Association of Pesticide Exposure With Neurologic Dysfunction and Disease

Freya Kamel; Jane A. Hoppin

Disclosures

Environ Health Perspect. 2004;112(9) 

In This Article

Neurodegenerative Disease

An extensive literature suggests that pesticide exposure may increase risk of Parkinson disease (Le Couteur et al. 1999). Many studies have found an association of Parkinson disease risk with living in rural areas, drinking well water, and farming as an occupation (Priyadarshi et al. 2001). More specifically, case-control studies have observed that pesticide exposure is associated with increased Parkinson disease risk, although results are not fully consistent. Studies published before 1999 were reviewed by Le Couteur et al. (1999), who noted that 12 of 20 studies found a positive association, with 1.6- to 7-fold increases in risk. Some of these studies evaluated risks associated with ever exposure to any pesticide. This broad definition of exposure permits significant misclassification, which could minimize the magnitude of any association observed.

Recent studies with more detailed exposure assessment have generally found an association of pesticide exposure with Parkinson disease, with 1.5- to 7-fold increases in risk. Case-control studies found increased risk associated with possession of a pesticide use license (Baldereschi et al. 2003), cumulative pesticide exposure based on complete occupational histories (Baldi et al. 2003a; Fall et al. 1999), or occupational or other pesticide use (Herishanu et al. 2001). A cross-sectional study found an association of parkinsonism with exposure to any pesticide, although not with specific pesticides or pesticide classes (Engel et al. 2001), and an ecologic study found that Parkinson disease mortality was higher in California counties where pesticides were used than in counties where they were not (Ritz and Yu 2000). Two cohort studies with detailed exposure information confirmed these findings: Risk was related to years of plantation work and to self-reported pesticide exposure in men enrolled in the Honolulu Heart Program cohort (Petrovitch et al. 2002), and occupational exposure to pesticides assessed with a job-exposure matrix was strongly associated with Parkinson disease risk (5.6-fold increase in risk) in an older cohort living in a vineyard-growing region of France (Baldi et al. 2003b). Three case-control studies found no association of pesticide exposure with Parkinson disease (Behari et al. 2001; Kuopio et al. 1999; Taylor et al. 1999).

Most studies of pesticide exposure and Parkinson disease risk have been unable to implicate specific pesticides. Several studies found increased risk associated with exposure to either insecticides or herbicides (Butterfield et al. 1993; Gorell et al. 1998; Semchuk et al. 1992), and one study indicated that risk was elevated by exposure to organochlorines, OPs, or carbamates (Seidler et al. 1996). Several studies have implicated the herbicide paraquat (Hertzman et al. 1990; Liou et al. 1997), which produces selective degeneration of neurons involved in Parkinson disease (McCormack et al. 2002). Case reports have described Parkinson disease in individuals exposed to OPs (Bhatt et al. 1999; Davis et al. 1978); to herbicides including glyphosate (Barbosa et al. 2001), paraquat (Sanchez-Ramon et al. 1987), and diquat (Sechi et al. 1992); and to fungicides including maneb (Meco et al. 1994) and other dithiocarbamates (Hoogenraad 1988). Higher concentrations of organochlorines, particularly dieldrin, have been found in postmortem brains of Parkinson disease patients compared to patients with other neurologic diseases (Corrigan et al. 2000; Fleming et al. 1994).

Animal models have also implicated pesticide exposure in the etiology of Parkinson disease. In rats, systemic administration of rotenone has been shown to produce highly selective neural degeneration similar to that found in Parkinson disease as well as a parkinsonian behavioral disorder (Betarbet et al. 2000). Treatment of mice with both paraquat and maneb reduced motor activity and striatal tyrosine hydroxylase activity, at doses at which neither compound was effective alone (Thiruchelvam et al. 2000).

Information on pesticide exposure and other neurologic diseases is more limited. Several studies have suggested that risk of amyotrophic lateral sclerosis (ALS) is related to farming as an occupation, although not necessarily to living in rural areas (Nelson 1995-1996). Pesticide exposure has been considered in six case-control studies; three found some evidence for an association (Deapen and Henderson 1986; McGuire et al. 1997; Savettieri et al. 1991), whereas three others found none (Chancellor et al. 1993; Granieri et al. 1988; Gunnarsson et al. 1992). Only one study presented detailed exposure information (McGuire et al. 1997): Based on an industrial hygiene assessment of a complete occupational history, pesticide exposure was associated with > 2-fold increase in ALS risk, with greater risk at higher levels of exposure. This study did not implicate specific pesticides in ALS etiology. However, a cohort study found increased risk of ALS among workers exposed to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) compared to other company employees, although this result was based on only three deaths (Burns et al. 2001). Case reports have described ALS after exposure to OPs (Bidstrup et al. 1953) and organochlorines (Fonseca et al. 1993).

Dementia has also been related to pesticide exposure. Occupational exposure to unspecified pesticides and fertilizers was associated with risk of Alzheimer disease in a large case-control study (McDowell et al. 1994), although another smaller study of environmental exposure in the general population found no relationship to herbicides, insecticides, or pesticides (Gauthier et al. 2001). Occupational exposure to any pesticide assessed with a job-exposure matrix was associated with 2-fold increase in risk of Alzheimer disease in a cohort of older individuals living in a vineyard-growing region of France and exposed primarily to dithiocarbamate fungicides (Baldi et al. 2003b). Occupational pesticide exposure was also associated with mild cognitive dysfunction in a population-based prospective study (Bosma et al. 2000), with vascular dementia (Lindsay et al. 1997), and with risk of dementia among Parkinson disease patients (Hubble et al. 1998). Understanding the relationship of pesticide exposure to Alzheimer disease may be complicated by the fact that the basic neurochemical defect in Alzheimer disease is loss of cholinergic neurons, and that to increase cholinergic tone Alzheimer disease is sometimes treated with OP cholinesterase inhibitors (Ringman and Cummings 1999).

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