Evaluating Risk in Older Adults Using

Physiologically Based Pharmacokinetic Models

Miles S. Okino1, Marina V. Evans2, Sastry S. Isukapalli3, Sheng-Wei Wang3, Panos G. Georgopoulos3, Myra
Karstadt4, RogeiioTomero-Velez1, Michael DeVito5, Linda Birnbaum2, Jerry N. Blancato3, Andrew M, Geller2

1ORD/National Exposure Research Laboratory (NERL)

2ORD/National Health and Environmental Effects Research Laboratory (NHEERL)

Environmental and Occupational Health Sciences Institute (EOHSI),University of Medicine and Dentistry of New Jersey (UMDNJ), R.W. Johnson

Medical School and Rutgers University
40ffice of Prevention, Pesticides, and Toxic Substances
5ORD/National Center for Computational Toxicology

1. Introduction

The rapid growth in the number of older Americans has many implications
for public health, including the need to better understand the risks posed by
environmental exposures to older adults

Physiological and biochemical changes that occur during aging may affect
chemical absorption, distribution, metabolism and elimination (ADME).
A few examples of known changes are in the table below

Absorption

•	Reduced gastric acid production

•	Changes in dermal absorption, barrier function

•	Reduced lung volume, elasticity

Distribution

•	Decreased total body water in older adults

•	Decreased muscle mass, increased relative adipose level

•	Plasma protein levels associated with binding

•	Potential for altered permeability of blood-brain barrier with

concurrent disease

Metabolism

•	Reduced liver volume and liver blood flow

•	Decline in specific cytochrome P450 content

•	Polypharmacy

Elimination

•	Reduced renal function

•	Reduced biliary excretion

•	Reduced pulmonary excretion

2. Methods

Investigate prototype toxicants with diverse physical, pharmacokinetic,
and toxicological properties, including

• Schematic representation of a
PBPK model from EPA's
Exposure Related Dose
Estimating Model (ERDEM).

•	Subject-specific
organ/tissue volumes,
respiration volumes, and
blood flows are represented

•	Distribution characteristics
can be changed based on
changes in tissue and blood
composition

•	Rates associated with
metabolism and clearance
pathways are modeled

In this 2-dimensional example (2
parameters), the slope of the dose metric is
steeper as the value of Parameter B is
changed, compared to the slope of Parameter
A. These relations indicate a greater impact
on the dose metric for the biological
processes associated with Parameter B.
Stochastic Response Surface and Reduced
Model methods enable the investigation of
the N-dimensional parameter space of a
PBPK model more efficiently than
deterministic or traditional Monte-Carlo
investigations.

Chemical class and
properties

Toxicity

Dose metrics

•	Volatile organics

•	Metals

•	Pesticides

•	Air pollutants

•	High and low
lipophilicity

•	Receptor mediated

•	Metabolic activation

•	Endpoints, including
cancer, neurological,
immune, reproductive

•	Parent chemical and
metabolites

•	Peak concentrations

•	Integrated amounts
(area under the
curve)

.

Candidate chemicals currently include trichloroethylene, benzene,
toluene, ozone, arsenic, dioxin, chlorpyrifos, and pyrethroids
Physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD)
models mathematically represent the biological processes associated
with chemical ADME.

This enables the incorporation of the changes associated with aging.
Sensitivity analyses allow for systematic investigation of PBPK models
to reveal the biological processes associated with risk.

Identification of the important biological processes provides focus for
future research efforts.

—	Literature search

—	Laboratory experiments

Disclaimer: Although this work was reviewed by the U.S. Environmental Protection Agency (U.S. EPA) and
approved for publication it may not necessarily reflect official Agency policy.

3. Illustration

PBPK models of trichloroethylene (TCE)were developed for aged and
adult rats		

The healthy aged rat shows similar brain TCE
concentrations as the adult

The impact of changes in blood flow to the kidney are
illustrated by the time course of the metabolite TCOG
in kidney

Research is ongoing to

-	Compile physiologic data, including variability, for parameters required for PBPK
modeling of the aged population that include:

•	Cardiac output	• Ventilation rate

•	Blood flows to organs • Organ volumes

•	Blood lipid content	• Glomerular filtration rate

-	Develop PBPK models for the prototype chemicals

-	Perform formal sensitivity analyses to highlight the important biological processes

4. Future Directions

Create a broadly accessible database for PBPK/PD modeling of older
adults

Develop models to account for disease states and polypharmacy
Design experiments to address specific hypotheses identified in the
sensitivity analysis, including

-	In vitro experiments to address specific biochemical pathways

-	Animal experiments, where the comparison of models and results allows for the
selection of the most representative animal for human extrapolation


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