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Manganese encephalopathy is a known disorder in occupational medicine. A serious phenomenon has been the emergence of manganese encephalopathy in intravenous users of homemade methcathinone (ephedrone). A short survey was developed for clinical environments dealing with people who use psychoactive substances. The data were obtained from 72 rehabilitation therapy centers. Surveys carried out in about a third of Polish centers dealing with providing medical assistance to people addicted to substances other than alcohol and tobacco have shown that over 4% of people treated there had symptoms of manganese encephalopathy, of which more than half are people in whom the probability of a clinical diagnosis of this disorder is significant. It has been shown that knowledge of manganese encephalopathy is none or minimal in more than 70% of the surveyed institutions. An urgent need for personnel training in this field was pointed out. Attention was paid to the importance of disseminating good review articles on new and dynamically developing problem phenomena.

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.)

Manganese (Mn) is the twelfth most abundant element on the earth and an essential metal to human health. Mn is present at low concentrations in a variety of dietary sources, which provides adequate Mn content to sustain support various physiological processes in the human body. However, with the rise of Mn utility in a variety of industries, there is an increased risk of overexposure to this transition metal, which can have neurotoxic consequences. This risk includes occupational exposure of Mn to workers as well as overall increased Mn pollution affecting the general public. Here, we review exposure due to air pollution and inhalation in industrial settings; we also delve into the toxic effects of manganese on the brain such as oxidative stress, inflammatory response and transporter dysregulation. Additionally, we summarize current understandings underlying the mechanisms of Mn toxicity., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. 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.)

Studies have demonstrated that, for urban children, dust represents the main exposure to sources of metals like lead (Pb) and manganese (Mn). We aimed to investigate the exposure to these metals and their association with intellectual deficit in children living in an industrial region. This cross-sectional study recruited volunteers from four elementary schools in the town of Simões Filho, Brazil. We evaluated 225 school-aged children (7⁻12 years) for blood lead (PbB) and manganese hair (MnH) and toenails (MnTn) by graphite furnace atomic absorption spectrometry. Child and maternal IQs were estimated using the Wechsler Abbreviated Scale for Intelligence (WASI). Median and range PbB were 1.2 (0.3⁻15.6) μg/dL. MnH and MnTn medians (ranges) were 0.74 (0.16⁻8.79) μg/g and 0.85 (0.15⁻13.30) μg/g, respectively. After adjusting for maternal IQ, age and Mn exposure, child IQ drops by 8.6 points for a 10-fold increase in PbB levels. Moreover, an effect modification of Mn co-exposure was observed. In children with low MnTn, association between Pb and child IQ was not significant (β = -6.780, p = 0.172). However, in those with high MnTn, the association was increased by 27.9% (β = -8.70, p = 0.036). Low Pb exposure is associated with intellectual deficit in children, especially in those with high MnTn.

The history of the biomedical recognition manganese-caused neurotoxicity mirrors changing technologies as much as it does the ontology of parkinsonism. The initial 1837 report of manganese-induced neurologic injury was made by John Couper, a university-based physician in Scotland. He made clear that the outbreak occurred among workers at the Charles Tennant bleach manufactory in the environs of Glasgow. The relatively new technology of chlorine generation using manganese accounted for the novel exposure involved. At the time, this factory was the largest hypochlorite bleaching powder producer in the world. As the 19th century progressed, technological change in steel fabrication requiring higher manganese content greatly increased demand for the metal. Nonetheless, more than six decades elapsed before the next reports of manganese neurotoxicity emerged. Two unrelated outbreaks (both on Continental Europe) were reported within weeks of each other in 1901, one by von Jaksch and the other by Embden. All the cases were heavily exposed to manganese-containing dust. By the eve of the First World War, a total of 9 patients with manganese-caused neurologic illness had been reported in five separate Continental European publications. Meanwhile, new technology led to another exposure source. Magnetic separation techniques allowed the extraction of zinc from mixed ore also containing iron and manganese, leading to exploitation of a unique source of high manganese-content ore found in New Jersey. Not long after that technology's introduction, in 1912 Casamajor reported the first U.S. cases of manganism, detailing classic findings. Additional cases from the same cohort were reported a few years later, with continued exposure driven by First World War-driven demand for manganese to be used in armaments. The nosology of chronic manganese neurotoxicity remained in flux, with considerable emphasis on shared attributes with Wilson's disease, a syndrome only then recently described. A landmark 1924 primate study by Mella showed manganese-induced basal ganglion damage; human autopsy study data in the years following further supported the view that manganese toxicity represented a parkinsonian syndrome. As the 1937 centenary of Couper's first report approached, newer technologies (electric arc welding and battery making) were being linked to manganese-caused disease, even as mineral extraction was expanding as a global source of exposure., (Published by Elsevier B.V.)

In the 1990's, the proposed use of methylcyclopentadienyl manganese tricarbonyl (MMT) as an octane-enhancing gasoline fuel additive led to concerns for potential public health consequences from exposure to manganese (Mn) combustion products in automotive exhaust. After a series of regulatory/legal actions and negotiations, the U.S. Environmental Protection Agency (EPA) issued under Clean Air Act (CAA) section 211(b) an Alternative Tier 2 Test Rule that required development of scientific information intended to help resolve uncertainties in exposure or health risk estimates associated with MMT use. Among the uncertainties identified were: the chemical forms of Mn emitted in automotive exhaust; the relative toxicity of different Mn species; the potential for exposure among sensitive subpopulations including females, the young and elderly; differences in sensitivity between test species and humans; differences between inhalation and oral exposures; and the influence of dose rate and exposure duration on tissue accumulation of Mn. It was anticipated that development of specific sets of pharmacokinetic (PK) information and models regarding Mn could help resolve many of the identified uncertainties and serve as the best foundation for available data integration. The results of the test program included development of several unique Mn datasets, and a series of increasingly sophisticated Mn physiologically-based pharmacokinetic (PBPK) models. These data and models have helped address each of the uncertainties originally identified in the Test Rule. The output from these PBPK models were used by the Agency for Toxic Substances and Disease Registry (ATSDR) in 2012 to inform the selection of uncertainty factors for deriving the manganese Minimum Risk Level (MRL) for chronic exposure durations. The EPA used the MRL in the Agency's 2015 evaluation of potential residual risks of airborne manganese released from ferroalloys production plants. This resultant set of scientific data and models likely would not exist without the CAA section 211(b) test rule regulatory procedure., (Published by Elsevier B.V.)

Similar patterns of cognitive and motor deficits have been widely reported from manganese exposures in welding, metallurgical and chemical industry workers. A risk assessment was performed based on studies reported in the literature, extending some earlier work, and deriving new estimates of exposure response and excess risk. Many investigations of manganese neurological effects in humans have insufficient information to derive an exposure response; however, findings from a chemical manufacturer, two smelter and two welder populations permitted application of the benchmark dose procedure for continuous end-points. Small particles and aggregates of condensation fume (condensing vaporized metal, <0.1μm in diameter) appear to have a higher potency per unit mass than larger particles from dusts (>1.0μm). Consideration was given to long-term effects of continuous low exposures that instead of producing increasing toxicity attain a steady-state condition. Impairment was defined as excursions beyond the 5th percentile in a normal population and the concentrations of manganese predicted to result in 1% excess prevalence of impairment over different time periods were calculated. Over five years, exposures resulting in 1% excess prevalence of impairment (for purposes of discussion) were in the vicinity of 10μg/m 3 for manganese fume and 25μg/m 3 for larger particle dusts. These levels are below current recommendations for occupational limits on manganese exposure in the United States., (Published by Elsevier B.V.)

Background: East Liverpool, Ohio, the site of a hazardous waste incinerator and a manganese (Mn) processor, has had air Mn concentrations exceeding United States Environmental Protection Agency reference levels for over a decade. Save Our County, Inc., a community organization, was formed to address community environmental health concerns related to local industry. Researchers from the University of Cincinnati partnered with Save Our County to determine if air Mn had an impact on the neurocognitive function of children in the community., Methods: Children 7-9 years of age from East Liverpool and its surrounding communities, were enrolled (N=106) in the Communities Actively Researching Exposure Study from between March 2013-June 2014. Blood and hair were analyzed for Mn and lead, and serum was analyzed for cotinine. We used linear regression to assess associations between biological measures and IQ subscale scores., Results: Geometric mean blood lead (n=67), blood Mn (n=66), hair Mn (n=98), and serum cotinine (n=69) concentrations were 1.13±1.96μg/dL, 10.06±1.30μg/L, and 360.22±2.17ng/g, 0.76±6.12μg/L respectively. After adjusting for potential confounders, hair Mn was negatively associated with Full Scale IQ., Conclusions: Hair Mn was negatively associated with child IQ scores. Community partners were instrumental in the conception and implementation of this study., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Manganese (Mn) exposure is associated with increased T1-weighted magnetic resonance imaging (MRI) signal in the basal ganglia. T1 signal intensity has been correlated with occupational Mn exposure but not with clinical symptomatology or neuropathology., Objectives: This study investigated predictors of ex vivo T1 MRI basal ganglia signal intensity in neuropathologic tissue obtained from deceased South African mine workers., Methods: A 3.0 T MRI was performed on ex vivo brain tissue obtained from 19 Mn mine workers and 10 race- and sex-matched mine workers of other commodities. Basal ganglia regions of interest were identified for each subject with T1-weighted intensity indices generated for each region. In a pathology subset, regional T1 indices were compared to neuronal and glial cell density and tissue metal concentrations., Results: Intensity indices were higher in Mn mine workers than non-Mn mine workers for the globus pallidus, caudate, anterior putamen, and posterior putamen with the highest values in subjects with the longest cumulative Mn exposure. Intensity indices were inversely correlated with the neuronal cell density in the caudate (p=0.040) and putamen (p=0.050). Tissue Mn concentrations were similar in Mn and non-Mn mine workers. Tissue iron (Fe) concentration trended lower across all regions in Mn mine workers., Conclusions: Mn mine workers demonstrated elevated basal ganglia T1 indices when compared to non-Mn mine workers. Predictors of ex vivo T1 MRI signal intensity in Mn mine workers include duration of Mn exposure and neuronal density., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: In occupational epidemiologic studies, the low incidence and chronic process of central nervous system (CNS) diseases has complicated the determination of the relationship between increased morbidity and manganese (Mn) exposure. Therefore, through this large cohort study, we evaluated CNS disease morbidity among Korean workers exposed to Mn, Methods: Data were collected from Mn-associated specialized medical check-up 2000 and 2004 in Korea. The number of workers admitted to hospital because of clinically diagnosed CNS disease was analyzed in male workers exposed to Mn (n = 104,544). As a control reference population, 2% of Korean men were randomly selected and their hospital admission data were analyzed. For Mn-exposed workers, Standardized admission ratios (SARs) for CNS disease, as determined by ICD-10 classifications, were estimated in reference to the control population, Results: During follow up, 64 workers admitted because of CNS diseases. Chronic exposure to Mn (≥ 10 years) was significantly associated with the SAR (95% CI) of extrapyramidal and movement disorders (SAR: 2.03, 95% CI: 1.05-3.55), in particular, other extrapyramidal and movement disorders (SAR: 4.81, 95% CI: 1.29-12.32). Also borderline association (SAR = 4.88, 90% CI: 1.05-7.04) was noted for secondary Parkinsonism among workers with chronic Mn exposure. SARs (95% CI) for other degenerative nervous system diseases were significantly higher in Mn-exposed workers compared with the control population (SAR: 3.60, 95% CI: 1.16-8.40) CONCLUSION: In conclusion, Mn-exposed workers exhibited significantly elevated SARs for degenerative nervous system diseases and extrapyramidal and movement disorders, compared to the age-matched reference population, suggesting a relatedness with Mn exposure., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Results from a meta-analysis of aggregated data provoked a new analysis using individual data on the neuropsychological performance of occupationally exposed workers. Data from eight studies examining 579 exposed and 433 reference participants were included, 28 performance variables analyzed. The performance scores were adjusted for well-known individual-level covariates; the influence of possible, but unknown study-level covariates was attenuated by means of a z-normalization. Associations between performance and exposure were estimated by ANOVAs and ANCOVAs, the latter representing multi-level models. Four cognitive and motor performance variables each indicated significantly lower performances of exposed individuals when confounding was considered; slowed motor performances and deficits in attention and short-term memory were found. Performance on a single test was significantly related to the biomarker manganese in blood. The outcomes on susceptibility were weak. The slowing of responses was the most distinct feature of performances of exposed workers. It remains unclear, whether this result is related to the employed tests or provides important information about early stages of the neurotoxic impairment. More specific cognitive tests need to be employed to answer this question. The lack of dose-response relationships was related to features of the biomarker: it does not reflect the Mn in brain responsible for changes in performances., (Copyright © 2013 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.)

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: 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.)

Manganese (Mn) is an essential element, yet is neurotoxic in excess. The majority of Mn research has been conducted on occupationally exposed adults with few studies focused on an environmentally exposed population. Marietta, OH is home to one of the largest airborne Mn emission sources in the United States, a ferromanganese refinery. In preparation for a community-based participatory research study, a preliminary pilot study was initiated to characterize the community's exposure to Mn in ambient air and to evaluate the relationship between biological indices of Mn exposure and genes associated with Mn metabolism in Marietta area residents. Participants in the pilot study were recruited through newspaper advertisement, fliers and direct mailing. Exposure to ambient Mn was estimated using an air pollution dispersion model, AERMOD. A total of 141 residents participated in the pilot study ranging in age from 2 to 81 years. Estimated annual average ambient air Mn concentrations in the study area obtained from AERMOD varied from 0.02 to 2.61 microg/m(3). Mean blood and hair Mn values were 9.12 microg/L (SD 3.90) and 5.80 microg/g (SD 6.40 microg/g), respectively and were significantly correlated (r=0.30, p<0.01). Blood and hair Mn was significantly associated within families (r=0.27, p=<0.02 and r=0.43, p<0.01), respectively. The relationship between hair Mn and estimated ambient air Mn became significant when genes for iron metabolism were included in linear models. The preliminary ambient air and biological concentrations of Mn found in this population demonstrate the need for further research into potential health effects., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Recent studies in Bangladesh indicate that arsenic and manganese in tube-well water may increase the incidence of infant mortality. The study reported here examined whether these findings could be replicated. Data available from some 600 villages under the care of the nongovernmental organization (NGO) Gonoshasthaya Kendra included details of 29744 live births and 934 infant deaths in a 2-year period, with age and cause. These were analyzed by mean well levels of arsenic and manganese as reported by the British Geological Survey for the 12 upazillas. Odds ratios were calculated by age at death and cause. The effect of arsenic on all-cause infant mortality, although small and not significant, was consistent with earlier reports. The previous finding of an increased risk of infant mortality at concentrations of manganese > or =0.4 mg/L was not evident.

Objectives: Manganese (Mn) is an essential element, but overexposure can have neurotoxic effects., Methods: In this article, we review and summarize studies on exposure to Mn and nervous system impairments in children., Results: We identified 12 original articles published between 1977 and 2007. Overexposure to Mn was suspected to occur through diverse sources: infant milk formula, drinking water, industrial pollution, and mining wastes. The most common bioindicator of exposure to Mn was hair Mn content, but some studies measured Mn in blood, urine, or dentin; one study on prenatal exposure measured Mn content in cord blood. Most studies indicate that higher postnatal exposure to Mn is associated with poorer cognitive functions and hyperactive behavior., Conclusions: The limitations of the existing studies are numerous: most were cross-sectional, had a modest sample size, and lacked adjustment for important confounders. Future investigations should be performed on a larger sample size and include a more detailed exposure assessment, addressing multiple sources of exposure such as food, water, and airborne particulates.

Manganese is an element essential in trace quantities but toxic in high concentrations. As a naturally occurring element in groundwater and a chemical of increasing global significance due to its growing trend of replacing lead in gasoline, vigilant assessment of its detrimental effects is essential. In response to previous research that showed a potential link between manganese and well water, we performed a pilot ecological study using data obtained from the North Carolina Center for Health Statistics, the North Carolina Geological Survey, and the U.S. Census. Our pilot study investigated the relationship between logarithmically transformed county level groundwater manganese concentrations with county level infant mortality rates (reported as deaths/1,000) within the state of North Carolina (n = 100 counties; North Carolina 2000 population = 8,049,313) using stepwise, multiple regression. Our model accounted for such confounders as low birth weight, economic status, education, and ethnicity. Across North Carolina counties, for every log increase in groundwater manganese concentration, there was a 2.074 increase in county level infant deaths per 1,000 live births. This study is the first to show on a statewide basis adverse infant mortality effects of environmental manganese. These pilot data argue for further research into a broad range of developmental effects and also may be useful to regulatory agencies interested in protecting communities' health.

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.

Manganese is an essential nutrient, and a healthy human with good liver and kidney function can easily excrete excess dietary manganese. Inhaled manganese is a greater concern, because it bypasses the body's normal homeostatic mechanisms and can accumulate in the brain. Prolonged exposure to high manganese concentrations (>1mg/m(3)) in air leads to a Parkinsonian syndrome known as "manganism." Of greatest concern are recent studies which indicate that neurological and neurobehavioral deficits can occur when workers are exposed to much lower levels (<0.2mg/m(3)) of inhaled manganese in welding fumes. Consequently, researchers at NIOSH are conducting a risk assessment for inhaled manganese. Novel components of this risk assessment include an attempt to quantify the range of inter-individual differences using data generated by the Human Genome Project and experimental work to identify genetically based biomarkers of exposure, disease and susceptibility. The difficulties involved in moving from epidemiological and in vivo data to health-based quantitative risk assessment and ultimately enforceable government standards are discussed.

Work-related health complaints occur frequently. Occupational health departments and primary and secondary care physicians are confronted with these patients. Awareness of work-related disease is crucial. Three case histories with work-related diseases are described. The first concerned a 39-year-old woman who showed acute neurotoxicity due to inhalation of formaldehyde and methanol after opening a coffin with an embalmed corpse. Within weeks the symptoms diminished and complete recovery occurred within nine months. The second was a 61-year-old carpenter who experienced acute and chronic pulmonary and neurotoxic effects after exposure to organic solvents during ground and carpenter's work on a terrain of a former gas plant. He developed severe chronic toxic encephalopathy. The last patient was a 61-year-old man who developed acute and chronic manganese toxicity leading to inability to work while employed at a brick factory where manganese was used to colour the bricks. The acute effects subsided, but chronic neuropsychological symptoms remained.

Peculiarities of nervous system functional state in electric welders exposed to manganese compounds. To evaluate nervous system functional state in electric welders exposed to manganese compounds, the authors conducted transverse study with matched pairs. The electric welders' tests for response rate, diadochokinesis and grasping power were not reliable. No changes were found in tremor characteristics and posture steadiness. Bradykinesia appeared to prevail in welders.

Long-term exposure to manganese (Mn) particulates through inhalation can be neurotoxic, with deficits in neuromotor and cognitive domains. Mn-exposed individuals also report symptoms, including fatigue, mood changes, irritability, concentration difficulties, and sweating in the absence of physical effort. The long-term course of Mn-related symptoms after cessation of exposure has never been examined. Male workers from a Mn-alloy production plant participated in a study on nervous system functions (initial examination), and were followed-up 14 years after plant closure. The relation between self-reported symptoms and Mn cumulative exposure index (CEI) was examined among 71 Mn-alloy workers and 71 referents. Symptoms from the questionnaire were grouped into categories, and the reported frequency was compared between referents and Mn-alloy workers in each Mn CEI tertile using General Linear Models, controlling for age, education, and alcohol consumption. A gradual increase in symptoms frequency was observed for complaints related to hearing and movement control both at initial and follow-up examination, and fatigue and autonomic nervous system only at initial examination. In addition, an exposure-effect relation was apparent for symptoms related to memory, concentration and balance reported at both examinations, with Mn-workers in the highest CEI tertile reporting the highest level of symptomatology. Sleeping complaints were not associated with exposure to Mn, while musculoskeletal pain and muscular weakness were reported more often by Mn-workers than referents but were not clearly related to CEI. The findings suggest that former Mn-alloy workers continue to perceive symptoms many years after cessation of exposure. Despite the limitations of self-reported symptoms, subjective complaints are an important part of a health assessment since they relate directly to perceived health status and day-to-day functioning.

Recent studies report that exposure to manganese (Mn), an essential component of welding electrodes and some steels, results in neurotoxicity and/or Parkinson's disease (PD) in welders. This "state-of-the-science" review presents a critical analysis of the published studies that were conducted on a variety of Mn-exposed occupational cohorts during the last 100 yr, as well as the regulatory history of Mn and welding fumes. Welders often perform a variety of different tasks with varying degrees of duration and ventilation, and hence, to accurately assess Mn exposures that occurred in occupational settings, some specific information on the historical work patterns of welders is desirable. This review includes a discussion of the types of exposures that occur during the welding process--for which limited information relating airborne Mn levels with specific welding activities exists--and the human health studies evaluating neurological effects in welders and other Mn-exposed cohorts, including miners, millers, and battery workers. Findings and implications of studies specifically conducted to evaluate neurobehavioral effects and the prevalence of PD in welders are also discussed. Existing exposure data indicate that, in general, Mn exposures in welders are less than those associated with the reports of clinical neurotoxicity (e.g., "manganism") in miners and smelter workers. It was also found that although manganism was observed in highly exposed workers, the scant exposure-response data available for welders do not support a conclusion that welding is associated with clinical neurotoxicity. The available data might support the development of reasonable "worst-case" exposure estimates for most welding activities, and suggest that exposure simulation studies would significantly refine such estimates. Our review ends with a discussion of the data gaps and areas for future research.

In a cross-sectional study, the serum concentrations of inhibin B and prolactin of 96 male current welders were compared with the concentrations measured in 96 age-matched referents. Also, 23 patients who were all former welders diagnosed as having welding-related manganism were studied. The current welders' geometric mean (GM) airborne exposure to manganese (Mn) was 121 microg m(-3) (range 7-2320). The serum concentrations of prolactin adjusted for age and smoking habits (GM 193 mIU l(-1) vs. 166 mIU l(-1); p=0.047) and inhibin B adjusted for alcohol consumption (arithmetic mean (AM) 151 ng l(-1) vs. 123 ng l(-1); p=0.001) were higher in the welders compared with the referents. The whole blood Mn concentration was associated with the serum prolactin concentrations. Tobacco smoking resulted in lower serum prolactin concentrations. The GM serum prolactin concentrations of the patients did not significantly differ from that of the referents, but their AM serum inhibin B concentration was statistically significantly lower. The results may suggest an effect of Mn on the pituitary that is reversible upon cessation of exposure. Lower inhibin B concentrations in the patients could point to a functional impairment of the testicular Sertoli cells, that may be caused by a welding fume component or other factors in their work environment.

Information on changes in the central nervous system (CNS) cholinergic systems following exposure to manganese are considerably less extensive than that associated with other neurotransmitter systems. However, experimental and clinical evidence support the notion that cholinergic activity plays a key role in the pathophysiology of manganese-induced neurotoxicity. Manganese acts as a chemical stressor in cholinergic neurons in a region-specific manner causing breakdown of the cellular homeostatic mechanisms. In fact, a number of cholinergic synaptic mechanisms are putative targets for manganese activity: presynaptic choline uptake, quantal release of acetylcholine into the synaptic cleft, postsynaptic binding of acetylcholine to receptors and its synaptic degradation by acetylcholinesterase. Moreover, manganese significantly influences astrocytic choline transport systems and astrocytic acetylcholine-binding proteins. Thus, manganese exerts its effect on the highly dynamic reciprocal relationship between astrocytes and cholinergic neurons. Cholinergic afferents are crucial in the physiology of locomotion, cognition, emotion and behavioral response, and therefore, it is not surprising that the anatomical selectivity of most manganese-induced cholinergic effects is compatible with the clinical correlates of manganism, which involves impairment of emotional response, decline in higher cortical functions and movement disorder. Manganism, also referred to as Parkinson's-like disorder, is initially manifested by a neuropsychiatric syndrome (locura manganica), the most frequent symptoms and signs of which are compulsive behavior, emotional lability, visual hallucinations and flight of ideas, cognitive decline and memory loss. These signs and symptoms are followed by an extrapyramidal syndrome, which shares numerous clinical and pathophysiological characteristics with idiopathic Parkinson's disease (PD). This natural history of disease could be a clinical reflection of the preferential involvement of the cholinergic systems, initially in the septo-hippocampus and later in the basal ganglia. These observations highlight the importance of studying the role of the CNS cholinergic systems in manganese-mediated neurotoxicity.

The etiology of manganese neurotoxicity is heterogenous and includes exposure to welding fumes, chronic liver failure, and chronic total parental nutrition (TPN). We recently reported that cognitive impairment occurs in welders and patients with chronic liver failure who had evidence of manganese neurotoxicity including abnormal magnetic resonance imaging (MRI) basal ganglia T1 hyperintensity. In this study, we compared the neuropsychological profiles of patients with manganese neurotoxicity and basal ganglia T1 hyperintensities from three different etiologies: welding, chronic liver failure, and chronic TPN. Across all three groups, the neuropsychological profiles suggest frontal and subcortical cognitive impairment, with more widespread abnormalities occurring in the non-welding groups.

There is increased interest within the scientific community concerning the neurotoxicity of manganese owing in part to the use of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline fuel additive and an enhanced awareness that this essential metal may play a role in hepatic encephalopathy and other neurologic diseases. Neurotoxicity generally arises over a prolonged period of time and results when manganese intake exceeds its elimination leading to increases in brain manganese concentration. Neurotoxicity can occur following high dose oral, inhalation, or parenteral exposure or when hepatobiliary clearance of this metal is impaired. Studies completed during the past several years have substantially improved our understanding of the health risks posed by inhaled manganese by determining exposure conditions that lead to increased concentrations of manganese within the central nervous system and other target organs. Many of these studies focused on phosphates, sulfates, and oxides of manganese since these are formed and emitted following MMT combustion by an automobile. These studies have evaluated the role of direct nose-to-brain transport of inhaled manganese and have examined differences in manganese toxicokinetics in potentially sensitive subpopulations (e.g., fetuses, neonates, individuals with compromised hepatic function or sub-optimal manganese intake, and the aged). This manuscript reviews the U.S. Environmental Protection Agency's current risk assessment for inhaled manganese, summarizes these contemporary pharmacokinetic studies, and considers how these data could inform future risk assessments of this metal following inhalation.

The goal of occupational risk assessment is often to estimate excess lifetime risk for some disabling or fatal health outcome in relation to a fixed workplace exposure lasting a working lifetime. For sub-chronic or sub-clinical health effects measured as continuous variables, the benchmark dose method can be applied, but poses issues in defining impairment and in specifying acceptable levels of excess risk. Such risks may also exhibit a dose-rate effect and partial reversibility such that effects depend on how the dose is distributed over time. Neurological deficits as measured by a variety of increasingly sensitive neurobehavioral tests represent one such outcome, and the development of a parkinsonian syndrome among welders exposed to manganese fume presents a specific instance. Welders employed in the construction of piers for a new San Francisco-Oakland Bay Bridge in San Francisco were previously evaluated using a broad spectrum of tests. Results for four of those tests (Rey-Osterrieth Complex Figure Test, Working Memory Index, Stroop Color Word Test and Auditory Consonant Trigrams Test) were used in the benchmark dose procedure. Across the four outcomes analyzed, benchmark dose estimates were generally within a factor of 2.0, and decreased as the percentile of normal performance defining impairment increased. Estimated excess prevalence of impairment, defined as performance below the 5th percentile of normal, after 2 years of exposure at the current California standard (0.2 mg/m3, 8 h TWA), ranged 15-32% for the outcomes studied. Because these exposures occurred over a 1-2-year period, generalization to lifetime excess risk requires further consideration of the form of the exposure response and whether short-term responses can be generalized to equivalent 45-year period. These results indicate unacceptable risks at the current OSHA PEL for manganese (5.0 mg/m3, 15 min) and likely at the Cal OSHA PEL as well.

Parkinsonism is a clinical syndrome consisting of tremor, bradykinesia, rigidity, gait, balance problems, in addition to various non-motor symptoms. There are many causes of parkinsonism such as neurodegenerative disease, drugs, vascular causes, structural lesions, infections, and toxicants. Parkinson's disease, or idiopathic parkinsonism, is the most common form of parkinsonism observed in the clinic. There is degeneration of the substantia nigra, pars compacta, which results in loss of striatal dopamine. Parkinson's disease is a slowly progressive condition in which there is a dramatic and sustained responsiveness to levodopa therapy. Manganese is an essential trace element that can be associated with neurotoxicity. Hypermanganism can occur in a variety of clinical settings. The clinical symptoms of manganese intoxication include non-specific complaints, neurobehavioral changes, parkinsonism, and dystonia. Although the globus pallidus is the main structure of damage, other basal ganglia areas can also be involved. MRI scans may show globus pallidus changes during (and for a short period after) exposure. Fluorodopa PET scans that assess the integrity of the substantia nigra dopaminergic system are abnormal in Parkinson's disease. However, these scans re-reported to be normal in a few cases studied with manganese-induced parkinsonism. The parkinsonism due to manganese may have some clinical features that occur less commonly in Parkinson's disease, such as kinetic tremor, dystonia, specific gait disturbances, and early mental, balance and speech changes. The clinical signs tend to be bilateral whereas Parkinson's disease begins on one side of the body. Patients with manganese-induced parkinsonism may be younger at the onset of the disease than with Parkinson's disease. Lastly, there appears to be a lack of response to levodopa therapy in manganese-induced parkinsonism. In summary it may be possible to differentiate manganese-induced parkinsonism from Parkinson's disease using clinical and imaging studies.

This paper describes the strategy developed in Quebec to deal with an emerging problem: manganism in welders. Only two cases of manganism had been reported to the Commission de la santé et de la sécurité du travail (CSST, Workers Compensation Board in Quebec) before 2000. In the fall of 2001, the CSST was informed of a possible cluster of manganism and received 20 compensation claims from one plant. Action was rapidly taken to understand and tackle this emerging problem. Under the leadership of the CSST, a coordinating working group implemented medical and environmental subcommittees involving representatives of the different partners of the prevention network. After a literature review to document the health risks associated with manganese and the lack of some important information, a panel of international experts was formed to try to reach agreement on the parameters to consider in the diagnosis and management of manganism. The CSST compensation management policies would be adjusted accordingly. Simultaneously, all the available industrial hygiene data were analyzed to estimate where and at what levels workers were exposed to manganese. To complete these data, the exposure of workers in more than 50 industrial plants was evaluated and existing control measures were documented. All these data have been presented for a revision of the Quebec permissible exposure limit (PEL). In this integrated approach, the next step targets the formation of neurologists and neuropsychologists for a standardized medical evaluation, to complete workplace evaluation in the high risk sectors, inform workers and employers and recommend control measures where required, based on a revised PEL. Many strategies will be used to inform the prevention network (about 1000 people), employers and employees of the risks of overexposure to manganese and of the measures to control exposure in all the plants where workers are susceptible to be exposed to manganese.

Manganese and its inorganic compounds are widely used in many industries and have been accepted as occupational neurotoxins that have caused a distinct and disabling clinical entity, manganism, in several types of work, notably where exposure is by way of dust. There is inconclusive and inconsistent evidence that, in these occupations, subclinical neurological effects, detectable only by neurobehavioural studies, may be caused by low doses. This has prompted a re-evaluation of occupational exposure limits. Some countries, including the UK, already demand much higher levels of protection against exposure than 5 years ago. Welding is the most common source of occupational exposure as manganese is an essential component of steel and so its compounds are inevitable components of fume emitted from steel welding processes. There it is found in respirable particles, often as complex oxides (spinels), sometimes within a core protected by a silicon oxide shell - as distinct from the much simpler form of particle formed by disintegration in processes such as mining and ore milling where manganism has been diagnosed convincingly. Millions of workers are at risk of exposure to manganese-containing compounds in fumes from electric arc welding of steel. In recent years it has been asserted that neurological and neurobehavioural disorders may develop consequent to exposure to steel welding fumes and that employment as a welder is associated with the unusually early onset of Parkinson's disease. Causal relationships have been postulated. Welders have been recorded as having been exposed to high levels of manganese-containing fume, especially where they have worked in confined, unventilated spaces, although this appears from limited data to be the exception rather than the rule. Even then the dose received is generally less than in mining or ore crushing. When care is taken to exclude exposures from hardfacing and burning and cutting arc processes, where manganese may form a high percentage of the fume, manganese compounds usually form a relatively low percentage of the composition of welding fume particles, <2.0%, much outweighed by iron. Although these manganese-compound-containing welding fume particles are insoluble in water, the manganese compounds in particles that are retained in the alveoli may be absorbed, at least in part. Manganese concentrations in biological material samples in some exposed groups reflect this relative to unexposed workers. Some of the transfer systems for absorption and transport, including across the blood-brain barrier, are used in competition with iron which is present in abundance in welding fume. This may reduce absorption of manganese in welders and thus reduce the opportunity for sufficient doses to cause neurotoxicological consequences. Scrutiny of the literature covering the last 40 years has revealed only five cases that meet sufficient criteria for manganism to just cross the diagnostic threshold, and even then they carry a degree of doubt with them. This low incidence alone gives notice that welders have not been and are not at high risk of clinically apparent damage from exposure to manganese. If this needs to be further emphasised, there is the fact that the literature contains no confirmed cases of manganism in welders. Assertions of abnormal results in neurobehavioural studies of welders have raised the possibility of there being a subclinical form of manganism with loss of fine motor control as one of its features. While observations of such changes in workers in other industries have caused regulators in some countries to apply more stringent controls of exposure, as yet the results lack convincing consistency and there is no indication of any dose-effect relationship. If welding fume can have these motor effects it would be a heavy and perhaps career-ending blow to those affected. It would not be prudent to dismiss the warnings sounded by the results of studies of welders, no matter how flawed these investigations are, but wiser and better to act with vigour to reduce exposure and monitor the effectiveness of this additional protection whilst conducting high quality research to allow sound conclusions to be drawn as to whether there actually is a subclinical disorder. Idiopathic Parkinson's disease is a common disorder affecting 1-2% of those in the general population aged >65 years. It has been suggested, on flawed and contested evidence, not that welding causes the disease but rather that employment as a welder carries with it the risk of developing this disease at a younger age than if that trade had not been followed. Manganese in welding fume has been nominated as the neurotoxin. This may be biologically feasible if manganese destroys insufficient receptor cells to produce clinical manganism but sufficient to enhance the effects of a reduced supply of dopamine to give the manifestations of already developing idiopathic Parkinson's disease earlier in the course of destruction of the substantia nigra than if all receptors were intact.

Occupational exposure to airborne manganese dust has been shown to produce adverse effects on the central nervous system. Four hundred and eighty-nine blue and white collar manganese mineworkers from South Africa were studied cross-sectionally to investigate the nervous system effects of medium to low occupational manganese exposures. The different facilities included underground mines, surface processing plants, and office locations. A job exposure matrix was constructed using routine occupational hygiene data. Exposure variables included years of service, a cumulative exposure index (CEI) and average intensity of exposure (AINT) across all jobs, and blood manganese. Endpoints included items from the Q16, WHO-NCTB, SPES, and Luria-Nebraska test batteries, and a brief clinical examination. Potential confounders and effect modifiers included age, level of education, past medical history including previous head injury, previous neurotoxic job exposures, tobacco use, alcohol use and home language. Associations were evaluated by multiple linear and logistic regression modeling. Average exposure intensity across all jobs was 0.21mg/m(3) manganese dust. Multivariate analyses showed that none of the symptom nor test results were associated with any measure of exposure including blood manganese, after adjustment for confounders. This relatively large null study indicates that manganese miners exposed on average across all jobs to MnO(2) at levels near the American Conference of Governmental Industrial Hygienists Threshold Limit Value (ACGIH TLV) are unlikely to have a subclinical neurotoxicity problem.

Manganese, which enters the body primarily via inhalation, can damage the nervous system and respiratory tract, as well as have other adverse effects. Occupational exposures occur mainly in mining, alloy production, processing, ferro-manganese operations, welding, and work with agrochemicals. Among the neurologic effects is an irreversible parkinsonian-like syndrome. An estimated 500,000 to 1.5 million people in the United States have Parkinson's disease, and physicians need to consider manganese exposure in its differential diagnosis. Since 1837, there have been many reports of cases and case series describing manganese toxicity. More recently, there have been epidemiologic studies of its adverse effects on health. Occupational medicine physicians can play critical roles in preventing the adverse health effects of manganese.