vxEPA
United States
Environmental Protection
Agency
Exposure Related Dose
Estimating Model (ERDEM)
A Physiologically-Based
Pharmacokinetic and
Pharmacodynamic (PBPK/PD)
Model for Assessing
Human Exposure and Risk
RESEARCH AND DEVELOPMENT
-------
EPA/600/R-06/061
June 2006
vwwv.epa.gov
Exposure Related
Dose Estimating Model (ERDEM)
A Physiologically-Based
Pharmacokinetic and
Pharmacodynamic (PBPK/PD) Model
for Assessing Human Exposure
and Risk
Jerry N. Blancato
Fred W. Power
Robert N. Brown
Curtis C. Dary
Notice: Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official
Agency policy. Mention of trade names and commercial products does not constitute endorsement or
recommendation for use.
U.S. Environmental Protection Agency
Office of Research and Development
Human Exposure and Atmospheric Sciences Division
Exposure and Dose Research Branch
Post Office Box 93478
Las Vegas, NV 89193-3478
237EDRB05.RPT * 7/31/06
-------
Table of Contents
Section 1 Introduction 1
Section 2 ERDEM Front End User Guide (Beta Version 4.1.1) 7
2.1 Installation 7
Section 3 Using the ERDEM Front End 9
3.1 Introduction 9
3.1.1 Recommended Screen Settings 9
3.1.2 Model Data Sets 9
3.1.3 Data Entry Pipeline 10
3.2 Accessing the Data: Overview of the ERDEM Menu System 10
3.2.1 Main Menu 10
3.2.2 Additional Menu Features 11
3.3 Organizing the Data: The Model Data Set Concept 11
3.3.1 Define aNew Model Data Set 11
3.3.2 Save the Entered Data 13
3.3.3 Open an Existing Model Data Set 14
3.3.4 Copy/Delete Model Data Set 15
3.3.4.1To Copy the Current MDS 15
3.3.4.2To Delete an MDS 18
3.3.5 Open User Database 20
3.3.6 Open SAMPLE Database 21
3.3.7 Special Processes - Copy Current Database 23
3.3.8 Special Processes - Convert Database 24
3.3.8.1MethodOne 24
3.3.8.2Method Two 26
3.4 Maintaining Data Integrity: The ERDEM Data Entry Pipeline 32
3.4.1 The Pipeline Report 32
3.5 Editing the Data: Adding, Deleting, Saving 34
3.5.1 Change An Entry 34
-------
3.5.2 Insert, Add, or Delete a Row 35
3.5.2. ITo Insert a Row 36
3.5.2.2To Add a Row 36
3.5.2.3To Delete a Row 36
3.5.3 Saving Changes 37
3.6 Required Fields and Unavailable Fields 37
3.6.1 Required Fields 37
3.6.2 Unavailable Fields 38
3.7 Maintaining Productivity: ERDEM Window Features and Shortcuts .... 39
3.7.1 Non-Filtering Dropdowns 39
3.7.2 Filtering Dropdowns 40
3.7.3 Filtering Dropdowns and Reference Data Lists 42
3.7.4 Reference Data Lists 44
3.8 Switching Between Model Data Sets 45
3.8.1 To Switch to Another MDS 46
3.9 Using Context Help 48
3.10 To Turn Off "Context Help" 49
Section 4 Exporting and Running a Model Data Set 51
4.1 Preparing the Model Data Set for Export 51
4.2 Exporting the Model Data Set from the ERDEM Database 52
Section 5 Starting the ACSL Viewer and Running the ERDEM Model 55
5.1 Starting the ACSL Viewer 55
5.2 Running the Model 61
5.3 Specifying the Scenario 65
5.4 Exit ACSL 68
5.5 Exit ACSL/Graphic Modeller 69
5.6 Exit ERDEM Front End 69
Section 6 Descriptions of Exposure Related Dose Estimating Model
(ERDEM) 71
6.1 Experimental Pathways and Routes of Entry 72
6.1.1 Intraperitoneal Injection 72
6.1.2 Intramuscular Injection 72
6.1.3 Intravascular Administration 73
-------
6.1.3.1 Infusion into the Venous Blood 73
6.1.3.2Bolus Intravenous Injections 74
6.1.4 Inhalation Administration 75
6.2 Exposure for Bolus Ingestion, Rate Ingestion, Inhalation, and Skin Surface
Exposures 76
6.2.1 Ingestion Into the Stomach and the Stomach Lumen 77
6.2.1.1Bolus Dose Ingestion 77
6.2.1.2Rate Ingestion 78
6.2.2 Inhalation Exposure 79
6.2.3 Dermal Exposure 79
6.2.3.1 Skin Surface Exposure to a Chemical in an Aqueous Vehicle^
6.2.3.2Skin Surface Exposure to Transfer from a Dry Surface ... 79
6.3 Variable Definitions 81
Section 7 Descriptions of Absorption and Circulation in Model
Compartments 85
7.1 The Closed Chamber for the Static Lung 85
7.1.1 Elimination in the Static Lung 86
7.1.2 Binding in the Static Lung 86
7.1.3 Calculation of Free Chemical in the Static Lung 86
7.1.4 Metabolism in the Static Lung 87
7.1.5 Arterial Blood and the Static Lung 87
7.1.6 Venous Blood Input to the Static Lung 87
7.2 The Breathing Lung 88
7.2.1 Flow of Air in the Breathing Lung 90
7.2.2 Factors to Multiply Terms for Inspiration and Expiration 91
7.2.3 Equation for the Closed Chamber 92
7.2.4 Equations for Upper Dead Space 92
7.2.5 Equations for the Lower Dead Space 93
7.2.6 The Equation for the Alveoli 93
7.2.7 Lung Tissue Equation 94
7.2.7.1 Elimination in the Lung Tissue 94
7.2.7.2Binding in the Lung Tissue 95
7.2.7.3 Calculation of Free Chemical in the Lung Tissue 95
7.2.8 Metabolism in the Lung Tissue 95
7.2.9 Equation for the Pulmonary Capillaries 95
7.2.10 Binding in the Pulmonary Capillaries 96
in
-------
7.2.11 Calculation of Free Chemical in the Pulmonary Capillaries 96
7.2.12 Blood Flow for the Breathing Lung 96
7.2.13 Arterial Blood and the Breathing Lung 97
7.2.14 Venous Blood Input to the Breathing Lung 97
7.2.15 Calculation of Uptake and Chemical in Exhaled Breath 98
7.2.16 Variable Definitions for Breathing Lung 98
7.3 Equations for the Four Compartment Gastro-Intestinal (GI) Simulation 100
7.3.1 Flow Through the Stomach Wall 102
7.3.2 Flow Through the Stomach Lumen 103
7.3.3 Flow Through the Duodenum Wall 104
7.3.4 Flow Through the Duodenum Lumen 105
7.3.5 Flow Through the Lower Small Intestine Wall 106
7.3.6 Flow Through the Lower Small Intestine Lumen 107
7.3.7 Flow Through the Colon 108
7.3.8 Flow Through the Colon Lumen 109
7.3.9 Flow Through the Lymph Pool 110
7.3.10 Portal Blood and Bile Flow Ill
7.3.11 Flow in the Liver Compartment and Bile Flow to the Duodenum
Lumen 112
7.3.12 Chylomicron Flow in the Other Compartments 114
7.4 Dermal Exposure 114
7.4.1 Skin Surface Exposure to Water or Other Vehicle 115
7.4.2 Skin Surface Exposure to Transfer from a Dry Surface 117
Section 8 Chemical Disposition in silico 121
8.1 Distribution of Chemical from Blood to Tissues, Organs and in Fluids . 121
8.1.1 Binding in the Arterial Blood 121
8.1.2 Calculation of Free Chemical in the Arterial Blood 122
8.1.3 The Venous Blood 122
8.1.3.1Binding in the Venous Blood 122
8.1.3.2Calculation of Free Chemical in the Venous Blood 122
8.1.4 Distribution in Tissues 122
8.1.4.1Distribution in the Residual Carcass 122
8.1.4.2Distribution in Fat Tissue 124
8.1.4.3Distribution in Slowly Perfused Tissue 125
IV
-------
8.1.4.4Distribution in Rapidly Perfused Tissue 126
8.1.5 Distribution of Chemical in Organs 127
8.1.5.1 Distribution of Chemical from Blood to the Brain 127
8.1.5.2Distribution of Chemical to the Liver 129
8.1.5.3Absorption and Distribution in the Stomach 131
8.1.5.4The Intestine 131
8.1.5.5The Kidney 131
8.1.5.6The Spleen 132
8.1.5.7The Dermal Tissue 134
8.2 Metabolism in Selected Tissues and Organs 134
8.2.1 Implementation Outline 135
8.2.2 Variable Names for Metabolism Parameters 136
8.2.3 Calculation of Maximum Rate of Change of Metabolism 137
8.2.4 Calculations When Including Enzyme Destruction and Re-syntheslii8
8.2.5 The Rate of Formation of Saturable and Linear Metabolite in the
Liver 138
8.2.6 Circulating Compounds which are Metabolites 139
8.2.7 Inhibition in the Metabolism Process 139
8.2.8 Metabolism in the Other Organs and Tissues 140
8.2.8.1 Metabolism in the Brain 140
8.2.8.2Metabolism in the Kidney 140
8.2.8.3Metabolism in the Carcass 140
8.2.8.4Metabolism in the Fat 141
8.2.8.5Metabolism in the Slowly Perfused Tissue 141
8.2.8.6Metabolism in the Rapidly Perfused Tissue 141
8.2.8.7Metabolism in the Spleen 141
Section 9 Exposure Related Dose Estimating Model (ERDEM) Enzyme
Kinetics Implementation 143
9.1 The ERDEM Equations for Enzyme Kinetics 143
9.2 Elimination of Chemical Due to Competition with Enzyme Metabolism 143
9.3 Enzymatic Reactions in the Liver 144
9.3.1 Enzymatic Inhibition 144
9.3.2 Enzyme Regeneration 145
9.3.3 Enzyme Re-synthesis 145
-------
9.3.4 Enzyme Aging and Degradation 145
9.4 Nomenclature for the Liver Enzyme Equations 146
9.4.1 Amounts in the Liver 146
9.4.2 Concentrations in the Liver 147
9.4.3 Rates of Change of the Amount of Enzyme in the Liver 147
9.4.4 Rate Constants for the Reactions 148
References 149
VI
-------
Section 1
Introduction
The U.S. EPA, as part of its mission to protect human health, develops tools (methods,
measures and models) to improve the risk assessments that are used by the Agency to
predict adverse effects from exposure to environmental agents. As with any predictive
approach, there is often considerable uncertainty associated with these assessments. To
reduce this uncertainty and to increase confidence in our policy decisions, the Agency
must use the best and most-up-to-date science. Current approaches include the use of
state-of-the-science predictive models to describe the physical, chemical, and biological
processes that may be impacted by an exposure to a chemical of concern. Scientists often
need to predict the dose of chemicals within the body that results from an environmental
exposure. This requires the knowledge of many biological processes and chemical
factors both inside and outside of the body. Predictive mathematical models, which can
accurately describe the biology and chemistry within the human body, are used to
estimate and predict the dose. With improved dose models, risk assessors can better
predict possible health impacts and insure that the Agency's risk management decisions
are founded on high quality science.
Over recent years, physiologically based pharmacokinetic (PBPK) models have been used
to better describe internal doses resulting from exposures to chemicals in the
environment. PBPK models are mathematical descriptions of how chemicals are absorbed
into, transported through, eliminated from, and stored in the body. More recently,
physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models are
being used to mathematically describe not only the disposition of a chemical in the body,
but also how some normal biologic processes are altered as a result of the chemical in the
body. PBPK/PD models should provide the ability to evaluate, estimate, and predict
measures of toxicologically relevant doses.
The Exposure Related Dose Estimating Model (ERDEM) is a PBPK/PD modeling system
that was developed by EPA's National Exposure Research Laboratory (NERL). The
ERDEM framework provides the flexibility either to use existing models and to build
new PBPK and PBPK/PD models to address specific science questions. Over the past
several years, ERDEM has been enhanced to improve ease of operation and to provide
additional modeling capabilities. With these enhancements, ERDEM has been applied to
a variety of chemicals as part of the regulatory risk assessment process. Applications for
malathion and N- methyl carbamate were presented to and peer-reviewed by the FIFRA
Scientific Advisory Panel.
-------
This report provides information on the use of ERDEM and related software. ERDEM
can be found on the web at: For the user,
ERDEM requires no special software other than the basic Windows environment
commonly used on PCs. The ERDEM system includes three components
• the ERDEM Front End,
• the ERDEMModel(s) built in Advanced Continuous Simulations Language
(ACSL),
• the ACLS Viewer.
The ERDEM Front End is a Windows-based application that allows the user to enter
exposure, pharmacokinetic, and pharmacodynamic parameters and data and to store them
in a database for later use and export to a command file for input to the ERDEM Model.
The ERDEM modeling engine contains differential equations that use the physiological,
biological, and pharmacodynamic modeling data that are entered via the ERDEM Front
End. The various features (compartments, metabolism, exposure, and enzyme inhibition)
of the modeling engine are accessed by flags that are set by the user. The ACSL viewer is
part of the ACSLTOX modeling engine environment that allows the user to start and view
model run results.
This introduction is dedicated to explaining and exploring the ERDEM system. Section 2
takes the user through the installation process. Section 3 introduces the computer screens
of the ERDEM Front End, where toxicologists and risk assessors may enter exposure,
pharmacokinetic (PK) and pharmacodynamic (PD) parameters and data.. Section 4
presents the export of the entered data into a command file for input to the ERDEM
model engine(s). Section 5 discusses the use of the ACSL Viewer used to run the model.
This is followed by a mathematical description of the exposure pathways (Section 6), the
absorption and of the exposure chemicals through the lung, gastro-intestinal (GI) tract,
and the skin (Section 7), the disposition and metabolism throughout the various
compartments (Section 8), and the pharmacodynamics of enzyme kinetics provided in
Section 9.
ERDEM consists of the following compartments: Arterial Blood, Brain, Carcass, Closed
Chamber, Derma, Fat, Intestine, Kidney, Liver, Rapidly Perfused Tissue, Slowly Perfused
Tissue, Spleen, Static Lung, Stomach, and Venous Blood. The mathematical equations for
these compartments are presented in Section 7. Each of the compartments (Brain,
Carcass, Fat, Kidney, Liver, Lung Tissue, Rapidly and Slowly Perfused Tissues, Spleen,
and the Static Lung) have two forms of elimination, an equilibrium binding process, and
multiple metabolites. System diagrams for the Static Lung (Figure 1) and Breathing Lung
(Figure 2) are presented. The model diagram of the Breathing Lung shows the movement
of chemical across the three boundaries. The Breathing Lung utilizes the compartments:
Alveoli, Lower Dead Space, Lung Tissue, Pulmonary Capillaries, and Upper Dead Space.
Lastly, there are two diagrams showing the Gastro-intestinal (GI) Model (Figure 3) and
further details (Figure 4) of the GI. ERDEM allows for multiple circulating compounds
with multiple metabolites entering and leaving each compartment. The Gastro-intestinal
-------
model consists of the Wall and Lumen for the Stomach, Duodenum, Lower Small
Intestine, and Colon with Lymph Pool and Portal Blood compartments included. Bile
flow is treated as an output from the Liver to the Duodenum Lumen. All chemicals
including their metabolites are treated as circulating. Nonspecific ligand binding, e.g.,
plasma protein binding, is represented in Arterial Blood, Pulmonary Capillaries, Portal
Blood, and Venous Blood.
REFERENCES
Okino, M.S., Power, F.W., Tornero-Velez, R., Blancato, J.N., and Dary, C.C.,
Assessment of Carbaryl Exposure Following Turf Application Using a Physiologically
basedPharmacokinetic/Pharmacodynamic Model. FIFRA Science Advisory Panel Open
Meeting, Arlington, VA, February 15-18, Docket Number: OPP-2004-0405, Washington
DC., 2005.
Report, "Use of Exposure-Related Dose Estimating Model (ERDEM) for Assessment of
Aggregate Exposure of Infants and Children to N-Methyl Carbamate Insecticides".
Appendix to "ESTIMATION OF CUMULATIVE RISK FROM N-METHYL
CARBAMATE PESTICIDES: Preliminary Assessment", to FIFRA Scientific Advisory
Panel (SAP) Open Meeting, August 23-26, 2005, Docket Number: OPP-2004-0172,
Washington DC.
-------
Inputs
1 Bolus Dose I.,..,
ingestions
X~~™»~..™~™— ..™™~_ ~~~^ *»-»»*«--- *a.~
r«w L^WSJ
Inqestions
v_f ___J o 00
:intraperitoneat \
Injection J
23 97'
0?7.
2397*
479'
f*~7~ " "N 1343*
Intramuscylar I
injection j
2493'
Skin Surface I ,-
I
V «™™™*«('1'
j Bolus Dose L.,
I Infusions J—
•Percent of Total Blood Flow
"Percent of Body Volume
(Excluding Air
***Perc®nt of the Tsdal Volum©
KST.IN
S*JsP Spleen 000 "K^iVa"^
L ^
OR-n V
j^ ' P"i-fftl Ploof
T
' »j LV I wer 3 14" '
QBtv
»»j CR Caicass 043 LlL,
QBoH " "
*»s KD Kidney 044 ^~~^
QB~M>""T"
^_i FT Fat 23 1 _^.
^-! j^ _,
QBs-V"
I *H SL Slowly Perfused
V">"' 46 77 H""
1 f
QB&.
**j RP Rapidly r-».
j Perfused 327 ^ y
" "9^"; OR Derma W,29.___^
>>-
I j — r
IBR o.oo £___/
QBBR
H_ _____,^^
VB Venous 5,19 "**"' ' '
KlN.FEC
^, IN Intestine !""•*•, Jntesttnal
KlN" t'6 — '
»-Spieen Metabolites There are N chemicals modeled
Liver Kidney, Fat, Carcass,
Brain, Slowly Perfused Rapidly
Perfused Tissue and Spleen
The Static Lurtg, and Lung Tissue
>Liver Metabolites are modeled with binding
elimination and metabolism
>4->Careaas Metabolites
*u--$Hf at Metabolites
There are op to K metabolites
of each of the N chemicals Each
Slowly metabolite is one of the
•»__-^Perfused N chemicals There is binding in
Tissue the Artersa! Blood and Venous Blood.
Metabolites
'\ is» Rapidly Perfused
Tissue Metabolites
\.V Brain
"^
j Ooen Chamber 1
PU Lung
i
AB 2,5?
., . ' Inhalation J
Open Chamber \ ~ • — — — — —
Exhalation
_ung Metabolites
Figure 1. ERDEM System Flow with Static Lung and Stomach Intestine.
-------
VB Venoys
i
QWJ
Bionchial W
ftrterv
Pulmonary
GAB.CP
QB ,
AB /
- b
Capillaries
___^_J*--
j
I
i
j
f * *«
arterial
c
Bronchial vein
QCP.VB
a
• PcP.AI.AAt — •>
— RW..CP ACP
Diffysion
PAI ir.t
— -—pLGiCpA CP — —
Diffusion
CC Closed
Chamber Inhalation
A
^/ Open Chamber '*
\ Exhalation J
,...[ Open Chamber 1
QAIR\I/ i 1 Inhalation J
i J JL:;
UD
Upper Dead space
}«« J i
4 !
LD
Lower Dead Space .
' i "A :
AL Alveo
k
I PlGAlAAL
MI i
LG | j Diffusion
LG Lung Tissue
i
«— — ••> Lung Metabolites
Figure 2. Breathing Lung Compartment Flow.
Inputs
i ingestions 1 __ ^J" CT 0(m_^^k [_ J IN Intestine I™*/" Intestinal
Rate 1
Ingestions .
V / Q A0
1
J
23.9?'
KMI>BT
A^JSP Spleen 000 j-4>i-/'<
%,,„ .,j^J Portal Bloc
^ ___
'—^ LV Liver 3 14**
QBiv
i I I Elimination
"KlN.PS
>»-Spleen Metabolites
^I\
"S'-Liver Metabolites
Venous
i f
Figure 3. Stomach/Intestine Gastro-lntestinal Model.
-------
1
AB Arterial f
__^ 1
Bolus Dose I
Ingestion [
Arteria
The three Walls, DU,
SI, and CN
chemical in the lipids
to the Lymph Pool(LP).
**
^_ LV LIWBI *
4 PB
1
i
rJ ""if
if '' Blle Non Ltpid
KlfLV Flow Row
Lymph <
( . . _ L ....... .' r. - . .. . . ..
i
Food Flow
\t y
Mood DUL Duodenym Lumen
L^ ^^^
Flow ^ ^
•«* 1
DU Duodenum Wall ^
Food Flow
( |^
-* 1 SI Lower Small Intestine Wall
*fcj
"
1 i
A |
Lipirf ! Non-UpitJ
Flow ! Flow W
1 i t _ .
I SI Lower Small Intestine Lumen
i r*\
~* 1 CN Colon Wall
„„„„„„„„„„ ,^j
1
, . , , i i Food Flow
tipid * ^
Flow | Non-Ltpid
r—^JL^^Sffi^^^^
^
CN Colon Lumen
Portal Blood
I
_»»,
Po
Bl(
.,-**
tal The Lymph flow consist
od Chylomicrons that are fa
in the blood, To find the
a chemical in the blood,
amoynt must be added
% Lymph
.. ^^ ^ xx Comp3rtn.
KtP.xx
lymph flow ts t
following comp
Liver, Spleen C
Ktdney. Fat,
Slowly Perfuse
Rapidly Perfus<
Derma. Brain !
and ihe Pylmof
Capillaries.
Lymph
Pool
Qpeces
Intestinal
riimmahon
Figure 4. Detailed Gastro-lntestinal Tract Model.
-------
Section 2
ERDEM Front End User Guide
Beta Version 4.1.1
2.1 Installation
1. Insert the ERDEM Beta, Version 4.1.1 CD-ROM into your CD-ROM drive.
If Auto Run is active on your system, the "ERDEM Installer" window will
automatically appear.
2a. Follow the "ERDEM Installer" instructions that are displayed.
-OR-
2b.If AutoRun is not active on your system, do the following:
bl. Select "Run" from the Windows Start menu.
b2. Type the drive letter for your CD-ROM and the following path:
D:\ERDEM_INSTALLER.HLP (In this instance, "D:" is the CD-ROM drive
path; it may be different on your computer.)
Note: You can also use Windows Explorer to navigate to your CD-ROM drive and
double-click on the "ERDEM-INSTALLER.HLP" file.
b3. Press the "Enter" key.
The "ERDEM Installer" window will appear.
b4. Follow the "ERDEM Installer" instructions that are displayed.
Important:
If you have a previous version of ERDEM installed, the system will inform you that
the previous version must first be uninstalled. This installation then will guide you
through the uninstall of your previous version, back up the user's database, if it exists,
-------
and return you to the ERDEM Install program. As directed, click the "ERDEM
Install" icon again to complete the installation.
It is recommended that you do a standard installation, accepting all default settings.
That is, click "Yes," "OK," "Next," or "Finished," as appropriate on the various
windows. The Install program will install ERDEM and all related components.
For your convenience, this user guide is also available from ERDEM Online Help.
-------
Section 3
Using the ERDEM Front End
3.1 Introduction
As a comprehensive modeling system, ERDEM contains a PBPK model engine
component that can create scenario-based simulations and target dose estimates for
exposure of a species to multiple chemicals, metabolites, compartments, enzymes, and
exposures. The input management component uses a Windows-based graphical user
interface and relational database that enables the user to enter, edit, report, and export
data sets of user-assigned physiological information. ERDEM takes away the tedious and
error-prone activities associated with entering, maintaining, and exporting physiological
inputs and assessing outputs for PBPK models.
The ERDEM Graphical User Interface (GUI), also known as the ERDEM Front End,
provides an efficient method for entering pharmacokinetic modeling and exposure
parameters and storing them in a database for later use and export to the ERDEM Model.
This section introduces you to the ERDEM Front End interface. Details on data entry and
window dependencies are provided in the ERDEM Online Help and the Tutorial, using
icons that can be found on your desktop after installation.
3.1.1 Recommended Screen Settings
It is recommended that your screen resolution be set to 1024 x 768 pixels and that your
screen colors be set to Windows Standard or Windows Classic. This will ensure that you
can see complete windows and that marks in selection boxes are visible.
3.1.2 Model Data Sets
The ERDEM Front End uses the concept of the Model Data Set (MDS) to organize, store,
and retrieve entered data. All data entered via the ERDEM Front End must belong to a
model data set. An MDS consists of a full set of simulation data records. That is, it
contains all the data that was entered via the ERDEM windows and that eventually will
be exported to the ERDEM Model for estimating exposure-related dose. The MDS you
have open at a given time is called the current MDS.
-------
3.1.3 Data Entry Pipeline
Data is entered in a specified sequence, or pipeline, that validates for data integrity as data
entry proceeds. The steps of this sequence are accessed as individual windows that allow
for adding, saving, editing, or deleting data. The menu selections can be thought of as
joints, or segments, in the pipeline. The sequence proceeds from left to right across the
"Main" menu, and from top to bottom on each submenu.
The ERDEM Front End has built-in safeguards that prevent you from missing steps in the
pipeline. For example:
• Required data entry fields have blue field names. If you attempt to save a window
before completing all the required fields, you will be prompted to fill in the required
fields and you will be directed to the appropriate fields.
• If you attempt to enter data at some stage of the pipeline before opening an MDS, you
will be given an opportunity at that stage to open an MDS. The MDS you open then
becomes the current MDS.
• If you attempt to enter data at a later stage of the pipeline (i.e., a later menu) before
completing required data entry at an earlier stage (i.e., on an earlier menu), you will be
prompted to fill in the missing data and you will be directed to the appropriate
menu/window.
ERDEM Front End features include window shortcuts to help you be more productive.
Everything in the system has been designed to relieve your burden in terms of accessing
and organizing data, maintaining data integrity, and editing data.
These and other ERDEM Front End features will be discussed in the following sections.
3.2 Accessing the Data: Overview of the ERDEM Menu System
3.2.1 Main Menu
1. Double-click the ERDEM software icon, located on your desktop.
The "ERDEM" software will open; the "Main" menu will appear as shown below.
File Model Activity Chemical Chemical Compartments Enzymes Exposure Special Processes Repotting System Export Help
a * 00 '.' £ 11 m : aP to i? ;; e II BX
10
-------
The menu items are icons that provide shortcuts to
frequently used functions. Screen tips describing
each icon's function appear when you place the
mouse pointer over the icon. For example, the
heart icon is a shortcut to the "Compartment Blood
Flow" entry window, as shown at right.
3.2.2 Additional Menu Features
File Mode! Activity Chemical Chemical Cornpartme
•;CH A •-Q ' «P CO '•"•; £> f'f i ?-; aP
[Compartment Blood Flow;
When a data entry window is open, another row of icons providing additional functions
appear below the "Main" menu, as shown below.
File Edit Model Activity Chemical Chemical Compartments Enzymes
•ffl
Q • # CO
y i-* Q
ft \
B-B
Again, screen
tips describing
each icon's
function appear
when you place the mouse pointer over the icon. For example,
as shown at right, the diskette icon is a shortcut to the "Save"
function.
File Edit Model Activity Chemical
H ft Q * CO
&•-• 1* H.i-* Q '
Note: This manual provides an overview of the ERDEM Front End menu and window
system. Details on menu items, data entry, and window dependencies are provided
in the ERDEM Online Help and the Tutorial.
3.3 Organizing the Data: The Model Data Set Concept
The first step in the data entry pipeline is to define a Model Data Set (MDS). Complete
the following steps to create a new MDS:
From the "Main" Menu
1. Select "File".
The File menu will appear, as shown at right.
The File menu options allow you to (1) create a New Model
Data Set, (2) open an existing Model Data Set, (3) open a User
Database, (4) open a SAMPLE Database that is provided by
default as part of the ERDEM Install program or (5) Exit the
ERDEM Front End.
Model Activity Chemical
New Model Data Set '• ^
Open Model Data Set
Open User Database
Open SAMPLE Database
Exit
3.3.1 Define a New Model Data Set
11
-------
2. Select "New Model Data Set," as shown at right.
The "Definition of Model Data Set" window will appear, with
the "Definition" tab active, as shown below. This window
enables you to enter the initial simulation data. (This is the first
window in the data entry pipeline. The initial data entered on this
window provides the starting data record framework for
subsequent windows that are used to build the MDS.)
Open Model Data Set
Open User Database
Open SAMPLE Database
Exit
r Definition
i Settings
i ©Units
Name. 1
Description
Species:
Avg Age:
Vet sion
Log Path:
Sub Species: i
Sex:'n/a »<
Pjint Final Results
Active
Variable History Path:,
Remember that on all windows in this program, fields with blue field names require
information entered in them. Data may be entered in the other fields as appropriate for
your Model Data Set. For fields with down arrows, you can enter data by selecting
from a drop down, or pick list, as shown below.
iff Definition
Name '
Species:
Avg Age: ;
j laP Settings
©Units
Log Path:
2.02S
.020
2.02L
.02K
Sub Species: '
Sex: in/a j^j '" Print Final Results
" j*'l I" Active
ory Path: j
3. Click on the "Settings" tab. This selection provides for entry of other parameters.
12
-------
gf Definition
Volume
3 Settings
j© Units
Body Volume:;
, Cardiac
n_i — <--When checked, Activity Cardiac Output
; iood Flow By Pct l required on Model Data Set Activfr window.
Integration - -
Communication Intervals." Integration intervals: J1
' Relative Err or Limit: -i .OOE-04 Integration Settings Help j
Duration
Start Time:• Stop Time: ]
4. Select the "Units" tab. This selection provides for the setting of measurement
units, as shown below.
efinition
Present Units
Mass Units: M
JlfflS
Volume Units: L
Time Units: IhT
\ fi Settings
©Units
!j Convert To Units
] !! Mass Units: Jmg
j ;! Volume Units: jl_
1 I! Time Units: JlT"
3.3.2 Save the Entered Data
5. Click on the "Save" icon (the diskette icon) below the "Main" menu, or select
"File," "Save" from the "Main" menu, or use key strokes "Ctrl+S."
When you save data, if any of the required fields do
not contain data, you will be prompted to enter data in
those fields. For example, if you did not enter a Model
Data Set name, you would see a message like the one
shown at right.
Please enter a model data set name.
OK
13
-------
File Edit Model Activity Chemical Chemical Compartments Enzymes Exposure 5p
' ffl A >'Q -f 00 ".' a 11 ?-• a? B • 3? - O II' i. t*
^Definition
'; JJ Settings
! 0 Units
When you have saved your
MDS definition, its name
appears at the top of the screen.
For example, if you named your
MDS "TESTING123", the
name "TESTING123" would
appear at the top of the screen.
In the example at right, note that
the "Print Final Results" and
"Active" fields are checked.
6. Perform one of the following
three functions to close the
"Definition of Model Data
Set" window: (1) click the red
and white "x" in the top right
corner of the window, or (2)
Select "File," "Close" from
the "Main" menu, or (3) if you prefer to use keystrokes, you can close the window
by pressing "Ctrl+F4".
7. If you have not saved the MDS definition, a box
will pop-up (as shown at right) giving you three
options to choose from: (1) Yes: To save changes,
(2) No: To not save changes, or (3) Cancel: Return
to the "Definition of Model Data Set" window.
Name |
Description This 15 a test
Species. '
Avg Age.!
Version i2Q2x
Log Path' (
Sub Species '
Sex: 'n/a _»', y Print Final Results
»' y Active
: Variable History Path: <
f \ Do you want to save changes?
No
Cancel
3.3.3 Open an Existing Model Data Set
If the desired MDS already exists in the system, you do not
need to re-create it; you need only to open it.
From the "File" Menu
1. Select "Open Model Data Set", as shown at right.
' ,,fYTC R^mJ-| rt_J.,, ,.(.., S~l-.J-.ri.:,!- -tl
Activity Chemical
New Model Data Set
Open User Database
Open SAMPLE Database
Exit
The "Open Model Data Set" window will appear, as shown
below. Existing MDSs are listed in the upper part of the window. A description of the
highlighted MDS appears in the lower part of the window.
2. Choose an MDS and click on the "Select" button.
14
-------
Model Data Set
HUMAN_BDCM_IMHSRI': SLKW_MCEa
I HUMAN_DCA_RIGSSKW_NCEA
j HUMAN_MAL_EZ_SKS
|HUMAN_MTBE_INH_CORLEY v
Description
Fisher version of the TCE model for a human female - one metabolite TCA, one activity
and Inhalation exposure.
Include Inactive Data Sets: j~
Close
Help
The selected MDS becomes the current MDS,
and its data will appear in subsequent windows,
as shown at right.
File Model Activity Chemical Chemical Compartments
,CH A; -Q € CD '" 'Oil- »•• s? 10 '. I
Note that the name of the current MDS appears
at the top of the screen. This MDS name will remain at the top of the screen until you
open a different MDS. It will be there as you open and work in the various ERDEM
windows, so that you will always know which MDS you are working in.
3.3.4 Copy/Delete Model Data Set
3.3.4.1 To Copy the Current MDS:
From the "Special Processes" Menu
1. Select "Copy/Delete Model Data Set," as shown below.
15
-------
File Model Activity Chemical Chemical Compartments Enzymes Exposure Reporting System Export Help
|Jj Data Set Process
—.,» System Variable Processing
• Special Variable Setting
j Plot Groups (Chem/Metab)
•' Plot Groups (Enzymes)
I Experimental Data
Delete Chemical/Metabolism Reaction/Enzyme
COPY CURRENT DATABASE
CONVERT DATABASE
RESTORE SAMPLE DATABASE
Run ACSL Viewer
Radio Label Groups
The "Copy/Delete Model Data Set" window appears, as shown below.
Note that the name of the current MDS appears in the upper part of the window.
COPYING/DELETING: FEMALE TCE INH
COPY PROCESS
; Hew
'; Copying Pi ocess
' | Loading Selected Model Data Set Records
i;; Copying Basic Model Data Set
I'! Copying Model Data Set Activities
| I Copying Model Data Set Subsystems
I I Copying Model Data Set Subsystem Activities
I » Copying Scaling Variables
j Copying System Variables
DELETE PROCESS
delete MwM Data Set:lFEMALE_TCE_INH
Complete
2. In the "New Model Data Set Name" field, enter a new MDS name. In the example
below, the new MDS name is "TESTING987".
16
-------
COPYING/DELETING: FEMALE TCE INH
COPY PROCESS
Hew Model O.ita Set Nam«:JTESTiNG987|
i Copying Process
Copying Mode! Data Set Plot Group
| Copying Special Variables
? Copying Model Data Set individual Plot
j Copying Model Data Set Plot Variable List
I Copying Radio Label Group
I Copying Radio Label Chemical Group
Copy Finaliiation
DELETE PROCESS r,,«,:,:,_;:,„:;;;
Data Set;«FEMALE_fcEJNH
Complete A
p-
NO RECORDS f~
NO RECORDS
NO RECORDS !""
Print
Delete Start
3. Click on the "Copy Start" button.
As each copy process is running, the word "Processing" appears to the right of the
process name. When a process is complete, a check mark appears in its "Complete"
box. When all the processes are complete, a message box, like the one shown below,
appears on top of the window informing you that the MDS was copied successfully.
COPYING/DELETING: FEMALEJTCEJNH
COPY PROCESS
lie* Model QafA Set ll.une:{TEsflNG987 '" " '" -.— -..--
! Copyln
I Copyinj
i Copyin<
; Copyini
• Copyinj
', Copyini
' Copyinj
i Copy Fi
The current Model Data Set (MDS) was copied Successfully!
The new MDS is called; 'TESTING987'
te
DELETE PROCESS
Delete Model O.it.i Set: JEMALEJTCEJNH
Delete Start J
4. Click on the "OK" button.
17
-------
The message box will disappear, revealing the "Copy/Delete Model Data Set" window,
as shown below. Boxes will be checked, indicating that copying processes are
complete.
COPYING/DELETING: FEMALE TCE INH
COPY PROCESS
Hew Data Set Name:: TBTTNG987]"
* Copying Process
} Copying Model Data Set Plot Group
| Copying Special Variables
j Copying Model Data Set individual Plot
} Copying Model Data Set Plot Variable List
j Copying Radio Label Group
I Copying Radio Label Chemical Group
\ Copy Penalization
DELETE PROCESS --„„„::.:-,__„„_—
S*t]FEMALE_TCE_INH
Complete
v
NO RECORDS
V
y
NO RECORDS
NO RECORDS
Delete Start ]
Print !
3.3.4.2 To Delete an MDS:
From the "Special Processes" Menu
1. Select "Copy/Delete Model Data Set," as shown below.
File Model Activity Chemical Chemical Compartments Enzymes Exposure
•H A :Q ! * CD ;1£ : 5 !;1 ! ^ sf W ' f " B M ! it
v,H Reporting System E-port Help
Daha 5et Process ,
System Variable Processing
Special Variable Setting
Plot Groups (Chem/Metab)
Plot Groups (Enzymes)
Experimental Data
Delete Chemical/Metabolism Reaction/Enzyme
COPY CURRENT DATABASE
CONVERT DATABASE
RESTORE SAMPLE DATABASE
Run ACSL Viewer
Radio Label Groups
The "Copy/Delete Model Data Set" window will appear, as shown below.
18
-------
2. Enter the name of the MDS to be deleted in the "Delete Model Data Set" field. (In
the example below, the MDS to be deleted is "TESTING987".)
3. Click on the "Delete Start" button.
COPYING/DELETING: FEMALE_TCE_INH
COPY PROCESS
Hew Set HainejiNTER'NES'TvlODEL'DAtA SETNAME HERB
! Copying Process
1 Loading Selected Model Data Set Records
f Copying Basic Model Data Set
I Copying Model Data Set Activities
j Copying Model Data Set Subsystems
j Copying Model Data Set Subsystem Activities
j Copying Scaling Variables
•i Copying System Variables
DELETE PROCESS
Belete Model Data Set:
Complete
f"~
r
!
„.,
A message will appear, asking "Do You Really Want to Delete Model Data Set
(MDS): 'TESTING987'?" (as shown below).
COPYING/DELETING: FEMALE_TCE_INH
COPY PROCESS
He* Model Data Set Hani*: ENTER NEW MODEL DATA SET NAME HERB
Co:
Co;
CO;
Co;
Co;
Co,
• / Do You Really Want to Delete Model Data Set (MDS): 'TESTIHG987'?
Yes
Copy Start
DELETE PROCESS
Delete Motlel D.n.i Set:;TESTING987
Delete Start ;
4. Click on the "Yes" button.
19
-------
When the deletion is complete, a message will appear, as shown below, informing you
that the deletion was successful.
COPYING/DELETING: FEMALE_TCE_INH
COPY PROCESS
i Copying Moc
i Copying Moc
i Copying Moc
5 Copying Sea
I Copying Sys
The deletion of the Model Data Set 'TESTING987'
was Successful!
DELETE PROCESS
Delete Model Data Set:!
5. Click on the "OK" button.
6. Close the "Copy/Delete Model Data Set" window.
3.3.5 Open User Database
When you start the "ERDEM" Front End, the application automatically connects to the
"SAMPLE DB" (Database), which is shown in the active title bar in the following
illustration.
File Model Activity Chemical Chemical Compartments Enzymes Exposure Special Processes Reporting System Export Help
: a * a # CD s 11; ffl' &? io, w :f o n a i-*
The SAMPLE Database contains carefully prepared and quality assured MDSs that can
be exported to produce consistent ERDEM Model run results. These MDSs may be used
as examples or templates for developing your own model
simulation. They may also be copied, edited, and renamed for your
own modeling purposes.
From the "File" menu
Model Activity Chemic
New Model Data Set
Open Model Data Set
Open SAMPLE Database
20
-------
1. Select "Open User Database," as shown at right.The "Select A User Database"
window appears, as shown below.
Look in- i,,.' ERDEM Te;l Database>
; Eugenia Silva Model. db ; J Human PBPK Copy III, db
,,') Eugenia Silva ModeljjP IGINALv 36. db ~' Human PBPK Model. db
_'; Eugenia Silva Model_OP.IGINALv40.db
,(Human PBPt. Copy Il_ORKINALv36,db
.; ; Human PBPt Copy II_OPKINALv40,db
Filename: | H urnan PB PK C opy 11 db
Files otijipe. j D atabase File: f db I
Cancel i
This window allows you to browse to the folder containing the desired user database.
2. Choose a database and click on the "Open" button.
The "Open Database Status" window will appear, as shown below.
Selected Database
Hum,™ PBPK Copy II
When the connection is made, the selected database name appears in the active title bar
at the top of the screen, as shown below.
I File Model Activity Chemical Chemical Compartments Enzymes Exposure Special Processes Reporting System Export Help
3.3.6 Open SAMPLE Database
From the "File" Menu
1. Select "Open SAMPLE Database".
Note: When an MDS is selected and an ERDEM window is open, the "Open User
Database" and the "Open SAMPLE Database" menu options are not available.
21
-------
In the following example, the MDS is "FEMALE_TCE_INH," and the "Definition of
Model Data Set" window is open. Note that on the "File" menu, the "Open User
Database" and "Open SAMPLE Database" options are not available. Note also that
"Exit" is not available.
IS Edit Model Activity Chemical Chemical Compartments Enzymes Exposure Special Processes Reporting System
New Model Data Set j5| K; gjl JQ ! f ^ H] Jfl : §, i §*
Open Model Data Set ! " ' " "
Close f
Delete Model Data Set Ctrl+D
Save Ctrl+S
f!fp Definition
i SP Settings
1 0 Units
Description: psher version of the TCE model tor a human female - one
metabolite TCA, one activity and Inhalation exposure.
i
Species: JHUMAN~"~ Sub Species: JFEMALE
AvgAge:f 30 Sex: !F ;»j P Print Final Results
Version: 12.02S _jj jV Active
Log Path: i5riRDM202siR Variable History Path: EiRDM202s'iR
Note:To guard against accidental deletion of a model data set, the "Delete Model Data
Set" option is not available when a window other than the Definition of Model
Data Set window is open, as shown below.
Edit Model Activity Chemical Chemical Compartments Enzymes Exposure Special Processes Reporting System Expo
New Model Data Set jfl ;?,? rf
Open Model Data Set 'r
Close f
Save Ctrl+S f**»-'- • - , •
Total Metabolites: II
Metabofte i Metab. j Metabolism j Metabolism I Inhibitor j
Short Name _! Ref, He. i ^ ^ Description • ^ Type . L. , , i
22
-------
3.3.7 Special Processes - Copy Current Database
From the "Special Processes" Menu
1. Select "COPY CURRENT DATABASE," as shown below.
File Model Activity Chemical Chemical Compartments Enzymes Exposure !
[ Reporting System Export Help
i • a. # CDS &
" 6 Bfl-i> Data Set Process
™;»i™™™™™»™™;»i;™™™;;™™»^ System Variable Processing
; Special Variable Setting
™ ^ | Plot Groups (Chem/Metab)
-*. . - i Plot Groups (Enzymes)
,*, „ ™ i Experimental Data
Copy/Delete Model Data Set
Delete Chemical/Metabolsm Reaction/Enzyme
CONVERT DATABASE
RESTORE SAMPLE DATABASE
Run ACSL Viewer
Radio Label Groups
Note: The choices "CONVERT DATABASE" and "RESTORE SAMPLE
DATABASE" are not available if a database other than the "SAMPLE DB" is
open.
Save in ' .. • ERDEM Test Databa;e:
i' } Eugenia Silva Model,db
y Eugenia Silva Model_OPIGINALv36,db
, _' Eugenia Silva Model_ORIGINALv4Q,db
• . Human PBPI- Copy IIjjP ISINALv 36. db
\ Human PBPK Copy II_OPIGINALv40,db
, '_! Human PBPt Copy III,db
H*
"iHumanPBPI Model. db
The "Select File Name for Copy of
Current Database" window opens, as
shown at right.
2. Browse to the desired folder for the
"Save in" field.
3. Enter the desired File name.
4. To save a copy of the current
database, click on the "Save" button.
The following message will appear, informing you that the copy process has been
completed.
Filename
Save a: type "Databaie File: I'dbl
Save
Cancel
23
-------
COPIED: Human PBPK Copy II ->
; iHuman PBPK Copy IV"
* >/U-: 'i»'f'.Vj-SRJLl VCUPIH
sj.wi i o >viir
-------
You are attempting to open a User Database that does not match the current ERDEM system version. If you choose
not to convert at this time your User Database request will be cancelled and the connection to the SAMPLE Database
will be restored
Do you want to go now to the ERDEM Database Conversion Utility?
2. If you click on the "Yes" button, the "ERDEM Database CONVERSION V.4.1
Utility" window will appear, as shown below.
SELECTED DATABASE RECORD STATUS , SELECTED DATABASE STATUS
Rows Read , Rows Written Rows in Error \ Db Name Dl> Connections
Jione
none
CONVERSION STATUS --- -
Table Processing Status
"ERDEM Database CONVERSION' V.4.1': User Database —> none
!Date Stamp' 09/29/2005 - 12:28:47
Select a Database for Conversion
Click Button Below To 'Select User DB for Conversion"
right 'X' button will utility)
Select User DB for Conversion i
3. From here, proceed as in Method Two, below, beginning with the "ERDEM
Database CONVERSION V.4.1 Utility" window.
25
-------
3.3.8.2 Method Two
The second method for converting a database is in the "Special Processes" menu, which
gives you access to the ERDEM Database Conversion Utility.
From the "Special Processes" Menu
1. Select "CONVERT DATABASE," as shown below.
File Mode! Activity Chemical Chemical Compartments Ensymes Exposure j
I Reporting System Export Help
System Variable Processing
Special Variable Setting
Plot Groups (Chem/Metab)
Plot Groups (Enzymes)
Experimental Data
Copy/Delete Model Data Set
Delete Chemical/Metabolism Reaction/Ensyme
COPY CURRENT DATABASE
RESTORE SAMPLE DATABASE
Run ACSL Viewer
Radio Label Groups
The "ERDEM Database CONVERSION V.4.1 Utility" window will appear, as shown
below.
SELECTED DATABASE RECORD STATUS SELECTED DATABASE STATUS
RowfsReael ftowsWfritten Rows in Error - niilliime Db Connections
CONVERSION STATUS
Table Processing Status
; ERDEM Database CONVERSION V.4.1 : User Database — > none
JDate Stamp: 09/29/2005 - 12:28:47
Selec
f@f €
Click Button Below To 'Select User DB for Conversion'
(top right "X" button will close utility)
2. Click on the "Select User DB for Conversion" button.
26
-------
The "Select File" window will appear over the "ERDEM Database CONVERSION
V.4.1 Utility" window.
SulN "" * JL J "• " ti f ' ^ ' *
^&t
,ii£
Loot in ji .1 ERDEM Test Database: »
1 ,'<} Eugenia Silva Model. db
i ' ; t Eugenia Silva Model_OP I>
""*•"" 'iffisii
a a H*
j Human PBPk Copy III, db
;il\IALv36,db
> • ' Euqenia 5ilva Model OPIGINALv4G,db
; ;; Human PBPt Copy II, db
'.1 Human PBPk Copy IV. db
"iHunianPRPl Mnrlpl.rih
_ J-, Human PBP^ Copy II_ORIGINALv36,db
'' i Human PBW Copy I!_ORIGINALv40.db
% )•
File name ,
File: of type ( Database Files \" dbl »;
i
,. 1 . :
Open j
Cancel ,
i*» y"j^ ". *; ..t/.y^''!, .t
Db Conneetions '
none
* .
3. Select a file and click on the "Open" button.
ERDEM determines the version of the database to be converted and retains a copy of
the database in that version. The new database will have the same name as the original.
The backup of the original database will be saved with the naming convention
"Userdbname_ORIGINALv36.db," where "ORIGINALv36" denotes the version (3.6)
of the original database. An additional backup with the naming convention
"Userdbname_ORIGINALv40.db" will also be saved. The previous illustration shows
such files.
Note:If any errors are encountered during the conversion process, all database
conversion changes are returned to their original state, so that no data is lost.
While ERDEM is performing these and other preparatory actions, a series of messages
will appear in the "ERDEM Database CONVERSION V.4.1 Utility" window
informing you as each is processing. When the "READY, Press START
CONVERSION Button Below!" message appears in the "ERDEM Database
CONVERSION V.4.1 Utility" window, as shown below, the actual conversion can be
started.
27
-------
, SELECTED DATABASE RECORD STATUS SELECTED DATABASE STATUS
Rows Read Rows Written Rows in Error Db Name . Db Connections
tame' \ hone' " jrione"" : . ^hJman'PBPKCopy ESTABUSHED!'
CONVERSIOH STATUS - -- -
Table Processing Status
JERDEM'DatabVse CONVERSION V.4 1: User'batabase--"-> HumanIPBPK Copy'li
. Date Stamp: 09/29/2005 -12'40:07
Database Conversion notices
{top right "X" button will close utility)
Start Conversion |
4. Click on the "Start Conversion" button (located in the lower right corner of the
window).
The processing information will appear in the "Table Processing Status" window, as
shown below.
SELECTED DATABASE RECORD STATUS SELECTED DATABASE STATUS
Rows Read Rows Written Rows In Error Db Name Db Connections
iW " Wo"" .»"'*' fturrian PBPK Com ESTABLISHED!
CONVERSION STATUS
; Table Processing Status
;ERDEM~Dal:abaseC DIVERSION V4.T UsaA5alabase ---^Human PBPKConv II *
' Date Sjamp 09/29/2pp5_- 1243-19
'{CHEMICAL ji I AT A j01204--> COMPLETED .................... tf
i)ATA_SETjCHEMICALipS0404^> COMPLETED ' ..... ' " "' W1
.SEflMETABOUTE Jl504oV-> COMPLETED* """" ................................... V
.
%ATAlsEf_SUBS¥STEM_cifEMicAllosO«t4--> COMPLETED
Database Conversion Notice
Databoce- CONVCR5IOH STARTED: V.3,t~ to V.4,0
When the conversion is almost done, a "PART 1: Database CONVERSION
Finalization from V.3.6 to V.4.0" pop-up box will appear (see below). Note that if the
original database was in version 3.6, the fmalization is in two parts: from V.3.6 to
V.4.0, and then from V. 4.0 to V.4.1.
28
-------
Note: If the original database was in version 4.0, the conversion will be completed in a
single step.
SELECTED DATABASE RECORD STATUS SELECTED DATABASE STATUS
Rows Read Rows Written , Rows in Error Dblkune Db Connections
to *""* JD , . «"" 'HuniaTip'BPKCow' ' (ESTABLISHED!
CONVERSION.SIAT1
ACTUAI
'JCOMMI
'PLEAS!
1, Finalise the database CONVERSION Ftorn ¥, 3,6 to V.4,0,
:, Continue to PART 2, database CONVERSION ftom V.4.0 to V.4.1
5. Click on the "OK" button.
If you started with a V.3.6 database, the "Database Conversion Notices" portion of the
window (see below) would indicate that the conversion from V.4.0 to V.4.1 has
started.
SELECTED DATABASE RECORD STATUS SELECTED DATABASE STATUS
' Rows Read , Row® Written Rows in Error Ob Name Ob Connection®
Jj " ' !j " ' " »"' ' ' jlumanPBPKCo|»y" ESTABLISHED!
CONVERSION STATUS
' Table Processing Status
, (ERDEMDalabaVe'cOIWERSIONvVl Use'r'batabase -j Human>BPK Copvll' A
. 'Date Sta_mp 09/29/2005-, 12 48 08,
' ...............
.fcHEMICAL_DATAJ»21805- > COMPLETED
.PATA_GRQUPJ>2180S-"> COMPLETED - • •-
ICLASS js«i)5--« COMPLETED
Database Conwersioit Notices
D \TAE'ACE COlJVGRilC-M STATED: -'.4.010 V.4.1
29
-------
A "Part 2: Database CONVERSION V.4.0 to V.4.1 Finalization" pop-up window will
appear, as shown below.
SELECTED DATABASE RECORD STATUS « SELECTED DATABASE STATUS
Rows fead RJOKSIS Written Rows in Error -BbNams - , Dri Connections >
» * » « " " " Human PBPK Copy "' ESTABLISHED!
COHWERSIOH STATUS
;AC
SCO
"*€
Please did. 'OK' to finalce PART 2 OF 2, database CONVERSION From V.4,0 to V,4,1
TMHBSseCorWerliofiHllices
6. Click on the "OK" button.
A "Database CONVERSION COMPLETED!" pop-up window will appear.
SELECTED DATABASE RECORD STATUS SELECTED DATABASE STATUS
COHVEf
• IERC
Bate
HE*
' 1
I i The database CONVERSION COMPLETED SUCCESSFULLY for :
X 1, Database CONVERSION V, 3, 6 to V.4,0
2. Database CONVERSION V.4.0 to V.4.1
Back-up copies of V.3,6 and V.4.0 of yout databases
(ex. UserdbnamejConvertedv,4.Q) have been created in their home location.
After clicking OK, you will have the option to;
1, CLICK the HDS NOTES button for a report of IMPORTANT conversion effects
on your Model Data Sets (MDS)I
2. CLICK the Print button for a report of the current conversion process,
OK |
&sm
A
V,
A
i i * '
7. Click on the "OK" button.
30
-------
Note that the "MDS NOTES" button and the "Print" button in the lower left corner of
the window are now active, as shown below.
SELECTED DATABASE RECORD STATUS - SELECTED DATABASE STATUS
Row® Read Rows bitten - Row&s in Err@r Db Name - Dfo Connections
' JD , » to Jkiman PBPK Cony , ESTABLISHED!
CONVERSION STATUS
; Table Processing Status
:ERDEM DatabaseVoNVERSION V4 1 ' User Database ---> Human" PBPh CODY if
'pate Stamp. Oara/p6:12 54-52
! ^CTU«L_DATA_V/ii.UESJi!1J«S--:> COMPLETED * '" V
JCOMilENVREFERENCE jJ21M5--> COMPLETED' IV
'PLEASE WAIT... PART Z OF 2: STARTING FIHAL DATABASE UPDATES! ;«/
VART 2*oF2:VlHAL"cOH VERSION UPDATES COMPLETE!""" " ~ V
Seteet a PMaisise fw Coiwersron
Click Below To 'Select User DB for Conversion'
(top right 'X' will close utility)
Select User DB for Coiwersien
8. To obtain a printout of the items in the "Table Processing Status" list, as shown
above, click on the "Print" button.
The "MDS NOTES" are comments regarding the important conversion effects on your
Model Data Sets.
9. To see the "MDS NOTES," click on the "MDS NOTES" button. The notes
information will appear in a Notepad window, as shown below.
File Edit Format View Help
[INTRODUCTION:
The new EPDEM Database version 4.1 conversion utility allows users to •:
a starting EPDEM database v.?,6 or database v.4.u.
The following describes the new conversion process in that order:
changes made to the database model data sets after conversion from an
EPDEM 3.6 database to an EROEM 4.0 database.
1] in the Model Data Set Definition screen, the ERDEM version field wa
to reflect the proper new EPDEM version number. Model Data sets were a
to the new version number which most closely matches the parameters of
version. Thus, versions previously assigned to version 2.01 were conve
to 2.021' and versions previously assigned to version 2.02 were converte
2] For model data sets involving dermal exposures, the user should revi
the Model Data set exposure route in the converted database. The new E
version v. 4.0 provides for three types of dermal exposure; Dry surface,
water and vapor. The previous version, ERDEM v. 3.6, provided for only
dermal exposure type (skin surface water), on the Data set Exposure sc
screen, the converted v.4.0 database has no default exposure type.
The user will have to revise the screen to indicate the proper exposure
31
-------
3.4 Maintaining Data Integrity: The ERDEM Data Entry Pipeline
In the EDREM data entry pipeline, before any data can be added or changed, it must pass
through each pipeline segment's data validation check. This check proceeds from left to
right across the "Main" menu.
Whenever you open a window, the pipeline will
validate that the window being requested is part of
the next segment in the pipeline and that no data
integrity rules have been violated. For example,
look at the "Chemical" menu (shown at right), with
the "Model Data Set Metabolites" option selected.
File Model Activity Chemical Compartments
Model Data Set Chemicals J
-St T
You have not entered any Chemical data,
Please enter data via;
1, Data Set Chemical (Chemical menu) window
This will not affect further processing and the requested window will be closed,
If you attempt to enter metabolite
data before entering chemical data,
you will receive a message
reminding you to enter chemical
data before entering metabolite
data. The message also indicates the
menu on which you will find the
appropriate window, as shown at
right.
3.4.1 The Pipeline Report
You can easily check the status of the data entry pipeline for the current MDS:
From the "Main" Menu
1. Select "Reporting".
The "Reporting" drop-down menu will appear, as shown below.
File Model Activity Chemical Chemical Compartments Enzymes Exposure Special Processes System Export Help
I i «Q i 3? CO *? ! <5 1*1 : ?;\ iJ 10 '< & SS Hi B-fl ' Hi- : i-* 1 ': Structure Report
'—'- -;.„-.-—-;.».. -..„,.»»,»,„„,„.,_„.„„,.,-.^,£,-i::.::^:,,.:£Si..,._..,:£..::.a^a^lls_s^^^.'^^, ,i ,„..,.,;-,„„.,; Value Report
" " .. • - • .. . ^ Citation Report
2. Select "Structure Report".
The ERDEM "Structure Report" screen for the current MDS (TESTING123) will
appear.
32
-------
Because this MDS is incomplete, the report will not show information in the parts of
the MDS that require data entry, as shown on the next page.
ERDEM Structure Report
Model Data Set: TESTING123
Run Date: 15:09
ERDEM Version: 2.02X
General Chemical Comments:
None
General Exposure Comments:
None
No Compartments Have Binding
There Is No Binding In The Bleed
There Are No Radio Labels
A completed MDS (for example "FEMALE_TCE_INH," as shown below), will
contain data in the "ERDEM Structure Report".
Print
Clone
ERDEM Structure Report
Model Data Set: FEMALE_TCE_INH
Run Date: 95910515:11
ERDEM Version: 2.02S
Chemistry For This Simulation
Cham (Short) Chemical Hong)
TCE trichloroethylene
TCA trichloroacetic acid
General Chemical Comments:
None
Metabolites For Each Chemical
Parent Chemical Metabolite
TCE TCA
Metabolite Comments By Parent Chemical
Parent Chemical Comment
TCE None
Type Of
ietabolism
Salurable Michaelis-Menten
33
-------
3.5 Editing the Data: Adding, Deleting, Saving
ERDEM data consists of records stored in ERDEM database tables organized primarily
according to unique model data sets (MDSs). New data is referred to as data lines or data
records. This section covers adding and deleting data lines/records, and saving newly
entered data.
Note:In some ERDEM windows, data lines/records cannot be added, inserted, or deleted.
This is because these data lines/records are being used for reference purposes only.
From the "Main" Menu
1. Select "Model".
The "Model" menu will appear, as shown at right.
2. Select "Model Data Set Scaling".
Chemical Cher
[g Model Data Set Definition
K \ f ;: IB m', t>; i*;
Reference Body Volume:'
1 L
Scaling Type
i Scaling j User I User j Default j
I Scaling ftagj Scaling Value j Value ]
~
3.5.1 Change An Entry
1. Click on the down arrow under "Scaling type"; a drop-down list will appear, as
shown on the following page.
34
-------
Reference Body Volume:
1 L
Scaling Type
{Maximum Velocity of Metabolism
} Scaling ; User User j Default <
j Type Flag • Scaling Flag Scaling Value Value .'
'•*•' !'"' " " "" f 0.70
Maximum Amount of Binding
Pate Constant tor Elimination
Rate Constant for Metabolism
Breathing Frequency
Maximum Velocity of Elimination
Permeation Coefficient for the Skin Surface Water
3.5.2 Insert, Add, or Delete a Row
To insert, add, or delete a row:
1. Right-click anywhere in the gray area of the window.
A "Model Data Set Scaling" window will appear, providing options to Insert, Add, or
Delete, as shown below.
Reference Body Volume: j
1 L
Scaling Type
| Scaling i User ] User i Default j
i Type Flag i Scaling Flag j Scaling Value | Value j
PT"~~""" f"~"" "" j~~ " 0.70
Insert
Add
Delete
Note that other functions on the pop-up menu (Cut, Copy, Paste, Select All) are grayed
out. These functions are not available on the "Model Data Set Scaling" window.
35
-------
3.5.2. •/ To Insert a Row
1. Select the "Insert" option from the pop-up menu.
The newly inserted row will appear above the previous row, as shown below.
Reference Body Volume: i 1 L
Scaling Type ' Scaling , User : User ', Default<
', Type Flag < Scaling Flag j Scaling Value j Value
i Velocity of Metabolism |]V i. ' ! 0 70
3.5.2.2 To Add a Row
1. Select the "Add" option from the pop-up menu.
The added row will appear below the previously existing rows, as shown below
Reference Body Volume: i 1 L
Scaling Type • Scaling | User | User < Default',
" ! Type Flap Scaling Flag > Scaling Value ' Value
t/la/imum Velocity of Metabolism jlv1 j, i 0.70
3.5.2.3 To Delete a Row
1. Before deleting the row, confirm that the row to be deleted is active and/or
highlighted.
2. Select "Delete" from the pop-up menu.
The row should now be deleted, as shown below.
36
-------
Scaling Type
s Bodjf Volume:; 1 L
' Scaling ', User
User |Default-
j Type Flag' Scaling Flag ( Scaling Value ! Value t,
o.?o
3.5.3 Saving Changes
Changes you have made are not permanent until you save them.
You can save your changes in one of three ways: (1) Click on the Save icon (the diskette
below the "Main" menu), or (2) Select "File," "Save" from the "Main" menu, or (3) Use
keystrokes "Ctrl+S".
The Save action applies only to the active window (the window with the bright colored
title bar). It does not apply to any windows whose title bars are "ghosted."
As an example, in the illustration below, "Lung Activity" is the inactive window and
"Compartment Blood Flow" is the active window.
lie Edit Model Activity Chemical Chemical Compartments Ercymes Exposure Special Processes Reporting System Export F
H Jl Q ' 5? CD ??. 6 n's-, sp io : f :: ft Bfl a f*'
* a t* ^>,
Compartment Name * Subsystem Model:-Main
CARCASS
IFAT
iKIDNEY
'LIVER
JOV ARIES
IRAPIOLY PERFUSED TISSUE
•SLOWLY PERFUSED TISSUE
• Blood Flow Entry - -
' Blood Flow Ptt ;|" " ';
Blood Floss Percentage Total = 109.0(1%
Blood Flow Pet. (Max = «(Bi). Totals are CaMated for
As^l¥® Sub^retem® mil Csw
.. ,c
3.6 Required Fields and Unavailable Fields
3.6.1 Required Fields
37
-------
! Jp Settings
'ABC
Species )
Avg Age: ;
Vetiion '202S
Log Path: if 1EFDM
Please enter a model data set description,
Required fields are fields that must
contain data in order for a record to
be saved. Required data entry fields
have blue field names. If you attempt
to save a window before completing
all the required fields, you will be
prompted to fill in the required
field(s), and you will be directed to
the appropriate field(s). For example,
if you are trying to save a "Definition
of Model Data Set" window without
entering a description, you will be
prompted to fill in the model data set "Description" field, as shown at right.
3.6.2 Unavailable Fields
I ©Units
OK
Some data line/record fields are not available, depending on the type of data being
entered on the window. When a field is unavailable, the field background color will be
gray and the field will not be active for data entry.
For example, the "Model Data Set Metabolites" window (available from the "Chemical"
submenu) may, upon opening, show the "Inhibitor" field unavailable, as shown below.
f^f^^^^HHHS^^^^^^^^S^^^^f^^^^^^^^^^P
Parent Chemical:
i Metab. J
flame ! Ref. No. !
'
Total Metabolites; 8
i Inhibitor }
Metabolism I Metabolism
Description -i Type J \
j Linear-Rate Prop. To Parent Chem. ,fj].':- :".'.•'/..•.,'-' .J.j
However, if the "Metabolism Type" is changed, the "Inhibitor" field becomes active and
data may be entered in it, as shown below.
38
-------
Parent Chemical; TCA
WtetatwJfte ! Metali. j
Short Name ' Ref.Ho. j
Metabolism
Description
Metabolism
Type
fetal Metabolites; J
1 Inhibitor (
TCA
3.7 Maintaining Productivity: ERDEM Window Features and Shortcuts
The ERDEM Front End has features that can increase your productivity. It allows you to:
• Use non-filtering and filtering dropdowns to view and edit complex chemical data
• Use reference data lists to display and sometimes filter data lines/records
• Track and switch between multiple MDSs
• Get context help for data line/record field definitions
This section will discuss non-filtering and filtering dropdowns. It will also discuss
reference data lists. Subsequent sections will discuss switching between MDSs and
getting context help.
3.7.1 Non-Filtering Dropdowns
ERDEM uses dropdowns to provide lists of selectable data or to filter data lines/records
in a window. The following is an idea of how these work:
From the "Main" menu:
1. Select "Chemical", then "Model Data Set Chemicals."
The "Model Data Set Chemicals" window will appear, as
shown at right.
Chemical ' Exposure j
Short Name ' Chemical flag]
Total Chemicals: 2
39
-------
2. Right-click in the gray area of the window to reveal the pop-up editing menu, as
shown below in "Illustration 1."
3. Click on the "Add" option.
A new row appears, as shown below in "Illustration 2."
4. Click on the down arrow in the new row (or click anywhere in the new row).
A dropdown list showing available chemicals will appear, as shown below in
"Illustrations."
5. Select a chemical to enter into the field.
Totii
Add
Delete
ESJJOSUI «
Short Hame
iTCA " i
Totnl Chemicala: 2
Shuit Hanie \ Ch«nlcal Flap;
Illustration 1
Illustration 2
AP1
AP2
BDCM
CARS
CB4OH
:B40H'?
CB4OHS
CBSijHC-
CB5OHS
4l Chemicals: 2
Illustration 3
3.7.2 Filtering Dropdowns
Certain ERDEM dropdowns serve to filter the data lines/records. As more and more data
is entered along the data entry pipeline, it becomes more and more difficult to view the
increasing amounts of data. To alleviate this problem, filtering dropdowns are used to
limit the amount of data on the screen at any one time so that you can edit it more easily.
The following steps show how filtering dropdowns work:
From the "Main" menu:
1. Select "Chemical," and then"Model Data Set Metabolites."
The "Model Data Set Metabolites" window will appear, as shown below.
40
-------
Parent Chemical:'43
' j
Metabolite , Metab. 1 Metabolism
Short flame ' Ref, No, j Description
API y_.'' 342 Satutable
f;fp ;• >~' 343"'' stable
fatal MetiboBes; 2
Inhibitor I
, Saturable Michaeta-Menten
1 Satutable Michaelre-Menten
In the example above, the "Parent Chemical" at the top of the window is set to CPFO.
The data lines/records displayed are for the metabolites "AP2" and "TCP." These
metabolites were entered previously when the filtering dropdown was set to "CPFO".
If you reset the filtering dropdown to "PAR," the related metabolites entered
previously for "PAR" will appear, as shown below.
•JwjJS.
Parent Chemieal: i jLi
Metabolite ! Metab. i Metabolism
Stwrt feme i Ref. Ho. ' Description
Total Metaboiites: 3
Inhibitor j
Type
ipOKON
TOP
'API
j"!i 333 isaturable
•r]' 334 "saturable
V||" 335™" SaluraEie™'
I Saturable Michaelis-Menten
I Saturable Michaelis-Menten
1 Saturable Michaelts-Menten
41
-------
If you reset the filtering dropdown to "API", no related metabolites will appear
because none have been entered previously, as shown below.
; { Mei,ih. I Metabolism
; Stwrt flame ] Ref. Mo. | Description
P^^^P^^P^^^.^-^
Metabolism
Total Metabolites: 0
\ Inhibitor
SSSH8 S | IIIIHIJIlUi
\
j«'«»f.5*;*.ii»»M«^^
VI if '."""''. '•• ..' ', T 1
To view the metabolites that have been entered for any parent chemical:
1. Click on the "Parent Chemical" field down arrow (or click in the field) to display
the dropdown list, as shown below.
2. With the dropdown list displayed, use the up and down arrow keys to highlight a
selection.
The window display will change to show the related metabolite rows.
Metabolite ! Metab. ; Metabolism
Short Haran \ Ref, Ho. Description
AP2
CPF
CPFO
PAR
PNP
PNPO
POXCiN
TCP
TCPG
altoltein
Inhibitor
3.7.3 Filtering Dropdowns and Reference Data Lists
Filtering dropdowns can be used in conjunction with reference data lists to filter
extremely complex sets of data lines/records.
To see how this feature works, do the following steps ~ starting from the "Main" menu:
42
-------
1. Select "Chemical Compartments."
2. Select "Data Set Chemicals in Compartment."
The "Data Set Chemicals in Compartment" window will appear, as shown below.
; Chernic.il:;
Active Compartments
Subsystem Model: Main - Group Name: BIND
Compartment Chemical Data Entry
ARTERIAL BLOOD
BRAIN
CARCASS
FAT
m
LIVER
OVARIES
RAPIDLY PERFUSED TISSUE
SLOWLY PERFUSED TISSUE
SPLEEN
VENOUS BLOOD
(CURRENT CHEMICAL:|rCA~
JCHYLGM_FLW_R_CON: p
:JBILE_DUO_PART_COEF: I":
JNON_LIP_FLW_R_CON: f?
]|NIT_AMT: I?
JCOMP_ACT_CH_FLG: |X
i ,—
MAX_HND_CAP: |
BIND CHEM FLAG: L
J
1JH PART_COEF_BLD:
'. PART_COEF_AIR: f
' 1/H LIP_FLW_R_CON: !>
mg INIT.CONC: !
mgfl.
DIS EQ BD CON: i
*: 1/H
mg/L
mgil
The portion of the window called "Active Compartments" contain an example of a
Data List. Data lists, which are used only for reference information or for filtering
purposes, cannot be edited. Data lists will be considered in more detail presently.
In the example above, "TCA" is the chemical selected in the "Chemical" field, and
"KIDNEY" is selected in the "Active Compartments" section. For these selections, the
tissue to venous blood kidney partition coefficient ("PART_COEF_BLD") field value
is 0.66000003.
If a different chemical (e.g., "TCE") is selected in the "Chemical field" and
"KIDNEY" is selected in the "Active Compartments" section, the value in the
"PART_COEF_BLD" field will change accordingly, as shown below.
43
-------
Compartments
Subsystem Model:JMain -r^ Group Name:
Compartment Chemical Data Entry
iBIND
ARTERIAL BLOOD
BRAIN
CARCASS
FAT
LIVER
OVARIES
RAPIDLY PERFUSED TISSUE
SLOWLY PERFUSED TISSUE
SPLEEN
VENOUS BLOOD
iCURRENT CHEMICAL: [TCE
|CHYLOM_FLW_R_CON: F
I BILE_DUO_P ART_COEF: f"'
JNON LIP_FLW R_CON: f"
I |
I |INIT_AMT: j.
!COMP_ACT_CH_FLG: {x
tMAX_BIND_CAP:
BIND CHEM FLAG:
J
' 1/H
PART_COEF_BLD: ff "S"
PART_CQEF_AIR: f^T'"
LIP_FLW_R_CON: f" ™
INIT_CONC: I"""""
US EQ BD CON: f""~
mg/L
mg^L
If you select a different "Subsystem Model," the information in the "Active
Compartments" and "Compartment Chemical Data Entry" portions of the window
changes, as shown below.
Chemical:| TCE _T,j
Active Compartments
Subsystem Model:;
CURRENT CHEMICALffCE
CHYLOM_FLW_R_CON: j '
BILEJXIO _PART_COEF: r
NON_LIP_FLW_R_CON: f;
INIT_AMT:
COMP_ACT_CH_FLO:
Skin Permeation
Main
Stgftic lung
Stomaehflntestine
rng
Group Name:)
il Data Entry
_COEF_BLD: ft .38
PARTjCOEFJkIR: -
LIP_FLW_R_CON: 1
INIT CONC: f
3.7.4 Reference Data Lists
Data lists contain static, non-editable reference information used to display, and
sometimes filter, data lines/records.
In the "Data Set Chemicals in Compartment" window (accessed from the "Chemical
Compartments" submenu), click on an item in the "Active Compartments" list. Notice
that the item name appears in reverse video, with an open area extending to the right of
the area of reverse video, as shown below.
44
-------
Chemical;; TC A ^j
Active Compartment®
Subsystem Model: Main
Group Name: BIND
Compartment Chemical Data Entry
BRAIN
CARCASS
FAT
KIDNEY
LIVER
OVARIES
RAPIDLY PERFUSED TISSUE
SLOWLY PERFUSED TISSUE
SPLEEN
VENOUS BLOOD
; CURRENT CHEMICAL |TCA~
! JCHYLOM_FLW_R_CON: ! * '
|BILE_DUO_PART_COER j '
JNQN_LIP_FLW_R_CON. f"
i|NIT_AIVlT: j'~
!cOMP_ACT_CH_FLG: 6
-------
For example, you might have five windows open at one time. The current window is the
one on top - with the brighter colored title bar - as shown below.
File Edit Model Activity Chemical Chemical Compartments Enzymes Exposure Special Pr ocesses Reporting System E>
ffl ^ Q ^ CO * £> It ffl -' iP B f? -<:: d Ifl BI, , W-*.
' par y JB-* Q ,
Total Clieniitdis: 2
Pet, = 100%). Totals are CaluLitetl to
i and C^
3.8.1 To Switch to Another MDS
From the "Main" Menu
1. Select "File," then "Open Model Data Set".
The "Open Model Data Set" window will appear on top of the other windows, as shown
below.
46
-------
CNemic.it
Shnrtltome . Cltennral Flag
1 J . HUMAN_BDCM JNHSRIGaSKW_NCEA
i HUMAN_DCA_RIGSSKW'_NCEA
i HUMAN_MAL_EZ_SKS
1 HUMAN_MTBEJNH_CORLEY
Knaak version of the PAR model for human children - with Inhalation, Rate Ingestion
5 and Skin Surf ace Water exposures.
Select | Close ! Help
Inducfe Inactive Data Sets: T"
2. Choose the desired MDS, and then click on the
"Select" button.
The back window closes and the new MDS
information opens in the window that was active, as
shown at right.
File Edit Model Activity Chemical Chemical Compart
i B A ''Q sf DD ~- SIS ^ s? K •
•fg B i-* Q .
Slwrt Hame i Ciiemieal
Total Clieroicals: 1
47
-------
3.9 Using Context Help
On some windows, because of space limitations, data line/record fields must be
abbreviated. The context-related help feature allows you to quickly see the definition for a
particular field you may not be familiar with.
From the "Main" Menu
1. Select "Help," and then "Context Help."
A check mark will appear next to "Context Help" on the "Help" menu, as shown
below.
File Model Activity Chemical Chemical Compartments Enzymes Exposure Special Processes Reporting System Export
iiffl A la 2? CD ""'"''" ; £> ti ; f'; y B : I? ** d 11 • B> i fll* i • He|PT°Pics F1
About
When "Context Help" has been selected, a "Context Help" window will appear at the
bottom of the screen, as shown below. The "Context Help" window displays
information for whatever data entry field you place the mouse pointer over. In this
example, the mouse pointer has been placed over the data entry field for
"DIS_EQ_BD_CON," and an explanation of that field appears. If no help is available
for a particular field, the message will read "Help is not available for this field or no
field has been selected."
48
-------
File Edit Model Activity Chemical Chemical Compartments Enzymes Exposure Special Processes Reporting System Export Refresh Window
= • jfc 'Q ; * CD 9 • c- FI' 5;: sP B : W :s IB Bfl i •,, i i^ i
M'SLS^L r,,»,,™_.-».l»,'-,_ _..-l_'....
____________
ChemicahfTCA t^| Sutasysteni Rflodel:fMain ^J Group NamerjEiiSb
Aetiwe Comisartment® C0m|sartrnent Chemical Data Entry
fcURRENT CHEMICAL:[TCA ' |
IcHYLOM_FLVV_RjCON: jT"*""; -j-^- ^ ^ PART_COEF_BLD: j--'-~~-j7-~7
, JBILE_DUO_PARTjCOEF: { " ~ -,-: PART_COEF_AIR: j'"';* " ~~v!7
]FAT JNON_LIP_FLW_R_CON: f *' """-y 1/H LIP_FLW_R_CON: p"""~--->-—-i- 1(H
KIDNEY JlMTJMVtT: \'f~:j*~'?~i~J'f'~ m3 IWIT_CONC: fTSf,'"'"*'™^ mg/l
LlvER JCOMP_ACT_CH_FLO: S
'OVARIES I
JRAPIDLY PERFUSED TISSUE JMAX_BIND__CAP: I mgIL DIS_EQ__BD_COM: i mg/
ISLCWLY PERFUSED TISSUE |BIND_CHEM_FLAO: £~)
SPLEEN |
j VENOUS BLOOD S
The dissociation equilibrium constant for equilibrium saturable binding. It corresponds to the Michaelis-Menten constant in the Michaelis-Menten equation for saturabli
Ready
As long as it is selected, the "Context Help" window will appear at the bottom of all
windows.
3.10 To Turn Off "Context Help"
1. Return to the "Main" menu.
2. Select "Help," then "Context Help."
49
-------
50
-------
Section 4
Exporting and Running a Model Data Set
The ERDEM Front End converts your data into a command file format that can be
exported to and run by the ACSL/Graphic Modeller (sic) software.
4.1 Preparing the Model Data Set for Export
From the "Main" Menu
1. Select "File," then "Open Model
Data Set."
2. Highlight the MDS called
"MALE TCE METAB&ELIM,"
then press the "Select" button, as
shown at right.
From the "Main" Menu
Model Data Set
: MALE_MTBE_BIND
MALE_T':E_C-IBL
MOUSE_MTBE_BIOSINH
RAT_CARB_EZ_BIG
RAT_MTBE_BIGSINH_BORGHOFF
Pe;Cri|3tion
Fisher version of the TCE model for a human male - with volume and blood flow
amounts, metabolism and elimination in kidney and liver
Include Inactive Data Set?
Select
Help
3. Select "Model," then "Model Data Set Definition."
The "Definition of Model Data Set"
window will appear with
"MALE_TCE_METAB&ELIM" as
the current MDS, as shown at right.
On the "Definition of Model Data Set"
window, the "Log Path" and "Variable
History Path" should be automatically
filled in to match the path where the
ERDEM Model was installed. No
further action is required.
if Definition
Narre
• J5 Setting ;
'• Q Units
escriptor* Fisher version of the TCE model tor a human male -with
Volume and blood flow amounts, metabolism and
(elimination in hidney and liver
Species: JHUMAN Sub Species' tilALE
AvgAge < 30 Sev ;M ,^! V Print Final Results
Vtrsion '202D ^ «/ Active
Log Path t \ERDM202D\ER Variable History Path C 'iRDM202D€R
Note:In the example shown here and on the following pages, the Log Path and
Variable History Path were C:\ERDM202D\ERDM202D.log and
51
-------
C:\ERDM202D\ERDM202D.rrr, respectively. They may be different for your
particular version of the software.
4.2 Exporting the Model Data Set from the ERDEM Database
From the "Main" Menu
1. Select "Export," then "Run Model," as shown below.
File Model Activity Chemical '_hernical Compartments Enzymes Exposure Special Processes Reporting System g^S^ Help
QiJici sp CD . £> 11 m rflo f? 4 -. Hi i B' tk IB-*
The "Export Model" window will appear, as shown below.
Exporting MALE_TCE_METAB£LIM
Proc Filename: ,'^:€RDM202DiERCPM202D.CMb"
History filename: jC:iRDM202D€RDM202b rrr""'
Log Filename: C.lERD"M202D€RDM2b2D.log'"
j EKport Process
Complete
j Loading Wipeout Info
\ Exporting Model Data Set
\ Exporting Model Compartments
) Exporting Exposure Routes
! Exporting Model Data Set Subsystems
I Exporting Model Dsta Set Activities
Start
Close
Notice the warning above the "Start" and "Close" buttons. If your "ACSL/Graphic
Modeller" is open and "Load ACSL" has been selected, the export will experience a
file generation conflict until you have closed the Modeller. It is therefore
recommended that you close your "ACSL/Graphic Modeller" before proceeding.
From the "Export Model" Window
2. Set the "Proc Filename" to "C:\ERDM202D\ERDM202D.CMD".
52
-------
When the Export is completed, the .cmd file will contain the exported current MDS
that was entered and saved in the ERDEM Front End database, with the MDS
parameters specifically formatted to run in the ERDEM Model.
3. Click on the "Start" button.
As each Export Process is running, the word "processing" appears to the right of the
process name. When a process is complete, a check mark will appear in its "Complete"
box. When all processes are complete, an "Export Notice" message box will appear
informing you that the export was successful, as shown below.
Exporting MALE_TCE_METAB£LIM
Proe Filename; € eRDM2Q2DeRDM202b CMlf ''
Wariabte History Hleiiame; ttRDM202D€BDM202D'rrr
The Export of the current Model Data Set (MDS) was SUCCESSFULi
Exporting Prepare Variables
Evporting Plots
Gore
4. Click on the "Export Notice" message box "OK" button.
5. Close the "Export Model" window.
53
-------
54
-------
Section 5
Starting the ACSL Viewer and Running the ERDEM Model
5.1 Starting the ACSL Viewer
From the "Main" Menu
1. Select "Special Processes," then "Run ACSL Viewer," as shown below.
; 00
II ! S3 il* B i f :;
Reporting System Export Help
system Variable Processing
Special Variable Setting
Plot Groups (Chem/Metab)
Plot Groups (Enzymes)
Experimental Data
Copy/Delete Model Data Set
Delete Chemical/Metabolism Reaction/Enzyme
COPY CURRENT DATABASE
CONVERT DATABASE
RESTORE SAMPLE DATABASE
> Radio Label Groups
Please enter the PATH to your ACSL Viewer:
Default Path:
OK
Cancel i
A "Run ACSL Viewer" window will
appear, as shown at right.
2. Set the "Default Path" to match
the path where the ACSL
Viewer was installed, as shown
at right.
3. Click on the "OK" button.
The "ACSL/Graphic Modeller" (sic) vendor window will appear, as shown on the top of
the following page.
55
-------
ACSL Graphic Modeller will function in viewer-only mode, You can edit and run pre-defined models but you cannot
save the models, To license the full functionality; please contact AEgis Research Corp, at 800-647-ACSL or
256-922-0802,
If you have purchased the product, please run the ACSL Security Key Utility (from the ACSL program group) to
request or install a security key.
' * i
Cancel j
4. Click on the "OK" button for this and any other vendor windows that pop-up
until the "ACSL/Graphic Modeller" window appears, showing an inner window
called "modell.gm [Viewer Mode]," as shown below.
Note: If this is the first time the ACSL/Graphic Modeller has been run, the "Viewer
Mode" window may appear minimized on the task bar. If so, click on it and it
will open up (as shown below).
fft'"l,^V;;?i;^^;;u^ffi;-:ft;:i;:^1^li4;;;::C<,r,
iUSs
fe-fS
/ll" • ' ' " ™ "• gg°™ ™"°1""
^ Jm. , T '", ^ iw ,,, ^
gl&?i~ii:--
111 '««iiiL»iH«umwiw«mww««ii«
J|t- ,, , A '
WW^a^wwHW
56
-------
From the "ACSL/Graphic Modeller" Window
1. Select "File," then "Open," as shown below.
Sxsl
j
The "Open Graphic Model or block
Rack" window will appear, as
shown at right.
!' JiDMGM2DZD
1d|Erdm202D,gm
File name: '
Filesofjype- i Files I'. gm.' rac J
1 Openastead-onlj)
flpen
Cancel ^
57
-------
2. Click on the down arrow in the "Look in" field (or click anywhere in the field).
The directory list will appear, as shown below.
Loo\ in
I DM*
i £3] ErdmS
i
!
File name
Files of ly
* Local Di:MCI ' ' -; - E) O &
k-,i' Desktop
} My Documents
My Computer
i 3't Floppy (A:)
"
ERDM202D
.i CD Drive (D:)
_**, PStephan on 'Iv-ps1 MJsetApps' (F:)
_£ Cjhornpson on V-fsV (G:)
*j LI :erApps on 'Iv-ps1 ' (K:)
_*^ erdenishared on 'Iv-fsl' (M:)
j*. dataanalysis on 'Iv-fsT (Q:)
•• •* PStephan on Vfs1 \uservol' fU:l
Qpen 1
"""~'t cancel j
.-
3. Select the drive where the software has been installed.
DRIVERS
iEPDEM Tutorials
Look in ; '* Local Di-k(C 1
. jAcslview
" 1 Cor el
•i jdb_conversion
"^ideemfe ,;EPDM202L
: jDELL tEPDM202S
.'^Documents and Settings ,; EPDM202 <
7"
-------
Files that are in the "ERDM202D" directory will appear, as shown below.
tool- in ' .. ERDM202D
3jEtdm;Q2D,gm
File name: ;
Files of type: '• Files (".gmf.rac)
Open as read-only
Open
Cancel
6. Select "Erdm202D.gm," as shown below, then click on the "Open" button.
Loot- in , J ERDM202D
DMGtCCCD
Filename: !Erdm202D.gm
Files of type: .' Files (*.gm;*.rac)
1 Open as read-only
Open
Cancel i
The "ACSL/Graphic Modeller - [Erdm202D.gm [Viewer Mode]]" window will appear,
as shown at the top of the following page.
59
-------
Q i # 03
n m;
•v£ File Edit View Browse Blocks Simulate Window Help
''
c
Left-dick to select Shift-left-dfagtomove. Right-click for menu,
^eadv
7. Maximize the "ACSL/Graphic Modeller - [Erdm202D.gm [Viewer Mode]]"
window (click on the Maximize icon (the middle button at the top right corner of
the window)).
This will give you a full-screen view of the ERDEM Model, as shown at the top of the
next page.
60
-------
!" Fie Edit View Browse Blocks Simulate Window Help
ERDE M 2 02 D
MARCH 11, 2005
j 1
1 m'
Gas ro Internal
Tract
if
L-
— ».
— IP.
Spleen and.. ^
Metaboliirn
Liver with
E xposure a
Metabolisn
j ' !
ft
1
_j
Un : Converron
Absolute Errors
nitial
Segment
1 How o Choose
Absolute Error;
i
* 1' 1 1 "*""*
Metabolism
! r— ;==
Metabolsm «*-
Tectei a
Metabol
Metabolite arid
Enzyme
(realization
Structure
of Model
— j
E
Te mination
k.
Terminal
3od>( Summar
Def nitrons
1»
1 b
R
J
n^
ep
i
yrne
ott>
JL
E
B
0
D
V
M
A
eft-did, to se eet, Shift-left-draa to move, Riqht-did fot menu,
NUH
5.2 Running the Model
From the "ACSL/Graphic Modeller"
Menu
1. Select "Simulate," then select "Load
ACSL," as shown at right.
Two initialization messages will appear
and disappear. Then the minimized
ACSL Run Time icon will appear on the
right end of the task bar (bottom of the
screen), as shown below.
^ File
r(«w»
D.G3
Edit View Browse Help
V^Y_^^^ Run Options , , ,
r1r
Generate Code >
fi*sV**J\^,'ww*'R>*w» i»
Start ACSL
|
Gastro-lntestir
Tract
E ,it ACSL
Below is an example of a minimized window from which ERDEM Model runs can be
viewed.
61
-------
To See the Results
1. Click on the icon.
The results will appear, as shown below.
This window shows the beginning of the command (.cmd) file, the program that runs
the model simulation.
File Edit Setu[3 Simulation Analysis Linear Help
Switching CMD unit to 4 to read Erdm202D.cmd
MODEL DHTfl SET: MflLE_JCEJ1ETflB&ELIM
SPECIES: HUMflN
SUB-SPECIES: MflLE
RUG RGE: 38
GENDER: M
DESCRIPTION:
Fisher uersion of the TCE model for a human
male - with volume and blood flow amounts,
metabolism and elimination in kidney
and liuer.
PROC EXPORT FOR DEEM 202D 09302005 0946
f STflRT OF 'WIPEOUT1 SECTION
fPROC UIPEOUT tPROC TO INITIflLIZE UHRIflBLES SET IN THE MODEL TO DIFFERENT UflLUES
!SET UflLUES FOR ftDDITIONflL UflRIflBLES NOT IN CQNSTflNT STflTEMENTS.
•SET TINTEG=fl.00001,NSTP=12*1,MINT(1)=1.E-20
SET ls_big=.F.,ls_biu=.F.,ls_inm=.F.,ls_inp=.F.
SET ls_inf=.F.,ls_INH=.T.,ls_rig=.F.,ls_skw=.F.
SET MW=10*119.37812
SET T0=0.
SET BIGD_1t_big_B=1.E20,BIGD_1t_big_E=1.E20
SET BLIU__1tJjiu_B=1 .E20,BLIU__1t__biu_E=1 .E20
SET BRTHL_1t_brth_st=1.E2fl,BRTHL_1t_exh_st=1.E20,BRTHL_1t_inh_st=1.E20
Start ,:
62
-------
You can maximize the window to enhance the view, as shown below.
File Edit Setup Simulation Analysis Linear Help
Hitching CMD unit to * to read Erdn2B2D.cmd
MODEL DBTfl SET: MBLE_TCE_METf»B&ELIM
SPECIES: HUMBN
SUB-SPECIES: MflLE
RUG BGE: 30
GENDER: M
DESCRIPTION:
Fisher version of the TCE model for a human
male - with uolume and blood flow amounts,
metabolism and elimination in kidney
and liuer.
ROC EXPORT FOR DEEM 2B2D B93020B5 09M6
, STftBT Of 'WIPEOUT1 SECTION
PROC WIPEOUT !PROC TO INITIBLIZE UflRIRBLES SET IN THE MODEL TO DIFFERENT UHLUES
!SET URLUES FOR BDDITIONBL UHRIflBLES NOT IN CONSTRNT STHTEMENTS.
ISET TINTEG=B.80081,NSTP-12*1,MINT(1)-1.E-20
SET ls_big=.F.,ls_biu=.F.,ls_inm=.F.,ls_inp=.F.
SET ls_inf=.F,,ls_INH=.T.,ls_rig=.F.,ls_skw=.F.
SET MW=10*119.37812
SET TB=0.
SET BIGD_1t_big_B=1.E28,BIGD_1t_big_E=1.E20
SET BLIU_1t_biu_B=1-E28,BLIU_1t_biu_E=1.E20
SET BRTHL_1t_brth_st=1.E20,BRTHL_1t_exh_st=1.E28,BRTHL_1t_inh_st=1.E2B
SET INFD_1t_inf_INE=1.E2B
SET RIGD_1t_rig_INE=1.E2B
SET SKSW_1t_skw_INE=1.E2B
SET TSTOP=B.
SET BCTPD_1ls_ap_B_J=9».FBLSE.
SET LS_BRTHL= .TRUE . ,LS_PU= .FHLSE.
SET LS_CC_BC=1B*.FBLSE.
SET LS_CC=.FBLSE.,INHL_1ls_cc_b_J=9».FBLSE.
SET LS_TRM_PHT=.T.
SET LSJJI=.THUE.,LS_STIN=.FBLSE.
SET N_EXP_CMPDS=0,N_BIG_ESP=B,N_RIG_EXP=B,N_INP_EXP=B,N_SKW_EKP=0
SET N_INF_EXP=B,N_BIU_EXP=B,N_INHJXP=B
SET NCINT=1.,NIINT=1.,N_SBJ_CC=B.
SET LS BPCT INP=.T..LS UPCT INP=.T.
Start
To Stop the Run
1. Click on the "Start" button.
63
-------
To Run the MDS
1. Type in: "RUN_MDS" in the field next to the "Start" button (bottom of the
window), as shown below.
2. Press the "Enter" key.
File Edit Setujj Simulation Analysis Linear Help
'ROC EXPORT FOR DEEM 282D B93B2B85 091(6
--------- STftRT OF 'WIPEOUT1 SECTION ---------
PROC UIPEOUT fPROC TO INITIflLIZE UftRIflBLES SET IN THE MODEL TO DIFFERENT UfiLUES
'SET UflLUES FOR flDDITIONflL UflRIflBLES NOT IN CONSTflNT STflTEMENTS.
ISET TINTEG=0. 08801 ,NSTP=12*1 ,MINT(1 )=1 .E-28
SET ls_big=.F. ,ls_biu=.F. ,ls_iniii=.F. ,ls_inp=.F.
SET ls_inf=.F.,ls_INH=.T.,ls_rig=.F.,ls_skw=.F.
SET MU=1 8*119. 37812
SET T8=fl.
SET BIGD_1t_big_B=1 .E2B,BIGD_1t_big_E=1 .E2B
SET BLIU_1t_biu_B=1 .E2B,BLIU_1t_biu_E=1 -E2B
SET BRTHL_1t_bi-th_st=1 .E2B,BRTHL_1t_exh_st=1 .E28,BRTHL_1t_inh_st=1 .E2B
SET INFD_1t_inf_INE=1.E28
SET RIGD 1t rig INE=1.E28
SET SKSW_1t_SkW_INE=1.E28
SET TSTOP=0.
SET flCTPD_1ls_ap_B_J=9*.FflLSE.
SET LS_BRTHL=.TRUE. ,LS_PU=.FflLSE.
SET LS_CC_flC=1B*.FflLSE.
SET LS_CC=.FftLSE.,INHL_1ls_cc_b_J=9*.FflLSE.
SET LS_TRM_PRT=.T.
SET LS_GI=.TRUE.,LS_STIN=.FflLSE.
SET N_EXP_CMPDS=B,N_BIG_EXP=8,N_RIG_EXP=B,N_INP_EXP=B,N_SKW_EXP=B
SET N_INF_EXP=B,N_BIU_EXP=B,N_INH_EXP=B
SET NCINT=1 . ,NIINT=1 . ,N_SBJ_CC=8.
Start rRUN_MDS|
64
-------
The following window shows the .log file. The beginning of the file shows the
OUTPUT variables that were previously requested, but not shown in this view. The file
then shows the chemical analyses output results by default. At the end of the file, the
PRINT variables you requested are displayed, as shown below. At the very end of the
file are the words "END OF 'PENALIZATION' SECTION." This indicates that the
simulation run for this MDS is complete.
File Edit
980
981
982
983
984
985
986
987
988
989
990
991
992
993
994
995
996
997
998
999
1000
1881
1002
£
*
f
t
Start
Setug Simulation
93
93
94
94
94
94
94
94
94
94
94
94
95
95
95
95
95
95
95
95
95
95
96
! I
.8880000
.9840000
.0800000
.1760000
.2720000
.3680000
.4640000
.5600000
.6560000
.7520000
.8480000
.9440000
.0400000
.1360000
.2320000
.3280000
.4240000
.5200000
.6160000
.7120000
.8080000
.9040000
.0000000
run ncr •
tnu ur
Analysis Linear
33
33
33
33
33
33
33
33
33
33
33
33
33
33
33
33
33
33
33
33
.4300000
.4351000
.4402000
.4453000
.4503000
.4554000
.4605000
.4655000
.4706000
.4756000
.4806000
.4856000
.4906000
.4956000
.5006000
.5056000
.5106000
.5156000
.5205000
.5255000
33.5304000
33
33
C T
.5353000
.5402000
hi A I f-FATTflhf
r 1 nrtL i en i i u n
Mi
Help
121.
121.
121.
121.
121.
121.
121.
121.
121.
121.
121.
121.
121.
121.
121.
121.
122.
122.
122.
122.
122.
122.
122.
" CC
721000
739000
758000
777000
796000
814000
833000
851000
870000
889000
907000
925000
944000
962000
981000
999000
017000
036000
054000
072000
090000
108000
126000
f»T T fkU
in
56
56
56
56
56
56
56
56
56
56
56
56
56
56
56
56
56
56
56
56
56
56
56
.6161000 *>>
.6249000
.6336000
.6423000
.6510000
.6596000
.6683000
.6769000
.6856000
.6942000
.7028000
.7114000
.7199000
.7285000
.7370000
.7455000
.7540000
.7625000
.7710000
.7795000
.7879000
.7963000
.8048000
V
*,;
3. Minimize this window.
5.3 Specifying the Scenario
To See Plots
From the "ACSL/Graphic Modeller" menu:
1. Select "Simulate," then "Run Scenario," as
shown at right.
Start ACSL
Continue ACSL run.,,
Display Variables
Plot Variables,,,
ACSL Command,
Tract
65
-------
The "Specify Scenario Procedure"
window will appear, as shown at right.
2. Select the desired scenario procedure
from the "Name" list.
3. Click on the "Execute" button.
The plots are available for viewing in
separate windows.
To view the plots, minimize the active window
The plots will be "stacked" on top of each
other, as shown at right.
To View the Plots Separately
1. Move their windows (click on the
colored title bar, hold the mouse button
down, and drag the window to another
position).
Separated plot windows are shown below.
You can also minimize and maximize each
plot window.
File Edit Help
0» fUEfi UNDER IMF OIRVF
oNtr. mm MO '/EMM aaop
75 *D
ile E
J"
u.
f
*
11
f
s1
Help
ICE «» WIBER 1HE OJBVE
i HOUEf. LWER WlO VEWIfi BtOOD
tL
m1
3*
l'
:/"
D Zl *0 5D 31 ]
O
in
1
m
r'j;;^?''^->;>'u>'u:'^:'T':if >' v^W'^' Vv'; ;*:v"-Vx't;;; ;-' ^/ri^v'J,;',*
K
R
B
s
a
i
*
j«.
i
TCOH HSB U(CER THE CUWE
S MOItr. U«R SB tEMW a»D
3
i
L\ *> d~84 "
3
4.
/
?
i
i/
);/"
•-""
^^
~-~~~
"
_-
s s
1 1*.
s ij
8 1 ',
1 1 %
» S 5
l j ='
a
9
1
a
D TD *a ED ai jm E
1
IS
„ DCH MB UNOER 1HE OJBVE
a. KlONEf. LIUS WlO VEWIfi BtOOD
S
ks
1L
1
a
il
if
/
j,.-' "
D Zl *0 5D 31 ]
o
in
R
1
O2
66
-------
The plots are also available as minimized window icons on the task bar. In the illustration
below, they are the last three to the far right in the lower row.
If you prefer, you can view the plots separately by clicking on the minimized icons.
Note: The plots do not automatically save. To have a record of a plot, you can do one of
two things: print it, or save it as a bitmap.
To Print a Plot
1. Select "File," then "Print" from the plot
window's menu, as shown at right.
To Save a Plot
1. Maximize the plot window (to full screen).
2. Click on "Edit," then "Copy Bitmap" (as
shown below) and follow the prompts.
HE;
Edit Help
67
-------
Sge*
Copy Neu
Set Size
a
o
a
CO
X
L
1
C"
G
a
CO"
u_
O
if
D
i
Z
a
or
se
^sii:
tral
D
o
O
CO
X
JI
1
e
o_
u_
D
ID
M"
TCE RREfi UNDER THE CURVE
g KIDNEY, UVER fiND VENOUS BLOOD
a
CO
X
e
_c
I
e
a
u_
t
m
D
i
i
CO
•z.
O D O~t
0
'I"
,./!
in
o
o
C\j
in
in
O
m
a.
Ql
CD
20 40 60 80 100
TIME Hours
To View Additional Plots
1. Go back to the beginning of subsection 5.3 and select a different scenario
procedure.
5.4 ExitACSL
From the "ACSL/Graphic Modeller"
Menu
1. Select "Simulate," then "Exit
ACSL," as shown at right.
This will close all ACSL windows.
It also saves the ".log" file, a record
of your MDS simulation run, in the
location specified in the "Export
Model" window, as previously
lia
;IF
D
sty
lie
G3
~4»
Ed
f
m
t V
\
ew Browse Blocks Window Help
" ", r" " . . "' " .'", Run Options,,,
Generate Code *
Start AC5L
1 Display Variables
Plot Variables,,,
AC5L Command...
Tract Run Scenario,,,
68
-------
shown in subsection 5.2. In addition, it saves the ".CMD" and ".rrr" files identified in
the "Export Model" window.
A view of the "Export Model" window, showing the file names, is shown below.
Exporting MALE TCE METABELIM
3C:VERDM202D\ERDM2Q2D.irr
L«j
1 Export Process
I Loading Data
I Loading Wipeout Info
I Exporting Model Data Set
| Exporting Model Compartments
I Exporting Exposure Routes
| Exporting Model Data Set Subsystems
5 Exporting Model Data Set Activities
Please riS'Stt Ui5»? ACSL
Close
Complete
Note: The version used for this demonstration was "ERDEM202D." By default,
subsequent model runs using version "ERDM202D" will be saved to the same
directory and use the same three file names shown above. If you wish to keep the
files from the previous model run, it is recommended that you copy the three files
to a different directory and rename them for identification.
5.5 Exit ACSL/Graphic Modeller
1. Select "File," then "Exit" from the menu, or click on the red and white "x" at the
top right corner of the window.
5.6 Exit ERDEM Front End
1. Select "File," then "Exit," as shown at right, or click on the
red and white "x" located at the top right corner of the
window.
<'l Model Activity Chemic
*. *\
Mew Model Data Set
Open Model Data Set
Open User Database
Open SAMPLE Database
69
-------
70
-------
Section 6
Descriptions of
Exposure Related Dose Estimating Model (ERDEM)
Exposure occurs at the boundary of the body or test system. It is of considerable interest
to EPA to limit, reduce and, in specific instances, eliminate exposure. Humans become
exposed to chemical and biological substances, physical energy and radiation through the
activities they perform routinely in everyday life or occupationally as part of certain
policies, practices or procedures. Exposure can occur accidentally as a random event, or
during an occupationally related task or as a result of a purposeful action such as a
(terrorist) attack.
Humans may become incidentally and unknowingly exposed. Exposure to particles and
gasses in the air we breathe may be unavoidable. Dermal contact with surface residues
may be unforseen and unrecognizable. Ingestion of particles and residues in food may be
unintended and unsuspected. Under certain conditions, exposure can be limited or
reduced through education, managerial oversight, regulatory responsiveness, and use of
proper personal protection devices (Ness, 1994).
Exposure events in time and space under certain recognizable exposure scenarios may be
accomplished more easily for occupationally related exposures where policies, practices
and procedures have been established than for those that occur randomly or incidentally.
However, regardless of the nature of the exposure, exposure follows along recognized
pathways, e.g., inhalation, ingestion, and dermal, and routes, respiratory, oral, and
percutaneous.
ERDEM was designed to examine three pathways of exposure, inhalation, ingestion and
dermal, and eight routes of entry into the in silico test system. Experimental pathways and
routes of entry were included (subsection 6.1), along with what might be perceived as
naturally occurring unscheduled or not experimentally controlled pathways and routes
(subsection 6.2). This approach greatly enhanced the database to include laboratory
animal and clinical studies in addition to environmental field studies. For example, enteral
administration is represented by intraperitoneal injection (IP) of chemical into the GI tract
via the Portal Blood (Liver for the Stomach/Intestine Gastro-Intestinal model).
71
-------
6.1 Experimental Pathways and Routes of Entry
6.1.1 I ntraperitoneal Injection
Intraperitoneal Injections (IP) into the Portal Blood may be given for multiple chemicals
for up to nine scenarios starting at time TINP , and repeated at the interval TINPiTr . The
amount of chemical to be injected is calculated from the concentration of the chemical
times the Body Volume. The amount injected decreases at an exponential rate. All
injections start before the simulation start time (T0). When the scheduled event occurs to
start the injection, the amount is calculated as:
.
B > (1)
where ^-INP.CURJ. is the amount remaining to be absorbed from the previous interval. The
amount of the ith chemical from the jth exposure remaining to be absorbed is:
' '
where, AT = T— Timsru., TmsTLJ, is the start time for the last IP Injection for the jth
exposure, and MIN is the minimum of the two terms. The amount of the ith chemical
remaining to be absorbed for all exposures is:
Sw'M/1
•"•INP.CURj Z_j ''AJ't i;KJ, .
and the rate of change of the amount of chemical injected into the Portal Blood is given
by:
dAmp,
(4)
At the start of the next injection interval, the IP amount remaining to be absorbed is
accumulated for each chemical; the elapsed IP simulation time is reset to zero, and the
next injection occurrence is scheduled.
6.1.2 Intramuscular Injection
Parenteral administration is represented by intramuscular injection (IM) in the muscle
(Slowly Perfused Tissue). Intramuscular Injections may be given for multiple chemicals
72
-------
and up to nine scenarios starting at time TmMft and repeat at the interval Timin,, The amount
of chemical to be injected is calculated from the concentration of the chemical times the
Body Volume. The amount injected decreases at an exponential rate. All injections that
start before the simulation start time (T0) and before the simulation end time are
scheduled. When the scheduled event occurs, to start the injection the amount is
calculated as:
= ^INM.CLWJ. . ~^~ ^-INMJ, . VB - (5)
-------
in each infusion, each with its own concentration. The rate of change of the amount of the
ith chemical infused into the venous blood versus time is given by:
The flow rate, Q,NFi , is independent of the chemical. There is one flow rate for each
exposure. However, the concentration of the ith chemical in the jth exposure, CShTj , can be
different for each chemical. The total amount of the ith chemical passed to the venous
blood by Infusion is:
U/i ft\/f j £f
6.1.3.2 Bolus Intravenous Injections
Bolus dose Intravenous (IV) Injections start at a given time, TB,y. , and may be repeated at
an input interval, TKIGJT. . Bolus dose Intravenous Injections (IVs) injected before
simulation start time are not modeled. Those that occur at simulation start time (TO) are
modeled as true bolus doses into the venous blood. The equation for the initial values for
the amount of chemical in the Bolus IV Dose and in the venous blood are given by:
NBIG
(11)
(12)
for the exposures that start at simulation start time. A bolus dose IV that occurs after the
simulation start time is simulated with a rate input normally having a time duration of
one-quarter of a communication interval or one-quarter of a maximum integration step,
whichever is less. The equation for the jth exposure for the ith chemical then takes the
form:
dAg,y dgtt,
Ml 1 HIV.. * BIVo
rs
and for all exposures to the ith chemical at time t:
74
-------
dAi
m¥
ft
¥n = J Tg
,
tit + A
m,
6.1.4 Inhalation Administration
There are two types of inhalation, Open or Closed Chamber Inhalation. Open Chamber
Inhalation is assumed.
The subjects in each simulation are in a closed chamber or an open chamber. They cannot
be mixed. If the simulation uses an open chamber then:
• If no exposure is defined then the simulation starts with an open chamber with no
concentration of chemical.
• There is no change in the concentration of chemical in an open chamber due to
exhaled air.
• If one or more open chamber exposures are defined and none are designated the
starting exposure then exposure number one is the exposure starting the simulation.
• Any number of chemicals can have a concentration in an Open Chamber exposure.
• The simulation cannot switch in the middle from Open to Closed Chamber
Inhalation.
If the simulation uses a closed chamber then:
• There must be a Closed Chamber exposure defined to start the simulation.
• Only one Closed Chamber exposure can be active at once.
• Any number of chemicals can be assigned a concentration for a Closed Chamber
exposure.
• The chemicals in the exhaled air change the concentration of each chemical in the
closed chamber.
• If Closed Chamber Inhalation is chosen then the whole simulation will be with a
closed chamber.
• Open Chamber Inhalation can be approximated with an extremely large closed
chamber.
75
-------
The input concentration for an Open Chamber is in units of parts per million. The input
for Closed Chamber Inhalation can be the amount (mass units), or the concentration (units
of parts per million). The Open Chamber concentration for the ith chemical in mass per
unit volume is calculated from:
!tKJ ' '
For Closed Chamber Inhalation the volume of the chamber is required. The volume of the
air in the chamber is calculated by subtracting the volume of the number of subjects:
*CCGtf,= VcCj-NsBjV* (17)
If the input into the Closed Chamber is a concentration then it is given in parts per million
and converted to mass per unit volume units. But, if the input is an amount, then the
amount is converted to concentration by:
'CC.GASj
There are two types of lung included in ERDEM, static lung and Breathing Lung. These
compartments are described in subsections 7.1 and 7.2. The inhalation pathway involves
entry through the Open or Closed Chamber static lung or the Breathing Lung.
6.2 Exposure for Bolus Ingestion, Rate Ingestion, Inhalation, and Skin
Surface Exposures
Exposure time histories have been implemented in ERDEM for rate ingestion, open
chamber Inhalation, and skin surface exposure, but not for bolus dose, or Closed Chamber
Inhalation. There can be up to nine time histories for each exposure type (except for skin
surface exposure which can have up to five exposures), but only one for each chemical.
The time histories may be repeated periodically. Each time history will have a start time
and duration interval. Any exposure can be expressed as an exposure time history.
Each exposure route has most of these variables:
• Concentration of chemical in a volume of food, water, or air (usually the dependent
variable in a time history);
76
-------
• Volume of the food, water or air;
• Flow rate - volume per unit time;
• Start time of exposure, duration of exposure, and interval between exposures.
If an exposure starts on or before the simulation start time, then the simulation starts with
the exposure in effect. Otherwise, there is an event to start and one to terminate the
exposure. There can be overlapping exposures of the same type in most cases (not for
Closed Chamber Inhalation exposures). If the exposure is an exposure time history, then
only one chemical can be modeled and there can be only one exposure time history of a
particular type in any one simulation.
6.2.1 Ingestion Into the Stomach and the Stomach Lumen
If Rate ingestion input is a time history, then time and the amount per unit time
(concentration times flow rate) of the chemical are provided. Linear interpolation is used
to obtain intermediate values.
6.2.1.1 Bolus Dose Ingestion
Bolus dose ingestion occurs when chemical is taken into the Gastro-Intestinal tract very
rapidly; for instance in one big bite or drink (there is no time history input). Bolus dose
inputs that occur at simulation start time (T0) are modeled as true bolus doses. The initial
value for the integration in the stomach or stomach lumen is the sum of all exposures that
start at simulation start time. The equation is:
for all exposures to the ith chemical at time T0.
Bolus dose inputs with start time TB,Cj that are greater than the simulation start time and
before the simulation stop time are simulated by rate inputs that start at the scheduled
bolus dose start time with a duration of 1A of a communication interval, or 1A of a
maximum integration interval, whichever is less. The bolus dose for the jth exposure can
be repeated at the input interval, TmJT/. The approximation of a bolus dose input via a rate
input of a relatively short duration produces results very similar to those achieved with an
actual bolus dose while allowing a more accurate evaluation of amounts and
concentrations via numerical integration. The equation for the jth exposure for the ith
chemical then takes the form:
77
-------
dt TK,r,. - T
cs/C|/«, (2o)
and for all exposures to the ith chemical at time t:
dABIG
__J£
dt •
The variable ^a«;rei is the initial value in the numerical integrations for the total amount of
the ith chemical in the bolus dose ingestion, and the amount in the stomach or stomach
lumen:
(22)
6.2.1.2 Rate Ingestion
The Rate Ingestion (may be a time history input, see 6.2. 1 above) for each exposure starts
at a given time, TKKi, occurs over a duration of time, fwco/ , and may be repeated at an input
interval, Tuarr , The concentration of the chemical in the food or drink and the flow rate
are required inputs. The product results in the rate of change of chemical in the stomach
or stomach lumen versus time. Overlapping exposures are allowed. The rate of change of
the ith chemical in rate ingestion versus time is given by:
w. %G
(23)
Thus there is one flow rate for each exposure. But the concentration of each chemical in
the jth exposure may be different. The numerical integration to obtain the total amount of
the ith chemical passed to the stomach by Rate Ingestion is:
~J5
dt
78
-------
6.2.2 Inhalation Exposure
If Inhalation exposure input is a time history then time and concentration in Parts Per
Million (PPM) of chemical are input (conversion from other units may occur). Linear
interpolation is used to obtain intermediate values. The inhalation pathway involves entry
through the Open or Closed Chamber static lung or the Breathing Lung. These
compartments are described in subsections 7.1 and 7.2.
6.2.3 Dermal Exposure
There are two types of dermal exposure modeled in ERDEM, one for chemicals in an
aqueous vehicle, most often a water based diluent, and chemicals as a dried residue or
adsorbed onto particles as a dry source.
6.2.3.1 Skin Surface Exposure to a Chemical in an Aqueous Vehicle
Skin Surface exposure due to chemical in an aqueous vehicle may be input as a time
history of time, the surface area of the skin (square centimeters) that becomes exposed to
the chemical, and the concentration (mass per unit volume) of the chemical in the vehicle.
This concentration and area of the skin are used to compute the rate of change of the
amount of chemical absorbed. Linear interpolation is used to obtain intermediate values.
The skin surface is exposed to chemical in an aqueous vehicle (water) at time ?W. for a
period of time, ram), which can be repeated at the interval, TSKWfTj. Skin surface (water)
exposures progress from a simulation start time and end at a scheduled termination time
point. If a fixed scenario is used then the concentration of the ith chemical at the skin
surface is found from summing the concentrations from each of the up to five exposure
scenarios:
SKSi SKW'Ji,i
The rate of change of chemical in the epidermis due to the concentration CSKS_ on the skin
surface is given by:
(26)
6.2.3.2 Skin Surface Exposure to Transfer from a Dry Surface
79
-------
A chemical exists on a surface represented as a mass per unit area. It is transferred to the
skin of a subject represented by a transfer coefficient. A short exposure period would
represent a bolus.
The rate of change of chemical on the dermis due to a dry exposure is:
yLri CJL,,,, ,™
'**•**' = A K (27)
^T|. ^•iiurf.^sks.rt,
Integrating this equation gives the total applied dose.
The rate of loss of chemical from the skin surface due to evaporation is given by:
(28)
where 8W({/ = 1 if a wash-off is in progress, and zero otherwise,
§w! = 1 if the first evaporation rate constant is active, and zero otherwise,
<5»2 = 1 if the second evaporation rate constant is active and zero otherwise.
The rate that the ith chemical moves from the skin surface into the dermis is given by:
^ = K, , A.C, (29)
_ Asksi
where sfov ~ Vsk
If no wash-off is in progress, then the rate of change of the amount of the ith chemical on
the skin is given by the rate of application minus the rate of chemical moving into the
dermis minus the rate of loss due to evaporation:
ill ...... "dt ....... ~ dt ~ dt
If a wash-off is in progress, then:
_
dt dt
80
-------
where the wash-off is scheduled at time 4«/ for one time step, At, to remove all chemical
on the dermis:
"- ^STWjIWf,. , v "MSY - , /*>*>\
^^^^JL.....!! f 4- \ _ .mm,,,,,.,,,.i. /* \ 1331
,, * j ... 1 -— . i/ ,, I \ww/
Wif Vwe// A # \*w-'q//
6.3 Variable Definitions
Bolus Dose Inqestions
ABIG! = The amount of the ith chemical in all of the bolus dose Ingestions at time t,
A»icm = The total amount of the ith chemical in the bolus dose at simulation start
time,
Cg|G. = The concentration of the ith chemical in the jth bolus dose,
NBIG = The number of bolus dose Ingestion exposures,
TUG = The time that the bolus dose Ingestion starts,
TBIGE = The time that the bolus dose Ingestion ends, and
FB/C = The volume of the jth bolus dose.
' J
Rate Inqestions
= The initial value for the ith chemical in the Rate Ingestions,
AMG.STJJ = The total amount of the ith chemical passing from Rate Ingestions to the
Stomach at time t,
CjyC = The concentration of the ith chemical in the jth Rate Ingestion exposure,
:jl(i! = The rate of change of the ith chemical in the Rate Ingestions at time t,
NRJG = The number of Rate Ingestion exposures, and
QR!G. = The flow rate for the jth Rate Ingestion.
Infusions
AIM-.\HJ. = The total amount of the ith chemical in Infusions to venous blood at time t,
dA
']'in> = The rate of change of the ith chemical in Infusions versus time at time t,
at
81
-------
CINF>. = The concentration of the ith chemical in the jth Infusion,
Q,NF, = The Infusion flow rate for the jth exposure.
Bolus Dose Intravenous Injection (Bolus IV)
Amv. = The amount of the ith chemical in the jth bolus dose IV,
^siyroi = Thg total amount of the ith chemical in the bolus dose IV at simulation start
time,
NBIY = The number of bolus dose IV exposures,
TBltrg = The time that the bolus dose IV starts,
TB,V = The time that the bolus dose IV ends.
'£
Intraperitoneal Injection
= The amount of the ith chemical remaining to be absorbed from the previous
interval for the jth IP scenario,
= The amount of the ith chemical currently in the IP Injection for the jth
scenario,
AlNPj = The amount of the ith chemical currently in the IP Injection,
CMPJ. = The concentration of the ith chemical in the IP Injection for the jth scenario,
: ^Pi = The rate of change of the amount of the ith chemical in the IP Injection,
K/NP,ABS,JU = The first order absorption rate constant for the jth set of IP Injections of the
ith chemical,
KINP.UMJ = The factor to limit the minimum amount of the ith chemical from IP
Injections remaining to be absorbed.
VB = Volume of the Body of each subject.
Intramuscular Injection
82
-------
AINM,CVRJU = The amount of the ith chemical remaining to be absorbed from the previous
interval for the jth IM Injection scenario,
AiNMjf = The amount of the ith chemical currently in the IM Injection for the jth
scenario,
A{NM. = The amount of the ith chemical currently in the IM Injection,
CINMJ, = The concentration of the ith chemical in the IM Injection for the jth
scenario,
dA
:,,,,f!*i = The rate of change of the amount of the ith chemical in the IM Injection,
dt
KiNM,ABsjj = The first order absorption rate constant for the jth set of IM Injections and
the ith chemical,
KINM.UM, = The factor to limit the minimum amount of the ith chemical from IM
Injections remaining to be absorbed.
Skin Surface Exposure (Water)
ASK = Area of the skin covered by the solution containing the chemical,
ASKW.DR = The amount of the ith chemical that has moved from the skin surface to the
Dermis,
dA
. fEEJfi = The rate of change in the amount of the ith chemical moving from the skin
surface to the Dermis,
CSKS = The concentration of the ith chemical on the skin surface due to all
overlapping exposures,
CSKW.J, , = The concentration of the ith chemical for the jth exposure on the skin
surface,
KSKS,DR.PRM. = The permeation coefficient for the ith chemical from Skin Surface to
Dermis,
Inhalation
ACCJj = The amount of the ith chemical in the jth Closed Chamber,
83
-------
CAIR, i PPM, = The concentration of ith chemical in air for one part per million at one
atmosphere and 25 °C. This is used to convert concentration in PPM to mass
per unit volume.
CAIR.JI = The concentration of the ith chemical in the jth exposure in parts per
million.
CINH = The concentration of the ith chemical in inhaled air, units of mass per unit
volume.
NSBJ = The number of subjects in the jth Closed Chamber,
Vcc. = The volume of the Closed Chamber for the jth inhalation exposure,
.
The volume of the gas in the chamber adjusted for the volume of the
subjects.
84
-------
Section 7
Descriptions of
Absorption and Circulation in Model Compartments
ERDEM has the capacity to test spatial and temporal exposure scenarios involving
multiple parent compounds, each with multiple metabolites, in a dynamic virtual
biological "in silico" system. Individual or collective exposure may be punctuated over
time with biological contact occurring randomly or episodically as a series of acute events
or multiple chronic events where upon the exposure dose metric enters the "in silico"
biological system through recognized portals of entry (U.S. EPA, 1992). Only the
absorbed dose, as a portion of the exposure dose, is of interest toxicologically.
Consideration of this relationship between exposure dose and absorbed dose begins at the
physiological boundaries of exposure, the laryngeal-tracheal system (static or breathing
lung), the skin, gastro-intestinal (GI) tract. ERDEM considers these physiological
boundaries of exposure separately.
7.1 The Closed Chamber for the Static Lung
The static lung is modeled by finding the rate that the ith chemical in inhaled air is
transferred to arterial blood and the rate that chemical in the static lung/arterial blood is
transferred to Exhaled Air. The rate of change of the amount of the ith chemical in the
Closed Chamber is simply the rate of change of the amount exhaled into the chamber
minus the rate of change of the amount inhaled from the chamber by the subjects as
represented in equation (34):
where N is the number of subjects in the Closed Chamber. In addition, the ith chemical is
moving from the venous blood to the static lung, from the static lung to arterial blood, and
in the chylomicrons from the Lymph Pool (when the four walled Gastro-intestinal model
is used). Binding of the ith Chemical is modeled in the static lung and is used to reduce
the amount of free chemical. The bound chemical does not metabolize and does not pass
to the arterial blood. Each of the Nc circulating compounds can metabolize into up to NMri
metabolites. Each metabolite could be the ith chemical. Thus the rates of formation of
85
-------
each of these metabolites must be added. The equation for the rate of change of the
concentration of the ith chemical in the static lung is represented in equation (35):
dCfu. _
jt ~~ Qii (~ i
(35)
L,-pf ! MjfTUsf/B
where the variable Ilm is the circulating compound that is the mth metabolite of the /th
circulating compound. The equations for metabolism are presented in subsection 8.2.
Binding and elimination equations are presented below.
7.1 .1 Elimination in the Static Lung
There are two types of elimination currently implemented in ERDEM. A linear form in
which the
rate of elimination is proportional to the rate of change of the amount of the free ith
chemical in the static lung and a saturable Michaelis-Menten form. The linear form is:
J _ r , (36)
"-PUE, "-PU.F! * '
and the saturable form for elimination is:
dt ^£, (A- + ABS(CPV.Fi))
7.1 .2 Binding in the Static Lung
The binding in the static lung is of the Michaelis-Menten form but the amount of the ith
chemical that is bound is calculated rather than the rate. The equilibrium equation is:
(38)
7.1 .3 Calculation of Free Chemical in the Static Lung
The free chemical in the static lung is calculated by subtracting the amount bound from
the total amount as follows:
86
-------
(39)
7.1.4 Metabolism in the Static Lung
The static lung metabolism equations are the same as those for the Liver given in
subsection 8.2.5, except that the equation for the V-Max is given as a function of the
Liver value from the equation
Y™.
*MX,PU, , ~ * MX.LV, , "•M.PU.LV, , v > ' '
w i,.; ',i v LY
where RM.PV.LV.. is a scaling factor for V-Max in the static lung relative to the Liver for the
jth metabolite of the ith chemical.
7.1.5 Arterial Blood and the Static Lung
The equation for arterial blood (AB) is slightly different for the static lung (PU) and the
breathing lung. Arterial blood is output from the lung and is input to most of the
compartments. The rate of change of the amount of the ith chemical in the arterial blood
for the static lung is the rate that chemical is moved into the arterial blood from the static
lung minus the rates that the free arterial blood loses chemical to the other compartments
(Brain, Carcass, Derma, Fat, Kidney, Liver, Rapidly Perfused and Slowly Perfused
Tissue, Spleen, and for the new GI - the Walls of the Stomach, Duodenum, Lower Small
Intestine, and the Colon). The equation is:
(41)
[XX] Ut
where
dA.
(42)
and [XX] = {BN , CR, DR, FT, KD, LV, RP, SL, SP, SW, DU, SI, and CN}.
7.1.6 Venous Blood Input to the Static Lung
The rate of change of the amount of chemical in the venous blood is given by the rate due
to Bolus Intravenous injections and Infusions plus the rate of gain from each
compartment minus the rate of loss of free chemical to the static lung. The equation is
given by:
87
-------
(43)
dt ~ dt dt ' (#, dt -~^vw«
where [YY] = {BN, CR, DR, FT, KD, LV, RP, SL}.
7.2 The Breathing Lung
The breathing lung is modeled with five compartments: Upper Dead Space, Lower Dead
Space, Alveoli, Pulmonary Capillaries, and Lung Tissue. In addition, flows for the
bronchial artery and the bronchial vein are modeled. Diffusions are modeled for the
Alveoli - Pulmonary Capillaries, Alveoli - Lung Tissue, and Pulmonary Capillaries -
Lung Tissue interfaces. The system chart for the model using the Breathing Lung is given
in Figure 5. Metabolism is modeled in the Lung Tissue. An anatomy chart for the
breathing lung model is displayed in Figure 6. Terminology is defined in subsection
7.2.16.
-------
CC Closed
Chamber Inhalation
i
VB Venous
Q
!B
Bronchial
Artery
/ Open Chanber \
Exhalation )
Open Chamber
Inhalation
UD
Upper Dead
QAIR
i
QAB.CP
CP
Pulmonary Capillaries
i i
i
Bronchial
vein
QCP.VB
LD
Lower Dead Space
QAIR
i
QB
AL Alveoli
Diffusion
\ PiGAtA AL
V •_
AB Arterial
LG Lung Tissue
Diffusion
Metabolites
Figure 5. Breathing Lung Model.
89
-------
Blood Flow and Diffusion in the Alveolar
^-— -~^,
Bronchraf Artery
Pulmonary Artery
(Systemic Venous)
Pulmonary
Capillaries
with lung tissue
Pulmonary Vein
(Systemic Artery)
Alveolar Air Space
Lung Tissue
Diffusions for Alveolar, Capillaries, and Lung Tissue
Pulmonary
Lung Tissue
A
A 1 ¥ e o I a r
Air Space
H
Figure 6. Breathing Lung - Anatomical Description.
7.2.1 Flow of Air in the Breathing Lung
Alveoli volume (V^ and volumetric flow rate of the air
breathing frequency, FB, as
are calculated from the
VAL =
V,
(44)
and,
fi
•AIR
V, SIN (fit)
(45)
90
-------
where
VFRC = Functional residual capacity,
Fr = Tidal volume,
t = Time;
and,
(46)
where FB is the Breathing Frequency.
The volume of the Alveoli versus time is plotted in Figure 7a and the volumetric flow rate
of the air versus time is plotted in Figure 7b.
The breathing cycle consists of one inspiration (QM > 0) followed by one expiration
1.70
1,40
0,0 0,4 0,8 1,2 1.6 2,0
TIME *10'2 Hoyrs
Figure 7a. Alveolar Volume Versus Time.
300
180
o
&
HJ V.
-------
equation by using multipliers. Each inspiration term in the enclosed equations has the
multiplier:
I =[1+SIGN (&,„)}&, (47)
where
SIGN(X) = 1 if X > 0, and
SIGN(X) =-lifX<0.
Thus
/ = 1 for QMR > 0, and
I=OfarQMR<0.
Every expiration term has the multiplier
(48)
where
E = 1 for QMR <0, and
E = 0 for QMR > 0.
7.2.3 Equation for the Closed Chamber
The closed chamber compartment is shown in the breathing lung system chart (Figure 5).
If an open chamber is used then the input concentration is fixed and exhaled air is lost.
The rate of change of the amount of the ith chemical in the closed chamber (CC) is:
dCcr
I/ __J±L = _ A/ * /•) f * C + JV * O F * C (49)
' CC rff JV \£Am* <-CC, T n SsJ,ffflC ^-UD,
where inspiration is from the Closed Chamber to the Upper Dead Space and expiration is
from the Upper Dead Space to the Closed Chamber. The terms I and E are given by
equations (47) and (48) respectively and N is the number of subjects in the Closed
Chamber (only one subject is modeled).
7.2.4 Equations for Upper Dead Space
The equation for the rate of change of the ith chemical in the Upper Dead Space is given
by:
92
-------
f^'
- - _l = /i T * f — f) f * f 4-/1 J7*/"1 /I C* * /"* (50)
dt is/fa1 '-•/AW, xfAiR* ^vot~ \£AIR-CI ^UD, KMRJ~' ^u>t
where ClNHi is the concentration of the ith chemical in inhaled air from either an open or
closed chamber, and C,D| is the concentration of the ith chemical in air exhaled into the
closed chamber or lost in an open chamber. The quantities / and E are the inspiration and
expiration coefficients given in equations (47) and (48) respectively. The concentration of
the ith chemical in exhaled breath C£wa is given in equation (71) (see subsection 7.2.13)
and is different from CVOj above.
During inspiration, chemical moves from the air in the chamber to the Upper Dead Space,
and from the Upper Dead Space to the Lower Dead Space. Exhaled air moves from the
Lower Dead Space to the Upper Dead Space, and from the Upper Dead Space to the
Closed Chamber or is lost to exhaled air.
7.2.5 Equations for the Lower Dead Space
The Lower Dead Space exchanges air with the Upper Dead Space and the Alveoli. The
equation for the rate of change of the ith chemical in the Lower Dead Space is:
/) f*c — (1 j*C + O F * C — f") F * C (51)
\fAlK,1 t-(/0, \£.AIR1 ^LDS ' ^AIK^ ^LDf <*£AIR^ H«,Y
where I and E are the inspiration and expiration coefficients from equations (47) and (48)
respectively.
During inspiration the ith chemical moves from the Upper Dead Space to the Lower Dead
Space, and from the Lower Dead Space to the Alveoli. Exhaled air moves from the
Alveoli to the Lower Dead Space, and from the Lower Dead Space to the Upper Dead
Space.
7.2.6 The Equation for the Alveoli
The Alveoli exchanges the ith chemical in the air with the Lower Dead Space and
exchanges the ith chemical by diffusion with the Pulmonary Capillaries and the Lung
tissue. In addition, the volume of the Alveoli varies with time (equation (44)).
The equation for the Alveoli (AL) compartment is written as rate of change of amount:
dA4L
——'- = n Tf + n vr + p cr* ^p c<"4,
^|> ' \£.AIRl^LD, \£.AI«*-'^ALj r LG,ALit3AL^LG,F, r ALLGf^LG *"AL, ,-o\
P c r — P v c
1 CKAtAL^CKf f ALCPCP^AL •
93
-------
The concentration of chemical in the Alveoli is found from the amount as
Au ft)
~
IK1\
(53)
The first term is the movement of chemical in the air during the breathing cycle with
coefficients / and E given by equations (47) and (48) respectively. The second and third
terms represent diffusion of chemical across the membrane from Lung Tissue to Alveoli
and vice versa, respectively. The diffusion of chemical from the Pulmonary Capillaries to
the Alveoli and back is given by the fourth and fifth terms respectively.
7.2.7 Lung Tissue Equation
The ith chemical in the Lung Tissue compartment diffuses in exchanges with the Alveoli
and the Pulmonary Capillaries. Elimination is modeled and the rate of elimination of the
ith chemical is subtracted. Chemical may be metabolized and the rate of metabolism
further reduces the rate of increase of the chemical in the Lung Tissue. Other metabolites
may metabolize to the ith chemical and their rate of formation is added. The equation is:
dCIG
is — _L — p c r* — P 9 '• c + P
LG rALLG&LG^AL r LGAL &AL ^'LGF ^ * CPLG'
_ —
dt rAL.LGi&LG^AL, r LG.AL,
where the first and second terms show the diffusion of chemical from Alveoli to the Lung
Tissue, and vice versa. The third and fourth terms represent the diffusion of chemical
from the Lung tissue to the Pulmonary Capillaries and the variable //,„ is the circulating
compound that is the mth metabolite of the /th circulating compound. The equations for
metabolism are presented in the attached metabolism report. Binding and elimination
equations are presented below.
7.2.7. •/ Elimination in the Lung Tissue
There are two types of elimination currently implemented in ERDEM. A linear form in
which the rate of elimination is proportional to the rate of change of the amount of the
free ith chemical in the static lung and a saturable Michaelis-Menten form. The linear
form is:
dt
'%- = K A (55)
"~LG.E,'iLG.Ft>
94
-------
and the saturable form for elimination is:
"•"!G.£, (-'i.G.F,
___ = Vm^ Kf (56)
7.2. 7.2 Binding in the Lung Tissue
The binding in the Lung Tissue is of the Michaelis-Menten form but is an equilibrium
relationship so that the amount of the ith chemical that is bound is calculated rather than
the rate. The equation is:
"•/• \h
ll:)) VLG (57)
7.2. 7.3 Calculation of Free Chemical in the Lung Tissue
The free chemical in the Lung Tissue is calculated by subtracting the amount bound from
the total amount as follows:
(58)
7.2.8 Metabolism in the Lung Tissue
The Lung Tissue metabolism equations are the same as those for the Liver given in
subsection 8.2, except that the equation for the V-Max is given as a function of the Liver
value from equation:
V
where RMtLC,,jr is a scaling factor for V-Max in the Lung Tissue for the jth metabolite of
the ith chemical.
7.2.9 Equation for the Pulmonary Capillaries
The ith chemical in the Pulmonary Capillary compartment (CP) is moved by diffusions
with the Alveoli and the Lung Tissue and with the two input and two output blood flows.
The equation is:
95
-------
CCP.F,
C/J fit iJWJ^-TAF, ' C/CRI-tS D """ * ttl.CP.^CI'^jili ~ * CP.AL.&Al t-'CW".
«<• ' HOOT
(60)
'LG.CPj&CP t-'£G,Fj ~ "cKLC, "LG ^Cl'f, ~ KB ^-CP.fl K-B.CP ^/III.Fj
The first two terms represent input to the Pulmonary Capillaries from venous blood and
output, via the Bronchial Vein, to the venous blood. The third and fourth terms represent
the diffusion of chemical in the Alveoli to or from the Pulmonary Capillaries. The next
two terms show the diffusion with the Lung tissue. The last two terms are output from the
Pulmonary Capillaries to arterial blood via the Cardiac Output, and the input from arterial
blood to the Pulmonary Capillaries via the Bronchial Artery. Note that the free ith
chemical is used in the venous blood, arterial blood, the Lung Tissue, and the Pulmonary
Capillaries.
7.2.10 Binding in the Pulmonary Capillaries
The binding in the Pulmonary Capillaries is of the Michaelis-Menten form but is an
equilibrium relationship so that the amount of the ith chemical that is bound is calculated
rather than the rate. The equation is:
(61)
7. 2. 11 Calculation of Free Chemical in the Pulmonary Capillaries
The free chemical in the Pulmonary Capillaries is calculated by subtracting the amount
bound from the total amount as follows:
•"•CP.FJ = ^-CPJ ~Acp.st (62)
7.2.12 Blood Flow for the Breathing Lung
The Cardiac Output QB, the sum of all the flows through the Liver, Fat, Kidney, Slowly
Perfused Tissue, Rapidly Perfused tissue, Derma, Brain, Pulmonary Capillaries, and
Walls of the Full GI is:
CiS ~ KB,SP CtB.iF """ $£B,CR KB.KD "^ CiA/'T "^ (dB,SL KB.KP ,-,,
""" \la,BN ~*~ KB.CP "*" tips
where the flow in the Portal Blood of the Full GI is:
GPB ~ QB.SW ~*~ QB.DV "*" QB.SI ^ QB.CN • (64)
96
-------
The blood flow out of the Pulmonary Capillaries (for the Breathing Lung) is equal to the
input, thus:
QB = QVB "*" QB.CP ~ QCP.VB (65)
The venous blood flow into the Pulmonary Capillaries, Qt?B, is:
QVB ~ QB.SP "*" QBJJ-' "^ I/B.CK "*" QB.KD ~^~ QB.FT ~^~ Qn.si ~^~ QB.RP ~^~ .RR.
" ""
7.2.13 Arterial Blood and the Breathing Lung
The ith chemical in the arterial blood (AB) flows from the Pulmonary Capillaries (CP)
and the free chemical flows into the Brain, Carcass, Derma, Fat, Kidney, Liver, Rapidly
and Slowly Perfused Tissue, and Spleen. It also flows into the GI Walls - Stomach,
Duodenum, Lower Small Intestine, and the Colon, arterial blood flows into the
Pulmonary Capillaries via the bronchial artery.
The equation for the arterial blood is expressed in terms of rate of change of amount as
(the rates of change for the blood flow through each compartment is calculated as above
for the static lung)
ft A /"/ js
€4/1 JB, __ UAtnvy,
7.2.14 Venous Blood Input to the Breathing Lung
The ith chemical in the venous blood flows into the Breathing Lung from each of the
compartments into the Pulmonary Capillaries (except the new GI Walls, see above).
There is also flow of the ith chemical from the Pulmonary Capillaries into the venous
blood via the bronchial vein.
The equation for venous blood (VB) must take into account the gain in chemical from the
Pulmonary Capillaries via the bronchial vein (the first term). The gain in chemical from
the body organs is followed by the term representing the loss of free chemical to the
Pulmonary Capillaries. The equation in terms of rate of change of amount is:
dAvn, CCP,F, , dABI¥t dA,NFj — dAnvBi
^ ^ + ^ + ^' ~ QS€ (68)
where [YY] = {BN, CR, DR, FT, KD, LV, RP, SL, SP}.
97
-------
7.2.15 Calculation of Uptake and Chemical in Exhaled Breath
The equations for the breathing lung are discontinuous when the breathing switches from
inspiration to expiration. The amount of the ith chemical is recorded at the start and end
of inspiration and the difference is taken to get the amount of chemical inhaled during a
breath (AlmB). The amount of the ith chemical exhaled during a breath (AfsmB) is found by
recording the amount at the start and end of exhalation and taking the difference. Then the
uptake is obtained from:
AVPBI ~ A,NHiBj —AEXHiBf (69)
The Percent Uptake is:
A
a upg.
PCT(Aun) = m-r!-. (70)
' Alt\'H,
The uptake values for the ith chemical only make sense when breathing contaminated air
is the only exposure. The average concentration of chemical in exhaled breath is found,
using the volume of air flow during exhalation (F,m/2), to be:
r = (71)
'-'EOT,*, V v '
' r TDL
7.2.16 Variable Definitions for Breathing Lung
The variables used in the Breathing Lung equations are defined as:
Area Variables
SAL = Area of the Alveoli;
SLG = Area of the Lung Tissue.
SCP = Area of the Pulmonary Arteries;
Variables for the Amount of Chemical
AAL = Amount of ith chemical in the Alveoli,
AEXH.B, = Amount of ith chemical exhaled during a breath;
AW,J?, = Amount of ith chemical inspired during a breath;
A/», = Amount of ith chemical in uptake in one breath.
Variables for the Concentration of Chemical
C,fl = Concentration of ith chemical in the Alveoli;
CCCf = Concentration of ith chemical in the Closed Chamber;
98
-------
Qp = Concentration of ith chemical in the Pulmonary Capillaries;
CCP.B, = Concentration of bound ith chemical in the Pulmonary Capillaries;
CCPiF = Concentration of free ith chemical in the Pulmonary Capillaries;
CEXH.B, = Concentration of ith chemical in exhaled breath;
Ciw = Concentration of ith chemical in the inhaled air;
C£D = Concentration of ith chemical in the Lower Dead Space;
CLG. = Concentration of ith chemical in the Lung Tissue;
CLG.B, = Concentration of bound ith chemical in the Lung Tissue;
CLc,Fi = Concentration of free ith chemical in the Lung Tissue;
CUD = Concentration of ith chemical in the Upper Dead Space;
Variables for the Coefficients for Inspiration and Expiration
/ = Coefficient for inspiration terms, see equation 47;
E = Coefficient for expiration terms, see equation 48.
Variables for the Binding in the Pulmonary Capillaries
KCRDB, = Equilibrium binding constant for the ith chemical in the Pulmonary Capillaries
corresponding to the Michaelis-Menten constant.
KCP.MXB, = Maximum amount of binding for the ith chemical in the Pulmonary Capillaries
corresponding to V-Max in the Michaelis-Menten equation.
Variable for the Number of Subjects
TV = Number of subjects in the closed chamber.
Variables for the Permeation Coefficients
PAL.CP, = Alveoli to Pulmonary Capillaries permeation coefficient for the ith chemical;
PALLG, = Alveoli to Lung Tissue permeation coefficient for the ith chemical;
PCP,AL, = Pulmonary Capillaries to Alveoli permeation coefficient for the ith chemical;
PCKLG, = Pulmonary Capillaries to Lung Tissue permeation coefficient for the ith
chemical;
PLG.AL, = Lung Tissue to Alveoli permeation coefficient for the ith chemical;
PLG.CP, = Lung Tissue to Pulmonary Capillaries permeation coefficient for the ith
chemical.
Variables for Volumetric Flow rates
QAIK = Volumetric flow rate of air during the breathing process;
QB = Cardiac Output (L/H) from current model;
99
-------
QBCP = Volumetric flow rate of chemical from arterial blood to the Pulmonary
Capillaries;
QCP.VB = Volumetric flow rate of the chemical from Pulmonary Capillaries to venous
blood.
QyB = Venous blood flow rate.
Variable for the Partition Coefficients
RCKIV, = Pulmonary Capillaries to venous blood partition coefficient for the ith chemical.
7.3 Equations for the Four Compartment Gastro-lntestinal (Gl) Simulation
The basic abridged Gastro-lntestinal (GI) Model has a Stomach and Intestine (Figure 8)
with Rate and Bolus Ingestion into the Stomach, flow from the Stomach to the Intestine
and from the Intestine to Intestinal Elimination. In addition, there is flow from the Spleen,
the Stomach and the Intestine to the Liver via Portal Blood. There is no Bile flow from
the Liver to the Intestine and no Lymph flow or pool. Arterial blood is an input only to
the Liver, not the Stomach or the Intestine.
Inputs
________ KST.IN
| Bolus Dose L....
Rate """"),„„,
Ingestions I
Infraperitoneal |
Injection |
23,8?'
Arterial Blood
,, , , _________ Ksirnj-Kt
,j»~jSP Spleen 000 l-/h.^>j^-
' " _ f \i
nR-n ' "
>. ^, I portal Rlnnfj
""•• ""T^iT ^
*• LV Liver 3 14" __/ '
QBw r^^
U
KlN.FEC
.»' IN Intestine —-• -W^ Intestinal
. l^ Elimination
M pp — '
Spleen Metabolites
i
_iver Metabolites
Venous
Figure 8. Stomach/Intestine Gastro-lntestinal Model.
100
-------
In the Full unabridged GI model (Figure 9), the terminology and the compartments are
changed from the basic abridged Gastro-Intestinal (GI) Model. The variable names used
in ERDEM and the variables used in these equations are given in tables by compartment.
The equations are written for a more general case where there are a number of circulating
compounds.
AB Arterial Blood 1
B'Oius Dose t
Ingestion (
Metis
The three Walts, DU,
S!, and CN
shemieal in the lip-ids
o the Lymph Pt»l{lP)
^ LV Liver
A
I/ * Blle Non-Lipid
; " How Ho*
""- -- Flow '" '' ->• STl Starr
! 1
t
r**- , • ~* ' *..w^™ ™.WWW|
^" [ 1
PB
ach Wall h"
ath Lumen
I Food Flow
j I Y
Blood j nui Duodenum t umer
i Lip'd • NotAipid
! Flow t |
! OU Duoctenun Woll L
! Fooc
!•* ' SI Lower Small Intestine Wall
i L'P'd j Non-Lipid
i f"'0* ! Flow 1
j 1 -i
| SI Lower Small Intestin
i
i
i f
j-«e- 1 CM Colon Wall
j
j Lipid A A
j How j Non-Liprd
i i Flow
! CN Colon Luiien
,
%
Flow
\
Lumen
I
%
Food Flow
L
Portal Blood
t
-*»
Po
Blc
,-j
tal The lymph ftew consists of
od ChytomlCirons that are fat
in ttie blood, To ted the aFtioii
a chemical in the blood, ft» Ly
amount must be adde^f,
\ Lymph
™«™.,™»™,.«. i^ -i^. xx Compartments
Lymph is t© the
fallowing cosrtpartrae
Lwer, Spleen, Caress
Kktney, Fai
Rapidly Perfy&^d Its
D^fma, Brainr Slalic
and the Pulmonary
Capillaries,
Lymph
Pool
/•-
Qr'cces,
^jL
intestinal
Elimsnali-on
Figure 9. Full Gastro-Intestinal Tract Model.
101
-------
There are eight compartments and four sections. Each section consists of a Wall and a
Lumen. The wall of the Stomach is designated SW and the lumen is STL. In a similar
manner the designations for the Duodenum are DU and DUL for the Duodenum Luman,
for the Lower Small Intestine, SI and SIL, and for the Colon, CN and CNL.
Arterial blood flows into the Liver and the wall of each section. Bile flows from the Liver
to the Duodenum. Food flows from the Stomach through the other three sections to the
Feces. Portal Blood (PB) flows from the Stomach, Duodenum, Lower Small Intestine,
and the Colon Walls to the Liver. There is a Non-Lipid (NL) flow from the Lumens to the
Walls of these four compartments.
There is chylomicron flow from the Lymph Pool to the Brain, Carcass, Derma, Kidney,
Liver, Fat, Rapidly Perfused Tissue, Slowly Perfused Tissue (Muscle), and the Spleen. In
addition there is chylomicron flow to the static lung and to the Pulmonary Capillaries of
the Breathing Lung. Lipid absorption occurs from the Lumen to the Wall for each of the
Duodenum, Lower Small Intestine and the Colon as well as from the respective Walls to
the Lymph Pool. And of course there is flow from the Liver to the venous blood.
Metabolism is modeled in the walls of the Stomach, Duodenum, Lower Small Intestine
and the Colon.
7.3.1 Flow Through the Stomach Wall
The mass balance input equation for the ith circulating chemical in the Stomach Wall
(SW) enters from the arterial blood, non-lipid flow from the Stomach Lumen, and
metabolites of other chemicals which represent the ith chemical. The outputs go to the
Portal Blood as parent compound and metabolites. The terminology in ERDEM indicates
flow as subscripts from the left to the right entering a compartment. The equation is:
_ ............
(72)
dt >
where
NMj = the number of metabolites of the ith chemical,
Ilm = the circulating compound that is the mth metabolite of the /th circulating
compound, and
C = the concentration of the ith chemical in the arterial blood.
ABi
The variables for the Stomach Wall are given in Table 1.
102
-------
Table 1. Variables for the Stomach Wall
Variable in
Documents
"A-SWMij
dt
swt
dC<,w
bWt
ls- dt
&B,SW
r>
/\W,PB,.
vsw
Variable in ERDEM
(for the Stomach Wall)
STME_1DA_SW_M(I,J)
STWL_1C_SW(I)
STWL_1DA_SW(I)
QB_SW
STWL_1R_SW_PB(I)
STWL_1V_SW
Description
The rate of formation of thejth Stomach Wall
metabolite of the ith chemical.
The concentration of the ith chemical in the
Stomach Wall.
The rate of change of the amount of the ith
chemical in the Stomach Wall.
The volume rate of Arterial Blood flow through the
Stomach Wall.
The partition coefficient for the ith chemical
moving from the Stomach Wall to Portal blood.
The volume of the Stomach Wall.
7.3.2 Flow Through the Stomach Lumen
The flow of the ith chemical through the Stomach Lumen (with no delay currently
implemented) is due to input from Rate Ingestion or bolus dose, and output food flow into
the Duodenum and Non-Lipid absorption into the Stomach Wall,
Vv
STLL
7T~
_
(73)
where
dA
and
-r— = the rate of change of the amount of the ith chemical in the bolus dose,
—-rp1 = the rate of change of the amount of the ith chemical in the Rate
Ingestion.
The data for the Stomach Lumen is given in Table 2.
103
-------
Table 2. Stomach Lumen Variables
Variable in
Documents
AsTLt
^STit
Ct\_- ci'T'T
Tr ^1L'
fm dt
dp, STL
v~
^NL,SWi
VSTL
Variable in ERDEM
(for the Stomach Lumen)
STLM_1A_STL(I)
STLM_1C_STL(I)
STLM_1DA_STL(I)
STLM_1QF_STL_DUL
STLMJ K_STL_SW_NL(I)
STLM_1V_STL
Description
The amount of the ith chemical in the Stomach Lumen.
The concentration of the ith chemical in the Stomach Lumen.
The rate of change of the amount of the ith chemical in the
Stomach Lumen.
The volume rate of food flowing through the Stomach Lumen to
the Duodenum.
The rate constant for the amount of the ith chemical in Non-
Lipid flow from the Stomach Lumen to the Stomach Wall,
The volume of the Stomach Lumen.
7.3.3 Flow Through the Duodenum Wall
The rate of change of the ith chemical in the Duodenum Wall is due to input from arterial
blood, Lipids from the Lumen, Non-lipids absorbed from the Lumen, and metabolites
from chemicals which are the ith chemical. The ith chemical is output by flow from the
Duodenum Wall to the Lymph Pool and the Portal Blood, as well as metabolized
chemical. The equation for the Duodenum Wall is given by:
v
V
DV
dt
where Table 3 presents the variables for the Duodenum Wall.
(74)
104
-------
Table 3. Variables for the Duodenum Wall
Variable in
Documents
DUt
dADUMij
dt
CDUi
dCDUi
DU dt
v~
^DU,LPt
&B,DU
r>
I^DU,PBi
VDU
Variable in ERDEM
(for the Duodenum Wall)
DUWL_1A_DU(I)
DUME_1A_DU_M(I,J)
DUWL_1C_DU(I)
DUWL_1DA_DU(I)
DUWL_1K_DU_LP(I)
QB_DU
DUWL_1R_DU_PB(I)
DUWL_1V_DU
Description
The amount of the ith chemical in the Duodenum Wall.
The rate of change of the amount of the jth Duodenum metabolite
of the ith chemical.
The concentration of the ith chemical in the Duodenum Wall.
The rate of change of the amount of the ith chemical in the
Duodenum Wall.
The rate constant for the ith chemical in Lipids moving from the
Duodenum Lumen to the Wall, and from the Wall to the Lymph
Pool.
The volume rate of Arterial Blood flow through the Duodenum
Wall.
The partition coefficient for the ith chemical moving from the
Duodenum Wall to Portal blood.
The volume of the Duodenum Wall.
7.3.4 Flow Through the Duodenum Lumen
The rate of change of the ith chemical in the Duodenum Lumen is determined by the rate
that food enters from the Stomach Lumen and exits to the Lower Small Intestine Lumen
as well as output by absorption to the Stomach Wall. In addition the Bile from the Liver
flows in and Lipid flows out to the Wall. The equation for the rate of change of the ith
chemical in the Duodenum Lumen is:
Ul
STL
*-BL,DUL
(75)
where
CLV. = the concentration of the ith chemical in the Liver,
GBL.DUL, = the volumetric flow rate of Bile from the Liver to the Duodenum
Lumen for the ith chemical, and
105
-------
RBL.DUL. = the partition coefficient for the ith chemical Bile flow from the Liver to
the Duodenum Lumen.
The other variables for the Duodenum Lumen are given in Table 4:
Table 4. Duodenum Lumen Variables
Variable in
Documents
A
DULt
DULt
dCDULi
DUL dt
&F,DUL
v~
1^NL,DUi
VDUL
Variable in ERDEM
(for the Duodenum Lumen)
DULM_1A_DUL(I)
DULM_1C_DUL(I)
DULM_1DA_DUL(I)
DULM_1QF_DUL
DULM_1 K_DUL_DU_NL(I)
DULM_1V_DUL
Description
The amount of the ith chemical in the Duodenum Lumen.
The concentration of the ith chemical in the Duodenum
Lumen.
The rate of change of the amount of the ith chemical in the
Duodenum Lumen.
The volume rate of food flowing through the Duodenum
Lumen to the Small intestine.
The rate constant for the amount of the ith chemical in Non-
Lipids moving from the Duodenum Lumen to the Duodenum
Wall.
The volume of the Duodenum Lumen.
7.3.5 Flow Through the Lower Small Intestine Wall
The ith chemical is input to the Lower Small Intestine Wall (SI) from the arterial blood,
in Lipids from the Lumen, and Non-Lipid absorption from the Lumen. The output of the
ith chemical is to Portal blood, and Lipids to the Lymph Pool. The equation for the Lower
Small Intestine Wall is:
si
dt
a
B.SI
(76)
dt T^ dt
where Table 5 contains the variables for the Lower Small Intestine Wall.
106
-------
Table 5. Variables for the Lower Small Intestine Wall
Variable in
Documents
ASI,
CSI,
y K*.
IS' dt
&si,LPt
&B,SI
r>
^SI.PB,
vsl
Variable in ERDEM2.01
(for the Lower Small Intestine Wall)
SIWL_1A_SI(I)
SIWL_1C_SI(I)
SIWL_1DA_SI(I)
SIWL_1K_SI_LP(I)
QB_SI
SIWL_1R_SI_PB(I)
SIWL_1V_SI
Description
The amount of the ith chemical in the Lower Small
Intestine Wall.
The concentration of the ith chemical in the Lower
Small Intestine Wall.
The rate of change of the amount of the ith chemical in
the Lower Small intestine Wall.
The rate constant for the ith chemical in Lipids moving
from the Lower Small Intestine Lumen to the Wall, and
from the Wall to the Lymph Pool.
The volume rate of Arterial Blood flow through the
Lower Small Intestine Wall.
The partition coefficient for the ith chemical moving
from the Lower Small Intestine Wall to Portal blood.
The volume of the Lower Small Intestine Wall.
7.3.6 Flow Through the Lower Small Intestine Lumen
For the Lower Small Intestine Lumen, the ith chemical is input in the food from the
Duodenum Lumen and output via the food to the Colon. The ith chemical is also output in
the Lipids to the Wall and absorption of Non-Lipids to the Wall. The equation for the
Lower Small Intestine Lumen is given by
SIL
C/RPl/I, ^IMJL,
lf KF.
F.Sll
(77)
where the variables for the Lower Small Intestine Lumen are given in Table 6.
107
-------
Table 6. Lower Small Intestine Lumen Variables
Variable in
Documents
SILt
SILi
dCs,L:
ISIL dt
&F,SIL
v~
^NL^I,
VS1L
Variable in ERDEM
(for the Lower Small Intestine Lumen)
SILM_1A_SIL(I)
SILM_1C_SIL(I)
SILM_1DA_SIL(I)
SILM_1QF_SIL
SILM_1K_SIL_SI_NL(I)
SILM_1V_SIL
Description
The amount of the ith chemical in the Lower Small
Intestine Lumen.
The concentration of the ith chemical in the Lower
Small Intestine Lumen.
The rate of change of the amount of the ith chemical
in the Lower Small Intestine Lumen.
The volume rate of food flowing through the Lower
Small Intestine Lumen to the Colon.
The rate constant for the amount of the ith chemical
in Non-Lipids moving from the Lower Small Intestine
Lumen to the Lower Small Intestine Wall.
The volume of the Lower Small Intestine Lumen.
7.3.7 Flow Through the Colon
The input to the Colon Wall (SI) is the ith chemical from the arterial blood, the Lipids
from the Lumen, and the Non-Lipid absorption from the Lumen. The output is to Portal
Blood and Lipids to the Lymph Pool. The equation for the Colon Wall is:
(7
B,CN
____
D
J\r
CN'.PB,
£_ \ i
/ ~
i
(78)
dt
(It
where the variables for the Colon Wall are presented in Table 7.
108
-------
Table 7. Variables for the Colon Wall
Variable in
Documents
CW,
QA,
dCCNi
ICN dt
^CN,LPi
Q^B,CN
*^CN,PBt
VCN
Variable in ERDEM
(for the Colon Wall)
CNWL_1A_CN(I)
CNWL_1C_CN(I)
CNWL_1DA_CN(I)
CNWL_1K_CN_LP(I)
QB_CN
CNWL_1R_CN_PB(I)
CNWL_1V_CN
Description
The amount of the ith chemical in the Colon Wall.
The concentration of the ith chemical in the Colon Wall.
The rate of change of the amount of the ith chemical in the Colon Wall.
The rate constant for the ith chemical in Lipids moving from the
Lumen to the Wall, and from the Wall to the Lymph Pool,
Colon
The volume rate of Arterial Blood flow through the Colon Wall.
The partition coefficient for the ith chemical moving from the Colon
Wall to Portal blood.
The volume of the Colon Wall.
7.3.8 Flow Through the Colon Lumen
For the Colon Lumen, the input is the ith chemical in the food from the Lower Small
Intestine Lumen, and the output is the ith chemical in the lipids to the Wall, the
absorption of chemical in the Non-Lipids to the Wall, and Feces elimination.
The equation for the Colon Lumen is given by:
V ~ "V N ~
* CNL (j'f
/V.iPi OVi,
(79)
where Table 8 contains variable definitions for the Colon Lumen.
109
-------
Table 8. Colon Lumen Variables
Variable in
Documents
CM,
CM,,.
dCCNLi
CNL dt
&CNL,FEC
v~
1^NL,CNi
VCNL
Variable in ERDEM
(for the Colon Lumen)
CNLM_1A_CNL(I)
CNLM_1C_CNL(I)
CNLM_1DA_CNL(I)
CNLM_1QF_CNL_FEC
CNLM_1 K_CNL_CN_NL(I)
CNLM_1V_CNL
Description
The amount of the ith chemical in the Colon Lumen.
The concentration of the ith chemical in the Colon Lumen.
The rate of change of the amount of the ith chemical in the
Colon Lumen.
The volumetric rate of excretion from the Colon to the feces
for the ith chemical
The rate constant for the amount of the ith chemical in Non-
Lipids moving from the Colon Lumen to the Colon Wall.
The volume of the Colon Lumen.
7.3.9 Flow Through the Lymph Pool
The ith chemical is input to the Lymph Pool from the Wall of the Duodenum, Lower
Small Intestine and Colon. The ith chemical is output to the Brain, Carcass, Derma,
Kidney, Liver, Fat, Rapidly Perfused Tissue, Slowly Perfused Tissue and the Spleen from
the chylomicrons in the Lymph Pool. The ith chemical in the chylomicrons is also passed
to the static lung and the Pulmonary Capillaries (Breathing Lung). The chemical in the
Lipids is passed from the Lumen to the Wall of these compartments and from the Wall to
the Lymph Pool. The equation is:
dA
IP,
dt
"•'LKPr^Lf1,
"./PHW."/P. "/pr*e."ip.
(80)
where the variables for the Lymph Pool are defined in Table 9.
no
-------
Table 9. Variables for the Lymph Pool
Variable in
Documents
LPi
dALPi
dt
V
^LP.BN,
^LP,CR,
V
JVLP,£«,.
V
^LPfTt
V
r^LP,KDi
V
r^LP,LVi
V
^LP,RPt
^LP,SLt
^LP,SPi
V
JviP,C^.
V
^LP,PUt
Variable in ERDEM
(for the Lymph Pool)
LPYL_1A_LP(I)
LPYL_1DA_LP(I)
LPYL_1K_LP_BN(I)
LPYL_1K_LP_CR(I)
LPYL_1K_LP_DR(I)
LPYL_1K_LP_FT(I)
LPYL_1K_LP_KD(I)
LPYL_1K_LP_LV(I)
LPYL_1K_LP_RP(I)
LPYL_1K_LP_SL(I)
LPYL_1K_LP_SP(I)
LPYL_1K_LP_CP(I)
LPYL_1K_LP_PU(I)
Description
The amount of the ith chemical in the Lymph Pool.
The rate of change of the amount of the ith chemical in the Lymph
Pool.
The rate constant for flow in the Lipids from the Lymph Pool to the
Brain.
The rate constant for flow in the Lipids from the Lymph Pool to the
Carcass.
The rate constant for flow in the Lipids from the Lymph Pool to the
Derma.
The rate constant for flow in the Lipids from the Lymph Pool to the Fat.
The rate constant for flow in the Lipids from the Lymph Pool to the
Kidney.
The rate constant for flow in the Lipids from the Lymph Pool to the
Liver.
The rate constant for flow in the Lipids from the Lymph Pool to the
Rapidly Perfused Tissue.
The rate constant for flow in the Lipids from the Lymph Pool to the
Slowly Perfused Tissue.
The rate constant for flow in the Lipids from the Lymph Pool to the
Spleen.
The rate constant for flow in the Lipids from the Lymph Pool to the
Pulmonary Capillaries.
The rate constant for flow in the Lipids from the Lymph Pool to the
Static Lung.
The amount of the ith chemical in the venous blood is given by:
^4 ra. = A ra. + ALPj, (81)
where AVBj = the amount of the ith chemical in the venous blood.
7.3.10 Portal Blood and Bile Flow
The volumetric flow rate of the Portal Blood is determined by the flows from each of the
compartment Walls (Stomach, Duodenum, Lower Small Intestine, and the Colon) and
from the Spleen. This flow is a constant in this implementation. The value is given by:
ill
-------
"•" V?S;DI/ " tfs,s/~"~ ijs.ov ~"~ Ha.s/*
and the rate of change of the amount of the ith chemical in Portal Blood is given by the
contributions from the Walls of the GI, the rate that chemical passes from the Spleen (SP)
and the rate of injection of chemical from Intraperitoneal Injection (INP). The ith
chemical is passed from the Portal Blood to the Liver:
(83)
where the Portal Blood variables are presented in Table 10.
Table 10. Variables for the Portal Blood
Variable in
Documents
PBi
PBi
dAPBi
dt
&PB,LV
Variable in ERDEM
(for the Portal Blood)
PRBL_1A_PB(I)
PRBL_1C_PB(I)
PRBL_1DA_PB(I)
Q_PB
Description
The amount of the ith
chemical in the Portal Blood.
The concentration of the ith chemical in the Portal Blood.
The rate of change of the amount of the ith chemical in the Portal
Blood.
The volumetric Portal
Blood flow rate.
7.3.11 Flow in the Liver Compartment and Bile Flow to the Duodenum Lumen
In the Liver the ith chemical is (1) output from the Liver to venous blood, (2) contained in
the Bile flow to the Duodenum Lumen, (3) eliminated by some process to be defined, and
(4) metabolized to other compounds (metabolites). Input of the ith chemical is from (1)
Intraperitoneal Injection, (2) the arterial blood, (3) the Walls of the Stomach, Duodenum,
Lower Small Intestine and Colon via Portal blood, and (4) metabolites which are the same
chemical (resulting from metabolism of any of the circulating compounds). The rate of
change of the ith chemical in the Bile flowing to the Duodenum from the Liver is given
by:
dA
BL
dt
Q,
R
(84)
BI..DVI.
112
-------
and the rate of change of the ith chemical in the Liver is:
jQi.-L _
"HP ~ SRir<
__
C
LKF,
, - 0
"
B>
"
•LKLy^LP, ~~ Qei,
^BL.OUL,
2£ . V
i - fit
*Clw^
(85)
where the variables for the Liver and Bile flow are presented in Table 11.
Table 11. Variables for the Liver and Bile
Variable in
Documents
ABL,
Q,
LV,F,
dABLi
dt
^LV,Ei
dt
dAM LV
1 ->j
dt
R
BL,DUL
i
v dc^
l»- dt
*C,l,m
NM,
QB,LV
n
^LVyBt
Variable in ERDEM
(for the Liver and Bile)
LIVR_1A_BL(I)
LIVR_1C_LV(I)
LIVR_1C_LV_F(I)
LIVR_1DA_BL(I)
LIVR_1DA_LV_E(I)
LIVR_1DA_LV_M(I,J)
LIVR_1R_BL_DUL(I)
LIVR_1DA_LV(I)
I_CMPD(I,M)
N_M(I)
QB_LV
LIVR_1R_LV_VB(I)
Description
The amount of the ith chemical in the Bile.
The concentration of the ith chemical in the Liver.
The concentration of Free ith chemical in the Liver.
The rate of change of the amount of the ith chemical in the
Bile.
The rate of elimination of the ith chemical from the Liver.
The rate of formation of the jth Liver metabolite of the ith chemical.
Bile to Duodenum lumen partition coefficient for the ith chemical.
The rate of change of the amount of the ith chemical in the
The index of the chemical that is the mth metabolite of the
chemical.
Liver.
Ith
The number of metabolites for the ith chemical.
The volumetric flow rate of blood through the Liver.
The partition coefficient for flow of the ith chemical from the Liver to
the Venous Blood.
113
-------
7.3.12 Chylomicron Flow in the Other Compartments
An additional term representing Chylomicron flow is added to the equations previously
specified for the compartments, Brain, Carcass, Derma, Fat, Kidney, Liver, Pulmonary
Capillaries, Rapidly Perfused Tissue, Spleen, Slowly Perfused Tissue, and the static lung.
Using the Fat compartment as an example, Chylomicrons enter the Fat via the arterial
blood (Lipids from the Lymph Pool). The Chylomicrons are mostly removed from the
blood by the Liver and the Fat. Table 12 contains the description of the variables used in
the equation for the Fat.
Table 12. Variables for the Fat
Variable in
Documents
L-FTi
^FT,Ft
^FT,Et
dt
A
^M,FTtJ
dC^
l" dt
&B,FT
r>
I^FT,VBi
Variable in ERDEM
FAT_1C_FT(I)
FAT_1C_FT_F(I)
FAT_1DA_FT_E(I)
FTME_1DA_FT_M(I,J)
FAT_1DA_FT(I)
QB_FT
FAT_1R_FT_VB(I)
Description
The concentration of the ith chemical in the Fat.
The concentration of Free ith chemical in the Fat.
The rate of elimination of the ith chemical from the Fat.
The rate of formation of thejth Fat metabolite of the ith
The rate of change of the amount of the ith chemical in
chemical.
the Fat.
The volumetric flow rate of blood through the Fat.
The partition coefficient for flow of the ith chemical from
the Venous Blood.
the Fat to
FT
FT,
dt
QB.FT ^-AB, "*" '^LP,FTi ^LP,: QB.FJ
1 M.FTn
(86)
dt
7.4 Dermal Exposure
Dermal exposure involves contact with surfaces that results in transfer of surface
residues. The mass of residue transferred to the skin is dependent on the frequency
(events/unit time), duration (time/event), and magnitude or extent of body surface area
114
-------
(cm2) contacted and the transferability of the surface residue. It therefore follows
intuitively, that dermal exposure is not measurable in the absence of surface contact with
resultant surface-to-skin transfer of residues.
Humans come into contact with surfaces through the actions they perform in space
(micro-environments) over a random or stratified period of time. This time-motion
relationship has been termed the "biomechanics" of dermal exposure. The frequency,
duration and magnitude of surface contact can be discerned for occupational exposure
where activities are assigned and followed according to established practices, policies and
procedures. Incidental dermal exposure is more problematic than occupational exposure
given the random and generally unpredictable nature of contact events. Clearly, the
measurement, estimation or prediction of a dermal exposure dose metric based on the
biomechanics of dermal exposure is research intensive and fraught with uncertainty. We
are confronted not only with the uncertainties surrounding the biomechanics of exposure
but with dermal transfer factors that are residue and surface media dependent (U.S. EPA,
1998b).
One solution to this problem is to acknowledge the complexities and uncertainties of
occupational and incidental dermal exposure and deal with dermal absorption at the
boundary of exposure. The dermal dose metric would involve the delivered mass of
chemical in a vehicle as represented by a transfer relationship from a surface medium. We
are therefore interested in the absorption of the delivered dose into the test system as a
means to test metabolism, distribution, elimination and untoward effects of any assigned
dermal dose metric, from the perceivable low dose minimum to the most unlikely dose
maximum. Dermal exposure is modeled in ERDEM according to presumed outdoor or
indoor exposure as chemical residue in a vehicle on the surface of the skin. The default
vehicle is aqueous (water) as used to derive the permeation coefficient (Kp) through in
vitro testing of dermal flux (U.S. EPA, 1992). Dermal absorption from an aqueous
vehicle may be compared with absorption from dry residues transferred to the skin from
contact with foliage, turf, and solid indoor surfaces, e.g. carpet, vinyl flooring, and
painted sheetrock (U.S. EPA, 1998b).
7.4.1 Skin Surface Exposure to Water or Other Vehicle
The skin surface is exposed to chemical in a vehicle (specified as water here) at time Tsmf/
for a period of time, TSKWJ)I , which can be repeated at the interval, Tsm,;7I/. Skin surface
water exposures in progress at simulation start time are started and their termination is
scheduled.
The concentration of the ith chemical at the skin surface is found from summing the
concentrations from each of up to five exposure scenarios:
115
-------
= T c (87)
Af ^SKWJjj V '
The rate of change of chemical in the dermis due to the concentration CSKSt on the skin
surface is given by:
(88)
116
-------
Variable Definitions for Skin Surface Water Exposure
ASK = Area of the skin covered by the solution containing the chemical,
^SKW.DK = The amount of the ith chemical that has moved from the skin surface to the
Dermis in a water exposure,
^:^*5ggL = The rate of change in the amount of the ith chemical moving from the skin
surface to the Dermis in a water exposure,
CSKS = The concentration of the ith chemical on the skin surface due to all
overlapping exposures,
CSKWJ, = The concentration of the ith chemical for the jth exposure on the skin
surface,
KSKS.DK.PRM- = The permeation coefficient for the ith chemical from Skin Surface to
Dermis.
7.4.2 Skin Surface Exposure to Transfer from a Dry Surface
A chemical exists on a surface represented as a mass per unit area. It is transferred to the
skin of a subject represented by a transfer coefficient. A short exposure period would
represent a bolus.
The rate of change of chemical on the dermis due to a dry exposure is:
= A r (89)
Integrating this equation gives the total applied dose.
The rate of loss of chemical from the skin surface due to evaporation is given by:
dA.
r-1- = (1.0 - dwt!/)/fsfa,(6CT, Ksf,s>ev1i + 8CT2JLsfeer2()
where 6,,a/ = 1 if a wash-off is in progress, and zero otherwise,
dei,i = 1 if the first evaporation rate constant is active and zero otherwise,
6ev2 = 1 if the second evaporation rate constant is active and zero otherwise.
(90)
117
-------
The rate that the ith chemical moves from the skin surface into the dermis is given by:
-^-^ =K 4 C
(ft -<\ffo-Ap™/J.rt *-.tfa,
where
(92)
If no wash-off is in progress, then the rate of change of the amount of the ith chemical on
the skin is given by the rate of application minus the rate of chemical moving into the
dermis minus the rate of loss due to evaporation:
_
dl ~ dt dt ~ dt
,93)
If a wash-off is in progress, then:
dAsiaij _ dAsbiWgf.
dt = ^ dt
where the wash-off is scheduled at time twoffor one time step, At, to remove all chemical
on the dermis:
(95)
dt v™*>- At wof-
Variable Definitions for Dry Skin Surface Exposure
The variables used to model the exposure to a chemical on a dry surface are:
•Ask,. = The amount of the ith chemical on the skin,
A3ks
-------
Asurfj = The amount of the ith chemical per unit area on the surface object for the jth
scenario - in mass/cm2;
Dsk = The depth of the skin (in some cases it is taken as one centimeter)
KskS:,.,t = The residue transfer coefficient for the ith chemical moving from the
surface object to the skin of the subject - in cm2/time;
KsKs,EY\i = The rate of loss of chemical from the skin just after application due to
processes such as evaporation for the ith chemical - in I/time (used only if it
is a bolus dermal exposure);
Ksics,En. = The rate of loss of the ith chemical from the skin due to processes such as
evaporation, from the end of the initial evaporation until wash-off, the end
of the simulation, or the next exposure, - in I/time;
Vsk = Volume of the treated skin,
Afev, = The time interval between the use of the first and second evaporation rate
constant.
119
-------
120
-------
Section 8
Chemical Disposition in silico
Absorption involves entry of a drug or chemical into the body. We have observed that a
chemical may enter directly into the GI tract from intraperitoneal injection (subsection
6.1.1) or more naturally from ingestion of food or from purposeful or accidental "non-
dietary" ingestion of filth and extraneous matter (pica or geophagia). Mathematical
expressions used to describe absorption into the GI tract were presented in subsection 7.3
for the enteral route of exposure.
The parenteral route involving inhalation exposure was explored in subsection 7.1 for the
static lung and subsection 7.2 for the breathing lung. The parenteral route bypasses the GI
tract as an organ system of entry. Subsection 7.4 examined the dermal route of parenteral
exposure.
Intravascular parenteral administration directly into the blood stream, intravenously or
intra-arterially, was considered as an exposure route although this route of administration
is important for laboratory or clinical testing (subsection 6.1.3). This approach was also
developed for intramuscular injection (subsection 6.1.2) as an avenue of comparison with
other parenteral routes of exposure, especially dermal.
Once the drug or chemical enters the blood stream, its disposition in blood and other
fluids, e.g. cerebrospinal fluid (CSF), organs and tissues determines its access to the site
or sites of action. Drug and chemical disposition involves distribution from blood and
fluids to tissues and organs, metabolism in liver and other organs of metabolism, and
elimination in exhaled breath, fluids, e.g. milk, and excreta.
8.1 Distribution of Chemical from Blood to Tissues, Organs and in Fluids
8.1.1 Binding in the Arterial Blood
The binding in the arterial blood is of the Michaelis-Menten form but is an equilibrium
relationship so that the amount of the ith chemical that is bound is calculated rather than
the rate. The equation is
121
-------
,t ,t
AB,Bt = ~7~j~^ , ATtvfr1 v\" AB
(KAB,DBi + Alj^(LAB,Fi))
8.1 .2 Calculation of Free Chemical in the Arterial Blood
The free chemical in the arterial blood is calculated by subtracting the amount bound
from the total amount as follows:
•"•AB,Ff ~ -n-ABi ~ -AjtBj. (97)
8.1.3 The Venous Blood
The venous blood contains chemical output from the compartments and input to the static
lung or the breathing lung. The chemical output to blood from the new GI walls is passed
to the portal blood.
8.1.3.1 Binding in the Venous Blood
The binding in the venous blood is of the Michaelis-Menten form but an equilibrium
relationship so that the amount of the ith chemical that is bound is calculated rather than
the rate. The equation is:
^m,MxBi VB,FI
= ~
8.1.3.2 Calculation of Free Chemical in the Venous Blood
The free chemical in the venous blood is calculated by subtracting the amount bound
from the total amount as follows:
^ FRF,. = A. m, — A ygiB( (99)
8.1.4 Distribution in Tissues
8.1.4.1 Distribution in the Residual Carcass
The rate of change of the ith chemical in the carcass is given by the rate that chemical
enters from the arterial blood, and in the chylomicrons from the lymph pool (when the
four walled GI model is used), and exits via the venous blood. Elimination is modeled
and the rate of elimination of the ith chemical is subtracted. Chemical may be
metabolized and the rate of metabolism further reduces the rate of increase of the
122
-------
chemical in the carcass. Other metabolites may metabolize to the ith chemical and their
rate of formation is added. The equation is:
•?.[-*
(100)
AW
where MW is molecular weight (not needed if mass units are in moles), and the variable
/c/m is the circulating compound that is the mth metabolite of the /th circulating
compound. The equations for metabolism are presented in subsection 8.2. Binding and
elimination equations are presented below.
Binding in the Carcass
The binding in the carcass is of the Michaelis-Menten form but is an equilibrium
relationship so that the amount of the ith chemical that is bound is calculated rather than
the rate. The equation is
CR,F,
. ^VCR (101)
CR,DBi + CR,Fi))
Calculation of Free Chemical in the Carcass
The free chemical in the carcass is calculated by subtracting the amount bound from the
total amount as follows:
ACIF^ACR-ACR* (102)
Elimination in the Carcass
There are two types of elimination currently implemented in ERDEM. A linear form in
which the rate of elimination is proportional to the rate of change of the amount of the
free ith chemical in the static lung and a saturable Michaelis-Menten form. The linear
form is
(103)
and the saturable form for elimination is:
123
-------
C
*-'Q?HP
(104)
8.1.4.2 Distribution in Fat Tissue
The rate of change of the ith chemical in the fat tissue is given by the rate that chemical
enters from the arterial blood and the chylomicrons from the lymph pool and exits via the
venous blood. Elimination is modeled and the rate of elimination of the ith chemical is
subtracted. Chemical may be metabolized and the rate of metabolism further reduces the
rate of increase of the chemical in the fat tissue. Other metabolites may metabolize to the
ith chemical and their rate of formation is added. The equation is:
dC,r C,r,
it ~ ........ QHII^~UI
(105)
The equations for metabolism are presented in the beginning of this section. Binding and
elimination equations are presented below.
Binding in Fat Tissue
The binding in the fat is of the Michaelis-Menten form but is an equilibrium relationship
so that the amount of the ith chemical that is bound is calculated rather than the rate. The
equation is:
if c<
r^FT,MxBl ^FT,Ft
AFT,B, = 7^ . PT (106>
(KFT,DBl
Calculation of Free Chemical in Fat Tissue
The free chemical in the fat tissue is calculated by subtracting the amount bound from the
total amount as follows:
AFTiFj — AW. ~ ^FiBj (107)
Elimination in Fat Tissue
There are two types of elimination currently implemented in ERDEM. A linear form in
which the rate of elimination is proportional to the rate of change of the amount of the
124
-------
free ith chemical in the static lung and a saturable Michaelis-Menten form. The linear
form is
*' H:S' i (108)
(ff
and the saturable form for elimination is
PT,E, ^TF,f",
(1U9)
dt r *ro> (KmM,FlEt + ABS(CF1:F))
8.1.4.3 Distribution in Slowly Perfused Tissue
The rate of change of the ith chemical in the slowly perfused tissue is given by the rate
that the chemical is input from intramuscular injections, from the lymph pool as
chylomicrons and as input from the arterial blood that exits via the venous blood.
Elimination is modeled and the rate of elimination of the ith chemical is subtracted.
Chemical may be metabolized and the rate of metabolism further reduces the rate of
increase of the chemical in the slowly perfused tissue. Other metabolites may metabolize
to the ith chemical and their rate of formation is added. The equation is:
.(«;
(110)
The equations for metabolism are presented in subsection 8.2. Binding and elimination
equations are presented below.
Binding in the Slowly Perfused Tissue
The binding in the slowly perfused tissue is of the Michaelis-Menten form but is an
equilibrium relationship so that the amount of the ith chemical that is bound is calculated
rather than the rate. The equation is:
, ,t
=
SL,DBi
SL,Bi = , /fOCY/^ \\ SL
(KS
Calculation of Free Chemical in the Slowly Perfused Tissue
125
-------
The free chemical in the slowly perfused tissue is calculated by subtracting the amount
bound from the total amount as follows:
ASLF,=^SLI-^SL,BI (112)
Elimination in the Slowly Perfused Tissue
There are two types of elimination currently implemented in ERDEM. A linear form in
which the rate of elimination is proportional to the rate of change of the amount of the
free ith chemical in the static lung and a saturable Michaelis-Menten form. The linear
form is:
j?^b«« y A MIS)
i~= A _. „ /4_. _ » '
and the saturable form for elimination is:
JV ¥ m of jr / E/" s A D'CY/"""* \\ ' '
at "-«•*» (f£,,lM,Sl,E, + ^•O^l^SI.Fj)
8.1.4.4 Distribution in Rapidly Perfused Tissue
The rate of change of the ith chemical in the rapidly perfused tissue is given by the rate
that chemical enters from the lymph pool as chylomicrons and from the arterial blood and
exits via the venous blood. Elimination is modeled and the rate of elimination of the ith
chemical is subtracted. Chemical may be metabolized and the rate of metabolism further
reduces the rate of increase of the chemical in the rapidly perfused tissue. Other
metabolites may metabolize to the ith chemical and their rate of formation is added. The
equation is:
(115)
The equations for metabolism are presented in subsection 8.2. Binding and elimination
equations are presented below.
Binding in the Rapidly Perfused Tissue
The binding in the rapidly perfused tissue is of the Michaelis-Menten form but is an
equilibrium relationship so that the amount of the ith chemical that is bound is calculated
rather than the rate. The equation is:
126
-------
A
RP,BI .
RP,DBi+
Calculation of Free Chemical in the Rapidly Perfused Tissue
The free chemical in the Rapidly Perfused Tissue is calculated by subtracting the amount
bound from the total amount as follows:
Elimination in the Rapidly Perfused Tissue
There are two types of elimination currently implemented in ERDEM. A linear form in
which the rate of elimination is proportional to the rate of change of the amount of the
free ith chemical in the static lung and a saturable Michaelis-Menten form. The linear
form is:
(118)
and the saturable form for elimination is:
«/>£, KP.f'f
\\ ' '
dt ¥'^< (
8.1.5 Distribution of Chemical in Organs
8.1.5.1 Distribution of Chemical from Blood to the Brain
The rate of change of the ith chemical in the brain is given by the rate that chemical enters
from the arterial blood and in the chylomicrons from the lymph pool (when the four
walled gastro-intestinal model is used), and exits via the venous blood. The blood/brain
barrier is modeled by properly choosing the partition coefficients. Elimination of
chemical from the brain is modeled and the rate of elimination of the ith chemical is
subtracted. Chemical may be metabolized and the rate of metabolism further reduces the
rate of increase of the chemical in the brain. Other metabolites may metabolize to the ith
chemical and their rate of formation is added. The equation is:
127
-------
17 - n r 4- A i n
»* /ft ~ X,B.BN**-AB.F. ~ *V/' fl\ *"*'," 1/R/n 0
Ml • ' *VI\ I ,'(,
(120)
_
The equations for metabolism are presented at the beginning of this section. Binding and
elimination equations are presented below.
Binding in the Brain
The binding in the Brain is of the Michaelis-Menten form but is an equilibrium
relationship so that the amount of the ith chemical that is bound is calculated rather than
the rate. The equation is:
,ii
BN,B = ~ i BN
Calculation of Free Chemical in the Brain
The free chemical in the Brain is calculated by subtracting the amount bound from the
total amount as follows:
(122)
Elimination from the Brain
There are two types of elimination currently implemented in ERDEM. A linear form in
which the rate of elimination is proportional to the rate of change of the amount of the
free ith chemical in the Static Lung and a saturable Michaelis-Menten form. The linear
form is:
(123)
128
-------
and the saturable form for elimination is
"-^/«,/•;, £-«\./,
dt ~ 'm,BN.E, (K 4- Af!<\lC \\
Ut i lAmMW,£, ^ /iQiJ^Lg^lJ
8.1.5.2 Distribution of Chemical to the Liver
Stomach/Intestine Model of Distribution to the Liver
The liver compartment has the ith chemical input from the stomach and intestine
following intraperitoneal injections. Input from the arterial blood is also included. The ith
chemical is moved from the liver to venous blood where it may be lost due to elimination.
Additional chemical is bound in the liver using an equilibrium process. Chemical may be
metabolized and the rate of metabolism further reduces the rate of increase of the
chemical in the Liver. Other metabolites may metabolize to the ith chemical and their rate
of formation is added. The equation is:
17 . — = *"" '' -f ——"- + — 4-
"' dt dt dt dt ' ~- "--; —"-' A/,Kra
\w_ JA IM \ ' (125)
?t dt '' +/,.?-/!" " eft"
where the equations for the input to portal blood from the stomach and the intestine are
respectively:
= ^ A *126)
and
Ct/li t\< i>w
'
=K A (127>
' "^'' >
where the variable /c/m is the circulating compound that is the mth metabolite of the /th
circulating compound. The equations for metabolism are presented at the beginning of
this section. Binding and elimination equations are presented below.
129
-------
Gastro-lntestinal Model of Distribution to the Liver
The liver compartment for the complete GI tract (subsection 7.3) has the ith chemical
input from the portal blood (from intraperitoneal injections) and lymph pool as
chylomicrons in addition to the input from the Arterial Blood. The ith chemical is moved
from the liver to the venous blood to the bile which is passed to the Duodenum Lumen,
and may be lost due to elimination. Additional chemical is bound in the Liver using an
equilibrium process. Chemical may be metabolized and the rate of metabolism further
reduces the rate of increase of the chemical in the Liver. Other metabolites may
metabolize to the ith chemical and their rate of formation is added. The equation is:
f/ wmmflJaJL — /"If //"'"'' ™~™wm™,-™i- \ J,
^f T iVmK^-ysi P -*- £// ^i {//
(^
(128)
The intraperitoneal injection in this case is passed to the portal blood.
Binding in the Liver
The binding in the liver is of the Michaelis-Menten form but is an equilibrium
relationship so that the amount of the ith chemical that is bound is calculated rather than
the rate. The equation is
V (~<
^Bi LV,F,
LV,DBi
Calculation of Free Chemical in the Liver
The free chemical in the liver is calculated by subtracting the amount bound from the
total amount as follows:
A-LVft ~ A.IV( — AU/BI (1 30)
Elimination in the Liver
There are two types of elimination currently implemented in ERDEM. A linear form in
which the rate of elimination is proportional to the rate of change of the amount of the
free ith chemical in the liver and a saturable Michaelis-Menten form. The linear form is:
130
-------
A
/t/
and the saturable form for elimination is:
tt.ilu C,,,
dt
(132)
8.1.5.3 Absorption and Distribution in the Stomach
The stomach has the ith chemical input by bolus ingestion (a plug of food or drink) and
rate ingestion (food or drink input over time), with chemical output to portal blood via the
liver to the intestine. The equation for the rate of change of ith chemical in the stomach is:
(133)
dt ~ ~ '
where the bolus ingestion and the rate ingestion exposures are discussed in subsection
6.2.1.
8.1.5.4 The Intestine
The rate of change of the ith chemical in the intestine is given by the rate of input from
the stomach and the rate of output to the portal blood via the liver to feces. The equation
is:
4 — jr 4 034)
•ABS,/N,PBi-ftlNi •*vyl.
8.1.5.5 The Kidney
The rate of change of the ith chemical in the kidney is given by the rate that chemical
enters from the arterial blood and in the chylomicrons from the lymph pool (when the
four walled GI model is used), and exits via the venous blood and the urine. Chemical
may be metabolized and the rate of metabolism further reduces the rate of increase of the
chemical in the kidney. Other metabolites may metabolize to the ith chemical and their
rate of formation is added. The equation is:
<-" *.c, , . '•'*', "-'*Am*\
(135)
..?' , v rMv".- 'V».';-,i
jt
131
-------
The equations for metabolism are presented at the beginning of this section. Binding and
elimination equations are presented below.
Binding in the Kidney
The binding in the kidney is of the Michaelis-Menten form but is an equilibrium
relationship so that the amount of the ith chemical that is bound is calculated rather than
the rate. The equation is:
,, ,,
AKD,BI = ~7~ *° (136)
KD,DBi
Calculation of Free Chemical in the Kidney
The free chemical in the kidney is calculated by subtracting the amount bound from the
total amount as follows:
A KD, ~ KD.B, (1 37)
Elimination in the Kidney
There are two types of urine elimination currently implemented in ERDEM. A linear
form in which the rate of elimination is proportional to the rate of change of the amount
of the free ith chemical in the Static Lung and a saturable Michaelis-Menten form. The
linear form is
u<>a\
(138)
and the saturable form for elimination is:
A A C
«•" If D, URN, *- KD. f",
' ~ "~ ~ '
ia.KO.URN, (If
' (AmM.KD.WW,
8.1.5.6 The Spleen
The rate of change of the ith chemical in the spleen is given by the rate that chemical
enters from the arterial blood, and in the chylomicrons from the lymph pool (when the
four walled GI model is used), and exits via the portal blood (or into the liver if the
stomach/intestine GI is used). Elimination is modeled and the rate of elimination of the
ith chemical is subtracted. Chemical may be metabolized and the rate of metabolism
132
-------
further reduces the rate of increase of the chemical in the spleen. Other metabolites may
metabolize to the ith chemical and their rate of formation is added. The equation is:
^Sl'1' "" ,»!£"
#«.,.„,
(140)
fit
The equations for metabolism are presented at the beginning of this section. Binding and
elimination equations are presented below.
Binding in the Spleen
The binding in the spleen is of the Michaelis-Menten form but is an equilibrium
relationship so that the amount of the ith chemical that is bound is calculated rather than
the rate. The equation is:
•VSP
^SP,DB,
Calculation of Free Chemical in the Spleen
The free chemical in the spleen is calculated by subtracting the amount bound from the
total amount as follows:
Asp,Fi~ ASP. —ASPJ. (142)
Elimination in the Spleen
There are two types of elimination currently implemented in ERDEM. A linear form in
which the rate of elimination is proportional to the rate of change of the amount of the
free ith chemical in the static lung and a saturable Michaelis-Menten form. The linear
form is:
tiLo. op &
*p'"' (143)
and the saturable form for elimination is:
133
-------
///I f
«yl %p F I*** ^l
17
"n.SKE,
' '
8.1.5.7 The Dermal Tissue
The dermal tissue receives the ith chemical by permeation through the skin and from the
arterial blood and is released to the venous blood according to the equation:
Mvxjrjjt WL/I ^/(^ i)f^ ^D./?
(145)
where
"•"•SK5.DR, HAC\
= r1 ft' JJfFA (146)
^ ^^
8.2 Metabolism in Selected Tissues and Organs
The term metabolism refers to any reaction that produces a new compound. ERDEM has
been designed to handle multiple circulating compounds. It is assumed that all
metabolites are circulating and the metabolism structure is the same in all compartments.
The metabolism parameters, however, can be different in each compartment. The
equations implemented in ERDEM are presented for the following areas:
• Enzyme Destruction and Re-synthesis:
Maximum rate of change of metabolite formation, taking enzyme destruction and
re-synthesis into consideration, is calculated.
• Maximum Rate of Metabolite Formation:
The maximum rate of formation of the metabolite is found for the liver by scaling
for species and body volume. The maximum rate for other compartments is scaled
from the Liver value.
• Saturable and Linear Metabolites:
Equations and parameters for calculating the rate of metabolite formation.
• Inhibition:
A metabolite or circulating compound may work in such a manner as to inhibit the
formation of another metabolite. There are four types of inhibition modeled here,
134
-------
competitive inhibition, mixed inhibition, strictly non-competitive Inhibition, and
uncompetitive Inhibition.
Equations are presented for the liver metabolism with circulating metabolites. The other
compartments use similar equations. This is a general form which can be applied to the
test case for trichloroethylene (TCE). Chart 1 shows one rendering of TCE which has five
(six if DCA is included) circulating compounds including the parent chemical. The
chloral and DCA may be treated as if they are circulating compounds in the metabolism
structure, but metabolism parameters would be set so that they do not circulate (the DCA
is excreted completely in feces and urine so there must be some circulation). The
chemical CH is a metabolite of chloral and of TCOH. There is no inhibition depicted in
this chart. All seven compounds are handled as circulating compounds in all
compartments. The equation for each metabolism process would be the same in each
compartment.
The metabolism parameters, maximum velocity (V-Max) and the Michaelis-Menten
constant (Km) could be different in each compartment. Each circulating compound may
or may not be metabolized in any compartment. Chart 2 shows the separate metabolism
for each compound from Chart 1 with the numbering that would be applied. Each
circulating compound is shown with its metabolites. The separate numbering of the
metabolites of a circulating compound is required since separate metabolism parameters
are required for each metabolite.
We are only concerned with the V-Max for metabolism in the Liver. The V-Max for
metabolism in other compartments is calculated from that used in the Liver. If the units of
volume are changed, the units of the input V-Max cannot be changed. Also the units of
the volume of the body used for the scaling conversion cannot be changed. In other
words, there can be no volume units conversion before the calculation of the scaled
version of the V-Max.
An input reference body volume is assumed (currently one unit) and the V-Max input is
assumed to be in units of amount per unit time. The calculation of V-Max then always
works. A volume units change is applied both to the reference body volume as well as the
current body volume. This then would be consistent for the scaling of the V-Max for
elimination as will the maximum binding value in the calculation of the amount bound.
This ratio of body volumes will be used throughout the scaling processes in ERDEM.
8.2.1 Implementation Outline
If a circulating compound is metabolized, then one or more metabolites are defined.
These may be linear, saturable, or be effected by one of four types on inhibition. Each of
these metabolites are themselves considered to be circulating.
135
-------
The user will input the circulating compound number for each metabolite. The number of
metabolites for each circulating compound is used as the input. These metabolites are also
assumed to be circulating. The user will input metabolism parameters using ij with "i"
being the index to the circulating compound and "j" being the metabolite counter for the
metabolites of circulating compound i. The user will need to input set, print, display and
plot statements using the index i.
The individual metabolite amounts are calculated in the compartmental calculations for
the individual chemical. The metabolism section for each compartment calculates two
sums. The first is the sum of all rates of metabolite formation of the ith circulating
compound. The second is the sum of the rate of formation of all metabolites that are the
same as the ith circulating compound. These rate sums are integrated in the circulating
compound section for each compartment.
8.2.2 Variable Names for Metabolism Parameters
Table 13 presents variable names, with a short description, that are used globally in all
compartments. The variables used in the metabolism calculations are shown in Table 14
(the liver compartment for example). Those variables that now have one or two indices
but have unchanged names are not listed.
Table 13. Metabolism Variables Used in All Compartments
Variable Name
CH_NM_SH(I)
CH_NM_LG(I)
N_M(I)
I_CMPD(I,J)
TYPE_M(I,J)
Variable Description
Chemical Short Name for ith circulating compound. In SET
statements use CH_NM_SH(1,I)
Chemical Long Name for ith circulating compound.
Number of metabolites of the ith circulating compound.
Number of the circulating compound that is the jth metabolite
of the ith circulating compound.
Type of the jth metabolite (equation(s) to use) of the ith
circulating compound. In SET statements use TYPE_M(1,I,J).
Notes
Eight characters, used in
error statements.
Thirty characters for use in
descriptive text.
A two digit integer. Maximum
value is six. A/M,
Forj=1 toN_M(i)
In eqns: lcij
Up to three characters to
specify equation(s) to use.
136
-------
Table 14. Variables Used in Metabolism Calculations (Liver Example)
Variable Name
(Used in Program)
A_LV_F(I)
C_LV_F(I)
A_LV_M_SUM(I)
A_LV_MC_SUM(I)
DA_LV_M(I,J)
DA_LV_M_SUM(I)
DA_LV_MC_SUM(I)
DCM_M_LV(I,J)
DRM_LV_MEDR(I,J)
K_LV_ML(I,J)
K_MD1_LV(I,J)
K_MD2_LV(I,J)
K_MM_LV(I,J)
K1_MER(I,J)
K2_MED(I,J)
VM_M_LV(I,J)
VM_MEDR_LV(I,J)
Variable Description
Amount of the ith chemical that is free.
Concentration of the ith circulating compound that is free.
Sum of the amounts of Liver metabolite of the ith chemical, (mg)
Sum of amounts of Liver metabolite that are the same as the ith
chemical, (mg)
Rate of formation for the kth Liver metabolite for the ith chemical.
(mg/H)
Sum of rates of formation for all Liver metabolites of the ith
chemical. (mg/H).
Sum of rates of formation of all metabolites that are the same
chemical as the ith circulating compound. (mg/H)
Maximum rate of change of kth Liver metabolite concentration
for the ith chemical. (mg/L/H).
Rate of change of the maximum jth Liver metabolite metabolic
rate including enzyme destruction and resynthesis for the ith
chemical.
The rate constant for the Linear form of the metabolism
calculation.
First dissociation constant for the inhibitor to formation of the jth
Liver metabolite of the ith chemical.
Second dissociation constant for the inhibitor to formation of the
jth Liver metabolite of the ith chemical.
Michaelis-Menten constant for jth Liver metabolite of ith
chemical. (mg/L)
First order rate of jth Liver metabolite enzyme resynthesis for ith
chemical, (for CHCL3, zero for human and rat). (1/H)
Second order rate of jth Liver metabolite enzyme destruction for
the ith chemical, (for CHCL3, zero for human and rat). (L/MG)
Maximum rate of jth Liver metabolite metabolism for the ith
chemical. (MG/H)
Maximum rate of jth Liver metabolite metabolism after taking
enzyme change into account for the ith chemical. (MG/H)
Variable Name
(In documents)
"•Uffi
r
^LV.Fi
"•Kt.LKSUM,
"-MC.LV.SVMi
dAUM,ti
dt
dA
uft M.IV.SUM,
dt
.-1 4
"",«(::,«;,««,.
dt
^«»t,i»'*y
<*' \f\,U'ntl, (
dt
V
""•MiJJ'y
•"•MOl.U'u
'™*MDiU'tij
•*«an,LVlj
•™-IM,fi-tf
f^2M,edtJ
VMx,LViJ
' hh,LV,tflrt f
8.2.3 Calculation of Maximum Rate of Change of Metabolism
The equation for the maximum rate of change of metabolism in the Liver for the jth
metabolite of the ith chemical is given by
V =V
^ V
^.ll'lj. V .
137
-------
where
Va = volume of the body,
VKf = reference volume for VM^LV{.
rm = power of the volume of the body for interspecies scaling.
8.2.4 Calculations When Including Enzyme Destruction and Re-synthesis
The equation for the rate of change of maximum metabolic rate in the liver including
enzyme destruction and re-synthesis for the jth metabolite of the ith circulating compound
is given by:
dV
u * Mx.LV.edr. •
_JJ_ 'v~ /1/- V \
(148)
where the variable definitions are given in Table 14, and VLV = the volume of the Liver.
The value of the maximum metabolic rate taking enzyme destruction and re-synthesis into
consideration is obtained by integration as:
f " Mx,LV.eilrn ,AAQ\
y =1— — — — ^ At + V (149)
r Mx,LV.edr(J J Jt ul ^ r M»-,/J"'y •
8.2.5 The Rate of Formation of Saturable and Linear Metabolite in the Liver
The rate of formation of the jth metabolite, when saturable, in the liver from the ith
circulating compound is given by:
W^ = y*J**X '(r +ir i\ <150>
where the indices /, andy are defined above and parameters are defined in Table 14. For
those metabolites which the user wants to be strictly linear, then the linear form of the
equation would apply. The rate of formation of a linear metabolite in the liver is:
A (151)
A •
Jit
The sum of the rates of formation of the metabolites for the ith circulating compound can
be calculated according to where the rate of formation of metabolites determines the loss
in the rate of increase of amount in the liver for the ith circulating compound:
138
-------
s
(152)
8.2.6 Circulating Compounds which are Metabolites
The rates of formation of metabolites, in this case in the liver, which are the same as one
of the circulating compounds are summed and then added to the rate of increase of the
amount of the circulating compound. This is accomplished by assuming that every
metabolite could be any of the circulating compounds. An index ICjiJ is saved for each
metabolite. If theyth metabolite of the ith circulating compound is the same compound as
the Mi circulating compound, then the index k for the circulating compound is saved in
/cu otherwise the index/cy is set to zero. If the index is non-zero, then the rate of
formation of that metabolite is added to a sum for that circulating compound. The rate of
formation of a circulating metabolite may be linear or saturated (with inhibition if
applicable) where equations (150) and (151) apply. Then
dA,
dt
=,?,
(dA
\ t
MW(k\
MWa)>
(153)
ifl
where ~~^~~*"= the contribution to the rate of change of the Mi chemical in the Liver
from the rate of formation of the jth metabolite of the ith chemical.
8.2.7 Inhibition in the Metabolism Process
Compounds elsewhere in the metabolism chains for any of the circulating compounds
may inhibit the formation of a given metabolite. There are four kinds of inhibition
addressed here. They are defined by the formulas for an apparent Vmax, and an apparent
Michaelis-Menten constant Kmm (See Table 15).
dA
Q,,,
dt
A
-/.W, \)
(154)
where VmaxApp and KmmApp are taken from Table 15 for the inhibition case that applies.
Table 15. Parameter Formulas for Four Types of Inhibition of Metabolism
Type of Inhibition
Competitive Inhibition
Mixed Inhibition
r max,Apf
^w.«,,
V\ftlVtdr
{l+CWFiijIKMDlMrij)
KmmA
KmmJ^(l + CUVttj/KMDU¥ij)
K" " ' ' '
mm'L¥» (I \ CIUiijl
KmilJflJ)
^ MD2,Lt',j )
139
-------
Table 15. Parameter Formulas for Four Types of Inhibition of Metabolism
Type of Inhibition
Pure non-competitive
Inhibition
Uncompetitive Inhibition
VmaXiA,
* Mx.U'.eilr, f
/ '] -1" /™* l K°* ^
V.kMij
(l+CLKFiJKMiyu^)
Kmmi
KmatiVii
"-miiiM'i i j
(l. + Cufiij/Kum,LVij)
where ItJ = zero or the index to the chemical that is the inhibitor to the jth metabolite of
the ith circulating compound
8.2.8 Metabolism in the Other Organs and Tissues
8.2.8. 1 Metabolism in the Brain
The brain metabolism equations are the same as those for the liver except that the
equation for the V-Max is given as a function of the Liver value from the equation:
~ '
'
BN
.LV, , y
• >J V
' '
where RM.BN.LVU is a scaling factor for V-Max in the Brain for the jth metabolite of the ith
chemical.
8.2.8.2 Metabolism in the Kidney
The kidney metabolism equations are the same as those for the liver except that the
equation for the V-Max is given as a function of the liver value from the equation:
v = v f?
' Mx,KD, , r M$,LV, , IVM,KD,L¥, ,
'•I *;f *•/
VK
—
17
f I
(156)
v '
LV
where AWJHW is a scaling factor for V-Max in the Kidney for the jth metabolite of the ith
chemical.
8.2.8.3 Metabolism in the Carcass
The carcass metabolism equations are the same as those for the liver except that the
equation for the V-Max is given as a function of the Liver value from the equation:
(157)
140
-------
where RM.CR.LV,, is a scaling factor for V-Max in the Carcass for the jth metabolite of the ith
chemical.
8.2.8.4 Metabolism in the Fat
The fat metabolism equations are the same as those for the liver except that the equation
for the V-Max is given as a function of the liver value from the equation:
¥ pj-
'Mx,FTu = ?'MxJJ'li^M,FTM\j~j7~ (158)
where RM.FT.U^ is a scaling factor for V-Max in the Fat for the jth metabolite of the ith
chemical.
8.2.8.5 Metabolism in the Slowly Perfused Tissue
The slowly perfused tissue metabolism equations are the same as those for the Liver
except that the equation for the V-Max is given as a function of the Liver value from the
equation:
' Mx,SLtJ = ^Mx,Uru'^M,SL,Llfij |7. (159)
where RM,SLM',J is a scaling factor for V-Max in the slowly perfused tissue for the jth
metabolite of the ith chemical.
8.2.8.6 Metabolism in the Rapidly Perfused Tissue
The rapidly perfused tissue metabolism equations are the same as those for the liver
except that the equation for the V-Max is given as a function of the Liver value from the
equation:
ZSL
'Mx.RPy ~ rMx.UfiijRM.RP.l*flij J7 f (160)
where RM,RP,LVU is a scaling factor for V-Max in the rapidly perfused tissue for the jth
metabolite of the ith chemical.
8.2.8.7 Metabolism in the Spleen
The spleen metabolism equations are the same as those for the liver except that the
equation for the V-Max is given as a function of the liver value from the equation:
141
-------
Ik
y
where "RM,SP,L¥U is a scaling factor for V-Max in the spleen for the jth metabolite of the ith
chemical.
142
-------
Section 9
Exposure Related Dose Estimating Model
(ERDEM)
Enzyme Kinetics Implementation
9.1 The ERDEM Equations for Enzyme Kinetics
A set of enzymes is defined for each compartment. This section of the report only
presents equations for the liver but these equations are the same for all other
compartments: brain, arterial blood, venous blood, kidney, slowly perfused tissue, lung
tissue or static lung, portal blood, and, pulmonary capillaries. There is currently no
enzyme kinetics in the spleen, stratum corneum, testicles, ovaries, carcass, fat, or, rapidly
perfused tissue. Variable definitions are provided at the end of this section.
The user is expected to input the set of chemicals which must include the substrate and
metabolites. In addition, the user inputs a set of enzymes for a given simulation. The user
sets flags for the enzymes used in each compartment and the chemicals that serve as
substrates for the designated enzymes. A given compartment may have only one enzyme
and another may have more. The rate, amount, and concentration variables are referenced
by the ith chemical and 1th enzyme, where the inputs from the ERDEM front end are by
chemical and enzyme name where N_Z is the number of enzymes for the simulation.
Flags are used in ERDEM that indicate which enzymes are active for the simulation, and
which chemicals are competing with the substrate being acted on by an enzyme:
L_LV_Z is a logical flag set to true if there is any enzyme reaction in the
Liver.
L_LV_Z_L(l) (LLV_Z:LI ) is a logical flag set to true if there is an enzyme reaction in the
Liver for the 1th enzyme.
L_LV_Z_I_L(i,l) (v.z.i.i,, ) is a logical flag set to true if the 1th enzyme is inhibited by the ith
chemical. When using the front end, the enzymes and chemicals
are input by name, not by index.
9.2 Elimination of Chemical Due to Competition with Enzyme Metabolism
143
-------
The loss of ith chemical due to competition with the substrate during the metabolism by
the 1th enzyme is given by
dt dt
This equation is an additional elimination term that is included in the body mass balance
for the liver.
9.3 Enzymatic Reactions in the Liver
The enzyme reaction in the Liver is a function of each enzyme and the current chemical.
Equation 162 expresses the rate of loss of the current chemical due to interaction with
each enzyme in the liver. This involves formation of a substrate-enzyme complex which
reduces the expected steady state level of free enzyme. A regeneration function replaces
some of the enzyme that was lost due to formation of the substrate-enzyme complex. A
enzyme re-synthesis function also replaces some enzyme that was degraded. This is
expressed in the equation below where the first term is the regeneration, the second is the
re-synthesis term and the third represents substrate-enzyme complex formation. The
degradation term was removed because it operates on enzyme that has been inhibited and
then aged. The mass balance equation for the rate of change of activity (mass) of kth free
enzyme in the liver due to one or more chemicals is given by
( + ~ ) (163)
"ly.zji.k
where the kth enzyme may bind with more than one chemical. The set of chemicals that
may bind the kth enzyme is in NLV z L .
9.3.1 Enzymatic Inhibition
The rate of change of the kth enzyme due to the ith inhibiting chemical is determined by
the concentration of kth free enzyme and the concentration of the ith chemical causing the
inhibition.
,V (164)
where the concentration of free kth enzyme in the liver is found by integrating equation
163 and dividing by the volume of the liver to get the concentration.
144
-------
9.3.2 Enzyme Regeneration
Enzyme regeneration occurs when enzyme titer is reduced due to binding activity. The
regeneration process acts only when enzyme-substrate or inhibitor complexes are formed
(reduced by the amount that is aged, regenerated and re-synthesized) and is dependent on
the affinity of the substrate chemical or competing inhibiting chemical for the enzyme.
Thus regeneration occurs for the current titer of kth enzyme caused by binding of the ith
chemical. Each chemical may influence a different rate of regeneration.
Cfc/T. T
dt
= KTV
A
-"-
A
^
A
-"-
(165)
where the amount of inhibited kth enzyme is obtained by integrating equation 164. Or in a
saturable form where V and
"
dt
are not defined at this time.
KmmZA* +
C - C - C - C
^LV,ZJit ^LV,Z,Rik ^LV,Z,Si:k ^LV,Z,At_
(166)
9.3.3 Enzyme Re-synthesis
dA
LVZ,Sitk
dt
(167)
Enzyme re-synthesis acts to replace degraded enzyme (lost). Aging involves tightly
bound enzyme-substrate or more likely, enzyme-inhibitor complexes. The degradation is
modeled to act on the aged enzyme and the bound enzyme. The enzyme re-synthesis is a
function of the enzyme only and is given by (linear form)
where the concentration of the degraded kth enzyme is found by summing the amounts
found from integrating equations 170 and 171. The saturable form might be given by
(where Vmx and K^ are not defined at this time)
'
dt
(168)
9.3.4 Enzyme Aging and Degradation
145
-------
Enzyme degradation is modeled to act on bound enzymes and aged enzyme. The
degraded enzyme no longer exists (replaced by re-synthesis). The amount of bound and
aged enzyme is then reduced by the degradation. The rate of formation of aged enzyme is
a function of the amount of bound enzyme (reduced by the amount aged, regenerated, and
re-synthesized), and is given by (in a linear form)
1 V 7 A
' ' a A A A ^ (169>
^ ^ ^
The equation for the rate of formation of degraded bound enzyme consists of the amount
bound, reduced by the amount aged, regenerated, and re-synthesized.
dA
LV^IiJC - ' * -A -A -A \ d70)
dt Ly,z,DiL
The equation for the rate of formation of aged bound enzyme is the amount of aged
enzyme reduced by the amount of bound enzyme already aged:
,..-,..,
(171)
The total amount degraded enzyme is then
^LV,Z,Dik = ^LV,Z,DAik + ^LV,Z,DJjk (172)
9.4 Nomenclature for the Liver Enzyme Equations
9.4.1 Amounts in the Liver
^LV,Z,A! j = Amount of kth enzyme resulting from aging of the enzyme bound to the ith
chemical,
ALV,Z,D. k = Amount of the kth enzyme that is degraded, due to the action of the ith
chemical,
ALV z DA. = Amount of the aged kth enzyme that is degraded, due to the action of the ith
chemical,
ALV z E. = Amount of the kth enzyme that is eliminated due to binding of the ith
chemical,
146
-------
^Lv,z,i.k = Amount of the kth enzyme that is bound by the ith chemical,
ALV z R = Amount of the bound kth enzyme that is regenerated, due to the action of
the ith chemical,
^ _ Amount of the degraded kth enzyme that is re-synthesized, due to the action
LV-z-si,k Of me jm chemical.
9.4.2 Concentrations in the Liver
= Concentration of the kth enzyme resulting from aging of the enzyme bound
Q,K,Z,£>, k = Concentration of the kth enzyme that is degraded, due to the action of the
ith chemical,
CLV z L = Concentration of the kth enzyme that is bound by the ith chemical,
£• _ Concentration of the bound kth enzyme that is regenerated, due to the action
Lv,z,RtJ of me im chemical,
^ _ Concentration of the degraded kth enzyme that is re-synthesized, due to the
LV,z>si,k action of the ith chemical.
9.4.3 Rates of Change of the Amount of Enzyme in the Liver
dA
LV>z>A>,k = Rate of change of the amount of kth enzyme resulting from aging of the
dt enzyme bound to the ith chemical,
dA
LV'z'Di,k _ Rate of change of the amount of the kth enzyme that is degraded, due to
dt the action of the ith chemical,
dALV,ZJr k
——'— = Rate of change of the amount of the kth enzyme that is bound to the ith
^ chemical,
dA
LV'Z'R,,k _ Rate of change of the amount of the bound kth enzyme that is
dt regenerated, due to the action of the ith chemical,
dA
LV'z-si,t _ Rate of change of the amount of the degraded kth enzyme that is re-
dt synthesized, due to the action of the ith chemical.
147
-------
9.4.4 Rate Constants for the Reactions
K A = Rate constant for the aging of the kth enzyme that was bound by the ith
LV>t-,Aik .
chemical,
^ _ Rate constant for the degradation of the aged kth enzyme that occurs due
Lv,z,DAiik to ^g actjon Of me jm chemical,
v- _ Rate constant for the degradation of the bound kth enzyme that occurs due
_/V r T/ 7 r\j —
' ' a to the action of the ith chemical,
K = Rate constant for the bound of the kth enzyme by the ith chemical,
LV,Z,liik
g _ Rate constant for the regeneration of the bound kth enzyme that is due to
Lv,z,Ritk ^ actjon Of the ith chemical,
is- _ Rate constant for the re-synthesis of the degraded kth enzyme, due to the
Lv,z,sitk action of the ith chemical.
148
-------
References
Abbas, R., Fisher, W.F. (1997). A Physiologically Based Pharmacokinetic Model for
Trichloroethylene and Its Metabolites, Chloral Hydrate, Trichloroacetate,
Dichloroacetate, Trichloroethanol, and Trichloroethanol Glucuronide in B6c3f 1 Mice.
Toxicology and Applied Pharmacology 147', 15-30 (Page 18).
Fisher, J.W., Mahle, D., Abbas, R. (1998). A Human Physiologically Based
Pharmacokinetic Model for Trichloroethylene and Its Metabolites, Trichloroacetic
Acid and Free Trichloroethanol. Toxicology and Applied Pharmacology 152, 339-359.
Ness, Shirley A., 1994. Surface and Dermal Monitoring for Toxic Exposure, Van
Nostrand Reinhold, New York, NY.
U.S. EPA, 1992. Dermal Exposure Assessment: Principles and Applications, January
1992. EPA/600/8-01/01 IB, Interim Report.
U.S. EPA, 1998b. Assessment of Time-Motion Videoanalysis for the Acquisition of
Biomechanics Data in the Calculation of Exposure to Children, February 1998.
EPA/600/X-98/002A-D.
149
-------
150
-------
151
-------
United States
Environmental
Agency
Protection
Offic
Please make all necessary changes on
the below label, detach or copy, and
return to the address In the upper
left-hand corner.
If you do not wish to receive these reports
CHECK HERE D; detach, or copy this
e of Research
and Development (8101R)
Washington, DC 20460
Official Business
Penalty for Private Use
$300
EPA/600/R-06/061
June 2006
www.epa.gov
PRESORTED
STANDARD
POSTAGE AND FEES
PAID
EPA PERMIT NO.
G-35
Recycled/Recyclable
Printed with vegetable-
based ink on
paper that contains a
minimum of
------- |