Download - 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
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Chemical Quest ,
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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
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+
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SHrd!,
HELP •
ICE Search Chemical Selection and Quick Lists
• Users can select from predefined lists of chemicals that are related to specific toxicity endpoints.
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• 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
0 > Epigenetic Process
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• Curated high-throughput screening data (cHTS) starts with EPA invitrodb and incorporates chemical QC information and technology-specific flags
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• 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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Bis(2-ethylhexyl)hexanedioate
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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visualization ::,:
provides graphical :::J
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overview of summary level
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 (#
Assays=4)
.I.J .I.J .I.J BACHBFV ...
Active(N=l... DTXS I D0032605 UHFFFAOY ...
N Omit(N=l)
KJPRLNW ...
DTXS I D6024834 UHFFFAOY ... QC-
N Omit(N=4)
Se&rdl,
Oxidative p53 Energy
Histone Protein Signaling Metaboli ...
Stress Call Modificat... Deacetyl... Pathway Process
(# Call (ii Call (ii
Call (# Call (ii
As5ays=22) As5ays=12) As5ays=23)
As5ays=4) As5ays=3)
.I.J .I.J .I.J .I.J .I.J
lnactive(N ... lnactive(N .. . lnactive(N ... lnactive(N ...
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Tested(N= ... Tested(N=6) Test ed (N= ... Tested (N=2)
ICE Search Results Table
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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) Ready ID Call (#
Assays=4)
.I.J .I.J .I.J BACHBFV ...
Active(N=l... DTXS I D0032605 UHFFFAOY ...
N Omit(N=l)
KJPRLNW ...
DTXS I D6024834 UHFFFAOY ... QC-
N Omit(N=4)
Oxidative p53 Energy
Histone Protein Signaling Metaboli ...
Stress Call Modificat... Deacetyl... Pathway Process
(# Call (ii Call (ii
Call (# Call (ii
As5ays=22) As5ays=12) As5ays=23)
As5ays=4) As5ays=3)
.I.J .I.J .I.J .I.J .I.J
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Tested(N= ... Tested(N=6) Test ed (N= ... Tested (N=2)
Results Table Filterable Results
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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 ... 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
DNA DTXSI D (Dashboard QSAR Damage
"" Link) Ready ID Call (#
Assays=4)
.I.J .I.J .I.J BACHBFV ...
Active(N=l... DTXS I D0032605 UHFFFAOY ...
N Omit(N=l)
KJPRLNW ...
DTXS I D6024834 UHFFFAOY ... QC-
N Omit(N=4)
Oxidative p53 Energy
Histone Protein Signaling Metaboli ...
Stress Call Modificat... Deacetyl... Pathway Process
(# Call (ii Call (ii
Call (# Call (ii
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As5ays=4) As5ays=3)
.I.J .I.J .I.J .I.J .I.J
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Tested(N= ... Tested(N=6) Test ed(N= ... Tested (N=2)
Results Table
Filterable Results
Filtered results can be sent to other ICE TOOLS
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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 ... 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
DNA DTXSI D (Dashboard QSAR Damage
"" Link) Ready ID Call (#
Assays=4)
.I.J .I.J .I.J BACHBFV ...
Active(N=l... DTXS I D0032605 UHFFFAOY ...
N Omit(N=l)
KJPRLNW ...
DTXS I D6024834 UHFFFAOY ... QC-
N Omit(N=4)
Oxidative p53 Energy
Histone Protein Signaling Metaboli ...
Stress Call Modificat... Deacetyl... Pathway Process
(# Call (ii Call (ii
Call (# Call (ii
As5ays=22) As5ays=12) As5ays=23)
As5ays=4) As5ays=3)
.I.J .I.J .I.J .I.J .I.J
lnactive(N ... lnactive(N .. . lnactive(N ... lnactive(N ...
Tested (N=7) Tested (N=2)
Active(N=l... lnactive(N ... lnactive(N ... QC-
Omit (N=3) ... Omit(N=S) ... Omit(N=2) ... Omit(N=2) ...
Tested(N= ... Tested(N=6) Test ed(N= ... Tested (N=2)
Results Table
Filterable Results
Filtered results can be sent to other ICE TOOLS
> 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
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Select Assay Type(s)
In Vitro X +
0
X V
Legend O
- Act ive
- Inactive
[=:J QC-omit
[=:J Flag-omit
[=:J
r::7 ( + -)-Diclofop- methyl (5133 8-27-3) L.::::.J Number of Assays=305
Number of Assay Categories=13/25
Se&rdl,
::,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
Filtered results can be sent to other ICE TOOLS
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Details.
~
Summa
Hoverc,
intera
PlotT
a-Mi·!d-1 Curve Surfer
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
Active Ingredient Box and Whisker
100-
80-
, 60-
40-
.............. ... ~'--'-....:.-~
-· :9: \
20-... / -..::,._.._.,._•,...-.:_, =."- \ /
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
KOA log10 __ 9
LogD, pH 5.5 log10_ !
LogD, pH 7.4 log1 o_ 0
LogPlog109
MPC O
MWg/ mol __ ! pKa, Ionizations_.~
pKa, Acidic_O
pKa, Basic_·~ -
VP log10, mmHg_ 0
ws loglO, moles/ L __ 9_
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
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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
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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
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ICE Tools: PBPK
Seled Comp:irtment(s)
Ovalues
CASRN: 51-28-5
Chemical Name: "2,4-dinit rophenol"
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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
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 ~ -
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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
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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
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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.
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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
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64-17-5
111-76-2
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SubCategoril!~ Count
27
27
24
21
■ Active
■ Inactive
■ QCOIT'llt
ICE Tools: Chemical Characterization
Dynamic PCA CASRN Data (Chemical Properties)
..; -so · ~~, 111,M&I
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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
-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
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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
DTXSID: DTXSID1033664
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
DTXSID: DTXSID8022371
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
ICE Tools: Chemical Quest
.• 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
DTXSID: DTXSID1033664
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
DTXSID: DTXSID8022371
Tanimot o: top 10 hit s and >0. 7
Hi t Count : 10
Passed Fi lter (s): 10/ 10
View Results
Results can be sent to other
ICE tools
ICE Tools: Chemical Quest
.• 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
DTXSID: DTXSID1033664
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
DTXSID: DTXSID8022371
Tanimot o: top 10 hit s and >0. 7
Hi t Count : 10
Results can be sent to other
ICE tools
I 1------------------------------~
ICE Tools: Chemical Quest
.• 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
DTXSID: DTXSID1033664
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
DTXSID: DTXSID8022371
Tanimot o: top 10 hit s and >0. 7
Hi t Count : 10
Results can be sent to other
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
ICE Tools: Chemical Quest
.• 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
DTXSID: DTXSID1033664
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
DTXSID: DTXSID8022371
Tanimot o: top 10 hit s and >0. 7
Hi t Count : 10
Results can be sent to other
ICE tools
View results button opens new window displaying similar chemicals
ICE Tools: Chemical Quest Curve Surfer
.• Chemical Quest Results
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
DTXSID: DTXSID30745538
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
DTXSID: DTXSID40662202
Chemical Name: (17beta)-17-
Hydroxy(l 6, 16, 17-~2~H_3_)androst-4-en-
3-one
Tanimoto Value: 1.0
PBPK
CASRN: 52844-06-1
DTXSID: DTXSID90967315
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
ICE Tools: Chemical Quest
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
DTXSID: DTXSID30745538
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
DTXSID: DTXSID40662202
Chemical Name: (17beta)-17-
Hydroxy(l 6,16,1 7-~2~H_3_)androst-4-en-
3-one
Tanimoto Value: 1 _o
CASRN: 52844-06-1
DTXSID: DTXSID90967315
Chemical Name: 17-Hydroxy(7-
~3~H_ 1 _)androst-4-en-3-one
Tanimoto Value: 1-0
H
CASRN: 481-30-1
DTXSID: DTXS!D8022329
Chemical Name: Epitestosterone
Tanimoto Value: 1.0
HO 0
CASRN: 117338-89-3
DTXSID: DTXSID601016404
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
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"
Computational Toxicology
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,
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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
Computational Toxicology
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
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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
https://ice.ntp.niehs.nih.gov/
Partnership with:
34 Acknowledgments: The NICEATM Group
35 Acknowledgments: The NICEATM Group
36
Questions?