Overview of CompTox Research Effort

Overview of the CompTox Research Effort

Russell ThomasDirectorNational Center for Computational Toxicology

ECHO SeminarApril 21, 2017

The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. EPA

National Center forComputational Toxicology

Outline

• Short overview of CompTox research effort

• Availability of research data

• Potential application to prioritizing for exposure monitoring

1


Understanding ‘Why’ We Need to Innovate In This Space…

0

10

20

30

40

50

60

70

Per

cent

of C

hem

ical

s

Acute Cancer

Gentox Dev Tox

Repro Tox EDSP Tier 1

<1%

Modified from Judson et al., EHP 2010

$1,000

$10,000

$100,000

$1,000,000

$10,000,000

Cos

t

Number of Chemicals /Combinations

Ethics Concerns Economics

Lack of Data


3

Risk Assessments Generally Contain a Standard Set of Components

New technologies and approaches will also have to cover these basic components

Phys Chem

Exposure

HazardDose Response, PK, and PODs

Risk SummaryUncertainty

Variability


4

It All Starts With Chemistry…

• Chemical structure database of >700,000 unique substances with QC flags to link chemical structure with names and identifiers

• Consensus QSAR models for a range of physical chemical properties, environmental fate, and hazard characteristics

• Comprehensive physical-chemical property database (experimental and predicted)

https://comptox.epa.gov/dashboard


5

Adding the High-Throughput Hazard Screening Component

ToxCast

Concentration

Res

pons

e

~600 Cell & biochemical

assays

~1,000 Chemicals

Tox21

~30 Cell & biochemical

assays

~8,000 Chemicals

Set Chemicals Assays Completion

ToxCast Phase I 293 ~600 2011

ToxCast Phase II 767 ~600 2013

ToxCast Phase III 1001 ~100 Ongoing

E1K (endocrine) 880 ~50 2013


6

Broad Success Derived from High-Throughput Screening Approaches

Provide Mechanistic Support for Hazard ID

Group Chemicals by Similar Bioactivity and Predictive Modeling

Prioritization of Chemicals for Further Testing

Assays/Pathways

Che

mic

als

IARC Monographs 110, 112, 113

FIFRA SAP, Dec 2014


7

Selected Criticisms of ToxCast

• You don’t include metabolism in your in vitro assays

• You don’t measure my favorite endpoint

• You don’t cover all of biological space

• In vitro assays are not normal biology

• Assay (x) in your battery did not get the right answer for my chemical

• My assay disagrees with your assay (x), so your approach is flawed

• You can’t test my favorite chemicals because of limitations in your methods (e.g., solvents, high LogP)

• Your assay descriptions to do not allow me to reproduce your results

• I get different answers when I analyze your dataUpdated from Bob K’s original list


8

Beginning to Address Concerns for Increased Biological Coverage

Requirements:

• Whole genome• 384 well• Automatable

• Low cost

Thousands of chemicals Multiple Cell Types

X


9

Comparing Sequencing Platforms and Developing Analysis Approach

TruSeqr2 0.74

TempO-Seqr2 0.75

Low Coverager2 0.83

Currently capable of assigning to >40 MOAs/MIEs based on transcriptional responses

MOA/MIE Analysis Pipeline

• Large scale screen of 1,000 chemicals (ToxCast I/II) in single cell type this summer

• Additional screens across multiple cell types/lines• Additional reference chemicals and genetic

perturbations (RNAi/CRISPR/cDNA)


10

Beginning to Address Metabolic Competence

“Extracellular”Approach

“Intracellular”Approach

Chemicals metabolism in the media or buffer of cell-based and cell-free assays

Capable of metabolizing chemicals inside the cell in cell-based assays

More closely models effects of hepatic metabolism and generation of circulating

metabolites

More closely models effects of target tissue metabolism

Integrated approach to model in vivometabolic bioactivation and detoxification

-9 -8 -7 -6 -5 -40

1

2

3

4

5

L o g M e th o x y c h lo r (M )

Fo

ld I

nd

uc

tio

n

A c tive In a c tiv e E m p ty

C Y P 3 A 4 m R N A (n g )

RL

U

0 5 0 1 0 0 1 5 00

5 0 0 0 0

1 0 0 0 0 0

1 5 0 0 0 01 2 H o u rs

1 8 H o u rs

2 4 H o u rs

3 6 H o u rs

4 8 H o u rs

Collaboration with Unilever


11

Framework for Integrating Hazard Components…

Tier 2Select In Vitro

Assays

Tier 1High-Throughput Transcriptomic

Assay

No Defined Biological Target or Pathway

Defined Biological Target or Pathway

Tier 3

Organotypic Assays and Microphysiological

Systems

Estimate Point-of-Departure Based on Likely Tissue- or Organ-level Effect without

AOP

Estimate Point-of-Departure Based on Pathway

Transcriptional Perturbation

Orthogonal confirmation

Identify Likely Tissue-, Organ-, or Organism

Effect and Susceptible Populations

In VitroAssays for other KEs

and Systems Modeling

Existing AOP No AOP

Estimate Point-of-Departure Based on AOP

Multiple Cell Types+/- Metabolic Competence

MOA/MIE Identification

-4

-3

-2

-1

0

1

2

3

-4 -3 -2 -1 0 1 2 3

Min

imum

In V

ivo

ToxR

efLo

w E

ffect

Lev

el

for R

at O

nly

(mg/

kg/d

)

Minimum In Vitro Rat Oral Equivalent Dose (mg/kg/d)


Adding the High-Throughput Toxicokinetic Component

Rotroff et al., Tox Sci., 2010Wetmore et al., Tox Sci., 2012

Reverse Dosimetry

Oral Exposure

Plasma Concentration

In Vitro Potency Value

Oral Dose Required to Achieve Steady

State Plasma Concentrations

Equivalent to In VitroBioactivity

Human Liver Metabolism

Human Plasma Protein Binding

Population-Based IVIVE Model

Upper 95th Percentile CssAmong 100 Healthy

Individuals of Both Sexes from 20 to 50 Yrs Old

EPA ToxCast Phase I and II Chemicals • Currently evaluated ~700 ToxCast Phase I and II

chemicals• Models available through ‘“httk” R package

(https://cran.r-project.org/web/packages/httk/)

https://cran.r-project.org/web/packages/httk/


Comparing Dosimetry Adjusted Bioactivity with Exposure

Wetmore et al., Tox Sci., 2012

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anthro

l

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[b]fluoran

thene

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g/kg

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2,6

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citrat

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phthalate

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th

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3H)-f

uranone

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dine

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phosphate

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fluoren

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amine

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hthylamine

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ol B

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n

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yl)ad

ipate

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-4-meth

oxy-phen

ol

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ylanilin

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iphenylg

uanidine

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ine

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e

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dol

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tin

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azep

ine

PK 1119

5

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dimeth

yl

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8-Hyd

roxy

quinoline

3-Nitr

otoluene

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ylphen

ol

4,4'-M

ethyle

ne bis(

2-meth

ylani

Androste

nedione

Diisopro

pyl meth

ylphosp

honate

Phenolphthale

in0.00001

0.0001

0.001

0.01

0.1

1

10

100

1000

10000Gen. USMHE

Ora

l Equ

ival

ent D

ose

or E

stim

ated

Exp

osur

e(m

g/kg

/day

)

Bioactivity from Wetmore et al., Tox Sci., 2015


15

Adding the High-Throughput Exposure Component

(Bio) Monitoring

Dataset 1

Dataset 2…

e.g., CDC NHANES study

Wambaugh et al., 2014

Predicted Exposures

…

Use

Production Volume

Inferred Exposures

Pharmacokinetic Models

Estimate Uncertainty

Calibrate models

Infe

rred

Exp

osur

e

Predicted Exposure

• Exposures estimated for >8,000 chemicals

• 4 product use categories plus production volume explain ~50% of the variance in the NHANES data

• The same five variables work for all NHANES demographic groups analyzed – stratified by age, sex, and body-mass index

• Uncertainty captured in exposure estimates


16

Comparing Bioactivity with Exposure Predictions for Risk Context

Wetmore et al., Tox Sci., 2015

Chemicals

In Vitro Bioactivity

Exposure Predictions

With Uncertainty


17

Adding in Uncertainty and Variability for PD and PK

Propagation of Experimental Uncertainty in High-Throughput Toxicokinetic Estimates

Propagation of Experimental Uncertainty in Models of ER Potency

Chemical Rank

ER

Mod

el S

core

Rat

io o

f Css

95th

Per

cent

ile to

Med

ian

Est

imat

e

Chemical Rank

Variability Predominates

Uncertainty Predominates


18

Covering All the Components of a 21st Century Risk Assessment

Phys Chem

Exposure

HazardDose Response, PK, and PODs

Risk SummaryUncertainty

Variability


Outline




19


20

Regulatory Applications Require More Focus on Quality and Transparency

• Public release of Tox21 and ToxCast data on PubChem and EPA web site (raw and processed data)

• Publicly available ToxCast data analysis pipeline• Data quality flags to indicate concerns with chemical

purity and identity, noisy data, and systematic assay errors

• Tox21 and ToxCast chemical libraries have undergone analytical QC and results publicly available

• Public posting of ToxCast procedures• Chemical Procurement and QC• Data Analysis • Assay Characteristics and Performance

• External audit on ToxCast data and data analysis pipeline

• Migrating ToxCast assay annotations to OECD 211 compliant format

FLAGS:Only one conc above baseline, activeBorderline active


21

Effort to Provide Data Through Display and Decision Support Dashboards

Enhanced Chemistry Dashboard(https://comptox.epa.gov/dashboard)

ToxCast Dashboard(https://actor.epa.gov/dashboard)

EDSP21 Dashboard(https://actor.epa.gov/edsp1)


Dashboard Allows Chemical Specific Queries or List Retrieval

Data Currently Organized and Presented as Simple Tabs


23

Chemical Properties Tab Builds on Chemistry Dashboard Foundation


Data “Layers” Allow User Interaction with Underlying Models and Data


Data “Layers” Allow User Interaction with Underlying Models and Data


Environmental Fate, and Transport


Quantitative In Vivo Toxicity Values Assembled From Multiple Sources

Sources include EPA and public sources


Integration of Exposure Data






31



32

Identifying Perturbed Pathways


33

Displaying Similar Chemicals


Beginning to Fold In Literature Mining Capabilities


Outline




35


36

Integrating Different Components for Prioritization

Hazard

Dev Tox Repro Tox Cancer

Endocrine

In VivoX In VivoX In VivoX

Human Health

Estrogen AgonistX In Vitro

QSARX

Androgen AgonistX In Vitro

QSARX

Androgen AntagonistX In Vitro

QSARX

ExposureCPCat

X Present in Children’s ProductsPresent in Consumer ProductsX

Physical Chemical PropertiesX Appropriate mass range

X Exclude polymers

X Pesticide Home Use

LiteratureX Male reproduction

X Female reproduction

X Embryo or embryonic development

Prioritize


37

Thank You for Your Attention!

Tox21 Colleagues:NTP CrewFDA CollaboratorsNCATS Collaborators

EPA Colleagues:NERLNHEERLNCEA

Collaborators:Unilever

EPA’s National Center for Computational Toxicology

Documents

Overview of CompTox Research Effort