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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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 What are the long-term health effects of an acute episode of OP poisoning? 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)? 1 “Pesticides” is an umbrella term for any chemicals designed for pest control. They include insecticides, fungicides, and herbicides. 2 An OP poisoning refers to having symptoms or signs of an acute cholinergic syndrome.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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 3 A similar yet more inclusive review of the health effects of organophosphate exposure has been conducted by the United Kingdom Department of Health Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (Woods, 1999). That report provides a more detailed review of 27 studies of the health effects of OP exposure.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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,
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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 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
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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 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
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 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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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines REFERENCES Ames RG, Steenland K, Jenkins B, Chrislip D, Russo J. 1995. Chronic neurologic sequelae to cholinesterase inhibition among agricultural pesticide applicators. Arch Environ Health 50(6):440–444. Amr MM, Abbas EZ, El-Samra M, El Batanuoni M, Osman AM. 1997. Neuropsychiatric syndromes and occupational exposure to zinc phosphide in Egypt. Environ Res 73(1–2):200–206. Azaroff LS, Neas LM. 1999. Acute health effects associated with nonoccupational pesticide exposure in rural El Salvador. Environ Res 80(2 Pt 1):158–164. Burns CJ, Cartmill JB, Powers BS, Lee MK. 1998. Update of the morbidity experience of employees potentially exposed to chlorpyrifos. Occup Environ Med 55(1):65–70. Ciesielski S, Loomis DP, Mims SR, Auer A. 1994. Pesticide exposures, cholinesterase depression, and symptoms among North Carolina migrant farmworkers. Am J Public Health 84(3):446–451. Daniell W, Barnhart S, Demers P, Costa LG, Eaton DL, Miller M, Rosenstock L. 1992. Neuropsychological performance among agricultural pesticide applicators. Environ Res 59:217–228. Fiedler N, Kipen H, Kelly-McNeil K, Fenske R. 1997. Long-term use of organophosphates and neuropsychological performance. Am J Ind Med 32(5):487–496. Gomes J, Lloyd O, Revitt MD, Basha M. 1998. Morbidity among farm workers in a desert country in relation to long-term exposure to pesticides. Scand J Work Environ Health 24(3):213–219. Levin HS, Rodnitzky RL. 1976. Behavioral effects of organophosphate pesticides in man. Clin Toxicol 9(3):391–405. London L, Nell V, Thompson ML, Myers JE. 1998. Effects of long-term organophosphate exposures on neurological symptoms, vibration sense and tremor among South African farm workers. Scand J Work Environ Health 24(1):18–29. Pickett W, King WD, Lees RE, Bienefeld M, Morrison HI, Brison RJ. 1998. Suicide mortality and pesticide use among Canadian farmers. Am J Ind Med 34:364–372. Reidy T, Bowler R. 1992. Pesticide exposure and neuropsychological impairment in migrant farm workers. Arch Clin Neuropsychol 7:85–95. Rodnitzky RL, Levin HS, Mick DL. 1975. Occupational exposure to organophosphate pesticides. Arch Environ Health 30:98–103. Roland PS, Haley RW, Yellin W, Owens K, Shoup AG. 2000. Vestibular dysfunction in Gulf War syndrome. Otolaryngology—Head and Neck Surgery 122:319–329. Rosenstock L, Keifer M, Daniell WE, McConnell R, Claypoole K. 1991. Chronic central nervous system effects of acute organophosphate pesticide intoxication. Lancet 338(8761):223–227. Savage EP, Keefe TJ, Mounce LM, Heaton RK, Lewis JA, Burcar PJ. 1988. Chronic neurological sequelae of acute organophosphate pesticide poisoning. Arch Environ Health 43(1):38–45. Sidell FR, Borak J. 1992. Chemical warfare agents: II. Nerve agents. Ann Emerg Med 21(7):865–871. Steenland K, Jenkins B, Ames RG, O’Malley M, Chrislip D, Russo J. 1994. Chronic neurological sequelae to organophosphate pesticide poisoning. Am J Public Health 84(5):731–736. Stephens R, Spurgeon A, Calvert IA, Beach J, Levy LS, Berry H, Harrington JM. 1995. Neuropsychological effects of long-term exposure to organophosphates in sheep dip. Lancet 345(8958):1135–1139.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Tabershaw IR, Cooper WC. 1966. Sequelae of acute organic phosphate poisoning. J Occup Med 8:5–10. Woods FH. 1999. Organophosphates. London: U.K. Department of Health.
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