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

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a query in the ICE In Vitro
to In Vivo Extrapolation or IVIVE tool.

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To run the IVIVE tool,

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you must specify both the chemicals
and the in vitro assay data.

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Before we review those inputs, though,

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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, type of pharmacokinetic
model, and dosing parameters.

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Default settings are
provided and are shown here.

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For the in vitro endpoint,

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you can choose between the default option,
which is the half-maximal activity

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concentration, or AC50, 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 as the default

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option. For certain
pharmacokinetic parameters,

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if rat values are not available,

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human values are substituted
with proper allometric scaling.

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Next, we select the source of the ADME
data used in pharmacokinetic modeling.

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Specifically, these are the hepatocyte

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intrinsic clearance rate and fraction
of chemical unbound in plasma.

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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 when
experimental data are not available.

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The second option,
Measured, only uses experimentally measured

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values, 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

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by the OPEn structure-activity/property Relationship App, or OPERA.

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The IVIVE tool allows you to select one

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of four pharmacokinetic models
for calculating an EAD.

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These include: a one-compartment,

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population-based pharmacokinetic model,
a three-compartment pharmacokinetic model,

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a multi-compartment PBPK model for oral
and injection exposure routes,

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a multi compartment PBPK model
for the inhalation exposure route.

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The three compartment and multi-compartment
models are from the EPA's httk R package.

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The one-compartment model bases its EAD

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

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The three-compartment and multi-compartment
models based their EAD predictions

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on simulations of maximum
plasma concentration, or Cmax.

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Depending on model type,

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you can specify parameters for the model

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like 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

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and in vitro assay data are 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

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by clicking on the
"Select Chemicals" button.

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For this 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

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of the following identifiers, CASRNs,
DTXSIDs, SMILES, and InChiKeys.

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An example of these identifiers is

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provided in the information box
located in the Chemical Input field.

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

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to the right 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

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high-throughput assays organized
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 check boxes to select
the assay category of interest

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under either tab.
Assay selection is limited to the curated

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ToxCast and Tox21, or
cHTS data available in ICE.

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

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will choose the assay category
"Endocrine-related Processes".

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When you are 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 vitro

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and in vivo assay data to your query.
To the right of the "Data Input" field.

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The "Upload Custom Data" fields
allow you to upload your own data.

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The upper custom data field allows you
to upload in vivo data that can be

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displayed in the results view
to compare to your model predictions.

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The lower custom data field allows you

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to upload in vitro data to be
used as input for the model.

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Note that only chemicals with parameter

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values available in ICE
will be used for modeling.

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To download a text or an Excel template

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file for getting your data ready
for uploading,

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click on the green information
button beside the field heading,

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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 or drag

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and drop your input file
from a file explorer window.

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The in vivo data will not be displayed

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in input view but can be viewed
in the Results view graphs.

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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

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in the Results
view outputs. Now that you have built your

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IVIVE query, click on "Run"
at the top 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

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the IVIVE tool, go to "Help"
and select "User Guides".