Grantee Research Project Results

2018 Progress Report: Integrating Liver, Kidney and Testis Nanomaterial Toxicity using the Adverse Outcome Pathway Approach

EPA Grant Number: R835738C005
Subproject: this is subproject number 005 , established and managed by the Center Director under grant R835738
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Center for Air, Climate, and Energy Solutions
Center Director: Robinson, Allen
Title: Integrating Liver, Kidney and Testis Nanomaterial Toxicity using the Adverse Outcome Pathway Approach
Investigators: Griffith, William C. , Faustman, Elaine , Gao, Xiaohu
Institution: University of Washington
EPA Project Officer: Aja, Hayley
Project Period: December 1, 2014 through November 30, 2018 (Extended to November 30, 2019)
Project Period Covered by this Report: December 1, 2017 through November 30,2018
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability

Objective:

The goal of this project is to develop models for integrating organotypic culture responses to ENMs across the lung, liver, kidney and testis and to predict whole organism response. We will use a systems-based AOP approach linked with toxicokinetic and dynamic models to identify key molecular initiating events and cellular, tissue, and organ responses from each organotypic model. These AOPs will then be integrated with lifestage and genetic susceptibility factors to model ENM toxicity response across organ systems, organisms and populations. This project will also identify critical data gaps and make recommendations for further testing of ENMs.

Progress Summary:

Comparison databases for chemicals in consumer products: Washington State enacted the Children's Safe Product Act (CSPA) in 2009. CSPA requires manufacturers to report chemical use in any product sold or manufactured in Washington, according to the list of 88 chemicals of high concern to children, to the CSPA Manufacturers Database (CSPA-MD). Washington State also maintains a Product Testing Database (PTD) in which children's products are purchased and tested for chemicals of high concern to children. Building upon our previous study that suggested predictive toxicology tools can fill knowledge gaps, this project aimed to compare CSPA-MD and PTD to determine if there are systematic differences in product chemical combinations and if the reported concentrations are different between databases. Comparing records between databases, we merged individual records from CSPA-MD (40,204) and PTD (8,344) to compare averages within each product-family chemical combination for which we had 373 and 365, respectively. Of the product-family chemical combinations detected by the state and reported by manufacturers, the manufactures reported higher concentrations in 69-84% of product-family chemical comparisons. For regulated chemicals, manufacturers reported higher concentrations in 59% of the product-family chemical comparisons. Manufacturers reported higher concentrations because CSPA requires manufacturers to report the highest found concentration. This comparison allows us to hone in on which toxic chemicals are found in consumer products.

Using BMD based dosimetric approaches to interpret in vitro responses: We used BMD and dosimetric assessment methods used in Weldon et al. 2018 as our translational framework for interpreting in vitro results in the context of current regulatory and risk assessment needs. We compared sensitivity to AgNP toxicity in organotypic cultures of murine tracheal epithelial cells from two mouse strains, C57BL/6 and AJ. In this study, we used particle dosimetry to define physiologically-relevant dose-response relationships. We also used a dosimetrically-adjusted BMD approach to compare the mediating effects of G&E on sensitivity to adverse cellular responses by accounting for differences in the effective dose ranges to induce AgNP toxicity. We observed strain differences based on exposure conditions and endpoints.

Applications of AOPs to in vitro cultures: We are continuing our work on an AOP for the testis and are working on AOP for the lung by utilizing our organotypic culture systems. Our AOP development is based on the biological changes associated with AgNP exposure in these organotypic cultures, including 3-D testis co-culture and murine tracheal epithelial cells system. We expect that some of these same pathways (e.g. inflammation and reactive oxygen species) may be perturbed following both metal and ENM exposure. As our body of results from ENM exposure in the four 3-D organotypic models grows, we will develop and link AOPs specific to the pathways perturbed by ENMs across all organ systems under investigation to better characterize the organ response.

Future Activities:

Moving forward, the core will continue to utilize the BMD and AOP approaches exemplified in the progress summary to develop and link adverse outcome pathways across the four organogtypic models currently testing metals and ENM toxicity. We will continue to explore the implications of genetic susceptibility factors through characterizing differences in strain responses. The utility of the results will allow us to identify unique toxicity profiles of ENMs and develop prioritization and translational frameworks to inform risk.

Journal Articles on this Report : 5 Displayed | Download in RIS Format

Publications Views
Other subproject views:	All 56 publications	15 publications in selected types	All 15 journal articles
Other center views:	All 150 publications	50 publications in selected types	All 49 journal articles

Publications
Type	Citation	Sub Project	Document Sources
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) R835738C001 (2018) R835738C004 (2018) R835738C005 (2018)	Full-text from PubMed Abstract from PubMed Full-text: Nanotoxicology - Full Text HTML and PDF Exit Abstract: Taylor and Francis-Abstract Exit
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) R835738C001 (2018) R835738C004 (2018) R835738C005 (2018)	Abstract from PubMed Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
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 2018:354;215-224	R835738 (2017) R835738C004 (2017) R835738C004 (2018) R835738C005 (2017) R835738C005 (2018)	Abstract from PubMed Full-text: Science Direct-Full Text HTML and PDF Exit Abstract: Science Direct-Abstract Exit Other: Science Direct-Full Text PDF Exit
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	R835738C004 (2018) R835738C005 (2018)	Abstract from PubMed Full-text: Springer Link - Full Text HTML and PDF Exit
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) R835738C001 (2018) R835738C004 (2017) R835738C004 (2018) R835738C005 (2017) R835738C005 (2018)	Full-text from PubMed Abstract from PubMed Abstract: Wiley-Abstract Exit

Supplemental Keywords:

airway, lung, engineered nanomaterials, asthma, chronic obstructive lung disease, kidney, quantum dots, cadmium, kidney injury, KIM-I (Kidney Injury Molecule), 3-D organotypic cultures, microphysiological systems, hepatocytes, mouse, human, nanoparticles, aristolochic acid, silver, cytotoxicity, redox status, cellular stress response, Nrf2 reporter assay, induced pluripotent stem cells, genetics, reproductive and developmental toxicity, chemical screening, testicular development, in vitro model, gender comparison, adverse outcome pathway, AOP, chemical prioritization, dose-response modeling, benchmark dose

Relevant Websites:

The Predictive Toxicology Center (PTC) for Organotypic Cultures Exit

Progress and Final Reports:

Original Abstract

Main Center Abstract and Reports:

R835738 Center for Air, Climate, and Energy Solutions

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 forAdverseOutcomesPathway 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

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.