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7. Neurologic Effects
Pages 350-449

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From page 350...
... All of the studies evaluated in this chapter examine the relationship between insecticide or solvent exposure and neurologic effects. Clinicians diagnose neurologic diseases and disorders by administering necrologic tests.
From page 351...
... . The committee reviewed the epidemiologic literature on neurologic effects of insecticide and solvent exposure, focusing on studies that examined Tong-term effects.
From page 352...
... For studies of peripheral neuropathy and neurology diseases, the committee did not require an exposure-free interval, because these necrologic effects are almost always long-tenn effects (although some degree of recovery or lack of progression is possible)
From page 353...
... 2 Is the evidence strong enough to justify particular conclusions regarding Gulf War veterans, or can it be marshaled to support the committee's conclusions drawn from other populations, mostly workers with occupational exposure to relevant pesticides or solvents? To answer those questions, the committee focused its evaluation on the subset of well-designed studies of Gulf War veterans that contained analyses of neurologic effects in relation to pesticide or solvent exposures.
From page 354...
... When insecticide or solvent exposures were assessed, few investigators attempted to quantify exposures to specific agents. Questions asked were very general for example "Did you handle pesticides?
From page 355...
... That combined approach was undertaken for only two neurologic effectsperipheral neuropathy and neurobehavioral effects because there were no peer-reviewed 3The studies are not reported in Table 7.1 if they did not address symptom-exposure relationships.
From page 356...
... . Gulf War Veterans and Peripheral Neuropathy Three studies of Gulf War veterans assessed the relationship between insecticide or solvent exposures in the Persian Gulf and peripheral neuropathy (Table 7.1~.
From page 357...
... 357 o an C~ .= U
From page 359...
... Almost 35% of Gulf War veterans who reported handling pesticides for more than a month indicated numbness or tingling on the mannequin diagrams, compared with 13.6% of veterans who did not report handling pesticides. This study was well designed and reveals a dose-response relationship, but it is limited by potential recall bias and lack of clinical evaluations or nerve-conduction studies.
From page 360...
... ~ s) .5 No associations were found between syndrome 3 and three other pesticide exposures—environmental pesticides, pesticides in uniforms, and pesticides in flea collarsor the single solvent exposure CARC paint on vehicles.
From page 361...
... . None of the questions addressed relevant solvent exposures.
From page 362...
... None of the studies found a relationship between solvent exposures and peripheral neuropathy, but very few asked about solvent exposures on the exposure questionnaire. The committee was unable to draw particular conclusions from these studies, because of their limitations, both study-specific and more general.
From page 363...
... That is less of a problem for peripheral neuropathy than for neurobehavioral effects. Peripheral neuropathy, based on clinical examination and confirmed by electrophysiologic alterations (such as decreased conduction velocity or pathologic evidence of denervation)
From page 364...
... and the comparison group (up to 52%) also had a history of occupational solvent exposure.
From page 365...
... 365 cn 0 .~ ._ u' ˘ Om 0 0 ~ ~ 0 LM O 2 c., id =, _.
From page 366...
... 366 C 5 ~ a X ' ~ X ~ ~ ~ ~ ~ ~ ~ ~ j ~ ~ ~ 0 E ~ ~ c _ ~ _ E ,0 c E ou e ~ — A,, O E ~ c ~ C ~ ~ oc ~ ~ ~ ~ bC o v' O -~ O C ~ ~ ~ ~ a_ ~ ~ ~ 11 0 ~ ~ , - ~ ~ ~ ~ ~ ~ ~ ~ ~ ^3 E O ~ E—-° ° O - c 0 , > ~ D O 3 D z ~< ~ C g o I ~ .
From page 368...
... Another limitation was the history of occupational solvent exposure among exposed and controls. Jamal and colleagues (2001)
From page 369...
... Testing of the formulators revealed increases in clinical symptoms and signs of peripheral neuropathy, including sensory hypoesthesia, muscle weakness, static tremor,
From page 370...
... There was also no measurement of nerve-conduction velocity. Summary and Conclusion The two stronger studies covered in this section did not find peripheral neuropathy associated with occupational exposure to OF insecticides (Savage et al., 1988 and Steeniand et al., 2000~.
From page 371...
... In mild cases, symptoms eventually resolve; in more severe cases, residual disability persists for a long time (Arlien-S0borg, ~ 992; Feldman, 1999~. On the basis of onset and clinical course, peripheral neuropathy caused by solvent exposure (or, as discussed earlier, by insecticide exposure)
From page 372...
... 372 o o Ct o Cal .= a; Am A: ·_ .g .~ in ~4 `: U
From page 375...
... The investigators found a single case of"plausible" peripheral neuropathy and two cases of"suspected' peripheral neuropathy in the 42 exposed workers, although no case definition was presented. None of the reference subjects showed any signs of peripheral neuropathy.
From page 376...
... On clinical examination, the investigators did not report any cases of peripheral neuropathy among the exposed workers, although they found a higher prevalence of self-reported acute symptoms during work (sleepiness and dizziness) and chronic symptoms—such as weakness in limbs, paresthesia and hypoesthesia but not cramps, neurasthenic syndrome, or sleep disturbances.
From page 377...
... This section evaluates the accumulated evidence Dom studies of Gulf War veterans and workers exposed to OF insecticides and solvents.
From page 378...
... Two follo~vup studies by Haley and colleagues included NB testing but did not evaluate associations between pesticide or solvent exposure and test abnormalities (Haley et al., 1997b, Hom et al., 1997~.
From page 381...
... 381 ~ '~3 ~ ~ to · ]
From page 382...
... found "a generalized pattern of neuropsychological deficit" among the veterans with one of the three syndromes, as measured by a number of tests, including the Halstead Impairment index and three subscales of the WATS. Neither of the articles reported on pesticide or solvent exposures of the affected veterans.
From page 383...
... Two studies of Gulf War veterans searched for associations between chronic multisymptom illness and pesticide or solvent exposure (Nisenbaum et al., 2000; Unwin et al., ~ 999~. Nisenbaum and colleagues (2000)
From page 384...
... used rigorous methods and a random sample of UK Gulf War veterans; it found an association between chronic multisymptom illness and each of the relevant pesticide or solvent exposures, but a similar association was found with all but one of the other exposures. Therefore, the association found in this study might have been due to confounding by some other exposure that was correlated with the pesticide and solvent exposures.
From page 385...
... was a large population-based study of US Gulf War veterans. It surveyed a representative sample of 4886 military personnel who had active service dunng the Gulf War and who listed Iowa as their home of record at the time of enlistment (Iowa Persian Gulf Study Group, 19971.
From page 386...
... The authors did not report on associations with single pesticide or solvent exposures but grouped a number of pesticide and solvent exposures as "CNS factors." They reported an association between "CNS factors" and cognitive dysfunction, with an OR of 1.45 (95% CI= I.19-~.76~. Summary and Conclusion In summary, difficulties with memory and concentration have been consistently shown to be more prevalent among Gulf War veterans than among comparison groups.
From page 387...
... No clear dose-response association was found with daYs of exposure to pesticide handling. Personal use of insect repellent and other pesticide and solvent exposures were not statistically significant associated with the neurologic factor.
From page 388...
... In the study by Cherry and colleagues (2001 a) , some pesticide exposures were associated with the symptom factor related to dizziness and balance; the study did not find a dose-response relationship, and found no relationship to solvent exposure.
From page 389...
... OP poisoning results in symptoms or signs of the acute cholinergic syndrome (Chapter 3) , which, because of its life-threatening nature, typically requires hospitalization.
From page 390...
... 390 .= o GO · o o of o Id · · 3 Cal Cal Ct o ._ o in Em In .° ._ .s Cq U
From page 391...
... The poisoned subjects performed significantly worse than referents on four of five summary measures and on ~ 8 of 34 individual tests. The differences occurred on tests of intellectual functioning, academic skills, abstraction, flexibility of thinking, and simple motor skills (speed and coordination)
From page 392...
... The OPpoisoned workers performed significantly worse than the referents on five domains: attention, memory, visuomotor, motor, and symptoms. Individual NB tests on which performance was worse included digit vigilance (attention)
From page 393...
... and long-term neurobehavioral effects assessed with neurobehavioral testing and symptom reporting. The affected neurobehavioral domains include visuomolor, attention/executive functioning, motor functioning and mood symptoms.
From page 396...
... 396 u, a: .° .§ ._ u, u, c, ._ cat c: ~ c ~ x 0 O In O c, 0 ~ ~ EN cd cat =: ~ ..
From page 398...
... studied 45 pesticide applicators that had participated in the California medical-surveilIance program for OF insecticides. All had been found to have substantial declines in AChE, requiring removal from work, even though they had no evidence of frank poisoning (the acute cholinergic syndrome)
From page 399...
... to measure subjects' own assessment of memory, a retrospective exposure questionnaire, and eight computer-administered NB tests. The farmers scored significantly worse in three tests of motor skills (that is, simple reaction time, visuomotor skills, digit-symbol substitution)
From page 400...
... Applicators had worked a median of ~ .8 years in applying termiticides. (Further details of the study were given earlier in this chapter in the section on peripheral neuropathy.)
From page 401...
... Long-term exposure was calculated with a job~xposure matrix. According to a multiple-regression model, cumulative lifetime occupational exposure was significantly associated with a reduction in the number of correct trials on pursuit aiming and on the Santa Ana test of the nondominant arm.
From page 402...
... found abnormalities on simple-reaction time and on the aiming test, but measured performance on only six NB tests and was sparse on some aspects of methodology. A population-based study of Gulf War veterans (discussed earlier in this chapter)
From page 403...
... and short-term effects of solvent exposure. The criterion turned out to be very restrictive as the vast majority of the more than 300 solvent studies in the peer-reviewed literature focus on workers with both current and past exposure.
From page 404...
... A separate analysis of current vs formerly exposed workers was not conducted, but the overwhelming majority of the workers did not report exposure within 2 days of the evaluation, and 49°/O had not been exposed for a year or more. In summary, the study found that solvent exposure adversely affected tests of visuomotor and visuospatial skills.
From page 405...
... 405 au a, o x o cO me ct o > cd to o ~ 7i 8 JO 2~ !
From page 407...
... There was, however, no direct statistical comparison between the formerly exposed and the reference twins, but only between the formerly and currently exposed twins. The overall conclusion of the study was that solvent exposure affected primarily measures of attention and concentration and of visuospatial relations.
From page 408...
... investigated the long-tenn effects of exposure to organic solvents in a followup study of women working in a tennis-ball factory who were exposed to high concentrations of toluene and other aliphatic hydrocarbons as a result of a ventilation accident; atmospheric monitoring was not conducted at the time of the accident, but solvents then used were toluene anal SPB-7, a proprietary solvent containing hexane, heptane, octane, anal nonane. Solvent exposure occurred over a 3-day Tenon apparently because of failure of the ventilation system.
From page 409...
... , in a separate study, focused exclusively on retired workers with prior chronic solvent exposure. The study is distinguished by its sole focus on prior occupational exposure, its array of outcome measures, and its method of assessing the clinical significance of the NB effects.
From page 410...
... Summary and Conclusion Using strict inclusion criteria, the committee evaluated several studies of chronic occupational solvent exposure and NB effects. The studies, of workers with years-Ion" or career-Ion" exposure, were selected by the committee on the basis of an exposure-free interval to ensure that the effects were long-term rather than short-term.
From page 411...
... The clinical significance of the NB effects reported here is supported by the study of Daniell and colleagues (1 999~. It is also consistent with the body of case-control and retrospective cohort studies of chronic occupational solvent exposure, which found an excess of assorted psychiatric or neurologic diagnoses.
From page 412...
... Many epidemiologic studies have attempted to ascertain environmental risk factors for the development of PD. Respondents in epidemiologic studies often have difficulty in remembering specific agricultural exposures, so many investigators have simply asked generic questions about exposure to "pesticides." Much of the literature deals with pesticide exposures that may include exposure to herbicides as well as to the insecticides of interest to the committee.
From page 413...
... ~ 8~. The subset of people with occupational exposures of over ~ O years had higher odds ratios than the subset with less than 10 years.
From page 414...
... 414 as CO o x a' ._ · _ C)
From page 416...
... 416 a, V cr _ o ._, o <: V o V o U
From page 417...
... . which _ 11__ _ _ 11 `1_ _ _ 1 1 _ _ _ · , 1 a, , · , ~ ~~ ~ ~ 1ntrocucec the problems associated With patients recall ot~predlsease risk factors and the potential for survival bias.
From page 418...
... Amyotrophic Lateral Sclerosis and Insecticide Exposure: Background and Epidemiologic Studies Amyotrophic lateral sclerosis (ALS) is a rapidly fatal necrologic disorder characterized by progressive muscle weakness, muscle atrophy, and fasciculations.
From page 419...
... None of the reports about Gulf War veterans published in peer-reviewed journals specifically addressed ALS. However, a large government-funded epidemiologic study provides preliminary evidence that veterans who served in the Gulf War are nearly twice as likely as their nondeployed counterparts to develop ALS (Feussner, 2002~.
From page 420...
... . Occupational exposures included "organophosphates" and "hydrocarbon solvents." Occupational histories were gathered from informants (proxies)
From page 421...
... Those limitations are described in the context of each study that the committee evaluated. Parkinson's Disease and Solvent Exposure: Epidemiologic Studies PD is described earlier in this chapter.
From page 423...
... When cases were compared with controls from the electoral rolls, a moderate association between occupational exposure to any solvents before disease onset was found for men (OR = 2.16, 95% CI = I.07~.37~. No association was found for men in comparison with the cardiac-disease controls or for women in comparison with either control group.
From page 424...
... The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to ~letermine whether an association exists between exposure to the solvents under review and Parkinson's disease. Amyotrophic Lateral Sclerosis and Solvent Exposure: Epidemiologic Studies This section addresses the association between solvent exposure and ALS.
From page 425...
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From page 426...
... 426 as v° O ~ V 7~ V to or _ O o _ c, E 2 .o ~ ~ ct .a, ~ .= ~ To lo=: ~ e ˘ o E 3 so ~ o V To ~ o too o<= b Cd ~ ~ IRAQ-)
From page 428...
... No associations between ALS and occupational history of solvent exposure were found. The small sample in this study is an important limitation but even so the saint estimate for solvent exposure is small (~.2)
From page 429...
... The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to the solvents under review and amyotrophic lateral sclerosis. Multiple Sclerosis and Solvent Exposure: Background and Epidemiologic Studies Multiple sclerosis (MS)
From page 430...
... Gronning and colleagues found no evidence to support an association between exposure to organic solvents and the occurrence of MS. Compared with no exposure, occupational exposure to solvents for 1-5 years and more than 5 years yielded ORs of 1.23 (95% CI = 0.55-2.76)
From page 431...
... 431 r So Cal o y o Ct U
From page 432...
... 432 U' :: V UP o ~ no ~o o ~ ~~ ~2 ~ ° ~ ~T ~ ~ E ~ ~ e ~ ~ ~ -E ~.o con ~ E ~ 2 E to ~ ~ ~ O U
From page 433...
... The authors speculated that solvents milt contribute to MS by enhancing viral entry across the blood-brain battier into the CNS. Summary and Conclusion = Two case-control studies found no association between occupational solvent exposure and MS (Groping et al., 1993; Juntenen et al., 1989~.
From page 434...
... Kukull and colleagues (l 995) reported an association between occupational solvent exposure and AD in men.
From page 435...
... 43s an o En Cal Cal an U
From page 438...
... After adjusting for family history of AD, the study did not report any significant associations between AD and occupational solvent exposure. The relevant solvent exposures listed in the study were to aromatic hydrocarbons, chlorinated hydrocarbons, and any hydrocarbons.
From page 439...
... Several authors comment that occupational solvent exposure is most likely to occur in men, but a male-only study by Shalat and colleagues (1988) did not find a relationship, and the positive results in men were discounted by Kukull and colleagues (1995~.
From page 440...
... Two studies (Morata et al., 1993, 1997b) found mild hearing loss with mixed solvent exposure (but it is not clear whether the population was the same for both studies)
From page 441...
... . The committee did not identify any epidemiologic studies of relevant solvent exposure and hearing loss with an exposure-free interval.
From page 442...
... 1992. Organic brain damage and occupational solvent exposure.
From page 443...
... 2002. Research and Treatment of Gulf War Veterans ' Illnesses.
From page 444...
... 1994. Symptoms indicative of the effects of organic solvent exposure in Dutch painters.
From page 445...
... 1984. Occupational solvent exposure and neuropsychiatric disorders.
From page 446...
... 2000. Deployment stressors and a chronic multisymptom illness among Gulf War veterans.
From page 447...
... 1998. Health status of Persian Gulf War veterans: Self-reported symptoms, environmental exposures and the effect of stress.
From page 448...
... 1989. Exposureoutcome relationships between organic solvent exposure and neuropsychiatric disorders: Results from a Dutch case-control study.
From page 449...
... 1998b. Assessment of colour vision impairment in male workers exposed to toluene generally above occupational exposure limits.


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