In 1982, a Californian hospitaladmitted several relatively young

people suffering from symptoms ofParkinson’s disease. Investigationstraced the parkinsonism to heroincontaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP),1 which monoamine oxidase B converts to the neuro-toxin MPP+, a substrate for thedopamine reuptake pathway. Asdopamine neurones selectivelyaccumulate MPP+, MPTP can rap-idly degrade the substantia nigraand potentially induces parkinson-ism within 7 to 14 days.2

The discovery marked a turn-ing point in attempts to resolve theenigma of Parkinson’s disease. AsWarner and colleagues remark,MPTP ‘clearly established’ that an‘environmental’ toxin could targetthe substantia nigra, causingdegeneration and parkinsonism.2

Studies now show that numer-ous toxins can cause parkinsonism.For instance, occupational expo-sure to copper for 20 years mayincrease Parkinson’s disease riskalmost 2.5-fold.3 Women occupa-tionally exposed to high levels ofpolychlorinated biphenyls showedan almost three-fold increase instandardised mortality ratios forParkinson’s disease.4 Further -more, recent studies help clarifythe role of pesticides and herbi-cides in Parkinson’s disease patho-genesis.

Accumulating evidenceEvidence linking pesticides andherbicides to Parkinson’s disease

accumulated gradually over manyyears. For example, several epi-demiological studies suggest thatParkinson’s disease is particularlyprevalent in rural agriculturalareas.5,6 In one study, people work-ing as farmers for 10 and 20 yearswere 17 and 16 per cent respec-tively more likely to haveParkinson’s disease than controls.6

Furthermore, the link seemsbiologically plausible. Forinstance, MPTP is structurally similar to some pesticides and her-bicides, including paraquat.5

Animal studies suggest that certainpesticides and herbicides selec-tively destroy dopaminergic path-ways and induce parkinsonism-likebehaviours.2

Moreover, increasing evidencelinks pesticides to other neuro -behavioural problems, includinganxiety, depression andAlzheimer’s disease. For example,a study of French vineyard workersfound that, depending on theneuro behavioural test, the relativerisk of poor performance amongthose exposed to pesticides rangedfrom 1.35 to 5.60 compared withunexposed controls. After a meanfollow up of 4.7 years, peopleexposed to pesticides were 97 percent and 64 per cent more likely toshow a decline of two and threepoints on the Mini-Mental StateExamination (MMSE) comparedwith controls.7 However, not everystudy linked environmental pesti-cides and herbicides to Parkinson’sdisease and proof of causalityremained elusive.5,6

Against this background, arecent systematic review estimatedthe relative risk for the associationbetween occupational exposure topesticides and Parkinson’s diseasebased on 12 studies publishedbetween 1985 and 2011. Theresults were heterogeneous andinconsistent. Overall, however,occupational exposure to pesti-cides increased Parkinson’s diseaserisk by 28 per cent.6

Importantly, the strongest asso-ciation emerged from the most rig-orous studies. For example, themeta-analysis found that occupa-tional exposure to pesticidesapproximately doubled the risk ofParkinson’s disease in cohort stud-ies reporting incidence (meta-rateratio estimates [mRR]=1.95).Furthermore, autopsies suggestthat up to 24 per cent of clinicaldiagnoses of Parkinson’s diseaseare incorrect. Conversely, doctorshad incorrectly clinically diag-nosed about 20 per cent of patientswith Parkinson’s disease onautopsy with different disorders. Incontrast, the diagnostic accuracyof movement disorder specialists isaround 90 per cent. In the meta-analysis, exposure to pesticidesmore than doubled the risk ofParkinson’s disease confirmed bya neurologist (mRR=2.56).6

Moreover, Parkinson’s diseaserisk rose with increasing exposure,further strengthening the link. Forexample, despite intensive use ofpesticides in plantations, workingconditions are often insufficientlycontrolled. Pesticides exposure on

Research z PD and pesticides

20 Progress in Neurology and Psychiatry January/February 2013 www.progressnp.com

Pesticides and Parkinson’s diseasepathogenesis: the controversy continuesMark Greener

A possible link between pesticide exposure and Parkinson’s disease has been postulatedfor many years and recent studies help clarify this association. Mark Greener reports.

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PD and pesticides z Research

Progress in Neurology and Psychiatry January/February 2013www.progressnp.com

banana, sugarcane and pineappleplantations doubled the risk ofdeveloping Parkinson’s disease(mRR=2.05). In one study includedin the review, people working on aplantation for 11-20 years andmore than 20 years were 70 percent (not statistically significant)and 90 per cent (which attainedstatistical significance) more likelyto develop Parkinson’s disease.6

Another study included in thereview enrolled elderly Frenchpeople. The adjusted relative riskof Parkinson’s disease in men was5.3 and 5.7 in the first and secondquartile of pesticide exposurerespectively. Neither differencewas statistically significant.However, the adjusted relative riskof Parkinson’s disease of 10.9 inthe third quartile attained statisti-cal significance. (No Parkinson’sdisease patients were exposed tofourth quartile levels.)8

Outstanding issuesCharacterising the environmentaltriggers for Parkinson’s disease iscritical to elucidate the pathogen-esis of this common, but enig-matic, disease. For example, whilegenetic research implicated severalgenetic mutations as risk factors,currently identified polymor-phisms account for only 5-10 percent of Parkinson’s disease cases.3

Indeed, only ‘a small fraction’ ofpeople exposed to the potentneuro toxin MPTP developedparkinsonism.2 However, as arecent review notes, ‘there is verylimited information on gene-envi-ronment interactions’ in deter-mining Parkinson’s disease risk.

Future studies could, for example,focus on polymorphisms in genesencoding cytochrome p450 andother metabolic pathways.5

Nevertheless, as Wirdefeldt andcolleagues remark, aetiologicalstudies into ‘Parkinson’s diseasetake place at the border of what canbe accomplished through observa-tional research’.5 For example, sev-eral factors complicate studies ofthe relationship between environ-mental toxins and Parkinson’s dis-ease, including ‘the insidious onsetand the long preclinical period’before motor symptoms emerge. Asa result, standardised identificationof incident cases is ‘challenging’and, in turn, studies are prone toselection bias, reverse causation andother limitations. Moreover, whileParkinson’s disease is heteroge-neous, the lack of accepted criteria that differentiate clinicallyrelevant subtypes hinders research.5

Furthermore, aetiologicalanalyses may need to allow for aplethora of possible risk factors forParkinson’s disease. Unfortunately,the evidence for some of these pos-sible risk factors – such as diabetes,head trauma and vascular disease –is inconsistent, limited and incon-clusive.5 In addition, many possiblechemical causes of Parkinson’s dis-ease ‘are extraordinarily difficult toascertain and are often mutuallyconfounded’.5 Indeed, a singleFrench farm can use between threeand 23 different pesticides eachyear.8 Studies also differ in theirdefinition of exposed occupations:some, but not all, regarded profes-sions such as fishermen, fire-fight-ers, veterinarians, forestry workers,

or woodworkers as being exposedto pesticides.6

New insightsWhile the evidence is inconsistentand while the association is difficultto investigate, the weight of evi-dence seems to support a linkbetween pesticides and Parkinson’sdisease. But, clearly, there is a press-ing need for further studies. Suchinvestigations will not only helplimit the risk in our rural commu-nities, but also offer new patholog-ical insights into one of the mostenigmatic neurological disorders.

Mark Greener is a freelance medicalwriter

References1. A USVH Quick Guide to Parkinson’s Disease.United Students for Veterans’ Health.(Accessed at http://www.stanford.edu/group/usvh/stanford/misc/Parkinsons%201.pdf.)2. Warner TT, Schapira AHV. Genetic and envi-ronmental factors in the cause of Parkinson'sdisease. Ann Neurol 2003;53:S16-S25.3. Caudle WM, Guillot TS, Lazo CR, Miller GW.Industrial toxicants and Parkinson’s disease.NeuroToxicology 2012;33:178-88.4. Steenland K, Hein MJ, Cassinelli RTI, et al.Polychlorinated biphenyls and neuro -degenerative disease mortality in anOccupational Cohort. Epidemiology 2006;17:8-13. 0.1097/01.ede.0000190707.51536.2b.5. Wirdefeldt K, Adami H-O, Cole P, et al.Epidemiology and etiology of Parkinson’s dis-ease: a review of the evidence. Eur J Epidemiol2011;26:1-58.6. Van Maele-Fabry G, Hoet P, Vilain F, Lison D.Occupational exposure to pesticides andParkinson’s disease: A systematic review andmeta-analysis of cohort studies. EnvironmentInt 2012;46:30-43.7. Baldi I, Gruber A, Rondeau V, et al.Neurobehavioral effects of long-term expo-sure to pesticides: results from the 4-year fol-low-up of the PHYTONER Study. Occupationaland Environmental Medicine 2011;68:108-15.8. Baldi I, Lebailly P, Mohammed-Brahim B, etal. Neurodegenerative diseases and exposureto pesticides in the elderly. Am J Epidemiol2003;157:409-14.

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