neurodevelopmental impacts of prenatal drinking water exposure to manganese and other metals on...
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Manganese Exposure 1
Neurodevelopmental impacts of prenatal drinking water exposure to manganese
and other metals on children
Jeronda Scott and Melissa Miller
Clark University
Manganese Exposure 2
Neurodevelopmental impacts of prenatal drinking water exposure to manganese
and other metals on children
Jeronda Scott and Melissa Miller
Abstract
The aim of this paper was to review the scientific research published to date on the
potential effects on neurodevelopment and behavioral disorders in children
exposed to manganese and other metals via drinking water and optimum
biomarkers to measure exposure. This was done by using online research databases
such as Google Scholar and PubMed, etc. It was found that there is an association
between exposure to manganese and neurodevelopmental deficits in young
children, and that there are large gaps in the body of research that must be done to
better understand these issues. Improvements to exposure limits must be made. We
hope that further research on optimal biomarkers, such as dentine, will help to
contribute to the knowledge of negative neurological impacts from manganese
exposure.
1. Introduction
Manganese (Mn) is an essential nutrient found in all living organisms and is
naturally present in rocks, soil, water, and food making it abundant in the
environment. It is important to understand its potential impacts not only because of
its natural abundance but also because it is a recent gasoline additive and may be
even more widespread in the environment in the future (Schettler, Solomon, &
Manganese Exposure 3
Valenti, 2000). Mn is required for normal amino acid, lipid, protein, and
carbohydrate metabolism (Erikson,Thompson, & Aschner, 2007)). However,
overexposure to Mn can have significant neurotoxic effects, and it is likely that there
is a greater effect on fetuses, newborns, and young children. Due to lack of research,
Mn concentrations in drinking water are not currently regulated in the United
States. Health based guidelines for the maximum level of Mn in drinking water have
been established by the EPA, and are currently set at 300 µg/L (U.S. EPA 2004).
While there is a healthy amount of research analyzing the effects of postnatal and
occupational exposure to Mn, there is a lack of research and evidence of the effects
of Mn exposure on a more vulnerable group, babies in utero and young children.
The Holliston Health Project is a collaborative initiative to examine if
children in the town of Holliston, Massachusetts are being exposed to detrimental
levels of chemicals, and if this exposure is leading to any adverse health effects. In
this literature review we closely examine Mn and other heavy metals and their
effects on children from in utero to age 10. The purpose of this literature review is to
support the Holliston Health Project by providing an in-‐depth look at the state of
research for a variety of chemicals and their potential impact on
neurodevelopmental-‐cognitive-‐behavioral outcomes from exposure during
pregnancy, and biomarkers that can be used to measure those exposures.
2. Background
2.1 Manganese Metabolism in Children
Manganese Exposure 4
Mn is crucial to bone and tissue development as well as the immune system.
However, there are many correlations between excessive postnatal exposure to Mn
and interference with normal brain development (Wasserman et al. 2006, Bouchart
et al. 2010, Khan et al. 2011). Too much exposure can cause Mn to accumulate in the
brain, particularly the central nervous system, leading to neurological damage. Since
Mn is an essential element, it stands that there should be a level above which
negative impacts will occur.
Infants and young children face higher risks from exposure to metals than
adults because adults have fully developed homeostatic mechanisms which limit
absorption of ingested metals. Because infants and young children have not
completely developed these mechanisms, their bodies are unable to correctly
process these metals, and retention of metals is higher in infants than in adults.
According to Lönnerdal (1994) bile flow is low in infants, which may result in a
lower excretion of Mn via bile, causing higher retention of Mn in tissue. Moreover,
certain tissue sites have a high affinity for Mn, and although these sites are saturated
in adults, they strongly retain Mn in infants (Ljung & Vahter, 2007).
There is an increasing body of evidence that internal and external exposures
to chemicals and metals cause a variety of physiological impacts at different
developmental stages. As a consequence, windows of vulnerability open when
susceptibility to environmental chemicals is heightened. Therefore it is crucial to
look at the timing of exposures in addition to levels of exposure. The prenatal period
is specifically important when examining critical windows of exposure. During in
utero development and early childhood, the tissues and organs of the body undergo
Manganese Exposure 5
stages of rapid development, during which toxic exposure or nutrient deficiency can
lead to long-‐term effects. (Andra, Austin, Wright, & Arora, 2015).
There are two instances of rapid brain development for infants. The first is
during pregnancy, and the second occurs several months after birth. The fetus is
especially vulnerable to Mn during the development period in utero; Mn easily
crosses the placenta through active transport mechanisms, where it results in
increased levels in fetal circulation (Andra et al. 2015). Thus, fetal life can be
regarded as a period of great vulnerability to Mn, even at low environmental levels.
Mn specifically targets the nervous system, and for a developing child, this can mean
interruption of crucial development of the nervous system (Yu, Zhang, Yan, & Shen,
2014).
Since the central nervous system develops sequentially and are
interdependent, any interruption in the fetal development may lead to deficiencies
in later stages of development (Rodríguez-‐Barranco, et al. 2013). Beginning as soon
as the second week of gestation, the outer layer of the embryo begins to fold to
develop the neural tube, the early beginnings of the brain. After, the central nervous
system begins to develop, creating 100 billion nerve cells and 1 trillion glial cells,
which must undergo a slew of changes and formations during the process of
development (Sanders et al. 2015). Because these developments are successive, a
reliable and effective biomarker provides the possibility of determining when
exposure occurred, and what interruptions took place, which can then determine
how these interruptions affect neurological development. The timing of
environmental exposures is incredibly important; the time at which the child is
Manganese Exposure 6
exposed to the metal is equally important as the level of exposure. (Andra et al.
2015)
2.2 Manganese Guidelines for Drinking Water Quality
The current United States health-‐based guideline for Mn in drinking water is
partly based on debatable assumptions, without deeper research. The previous
guideline value of 500 µg/L was set originally in 1958 and was based on the distinct
impairment of water potability by excessive Mn concentrations (WHO 2004). Due to
the staining properties of Mn, the guideline value was lowered to 100 µg/ in the
World Health Organization’s (WHO) first edition guidelines for drinking water
quality (Ljung et al. 2007). Various countries have set standards for Mn of 0.05
mg/liter, to prevent problems with discoloration (WHO 2011). At concentrations
above 0.1mg/liter,Mn gives water an undesirable taste and stains plumbing fixtures
and laundry, and at concentrations as low as 0.02 mg/litre, Mn can form coatings on
water pipes that may later slough off as a black precipitate (U.S. EPA. 2004). Based
on health motives, the guideline value was raised to 500 µg/L in the 1993 second
edition (WHO 2004).
Currently, the health-‐based guideline value for Mn in water is in the United
States 400 µg/L. It is based on an estimated no observed adverse effect level
(NOAEL) for Mn in food. The NOAEL of 11 mg of Mn a day, is partly based on a
review by Greger (1998), who studied adults with Western diets. The current
guideline value for drinking water is likely low enough to protect adolescents and
adults but not younger children. Mn is often considered one of the least toxic metals
Manganese Exposure 7
via the oral route due to homeostasis mechanisms in the body that limit
gastrointestinal absorption. However, with the growing evidence of neurotoxicity
through oral routes, especially in infants and young children, the guideline needs to
be reevaluated. Infant formula already contains high levels of Mn (300 µg/L on
average, but ranging between 66 and 856 µg/L, depending on the brand). If formula
is prepared with water containing acceptable levels of Mn based on WHO guidelines,
it is highly possible that infants will receive an unacceptable dose of Mn.(Ljung et al.
2007).
3. Methods
To understand the state of the research, papers were found from a wide
variety of subjects and compared. Research was compiled from PubMed and Google
Scholar using combinations of search terms such as “manganese”, “in utero
exposure”, “prenatal exposure”, “drinking water”, “neurodevelopment”,
“neurotoxin”, “co-‐exposure” and so on. Additional papers were also found through
citations from particularly relevant papers.
When using PubMed, MeSH terms were used to find similar papers listed
under the same topic. MeSH terms that were particularly useful included
“pregnancy” “manganese” “drinking water” “neurodevelopment” and
“women’s/children’s health”.
Papers that were selected contained material that demonstrated relevance to
our research question, or that demonstrated holes in the current state of research.
4. Results
4.1 Biomarkers
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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 is a great need for an effective biomarker to analyze
health impacts from prenatal exposures, but they are often difficult to find, and are
not always accurate; no specific accurate biomarker for Mn has been determined.
Research has so far relied on urine, umbilical cord blood and serum, and hair. There
is new research analyzing the usefulness of tooth dentine, which shows promise.
(Santamaria 2008, Arora et al. 2015),
4.1.1Hair
Hair is a common biomarker used to study the neurological effects of Mn
contamination on young children. Using hair, Rodríguez-‐Barranco et al. (2013),
found that,in relation to Mn, results of a meta-‐analysis suggest that a 50% increase
in hair levels would be associated with a 0.7 IQ decrease of children aged 6-‐13.
There are other studies that have found an association with adverse health effects
on children using hair. However, hair reflects past exposure and exposure over the
past few months, and with age, Mn concentrations decrease in hair. Researchers
(Sanders, Henn, & Wright 2015) suggested that hair is not a reliable biomarker due
to the potential for external Mn exposures that may affect Mn levels in hair, limiting
its use as an indicator of internal dose, and that it also may be affected by the degree
of pigmentation.
4.1.2 Urine and Blood
A large portion of the research on Mn exposure and its neurological and
behavioral effects have measured Mn in blood or urine. There are several tests
Manganese Exposure 9
available that can measure Mn levels in whole blood, serum, or urine. However, Mn
is naturally present in the body, thus some Mn is always found in these fluids
(Santamaria 2008). Both blood and urine have relatively short half-‐lives, which
makes them more indicative of recent exposure, rather than serving as a marker or
long-‐term or chronic exposure. Due to high variability of the results, they cannot be
considered as suitable biomarkers of exposure (Apostoli 2000). This is in agreement
with Droz (1993) who, on the basis of pharmacokinetic modeling, stated that for
half-‐lives below 10 h, there is no statistical advantage in using biological monitoring.
According to Santamaria (2008) urinary Mn is not a less suitable biomarker
because it is primarily excreted in the bile, and only approximately 1% is excreted in
the urine. Blood Mn has been the most commonly used biomarker of exposure, but
the short half-‐life of Mn in blood may miss periods of peak exposure and Mn is also
not reliable in blood due to well-‐regulated by homeostatic mechanisms in adults
(Gunier 2013). Change in dietary intake may also influence blood Mn levels which
may invalidate study results (Santamaria 2008).
Despite urine and blood not being ideal biomarkers, they have still been
useful in contributing to the increase of knowledge of Mn exposure. Many studies
have found associations using urine and blood as biomarkers. Yu et al. (2014)
compared levels of Mn in serum from umbilical cord blood with results from
neonatal behavioral neurological assessment (NBNA). They found that high Mn
levels in umbilical cord serum were correlated with poor NBNA performance. Based
on their results, they determined that any Mn concentration in blood over 50 ug/L is
Manganese Exposure
10
unsafe. This study showed that prenatal exposure to Mn at environmentally relevant
level was significantly and negatively associated with fetal neurodevelopment.
4.1.3. Dentine
It is widely regarded (Arora et al., Andra et al., Gunier et al., Hare et al.) that,
despite the usefulness of urine, umbilical cord blood, and hair, there is a need to find
a more effective biomarker for Mn exposure, particularly one that can be used
retrospectively. In determining the effects of Mn exposure in utero, it is important to
find a reliable, retrospective biomarker in order to demonstrate the levels of Mn
exposure during development.
The biomarkers that have been extensively used thus far (hair, blood, and
urine) tend to be unreliable and variable, and their accuracy is limited (kasperson).
They fail to provide exposure timing, levels of cumulative exposure, and lack the
potential to provide information on the specific source (Andra et al. 2015). Blood
has been used quite frequently, but may not be the most reliable measurement tool
because fully matured bodies regulate Mn concentrations effectively and the half-‐
life of Mn is brief. Hair has also been useful, but can easily be contaminated by
external environmental factors. For these reasons, commonly used biomarkers are
not the most effective measure of exposure. (Gunier et al. 2013).
Dentine in baby teeth may be an ideal way to measure in utero exposure to metals.
Unlike other the biomarkers, dentine provides exposure data that is comparable to
data from a longitudinal study, but can be obtained retroactively. Dentine, a tissue in
the teeth, begins to develop as early as the second trimester (between the 13th and
19th weeks of gestation), and then enamel and dentine begin to form outward,
Manganese Exposure
11
similarly to the formation of growth rings on trees (Gunier et al. 2013). Mn is
absorbed by the tissue as the teeth form. Due to disturbances caused by protein
matrix deposition during birth, the teeth form a neonatal line, and that line can be
used to distinguish between prenatal and postnatal exposures. Afterwards, the teeth
develop daily growth lines, which create an image of daily exposures after birth.
Measurements of Mn exposures from this point until almost a year after birth can be
taken, which can be used to characterize both prenatal and postnatal exposures.
Analytical technology can pinpoint when the exposure occurred, and how much of
the exposure was incorporated into the teeth (Gunier et al. 2013, Andra et al. 2015).
Both Gunier et al. and Arora et al. analyzed the usefulness of dentine as a biomarker.
In a study analyzing the distribution of Mn in primary teeth, Arora et al. found not
only that Mn is distributed in a distinct and consistent pattern, but also that Mn
leaves a distinct high concentration area in the prenatally formed dentine. This
finding suggests that deciduous teeth have great potential as a useful biomarker for
prenatal Mn exposures (Arora et al 2011). Both groups used laser-‐ablation-‐
inductively coupled plasma-‐mass spectrometry (LA-‐ICP-‐MS) to analyze Mn
exposures through deciduous teeth. Gunier et al. found that their findings using LA-‐
ICP-‐MS were correlated with their estimates of prenatal environmental exposures to
Mn. LA-‐ICP-‐MS allowed them to retroactively gain a characterization of exposure as
it occurred
In the study conducted by Gunier et al., it was found that Mn levels in teeth
were higher during the second trimester than the third, which conflicts with
findings from previous studies using cord blood as a biomarker that found highest
Manganese Exposure
12
levels near the end of pregnancy. Dentine reflects direct exposure to Mn, and while
there are fluctuations in Mn concentrations in blood during pregnancy, there is no
known instability in tooth mineralization. This pattern found by Gunier et al.
suggests that fetal uptake of Mn in the second trimester is higher than in later stages
of pregnancy, and that dentine is a more effective measure of this uptake.
Arora et al. found similar results; they found that the cord blood levels of Mn were
significantly positively correlated with the Mn concentrations in dentine adjacent to
the neonatal line, suggesting that dentine is an effective biomarker. At other points
in the neonatal line, however, there is not an association. This is not surprising;
deposits of Mn in dentine are a direct reflection of the exposure, while cord blood is
only a direct reflection of Mn levels in the fetus at the time of birth. Blood Mn can
vary during pregnancy, and has a half-‐life of approximately four days. (Arora et al.
2013).
Gunier et al. also argues that previous studies measuring Mn exposures with
enamel instead of dentine (Ericson et al. 2007) are less effective at determining the
timing of exposure than dentine because of differences in formation; dentine is
mineralized immediately to its almost final stage, while enamel is mineralized
slowly throughout development (Arora et al. 2013). Arora et al. agrees, because
most metals being incorporated into the tooth are absorbed after all of the enamel
matrix is formed in the tooth, and therefore, enamel cannot be used to determine
the timing of exposure. More research should be conducted to analyze the
differences and advantages in these two tissues as biomarkers
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4.2 Effects from Exposure through Drinking Water
Approximately 20% of drinking water, both public and individual, is sourced
from groundwater, and 50% of United States citizens receive their drinking water
from a groundwater source. It has recently been recognized that groundwater is
susceptible to contamination, particularly from organic chemicals that result from
agricultural activities (Safe Drinking Water). Mn is also commonly found in
groundwater because of the weathering and leaching of rocks or minerals, which
release Mn into aquifers. Although there is currently no public policy regulating
drinking water concentrations of Mn, the EPA has released a health advisory for its
adverse neurological effects associated with oral ingestion and has set a health-‐
based guideline of 300 µg/L (EPA 2004). The World Health Organization has set its
own guideline as 400 µg/L, slightly higher than the EPA (WHO 2008).
Approximately 45% of wells for public use in New England have drinking water
concentrations of Mn greater than 30 µg/L, and nationally, and close to 5% of
household wells in the United States have concentrations of Mn greater than 300
µg/L (Groschen et al. 2009, U.S. Geological Survey 2009).
The neurodevelopmental and behavioral effects of children’s exposure to Mn
in drinking water are varied, but well established. Water Mn has been significantly
negatively associated with academic performance in several studies; Zhang et al.
(1995) found children with elevated hair concentrations of Mn had poorer school
records than their peers, and performed more poorly on mathematics and language
tests, while Khan et al. (2011) found that concentrations of Mn over 400 µg/L were
Manganese Exposure
14
significantly negatively associated with poor performance on math exams, but not
on language exams. In another study, it was found that children exposed to water
with high Mn concentrations had a 6.2 full scale IQ point difference than other
children who had not been exposed (Bouchard et al. 2010)3. Wasserman et al.
(2006) studied an area in which 80% of the wells in the study area had Mn levels
over 400 µg/L, with the average concentration being 795 µg/L. Children exposed to
the contaminated drinking water in this area had significantly lower Full-‐Scale,
Performance, and Verbal raw scores on the Wechsler Intelligence Scale for Children.
A separate study analyzing the effects on IQ found that, with a median water
concentration of Mn of 34 µg/L, there was a significant negative association
between IQ and exposure to Mn (Bouchard et al. 2011).
He et al. (1994) tested neurobehavioral behaviors of 92 children aged 11-‐13
who lived in an area with high levels of Mn in sewage irrigation and a control area.
The area with sewage irrigation had significantly higher levels of Mn in the drinking
water during the study period, and the children in that area had significantly higher
concentrations of Mn in their hair. Mn levels in hair correlated negatively with
performance on a number of neurobehavioral tests. The concentrations of Mn in the
drinking water in the control group were 30-‐40 ug/L, while the sewage irrigation
group had levels between 240-‐350 ug/L.
It is also suggested that Mn exposure has an inverted U-‐shaped association
with Mn levels and blood and neurodevelopment, suggesting that both low and high
levels can be detrimental to development (Claus Henn et al. 2010).
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15
There is a small but notable body of literature studying the effects of prenatal
exposure to Mn in drinking water, and the consequential effects on the
neurodevelopment of the child through early childhood. Gunier et al. (2015) and
Chung et al. (2011) enlisted a cohort of pregnant women, and followed their
children as they grew older to study neurodevelopmental effects. Both Gunier et al.
and Chung et al. found that there were significant deficiencies in motor development
related to exposure to water Mn,, and while Gunier et al. found additional
deficiencies in mental development, Chung et al. did not. Also, Gunier et al. found
that there was a significant relationship between prenatal Mn levels and 6-‐month
mental and motor development for children born to mothers with low
concentrations of hemoglobin, and therefore lower iron levels, during pregnancy.
Children in a study in Bangladesh were found to be significantly more likely
to display aggressive behaviors at age 10 after prenatal Mn exposure from drinking
water. As with Gunier et al.’s findings, results from this study also showed that there
was a tendency for lower IQ in girls who were born to mothers with low iron levels.
The finding that prenatal Mn exposure can lead to behavioral effects in
childhood is supported by Ericson et al. (2007) who, although the source of Mn is
unknown, found that there is an association between Mn deposits in tooth enamel
and behavioral outcomes in childhood. Levels of Mn from the 20th week of pregnancy
were significantly and positively associated with measures of behavioral
disinhibition.
4.3 Risks from Metals
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4.3.1 Lead
Lead can be present in drinking water delivered through lead pipes or pipes
joined with lead solder may contain lead. Unlike other heavy metals, there is
extensive research that address leads adverse health effects in humans and early
life. In utero exposure to lead was adversely associated with cognitive and social
development (Kim 2009, Claus Henn 2011, WHO 2014). There is no known level of
lead exposure that is considered safe
Young children in particular are vulnerable to the toxic effects of lead and
can suffer profound, permanent adverse health effects, mainly affecting the
development of the brain and nervous system. Pregnant women exposed to high
levels of lead can be subject to miscarriage, stillbirth, premature birth and low birth
weight, as well as minor malformations. Young children are specifically vulnerable
because they absorb 4 -‐ 5 times as much ingested lead as adults from a given source
(WHO, 2004). Strong evidence suggests that lead exposure also leads to subtle
neurological effects, developmental delays, and behavioral abnormalities in
otherwise normal-‐appearing children. (Schettler et al. 2000). In addition, Wright &
Baccarelli (2009) establish that co-‐exposure to Mn and lead may decrease
spontaneous motor activity and learning ability in rats as compared with exposure
to only one of these metals, which may cause damage to brain development during
pre-‐ and post-‐natal life.
4.3.2. Arsenic
Arsenic is naturally present at high levels in groundwater of numerous
countries. There has been a number of research done on Arsenic showing that,
Manganese Exposure
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water contaminated with high levels of Arsenic and used for drinking, food
preparation and irrigation of food crops poses a great threat to public health.
Arsenic exposure affects almost every organ system in the body including the brain.
Still, there is limited studies on the effect of exposure in early life.
In lab animals, it has been found that high exposure of Arsenic causes
malformations. In addition, some studies suggest that arsenic exposure may lead to
spontaneous abortion and stillbirth and may affect neurological development,
particularly the development of hearing (Schettler et al. 2000). Drinking water is
one of the main pathways of arsenic ingestion. It has been well established that
arsenic exposure negatively correlates with neurodevelopment. Studies have found
that lowered IQ is one of the most commonly reported significant effect (Tyler &
Allan, 2014). Results of meta-‐analysis show that for every 50% increase in arsenic
levels, there could be a 0.5 decrease in the IQ of children aged 5-‐15 years
(Rodríguez-‐Barranco et al. 2013).
4.3.3.Trichloroethylene (TCE)
There is a wide body of evidence suggesting connections between exposure to
TCE contamination of drinking water during pregnancy and the development of
congenital heart defects (Forand et al. 2011, Watson et al. 2005). In a study in
Endicott, New York, which experienced a massive chemical spill in 1979, that
contaminated the drinking water supply with TCE, 44 children that lived in the area
of analysis were born with at least one birth defect between 1983 and 2000,
including cardiac birth defects. The increase in cardiac defects in children was
significant. (Forand et al. 2011).
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Additionally, there is a building body of evidence that prenatal exposure to
TCE impairs neurodevelopment, and it has been studied well in rodents. Noland-‐
Gerbec et al. described altered brain chemistry in the offspring of rats exposed to
TCE during pregnancy, and another study found that prenatal exposure to TCE
caused increased exploratory and locomotive behaviors in rats (Taylor, et al. 1985).
A similar study found that maternal ingestion of TCE through drinking water during
pregnancy resulted in altered social behaviors, particularly autism-‐like social
behaviors and increased aggression in male mice (Blossom 2008).
In humans, exposures to TCE in water during pregnancy have been linked to
developmental impacts in children. In 1979, 4,100 gallons of 1,1,1,-‐TCE spilled at a
manufacturing facility in Endicott, New York. The next year, groundwater samples
revealed a large amount of contamination of both TCE and tetrachloroethylene,
along with a number of other volatile organic contaminants in addition to
contaminants from previous spills and incidents. Populations were exposed to the
contamination through soil vapor intrusion (SVI), where volatized contaminants
rose through air pockets in soil into nearby building structures. It was found that
women living in areas with risk of exposure to TCE from SVI experienced low birth
weight (LBW) or were small for gestational age (SGA), possibly as a result of growth
restriction in utero. Similar results of LBW were found in northern New Jersey and
Tuscon, Arizona, both of which also had groundwater contaminated with TCE (Bove
et al. 1995, Rodenbeck et al. 2000). In addition, SGA was significantly more
prevalent in a retrospective study of Woburn, Massachusetts, when mothers had
been exposed to TCE contaminated drinking water (MDPH, CDC, and MHRI 1996).
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Analysis of the public drinking water contamination in New Jersey also
correlated prenatal trichloroethylene exposure with a number of adverse effects
including defects in the central nervous system and neural tube development, and
oral clefts (Bove et al. 1995).
There is still limited information on the effects of TCE exposure during
pregnancy on neurological development.
4.3.4Cadmium
Cadmium is a scarce element, but is seventh in the Agency for Toxic
Substances and Disease Registry’s list of elements that create the most significant
risks for human health and the environment. In addition to its neurological
impairment, cadmium is toxic to the digestive system, kidneys, lungs and liver. Only
four studies have been undertaken to study the neurodevelopmental effects of
cadmium exposure in utero (Cao et al. 2009, Tian et al. 2009, Wright et al. 2006,
Torrente et al. 2005). Only one of the studies (Tian et al. 2009) found significant
results; they found that children with higher blood levels of cadmium at birth scored
lower on Full-‐Score and Performance IQ tests at four years of age. Both Bao et al.
(2009) and Yousef et al. (2011) studied the behavioral effects of prenatal exposure,
but only Bao et al. found that children with higher levels of cadmium in their hair
experienced more social and attention problems. Yousef et al. found that there was
no significant relationship between cadmium exposure and ADHD. The information
on cadmium exposure and its neurological effects is conflicting and extremely
limited, leaving a wide gap in the knowledge of understanding the effects of metals
on neurological development.
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4.3.5. Co exposure
Co-‐exposure to multiple neurotoxins may increase their toxicity, but few
studies have investigated the interactions between multiple metals. There have
been a handful of studies analyzing the interactions between lead and Mn, all of
which conclude that the combined neurological effects are greater than the effects a
single exposure would cause. It is important to acknowledge the potential for
adverse outcomes from co-‐exposure during early childhood because of the
particularly vulnerable developmental periods. Lead and Mn co-‐exposure may cause
a significant risk as increased levels of Mn in the brain may cause the brain to
produce lead-‐binding proteins, increasing the exposure to lead. Animal studies have
shown that co-‐exposure to Mn and lead may decrease spontaneous motor activity
and learning ability more compared with exposure to only one of these metals,
which may impair both pre-‐ and post-‐natal neurodevelopment. (Wright 2009)
Kim et al. (2009) found an association between co-‐exposure to lead and Mn
and intelligence in school-‐aged children. Findings indicated that in utero co-‐
exposure to environmental Mn and lead were adversely related to
neurodevelopment in 2 year-‐old children, and reported significant negative
associations between lead and Mn levels and full-‐scale and verbal IQ. These results
are similar to those found by Henn et al. (2008), who observed that joint exposure
to both lead and Mn were correlated with mental and psychomotor deficits. These
were higher than the estimated deficits for individual lead or Mn exposure.
5. Discussion
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The body of literature on Mn exposure through drinking water reveals many
things about what we do and do not know. We know that there are associated
neurological deficiencies and behavioral changes that can arise from possibly even
low level exposures. While these findings are important, and can be applied to
public policy to better protect pregnant women and young children, they also shine
a light on the gaping holes in the research that need to be addressed for us to better
understand the true neurodevelopmental impacts associated with Mn exposure.
The results from these studies found negative impacts associated with the
exposure of children to Mn, but they all had different methods of doing so. Different
neurological tests were administered, different levels of exposures were measured,
and different biomarkers were used. Consequently, these studies have found a slew
of different impacts, ranging in type and severity.
The lack of a consistent biomarker is another factor that needs to be
addressed to better understand the complex issue of Mn exposure. Many studies
that have been conducted, and that are discussed here, use hair or blood to measure
exposures. These biomarkers are highly variable and, ultimately, may not be an
accurate reflection of Mn exposures. Tooth dentine shows a great amount of
promise to overcome the shortcomings of biomarkers, but the evidence of its use
and effectiveness is extremely limited. The lack of a consistent and accurate
biomarker is a possible contributor to why there are still no concrete answers to the
effects of prenatal Mn exposure.
There is an incredibly limited amount of research done on the effects of
drinking water Mn concentrations on prenatal and early childhood
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neurodevelopment. The scientific community has, in multiple papers, acknowledged
that this is an extremely vulnerable population and an area of research that needs to
be addressed. Based on the conclusions that children are incredibly vulnerable
during rapid stages of prenatal development, and that Mn is a commonly known
toxicant that is known to have significant negative effects in school-‐age children, it
leads one to believe that there is a notable risk for prenatal Mn exposure,
particularly through drinking water. Despite this, there is not a significant body of
research to support this line of thinking.
It was also found that there are significant negative effects associated with
prenatal exposures to other metals. Lead is well established in this sense, and there
is a lot of evidence finding that there are significant and extremely harmful effects
from prenatal exposures to lead. Arsenic, Cadmium, and Trichloroethylene are all
also acknowledged as being extremely toxic, but their effects on prenatal
development are less established. Cadmium is best associated with attention
disorders, and Arsenic has been found to produce lower IQ, and TCE is linked to
congenital heart defects and low birth weight. Coexposures can cause an even more
significant effect than individual exposures, and draws attention to the fact that
there are a large amount of metals and chemicals that likely have negative impacts
on prenatal or early childhood development, but are not yet understood.
Based on these findings, and on the fact that neurodevelopmental deficits can
occur from such low exposures to metals, particularly Mn, it is clear that the
measures set out by the United States government are not enough to adequately
protect the public. Although there is a health advisory for Mn, it is not considered to
Manganese Exposure
23
be enough of a risk for the EPA to make an enforceable limit on it. The WHO has a
tighter guideline for an acceptable level of exposure to Mn from drinking water than
the EPA does, and the exposures in a number of the studies that caused significant
negative cognitive defects in children occurred from exposures that were even
lower than either of these guidelines. The guidelines for Mn have not been updated
since 2004, and need to be re-‐evaluated, taking into account this new research, and
initiating further research to more fully understand the health risks that are faced
by children through such high exposures to Mn.
6. Conclusions
In the United States, approximately 6% of domestic household wells have Mn
concentrations exceeding 300 µg Mn/L, which is the current EPA lifetime health
advisory level (Wasserman et al. 2006). In New England, 45% of wells for public use
have Mn concentrations greater than 30 µg/L. According to a 2009 report by the U.S.
Geological Survey, approximately 5% of domestic household wells in the United
States have Mn concentrations greater than 300 µg/L. (U.S. Geological Survey 2009).
This indicates that some children in the U.S. are at risk for Mn-‐induced neurotoxicity
due to drinking water exposure.
Too much exposure can cause Mn to accumulate in the brain, in particular
the central nervous system, leading to neurological damage and long-‐term effects.
Mn retention is higher in infants than in adults meaning Infants and young children
face higher risks from exposure to heavy metals than adults due to underdeveloped
homeostasis system that limit the absorption of Mn ingested. The time at which the
Manganese Exposure
24
child is exposed to the metal has been shown to be equally important as the level of
exposure (Andra et al. 2015). Our current health-‐based guideline value for Mn of
400 µg/L in drinking water is based partly on debatable assumptions. This value for
drinking water may be low enough to protect adolescents and adults, but not
younger children.
Biomarkers are used to measure to estimate external exposure levels in the
body, to date, blood, hair, urine, and dentine from primary teeth have been used.
They’ve contributed to our increasing body of knowledge about Mn neurotoxicity.
However, blood, urine, and hair have been found to be unreliable or not ideal
biomarkers. They fail to provide exposure timing, levels of cumulative exposure, and
lack the potential to provide information on the specific source (Andra et al. 2015).
New research is emerging using dentine as an ideal biomarker to measure Mn
exposure, and it is showing great promise. Dentine reflects direct exposure to Mn
and there is no known instability in tooth mineralization. There is a growing body of
research showing an association between Mn exposure and its neurological effects
on children. Further research needs to be done on optimum biomarker such as
dentine, measuring exposure limits to set new guidelines to protect the public and
children from the long terms effects of Mn exposure.
Manganese Exposure
25
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