WEBVTT

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Welcome to the Integrated Chemical
Environment, also known as ICE.

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This video will show you how to build
a query in the ICE in vitro

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to in vivo extrapolation (or IVIVE) tool.

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To run the IVIVE tool,
you must specify both the chemicals

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and the in vitro assay data.

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Before we review those inputs, we're
going to look at the modeling options.

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You will need to specify an in vitro

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endpoint, species, body weight,

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type of pharmacokinetic model,
and dosing parameter.

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Depending on the type of PK or PBPK model
you selected, additional parameters

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may need to be specified.

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Default settings are
provided and are shown here.

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For the in vitro endpoint,
you can choose between the default option,

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which is the half maximal activity
concentration or AC50,

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or the activity
concentration at cutoff, or ACC.

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You must choose a species
to use for modeling.

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Currently, selections are limited to rat
and human, with human

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as the default option.

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For certain pharmacokinetic parameters,
if rat values are not available,

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human values are substituted
with proper allometric scaling.

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You can also specify the body
weight of the subject.

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The default value is 70
kilograms for human and

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0.25 kilograms for rat.

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Next, let's select the source
of the absorption, distribution,

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metabolism, and excretion, or ADME,
data used in pharmacokinetic modeling.

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We have three options here:

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the Default option uses available
experimentally measured values,

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with in silico predictions used where
experimental data are not available.

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The second option, Measured,
only uses experimentally measured values,

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which may result in fewer predictions.

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Lastly, the In Silico option uses
only in silico predictions as inputs.

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These are generated
by the OPEn structure–activity/property

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Relationship App, also known as OPERA.

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The IVIVE tool allows you to select one
of five pharmacokinetic models

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for calculating an equivalent
administered dose, or EAD.

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These include: a one-compartment
population-based pharmacokinetic model,

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a three-compartment pharmacokinetic model,
a multi-compartment,

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generic PBPK model for oral and injection
exposure routes,

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a multi-compartment,
PBPK model for the inhalation exposure

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route,
and a multi-compartment PBPK model,

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including maternal, fetal,
and placental compartments.

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The one-compartment model was created
in house and bases its EAD predictions

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on simulations of steady-state
plasma concentration, or Css.

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The three-compartment
and multi-compartment PBPK models are

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from the US Environmental Protection
Agency's httk R package,

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and except for the maternal-fetal model,
base their EAD predictions on simulations

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of maximum plasma concentration or Cmax.

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The maternal-fetal multi-compartment model
returns both an EAD.50 value,

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which corresponds to maternal
plasma Cmax, and a EAD.fmax.50 value

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which corresponds
to the fetal plasma Cmax.

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Depending on model type,
you can specify parameters for the model,

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such as exposure route, exposure interval,
exposure length, and simulation length.

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Additional model information can be
found in the downloadable user guide.

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The input fields for chemicals
and in vitro assay data are

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located below the modeling options.

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Select chemicals for your query
in the "Chemical Input" field on the left.

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You can choose an ICE Chemical quick list
by clicking on the

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"Select Chemicals" button.

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For this query example, we will choose
the "ER In Vitro Agonist" Chemical quick list.

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You can also enter chemical identifiers in
the User Chemical Identifier box.

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You can do this by typing in one or
more individual chemical identifiers.

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For this example, we can type in "50-28-2",

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the CASRN for the chemical estradiol.

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You can also paste in a list
of chemical identifiers.

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You can use any combination
of the following identifiers:

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chemical names,
CASRNs, DTXSIDs, SMILEs, and InChIKeys.

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An example of these identifiers is
provided in the information box

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located in the Chemical Input field.

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Add in vitro data to your query by using
the "Data Input" field to the right

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of the "Chemical Input" field.

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Select Assays from the ICE database
by clicking the "Select Assays" button.

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A dialog box will open showing two tabs,
"cHTS" and "Mode of Action".

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Click on the "cHTS" tab to view
high-throughput assays organized

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into mechanistic target categories.

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Click on the "Mode of Action" tab to view
assays organized by mode of action.

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Use the checkboxes to select the assay
category of interest under either tab.

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Assay selection is limited to the curated
ToxCast and Tox21, or cHTS, data

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available in ICE.

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For this query example,
under the "cHTS" tab,

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we will choose the assay category,
"Thyoid Hormone Metabolic Process".

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When you're finished selecting
assays, click on "Finished."

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The assay categories you have selected
will be displayed in the text box.

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You can also add your own in vivo or
exposure data and in vitro

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assay data to your query.

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To the right of the "Data Input" field,
the "Upload Custom Data" fields

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allow you to upload your own data.

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The upper custom data field
allows you to upload in vivo data or

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exposure data that can be displayed
in the Results view to compare

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to your model predictions.

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The lower custom data field allows you
to upload in vitro data to be

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used as input for the IVIVE.

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Note that only chemicals with parameter
values available in ICE

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will be used for IVIVE.

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To download a text or an Excel template
file for getting your data ready

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for uploading,
click on the green Information button

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beside the field heading,
and then click on the appropriate link

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to download the template file
that will work best for your data.

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To upload your file,
you can use the "Upload" button

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or drag and drop your input file
from a file explorer window.

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The in vivo or exposure data will not be
displayed in Input view,

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but can be viewed in the Results
view graphs for graphic overlaying.

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Data from an in vitro data file will be
displayed in the Chemical Input and Data

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Input fields in Input view and will also
be visible in the Results view outputs.

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Now that you have built your IVIVE query,
click on "Run" at the top

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of the page to run it.

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The query may take a few moments to run.

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We'll review the query results and how
to interpret them in a separate video.

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Thank you for watching our video
on how to build an IVIVE query in ICE.

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For more detailed information about
the IVIVE tool,

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go to "Help" and select "User Guides".