&EPA
www.epa.gov/airscience
science in ACTION
CLEAN AIR RESEARCH
PROGRAM
RESEARCH DETERMINES THE TOXIC MECHANISMS OF PARTICULATE
MATTER AT THE CELLULAR AND MOLECULAR LEVELS
Issue:
Exposure to airborne particle
pollutants, known as particulate
matter (PM), has been linked with
health hazards, including heart
disease, diminished lung function,
and lung cancer. While these
adverse health connections have
been proven through extensive
scientific research, the underlying
mechanisms for these effects have
been harder to identify.
PM is a complex and varying
mixture that can include
thousands of organic and
inorganic compounds, derived
from both anthropogenic (human-
made) and natural sources.
Epidemiological evidence
suggests that, rather than causing
specific diseases, PM exposure is
linked to exacerbations of and
increased predisposition to a wide
range of common adverse
cardiovascular and pulmonary
effects in humans. As a further
complication, there appears to be
great variability in the human
effects of PM exposure from
person to person—variations that
are not well understood presently.
In addition, much uncertainty
remains regarding the specific
toxic agents in PM and their
toxicological effects on humans.
Currently, there is not enough
data to provide a full assessment
of the risks to human health that
PM exposure entails, especially
given the wide range of
individual responses to these
airborne pollutants.
Understanding the toxicity of PM
at the cellular and molecular level
is essential for the U.S.
Environmental Protection Agency
to better protect exposed
populations.
Scientific Objective:
EPA's Clean Air Research
Program in the Office of
Research and Development
(ORD) is working in close
partnership with EPA's
regulatory programs and other
organizations outside the Agency
to identify, characterize, and
model the cellular and molecular
events that lead to adverse
reactions to airborne pollutant
exposure. This research effort
seeks to answer relevant scientific
questions about the nature of
ambient particulate matter and its
toxicity in humans.
These questions include, but are
not limited to:
• What are the earliest molecular
events that define lung cellular
responses to PM exposure?
• What are the physical and
chemical properties of PM that
are associated with adverse
reactions?
• Is it possible to develop
predictive mathematical models
of the activation of cellular
responses to PM inhalation?
continued on back
U.S. Environmental Protection Agency
Office of Research and Development
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&EPA
www.epa.gov/airscience
science in ACTION
CLEAN AIR RESEARCH PROGRAM
continued from front
The answers to these questions
are being pursued through
research studies using advanced
cellular, biochemical and
molecular biology approaches.
Ultimately, these efforts will
provide the basis for the
generation of reliable models for
predicting the effects of airborne
particulate pollution across the
widely varied ranges of PM and
the populations that it affects.
Application and Impact:
Filling the knowledge gaps
surrounding the adverse effects of
airborne contaminants at the
cellular and molecular levels will
enable EPA to develop and
implement regulatory measures to
mitigate the adverse effects of
PM exposure on human health
with greater accuracy and
efficiency.
Specifically, EPA expects this
research effort to achieve the
following:
PM types that are responsible
for adverse health effects
Aid in the translation of
laboratory data in cells and
laboratory animals to the
human situation
Develop a predictive
computational model of the
intracellular pathways that lead
to adverse cellular responses to
PM inhalation. These models
can be used for risk assessment
in support of protective
regulatory strategies
REFERENCES
Cao D, Bromberg PA, Samet JM. Cox-2
expression induced by diesel particles involves
chromatin modification and degradation of hdacl.
Am J Respir Cell Mol Biol 2007;37(2):232-239.
Kim YM, Cao D, Reed W, Wu W, Jaspers I, Tal T,
Bromberg PA, Samet JM. Zn2+-induced nf-
kappab-dependent transcriptional activity involves
site-specific p65/rela phosphorylation. Cell Signal
2007;19(3):538-546.
Tal TL, Graves LM, Silbajoris R, Bromberg PA,
Wu W, Samet JM. Inhibition of protein tyrosine
phosphatase activity mediates epidermal growth
factor receptor signaling in human airway
epithelial cells exposed to zn2+. Toxicol Appl
Pharmacol 2006;214(l):16-23.
CONTACT
James M. Samet, National Health and
Environmental Effects Research Laboratory,
EPA's Office of Research and Development,
919-966-0665, samet.james@epa.gov
Urmila Kodavanti, National Health and
Environmental Effects Research Laboratory,
919-541-4963, kodavanti.urmila@epa.gov
JANUARY 2009
Elucidate critical cellular and
molecular events that underlie
adverse cellular responses to
PM exposure
Identify critical
physicochemical properties of
U.S. Environmental Protection Agency
Office of Research and Development
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