TOTAL URINARY ARSENIC, SELENIUM AND ANTIMONIUM:

AGE, GENDER AND MUTUAL CORRELATION IN POPULATION EXPOSED TO

HYDROARSENICISM

Analía Boemo1*, Irene M. Lomniczi1 and Elsa Mónica Farfán Torres2

1.
Facultad de Ciencias Exactas y Consejo de Investigación, Universidad Nacional de Salta
Av. Bolivia 5150, 4400 Salta, Argentina. aboemo@unsa.edu.ar
* Tel: 0054-387-4255354; Fax: 0054-387-4255449
2.
Facultad de Ciencias Exactas, Consejo de Investigación and INIQUI/CONICET, Universidad Nacional de
Salta, Av. Bolivia 5150, 4400 Salta, Argentina.

Abstract

The Chaco plain is a geographic region in the East of Salta province, Argentina.
Superficial water is very scarce, and underground water, the main drinking water
supply, is often of high natural arsenic content. Autochthon population is mainly
conformed by “criollos”, descendants of Spanish conquerors. Former epidemiological
studies showed evidence of arsenical keratoses, the most characteristic skin lesion for
chronic ingestion of arsenic.
60 urine samples, screening different age and gender population groups exposed to
hydroarsenicism, were analyzed for total concentration of arsenic, selenium and
antimony; their median standardized values (related to urinary creatinine) are 156 μg
As/gUC, 48 μg Se/gUC and 10 μg Sb/gUC respectively. Spiked sample recoveries
were performed for quality control. Statistical analysis of data indicates that urinary
excretion of arsenic and selenium follows different patterns when population is
discriminated by age and gender, also showing a significant mutual correlation.

Key words
hydroarsenicism, urinary arsenic, urinary selenium, urinary antimony, arsenic
modulation factors, environmental toxicity.

1. Introduction

Arsenic (As) is a naturally occurring element of groundwater in extended areas of

South America; in Argentina, its dispersion over wide areas is due to Andean
volcanism in the Quaternary era, which produced stratigraphic deposits of volcanic
ashes in the Puna region as well as on the Chaco and Pampean plains (Galindo et al.,
2005). In the Chaco region of Salta province arsenic concentration in groundwater
varies in a wide range, from less than 0.005 mg/L up to 8 mg/L (Rodríguez Rey et al.,
1999). Hydroarsenicism is an alteration of health related to chronic intake of arsenic via
water consumption. The maximum acceptable concentration for arsenic in drinking
water was established at 0.010 mg Astotal/L by the Argentine Alimentary Codex (AAC,
Código Alimentario Argentino, 2007), in coincidence with the value recommended by
the World Health Organization (WHO, 2006).
Arsenic is classified as a human carcinogen. Chronic exposure to arsenical drinking
water has been related to increasing risk of internal and skin cancer, and non
carcinogenic effects as psychiatric disturbances and disorders of the cardiovascular
and peripheral nervous systems (NRC-US, 2001).
Most epidemiologic studies to estimate exposure level relied on measurements of As in
drinking water; an improved estimation of exposure to As consists in quantification of
the total amount of As (inorganic and its metabolites) excreted in the urine. The linear
relationship between urinary arsenic and its content in drinking water is well known
(Concha et al., 2006). However, the sole appearance of As in urine is not enough for
risk assessment, due to the existence of parallel nutritional factors such as the
selenium (Se) and antimony (Sb) intake, trace elements that interact with
environmental As as toxicity modulators (Gebel, 2000).
Se is an essential nutrient involved in the normal functioning of the immune system and
of the thyroid gland, food dietary ingestion being its main route of intake; its behavior as
diet supplement on human health is under discussion, owing to the narrow range
between nutritional dose and toxicity (CSQG, 2007). As and Se are mutual antagonists,
each one inhibiting the other one’s toxicity. Se increases the amount of methylated
urinary arsenic, the metabolic pathway for detoxification, but if Se is depleted in a
human organism suffering of arsenicism, As takes its place in the selenium dependent
enzymes, as glutathione peroxidase, making them inactive. In contrast with As, Se is
considered anti-carcinogenic, although its anti-oxidant properties are still under
examination. Sb is rarely present in biologic samples, and usually it is not included in
toxicological essays; its role in modulating As toxicity is ambiguous, enhancing it by
inhibition of the metabolic methylation of As, and acting as a suppressor by obstruction
of the sister chromatid exchange induced by As(III) (Gebel, 1998).
In earlier studies, trace element analysis and major components characterization of 16
ground waters from Rivadavia Banda Sur (Salta) showed high concentration of arsenic
in sodium sulfate, acid carbonate or chloride waters (0.13 to 1.22 mg As/L), while in
hard waters arsenic concentrations were below 0.06 mg/L (Farfán Torres et al., 2008).
69% of the tested wells were not suitable for human consumption according to AAC.
Local population settled in small towns or dispersed in communities near rural schools,
use rain water stored during the summer rainy season because the incapability in
acceding other sources of drinking water with low arsenic content. Governmental
actions usually consist in drilling new, much deeper wells (100-150 m), with a
satisfactory improvement in the amount of water supply, but not always of low enough
arsenic concentration.
In the present study, total content of As, Se and Sb were analyzed in 60 urine samples
of local residents from Rivadavia (Rivadavia Banda Sur) and other smaller nearby
locations at the northern corner of the Chaco plain in Salta, Argentina. Age, gender
and mutual correlation of these urinary analytes are first described for this population in
Salta, Argentina.

2. Method

2.1. Urine as biomarker

A reliable assessment of exposure to a toxic substance is achieved when it is

evaluated not by the contaminant intake but from the direct measure of the level of the
substance of concern in tissues or body fluids. For this purpose, arsenic can be
measured in hair, fingernails, blood and urine (TDH/ASTR, 2003). Besides the
operating drawbacks of sample acquisitions, blood is not considered to be a reliable
indicator of chronic exposure to low levels of arsenic, because it is removed from the
blood torrent within a few hours of its intake. Nail and hair samples are not considered
consistent indicators owing to the great individual variability and easy contamination
from other sources. Urinary arsenic concentration is the most reliable method for
measuring exposure to arsenic; sampling is not invasive and responds to acute and
chronic ingestion. Disagreement in As contents in individual urine excretions makes the
24-hour cumulative sample the optimal collection; however, as a consequence of the
handling difficulties associated, the use of a first-morning void or random spot samples
is of common use in most exposure studies (TDH/ASTR, 2003). To reduce the
influence of the differences in urine output and the state of hydration (the concentration
or dilution of the individual’s urine at the time of sampling), urine density or creatinine
adjustment is routinely used. In the present research, the urinary element contents,
related to urinary creatinine (UC), are expressed as µg/gUC.
2.2. Quantification of urinary analyte total concentration

In three sampling campaigns during 2006, 2007 and 2008, 16 groundwater samples,
22 samples of unprocessed and composite food, and 60 samples of urine were
collected simultaneously, in an attempt to find correlation between ambient exposure
and urinary detoxification. The subject group is conformed by municipal workers and
grade school students and teachers belonging to the Wichí and Spanish descendants’
ethnics, all lifetime residents in the area. Demographic data, according to WHO
guidelines (PAHO/WHO, 2003), was split in two categories “minor 15 years old” and
“adults” (with no further distinction in age): 55% are children (45.5% female and 54.5%
male) and 45% are adults (44.4% female and 55.6% male).
All urine samples correspond to random spot samples; they were stored in sterilized
polyethylene bottles and frozen at -20 ºC until analysis. For quantification of urinary
analyte total concentration liquid samples were dry ashed in a programmed furnace
using MgO/Mg(NO3)2/HNO3, a digesting procedure that inhibits volatilization, improves
precision and gives better recoveries of inorganic substances (Cervera ML, Montoro R,
1994). Chemical quantification of total urinary content of As and Sb (UAsT; USbT) was
achieved by Hydride Generation Atomic Absorption (HGAAS) (GBC 904 AA with flow
injector GBC-HG3000), using NaBH4 (0.45% w/v) / NaOH (0.45% w/v) / HCl (20% v/v)
as reducing agent, prior reduction to the lower oxidation state with KI (15 % w/v). The
first batch of urine samples was analyzed for total urinary Se (USeT) by reflux wet
digestion (HNO3(c)/H2O2 30%) in a digestor block at 150ºC, followed by atomic
absorption by electrothermal atomization (ET-AAS) using Cu(NO3)2/Mg(NO3)2 as
atomization modifier; in the second and third batches the same digestion and
quantification procedure used for UAsT and USbT was employed, spiked samples
recovery assuring the equivalence of both methods (Table 1).
Urinary creatinine was tested using the Wierner Lab kit for routine biochemical
analysis.

2.3. Quality assurance

All chemicals were analytical reagent grade. Samples were treated by duplicates, and
chemical blanks prepared by triplicates. Three to five samples from each batch of
samples under chemical analysis were spiked adding suitable volumes of standard
solutions of As, Se and Sb in the digestion stage, for recovery assessment. Results are
presented in Table 1 for the total of 21 spiked samples (HG-AAS) and 24 when ET-
AAS was used.

Spiked samples recovery (%)

Technique UAsT USeT USbT
Minimum 69 75 85
HG-AAS Maximum 127 125 105
Mean 98 97 97
N 11 5 5
Minimum - 73 -
ET-AAS Maximum - 126 -
Mean - 92 -
N - 24 -

Table 1. % Recovery for urinary analytes in fortification assays

Sample fortification solutions and daily calibration curves were prepared from Merck
standard solutions (Merck Titrisol 1.09939 1000 mg As/L, Merck CertiPur 1.19796.0500
10025 mg Se/L and Merck CertiPur 1.70204.0500 9952 mg Sb/L).
Up to 30% discrepancy in the relative deviation (%SDR) of each analyte concentration
was considered acceptable; results differing in a larger amount were re-analyzed.
Four urine samples, out of the original sixty, were rejected before data treatment, due
to their extremely low content of urinary creatinine that distorted the element
concentration when normalized.
Statistical treatment of data was performed using “XLSTAT” software (XLSTAT 2007 -
Microsoft Excel). Locations were georeferenced by Garmin GPS II.

3. Results

3.1. Frequency distributions

For chronic exposure assessment, the relationship between groundwater As content in

the wells used as water supply by the sampled population and its urinary excretion was
evaluated. Data of water and urine concentrations was found to follow normal
distributions when log transformed. The solid correlation between them for the whole
set of data is shown in Figure 1.

log As (urinary) / log As (groundwater) correlation

log U AsT

4.0

3.5

3.0
r(54) = 0.667; p < 0.005
2.5

2.0

1.5

1.0

0.5

0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

log W AsT

Figure 1. Statistical correlation and significance between WAsT and UAsT

According to the established correlation, and in account of the accepted maximum

tolerable total concentration of As in water (WAsT), data were partitioned into two
groups: “control” (N = 10) and “exposed” (N = 46) with 0.01 mg As/L as the cutoff
value. The application of t test to compare the means of each group, confirms that the
two sets of data belong to different distributions (t exp > t (p = 0.01)).

Control group (N = 10) Exposed group (N = 46)

Analyte concentration in μg/gUC Analyte concentration in μg/gUC
Analyte UAsT USeT USbT UAsT USeT USbT
Median 36 28 20 154 50 9
Range 8 to 103 13 to 254 5 to 70 9 to 2379 6 to 653 1 to 77
MTV 50 25 1 50 25 1
Reference (Amster, 2007) (Lauwerys, 1999) (Lauwerys, 1999) (Amster, 2007) (Lauwerys, 1999) (Lauwerys, 1999)

Table 2. Urinary concentration parameters in the “control” and “exposed” groups

Median, range, Maximum Tolerable Value (MTV) and their references are shown in
Table 2. In the control group, UAsT is below MTV for every person but one (103
μg/gUC); in the exposed group, only 11% of individuals met MTV requirement for UAsT.
The remaining urinary analytes showed a differentiated behavior in each category:
USeT is higher, and USbT is lower for the exposed group, when compared to the control
group. Percentage of the tested population with urinary content below MTV was 21.4%
for UAsT, 19.6% for USeT and 14.3% forUSbT.; no one of the subject group achieved
MTV condition concurrently for the three analytes.
Data belonging to each subject group was checked for normality by the Shapiro-Wilk
(SWNT), Anderson-Darling (ADNT), Lilliefors (LNT) and Jarque-Bera (JBNT) tests, with
p = 0.05 (XLSTAT). Control group (N = 10) did not show normal distribution for any
urinary analyte when the Sturges formula was used for setting the number of classes of
the frequency distribution; the abnormality is possibly due to the small sample size.
In the exposed group (N = 46), 6 classes arose by the application of Sturges´ formula,
and, if the maximum value of the first class was set at the respective Maximum
Tolerable Value (MTV) for UAsT, USeT and USbT, all three frequency distributions
exhibited a log-normal type. When logarithm transformation was performed for every
analyte, their frequency distribution proved to be normal for every test for UAsT, USbT,
and by SWNT and JBNT for USeT. Therefore, statistical treatments were applied to the
log-transformed data of the exposed group.
3D graphics for each ethnic fraction revealed the presence of at least two doubtful
values: the individual with UAsT = 103 µg/gUC (control group) and the one with 2379
µg/gUC (exposed group) (Figure 2). This last individual was excluded from data
statistical analysis, and its character of outlier confirmed when correlation of logUAsT
with age was attempted (Section 3.2).

Figure 2. 3D graphics for “control group” (green) and “exposed group” (red)

3.2. Age and gender correlations

The existence of linear correlation between two variables can be tested by adjusting a
straight line to the representation of one of them as a function of the other. A positive
(negative) slope means that a positive (negative) correlation might exist. The
magnitude of the slope is statistically relevant if the statistical r (Pearson) parameter of
the slope is bigger than the tabulated value of r for N-2 degree of freedom for a given
probability level (p) in a one-tailed test (Kash Kachigan, 1991).
15 years old was considered the age cut-off value to separate children from adults, and
as recommended, children faction was not divided by gender.
In a previous communication (Boemo, 2008), negative relationship between UAsT and
age for children, and a positive one for adults, was recognized for the Chaco
population, but a low probability level was achieved due to the small sample size (30
individuals). With the addition of another 26 samples (N = 56), the same type of
correlations are now confirmed at high levels of probability (0.025% and 0.05%, Figure
3).
 log UAsT/ Age correlation
Exposed group
< 15 YEARS OLD ADULTS OUTLIER
4.0

log UAs
3.5

3.0

2.5

2.0
r(18) = 0.524; p < 0.01
1.5

1.0 r(23) = 0.457; p < 0.025

0.5

0.0
0 20 40 60 80
Age (years)

Figure 3. logUAsT/Age correlation, population separated by age

Outlier condition of the data point identified in the 3D graphics (UAsT = 2379 μg/gUC) is
here established by the Fisher r-to-z transformation (Lowry, 2009) for significance
assignation to the difference between two correlation coefficients (z > p value, one-
sided test), so correlations for adult sub-group ware evaluated after excluding it from
the data set.
logSe data showed the same distinctive behavior: a negative correlation for children
and a positive one for adults, being logUAsT in adults stronger correlated (Figure 3 and
Figure 4).

log USeT/ Age correlation

Exposed group
< 15 YEARS OLD ADULTS OUTLIER
3.0
log USe

2.5

2.0
r(18) = 0.373; p < 0.05

1.5

1.0 r(23) = 0.454; p < 0.025

0.5

0.0
0 20 40 60 80
Age (years)

Figure 4. logUSeT/Age correlation, population separated by age.

When data corresponding to adult population was separated according to gender, two
lines of different slopes were obtained for the correlation logAsT /Age.
 log UAsT/Age by gender
AD. FEM. AD. MASC.

log UAsT
3.5

3.0 y = 0.0216x + 1.4374

r(6) = 0.692; p < 0.05
2.5

2.0

1.5

1.0 y = 0.0454x + 0.2519

r(10) = 0.508; p < 0.05
0.5

0.0
0 10 20 30 40 50 60 70 80

Age (years)

Figure 5. Adult logUAsT/Age correlation according to gender.

Significance on logUAsT/Age correlation, for the adult subject group, relies on both
genders, being the female group correlation stronger, steadier and shifted to upper
concentration values compared to the male distribution (Figure 5). The weaker
correlation found in logUSeT/Age cannot be assigned to different gender, since each
one by its own did not present any significative correlation (p > 0.05). LogUSbT showed
no correlation with age, neither for children nor for adult population group (p > 0.05).

3.3. logUAsT, log USeT and logUSbT correlations

A statistically significant (p < 0.01) positive correlation was found between logUAsT and
logUSeT, with a slope close to 0.3, indicating that a small increase in UAsT is
accompanied by a great increase in the urinary Se excretion. (Figure 6).

log UAsT / log USeT correlation

Exposed group
3.5

3.0

2.5
log UAsT

2.0

1.5

1.0 y = 0.3035x + 1.7473

r(42) = 0.375; p < 0.01
0.5

0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

log USeT

Figure 6. Correlation logUAsT/logUSeT

When logUAsT and logUSbT were confronted, no significative correlation (p > 0.05) was
found between them, that is, there seems to be no interaction in their respective urinary
analyte content. Yet, if the three other family members of the identified outlier are also
excluded (BP4 family), the significance of the positive lineal regression between the
two variables unexpectedly rises to p < 0.01, very close to the log UAsT/log USeT
relationship (Figure 7).
 Exposed group correlation

N = 45 Without BP4 Family OUTLIER

4.0

log UAsT
3.5
r (44) = 0.120; p > 0.05)
3.0

2.5

2.0

1.5
y = 0.2945x + 1.9161
1.0 r(42) = 0.378; p < 0.01

0.5

0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
log USbT

Figure 7. Log UAsT / log USbT correlation.

BP4 family is very distinctive when considering As and Sb content: their urinary As
concentrations are the highest (in concordance with As concentration in their water
supply, 1.22 mg/L), but their USbT is among the lowest in the exposed group; medical
consulting reveals hyperkeratosis even in the 3 years old child, and skin carcinoma in
the elderly grandmother.

4. Discussion

In previous research (Farfán Torres et al., 2008), arsenic contents found in food
samples indicate that in the population under study the major intake of As is via
drinking water (4.8 μg/kg bw/day vs. daily tolerable limit of 3 μg/kg bw/day). Evaluation
of dietary exposure to Se and Sb indicate that Sb ingestion is below the tolerable limit
stated by ANZFA, 1999 (0.4 μg/kg bw/day), while Recommended Daily Intake for Se is
achieved only in red meat and its composite food (12.5 μg/kg bw/day vs. 1.04 μg/kg
bw/day).
Water concentrations of both elements in every sampled district were below the local
tolerable limit, 0.05 mg Se/L and 0.01 mg Sb/L respectively (AAC, 2007). When the
total sampled population is split into children and adults, the significative correlations
found for both UAsT and USeT with age evidenced a disparity behavior in the sub-
groups, the youngest and oldest fraction showing higher urinary excretion, and so,
being differentially exposed to hydroarsenicism by distinct detoxification pattern.
Sample size for adult subject group probed to be adequate to ascertain gender
correlation for UAsT; the absence of significance for a correlation USeT/age by gender,
but not for the whole adult population, may be related to insufficient data.
Since Sb interacts with the methylation pathway of As metabolic detoxification,
quantification of urinary species of arsenic could help to reveal any possible correlation
of USbT with age, gender as well as between UAsT and USeT.

5. Conclusion

High urinary detoxification ability for UAsT, USeT and USbT was recognized in 60
individuals from the northeastern region of Salta, Argentina, compatible with the dietary
intake of As, but not with Se and Sb ingestion.
Significative correlations with age were established for UAsT and USeT, negative for
children and positive for adults. Available data was sufficient for identification of
gender correlation for UAsT, and appears that the same asseveration could be valid for
USeT for a larger sample size. USbT showed no correlation with USeT nor with age and
gender; positive correlation with UAsT was only significative when individuals with high
UAsT and low USbT were rejected.
Urinary arsenic speciation is mandatory in further research.
Acknowledgements

This study was supported by the Research Council of the National University of Salta,
Argentina (CIUNSa), and Chemical Research Institute/National Council of Scientific
and Technological Research (INIQUI/CONICET), Argentina.

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