E
Effects of Long-Term Exposure to Organophosphate Pesticides in Humans
This appendix briefly reviews the epidemiological evidence for the long-term health effects of human exposure to organophosphates (OP) used as pesticides.1 OP pesticide epidemiology has a bearing on the question of sarin toxicity for two primary reasons. First, the mechanism of action of OP pesticides and sarin is similar: they both bind to and inactivate acetylcholinesterase (AChE), thereby inducing elevations in the neurotransmitter acetylcholine (ACh) leading to an acute cholinergic syndrome. Their differences relate primarily to potency and duration of binding to AChE (Sidell and Borak, 1992). Second, OP pesticide exposures are much more common than sarin exposure, yielding greater evidence for examining potential health effects. There are about 10,000 cases of OP pesticide poisoning in the United States each year (cited in Steenland et al., 1994). This appendix addresses two questions related to OP poisoning:2
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What are the long-term health effects of an acute episode of OP poisoning?
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What are the long-term health effects of chronic low-level OP exposure (i.e., at levels insufficient to produce symptoms or signs of an acute cholinergic syndrome)?
The committee restricted its review to major controlled epidemiologic studies that evaluated neurological, neuropsychological, and/or psychiatric symptoms and conditions in exposed versus unexposed individuals.3 The committee excluded papers with only neurophysiological outcome measures, such as nerve conduction velocity or vibrotactile thresholds, because these appeared to be further removed from the symptoms typically reported by Gulf War veterans at the time of the committee’s literature review. It was only later that Roland and colleagues (2000) reported on vestibular dysfunction in a small group of Gulf War veterans. This review is limited to publications after 1980, but earlier research supports the basic findings described here (Tabershaw and Cooper, 1966; Rodnitzky et al., 1975; Levin and Rodnitzky, 1976). A complete review of the health effects of OP pesticide exposure will be undertaken by the Institute of Medicine (IOM) in the second phase of this study.
Tables E.1 and E.2 summarize the major features of 15 published studies since 1980 that compare exposed and unexposed individuals to estimate the health effects of OP pesticide exposure. Table E.1 summarizes six studies that demonstrate the longer-term sequelae of OP pesticide poisoning. Table E.2 summarizes 10 studies, one of which is also included in Table E.1, that provide evidence of the longer-term health effects of chronic exposure to OP pesticides at levels insufficient to cause acute effects. Nearly all such studies are cross sectional, observational studies, which by nature are subject to common epidemiologic biases, including selection bias and reporting or information bias (see Chapter 3).
LONGER-TERM HEALTH EFFECTS OF ACUTE OP PESTICIDE POISONING
Table E.1 presents findings from six studies reporting on five distinct populations. All the studies were cross sectional, with neurological, neuropsychological, and/or psychiatric outcomes and with previous poisoning by an organophosphate as the main exposure variable. The time at which the health outcome was typically measured was years after the reported poisoning.
In four of the five populations, neuropsychological performance was significantly poorer in the group with previous poisoning (Savage et al., 1988; Rosenstock et al., 1991; Reidy and Bowler, 1992; London et al., 1998). In the fourth population (Steenland et al., 1994), the trend for neuropsychological performance was in the same direction as in the other four studies, but the difference did not achieve statistical significance. The fifth population was actually a subgroup of the fourth. In this subgroup, the poisoning was not sufficient to
cause hospitalization but was significant enough to depress blood cholinesterase levels by 60–70 percent. This study did not find consistent differences between exposed and unexposed populations (Ames et al., 1995). Three of the five populations exhibited increased rates of neurological or psychiatric symptoms in the previously poisoned group (Rosenstock et al., 1991; Reidy and Bowler, 1992; London et al., 1998).
Taken together, these cross sectional studies report a consistent tendency toward poorer neuropsychological performance and increased rates of neurological or psychiatric symptoms among persons with prior acute OP poisoning. The time from poisoning until evaluation in these studies is poorly documented but is typically on the order of years.
In each of these studies, analyses were conducted using exposure measured by previous acute exposure (“poisoning”). The poisonings were documented in most subjects on the basis of symptom reporting, hospitalization, and/or depressed cholinesterase levels. For example, the poisoned group studied by Rosenstock and colleagues (1991) had been hospitalized for OP poisoning and had no previous serious neurological or mental disorders. Steenland and colleagues (1994) obtained subjects from the State of California registry of OP poisoning. Given the severity of OP poisoning, there is likely to be little misclassification on this measure. The neuropsychological tests used in these investigations are varied, but are typically standardized and well defined, so that differential misclassification of the response is also unlikely.
Information bias is of greater concern in self-reported psychiatric and neurological symptoms. Persons previously poisoned who had suffered significant health consequences of OP pesticide exposure might be likely to report current symptoms differentially from persons not previously poisoned. The other major potential source of bias in these studies involves confounders that have not been adequately controlled for. Only one of the four studies (London et al., 1998) controlled for chronic OP exposures since the acute event. Hence, it is not possible to be sure that the longer-term sequelae of OP poisoning were due to the exposure that caused the original “poisoning” rather than to subsequent chronic exposures. London and colleagues (1998) did include prior poisoning and current job status as predictors of neurological symptoms and both were statistically significant—indicating that there may be health effects from chronic exposure (job status) over and above those from an acute exposure. There was little control for confounding in the study by Rosenstock and colleagues (1991) where OP exposure effects were most substantial. However, London and colleagues (1998) had the most detailed control for confounders and still found differences between exposed and unexposed groups.
In summary, the available literature indicates that exposure to OP pesticides at levels sufficient to cause acute health effects requiring medical reporting or treatment is associated with elevated rates of neurological or psychiatric symptoms and poorer performance on standardized neuropsychological tests several years after the acute exposure.
HEALTH EFFECTS OF CHRONIC LOW-LEVEL EXPOSURE TO OP PESTICIDES
Evidence on the health effects of chronic exposure to OP pesticides is presented in Table E.2, which lists results from 10 studies. Eight were cross sectional, one was longitudinal (Daniell et al., 1992), and another was a case-control study (Pickett et al., 1998). The cross sectional and longitudinal studies studied a total of 1,456 chronically exposed individuals and 817 controls. The case-control study compared the exposure to pesticides in 1,457 suicide cases to the exposure for 11,656 controls matched by age and province. One additional study by Burns and colleagues (1998) was not included in this review. Although this study presented important evidence on 496 workers at Dow Chemical who were chemically exposed to chlorpyrifos over a 17-year period compared to 911 workers who were not exposed, it was not possible to evaluate the findings because the duration of exposure, which differed substantially between the two groups, was not available from the paper, and apparently was not taken into account in the analysis. The study by London and colleagues (1998) is also included in the previous section.
The health outcomes in the eight cross sectional and one longitudinal study include neurological symptoms, neuropsychological tests, and psychiatric symptoms. The exposure variable was, in most cases, an indicator of whether the person’s job involved exposure to OP pesticides or not. In cases where more detailed exposure information was available, it was most often not used in the formal analysis.
The only longitudinal study with repeated health assessments tested 57 applicators and 50 controls before and after a 6-month spraying season (Daniell et al., 1992). They found a pre–post change for only one neuropsychological (NP) test—the Symbol Digit test—which was significantly worse among applicators. Among the cross sectional studies, four conducted NP test batteries (Stephens et al., 1995; Fiedler et al., 1997; Gomes et al., 1998; London et al., 1998). Only Gomes and colleagues (1998) found poorer performance among exposed individuals on a substantial number of tests. This result was not replicated in the other three studies. These findings contrast with those studying people who were acutely poisoned (see previous section) where many NP test results were consistently poorer in the exposed group.
Six of the studies assessed neurological or psychiatric symptoms either by physician examination or by self-report. In five of the six studies, there was a statistically significant increase in the prevalence of symptoms. For example, Ciesielski and colleagues (1994) found increased likelihood of symptoms among persons with self-reported exposures. Stephens and colleagues (1995) reported increased vulnerability to psychiatric disorder as measured by the General Health Questionnaire. In the study of an Egyptian population, exposed workers had higher prevalence of depression, irritability, and erectile dysfunction (Amr et al., 1997). London and colleagues (1998) found that applicators were twice as likely as nonapplicators to have a higher overall neurological symptom score,
TABLE E.1 Human Studies of Organophosphate (OP) Pesticide Poisonings
Reference |
Population |
|
||||
Exposed |
Control |
Health Outcomes |
Exposure |
Adjustment |
Results |
|
Rosenstock et al., 1991 |
35 hospitalized for OP poisoning |
25 no prior OP poisoning |
NP battery, psychiatric exam 1–3 years after hospitalization |
OP poisoned or not |
Matching: age |
NP and psychological symptoms poorer in exposed group |
|
Population based; Leon, Nicaragua |
|
||||
Reidy and Bowler, 1992 |
21 field workers with documented acute toxicity |
11 cannery workers |
NP battery; symptoms questionnaire |
Acute toxicity or not |
Matching: age, sex, education, SES |
NP poorer for acute toxicity group |
Steenland et al., 1994 |
128 men; OP poisoning |
90 male friends of exposed; no poisoning |
Neurological tests; NP battery; Neurological exam 1–9 years after poisoning |
OP poisoned or not |
Regression: age, race, body mass index, language, alcohol, sleep, smoking, coffee, medications, current exposure |
Trend only for NP poorer in exposed group |
|
California registry—same as Ames, 1995 |
Savage et al., 1988 |
100 OP poisonings |
100 no poisoning |
EEG and NP battery; neurological exam decades after poisoning |
OP poisoned or not |
Matching: age, gender, education, occupation, socioeconomic status (SES), race, ethnicity |
NP and EEG tests poorer in exposed group; no differences in physical or neurological exams |
|
Colorado and Texas registries, 1950–1976 |
|||||
Ames et al., 1995 |
45 men cholinesterase inhibited (CI) |
90 friends not CI |
See Steenland et al., 1994 |
Cholinesterase inhibited or not |
See Steenland et al., 1994 |
No differences |
|
California—same as Steenland et al., 1994 |
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London et al., 1998 |
164 pesticide applicators |
83 workers |
NP battery, neurological symptoms, vibration sense, motor tremor |
Prior poisoning, current applicator; long-term exposure by questionnaire |
Regression: age, height, education, numeracy, visual acuity, alcohol, prior brain injury, current applicator |
Neurological symptoms more prevalent among persons with prior poisoning controlling for current applicator status |
|
South African fruit farms |
TABLE E.2 Studies on Persons Not Previously Poisoned by Organophosphate (OP) Pesticides
Reference |
Population |
|
||||
Exposed |
Controls |
Health Outcomes |
Exposure |
Adjustment |
Results |
|
Daniell et al., 1992 |
49 male pesticide applicators in orchards |
40 slaughterhouse workers |
Pre–Post NP battery |
Pre–post measures over few months; applicator vs. control; cholinesterase levels |
Preseason NP performance |
Controlling for baseline NP performance, only symbol digit was worse in postseason for applicators |
|
Washington State |
|||||
Ciesielski et al., 1994 |
202 farmworkers |
42 nonfarmworkers |
Self-reported symptoms over prior week |
Self-reported pesticide exposure over prior month; erythrocyte cholinesterase levels |
None |
Only odds of diarrhea higher for subjects with low AChE; odds of many symptoms higher among persons with higher self-reported exposures including dysgeusia |
|
Two community health centers in North Carolina |
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Stephens et al., 1995 |
146 sheep farmers or dippers, no dipping in prior 2 months |
143 quarry workers |
NP battery, psychiatric symptoms (GHQ) |
Sheep farmer vs. control; lifetime exposure by questionnaire |
Regression: age, education, alcohol, comp. experience, language, time of day, smoking, accuracy |
Sheep farmers worse on sustained attention and processing speed; greater vulnerability to psychiatric disorder on GHQ |
|
British Wool Marketing Board |
Beach et al., 1996 |
20 sheep farmers, 10 highest symptoms; 10 lowest symptoms after dipping |
10 quarry workers |
Neurological exam several months after dipping |
Farmers with or without acute symptoms vs. quarry workers |
None |
Only two-point discrimination on hand– foot poorer among exposed farmers |
|
Population-based sample—British Wool Marketing Board |
|||||
Amr et al., 1997 |
208 workers at chemical (OP) manufacturing plant; 172 pesticide applicators |
72 textile workers; 151 community controls |
Psychiatric symptoms by GHQ |
Chemical vs. textile workers |
Matched by community, age, SES |
Chemical workers or applicators had higher prevalence of depression, irritability, and erectile dysfunction |
Fiedler et al., 1997 |
57 male tree fruit farmers; no poisoning |
42 berry farmers or hardware store workers |
NP battery (NES); psychiatric assessment (MMPI-2) |
Exposed group or not; lifetime exposure by questionnaire |
None; regression: age, reading score |
Only simple reaction time poorer in high-exposure group |
|
New Jersey |
|||||
Gomes et al., 1998 |
226 farmworkers in United Arab Emirates |
226 nonagricultural workers |
Neuropsychological tests |
Farm vs. non farmworkers |
Matched by age and nationality |
Farmworkers poorer on aiming and digit symbol tests |
Reference |
Population |
|
||||
Exposed |
Controls |
Health Outcomes |
Exposure |
Adjustment |
Results |
|
London et al., 1998 (see also Table E.1) |
See London above |
|
NP battery, vibration sense, motor tremor, neurological symptoms |
Applicator vs. control, lifetime exposure by questionnaire; plasma cholinesterase; occupation vs. nonoccupation |
Regression: age, height, education, numeracy, visual acuity, alcohol |
Applicators had 2.25 greater odds of high neurological symptoms controlling for past poisoning and other covariates; trend of more neurological findings among applicators |
Pickett et al., 1998 |
Case-control study: 1,457 suicide cases vs. 11,656 controls |
Suicide |
Acres sprayed with herbicides, insecticides; costs of agricultural chemicals |
Controls matched by age, province; logistic regression |
No associations of suicide and insecticide or pesticide exposure |
|
Azaroff and Neas, 1999 |
247 persons from 103 households |
|
WHO symptom questionnaire and three dummy symptoms |
Questionnaire of recent exposure (2 weeks, 1 year); urinalysis for alkylphosphate |
Regression: age <18, gender, and their interaction |
Several symptoms higher among OP+ who report exposure in last 2 weeks; several symptoms higher in persons living with a farmer who reported use of methylparathion in past 2 weeks |
|
Mestizo Indians—El Salvador |
|||||
NOTE: EEG = electroencephalogram; GHQ = General Health Questionnaire; NES = Neurobehavioral Evaluation System; NP = neuropsychological; WHO = World Health Organization. OP+ = Individuals with a urinary test indicating detectable OP metabolites. |
after controlling for past poisonings and other covariates. Finally, Azaroff and Neas (1999) reported increased rates of several symptoms among persons who had positive alkylphosphate, a biomarker of OP exposure, and a self-reported exposure in the past 2 weeks. Fiedler and colleagues (1997) performed a systematic psychiatric assessment using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), but did not find statistically significant differences between exposed fruit farmers and unexposed controls. In summary, there appear to be consistent patterns of increased symptom reporting among people whose jobs chronically expose them to OP pesticides but equivocal findings on standardized neuropsychological tests.
Pickett and colleagues (1998) conducted a case-control study comparing 1,457 Canadian farm operators who committed suicide over the period 1971–1987 to roughly eight times as many controls, matched for age and province. Their hypothesis was that exposure to pesticides was an important risk factor for suicide among farmers. This hypothesis was not supported because suicide cases did not have significantly increased past exposure, as measured by elevated acres sprayed with herbicide, acres sprayed with insecticide, or total expenditures on agricultural chemicals (after researchers controlled for a number of variables by logistic regression).
Taken together, these 10 studies provide mixed evidence about the association of standardized neuropsychological tests with chronic, subacute OP exposure. However, there are consistently higher prevalences of neurological and/or psychiatric symptoms, measured through either self-report or a standardized questionnaire such as the General Health Questionnaire, and no association with the occurrence of suicide.
Information, or reporting bias, is a serious consideration for this set of studies because persons who worked in jobs that exposed them to OP pesticides might differentially report symptoms thought or known to be associated with such exposures. The association with OP exposure was weakest for the suicide and standardized NP test outcomes, which are least subject to reporting bias. This association was greatest for the symptom data where reporting bias is more likely.
In summary, the extensive epidemiological evidence on the association of OP pesticide exposure and adverse health effects is consistent with and supports the more limited evidence on human exposure to sarin described in Chapter 5. There is consistent evidence that OP pesticide exposures sufficient to produce acute symptoms requiring medical care or reporting are associated with longer-term (1–10 years) increases in reports of neuropsychiatric symptoms and poorer performance on standardized neuropsychological tests. Workers exposed to OP pesticides at lower levels that did not produce acute effects also consistently reported higher rates of symptoms than controls but did not consistently perform poorer on objective NP tests.
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