neurodevelopmental impacts of prenatal drinking water exposure to manganese and other metals on...

Manganese Exposure 1

Neurodevelopmental impacts of prenatal drinking water exposure to manganese

and other metals on children

Jeronda Scott and Melissa Miller

Clark University


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, &


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


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


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


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


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


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


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

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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,

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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

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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

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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,

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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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