Association of pesticide exposure with neurologic dysfunction and disease

Environmental Health Perspectives, June 15, 2004 by Freya Kamel, Jane A. Hoppin

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 neurotoxic 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. Key words: fumigant, fungicide, insecticide, neurobehavioral performance, neurodegenerative disease, neurologic symptoms, organophosphate, Parkinson disease, pesticide. Environ Health Perspect 112:950-958 (2004). doi:10.1289/ehp.7135 available via http://dx.doi.org/[Online 20 May 2004]

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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 [greater than or equal to] 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 farmworkers 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.

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, farmworkers 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.