NERL Research Abstract Exposure Related Dose Estimating Model ERDEM A Physiologically Based Pharmacokinetic and Pharmacodynamic PBPK PD model for Assessing Human Exposure and Risk


United States Environmental Protection Agency

Office of Research and Development

National Exposure Research Laboratory
Research Abstract

Government Performance Results Act (GPRA) Goal #4.5
Annual Performance Measure #32

Significant Research Findings:

Exposure Related Dose Estimating Model (ERDEM):
A Physiologically-Based Pharmacokinetic and Pharmacodynamic
(PBPK/PD) model for Assessing Human Exposure and Risk

Scientific
Problem and
Policy Issues

Research
Approach

The U.S. EPA, as part of its mission to protect human health and the environment,
develops tools (methods, measures and models) that can be readily used to
improve risk and exposure assessments. Risk assessments are used at EPA to
predict potential adverse effects that may result from exposure to environmental
agents. As with any predictive approach, there is often considerable uncertainty
associated with the assessment. To reduce this uncertainty and to increase
confidence in risk assessments supporting policy decisions, the Agency seeks to
ensure that its assessments incorporate 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. In particular, scientists often need to
describe, estimate, and predict the dose of foreign 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. By
improving such models and their predictions of dose, risk assessors can better
predict the possible health impacts and can assure that the Agency's risk
management decisions are founded on high quality science.

Over recent years, the Agency and others have used physiologically based
pharmacokinetic (PBPK) models to better describe internal doses resulting from
human exposures to chemicals in the environment. PBPK models are
mathematical descriptions of how chemicals enter the body, are transported in the
body, are eliminated from the body, and stored in the body. More recently the
Agency has sought to develop and use physiologically based pharmacokinetic and
pharmacodynamic (PBPK/PD) models. The PBPK/PD models not only describe
the disposition of a chemical in the body, but they also attempt to mathematically
describe how some normal biologic processes are altered (and might lead to
disease) as a result of the chemical in the body. PBPK/PD models developed
within the National Exposure Research Laboratory's Exposure Related Dose
Estimating Model (ERDEM) platform hold great promise for evaluating,
estimating, and predicting measures of toxicologically relevant doses within the
body. PBPK/PD models may be essential for predicting actual organ level
exposures to chemicals producing cancer and non-cancer effects, especially as

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they may occur as mixtures in the environment.

ERDEM is a PC-based modeling framework that allows for using existing models
and for building new PBPK and PBPK/PD models to address specific science
questions. The ERDEM framework provides a modeling tool for characterizing
exposures of children and other groups and calculating estimated internal doses.
This framework consists of two parts: the model engine, built in Advanced
Continuous Simulation Language (ACSL), and a user friendly front-end for
creating and executing models. The model engine contains the mathematical
descriptions of the PBPK and PBPK/PD models.

ERDEM has recently been updated to improve the way it handles important
pollutants. Improvements include improved dermal uptake modeling and the
inclusion of intracellular processes in the model. Special attention was paid to
developing accurate descriptions for absorption into the body. Gastrointestinal
absorption can be modeled as simple absorption from the stomach and intestine
into the blood flowing to the liver. The user may also model absorption across the
membranes of several sections of the small intestine. Each absorption path allows
for gall bladder activity and for fecal elimination. Dermal absorption is also
modeled in more than one way. One approach assumes a rapid and direct
absorption across the skin: it is used for vapors and chemicals in water where
exposure would normally occur during showering and bathing. A second
approach allows for chemicals to be "deposited" on the skin, either as a result of
occupational practices or simply from the activities of daily life, and then slowly
absorbed across the dermal barrier. Absorption of pesticides has been modeled in
this fashion. In addition, absorption from inhalation is also modeled in ERDEM.
For the user, ERDEM requires no special software other than the basic Windows
environment commonly used on PCs.

Results and	Recent improvements in ERDEM have allowed the model to be applied more

Impact	rigorously to a variety of chemicals, including trichloroethylene, methyl tertiary

butyl ether (MTBE), malathion, and the N-methyl carbamates. Highlights of
recent research and technical transfer activities are provided below:

Trichloroethylene Revised Risk Assessment: ERDEM was used to
develop a PBPK model of trichloroethylene uptake and distribution throughout the
human body. This effort was central to the development of a revised risk
assessment based upon recent developments in the field and upon NAS comments
on the 2001 draft risk assessment. This work served as an example for the use of
PBPK models in investigating scientific uncertainties in risk assessment. The
ERDEM-based approach was described in a white paper delivered to the NAS
panel "Issues in Trichloroethylene Pharmacokinetics" (EPA/600/R-05/022).
Findings from the work have also been presented at the EPA 2004 Science Forum
(Okino et al. "Harmonization and Communication of PBPK Models using the
Exposure Related Dose Estimation Model (ERDEM) System: Trichloroethylene")
and submitted to Environmental Health Perspectives in 2005 for publication (Chiu
et al. "Issues in the Pharmacokinetics of Trichloroethylene and Its Metabolites".

Methyl-Tertiary Butyl Ether (MTBE). ERDEM was used to estimate the
human exposure related concentrations of MTBE in human tissues and excreta that
were equivalent to doses used in animal tests. The model was also used to
estimate body burden for a range of exposures and age groups. Sensitivity and
Monte Carlo analyses were performed. Model runs were performed for risk

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assessment and applied in route-to-route applications. The results will be
reviewed by a National Academy of Sciences (NAS) panel in the near future and
incorporated into IRIS where they will become publicly available. This research is
a collaborative effort between the client office, NCEA, and the National
Computational Toxicology Center (NTCT), the NHEERL, and the NERL (points
of contact, Dr. Jerry N. Blancato, Dr. Marina Evans, and Mr. Fred Power,
respectively).

•	Malathion. Malathion was modeled in ERDEM as a formulation in
shampoo to kill lice. The model assumed the user places the shampoo on the scalp
and allows it to remain on the scalp for 12 hours. A given percentage is absorbed
through the scalp and the hair roots before the shampoo is then washed off. The
amount of modeled enzyme inhibition was very small, although it lasted for up to
three days. The results indicated that, if consumers use such over the counter
preparations as directed on the label, there is little or no chance of an adverse
event.

N-methvl Carbamate Cumulative Risk Assessment: A PBPK/PD model
of carbaryl demonstrated how NERL and ORD can help estimate relevant dose
and inform risk assessments. This work also serves as an example for further
work in the area of cumulative risk assessment for other compounds of regulatory
interest. The ERDEM model and results were presented at a FIFRA Scientific
Advisory Panel (SAP) Open Meeting, February 15-18, 2005, Docket Number:
OPP-2004-0405, Washington DC as a presentation and companion report
"Assessment Of Carbaryl Exposure Following Turf Application Using A
Physiologically Based Pharmacokinetic Model" The SAP panel gave favorable
reviews to the PBPK/PD modeling approach, including the development,
documentation and communication of the model in the ERDEM platform. The
model provided estimates of target tissue dose in brain and blood with concomitant
estimates of acetylcholinesterase (AChE) inhibition. These findings were accepted
by the Office of Pesticide Programs (OPP) as a proof of concept, although the OPP
made the decision not to directly incorporate the PBPK/PD results in the TV-methyl
carbamate risk assessment. Most substantively, the OPP accepted the SAP
comments as guidance in future cumulative risk assessments that will use
PBPK/PD models.

U.S.-Mexico Border 2012: ERDEM was used to develop a PBPK model
for chlorpyrifos, and to extrapolate the animal and adult models to children. The
child model was implemented to evaluate exposure to pesticides based on
previously collected urinary biomarker concentrations "Urinary Biomarker Data
Analysis and Study Design for Children Along the U.S.-Mexico Border"
(http://www.epa.gov/orsearth/projects_publications/urincary_biomarker_data_anal
ysis_and_study_design_for_children.html). Results for estimated exposure levels
were presented at the 2005 ISEA meeting (Okino et al. "Use of Pharmacokinetic
Models to Assess Occupational and Residential Pesticide Exposure"). The
dynamic model provides a platform to quantitatively investigate the uncertainties
associated with biomarker interpretation.

•	Training to the Office of Pesticide Programs (OPP): ERDEM developers
and users provided training to OPP on the uses of PBPK models in risk
assessment. The session "PBPK Modeling in Risk Assessment" was part of a two-
day training session as part of the OPP Health Effects Division Risk Assessor
Training and Certification program, August 10-11, 2004, Washington DC. The
training described the use of the ERDEM platform, illustrated by examples of
ERDEM applications.

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Research
Collaboration
and Research
Products

As an exposure-to-dose modeling tool, ERDEM, has been used to identify quality
assurance features that are critical for verification of model structure to test the
reasonableness of regulatory default assumptions, such as the OPP residential
standard operating procedures that have been previously set in the absence of data.
The ability of ERDEM to interpret children's aggregate exposure and cumulative
risk assisted in identifying critical data gaps in important risk assessments. These
included critical windows of susceptibility during the prenatal and childhood
development stages. PBPK/PD models have the ability to examine animal
systems as a means of predicting different human life stage susceptibility and to
explore modes of action of chemicals/pesticides.

Details of ERDEM and how it has been applied to address key scientific issues are
outlined in a variety of reports, presentations, and publications. Examples of recent
publications from this study include:

Power FW, Knaak JB, Okino MS, Tornero-Velez R, Lowit A, Blancato JN, Dary CC. "Use of
Exposure-Related Dose Estimating Model (ERDEM) for Assessment of Aggregate Exposure of
Infants and Children to N-Methyl Carbamate Insecticides." At the 44th Annual Meeting of the
Society of Toxicology (SOT), New Orleans, LA, March 6-10, 2005.

Okino MS, Power FW, Knaak JB, Tornero-Velez R, Lunchick C, Lowit A, Blancato JN, Dary CC.
"Use of a Physiologically-Based Pharmacokinetic Model to Estimate Absorbed Carbaryl Dose in
Children after Turf Application." At the 44th Annual Meeting of the Society of Toxicology (SOT),
New Orleans, LA, March 6-10, 2005.

Okino MS, Power FW, Tornero-Velez R, Blancato JN, Dary CC. "Assessment Of Carbaryl
Exposure Following Turf Application Using A Physiologically Based Pharmacokinetic Model."
FIFRA Scientific Advisory Panel (SAP) Open Meeting, Docket Number: OPP-2004-0405,
Washington, DC, February 15-18,2005.

Knaak, JB, Dary, CC, Power, F, Thompson, C, Blancato, JN. "Review of Physicochemical and
Biological Data available for the Development of Predictive Organophosphorus Pesticide QSARs
and PBPK/PD Models for Human Risk Assessment." Critical Reviews in Toxicology, 34 (2): 143-
207,2004.

Ruiz A., Tsang A., Power F.W., Lucitra J., Blancato J.N., Dary C.C., and Evans M.V.
"Comprehensive PBPK Modeling Approach Using the Exposure Dose Estimating Model
(ERDEM)." At the 43rd Annual Meeting of the Society of Toxicology (SOT), Baltimore, MD,
March 21-25, 2004.

Evans M.V., Power F.W., Dary C.C., Tornero-Velez R., and Blancato J.N. "Application of the
Exposure Dose Estimating Model (ERDEM) to the Assessment of Dermal Exposure in the Rat to
Malathion." At the 43rd Annual Meeting of the Society of Toxicology (SOT), Baltimore, MD,
March 21-25, 2004.

Tornero-Velez R., Nichols H., Evans M.V., DeVito M., Dary C.C., and Blancato J.N. "Towards a
Generic PBPK Model of Pyrethoid Pesticides: Modeling Deltamethrin and Permethrin in the Rat."
At the 43rd Annual Meeting of the Society of Toxicology (SOT), Baltimore, MD, March 21-25,
2004.

Knaak, JB, Dary, CC, Patterson, GT, Blancato, JN. "Worker Hazard Posed by Reentry into
Pesticide-Treated Foliage: Reassessment of Reentry Levels/Intervals Using Foliar Residue Transfer-
Percutaneous Absorption PBPK/PD Models, with Emphasis on Isofenphos and Parathion." In
Human and Ecological Risk Assessment: Theory and Practice, Paustenbach, DJ, ed., John Wiley &
Sons, Inc. 2002.

Wilkes, C, Blancato, J, Hern, S, Power, F, and Olin, S. "Integrated Probabilistic and Deterministic
Modeling Techniques in Estimating Exposure to Water-Borne Contaminants: Part 1: Exposure

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Modeling." Proceedings: 9th International Conference on Indoor Air Quality and Climate,
Monterey, California, June 30-July 5,2002.

Blancato, J., Power, F., Wilkes, C., Tsang, A., Hern, S., and Olin, S. "Integrated Probabilistic and
Deterministic Modeling Techniques in Estimating Exposure to Water-Borne Contaminants: Part 2:
Pharmacokinetic Modeling." Proceedings: 9th International Conference on Indoor Air Quality and
Climate, Monterey, California, June 30-July 5, 2002.

Knaak J.B., Power F.W., Blancato J.N. and Dary C.C. Poster presentation, "Use of Exposure-
Related Dose Estimating Model (ERDEM) for Assessment of Aggregate Exposure of Infants and
Children to Organophosphorus Insecticides." At the 40th Annual Meeting of the Society of
Toxicology (SOT), San Francisco, CA, Abstract (#84). In: the Toxicologist, Volume 60 (1) 17,
March 25-29, 2001.

Knaak J.B.

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