Pesticide-Induced Diseases: Parkinson’s Disease
The second most common neurodegenerative disease, Parkinson’s
disease (PD) 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. People
with PD have a variety of symptoms including loss of muscle control, trembling
and lack of coordination. They may also experience anxiety, constipation,
dementia, depression, urinary difficulties, and sleep disturbances. Over
time, symptoms intensify. At least one million Americans have PD and about
50,000 new cases are diagnosed each year. With less than one percent of
cases caused by genetics, researchers have been looking for the potential
risk factors for developing Parkinson’s disease (PD). The epidemiological
and toxicological evidence is repeatedly identifying exposure to pesticides,
as well as specific gene-pesticide interactions, as significant adverse
risk factors that contribute to PD. See Beyond Pesticides' Parkinson's
Disease article from the Spring 2008 issue of Pesticides and You.
- Rotenone and paraquat perturb dopamine metabolism: A computational analysis of pesticide toxicity.
To explore the relationship between pesticide exposure and dopaminergic toxicity, authors developed a custom-tailored mathematical model of dopamine metabolism and utilized it to infer potential mechanisms underlying the toxicity of rotenone and paraquat, asking how these pesticides perturb specific processes. Authors performed two types of analyses, which are conceptually different and complement each other. The first analysis, a purely algebraic reverse engineering approach, analytically and deterministically computes the altered profile of enzyme activities that characterize the effects of a pesticide. The second method consists of large-scale Monte Carlo simulations that statistically reveal possible mechanisms of pesticides. The results from the reverse engineering approach show that rotenone and paraquat exposures lead to distinctly different flux perturbations. Rotenone seems to affect all fluxes associated with dopamine compartmentalization, whereas paraquat exposure perturbs fluxes associated with dopamine and its breakdown metabolites. The statistical results of the Monte-Carlo analysis suggest several specific mechanisms. The findings are interesting, because no a priori assumptions are made regarding specific pesticide actions, and all parameters characterizing the processes in the dopamine model are treated in an unbiased manner. Our results show how approaches from computational systems biology can help identify mechanisms underlying the toxicity of pesticide exposure.
[Qi Z, Miller GW, Voit EO. 2014. Toxicology. 315:92-101]
- Environmental toxins and Parkinson's disease.
Parkinson's disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life and is characterized by motor impairment, autonomic dysfunction, and, in many, psychological and cognitive changes. Recent advances have helped delineate pathogenetic mechanisms, yet the cause of PD in most individuals is unknown. Although at least 15 genes and genetic loci have been associated with PD, identified genetic causes are responsible for only a few percent of cases. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, solvents, metals, and other pollutants, and many of these compounds recapitulate PD pathology in animal models. This review summarizes the environmental toxicology of PD, highlighting the consistency of observations across cellular, animal, and human studies of PD pathogenesis
[Goldman SM. 2014. Annu Rev Pharmacol Toxicol.54:141-64]
- Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: Relevance to sporadic Parkinson's disease.
Despite several years of research, the aetiology of Parkinson's disease (PD) is quite far from being solved. Considering the nonrestricted commercial availability and common use of several pesticides, such as paraquat and maneb, in agriculture of less developed countries, the aim of this study was to investigate the involvement of nociceptin/orphanin-NOP and prodynorphin-KOP systems in a chronic paraquat and maneb animal model of Parkinson's disease. Results showed that after paraquat/maneb treatment, a significant reduction in tyrosine hydroxylase (TH) levels, the rate-limiting enzyme for dopamine synthesis, was observed. Also, the association of paraquat and maneb induced an increase in nociceptin/orphanin and a decrease of prodynorphin gene expression levels in the substantia nigra with a down-regulation of NOP and KOP receptors after both treatments in the substantia nigra and caudate putamen. These data further confirm that paraquat and maneb toxicity can modulate gene expression of the nociceptin/orphanin-NOP receptor and prodynorphin-KOP receptor systems in the substantia nigra and caudate putamen, offering further support to the hypothesis that chronic exposure to these agrochemicals might be implicated in the mechanisms underlying sporadic Parkinson's disease.
[Bastías-Candia S, Di Benedetto M, D'Addario C, Candeletti S, Romualdi P. 2013. Environ Toxicol. doi: 10.1002/tox.21943]
- Parkinson's disease: evidence for environmental risk factors.
Parkinson's disease (PD) has no known cause. Although recent research has focused particularly on genetic causes of PD, environmental causes also play a role in developing the disease. This article reviews environmental factors that may increase the risk of PD, as well as the evidence behind those factors. Enough evidence exists to suggest that age has a causal relationship to PD. Significant evidence exists that gender, tobacco use, and caffeine consumption are also associated with the development of PD. Other environmental factors (pesticide exposure, occupation, blood urate levels, NSAID use, brain injury, and exercise) have limited or conflicting evidence of a relationship to PD. Future research must not neglect the impact of these environmental factors on the development of PD, especially with respect to potential gene-environment interactions.
[Kieburtz K, Wunderle KB. 2013. Mov Disord. 28(1):8-13]
- Parkinson's disease and pesticide exposure--a new assessment.
Some commonly used pesticides possess neurotoxicity, and exposure to such compounds may trigger mechanisms similar to those in the development of idiopathic Parkinson's disease (PD). Authors conducted a systematic review of epidemiological studies, aiming at a critical evaluation of the association between the development of PD and pesticide exposure. Reported effect sizes (ES) in the relevant studies were pooled into the meta-analysis to derive summary ES. The summary ES suggested a significantly positive association between PD and overall pesticide use (non-occupational and/or occupational pesticide use), as well as between PD and occupational pesticide exposure. Both occupational herbicide and occupational insecticide exposure showed a significant association with PD. The results of the meta-analysis reported in this study suggest the existence of a statistically positive association between PD and pesticide exposure. The majority of the studies that were pooled in the meta-analysis were case-control design with very few cohort studies and most with poor exposure characterization thus, any further case-control studies using similar methodologies are unlikely to have a significant impact or understanding on the currently-reported association between pesticide exposure and the development of idiopathic PD. Therefore, authors believe that if further epidemiological studies are going to be conducted in the area, they should be prospective cohort studies that will include accurate exposure assessment.
[Allen MT, Levy LS. 2013. Crit Rev Toxicol. 43(6):515-34]
- Chronic exposure to rotenone, a dopaminergic toxin, results in peripheral neuropathy associated with dopaminergic damage.
Rotenone, a widely used pesticide, causes a syndrome in rats that replicates, both pathologically and behaviorally, the symptoms of Parkinson's disease (PD). In the present study, authors sought to determine if a chronic exposure to rotenone, resulting in dopaminergic loss, could also lead to peripheral neuronal damage related to motor dysfunction. Adult male Sprague-Dawley rats were treated with rotenone. The motor nerve conduction velocity (MCV) was assessed using action potentials detected from the tail muscle through surface receiver electrodes installed around the distal portion of the tail. Rats exposed to rotenone often developed hind limb paresis with a significant decrease in MCV as detected in tail nerves. Time-dependent rotenone-induced striatal depletion of DA (60% after 7 days and 80% after 27 days) was observed. Furthermore, Neurofilament-neurofilament B, Flouro-Jade C and myelin basic protein analyses suggested a time-dependent rotenone-induced neurodegeneration in sciatic nerves. These data, for the first time, indicate an association between dopaminergic damage and peripheral motor nerve degeneration in an animal model of dopaminergic toxicity. Peripheral motor nerve dysfunction in rats following a chronic exposure to rotenone may serve not only as a relevant experimental model of motor neuropathy but also as a peripheral marker of dopaminergic neuronal damage to the central nervous system.
[Binienda ZK, Sarkar S, et al. 2013. Neurosci Lett. 541:233-7]
- Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinson׳s disease.
Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson's disease (PD) pathology, may protect against cytotoxic proteins. Since the ubiquitin-proteasome system (UPS) degrades cytotoxic proteins, dysfunction in the UPS may contribute to PD etiology. The goal in this study was to screen pesticides for proteasome inhibition and investigate (i) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and (ii) whether genetic variation in candidate genes of the UPS pathway modify those increased risks. Study assessed 26S UPS activity in SK-N-MC(u) cells by fluorescence. We recruited idiopathic PD cases and population-based controls from three counties in California with considerable commercial agriculture. Study determined ambient pesticide exposure by our validated GIS-based model utilizing residential and workplace address histories. Study limited effect measure modification assessment to Caucasians. Eleven of 28 pesticides screened inhibited 26S UPS activity at 10 µM. Benomyl, cyanazine, dieldrin, endosulfan, metam, propargite, triflumizole, and ziram were associated with increased PD risk. Authors estimated an odds ratio of 2.14 for subjects with ambient exposure to any UPS-inhibiting pesticide at both residential and workplace addresses; this association was modified by genetic variation in the s-phase kinase-associated protein 1 gene. Results provide evidence that UPS-inhibiting pesticides play a role in the etiology of PD and suggest that genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures.
[Rhodes SL, Fitzmaurice AG, Cockburn M, et al. 2013. Environ Res. 126:1-8]
- Pesticide-induced gene mutations and Parkinson disease risk: a meta-analysis.
Increasing scientific evidence suggests that pesticide-induced gene mutations may contribute to increasing susceptibility to Parkinson disease (PD), but many existing studies have yielded inconclusive results. This meta-analysis aims at assessing the exact roles of pesticide-induced gene mutations in the development of PD. An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. Ten case-control studies were included with a total of 1248 PD patients and 1831 healthy controls. Our meta-analysis revealed that PD patients with pesticide exposure had higher gene mutation rates than those of healthy controls. Subgroup analysis by gene type indicated that the mutation rates in the GSTP1, SLC6A3, and MDR1 genes of PD patients with pesticide exposure were higher than those of healthy controls. The current meta-analysis indicates that pesticide-induced gene mutations may contribute to increasing susceptibility to PD, especially in the GSTP1, SLC6A3, and MDR1 genes.
[Liu X, Ma T, Qu B, et al. 2013. Genet Test Mol Biomarkers. 17(11):826-32]
- The role of pesticide exposure in the genesis of Parkinson's disease: epidemiological studies and experimental data.
The aim of this study is to address the uncertainties provided by epidemiological studies on the role of pesticide exposures in the development of Parkinson's disease (PD), with the help of experimental toxicological data. Animal models that reproduce all clinical and pathological features of human PD are not available. In addition, the fundamental questions relate to the extrapolation from experimental to actual human exposure, taking also into account the role of genetic factors. Available measurements or estimates of human exposure levels that are significantly lower than those used in animal experimentation provide little support for a causal correlation between pesticide exposure and development of PD in humans. A possible role of acute poisonings or episodes of excessive exposure, and/or of combined exposures especially at early age and/or in the presence of certain genetic variants can be hypothesised. Follow up of survivors of acute poisonings by pesticides would provide information useful in this respect. According to the available data, from a public health point of view, prevention of "high" exposures, even asymptomatic ones, especially in utero and during early age is a priority.
[Moretto A, Colosio C. et al. 2013. Toxicology. 307:24-34]
- Exposure to pesticides or solvents and risk of Parkinson disease.
Study investigated the risk of Parkinson disease (PD) associated with exposure to pesticides and solvents using meta-analyses of data from cohort and case-control studies. A total of 104 studies/3,087 citations fulfilled inclusion criteria for meta-analysis. In prospective studies, study quality was not a source of heterogeneity. PD was associated with farming and the association with pesticides was highly significant in the studies in which PD diagnosis was self-reported. In case-control studies, study quality appeared to be a source of heterogeneity in risk estimates for some exposures. Higher study quality was frequently associated with a reduction in heterogeneity. In high-quality case-control studies, PD risk was increased by exposure to any-type pesticides, herbicides, and solvents. Exposure to paraquat or maneb/mancozeb was associated with about a 2-fold increase in risk. In high-quality case-control studies including an appreciable number of cases (>200), heterogeneity remained significantly high (>40%) only for insecticides, organochlorines, organophosphates, and farming; also, the risk associated with rural living was found to be significant. The literature supports the hypothesis that exposure to pesticides or solvents is a risk factor for PD. Further prospective and high-quality case-control studies are required to substantiate a cause-effect relationship. Future studies should also focus on specific chemical agents.
[Pezzoli G, Cereda E. 2013. Neurology. 80(22):2035-41]
- Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease.
Genetic and environmental factors affect the pathogenesis of Parkinson's disease (PD). Genetic variants of the enzyme glutathione S-transferases (GST) may be related to the disease. This study aimed to evaluate the influence of genetic variants of GST (GSTT1/GSTM1) and their association with the exposure to environmental toxins in PD patients. 254 patients with PD and 169 controls were studied. The GSTM1/GSTT1 variants were analyzed by polymerase chain reaction. The present and absence for GSTT1 and GSTM1 were similar in patients and controls. The null for GSTT1 and GSTM1 (0/0) and exposure to pesticides prevailed in patients (18%) compared to controls. This study suggests the association between PD and previous exposure to pesticides, whose effect may be enhanced in combination with null for GSTT1/GSTM1.
[Pinhel MA, Sado CL, Longo Gdos S, Gregório ML, et al. 2013. Arq Neuropsiquiatr. 71(8):527-32]
- Neurotoxicity of pesticides: its relationship with neurodegenerative diseases
Several epidemiological studies suggest that pesticides could lead to neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Among pesticides, insecticides appear more neurotoxic than others but the neurotoxic mechanisms leading to adverse health effects remain unclear. The currently used pesticides such as rotenone and paraquat could disrupt mitochondrial bioenergetic function, reactive oxygen metabolism, redox function and promote α-synuclein aggregation. In addition, recent studies demonstrate that genetic susceptibility to Parkinson's disease could monitor pesticide susceptibility, as demonstrated for polymorphisms in pesticide metabolizing enzymes that are involved in organophosphorus sensitivity.
[Thany SH, Reynier P, Lenaers G. 2013. Med Sci (Paris). 29(3):273-8]
- The interplay between environmental and genetic factors in Parkinson's disease susceptibility: the evidence for pesticides.
Several genetic and environmental factors have been implicated in the pathogenesis of PD. Single risk factors are likely to exert relatively minor effects, whereas their interaction may prove to be sufficient to cause PD. In the present review authors summarize current knowledge from human genetic association studies regarding the interaction between gene polymorphisms and pesticide exposure in the risk of PD. A number of genetic association studies have investigated joint effects between genes and pesticides on PD risk. They have provided some evidence that genetic susceptibility either in metabolism, elimination and transport of pesticides or in the extent of mitochondrial dysfunction, oxidative stress and neuronal loss may predispose individuals to PD if they have been exposed to pesticides. These findings confirm the importance of considering pesticide-gene interactions in future studies in order to gain a better understanding of the pathogenic mechanisms of PD.
[Dardiotis E, Xiromerisiou G, et al. 2013. Toxicology. 307:17-23]
- Dietary fat intake, pesticide use, and Parkinson's disease.
Dietary fat intake may modify Parkinson's disease (PD) risk directly or by altering the response to environmental neurotoxicants including pesticides. Authors conducted a case-control study of PD nested in the Agricultural Health Study (AHS), a cohort of pesticide applicators and spouses.Diet and pesticide use before diagnosis in 89 PD cases, confirmed by movement disorder specialists, or a corresponding date in 336 frequency-matched controls were evaluated. In the AHS, PD was inversely associated with N-3 polyunsaturated fatty acids (PUFAs) and the N-3 precursor α-linolenic acid. In a meta-analysis of nine studies, including the present one, PD was inversely associated with α-linolenic acid. In the AHS, associations of PD with the pesticides paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 in individuals with PUFA intake below the median but 1.2 in those with higher intake. The OR for rotenone was 5.8 in those with saturated fat intake above the median but 1.5 in those with lower intake. PUFA intake was consistently associated with lower PD risk, and dietary fats modified the association of PD risk with pesticide exposure. If confirmed, these findings suggest that a diet high in PUFAs and low in saturated fats might reduce risk of PD.
[Kamel F, Goldman SM, Umbach DM, Chen H, et al. 2013. Parkinsonism Relat Disord. pii: S1353-8020(13)00353-2]
- Household organophosphorus pesticide use and Parkinson's disease.
In a population-based case-control study, authors assessed frequency of household pesticide use for 357 cases and 807 controls, relying on the California Department of Pesticide Regulation product label database to identify ingredients in reported household pesticide products and the Pesticide Action Network pesticide database of chemical ingredients. Frequent use of any household pesticide increased the odds of PD by 47% ; frequent use of products containing OPs increased the odds of PD more strongly by 71% and frequent organothiophosphate use almost doubled the odds of PD. Sensitivity analyses showed that estimated effects were independent of other pesticide exposures (ambient and occupational) and the largest odds ratios were estimated for frequent OP users who were carriers of the 192QQ paraoxonase genetic variant related to slower detoxification of OPs. Study provides evidence that household use of OP pesticides is associated with an increased risk of developing PD.
[Narayan S, Liew Z, Paul K, et al. 2013. Int J Epidemiol. 42(5):1476-85]
- Occupational pesticide exposure and screening tests for neurodegenerative disease among an elderly population in Costa Rica
Researchers conducted screening tests for neurologic disease and occupational pesticide use in a population-based sample of 400 elderly subjects at two government-run clinics in Costa Rica.Past occupational pesticide exposure was reported by 18% of subjects. Exposed subjects performed worse on the MMSE than the non-exposed. The exposed had significantly elevated risks of abnormal scores on two UPDRS items, tremor-at-rest, and finger-tapping. Thirty-three (23%) of those examined by the neurologist were diagnosed with possible/probable PD, 3–4 times the expected based on international data; 85% of these cases had not been previously diagnosed. Researchers report that elderly subjects with past occupational pesticide exposure performed significantly worse on screening tests for dementia and PD, and had an increased risk of an eventual PD diagnosis.
[Steenland, K, Wesseling, C, Roman, N, Quiros, I and Juncos, JL. 2013. Environmental Research. 120:96-101]
- Genetic modification of the association of paraquat and Parkinson's disease
Authors investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione S-transferase M1 (GSTM1) or T1 (GSTT1). Eighty-seven PD subjects and 343 matched controls were recruited from the Agricultural Health Study, a study of licensed pesticide applicators and spouses in Iowa and North Carolina. Two hundred and twenty-three (52%) subjects had GSTM1*0, 95 (22%) had GSTT1*0, and 73 (17%; all men) used paraquat. GSTT1 genotype significantly modified the association between paraquat and PD. In men with functional GSTT1, the odds ratio (OR) for association of PD with paraquat use was 1.5; in men with GSTT1*0, the OR was 11.1. Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. GSTT1*0 is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat.
[Goldman, S, Kamel, F, Webster Ross, G, et al. 2012. Movement Disorders. 27(13):1652-1658]
- Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease
Traumatic brain injury (TBI) increased risk of Parkinson disease (PD) in many but not all epidemiologic studies, giving rise to speculations about modifying factors. The objective of this study was to investigate PD risk due to both TBI and paraquat exposure in humans.From 2001 to 2011, study enrolled 357 incident idiopathic PD cases and 754 population controls in central California. Study participants were asked to report all head injuries with loss of consciousness for >5 minutes. Paraquat exposure was assessed via a validated geographic information system (GIS) based on records of pesticide applications to agricultural crops in California since 1974. Study observed a 2-fold increase in risk of PD for subjects who reported a TBI and a weaker association for paraquat exposures. However, the risk of developing PD was 3-fold higher in study participants with a TBI and exposure to paraquat than those exposed to neither risk factor. While TBI and paraquat exposure each increase the risk of PD moderately, exposure to both factors almost tripled PD risk. These environmental factors seem to act together to increase PD risk in a more than additive manner.
[Lee PC, Bordelon Y, Bronstein J, Ritz B. 2012. Neurology. 79(20):2061-6]
- Is Pesticide Use Related to Parkinson Disease? Some Clues to Heterogeneity in Study Results
This study is updates the literature published on PD and exposure to pesticides by performing a systematic review and meta-analysis.Summary estimates for subclasses of pesticides indicated a positive association with herbicides and insecticides, but not with fungicides. This review affirms the evidence that exposure to herbicides and insecticides increase the risk of PD. Future studies should focus on more objective and improved methods of pesticide exposure assessment.
[van der Mark, M, Brouwer, M et al. 2012. Environ Health Perspect. 120(3):340-347]
- Occupational exposure to pesticides and Parkinson's disease: A systematic review and meta-analysis of cohort studies
The aim of this study was to systematically review available cohort studies and estimate quantitatively the association between occupational exposure to pesticides and Parkinson's disease (PD). Relative risk (RR) estimates were extracted from 12 studies published between 1985 and 2011. Meta-analyses were performed on the whole set of data and separate analyses were conducted after stratification for gender, exposure characterisation, PD cases identification, geographic location, reported risk estimator and cohort study design.A statistically significant increased risk of PD was observed when all studies were combined. A significant increased risk was also seen for banana, sugarcane and pineapple plantation workers. Study concludes that there is some support for the hypothesis that occupational exposure to pesticides increases the risk of PD.
[Van Maele-Fabry, G, Hoet, P, Vilain, F and Lison, D. 2012. Envrionment International. 46:30-43]
- Parkinson’s disease risk from ambient exposure to pesticides
A study has found that people whose workplaces were close to fields sprayed with chemicals — not just those who live nearby — are at higher risk of developing Parkinson’s disease (PD). From 2001 to 2007, researchers enrolled 362 incident PD cases and 341 controls living in the Central Valley of California and estimated ambient exposures to the pesticides ziram, maneb, and paraquat at work places and residences from 1974 to 1999. Risk estimates for ambient workplace exposure were greater than for exposures at residences and were especially high for younger onset PD patients and when exposed in both locations. Study is the first to implicate ziram in PD etiology. Combined ambient exposure to ziram and paraquat as well as combined ambient exposure to maneb and paraquat at both workplaces and residences increased PD risk substantially. Those exposed to ziram, maneb, and paraquat together experienced the greatest increase in PD risk. Results suggest that pesticides affecting different mechanisms that contribute to dopaminergic neuron death may act together to increase the risk of PD considerably. Daily News
[Wang A, et al. 2011. Eur J Epidemiol. DOI: 10.1007/s10654-011-9574-5]
Paraquat and Parkinson's Disease
Study investigated whether pesticides that cause mitochondrial dysfunction
or oxidative stress are associated with PD or clinical features of parkinsonism
in humans. Reserachers assessed lifetime use of pesticides selected
by mechanism in a casecontrol study nested in the Agricultural Health
Study (AHS). PD was diagnosed by movement disorders specialists.n 110
PD cases and 358 controls, PD was associated with use of a group of
pesticides that inhibit mitochondrial Complex I including rotenone and
with use of a group of pesticides that cause oxidative stress including
paraquat.PD was positively associated with two groups of pesticides
defined by mechanisms implicated experimentally: those which impair
mitochondrial function and those which increase oxidative stress, supporting
a role for these mechanisms in PD pathophysiology.
[Tanner, CM. et al. 2011. Environ Health Perspect.doi:10.1289/ehp.1002839]
Between ABCB1 and Professional Exposure to Organochlorine Insecticides
in Parkinson Disease
Study examined the association between Parkinson disease (PD) and 2
polymorphisms in ABCB1 among subjects enrolled in the French health
system for agricultural workers, as well as the interaction between
ABCB1 and organochlorine insecticides. Among 101 male cases and 234
matched controls, the odds ratio for organochlorines was 3.5 times higher
among homozygous carriers of variant G2677(A,T) alleles than noncarriers.
Among cases only, study found an association between carrying 2 variant
G2677(A,T) alleles and organochlorines as well as with the number of
cumulative lifetime number of hours of exposure. Findings suggest that
the ABCB1 gene and exposure to organochlorine insecticides interact
to increase PD risk: in subjects professionally exposed to organochlorines,
polymorphisms associated with a decreased ability of ABCB1 to clear
xenobiotics from the brain increased the risk of PD. These findings
support the hypothesis of gene x pesticides interactions in PD.
[Dutheil. F. et al. 2010. Arch Neurol;67(6):739-745]
1, agricultural organophosphate exposure, and Parkinson disease
Study found that participants with two copies of a common gene variant
showed an increased risk of Parkinson's disease (PD) when exposed to
pesticides used in agriculture. In the study group, 14 percent of the
pesticide-exposed subjects and 10 percent of the control subjects had
the genotype with two copies of the methionine PON1 variant - the MM
PON1-55 genotype. Individuals with the variant genotype have an increased
risk of Parkinson's disease with exposure to specific insecticides.
Participants with the MM PON1-55 genotype and exposed to diazinon or
chlorpyrifos showed a twofold increased risk of Parkinson's disease
(PD) compared to exposed subjects with wildtype genotype or only one
variant copy or non-pesticide exposed subjects. The authors found no
increased risk of PD with parathion exposure regardless of genotype.
[Manthripragada AD, et al. 2010. Epidemiology 21(1):87-94]
Transporter Genetic Variants and Pesticides in Parkinson’s Disease
324 incident PD patients and 334 population controls from this rural
California case–control study were genotyped; rs2652510, rs2550956
(for the DAT 5' clades), and 3' variable number of tandem repeats (VNTR).
Using geographic information system methods, authors determined residential
exposure to agricultural maneb and paraquat applications. Occupational
pesticide use data was also collected. PD risk was increased separately
in DAT A clade diplotype carriers and 3' VNTR 9/9 carriers, and data
suggest a gene dosing effect. Importantly, high exposure to paraquat
and maneb in carriers of one susceptibility allele increased PD risk
3-fold, and in carriers of two or more alleles more than 4-fold. Similar
results for occupational pesticide measures were obtained.
[Ritz BR, et al. 2009. Environ Health Perspect 117(6)]
Consumption and Parkinson’s Disease in Rural California
Study investigated whether consuming water from private wells located
in areas with documented historical pesticide use was associated with
an increased risk of PD.Cases were more likely to have consumed private
well water and to have consumed it on average 4.3 years longer than
controls. High levels of possible well-water contamination with methomyl,
chlorpyrifos, and propargite resulted in approximately 70–90%
increases in relative risk of PD. Exposure to a higher number of water-soluble
pesticides and organophosphate pesticides also increased the relative
risk of PD.
[Gatto NM, et al. 2009. Environ Health Perspect 117:1912-1918]
Disease and Residential Exposure to Maneb and Paraquat From Agricultural
Applications in the Central Valley of California
In 1998–2007, the authors enrolled 368 incident PD cases and 341
population controls from the Central Valley of California in a case-control
study. They generated estimates for maneb and paraquat exposures incurred
between 1974 and 1999. Exposure to both pesticides within 500 m of the
home increased PD risk by 75% (95% confidence interval (CI): 1.13, 2.73).
Persons aged =60 years at the time of diagnosis were at much higher
risk when exposed to either maneb or paraquat alone (odds ratio = 2.27,
95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio
= 4.17, 95% CI: 1.15, 15.16) in 1974–1989. This study provides
evidence that exposure to a combination of maneb and paraquat increases
PD risk, particularly in younger subjects and/or when exposure occurs
at younger ages.
[Costello, S. et al. 2009. American Journal of Epidemiology, doi:10.1093/aje/kwp006]
and Risk of Parkinsonism: A
Multicenter Case-Control Study
This multicenter case-control study compared lifelong occupational and
job task histories to determine associations with parkinsonism and certain
clinical subtypes (postural instability and gait difficulty and age
at diagnosis). Risk of parkinsonism increased with pesticide use (odds
ratio, 1.90; 95% confidence interval, 1.12-3.21), use of any of 8 pesticides
mechanistically associated with experimental parkinsonism (2.20; 1.02-4.75),
and use of 2,4-dichlorophenoxyacetic acid (2.59; 1.03-6.48).
[Tanner, C.M. 2009. Arch Neurol ;66(9):1106-1113]
exposure to pesticides and Parkinson disease
Study found a positive association between PD and overall professional
pesticide use (odds ratio [OR] = 1.8, 95% confidence interval [CI] =
1.1-3.1), with a dose-effect relation for the number of years of use
(p = 0.01). In men, insecticides were associated with PD (OR = 2.2,
95% CI = 1.1-4.3), in particular organochlorine insecticides (OR = 2.4,
95% CI = 1.2-5.0). These associations were stronger in men with older
onset PD than in those with younger onset PD, and were characterized
by a dose-effect relation in the former group. Results support an association
between PD and professional pesticide exposure, and show that some pesticides
(ie, organochlorine insecticides) may be more particularly involved.
[Elbaz, A.et al. 2009. Ann Neurol;66:494-504]
Causes Dopaminergic Cell Damage by Inhibiting E1 Ligase of the Proteasome
Study measured the relative toxicity of ziram (a UPS inhibitor) and
analogs to dopaminergic neurons and examined the mechanism of cell death.
Results demonstrate that ziram causes selective dopaminergic cell damage
in vitro by inhibiting an important degradative pathway implicated in
the etiology of PD. Chronic exposure to widely used dithiocarbamate
fungicides may contribute to the development of PD.
[Chou, A. et al. 2008. Journal of Biological Chemistry; 283 pp.34696-34703]
exposure and risk of Parkinson's disease: A family-based case-control
Associations of direct pesticide application did not vary by sex but
were modified by family history of PD, as significant associations were
restricted to individuals with no family history. When classifying pesticides
by functional type, both insecticides and herbicides were found to significantly
increase risk of PD. Two specific insecticide classes, organochlorines
and organophosphorus compounds, were significantly associated with PD.
Consuming well-water and living/working on a farm were not associated
with PD. Data corroborate positive associations of broadly defined pesticide
exposure with PD in families, particularly for sporadic PD.
[Hancock, D.B., et al. 2008. BMC Neurology 8(6):1471-2377]
exposure and risk of Parkinson's disease: A family-based case-control
Using 319 cases and 296 relative and other controls, associations of
direct pesticide application, well-water consumption, and farming residences/occupations
with PD were examined using generalized estimating equations while controlling
for age-at-examination, sex, cigarette smoking, and caffeine consumption.
Overall, individuals with PD were significantly more likely to report
direct pesticide application than their unaffected relatives (odds ratio
= 1.61; 95% confidence interval, 1.13–2.29). Frequency, duration,
and cumulative exposure were also significantly associated with PD in
a dose-response pattern (p = 0.013). Associations of direct pesticide
application did not vary by sex but were modified by family history
of PD, as significant associations were restricted to individuals with
no family history. When classifying pesticides by functional type, both
insecticides and herbicides were found to significantly increase risk
of PD. Two specific insecticide classes, organochlorines and organophosphorus
compounds, were significantly associated with PD.
[Hancock, D,B. et al. 2008. BMC Neurology 8(6)]
risk factors for Parkinson’s disease and parkinsonism: the Geoparkinson
A case–control study of 959 prevalent cases of parkinsonism (767
with Parkinson’s disease) and 1989 controls in Scotland, Italy,
Sweden, Romania and Malta was carried out. Adjusted logistic regression
analyses showed significantly increased odds ratios for Parkinson’s
disease/parkinsonism with an exposure–response relationship for
pesticides. Hypnotic, anxiolytic or antidepressant drug use for more
than 1 year and a family history of Parkinson’s disease showed
significantly increased odds ratios. The association of pesticide exposure
with Parkinson’s disease suggests a causative role. Repeated traumatic
loss of consciousness is associated with increased risk.
[Dich, F.D. et al. 2007. Occup Environ Med;64:666-672]
exposure on southwestern Taiwanese with MnSOD and NQO1 polymorphisms
is associated with increased risk of Parkinson's disease.
From southwestern region of Taiwan, 153 patients with idiopathic PD
and 155 healthy control subjects matched for age, sex and origin were
studied. Exposure to pesticides associated with PD was significant among
patients with an increased odds ratio (OR) of 1.69 (95%CI, 1.07-2.65),
and this association remained significant after adjustment for age,
sex, and cigarette smoking (aOR=1.68, 95%CI, 1.03-2.76, P=0.023). Considering
genetic factors, there were no significant differences in frequencies
of both genotypes of manganese-containing superoxide dismutase (MnSOD)
and quinone oxidoreductase 1 (NQO1) polymorphisms between PD patients
and the control subjects (P>0.05). However, this difference in genotype
distribution was significant among subjects who had been exposed to
pesticide, for MnSOD C allele and for NQO1 T allele, respectively. Moreover,
among subjects exposed to pesticide, the combined MnSOD/NQO1 variant
genotype was significantly associated with a 4.09-fold increased risk
of PD (95%CI, 1.34-10.64, P=0.0052).
[Fong, C., et al. 2007. Clinica Chimica Acta 378(1-2):136-141]
exposure to pesticides zineb and/or endosulfan renders the nigrostriatal
dopamine system more susceptible to these environmental chemicals later
The purpose of this study was to test the hypothesis that exposure to
pesticides such as endosulfan and/or zineb during critical periods of
postnatal development could result in neuronal dysfunction and enhance
the impact of these pesticides during exposure as adults. Mice exposed
to these pesticides as juveniles and re-exposed at 8 months of age had
significantly altered striatum and brain cortex neurotransmitter levels.
Thus, mice re-exposed during adulthood to zineb, endosulfan and their
mixtures showed a significantly depleted striatal dopamine levels, to
22, 16 and 35% of control, respectively. Acetylcholinesterase activity
in the cerebral cortex was significantly increased in all pesticide
treated groups (rho< or =0.05) upon repeated exposure, and pesticide
mixture treatment also significantly increased levels of normal and
aggregated alpha-synuclein. Collectively, these findings support our
hypothesis that exposure to pesticides such as endosulfan and zineb
during critical periods of postnatal development contributes to neurotransmitter
changes upon re-challenge in adulthood.
[Jia, Z., et al. 2007. Neurotoxicology 28(4):727-735]
activation as a priming event leading to paraquat-induced dopaminergic
Authors found that a single paraquat exposure was followed by an increase
in the number of cells with immunohistochemical, morphological and biochemical
characteristics of activated microglia, including induction of NADPH-oxidase.
If this microglial response was inhibited by the anti-inflammatory drug
minocycline, subsequent exposures to the herbicide failed to cause oxidative
stress and neurodegeneration. On the other hand, if microglial activation
was induced by pre-treatment with lipopolysaccharide, a single paraquat
exposure became capable of triggering a loss of dopaminergic neurons.
Finally, mutant mice lacking functional NADPH-oxidase were spared from
neurodegeneration caused by repeated paraquat exposures. Data indicate
that microglial activation and consequent induction of NADPH-oxidase
may act as risk factors for Parkinson’s disease by increasing
the vulnerability of dopaminergic cells to toxic injury.
[Purisai, M.G., et al. 2007. Neurobiology of Disease 25(2):392-400]
- Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids.
Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood-brain barrier and exert their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson's disease through several pathways. The aim of this study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL(50)) in rats from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was reduced in the pyrethroid-treated groups compared to the control group. Study suggests that neonatal exposition to permethrin or cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction with the extracellular side of plasma membrane proteins can be observed.
[Nasuti C, Gabbianelli R, Falcioni ML, et al.2007. Toxicology. 229(3):194-205.]
exposure and self-reported Parkinson's disease in the agricultural health
The authors used data obtained from licensed private pesticide applicators
and spouses participating in the Agricultural Health Study to evaluate
the relation of self-reported PD to pesticide exposure. Cohort members,
who were enrolled in 1993-1997, provided detailed information on lifetime
pesticide use. Incident PD was associated with cumulative days of pesticide
use at enrollment (for highest quartile vs. lowest, odds ratio (OR)
= 2.3, 95% confidence interval: 1.2, 4.5; p-trend = 0.009), with personally
applying pesticides more than half the time (OR = 1.9, 95% confidence
interval: 0.7, 4.7), and with some specific pesticides (ORs > or
= 1.4). Prevalent PD was not associated with overall pesticide use.
This study suggests that exposure to certain pesticides may increase
[Kamel, F., et al. 2007. American Journal of Epidemiology 165(4):364-74]
expression mediates dopaminergic neuron sensitivity in experimental
Study uses a MPTP model of parkinsonism to examine the role of a dual
function protein, GSTpi, in dopaminergic neuron death. GSTpi is the
only GST family member expressed in substantia nigra neurons. GSTpi
reduction by pharmacological blockade, RNA inhibition, and gene targeting
increases sensitivity to the pesticide MPTP, suggesting that differential
expression of GSTpi contributes to the sensitivity to xenobiotics in
the substantia nigra and may influence the pathogenesis of reactive
oxygen species-induced neurological disorders including PD.
[Smeyne, M., et al. 2007. Proceedings of the National Academy of Sciences
between genes and environment in neurodegenerative diseases.
Study found that the inverse association between smoking and the risk
of PD depended on a polymorphism of the iNOS (inducible NO synthase)
gene. We also found that the cytochrome P450 2D6 gene could have a modifying
effect on the risk of PD among persons exposed to pesticides. Both interactions
have biological plausibility supported by laboratory studies and could
contribute to better understand the aetiology of PD.
[Elbaz, A. et al. 2007. Comptes Rendus Biologies 330(4):318-328]
and Parkinson’s Disease—Is There a Link?
A comprehensive review of the published epidemiologic and toxicologic
literature and critical evaluation of whether a relationship exists
between pesticide exposure and PD. From the epidemiologic literature,
there does appear to be a relatively consistent relationship between
pesticide exposure and PD. This relationship appears strongest for exposure
to herbicides and insecticides, and after long durations of exposure.
Toxicologic data suggest that paraquat and rotenone may have neurotoxic
actions that potentially play a role in the development of PD, with
limited data for other pesticides. At present, the weight of evidence
is sufficient to conclude that a generic association between pesticide
exposure and PD exists but is insufficient for concluding that this
is a causal relationship or that such a relationship exists for any
particular pesticide compound or combined pesticide and other exogenous
[Brown, T.P., et al. 2006. Environmental Health Perspectives 114(2):156-164]
- Pyrethroid pesticide-induced alterations in dopamine transporter function.
Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Study reports that repeated exposure of mice to two commonly used pyrethroid pesticides, deltamethrin and permethrin, increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, study determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 microM) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 microM) or 24 h (1, 5, and 10 microM) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD.
[Elwan MA, Richardson JR, Guillot TS, et al. 2006. Toxicol Appl Pharmacol.211(3):188-97]
exposure and risk for Parkinson's disease
Exposure to pesticides was reported by 7,864 participants (5.7%), including
1,956 farmers, ranchers, or fishermen. Individuals exposed to pesticides
had a 70% higher incidence of PD than those not exposed (adjusted relative
risk, 1.7; 95% confidence interval, 1.2-2.3; p = 0.002). The relative
risk for pesticide exposure was similar in farmers and nonfarmers. No
relation was found between risk for PD and exposure to asbestos, chemical/acids/solvents,
coal or stone dust, or eight other occupational exposures. These data
support the hypothesis that exposure to pesticides may increase risk
[Ascherio, Al, et al. 2006. Annals of Neurology 60(2): 197-203.]
for evaluating health risks in children associated with exposure to
The United Nation’s World Health Organization report on children’s
heightened vulnerability to chemical exposures at different periods
of their growth and development states, “neurotoxic insults during
development that result in no observable phenotype at birth or during
childhood could manifest later in life as earlier onset of neurodegenerative
diseases such as [PD].”
[Louis, G.B., et al. 2006. Environmental health criteria: 237. World
Health Organization. Geneva, Switzerland]
exposures and Parkinson's disease: a population-based case-control study.
Study identified all subjects who developed PD in Olmsted County,
Minnesota, from 1976 through 1995, and matched them by age (+/- 1 year)
and sex to general population controls. Authors assessed exposures to
chemical products by means of telephone interview with cases, controls,
or their proxies (149 cases; 129 controls). Exposure to pesticides related
or unrelated to farming was associated with PD in men (odds ratio, 2.4;
95% confidence interval, 1.1-5.4; P = 0.04). The association remained
significant after adjustment for education or smoking. This population-based
study suggests a link between pesticides use and PD that is restricted
to men. Pesticides may interact with other genetic or nongenetic factors
that are different in men and women.
[Frigerio, R., et al. 2006. Movement Disorders 21(10): 1688-1692]
exposure to the pesticide dieldrin alters the dopamine system and increases
neurotoxicity in an animal model of Parkinson’s disease
Study reports that perinatal exposure of mice during gestation and lactation
to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic
neurochemistry in their offspring and exacerbates MPTP toxicity. Results
suggest that developmental exposure to dieldrin leads to persistent
alterations of the developing dopaminergic system and that these alterations
induce a "silent" state of dopamine dysfunction, thereby rendering
dopamine neurons more vulnerable later in life. In all cases there were
greater effects observed in the male offspring than the female, similar
to that observed in human cases of PD.
[Richardson, J.R., et al. 2006. The FASEB Journal 20(10):1695-1697]
Disease: PD Gene and Oxidative Stress
Drosophila flies lacking the DJ-1 gene showed selective sensitivity
to widely used agricultural toxicants that kill neurons mainly through
oxidative stress. DJ-1 mutant flies exposed to the herbicide paraquat
died much sooner than normal flies. The mutants also showed marked sensitivity
to the insecticide rotenone and to hydrogen peroxide-both agents that
promote oxidative stress. These results suggest that DJ-1 normally protects
against oxidative stress and that its inactivation may leave neurons
susceptible to oxidative damage. The study also found that exposure
to paraquat led to biochemical modification of the DJ-1ß protein,
a change which may influence the ability of DJ-1 to protect neurons
from oxidative damage. Studies of DJ-1 in Drosophila will provide greater
understanding of fundamental activities of the gene, helping to elucidate
how its function may be critical in PD.
[Phillips, M.L. 2006. Environmental Health Perspectives 114(2)]
heptachlor exposure increases expression of presynaptic dopaminergic
markers in mouse striatum.
In this study, authors examined the effects of developmental exposure
to heptachlor on the dopamine transporter (DAT), and other key components
of the dopaminergic system, including the vesicular monoamine transporter
2 (VMAT2), tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase
(AADC). On postnatal day 28, DAT, VMAT2, and TH levels were increased
by 100, 70, and 30%, respectively, with no change in AADC levels or
total dopamine levels. The ratio of DAT:VMAT2 was increased 29%. Since
an increase in the DAT:VMAT2 ratio appears to predict susceptibility
of brain regions to Parkinson's disease (PD) and results in increased
toxicity of MPTP, these results suggest that alterations of the dopaminergic
system by developmental heptachlor exposure may increase the susceptibility
of dopamine neurons to toxic insult.
[Caudle, W.M., et al. 2005. NeuroToxicology 26(4):721-728]
DJ-1 mutants are selectively sensitive to environmental toxins associated
with Parkinson's disease.
Study involoving Drosophila flies to develop an animal model that would
allow integrative study of genetic and environmental influences. Study
demonstrates that fly DJ-1 activity is selectively involved in protection
from environmental oxidative insult in vivo and that the inherited PD
gene, DJ-1beta protein, is biochemically responsive to oxidative stress.
Study of these flies will provide insight into the critical interplay
of genetics and environment in PD.
[Meulener, M., et. al. 2005. Current Biology 15(17): 1572-1577]
pesticide exposures and the Parkinson's disease phenotype.
Study found that postnatal exposures of mice to pesticides, paraquat
+ maneb, led not only to a permanent and selective loss of dopaminergic
neurons in the substantia nigra pars compacta but also enhanced the
impact of these pesticides administered during adulthood relative to
developmental only or adult only treatment. Exposure to maneb alone
during gestation resulted in a dramatic response to paraquat in adulthood,
including notable reductions in levels of dopamine and metabolites and
a loss of nigral dopamine (DA) neurons, despite the fact that paraquat
does not share structural similarity to or mechanisms of action with
maneb. Collectively, these studies provide developmental environmental
models of the PD phenotype.
[Cory-Slechta D.A., et al. 2005. Birth Defects Res A Clin Mol Teratol
and risk of Parkinson disease: a population-based case-control study.
Study investigated associations between pesticide exposures and idiopathic
PD and found significantly increased ORs from lifelong well water consumption
(OR, 1.81; 95% CI, 1.02-3.21). Study also found elevated ORs from herbicides
(OR, 1.41; 95% CI, 0.51-3.88) and paraquat (OR, 1.67; 95% CI, 0.22-12.76).
[ J.A., et al. 2005. Archives of Neurology 62(1):91-95]
of antioxidant defense systems by the environmental pesticide maneb
in dopaminergic cells.
Authors believe environmental contaminants such as pesticides make dopamine
cells more vulnerable to damage from normal aging, infection, or subsequent
exposure to pollutants. Study primarily utilized the PC12 cell line,
which displays a catecholaminergic phenotype. Low concentrations of
maneb (50-1000 ng/ml) had little effect on cell viability, as measured
by LDH release. hese same concentrations, however, led to increases
in glutathione (GSH) and its oxidized form, GSSG. Results suggest that
following an insult to the GSH antioxidant system, maneb can act as
an additional insult to the system and prevent the normal recovery of
those defenses. Dopaminergic neurons, as a population, are inherently
vulnerable to oxidative stress, and the disruption of antioxidant systems
by the fungicide maneb may contribute to the neurodegeneration of these
cells, especially with concurrent exposures to other environmentally
relevant oxidative stressors.
[Barlow, B.K., et al. 2005. Neurotoxicology 26(1):63-75]
fetal risk factor for Parkinson's disease.
This study hypothesized that prenatal exposure to pesticides would disrupt
the development of the nigrostriatal dopamine (DA) system and enhance
its vulnerability to dopaminergic neurotoxicant exposures later in life.
One week after the last exposure to maneb or paraquat, only male mice
exposed to prenatal maneb and adulthood paraquat showed significant
reductions in locomotor activity (95%) and changes in striatal neurochemistry.
Stereological assessment of the substantia nigra pars compacta (SNpc)
and ventral tegmental area correspondingly confirmed selective dopaminergic-neuron
loss in SNpc. The lack of changes in other exposure groups suggests
a specificity to the sequence of exposures as well as gender specificity.
These results suggest that prenatal exposure to maneb produces selective,
permanent alterations of the nigrostriatal dopaminergic system and enhances
adult susceptibility to paraquat exposure.
[Barlow, B.K., et al. 2004. Dev Neurosci 26(1):11-23]
evidence for heritability of Parkinson disease in Swedish twins
The aim of the study was to evaluate heritability of PD in same-sexed
and opposite-sexed twin pairs in the Swedish Twin Registry (STR). For
possible PD, there were only two concordant pairs, both female dizygotic.
Similarly, concordances were low in all zygosity groups when the definition
of affected was expanded to include twins with suspected parkinsonism
or movement disorder in addition to possible PD. Sex differences in
the relative importance of genetic and environmental effects were indicated
with a marginally larger familial component in women. Results suggest
that environmental factors are most important in the etiology of PD.
Compared with other complex diseases, the importance of genetic effects
in PD is notably low. The preponderance of discordant twin pairs provides
an ideal material for studying environmental risk factors and potential
[Wirdefeldt, K., et al. 2004. Neurology 63(2):305-311]
case-control study of Parkinson's disease in a horticultural region
of British Columbia
Study compared personal histories of 127 cases and 245 controls to identify
possible environmental risk factors for idiopathic parkinsonism (IP).
Data found a significant association between IP and having had an occupation
in which exposure through handling or directly contacting pesticides
was probable, but no specific chemicals were associated with IP. Study
concluded that although occupations involving the use of agricultural
chemicals may predispose to the development of IP, it seems likely that
the pathogenesis is multifactorial rather than related to a specific
[Hertzman, C., et al. 2004. Movement Disorders 9(1):69-75]
between Parkinson’s disease and exposure to pesticides in southwestern
A case-control study was performed in southwestern France in order to
assess the relationship between pesticide exposure and Parkinson's disease
(PD) in the elderly. During the period from 1997 to 1999, 84 cases were
recruited together with 252 population-based controls. A positive association
was found with occupational pesticide exposure (odds ratio = 2.2, 95%
confidence interval 1.1-4.3) in conditional logistic multiple regression
analysis taking into account age, sex, educational level and smoking;
however, no clear dose relationship was found.
[Baldi, I., et al. 2003. Neuroepidemiology 22(5):305-310]
Diseases and Exposure to Pesticides in the Elderly
The authors investigated the hypothesis that exposure to pesticides
could be related to central nervous system disorders in a prospective
cohort study of 1,507 French elderly (1992–1998). Lower cognitive
performance was observed in subjects who had been occupationally exposed
to pesticides. In men, the relative risks of developing Parkinson’s
disease and Alzheimer’s disease for occupational exposure assessed
by a job exposure matrix were 5.63 (95% confidence interval: 1.47, 21.58)
and 2.39 (95% confidence interval: 1.02, 5.63), respectively, after
confounding factors were taken into account. These results suggest the
presence of neurologic impairments in elderly persons who were exposed
occupationally to pesticides.
[Baldi, I., et al. 2003. American Journal of Epidemiology 157(5):409-414]
irreversible progressive nigrostriatal dopaminergic neurotoxicity in
the paraquat and maneb model of the Parkinson's disease phenotype.
Study tested exposed C57BL/6 mice that were 6 weeks, 5 months or 18
months old to the herbicide paraquat, the fungicide maneb or paraquat
+ maneb, a combination that produces a Parkinson's disease phenotype
in young adult mice. Paraquat + maneb-induced reductions in locomotor
activity and motor coordination were age dependent, with 18-month-old
mice most affected and exhibiting failure to recover 24 h post-treatment.
Three months post-treatment, reductions in locomotor activity and deficits
in motor coordination were sustained in 5-month-old and further reduced
in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine
metabolites and dopamine turnover were greatest in 18-month-old paraquat
+ maneb and paraquat groups 3 months post-treatment. Collectively, these
data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine
pathway to these pesticides, particularly paraquat + maneb, resulting
in irreversible and progressive neurotoxicity.
[Thiruchelvam, M., et al. 2003. Eur J Neurosci 18(3):589-600]
and environmental risk factors in Parkinson's disease: a case-control
study in north-east Italy.
Study of136 patients with neurologist confirmed PD and 272 age- and
sex-matched controls, affected by neurological diseases not related
to PD. The risk of developing idiopathic PD associated with the following
familial and environmental factors: positive family history of PD, positive
family history of essential tremor (ET), age of mother at subject's
birth, rural birth, rural living, well water use, farming as an occupation,
exposure to pesticides, head tremor, exposure to general anaesthesia
and to ionizing radiations, food restriction, concentration camp imprisonment
and smoking has been assessed by using univariate and multivariate statistical
[Zorzon, M., et al. 2002. Acta Neurol Scand 105(2):77-82]
work and risk of Parkinson disease in a population-based longitudinal
Objective of this study was to determine whether working on a plantation
in Hawaii and exposure to pesticides are associated with an increased
risk of PD decades later. During follow-up, 116 men developed PD. Age-adjusted
incidence increased significantly among men who worked more than 10
years on a plantation. The relative risk of PD was 1.0 (95% confidence
interval, 0.6-1.6), 1.7 (95% confidence interval, 0.8-3.7), and 1.9
(95% confidence interval, 1.0-3.5) for men who worked on a plantation
1 to 10 years, 11 to 20 years, and more than 20 years compared with
men who never did plantation work (P =.006, test for trend). These longitudinal
observations regarding plantation work in Hawaii support case-control
studies suggesting that exposure to pesticides increases the risk of
[Petrovitch, H., et al. 2002. Archives of Neurology 59(11):1787-1792]
exposure to the pesticides paraquat and maneb and the Parkinson's disease
This study hypothesized that paraquat (PQ) and maneb (MB) exposure during
critical periods of development could permanently change the nigrostriatal
dopamine (DA) system and enhance its vulnerability to subsequent neurotoxicant
challenges. Mice exposed developmentally to PQ + MB and rechallenged
as adults were the most affected, showing a 70% reduction in motor activity
2 weeks following the last rechallenge dose. Striatal DA levels were
reduced by 37% following developmental exposure to PQ + MB only, butfollowing
adult re-challenge levels were reduced by 62%. A similar pattern of
nigral dopaminergic cell loss was observed, with the PQ + MB treated
group exhibiting the greatest reduction, with this loss being amplified
by adult re-challenge. Following adult re-challenge, significant decreases
in DA and nigral cell counts were observed, suggesting that exposure
to either neurotoxicant alone produced a state of silent toxicity that
was unmasked following adult re-exposure. Taken together, these findings
indicate that exposure to pesticides during the PN period can produce
permanent and progressive lesions of the nigrostriatal DA system, and
enhanced adult susceptibility to these pesticides, suggesting that developmental
exposure to neurotoxicants may be involved in the induction of neurodegenerative
disorders and/or alter the normal aging process.
[Thiruchelvam, M., et al. 2002. Neurotoxicology 23(4-5):621-633]
Risk Factors and Parkinson's Disease: A Metaanalysis
A series of metaanalyses of peer-reviewed studies were performed, using
16 studies for living in rural area, 18 studies for well water drinking,
11 studies for farming, and 14 studies for pesticides.The majority of
the studies reported consistent elevation in the risk of PD with exposure
to environmental factors such as rural living and farming. Findings
suggest that living in a rural area, drinking well water, farming, and
exposure to pesticides may be a risk factor for developing PD.
[Priyadarshi, A., et al. 2001.Environ Res 86(2):122-127]
and occupational exposure to pesticides
Parkinsonism may be associated with long term occupational exposure
to pesticides, although no associations with specific pesticides could
be detected. This finding is consistent with most of the publications
on this topic.
[Engel, L.S., et al. 2001.Occupational and Environmental Medicine 58(9):582-589]
disease mortality and pesticide exposure in California 1984-1994.
A California mortality study of individuals whose death certificates
mention PD as an underlying cause of death and cross-referenced with
agricultural and pesticide use data finds that the counties using restricted
use pesticides (RUP) for agricultural purposes have about a 40 percent
increase in PD mortality when compared to those counties reporting no
[Ritz B, and Yu F. 2000. International Journal of Epidemiology 29(2):323-329]
work and the risk of Parkinson's disease in Denmark, 1981-1993
This study examined the possible association between agricultural and
horticultural work and the subsequent morbidity of Parkinson's disease.
A high risk of Parkinson's disease was found for the men and women in
agriculture and horticulture (134 cases, SHR 132, 95% CI 111-156). Statistically
significantly high risks were found for farmers (79 cases, SHR 130,
95% CI 103-163) and for all men in agriculture and horticulture (109
cases, SHR 134, 95% CI 109-162).
[Tuchsen, F., et al. 2000. Scand J Work Environ Health 26(4):359-362]
to home pesticides linked to Parkinson disease.
This study raises concerns for residential pesticide exposure. Stanford
University researchers find a 70 percent increased risk of developing
PD for individuals that use pesticides in their home. Exposure to garden
insecticides carries a 50 percent increased risk of developing the disease.
Among herbicide users, the risk of developing PD increases as the number
of days in contact with herbicides grows. Respondents who reported handling
or applying herbicides for up to 30 days are 40 percent more likely
to develop the disease, whereas respondents that reported 160 days exposure,
have a 70 percent increase.
[Stephenson, J. 2000. JAMA 283:3055-3056]
meta-analysis of Parkinson's disease and exposure to pesticides.
A series of meta-analysis of peer-reviewed studies were performed, using
19 studies published between 1989 and 1999. The majority of the studies
reported consistent elevation in the risk of PD with exposure to pesticides.
The combined OR studies was 1.94 [95% confidence interval (95% CI) 1.49-2.53]
for all the studies, and 2.15 (95% CI 1.14-4.05) for studies performed
in United States. Although the risk of PD increased with increased duration
of exposure to pesticides, no significant dose-response relation was
established, and no specific type of pesticide was identified. Findings
suggest that exposure to pesticides may be a significant risk factor
for developing PD.
[Priyadarshi, A., et al. 2000. Neurotoxicology 21(4):435-440.]
and occupational factors influencing the risk of Parkinson's disease:
a case-control study in southeastern Sweden.
Study investigates the possible impact of nutritional and environmental
risk factors for idiopathic Parkinson's disease (IP), a case-control
study was performed in the county of Ostergötland in southeastern
Sweden. The study involved 113 cases of IP and 263 control subjects.
A reduced risk was found for coffee, wine, and liquor at various consumption
levels but also for fried or broiled meat, smoked ham or meat, eggs,
French loaf or white bread, and tomatoes. All these food and drink items
contain niacin. As in many studies, the frequency of preceding and present
smoking was reduced in IP patients. Various occupational groups and
exposures were analyzed and increased risks of IP in men were found
for agricultural work along with pesticide exposure; this was also the
case for male carpenters and female cleaners.
[Fall, P., et al. 1999. Movement Disorders 14(1):28-37]
and environmental risk factors for Parkinson’s disease in a Chinese
An epidemiological study of the environmental and genetic factors as
well as the possible interplay between them was conducted among 215
patients with Parkinson’s disease and 313 controls in a Chinese
population in Hong Kong. In multivariate analysis, current smoking reached
borderline significance at the 5% level and the variables, years exposed
to pesticides and family history were significant at the 10% level.
[Chan, D.K. 1998. Journal of Neurology, Neurosurgery and Psychiatry
disease, pesticides, and glutathione transferase polymorphisms.
Study investigated the role of GST polymorphisms in the pathogenesis
of idiopathic Parkinson's disease. Authors genotyped by PCR polymorphisms
in four glutathione transferases (GST) classes (GSTM1, GSTT1, GSTP1,
and GSTZ1) in 95 Parkinson's disease patients and 95 controls. The distribution
of the GSTP1 genotypes differed significantly between patients and controls
who had been exposed to pesticides No association was found with any
of the other GST polymorphisms. Pesticide exposure and a positive family
history were risk factors for Parkinson's disease. GSTP1-1, which is
expressed in the blood-brain barrier, may influence response to neurotoxins
and explain the susceptibility of some people to the parkinsonism-inducing
effects of pesticides.
[Menegon, A., et al. 1998. The Lancet 352(9137):1344-1346]
Epidemiology of Parkinson’s Disease in an Australian Population
A prevalence study of Parkinson’s disease (PD) was conducted in
the rural town of Nambour, Australia. A positive family history of PD
was the strongest risk factor for the development of the disease (odds
ratio = 3.4; p < 0.001). In addition, rural residency was a significant
risk factor for PD (odds ratio = 1.8, p < 0.001).
[McCann, S.J., et al. 1998. Neuroepidemiology 17(6):310-317]
risk of Parkinson's disease with exposure to pesticides, farming, well
water, and rural living.
Study assessed exposure to pesticides, farming, well water use, and
rural living as risk factors for Parkinson's disease (PD) in a population-based
case-control study consisting of men and women > or = 50 years of
age. Farming as an occupation was significantly associated with PD (OR,
2.79; 95% CI, 1.03, 7.55). The association of occupational exposure
to herbicides or insecticides with PD remained after adjustment for
farming. The association of farming with PD was maintained after adjustment
for occupational herbicide exposure and was of borderline significance
after adjustment for occupational insecticide exposure. These results
suggest that PD is associated with occupational exposure to herbicides
and insecticides and to farming and that the risk of farming cannot
be accounted for by pesticide exposure alone.
[Gorell, J.M., et al. 1998. Neurology 50:1346-1350]
interaction as a putative risk factor for Parkinson's disease with dementia.
Study explores the hypothesis that genetic traits coupled with nongenetic
factors may raise the risk of development of Parkinson's disease with
dementia (PD + D). The study cohort of 43 PD + D and 51 PD-D subjects
was analyzed examining environmental, sociodemographic and clinical
variables along with 3 candidate gene markers. Subjects who had pesticide
exposure and at least 1 copy of the CYP 2D6 29B+ allele had 83% predicted
probability of PD + D (stepwise logistic regression model: p = 0.0491).
This case-control study provides preliminary evidence that a gene-toxin
interaction may play an etiological role in PD + D.
[Hubble, J.P., et al. 1998. Neuroepidemiology 17(2):96-104]
environmental, occupational, and other etiologic factors for Parkinson's
disease: A case-control study in Germany
A case-control study investigated the possible etiologic relevance to
Parkinson's disease (PD) of rural factors such as farming activity,
pesticide exposures, well-water drinking, and animal contacts; toxicologic
exposures such as wood preservatives, heavy metals, and solvents; general
anesthesia; head trauma; and differences in the intrauterine environment.
There were significantly elevated odds ratios (OR) for pesticide use,
in particular, for organochlorines and alkylated phosphates, but no
association was present between PD and other rural factors. A significantly
elevated OR was present for exposure to wood preservatives.
[Seidler, A. et al. 1996.Nuerology; 46:1275]
Role of the Environment in Parkinson's Disease
Thirty leading scientists in the field of Parkinson's disease research
attended a conference, "The Role of the Environment in Parkinson's
Disease," 17-19 September 1995, sponsored and hosted by the National
Institute of Environmental Health Sciences. The role of the environment
was highlighted, but considerable attention was given to pathological
neurochemistry and genetic issues in the etiopathogenesis of Parkinson's
[Gorrell, J.M. et al. 1996. Meeting Report. National Institute of Environmental
Health Sciences. Environmental Health Perspectives;104(6)]
diseases: occupational occurrence and potential risk factors, 1982 through
To identify potential occupational risk factors, this study examined
the occupational occurrence of various neurodegenerative diseases:presenile
dementia, Alzheimer's disease, Parkinson's disease, and motor neuron
disease. Excess mortality was observed for all four categories in the
following occupational categories: teachers; medical personnel; machinists
and machine operators; scientists; writers/designers/entertainers; and
support and clerical workers. Clusters of three neurodegenerative diseases
were also found in occupations involving pesticides, solvents, and electromagnetic
fields and in legal, library, social, and religious work.
[Schulte, P.A., et al. 1996. American Journal of Public Health 86(9):1281-1288]
antecedents of young-onset Parkinson's disease
An exploratory study of young-onset Parkinson's disease (YOPD) to examine
occupational and environmental factors associated with disease risk.PD
was positively associated with insecticide exposure (OR = 5.75, p <
0.001), past residency in a fumigated house (OR = 5.25, p = 0.046),
herbicide exposure (OR = 3.22, p = 0.033), rural residency at time of
diagnosis (OR = 2.72, p = 0.027), and nuts and seed eating 10 years
before diagnosis (OR = 1.49, p = 0.021). These findings are consistent
with hypotheses linking PD to exposure to pesticide agents.
[Butterfield, P.G., et al. 1993. Neurology 43(6):1150-1158.]
factors for Parkinson's disease
Study examined social and medical histories of predominantly rural populations
to determine relative risk factors for PD. Significant predictors of
PD emerged (in order of strength): pesticide use, family history of
neurologic disease, and history of depression. The predicted probability
of PD was 92.3% (odds ratio = 12.0) with all three predictors positive.
Pesticide use (distinguishable from rural living) can be considered
a risk factor for the development of PD, with family history of neurologic
disease and history of depression serving as weaker predictors of PD.
[Hubble, J.P., et al. 1993. Neurology 43:1693-97]
disease and exposure to agricultural work and pesticide chemicals.
A population-based case-control study of 130 Calgary residents with
neurologist-confirmed idiopathic Parkinson's disease (PD) and 260 randomly
selected age- and sex-matched community controls to determine whether
agricultural work or the occupational use of pesticide chemicals is
associated with an increased risk for PD. In the multivariate analysis,
which controlled for potential confounding or interaction between the
exposure variables, previous occupational herbicide use was consistently
the only significant predictor of PD risk.
[Semchuk, K.M., et al. 1992. Neurology 42:1328-1335]
disease in Ferrara, Italy, 1967 through 1987.
Authors studied the frequency of Parkinson's disease in the Local Health
Service of Ferrara, northeastern Italy. The study revealed a significantly
higher incidence rate among agricultural workers (20.6/100,000). These
results would seem to give further support to the hypothesis of a possible
causal role of environmental factors that are mainly linked to agriculture,
most likely due to the continual exposure to toxic agents in this area.
[Granieri, E., et al. 1991. Archives of Neurology 48(8):854-857]
risk factors in Parkinson's disease
Study investigated possible risk factors for Parkinson's disease (PD)
and conducted a case-control study of 150 PD patients and 150 age- and
sex-matched controls. Rural living and drinking well water were significantly
increased in the PD patients. This was observed regardless of age at
disease onset. Drinking well water was dependent on rural living. There
were no significant differences between cases and controls for farming
or any measure of exposure to herbicides or pesticides. These data provide
further evidence that an environmental toxin could be involved in the
etiology of PD.
[Koller, W. et al. 1990. Neurology. 40(8):1218-1221]
of Parkinson's disease: prevalence and environmental aspects in rural
Study demonstrates that the prevalence of Parkinson's disease is of
uneven distribution within rural areas of Quebec, Canada. Study further
investigates the characteristics of the regions of high prevalence.
These regions which are predominantly agricultural and areas of intensive
market gardening were also the areas with the highest use of pesticides.
[Barbeau, A., et al. 1987. Can J Neurol Sci 14(1) 36-41]