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Abstract Read article for free, via Unpaywall a legal, open copy of the full text. Alavanja MC ,. Hoppin JA ,. Kamel F. Affiliations All authors 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook. 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. However, other studies of individuals exposed to OPs Ames et al. 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. Visual contrast sensitivity was not affected by exposure to OPs Steenland et al. Retinal degeneration was associated with fungicide exposure in a case—control study of licensed pesticide applicators Kamel et al.
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. Grip strength was not related to exposure to fumigants Anger et al.
Balance is an integrated sensorimotor function. An early study found deficits in balance in apple farmers exposed to multiple pesticides Davignon et al. 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. Effects were most evident when both visual and proprioceptive inputs were removed, suggesting that vestibular function may be affected Kamel et al. 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. One study of fumigators found deficits in nerve conduction Calvert et al. 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.
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. 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.
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. Animal studies suggest that changes in serum paraoxonase activity alter susceptibility to OP toxicity Costa et al. In humans, paraoxonase polymorphisms affect the relationship of OP exposure to both erythrocyte AChE inhibition and symptom prevalence Lee et al. Although Costa et al.
An extensive literature suggests that pesticide exposure may increase risk of Parkinson disease Le Couteur et al. 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. 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 were reviewed by Le Couteur et al. 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. Case—control studies found increased risk associated with possession of a pesticide use license Baldereschi et al.
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. 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. Three case—control studies found no association of pesticide exposure with Parkinson disease Behari et al.
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. Several studies have implicated the herbicide paraquat Hertzman et al. Case reports have described Parkinson disease in individuals exposed to OPs Bhatt et al. 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.
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.
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.
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 — Pesticide exposure has been considered in six case—control studies; three found some evidence for an association Deapen and Henderson ; McGuire et al. Only one study presented detailed exposure information McGuire et al. 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. 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.
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.
Occupational pesticide exposure was also associated with mild cognitive dysfunction in a population-based prospective study Bosma et al. 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 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. 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. 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. 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 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.
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.
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. National Center for Biotechnology Information , U. Journal List Environ Health Perspect v.
Environ Health Perspect. Published online May Freya Kamel and Jane A. Author information Article notes Copyright and License information Disclaimer. Address correspondence to F. Telephone: Fax: E-mail: kamel niehs.
We appreciate the thoughtful comments of D. Baird and M. Longnecker on an earlier version of this paper. Received Mar 30; Accepted May Copyright notice.
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This article has been cited by other articles in PMC. 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. Keywords: fumigant, fungicide, insecticide, neurobehavioral performance, neurodegenerative disease, neurologic symptoms, organophosphate, Parkinson disease, pesticide.
Pesticide Exposure Pesticides are a broad range of substances most commonly used to control insects, weeds, and fungi plant diseases.
Table 1 Studies of chronic pesticide exposure and neurotoxicity: exposure measurement. Reference Exposed population Chemical b Exposure measure c No. Comparison group No. Ames et al. Open in a separate window. 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 Neurotoxicity of Low-Level Exposure Findings from studies of acute exposure to moderate levels of pesticides are inconsistent.
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. Sensory and Motor Dysfunction Neurobehavioral test batteries are often supplemented with tests of sensory or motor function. Nerve Function Studies that have evaluated peripheral nerve conduction have produced largely negative results. Genetic Susceptibility to Pesticide Neurotoxicity Individual response to pesticide exposure may be affected by polymorphisms in genes affecting pesticide metabolism.
Neurodegenerative Disease Parkinson Disease An extensive literature suggests that pesticide exposure may increase risk of Parkinson disease Le Couteur et al. Other Neurodegenerative Diseases Information on pesticide exposure and other neurologic diseases is more limited. Despite the well-documented deleterious effects of pesticides on biological pest control function, the environment, and food safety [ 5 — 7 ], the health effects of these agents have also attracted substantial attention [ 8 ].
Previous studies showed that pesticide exposure often induces acute and chronic neurological toxicity [ 9 — 14 ] and dysfunctional lipid, protein, and carbohydrate metabolism [ 15 ]. However, most surveys used subjective or qualitative measurements, such as symptoms, psychological scales, or clinical signs, to evaluate the health effects of pesticide use [ 16 — 18 ]. For example, one study found that farmers who used a greater amount of pesticides were more likely to suffer from headache, nausea, and skin problems [ 13 ].
These outcomes had limitations in the following two aspects. First, the reported symptoms may not be necessarily pathological. Second, there may be subclinical neuroelectrophysiological changes when no clinical symptoms or signs were found. Our study relies on objective and quantitative measures of neuroelectrophysiology to evaluate health effects of pesticide exposure. Furthermore, the relationship between pesticide exposure and human health remains unclear because the time and extent of pesticide exposure were not sufficiently estimated in many previous studies [ 19 ].
The majority of studies used one-time household survey data to examine the health effects of pesticide exposure [ 9 , 13 , 20 ], and used nonspraying workers [ 21 ] or the general population [ 16 ] as non-exposed controls. While these studies did provide evidence of the adverse health effects of pesticide exposure, it was difficult to effectively control for the potentially confounding health-related factors of each participant and to accurately define exposure level.
The objective of the present study is to use the most detailed neuroelectrophysiological methods to examine the clinical and subclinical health effects of pesticide exposures based on a unique dataset that covers 2 time periods in China.
This study was conducted in Guangdong, Jiangxi, and Hebei provinces, which represent high, middle, and low levels of pesticide applications in China, respectively.
In each province, 2 counties and 2 villages from each county were randomly selected. In each village, 20—25 households were randomly sampled.
In total, households participated in this study. The samples differ slightly in terms of health examinations because a few participants were absent during health investigations S1 Table. Pesticide exposure information was obtained from 2 datasets. We first collected baseline data regarding pesticide use history, household and individual characteristics, and pesticide-related poisoning events via face-to-face interviews.
Participants were asked to report the frequency of pesticide application, and whether they had suffered from headache, nausea, skin irritation, or digestive discomfort that was severe enough to interfere with their work during the past three years — These data were used to assess the long-term health effects of pesticide exposure.
All participants were divided into 2 groups. One group had been exposed to relatively high pesticide levels more than 50 times of pesticide application in —, Group H , and the other group had been exposed to lower pesticide levels less than 50 times of pesticide application in —, Group L. Secondly, participants were asked to record each pesticide application in on the specially designed calendar we had provided them. Moreover, this recording process was supervised by the village leaders under the guidance of the research team.
We checked the record at least once a month to ensure its validity and reliability. We used the frequency of pesticide application in the previous 3 days and 4—10 days to analyze short-term effect of pesticide application. Two rounds of health investigation were conducted. The first was in March , before participants had applied pesticides for their crop production.
The second one was during the course of crop production but prior to crop harvesting. In total, 66 health indicators were examined during health investigations. The list of measured health indicators is shown in S1 Table. Definitions of all measured health variables are provided in S2 and S3 Tables. For each health indicator, abnormality was defined as the corresponding value falls out of the normal range.
All blood samples were obtained after participants had fasted for 12 hours. Samples were centrifuged immediately and transported in a refrigerated state to the same laboratory in Beijing within 8 hours. The tests included a complete blood count CBC , blood chemistry panel e.
The clinical examinations consisted of general and neurological examinations. The former comprised height, weight, and blood pressure measurements. The TNSc was administered to all subjects by two certified neurologists who were trained to ensure the results were comparable.
The TNSc is composed of seven items: sensory symptoms, motor symptoms, autonomic symptoms, pin sensibility, vibration sensibility, muscle strength, and deep tendon reflexes [ 22 ].
For each item, the score ranged between 0 normal and 4 worst , so that the total score range was 0— Participants who received a score of 2 or greater were judged to be abnormal. To control for the impact of confounding factors, multivariate regression analysis was performed. The independent variable of interest, pesticide , takes value of 1 if farmer i is in Group H and zero for Group L. Finally, regional dummies, Guangdong and Jiangxi, were added into the equation.
When, Eq 1 is estimated by the OLS model when indicator is a continuous variable. Otherwise, it is an ordered probit model Dprobit if indicator is a dichotomous variable. In general, pesticides are extensively used by farmers in China. The means of the measured participant characteristics are similar to that of the average farmer in China S4 Table.
On average, participants in the present study applied pesticides on There were varieties of pesticides applied by the farmers between the two rounds of health investigations. Most of them are pyrethroid, organophosphates and others. This may be explained by the fact that farmers in Guangdong used a greater amount of pesticides than those in the other two provinces Table 1.
Table 2 shows the results of two rounds of health investigations. CBC analysis in the first round showed that Blood chemistry tests indicated abnormal renal function in 5. Nerve conduction studies showed high percentages of abnormal DML Similar findings were observed in the TNSc Details of these results are presented in S5 Table.
The number of abnormal health indicators increased significantly in the second round of investigation. For example, results of CBC analysis showed that nearly all participants A large percentage of subjects also demonstrated abnormalities in hepatic function, renal function, electrolyte balance, and TNSc in the second round.
Fig 1 presents the percentages of abnormal cases of major health indicators for Group H and Group L in — The results show a consistent positive relationship between abnormal test results and intensity of pesticide use. This indicates that participants more frequently exposed to pesticides may suffer from CBC, hepatic, renal, glucose metabolic, peripheral, and central neurological ailments.
The eight bar charts showed that the percentages of abnormal cases of major health indicators, including blood routine, hepatic function, renal function, vitamins, glucose, C-reactive protein, TNSc, MMSE, conduction velocity and amplitude, were higher in Group H than in Group L. Multivariate regression analysis was conducted to control for the impact of other factors.
Results showed significant differences in five health indicators between Group H and Group L Table 3 , while no difference was found in the other indicators.
Specifically, participants with greater pesticide exposure had higher white blood cell counts, but lower creatinine and potassium levels. Province dummy variables were included, but not reported.
However, while increases or decreases in the above health indicators were observed in Group H, some scores were still within the normal range. A Probit model was used for estimation. A significant increase in sensory nerve abnormalities relative to motor nerve abnormalities was observed in peripheral nervous system Table 4.
The two rounds of health investigations in the present study allowed for the analysis of the short-term effects of pesticide exposure frequency of pesticide application in the previous three days and in the previous 4—10 days on health indicators. To accomplish this, a fixed effect model was used to control for individual differences, including the accumulated health effects of pesticide exposure prior to the first round of investigation.
CBC analysis showed that pesticide application during the previous three days had significant effects on the majority of selected health indicators, such as monocytes, monocyte percentage, red blood cell, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red cell distribution width coefficient of variation, platelet count, and platelet distribution width Table 5.
However, the effect of prior pesticide exposure on most indicators was absent red blood cell, hemoglobin, platelet count, etc. Similar results were observed in the analysis of short-term health effects of pesticide exposure on blood chemistry tests Table 5 and nerve conduction studies Table 6.
Blood chemistry results from three days post-exposure showed a significant increase in liver enzyme, blood urea nitrogen, and inorganic phosphorus levels; and a decrease in plasma cholinesterase, total protein, sodium, and fasting plasma glucose levels.
However, these effects were not observable at 4—10 days post-exposure. Three CV indicators median motor, ulnar motor, and ulnar sensory were significantly increased at three days post-exposure, but not at 4—10 days post-exposure. The effects of pesticide exposure on health indicators related to DMLs ulnar nerve and amplitudes of CMAP median, ulnar, peroneal and SNAP median, ulnar were negative, which differs from the positive effects on CVs; however, the impact patterns over time are similar.
This study was the first to comprehensively examine the human health effects of frequent pesticide exposure in China. Organophosphate-induced delayed polyneuropathy OPIDN might develop after acute organophosphates exposure [ 12 ], but there was no evidence of such dysfunction after prolonged low-level exposure to organophosphates or other pesticide species [ 23 ].
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