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EC number: 231-901-9
CAS number: 7778-39-4
the derivation of a DNEL for arsenic acid, carcinogenicity appears as
the critical end-point with lowest NOAEL and will therefore be used to
derive the DNEL. Rat and mouse, the two rodents which are normally used
for chemical carcinogenicity testing appear as very poor and insensitive
models to evaluate arsenic carcinogenicity potential. However, there is
evidence from a large number of epidemiological studies that inhalation
and oral exposure to inorganic arsenic increases the risk of lung
cancer. Among these epidemiological studies on the carcinogenic
potential of arsenic, only few of them are dealing with pentavalent (or
non specified) mineral arsenic and are of sufficient quality to allow
derivation of a NOAEL (or LOAEL).
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. Therefore no reliable NOAEL can be estimated from this study
and the LOAEL is probably <50 mg*years/m3.
these cancers are also present after oral absorptionof
excessive amount of inorganic arsenic, mainly in drinking water, the
NOAEL derived from these studies will be used to derive also the
inhalation DNEL. 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.
the most relevant and sensitive study is from Ashan (2006) conducted 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. Several measures of arsenic exposure were estimated for each
participant based on well-water arsenic concentration and usage pattern
of the wells and on urinary arsenic concentration. In different
regression models, consistent dose-response effects were observed for
ail arsenic exposure measures. Control group consists in people with
drinking water containing <8.1 µg/L of arsenic. Drinking water
containing 8.1-40:0, 40.1-91.0, 91.1-175.0, and 175.1-864.0 µg/L of
arsenic was associated with adjusted prevalence odds ratios (OR) of skin
lesions of 1,91 (95% confidence interval (CI): 1.26, 2,89), 3.03 (95%
CI: 2.05, 4.50), 3.71 (95% Cl: 2,53, 5.44), and 5.39 (95% CI: 3.69,
7.86), respectively. To take into account water intake, the authors used
also a Cumulative Arsenic Index (well concentration * daily consumption
* days of use/year). When considering this value the median of the NOAEL
group is 24 g and the median of the LOEL group (prevalence OR: 1.83 and
range: 1.25-2.69) is 137 mg. This is equivalent per day to 66 and 675
µg/day for NOAEL and LOAEL respectively. When arsenic urinary excretion
is considered this value the median of the NOAEL group is 48.3 µg/g of
creatinine and the median of the LOEL group (prevalence OR: 1.75 and
range: 1.23-2.48) is 124.3 µg/g of creatinine. With the hypothesis that
urinary excretion is equivalent to 60% of the intake (Buchet et al,
1981) and the creatinine excretion is 1300 mg/day for a 60 kg adult;
this is equivalent per day to 1.7 and 4.5 µg/kg/day for NOAEL and LOAEL
respectively. This study has identified a large number of people
presenting lesions (between 57 and 242 in low and high dose group
respectively) and is therefore statistically robust. However, the
lesions identified were not malignant lesions and can be considered as
very early indicators of arsenic overload. The 2.5% prevalence of
lesions in the control group tends to indicate a high sensitivity in the
lesion identification. Therefore the LOAEL in this study can be
considered as the median value of the lowest category with an OR of
1.91, i.e. 24 µg/L. This value is close from the NOAEL of 0.8 µg/L
derived from Tseng, 1968 (Tseng, W.P., H.M. Chu, S.W. How, J.M. Fong,
C.S. Lin and S. Yeh. 1968. Prevalence of skin cancer in an endemic area
of chronic arsenicism in Taiwan. J. Natl. Cancer Inst. 40: 453-463) used
by EPA (*EPA. 1998d. National emissions standards for hazardous air
pollutants for primary lead smelters. U.S. Environmental Protection
Agency. Code of Federal Regulations. 40 CFR 63.Fed
Regist 63(74)19200. ) to derive acceptable values in drinking water.
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.
Cox proportional hazards regression analysis was used to estimate
multivariate-adjusted relative risks and 95% confidence intervals. There
was a significantly increased incidence of urinary cancers for the study
cohort compared with the general population in Taiwan (standardized
incidence ratio = 2.05; 95% confidence interval (CI): 1.22, 3.24). A
significant dose-response relation between risk of cancers of the
urinary organs, especially TCC, and indices of arsenic exposure was
observed after adjustment for age, sex, and cigarette smoking. The
multivariate-adjusted relative risks of developing TCC were 1.9, 8.2,
and 15.3 for arsenic concentrations of 10.1-50.0, 50.1-100, and >100
pg/L, respectively, compared with the referent level of <10.01µg/L.
However, this was significant only for the highest exposure group (>100
µg/L ). Therefore the LOAEL in this study can be considered as100 µg/L.
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.
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. The excretion of 35
µg/day corresponds to a daily intake of 58 µg/day equivalent to 0.83
µg/kg for a 70 kg man. 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, as follows: 1, 1.6 (95% CI = 0.5-5.3), 3.9
(95% CI = 1.2-12.3), 5.2 (95% CI = 2.3-11.7), and 8.9 (95% CI =
4.0-19.6), for arsenic concentrations 0-10 µg/L , 10-29 µg/L , 30-49
µg/L , 50-99 µg/L and 200-400 µg/L respectively. 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 nonsmokers 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 (arithmetic
mean of the 60-89 µg/L group) and risk of human lung cancer and the
NOAEL can be estimated at 29 µg/L.
of NOAEL from these studies:
to DNEL/DMEL derivation for human data document
If the exposure range categories form a continuum and the number of
individuals in the exposure category showing no effect is sufficient to
exclude an effect, the NOAEL lies in the lowest exposure category with
an effect but one can’t know at which exact value within this category.
If the exposure categories form a continuum, the upper exposure limit of
the range of exposures in the no-effect category is the same as the
lower limit of the range of exposure in the lowest category showing an
effect. In the absence of more details on the distribution of exposures
this value should be used as a NOAEL.
has been used for some studies like Guo et al (2000) and Guo et al
(2000). However it was not possible for some studies like Ahsan where
the NOAEL was define by the boundaries of the lowest exposure subgroup.
In this case, the median value of the groups have been used.
1: NOAEL summaries:
Premalignant skin lesions
1.7 µg/kg bw day
4.5 µg/kg bw day
Median value of the group with the lowest increase
≥0.83 µg/kg bw day
No effect in a population with a mean urinary excretion of 35 µg/day
Highest value of the group with no significant increased incidence.Very small number of cases
No effects up to >200µg/L but very small number of cases.
Highest value of the group with no significant increased incidence. Issue with selection of controls which may have lead to OR overestimate in the low ranges.
<50 mg years/m3
Lack of reliable information on smoking pattern of many subjects
lowest NOAEL is found with Ferreccio et al (2000). However, the issues
with control selection cast some doubts about the precision of this
case-control study. The best estimate seems then to be the study by
Ahsan et al (2006) which have the advantage of having measured exposure
as µg/L, an integrated value over the year and individual exposure
values. The latest will be used to derive the DNEL.
to DNEL/DMEL derivation for human data document:
1. Intraspecies differences
of the population is suspected to be more susceptible to cancer due to
genetic properties (such as having specific polymorphisms).The NOAEL for
arsenic acid is derived from a large variety of population from E.U.,
Asia and South America which is expected to cover most of the
variability in the general population. In addition, the final NOAEL from
which the DNEL is derived has been determined from the effects of
exposure in the general population, many of these people having been
exposed also during childhood and infancy. This population is therefore
expected to be at least and probably more variable than an healthy adult
worker population which will be the target for the DNEL. Therefore
there is no need to use AFs for extrapolation of a DNEL derived from the
general population to one subgroup (in this case a worker population).
DNEL approach has been chosen instead of the DMEL approach for two main
a very large number of mutagenicity studies conducted with different
forms of Arsenic, a direct effect of arsenic on DNA has never been
in a natural element widely present in earth crust with a widely present
background exposure and the effects of very low level of exposure as
positive or negative have never been elucidated.
is a sufficient diversity and sufficiently large population studied to
consider that the intraspecies differences are fully covered. Many of
these studies have considered populations which have been exposed from
infancy to adult age and in whatever circumstances and in many cases
with a less than adequate nutritional status. In addition for some of
these populations a significant part of the exposure may have been to
trivalent arsenic known to be much more toxic than pentavalent arsenic.
these studies, well water as drinking water and also as cooking water.
When using Ahsan study, it seems that correspondence between Time
weighted well As concentration/cumulative index/Arsenic in urine
corresponds to water intake in the range of 4-5 litres. For 3
litres/day, 64 µg/L will corresponds for a 60kg adult to 3,2 µg/kg
bw/day and 29 µg/L will corresponds for a 60kg adult to 1,45 µg/kg
bw/day. Therefore the value of 1.7 µg/kg bw day in the study from Buchet
can be use to derive the DNEL without intra or between species
difference. The oral DNEL for chronic exposure is therefore 1.7 µg/kg bw
penetration human skin (in vitro) has been studies by Wester et al
(1993). Water solutions of arsenic-73 at a low (trace) level of 0.000024μg/cm2
and a higher dose of 2.1μg/cm2were
prepared for comparative analysis. In vitro percutaneous absorption of
the low dose from water with human skin resulted in 24-hr receptor fluid
(phosphate-buffered saline) accumulation of 0.93±1.1% dose and skin
concentration (after washing) of 0.98±0.96%. Combining receptor fluid
accumulation and skin concentration gave a combined amount of 1.9%.
Washing with soap and water readily removed residual skin surface
arsenic, both in vitro and in vivo. Therefore, a penetration coefficient
of 2% will be used to derive a dermal DNEL.
dermal DNEL = 1.7 µg/kg bw day (Oral DNEL) / 2% = 85 µg/kg bw day.
reliable quantitative information can be taken from the existing
epidemiological studies where inhalation was said to be the main route
common limitation of these studies is confounding exposure to other
chemicals, such as sulfur dioxide, and cigarette smoking.In
addition, none of these studies has considered dermal exposure which is
expected to be significant in environment where significant amount of
dust may have deposited on equipment surfaces. For these reasons,
chronic inhalation DNEL will be derived from oral DNEL. An assessment
factor of two will be added considering that in the case of inhalation,
exposure will be directly on one of the potential target, the lungs.
inhalation DNEL:: 1.7 µg/kg bw day * 70 kg / 2 (AF) * 10 m3/day
: 6 µg/m3
levels set for chronic DNEL’s will oblige to very strict OC and RMM. No
acute or subchronic DNEL’s are considered necessary.
will not be sold in a form making exposure possible to the general
public. Therefore no consumer DNEL’s are considered necessary.
1: DNEL derivation summary:
85 µg/kg bw day
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