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New Evidence for Association of Pesticides with Parkinson Disease

Shaw, Gina

doi: 10.1097/01.NT.0000397213.59588.f1
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THE PESTICIDES — atrazine, simazine, alachlor, and metachlor — are commonly used for spraying in agricultural areas

THE PESTICIDES — atrazine, simazine, alachlor, and metachlor — are commonly used for spraying in agricultural areas

Researchers at the University of Colorado have found that higher concentrations of four pesticides — atrazine, simazine, alachlor, and metachlor — in groundwater are significantly associated with higher levels of Parkinson disease.

Back in 1982, a cluster of young heroin addicts in the San Francisco Bay area suddenly — virtually overnight — developed symptoms that were almost identical to those of Parkinson disease (PD). Neurologist William J. Langston, MD, was summoned to help deal with the outbreak, which was ultimately traced to a bad batch of heroin that had been contaminated with a neurotoxin called MPTP (1-methyl-4-phenyl-1,2,3, 6–tetrahydropyridine). In a controlled laboratory environment, MPTP was used to induce Parkinson-like conditions in animals, and quickly became the best model for research into the disease.

The toxic metabolite of MPTP (MPP+) is also very similar to paraquat, one of the most widely used herbicides in the world — so the discovery set off a rush of epidemiological research looking for environmental toxins that might contribute to PD. Since then, a number of studies have implicated various pesticides; in addition to paraquat, the most common culprits have been organochlorines in the pathogenesis of Parkinson disease.

“To date, there have been over 50 studies showing various associations between pesticides and herbicides and the risk for Parkinson disease, and it's worldwide. This is a hypothesis that hasn't gone away,” said Dr. Langston, the founder, scientific director and CEO of the Parkinson's Institute in Sunnyvale, CA.

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Now, a new epidemiologic study released at the AAN annual meeting this week in Hawaii has added another piece to the puzzle. Researchers at the University of Colorado have found that higher concentrations of four pesticides — atrazine, simazine, alachlor, and metachlor — in groundwater are significantly associated with higher levels of PD.



“For every 10 mcg per liter increase of pesticide levels in the drinking water, we found that the risk for Parkinson disease increases by 3 percent. And our samples had pesticide concentrations ranging from 0.0005-20 mcg per liter,” said Kathy James, PhD, an instructor in the department of family medicine and the School of Public Health at the University of Colorado-Denver, who served as lead investigator for the study. “By comparison, for every year you age, your risk of developing Parkinson disease increases by 7 percent. So it's nearly half the risk we have from aging.”

To develop their findings, Dr. James and her team used the Colorado Medicare Beneficiary Database, which includes residents' nine-digit zip codes, and identified Parkinson cases using the ICD-9 code 332.X. They then used a geographic information system (GIS) model based on 236 samples of the four herbicides to estimate residential pesticide levels.

“Most of the evidence for this association to date has been based on ecologic studies, where an environmental value applied to a large community is used to assess exposure,” said Dr. James. “Other studies have looked at well water or at pesticide application rates, and used those to predict what the approximate water levels would be.”

Dr. James acknowledged that there are limitations to her findings. “We were able to predict an individual-level exposure to groundwater pesticides, but we couldn't determine actual individual exposure in the sense of how much water was consumed by each individual, because it's an extremely large cohort study,” she said.

“It's also a cross-sectional study, so the exposure is assessed at the time the outcome of Parkinson disease is already diagnosed,” she said. “In other studies I've worked on with other contaminants and outcomes, we've done full lifetime exposure assessments based on where individuals lived, and the temporal and spatial predictions for the contaminant of interest.”

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There are plausible biological mechanisms behind an association of Parkinson with pesticides, said Marc Weisskopf, PhD, ScD, assistant professor in the departments of environmental health and epidemiology at the Harvard School of Public Health, who was not involved with the study. “First, pesticides generally increase the levels of oxidative stress in the brain,” Dr. Weisskopf said. “There are pesticides and herbicides that target molecules in the mitochondria that are particularly known to play an important role in Parkinson, having to do with energy production systems in nerve cells. Some pesticides have also been shown to lead to disruption of the ubiquitin system, which also appears to play a role in the disease.”

The ability to use the GIS water data to get at specific pesticide levels is a new factor, and a strength of the study, Dr. Weisskopf said. “Being able to get data at this level is very intriguing.”

Dr. Weisskopf pointed to work done by Beate Ritz, MD, PhD, professor and vice chair of epidemiology in the School of Public Health at the University of California-Los Angeles, which has taken a similar approach by incorporating GIS models of pesticide exposures from use on farms in California into case-control studies of PD.

In a 2009 study published in the American Journal of Epidemiology, Dr. Ritz and colleagues found that residents of the California Central Valley who lived within 500 meters of fields sprayed with the fungicide maneb and the herbicide paraquat between 1974 and 1999 had a 75 percent increased risk for Parkinson disease. DThe James group gets to larger numbers, I think, by using Medicare data, but the down side is the less rigorous case definition,” he said.

“The early work on Parkinson disease and pesticides has drifted off the radar screen, and this team is to be congratulated for looking at it again,” Dr. Langston said. “This is a pretty good-sized epidemiological undertaking. They have to go in and confirm that these are real cases with individual level data, but it's a clever way to get started.”

He also observed that the pesticides in this study are not the ones most commonly associated with PD in the past. “It may be that these agents have effects that were previously unknown, and it's also possible that if these pesticides are there, others such as paraquot and rotenone are there as well. Or are atrazine and others going to turn out to be new and important agents of interest?”

Dr. James believes that geographic information systems technology will be key to deciphering the pathobiology of contaminants such as pesticides and their association with diseases like PD. “Now we have the technology to conduct a good environmental epidemiology-based study, and tie environmental data — of which there is an abundance — with epidemiological and clinical data.”



She hopes next to be able to move away from the larger scale and do an individual exposure assessment to help confirm the initial findings. “You need to bore down into people's drinking water habits, occupational exposure, and residential histories,” she said. “Where did they live? What were they exposed to? You also need to ensure that the cases you have are indeed cases, through good chart review and analysis. And ideally, you would incorporate a genetic component. Those are our next steps.”

“Epidemiology is challenging,” Dr. Langston said. “People often have to use already available databases like this — which they've done in a very clever manner — and put things together. But then you have to follow up and see if you can document pesticides in the groundwater in these areas, and confirm that these people do have Parkinson. That's the hard part, but I'd say they've thrown the gauntlet down with this study.”

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Costello S, Cockburn M, Ritz B, et al. Parkinson's disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol 2009;169(8):919–926.
©2011 American Academy of Neurology