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Background: Selenium (Se), Manganese (Mn), and Chromium (Cr) are dietary minerals ingested from specific grains, vegetables, and animal meats. Prior research showed that these minerals affect animal erythrocyte health but have unknown effects on human red blood cells (RBCs) and hematology. This study evaluated the effects of these dietary minerals on RBC count, hematocrit, and hemoglobin., Methods: We conducted a cross-sectional analysis of 23,844 American participants from the 2015-2016 and 2017-2020 National Health and Nutrition Examination Survey. We evaluated sex, age, ethnicity, education, income, and smoking status as covariates. Linear regression analyses were conducted to evaluate the effect of Cr, Se, and Mn on RBC count, hematocrit, and hemoglobin levels. We employed subpopulation-exclusion regressions further to explore the distinct effects of mineral elevation and deficiency. Additional analyses were performed to examine the relationship between Mn and RBC hemoglobin, RBC distribution width, transferrin receptor concentrations, transferrin saturation, and serum iron levels to support the interpretation of our findings. Optimizable ensemble machine learning models were used to corroborate regression results., Results: Adjusting for covariates, Cr was inversely associated with RBC count (Exp(b) = 0.954), hemoglobin (Exp(b) = 0.868), and hematocrit (Exp(b) = 0.668). Conversely, Se was positively associated with RBC count (Exp(b) = 1.003), hemoglobin (Exp(b) = 1.012), and hematocrit (Exp(b) = 1.032). Mn was positively associated with RBC count (Exp(b) = 1.020) but inversely associated with hemoglobin (Exp(b) = 0.945) and hematocrit (Exp(b) = 0.891)., Conclusions: Cr was harmful to RBC health in all subpopulations, whereas Se was protective. Mn appears to contribute to the development of microcytic anemia, but only in subjects with clinically elevated Mn levels. Thus, excessive consumption of foods and supplements rich in Cr and Mn may harm human erythrocyte health and hematology.

Although overexposure to manganese (Mn) is known to cause neurotoxic damage, effective exposure markers for assessing Mn loading in Mn-exposed workers are lacking. Here, we construct a Mn-exposed rat model to perform correlation analysis between Mn-induced neurological damage and Mn levels in various biological samples. We combine this analysis with epidemiological investigation to assess whether Mn concentrations in red blood cells (MnRBCs) and urine (MnU) can be used as valid exposure markers. The results show that Mn exposure resulted in neurotoxic damage in rats and that MnRBCs correlated well with neurological damage, showing potential as a novel Mn exposure biomarker. These findings provide a basis for health monitoring of Mn-exposed workers and the development of more appropriate biological exposure limits., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The aim of the present study was to determine changes occurring in the erythrocyte concentrations of chromium (Cr), copper (Cu), manganese (Mn), molybdenum (Mo), selenium (Se) and zinc (Zn) in male subjects with different training levels living in the same region (Spain)., Methods: Thirty sedentary subjects (24.34 ± 3.02 years) formed the control group (CG); 24 moderately trained (4-7 h/week) subjects (23.53 ± 1.85 years) formed the group with a moderate degree of training (MTG) and 22 professional cyclists (23.29 ± 2.73 years), who performed more than 20 h/week of training, formed the high-level training group (HTG). Erythrocyte samples were collected from all subjects in fasting conditions, washed and frozen at - 80 °C until analysis. Erythrocyte analysis of trace elements was performed by inductively coupled plasma mass spectrometry (ICP-MS)., Results: The results showed that there was a statistically significant lower erythrocyte concentration of Cu, Mn, Mo and Zn in the MTG and HTG than CG. Se was only significantly lower in HTG than CG. The correlation analysis indicates that this change was correlated with training in the case of Cu, Mn, Se and Zn. All results are expressed in μg/g Hb., Conclusions: We can conclude that physical training produces a decrease in erythrocyte concentrations of Cu, Mn, Se and Zn, which can cause a decrement in athletes' performance given the importance of these elements. For this reason, erythrocyte monitoring during the season would seem to be advisable to avoid negative effects on performance.

We examined serum and erythrocyte lead and manganese levels in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), which contains over 1000 registrants including over 200 cases of Alzheimer's disease (AD) and 100 mildly cognitively impaired (MCI) individuals. After correcting for confounding effects of age, collection site and sex, we found a significant decrease in serum manganese levels in AD subjects compared to healthy controls. Analysis of smaller subset of erythrocytes revealed no difference in either lead or manganese levels in AD. Although lead and manganese have neurotoxic effects and may be involved in AD pathology, our results showed that neither metal in serum nor erythrocytes are suitable biomarkers in our cohort. However, prospective studies might reveal whether the burden of either metal modifies disease outcomes.

The MRI technique has been used in diagnosis of manganism in humans and non-human primates. This cross-sectional study was designed to explore whether the pallidal signal intensity in T1-weighted MRI correlated with Mn levels in the blood compartment among Mn-exposed workers and to understand to what extent the MRI signal could reflect Mn exposure. A group of 18 randomly selected male Mn-exposed workers of which 13 were smelting workers with high exposure (mean of airborne Mn in work place: 1.26 mg/m3; range: 0.31-2.93 mg/m3), and 5 power distribution control workers with low exposure (0.66 mg/m3 and 0.23-0.77 mg/m3) from a ferroalloy factory, and another group of 9 male subjects as controls from a non-smelting factory who were office or cafeteria workers (0.01 mg/m3 and 0-0.03 mg/m3) were recruited for neurological tests, MRI examination, and analysis of Mn in whole blood (MnB), plasma (MnP) or red blood cells (MnRBC). No clinical symptoms and signs of manganism were observed among these workers. MRI data showed average increases of 7.4% (p<0.05) and 16.1% (p<0.01) in pallidal index (PI) among low- and high-exposed workers, respectively, as compared to controls. Fourteen out of 18 Mn-exposed workers (78%) had intensified PI values, while this proportion was even higher (85%) among the high Mn-exposed workers. Among exposed workers, the PI values were significantly associated with MnRBC (r=0.55, p=0.02). Our data suggest that the workers exposed to airborne Mn, but without clinical symptoms, display an exposure-related, intensified MRI signal. The MRI, as well as MnRBC, may be useful in early diagnosis of Mn exposure.

Unlabelled: Manganese (Mn) is widely distributed in the biosphere but occurs in only trace amounts in animal tissues. Although Mn deficiency and toxicity both have pathological consequences, the underlying biochemical lesions have not been well defined. In vitro studies suggest that transport proteins are affected by Mn, lead (Pb), and selenium (Se). Among these transport proteins, the calmodulin-regulated calcium pump (Ca(2+)Mg(2+)ATPase) could be inhibited by Mn. In order to understand Mn biochemical pathways, we examined the relationships between Mn blood levels and red blood cell Ca-pump activity among 248 mothers and newborns, environmentally exposed to Mn, Pb, and Se., Population and Methods: 248 mother-newborn pairs were recruited at Robert Debré University Hospital (Paris). Blood Mn and Pb concentrations were measured by absorption spectrophotometry. Se was measured by fluorometric method. Red blood cell membrane suspensions were obtained for Ca-pump activity measurements. Linear and quadratic regression models and Pearson correlation were performed., Results: A non-linear parabolic relationship between maternal Mn blood levels and newborn Ca-pump activity was discovered from the analysis of the observed data. The peak level of maternal Mn that corresponded to a maximal activity of the newborn Ca-pump was estimated at 23.9 microg/l with a 95% confidence interval of 17.6 to 32.4 microg/l. An inhibition of this enzyme was observed at low and high levels of maternal Mn. The relationships between the newborn Ca-pump activity and maternal Se and Pb levels became non-significant after adjustment on all the co-factors included in the final model., Conclusion: Maternal environmental exposure to Mn, as reflected by maternal blood levels of this metal, is associated with a reduced activity of newborn erythrocyte Ca-pump in a non-linear pattern. Mn levels between 17.6 and 32.4 microg/l in maternal blood probably correspond to the optimal physiological concentration for the metabolism of this enzyme in newborns.

We examined whole blood (MnB), red blood cell (MnRBC), plasma (MnP) and urinary Mn (MnU) concentrations in 22 liver cirrhotics and 10 healthy controls to evaluate Mn concentration in which a fraction of biological samples best reflects pallidal signal intensities (pallidal index; PI) on T1-weighted magnetic resonance images (MRI) in liver cirrhotics. Increased signal intensity in the globus pallidus was observed in 18 (81.8%) of the 22 patients with liver cirrhosis. In a transplanted patient, increased pallidal signals also resolved as his liver function tests normalized after liver transplantation. There were significant correlations between MnB/MnRBC and PI (rho=0.529, rho=0.573, respectively) in liver cirrhotics, although no significant correlation was observed between MnP/MnU and PI. According to a multiple linear regression, MnB and MnRBC reflected the signal intensities of T1-weighted MRI better than MnP or MnU.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is the most common human enzymopathy in the world. Trace elements are important for normal hematopoiesis and can play a role in acute hemolytic anemia induced by G-6-PD deficiency. For this purpose, we studied two groups consisting of 10 male children who are G-6-PD-deficient and 12 age-matched normal male children to compare plasma and erythrocyte magnesium, manganese, zinc, and plasma calcium levels between G-6-PD-deficient and normal children. All assays were performed under normal conditions free of any oxidative attack that may result in hemolytic crisis in G-6-PD-deficient subjects. All parameters in each group did not differ significantly except for erythrocyte G-6-PD activities. These data show that plasma and erythrocyte trace element contents of G-6-PD-deficient subjects do not differ in normal conditions.

The aim of this study was to investigate the effect of supplemental antioxidant vitamins and minerals on the erythrocyte concentrations of zinc and copper in rabbits after exposure to X-rays. The animals were divided into two experimental and one control group (CG). The first group (VG) was given daily oral doses of vitamins E and C; supplemental amounts of manganese, zinc, and copper were mixed with the feed and given to the second group of experimental animals (MG). Blood samples were taken from all groups before and after 4 wk of vitamin and mineral administration and after irradiation with a total dose of 550-rad X-rays. The administration of minerals caused the most significant increases of Zn and Cu. Even after irradiation, the zinc levels in the irradiated animals were higher than in the nonirradiated vitamin-supplemented animals (p<0.05). The results suggest that supplementation with antioxidant vitamins and minerals may have a protective effect against X-ray-induced damage.

In order to determine the probable role of trace elements in the maintenance of trypanotolerance in tropical cattle, the levels of zinc (Zn), copper (Cu), manganese (Mn) and iron (Fe) in plasma/serum and erythrocytes of trypanotolerant Keteku (Kt) and trypanosusceptible White Fulani (WF) cattle were measured by atomic absorption spectrophotometry (AAS) and compared by breed or sex. Trypanotolerance was associated with significantly higher (P < 0.05) erythrocyte levels of Zn and Mn. The Kt breed showed higher erythrocyte levels of Zn and Mn than the WF. Serum Mn level was also significantly higher (P < 0.01) in Kt than WF cattle. However, PCV and total protein concentration were not significantly different by breed or sex.

Guanylate cyclase activity in human erythrocytes is investigated by evaluating the intracellular guanosine 3',5'-cyclic monophosphate (cGMP) content in the presence of various agents that exert specific effects on soluble or particulate guanylate cyclase. The increase in the intraerythrocyte cGMP content by the soluble guanylate cyclase activators nitroprusside and NaNO2 suggests the presence of this enzyme in human erythrocytes. The effects of four different atrial natriuretic peptide (ANP) fragments on the intraerythrocyte cGMP content is also studied. ANP II and ANP III increase the intraerythrocyte cGMP content, whereas ANP I and des-Ser5,des-Ser6-ANP III are ineffective. Thus our data show that human erythrocytes possess particulate guanylate cyclase together with the soluble enzyme. The ANP fragments ANP II and ANP III also activate the erythrocyte Na+/H+ exchange. Nitroprusside, M & B 22948 (an inhibitor of cGMP phosphodiesterase), and the cGMP analogues dibutyryl cGMP and 8-bromoguanosine 3',5'-cyclic monophosphate also increase the erythrocyte Na+/H+ exchange rate. The latter data also suggest that the erythrocyte Na+/H+ exchange is regulated by cGMP.

In this study, 56 (14 control and 42 addicts) adult human subjects of both sexes of different periods of heroin dependence were subjected to the measurement of whole blood, serum, and red blood cell levels of some trace elements (zinc, manganese, iron copper, and bromine), as well as some major elements (phosphorus, sulfur, calcium, potassium, and chlorine). This was done by the energy-dispersive X-ray fluorescence (EDXRF) technique, in which copper and bromine showed a significant rise in whole blood (male) (22 and 32%, respectively), while zinc, iron, manganese, calcium, sulfur phosphorus, potassium, and chlorine showed a significant drop (49, 8, 25, 34, 21, 51, 61, and 72%, respectively) in proportion to the period of heroin intake (6 yr) and in comparison with the control group. No significant sexual variation has been reported.

This study was carried out to assess manganese (Mn) status after an acute episode of myocardial infarction. Plasma and erythrocyte Mn concentrations were measured from admission to hospital to day 15 postadmission in 21 patients suffering from acute myocardial infarction and in three control groups. The determination of Mn in these biological fluids was performed by electrothermal atomic absorption spectrometry. Plasma Mn was higher (p < 0.01) and erythrocyte Mn was similar in the acute myocardial infarction group compared to healthy age-matched control group. Plasma and erythrocyte Mn remained unchanged during the 2 wk after acute myocardial infarction and were not correlated to enzyme activities. A decrease of erythrocyte Mn with age, expressed in nmol/L, was noted (p < 0.02). These results suggest that plasma and erythrocyte Mn do not provide an indication of myocardial damage. Nonetheless, Mn status in elderly merits further attention.

Trace elements and lipid peroxidation in 26 patients with chronic renal failure treated with hemodialysis and 25 healthy subjects were observed. Both plasma and erythrocyte trace elements and plasma malon dialdehyde (MDA) were examined immediately before and after hemodialysis. Increased levels of plasma Cu, MDA, and erythrocyte Pb, Mn, Zn, and a significantly decreased plasma Se, Zn, and erythrocyte Se were found in patients before hemodialysis. After a single hemodialysis, erythrocyte Mn, Cu, Zn, and plasma Cu, Al, and MDA were significantly increased whereas both plasma and erythrocyte Se were lower in patients than in healthy subjects. The level of MDA was not significantly changed during the single hemodialysis. Both plasma and erythrocyte Zn levels and plasma Cu and Al were significantly higher after hemodialysis than before hemodialysis. In conclusion, levels of trace elements are altered by hemodialysis, which may increase patient susceptibility to lipid peroxidation in uremia.

1. The water permeabilities of the red blood cell (RBC) membranes of five species of macropodid marsupials were monitored by using a Mn(2+)-doping 1H nuclear magnetic resonance (NMR) technique. 2. Since this appears to be the first time that this type of measurement at 400 MHz for 1H has been reported, an analysis of instrumental parameters influencing the estimated value of the water exchange time (Te), and of the diffusional water permeability (Pd), was performed on samples of human RBC. 3. It was found that a short interpulse delay in the Carr-Purcell-Meiboom-Gill pulse sequence had to be used (around 100 microseconds) to avoid an underestimation of the relaxation times, that occurred as the result of molecular diffusion through non-uniform local magnetic fields in and around the cells. 4. There were no significant differences, in the water permeabilities of the RBC membranes, between the five species (Macropus rufogriseus, M. parma, M. eugenii, M. parryi and Wallabia bicolor). 5. There were also no significant differences between various colonies of M. eugenii living in different habitats. 6. The average values of Pd were 9.1 x 10(-3) cm/sec at 24.6 degrees C, 10.4 x 10(-3) cm/sec at 30 degrees C, 12.6 x 10(-3) cm/sec at 37 degrees C, and 14.7 x 10(-3) cm/sec at 42.1 degrees C; these were more than twice as high as those for human RBC. 7. In agreement with the high water permeability the RBC of macropodids displayed a relatively low activation energy of water diffusion across their membranes, approximately 21 kJ/mol, compared with 25 kJ/mol for human RBC.

Ca influx via the Na-Ca exchanger into ferret red blood cells is easily measured from a Na-free solution; the intracellular Na concentration is normally approximately 150 mM in ferret red blood cells. We have found that Mn and Cd competitively inhibit Ca influx. Mn influx and Cd influx were a saturable function of the divalent cation concentration, consistent with a carrier mechanism. Indeed, the Km (approximately 10 microM) and the Vmax (usually 1-3 mmol.l packed cells-1.h-1) were similar for Ca, Cd, and Mn. Extracellular Na inhibited divalent cation influx, and intracellular Na stimulated influx. These results are consistent with Na-Cd and Na-Mn influx pathways in ferret red blood cells. Ca (1 mM) almost completely inhibited Mn influx and Cd influx, whereas 1 mM Mg inhibited 5-15%. These results strongly support the notion that Mn and Cd are alternative substrates for Ca on the ferret red cell Na-Ca exchanger. The similarity in the behavior of all three divalent cation places important constraints on kinetic and structural models of the exchanger.

Using inductively coupled plasma source mass spectrometry, we have studied the red cell element concentrations of alcoholic subjects with different periods of abstinence before testing. We found consistently elevated red cell caesium concentrations and also reduced red cell selenium concentrations. These may represent persistent abnormalities in oxidation/anti-oxidation mechanisms, and red cell caesium in particular may be a long-term marker of alcohol dependence. Erythrocyte lithium, cerium and boron concentrations were also reduced in the abstinent alcoholic groups.

Chicken erythrocytes preloaded with Mg2+ exchange one extracellular Mn2+ for two intracellular H+. Chicken erythrocytes preloaded with Mn2+ alone or with Mg2+ plus Mn2+ performed efflux of Mn2+, which was higher at pH 6 than at pH 7.4, indicating reversibility of Mn2+/H+ antiport. Mn2+/H+ antiport was not inhibited by 1 mM KCN plus 1 mM iodoacetic acid or 1 mM amiloride. Mn2+ influx was activated by anions. Mn2+ efflux via Mn2+/H+ antiport was inhibited by competition between H+ and K+.

We measured the manganese content of whole blood, plasma, platelets, mononucleated cells, polymorphonucleated cells, and erythrocytes. Platelets and blood cells were separated from whole blood by use of discontinuous gradients of colloidal polyvinylpyrrolidone-coated silica (Percoll), and their manganese content was measured by Zeeman graphite furnace atomic absorption spectrophotometry, after digestion with nitric acid and hydrogen peroxide. Erythrocytes account for about 66% of the manganese in whole blood, whereas the "buffy coat"--platelets and leukocytes--accounts for about 30%. The "buffy coat" components turn over more rapidly than do erythrocytes, so their manganese content may better indicate the body's manganese status.

Mg2(+)-loaded rat erythrocytes performed Mn2+/Mg2+ antiport, which was nonspecifically stimulated by anions and cations. Mn2+/Mg2+ antiport was shown to operate via the Na+/Mg2+ antiporter because extracellular Na+ and Mn2+ inhibited the intracellular uptake of each other's ions competitively. Furthermore, Mn2+/Mg2+ antiport and Na+/Mg2+ antiport were identically inhibited by various amiloride derivatives. Na+/Mg2+ antiport of chicken and human erythrocytes cannot perform Mn2+/Mg2+ antiport although chicken erythrocytes took up more Mn2+ than rat erythrocytes.

A new analysis is presented which links real volume fractions, relaxation rates, and intracompartmental exchange rates directly with apparent volume fractions and relaxation rates obtained from biexponential fits of transverse magnetization decay curves. The analysis differs from previous methods in that measurements from two paramagnetic doping levels are used to close the two-site exchange equations. Both the new method and one previously described by Herbst and Goldstein (HG) have been applied to paramagnetically doped whole-blood data sets. Significant differences in the calculated exchange parameters are found between the two methods. A small dependence of the intracellular relaxation rate on extracellular paramagnetic agent concentration, assumed nonexistent with the HG method, is inferred from the new analysis. The analysis was also applied to published data on perfused rat hearts, and we obtained a limited assessment of two-site exchange in this system.

This study showed differences in erythrocyte manganese concentrations in different age groups and in cord blood. All determinations were performed with a flameless atomic absorption spectrophotometer. The mean erythrocyte manganese concentration at one month of age was 435.1 +/- 118.7 ng/g Hb, three to four times higher than in adults. Thereafter, it decreased rapidly and was constant from 4 months to 11 yr of age. However, at 12 to 19 yr of age the concentration in males decreased (108.1 +/- 20.2 ng/g Hb) and was significantly lower than in females (141.7 +/- 25.5 ng/g Hb) (p less than 0.01). This sex difference became even greater in adults aged 20 to 40 yr, when it was 91.5 +/- 22.4 ng/g Hb in males and 141.2 +/- 19.8 ng/g Hb in females (p less than 0.001). The erythrocyte manganese concentration in adults was 31.6 +/- 9.2 ng/ml, somewhat higher than the value previously reported, which may reflect dietary habits in Japan or a racial difference.

Manganese was measured in blood of a patient with prolidase deficiency by neutron activation analysis. The manganese content of packed blood cells was 48.9 ng/g wet weight (controls 18.4 +/- 4.3 ng/g wet weight). It was proportionately increased in whole blood, whereas the serum manganese concentration was unchanged. The erythrocyte arginase activity was reduced to 46% of the mean control value. The reduced activities of two manganese-dependent enzymes, prolidase and arginase in erythrocytes in combination with an increased manganese content cannot be explained at the moment and leads to the speculation that manganese is inaccessible for enzyme activation.

Mg2+ efflux in rat erythrocytes was stimulated by increases in external Na+ concentration following a Michaelian-like function with an apparent dissociation constant (KNa) of 11 +/- 3 mM (mean +/- S.D. of three experiments) and a variable maximal rate ranging from 150 to 1200 mumol (liter (1) cells X h)-1. Na+-stimulated Mg2+ efflux was inhibited by quinidine and by ATP depletion. In the absence of external Na+, Mg2+ efflux was stimulated by increases in external Mn2+ concentration following a Michaelian-like function with an apparent dissociation constant (KMn) of 35 +/- 15 microM (mean +/- S.D. of four experiments) and a variable maximal rate ranging from 350 to 1400 mumol (1 cells X h)-1. Mn2+-stimulated Mg2+ efflux was inhibited by quinidine, by ATP depletion, and by increasing the external Na+ concentration. Quinidine-sensitive (or ATP-dependent) Mg2+ efflux exhibited very similar values when compared with quinidine-sensitive (or ATP-dependent) Mn2+ influx. Mn2+ efflux in rat erythrocytes (loaded with total internal Mn2+ contents of 230-450 mumol/l cells) was stimulated by increases in external Na+ concentration and inhibited by quinidine. In the absence of external Na+, Mn2+ efflux was stimulated by increases in external Mg2+ concentration following a Michaelian-like function with an apparent dissociation constant (KMg) of about 35 +/- 5 microM (mean +/- range of two experiments) and a maximal rate of about 60-100 mumol (1 cells X h)-1. In conclusion, the Na+-stimulated Mg2+ carrier of rat erythrocytes may catalyze a one-to-one and reversible Mn2+:Mg2+ exchange in the absence of external Na+.

Plasma copper was significantly reduced in Wilson's disease with decreased ceruloplasmin levels, while there was no significant difference in erythrocyte copper levels between Wilson's disease and controls. Mean zinc and manganese levels in plasma were increased in Wilson's disease, but these differences were not significant. Mean magnesium level in plasma was normal. The levels of these metals in erythrocytes showed no difference between Wilson's disease and controls. Our results suggest that the abnormal copper level in plasma is not due to the primary metabolic defects, but is probanly due to the level of the binding proteins in plasma to this metal, ceruloplasmin, in Wilson's disease.

At physiological pH and concentrations of Mn(++) in excess of 5 x 10(-4)M, study of the Mn(++) ion movement into human red cells is complicated by physicochemical alterations of the ion itself. At concentrations below 5 x 10(x4)M, the rate of uptake bears a linear relationship to the Mn(++) concentration. The permeability constant for inward movement of Mn(++) is 2.87 +/- 0.13 (S.E.) x 10(-9) cm./sec. The rate is not influenced by the addition of metabolic substrates such as glucose or adenosine or the metabolic inhibitors iodoacetate or fluoride. Co(++), Ca(++), and Mg(++) do not appear to compete with Mn(++) for entry, but at high concentrations relative to Mn(++), they reduce the rate of entry. Ca(++) is far more effective than Co(++) or Mg(++) in this regard. The permeability constant for outward Mn(++) movement is 1.38 +/- 0.21 (S.E.) x 10(-9) cm./sec., about half of that for entry. This slower rate of outward movement is consistent with the finding that 40 to 60 per cent of the Mn(++) taken up by the red cells is non-ultrafilterable. Less than 5 to 10 per cent of the Mn(++) appears to be bound to the stroma. It is concluded that entry and exit of Mn(++) is a process of passive diffusion involving no carriers, transport, or metabolic linkage.