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Project A1: Assessment of VOC (Volatile
Organic Compound) Exposure, by Route,
in Populations Living Adjacent to Superfund
Sites
Karla
D. Thrall, PI
Battelle, Pacific Northwest National Laboratory
Research Objectives
-
Generate physiologically based pharmacokinetic
models to describe target organ dosimetry by route of exposure.
-
Use models to predict human dosimetry under
environmentally relevant exposure conditions.
-
Conduct field studies to provide actual exposure
assessments and target-organ dose estimates by each route of
exposure.
 Neurotoxic
chemical contaminants found at Superfund
sites have the potential to pollute water
supplies and expose humans while showering,
bathing, washing dishes, doing laundry
and drinking water. Little is known, however,
about the magnitude of exposure that may
occur by each of the various exposure
routes (inhalation, ingestion, dermal
absorption). We are addressing this problem
by using a novel breath analysis system
that allows us to determine the amount
of volatile organic chemical that has
entered the body by any route of exposure
and are developing mathematical models
to describe the absorption, distribution,
metabolism, and excretion of these chemicals.
By interpreting the exhaled breath data
with our mathematical models, we can estimate
the amount of contaminant that has entered
particular tissues and thereby provide
data that will allow scientists to more
accurately assess the toxicological risks
that are involved.
We have performed a series of controlled dermal and inhalation
studies to compare the bioavailability of toluene in human volunteers
under exposure conditions designed to mimic bathing scenarios.
Our data suggest that human skin is more than 80 times less permeable
to toluene than previous U.S. EPA estimates. We have also compared
species differences between rats and human volunteers in the dermal
bioavailability of aqueous xylene. These studies indicate that,
while aqueous xylene is rapidly absorbed through the skin of both
rats and humans, rat skin is approximately 12 times more permeable
to aqueous xylene than human skin.
Another research effort has focused on development of a preliminary
mathematical model to describe the absorption, distribution, metabolism
and elimination of 1,2-diethylbenzene (1,2-DEB) in rats. The completed
model was evaluated against real-time exhaled breath and blood
samples collected from rats receiving intraperitoneal (IP) injections
of 1,2-DEB. Exhaled breath profiles from animals treated with
1,2-DEB by IP injection are being analyzed and the absorption
rate (Ka) determined. Finally, in collaboration with Dr. Chris
Wallace (Project A4), we have evaluated the in vivo kinetics of
2-chloroacetaldehyde (2-CA), a metabolite of vinyl chloride and
other chlorinated solvents, in young (post-natal day 6) rats following
oral dosing. Our results show that 2-CA is rapidly distributed
into liver and brain; however, while clearance of 2-CA from the
liver is rapid, its clearance from the brain is much slower.
The development of reliable human-specific
data describing the dermal bioavailability
of two commonly encountered solvents (xylene
and toluene) has important implications
for the re- assessment of current EPA
exposure standards and for improving overall
risk assessments for these compounds.
These experiments also provide an opportunity
to better understand species differences
in dermal bioavailability and may ultimately
aid in developing more predictive models
for human dermal absorption from rodent
data. Development of a physiologically
based pharmacokinetic model for 1,2-DEB
in rats is the first step toward future
extrapolations to understand the kinetics
in humans.
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