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Occupational exposure to manganese (Mn) primarily occurs through the inhalation of manganese-containing fumes and dust, with welding environments being significant sources of such exposure. Elevated levels of Mn in welding fumes can lead to a neurological syndrome known as manganism. A 28-yr-old male welder with 14 yr of experience, is presenting with complaints of forgetfulness, reasoning disorder, and decreased mental functions persisting for 10 yr. Three months ago, when he started working at the new workplace, he underwent employment screening conducted by the workplace physician. During this screening process, the physician identified a high whole blood Mn level of 25.9 µg/l. The diagnosis of manganism in this patient was established based on exposure to Mn and its compounds, high levels of Mn detected in the whole blood, hyperactive patellar reflexes observed during the physical examination, cranial Magnetic Resonance Imaging (MRI) findings consistent with manganism and complaints reported by the patient that are characteristic of manganism. In this report, the aim is to emphasize the significance of taking a comprehensive occupational history and to draw attention the potential health hazards associated with Mn and its compounds.

Jean Rodier (1920-2003), distinguished researcher and scientist, directed the Toxicology Department of Hygiene Institute of Rabat under the French Protectorate. From 1946, he developed numerous lines of research in occupational health, in particular on Manganism, a neurological disorder that impacted miners in his home country of Morocco. His many papers on Manganism, only one of which was published in English, describe field and laboratory research studies that focused its prevention and management., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of this study was to analyse the published literature on the potential effects of manganese exposure from drinking water on school-age children, with emphasis on cognitive, and neurodevelopment and behavioural effects. A systematic review of up-to-date scientific evidence published from 2006 to 2017 was conducted using Science Direct. A further search was carried out using PubMed and Web of Science. A total of 21 studies were reviewed and categorised into 12 cognitive and 9 neurodevelopment and behavioural effects. The most utilised cognitive test was the Wechsler Intelligence Scale for Children (WISC) or some subtests from it. 10 of the 12 studies on cognitive effects reported an adverse effect of manganese exposure from drinking water on children. 3 out of the 9 studies on neurodevelopment and behavioural effects reported that manganese exposure from drinking water was associated with poorer neurobehavioural performances in school children. 4 others implied the presence of some sex-specific associations with manganese exposure. 1 study suggested that children suffering from attention deficit hyperactivity disorder (ADHD) may be more susceptible to manganese exposure. Another study suggested that manganese was a beneficial nutrient as well as a neurotoxicant. Regardless of the limitations of the studies analysed, the adverse effects of manganese exposure from drinking water on school-aged children is sufficiently demonstrated. Further investigation into the subject to address inconsistencies in existing studies is recommended., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Lead (Pb) and manganese (Mn) are confirmed neurotoxins but it is unclear to what extent low-level exposure produces a unique behavioral signature. The objective of this study was to investigate latent cognitive profiles among children (6-8 years) from Montevideo, Uruguay co-exposed to these metals., Method: Among 345 children, blood Pb and hair Mn were measured using atomic absorption spectroscopy and ICP-MS, respectively. Sixteen measures, reflecting multiple domains of cognitive functioning were gathered: (1) three tests from Cambridge Neuropsychological Test Automated Battery (CANTAB): Intra-Extra Dimensional Shift (IED), Spatial Span (SSP) and Stockings of Cambridge (SOC), (2) ten tasks from Woodcock-Muñoz Achievement Battery, Revised (WM): Visual-Motor Integration, Verbal Comprehension (Vocabulary, Synonyms, Antonyms, Analogies), Visual-Auditory Comprehension, Concept Formation, Visual Spatial Thinking, Number Inversion and Spatial Relations, (3) Bender Gestalt task, and (4) Weschler block design task. Scores were modeled using latent profile analysis (LPA). Association between blood Pb and hair Mn on performance profiles was assessed using ordinal regression, controlling for confounders. An interaction between Pb and Mn was tested., Results: Mean ± SD of blood Pb was 4.1 ± 2.1 μg/dL and 35% of children had blood Pb ≥ 5 μg/dL. Median [5%, 95%] hair Mn level was 0.8 [0.3, 4.1] ppb. Three latent cognitive performance profiles were identified: high (n = 46, 13%), average (n = 209, 61%) and low (n = 90, 26%). Each one-unit increase in blood Pb was associated with a 28% greater likelihood of belonging to a poorer-performing profile. The association was non-linear, with the effect of Pb on profile membership strongest at lower levels of exposure. There was no meaningful interaction between Pb and Mn., Conclusions: A behavioral signature for low-level Pb & Mn exposure was not identified, but the likelihood of membership in low-performing profile was higher at lowest levels of blood Pb. There was no effect measure modification between Pb and Mn. Future research should address how complex environments created by chemical exposures and the social context relate to cognitive performance in young children., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Neurotoxic effects of high-level occupational exposure to manganese (Mn) are well established; however, whether lower-level environmental exposure to Mn in early life causes neurodevelopmental toxicity in children is unclear., Methods: A systematic literature review was conducted to identify and evaluate epidemiologic studies of specific Mn biomarkers assessed during gestation, childhood, or adolescence in association with neurodevelopmental outcomes, focusing on quantitative exposure-response estimates with specific endpoints that were assessed in multiple independent study populations. Study quality was evaluated using the revised RTI item bank and the Cochrane Risk of Bias tool, and the overall weight of epidemiologic evidence for causality was evaluated according to the Bradford Hill considerations., Results: Twenty-two epidemiologic studies were identified that estimated associations between early-life Mn biomarkers and neurodevelopmental outcomes. Seven of these studies provided adjusted estimates for the association with child intelligence assessed using versions of the Wechsler Intelligence Scales for Children; no other specific neurodevelopmental endpoints were assessed in more than three independent study populations each. Among the studies of child intelligence, five studies in four independent populations measured blood Mn, three studies measured hair Mn, and one measured dentin Mn. Overall, cross-sectional associations between Mn biomarkers and measures of child intelligence were mostly statistically nonsignificant but in a negative direction; however, the lone prospective cohort study found mostly null results, with some positive (favorable) associations between dentin Mn and child intelligence. Studies were methodologically limited by their cross-sectional design and potential for confounding and selection bias, as well as unaddressed questions on exposure assessment validity and biological plausibility., Conclusions: The statistical associations reported in the few studies of specific Mn biomarkers and specific neurodevelopmental endpoints do not establish causal effects based on the Bradford Hill considerations. Additional prospective cohort studies of Mn biomarkers and validated neurodevelopmental outcomes, and a better understanding of the etiologic relevance of Mn biomarkers, are needed to shed light on whether environmental exposure to Mn causes adverse neurodevelopmental effects in children., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Iron (Fe) and manganese (Mn) are essential nutrients for humans. They act as cofactors for a variety of enzymes. In the central nervous system (CNS), these two metals are involved in diverse neurological activities. Dyshomeostasis may interfere with the critical enzymatic activities, hence altering the neurophysiological status and resulting in neurological diseases. Areas covered: In this review, the authors cover the molecular mechanisms of Fe/Mn-induced toxicity and neurological diseases, as well as the diagnosis and potential treatment. Given that both Fe and Mn are abundant in the earth crust, nutritional deficiency is rare. In this review the authors focus on the neurological disorders associated with Mn and Fe overload. Expert commentary: Oxidative stress and mitochondrial dysfunction are the primary molecular mechanism that mediates Fe/Mn-induced neurotoxicity. Although increased Fe or Mn concentrations have been found in brain of patients, it remains controversial whether the elevated metal amounts are the primary cause or secondary consequence of neurological diseases. Currently, treatments are far from satisfactory, although chelation therapy can significantly decrease brain Fe and Mn levels. Studies to determine the primary cause and establish the molecular mechanism of toxicity may help to adapt more comprehensive and satisfactory treatments in the future.

Manganese (Mn) over-exposure in occupational settings is associated with basal ganglia toxicity and a movement disorder characterized by parkinsonism (i.e., the signs and symptoms of Parkinson disease). A simple test to help non-neurologists identify workers with clinical Mn neurotoxicity represents an unmet need. In a cohort of Mn-exposed workers from welding worksites, with extensive clinical data, we developed a linear regression model to predict the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) score. We primarily considered factors easily obtained in a primary care or occupational medicine clinic, specifically easily assessed signs of parkinsonism and factors likely to be associated with UPDRS3 such as age, timed motor task results, and selected symptoms/conditions. Secondarily we considered other demographic variables and welding exposure. We based the model on 596 examined workers age≤65years and with timed motor task data. We selected the model based on simplicity for clinical application, biologic plausibility, and statistical significance and magnitude of regression coefficients. The model contained age, timed motor task scores for each hand, and indicators of action tremor, speech difficulty, anxiety, depression, loneliness, pain and current cigarette smoking. When we examined how well the model identified workers with clinically significant parkinsonism (UPDRS3≥15) the receiver operating characteristic area under the curve (AUC) was 0.72 (95% confidence interval [CI] 0.67, 0.77). With a cut point that provided 80% sensitivity, specificity was 52%, the positive predictive value in our cohort was 29%, and the negative predictive value was 92%. Using the same cut point for predicted UPDRS3, the AUC was nearly identical for UPDRS3≥10, and was 0.83 (95% CI 0.76, 0.90) for UPDRS3≥20. Since welding exposure data was not required after including its putative effects, this model may help identify workers with clinically significant Mn neurotoxicity in a variety of settings, as a first step in a tiered occupational screening program., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study examines the results of neuropsychological testing of 26 active welders and 17 similar controls and their relationship to welders' shortened MRI T1 relaxation time, indicative of increased brain manganese (Mn) accumulation. Welders were exposed to Mn for an average duration of 12.25 years to average levels of Mn in air of 0.11±0.05mg/m 3 . Welders scored significantly worse than controls on Fruit Naming and the Parallel Lines test of graphomotor tremor. Welders had shorter MRI T1 relaxation times than controls in the globus pallidus, substantia nigra, caudate nucleus, and the anterior prefrontal lobe. 63% of the variation in MRI T1 relaxation times was accounted for by exposure group. In welders, lower relaxation times in the caudate nucleus and substantia nigra were associated with lower neuropsychological test performance on tests of verbal fluency (Fruit Naming), verbal learning, memory, and perseveration (WHO-UCLA AVLT). Results indicate that verbal function may be one of the first cognitive domains affected by brain Mn deposition in welders as reflected by MRI T1 relaxation times., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Manganese regulates many enzymes and is essential for normal cell function. Chronic manganese intoxication has an insidious and progressive course terminating to atypical parkinsonism with little therapeutic efficacy. For subjects with chronic manganese exposure such as welders, manganese intoxication can be detected early based on the presence of hyperintensity in the globus pallidus on T(1)-weighted MRI and abnormally high urinary excretion of manganese with a chelating agent even in cases of normal serum/urine level of manganese.

Manganism has captured the imagination of neurologists for more than a century because of its similarities to Parkinson disease and its indirect but seminal role in the "l-dopa miracle." We present unpublished footage of the original case series reported in Neurology® in 1967 by Mena and Cotzias depicting the typical neurologic signs of manganism in 4 Chilean miners and their response to high doses of l-dopa., (© 2015 American Academy of Neurology.)

Background: Manganese, an essential metal for normal growth and development, is neurotoxic on excessive exposure. Standard trace element-supplemented neonatal parenteral nutrition (PN) has a high manganese content and bypasses normal gastrointestinal absorptive control mechanisms, which places infants at risk of manganese neurotoxicity. Magnetic resonance (MR) relaxometry demonstrating short T1 relaxation time (T1R) in the basal ganglia reflects excessive brain manganese accumulation., Objective: This study tested the hypothesis that infants with greater parenteral manganese exposure have higher brain manganese accumulation, as measured by MR imaging, than do infants with lower parenteral manganese exposure., Design: Infants exposed to parenteral manganese were enrolled in a prospective cohort study. Infants classified as having high manganese exposure received >75% of their nutrition in the preceding 4 wk as PN. All others were classified as having low exposure. Daily parenteral and enteral manganese intakes were calculated. Whole-blood manganese was measured by high-resolution inductively coupled plasma mass spectrometry. Brain MR relaxometry was interpreted by a masked reviewer. Linear regression models, adjusted for gestational age (GA) at birth, estimated the association of relaxometry indexes with total and parenteral manganese exposures., Results: Seventy-three infants were enrolled. High-quality MR images were available for 58 infants, 39 with high and 19 with low manganese exposure. Four infants with a high exposure had blood manganese concentrations >30 μg/L. After controlling for GA, higher parenteral and total manganese intakes were associated with a lower T1R (P = 0.01) in the globus pallidus and putamen but were not associated with whole-blood manganese (range: 3.6-56.6 μg/L). Elevated conjugated bilirubin magnified the association between parenteral manganese and decreasing T1R., Conclusion: A short T1R for GA identifies infants at risk of increased brain manganese deposition associated with PN solutions commonly used to nourish critically ill infants. These trials were registered at clinicaltrials.gov as NCT00392977 and NCT00392730., (© 2015 American Society for Nutrition.)

Manganese (Mn) is an essential heavy metal that is naturally found in the environment. Daily intake through dietary sources provides the necessary amount required for several key physiological processes, including antioxidant defense, energy metabolism, immune function and others. However, overexposure from environmental sources can result in a condition known as manganism that features symptomatology similar to Parkinson's disease (PD). This disorder presents with debilitating motor and cognitive deficits that arise from a neurodegenerative process. In order to maintain a balance between its essentiality and neurotoxicity, several mechanisms exist to properly buffer cellular Mn levels. These include transporters involved in Mn uptake, and newly discovered Mn efflux mechanisms. This review will focus on current studies related to mechanisms underlying Mn import and export, primarily the Mn transporters, and their function and roles in Mn-induced neurotoxicity. Though and essential metal, overexposure to manganese may result in neurodegenerative disease analogous to Parkinson's disease. Manganese homeostasis is tightly regulated by transporters, including transmembrane importers (divalent metal transporter 1, transferrin and its receptor, zinc transporters ZIP8 and Zip14, dopamine transporter, calcium channels, choline transporters and citrate transporters) and exporters (ferroportin and SLC30A10), as well as the intracellular trafficking proteins (SPCA1 and ATP12A2). A manganese-specific sensor, GPP130, has been identified, which affords means for monitoring intracellular levels of this metal., (© 2015 International Society for Neurochemistry.)

Intravenous injection of self-produced ephedrone (metcathinone) using potassium permanganate as an oxidant can lead to severe, fixed encephalopathy. This risk applies mainly to young individuals experimenting with "home-made" drugs and results in an irreversible aggravation of overall functioning. Besides multiple neurological symptoms and movement disorders, affected individuals also experience cognitive dysfunction. No systematic research has been conducted in this field. Single case reports and small group descriptions show that assessment with screening tools such as the Mini-Mental State Examination (MMSE) is ineffective. Neuropsychological assessment conducted with other tests indicates significant dysarthric speech disorders, psychomotor function impairment, attentional disorders of varying intensity as well as dysfunctions of verbal and visual working memory processes. Some studies of this group of subjects also indicate working memory and executive function disorders. These dysfunctions seem to be permanent and do not recede following manganese use discontinuation and an improvement of the neuroradiological picture in MRI assessment. A standard test battery should be developed enabling the assessment of both cognitive and neurological dysfunctions that otherwise render some tests impossible to administer.

Background: A great deal of research has been devoted to identifying subclinical functional brain abnormalities in manganese (Mn)-exposed welders. However, no previous study has investigated morphological brain abnormalities, such as changes in brain volume, in welders. This study evaluates morphological changes in brain volume among welders, and investigates the relationship between structural brain abnormalities and subclinical dysfunction in this population., Methods: We used voxel-based morphometry (VBM) to assess differences in gray and white matter brain volumes between 40 welders with chronic Mn exposure and 26 age-matched control subjects. Correlation analyses were used to investigate the relationship between brain volume changes and decreased performance on neurobehavioral tests., Results: Brain volumes in the globus pallidus and cerebellar regions were significantly diminished in welders with chronic Mn exposure compared to controls (FDR-corrected P<0.05). These changes in brain volume were negatively correlated with cognitive performance and grooved pegboard scores., Conclusion: There are measurable brain volume reductions in the globus pallidus and cerebellum of welders chronically exposed to Mn, and these volume reductions correlate with cognitive and motor neurobehavioral deficits. Our findings therefore indicate that volumetric measurement could be a useful subclinical marker among welders that show no signs of manganism., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Encephalopathy caused by manganese compounds used for illicit production of ephedrone (methcathinone) is described. The onset of disease could be observed after some months of regular intravenous use of ephedrone contaminated with manganese. In clinical picture dominate neurological signs and symptoms, mainly extrapyramidal syndromes: parkinsonism, tremor, muscle distonia, pro- and retropulsion. Some other symptoms may be observed: hypophonia or dysarthria, gain disturbances, impairment of precise movement, and micrographia. In cranial NMR often appears bilaterally an increase of an intensity of T1 signal in globus pallidus and in some other brain structures. Elimination of manganese with the use of chelating therapy as well as symptomatic treatment, mainly with the antyparkinsonic drugs, seems to be ineffective.

The Occupational Medicine Forum is prepared by the ACOEM Occupational and Environmental Medical Practice Committee and does not necessarily represent an official ACOEM position. The Forum is intended for health professionals and is not intended to provide medical or legal advice, including illness prevention, diagnosis or treatment, or regulatory compliance. Such advice should be obtained directly from a physician and/or attorney.

Male Wistar rats wearing chronically implanted cortical electrodes were exposed to Mn-containing nanoparticles via the airways for 8 weeks following a 2-week pre-exposure period. The rats' cortical electrical activity and open field motility was recorded simultaneously, in weekly repetitions. It was supposed that this technique can provide better insight in the development of Mn-induced CNS damage. Decreased motility (less distance covered, longer periods of immobility) and increased total power of cortical electrical activity developed in parallel in the first 4-5 weeks of treatment but showed little change afterwards. Both the behavioral and the electrophysiological effect were in fair correlation with the rats' internal Mn exposure determined from brain samples. The results confirmed the non-linear dose- and time-dependence of Mn effects suggested by previous studies. Repeated simultaneous behavioral and electrophysiological recording during a longer treatment with neurotoxic metals (or other xenobiotics) seems to be a promising method.

Background and Objective: Increased prevalence of Parkinsonism was observed in Valcamonica, Italy, a region impacted by ferroalloy plants emissions containing manganese and other metals for a century until 2001. The aim of this study was to assess neurobehavioral functions in adolescents from the impacted region and the reference area of Garda Lake., Methods: Adolescents age 11-14 years were recruited through the school system for neuro-behavioral testing. Metals including manganese, lead, iron, zinc, copper were measured in airborne particulate matter collected with 24-h personal samplers, and in soil, tap water, blood, urine and hair. Independent variables included parental education and socio-economic status, children's body mass index, number of siblings, parity order, smoking and drinking habits., Results: A total of 311 subjects (49.2% females), residing in either the exposed (n=154) or the reference (n=157) area participated. Average airborne and soil manganese were respectively 49.5 ng/m(3) (median 31.4, range 1.24-517) and 958 ppm (median 897, range 465-1729) in the impacted area, and 27.4 ng/m(3) (median 24.7, range 5.3-85.9) ng/m(3) and 427 ppm (median 409 range 160-734) in the reference area. Regression models showed significant impairment of motor coordination (Luria-Nebraska test, p=0.0005), hand dexterity (Aiming Pursuit test, p=0.0115) and odor identification (Sniffin' task, p=0.003) associated with soil manganese. Tremor intensity was positively associated with blood (p=0.005) and hair (p=0.01) manganese., Conclusion: Historical environmental exposure to manganese from ferroalloy emission reflected by the concentration in soil and the biomarkers was associated with sub-clinical deficits in olfactory and motor function among adolescents., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: A higher prevalence of individuals affected by Parkinsonism was found in Valcamonica, Italy. This may be related to ferro-alloy smelters in the area, releasing manganese (Mn) in the air, soil and water for about a century. There exists individual susceptibility for Mn neurotoxicity., Aim: To analyse how polymorphism in genes regulating Mn metabolism and toxicity can modify neurophysiological effects of Mn exposure., Materials and Methods: Elderly (N=255) and adolescents (N=311) from Northern Italy were examined for neuromotor and olfactory functions. Exposure to Mn was assessed in blood and urine by atomic absorption spectroscopy and in soil by a portable instrument based on X-Ray fluorescence technology. Polymorphisms in the Parkinson-related gene ATPase type 13A2 (ATP13A2, also called PARK9: rs3738815, rs2076602, rs4920608, rs2871776 and rs2076600), and in the secretory pathway Ca(2+)/Mn(2+) ATPase isoform 1 gene (SPCA1: rs218498, rs3773814 and rs2669858) were analysed by TaqMan probes., Results: For both adolescents and elderly, negative correlations between Mn in soil and motor coordination (R(s)=-0.20, p<0.001; R(s)=-0.13, p=0.05, respectively) were demonstrated. Also among adolescents, negative correlations were seen between Mn in soil with odor identification (R(s)=-0.17, p<0.01). No associations were seen for Mn in blood or urine. ATP13A2 polymorphisms rs4920608 and rs2871776 significantly modified the effects of Mn exposure on impaired motor coordination in elderly (p for interaction=0.029, p=0.041, respectively), also after adjustments for age and gender. The rs2871776 altered a binding site for transcription factor insulinoma-associated 1., Conclusions: ATP13A2 variation may be a risk marker for neurotoxic effects of Mn in humans., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Manganese (Mn) is a common occupational exposure worldwide. Recent studies indicate clinical and imaging evidence of neurotoxicity in chronically exposed workers. The pathologic significance of these findings is unclear. South Africa produces over 80% of the world's Mn from mines from a desert region in the Northern Cape Province. An autopsy program at the National Institute for Occupational Health (NIOH) in South Africa has provided compensation to families for mining-related lung diseases for almost 100 years. Building on this, we implemented a brain autopsy program to investigate the feasibility of obtaining brains from South African Mn miners and non-exposed reference miners to investigate neuropathologic consequences of chronic Mn exposure. Employing an experienced occupational health nurse, we identified deceased miners within 100 square km of the Mn mines. The nurse was notified of any Mn (case) or other (reference) miner or ex-miner death by local medical practitioners, occupational health and mine physicians, and community members, and families were approached for consent to remove the brains in addition to the cardio-respiratory organs. Families of deceased miners who had an autopsy at the NIOH in Johannesburg were also approached. To confirm exposure in Mn miners, mean pallidal indices were compared between Mn miners and non-exposed reference miners. Sixty-eight potential brain donors were identified; we obtained consent from the families to remove 51 (75%). The mean autopsy interval was seven days. With optimized fixation methods, the tissue quality of the brains for gross and regular microscopic examination was excellent. Ex vivo MRI demonstrated increased pallidal index in Mn miners compared to reference miners. We conclude that obtaining brain tissue from deceased miners in South Africa is highly successful with only a modest investment in local infrastructure. Tissue quality was excellent and should be ideal to investigate the neuropathologic consequences of chronic occupational Mn exposure., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Manganese (Mn) is a well established neurotoxin associated with specific damage to the basal ganglia in humans. The phenotype associated with Mn neurotoxicity was first described in two workers with occupational exposure to Mn oxide (Couper, 1837). Although the description did not use modern clinical terminology, a parkinsonian illness characterized by slowness of movement (bradykinesia), masked facies, and gait impairment (postural instability) appears to have predominated. Nearly 100 years later an outbreak of an atypical parkinsonian illness in a Chilean Mn mine provided a phenotypic description of a fulminant neurologic disorder with parkinsonism, dystonia, and neuropsychiatric symptoms (Rodier, 1955). Exposures associated with this syndrome were massive and an order of magnitude greater than modern exposures (Rodier, 1955; Hobson et al., 2011). The clinical syndrome associated with Mn neurotoxicity has been called manganism. Modern exposures to Mn occur primarily through occupations in the steel industry and welding. These exposures are often chronic and varied, occurring over decades in the healthy workforce. Although the severe neurologic disorder described by Rodier and Couper are no longer seen, several reports have suggested a possible increased risk of neurotoxicity in these workers (Racette et al., 2005b; Bowler et al., 2007; Harris et al., 2011). Based upon limited prior imaging and pathologic investigations into the pathophysiology of neurotoxicity in Mn exposed workers (Huang et al., 2003), many investigators have concluded that the syndrome spares the dopamine system distinguishing manganism from Parkinson disease (PD), the most common cause of parkinsonism in the general population, and a disease with characteristic degenerative changes in the dopaminergic system (Jankovic, 2005). The purpose of this symposium was to highlight recent advances in the understanding of the pathophysiology of Mn associated neurotoxicity from Caenorhabditis elegans to humans. Dr. Aschner's presentation discussed mechanisms of dopaminergic neuronal toxicity in C. elegans and demonstrates a compelling potential role of Mn in dopaminergic degeneration. Dr. Guilarte's experimental, non-human primate model of Mn neurotoxicity suggests that Mn decreases dopamine release in the brain without loss of neuronal integrity markers, including dopamine. Dr. Racette's presentation demonstrates a unique pattern of dopaminergic dysfunction in active welders with chronic exposure to Mn containing welding fumes. Finally, Dr. Dydak presented novel magnetic resonance (MR) spectroscopy data in Mn exposed smelter workers and demonstrated abnormalities in the thalamus and frontal cortex for those workers. This symposium provided some converging evidence of the potential neurotoxic impact of Mn on the dopaminergic system and challenged existing paradigms on the pathophysiology of Mn in the central nervous system., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This symposium comprised five oral presentations dealing with recent findings on Mn-related cognitive and motor changes from epidemiological studies across the life span. The first contribution highlighted the usefulness of functional neuroimaging of the central nervous system (CNS) to evaluate cognitive as well as motor deficits in Mn-exposed welders. The second dealt with results of two prospective studies in Mn-exposed workers or welders showing that after decrease of Mn exposure the outcome of reversibility in adverse CNS effects may differ for motor and cognitive function and, in addition the issue of plasma Mn as a reliable biomarker for Mn exposure in welders has been addressed. The third presentation showed a brief overview of the results of an ongoing study assessing the relationship between environmental airborne Mn exposure and neurological or neuropsychological effects in adult Ohio residents living near a Mn point source. The fourth paper focused on the association between blood Mn and neurodevelopment in early childhood which seems to be sensitive to both low and high Mn concentrations. The fifth contribution gave an overview of six studies indicating a negative impact of excess environmental Mn exposure from air and drinking water on children's cognitive performance, with special attention to hair Mn as a potential biomarker of exposure. These studies highlight a series of questions about Mn neurotoxicity with respect to cognitive processes, forms and routes of exposure, adequate biomarkers of exposure, gender differences, susceptibility and exposure limits with regard to age., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: In a group of 43 confined space welders dose-effect relationships had been identified for adverse neurological/neuropsychological functional effects in relation to manganese (Mn) in blood or air (cumulative exposure index). The welders' exposure to Mn was unprotected and with poor ventilation, lasting on average 16.5 months. A follow-up examination 3.5 years later, after cessation of confined space welding, was carried out to re-assess the status of mood, movement/neuromotor and cognitive functions, and olfaction., Methods: In 2008, 26 welders (70% response rate) were retested using a similar methodology as at baseline (Bowler et al., 2007). A general linear model was used to estimate individual-specific endpoint differences over time. Mean age was 47 years, mean years of education 12.4, and mean total years of welding 16.9 years. Thirteen participants no longer welded., Results: At follow-up, mean blood Mn concentration had decreased from 10.0 to 8.4 μg/L (p=0.002). Those still welding had higher blood Mn than those no longer welding (9.9 μg/L vs. 6.8 μg/L, p=0.002). Several domains of cognitive functioning improved substantially as shown by large effect sizes. Emotional disturbance improved only slightly clinically, but complaints of depression and anxiety persisted. Motor dexterity/tactile function and graphomotor tremor improved significantly, while psychomotor speed remained unchanged. The findings of the neurological examination (UPDRS) did not change compared to baseline, whereas rigidity, dominant postural hand tremor and body sway worsened. Olfactory test scores remained depressed., Conclusion: After 3.5 years of cessation of confined space welding, only cognitive function improved significantly, while olfactory, extrapyramidal, and mood disturbances remained constant or were exacerbated. This suggests differential intrinsic vulnerabilities of the brain loci involved with Mn exposure. As the Mn exposure of the Bay Bridge welders frequently exceeded the Cal-OSHA TLV of 0.2 mg Mn/m(3) at baseline, a more stringent preventive measure is recommended for confined space welding., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To examine the long-term consequences of manganese exposure due to the use of manganese-enhanced magnetic resonance imaging (MEMRI) in a model of closed head injury, the fluid-percussion injury (FPI) model., Materials and Methods: Two groups of adult male Wistar rats (n = 72) were studied with either MEMRI, whereby rats receive MnCl(2) (100 mg/kg intraperitoneally) 24 hours prior to scanning, or standard MRI (sMRI) with no contrast agent. Rats from both groups underwent FPI or sham injury and were longitudinally assessed for 6 months for neurological toxicity using behavioral tests, EEG recording, and MRI scanning., Results: Regardless of whether they received FPI, MEMRI animals showed progressive signs of cerebral toxicity compared with sMRI rats, including significantly reduced weight gain, progressive brain volume decrease, and increased anxiety and depressive-like behaviors., Conclusion: Long-term structural and functional consequences of using manganese as a contrast agent for MRI can confound experimental outcomes and must be taken into account when designing longitudinal imaging studies using manganese-enhanced MRI., (Copyright © 2011 Wiley-Liss, Inc.)

Objectives: The objective of the present study was to evaluate motor function in order to assess the effects of long-term, low-level environmental manganese (Mn) exposure in residents of an Ohio community where a large ferro- and silico-Mn smelter has been active for more than 50 years., Methods: One hundred residents from the Mn-exposed Ohio community were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS), a postural sway test, and a comprehensive questionnaire exploring demographics and general health. The results were compared to those of 90 residents from a demographically similar comparison town in Ohio. Mn exposure was assessed using modeled airborne Mn and blood Mn (Mn-B). The UPDRS was employed to evaluate parkinsonian motor features. Postural sway was measured using a CATSYS 2000 (Danish Product Development)., Results: No significant difference between the exposed and comparison groups was evident as to Mn-B, demographics or major health outcomes. The risk of abnormal UPDRS performance using "Motor and Bradykinesia" criteria was increased in the Mn-exposed group after adjustment for potential confounders such as the presence of other neurotoxic metals, factors affecting susceptibility to Mn, potential factors influencing motor performance, and other possible demographic confounders. No participant was diagnosed with clinical manganism by neurological examination. After adjustment for various potential confounders, the Mn-exposed group showed significantly higher postural sway scores under eyes-open conditions than the comparison group., Conclusions: Subclinical findings on the UPDRS and postural sway in the Mn-exposed group may possibly reflect early subtle effects of chronic low-level Mn exposure. However, the cross-sectional study design, the small to medium effect sizes, and the little biological plausibility are limiting the possibility of a causal relationship between the environmental Mn-air exposure and the early subclinical neurotoxic effects observed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: Occupational manganese (Mn) exposure has been associated with motor deficits in adult workers, but data on the potential effects of environmental exposure to Mn on the developing motor function for a children population is scarce. The aim of this study was to evaluate the association between exposure to Mn and motor function of school aged children., Methods: We conducted a cross-sectional study selecting 195 children (100 exposed and 95 unexposed) between 7 and 11 years old. The following tests were used to evaluate the motor function: Grooved pegboard, finger tapping, and Santa Ana test. Mn exposure was assessed by blood (MnB) and hair concentrations (MnH). We constructed linear regression models to evaluate the association between exposure to Mn and the different test scores adjusting for age, sex, maternal education, hemoglobin and blood lead., Results: The median concentration of MnH and MnB was significantly higher in exposed (12.6 μg/g and 9.5 μg/L) compared to unexposed children (0.6 μg/g and 8.0 μg/L). The exposed children on average performed the grooved pegboard test faster, but made more errors, although these results did not reach statistical significance with neither one of the Mn exposure biomarkers. MnB showed an inverse association on the execution of the finger tapping test (average in 5 trials β -0.4, p=0.02), but no association was observed with MnH., Conclusions: A subtle negative association of Mn exposure on motor speed and coordination was shown. In adults, the main effect of environmental Mn exposure has been associated with motor skills, but these results suggest that such alterations are not the main effect on children., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Manganese encephalopathy is a potential complication of parenteral nutrition. Lack of early recognition leads to unnecessary testing and to continued exposure to manganese., Methods: Case report and review of the literature., Results: We describe the clinical and imaging findings of a patient with manganese encephalopathy in whom the diagnosis was delayed due to lack of recognition of the characteristic imaging findings., Conclusion: Manganese encephalopathy has protean clinical and imaging findings that can easily be overlooked.

Manganese is an important element essential for human functioning. Pathogenesis of manganese intoxication remains unclear. Specification of differential diagnostic criteria is required for diagnosis of occupational manganese intoxication and ruling out Parkinson disease and secondary parkinsonism in the patients.

Objective: To identify biomarkers supporting the clinical diagnosis of manganism in patients several years after exposure to manganese (Mn)., Methods: Neurophysiological examinations, magnetic resonance imaging (MRI), single-photon emission computed tomography and fluorodeoxyglycose (FDG) positron emission tomography were performed in four former ephedrone addicts with extrapyramidal symptoms., Results: Peripheral nervous system was not affected. No patients had reduced uptake of (123)I Ioflupane in the striatum. MRI signal intensities were slightly changed in the basal ganglia. All patients showed a widespread, but not uniform, pathological pattern of FDG uptake with changes mainly located to the central part of the brain including the basal ganglia and the surrounding white matter., Conclusions: Presynaptic neurons in the nigrostriatal pathway are intact in Mn-induced parkinsonism after prolonged abstinence from ephedrone. The diagnosis is principally based on clinical signs and the history of drug abuse.

Introduction: Hypermanganism is primarily linked to inhalation exposure. Several observations of exogenous manganese poisoning have been reported associating neuropsychiatric symptoms, parkinsonian syndrome and hyperintensities of the two pallida on T1 weighted sequences on brain MRI. Recently, similar neurological and radiological signs have been described without exogenous exposure to manganese but in the framework of endogenous poisoning particularly in chronic hepatic failure., Case Report: We report the case of a 41-year-old HIV-positive and HVC-positive man who presented psychomotor impairment associated with bipallidal T1 hyperintensities on the brain MRI. The diagnosis of a hypermanganesemia was made on blood samples. We present a literature review on exogenous and endogenous hypermanganesemia and discuss differential diagnosis in the radiological setting of bipallidal T1 hyperintensities., Conclusion: Bipallidal T1 hyperintensities on brain MRI may suggest hypermanganism even in the clinical setting of a non-specific neurological disorder such as psychomotor impairment., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Biologic monitoring data in electric welders revealed reliable correlation between manganese concentration in the whole blood and manganese concentrations in the workplace air. The chronic manganese intoxication patients showed reliable lower levels of urinary iron, cobalt and manganese vs. those values in the reference group.

Objectives: A diagnostic algorithm for clinical manganism was developed to screen all employees at a South African manganese smelter., Methods: The study design was for all 754 smelter employees in 2006/7 to be screened by an occupational health nurse using nine questions and nine brief neurological examination procedures. More than one symptom, any neurological sign, or blood manganese exceeding 40 microg/l triggered referral for neurological examination by an Occupational Medical Practioner (OMP). Abnormal findings by the OMP triggered referral to a movement disorders specialist neurologist and to a neuropsychologist. Features of parkinsonism and a clinical picture consistent with the scientific literature were used to diagnose manganism., Results: Total manganese dust was mostly within (<5 mg/m(3)) or near (<9 mg/m(3)) the South African Occupational Exposure Limit, with one outlier near 20 mg/m(3). Occupational Health Service problems and uncertainty about the nature of manganism before the full diagnostic algorithm was developed, resulted in 10 referrals who were certified as manganism cases by the state compensation authorities. They were only assessed in the early stages of this screening programme, and never examined by the above specialists. Of 744 employees screened with the full diagnostic algorithm, the nurse referred 152 (20.3%) and the OMP 27 (3.5%) of all those screened respectively. No definite manganism cases were diagnosed, while one (0.13%) employee was found to have possible manganism and another had an indeterminate neurological diagnosis. A sensitivity analysis assuming that all 10 compensated cases were either normal, or alternatively had definite manganism, yielded a prevalence range for definite manganism from 0% to 1.3%., Conclusion: Acknowledging possible downward bias when excluding the 10 employees who did not receive the full workup, the true prevalence of definite manganism was likely to be either zero or close to zero.

Objective: The exposure-response relationship for manganese (Mn)-induced adverse nervous system effects is not well described. Symptoms and neuropsychological deficits associated with early manganism were previously reported for welders constructing bridge piers during 2003 to 2004. A reanalysis using improved exposure, work history information, and diverse exposure metrics is presented here., Methods: Ten neuropsychological performance measures were examined, including working memory index (WMI), verbal intelligence quotient, design fluency, Stroop color word test, Rey-Osterrieth Complex Figure, and Auditory Consonant Trigram tests. Mn blood levels and air sampling data in the form of both personal and area samples were available. The exposure metrics used were cumulative exposure to Mn, body burden assuming simple first-order kinetics for Mn elimination, and cumulative burden (effective dose). Benchmark doses were calculated., Results: Burden with a half-life of about 150 days was the best predictor of blood Mn. WMI performance declined by 3.6 (normal = 100, SD = 15) for each 1.0 mg/m3 x mo exposure (P = 0.02, one tailed). At the group mean exposure metric (burden; half-life = 275 days), WMI performance was at the lowest 17th percentile of normal, and at the maximum observed metric, performance was at the lowest 2.5 percentiles. Four other outcomes also exhibited statistically significant associations (verbal intelligence quotient, verbal comprehension index, design fluency, Stroop color word test); no dose-rate effect was observed for three of the five outcomes., Conclusions: A risk assessment performed for the five stronger effects, choosing various percentiles of normal performance to represent impairment, identified benchmark doses for a 2-year exposure leading to 5% excess impairment prevalence in the range of 0.03 to 0.15 mg/m3, or 30 to 150 microg/m3, total Mn in air, levels that are far below those permitted by current occupational standards. More than one-third of workers would be impaired after working 2 years at 0.2 mg/m3 Mn (the current threshold limit value).

Known as an occupational disease, chronic manganese intoxication is recently being observed among abusers of psychoactive substances. Methcathinone hydrochloride is obtained by combining ephedrine/pseudoephedrine and potassium permanganate. Various neuropsychiatric symptoms have been reported among Efedron users. Our patient is a 29 year old male, who was referred to our hospital from a state general hospital with a diagnosis of Conversion Disorder. He was hospitalized and preliminary diagnoses of Facititous Disorder, Conversion Disorder, Psychiatric Disorder due to a General Medical Condition and Antisocial Personality Disorder. He was abstinent from any substance for five years upon referral to our hospital and had a history of methcathinone abuse for 4.5 years. The backache dated back to 6 years ago and a disturbance of gait was added to the clinical picture. A speech disturbance, falling while walking downhill and walking on tiptoe were added in the last 2-3 years. In the neurological examination, extrapyramidal system findings, gait disturbance and the report on use of manganese compunds were found. The setting was changed from psychiatric ward to neuorology ward and evaluated by consultant neurologist. The case was diagnosed as ?Manganese Intoxication'. The aim of this report is to demonstrate and emphasize the importance of questioning the presence of manganese compounds in case of history of substance abuse. Other areas of interest are the shortage of data on the intravenous use of manganese and the cases reported in the literature coming from the former Soviet Union.

Classic symptoms of manganese intoxication are very rarely seen nowadays. Clinic in Angarsk Research Institute for Occupational medicine and Human ecology registered two cases of stage I and II chronic manganese intoxication over 10 years among electric welders. The cases were diagnosed with consideration of long length of exposure to manganese with the ambient air level exceeding the MAC 1.5 times, the disease manifestation at middle age, high manganese level in serum and urine, characteristic neurologic symptoms in association with organic psychopathologic defects and polyneuropathy of limbs.

Objective: To examine the clinical presentation of movement disorder in patients who reported a history of welding., Methods: A retrospective chart review during a three-year period was performed on all movement disorders and patients who had been welders were identified. The clinical presentation of these patients was categorized by the movement disorder at the time of the initial neurological evaluation and by the therapy response. A comparison group was created by randomly selecting four non-welders for each welder., Results: Among 1126 charts reviewed, eleven patients presented with a welder history. Parkinsonism was a common presentation in both groups: three of the eleven welders (27%) and five of the forty-one controls (12%). Dystonia was also common with 27% and 20%, respectively. Using the chi-squared analysis, the prevalence rates for both parkinsonism and dystonia were similar to controls. All of the welder patients with parkinsonism responded to dopaminomimetic therapy. Six of the eleven welders had elevated manganese levels in either blood or urine., Conclusions: Welders who present with a movement disorder such as parkinsonism or dystonia, have the prevalence rates for these disorders similar to the non-welder population (Fig. 2, Ref. 15).

Background: Manganism is a central nervous system disorder caused by toxic exposure to manganese. Manganism has been related to occupational exposures, liver diseases, prolonged parenteral nutrition, and abuse of illicit drugs. Initially manifested by a reversible neuropsychiatric syndrome (locura manganica), the main symptoms and signs of manganism are emotional lability, compulsive behavior and visual hallucinations. Locura manganica is followed by an irreversible extrapyramidal syndrome, the onset of which occurs years after chronic exposure., Objectives: To characterize the regional distribution of Mn in the rat brain after subchronic exposure to Mn. This animal model holds special clinical relevance, reflecting the earlier clinical stages of manganism before chronic exposure to Mn exerts its irreversible effects., Methods: Sprague-Dawley rats were intravenously injected with MnCl2 weekly, for a total of 14 weeks - approximately 1/10 of the lifetime of the rat. T1-weighted magnetic resonance imaging was used to detect the distribution of Mn deposition in brain tissues, as evidenced by areas of T1-weighted hyperintense signals., Results: A consistent region-specific pattern of T1-weighted hyperintensities was observed in the brains of Mn-treated rats. Cortical hyperintensities were prominent in the hippocampus and dentate gyrus. Hyperintensities were also observed in the olfactory bulbs, pituitary gland, optic nerves and chiasma, pons, midbrain tegmentum, habenula, lentiform and caudate nuclei, thalamus, chorioid plexus and cerebellar hemispheres., Conclusions: Prominent Mn depositions, evidenced by T1-weighted hyperintensities in the hippocampus after subacute exposure to Mn, are compatible with the clinical picture of manganism during its early stages, and may explain its pathophysiology.

Purpose/background: The aim of this study was to investigate latent manganese toxicity in patients with biliary atresia and to use this tool to predict the prognosis of biliary atresia patients after Kasai's portoenterostomy., Methods: 14 patients who underwent Kasai's portoenterostomy between 1993 and 2005 were included in the study. Whole blood manganese assays were performed using atomic adsorption spectroscopy (Philips PU 9200, Cambridge, UK) and verified by repeat analysis; these were done at the time of surgery and 6 months later. All blood samples were collected in an identical manner, blinded and then assayed by technicians. Whole blood manganese levels were correlated with the development of manganese deposits in the globus pallidus on T1-weighted images on magnetic resonance imaging (MRI) of the brain. Serum bilirubin of all 14 patients were noted both at the time of surgery and 6 months later. A hepatobiliary (HIDA) scan was done in all patients 6 months after Kasai's portoenterostomy., Results: The bilirubin declined in all except 2 patients after surgery. Both these patients developed ascites and severe jaundice and 1 expired one year after surgery. HIDA scan was excretory in all 14 patients. Whole blood manganese ranged from 1.26 - 27.58 microg/dl (mean 4.63 +/- 7.00) at the time of surgery; the levels were normal in 11 patients and elevated in 3. The postoperative assay at 6 months after surgery demonstrated values from 1.08 - 74.46 microg/dl (mean 13.55 +/- 24.17); 4 patients showed an increase from the previous value. Globus pallidus hyperintensity on T1-weighted images was noted in 1 patient on MRI; this patient had a sharp rise in the postoperative manganese level. All other MRI examinations were normal. All 14 patients were neurologically intact., Conclusions: Although the study size is small, it shows that there is a risk of latent manganese toxicity in patients with biliary atresia who have undergone Kasai's portoenterostomy. Whole blood manganese assay in conjunction with brain MRI can be used to serially monitor these patients for early detection of these complications. This tool can be used for prognosis after Kasai's portoenterostomy and can also be extremely useful in selecting patients who will need a liver transplant on a priority basis.

Background: Manganese exposure can cause neurobehavioral and neurological signs and symptoms. A review of the literature was carried out in order to identify the most sensitive and effective methods to assess these outcomes., Methods: Studies on manganese exposure performed with neuropsychological tests were reviewed using Medline. Test methods, obtained outcomes, and dose-response relationships were considered. Based on the review and additional considerations, a testing battery for adult and children was identified., Results: A total number of 31 studies were reviewed and divided in 18 occupational, 7 environmental, and 6 on children. A large variety of tests exploring motor and cognitive functions and mood were applied. Neurobehavioral effects were dose-dependent in several studies and determined by much lower exposure levels compared to 1 mg Mn/m(3) in total dust which is considered to be the minimum concentration able to induce the classical clinical features of "manganism." Although through a wide variety of tests, the observed outcomes support the knowledge that manganese exposure can cause neurobehavioral effects. Motor functions are mainly affected in adults, and cognitive functions and behavior are more affected in children., Conclusions: Literature on manganese neurobehavioral effect is quite consistent, however, further improvement may be achieved by using better structured and more comparable evaluation methods. Based on the analysis of the existing experiences a test battery including tests of motor functions, response speed, cognitive functions, intellectual abilities, mood, and symptom questionnaires is suggested. We recommend that the tests indicated should always be included in future studies as a core battery., ((c) 2007 Wiley-Liss, Inc.)

Introduction: Chronic overexposure to manganese (Mn) may cause neuronal degeneration. Manganese intoxication is well known to induce parkinsonism. Manganese intoxication may be associated with abnormal magnetic resonance (MR) imaging (abnormal signal hyperintensity in the globus pallidus and substantia nigra on T1-weighted images)., Cases: We report an unusual presentation of manganese intoxication due to administration of a combination of acetylsalicylic acid and ephedrine HCl, potassium permanganate, and vinegar melted in tap water and administered parenterally as a psychostimulant substance in 2 cases who developed symptoms resembling parkinsonism. Neurologic examination of both cases revealed disturbances of the extrapyramidal system and a characteristic "cock walk." Tremor was present in the first case, whereas it was lacking in the second one. Cranial MRI showed bilateral symmetric T1-weighted hyperintense patterns in the globus pallidus, probably because of manganese accumulation. Different levels of response to levodopa were reported in the literature; in our cases, there was no response to levodopa., Conclusion: Chronic overexposure to manganese may cause an atypical form of parkinsonism associated with increased T1 signal in the basal ganglia on magnetic resonance imaging.

The trace element manganese is usually supplied when total parenteral nutrition is used. However, long-term parenteral administration of manganese, which bypasses the normal regulatory mechanism, may cause hypermanganesemia. Manganese poisoning presents clinically with parkinsonian-like symptoms and psychological changes. Seizures are a rare presentation of this disease. This report describes a 10-year-old female who had received total parenteral nutrition for 3 months because of short bowel syndrome, and presented with tonic-clonic seizure, decreased level of consciousness, and fever. The serum electrolytes, glucose and the cerebrospinal fluid examination were normal. The blood culture grew Pantoea agglomerans. The brain magnetic resonance imaging disclosed no evidence of central nervous system infection. However, symmetric high-intensity signal on T1-weighted images was documented in the basal ganglia, especially in the globus pallidus. Her whole blood manganese level was 3.7 microg/dL, which was significantly higher than the normal range (0.4-1.4 microg/dL). Diagnosis of hypermanganesemia related to total parenteral nutrition was made.

Acute exposure to manganese is associated with complex behavioral/psychiatric signs that may include Parkinsonian motor features. However, little is known about the behavioral consequences of chronic manganese exposures. In this study, cynomolgus macaque monkeys were exposed to manganese sulfate (10-15 mg/kg/week) over an exposure period lasting 272+/-17 days. Prior to manganese exposure, animals were trained to perform tests of cognitive and motor functioning and overall behavior was assessed by ratings and by videotaped analyses. By the end of the manganese exposure period, animals developed subtle deficits in spatial working memory and had modest decreases in spontaneous activity and manual dexterity. In addition, stereotypic or compulsive-like behaviors such as compulsive grooming increased in frequency by the end of the manganese exposure period. Blood manganese levels measured at the end of the manganese exposure period ranged from 29.4 to 73.7 micro g/l (mean=55.7+/-10.8 (compared to levels of 5.1-14.2 micro g/l at baseline (mean=9.2+/-2.7)), placing them within the upper range of levels reported for human environmental, medical or occupational exposures. These results suggest that chronic exposure to levels of manganese achieved in this study may have detrimental effects on behavior, cognition and motor functioning.