Spacecraft Water Exposure Guidelines for Selected Contaminants Volume 2 (2007) / Chapter Skim
Currently Skimming:
Appendix 9 Manganese (Inorganic Salts)
Appendix 9 Manganese (Inorganic Salts)
Pages 364-452
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 364... ...
Manganese chloride (MnCl2) , MnSO4, and manganese acetate are the most soluble forms.
|
From page 365... ...
. Food is the major source of manganese, and different foods vary widely in manganese concentration.
|
From page 366... ...
interim levels, a spacecraft water exposure guideline (SWEG) is determined.
|
From page 367... ...
In a recent study, the toxicokinetics of manganese were investigated in male and female rats following a single iv or oral dose of MnCl2 (6 mg/kg) (Zheng et al.
|
From page 368... ...
reported that in rats fed diets containing manganese at between 1.3 and 82.4 mg/kg for 7 or 14 d and administered a tracer dose of 54Mn by gavage, increasing dietary manganese reduced manganese absorption and enhanced 54Mn excretion. Absorption of 54Mn by fasted, gavaged rats was four times higher than in unfasted gavaged rats (Lee and Johnson 1988)
|
From page 369... ...
(1991) studied in humans the effect of adding phytate, phosphate, and ascorbic acid to infant formula and studied manganese absorption using radionuclide techniques.
|
From page 370... ...
They found that higher ferritin concentrations reduced manganese absorption in young women. Although men absorbed much less manganese than women, manganese had a longer half-life in men (Finley
|
From page 371... ...
In an another study (Finley 1999) , it was reported that dietary-manganese concentrations did not affect manganese status, but the absorption of manganese from a low-manganese diet by women with high ferritin concentrations was very low compared to the absorption by women with low ferritin concentrations.
|
From page 372... ...
An inhibitory effect of calcium on manganese absorption in humans was found in women consuming calcium at 400 and 6.3 mg/d, and manganese negative balance was found in men who took supplements of calcium at 916 mg either as lactate or as milk (McDermott and Kies 1987)
|
From page 373... ...
Tissue manganese concentrations are controlled by the homeostatic control mechanism through absorption and elimination; thus, the liver and intestines play important roles in maintaining manga
|
From page 374... ...
in drinking water increased brain manganese concentrations; rats exposed to manganese from conception to 120 d had much higher concentrations than controls.
|
From page 375... ...
Prolonged oral exposure to manganese compounds results in increased manganese concentrations in all tissues, but the magnitude of the increase diminishes over time. Rehnberg et al.
|
From page 376... ...
Gavage resulted in a lower increase in cerebellum manganese than other routes did. However, when the results from the oral doses of the chloride and the oxide form of manganese were compared, the increase in steadystate blood manganese concentrations over those of the controls (about 1,000 nanograms [ng]
|
From page 377... ...
It was shown in this study that young rats fed manganese at 45 mg/kg/d absorbed 8% of the manganese intake and that 37% of the amount absorbed was lost through the intestinal wall. Although manganese is excreted in urine, urinary manganese did not increase with an increasing duration of supplemental oral manganese intake (Davis and Greger 1992)
|
From page 378... ...
In miners suffering from manganese intoxication, the half-life of manganese is 34 d, whereas healthy miners had a fast turnover of only 15 d. Also, in mice, Britton and Cotzias (1966)
|
From page 379... ...
. Although the primary objective of this document is to derive a SWEG for manganese from data relevant to exposures through the oral route, a review of the neurophysiologic, neurofunctional, and neuropathologic effects of manganese exposure from inhalation-exposure studies has led to a valuable understanding of the progression of adverse health effects from the early signs of manganese toxicity to the onset of clinically observable conditions, such as manganism, a disease that resembles PD.
|
From page 380... ...
In cases of low-dose exposure, one can detect changes in neuromotor functions such as poorer subtle motor activity. Manganese Neurotoxicity from Inhalation Exposures A vast amount of data has accumulated regarding the toxicity of manganese to nervous system parameters and functions.
|
From page 381... ...
(1987) conducted a cross-sectional epidemiologic study among 141 male subjects exposed to inorganic manganese in a plant that produced manganese oxide and salt (mean age, 34.3 years [y]
|
From page 382... ...
The concentration of respirable and total manganese dust in air, as measured by personal sampling, was about 0.2 mg/m3 and 0.95 mg/m3, respectively. Although no differences in neurologic symptoms were found between exposed and control workers, the visual reaction time, hand-eye coordination, and hand steadiness of both group were significantly impaired.
|
From page 383... ...
for manganese and to elucidate the interaction of other minerals (especially iron and calcium) with manganese absorption.
|
From page 384... ...
conducted a study with human subjects in which six young adults (18-26 y of age; gender not provided) , were administered manganese as MnCl2 at 40 mg as a gelatin capsule, and plasma uptake of manganese was measured over 4 h.
|
From page 385... ...
No well-designed toxicity studies were conducted on the adverse effect of manganese ingestion, probably for ethical reasons. However, the literature is replete with human subject studies designed to evaluate manganese balance and absorption and the interaction of manganese with metals such as calcium and iron.
|
From page 386... ...
Even at this high dose, the liver manganese concentration was only twice that of control male and female rats. In male and female mice, the liver manganese concentration was 8 to 15 times that of controls (the dose was threefold greater in mice than in rats)
|
From page 387... ...
with a mean age of 35.7 ± 8 y and a mean body weight of 72.9 ± 13 kg. The aim of the study was to find out whether there are significant changes in the manganese status in the range of manganese concentrations that are present in a mixed Western diet and also to determine whether the type of dietary fat has any effect on manganese
|
From page 388... ...
In this study, manganese absorption and retention in the body were estimated from the retention of a test dose of orally administered 54Mn. The authors conducted this study using two different types of fats, one enriched in saturated fatty acids (cocoa butter)
|
From page 389... ...
, glucose, glucose tolerance tests, insulin, ironbinding capacity, and indicators of manganese and iron status were collected at the end of the dietary period. Manganese status was measured by lymphocyte manganese superoxide dismutase activity.
|
From page 390... ...
The author speculated that the increase may be because of the inhibition of GABA outflow. Spontaneous motor activity was not measured in this study, and hence, the direct relevance of observed changes could not be determined.
|
From page 391... ...
administered manganese as MnCl2·4H2O at 357 and 714 g/kg in water intragastrically to 2-mo-old female albino rats for 30 d. Increased manganese concentrations in brain regions and slower learning, determined by the T-maze food retrieval method, were seen.
|
From page 392... ...
. The authors reported that they found no statistically significant effects on motor activity that were related to manganese exposure.
|
From page 393... ...
. The rats were tested for locomotor activity, reactivity to object novelty in an open field, and radial maze performance.
|
From page 394... ...
The investigators observed few differences between the responses of male and female rats. Absolute and relative liver weights of all exposed males and females in the highest-dose group were significantly lower than those of controls.
|
From page 395... ...
Three areas in northwest Greece that had a range of manganese concentrations in drinking water were chosen for this study. The areas were categorized as areas A, B, and C
|
From page 396... ...
The authors did correlate the prevalence of neurologic symptoms with the progressive concentration of manganese in the hair of the elderly subjects. Using hair manganese concentrations may have only a limited value as a measure of manganese body burden.
|
From page 397... ...
who were exposed to increased manganese concentrations (about 0.24 mg/L) in water and wheat irrigated with sewage for 3 y performed poorly in neurobehavioral tests and performed poorly at school compared to control children from a nearby village.
|
From page 398... ...
of the psychiatric and neurologic phases of chronic manganese poisoning is known, it is difficult to determine a NOAEL for the interim duration of 100 d, because it is not clear that the early increase is an adverse effect. Gianutsos and Murray (1982)
|
From page 399... ...
(1986) examined the effects of chronic manganese exposure on locomotor activity in rats maintained on MnCl2·4H2O at 0 or 1 mg/mL in drinking water for 65 wk.
|
From page 400... ...
In addition, the amount of brain manganese correlated well with the extent of suppression of spontaneous motor activity measured using an Animex Activity Meter. Paradoxically, the largest manganese content was found in the cerebral cortex of mice treated with insoluble manganese compounds, MnCO3 and MnO2.
|
From page 401... ...
MnSO4 was tested in two laboratories. Several manganese salts (MnCl2, manganese nitrate, MnSO4, manganese acetate)
|
From page 402... ...
The chromosomal aberrations in both bone marrow and micronuclei were significantly increased. In contrast, in earlier work in albino rats treated with oral doses of MnCl2, tests for induction of chromosomal aberrations in the bone marrow cells were negative.
|
From page 403... ...
But there was equivocal evidence of carcinogenic activity in male and female B6C3F1 mice based on the marginally increased incidence of thyroid gland follicular cell adenoma and the significantly increased incidence of follicular cell hyperplasia. Biologically significant changes did occur in the incidences of neoplasms and/or non-neoplastic lesions in the thyroid gland, forestomach, and liver of male and female mice.
|
From page 404... ...
Because these groups also had lower mean body weights and relative liver weights were similar to those of controls, the lower absolute liver weights cannot be considered an adverse effect of the manganese dose. Reproductive Toxicity Few reports exist on the reproductive toxicity of manganese compounds in humans or experimental animals.
|
From page 405... ...
When male and female rats were fed a diet containing Mn3O4 at 3,500 ppm/kg/d for about 100 d before breeding, male fertility was reduced; female reproductive parameters were unaffected (Laskey et al.
|
From page 406... ...
Although ingestion of MnSO4·2H2O in drinking water for 12 wk did not affect male rat fertility, the total number of resorptions increased in female rats impregnated by treated males. Only one dose was used.
|
From page 407... ...
, no physical abnormalities were observed in the offspring. The rats exposed to MnCl2 at 10 mg/mL had increased cortical manganese concentrations and were hyperactive at PND-17.
|
From page 408... ...
min increased heart rate and blood not calculated Price 1982 report pressure; acute pancreatitis on day 2 Women Capsule, single 40 mg No adverse effect reported NOAEL = 0.57 FreelandMnCl2 dose Graves and Lin 1991 Manganese Women Oral, 1, 25, 60, 15 mg No adverse effects on hematocrit, NOAEL = 15 Davis and supplement (60 kg) 89, and 124 d serum iron, zinc and copper, or mg/d for up to 89 Greger 1992 aminoacid indexes of iron status; lymphocyte d; or 0.25 mg/d chelated manganese superoxide dismutase as supplement (manganese status)
|
From page 409... ...
Swiss Gavage, 2 doses 33, 66, and Increased frequency of LOAEL = 33 Joardar and MnSO4·H2O albino 198 mg/kg/d micronucleated polychromatic and Sharma 1990 mouse, normochromatic erythrocytes as a male function of dose Swiss Gavage, 5 doses 33, 66, and Increased sperm head LOAEL = 33 Joardar and MnSO4·H2O albino 198 mg/kg/d abnormalities as a function of dose Sharma 1990 mouse, male F344/N In feed, 14 d 0, 84, 165, Decreased neutrophils and LOAEL = 1,264; NTP 1993 MnSO4 rat, male 340, 665, leukocyte counts; reduced liver NOAEL = 665 and 1,264 weight; decreased body weight mg/kg/d F344/N In feed, 14 d 0, 84, 159, Decreased body weight; No LOAEL=1275; NTP 1993 MnSO4 rat, 340, 675, hematolog , neurologic, NOAEL = 675 female and 1,275 reproductive, hepatic, or renal mg/kg/d system effects B6C3F1 In feed, 14 d 0,121, 262, No effect on body weight, LOAEL = none; NTP 1993 MnSO4 mouse, 669, 1,603, hematologic , respiratory, hepatic, NOAEL = 3,200 male and 3,212 renal, reproductive, or mg/kg/d cardiovascular systems B6C3F1 In feed, 14 d 0, 240, 488, No changes in body weight; no LOAEL = none; NTP 1993 MnSO4 mouse, 1,068, effect on hematologic , respiratory, NOAEL = 3,500 female 2,494, and hepatic, renal, reproductive. or 3,560 cardiovascular system.
|
From page 410... ...
MnCl2·4H2O male at 0, 25, and 50 mg/kg observations; no change in striatal 2000 mg/kg DA or DOPAC; no changes in spontaneous motor activity; decreased acoustic startle reflex was noted only in low-dose group ITRC Drinking water, 140 Hyperactivity, aggression, altered LOAEL = 140; Chandra et al. MnCl2 rats, male 30 d mg/kg/d neurotransmitter levels, increased only dose 1983 turnover of striatal DA (serious effects)
|
From page 411... ...
MnCl2 (20 d old) 10 wk at 20 field tests; manganese 2001 mg/L concentrations in brain regions, morphologic assessments and electrophysiologic tests done; no overt signs of brain damage; no obvious morphologic or cytologic or cytochemic characteristics of striatum or substantia nigra Manganese- Human, Drinking water, 28 mg/L Lethargy, increased muscle tonus, LOAEL = 28 Kawamura et contaminated male and 2-3 mo estimated tremor; children not affected; mg/L al.
|
From page 412... ...
MnSO4 dihydrate Dawley 12 wk males and aggression; number of NOAEL not 1998 rat, male resorptions increased in females known. impregnated by exposed males Swiss Drinking water, 0, 38, 76, Reduced male fertility, but no LOAEL = 152; Elbetieha et al.
|
From page 413... ...
activity in manganese acetate MnCO3, MnO2 group; none in MnCl2 group CD-1 In feed, 180 d 2,300 Decreased levels of DA; increased LOAEL = 2,300 Gianutsos and MnCl2 mouse, mg/kg/d GABA in striatum (one dose only) Murray 1982 male Sprague- Drinking water, 4 and 40 Decrease neurotransmitter LOAEL = 4 Bonilla and MnCl2 Dawley, 8 mo at 0.1 and mg/kg/d norepinephrine in striatum and Prasad 1984 rat, male 1 mg/mL pons; significant decreases in DOPAC in striatum and hypothalamus at both doses; magnitude of decrease was not dose related (Continued)
|
From page 414... ...
MnCl2·4H2O Rhesus monkey, mg/kg/d lower limbs; histopathology (only one dose) 1980 male confirmation F344/N In feed, 2 y 0, 20, 65, Chronic progressive nephropathy; LOAEL = 200; NTP 1993 MnSO4 rat, male and 200 reduced body weight; no changes in NOAEL = 65 mg/kg/d lung weight; no hematologic , GI, cardiovascular, hepatic, endocrine, reproductive, or immunologic effects
|
From page 415... ...
F344/N In feed, 2 y 0, 23, 75, No changes in lung weight; no NOAEL = 232 NTP 1993 MnSO4 rat, and 232 hematologic , respiratory, female mg/kg/d cardiovascular, renal, hepatic, endocrine, reproductive, or immunologic effects B6C3F1 In feed, 2 y 0, 52, 175, Hyperplasia and erosion of GI tract; LOAEL =175; NTP 1993 MnSO4 mouse, and 585 forestomach ulceration and NOAEL = 52 for male mg/kg/d inflammation; increased hematocrit, renal and body hemoglobin, and erythrocyte count; weight follicular hyperplasia of thyroid and dilation; no effect on body weight or respiratory, renal, reproductive, or cardiovascular systems B6C3F1 In feed, 2 y 0, 65, 228, Ulceration and inflammation of LOAEL = 65 for NTP 1993 MnSO4 mouse, and 731 forestomach; thyroid follicular thyroid effect; female mg/kg/d hyperplasia; 13% decrease in body NOAEL = not weight; no significant changes in known liver weight; no hematologic effects; no effect on respiratory, renal, reproductive, or cardiovascular systems (Continued)
|
From page 416... ...
1999 MnCl2·4H2O rat, male 2y mg/mL from in utero to 2 y; brain regional point studied and distribution of manganese and other female metals studied; increase in manganese accumulation caused region-specific changes in the brain iron, copper, selenium, zinc, calcium, and magnesium concentrations; subcellular fractionation indicates selective enhancement of manganese accumulates in brain mitochondria Manganese Human Parenteral 2.2 mg/d, Developed symptoms characteristic Serious effect; Ejima et al. salt form not case nutrition (iv)
|
From page 417... ...
Salt form not Human, Drinking water, <0.05 A German cohort study: no NOAEL = 0.3- Vieregge et al. known; well male and 10-40 y mg/L or detectable neurologic impairment as 2.16 mg/L 1995 water female 0.3 to determined by structured 2.16 mg/L questionnaire, standardized neurologic examinations, and fine motor coordination measurements Abbreviations: DA, dopamine; DOPAC, dihydroxyphenylacetic acid; GABA, gamma-aminobutyric acid; GI, gastrointestinal; GP, globus pallidus; HVA, homovanillic acid; LOAEL, lowest- observed-adverse-effect level; MAO, monoamine oxidase; NOAEL, no-observed-adverse-effect level.
|
From page 418... ...
b Group D: Not classifiable as a carcinogen; inadequate or no human and animal evidence of carcinogenicity. Abbreviations: HA, Health Advisory; MCL, maximum contaminant level; MCLG, maximum contaminant level goal; MRL, minimal risk level; RfD, reference dose, an estimate of a daily oral exposure to the human population (including sensitive subgroups)
|
From page 419... ...
Several studies have shown that DA levels of rodents are TABLE 9-8 Spacecraft Water Exposure Guidelines for Soluble Manganese (Salts) SWEG Duration (mg/L)
|
From page 420... ...
Rodents seem to tolerate much higher supplemental doses than humans, and thus, caution must be exercised when using species factors to extrapolate rodent data to humans. Rodents, like primates including humans, exhibit neurobehavioral effects attributed to manganese poisoning, but the neurologic symptoms seem to be different (McMillan 1999)
|
From page 421... ...
on differences in manganese status between individuals consuming a Western diet and a vegetarian diet indicated that there were no adverse effects in subjects consuming a diet containing manganese at 10.9 mg/d. This somewhat supports the extra allowance in the NRC's ESADDI.
|
From page 422... ...
(1997) , using MnO2 and MnCl2 and orally administering these manganese compounds to adult rats, observed significant differences in manganese concentrations in blood, liver, and cerebral tissues such as cortex, cerebellum, and striatum.
|
From page 423... ...
in rats after manganese administration and the fact that rats do not have pigmentation in the substantia nigra, manganese compounds produce behavioral effects and neurochemical (neurotransmitter) alterations in rats that are similar to those seen in subhuman primates and in humans.
|
From page 424... ...
. 10-d AC for Ingestion Human subject studies designed to study manganese absorption and retention were evaluated to derive an AC for 10 d.
|
From page 425... ...
of manganese supplementation on manganese status in healthy nonsmoking premenopausal women (n = 17) .1 These manganese concentrations are usually present in a mixed Western diet.
|
From page 426... ...
, the number of leukocytes and segmented neutrophils increased in male rats and in female rats only at the highest dose. Male rats seemed to be more sensitive, and a NOAEL of 84 mg/kg/d for an
|
From page 427... ...
In this study, the authors reported that female rats of all treated groups had diarrhea during the second wk. This may have been because of some GI disturbances.
|
From page 428... ...
. There were no statistically significant effects related to manganese exposure on motor activity.
|
From page 429... ...
The NTP (1993) study in which both male rats and male mice were fed diets containing manganese as MnSO4 at much higher doses than used in the Joardar and Sharma study (about 1,300 mg/kg for 14 d)
|
From page 430... ...
Similarly, changes seen in the female rats at 13 wk were not seen at later times. Because of the transient nature of these changes, the data were not used for AC derivation.
|
From page 431... ...
, serum iron, or serum copper. Even for the manganese status as measured by the lymphocyte manganese-superoxide dismutase, an increase was seen only after 89 d of administration of the supplement.
|
From page 432... ...
of manganese supplementation in healthy nonsmoking premenopausal women (n = 17) with a mean age of 35.7 ± 8 y and a mean body weight of 72.9 ± 13 kg.
|
From page 433... ...
. Mean age and body weight of women used in the Finley study were 35 y old and 70 kg, respectively; therefore, there is no need to use any adjustment factor for body weight.
|
From page 434... ...
Assuming that this is a NOAEL, the AC will be 0.167 mg/L. The mean manganese concentrations in hair were 3.51, 4.49, and 10.99 g/g dry weight of hair for areas A, B, and C, respectively.
|
From page 435... ...
The authors reported that there were no neurologic effects of exposure, even when the manganese concentrations in the well water were in the range of 0.3-2.1 mg/L for up to 40 y. Because it has the strength of presenting human population data that assessed a critical toxicologic end point, this study was chosen for deriving a 1,000-d AC.
|
From page 436... ...
, where 65 mg/kg/d = NOAEL; 70 kg= nominal body weight; 10 = species extrapolation factor; and 2.8 L/d = nominal water consumption. In both male and female mice in the 2-y NTP (1993)
|
From page 437... ...
Factors of 70 kg for nominal body weight, 10 for species extrapolation, and 2.8 L/d for nominal water consumptions were used. A time factor to extrapolate to 1,000 d was not used.
|
From page 438... ...
, where 6.9 mg/kg/d = LOAEL; 10 = LOAEL to NOAEL; 70 kg = nominal body weight; 3 = species extrapolation factor; 2.8 L/d = nominal water consumption; and 1,000 d/540 d = time extrapolation factor from 18 mo to 1,000 d. A summary of ACs and SWEGs for various durations is listed in Table 9-12.
|
From page 439... ...
To Species Time Spaceflight 10 100 1,000 Primary Toxicity End Point Exposure Species NOAEL Factor Factor Factor 1d d d d Study No adverse effects NOAEL= Human 1 1 1 1 14 -- -- -- Freeland(human subjects) 40 mg/d Graves and Lin 1991 No adverse effect on Davis and NOAEL = Human 1 1 1 1 -- 5.4 -- -- Greger 1992 hematologic parameters 15 mg/d or iron or copper status No adverse effect on Finley et NOAEL = Human 1 1 1 1 -- 7.0 -- -- al.2003 neurologic parameters or 20 mg/d serum clinical chemistry No abnormal -- Davis and NOAEL = Human 3.02 for 1 1 1 -- -- 2 Greger 1992 hematologic parameters 0.25 low n or iron or copper status mg/kg/d Finley et al.
|
From page 440... ...
TABLE 9-12 Continued 440 Modificaton Factors AC (mg/L) To Species Time Spaceflight 10 100 1,000 Primary Toxicity End Point Exposure Species NOAEL Factor Factor Factor 1d d d d Study Thyroid lesions: 1 10 1 1 -- -- -- 44 NTP 1993 BMDL01 = Mice follicular cell 17.5 mg/kg hyperplasia 1,000 d/ Neurotoxicity Gupta et al.
|
From page 441... ...
1991. Manganese neurotoxicity: cellular effects and blood-brain barrier transport.
|
From page 442... ...
1984. Effects of chronic manganese intake on the levels of biogenic amines in rat brain regions.
|
From page 443... ...
Clearance of tissue manganese concentrations with persis tance of the neurological picture. Neurology 18:376-382.
|
From page 444... ...
2001. Effects of long-term exposure to manganese chloride on fertility of male and female mice.
|
From page 445... ...
1999. Manganese absorption and retention by young women is as sociated with serum ferritin concentration.
|
From page 446... ...
1996. Blood manganese correlates with brain magnetic resonance imaging changes in patients with liver disease.
|
From page 447... ...
1991. Effects of chronic manganese treatment on rat brain regional sodium-potassium activated and magnesium-activated adenosine triphosphatase activities during development.
|
From page 448... ...
1967. Chronic manganese poisoning.
|
From page 449... ...
2000. Methods for Developing Spacecraft Water Exposure Guidelines.
|
From page 450... ...
1997. Perinatal manganese exposure: behavioral, neurochemical, and histopathological effects in the rat.
|
From page 451... ...
1992. Assessment of the permissible exposure level to manganese in workers exposed to manganese dioxide dust.
|
From page 452... ...
1982. Acute manganese intoxication and pancreati tis in a patient treated with a contaminated dialysate.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.