2016 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: Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials
Center Director: Faustman, Elaine
Title: Integrating Liver, Kidney and Testis Nanomaterial Toxicity using the Adverse Outcome Pathway Approach
Investigators: Griffith, William C. , Gao, Xiaohu
Current Investigators: Griffith, William C. , Faustman, Elaine , Gao, Xiaohu
Institution: University of Washington
EPA Project Officer: Klieforth, Barbara I
Project Period: December 1, 2014 through November 30, 2018
Project Period Covered by this Report: December 1, 2015 through November 30,2016
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Safer Chemicals , Health , Human Health

Objective:

The goal of this project is to develop models for integrating organotypic culture responses to engineered nanomaterials (ENMs) across the lung, liver, kidney, and testis and to predict whole organism response. We will use a systems-based Adverse Outcomes Pathway (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 then will be integrated with lifestage and genetic susceptibility factors to model ENM toxicity response across organ systems, organisms, and populations. This project also will identify critical data gaps and make recommendations for further testing of ENMs. 

Progress Summary:

Applications of AOPs to In Vitro Cultures

The first adverse outcome pathway under construction is for the testis. In this preliminary AOP, we have identified cellular and organ responses from pathways associated with endocrine disruption, increased reactive oxygen species, and inflammation. This AOP development is based on the biological changes associated with phthalate exposure in our 3-dimensional testis co-culture system. We expect that some of these same pathways may be perturbed following metal and ENM exposure. As our body of results from ENM exposure in the four 3D organotypic models grows, AOPs specific to the pathways perturbed by ENMs will be developed and linked across all organ systems to better characterize the organ response.

Using Benchmark Dose-Based Dosimetric Approaches to Interpret In Vitro Responses

This modeling and translation core has focused on projects that build the translational framework for interpreting our in vitro results in the context of current regulatory and risk assessment needs. We have three ongoing projects related to building this capacity. Two of these projects leverage work from the University of Washington’s Nanotoxicology Center and the third project forms a unique partnership with the Washington State Department of Ecology to leverage EPA predictive toxicology tools, such as ExpoCast and ToxCast, for interpreting reports of metals, phthalates, and other chemicals of concern found in children’s products.

Members of the modeling and translation core also have used the benchmark dose approach for nanomaterials to publish the first proposed occupational exposure limit (OEL) for silver nanoparticles (Weldon, et al., 2016). Dosimetric evaluations in our study identified the liver as the most sensitive target organ following inhalation exposure, and as such serves as the critical target organ for setting an occupational exposure standard for airborne silver nanoparticles.

Children’s Safe Product Act

To do this, we built a prioritization framework using international and national data sources including the International Agency for Research on Cancer, the European Chemical Agency’s existing substances and substances of concern databases, and the U.S. EPA's Integrated Risk Information System, ToxCast, and ExpoCast. Based on the chemicals reported in the current CSPA database, the framework identified formaldehyde, dibutyl phthalate, and styrene as the three highest scoring chemicals.

Future Activities:

Moving forward, the core will utilize the BMD and AOP approaches exemplified in the progress summary to develop and link adverse outcome pathways across the four organotypic models currently testing metals and ENM toxicity. The work on the framework for the interpretation of CPSA will be extended to consider ENMs. The results will allow us to identify unique toxicity profiles of ENMs and develop prioritization and translational frameworks to inform risk. A training session is in planning for the 10th World Congress on Alternatives and Animal Use in Seattle, WA, that will highlight PTC-EPA methods for organotypic cultures.


Journal Articles on this Report : 2 Displayed | Download in RIS Format

Other subproject views: All 53 publications 12 publications in selected types All 12 journal articles
Other center views: All 134 publications 39 publications in selected types All 38 journal articles
Type Citation Sub Project Document Sources
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)
R835738 (2017)
R835738 (2018)
R835738C005 (2015)
R835738C005 (2016)
R835738C005 (2017)
R834514 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: IJERPH-Full Text HTML
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  • Abstract: IJERPH-Abstract
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  • Other: IJERPH-Full Text PDF
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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)
    R835738 (2016)
    R835738 (2017)
    R835738 (2018)
    R835738C005 (2015)
    R835738C005 (2016)
    R835738C005 (2017)
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  • Other: ResearchGate-Abstract
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  • Supplemental Keywords:

    adverse outcome pathway, chemical prioritization, dose-response modeling, benchmark dose

    Relevant Websites:

    Predictive Toxicology Center | University of Washington School of Public Health Exit

    Progress and Final Reports:

    Original Abstract
  • 2015 Progress Report
  • 2017 Progress Report
  • Final

  • Main Center Abstract and Reports:

    R835738    Predictive Toxicology Center for Organotypic Cultures and Assessment of AOPs for Engineered Nanomaterials

    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