0373
Manganese; CASRN 7439-96-5
Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website.
STATUS OF DATA FOR Manganese
File First On-Line 09/26/1988
Category (section) |
Status |
Last Revised |
Oral RfD Assessment (I.A.) |
on-line |
05/01/1996
|
Inhalation RfC Assessment (I.B.) |
on-line |
12/01/1993 |
Carcinogenicity Assessment (II.) |
on-line
|
12/01/1996
|
_I.
Chronic Health Hazard Assessments for Noncarcinogenic Effects
_I.A.
Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — Manganese
CASRN — 7439-96-5
Last Revised — 05/01/1996
The oral Reference Dose (RfD) is based on the assumption
that thresholds exist for certain toxic effects such as cellular necrosis.
It is expressed in units of mg/kg-day. In general, the RfD is an estimate
(with uncertainty spanning perhaps an order of magnitude) of a daily exposure
to the human population (including sensitive subgroups) that is likely
to be without an appreciable risk of deleterious effects during a lifetime.
Please refer to the Background Document for an elaboration of these concepts.
RfDs can also be derived for the noncarcinogenic health effects of substances
that are also carcinogens. Therefore, it is essential to refer to other
sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogenicity,
a summary of that evaluation will be contained in Section II of this file.
NOTE: This reference dose is for the total oral intake
of manganese. As discussed in the Principal and Supporting Studies and
Uncertainty and Modifying Factors Sections, it is recommended that a modifying
factor of 3 be applied if this RfD is used for assessments involving nondietary
exposures.
__I.A.1.
Oral RfD Summary
Critical Effect |
Experimental Doses* |
UF
|
MF
|
RfD
|
CNS effects
Human Chronic
Ingestion Data
NRC, 1989; Freeland-
Graves et al., 1987;
WHO, 1973;
|
NOAEL (food): 0.14
mg/kg-day
LOAEL: None
|
1
|
1
|
1.4E-1
mg/kg-day
|
*Conversion Factors and Assumptions — The NOAEL of 10 mg/day (0.14 mg/kg-day
for 70 kg adult) for chronic human consumption of manganese in the diet is
based on a composite of data from several studies.
__I.A.2. Principal and Supporting Studies (Oral RfD)
Freeland-Graves, J.H., C.W. Bales and F. Behmardi. 1987. Manganese
requirements of humans. In: Nutritional Bioavailability of Manganese, C.
Kies, ed. American Chemical Society, Washington, DC. p. 90-104.
NRC (National Research Council). 1989. Recommended Dietary Allowances, 10th
ed. Food and Nutrition Board, National Research Council, National Academy
Press, Washington, DC. p. 230-235.
WHO (World Health Organization). 1973. Trace Elements in Human Nutrition:
Manganese. Report of a WHO Expert Committee. Technical Report Service, 532,
WHO, Geneva, Switzerland. p. 34-36.
Manganese is a ubiquitous element that is essential for normal physiologic
functioning in all animal species. Several disease states in humans have been
associated with both deficiencies and excess intakes of manganese. Thus any
quantitative risk assessment for manganese must take into account aspects of
both the essentiality and the toxicity of manganese. In humans, many data are
available providing information about the range of essentiality for manganese.
In addition, there are many reports of toxicity to humans exposed to manganese
by inhalation; much less is known, however, about oral intakes resulting in
toxicity. As discussed in the Additional Studies / Comments Section, rodents
do not provide a good experimental model for manganese toxicity, and only one
limited study in primates by the oral route of exposure is available. The
following assessment, therefore, focuses more on what is known to be a safe
oral intake of manganese for the general human population. Finally, it is
important to emphasize that individual requirements for, as well as adverse
reactions to, manganese may be highly variable. The reference dose is
estimated to be an intake for the general population that is not associated
with adverse health effects; this is not meant to imply that intakes above the
reference dose are necessarily associated with toxicity. Some individuals
may, in fact, consume a diet that contributes more than 10 mg Mn/day without
any cause for concern.
The Food and Nutrition Board of the National Research Council (NRC, 1989)
determined an "estimated safe and adequate daily dietary intake" (ESADDI) of
manganese to be 2-5 mg/day for adults. The lower end of this range was based
on a study by McLeod and Robinson (1972), who reported equilibrium or positive
balances at intakes of 2.5 mg Mn/day or higher. The range of the ESADDI also
includes an "extra margin of safety" from the level of 10 mg/day, which the
NRC considered to be safe for an occasional intake.
While the NRC determined an ESADDI for manganese of 2-5 mg/day, some
nutritionists feel that this level may be too low. Freeland-Graves et al.
(1987) have suggested a range of 3.5-7 mg/day for adults based on a review of
human studies. It is noted that dietary habits have evolved in recent years
to include a larger proportion of meats and refined foods in conjunction with
a lower intake of whole grains. The net result of such dietary changes
includes a lower intake of manganese such that many individuals may have
suboptimal manganese status. This is discussed in more detail in the
Additional Studies / Comments Section.
The World Health Organization (WHO, 1973) reviewed several investigations
of adult diets and reported the average daily consumption of manganese to
range from 2.0-8.8 mg Mn/day. Higher manganese intakes are associated with
diets high in whole-grain cereals, nuts, green leafy vegetables, and tea.
From manganese balance studies, the WHO concluded that 2-3 mg/day is adequate
for adults and 8-9 mg/day is "perfectly safe."
Evaluations of standard diets from the United States, England, and Holland
reveal average daily intakes of 2.3-8.8 mg Mn/day. Depending on individual
diets, however, a normal intake may be well over 10 mg Mn/day, especially from
a vegetarian diet. While the actual intake is higher, the bioavailability of
manganese from a vegetarian diet is lower, thereby decreasing the actual
absorbed dose. This is discussed in more detail in the Additional Studies /
Comments Section.
From this information taken together, EPA concludes that an appropriate
reference dose for manganese is 10 mg/day (0.14 mg/kg-day). In applying the
reference dose for manganese to a risk assessment, it is important that the
assessor consider the ubiquitous nature of manganese, specifically that most
individuals will be consuming about 2-5 mg Mn/day in their diet. This is
particularly important when one is using the reference dose to determine
acceptable concentrations of manganese in water and soils.
There is one epidemiologic study of manganese in drinking water, performed
by Kondakis et al. (1989). Three areas in northwest Greece were chosen for
this study, with manganese concentrations in natural well water of 3.6-14.6
ug/L in area A, 81.6-252.6 ug/L in area B, and 1600-2300 ug/L in area C. The
total population of the three areas studied ranged from 3200 to 4350 people.
The study included only individuals over the age of 50 drawn from a random
sample of 10% of all households (n=62, 49 and 77 for areas A, B and C,
respectively). The authors reported that "all areas were similar with respect
to social and dietary characteristics," but few details were reported. The
three areas are located within a 200-square km region. Although the amount of
manganese in the diet was not reported, the authors indicated that most of the
food was purchased from markets and is expected to be comparable for all three
areas. Chemicals other than manganese in the well water were reported to be
within Economic Community (EC) standards, except for hardness (120-130 mg
calcium carbonate per liter). The individuals chosen were submitted to a
neurologic examination, the score of which represents a composite of the
presence and severity of 33 symptoms (e.g., weakness/fatigue, gait
disturbances, tremors, dystonia). Whole blood and hair manganese
concentrations also were determined. The mean concentration of manganese in
hair was 3.51, 4.49 and 10.99 ug/g dry weight for areas A, B and C,
respectively (p<0.0001 for area C versus A). The concentration of manganese
in whole blood did not differ between the three areas, but this is not
considered to be a reliable indicator of manganese exposure. The mean (x) and
range (r) of neurologic scores were as follows: Area A (males: x=2.4, r=0-21;
females: x=3.0, r=0-18; both x=2.7, r=0-21); Area B (males x=1.6, r=0-6;
females: x=5.7 r=0-43; both: x=3.9, r=0-43); and Area C (males: x=4.9, r=0-29;
females: x=5.5, r=0-21; both x=5.2, r=0-29). The authors indicate that the
difference in mean scores for area C versus A was significantly increased
(Mann-Whitney z=3.16, p=0.002 for both sexes combined). In a subsequent
analysis, logistic regression indicated that there is a significant difference
between areas A and C even when both age and sex are taken into account
(Kondakis, 1990).
The individuals examined in the Kondakis study also had exposure to
manganese in their diet. This was originally estimated to be 10-15 mg/day
because of the high intake of vegetables (Kondakis, 1990). This estimate was
subsequently lowered to 5-6 mg/day (Kondakis, 1993). Because of the
uncertainty in the amount of manganese in the diet and the amount of water
consumed, it is impossible to estimate the total oral intake of manganese in
this study. These limitations preclude the use of this study to determine a
quantitative dose-response relationship for the toxicity of manganese in
humans.
This study, nevertheless, raises significant concerns about possible
adverse neurological effects at doses not far from the range of essentially.
Because of this concern, it is recommended that a modifying factor of 3 be
applied when assessing risk from manganese in drinking water or soil. This is
discussed more fully in the Uncertainty and Modifying Factors Section.
__I.A.3.
Uncertainty and Modifying Factors (Oral RfD)
UF — The information used to determine the RfD for manganese was taken from
many large populations consuming normal diets over an extended period of time
with no adverse health effects. As long as physiologic systems are not
overwhelmed, humans exert an efficient homeostatic control over manganese such
that body burdens are kept constant with variation in the manganese content of
the diet. The information providing a chronic NOAEL in many cross-sections of
human populations, taken in conjunction with the essentiality of manganese,
warrants an uncertainty factor of 1.
MF — When assessing exposure to manganese from food, the modifying factor is
1; however, when assessing exposure to manganese from drinking water or soil,
a modifying factor of 3 is recommended. As discussed more fully in the
Additional Studies/Comments Section, there are four reasons for this
recommendation. First, while the data suggest that there is no significant
difference between absorption of manganese as a function of the form in which
it is ingested (i.e., food versus water), there is some degree of increased
uptake of manganese from water in fasted individuals. Second, the study by
Kondakis et al. (1989) raises some concern for possible adverse health effects
associated with a lifetime consumption of drinking water containing about 2
mg/L of manganese. Third, although toxicity has not been demonstrated, there
is concern for infants fed formula that typically has a much higher
concentration of manganese than does human milk. If powdered formula is made
with drinking water, the manganese in the water would represent an additional
source of intake. Finally, there is some evidence that neonates absorb more
manganese from the gastrointestinal tract, that neonates are less able to
excrete absorbed manganese, and that in the neonate the absorbed manganese
more easily passes the blood-brain barrier. These findings may be related to
the fact that manganese in formula is in a different ionic form and a
different physical state than in human milk. These considerations concerning
increased exposure in an important population group, in addition to the
likelihood that any adverse neurological effects of manganese are likely to be
irreversible and not manifested for many years after exposure, warrant caution
until more definitive data are available.
__I.A.4.
Additional Studies/Comments (Oral RfD)
The biochemical role of manganese is to serve as an activator of several
enzymes including hydrolases, kinases, decarboxylases and transferases. It is
also required for the activity of three metalloenzymes: arginase, pyruvate
carboxylase and mitochondrial superoxide dismutase. A review of the
biochemical and nutritional roles of manganese in human health, as well as a
list of disease states related to manganese deficiency or excess, is provided
by Wedler (1994).
Because of the ubiquitous nature of manganese in foodstuffs, actual
manganese deficiency has not been observed in the general population. There
are, however, only two reports in the literature of experimentally induced
manganese deficiency in humans. The first was a report by Doisy (1972), who
inadvertently omitted manganese from a formulated diet. One of two subjects
developed a slight reddening of the hair, a scaly transient dermatitis, marked
hypocholesterolemia, and moderate weight loss. The diet was subsequently
determined to contribute 0.34 mg Mn/day, a level that resulted in manganese
deficiency. The second report was a metabolic balance study conducted by
Friedman et al. (1987) in which seven male volunteers were fed a semipurified
diet containing 0.11 mg Mn/day for 39 days. Transient dermatitis developed in
five of the seven subjects by the 35th day, which the authors speculate was a
result of decreased activity of glycosyltransferases or prolidase, manganese-
requiring enzymes that are necessary for dermal maintenance.
Hypocholesterolemia was also observed in this study, which the authors suggest
was a result of the need for manganese at several steps in the cholesterol
biosynthesis pathway.
While an outright manganese deficiency has not been observed in the
general human population, suboptimal manganese status may be more of a
concern. As reviewed by Freeland-Graves and Llanes (1994), several disease
states have been associated with low levels of serum manganese. These include
epilepsy, exocrine pancreatic insufficiency, multiple sclerosis, cataracts,
and osteoporosis. In addition, several inborn errors of metabolism have been
associated with poor manganese status (e.g., phenylketonuria, maple syrup
urine disease). While a correlation has been shown for low levels of serum
manganese and these disease states, a causal relationship has not been
demonstrated, and this remains an area in which additional research is needed.
To better understand the consequences of manganese deficiency, several
animal models have been studied. These have also been reviewed by Freeland-
Graves and Llanes (1994). Experiments in several species have shown a
deficiency in dietary manganese to result in disorders in lipid and
carbohydrate metabolism, impaired growth and reproductive function, and ataxia
and skeletal abnormalities in neonates.
While manganese is clearly an essential element, it has also been
demonstrated to be the causative agent in a syndrome of neurologic and
psychiatric disorders that has been described in manganese miners. Donaldson
(1987) provides a summary of this documented toxicity of manganese to humans,
which has been primarily limited to workers exposed by inhalation. In
contrast to inhaled manganese, ingested manganese has rarely been associated
with toxicity. A review of manganese toxicity in humans and experimental
animals has been provided by Keen and Zidenberg-Cherr (1994).
A report by Kawamura et al. (1941) is the only epidemiologic study
describing toxicologic responses in humans consuming large amounts of
manganese dissolved in drinking water. The manganese came from about 400 dry-
cell batteries buried near a drinking water well, resulting in high levels of
both manganese and zinc in the water. Twenty-five cases of manganese
poisoning were reported, with symptoms including lethargy, increased muscle
tonus, tremor and mental disturbances. The most severe symptoms were observed
in elderly people, while children appeared to be unaffected. Three
individuals died, one from suicide. The cause of death for the other two was
not reported, but the autopsy of one individual revealed manganese
concentration in the liver to be 2-3 times higher than in control autopsies.
Zinc levels also were increased in the liver. The well water was not analyzed
until 1 month after the outbreak, at which time it was found to contain
approximately 14 mg Mn/L. When re-analyzed 1 month later, however, the levels
were decreased by about half. Therefore, by retrospective extrapolation, the
concentration of manganese at the time of exposure may have been as high as 28
mg Mn/L. No information regarding dietary levels of manganese was available
in this study.
A few case studies have also pointed to the potential for manganese
poisoning by routes other than inhalation. One involved a 59-year-old male
who was admitted to the hospital with symptoms of classical manganese
poisoning, including dementia and a generalized extrapyramidal syndrome (Banta
and Markesbery, 1977). The patient's serum, hair, urine, feces and brain were
found to have manganese "elevated beyond toxic levels," perhaps a result of
his consumption of "large doses of vitamins and minerals for 4 to 5 years."
Unfortunately, no quantitative data were reported.
Another case study of manganese intoxication involved a 62-year-old male
who had been receiving total parenteral nutrition that provided 2.2 mg of
manganese (form not stated) daily for 23 months (Ejima et al., 1992). The
patient's whole blood manganese was found to be elevated, and he was diagnosed
as having parkinsonism, with dysarthria, mild rigidity, hypokinesia with
masked face, a halting gait and severely impaired postural reflexes. To be
able to compare the manganese load in this individual with that corresponding
to an oral intake, the difference between the direct intravenous exposure and
the relatively low level of absorption of manganese from the GI tract must be
taken into account. Assuming an average absorption of roughly 5% of an oral
dose, the intravenous dose of 2.2 mg Mn/day would be approximately equivalent
to an oral intake of 40 mg Mn/day.
A third case study involved an 8-year old girl with Alagille's syndrome
(an autosomal dominant disorder manifested principally by neonatal cholestasis
and intrahepatic bile duct paucity) and end-stage liver disease (Devenyi et
al., 1994). The patient had a stable peripheral neuropathy and for 2 months
manifested with episodic, dystonic posturing and cramping of her hands and
arms. Whole blood manganese was elevated (27 ug/L; normal range: 4-14 ug/L)
and cranial T1-weighted magnetic resonance imaging (MRI) revealed symmetric
hyperintense globus pallidi and subthalamic nuclei. These were taken as
indications of manganese neurotoxicity. Following liver transplantation, the
patient's manganese levels returned to normal, neurological symptoms improved
and MRI appeared normal. It appeared, then, that the progression of liver
dysfunction had resulted in inadequate excretion of manganese into the bile,
ultimately leading to neurotoxicity. With restoration of liver function, this
was remedied. This case study suggests that for individuals with impaired
liver function, intakes of manganese that would otherwise be safe may present
a problem.
Although conclusive evidence is lacking, some investigators have also
linked increased intakes of manganese with violent behavior. Gottschalk et
al. (1991) found statistically significant elevated levels of manganese in the
hair of convicted felons (1.62 +/- 0.173 ppm in prisoners compared with 0.35
+/- 0.020 ppm in controls). The authors suggest that "a combination of
cofactors, such as the abuse of alcohol or other chemical substances, as well
as psychosocial factors, acting in concert with mild manganese toxicity may
promote violent behavior." Caution should be exercised to prevent reading too
much into these data, but support for this hypothesis is provided by studies
of a population of Aborigines in Groote Eylandt. Several clinical symptoms
consistent with manganese intoxication are present in about 1% of the
inhabitants of this Australian island, and it may not be coincidental that the
proportion of arrests in this native population is the highest in Australia
(Cawte and Florence, 1989; Kilburn, 1987). The soil in this region is very
high in manganese (40,000-50,000 ppm), and the fruits and vegetables grown in
the region also are reported to be high in manganese. Quantitative data on
oral intakes have not been reported, but elevated concentrations of manganese
have been determined in the blood and hair of the Aborigines (Stauber et al.,
1987). In addition to the high levels of environmental manganese, other
factors common to this population may further increase the propensity for
manganism: high alcohol intake, anemia, and a diet deficient in zinc and
several vitamins (Florence and Stauber, 1989).
Only one limited oral study has been performed in a group of four Rhesus
monkeys (Gupta et al., 1980). Muscular weakness and rigidity of the lower
limbs developed after 18 months of exposure to 6.9 mg Mn/kg-day (as
MnC12.4H2O). Histologic analysis showed degenerated neurons in the substantia
nigra and scanty neuromelanin granules in some other pigmented cells. While
it is clear that neurotoxicity resulting from excessive exposure to manganese
is of primary concern, the exact mechanism is not clear. Histopathologically,
the globus pallidus and substantia nigra appear to be most affected.
Biochemically, deficiencies of striatal dopamine and norepinephrine appear to
be fundamental. As reviewed by Aschner and Aschner (1991), multiple pathways
that contribute to manganese-induced neurotoxicity are likely.
Several oral studies have been performed in rodents, also demonstrating
biochemical changes in the brain following administration of 1 mg
MnC12.4H2O/mL in drinking water (approximately 38.9 mg Mn/kg-day) (Chandra and
Shukla, 1981; Lai et al., 1981, 1982; Leung et al., 1981). However, rodents
do not exhibit the same neurologic deficits that humans do following exposure
to manganese; thus the relevance of these biochemical changes has been
challenged. The problem with using rodents is exemplified by the disease of
parkinsonism, which is characterized by effects very similar to those seen in
manganese poisoning. Marsden and Jenner (1987) hypothesize that the ability
of certain drugs to induce parkinsonism in primates but not in rodents is due
to the relative lack of neuromelanin in rodents. Because manganese
selectively accumulates in pigmented regions of the brain (e.g., the
substantia nigra), this species difference is fundamentally important.
EPA initiated an investigation of the literature to determine the relative
bioavailability of manganese in food and water (Ruoff, 1995). The conclusions
from this research were that under a wide variety of exposure scenarios in
humans, the bioavailability of manganese ingested in water was essentially
equal to the bioavailability of manganese in food. Total diet, rather than
the actual medium of exposure, appears to be more of a determining factor for
the uptake of manganese from the GI tract. Specifically, the relative
bioavailability of manganese from food compared with that from drinking water
was determined to be 0.7, and not statistically significantly different. When
the data were reanalyzed to include only the ingestion of manganese in
drinking water by fasted individuals, the relative bioavailability was 0.5,
indicating roughly a 2-fold greater uptake of manganese from drinking water
compared with uptake from food.
Another issue of great importance to consider in the risk assessment for
manganese concerns the bioavailability of different forms of manganese
consumed under different exposure conditions. Various dietary factors as well
as the form of manganese can have a significant bearing on the dose absorbed
from the GI tract. Many constituents of a vegetarian diet (e.g., tannins,
oxalates, phytates, fiber) have been found to inhibit manganese absorption
presumably by forming insoluble complexes in the gut. In addition, high
dietary levels of calcium or phosphorus have been reported to decrease
manganese absorption. Individuals who are deficient in iron demonstrate an
increase in manganese absorption. It is also recognized that manganese uptake
and elimination are under homeostatic control, generally allowing for a wide
range of dietary intakes considered to be safe. These factors and others are
described in a review by Kies (1987). In addition to the influence of
extrinsic variables, significant interindividual differences in manganese
absorption and retention have been reported. In humans administered a dose of
radiolabeled manganese in an infant formula, the mean absorption was 5.9 +/-
4.8%, but the range was 0.8-16%, a 20-fold difference (Davidsson et al.,
1989). Retention at day 10 was 2.9 +/- 1.8%, but the range was 0.6-9.2%,
again indicating substantial differences between individuals.
In a 100-day dietary study in 6-week-old male mice, Komura and Sakamoto
(1991) demonstrated significant differences in tissue levels of manganese in
mice fed equivalent amounts of manganese as MnCl2.4H2O, Mn(Ac)2.4H2O, MnCO3
and MnO2. Mice receiving the two soluble forms of manganese (the chloride and
acetate salts) were found to gain significantly less weight than controls,
while mice consuming the insoluble forms of manganese (the carbonate and
dioxide salts) appeared to actually gain slightly more weight than controls.
The acetate and carbonate groups, however, had significantly higher manganese
levels in the liver and kidney compared with the chloride and dioxide groups,
both of which were elevated above control levels. Reduced locomotor activity
in the carbonate and acetate groups was also reported, perhaps related to the
higher tissue levels of manganese. This study points out a need for
understanding the effects of the various chemical species of manganese, of
which relatively little is known. More information on manganese speciation
can be found in the RfC file on IRIS.
It is also recognized that neonates may be at increased risk of toxicity
resulting from exposure to manganese because of a higher level of uptake from
the GI tract and a decreased ability to excrete absorbed manganese. The
uptake and retention of manganese have been reviewed by Lonnerdal et al.
(1987). In rats, manganese absorption decreased dramatically as the animals
matured. While 24-hour retention values are as high as 80% in 14-day-old
pups, this value drops to about 30% by day 18. Low levels of manganese
absorption (about 3-4%) have also been reported for mature humans, but few
data are available for infants.
No reports of actual manganese toxicity or deficiency have been reported
for infants. As with adults, however, the potential for effects resulting
from excess manganese or suboptimal manganese appears to exist (reviewed by
Lonnerdal, 1994). In particular, suboptimal manganese may be a problem for
preterm infants given calcium supplementation, which is known to inhibit the
absorption of manganese. Because manganese is required for adequate bone
mineralization, it is suggested that insufficient absorption of manganese in
preterm infants may contribute to poor bone growth. On the other hand, excess
manganese may be a problem for infants with low iron status, as this is known
to increase the absorption of manganese.
An additional concern for infants has been expressed because of the often
high levels of manganese in infant formulas, particularly compared with breast
milk. Also, manganese in human milk is in the trivalent form bound to
lactoferrin, the major iron-binding protein. Lactoferrin receptors are
located in the brush border membranes of epithelial cells throughout the
length of the small intestine, thus allowing for regulation of the uptake of
manganese. In infant formulas, however, because manganese is in the divalent
state, absorption through the GI tract cannot be regulated by lactoferrin
receptors. Collipp et al. (1983) found that hair manganese levels in newborn
infants increased significantly from birth (0.19 ug/g) to 6 weeks of age
(0.865 ug/g) and 4 months of age (0.685 ug/g) when the infants were given
formula, but that the increase was not significant in babies who were breast-
fed (0.330 ug/g at 4 months). While human breast milk is relatively low in
manganese (7-15 ug/L), levels in infant formulas are much higher (50-300
ug/L). It was further reported in this study that the level of manganese in
the hair of learning-disabled children (0.434 ug/g) was significantly
increased in comparison with that of normal children (0.268 ug/g). Other
investigators also have reported an association between elevated levels of
manganese in hair and learning disabilities in children (Barlow and Kapel,
1979; Pihl and Parkes, 1977). Although no causal relationship has been
determined for learning disabilities and manganese intake, further research in
this area is warranted. High levels of manganese in infant formulas may be of
concern because of the increased absorption and retention of manganese that
has been reported in neonatal animals (Lonnerdal et al., 1987). Also,
manganese has been shown to cross the blood-brain barrier, with the rate of
penetration in animal experiments being 4 times higher in neonates than in
adults (Mena, 1974).
__I.A.5.
Confidence in the Oral RfD
Study — Medium
Database — Medium
RfD — Medium
Many studies have reported similar findings with regard to the normal
dietary intake of manganese by humans. These data are considered to be
superior to any data obtained from animal toxicity studies, especially as the
physiologic requirements for manganese vary quite a bit among different
species, with man requiring less than rodents. There is no single study used
to derive the dietary RfD for manganese. While several studies have
determined average levels of manganese in various diets, no quantitative
information is available to indicate toxic levels of manganese in the diet of
humans. Because of the homeostatic control humans maintain over manganese, it
is generally not considered to be very toxic when ingested with the diet. It
is important to recognize that while the RfD process involves the
determination of a point estimate of an oral intake, it is also stated that
this estimate is associated "with uncertainty spanning perhaps an order of
magnitude." Numerous factors, both environmental factors (e.g., the presence
or absence of many dietary constituents) and biological or host factors (e.g.,
age, alcohol consumption, anemia, liver function, general nutritional status)
can significantly influence an individual's manganese status. As discussed in
the Additional Studies / Comments Section, there is significant variability in
the absorption and elimination of manganese by humans. Confidence in the data
base is medium and confidence in the dietary RfD for manganese is also medium.
__I.A.6.
EPA Documentation and Review of the Oral RfD
Source Document — This assessment is not presented in any existing EPA
documentation.
This summary has been peer reviewed by three external scientists and has
also received internal EPA review. The review was completed on 07/06/1995.
The comments of the reviewers have been carefully evaluated and considered in
the revision and finalization of this IRIS Summary. A record of these
comments is included in the IRIS documentation files.
Other EPA Documentation — U.S. EPA, 1984
Agency Work Group Review — 05/17/1990, 06/21/1990, 06/24/1992, 09/22/1992, 03/31/1993,
12/14/1993, 05/12/1995
Verification Date — 05/12/1995
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Manganese conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__I.A.7.
EPA Contacts (Oral RfD)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general,
at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov
(internet address).
Top of page
_I.B.
Reference Concentration for Chronic Inhalation Exposure (RfC)
Substance Name — Manganese
CASRN — 7439-96-5
Last Revised — 12/01/1993
The inhalation Reference Concentration (RfC) is analogous to
the oral RfD and is likewise based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. The inhalation RfC
considers toxic effects for both the respiratory system (portal-of-entry)
and for effects peripheral to the respiratory system (extrarespiratory
effects). It is expressed in units of mg/cu.m. In general, the RfC is
an estimate (with uncertainty spanning perhaps an order of magnitude)
of a daily inhalation exposure of the human population (including sensitive
subgroups) that is likely to be without an appreciable risk of deleterious
effects during a lifetime. Inhalation RfCs were derived according to the
Interim Methods for Development of Inhalation Reference Doses (EPA/600/8-88/066F
August 1989) and subsequently, according to Methods for Derivation of
Inhalation Reference Concentrations and Application of Inhalation Dosimetry
(EPA/600/8-90/066F October 1994). RfCs can also be derived for the noncarcinogenic
health effects of substances that are carcinogens. Therefore, it is essential
to refer to other sources of information concerning the carcinogenicity
of this substance. If the U.S. EPA has evaluated this substance for potential
human carcinogenicity, a summary of that evaluation will be contained
in Section II of this file.
__I.B.1.
Inhalation RfC Summary
Critical Effect |
Exposures* |
UF
|
MF
|
RfC |
Impairment of neuro-
behavioral function
Occupational exposure
to manganese dioxide
Roels et al., 1992
|
NOAEL: None LOAEL: 0.15 mg/cu.m
LOAEL(ADJ): 0.05 mg/cu.m
LOAEL(HEC): 0.05 mg/cu.m
|
1000
|
1
|
5E-5
mg/cu.m
|
Impairment of neuro-
behavioral function
Occupational exposure
to manganese oxides
and salts
Roels et al., 1987
|
NOAEL: None LOAEL: 0.97 mg/cu.m
LOAEL(ADJ): 0.34 mg/cu.m
LOAEL(HEC): 0.34 mg/cu.m
|
|
|
|
*Conversion Factors and Assumptions: Roels et al., 1992: The LOAEL is
derived from an occupational-lifetime integrated respirable dust (IRD)
concentration of manganese dioxide (MnO2) (based on 8-hour TWA occupational
exposure multiplied by individual work histories in years) expressed as mg
manganese (Mn)/cu.m x years. The IRD concentrations ranged from 0.040 to
4.433 mg Mn/cu.m x years, with a geometric mean of 0.793 mg Mn/cu.m x years
and a geometric standard deviation of 2.907. The geometric mean concentration
(0.793 mg/cu.m x years) was divided by the average duration of MnO2 exposure
(5.3 years) to obtain a LOAEL TWA of 0.15 mg/cu.m. The LOAEL refers to an
extrarespiratory effect of particulate exposure and is based on an 8-hour TWA
occupational exposure. MVho = 10 cu.m/day, MVh = 20 cu.m/day. LOAEL(HEC) =
0.15 mg/cu.m x (MVho/MVh) x 5 days/7 days = 0.05 mg/cu.m.
Roels et al., 1987: The LOAEL is based on an 8-hour TWA occupational
exposure. The TWA of total airborne manganese dust ranged from 0.07 to 8.61
mg/cu.m, and the median was 0.97 mg/cu.m. This is an extrarespiratory effect
of a particulate exposure. MVho = 10 cu.m/day, MVh = 20 cu.m/day. LOAEL(HEC)
= 0.97 mg/cu.m x (MVho/MVh) x 5 days/7 days = 0.34 mg/cu.m.
__I.B.2.
Principal and Supporting Studies (Inhalation RfC)
Roels, H., R. Lauwerys, J.-P. Buchet et al. 1987. Epidemiological survey
among workers exposed to manganese: Effects on lung, central nervous system,
and some biological indices. Am. J. Ind. Med. 11: 307-327.
Roels, H.A., P. Ghyselen, J.P. Buchet, E. Ceulemans, and R.R. Lauwerys. 1992.
Assessment of the permissible exposure level to manganese in workers exposed
to manganese dioxide dust. Br. J. Ind. Med. 49: 25-34.
Roels et al. (1992) conducted a cross-sectional study of 92 male workers
exposed to manganese dioxide (MnO2) dust in a Belgian alkaline battery plant.
A control group of 101 male workers was matched for age, height, weight, work
schedule, coffee and alcohol consumption, and smoking; educational level was
slightly higher in the control group (p = 0.046 by chi square test).
The manganese (Mn)-exposed group had been exposed to MnO2 for an average
of 5.3 years (range: 0.2-17.7 years). The geometric means of the workers' TWA
airborne Mn concentrations, as determined by personal sampler monitoring at
the breathing zone, were 0.215 mg Mn/cu.m for respirable dust and 0.948 mg
Mn/cu.m for total dust. No data on particle size or purity were presented,
but the median cut point for the respirable dust fraction was 5 um according
to information provided by Roels et al. (1992) and Roels (1993). Total and
respirable dust concentrations were highly correlated (r = 0.90, p < 0.001),
with the Mn content of the respirable fraction representing on average 25% of
the Mn content in the total dust. The authors noted that the personal
monitoring data were representative of the usual exposure of the workers
because work practices had not changed during the last 15 years of the
operation of the plant.
Occupational-lifetime integrated exposure to Mn was estimated for each
worker by multiplying the current airborne Mn concentration for the worker's
job classification by the number of years for which that classification was
held and adding the resulting (arithmetic) products for each job position a
worker had held. The geometric mean occupational-lifetime integrated
respirable dust (IRD) concentration was 0.793 mg Mn/cu.m x years (range:
0.040-4.433 mg Mn/cu.m x years), with a geometric standard deviation of 2.907
mg Mn/cu.m x years, based on information provided by Roels (1993). The
geometric mean occupational-lifetime integrated total dust (ITD) concentration
was 3.505 mg Mn/cu.m x years (range: 0.191-27.465 mg Mn/cu.m x years).
Geometric mean concentrations of blood Mn (MnB) (0.81 ug/dL) and urinary Mn
(MnU) (0.84 ug/g creatinine) were significantly higher in the Mn-exposed group
than in the control group, but on an individual basis no significant
correlation was found between either MnB or MnU and various external exposure
parameters. Current respirable and total Mn dust concentrations correlated
significantly with geometric mean MnU on a group basis (Spearman r = 0.83, p <
0.05).
A self-administered questionnaire focused on occupational and medical
history, neurological complaints, and respiratory symptoms. Lung function was
evaluated by standard spirographic measures. Neurobehavioral function was
evaluated by tests of audio-verbal short-term memory, visual simple reaction
time, hand steadiness, and eye-hand coordination. Blood samples were assayed
for several hematological parameters (erythrocyte count, leukocyte count,
hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin,
platelets, and differential leukocyte count); Mn; lead; zinc protoporphyrin;
and serum levels of calcium, iron, follicle stimulating hormone (FSH),
luteinizing hormone (LH), and prolactin. Urinary Mn, cadmium, and mercury
concentrations were also determined.
Responses to the questionnaire indicated no significant differences
between groups in either respiratory or neurological symptoms, nor were
spirometric, hormonal, or calcium metabolism measurements significantly
different for the two groups. In addition, a separate report (Gennart et al.,
1992) indicated no significant difference in the fertility of 70 of these
workers, in contrast to earlier findings in 85 workers exposed not only to
MnO2 but also to other Mn oxides and salts at higher concentrations (Lauwerys
et al., 1985). Erythropoietic parameters and serum iron concentrations were
consistently and significantly lower in the Mn-exposed workers, albeit within
the normal range of values.
Of particular note, Mn workers performed worse than controls on several
measures of neurobehavioral function. Visual reaction time was consistently
and significantly slower in the Mn-exposed workers measured in four 2-minute
periods, with more pronounced slowing over the total 8-minute period and
significantly greater variability in reaction times for the Mn-exposed group.
Abnormal values for mean reaction times (defined as greater than or equal to
the 95th percentile of the control group) also were significantly more
prevalent in the Mn-exposed group during three of four 2-minute intervals of
the 8-minute testing period.
Five measures of eye-hand coordination (precision, percent precision,
imprecision, percent imprecision, and uncertainty) reflected more erratic
control of fine hand-forearm movement in the Mn-exposed group than in the
controls, with mean scores on all five measures being highly significantly
different for the two groups. There was also a significantly greater
prevalence of abnormal values for these five measures in the Mn-exposed group.
The hole tremormeter test of hand steadiness indicated a consistently greater
amount of tremor in the Mn-exposed workers, with performance for two of the
five hole sizes showing statistically significant impairment.
Roels et al. (1992) performed an exposure-response analysis by classifying
IRD values into three groups (<0.6, 0.6-1.2, and >1.2 mg Mn/cu.m x years) and
comparing the prevalence of abnormal scores for visual reaction time, hand
steadiness, and eye-hand coordination with controls. This analysis indicated
that the prevalence of abnormal eye-hand coordination values was significantly
greater in workers whose IRD levels were less than 0.6 mg Mn/cu.m x years.
However, the relationship between exposure and response was not linear across
groups. Visual reaction time and hand steadiness showed linear exposure-
related trends but did not achieve statistical significance except at levels
of >1.2 mg Mn/cu.m x years. As noted by the authors, "analysis of the data on
a group basis ... does not permit us to identify a threshold effect level for
airborne Mn." Although suggestive of a LOAEL of <0.6 mg Mn/cu.m x years, the
exposure-response analysis by Roels et al. (1992) possibly could reflect the
small disparity in educational level between exposed and control workers that
was noted above with regard to the matching criteria for this study. If
educational level were in fact a covariate of exposure as well as
neurobehavioral performance, it could confound the exposure-response analysis.
Although it is not clear that such was the case, the possibility of
confounding suggests that the LOAEL should not be based on the results of the
exposure-response analysis until these results can be confirmed by other
studies. Also, statistical correction for multiple comparisons should be
included in the exposure response analysis.
A LOAEL may be derived from the Roels et al. (1992) study by using the IRD
concentration of MnO2, expressed as mg Mn/cu.m x years (based on 8-hour TWA
occupational exposures for various job classifications, multiplied by
individual work histories in years). Dividing the geometric mean IRD
concentration (0.793 mg/cu.m x years) by the average duration of the workers'
exposure to MnO2 (5.3 years) yields a LOAEL of 0.15 mg/cu.m. The LOAEL(HEC)
is 0.05 mg/cu.m.
Roels et al. (1987) conducted a cross-sectional study in 141 male workers
exposed to MnO2, manganese tetroxide (Mn3O4), and various Mn salts (sulfate,
carbonate, and nitrate). A matched group of 104 male workers was selected as
a control group. The two groups were matched for socioeconomic status and
background environmental factors; in addition, both groups had comparable
work-load and work-shift characteristics.
The TWA of total airborne Mn dust ranged from 0.07 to 8.61 mg/cu.m, with
an overall arithmetic mean of 1.33 mg/cu.m, a median of 0.97 mg/cu.m, and a
geometric mean of 0.94 mg/cu.m. The duration of employment ranged from 1 to
19 years, with a mean of 7.1 years. The particle size and purity of the dust
were not reported. Neurological examination, neurobehavioral function tests
(simple reaction time, short-term memory, eye-hand coordination, and hand
tremor), spirographic measurements, blood and urine tests, and a self-
administered questionnaire were used to assess possible toxic effects of Mn
exposure. The questionnaire was designed to detect CNS and respiratory
symptoms.
Significant differences in mean scores between Mn-exposed and reference
subjects were found for objective measures of visual reaction time, eye-hand
coordination, hand steadiness, and audio-verbal short-term memory. The
prevalence of abnormal scores on eye-hand coordination and hand steadiness
tests showed a dose-response relationship with blood Mn levels; short-term
memory scores were related to years of Mn exposure but not to blood Mn levels.
The prevalence of subjective symptoms was greater in the exposed group than in
controls for 20 of 25 items on the questionnaire, with four items being
statistically significant: fatigue, tinnitus, trembling of fingers, and
irritability.
A significantly greater prevalence of coughs during the cold season,
dyspnea during exercise, and recent episodes of acute bronchitis was self-
reported in the exposed group. Lung function parameters were only slightly
(<10%) lower in the Mn-exposed workers, with the only significant alterations
evident in Mn-exposed smokers. These mild changes in Mn-exposed workers
(apart from the effects of smoking) and the absence of respiratory effects in
the more recent study by Roels et al. (1992) suggest that the nervous system
is a more sensitive target for Mn toxicity.
Based upon the findings of impaired neurobehavioral function in workers
whose average Mn exposure was estimated by the geometric mean TWA of total
airborne Mn dust at the time of the study, a LOAEL of 0.97 mg/cu.m was
identified, with a LOAEL(HEC) of 0.34 mg/cu.m. Note that this LOAEL(HEC) is
based on total Mn dust of mixed forms, whereas the LOAEL(HEC) from the more
recent Roels et al. (1992) study is based on the measured respirable dust
fraction of MnO2 only. However, the geometric mean total dust concentrations
in the 1987 and 1992 studies by Roels et al. were approximately the same (0.94
and 0.95 mg/cu.m, respectively).
The findings of Roels et al. (1987, 1992) are supported by other recent
reports that provide comparable and consistent indications of neurobehavioral
dysfunction in Mn-exposed workers (Mergler et al., 1993; Iregren, 1990;
Wennberg et al., 1991, 1992).
Mergler et al. (1993) conducted a cross-sectional study of 115 male
ferromanganese and silicomanganese alloy workers in southwest Quebec. A
matched-pair design was employed because of presumptively high environmental
pollutant levels; 74 pairs of workers and referents were matched on age,
educational level, smoking status, number of children, and length of residency
in the region.
Air concentrations of respirable and total dust were sampled by stationary
monitors during silicomanganese production. The geometric mean of a series of
8-hour TWAs was 0.035 mg Mn/cu.m (range: 0.001-1.273 mg Mn/cu.m) for
respirable dust and 0.225 mg Mn/cu.m (range: 0.014-11.480 mg Mn/cu.m) for
total dust. The authors noted that past dust levels at certain job sites had
been considerably higher. The mean duration of the workers' Mn exposure was
16.7 years and included Mn fumes as well as mixed oxides and salts of Mn.
Geometric mean MnB was significantly higher in the Mn alloy workers, but MnU
did not differ significantly between exposed workers and controls.
The number of discordant pairs, in which workers reported undesirable
symptoms on a self-administered questionnaire but their matched pairs did not,
was statistically significant for 33 of 46 items, including the following:
fatigue; emotional state; memory, attention, and concentration difficulties;
nightmares; sweating in the absence of physical exertion; sexual dysfunction;
lower back pain; joint pain; and tinnitus. Workers did not report symptoms
typical of advanced Mn poisoning (e.g., hand tremor, changes in handwriting,
loss of balance when turning, difficulty in reaching a fixed point)
significantly more than referents, which suggests that the other reported
symptoms were probably not due to bias on the part of the workers.
The greatest differences in neurobehavioral function were evident in tests
of motor function, especially tests requiring coordinated alternating and/or
rapid movements. Workers performed significantly worse on the motor scale of
a neuropsychological test battery both in overall score and in eight subscales
of rapid sequential or alternating movements. Worker performance also was
significantly worse on tests of hand steadiness, parallel-line drawing
performance, and ability to rapidly identify and mark specified alphabetic
characters within strings of letters. Performance on a variety of other tests
of psychomotor function, including simple reaction time, was worse in Mn-
exposed workers but marginally significant (0.05 < p < 0.10). In addition, Mn
alloy workers differed significantly from referents on measures of cognitive
flexibility and emotional state. Olfactory perception also was significantly
enhanced in the Mn-alloy workers.
The matched-pair design of Mergler et al. (1993) helped reduce differences
between exposed and referent subjects that might otherwise have confounded the
study. However, to the extent that the referents also may have had
significant exposure to Mn in the ambient atmosphere, such exposure may have
reduced the differences in neurobehavioral performance between workers and
referents. This possibility is supported by the fact that the finger-tapping
speed of both workers and referents on a computerized test was slower than
that of Mn-exposed workers assessed on the same test by Iregren (1990) in
Sweden. In the absence of a NOAEL, the LOAEL from the study of Mergler et al.
(1993) is based on the geometric mean respirable dust level (0.035 mg
Mn/cu.m), with a LOAEL(HEC) of approximately 0.01 mg/cu.m, which is about
five-fold lower than the LOAEL(HEC) identified in the study by Roels et al.
(1992).
Workers exposed to Mn in two Swedish foundries (15 from each plant) were
evaluated in a study first reported by Iregren (1990). The exposure to Mn
varied from 0.02 to 1.40 mg/cu.m (mean = 0.25 mg/cu.m; median = 0.14 mg/cu.m)
for 1-35 years (mean = 9.9 years). Earlier monitoring measurements made in
both factories suggested that essentially no changes in exposure had occurred
in either factory for the preceding 18 years. Each exposed worker was matched
for age, geographical area, and type of work to two workers not exposed to Mn
in other industries. Neurobehavioral function was assessed by eight
computerized tests and two manual dexterity tests. There were significant
differences between exposed and control groups for simple reaction time, the
standard deviation of reaction time, and finger-tapping speed of the dominant
hand. In addition, digit-span short-term memory, speed of mental addition,
and verbal (vocabulary) understanding differed significantly between exposed
and control groups. The difference in verbal understanding suggested that the
two groups were not well matched for general cognitive abilities. With verbal
performance used as an additional matching criterion, differences between the
groups in simple reaction time, the standard deviation of reaction time, and
finger-tapping speed remained statistically significant, despite a decrease in
statistical power due to reducing the size of the reference group to 30
workers. Further analyses using verbal test scores as a covariate also
indicated that these same three measures of neurobehavioral function were
statistically different in exposed and control workers. No significant
correlation was found within the exposed group to establish a concentration-
response relationship.
Additional reports of neurobehavioral and electrophysiological evaluations
of these same workers have been published by Wennberg et al. (1991, 1992).
Although none of the latter results achieved statistical significance at p =
0.05, increased frequency of self-reported health symptoms, increased
prevalence of abnormal electroencephalograms, slower brain-stem auditory-
evoked potential latencies, and slower diadochokinesometric performance were
found in the exposed workers. Diadochokinesis refers to the ability to
perform rapidly alternating movements such as supination and pronation of the
forearm, and is an indicator of extrapyramidal function (see Additonal
Comments/Studies). Also, an increase in P-300 latency, as suggested by these
results, has been observed in patients with parkinsonism according to Wennberg
et al. (1991), who viewed these results in Mn-exposed workers as early
(preclinical) signs of disturbances similar to parkinsonism. Based on the
impairments in reaction time and finger-tapping speed reported in the Swedish
studies (Iregren, 1990; Wennberg et al., 1991, 1992), the LOAEL(HEC) is
calculated to be 0.05 mg/cu.m. Although numerically the same value as that
derived from Roels et al. (1992), the Swedish study measured total dust.
However, Wennberg et al. (1991) stated that the respirable dust level was 20-
80% of total dust, which implies that the LOAEL(HEC) from the Swedish studies
could be somewhat lower than that from Roels et al. (1992).
All of the above studies taken together provide a consistent pattern of
evidence indicating that neurotoxicity is associated with low-level
occupational Mn exposure. The fact that the speed and coordination of motor
function are especially impaired is consistent with other epidemiological,
clinical, and experimental animal evidence of Mn intoxication (see Additional
Comments/Studies). Moreover, the LOAEL(HEC)s obtained from these studies are
not appreciably different. Nevertheless, some differences between the studies
are evident in the durations of exposure and forms of Mn to which workers were
exposed. In the Roels et al. (1992) study, the mean period of exposure was
5.3 years (range: 0.2-17.7 years), and exposure was limited to MnO2. In the
other studies, mixed forms of Mn were present, and the mean durations of
exposure were longer: 7.1 years in Roels et al. (1987), 9.9 years in Iregren
(1990), and 16.7 years in Mergler et al. (1993). The findings of Mergler et
al. (1993) suggest that the LOAEL(HEC) could be at least as low as
approximately 0.01 mg/cu.m. However, the variable concentrations and mixed
compounds of Mn to which workers were exposed make it difficult to rely
primarily upon the findings of Mergler et al. (1993) in deriving the RfC.
Nevertheless, their results provide support for the findings of Roels et al.
(1992) and suggest that the longer period of exposure (16.7 years in Mergler
et al. (1993) vs. 5.3 years in Roels et al., 1992) may have contributed to the
apparent differences in sensitivity. Although analyses by Roels et al. (1987,
1992) and Iregren (1990) generally did not indicate that duration of exposure
correlated significantly with neurobehavioral outcomes, none of these studies
involved average exposures as long as those in the Mergler et al. (1993)
study. Also, the oldest worker in the Roels et al. (1992) study was less than
50 years old, and the average age in that study was only 31.3 years vs. 34.3
years in Roels et al. (1987), 43.4 years in Mergler et al. (1993), and 46.4 in
Iregren (1990). These points suggest that chronic exposure to Mn and/or
interactions with aging could result in effects at lower concentrations than
would be detected after shorter periods of exposure and/or in younger workers.
Based on the findings of neurobehavioral impairment by Roels et al. (1987,
1992), with supporting evidence from Mergler et al. (1993) and the Swedish
reports (Iregren, 1990; Wennberg et al., 1991, 1992), the LOAEL for derivation
of the RfC is 0.15 mg/cu.m, and the LOAEL(HEC) is 0.05 mg/cu.m.
__I.B.3.
Uncertainty and Modifying Factors (Inhalation RfC)
UF — An uncertainty factor of 1000 reflects 10 to protect sensitive
individuals, 10 for use of a LOAEL, and 10 for database limitations reflecting
both the less-than-chronic periods of exposure and the lack of developmental
data, as well as potential but unquantified differences in the toxicity of
different forms of Mn.
MF — None
__I.B.4.
Additional Studies/Comments (Inhalation RfC)
Manganese toxicity varies depending upon the route of exposure. When
ingested, Mn is considered to be among the least toxic of the trace elements.
In the normal adult, between 3 and 10% of dietary Mn is absorbed. Total body
stores normally are controlled by a complex homeostatic mechanism regulating
absorption and excretion. As detailed in the Uncertainty Factor Text and the
Additonal Comments/Studies for the oral RfD, toxicity from ingested Mn is
rarely observed. However, deficiencies of calcium and iron have been noted to
increase Mn absorption (Mena et al., 1969; Murphy et al., 1991). Also, Mena et
al. (1969) found that anemic subjects absorbed 7.5% of ingested Mn, whereas
normal subjects absorbed 3%. Interestingly, manganism patients absorbed 4%,
and apparently healthy Mn miners absorbed only 3%. These differences suggest
that certain subpopulations, such as children, pregnant women, elderly
persons, iron- or calcium-deficient individuals, and individuals with liver
impairment, may have an increased potential for excessive Mn body burdens due
to increased absorption or altered clearance mechanisms, which may be of
particular importance for those exposed to Mn by multiple routes.
As a route of Mn exposure, the respiratory tract is the most important
portal of entry. The inhalation toxicity of Mn is in part a function of
particle dosimetry and subsequent pharmacokinetic events. Particle size
determines the site of deposition in the respiratory tract. Generally, in
humans, fine mode particles (<2.5 um) preferentially deposit in the pulmonary
region, and coarse mode particles (>2.5 um) deposit in the tracheobronchial
and extrathoracic regions. Those particles depositing in the extrathoracic
and tracheobronchial regions are predominantly cleared by the mucociliary
escalator into the gastrointestinal tract where absorption is quite low (about
3%). Particles deposited in the pulmonary region are cleared predominantly to
the systemic compartment by absorption into the blood and lymph circulation.
Disregarding the possibility of counteracting mechanisms, 100% absorption of
particles deposited in the pulmonary region is assumed. Another possible
route of exposure may exist. Studies such as those of Perl and Good (1987)
and Evans and Hastings (1992) have indicated that neurotoxic metals such as
aluminum and cadmium can be directly transported to the brain olfactory bulbs
via nasal olfactory pathways (i.e., from extrathoracic deposition). The
alteration in olfactory perception that Mergler et al. (1993) found in Mn-
exposed workers lends support to the speculation that this pathway may also
operate for Mn, which would further complicate understanding of target-site
dosimetry.
The human health effects database on Mn does not include quantitative
inhalation pharmacokinetics information on the major oxides of Mn. Two of the
studies described in the Principal and Support Studies (Roels et al., 1992;
Mergler et al., 1993) measured respirable as well as total Mn dust, and one
study (Roels et al., 1992) dealt with workers exposed to only one form of Mn,
namely MnO2. However, this information does not allow quantitative
determinations of the dose delivered to the respiratory tract or estimates of
target-site doses. After absorption via the respiratory tract, Mn is
transported through the blood stream directly to the brain, bypassing the
liver and the opportunity for first-pass hepatic clearance. This direct path
from the respiratory tract to the brain is the primary reason for the
differential toxicity of inhaled and ingested Mn. Pharmacokinetic analyses
based on inhalation of manganese chloride (MnCl2) by macaque monkeys (Newland
et al., 1987) indicated that clearance from the brain was slower than from the
respiratory tract and that the rate of clearance depended on the route of
exposure. Brain half-times were 223-267 days after inhalation vs. 53 days
following subcutaneous administration (Newland et al., 1987) or 54 days in
humans given Mn intravenously (Cotzias et al., 1968). These long half-times
were thought to reflect both slower clearance of brain stores and
replenishment from other organs, particularly the respiratory tract. In rats,
Drown et al. (1986) also observed slower clearance of labeled Mn from brain
than from the respiratory tract. Several occupational physicians have
reported large individual differences in workers' susceptibility to Mn
intoxication, which Rodier (1955) speculated might be due in part to
differences in the ability to clear particulate Mn from the lung.
The bioavailability of different forms of Mn is another matter for
consideration. Roels et al. (1992) noted that geometric mean blood and
urinary Mn levels of workers exposed only to MnO2 in their 1992 report were
lower (MnB: 0.81 ug/dL; MnU: 0.84 ug/g creatinine) than those of workers
exposed to mixed oxides and salts in their 1987 report (MnB: 1.22 ug/dL; MnU:
1.59 ug/g creatine), even though airborne total dust levels were approximately
the same (geometric means of 0.94 and 0.95 mg/cu.m, respectively). Mena et
al. (1969) observed no difference between the absorption of 1 um particles of
MnCl2 and manganese sesquioxide (Mn2O3) in healthy adults. Drown et al.
(1986) found that following intratracheal instillation of MnCl2 and Mn3O4 in
rats, the soluble chloride cleared four times faster than the insoluble oxide
from the respiratory tract. However, despite this initial difference, after 2
weeks the amounts of labeled Mn in the respiratory tract were similar for the
two compounds. Recent work by Komura and Sakamoto (1993) comparing different
forms of Mn in mouse diet suggested that less soluble forms such as MnO2 were
taken up to a significantly greater degree in cerebral cortex than the more
soluble forms of MnCl2 and manganese acetate [Mn(CH3COO)2]; however, the
corpus striatal binding characteristics of the +4 valence state of Mn in MnO2
were not substantially different from those of the divalent forms in MnCl2,
Mn(CH3COO)2, and manganese carbonate. Different oxidation states of certain
metals (e.g., chromium, nickel, mercury) are known to have different
toxicities, and some researchers have suggested that endogenous Mn can have
quite different roles in Mn neurotoxicity depending on its oxidation state
(e.g., Archibald and Tyree, 1987; Donaldson et al., 1982). There have been
unsubstantiated claims that the higher valence states of Mn (Mn+3, Mn+4) and
the higher oxides in ores (Mn2O3 and Mn3O4) are more toxic (Oberdoerster and
Cherian, 1988). At present, however, insufficient information exists by which
to determine the relative toxicities of different forms of Mn, and thus, for
the purpose of deriving an RfC for Mn, no distinction is made among various
compounds of Mn.
Because Mn is an essential element and is commonly ingested in diet, total
Mn exposure is an issue. It would be desirable to know the effective target-
site doses and apportion the dose to both the inhalation and oral routes of
exposure. However, given the lack of data regarding oral and inhalation
pharmacokinetics under environmental conditions, such quantitative
apportionment is not possible at present.
Among the primary effects associated with Mn toxicity from inhalation
exposure in humans are signs and symptoms of CNS toxicity. The first medical
description of chronic Mn neurotoxicity (manganism) in workers is generally
credited to Couper in the 1830s (NAS, 1973). Although the course and degree
of Mn intoxication can vary greatly among individuals, manganism is generally
considered to consist of two or three phases (Rodier, 1955). The first is the
psychiatric aspect, which includes disturbances such as excessive weeping and
laughing, sleep disturbance, irritability, apathy, and anorexia. These
symptoms can occur independently of the second phase, neurological signs. The
latter may include gait disturbances, dysarthria, clumsiness, muscle cramps,
tremor, and mask-like facial expression. In addition, there may be a final
stage of Mn intoxication involving symptoms of irreversible dystonia and
hyperflexion of muscles that may not appear until many years after the onset
of exposure (Cotzias et al., 1968). Cotzias et al. (1976) noted a parallel
between these stages of symptoms and the biphasic pattern of dopamine levels
over time in the Mn-exposed individuals noted above. Indeed, various specific
features of Mn toxicity show biphasic patterns in which there is generally
first an increase then a decrease in performance (e.g., a notable increase in
libido followed by impotence, or excitement followed by somnolence) (Rodier,
1955).
In addition to studies described in the Principal and Supporting Studies,
numerous investigators have reported CNS effects in workers exposed to Mn dust
or fumes (Sjoegren et al., 1990; Huang et al., 1989; Wang et al., 1989; Badawy
and Shakour, 1984; Siegl and Bergert, 1982; Chandra et al., 1981; Saric et
al., 1977; Cook et al., 1974; Smyth et al., 1973; Emara et al., 1971; Tanaka
and Lieben, 1969; Schuler et al., 1957; Rodier, 1955; Flinn et al., 1941).
Limitations in these studies generally preclude describing a quantitative
concentration-response relationship. Exposure information is often quite
limited, with inadequate information on the historical pattern of Mn
concentrations or on the chemical composition and particle size distribution
of the dust. In addition, exposure to other chemicals in the workplace is
often not adequately characterized. Despite these limitations, such studies
collectively point to neurobehavioral dysfunction as a primary endpoint for Mn
toxicity.
The neuropathological bases for manganism have been investigated by many
researchers and have indicated the involvement of the corpus striatum and the
extrapyramidal motor system (e.g., Archibald and Tyree, 1987; Donaldson and
Barbeau, 1985; Donaldson et al., 1982; Eriksson et al., 1987, 1992).
Neuropathological lesions have generally been associated with the basal
ganglia, specifically involving neuronal degeneration in the putamen and
globus pallidus (e.g., Newland et al., 1987). Brain imaging studies (e.g.,
Wolters et al., 1989; Nelson et al., 1993) more recently have begun to provide
additional insight into the brain structures involved in Mn toxicity.
In terms of the neurochemistry of Mn toxicity, several studies have shown
that dopamine levels are affected by Mn exposure in humans, monkeys, and
rodents, with various indications of an initial increase in dopamine followed
by a longer term decrease (e.g., Cotzias et al., 1976; Bird et al., 1984;
Barbeau, 1984; Brouillet et al., 1993). Some theories of Mn neurotoxicity
have focused on the role of excessive Mn in the oxidation of dopamine
resulting in free radicals and cytotoxicity (e.g., Donaldson et al., 1982;
Barbeau, 1984). In addition, the fundamental role of mitochondrial energy
metabolism in Mn toxicity has been indicated by the studies of Aschner and
Aschner (1991), Gavin et al. (1992), and others. Brouillet et al. (1993) have
suggested that the mitochondrial dysfunctional effects of Mn result in various
oxidative stresses to cellular defense mechanisms (e.g., glutathione) and,
secondarily, free radical damage to mitochondrial DNA. In view of the slow
release of Mn from mitochondria (Gavin et al., 1992), such an indirect effect
would help account for a progressive loss of function in the absence of
ongoing Mn exposure (Brouillet et al., 1993), as Mn toxicity has been known to
continue to progress in humans despite the termination of exposure (Cotzias et
al., 1968; Rodier, 1955).
Because of the involvement of the dopaminergic system and extrapyramidal
motor system in both Parkinson's disease and manganism, symptoms of the two
diseases are somewhat similar, and several writers have suggested the
possibility of a common etiology; however, many neurological specialists make
a clear distinction in the etiologies and clinical features of Parkinson's
disease and manganism (Barbeau, 1984; Langston et al., 1987).
Another primary endpoint of Mn toxicity has been male reproductive
dysfunction, often manifesting in symptoms such as loss of libido, impotence,
and similar complaints (e.g., Rodier, 1955; Cook et al., 1974). Some
neuropathological evidence suggests that the hypothalamus is a site of Mn
accumulation (Donaldson et al., 1973); thus, disturbance of the hypothalamic-
pituitary-gonadal axis hormones might be expected (Deskin et al., 1981) and
has been examined in a few occupational studies. Lauwerys et al. (1985)
reported the results of a fertility questionnaire administered to male factory
workers (n = 85) exposed to Mn dust. This study involved the same population
of workers for which Roels et al. (1987) reported neurobehavioral
disturbances. The range of Mn levels in the breathing zone was 0.07-8.61
mg/cu.m, with a median concentration of 0.97 mg/cu.m. Average length of
exposure was 7.9 years (range of 1-19 years). A group of workers (n = 81)
with a similar workload was used as a control group. The number of births
expected during different age intervals of the workers (16-25, 26-35, and 36-
45 years) was calculated on the basis of the reproductive experience of the
control employees during the same period. A decrease in the number of
children born to workers exposed to Mn dust during the ages of 16-25 and 26-35
was observed. No difference in the sex ratio of the children was found. The
same apparent LOAEL(HEC) (0.34 mg/cu.m) that was identified in Roels et al.
(1987) for neurobehavioral effects is identified in this study for human
reproductive effects.
However, a more recent report from the same group of investigators
(Gennart et al., 1992), based on 70 of the alkaline battery plant workers
evaluated by Roels et al. (1992), indicated that the probability of live birth
was not different between the Mn-exposed and control workers. Also, in the
study by Roels et al. (1992), serum levels of certain hormones related to
reproductive function (FSH, LH, and prolactin) were not significantly
different for the full group of 92 Mn workers vs. 102 controls. The latter
results are partially supported by a preliminary report by Alessio et al.
(1989), who found that serum FSH and LH levels were not significantly
different in 14 workers generally exposed to <1 mg Mn/cu.m compared to
controls, although prolactin and cortisol levels were significantly higher in
the Mn-exposed workers. It is possible that differences in the forms of Mn to
which workers were exposed in these studies may have contributed to the
similarities and differences in the results, but insufficient information
exists to substantiate this speculation.
Average concentrations of airborne Mn differed slightly in the reports of
Gennart et al. (1992) and Roels et al. (1992), evidently because only a subset
of Mn workers, presumably with different job functions, was used in the
Gennart et al. (1992) analysis. The median respirable dust concentration was
0.18 mg/cu.m, and the median total dust concentration (comparable to Roels et
al., 1987, and Lauwerys et al., 1985) was 0.71 mg/cu.m. Thus, if 0.34 mg/cu.m
is identified as a LOAEL(HEC) based on the reports of Lauwerys et al. (1985)
and Roels et al. (1987), 0.25 mg/cu.m total dust is the NOAEL(HEC) for
reproductive effects based on the report of negative findings by Gennart et
al. (1992).
The respiratory system is another primary target for Mn toxicity; numerous
reports of Mn pneumonitis and other effects on the respiratory system have
appeared in the literature, dating back to 1921 (NAS, 1973). In their cross-
sectional study of workers exposed to mixed Mn oxides and salts (described in
the Principal and Supporting Studies), Roels et al. (1987) found that
significantly greater prevalences of coughs during the cold season, dyspnea
during exercise, and recent episodes of acute bronchitis were reported in the
exposed group on a self-administered questionnaire. However, objectively
measured lung function parameters were only slightly altered and only in Mn-
exposed smokers (also see Saric and Lucic-Palaic, 1977, regarding a possible
synergism between Mn and smoking in producing respiratory symptoms). In their
more recent study, Roels et al. (1992) found no significant differences
between MnO2-exposed and control workers in responses to a questionnaire
regarding respiratory symptoms. Nor were objective spirometric measurements
significantly different for the two groups. The LOAEL(HEC) for respiratory
effects is 0.34 mg/cu.m total dust, based on the Roels et al. (1987) study,
and the NOAEL(HEC) is 0.05 mg/cu.m respirable dust, based on the Roels et al.
(1992) study. In view of the near equivalence of the geometric mean total
dust concentrations in the 1987 and 1992 studies by Roels et al. (0.94 and
0.95 mg/cu.m, respectively), there in fact may be little difference between
the LOAEL(HEC) and the NOAEL(HEC) in terms of air concentrations; however,
differences in the forms of Mn (MnO2 vs. mixed Mn oxides and salts) to which
the workers in the two studies were exposed make it difficult to compare these
values quantitatively.
Nogawa et al. (1973) investigated an association between atmospheric Mn
levels and respiratory endpoints in junior high school students. A
questionnaire focusing on eye, nose, and throat symptoms and pulmonary
function tests were given to students attending junior high schools that were
100 m (enrollment = 1258) and 7 km (enrollment = 648) from a ferromanganese
plant. Approximately 97-99% of the students participated. Based on
measurements obtained at another time by a government agency, the 5-day
average atmospheric Mn level 300 m from the plant was reported to be 0.0067
mg/cu.m.
Significant increases in past history of pneumonia, eye problems, clogged
nose, nose colds, throat swelling and soreness, and other symptoms were noted
among the students in the school 100 m from the plant. Those living closest
to the plant reported more throat symptoms and past history of pneumonia than
did students living farther away. Pulmonary function tests revealed
statistically significant decreases in maximum expiratory flow, forced vital
capacity (FVC), forced expiratory volume at 1 second (FEV-1), and the FVC:FEV-
1 ratio in the students attending the school closer to the plant, with some
measures suggesting a relationship between performance and distance of
residence from the plant.
Although the results from the study of Nogawa et al. (1973) suggest an
association between ambient Mn exposure and respiratory problems, limitations
in the study make it difficult to interpret. No direct measurements were made
of atmospheric Mn levels either in the schools or homes, and exposure levels
were inferred from the distance from the plant and other indirect measures of
Mn in the environment. Also, the authors did not note whether socioeconomic
variables were controlled, and this factor could well be confounded with both
distance from the plant and health problems. A follow-up study by Kagamimori
et al. (1973) suggested that, following reductions in Mn emissions (with
apparently no reduction in sulfur dioxide or total dust) from the
ferromanganese plant, students nearest the plant showed improvements in
subjective symptoms and pulmonary function tests. As before, however,
exposure levels were not adequately characterized to allow clear-cut
conclusions.
Lloyd-Davies (1946) reported an increased incidence of pneumonia in men
employed at a potassium permanganate manufacturing facility over an 8-year
period. During that period, the number of workers in the facility varied from
40 to 124. Dust measurements were well described in terms of collection
conditions and particle size and composition, but actual exposure levels were
not evaluated. Air concentrations ranged from 9.6 to 83.4 mg/cu.m as MnO2,
which constituted 41-66% of the dust. The incidence of pneumonia in the
workers was 26 per 1000, compared to an average of 0.73 per 1000 in a
reference group of over 5000 workers. Workers also complained of bronchitis
and nasal irritation. In a continuation of this study, Lloyd-Davies and
Harding (1949) reported the results of sputum and nasopharynx cultures for
four men diagnosed as having lobar- or bronchopneumonia. With the exception
of one of these cases, they concluded that Mn dust, without the presence of
bacterial infection or other factors, caused the observed pneumonitis.
Evidence from several laboratory animal studies supports findings in Mn-
exposed humans. For example, inhaled Mn has been shown to produce significant
alterations in dopamine levels in the caudate and globus pallidus of Rhesus
monkeys (Bird et al., 1984) and behavioral changes in mice (Morganti et al.,
1985). However, species differences may complicate interpretation of certain
neurobehavioral findings in laboratory animals. Unlike primates, rodents do
not have pigmented substantia nigra, which is a brain region of relatively
high Mn uptake and consequent involvement in neurobehavioral dysfunction.
Nevertheless, rodent and primate studies show various neurochemical,
neuropathological, and neurobehavioral effects resulting from Mn exposure.
However, because most laboratory animal studies of Mn neurotoxicity involve
exposure by routes other than inhalation, they are not described here.
Other endpoints of Mn toxicity also have been investigated with laboratory
animal models of inhalation exposure. Experimental animal data qualitatively
support human study findings of respiratory effects in that Mn exposure
results in increased incidence of pneumonia in rats exposed to 68-219 mg/cu.m
MnO2 for 2 weeks (Shiotsuka, 1984), pulmonary emphysema in monkeys exposed to
0.7-3.0 mg/cu.m MnO2 for 10 months (Suzuki et al., 1978), and bronchiolar
lesions in rats and hamsters exposed to 0.117 mg/cu.m Mn3O4 for 56 days (Moore
et al., 1975). Also, Lloyd-Davies and Harding (1949) induced bronchiolar
epithelium inflammation, widespread pneumonia, and granulomatous reactions in
rats administered 10 mg MnO2 by intratracheal injection, and pulmonary edema
in rats administered 5-50 mg MnCl2 in the same fashion. However, no
significant pulmonary effects were detected in other studies of rats and
monkeys exposed to as much as 1.15 mg Mn/cu.m as Mn3O4 for 9 months (Ulrich et
al., 1979a,b,c) or rabbits exposed to as much as 3.9 mg Mn/cu.m as MnCl2 for
4-6 weeks (Camner et al., 1985).
Laboratory animal studies also have shown that inhaled Mn may increase
susceptibility to infectious agents such as Streptococcus pyogenes in mice
(Adkins et al., 1980), Enterobacter cloacae in guinea pigs (Bergstrom, 1977),
Klebsiella pneumoniae in mice (Maigetter et al., 1976), and Streptococcus
hemolyticus in mice (Lloyd-Davies, 1946). In general, Mn concentrations were
relatively high (>10 mg/cu.m) in these studies. However, Adkins et al. (1980)
concluded that, based on the regression line of the relationship between
concentration and mortality in Mn-exposed mice, exposure to <0.62 mg/cu.m
would result in a mortality rate that differed from controls by at least 10%.
The developmental effects of Mn have been investigated primarily from the
viewpoint of the nutritional role of this element and therefore have generally
involved oral exposure. Some studies indicate that neonates of various
species have a greater body burden of Mn than mature individuals have,
possibly because neonates do not develop the ability to eliminate Mn--and
thereby maintain Mn homeostasis--until some time after birth (Miller et al.,
1975; Cotzias et al., 1976; Wilson et al., 1991). Moreover, some evidence
suggests that the neonate's inability to maintain Mn homeostasis is due to a
limitation in the elimination of Mn rather than in its gastrointestinal
absorption (Bell et al., 1989), which would suggest a potentially greater
vulnerability of young individuals to excessive Mn exposure regardless of the
route of exposure.
Several studies have demonstrated neurochemical alterations in young rats
and mice exposed postnatally to Mn by routes other than inhalation (e.g.,
Kontur and Fechter, 1988; Seth and Chandra, 1984; Deskin et al., 1981; Cotzias
et al., 1976). The only inhalation study of the developmental toxicity of Mn
appears to be that of Lown et al. (1984). Female mice were exposed to MnO2 7
hours/day, 5 days/week for 16 weeks prior to conception and for 17 days
following conception (i.e., gestational days 1-18). For the first 12 weeks,
the air concentration was 49.1 mg Mn/cu.m; all later exposures were at 85.3 mg
Mn/cu.m. To separate prenatal and postnatal exposure effects, a cross-
fostering design was used. Although mothers exposed to MnO2 prior to
conception produced significantly worse pups per litter, prenatally exposed
offspring showed reduced scores on various activity measures (open field,
roto-rod, and exploration) and retarded growth that persisted into adulthood.
A decrease in roto-rod performance was also observed in the offspring of
nonexposed mice that were fostered to Mn-exposed females during lactation.
Thus, balance and coordination were affected by either gestational or
postpartum exposure to MnO2.
__I.B.5.
Confidence in the Inhalation RfC
Study — Medium
Database — Medium
RfC — Medium
Confidence in the principal studies (Roels et al., 1987, 1992) is medium.
Neither of the principal studies identified a NOAEL for neurobehavioral
effects, nor did either study directly measure particle size or provide
information on the particle size distribution. The 1992 study by Roels et al.
did provide respirable and total dust measurements, but the 1987 study
measured only total dust. These limitations of the studies are mitigated by
the fact that the principal studies found similar indications of
neurobehavioral dysfunction, and these findings were consistent with the
results of other human studies (Mergler et al., 1993; Iregren, 1990; Wennberg
et al., 1991, 1992; as well as various clinical studies). In addition, the
exposure history of the workers in the 1992 study by Roels et al. was well
characterized and essentially had not changed over the preceding 15 years,
thereby allowing calculation of integrated exposure levels for individual
workers. However, individual integrated exposures were not established in the
1987 study of Roels et al.
Confidence in the database is medium. The duration of exposure was
relatively limited in all of the principal and supporting studies, ranging
from means of 5.3 and 7.1 years in the co-principal studies by Roels et al.
(1992 and 1987, respectively) to a maximum of 16.7 years in the study by
Mergler et al. (1993). Moreover, the workers were relatively young, ranging
from means of 31.3 and 34.3 years in the co-principal studies (Roels et al.,
1992 and 1987, respectively) to a maximum of 46.4 years (Iregren, 1990).
These temporal limitations raise concerns that longer durations of exposure
and/or interactions with aging might result in the detection of effects at
lower concentrations, as suggested by results from studies involving longer
exposure durations and lower concentrations (Mergler et al., 1993; Iregren,
1990). In addition, except for the 1992 study by Roels et al., in which Mn
exposure was limited to MnO2, the other principal and supporting studies did
not specify the species of Mn and the proportions of the different compounds
of Mn to which workers were exposed. It is not clear whether certain
compounds or oxidation states of Mn are more toxic than others. Thus, it is
not possible to distinguish the relative toxicity of different Mn compounds in
these studies, despite some indications in the literature regarding the
differential toxicity of various oxidation states of Mn. Although the primary
neurotoxicological effects of exposure to airborne Mn have been qualitatively
well characterized by the general consistency of effects across studies, the
exposure-effect relationship remains to be well quantified, and a no-effect
level for neurotoxicity has not been identified in any of these studies thus
far. Finally, the effects of Mn on development and reproduction have not been
studied adequately. Insufficient information on the developmental toxicity of
Mn by inhalation exposure exists, and the same is true for information on
female reproductive function. The study of the reproductive toxicity of
inhaled Mn in males also needs to be characterized more fully.
Reflecting medium confidence in the principal studies and medium
confidence in the database, confidence in the inhalation RfC is medium.
__I.B.6.
EPA Documentation and Review of the Inhalation RfC
Source Document — This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation — U.S. EPA, 1984
Agency Work Group Review — 08/23/1990, 09/19/1990, 09/23/1993
Verification Date — 09/23/1993
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Manganese conducted in September 2002 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__I.B.7.
EPA Contacts (Inhalation RfC)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general,
at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov
(internet address).
Top of page
_II.
Carcinogenicity Assessment for Lifetime Exposure
Substance Name — Manganese
CASRN — 7439-96-5
Last Revised — 12/01/1996
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
NOTE: Manganese is an element considered essential to human health.
_II.A.
Evidence for Human Carcinogenicity
__II.A.1.
Weight-of-Evidence Characterization
Classification — D; not classifiable as to human carcinogenicity
Basis — Existing studies are inadequate to assess the carcinogenicity of
manganese.
__II.A.2.
Human Carcinogenicity Data
None.
__II.A.3.
Animal Carcinogenicity Data
Inadequate. DiPaolo (1964) subcutaneously or intraperitoneally injected
DBA/1 mice with 0.1 mL of an aqueous of solution 1% manganese chloride twice
weekly for 6 months. A larger percentage of the mice exposed subcutaneously
(24/36; 67%) and intraperitoneally (16/39; 41%) to manganese developed
lymphosarcomas compared with controls injected with water (16/66; 24%). In
addition, tumors appeared earlier in the exposed groups than in the control
groups. The incidence of tumors other than lymphosarcomas (i.e., mammary
adenocarcinomas, leukemias, injection site tumors) did not differ
significantly between the exposed groups and controls. A thorough evaluation
of the results of this study was not possible because the results were
published in abstract form.
Stoner et al. (1976) tested manganous sulfate in a mouse lung adenoma
screening bioassay. Groups of strain A/Strong mice (10/sex), 6-8 weeks old,
were exposed by intraperitoneal injection to 0, 6, 15 or 30 mg/kg manganous
sulfate 3 times/week for 7 weeks (a total of 21 injections). The animals were
observed for an additional 22 weeks after the dosing period, before sacrifice
at 30 weeks. Lung tumors were observed in 12/20, 7/20, and 7/20 animals in
the high, medium, and low dosage groups, respectively. The percentage of mice
with tumors was elevated, but not significantly, at the highest dose level
(Fisher Exact test) compared with that observed in the vehicle controls. In
addition, there was an apparent increase in the average number of pulmonary
adenomas per mouse both at the mid and high doses, as compared with the
vehicle controls (10 mice/sex), but the increase was significant only at the
high dose (Student's t-test, p<0.05).
In the mouse lung adenoma bioassay, certain specific criteria should be
met in order for a response to be considered positive (Shimkin and Stoner,
1975). Among these criteria are an increase in the mean number of tumors per
mouse and an evident dose-response relationship. While the results of this
study are suggestive of carcinogenicity, the data cannot be considered
conclusive since the mean number of tumors per mouse was significantly
increased at only one dose, and the evidence for a dose-response relationship
was marginal.
Furst (1978) exposed groups of F344 rats (25/sex) intramuscularly or by
gavage to manganese powder, manganese dioxide, and manganese (II)
acetylacetonate (MAA). Treatment consisted of either 9 i.m. doses of 10 mg
each of manganese powder or manganese dioxide, 24 doses of 10 mg manganese
powder by gavage, or 6 i.m. doses of 50 mg of MAA. In addition, female swiss
mice (25/group) were exposed intramuscularly to manganese powder (single 10 mg
dose) and manganese dioxide (6 doses of 3 or 5 mg each). There was an
increased incidence of fibrosarcomas at the injection site in male (40%) and
female (24%) rats exposed intramuscularly to MAA compared with vehicle
controls (4% male, 4% female). EPA (1984) determined that these increases
were statistically significant and noted that the study results regarding MAA,
an organic manganese compound, cannot necessarily be extrapolated to pure
manganese or other inorganic manganese compounds. No difference in tumor
incidence was found between rats and mice exposed to manganese powder and
manganese dioxide and controls.
Sunderman et al. (1974, 1976) exposed male 344 rats to 0.5 to 4.4 mg
manganese dust intramuscularly and found that no tumors were induced at the
injection site. It was further observed that co-administration of manganese
with nickel subsulfide resulted in decreased sarcoma production by comparison
to nickel subsulfide alone. Subsequent studies by Sunderman et al. (1980)
suggest that manganese dust may inhibit local sarcoma induction by
benzo(a)pyrene.
Witschi et al. (1981) exposed female A/J mice intraperitoneally to 80
mg/kg methylcyclopentadienyl manganese tricarbonyl (MMT) and found that
although cell proliferation was produced in the lungs, lung tumor incidence
did not increase.
__II.A.4.
Supporting Data for Carcinogenicity
None.
Top of page
_II.B.
Quantitative Estimate of Carcinogenic Risk from Oral Exposure
Not available.
Top of page
_II.C.
Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure
Not available.
Top of page
_II.D.
EPA Documentation, Review, and Contacts (Carcinogenicity Assessment)
__II.D.1.
EPA Documentation
Source Document — U.S. EPA, 1984, 1988
The Drinking Water Criteria Document for Manganese has received OHEA review.
__II.D.2.
EPA Review (Carcinogenicity Assessment)
Agency Work Group Review — 05/25/1988
Verification Date — 05/25/1988
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Manganese conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__II.D.3.
EPA Contacts (Carcinogenicity Assessment)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general,
at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov
(internet address).
Top of page
_III.
[reserved]
_IV. [reserved]
_V. [reserved]
_VI.
Bibliography
Substance Name — Manganese
CASRN — 7439-96-5
Last Revised — 11/01/1995
_VI.A. Oral RfD References
Aschner, M. and J.L. Aschner. 1991. Manganese neurotoxicity: Cellular
effects and blood-brain barrier transport. Neurosci. Behav. Rev. 15: 333-
340.
Banta, R.G. and W.R. Markesbery. 1977. Elevated manganese levels associated
with dementia and extrapyramidal signs. Neurology. 27: 213-216.
Barlow, P.J. and M. Kapel. 1979. Hair metal analysis and its significance to
certain disease conditions. 2nd Ann. Trace Minerals Health Seminar, Boston,
MA.
Cawte, J. and M.T. Florence. 1989. A manganic milieu in North Australia:
Ecological manganism: Ecology; diagnosis; individual susceptibility;
synergism; therapy; prevention; advice for the community. Int. J. Biosocial
Med. Res. 11(1): 43-56.
Chandra, S.V. and G.S. Shukla. 1981. Concentrations of striatal
catecholamines in rats given manganese chloride through drinking water. J.
Neurochem. 36(2): 683-687.
Collipp, P.J., S.Y. Chen and S. Maitinsky. 1983. Manganese in infant
formulas and learning disability. Ann. Nutr. Metab. 27: 488-494.
Davidsson, L., A. Cederblad, B. Lonnerdal and B. Sandstrom. 1989. Manganese
retention in man: A method for estimating manganese absorption in man. Am. J.
Clin. Nutr. 49: 170-179.
Devenyi, A.G., T.F. Barron and A.C. Mamourian. 1994. Dystonia, hyperintense
basal ganglia, and high whole blood manganese levels in Alagille's syndrome.
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Top of page
_VI.B.
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manganese poisoning: Clearance of tissue manganese concentrations with
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Deskin, R., S.J. Bursian, and F.W. Edens. 1981. The effect of chronic
manganese administration on some neurochemical and physiological variables in
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Donaldson, J., T. St. Pierre, J.L. Minnich, and A. Barbeau. 1973.
Determination of Na+, K+, Mg2+, Cu2+, Zn2, and Mn2 in rat brain regions. Can.
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on the respiratory organs of air pollution consisting of dusts composed mainly
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Davis, Environmental Criteria and Assessment Office (MD-52), U.S. EPA,
Research Triangle Park, NC 27711, October 19.
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1978. Effects of the inhalation of manganese dioxide dust on monkey lungs.
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Top of page
_VI.C.
Carcinogenicity Assessment References
DiPaolo, J.A. 1964. The potentiation of lymphosarcomas in mice by manganous
chloride. Fed. Proc. 23: 393. (Abstract).
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013F.
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tumor development in A/J mice. Toxicology. 21: 37-45.
Top of page
_VII.
Revision History
Substance Name — Manganese
CASRN — 7439-96-5
Date |
Section |
Description |
09/26/1988 |
II. |
Carcinogen summary on-line |
09/01/1989 |
VI. |
Bibliography on-line |
06/01/1990 |
I.A. |
Oral RfD now under review |
08/01/1990 |
I.A. |
Oral RfD summary on-line |
08/01/1990 |
II. |
Text edited |
08/01/1990 |
VI. |
Oral RfD references added |
09/01/1990 |
I.B. |
Inhalation RfC now under review |
12/06/1990 |
I.B. |
Inhalation RfC on-line |
12/06/1990 |
VI.B. |
Inhalation RfC references added |
01/01/1992 |
IV. |
Regulatory Action section on-line |
06/01/1992 |
VI.B. |
Iregren, 1990 and Nishiyama et al., 1975 pages corrected |
08/01/1992 |
I.A. |
Oral RfD noted as pending change |
08/01/1992 |
I.A.6. |
Work group review date added |
10/01/1992 |
I.A. |
Oral RfD withdrawn; new summary in preparation |
10/01/1992 |
I.A.6. |
Work group review date added |
10/01/1992 |
VI.A. |
Oral RfD references withdrawn |
01/01/1993 |
I.A. |
Oral RfD replaced (RfD changed) |
01/01/1993 |
VI.A. |
Oral RfD references replaced |
05/01/1993 |
I.A. |
Work group review date added |
07/01/1993 |
II.A.3. |
'Inadequate' added to 1st paragraph |
07/01/1993 |
II.D.1. |
EPA Documentation clarified |
11/01/1993 |
I.B. |
Inhalation RfC noted as pending changed |
11/01/1993 |
I.B.6. |
Work group review date added |
12/01/1993 |
I.B. |
Inhalation RfC replaced; RfC changed |
12/01/1993 |
VI.B. |
Inhalation RfC references replaced |
01/01/1994 |
I.A. |
Oral RfD noted as pending change |
01/01/1994 |
I.A.6. |
Work group review date added |
03/01/1994 |
II.D.3. |
Primary contact changed |
04/01/1994 |
I.A.2. |
Text revised |
04/01/1994 |
I.A.3. |
Text revised |
04/01/1994 |
I.A.4. |
Text revised |
04/01/1994 |
I.A.5. |
Text revised |
04/01/1994 |
VI.A. |
Oral RfD references revised |
06/01/1995 |
I.A. |
Oral RfD noted as pending change |
06/01/1995 |
I.A.6. |
Work group review date added |
08/01/1995 |
I.A., I.A.6. |
EPA's RfD/RfC and CRAVE workgroups were discontinued in May,
1995. Chemical substance reviews that were not completed by
September 1995 were taken out of IRIS review. The IRIS Pilot
Program replaced the workgroup functions beginning in
September, 1995. |
11/01/1995 |
I.A. |
Oral RfD assessment replaced |
11/01/1995 |
VI.A. |
Oral RfD assessment replaced |
05/01/1996 |
I.A.7. |
Secondary contact's phone number changed |
12/01/1996 |
II.D.3. |
Primary contact removed |
04/01/1997 |
III., IV., V. |
Drinking Water Health Advisories, EPA Regulatory Actions, and
Supplementary Data were removed from IRIS on or before April
1997. IRIS users were directed to the appropriate EPA Program
Offices for this information. |
12/03/2002 |
I.A.6., I.B.6., II.D.2. |
Screening-Level Literature Review Findings message has been added. |
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_VIII.
Synonyms
Substance Name — Manganese
CASRN — 7439-96-5
Last Revised — 09/26/1988
- 7439-96-5
- COLLOIDAL MANGANESE
- MAGNACAT
- MANGAN
- Manganese
- MANGAN NITRIDOVANY
- TRONAMANG
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