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Elucidating Environmental Dimensions of Neurological Disorders and Diseases: Elucidating Environmental Dimensions of Neurological Disorders and Diseases:

Elucidating Environmental Dimensions of Neurological Disorders and Diseases: - PowerPoint Presentation

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Elucidating Environmental Dimensions of Neurological Disorders and Diseases: - PPT Presentation

Understanding New Tools from Federal Chemical Testing Programs Linda Birnbaum PhD DABT ATS Director National Institute of Environmental Health Sciences and National Toxicology Program ID: 719177

ntp tox21 high throughput tox21 ntp throughput high toxicology niehs data toxicity ipsc cells human biological screening epa century

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Slide1

Elucidating Environmental Dimensions of Neurological Disorders and Diseases: Understanding New Tools from Federal Chemical Testing Programs

Linda Birnbaum, Ph.D., D.A.B.T., A.T.S.Director, National Institute of Environmental Health Sciences and National Toxicology Program

UC Davis Conference Center, Davis CA

June 18-19, 2015 Slide2

2004 NTP Vision and Roadmap for the 21st Century

To meet the challenges of 21st century toxicology, the 2005 NTP Roadmap included a major initiative to develop a high throughput screening (HTS) program with 3 main goals:

To prioritize chemicals for further in-depth toxicological evaluation.

To identify mechanisms of toxicity (

characterize toxicity pathways, facilitate cross-species extrapolation, provide input to models for low-dose extrapolation

).

To develop predictive models for

in vivo

biological response in humans.Slide3

Formation of the Tox21 Program

5-year Memorandum of Understanding (MoU) on “High-Throughput Screening, Toxicity Pathway Profiling, and Biological Interpretation of Findings”

.

Released on Feb 2008, signed by NHGRI (Collins), NIEHS/NTP (Wilson), and EPA (Gray).

Revised 5-year MoU to add FDA signed in

July 2010, by NHGRI (Green), NIEHS/NTP (Birnbaum), EPA (Anastas), and FDA (Woodcock).Renewed for an additional 5 years in May 2015, by NCATS (Austin), NIEHS/NTP (Birnbaum), EPA (Kadeli), and FDA (Mayne)Known informally as Tox21 for Toxicology in the 21st Century.Slide4

Support the evolution of toxicology from a mostly observational science to a predominantly predictive science focused upon mechanism-based, biological observations using cultured cells, model tissues, and lower organisms.

Purpose of Tox21: Bringing a New Era in ToxicologySlide5

Tox21 Milestones

Have been making all Tox21 Phase I and Phase II data public.Identified artifacts in high throughput screening data that lead to false results.Made chemical libraries available to investigators to evaluate new testing platforms and to expand the breadth of toxicological information.

Made progress in data analysis and development of tools for prioritizing chemicals for more extensive testing using traditional methods.

Exchanged assays and data with other organizations (e.g., EU Joint Research Centre, Health Canada, SEURAT,

OpenTox

).Evaluating Tox21 data for use by regulatory agencies.Slide6

Collaboration with Molecular Devices and Cellular Dynamics (focus on

neurotoxicants, cardiotoxicants, mitochondrial toxicants) in:Beating cardiomyocyte

assay

/mitochondrial membrane potential

Neurite

outgrowth assay/mitochondrial membrane potential Collaboration with QPS, PhoenixSongs Biologicals, & the Hamner Institute to evaluate various human and rat neuronal cell culture systemsCollaboration with the Univ. Konstanz to screen in assays that evaluate migration of human neural crest cells and neurite outgrowthCollaboration with XCell Sciences

Inc

to e

valuate

comparative cytotoxicity in

iPSC

as well as isogenic

iPSC

-derived

neural stem cells (NSC)

,

neurons

,

and astrocytes Collaboration with the Buck Institute for Research on Aging to screen in primary human astrocyte cultures to identify senescence-inducing agents

Moving Forward with Tox21 using iPSC-differentiated PopulationsSlide7

The Goal:

Bring mid- to high-throughput transcriptomics into assessment of chemical effects on biological systemsAt this time, whole transcriptome technologies are not yet feasible for high throughput applications

Currently focusing on a subset of genes to use in a rapid, low-cost technology suitable for high throughput studies

The Solution –

The S1500+ Gene Set

Initially apply to human in vitro model systems (iPS cells, 2D & 3D hepatocytes, mixed cell tissue models, etc.)Apply to genetic diversity studies with mouse diversity outbred ES and ES-derived iPSC neuronal progenitor cell linesApply to developmental and behavioral toxicity studies with zebrafish embryos exposed to a variety of compounds, with specific interest in environmental neurotoxicantsMoving Forward with Tox21 – S1500+ Gene ProjectSlide8

Thank you!

http://www.niehs.nih.gov

http://ntp.niehs.nih.gov