Blood Mn Concentrations Research Articles

Whole Blood Manganese Correlates with High Signal Intensities on T1-Weighted MRI in Patients with Liver Cirrhosis

We examined whole blood (MnB), plasma (MnP) and urinary Mn (MnU) concentrations in 33 cirrhotics and 11 healthy controls to clarify: (1) whether, in chronic liver diseases, MnB or MnP reflects pallidal signal intensities in magnetic resonance imaging (MRI); and (2) which factors in chronic liver diseases correlate with pallidal signal intensities in T1-weighted MRI. Increased signal intensity in the pallidum was observed in 27 (81.8%) of 33 patients with liver cirrhosis in T1-weighted MRI. There was a significant correlation between MnB and pallidal index (PI) ( γ = 0.559, P < 0.01) in the patients. However, no significant correlation was observed between MnP and PI ( γ = 0.353, P > 0.05). According to a multiple linear regression, MnB reflected the signal intensities of T1-weighted MRI better than MnP or MnU. Child/Pugh score and total bilirubin level also correlated with PI. However, the hemoglobin level did not correlate with PI significantly.

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 μg/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 μg/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 μg/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.

A longitudinal follow-up of pulmonary function and respiratory symptoms in workers exposed to manganese.

The purpose of the investigation was to study the effects on the respiratory system in mine workers with long-term exposure to manganese (Mn) in the workplace. The study included a follow-up of pulmonary function and respiratory symptoms among 145 workers employed in a large Mn mine and 65 matched controls, and the assessment of Mn concentrations in environment and biological samples. Lung function was measured by recording spirometric parameters. The Mn-exposed workers reported more respiratory symptoms and a significantly higher prevalence of all grades of pulmonary function impairment. All predicted symptoms except for asthma increased significantly in the current smoking group compared with the non-smoking group. There was a significant decrease in FEV1, FVC, and FEV1% values in exposed workers compared with controls at stages 2 and 3, with an additive effect of the smoking habit. The Mn concentrations in blood, urine, and hair were significantly higher in the exposed workers than in the controls. The level of cumulative exposure index of workplace Mn was notable and did not change significantly over this study. The respiratory effects found in Mn-exposed workers were probably caused by the Mn in the workplace and the synergistic effect of smoking. These effects indicate a need for respiratory protection and improvements in the work environment.

Neurological Effects in Workers Exposed to Manganese

The purpose of this study was to examine the effects on the nervous system in enamels-production workers who have low levels of and long exposure to manganese (Mn). The study included 138 Mn-exposed workers and 137 controls who received questionnaires on symptoms, a battery of psychological tests, and assessments of blood concentrations of metal. The exposure levels to airborne Mn concentrations were determined by personal and stationary samplings. The mean duration exposure to Mn was 19.87 years (SD +/- 9). The workers exposed to Mn reported more nonspecific subjective complaints than the control group. No effect of Mn exposure was indicated by the results of any of the neuropsychological tests. The Mn workers did not have higher concentrations of Mn in blood than the controls. Exposures of workers currently working with Mn averaged 57 micrograms/m3 respirable (personal samplings) and 12 g/m3 (stationary samplings). In conclusion, long exposure to low levels of Mn (approximately 200 micrograms/m3), as induced in our study, showed no significant disturbance of neurological performance.

In vitro and in vivo studies on chelation of manganese.

This work deals with new chelating agents of manganese (Mn). Out of 24 compounds chosen for their chemical structure supposed to be favorable for Mn complexation, six polyaminopolycarboxylic acids proved to be efficient for displacing Mn bound to serum bovine proteins in vitro: TTHA, DTPA, DPTA, DPTA-OH, HBED, EDTA (mobilization > or =50%). The first five compounds were then tested in vivo on rats pretreated with MnCl2. They exhibited only slight to moderate efficacy to diminish Mn in tissues and were ineffective on increased Mn concentration in whole blood; in addition, they had different and specific mobilizing effects on other essential elements (Fe, Zn, Cu). Their limited efficacy in vivo could be due to the formation of very stable complexes between Mn2+ and different molecules such as hemoglobin and certain cytochromes, instead of Fe2+. This could disturb the functioning of the cellular respiratory chain, leading to an incomplete reduction of O2 with formation of free oxygenated radicals, reduction in the energy supply, and disturbance of the cytochromes renewal mechanism. All of these phenomena could accelerate cellular aging and explain the lack of efficacy of the chelating agents towards Mn neurotoxicity (Parkinson's syndrome).

Magnetic resonance image and blood manganese concentration as indices for manganese content in the brain of rats.

Neurological disorders similar to parkinsonian syndrome and signal hyperintensity in brain on T1-weighted magnetic resonance (MR) images have been reported in patients receiving long-term total parenteral nutrition (TPN). These symptoms have been associated with manganese (Mn) depositions in brain. Although alterations of signal intensity on T1-weighted MR images in brain and of Mn concentration in blood are theoretically considered good indices for estimating Mn deposition in brain, precise correlations between these parameters have not been demonstrated as yet. Male Sprague-Dawley rats received TPN with 10-fold the clinical dose of the trace element preparation (TE-5) for 7 d. At 0, 2, 4, 6, and 8 wk post-TPN, the cortex, striatum, midbrain, and cerebellum were evaluated by MR images, and Mn concentration in blood and Mn content in these brain sites were measured by atomic absorption spectrometry. Immediately after TPN termination, signal hyperintensity in brain sites and elevated Mn content in blood and brain sites were observed. These values recovered at 4 wk post-TPN. A positive correlation was observed between either the signal intensity in certain brain sites or Mn content in blood and the relevant brain sites. Our observations suggest that the Mn concentration in blood and signal intensity in the brain sites on T1-weighted MR images are reliable indices for monitoring Mn contents in brain.

Significance of magnetic resonance image and blood manganese measurement for the assessment of brain manganese during total parenteral nutrition in rats

In this study, we report on the influence of trace elements (TE) on signal intensities of nuclear magnetic resonance images (MRI), both in vivo and in vitro. Optimal parameters for the assessment of Mn concentration in the brain of rats on total parenteral nutrition were established. For the in vitro study, Mn and trace element solutions, one containing Zn, Cu, Fe, and I (TE-4) and another containing the above elements plus Mn (TE-5), were diluted with physiological saline or with rat brain homogenate and used to measure signal intensities in MRI. Concentration-dependent signal hyperintensity was observed in both cases in the Mn and the TE-5 solutions, but no effect was observed with the TE-4 solution. The signal increase was greater for brain tissue homogenates. In the in vivo study, the experimental animals were maintained under total parenteral nutrition (TPN) with a standard clinical dose of TE-5 and/or with 10-fold the clinical dose of TE-4 and TE-5 for 1 wk. Only rats that were receiving the increased TE-5 dose showed signal hyperintensity on MRI. Positive correlations were observed among the signal hyperintensity, the blood Mn concentrations, and that of the rat brain. Our results suggest that Mn in TE preparations may be the cause of signal hyperintensity on MRI in a concentration-dependent fashion, and that MRI and measurement of blood Mn may be used to estimate Mn accumulation in brain tissue.

Trace element concentrations in blood and hair of young apprentices of a technical-professional school

The concentrations of total Fe, Cu, Mn, Zn, Pb, Cr, Ni and Ca in the whole blood of young male apprentices of a technical-professional school, who are exposed to low doses of fumes from nanual metal arc welding of mild steel, were monitored over their 2 years of apprenticeship in order to evaluate the influence of occupational exposure on biological metal levels. The results were compared with those from a control group of the same sex and age and living in the same geographic area. For comparison, monitoring of the same metal levels in the hair of both groups of individuals were also carried out. In the apprentices, the mean metal concentrations in blood at the end of the study were statistically significantly higher for Cu, lower for Fe and Mn and similar for the remaining metals. The levels of Fe significantly decreased whereas the levels of Cu were significantly increased during the study. A systematic influence of the exposure period on the levels of Mn was not observed. All the metal concentrations measured in the blood and hair of both apprentices and controls fell in the very large range of published reference levels. Seasonal variation (higher levels in the summer) of the hair metal concentrations were observed for Mn, Cu, Pb, Ni, Zn and Ca.

Manganese and chronic hepatic encephalopathy

SummaryClinical observations and animal studies have raised the hypothesis that increased concentrations of manganese (Mn) in whole blood might lead to accumulation of this metal within the basal ganglia in patients with end-stage liver disease. We studied ten patients with liver failure (and ten controls) by magnetic resonance imaging (MRI) and measurement of Mn in brain tissue of three patients who died of progressive liver failure (and three controls) was also done.Whole blood Mn concentrations in patients with liver cirrhosis were significantly increased (median 34·4 μg/L vs 10·3 μg/L in controls; p=0·0004) and pallidal signal intensity indices correlated with blood Mn (Rs=0·8, p=0·0058). Brain tissue samples reveal highest Mn concentrations in the caudate nucleus, followed by the quadrigeminal plate and globus pallidus.Mn accumulates within the basal ganglia in liver cirrhosis. Similarities between Mn neurotoxicity and chronic hepatic encephalopathy suggest that this metal may have a role in the pathogenesis of chronic hepatic encephalopathy. Further studies are warranted because the use of chelating agents could prove to be a new therapeutic option to prevent or reverse this neuropsychiatric syndrome.

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 microgram/m3) than the blue-collar workers (0.04 microgram/m3). However, the contribution of atmospheric Mn to the total absorbed dose was less than 1%, and well below the standards established 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 microgram/100 ml) and fall within the normal adult range. The average hair Mn concentrations were significantly higher for the garage mechanics (0.66 microgram/g) than for the blue-collar workers (0.39 microgram/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.

Anticonvulsant-induced changes in tissue manganese, zinc, copper, and iron concentrations in Wistar rats

Human epileptics have been reported to have low blood manganese (Mn) concentrations in comparison to nonepileptics, an observation that is important because Mn deficiency can increase seizure susceptibility in experimental animals. Factors that have been suggested to contribute to the low blood Mn levels in epileptics include anticonvulsant use, seizure-induced tissue redistribution of Mn, and genetics; in the present study, the first of these possibilities was tested. Wistar rats were fed semipurified diets containing diphenylhydantoin ([DPH] 3 g/kg diet), phenobarbital ([PB] 2 g/kg diet), or primidone ([PRIM] 3 g/kg diet) for 7 weeks, at which time they were killed and tissues collected and analyzed for Mn, zinc (Zn), copper (Cu), and iron (Fe) concentrations. In comparison to pair-fed rats, DPH- and PRIM-fed rats had significantly elevated liver Mn concentrations, while Mn concentrations in blood, brain, heart, and kidney were unaffected by anticonvulsant exposure. Changes in the concentrations of Zn, Cu, and Fe in specific tissues were also found. Overall, these findings suggest that the anticonvulsants tested do not lead to significant derangements in the metabolism of Mn.

Determination of blood and urine manganese (Mn) concentrations and the application of static sensography as the indices of Mn-exposure among Mn-refinery workers.

Early detection of neurophysiological abnormalities is believed to be most effective for the early diagnosis of chronic manganism. The static sensography was applied during the periodical health examination and the significance of total distance of the postural sway (i. e. postural sway index) as a neurophysiological index was studied in relation to the blood and urine manganese concentrations. Sixty-six workers in a manganese (Mn)-refining factory, aged 29-59 (mean 47) years, were examined from 1984 to 1989. Mn-exposed workers had been engaged in alternating shifts and the mean duration of Mn exposure was 22.6 years before the health examination in 1984. Air-borne dust and Mn levels in the working environment were 0.07-2.74 mg/m3 and 0.02-0.46 mg/m3. The mean values of the parameters in Mn-exposed workers fluctuated as follows: blood Mn concentrations 19.1-26.9 micrograms/l [control; Mean 17.8 (Standard deviation 5.2) micrograms/l], urine Mn concentration 2.60-4.22 micrograms/g Creatinine [control; Geometric mean 1.16 (Geometric standard deviation 1.93) micrograms/g Creat.] and postural sway index 51.4-94.6 cm/30 sec [control; Geometric mean 59.7 (Geometric standard deviation 1.4) cm/30 sec.]. Although there were no significant correlations between the postural sway index and blood and urine manganese concentrations, the usefulness of this kind of simple neurophysiological test should be further investigated in combination with other established examinations.

Assessment of the permissible exposure level to manganese in workers exposed to manganese dioxide dust.

The prevalence of neuropsychological and respiratory symptoms, lung ventilatory parameters, neurofunctional performances (visual reaction time, eye-hand coordination, hand steadiness, audioverbal short term memory), and several biological parameters (calcium, iron, luteinising hormone (LH), follicle stimulating hormone (FSH), and prolactin concentrations in serum, blood counts, manganese (Mn) concentration in blood and in urine) were examined in a group of workers (n = 92) exposed to MnO2 dust in a dry alkaline battery factory and a matched control group (n = 101). In the battery plant, the current exposure of the workers to airborne Mn was measured with personal samplers and amounted on average (geometric mean) to 215 and 948 micrograms Mn/m3 for respirable and total dust respectively. For each worker, the lifetime integrated exposure to respirable and total airborne Mn dust was also assessed. The geometric means of the Mn concentrations in blood (MnB) and in urine (MnU) were significantly higher in the Mn exposed group than in the control group (MnB 0.81 v 0.68 microgram/100 ml; MnU 0.84 v 0.09 microgram/g creatinine). On an individual basis, MnU and MnB were not related to various external exposure parameters (duration of exposure, current exposure, or lifetime integrated exposure to airborne Mn). On a group basis, a statistically significant association was found between MnU and current Mn concentrations in air. No appreciable difference between the exposed and the control workers was found with regard to the other biological measurements (calcium, LH, FSH, and prolactin in serum). Although the erythropoietic parameters and serum iron concentration were in the normal range for both groups, there was a statistically significant trend towards lower values in the Mn exposed workers. The prevalences of reported neuropsychological and respiratory symptoms, the lung function parameters, and the audioverbal short term memory scores did not differ between the control and exposed groups. The Mn workers, however, performed the other neurofunctional tests (visual reaction time, eye-hand coordination, hand steadiness) less satisfactorily than the control workers. For these tests, the prevalences of abnormal results were related to the lifetime integrated exposure to total and respirable Mn dust. On the basis of logistic regression analysis it may be inferred that an increased risk of peripheral tremor exists when the lifetime integrated exposure to Mn dust exceeds 3575 or 730 micrograms Mn/m3 x year for total and respirable dust respectively. The results clearly support a previous proposal by the authors to decrease the current time weighted average exposure to Mn dust.

THE EFFECTS OF CAPTOPRIL AND ENALAPRIL ON TISSUE LEVELS OF VARIOUS ELEMENTS IN SPONTANEOUSLY HYPERTENSIVE RATS

The effects of two inhibitors of angiotensin I converting enzyme, captopril and enalapril, on the concentrations of Na, K, Ca, Mg, Fe, S, P, Sr, Mn, Cu and Zn ions in blood, plasma, heart, skeletal muscle, liver and kidney of spontaneously hypertensive rats (SHR) were studied. Captopril and enalapril were given by the intraperitoneal route for 15 days, at 160 mumols/kg/d and 40 mumols/kg/d, respectively. Elements in tissues were determined by inductively coupled plasma emission spectrometry with a JY 48 instrument. The common changes produced with the two drugs were: a decrease of Na in muscle (-10%), a decrease of Ca in plasma and kidney (less than -10%) and a decrease of Mn in liver (-15%). The main effects observed with only one of the two drugs were: an increase of Cu in plasma (+26%) with captopril, and increases of Sr in heart (+56%), muscle (+79%) and liver (+74%) with enalapril. Zinc concentration in tissues was not modified, except for an increase in liver with captopril (+13%) and a decrease in heart with enalapril (-11%).

Trace elements in human clinical specimens: evaluation of literature data to identify reference values.

Reference values are proposed for the concentrations of As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Mo, Pb, Se, and Zn in whole blood, blood serum, urine, milk, liver, and hair from adult human subjects. For F, I, and Ni, it was not possible to evaluate reference intervals for all the specimens mentioned above. For several elements, including Al, B, Br, Cs, Li, Rb, U, and V, the present status of the literature does not provide an adequate basis for formulating baseline concentrations; therefore, results from selected investigations are listed for information only. For elements such as Cu, Fe, and Zn, which are known to be homeostatically controlled, the concentrations in whole blood and blood serum follow a gaussian-like frequency distribution, and we could consider both median and mean values for evaluation. On the other hand, elements whose concentrations in tissues and body fluids are influenced by dietary availability (e.g., As and Se) or environmental factors (e.g., Cd, Hg, and Pb) show wide scatter. In these cases, the median appeared to be a better indicator of the central tendency than the mean, when different populations are involved. These points are illustrated.

Epidemiological survey among workers exposed to manganese: effects on lung, central nervous system, and some biological indices.

A cross-sectional epidemiological study was carried out among 141 male subjects exposed to inorganic manganese (Mn) in a Mn oxide and salt producing plant (mean age 34.3 years; duration of exposure, mean 7.1 years, range 1-19 years). The results were compared with those of a matched control group of 104 subjects. The intensity of Mn exposure was moderate as reflected by the airborne Mn levels and the concentrations of Mn in blood (Mn-B) and in urine (Mn-U). A significantly higher prevalence of cough in cold season, dyspnea during exercise, and recent episodes of acute bronchitis was found in the Mn group. Lung ventilatory parameters (forced vital capacity, FVC; forced expiratory volume in one second, FEV1; peak expiratory flow rate, PEFR) were only mildly altered in the Mn group (smokers) and the intensity and the prevalence of these changes were not related to Mn-B, Mn-U, or duration of exposure. There was no synergistic effect between Mn exposure and smoking on the spirometric parameters. Except for a few nonspecific symptoms (fatigue, tinnitus, trembling of fingers, increased irritability), the prevalence of the other subjective complaints did not differ significantly between the control and Mn groups. Psychomotor tests were more sensitive than the standardized neurological examination for the early detection of adverse effects of Mn on the central nervous system (CNS). Significant alterations were found in simple reaction time (visual), audioverbal short-term memory capacity, and hand tremor (eye-hand coordination, hand steadiness). A slight increase in the number of circulating neutrophils and in the values of several serum parameters (ie, calcium, ceruloplasmin, copper, and ferritin) was also found in the Mn group. There were no clear-cut dose-response relationships between Mn-U or duration of Mn exposure and the prevalence of abnormal CNS or biological findings. The prevalences of disturbances in hand tremor and that of increased levels of serum calcium were related to Mn-B. The response to the eye-hand coordination test suggests the existence of a Mn-B threshold at about 1 microgram Mn/100 ml of whole blood. This study demonstrates that a time-weighted average exposure to airborne Mn dust (total dust) of about 1 mg/m3 for less than 20 years may present preclinical signs of intoxication.

Association of low blood manganese concentrations with epilepsy.

A comparison of hospitalized epileptic patients with matched normals showed that the mean whole blood manganese (Mn) concentration of the epileptic population was significantly lower than the mean of the normal population. The whole blood Mn concentration in the epileptics did not correlate either with seizure frequency or with anticonvulsant therapy. It was observed, however, that patients whose epilepsy was a result of trauma had significantly higher blood Mn concentrations than patients whose history was negative for trauma.

EFFECTS OF DIETARY MANGANESE LEVELS ON REPRODUCTIVE PERFORMANCE OF EWES AND ON TISSUE MINERAL COMPOSITION OF EWES AND DAY-OLD LAMBS

Two groups of eight 2-yr-old ewes were fed a low manganese (Mn) synthetic diet (8 ppm Mn) either with or without Mn supplementation (60 ppm Mn). The diets were fed for a 5-mo period prior to breeding and throughout gestation. Manganese supplementation of the diet resulted in higher blood Mn concentration. More services per conception were required for the ewes fed the low Mn diet than were required for the ewes fed the Mn-supplemented diet. The calcium content of kidney and muscle tissues, the magnesium content of spleen and the zinc content of the heart were found to be lower in ewes fed supplemental Mn, while the zinc content of the spleen was found to be higher. The calcium levels in the heart and kidney and iron levels in the liver and lung were higher in the day-old lambs born to Mn-supplemented ewes, while the magnesium level in the heart was lower. It is suggested that the calcium response of the ewes on low Mn diet to the physiological demands of fetal development may have been impaired by a reduction in dietary Mn.