TestSmart DNT 2 Conference Washington DC, November 1214 2008 - PowerPoint PPT Presentation

Loading...

PPT – TestSmart DNT 2 Conference Washington DC, November 1214 2008 PowerPoint presentation | free to view - id: f000b-ZDc1Z



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

TestSmart DNT 2 Conference Washington DC, November 1214 2008

Description:

TestSmart DNT 2 Conference Washington DC, November 12-14 2008 ... aliphatic organothiophosphate insecticides. amide herbicides. aromatic fungicides ... – PowerPoint PPT presentation

Number of Views:31
Avg rating:3.0/5.0
Slides: 31
Provided by: caatJ
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: TestSmart DNT 2 Conference Washington DC, November 1214 2008


1
Developing Predictive Bioactivity Signatures
from ToxCasts HTS Data
  • TestSmart DNT 2 Conference Washington DC,
    November 12-14 2008
  • Co-authors David Dix, Keith Houck, Matt Martin,
    David Reif and Richard Judson

2
A Dream from TestSmart 1
Increasing Biological Relevance
Increasing Cost
3
Future of Toxicity Testing
in silico analysis
in vitro testing
Thousands
Bioinformatics/ Machine Learning
HTS -omics
EPAs Contribution The ToxCast Research Program
www.epa.gov/ncct/toxcast
4
Too Many Chemicals
Change Needed Because …..
Too High a Cost
Cancer DevTox NeuroTox ReproTox ImmunoTox Pulmonar
yTox
…and not enough data.
Judson, et al EHP submitted
5
ToxCastTM Background
  • Research program of EPAs National Center for
    Computational Toxicology
  • Addresses chemical screening and prioritization
    needs for pesticidal inerts, anti-microbials,
    CCLs, HPVs and MPVs
  • Comprehensive use of HTS technologies to generate
  • biological fingerprints and predictive
    signatures
  • Coordinated with NTP and NHGRI/NCGC via Tox21
  • Committed to stakeholder involvement and public
    release of data
  • Communities of Practice- Chemical
    Prioritization Exposure
  • NCCT website- http//www.epa.gov/ncct/toxcast
  • ACToR- Aggregated Computational Toxicology
    Resource
  • http//www.epa.gov/actor/

6
Implications for Success
  • Hazard Identification
  • Closing Data Gaps
  • Reductions in Cost
  • Hypothesis Generation
  • Reduced Animal Usage
  • Ancillary Applications
  • Mixtures
  • Chirals
  • Nanomaterials
  • Green Chemistry
  • Lot variations
  • Risk Assessment
  • Providing MOA(s)
  • Targeted Testing
  • Identifying Susceptible Populations

7
Key Challenges Of Pathway Profiling
  • Find the Toxicity Pathways
  • Hepato vs developmental nuerotoxicity
  • Obtain HTS Assays for Them
  • Including metabolic capability
  • Screen Chemical Libraries
  • Coverage of p-chem properties
  • Link Results to in vivo Effects
  • Gold standard and dosimetry

8
Phased Development of ToxCast
1Initiated April 2007
9
The ToxCast_320
309 Unique Structures Replicates for QC 291
Pesticide Actives 9 Industrial Chemicals 8
Metabolites 56/73 Proposed Tier 1 EDSP 53 of
80 with DNTs 122 in IRIS 14 HPV 11 HPV
Challenge
Classes with gt 3 chemicals
Misc
Misc MOA classes with 3 or fewer representatives
Classification based on OPPIN
10
Physical-Chemical Properties
11
gt1B in Toxicology Now Stored in ToxRefDB
Martin, et al EHP, in press
12
ToxRefDB website http//www.epa.gov/ncct/toxrefd
b/
13
ToxRefDB Multigeneration Studies
114 effects induced by least 5 chemicals
Liver Pathologies
Liver and Kidney Wts
Pup body wt
Martin et al, ToxSci, submitted
14
ToxRefDB Multigeneration Studies
114 effects induced by least 5 chemicals
Thyroid effects
Cholinesterase effects
Neurological effects
Martin et al, ToxSci, submitted
15
ToxRefDB Multigeneration Studies
114 effects induced by least 5 chemicals
F1 Actives
Neurological effects
Martin et al, ToxSci, submitted
16
ToxRefDB Multigeneration Studies
F1 Actives
114 effects induced by least 5 chemicals
Thyroid effects
Martin et al, ToxSci, submitted
17
ToxCast Contracts for Generating HTS Data
Receptors, Enzymes
Cell Signaling
Transcription Factors
Metabolic Transformation
Cell Function
Cell Function
Nine contracts provide chemical procurement
hundreds of biochemical, cellular, tissue and
genomic assays model organisms and the capacity
to screen up to 10,000 chemicals
In vitro Genomics
Alternative Species
18
320 Chemicals
Transporter
GPCR
Enzyme, other
Ion channel
NR
Kinase
CYP450
Phosphatase
Protease
Activity ( of Control)
19
NovaScreen Descriptive Statistics (30 Cutoff)
X10.22 assays
X14.27 chemicals

Cyp2C19_H Cyp1A2_H Cyp2C9_1H
Metiram-sodium Emamectin benzoate
11
6
20
SOME NEUROTRANSMITTER TARGETS
DOPAMINERGIC
NICOTINIC
GABA
MUSCARINIC
SEROTONERGIC
ADRENERGIC
21
Transcription Factor Activity Profiling
43 transcription factors
24 nuclear receptors
22
Hierachical Cluster Attagene Results
320 Chemicals
RTUs
Fold Induction (log 2)
23
ToxCast Phase I Assays/Datasets/Publications
  • ToxCast 1.0 (April, 2007)
  • Enzyme inhibition/receptor binding HTS
    (Novascreen)
  • NR/transcription factors (Attagene, NCGC)
  • Cellular impedance (ACEA)
  • Complex cell interactions (BioSeek)
  • Hepatocelluar HCS (Cellumen)
  • Hepatic, renal and airway cytotoxicity (IVAL)
  • In vitro hepatogenomics (IVAL, Expression
    Analysis)
  • Zebrafish developmental toxicity (Phylonix)
  • ToxCast 1.1 (January, 2008)
  • Neurite outgrowth HCS (NHEERL)
  • Cell proliferation (NHEERL)
  • Zebrafish developmental toxicity (NHEERL)
  • ToxCast 1.2 (June, 2008)
  • NR Activation and translocation (CellzDirect)
  • HTS Genotoxicity (Gentronix)
  • Organ toxicity dosimetry (Hamner Institutes)
  • Toxicity and signaling pathways (Invitrogen)
  • C. elegans WormTox (NIEHS)

21 Assay Sources gt550 Endpoints
Nearing publication
24
Correlating HTS to Toxicity
Physical chemical properties
In silico Predictions
Cellular Assays
ToxMiner
Antikythera
Biochemical Assays
Toxicology Endpoints
Genomic Signatures
25
ToxCast MoA Profiling Endocrine Targets
26
ToxCast Predictive Modeling for Toxicity
Endpoints
(15)
Chronic Rat Liver Apoptosis/Necrosis
(23)
Methods in Judson et al 2008 A comparison of
machine learning algorithms for chemical toxicity
classification using a simulated multi-scale data
model. BMC Bioinformatics 9241
27
A High Throughput Vision for the Source to
Outcome Continuum
Effect/Outcome
Source/Stressor Formation
ToxRefDB
ACToR
Biological Event
Environmental Conc.
ToxMiner
ToxCast
ExpoCast
External Dose
Target Dose
rTK
28
Summary
  • The international community needs better
    predictive tools for assessing the hazards and
    risks of chemicals
  • It is technically feasible to collect bioactivity
    data on virtually all chemicals of potential
    concern
  • ToxCast is providing a proof of concept for
    obtaining predictive, broad-based spectra of
    bioactivity
  • A critical need remains the elucidation of the
    majority of key biological processes involved in
    toxic responses
  • The time is right to rapidly move this field along
  • ToxCast Website www.epa.gov/ncct/toxcast

29
(No Transcript)
30
ToxCast Website www.epa.gov/ncct/toxcast
About PowerShow.com