List of IRIS Substances Search IRIS by Keyword

IRIS Summaries/Toxicological Reviews Entire IRIS Website

Category (section) Status Last Revised You are here: EPA Home Research Environmental Assessment IRIS IRIS Summaries

view QuickView

Reference Dose for Chronic Oral Exposure( RfD ) 

## 

You will need Adobe Reader to view some of the files on this page. See EPA's PDF page to learn more.

[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. Supp orting information and explanations of the methods used to derive the values given in IRISare 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 Assessmen t (II.) on-line 04/10/1998 

### _I. Chronic Health Hazard Assess ments 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.htmCritical 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 a ssumption that thresholdsexist 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. Plea se refer to the Background Document for an elaboration of these concepts. RfDs can also be derived for the noncarcino genic 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 Agencyscientists on the oral RfD. Applying the Agency's RfD methodology, strong scientific argu ments 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, bydefinition, yields a number with inherent uncertainty spanning perhaps an order of magn itude. 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 flexib ility afforded them in formulating regulatory decisions when uncert ainty and lack of clear consen sus 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 assu mptions 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 rela tionships of skin cancer and blackfoot disease with arsenic. Environ. He alth Perspect. 19: 109-119. 

### http://www.epa.gov/iris/subst/0278.htmTseng, W.P., H.M. Chu, S.W. Ho w, J.M. Fong, C.S. Lin and S. Yeh. 1968. Prevalence of skin cancer in an endemic area of chronic arsenici sm in Taiwan. J. Natl. Cancer Inst. 40: 453-463. The data reported in Tseng ( 1977) show an increased incidenc e of blackfoot disease that increases with age and dose. Blac kfoot disease is a significant adverse effect. The prevalences (males and females combined) at the low doseare 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 strictlydue to arsenic exposure (Lu, 1990). The data in Tseng et al. (1968) also show increased incidencesof hyperpigmentation an d keratosis with age. The overall prevalences of hyperpigmentation an d keratosis in the exposed groups are 184 and 71 per 1000, respectively. The text states that the incidence increa ses with dose, but data for the individual doses are not shown. These data show that the s kin lesions are the more sensitive endpoint. The low dose in the Tseng (1977) study isconsidered a LOAEL. The control group described in Tseng et al. (1968; Table 3) shows no eviden ce 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) (Abernat hy et al., 1989). The ar ithmetic mean of the arsenic concentration in the well s used by the individuals in th e 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 cont ained 2552 individuals, only 957 (approximately 38%) were older than 20, and only 431 (approximate ly 17%) were older than 40. Th e 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 stud y is less powerful than it appears at first glance. However, it is certainly the most powe rful 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 th e participants (we therefore assume 55 kg). The paper states that exposure time s are directly related to chronolo gical 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 istherefore designated a LOAEL. There is some question whether the low dose is a NOAEL or a LO AEL 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.htmThe Southwick et al. (1983) study shows a marginally increased in cidence of a variety of skin lesions (palmar and plantar kera tosis, diffuse palmar or pl antar hyperkeratosis, diffuse pigmentation, and arterial insuffic iency) in the individu als exposed to arsenic. The incidences are 2.9% (3/105) in the control grou p and 6.3% (9/144) in the expose d 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 indivi duals older than 47 from the ne rve conduction portion of the study. These are the individuals most likely to have the longest exposure to arsenic. Although neither the increased in cidence of skin lesi ons 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 numb er of subjects in this study was insufficient to establish statistical significance. Table 3 (Southwick et al., 1983) sh ows 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, an d dose groups are ranges of exposure. Exposure estimates (water onl y) are: dosed group - 152.4 mg/yea r 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 expo sed 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 descri bed below. The control dose is comparable to the dose to the control group in the Tseng et al. (1968) and Hi ndmarsh 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 increase d incidence of abnormal clin ical findings and abnormal electromyographic findingswith 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 th e arsenic concentration in the high-dose and middose wells is 680 and 70 ug/L, respectively. Figu re 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 wate r consumption of 2 litersand 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 noway of knowing if the low dose is a no-effect level or another marginal effect level for abnorm al clinical findings. The low dose is comparable to the dose received by the control group in the Tseng (1977) and Southw ick et al. (1983) studies. 

### http://www.epa.gov/iris/subst/0278.htmThe 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 knowin g whether the low doses in the Cebrian et al. (1983), Southwick et al. (1983) and Hindmarsh et al. (1977) studie s are NOAELs for skin lesions and/or abnormal nerve conduction. However, beca use the next higher dose in the Southwick and Hindmarsh studies only shows marg inal effects at doses 3-7 times higher, the Agency feels comfortable in assigning the low do ses in these studies as NOAELs. The Tseng (1977) and Tseng et al. (1968) studie s 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 co ntrol 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 (equivoc al effects at 2E-3) __I.A.3. Uncertainty and Mo difying 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 Stud ies/Comments (Oral RfD) Ferm and Carpenter (1968) produced malformati ons in 15-day hamster fe tuses via intravenous injections of sodium arsenate into pregnant damson day 8 of gestation at dose levels of 15, 17.5, or 20 mg/kg bw. Ex encephaly, encephaloceles, skeletal defects and genitourinary systems defects were produced. These and other terata we re 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). Na deenko et al. (1978) repo rted 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 ef fects and only infrequent slight expansion of ventricles of the cerebrum, renal pelves and urin ary bladder. Hood et al. (1977) reported that very high single oral doses of arsenate solution s (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, enzy mic and long-term information is known about arsenic and its metabolism. Valent ine et al. (1987) established that huma n blood arsenic levels did not increase until daily wa ter ingestion of arsenic exce eded approximately 250 ug/day 

### http://www.epa.gov/iris/subst/0278.htm(approximately 120 ug of arsenic/ L. Methylated specie s of arsenic are succe ssively 1 order of magnitude less toxic and less te ratogenic (Marcus and Rispin, 1988). Some evid ence suggests that inorganic arsenic is an esse ntial nutrient in goat s, 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 me dium. An extremely large number of people were included in the assessment ( > 40,000) but the doses were not well-cha racterized and other contaminants were present. The supporting human toxicity databa se is extensive but somewhat flawed. Problems exist with all of the epidemiolo gical studies. For exampl e, the Tseng studies do not look at potential exposure from food or othe r source. A similar criticism can be made of the Cebrian et al. (1983) study. The U.S. studies are too small in nu mber to resolve several issues. However, the database does support the choice of NOAEL. It garners medi um 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 Counci l on 11/15/1990. This assessment was discussed by the Risk Assessme nt 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 literat ure pertinent to the RfD for Arsenic (inorganic) conducted in September 2002 identified one or more significant new st udies. IRIS users may request the references for those studies from th e IRIS Hotline at hotlin e.iris@epa.gov or (202) 566-1676. __I.A.7. EPA Contacts (Oral RfD) Please contact the IRIS Hotline for all questions co ncerning 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.htmNot available at this time.



### _II. Carcinogenicity Asse ssment 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 extrap olation procedure and is presente d as the risk per (mg/kg)/day. The unit risk is the quantitative estimate in terms of either risk per ug/L dr inking water or risk per ug/cu.m air breathed. The third form in which ri sk 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 (E PA/600/8-87/045) and in the IRISBackground Document. IRIS summaries developed since the pu blication 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-Evid ence Characterization Classification — A; human carcinogen

Basis — based on sufficient evidence from huma n data. An increased lung cancer mortality was observed in multiple human populations expose d primarily through inhalation. Also, increased mortality from multiple internal organ cancers (l iver, kidney, lung, and bladder) and an increased incidence of skin cancer were observed in popula tions consuming drinking water high in inorganic arsenic. __II.A.2. Human Carcinogenicity Data Sufficient. Studies of smelter worker popula tions (Tacoma, WA; Magma, UT; Anaconda, MT; Ronnskar, Sweden; Saganoseki-M achii, Japan) have all fo und an association between occupational arsenic exposureand lung cancer mortality (Enterline and Marsh, 1982; LeeFeldstein, 1983; Ax elson et al., 1978; Tokudo me 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 residi ng near a pesticide manufactur ing plant revealed that these residents were also at an excessrisk of lung cancer (Matanos ki et al., 1981). Case reports of arsenical pesticide applicators have also corrobo rated an association be tween arsenic exposure and lung cancer (Roth, 1958). A cross-sectional study of 40,000 Taiwanese ex posed to arsenic in drinking water found significant excess skin cancer prevalence by comparison to 7500residents of Ta iwan and Matsu who consumed relatively arsenic- free water (Tseng et al., 1968; Tseng, 1977). Although this 

### http://www.epa.gov/iris/subst/0278.htmstudy demonstrated an associatio n between arsenic expo sure and development of skin cancer, it has several weaknesses and uncertainties, incl uding poor nutritional status of the exposed populations, their geneti c 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 potentia l 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. populati on because of different background rates of cancer, possibly genetically determined, an d differences in diet ot her than arsenic (e.g., low protein and fat and high carbohydrate) (U.S. EPA, 1988). A prevalence study of sk in lesions was conducted in two town s in Mexico, one with 296 persons exposed to drinking wa ter with 0.4 mg/L arse nic and a similar group with exposure at 0.005 mg/L. The more exposed group had an increa sed incidence of palmar keratosis, skin hyperpigmentation and hypopigmen tation, and four skin cancers (histologically unconfirmed) (Cebrian et al. (1983). The associ ation 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 incidenc e has been observed in U.S. residents consuming relatively high levels of arsenic in drinking water but the numbers of exposed persons were low (Morto n et al., 1976; Southwick et al ., 1981). Therapeutic use of Fowler's solution (potassium arse nite) has also been associated wi th 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. Bl ackfoot 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 arte sian well water (high in arsenic) compared with villages that partially or completely used surface well water (low in arsenic). However, doseresponse data were not de veloped (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 bladde r (Chen et al., 1986). In this study, cancer deathsin the Blackfoot disease ende mic area between January 1980 and December 1982 were chosen for the case grou p. About 90% of the 86 lung cancers and 95 bladder cancers in the registry we re histologically or cytologicall y 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 controlsdetermined the history of artesian well water use, socioeconomic variables, dise ase history, dietary ha bits, and lifestyle. Fo r 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 popula tion of Taiwan. Multiple logistic regression 

### http://www.epa.gov/iris/subst/0278.htmanalysis 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 mort ality 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 morta lity rates and arsenic levels in drinking water in 314 townships in Taiwan also corroborated the asso ciation between arsenic levels an d mortality from the internal cancers (Chen and Wang, 1990). Chen et al.(1992) cond ucted a recent analysis of cancer mo rtality data from the arsenic-exposed population to compare risk of various intern al 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 drinki ng 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 a ccording 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 in crease 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 arse nic in drinking water and duration of exposure with the rate of mortality from cancers of the liver, lung, bladde r, and kidney. Dose-res ponse relationships are clearly shown by the tabulated data (Tables II-V of Chen et al., 1992). Previous studies summarized in U.S. EPA (1988) sh owed a similar association in the same Taiwanese population with the prevalence of skin canc ers (which are often non-fatal). Bates et al. (1992) and Smith et al. (1992) have recently reviewed and evaluated th e evidence for arsenic ingestion and internal cancers. __II.A.3. Animal Carcinogenicity Data Inadequate. There has not been consistent demons tration of carcinogenicity in test animals for various chemical forms of arseni c administered by different routes to several species (IARC, 1980). Furst (1983) has cited or revi ewed animal carcinogenicity test ing studies of nine inorganic arsenic compounds in over nine st rains 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 st udy demonstrated that inorgani c arsenic was carcinogenic in animals. Dimethylarsonic acid (DMA), the end metabolite predominant in humans and animals, has been tested for carcinogenicity in two strain s of mice and was not found positive (Innes et al., 1969); however, this was a sc reening study and no data wereprovided. The meaning of nonpositive data for carcinogenicity of inorganic arsenic is uncertain, the mechanism of action in causing human cancer is not known, and ro dents 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 beincreased (Pershagen et al., 1982, 1984). __II.A.4. Supporting Data for Carcinogenicity A retrospective cohort mortality study was conducted on 478 Brit ish patients treated between 1945-1969 with Fowler's solution (p otassium arsenite). The mean duration of treatment was 8.9 months and the average total oral consumptio n of arsenic was about 1890 mg (daily dose x 

### http://www.epa.gov/iris/subst/0278.htmduration). In 1980, 139 deaths had occurred. No excess deaths from internal cancers were seen after this 20-year follow-up. Three bladder canc er deaths were observed (1.19 expected, SMR 2.5) (Cuzick et al., 1982). A re cent follow-up (Cuzick et al., 1992) indicated no increased mortality from all cancers but a significant exce ss from bladder cancer (5 cases observed/1.6 expected; SMR of 3.07). A subsetof the original cohort (143 pe rsons) had been examined by a dermatologist in 1970 for signs of arsenicism (p almar keratosis). In 1990, there were 80 deaths in the subcohort and 11 deaths from internal cancers. All 11 subj ects had skin signs (keratosis10, hyperpigmentation-5 and skin cancer-3). A ca se-control study of the prevalence of palmar keratoses in 69 bladder cancer patients, 66 lung ca ncer 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 ca ncer. 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 in gestion or specifically with use of Fowler's solution but the associations are tentative (U.S. EPA, 1988). Sodium arsenate has been shown to transform Sy rian 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 Montalba no (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 th an pentavalent arsenic. Both the pentavalent and trivalent forms of inorgani c 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 mononometh ylarsinic 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 DM A 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/m L and 10 mg/mL, respectively, to induce a genotoxic response. Based on sm all colony size the mutations induced were judged chromosomal rather than point mutations. The authors havepreviously shown that for chemicals having clastogenic activity (i.e., cause chromosomal muta tions), the mutated cell s grow more slowly than cells with single gene mutations and this results in small colony size. In the mouse lymphoma assay, chromosomal abberations were se en at approximately th e 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 clas togen. Since arsenic exerts its genotoxicity by causing chromoso mal 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 meth otrexate 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 arse nic has not been shown to mutate bacterial strains, it produces preferenti al 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 excisi on and ligation (Jha et al., 1992; Lee-Chen et al., 1993). 

### http://www.epa.gov/iris/subst/0278.htmThe inhibitory effect of arsenite on strand-bre ak rejoining during DNA repair was found to be reduced by adding glutathione tocell cultures (Huang et al., 1993). The cytotoxic effects of sodium arsenite in Chinese hamster ovary cell s 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 abnormalitie s 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 marro w cells but not spermatogonia (Poma et al., 1987); micronuclei in bone marrow cells were also in duced by intraperitoneal dosing of mice with arsenate (DeKnudt et al., 1986; Tinwell et al., 1991). Chromo somal 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 ex posed occupationally (Bec kman et al., 1977) but no increase in either endpoint was seen in lympho cytes of subjectsexposed to arsenic in drinking water (Vig et al., 1984).

_II.B. Quantitative Estimate of Carcin ogenic 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 (C arcinogenicity, Oral Exposure) The Risk Assessment Forum has completed a reasse ssment 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 wate r 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 du rations, for males and fe males 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 co nsumed 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 an d 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.htmskin cancer prevalance rates associated with in gestion of inorganic arse nic; 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 th e assessment are in U.S. EPA (1988). Dose response data have not been developed fo r internal cancers for the Taiwanese population. The data of Chen et al. (1992) are considered inadequate at present. __II.B.3. Additional Comments (C arcinogenicity, Oral Exposure) Eastern Research Group, under contract to EPA, convened an Expert Panel on Arsenic Carcinogenicity on May 21 and 22, 1997 (Easte rn 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 co ncluded, "that one import ant 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 ad dition, 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, ho wever, "that the dose-response for arsenic at low doses would likely be truly no nlinear, 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 prev alence of skin cancer rather th an mortality because the types of skin cancer studied are not normally fatal. Howe ver, competing mortality from Blackfoot disease in the endemic area of Taiwan would cause the ri sk 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. Seve ral uncertainties in exposure me asurement reliability existed and subsequent analysis of drinking water found fl uorescent substances in water that are possible confounders or caused synergistic effects. Uncertainties have been discussed in detail in U.S. EPA (1988). Uncertainties in exposu re measurement can affect the outcome of dose- response estimation.

_II.C. Quantitative Estimate of Carcinog enic 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.htmAir 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, o ccupational exposure Reference — Brown and Chu, 1983a,b,c; Lee-Feld stein, 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 Comm ents (Carcinogenicity, Inhalation Exposure) A geometric mean was obtained for data sets ob tained with distinct exposed populations (U.S. EPA, 1984). The final estimate is the geometric mean of those tw o 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 co ncentration exceeds 2 ug/c u.m, since above this concentration the unit risk may not be appropriate. __II.C.4. Discussion of Confidence (Carcinogenicity, In halation Exposure) Overall a large study population was observed. Ex posure assessments included air measurements for the Anaconda smelter and both air meas urements and urinary arsenic for the ASARCO smelter. Observed lung cancer incidence was si gnificantly 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 (C arcinogenicity Assessment) __II.D.1. EPA Documentation U.S. EPA. 1984, 1988, 1993 

### http://www.epa.gov/iris/subst/0278.htmA draft of the 1984 Health Asse ssment Document for Inorgani c Arsenic was independently reviewed in public session by the Environment al 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 Drin king 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 to xicology literature pertinent to th e cancer assessment for Arsenic (inorganic) conducted in Septembe r 2002 identified one or more significant new studies. IRIS users may request the refe rences 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 co ncerning 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 Abernathy, C.O., W. Marcus, C. Chen, H. Gibb and P. White. 1989. Officeof Drinking Water, Office of Research and Development, U.S. EPA. Memorandum to P. Cook, Office of Drinking Water, U.S. EPA and P. Preuss, Office of Regulatory Support an d Scientific Management, U.S. EPA. Report on Arsenic (As) Wo rk Group Meetings . February 23. Cebrian, M.E., A. Albores, M. Ag uilar and E. Blakely. 1983. Chroni c arsenic poisoning in the north of Mexico. Human Toxicol. 2: 121-133. Ferm, V.H. and S.J. Carpenter. 1968. Malformations induced by so dium arsenate. J. Reprod. Fert. 17: 199-201. 

### http://www.epa.gov/iris/subst/0278.htmHindmarsh, J.T., O.R. McLetchie, L.P.M. Heffernan et al. 1977. Electromyographic abnormalities in chronic environmental arsenicalism. J. Analyt . Toxicol. 1: 270-276. 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: Arseni c 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, Vo l. XV. Risk Assessmentand Risk Management of Industrial and Evironmental Chemicals, C.R. Cothern, M.A. Mehlman and W.L. Marcus, Ed. Princeton Scientific Publishing Co mpany, Princeton, NJ. p. 133-158. Nadeenko, V.G., V. Lenc henko, S.B. Genkina and T.A. Ar khipenko. 1978. Th e influence of tungsten, molibdenum, copper and arsenic on the intrauterine development of the fetus. TR-79- 0353. Farmakologiya i Toksikologiya. 41: 620-623. NRC (National Research Council). 1989. Recommend ed Dietary Allowances, 10th ed. Report of the Food and Nutrition Board, National Academy of Sciences, Washington, National Academy Press, Washington, DC. 285 p. Schroeder, H.A. and M. Mitchner . 1971. Toxic effects of trace elem ents on the reproduction of mice and rats. Arch. Envi ron. Health. 23(2): 102-106. Southwick, J.W., A.E. Western, M.M. Beck, et al . 1983. An epidemiological study of arsenic in drinking water in Millard County, Utah. In: Arsenic: Industrial, Biom edical, Environmental 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 rela tionships of skin cancer and blackfoot disease with arsenic. Environ. Health Perspect. 19: 109-119. Tseng, W.P., H.M. Chu, S.W. Ho w, J.M. Fong, C.S. Lin and S. Yeh. 1968. Prevalence of skin cancer in an endemic area of chronic arsenici sm in Taiwan. J. Natl. Can0cer. Inst. 40(3): 453- 463. Valentine, J.L., L.S. Reisbord, H.K. Kang and M.D Schluchter. 1987. Arsenic effects on population health histories. In: Trace Elemen ts in Man and Animals - TEMA 5, C.F. Mills, I. Bremner and J.K. Chesters, eds. Commonwealth Agricult ural Bureaux, Aberdeen, Scotland.

U.S. EPA. 1984. Health As sessment Document for Inorganic Arse nic. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA 600/8-83-021F. U.S. EPA. 1988. Quantitative Toxi cological Evaluation of Ingested Arsenic. Office of Drinking Water, Washington, DC. (Draft)

_VI.B. Inhalation RfD References

None 

### http://www.epa.gov/iris/subst/0278.htm_VI.C. Carcinogenicity Assessment Reference s Axelson, O., E. Dahlgren, C.D. Jansson an d S.O. Rehnlund. 1978. Arsenic exposure and mortality: A case referent study from a Swedis h copper smelter. Br. J. Ind. Med. 35: 8-15. Andersen, O. 1983. Effects of coal combustion products an d metal compounds on sister chromatid exchange (SCE) in a macrophage like cell line. Environ. Health Pers pect. 47: 239-253. Bates, M.N., A.H. Smith and C. Hopenhayn-Rich. 1992. Arsenic ingestion and in ternal cancers: A review. Am. J. Epidemiol. 135(5): 462-476. Beckman, G., L. Beckman and I. Nordenson. 1977. Chromosome aberrations in workers exposed to arsenic. Environ. Heal th Perspect. 19: 145-146. Brown, C.C. and K.C. Chu. 1983a. Approaches to epidemiologic analysis of prospective and retrospective studies: Example of lung cancer an d exposure to arsenic. In: Risk Assessment Proc. SIMS Conf. on Environ. Epidemiol. June 28-Ju ly 2, 1982, Alta, VT. SIAM Publications. Brown, C.C. and K.C. Chu. 1983b. Implications of the multistage th eory of carcinogenesis applied to occupational arsenic exposure. J. Natl. Cancer Inst. 70(3): 455-463. Brown, C.C. and K.C. Chu. 1983c. A new method for the analysis of cohort studies: Implications of the multistage theory of carcinogenesis appl ed to occupational arse nic exposure. Environ. Health Perspect. 50: 293-308. Burgdorf, W., K. Kurvink and J. Cervenka. 1977. Elevated sister chromatid exchange rate in lymphocytes of subjects treated with arsenic. Hum. Genet. 36(1): 69-72. Cebrian, M.E., A. Albores, M. Aq uilar and E. Blakely. 1983. Chroni c arsenic poisoning in the north of Mexico. Human To xicol. 2: 121-133. Chen, C-J. and C-J. Wang. 1990. Ec ological correlation between arsenic level in well water and age-adjusted mortality from malignant neoplasms. Cancer Res. 50(17): 5470-5474. Chen, C-J., Y-C. Chuang, T-M. Lin and H-Y. Wu. 1985. Malignant neoplasms among residents of a Blackfoot disease-endemic area in Taiwan: High-a rsenic artesian well wate r and cancers. Cancer Res. 45: 5895-5899. Chen, C-J., Y-C. Chuang, S-L. You, T-M. Li n and H-Y. Wu. 1986. A retrospective study on malignant neoplasms of bladder, lung, and liver in blackfoot disease endemic area in Taiwan. Br. J. Cancer. 53: 399-405. Chen, C-J., M-M. Wu, S-S. Lee, J-D. Wang, S-H. Cheng and H- Y. Wu. 1988. Atherogenicity and carcinogenicity of high-arsenic artesian well wate r. Multiple risk factors and related malignant neoplasms of Blackfoot disease. Arteriosclerosis. 8(5): 452-460. Chen, C-J., CW. Chen, M-M. Wu an d T-L. Kuo. 1992. Cancer potent ial in liver, lung bladder and kidney due to ingested inorganic arsenic in drinking water. Br. J. Cancer. 66(5): 888-892. Crossen, P.E. 1983. Arsenic and SCE in huma n lymphocytes. Mutat. Res. 119: 415-419. 

### http://www.epa.gov/iris/subst/0278.htmCuzick, J., S. Evans, M. Gill man and D.A. Price Evans. 1982. Medicinal arsenic and internal malignancies. Br. J. Cancer. 45(6): 904-911. Cuzick, J., R. Harris, P.S. Mortimer. 1984. Palmar keratoses and cancers of the bladder and lung. March 10. The Lancet. 1(8376): 530-533. Cuzick, J., P. Sasieni and S. Evan s. 1992. Ingested arsenic, kerato ses, and bladder cancer. Am. J. Epidemiol. 136(4): 417-421. Datta, S., G. Talukder and A. Sharma. 1986. Cyto toxic effects of arsenic in dietary oil primed rats. Sci. Culture. 52: 196-198. DeKnudt, G., A. Leonard, A. Aran y, G.D. Buisson and E. Delavignette. 1986. In vivo studies in male mice on the mutagenic effects of in organic arsenic. Muta genesis. 1(1): 33-34. DiPaolo, J.A. and B.C. Casto. 1979. Qantitative studies of in vitro morphological transformation of Syrian hamster cells by inorganic metal salts. Cancer Res. 39: 1008-1013. Dong, J-T., X-M. Luo. 1993. Arsenic-induced DNA-stra nd breaks associated with DNA-protein crosslinks in human fetal lung fibroblasts. Mutat. Re s. 302(2): 97-102. Eastern Research Group. 1997. Repo rt on the expert panel on arse nic carcinogenicity: review and workshop. Prepared by Eastern Research Group, Lexington, MA, for the National Center for Environmental Assessment, Washington, DC, under EPA contract no. 68-C6-0041. Enterline, P.E. and G.M. Mars h. 1982. Cancer among workers exposed to arsenic and other substances in a copper smelter. Am. J. Epidemiol. 116(6): 895-911. Fierz, U. 1965. Catamnestic investigations of the side effects of therapy of skin diseases with inorganic arsenic. Dermatologica. 131: 41-58. Furst, A. 1983. A new look at arsenic carcinogenesis. In: Arseni c: Industrial, Biomedical, and Environmental Perspectives, W. Lederer and R. Fensterheim, Ed . Van Nostrand Reinhold, New York. p. 151-163. Harrington-Brock, K., T.W. Smith, C.L. Doerr, and M.M. Moore. 1993. Mutagenicity of the human carcinogen arsenic and its methylated metabolite s monomethylarsonic and dimethylarsenic acids in L5178Y TK+/- mouse lymphoma cells (abstract) . Environ. Mol. Mutage n. 21(Supplement 22): 27. Higgins, I. 1982. Arsenic and respiratory cancer among a sample of Anac onda smelter workers. Report submitted to the Occupatinal Safety and Health Admi nistration in the comments of the Kennecott Minerals Company on the inorga nic arsenic rulemaki ng. (Exhibit 203-5) Higgins, I., K. Welch and C. Burchfield. 1982. Mortality of Anacon da smelter workers in relation to arsenic and other exposures. University of Michigan, Dept. Epidemiology, Ann Arbor, MI. Huang, H., C.F. Huang, D.R. Wu, C.M. Jinn and K.Y. Jan. 1993. Gl utathione as a cellular defence against arsenite toxicity in cultured Chinese hamster ovary cells. Toxicology. 79(3): 195-204. 

### http://www.epa.gov/iris/subst/0278.htmIARC (International Agency for Research on Cancer). 1980. IARCMonographs on the Evaluation of Carcinogenic Risk of Chemicals to Man, Vol. 23. Some metals and metallic compounds. World Health Organization, Lyon, France. Innes, J.R.M., B.M. Ulland, M.G. Valerio, et al. 1969. Bioassay of pesticides and industrial chemicals for tumorigenici ty in mice: A preliminary note. JNCI. 42: 1101-1114. Jacobson-Kram, D. and D. Montal bano. 1985. The reproductive effe cts assessment group's report on the mutagenicity of inorganic arse nic. Environ. Mutagen. 7(5): 787-804. Jha, A.N., M. Noditi, R. Nilsson and A.T. Natarajan. 1992. Genoto xic effects of sodi um arsenite on human cells. Mutat. Res. 284(2): 215-221. Larramendy, M.L., N.C. Popescu and J.A. DiPaolo. 1981. Inductio n by inorganic metal salts of sister chromatid exchanges and chromosome aber rations in human and Sy rian hamster strains. Environ. Mutage n. 3: 597-606. Lee, Te-Chang, J. Ko and K.Y. Ja n. 1989. Differential cytotoxocityof sodium arsenite in human fibroblasts and chinese hamster ovary cells. Toxicology. 56(3): 289-300. Lee, Te-Chang, N. Tanaka, P.W. Lamb, T.M. Gilmer and J.C. Barrett. 1988. Induction of gene amplification by arsenic. Science. 241(4861): 79-81. Lee-Chen, S.F., J.R. Gu rr, I.B. Lin and K.Y. Jan. 1993. Arsenite enhances DNA double-strand breaks and cell killing of methyl methanesulfonate-treated cells by inhibiting the excision of alkali-labile sites. Mutat. Res. 294(1): 21-28. Lee-Feldstein, A. 1983. Arsenic and respiratory cancer in man: Follow-up of an occupational study. In: Arsenic: Indu strial, Biomedical, and Environmenta l Perspectives, W. Lederer and R. Fensterheim, Ed. Van Nostrand Reinhold, New York. Mabuchi, K., A. Lilienfel d and L. Snell. 1979. Lung cancer among pesticide workers expsoed to inorganic arsenicals. Arch. Environ. Health. 34: 312-319. Matanoski, G., E. Landau, J. Tonascia, et al. 1981. Cancer mortality in an industrial area of Baltimore. Environ. Res. 25: 8-28. Moore, M.M., K. Harrington-Brock and C.L. Do err. 1995. Genotoxicity of arsenic and its methylated metabolites. Mutagenesis and Cellu lar Toxicology Brance, Genetic Toxicology Dividion, Health Effects Research Laboratory, U.S. Environm ental Protection Agency, Research Triangle Park, NC. (In press). Morton, W., G. Starr, D. Pohl, J. Stoner, S. Wa gner, and P. Weswig. 1976. Skin cancer and water arsenic in Lane County, Oregon. Cancer. 37: 2523-2532. Ohno, H., F. Hanaoka and M. Yamada. 1982. Indu ctibility of sister ch romatid exchanges by heavy-metal ions. Mutat. Res. 104(1-3): 141-146. Ott, M.G., B.B. Holder and H.L. Gordon. 1974. Respiratory cancer and occupational exposure to arsenicals. Arch. Enviro n. Health. 29: 250-255. 

### http://www.epa.gov/iris/subst/0278.htmPershagen, G., B. Lind and N.E. Bjorklund. 1982. Lung retention an d toxicity of some inorganic arsenic compounds. Envi ron. Res. 29: 425-434. Pershagen, G., G. Norberg and N.E. Bjorklund. 1984. Carcinomasof the respiratory tract in hamsters given arsenic trioxide and/or benxo(a)pyrene by the pu lmonary route. Environ. Res. 34: 227-241. Poma, K., N. Degraeve and C. Susanne. 1987. Cytoge nic effects in mice afte r chronic exposure to arsenic followed by a single dose of ethy l methanesulfonate. Cyto logia. 52(3): 445-450. Rencher, A.C., M.W. Carter an d D.W. McKee. 1977. A retrospect ive epidemiological study of mortality at a large western copper smel ter. J. Occup. Me d. 19(11): 754-758. Rossman, T.G. 1981. Enhancement of UV-mutagenes is by low concentrations of arsenite in Escherichia coli. Muta t. Res. 91: 207-211. Roth, F. 1958. Uber den Bronchialkrebs Arseng eschadigter Winzer. Virchows Arch. 331: 119-137. Smith, A.H., C. Hopenhayn-Rich, M. N. Bates, et al. 1992. Cancer risks from arsenic in drinking water. Environ. Health Perspect. 97: 259-267. Sommers, S.C. and R.G. McManus. 1953. Multible arsenical canc ers of the skin and internal organs. Cancer. 6: 347-359. Southwick, J., A. Western, M. Beck, et al. 1981. Community health associ ated with arsenic in drinking water in Millard County, Utah. Health Effects Research Laborato ry, Cincinnati, OH. EPA600/1-81-064. Tinwell, H., S.C. Stephe ns, J. Ashby. 1991. Arsenite as the probable active spec ies in the human carcinogenicity of arsenic: Mo use micronucleus assays on Na and K arsenite, orpiment, and Fowler's soluti on. Environ. Health Perspec. 95: 205-210. Tokudome, S. and M. Kuratsune. 1976. A cohort study on mortality from cancer and other causes among workers at a metal refine ry. Int. J. Cancer. 17: 310-317. Tseng W.P., H.M. Chu, S.W. How, J.M. Fong, C.S. Lin, and S. Yen. 1968. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J. Natl. Ca ncer Inst. 40(3): 453-463. Tseng W.P. 1977. Effects and dose -response relationships of skin cancer and Blackfoot disease with arsenic. Environ. He alth Perspect. 19: 109-119.

U.S. EPA. 1984. Health As sessment Document for Inorganic Arse nic. Prepared by the Office of Research and Development, Environmental Criter ia and Assessment Office , Reasearch Triangle Park, NC. U.S. EPA. 1988. Special Report on Ingested Inorganic Arsenic; Skin Cancer; Nutritional Essentiality Risk Assessment Fo rum. July 1988. EPA/625/3-87/013. U.S. EPA. 1993. Drinking Water Cr iteria Document for Arsenic. O ffice of Water, Washington, DC. Draft. 

### http://www.epa.gov/iris/subst/0278.htmDate Section Description Vahter, M. and E. Marafante. 1988. In vivo methylation and detoxifi cation 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 toarsenic 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 vit ro. Environ. Mutag. 4: 493-498. Welch, K., I. Higgins, M. Oh an d C. Burchfield. 1982. Arsenic expo sure, 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 ad ded 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 

### http://www.epa.gov/iris/subst/0278.htmIRIS Home 01/01/199 2 IV

. Regulatory actions updated 08/01/1992 II. Note added to indicatetext 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 assessm ent 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. Carcinogenic ity assessment replaced 06/01/1995 VI.C. Carcinogenic ity referencesreplaced 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 be ginning 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 ri sks 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 bein g 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 

### http://www.epa.gov/iris/subst/0278.htmChronic HealthHazards for NonCarcinogenic Effects Reference Dose for Chronic Oral Exposure (RfD) • Oral RfD Summary • Principal and Supporting Studies • Uncertainty and Modifying Factors • Additional Studies/Comments • Confidence in the Oral RfD • EPA Documentation and Review

Reference Concentration for Chronic Inhalation

Exposure (RfC) • Inhalation RfC Summary • Principal and Supporting Studies • Uncertainty and Modifying Factors • Additional Studies/Comments • Confidence in the Inhalation RfC • EPA Documentation and Review Carcinogenicity Assessment for Lifetime Exposure Evidence for Human Carcinogenicity• Weight-ofEvidence Characterization • Human Carcinogenicity Data • Animal Carcinogenicity Data • Supporting Data for Carcinogenicity Quantitative Estimate of Carcinogenic Risk from Oral Exposure 

### http://www.epa.gov/iris/subst/0278.htm• Summary of Risk Estimates • Dose-Response Data • Additional Comments • Discussion of Confidence Quantitative Estimate of Carcinogenic Risk

from Inhalation Exposure • Summary of Risk Estimates • Dose-Response Data • Additional Comments • Discussion of Confidence • EPA Documentation, Review and, Contacts Bibliography Revision History Synonyms 

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