Neural and Behavioral Teratogenicity

of Endocrine Disruptors and Mercury:

A Review

Patrick Scannell
JHSPH
Requirement for Master of Health Science

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 Te ararau o Tangaroa e rere ki te papa’urunui
Tahora nui ātea, te manawa o te moana
Te mauri o Tangaroa, Tangaroa whakamautai

Tūtara kauika, he poutiriao te wai o Tangaroa

Te tangi a te tohorā he tohu nō aituā
Te mau a Tangaroa, Tangaroa whakamautai

He kaitiaki, he taonga, he tipua,

He ariki, he taniwha, he tipua
Tangaroa whakamautai

-Adapted from Maisey Rika: Maori ode to the Spirit of the ocean

English translation:

The various waterways of the Sea God flow back into its voluminous source
The vast expanse, the heart of the ocean
The life-force of the Sea God, the Sea God commander of the tides.

A pod of whales, a supernatural phenomenon evolving from the waters of the sea God
The cry of the whale signals a warning
The power of the Sea God: the Sea God, commander of the tides.

A guardian, a precious treasure, a strange/supernatural being

A god of the ancient prehistoric realm
The Sea God, commander of the tide

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 PREFACE
Since the discovery of fire, mankind has developed increasingly complex
technologies. Many of these have led to widespread human exposures to a plethora
of chemicals that are not or much less present in the background human exposome.
These include metals such as lead, which the hunter-gatherer had little to no
exposure to in comparison with the modern-day human (Lambert et al., 2984). Since
the development of metalworking and mining, and especially since the industrial
revolution, exposure to such chemicals has dramatically increased in the population.
They include novel organic molecules such as polystyrene and bisphenol A, used in
the production of plastics, which were completely absent from the biosphere
previously and are purported to be involved in a number of human and ecological
health effects (Alissa and Ferns, 2011).

Due to the ever-accelerating pace of modern technological development, increasing

consumption and disposal patterns, the modern human is exposed throughout the
life course and beginning in utero, to an increasingly complex mixture of chemicals.
These exposures may be related to an ever-increasing number of diseases for which
the etiologies are not well-known, such as obesity, diabetes, cancers, and
neurodevelopmental changes (discussed below). Some of these chemicals have been
studied in isolation and it is upon this research that most regulation is based.
However, there is still a great lack of knowledge on most chemicals and even less so
on how different chemicals may interact. A prime example are endocrine disrupting
chemicals which are often found in complex mixtures, including pesticides, dioxins,
phthalates and even some heavy metals. The book “Silent Spring” by Rachel Carson
made the connection between human pesticide usage and a disturbingly high
mortality rate among birds. Another example of anthropogenic contamination
include heavy metals such arsenic, lead and mercury through industrial discharge.
Many of these are theorized to have no place in human metabolism and some are
well-known to be important poisons and/or toxicants.

The heavy discharge of pollutants into the environment is highly problematic, not
just for ecological reasons, but also for the future of the human race as a whole.
Many of these molecules build up in the biosphere and noticeably impact humans
and other organisms. Some of the highest levels are found in the Arctic, where they
are affecting the health of both human populations and of the animals that live there
(discussed below). As the poles tend to accumulate pollutants from large areas of
the globe through the hydro- and geological cycles, the Arctic could be considered
the canary in the goldmine: the first to be systematically heavily affected by the
accumulation of pollutants and arguably climate change (discussed below). We can
expect to see more of the health effects across the globe as pollution continues
unabated. Thus, it is important to increase scientific understanding of the exposome.
For this, we must go beyond the study of single chemicals, towards a study of mixed
exposures. Multiple research efforts are currently ongoing in this field. The present
essay aims to provide a “snapshot” of the extent of those efforts.

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 OBJECTIVE

To conduct a systematic scoping review of the scientific literature on the effect of

concomitant exposure to mercury and endocrine disruptors on neural,
neurodevelopmental and behavioral toxicity.

The primary goal is to describe the available body of research on neurobehavioural

health effects of combined exposure. The secondary goal is to identify gaps in
current knowledge.

BACKGROUND

It is suspected that neurodevelopmental disorders such as autism spectrum (ASD)

and attention-deficit (ADD) in children are on the rise (Szpir et al., 2006). The
causes of this increase are unclear. As no single agent has been identified to be
causative on its own, it is proposed that a complex mixture of chemicals may play a
role. Much research has shown that endocrine disrupting compounds (EDC’s) are
important neurodevelopmental and behavioral toxins. In fish-eating populations,
high levels of PCB’s and other EDC’s in consumed fish have been linked with
neurodevelopmental deficiencies. Mercury is one of the most important EDC’s
implicated in such defects. Meanwhile, significant variability exists in incidence and
prevalence of neurodevelopmental outcomes worldwide from mercury and EDC
exposures. It has been postulated that interaction between multiple contaminants
may play a role in this variability. This has made the determination of safe levels of
the contaminants difficult.

Currently in the sciences, there is an increasing shift in the paradigm from defined
disciplines to interdisciplinary research and systems thinking, where socio-cultural
and biological factors are all considered to be interacting. Learning about the
interaction of many exposure factors is one step in the process of integrating the
scientific knowledge on disease etiology, and it is in light of this process that this
essay is written. The aim of this essay is to review the literature on the interaction of
two important contaminants: mercury and non-mercury endocrine disrupting
chemicals, towards an integrated view of their toxicity mechanisms and outcomes as
they occur in the real world.

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ENDOCRINE DISRUPTORS

History of human exposure

Endocrine disruption refers to the activity of a chemical on the hormonal system of

an organism, either mimicking or antagonising the hormone through a variety of
mechanisms and pathways. The term was first used in the medical literature by
Colborn in 1993 (Colborn et al, 1993). However, Matthiessen contends that the
study of endocrine disruption has a longer history (Matthiessen 2003). and that it
was first reported in studies of wildlife. Mathiessen gives as example experiments in
the 1920’s that showed sexual maturation in rats given pig follicular hormone. Thus,
endocrine disruption as an object of study can be said to be as old as the discovery
of hormones themselves. Colborn’s publication did prove to be a landmark in the
recognition that foreign chemicals, widely distributed throughout the biosphere,
could have widespread effects across whole populations of species, including
humans. Arguably the most important book on the subject, “Silent Spring” by Rachel
Carson, covered the population-wide effects of organochlorine pesticides, foremost
being dichlorodiphenyltrichloroethane (DDT), on bird reproduction. Published in
1962, Carson correctly contended that these chemicals could be decimating
populations of wild birds. Her book has arguably been a harbinger to the
environmental movement and the widespread recognition by the scientific
recognition of the dangers of endocrine disruption, without so much as ever
mentioning the term. Her publication shows that endocrine disruptors have been
major players in environmental public health effects for longer than they have
carried the name.

Because of the relative novelty of the term endocrine disruption, it is difficult to give
an exact history of human exposure. In Colborn’s paper human exposure is
addressed since World War II, where chemicals were used in warfare. Another one
mentioned is diethylstilbesterol, first used in the 1940’s and causing cervical cancer
in girls of mothers who took it during pregnancy. Indeed, Colborn also mentions that
many other contaminants, naturally occurring, such as mercury, lead and cadmium,
all have been identified as having endocrine disruptive effects. In fact, it is well
known that many pharmacologically active chemicals in plants have endocrine
effects, where they are often termed “phyto-estrogens” (Santti et al, 1998). Many
indigenous women employ ethnobotanicals for the specific purpose of labour
induction and pregnancy prevention (Plotkin M., 1994). These ethno-botanicals far
outnumber the scope of this essay but examples are Blue Cohosh, used by the
indigenous of North America (Castleman M., 1991) as well as unripe Papaya,
employed in Asia to this day as an abortificient (Iyer et al., 2011). Thus, human
exposure to endocrine disruptors is arguably not a novel phenomenon.
However, currently many anthropogenic organic chemicals resistant to
environmental and biological degradation are accumulating in the environment.

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They include the persistent organic pollutants (POP’s) covered by the Stockholm
Convention, such as poly-chlorinated biphenyls (PCB’s). Similar to DDT, these
lipophilic compounds are not readily degraded or metabolized, accumulating
instead in fatty tissues of higher predatory organisms.

POP’s in the Arctic were first covered in the literature in 1992 by Barrie (Barrie et al,
1992) and it became clear that these pollutants were being carried to polar latitudes
through long-range transport in the geosphere, . This phenomenon is also known as
the “global distillation effect” (Simonich and Hites, 1995) and it is said to have led to
the Arctic being home to the most contaminated people and wildlife in the world.
Marla Cone highlighted the paradox of these high levels in this pristine environment
in “Silent Snow: the Slow Poisoning of the Arctic” (Cone, 2005). In 1995, Renner
reports on the advocated need for global reporting of “endocrine-modulating
chemicals”, (Renner 1996). In the same year, the United Nations developed the
Inter-Organisation Programme for the Sound Management of Chemicals (IOMC) in
response to the first Rio Summit (IOMC, 2014). Subsequently, the Stockholm
Convention on Persistent Organic Pollutants was signed in 2001 and entered into
force in 2004 (Stockholm Convention, 2014).

Current situation

Today, the term endocrine disruption is ubiquitous across the literature. A Pubmed
search of the term conducted March 1st, 2014 returned 2386 hits, with up to 94
publications in the months of January and February of 2014 alone. This is indicative
of several aspects: firstly the much increased interest in endocrine disruption as a
recognized and persistent health effect, secondly the far greater number of
anthropogenically discharged molecules that are found to be endocrine disruptive.
Thirdly, the trend may be indicative of a tendency to use the term as a “catch-all” for
any endocrine effect that a substance can have. This includes the effects at certain
doses of commonly used pharmaceuticals such as aspirin and paracetamol (Albert et
al., 2013).

Some endocrine disruptors have been shown to display a degradation-

reconstitution process under natural conditions (Qu et al., 2013.) Many of these
chemicals may reconstitute into unknown substances, so that our chemical assays
will miss part of the endocrine disruptiveness of human discharge. One recent
bioassay on endocrine bio-activity of surface water showed 27 to 35% more
endocrine activity than could have been expected from chemical assays alone,
showing that a large amount of such chemicals may exist that science has not yet
identified (Stavevra et al., 2012). A large number of endocrine disruptive chemicals
tend to bioaccumulate in the food web, such as PCB’s and methylmercury (meHg),
already clearly seen in the Arctic populations. Certainly, EDC’s can now be found in
wildlife and human populations globally.

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Many chemicals are currently strictly regulated, with PCB’s, polybrominated
diphenyl ethers (PBDE’s), many pesticides and polycyclic aromatic hydrocabons
(PAH’s) falling under POP regulation.. In the Arctic, they have been monitored since
their discovery, among others by the Northern Contaminants Programme in Canada.
Since the worldwide ban of the use of PCB’s, these chemicals have been reported to
be decreasing in the tissues of wildlife and the indigenous people there (Dallaire et
al., 2001). Regulatory bodies on endocrine disruptors in Europe include the REACH
(Registration, Evaluation and Authorisation of Chemicals) laws since 2009. For risk
assessment of new toxins, the European Centre for Ecotoxicology and Toxicology of
Chemicals (ECETOC) has a protocol to be employed (ECOTOC, 2014).

However, the legislation does not apply globally, as many low- and middle income
countries see unregulated levels of EDC’s in populations working with e-waste
(Zhou et al., 2013; Song and Li, 2014). Furthermore, legislation is unable to keep up
with the constant development of new chemicals: yearly registration of new
chemicals in the Chemical Abstracts Service between 1965 and 2006 saw yearly
increases from over 200,000 to close to over 17 million in a single year (Binetti et
al., 2008). Ubiquitous in the environment are increasing amounts of plastic waste
that are both leaching EDC’s, such as phthalates (Rustagi et al., 2011). Once
degraded into micro-plastic pellets, the waste adsorbs additional chemicals causing
them to be a possible vehicle for transmission into the food chain (Hollman et al.,
2013). Plastic trash is now found from the Great Lakes to every single ocean in the
world, with areas of coverage the size of whole continents such as Australia. (Law et
al., 2014). Plastic products that do not contain known endocrine disruptors, may
still leach chemicals with endocrine disruptive properties not yet recorded
previously: a study utilizing a cell proliferation assay found significant estrogenic
activity (EA) in leachate of many plastics tested, even if those plastics were touted to
be EA-free (Yang et al., 2011). Thus, the current situation is that much of human
discharge into the biosphere and its ultimate effects is not clear, and this highlights
the need for the precautionary principle to be employed in policy.

Health concerns

Endocrine disruptors may effect pathophysiology in several points of a hormone

signaling pathway (Shanle and Xu, 2011):

1) interaction with a hormone receptor

2) dysregulating of hormone production and/or secretion,
3) modifying cell function, i.e. via the aryl hydrocarbon receptor.

The above description would include artificial lighting as it disrupts nocturnal

melatonin production in the pineal gland and alters circadian rhythms (Stevens and

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Rea, 2001). For practical purposes, The Endocrine Society in 2012 defined an
endocrine disrupting chemical (EDC) as being an “exogenous chemical, or mixture of
chemicals, that can interfere with any aspect of hormone action” (Nassouri et al
2012). For the present discussion, we will employ this definition in the present
essay.

EDC’s have been implicated globally in diverse diseases. Links have been proposed
with the reproductive functions, from reduction of semen quality and early puberty
in girls to changes in behavior and loss of fecundity in wildlife. Other effects include
neurological effects, immune dysfunction, obesity, cancer and effects on the
cardiovascular system. (Hotchkiss et al., 2008) As hormones function as
intermediaries in the body’s signaling pathways, EDC’s may interact with or modify
signals to receptors on anything from immune cells to neurons, as well as intra-
cellular pathways such as via the aryl-hydrocarbon receptor in the cytoplasm. As
teratogens, their effects on behavior have been noted in the modulation of gener-
typical behavior in humans, where EDC’s are linked to feminization of human male
child play behavior (Vreugdenhil et al., 2002; Winneke et al., 2014).

MERCURY

History of human exposure

Mercury (Hg), a naturally occurring heavy metal, is one of the endocrine disruptors
on Colborn’s original list of 1983. In one form or another, this metal has been known
to humankind as far as historical and pre-historical records show. Earliest known
uses include cinnabar, a bright red mercury-rich mineral used in vermillion paints.
Its earliest use has been found in Turkey up to 10,000 years ago. It has been mined
in Spain as far back as the 6th millennium BC and has been found in ancient tombs.
The element has been revered and used as a talisman and medicine throughout
known cultures and history, including ancient Greece, China and the Mayan
civilization. In ancient India, a skilled alchemist was known in Sanskrit as a
“rasasiddhi” which translates as “perfection through quicksilver.” The latter is the
English name for mercury, alluding to its quality of fluid silver at room temperature.
For this quality, it was called “hydrargos” (silver water) by the Greeks, hence the
scientific term “Hg.” Mercury’s modern English name derives from the planet and
god Mercury, the swift-footed roman deity of the dead, luck, communication,
eloquence, travel, thievery and finance. The deity’s name may be cognate with
modern English “merchant,” “market” and “commerce.” Furthermore, the
association of “fluid silver” with wealth has given us many modern financial terms
(“currency,” “liquids,” French “argent”).

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However revered the watery silver, the Romans seem to have caught on to the
poisonous effects of cinnabar, as they would condemn prisoners to a life of working
in the mines. Here they were doomed to an early death, as mercury is poisonous
when inhaled. Between the 17th and 19th century, mercury’s neurotoxic effect was
also seen among hat makers who used it to produce hat felt, hence the English
expression “mad as a hatter.” The population-wide hazards of mercury became clear
to modern science in a mass poisoning event in Minimata on the island of Kushu in
Japan in 1958. Here, industrial discharge of mercury into the bay caused hundreds
of people to regularly ingest contaminated fish, causing 68 deaths, 397 ill with
neurological symptoms, and many children born with a condition similar to cerebral
palsy as their mothers were consuming the fish during pregnancy. Since then,
multiple events have been recorded throughout the world, including an exposure
event in Japan in 1968 and Iraq in 1972 (Harada, 1995; Skerfving and Copplestone,
1976). In our time, regulations on industrial discharge of mercury have become
more stringent. However, mercury continues to be used in gold mining, an activity
currently considered to be an important source of contamination and disease in
people living in the Amazon basin (Passos and Muckle, 2008).

Current situation

Mercury exists naturally in the environment and can be found in soil: parts of the
Amazon basin are especially rich in mercury, and deforestation for agriculture has
been identified as major cause of leakage and contamination into the Amazon’s
waterways through the loss of rhizosphere sequestration (Mainville et al., 2006;
Grigal, 2003). As mentioned above, industrial activity has historically also been a
major cause of discharge, currently emitting an estimated 7.5 million kg into the
atmosphere of which 10.7% is from fossil fuel-fired power plants (Pirrone, 2010).
Once this mercury is released into the environment, microbial activity causes
conversion into organic compounds such as methylmercury, which are lipophilic
and begin to bioaccumulate in fatty tissues of wildlife, as with other endocrine
disruptors. Because of this, health effects of mercury may be more common in
humans and other animals on high fish diets: notable examples being riparian
populations in the Amazon and coastal populations in the Arctic and Japan. As with
other endocrine disruptors, the Arctic especially has seen a great increase in
mercury contamination as anthropogenic pollution tends to accumulate around the
poles. Notable effects are seen among the Inuit in Canada and among children in the
Faroe islands, where a higher prevalence of mercurial toxicity is reported in the
literature. Because of this, specific advice is given to these populations to avoid
predatory fish and fish-eating mammals such as whales, which bio-accumulate
mercury several thousand to perhaps a million fold. Similarly in the Amazon, where
riverine populations are sometimes required to adapt their consumption patterns to
avoid upper trophic levels of the aquatic food chain (Peplow and Augustine, 2012).

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In addition to consumption advisories, several international bodies such as the
World Health Organization have taken steps to reduce exposure to mercury
worldwide, to which the Minimata convention was signed in 2013 (WHO, 2014).
Specific policies concern the use of mercury in gold mining, a common practice in
places such as the Amazon and in Africa. However, because much of the mining
there takes place illegally and with encroachment upon rural areas with large
numbers of indigenous and seafood-dependent peoples, gold mining is still an
important cause of mercury poisoning, both occupationally through inhalation by
miners and via contamination of aquatic wildlife indirectly. In these populations,
more stringent international regulations do not always work if political will is sorely
lacking. Likewise, the global practice of fossil fuel combustion as an energy source is
still increasingly discharging mercury into the atmosphere, so that mercury levels in
oceanic fish around the Arctic and elsewhere could only be expected to increase in
the current situation. With the current state of fisheries worldwide beginning to
collapse, the food industry is beginning to rely more heavily on aquaculture as a
much-needed food source. However, most studies have shown that due to
overcrowding, proximity to pollutant sources, and being fed fish feed processed
from wild –caught fish, many aquaculture-derived fish bio-accumulate more
mercury than the former and are thus not a healthy alternative in many cases
(Easton et al., 2002).

Health concerns

Mercury poisoning as an acute effect of exposure is also known as hydrarguria or

mercurialism (Faria Mda A, 2003). Chronic exposure can lead to diverse disease
including Minimata disease, which may surface with a latency of months to years
after exposure. Depending on the speciation of the atom and its binding to other
substances (such as in methylmercury or ethylmercury) its toxicity and health
effects are modified. Metallic or inorganic mercury is not readily absorbed through
the digestive tract, but chronic inhalation, i.e. in gold miners, causes a variety of
neuropathies, including tremors, stocking-glove sensory loss, cognitive deficits and
irritability. The latter was most likely the reason for Abraham Lincoln discontinuing
the use of “blue mass” a pill remedy containing 33% mercury that he had been
taking against “melancholy” (nowadays most likely to be considered clinical
depression).

“Lincoln’s melancholy never failed to impress any man who ever saw or knew
him. The perpetual look of sadness was his most prominent feature. The cause
of this peculiar condition was a matter of frequent discussion among his
friends. His liver failed to work properly—did not secrete bile—and his bowels
were equally as inactive. ‘I used to advise him to take blue-mass pills,’ related
Stuart, ‘and he did take them before he went to Washington, and for five
months while he was President, but when I came on to Congress he told me had
ceased using them because they made him cross.’” (Herndon and Weik, 1888)

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Mercury in its ionic form, such as in mercury chloride, is particularly toxic to the
kidneys. Mercury salts that have a divalent ion are more readily absorbed in the
digestive tract than those with a monovalent ion and thus have greater toxicity.
However, the most toxic forms of mercury are organic compounds, such as
methylmercury (MeHg), which is the main culprit in mercury poisonings worldwide
due to fish consumption. As it is lipophilic, it is especially prone to bioaccumulation
and biomagnification. Microorganisms metabolize environmental mercury to this
compound and they are subsequently ingested by higher life-forms which do not
excrete and therefore accumulate the MeHg in fatty tissue. This process continues
up the food chain into apex species, including humans, accumulating more MeHg in
fatty tissue at every trophic level. Through maternal exposure in pregnancy,
methylmercury is a known culprit for cognitive deficits in children in the Amazon
basin and the Circumpolar regions. As an endocrine disruptor, mercury is known to
operate through several mechanisms: interaction with hormones, deregulation of
steroidogenesis and insult to endocrine cells among others. (Tan et al., 2009). The
range of health effects on endocrine function is wide: one example is changed
reproductive behavior and altered adrenal stress responses in birds (Moore et al.,
2014). An exhaustive list of these effects lies outside the scope of the present review.

Combined exposure

To our present knowledge, only one review has attempted to schematize neurotoxic
effects of both EDC’s and mercury. This review covered PCB’s and collected studies
to describe the overlap in neurotoxic effects with mercury. Their review concluded
that PCB’s and meHg further contrasted in their effects on discrimination and
memory, with mixtures of both toxicants leading to altered spatial discrimination:
whereas PCB’s caused mostly deficits, a combination with meHg saw improvement
at times. (Newland and Paletz, 2000). No reviews on human epidemiology of
combined exposure was found with our scoping search method outlined below.

METHODS

RESEARCH QUESTION (OBJECTIVE)

The primary objective is to conduct a scoping review of the literature on the

neurotoxic effects of concomitant exposure to mercury and one or more EDC’s as
defined by the Endocrine Society in 2012, including both the epidemiologic and
experimental literature.

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Aims include:

- assess the state of the scientific literature on health effects of combined

exposures
- identifying gaps in the body of research literature

SEARCH STRATEGY

In Pubmed, a search was performed with the following terms:

(mercury OR methylmercury OR hg OR mehg)

AND

(dioxin OR "endocrine disruptor" OR "endocrine disruption" OR "endocrine

disrupting chemical" OR organochlorine OR organophosphate OR "flame
retardant" OR pcb OR pcdd OR pcdf OR bpa OR bps OR bisphenol OR
phytoestrogen OR 3-methylcholanthrene OR hcb OR pbde OR phthalate OR pfoa
OR pah OR ddt OR pop OR "persistent organic pollutant" OR "organic
pollutant" OR tcdd OR estrogen OR androgen OR antiestrogen OR antiandrogen
OR anti-estrogen OR anti-androgen OR estrogenic OR androgenic OR furan OR
aldrin OR dieldrin OR "flame retardant" OR poly-brominated OR
organohalogenated OR organohalogen OR dde OR pbts OR ohp OR halogenated OR
Ahr OR HAH OR "Ahr ligand" OR pesticide OR obesogen OR obesogenic)

AND

(neuroendocrine OR neural OR neurotoxic OR neuroinflammation OR

neuroinflammatory OR neuropathogenesis OR neuropathology OR neuropathic OR
neuropathy OR behaviour OR behavior OR behavioural OR behavioral OR mental
OR "heart rate variability" OR emotional OR emotion OR anxiety OR
neurodevelopment OR "neural development" OR attention OR "attention
deficit" OR cognitive OR "cognitive development" OR iq OR adhd OR autism
OR asd)

Subsequently, studies were selected based on excluding criteria (see below).

Additionally, we searched the references of remaining studies for additional
publications that satisfied the criteria and included them in the review.

EXCLUDING/INCLUDING CRITERIA

excluded:
- reviews, letters or comments
- studies without neural or behavioral endpoint
- studies that do not include both an endocrine disruptor and mercury in
exposure

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DATA COLLECTION

The Pubmed search was conducted on February 1st, 2014 and yielded 500 studies
hits. Following title and abstract screening, 51 studies were selected that had
measured mercury and at least one other endocrine disruptor. After a full text
review, 13 studies were further removed based on exclusion criteria, resulting in 38
studies (figure 1). Of these, 25 were experimental studies and 13 were
epidemiologic studies. The epidemiological studies were reviewed and an online
search performed for additional studies utilizing the same cohorts at baseline and
follow-up. This resulted in 4 more studies for a total of 17. References in the
experimental studies identified an additional 2 studies that satisfied the research
criteria, for a total of 27. Studies were categorized by epidemiological study type,
endocrine disruptor type, mercury speciation, population source if epidemiological,
animal or cell type if experimental, types of endpoint evaluated, and results on
common endpoints found. Because in the review process only cohort studies were
found among the epidemiological studies, these were tallied for number of studies
per cohort also.

After the initial scoping review an executive decision was made to include only
epidemiological studies that evaluate prenatal exposure to PCB’s in combination
with Hg (n=16). This decision was made because of practical concerns and that
these studies:

1) All concerned PCB’s and related substances; only one to two studies
concerned non-PCB EDC’s with mercury
2) All were in a Northern birth cohort region with high fish-eating populations;
few concerned smoking and/or insecticide sprays as exposure routes
3) All utilised biomarkers for all exposures, one or two other studies used
questionnaires to assess exposure
4) No experimental studies utilized human cells, making comparisons between
epidemiological and experimental data difficult.
5) No epidemiological review has been performed as yet, to our knowledge.

The studies included were reviewed for outcomes with regression, correlation, and
interaction coefficients with their p-values. In the interest of not being repetitive, all
values said to be significant in this review represent p-values of 0.05 or less. All
other coefficients with p > 0.05 are noted in this review as not significant. Also,
regression coefficients that were unadjusted for the other contaminant were
excluded as not relevant in order to minimize confounding in the presented data.

RESULTS

STUDY CHARACTERISTICS

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The reviewed studies were published between 1997 and 2014. All epidemiological
studies found in this review were part of longitudinal analyses of six birth cohorts
from prenatal exposure to neurodevelopmental toxicants: three in the Faroe Islands,
two in Arctic Quebec and one in New York State (Tables 1-3). Samples collected for
mercury included cord blood mercury levels, placental mercury, and hair
methylmercury. 16 studies concerned PCB’s as the EDC in combination with
hexachlorobenzene (HCB), DDT and/or DDE, as well as organochlorine pesticides
(OC’s). All studies evaluated pre- and post-natal exposures. For the purpose of this
review we only considered the pre-natal exposures. EDC’s were measured via cord
blood and serum, maternal blood and serum, maternal hair and placental samples.
Outcomes tested are described by cohort place and time below.

The five Canadian publications utilized data from two Canadian aboriginal (Inuit)
birth cohorts assembled in Nunavik, Quebec (Table 1, rows 1-5). One of these was
assembled between 1993 and 1998 (Cord Blood Monitoring Program: CBMP) and
the other between 1996 and 2000 (Nunavik Environmental Contaminants and Child
Development Study: NECCDS). Publications covered longitudinal follow-up until
around 13 years of age. Neurological and behavioural tests included the Delis-
Kaplan Verbal Fluency test, the Bailey’s Developmental Scale for Infants and
Toddlers (BDS), the BDS Infant Behavior Rating Scale (IBRS), the Boston Naming
Test (BNT), heart rate variability (HRV), Fagan Test of Intelligence (FTII), Wechsler
Intelligence Scale (WIS), and electro-physiological evaluations.

The following six studies concern the Oswego birth cohort, which was assembled in
New York State between 1991 and 1994 (Table 2, rows 1-6). Mothers belonged to
mostly Caucasian population as per the population description. Neonates were
assessed with the Neonatal Behaviour Assessment Scale (NBAS); follow-up studies
utilized FTII, WIS, performance ratings on a Differential Reinforcement of Low Rate
Schedule task, and McCarthy scores.

Six of the studies in this review comprise publications on three Europoid birth
cohorts from the Faroe Islands (Table 3, rows 1-6), the earliest of which was
assembled from 1986 to 1987 (n=1022: Table 3, rows 1-4,) and tested a Neurologic
Optimality Scale and thyroid function at birth. The second cohort was assembled
from 1994-1995 (n=182: Table 3, row 5) was followed up to the age of 14: tests
carried out were thyroid function, neurophysiology, postural sway, audiometry, the
BDS, BNT, Wechsler Intelligence Scale (WIS), HRV, the California Verbal Learning
Test (CVLT), the Bender Visual Motor Gestalt Test, Functional Acuity Contrast Test,
Neurobehavioral Evaluation System (NES), Tactual Performance Test (TPT), Non-
Verbal Analogue Profile of Mood States (NVAPMS), HRV, and functional Magnetic
Resonance Imaging (fMRI).

SYSTEMATIC REVIEW

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Quebec

In Arctic Canada, the CBMP cohort of 1993-1998 and the NECCDS cohort of 1996-
2000 comprised 475 and 98 children respectively (Levesque et al., 2003; Muckle et
al., 2001). Cord blood was sampled and tested for PCB’s and organochlorine
pesticides through high-resolution gas chromatography. Total mercury in these
same samples was assessed with cold vapor atomic absorption spectrometry.
PCB153, the most prevalent PCB congener in the samples, was found to be
detectable in 70% of samples (n=98) and correlated well with total organochlorine
body burden as described by Muckle (median Pearson r = 0.90, p < 0.000 for all
correlations reported). Therefore, PCB153 was used as a marker for total
organochlorine exposure. The NECCDS reported a geometric mean for 86.9 μg/kg of
lipid weight (SD = 2.2) for cord blood PCB153 in 98 children. Total Hg geometric
mean in this group cord blood was 18.5 μg/L (SD = 0.4). Additional data collected
included blood lead, maternal smoking and alcohol use, maternal Raven score and
socio-economic status, cord plasma nutrients, breastfeeding, breast milk and
maternal plasma contaminants.

For the NECCDS population, BSID-II scores at 11 months of age were not found to be
statistically significantly associated with the cord blood contaminants of interest (all
p > 0.05; Boucher et al., 2014). However, the Mental Development Index (MDI)
trended to more positive association coefficients (Hg: β = 0.08, PCB: β = 0.03) than
the Psychomotor Development Index (PDI) for both contaminants (Hg: β = 0.01,
PCB: β = -0.05). Also, PCB153 associations trended to lower coefficients, albeit
insignificant, than Hg (see previous). In the same study, significant associations
were found for FTII novelty preference with PCB’s and for an A-not-B delay with Hg
(Table 1). In this, the authors noted a clear dose-response trend for both
contaminants across tertile strata (data not shown). At 11 years of age, 193 Inuit
children drawn from both cohorts were given a visual go/no-go task and
associations calculated with event-related potentials (ERP’s) as measured with an
encephalogram. The purpose of this task was to evaluate response inhibition. They
tested for modification by PCB’s and Hg with interaction terms in multi-linear
regression, as well as through stratification into two populations split at the median
(Boucher et al., 2012). Though the contaminants were reported to be non-
significantly associated with the outcomes (minimum p > 0.52) the researchers did
note significant interaction between the two cord contaminants PCB153 and Hg on
no-go N2-wave latency (β = 0.16, p = 0.05) and no-go P3-wave amplitude (β= –0.20,
p = 0.02). Another subsample of 118 children was tested on an auditory oddball
performance task and ERP’s recorded (Boucher et al., 2010): Hg was significantly
associated with four N1 outcomes, while PCB153 was significantly negatively
associated with P3b amplitude (β = -0.32, p < 0.05).

Two studies addressed sympathetic nervous system effects of heart rate and anxiety
(Table 1, rows 5 and 6). Heart rate variability was tested in a subsample of 224 11-

15
year old children by measuring the variability in R-R interval length over QRS
complexes. The variability was reported to be not significant for cord blood Hg (p >
0.31) and this replicates the finding in the Faroe Islands cohort mentioned below (p
= 0.29). Interaction with PCB153 on RR-interval length variability was tested but
reported to be not significant, though no p-values were mentioned (Valera et al.,
2012). Interestingly, current blood Hg levels were reported to associate significantly
with the standard deviation of the R-R interval over 5-minute periods (β = -0.32, p =
0.01), but this lies outside the scope of the present essay. IBRS was found to
associate with PCB-153 on anxiety (ANX), emotional tone (ET), and positive affect
rate (PAR). Cord blood Hg was not found to be statistically significantly associated
here (Plusquellec et a., 2010).

Overall, it would seem that in this population, PCB’s and mercury tend to be
associated with, and show some evidence of interaction, on tasks that require
attention and response inhibition, both necessary mental processes in executive
function. However, it seems from the ERP’s on response inhibition tasks that the two
contaminants affect different stages of information processing in the brain more
acutely. There does not seem to be significant evidence in this population of effects
of mercury on emotional processes.

New York

In the Oswego birth cohort of New York State, mothers were recruited for having
consumed (n=141) or not consumed (n=152) contaminated Lake Ontario fish. Cord
blood was tested via gas chromatography for 69 PCB congeners, HCB, mirex and
DDE (Stewart et al., 1999). 5 cm of maternal hair was taken within 24 hours of birth
for mercury analysis. Methods of mercury assessment were not stated, but one
reference was made to a publication on atomic absorption for determination of
organic and inorganic mercury (Magos and Clarkson, 1972). This paper was not
available at the time of writing. Mercury levels were reported in quartiles for two
sample distributions: one for the first half, and one for the latter half of pregnancy.
The first quartiles (0.4 ng/mg) and medians of these distributions are the same (0.5
ng/mg) and are therefore not separately noted in Table 3. The third quartiles were
given in as 0.60 ng/mg for the 1st half and 0.70 ng/mg for the 2nd half of pregnancy.
Of the publications reviewed here, only the most recent reported standard
deviations for the contaminants, while only the second-most recent reported a mean
(see Table 2). The last publication utilized assessments of placental contaminants in
addition to the exposure methods previously mentioned. In statistical analysis,
highly chlorinated PCB (hcPCB) congeners with seven to nine chlorine atoms (hepta,
octa- and nonachlorinated PCB’s) were more frequently utilized rather than total
PCB’s (Stewart et al., 2000). The authors noted the rationale that these congeners
correlated well with fish consumption (data not reported) and total body burden
through a significant correlation they found between these congeners and breast
milk total PCB’s (r = 0.19, p = 0.05). In this review, total PCB (tPCB) is given as
reported in cord blood and specifies the authors’ use of hcPCB if done so (Table 2).
58 confounders were reported, including infant weight, maternal smoking, stress,

16
marital status, alcohol use, caffeine use, maternal IQ, maternal NES2 scores, and
socio-economic status. A full discussion of the confounders lies outside the scope of
this review.

Neonates born to these women were administered the NBAS for seven clusters of 28
behavioral and 20 reflex items (Lonky et al, 1996). Infants were grouped into four
clusters with non-detectable, low, middle, or high exposures, so that most of the
studies in this cohort return F-values rather than association coefficients (see Table
2). Authors note that neurological deficits began to appear at 25 to 48 hours after
birth, with significant deficits on habituation and autonomic scores (F = 3.95 and
4.40, respectively, all p < 0.05). None of the other contaminants, including DDE, lead
or mercury, showed significant associations in this study. At 38 months, the children
in the highest PCB exposure group showed significant deficits on the McCarthy
General Cognitive Index, Quantitative and Perceptual Scales (p < 0.05). Both a
stratified and an interaction analysis showed significant interaction with MeHg as
measured from the first half of pregnancy (p = 0.01). The authors noted this
interaction was stronger with lipid-adjusted than with wet weight PCB, but did not
report any p-values. At 54 months of age, none of the associations or interactions of
the contaminants with the McCarthy scores returned significant, with the McCarthy
Word Knowledge score actually being increased in the high exposure group
(Stewart et al., 2003a).

At 4.5 years of age (Table 2, row 2), the children were tested for response inhibition
with the Michigan Catch-The-Cat CPT. Following this, they were asked to score
themselves for Child Satisfaction Rating (CSR) through a Likert scale. 60 children
were additionally given an fMRI 24 months later, with 30 being selected from the
highest and 30 from the lowest exposure groups. MeHg was found to be associated
only with the CSR scale, while PCB’s were inversely associated with percentage of
correct responses in the CPT (Stewart 2003b). To test the longitudinal continuity of
this effect on impulsivity (Table 2, row 3), additional CPT tests, namely the NES2
CPT and the extended (E)-CPT were administered at ages 8 and 9.5, respectively
(Stewart et al., 2005) as well as a Differential Reinforcement of Low Rate Schedule
(DRL) task at the latter age (Stewart et al., 2006). Both CPT tests returned
significant results: Total commission errors (TCE) at 8 years of age showed
increased with PCB body burden (linear F = 5.07, p = 0.26) and percentage of
commission errors did so at 9.5 years (linear F = 5.56, p + 0.02), while mercury
showed no significant associations with these parametres (all p > 0.2). By contrast,
on the DRL task, inter-response times (IRT’s) were negatively associated with both
contaminants (MeHg first half of pregnancy β –0.179, p = 0.040; second half β = –
0.219, p = 0.015; total PCB’s β = –0.215, p = 0.008) as were fewer reinforcements
earned (MeHg 1st half β = –0.194, p = 0.026; MeHg 2nd half β = –0.203, p = 0.027 ;
total PCB’s = –0.208, p = 0.010). Interaction values for the two contaminants
returned non-significant (p> 0.2).

In the latest New York publication (Table 2, row 6), the WISC 3rd edition (WISC-III)
was used to assess child IQ at age 9. Mutual adjustment in multi-linear regression

17
showed PCB’s to be negatively associated with Verbal IQ, Performance IQ and Full
Scale IQ, while both PCB’s and MeHg significantly affected Freedom From
Distractibility scores (see Table 3, all p < 0.05). Notable in this study was the
separate regression analysis of four PCB congeners on the above IQ scales: PCB153
and PCB180 returned significant results (all p < 0.008) whereas PCB118 and PCB
138 did not (all p > 0.102)

Overall, it would seem from these studies that certain PCB congeners have more
important associations with behavioral outcomes than other congeners, that
mercury and PCB’s may both affect tasks that require response inhibition, but via
different mental pathways, and that early neurological deficits may be resolved at
later developmental stages. In contrast to the Quebec studies, mercury here seems
to have an effect on emotion, with self-reported satisfaction increasing with pre-
natal mercury exposure.

Faroe Islands

In the first Faroe Islands cohort of 1022 singletons, cord blood PCB’s from 435
samples were determined with capillary gas chromatography and solid phase
extraction. A surrogate for total PCB exposure was calculated by adding congeners
138, 153 and 180 and multiplying by 2.0. This was justified by the authors on the
basis that most of the contaminants were well-correlated (median Spearman’s r =
0.85, lipid-adjusted; p-value not reported). Only one of the publications mentioned a
standard deviation for any contaminant (see Table 3). Total mercury from cord
blood and maternal hair mercury were found with cold vapor atomic absorption;
the authors reported this result to be almost all MeHg in this population. Notably,
mercury was found to correlate more moderately with PCB’s (median Spearman’s r
= 0.31, lipid-adjusted, p-value not reported), allowing for elucidation of differential
health outcomes (Grandjean et al., 1997; Grandjean et al., 2001; Grandjean et al.,
2012). Confounders included maternal Raven score, maternal smoking and alcohol
use, parental occupation, birth weight, child sex, age and height, and breastfeeding
duration.

In the 1997 analysis (Table 1, row 1), heart rate variability (HRV) was assessed with
R-R intervals on an electrocardiogram (ECG) and found to be non-significant in
association with maternal hair mercury (discussed below). Brain stem auditory
evoked potentials (BAEP: I, III and V waves) and visual evoked potentials (N75,
P100 and N145 waves) were recorded with electro-encephalogram (EEG). Of these,
only wave V of the BAEP at 40Hz showed a significant association between latency
and cord blood mercury (β = 0.059, p = 0.01). Both wave III (β = 0.056, p = 0.02) and
V (β = 0.046, p = 0.04) did so at 20 Hz. Other significant associations (p =< 0.05)
were found with the NES2 finger tapping (β = -1.10), the CPT (total missed
responses or TMR: β = 0.12; average reaction time or ART: β = 40.3), the WISCR
digit spans (β =-0.27), the BNT (no cues [NC]: β = -1.77; with cues [WC]: β = -1.91),
and the CVLT (short-term [STR] and long-term reproduction [LTR]: β = -0.57 and -

18
0.55 respectively). NVAPMT showed a positive trend with average positive mood (β
= 2.61) but this was far from significant (p > 0.31).

The 2001 publication (Table 1, row 2) additionally tested thyroid-stimulating

hormone (TSH) and tetraiodothyronine (T4) through dried blood spot samples in
405 of the original 435 samples of the 1997 study. This time, total PCB’s (both wet
weight and lipid-adjusted), DDE and PCB153 from cord tissue were used as
independent covariates in multilinear regression. Lipid-adjustment led to no
significant associations with cord PCB’s. Therefore, only two outcomes for
associations with wet weight PCB’s are given in Table 2 for the 2001 publication.
For the 2012 publication (row 3, Table 1), additional data allowed for analysis with
694 samples on the same outcomes. Here, significant (p < 0.5) associations with
PCB’s were shown for BNT WC (PCB118: β = -0.995, PCB153: β = -0.981), the NES2
CPT TMR (PCB118: β = 2.02, DDE: β = 0.221), WISCR Block Design or BD (PCB138: β
= -0.2.09). Notably, none of these associations were sufficiently significant with the
sum-PCB calculation (all p >= 0.52).

To test for any modifications on the outcomes in this cohort, the 1997 publication
reported initially stratifying by gender and testing for interaction between mercury
and sex, but not with PCB’s. Data on these results was not provided. The authors
noted a lack of association of PCB’s with the data tested before adjustment for
mercury, with the greatest associations seen for the CPT ART, BNT’s and CVLT LTR
(all p < 0.1). When a regression analysis was done with mercury alone and then with
PCB as independent variables, the greatest influence was seen on the BNT, where
inclusion of PCB’s caused the Hg regression coefficient to drop from -2.03 (p =
0.007) to -1.36 (Hg: p = 0.10, PCB: p = 0.08, PCB with Hg: p = 0.008). Interestingly,
the 2001 publication re-analysed these data by stratifying the sample into tertiles of
low, middle, and high Hg exposure. Of these strata, the CPT outcome showed a
negative mercury-adjusted regression coefficient with PCB’s (β = -6.6) that fell
outside the 95% CI for the whole sample population (2.0, 42.7). A clear dose-
response trend was additionally seen, with the PCB regression coefficient becoming
greater (and more positive) with increasing Hg for all tertiles on all four outcomes
with (data not shown). The authors reported the data not to be significant, but
mentioned no p-values. In the 2012 publication, interaction terms for the two
contaminants in a structural equation model were said to show no significance in
these same outcomes, but no p-values were reported here.

One study (row 4, Table 1) selected twelve clinically healthy boys of 15 years of age
from this cohort and separated them into four groups of three boys each: low mixed,
high mixed, high PCB, and high Hg (White et al., 2011). PCB’s here refer to the three
congeners added and multiplied by 2 (discussed above). Table 1 shows the range of
full prenatal exposures for all 12 boys. Notably, the high mixed and high PCB groups
overlapped closely in their prenatal PCB exposure (4.60–6.91 ng/g wet weight of
cord tissue for high mixed, 4.60–6.91 for high PCB). The high PCB group and low
mixed group also displayed some overlap in prenatal Hg (4.30–13.80 mg/L cord
blood in low mixed, 10.10–13.30 for high PCB). None of the other ranges

19
overlapped. Significant differences in brain activation were seen on fMRI upon
finger tapping tasks and visual stimuli. Upon finger tapping, control individuals (low
mixed exposure) were shown to predominantly activate the contralateral
hemisphere, whereas all high exposure groups showed bilateral activation.

In the second Faroe Islands cohort (row 5, Table 1), maternal hair and cord blood
mercury were examined with flow-injection cold vapor atomic absorption
spectrometry. Gas chromatography was used to identify 28 PCB congeners and 18
OC’s. This study reported lipid-adjusted PCB levels, utilizing the same method of
adding and multiplying by 2 the three congeners as discussed above. Time-resolved
fluoroimmunoassay was used to obtain maternal and cord blood serum thyroid
stimulating hormone (TSH); thyroxine and T4 uptake were measured by
immunoassay. Only the latter was found to be associated, negatively, with cord
blood PCB (r = -0.21, p = 0.01). Conversely, PCB-adjusted cord blood mercury was
associated negatively with the Neurologic Optimality Score in the neonates (r = -2.1,
p = 0.03). Maternal smoking, alcohol consumption, maternal serum PCB’s and cord
serum selenium and polyunsaturated fatty acids were controlled for confounding
(Steuerwald et al., 2000).

Overall in the FI population, mercury seems to be the more important than PCB for
neurobehavioral outcomes, with only T4 and select tests for attentional and verbal
processes bearing significant results for PCB’s. The MRI study on boys seems to
suggest that prenatal insults can be overcome through adaptive mechanisms of
brain plasticity that leads to bilateral activation instead of contralateral activation of
the motor cortex. Additionally, this cohort seems to show that certain PCB
congeners are more important for developmental outcomes than sum-PCB’s, partly
corroborating the evidence from the New York cohort.

DISCUSSION

A difficulty in interpreting the results of the studies lies in the varied methods of
assessment and presentation of exposure data. The Faroe Islands (FI) and Quebec
(QC) studies utilized cord blood for both contaminants, whereas all but one New
York (NY) study used hair Hg. In addition, the NY studies often used the most highly
chlorinated PCB congeners in statistical analysis (heptachlorinated: PCB170-193,
octachlorinated: PCB194-205, nonachlorinated: PCB206-208). The QC study used
PCB153, and the FI studies created a surrogate of 2.0 times three congeners. For
presentation, some studies gave means, others medians, and only some studies
provided standard deviations, some percentiles and ranges.

The larger QC cohort in a study not reviewed here, showed total PCB’s to consist of
34.6% PCB153, 14.8% PCB180, 18.6% PCB138, and 4.7% PCB118 (Muckle et al.,
2001). Geometric mean for total PCB’s was reported to be 313.2 ng/g (n=159),

20
which is an expected three times higher than most of the PCB153 concentrations
reported in Table 1. Using the FI approach to calculating sum-PCB with QC data
would yield exposures greater than 100%: this shows there may be differences in
PCB-congener content of the FI and QC mixtures. Additionally, an NY and an FI study
in the review obtained slightly different, but more significant results when PCB-
congeners rather than mixtures were used in data analysis, casting some doubt on
the adequacy of total or sum-PCB’s to elucidate health effects. Nonetheless, prenatal
PCB measurements for all populations reviewed seem to be similarly high (median
placental and geometric means of all cord blood tPCB > 200 ng/g l.a.) and consistent
on several health points (response inhibition, attention).

Analysing Hg exposures poses similar complications: maternal hair, placental,

maternal serum, cord tissue, cord serum and cord blood can give different results,
while total Hg may give different results from total MeHg. Grandjean did mention
that almost all Hg found in the FI was MeHg, but no exact values were given
(Grandjean et al, 2001). However, most of the mercury in the Arctic populations can
be expected to be from fish consumption, and could therefore very well be MeHg.
Furthermore, prenatal Hg exposures in NY seem to be consistently about five to ten
times lower (median placental MeHg < 3.0) than in most Arctic cohorts (geometric
mean cord blood Hg > 20). Though no definitive conclusions can be taken with the
present data, we may be able to draw broad comparisons and tentative hypotheses
for dose-response differences.

As can be seen from the tables 1-3, both mercury and PCB’s showed significant
associations were with tests of response inhibition, attention and anxiety, such as
the DLR, CPT and Freedom from Distraction scales. This was not entirely consistent,
as CPT and ECPT were not associated with mercury in NY, but associated much
more strongly in the Faroe Islands, as did the DLR in Quebec. Therefore, we can
posit that in this review, response inhibition tasks seem to associate with mercury
more strongly in the Arctic, and more strongly with PCB’s in NY. Another differential
is that anxiety and mood disturbance associated with PCB’s in the Arctic, whereas
mercury was associated with higher child satisfaction ratings in NY. We can see here
a paradoxical association: it seems more mercury leads to happier children in NY,
and PCB’s lead to unhappier children in QC. However, in the FI, mercury was
associated, albeit insignificantly, with both positive (β = 3.66, p = 0.20) and negative
mood (β = 1.83, p = 0.51) in at maternal hair concentrations below 10 μg/g
(Grandjean et al., 1997). This is still much higher than the NY maternal hair levels,
but shows the complexity of moods: both positive and negative moods may be being
exacerbated by endocrine disruption, causing mood instability, an aspect not tested
here. Besides anxiety, one other aspect of the sympathetic nervous system, heart
rate variability, showed no association with prenatal contaminants in QC and FI.
This could be indicative that HRV, unlike anxiety, is unaffected.

Intelligence tests, such as the Wechsler, Fagan, and cognitive tests, such as the
McCarthy, all seem to be affected by PCB’s predominantly in NY. However, the BNT
and the CVLT both showed associations with mercury in the FI, as did several points

21
of the Wechsler. It is plausible that the higher dose of mercury in the Arctic is
masking the effects of PCB’s. If so, we should see similar affects on intelligence and
cognitive functioning in QC. Here, Wechsler, Fagan and Bailey’s were administered
to the study population at age 11, but the Wechsler and Fagan data for this cohort is
not available. Bailey’s did now show any significance in deficits however (all p >
0.05), so that the causes of this discrepancy are not yet clear. It is notable that in NY,
the McCarthy scores showed clear deficits at 38 months, but a complete resolution
of these differences at 54 months. In FI, fMRI’s of healthy functioning children
showed clear changes in brain activation. Both studies may be indicative of brain
plasticity and ability to recover after neurologic insult.

LIMITATIONS OF AVAILABLE RESEARCH

The studies found in this review concerned mostly PCB’s in fish-eating populations
around the Arctic and North American Great Lakes. Other such populations in the
Amazon and Seychelles have been studied for MeHg, but not for PCB or other EDC
exposure. This is a concern, as such chemicals have been found in upper trophic
level wildlife in those regions, such as Amazon dolphins and West Pacific Ocean tuna
(Torres et al., 2009a; Torres et al., 2009b). Other endocrine disruptors, such as
organophosphate pesticides and PAH’s were under-represented. Such EDC’s can be
of concern to non-fish eating populations and should therefore be further studied.

None of the studies reviewed here reported any data analysis being performed for
boys and girls separately. This is a serious limitation to understanding endocrine
disruptor interactions, as studies that incorporated gender have shown a range of
neurobehavioral effects to be sex-differential: endocrine disruptors and mercury
being antagonistic in some cases, synergistic in others, and significant differences in
outcomes for males and females (Sugawara et al., 2008; Roegge et al., 2004). In one
such study (Spulber et al., 2010), cord blood Hg was found to associate negatively
with BDNF only in girls whose mothers did not smoke during pregnancy (Pearson r
=􏰃0.149, p = 0.04). As cigarette smoke has hormone effects, it falls under the
definition of EDC as defined by the Endocrine Society in 2012 (Band et al., 2002;
Dechanet et al., 2010, Windham et al., 2005). Surprisingly, when the authors of the
Spulber study employed an un-stratified regression model without accounting for
sex, a two-way interaction term for maternal smoking and Hg returned far from
significant in this study (p = 0.512). The implications of this are, that if interactional
analysis of two endocrine-disrupting compounds does not take gender into account,
either through stratification or with a three-way interaction term, the results will
return statistically insignificant.

The lack of gender analysis we found here forms a serious barrier to discovering
interactive effects of mixtures, which is especially concerning for the study of joint
effects on neurobehavioral outcomes, as verbal ability, visuo-spatial processing,
response inhibition, mood, anxiety, etc. are largely sex-differential in humans.

22
Animal studies have reported significant gender-differential neuro-endocrine,
neuro-immuno-modulatory and behavioral effects of combined exposure to
mercury and EDC’s (Cauli et al., 2013; Vitalone et al., 2009; Sable et al., 2009;
Sugawara et al., 2008; Roegge et al., 2004; Hayley et al., 2011). In humans, in utero
exposures to maternal antibodies and endocrine active compounds have been
implicated in sex-specific behavioral teratogenic outcomes, such as schizophrenia
(Brown et al., 2014), ASD (Braunschweig et al., 2013), AD(H)D (Pakkila et al., 2014),
and sex-typed behavior (see above). Considering the sex-specificity of human
neurobehavioral development, it is reasonable to suspect that multiple interactions
of gender and combined exposures may be occurring, but are largely being missed.

CONCLUSION

Of the outcomes most commonly found to be significantly associated with PCB’s and
mercury, response inhibition, attention and executive function seemed to be most
important in this review, and in some studies they were found to be significantly
interactive (Stewart et al., 2008; Stewart et al., 2003b; Boucher et al., 2014; Boucher
et al., 2012; Boucher et al., 2010; Grandjean et al., 2001). Heart rate variability was
found in both FI and QC studies not to be associated with prenatal PCB nor mercury
exposure (Grandjean et al., 1997, Valera et al., 2012). Intelligence, cognitive
function, emotion and verbal ability seem to show differential effects in the different
regions: Intelligence and verbal tests seem significantly associated with mercury in
the FI, but with PCB’s in NY (Darvill et al., 2000; Stewart et al., 2008; Grandjean et
al., 1997), while non-significant trends were seen in QC (Boucher et al., 2014).
Similarly, associations with emotion are seen with mercury in NY, with PCB’s in QC,
and non-significant results in the FI (Stewart et al., 2003b; Plusquellec et al., 2010;
Grandjean et al., 1997). The cause for this is unclear but could possibly be related to
subtle differences in the exposure levels for these groups. At least in some cases,
functional adaptation and recovery seems possible (White et al., 2011; Stewart et al.,
2003a). Gender differences have not been assessed systematically for any joint
effect of mercury and PCB’s. More research is needed on non-PCB endocrine
disruptors in populations outside the Arctic to gain a better understanding of their
combined effect with mercury.

23
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 Fig 1. Study selection flow diagram

Electronic search PUBMED

N = 500

Title & Abstract Screening

N = 500
Excluded at screening

N = 449
Full Text Review

N = 51
Excluded at full text review

N = 12
Retained for scoping

N = 39

Additional studies found

through review

N=7
Included in scoping
review
N = 46
Excluded based on new criteria:

-PCB’s
-biomarkers
-human data

N = 30
Included in systematic
review
Fig 2. Map with cohort locations
N = 16

30
31
Table 1. Prenatal exposures, outcome and interaction coefficients: Birth cohorts in Nunavik, Quebec, Canada.

POP = population, PCB = polychlorinated biphenyl, SD = standard deviation, HG = mercury, FTII = Fagan Test of Intelligence for Infants, A-not-B = A-not-B task delay
length, ERP = evoked reaction potential, NS = not significant, P3bA = P3b-wave amplitude, MHR = mean hit reaction time, RFA = rate of false alarms, N1A = N1-wave
amplitude, N1L = N1-wave latency, NR = not reported, ET = Emotional Tone, ANX = anxiety, PAR = Positive Affect Rating

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Table 2. Prenatal exposures, outcome and interaction coefficients: Birth cohorts in Oswego, New York, USA.

POP = population, PCB = polychlorinated biphenyl, SD = standard deviation, HG = mercury, tPCB = total PCB’s., NBAS = neonatal behavioral assessment scale, H = NBAS
Habituation rating, A = NBAS autonomic rating, hcPCB’s = highly chlorinated PCB’s, NS = non-significant, 6m = 6 months old, 12m = 12 months old, FTII = Fagan Test of
Infant Intelligence, l.a. = lipid adjusted, CPT = continuous performance task, CE = commission errors, CSR = child satisfaction rating, NR = not reported, NS = not
significant, ECPT = extended CPT, WISC = Wechsler Intelligence Scale for Children, F = Full Scale IQ, V = Verbal IQ, FD = Freedom from Distractibility, P = Performance IQ,
GCI = General Cognitive Index, log = log-transformed

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Table 3. Prenatal exposures, outcome and interaction coefficients: Birth cohorts in the Faroe Islands, Denmark.

POP = population, PCB = polychlorinated biphenyl, SD = standard deviation, HG = mercury, w.w.=wet weight, l.a.=lipid-adjusted, NES2 = Neurobehavioral Evaluation
System 2, CPT = Continuous Performance Task, TMR = Total Missed Responses, ART = A Reaction Time, BNT = Boston Naming Test, NC = no cues, WC = with cues, CVLT
= California Verbal Learning Test, STR = Short-term Response, LTR = Long-term Response, fMRI = functional Magnetic resonance Imaging, NA = not applicable, NS = not
significant d = day

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