Neuropsychiatric Evaluation in Subjects Chronically Exposed to Organophosphate Pesticides

Rosane Maria Salvi 1 Diogo R. Lara 1 Eduardo S. Ghisolfi 1 Luis V. Portela 1 Renato D. Dias 1 Diogo O. Souza 0 0 Instituto de Ciencias Ba sicas da Sau de, Departamento de Bioqu mica, Universidade Federal do Rio Grande do Sul , 90035- 003 Porto Alegre, RS , Brazil 1 Departamento de Ciencias Fisiolo gicas, Faculdade de Biociencias, Pontif cia Universidade Cato lica do Rio Grande do Sul (PUCRS) , Porto Alegre , Brazil Long-term exposure to low levels of organophosphate pesticides (OP) may produce neuropsychiatric symptoms. We performed clinical, neuropsychiatric, and laboratory evaluations of 37 workers involved in family agriculture of tobacco from southern Brazil who had been exposed to OP for 3 months, and in 25 of these workers, after 3 months without exposure to OP. Plasma acetylcholinesterase activity levels of all subjects were within the normal range (3.2 to 9.0 U/l) and were not different between on- and off-exposure periods (4.7 0.9 and 4.5 1.1 U/l, respectively). Clinically significant extrapyramidal symptoms were present in 12 of 25 subjects, which is unexpected in such a population. There was a significant reduction of extrapyramidal symptoms after 3 months without exposure to OP, but 10 subjects still had significant parkinsonism. Mini-mental and word span scores were within the expected range for this population and were not influenced by exposure to OP. Eighteen of the 37 subjects (48%) had current psychiatric diagnoses in the first interview (13 with generalized anxiety disorder and 8 with major depression). Among the 25 subjects who completed both evaluations, the total number of current psychiatric diagnoses, after 3 months without using OP, dropped from 24 to 13 and the number of affected individuals with any psychiatric diagnosis dropped from 11 to 7. In conclusion, this study reinforces the need for parameters other than acetylcholinesterase activity to monitor for chronic consequences of chronic low-dose OP exposure, and it suggests that subjects have not only transient motor and psychiatric consequences while exposed, but may also develop enduring extrapyramidal symptoms. - Long-term exposure to relatively low levels of organophosphate pesticides (OP) agents occurs in a variety of environments. Pesticides are often applied in a combination with several classes of compounds featuring synergistic interactions. In southern Brazil, agricultural workers involved in 1 Present address: Departamente de Ciencias de Saude da Universidade Regional Integrada do Alto Uruguai e das Missoes (URI), Frederico Westphalen, RS, Brazil. 2 To whom correspondence should be addressed. Fax: (55 51) 3316 5540. E-mail: . tobacco plantation use a combination of OP (chlorpyrphos and acephate), herbicides (glyphosate and clomazone), plant growth regulators (flumetralin), fungicides (iprodione), and insecticides (imidacloprid). Exposure to OP is known to induce clinical syndromes and biochemical alterations in humans. Besides acute cholinergic symptoms, which are related to the inhibition of acetylcholinesterase activity, acute or chronic OP exposure can also induce delayed toxic and behavioral effects not clearly related to the inhibition of esterases (Brown and Brix, 1998; Jamal, 1997; Mileson et al., 1998; Peter and Cherian, 2000; Sudakin et al., 2000). Most of the actions of OP on the nervous system seem to be related to organophosphorylation of protein targets, as acetylcholinesterase and neuropathy target esterase, or directly to binding of OP to nicotinic receptors (Mileson et al., 1998). The clinical syndromes regarding organophophorus toxicity are: Acute cholinergic syndrome, due to the inhibition of acetylcholinesterase activity, which occurs within minutes or hours following exposure, usually subside within days or weeks, and plasma or erythocytic acetylcholinesterase activity are used for monitoring acute exposure to OP (Lessenger and Reese, 1999); Intermediate syndrome, which usually starts 24 to 96 hours after the acute syndrome and is characterized by respiratory paresis, weakness, depressed tendon reflexes, and transient extrapyramidal symptoms, without response to treatment with the cholinergic receptor antagonist atropine (Bhatt et al., 1999; Guadarrama-Naveda et al., 2001; Mileson et al., 1998; Mu ller-Vahl et al., 1999; Senanayake and Johnson, 1982; Shahar and Andraws, 2001); Organophosphate-induced delayed neuropathy, which is a symmetric distal neuropathy, usually occurring weeks following an acute exposure probably related to the inhibition of the enzyme neuropathy-target esterase present in the nervous system (Aiuto et al., 1993; Moretto and Lotti, 1998; Ray and Richards, 2001). Chronic organophosphate-induced neuropsychiatric disorders (COPIND) are a less well-characterized syndrome in chronic OP poisoning. COPIND may be caused by chronic low-level exposure to OP, without cholinergic symptoms (Ray and Richards, 2001). The underlying mechanisms are not established, but are not dependent on inhibition of esterases (Levin et al., 1976; Prendergast et al., 1998). The most common clinical symptoms include impairment in memory, concentration, and learning; anxiety, depression, psychotic symptoms, chronic fatigue, peripheral neuropathy, autonomic dysfunction and extrapyramidal symptoms such as dystonia, resting tremor, bradikynesia, postural instability and rigidity of face muscles; and nonresponsiveness to levodopa treatment. Regarding psychiatric symptoms, Amr et al. (1997) found that, compared to controls, subjects heavily exposed to pesticides (40 h/week, 9 months/year) had a significant increase in the frequency of psychiatric disorders, especially depressive neurosis and dysthymic disorder (DSM-III-R). These results left unresolved the issue of reversibility of psychiatric symptoms after a pesticide-free period and the occurrence of the syndrome in subjects not so heavily exposed to OP compounds. Another confounding factor in these studies has been the exposure to several types of pesticides, including pyridine compounds, which have been shown to reproduce features of Parkinsons disease (Betarbet et al., 2000). Among OP commonly used in our population, chlorpyriphos has been reported to induce these syndromes, including anxiety, depression, and transient parkinsonism (Aiuto et al., 1993; Guadarrama-Naveda et al., 2001; Kaplan et al., 1993; Moretto and Lotti, 1998; Richardson, 1995; Steenland et al., 1994; Stokes et al., 1995). Other pesticides currently used (glyphosate, clomazone, flumetralin, iprodione, and imidacloprid) have not been related to neurotoxicity. The present study was undertaken at two different moments (under current use of OP for 3 months, and after 3 months without OP exposure) to evaluate clinical, psychiatric, and extrapyramidal symptoms, as well as plasma acetylcholinesterase activity, in a sample of workers chronically exposed to these OP. MATERIALS AND METHODS This observational study was approved by the Ethics C (...truncated)