2017 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, 2016 through November 30,2017
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 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.

Specific Aims and Hypotheses

Hypothesis 1: Differentiation status of organotypic cultures will define response to ENMs.

Risk Assessment Question: Organotypic cultures that reflect different lifestages will provide an important insight into defining “critical windows of susceptibility” for risk characterization and dose-response.

Hypothesis 2: Assessing oxidative stress responses within organotypic cultures will be a key common response pathway across organ systems to engineered nanomaterials.

Risk Assessment Question: Basic cellular responses such as oxidative stress response will be less organ and more chemical specific than organotypic cellular responses and will represent a common “molecular initiating event” that defines organotypic response.

Hypothesis 3: Inflammatory pathways within organotypic cultures will have significant and specific impacts beyond general oxidative stress and that can be used to improve our definition of AOP pathways.

Risk Assessment Question: Inflammatory response across time will provide a “molecular initiating event” (biomarker) that goes beyond general oxidative stress to better predict organ specific and strain specific responses.

Hypothesis 4: Genetic (strain) differences between organotypic cultures will be a critical factor in interpreting organ specific responses.

Risk Assessment Question: Genetic background will influence organotypic responses to ENMs and this influence will provide important clues for understanding discreet genetic susceptibility factors and defining ENM response.

Hypothesis 5: Using a systems-based Adverse Outcome Pathway analysis with toxicokinetic and dynamic models as a part of the risk assessment framework will allow for cross assay and organ interpretation.

Risk Assessment Question: Integrating dosimetry to interpret kinetic and dynamic responses is an essential part of using AOP analysis within risk assessments for ENMs

Progress Summary:

Predictive Toxicology for Alternatives Analyses: Children’s consumer products represent an important exposure source for many toxicants due to their intended uses, which lead to direct contact with children. Alternatives assessments are used to identify safer chemical alternatives, however, many times these assessments are limited by lack of toxicity data. This project examines how predictive toxicology tools fill gaps in alternatives assessments for chemicals found in children’s consumer products. Formal national and international lists, such as the European Chemical Agency’s (ECHA) Endocrine Disruptor Substances of Concern classification were compared with the toxicological prioritization index (ToxPi) score. We used ExpoCast and CPCat to assess exposure. Alternative chemicals were rarely classified as endocrine disruptors by the ECHA, yet the in vitro ToxPi scores for alterative chemicals were similar to the conventional chemicals. ExpoCast scores for conventional chemicals were higher than alternative chemicals. Our results suggest that predictive toxicology tools can fill gaps when existing classifications are incomplete.

Using Benchmark Dose based dosimetric approaches to interpret in vitro responses: We have built a translational framework for interpreting our in vitro results in the context of current regulatory and risk assessment needs. We developed frameworks to compare relationships between previously published in vitro and in vivo toxicity assessments of cadmium-selenium containing quantum dots (QDs) using benchmark dose (BMD) and dosimetric assessment methods (Weldon et al. 2018). This approach was useful for identifying sensitive assays and strains. We found consistent responses in common endpoints between in vitro and in vivo studies. Dosimetric adjustments identified similar sensitivity among cell types. BMD analysis can be used as an effective tool to compare the sensitivity of different strains, cell types, and assays to QDs. These methods allow in vitro assays to be used to predict in vivo responses, improve the efficiency of in vivo studies, and allow for prioritization of nanomaterial assessments.

Applications of AOPs to in vitro cultures: We are continuing to work on an adverse outcome pathway for the testis and that is able to not only relate molecular markers to tissue effects but also can account for the dynamic developmental changes observed in our in vitro system. 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 (e.g. inflammation and reactive oxygen species) may be perturbed following metal and ENM exposure. As we generate more data from ENM exposure in the four 3D organotypic models, AOPs specific to the pathways perturbed by ENMs will be developed and linked across all organ systems to better characterize the organ response.

Future Activities:

The core will continue 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. We will explore the implications of genetic susceptibility factors through characterizing differences in strain responses. The results will allow us to identify unique toxicity profiles of ENMs and develop prioritization and translational frameworks to inform risk.

References:

Kavlock, R. J., Allen, B.C., Faustman, E. M., and Kimmel, C. A. (1995).Dose-Response Assessments for Developmental Toxicity. IV. Benchmark Doses for Fetal Weight Changes. Fundam. Appl. Toxicol. 26, 211-222.

The National Academy Press, A Framework to Guide Selection of Chemical Alternatives. https://www.nap.edu/catalog/18872/a-framework-to-guide-selection-of-chemical-alternatives, 2014.

Rozman, K.K. and C.D. Klaassen, Casarett and Doull’s toxicology: the basic science of poisons. 2007, McGraw-Hill, New York.

Smith, M.N., et al., A Toxicological Framework for the Prioritization of Children's Safe Product Act Data. Int J Environ Res Public Health, 2016. 13(4).

Wambaugh, J.F., et al., High-throughput models for exposure-based chemical prioritization in the ExpoCast project. Environ Sci Technol, 2013. 47(15): p. 8479-88.

Dionisio, K.L., et al., Exploring consumer exposure pathways and patterns of use for chemicals in the environment. Toxicol Rep, 2015. 2: p. 228-237


Journal Articles on this Report : 12 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 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)
R835738 (2017)
R835738 (2018)
R835738C002 (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):e95978 (15 pp.). R835738C003 (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 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.). R835738 (2018)
    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)
    R835738C003 (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 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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  • 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)
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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)
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  • Supplemental Keywords:

    Adverse Outcome Pathway, Chemical prioritization, Dose-response modeling, Benchmark dose

    Relevant Websites:

     Predictive Toxicology Center Exit

    Progress and Final Reports:

    Original Abstract
  • 2015 Progress Report
  • 2016 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