Pesticides And Parkinson Disease A Critical Review

Children Are Especially At Risk

Pesticide exposures during the neurodevelopmental phases contribute to the development of Parkinsons disease by damaging the dopaminergic system and increasing its sensitivity to subsequent exposures. Exposure during childhood increases the risk of developing Parkinsons disease by up to 6 times.

Parkinsons disease has been recognized as an occupational disease in France since 2012 and in Sweden since 2017. Quebec has become the third territory to apply this recognition. This is a great victory, but the fight does not end there.

Exposure To Pesticides And Welding Hastens The Age

Published online by Cambridge University Press: 25 July 2019

Pierre-Luc Gamache*

Affiliation:Département des Sciences Neurologiques, Centre Hospitalier Universitaire de Québec, Québec City, Québec, CanadaFaculté de médecine, Université Laval, Québec City, Québec, Canada

Ikhlass Haj Salem

Faculté de médecine, Université Laval, Québec City, Québec, Canada

Noémie Roux-Dubois

Affiliation:Département des Sciences Neurologiques, Centre Hospitalier Universitaire de Québec, Québec City, Québec, CanadaFaculté de médecine, Université Laval, Québec City, Québec, Canada

Jacques Le Bouthillier

Faculté de médecine, Université Laval, Québec City, Québec, Canada

Ziv Gan-Or

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec City, Québec, Canada

Nicolas Dupré

Affiliation:Département des Sciences Neurologiques, Centre Hospitalier Universitaire de Québec, Québec City, Québec, CanadaFaculté de médecine, Université Laval, Québec City, Québec, Canada

*

Correspondence to: Pierre-Luc Gamache, CHU de Québec, 1401, 18è rue, Québec City, Québec G1J 1Z4, Canada. Email:

Frequency Of Exposures To Pesticides

The mean AAO according to frequency groups is depicted in Figure 1. The linear regression model including frequency and the number of VRFs also significantly predicts AAO . Proximity is a significant, negatively correlated, independent predictor , and the number of VRFs remains significantly positively correlated to AAO .

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One Of The First Studies To Look At Human Cells

The researchers used stem cells from patients with Parkinsons disease who had a mutation in the gene responsible for encoding the -synuclein protein.

At least 30 alterations in this gene have been associated with Parkinsons, and -synuclein protein clumps are a well-documented, albeit poorly understood, hallmark of the disease.

For the new research, the scientists also worked with normal embryonic cells that they modified using genetic editing to replicate the -synuclein genetic mutation.

Prof. Ryan explains why using human cells makes this study particularly valuable. Until now, he says, the link between pesticides and Parkinsons disease was based primarily on animal studies as well as epidemiological research that demonstrated an increased risk among farmers and others exposed to agricultural chemicals.

We are one of the first to investigate what is happening inside human cells, explains Prof. Ryan.

Stem cells are undifferentiated cells that go on to individualize into specific types of cells. Prof. Ryan and his colleagues used the two types of stem cells to derive dopamine-producing nerve cells from them.

Then, they exposed these dopaminergic neurons which are known to be affected the most by Parkinsons disease to the two pesticides.

Proximity Of Exposures To Pesticides

The mean AAO according to proximity groups is depicted in Figure 1. The linear regression analysis shows that a model including proximity and the number of VRFs significantly predicts AAO . Proximity is a significant, negatively correlated, independent predictor , and the number of VRFs is significantly positively correlated to AAO .

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Data Synthesis And Statistical Analysis

Meta-analysis of results will be considered by investigating heterogeneity among animal and human studies, separately. It is common, though, that environmental health studies have some differences regarding outcome assessments and exposure definitions that could be an obstacle to formal statistical meta-analysis . The heterogeneity associated with pooled effect estimates will be assessed with the use of a 2 test and the I2 statistic . Heterogeneity will be classified as follows: 0 to 40% 30 to 60% 50 to 90% and 75 to 100% .

Statistical analysis will be conducted using the Comprehensive Meta-Analysis STATA software . If considerable heterogeneity is detected among studies, meta-analysis will not be indicated and results will only be presented in tables or in a narrative synthesis. However, if heterogeneity does not exceed 75%, we will use random effects meta-analysis , which is a more conservative approach of pooling the results. In this case, the measure of association will be presented as odds ratios and mean difference, both with a 95% confidence interval , for studies with dichotomous and continuous data, respectively .

Integrated Evidence For Paraquat Hazard Identification

For proper categorization of paraquat in one of the five categories of hazard , evidence coming from human and animal studies will be integrated with mechanistic data that may be relevant to support biological plausibility and increase or decrease the hazard classification.

Among the factors that can support biological plausibility and increase the hazard classification, the magnitude of the effect, the doseresponse gradient, and the direct and indirect consistencies between outcomes from studies with different biological levels will be considered. On the contrary, hazard classification may be reduced by the identification of risk of bias, unexplained inconsistencies between studies with related outcomes, non-relevance of the paraquat mechanism of toxicity to humans and dose levels not relevant to real human exposure.

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Interaction Of Pesticides With

The formation of Lewy bodies may be integral to the cause of the disease rather than being an accompanying effect. Studies in vitro have suggested that a number of pesticides may induce a conformational change in -synuclein and accelerate the formation of -synuclein fibrils . Pesticides known to induce this effect are hydrophobic and include rotenone, DDT, 2,4-dichlorophenoxy-acetic acid, dieldrin, diethyldithiocarbamate, paraquat, maneb, trifluralin, parathion, and imidazoldinethione those having no significant effect include iprodione, glyphosate, methomyl, thiuram, mevinphos, carbaryl, alachlor, thiobencarb, and also MPP+ .

The Link Between Parkinsons Disease And Toxic Chemicals

A new book calls the increasing prominence of Parkinsons a man-made pandemic.

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Michael Richard Clifford, a 66-year-old retired astronaut living in Cary, N.C., learned before his third spaceflight that he had Parkinsons disease. He was only 44 and in excellent health at the time, and had no family history of this disabling neurological disorder.

What he did have was years of exposure to numerous toxic chemicals, several of which have since been shown in animal studies to cause the kind of brain damage and symptoms that afflict people with Parkinsons.

As a youngster, Mr. Clifford said, he worked in a gas station using degreasers to clean car engines. He also worked on a farm where he used pesticides and in fields where DDT was sprayed. Then, as an aviator, he cleaned engines readying them for test flights. But at none of these jobs was he protected from exposure to hazardous chemicals that are readily inhaled or absorbed through the skin.

Now Mr. Clifford, a lifelong nonsmoker, believes that his close contact with these various substances explains why he developed Parkinsons disease at such a young age. Several of the chemicals have strong links to Parkinsons, and a growing body of evidence suggests that exposure to them may very well account for the dramatic rise in the diagnosis of Parkinsons in recent decades.

Sometimes, though, the links are so strong and the evidence so compelling that there can be little doubt that one causes the other.

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Assessment Of Internal Validity Of Individual Studies

Reviewers, working in pairs, will independently assess the risk of bias of each human or animal study a specific protocol to address the risk of bias of mechanistic studies is still in development. Possible sources of bias will be assessed through 11 pre-defined questions considering potential confounders, confidence in exposure characterization, and confidence in the outcome assessment . The answer to each question is assigned to one of the four following categories of risk of bias: definitely low, probably low, probably high, or definitely high. After assigning each response to one of the categories, we will also use a three-tier system to classify the studies regarding their overall methodological quality. Studies considered at definitely or probably low risk of bias will be grouped as tier 1 studies. Tier 3 studies refer to the ones considered to be at definitely or probably high risk of bias tier 2 will encompass studies that did not meet the criteria for tier 1 and tier 3 and therefore fall into an in-between category .

Does Exposure To Pesticides Herbicides Or Other Pollutants Increase The Risk Of Developing Parkinson Disease

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A meta-analysis of 89 studies, including 6 prospective and 83 case-control studies, found that exposure to pesticides may increase the risk for PD by as much as 80%. Exposure to the weed killer paraquat or to the fungicides maneb or mancozeb is particularly toxic, increasing the risk for PD about 2-fold. Many of the agents studied are no longer used in the United States and Europe however, some are still found in developing parts of the world.

In case-control studies, PD was associated with exposure to any type of pesticide, herbicide, insecticide, and solvent, with risks ranging from 33% to 80%. Increased PD risk was also associated with proxy conditions of exposure to organic pollutants, such as farming, well-water drinking, and rural living. In addition, risk seemed to increase with length of exposure.

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Association Between Parkinsons Disease And Cigarette Smoking Rural Living Well

• Affiliation Syngenta Crop Protection, LLC, Greensboro, NC, 27419, United States of America

• Affiliation Queen Mary, Univ. of London, London, E1 4NS, United Kingdom

• Affiliation Exponent, Inc., Menlo Park, CA, 94025, United States of America

• Affiliation Sielken & Associates Consulting, Inc., College Station, TX, 77845, United States of America

Subgroup And Sensitivity Analysis

Subgroup analysis will be conducted to investigate possible heterogeneity causes and other risk factors that could be potential cofounders. Studies will be allocated into groups according to common characteristics, as described below. The outcomes are assessed to determine if exposure caused a significant effect due to a specific feature. For human studies, subgroup analyses will be conducted for different exposure periods , co-exposures to other pesticides also related to PD , different comorbidities , different age groups , and presence or absence of family history of PD.

For experimental animal studies, subgroup analyses will be conducted for dose , duration of paraquat exposure in multidose studies, and routes of administration .

If there are enough studies, we will develop sensitivity analyses to explore robustness of the results for each type of study design e.g., observational studies vs. experimental animal studies, cohort vs. casecontrol vs. cross-sectional and studies with low risk of bias vs. those with high risk of bias.

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Specific Pesticides And Their Link To Pd

The evidence that pesticide use is associated with an increased risk in PD, begs the question are there specific pesticides that are most concerning? When data is collected on this topic in large populations, often the participants in the study are unaware of which specific pesticide exposures they have had. This makes it difficult to determine which pesticides to avoid.

Some studies however were able to investigate the risks of specific chemicals. A recent review summarized the current state of knowledge on this topic. The chemical with the most data linking it to an increased PD risk is paraquat, with exposure associated with a 2-3 fold increased PD risk over the general population.

One particularly comprehensive study investigated exposure to 31 pesticides and their association with PD risk. From that data emerged paraquat and rotenone as the two most concerning pesticides.

• Paraquats mechanism of action is the production of reactive oxygen species, intracellular molecules that cause oxidative stress and damage cells.
• Rotenones mechanism of action is disruption of the mitochondria, the component of the cell that creates energy for cell survival.

Interestingly, both mitochondrial dysfunction and oxidative stress are common themes in our general understanding of what causes death of nerve cells in PD.

The Organochlorine Pesticides: The Case Study Of Dieldrin

Brief History of Use

Mechanism of Action

One of the primary mechanisms of action of dieldrin is to bind to, and block the gamma-aminobutyric acid A receptor-chloride channel complex . GABA is an inhibitory neurotransmitter in the central nervous system and opens GABAA channels to chloride in order to hyperpolarize cells. Dysfunction in these receptors result in over-excitation, seizures, and death. Studies have shown some activity as a mitochondrial toxicant and endocrine disruptor, and dieldrin has been reported to disrupt the mitochondrial electron transport chain and to act as weak estrogen receptor agonists and antagonists in estrogen and androgen transactivation assays. Detailed structure-activity relationships have also been investigated for dieldrin in terms of cellular interactions and dieldrin was found to disrupt a wide number of cellular processes including the dopamine synthesis pathway that were dependent upon both its stereochemistry and structure . Thus, while dieldrin is a potent GABAA receptor antagonist, the modes of action for dieldrin are diverse in the CNS.

Epidemiological Evidence

Cellular and Molecular Responses

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Neurochemical And Neuropathological Studies In Pd And Mn

As pointed out by Perl and Olanow , a very limited number of autopsy studies have been performed on workers who were exposed to Mn or on persons with other related conditions in which Mn was increased in the brain . Most of the neuropathological studies associated with occupational Mn exposures were performed in the early 1900s and lacked detailed examination of brain tissue. Neurochemical methods used in the early studies did not have the sensitivity and specificity available today. Nevertheless, most studies described marked changes in the globus pallidus of Mn-exposed individuals, with no remarkable effects on pigmented cells of the substantia nigra, which indicates a lack of an effect on dopamine cell bodies, the only midbrain neurons that contain melanin . Neurochemical studies of the brains of patients with liver disease have confirmed for the most part the results from neuroimaging studies: a significant decrease in D2R levels in the basal ganglia and no observed decrease in dopamine levels . In one study, Mousseau et al. used in vitro autoradiography and found decreased D2R levels in the globus pallidus and putamen with no change in D1-dopamine receptors in the basal ganglia of patients with liver disease .

Table 3 Neurochemical studies in human postmortem brain tissue.

Reference
DA/HPLC not changed in the caudate HVA increased

Abbreviations: DA, dopamine GP, globus pallidus Mn-O, occupational Mn exposure SN, substantia nigra.

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Parkinsons And Occupational Pesticides

A 2012 review of research from Belgiums Catholic University of Louvain confirmed that Parkinsons disease is linked to occupational exposure to pesticides.

The researchers, working with the Louvain Center for Toxicology and Applied Pharmacology, analyzed studies between 1985 and 2011 that looked at pesticide exposure by workers who handled pesticides. These included farm workers who sprayed pesticides.

The research found that those who handled pesticides were significantly more likely to contract Parkinsons disease. In four studies, where the Parkinsons diagnoses were confirmed by neurologists, those handling pesticides had an average of over two-and-a-half times the risk of contracting Parkinsons disease. The increased risk ranged from 46% higher to almost four-and-a-half times higher among the workers.

Three cohort studies, which followed larger populations and compared them to the general population, concluded that workers handling pesticides had close to twice the risk of contracting Parkinsons disease than the rest of the population.

One of these cohort studies showed workers handling pesticides had almost three times the rate of contracting Parkinsons disease.

Their meta-analysis found that all twelve studies individually and combined, established a link between pesticide exposure and Parkinsons disease.

The researchers concluded:

What Are The Common Transcriptome Responses Observed With Pd

Our next objective was to determine which transcripts are those most likely regulated by these specific PD-associated chemicals. We extracted data from the Comparative Toxicogenomics Database to compile information on gene expression responses for each of the pesticides. The language of CTD is a structured hierarchical vocabulary that describes relationships among chemicals, genes, and proteins based upon interaction data . Examples of pesticides associated with PD, based upon expression data evidence in the Comparative Toxicogenomics Database is presented in Table 3. The inference score reflects the degree of similarity between CTD chemicalgenedisease networks and a higher score indicates a higher likelihood of interconnectivity among entities. Rotenone, not surprising as a mitochondrial toxicant, was ranked 5th of all chemicals, based upon molecular data associating this chemical to PD. Transcriptome profiles generated by rotenone were strongly associated with those observed in studies of PD. As expected, paraquat and maneb were also associated with PD based upon toxicogenomics responses. The table also depicts other pesticides such as permethrin, a pyrethroid insecticide, and chlorpyrifos, an organophosphate pesticide that have suggested links to Parkinson’s disease.

Table 3. Examples of pesticides associated with Parkinson’s disease , based upon expression data from chemicals in the Comparative Toxicogenomics Database .

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Modelling Pd In Rodents And Simple Organisms

Impaired mitochondrial function is a predominant feature in cases of Parkinson’s disease due to genetic or environmental modifications, which result in mitochondrial stress. This may directly compromise the neuron or cause alterations in neurotransmitter release, resulting in post-synaptic damage. A pro-inflammatory component is increasingly considered to be important in the pathogenesis of several neurodegenerative conditions including PD, and pro-inflammatory activation of glial cells may be pivotal in disease onset.,

Although many of the genes involved in PD have been identified, their interactions are still unclear. Mutations of -synuclein or duplications of -synuclein are linked to familial PD and -synuclein is a component of Lewy bodies. -synuclein tends to form intracellular fibrils and aggregates, particularly after oxidative stress. Loss of an ubiquitin ligase, Parkin, is responsible for autosomal recessive juvenile parkinsonism. Finally, mutations in genes coding for UCH-L1 and Pink-1 are linked to autosomal recessive PD, whereas mutations in LRRK2 are linked with autosomal dominant PD. Recent work has shown that mutations in the mitochondrial protease HtrA2 are also linked to PD downstream of the kinase, Pink 1. Mutations in Parkin are recognized as the most common cause of familial parkinsonism and may be involved in sporadic PD. Parkin seems to work as a broad-spectrum neuroprotectant, the efficacy of which decreases with ageing.