Toxicological Sciences 72, 267-271 (2003)
Copyright © 2003 by the Society of Toxicology
ENVIRONMENTAL TOXICOLOGY |
Neuropsychiatric Evaluation in Subjects Chronically Exposed to Organophosphate Pesticides
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* Departamento de Ciências Fisiológicas, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; and
Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, 90035–003 Porto Alegre, RS, Brazil
Received November 12, 2002; accepted January 6, 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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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.
Key Words: organophosphate pesticides; parkinsonism; occupational exposure; acetylcholinesterase; psychiatry.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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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 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; Müller-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 Parkinson’s 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.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This observational study was approved by the Ethics Committee of Hospital São Lucas from Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS).
The first clinical and laboratory evaluation was conducted in a sample of 37 workers from southern Brazil involved in family agriculture of tobacco in December 2001, when they had been working with OP for 3 months. At the time of evaluation, all subjects had been exposed to OP within the last day. The second evaluation was conducted in 25 workers from the initial sample who returned in March 2002, when they had been off exposure for 3 months.
Clinical evaluation.
Demographic features, alcohol and tobacco use, OP exposure (time and type of exposure, use of protective equipment, and history of acute toxicity) were evaluated using a structured questionnaire by RMS. Two trained psychiatrists (D.R.L. and E.S.G.) assessed the presence of:
- Psychiatric symptoms using the Mini-International Neuropsychiatric Interview (M.I.N.I.) (Sheehan et al., 1998), which is a structured interview that allows rapid diagnosis of the main psychiatric disorders;
- Parkinsonism using the Extrapyramidal Symptom Rating Scale (ESRS) (Chouinard et al., 1980), which includes a questionnaire for complaints and a physical examination concerning parkinsonian symptoms;
- Cognitive ability using the mini-mental and word span tests, which address major cognitive function such as orientation, immediate and short-term memory, and naming and sequencing (Folstein et al., 1975).
Cholinesterase monitoring.
Acetylcholinesterase activity was measured in a blood sample (10 ml) collected in tubes containing EDTA. The activity was determined in plasma by using a colorimetric technique previously described by Ellman et al. (1961) and Kolf-Clauw et al. (2000).
Statistical analysis.
Comparisons between the two evaluations were performed with ANOVA for symmetric variables and the Wilcoxon test for asymmetric variables such as the scales scores. Statistical significance was defined as p < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The demographic characteristics and exposure history of subjects are listed in Table 1
. Importantly, although all subjects had a clear exposure to OP, only a minority used individual protection, which was considered unimportant, expensive, or uncomfortable to use for many hours. The OPs chlorpyriphos and acephate were the predominant pesticides used by this group of workers for the past 4 years.
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The most common symptoms found in the clinical examination and interview were fatigue (12), headache (5), hypertension (3), and dermatitis (3). Thirteen workers (52%) had a lifetime history of at least mild cholinergic syndrome, with diarrhea, abdominal pain, and sialorrhea, but only one had to be hospitalized and treated pharmacologically. However, none had a history of acute manifestations of cholinergic syndrome within the previous year.
Plasma acetylcholinesterase activity levels of all subjects were within the normal range according to Brazilian policies (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), although the time off exposure had been sufficient (more than 60 days) to normalize the enzyme activity if it had been inhibited (Cocker et al., 2002).
Clinically significant extrapyramidal symptoms were present in 12 subjects (Fig. 1), as evidenced by a total score of parkinsonism of 5 or more in the ESRS, which can be considered above the normal range, especially in a population of this age. As can be seen in Table 2 and Figure 1, although there was a considerable and statistically significant reduction of extrapyramidal symptoms after 3 months without exposure to OP, 9 subjects still had clinically significant symptoms as evidenced by a total score of 5 or more in the ESRS. Unlike what is observed with antipsychotic treatment, which also induces parkinsonism, significant akathisia was not observed and did not change after washout of OP. Tremor was the predominant symptom in 6 and absent in 3 of these 12 subjects with clinically significant parkinsonism. Facial mask and reduced pendular arm movement were commonly observed. Improvement in the second evaluation was quite uniform for all symptoms. Mini-mental and word span scores were within the expected range for this population and were not influenced by exposure to OP (Table 2).
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The number of current AXIS I psychiatric diagnoses (36 for 37 subjects) during exposure to OP was higher than expected, particularly anxiety disorders and depression (Table 3
). Eighteen of the 37 subjects (48%) had a current psychiatric diagnosis in the first interview, 13 (35%) with a current diagnosis of generalized anxiety disorder and 8 (21%) with a current episode of major depression. Among the 25 subjects who completed both evaluations, the total number with psychiatric diagnoses, after 3 months without OP exposure, declined from 24 to 13, and the number of affected individuals with any psychiatric diagnosis dropped from 11 to 7, which is close to what is expected for this group according to epidemiological studies in our state (Almeida-Filho et al., 1997).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Family agriculture workers are prone to long-term exposure to relatively low levels of OP agents. These workers are daily exposed, use little protection due to cultural and economic reasons, and underestimate the toxicity of OP. In this context, it is expected that adaptations and tolerance to the effects of OP take place. Acetylcholinesterase activity was not a valid parameter for monitoring health consequences of chronic OP exposure, since there was a relatively high rate of extrapyramidal and psychiatric symptoms, which considerably declined after OP washout for 3 months despite unchanged plasma acetylcholinesterase activity. Our results are in accordance with those of Nava et al. (1999)
, who found normal acetylcholinesterase activity in patients exposed to OP who also presented psychomotor alterations, cognitive slowing, memory and attention deficits, and other psychiatric symptoms. Indeed, long-term exposure to relatively low levels of OP may result in the development of tolerance to many clinical effects seen after acute exposures, possibly due to downregulation or functional adaptation of central muscarinic and nicotinic receptors, a compensatory response to elevated acetylcholine levels (Prendergast et al., 1998). However, these alterations are expected to be associated with inhibited acetylcholinesterase activity, which was not found in our study.
Descriptions of enduring parkinsonism following chronic OP occupational exposure are scarce. Despite the reduction in extrapyramidal symptoms seen in the second examination, parkinsonism remained clearly higher than expected for a healthy population of this age, which included mostly subjects under the age of 60, when primary Parkinson’s disease is rare. The pathophysiological mechanisms for this condition are unclear, but Bhatt et al. (1999) suggested that the absent response to levodopa might indicate striatal dopamine receptor dysfunction. Our results indicate that whatever the mechanism involved, alterations are likely to be permanent. Moreover, although parkinsonism was found in this sample, cognition was not clearly affected and was unchanged after washout of OP, suggesting at least some degree of specificity towards the motor system.
The present results reinforce the previous observations from Stallones and Beseler (2002) of behavioral changes, such as anxiety and depression, as sequelae of OP poisoning in a population exposed to OP agents. Another case-control study (79 subjects) conducted by Jamal et al. (2002) found that increasing severity of neuropathy induced by OP was accompanied by anxiety and depression as measured with neuropsychological tests. Finally, the study conducted by Sánchez-Amate et al. (2001) in rats showed clear behavioral changes as an acute effect of chlorpyriphos poisoning in the absence of any classic sign of cholinergic syndrome.
Certain methodological issues of our study must be considered. First, this series consisted only of chronically exposed workers, so these findings must be recognized as being limited to a special group of subjects. Second, the study investigators were actively looking for psychiatric and neurologic morbidity; therefore, the inclusion of an unexposed group keeping the interviewers blind to history of pesticide exposure could be useful; on the other hand, the use of structured interview and physical examination attenuated this bias and there was no a priori hypothesis regarding the persistence of symptoms in the follow-up examination. Third, affected subjects might have enrolled at a higher rate in the study because of their awareness of potential health problems produced by pesticides. Moreover, the lack of a healthy comparison group without OP exposure in this study precludes more definite conclusions, and it also should be taken into account that subjects in our study frequently used two or more compounds, possibly resulting in drug interactions among these compounds, their metabolites, and also with organic solvents often present in commercial formulations. Finally, subjects may have been exposed to a residual level of OP in clothes, equipment, and food, even after occupational use was halted; and other uncontrolled factors present in only one of the examined subjects might have influenced the results.
In conclusion, this study reinforces the need for parameters other than acetylcholinesterase activity to monitor for chronic consequences of low-dose OP exposure and suggests that subjects have not only transient motor and psychiatric consequences while exposed, but may also present enduring extrapyramidal symptoms. We also emphasize that pesticides other than pyridine-like compounds and rotenone, such as those evaluated in this study, may induce significant neurological and psychiatric symptoms, warranting further investigation and prompting further educational and safety measures for exposed subjects.
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ACKNOWLEDGMENTS |
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This study was supported by CNPq, PRONEX (#41960904) and Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS). We are grateful for the collaboration of Instituto de Toxicologia and Pró-Reitoria de Pesquisa e Pós-Graduação of PUCRS, and the communities involved.
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NOTES |
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1 Present address: Departamente de Ciências de Saúde 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: diogo{at}ufrgs.br.
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