(Beyond Pesticides, March 16, 2009)
Exposure to a mixture of the fungicide maneb and the herbicide paraquat significantly increases the risk of developing Parkinson’s disease, according to a new University of California, Berkeley study, “Parkinson’s Disease and Residential Exposure to Maneb and Paraquat from Agricultural Applications in the Central Valley of California.” Published in the American Journal of Epidemiology, the study findings show that exposure to both pesticides within 500 meters of an individual’s home increases the risk of developing Parkinson’s by 75 percent. For individuals 60 years of age or younger at the time of diagnosis, there is a more than four-fold increase in risk of the disease when exposed to a combination of maneb and paraquat and a more than doubling of risk when exposed to either maneb or paraquat alone.
The Berkeley researchers used geographic information systems that analyzed data from California Pesticide Use Reports and land-use maps to calculate historical residential exposure to agricultural exposure to the two pesticides. From 1998 to 2007, the researchers enrolled 368 incident Parkinson’s disease cases and 341 population controls from California’s Central Valley and developed potential exposure estimates incurred between 1974 and 1999.
Also published this month by some of the same researchers, “Dopamine Transporter Genetic Variants and Pesticides in Parkinson’s Disease,” finds that certain genes and these same pesticides, maneb and paraquat, interact to increase to the risk factor for Parkinson’s disease. This University of California, Los Angeles study looks at pesticide exposure and genetic variability in the dopamine transporter (DAT), a protein that plays a central role in dopaminergic neurotransmission of the brain which makes them more susceptible to Parkinson’s. In this study, high residential exposure to maneb and paraquat increases risk almost 3-fold in individuals who have one DAT susceptibility allele and 4.5 fold in those with two or more susceptibility alleles.
The second most common neurodegenerative disease affecting more than one million people in the U.S., Parkinson’s disease occurs when nerve cells in the substantia nigra region of the brain are damaged or destroyed and can no longer produce dopamine, a nerve-signaling molecule that helps control muscle movement.
Exposure to the herbicide paraquat has long been associated with Parkinson’s disease. Several studies show an increased risk for Parkinson’s with occupational exposure to and contact with paraquat. A case-control study in Taiwan found that those who had used paraquat were at greater risk of developing the disease than those that had used other pesticides. A 2007 study examined a cohort of 80,000 licensed private applicators and spouses and found that farmworkers exposed to paraquat have twice the expected risk of developing the Parkinson’s. For those that were exposed to herbicides and could recall their exposure history, a Canadian population-based case-control study reported one individual using paraquat, between the ages of 26 and 31 years, and was the only herbicide-exposed case in the study whose onset of symptoms occurred before the age of 40.
Paraquat induces dopaminergic nigral apoptosis and acts through oxidative stress-mediated mechanisms. In laboratory animal studies, paraquat exposure triggers processes characteristic of early stages of dopaminergic neuron degeneration by stimulating an increase in the protein alpha-synuclein in the brain, likely due to preferential binding of the pesticides to a partially folded alpha -synuclein intermediate. The protein kills the dopamine-producing brain cells which lead to Parkinson’s. In 2002, researchers from the Parkinson’s Institute published that their findings “unequivocally show that selective dopaminergic degeneration, one of the pathological hallmarks of Parkinson’s disease, is also a characteristic of paraquat neurotoxicity.”
For researchers testing the role of oxidative stress in paraquat exposed mice, they find that the “initial exposure acts as a priming’ event, enhancing neuronal vulnerability to a subsequent toxic insult.” Suggesting that dopaminergic cell degeneration appears to be dependent on the sequence of toxic challenges and the interaction between cell vulnerability, damaging effects and protective responses. Nigrostriatal neurons are vulnerable to oxidative processes. Depending on the paraquat exposure, oxidative stress may be reversible or lead to neurodegeneration.
The synergistic effects of maneb and paraquat together have previously been linked to Parkinson’s disease as well. In lab studies, University of North Dakota researchers find maneb affects rat brain mitochondria. Low levels of maneb can injure the antioxidant system in the dopamine neurons, especially with concurrent exposure to other environmentally relevant oxidative stressors, such as paraquat. University of Rochester scientists discovered that the synergistic effects of paraquat and maneb target the nigrostriatal dopamine system and indicate progressive neurotoxicity with continuing exposure. Their findings show that while there are no or only marginal effects when these chemicals are administered individually, together they produce synergistic effects when given in combination. In another study, these researchers again chronically expose mice to a low-level combination of maneb and paraquat, resulting in significant reductions in locomotor activity, levels of striatal dopamine and dopaminergic neurons in the substantia nigra, more so than when exposed individually.
A laboratory study finds that “prenatal exposure to the pesticide maneb produces selective, permanent alterations of the nigrostriatal dopaminergic system and enhances adult susceptibility to paraquat exposure.” Additional studies show that exposure to maneb and paraquat during the post-natal and juvenile period causes Parkinson-like declines in dopaminergic neurons and makes the substantia nigra more susceptible to additional exposures in adulthood, “suggesting that developmental exposure to neurotoxicants may be involved in the induction of neurodegenerative disorders and/or alter the normal aging process.”