• Barbeau, A., M. Roy, et al. (1987).
    Ecogenetics of Parkinson's disease: prevalence and environmental aspects in rural areas.
    Can J Neurol Sci 14(1): 36-41.
    We make use of the unique combination of a homogeneous genetic and racial origin in the rural population of Quebec and the facilities of free and universal access to medical care, to study the distribution of the prevalence of Parkinson's disease in the 9 rural hydrographic regions of the Province. Through 3 different methods of ascertainment, confirmed by two control probes, we demonstrate that the prevalence of Parkinson's disease is of uneven distribution within rural areas. We further investigated the characteristics of the regions of high prevalence. These regions which are predominantly agricultural and areas of intensive market gardening were also the areas with the highest use of pesticides.
     
  • Burkhardt, C. R. and H. K. Weber (1994).
    Parkinson's disease: a chronic, low-grade antioxidant deficiency?
     Med Hypotheses 43(2): 111-4.

    The cause of Parkinson's disease (PD) is aggressively being pursued. Several hypotheses have been advanced, yet none of these completely explains the large body of evidence research has already uncovered. A new hypothesis, that PD is caused by a chronic antioxidant deficiency state, is outlined in this article. Oxidative stress, mitochondrial abnormalities, epidemiology, genetics, toxins, history of PD and diet are discussed.
     
  • Calne, D. B. and J. W. Langston (1983).
    Aetiology of Parkinson's disease.
    Lancet 2(8365-66): 1457-9.
    It is suggested here that in most cases of Parkinson's disease the cause may be an environmental factor, possibly toxic, superimposed on a background of slow, sustained neuronal loss due to advancing age.
     
  • Checkoway, H. and L. M. Nelson (1999).
    Epidemiologic approaches to the study of Parkinson's disease etiology.
    Epidemiology 10(3): 327-36.

    The etiology of Parkinson's disease has been enigmatic to clinicians, epidemiologists, and basic scientists since the clinical syndrome was first described in 1817. Mendelian inheritance probably accounts for a small proportion of Parkinson's disease. Apart from an increasing risk with age, the most consistent epidemiologic observation has been an inverse relation with cigarette smoking. Neither selective survival of nonsmokers nor behavioral characteristics of smokers can explain this seemingly protective association. Interest in environmental exposures, particularly pesticides, metals, and industrial solvents, heightened substantially following the discovery of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), a street drug contaminant, as a cause of human parkinsonism. Epidemiologic and toxicologic research has since been guided to a great extent, although not exclusively, by mechanisms of MPTP toxicity. Efforts to characterize gene/environment interactions have also intensified in recent years. In this review, we evaluate recent evidence concerning the etiology of Parkinson's disease, with emphasis on environmental and lifestyle exposures and their potential interactions with genetic susceptibility traits. The most challenging aspects of epidemiologic research into Parkinson's disease causation include methodologic difficulties surrounding case definition, completeness of case ascertainment, selection of appropriate controls in case-control studies, and assessment of environmental exposures. We conclude with recommendations for future research directions.
     
  • Davanipour, Z., E. Sobel, et al. (1997).
    Amyotrophic lateral sclerosis and occupational exposure to electromagnetic fields.
    Bioelectromagnetics 18(1): 28-35.
    In an hypothesis-generating case-control study of amyotrophic lateral sclerosis, lifetime occupational histories were obtained. The patients (n = 28) were clinic based. The occupational exposure of interest in this report is electromagnetic fields (EMFs). This is the first and so far the only exposure analyzed in this study. ..Twenty (71%) cases and 28 (88%) controls had at least 20 years of work experience covering the exposure period. The occupational history and task data were used to classify blindly each occupation for each subject as having high, medium/high, medium, medium/low, or low EMF exposure, based primarily on data from an earlier and unrelated study designed to obtain occupational EMF exposure information on workers in "electrical" and "nonelectrical" jobs. By using the length of time each subject spent in each occupation through the exposure period, two indices of exposure were constructed: total occupational exposure (E1) and average occupational exposure (E2). This study should be considered an hypothesis-generating study. Larger studies, using incident cases and improved exposure assessment, should be undertaken.
     
  • Dexter, D. T., P. Jenner, et al. (1992).
    Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson's Disease Research Group.
    Ann Neurol 32(Suppl): S94-100.
    Previously we have shown that cell death in the substantia nigra (SN) in Parkinson's disease (PD) is associated with an increase in iron content but a decrease in the level of the iron-binding protein ferritin. Alterations in other metal ion levels were also observed; copper levels were reduced, whereas zinc levels were increased. The importance of these changes in iron, ferritin, and other metal ions in the pathophysiology of PD depends on whether they are specific to the illness. We measured levels of iron, copper, zinc, manganese, and ferritin in postmortem tissue from patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (which shows pathology in the SN and striatum) and Huntington's disease (HD) (which shows pathological changes in the striatum, compared with control subjects). Total iron levels were elevated in areas of the basal ganglia showing pathological changes in these disorders. In particular, total iron content was increased in SN in PD, PSP, and MSA, but not in HD. Total iron levels in the striatum (caudate nucleus and/or putamen) were increased in PSP, MSA, and HD, but not in PD. There were no consistent alterations in manganese levels in the basal ganglia in any of the diseases studied. Copper levels were decreased in the SN in PD and in the cerebellum in PSP, and were elevated in the putamen and possibly the SN in HD. Zinc levels were only increased in PD in the SN, the caudate nucleus, and the putamen.
     
  • Ferraz, H. B., P. H. Bertolucci, et al. (1988).
    Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication.
    Neurology 38(4): 550-3.
    Manganese (Mn) poisoning, a well-known hazard in miners and industrial workers, shares many features with Parkinson's disease. Two young agricultural workers with a parkinsonian syndrome, who mentioned exposure to the fungicide maneb (manganese ethylene-bis- dithiocarbamate), led us to investigate a new possible source of Mn intoxication. Fifty male rural workers with occupational exposure to maneb were compared with 19 rural workers without fungicide exposure. We noted significantly higher prevalence of plastic rigidity with cogwheel phenomenon, headache, fatigue, nervousness, memory complaints, and sleepiness in the exposed group. In addition, we saw other neurologic signs, such as postural tremor, cerebellar signs, and bradykinesia, although without statistical significance. The data suggest that occupational exposure to pesticides containing Mn is a possible source of Mn intoxication of the CNS.
     
  • Golbe, L. I., T. M. Farrell, et al. (1990).
    Follow-up study of early-life protective and risk factors in Parkinson's disease.
    Mov Disord 5(1): 66-70.
    Previous studies suggest that Parkinson's disease (PD) is negatively associated with early-life intake of vitamin E-rich foods and positively associated with rural experience. Using a new survey design, we attempted to confirm and extend these results. We gave a telephone questionnaire to 106 patients with PD and to their spouses as controls. It assessed premarital consumption of 31 foods of various vitamin E content, vitamin supplements, and exposure to rural living. Respondents rated food consumption with respect to what they perceived as the average for their sex and age at that time. We found female patients with PD less likely than spouses to have eaten "peanuts and peanut butter" (p less than .05), which are high in vitamin E. "Salad with dressing," also high in vitamin E, gave a similar result (p less than .05) for a male-predominant patient group. Separate comparison of male controls with female controls ruled out sex-related preferences as the explanation of our findings. Patients had more extensive rural experience and were more likely to have frequently sprayed pesticides (p less than .05) than had controls. Our results justify further investigations into early-life vitamin E intake, pesticides, and neurotoxins associated with rural life.
     
  • Goldstein, J. M., A. Barnett, et al. (1975).
    The evaluation of anti-parkinson drugs on reserpine-induced rigidity in rats.
    Eur J Pharmacol 33(1): 183-8.
    The effect of anti-parkinson drugs on reserpine-induced rigidity was examined using a technique which measured rigidity by hind limb palpation. Centrally acting dopaminergic and anti-cholinergic drugs were able to antagonize reserpine-induced rigidity, whereas peripherally acting drugs had no effect. Results are discussed in terms of possible modes of action. Relative potencies of the drugs studied in this model were well correlated with the dose ranges of clinically established anti-parkinson drugs. It is concluded that measurement of reserpine-induced rigidity by hind limb palpation is a rapid and sensitive technique to evaluate potential anti-parkinson drugs.
     
  • Gorell, J. M., C. C. Johnson, et al. (1997). |
    Occupational exposures to metals as risk factors for Parkinson's disease.
    Neurology 48(3): 650-8.
    In a population-based case-control study, we investigated the potential role of occupational exposure to iron, copper, manganese, mercury, zinc, and lead as risk factors for Parkinson's disease (PD). Concurrently recruited, nondemented patients (n = 144) with idiopathic PD and controls (n = 464) consisting of men and women > or =50 years of age, frequency-matched for age (within 5 years), race, and sex were enrolled. All had primary medical care at Henry Ford Health System in urban/suburban metropolitan Detroit. Subjects were given an extensive risk-factor questionnaire detailing actual worksite conditions of all jobs held for more than 6 months from age 18 onward. An industrial hygienist, blinded to the case-control status of subjects, rated occupational exposure to each of the metals of interest. When adjusted for sex, race, age, and smoking status, we found in those with more than 20 years' exposure a significantly increased association with PD for copper (OR = 2.49, 95% CI = 1.06, 5.89) and manganese (OR = 10.61, 95% CI = 1.06, 105.83). For more than 20 years' exposure to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead- iron (OR = 2.83, 95% CI = 1.07, 7.50), and iron-copper (OR = 3.69, 95% CI = 1.40, 9.71), there was a greater association with PD than with any of these metals alone. These findings suggest that chronic exposure to these metals is associated with PD, and that they may act alone or together over time to help produce the disease.
     
  • Gorell, J. M., C. C. Johnson, et al. (1999).
    Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease.
    Neurotoxicology 20(2-3): 239-47.
    A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron, mercury and zinc as risk factors for Parkinson's disease (PD). Non-demented men and women 50 years of age who were receiving primary medical care at HFHS were recruited, and concurrently enrolled cases (n = 144) and controls (n = 464) were frequency-matched for sex, race and age (+/- 5 years). A risk factor questionnaire, administered by trained interviewers, inquired about every job held by each subject for 6 months from age 18 onward, including a detailed assessment of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to subjects' case-control status, used these data to rate every job as exposed or not exposed to one or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of occupational exposure to any metal was not associated with PD. However, more than 20 years exposure to manganese (Odds Ratio [OR] = 10.61, 95% Confidence Interval [CI] = 1.06, 105.83) or copper (OR = 2.49, 95% CI = 1.06,5.89) was associated with PD. Occupational exposure for > 20 years to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead- iron (OR = 2.83, 95% CI = 1.07,7.50), and iron-copper (OR = 3.69, 95% CI = 1.40,9.71) was also associated with the disease. No association of occupational exposure to iron, mercury or zinc with PD was found. A lack of statistical power precluded analyses of metal combinations for those with a low prevalence of exposure (i.e., manganese, mercury and zinc). Our findings suggest that chronic occupational exposure to manganese or copper, individually, or to dual combinations of lead, iron and copper, is associated with PD.
     
  • Gorell, J. M., C. C. Johnson, et al. (1998).
    The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living.
    Neurology 50(5): 1346-50.
    We assessed exposure to pesticides, farming, well water use, and rural living as risk factors for Parkinson's disease (PD) in a population- based case-control study consisting of men and women > or = 50 years of age who had primary medical care at Henry Ford Health System in metropolitan Detroit. Enrolled PD patients (n = 144) and control subjects (n = 464) were frequency-matched for age, race, and sex. When adjusted for these variables and smoking status, there was a significant association of occupational exposure to herbicides (odds ratio [OR], 4.10; 95% CI, 1.37, 12.24) and insecticides (OR, 3.55; 95% CI, 1.75, 7.18) with PD, but no relation was found with fungicide exposure. Farming as an occupation was significantly associated with PD (OR, 2.79; 95% CI, 1.03, 7.55), but there was no increased risk of the disease with rural or farm residence or well water use. The association of occupational exposure to herbicides or insecticides with PD remained after adjustment for farming. The association of farming with PD was maintained after adjustment for occupational herbicide exposure and was of borderline significance after adjustment for occupational insecticide exposure. These results suggest that PD is associated with occupational exposure to herbicides and insecticides and to farming and that the risk of farming cannot be accounted for by pesticide exposure alone.
     
  • Gorell, J. M., R. J. Ordidge, et al. (1995).
    Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease.
    Neurology 45(6): 1138-43.
    Elevated iron levels in the substantia nigra (SN) of the brain in Parkinson's disease (PD) may mediate lipid peroxidative reactions, promoting SN neuronal death. To assess SN iron accumulation in living PD patients and its relation to motor performance, we measured, in 13 nondemented PD patients and 10 normal control subjects, simple reaction time (SRT) and simple movement time (SMT), followed by head MRI in a 3- tesla system. .. These results strongly suggest that the increases in iron levels seen postmortem in the SN in PD are reflected in increased iron-related MRI contrast at 3 tesla in living PD patients. Correlations with motor performance in PD suggest that the clinical severity of PD may be related to SN iron accumulation.
     
  • Gorell, J. M., B. A. Rybicki, et al. (1999).
    Occupational metal exposures and the risk of Parkinson's disease.
    Neuroepidemiology 18(6): 303-8.
    Occupational exposure to specific metals (manganese, copper, lead, iron, mercury, zinc, aluminum and others) appears to be a risk factor for Parkinson's disease (PD) in some, but not all, case-control studies. These epidemiological studies are reviewed. Several methodological issues that may account for the lack of unanimity of findings are discussed, and suggestions for improved case-control methodology are offered. The study of the neurological disease outcome of workers who have had long-term, well-defined occupational exposure to one or more metals is also urged, with collaborative work including industrial hygienists, occupational toxicologists, neurologists, epidemiologists and biostatisticians. Such efforts, employing state-of- the-art case and control ascertainment and enrollment from suitable population bases, neurological diagnostic rigor and exposure assessment, will help to further define the potentially important roles played by metals in PD and other neurodegenerative disorders.
     
  • Jenner, P., A. H. Schapira, et al. (1992).
    New insights into the cause of Parkinson's disease.
    Neurology 42(12): 2241-50.
    Current concepts as to the cause of Parkinson's disease (PD) suggest an inherited predisposition to environmental or endogenous toxic agents. Study of the substantia nigra after death in PD has highlighted three major changes: (1) evidence of oxidative stress and depletion of reduced glutathione; (2) high levels of total iron, with reduced ferritin buffering; and (3) mitochondrial complex I deficiency. Which of these is the primary event, generating a secondary cascade of changes culminating in nigral cell death, is unknown. In presymptomatic Lewy body-positive control brains, the nigra shows depletion of reduced glutathione content and, possibly, a reduction of complex I activity. Whatever the significance of these various abnormalities, be they causal or secondary, they provide novel targets for the development of new strategies to treat the cause of PD.
     
  • Kirkey, K. L., C. C. Johnson, et al. (2001).
    Occupational categories at risk for Parkinson's disease.
    Am J Ind Med 39(6): 564-71.
    BACKGROUND: The etiology of Parkinson's disease (PD) is considered to have a strong environmental component, but relatively few studies have investigated the potential association between occupation and the disease. METHODS: In a population-based case-control study, we collected comprehensive occupational histories from all study participants, 144 case and 464 control subjects. RESULTS: Chi-square analysis revealed that working in an agricultural occupation increased estimated PD risk (OR = 1.74; 95% CI = 0.85, 3.60). In contrast, a history of ever working in a service occupation was negatively associated with PD risk (OR = 0.69; 95% CI = 0.47, 1.00). Risk estimates were close to one for specific service occupations. Adjusted odds ratios for all non-service occupational and industrial categories were similar, and working in a service occupation was the only significant inverse predictor of PD risk. CONCLUSIONS: Future investigations focusing on lifestyle factors and environmental exposures within the agricultural and service occupational categories are warranted. Copyright 2001 Wiley-Liss, Inc.
     
  • Klawans, H. L., R. W. Stein, et al. (1982).
    A pure parkinsonian syndrome following acute carbon monoxide intoxication.
    Arch Neurol 39(5): 302-4.
    A 50-year-old woman with carbon monoxide (CO)-induced parkinsonism was found to have bilateral lucencies of the globus pallidus on computed tomographic (CT) scan consistent with old necrotic lesions. She showed no clinical response to levodopa therapy, although she did improve with anticholinergic therapy. It is suggested that the parkinsonism in this patient is due to the pallidal lesions demonstrated on CT scan, and that such pallidal-related parkinsonism may not respond to dopaminergic therapy.
     
  • Koller, W., B. Vetere-Overfield, et al. (1990).
    Environmental risk factors in Parkinson's disease.
    Neurology 40(8): 1218-21.
    To investigate possible risk factors for Parkinson's disease (PD) we conducted a case-control study of 150 PD patients and 150 age- and sex- matched controls. We interviewed and examined all 300 subjects. We collected demographic data including lifetime histories of places of residence, source of drinking water, and occupations such as farming. Subjects completed a detailed questionnaire regarding herbicide/pesticide exposure. Rural living and drinking well water were significantly increased in the PD patients. This was observed regardless of age at disease onset. Drinking well water was dependent on rural living. There were no significant differences between cases and controls for farming or any measure of exposure to herbicides or pesticides. These data provide further evidence that an environmental toxin could be involved in the etiology of PD.
     
  • Kondo, K. (1984).
    Epidemiological clues for the etiology of Parkinson's disease.
    Adv Neurol 40: 345-51
     
  • Kuopio, A. M., R. J. Marttila, et al. (1999).
    Changing epidemiology of Parkinson's disease in southwestern Finland.
    Neurology 52(2): 302-8.
    OBJECTIVE: Investigation of the epidemiology of PD in southwestern Finland in 1992 (population 196,864), including urban and rural areas, with a comparison with a similar study, done in the same area in 1971, to evaluate the temporal pattern.  CONCLUSIONS: A very significant male and a significant rural predominance, not seen in 1971, suggests a possible environmental causative factor, perhaps more frequent in the rural environment, associated with PD. Men may be either more exposed to it or more susceptible to its effects than women.
     
  • Kuopio, A. M., R. J. Marttila, et al. (1999).
    Environmental risk factors in Parkinson's disease.
    Mov Disord 14(6): 928-39.
    We studied the environmental risk factors of Parkinson's disease (PD) in Finland, particularly those related to rural environment, in a prevalence material in 1992. The population numbered 196,864 people, including urban and rural areas. In this community-based study, we used a case-control method with personal investigation of the case subjects (n = 123) and matched control subjects (n = 246). Analyses were carried out by conditional logistic regression model. Case subjects had far fewer domestic animals at home during their lifetime, including cows, sheep, pigs, and chickens. The difference was even more obvious in those under the age of 20 years, including also cats and horses, but diminished after 20 years. The number of different animal species was smaller with case subjects as was the duration of animal contacts. Case subjects found their work physically heavier and exercised more. The mean age at onset in ever-smoking men was significantly higher than in never-smoking men. No special reason for non-smoking increased, and a physical reason decreased the risk of PD. Area of birth or living, farming and other occupations, types of drinking water, pesticide and herbicide use, head injuries, use of alcohol, education, and carbon monoxide poisonings were similar among case subjects and control subjects. In conclusion, domestic animals, or something that is connected with the animals, may have a protecting effect against PD. Alternatively, the observed negative associations of domestic animals at home and subsequent PD may only be a marker of other environmental conditions or lifestyles.
     
  • Kuopio, A. M., R. J. Marttila, et al. (2000).
    The quality of life in Parkinson's disease.
    Mov Disord 15(2): 216-23.
    The objective of this study was to examine the quality of life in patients with Parkinson's disease (PD) in a community-based sample (n = 228 patients) using a Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) as a measure. Associations to the variables age, age at onset, duration, clinical stage (Hoehn and Yahr), depression (Zung), and dementia (MMSE) were studied. Women scored significantly lower on five of the eight dimensions of SF-36. Depression, as measured in this study, was more common among parkinsonian women than men. Depression was the factor that was associated most significantly with the experienced quality of life, according to SF-36. With physical functioning, only the clinical stage had a more significant association than depression. To improve the quality of life in patients with PD, it is necessary to make every effort to recognize and relieve the depression of patients with PD
    .
     
  • Larumbe Ilundain, R., J. V. Ferrer Valls, et al. (2001).
    Case-control study of markers of oxidative stress and metabolism of blood iron in Parkinson's disease].
    Rev Esp Salud Publica 75(1): 43-53.
    BACKGROUND: Increasingly growing evidence exists of the involvement of oxidative stress mechanisms in Parkinson's disease. Lower levels of GSH in the sustantia nigra, an increase in iron buildup, an increase in the byproducts of lipid peroxidation and alterations in the mitochondrial complex I have been described. However, few studies have been made of levels of antioxidants in the peripheral bloodstream and of the influence of the intake of nutrients on the development of this disease. CONCLUSIONS: The results of this study support the possible involvement of oxidative stress in the pathogenesis of Parkinson's disease and reveal, in turn, alterations in some peripheral blood parameters in keeping with known findings in the sustantia nigra.
     
  • Lewin, R. (1985).
    Parkinson's disease: an environmental cause?
    Science 229(4710): 257-8.
     
  • Lorenc-Koci, E., K. Ossowska, et al. (1995).
    Does reserpine induce parkinsonian rigidity?
    J Neural Transm Park Dis Dement Sect 9(2-3): 211-23.
    The aim of the study was to find out whether the reserpine-induced rigidity is similar to that seen in parkinsonism. Simultaneous measurements of the muscle resistance of the hind foot to passive bending and stretching in the ankle joint, as well as of the electromyographic (EMG) activity of the gastrocnemius and tibialis anterior muscles of rats were carried out. Reserpine was injected in a dose of 10 mg/kg alone or with alpha-methyl-p-tyrosine (250 mg/kg) 1, 4 and 27.5 h before the measurements. Reserpine increased the muscle resistance of the rat's hind leg to passive movements. That effect was the strongest at 1-2 h after the injections, and diminished markedly afterwards. The rigidity was accompanied with an increase in the resting, as well as in the stretch-induced short- and long-latency EMG activity in the gastrocnemius muscle. However, the intensity of the latter symptom did not change for a long period of time, which seems to correlate with the striatal dopamine depletion. The results suggest that the reserpine-increased EMG activity is a good model of parkinsonian rigidity.
     
  • Menegon, A., P. G. Board, et al. (1998).
    Parkinson's disease, pesticides, and glutathione transferase polymorphisms.
    Lancet 352(9137): 1344-6.
    BACKGROUND: Parkinson's disease is thought to be secondary to the presence of neurotoxins, and pesticides have been implicated as possible causative agents. Glutathione transferases (GST) metabolise xenobiotics, including pesticides. Therefore, we investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinson's disease. FINDINGS: The distribution of the GSTP1 genotypes differed significantly between patients and controls who had been exposed to pesticides (controls vs patients... No association was found with any of the other GST polymorphisms. Pesticide exposure and a positive family history were risk factors for Parkinson's disease. INTERPRETATION: GSTP1-1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides.
     
  • Nee, L. E., M. R. Gomez, et al. (1991).
    Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation.
    Clin Auton Res 1(1): 9-13.
    We studied 60 patients with multiple system atrophy and autonomic failure and 60 control subjects matched for age, sex and race. Their psychosocial history, pedigree and occupation were obtained by personal interview. An inventory of autonomic and neurologic symptoms was obtained from 148 first-degree relatives of the patients and 80 controls by a self-administered questionnaire. Patients with multiple system atrophy had significantly more potential exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, and pesticides than the control population. The potential exposures were determined in most subjects by their reported usual occupation. Clinical symptoms of multiple system atrophy were reported by a significantly larger group of patients' relatives than controls. These findings are possibly consistent with the hypothesis that multiple system atrophy develops as a result of a genetically determined selective vulnerability in the nervous system. Specific neuronal systems may become targets for environmental insults or toxins, and the disease state may occur when ageing neuronal systems can no longer sustain functional capacity. This preliminary study supports the need to further explore possible environmental, occupational, and familial contributions to the aetiology of multiple system atrophy
    .
     
  • Ngim, C. H. and G. Devathasan (1989).
    Epidemiologic study on the association between body burden mercury level and idiopathic Parkinson's disease.
    Neuroepidemiology 8(3): 128-41.
    A case-control study was conducted among the multiethnic population of Singapore to test the hypothesis that a high level of body burden mercury is associated with an increased risk of Parkinson's disease (PD). Selected factors investigated that could contribute to the body burden of mercury included dietary fish intake, ethnic over-the-counter medications, occupational exposures and possession of dental amalgam fillings. Detailed interviews were completed in 54 cases of idiopathic PD and 95 hospital-based controls, matched for age, sex and ethnicity, between July 1985 and July 1987. After adjusting for potential confounding factors, including dietary fish intake, medications, smoking and alcohol consumption, there was clear monotonic dose- response association between PD and blood mercury levels. .. When the body burden mercury indicators were mutually adjusted in addition to the four confounding factors, blood and urinary mercury levels showed ORs of 21.00 and 18.65, respectively. These ORs were statistically different from unity (p less than 0.05, 2-sided test). After adjustment, scalp hair mercury was shown to be a poor predictor of PD risk.
     
  • Ohlson, C. G. and C. Hogstedt (1981).
    Parkinson's disease and occupational exposure to organic solvents, agricultural chemicals and mercury--a case-referent study.
    Scand J Work Environ Health 7(4): 252-6.
    Parkinson's disease has been associated with heavy occupational exposure to carbon disulfide, and this solvent, as well as other organic solvents, may cause neurotoxic effects. Therefore, the hypothesis was raised that organic solvents in general may be associated with Parkinson's disease. A case-referent study design was applied, and some other suspected exposures were studied as well.... No differences in exposure frequency to organic solvents in general were observed, but three cases had been exposed to carbon disulfide compared to none of the referents. Six cases, but only two referents, had been exposed to mercury, and further exploration of a possible association between exposure to mercury and Parkinson's disease is recommended. The outcome of the study does not support the hypothesis that occupational exposure to organic solvents in general increases the risk of Parkinson's disease, but the confidence intervals of the odds ratios do not rule out such possibilities
    .
     
  • Pezzoli, G., O. Strada, et al. (1996).
    Clinical and pathological features in hydrocarbon-induced parkinsonism.
    Ann Neurol 40(6): 922-5.
    A neuropathological examination was performed on a patient with parkinsonism induced by prolonged exposure to a mixture of aliphatic hydrocarbons, mainly n-hexane and halogenated compounds. The patient developed a rapid-course disease that progressed even after withdrawal from the toxic exposure. Pathological examination and immunohistochemical analysis of the brain revealed severe and widespread dopaminergic neuronal loss, associated with severe gliosis, in the substantia nigra, and almost complete loss of tyrosine hydroxylase immunostaining in the striatum. No Lewy bodies were detected. Neuronal loss was also observed in the periaqueductal gray matter, locus ceruleus, and pedunculopontine nucleus. These changes, combined with the moderate anemia due to marrow suppression, and the mild axonal neuropathy observed in vivo, are suggestive of a hydrocarbon toxic insult.
     
  • Rajput, A. H. (1993).
    Environmental causation of Parkinson's disease.
    Arch Neurol 50(6): 651-2.
     
  • Rajput, A. H. (2001).
    Environmental toxins accelerate Parkinson's disease onset.
    Neurology 56(1): 4-5.
     
  • Rajput, A. H., R. J. Uitti, et al. (1986).
    Early onset Parkinson's disease in Saskatchewan--environmental considerations for etiology.
    Can J Neurol Sci 13(4): 312-6.
    The cause of idiopathic Parkinson's Disease (PD) is not known but it is believed to be related to some environmental agent(s). Given a long preclinical interval and onset of symptomatology around age 60 years, it becomes impossible to identify and analyze all prior environmental factors satisfactorily. To circumvent these difficulties we evaluated the childhood environment in those PD patients whose symptoms began at age 40 years or earlier. Twenty-one such cases were born and raised in the province of Saskatchewan. Nineteen of these 21 patients spent the first 15 years of life exclusively in rural Saskatchewan. Detailed population analysis indicates a strong predisposition to early onset idiopathic Parkinson's Disease (EPD) in those raised in rural areas (p = 0.0154). All but one case utilized exclusively well water for the first 15 years of life--a trait significantly different from that expected in the provincial population. It is concluded that rural Saskatchewan environments contribute to EPD and that well water used in childhood should be considered as a potential vehicle for the etiological agent.
     
  • Rajput, A. H., R. J. Uitti, et al. (1987).
    Geography, drinking water chemistry, pesticides and herbicides and the etiology of Parkinson's disease.
    Can J Neurol Sci 14(3 Suppl): 414-8.
    In 1984 we made the first observation of a correlation between early age exposure to rural environment (and drinking well water) and development of idiopathic Parkinson's disease (IPD). These findings were subsequently confirmed elsewhere (Barbeau, 1985;25 Tanner, 1985). Analysis of all early age onset IPD (EPD) cases born and raised in Saskatchewan revealed that 20 of 22 had exclusively rural exposure during the first 15 years of life. This distribution was significantly different from the general population (p = 0.0141). Further study of the EPD group included sampling and metal analysis of childhood sources of drinking water in 18 cases and 36 age and sex-matched controls. Water collected from the two groups was analyzed for 23 metals (including 7 elements implicated in the etiology of IPD). There was no difference in the metal composition of the water between the two groups. Finally, a review of herbicide and pesticide use in Saskatchewan agriculture was undertaken to determine if there was an increased incidence of EPD following utilization of any particular chemical. No increase was found in the incidence of EPD with the introduction of any pesticide or herbicide, including Paraquat, for agricultural use. We conclude that there is a strong correlation between early age rural environmental exposure and development of IPD. We believe well water is a likely vehicle for the causal agent, but neither water metal concentration nor any of the herbicides and pesticides used in Saskatchewan agriculture are related to the cause.
     
  • Rushkevich, I. E. (1987).
    [Age characteristics of the development of a reserpine model of parkinsonism in rats].
    Biull Eksp Biol Med 104(12): 654-7.
    The studies were performed on 9-month- and 26-month-old rats. Electrodes were implanted into the nucleus caudatus, globus pallidus and substantia nigra. It has been found that with ageing the greatest decrease in the background electrical activity was found in n. caudatus and the least in globus pallidus. Old rats showed the signs of relative extrapyramidal insufficiency, i. e. hypokinesia and enhanced tremor. Due to 7-day reserpine administration the adult animals developed a marked hypokinesia, while the old rats showed an enhanced tremor.
     
  • Rybicki, B. A., C. C. Johnson, et al. (1993).
    Parkinson's disease mortality and the industrial use of heavy metals in Michigan.
    Mov Disord 8(1): 87-92.
    Parkinson's disease (PD) mortality rates in Michigan counties for 1986- 1988 were calculated with respect to potential heavy metal exposure (iron, zinc, copper, mercury, magnesium, and manganese) from industry based on recent census data. Individuals were counted as a PD death if the diagnosis was listed as an "underlying" or "related" cause of death on the death certificate. Counties with an industry in the paper, chemical, iron, or copper related-industrial categories (ICs) had statistically significantly (p < 0.05) higher PD death rates than counties without these industries. .. These ecologic findings suggest a geographic association between PD mortality and the industrial use of heavy metals.
     
  • Schapira, A. H. (2001).
    Causes of neuronal death in Parkinson's disease.
    Adv Neurol 86: 155-62.
    The etiology of PD is complex and may depend on multiple factors, both hereditary and environmental. A proportion of PD disease patients show a deficiency in mitochondrial respiratory chain function, in particular a defect of complex I, within neurons of the substantia nigra. Both mitochondrial mutations and toxic agents (endogenous and exogenous) have been demonstrated to cause a deficiency in complex I function. This is achieved by increasing the degree of, or susceptibility to, oxidative stress, which may contribute to apoptopic cell death. Future research directed toward developing neuroprotective strategies may reduce oxidative stress and stabilize or improve mitochondrial function.
     
  • Schapira, A. H., M. Gu, et al. (1998).
    Mitochondria in the etiology and pathogenesis of Parkinson's disease.
    Ann Neurol 44(3 Suppl 1): S89-98.
    Mitochondria play a critical role in cellular energy metabolism. The identification of a respiratory chain defect in Parkinson's disease (PD) provides not only a direct link with toxin models of parkinsonism but also insight into the mechanisms involved in etiology and pathogenesis. ... Identification of the mtDNA genotype responsible for PD may allow the testing of neuroprotective strategies in appropriate patients.
     
  • Seidler, A., W. Hellenbrand, et al. (1996).
    Possible environmental, occupational, and other etiologic factors for Parkinson's disease: a case-control study in Germany.
    Neurology 46(5): 1275-84.
    In a case-control study, we investigated the possible etiologic relevance to Parkinson's disease (PD) of rural factors such as farming activity, pesticide exposures, well-water drinking, and animal contacts; toxicologic exposures such as wood preservatives, heavy metals, and solvents; general anesthesia; head trauma; and differences in the intrauterine environment. We recruited 380 patients in nine German clinics, 379 neighborhood control subjects, and 376 regional control subjects in the largest case-control study investigating such factors and collected data in structured personal interviews using conditional logistic regression to control for educational status and cigarette smoking. The latter was strongly inversely associated with PD. There were significantly elevated odds ratios (OR) for pesticide use, in particular, for organochlorines and alkylated phosphates, but no association was present between PD and other rural factors. A significantly elevated OR was present for exposure to wood preservatives. Subjective assessment by the probands indicated that exposure to some heavy metals, solvents, exhaust fumes, and carbon monoxide was significantly more frequent among patients than control subjects, but this was not confirmed by a parallel assessment of job histories according to a job exposure matrix. Patients had undergone general anesthesia and suffered severe head trauma more often than control subjects, but a dose-response gradient was not present. Patients reported a significantly larger number of amalgam-filled teeth before their illness than control subjects. The frequency of premature births and birth order did not differ between patients and control subjects. Patients reported significantly more relatives affected with PD than control subjects. These results support a role for environmental and genetic factors in the etiology of PD.
     
  • Smargiassi, A., A. Mutti, et al. (1998).
    A case-control study of occupational and environmental risk factors for Parkinson's disease in the Emilia-Romagna region of Italy.
    Neurotoxicology 19(4-5): 709-12.
    A questionnaire-based case-control study was carried out on 86 patients with neurologist-confirmed idiopathic Parkinson's disease (PD) and 86 controls similar in sex and age. The control group was recruited in outpatient specialist centers of the same University Hospital (glaucoma, psoriasis vulgaris, essential arterial hypertension and renal diseases). Exposure was defined as occupational or residential contact with a given factor for at least 10 consecutive years prior to the onset of PD. Smoking habits were defined by exclusion of those subjects who never smoked. The following risk factors were identified: cranial trauma (OR: 2.88; 95% CI: 0.98-8.49), well water use (OR: 2.78; 95% CI: 1.46-5.28) and occupational exposure to industrial chemicals (OR: 2.13; 95% CI: 1.16-3.91). Among industrial chemicals, only organic solvents were identified as significant risk factors for PD (O.R. : 2.78, 95% C.I. : 1.23-6.26). Whereas no exposure to neurotoxic metals occurred among controls, making the assessment of the O.R. impossible, exposure pesticides and herbicides was similar in the two groups (O.R. : 1.15; 95% C. : 0.56-2-36). Smoking habits was negatively associated with PD (OR: 0.41; 95% CI: 0.22-0.75), confirming the "protective" role of tobacco smoking suggested by many studies. As a whole, these results support the role of environmental factors in the etiology of PD.
     
  • Sobel, E., Z. Davanipour, et al. (1995).
    Occupations with exposure to electromagnetic fields: a possible risk factor for Alzheimer's disease.
    Am J Epidemiol 142(5): 515-24.
    The authors present analyses of data from three independent clinical series and controls indicating an association between working in occupations with probable medium to high exposure to extremely low frequency (< 300 Hz) electromagnetic fields and sporadic Alzheimer's disease. The most obvious, possibly etiologically relevant exposure is that of electromagnetic fields, which may have biologic plausibility because they may adversely influence calcium homeostasis and/or inappropriately activate immune system cells such as microglial cells, initiating events that result in neuronal degeneration.
     
  • Sobel, E., M. Dunn, et al. (1996).
    Elevated risk of Alzheimer's disease among workers with likely electromagnetic field exposure.
    Neurology 47(6): 1477-81.
    We conducted a case-control study of the possible association of occupations with likely exposure to electromagnetic fields and Alzheimer's disease (AD) with patients from the Alzheimer Disease Treatment and Diagnostic Center, Rancho Los Amigos Medical Center, Downey, CA. Patients with definite or probable AD were the case subjects (86 male, 240 female). ..These results are consistent with previous findings regarding the hypothesis that electromagnetic field exposure is etiologically associated with the occurrence of AD
    .
     
  • Tanner, C. M. (1989).
    The role of environmental toxins in the etiology of Parkinson's disease.
    Trends Neurosci 12(2): 49-54.
    The production by the pyridine MPTP of a parkinsonian syndrome strikingly similar to the 'idiopathic' disorder, and the paucity of evidence supporting a hereditary or infectious etiology for Parkinson's disease (PD), have stimulated a search for environmental chemicals resembling MPTP that might cause PD. In support of this, descriptive epidemiological studies have found higher prevalences of PD in highly industrialized countries. In North America and Europe, early onset PD appears to be associated with rural residence. Factors associated with this include vegetable farming, well water drinking, wood pulp, paper and steel industries. In China, living in industrialized urban areas increases the risk of developing PD. Preliminary epidemiological evidence supports the hypothesis that environmental chemicals may be related to the development of PD, but specific chemicals and their specific mechanism(s) have not been identified.
     
  • Tanner, C. M. (1992).
    Occupational and environmental causes of parkinsonism.
    Occup Med 7(3): 503-13.
    Occupational causes of parkinsonism have usually been identified by direct temporal association of an exposure with disease symptoms, although recently a latent period between exposure and disease causation is being investigated. This review presents the definition of parkinsonism as contrasted with Parkinson's disease, notes the general concepts important to the consideration of toxic effects on the central nervous system, and addresses each group of agents known to cause parkinsonism, including common sources of exposure, clinical course, and proposed mechanisms of toxicity. Agents discussed include manganese, carbon disulfide, organic solvents, carbon monoxide, and MTPT and similar agents.
     
  • Tanner, C. M., B. Chen, et al. (1989).
    Environmental factors and Parkinson's disease: a case-control study in China.
    Neurology 39(5): 660-4.
    We studied the role of environment in the development of Parkinson's disease (PD) in China, where industrialization is relatively recent and the population geographically stable. Using a case-control method, we investigated the relationship between PD and exposure to the following factors before disease onset: place of residence, source of drinking water, environmental and occupational exposure to various agricultural and industrial processes. Occupational or residential exposure to industrial chemicals, printing plants, or quarries was associated with an increased risk of developing PD. In contrast, living in villages and exposure to the common accompaniments of village life, wheat growing and pig raising, were associated with a decreased risk for PD. PD cases and controls did not differ with respect to other factors investigated. These findings are consistent with the hypothesis that environmental exposure to certain industrial chemicals may be related to the development of PD.
     
  • Tanner, C. M. and J. W. Langston (1990).
    Do environmental toxins cause Parkinson's disease? A critical review.
    Neurology 40(10 Suppl 3): suppl 17-30; discussion 30-1.
     
  • Vieregge, P., D. Kompf, et al. (1988).
    Environmental toxins in Parkinson's disease.
    Lancet 1(8581): 362-3.
     
  • Nat Neurosci 2000 Dec; 3(12):1301-6
    Chronic systemic pesticide exposure reproduces features of Parkinson's disease.
    Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT
    [1] Department of Neurology, Emory University, 1639 Pierce Drive, WMB 6000, Atlanta, Georgia 30322, USA[2] The first two authors contributed equally to this work.
    The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.
     
  • J Neural Transm 2000;107(8-9):979-83
    Paraoxonase polymorphisms, pesticide exposure and Parkinson's disease in a Caucasian population.
    Taylor MC, Le Couteur DG, Mellick GD, Board PG
    Molecular Genetics Group, John Curtin School of Medical Research, Acton, ACT, Australia.
    Parkinson's disease (PD) has been associated with exposure to pesticides and oxidative injury. The involvement of paraoxonase in both pesticide metabolism and lipid peroxidation suggests that it may play a role in the pathogenesis of PD. We examined the frequency of polymorphic alleles of the PON1 and PON2 genes in a sample of caucasian subjects with PD. The frequency distribution of these genotypes did not differ significantly between patients and controls, including those who had reported exposure to pesticides.
     
  • Neurotoxicology 2000 Aug;21(4):435-40
    A meta-analysis of Parkinson's disease and exposure to pesticides.
    Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S
    Department of Public Health, Medical College of Ohio, Toledo, USA.
    This study examined the association between Parkinson's disease (PD) and exposure to pesticides. A series of meta-analysis of peer-reviewed studies were performed, using 19 studies published between 1989 and 1999... Although the risk of PD increased with increased duration of exposure to pesticides, no significant dose-response relation was established, and no specific type of pesticide was identified. Our findings suggest that exposure to pesticides may be a significant risk factor for developing PD.
     
  • Brain Res 2000 Aug 11;873(2):225-34
    Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson's disease?
    Thiruchelvam M, Brockel BJ, Richfield EK, Baggs RB, Cory-Slechta DA
    Departments of Environmental Medicine, Pathology and Laboratory Medicine, Laboratory Animal Medicine and the NIEHS Environmental Health Sciences Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.
    The absence of any compelling basis for a heritable basis of idiopathic Parkinson's disease (PD) has focused attention on environmental exposures as causative agents. While the herbicide paraquat has repeatedly been implicated, its impact on dopamine systems following systemic exposures is equivocal. The restricted focus on paraquat also ignores the extensive geographical overlap of its use with other agrichemicals known to adversely impact dopamine systems, including ethylenebisdithiocarbamate fungicides such as maneb. The present study sought to determine whether combined exposures to paraquat and maneb would produce additive effects and support a multiple-hit environmental contribution to PD. ..The fact that combined exposures resulted in potentiated effects that appear to target nigrostriatal dopamine systems suggests that these combinations may be important environmental risk factors for Parkinsonism. These findings also raise questions about the adequacy of current risk assessment guidelines for these chemicals which are based on effect levels derived from exposures to single agents.
     
  • Int J Epidemiol 2000 Apr;29(2):323-9
    Parkinson's disease mortality and pesticide exposure in California 1984-1994.
    Ritz B, Yu F
    Department of Epidemiology, Center for Occupational and Environmental Health, School of Public Health, UCLA, Los Angeles, CA 90095-1772, USA.
    BACKGROUND: In the last two decades reports from different countries emerged associating pesticide and herbicide use with Parkinson's disease (PD). California growers use approximately 250 million pounds of pesticides annually, about a quarter of all pesticides used in the US. .. RESULTS: Mortality from PD as the underlying cause of death was higher in agricultural pesticide-use counties than in non-use counties. A dose response was observed for insecticide use per county land treated when using 1982 agricultural census data, but not for amounts of restricted pesticides used or length of residency in a country prior to death. CONCLUSIONS: Our data show an increased PD mortality in California counties using agricultural pesticides. Unless all of our measures of county pesticide use are surrogates for other risk factors more prevalent in pesticide use counties, it seems important to target this prevalent exposure in rural California in future studies that use improved case finding mechanisms and collect pesticide exposure data for individuals.
                                
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