Joseph Zayed

Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction

BACKGROUND & AIMS Manganese (Mn) deposition could be responsible for the T(1)-weighted magnetic resonance signal hyperintensities observed in cirrhotic patients. These experiments were designed to assess the regional specificity of the Mn increases as well as their relationship to portal-systemic shunting or hepatobiliary dysfunction. METHODS Mn concentrations were measured in (1) brain samples from basal ganglia structures (pallidum, putamen, caudate nucleus) and cerebral cortical structures (frontal, occipital cortex) obtained at autopsy from 12 cirrhotic patients who died in hepatic coma and from 12 matched controls; and from (2) brain samples (caudate/putamen, globus pallidus, frontal cortex) from groups (n = 8) of rats either with end-to-side portacaval anastomosis, with biliary cirrhosis, or with fulminant hepatic failure as well as from sham-operated and normal rats. RESULTS Mn content was significantly increased in frontal cortex (by 38%), occipital cortex (by 55%), pallidum (by 186%), putamen (by 66%), and caudate (by 54%) of cirrhotic patients compared with controls. Brain Mn content did not correlate with patient age, etiology of cirrhosis, or history of chronic hepatic encephalopathy. In cirrhotic and portacaval-shunted rats, Mn content was increased in pallidum (by 27% and 57%, respectively) and in caudate/putamen (by 57% and 67%, respectively) compared with control groups. Mn concentration in pallidum was significantly higher in portacaval-shunted rats than in cirrhotic rats. No significant changes in brain Mn concentrations were observed in rats with acute liver failure. CONCLUSIONS These findings suggest that brain Mn deposition results both from portal-systemic shunting and from liver dysfunction.

Manganese and lead concentrations in ambient air and emission rates from unleaded and leaded gasoline between 1981 and 1992 in Canada: A comparative study

Abstract Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic derivative of manganese (Mn) used as an additive in unleaded gasoline. Its use in Canada has increased since 1976 until it completely replaced lead (Pb) in gasoline in 1990. Canada is the only country in the world to have authorized the replacement of Pb in gasoline by MMT. The aim of this study is to compare the concentrations of Mn, Pb and suspended particulates (TSP) in Montreal air from 1981 to 1992, as well as the emission rates of Mn and Pb from mobile sources from the same period. The atmospheric concentrations of Mn, Pb and TSP were measured by the Montreal Urban Community at three sampling stations located in areas of low and high traffic density. The data on emission rates were obtained from Environment Canada and from the Canadian Petroleum Products Institute. Multiple regression and non-parametric correlation analysis were used to predict and to compare the evolution of the chosen variables. Discriminant analysis was used to determine the variables which best distinguish low and high traffic density areas. The results indicate stable Mn concentrations between 1981 and 1990 followed by a substantial decrease, in spite of annual increases of about 10% in Mn emissions from the combustion of MMT since 1981. The decrease observed since 1991 is attributed to the closing of a ferromanganese plant near Montreal. The decrease in atmospheric Pb concentrations observed since 1981 corresponds to the decrease of about 30% per year of emissions from mobile sources over the same period. A definitive evaluation of the environmental contamination and exposure due to Mn from MMT will require an improved estimation of the dispersion of particulates near motorways using dispersion models, as well as receptor modeling based on the physicochemical analysis of particulates using electron microscopy.

Role of manganese in the pathogenesis of portal-systemic encephalopathy.

Amongst the potential neurotoxins implicated in the pathogenesis of hepatic encephalopathy, manganese emerges as a new candidate. In patients with chronic liver diseases, manganese accumulates in blood and brain leading to pallidal signal hyperintensity on T1-weighted Magnetic Resonance (MR) Imaging. Direct measurements in globus pallidus obtained at autopsy from cirrhotic patients who died in hepatic coma reveal 2 to 7-fold increases of manganese concentration. The intensity of pallidal MR images correlates with blood manganese and with the presence of extrapyramidal symptoms occurring in a majority of cirrhotic patients. Liver transplantation results in normalization of pallidal MR signals and disappearance of extrapyramidal symptoms whereas transjugular intrahepatic portosystemic shunting induces an increase in pallidal hyperintensity with a concomitant deterioration of neurological dysfunction. These findings suggest that the toxic effects of manganese contribute to extrapyramidal symptoms in patients with chronic liver disease. The mechanisms of manganese neurotoxicity are still speculative, but there is evidence to suggest that manganese deposition in the pallidum may lead to dopaminergic dysfunction. Future studies should be aimed at evaluating the effects of manganese chelation and/or of treatment of the dopaminergic deficit on neurological symptomatology in these patients.

Occupational and Environmental Exposure of Garage Workers and Taxi Drivers to Airborne Manganese Arising from the Use of Methylcyclopentadienyl Manganese Tricarbonyl in Unleaded Gasoline

Occupational and environmental exposure to airborne manganese has been measured for two groups of workers in Montreal, taxi drivers and garage mechanics. In Canada methylcyclopentadienyl manganese tricarbonyl (MMT) has replaced lead as an anti-knock agent in gasoline and represents a potentially important source of manganese contamination for the population in general and for the two chosen groups of workers in particular. Twenty workers (10 taxi drivers and 10 garage mechanics) wore a personal air sampler for five consecutive working days and two off-work periods. The amount of total Mn on each filter was determined by neutron activation analysis and then converted to atmospheric Mn concentrations. The values obtained varied from 0.004 microgram m-3 to 2.067 micrograms m-3. At work the garage mechanics were exposed to an average of 0.250 microgram m-3 and the taxi drivers to 0.024 microgram m-3. Off-work, the two groups were exposed respectively to an average of 0.007 microgram m-3 and 0.011 microgram m-3. In the garages there was twice as much Mn in the air on days when the doors were closed compared to days when they were left opened (0.314 micrograms m-3/0.152 microgram m-3). The levels found in this study remain well below the established limits for occupational and environmental airborne exposure. These results will lead to further studies to positively identify the source of Mn as MMT and to explore other pathways leading to the contamination of the general population.

Environmental Contamination and Human Exposure to Airborne Total and Respirable Manganese in Montreal

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organometallic compound used as an octane improver in unleaded gasoline. The combustion of MMT leads to the formation of manganese (Mn) oxides, mainly Mn3O4. The objective of this study is to assess the variations over time and space of respirable (MnR) and total (MnT) Mn in the urban atmosphere and to evaluate human exposure by inhalation. Two sampling sites were selected on the island of Montreal based on their local traffic density (municipal botanical garden, C- = 10,000-15,000 vehicles d-1; Montreal Waterworks, C+ = 100,000-130,000 vehicles d-1). Air samplings were made during the day at stations located 10 m from the road using portable pumps, some of which were equipped with a cyclone. MnR and MnT and other metals were measured on Teflon filters by neutron activation. Mn exposure doses by inhalation were calculated using Monte-Carlo simulations. MnR and MnT average concentrations were significantly higher at site C+ (MnR = 0.024 microgram m-3; MnT = 0.050 microgram m-3) than at site C- (MnR = 0.015 microgram m-3; MnT = 0.027 microgram m-3). Temporal profiles at sites C+ and site C- were similar, with a coefficient of correlation of 0.24 for MnR and 0.26 for MnT. Trend analyses (ARIMA) also showed that the period of the week (work days vs. off days) was significantly related to MnR and MnT variations at both sites. The average exposure dose by inhalation to MnR and MnT ranged from 0.001 to 0.030 microgram kg-1 day-1 and 0.001 to 0.05 microgram kg-1 day-1. MnR and MnT concentrations reflected a positive relationship with traffic density. However, it remains difficult to attribute these results directly to the combustion of MMT in unleaded gasoline. On average, the MnR and MnT inhalation doses were 2 to 15 times lower than the reference dose (RfC) proposed by the U.S. Environmental Protection Agency (EPA) for the general population.

Bioaccumulation and locomotor effects of manganese phosphate/sulfate mixture in Sprague-Dawley rats following subchronic (90 days) inhalation exposure

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese (Mn) compound added to unleaded gasoline in Canada. The primary combustion products of MMT are Mn phosphate, Mn sulfate, and a Mn phosphate/Mn sulfate mixture. Concerns have been raised that the combustion products of MMT containing Mn could be neurotoxic, even at low levels of exposure. The objective of this study is to investigate exposure-response relationships for bioaccumulation and locomotor effects following subchronic inhalation exposure to a mixture of manganese phosphates/sulfate mixture. A control group and three groups of 30 male Sprague-Dawley rats were exposed in inhalation chambers for a period of 13 weeks, 5 days per week, 6 h a day. Exposure concentrations were 3000, 300, and 30 microg/m(3). At the end of the exposure period, locomotor activity and resting time tests were conducted for 36 h using a computerized autotrack system. Rats were then euthanized by exsanguination and Mn concentrations in different tissues (liver, lung, testis, and kidney) and blood and brain (caudate putamen, globus pallidus, olfactory bulb, frontal cortex, and cerebellum) were determined by neutron activation analysis. Increased manganese concentrations were observed in blood, kidney, lung, testis, and in all brain sections in the highest exposure group. Mn in the lung and in the olfactory bulb were dose dependent. Our data indicate that the olfactory bulb accumulated more Mn than other brain regions following inhalation exposure. Locomotor activity was increased at 3000 microg/m(3), but no difference was observed in resting time among the exposed groups. At the end of the experiment, rats exposed to 300 and 3000 microg/m(3) exhibited significantly decreased body weight in comparison with the control group. Biochemical profiles also revealed some significant differences in certain parameters, specifically alkaline phospatase, urea, and chlorate.

Manganese neurotoxicity: behavioral, pathological, and biochemical effects following various routes of exposure.

The human central nervous system is an important target for manganese intoxication, which causes neurological symptoms similar to those of Parkinsons disease. With the increasing use of methylcyclopentadienyl manganese tricarbonyl (MMT) as an octane-improving additive to unleaded gasoline, the prospect of worldwide manganese exposure is once again attracting attention as increases in environmental manganese concentrations have been recorded relative to traffic density. One crucial question is whether a small increase of manganese contamination resulting from the widespread use of MMT could have neurotoxic effects. In this review we concentrate on central nervous system abnormalities and neurobehavioral disturbances. Most experimental animal studies on manganese neurotoxicity have been conducted in nonhuman primates and rodents. Most studies performed in rodents used oral manganese administration and did not assess bioaccumulation or central nervous system changes. The major effect found was transient modification of spontaneous motor activity. Very few inhalation toxicological studies were carried out. As manganese intoxication in humans usually occurs via inhalation, more studies are required using the respiratory route of administration. Given the proven neurotoxic effects of manganese and the prospect of worldwide MMT usage, this metal should be considered a new environmental pollutant having potentially widespread public health consequences.

Environmental and occupational exposure to manganese: a multimedia assessment

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic additive used in Canada since 1976 as an anti-knock agent in unleaded gasoline. Its combustion leads to the emission of Mn oxides, especially Mn3O4. Since no study has assessed the potential risk of chronic exposure to low concentrations resulting from these emissions, the present investigation was undertaken to assess the level of environmental and occupational exposure of the human population. The multimedia exposure of two groups of workers (garage mechanics and blue-collar workers) potentially exposed to different levels of Mn from the combustion of MMT was assessed using personal air samplers, a dietary compilation, water samples at their places of residence, an epidemiological questionnaire and blood and hair samples. Results show that garage mechanics were exposed on average to higher atmospheric Mn at work (0.42 µg/m3) than the blue-collar workers (0.04 µg/m3). However, the contribution of atmospheric Mn to the total absorbed dose was less than 1%, and well below the standards estabished for occupational or environmental exposure; food contributes more than 95% of the multimedia dose. The average whole blood Mn concentrations were similar for the two groups (0.67–0.76 µg/100 ml) and fall within the normal adult range. The average hair Mn concentrations were significantly higher for the garage mechanics (0.66 µg/g) than for the blue-collar workers (0.39 µg/g). The contribution of exogenous Mn versus endogenous Mn is questioned. As judged by the governmental standards or criteria for occupational and non-occupational environments, the current Mn levels in food, water and air may not cause any problems for the workers.

Human Exposure to Respirable Manganese in Outdoor and Indoor Air in Urban and Rural Areas

Methylcyclopentadienyl manganese tricarbonyl (MMT) is used as an additive in gasoline, and its combustion leads to the emission of Mn particles, which increase atmospheric metal con-centrations. The objective of this study was to determine the level of outdoor and indoor respirable Mn (MnR) in Montreal, Canada, where MMT has been used since 1976. Ten women were involved in this study: five living in an urban area, near an expressway with high traffic density, and five residing in a rural area characterized by low traffic density. Outdoor and indoor air samples were collected each week (5 in total) during 3 consecutive days; blood sam-ples were collected at the end of the air sampling period. The average concentration of out-door MnR in the urban area was 0.025 μg/m3, which is significantly different from the average of 0.005 μg/m3 found in the rural area. The average indoor MnR concentration was also signif-icantly different between the urban area (0.017 μg/m3) and the rural area (0.007 μg/m3). The average outdoor MnR concentrations were not significantly different from the average MnR indoor concentrations within both areas. The mean blood Mn concentrations were not signifi-cantly different between the two groups. Data suggest that a high outdoor atmospheric MnR leads to a high indoor MnR, but not to an increase in blood Mn levels.

BIOACCUMULATION AND LOCOMOTOR EFFECT OF MANGANESE DUST IN RATS

The primary goal of this study is to determine the effects of Mn exposure via inhalation. The bioaccumulation of Mn in different organs and tissues, the alteration of biochemical parameters, and the locomotor activity were assessed. A group of 26 male Sprague-Dawley rats (E) were exposed to 3750 µg/m3 of Mn dust for 6 h/day, 5 days/wk for 13 consecutive weeks and compared to a control group of 12 rats (C) exposed to 4 µg/m3. After exposure, neurological evaluation was carried out for 36 h (a night-day-night cycle) using a computerized autotrack system. Rats were then sacrificed by exsanguination, and Mn content in organs and tissues was determined by neutron activation analysis. Mn concentrations in lung, putamen, and cerebellum were significantly higher in E than in C (0.30 vs. 0.17, 0.89 vs. 0.44, 0.63 vs. 0.48 ppm; p < .01), as well as in the kidney, frontal cortex, and globus pallidus (1.15 vs. 0.96, 0.84 vs. 0.47, 1.28 vs. 0.55 ppm; p < .05). Potassium concentration was significantly lower in E than in C (5.11 vs. 5.79 mmol/L; p < .05), as was alkaline phosphatase (106.9 vs. 129.6 U/L; p < .01). Locomotor activity indicated higher distance covered in the first 12-h period for E (45 383 vs. 36 098 cm; p < .05) and lower resting time in the last 12-h period for E (36 326 vs. 37 393 s; p < .05). This study is the first of several ongoing studies in our laboratory that address health concerns associated with inhalation exposure to different Mn species and to different levels of exposure.