk

and fracking

105

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12. Outreach and Knowledge Transfer One of the major goals of the Center is to train the next generation of nano-scale scientists, engineers, and regulators to anticipate and mitigate potential environmental hazards associated with nanotechnology, while at the same time seeking to impact the scientific, educational, and policy communities both nationally and internationally. We seek to educate the broader community through both Center-sponsored seminars and workshops and by participating in scientific meetings nationally and internationally across the range of UC CEIN disciplines. The Center has become a valuable resource, and our public profile as that of a leading Center for research on nanotechnology and Environmental Health and Safety continues to rise at all levels- local, regional, national, and international. Workshops hosted by UC CEIN Implementing Environmentally-Relevant Exposures for Improved Interpretation of Laboratory Toxicology Studies of Manufactured and Engineered Nanomaterials (M&ENMs)- UCLA

• March 19-20, 2015- This workshop brought together an international representation of ecotoxicology researchers, exposure modelers, material manufacturers, and government representatives for a two-day roundtable to address the following questions: (1) What is the state of the knowledge regarding M&ENM environmental exposure conditions, via measurements or modeling simulations?; (2) What exposure conditions are used in assessing M&ENM ecological hazard potential, and how do they compare to measured or modeled exposure values?; (3) What conditions should be simulated in ecological nanotoxicological research to best inform risk management and also mechanistic understanding?; and (4) How should concepts such as environmental (or laboratory) concentration, exposure, speciation, dose, and body burden be utilized in interpreting biological and computational findings? This workshop produced and will disseminate a consensus statement that addresses the motivating questions and provides guidance into the future.

Advanced Materials Partnering Conference – UCLA

• November 5, 2014 – CEIN co-sponsored a day long forum designed to engage industry in discussions regarding the commercialization of new technologies and increasing interactions with University researchers. The CEIN invited representatives from the US EPA and Cal EPA to discuss the regulatory considerations for commercialization of new technologies, including nanomaterial enabled products. The nanosafety and materials development achievements of the CEIN were highlighted to the 150+ meeting participants in attendance. Co-sponsored by the UCLA Office of Intellectual Property Industry Sponsored Research Office, the forum included industrial participants from across California and researcher and startups from Caltech, USC, UC Irvine and UC Santa Barbara.

Alternatives Analysis Workshop. Making Prevention Real: Evaluating Potentially Safer Alternatives to Toxic Chemicals and Hazardous Processes- UCLA

• October 9-10, 2014- CEIN sponsored a two-day workshop on Alternatives Analysis, utilizing engineered nanomaterials (ENMs) and the expertise of the CEIN as a case study. Alternatives analysis brings a range of disciplines to bear, including toxicology, engineering, economics, chemistry, decision analysis, risk communication, and law. Existing frameworks, tools, and methods for alternatives analysis do not integrate these disciplines in a systematic or rigorous way, creating a barrier to meaningful adoption of prevention in chemical management. The conference will bring together scientists, researchers, and scholars from these diverse

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disciplines, as well as policymakers, non-governmental organizations, and businesses. Its goal is to begin building the knowledge and networks necessary to integrate these largely disparate disciplines in developing effective alternatives analysis tools and methods. It will build connections across these disciplines in this context, identifying opportunities and challenges for integration, and develop a preliminary roadmap for integration.

Second Annual Governance of Emerging Technologies: Law, Policy and Ethics- Scottsdale, AZ (CEIN co-sponsor)

• May 27-29, 2014- CEIN co-sponsored the Arizona State University-led 2nd annual GET conference, which addressed the regulatory, governance, legal, policy, social, and ethical aspects of emerging technologies. Theme 7 faculty Tim Malloy served on the organizing committee for the conference, and both he and CEIN postdoc Ela Beryt presented CEIN research at the conference.

Categorization Strategies for Engineered Nanomaterials in a Regulatory Context- Woodrow Wilson Center, Washington, DC.

• May 19-20, 2014- CEIN convened an expert group of opinion leaders in academia, industry, government, and non-governmental organizations in a roundtable discussion on engineered nanomaterial (ENM) categorization, grouping (the arrangement of nanomaterials into groups based on common attributes), ranking, and read-across strategies for testing, evaluation, decision analysis, risk guidance, and regulation. Discussion focused on recent advancements in the field and ongoing research. The workshop resulted in a Nano Focus article in ACS Nano on the use of categorization of CNTs for regulatory decision making and meeting participants have begun work on a research study to validate the relationships of HTS in vitro techniques to known in vivo outcomes in select CNT materials across a range of laboratories.

UC CEIN Santa Barbara Monthly Seminar Series

Speaker(s) Speaker(s) Title

April 15, 2014 Sheetal Gavankar Graduate student

May 27 Erik Muller & Tin Klanjescek Research staff; Postdoc

June 17 Louise Stevenson & Tyronne Martin Graduate students

August 19 John Priester Postdoc

September 23 Arielle Beaulieu & Katherine Krattenmaker Undergraduates

October 21 Trish Holden Faculty

November 18 Yuan Ge Postdoc

January 20, 2015 Lijuan Zhao Postdoc

February 17 Jon Conway Graduate student

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Lectures, Seminars, and Presentations by UC CEIN members to external audiences Adeyemi Adeleye, University of California Santa Barbara

• Effect of extracellular polymeric substances on fate and transformations of engineered nanomaterials (Talk), 249th American Chemical Society National Meeting, Denver, Colorado, March 22, 2015.

• Release of nanoparticle copper from an antifouling paint in natural waters (Talk), Sustainable Nanotechnology Organization Conference, Boston, MA, November 2-4, 2014.

• Release of nanosized copper particles from an antifouling paint (Poster), SETAC North America 35th Annual Meeting, Vancouver, British Columbia, Canada, November 9-11, 2015.

• Long-term dissolution and speciation of copper-based nanoparticles in aqueous media: Effect of extracellular polymeric substances, pH, and ionic strength (Poster), 248th National American Chemical Society Meeting, San Francisco, CA, August 10, 2014.

Elizabeth Beryt, University of California Los Angeles • The role of institutionalized validation in integrating emerging science into regulatory decision-

making (Talk), SNO Conference, Boston, MA, November 2-4, 2014. • When is a test method ready for regulatory use? The role of validation in the acceptance of

alternative testing strategies (Talk), Sustainable Nanotechnology Organization Conference, Boston, MA, November 2-4, 2014.

• Alternative Testing Strategies in TSCA Decision-Making: Past, Present and Future (Talk), Society for Risk Analysis, Nano Risk Analysis (II): A Workshop to Explore How A Multiple Models Approach Can Advance Risk Analysis of Nanoscale Materials, Washington D.C., September 2014.

• The Role of Institutionalized Validation in Integrating Emerging Science into Regulatory Decision-Making (Talk), Second Annual Conference on Governance of Emerging Technologies: Law, Policy, and Ethics, Scottsdale, AZ, May 27-29 2014.

Muhammed Bilal, University of California Los Angeles

• Probabilistic Nanoinformatics Modeling Platform for Assessing the Potential Environmental Impact of Engineered Nanomaterials (Talk), 248th National American Chemical Society Meeting, San Francisco, CA, August 11, 2014.

C. J. Brinker, University of New Mexico and Sandia National Laboratories

• Development of targeted mesoporous silica supported lipid bilayer nanoparticles for delivery of nucleic acid cargo (Talk), Society for Advancement of Hispanics/Chicanos and Native Americans in Science National Meeting, Los Angeles, CA, October 16-18, 2014.

• Protocells for Synthetic Biology (Talk), DOE Workshop on Dissipative Self-Assembly as a Foundation for Biomimetic Systems, Pittsburgh, PA, August 14-15, 2014.

• Silica @ Cells (Talk), Gordon Conference on Bio-Interface Science, Lucca, Italy, June 15-20, 2014.

• Nanoporous Particle-Tethered Multilamellar Lipid-Polymer Hybrids for Enhanced Gastrointestinal Stability and Oral Delivery of Antibacterial Agents (Talk), Materials Research Society Spring 2014 Meeting, San Francisco, CA, April 21-25, 2014.

• Targeted Delivery of Therapeutic Nucleic Acids to Hepatocellular Carcinoma via Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Talk), Materials Research Society Spring 2014 Meeting, San Francisco, CA, April 21-25, 2014.

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• Selective, Long-Term Transfection of Dividing and Non-Dividing Cells using Plasmid DNA-Loaded Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Talk), Materials Research Society Spring Meeting, San Francisco, CA, April 21-25, 2014.

• Targeted, Triggerable Delivery of Novel and Traditional Anti-Virals to Infected Cells via Biomimetic Hybrid Nanoparticles (Talk), Materials Research Society Spring Meeting, San Francisco, CA, April 21-25, 2014.

• Molecular Veneers and MoS2 Sheets (Talk), Materials Research Society Spring Meeting, San Francisco, CA, April 21-25, 2014.

• Targeted Delivery of Antibiotics to Cells Infected with Francesella tularensis using Mesoporous Silica Nanoparticle-Supported Lipid Bilaers (Talk), Materials Research Society Spring Meeting, San Francisco, CA, April 21-25, 2014.

• Mesoporous Oxide Nanoparticles for Controlled Release and Targeted Delivery of Antigens (Poster), Materials Research Society Spring Meeting, San Francisco, CA, April 21-25, 2014.

• Protocells: Mesoporous silica nanoparticles encapsulated within synthetic or active cell membranes for drug delivery (Talk), 5th Annual Nanotechnology for Health Care Conference, Winthrop Rockefeller Institute/University of Arkansas, Morrilton, AK, April 2-4, 2014.

Chong Hyun Chang, University of California Los Angeles

• Establishing compositional and combinatorial libraries to study structure-activity relationships at bio-interfaces (Talk), 18th Annual California United Program Training Conference, San Diego, CA, February 4, 2015.

Gary Cherr, University of California Davis Bodega Marine Laboratory

• Metal oxide nanomaterials induce oxidative stress and act as chemosensitizers in sea urchin embryos (Talk), 2nd Marine Nanoecosafety Workshop, Palermo, Italy, November 2014.

Yoram Cohen, University of California Los Angeles

• Nanoinformatics tools for analysis and modeling of toxicity of engineered nanomaterials (Talk), The 7th International Nanotoxicology Congress- NanoTox 2014, Antalya, Turkey, April 23-26, 2014.

• Toxicity of Nanomaterials: Knowledge Extraction from High Content Experimental Data (Webinar), National Cancer Institute Nano Working Group Meeting, July 24, 2014.

Bryan Cole, University of California Davis Bodega Marine Laboratory

• Impacts of engineered nanomaterials on marine phytoplankton across levels of biological organization (Talk), 248th American Chemical Society National Meeting, San Francisco, CA, August 10, 2014.

Jon Conway, University of California Santa Barbara • Gravity-driven transport of three engineered nanomaterials in unsaturated soils and effects on

soil pH and phosphate mobility (Talk), Sustainable Nanotechnology Organization Conference, Boston, November 2-4, 2014.

Jorge Gardea-Torresdey, University of Texas El Paso • Colloidal Silver Reduces Water Content, Root Growth and Modifies Macromolecules in Radish

(Raphanus sativus) Seedlings (Talk), Materials Research Society (MRS), Boston, MA, Nov. 30 - Dec. 5th, 2014.

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• Locating metal oxide nanoparticle transformation in plants using synchrotron X-Ray (Talk), 2014 Eastern Analytical Symposium & Exposition: The Art and Science of Analysis. Somerset, NJ, November 17-19, 2014.

• Environmental implications of nanotechnology: tracing nanoparticle transformations in terrestrial plants using synchrotron techniques (Talk), Nano Monterrey 2014 International Forum, Monterrey, Mexico, November 10-11, 2014.

• Scaling Environmental Nanotoxicology to Ecological Endpoints: a “white paper” for Nano Risk Analysis (II) (Talk), A Workshop to Explore How a Multiple Models Approach can Advance Risk Analysis of Nanoscale Materials, organized by the Society for Risk Analysis (SRA) Emerging Nanoscale Materials Specialty Group (ENMSG) Washington, DC, September 15-16, 2014.

• Effects of copper nanoparticles on the growth and nutrient uptake of sugar cane (Saccharum officinarium) (Talk), Third Symposium on Agriculture and Related Sciences, Center for Education and Training in Agricultural and Related Sciences, Mayaguez, Puerto Rico, August 11-12, 2014.

• Comparison of coated and uncoated cerium oxide nanoparticles and their impact on tomato (Solanum lycopersicum L.): A toxicity study of plants grown inorganic soil (Talk), Third Symposium on Agriculture and Related Sciences, Center for Education and Training in Agricultural and Related Sciences, Mayaguez, Puerto Rico, August 11-12, 2014.

• Nanoparticles ecosystems impact: Plant nano-ecotoxicology issues and concerns (Webinar), UCSB, June 10, 2014.

• Environmental implications of nanotechnology: Locating metal oxide nanoparticle transformation in plants using synchrotron techniques (Talk), Southwest University of Science and Technology, Minyang, China, June 4, 2014.

• Tracing nanoparticle fate in plants using synchrotron techniques: Is there a potential risk of the transfer of nanoparticles into the food chain? (Talk), Nanofair 2014, 10th International Nanotechnology Symposium-New Ideas for Industry, Dresden, Germany, July 1-3, 2014.

Yuan Ge, University of California Santa Barbara

• Interactive effects of plants and metal oxide nanoparticles on soil bacterial communities (Talk), The ASA-CSSA-SSSA 2014 International Annual Meetings, Long Beach, CA, November 2-5, 2014.

Linda Guiney, Northwestern University • Investigating the toxicity and environmental fate of graphene nanomaterials (Talk), ACS 248th

National Meeting, San Francisco, CA, August 10th, 2014 Barbara Herr Harthorn, University of California Santa Barbara

• What are STS data? (Talk), NSF Data Management Workshop, Arlington, VA, January 2015. • Societal Aspects of Nanotechnology-Responsible Development, Innovation, and Public

Engagement (Talk), NSF NSE PI meeting, Arlington, VA, December 10, 2014. • Gender & Risk Perception (Talk), Understanding Risk Centre, Cardiff University, Wales, UK, June

24, 2014. • Understanding Society Aspects of Emerging NanoTechnologies (Talk), WM Keck Foundation,

Program on Waste Management Aspects of Nanotechnologies, School of Engineering, Cal Poly San Luis Obispo, San Luis Obispo, CA, May 9, 2014.

Mark C. Hersam, Northwestern University

• Carbon nanomaterial heterostructure devices (Talk), 249th American Chemical Society National Meeting, Denver, Colorado, March 22, 2015.

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• Nanomaterial heterostructures for electronic and energy technologies (Talk), Muju International Winter School, Muju Deogyusan Resort, Korea, January 29, 2015.

• Integrating nanomaterials into heterostructure devices and systems (Talk), National Research Council of Canada Colloquium, Ottawa, Canada, January 23, 2015.

• Integrating nanomaterials into heterostructure devices and systems (Talk), Northwestern University Department of Physics and Astronomy Colloquium, Evanston, IL, January 9, 2015.

• Nanomaterial inks for roll-to-roll manufacturing of flexible electronics (Talk), Materials Research Society Fall Meeting, Boston, MA, December 3, 2014.

• Fundamentals and applications of carbon nanomaterial heterostructures (Talk), 2014 STLE Tribology Frontiers Conference, Chicago, IL, October 29, 2014.

• Integrating multifunctional oxides into monodisperse nanomaterial heterostructures and composites (Talk), Materials Science & Technology 2014, Pittsburgh, PA, October 15, 2014.

• Nanomaterial heterostructures for electronic and energy technologies (Talk), Georgia Institute of Technology School of Chemical and Biomolecular Engineering Seminar Series, Atlanta, GA, September 10, 2014.

• Thin-film electronics and optoelectronics based on monodisperse nanomaterial heterostructures (Talk), International Meeting on Information Display 2014, Daegu, Korea, August 28, 2014.

• Monodisperse carbon nanomaterial heterostructures (Talk), KAIST Department of Materials Science and Engineering Seminar Series, Daejeon, Korea, August 27, 2014.

• Electronics and optoelectronics based on carbon nanomaterial heterostructures (Talk), SPIE Nanoscience and Engineering Conference, San Diego, CA, August 20, 2014.

• Integration of carbon nanomaterials into heterostructure devices (Talk), American Chemical Society National Meeting, San Francisco, CA, August 13, 2014.

• Processing and applications of graphene and related nanomaterials (Talk), 248th American Chemical Society National Meeting, San Francisco, CA, August 10, 2014.

• Functional nanomaterial heterostructures (Talk), 8th Annual International Workshop on Nanoscale Spectroscopy and Nanotechnology, Chicago, IL, July 28, 2014.

• Functional carbon nanomaterial heterostructures (Talk), XII International Conference on Nanostructured Materials, Moscow, Russia, July 14, 2014.

• Chemically modified graphene heterostructures (Talk), 1st Annual Workshop of the IBS Center for Artificial Low Dimensional Electronic Systems, Pohang, Korea, July 11, 2014.

• Chemically modified graphene heterostructures (Talk), CIMTEC International Conference on Novel Functional Carbon Nanomaterials, Montecatini, Italy, June 18, 2014.

• Chemistry and applications of monodisperse carbon nanomaterial heterostructures (Talk), The 97th Canadian Chemistry Conference and Exhibition, Vancouver, Canada, June 2, 2014.

• Monodisperse carbon nanomaterial thin film heterostructures (Talk), Second Annual Carbon Nanotube Thin Film Applications Symposium, Los Angeles, CA, June 1, 2014.

• Monodisperse carbon nanomaterial heterostructures (Talk), New Diamond and Nano Carbons Conference, Chicago, IL, May 26, 2014.

• Carbon nanotube heterostructure devices (Talk), Electrochemical Society Spring Meeting, Orlando, FL, May 13, 2014.

• Chemically functionalized graphene heterostructures (Talk), Materials Research Society Spring Meeting, San Francisco, CA, April 23, 2014.

• Centrifugal size and shape sorting of polyhedral metal nanoparticles (Talk), Materials Research Society Spring Meeting, San Francisco, CA, April 22, 2014.

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• Chemically enhanced carbon nanomaterials for electronics, energy, and medicine (Talk), IEEE-NEMS 2014 Conference, Honolulu, HI, April 16, 2014.

Trish Holden, University of California Santa Barbara

• Alternative Testing Approaches: Using Bacteria to Assess Manufactured Nanomaterial Environmental Hazards (Talk), Society for Risk Analysis Annual Meeting, Denver, CO, December 9, 2014.

• State of the Science: Applying a Multiple Models Approach to Inform Ecological Risk Assessment (Talk), Society for Risk Analysis Workshop: Nano Risk Analysis II, Washington, DC, September 2014.

• Abiotic and biotic interactions of manufactured nanomaterials in the terrestrial environment (Talk by Holden, delivered by Dr. Yuan Ge), ACS 248th National Meeting, San Francisco, CA, August 13, 2014.

• Nanoparticles ecosystems impact: Plant nano-ecotoxicology issues and concerns (Talk), Center for Nanotechnology in Society at UCSB, June 10, 2014.

• Ecological Considerations of Manufactured Nanomaterials (Talk), NanoTox2014, Antalya, Turkey, April 25, 2014.

Chitrada Kaweeteerawat, University of California Los Angeles • Effects of Cu nanoparticles and their micron and ionic analogs in Escherichia coli and

Lactobacillus brevis (Poster), Society of Toxicology 2015, San Diego, CA, March 22-26, 2015. • High throughput dose response analysis reveals unique mode of toxicity of Cu nanoparticles

(Poster), 2014 Society of Risk Analysis Annual Meeting, Denver, CO, December 7-11, 2014. • High Throughput Screening of toxicity of 24 metal oxide nanoparticles in Escherichia coli

(Poster), Nano Risk Analysis II Workshop, Washington, DC, September 15-16, 2014. • Effects of Cu nanoparticles and their micron and ionic analogs in Escherichia coli and

Lactobacillus brevis (Poster), American Society of Microbiology 114th Annual Meeting, Boston, MA, May 17-20, 2014.

Arturo Keller, University of California Santa Barbara

• Environmental Implications of Nanotech (Talk), Association of Environmental Health and Safety’s 25th Annual International Conference on Soil, Water, Energy, and Air, San Diego, CA, March 25, 2015.

• Role of Heterogeneous Aggregation in NP Fate (Talk), Duke University, January 14, 2015. • Emerging trends of nanoparticle fate and transport (Talk), American Geophysical Union Fall

Meeting 2014, San Francisco, CA, December 15-19. • Overview of release estimates for engineered nanomaterials (Talk), Sustainable Nanotechnology

Organization Conference, Boston, MA, November 2-4, 2014. • Environmental Implications of Nanotechnology (Talk), King Abdullah University of Science &

Technology, Saudi Arabia September 15 & 17, 2014. • Nanotechnology: What is that? How does it influence my lifestyle? Is there a downside? (Talk),

CNSI at UCSB, August 2014 • Environmental Implications of Nanotech (Talk), ACS 248th National Meeting, San Francisco, CA,

August 13, 2014. • Life cycle of ENMs (Talk), US Environmental Protection Agency, Arlington VA, June 23, 2014. • Life cycle environmental implications of nanomaterials (Talk), IWA Conference, Shanghai, China,

May 21, 2014.

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• Life cycle environmental implications of nanomaterials (Talk), Tongji Univeristy, Shanghai, China, May 21, 2014.

Fred Klaessig, Pennsylvania Bio Nano Systems, LLC

• Providing Commercial Context to Nanomaterial Studies (Talk), Nanomaterial 14, SETAC, Columbia, SC, September 8, 2014.

Tin Klanjscek, Rudjer Boskovic Institute, Croatia

• Incorporating dynamics of oxidative stress and damage into models of organismal response to environmental stress (Talk), Joint conference- Society for Mathematical Biology and Japanese Society for Mathematical Biology, Osaka, Japan, July 30, 2014.

Jacob Lanphere and S. Drew Story, University of California Riverside

• Environmentally relevant conditions impacting graphene oxide transport in aqueous environments (Talk), 248th National American Chemical Society Meeting, San Francisco, CA, August 10, 2014.

Anastasia Lazareva, University of California Santa Barbara

• Release of engineered nanomaterials via wastewater treatment plants (Talk), Sustainable Nanotechnology Organization Conference, Boston, MA, November 2-4, 2014.

Ruibin Li, University of California Los Angeles

• Surface interactions with compartmentalized cellular phosphates explain rare earth oxide nanoparticle hazard and provide opportunities for safer design (Talk), 248th ACS National Meeting, San Francisco, CA, October 14, 2014.

Rong Liu, University of California Los Angeles • Nanoinformatics Approach to Literature Data Mining of ENM Toxicity: Quantum Dots Case Study

(Poster), The 7th International Nanotoxicology Congress- NanoTox 2014, Antalya, Turkey, April 23-26, 2014.

• Regional Multimedia Distribution of Nanomaterials and Associated Exposures (Poster), The 7th International Nanotoxicology Congress- NanoTox 2014, Antalya, Turkey, April 23-26, 2014.

Lutz Madler, Universitat Bremen

• Multidisciplinary Approach for the Safe Implementation of Nanotechnology (Talk), FZ Borstel, Germany, September 2014.

• Introduction to a Multidisciplinary Approach for the Safe Implementation of Nanotechnology in the Environment (Talk), 2014 DGfZ Conference, Dresden, Germany, June 23, 2014.

• Spinel based nanoparticle library for toxicity evaluation (Poster), The 7th International Nanotoxicology Congress- NanoTox 2014, Antalya, Turkey, April 23-26, 2014.

Timothy Malloy, University of California Los Angeles

• Complexity, It’s Complicated (Talk), Second Annual Conference on Governance of Emerging Technologies: Law, Policy and Ethics, Arizona State University, Tuscon, AZ, May 27-29, 2014.

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Niki Mansukhani, Northwestern University • High concentration aqueous dispersions of molybdenum disulfide using nonionic biocompatible

block copolymers (Poster), ACS 248th National Meeting, San Francisco, CA, August 13, 2014. Monika Mortimer, University of California Santa Barbara

• Protozoa Tetrahymena thermophila – a versatile model organism for nanotoxicology (Poster), SETAC North America 35th Annual Meeting, Vancouver, British Columbia, Canada, November 9-11, 2014.

Erik Muller, University of California Santa Barbara

• A dynamic energy budget approach to mechanistic models of toxicodynamics with applications to nanotoxicity (Talk), SETAC, Vancouver, Canada, November 13, 2014.

Andre Nel, University of California Los Angeles • How events at the Nano/Bio interface determine adverse and therapeutic useful biological

outcomes for silica nanomaterials (Talk), 8th International Symposium on NanoBiotechnology, Beijing, China, October 2014.

• Engineered Nanomaterials Interacting with Natural and Engineered Interfaces (Talk), 248th American Chemical Society National Meeting & Exposition, San Francisco, CA, August 2014.

• Understanding the nanobio interface for making decisions on nanomaterial safety and nanotherapeutics (Talk), The Royal Society Main Meeting: Cell adhesion century: culture breakthrough, London, United Kingdom, April 2014.

• What data we have to support the use of Predictive Modeling and Alternative Strategies for Regulatory Decision Making (Talk), The Royal Society Main Meeting: Cell adhesion century: culture breakthrough, London, United Kingdom, April 2014.

• Use of high content discovery at the nano/bio interface for decision analysis of nanosafety (Talk), The 7th International Nanotoxicology Congress- NanoTox 2014, Antalya, Turkey, April 23-26, 2014.

Roger Nisbet, University of California Santa Barbara

• Extrapolating ecotoxicological effects from individuals to populations using Dynamic Energy Budget theory and individual based modeling (Talk), SETAC Annual Meeting, Vancouver, British Columbia, Canada, November 11, 2014.

• Ecological models for assessing the risks of chemicals and other stressors - Part 1: From molecules to individuals (Talk), SETAC Annual Meeting, Vancouver, British Columbia, Canada, November 11, 2014.

• Ecological models for assessing the risks of chemicals and other stressors - Part II: From individuals to ecosystems (Talk), SETAC Annual Meeting, Vancouver, British Columbia, Canada, November 11, 2014.

• Dynamic Energy Budget models relating molecular, organismal and ecological responses to environmental change (Talk), Joint conference- Society for Mathematical Biology and Japanese Society for Mathematical Biology, Osaka, Japan, July 30, 2014.

• Linking organismal and suborganismal mechanisms to population dynamics for ecological risk assessment (Talk), National Center for Mathematical and Biological Synthesis (NIMBioS) at workshop on Mechanistic Models for Ecological Risk Assessment, Knoxville, TN, 29 April 2014.

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Suman Pokhrel, Universitat Bremen

• Nanoparticle design and assessment of toxicity paradigms (Talk), School of Chemical & Biomedical Engineering Singapore, Nanyang Technical University, Singapore, November 2014.

• Flame spray pyrolysis for the production of ultrafine nanoparticles and their applications (Talk), Centre for Sustainable Nanotechnology, School of Chemical & Life Sciences, Nanyang Polytechnic, Singapore, November 2014.

• Multidisciplinary approach for nanoparticle categorization (Talk), Organization of Economic Cooperation and Development (OECD), Categorization of Manufactured Nanomaterials, Washington, DC, September 2014.

• Heterojunctions in Toxicology (Talk), Mechanische Verfahrenstechnik, University of Bremen, Bremen, Germany, May 2014.

• Spinel based nanoparticle library for toxicity evaluation (Talk), The 7th International Nanotoxicology Congress- NanoTox 2014, Antalya, Turkey, April 23-26, 2014.

Cyren Rico, University of Texas, El Paso • Cerium oxide nanoparticles modify crop physiology and grain quality in cereals, (Talk), UTEP

Graduate Research Expo, El Paso, TX, November 14, 2014. Galen D. Stucky, University of California Santa Barbara

• Multiscale materials systems (Talk), Fundación Príncipe de Asturias, Ovieda, Spain, October 22, 2014.

• Synthetic design and applications of ordered macro-mesoporous nitrides and carbides (Talk), PIRE-II US-Chinese PI Collaborative Summer Workshop, Shanghai, China, June 28, 2014.

• System considerations for sustainability (Talk), Interface Chemistry of Materials, Dow Chemical, Shanghai, China, June 26, 2014.

Alicia A. Taylor, University of California Riverside

• Understanding the transformation, speciation, and hazard potential of copper-based particles in a model septic tank using a zebrafish high throughput screening assay (Poster), Society of Toxicology 2015, San Diego, CA, March 22-26, 2015.

• Use of a model laboratory-scale septic system for studying emerging contaminants (Talk), 2014 Annual Meeting of the Southern California Society of Toxicology, San Diego, CA, October 16, 2014.

• Release and impact of copper nanoparticles on a model septic system (Talk), 248th ACS National Meeting, San Francisco, CA, August 10-14, 2014.

• Impact and fate of copper nanoparticles on a model septic system (Poster), Gordon Research Conferences- Environmental Sciences: Water, Holderness, NH, June 22-27, 2014.

• Impact of Copper Nanoparticles on the Function of a Model Septic System and Microbial Community (Talk), Israel Society for Microbiology Annual Meeting, Haifa, Israel, April 7, 2014.

Cristina Torres, University of California Davis Bodega Marine Laboratory

• Oxidative stress responses in sea urchin embryos exposed to copper oxide nanoparticles (Talk), 248th American Chemical Society National Meeting and Exposition, San Francisco, CA, August 10, 2014.

• Nanomateriales: Destino, potenciales riesgos e impactos (Talk), Cuernavaca, Mexico, May 27, 2014.

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Sharon L. Walker, University of California Riverside

• From ideal to real: utilizing a model colon and septic system to elucidate the impacts of bacterial and nanoparticle contamination (Talk), 248th ACS National Meeting, San Francisco, CA, August 10-14, 2014.

Zoe Welch, University of California Santa Barbara

• Investigating toxicity to the diazotrophic soybean symbiont, Bradyrhizobium japonicum USDA110, using agriculturally-relevant metal nanomaterials (Talk), Interdepartmental Graduate Program in Marine Science Seminar Series, Santa Barbara ,CA, February 24, 2015.

Bing Wu, UC Davis Bodega Marine Laboratory

• Metal oxide nanomaterials as chemosensitizers in marine organisms (Talk), 248th American Chemical Society National Meeting, San Francisco, CA, August 10, 2014.

Tian Xia, University of California Los Angeles

• Establishment of structure activity relationships in nanomedicine and nanosafety studies (Talk), The Technical Institute of Physics and Chemistry of the Chinese Academy of Sciences (TIPCCAS), Beijing, China, October 14, 2014.

• Smart Designed Engineered Nanoparticles for Drug and siRNA Delivery to Treat Cancer (Talk), Zhengzhou Central Hospital, Zhengzhou, China, October 11, 2014.

• Rare Earth Material Induced Toxicological Responses (Talk), National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, China, August 22, 2014.

• Advancement of NanoMedicine Research at UC-CEIN and CNPT (Talk), Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China, August 21, 2014.

• Medicinal applications of Biomineralization Techniques (Talk), Harbin Fifth Municipal Hospital, Harbin, China, August 19, 2014.

• Predictive toxicological approach linking the physicochemical properties of nanomaterials to pulmonary toxicity in animals (Talk), Safe & Sustainable S2NANO: QNTR Workshop 2014, Korea Institute of Toxicology, Taejun, South Korea, April 2014.

• Establishment of in vivo zebrafish embryos and larvae models for nanomaterial toxicity screening (Talk), Korea Institute of Toxicology, Jinju, South Korea, April 2014.

Jeffrey I. Zink, University of California Los Angeles

• Silicon-based Inorganic Nanomaterials in Medicine (Talk), 248th National American Chemical Society Meeting, San Francisco, CA, August 10-14, 2014.

• Multifunctional Inorganic Nanoparticles Controlled by Nanomachines for In Vitro and In Vivo Drug Delivery (Talk), 248th National American Chemical Society Meeting, San Francisco, CA, August 10-14, 2014.

• Mesoporous Silica Nanoparticles as Drug Delivery and Diagnostic Agents (Talk), Gordon Research Conference on Metals in Medicine, Andover, NH, June 22-24, 2014.

• Mechanized Multifunctional Inorganic Nanoparticles for Imaging, Targeting and Drug Delivery (Talk), Santa Clara University, Santa Clara, CA, April 11, 2014.

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13. Shared and Experimental Facilities

UCLA (1) CEIN Laboratory(2600sq+): housed in the California NanoSystems Institute (CNSI) building, centrally located on the UCLA campus. The CEIN has recently installed a Perkin-Elmer AAnlyast Graphite Spectrometer and a Shimadzu ICPE-9000 to expand characterization. This equipment joins our existing CEIN characterization and HCS equipment: Quadrasorp SI to analyze surface area and pore size of our library NMs; Wyatt DynaPro Plate Reader Dynamic Light Scattering instrument; a Brookhaven Zeta Potential analyzer; and an Elisa Plate. Bench space has also been outfitted to accommodate approximately 10 working bays. (2) Molecular Screening Shared Resource (MSSR): houses two fully integrated HTS systems: (i) Automated liquid handling, multiple plate reading, plate filling and washing, deshielding, and delidding, and online incubators for cell-based assays using a Beckman/Sagian system equipped with an Orca robotic arm that delivers plates to individual work stations; Beckman Biomek FX liquid handling robot (96-well pipetting, 96- or 384-pin transfer); Perkin–Elmer Victor3(V) plate reader (96–1536 well plates) to assess luminescence, fluorescence, fluorescence polarization, time-resolved fluorescence, UV–Vis absorbance modes); Molecular Devices FlexStation II plate reader equipped with an integrated pipetter and general fluorescence and luminescence plate applications in 96- or 384-well format; Cytomat 6001 incubator: CO2 incubator; Multidrop 384: manifold liquid dispensing into 96- or 384-well plates; ELx 405 plate washer: well washing, aspiration, dispensing. The current capacity of cell-based assay is ca. 105 wells (conditions)/day. Multiple plate readers allow fluorescence, FRET, BRET, time-resolved fluorescence, fluorescence polarization, luminescence, and UV–Vis absorption assays. (ii) A second Beckman/Sagian Core system for HCS using automated microscopy with an Orca arm; Molecular Devices ImageXpress (micro) automated fluorescence microscope and a Cytomat 6001 incubator. (3) Zebrafish Facility: under the direction of Dr. Shuo Lin, this state of the art facility in the UCLA Life Sciences Building facilitates the use and quick access of common mutations, genetically engineered transgenic zebrafish and routine techniques of zebrafish manipulations. The core provides four major categories of service: i) space for housing and performing larger scale genetic or chemical genomic screens; ii) assistance in development of zebrafish experiments; iii) generation of transgenic zebrafish; and iv) cryostorage of zebrafish sperm and re-derivation of live fish. (4) Molecular Instrumentation Center is a state-of-the-art campus-wide facility dedicated to molecular characterization housed in the Department of Chemistry. With focus on Magentic Resonance, Mass Spectrometry, Materials Characterization, and X-Ray Diffraction, equipment includes SEM, differential scanning calorimetry, thermogravimetric analysis, magnetic resonance imaging, X-ray diffractometers, mass spectrometry for proteomics and biochemistry instrumentation, ICP-AES for elemental analysis and speciation. (5) CNSI Core Facilities provide additional equipment not found in the above laboratories on a recharge basis. Nanoelectronics Research Facility includes scanning electron microscopy (SEM) with energy-dispersive analysis of X-rays; transmission electron microscopy; surface profilometers and ellipsometers. UCLA’s Environmental Nanotechnology Research Laboratory includes a programmable oven, furnace, and microwave systems for NM synthesis, bench-top micro-centrifuge and stirred filtration cells for NM isolation, BET analyzer for powder surface area and pore size analyses, equipment for polymer phase inversion, interfacial polymerization, and solution casting. Nano-Bio Interfacial Forces Laboratory includes a contact angle goniometer for powder/substrate wetting and surface energy analyses; particle

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micro-electrophoresis system for particle electrophoretic mobilities (zeta potentials); dynamic and static light scattering for evaluating particle sizes and polymer molecular weights; upright optical and epi fluorescence microscope; and AFM integrated with inverted optical microscopy. UC Santa Barbara: Four clusters of laboratories are available to CEIN: (1) CNSI-UCSB provides recharge access to the Microscopy and Microanalysis Facility: three transmission electron microscopes (FEI Titan FEG and two FEI Tecnai G2 Sphera), three SEMs (FEI XL40 Sirion FEG, FEI XL30 Sirion, FEI Inspect S), five scanning probe STM/AFM microscopes (Digital Multi-mode Nanoscope, Digital Dimension 3000, Digital Dimension 3100, Asylum MFP-3D SL, Asylum MFP-3D Bio), a secondary ion mass spectrometer (Physical Electronics 6650 Quadrupole), X-ray Photoelectron Spectroscopy Kratos Axis Ultra System, Focused Ion Beam System (Model DB235 Dual Beam). The Spectroscopy Facility has seven state-of-the-art spectrometers (Nicolet Magna 850 IR/Raman, Varian Cary Eclipse Fluorimeter, Bruker DPX200 SB NMR for solutions, DSX300 WB NMR for solids, DMX500 SB NMR for solutions, Bruker IPSO500 WB NMR for solids, Bruker EMX Plus EPR spectrometer). (2) Bren School of Environmental Science and Management. The School Infrastructure Lab (2350 sf) includes a Shimadzu HPLC with fluorescence and diode array detectors, Shimadzu GC/FID, Beckman scintillation counter, total-carbon analyzer, –80 °C Revco freezer, high-speed refrigerated Sorvall centrifuge, two static incubators for cultivation at 37 and 41 °C, refrigerator, water baths, spectrophotometers, hybridization oven, UV crosslinker, Nanopure water system, autoclave, icemaker, laboratory microwave, two multi-user walk-in 4 ºC rooms for sample storage and two walk-in freezers, and two variable-temperature rooms. Holden’s lab (930 sf) includes: HP 6890 GC/MS with autosampler; Baker biological control cabinet; Sorvall microcentrifuge; New Brunswick shaker/incubator; analytical balances; Nikon E-800 epifluorescent microscope equipped with a CCD camera and NIS-Elements acquisition and analysis software; BioTek Synergy2 microplate shaker/incubator/reader with UV/Vis/TRF detectors; PCR and qPCR thermal cyclers and other equipment related to electrophoresis, PCR product quantification, and analyzing terminal labeled restriction fragment length polymorphisms. Micro-Environmental Imaging and Analysis Facility (MEIAF), an environmental SEM with a cryo-stage for imaging frozen materials and an X-ray detector for elemental analysis (300 sf). The MEIAF is available to the public on a recharge basis. Keller’s lab (940 sf) includes: Malvern Zetasizer nano series Nano-ZS90; and QSonica Misonix Sonicator S-4000; Shimadzu high performance liquid chromatography (HPLC) system (SPD-M10AVP); Varian Saturn 2100T GC/MS with autosampler; Nikon Optiphot-M epi-fluorescent microscope with CCD camera; Thermo Cahn Radian 315 dynamic contact angle analyzer; Brookfield viscometer; column transport pumps and controllers. (3) Department of Ecology, Evolution, and Marine Biology. Schimel’s lab includes: two Finnegan MAT Delta Plus MS systems equipped with elemental analyzer, gas bench, pyrolysis, and GC inlet systems (available through MSI analytical lab); two multichannel Lachat autoanalyzers for dissolved nutrients; C/N analyzer for solid samples; Shimadzu GC 14 for simultaneous CO2, CH4, and N2O analyses; microtiter plate reader (UV/Vis) for enzyme and chemical assays. Nisbet’s lab has high-end PCs for DEB modeling, additional access to a high-performance computing multi-node facility at UCSB is available on a recharge basis; Leica Dissecting scope with digital color camera; Leica inverted microscope, fully motorized, with monochrome camera; Molecular Devices Gemini EM scanning spectrofluorometer (top and bottom reads); C/N Analyzer for solid samples; Ocean Optics Jaz portable spectrofluorometer; four peristaltic pumps; Mettler-Toledo Ultra-microbalance; Millipore Elix water system; bath sonicator; two incubators.

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(4) MRL Facilities provide access on a recharge basis: Thermo iCAP 6300 Inductively Coupled Plasma ICP Spectrometer; Shimadzu UV3600 UV-Nir-NIR Spectrometer; Mettler 851e TG coupled to a Pfeiffer ThermoStar Mass Spectrometer TGA-MS for thermo gravimetric analysis; Quantum Design MPMS 5XL SQUID Magnetometer; Bruker D8 Theta-Theta XRD; MicroMeritics TriStar Porosimeter for surface area, pore volume, and pore size distribution measurements; Perkin Elmer LS 55 Luminescence Spectrometer. UC Davis: Bodega Marine Laboratory (BML) houses 16 specialized wet labs. Equipment includes state-of-the-art fluorescence imaging facility, ultracentrifuges, ultra-cold freezers, autoclaves, a 28-ft flow-visualization water tunnel/flume, OES mass spectrometer, and experimental climate change laboratories. Support buildings include terrestrial and marine greenhouses, animal resources, marine operations (diving, vessels and ocean observing), and an industrial shop (engineering, fabrication, and maintenance). Seawater Laboratory Sensor Network: a sophisticated computer-controlled, up to 1,000,000-gallon/day seawater system that provides seawater to the wet labs, classrooms and public displays. Specialized laboratories on the Seawater Sensor Network include a marine pathology laboratory (the only State-approved facility for marine pathology studies) and salt and freshwater laboratory for studies of threatened and endangered species. Cherr’s laboratory houses BML’s Fluorescence Imaging Facility, which includes a Photon Technology spectrofluorometer with ratiometric and ion quantitation software; high-speed fluorescence video imaging system on a fixed stage microscope controlled by Metamorph software; three epifluorescence microscopes; UVP Epichem II fluorescence/chemiluminescence gel documentation system; Tecan Genios time-resolved fluorescence/ and luminescence/absorbance plate reader; Olympus Fluoview 500 confocal scanning laser microscope with temperature controlled stage and water immersion objective lenses; Expert Vision System motion analysis software; and a Nikon AZ100 fluorescence stereo zoom microscope with a computer controlled stage HCS software capabilities UC Riverside: Walker‘s laboratory is equipped with an inverted Olympus IX70 microscope (phase contrast or fluorescent mode), used to image bacterial cells or particle attachment to test surfaces within a parallel plate flow cell or a radial stagnation point flow cell. The lab is also equipped with an Electrokinetic Analyzer for streaming potential measurements and a ZetaPal machine for particle electrophoretic mobility and dynamic light scattering (both pieces by Brookhaven Corp.). Columbia University: Shared resources in the MRSEC and Chemistry Departments for work on this project: Hitachi 4700 SEM; JEOL SEM and TEM; Inel X-ray diffractometer; Bruker NMR spectrometer; PHI 5500 XPS; ellipsometer. Somasundaran’s laboratory includes: Horiba Aramis Raman microscope with four lasers; Digital Instruments AFM; PenKem 3.0+ Zeta meters; Perkin–Elmer Spectrum100 FTIR spectrophotometer; Horiba Jobin Yvon Fluorolog fluorescence spectrophotometer (steady state); Horiba Jobin Yvon IBH5000F fluorescence spectrophotometer (time-resolved); Quantachrome Instruments Quantasorb surface area analyzer; Bruker EMX EPR spectroscope; Perkin–Elmer Plasma 400 ICP spectrophotometer; Perkin-Elmer UV-Vis Lambda-25 Spectrophotometer, Kruss K12 surface and interfacial tensiometers; NIMA Tech DST9005 dynamic surface tension analyzer; Nikon optical microscope; Beckman–Coulter Optima XL-1 analytical ultracentrifuge; SORVALL RC-5B bench-scale and temperature-controlled centrifuge, HF scientific turbidity meter, flotation equipment. Northwestern University: The Hersam Laboratory (3000 sq. ft.) houses five fume hoods and the following major pieces of instrumentation: (i) 2 Thermomicroscopes CP Research Atomic Force Microscopes (AFMs): characterize

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http://www.mrl.ucsb.edu/mrl/centralfacilities/chemistry/icp.html

http://www.mrl.ucsb.edu/mrl/centralfacilities/chemistry/uvnir.html

http://www.mrl.ucsb.edu/mrl/centralfacilities/chemistry/tga-ms.html

http://www.mrl.ucsb.edu/mrl/centralfacilities/chemistry/quantum.html

http://www.mrl.ucsb.edu/mrl/centralfacilities/chemistry/HTXRD.html

http://www.mrl.ucsb.edu/mrl/centralfacilities/chemistry/porosimeter.html

http://www.mrl.ucsb.edu/mrl/centralfacilities/chemistry/LS55.html


mechanical (force-distance spectroscopy) and electronic (electric force microscopy and scanning potentiometry) properties of materials at the nanometer scale in ambient, controlled atmosphere, and liquid environments; (ii) 2 Room Temperature Ultra-high Vacuum (UHV) Scanning Tunneling Microscopes (STMs): These home-built multi-chamber systems are used to prepare pristine surfaces, which are then characterized at the atomic-scale with STM and scanning tunneling spectroscopy. Feedback controlled lithography has also been implemented to isolate and pattern individual molecules on surfaces in atomically precise geometries. The UHV chambers (base pressure ~ 2×10-11 Torr) are directly interfaced to a controlled atmosphere glove box (oxygen and water concentrations < 1 ppm) to enable combined UHV and wet chemical processing with minimal contamination; (iii) 1 Cryogenic Variable Temperature UHV STM: this system controls the temperature of the sample and the microscope between 10 K and 400 K, ideal for cryogenic studies and high resolution scanning tunneling spectroscopy; (iv) 1 Nanoelectronic Charge Transport Measurement Apparatus: Enables electrical characterization of nanoscale devices and sensors. The apparatus includes a wafer prober, hall measurement apparatus, high sensitivity source-measure unit, spectrum analyzer, current preamplifier, lock-in amplifier, and 4-channel digital oscilloscope. (v) 3 Density Gradient Ultracentrifugation (DGU) Apparatuses: Used to sort carbon nanotube and graphene samples by their physical and electronic structure. Each apparatus includes a horn ultrasonicator, a Beckman Coulter Optima L-90 K Preparative Ultracentrifuge, and a BioComp Piston Gradient Fractionator. University of New Mexico/Sandia National Lab: Brinker's Biocharacterization laboratory integrates biological organisms/components with engineered platforms. Capable of handling Biosafety Level 2 organisms and cell lines and the isolation and analysis of DNA, RNA, and proteins. Methods used to incorporate biological organisms/components onto engineered platforms: vesicle fusion; multiple tethering schemes; and plugged flow packing. Other capabilities include: ellipsometry for film characterization; electrochemistry; a PCR instrument for DNA amplification; a laser connected to an inverted microscope for fluorophore interrogation; and a hyperspectral microarray scanner for microarray analysis. The AML facility contains standard microbiological and biochemical equipment and supplies for handling the microorganisms and cell lines proposed for use on this project: Class II flow bench; standard and CO2 incubators; cryo-storage; freezers and refrigerators; autoclave; and a fluorescence microscope. The laboratory includes a new Asylum Research MFP-3D-BioAFM integrated with a Nikon TE2000-U inverted fluorescence microscope, which combines molecular resolution imaging and picoNewton force measurements on an inverted optical microscope to allow: in situ imaging of the surfaces of living cells upon exposure to NMs; measurement of adhesive forces of proteins/NMs on cell surfaces; single-molecule force spectroscopy of single NPs; and nanolithography and manipulation of samples on the nanometer and picoNewton scale. University of Texas, El Paso: Gardea-Torresdey’s laboratory: 3100 Perkin–Elmer flame atomic absorption spectrometer; 4100 ZL Perkin–Elmer Zeeman graphite furnace atomic absorption spectrometer; 4300 DV Perkin–Elmer ICP OES; Perkin–Elmer Elan DRC IIe Laser ablation/HPLC/ICP-MS; EG&G Model 394 electrochemical trace analyzer; Hewlett–Packard 5890 GC; Hewlett–Packard 5972 GC/MS; Perkin–Elmer Spectrum 100 FTIR spectrometer coupled to a Perkin–Elmer Spectrum spotlight 300 FTIR microscope; Nano-ZS 90, Malvern; Fisher XRF. Additional shared resources: Bruker 250-MHz NMR spectrometer; Bruker 300-MHz multi-nuclei NMR spectrometer; Electroscan 2020 environmental SEM; Kevex omicron X-ray microfluorescence spectrometer; Hitachi S-4800-II SEM with EBSD; EDAX/TSL X-ray analyzer and electron backscatter diffraction imaging equipment; Zyvex Nanomanipulator and Nanoprobe; Hitachi H-8000 TEM; Fluorescence microscopy; confocal microscope; conductivity meter; AFM. The XAS studies

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planned for this project will be performed at Stanford Synchrotron Radiation Laboratories (SSRL), Stanford, CA, where Gardea-Torresdey has received beam time the duration of this project. University of Bremen: Foundation Institute for Materials Science material characterization equipment available: X-ray diffraction (with extended Rietveld analysis); TEM and SEM; surface adsorption analysis (adsorption isotherms), UV-vis spectroscopy, Dynamic Light scattering, Zeta-potential und centrifugal particle sizer. Mädler’s laboratory has state-of-the-art flame spray pyrolysis reactors for the synthesis of various metal oxide-based NMs, including their functionalization with noble metals as well as double flame reactors.

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14. Personnel Management and Organization Strategy The UC CEIN organizational strategy is to maintain a strong infrastructure that supports and integrates our research, technology development, educational, outreach and diversity efforts. By facilitating communication across our participating communities, our organizational structure allows for selection, prioritization, distribution, and management of resources within a multi-institutional structure. By combining management of our financial operations with our programmatic operations, UC CEIN has been able to create an infrastructure designed to streamline the Center's activities while meeting the reporting requirements of the funding agency and the University. Leadership Andre Nel (UCLA) serves as the Center Director and Principal Investigator. As Director, Dr. Nel is responsible for the integration of the Center’s overall research, education and outreach activities. Arturo Keller (UCSB) is the Associate Director, responsible for coordinating the research integration, seminars, student training, and outreach activities at UC Santa Barbara to provide seamless integration with the activities at UCLA. Focused leadership for the education and outreach components of the Center is provided by Hilary Godwin (UCLA). This faculty management team provides complimentary expertise and strategic leadership to ensure the Center’s vision and mission. Research Themes UC CEIN research is organized into seven themes, each under the leadership of a CEIN faculty member. Each theme engages several faculty, postdoctoral researchers, research staff, and graduate students. Key to the success of the CEIN is the integration of research within and across themes. Theme leaders (who are also members of the CEIN Executive Committee) are responsible for setting priorities, allocating resources, and tracking progress towards achievement of the theme's goals. Frequent formal communication between theme leaders is key to ensuring that progress is made across all groups, and the findings of one theme are rapidly disseminated other themes. Projects submit periodic progress updates to their theme leader, the results of which are shared and discussed by the UC CEIN Executive Committee. Executive Committee The Executive Committee is composed of the Director, Associate Director, Education/Outreach Director, Co-PIs, Theme leaders, and the Center Chief Administrative Officer. In fall 2012, CEIN faculty member Jorge Gardea-Torresday (University of El Paso Texas) joined the Executive Committee to provide additional input and guidance. The Executive Committee meets at least once per month and is responsible for assisting the Director with integration and coordination of research and education, overall resource allocation, and outreach to the scientific, industrial, and policy community. Several times a year, the Executive Committee reviews long-term directions of the Center and possible strategic redirections. Prior to any Research Reviews, Site Visits, and External Science Advisory Committee meetings the EC focuses on strategic planning. Research progress for all projects is reviewed on an ongoing basis, with projects submitting Quarterly progress updates. Allocation of Center resources is based on the following metrics: (i) contribution of the proposed work to the CEIN’s core goals; (ii) productivity, publication, and product delivery record; (iii) novelty; (iv) integration and cooperation with other funded CEIN projects; (v) availability of resources and facilities to carry out proposed projects; and (vi) timely delivery of tangible results. Approximately 3% of the total research budget is designated for new and exploratory integrated research seed funding. Proposals for seed funding are reviewed by the EC on an annual basis.

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One to two times per year, the Executive Committee meets for a day long research retreat. The retreat focuses on the review of overall Center priorities and is a forum for discussing and establishing key short and long term goals for the Center, with particular focus on strengthening integration across all Themes. External Science Advisory Committee The UC CEIN has convened an External Science Advisory Committee (ESAC) comprised of scientists, technologists, industry members, and policy and education specialists. The ESAC advises the Center’s Executive Committee with respect to CEIN strategic directions and management policies. The ESAC provides feedback on the focus and direction of CEIN research, progress made toward achieving Center goals, and illuminating new research and educational opportunities. The diversity of this group provides a comprehensive perspective on the major advances in nanotechnology and key issues with regards to potential environmental implications. In response to the most recent Site Visit comments, we expanded the ESAC committee in 2013 to include a more diverse pool of advisors. The ESAC meets twice a year by teleconference and holds an in-person meeting at UCLA every other year. In addition to the group meetings, UC CEIN Executive Committee members engage ESAC members on an individual basis throughout the year based on their expertise. Additionally, ESAC members are invited to Center public events, including our Outreach workshops and scientific meetings. The composition of the ESAC is reviewed by the Executive Committee every two years. Current External Science Advisory Committee member: • Pedro Alvarez, Rice University • Ahmed Busnaina, Northeastern University • Sharon Dunwood, University of Wisconsin-Madison • C. Michael Garner, Retired (formerly Intel) • Agnes Kane, Brown University • Mark Lafranconi, Tox Horizons • Kent Pinkerton, UC Davis • Rick Pleus, Intertox • Omowunmi Sadik, SUNY Binghamton • Ron Turco, Purdue University • Isiah Warner, Louisana State University • Jeff Wong, CA Department of Toxic Substances Control • Paul Zimmerman, Intel Student-Postdoctoral Advisory Committee A Student-Postdoctoral Advisory Committee (SPAC) continues to be active and key role within the CEIN. The committee includes graduate student and postdoctoral scholar representatives from each of the Center's themes. The SPAC provides ongoing input into the development of the CEIN education program (including development of undergraduate mentoring opportunities), development of full-day annual leadership workshops (latest held September 2014), and formulation of goals for future Center workshops and seminar series. With input from the SPAC, the Education/Outreach Director and Coordinator have refined our annual evaluative survey which among other topics, documents educational and training achievements of Center trainees, results of which are discussed with the SPAC. Support Cores The UC CEIN has identified four key Core function areas that form the basis for the Center's research infrastructure and provide support to enable the execution of research of the highest caliber. The Core areas interact across the Center's projects to enable smooth cross-disciplinary integration. The Cores are

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key in the ability to expand the scope of research within the Center and to maintain the flexibility necessary to conduct complex multidisciplinary research across a range of themes. Each of the Cores is housed within the California NanoSystems Institute (CNSI) facility at UCLA. Each of the Center's Core functions to provide the infrastructure and key support needed to carry out the wide range of multidisciplinary activities within the Center. Each Core serves a unique and necessary function. Cores B, C, and D are all adaptations of previously existing research projects with the Center. The interactions with the Cores and the Themes are essential to the scientific research advances of the Center. As the Center's mission leads to the exploration of new questions about the environmental implications of nanomaterials, whether that involves new materials, new environmental conditions, or new types of data collected, the Cores will continue to play a key integrated role in the mission of the Center. The Cores are led by research staff who have the technical skills to interact across Center projects. Ideas for future development of Core activities arise through ongoing discussion with theme leaders based on the direction and findings of the Center's overall research agenda.

• Core A: Administrative Core • Core B: ENM Acquisition, Characterization, and Distribution • Core C: Data Management Core • Core D: Molecular Shared Screening Resource

Core A: Administrative Support An administrative staff has been compiled at UCLA to support streamlined operations of the Center. Since establishment of the Center in September 2008, the administration of the Center has operated under continuous management of the Center's Chief Administrative Officer (CAO). Utilizing experience in managing other large federally funded research, the CEIN administration is organized to provide maximized support to all Center projects in the most efficient manner possible. The CAO assists the Director by overseeing the general administration, cooperation, communication, planning, financial implementation, goals setting, and development of Center activities. The CAO is supported by the following dedicated staff:

o Financial/Budget Coordinator – responsible for financial management and reporting systems across partner institutions

o Administrative Assistant – provides general support for all Center activities including meeting coordination

o Education Coordinator – under joint supervision of the CAO and Education/Outreach Director, organizes the training, communication, diversity, and evaluation components of the program.

o Outreach Coordinator - in Spring 2012, CEIN recruited an Outreach Coordinator who works under the direction of the CAO, the Director, and the Education/Outreach Director to develop and implement our Center's outreach activities targeted towards stakeholders in academia, industry, and policy makers.

o To assist in the administrative coordination of the UC Santa Barbara activities, a half time administrative support staff position has been allocated to UCSB.

Core B: ENM Acquisition, Characterization, and Distribution Core B is closely tied to the activities of Theme 1 and operates under the direction of Theme 1 leader Jeffrey I. Zink, who oversees the technical director, Dr. Zhaoxia Ivy Ji. Core B maintains the Centers nanomaterials library and coordinates the synthesis or acquisition and the distribution of ENMs across research projects and themes. This process necessitates close interaction with the toxicity groups to understand the major findings of current ongoing studies and to work with the material synthesis projects to redesign materials as needed to affect material properties. In order to conduct material characterization under relevant exposure conditions, Core B is closely affiliated with the cellular and environmental study investigators to determine the relevant range of characterization procedures and media to be conducted

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for each material. Characterization parameters that are key to our ongoing studies are: size and distribution analysis in relevant media, agglomeration kinetics, sedimentation studies, and surface charge analysis. Core B has four main responsibilities: 1. The standard reference and combinatorial nanomaterial libraries are the sources of materials for

mechanistic and high-throughput studies designed to probe environmental fate and transport of these materials as well as their cellular, organism, and ecosystem toxicity. Currently more than 100 different nanomaterials, varying from metals, metals oxides, to carbon nanotubes, have been introduced into the library.

2. The major “service” function of Core B involves characterization of the nanomaterials as they are synthesized or acquired. Its goals are to thoroughly characterize nanoparticles of commercial importance and make them available in usable forms and quantities for in vitro and in vivo studies. “Conventional” particles of commercial importance and scientifically-important high value particles are characterized by Core B.

3. Development of methods of dispersing nanoparticles in biologically relevant media is another major service function. Important insight has been gained by the Center, particularly regarding the influence of cell culture media as they influence dose metrics. For each type of particle introduced into the Center, Core B explores the best method of dispersion and documents these methods.

4. Core B is also responsible for the distribution and tracking of materials across Center projects. The inter- and intra-campus distributions of both the particles and the characterization information associated with them have been very reliable and efficient.

Core C: Data Management Core The UC CEIN Data Management Team, under the supervision of Theme 6 leader Cohen, is responsible for development and maintenance of the computational infrastructure and data management system of the Center. Core C provides core support for data management, data storage, IT support, the web-based collaborative infrastructure and the computational needs of the Center. The technological infrastructure of the Center was developed to keep pace with the data generated by Center projects and to meet the computational needs of the Center's data analysis and modeling projects. Core C has implemented a center-wide file and data repository, hosts the Center's public website, and hosts software that allows for the searching/organizing/mining of research data uploaded to the system. The data manager (Bacsafra) works with each project's investigators to facilitate the uploading of data and to adapt the data repository system to meet the specific data needs of each project. The CEIN Data Management group plays a key role in the national Nanoinformatics effort. Our computational capabilities have enabled collaborations with external groups, including the EPAs ToxCast Program and NSF's iPlant Collaborative. Core D: Molecular Shared Screening Resource Core D provides scientific and technical consultation in the planning and execution of high throughput experiments conducted by UC CEIN researchers. The Molecular Shared Screening Resource (MSSR), under the direction of MSSR Scientific Director Robert Damoiseaux, assists in the translation of existing low throughput assays and the de novo establishment of novel assays. The expertise and technical capabilities available through the MSSR make this facility uniquely suited to handle a wide variety of assays, including those aimed at exploring the interaction between nanomaterials and bacteria, yeast, animal cells, and whole animals (zebrafish). Core D (MSSR) is most closely linked to the research in Themes 2 and 4, working with projects to develop and validate HTS techniques for the screening of cells, bacteria, yeast, and whole animals (zebrafish) for the effects of interactions with nanomaterials. MSSR staff work closely with project researchers to translate

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existing assays to high throughput format, which includes adaptation of the assays for implementation on the robotics systems and providing assistance in conducting validation studies and data analysis. Once assays have been validated for HTS, screens may be conducted using additional Center library nanomaterials as dictated by the ongoing research project hypotheses. Organization Chart

Changes in Personnel No changes to key Center personnel to report.

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130


15. Publications

Primary Publications

1. Adeleye, A. S., Conway, J. R., Perez, T., Rutten, P., & Keller, A. A. (2014). Influence of Extracellular Polymeric Substances on the Long-Term Fate, Dissolution, and Speciation of Copper-Based Nanoparticles. Environmental Science & Technology, 48(21), 12561-12568. doi: 10.1021/es5033426

2. Beaudrie, C. E. H., Satterfield, T., Kandlikar, M., & Harthorn, B. H. (2014). Scientists versus Regulators: Precaution, Novelty & Regulatory Oversight as Predictors of Perceived Risks of Engineered Nanomaterials. PLoS ONE, 9(9), e106365. doi: 10.1371/journal.pone.0106365

3. Bielmyer-Fraser, G. K., Jarvis, T. A., Lenihan, H. S., & Miller, R. J. (2014). Cellular Partitioning of Nanoparticulate versus Dissolved Metals in Marine Phytoplankton. Environmental Science & Technology, 48(22), 13443-13450. doi: 10.1021/es501187g

4. Chowdhury, I., Duch, M. C., Mansukhani, N. D., Hersam, M. C., & Bouchard, D. (2014). Interactions of Graphene Oxide Nanomaterials with Natural Organic Matter and Metal Oxide Surfaces. Environmental Science & Technology, 48(16), 9382-9390. doi: 10.1021/es5020828

5. Collin, B., Auffan, M., Johnson, A. C., Kaur, I., Keller, A. A., Lazareva, A., . . . Unrine, J. M. (2014). Environmental release, fate and ecotoxicological effects of manufactured ceria nanomaterials. Environmental Science: Nano, 1(6), 533-548. doi: 10.1039/c4en00149d

6. Conway, J. R., Adeleye, A. S., Gardea-Torresdey, J., & Keller, A. A. (2015). Aggregation, Dissolution, and Transformation of Copper Nanoparticles in Natural Waters. Environmental Science & Technology, 49(5), 2749-2756. doi: 10.1021/es504918q

7. Corral-Diaz, B., Peralta-Videa, J. R., Alvarez-Parrilla, E., Rodrigo-García, J., Morales, M. I., Osuna-Avila, P., . . . Gardea-Torresdey, J. L. (2014). Cerium oxide nanoparticles alter the antioxidant capacity but do not impact tuber ionome in Raphanus sativus (L). Plant Physiology and Biochemistry, 84(0), 277-285. doi: http://dx.doi.org/10.1016/j.plaphy.2014.09.018

8. Corsi, I., Cherr, G. N., Lenihan, H. S., Labille, J., Hassellov, M., Canesi, L., . . . Matranga, V. (2014). Common Strategies and Technologies for the Ecosafety Assessment and Design of Nanomaterials Entering the Marine Environment. ACS Nano, 8(10), 9694-9709. doi: 10.1021/nn504684k

9. Gardea-Torresdey, J. L., Rico, C. M., & White, J. C. (2014). Trophic Transfer, Transformation, and Impact of Engineered Nanomaterials in Terrestrial Environments. Environmental Science & Technology, 48(5), 2526-2540. doi: 10.1021/es4050665

10. Garner, K., & Keller, A. (2014). Emerging patterns for engineered nanomaterials in the environment: a review of fate and toxicity studies. Journal of Nanoparticle Research, 16(8), 1-28. doi: 10.1007/s11051-014-2503-2

11. Ge, Y., Priester, J. H., Van De Werfhorst, L. C., Walker, S. L., Nisbet, R. M., An, Y.-J., . . . Holden, P. A. (2014). Soybean Plants Modify Metal Oxide Nanoparticle Effects on Soil Bacterial Communities. Environmental Science & Technology, 48(22), 13489-13496. doi: 10.1021/es5031646

12. Ge, Y., Schimel, J. P., & Holden, P. A. (2014). Analysis of Run-to-Run Variation of Bar-Coded Pyrosequencing for Evaluating Bacterial Community Shifts and Individual Taxa Dynamics. PLoS ONE, 9(6), e99414. doi: 10.1371/journal.pone.0099414

13. Godwin, H., Nameth, C., Avery, D., Bergeson, L. L., Bernard, D., Beryt, E., . . . Nel, A. E. (2015). Nanomaterial Categorization for Assessing Risk Potential To Facilitate Regulatory Decision-Making. ACS Nano. doi: 10.1021/acsnano.5b00941

131

http://dx.doi.org/10.1016/j.plaphy.2014.09.018


14. Hanna, S., Miller, R., & Lenihan, H. (2014). Accumulation and Toxicity of Copper Oxide Engineered Nanoparticles in a Marine Mussel. Nanomaterials, 4(3), 535-547. doi: 10.3390/nano4030535

15. Hanna, S. K., Miller, R. J., & Lenihan, H. S. (2014). Deposition of carbon nanotubes by a marine suspension feeder revealed by chemical and isotopic tracers. Journal of Hazardous Materials, 279(0), 32-37. doi: http://dx.doi.org/10.1016/j.jhazmat.2014.06.052

16. Hawthorne, J., De la Torre Roche, R., Xing, B., Newman, L. A., Ma, X., Majumdar, S., . . . White, J. C. (2014). Particle-Size Dependent Accumulation and Trophic Transfer of Cerium Oxide through a Terrestrial Food Chain. Environmental Science & Technology, 48(22), 13102-13109. doi: 10.1021/es503792f

17. Holden, P. A., Klaessig, F., Turco, R. F., Priester, J. H., Rico, C. M., Avila-Arias, H., . . . Gardea-Torresdey, J. L. (2014). Evaluation of Exposure Concentrations Used in Assessing Manufactured Nanomaterial Environmental Hazards: Are They Relevant? Environmental Science & Technology, 48(18), 10541-10551. doi: 10.1021/es502440s

18. Hong, J., Peralta-Videa, J. R., Rico, C., Sahi, S., Viveros, M. N., Bartonjo, J., . . . Gardea-Torresdey, J. L. (2014). Evidence of Translocation and Physiological Impacts of Foliar Applied CeO2 Nanoparticles on Cucumber (Cucumis sativus) Plants. Environmental Science & Technology, 48(8), 4376-4385. doi: 10.1021/es404931g

19. Hong, J., Rico, C. M., Zhao, L., Adeleye, A. S., Keller, A. A., Peralta-Videa, J. R., & Gardea-Torresdey, J. L. (2015). Toxic effects of copper-based nanoparticles or compounds to lettuce (Lactuca sativa) and alfalfa (Medicago sativa). Environmental Science: Processes & Impacts, 17(1), 177-185. doi: 10.1039/c4em00551a

20. Kaweeteerawat, C., Ivask, A., Liu, R., Zhang, H., Chang, C. H., Low-Kam, C., . . . Godwin, H. (2015). Toxicity of Metal Oxide Nanoparticles in Escherichia coli Correlates with Conduction Band and Hydration Energies. Environmental Science & Technology, 49(2), 1105-1112. doi: 10.1021/es504259s

21. Keller, A., Vosti, W., Wang, H., & Lazareva, A. (2014). Release of engineered nanomaterials from personal care products throughout their life cycle. Journal of Nanoparticle Research, 16(7), 1-10. doi: 10.1007/s11051-014-2489-9

22. Lanphere, J. D., Rogers, B., Luth, C., Bolster, C. H., & Walker, S. L. (2014). Stability and Transport of Graphene Oxide Nanoparticles in Groundwater and Surface Water. Environmental Engineering Science, 31(7), 350-359. doi: 10.1089/ees.2013.0392

23. Lanphere, J. D., Luth, C. J., Guiney, L. M., Mansukhani, N. D., Hersam, M. C., & Walker, S. L. (2014). Fate and Transport of Molybdenum Disulfide Nanomaterials in Sand Columns. Environmental Engineering Science, 32(2), 163-173. doi: 10.1089/ees.2014.0335

24. Lazareva, A., & Keller, A. A. (2014). Estimating Potential Life Cycle Releases of Engineered Nanomaterials from Wastewater Treatment Plants. ACS Sustainable Chemistry & Engineering, 2(7), 1656-1665. doi: 10.1021/sc500121w

25. Lin, S., Taylor, A. A., Ji, Z., Chang, C. H., Kinsinger, N. M., Ueng, W., . . . Nel, A. E. (2015). Understanding the Transformation, Speciation, and Hazard Potential of Copper Particles in a Model Septic Tank System Using Zebrafish to Monitor the Effluent. ACS Nano, 9(2), 2038-2048. doi: 10.1021/nn507216f

26. Lin, S., Wang, X., Ji, Z., Chang, C. H., Dong, Y., Meng, H., . . . Nel, A. E. (2014). Aspect Ratio Plays a Role in the Hazard Potential of CeO2 Nanoparticles in Mouse Lung and Zebrafish Gastrointestinal Tract. ACS Nano, 8(5), 4450-4464. doi: 10.1021/nn5012754

27. Liu, H. H., Lanphere, J., Walker, S., & Cohen, Y. (2015). Effect of hydration repulsion on nanoparticle agglomeration evaluated via a constant number Monte–Carlo simulation. Nanotechnology, 26(4), 045708. doi: doi:10.1088/0957-4484/26/4/045708

132

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28. Liu, R., France, B., George, S., Rallo, R., Zhang, H., Xia, T., . . . Cohen, Y. (2014). Association rule mining of cellular responses induced by metal and metal oxide nanoparticles. Analyst, 139(5), 943-953. doi: 10.1039/c3an01409f

29. Majumdar, S., Peralta-Videa, J. R., Bandyopadhyay, S., Castillo-Michel, H., Hernandez-Viezcas, J.-A., Sahi, S., & Gardea-Torresdey, J. L. (2014). Exposure of cerium oxide nanoparticles to kidney bean shows disturbance in the plant defense mechanisms. Journal of Hazardous Materials, 278(0), 279-287. doi: http://dx.doi.org/10.1016/j.jhazmat.2014.06.009

30. Martin, B., Jager, T., Nisbet, R. M., Preuss, T. G., & Grimm, V. (2014). Limitations of extrapolating toxic effects on reproduction to the population level. Ecological Applications, 24(8), 1972-1983. doi: 10.1890/14-0656.1

31. Moreno-Olivas, F., Gant, V., Jr., Johnson, K., Peralta-Videa, J., & Gardea-Torresdey, J. (2014). Random amplified polymorphic DNA reveals that TiO2 nanoparticles are genotoxic to Cucurbita pepo. Journal of Zhejiang University SCIENCE A, 15(8), 618-623. doi: 10.1631/jzus.A1400159

32. Mukherjee, A., Peralta-Videa, J. R., Bandyopadhyay, S., Rico, C. M., Zhao, L., & Gardea-Torresdey, J. L. (2014). Physiological effects of nanoparticulate ZnO in green peas (Pisum sativum L.) cultivated in soil. Metallomics, 6(1), 132-138. doi: 10.1039/c3mt00064h

33. Mukherjee, A., Pokhrel, S., Bandyopadhyay, S., Mädler, L., Peralta-Videa, J. R., & Gardea-Torresdey, J. L. (2014). A soil mediated phyto-toxicological study of iron doped zinc oxide nanoparticles (Fe@ZnO) in green peas (Pisum sativum L.). Chemical Engineering Journal, 258(0), 394-401. doi: http://dx.doi.org/10.1016/j.cej.2014.06.112

34. Peralta-Videa, J. R., Hernandez-Viezcas, J. A., Zhao, L., Diaz, B. C., Ge, Y., Priester, J. H., . . . Gardea-Torresdey, J. L. (2014). Cerium dioxide and zinc oxide nanoparticles alter the nutritional value of soil cultivated soybean plants. Plant Physiology and Biochemistry, 80(0), 128-135. doi: http://dx.doi.org/10.1016/j.plaphy.2014.03.028

35. Ponnurangam, S., O'Connell, G. D., Chernyshova, I. V., Wood, K., Hung, C. T.-H., & Somasundaran, P. (2014). Beneficial Effects of Cerium Oxide Nanoparticles in Development of Chondrocyte-Seeded Hydrogel Constructs and Cellular Response to Interleukin Insults. Tissue Engineering Part A, 20(21-22), 2908-2919. doi: 10.1089/ten.tea.2013.0592

36. Priester, J. H., Singhal, A., Wu, B., Stucky, G. D., & Holden, P. A. (2014). Integrated approach to evaluating the toxicity of novel cysteine-capped silver nanoparticles to Escherichia coli and Pseudomonas aeruginosa. Analyst, 139(5), 954-963. doi: 10.1039/c3an01648j

37. Priester, J. H., Van De Werfhorst, L. C., Ge, Y., Adeleye, A. S., Tomar, S., Tom, L. M., . . . Holden, P. A. (2014). Effects of TiO2 and Ag Nanoparticles on Polyhydroxybutyrate Biosynthesis By Activated Sludge Bacteria. Environmental Science & Technology, 48(24), 14712-14720. doi: 10.1021/es504117x

38. Rico, C., Peralta-Videa, J. R., & Gardea-Torresdey, J. L. (2015). Differential Effects of Cerium Oxide Nanoparticles on Rice, Wheat, and Barley Roots: A Fourier Transform Infrared (FT-IR) Microspectroscopy Study. Applied Spectroscopy, 69(2), 287-295. doi: 10.1366/14-07495

39. Rico, C. M., Lee, S. C., Rubenecia, R., Mukherjee, A., Hong, J., Peralta-Videa, J. R., & Gardea-Torresdey, J. L. (2014). Cerium Oxide Nanoparticles Impact Yield and Modify Nutritional Parameters in Wheat (Triticum aestivum L.). Journal of Agricultural and Food Chemistry, 62(40), 9669-9675. doi: 10.1021/jf503526r

40. Song, H.-M., Zink, J. I., & Khashab, N. M. (2014). Investigating Unexpected Magnetism of Mesoporous Silica-Supported Pd and PdO Nanoparticles. Chemistry of Materials, 27(1), 29-36. doi: 10.1021/cm502448p

41. Trujillo-Reyes, J., Majumdar, S., Botez, C. E., Peralta-Videa, J. R., & Gardea-Torresdey, J. L. (2014). Exposure studies of core–shell Fe/Fe3O4 and Cu/CuO NPs to lettuce (Lactuca sativa)

133


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http://dx.doi.org/10.1016/j.plaphy.2014.03.028


plants: Are they a potential physiological and nutritional hazard? Journal of Hazardous Materials, 267(0), 255-263. doi: http://dx.doi.org/10.1016/j.jhazmat.2013.11.067

42. Wang, H., Qi, J., Keller, A. A., Zhu, M., & Li, F. (2014). Effects of pH, ionic strength and humic acid on the removal of TiO2 nanoparticles from aqueous phase by coagulation. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 450(0), 161-165. doi: http://dx.doi.org/10.1016/j.colsurfa.2014.03.029

43. Zhang, H., Pokhrel, S., Ji, Z., Meng, H., Wang, X., Lin, S., . . . Nel, A. E. (2014). PdO Doping Tunes Band-Gap Energy Levels as Well as Oxidative Stress Responses to a Co3O4 p-Type Semiconductor in Cells and the Lung. Journal of the American Chemical Society, 136(17), 6406-6420. doi: 10.1021/ja501699e

44. Zhao, L., Peralta-Videa, J. R., Peng, B., Bandyopadhyay, S., Corral-Diaz, B., Osuna-Avila, P., . . . Gardea-Torresdey, J. L. (2014). Alginate modifies the physiological impact of CeO2 nanoparticles in corn seedlings cultivated in soil. Journal of Environmental Sciences, 26(2), 382-389. doi: http://dx.doi.org/10.1016/S1001-0742(13)60559-8

45. Zhao, L., Peralta-Videa, J. R., Rico, C. M., Hernandez-Viezcas, J. A., Sun, Y., Niu, G., . . . Gardea-Torresdey, J. L. (2014). CeO2 and ZnO Nanoparticles Change the Nutritional Qualities of Cucumber (Cucumis sativus). Journal of Agricultural and Food Chemistry, 62(13), 2752-2759. doi: 10.1021/jf405476u

46. Zhu, M., Wang, H., Keller, A. A., Wang, T., & Li, F. (2014). The effect of humic acid on the aggregation of titanium dioxide nanoparticles under different pH and ionic strengths. Science of The Total Environment, 487(0), 375-380. doi: http://dx.doi.org/10.1016/j.scitotenv.2014.04.036

Leveraged Publications

47. Adegboyega, N. F., Sharma, V. K., Siskova, K. M., Vecerova, R., Kolar, M., Zbořil, R., & Gardea-Torresdey, J. L. (2014). Enhanced Formation of Silver Nanoparticles in Ag+-NOM-Iron(II, III) Systems and Antibacterial Activity Studies. Environmental Science & Technology, 48(6), 3228-3235. doi: 10.1021/es405641r

48. Ananthasubramaniam, B., McCauley, E., Gust, K. A., Kennedy, A. J., Muller, E. B., Perkins, E. J., & Nisbet, R. M. (2014). Relating suborganismal processes to ecotoxicological and population level endpoints using a bioenergetic model. Ecological Applications. doi: 10.1890/14-0498.1

49. Bimber, B., Cunill, M. C., Copeland, L., & Gibson, R. (2015). Digital Media and Political Participation: The Moderating Role of Political Interest Across Acts and Over Time. Social Science Computer Review, 33(1), 21-42. doi: 10.1177/0894439314526559

50. Chin, R. M., Fu, X., Pai, M. Y., Vergnes, L., Hwang, H., Deng, G., . . . Huang, J. (2014). The metabolite [agr]-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature, 510(7505), 397-401. doi: 10.1038/nature13264

51. Choi, E., Lu, J., Tamanoi, F., & Zink, J. I. (2014). Drug Release from Three-Dimensional Cubic Mesoporous Silica Nanoparticles Controlled by Nanoimpellers. Zeitschrift für anorganische und allgemeine Chemie, 640(3-4), 588-594. doi: 10.1002/zaac.201300503

52. Copeland, L., & Römmele, A. (2014). Beyond the Base? Political Parties, Citizen Activists, and Digital Media Use in the 2009 German Federal Election Campaign. Journal of Information Technology & Politics, 11(2), 169-185. doi: 10.1080/19331681.2014.902783

53. Croissant, J., Chaix, A., Mongin, O., Wang, M., Clément, S., Raehm, L., . . . Zink, J. I. (2014). Two-Photon-Triggered Drug Delivery via Fluorescent Nanovalves. Small, 10(9), 1752-1755. doi: 10.1002/smll.201400042

134


http://dx.doi.org/10.1016/j.colsurfa.2014.03.029

http://dx.doi.org/10.1016/S1001-0742(13)60559-8

http://dx.doi.org/10.1016/j.scitotenv.2014.04.036


54. Damoiseaux, R. (2014). UCLA’s Molecular Screening Shared Resource: Enhancing Small Molecule Discovery with Functional Genomics and New Technology. Combinatorial Chemistry & High Throughput Screening, 17(4), 356-368. doi: 10.2174/1386207317666140323134621

55. Dong, J., & Zink, J. I. (2014). Taking the Temperature of the Interiors of Magnetically Heated Nanoparticles. ACS Nano, 8(5), 5199-5207. doi: 10.1021/nn501250e

56. Gavankar, S., Suh, S., & Keller, A. A. (2015). The Role of Scale and Technology Maturity in Life Cycle Assessment of Emerging Technologies: A Case Study on Carbon Nanotubes. Journal of Industrial Ecology, 19(1), 51-60. doi: 10.1111/jiec.12175

57. Guardado-Alvarez, T. M., Devi, L. S., Vabre, J.-M., Pecorelli, T. A., Schwartz, B. J., Durand, J.-O., . . . Zink, J. I. (2014). Photo-redox activated drug delivery systems operating under two photon excitation in the near-IR. Nanoscale, 6(9), 4652-4658. doi: 10.1039/c3nr06155h

58. Hung, A. H., Holbrook, R. J., Rotz, M. W., Glasscock, C. J., Mansukhani, N. D., MacRenaris, K. W., . . . Meade, T. J. (2014). Graphene Oxide Enhances Cellular Delivery of Hydrophilic Small Molecules by Co-incubation. ACS Nano, 8(10), 10168-10177. doi: 10.1021/nn502986e

59. Li, R., Ji, Z., Qin, H., Kang, X., Sun, B., Wang, M., . . . Xia, T. (2014). Interference in Autophagosome Fusion by Rare Earth Nanoparticles Disrupts Autophagic Flux and Regulation of an Interleukin-1β Producing Inflammasome. ACS Nano, 8(10), 10280-10292.. doi: 10.1021/nn505002w

60. Li, R., Ji, Z., Dong, J., Chang, C. H., Wang, X., Sun, B., . . . Xia, T. (2015). Enhancing the Imaging and Biosafety of Upconversion Nanoparticles through Phosphonate Coating. ACS Nano, 9(3), 3293-3306. doi: 10.1021/acsnano.5b00439

61. Muller, E. B., & Nisbet, R. M. (2014). Dynamic energy budget modeling reveals the potential of future growth and calcification for the coccolithophore Emiliania huxleyi in an acidified ocean. Global Change Biology, 20(6), 2031-2038. doi: 10.1111/gcb.12547

62. Padilla-Rodríguez, A., Hernández-Viezcas, J. A., Peralta-Videa, J. R., Gardea-Torresdey, J. L., Perales-Pérez, O., & Román-Velázquez, F. R. (2015). Synthesis of protonated chitosan flakes for the removal of vanadium(III, IV and V) oxyanions from aqueous solutions. Microchemical Journal, 118(0), 1-11. doi: http://dx.doi.org/10.1016/j.microc.2014.07.011

63. Parsons, J. G., Hernandez, J., Gonzalez, C. M., & Gardea-Torresdey, J. L. (2014). Sorption of Cr(III) and Cr(VI) to high and low pressure synthetic nano-magnetite (Fe3O4)particles. Chemical Engineering Journal, 254(0), 171-180. doi: http://dx.doi.org/10.1016/j.cej.2014.05.112

64. Sharma, V. K., Siskova, K. M., Zboril, R., & Gardea-Torresdey, J. L. (2014). Organic-coated silver nanoparticles in biological and environmental conditions: Fate, stability and toxicity. Advances in Colloid and Interface Science, 204(0), 15-34. doi: http://dx.doi.org/10.1016/j.cis.2013.12.002

65. Su, Y., Adeleye, A. S., Huang, Y., Sun, X., Dai, C., Zhou, X., . . . Keller, A. A. (2014). Simultaneous removal of cadmium and nitrate in aqueous media by nanoscale zerovalent iron (nZVI) and Au doped nZVI particles. Water Research, 63(0), 102-111. doi: http://dx.doi.org/10.1016/j.watres.2014.06.008

66. Su, Y., Adeleye, A. S., Zhou, X., Dai, C., Zhang, W., Keller, A. A., & Zhang, Y. (2014). Effects of nitrate on the treatment of lead contaminated groundwater by nanoscale zerovalent iron. Journal of Hazardous Materials, 280(0), 504-513. doi: http://dx.doi.org/10.1016/j.jhazmat.2014.08.040

67. Sun, B., Wang, X., Ji, Z., Wang, M., Liao, Y.-P., Chang, C. H., . . . Xia, T. (2015). NADPH Oxidase-Dependent NLRP3 Inflammasome Activation and its Important Role in Lung Fibrosis by Multiwalled Carbon Nanotubes. Small, n/a-n/a. doi: 10.1002/smll.201402859

135

http://dx.doi.org/10.1016/j.microc.2014.07.011

http://dx.doi.org/10.1016/j.cej.2014.05.112

http://dx.doi.org/10.1016/j.cis.2013.12.002

http://dx.doi.org/10.1016/j.watres.2014.06.008



68. Sun, Y., Niu, G., Osuna, P., Zhao, L., Ganjegunte, G., Peterson, G., . . . Gardea-Torresdey, J. L. (2014). Variability in Salt Tolerance of Sorghum bicolor L. Agricultural Science, 2(1), 09-21. doi: 10.12735/as.v2i1p9

69. Tarn, D., Ferris, D. P., Barnes, J. C., Ambrogio, M. W., Stoddart, J. F., & Zink, J. I. (2014). A reversible light-operated nanovalve on mesoporous silica nanoparticles. Nanoscale, 6(6), 3335-3343. doi: 10.1039/c3nr06049g

70. Trujillo-Reyes, J., Peralta-Videa, J. R., & Gardea-Torresdey, J. L. (2014). Supported and unsupported nanomaterials for water and soil remediation: Are they a useful solution for worldwide pollution? Journal of Hazardous Materials, 280(0), 487-503. doi: http://dx.doi.org/10.1016/j.jhazmat.2014.08.029

71. Walkey, C. D., Olsen, J. B., Song, F., Liu, R., Guo, H., Olsen, D. W. H., . . . Chan, W. C. W. (2014). Protein Corona Fingerprinting Predicts the Cellular Interaction of Gold and Silver Nanoparticles. ACS Nano, 8(3), 2439-2455. doi: 10.1021/nn406018q

72. Wang, X., Duch, M. C., Mansukhani, N., Ji, Z., Liao, Y.-P., Wang, M., . . . Nel, A. E. (2015). Use of a Pro-Fibrogenic Mechanism-Based Predictive Toxicological Approach for Tiered Testing and Decision Analysis of Carbonaceous Nanomaterials. ACS Nano, 9(3), 3032-3043. doi: 10.1021/nn507243w

73. Xue, M., & Zink, J. I. (2014). Probing the Microenvironment in the Confined Pores of Mesoporous Silica Nanoparticles. The Journal of Physical Chemistry Letters, 5(5), 839-842. doi: 10.1021/jz402760b

74. Yoon, S.-J., Kwak, J. I., Lee, W.-M., Holden, P. A., & An, Y.-J. (2014). Zinc oxide nanoparticles delay soybean development: A standard soil microcosm study. Ecotoxicology and Environmental Safety, 100(0), 131-137. doi: http://dx.doi.org/10.1016/j.ecoenv.2013.10.014

Other Publications (Books/Book Chapters/ Patents/Conference Papers and Proceedings)

75. Brinker, C., Dunphy, D., Lin, Y., Xia, T., Sun, B., Zhang, H., . . . Pokhrel, S. STC Ref No. 2014-098 76. Copeland, L., & Smith, E. (2014). Consumer Political Action on Climate Change. In Y. Wolinsky-

Nahmias (Ed.), Changing Climate Politics: U.S. Policies and Civic Action. Washington DC: CQ Press.

77. Holden, P. A., Nisbet, R. M., Lenihan, H. S., Schimel, J. P., Gardea-Torresdey, J. L., & Godwin, H. A. (2014). Scaling Environmental Nanotoxicology to Ecological Endpoints. Paper presented at the Nano Risk Analysis (II): A Workshop to Explore How a Multiple Models Approach can Advance Risk Analysis of Nanoscale Materials, Washington, D.C.

78. Liu, H. H., Bilal, M., Lazareva, A., & Cohen, Y. (2014). Regional multimedia distribution of nanomaterials and associated exposures: A software platform. Paper presented at the 2014 IEEE International Conference on Bioinformatics and Biomedicine, Belfast, United Kingdom.

79. Liu, R., Ge, Y., Holden, P. A., & Cohen, Y. (2014). Visual data exploration of soil bacteria susceptible to engineered nanomaterials. Paper presented at the 2014 IEEE International Conference on Bioinformatics and Biomedicine, Belfast, United Kingdom.

80. Rico, C., Peralta-Videa, J., & Gardea-Torresdey, J. (2015). Chemistry, biochemistry of nanoparticles and their role in antioxidant defense system in plants. In M. Siddiqui, M. Al-Whaibi & F. Mohammed (Eds.), Nanotechnology and Plant Sciences-Nanoparticles and Their Impact on Plants (Vol. XII): Springer.

81. Truong, C., & Nameth, C. (2015, March). Oil Spill Clean Up Simulation. In NISE Network. Retrieved from http://www.nisenet.org/catalog/oil-spill-clean-simulation

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http://dx.doi.org/10.1016/j.ecoenv.2013.10.014

http://www.nisenet.org/catalog/oil-spill-clean-simulation


17. Honors and Awards • Adeyemi Adeleye, 2015 ACS Environmental Chemistry Graduate Student Award • Jeff Brinker (UNM Faculty) – Awarded the 2014 Federal Laboratory Consortium, Notable

Technology Development Award, Nano-Stabilized Enzymatic Membrane for CO2 Capture • Brinker group (UNM students/Brinker) Bouvie, C. (MS student); Epler, K. (undergrad); Padilla, D.

(PharmD/PhD student); Gomez, A. (MS student); Anderson, M.; Fleig, P.; Chackerian, B.; Brinker, C. J.; Ashley, C. E.; Carnes, E. C. Mesoporous Oxide Nanoparticles for Controlled Release and Targeted Delivery of Antigens, MRS Spring 2014 Meeting. Best Poster award, Symposium Y: Biomaterials for Biomolecule Delivery and Understanding Cell-Niche Interactions., San Francisco, CA, April 2014.

• Terisse Brocato (UNM PhD student/Brinker) School of Engineering Award – the Charlotte and William Kraft Graduate Fellowship, the University of New Mexico, 2013-2015

• Paul Durfee (UNM PhD student/Brinker)) Best poster award “Size and Surface Engineered Mesoporous Nanoparticles Direct Altered Biodistribution and Clearance”, P. Durfee, Y.S. Lin, J. Townson, J. Minster, C.J. Brinker. Rio Grande Symposium on Advanced Materials, RGSAM, October 2014, Albuquerque, NM

• Paul Durfee (UNM PhD student)/Brinker) School of Engineering Award – the Charlotte and William Kraft Graduate Fellowship, the University of New Mexico, 2013-2014

• Paul Durfee (UNM PhD student/Brinker) Awarded the Edmund J. and Thelma W. Evans Charitable Trust Scholarship, the University of New Mexico, 2013-2014.

• Mark Hersam (Northwestern Faculty)- Named a 2014 MacArthur Fellow • Chitrada Kaweeteerawat (UCLA Student) –Student merit award from Society of Risk Analysis for

her abstract, High Throughput Dose Response Analysis Reveals Unique Mode of Toxicity of Cu Particles

• Ruibin Li (UCLA Postdoc), Tian Xia, Andre E. Nel (UCLA Faculty), and C Jeffrey Brinker (Sandia National Laboratory Faculty)-The 2014 ACS Nano article “Surface Interactions with Compartmentalized Cellular Phosphates Explains Rare Earth Oxide Nanoparticle Hazard and Provides Opportunities for Safer Design” was selected as an American Chemistry Society (ACS) Editor’s Choice article. The ACS Editor’s Choice article is selected as being most important to the public among those published by the American Chemical Society's 40+ journals.

• P. Somasundaran (Columbia University Faculty) has been appointed to EPA’s Board of Scientific Counselors and serves as a chair for combined BOSC Subcommittees for Chemical Safety for Sustainability and Human Health Risk Assessment research program.

• Galen D. Stucky (UCSB Faculty)- Selected as a Thomson Reuters’ Highly Cited Researcher 2014 • Galen D. Stucky (UCSB Faculty)- 2014 Prince of Asturias Award for Technical and Scientific

Research, with Avelino Corma and Mark E. Davis • Alicia A. Taylor and Sharon Walker (UC-Riverside)- Poster prize at 2014 Annual Meeting of the

Southern California Society of Toxicology, for Use of a model laboratory-scale septic system for studying emerging contaminants

• Jeffrey I. Zink (UCLA Faculty)- Selected as a Thomson Reuters’ Highly Cited Researcher 2014 18. Fiscal Information Statement of Residual Unobligated Funds Allocations were made to all UC CEIN projects according to the final approved budget for Year 7, which began on September 1, 2014. Funds were allocated across projects at UCLA, UC Santa Barbara, UC

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