FOR IMMEDIATE RELEASE: 3 JANUARY 2001
Contact: Tom Rickey
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University of Rochester

Combination of two widely used pesticides linked to Parkinson's disease

Scientists have shown that the combination of two widely used
agricultural pesticides-but neither one alone-creates in mice the exact
pattern of brain damage that doctors see in patients with Parkinson's
disease. The research offers the most compelling evidence yet that
everyday environmental factors may play a role in the development of
the disease.

The latest findings of the team led by Deborah Cory-Slechta, Ph.D.,
professor of environmental medicine and dean for research at the
University of Rochester School of Medicine and Dentistry, appear in the
Dec. 15 issue of the Journal of Neuroscience. The scientists caution that
more studies are necessary to explain the link, since it's probable that
many factors contribute to a complex disease like Parkinson's, and they
say it's unlikely that the pesticides on their own actually cause the
disease.

Cory-Slechta's team studied the effects of a mixture of two very common
agrichemicals, the herbicide paraquat and the fungicide maneb. Each is
used by farmers on millions of acres in the United States alone: Maneb
is applied widely on such crops as potatoes, tomatoes, lettuce and corn,
and paraquat is used on corn, soybeans, cotton, fruit, and a variety of
other products. In the experiment, mice exposed to either one had little or
no brain damage, but mice exposed to both share a significant trait with
people in the very early stages of the disease: Though they appear
healthy, key brain cells known as dopamine neurons are dying. The mice
exposed to the mixture carried nearly all of the molecular hallmarks of
Parkinson's disease as seen in humans.

"The environmental reality is that several of these chemicals are used on
the same crops and in the same geographical locations. You've got to
get rid of the weeds. Then the insects. Then funguses. These are
different chemicals that do different things, but they're often applied in
the same fields," says Cory-Slechta, who was joined in the research by
graduate student Mona Thiruchelvam and faculty members Eric
Richfield, Raymond Baggs, and A. William Tank.

The study is one of the first to examine the effects of such chemicals in
tandem. Cory-Slechta notes that current regulations and determinations
of safety levels are usually based on the effects of single chemicals. "In
the real world, we're exposed to mixtures of chemicals every day. There
are thousands upon thousands of combinations; I think what we have
found is the tip of the iceberg," she says. "There are a dozen different
fungicides related to maneb alone. I don't think we just happened to pick
the right chemicals to see such an effect."

Maneb, paraquat, and many other pesticides are used in the same
agriculture-rich areas of the country, including the Midwest, California,
Florida and the Northeast. The map of their use mirrors areas of the
country where people are more likely to die of Parkinson's disease.

Several epidemiological studies have hinted at a role for pesticides in the
development of the disease. Studies have found that farmers, people
who live in rural areas, and people who drink well water are more likely to
have the disease than people who don't. In addition, just last month,
scientists at Emory University presented evidence that rats given a
steady dose of the natural pesticide rotenone, used on home-grown
fruits and vegetables, develop Parkinson's-like symptoms. Cory-
Slechta's study, which used much lower levels of chemicals than the
Emory research, is the first to link a combination of more widely used
pesticides to the disease.

"No one has looked at the effects of studying together some of these
compounds that, taken by themselves, have little effect," says Cory-
Slechta. "This has enormous implications."

Currently scientists have little understanding of what causes
Parkinson's, where a tiny group of dopamine-producing neurons deep
within an area of the brain known as the substantia nigra die. This cell
death leads to a shortage of the neurotransmitter dopamine and to the
tremors, rigidity, and slow movement that mark the disease as it
progresses slowly over a period of years or decades. Parkinson's affects
about 1 million people in North America.

There is a growing consensus among scientists that both genetic
predisposition and environmental agents may play a role in the disease.
Doctors see a similar effect in heart disease, where a patient might have
both a family history and a sedentary lifestyle, or in cancer, where
certain genes may make one prone to develop colon cancer and a poor
diet makes the disease even more likely.

Cory-Slechta thinks it's unlikely that exposures to such chemicals
actually cause Parkinson's on their own, but they may contribute to the
development of the disease. "This is the first time that truly
environmental risk factors for Parkinson's disease have been identified,"
she says.

Cory-Slechta heads a research center funded by the National Institute of
Environmental Health Sciences where researchers study the effects of
environmental agents like cigarette smoke, air pollution, and metals like
mercury and lead on human health. She believes scientists must do more
research on the effects of exposure to multiple chemicals. "It's a huge
problem to start thinking about a nearly infinite array of mixtures of
chemicals, instead of the risk that a single chemical might pose," she
says.

She also says more work must be done to see how much of these
chemicals people are actually exposed to. Usually it's not clear exactly
how much of a pesticide remains on crops by the time they reach the
dinner table. Maneb frequently shows up as a slight residue, she says,
while paraquat usually shows up just in trace amounts; exposures can
also occur via other routes. Oftentimes the two are used at different
stages of the growing cycle. "The real issue is what happens when they
hit humans in the food chain. If they're both present, then you are
exposed to the combination."

In the Journal of Neuroscience paper, and in an earlier paper in Brain
Research, the scientists showed how mice injected with both maneb and
paraquat differed from normal mice in many ways. Most obviously, the
mice moved around much less; immediately after the last of 12 injections
over six weeks, the mice ran around their cages just one-tenth as much
as their normal counterparts. More importantly, the mice that received
both chemicals showed brain damage in exactly the same way as
humans with Parkinson's:

The amount of a key molecular marker, tyrosine hydroxylase, that is one
measure of the health of the dopamine system was lower by about 15
percent in the mice, in the exact same areas of the brain that are damaged
by the disease. Other closely related areas of the brain were spared, as in
humans.

The mice had nearly four times as many "reactive astrocytes," structures
which indicate brain damage, compared to the control mice, in areas
affected by Parkinson's disease.

The mice had about 15 percent fewer dopamine neurons and ultimately
produced about 15 percent less dopamine than normal mice.

The team is currently pursuing several new avenues of research, with
funding from NIEHS. For instance, preliminary findings indicate that the
Parkinson's-like effects on mice may be permanent, and that older mice
may be more sensitive to the combination than younger mice. The team
is also studying the effects of exposure to the mixture early in life, and
they've shown that mice with the same genetic abnormality that causes
some people to develop Parkinson's are specially vulnerable to the
mixture.

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http://www.eurekalert.com/releases/uor-cot010301.html