2016 Progress Report: Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials

EPA Grant Number: R835738
Center: Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials
Center Director: Faustman, Elaine
Title: Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials
Investigators: Faustman, Elaine , Altemeier, William , Eaton, David , Gao, Xiaohu , Griffith, William C. , Kavanagh, Terrance J , Kelly, Edward J.
Institution: University of Washington
EPA Project Officer: Klieforth, Barbara I
Project Period: December 1, 2014 through November 30, 2019
Project Period Covered by this Report: December 1, 2015 through November 30,2016
Project Amount: $6,000,000
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Human Health , Health , Safer Chemicals

Objective:

The Predictive Toxicology Center for Assessment of AOPs of Engineered Nanomaterials is developing innovative organotypic culture models (OCMs) to evaluate potential cellular and organ toxicity from exposure to metal-based Engineered Nanomaterials within an adverse outcome pathway model. The Center has produced OCMs for four target organs: lung, kidney, liver, and testis.  The Center’s work on improving the understanding of the normal cell signaling pathways in OCM systems is putting the results of in vitro science into the context of existing in vivo data. By understanding how in vitro responses change over time under normal conditions, we are better able to understand the biological meaning behind toxicant perturbations. The Center observed life stage specific differences in susceptibility to cadmium in both the tests and the lung cultures. Their work already is impacting how in vitro data are incorporated into public health decisions.  The Center is conducting the following projects:

Project 1: Airway Epithelium Organotypic Culture as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
Project 2: Organotypic Model of Human Kidney as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
Project 3: Organotypic Models of Mammalian Liver as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
Project 4: Organotypic Model of Testis as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
Project 5: Integrating Liver, Kidney and Testis Nanomaterial Toxicity using the Adverse Outcome Pathway Approach

Progress Summary:

The progress on the five Center projects are reported in separate progress reports. See the reports for R835738C001 through R835738C005.  The progress for the Administrative Core Unit is reported here.

The Administrative Core Unit works in close collaboration with investigators of all the Center’s projects to move forward collectively on Center objectives. The Administrative Core Unit continues to facilitate meeting coordination and collaborations in addition to a wide array of Center activities. The Administrative Core Unit is housed at the Institute for Risk Analysis and Risk Communication (IRARC), in the University of Washington’s Department of Environmental and Occupational Health Sciences (DEOHS).

Center Oversight, Coordination and Integration

The Administrative Core Unit continues to provide administrative support for Center investigators. Examples include but are not limited to fiscal management and budget reporting, purchasing and budget management,  reporting progress to sponsors and participating in conferences and webinars.

Following the Administrative Core’s comprehensive Quality Management Plan (QMP), the Center continues to integrate quality management practices for activities in the various Center laboratories. In doing so, the Center has established a number of Standard Operating Procedures (SOPs), protocols and policies to standardize laboratory work. The Administrative Core ensures that the various project investigators remain current on

protocols, certifications, and training. Within the QMP, the Quality Assurance Project Plans continue to generate the high quality data needed to accomplish Center objectives. Quality management is thereby practiced at many levels in the Center, namely in the community and in the laboratory. SOPs support quality management and assurance and individual roles and responsibilities.

Tracking Progress Toward Center Outcomes

Central elements of tracking progress toward Center outcomes include preparation of annual and special reports, interaction of the Internal Steering Committee, engagement of the External Advisory Committee, involvement in the Virtual Tissue Models weekly meetings, and collaboration with Nortis Inc.

Center Investigator Meetings

To share research updates and to plan future work, the Center facilitates monthly investigator meetings. Investigators share research updates through formal presentations and in-depth discussions regarding the five projects as well as related Center activities and interactions. Members of the Internal Steering Committee, staff, and students participate in these monthly meetings. Members of the Internal Steering Committee are continuing to participate in a series of focused program evaluation and planning meetings to identify Center needs and opportunities for collaborations. These meetings have helped investigators to work towards Center deliverables and regular interactions among investigators and encourage further communication within the Center. These meetings are strategic, project-oriented, and geared towards setting interim research goals and targets.

Science Advisory Committee Meeting

The Science Advisory Committee (SAC) boasts a balance of basic, clinical, and applied researchers in academia and industry contexts with Dr. Denny Liggitt as the chair. On December 1, 2015, the Center hosted an initial SAC meeting in the form of a conference call to introduce the Center’s projects, investigators and SAC members. The introductory conference call covered the goals of the Center, an overview of the research projects and feedback regarding the type of interactions SAC members wanted in preparation for the face-to-face meeting the following month. On January 28-29, 2016, the Center hosted the first in-person SAC meeting to evaluate Center activities and progress toward objectives. This was a highly successful meeting and energized Center investigators. This interaction with SAC members provided Center investigators an important platform for gaining feedback and insight into current and future Center research. SAC members were very responsive and gave highly relevant and insightful responses to our updates. This feedback will not only impact current Center research, but also has stimulated discussions of future research goals.

Interactions with EPA

USEPA-NHEERL-University of Washington PTC Cooperative Meeting was held in August 2016. Key objectives of the meeting were: (1) learn about University of Washington Predictive Toxicology Center research activities and capabilities; (2) introduce NHEERL Integrated Systems Toxicology Divsion research activities and capabilities in the areas of AOP development, complex experimental models, and nanomaterial/metals toxicology; and (3) identify opportunities for collaboration between the EPA Integrated Systems Toxicology Division and University of Washington Predictive Toxicology Center. The following key topics were discussed during the meeting:

  • Linking computational strengths with experimental models across systems to provide predictive tools
  • Implications of normal and perturbed biological responses in disease models–predicting departure from normal processes that leads to adverse phenotypes
  • AOP-based models; kinetic and dynamic information required to support quantitative approaches
  • Complexities of predictive toxicology
  • Goals for in vitro models
  • Capturing complexity of biological context, signaling
  • Contributions of systems biology for predictive toxicology

In July of 2015, the Center held a conference call with William Boyes from EPA to discuss research contributions, the testing of nanomaterials and compounds that EPA would like the Center to evaluate. The conference call initiated the Center’s cooperative agreement with EPA to discuss various systems, models, and a plan to share the Center’s common endpoints across all of the projects. William Boyes and Elaine Cohen Hubal also joined the initial SAC conference call December 2015 to further discuss the collaboration between the Center and EPA. Elaine Faustman also had a meeting with William Boyes and Elaine Cohen Hubal after the in-person SAC meeting January 2016 to discuss the cooperative agreement and steps to take moving forward.

At the face to face SAC meeting in January Dr. William Boyes was able to tour the Respiratory Biology Facility and specifically to meet with Dr. William Altemeier and his students and staff. Dr. Elaine Cohen-Hubal joined Dr. Faustman and her staff and discussed the need to include exposure considerations in to the grant structure and into the AOP pathway considerations. They also discussed the child health safety project that Ms. Marissa Smith is working on. In October of 2015, the Center hosted a poster session event with attendees from EPA Region 10, EPA Office of Science Coordination and Policy, Nortis Inc., as well as Center investigators, staff and students. Attendees from EPA included Dr. Bruce Duncan from Region 10, Ms. Karen Chu who reports to the Office of Research and Development Sustainable and Healthy Communities. This poster session served as an informal gathering for discussion on current, relevant research as well as an update on the Center’s activities.

The Center’s EPA Project Officer, Dr. Barbara Klieforth, also has joined in over the phone as an observing participant on our initial SAC phone call in December and our full SAC meeting in January.

Communication and Public Outreach

A critical function of the Administrative Core is to facilitate communication about Center research to the UW community and beyond. The Center has implemented a variety of efforts to encourage data sharing and translation across the different projects, throughout the scientific community and to the general public. The Center has worked closely with the DEOHS communications and web development team on announcing

the center through press releases as well as planning the design of the Center website. The Center’s website was published on January 4, 2016.

Educational Opportunities for Technology Transfer

Researchers in the Center engage in substantive educational, training and other enrichment activities. These activities use the work of the Center as a learning tool and are instrumental in equipping future public health researchers and practitioners for work in new in vitro methods and in computational toxicology. A hallmark of the Center is its emphasis on cultivating and training the Center’s mentored fellows, postdocs, undergraduate and graduate students, who collaborate on projects and related training grants.

Center Director Dr. Faustman presented Center research at a number of venues across the country, as well as internationally, enhancing the visibility of the Center. These opportunities to share Center accomplishments are a key feature of the Center’s administrative and outreach efforts. Dr. Faustman was directly involved in the planning of the US EPA’s Science to Achieve Results (STAR) Organotypic Culture Models for Predictive Toxicology Centers Satellite Meeting titled, “3-D or note 3-D: That is the [predictive toxicology] question...” at the 2016 Society of Toxicology Annual Meeting. Currently she is working with one of three co-directors of 10th World Congress of Alternative and Animal Use that will take place in Seattle, WA August 20-24, 2017. In that capacity, she is highlighting both USEPA and the PTC researchers in this international venue.

Future Activities:

The Administrative Core Unit will continue to work with Center directors and investigators to support the mission and specific aims of the Center. Continued interactions with EPA Region 10 as well as future meetings with William Boyes and Elaine Cohen Hubal are planned for the subsequent reporting period. A second annual Science Advisory Committee Meeting is planned for the next funding period.


Journal Articles: 34 Displayed | Download in RIS Format

Other center views: All 127 publications 34 publications in selected types All 33 journal articles
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Journal Article Cartwright MM, Schmuck SC, Corredor C, Wang B, Scoville DK, Chisholm CR, Wilkerson HW, Afsharinejad Z, Bammler TK, Posner JD, Shutthanandan V, Baer DR, Mitra S, Altemeier WA, Kavanagh TJ. The pulmonary inflammatory response to multiwalled carbon nanotubes is influenced by gender and glutathione synthesis. Redox Biology 2016;9:264-275. R835738 (2016)
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  • Journal Article Chang S-Y, Weber EJ, Van Ness KP, Eaton DL, Kelly EJ. Liver and kidney on chips: microphysiological models to understand transporter function. Clinical Pharmacology & Therapeutics 2016;100(5):464-478. R835738 (2016)
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  • Journal Article Chang S-Y, Weber EJ, Sidorenko VS, Chapron A, Yeung CK, Gao C, Mao Q, Shen D, Wang J, Rosenquist TA, Dickman KG, Neumann T, Grollman AP, Kelly EJ, Himmelfarb J, Eaton DL. Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight 2017;2(22):95978 (15 pp.). R835738 (2017)
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  • Journal Article Chang S-Y, Weber EJ, Sidorenko VS, Chapron A, Yeung CK, Gao C, Mao Q, Shen D, Wang J, Rosenquist TA, Dickman KG, Neumann T, Grollman AP, Kelly EJ, Himmelfarb J, Eaton DL. Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight 2017;2(22):e95978 (15 pp.). R835738C003 (2017)
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  • Journal Article Chang S-Y, Weber EJ, Sidorenko VS, Chapron A, Yeung CK, Gao C, Mao Q, Shen D, Wang J, Rosenquist TA, Dickman KG, Neumann T, Grollman AP, Kelly EJ, Himmelfarb J, Eaton DL. Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight 2017;2(22):95978 (15 pp.). R835738 (2017)
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  • Journal Article Chang S-Y, Voellinger JL, Van Ness KP, Chapron B, Shaffer RM, Neumann T, White CC, Kavanagh TJ, Kelly EJ, Eaton DL. Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity. Toxicology In Vitro 2017;40:170-183. R835738 (2016)
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  • Journal Article Harris S, Hermsen SA, Yu X, Hong SW, Faustman EM. Comparison of toxicogenomic responses to phthalate ester exposure in an organotypic testis co-culture model and responses observed in vivo. Reproductive Toxicology 2015;58:149-159. R835738 (2016)
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  • Journal Article Harris S, Wegner S, Hong SW, Faustman EM. Phthalate metabolism and kinetics in an in vitro model of testis development. Toxicology in Vitro 2016;32:123-131. R835738 (2016)
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  • Journal Article Harris S, Shubin SP, Wegner S, Van Ness K, Green F, Hong SW, Faustman EM. The presence of macrophages and inflammatory responses in an in vitro testicular co-culture model of male reproductive development enhance relevance to in vivo conditions. Toxicology In Vitro 2016;36:210-215. R835738 (2016)
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  • Journal Article Kim YH, Jo MS, Kim JK, Shin JH, Baek JE, Park HS, An HJ, Lee JS, Kim BW, Kim HP, Ahn KH, Jeon KS, Oh SM, Lee JH, Workman T, Faustman EM, Yu IJ. Short-term inhalation study of graphene oxide nanoplates. Nanotoxicology 2018;12(3):224-238. R835738 (2017)
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  • Journal Article Kimmel DW, Rogers LM, Aronoff DM, Cliffel DE. Prostaglandin E2 regulation of macrophage innate immunity. Chemical Research in Toxicology 2016;29(1):19-25. R835738 (2017)
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  • Journal Article Knudsen TB, Keller DA, Sander M, Carney EW, Doerrer NG, Eaton DL, Fitzpatrick SC, Hastings KL, Mendrick DL, Tice RR, Watkins PB, Whelan M. FutureTox II: in vitro data and in silico models for predictive toxicology. Toxicological Sciences 2015;143(2):256-267. R835738 (2016)
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  • Journal Article Lee JH, Han JH, Kim JH, Kim B, Bello D, Kim JK, Lee GH, Sohn EK, Lee K, Ahn K, Faustman EM, Yu IJ. Exposure monitoring of graphene nanoplatelets manufacturing workplaces. Inhalation Toxicology 2016;28(6):281-291. R835738 (2016)
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  • Journal Article Lee JH, Sung JH, Ryu HR, Song KS, Song NW, Park HM, Shin BS, Ahn K, Gulumian M, Faustman EM, Yu IJ. Tissue distribution of gold and silver after subacute intravenous injection of co-administered gold and silver nanoparticles of similar sizes. Archives of Toxicology 2018;92(4):1393-1405. R835738 (2017)
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  • Journal Article Nolin JD, Lai Y, Ogden HL, Manicone AM, Murphy RC, An D, Frevert CW, Ghomashchi F, Naika GS, Gelb MH, Gauvreau GM, Piliponsky AM, Altemeier WA, Hallstrand TS. Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen. JCI Insight 2017;2(21):e94929 (18 pp.). R835738 (2017)
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  • Journal Article Nolin JD, Lai Y, Ogden HL, Manicone AM, Murphy RC, An D, Frevert CW, Ghomashchi F, Naika GS, Gelb MH, Gauvreau GM, Piliponsky AM, Altemeier WA, Hallstrand TS. Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen. JCI Insight 2017;2(21):94929 (18 pp.). R835738C001 (2017)
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  • Journal Article Park JJ, Weldon BA, Hong S, Workman T, Griffith WC, Park JH, Faustman EM. Characterization of 3D embryonic C57BL/6 and A/J mouse midbrain micromass in vitro culture systems for developmental neurotoxicity testing. Toxicology In Vitro 2018;48:33-44. R835738 (2017)
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  • Journal Article Ramaiahgari SC, Waidyanatha S, Dixon D, DeVito MJ, Paules RS, Ferguson SS. From the cover: three-dimensional (3D) hepaRG spheroid model with physiologically relevant xenobiotic metabolism competence and hepatocyte functionality for liver toxicity screening. Toxicological Sciences 2017;159(1):124-136. R835738 (2017)
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  • Journal Article Rountree A, Karkamkar A, Khalil G, Folch A, Cook DL, Sweet IR. BaroFuse, a novel pressure-driven, adjustable-throughput perfusion system for tissue maintenance and assessment. Heliyon 2016;2(12):e00210 (18 pp.). R835738 (2017)
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  • Journal Article Scoville DK, Botta D, Galdanes K, Schmuck SC, White CC, Stapleton PL, Bammler TK, MacDonald JW, Altemeier WA, Hernandez M, Kleeberger SR, Chen LC, Gordon T, Kavanagh TJ. Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice. FASEB Journal 2017;31(10):4600-4611. R835738 (2017)
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  • Journal Article Shaffer R, Smith MN, Faustman EM. Developing the regulatory utility of the exposome: mapping exposures for risk assessment through Lifestage Exposome Snapshots (LEnS). Environmental Health Perspectives 2017;123(8):085003 (8 pp.). R835738 (2017)
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  • Journal Article Smith MN, Grice J, Cullen A, Faustman EM. A toxicological framework for the prioritization of Children’s Safe Product Act data. International Journal of Environmental Research and Public Health 2016;13(4):431 (24 pp.). R835738 (2016)
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  • Journal Article Van Ness KP, Chang SY, Weber EJ, Zumpano D, Eaton DL, Kelly EJ. Microphysiological systems to assess nonclinical toxicity. Current Protocols in Toxicology 2017;73(1):14.18.1-14.18.28. R835738 (2017)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (14 pp.). R835738C002 (2017)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (15 pp.). R835738 (2016)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (14 pp.). R835738 (2017)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Corrigendum: Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:44517. R835738 (2016)
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  • Journal Article Wallace JC, Port JA, Smith MN, Faustman EM. FARME DB:a functional antibiotic resistance element database. Database 2017;2017(1):1-7. R835738 (2016)
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  • Journal Article Weber EJ, Chapron A, Chapron BD, Voellinger JL, Lidberg KA, Yeung CK, Wang Z, Yamaura Y, Hailey DW, Neumann T, Shen DD, Thummel KE, Muczynski KA, Himmelfarb J, Kelly EJ. Development of a microphysiological model of human kidney proximal tubule function. Kidney International 2016;90(3):627-637. R835738 (2016)
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  • Journal Article Weber EJ, Himmelfarb J, Kelly EJ. Concise review: current and emerging biomarkers of nephrotoxicity. Current Opinion in Toxicology 2017;4:16-21. R835738 (2017)
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  • Journal Article Wegner SH, Yu X, Pacheco Shubin S, Griffith WC, Faustman EM. Stage-specific signaling pathways during murine testis development and spermatogenesis: a pathway-based analysis to quantify developmental dynamics. Reproductive Toxicology 2015;51:31-39. R835738 (2016)
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  • Journal Article Weldon BA, Faustman EM, Oberdorster G, Workman T, Griffith WC, Kneuer C, Yu IJ. Occupational exposure limit for silver nanoparticles: considerations on the derivation of a general health-based value. Nanotoxicology 2016;10(7):945-956. R835738 (2015)
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  • Other: ResearchGate-Abstract
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  • Journal Article Weldon BA, Park JJ, Hong S, Workman T, Dills R, Lee JH, Griffith WC, Kavanagh TJ, Faustman EM. Using primary organotypic mouse midbrain cultures to examine developmental neurotoxicity of silver nanoparticles across two genetic strains. Toxicology and Applied Pharmacology 2018 (April 17), 10 pp. [epub ahead of print]. R835738 (2017)
    R835738C004 (2017)
    R835738C005 (2017)
  • Abstract from PubMed
  • Full-text: Science Direct-Full Text HTML
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  • Abstract: Science Direct-Abstract
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  • Other: Science Direct-Full Text PDF
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  • Journal Article Weldon BA, Griffith WC, Workman T, Scoville DK, Kavanagh TJ, Faustman EM. 2018. In vitro to in vivo benchmark dose comparisons to inform risk assessment of quantum dot nanomaterials. Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology 2018;10(4):e1507. R835738 (2017)
    R835738C004 (2017)
    R835738C005 (2017)
  • Abstract from PubMed
  • Abstract: Wiley-Abstract
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  • Relevant Websites:

    Predictive Toxicology Center (PTC) for Organotypic Cultures| UW School of Public Health Exit

    Webinars | Pediatric Environmental Health Specialty Units Exit

    Progress and Final Reports:

    Original Abstract
  • 2015 Progress Report
  • 2017 Progress Report
  • 2018
  • Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R835738C001 Airway Epithelium Organotypic Culture as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
    R835738C002 Organotypic Model of Human Kidney as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
    R835738C003 Organotypic Models of Mammalian Liver as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
    R835738C004 Organotypic Model of Testis as a Platform for Adverse Outcomes Pathway Assessment of Engineered Nanomaterials
    R835738C005 Integrating Liver, Kidney and Testis Nanomaterial Toxicity using the Adverse Outcome Pathway Approach