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Combination of Pesticides Linked to Parkinson's Disease

Cat Lazaroff / ENS 3jan01

ROCHESTER, NY -- A 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 scientists caution that more studies are necessary to explain the link, since it is probable that many factors contribute to a complex disease like Parkinson's. The researchers say it is unlikely that the pesticides on their own actually cause the disease.


Spraying pesticide on peas in Washington state (Photo by Doug Wilson, courtesy U.S. Department of Agriculture (USDA))

The latest findings of a 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 December 15 issue of the "Journal of Neuroscience." [abstract below]

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 on such crops as potatoes, tomatoes, lettuce and corn. 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," said Cory-Slechta, who was joined in the research by graduate student Mona Thiruchelvam and faculty members Eric Richfield, Raymond Baggs, and A. William Tank.


Cotton crops, like this one in Mississippi, may be treated with an herbicide like paraquat to reduce competition by weeds (Photo by Bill Tarpenning, courtesy USDA)

The study is one of the first to examine the effects of such chemicals in tandem. Previous studies on single pesticides have shown a link between indoor pesticide use and Parkinson's in humans, but have found no link between outdoor pesticide use and the disease.

Cory-Slechta noted 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," Cory-Slechta said. "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. A map of their use mirrors areas of the country where people are more likely to die of Parkinson's disease.


Pesticide being applied to a soybean crop in Illinois (Photo by Ken Hammond. Three photos courtesy Agricultural Research Service)

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 do not.

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 symptoms similar to those of Parkinson's. 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," said Cory-Slechta. "This has enormous implications."

Scientists have little understanding of what causes Parkinson's, which is characterized by the death of a tiny group of dopamine producing neurons deep within an area of the brain known as the substantia nigra. 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 one 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.

hooded sprayers

Hooded pesticide sprayers, like these being used on a sorghum crop, can help keep pesticides from drifting away from agricultural areas. But they do not address the problem of pesticide residues on food (Photo by Jack Dykinga)

Cory-Slechta thinks it is unlikely that exposures to such chemicals 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 said.

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," Cory-Slechta said.

She also says more work must be done to see how much of these chemicals people are exposed to. It is often not clear exactly how much of a pesticide remains on crops by the time they reach the dinner table, she said.


Without the use of herbicides like paraquat, crops can be choked by weeds. The field on the left has been treated with an herbicide that blocks the growth of a weed called giant foxtail; the field on the right is untreated (Photo by Doug Buhler)

Maneb frequently shows up as a slight residue, while paraquat usually shows up just in trace amounts, said Cory-Slechta. Exposures can also occur via other routes.

Often the two pesticides 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," said Cory-Slechta.

The University of Rochester team is currently pursuing several new avenues of research, with funding from the National Institutes of Environmental Health and Safety. 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 have shown that mice with the same genetic abnormality that causes some people to develop Parkinson's are particularly vulnerable to the mixture.

The Nigrostriatal Dopaminergic System as a Preferential Target of Repeated Exposures to Combined Paraquat and Maneb: Implications for Parkinson's Disease

The Journal of Neuroscience, 20(24):9207-9214 15dec00

Mona Thiruchelvam1, Eric K. Richfield2, 6, Raymond B. Baggs5, 6, Arnold W. Tank3, and Deborah A. Cory-Slechta4, 6

1 Interdepartmental Program in Neuroscience, Departments of 2 Pathology and Laboratory Medicine, 3 Pharmacology and Physiology, and 4 Environmental Medicine, the 5 Division of Laboratory Animal Medicine, and the 6 National Institute of Environmental Health Sciences Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Experimental evidence supporting 1,1'-dimethyl-4,4'-bipyridinium [paraquat (PQ)] as a risk factor for Parkinson's disease (PD) is equivocal. Other agricultural chemicals, including dithiocarbamate fungicides such as manganese ethylenebisdithiocarbamate [maneb (MB)], are widely used in the same geographical regions as paraquat and also impact dopamine systems, suggesting that mixtures may be more relevant etiological models. This study therefore proposed that combined PQ and MB exposures would produce greater effects on dopamine (DA) systems than would either compound administered alone. Male C57BL/6 mice were treated twice a week for 6 weeks with intraperitoneal saline, 10 mg/kg paraquat, 30 mg/kg maneb, or their combination (PQ + MB). MB, but not PQ, reduced motor activity immediately after treatment, and this effect was potentiated by combined PQ + MB treatment. As treatments progressed, only the combined PQ + MB group evidenced a failure of motor activity levels to recover within 24 hr. Striatal DA and dihydroxyphenylacetic acid increased 1-3 d and decreased 7 d after injections. Only PQ + MB reduced tyrosine hydroxylase (TH) and DA transporter immunoreactivity and did so in dorsal striatum but not nucleus accumbens. Correspondingly, striatal TH protein levels were decreased only by combined PQ + MB 5 d after injection. Reactive gliosis occurred only in response to combined PQ + MB in dorsal-medial but not ventral striatum. TH immunoreactivity and cell counts were reduced only by PQ + MB and in the substantia nigra but not ventral tegmental area. These synergistic effects of combined PQ + MB, preferentially expressed in the nigrostriatal DA system, suggest that such mixtures could play a role in the etiology of PD.

Key words: dopamine; striatum; nucleus accumbens; substantia nigra; tyrosine hydroxylase; dopamine transporter; locomotor activity; gliosis

source: http://www.jneurosci.org/cgi/content/abstract/20/24/9207 8jan01

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