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Arsenic, inorganic
CASRN 7440-38-2
04/10/1998
Contents
0278
Arsenic, inorganic; CASRN 7440-38-2 (04/10/1998)
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Arsenic, inorganic
File On-Line 02/10/1988
|
Category (section) | Status | Last Revised |
|
--------------------------------------------- | ------------ | --------------- |
| Oral RfD Assessment (I.A.) | on-line | 02/01/1993 |
| Inhalation RfC Assessment (I.B.) | no data | |
| Carcinogenicity Assessment (II.) | on-line | 04/10/1998 |
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR
NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Arsenic, inorganic
CASRN -- 7440-38-2
Last Revised -- 02/01/1993
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
NOTE: There was not a clear consensus among Agency scientists on the oral
RfD. Applying the Agency's RfD methodology, strong scientific arguments can
be made for various values within a factor of 2 or 3 of the currently
recommended RfD value, i.e., 0.1 to 0.8 ug/kg/day. It should be noted,
however, that the RfD methodology, by definition, yields a number with
inherent uncertainty spanning perhaps an order of magnitude. New data that
possibly impact on the recommended RfD for arsenic will be evaluated by the
Work Group as it becomes available. Risk managers should recognize the
considerable flexibility afforded them in formulating regulatory decisions
when uncertainty and lack of clear consensus are taken into account.
___I.A.1. ORAL RfD SUMMARY
| Critical Effect | Experimental Doses* | UF | MF | RfD |
| -------------------------- | ------------------------------------- | ----- | ------ | --------- |
| Hyperpigmentation, | NOAEL: 0.009 mg/L | 3 | 1 | 3E-4 |
| keratosis and | converted to 0.0008 | | | mg/kg-day |
| possible vascular | mg/kg-day | | | |
| complications | | | | |
| | LOAEL: 0.17 mg/L converted | | | |
| Human chronic | to 0.014 mg/kg-day | | | |
| oral exposure | | | | |
Tseng, 1977;
Tseng et al., 1968
*Conversion Factors: NOAEL was based on an arithmetic mean of 0.009 mg/L in a
range of arsenic concentration of 0.001 to 0.017 mg/L. This NOAEL also
included estimation of arsenic from food. Since experimental data were
missing, arsenic concentrations in sweet potatoes and rice were estimated as
0.002 mg/day. Other assumptions included consumption of 4.5 L water/day and
55 kg bw (Abernathy et al., 1989). NOAEL = [(0.009 mg/L x 4.5 L/day) + 0.002
mg/day] / 55 kg = 0.0008 mg/kg-day. The LOAEL dose was estimated using the
same assumptions as the NOAEL starting with an arithmetic mean water
concentration from Tseng (1977) of 0.17 mg/L. LOAEL = [(0.17 mg/L x 4.5
L/day) + 0.002 mg/day] / 55 kg = 0.014 mg/kg-day.
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Tseng, W.P. 1977. Effects and dose-response relationships of skin cancer and
blackfoot disease with arsenic. Environ. Health Perspect. 19: 109-119.
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.
The data reported in Tseng (1977) show an increased incidence of blackfoot
disease that increases with age and dose. Blackfoot disease is a significant
adverse effect. The prevalences (males and females combined) at the low dose
are 4.6 per 1000 for the 20-39 year group, 10.5 per 1000 for the 40-59 year
group, and 20.3 per 1000 for the >60 year group. Moreover, the prevalence of
blackfoot disease in each age group increases with increasing dose. However,
a recent report indicates that it may not be strictly due to arsenic exposure
(Lu, 1990). The data in Tseng et al. (1968) also show increased incidences of
hyperpigmentation and keratosis with age. The overall prevalences of
hyperpigmentation and keratosis in the exposed groups are 184 and 71 per 1000,
respectively. The text states that the incidence increases with dose, but
data for the individual doses are not shown. These data show that the skin
lesions are the more sensitive endpoint. The low dose in the Tseng (1977)
study is considered a LOAEL.
The control group described in Tseng et al. (1968; Table 3) shows no evidence
of skin lesions and presumably blackfoot disease, although this latter point
is not explicitly stated. This group is considered a NOAEL.
The arithmetic mean of the arsenic concentration in the wells used by the
individuals in the NOAEL group is 9 ug/L (range: 1-17 ug/L) (Abernathy et al.,
1989). The arithmetic mean of the arsenic concentration in the wells used by
the individuals in the LOAEL group is 170 ug/L (Tseng, 1977; Figure 4). Using
estimates provided by Abernathy et al. (1989), the NOAEL and LOAEL doses for
both food and water are as follows: LOAEL - [170 ug/L x 4.5 L/day + 2 ug/day
(contribution of food)] x (1/55 kg) = 14 ug/kg/day; NOAEL - [9 ug/L x 4.5
L/day + 2 ug/day (contribution of food)] x (1/55 kg) = 0.8 ug/kg/day.
Although the control group contained 2552 individuals, only 957 (approximately
38%) were older than 20, and only 431 (approximately 17%) were older than 40.
The incidence of skin lesions increases sharply in individuals above 20; the
incidence of blackfoot disease increases sharply in individuals above 40
(Tseng, 1968; Figures 5, 6 and 7). This study is less powerful than it
appears at first glance. However, it is certainly the most powerful study
available on arsenic exposure to people.
This study shows an increase in skin lesions, 22% (64/296) at the high dose
vs. 2.2% (7/318) at the low dose. The average arsenic concentration in the
wells at the high dose is 410 ug/L and at the low dose is 5 ug/L (Cebrian et
al., 1983; Figure 2 and Table 1) or 7 ug/L (cited in the abstract). The
average water consumption is 3.5 L/day for males and 2.5 L/day for females.
There were about an equal number of males and females in the study. For the
dose estimates given below we therefore assume an average of 3 L/day. No data
are given on the arsenic exposure from food or the body weight of the
participants (we therefore assume 55 kg). The paper states that exposure
times are directly related to chronological age in 75% of the cases.
Approximately 35% of the participants in the study are more than 20 years old
(Figure 1).
Exposure estimates (water only) are: high dose - 410 ug/L x 3 L/day x (1/55
kg) = 22 ug/kg/day; low dose - 5-7 ug/L x 3 L/day x (1/55 kg) = 0.3-0.4
ug/kg/day.
The high-dose group shows a clear increase in skin lesions and is therefore
designated a LOAEL. There is some question whether the low dose is a NOAEL or
a LOAEL since there is no way of knowing what the incidence of skin lesions
would be in a group where the exposure to arsenic is zero. The 2.2% incidence
of skin lesions in the low-dose group is higher than that reported in the
Tseng et al. (1968) control group, but the dose is lower (0.4 vs. 0.8
ug/kg/day).
The Southwick et al. (1983) study shows a marginally increased incidence of a
variety of skin lesions (palmar and plantar keratosis, diffuse palmar or
plantar hyperkeratosis, diffuse pigmentation, and arterial insufficiency) in
the individuals exposed to arsenic. The incidences are 2.9% (3/105) in the
control group and 6.3% (9/144) in the exposed group. There is a slight, but
not statistically significant increase in the percent of exposed individuals
that have abnormal nerve conduction (8/67 vs. 13/83, or 12% vs. 16% (Southwick
et al., 1983; Table 8). The investigators excluded all individuals older than
47 from the nerve conduction portion of the study. These are the individuals
most likely to have the longest exposure to arsenic.
Although neither the increased incidence of skin lesions nor the increase in
abnormal nerve conduction is statistically significant, these effects may be
biologically significant because the same abnormalities occur at higher doses
in other studies. The number of subjects in this study was insufficient to
establish statistical significance.
Table 3 (Southwick et al., 1983) shows the annual arsenic exposure from
drinking water. No data are given on arsenic exposure from food or the body
weight (assume 70 kg). Exposure times are not clearly defined, but are > 5
years, and dose groups are ranges of exposure.
Exposure estimates (water only) are: dosed group - 152.4 mg/year x 1 year/365
days x (1/70) kg = 6 ug/kg/day; control group - 24.2 mg/year x year/365 days x
(1/70) kg = 0.9 ug/kg/day.
Again because there are no data for a group not exposed to arsenic, there is
some question if the control group is a NOAEL or a LOAEL. The incidence of
skin lesions in this group is about the same as in the low-dose group from the
Cebrian et al. (1983) study; the incidence of abnormal nerve conduction in the
control group is higher than that from the low-dose group in the Hindmarsh et
al. (1977) study described below. The control dose is comparable to the dose
to the control group in the Tseng et al. (1968) and Hindmarsh et al. (1977)
studies. The dosed group may or may not be a LOAEL, since it is does not
report statisically significant effects when compared to the control.
This study shows an increased incidence of abnormal clinical findings and
abnormal electromyographic findings with increasing dose of arsenic (Hindmarsh
et al., 1977; Tables III and VI). However, the sample size is extremely
small. Percentages of abnormal clinical signs possibly attributed to As were
10, 16, and 40% at the low, mid and high doses, respectively. Abnormal EMG
were 0, 17 and 53% in the same three groups.
The exact doses are not given in the Hindmarsh et al. (1977) paper; however,
some well data are reported in Table V. The arithmetic mean of the arsenic
concentration in the high-dose and mid-dose wells is 680 and 70 ug/L,
respectively. Figure 1 (Hindmarsh et al., 1977) shows that the average
arsenic concentration of the low-dose wells is about 25 ug/L. No data are
given on arsenic exposure from food. We assume daily water consumption of 2
liters and body weight of 70 kg. Exposure times are not clearly stated.
Exposure estimates (water only) are: low - 25 ug/L x 2 L/day x (1/70) kg =
0.7 ug/kg/day; mid - 70 ug/L x 2 L/day x (1/70) kg = 2 ug/kg/day; high - 680
ug/L x 2 L/day x (1/70) kg = 19 ug/kg/day.
The low dose is a no-effect level for abnormal EMG findings. However, because
there is no information on the background incidence of abnormal clinical
findings in a population with zero exposure to arsenic, there is no way of
knowing if the low dose is a no-effect level or another marginal effect level
for abnormal clinical findings. The low dose is comparable to the dose
received by the control group in the Tseng (1977) and Southwick et al. (1983)
studies.
The responses at the mid dose do not show a statistically significant increase
but are part of a statistically significant trend and are biologically
significant. This dose is an equivocal NOAEL/LOAEL. The high dose is a clear
LOAEL for both responses.
As discussed previously there is no way of knowing whether the low doses in
the Cebrian et al. (1983), Southwick et al. (1983) and Hindmarsh et al. (1977)
studies are NOAELs for skin lesions and/or abnormal nerve conduction.
However, because the next higher dose in the Southwick and Hindmarsh studies
only shows marginal effects at doses 3-7 times higher, the Agency feels
comfortable in assigning the low doses in these studies as NOAELs.
The Tseng (1977) and Tseng et al. (1968) studies are therefore considered
superior for the purposes of developing an RfD and show a NOAEL for a
sensitive endpoint. Even discounting the people < 20 years of age, the control
group consisted of 957 people that had a lengthy exposure to arsenic with no
evidence of skin lesions.
The following is a summary of the defined doses in mg/kg-day from the
principal and supporting studies:
1) Tseng (1977): NOAEL = 8E-4; LOAEL = 1.4E-2
2) Cebrian et al. (1983): NOAEL = 4E-4; LOAEL = 2.2E-2
3) Southwick et al. (1983): NOAEL = 9E-4; LOAEL = none (equivocal effects at
6E-3)
4) Hindmarsh et al., 1977: NOAEL = 7E-4; LOAEL = 1.9E-2 (equivocal effects at
2E-3)
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- The UF of 3 is to account for both the lack of data to preclude
reproductive toxicity as a critical effect and to account for some uncertainty
in whether the NOAEL of the critical study accounts for all sensitive
individuals.
MF -- None
___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD)
Ferm and Carpenter (1968) produced malformations in 15-day hamster fetuses via
intravenous injections of sodium arsenate into pregnant dams on day 8 of
gestation at dose levels of 15, 17.5, or 20 mg/kg bw. Exencephaly,
encephaloceles, skeletal defects and genitourinary systems defects were
produced. These and other terata were produced in mice and rats all at levels
around 20 mg/kg bw. Minimal effects or no effects on fetal development have
been observed in studies on chronic oral exposure of pregnant rats or mice to
relatively low levels of arsenic via drinking water (Schroeder and Mitchner,
1971). Nadeenko et al. (1978) reported that intubation of rats with arsenic
solution at a dose level of 25 ug/kg/day for a period of 7 months, including
pregnancy, produced no significant embryotoxic effects and only infrequent
slight expansion of ventricles of the cerebrum, renal pelves and urinary
bladder. Hood et al. (1977) reported that very high single oral doses of
arsenate solutions (120 mg/kg) to pregnant mice were necessary to cause
prenatal fetal toxicity, while multiple doses of 60 mg/kg on 3 days had little
effect.
Extensive human pharmacokinetic, metabolic, enzymic and long-term information
is known about arsenic and its metabolism. Valentine et al. (1987)
established that human blood arsenic levels did not increase until daily water
ingestion of arsenic exceeded approximately 250 ug/day (approximately 120 ug
of arsenic/L. Methylated species of arsenic are successively 1 order of
magnitude less toxic and less teratogenic (Marcus and Rispin, 1988). Some
evidence suggests that inorganic arsenic is an essential nutrient in goats,
chicks, minipigs and rats (NRC, 1989). No comparable data are available for
humans.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Medium
RfD -- Medium
Confidence in the chosen study is considered medium. An extremely large
number of people were included in the assessment ( > 40,000) but the doses were
not well-characterized and other contaminants were present. The supporting
human toxicity data base is extensive but somewhat flawed. Problems exist
with all of the epidemiological studies. For example, the Tseng studies do
not look at potential exposure from food or other source. A similar criticism
can be made of the Cebrian et al. (1983) study. The U.S. studies are too
small in number to resolve several issues. However, the data base does
support the choice of NOAEL. It garners medium confidence. Medium confidence
in the RfD follows.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
This analysis has been reviewed by EPA's Risk Assessment Council on 11/15/1990.
This assessment was discussed by the Risk Assessment Council of EPA on
11/15/1990 and verified through a series of meetings during the 1st, 2nd and 3rd
quarters of FY91.
Other EPA Documentation -- U.S. EPA, 1984, 1988
Agency Work Group Review -- 03/24/1988, 05/25/1988, 03/21/1989, 09/19/1989, 08/22/1990,
09/20/1990
Verification Date -- 11/15/1990
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the IRIS Hotline for all questions concerning this
assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (FAX)
or Hotline.IRIS@epamail.epa.gov (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Arsenic, inorganic
CASRN -- 7440-38-2
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Arsenic, inorganic
CASRN -- 7440-38-2
Last Revised -- 04/10/1998
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- A; human carcinogen
Basis -- based on sufficient evidence from human data. An increased lung
cancer mortality was observed in multiple human populations exposed primarily
through inhalation. Also, increased mortality from multiple internal organ
cancers (liver, kidney, lung, and bladder) and an increased incidence of skin
cancer were observed in populations consuming drinking water high in inorganic
arsenic.
___II.A.2. HUMAN CARCINOGENICITY DATA
Sufficient. Studies of smelter worker populations (Tacoma, WA; Magma, UT;
Anaconda, MT; Ronnskar, Sweden; Saganoseki-Machii, Japan) have all found an
association between occupational arsenic exposure and lung cancer mortality
(Enterline and Marsh, 1982; Lee-Feldstein, 1983; Axelson et al., 1978;
Tokudome and Kuratsune, 1976; Rencher et al., 1977). Both proportionate
mortality and cohort studies of pesticide manufacturing workers have shown an
excess of lung cancer deaths among exposed persons (Ott et al., 1974; Mabuchi
et al., 1979). One study of a population residing near a pesticide
manufacturing plant revealed that these residents were also at an excess risk
of lung cancer (Matanoski et al., 1981). Case reports of arsenical pesticide
applicators have also corroborated an association between arsenic exposure and
lung cancer (Roth, 1958).
A cross-sectional study of 40,000 Taiwanese exposed to arsenic in drinking
water found significant excess skin cancer prevalence by comparison to 7500
residents of Taiwan and Matsu who consumed relatively arsenic-free water
(Tseng et al., 1968; Tseng, 1977). Although this study demonstrated an
association between arsenic exposure and development of skin cancer, it has
several weaknesses and uncertainties, including poor nutritional status of the
exposed populations, their genetic susceptibility, and their exposure to
inorganic arsenic from non-water sources, that limit the study's usefulness in
risk estimation. Dietary inorganic arsenic was not considered nor was the
potential confounding by contaminants other than arsenic in drinking water.
There may have been bias of examiners in the original study since no skin
cancer or preneoplastic lesions were seen in 7500 controls; prevalence rates
rather than mortality rates are the endpoint; and furthermore there is concern
of the applicability of extrapolating data from Taiwanese to the U.S.
population because of different background rates of cancer, possibly
genetically determined, and differences in diet other than arsenic (e.g., low
protein and fat and high carbohydrate) (U.S. EPA, 1988).
A prevalence study of skin lesions was conducted in two towns in Mexico,
one with 296 persons exposed to drinking water with 0.4 mg/L arsenic and a
similar group with exposure at 0.005 mg/L. The more exposed group had an
increased incidence of palmar keratosis, skin hyperpigmentation and
hypopigmentation, and four skin cancers (histologically unconfirmed) (Cebrian
et al. (1983). The association between skin cancer and arsenic is weak
because of the small number of cases, small cohort size, and short duration
follow-up; also there was no unexposed group in either town. No excess skin
cancer incidence has been observed in U.S. residents consuming relatively high
levels of arsenic in drinking water but the numbers of exposed persons were
low (Morton et al., 1976; Southwick et al., 1981). Therapeutic use of
Fowler's solution (potassium arsenite) has also been associated with
development of skin cancer and hyperkeratosis (Sommers and McManus, 1953;
Fierz, 1965); several case reports implicate exposure to Fowler's solution in
skin cancer development (U.S. EPA, 1988).
Several follow-up studies of the Taiwanese population exposed to inorganic
arsenic in drinking water showed an increase in fatal internal organ cancers
as well as an increase in skin cancer. Chen et al. (1985) found that the
standard mortality ratios (SMR) and cumulative mortality rates for cancers of
the bladder, kidney, skin, lung and liver were significantly greater in the
Blackfoot disease endemic area of Taiwan when compared with the age adjusted
rates for the general population of Taiwan. Blackfoot disease (BFD, an
endemic peripheral artery disease) and these cancers were all associated with
high levels of arsenic in drinking water. In the endemic area, SMRs were
greater in villages that used only artesian well water (high in arsenic)
compared with villages that partially or completely used surface well water
(low in arsenic). However, dose-response data were not developed (Chen et al.
1985).
A retrospective case-control study showed a significant association
between duration of consuming high-arsenic well water and cancers of the
liver, lung and bladder (Chen et al., 1986). In this study, cancer deaths in
the Blackfoot disease endemic area between January 1980 and December 1982 were
chosen for the case group. About 90% of the 86 lung cancers and 95 bladder
cancers in the registry were histologically or cytologically confirmed and
over 70% of the liver cancers were confirmed by biopsy or à-fetoprotein
presence with a positive liver x-ray image. Only confirmed cancer cases were
included in the study. A control group of 400 persons living in the same area
was frequency-matched with cases by age and sex. Standardized questionnaires
of the cases (by proxy) and controls determined the history of artesian well
water use, socioeconomic variables, disease history, dietary habits, and
lifestyle. For the cancer cases, the age-sex adjusted odds ratios were
increased for bladder (3.90), lung (3.39), and liver (2.67) cancer for persons
who had used artesian well water for 40 or more years when compared with
controls who had never used artesian well water. Similarly, in a 15-year
study of a cohort of 789 patients of Blackfoot disease, an increased mortality
from cancers of the liver, lung, bladder and kidney was seen among BFD
patients when compared with the general population in the endemic area or when
compared with the general population of Taiwan. Multiple logistic regression
analysis to adjust for other risk factors including cigarette smoking did not
markedly affect the exposure-response relationships or odds ratios (Chen et
al., 1988).
A significant dose-response relationship was found between arsenic levels
in artesian well water in 42 villages in the southwestern Taiwan and age-
adjusted mortality rates from cancers at all sites, cancers of the bladder,
kidney, skin, lung, liver and prostate (Wu et al., 1989). An ecological study
of cancer mortality rates and arsenic levels in drinking water in 314
townships in Taiwan also corroborated the association between arsenic levels
and mortality from the internal cancers (Chen and Wang, 1990).
Chen et al.(1992) conducted a recent analysis of cancer mortality data
from the arsenic-exposed population to compare risk of various internal
cancers and compare risk between males and females. The study area and
population have been described by Wu et al. (1989). It is limited to 42
southwestern coastal villages where residents have used water high in arsenic
from deep artesian wells for more than 70 years. Arsenic levels in drinking
water ranged from 0.010 to 1.752 ppm. The study population had 898,806
person-years of observation and 202 liver cancer, 304 lung cancer, 202 bladder
cancer and 64 kidney cancer deaths. The study population was stratified into
four groups according to median arsenic level in well water ( < 0.10 ppm, 0.10-
0.29 ppm, 0.30-0.59 ppm and 60+ ppm), and also stratified into four age groups
( < 30 years, 30-49 years, 50-69 years and 70+ years). Mortality rates were
found to increase significantly with age for all cancers and significant dose-
response relationships were observed between arsenic level and mortality from
cancer of the liver, lung, bladder and kidney in most age groups of both males
and females. The data generated by Chen et al. (1992) provide evidence for an
association of the levels of arsenic in drinking water and duration of
exposure with the rate of mortality from cancers of the liver, lung, bladder,
and kidney. Dose-response relationships are clearly shown by the tabulated
data (Tables II-V of Chen et al., 1992). Previous studies summarized in U.S.
EPA (1988) showed a similar association in the same Taiwanese population with
the prevalence of skin cancers (which are often non-fatal). Bates et al.
(1992) and Smith et al. (1992) have recently reviewed and evaluated the
evidence for arsenic ingestion and internal cancers.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Inadequate. There has not been consistent demonstration of
carcinogenicity in test animals for various chemical forms of arsenic
administered by different routes to several species (IARC, 1980). Furst
(1983) has cited or reviewed animal carcinogenicity testing studies of nine
inorganic arsenic compounds in over nine strains of mice, five strains of
rats, in dogs, rabbits, swine and chickens. Testing was by the oral, dermal,
inhalation, and parenteral routes. All oxidation states of arsenic were
tested. No study demonstrated that inorganic arsenic was carcinogenic in
animals. Dimethylarsonic acid (DMA), the end metabolite predominant in humans
and animals, has been tested for carcinogenicity in two strains of mice and
was not found positive (Innes et al., 1969); however, this was a screening
study and no data were provided. The meaning of non-positive data for
carcinogenicity of inorganic arsenic is uncertain, the mechanism of action in
causing human cancer is not known, and rodents may not be a good model for
arsenic carcinogenicity testing. There are some data to indicate that arsenic
may produce animal lung tumors if retention time in the lung can be increased
(Pershagen et al., 1982, 1984).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
A retrospective cohort mortality study was conducted on 478 British
patients treated between 1945-1969 with Fowler's solution (potassium
arsenite). The mean duration of treatment was 8.9 months and the average
total oral consumption of arsenic was about 1890 mg (daily dose x duration).
In 1980, 139 deaths had occurred. No excess deaths from internal cancers were
seen after this 20-year follow-up. Three bladder cancer deaths were observed
(1.19 expected, SMR 2.5) (Cuzick et al., 1982). A recent follow-up (Cuzick et
al., 1992) indicated no increased mortality from all cancers but a significant
excess from bladder cancer (5 cases observed/1.6 expected; SMR of 3.07). A
subset of the original cohort (143 persons) had been examined by a
dermatologist in 1970 for signs of arsenicism (palmar keratosis). In 1990,
there were 80 deaths in the subcohort and 11 deaths from internal cancers.
All 11 subjects had skin signs (keratosis-10, hyperpigmentation-5 and skin
cancer-3). A case-control study of the prevalence of palmar keratoses in 69
bladder cancer patients, 66 lung cancer patients and 218 hospital controls
(Cuzick et al., 1984), indicated an association between skin keratosis (as an
indicator of arsenic exposure) and lung and bladder cancer. Above the age of
50, 87% of bladder cancer patients and 71% of lung cancer patients but only
36% of controls had one or more keratoses. Several case reports implicate
internal cancers with arsenic ingestion or specifically with use of Fowler's
solution but the associations are tentative (U.S. EPA, 1988).
Sodium arsenate has been shown to transform Syrian hamster embryo cells
(Dipaolo and Casto, 1979) and to produce sister chromatid-exchange in DON
cells, CHO cells, and human peripheral lymphocytes exposed in vitro (Wan et
al., 1982; Ohno et al., 1982; Larramendy et al., 1981; Andersen, 1983;
Crossen, 1983). Jacobson-Kram and Montalbano (1985) have reviewed the
mutagenicity of inorganic arsenic and concluded that inorganic arsenic is
inactive or very weak for induction of gene mutations in vitro but it is
clastogenic with trivalent arsenic being an order of magnitude more potent
than pentavalent arsenic.
Both the pentavalent and trivalent forms of inorganic arsenic are found in
drinking water. In both animals and humans, arsenate (As+5) is reduced to
arsenite (As+3) and the trivalent form is methylated to give the metabolites
mononomethylarsinic acid (MMA) and dimethylarsonic acid (DMA) (Vahter and
Marafante, 1988). The genotoxicity of arsenate (As+5) and arsenite (As+3) and
the two methylated metabolites, MMA and DMA were compared in the thymidine
kinase forward mutation assay in mouse lymphoma cells (Harrington-Brock et al.
1993; Moore et al., 1995, in press). Sodium arsenite (+3) and sodium arsenate
(+5) were mutagenic at concentration of 1-2 ug/mL and 10-14 ug/mL,
respectively, whereas MMA and DMA were significantly less potent, requiring
2.5-5 mg/mL and 10 mg/mL, respectively, to induce a genotoxic response. Based
on small colony size the mutations induced were judged chromosomal rather than
point mutations. The authors have previously shown that for chemicals having
clastogenic activity (i.e., cause chromosomal mutations), the mutated cells
grow more slowly than cells with single gene mutations and this results in
small colony size. In the mouse lymphoma assay, chromosomal abberations were
seen at approximately the same arsenic levels as TK forward mutations.
Arsenate, arsenite and MMA were considered clastogenic but the abberation
response with DMA was insufficient to consider it a clastogen. Since arsenic
exerts its genotoxicity by causing chromosomal mutations, it has been
suggested by the above authors that it may act in a latter stage of
carcinogenesis as a progressor, rather than as a classical initiator or
promotor (Moore et al., 1994). A finding which supports this process is that
arsenate (8-16 uM) and arsenite (3 uM) have been shown to induce 2-10 fold
amplification of the dihydrofolate reductase gene in culture in methotrexate
resistant 3T6 mouse cells (Lee et al., 1988). Although the mechanism of
induction in rodent cells is not known, gene amplification of oncogenes is
observed in many human tumors. Inorganic arsenic has not been shown to mutate
bacterial strains, it produces preferential killing of repair deficient
strains (Rossman, 1981). Sodium arsenite (As+3) induces DNA-strand breaks
which are associated with DNA-protein crosslinks in cultured human fibroblasts
at 3 mM but not 10 mM (Dong and Luo, 1993) and it appears that arsenite
inhibits the DNA repair process by inhibiting both excision and ligation (Jha
et al., 1992; Lee-Chen et al., 1993).
The inhibitory effect of arsenite on strand-break rejoining during DNA
repair was found to be reduced by adding glutathione to cell cultures (Huang
et al., 1993). The cytotoxic effects of sodium arsenite in Chinese hamster
ovary cells also has also found to correlate with the intracellular
glutathione levels (Lee et al., 1989).
In vivo studies in rodents have shown that oral exposure of rats to
arsenate (As+5) for 2-3 weeks resulted in major chromosomal abnormalities in
bone marrow (Datta et al., 1986) and exposure of mice to As (+3) in drinking
water for 4 weeks (250 mg As/L as arsenic trioxide) caused chromosomal
aberrations in bone marrow cells but not spermatogonia (Poma et al., 1987);
micronuclei in bone marrow cells were also induced by intraperitoneal dosing
of mice with arsenate (DeKnudt et al., 1986; Tinwell et al., 1991).
Chromosomal aberrations and sister chromatid exchange have been seen in
patients exposed to arsenic from treatment with Fowler's solution (Burgdorf et
al., 1977) and subjects exposed occupationally (Beckman et al., 1977) but no
increase in either endpoint was seen in lymphocytes of subjects exposed to
arsenic in drinking water (Vig et al., 1984).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 1.5E+0 per (mg/kg)/day
Drinking Water Unit Risk -- 5E-5 per (ug/L)
Extrapolation Method -- Time- and dose-related formulation of the multistage
model (U.S. EPA, 1988)
Drinking Water Concentrations at Specified Risk Levels:
| Risk Level | Concentration |
| ------------------------- | ---------------- |
| E-4 (1 in 10,000) | 2E+0 ug/L |
| E-5 (1 in 100,000) | 2E-1 ug/L |
|
E-6 (1 in 1,000,000) |
2E-2 ug/L |
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
The Risk Assessment Forum has completed a reassessment of the
carcinogenicity risk associated with ingestion of inorganic arsenic (U.S. EPA,
1988). The data provided in Tseng et al., 1968 and Tseng, 1977 on about
40,000 persons exposed to arsenic in drinking water and 7500 relatively
unexposed controls were used to develop dose-response data. The number of
persons at risk over three dose intervals and four exposure durations, for
males and females separately, were estimated from the reported prevalence
rates as percentages. It was assumed that the Taiwanese persons had a
constant exposure from birth, and that males consumed 3.5 L drinking water/day
and females consumed 2.0 L/day. Doses were converted to equivalent doses for
U.S. males and females based on differences in body weights and differences in
water consumption and it was assumed that skin cancer risk in the U.S.
population would be similar to the Taiwanese population. The multistage model
with time was used to predict dose-specific and age-specific skin cancer
prevalance rates associated with ingestion of inorganic arsenic; both linear
and quadratic model fitting of the data were conducted. The maximum
likelihood estimate (MLE) of skin cancer risk for a 70 kg person drinking 2 L
of water per day ranged from 1E-3 to 2E-3 for an arsenic intake of 1
ug/kg/day. Expressed as a single value, the cancer unit risk for drinking
water is 5E-5 per (ug/L). Details of the assessment are in U.S. EPA (1988).
Dose response data have not been developed for internal cancers for the
Taiwanese population. The data of Chen et al. (1992) are considered
inadequate at present.
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
Eastern Research Group, under contract to EPA, convened an Expert Panel on Arsenic Carcinogenicity on May 21 and 22, 1997 (Eastern Research Group, 1997). The Expert Panel believed that, "it is clear from epidemiological studies that arsenic is a human carcinogen via the oral and inhalation routes (p. 20)." They also concluded, "that one important mode of action is unlikely to be operative for arsenic". The panel agreed that arsenic and its metabolites do not appear to directly interact with DNA (pp. 30-31)." In addition, the panel agreed that, "for each of the modes of action regarded as plausible, the dose-response would either show a threshold or would be nonlinear (p. 31)". The panel agreed, however, "that the dose-response for arsenic at low doses would likely be truly nonlinear, i.e., with a decreasing slope as the dose decreased. However, at very low doses such a curve might be linear but with a very shallow slope, probably indistinguishable from a threshold (p. 31)."
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
This assessment is based on prevalence of skin cancer rather than
mortality because the types of skin cancer studied are not normally fatal.
However, competing mortality from Blackfoot disease in the endemic area of
Taiwan would cause the risk of skin cancer to be underestimated. Other
sources of inorganic arsenic, in particular those in food sources have not
been considered because of lack of reliable information. There is also
uncertainty on the amount of water consumed/day by Taiwanese males (3.5 L or
4.5 L) and the temporal variability of arsenic concentrations in specific
wells was not known. The concentrations of arsenic in the wells was measured
in the early 1960s and varied between 0.01 and 1.82 ppm. For many villages 2
to 5 analyses were conducted on well water and for other villages only one
analysis was performed; ranges of values were not provided. Since tap water
was supplied to many areas after 1966, the arsenic-containing wells were only
used in dry periods. Because of the study design, particular wells used by
those developing skin cancer could not be identified and arsenic intake could
not be assigned except by village. Several uncertainties in exposure
measurement reliability existed and subsequent analysis of drinking water
found fluorescent substances in water that are possible confounders or caused
synergistic effects. Uncertainties have been discussed in detail in U.S. EPA
(1988). Uncertainties in exposure measurement can affect the outcome of dose-
response estimation.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
___II.C.1. SUMMARY OF RISK ESTIMATES
Inhalation Unit Risk -- 4.3E-3 per (ug/cu.m)
Extrapolation Method -- absolute-risk linear model
Air Concentrations at Specified Risk Levels:
| Risk Level | Concentration |
| ------------------------ | ------------- |
| E-4 (1 in 10,000) | 2E-2 per (ug/cu.m) |
| E-5 (1 in 100,000) | 2E-3 per (ug/cu.m) |
| E-6 (1 in 1,000,000) | 2E-4 per (ug/cu.m) |
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Tumor Type -- lung cancer
Test Animals -- human, male
Route -- inhalation, occupational exposure
Reference -- Brown and Chu, 1983a,b,c; Lee-Feldstein, 1983; Higgins, 1982;
Enterline and Marsh, 1982
| Ambient Unit Risk Estimates (per µg/cu.m) |
Exposure
Source |
Study |
Unit Risk |
Geometric Mean
Unit Risk |
Final Estimated
Geometric Mean
Unit Risk |
Anaconda
smelter |
Brown and Chu
Lee-Feldstein
Higgins et al. |
1.25E-3
2.80E-3
4.90E-3 |
2.56E-3 |
4.29E-3 |
ASARCO
smelter |
Enterline & Marsh |
6.81E-3
7.60E-3 |
7.19E-3 |
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
A geometric mean was obtained for data sets obtained with distinct exposed
populations (U.S. EPA, 1984). The final estimate is the geometric mean of
those two values. It was assumed that the increase in age-specific mortality
rate of lung cancer was a function only of cumulative exposures.
The unit risk should not be used if the air concentration exceeds 2
ug/cu.m, since above this concentration the unit risk may not be appropriate.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
Overall a large study population was observed. Exposure assessments
included air measurements for the Anaconda smelter and both air measurements
and urinary arsenic for the ASARCO smelter. Observed lung cancer incidence
was significantly increased over expected values. The range of the estimates
derived from data from two different exposure areas was within a factor of 6.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
U.S. EPA. 1984, 1988, 1993
A draft of the 1984 Health Assessment Document for Inorganic Arsenic was
independently reviewed in public session by the Environmental Health Committee
of the U.S. EPA Science Advisory Board on September 22-23, 1983. A draft of
the 1988 Special Report on Ingested Inorganic Arsenic; Skin Cancer;
Nutritional Essentiality was externally peer reviewed at a two-day workshop of
scientific experts on December 2-3, 1986. A draft of the Drinking Water
Criteria Document for Arsenic was reviewed by the Drinking Water Committee of
the U.S. EPA Science Advisory Board on March 10, 1993. The comments from
these reviews were evaluated and considered in the revision and finalization
of these reports.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 01/13/1988, 12/07/1989, 02/03/1994
Verification Date -- 02/03/1994
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the IRIS Hotline for all questions concerning this
assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (FAX)
or Hotline.IRIS@epamail.epa.gov (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Arsenic, inorganic
CASRN -- 7440-38-2
Last Revised -- 04/10/1998
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None
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Vig, B.K., M.L. Figueroa, M.N. Cornforth, S.H. Jenkins. 1984. Chromosome
studies in human subjects chronically exposed to arsenic in drinking water.
Am. J. Ind. Med. 6(5): 325-338.
Wan, B., R.T. Christian and S.W. Soukup. 1982. Studies of cytogenetic
effects of sodium arsenicals on mammalian cells in vitro. Environ. Mutag. 4:
493-498.
Welch, K., I. Higgins, M. Oh and C. Burchfield. 1982. Arsenic exposure,
smoking, and respiratory cancer in copper smelter workers. Arch. Environ.
Health. 37(6): 325-335.
Wu, M-M., T-L. Kuo, Y-H Hwang and C-J. Chen. 1989. Dose-response relation
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vascular diseases. Am. J. Epidemiol. 130(6): 1123-1132.
_VII. REVISION HISTORY
Substance Name -- Arsenic, inorganic
CASRN -- 7440-38-2
| ----------- |
----------- |
--------------------------------------------------------
|
| Date |
Section |
Description |
| ----------- |
----------- |
--------------------------------------------------------
|
| 06/30/1988 |
II.B. |
Revised last paragraph |
| 06/30/1988 |
II.C.1. |
Inhalation slope factor changed |
| 06/30/1988 |
II.C.3. |
Paragraph 2 added |
| 09/07/1988 |
II.B. |
Major text changes |
| 12/01/1988 |
II.A.2. |
Mabuchi et al. citation year corrected |
| 12/01/1988 |
II.A.3. |
Pershagen et al. citation year corrected |
| 09/01/1989 |
II.C.2. |
Citations added to anacondor smelter |
| 09/01/1989 |
VI. |
Bibliography on-line |
| 06/01/1990 |
II.A.2. |
2nd & 3rd paragraph - Text revised |
| 06/01/1990 |
II.A.4. |
Text corrected |
| 06/01/1990 |
II.C.1. |
Inhalation slope factor removed (format change) |
| 06/01/1990 |
IV.F.1. |
EPA contact changed |
| 06/01/1990 |
VI.C. |
References added |
| 12/01/1990 |
II.B. |
Changed slope factor to "unit risk", 2nd para, 1st
sen |
| 02/01/1991 |
II.C.3. |
Text edited |
| 09/01/1991 |
I.A. |
Oral RfD summary now on-line |
| 09/01/1991 |
I.A. |
Oral RfD bibliography added |
| 10/01/1991 |
I.A.1. |
Conversion factor text clarified |
| 10/01/1991 |
IV.B.1. |
MCLG noted as pending change |
| 01/01/1992 |
IV. |
Regulatory actions updated |
| 08/01/1992 |
II. |
Note added to indicate text in oral quant. estimate
|
| 10/01/1992 |
VI.C. |
Missing reference added to bibliography |
| 02/01/1993 |
I.A.4. |
Citations added to second paragraph |
| 02/01/1993 |
VI.A. |
References added to bibliography |
| 03/01/1993 |
VI.A. |
Corrections to references |
| 03/01/1994 |
II.D.2. |
Work group review date added |
| 06/01/1994 |
II. |
Carcinogen assessment noted as pending change |
| 01/01/1995 |
II. |
Pending change note revised |
| 01/01/1995 |
II.B. |
Dates and document no. added to oral quant. estimate
|
| 06/01/1995 |
II. |
Carcinogenicity assessment replaced |
| 06/01/1995 |
VI.C. |
Carcinogenicity references replaced |
| 07/01/1995 |
II.D.1. |
Documentation year corrected; review statement revised
|
| 07/01/1995 |
VI.C. |
U.S. EPA, 1994 corrected to 1993 |
| 08/01/1995 |
II.D.2. |
EPA's RfD/RfC and CRAVE workgroups were discontinued
in May, 1995. Chemical substance reviews that were not completed
by September 1995 were taken out of IRIS review. The IRIS Pilot
Program replaced the workgroup functions beginning in September,
1995. |
| 04/01/1997 |
III.,IV.,V. |
Drinking Water Health Advisories, EPA Regulatory Actions,
and Supplementary Data were removed from IRIS on or before April
1997. IRIS users were directed to the appropriate EPA Program Offices
for this information. |
| 04/10/1998 |
II.B.3 |
Added discussion on expert panel workshop |
| 02/11/2000 |
II.C.2 |
Corrected alignment of unit risks in table with corresponding
studies |
_VIII. SYNONYMS
Substance Name -- Arsenic, inorganic
CASRN -- 7440-38-2
Last Revised -- 02/10/1988
7440-38-2
Arsenic
Arsenic, inorganic
gray-arsenic
Last updated: 12 June 2000
|
