Environment International 109 (2017) 20–28

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Environment International
journal homepage: www.elsevier.com/locate/envint

Blood levels of toxic metals and rare earth elements commonly found in e- MARK
waste may exert subtle effects on hemoglobin concentration in sub-Saharan
immigrants
Luis Alberto Henríquez-Hernándeza,1, Luis D. Boadaa,b,1, Cristina Carranzac,d,
José Luis Pérez-Arellanoc,d, Ana González-Antuñaa, María Camachoa, Maira Almeida-Gonzáleza,
Manuel Zumbadoa, Octavio P. Luzardoa,b,⁎
a
Toxicology Unit, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe s/n, 35016 Las
Palmas, Spain
b
Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBERObn), Paseo Blas Cabrera Felipe s/n, 35016 Las Palmas, Spain
c
Infectious Diseases and Tropical Medicine Unit, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain
d
Medical Sciences and Surgery Department, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

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

Keywords: Pollution by heavy metals and more recently by rare earth elements (REE) and other minor elements (ME) has
Immigrants increased due in part to their high use in technological and electronic devices. This contamination can become
Canary Islands very relevant in those sites where e-waste is improperly processed, as it is the case in many countries of the
Heavy metals African continent. Exposure to some toxic elements has been associated to certain hematological disorders,
Rare earth elements
specifically anemia. In this study, the concentrations of 48 elements (including REE and other ME) were de-
Human biomonitoring
termined by ICP-MS in whole blood samples of sub-Saharan immigrants with anemia (n = 63) and without
Anemia
anemia (n = 78). We found that the levels of Fe, Cr, Cu, Mn, Mo, and Se were significantly higher in the control
group than in the anemia group, suggesting that anemia was mainly due to nutritional deficiencies. However,
since other authors have suggested that in addition to nutritional deficiency, exposure to some elements may
influence hemoglobin levels, we wanted to explore the role of a broad panel of toxic and “emerging” elements in
hemoglobin deficiency. We found that the levels of Ag, As, Ba, Bi, Ce, Eu, Er, Ga, La, Nb, Nd, Pb, Pr, Sm, Sn, Ta,
Th, Tl, U and V were higher in anemic participants than in controls. For most of these elements an inverse
correlation with hemoglobin concentration was found. Some of them also correlated inversely with blood iron
levels, pointing to the possibility that a higher rate of intestinal uptake of these could exist in relation to a
nutritional deficiency of iron. However, the higher levels of Pb, and the group of REE and other ME in anemic
participants were independent of iron levels, pointing to the possibility that these elements could play a role in
the development of anemia.

1. Introduction
Environmental pollution has increased greatly in recent years, and
in some areas it has reached levels that may even be toxic to living
beings (Luzardo et al., 2014; Shakir et al., 2017). Among environmental
pollutants, toxic heavy metals and metalloids are among the most
dangerous since they are also not biodegradable and tend to accumulate
in environmental compartments (Hussain and Mumtaz, 2014;
Kakuschke et al., 2010; Shakir et al., 2017). While small concentrations
of some elements are needed for life, most are considered non-essential
and some are very toxic to most vertebrates including humans, even at
very low concentrations (Tchounwou et al., 2012). In addition, ele-
ments considered essential follow an hormetic dose-response curve, and
may also be toxic to living organisms if some concentrations are ex-
ceeded (Tchounwou et al., 2012).
According to their high degree of toxicity, four elements are usually
highlighted among others: arsenic (As), cadmium (Cd), lead (Pb), and
mercury (Hg) (Camacho et al., 2014; Hussain and Mumtaz, 2014;

⁎
Corresponding author at: Toxicology Unit, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe s/n,
35016 Las Palmas, Spain.
E-mail address: octavio.perez@ulpgc.es (O.P. Luzardo).
1
Both authors have contributed equally to this work and both should be considered as first authors.

http://dx.doi.org/10.1016/j.envint.2017.08.023
Received 3 July 2017; Received in revised form 30 August 2017; Accepted 31 August 2017
Available online 17 September 2017
0160-4120/ © 2017 Elsevier Ltd. All rights reserved.
L.A. Henríquez-Hernández et al.
Wittsiepe et al., 2016). However, every two years the Agency for Toxic
Substances and Disease Registry (ATSDR) publishes a list of priority
chemicals that are determined to represent the most significant po-
tential threat to human health because of their known or suspected
toxicity, together with the potential human exposure. In this list there
are currently 19 other elements that add up to the four already in-
dicated [silver (Ag), aluminum (Al), barium (Ba); beryllium (Be), cobalt
(Co), chromium (Cr), copper (Cu), manganese (Mn), nickel (Ni), pal-
ladium (Pd), plutonium (Pu), antimony (Sb), selenium (Se), strontium
(Sr), thallium (Tl), thorium (Th), uranium (U), vanadium (V), and zinc
(Zn)] (CDC, 2017). It is well documented that Co, Cr, Cu, Mn, Ni, Se,
and Zn are life essential elements when at low levels of exposure.
However, for all these elements, including the essential elements, there
is relevant scientific literature documenting their toxic effects, having
been reported as damaging organelles and cellular components, as well
as enzymes, proteins and macromolecules, some of them even at low
levels of exposure. Many of these metals are also involved in the gen-
eration of reactive oxygen species and free radicals. Moreover, some of
them are also classified as either “known” or “probable” human carci-
nogens based on epidemiological and experimental studies showing an
association between exposure and cancer incidence in humans and
animals (Tchounwou et al., 2012).
Additionally, there are a number of elements, the rare earth ele-
ments (REE) and other minor elements (ME), which are increasingly
coveted due to the large number of technological applications for which
they are already indispensable (Tansel, 2017). In geochemical terms
these elements would be those whose concentrations in the earth's crust
are higher than 100 ppm but lower than 0.1%. However, this rule is
loosely applied, and despite their name, some of these elements are
relatively abundant in the earth's crust (i.e. cerium is as abundant as
copper). However, it is true that their location in the crust is very ir-
regular and tends to concentrate on certain points of the planet, and
also tends to occur together in nature, and is difficult to separate from
each other. This set of elements, dubbed “the new petroleum”, is of
growing concern because its enormous range of applications makes
them mobilized from the few sites where they are abundant - 90% of
known mines are currently located in China (Zhuang et al., 2017) - to be
distributed all over the planet (Bozlaker et al., 2013), especially once
the useful life of the devices containing them ends (Hussain and
Mumtaz, 2014). For this reason, REE have been included among the
new and emerging occupational and environmental health risks by
several international organizations (Pagano et al., 2015a). However, to
date, very little is known about the toxic effects of long-term exposure
to such substances. Some toxic effects have been documented at high
exposures in vivo, in vitro, or in clinical studies, including cytotoxicity,
cytogenetic effects and organ damage (Pagano et al., 2015a; Pagano
et al., 2015b), but to the best of our knowledge, no toxicity study has
been done at levels similar to those of environmental exposure.
The hematological system is a frequent target of the toxic effects of
many heavy metals (Dai et al., 2017; Jomova and Valko, 2011; López-
Rodríguez et al., 2017), and it has been demonstrated that environ-
mental exposure to some of them has a strong influence on the hema-
tological parameters in some vertebrates, such as common carp
(Vinodhini and Narayanan, 2009). In particular, some elements, such as
titanium, arsenic, cadmium, lead or copper, have been associated with
the development of anemia (mainly by hemolysis) in people exposed to
high concentrations of these heavy metals (López-Rodríguez et al.,
2017; Parvez et al., 2017). However, some hematological effects have
also been related to environmental low-level exposure to certain ele-
ments. Thus, it has been reported that the environmental exposure to
low concentrations of arsenic seems to produce a subtle decrease in
hemoglobin concentration (López-Rodríguez et al., 2017). This toxic
effect of arsenic could be considered a contributor, as an environmental
cause, to the development of anemia in children (López-Rodríguez
et al., 2017).
Recent studies in sub-Saharan African immigrants have revealed
21
Environment International 109 (2017) 20–28
they pose a high prevalence of red cell abnormalities, with an incidence
of anemia of up to 10%, microcytosis of up to 25%, and hemoglobi-
nopathies of up to 12% (de-la-Iglesia-Inigo et al., 2013). In the parti-
cular case of anemia, especially in the inhabitants of developing
countries, it is generally assumed that iron deficiency is the main cause
(Camaschella, 2017; van den Broek et al., 1998), and at least 50% of the
anemia cases have been blamed on iron deficiency (van den Broek
et al., 1998). However, it has been described that there are complex
interactions between the different essential elements with iron, so that
they potentially may have a role on the development of IDA. Thus,
synergistic deficiencies of iron and other essential elements involved in
hematopoiesis, such as copper, chromium or nickel, or macroelements
such as sodium and potassium, could hypothetically contribute to the
development of IDA. On the other hand, it has been described that the
increase in the exposure to iron-antagonistic elements such as cobalt,
zinc, or high copper or chromium, as well as macroelements such as
calcium, may limit the intestinal absorption of iron, also leading to the
development of IDA (Bjorklund et al., 2017). However, the role of other
contributing factors, whether of nutritional, infectious, genetic or en-
vironmental type, is seldom studied simultaneously (Foote et al., 2013).
At the same time it has been described that in Africa environmental
levels of contamination by heavy metals (and more recently by REE and
MM) are increasing, especially in relation with the informal e-waste
processing (Nnorom and Osibanjo, 2008; Wittsiepe et al., 2016).
So, we have designed this study, in which we determined the blood
concentrations of a panel of 48 elements, including essential elements
as well as elements related to electronic waste in a group of 63 sub-
Saharan immigrants with anemia. These results were compared with
those obtained from a group of 78 sub-Saharan immigrants without
anemia, who were matched by age, sex and geographical origin with
the participants in the anemia group. Using these two groups, the main
goal of this investigation was to explore the possibility that a potential
relationship exists between anemia and toxic and emerging minor ele-
ments, in addition to essential elements. Another relevant goal of this
work was to investigate if immigrants from e-waste recycling sub-
Saharan countries show higher exposure to e-waste related elements
than those from other countries.
2. Material and methods
2.1. Study population
In this study we used a part of a series of whole blood samples that
were prospectively and sequentially obtained from sub-Saharan im-
migrants irregularly arrived to the island of Gran Canaria (Canary
Islands, Spain) during the last years of 2010 decade. The samples were
obtained in the context of their general health examination and
screening of imported diseases (Luzardo et al., 2014), within the first
two months of their temporal lodging in shelters. In a retrospective
search on the biobank we selected whole blood samples from patients
with anemia (n = 63), and we searched for blood samples that would
make up the control group among immigrants without anemia
(n = 78). Blood samples from the control group were selected ac-
cording to gender, age and country of origin to seek parity with the
group of immigrants with anemia. All participants from the original
series (and subsequently those in this study) underwent a physical ex-
amination to rule out the presence of signs or symptoms of disease and
provided their written consent for the use of their biological samples for
research. A supplementary face-to-face interview in English or French
following a pre-established questionnaire was performed (Sanz-Peláez
et al., 2008). All patients whose samples were included in the biobank
(and therefore in this study) had a complete biochemical and hemato-
logical analysis, as well as a complete serological study, both for viral
and parasitic diseases. Additionally, all subjects were evaluated for the
presence of parasites by performing fecal exams (Ritchie and Kato
techniques), urinalysis and a Knott test. For this study only patients who
L.A. Henríquez-Hernández et al. Environment International 109 (2017) 20–28

Table 1 curves (ten points, 20 ng/mL–0.005 ng/mL) were made to avoid in-
Characteristics of participants in the study. Number and percentage were included, except terferences between elements: a) one using a commercial multi-element
for continuous variables, which were described as mean ± standard deviation (SD),
mixture (CPA Chem Catalog number E5B8·K1.5N.L1, 21 elements,
median and global range.
100 mg/L, 5% HNO3) containing all the essential elements and main
Anemic group Non-anemic group heavy metals; and b) other multi-element mixture tailor-made in our
laboratory from individual elements (CPA Chem), which contained the
Total samples 63 (100%) 78 (100%)
REE and MM.
Hemoglobin (g/dL)
Mean ± SD 11.1 ± 1.5 14.7 ± 1.3
Median 11.6 14.7 2.3. Analytical methods
Range 7.7–11.8 12.1–18.4
Fe (iron) (mg/mL) An Agilent 7900 ICP-MS (Agilent Technologies, Tokyo, Japan) with
Mean ± SD 0.31 ± 0.05 0.43 ± 0.07
standard nickel cones, MicroMist glass concentric nebulizer, and Ultra
Median 0.31 0.42
Range 0.17–0.41 0.25–0.63 High Matrix Introduction (UHMI) system was used for all measure-
Gendera ments. The Integrated Sample Introduction System (ISIS) was config-
Men 34 (54.0%) 43 (55.1%) ured for discrete sampling. The UHMI system was operated in robust
Women 29 (46.0%) 35 (44.9%)
mode. The 4th generation Octopole Reaction System (ORS4) was op-
Age (years)b
Mean ± SD 25.9 ± 8.9 24.7 ± 9.3 erated in helium (He) mode to reduce polyatomic interferences, im-
Median 24 24 proving detection limits for several elements and completely elim-
Range 17–48 18–46 inating the need for mathematical interference correction (Agilent,
Origin 2014). A tuning solution consisting in a mix of Cs (cesium), Co (cobalt),
Benin 1 (1.6%) 2 (2.6%)
Li (lithium), Mg (magnesium), Tl (thallium), and Y (yttrium) was used
Equatorial Guinea 1 (1.6%) 1 (1.3%)
Gambia, The 1 (1.6%) 2 (2.6%) before the analysis for optimization of instrumentation. Quantification
Ghana 13 (20.6%) 16 (20.5%) of the elements was made in the MassHunter v.4.2. ICP-MS Data Ana-
Guinea Bissau 2 (3.2%) 2 (2.6%) lysis software (Agilent Technologies).
Guinea Conakry 1 (1.6%) 2 (2.6%)
For the optimization of the analytical method we first performed
Ivory Coast 3 (4.8%) 5 (6.4%)
Mali 3 (4.8%) 3 (3.8%)
recovery studies using alkaline solution instead of blood, which was
Mauritania 2 (3.2%) 2 (2.6%) fortified at five levels with all the elements (0.01, 0.1, 0.5, 5 and 20 ng/
Nigeria 21 (33.3%) 24 (30.7%) mL) by triplicate. We employed alkaline solution for this experiment
Senegal 8 (12.7%) 9 (11.5%) because commercial whole blood free of the target elements is not
Sierra Leona 7 (11.0%) 10 (12.8%)
available. Recoveries were calculated by dividing the obtained con-
Importer of e-waste
Yes 35 (55.5%) 42 (53.8%) centration by the theoretical concentration added. Recoveries obtained
No 28 (44.4%) 36 (46.2%) ranged from 89 to 128% for REE and ME, and from 87 to 118% for
ATSDR's toxic heavy elements and essential elements. Linear calibration
a
Gender was equally distributed among anemic and non-anemic subjects (Chi square curves were found for all elements (regression coefficients > 0.998).
test, P value = 0.513).
b The method limits of detection (LOD) and quantification (LOQ) were
Age was equally distributed among anemic and non-anemic subjects (mean
age = 25.8 vs. 24.7, respectively; Mann-Whitney-Wilcoxon test, P = 0.060). calculated by quantifying ten replicates of blanks, using 0.130 μL of
alkaline solution instead of blood. The LODs were calculated as the
were free of infectious and parasitic diseases were selected. Male par- concentration of the element that produced a signal that is three times
ticipants with hemoglobin levels below 13 g/dL, and women with he- higher than that of the averaged blanks, and the LOQ that concentration
moglobin levels below 12 g/dL were included in the anemia group. The which produces a signal six times higher than that of the blank
characteristics of the participants in this study are detailed in Table 1. (Supplementary Table 1). The accuracy and precision of this method
was assessed, again using fortified alkaline solution (0.05, 0.5, and
5 ng/mL) in substitution of sample. In general, the calculated relative
2.2. Standards, samples and elements standard deviations (RSD) were lower than 8%, except for some few
elements (Ti, Cr, Cu, Ni, Se, Fe, Ba, Zn, Sm), as the RSD raised to
We determined the whole blood concentration levels of 48 ele- 15–16% at the at the lowest level of fortification. On the other hand, the
ments, including the essential elements and those elements (toxic heavy precision improved at the highest level of concentration, as it was lower
metals, REE and MM) that are frequently employed in electronic con- than 5% for all elements.
sumer products (Hussain and Mumtaz, 2014; Tansel, 2017): Ag (silver); The validity of the proposed methodology for the quantification of
As (arsenic); Au (gold); Ba (barium); Be (beryllium); Bi (bismuth); Cd elements in human blood was assessed by analyzing sextuplicate ali-
(cadmium); Ce (cerium); Co (cobalt); Cr (chromium); Dy (dysprosium); quots of a human blood material with certified concentration of several
Eu (europium); Er (erbium); Fe (iron); Ga (gallium); Gd (gadolinium); of the elements included in the method (ClinCal whole blood calibrator,
Hg (mercury); Ho (holmium); In (indium); La (lanthanum); Lu (lute- RECIPE Chemicals + Instruments GmbH, Munich, Germany). For the
tium); Mn (manganese); Mo (molybdenum); Nb (niobium); Nd (neo- rest of elements, whose concentrations were not certified by the man-
dymium); Ni (nickel); Os (osmium); Pb (lead); Pd (palladium); Pr ufacturer, an addition of two concentrations was performed (0.2 and
(praseodymium); Pt (platinum); Ru (ruthenium); Sb (antimony); Se 1 ng/mL). The accuracy for all the elements was good, and the calcu-
(selenium); Sm (samarium); Sn (tin); Sr (strontium); Ta (tantalum); Tb lated concentrations were in agreement with the certified values for all
(terbium); Th (thorium); Ti (titanium); Tl (tallium); Tm (thulium); U elements reported, as well as with the theoretical concentration for the
(uranium); V (vanadium); Y (yttrium); Yb (ytterbium); and Zn (zinc). fortified elements (Supplementary Table 2).
Samples consisted of 130 μL of blood, 1120 μL of ammonia solution
(0.05% of EDTA, 0.05% of Triton X-100, and 1% of NH4OH), and 50 μL 2.4. Statistical analysis
of internal standards (ISTD) until a total final volume of 1.3 mL. ISTD
solution was composed by Sc (scandium), Ge (germanium), Rh (rho- Descriptive analyses were conducted for all variables. Arithmetic
dium), and Ir (iridium) at a stock concentration of 20 mg/mL each. Pure means, standard deviation (SD), medians and ranges were calculated
standards of elements in acid solution (5% HNO3, 100 mg/L) were for continuous variables. Proportions were calculated for categorical
purchased from CPA Chem (Stara Zagora, Bulgary). Two standard variables. A zero value was assigned to all the compounds below the

22
L.A. Henríquez-Hernández et al. Environment International 109 (2017) 20–28

LOD, and for those compounds below the limit of quantification (LOQ)
but above the LOD, the value was assumed to be ½ LOQ. We first tested
the normality of the data using both, the Kolgomorov-Smirnov test
(with Dallal-Wilkinson-Lilie for P value), and the D'Agostino-Pearson
omnibus test. As expected, most of the data series (i.e. concentrations of
elements) did not follow a normal distribution. As a consequence we
chose not assuming a normal distribution in any case, and comparisons
between groups were performed using a non-parametric test (Mann-
Whitney-Wilcoxon test). Differences in the categorical variable “age”
were tested by means of the chi-squared test. The correlation of in-
organic elements with continuous variables was analyzed by the
Spearman's correlation test. The associations between inorganic ele-
ments and anemia were analyzed using binary logistic regressions. We
used PASW Statistics v 19.0 (SPSS Inc., Chicago, IL, USA) to manage the
database of the study and to perform statistical analyses. Probability
levels of < 0.05 (two tailed) were considered statistically significant.
3. Results and discussion
3.1. Essential element status
As expected, we found both, that hemoglobin levels were sig-
nificantly lower in participants with anemia, and that iron levels were
also significantly lower in all samples of immigrants with anemia than
in controls (Mann-Whitney-Wilcoxon P < 0.0001, in both cases)
(Table 1). This would allow us to hypothesize that the majority of cases
included in this study may be classified as iron deficiency anemia (IDA),
and probably due to nutritional deficiencies in these immigrants.
In this study, we found that in addition to iron levels, the levels of
chromium, copper, manganese, molybdenum and selenium were sig-
nificantly higher in the non-anemia group than in the anemia group,
while the levels of cobalt, nickel and zinc did not show statistically
significant differences (Table 2).
The lower levels of selenium found in anemic subjects compared to
non-anemic people have been previously reported, and the authors
suggested that this is an independent factor in the development of this
disease in the elderly (Semba et al., 2009), and also in children
(Gurgoze et al., 2004). Semba et al. (2009) suggested that low selenium
levels could affect the maintenance of optimal levels of glutathione
peroxidase, which is a fundamental antioxidant selenoenzyme for ery-
throcyte integrity. However, in this investigation the logistic binary
regression using anemia as the endpoint suggested that Se cannot be
considered a relevant risk factor for anemia (Exp (B) = 1.003; 95%
CI = 0.996–1.016) for the studied population.
On the other hand, some authors have also found low blood copper
levels in up to 15% of patients with IDA (De la Cruz-Gongora et al.,
2012; Ramakrishnan, 2002). The relationship between hypocupremia
and hematological alterations (including anemia) has been previously
described, mainly related to gastric resection (Halfdanarson et al.,
2008). Our results seem to support this, since not only Cu levels are
significantly lower in patients with anemia than in controls (Mann
Whitney's test, P = 0.0035), but also the logistic binary regression be-
tween Cu and anemia indicates that the low levels of this element
would be a risk factor (Exp (B) = 0.994; 95% CI = 0.091–0.997;
P < 0.0001) for this condition. Nutritional deficiency of copper is
rarely described. This is attributed to the fact that blood concentrations
of copper and zinc are strictly regulated by compensatory mechanisms
that act to stabilize them within certain ranges of nutritional con-
sumption (Malavolta et al., 2015). However, in the present study the
zinc/copper ratio was also lower in patients with anemia than in con-
trols, although the difference did not reach statistical significance
(Mann-Whitney-Wilcoxon, P = 0.071), suggesting that these compen-
satory mechanisms have not been sufficient in these patients. In fact,
zinc blood levels also tend to be lower in immigrants with anemia
(although again without reaching statistical significance, Table 2).
Some authors have indicated that Cu and Zn deficiencies are prevalent
but often undiagnosed health risks (Wisniewska et al., 2017).
Regarding the other elements, there are not many studies on the
relationship of levels of chromium, manganese and molybdenum to
anemia. However, chromium and manganese are considered synergists
with iron (Angelova et al., 2014; Bjorklund et al., 2017), and therefore a
nutritional deficiency of iron might be a risk factor for developing IDA.
According to these results, it does not appear that the cause of the
iron deficiency in these patients is due to an excess of the dietary ex-
posure to other antagonistic essential elements. The lower concentra-
tions of chromium, copper, manganese, molybdenum, and selenium in
the anemia group suggest that anemia in these patients is mainly due to
an inadequate dietary intake, malabsorption, and/or to interactions
among synergistic micronutrients, as described by other authors.
However, not only dietary intake might be important, as deficiencies of
micronutrients are not always related to the nutritional status of the
population (Amare et al., 2012). Moreover, other (non-essential) ele-
ments may be involved in the development of the IDA, at least as
contributing factors. For this reason, we wanted to explore the role of
other non-essential elements in relation to anemia and hemoglobin le-
vels, with special focus on those that are closely related to electric and
electronic equipment.
3.2. Toxic elements in the ATSDR's priority contaminant list
The concentrations and the results of the comparative study of this
group of elements of recognized and widely studied toxicity are shown
in Table 3. As can be observed, the levels of several of them (Ag, As, Ba,
Pb, Th, Tl, U and V) were significantly higher in participants with

Table 2
Quantitative levels of essential elements in blood of anemic and non-anemic Sub-Saharan immigrants. The results are presented in ng/mL.

Element Anemia group Non-anemia group Pc

Median 95% CI of median Range Median 95% CI of median Range

Co 0.29 0.16–0.52 0.04–1.59 0.35 0.25–0.41 0.09–1.25 n.s.

Cr 2.24 1.98–2.72 1.02–9.19 4.34 4.05–4.81 0.14–2932 0.0002
Cu 827.9 751.8–864.3 526.8–1062.0 881.9 850.1–915.5 659.9–1368 0.0035
Fea 0.32 0.28–0.34 0.17–0.40 0.42 0.40–0.43 0.24–0.62 < 0.0001
Mn 8.45 6.63–11.18 2.86–39.92 10.22 8.57–11.34 4.40–93.76 0.046
Mo 0.54 0.50–0.60 0.14–13.38 0.70 0.62–0.85 0.20–2.14 0.0032
Ni 0.53 0.40–0.98 0.11–137.7 0.52 0.44–0.63 0.16–34.16 n.s.
Se 147.8 141.8–157.5 102.0–378.4 168.4 155.9–182.0 110.8–290.1 0.0024
Znb 6.63 6.05–7.91 4.12–10.06 7.16 6.57–7.44 3.36–35.16 n.s.

Abbreviations: SD, standard deviation; n.s., not significant.

a
Results expressed in mg/mL.
b
Results expressed in μg/mL.
c
Mann-Whitney-Wilcoxon test.

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L.A. Henríquez-Hernández et al. Environment International 109 (2017) 20–28

Table 3
Quantitative levels of trace metals in the ATSDR's priority pollutant list in blood of anemic and non-anemic Sub-Saharan immigrants. The results are presented in ng/mL.

Elementa,b Anemia group Non-anemia group Pc

Median 95% CI of the median Range Median 95% CI of the median Range

Ag 0.04 0.02–0,05 0.0–0.72 0.01 0.01–0.02 0.0–0.32 0.003

As 3.08 2.06–3.51 0.56–9.61 1.51 1.21–2.08 0.42–5.71 0.0001
Ba 1.17 0.96–1.51 0.26–12.74 0.0 0.0–0.0 0.0–11.02 < 0.0001
Be 0.03 0.01–0.04 0.0–0.12 0.0 0.0–0.0 0.0–0.08 n.s.
Cd 0.32 0.21–0.42 0.07–1.13 0.28 0.23–0.43 0.03–1.7 n.s.
Hg 6.13 5.26–7.81 1.76–84.91 5.83 5.25–7.93 1.46–25.88 n.s.
Pb 28.95 20.79–38.40 10.05–110.91 23.19 17.39–27.16 5.24–128.63 0.043
Sb 3.35 2.93–4.34 0.03–10.68 2.88 2.61–3.25 1.21–6.34 n.s.
Sr 23.31 20.45–29.13 8.8–49.97 25.95 23.79–28.85 9.8–73.51 n.s.
Th 0.03 0.01–0.04 0.0–0.41 0.01 0.0–0.02 0.0–0.76 0.017
Ti 15.46 14.59–17.14 10.32–29.34 15.69 14.92–16.75 10.29–553.3 n.s.
Tl 0.03 0.02–0.03 0.01–0.04 0.02 0.02–0,02 0.01–0.03 0.043
U 0.03 0.02–0.04 0.0–0.13 0.0 0.0–0.0 0.0–0.18 < 0.0001
V 0.08 0.07–0.14 0.03–0.87 0.07 0.05–0.08 0.01–0.26 0.012

Abbreviations: SD, standard deviation; n.s., not significant.

a
Aluminum (Al) and plutonium (Pu) were not analyzed due to method interferences; The element palladium (Pd) was not detected in any sample.
b
Results of elements included in ATSDR's priority list but also considered essential elements (Cu, Co, Mn, Mo, Ni, Se and Zn) have been presented in Table 2.
c
Mann-Whitney U test.

Fig. 1. Scatterplots and Spearman's correlation coefficients

of blood concentrations between arsenic and iron (A), and
between arsenic and hemoglobin (B).

anemia than in the non-anemia group.
First, regarding arsenic, and consistently with our results, López-
Rodríguez et al. (2017) found significantly higher levels of this me-
talloid in anemic children than in controls, and that arsenic levels
correlated negatively with hemoglobin concentrations. Arsenic, ac-
cording to these authors, was an independent factor related to the de-
crease in hemoglobin levels. Other authors have also found associations
between exposure to arsenic and anemia, in pregnant women
(Hopenhayn et al., 2006; Surdu et al., 2015). Something similar oc-
curred in our study, where we found both, a negative correlation of As
with hemoglobin (Spearman's r = −0.418; P < 0.0001), and with
iron (Spearman's r = −0.216; P = 0.0228) (Fig. 1) (all the results of
correlation coefficients and significances for the associations between
iron and all the elements can be consulted in Supplementary Table 3).
In other terms, at higher arsenic concentrations we found lower con-
centrations of iron and hemoglobin. Moreover, this correlation was also
statistically significant when only participants without anemia (the
control group) were considered. In these people, the highest con-
centrations of arsenic were also associated with the lowest levels of
hemoglobin, although within the normal range (Spearman's
r = −0.1872; P = 0.038). This hypothesis that at higher As levels,
lower hemoglobin concentration is strongly supported by the results of
binary logistic regression between anemia (as endpoint) and blood
concentration of As (Exp (B) = 1607, 95% CI = 1255–2059;
P < 0.0001). It has been reported that arsenic binds strongly to pro-
teins, in particular to the sulfhydryl groups of cysteine residues
(ATSDR, 2007a; Shen et al., 2013). The binding of arsenic to a specific
protein could alter the conformation and function of that protein, as
well as its recruitment and interaction with other functional proteins.
Among the proteins that bind arsenic, experimental studies indicate
that hemoglobin has high affinity for this metalloid (Lu et al., 2004).
Thus, it is possible that this binding of arsenic to hemoglobin is capable
of producing conformational alterations of the same, limiting its func-
tionality, and therefore contributing to the development of anemia.
Hematological effects have been also described in relation to the
exposure to lead, mainly as a result of its perturbation of the heme
biosynthesis pathway (ATSDR, 2007b). In our study, not only were
blood levels of Pb higher in immigrants with anemia (Table 1), but they
also correlated negatively with hemoglobin concentrations (Spearman's
r = −0.3012; P = 0.0023) in the whole series. It has been described
that because iron is absorbed through mechanisms similar to those of
other divalent metal ions, including manganese and lead, a dietary iron

24
L.A. Henríquez-Hernández et al. Environment International 109 (2017) 20–28

deficiency could lead to excessive absorption of lead (Park et al., 2014).
Therefore, it could be possible that the higher lead levels that we have
found in this study in participants with anemia are due to iron defi-
ciency, not being an independent factor (as the abovementioned case of
arsenic). We explored such a possibility studying the correlation be-
tween iron and lead, and we did not find that levels of these two metals
correlated in any way, neither studying the whole series, nor when
anemic and non-anemic participants were studied separately. So, our
results point to the possibility that levels of Pb are increased in anemic
persons independently of the iron deficiency, although checking for this
would require additional research.
Regarding the rest of the priority elements—Ag, Ba, Th, Tl, U, and
V, blood levels were significantly higher in the anemic participants, but
none of them separately correlated with hemoglobin or iron levels.
Some hematological effects have been previously reported for the ex-
posure of some of these elements, such as vanadium or uranium, but at
much higher doses. Thus it has been reported that rats chronically ex-
posed to 5 mg/kg/day of ammonium metavanadate experience a sig-
nificant reduction in their hemoglobin concentration (ATSDR, 2012),
and a similar effect was observed in rats after the inhalatory exposure to
7 mg/m3 of uranium during 60 days (ATSDR, 2013). Unfortunately, the
lack of supporting bibliography on the effects of the exposure to en-
vironmentally relevant concentrations of these elements makes it dif-
ficult to discuss the results obtained. However, we considered inter-
esting to highlight that the results of the logistic binary regressions
between each of these elements and anemia indicated that Ba could be
considered a risk factor (Exp (B) = 1.370; 95% CI = 1.065–1.763;
P = 0.014). As they occurred simultaneously in many of the partici-
pants, we studied the summed levels of these six elements, and found an
inverse correlation with hemoglobin concentration (Spearman's
r = −0.4517; P < 0.0001), and with iron levels (Spearman's
r = −0.3020; P = 0.0014). The logistic binary regression between the
summed concentrations of these six elements and anemia supported
these analyses (Exp (B) = 1.381; 95% CI = 1.173–1.791; P = 0.011).
Thus, the same could occur with these elements as described above for
arsenic, increasing their absorption when lower iron levels occur.
3.3. Rare earth elements and other minor elements
Table 4 summarizes the blood concentrations and the results of the
comparative study of the REE and other ME levels between anemic and
non-anemic participants. The elements Dy, Gd, Ho, In, Lu, Os, Ru, Tb,
Tm, Y, and Yb were all below the LOD in all of the samples, and
therefore these elements were not further considered. The rest of in-
organic elements, although at very low concentrations, were frequently
detected both in anemic and in non-anemic donors (> 50% detection
rate). It is noteworthy that the blood levels of 12 out of the 14 elements
detected were significantly higher in anemic participants than in the
controls (Table 4). In spite of this, the bivariate logistic regression study
between each of them and the anemia was not statistically significant in
any of the cases. For this reason, and also given the low values for many
elements, we considered more interesting to study the sum of elements.
As shown in Fig. 2A, the median value of the sum of these elements is
approximately five-fold higher in the blood of the participants with
anemia than in the controls (2.03 vs. 0.39 ng/mL, respectively). In this
case, the summed REE and other ME also showed a very clear inverse
correlation with hemoglobin levels (Fig. 2B), meaning that the higher
the levels of these elements the lower the concentration of hemoglobin
(Spearman's r = −0.4261; P < 0.0001). This inverse correlation was
maintained even when we considered only the group of anemic parti-
cipants (Spearman's r = − 0.3262; P = 0.043), indicating that the
highest the levels of these minority elements in blood the lowest the
concentration of hemoglobin (more severe anemia). However, there
was no correlation of REE + ME with the blood iron levels. These data
may be suggesting that these elements are absorbed into the blood of
patients with anemia independently of that of iron absorption. How-
ever, it should be noted that alternatively the statistical power of the
study might be too low to find correlations with blood iron.
3.4. e-Waste and exposure to rare earth elements and other minor elements
Although this is a study carried out in non-occupationally exposed
population, approximately half of the immigrants came from areas
where the accumulation of e-waste is relevant. In countries such as
Nigeria and Ghana, informal processing of e-waste is a major economic
activity that allows a subsistence economy for many families, and it has
been shown that the population of these countries is more exposed to
toxic (organic) substances, probably due in part to this reason (Luzardo
et al., 2014). Due to this we wanted to study if there were differences in
the levels of these emerging pollutants among immigrants from these e-
waste importing countries compared to those from countries where this
is a very minor activity. Although there were no significant differences
for the ATSDR priority list elements (Fig. 3A), we found that the blood
levels of the sum of REE + ME were significantly higher in participants
from processing/importing countries of e-waste than in the participants
from countries that do not (median values = 1.21 vs. 0.32 ng/mL,

Table 4
Quantitative levels of rare earth elements and other minor elements related to e-waste in blood of anemic and non-anemic Sub-Saharan immigrants. The results are presented in ng/mL.

a
Element Anemia group Non-anemia group Pb

Median 95% CI of the median Range Median 95% CI of the median Range

Au 0.0 0.0–0.0 0.0–0.04 0.0 0.0–0.0 0.0–0.75 n.s.

Bi 0.0 0.0–0.01 0.0–0.12 0.0 0.0–0.0 0.0–0.09 < 0.0001
Ce 0.02 0.02–0.03 0.0–0.04 0.0 0.0–0.0 0.0–0.01 < 0.0001
Eu 0.02 0.01–0.03 0.0–0.04 0.0 0.0–0.0 0.0–0.01 < 0.0001
Er 0.01 0.01–0.01 0.0–0.02 0.0 0.0–0.0 0.0–0.01 < 0.0001
Ga 0.03 0.02–0.12 0.01–1.88 0.01 0.01–0.02 0.0–0.03 < 0.0001
La 0.01 0.01–0.02 0.0–0.03 0.0 0.0–0.0 0.0–0.01 < 0.0001
Nb 0.01 0.01–0.02 0.0–0.02 0.0 0.0–0.0 0.0–0.01 < 0.0001
Nd 0.05 0.04–0.06 0.0–4.8 0.01 0.01–0.02 0.0–0.04 < 0.0001
Pr 0.01 0.01–0.02 0.0–0.04 0.0 0.0–0.0 0.0–0.01 < 0.0001
Pt 0.0 0.0–0.01 0.0–0.04 0.0 0.0–0.0 0.0–0.05 n.s.
Sm 0.02 0.01–0.03 0.0–0.42 0.01 0.01–0.02 0.0–0.07 < 0.0001
Sn 0.15 0.12–0.21 0.0–2.65 0.07 0.03–0.10 0.0–50.83 0.003
Ta 0.0 0.0–0.01 0.0–0.03 0.0 0.0–0.0 0.0–0.01 0.003

Abbreviations: SD, standard deviation; n.s., not significant.

a
The elements dysprosium (Dy); gadolinium (Gd); holmium (Ho); Indium (In); lutetium (Lu); osmium (Os); ruthenium (Ru); terbium (Tb); thulium (Tm); yttrium (Y); and ytterbium
(Yb) were not detected in any sample.
b
Mann-Whitney U test.

25
L.A. Henríquez-Hernández et al.
respectively; Mann Whitney-Wilcoxon's P = 0.016) (Fig. 3B). Although
almost there are no studies in general populations in which the levels of
these pollutants have been monitored, it is important to note that REE
and other ME have become the new “essential elements” of consumer
electronics manufacturing. While the essential elements for living
beings amount to a couple of dozens, > 60 elements are needed to
make, for example, a mobile phone (Tansel, 2017). Thus, the manu-
facture of the different today's technologies virtually uses the entire
periodic table (Nuss and Eckelman, 2014). From an environmental
point of view, what this means is: i) human activity extracts this type of
elements in the earth's crust from those places where they are im-
mobilized (mines); ii) they are massively employed, contributing to
their dispersion throughout the planet, and finally; iii) these elements
are re-concentrated in the places where the useless electronic devices
are discarded. In this scenario, it is currently estimated that, even under
the best conditions of recycling, the recovery of some of the rarest
elements (yttrium or scandium, for example) is < 1% (Nuss and
Eckelman, 2014). The situation may be even more uncontrolled if the
recycling of e-waste takes place in an open and informal way, as it is
unfortunately the case in many developing countries, especially in Asia
and Africa. In other words, despite their high and increasing use in
industry, the environmental loads of most of these minor metals are to
date essentially unknown. And what is more worrying, their tox-
icological effects, and the scope of the interactions that they can have
with the biological macromolecules are also broadly unknown.
In any case, the high percentage of detection in blood of most REE
and other ME in human beings is remarkable, especially considering the
fact that to date there are very few references in the scientific literature
dealing with the adverse effects on the health of animals and humans of
the chronic exposure to these minority elements. Most of the scarce
studies devoted to this topic refer to case reports of individual REE-
exposed workers (Rim et al., 2013; Sabbioni et al., 1982; Yoon et al.,
2005), or to groups of professionally exposed people, or when en-
vironmental exposure is studied, the research is mainly focused in
particularly exposed groups of population, for instance those living in
26
Environment International 109 (2017) 20–28
Fig. 2. (A) Bar diagram showing the comparison between
the sum of rare earth elements and other minority elements
in non-anemic (left) and anemic (right) participants; (B)
Scatterplot and Spearman's correlation coefficient of blood
concentrations between hemoglobin and the sum of rare
earth elements and other minority elements.
mining areas (Pagano et al., 2015a; Pagano et al., 2015b). However,
very few investigations have focused, as this one, on the study of the
non-occupationally exposed population as regards the exposure to these
minerals and still less in relation to a health end-point. Our findings
indicate that it is worthwhile to include the screening of these new
pollutants in human biomonitoring studies in the future.
4. Strengths and limitations of the study
One of the major limitations of this study is that the groups (anemic
vs. control participants) are relatively small, which reduces statistical
power. Furthermore, blood iron is known to be very variable, which
further reduces statistical power for tests in which it is involved.
Besides, the study design does not allow to differentiate whether ele-
ments are higher in the anemic population because they are antag-
onistic with iron for uptake, because they have a direct influence on
hemoglobin concentrations, or because they do not have any effect but
people are co-exposed to this element along with an element that does
have an effect. On the other hand, there also some limitations that
should be considered regarding the hypothesis that informal e-waste
recycling activities could be influencing the degree of contaminations of
the general population of these countries. First, because in many of
those countries where this informal recycling is done, other indicators
of socioeconomic development are also better than in the neighboring
countries (gross national income, number of motor vehicles per 1000
inhabitants, number of telephone lines per 1000 inhabitants, use of
internet, etc.), and this study does not allow to discriminate among
sources of contamination, so we cannot directly obtain the conclusion
that the informal processing of e-waste in the countries of origin of
these immigrants is the cause of the higher levels of these contaminants
detected in their blood, because there may be many other potential
causes which can contribute to it. In addition, we do not know if the
immigrants lived in their countries of origin in places close to the e-
waste processing sites or not. However, in view of the results of this
study we consider that it is a plausible hypothesis to think that the
Fig. 3. Box plots illustrating the comparison of the sum of
ATSDR priority elements (A), and rare earth elements and
other minority elements (B) between immigrants coming
from e-waste importing countries and those coming from
non-importing countries. The lines show the medians, the
boxes cover the 25th to 75th percentiles, and the minimal
and maximal values are shown by the ends of the bars.
L.A. Henríquez-Hernández et al.
background environmental contamination by this type of minerals
could be increasing in certain zones of developing countries, in such a
way that could be affecting the contamination level of their inhabitants.
Obviously the verification of this hypothesis requires the carrying out of
case-control studies with a greater number of participants, and in which
the variable of exact geographical location of residence of the partici-
pants is perfectly controlled.
Notwithstanding these limitations we consider that this work has
important strengths. First, this population is rarely assessed at all, and
most of these elements have been rarely, if at all, determined by bio-
monitoring environmental exposure. For many of these elements the
provenance from informal e-waste processing has never been linked to
higher concentrations of several of these metals in blood before.
Although populations were limited, for many elements a statistical
difference was found between anemic and non-anemic populations. The
limited possibility to establish causality and to consider other variables
that could explain the differences in concentrations is in part due to
how difficult it is to get reliable personal information for this popula-
tion. In that context these results, even with their limitations, are highly
interesting and encourage further research.
5. Conclusions
The low blood iron concentration (in absence of inflammation)
could be related to an increase in the blood levels of other toxic metals,
whose absorption is likely to be favored in the absence of high dietary
iron levels. The higher blood levels of toxic elements in anemic persons
indicate that they are potentially more exposed to their systemic ad-
verse effects. Moreover, people with anemia also had higher levels of
lead, and also of the rare earth elements and minority minerals that are
intensively used in the manufacture of consumer electronic devices. In
this study, the blood levels of these elements were negatively correlated
with hemoglobin levels, suggesting that they could play a role in the
etiology of anemia. It is interesting to note that the summed blood le-
vels of these elements were even higher in the participants from
countries where large amounts of electronic waste are informally re-
cycled. Given the intensive and increasing use of these minerals and
considering results such as those presented in this study, it seems ne-
cessary to establish programs for human biomonitoring that include
these – so far neglected – occupational agents, as well as studies eval-
uating the toxicity of the exposure of the populations to these emerging
environmental pollutants.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.envint.2017.08.023.
Acknowledgements
The authors thank Mrs. María de los Reyes Suárez Hanna for her
technical assistance.
Competing financial interests declaration
There are no actual or potential conflicts of interest to declare for
any author.
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