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 485

environment. Uses of Mn include: (i) iron and steel enzymes, nervous system function, immunological
production; (ii) manufacture of dry cell batteries; (iii) system function, and reproductive hormone function, and
production of potassium permanganate and other Mn is an antioxidant that protects cells from damage due to
chemicals; (iv) oxidant in the production of free radicals3,12. Mn also plays an essential role in
hydroquinone; (v) manufacture of glass; (vi) textile regulation of cellular energy, bone and connective tissue
bleaching; (vii) oxidizing agent for electrode coating growth and blood clotting13. In the brain, Mn is an
in welding rods; (viii) matches and fireworks; and (ix) important cofactor for a variety of enzymes, including
tanning of leather1. Organic compounds of Mn are the antioxidant enzyme superoxide dismutase, as well as
present in the fuel additive, methylcyclopentadienyl enzymes involved in neurotransmitter synthesis and
manganese tricarbonyl (MMT), fungicides (e.g., maneb metabolism14. Manganese has three primary metabolic
and mancozeb), and in contrast agents used in magnetic functions: (i) it acts as an activator of the gluconeogenic
resonance imaging. Mn is naturally present in food, with enzymes pyruvate carboxylase and isocitrate
the highest concentrations typically found in nuts, dehydrogenase, (ii) it is involved in protecting
cereals, legumes, fruits, vegetables, grains, and tea - it mitochondria1 membranes through superoxide
is also present at low levels in drinking water2,3. Typical, dismutase; and (iii) it activates glycosyl transferase,
daily intakes range from 2-9 mg/day for adults and which is involved in mucopolysaccharide synthesis15.
approximately 3-5 per cent is absorbed from the The most important source of Mn for the general
gastrointestinal tract3. Absorption of Mn from the diet population is diet, and the average intake of Mn from
occurs in the divalent and tetravalent state4. Mangenese food ranges from 2 to 9 mg/day3. In addition, vitamin
balance studies and excretion data indicate that low and mineral supplements may contain 1 to 20 mg Mn/
gastrointestinal absorption and rapid elimination of Mn tablet16. The Food and Nutrition Board of the National
limits the toxicity of the Mn following the ingestion of Research Council (NRC) determined that insufficient
high doses4. Chronic inhalation exposure to relatively information exists to develop a recommended daily
high levels of Mn has been associated with adverse allowance (RDA) for Mn, but sufficient information is
neurological effects and a few studies have reported available to provide estimated safe and adequate daily
the same following the ingestion of high levels or dietary intake (ESADDI) levels for various age groups.
chronic exposure to Mn in drinking water3,5. Clinical The ESADDI for adolescents and adults ranges from 2
Mn neurotoxicity has been reported in patients receiving to 5 mg/day and for infants and children up to age 10,
long-term parenteral nutrition and in patients with the ESADDI levels range from 0.3 to 2 mg/day12.
chronic liver dysfunction or renal failure, as a result of
Manganese deficiency has been demonstrated in
their inability to eliminate and clear Mn from the blood6-10.
several species, including rats, mice, pigs, chickens, and
The primary anthropogenic sources of Mn in ambient
cattle, and can result in several biochemical and
air include emission of Mn from industrial sources such
structural defects in experimental animals 17,18 .
as ferroalloy production plants, iron and steel foundries,
Manganese deficiency in animals has significant effects
power plants, and coke ovens and reentrainment of soils
on the production of hyaluronic acid, chondroitin
containing Mn3,4,11. The background levels of Mn in rural
sulphate, heparin, and other forms of
and urban areas without point sources of Mn range from
mucopolysaccharides that are important for growth and
about 0.005-0.07 µg Mn/m3, while average ambient air
maintenance of connective tissue, cartilage, and bone15.
levels of Mn near industrial sources range from 0.13-
The consequences of Mn deficiency include altered
0.3 µg Mn/m3,4,5. Exposure to Mn from the erosion of
carbohydrate metabolism, reduced glucose metabolism,
soil is the most important natural source of Mn in the
abnormal lipid metabolism, and impaired insulin
ambient air, but little data are available to estimate the
synthesis and action18.
contribution of Mn in ambient air from this source.
Higher inhalation exposures may be experienced in Only a few instances of Mn deficiencies have been
occupational settings such as Mn mines, foundries, reported in humans, with symptoms including
smelters, and battery manufacturing facilities. dermatitis, slowed growth of hair and nails, decreased
serum cholesterol levels, and decreased levels of clotting
Manganese essentiality
proteins3,19,20. Friedman et al20 induced Mn deficiency
Mn is necessary for a variety of metabolic functions in adult male subjects by administering a diet deficient
including those involved in skeletal system in Mn for 39 days. The subjects developed a temporary
development, energy metabolism, activation of certain dermatitis, increased serum calcium and phosphorous
486 INDIAN J MED RES, OCTOBER 2008

concentrations, and increased alkaline phosphate Manganese toxicity

activity suggestive of bone resorption18. In addition,
It has long been known that Mn, an essential
several diseases have been reported to be characterized
element for humans and the fourth most widely used
by low blood Mn concentrations, including epilepsy,
metal in the world, is a neurotoxic substance. But just
mseleni disease, Down’s syndrome, osteoporosis, and
as in the case of any chemical substance, the dose makes
Perthest disease18. Manganese deficiency has also been the poison; therefore, Mn toxicity has primarily been
cited as a possible aetiologic factor for some congenital observed in occupational settings where there is the
malformations and several inborn errors of metabolism potential for chronic exposure to high levels or
have been associated with poor Mn status (e.g., following the accidental ingestion of large quantities.
phenylketonuria, maple syrup urine disease)18. The John Couper was the first to report neurological effects
finding of low blood Mn levels in subsets of individuals associated with exposure to Mn in the scientific
with some of these diseases is significant, because blood literature in 1837, when he described muscle weakness,
Mn levels can reflect soft tissue Mn concentrations18, limb tremor, whispering speech, salivation, and a bent
however, the role of Mn deficiency in these diseases is posture in five men working in a Mn ore crushing plant
unclear. in France 24. He called this collection of symptoms
Dietary studies have demonstrated that daily “manganese crusher’s disease”, which was later
intakes of high doses of Mn can be safely tolerated by recognized as “manganism”. Chronic inhalation of high
healthy adults21. Davis and Greger22 treated women levels of Mn has been associated with a
with supplements containing 15 mg of Mn/day for 124 neurodegenerative disorder characterized by both
days and reported only elevated plasma Mn central nervous system abnormalities and
concentrations and lymphocyte Mn superoxide neuropsychiatric disturbances. Historically, Mn
dismutase activity. Urinary Mn, an excretory route that neurotoxicity has been most commonly associated with
becomes more important at high Mn intakes, was not occupations such as Mn mining and smelting, battery
elevated in the treated subjects. In a study conducted manufacturing, and steel production25. The brain is
by Finley et al23 women were treated with either <1 or particularly susceptible to excess Mn. In humans, it has
9.5 mg Mn/day for 60 days. They reported that the been postulated that there is a spectrum of
high treatment group subjects had decreased neurobehavioural and neurophysiological effects
absorption and increased excretion of Mn. In a follow associated with Mn toxicity, including both subclinical
up study, female subjects were fed 1.0 or 20 mg Mn/ and clinical symptoms 26. However, a recent meta-
day for 60 days to determine whether diets containing analysis of 19 studies that evaluated neuropsychological
very low or very high amounts of Mn and enriched in effects in Mn-exposed workers by Greiffenstein and
either saturated or unsaturated fats affected measures Lees Haley27 reported a lack of scientific support for
of neuropsychological and basic metabolic function19. the existence of “preclinical” neuromotor or cognitive
Subjects were administered a battery of psychological dysfunction or the “continuum hypothesis” of
tests and neurological exams before and after dietary neurotoxicity in Mn-exposed individuals. The authors
periods. In addition, 54Mn whole-body counting was concluded that the neurobehavioural effects reported
used to estimate Mn absorption retention and turnover. to be associated with Mn-exposure in the studies were
Measures of Mn in plasma and lymphocytes were not more likely due to covariate effects27. In addition, a few
affected by dietary Mn and the efficiency of Mn studies have reported adverse haematological,
absorption and biologic half-life were almost twice as endocrine, or male reproductive effects following
great in subjects in the low dietary Mn group than in occupational exposure to Mn3,28-36.
subjects in the high dietary Mn group, demonstrating Manganism is a neurological syndrome that
homeostatic control of Mn retention and excretion. resembles Parkinson’s disease (PD), but there is
There was no association between Mn intake and considerable evidence that Mn preferentially damages
performance on neurological tests. The authors different areas of the brain from those that are affected
concluded that efficient mechanisms operate to in PD 37,38 . The similarities between the clinical
maintain Mn homeostasis over a broad range of Mn manifestations of Parkinson’s disease and manganism
intake levels that may be encountered in the diet and include the presence of generalized bradykinesia and
dietary intakes of Mn from 0.8 to 20 mg for 8 wk do widespread rigidity and dissimilarities include less-
not result in Mn toxicity in healthy adults19. frequent resting tremor, more frequent dystonia,
 SANTAMARIA: MANGANESE TOXICITY 487

symmetry of effects, a particular propensity to fall mechanism(s) of toxicity, types of neurological effects,
backward, a characteristic “cock-walk”, in which dose-response relationship, the tissue distribution of
patients walk on their toes with elbows flexed and spine Mn, and homeostatic regulation of inhaled and ingested
erect in manganism37. The similarities between the two Mn. Most animal models are inadequate for evaluating
disorders can be partially explained by the fact that the the types of neurological effects observed in humans,
basal ganglia accumulate most of the excess Mn making it difficult to study the mechanism(s) involved
compared with other brain regions in manganism, and and to elucidate a dose-response relationship for
dysfunction in the basal ganglia is involved in neurotoxicity. There have been a few systematic
Parkinson’s disease39. Parkinson’s disease is primarily attempts to study the effects of Mn on behaviour using
associated with the loss of dopaminergic neurons within animal models, and most of the studies have focused
the substantia nigra, allowing the caudate and putamen on evaluating the neurochemical effects of Mn41,45. The
to become overly active and possibly cause continuous clinical neurological effects observed in manganism has
output of excitatory signals to the corticospinal motor been observed in studies with non-human primates41,45-49.
control system 40. The substantia nigra is spared in Early studies used extremely high doses of Mn in
manganism, which is linked to the degeneration of attempting to mimic human exposure while more recent
GABAminergic neurons within the globus pallidus in studies have used lower doses for longer periods of
pathways postsynaptic to the nigrostriatal system9,41. exposure and in general, the behavioural,
There are a few imaging procedures that may be used neurochemical, and neuropathological findings in
to distinguish manganism from Parkinson’s disease, primates agree strongly with findings documented in
including positron emission tomography (PET), the human literature14. One study that reported similar
computerized tomography (CT), and magnetic neurological effects to those observed in humans with
resonance imaging (MRI). The CTs and MRIs are manganism involved the administration of high doses
typically normal in Parkinson’s disease patients, of Mn oxide subcutaneously in monkeys for 5 months
whereas the PET is abnormal in patients with (total of 8 g Mn), causing dystonic posture, hyperactivity
Parkinson’s disease 37 . PET provides a means of with an unsteady gait, and an action tremor at the high
discriminating between Parkinson’s disease and exposure levels47. The serum concentration of Mn rose
manganism, as there is typically a reduced uptake of 10-40 times during the exposure period and the content
18
F-6-fluorodopa in the striatum of Parkinson’s disease in brain was generally increased more than 10 times,
patients due to the loss of dopaminergic cells in the with the highest concentration found in the globus
nigrostriatal pathway, whereas PET is generally normal pallidus and putamen. Although these observations
in manganism37,38. Manganism is generally associated provide some information about Mn neurotoxicity, the
with hyperintense signal abnormalities in the globus dose was very high and the route of administration
pallidus, striatum, and substantia nigra bilaterally on makes it difficult to extrapolate these results to humans.
an MRI, whereas the MRI is normal in Parkinson’s
In order to address many of the critical data gaps
disease patients38,42,43. There are also differences with
regarding the dose-response relationships for subclinical
respect to treatment response – although there may be
or clinical effects in humans exposed to Mn, researchers
an initial response to levodopa, the primary treatment
have used a variety of sensitive neurophysiological,
option for Parkinson’s disease, there is typically a failure
neuropsychological, and neurobehavioural methods to
to achieve a sustained therapeutic response in patients
identify early nervous system alterations in a variety of
with manganism37.
occupational settings, including welding, mining, and
A critical first step in understanding the role that ferroalloy, steel, and dry alkaline battery manufacturing.
Mn plays in neurotoxicity is to determine exposure The types of subclinical neuromotor or
conditions that lead to increased concentrations of the neurobehavioural symptoms reported in the workers
metal within the central nervous system 44 . This exposed to Mn include decreased motor functions, mood
understanding is especially critical for Mn, because its alterations, decreased hand steadiness, insomnia,
mechanism of toxicity is poorly understood. Many decreased eye-hand co-ordination, increased tremor,
experimental studies have been conducted to evaluate decreased response speed, limb paresthesia and
several fundamental issues of Mn toxicity, including decreased memory. There is not a general consensus
the absorption and bioavailability of various chemical on what is the most sensitive neurological endpoint for
forms of Mn following ingestion or inhalation exposure, 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 In a subsequent study, Greiffenstein and Lees-
sensitive to Mn exposure are those that require the Haley 27 conducted a meta-analysis on 41
participant to perform co-ordinated, sequential, neuropsychological variables from 19 studies that
alternating movements at maximum speed. Iregren51 evaluated Mn-exposed workers. The authors reported
suggested that the ability to repeat simple movements that the Mn cognition literature shows substantially
might be particularly sensitive to Mn exposure and conflicting results because of several reasons, including
emphasized the need for investigations to study early (i) studies differ widely in neuropsychological tasks
signs of Mn neurotoxicity by the use of behavioural selected, (ii) the total number of measures, (iii) sample
methods in groups of active workers before the onset size, (iv) subject demographics, (v) cultural context, (vi)
of clinically observable symptoms. Some investigators subjective versus objective data, (vii) amount of
report that neuropsychological tests are more sensitive exposure, industrial context, and (viii) weak/normal
than neurological tests, and that subtle deficits detected neuropsychological patterns. The purpose of the meta-
by neuropsychological testing are precursors of more analysis was to quantify the association between
serious, clinical neurological effects such as occupational Mn exposure, neurocognitive tests, and
manganism51,52. potentially confounding demographics by pooling data
from relevant studies. Greiffenstein and Lees-Haley27
In order to identify a dose-response for Mn calculated effect sizes (ES) between Mn exposed and
neurotoxicity, Lees-Haley et al53 conducted a meta- non-exposed referent groups for five types of variables,
analysis of 20 peer-reviewed published including specific neuropsychological tasks, preclinical
neuropsychological studies that evaluated the cognitive, neurological indicators, biological body burden, subject
psychological, motor, and sensory/perceptual effects of (demographic) variables, and dose-response
exposure to Mn in 1,410 exposed subjects and 1,322 correlations. In contrast to Lees-Haley et al53 study, the
controls. These studies included Mn workers employed goal of this study was to examine the association
in a variety of industries, including Mn milling and between specific neurobehavioural measures and
mining, Mn ferroalloy plants, MnO2 salt plants, welding, various covariates such as demographics as they relate
and battery manufacturing. The authors focused on to the basal ganglia theory of Mn exposure. This study
neuropsychological effects, because many studies of Mn- improves on the meta-analysis by Lees-Haley et al53 in
exposed workers were conducted to evaluate those that it included more recent research and previously
endpoints in asymptomatic workers to develop early unpublished studies, included only occupational studies
detection methods or measures of “subclinical” involving inhalation exposure, excluded studies that
neurological effects. Dose-response relationships were only included former workers involved in workplace-
evaluated for neuropsychological effects and several related litigation, and was more focused on evaluating
parameters, including: (i) measures of Mn levels in air the effects of confounding variables such as cognitive
and dust; (ii) reported years of exposure; (iii) blood Mn ability and education. Two general hypotheses were
levels; (iv) urine Mn; and (v) hair Mn. A statistically evaluated: (i) if low-dose Mn exposure is associated
significant weighted mean effect size of -0.17, suggestive with neurocognitive deficits, the effect size for specific
of impairment, was calculated for neuropsychological tasks should exceed the ES accounted for by subject
symptoms and Mn exposure (defined as exposed to Mn variables such as education, and psychometric
at the time of the respective study). However, there were intelligence and, (ii) any significant ES for motor tasks
no significant associations between neuropsychological without cognitive components should exceed those for
effects and (i) years of exposure, (ii) levels of Mn in air, tasks with cognitive components, if the “early
(iii) Mn concentration in blood, or (iv) Mn levels in urine. Parkinson” model of Mn-neurotoxicity is feasible. The
The authors concluded that occupational exposure to Mn results of the analysis did not support either hypothesis.
at levels that typically occur in the milling and mining, Overall, there was no relationship between Mn in the
ferroalloy, MnO 2 salt, and battery manufacturing blood, urine, or air and neuropsychological function
industries may exert a small deleterious effect on identified in this analysis. The authors reported that a
cognitive and sensory motor performance, which may small group of tests showed minor strength of
be detectable in population studies; however, it is association with exposure-group membership; all test
generally too small to be detected in any one individual scores lacked a dose-response relation to internal or
through current clinical assessment, and it is not clear external Mn levels; subject variables showed medium
that such effects possess any clinical significance. 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 Most of the studies of Mn-exposed cohorts have
offspring following combined in utero and lactation measured Mn in blood or urine in an attempt to serve
exposure to inhaled Mn SO477,78; in young rats exposed as a measure of recent or past Mn exposure or as a
by inhalation to MnSO470; and in old rats exposed to measure of cumulative dose. Several tests are available
MnSO4 or Mn5PO469. These studies provide valuable for measuring Mn levels in whole blood, serum, urine,
information and pharmacokinetic data that are being or hair, and because Mn is naturally present in the body,
used to develop physiologically based pharmacokinetic some Mn is always found in these fluids. Serum Mn
(PBPK) models for Mn. PBPK models are being concentrations in combination with lymphocyte Mn
developed to provide for the ability to conduct route- superoxide dismutase activity appear to be the most
to-route extrapolations, evaluate nasal uptake to the appropriate ways to monitor insufficient Mn intake80.
CNS, and evaluate lifestage differences in Mn On the other hand, studies have attempted to use Mn
pharmacokinetics. Such models will facilitate more biomarkers as a measure of cumulative exposure or to
rigorous quantitative analysis of the available correlate exposure with subclinical or clinical
toxicokinetic data for Mn and will be used to identify neurological effects26,34,55,57,60,81-84. Some studies have
situations that may lead to increased brain accumulation reported that blood Mn was associated with exposure
related to altered Mn metabolism in different human and adverse neurological effects26,52,83,85-88 while others
populations, and develop quantitatively accurate have reported that Mn levels in hair89-91, tooth enamel92,
predictions of increased Mn levels that may serve as a urine 93, or the exposure medium was a significant
basis of dosimetry-based risk assessment 79 . Such predictor of exposure and/or effect outcomes94.
dosimetry-based risk assessments will permit for the
development of more scientifically refined and robust These studies are often difficult to interpret in terms
recommendations, guidelines, and regulations for Mn of prior Mn exposure from ingestion or inhalation
levels in the ambient environment and occupational exposures, due to the fact that Mn is a normal dietary
settings. component and is present in all human tissues and fluids,
so baseline levels must be considered when evaluating
Mn biomarkers of exposure and/or effect studies involving the use of biomarkers of exposure for
Many studies have been conducted in Mn-exposed Mn. A variety of potentially confounding factors must
cohorts to determine whether the detection of Mn in also be considered when evaluating any reported
biological tissues or fluids can serve as biomarkers to correlations between Mn biomarkers and exposure
predict past or current exposure levels and/or the levels. For example, some studies have reported that
potential for adverse health effects. A biomarker is any levels of essential elements such as Mn in human tissues
substance or metabolite that may be measured in the and body fluids may be altered in various disease
body to estimate external exposure levels or to predict states1,95. In addition, the usefulness of biomarkers for
the potential for adverse health effects or disease. There assessing past exposures to Mn is debatable. Because a
are three main classes of biomarkers: biomarkers of variety of factors can influence the levels of Mn in
exposure, effect, and susceptibility. Because Mn can biological samples, it is difficult to develop valid
be measured directly in blood, serum, cerebrospinal biomarkers for use in evaluating workplace exposures
fluid, faeces, or hair, it has been used as a biomarker of or impairment. Because the average intake of Mn from
exposure in occupational studies; however, the food ranges from 2 to 9 mg/day and vitamin and mineral
usefulness of a biomarker of exposure depends on how supplements may also provide up to 20 mg Mn/day,
accurately it reflects the environmental exposure level, these alternative exposures may confound the Mn
which typically requires studies to validate the results reported from screenings or studies when
biomarker. Reliable exposure biomarkers or specific attempting to correlate biological levels with workplace
early biomarkers of effect, such as preclinical exposures to Mn.
neurobehavioural or neurological changes, have not Blood and urine Mn levels have been the most
been established or validated for Mn. In addition, widely used biomarkers of exposure in occupational
although some studies have suggested that some genes studies. Normal whole blood levels of Mn (MnB) range
may serve as susceptibility biomarkers for Mn from 7-12 µg/l and 0.6 to 4.3 µg/l in serum1. Blood Mn
neurotoxicity, there are not any validated biomarkers is not a good indicator of the amount of Mn absorbed
of susceptibility35. shortly before sampling or occurring during the
 SANTAMARIA: MANGANESE TOXICITY 491

preceding days, because it changes very little with correlation between MnB or MnU with various external
inhalation exposure35. Blood Mn may also be influenced exposure parameters on an individual basis, although
and change as a result of dietary intake, which may also there was a difference in the mean levels of MnB and
confound study results96. There is also a lot of inter- MnU between the exposed and control groups. Apostoli
and intra-individual variability in MnB levels, making et al85 evaluated the relationship between Mn exposure
it a more useful parameter to evaluate external exposure levels in air and whole blood and urine Mn levels in a
on the population level rather than on an individual group of ferroalloy production workers. They reported
level. Urinary Mn (MnU) excretion is not a good that these biomarkers could discriminate between
indicator of Mn exposure because Mn is primarily groups of exposed and unexposed control subjects, but
excreted in the bile, and only approximately 1 per cent because of the high variability in the results, these
is excreted in urine1. Hair is also not a reliable indicator biomarkers are not suitable for use on an individual
of exposure, as there is potential for external Mn basis. Levels of MnB have also not been correlated with
exposures that may affect Mn levels in hair, limiting its duration of exposure. Järvisalo et al 97 conducted
use as an indicator of internal dose. The concentration biological monitoring in MMA/MS welders and
of Mn in hair may also be affected by the degree of reported that individual differences were great and that
pigmentation9. Normal urine levels are typically less measurement of Mn in blood or urine may only be useful
than 1 µg/l and hair levels are typically are below 4 for monitoring Mn exposure at the group level. The
mg/kg1. Mn has a half-life in blood of 10 to 42 days43 authors reported that blood and urine Mn levels were
and a half-life of less than 30 hours in urine83. These higher in welders than unexposed controls; however,
relatively brief half-lives make MnB or MnU more the levels were not statistically significantly different
indicative of recent exposure, rather than serving as a and urinary Mn excretion was not correlated with levels
marker of long-term or chronic exposure. In general, of Mn or duration of exposure. Tsalev et al84 reported a
MnB has been used as an indicator of the previous few mean MnB level of 10 µg/l in unexposed workers and
weeks of exposure, generally less than one month and in Mn alloy workers exposed to 1 mg Mn/m3 for 1, 5,
MnU may indicate exposure within the past day or two. 10, and >10 yr, the mean MnB levels were 16, 11, 13,
However, with the exception of individuals with liver and 13 µg/l, respectively, indicating that the
disease, excess Mn is usually removed from the body concentration of MnB did not increase with duration
within several days after exposure ceases, making it of employment. In addition, most studies have not
difficult to measure past exposure. reported a dose-response relationship between exposure
levels and MnB, further limiting the use of Mn
Because the relationship between external and
biomarkers of exposure.
internal measures of Mn has not been clearly elucidated,
studies have attempted to correlate Mn biomarkers with Specific early biomarkers of effect, such as
external exposure levels. Studies have also attempted subclinical neurobehavioural or neurological changes
to use Mn biomarkers as a measure of cumulative or MRI changes have not been established or validated
exposure. Some studies have reported that Mn exposed for Mn although some studies have attempted
workers excreted more Mn in urine and/or had higher to correlate biomarkers and neurological
blood Mn levels as a group than unexposed control effects26,52,55,57,60,82,88. Mergler and Baldwin50 pointed out
subjects. Roels et al83 reported that there was little or a lack of consistency or dose-response relationship
no correlation between MnU or MnB with the current between internal (MnB, MnU, and hair Mn) and
levels of Mn in air or duration of Mn exposure on an external parameters of exposure or neurobehavioral
individual basis in workers from a plant producing Mn outcomes. In addition, the MnB level associated with
oxides and salts. On a group basis, MnB did not correlate neurological effects is not known. Lander et al98 reported
with current Mn air levels, although there was a that although there are no biological limit values for
significant correlation between MnB and past-integrated Mn in blood, subclinical effects have been observed in
exposure. There was a slight correlation between MnU workers with moderate (1-4 µg/l) increases in MnB
and the current Mn exposure levels, but not the past above control groups34,52,88. In a community-based study
exposure estimates. The authors concluded that on a of blood Mn and neurotoxicity, Mergler et al26 suggested
group basis, MnU appears to reflect very recent that blood levels as low as 7.5 µg/l can be associated
exposure while MnB may reflect the body burden of with neurological dysfunction. However, this is within
Mn. Another study by Roels et al34 on workers in a dry the normal range of blood Mn levels (7-12 µg/l), which
alkaline battery plant also reported the lack of casts some doubt on the clinical significance of this
492 INDIAN J MED RES, OCTOBER 2008

MnB level. Most biomarker data have been reported lead, and Mn levels were measured and a statistical
following inhalation exposure in occupational studies, association between blood Mn levels and serum
although there are data on the levels of Mn in biological prolactin levels was reported.
samples in individuals exposed to Mn in drinking water,
Studies have been conducted to evaluate the
food, or parenterally.
relationship between Mn exposure and high signal
Studies of Mn-exposed workers have not been able intensities on T1-weighted brain MRIs and whether such
to detect correlations between blood or urine levels and findings can serve as biomarkers of exposure and/or
neurological measures 60,81,99,100 , while others have effect for Mn9,43,102. It has been observed by using brain
reported an association, typically on a group level rather MRI that Mn can accumulate in the globus pallidum
than on the individual level33,34,52,55,57. Kaji et al81 did after exposure to high concentrations of welding
not detect any significant correlations between MnB or fumes103. However, the clinical significance of elevated
MnU and postural sway index, an early measure of signals detected on MRIs is not established, making it
neurotoxicity in workers at a Mn-refining factory. Smyth difficult to use such data as biomarkers of effect. In
et al100 did not detect a correlation between MnB and addition, the elevated intensities are not necessarily
neurological symptoms or exposure levels in ferroalloy evidence of Mn exposure, as other factors may cause
workers. Based on a lack of an association between increased intensities on MRIs. Other investigators have
blood Mn levels and exposure levels, length of reported that altered responses to a battery of
employment, or neurological findings in workers in an neurofunctional tests (e.g., postural instability when
enamels production facility, along with the abundance visual input is prevented, slowed finger tapping speed,
of negative findings in the literature, Deschamps et al99 increased reaction times or decreased hand steadiness)
concluded that the biological significance of Mn in were useful in identifying early indications of
blood is far from clear. A group of welders exposed to neurotoxicity.
Mn did not have higher Mn levels in blood than the
There are also a variety of potentially confounding
controls and the MnB or MnU levels were not correlated
factors that must be considered whenever evaluating
with the reported decrements in motor function60. The
any reported correlations between Mn biomarkers and
studies that detected elevated MnB and or MnU levels
exposure levels. Elevated serum levels have been
in groups of workers with preclinical neurological
reported in patients with liver failure, congestive heart
symptoms have not identified a dose-response to
failure, infection, rheumatoid arthritis, and psychoses1.
correlate the biomarker with effects, so it is difficult to
The potential for excess Mn accumulation and toxicity
interpret the clinical significance of the reported MnB
is higher whenever liver function and biliary secretion
or MnU levels. Chandra et al55 reported that welders
is decreased and the normal homeostatic functions that
from three plants with Mn levels ranging from 0.44 to
regulate Mn levels are perturbed. Such physical
2.6 mg/m3 had higher MnU levels than control subjects
conditions could lead to the erroneous conclusion that
that were not exposed to Mn and that the serum levels
were too variable to be considered of diagnostic elevated levels of Mn in biological samples are primarily
significance. They also reported that because the due to high external exposures.
welders had higher MnU levels than controls, and also There are also a variety of methods that may be
had more self-reported neurological symptoms, elevated used to analyze MnB or MnU, and there may be
MnU may serve as a biomarker of effect. Luse et al57 differences in how samples are collected, stored, and
reported elevated MnB and Mn in the hair of welders assayed for Mn content. Although there are several
and some neurobehavioural effects in welders exposed methods that may be used to detect Mn in biological
to 0.003 to 2.6 mg/m3 Mn compared to control subjects. samples, atomic absorption spectrophotometry is the
They reported that the welders had significantly higher most common method for detecting Mn in biological
levels of Mn in blood and hair than the control group - samples; however, this method is not very specific or
7.6 and 3.2 times higher, respectively. A recent study sensitive 4. Further research is needed to develop
by Montes et al101 evaluated the relationship between validated biomarkers of exposure, effect, and
blood Mn and prolactin as marker of effect in subjects susceptibility for Mn and to be able to elucidate their
living in a mining district in central Mexico biological and clinical significance. Increased
environmentally exposed to Mn. Blood samples were knowledge of the pharmacokinetics of Mn from recent
obtained from 230 subjects and haemoglobin, prolactin, studies will increase the understanding between external
 SANTAMARIA: MANGANESE TOXICITY 493

exposure parameters, biologic measures, and subclinical neurological effects of Mn. For example, a
neurological outcomes. study by Deschamps et al 99 in enamel production
workers exposed to Mn reported that chronic exposure
Threshold exposure levels for neurotoxicity
(~20 yr) to approximately 0.2 mg/m3 respirable Mn may
There are difficulties with trying to determine the induce potentially mild subjective symptoms (e.g., sleep
dose-response relationship for Mn and subclinical disturbance, headache, weakness) but did not lead to
neurological effects from many of the occupational adverse effects on nervous system function. Gibbs
cohort studies, because in many cases, individual et al108 did not observe neurological effects in workers
personal exposures to respirable Mn with subject- in a metal-producing plant exposed to levels averaging
specific linked results from neurological tests were not 0.18 mg/m3 total Mn dust (0.066 mg Mn/m3 respirable
evaluated or reported in the studies. In addition, there dust). More recently, studies by Myers et al112,114 did
are difficulties in establishing a dose-response for Mn not detect any subclinical or clinical neurological effects
from the studies of Mn-exposed workers because (i) or deficits deemed to be associated with Mn exposure
the chemical forms of Mn differ in these industries in large cohorts of miners exposed to a mean of 0.21
(salts, dust, oxides, fumes), (ii) there are different mg Mn/m3 respirable dust (arithmetic mean) and smelter
exposure scenarios involving different activities, (iii) workers exposed to 0.82 mg Mn/m3 respirable dust
the studies report different exposure measures (TWA (arithmetic mean). The authors evaluated a
vs. peak samples; area vs. personal; total dust vs. comprehensive range of nervous system endpoints in
respirable), (iv) the neurological endpoints differ among 489 mine workers and 509 smelter workers and
studies, and (v) many studies have design limitations. examined exposures ranging from 0 to 5 mg/m3, using
It has been known for several decades that chronic inhalable Mn as the exposure metric. For the study with
exposure to elevated airborne levels of Mn in mining smelter workers114, the authors concluded that the most
and manufacturing settings is associated with an likely explanation for weak and inconsistent findings
increased risk of certain neurological effects. In with implausible or counterintuitive exposure–response
addition, subclinical neurological effects have been relationships is chance, and that this is essentially a
reported in Mn-exposed cohorts such as welders, negative study, providing only weak and unconvincing
reportedly as a result of using Mn-containing evidence for exposure effects in general, or for the
consumables (e.g., electrodes and wires) and exposure notion of a continuum of effects. Young et al113 re-
to Mn in steel components25,54,55,104. However, because evaluated the worker cohort evaluated by Myers et al114,
Mn homeostasis is so effective and because of which included 509 exposed workers from Mn smelters
competition with iron for availability of transferrin to and 67 unexposed workers. Young et al113 concluded,
transport Mn across the blood–brain barrier, Mn “despite a comprehensive range of endpoints and levels
neurotoxicity is quite rare105. There is debate about what of exposure ranging from environmental to industrial,
the threshold of Mn exposure is for the potential the large smelter study of Mn workers found no
induction of subclinical neurological effects106. Several convincing effects at exposure levels (expressed as
studies during the last two decades provide for the inhalable dust) at, and considerably above, the current
determination of Lowest Observed Adverse Effect ACGIH TLV of 0.2 mg/m3”. Thompson and Myers115
Levels (LOAELs) or No Observed Adverse Effect conducted a more in-depth statistical analysis of the
Levels (NOAELs) for neurological effects in workers neurobehavioural data from the study of Myers et al114.
exposed to Mn in settings such as smelters, dry alkaline The association between neurobehavioural test scores
battery manufacturing facilities, and ferromanganese and cumulative Mn exposure was estimated, and the
alloy production plants33,34,52,62,82,88,99,107-114. Scientific investigators demonstrated that a linear model could
understanding of the impact of Mn exposure on nervous be fit to these data with a statistically significant trend
system function leads to the hypothesis as there should of an association between neurological effects and
be no adverse impact on function at low exposures, increasing exposure levels; however, the exposure-
given that Mn is an essential element in human nutrition; response relationship was highly nonlinear. Fitting a
that there should be some threshold for exposure above linear regression inappropriately to a nonlinear function
which adverse effects may occur; and that these adverse can lead to misinterpretation of the results, and can
effects may increase in frequency with higher levels of obscure the existence of a threshold and this type of
exposure beyond that threshold114. There are data to error is most likely to occur with small data sets that
indicate that an exposure threshold exists for the are frequently evaluated in occupational studies.
494 INDIAN J MED RES, OCTOBER 2008

Other studies report the potential for subclinical most informative in terms of dose-response
effects at lower Mn exposure levels in the workplace. interpretation, because the study examined a well-
Lucchini et al82 reported that neurobehavioural effects defined exposed population with apparently little or no
in ferroalloy workers at levels around 0.19 mg Mn/m3 mixed exposure to other neurotoxicants; had a well-
total dust and Mergler et al52 reported subclinical matched control group by age, gender, race, and pay
neurological effects in workers exposed to a mean of grade; used well-established and relatively objective
0.112 mg Mn/m3 respirable dust. Roels et al33 conducted measures of neurological deficits (as opposed to self-
a cross-sectional study of 141 male workers exposed to reported symptoms); reported air data in terms of TWA
MnO2, Mn tetroxide (Mn3O4), and various Mn salts respirable fractions; and perhaps most importantly,
(sulphate, carbonate, and nitrate) in a manganese oxide reported individual exposure data and response
and manganese salts production facility. EPA information for each individual worker106. It should be
determined a LOAEL of 0.97 mg/m3 from the Roels noted that Gibbs et al 108 examined relatively low
et al 33 study, based upon the findings of impaired exposure conditions, with mean airborne respirable
neurobehavioural function in workers whose average levels of 0.066 mg/m3, and did not find an increased
Mn exposure was estimated by the geometric mean incidence of neurobehavioural effects in the Mn
TWA of total airborne Mn dust at the time of the study. exposed workers106. The Roels et al34 study, which
A follow-up study on the 1987 cohort was conducted reported increased neurobehavioural deficits in workers
by Crump and Rousseau62. The follow-up study reported in a dry alkaline battery plant exposed to mean airborne
that there was no significant progression of any respirable levels of 0.215 mg Mn/m3, also has the
previously reported neurological effect during a chronic methodological attributes described above; however,
exposure period of 14 years to relatively constant they examined fewer endpoints (three measures of
exposure levels. Roels et al 34 conducted a cross- psychomotor function, compared to five measured by
sectional study of 92 male workers exposed to MnO2 Gibbs et al108), and the response data were reported in
dust in a Belgian alkaline battery plant. The Mn exposed quantal terms, rather than continuous, which limits the
group had been exposed to MnO2 for an average of 5.3 information that can be obtained from dose-response
yr and the geometric mean of the workers’ TWA airborne modeling.
Mn concentrations was 0.215 mg Mn/m3. Roels et al34
reported increased neurobehavioural deficits in workers Benchmark modeling conducted with the data from
exposed to mean respirable levels of 0.215 mg Mn/m3 Roels et al 34 and Gibbs et al 108 battery and metal
and EPA derived a LOAEL of 0.15 mg Mn/m3 from the producing workers by Clewell et al 61 resulted in
Roels et al34 study, based on an occupational lifetime BMDL10 ranges of 0.10-0.27 mg/m3. The results suggest
integrated respirable dust concentration divided by years that chronic exposure to airborne respirable levels up
of exposure. The LOAEL from the Roels et al33 study to approximately 0.1-0.3 mg Mn/m3 as an 8-hour time
was based on total Mn dust of mixed forms, whereas weighted average should pose little to no risk of
the LOAEL from the other study34 was based on the developing subclinical signs of neurobehavioural
measured respirable dust fraction of MnO 2. Roels effects. This evaluation provides the best indication that
et al63 conducted an eight-year follow-up of the 1992 a TWA occupational exposure limit between 0.1 and
cohort and reported a complete reversal of one of the 0.3 mg/m 3 respirable Mn should be protective of
neurofunctional endpoints, even though these workers subclinical neurological effects in the workplace. Such
were still exposed to air concentrations above 0.1 mg benchmark modeling and the calculated doses may also
Mn/m3. There were no adverse effects reported in the be used to establish recommended inhalation reference
low exposure group at follow up and the previously values for ambient air levels of Mn. Benchmark
abnormal “precision of hand-forearm movement” eye- modeling of these studies34,108 in battery and metal
hand co-ordination test normalized in this group. In the producing workers has been conducted by governmental
agencies and the resulting values have been used to
low exposure group, Mn levels decreased from 0.4 mg
develop reference concentrations or suggested ranges
Mn/m³ in 1987 (measured as total dust) to 0.13 mg/m3
for ambient or occupational air levels3,116,117.
in 1995. These results suggest that there is a threshold
for at least one of the end-points evaluated and that the Risk assessment of an essential element
effect of Mn on this particular effect was reversible.
The conduct of risk assessments for an essential
The study by Gibbs et al108 on 75 workers in an element such as Mn presents challenges because of the
electrolytic Mn metal-producing plant is perhaps the need to consider the balance between essentiality and
 SANTAMARIA: MANGANESE TOXICITY 495

toxicity. For each essential trace element, there are two Concepts and progress in setting intake guidelines
ranges of intake associated with adverse health effects: for essential elements have been reviewed by Mertz121,
intakes that are too low and can lead to nutritional Olin118, Sandström 122, Goldhaber et al123 and Fraga124
deficits and intakes that are too high and can lead to and a Nordic Working Group on Food and Nutrition
toxicity. Between these two ranges, there is a range of prepared a report entitled “Risk evaluation of essential
safe and adequate intakes that is compatible with good trace elements – essential versus toxic levels of
health; however, the challenge is to define that range intake”125.
quantitatively118. Importantly, essential trace elements
Recommended and regulatory levels for
such as Mn are subject to homeostatic control
environmental Mn
mechanisms that may include regulation of absorption,
excretion, and tissue retention. The ability to regulate A variety of agencies have prepared risk
tissue levels is important to consider when conducting assessments for Mn and developed recommended
a risk assessment to determine safe exposure levels for reference concentrations or regulations for chronic oral
an essential element such as Mn. Recent or inhalation exposure levels for Mn in the
pharmacokinetic studies conducted with Mn provide environment. This discussion does not include
invaluable information about the ability to workplace regulations for Mn, which are reviewed in
homeostatically regulate Mn following oral or Santamaria et al25 Exposure guidelines for ambient
inhalation exposure79. inhalation exposure to Mn include the following: the
U.S. Environmental Protection Agency reference
Based on an ambient air concentration of 0.023 µg
concentration (RfC) is 0.05 µg/m3, the Health Canada
Mn/m3 cited by the Agency for Toxic Substances and
tolerable daily intake (TDI) is 0.11 µg/m3; the World
Disease Registry (ATSDR), the estimated average daily
Health Organization (WHO) air quality guideline is
intake of Mn would be 0.46 µg Mn/day (assuming 20
0.15 µg/m 3; the Agency for Toxic Substances and
m3/day inhaled and 100 per cent Mn is deposited in the
Disease Registry (ATSDR) minimum risk level is 0.4
lungs and 100 per cent is absorbed, very conservative
µg/m3; and the California EPA reference exposure level
assumptions)3. In comparison, the daily “dose” from
(REL) is 0.2 µg/m3 - (CalEPA has a current draft REL
food and drinking water may be 114.24 µg/day
of 0.09 µg/m3). In 1994, the US EPA developed a range
(assuming 3.8 mg/day ingested from food and water,
of possible RfC values of 0.09 – 0.2 µg/m 3 using
3% absorption) 3. Using the aforementioned highly
benchmark doses developed from the Roels et al 34
conservative assumptions, the amount of Mn absorbed
cohort 116. These recommendations and guidelines
from food may be greater than 250 times of the amount
apply to respirable dust, which corresponds roughly
of Mn inhaled in ambient air (using an assumption that
to PM 5 (fraction of airborne particles with an
10 per cent inhaled Mn is absorbed through the lungs,
aerodynamic diameter of 5 µm or less). The oral
the difference is 2,500-fold). Although the potential dose
exposure recommendations and guidelines include
of Mn resulting from inhalation is so low compared to
EPA’s oral reference concentration of 0.14 mg/kg/day,
the dose from dietary sources, there have been
EPA’s maximum contaminant level (MCL) of 0.05 mg/l
uncertainties expressed about the potential differences
in water (based on aesthetic properties), and the WHO
in homeostatic regulation of Mn following inhalation
drinking water guideline of 0.4 mg/l (health-based)119.
versus oral exposure 119,120 . To address these
uncertainties, there have been several pharmacokinetic There are significant differences in magnitude
studies in rats and monkeys conducted over the last between the recommended exposure levels for oral
fifteen years by scientists at the Hamner Institutes for versus inhalation exposure to Mn. The existence of well-
Health Sciences79. Study results indicate homeostatic known homeostatic mechanisms has led regulatory
mechanisms control excess inhaled Mn by increasing authorities to conclude that the body is able to handle
biliary excretion similar to excess oral Mn intake and substantial variations in dietary Mn on a daily basis
data from the pharmacokinetic studies will be used to without adverse consequences due to hepatic excretion
develop and validate PBPK models that will address of Mn and the low absorption of Mn through the
remaining uncertainties regarding how the body handles gastrointestinal tract. However, there have been
inhaled versus oral Mn (e.g., absorption, tissue uncertainties expressed regarding the pharmacokinetics
distribution, excretion). Such information may be used of Mn following inhalation exposure versus oral
to develop more scientifically robust risk assessments exposure and concerns expressed about the potential
for this essential element. 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 response evaluation as recommended by WHO129. The
range of recommended exposure levels for Mn exposure use of CSAFs and PBPK models can reduce the need
by inhalation, reflecting the different quantitative for the application of various uncertainty factors when
approaches taken and different qualitative assumptions developing reasonable and appropriate reference values,
used by the Agencies in developing the recommended guidelines, and regulations for this essential element.
levels. Although all of these Agencies used the same
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