Logo of envhperEnvironmental Health PerspectivesBrowse ArticlesAbout EHPGeneral InformationAuthorsMediaProgramsPartnerships
Environ Health Perspect. Jun 2004; 112(9): 950–958.
Published online May 20, 2004. doi:  10.1289/ehp.7135
PMCID: PMC1247187
Research Article
Reviews

Association of Pesticide Exposure with Neurologic Dysfunction and Disease

Abstract

Poisoning by acute high-level exposure to certain pesticides has well-known neurotoxic effects, but whether chronic exposure to moderate levels of pesticides is also neurotoxic is more controversial. Most studies of moderate pesticide exposure have found increased prevalence of neurologic symptoms and changes in neurobehavioral performance, reflecting cognitive and psychomotor dysfunction. There is less evidence that moderate exposure is related to deficits in sensory or motor function or peripheral nerve conduction, but fewer studies have considered these outcomes. It is possible that the most sensitive manifestation of pesticide neurotoxicity is a general malaise lacking in specificity and related to mild cognitive dysfunction, similar to that described for Gulf War syndrome. Most studies have focused on organophosphate insecticides, but some found neuro-toxic effects from other pesticides, including fungicides, fumigants, and organochlorine and carbamate insecticides. Pesticide exposure may also be associated with increased risk of Parkinson disease; several classes of pesticides, including insecticides, herbicides, and fungicides, have been implicated. Studies of other neurodegenerative diseases are limited and inconclusive. Future studies will need to improve assessment of pesticide exposure in individuals and consider the role of genetic susceptibility. More studies of pesticides other than organophosphates are needed. Major unresolved issues include the relative importance of acute and chronic exposure, the effect of moderate exposure in the absence of poisoning, and the relationship of pesticide-related neurotoxicity to neurodegenerative disease.

Keywords: fumigant, fungicide, insecticide, neurobehavioral performance, neurodegenerative disease, neurologic symptoms, organophosphate, Parkinson disease, pesticide

Pesticides are used extensively throughout the world. In the United States, more than 18,000 products are licensed for use, and each year > 2 billion pounds of pesticides are applied to crops, homes, schools, parks, and forests [U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs 2002]. Such widespread use results in pervasive human exposure.

Evidence continues to accumulate that pesticide exposure is associated with impaired health. Occupational exposure is known to result in an annual incidence of 18 cases of pesticide-related illness for every 100,000 workers in the United States (Calvert et al. 2004). The best-documented health effects involve the nervous system. The neurotoxic consequences of acute high-level pesticide exposure are well established: Exposure is associated with a range of symptoms as well as deficits in neurobehavioral performance and abnormalities in nerve function (Keifer and Mahurin 1997). Whether exposure to more moderate levels of pesticides is also neurotoxic is more controversial. Pesticide exposure may also be associated with increased risk of neurodegenerative disease, particularly Parkinson disease (Le Couteur et al. 1999).

In this review, we summarize briefly what is known about the neurotoxic effects of high-level exposure, describe in more detail the existing data on neurotoxic effects of chronic exposure at lower levels, and then discuss the relationship of pesticide exposure to neurologic disease. Although pesticide exposure may have significant effects on neurodevelopment (Eskenazi et al. 1999), this review focuses on effects in adults ≥ 18 years of age. Since differences in approach to evaluating pesticide exposure may play a crucial role in creating inconsistencies among studies, we first consider pesticide exposure assessment.

Pesticide Exposure

Pesticides are a broad range of substances most commonly used to control insects, weeds, and fungi (plant diseases). They are frequently classified by target organism or mode of use as insecticides, herbicides, fungicides, or fumigants. Insecticides are often subclassified by chemical type as organophosphates (OPs), organochlorines, carbamates, and pyrethroids. Individuals are frequently exposed to many different pesticides or mixtures of pesticides, either simultaneously or serially. These exposures are often highly correlated, particularly within functional or chemical groups, making it difficult to identify effects of particular agents.

Studies of pesticide neurotoxicity have typically evaluated either the long-term sequelae of pesticide poisoning or the effects of occupational exposure (Table 1). Pesticide poisoning may go undiagnosed, especially among farm-workers with poor access to medical care (Moses et al. 1993) and particularly among women (London et al. 2002). Thus, workers who have never been diagnosed with pesticide poisoning may still have sustained high exposures or experienced pesticide-related illness; therefore using diagnosed poisoning as a criterion for inclusion in an exposed group or exclusion from a comparison group may incorrectly classify individuals.

Table 1
Studies of chronic pesticide exposure and neurotoxicity: exposure measurement.a

Some studies of occupational pesticide exposure have classified as exposed all members of an occupational group—typically farmers or farmworkers—sometimes also considering job duration. The potential for misclassification with this approach is high. Farm owners who employ others to apply pesticides may have limited personal exposure to pesticides. Even among pesticide applicators, exposure can vary widely. For example, farmworkers with little access to information about safety practices or protective equipment (Gomes et al. 1999) may sustain far more exposure than well-trained and equipped commercial applicators (Maizlish et al. 1987). Further, farm-workers who do not apply pesticides as part of their job may still be exposed, and even family members with no direct occupational exposure may be exposed at home or elsewhere (Fenske 1997; Gladen et al. 1998), so neither of these may be an appropriate comparison group.

Factors such as application method, use of personal protective equipment, work practices related to hygiene, spills, and attitudes toward risk may all influence the degree of pesticide exposure and can be incorporated into exposure estimates (Alavanja et al. 2004; Buchanan et al. 2001; Dosemeci et al. 2002; Gomes et al. 1999; Hernandez-Valero et al. 2001; London and Myers 1998; Ohayo-Mitoko et al. 1999; Stewart et al. 2001). The relationship of these factors to exposure can be complex. For example, wearing gloves can increase exposure under some circumstances (Hines et al. 2001), perhaps because fabric (as opposed to chemically impervious) gloves can become impregnated with pesticide and serve as a reservoir of exposure. The same may be true of other types of protective clothing (Ohayo-Mitoko et al. 1999). In developing countries, use of closed pesticide mixing and loading systems may increase exposure when the equipment is used to speed up work and increase productivity rather than to protect workers (McConnell et al. 1992). Additional factors may be crucial for evaluating exposure in farmworkers, such as availability of washing and drinking water, interval between application of pesticides to a field and re-entry of workers, and housing conditions (Arcury and Quandt 1998; Gomes et al. 1999; Hernandez-Valero et al. 2001; Tielemans et al. 1999). Studies of neurotoxicity have used all these kinds of information to evaluate pesticide exposure (Gomes et al. 1999; Ohayo-Mitoko et al. 1999). The most sophisticated approaches were employed by London and Myers (1998), who used a crop-and job-specific job exposure matrix to evaluate exposure in a study of the neurotoxicity of chronic OP exposure among South African farmworkers, and by Buchanan et al. (2001), who developed an exposure algorithm to predict diazinon exposure for a study of chronic neurologic effects among sheep dippers in the United Kingdom.

Both historic and current exposures may be relevant to neurotoxicity and need to be characterized. Even among people who remain in the same occupation, current exposure may not reflect past exposure patterns because both available products and methods of use change over time. The need to evaluate past as well as current exposure has limited the utility of bio-markers; most modern pesticides are not persistent, so studies of chronic exposure rely primarily on questionnaire-based methods. Biomarkers are, however, useful in some situations. For example, organochlorines have a long half-life, so serum levels can be used as a marker of exposure to these pesticides. OP inhibition of erythrocyte acetylcholinesterase (AChE) can also be used as an exposure marker. The effect lasts 3–4 months, so AChE activity in whole blood or erythrocytes can be used to evaluate subchronic exposure, although interpretation can be complicated by acute exposure. Although the clinical utility of this biomarker in individuals may be limited by variability in baseline levels, in populations chronic OP exposure is associated with small but reliable decreases in erythrocyte AChE activity (Karr et al. 1992; Ohayo-Mitoko et al. 1997). OPs also inhibit plasma butylcholinesterase, but the effect lasts at most a few weeks and is therefore not useful for evaluating chronic exposure. Cholinesterase inhibition by carbamates lasts only minutes, so it is not a useful marker of chronic exposure to these pesticides.

Estimating lifetime pesticide exposure quantitatively is difficult because it is affected by many factors, including the multiple chemicals involved, uncertainty regarding the degree of exposure related to specific job tasks or other events, and contributions from multiple sources of exposure, including sources unrelated to occupation. Further, the biologically relevant exposure measure is not known: Peak or average exposure intensity might be more important than cumulative exposure. Thus, attempts to assess quantitative dose–response relationships may be problematic. The goal of exposure assessment in epidemiologic studies is not, however, to assign quantitative dose estimates but rather to rank individuals by relative exposure level. Assignment of either exposed or unexposed individuals to the wrong category can be a significant problem, as can combining individuals with low and high levels of exposure into one group. Random misclassification of exposure, unrelated to health outcome, will typically weaken studies by making associations more difficult to detect, although it will not undermine the validity of any association that is observed. As discussed above, assuming that all farmers or even all pesticide applicators are equally exposed is likely to entail significant misclassification, as is assuming that all farmworkers who are not applicators are not exposed. Further, studies that identify only a single highly exposed group for study cannot evaluate the neurotoxicity of moderate exposure, which may have great significance to public health. Methods described above can correctly categorize study participants with respect to their relative exposure levels, and using such methods to increase precision of exposure assessment may help minimize inconsistencies among studies.

Neurotoxicity of High-Level Exposure

Most types of pesticides, including OP, carbamate, and organochlorine insecticides as well as fungicides and fumigants, can be neurotoxic, but only OPs have been studied in detail (Keifer and Mahurin 1997). The response to OPs can occur within minutes. Less severe cases of OP poisoning display symptoms including headache, dizziness, nausea, vomiting, pupillary constriction, and excessive sweating, tearing, and salivation. More severe cases develop muscle weakness and twitches, bronchospasm, and changes in heart rate and can progress to convulsions and coma. The mechanism of OP neurotoxicity in most cases involves overstimulation of postsynaptic cholinergic receptors after inhibition of AChE (Keifer and Mahurin, 1997), although other macromolecular targets may also be involved (Pope 1999). An intermediate syndrome, occurring 1–4 days after exposure, is characterized by muscle weakness and can be fatal if respiratory muscles are affected. Two to five weeks after exposure, some patients develop OP-induced delayed polyneuropathy, a well-characterized syndrome involving sensory abnormalities, muscle cramps, weakness, and even paralysis, primarily in the legs. These symptoms are a consequence of axonal death following OP inhibition of a neural enzyme called neuropathy target esterase and may be irreversible (Keifer and Mahurin 1997).

Several studies have shown that OP poisoning has additional long-term sequelae. Studies of individuals with a history of pesticide poisoning—farmworkers (London et al. 1998; McConnell et al. 1994; Rosenstock et al. 1991; Wesseling et al. 2002), farmers (Stallones and Beseler 2002), rescue workers (Nishiwaki et al. 2001), or individuals identified from hospitals or pesticide registries (Miranda et al. 2002; Savage et al. 1988; Steenland et al. 1994)—have found that increased symptom prevalence, deficits in cognitive and psychomotor function, decreased vibration sensitivity, and motor dysfunction can occur long after the immediate episode is resolved. In some cases, effects were observed ≥ 10 years after poisoning (Savage et al. 1988), suggesting that the residual damage is permanent. Even less severe poisoning can have long-term consequences: Banana farm workers who had been treated for intoxication with OPs or carbamates but did not require hospitalization performed worse on tests of cognitive and psychomotor function than did nonpoisoned workers when tested > 2 years later (Wesseling et al. 2002).

Neurotoxicity of Low-Level Exposure

Findings from studies of acute exposure to moderate levels of pesticides are inconsistent. Some studies of well-trained and -equipped pesticide applicators in the United States reported that exposure to OPs sustained during a single work shift (Maizlish et al. 1987) or assessed using a short-lived urinary bio-marker (Dick et al. 2001) was associated with little neurotoxicity. However, several studies in developing countries, where exposures may have been higher, found that acute exposure to OPs was associated with increased symptom prevalence in commercial applicators (Misra et al. 1985) and farmworkers (London et al. 1998; Ohayo-Mitoko et al. 2000). Acute and chronic exposures are often correlated, sometimes making it difficult to separate their effects. The following discussion focuses on the effects of chronic exposure to moderate levels of pesticides, although in many studies acute exposure may also have occurred. Several types of neurologic end points are considered, including symptom prevalence, neurobehavioral performance, sensory and motor dysfunction, and direct measures of nerve function. Studies are summarized in Table 2.

Table 2
Studies of chronic pesticide exposure and neurotoxicity: neurologic outcomes.

Symptom Prevalence

Studies of symptom prevalence are often based on variations of an established checklist (Lundberg et al. 1997) and evaluate a broad range of symptoms, including headache, dizziness, fatigue, insomnia, nausea, chest tightness, and difficulty breathing as well as symptoms suggesting cognitive (confusion, difficulty concentrating), motor (weakness, tremor), and sensory (numbness, tingling, visual disturbance) dysfunction. Pesticide exposure is associated with increases in prevalence of many symptoms, with little evidence for specificity. Most studies have focused on OPs; most of these found an association of exposure with increased symptom prevalence. Farmworkers (Gomes et al. 1998), greenhouse workers (Bazylewicz-Walczak et al. 1999), and factory workers (Bellin and Chow 1974) exposed to OPs reported increased symptom prevalence compared to unexposed workers. In particular, farmers and farmworkers who applied OPs had higher symptom prevalence than nonapplicators (London et al. 1998; Ohayo-Mitoko et al. 2000; Smit et al. 2003), as did commercial applicators (Misra et al. 1985; Steenland et al. 2000) and sheep dippers (Pilkington et al. 2001). Pesticides other than OPs also affect symptom prevalence: one study found that exposure to dichlorodiphenyl-trichloroethane (DDT) was associated with increased symptom prevalence (van Wendel de Joode et al. 2001), as did one study of fumigants (Anger et al. 1986) although not another (Calvert et al. 1998). Additional studies have evaluated changes in mood and affect, using either self-report or validated scales. Workers exposed to OPs (Bazylewicz-Walczak et al. 1999; Steenland et al. 2000; Stokes et al. 1995) or DDT (van Wendel de Joode et al. 2001) reported higher levels of tension, anger, or depression on standard symptom questionnaires, and OP applicators showed elevated levels of anxiety on personality tests (Levin et al. 1976). Three studies found no association of OPs with symptom prevalence or affect (Ames et al. 1995; Fiedler et al. 1997; Korsak and Sato 1977).

Increased symptom prevalence was correlated with inhibition of erythrocyte AChE in four studies of OP exposure (Bellin and Chow 1974; Gomes et al. 1998; Leng and Lewalter 1999; Ohayo-Mitoko et al. 2000) and with inhibition of both erythrocyte AChE and plasma cholinesterase in two of these (Bellin and Chow 1974; Leng and Lewalter 1999). Another study found no relationship of symptom prevalence to inhibition of either erythrocyte or plasma cholinesterase (Lee et al. 2003). One study found that increased symptom prevalence was associated with self-reported pesticide exposure but not with depressed erythrocyte AChE activity (Ciesielski et al. 1994). Effects of OP exposure may not necessarily be caused by AChE inhibition (Pope 1999). Further, farmworkers have complex work histories and are likely to be exposed to pesticides other than OPs that may affect symptom prevalence without affecting AChE.

Neurobehavioral Performance

Neurobehavioral test batteries, including the World Health Organization Neurobehavioral Core Test Battery (Anger et al. 2000), the Neurobehavioral Evaluation System (Letz et al. 1996), and portions of other batteries, have been used to evaluate pesticide effects on cognitive and psychomotor function. Tests included in these batteries assess memory, attention, visuospatial processing, and other aspects of cognitive function; commonly used tests include symbol digit, digit span, visual retention, pattern memory, trail making, and others. Most studies indicate that pesticide exposure is associated with deficits in cognitive function. Sheep dippers (Stephens et al. 1995), nursery workers (Bazylewicz-Walczak et al. 1999), and other workers (Korsak and Sato 1977) exposed to OPs, malaria-control workers who sprayed DDT (van Wendel de Joode et al. 2001), vineyard workers exposed to fungicides (Baldi et al. 2001), fumigators exposed to sulfuryl fluoride but not those exposed to methyl bromide (Anger et al. 1986; Calvert et al. 1998), and farmers (Cole et al. 1997), farm-workers (Gomes et al. 1998; Kamel et al. 2003), and pesticide applicators (Farahat et al. 2003) exposed to multiple pesticides all performed worse on tests of cognitive function. There are some inconsistencies among these studies. Although most studies found deficits on one or more tests of cognitive function, different tests were affected in different studies, and a few studies found no relationship of OP exposure to any test (Ames et al. 1995; Daniell et al. 1992; Fiedler et al. 1997; Rodnitzky et al. 1975; Steenland et al. 2000).

Deficits in psychomotor function could be caused by impairment of sensory input, motor output, or associative delays; tests used include reaction time, tapping, pursuit aiming, Santa Ana and other pegboard tests, and others. Most studies indicate that pesticide exposure is associated with deficits in psychomotor function. Farmworkers (Daniell et al. 1992; London et al. 1997), farmers (Fiedler et al. 1997) and termiticide applicators (Steenland et al. 2000) exposed to OPs, malaria-control workers who sprayed DDT (van Wendel de Joode et al. 2001), vineyard workers exposed to fungicides (Baldi et al. 2001), fumigators exposed to methyl bromide or sulfuryl fluoride (Anger et al. 1986; Calvert et al. 1998), and farmworkers with multiple exposures (Gomes et al. 1998; Kamel et al. 2003) all showed worse performance on tests of psychomotor function. Again, results for individual tests were not fully consistent within or among studies, and no change in psychomotor function was evident in two studies of OP exposure (Ames et al. 1995; Cole et al. 1997).

Sensory and Motor Dysfunction

Neurobehavioral test batteries are often supplemented with tests of sensory or motor function. One frequently used test is vibration sensitivity, which evaluates peripheral somatosensory function. Most available evidence suggests this is not affected by moderate pesticide exposure. One study of farmers exposed to OPs found decreased sensitivity (Stokes et al. 1995), and another of farmers exposed to multiple pesticides found both decreased sensitivity and other signs of peripheral neuropathy (Cole et al. 1998). However, other studies of individuals exposed to OPs (Ames et al. 1995; London et al. 1998; Pilkington et al. 2001; Steenland et al. 2000), DDT (van Wendel de Joode et al. 2001), fumigants (Anger et al. 1986; Calvert et al. 1998), or multiple pesticides (Kamel et al. 2003) found no relationship of exposure to vibration sensitivity or other measures of somatosensory function.

Few studies have evaluated other aspects of sensory function. One study suggested that the sense of smell was not affected by OPs (Steenland et al. 2000); another study suggested a relationship with fumigants (Calvert et al. 1998). Visual contrast sensitivity was not affected by exposure to OPs (Steenland et al. 2000; van Wendel de Joode et al. 2001) or multiple pesticides (Kamel et al. 2003), but color vision was (Steenland et al. 2000). Retinal degeneration was associated with fungicide exposure in a case–control study of licensed pesticide applicators (Kamel et al. 2000). In general, these data are too limited to draw conclusions about the relationship to pesticide exposure to sensory function.

Similarly, few studies have considered motor function, and few inferences can be made about its relationship to pesticide exposure. Tremor was related to exposure to multiple pesticides in one study (Davignon et al. 1965) but not to OPs in two others (London et al. 1998; Steenland et al. 2000). Grip strength was not related to exposure to fumigants (Anger et al. 1986), DDT (van Wendel de Joode et al. 2001), or multiple pesticides (Kamel et al. 2003).

Balance is an integrated sensorimotor function. An early study found deficits in balance in apple farmers exposed to multiple pesticides (Davignon et al. 1965). In modern studies, balance is commonly evaluated by a test of postural sway; varying the conditions of the test may indicate whether impaired balance is related to deficits in visual, proprioceptive, or vestibular input. Three studies of individuals exposed to OPs (Steenland et al. 2000) or to multiple pesticides (Kamel et al. 2003; Sack et al. 1993) found that impaired postural sway was associated with exposure, but effects were small and another study found no relationship of OP exposure to postural sway (Ames et al. 1995). Effects were most evident when both visual and proprioceptive inputs were removed, suggesting that vestibular function may be affected (Kamel et al. 2003; Sack et al. 1993).

Nerve Function

Studies that have evaluated peripheral nerve conduction have produced largely negative results. Several studies of OPs found little evidence of impaired nerve conduction (Ames et al. 1995; Engel et al. 1998; Steenland et al. 2000). One study of fumigators found deficits in nerve conduction (Calvert et al. 1998), but another did not (Anger et al. 1986). In contrast, fungicide exposure was related to impaired nerve conduction in a study of bulb farmers, which also found deficits in autonomic nerve function (Ruijten et al. 1994). One study found changes in electroencephalogram (EEG) associated with OP exposure (Korsak and Sato 1977).

Three studies have performed clinical neurologic examinations in a subset of individuals identified by field studies as having deficits related to OP exposure. Beach et al. (1996) studied sheep dippers with increased symptom prevalence (Stephens et al. 1995); Horowitz et al. (1999) studied apple farmers with decreased vibration sensitivity (Stokes et al. 1995); and Jamal et al. (2002) studied sheep dippers with peripheral neuropathy (Pilkington et al. 2001). In general, clinical examination confirmed the results of the field studies, although clinically recognizable neurologic abnormalities were minor and not present in all individuals identified by the field studies.

Genetic Susceptibility to Pesticide Neurotoxicity

Individual response to pesticide exposure may be affected by polymorphisms in genes affecting pesticide metabolism. The best-known example is paraoxonase, an enzyme that hydrolyzes active metabolites of OPs (Costa et al. 2003). Animal studies suggest that changes in serum paraoxonase activity alter susceptibility to OP toxicity (Costa et al. 2003). In humans, paraoxonase polymorphisms affect the relationship of OP exposure to both erythrocyte AChE inhibition and symptom prevalence (Lee et al. 2003; Leng and Lewalter 1999; Mackness et al. 2003; Sozmen et al. 2002). Although Costa et al. (2003) have suggested that adequate evaluation of susceptibility requires measuring serum paraoxonase activity as well as genotype, recent population-based studies have suggested that the discrepancy between genotype and phenotype is relatively small and that nongenetic factors contribute relatively little to variation in serum activity (Ferre et al. 2003; Vincent-Viry et al. 2003).

Neurodegenerative Disease

Parkinson 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).

Other Neurodegenerative Diseases

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).

Conclusion

Most studies of neurotoxicity have documented an increase in symptom prevalence and changes in neurobehavioral performance reflecting cognitive and psychomotor dysfunction, but many found little effect of pesticide exposure on sensory or motor function or direct measures of nerve function. There are several potential explanations for these findings. Except for vibrotactile sensitivity, information on sensory and motor function is limited, and further study may reveal associations with pesticide exposure. Another possibility is that the increase in symptom prevalence is due to bias: Most studies were cross-sectional in design, and individuals with greater exposure or a history of poisoning may have been more motivated to recall or report symptoms. Confounding by head injury or neurologic disease, either of which might be related to both pesticide exposure and increased symptom prevalence, could also create the appearance of an association. Consistency of findings across many studies argues against these explanations, as do the positive findings of some studies that used more quantitative exposure measures. Further, bias and confounding are less likely to account for changes in neurobehavioral performance, which is assessed using objective test batteries. Thus, moderate pesticide exposure may in fact have greater effects on symptom prevalence and neurobehavioral performance than on sensory or motor function. The lack of specificity of the symptomatic response is also interesting. It is possible that the earliest or most general response to pesticide neurotoxicity is a general malaise lacking in specificity and related to mild cognitive dysfunction, similar to that described for Gulf War syndrome (White et al. 2001).

Although the weight of the evidence suggests that pesticide use is associated with increased symptom prevalence and deficits in neurobehavioral performance, there were some inconsistencies that future studies should attempt to resolve. It may be that certain functional domains are more sensitive to pesticides than others, but the current literature is too limited to resolve this question. Some of the inconsistencies among studies are likely due to methodologic differences. A critical concern is exposure assessment. Qualitative and quantitative aspects of the exposure under consideration differed among studies, as did the ability of the studies to assess exposure. Exposure measures ranged from job title to detailed assessment of cumulative exposure based on work history. There was, however, no clear-cut relationship between the quality of exposure assessment and the results of the studies.

The choice of comparison group may also influence results. Responses to symptom questionnaires and neurobehavioral performance are influenced by age, education, and cultural background (Anger et al. 1997), so it is important for comparison groups to be demographically similar to exposed populations. However, using a comparison group from the same community or workplace as the exposed participants can create problems. Although the former may have no documented exposure, they may nevertheless not be truly unexposed, limiting the power of the study to detect effects. There may be no one best solution to this problem.

Other aspects of study design, such as size, neurologic end points considered, and data analytic strategies including control for confounding, are likely to influence results. More than half of the studies considered were small, with < 100 exposed participants, and therefore had limited power to detect associations. Poor response rates in some studies may have biased results. Symptom questionnaires, neurobehavioral test batteries, and other methods for evaluating neurologic outcomes also varied among studies. In particular, different neurobehavioral batteries employ different tests of cognitive and psychomotor function. However, results were variable even for tests used in many studies. Implementation of a given test may vary between batteries; for example, a computerized version may differ from a paper-and-pencil model, but even this consideration may not explain all differences. A study of styrene found that grouping results of neurobehavioral tests provided increased power to detect effects of exposure, compared to evaluating individual tests (Heyer et al 1996). Use of similar analytic strategies might reduce inconsistencies among studies of pesticides.

Pesticide exposure may be associated with increased risk of Parkinson disease. Inconsistencies among studies are again likely to be caused by variations in study methodology, particularly lack of detailed exposure assessment in some earlier studies. The positive results from recent studies with more comprehensive exposure assessment, together with support from animal models, reinforces the hypothesis of an association. Results for ALS and Alzheimer disease are suggestive but too sparse to support firm conclusions. Whether the subtle signs of neurotoxicity found in studies of poisoning and occupational exposure are related to the later development of neurodegenerative disease is a question not adequately addressed by the literature, although one study showed that short- and long-term responses to moderate exposure are not necessarily related (Stephens et al. 1996).

Historically, most studies have focused on OPs, first to document sequelae of acute poisoning and then to explore the effects of chronic moderate exposure. There is also evidence suggesting that other types of pesticides, including organochlorines, carbamates, fungicides, and fumigants, are neurotoxic. No study has evaluated the association of herbicides with symptom prevalence or neurobehavioral performance, but these chemicals have been implicated as risk factors for Parkinson disease. Although it is important to identify classes of pesticides and even specific chemicals associated with neurotoxicity, it is also important to recognize that most workers are exposed to complex mixtures of pesticides, which may contribute synergistically to neurotoxicity.

Other aspects of the relationship of pesticide exposure to neurotoxicity remain to be clarified. Participants in most studies have sustained both chronic and acute exposures; because these are often correlated, the studies have not been able to disentangle their effects. It is also possible that studies of chronic moderate exposure have been influenced by inclusion of individuals with a history of pesticide poisoning in the exposed population. Several studies in which such individuals were excluded found no relationship of chronic exposure to neurobehavioral performance or nerve function (Ames et al. 1995; Engel et al. 1998; Fiedler et al. 1997), but other studies of nonpoisoned individuals have found associations (Kamel et al. 2003; Stephens et al. 1995; van Wendel de Joode et al. 2001), suggesting that moderate as well as high-level pesticide exposure is neurotoxic. An issue receiving increasing attention is genetic susceptibility to pesticide neurotoxicity. In particular, genetic variation in paraoxonase has been related to OP neurotoxicity.

In conclusion, there is mounting evidence that chronic moderate pesticide exposure is neurotoxic and increases risk of Parkinson disease. To substantiate these findings, future studies must employ more detailed assessment of exposure in individuals and consider the role of genetic susceptibility. More studies of pesticides other than OPs and greater attention to disentangling the effects of different types of pesticides are also needed. Better information is required to clarify the relative importance of acute and chronic exposure and the role of moderate exposure in the absence of poisoning. Finally, it will be important to clarify the relationship of pesticide-related neurotoxicity to neurodegenerative disease.

References

  • Alavanja M, Hoppin J, Kamel F. Health effects of chronic pesticide exposure: cancer and neurotoxicity. Annu Rev Public Health. 2004;25:155–197. [PubMed]
  • Ames R, Steenland K, Jenkins B, Chrislip D, Russo J. Chronic neurologic sequelae to cholinesterase inhibition among agricultural pesticide applicators. Arch Environ Health. 1995;50:440–444. [PubMed]
  • Anger W, Moody L, Burg J, Brightwell WS, Taylor BJ, Russo JM, et al. Neurobehavioral evaluation of soil and structural fumigators using methyl bromide and sulfuryl fluoride. Neurotoxicology. 1986;7:137–156. [PubMed]
  • Anger WK, Liang YX, Nell V, Kang SK, Cole D, Bazylewicz-Walczak B, et al. Lessons learned—15 years of the WHO-NCTB: a review. Neurotoxicology. 2000;21:837–846. [PubMed]
  • Anger WK, Sizemore OJ, Grossmann SJ, Glasser JA, Letz R, Bowler R. Human neurobehavioral research methods: impact of subject variables. Environ Res. 1997;73:18–41. [PubMed]
  • Arcury T, Quandt S. Chronic agricultural chemical exposure among migrant and seasonal farmworkers. Soc Nat Resour. 1998;11:829–843.
  • Baldereschi M, Di CA, Vanni P, Ghetti A, Carbonin P, Amaducci L, et al. Lifestyle-related risk factors for Parkinson’s disease: a population-based study. Acta Neurol Scand. 2003;108:239–244. [PubMed]
  • Baldi I, Cantagrel A, Lebailly P, Tison F, Dubroca B, Chrysostome V, et al. Association between Parkinson’s disease and exposure to pesticides in southwestern France. Neuroepidemiology. 2003a;22:305–310. [PubMed]
  • Baldi I, Filleul L, Mohammed-Brahim B, Fabrigoule C, Dartigues J, Schwall S, et al. Neuropsychologic effects of long-term exposure to pesticides: results from the French Phytoner study. Environ Health Perspect. 2001;109:839–844. [PMC free article] [PubMed]
  • Baldi I, Lebailly P, Mohammed-Brahim B, Letenneur L, Dartigues JF, Brochard P. Neurodegenerative diseases and exposure to pesticides in the elderly. Am J Epidemiol. 2003b;157:409–414. [PubMed]
  • Barbosa ER, Leiros da Costa MD, Bacheschi LA, Scaff M, Leite CC. Parkinsonism after glycine-derivate exposure. Mov Disord. 2001;16:565–568. [PubMed]
  • Bazylewicz-Walczak B, Majczakowa W, Szymczak M. Behavioral effects of occupational exposure to organophosphorous pesticides in female greenhouse planting workers. Neurotoxicology. 1999;20:819–826. [PubMed]
  • Beach JR, Spurgeon A, Stephens R, Heafield T, Calvert IA, Levy LS, et al. Abnormalities on neurological examination among sheep farmers exposed to organophosphorous pesticides. Occup Environ Med. 1996;53:520–525. [PMC free article] [PubMed]
  • Behari M, Srivastava AK, Das RR, Pandey RM. Risk factors of Parkinson’s disease in Indian patients. J Neurol Sci. 2001;190:49–55. [PubMed]
  • Bellin JS, Chow I. Biochemical effects of chronic moderate exposure to pesticides. Res Comm Chem Pathol Pharmacol. 1974;9:325–337. [PubMed]
  • Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci. 2000;3:1301–1306. [PubMed]
  • Bhatt MH, Elias MA, Mankodi AK. Acute and reversible parkinsonism due to organophosphate pesticide intoxication: five cases. Neurology. 1999;52:1467–1471. [PubMed]
  • Bidstrup P, Bonnel JA, Beckett AG. Paralysis following poisoning by a new organic phosphorus insecticide (Mipafox): report on two cases. Br Med J. 1953;1:1068–1072. [PMC free article] [PubMed]
  • Bosma H, van Boxtel MP, Ponds RW, Houx PJ, Jolles J. Pesticide exposure and risk of mild cognitive dysfunction. Lancet. 2000;356:912–913. [PubMed]
  • Buchanan D, Pilkington A, Sewell C, Tannahill SN, Kidd MW, Cherrie B, et al. Estimation of cumulative exposure to organophosphate sheep dips in a study of chronic neurological health effects among United Kingdom sheep dippers. Occup Environ Med. 2001;58:694–701. [PMC free article] [PubMed]
  • Burns CJ, Beard KK, Cartmill JB. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945-94: an update. Occup Environ Med. 2001;58:24–30. [PMC free article] [PubMed]
  • Butterfield PG, Valanis BG, Spencer PS, Lindeman CA, Nutt JG. Environmental antecedents of young-onset Parkinson’s disease. Neurology. 1993;43:1150–1158. [PubMed]
  • Calvert GM, Mueller CA, Fajen JM, Chrislip DW, Russo J, Briggle T, et al. Health effects associated with sulfuryl fluoride and methyl bromide exposure among structural fumigation workers. Am J Public Health. 1998;88:1774–1780. [PMC free article] [PubMed]
  • Calvert GM, Plate DK, Das R, Rosales R, Shafey O, Thomsen C, et al. Acute occupational pesticide-related illness in the US, 1998–1999: surveillance findings from the SENSOR-pesticides program. Am J Ind Med. 2004;45:14–23. [PubMed]
  • Chancellor AM, Slattery JM, Fraser H, Warlow CP. Risk factors for motor neuron disease—a case-control study based on patients from the Scottish motor neuron disease register. J Neurol Neurosurg Psychiatry. 1993;56:1200–1206. [PMC free article] [PubMed]
  • Ciesielski S, Loomis DP, Mims SR, Auer A. Pesticide exposures, cholinesterase depression, and symptoms among North Carolina migrant farmworkers. Am J Publ Health. 1994;84:446–51. [PMC free article] [PubMed]
  • Cole DC, Carpio F, Julian J, Leon N. Assessment of peripheral nerve function in an Ecuadorian rural population exposed to pesticides. J Toxicol Environ Health A. 1998;55:77–91. [PubMed]
  • Cole DC, Carpio F, Julian J, Leon N, Carbotte R, De Almeida H. Neurobehavioral outcomes among farm and nonfarm rural Ecuadorians. Neurotoxicol Teratol. 1997;19:277–286. [PubMed]
  • Corrigan FM, Wienburg CL, Shore RF, Daniel SE, Mann D. Organochlorine insecticides in substantia nigra in Parkinson’s disease. J Toxicol Environ Health. 2000;59:229–234. [PubMed]
  • Costa LG, Cole TB, Furlong CE. Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates. J Toxicol Clin Toxicol. 2003;41:37–45. [PubMed]
  • Daniell W, Barnhart S, Demers P, Costa LG, Eaton DL, Miller M, et al. Neuropsychological performance among agricultural pesticide applicators. Environ Res. 1992;59:217–228. [PubMed]
  • Davignon LF, St Pierre J, Charest G, Tourangeau FJ. A study of the chronic effects of insecticides in man. Can Med Assoc J. 1965;92:597–602. [PMC free article] [PubMed]
  • Davis K, Yesavage J, Berger P. Single case study. Possible organophosphate induced parkinsonism. J Nerv Ment Dis. 1978;166:222–225. [PubMed]
  • Deapen D, Henderson BE. A case-control study of amyotrophic lateral sclerosis. Am J Epidemiol. 1986;123:790–799. [PubMed]
  • Dick R, Steenland K, Krieg E, Hines C. Evaluation of acute sensory-motor effects and test sensitivity using termiticide workers exposed to chlorpyrifos. Neurotoxicol Teratol. 2001;23:381–393. [PubMed]
  • Dosemeci M, Alavanja MC, Rowland AS, Mage D, Zahm SH, Rothman N, et al. A quantitative approach for estimating exposure to pesticides in the Agricultural Health Study. Ann Occup Hyg. 2002;46:245–260. [PubMed]
  • Engel LS, Checkoway H, Keifer MC, Seixas NS, Longstreth WT, Jr, Scott KC, et al. Parkinsonism and occupational exposure to pesticides. Occup Environ Med. 2001;58:582–589. [PMC free article] [PubMed]
  • Engel LS, Keifer MC, Checkoway H, Robinson LR, Vaughan TL. Neurophysiological function in farm workers exposed to organophosphate pesticides. Arch Environ Health. 1998;53:7–14. [PubMed]
  • Eskenazi B, Bradman A, Castorina R. Exposures of children to organophosphate pesticides and their potential adverse health effects. Environ Health Perspect. 1999;107(suppl 3):409–419. [PMC free article] [PubMed]
  • Fall PA, Fredrikson M, Axelson O, Granerus AK. Nutritional and occupational factors influencing the risk of Parkinson’s disease: a case-control study in southeastern Sweden. Mov Disord. 1999;14:28–37. [PubMed]
  • Farahat T, Abdelrasoul GM, Amr MM, Shebl MM, Farahat FM, Anger WK. Neurobehavioral effects among workers occupationally exposed to organophosphorous pesticides. Occup Environ Med. 2003;60:279–286. [PMC free article] [PubMed]
  • Fenske RA. Pesticide exposure assessment of workers and their families. Occup Med. 1997;12:221–237. [PubMed]
  • Ferre N, Camps J, Fernandez-Ballart J, Arija V, Murphy MM, Ceruelo S, et al. Regulation of serum paraoxonase activity by genetic, nutritional, and lifestyle factors in the general population. Clin Chem. 2003;49:1491–1497. [PubMed]
  • Fiedler N, Kipen H, Kelly-McNeil K, Fenske R. Long-term use of organophosphates and neuropsychological performance. Am J Ind Med. 1997;32:487–496. [PubMed]
  • Fleming L, Mann JB, Bean J, Briggle T, Sanchez Ramos JR. Parkinson’s disease and brain levels of organochlorine pesticides. Ann Neurol. 1994;36:100–103. [PubMed]
  • Fonseca RG, Resende LAL, Silva MD, Camargo A. Chronic motor neuron disease possibly related to intoxication with organochlorine insecticides. Acta Neurol Scand. 1993;88:56–58. [PubMed]
  • Gauthier E, Fortier I, Courchesne F, Pepin P, Mortimer J, Gauvreau D. Environmental pesticide exposure as a risk factor for Alzheimer’s disease: a case-control study. Environ Res. 2001;86:37–45. [PubMed]
  • Gladen BC, Sandler DP, Zahm SH, Kamel F, Rowland AS, Alavanja MC. Exposure opportunities of families of farmer pesticide applicators. Am J Ind Med. 1998;34:581–587. [PubMed]
  • Gomes J, Lloyd O, Revitt MD, Basha M. Morbidity among farm workers in a desert country in relation to long-term exposure to pesticides. Scand J Work Environ Health. 1998;24:213–219. [PubMed]
  • Gomes J, Lloyd OL, Revitt DM. The influence of personal protection, environmental hygiene and exposure to pesticides on the health of immigrant farm workers in a desert country. Int Arch Occup Environ Health. 1999;72:40–45. [PubMed]
  • Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ. The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology. 1998;50:1346–1350. [PubMed]
  • Granieri E, Carreras M, Tola R. Motor neuron disease in the province of Ferrara, Italy, in 1964–1982. Neurology. 1988;38:1604–1608. [PubMed]
  • Gunnarsson LG, Bodin L, Soderfeldt B, Axelson O. A case-control study of motor neurone disease - Its relation to heritability, and occupational exposures, particularly to solvents. Br J Ind Med. 1992;49:791–798. [PMC free article] [PubMed]
  • Herishanu YO, Medvedovski M, Goldsmith JR, Kordysh E. A case-control study of Parkinson’s disease in urban population of southern Israel. Can J Neurol Sci. 2001;28:144–147. [PubMed]
  • Hernandez-Valero MA, Bondy ML, Spitz MR, Zahm SH. Evaluation of Mexican American migrant farmworker work practices and organochlorine pesticide metabolites. Am J Ind Med. 2001;40:554–560. [PubMed]
  • Hertzman C, Wiens M, Bowering D, Snow B, Calne D. Parkinson’s disease: a case-control study of occupational and environmental risk factors. Am J Ind Med. 1990;17:349–355. [PubMed]
  • Heyer NJ, Bittner AC, Jr, Echeverria D. Analyzing multivariate neurobehavioral outcomes in occupational studies: a comparison of approaches. Neurotoxicol Teratol. 1996;18:401–406. [PubMed]
  • Hines C, Deddens J, Tucker S, Hornung R. Distributions and determinants of pre-emergent herbicide exposures among custom applicators. Ann Occup Hyg. 2001;45:227–239. [PubMed]
  • Hoogenraad T. Dithiocarbamates and Parkinson’s disease [Letter] Lancet. 1988;1:767. [PubMed]
  • Horowitz SH, Stark A, Marshall E, Mauer MP. A multimodality assessment of peripheral nerve function in organophosphate-pesticide applicators. J Occup Environ Med. 1999;41:405–408. [PubMed]
  • Hubble JP, Kurth JH, Glatt SL, Kurth MC, Schellenberg GD, Hassanein RE, et al. Genetoxin interaction as a putative risk factor for Parkinson’s disease with dementia. Neuroepidemiology. 1998;17:96–104. [PubMed]
  • Jamal GA, Hansen S, Pilkington A, Buchanan D, Gillham RA, Abdel-Azis M, et al. A clinical neurological, neuro-physiological, and neuropsychological study of sheep farmers and dippers exposed to organophosphate pesticides. Occup Environ Med. 2002;59:434–441. [PMC free article] [PubMed]
  • Kamel F, Boyes WK, Gladen BC, Rowland AS, Alavanja MC, Blair A, et al. Retinal degeneration in licensed pesticide applicators. Am J Ind Med. 2000;37:618–628. [PubMed]
  • Kamel F, Rowland A, Park L, Anger W, Baird D, Gladen B, et al. Neurobehavioral performance and work experience in Florida farmworkers. Environ Health Perspect. 2003;111:1765–1772. [PMC free article] [PubMed]
  • Karr C, Demers P, Costa L, Daniell W, Barnhart S, Miller M, et al. Organophosphate pesticide exposure in a group of Washington State orchard applicators. Environ Res. 1992;59:229–237. [PubMed]
  • Keifer M, Mahurin R. Chronic neurologic effects of pesticide overexposure. Occup Med. 1997;12:291–304. [PubMed]
  • Korsak RJ, Sato MM. Effects of chronic organophosphate pesticide exposure on the central nervous system. Clin Toxicol. 1977;11:83–95. [PubMed]
  • Kuopio AM, Marttila RJ, Helenius H, Rinne UK. Environmental risk factors in Parkinson’s disease. Mov Disord. 1999;14:928–939. [PubMed]
  • Le Couteur DG, McLean AJ, Taylor MC, Woodham BL, Board PG. Pesticides and Parkinson’s disease. Biomed Pharmacother. 1999;53:122–130. [PubMed]
  • Lee BW, London L, Paulauskis J, Myers J, Christiani DC. Association between human paraoxonase gene polymorphism and chronic symptoms in pesticide-exposed workers. J Occup Environ Med. 2003;45:118–122. [PubMed]
  • Leng G, Lewalter J. Role of individual susceptibility in risk assessment of pesticides. Occup Environ Med. 1999;56:449–453. [PMC free article] [PubMed]
  • Letz R, Green RC, Woodard JL. Development of a computer-based battery designed to screen adults for neuropsychological impairment. Neurotoxicol Teratol. 1996;18:365–370. [PubMed]
  • Levin HS, Rodnitzky RL, Mick DL. Anxiety associated with exposure to organophosphate compounds. Arch Gen Psychiatry. 1976;33:225–228. [PubMed]
  • Lindsay J, Hebert R, Rockwood K. The Canadian Study of Health and Aging: risk factors for vascular dementia. Stroke. 1997;28:526–530. [PubMed]
  • Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, et al. Environmental risk factors and Parkinson’s disease: a case-control study in Taiwan. Neurology. 1997;48:1583–1588. [PubMed]
  • London L, De Grosbois S, Wesseling C, Kisting S, Rother H, Mergler D. Pesticide usage and health consequences for women in developing countries: out of sight, out of mind? Int J Occup Environ Health. 2002;8:46–59. [PubMed]
  • London L, Myers JE. Use of a crop and job specific exposure matrix for retrospective assessment of long-term exposure in studies of chronic neurotoxic effects of agri-chemicals. Occup Environ Med. 1998;55:194–201. [PMC free article] [PubMed]
  • London L, Myers JE, Nell V, Taylor T, Thompson ML. An investigation into neurologic and neurobehavioral effects of long-term agrichemical use among deciduous fruit farm workers in the western cape, South Africa. Environ Res. 1997;73:132–145. [PubMed]
  • London L, Nell V, Thompson M, Myers J. Effects of long-term organophosphate exposures on neurological symptoms, vibration sense and tremor among South African farm workers. Scand J Work Environ Health. 1998;24:18–29. [PubMed]
  • Lundberg I, Hogberg M, Michelsen H, Nise G, Hogstedt C. Evaluation of the Q16 questionnaire on neurotoxic symptoms and a review of its use. Occup Environ Med. 1997;54:343–350. [PMC free article] [PubMed]
  • Mackness B, Durrington P, Povey A, Thomson S, Dippnall M, Mackness M, et al. Paraoxonase and susceptibility to organophosphorus poisoning in farmers dipping sheep. Pharmacogenetics. 2003;13:81–88. [PubMed]
  • Maizlish N, Schenker M, Weisskoph C, Seiber J, Samuels S. A behavioral evaluation of pest control workers with short-term, low-level exposure to the organophosphate diazinon. Am J Ind Med. 1987;12:153–172. [PubMed]
  • McConnell R, Cordon M, Murray DL, Magnotti R. Hazards of closed pesticide mixing and loading systems—the paradox of protective pechnology in the phird world. Br J Ind Med. 1992;49:615–619. [PMC free article] [PubMed]
  • McConnell R, Keifer M, Rosenstock L. Elevated quantitative vibrotactile threshold among workers previously poisoned with methamidophos and other organophosphate pesticides. Am J Ind Med. 1994;25:325–334. [PubMed]
  • McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, et al. Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis. 2002;10:119–127. [PubMed]
  • McDowell I, Hill G, Lindsay J, Helliwell B, Costa L, Beattie L, et al. The Canadian study of health and aging: risk factors for Alzheimer’s disease in Canada. Neurology. 1994;44:2073–2080. [PubMed]
  • McGuire V, Longstreth W, Jr, Nelson L, Koepsell T, Checkoway H, Morgan M, et al. Occupational exposures and amyotrophic lateral sclerosis: a population-based case-control study. Am J Epidemiol. 1997;145:1076–1088. [PubMed]
  • Meco G, Bonifati V, Vanacore N, Fabrizio E. Parkinsonism after chronic exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate) Scand J Work Environ Health. 1994;20:301–305. [PubMed]
  • Miranda J, Lundberg I, McConnell R, Delgado E, Cuadra R, Torres E, et al. Onset of grip- and pinch-strength impairment after acute poisonings with organophosphate insecticides. Int J Occup Environ Health. 2002;8:19–26. [PubMed]
  • Misra U, Nag D, Bushan V, Ray PK. Clinical and biochemical changes in chronically exposed organophosphate workers. Toxicol Lett. 1985;24:187–193. [PubMed]
  • Moses M, Johnson ES, Anger WK, Burse VW, Horstman SW, Jackson RJ, et al. Environmental equity and pesticide exposure. Toxicol Ind Health. 1993;9:913–959. [PubMed]
  • Nelson LM. Epidemiology of ALS. Clin Neurosci. 1995–1996;3:327–331. [PubMed]
  • Nishiwaki Y, Maekawa K, Ogawa Y, Asukai N, Minami M, Omai K, et al. Effects of sarin on the nervous system in rescue team staff members and police officers 3 years after the Tokyo subway sarin attack. Environ Health Perspect. 2001;109:1169–1173. [PMC free article] [PubMed]
  • Ohayo-Mitoko GJ, Kromhout H, Karumba PN, Boleij JS. Identification of determinants of pesticide exposure among Kenyan agricultural workers using empirical modelling. Ann Occup Hyg. 1999;43:519–525. [PubMed]
  • Ohayo-Mitoko GJ, Kromhout H, Simwa JM, Boleij JS, Heederik D. Self reported symptoms and inhibition of acetyl-cholinesterase activity among Kenyan agricultural workers. Occup Environ Med. 2000;57:195–200. [PMC free article] [PubMed]
  • Ohayo-Mitoko GJA, Heederik DJJ, Kromhout H, Omondi BEO, Boleij JSM. Acetylcholinesterase inhibition as an indicator of organophosphate and carbamate poisoning in Kenyan agricultural workers. Int J Occup Environ Health. 1997;3:210–220. [PubMed]
  • Petrovitch H, Ross GW, Abbott RD, Sanderson WT, Sharp DS, Tanner CM, et al. Plantation work and risk of Parkinson disease in a population-based longitudinal study. Arch Neurol. 2002;59:1787–1792. [PubMed]
  • Pilkington A, Buchanan D, Jamal GA, Gillham R, Hansen S, Kidd M, et al. An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers. Occup Environ Med. 2001;58:702–710. [PMC free article] [PubMed]
  • Pope CN. Organophosphorus pesticides: do they all have the same mechanism of toxicity? J Toxicol Environ Health B Crit Rev. 1999;2:161–181. [PubMed]
  • Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS. Environmental risk factors and Parkinson’s disease: a metaanalysis. Environ Res. 2001;86:122–127. [PubMed]
  • Ringman JM, Cummings JL. Metrifonate: update on a new antidementia agent. J Clin Psychiatry. 1999;60:776–782. [PubMed]
  • Ritz B, Yu F. Parkinson’s disease mortality and pesticide exposure in California 1984–1994. Int J Epidemiol. 2000;292:323–329. [PubMed]
  • Rodnitzky RL, Levin HS, Mick DL. Occupational exposure to organophosphate pesticides: a neurobehavioral study. Arch Environ Health. 1975;30:98–103. [PubMed]
  • Rosenstock L, Keifer M, Daniell WE, McConnell R, Claypoole K. the Pesticide Health Effects Study Group. Chronic central nervous system effects of acute organophosphate pesticide intoxication. Lancet. 1991;338:223–227. [PubMed]
  • Ruijten M, Salle HJA, Verberk MM, Smink M. Effect of chronic mixed pesticide exposure on peripheral and autonomic nerve function. Arch Environ Health. 1994;49:188–195. [PubMed]
  • Sack D, Linz D, Shukla R, Rice C, Bhattacharya A, Suskind R. Health status of pesticide applicators: postural stability assessments. J Occup Med. 1993;35:1196–1202. [PubMed]
  • Sanchez-Ramon J, Hefti F, Weiner WI. Paraquat and Parkinson disease [Letter] Neurology. 1987;37:728.
  • Savage E, Keefe TJ, Mounce LM, Heaton RK, Lewis JA, Burcar PJ. Chronic neurological sequelae of acute organophosphate pesticide poisoning. Arch Environ Health. 1988;43:38–45. [PubMed]
  • Savettieri G, Salemi G, Arcara A, Cassata M, Castiglione MG, Fierro B. A case-control study of amyotrophic lateral sclerosis. Neuroepidemiology. 1991;10:242–245. [PubMed]
  • Sechi G, Agnetti V, Piredda M, Canu M, Deserra F, Omar HA, et al. Acute and persistent parkinsonism after use of diquat. Neurology. 1992;42:261–263. [PubMed]
  • Seidler A, Hellenbrand W, Robra BP, Vieregge P, Nischan P, Joerg J, et al. Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: a case-control study in Germany. Neurology. 1996;46:1275–1284. [PubMed]
  • Semchuk K, Love EJ, Lee RG. Parkinson’s disease and exposure to agricultural work and pesticide chemicals. Neurology. 1992;42:1328–1335. [PubMed]
  • Smit LAM, van Wendel de Joode BN, Heederik D, Peiris-John RJ, van der Hoek W. Neurological symptoms among Sri Lankan farmers occupationally exposed to acetyl-cholinesterase-inhibiting insecticides. Am J Ind Med. 2003;44:254–264. [PubMed]
  • Sozmen EY, Mackness B, Sozmen B, Durrington P, Girgin FK, Aslan L, et al. Effect of organophosphate intoxication on human serum paraoxonase. Hum Exp Toxicol. 2002;21:247–252. [PubMed]
  • Stallones L, Beseler C. Pesticide illness, farm practices, and neurological symptoms among farm residents in Colorado. Environ Res. 2002;90:89–97. [PubMed]
  • Steenland K, Dick RB, Howell RJ, Chrislip DW, Hines CJ, Reid TM, et al. Neurologic function among termiticide applicators exposed to chlorpyrifos. Environ Health Perspect. 2000;108:293–300. [PMC free article] [PubMed]
  • Steenland K, Jenkins B, Ames RG, O’Malley M, Chrislip D, Russo J. Chronic neurological sequelae to organophosphate pesticide poisoning. Am J Public Health. 1994;84:731–736. [PMC free article] [PubMed]
  • Stephens R, Spurgeon A, Berry H. Organophosphates: the relationship between chronic and acute exposure effects. Neurotoxicol Teratol. 1996;18:449–453. [PubMed]
  • Stephens R, Spurgeon A, Calvert IA, Beach J, Levy LS, Berry H, et al. Neuropsychological effects of long-term exposure to organophosphates in sheep dip. Lancet. 1995;345:1135–1139. [PubMed]
  • Stewart PA, Prince JK, Colt JS, Ward MH. A method for assessing occupational pesticide exposures of farmworkers. Am J Ind Med. 2001;40:561–570. [PubMed]
  • Stokes L, Stark A, Marshall E, Narang A. Neurotoxicity among pesticide applicators exposed to organophosphates. Occup Environ Med. 1995;52:648–653. [PMC free article] [PubMed]
  • Taylor CA, Saint-Hilaire MH, Cupples LA, Thomas CA, Burchard AE, Feldman RG, et al. Environmental, medical, and family history risk factors for Parkinson’s disease: a New England-based case control study. Am J Med Genet. 1999;88:742–749. [PubMed]
  • Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA. The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson’s disease. J Neurosci. 2000;20:9207–9214. [PubMed]
  • Tielemans E, Louwerse E, de Cock J, Brouwer D, Zielhuis G, Heederik D. Exposure to fungicides in fruit growing: re-entry time as a predictor for dermal exposure. Am Ind Hyg Assoc J. 1999;60:789–793. [PubMed]
  • U. S. EPA Office of Pesticide Programs 2002. FY 2002 Annual Report. Washington, DC:U.S. Environmental Protection Agency. Available: http://www.epa.gov/oppfead1/annual/2002/2002annualreport.pdf [accessed 25 March 2004].
  • van Wendel de Joode B, Wesseling C, Kromhout H, Monge P, Garcia M, Mergler D. Chronic nervous-system effects of long-term occupational exposure to DDT. Lancet. 2001;357:1014–1016. [PubMed]
  • Vincent-Viry M, Sass C, Bastien S, Aguillon D, Siest G, Visvikis S. PON1-192 phenotype and genotype assessments in 918 subjects of the Stanislas cohort study. Clin Chem Lab Med. 2003;41:535–540. [PubMed]
  • Wesseling C, Keifer M, Ahlbom A, McConnell R, Moon J, Rosenstock L, et al. Long-term neurobehavioral effects of mild poisonings with organophosphate and n-methyl carbamate pesticides among banana workers. Int J Occup Environ Health. 2002;8:27–34. [PubMed]
  • White RF, Proctor SP, Heeren T, Wolfe J, Krengel M, Vasterling J, et al. Neuropsychological function in Gulf War Veterans: relationships to self-reported toxicant exposures. Am J Ind Med. 2001;40:42–54. [PubMed]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Science
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...