Elsevier

Neurotoxicology and Teratology

Volume 27, Issue 2, March–April 2005, Pages 259-266
Neurotoxicology and Teratology

Neuropsychological effects of long-term exposure to organophosphate pesticides

https://doi.org/10.1016/j.ntt.2004.12.002Get rights and content

Abstract

Cholinesterase inhibitors, such as carbamates and organophosphates (OPs), are widely used as insecticides and pesticides and may be stored as biological weapons. The massive use of these products, along with a lack of personal protective equipment on the job, and accidental and intentional ingestions, has produced a great number of poisonings in farmers. A large part of the employment and income in southeastern Spain is concentrated in intensive greenhouse agriculture in which growers are exposed to a varying degree of subsymptomatic doses of a combination of pesticides, mainly OPs and carbamates. We conducted a cross-sectional survey of workers in high-exposure conditions to assess possible neurobehavioral deficits, using a wide array of tasks to test neuropsychological functioning and emotional status. Linear and logistic regression series revealed the importance of the variable “years working with pesticides” as a measure of cumulative exposure for risk of worsened perceptive function performance (odds ratio (OR)=6.93, 95% confidence interval (CI):1.52–31.51), visuomotor praxis (OR=5.00, 95% CI:1.22–20.40) and integrative task performance time (OR=4.12, 95% CI:1.18–14.39) with no relation to plasma cholinesterase activity as a measure of recent exposure. This association was statistically significant after controlling for confounds (age and educational level). The findings showed association of long-term exposure and worse performance in neuropsychological functions, which is interpreted as evidence of a chronic effect of cumulative high exposure to OPs and carbamates.

Introduction

Cholinesterase inhibitors (CEI), such as carbamates and organophosphates (OPs), have been widely used and studied since the 19th century. The discovery of the action of physostigmine (a reversible inhibitor of cholinesterase) in the treatment of myasthenia gravis, has since been extended to the synthesis and development of other carbamates and related substances (donepezil, tacrine) in the treatment of Alzheimer disease [8], [15], [16].

CEIs are also widely used as insecticides and pesticides, and some of them (extremely toxic) are manufactured and stored as biological weapons. This last use has generated several studies about the Gulf War syndrome in soldiers [20] and the chronic neurobehavioral effects of a terrorist attack using sarin in Tokyo [37].

The main acute effect of CEI poisoning is the cholinergic syndrome: muscarinic and nicotinic symptoms due to accumulated acetylcholine (ACh) in the synaptic space [21], [32]. This effect seems to be due to phosphorylation (OPs) or carbamylation (carbamates) of the active cholinesterase (ChEs) molecule site [15].

In some cases of CEI poisoning, the short and long-term chronic neurological and neuropsychological effects of severe poisoning have been shown. In addition to Organophosphorus Ester-Induced Delayed Neuropathy, neuropsychological sequelae have been reported [24], [25], [28], [29], [35], even when the cholinesterase level has returned to normal. Cognitive deficits vary in these studies, depending mainly on the type of tasks employed and poisoning variables (type of product, time since poisoning, physical sequelae). Language, attention and mnesic dysfunction have been described, as well as psychomotor, visuomotor and coding-skill disturbances and even irritability, depression and neuropsychiatric symptoms.

In recent decades, a number of studies have investigated the neurological, neuropsychological and neurophysiological symptoms caused by continuous or repeated exposure to CEIs, mainly in farm workers [11], sheep dippers [10], [30], and military personnel who took part in the Gulf War [20]. The results of studies that attempt to assess the central nervous system functions using standard neuropsychological tests point to diverse long-term deficits unrelated to the acute effects of enzyme inhibition in exposed groups. Age, education, smoking and coffee consumption were usually controlled. However, while they found different outcomes, they did share the idea of the existence of a neurocognitive dysfunction after long-term exposure. The more impaired functions were those involved in information selection, information processing, associative memory, reasoning and abstraction.

In southeastern Spain, a large part of employment and income is concentrated in intensive agriculture in greenhouses. The proliferation of pests due to the characteristics of greenhouses (enclosed, high temperature and humidity) is responsible for the continuous exposure of much of the population to varying degrees of sub-symptomatic doses of a combination of pesticides, mainly OPs and carbamates.

Therefore, the purpose of this study was to assess possible neurobehavioral deficits in agricultural workers from occupational exposure to pesticides, mostly, but not exclusively CEIs, for a varying number of years, under conditions that result in high levels of exposure.

Section snippets

Study subjects

We conducted a cross-sectional study in southeastern Spain during the months of March and April 1998. The exposed population was made up of current OP and/or carbamate pesticide sprayers in greenhouses in the province of Almería. A sample of farm workers who had been pesticide applicators for 6 months to 30 years was constructed. The workers recruited were of the same sex (male), ethnicity and culture, with at least 4 years of education (see Table 1). All had been chronically exposed to CEIs,

Characteristics of study group

Control subjects and exposed workers were similar in age, education and cholinesterase level as shown by t values and the associated probability (see Table 1). Logically, the exposed group had a higher cumulative value from occupational exposure during years of working with pesticides, due to the selection of the control subjects (exclusion criteria: exposure to toxic substances).

Analysis of lifetime cigarette smoking showed that the mean number of cigarettes per day was similar in both groups

Discussion

The purpose of this study was to assess neuropsychological dysfunctions and emotional disturbances due to continued subsymptomatic exposure to CEI pesticides, testing the performance of two groups of subjects, one chronically exposed to CEIs and a control, in a neuropsychological battery. Two measures of CEI exposure were taken: a marker of recent exposure (BuChE levels) and a measurement of cumulative exposure (the number of years working with pesticides with a lifetime questionnaire).

The mean

Acknowledgements

This research was supported by research grant PM 96-0102 (MEC, Spain) and PM 99-0146 (MCYT, Spain). Thanks to Deborah Fuldauer and Simon Peter K. Smith for the English language correction. We also wish to thank the two anonymous referees for their helpful comments on the original version of the manuscript.

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