Pesticides and Parkinson’s Disease–Is There a Link?

Environmental Health Perspectives Volume 114, Number 2, February 2006 Review

Terry P. Brown,1 Paul C. Rumsby,2 Alexander C. Capleton,1 Lesley Rushton,1 and Leonard S. Levy1
1Medical Research Council Institute for Environment and Health,University of Leicester, Leicester, United Kingdom; 2National Centre for Environmental Toxicology, WRc-NSF Ltd., Medmenham, Marlow, United Kingdom

Parkinson’s disease (PD) is an idiopathic disease of the nervous system characterized by progressive tremor, bradykinesia, rigidity, and postural instability. It has been postulated that exogenous toxicants, including pesticides, might be involved in the etiology of PD. In this article we present a comprehensive review of the published epidemiologic and toxicologic literature and critically evaluate 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. However, both the epidemiology and toxicology studies were limited by methodologic weaknesses. Particular issues of current and future interest include multiple exposures (both pesticides and other exogenous toxicants), developmental exposures, and gene-environment interactions. 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 toxicant exposure. Key words: epidemiology, literature review, Parkinson’s disease, pesticides, toxicology. Environ Health Perspect 114:156-164
(2006). doi:10.1289/ehp.8095 available via [Online 7 September 2005]

Overall Conclusions

The epidemiologic studies suggest a relatively consistent association between exposure to pesticides and an increased risk of developing Parkinson’s Disease (PD), despite differences in study design, case ascertainment and definition, control selection, and pesticide exposure assessment. Particular classes of pesticides found to be associated with PD include herbicides, particularly paraquat, and insecticides; evidence from case reports and case-control studies for an association with exposure to fungicides alone is equivocal. Duration of exposure has also been found to be a risk factor, with those exposed to pesticides for > 10 or 20 years being associated with an increased risk of developing PD. However, in addition to pesticides, several other risk factors are associated with an increased risk of developing PD, including rural living, well-water consumption, and farming. We found no studies that have been able to determine whether these risk factors are independent risk factors or correlated with pesticide exposure.

The toxicologic evidence suggests that, with certain routes of administration, rotenone and paraquat may have neurotoxic actions that could potentially play a role in the development of PD. These include effects on dopaminergic systems in the SN, and -synuclein aggregation. There is also some evidence that the mechanisms of neurotoxicity associated with exposure to pyrethroids are those that would be suggestive of a role in the development of PD and that dithiocarbamates may interact with other xenobiotic agents to increase neurotoxicity. Studies on various other pesticides suggest that, while they have neurotoxic actions, they do not act on systems in the brain of relevance to PD. However, many of these studies reviewed were designed to elicit acute toxicity in order to study the mechanisms of action. We identified no study that administered pesticides at levels comparable with those encountered by pesticides users, nor were the routes of administration those that would be experienced by pesticide users (i.e., oral, inhalation, or dermal). As a result, it is difficult to interpret the relevance of such studies to humans, although the difficulty in modeling a disease such as PD is acknowledged. Of potential toxicologic importance are the few studies that reported dopaminergic neurotoxicity after combined low-level exposure to multiple environmental neurotoxicants, including paraquat and maneb, the combined effects of pesticides and metals on -synuclein, and rotenone and lipopolysaccharide (which may be present due to inflammation or infection). For example, although PD is a disease of aging, the studies of Thiruchelvam et al. (2003) on the developmental exposure to maneb and paraquat indicate that early exposure may lead to PD-like toxic effects upon adult rechallenge. Such studies suggest that exposure to multiple low-level environmental neurotoxicants, perhaps at an early age, may be an etiologic factor in the development of PD.

Recent toxicologic studies have suggested that multiple genetic and environmental factors could be involved in the etiology of PD. Studies with transgenic mice suggest that the genetic background and expression of the -synuclein gene may have a role to play in neurodegeneration of the SN (Thiruchelvam et al. 2004) and may also lead to increased vulnerability to the neurotoxic effects of the pesticides maneb and paraquat. There is evidence that developmental exposure to pesticides may have an increased neurodegenerative effect as well as making the SN more susceptible to subsequent adult exposure to pesticides, and that combined exposure to pesticides such as maneb and paraquat has a greater neurotoxic effect than either pesticide alone (Cory-Slechta et al. 2005). Other recent studies also suggest some interaction between the neurodegenerative effects of pesticides and inflammatory proteins produced by microglia in the SN (Gao et al. 2003, Liu and Hong 2003).These genetic and environmental factors could be considered in future epidemiologic studies of this multifactorial disease.

Most of the epidemiologic studies that we reviewed used a case-control design with relatively small numbers of cases. Pesticide exposure history was, by necessity, collected retrospectively, generally using questionnaires. Information and recall bias are inherent limitations of this type of design. The exposure assessments were also limited in their collection of information on the types of pesticides, specific chemicals, and levels of exposure experienced. Of all the studies we reviewed, the two most reliable were large case-control studies that attempted to investigate exposure to different groups of pesticides (Semchuk et al. 1992; Seidler et al. 1996).

Despite these considerations, it seems unlikely that the relatively consistent association between PD and reported exposure to pesticides observed in the epidemiology studies could be explained wholly by a combination of chance, bias and confounding, and selective reporting. The toxicologic literature indicates several areas that would benefit from further research, including the effect of exposure at different ages, early exposure and developmental changes, the role of inflammatory disease, and the potential for gene-environment interactions. Epidemiologic studies of an appropriate design and size, that collect detailed information on exposure to specific pesticides and other chemicals, including early life exposures, would be required to investigate these issues. Studies to date have not had sufficient power to disentangle the relative importance of intercorrelated risk factors and to evaluate each risk with any confidence. We are aware of several ongoing studies that are addressing some of these areas of concern.

In conclusion, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists, but it is not sufficient to conclude that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined exposure to pesticides and other exogenous toxicants. In addition, the multifactorial etiology of PD hampers unequivocally establishing the role of any individual contributory causal factor.

Address correspondence to A.C. Capleton, MRC Institute for Environment and Health, University of Leicester, 94 Regent Rd., Leicester, LE1 7DD, UK. Telephone: 44-0-116-223-1606. Fax: 44-0-116-223-1601. E-mail: