Environmental Research 197 (2021) 111124

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Environmental Research
journal homepage: www.elsevier.com/locate/envres

Review article

Neurodevelopment and exposure to neurotoxic metal(loid)s in

environments polluted by mining, metal scrapping and smelters, and
e-waste recycling in low and middle-income countries
José G. Dórea
Universidade de Brasília, Brasília, 70919-970, DF, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: This review covers a wide body of literature to gain an understanding of the impacts of informal activities related
Neurotoxicity to metal extraction (primary mining and recycling) on early life exposure to neurotoxicants and on neuro­
Mining development. In primary mining, gold extraction with Hg amalgamation is the main environmental cause of Hg
Recycling
pollution in most artisanal small-scale gold mining (ASGM) activities around the world. Nevertheless, in Sub-
Neurodevelopment
Saharan Africa (SSA), Pb disrupted from gold-related ores, mining, and artisanal cookware production are an
Breast milk
Mercury important neurotoxicant that seriously contaminates the affected population, with devastating effects on chil­
Lead dren. In e-waste recycling settings, the range of neurotoxic substances that contaminate mothers and children is
wider than in primary mining environments. Thus, Hg and Pb are major pre- and postnatal neurotoxicants
affecting children in the informal metal extraction activities and SSA countries show the highest record of human
contamination and of neurotoxic effects on children. There are additional sources of neurotoxic contamination
from mining and metal processing activities (cyanide tailing in South America and SSA) and/or co-exposure to
Hg-containing products such as cosmetics (soaps and Hg-based skin lightning creams in Africa) and pediatric
Thimerosal-containing vaccines (TCVs, that breaks down to ethyl-mercury) in current use in middle and low
income countries. However, the action of these neurotoxicants (per se or in combination) on children needs more
attention and research. Studies show a negative association between biomarkers of all environmental metal(loid)
s (As, Cd, Hg, Mn, and Pb) studied and neurodevelopment in young children. Sadly, in many unregulated ac­
tivities, child labor is widely employed, thus presenting an additional occupational exposure. Children living in
polluted environments related to metal processing are disproportionately exposed to a wide range of co-
occurring neurotoxic substances. The review showed compelling evidence from highly representative parts of
the world (Africa, Asia, and Latin America) that the studied neurotoxic substances negatively affected areas of
the brain associated with language, memory and executive function, as well as psychosocial behavior. Protecting
the environment and children from unregulated and highly polluting metal extraction and processing are
inextricably intertwined and deserve urgent attention.

1. Introduction et al., 2020). Additionally, water in mining areas of Chile shows

Children living in environments which have undergone degradation
due to mining, waste recycling, and metal scrapping and smelting,
mainly occurring in low and middle-income countries (LMICs) are at
greater risk of exposure to neurotoxic metals and associated pollutants.
Poor families living in the vicinity of mineral deposits and metal pro­
cessing facilities are also subjected to exposure to high levels of Hg, As,
Mn, Pb, and Cd (Castro et al., 2014; Marques et al., 2013b, 2014).
Indeed, the main factors influencing Pb exposure of villagers in Kabwe
(Zambia) were distance and direction (down-wind) from the mine (Yabe
significantly higher As and Pb concentrations (Castro et al., 2014).
Health risks to miners and residents in artisanal small-scale gold
mining (ASGM) areas were studied by Pavilonis et al. (2017) in relation
to exposure to As, Mn, Co, Pb, and Hg. They found soil concentrations of
As above background-levels in the mining area and Hg vapor levels 30
times larger than the EPA reference concentration. Exposures to both As
and Hg were associated with the risk of developing non-cancerous
health effects. However, because there were no determinations of
chemical species and bioaccessibility, the authors recognized that the
risks could be overestimated (Pavilonis et al., 2017). Indeed, in addition

E-mail address: jg.dorea@gmail.com.

https://doi.org/10.1016/j.envres.2021.111124
Received 24 February 2021; Received in revised form 1 April 2021; Accepted 1 April 2021
Available online 13 April 2021
0013-9351/© 2021 Elsevier Inc. All rights reserved.
J.G. Dórea
to Hg in ASGM areas (in Tanzania), mothers were also exposed to As
(Nyanza et al., 2019), which negatively affected birth outcome (Nyanza
et al., 2020).
The rapid and exponential increase in electrical and electronic
equipment has created large quantities of waste (here referred to as e-
waste) that are dumped for reuse or recycling in low-income countries.
Zeng et al. (2018) reviewed studies showing the economics of urban
mining (recycling) versus virgin (primary) mining, i.e., extraction of
metals from their natural setting in ores. In all cases, environmental and
health-related issues continue to present enormous challenges, which
are worse in unregulated informal activities. A comprehensive review of
the e-waste environmental issues (Ádám et al., 2021) and health con­
sequences (Grant et al., 2013) can be found elsewhere.
Most informal metal extraction (primary mining, recycling and e-
waste) is done in LMICs leaving a trail of environmental (Veiga and
Gunson, 2020) and health consequences (Ádám et al., 2021) that affect
the most vulnerable, usually women and children; these activities thus,
contribute to accentuating environmental (Drace et al., 2016) and social
(Aschner et al., 2021) injustice in affected countries. The objective of
this narrative review is to address children neurodevelopment and
exposure to neurotoxic metal(loid)s in settings of extraction (primary
mining and recycling) in LMICs. The reviewed material was identified in
peer reviewed publications that addressed metal extraction (primary
and e-waste recycling) associated with pre- and postnatal exposures, and
neurodevelopmental outcomes in LMICs. Data bases (Medline, PubMed,
Web-of-Science, and Google scholar) were searched using the following
key-words: ‘mining’, ‘neurodevelopment’, ‘e-waste’, ‘recycling’, ‘metals’.
The retrieved papers were read and scrutinized for relevant content.
2. Metal contamination from primary mining, recycling (e-
waste) and smelting
2.1. Primary mining
In ASGM settings, metallic Hg is used to amalgamate gold during the
extraction process but it contaminates sites related to mining, processing
and commercialization (Garcia et al., 2015). However, toxic metals are
released from ores as a byproduct of the mining activity. In gold mining
tailings, it has been shown that Mn and Pb are the most labile and
bioavailable metals in the surrounding environment, thus more haz­
ardous than others such as As, Cd and Zn (Barcelos et al., 2020). The
most outstanding example is the Pb poisoning outbreak linked to ASGM
in Nigeria that killed circa 400 young children (<5 year-old) (Plumlee
et al., 2013), and left more than 2000 children with permanent dis­
abilities (Dooyema et al., 2012; Lo et al., 2012). Environmental Pb
pollution resulting from tin-ore mining and processing activities in
Western Amazonia (Brazil) was found to contaminate human milk
(Marques et al., 2013b, 2014).
Primary large-scale mining of Hg is currently limited, but artisanal
small-scale mining can be found in China (Li et al., 2012) and Mexico
(Marshall et al., 2021). Countries that engaged in large-scale Hg mining
continue to endure the legacy of contaminated soils. Indeed, rice culti­
vated in Hg mining areas can bioaccumulate methyl-Hg (MeHg) at
concentrations capable of contaminating children (Feng et al., 2020).
However, the main source of Hg contamination in mining activities is
from ASGM (Veiga and Fadina, 2020). Currently, the Hg used to amal­
gamate gold in ASGM in LMICs is the largest source of direct inorganic
Hg contamination of women and children. Additionally, children living
in ASGM areas can also be exposed to toxic levels of co-occurring
neurotoxic metals in the extracted ores (Biya et al., 2010).
Depending on the price of gold, ASGM activities can fluctuate, but it
is estimated that 10 to 19 million miners are spread across impoverished
areas of Asia, Africa and South America. This workforce involves circa 5
million women and children (Esdaile and Chalker, 2018). Indeed,
Butscher et al. (2020) called attention to the “invisibility” of women in
ASGM workforce. They claim that half of the people working in the
2
Environmental Research 197 (2021) 111124
ASGM are women, rendering all kind of services: in food preparation and
sex work, and in mining: digging, moving, washing or processing ores to
extract gold (Butscher et al., 2020). In certain regions, like Mongolia,
men engage in heavy physical digging, while women may engage in
smelting the amalgam in the traditional tent that may pollute the indoor
environment with Hg fumes (Steckling et al., 2011). A similar scenario
was reported in Colombia, where males perform strength-demanding
mining jobs such as crushing ores, manipulating Hg and the burning
of amalgam whereas women (65%) handle bartering, selling of gold, and
also the burning of amalgam (sometimes in home backyards) (Cal­
ao-Ramos et al., 2021).
The worst of all these unregulated activities is child-labor in ASGM.
Indeed, an elevated concentration of Hg in urine of children in ASGM-
related activities has been found in Ecuador (Harari et al., 1997).
Likewise, in Africa, child labor is reported in ASGM activities (Long
et al., 2015). In Côte d’Ivoire, Kouame et al. (2015) reported that many
students were dropping out of school to work in ASGM activities.
Kampalath and Jay (2015) reviewed the anthropogenic sources of Hg
emission, indicating that world metal mining is an important source of
contamination that affects children. Indeed, Hg exposure levels in chil­
dren were the highest in areas downstream from Hg mine sites (Du et al.,
2016).
Long et al. (2015) described some living conditions of ASGM families
in Ghana that can be characterized as lacking basic infrastructure and
access to safe water supplies; they have also enumerated risk factors
associated with poor respiratory health and deficiencies in maternal and
child health. These general descriptors of socioeconomic disadvantages
can also be found in ASGM in South America (Counter et al., 2002) and
small-scale tin mining activities (Marques et al., 2012).
2.2. Metal recycling
Activities related to e-waste recycling of metals are done informally
by poor demographics of third world countries. Recovery of valuable
components/materials is frequently a home-based activity that uses low-
tech methods. These processes require manual dismantling, cleaning
with hazardous solvents, open burning (and melting) and acid leaching
in order to recover valuable components (metals) (Cui et al., 2015;
Tansel, 2017), and are often performed by children and adolescents
(Souza, 2020).
Orisakwe et al. (2019) summarized e-waste contamination and
recycling practices in Africa; they reported e-waste neurotoxic metals
(Al, As, Cd, Co, Cr, Hg, Li, Pb, Sb) in association with recycling activities.
Health effects of exposure to organic (polybrominated biphenyls-PBBs,
tetrabromobisphenol-A-TBBP-A, and poly-brominated diphenyl
ethers-PBDEs) and inorganic mixtures of toxicants were summarized,
regarding the e-waste community (Orisakwe et al., 2019). Activities
related to recovering precious metals in e-waste dumps concur with the
volatilization of polychlorinated biphenyls (PCBs) and other
semi-volatile pollutants in the environment (Gioia et al., 2014). As a
result, toxic metals (Pb, Cr, and Cd) and persistent organic pollutants
(POPs) such as PCBs, PBDEs and polycyclic aromatic hydrocarbons
(PAHs) are commonly reported in such settings (Ádám et al., 2021).
Recently, Ádám et al. (2021) described recycling activities that can
be carried out directly on landfill sites or in small (home-based) recy­
cling shops. Thus, a variety of toxic substances (metals and organic
pollutants) generated in these processes can cause both occupational
exposure to those directly involved (and their family members) and also
environmental exposure to other residents living in the vicinity.
Potentially toxic metals (Al, Cd, Cr, Pb, Li, Hg, Ni, Ag, Pd, Pt, W) and
organic substances (flame retardants/organic solvents, plasticizers,
toxicant-laden dust and particulates, combustion products, such as
polycyclic aromatic hydrocarbons and dioxins) were reportedly elevated
in blood samples of e-waste recyclers (Ádám et al., 2021).
J.G. Dórea
2.3. Additional factors and neurotoxic co-exposures
Exposure to neurotoxic metal (Pb + Cd + As + Hg) mixtures pro­
duces more severe effects than exposure to binary or ternary combina­
tions. Indeed, synaptic structural alterations of NGF-differentiated PC12
cells are more severe when induced by metal (Pb + Cd + As + Hg)
combinations compared to the mixtures of two or three of these
neurotoxic elements (Zhou et al., 2018). Valeri et al. (2017) estimated
that compared with single-metal exposure, co-exposure to multiple
metals early in life can increase neurotoxicity. A more detailed review of
metal mixtures (that included Pb and Hg) and experimental and popu­
lational neurotoxic effects can be found elsewhere (Dórea, 2019a,
2019b, 2020).
There are specific environmental exposures to neurotoxicants
(especially Pb and Hg) occurring frequently in LMICs and affecting
targeted demographics: wood-burning in traditional cookstoves (Etchie
et al., 2020), leaded gasoline in some African countries (Bede-Ojimadu
et al., 2018), Hg-based beauty products (Dórea, 2021a), and TCVs
(Dórea, 2018, 2020; Tall et al., 2021). It should be noted that there have
been successful efforts to phase out Pb in the gasoline of African coun­
tries since 2006; indeed blood-Pb levels have diminished over time
(Bede-Ojimadu et al., 2018). Likewise, efforts to control (and abate)
environmental Hg (especially its use in ASGM) have been on the inter­
national agenda since the Minamata convention (Veiga and Fadina,
2020). Additionally, the use of Thimerosal in pediatric vaccines (as a
preservative and adjuvant) has been discontinued in all economically
developed countries but remains in use for most children in the devel­
oping world (WHO, World Health Organization, 2011). The Thimerosal
molecule decomposes rapidly into ethyl-mercury (EtHg; Geier et al.,
2015). Therefore, children exposure to neurotoxicants in the mining and
e-waste recycling environments may also be additionally co-exposed to
other unsuspected neurotoxicants such as the binary mixture of EtHg
and Al in the TCVs (Bastos et al., 2018).
In SSA, the use of Hg-based “skin bleaching” products during preg­
nancy is frequent, but not taken into consideration in children neuro­
development studies in ASGM settings (Dórea, 2021a). Additionally, the
use of cyanide in gold extraction also causes widespread environmental
contamination (Drace et al., 2016; Marshall et al., 2020), exposing
children (Kwaansa-Ansah et al., 2017; Wickre et al., 2004) and likely
affecting their neurodevelopment (Counter et al., 2002, 2012; Bumoko
et al., 2015). Indeed, animal experiments showed that the complexation
of Hg(CN)2 produced during the reprocessing of cyanide tailings accu­
mulates in the kidneys, liver and spleen but little accumulates in the
brain (Seney et al., 2020).
Cyanide exposure can also occur with high consumption of cassava
(Dórea, 2004a), and cassava-cyanogens may pose neurologic harm in
certain parts of Africa (Onabolu et al., 2001). When compared to con­
trols, neuro-motor impairments were observed in Congolese children
with konzo and low levels of trace (Se, Cu, and Zn) elements (Bumoko
et al., 2015); these children had low blood levels of Hg (1.3 ppb) and Pb
(1.2 ppb). Bumoko et al. (2015) attributed the neuro-motor impairments
to be associated with cassava cyanogenic exposure and Se deficiency.
Studies of Hg exposure during infancy need to assert all additional
sources of Hg (inorganic and organic). Cumulative health risks of Hg
derived from EtHg in TCVs deserve consideration (Dórea, 2018).
Depending on birth weight and the vaccine manufacturer, the
hepatitis-B vaccine (given early after birth) may raise blood-Hg con­
centrations to extremely high levels. The pediatric TCVs can vary in
Thimerosal formulations and because vaccines, different from pediatric
medications, are not prescribed as weight adjusted, their doses can vary
5fold in a newborn baby (Dórea and Marques, 2008; Dórea et al., 2009).
Indeed, these types of organic Hg exposures can be higher than that of
the breast-milk-Hg estimated for occupationally (ASGM) exposed
mothers in Zimbabwe (Dórea, 2009).
Kolbinger et al. (2019) reported differences in the manifestation of
neurological symptoms in Hg exposure among ASGM adults (including
3
Environmental Research 197 (2021) 111124
adolescent >13 years old) in Asia (Philippines, Indonesia) and Africa
(Tanzania, Zimbabwe). There were differences in the performance of
pencil tapping test between A-allele carriers in the African and Asian
populations. They suggested that certain ABCC2 polymorphisms may
influence the neurotoxic effects in amalgam-burning ASGM miners.
Genetic polymorphism and neurological expression of both Pb and Hg
has been shown in children (Liu et al., 2015; Snoj Tratnik et al., 2017;
Wang et al., 2017). Furthermore, Zeng et al. (2019) suggested that genes
involved in brain-neuron development are affected by prenatal exposure
to toxic metals (particularly Pb) in e-waste environments.
3. Biomarkers of metal exposure during early life
Due to simultaneous co-occurrence of neurotoxicants in polluted
environments of metal extraction (mining and recycling) commonly
found in LMICs, it is important to understand biomarkers of exposures
and early life susceptibility to neurotoxic effects; their choice and opti­
mality in relation to neurotoxic outcome was discussed elsewhere
(Dórea, 2021b).
Urine and blood Hg concentrations indicate mainly recent short-term
exposure. However, when measured in hair, total Hg concentrations are
known to reflect organic-Hg exposure (MeHg from fish consumption). In
the Amazon, there are differences in Hg concentrations in biological
matrices; while occupational exposure in ASGM shows a high urinary-
Hg and low hair-Hg concentration, indigenous inhabitants (Amerin­
dians and riverines) show low urinary-Hg but high hair-Hg concentra­
tions (Barbosa et al., 1995). Indeed, Basu et al. (2018) identified among
populations of concern for high Hg exposure “tropical riverine com­
munities (especially Amazonian) who consume fish and in some cases
may be exposed to mining” and “individuals who either work or reside
among artisanal and small-scale gold mining sites”. Although both forms
of Hg exposure (fish-MeHg and amalgam burning) can reach the brain,
elemental Hg exposure from amalgam burning can lead directly to its
deposition in the brain via inhalation.
Fetuses and breastfed infants are likely exposed to the same pollut­
ants in the maternal organism in utero and during breastfeeding;
nevertheless, environmental neurotoxic contaminants have a distinct
metabolism (acquisition, storage, and half-life) that influences different
neurodevelopmental outcomes (Dórea, 2021b). Environmental metal
(loid)s associated with neurotoxic outcomes in this review (Pb, Mn, Hg,
As) show a wide variation in compartmental (or body) half-life. While
Pb (a persistent contaminant) has a half-life of only a month in soft
tissues, it can reach 30 years in bones (Maret, 2017; Klotz and Göen,
2017). Inorganic Hg has a body half-life of 20 days, but as MeHg it
reaches 70 days (Clarkson et al., 2003); in young children, the blood
clearance of EtHg (after intramuscular injection) is even faster: 7 days
(Pichichero et al., 2002). However, Hg has a half-life of decades in the
brain (Rooney, 2014). Half-life for blood-Mn was estimated to be from
65 to 80 days (Park et al., 2014) and As in the body from 15 to 66 days
(Diacomanolis et al., 2014). A summary of the metabolic characteristic
of these neurotoxic elements is found elsewhere (Rebelo and Caldas,
2016). It is interesting to note that breast-milk concentrations of Cd, Hg,
and Pb decreased over time, but levels in newborn stools remained
stable from birth to one month of age (Astolfi et al., 2019).
In situations of acute accidental mass poisoning (maternal con­
sumption of bread contaminated with Hg-based fungicides) in Iraq,
human milk-Hg reached concentrations >1000 μg/L (5000 nmol/L), but
none of the breastfed infants (five) showed clinical signs of MeHg/EtHg
poisoning (Amin-Zaki et al., 1974). In chronic exposure, the total-Hg in
the cerebral cortex of older infants (11–50 weeks of life) was signifi­
cantly correlated with the maternal number of dental amalgam fillings
(Drasch et al., 1994). The tendency for Hg to appear in increasing
concentrations in the brain of fetuses and infants whose mothers showed
an increasing number of amalgam fillings was not found by Lutz et al.
(1996). But maternal amalgam fillings were significantly correlated with
Hg in breast milk (da Costa et al., 2005).
J.G. Dórea
Because of organ immaturity and an incomplete blood-brain barrier,
the younger the organisms, the more vulnerable they are when
compared to older children. The maximum vulnerability of the nervous
system is widely accepted to occur during the fetal period and early
postnatal life (Grandjean et al., 1994). Indeed, the maternal transfer of
neurotoxicants to infants continues in breastfeeding. Depending on the
toxicant and dose, any additional source of neurotoxicant exposure may
represent an increase risk for the still sensitive/developing nervous
system.
Maternal blood that matches the vulnerable time window of expo­
sure for certain neurological outcomes is desirable. The biomarkers of
prenatal exposure to metal contaminants are preferentially maternal
and umbilical cord blood. However, hair-Hg concentrations are widely
used for environmental fish-MeHg exposures. Indeed, postnatal expo­
sure can be measured in maternal blood and milk (and colostrum).
Often, umbilical cord blood and human milk are useful surrogate mea­
surements for early-life development and organogenesis during preg­
nancy and current exposure - lactation.
3.1. Prenatal exposure
Maternal blood and urine (during pregnancy), and umbilical cord
blood are useful assessing the burden of contaminants in the fetal body
(Kim et al., 2019). In the case of Pb exposure, maternal blood-Pb or
cord-blood-Pb concentrations were more accurate biomarkers than
urine (Kim et al., 2019). Liu et al. (2014b) showed that in environ­
mentally exposed mothers, fetal-Pb exposure as low as 5 μg/dL can
adversely affect neurodevelopment; this is mostly expressed during the
first trimester but it can be arrested by monitoring maternal blood-Pb.
Furthermore, higher concentrations of neurotoxic elements (Pb, As,
and Sb) in maternal blood were associated with smoking, a low educa­
tional level, and partners involved in mining activities (Barbieri et al.,
2016). Indeed, in a mining environment, Barbieri et al. (2016) reported
that maternal blood-Pb was significantly correlated with cord-blood-Pb.
During the dismantling of waste electronic appliances, plastic-coated
wires and cables are burned to recover precious metals. Song and Li
(2014) reviewed concentrations of neurotoxicants (Pb, Cd, Cr, Ni) in
placenta and cord blood from mothers in an e-waste recycling area of
Guiyu (China); mothers living near the e-waste recycling area had
higher concentrations of metals (Pb, Cd, Cr, Ni) compared to mothers at
other sites (Song and Li, 2014). Blood-Pb concentrations were signifi­
cantly higher in children from Guiyu than in a reference sample from
Haojiang (Cai et al., 2019).
In the case of MeHg exposure, its proxy (total-Hg) in umbilical-cord
blood is significantly correlated with maternal hair-Hg (Grandjean et al.,
1994). During pregnancy and lactation, total-Hg in maternal hair
decreased more during pregnancy than during lactation in mothers who
habitually ate fish (Barbosa et al., 1998; Marques et al., 2013a). The
maternal transfer (excretion) of total-Hg seems to be higher to the fetus
than to the breastfed infant. In the Philippines, Ramirez et al. (2000)
reported a higher prevalence of Hg in the fetuses than in their mothers.
In artisanal tin-mining settings (in the Western Amazon) with rela­
tively low fish consumption, the correlation between maternal hair-Hg
and breastfed infant’s hair-Hg was not statistically significant (Mar­
ques et al., 2013a). Indeed, exposure to Hg in an area with a legacy of
gold extraction in the Philippines (Tagum, Apokon Valley) showed that
“the prevalence of Hg in meconium was significantly related to the
prevalence of Hg in the mothers’ blood and length of stay in Tagum”
(Ramirez et al., 2000). In artisanal tin-mining settings (in the Western
Amazon) with relatively low fish consumption, the correlation between
maternal and newborn hair-Hg was not statistically significant (Marques
et al., 2013a). However, in China, Li et al. (2008) reported a significant
correlation between high Pb in the umbilical cord blood and in meco­
nium in neonates born to mothers exposed to e-waste recycling
activities.
Exposure transfer of neurotoxic elements (As, Cd, Hg, Mn, and Pb)
4
Environmental Research 197 (2021) 111124
from maternal stores is easier through the placenta than through the
mammary gland barrier (Bastos et al., 2018). Ramirez et al. (2000)
studied the Hg metabolism in mothers’ blood, urine and breast milk and
in newborns’ cord blood, infants’ hair, and meconium; they concluded
that higher prevalence and concentrations of total Hg in the fetal com­
partments reflected the ease of Hg transfer through the placenta.
3.2. Maternal exposure and lactation
Sharma et al. (2019) reviewed world data on Hg concentrations in
pregnant women and in breast milk. They reported a significant
decrease in milk-Hg for Asia, Europe, and North America, but not for
Africa and South America. In studies of populations in the Western
Amazon with a habitual high consumption of fish, the correlation be­
tween maternal hair-Hg and breastfed infant’s hair-Hg (at six months)
depends on the maternal fish consumption (Marques et al., 2013a).
Breast-milk concentrations of neurotoxic elements (Pb and Hg) are
reflective of prenatal exposure, when most neurotoxic insults by these
elements occur. In a review summarizing the World Health Organization
(WHO, 1989) study of human milk trace element concentrations,
Nigeria and Zaire showed similar mean Hg concentrations (Dórea
2004b); however, in these countries, mean Hg concentrations were
higher than in other countries (Dórea, 2004b). In the case of Pb, prior to
the leaded-gasoline ban (2006) in Africa (Bede-Ojimadu et al., 2018),
mean milk-Pb concentrations in Zaire were twice as high in urban than
in rural dwellers (Dórea 2004b).
Studies that measured both maternal blood and respective milk
element concentrations showed comparable ranges of blood:milk ratios
for Pb and Hg (Dórea, 2004b). The blood:milk ratio for Pb in occupa­
tionally exposed (lead-acid battery dismantling and Pb-glazing pottery)
environments in Ecuador (Counter et al., 2004) showed a mean ratio of
37.8. The blood:milk ratios estimated in mothers living in the vicinity of
a metal industry were as follows: Cd (1.7–7), Mn (1.7–4.1), THg
(0.5–2.4), As (0.5–2.8), and Pb (0.7–4.1) (Sharma and Pervez, 2005).
In a sub-sample that also measured the infant’s blood Pb concen­
tration, the ranges of maternal blood-Pb (39–335 μg/L) were higher than
milk-Pb (1.2–20.5 μg/L); however, the infant’s blood-Pb (46–274 μg/L)
ranges were also higher than milk-Pb. This could be interpreted as both
an efficient mammary gland barrier and an indication that pre-natal Pb
is contributing to current blood-Pb concentrations in breastfed infants
(Counter et al., 2004). In environmental exposure (from metal smelters)
in Mexico (Namihira et al., 1993), the blood:milk ratio for Pb was 18.35.
In an ASGM environment (Yargalma, Nigeria), Ojo et al. (2017) reported
blood:milk ratios for Pb and Hg of 12.35 and 0.63 respectively. In rural
Bangladesh, maternal exposure to Pb attributed to food cooked in
aluminum pots (likely made from cottage recycling industry) showed a
mean blood:milk ratio of 18.9 for Pb (Bergkvist et al., 2010).
3.2.1. Metal extraction settings and neurotoxic metal(loid)s in human milk
Specific maternal exposure studies in metal-extraction environments
that determined neurotoxic elements in human milk are summarized in
Table 1. Human milk concentrations of neurotoxic metal(loid)s were
studied in mothers who were environmentally exposed in ASGM settings
of Colombia (Molina et al., 2018), Ecuador (Counter et al., 2004, 2007,
2014), Nigeria (Ojo et al., 2017), Ghana (Asamoah-Antwi et al., 2020),
Philippines (Ramirez et al., 2000), Indonesia, Tanzania, and Zimbabwe
(Bose-O’Reilly et al., 2008a, 2020); the higher engagement in amalgam
burning in homes may explain higher milk-Hg concentrations. Some
studies were from women living in the vicinity of metal industries that
emitted Pb (Marques et al., 2013b, 2014; Sharma and Pervez, 2005).
Most studies determined Hg (Ramirez et al., 2000; Bose-ÒReilly et al.,
2008a, 2020), and Pb (Marques et al., 2013b, 2014, 2014; Castro et al.,
2014; Counter et al., 2007, 2014). In the ASGM environments, the
milk-Pb concentrations seemed higher (13.8–45 μg/L) in SSA than in
South American countries (3.76–4.6 μg/L) (Table 1).
Except for amalgam burning in ASGM that emits only Hg vapors,
J.G. Dórea Environmental Research 197 (2021) 111124

Table 1
Concentrations of neurotoxic metals in human milk from mothers living in metal processing and mining environments (listed by countries in alphabetical order).
Country Exposure environment [NT Metal] mean/ n Stage Comments Reference
1
median (range) μg.L− lactation,
ms

Brazil Mothers living in the vicinity of tin ore [Pb]: Smelter-11.3 v. 82 0.5–6 Milk-Pb concentrations were significantly Marques et al.
smelters (exposed) were compared to rural-1.9 μg.L− 1 higher in exposed mothers than in that of (2013a).
mothers of rural areas rural mothers. Most milk-Pb (79%) in the
exposed area were above the WHO critical
limit of 5.0 μg.L− 1.
Brazil Mothers living in the vicinity of TOKS [Pb]: TOKS-10.4 v. 31 NG Milk-Pb concentrations of mothers living Marques et al.
were compared to subsistence mothers. riverines-3.9 μg.L− 1 v. in the vicinity of TOKS were significantly (2014).
51 higher than in mothers from a fishing
village.
Chile Mothers living in mine-waste polluted [As]: 0.36 v 0.23; 35 2-4, 4-6 No statistically significant difference, but Castro et al.
area (Arica) were compared with a [Mn]:4.9 v 4.6; [Cd]: less toxic elements were transferred to (2014)
control area (Santiago). 0.23 v 0.22; [Pb]: 1.7 v exclusive breastfed infants compared with
1.0 those who additionally received formulas.
Colombia Milk, hair, and urine of mothers living in Total [Hg]: 2.5 150 NG The prevalence of Hg contamination in Molina et al.
ASGM areas (Antioquia, El Bagre, samples with a high concentration was (2018)
Segovia, Remedios and Zaragoza) and 11.7%. Significant correlation between Hg
74% reported burning amalgam at home. in mothers’ milk and urine.
Ecuador Mothers occupationally involved in [Pb]: (1.44–39) 4 NG The elevated Pb levels found in breast milk Counter et al.
dismantling Pb-acid discarded batteries were indicative of extensive Pb (2000).
and ceramic Pb-glazing activities. intoxication and environmental
contamination.
Ecuador Mothers occupationally involved in [Pb]: 4.6 13 NG The breast milk-Pb levels ranged from 0.4 Counter et al.
dismantling Pb-acid discarded batteries to 20.5 μg/L while maternal blood-Pb (2004).
and ceramic Pb-glazing activities. levels ranged 45–274 μg/L (mean, 171 μg/
L).
Ecuador Mothers occupationally involved in [Pb]: 7.5 22 NG This follow-up study showed breast milk- Counter et al.
dismantling Pb-acid discarded batteries Pb in the 2006 group were similar to the (2007).
and ceramic Pb-glazing activities. Pb levels found in breast milk of mothers
in the same study area in 2003.
Ecuador Mothers occupationally involved in [Pb]: 3.73 22 1–24 Maternal Pb exposure declined over time Counter et al.
dismantling Pb-acid discarded batteries along with milk-Pb levels. A high and (2014).
and ceramic Pb-glazing activities (La significant correlation (r = 0.687) between
Victoria, El Tejar, and Mulinliví) milk-Pb and maternal blood-Pb suggested
good predictability for maternal blood
concentrations.
Ghana Mothers living and working in two [As]: 26.70; 114 3 The amounts of most As (46.4%), Hg Bansa et al. (2017)
different ASGM communities (Obuasi [Cd]: 1.23; (33.3%) and Pb (4.4%) were higher than
and Tarkwa). Total [Hg]: 7.61; the WHO set limits and above the PTDI
[Pb]:13.83. values.
Ghana Mothers living and working in ASGM [Total-Hg]: 0.4043 48 1–13 Mean milk-Hg concentrations were low Asamoah-Antwi
communities (Obuasi). [MeHg]: 0.1829 compared to other ASGM areas in Ghana. et al. (2020)
India Mothers living in an integrated area of [As]: (BDL-5.2) [Pb]: 120 Newborn Blood:milk ratios from mothers living in Sharma and
steel-plant environment in Steel City – (BDL-16.7) [Mn]: 1wk the vicinity of a metal industry were in the Pervez (2005)
Bhilai. (0.8–21.5) [Total-Hg]: following range: Cd (1.7–7), Mn (1.7–4.1),
(BDL-16.7) [Cd]: THg (0.5–2.4), As (0.5–2.8), and Pb
(0.1–3.8) (0.7–4.1)
Mexico Mothers living in a 200 m radius of 3 (Pb- [Pb]: 25 μg/L 35 1–27 The maternal mean blood-Pb (458.8 μg/L) Namihira et al.
emitting) smelters in Mexico City. levels showed that women had high body (1993)
burdens, and infants had an additional risk
of Pb exposure via breast milk. Maternal
blood and milk Hg were significantly
correlated.
Nigeria Mothers recruited from areas with Total [Hg]:3.2 v 0.4 v 106 NG Pb concentrations were significantly Ojo et al. (2017)
different ASGM activities: Yargalma 0.5; higher in women from areas with high and
(active; n:27), Yperindo (legacy; n:31), [Pb]: 45.0 v 3.5 v 2.6. medium ASGM activities, but the mean
Ife-Ife (reference; n:48). blood Hg levels were similar in the three
sites.
Philippines Mothers from an area formerly with Total [Hg]: 0.036 78 Newborn Hg was present in 6.4% of maternal blood Ramirez et al.
intense ASGM activities and 6.4% of colostrum. (2000)
Tanzania, Pooled breast milk from women exposed [Hg]: 1.87 median 46 NG Some breast milk samples showed very Bose-O’Reilly
Zimbabwe, to very high background of Hg in ASGM high levels of mercury (<1.0 up to 149 μg/ et al. (2008)
Indonesia areas with no separation of housing and L). Fourteen of the 46 milk samples
working (Geita; Kadoma; Kalimantan and showed concentrations higher than 4 μg/L.
Sulawesi).
Zimbabwe Women living and working (directly Total [Hg]: 1.20 v 1.10 130 3–9 No infant from the control group, but Bose-O’Reilly
exposed to Hg) in ASGM; high, low v < 0.50 17.6% of the medium and 18.5% of the et al. (2020)
exposure groups were compared to high exposed group were above the
control. reference dose. Milk-Hg is higher in ASGM
areas. Breast fed infants were burdened
with additional Hg in breast milk and via
the general environment.

ASGM: artisanal small-scale gold mining; BDL:below detection limit; MeHg: methyl-Hg; NG: not given; TOKS: tin-ore kilns and smelters; PTDI: provisional tolerable
daily intake; WHO: World Health Organization.

5
J.G. Dórea
metal smelting is a high Pb-emitting activity. However, in artisanal
processing centers that leach the amalgamation tailings with cyanide,
gold is precipitated with other metals soluble in cyanide with zinc. The
final process of gold recovery occurs in urban areas where the Zn-loaded
shavings are evaporated at very high temperatures. In this process Zn,
Pb, Hg and other volatile elements are emitted to the atmosphere
intoxicating operators and neighbors (Veiga et al., 2014). Nevertheless,
different geochemisty determines Pb exposure in ASGM of different
countries. Milk-Pb concentrations ranged from 10.4 to 25 μg/L in
mothers living in the vicinities of smelting environments in Brazil
(Marques et al., 2013b, 2014) and Mexico (Namihira et al., 1993).
Breastfeeding mothers living in poor neighborhoods in the vicinity of
smelters showed altered levels, especially of Pb in Brazil (Marques et al.,
2013b), Chile (Castro et al., 2014), and Mexico (Namihira et al., 1993).
Clearly, metal processing is a source of environmental contamination
of neurotoxicants. Studies that compared exposed and reference groups
of mothers consistently showed a higher Pb concentration for the former
group in Chile (Castro et al., 2014), Brazil (Marques et al., 2013b, 2014)
and Nigeria (Ojo et al., 2017). Indeed, in areas where gold amalgam was
burned at home (Colombia), maternal urine and milk Pb concentrations
were significantly correlated (Molina et al., 2018). In impoverished
Andean Pb-glazing cottage industries, women of childbearing age and
children are occupationally involved in extracting Pb from discarded
Pb-acid automobile batteries and using it for glazing of ceramics
(Counter et al., 2004, 2007). In these industry settings, mean
breast-milk-Pb concentrations increased from 2003 to 2006 (Counter
et al., 2007). Nevertheless, it is of interest to note that when compared to
non-breastfed infants, the total amount of toxic elements consumed was
lower in the breastfed infants (Castro et al., 2014).
Comparability of these studies is challenging; stage of lactation
varied from colostrum to 24 months (7 out of 14 studies did not provide
this information). In addition, there was a wide variation in concen­
trations of the measured elements, and some studies analyzed only a
small sample of mothers. Nevertheless, in settings of metal extraction
and processing (mining and recycling), Pb and Hg were the most studied
in breast milk.
4. Neurodevelopment outcomes in mining and recycling
settings
The main health issues associated with exposure to mercury vapor in
ASGM workers and their families, as well as residents of nearby com­
munities were reviewed by Gibb and O’Leary (2014); they reported hair
and urine Hg concentrations above the WHO health guidance values in
men, women, and children (Gibb and O’Leary, 2014). Indeed, Cha­
tham-Stephens et al. (2014) estimated that circa 800,000 children <4
years of age were potentially exposed to Pb from 200 toxic waste sites
(and environmental “hotspots”) in 31 LMICs. In these countries, 632
million children were estimated to have a blood-Pb level exceeding the
reference value of 5 μg/dL (Ericson et al., 2021). Chen et al. (2011)
showed that “pregnant women and young children living close to
informal e-waste recycling sites are at risk of possible perturbations of
fetus and child neurodevelopment.” The estimates of attributable eco­
nomic costs have been modeled for Pb (Attina and Trasande, 2013), and
Hg in ASGM workers (Steckling et al., 2014). Attina and Trasande
(2013) estimated a total cost of $977 billion dollars for LMICs; in gross
domestic product (GDP) it is higher for poor countries: 4.03% in Africa,
2.04% in Latin America and the Caribbean, and 1.88% in Asia. There­
fore, the burden associated with childhood neurotoxicant exposure is
much higher in developing countries than in economically advanced
countries (Ericson et al., 2021).
It is challenging to assess neurological dysfunction (or develop­
mental delays) resulting from prenatal or postnatal exposure to metal
(loid)s from mining and recycling waste. Most studies were limited to
one exposant, but in most scenarios they occur in combination. Human
studies have abundantly shown adverse clinical and neurobehavioral
6
Environmental Research 197 (2021) 111124
outcomes in children associated with environmental and occupational
exposure in metal extraction settings (Table 2).
4.1. Clinical outcomes
Neurological impairments associated with occupational exposure in
ASGM activities are more frequently reported for adult men (Dórea and
Marques, 2016; Butscher et al., 2020). However, a few studies have
reported threshold abnormalities in the hearing of children living in
ASGM areas of Ecuador that were studied in relation to Hg exposure
(Counter et al., 1997, 2002, 2012; Peplow and Augustine, 2014). Coulter
et al. (2012) found that children’s high blood-Hg (15.6 μg/L) levels were
significantly correlated with Acoustic Stapedius Reflex thresholds
(ASRT); however, this same group reported no neurological effect in
relation to Pb exposure (Buchanan et al., 2011). In ASGM areas of
Indonesia and Zimbabwe, Bose-O’Reilly et al. (2008b) reported that
children that worked with Hg had high levels of this element in the
analyzed matrices (urine, blood, and hair) and showed clinical symp­
toms for Hg intoxication such as ataxia. Haefliger et al. (2009) retro­
spectively investigated the rapidly progressive central nervous system
(CNS) disease of unexplained origin that killed 18 children from the
NGagne Diaw neighborhood (Senegal); they concluded that all the dead
children were possible victims of Pb intoxication.
Bartrem et al. (2014) studied children from Zamfara (Nigeria,
emergency environmental remediation actions) exposed to neurotoxic
metals, namely Pb, Hg, Ar, Cd and Mn in mass poisoning resulting from
ASGM. Overlapping toxicodynamics and toxic endpoints were reported
for the studied metals; for instance, Pb, As and Cd were negatively
associated with IQ (Bartrem et al., 2014). Based on concentrations of
toxic metals in soils, co-exposure risks were calculated with
clinical-neurological endpoints, and hazard indices were ranked as fol­
lows: Pb > As > Hg ≫ Cd > Mn (Bartrem et al., 2014). In the same
Nigerian artisanal mining site (Zamfara), Jubril et al. (2019) reported
that goats showed brain concentrations of Pb and Cd that were much
higher than in the brains of unexposed animals. Indeed, Pb has a higher
gastro-intestinal absorption and longer half-life (in bone) than Cd
(Dórea, 2019a).
A summary of neurological (clinical and behavioral tests) studies for
the Amazon Basin illustrates the regional complexity involving inor­
ganic and organic Hg exposure (Dórea and Marques, 2016). Environ­
mental exposure to organic Hg in the Amazon is widespread due to
fish-methylmercury consumed traditionally by subsistence riverine
populations and habitually by urbanized inhabitants. In the same vast
region, unregulated clandestine ASGM activities use metallic Hg to
amalgamate gold (Barbosa et al., 1995).
Studies from areas impacted by e-waste recycling found a high
prevalence of young children to be negatively impacted by Pb and Cd
(Zhang et al., 2015). Socio-behavioral abnormalities were found in as­
sociation with S100 Ca-binding protein in serum of ADHD children (Liut
al., 2014a).
4.2. Neurodevelopmental tests
A summary of studies showing neurodevelopmental test outcomes as
a function of exposure to neurotoxic metal(loid)s is shown in Table 2.
The initiating event leading to neurological damage (frequently more
than one stressor) and the test outcome likely will take more than one
pathway. Not surprisingly, Pb singly or in combination with other
neurotoxicant was preponderant in both ASGM and smelting exposure
studies. In all cases, the pathway to an adverse neurological outcome can
involve thyroid hormone disruption (Pb and MeHg), oxidative stress (Pb
and MeHg), dopamine dysfunction (Pb, MeHg, and As) (Heyer and
Meredith, 2017; Rock and Patisaul, 2018). Moreover, in addition to
metals, e-waste recycling activities can add PBDEs (thyroid dysfunction,
oxidative stress), PCBs (neuroendocrine disruption), Polychlorinated
dibenzo-p-dioxins and dibenzofurans-PCDD/PCDFs, and PAHs
J.G. Dórea Environmental Research 197 (2021) 111124

Table 2
Exposure to environmental neurotoxicants and children neurodevelopment (ND) outcomes in metal extraction and/or processing settings.
Country Living settings of exposures Metal(loid)s n Aim of study Neuro-behavior Tests (ages): Outcomes Reference

Latin America
Bolivia Contaminated by mining Pb, As, Cd, 246 ND as a function of prenatal BSID (10.5–12.5 ms): The outcome did not Ruiz-Castell et al.
industries. Sb, Cs, Zn, (maternal) blood-Pb. show mental or psychomotor (2012).
Fe, Cu, Se, abnormalities. Surprisingly, at the observed
Rb, and Sr low levels of exposure, Pb was positively
associated with the children’s BSID
performance.
Bolivia Vicinities of mining NS 175 ND as a function of anthopometric BSID (10.5–12.5 ms): “Children born Ruiz-Castell et al.
industries. growth smaller were more likely to grow/develop (2013).
faster and attain greater weight and length.
Their cognitive development was not
affected by their growth patterns.”
Brazil Riverines living downstream Hg 351 Compared villages with different Stanford-Binet (7–12 ys): ND tests Grandjean et al.
of ASGM in the Tapajós mean total hair-Hg levels. (attention, visuo-spatial performance, and (1999).
River. motor function) showed decrements
associated with the hair-Hg levels.
Especially in the Santa Ana form board and
in the Stanford-Binet copying tests, similar
associations were also found in the 105
children from the village with hair-Hg <10
μg/g (except for 2).
Brazil versus Pproximity of ASGM (Sai Hg 263 Compare fish MeHg (hair-Hg) Stanford-Binet (7-12ys; 5-12ys): Hair-Hg Chevrier et al.
French Cinza) and Wayama –F. v. exposure and ND was negatively associated with scores on (2009).
Guyana Guyana 97 the drawing task: a score reduction of 1.2
points was observed in the children with a
hair-Hg concentration > 10 μg/g compared
to those with a hair-Hg <1 μg/g this effect
was stronger in the younger children.
Brazil Near a Fe–Mn alloy plant Mn 83 ND as a function of hair-Mn in RPM (6-12ys): Children’s hair-Mn was Menezes-Filho
(Bahia). children and mothers. negatively related to IQ and Verbal IQ. et al. (2011).
Maternal hair-Mn was negatively
associated with performance on the RPM
test.
Brazil Tin-mining area of Western Hg (MeHg 688 ND as a function of nutritional GDS (0–60 ms): No significant association Marques et al.
Amazon. and EtHg) status and exposure to fish-MeHg with total TCV-EtHg exposure at time of (2012).
and TCV-EtHg. test. Family fish-eating habits did not affect
children’s linear growth, but showed a
positive influence (along with other
maternal variables) on ND.
Brazil Vicinity of tin-ore kilns and Pb, Al, Hg 96 ND in exposed young children was BSID-II (6, 24 ms): MDI and PDI were Marques et al.
smelters. (MeHg, compared to children from a significantly lower for the exposed children (2014).
EtHg) fishing village. (that included higher TCV-EtHg) only at 24
ms of age. Multivariate regression showed
that MDI was negatively affected by milk-
Pb and hair-Hg. PDI was positively affected
by breastfeeding and negatively affected by
EtHg.
Brazil Vicinity of tin-ore kilns and MeHg, EtHg 299 Compare exposure in tin mining GDS (12–14 ms): Despite significantly Dórea et al. (2014).
smelters. and subsistence villagers. higher exposure to both forms of organic
Hg (MeHg from maternal fish consumption,
and EtHg from TCVs) exposure in toddlers
from fishing families, significant
differences were seen only among the
proportions of most severely affected
toddlers (GDS < 70). In conclusion,
milestone achievement was delayed in
toddlers from tin-ore mining communities.
Brazil Near a Fe–Mn alloy plant Mn 70 Hair-Mn and executive function IQ, TAVIS-3R, WCST, WISC (7–12ys): The Carvalho et al.
(Simões Filho, Bahia). and attention neuropsychological results suggest that airborne Mn exposure (2014).
tests. may be associated with lower IQ and
neuropsychological performance in tests of
executive function of inhibition responses,
strategic visual formation and verbal
working memory.
Brazil Near a Fe–Mn alloy plant Pb and Mn 83 Behavioral traits in exposed CBCL (7–12ys): Results suggest a positive Menezes-Filho
(Simões Filho). children (Blood Pb and hair Mn) association between elevated Mn exposure et al. (2014).
and externalizing behavioral problems and
inattention, with girls presenting more
pronounced effects.
Brazil Near a tin-ore open-pit Hg (MeHg, 294 ND and organic Hg exposure BSID-II (6–24 ms): No significant Marques et al.
mining environment. EtHg) association of BSID (MDI and PDI) scores (2015).
with total TCV-EtHg exposure. There was a
significant sex difference in ND, with boys
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7
J.G. Dórea
Table 2 (continued )
Country Living settings of exposures
Brazil Children living near a
Fe–Mn alloy plant (Bahia).
Brazil Children living in area
impacted by petrochemical,
cement, and shipyard, and a
Fe–Mn alloy plant (Bahia).
Brazil Children living in area
impacted by Pb-glazing
acivities.
Chile Children living in a Pb-waste
storage area and
remediation.
Ecuador Children living in ASGM
area
Ecuador Children living in area of Pb-
glazing activities.
Ecuador Children living in ASGM
contaminated environment.
Ecuador Children living in remote
ASGM settlements (Nambija
and Portovelo).
Ecuador Children living in ASGM of
Nambija and Portovelo.
Mexico Children living within 3.5
km of a smelter complex
(Torreón).
Mexico Children living within 3.5
km of a smelter complex
(Torreón).
Environmental Research 197 (2021) 111124
Metal(loid)s n Aim of study Neuro-behavior Tests (ages): Outcomes Reference
showing more sensitivity related to BSID
delays.
Mn 165 ND as a function of Mn exposure CBCL (7-12ys): Hair-Mn and blood-Mn Rodrigues et al.
(toenail-Mn) in school-aged. were not associated with any scale of the (2018).
CBCL behavior scores. There was a positive
association between log toenail-Mn and
raw total CBCL score. Results suggest that
toenail Mn, is associated with disruptive
behavior in children living near a Fe–Mn
alloy plant.
Pb and Mn 225 ND as a function of Pb (blood) and WASI (7–12 ys): Child IQ droped 8.6 points Menezes-Filho
Mn (toenail) exposure. for a 10-fold increase in blood-Pb levels. An et al. (2018).
effect modification of Mn co-exposure was
observed. In children with low toenail-Mn
the association between Pb and IQ was not
significant. In children with high toenail-
Mn the association increased by 27.9%.
Low Pb exposure was associated with IQ
deficit, especially in those with high
toenail-Mn.
Pb 142 Interaction of chronic T. gondii CBCL (6.1–14.3ys):The results suggest Martinez et al.
infection with blood-Pb and ND interaction between toxoplasmosis (2020)
outcomes prevalence and Pb exposure. Children
above the median blood Pb and positive for
IgG anti-T. gondii showed a 5.51-fold
increase in the chance of displaying
disobedient behavior.
NS 735 IQ in children born before, during, WISC (6-15ys): A difference of 10 points in Burgos et al.
and after remediation. the IQ average was observed between the (2017).
group born in the pre (81.9 points) and post
remediation period (91.1 points). The
difference between both groups was five
times higher as compared to children from
other cities of Chile.
Mn 93 ND and Mn exposure (hair-Mn). RPCM (School age): Children with elevated Betancourt et al.
levels of hair-Mn (>2 μg/g) had poor (2015).
performance in general intelligence test.
Pb 53 Pb exposure and DPOAE emanating DPOAE (6-16ys): Although the study group Buchanan et al.
from the outer hair cells of the was found to have abnormally elevated (2011).
inner ear. blood-Pb levels, in contrast to some earlier
reports, the results of the current study
showed no consistent Pb-induced sensory
effects on the cochlea of these children.
Pb and Hg 66 Pb and Hg exposure (blood levels) Auditory thresholds (4-15ys): Auditory Counter et al.
and auditory thresholds. brain stem response in 7 children with high (1997).
blood-Pb levels showed normal latencies.
There was no significant correlation
between Pb exposure and auditory
function.
Hg 114 To compare Neuro-otological Neuro-otological symptoms (mean 9.5 yr): Counter et al.
symptoms and blood-Hg between Blood-Hg for children from Nambija was (2002).
Saraguro and non-Saraguro higher than that from Portovelo. Children
(Mestizo) children. from Nambija (particularly the Saraguro
“Amer-Indians”) showed elevated blood-Hg
levels (from ASGM activities), and were at
risk for neurological impairment. The
children from Portovelo who reported
neuro-otological symptoms and low blood
-Hg levels were suspected of exposure to
sodium cyanide used in ASGM.
Hg 22 Andean children were screened for ASRT (6-17ys): The ASRT in the children Counter et al.
Hg-induced auditory brainstem increased significantly with blood-Hg level. (2012).
and facial nerve impairment.
Pb 602 To assess nutritional variables and Number Sequencing, PPVT, WISC-RM (6–8 Kordas et al.
effects of Pb exposure on cognition ys): In multivariate models, the association (2004).
between Pb and cognitive performance was
not affected by nutritional variables,
suggesting that the relation of lead to
cognition is not explained by lead’s relation
to iron deficiency anemia or growth
retardation.
Pb 602 To assess effects of blood Pb (<10 14 tests of global or specific cognitive Kordas et al.
μg/dL) levels on cognition. functions (6.2–8.5ys): After adjustment for (2006).
covariates, a higher blood lead level was
associated with poorer cognitive
performance on several cognitive tests. The
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8
J.G. Dórea Environmental Research 197 (2021) 111124

Table 2 (continued )
Country Living settings of exposures Metal(loid)s n Aim of study Neuro-behavior Tests (ages): Outcomes Reference

results suggest that n the absence of

information on Pb exposure in early
childhood, a test result with blood lead
<10 μg/dL should not be considered safe.
Mexico Children living within 3.5 Pb 602 To assess the role of Pb exposure Sleep, classroom behavior, and activity Kordas et al.
km of a smelter complex (and anemia) in children’s sleep (6–8 ys): Anemia was linked to more off- (2007).
(Torreón). problems task behaviors, lower physical activity,
earlier bedtime, and shorter sleep onset.
Mexico Children living within 3.5 As and Pb 602 To identify demographic and VSAFD, PPVT, WISC-RM, CAT: (6-8ys): Rosado et al.
km of a smelter complex nutritional factors associated with Significant inverse association between (2007).
(Torreón). As exposure and cognitive urine-As and VSAFD, PPVT, WISC-RM Digit
function. Span, Visual Search, and Letter Sequencing
Tests. Children living in an contaminated
area showed that As exposure can affect
ND, independent of any effect of Pb.
Mexico Children from mining and Mn 170 To compare biomarkers (blood and WISC (7-11ys): Exposed children had Riojas-Rodríguez
processing district hair-Mn) and ND between Molango significantly higher median values (hair et al. (2010).
(Molango). and non-exposed children. and blood Mn) than did nonexposed
children. The results suggest that Mn
environmental exposure is inversely
associated with intellectual function in
young school-age children.
Mexico Children living within 3.5 Pb 602 Tthe combined influence of Pb Eight tests of cognitive and behavioral Moodie et al.
km of a smelter complex exposure and home enriched functions (6–8 ys): Home Environment had (2013).
(Torreón). environment on cognition and a significant indirect mediation effect
behaviour. between lead and both Cognition and
Behaviour (p-value < 0.001). Home
Environment has a moderate mediation
effect with respect to Pb effects on
Behaviour and a lower mediation effect on
Cognition.
Mexico Children from mining and Mn 174 To compare biomarkers (blood and CAVLT (7-11ys): Hair Mn was inversely Torres-Agustín
processing district hair-Mn) on verbal memory and associated with most CAVLT subscales, et al. (2013).
(Molango). learning. mainly those evaluating long-term memory
and learning. Blood Mn levels showed a
negative but non-significant association
with the CAVLT scores. These results
suggest that Mn exposure has a negative
effect on children’s memory and learning
abilities.
Surinam Wayana community, Hg 9 Determine health impacts INI - neurologic dysfunction (5-18ys): In Peplow and
Puleowime (Apetina) associated with exposure to Hg children older than 11 ys of age, neurotoxic Augustine (2014).
contamination. effects moderate and higher were
documented (through a battery of
neurological tests).
Peru Children living near ASGM. Hg 164 Risk of exposure to Hg and IQ in Beery-VMI, Woodcock-Munoz (5-12ys): Reuben et al.
children ASGM. After adjustment for covariates, children (2020).
with hair-Hg levels > WHO reference level
scored 4.68 IQ points lower in Cognitive
Ability than peers.
Africa
Congo Pb exposure in the city of Pb 104 Infant exposed to Pb from Gensini–Gavito scale (12–24 ms): Children Kashala-Abotnes
Kinshasa handmade cooking ware made exposed to lead were reported with more et al. (2016)
with recycled Pb based material. temperament diffculties at even blood lead
levels <10 μg/dL
Nigeria Children living near small Pb 160 Compare IQ children living in a IQ (6–8 years): There was an inverse Dike et al. (2020)
scale Pb mining. lead mining area and a non-mining relationship between total concentrations
area. of ingested Pb and mean IQ scores.
Tanzania Children living near ASGM. Pb, Hg, Cd, 439 Infant ND and prenatal exposures MDAT (6–12 ms): Infants in ASGM areas Nyanza et al.,
and As (cord blood metals). are at significant risk for ND impairment 2021.
that is associated with exposure to higher
concentrations of Hg prenatally. Co-
exposure to high concentrations of Hg and
Pb, or Hg and As appeared to have
potentiating negative effect on infants’ ND.
Asia
China Children living in e-waste Pb 152 Association of cord Pb levels and NBNA (neonates): The cord-Pb levels were Li et al. (2008)
impacted area (Guiyu). ND in neonates from Guiyu and correlated with maternal occupation in e-
control areas. waste recycling. Neonates with high cord-
Pb had lower NBNA scores. There was a
statistically significant difference in NBNA
scores between the exposed and the control
group (P < 0.05). A negative correlation
was found between maternal blood Pb and
NBNA scores (P < 0.01). There is a
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9
J.G. Dórea
Table 2 (continued )
Country Living settings of exposures
China Children living in e-waste
impacted area (Guiyu).
China Children living in metal
processing areas in Zhejing
Province
China Children living in e-waste
impacted area (Guiyu).
China Children living in e-waste
impacted area (Guiyu).
China Children living in e-waste
impacted area (Guiyu).
China Children living in e-waste
impacted area (Guiyu).
China Children living in e-waste
impacted area (Guiyu).
China Children living in area of
inactive Hg mines
(Wanshan).
China
Environmental Research 197 (2021) 111124
Metal(loid)s n Aim of study Neuro-behavior Tests (ages): Outcomes Reference
correlation between cord-Pb meconium-Pb
(related to e-waste recycling).
Pb 303 Compared children blood-Pb from PTQ (3-7ys): Children blood-Pb levels were Liu et al. (2011)
Guiyu and Chendian (control higher in Guiyu than in Chendian.
group). Significant differences of mean scores in
activity level, approach-withdrawal, and
adaptability were found between Guiyu
and Chendian children (P < 0.01). Children
with high blood-Pb levels had higher mean
scores of approach-withdrawal when
compared with controls. Location of child
residence in Guiyu, and parents’
engagement in e-waste work were the risk
factors related to children blood Pb levels
and PTQ scores.
Pb 329 Health risks of Pb in a metal IQ (11–12ys): The blood-Pb levels in Wang et al. (2012)
processing areas: tinfoil (Lanxi), e- exposed areas were much higher than those
waste recycling (Luqiao) and in the control area. No significant
control (Chun’an). differences of IQ were observed between
Lanxi, Luqiao and Chun’an, however a
negative relationship between blood-Pb
levels and IQ was shown for the study
children.
Pb, Cd, and 243 Child blood metals (Pb, Cd, and ADHD (3-7ys): The ADHD prevalence in Liu et al. (2014a)
Mn Mn) and behaviors, and the Guiyu was 18.6%, and the percentage of
involvement of S100 calcium- children suspected to have behavior
binding protein b (S100b) in ADHD problems being 46.2% or 46.5. Child blood
metals (Pb, Cd, and Mn) correlated with
behavioral (conduct problems and
antisocial behavior) abnormalities. Serum
S100b levels were associated with
neurotoxic elements in blood, and
behavioral abnormalities.
Pb and Cd 243 To investigate ADHD in children in ADHD (3-7ys): This study suggests that Zhang et al. (2015)
relation to blood Pb and Cd. environmental lead contamination due to
e-waste recycling has an impact on
neurobehavioral development of preschool
children in Guiyu.
Pb 258 Comparing children blood-Pb from BSID-III (3ys): “Median values of blood Pb Liu et al. (2015)
Guiyu (exposed group) and Nanao in Guiyu was higher than in the control
(control group) group; e-waste exposed children have lower
cognitive scale scores and lower language
scale scores than controls. The three kinds
of genotype, A1/A1, A1/A2, and A2/A2,
had no significant influences on blood Pb,
cognitive scores and language scores.”
Pb and Cd 258 To compare thyroid disruption and BSID-III (3ys): In Guiyu, medians of blood Liu et al. (2018)
mental ND in children from Guiyu Pb and blood Cd, and means of FT4 and
(exposed group) and Nanao TSH were higher than in Nanao. Guiyu
(control group). children had lower cognitive scores and
lower language scores. Blood Pb negatively
correlated with both cognitive and
language scores.” Exposure to Pb reduces
cognitive and language skills, and affects
thyroid function, but fail to confirm that
thyroid disruption is involved in the
neurotoxicity induced by Pb–Cd co-
exposure.
Pb 574 Comparing exposed children SPM-HKC (3-6ys): The median Cai et al. (2019)
(Guiyu) and from a nearby town concentration of serum cortisol, an HPA-
(Haojiang) with no e-waste axis biomarker, in Guiyu children was
recycling activity significantly lower than in Haojiang, and
was negatively correlated with blood lead
levels. All subscale scores and the total
score of the SPM-HKC in Guiyu children
were higher than Haojiang children,
indicating greater difficulties, especially for
touch, body awareness, balance and
motion, and total sensory systems.
Hg 314 The relationship between hair-Hg WISC-IV (8-10ys): Children with hair Hg ≥ Feng et al. (2020)
levels and the IQ of children 1 μg g-1 were 1.58 times more likely to
exposed to MeHg in rice. have an IQ score < 80. Increasing of 1 μg
g− 1 hair Hg resulted in 1 point of IQ loss in
Wanshan children, which was.much higher
than that via fish consumption.
Pb 213 Zeng et al. (2020)
(continued on next page)
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J.G. Dórea Environmental Research 197 (2021) 111124

Table 2 (continued )
Country Living settings of exposures Metal(loid)s n Aim of study Neuro-behavior Tests (ages): Outcomes Reference

Children living in e-waste
impacted area (Guiyu).
Indonesia Children living near
informal e-waste (Bogor)
recycling sites
Thailand Villagers living near Pb
mining in Kanchanaburi
Province.
Comparing exposed children
(Guiyu) and from a nearby town
(Haojiang) with no e-waste
recycling activity
Pb, Hg, Mn, 44 Compared toxic metal in hair of
and Cd children exposed and non-exposed
areas
Pb 126 Compared blood-Pb between
exposed and non-exposed children
SDQ (3–7ys): The blood Pb level was
significantly higher in Guiyu than in
Haojiang. The serum NPY was significantly
lower in Guiyu children than those in
Haojiang. Behavioral symptom scores were
higher in children with blood Pb level
≥5.00 μg/dL than those with blood Pb
level <5.00 μg/dL.
TMT (6–9ys): Heavy metal concentrations Soetrisno et al.
in hair of children living near e-waste (2020).
facilities was higher than for children living
in non-exposed areas; Mn exposure was
associated with worse cognitive
performance in the domains of attention,
executive function and social sciences.
IQ (<15ys): IQ scores of the exposed group Pusapukdepob
were significantly inversely associated with et al. (2007)
the blood-Pb concentrations.

ADHD: Attention Deficit Hyperactivity Disorder; ASGM: artisanal gold mining; ASRT: Acoustic stapedius reflex thresholds; BSID: Bayley Scales of Infant Development;
CAT: Cognitive Abilities Test (Visual Search, and Letter Sequencing Tests); CAVLT: Children’s Auditory Verbal Learning Test CBCL: Child Behavior Check List; DPOAE:
distortion product otoacoustic emissions; EtHg: ethyl-Hg; FT4: free thyroxine; GDS: Gesell Development Score; HPA: hypothalamic-pituitary-adrenal; INI: Index of
Neurological Integrity; IQ: Intelligence quotient; MDAT: Malawi Developmental Assessment Tool; MeHg: methyl-Hg; ms: months; NBNA: neonatal behavioral
neurological assessment; ND: neurodevelopment; NPY: Neuropeptide Y; NS: not specified; PTQ: Parent Temperament Questionnaire; PPVT: Peabody Picture Vo­
cabulary Test; RPCM: Raven’s Progressive Color Matrices Scale; RPM: Raven Progressive Matrix; SDQ: Strengths and Difficulties Questionnaire; SPM-HKC: Sensory
Processing Measure (Hong Kong Chinese version; TAVIS-III: Visual Attention Test; TCVs: Thimerosal-containing vaccines; TMT: Trail Making Test; TSH: thyroid
stimulating hormone; WCST: Wisconsin Card Sorting Test-64; Beery-VMI: Developmental Test of Visual-Motor Integration; VSAFD: Visual–Spatial Abilities with
Figure Design; WASI: Wechsler Abbreviated Scale of Intelligence; WISC: Wechsler Intelligence Scale for Children 4th edition; WHO: World Helath Organization; ys:
years.

(epigenetic control), thus increasing pathways to neurotoxicity (Chen
et al., 2011).
Neurodevelopmental tests varied across studies from neonates to
adolescents; few studies were done in infants (neonates to one-year-old
infants) and toddlers. In these early ages (infancy), outcomes were
different: when measured by the Bayley Scale of Infant development
(BSID), Bolivian children did not show abnormalities in relation to
prenatal Pb exposure (Ruiz-Castell et al., 2012). However, in neighbor
Western Amazon, the combination of Pb and Hg (related to tin-smelting)
showed negative effects in BSID (Marques et al., 2014). Moreover the
combined effects of organic Hg (TCV-EtHg and fish-MeHg) also affected
BSID scores in an open-pit tin-mining environment (Marques et al.,
2015). Also, Tanzanian infants in a high-exposure environment of ASGM
showed a high risk of neurodevelopment impairment (Malawi Devel­
opmental Assessment Tool-MDAT) in association with prenatal Hg
exposure; the measured outcomes were negatively boosted by Pb and As
(Nyanza et al., 2020; Dórea, 2021a). In Philippine toddlers (two years
old), Ramirez et al. (2003) reported that prenatal Hg exposure (in an
area of ASGM legacy) correlated with lower scores in neuro­
developmental screening, especially in the linguistic pathway. Also, in
toddlers from tin-ore mining communities (Western Amazon), milestone
achievements were delayed (Dórea et al., 2014). Neonates prenatally
exposed to Pb in e-waste recycling in a Chinese setting showed signifi­
cant lower Neonatal Behavioral Neurological Assessment (NBNA) scores
(Li et al., 2008).
Pre-school children were tested in Brazil (tin-mining environment
and Hg exposure) and in an e-waste recycling environment in China
(Guiyu). While in Brazil there was no significant association of Gesell
development scores (GDS) with Hg exposure (Marques et al., 2012), in
China, BSID scores were negatively related to prenatal Pb (Liu et al.,
2015, 2018) and to both Pb and Cd exposures (Liu et al., 2018). Chinese
young children (three years-old) with higher blood-Pb levels showed
lower scores for cognition and language than controls (Liu et al., 2015).
The group confirmed that the combined Pb and Cd co-exposure affected
thyroid function, but it was independent from the neurotoxic effects on
cognition and language in an e-waste environment (Liu et al., 2018).
When studied as single stressor in schoolchildren (5–12years old)
living in ASGM-impacted areas of the Amazon, neurodevelopmental
decrements were reported in association with environmental fish-MeHg
(Grandjean et al., 1999; Chevrier et al., 2009; Peplow and Augustine,
2014; Reuben et al., 2020) and Mn (Betancourt et al., 2015) exposures.
However, in China, IQ scores decreased as a function of MeHg consumed
in rice grown in soils affected by Hg mining (Feng et al., 2020).
Pb as single stressor resulting from Pb-glazing ceramic activities
affected schoolchildren in Brazil; an increase in displaying disobedient
behavior was shown by Martinez et al. (2020). In a Pb mining town
(Ishiagu) in Nigeria, there was an inverse relationship between total
concentrations of ingested Pb and mean IQ scores (Dike et al., 2020).
Moreover, the combination of Pb and As (in a metal-smelter area of
Mexico) showed negative effects on motor and cognitive tests (Rosado
et al., 2007); the neurological effects of As were independent of the Pb
effects (Table 2).
Mn has been studied as another single stressor related to metal
pollution (smelting environments) in schoolchildren from middle-
income countries. Environmental exposure to airborne Mn was
inversely associated with IQ in young school-age children (7–11 years)
living in area of mining and processing Mn in Mexico (Riojas-Rodriguez
et al., 2010; Torres-Agustín et al., 2013) and Brazil (Menezes-Filho et al.,
2011; Carvalho et al., 2014). Combined exposure to Mn and Pb also
showed a negative effect on externalizing behavior (Menezes-Filho
et al., 2014) and IQ (Menezes-Filho et al., 2014).
4.3. Section summary considerations
Neurodevelopment is a dynamic and complex process with changes
resulting from multiple interactions between constitutional (genes,
brain growth, neuromuscular maturation) and environmental (positive
and/or negative) factors associated with nutrition, family and school
stimuli. Young children growing up in poverty in LMICs often with
limited household resources are exposed to crowded living conditions,
poor sanitation, and lack of psychosocial stimulation; such children are
likely to experience developmental delays (Walker et al., 2007; Dórea,
2021). In some African countries, childhood Pb exposure remains a
problem due to the wide use artisanal cooking utensils made from

11
J.G. Dórea
recycled materials (Weidenhamer et al., 2014; Mathee and Street,
2020). In one study, 79% of participants reported using pots for family
cooking made from recycled lead batteries (Kashala-Abotnes et al.,
2016); in this study, infants’ blood levels were elevated and affected
child neurodevelopment and temperament (Kashala-Abotnes et al.,
2016). Therefore, it is important to keep in mind that unaccounted-for
environmental factors contribute to exposure and contamination. Bod­
eau-Levinic et al. (2016) reported high levels of maternal blood-Pb
concentrations in Benin (a Sub-Sahara African country) in a setting
not involved with metal mining, and likely not associated with leaded
gasoline, eye cosmetics, clay, and battery smelting. Children (three to six
years old) in this rural population drifted away from norms which had
been developed for high income countries, with each passing year of
age, showing weaker standardized performance (Bodeau-Levinic et al.,
2019).
Children living in ASGM and polluted environments related to metal
processing are disproportionately exposed to a wide range of co-
occurring neurotoxic substances. Compelling evidence from represen­
tative parts of the world (Latin America, Africa, and Asia) shows that the
studied neurotoxic substances affected areas of the brain associated with
language, memory and executive function, as well as psychosocial
behavior (Table 2). These studies highlight environmental (Pb sources)
and constitutional (cultural neurodevelopmental trajectory) factors and
emphasize the need to have reference populations and/or specific sta­
tistical models to attenuate unaccounted confounders.
4.3.1. Limitations
It is of great importance to take into account the notorious difficulty
in collecting data from socio-economically marginalized populations
that make a living out of informal activities in ASGM settlements/vil­
lages or e-waste activities. Therefore, the studies could not be evaluated
or systematized by a standard of quality, except by being published in
peer-reviewed literature. Furthermore, different pathways (exposure
and neurotoxic effects), pollutants (neurotoxicants – metals and organic
substances), and vulnerable populations (pregnant and lactating
women, and children) were limited to the scope of the published studies
in these settings. Additionally, without considering all neurological
pathways, children’s ages and appropriate tests, the interpretation of
results and/or comparison among studies become limited. In the studies
reviewed here there was a wide range in age and instruments used to
evaluate neurodevelopment delays/impairments; thus, it is impossible
to identify differences in sensitivity of motor or behavioral tests.
Therefore, the neurodevelopment studies could only suggest that the
neurotoxic metals were associated with the measured outcomes.
5. Concluding remarks
- Informal metal extraction (primary mining and recycling) causes
neurotoxic contamination with short and long-term health and
neurobehavioral consequences.
- Significant associations exist between metal exposures and neuro­
toxicity in children from mining settings; neurodevelopment delays
showed a higher prevalence for Hg and Pb exposures.
- Unborn and young children are particularly vulnerable to neuro­
toxicity because of their neurological immaturity and formative
experiences.
- Most neurotoxic elements in mothers are transferred more to the
fetus (during pregnancy) than to the breastfed baby.
- Protection measure for children and the environment in relation to
unregulated and highly polluting metal extraction are inextricably
intertwined and deserve urgent attention.
- Poor countries and populations bear the brunt of neurotoxic pollu­
tion due to metal extraction (primary and e-waste recycling); co-
exposure patterns with other neurotoxicants depend on geography
and culture.
12
Environmental Research 197 (2021) 111124
- Child labor in ASGM and e-waste recycling environments is
frequently reported associated with direct (occupational) exposure
to neurotoxic agents.
- Besides numerous environmental hazards associated with these un­
regulated activities, including chemical factors related to metal
extraction, there are also physical factors such as those caused by
hazardous environments and injuries typical of the activities.
- There is a high need for studies in settings related to metal extraction
(primary mining and recycling), where relatively little research ex­
ists into any of the multiple factors that can impair
neurodevelopment.
- Neurodevelopment delays in children in the studied settings was
widespread and efforts (local and globally) should be raised to
remediate ongoing harm and to implement strategies to abate
exposure.
- Neurodevelopment studies are scarce for many countries with
disseminated ASGM.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
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