Los Angeles Times  [Printer-friendly version]
November 27, 2005


Scientists have amassed evidence that long-term exposure to toxic
compounds, especially pesticides, can trigger the neurological

[Rachel's introduction: "Pesticides and related industrial chemicals,
those classes of compounds, clearly are associated with some cases of
Parkinson's." -- Gary Miller, a toxicologist and associate professor
at Emory University's School of Public Health.]

By Marla Cone

MERCED, Calif. -- A thousand acres stretched before him as Gary Rieke
walked briskly behind a harvester, the parched, yellow stalks of rice
sweeping against his knees. Stopping to adjust a bolt on the machine,
Rieke struggled to maneuver a wrench with his trembling fingers.

It was 1988, and Rieke was in his mid-40s, too young and too fit to
feel his body betraying him. For two decades, he had farmed in the
heart of the San Joaquin Valley, and he knew what he wanted his hand
to do. But for some frustrating reason, it refused to obey.

Unbeknownst to Rieke, by the time he noticed the slightest tremor,
some 400,000 of his brain cells had been wiped out. Like an estimated
other 1 million Americans, most over 55, he had Parkinson's disease,
and his thoughts could no longer control his movements. In time, he
would struggle to walk and talk.

Rieke, who was exposed to weedkillers and other toxic compounds all
his life, has long suspected that they were somehow responsible for
his disease.

Now many experts are increasingly confident that Rieke's hunch is
correct. Scientists have amassed a growing body of evidence that long-
term exposure to toxic compounds, particularly pesticides, can destroy
neurons and trigger Parkinson's in some people.

So far, they have implicated several pesticides that cause Parkinson's
symptoms in animals. But hundreds of agricultural and industrial
chemicals probably play a role, they believe.

Researchers don't use the word "cause" when linking environmental
exposures to a disease. Instead, epidemiologists look for clusters and
patterns in people, and neurobiologists test theories in animals. If
their findings are repeatedly consistent, that is as close to proving
cause and effect as they get.

Now, with Parkinson's, this medical detective work has edged closer to
proving the case than with almost any other human ailment. In most
patients, scientists say, Parkinson's is a disease with environmental

Scientists are "definitely there, beyond a doubt, in showing that
environmental toxicants have to be involved" in some cases of
Parkinson's disease, said Freya Kamel, an epidemiologist with the
National Institute of Environmental Health Sciences who has documented
a high rate of neurological problems in farmers who use pesticides.

"It's not one nasty thing that is causing this disease. I think it's
exposure to a combination of many environmental chemicals over a
lifetime. We just don't know what those chemicals are yet, but we
certainly have our suspicions."

For almost two centuries, since English physician James Parkinson
described a "shaking palsy" in 1817, doctors have been baffled by the

In most people, a blackened, bean-size sliver at the base of the brain
-- called the substantia nigra -- is crammed with more than half a
million neurons that produce dopamine, a messenger that controls the
body's movements.

But in Parkinson's patients, more than two-thirds of those neurons
have died.

After decades of work, researchers are still struggling with many
unanswered questions, such as which chemicals may kill dopamine
neurons, who is vulnerable and how much exposure is risky.

Expressed in legal terms, pesticides are not guilty beyond a
reasonable doubt -- but there is a substantial, and rapidly growing,
body of evidence, many scientists say.

Clues and breakthroughs are emerging from an odd menagerie of
laboratory flies, mice, rats and monkeys, from bits of human brain,
and from farmers like Rieke.

And it all started with a junkie named George.

It was July 1982, and a 42-year-old patient named George Carrillo had
lingered in Santa Clara emergency rooms and psychiatric units for more
than two weeks. He seemed catatonic, unable to move or speak. Dr. Bill
Langston, who ran a neurology department, was brought in to try to
figure out what was wrong.

Langston gently lifted the man's elbow. His arm was stiff, moving like
a gearshift. Langston had seen this odd, rigid movement many times
before, in patients with Parkinson's disease.

But this was no ordinary Parkinson's patient. His symptoms had
developed virtually overnight.

The doctors soon tracked the source: a botched batch of synthetic
heroin that contained MPTP, a compound that acted like an assassin,
targeting the same neurons missing in Parkinson's patients.

Langston had stumbled across a powerful chemical that unleashed an
immediate, severe form of Parkinson's.

Still, it was obvious that synthetic heroin wasn't the culprit for
most Parkinson's patients. People are exposed to some 70,000 chemicals
in their environment. Which others could cause the disease?

A few days later, a chemist contacted Langston. The formula for the
heroin compound, the chemist said, "looks just like paraquat."
Paraquat has been one of the world's most popular weedkillers for
decades. It was a good place to start.

Since that discovery, scientists have conducted hundreds of animal
experiments, at least 40 studies of human patients, and three of human
brain tissue. They have found "a relatively consistent relationship
between pesticide exposure and Parkinson's," British researchers
reported online in September in the journal Environmental Health

The work has revolutionized the thinking about Parkinson's, shifting
the decades-long debate about whether its roots are genetic or
environmental. Among the research leaders are UCLA, the Parkinson's
Institute in Sunnyvale, Calif., which Langston founded and now
directs, and Atlanta's Emory University, each named national centers
for Parkinson's research in 2001 and given a total of $20 million in
federal grants.

Head trauma contributes to some cases of Parkinson's, and it probably
explains why boxer Muhammad Ali was stricken. But why does it afflict
others with seemingly nothing in common, such as the late Pope John
Paul II and actor Michael J. Fox?

A couple of genes seem to play a role in early onset of Parkinson's in
the small percentage of people who are afflicted at a young age. But
for 90% of people who get the disease, a broad array of environmental
factors are believed responsible. In fact, when Parkinson's patients
have identical twins who carry the exact same genes, most of the twins
do not contract the disease.

"All told, the forms of Parkinson's with a known or presumed genetic
cause account for a small fraction of the disease, likely 5% or less,"
epidemiologists Dr. Caroline Tanner of the Parkinson's Institute and
Lorene Nelson of Stanford University reported in 2003.

To pinpoint which environmental exposures are most important,
scientists are trying to unravel how genes and toxic chemicals
interact to destroy brain cells. One leading theory is that pesticides
cause over-expression of a gene that floods the brain with a neuron-
killing protein.

Exposure to chemicals early in life, followed by toxic exposures in
adulthood, may be especially important, triggering a slow death of
neurons that debilitates people decades later.

Compounds with little in common, such as a fungicide and an
insecticide, apparently can team up to administer a one-two punch,
decimating brain cells.

"Pesticides and related industrial chemicals, those classes of
compounds, clearly are associated with some cases of Parkinson's,"
said Gary Miller, a toxicologist and associate professor at Emory
University's Rollins School of Public Health. "The question is, how
many? 5%, 10%, 50%? In a chemical-free society, people would still get
Parkinson's disease. It would just occur later in life and at a lower

Even 5% would involve 50,000 Americans alive today.

More than 1 billion pounds of herbicides, insecticides and other pest-
killing chemicals are used on U.S. farms and gardens and in
households. Nearly all adults and children tested have traces of
multiple pesticides in their bodies.

So far, animal tests have implicated the pesticides paraquat,
rotenone, dieldrin and maneb -- alone or in combination -- as well as
industrial compounds called PCBs, or polychlorinated biphenyls.

Pesticide industry representatives stress that there are many risk
factors and insufficient evidence implicating any specific pesticide.
Scientists agree that they cannot specify an individual culprit.

"We know for sure that if you expose animals to certain pesticides, it
will kill the same neurons as Parkinson's disease. That's a fact. In
humans, there is high suspicion, but there is no definite proof," said
Dr. Marie-Francoise Chesselet, director of the UCLA Center for Gene-
Environment Studies in Parkinson's Disease.

A connection to rural living or farming has turned up worldwide.
Scientists first observed a high rate of Parkinson's in rural areas in
the early 1980s in Saskatchewan, Canada. Since then a dozen published
studies have reported an increase of 60% to 600% among people exposed
to pesticides, according to the British scientists' review.

Still, the science of epidemiology has inherent weaknesses. Most of
the human studies, for example, relied on patients' memories -- most
of which cannot be validated -- to report their pesticide exposures.

"You need to be cautious in drawing conclusions when you know there
are flaws in these studies," said Pamela Mink, an epidemiologist who
evaluated the human studies in a peer-reviewed report partly funded by
the pesticide industry.

Most patients probably were exposed decades before their diagnosis.
Because there is no national registry for Parkinson's, as there is for
cancer, no one knows whether rates are high in places such as the San
Joaquin Valley.

Among those trying to obtain more definitive answers, UCLA
environmental epidemiologist Dr. Beate Ritz has contacted nearly 300
Parkinson's patients and 250 healthy people in Tulare, Fresno and Kern
counties. She is pinpointing their pesticide exposures down to the
day, the pound and the street corner by overlaying their addresses
with California's extensive agricultural database, which details
pesticide use on farms since the 1970s.

Also, 52,000 farmers and other pesticide applicators have been tracked
by federal researchers since the mid-1990s and one goal is to document
their exposure and see how many wind up with Parkinson's.

Animal studies provide more evidence but also have weaknesses. Mink
and toxicologist Abby Li, who co-wrote the report financed partly by
industry, concluded that the human and animal data "do not provide
sufficient evidence" to prove pesticides cause Parkinson's.

Scientists first tested paraquat in rodents, but the findings were
inconclusive. Neurologist Tim Greenamyre showed that rotenone, a
pesticide, could kill rats' dopamine neurons and cause Parkinson's
symptoms. But since rotenone is a natural plant compound that is not
used much on farms, it was not a likely source of the human disease.

Neurotoxicologist Deborah Cory-Slechta has presented the most
compelling evidence yet on how everyday environmental factors can play
a role in Parkinson's disease. Her theory was that testing one
chemical at a time for its impact on the brain was misguided.

"It's not how humans are exposed," she said. "You don't get a single
dose of a pesticide. You get chronic, low-level exposure."

She injected mice with paraquat and the fungicide maneb. Use of the
two sometimes overlaps on farms. Alone, paraquat and maneb did not
harm mice in her laboratory. But "when we put them together, we were
astounded," Cory-Slechta said.

The most dramatic damage was in mice exposed to maneb as fetuses and
then to paraquat as adults. Their motor activity declined 90% and
their dopamine levels plummeted 80%.

The amounts used in those tests "are not high levels of exposure.
These are very, very low doses," said Cory-Slechta, who now directs
Rutgers University's Environmental and Occupational Health Sciences

Paraquat and maneb are unlikely to be the only combination with such a
devastating effect. Yet the U.S. Environmental Protection Agency
considers only single exposures when approving pesticides, an approach
that "doesn't mimic environmental reality," Cory-Slechta said.

"There may be hundreds, if not thousands, of other compounds that are
silent killers of dopamine neurons," said Dr. Donato Di Monte,
director of basic research at the Parkinson's Institute.

"Each of these risk factors, they kill 10, 20 or 30% of your neurons.
It's like eroding a house on a cliff, and the house finally falls

With so much emerging human and animal data, Chesselet predicts that
"in two years, we will have a preponderance of evidence" against some
classes of chemicals. Kamel thinks specific pesticides will be pinned
down within five years.

For Rieke, it is impossible to determine which chemicals may have
played a role in his disease. He owned two dry-cleaners -- handling
industrial solvents for seven years -- and for 25 years he mixed and
applied at least a dozen herbicides and insecticides on his Merced

At 59, Rieke had to sell the farm and retire. Now 64, he seems 10
years older despite taking seven medications daily.

"Every year, there are things that we all take for granted that my dad
can no longer do," said his son, Greg. "There's no cure, and it never
gets better. There's not a lot of hope, if you will."

Though it's too late for Rieke, scientists are confident they'll soon
be able to predict who is vulnerable to environmental assaults on
their brains.

"That would be the Holy Grail for us," Miller said. "To actually
pinpoint people at risk of this disease and protect them."


Parkinson's and pesticides

Scientists now believe that exposure to toxic substances, particularly
pesticides, could explain some brain cell degeneration that leads to
Parkinson's disease, a disorder that affects body movement and



Neurons or brain cells in the mid-brain produce dopamine, one of two
neurotransmitters that help the brain and body communicate to produce
smooth muscle movements and body coordination.


People with Parkinson's disease lose 60% to 80% of their dopamine-
producing neurons in a part of the mid-brain called the substantia
nigra, hindering communication between the mind and body. Scientists
think some pesticides may kill neurons in the substantia nigra.


When dopamine is present

In a normal mid-brain, the substantia nigra has cells that are
pigmented, or colored black, a byproduct of dopamine production.


Absence of dopamine

Parkinson's patients lack this pigmentation because they've lost so
many neurons.


Source: Medline Plus

Copyright 2005 Los Angeles Times