update on niceatm computational resources

le\ NTP National Toxicology Program

Update on NICEATM Computational Resources

SACATM September 28-29, 2021

Nicole Kleinstreuer Acting NICEATM Director

Resources

High-Quality Data

Reference Chemicals

Computationa l Tools

Outcomes

• Identify opportunities to develop new methods

• Compare method perform a nee • Identify data gaps • Obtain and examine toxicity

and chemica I data • Develop testing strategies

"•~ Notional Toxicology Program ~s~: ~ USDt"partmen1ol Healthand HumanSt>rv1c~\ -

A I ntegrated I I Chemical "-I!',. ,:,-• Environment

News & Events

ICE v3.4 Release

ICE updates include:

New tools and expanded capabilities:

Chemica l Quest {Beta)

Drawing of 2D structures

Query by multiple chemical ide ntifiers

Send Assays to oth er ICE tools

Learn about ICE updates

UPDATES

Search,

Chemical Quest ,

Curve Surfer ,

Chemical Characterization ,

HOME SEAACH TOOLS DATA ..- ABOUT "' HELP ....

~ C,, =----/1 -j Dose •

CL, + CL,, II

~ PBPK •

Contents lists available at ScienccDir«I

Computational Toxicology

Fl~<;FVIER jou rnal homepage: www.sciencedirect.com/]ournal/computatlonai.toxicology

Application of new approach methodologies: ICE tools to support chemical evaluations

Jaleh Abedini a, · , Bed1any Cook a, Shannon Bell 3 , Xiaoqing Chang 3 , Neepa Choksi 3 ,

Antber B. Daniel 3, David Hines '\ Agnes L. Karmaus 3, Kamel ManSOlffi h, Eric McAfee <, Jason Phillips <, John Rooney \ Catherine Sprankle ", David Allen '\ Warren Casey d, Nicole Klei..n.streuer b

• tntqraral Labwatory S)'stmu UC, P.O. llax USO/ , Jtumrch niangfe Part, NC 2170,, USA ~ National Taxkalogy l'rOflW'l lnm-q,rncyCcntu for the. ~UGlion a/ ,._ltanatk Taxkalop:al Methods., National 1/UMlleaf En""""1C111al Hcahh $ciolca, P.O. Ba.l" 1223.J, MD IC2-J7, Rucarch Tl1angk Park, NC 27709, LISA

' Sdomc UC, 2 ~ Dr., Racardt nicrngfc Pwk, NC 27709, USA

J Dfl.uian a/ dv, Naaanal Ta:ric<HOgy Proaram. NOlianal lnJlil'UU: a/ &Mranmrnral Hcalm $cknca, P.O. Ba.l" 1223.,, MD IQ. /6, Racanh Trianp: Parle. NC 27709,

USA

ARTICLE INPO

Kc.r-m-· New approach methodologies Non,anlmaJmeUlods

Physiologically ba:eu pharmacokiDHlcs lnvl1r<>-ln vivoum,polatlon Quantladve I IJUClw-&-activity nbtioruhlp

A B STRAC T

New :ippro.1ch melhodologles (NAMs) ror toxlcologlc.il :1ppUc:1tions such :is In viuo 3SS3)'S :md In sllico motlels e:eoer.ue d:t1a th.-u can be useful for assessing potemW heallh impacts oC chem.lcals. 1be National Toxicology Prognm's (ITT"P's) lnteU,'lted Olemical Envlronment (ICE; hnps://ke.mp.nldlS.nih. e:ov/) provides user-friendly 3CCes:s 10 NAM d.1ta a11d tools 10 explore :md comexnl.'lllz.e d,eni.lcal bl03Ctlvity and molecular propenles. ICE contains curated in vivo and in vitro 1oxicity tenine: data and experimental physlcochemlcal property dala e:alhered from dlfferem liter.uure sources. ICE :Ibo comalns compu1:ilion.,JJy zenern1ed toxicity d:lta :llld physlcochentic.il parameter predictions..

ICE provides Interactive compu1:ilion.1.I tools th.at ch:irac:1erlz.e, 3113.lyze, :ind predict blo:ictivhy for userdefined chemicals. ICE se:irch 31.lows users to select 3lld merge d:im secs for lists of chemic3ls :llld ntlx1ures, yleldlne: summ3ly-level Information, CW'3ted reference d:11:a , 31ld bl.03Ctivlty derails mapped to mechanb:tic care:ets :ind mode, oC :w:tlon. Wllh I.be Cwve Surfer tool., I.be user can e:xplore concentration- response rel.ation• ships of CW':lted hle:h•throughput screening =ys. 1be Physiolog:lcally Based Ph:innacoklnetics (PBPK) tool predicts tissue-level concentrations resulting from In vivo tJoses , while the In Vlrro-1.n Vivo £xtrnpol.ation (IVIVE) tool transl.ate-s In vlu-o activity coocenu-ation., to equlv:ilem in vivo do.se estim:i1e,. The Chemlc31 Charnc1er• lz:ition tool displays distributions of physlcochemlc.il propenles, bl03Ctivlty- 3lld structure-b:ised projections, 3lld consumer product use information. OJ.emical QUest, the DeY+-est ICE tool, 31.lows users to se3J"Ch ror scruc• rurn.lly slmil:ir chemic3ls 10 3 rare:et chemic31 or subsrrucrure from within I.be extensive ICE d31abase. Reaieved Infollll3tion on 13fllet che.mic3ls 3lld tho.se with similar strucrures can I.hen be used to queiy other ICE tools 311d

Integrated Chemical Environment: ICEv3.4

https://ice.ntp.niehs.nih.gov/ Bell et al. 2017 EHP

Bell et al. 2020 Tox In Vitro Abedini et al. 2021 Comp Tox

https://ice.ntp.niehs.nih.gov/

Chem1calQuest • CUrveSUrfer,

Published data

Data

PBPK,

Validation study data

,,--...... Cc=~ • I ss CL,+CL1i t

'--"' Chemical Characterization ,

What is ICE?

• Curated data and search tools • Organized by toxicity endpoints • Standardized terminology, units, and formatting

• Curated chemical lists • Reference lists with classifications and bioactivity • In vitro assays linked with defined terminology

• Computational workflows • In vitro to in vivo extrapolation (IVIVE) and

physiologically based pharmacokinetics (PBPK) • Quantitative structure-activity relationship

(QSAR) models • Interfaces to explore concentration-response

curves and chemical properties

In Vivo and In Vitro Data in ICE Toxicity endpoint Assays # of chemicals

Chemical Parameters Acute Oral Toxicity

Physchem, ADME, and toxicity Endpoints In vivo acute oral toxicity

~10000 * ~10000

Cancer In vivo and in vitro Cancer, and Weight of Evidence

3042

DART In vivo and in vitro DART 607

Skin Sensitization In vivo and in vitro skin sensitization 2181

Skin Irritation Eye Irritation

In vivo and in vitro skin irritation/corrosion In vivo and in vitro eye irritation/corrosion

1664 796

Endocrine

cHTS

In vivo and in vitro data on AR and ER agonist and antagonist activity Curated ToxCast and Tox21 assays

281

~9213

* in silico predictions are available for ~800,000 additional chemicals

In Silico Models in ICE

Endpoint Model # of chemicals*

Physicochemical Properties

OPEn (q)saR App (OPERA) Mansouri et al. J Cheminform 2018 800,000+

Acute Oral Toxicity Collaborative Acute Toxicity Modeling Suite (CATMoS) - Rat acute oral toxicity. Mansouri et al. EHP 2021 800,000+

Estrogen Receptor pathway Model. Browne et al. ES&T 2015 1812

Endocrine

Androgen Receptor Pathway Model. Kleinstreuer et al. Chem Res Tox 2017

Collaborative Estrogen Receptor Activity Prediction Project (CERAPP). Mansouri et al. EHP 2016

1855

800,000+

Collaborative Modeling Project for Androgen Receptor Activity (COMAPRA). Mansouri et al. EHP 2020 800,000+

Search ►

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ICE Search Overview

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HOM E SEARCH TOOLS

a The Search tool allows you to query ICE data (chemicals and mixtures) using predefined or user-defined chemical lists and assays from dozens of categories.

' Scope of Search

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Assay Description

DATA T ABOU

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ery assay and chemical property data for over 10,000 chemicals and mixtures. • User can qu• in silico predictions are available for ~800,000 additional chemicals

• New for 2021: • Query results now provides graphical visualizations of substance bioactivity in an assay. • Single chemicals and mixtures combined view. • Help videos to walk users through various parts of tools.

Integrated Chemical

Calendar & Events New! & Medta Get !nvol\led Support

,)•" ~~'.:~~'~'l"~~~i-~1~.l~~'..,'..r~~r~m _____ - SEARCH

~ Environment

ME Results Query ICE data (chemicals and

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~~ Union AR In Vitro Agonist (R) 0

AR In Vitro Antagonist (R) __ c, AR In Vivo Agonist _c, Chem ical Input

Select Chemicals

Quick Li.st CASRN.s

-·~ Jchemicalquick li

U.serCASRNs

Add chemicals w ith identical QSAR structures

0 BACKTOTOP

Calendar & Events News& Media

II AR In Vivo Antagonist __ c, EPA IRIS Carcinogenicity Classifications _ Q

EPA Pesticide Active Ingredients --~

EPA Pesticide Inert Ingredients, Food and Nonfood Use _ ~

ER In Vitro Agonist (R) _c, ER In Vivo Agonist (R) 0

Eye Irritation-Corrosion (R) 0

&I Genotoxicity (R) _c, IARC Classifications 0

NTP Cancer Bioassay Chemicals __ Q

Roe Classifications --~

II Skin Corrosion (R) __ c, Steroidogenesis - Androgen 0

steroidogenesis - Estrogen . 0

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X SEARCH TOOLS DATA • ABOUT ..,

~scription A.uayType

Web page !nt updated on Feb. 21, 2010

OUSA.gov

SHrd!,

HELP •

ICE Search Chemical Selection and Quick Lists

• Users can select from predefined lists of chemicals that are related to specific toxicity endpoints.

• Reference lists and common chemical sets (e.g. Tox21, pesticide AIs).

• Users can also enter their own chemical identifiers.

• New for 2021: In addition to CASRNs, DTSXIDs and Inchi Keys are accepted chemical identifiers.

--------c HTS Acute Lethality Sensitization

0 V cHTS

0 Abnormal Growth and Differentiation

0 Angiogenic Process

~ > Cellular Processes

0 > Cellular Stress Response

0 > Endocrine-Related Processes

0 Energy Metabolism Process

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0 > Immune and lnfiammatory Response

0 > Neuronal Transmission

0 Xenobiotic Metabolism

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Cardiotoxicity Chemical Parameters

ICE Search Curation to assi

X Select Assays 0

st meaningful assay selection and model building

• Curated high-throughput screening data (cHTS) starts with EPA invitrodb and incorporates chemical QC information and technology-specific flags

• Assays are grouped by biological process, mechanistic target, and MoA, and linked to ontologies

• New for 2021: • Addition of Cardiotoxicity annotations to cHTS assays (Krishna et al. 2021 Chem Res Tox). • Expanded and refined Mode of Action (MOA) and Mechanistic Target (MT) annotations.

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ICE Search Search Results: Table allows users to explore summary data in tabular format and filter on column values. • Interactive

visualization provides graphical overview of summary level bioactivity data.

• Upcoming: Details of AC50s of active chemicals in each category available by clicking bars in plot

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Medroxyprogesterone acetate

Testosterone

4-Hydroxybenzoic acid

Diethylstilbestrol

Flutamide

Bisphenol B

Pentabromodiphenyl ether

meso-Hexestrol

Z-Tetrachlorvinphos

17beta-Trenbolone

Cyfluthrin

Spironolactone

Linuron

Cycloheximide

Estrone

17alpha-Estradiol

Reserpine

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2, 2' ,4,4' -Tetrahydroxybenzophenone

Hydroxyflutamide

Search Results: Table allows users to explor-e summary data in tabular format and filter 80 -

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20

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• Upcoming: Details of AC50s of active chemicals in each category available by clicking bars in plot

ICE Search

> Selected Chemical Quick Lists (2)

> Selected Assays (28)

> Chemica l Identifiers Not Returned By Query (228)

Send filtered resu lts to:

Download I s I tt 1 _____ e ec oo ... V Clear Filter Long View

View Substance Substance Name CASRN (CEBS Link) 0

Detai ls 0 Type

.I.J .I.J .I.J

~ (+-)-Diclofop-methyl Chemical 51338-27-3

~ (2E)-3-Phenylprop-2-enal Chemical 14371-10-9

Number of chemicals= 773 0 ...

DNA DTXSI D (Dashboard QSAR Damage

"" Link) 0 Ready ID Call (#

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ICE Search Results Table

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Filterable Results

Filtered results can be sent to other ICE TOOLS

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ICE Search





Download I s I tt 1 _____ e ec oo ... Clear Filter Long View


Detai ls 0 Type

.I.J .I.J .I.J

@ (+-)-Diclofop-methyl Chemical 51338-27-3


Number of chemicals= 773



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Results Table

Filterable Results


> Select

> Select

> Chem1

Downl

View

Detai ls

, (+-)-Diclofop-methyl (51338-27-3)

Cl

h o~ oXo, c,N ~ o CH, CH ,

PhysChem Property (+-)-Diclol

BP C 0 349.27

HL log1 o, atm-m3/ mole _9 ... -8.04

KOA log10 O 9.82

Logo, pH 5.5 log1 o 0 _ 4.71

Logo, pH 7.4 log10 0 _ 4.71

LogP 109100 _ 4.71

M P C O 40.10

MWg/ mol O 341.19

pKa, Ionizations 0 0.00

pKa, Acid ic _9 ... NA

pKa, Basic 0 NA

VP log10, mmHg O -5.46

ws log10, moles/L 0 -5.13

Hover over graphic for interactive tools. View

interactive tools user guide.

Plot Type

0 Stacked Bar

Pie

Select Assay Type(s)

In Vitro X +

0

X V

Legend O

- Act ive

- Inactive

[=:J QC-omit

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r::7 ( + -)-Diclofop- methyl (5133 8-27-3) L.::::.J Number of Assays=305

Number of Assay Categories=13/25

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::,Tlil:;t: 111 .. :: I ~ f.11 1;. Curve Surfer

Assay Results (~- )-Didofop-methyl ( 513 38-27-3)

60 , --+--+ + ++ ++ ~ + 50 -'----+-- + ++ ++ ++ 40 ~ -+-- ++ ++ ++

+ + 1 + 10,

o-

ICE Search Results Table

Filterable Results


Vie w

Details.

~

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Q Active Ingredient CASRN Percent Al

■ Butoxypolypropylene glycol 9003-13-8 10.0

~ ctive Ingredient composition for Gordon 's Horse & Pony Spray (ICE_ 475386645 }

■ Permethrin

■ Piperonyl butoxide

■ Pyrethrins

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100-

80-

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40-

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52645-53--1 0.5

51-03-6 0.5

8003-34-7 0.05

Page 1 of 2 ► Active ingredient AC50 endpoints for Gordon's

Horse & Pony Spray (ICE_475386645)

_9

Propeny

BPG9

HL log10, atm-m3/ mole_ O

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MPC O

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Butoxypolypropylene glycol Permethrin Piperonyl butoxide

(9003 -13-8)

Structure Nol

Available

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

(52645-53-1) (51-03-6)

6 8 401.45 324.41

-7.62 -5.65

11.68 10.91

6.50 4.75

6.50 4-75

6.50 4.75

34.28 34-35

391.29 338-44

0.00 0.00

NA NA

NA NA

-7.66 -7.06

-6.67 -4.37

Pyrethrins

(8003-34-7)

Structure Nol

Avillable

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

0 s,-.._ _ _ ________________ .,... __________________________________________________________ _

Pie 3500

Se&rdl,

BOUT •

ICE Search Search Results - Mixtures Detail

• Mixtures Detail view incorporates data from individual active ingredients including:

• Percent composition, cHTS AC50s and phys-chem properties

Curve Surfer PB P K IVIVE Chemica l Characterization

r;-"'- The Curve Surfer tool allows you to view and interact with concentration response curves from cHTS. \l.._~-

Select Page

1 V of21 G

Order By

Chemical Name

S.elec.t Me-c.h e nistic. Ta rg et To Vie w Cu rves

All

Assay Ted =iL. Sele-ct Assa'/(s)

Ova lues

Assay: ACEA_AR_agonist_aohr

Mech anistic Target: Androge n Metabolic Process

CASRN: 58-18-4

DTXSID: DTXSI D1033664

Chemical Name: 17-Methyltestosterone

Winn ing Curve-Fit Model: Hill

AC50: 5.7E-4

ACC: 2.0E-4

Top of Curve: 110.66

Call: Act ive

Vi ew EPA curve (testing pu rposes on ly)

rt ACEA_AR_agonist_80hr

58-18-4

-- Hill

V Ase V

Only s howing curve s for 200 chemicals .

Please redu ce your query to view a ll

chemicals.

Seled CAS'\N(s)

Ova lues

Assay: ACEA_ER_aohr

Mech an istic Target: Est rogen Meta bolic Process

CASRN: 58-18-4

DTXSID: DTXSID1033664

Chemica l Name: 17-Methyltestosterone

Winning Curve-Fit Model, Hill

ACS0: 0.048

ACC: 0.016

Top of Curve: 8 9.94

Call: Active

Vi ew EPA curve (testing purposes o nly)

rt ACEA_ER_80hr

58-18-4

l -- Hill

Chemical Quest

• Con centration Response

••••• ACC 1201 T: . Conce ntration Respo ns e

- ACS0

: I ••••• ACC 100-

- - ACS0

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100µ 0 ,001 0.01 0 ,1 0.01 100

Concentra t ion (u M) Concentrat ion (u M)

ICE Tools: Curve Surfer

Curve Surfer is an interactive concentration response visualization tool for cHTS data

• Select/filter assays based on Mechanistic Target

• View specific assays/chemicals

• Filter on activity call, AC50

• Upcoming: Select subset of curves to send to other tool or export to PDF.

• In development: Overlay multiple curves on the same plot.

Curve Surfer PBPK Chemical Characterization

m. PBPK tool allows you to generate predictions of tissue-specific chemical concentration profiles following a dosing event

50k -

40k -

,,_ ·.· .. . .

~

Cki dney ~

d iver

Chemical Quest

□ Cart Cgut

Ckidney

Cl iver

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■ Cplasma

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■ Cven

ICE Tools: PBPK

Seled Comp:irtment(s)

Ovalues

CASRN: 51-28-5

Chemical Name: "2,4-dinit rophenol"

40k - + +

J Ok -

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10

S.eledCA.S~N(s)

Ovalues

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70 ~

80 90

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- Clung

- Cplasma

- Crest - even

PBPK tool allows users to calculate internal chemical concentrations using PBPK models from the EPA httk R package* and in-house code

• Tissue level concentrations • View individual chemical

curves • View overall distribution in

different tissue compartments for all query chemicals

* https://www.epa.gov/chemical-research/httk-epas-tool-high-throughput-toxicokinetics

https://www.epa.gov/chemical-research/httk-epas-tool-high-throughput-toxicokinetics

Curve Surfer PBPK !VIVE Chemical Characterization Chemical Quest

The IVIVE tool uses pharmacokinetic models to predict the equivalent administered dose (EAD) from the activity concentration of selected assays.

Chemic-al CASRN OTXSIO Flag Assay

..!J ..!J ..!J ..!J ..!J

Testosterone 58-22-0 DTXSID8022371 TOX2l_ERa_BLA_Agon ...

Select EAD to visua li ze: Select in vivo data to display.

EAD50th ! ion (Uterotrophic LEL) v ! ll Log Axis ' ................................... •

Show Name --~

Hover over graphic for interact i· Estrogen ·e tools user guide ~ -

rt

~ 0

~ ~0.0 1-

o'> E

100µ-

i +-

✓ Modulation (Uterotrophic LEL)

Acute Lethality (Acute Oral Toxicity Assay LOSO)

Androgen Modulation (Hershberger, rat agonlst LEL)

Androgen Modulation (Hershberger, rat antagonist LEL)

±

Mode of Action

estrog

Keceptor Med iated

Effects

Estrogen

Modulation,Gene

Expression

Regulat ion,KCC8:

Receptor Med iated

Effects

Mechanistic Targets

Estrogen Metabolic

Process

Toxicity 2nd points. rapre~ented: Endocrine

EAD 50th Box and Wh isker

AC50 uM

13.28

EAD 50th Percentile

(mg/ kg/day)

0.111

Cl int Fraction Unbound

..!J ..!J

1.46 0.39952

··: 0 C Cl :x ft --IVIVE Input Parameters

EAD

■ Uterotrophic Assay

ICE Tools: IVIVE

Transparency and annotation to help guide use and interpretation

Curve Su rfer PBPK !VIVE Chemica l Characterization Chemical Quest

The IVIVE tool uses pharmacokinetic models to predict the equivalent administered dose (EAD) from the activity concentration of select.ed assays.

Chemic-a l CASRN OTXSIO Flag Assay

..!J ..!J ..!J ..!J ..!J

Testosterone 58-22-0 DTXSID8022371 TOX2l_ERa_BLA_Agon ...

Select EAD to visua li ze: Select in vivo data to display.

EAD50th ! ion (Uterotrophic LEL) v ! ll Log Axis ' ................................... •

Show Name -·~

Hover over graphic for interact i· Estrogen ·e tools user guide ~ -

rt

~ 0

~ ~0.01-

o'> E

100µ-

i

✓ Modulation (Uterotrophic LEL)

Acute Lethality (Acute Oral Toxicity Assay LOSO)

Androgen Modulation (Hershberger, rat agonlst LEL)

Androgen Modulation (Hershberger, rat antagonist LEL)

±

Mode of Action

estrog

Keceptor Med iated

Effects

Estrogen

Modulation,Gene

Expression

Regulat ion,KCC8:

Receptor Med iated

Effects

Mechanistic Targets

Estrogen Metabolic

Process

Toxicity 2nd points. rapre~ented: Endocrine

AC50 uM EAD 50th Percentile

(mg/ kg/day) Cl int

..!J

Endpoint: AC50 Specie:s : human Model: Solve_pbtk

e Route: iv 4

Fraction Unbound

..!J

0.39952

C Cl ft --IVIVE Input Parameters

EAD

■ Uterotrophic Assay

ICE Tools: IVIVE

Transparency and annotation to help guide use and interpretation

Selected endpoints help guide further

overlay

Annotation provided for

filtering

Parameters included to aid reproducibility

Curve Surfer PBPK IVIVE Chemical Characterization Chemical Quest

r-1£: The Chemical Characterization tool allows you to view and compare one or two chemical lists based on their physicochemical properties. Comparisons are available in tabular format along with principal J)J :•: component analysis plots oflist against subsets of the ICE chemical inventory.

0

~ 0

10- r

-s

El. = OPERA, Octanol-Water Partition Coefficient

ICE Properties

□ !ARC Classifications

RoC Classifications

~ ~ Chemical Consumer Use (1875 Chemicals - 203 unique): Cleaning Products and Household Ca re Subcategory

- Genera l Household Cleaning

- Laundry and Fabric Treatment

- Carpet and Floor

- Air Freshener

- Dishwasher and Dishes

0

DTXSIO (Oashboa Substance Name

Id! OTXSI07020762 lsopropanot

Id! DTXSID9020584 Ethanol

Id! DTXSIDl024097 2-Butoxyelhanol

Id! DTXSIDl020778 D-Umonene

[D '

~ JOk- + a 20k-

Count

S1

40

38

20

7.◄ 1""' 20

Consumer Use Catecories by DTXSID, CASRN 0

CAS RN (CEBS Li nl

67-63·0

64-17-5

111-76-2

Assr,C.- llesub (OTXSJOs) (SOO'ltmoulll)

SubCategoril!~ Count

27

27

24

21

■ Active

■ Inactive

■ QCOIT'llt

ICE Tools: Chemical Characterization

Dynamic PCA CASRN Data (Chemical Properties)

..; -so · ~~, 111,M&I

-1-- 200 0 200

PCl, 63 .1 % variance

. .. • IARC Classifications

• Roe Classifications

• Both Lists

Chemic•! Consumer Use Det.ails: CIHnin1 Products and HouHhold C•re (270 Chemic.ab • 56 unique)

Chemical Characterization tool allows users to explore one or two chemical lists.

• Physicochemical property distributions

• Interactive PCA plots of chemical space coverage

• Presence in consumer products (EPA CPDat*)

* https://www.epa.gov/chemical-research/chemical-and-products-database-cpdat

https://www.epa.gov/chemical-research/chemical-and-products-database-cpdat

-Resu lts

Help

R:eport11n ~11e

Curve Surfer PBPK

. ~ -~ - The Chemical Quest tool uses fingerprints to predict structure similarity. (Beta)

Max hits per inp ut : 10

Chemical ID inpu t (one per line) .0 ..

10161-33-8

57-85-2 58-18-4 58-22-0 65-04-3 1071-83-6

Tan imoto Coefficien t : 0.7 ·or greater .. 0 ...

Smiles St ruct ures for similarity search .. 0 ...

1±1 Draw I 1±1 Enter I Chemical Structure

IVIVE Chemica l Cha racterization Chemical Quest

ICE Tools: Chemical Quest Structure based Similarity Search

Chemical Quest tool allows users search for structurally similar chemicals.

• Users can specify CASRN, DTSXID, Inchi Key or SMILES strings as inputs

• Chemical structures can also be drawn as input

-Resu lts

Help

R:eport11n ~ 11e

Ru1 •♦• The Chemical Quest tool uses fingerp >. Max h

E_j Reset I ( ax hits per input: 10 0

Chemical 10 input (one per line) O

10161-33-8

57-85-2

58-18-4

58-22-0

65-04-3

1071-83 -6

Tanimo

Coeffici

v-,..

If

/ff

0 ......

1 [ ]

% ➔

>Rl

0 □ "-OOOOL'.', 0 0 0

0

s

p

F

Cl

Br

ICE Tools: Chemical Quest Structure based Similarity Search

Chemical Quest tool allows users search for structurally similar chemicals.

• Users can specify CASRN, DTSXID, Inchi Key or SMILES strings as inputs

• Chemical structures can also be drawn as input

.• Chemical Quest Results

Send filtered results to: i ~ Select tool...

Chemical Name: Testosterone pro pionate

CASRN : 57-85-2

DTX5ID: DTXS!D9036515

Tan imoto: top 10 hits and >0. 7

Hit Count : 10

Passed Filter(s): 10/ 10

View Results

Curve Surfer

Clear Filter

PBPK

Chemical Name: 17-Methy ltestosterone

CASRN: 58-18-4


Tanimot o: top 10 hits and >0.7

Hi t Count: 10

Passed Filter (s): 10/ 10

View Results

IVIVE

0

Chemical Characteri za t ion

Chemical Nam e: Glyphosate

CASRN: 1071 -83 -6

DTXSID: DTXS!D1024122

Tanimoto: top 10 hits and >0.7

Hit Co unt : 10

Passed Filter(s) : 10/ 10

View Results

Chemical Quest

Chemical Name: Testost erone

CASRN: 58-2.2-0


Tanimot o: top 10 hit s and >0. 7

Hi t Count : 10

Passed Fi lter (s): 10/ 10

View Results

ICE Tools: Chemical Quest





CASRN : 57-85-2



Hit Count : 10


View Results

Curve Surfer

Clear Filter

PBPK


CASRN: 58-18-4



Hi t Count: 10


View Results

IVIVE

0



CASRN: 1071 -83 -6



Hit Co unt : 10


View Results

Chemical Quest


CASRN: 58-2.2-0



Hi t Count : 10

Passed Fi lter (s): 10/ 10

View Results

Results can be sent to other

ICE tools





CASRN : 57-85-2



Hit Count : 10


View Results

Curve Surfer

Clear Filter

PBPK


CASRN: 58-18-4



Hi t Count: 10


View Results

IVIVE

0



CASRN: 1071 -83 -6



Hit Co unt : 10


View Results

Chemical Quest


CASRN: 58-2.2-0



Hi t Count : 10


ICE tools

I 1------------------------------~





CASRN : 57-85-2



Hit Count : 10


View Results

Curve Surfer

Clear Filter

PBPK


CASRN: 58-18-4



Hi t Count: 10


View Results

IVIVE

0



CASRN: 1071 -83 -6



Hit Co unt : 10


View Results

Chemical Quest


CASRN: 58-2.2-0



Hi t Count : 10


ICE tools

Results page displays the chemical identification information for each source chemical input, as well as the number of hits and Tanimoto score stringency selected





CASRN : 57-85-2



Hit Count : 10


View Results

Curve Surfer

Clear Filter

PBPK


CASRN: 58-18-4



Hi t Count: 10


View Results

IVIVE

0



CASRN: 1071 -83 -6



Hit Co unt : 10


View Results

Chemical Quest


CASRN: 58-2.2-0



Hi t Count : 10


ICE tools

View results button opens new window displaying similar chemicals

ICE Tools: Chemical Quest Curve Surfer


Similar Structures to: C[C@]12CC[C@H)3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H)1CC[C@@H]20

Select Page

GJ of 1 0 Showingl-10of10hits.

Select CASRN(s)

a values

.. 0.... Tanimoto Filter .. f ... SMARTS Fiher

CASRN: 67308-98-9


Chemical Name: (17beta)-17-

Hydroxy(l, 1,2,2,6,6, 7,7-~3~ H_B_)androst-

4-en-3-one

Tanimoto Value: 1.0

Sort Results By

Tanimoto

CASRN: 77546-39-5

_O __ Direction _O_

Oesc



Hydroxy(l 6, 16, 17-~2~H_3_)androst-4-en-

3-one

Tanimoto Value: 1.0

PBPK

CASRN: 52844-06-1


Chemical Name: 17-Hydroxy(7-

~3~H_ 1 _)androst-4-en-3-one

Tanimoto Value: 1.0

IVIVE Chemical Characteri za t ion

CASR N: 481 -30-1

DTXSID: DTXSIDB022329

Chemical Name: Epitestosterone

Tanimoto Value: 1.0

Chemical Quest

CASRN: 117338-89-3

DT XSID: DTXSID601016404

Chemical Name: Epitestosterone-16,l 6-.d2

Tanimoto Value: 1.0

Testost erone

022371

1 hit s and >O. 7

D

View results button opens new window displaying similar chemicals


Similar Structures to: C(C@J12CC(C@H]3(C@@Hl(CCC

Select Page

of 1 0 Sllowing 1-10of10hits.

Select CASRN(s)

O values

Q __ Tanimoto Filter O SMARTS Filter

CASRN: 67308-98-9


Chemical Name: (1 7beta)-17-

Hydroxy(l,1,2,2,6,6, 7,7-~3~H_8_)androst-

4-en-3-one

Tanimoto Value: 1.0

H

Tanimoto

CASRN: 77546-39-5



Hydroxy(l 6,16,1 7-~2~H_3_)androst-4-en-

3-one

Tanimoto Value: 1 _o

CASRN: 52844-06-1


Chemical Name: 17-Hydroxy(7-

~3~H_ 1 _)androst-4-en-3-one

Tanimoto Value: 1-0

H

CASRN: 481-30-1


Chemical Name: Epitestosterone

Tanimoto Value: 1.0

HO 0

CASRN: 117338-89-3


Chemical Name: Epitestosterone-16, 16-d2

Tanimoto Value: 1.0

Results are sortable and

filterable

Upcoming: Users can select individual results to send to other tools.

SMARTS strings can be used to filter results based on chemical

substructures

ICE Improvements motivated by SACATM Feedback

• Increased usability for non-subject matter experts

• Ongoing: developing help videos, user guides and UI / visualization updates

• Increased technical documentation• Ongoing: data set harmonization, annotation and expansion of metadata

• Expanding connections with other resurces

• Complete: DTXSID and CASRN link out to EPA Dashboard and CEBS from all pages

• Planning: API for access to ICE data, API connection with CEBS

• Increase structure-based methods

• Complete: Chemical Quest Tool for structure-based similarity searching

• Ongoing: Implementing similarity searching for additional descriptor libraries

ICE: Future Plans

• Upcoming features in ICE 3.5 Release (early October 2021): • Inclusion of Saagar features for similarity searching in Chemical Quest Tool (Sedykh et

al. 2021 Chem Res Tox)

• Ability to select subsets of chemicals to send to other assays in Curve Surfer and Chemical Quest Tools

• AC50 detail view plots on cHTS summary charts and additional data download options included on plots

• Help videos: https://ice.ntp.niehs.nih.gov/test/Search

• In Development: • Further refinement of assay annotations, additional data sets

• Inclusion of additional search and filtering capabilities, further roll out of help videos

• Additional visualization tools and new visualizations for various data types

• Incorporating population variability in metabolic enzymes in ICE PBPK workflows

https://ice.ntp.niehs.nih.gov/test/Search

y

Connecting Metabolism and Variability in Humans: Toxicokinetics TOiicologyl.tners312(2019)173--180

Contentslistsa,'3.ilableat Sciencdlirtet

Toxicology Letters TL

ELSEVIER journalhomepage: www.elsevier.com/locate/loxlet

Metabolism of triflumuron in the human liver: Contribution of cytochrome f) P450 isoforms and esterases '=-

-Rim Timoumi ~•h, Franca M. Burattic••, Salwa Abid-Essefi\ Jean-Lou C.M. Domed, .Emanuela Testa{

Toxicology Letters

j ournal homep11ge: www. e lsevier .com/l ocateltox l et

lnter-phenotypic diffe rences in CYP2C9 and CYP2C19 metabolism: Bayesian meta-regression of human popu lation variabi lity in kinetics and application in chemical risk assessment

Nadia Quignor' ·1.", W itold Wi~ce-kb.1.+ , Leonie- Lautzc. Je-an -Lou Dorne-d. Bi lly Amza l"


journal homep1ge: www.1lsevier.com/loc1t111comtox

Inter-ethnic differences in CYP3A4 metabolism: A Bayesian meta-analysis for the refinement of uncertainty factors in chemical risk assessment

Keyvin Dame)"•, Emanucla Tcsrai \ Franca M. Buratti\ Emma Di Consiglio\ Emma EJ. Kastec!C, Nynke Kramer", Laura Turcob, Susanna Vichib, Alain-Claude Roudotd, Jean-Lou Domee, Camille Bccha -=.-~-~,.,---~-•Sat,qc.tNS£0.14 ........... -Qrio,~,-94101,

•o.,,,,-<#----~•--,,,,,,..--.IIOl61-IU(.flolY •-,-,---....-~,1'.0. -/JOIT1,l50r1V~n,,--~ .. --~--........ t-.(~'ll!J.V..-..,«T«Jo,;p,,,.t,A•.-k~Q93Q7,c.d,;rJ,

. ..__s.,,--,.., .. \'loo~---, ... ..,i:,11_,._.., -······----·-··--·--· ------··

Environment International

journal homepage, www.elsevier .comi locate/envin t

Bayesian meta-analysis of inter-phenotypic differences in human serum paraoxonase-1 activity for chemical risk assessment

K. Damey", E.E.J. Kasteelb, F.M. Buratti', L. Turco\ S. Vichi°, C. Bechaux", A.C. Roudotd, N.I. Kramer\ E. Testai', J.L.C.M. Dornee, E. Di Consiglioc, L.S. Lautz"••

ArchivesofToxlcolog)' hn p<;/ldoi.or<:,110.1007/..00204-020-02765-8

Human variabi lity in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors

E. E. J. Kasteel10 - K. Oarne ylO - N, I. Krame,14> -J, L. C. M. Dorne30 -LS. Lautr'O

~

ELSEVIER


iournal home~ge: www.alsevie, .com ltoUte.'comtox

'II)

A generic Bayesian hierarchical model fo r the meta-analysis of human population variability in kinetics and its applica tions in chemical risk assessment

'II)

Wimld Wiccck"-· , Jean-Lou Dorneb, Nadia Quignola, Camille Bcchaux<", Billy Am1,ala

'II)

Oral uptake

Gut lumen

2C9 CL 3000

Gut tissue

i C :8 2000

I 0

ijj 1000

0.00 0.25 0.50 0.75

enzyme functioning

Pharmacokinetic data on compounds lnterindividual differences in kinetics and polymorphisms "' metabolised by UGT isoforms is collected ____ ...;;>,,~ ~

and summarised in a database ;;;, c.

Data on polymorphism frequencies in different populations is collected and summarised

10 15 20 25 Time (h)

UGT-related uncertainty facto rs

European Food Safety Authorit

Covering Phase I PBPK models + virtual population CYP450 and Phase II

UGTs enzymes


Partnership with:


34 Acknowledgments: The NICEATM Group

35 Acknowledgments: The NICEATM Group

36

Questions?

update on niceatm computational resources

Documents