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Study Links Pesticides, Parkinson's

November 6, 2000

The Associated Press

New research using rats suggests that long-term exposure to a widely used pesticide kills brain cells and triggers debilitating physical symptoms associated with Parkinson's disease.

Scientists say the experiment's results strongly indicate what scientists have suspected for several years - that the most common form of Parkinson's disease might result from toxins in the environment.

The new study, published in the December issue of Nature Neuroscience, does not prove that the pesticide used in the test, rotenone, causes Parkinson's in humans.

But scientists who reviewed the experiment said the results are powerful and should reinvigorate the search for environmental toxins that may contribute to Parkinson's, the most common neurological disorder after Alzheimer's.

"This is more evidence that a class of compounds may increase the risk of developing Parkinson's," said J. William Langston, director of the Parkinson's Institute in Sunnyvale, Ca., who was not involved in the study. "It is not direct evidence that rotenone causes Parkinson's. The whole puzzle hasn't come together."

More than one million Americans suffer from Parkinson's. Muscle control ebbs as brain cells in a region called the substantia nigra produce less dopamine, a hormone vital to normal nerve function. The illness is marked by small tremors, such as facial tics and shaking hands. Advanced symptoms include a shuffling gait, speech difficulties and muscle weakness.

There is no cure, and current drug and surgical therapies tends to lose effectiveness over time. New therapies involving transplants of stem cells, the body's master cells from which all tissues grow, have been slowed by federal funding restrictions on experiments using embryonic tissues.

In about 10 percent of patients, Parkinson's strikes before age 50. These rare cases probably are caused by inherited genetic abnormalities.

However, most patients show their first Parkinson's symptoms after age 60. Researchers believe older patients may have suffered brain damage from chronic exposure to unspecified toxins. Among the suspects: pesticides, industrial chemicals and tobacco smoke.

In the experiment conducted at Emory University in Atlanta, neurologists implanted tiny pumps in the rats to continuously administer low doses of rotenone through the jugular vein for as long as five weeks.

Rotenone is an organic product made from extracts of tropical plants. It is widely used as an agricultural pesticide and to kill unwanted fish in reservoirs.

People most frequently would be exposed to rotenone by ingesting residue in food or by handling the compound.

Scientists acknowledged the pump method used in the experiment did not duplicate rotenone exposure in the real world, but said it was a more direct and reliable method for research purposes.

"Rats can be picky about what they eat and they might not like eating rotenone," said J. Timothy Greenamyre, the study's senior author. "Whether the pesticide would have the same effect in people via normal routes of exposure is not clear."

Greenamyre said half of the rats gradually showed Parkinson's symptoms.

Examination revealed that large numbers of dopamine-producing cells in the rats' brains had died or were damaged. In addition, the cells showed fibrous protein deposits that closely resemble Lewy bodies, deposits found in brain cells of Parkinson's patients.

"Together, it's what you see in Parkinson's," Greenamyre said. How rotenone might have triggered these changes in rat is unclear. University of Pennsylvania researchers Benoit I. Giasson and Virginia M.-Y. Lee, who reviewed the Emory experiment, suggest the pesticide might target the mitochondria, a genetic bundle that generates most of a cell's energy.

Such damage unleashes rogue molecules known as free radicals that wreak havoc in cells. Free radicals have been implicated in many degenerative diseases.

"Neurons are particularly sensitive," Giasson and Lee noted. Greenamyre said future rotenone experiments with rats would test new drugs aimed at protecting dopamine-producing cells.

In the meantime, he suggested that farmers and public health agencies reconsider pesticide usage.

"Pesticides are essential for growing crops, but we may need to think about minimizing their environmental impact," he said.

Appl Occup Environ Hyg 2000 Jul;15(7):542-9

Manganese dioxide exposures and respirator performance at an alkaline battery plant.

Hanley KW, Lenhart SW

National Institute for Occupational Safety and Health, Cincinnati, Ohio, USA.

Two industrial hygiene studies were conducted at an alkaline battery plant to evaluate worker exposures to manganese dioxide particulate and the effectiveness of filtering facepiece respirators. The work areas studied included the plant's powder-processing tower and press rooms where manganese was blended, compacted with graphite, and inserted into battery cans. Full-shift personal breathing zone monitoring was conducted to estimate manganese dust exposures of press operators, mechanics, and material handlers. In-facepiece and personal breathing zone air sampling pairs were also collected using a program protection factor protocol to estimate the protection provided by the respirators. Particle size evaluations were made using nylon cyclones and Marple personal multi-stage impactors. All samples were analyzed for manganese by inductively coupled argon plasma, atomic emission spectroscopy via NIOSH analytical method 7300 utilizing a modified acid digestion procedure. Fifty-four, full-shift, time-weighted average (TWA) exposures to total manganese ranged from 0.1 to 5.4 milligrams per cubic meter (mg/m3); worker exposures were substantially lower during a follow-up study due to engineering control improvements. Concurrent area sample comparisons of total and respirable manganese revealed that the respirable particulate mass fractions ranged from 6 to 32 percent, and mass median aerodynamic diameters determined from personal breathing zone air samples were mostly greater than 10 micrometers. Fifteen respirator performance evaluations were conducted using Moldex 2200 respirators fitted with 25 millimeter cassettes and light weight sampling probes. Protection factors ranged from 5 to 220, with a geometric mean and standard deviation of 31 and 2.97, respectively. The 5th percentile protection factor estimate was 5, as calculated from the protection factor distribution for this sample set. In 1995, the American Conference of Governmental Industrial Hygienists (ACGIH) lowered the elemental and inorganic manganese dust Threshold Limit Value (TLV) from 5 mg/m3 to 0.2 mg/m3 to address adverse pulmonary and central nervous system effects and male infertility. Although most personal breathing zone concentrations were above 0.2 mg/m3, none of the in-facepiece concentrations exceeded this concentration. Parkinson's-like symptoms have been reported in the literature for high manganese dust and fume exposures, but the importance of low dust exposures for producing neurological effects is uncertain.
Nervenarzt 2000 May;71(5):416-9

[Follow-up study after enteral manganese poisoning: clinical, laboratory and neuroradiological findings].

[Article in German]

Degner D, Bleich S, Riegel A, Sprung R, Poser W, Ruther E

Psychiatrische Klinik und Poliklinik, Georg-August-Universitat Gottingen.

Manganese intoxication is an unusual, severe form of intoxication. This report deals with a patient now 80 years old who accidentally ingested a solution of potassium permanganate for a period of at least 4 weeks 14 years ago. Since then, the patient suffers from a mild parkinsonian syndrome and distally accentuated polyneuropathies. Psychiatric disorders, especially demential or depressive symptoms, were not observed. Manganese analysis of his hair still shows a clear increase in manganese concentration. The MRI of his brain showed no pathological changes, in particular none of those often described with symmetric signal elevation in T1 in the area of the basal ganglia. In this study, we present clinical, laboratory, and neuroradiological findings. Unusual in this case with a short exposition is the long duration and clinical improvement without L-dopa treatment.
J Cell Physiol 2000 Oct;185(1):80-6

Role of heme oxygenase-1 in the regulation of manganese superoxide dismutase gene expression in oxidatively-challenged astroglia.

Frankel D, Mehindate K, Schipper HM

Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada.

Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that reduces superoxide anion to hydrogen peroxide in cell mitochondria. MnSOD is overexpressed in normal aging brain and in various central nervous system disorders; however, the mechanisms mediating the upregulation of MnSOD under these conditions remain poorly understood. We previously reported that cysteamine (CSH) and other pro-oxidants rapidly induce the heme oxygenase-1 (HO-1) gene in cultured rat astroglia followed by late upregulation of MnSOD in these cells. In the present study, we demonstrate that antecedent upregulation of HO-1 is necessary and sufficient for subsequent induction of the MnSOD gene in neonatal rat astroglia challenged with CSH or dopamine, and in astroglial cultures transiently transfected with full-length human HO-1 cDNA. Treatment with potent antioxidants attenuates MnSOD expression in HO-1-transfected astroglia, strongly suggesting that intracellular oxidative stress signals MnSOD gene induction in these cells. Activation of this HO-1-MnSOD axis may play an important role in the pathogenesis of Alzheimer disease, Parkinson disease and other free radical-related neurodegenerative disorders. In these conditions, compensatory upregulation of MnSOD may protect mitochondria from oxidative damage accruing from heme-derived free iron and carbon monoxide liberated by the activity of HO-1. Copyright 2000 Wiley-Liss, Inc.
J Neurosci Res 1999 Apr 15;56(2):113-22

Existing and emerging mechanisms for transport of iron and manganese to the brain.

Malecki EA, Devenyi AG, Beard JL, Connor JR

Department of Neuroscience and Anatomy, College of Medicine, Pennsylvania State University, Hershey 17033, USA.

The metals iron (Fe) and manganese (Mn) are essential for normal functioning of the brain. This review focuses on recent developments in the literature pertaining to Fe and Mn transport. These metals are treated together because they appear to share several transport mechanisms. In addition, several neurological diseases such as Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease are all associated with Fe mismanagement in the brain, particularly in the striatum and basal ganglia. Similarly, Mn accumulation in brain also appears to target the same brain regions. Therefore, stringent regulation of the concentration of these metals in the brain is essential. The homeostatic mechanisms for these metals must be understood in order to design neurotoxicity prevention strategies.
Arch Neurol 2000 Apr;57(4):597-9

Manganese intoxication.

Lee JW

Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul.

Manganese plays an important role as a cofactor in many enzymatic reactions in humans but in excess amounts can cause irreversible nervous system damage. Although manganism is a rare condition, it can be the cause of complex nervous system symptoms, especially in the setting of environmental exposure. Specifically, manganese is a well-known cause of dystonic parkinsonism. This article highlights several historical descriptions of the clinical manifestations, pathological changes, and attempted therapeutic intervention in manganese intoxication.
Rinsho Shinkeigaku 1999 Jul;39(7):693-9

[Diagnostic utility of positron emission tomography for parkinsonism after chronic manganese exposure].

[Article in Japanese]

Abe Y, Kachi T, Kato T, Ito K, Yanagisawa N, Sobue G

Department of Neurology, Chubu National Hospital, Obu, Japan.

Positron emission tomography (PET) with [18F] 6-fluoro-L-dopa (18F-FDOPA) was performed in three South Korean patients with parkinsonism who developed after chronic manganese exposure. A 51-year-old man (patient 1) suffered from masked face, marked postural tremor of hands, dystonia in the neck and the upper extremities, severe retropulsion and lateropulsion which were typical for chronic manganese intoxication. 18F-FDOPA scan was normal. Other two patients, a 46-year-old man (patient 2) and a 47-year-old man (patient 3), showed tremor at rest and rigidity predominantly on the right side, bradykinesia, stooped posture and postural instability; all of these were typical for Parkinson's disease (PD). There was reduced uptake of 18F-FDOPA in the striatum, particularly in the posterior putamen predominant on the left side, in both patient 2 and 3. From these results, patient 1 was diagnosed as pure manganism, while patient 2 and 3 were primarily as PD, because loss of nigrostriatal fibers was obvious with asymmetry of affection in the putamen. PET with 18F-FDOPA provides valuable information for differentiation between PD and manganism, although it is not clear whether development of parkinsonian symptoms in patient 2 and 3 was modified by excessive manganese exposure.
J Am Coll Nutr 1999 Oct;18(5):413-23

Multiple antioxidants in the prevention and treatment of Parkinson's disease.

Prasad KN, Cole WC, Kumar B

Center for Vitamins and Cancer Research, Department of Radiology, University of Colorado Health Sciences Center, Denver 80262, USA.

Parkinson's disease (PD) is one of the major progressive neurological disorders for which no preventative or long-term effective treatment strategies are available. Epidemiologic studies have failed to identify specific environmental, dietary or lifestyle risk factors for PD except for toxic exposure to manganese, meperidine (Demerol, the "designer drug" version of which often contains a toxic byproduct of the synthesis, 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine [MPTP]), and some herbicides and pesticides. The search for genetic risk factors such as mutation, overexpression or underexpression of nuclear genes in DA neurons in idiopathic PD has not been successful as yet. Polymorphism in certain genes appears to be a risk factor, but there is no direct evidence for the causal relationship between polymorphism and increased risk of PD. In familial PD, mutation in the alpha-synuclein gene is associated with the disease, but a direct role of this gene in degeneration of DA neurons remains to be established. Although mutations in the Parkin gene has been associated with autosomal recessive juvenile Parkinson's disease, the role of this gene mutation in causing degeneration of DA neurons has not been defined. We have reported that in hereditary PD, a mutation in the alpha-synuclein gene may increase the sensitivity of DA neurons to neurotoxins. We hypothesize that, in idiopathic PD, epigenetic (mitochondria, membranes, protein modifications) rather than genetic events are primary targets which, when impaired, initiate degeneration in DA neurons, eventually leading to cell death. Although the nature of neurotoxins that cause degeneration in DA neurons in PD is not well understood, oxidative stress is one of the intermediary risk factors that could initiate and/or promote degeneration of DA neurons. Therefore, supplementation with antioxidants may prevent or reduce the rate of progression of this disease. Supplementation with multiple antioxidants at appropriate doses is essential because various types of free radicals are produced, antioxidants vary in their ability to quench different free radicals and cellular environments vary with respect to their lipid and aqueous phases. L-dihydroxyphenylalanine (L-dopa) is one of the agents used in the treatment of PD. Since L-dopa is known to produce free radicals during its normal metabolism, the combination of L-dopa with high levels of multiple antioxidants may improve the efficacy of L-dopa therapy.
Neurotoxicology 1999 Apr-Jun;20(2-3):499-507 t

A brief history of the neurobehavioral toxicity of manganese: some unanswered questions.

McMillan DE

University of Arkansas for Medical Sciences, Little Rock 72205, USA.

It was observed by Couper in 1837 that manganese dust produces a neurological syndrome characterized by muscle weakness, tremor, bent posture, whispered speech and excess salivation. The similarity of these symptoms to those of Parkinson's disease were not recognized for many years. In addition to its Parkinson-like effects, manganese produces behavioral symptoms in humans including nervousness, hallucinations, memory loss, cognitive problems, bizarre behaviors and flight of ideas. Despite these signs and symptoms, there have been few systematic attempts to study the effects of manganese on behavior using animal models. The need to better understand the effects of manganese on behavior is becoming more important due to the potential of increased environmental exposure to manganese due to its use, or proposed use as a gasoline additive in a number of countries. However, there is debate as to which manganese compounds should receive priority for testing, what route of administration should be used in this testing, what dosing regimens should be used, what species are appropriate for behavioral testing, and what behavioral tests should be selected. Research to answer these questions is needed so that the behavioral effects of manganese can be described comprehensively and the mechanisms underlying these effects can be understood.
Kao Hsiung I Hsueh Ko Hsueh Tsa Chih 1999 May;15(5):297-301

Rapid progression of parkinsonism associated with an increase of blood manganese.

Kao HJ, Chen WH, Liu JS

Department of Neurology, Kaohsiung Medical College Hospital, Taiwan, Republic of China.

In this paper, we report a 72-year-old man whose parkinsonian pictures accelerated rapidly after an ingestion of unknown herb pills. His serum manganese and aluminum level increased 2-fold and 5-fold over physiological level respectively. A reverse of his parkinsonian deterioration was accompanied with a normalization of these metals. Exclusive heavy metals have been widely mentioned in parkinsonism. While industrial source of these metals has extensively been sought, pharmacology is rarely mentioned in this aspect, especially of herb medicine origin. We suggest that an acceleration of parkinsonian pictures should raise the need to re-evaluate the possibility of heavy metal intoxication in parkinsonism. Besides of industrial contamination, we should be alert for the nonindustrial source in our population.
Brain Res Mol Brain Res 1999 May 7;68(1-2):22-8

Manganese potentiates nitric oxide production by microglia.

Chang JY, Liu LZ

Department of Anatomy, Slot 510, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72205, USA.

Manganese toxicity has been associated with clinical symptoms of neurotoxicity which are similar to the symptoms observed in Parkinson's disease. Earlier reports indicated that reactive microglia was present in the substantia nigra of patients with Parkinson's disease. Using N9 microglial cells, the current study was designed to determine whether high levels of manganese were associated with microglial activation. Results indicated that manganese significantly increased the bacterial lipopolysaccharide-induced nitric oxide production. This potent activity of manganese was not shared by other transition metals tested, including iron, cobalt, nickel, copper and zinc. Immunohistochemical staining and Western blot analysis indicated that manganese increased the cellular production of inducible nitric oxide synthase. Northern blot analysis indicated that manganese likely increased iNOS gene transcription since this agent increased the mRNA level of the inducible nitric oxide synthase. In contrast to other transition metals tested, manganese did not appear to be cytotoxic to microglial cells. These results suggested that manganese could induce sustained production of neurotoxic nitric oxide by activated microglial cells, which might cause detrimental consequences to surrounding neurons.
Neurotoxicology 1995 Fall;16(3):511-7

Effects of calcium-deficient diets on manganese deposition in the central nervous system and bones of rats.

Yasui M, Ota K, Garruto RM

Division of Neurological Diseases, Wakayama Medical College, Japan.

The presence of both aluminum (Al) and manganese (Mn) in central nervous system tissues (CNS) has been reported in Parkinson's disease and in parkinsonism-dementia (PD) on Guam. Epidemiological surveys on Guam have suggested that low calcium (Ca), magnesium (Mg) and high Al and Mn in river, soil and drinking water may be implicated in the pathogenesis of PD. Experimentally, low Ca-Mg diets with or without added Al have been found to accelerate Al deposition in the CNS of rats and monkeys. Although excessive deposition of Mn produces similar neurotoxic action to Al in CNS tissues, the mechanism of Mn deposition coupled with Al loading in the presence of low Ca-Mg intake is not yet known. In this study, the deposition and mental-metal interaction of both Al and Mn in the CNS, visceral organs and bones of rats fed unbalanced mineral diets were analyzed. Male Wistar rats, weighing 200 g, were maintained for 90 days on the following diets: (A) standard diet, (B) low Ca diet, (C) low Ca-Mg diet, (D) low Ca-Mg diet with high Al. Al and Mn content were determined in the frontal cortex, spinal cord, kidney, muscle, abdominal aorta, femur and lumbar spine using neutron activation analysis (NAA). Our results demonstrate that serum Ca levels were decreased in the following dietary order: C<D<B<A. Serum Mg levels were significantly lower in rats from Groups C and D, compared with those in Groups A and B, reflecting the content of Mg and other interacting minerals in the diet. There was no significant difference in serum Al, zinc and phosphorus levels. Ca and Mg contents in lumbar vertebrae and the femur were significantly lower and Al levels significantly higher in rats maintained on the low Ca-Mg diet with or without added Al. Al content in CNS tissues and visceral organs were highest in rats fed diets deficient in Ca alone or low in Ca-Mg with or without added Al. Bone Mn levels significantly increased in rats fed the low Ca-Mg diet with added Al. Mn content in the frontal cortex significantly increased in rats fed diets low in Ca-Mg with or without added Al. But the Mn content of other tissues including the spinal cord, kidney, muscle and abdominal aorta was unchanged in rats given Ca deficient diets. Intake of low Ca and Mg with added Al in rats led to the high concentrations of Mn and Al in bones and in the frontal cortex. We conclude that unbalanced mineral diets and metal-metal interactions may lead to the unequal distribution of Al and Mn in bones and ultimately in the CNS inducing CNS degeneration.
J Neurol 1999 Mar;246(3):198-206

Parkinsonism, pyramidal signs, polyneuropathy, and cognitive decline after long-term occupational solvent exposure.

Hageman G, van der Hoek J, van Hout M, van der Laan G, Steur EJ, de Bruin W, Herholz K

Department of Neurology, Medical Spectrum Twente, Hospital Enschede, The Netherlands.

It is well known that exposure to manganese, solvents, or carbon monoxide in an occupational setting may lead to central nervous system damage and parkinsonism. The most important solvents in this respect are methanol, toluene, carbon disulfide, and n-hexane. We describe three patients who had been exposed to various solvents for more than 20 years (25, 34, and 46 years). They presented with parkinsonism, pyramidal signs, mild cognitive decline, and unresponsiveness to levodopa. Two patients had a predominantly axonal and sensory polyneuropathy of the lower legs with fasciculations in one of them. Parkinsonian features were progressive, even after the patients had stopped work. We present clinical data, neuropsychological findings, and results of brain computed tomography or magnetic resonance imaging, electroneuromyography, evoked potentials, single photon emission computed tomography, and positron-emission tomography. There is growing evidence that various organic solvents give rise to a parkinsonism syndrome with pyramidal features in susceptible individuals.
Mov Disord 2001 May;16(3):565-8

Parkinsonism after glycine-derivate exposure.

Barbosa ER, Leiros Da Costa MD, Bacheschi LA, Scaff M, Leite CC.

Divisao de Clinica Neurologica, do Hospital das Clinicas da Faculdade, de Medicina da Universidade, de Sao Paulo, Sao Paulo, Brazil.

This 54-year-old man accidentally sprayed himself with the chemical agent glyphosate, a herbicide derived from the amino acid glycine. He developed disseminated skin lesions 6 hours after the accident. One month later, he developed a symmetrical parkinsonian syndrome. Two years after the initial exposure to glyphosate, magnetic resonance imaging revealed hyperintense signal in the globus pallidus and substantia nigra, bilaterally, on T2-weighted images. Levodopa/benserazide 500/125 mg daily provided satisfactory clinical outcome.
Scand J Work Environ Health 1994 Aug;20(4):301-5

Parkinsonism after chronic exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate).

Meco G, Bonifati V, Vanacore N, Fabrizio E.

Department of Neurosciences, La Sapienza University, Rome, Italy.

Permanent parkinsonism was observed in a man with chronic exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate). Symptoms developed at 37 years of age, two years after exposure had ceased. To our knowledge, this is the second report on parkinsonism associated with exposure to maneb. Manganese is a well-known parkinsonigen toxin in humans. More recently, it has been shown that dithiocarbamates can also induce extrapyramidal syndromes. The biochemical effects of manganese and dithiocarbamates are reviewed and their possible neurotoxic mechanisms are discussed. Both of these components may have played a role in this case.
: Neurology 1988 Apr;38(4):550-3

Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication.

Ferraz HB, Bertolucci PH, Pereira JS, Lima JG, Andrade LA.

Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Sao Paulo, Brazil.

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.