Review Article

Indian J Med Res 128, October 2008, pp 484-500

Manganese exposure, essentiality & toxicity

A. B. Santamaria

ENVIRON International Corporation, Houston, Texas, USA

Received May 29, 2008

Manganese (Mn) is an essential element present in all living organisms and is naturally present in
rocks, soil, water, and food. Exposure to high oral, parenteral, or ambient air concentrations of Mn
can result in elevations in Mn tissue levels and neurological effects. However, current understanding
of the impact of Mn exposure on the nervous system leads to the hypothesis that there should be no
adverse effects at low exposures, because Mn is an essential element; therefore, there should be
some threshold for exposure above which adverse effects may occur and adverse effects may increase
in frequency with higher exposures beyond that threshold. Data gaps regarding Mn neurotoxicity
include what the clinical significance is of the neurobehavioural, neuropsychological, or neurological
endpoints measured in many of the occupational studies that have evaluated cohorts exposed to
relatively low levels of Mn. Specific early biomarkers of effect, such as subclinical neurobehavioural
or neurological changes or magnetic resonance imaging (MRI) changes have not been established or
validated for Mn, although some studies have attempted to correlate biomarkers with neurological
effects. Experimental studies with rodents and monkeys provide valuable information about the
absorption, bioavailability, and tissue distribution of various Mn compounds with different
solubilities and oxidation states in different age groups. Studies have shown that rodents and primates
maintain stable tissue manganese levels as a result of homeostatic mechanisms that tightly regulate
absorption and excretion. In addition, physiologically based pharmacokinetic (PBPK) models are
being developed to provide for the ability to conduct route-to-route extrapolations, evaluate nasal
uptake to the CNS, and evaluate lifestage differences in Mn pharmacokinetics. Such models will
facilitate more rigorous quantitative analysis of the available pharmacokinetic data for Mn and will
be used to identify situations that may lead to increased brain accumulation related to altered Mn
metabolism in different human populations, and develop quantitatively accurate predictions of
increased Mn levels that may serve as a basis of dosimetry-based risk assessments. Such assessments
will permit for the development of more scientifically refined and robust recommendations, guidelines,
and regulations for Mn levels in the ambient environment and occupational settings.

Key words Biomarkers - manganism - manganese - neurological effects - neurotoxicity

Introduction for humans, animals, and plants, and is required for

Manganese (Mn) is the twelfth most abundant growth, development, and maintenance of health. There
element in the earth’s crust and is naturally present in are inorganic and organic Mn compounds, with the
rocks, soil, water, and food. Mn is an essential element inorganic forms being the most common in the
484
 SANTAMARIA: MANGANESE TOXICITY
environment. Uses of Mn include: (i) iron and steel
production; (ii) manufacture of dry cell batteries; (iii)
production of potassium permanganate and other Mn
chemicals; (iv) oxidant in the production of
hydroquinone; (v) manufacture of glass; (vi) textile
bleaching; (vii) oxidizing agent for electrode coating
in welding rods; (viii) matches and fireworks; and (ix)
tanning of leather1. Organic compounds of Mn are
present in the fuel additive, methylcyclopentadienyl
manganese tricarbonyl (MMT), fungicides (e.g., maneb
and mancozeb), and in contrast agents used in magnetic
resonance imaging. Mn is naturally present in food, with
the highest concentrations typically found in nuts,
cereals, legumes, fruits, vegetables, grains, and tea - it
is also present at low levels in drinking water2,3. Typical,
daily intakes range from 2-9 mg/day for adults and
approximately 3-5 per cent is absorbed from the
gastrointestinal tract3. Absorption of Mn from the diet
occurs in the divalent and tetravalent state4. Mangenese
balance studies and excretion data indicate that low
gastrointestinal absorption and rapid elimination of Mn
limits the toxicity of the Mn following the ingestion of
high doses4. Chronic inhalation exposure to relatively
high levels of Mn has been associated with adverse
neurological effects and a few studies have reported
the same following the ingestion of high levels or
chronic exposure to Mn in drinking water3,5. Clinical
Mn neurotoxicity has been reported in patients receiving
long-term parenteral nutrition and in patients with
chronic liver dysfunction or renal failure, as a result of
their inability to eliminate and clear Mn from the blood6-10.
The primary anthropogenic sources of Mn in ambient
air include emission of Mn from industrial sources such
as ferroalloy production plants, iron and steel foundries,
power plants, and coke ovens and reentrainment of soils
containing Mn3,4,11. The background levels of Mn in rural
and urban areas without point sources of Mn range from
about 0.005-0.07 µg Mn/m3, while average ambient air
levels of Mn near industrial sources range from 0.13-
0.3 µg Mn/m3,4,5. Exposure to Mn from the erosion of
soil is the most important natural source of Mn in the
ambient air, but little data are available to estimate the
contribution of Mn in ambient air from this source.
Higher inhalation exposures may be experienced in
occupational settings such as Mn mines, foundries,
smelters, and battery manufacturing facilities.
Manganese essentiality
Mn is necessary for a variety of metabolic functions
including those involved in skeletal system
development, energy metabolism, activation of certain
485
enzymes, nervous system function, immunological
system function, and reproductive hormone function, and
is an antioxidant that protects cells from damage due to
free radicals3,12. Mn also plays an essential role in
regulation of cellular energy, bone and connective tissue
growth and blood clotting13. In the brain, Mn is an
important cofactor for a variety of enzymes, including
the antioxidant enzyme superoxide dismutase, as well as
enzymes involved in neurotransmitter synthesis and
metabolism14. Manganese has three primary metabolic
functions: (i) it acts as an activator of the gluconeogenic
enzymes pyruvate carboxylase and isocitrate
dehydrogenase, (ii) it is involved in protecting
mitochondria1 membranes through superoxide
dismutase; and (iii) it activates glycosyl transferase,
which is involved in mucopolysaccharide synthesis15.
The most important source of Mn for the general
population is diet, and the average intake of Mn from
food ranges from 2 to 9 mg/day3. In addition, vitamin
and mineral supplements may contain 1 to 20 mg Mn/
tablet16. The Food and Nutrition Board of the National
Research Council (NRC) determined that insufficient
information exists to develop a recommended daily
allowance (RDA) for Mn, but sufficient information is
available to provide estimated safe and adequate daily
dietary intake (ESADDI) levels for various age groups.
The ESADDI for adolescents and adults ranges from 2
to 5 mg/day and for infants and children up to age 10,
the ESADDI levels range from 0.3 to 2 mg/day12.
Manganese deficiency has been demonstrated in
several species, including rats, mice, pigs, chickens, and
cattle, and can result in several biochemical and
structural defects in experimental animals 17,18 .
Manganese deficiency in animals has significant effects
on the production of hyaluronic acid, chondroitin
sulphate, heparin, and other forms of
mucopolysaccharides that are important for growth and
maintenance of connective tissue, cartilage, and bone15.
The consequences of Mn deficiency include altered
carbohydrate metabolism, reduced glucose metabolism,
abnormal lipid metabolism, and impaired insulin
synthesis and action18.
Only a few instances of Mn deficiencies have been
reported in humans, with symptoms including
dermatitis, slowed growth of hair and nails, decreased
serum cholesterol levels, and decreased levels of clotting
proteins3,19,20. Friedman et al20 induced Mn deficiency
in adult male subjects by administering a diet deficient
in Mn for 39 days. The subjects developed a temporary
dermatitis, increased serum calcium and phosphorous
486 INDIAN J MED RES, OCTOBER 2008
concentrations, and increased alkaline phosphate
activity suggestive of bone resorption18. In addition,
several diseases have been reported to be characterized
by low blood Mn concentrations, including epilepsy,
mseleni disease, Down’s syndrome, osteoporosis, and
Perthest disease18. Manganese deficiency has also been
cited as a possible aetiologic factor for some congenital
malformations and several inborn errors of metabolism
have been associated with poor Mn status (e.g.,
phenylketonuria, maple syrup urine disease)18. The
finding of low blood Mn levels in subsets of individuals
with some of these diseases is significant, because blood
Mn levels can reflect soft tissue Mn concentrations18,
however, the role of Mn deficiency in these diseases is
unclear.
Dietary studies have demonstrated that daily
intakes of high doses of Mn can be safely tolerated by
healthy adults21. Davis and Greger22 treated women
with supplements containing 15 mg of Mn/day for 124
days and reported only elevated plasma Mn
concentrations and lymphocyte Mn superoxide
dismutase activity. Urinary Mn, an excretory route that
becomes more important at high Mn intakes, was not
elevated in the treated subjects. In a study conducted
by Finley et al23 women were treated with either <1 or
9.5 mg Mn/day for 60 days. They reported that the
high treatment group subjects had decreased
absorption and increased excretion of Mn. In a follow
up study, female subjects were fed 1.0 or 20 mg Mn/
day for 60 days to determine whether diets containing
very low or very high amounts of Mn and enriched in
either saturated or unsaturated fats affected measures
of neuropsychological and basic metabolic function19.
Subjects were administered a battery of psychological
tests and neurological exams before and after dietary
periods. In addition, 54Mn whole-body counting was
used to estimate Mn absorption retention and turnover.
Measures of Mn in plasma and lymphocytes were not
affected by dietary Mn and the efficiency of Mn
absorption and biologic half-life were almost twice as
great in subjects in the low dietary Mn group than in
subjects in the high dietary Mn group, demonstrating
homeostatic control of Mn retention and excretion.
There was no association between Mn intake and
performance on neurological tests. The authors
concluded that efficient mechanisms operate to
maintain Mn homeostasis over a broad range of Mn
intake levels that may be encountered in the diet and
dietary intakes of Mn from 0.8 to 20 mg for 8 wk do
not result in Mn toxicity in healthy adults19.
Manganese toxicity
It has long been known that Mn, an essential
element for humans and the fourth most widely used
metal in the world, is a neurotoxic substance. But just
as in the case of any chemical substance, the dose makes
the poison; therefore, Mn toxicity has primarily been
observed in occupational settings where there is the
potential for chronic exposure to high levels or
following the accidental ingestion of large quantities.
John Couper was the first to report neurological effects
associated with exposure to Mn in the scientific
literature in 1837, when he described muscle weakness,
limb tremor, whispering speech, salivation, and a bent
posture in five men working in a Mn ore crushing plant
in France 24. He called this collection of symptoms
“manganese crusher’s disease”, which was later
recognized as “manganism”. Chronic inhalation of high
levels of Mn has been associated with a
neurodegenerative disorder characterized by both
central nervous system abnormalities and
neuropsychiatric disturbances. Historically, Mn
neurotoxicity has been most commonly associated with
occupations such as Mn mining and smelting, battery
manufacturing, and steel production25. The brain is
particularly susceptible to excess Mn. In humans, it has
been postulated that there is a spectrum of
neurobehavioural and neurophysiological effects
associated with Mn toxicity, including both subclinical
and clinical symptoms 26. However, a recent meta-
analysis of 19 studies that evaluated neuropsychological
effects in Mn-exposed workers by Greiffenstein and
Lees Haley27 reported a lack of scientific support for
the existence of “preclinical” neuromotor or cognitive
dysfunction or the “continuum hypothesis” of
neurotoxicity in Mn-exposed individuals. The authors
concluded that the neurobehavioural effects reported
to be associated with Mn-exposure in the studies were
more likely due to covariate effects27. In addition, a few
studies have reported adverse haematological,
endocrine, or male reproductive effects following
occupational exposure to Mn3,28-36.
Manganism is a neurological syndrome that
resembles Parkinson’s disease (PD), but there is
considerable evidence that Mn preferentially damages
different areas of the brain from those that are affected
in PD 37,38 . The similarities between the clinical
manifestations of Parkinson’s disease and manganism
include the presence of generalized bradykinesia and
widespread rigidity and dissimilarities include less-
frequent resting tremor, more frequent dystonia,
 SANTAMARIA: MANGANESE TOXICITY
symmetry of effects, a particular propensity to fall
backward, a characteristic “cock-walk”, in which
patients walk on their toes with elbows flexed and spine
erect in manganism37. The similarities between the two
disorders can be partially explained by the fact that the
basal ganglia accumulate most of the excess Mn
compared with other brain regions in manganism, and
dysfunction in the basal ganglia is involved in
Parkinson’s disease39. Parkinson’s disease is primarily
associated with the loss of dopaminergic neurons within
the substantia nigra, allowing the caudate and putamen
to become overly active and possibly cause continuous
output of excitatory signals to the corticospinal motor
control system 40. The substantia nigra is spared in
manganism, which is linked to the degeneration of
GABAminergic neurons within the globus pallidus in
pathways postsynaptic to the nigrostriatal system9,41.
There are a few imaging procedures that may be used
to distinguish manganism from Parkinson’s disease,
including positron emission tomography (PET),
computerized tomography (CT), and magnetic
resonance imaging (MRI). The CTs and MRIs are
typically normal in Parkinson’s disease patients,
whereas the PET is abnormal in patients with
Parkinson’s disease 37 . PET provides a means of
discriminating between Parkinson’s disease and
manganism, as there is typically a reduced uptake of
18
F-6-fluorodopa in the striatum of Parkinson’s disease
patients due to the loss of dopaminergic cells in the
nigrostriatal pathway, whereas PET is generally normal
in manganism37,38. Manganism is generally associated
with hyperintense signal abnormalities in the globus
pallidus, striatum, and substantia nigra bilaterally on
an MRI, whereas the MRI is normal in Parkinson’s
disease patients38,42,43. There are also differences with
respect to treatment response – although there may be
an initial response to levodopa, the primary treatment
option for Parkinson’s disease, there is typically a failure
to achieve a sustained therapeutic response in patients
with manganism37.
A critical first step in understanding the role that
Mn plays in neurotoxicity is to determine exposure
conditions that lead to increased concentrations of the
metal within the central nervous system 44 . This
understanding is especially critical for Mn, because its
mechanism of toxicity is poorly understood. Many
experimental studies have been conducted to evaluate
several fundamental issues of Mn toxicity, including
the absorption and bioavailability of various chemical
forms of Mn following ingestion or inhalation exposure,
487
mechanism(s) of toxicity, types of neurological effects,
dose-response relationship, the tissue distribution of
Mn, and homeostatic regulation of inhaled and ingested
Mn. Most animal models are inadequate for evaluating
the types of neurological effects observed in humans,
making it difficult to study the mechanism(s) involved
and to elucidate a dose-response relationship for
neurotoxicity. There have been a few systematic
attempts to study the effects of Mn on behaviour using
animal models, and most of the studies have focused
on evaluating the neurochemical effects of Mn41,45. The
clinical neurological effects observed in manganism has
been observed in studies with non-human primates41,45-49.
Early studies used extremely high doses of Mn in
attempting to mimic human exposure while more recent
studies have used lower doses for longer periods of
exposure and in general, the behavioural,
neurochemical, and neuropathological findings in
primates agree strongly with findings documented in
the human literature14. One study that reported similar
neurological effects to those observed in humans with
manganism involved the administration of high doses
of Mn oxide subcutaneously in monkeys for 5 months
(total of 8 g Mn), causing dystonic posture, hyperactivity
with an unsteady gait, and an action tremor at the high
exposure levels47. The serum concentration of Mn rose
10-40 times during the exposure period and the content
in brain was generally increased more than 10 times,
with the highest concentration found in the globus
pallidus and putamen. Although these observations
provide some information about Mn neurotoxicity, the
dose was very high and the route of administration
makes it difficult to extrapolate these results to humans.
In order to address many of the critical data gaps
regarding the dose-response relationships for subclinical
or clinical effects in humans exposed to Mn, researchers
have used a variety of sensitive neurophysiological,
neuropsychological, and neurobehavioural methods to
identify early nervous system alterations in a variety of
occupational settings, including welding, mining, and
ferroalloy, steel, and dry alkaline battery manufacturing.
The types of subclinical neuromotor or
neurobehavioural symptoms reported in the workers
exposed to Mn include decreased motor functions, mood
alterations, decreased hand steadiness, insomnia,
decreased eye-hand co-ordination, increased tremor,
decreased response speed, limb paresthesia and
decreased memory. There is not a general consensus
on what is the most sensitive neurological endpoint for
subclinical Mn toxicity, although Mergler and Baldwin50
488 INDIAN J MED RES, OCTOBER 2008
report that the motor tasks that appear to be the most
sensitive to Mn exposure are those that require the
participant to perform co-ordinated, sequential,
alternating movements at maximum speed. Iregren51
suggested that the ability to repeat simple movements
might be particularly sensitive to Mn exposure and
emphasized the need for investigations to study early
signs of Mn neurotoxicity by the use of behavioural
methods in groups of active workers before the onset
of clinically observable symptoms. Some investigators
report that neuropsychological tests are more sensitive
than neurological tests, and that subtle deficits detected
by neuropsychological testing are precursors of more
serious, clinical neurological effects such as
manganism51,52.
In order to identify a dose-response for Mn
neurotoxicity, Lees-Haley et al53 conducted a meta-
analysis of 20 peer-reviewed published
neuropsychological studies that evaluated the cognitive,
psychological, motor, and sensory/perceptual effects of
exposure to Mn in 1,410 exposed subjects and 1,322
controls. These studies included Mn workers employed
in a variety of industries, including Mn milling and
mining, Mn ferroalloy plants, MnO2 salt plants, welding,
and battery manufacturing. The authors focused on
neuropsychological effects, because many studies of Mn-
exposed workers were conducted to evaluate those
endpoints in asymptomatic workers to develop early
detection methods or measures of “subclinical”
neurological effects. Dose-response relationships were
evaluated for neuropsychological effects and several
parameters, including: (i) measures of Mn levels in air
and dust; (ii) reported years of exposure; (iii) blood Mn
levels; (iv) urine Mn; and (v) hair Mn. A statistically
significant weighted mean effect size of -0.17, suggestive
of impairment, was calculated for neuropsychological
symptoms and Mn exposure (defined as exposed to Mn
at the time of the respective study). However, there were
no significant associations between neuropsychological
effects and (i) years of exposure, (ii) levels of Mn in air,
(iii) Mn concentration in blood, or (iv) Mn levels in urine.
The authors concluded that occupational exposure to Mn
at levels that typically occur in the milling and mining,
ferroalloy, MnO 2 salt, and battery manufacturing
industries may exert a small deleterious effect on
cognitive and sensory motor performance, which may
be detectable in population studies; however, it is
generally too small to be detected in any one individual
through current clinical assessment, and it is not clear
that such effects possess any clinical significance.
In a subsequent study, Greiffenstein and Lees-
Haley 27 conducted a meta-analysis on 41
neuropsychological variables from 19 studies that
evaluated Mn-exposed workers. The authors reported
that the Mn cognition literature shows substantially
conflicting results because of several reasons, including
(i) studies differ widely in neuropsychological tasks
selected, (ii) the total number of measures, (iii) sample
size, (iv) subject demographics, (v) cultural context, (vi)
subjective versus objective data, (vii) amount of
exposure, industrial context, and (viii) weak/normal
neuropsychological patterns. The purpose of the meta-
analysis was to quantify the association between
occupational Mn exposure, neurocognitive tests, and
potentially confounding demographics by pooling data
from relevant studies. Greiffenstein and Lees-Haley27
calculated effect sizes (ES) between Mn exposed and
non-exposed referent groups for five types of variables,
including specific neuropsychological tasks, preclinical
neurological indicators, biological body burden, subject
(demographic) variables, and dose-response
correlations. In contrast to Lees-Haley et al53 study, the
goal of this study was to examine the association
between specific neurobehavioural measures and
various covariates such as demographics as they relate
to the basal ganglia theory of Mn exposure. This study
improves on the meta-analysis by Lees-Haley et al53 in
that it included more recent research and previously
unpublished studies, included only occupational studies
involving inhalation exposure, excluded studies that
only included former workers involved in workplace-
related litigation, and was more focused on evaluating
the effects of confounding variables such as cognitive
ability and education. Two general hypotheses were
evaluated: (i) if low-dose Mn exposure is associated
with neurocognitive deficits, the effect size for specific
tasks should exceed the ES accounted for by subject
variables such as education, and psychometric
intelligence and, (ii) any significant ES for motor tasks
without cognitive components should exceed those for
tasks with cognitive components, if the “early
Parkinson” model of Mn-neurotoxicity is feasible. The
results of the analysis did not support either hypothesis.
Overall, there was no relationship between Mn in the
blood, urine, or air and neuropsychological function
identified in this analysis. The authors reported that a
small group of tests showed minor strength of
association with exposure-group membership; all test
scores lacked a dose-response relation to internal or
external Mn levels; subject variables showed medium
ES in a direction unfavourable to exposed worker
 SANTAMARIA: MANGANESE TOXICITY 489

groups; and neuromotor symptom tasks generally had Data gaps regarding Mn neurotoxicity remain,
lower or no ES values. The authors concluded that the including what the clinical significance is of the
data do not support a theory of preclinical or early neurobehavioural, neuropsychological, or neurological
neuromotor or cognitive dysfunction in Mn-exposed endpoints measured in many of the studies that have
workers and the pooled data are more consistent with evaluated Mn-exposed cohorts and the mechanism(s)
effects of confounding variables such as demographic of neurotoxicity. Experimental studies with rodents and
and biological covariates rather than Mn exposure. The monkeys provide valuable information about the
main implication of their findings was that demographic absorption, bioavailability, and tissue distribution of
variables remain important covariates in the various Mn compounds with different solubilities and
epidemiological studies that have evaluated oxidation states44,69-74. Data from such studies may be
neurobehavioural effects in Mn-exposed subjects. used to determine Mn-tissue levels associated with
adverse effects to develop a dose-response evaluation
Because of the potential for exposure to Mn during
for Mn neurotoxicity. In rats, increases in brain Mn
most types of welding activities, several studies have
delivery were observed with inhalation exposure
also been conducted to evaluate neurological effects in
following Mn absorption from the pulmonary tract and
welders 54-60 . The primary effects reported to be
direct transport of Mn to the central nervous system
associated with Mn exposure in welders include
along the olfactory nerve44,75,76. However, the relevance
subclinical neuropsychological and neurophysiological
of this route of delivery of Mn to the brain in humans is
effects such as insomnia, decreased motor function,
not clear because of the many physiological differences
decreased reaction time, reduced memory and
in the olfactory system and the brain between rodents
concentration, mood changes, limb paresthesias,
and humans. Differences in the relative size of the rat
abnormities in visual evoked potentials, reduced verbal
olfactory mucosa and olfactory bulb likely predispose
learning, and reduced cognitive flexibility. The very few
rats, more so than humans, to nasal deposition and
studies that report both Mn exposure data and indices
olfactory transport of Mn44. Although the rat is a good
of neurological deficits in welder populations do not
animal model for olfactory transport, it is a poor model
provide sufficient data to establish a dose–response
for Mn neurotoxicity in humans 44 . The form and
relationship or identify a threshold for neurological
solubility of Mn have been shown to impact the rate of
effects55-58,60. In addition, many of the subclinical effects
clearance from the lung and subsequent delivery to the
reported in the various Mn-exposed cohorts have the
brain. Dorman et al71 reported that inhalation exposure
potential for multiple aetiologies and confounding
to soluble Mn sulphate (MnSO4) resulted in higher brain
variables (e.g., other exposures, disease states), are self-
Mn concentrations than those resulting from exposure
reported and subjective, often are not reproducible, and
to insoluble Mn tetroxide (Mn3O4). A study conducted
are of uncertain functional significance61. Further, there
by Normandin et al74 evaluated the absorption and
is no evidence to support that subclinical effects in Mn-
distribution of Mn in the brain of rats following
exposed occupational cohorts will progress to
inhalation exposure to three chemical forms of Mn
preclinical and ultimately, clinical symptoms of
(metallic Mn, Mn phosphate (Mn 5 PO 4 )/MnSO 4
manganism, making it difficult to evaluate the clinical
mixture, or Mn 5PO 4 alone) and found that the Mn
relevance of the reported effects 61-63 . Humans
concentrations in the brain were significantly higher in
chronically exposed to high levels of Mn may be at an
rats exposed to Mn5PO4 and Mn5PO4/ MnSO4 mixture
increased risk of neurotoxicity, but the specific levels
than in control rats or rats exposed to metallic Mn.
at which Mn alters nervous system functions and the
Normandin et al74 concluded that species and solubility
dose-response relationship remain somewhat elusive.
have an influence on the brain distribution of Mn in
Studies of occupational groups chronically exposed to
rats. The results from such studies should provide
high Mn levels have reported clinical effects of Mn
valuable information for understanding the differences
toxicity such as manganism64-68. The cases of clinical
in the incidence of neurotoxicity observed in various
neurotoxicity or manganism typically occurred in
occupational cohort studies that typically involve
workers chronically exposed to levels higher than 5 mg/
exposure to different Mn compounds and forms.
m3 in mining, orecrushing, or steel manufacturing, rather
than in contemporaneous lower Mn exposure settings In addition, studies have been conducted to evaluate
such as welding, dry alkaline battery, or ferroalloy the effects of age and gender on the tissue distribution
production. of Mn. Studies have been conducted to evaluate the
490 INDIAN J MED RES, OCTOBER 2008
tissue distribution of Mn in lactating rats and their
offspring following combined in utero and lactation
exposure to inhaled Mn SO477,78; in young rats exposed
by inhalation to MnSO470; and in old rats exposed to
MnSO4 or Mn5PO469. These studies provide valuable
information and pharmacokinetic data that are being
used to develop physiologically based pharmacokinetic
(PBPK) models for Mn. PBPK models are being
developed to provide for the ability to conduct route-
to-route extrapolations, evaluate nasal uptake to the
CNS, and evaluate lifestage differences in Mn
pharmacokinetics. Such models will facilitate more
rigorous quantitative analysis of the available
toxicokinetic data for Mn and will be used to identify
situations that may lead to increased brain accumulation
related to altered Mn metabolism in different human
populations, and develop quantitatively accurate
predictions of increased Mn levels that may serve as a
basis of dosimetry-based risk assessment 79 . Such
dosimetry-based risk assessments will permit for the
development of more scientifically refined and robust
recommendations, guidelines, and regulations for Mn
levels in the ambient environment and occupational
settings.
Mn biomarkers of exposure and/or effect
Many studies have been conducted in Mn-exposed
cohorts to determine whether the detection of Mn in
biological tissues or fluids can serve as biomarkers to
predict past or current exposure levels and/or the
potential for adverse health effects. A biomarker is any
substance or metabolite that may be measured in the
body to estimate external exposure levels or to predict
the potential for adverse health effects or disease. There
are three main classes of biomarkers: biomarkers of
exposure, effect, and susceptibility. Because Mn can
be measured directly in blood, serum, cerebrospinal
fluid, faeces, or hair, it has been used as a biomarker of
exposure in occupational studies; however, the
usefulness of a biomarker of exposure depends on how
accurately it reflects the environmental exposure level,
which typically requires studies to validate the
biomarker. Reliable exposure biomarkers or specific
early biomarkers of effect, such as preclinical
neurobehavioural or neurological changes, have not
been established or validated for Mn. In addition,
although some studies have suggested that some genes
may serve as susceptibility biomarkers for Mn
neurotoxicity, there are not any validated biomarkers
of susceptibility35.
Most of the studies of Mn-exposed cohorts have
measured Mn in blood or urine in an attempt to serve
as a measure of recent or past Mn exposure or as a
measure of cumulative dose. Several tests are available
for measuring Mn levels in whole blood, serum, urine,
or hair, and because Mn is naturally present in the body,
some Mn is always found in these fluids. Serum Mn
concentrations in combination with lymphocyte Mn
superoxide dismutase activity appear to be the most
appropriate ways to monitor insufficient Mn intake80.
On the other hand, studies have attempted to use Mn
biomarkers as a measure of cumulative exposure or to
correlate exposure with subclinical or clinical
neurological effects26,34,55,57,60,81-84. Some studies have
reported that blood Mn was associated with exposure
and adverse neurological effects26,52,83,85-88 while others
have reported that Mn levels in hair89-91, tooth enamel92,
urine 93, or the exposure medium was a significant
predictor of exposure and/or effect outcomes94.
These studies are often difficult to interpret in terms
of prior Mn exposure from ingestion or inhalation
exposures, due to the fact that Mn is a normal dietary
component and is present in all human tissues and fluids,
so baseline levels must be considered when evaluating
studies involving the use of biomarkers of exposure for
Mn. A variety of potentially confounding factors must
also be considered when evaluating any reported
correlations between Mn biomarkers and exposure
levels. For example, some studies have reported that
levels of essential elements such as Mn in human tissues
and body fluids may be altered in various disease
states1,95. In addition, the usefulness of biomarkers for
assessing past exposures to Mn is debatable. Because a
variety of factors can influence the levels of Mn in
biological samples, it is difficult to develop valid
biomarkers for use in evaluating workplace exposures
or impairment. Because the average intake of Mn from
food ranges from 2 to 9 mg/day and vitamin and mineral
supplements may also provide up to 20 mg Mn/day,
these alternative exposures may confound the Mn
results reported from screenings or studies when
attempting to correlate biological levels with workplace
exposures to Mn.
Blood and urine Mn levels have been the most
widely used biomarkers of exposure in occupational
studies. Normal whole blood levels of Mn (MnB) range
from 7-12 µg/l and 0.6 to 4.3 µg/l in serum1. Blood Mn
is not a good indicator of the amount of Mn absorbed
shortly before sampling or occurring during the
 SANTAMARIA: MANGANESE TOXICITY
preceding days, because it changes very little with
inhalation exposure35. Blood Mn may also be influenced
and change as a result of dietary intake, which may also
confound study results96. There is also a lot of inter-
and intra-individual variability in MnB levels, making
it a more useful parameter to evaluate external exposure
on the population level rather than on an individual
level. Urinary Mn (MnU) excretion is not a good
indicator of Mn exposure because Mn is primarily
excreted in the bile, and only approximately 1 per cent
is excreted in urine1. Hair is also not a reliable indicator
of exposure, as there is potential for external Mn
exposures that may affect Mn levels in hair, limiting its
use as an indicator of internal dose. The concentration
of Mn in hair may also be affected by the degree of
pigmentation9. Normal urine levels are typically less
than 1 µg/l and hair levels are typically are below 4
mg/kg1. Mn has a half-life in blood of 10 to 42 days43
and a half-life of less than 30 hours in urine83. These
relatively brief half-lives make MnB or MnU more
indicative of recent exposure, rather than serving as a
marker of long-term or chronic exposure. In general,
MnB has been used as an indicator of the previous few
weeks of exposure, generally less than one month and
MnU may indicate exposure within the past day or two.
However, with the exception of individuals with liver
disease, excess Mn is usually removed from the body
within several days after exposure ceases, making it
difficult to measure past exposure.
Because the relationship between external and
internal measures of Mn has not been clearly elucidated,
studies have attempted to correlate Mn biomarkers with
external exposure levels. Studies have also attempted
to use Mn biomarkers as a measure of cumulative
exposure. Some studies have reported that Mn exposed
workers excreted more Mn in urine and/or had higher
blood Mn levels as a group than unexposed control
subjects. Roels et al83 reported that there was little or
no correlation between MnU or MnB with the current
levels of Mn in air or duration of Mn exposure on an
individual basis in workers from a plant producing Mn
oxides and salts. On a group basis, MnB did not correlate
with current Mn air levels, although there was a
significant correlation between MnB and past-integrated
exposure. There was a slight correlation between MnU
and the current Mn exposure levels, but not the past
exposure estimates. The authors concluded that on a
group basis, MnU appears to reflect very recent
exposure while MnB may reflect the body burden of
Mn. Another study by Roels et al34 on workers in a dry
alkaline battery plant also reported the lack of
491
correlation between MnB or MnU with various external
exposure parameters on an individual basis, although
there was a difference in the mean levels of MnB and
MnU between the exposed and control groups. Apostoli
et al85 evaluated the relationship between Mn exposure
levels in air and whole blood and urine Mn levels in a
group of ferroalloy production workers. They reported
that these biomarkers could discriminate between
groups of exposed and unexposed control subjects, but
because of the high variability in the results, these
biomarkers are not suitable for use on an individual
basis. Levels of MnB have also not been correlated with
duration of exposure. Järvisalo et al 97 conducted
biological monitoring in MMA/MS welders and
reported that individual differences were great and that
measurement of Mn in blood or urine may only be useful
for monitoring Mn exposure at the group level. The
authors reported that blood and urine Mn levels were
higher in welders than unexposed controls; however,
the levels were not statistically significantly different
and urinary Mn excretion was not correlated with levels
of Mn or duration of exposure. Tsalev et al84 reported a
mean MnB level of 10 µg/l in unexposed workers and
in Mn alloy workers exposed to 1 mg Mn/m3 for 1, 5,
10, and >10 yr, the mean MnB levels were 16, 11, 13,
and 13 µg/l, respectively, indicating that the
concentration of MnB did not increase with duration
of employment. In addition, most studies have not
reported a dose-response relationship between exposure
levels and MnB, further limiting the use of Mn
biomarkers of exposure.
Specific early biomarkers of effect, such as
subclinical neurobehavioural or neurological changes
or MRI changes have not been established or validated
for Mn although some studies have attempted
to correlate biomarkers and neurological
effects26,52,55,57,60,82,88. Mergler and Baldwin50 pointed out
a lack of consistency or dose-response relationship
between internal (MnB, MnU, and hair Mn) and
external parameters of exposure or neurobehavioral
outcomes. In addition, the MnB level associated with
neurological effects is not known. Lander et al98 reported
that although there are no biological limit values for
Mn in blood, subclinical effects have been observed in
workers with moderate (1-4 µg/l) increases in MnB
above control groups34,52,88. In a community-based study
of blood Mn and neurotoxicity, Mergler et al26 suggested
that blood levels as low as 7.5 µg/l can be associated
with neurological dysfunction. However, this is within
the normal range of blood Mn levels (7-12 µg/l), which
casts some doubt on the clinical significance of this
492 INDIAN J MED RES, OCTOBER 2008
MnB level. Most biomarker data have been reported
following inhalation exposure in occupational studies,
although there are data on the levels of Mn in biological
samples in individuals exposed to Mn in drinking water,
food, or parenterally.
Studies of Mn-exposed workers have not been able
to detect correlations between blood or urine levels and
neurological measures 60,81,99,100 , while others have
reported an association, typically on a group level rather
than on the individual level33,34,52,55,57. Kaji et al81 did
not detect any significant correlations between MnB or
MnU and postural sway index, an early measure of
neurotoxicity in workers at a Mn-refining factory. Smyth
et al100 did not detect a correlation between MnB and
neurological symptoms or exposure levels in ferroalloy
workers. Based on a lack of an association between
blood Mn levels and exposure levels, length of
employment, or neurological findings in workers in an
enamels production facility, along with the abundance
of negative findings in the literature, Deschamps et al99
concluded that the biological significance of Mn in
blood is far from clear. A group of welders exposed to
Mn did not have higher Mn levels in blood than the
controls and the MnB or MnU levels were not correlated
with the reported decrements in motor function60. The
studies that detected elevated MnB and or MnU levels
in groups of workers with preclinical neurological
symptoms have not identified a dose-response to
correlate the biomarker with effects, so it is difficult to
interpret the clinical significance of the reported MnB
or MnU levels. Chandra et al55 reported that welders
from three plants with Mn levels ranging from 0.44 to
2.6 mg/m3 had higher MnU levels than control subjects
that were not exposed to Mn and that the serum levels
were too variable to be considered of diagnostic
significance. They also reported that because the
welders had higher MnU levels than controls, and also
had more self-reported neurological symptoms, elevated
MnU may serve as a biomarker of effect. Luse et al57
reported elevated MnB and Mn in the hair of welders
and some neurobehavioural effects in welders exposed
to 0.003 to 2.6 mg/m3 Mn compared to control subjects.
They reported that the welders had significantly higher
levels of Mn in blood and hair than the control group -
7.6 and 3.2 times higher, respectively. A recent study
by Montes et al101 evaluated the relationship between
blood Mn and prolactin as marker of effect in subjects
living in a mining district in central Mexico
environmentally exposed to Mn. Blood samples were
obtained from 230 subjects and haemoglobin, prolactin,
lead, and Mn levels were measured and a statistical
association between blood Mn levels and serum
prolactin levels was reported.
Studies have been conducted to evaluate the
relationship between Mn exposure and high signal
intensities on T1-weighted brain MRIs and whether such
findings can serve as biomarkers of exposure and/or
effect for Mn9,43,102. It has been observed by using brain
MRI that Mn can accumulate in the globus pallidum
after exposure to high concentrations of welding
fumes103. However, the clinical significance of elevated
signals detected on MRIs is not established, making it
difficult to use such data as biomarkers of effect. In
addition, the elevated intensities are not necessarily
evidence of Mn exposure, as other factors may cause
increased intensities on MRIs. Other investigators have
reported that altered responses to a battery of
neurofunctional tests (e.g., postural instability when
visual input is prevented, slowed finger tapping speed,
increased reaction times or decreased hand steadiness)
were useful in identifying early indications of
neurotoxicity.
There are also a variety of potentially confounding
factors that must be considered whenever evaluating
any reported correlations between Mn biomarkers and
exposure levels. Elevated serum levels have been
reported in patients with liver failure, congestive heart
failure, infection, rheumatoid arthritis, and psychoses1.
The potential for excess Mn accumulation and toxicity
is higher whenever liver function and biliary secretion
is decreased and the normal homeostatic functions that
regulate Mn levels are perturbed. Such physical
conditions could lead to the erroneous conclusion that
elevated levels of Mn in biological samples are primarily
due to high external exposures.
There are also a variety of methods that may be
used to analyze MnB or MnU, and there may be
differences in how samples are collected, stored, and
assayed for Mn content. Although there are several
methods that may be used to detect Mn in biological
samples, atomic absorption spectrophotometry is the
most common method for detecting Mn in biological
samples; however, this method is not very specific or
sensitive 4. Further research is needed to develop
validated biomarkers of exposure, effect, and
susceptibility for Mn and to be able to elucidate their
biological and clinical significance. Increased
knowledge of the pharmacokinetics of Mn from recent
studies will increase the understanding between external
 SANTAMARIA: MANGANESE TOXICITY
exposure parameters, biologic measures, and
neurological outcomes.
Threshold exposure levels for neurotoxicity
There are difficulties with trying to determine the
dose-response relationship for Mn and subclinical
neurological effects from many of the occupational
cohort studies, because in many cases, individual
personal exposures to respirable Mn with subject-
specific linked results from neurological tests were not
evaluated or reported in the studies. In addition, there
are difficulties in establishing a dose-response for Mn
from the studies of Mn-exposed workers because (i)
the chemical forms of Mn differ in these industries
(salts, dust, oxides, fumes), (ii) there are different
exposure scenarios involving different activities, (iii)
the studies report different exposure measures (TWA
vs. peak samples; area vs. personal; total dust vs.
respirable), (iv) the neurological endpoints differ among
studies, and (v) many studies have design limitations.
It has been known for several decades that chronic
exposure to elevated airborne levels of Mn in mining
and manufacturing settings is associated with an
increased risk of certain neurological effects. In
addition, subclinical neurological effects have been
reported in Mn-exposed cohorts such as welders,
reportedly as a result of using Mn-containing
consumables (e.g., electrodes and wires) and exposure
to Mn in steel components25,54,55,104. However, because
Mn homeostasis is so effective and because of
competition with iron for availability of transferrin to
transport Mn across the blood–brain barrier, Mn
neurotoxicity is quite rare105. There is debate about what
the threshold of Mn exposure is for the potential
induction of subclinical neurological effects106. Several
studies during the last two decades provide for the
determination of Lowest Observed Adverse Effect
Levels (LOAELs) or No Observed Adverse Effect
Levels (NOAELs) for neurological effects in workers
exposed to Mn in settings such as smelters, dry alkaline
battery manufacturing facilities, and ferromanganese
alloy production plants33,34,52,62,82,88,99,107-114. Scientific
understanding of the impact of Mn exposure on nervous
system function leads to the hypothesis as there should
be no adverse impact on function at low exposures,
given that Mn is an essential element in human nutrition;
that there should be some threshold for exposure above
which adverse effects may occur; and that these adverse
effects may increase in frequency with higher levels of
exposure beyond that threshold114. There are data to
indicate that an exposure threshold exists for the
493
subclinical neurological effects of Mn. For example, a
study by Deschamps et al 99 in enamel production
workers exposed to Mn reported that chronic exposure
(~20 yr) to approximately 0.2 mg/m3 respirable Mn may
induce potentially mild subjective symptoms (e.g., sleep
disturbance, headache, weakness) but did not lead to
adverse effects on nervous system function. Gibbs
et al108 did not observe neurological effects in workers
in a metal-producing plant exposed to levels averaging
0.18 mg/m3 total Mn dust (0.066 mg Mn/m3 respirable
dust). More recently, studies by Myers et al112,114 did
not detect any subclinical or clinical neurological effects
or deficits deemed to be associated with Mn exposure
in large cohorts of miners exposed to a mean of 0.21
mg Mn/m3 respirable dust (arithmetic mean) and smelter
workers exposed to 0.82 mg Mn/m3 respirable dust
(arithmetic mean). The authors evaluated a
comprehensive range of nervous system endpoints in
489 mine workers and 509 smelter workers and
examined exposures ranging from 0 to 5 mg/m3, using
inhalable Mn as the exposure metric. For the study with
smelter workers114, the authors concluded that the most
likely explanation for weak and inconsistent findings
with implausible or counterintuitive exposure–response
relationships is chance, and that this is essentially a
negative study, providing only weak and unconvincing
evidence for exposure effects in general, or for the
notion of a continuum of effects. Young et al113 re-
evaluated the worker cohort evaluated by Myers et al114,
which included 509 exposed workers from Mn smelters
and 67 unexposed workers. Young et al113 concluded,
“despite a comprehensive range of endpoints and levels
of exposure ranging from environmental to industrial,
the large smelter study of Mn workers found no
convincing effects at exposure levels (expressed as
inhalable dust) at, and considerably above, the current
ACGIH TLV of 0.2 mg/m3”. Thompson and Myers115
conducted a more in-depth statistical analysis of the
neurobehavioural data from the study of Myers et al114.
The association between neurobehavioural test scores
and cumulative Mn exposure was estimated, and the
investigators demonstrated that a linear model could
be fit to these data with a statistically significant trend
of an association between neurological effects and
increasing exposure levels; however, the exposure-
response relationship was highly nonlinear. Fitting a
linear regression inappropriately to a nonlinear function
can lead to misinterpretation of the results, and can
obscure the existence of a threshold and this type of
error is most likely to occur with small data sets that
are frequently evaluated in occupational studies.
494 INDIAN J MED RES, OCTOBER 2008
Other studies report the potential for subclinical
effects at lower Mn exposure levels in the workplace.
Lucchini et al82 reported that neurobehavioural effects
in ferroalloy workers at levels around 0.19 mg Mn/m3
total dust and Mergler et al52 reported subclinical
neurological effects in workers exposed to a mean of
0.112 mg Mn/m3 respirable dust. Roels et al33 conducted
a cross-sectional study of 141 male workers exposed to
MnO2, Mn tetroxide (Mn3O4), and various Mn salts
(sulphate, carbonate, and nitrate) in a manganese oxide
and manganese salts production facility. EPA
determined a LOAEL of 0.97 mg/m3 from the Roels
et al 33 study, based upon the findings of impaired
neurobehavioural 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 follow-up study on the 1987 cohort was conducted
by Crump and Rousseau62. The follow-up study reported
that there was no significant progression of any
previously reported neurological effect during a chronic
exposure period of 14 years to relatively constant
exposure levels. Roels et al 34 conducted a cross-
sectional study of 92 male workers exposed to MnO2
dust in a Belgian alkaline battery plant. The Mn exposed
group had been exposed to MnO2 for an average of 5.3
yr and the geometric mean of the workers’ TWA airborne
Mn concentrations was 0.215 mg Mn/m3. Roels et al34
reported increased neurobehavioural deficits in workers
exposed to mean respirable levels of 0.215 mg Mn/m3
and EPA derived a LOAEL of 0.15 mg Mn/m3 from the
Roels et al34 study, based on an occupational lifetime
integrated respirable dust concentration divided by years
of exposure. The LOAEL from the Roels et al33 study
was based on total Mn dust of mixed forms, whereas
the LOAEL from the other study34 was based on the
measured respirable dust fraction of MnO 2. Roels
et al63 conducted an eight-year follow-up of the 1992
cohort and reported a complete reversal of one of the
neurofunctional endpoints, even though these workers
were still exposed to air concentrations above 0.1 mg
Mn/m3. There were no adverse effects reported in the
low exposure group at follow up and the previously
abnormal “precision of hand-forearm movement” eye-
hand co-ordination test normalized in this group. In the
low exposure group, Mn levels decreased from 0.4 mg
Mn/m³ in 1987 (measured as total dust) to 0.13 mg/m3
in 1995. These results suggest that there is a threshold
for at least one of the end-points evaluated and that the
effect of Mn on this particular effect was reversible.
The study by Gibbs et al108 on 75 workers in an
electrolytic Mn metal-producing plant is perhaps the
most informative in terms of dose-response
interpretation, because the study examined a well-
defined exposed population with apparently little or no
mixed exposure to other neurotoxicants; had a well-
matched control group by age, gender, race, and pay
grade; used well-established and relatively objective
measures of neurological deficits (as opposed to self-
reported symptoms); reported air data in terms of TWA
respirable fractions; and perhaps most importantly,
reported individual exposure data and response
information for each individual worker106. It should be
noted that Gibbs et al 108 examined relatively low
exposure conditions, with mean airborne respirable
levels of 0.066 mg/m3, and did not find an increased
incidence of neurobehavioural effects in the Mn
exposed workers106. The Roels et al34 study, which
reported increased neurobehavioural deficits in workers
in a dry alkaline battery plant exposed to mean airborne
respirable levels of 0.215 mg Mn/m3, also has the
methodological attributes described above; however,
they examined fewer endpoints (three measures of
psychomotor function, compared to five measured by
Gibbs et al108), and the response data were reported in
quantal terms, rather than continuous, which limits the
information that can be obtained from dose-response
modeling.
Benchmark modeling conducted with the data from
Roels et al 34 and Gibbs et al 108 battery and metal
producing workers by Clewell et al 61 resulted in
BMDL10 ranges of 0.10-0.27 mg/m3. The results suggest
that chronic exposure to airborne respirable levels up
to approximately 0.1-0.3 mg Mn/m3 as an 8-hour time
weighted average should pose little to no risk of
developing subclinical signs of neurobehavioural
effects. This evaluation provides the best indication that
a TWA occupational exposure limit between 0.1 and
0.3 mg/m 3 respirable Mn should be protective of
subclinical neurological effects in the workplace. Such
benchmark modeling and the calculated doses may also
be used to establish recommended inhalation reference
values for ambient air levels of Mn. Benchmark
modeling of these studies34,108 in battery and metal
producing workers has been conducted by governmental
agencies and the resulting values have been used to
develop reference concentrations or suggested ranges
for ambient or occupational air levels3,116,117.
Risk assessment of an essential element
The conduct of risk assessments for an essential
element such as Mn presents challenges because of the
need to consider the balance between essentiality and
 SANTAMARIA: MANGANESE TOXICITY
toxicity. For each essential trace element, there are two
ranges of intake associated with adverse health effects:
intakes that are too low and can lead to nutritional
deficits and intakes that are too high and can lead to
toxicity. Between these two ranges, there is a range of
safe and adequate intakes that is compatible with good
health; however, the challenge is to define that range
quantitatively118. Importantly, essential trace elements
such as Mn are subject to homeostatic control
mechanisms that may include regulation of absorption,
excretion, and tissue retention. The ability to regulate
tissue levels is important to consider when conducting
a risk assessment to determine safe exposure levels for
an essential element such as Mn. Recent
pharmacokinetic studies conducted with Mn provide
invaluable information about the ability to
homeostatically regulate Mn following oral or
inhalation exposure79.
Based on an ambient air concentration of 0.023 µg
Mn/m3 cited by the Agency for Toxic Substances and
Disease Registry (ATSDR), the estimated average daily
intake of Mn would be 0.46 µg Mn/day (assuming 20
m3/day inhaled and 100 per cent Mn is deposited in the
lungs and 100 per cent is absorbed, very conservative
assumptions)3. In comparison, the daily “dose” from
food and drinking water may be 114.24 µg/day
(assuming 3.8 mg/day ingested from food and water,
3% absorption) 3. Using the aforementioned highly
conservative assumptions, the amount of Mn absorbed
from food may be greater than 250 times of the amount
of Mn inhaled in ambient air (using an assumption that
10 per cent inhaled Mn is absorbed through the lungs,
the difference is 2,500-fold). Although the potential dose
of Mn resulting from inhalation is so low compared to
the dose from dietary sources, there have been
uncertainties expressed about the potential differences
in homeostatic regulation of Mn following inhalation
versus oral exposure 119,120 . To address these
uncertainties, there have been several pharmacokinetic
studies in rats and monkeys conducted over the last
fifteen years by scientists at the Hamner Institutes for
Health Sciences79. Study results indicate homeostatic
mechanisms control excess inhaled Mn by increasing
biliary excretion similar to excess oral Mn intake and
data from the pharmacokinetic studies will be used to
develop and validate PBPK models that will address
remaining uncertainties regarding how the body handles
inhaled versus oral Mn (e.g., absorption, tissue
distribution, excretion). Such information may be used
to develop more scientifically robust risk assessments
for this essential element.
495
Concepts and progress in setting intake guidelines
for essential elements have been reviewed by Mertz121,
Olin118, Sandström 122, Goldhaber et al123 and Fraga124
and a Nordic Working Group on Food and Nutrition
prepared a report entitled “Risk evaluation of essential
trace elements – essential versus toxic levels of
intake”125.
Recommended and regulatory levels for
environmental Mn
A variety of agencies have prepared risk
assessments for Mn and developed recommended
reference concentrations or regulations for chronic oral
or inhalation exposure levels for Mn in the
environment. This discussion does not include
workplace regulations for Mn, which are reviewed in
Santamaria et al25 Exposure guidelines for ambient
inhalation exposure to Mn include the following: the
U.S. Environmental Protection Agency reference
concentration (RfC) is 0.05 µg/m3, the Health Canada
tolerable daily intake (TDI) is 0.11 µg/m3; the World
Health Organization (WHO) air quality guideline is
0.15 µg/m 3; the Agency for Toxic Substances and
Disease Registry (ATSDR) minimum risk level is 0.4
µg/m3; and the California EPA reference exposure level
(REL) is 0.2 µg/m3 - (CalEPA has a current draft REL
of 0.09 µg/m3). In 1994, the US EPA developed a range
of possible RfC values of 0.09 – 0.2 µg/m 3 using
benchmark doses developed from the Roels et al 34
cohort 116. These recommendations and guidelines
apply to respirable dust, which corresponds roughly
to PM 5 (fraction of airborne particles with an
aerodynamic diameter of 5 µm or less). The oral
exposure recommendations and guidelines include
EPA’s oral reference concentration of 0.14 mg/kg/day,
EPA’s maximum contaminant level (MCL) of 0.05 mg/l
in water (based on aesthetic properties), and the WHO
drinking water guideline of 0.4 mg/l (health-based)119.
There are significant differences in magnitude
between the recommended exposure levels for oral
versus inhalation exposure to Mn. The existence of well-
known homeostatic mechanisms has led regulatory
authorities to conclude that the body is able to handle
substantial variations in dietary Mn on a daily basis
without adverse consequences due to hepatic excretion
of Mn and the low absorption of Mn through the
gastrointestinal tract. However, there have been
uncertainties expressed regarding the pharmacokinetics
of Mn following inhalation exposure versus oral
exposure and concerns expressed about the potential
for greater absorption through the respiratory tract than
496 INDIAN J MED RES, OCTOBER 2008
the gastrointestinal tract119,126 In addition, there is a broad
range of recommended exposure levels for Mn exposure
by inhalation, reflecting the different quantitative
approaches taken and different qualitative assumptions
used by the Agencies in developing the recommended
levels. Although all of these Agencies used the same
occupational study34 to derive the inhalation reference
values, the values derived from this study were different
and included NOAELs, LOAELs, or benchmark doses
as the point of departure for establishing the
recommended levels. Uncertainty factors were applied
to the various point of departure values to account for
human variability, sensitive subpopulations, potential
differences in the pharmacokinetics or toxicity of
different forms of Mn, and less than chronic exposure.
These modifying and uncertainty factors ranged from
50 to 1,000. Important and extensive research has been
conducted over the last 15 years to address many of
these uncertainties and it is anticipated that the
development of PBPK models will also permit for the
reduction of these uncertainties and permit for the
application of chemical-specific adjustment factors
(CSAFs), greatly improving risk assessments for Mn.
Conclusions
Mn is a neurotoxic substance at certain exposure
levels regardless of route of exposure; however, the
threshold exposure level for the development of
subclinical neurological or neurobehavioural effects has
not been clearly established, although benchmark
modeling of data from the various studies34,108 derived
benchmark dose level [BMDL10] [the 95 % lower bound
internal dose corresponding to a 10% increased
outcome] ranges of 0.10-0.27 mg/m3 respirable Mn,
encompasses a likely threshold for subclinical
neurological effects61. With the exception of a few
studies, most available epidemiological studies of Mn-
exposed cohorts are inadequate for determining a dose-
response relationship for subclinical or clinical
neurotoxicity and exposure to Mn. There may be other
studies that can be used to develop benchmark doses, if
there are individual-specific response data and personal
respirable Mn exposure data. Regulatory Agencies are
recommending the use of benchmark doses when the
data are available and the use of PBPK models for
conducting dosimetry-based risk assessments127,128. As
the understanding of the pharmacokinetics of Mn
continues to be developed for the diverse forms of Mn
and in different age groups, more refined and robust
risk assessments may be developed for Mn. Such data
will allow for the application of CSAFs in the dose-
response evaluation as recommended by WHO129. The
use of CSAFs and PBPK models can reduce the need
for the application of various uncertainty factors when
developing reasonable and appropriate reference values,
guidelines, and regulations for this essential element.
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