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Reference Dose for Chronic Oral Exposure (RfD) 

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[UPDATE] The (cancer) portion of this assessment is currently under development and the latest draft 

can be found at, IRIS Toxicological Review of Inorganic Arsenic (Cancer)(External Review Draft)

0278 

Arsenic, inorganic; CASRN 7440-38-2 (04/10/1998)

Human health assessment information on a chemical substance is included in the IRIS database 

only after a comprehensive review of toxicity data, as outlined in the IRIS assessment 

development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II 

(Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached 

during the assessment development process. Supporting information and explanations of the 

methods used to derive the values given in IRIS are provided in the guidance documents located 

on the IRIS website. 

STATUS OF DATA FOR Arsenic, inorganic

File First On-Line 02/10/1988

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)

Integrated Risk Information System

http://www.epa.gov/iris/subst/0278.htm

Last updated on Thursday, August 09, 2012

http://www.epa.gov/iris/subst/0278.htm
Critical Effect Experimental Doses*

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

UF MF RfD

Hyperpigmentation,

keratosis and 

possible vascular

complications

Human Chronic

oral exposure

Tseng, 1977; 

Tseng et al., 1968

NOAEL: 0.009 mg/L

converted to 0.0008

mg/kg-day

LOAEL: 0.17 mg/L converted

to 0.014 mg/kg-day

3 1 3E-4

mg/kg-day

*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. 

http://www.epa.gov/iris/subst/0278.htm
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). 

http://www.epa.gov/iris/subst/0278.htm
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 middose 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. 

http://www.epa.gov/iris/subst/0278.htm
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 

http://www.epa.gov/iris/subst/0278.htm
(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

Database — 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 database 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 database 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 

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA 

contractor of the more recent toxicology literature pertinent to the RfD for Arsenic (inorganic) 

conducted in September 2002 identified one or more significant new studies. IRIS users may 

request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)

566-1676.

__I.A.7. EPA Contacts (Oral RfD)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, 

at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).

_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)

Substance Name — Arsenic, inorganic

CASRN — 7440-38-2

http://www.epa.gov/iris/subst/0278.htm
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 Human Carcinogenicity

__II.A.1. Weight-of-Evidence Characterization

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; LeeFeldstein, 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 

http://www.epa.gov/iris/subst/0278.htm
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, doseresponse 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 

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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 nonpositive 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 

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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 (keratosis10, 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). 

http://www.epa.gov/iris/subst/0278.htm
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 

http://www.epa.gov/iris/subst/0278.htm
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

http://www.epa.gov/iris/subst/0278.htm
Air Concentrations at Specified Risk Levels: 

Risk Level Concentration

E-4 (1 in 10,000) 2E-2 ug/cu.m

E-5 (1 in 100,000) 2E-3 ug/cu.m

E-6 (1 in 1,000,000) 2E-4 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 4.29E-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

http://www.epa.gov/iris/subst/0278.htm
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. EPA Review (Carcinogenicity Assessment)

Agency Work Group Review — 01/13/1988, 12/07/1989, 02/03/1994

Verification Date — 02/03/1994

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA 

contractor of the more recent toxicology literature pertinent to the cancer assessment for Arsenic 

(inorganic) conducted in September 2002 identified one or more significant new studies. IRIS 

users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov 

or (202)566-1676.

__II.D.3. EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, 

at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).

_III. [reserved]

_IV. [reserved] 

_V. [reserved]

_VI. Bibliography 

Substance Name — Arsenic, inorganic

CASRN — 7440-38-2

Last Revised — 04/10/1998

_VI.A. Oral RfD References

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EPA. Report on Arsenic (As) Work Group Meetings. February 23. 

Cebrian, M.E., A. Albores, M. Aguilar and E. Blakely. 1983. Chronic arsenic poisoning in the north 

of Mexico. Human Toxicol. 2: 121-133.

Ferm, V.H. and S.J. Carpenter. 1968. Malformations induced by sodium arsenate. J. Reprod. Fert. 

17: 199-201.

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Hindmarsh, J.T., O.R. McLetchie, L.P.M. Heffernan et al. 1977. Electromyographic abnormalities in 

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Hood, R.D., G.T. Thacker and B.L. Patterson. 1977. Effects in the mouse and rat of prenatal 

exposure to arsenic. Environ. Health Perspect. 19: 219-222. 

Lu, F.J. 1990. Blackfoot disease: Arsenic or humic acid? The Lancet. 336: 115-116. 

Marcus, W.L. and A.S. Rispin. 1988. Threshold carcinogenicity using arsenic as an example. In: 

Advances in Modern Environmental Toxicology, Vol. XV. Risk Assessment and Risk Management 

of Industrial and Evironmental Chemicals, C.R. Cothern, M.A. Mehlman and W.L. Marcus, Ed. 

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Nadeenko, V.G., V. Lenchenko, S.B. Genkina and T.A. Arkhipenko. 1978. The influence of 

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Southwick, J.W., A.E. Western, M.M. Beck, et al. 1983. An epidemiological study of arsenic in 

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Perspectives, W.H. Lederer and R.J. Fensterheim, Ed. Van Nostrand Reinhold Co., New York. p. 

210-225. 

Tseng, W.P. 1977. Effects and dose-response relationships of skin cancer and blackfoot disease 

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Tseng, W.P., H.M. Chu, S.W. How, J.M. Fong, C.S. Lin and S. Yeh. 1968. Prevalence of skin 

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463. 

Valentine, J.L., L.S. Reisbord, H.K. Kang and M.D Schluchter. 1987. Arsenic effects on population 

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Water, Washington, DC. (Draft)

_VI.B. Inhalation RfD References

None

http://www.epa.gov/iris/subst/0278.htm
_VI.C. Carcinogenicity Assessment References

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cancer in an endemic area of chronic arsenicism in Taiwan. J. Natl. Cancer Inst. 40(3): 453-463. 

Tseng W.P. 1977. Effects and dose-response relationships of skin cancer and Blackfoot disease 

with arsenic. Environ. Health Perspect. 19: 109-119. 

U.S. EPA. 1984. Health Assessment Document for Inorganic Arsenic. Prepared by the Office of 

Research and Development, Environmental Criteria and Assessment Office, Reasearch Triangle 

Park, NC. 

U.S. EPA. 1988. Special Report on Ingested Inorganic Arsenic; Skin Cancer; Nutritional 

Essentiality Risk Assessment Forum. July 1988. EPA/625/3-87/013.

U.S. EPA. 1993. Drinking Water Criteria Document for Arsenic. Office of Water, Washington, DC. 

Draft. 

http://www.epa.gov/iris/subst/0278.htm
Date Section Description

Vahter, M. and E. Marafante. 1988. In vivo methylation and detoxification of arsenic. Royal Soc. 

Chem. 66: 105-119. 

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 between arsenic 

concentration in well water and mortality from cancers and vascular diseases. Am. J. Epidemiol. 

130(6): 1123-1132. 

_VII. Revision History

Substance Name — Arsenic, inorganic

CASRN — 7440-38-2

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 and 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

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IRIS Home

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

12/03/2002 I.A.6., 

II.D.2.

Screening-Level Literature Review Findings message has been added.

02/05/2003 I., II. This chemical is being reassessed under the IRIS Program.

_VIII. Synonyms

Substance Name — Arsenic, inorganic

CASRN — 7440-38-2

Last Revised — 02/10/1988

• 7440-38-2 

• Arsenic 

• Arsenic, inorganic 

• gray-arsenic

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