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EC number: 231-901-9
CAS number: 7778-39-4
Several studies have been conducted in rodents which appear to be very insensitive models for carciinogenicity. Epidemiology studies in human have consistently demonstrated that human exposure to inorganic arsenic lead to an increase incidence in cancer in several organs mainly skin, bladder and lungs.
Epidemiology studies in human have consistently demonstrated that human
exposure to inorganic arsenic lead to an increase incidence in cancer in
several organs mainly skin, bladder and lungs. In consequence, arsenic
acid should be classified as Carc. 1A – H350 according to CLP.
Most studies of animals exposed to arsenate or even arsenite
expected to be more toxic, have not detected any clear evidence for an
increased incidence of skin cancer or other cancers (Byron et al. 1967;
Kroes et al. 1974; Schroeder et al. 1968). The basis for the lack of
tumorigenicity in animals is not known, but could be related to
species-specific differences in arsenic distribution, and induction of
cell proliferation. Most of these studies are old, of limited quality
and do not bring relevant information. However, although it was
conducted on sodium arsenite, we reported a study conducted by Waalkes
et al (2004, 2007). In this study pregnant C3H mice were received sodium
arsenite in drinking water at 0 (control), 42.5, and 85 ppm arsenite ad
libitum from day 8 to 18 of gestation. After gestation day 18 there was
no further arsenic treatment and Dams were allowed to give birth. In
male offspring exposed to arsenic in utero developed liver carcinoma and
adrenal cortical adenoma in a dose-related manner. In female offspring,
a dose-related increase in ovarian tumors, lung carcinoma and
proliferative lesions of the uterus and oviduct was observed.
However, there is convincing evidence from a large number of
epidemiological studies and case reports that ingestion or inhalation of
inorganic arsenic increases the risk of developing skin bladder, kidney,
liver and lung cancer. A selection of these studies has been reported
there. Selection was mainly based on study quality and the possibility
to define a reliable dose effect relationship.
For inhalation exposure, most studies involved
workers exposed primarily to arsenic trioxide dust in air at copper
smelters and despite some good studies with some information on dose
effect relationship, these studies have many shortcomings and do not
allow the definition of a reliable NOAEL for arsenic acid to derive a
relevant DNEL. The more reliable is a study by Jarup et al, (1989) in
which the cause-specific mortality was followed through 1981 in a cohort
of 3,916 male Swedish smelter workers employed for at least 3 months
from 1928 through 1967. Arsenic levels in the air of all workplaces
within the smelter were estimated for three different time periods.
Using this exposure matrix and detailed information of the work history,
cumulative arsenic exposure could be computed for each worker.
Standardized mortality ratios (SMRs) were calculated for several dose
categories using age-specific mortality rates from the county where the
smelter was situated. A positive dose-response relationship was found
between cumulative arsenic exposure and lung cancer mortality with an
overall SMR of 372 (304-450, 95% confidence interval). The lung cancer
mortality was related to the estimated average intensity of exposure to
arsenic but not to the duration. SMR’s ranged from 271 (<0.25 mg year/m3)
to 1137 (<100 mg*year/m3). However, smoking pattern was
not recorded in this study and there was some indication that it was
different from the reference population. This may explain the lack of
dose response until 50 mg*years/m3in this study..
A number of epidemiological studies deal with oral absorptionespecially
with the carcinogenic effects of excessive amount of inorganic arsenic
in drinking water. The three main cancer types which have been
identified in these studies and for which NOAEL can be derived from
epidemiological studies are skin, bladder and lungs.
Carcinogenic effect of arsenic to skin is well known. It have been
reviewed recently by Yu et al (2006). The most common arsenic-induced
skin cancers are Bowen's disease (carcinoma in situ), basal cell
carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced
Bowen's disease (As-BD) is able to transform into invasive BCC and SCC.
Individuals with As-BD are considered for more aggressive cancer
screening in the lung and urinary bladder. However, Beane et al (2004)
also described an increased incidence of skin melanoma in correlation
with increased intake of inorganic arsenic in drinking water. As this
finding has not been confirmed so far, it has to be considered with
caution. Specific skin lesions will often appear before the cancer
lesions and they also have been well studied with a good correlation
with dietary exposure (Ashan et al, 2006) in Bangladesh. In this study
the authors evaluated dose-response relations between arsenic exposure
from drinking water and premalignant skin lesions by using baseline data
on 11,746 participants recruited in 2000-2002.
Bladder cancer incidence has been studied by Chiou (2001). In this
study the authors examined risk of transitional cell carcinoma (TCC) in
relation to ingested arsenic in a cohort of 8102 residents in
north-eastern Taiwan. Estimation of each study subject's individual
exposure to inorganic arsenic was based on the arsenic concentration in
his or her own well water. Information on duration of consumption of the
well water was obtained through standardized questionnaire interviews.
The occurrence of urinary tract cancers was ascertained by follow-up
interview and by data linkage with community hospital records, the
national death certification profile, and the cancer registry profile.
Two other publications report on dose effect relationship for bladder
cancer: Guo et al (2000) and Bates et al (2004). Guo et al (2000) is a
village based ecological study conducted in Taiwan using cancer registry
and death certificates; there is no increased incidence of bladder
cancer below an Arsenic water concentration of 0.64 mg/L. The next
lowest dose without effect is the group with water concentration between
0.33 and 0.64 mg/L. Bates et al (2004) is a case control study conducted
in Argentina. Cases were recruited in different clinics of the area and
exposure was assessed by measurement of the Arsenic concentration of
their residence. There found no increased incidence of bladder cancer
with an Arsenic water concentration up to 200 mg/L (group between 200
and 389 µg/L). There was a potential increase in subject who ever smoked
and were exposed more that 50 years to arsenic but the significance of
that is unclear.
Lung cancer incidence has been studied by Buchet et al (1998). A
cohort study was conducted to analyse the statistics of mortality in
Belgian population previously exposed to As from natural (drinking
water) and/or industrial (nonferrous metal smelter emissions) sources.
Mortality data and underlying causes were obtained from the Belgian
National Institute of Statistics. A moderately increased absorption of
As, leading to a 3- to 4- fold higher urinary excretion (35 µg/day as
compared with 6-10 µg As/day in nonexposed subjects) did not enhance the
mortality by diseases of the nervous system, liver and heart, and
cancers. An increase in mortality by lung cancer, however, was observed
in men but not women living around zinc smelters but might be related to
past occupational exposure and/or smoking habits. In conclusion, a low
to moderate level of environmental exposure to inorganic arsenic does
not seem to affect the causes of mortality, suggesting in particular
nonlinearity of the dose-response relationship for arsenic and cancer.
Ferreccio et al (2000) conducted a case-control study to assess the
relation between lung cancer and arsenic in drinking water in northern
Chile. Study identified 152 lung cancer cases (1994-1996) and 419
frequency-matched hospital controls. Information on drinking water
sources, cigarette smoking, and other variable was obtained through
standardized questionnaire interviews. Logistic regression analysis
revealed a clear trend in lung cancer odds ratios and 95% confidence
intervals (CIs) with increasing concentration of arsenic in drinking
water. There was evidence of synergy between cigarette smoking and
ingestion of arsenic in drinking water; the odds ratio for lung cancer
was 32.0 (95% CI = 7.2-198.0) among smokers exposed to more than 200
µg/L of arsenic in drinking water (lifetime average) compared with
non-smokers exposed to less than 50 µg/L. Under the conditions of the
study, an association was found between ingestion of inorganic arsenic
at more than 75 µg/L and risk of human lung cancer.
In conclusion, despite limited evidence from animal studies,
inorganic arsenic, including pentavalent form (and then arsenic acid)
can be considered as a proven human carcinogen. There is still
considerable controversy on the exact mechanism and the existence or not
of a threshold, although there is some in vitro positive mutagenicity
studies. As arsenic is a naturally occurring substance with an
unavoidable background exposure for the general population, a threshold
approach can be favoured for risk assessment.
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