2015 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. , 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, 2014 through November 30,2015
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Safer Chemicals , Health , Human Health

Objective:

The overall goal of this project is to utilize mouse lung organotypic culture systems to better evaluate for cellular and organ toxicity to relevant engineered nanoparticles. The lungs are a major route of exposure to environmental and occupational compounds, and the airway epithelium is the primary surface for initial contact and management of inhaled exogenous materials. This project therefore focuses on using primary epithelial cells differentiated at an air-liquid system as the basis for modeling. This cell system represents an organotypic model system consisting of a combination of ciliated epithelium and club (Clara) secretory cells. Furthermore, altering the defined culture medium can skew the cell phenotype towards a mucus secretory cell type (aka goblet cells) to model chronic airway diseases. The culture system also can be combined with stromal cells in the basal chamber and/or macrophages in the apical chamber to further extend the relevance of the model system. 

Progress Summary:

Applications of AOPs to in vitro cultures:

The first AOP 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-D 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.

We have developed dosimetry based models for extrapolating between our in vitro and in vivo ENM results that use a modified benchmark dose (BMD) approach to characterize responses across our common endpoints of cytotoxicity and inflammation. The BMD approach was employed when integrating adverse outcome pathways across organs and to assess changes in genetic susceptibility across rodent strains. We have already used this approach as a way to compare diverse types of assays by calculating a dose at which a common level of response occurs, such as the dose which a 10% increase above control values occurs. This approach has allowed us to quantify interstrain differences that may be indicative of enhanced exposure to ENMs across multiple assays. 

Members of the modeling and translation core have also used the benchmark dose approach for nanomaterials to publish (under final review) the first proposed occupational exposure limit (OEL) for silver nanoparticles. As our in vitro models continue to develop and report results for ENMs, more work will be translated into the regulatory context. 

We have worked on a collaborative project with the Washington Department of Ecology (Ecology) as a direct response to Ecology’s need to interpret the wealth of data reported under the Children’s Safe Produce Act (CSPA). This act requires manufacturers to report the presence of 66 chemicals of concern to children in any product sold in Washington state. However, the reports had previously not been linked with potential exposure routes, toxicokinetics, toxicity or potency. As a result, future actions to protect children’s health were difficult to prioritize. In our predictive toxicology center, we were interested in building the models to allow for incorporation of in vivo and in vitro studies to account for toxicokinetics, toxicity and potency. 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, the US EPA’s Integrated risk information system, ToxCast and ExpoCast. As consumer databases and other resources become available for ENMs, this framework will be adapted to prioritize ENMs for future action. 

Outreach Activities: This quarter, the modeling core is leading a journal club to discuss international data standards for nanomaterials in collaboration between NW green chemistry initiative, WA department of ecology and international data experts, such as Il Je Yu. 

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 assessment in the regulatory context. 


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)
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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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  • Supplemental Keywords:

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

    Relevant Websites:

    We have created an internal website to facilitate file sharing among investigators and linking with the ToxCast and ExpoCast databases. Shared files include datasets for common biostatistical analysis and standard operating procedures.

    http://deohs.washington.edu/ptc Exit

    Progress and Final Reports:

    Original Abstract
  • 2016 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