### 1 U.S. EPA Integrated Risk Information System (IRIS) National Center for Environmental Assessment. Washington, DC. Available online at: http://www.epa.gov/IRIS/ Steam Electric ELGs, DCN 01960

Oral Reference Doses Definition of Reference Dose (RfD) from Frequently Asked Questions Web Page ( http://www.epa.gov/iris/help_ques.htm ) : 

### What is an RfD and RfC?
EPA’s IRIS is a human health assessment program that evaluates quantitative and qualitative risk information on effects that may result from exposure to specific chemical substances found in the environment. The IRIS database contains infor mation that can be used to support the first two steps ( hazard identification and dose
- response evaluation ) of the risk assessment process . When supported by available data, IRIS provides oral reference doses (RfDs) and inhalation reference concentrations (RfCs) for chronic non
- cancer health effects, and oral slope factors and inhala tion unit risks for carcinogenic effects. Combined with specific exposure information, government and private entities use IRIS to help characterize public health risks of chemical substances in a site
- specific situation and thereby support risk management decisions designed to protect public health. More specifically, the reference dose (RfD) and reference concentration (RfC) provide quantitative information for use in risk assessments for health effects known or assumed to be produced through a nonlinear (possibly threshold) mode of action. The RfD (expressed in units of mg of substance/kg body weight
- day) is defined as an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive sub groups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. An RfD can be derived from a no
- observed
adverse
- effect level (NOAEL), lowest
- observed
- adverse
- effect level (LOAEL), or benchmark dose, with uncertainty fact ors generally applied to reflect limitations of the data used. The inhalation RfC (expressed in units of mg of substance/m 3 air) is analogous to the oral RfD but provides a continuous inhalation exposure estimate. The inhalation RfC considers toxic effects for both the respiratory system (portal of entry) and effects peripheral to the respiratory system (extrarespiratory or sy stemic effects). Reference values may also be derived for acute (≤24 hours), short

- term (>24 hours, up to 30 days), and subchronic (>30 days, up to approximately 10% of the life span) exposure durations, all of which are derived based on an assumption of c ontinuous exposure throughout the duration specified. RfDs and RfCs are generally used in noncancer health assessments.

### 2

Arsenic, inorganic ( http://www.epa.gov/iris/subst/0278.htm ) 

# Arsenic, inorganic (CASRN 7440 - 38 - 2)

[UPDATE] The (cancer) portion of this assessment is currently under development and the latest draft can be found at, IRIS Toxicological Review of Inorganic Ar senic (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 th e 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 t he 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 Category (section ) Status Last Revised Oral RfD Assessment (I.A.) on - line 02/01/1993 Inhalation RfC Assessment (I.B.) no data Carcinogenicity Assessment (II.) on - line 04/10/1998


### _I. Chronic Health Hazard Assessments for Noncarcinogenic Effects _I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name

— Arsenic, inorganic CASRN
— 7440
- 38
- 2

### 3

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 expre ssed 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 deleter ious 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 ot her 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 sho uld 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 bec omes available. Risk managers should recognize the considerable flexibility afforded them in formulating regulatory decisions when uncertainty and lack of clear consensus are taken into account. 

### __I.A.1. Oral RfD Summary Critical Effect Experimental Doses* UF MF RfD

Hyperpigmentation, 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
concen trations 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

-

### 4 day. The LOAEL dos e was estimated using the same assumptions as the NOAEL starting with an arithmetic mean water concentration from Tseng (1977) of 0.17 mg/L. LOAEL = [(0.17 mg/L x 4.5 L/day) + 0.002 mg/day] / 55 kg = 0.014 mg/kg

- day. 

### __I.A.2. Principal and Supporting Studies (Oral RfD)
Tseng, W.P. 1977. Effects and dose
- response relationships of skin cancer and blackfoot disease with arsenic. Environ. Health Perspect. 19: 109
- 119. Tseng, W.P., H.M. Chu, S.W. How, J.M. Fong, C.S. Lin and S. Yeh. 1968. Prevalence of ski n 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 grou p 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 pre valences 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 explic itly 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 (co ntribution 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 4 31 (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.

### 5

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 co ncentration 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 a bout 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). Th e 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 s ince 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, bu t the dose is lower (0.4 vs. 0.8 ug/kg/day). The Southwick et al. (1983) study shows a marginally increased incidence of a variety of skin lesions (palmar and plantar keratosis, diffuse palmar or plantar hyperkeratosis, diffuse pigmentation, and arterial insufficiency) in the individuals exposed to a rsenic. 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 inc reased 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 no t 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/k g/day.

### 6

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. (1 983) 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 a bnormal 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, m id 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 concentratio n in the high
- dose and mid
dose wells is 680 and 70 ug/L, respectively. Figure 1 (Hindmarsh et al., 1977) shows that the average arsenic concentration of the low
- dose wells is about 25 ug/L. No data are given on arsenic exposure from food. We assume daily water consumption of 2 liters and body weight of 70 kg. Exposure times are not clearly stated. Exposure estimates (water only) are: low
- 25 ug/L x 2 L/day x (1/70) kg = 0.7 ug/kg/day; mid
- 70 ug/L x 2 L/day x (1/70) kg = 2 ug/kg/day; high
- 680 ug/L x 2 L/day x (1/70) kg = 19 ug/kg/day.
The low dose is a no
- effect level for abnormal EMG findings. However, because there is no information on the background incidence of abnormal clinical findings in a population with zero exposure to arsenic, there is no w ay of knowing if the low dose is a no
- effect level or another marginal effect level for abnormal clinical findings. The low dose is comparable to the dose received by the control group in the Tseng (1977) and Southwick et al. (1983) studies. The responses at the mid dose do not show a statistically significant increase but are part of a statistically significant trend and are biologically significant. This dose is an equivocal NOAEL/LOAEL. The high dose is a clear LOAEL for both responses. As discussed pr eviously 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 S outhwick 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.

### 7

The Tseng (1977) and Tseng et al. (1968) studies are therefore considered superior fo r 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 (equivoc al 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 ha mster 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 wate r (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 s light 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

### 8

not increase u ntil daily water ingestion of arsenic exceeded approximately 250 ug/day (approximately 120 ug of arsenic/L. Methylated species of arsenic are successively 1 order of magnitude less toxic and less teratogenic (Marcus and Rispin, 1988). Some evidence suggest s 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 ex tensive 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. st udies 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
— Th is 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 serie s 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 L iterature 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.

### 9

__I.A.7. EPA Contacts (Oral RfD)
Please contact the IRIS Hotline for all questions concerning this asses sment or IRIS, in general, at (202)566
- 1676 (phone), (202)566
- 1749 (FAX) or hotline.iris@epa.gov (internet address).

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### _I.B. Reference C oncentration for Chronic Inhalation Exposure (RfC)

Substance Name

— Arsenic, inorganic CASRN
— 7440
- 38
- 2
Not available at this time.

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### _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 likeliho od 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 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 ai r 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 I RIS 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 r eferred to Section I of this IRIS file for information on long
- term toxic effects other than carcinogenicity.

### 10

_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 a n 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, Swe den; Saganoseki
- Machii, Japan) have all found an association between occupational arsenic exposure and lung cancer mortality (Enterline and Marsh, 1982; Lee
- Feldstein, 1983; Axelson et al., 1978; Tokudome and Kuratsune, 1976; Rencher et al., 1977). Both pr oportionate 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 r evealed 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
- sectiona l study of 40,000 Taiwanese exposed to arsenic in drinking water found significant excess skin cancer prevalence by comparison to 7500 residents of Taiwan and Matsu who consumed relatively arsenic
- free water (Tseng et al., 1968; Tseng, 1977). Although this study demonstrated an association between arsenic exposure and development of skin cancer, it has several weaknesses and uncertainties, including poor nutritional status of the exposed populations, their genetic susceptibility, and their exposure to inorg anic 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 exam iners 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.

### 11

The more exposed group had an increased incidence of palmar keratosis, skin hyperpigmentation and hypopi gmentation, 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 unexpose d 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 mortal ity 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 Taiw an. 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) c ompared with villages that partially or completely used surface well water (low in arsenic). However, dose
- response data were not developed (Chen et al. 1985).
A retrospective case
- control study showed a significant association between duration of consumi ng 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 ca ncers and 95 bladder cancers in the registry were histologically or cytologically confirmed and over 70% of the liver cancers were confirmed by biopsy or à

- fetoprotein presence with a positive liver x
- ray image. Only confirmed cancer cases were included in the study. A control group of 400 persons living in the same area was frequency
- matched with cases by age and sex. Standardized questionnaires of the cases (by proxy) and controls determined the history of artesian well water use, socioeconomic variables, disease history, dietary habits, and lifestyle. For the cancer cases, the age
- sex adjusted odds ratios were increased for bladder (3.90), lung (3.39), and liver (2.67) cancer for persons who had used artesian well water for 40 or more years when compared with controls who had never used artesian well water. Similarly, in a 15
- year study of a cohort of 789 patients of Blackfoot disease, an increased mortality from cancers of the liver, lung, bladder and kidney was seen among BFD patients when compared with the general population in the endemic area or when compared with the general population of Taiwan. Multiple logistic regression analysis to adjust for other risk factors including cigarette smoking did not markedly affect the exposure
- response relationship s or odds ratios (Chen et al., 1988).

### 12

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 bla dder, 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 in ternal 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 pop ulation 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
- resp onse 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 spec ies (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, inhal ation, 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 carci nogenicity in two strains of mice and was not found positive (Innes et al., 1969); however, this was a screening study and no data were provided. The meaning of non
- positive data for carcinogenicity of inorganic arsenic is uncertain, the mechanism of actio n in causing human cancer is not known, and rodents may not be a good model for arsenic carcinogenicity testing.

### 13

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., 1 982, 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 an d the average total oral consumption of arsenic was about 1890 mg (daily dose x duration). In 1980, 139 deaths had occurred. No excess deaths from internal cancers were seen after this 20
- year follow
- up. Three bladder cancer deaths were observed (1.19 expe cted, SMR 2.5) (Cuzick et al., 1982). A recent follow
- up (Cuzick et al., 1992) indicated no increased mortality from all cancers but a significant excess from bladder cancer (5 cases observed/1.6 expected; SMR of 3.07). A subset of the original cohort (143 persons) had been examined by a dermatologist in 1970 for signs of arsenicism (palmar keratosis). In 1990, there were 80 deaths in the subcohort and 11 deaths from internal cancers. All 11 subjects had skin signs (keratosis
- 10, hyperpigmentation
- 5 and ski n 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 expo sure) 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 specificall y 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 hum an 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 a rsenic 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 genoto xicity 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

### 14

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 abb eration 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, r ather 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 m ethotrexate resistant 3T6 mouse cells (Lee et al., 1988). Although the mechanism of induction in rodent cells is not known, gene amplification of oncogenes is observed in many human tumors. Inorganic arsenic has not been shown to mutate bacterial strains, it produces preferential killing of repair deficient strains (Rossman, 1981). Sodium arsenite (As+3) induces DNA
- strand breaks which are associated with DNA
- protein crosslinks in cultured human fibroblasts at 3 mM but not 10 mM (Dong and Luo, 1993) and it appears that arsenite inhibits the DNA repair process by inhibiting both excision and ligation (Jha et al., 1992; Lee
- Chen et al., 1993). The inhibitory effect of arsenite on strand
- break rejoining during DNA repair was found to be reduced by adding gluta thione 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 aberr ations 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 chrom atid 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 expo sed to arsenic in drinking water (Vig et al., 1984).

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### 15

_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure __II.B.1. Summary of Risk Estimates
Oral Slope Factor
— 1.5E+0 per (mg/kg)/day Drinking Water Unit Risk

— 5E
- 5 per (ug/L) Extrapolation Method

— Time
- and dose
- related formulation of the multistage model (U.S. EPA, 1988) Drinking Water Concentrations at Specified Risk Levels:

Risk Level Concentration
E
- 4 (1 in 10,000) 2E+0 ug/L
E
- 5 (1 in 100,000) 2E
- 1 ug/L
E
- 6 (1 in 1,000,000) 2E
- 2 ug/L



### __II.B.2. Dose - Response Data (Carcinogenicity, Oral Exposure)
The Risk Assessment Forum has completed a reassessment of the carcinogenicity risk associated with ingestion of inorganic arsenic (U.S. EPA, 1988). The data provided in Tseng et al., 1968 and Tseng, 1977 on about 40,000 persons exposed to arsenic in drinking water and 7500 relatively unexposed controls were used to develop dose
- response data. The number of persons at risk over three dose intervals and four exposure durations, for males and females separately, were estimated from the reported prevalence rates as percentages. It was assumed that the Taiwanese persons had a constant exposure from birth, and that males consumed 3.5 L drinking water/day and females consumed 2.0 L/day. Doses were converted to equivalent doses for U.S. males and females based on differences in body weights and differences in water consumption and it was assumed that skin cancer risk in the U.S. population would be similar to the Taiwanese population. The multistage model with time was used to predict dose
- specific and age
- specific skin cancer prevalance rates associated with ingestion of inorganic arsenic; both linear and quadrat ic 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 u nit risk for drinking water is 5E
- 5 per (ug/L). Details of the assessment are in U.S. EPA (1988).

### 16

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 pres ent. 

### __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 agr eed, 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 indistingui shable 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, comp eting 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 info rmation. 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 th e 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 i n 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). Uncertai nties in exposure measurement can affect the outcome of dose
- response estimation.

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### 17

_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure __II.C.1. Summary of Risk Estimates

Inhalation Unit Risk

— 4.3E
- 3 per (ug/cu.m) Extrapolation Method

— absolute
- risk linear model Air Concentrations at Specified Risk Levels:

Risk Level Concentration
E
- 4 (1 in 10,000) 2E
- 2 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; Higgi ns, 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

### 18

__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 exp ected values. The range of the estimates derived from data from two different exposure areas was within a factor of 6.

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### _II.D. EPA Documentation, Review, and Contacts (Carcinog enicity Assessment) __II.D.1. EPA Documentation
U.S. EPA. 1984, 1988, 1993 A draft of the 1984 Health Assessment Document for Inorganic Arsenic was independently reviewed in public session by the Environmental Health Committee of the U.S. EPA Science Advisory Board on September 22
- 23, 1983. A draft of the 1988 Special Report on I ngested 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

### 19

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 Arseni c (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.go v (internet address).

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### _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. Office of 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 Regulator y Support and Scientific Management, U.S. 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.

### 20

Hindmarsh, 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 prenat al 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 M odern 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. Princeton Scientific Publishing Company, Princeton, NJ. p. 133
- 158. Nadeenko, V.G., V. L enchenko, S.B. Genkina and T.A. Arkhipenko. 1978. The 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. Recomm ended 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 elements on the reproduction of mice and rats. Arch. Environ. 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, Biomedical, 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 relationships of skin cancer and blackfoot disease with arsenic. Environ. Health Perspect. 19: 109
- 119.
Tseng, W.P., H.M. Chu, S.W. How, J.M. Fong, C.S. Lin and S. Yeh. 1968. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J. Natl. 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 Elements in Man and Animals
- TEMA 5, C.F. Mills, I. Bremner and J.K. Chesters, eds. Commonwealth Agricultural Bureaux, Aberdeen, Scotland.

### 21

U.S. EPA. 1984. Health Assessment Document for Inorganic Arsenic. Prepare d 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 Toxicological Evaluation of Ingested Arsenic. Office of Drinking Water, Washi ngton, DC. (Draft)

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### _VI.B. Inhalation RfD References

None

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### _VI.C. Carcinogenicity Assessment Refer ences Axelson, O., E. Dahlgren, C.D. Jansson and S.O. Rehnlund. 1978. Arsenic exposure and mortality: A case referent study from a Swedish copper smelter. Br. J. Ind. Med. 35: 8
- 15. Andersen, O. 1983. Effects of coal combustion products and metal compound s on sister chromatid exchange (SCE) in a macrophage like cell line. Environ. Health Perspect. 47: 239
- 253. Bates, M.N., A.H. Smith and C. Hopenhayn
- Rich. 1992. Arsenic ingestion and internal 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. Health Perspect. 19: 145
- 146. Brown, C.C. and K.C. Chu. 1983a. Approaches to epidemiologic analysis of prospective and retrospective studies: Ex ample of lung cancer and exposure to arsenic. In: Risk Assessment Proc. SIMS Conf. on Environ. Epidemiol. June 28
- July 2, 1982, Alta, VT. SIAM Publications. Brown, C.C. and K.C. Chu. 1983b. Implications of the multistage theory of carcinogenesis applied t o occupational arsenic exposure. J. Natl. Cancer Inst. 70(3): 455
- 463.

### 22

Brown, C.C. and K.C. Chu. 1983c. A new method for the analysis of cohort studies: Implications of the multistage theory of carcinogenesis appled to occupational arsenic exposure. Envir on. 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. Aquilar and E. Blakely. 198 3. Chronic arsenic poisoning in the north of Mexico. Human Toxicol. 2: 121
- 133. Chen, C
- J. and C
- J. Wang. 1990. Ecological 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
- arsenic artesian well water and cancers. Cancer Res. 45: 5895
- 5899. Chen, C
- J., Y
- C. Chuang, S
- L. You, T
- M. Lin a nd 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 water. Multiple risk factors and related malignant neoplasms of Blackfoot disease. Arteriosclerosis. 8(5): 452
- 460. Chen, C
- J., CW. Chen, M
- M. Wu and T
- L. Kuo. 1992. Cancer potential 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 human lymphocytes. Mutat. Res. 119: 415
- 419. Cuzick, J., S. Evans, M. Gillman 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. Evans. 1992. Ingested arsen ic, keratoses, and bladder cancer. Am. J. Epidemiol. 136(4): 417
- 421. Datta, S., G. Talukder and A. Sharma. 1986. Cytotoxic effects of arsenic in dietary oil primed rats. Sci. Culture. 52: 196
- 198.

### 23

DeKnudt, G., A. Leonard, A. Arany, G.D. Buisson and E. D elavignette. 1986. In vivo studies in male mice on the mutagenic effects of inorganic arsenic. Mutagenesis. 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
- strand breaks associated with DNA
- protein crosslinks in human fetal lung fibroblasts. Mutat. Res. 302(2): 97
- 102. Eastern Research Group. 1997. Report on the expert p anel on arsenic 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. Marsh. 1982. Cancer a mong 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.

Fur st, A. 1983. A new look at arsenic carcinogenesis. In: Arsenic: 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. M oore. 1993. Mutagenicity of the human carcinogen arsenic and its methylated metabolites monomethylarsonic and dimethylarsenic acids in L5178Y TK+/
- mouse lymphoma cells (abstract). Environ. Mol. Mutagen. 21(Supplement 22): 27. Higgins, I. 1982. Arsenic an d respiratory cancer among a sample of Anaconda smelter workers. Report submitted to the Occupatinal Safety and Health Administration in the comments of the Kennecott Minerals Company on the inorganic arsenic rulemaking. (Exhibit 203
- 5)
Higgins, I., K. We lch and C. Burchfield. 1982. Mortality of Anaconda 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. Glutathione as a cellul ar defence against arsenite toxicity in cultured Chinese hamster ovary cells. Toxicology. 79(3): 195
- 204. IARC (International Agency for Research on Cancer). 1980. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man, Vol. 23. Some metals and metallic compounds. World Health Organization, Lyon, France.

### 24

Innes, J.R.M., B.M. Ulland, M.G. Va lerio, et al. 1969. Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: A preliminary note. JNCI. 42: 1101
- 1114.
Jacobson
- Kram, D. and D. Montalbano. 1985. The reproductive effects assessment group's report on the mutagenicity of i norganic arsenic. Environ. Mutagen. 7(5): 787
- 804. Jha, A.N., M. Noditi, R. Nilsson and A.T. Natarajan. 1992. Genotoxic effects of sodium arsenite on human cells. Mutat. Res. 284(2): 215
- 221. Larramendy, M.L., N.C. Popescu and J.A. DiPaolo. 1981. Inducti on by inorganic metal salts of sister chromatid exchanges and chromosome aberrations in human and Syrian hamster strains. Environ. Mutagen. 3: 597
- 606.
Lee, Te
- Chang, J. Ko and K.Y. Jan. 1989. Differential cytotoxocity of sodium arsenite in human fibrobla sts 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. Gurr, 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: Fol low
- up of an occupational study. In: Arsenic: Industrial, Biomedical, and Environmental Perspectives, W. Lederer and R. Fensterheim, Ed. Van Nostrand Reinhold, New York. Mabuchi, K., A. Lilienfeld and L. Snell. 1979. Lung cancer among pesticide workers exp soed 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. Doerr. 1995. Geno toxicity of arsenic and its methylated metabolites. Mutagenesis and Cellular Toxicology Brance, Genetic Toxicology Dividion, Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC. (In press).
Morton, W., G. St arr, D. Pohl, J. Stoner, S. Wagner, and P. Weswig. 1976. Skin cancer and water arsenic in Lane County, Oregon. Cancer. 37: 2523
- 2532.

### 25

Ohno, H., F. Hanaoka and M. Yamada. 1982. Inductibility of sister chromatid exchanges by heavy
metal ions. Mutat. Res. 10 4(1
- 3): 141
- 146. Ott, M.G., B.B. Holder and H.L. Gordon. 1974. Respiratory cancer and occupational exposure to arsenicals. Arch. Environ. Health. 29: 250
- 255. Pershagen, G., B. Lind and N.E. Bjorklund. 1982. Lung retention and toxicity of some inorganic a rsenic compounds. Environ. Res. 29: 425
- 434. Pershagen, G., G. Norberg and N.E. Bjorklund. 1984. Carcinomas of the respiratory tract in hamsters given arsenic trioxide and/or benxo(a)pyrene by the pulmonary route. Environ. Res. 34: 227
- 241.
Poma, K., N. Degraeve and C. Susanne. 1987. Cytogenic effects in mice after chronic exposure to arsenic followed by a single dose of ethyl methanesulfonate. Cytologia. 52(3): 445
- 450. Rencher, A.C., M.W. Carter and D.W. McKee. 1977. A retrospective epidemiological stu dy of mortality at a large western copper smelter. J. Occup. Med. 19(11): 754
- 758. Rossman, T.G. 1981. Enhancement of UV
- mutagenesis by low concentrations of arsenite in Escherichia coli. Mutat. Res. 91: 207
- 211. Roth, F. 1958. Uber den Bronchialkrebs Ar sengeschadigter 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 can cers of the skin and internal organs. Cancer. 6: 347
- 359. Southwick, J., A. Western, M. Beck, et al. 1981. Community health associated with arsenic in drinking water in Millard County, Utah. Health Effects Research Laboratory, Cincinnati, OH. EPA
600/1
- 81
- 064. Tinwell, H., S.C. Stephens, J. Ashby. 1991. Arsenite as the probable active species in the human carcinogenicity of arsenic: Mouse micronucleus assays on Na and K arsenite, orpiment, and Fowler's solution. Environ. Health Perspec. 95: 205
- 210.
Toku dome, S. and M. Kuratsune. 1976. A cohort study on mortality from cancer and other causes among workers at a metal refinery. Int. J. Cancer. 17: 310
- 317.

### 26

Tseng W.P., H.M. Chu, S.W. How, J.M. Fong, C.S. Lin, and S. Yen. 1968. Prevalence of skin cancer in a n 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. Vahter, M. and E. Marafante. 1988. In vivo methylation and deto xification 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. Christ ian 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 smelt er 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.

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### _VII. Revision History

Substance Name

— Arsenic, inorganic CASRN
— 7440
- 38
- 2

### 27 Date Section Description 06/30/1988 II.B. Revised last paragraph 06/30/1988 II.C.1. Inhalation slope factor changed 06/30/1988 II.C.3. Paragraph 2 added 09/07/1988 II.B. Major text changes 12/01/1988 II.A.2. Mabuchi et al. citation year corrected 12/01/1988 II.A.3. Pershagen et al. citation year corrected 09/01/1989 II.C.2. Citations added to anacondor smelter 09/01/1989 VI. Bibliography on
- line 06/01/1990 II.A.2. 2nd 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 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

### 28

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 Regul atory 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.

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### 29

_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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Chronic Health Hazards for Non - Carcinogenic 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

Ref erence 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

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Evidence for Human Carcinogenicity



###  Weight
- of
- Evidence Characterization 

###  Human Carcinogenicity Data 

###  Animal Carcinogenicity Data 

###  Supporting Data for Carcinogenicity

### 30 Quantitative Estimate of Carcinogenic Risk from Oral Exposure



###  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

Recent Additions | Search IRIS | IRIS Home | NCEA Home | ORD Home



###  EPA Home 

###  Privacy and Security Notice



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

Print As
- Is Last updated on Thursday, August 09, 2012

### 31

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

# Cadmium (CASRN 7440 - 43 - 9)

0141 Cadmium; CASRN 7440 - 43 - 9 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 . Secti ons 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 meth ods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website
. STATUS OF DATA FOR Cadmium
File First On - Line 03/31/1987 Category (section) Status Last Rev ised Oral RfD Assessment (I.A.) on - line 02/01/1994 Inhalation RfC Assessment (I.B.) no data Carcinogenicity Assessment (II.) on - line 06/01/1992


### _I. Chronic Health Hazard Assessments for Noncarcinogenic Effects _I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name

— Cadmium CASRN
— 7440
- 43
- 9 Last Revised

— 02/01/1994 The oral Reference Dose (RfD) is based on the assumption that thresholds exist for certain toxic

### 32

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 lifeti me. 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 c oncerning 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. 

### __I.A.1. Oral RfD Summary Critical Effect Experim ental Doses* UF MF RfD

Significant proteinuria
Human studies involving chronic exposures U.S. EPA, 1985 NOAEL (water): 0.005 mg/kg/day NOAEL (food): 0.01 mg/kg/day 10
10 1

1 5E
- 4 mg/kg/day

(water)

1E
- 3 mg/kg/day (food)

* Conversion Factors: See text for discussion 

### __I.A.2. Principal and Supporting Studies (Oral RfD)
U.S. EPA. 1985. Drinking Water Criteria Document on Cadmium. Office of Drinking Water, Washington, DC. (Final draft) A concentration of 200 ug cadmium (Cd) /gm wet human renal cortex is the highest renal level not associated with significant proteinuria (U.S. EPA, 1985). A toxicokinetic model is available to determine the level of chronic human oral exposure (NOAEL) which results in 200 ug Cd/gm wet human ren al cortex; the model assumes that 0.01% day of the Cd body burden is eliminated per day (U.S. EPA, 1985). Assuming 2.5% absorption of Cd from food or 5% from water, the toxicokinetic model predicts that the NOAEL for chronic Cd exposure is 0.005 and 0.01 m g Cd/kg/day from water and food, respectively (i.e., levels which would result in 200 ug Cd/gm wet weight human renal cortex). Thus, based on an estimated NOAEL of 0.005 mg Cd/kg/day for Cd in drinking water and ian UF of 10, an RfD of 0.0005 mg Cd/kg/day (water) was calculated; an equivalent RfD for Cd in food is 0.001 mg Cd/kg/day (see Section VI.A. for references).

### 33

__I.A.3. Uncertainty and Modifying Factors (Oral RfD)

UF
— This uncertainty factor is used to account for intrahuman variability to the toxi city of this chemical in the absence of specific data on sensitive individuals.

MF
— None 

### __I.A.4. Additional Studies/Comments (Oral RfD)
Cd is unusual in relation to most, if not all, of the substances for which an oral RfD has been determined in that a vast quantity of both human and animal toxicity data are available. The RfD is based on the highest level of Cd in the human renal cortex (i.e., the critical level) not associated with significant proteinuria (i.e., the critical effect). A toxicokinetic mo del has been used to determine the highest level of exposure associated with the lack of a critical effect. Since the fraction of ingested Cd that is absorbed appears to vary with the source (e.g., food vs. drinking water), it is necessary to allow for thi s difference in absorption when using the toxicokinetic model to determine an RfD. 

### __I.A.5. Confidence in the Oral RfD
Study

— Not applicable Database

— High RfD

— High The choice of NOAEL does not reflect the information from any single study. Rather, it reflects the data obtained from many studies on the toxicity of cadmium in both humans and animals. These data also permit calculation of pharmacokinetic parameters of cadmium absorption, distribution, metabolism and elimination. All of this information c onsidered together gives high confidence in the database. High confidence in either RfD follows as well. 

### __I.A.6. EPA Documentation and Review of the Oral RfD

Source Document
— U.S. EPA, 1985
Other EPA Documentation

— None Agency Work Group Review

— 05/ 15/1986, 08/19/1986, 09/17/1987, 12/15/1987, 01/20/1988, 05/25/1988
Verification Date

— 05/25/1988 

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

### 34

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).

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

Substance Name

— Cadmium CASRN
— 7440
- 43
- 9
Not available at this time.

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### _II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name

— Cadmium CASRN
— 7440
- 43
- 9 Last Revised

— 06/01/1992 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 es timates 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 wate r 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 info rmation 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 util ize 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.

### 35

_II.A. Evidence for Human Carcinogenicit y __II.A.1. Weight - of - Evidence Characterization

Classification

— B1; probable human carcinogen

Basis
— Limited evidence from occupational epidemiologic studies of cadmium is consistent across investigators and study populations. There is sufficient eviden ce of carcinogenicity in rats and mice by inhalation and intramuscular and subcutaneous injection. Seven studies in rats and mice wherein cadmium salts (acetate, sulfate, chloride) were administered orally have shown no evidence of carcinogenic response. 

### __II.A.2. Human Carcinogenicity Data

Limited. A 2
- fold excess risk of lung cancer was observed in cadmium smelter workers. The cohort consisted of 602 white males who had been employed in production work a minimum of 6 months during the years 1940
- 1969. Th e population was followed to the end of 1978. Urine cadmium data available for 261 workers employed after 1960 suggested a highly exposed population. The authors were able to ascertain that the increased lung cancer risk was probably not due to the presenc e of arsenic or to smoking (Thun et al., 1985). An evaluation by the Carcinogen Assessment Group of these possible confounding factors has indicated that the assumptions and methods used in accounting for them appear to be valid. As the SMRs observed were low and there is a lack of clear cut evidence of a causal relationship of the cadmium exposure only, this study is considered to supply limited evidence of human carcinogenicity. An excess lung cancer risk was also observed in three other studies which we re, however, compromised by the presence of other carcinogens (arsenic, smoking) in the exposure or by a small population (Varner, 1983; Sorahan and Waterhouse, 1983; Armstrong and Kazantzis, 1983). Four studies of workers exposed to cadmium dust or fumes provided evidence of a statistically significant positive association with prostate cancer (Kipling and Waterhouse, 1967; Lemen et al., 1976; Holden, 1980; Sorahan and Waterhouse, 1983), but the total number of cases was small in each study. The Thun et a l. (1985) study is an update of an earlier study (Lemen et al., 1976) and does not show excess prostate cancer risk in these workers. Studies of human ingestion of cadmium are inadequate to assess carcinogenicity. 

### __II.A.3. Animal Carcinogenicity Data
Exposure of Wistar rats by inhalation to cadmium as cadmium chloride at concentrations of 12.5, 25 and 50 ug/cu.m for 18 months, with an additional 13
- month observation period, resulted in significant increases in lung tumors (Takenaka et al., 1983). Intra tracheal instillation of cadmium oxide did not

### 36

produce lung tumors in Fischer 344 rats but rather mammary tumors in males and tumors at multiple sites in males (Sanders and Mahaffey, 1984). Injection site tumors and distant site tumors (for example, testic ular) have been reported by a number of authors as a consequence of intramuscular or subcutaneous administration of cadmium metal and chloride, sulfate, oxide and sulfide compounds of cadmium to rats and mice (U.S. EPA, 1985). Seven studies in rats and mic e where cadmium salts (acetate, sulfate, chloride) were administered orally have shown no evidence of a carcinogenic response. 

### __II.A.4. Supporting Data for Carcinogenicity
Results of mutagenicity tests in bacteria and yeast have been inconclusive. Posit ive responses have been obtained in mutation assays in Chinese hamster cells (Dom and V79 lines) and in mouse lymphoma cells (Casto, 1976; Ochi and Ohsawa, 1983; 0berly et al., 1982). Conflicting results have been obtained in assays of chromosomal aberrat ions in human lymphocytes treated in vitro or obtained from exposed workers. Cadmium treatment in vivo or in vitro appears to interfere with spindle formation and to result in aneuploidy in germ cells of mice and hamsters (Shimada et al., 1976; Watanabe et al., 1979; Gilliavod and Leonard, 1975).

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### _II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure
Not available. There are no positive studies of orally ingested cadmium suitable for quantitation.

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### _II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure __II.C.1. Summary of Risk Estimates

Inhalation Unit Risk

— 1.8E
- 3 per (ug/cu.m) Extrapolation Method

— Two stage; only first affected by exposure; extra risk Air Concentrations at Specified Risk Levels:

### 37 Risk Level Concentration
E
- 4 (1 in 10,000) 6E
- 2 ug/cu.m
E
- 5 (1 in 100,000) 6E
- 3 ug/cu.m
E
- 6 (1 in 1,000,000) 6E
- 4 ug/cu.m


### __II.C.2. Dose - Response Data for Carcinogenicity, Inhalation Exposure
Tumor Type
— lung, trachea, bronchus cancer deaths Test animals

— human/white male Route
— inhalation, exposure in the workplace Reference

— T hun et al., 1985

Cumulative Exposure (mg/day/cu.m) Median Observation 24 hour/

ug/cu.m Equivalent No. of Expected

Lung, Trachea and Bronchus Cancers Assuming No Cadmium Effect Observed No. of Deaths (lung, trachea, bronchus cancers) less than or equal to 584 280 168 3.77 2

585
- 2920 1210 727 4.61 7
greater than or equal to 2921 4200 2522 2.50 7

The 24
- hour equivalent = median observation x lE+3 x 8/24 x 1/365 x 240/365.


### __II.C.3. Additional Comments (Carcinogenicity, Inhalation Exposure)
The unit risk should not be used if the air concentration exceeds 6 ug/cu.m, since above this concentration the unit risk may not be appropriate. 

### __II.C.4. Discussion of Confidence (Carcinogenicity, Inhalation Exposure)

The data were derived fro m a relatively large cohort. Effects of arsenic and smoking were accounted for in the quantitative analysis for cadmium effects.

### 38

An inhalation unit risk for cadmium based on the Takenaka et al. (1983) analysis is 9.2E
- 2 per (ug/cu.m). While this estimate is higher than that derived from human data [1.8E
- 3 per (ug/cu.m)] and thus more conservative, it was felt that the use of available human data was more reliable because of species variations in response and the type of exposure (cadmium salt vs. cadmium f ume and cadmium oxide).

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### _II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment) __II.D.1. EPA Documentation

Source Document
— U.S. EPA, 1985 The Addendum to the Cadmium Health Assessment has received both Agency and external review. 

### __II.D.2. EPA Review (Carcinogenicity Assessment)
Agency Work Group Review

— 11/12/1986
Verification Date

— 11/12/1986 

### __II.D.3. EPA Contacts (Carcinogenicity As sessment)
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).

Top of page



### _III. [reserved] _IV. [reserved] _V. [reserved]

### 39

_VI. Bibliography

Substance Name

— Cadmium CASRN
— 7440
- 43
- 9 Last Revised

— 10/01/1989 

### _VI.A. Oral RfD References
Foulkes, E.C. 1986. Abs orption of cadmium. In: Handbook of Experimental Pharmacology, E.C. Foulkes, Ed. Springer Verlag, Berlin. Vol. 80, p. 75
- 100. Friberg, L., M. Piscator, G.F. Nordberg and T. Kjellstrom. 1974. Cadmium in the environment, 2nd ed. CRC Press, Inc., Boca Raton, FL. Shaikh, Z.A. and J.C. Smith. 1980. Metabolism of orally ingested cadmium in humans. In: Mechanisms of Toxicity and Hazard Evaluation, B. Holmstedt et al., Ed. Elsevier Publishing Co., Amsterdam. p. 569
- 574. U.S. EPA. 1985. Drinking Water Criteria Document on Cadmium. Office of Drinking Water, Washington, DC. (Final draft) WHO (World Health Organization). 1972. Evaluation of certain food additives and the contaminants mercury, lead, and cadmium. Sixteenth Rep ort of the Joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series No. 505, FAO Nutrition Meetings Report Series No. 51. Geneva, Switzerland. WHO (World Health Organization). 1984. Guidelines for drinking water quality
-- recommendat ions. Vol. 1. Geneva, Switzerland.

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### _VI.B. Inhalation RfC References

None

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### 40

_VI.C. Carcinogenicity Assessment References
Armstrong, B.G. and G. Kazantzis. 1983. The mortality of cadmium workers. Lancet. June 25, 1983: 1425
- 1427. Casto, B. 1976. Letter to Richard Troast, U.S. EPA. Enclosing mutagenicity data on cadmium chloride and cadmi um acetate. Gilliavod, N. and A. Leonard. 1975. Mutagenicity tests with cadmium in the mouse. Toxicology. 5: 43
- 47. Holden, H. 1980. Further mortality studies on workers exposed to cadmium fumes. Presented at Seminar on Occupational Exposure to Cadmium, M arch 20, 1980, London, England. Kipling, M.D. and J.A.H. Waterhouse. 1967. Cadmium and prostatic carcinoma. Lancet. 1: 730. Lemen, R.A., J.S. Lee, J.K. Wagoner and H.P. Blejer. 1976. Cancer mortality among cadmium production workers. Ann. N.Y. Acad. Sci. 271: 273. Oberly, T., C.E. Piper and D.S. McDonald. 1982. Mutagenicty of metal salts in the L5178 Y mouse lymphoma assay. J. Toxicol. Environ. Health. 9: 367
- 376. Ochi, T. and M. Ohsawa. 1983. Induction of 6
- thioguanine
- resistant mutants and single
- stra nd scission DNA by cadmium chloride in cultured Chinese hamster cells. Mutat. Res. 111: 69
- 78. Sanders, C.L. and J.A. Mahaffey. 1984. Carcinogenicity of single and multiple intratracheal instillations of cadmium oxide in the rat. Environ. Res. 33: 227
- 233
. Shimada, T., T. Watanabe and A. Endo. 1976. Potential mutagenicity of cadmium in mammalian oocytes. Mutat. Res. 40: 389
- 396. Sorahan, T. and J.A.H. Waterhouse. 1983. Mortality study of nickel
- cadmium battery workers by the method of regression models i n life tables. Br. J. Ind. Med. 40: 293
- 300. Takenaka, S., H. Oldiges, H. Konig, D. Hochrainer and G. Oberdoerster. 1983. Carcinogenicity of cadmium aerosols in Wistar rats. J. Natl. Cancer Inst. 70: 367
- 373. Thun, M.J., T.M. Schnorr, A.B. Smith and W.E. Halperin. 1985. Mortality among a cohort of U.S. cadmium production workers: An update. J. Natl. Cancer Inst. 74(2): 325
- 333.

### 41

U.S. EPA. 1985. Updated Mutagenicity and Carcinogenicity Assessment of Cadmium. Addendum to the Health Assessment Document for Cadmium (EPA 600/B
- B1
- 023). EPA 600/B
- 83
- 025F. Varner, M.O. 1983. Updated epidemiologic study of cadmium smelter workers. Prese nted at the Fourth International Cadmium Conference. Unpublished. Watanabe, T., T. Shimada and A. Endo. 1979. Mutagenic effects of cadmium on mammalian oocyte chromosomes. Mutat. Res. 67: 349
- 356.

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### _VII. Revision History

Substance Name

— Cadmium CASRN
— 7440
- 43
- 9
Date Section Description 05/21/1987 II.C. Slope factor corrected 03/01/1988 II.A.1. Text added 03/01/1988 II.C.3. Text revised 03/01/1988 II.C.4. Confidence statement revised 03/01/1988 II.D.3. Secondary contact changed 01/01/1989 IV.C.1. Water quality human health criteria added 01/01/1989 IV.C.2. Corrected marine acute criterion 08/01/1989 VI. Bibliography on
- line 10/01/1989 I.A. Oral RfD summary on - line 10/01/1989 VI.A. Oral RfD references added 12/01/1989 I.B. Inhalation RfC now under review 06/01/1990 IV.A.1. Area code for EPA contact corrected

### 42

06/01/1990 IV.F.1. EPA contact changed 08/01/1990 II.A.1. Basis statement revised 08/01/1990 II.A.2. Text revised, paragraph 1 08/01/1990 II.B. Text revised 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 03/01/1991 II.A.1. Text revised 03/01/1991 II.B. Text revised 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 05/01/1992 II.C.2. Number correction in data table 06/01/1992 II.A.2. Text revised, paragraph 1 06/01/1992 II.A.3. Text clarified 02/01/1994 I.A.7. Secondary contact changed 08/01/1995 I.B. 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. 01/02/1998 I., II. This chemical is bei ng reassessed under the IRIS Program.

Top of page

### 43

_VIII. Synonyms

Substance Name

— Cadmium CASRN
— 7440
- 43
- 9 Last Revised

— 03/31/1987



###  7440
- 43
- 9


###  C.I. 77180


###  Cadmium


###  KADMIUM

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IRIS Home

Chronic Health Hazards for Non - Carcinogenic 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 

###  Pr incipal 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
- of
- Evidence Characterization 

###  Human Carcinogenicity Data 

###  Animal Carcinogenicity Data 

###  Suppor ting Data for Carcinogenicity

### 44

Quantitative Estimate of Carcinogenic Risk from Oral Exposure



###  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

Recent Additions | Search IRIS | IRIS Home | NCEA Home | ORD Home



###  EPA Home 

###  Privacy and Security Notice



###  Contact Us http://www.epa.gov/iris/subst/0141.htm

Print As
- Is Last updated on Thursday, August 09, 2012

### 45

Chromium VI ( http://www.epa.gov/iris/subst/0144.htm ) 

# Chromium (VI) (CASRN 18540 - 29 - 9)

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

Note: A TOXICOLOGICAL REVIEW is available for this chemical in Adobe PDF Format (70 Pages,189 Kbytes). Similar documents can be found in the List of Available IRIS Toxicological Reviews
. Links to specific pages in the toxicological review are available throughout this summary . To utilize this feature, your Web browser and Adobe program must be configured properly so the PDF displays within the browser window. If your browser and Adobe program need configuration, please go to EP A's PDF page for instructions
. [UPDATE] This assessment is currently under development and the latest draft can be found at, IRIS Toxicological Review of Hexavalent Chromium ( External Review Draft)
0144 Chromium (VI) ; CASRN 18540 - 29 - 9; 09/03/1998
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 assessme nt 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
.

### 46

STATUS OF DATA FOR Chromium (VI)
File First On - Line 03/31/1987 Category (section) Status Last Revised Oral RfD Assessment (I.A.) on - line 09/03/1998 Inhalation RfC Assessment (I.B.) on - line 09/03/1998 Carcinogenicity Assessment (II.) on - line 09/03/1998


### _I. Chronic Health Hazard Assessments for Noncarcinogenic Effects _I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name

— Chromium (VI) CASRN
— 18540
- 29
- 9 Last Revised

— 09/03/1998 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 substanc es 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 evaluati on will be contained in Section II of this file. 

### __I.A.1. Oral RfD Summary

Critical Effect Experimental Doses* UF MF RfD None Reported Rat, 1
- year drinking water study MacKenzie et al., 1958 NOAEL: 25 mg/L of chromium as K 2 CrO 4 2.5 mg/kg
- day (adj.)
LOAEL: None 300 3 3E
- 3 mg/kg
- day

*Conversion Factors and Assumptions

— Drinking water consumption = 0.1 L/kg

- day (reported).

### 47

__I.A.2. Principal and Supporting Studies (Oral RfD)
MacKenzie, RD; Byerrum, RU; Decker, CF, et al. (1958) Chronic toxicity stu dies. II. Hexavalent and trivalent chromium administered in drinking water to rats. Am Med Assoc Arch Ind Health 18:232
- 234. Groups of eight male and eight female Sprague
- Dawley rats were supplied with drinking water containing 0.45
- 11.2 ppm (0.45
- 11.2 mg /L) hexavalent chromium (as K 2 CrO 4 ) for 1 year. The control group (10/sex) received distilled water. A second experiment involved three groups of 12 male and 9 female rats. One group was given 25 ppm (25 mg/L) chromium (as K 2 CrO 4 ), a second received 25 ppm chromium in the form of chromic chloride, and the controls again received distilled water. No significant adverse effects were seen in appearance, weight gain, or food consumption, and there were no pathologic changes in the blood or other tissues in any treatment group. The rats receiving 25 ppm of chromium (as K 2 CrO 4 ) showed an approximate 20% reduction in water consumption. Based on the body weight of the rat (0.35 kg) and the average daily drinking water consumption for the rat (0.035 l/day), this dose can be converted to give an adjusted NOAEL of 2.5 mg/kg
- day chromium(VI).
For rats treated with 0
- 11 ppm (in drinking water), blood was examined monthly, and tissues (livers, kidneys, and femurs) were examined at 6 mo and 1 year. Spleens were also examin ed at 1 year. The 25 ppm groups (and corresponding controls) were examined similarly, except that no animals were killed at 6 mo. An abrupt rise in tissue chromium concentrations was noted in rats treated with more than 5 ppm. The authors stated that "appa rently, tissues can accumulate considerable quantities of chromium before pathological changes result." In the 25 ppm treatment groups, tissue concentrations of chromium were approximately 9 times higher for those treated with hexavalent chromium than for the trivalent group. Similar no
- effect levels have been observed in dogs. Anwar et al. (1961) observed no significant effects in female dogs (2/dose group) given up to 11.2 ppm chromium(VI) (as K 2 CrO 4 ) in drinking water for 4 years. The calculated doses we re 0.012
- 0.30 mg/kg of chromium(VI). 

### __I.A.3. Uncertainty and Modifying Factors (Oral RfD)

UF = 300. The uncertainty factor of 300 represents two 10
- fold decreases in dose to account for both the expected interhuman and interspecies variability in the toxicity of the chemical in lieu of specific data, and an additional factor of 3 to compensate for the less
- than
- lifetime exposure duration of the principal study.

MF = 3.

### 48

The modifying factor of 3 is to account for concerns raised by the study of Zhang and Li (1987). 

### __I.A.4. Additional Studies/Comments (Oral RfD)
This RfD is limited to soluble salts of hexavalent chromium. Examples of soluble salts include potassium dichromate (K 2 Cr 2 O 7 ), sodium dichromate (Na 2 Cr 2 O 7 ), potassium chromate (K 2 Cr 2 O 4 ), and sodium chromate (Na 2 CrO 4 ). Trivalent chromium is an essential nutrient. There is evidence to indicate that hexavalent chromium is reduced in part to trivalent chromium in vivo (Petrilli and DeFlora, 1977, 1978; Gruber and Jennette, 1978). In 1965, a study of 155 subjects exposed to drinking water at concentrations of approximately 20 mg/L was conducted outside Jinzhou, China. Subjects were observed to have sores in the mouth, diarrhea, stomachache, indigestion, vomiting, elevated white blood cell counts wi th respect to controls, and a higher per capita rate of cancers, including lung cancer and stomach cancer. Precise exposure concentrations, exposure durations, and confounding factors were not discussed, and this study does not provide a NOAEL for the obse rved effects. However, the study suggests that gastrointestinal effects may occur in humans following exposures to hexavalent chromium at levels of 20 ppm in drinking water (Zhang and Li, 1987). Zahid et al. (1990) fed BALB/C albino Swiss mice trivalent ( chromium disulfate) and hexavalent (potassium dichromate) chromium at concentrations of 100, 200, and 400 ppm for 35 days in the diet. The author concluded that a small but significant increase of hexavalent chromium in the testes of fed animals induced si gnificant degeneration. The National Toxicology Program (1996a,b, 1997) recently conducted a three
- part study to investigate the potential reproductive toxicity of hexavalent chromium in rats and mice. The study included oral administration of potassium di chromate in Sprague
- Dawley rats, a repeat of the study of Zahid et al. (1990) using BALB/C mice, and a reproductive assessment by continuous breeding study in BALB/C mice. The reproductive assessment indicated that potassium dichromate administered at 15
- 4 00 ppm in the diet is not a reproductive toxicant in either sex of BALB/C mice or Sprague
- Dawley rats. Several reports of possible fetal damage caused by chromium compounds were located in the literature. High doses (250
- 1,000 ppm) of orally administered chromium (VI) compounds have been reported to cause developmental toxicity in mice (Trivedi et al., 1989). The authors observed significant increases in preimplantation and postimplantation losses and dose
- dependent reductions in total weight and crown
- rum p length in the lower dose groups. Additional effects included treatment
- related increases in abnormalities in the tail and wrist forelimbs, and subdermal hemorrhagic patches in the offspring. Junaid et al. (1996) and Kanojia et al. (1996) exposed female Swiss albino mice and female Swiss albino rats, respectively, to 250, 500, or 750 ppm potassium dichromate in drinking water to

### 49

determine the potential embryotoxicity of hexavalent chromium during days 6
- 14 of gestation. The authors reported retarded feta l development and embryo
- and fetotoxic effects including reduced fetal weight, reduced number of fetuses (live and dead) per dam, and higher incidences of stillbirths and post
- implantation loss in the 500 and 750 ppm dosed mothers. Significantly reduced o ssification in bones was also observed in the medium
- and high
- dose groups. Based on the body weight and the drinking water ingested by the animals in the 250 ppm dose group, the exposure levels in the 250 ppm groups can be identified as 67 mg/kg
- day and 3 7 mg/kg
- day in mice and rats, respectively. The Junaid et al. (1996) and Kanojia et al. (1996) studies utilized doses approximately 10
- fold higher than those used in Mackenzie et al (1958), but neither of the reproductive studies identified a clear NOAEL for the embryotoxic effects of hexavalent chromium. On the basis of the body weight and the drinking water ingested by the animals in the low
- dose groups (250 ppm), the LOAELs of 67 mg/kg
- day and 37 mg/kg
- day can be identified from Junaid et al. (1996) and Kanojia et al. (1996) in mice and rats, respectively. Application of 10
- fold uncertainty factor to extrapolate from LOAELs to NOAELs in these studies would generate NOAELs of 6.7 mg/kg
- day and 3.7 mg/kg
- day, respectively. These extrapolated NOAEL values a re similar to, and support the use of, the NOAEL of 2.5 mg/kg
- day identified from the study of MacKenzie et al. (1958) for development of the reference dose.
Elbetieha and Al
- Hamood (1997) reported impacts on fertility following potassium dichromate expos ures in mice; however, many of the observed effects did not occur in a clear dose
- dependent fashion. The authors did not indicate the amount of water ingested by the animals, and stated only that water ingestion was reduced in the treatment groups relative to the controls.
Chromium is one of the most common contact sensitizers in males in industrialized countries and is associated with occupational exposures to numerous materials and processes, including chrome plating baths, chrome colors and dyes, cement , tanning agents, wood preservatives, anticorrosive agents, welding fumes, lubricating oils and greases, cleaning materials, and textiles and furs (Burrows and Adams, 1990; Polak et al., 1973). Solubility and pH appear to be the primary determinants of the capacity of individual chromium compounds to elicit an allergic response (Fregert, 1981; Polak et al., 1973). The low solubility chromium (III) compounds are much less efficient contact allergens than chromium (VI) (Spruit and van Neer, 1966). Dermal exp osure to chromium has been demonstrated to produce irritant and allergic contact dermatitis (Bruynzeel et al., 1988; Polak, 1983; Cronin, 1980; Hunter, 1974). Primary irritant dermatitis is related to the direct cytotoxic properties of chromium, while alle rgic contact dermatitis is an inflammatory response mediated by the immune system. Allergic contact dermatitis is a cell
mediated immune response that occurs in a two
- step process. In the first step (induction), chromium is absorbed into the skin and trigg ers an immune response (sensitization). Sensitized individuals will exhibit an allergic dermatitis response when exposed to chromium above a threshold

### 50

level (Polak, 1983). Induction is generally considered to be irreversible. Concentrations of hexavalent c hromium in environmental media that are protective of carcinogenic and noncarcinogenic effects are likely to be lower than the concentrations required to cause induction of allergic contact dermatitis. However, these concentrations may not be lower than co ncentrations required to elicit an allergic response in individuals who have been induced. The RfD was updated in 1998. The RfD is similar to the previous value on IRIS but now incorporates a threefold uncertainty factor to account for the less
- than
- lifet ime exposure in the principal study and a threefold modifying factor to account for uncertainties related to reports of gastrointestinal effects following drinking water exposures in a residential population in China.
For more detail on other Hazard Identi fication Issues, exit to the toxicological review, Section 4.7 (PDF)
. 

### __I.A.5. Confidence in the Oral RfD
Study

— Low Database

— Low RfD

— Low
The overall confidence in this RfD asses sment is low. Confidence in the chosen study is low because of the small number of animals tested, the small number of parameters measured, and the lack of toxic effect at the highest dose tested. Confidence in the database is low because the supporting s tudies are of equally low quality and the developmental toxicity endpoints are not well studied. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)
. 

### __I.A.6. EPA Documentation and Review of the Oral RfD

Source Document
— U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in final ization of this IRIS Summary. A record of these comments is included as an appendix to the Toxicological Review of Acetonitrile in Support of Summary Information (a PDF document) on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, External Peer Review -- Summary of Comments and Disposition (PDF)
.

### 51

Other EPA Documentation

— U.S. EPA. (1984) Health effe cts assessment for hexavalent chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. (1985) Dri nking water health advisory for chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Drinking Water, Washington, DC (Draft). Agency consensus date
-- 04/28 /1998 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 Chromium (VI) conducted in August 2003 did not identify any critical new studies. I RIS users who know of important new studies may provide that information to 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 questio ns concerning this assessment or IRIS, in general, at (202)566
- 1676 (phone), (202)566
- 1749 (fax), or hotline.iris@epa.gov (Internet address).

Top of page



### _I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Chromium (VI) CASRN
— 18540
- 29
- 9 Last Revised

— 09/03/1998 The inhalation reference concentration (RfC) is analogous to the oral RfD and is likewise based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. The inhalation RfC considers toxic effects for both the respiratory system (portal
- of
- entry) and for effects peripheral to the respiratory system (extrarespiratory effects). It is genera lly expressed in units of mg/m 3 . In general, the RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs were derived according to the Interim Methods for Development of Inhalation Reference Doses

### 52

(U.S. EPA, 1989) and subsequently, according to Methods for Derivation of Inhalation Reference Conce ntrations and Application of Inhalation Dosimetry (U.S. EPA, 1994). RfCs can also be derived for the noncarcinogenic health effects of substances that are carcinogens. Therefore, it is essential to refer to other sources of information concerning the carci nogenicity 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. 

### __I.B.1. Inhalation RfC Summary

Critical Effect Experimental Doses* U F MF RfC (1) Chromic acid mists and dissolved Cr (VI) aerosols: Nasal septum atrophy Human subchronic occupational study Lindberg and Hedenstierna, 1983 NOAEL: none

LOAEL: 2E
- 3 mg/m 3 7.14 E
- 4 mg/m 3 (adj.) 90 1 8E
- 6 mg/m 3

(2) Cr(VI) particulates: Lactate dehydrogenase in bronchioalveolar lavage fluid Rat subchronic study Glaser et al., 1990 Malsch et al., 1994 BMD: 0.016 mg/m 3 0.034 mg/m 3 (adj.) 300 1 1E
- 4 mg/m 3

*Conversion Factors and Assumptions

— Breathing rate for 8
- hour occupational exposure = 10 m 3 ; breathing rate for 24
- hour continuous exposure = 20 m 3 ; occupational exposure = 5 days/week; continuous exposure = 7 days/week. RDDR (regional deposited dose ratio for particulates to account for differences between rats and humans) = 2.16 Nasal mucosal irritation, atrophy, and perforation have been widely reported following occupational exposures to chromic acid mists and dissolved hexavalent chromium aerosols. However, there is uncertainty regarding the relevance of occupational expos ures to chromic acid mists and dissolved hexavalent chromium aerosols to exposures to Cr(VI) dusts in the environment. Lower respiratory effects have been reported in laboratory animals following exposures to Cr(VI) dusts. However, these studies have not r eported on nasal mucosal effects following the exposures. The uncertainties in the database have been addressed through the development of two RfCs; one based on nasal mucosal atrophy following occupational exposures to chromic acid mists and dissolved hex avalent

### 53

chromium aerosols, and a second based on lower respiratory effects following inhalation of Cr(VI) particulates in rats. 

### __I.B.2. Principal and Supporting Studies (Inhalation RfC)

(1) Chromic acid mists and dissolved Cr (VI) aerosols
Three studi es have focused on nasal mucosal irritation, atrophy, and perforation following occupational exposures to chromic acid mists (Cohen et al., 1974; Lucas and Kramkowski, 1975; Lindberg and Hedenstierna, 1983). Of these, the study of Lindberg and Hedenstierna provides the most information on exposure levels and symptoms reported by exposed workers. Respiratory symptoms, lung function, and changes in nasal septum were studied in 104 workers (85 males, 19 females) exposed in chrome plating plants. Workers were i nterviewed using a standard questionnaire for the assessment of nose, throat, and chest symptoms. Nasal inspections and pulmonary function testing were performed as part of the study. The median exposure time for the entire group of exposed subjects (104) in the study was 4.5 years (0.1
- 36 years). A total of 43 subjects exposed almost exclusively to chromic acid experienced a mean exposure time of 2.5 years (0.2
- 23.6 years). The subjects exposed almost exclusively to chromic acid were divided into a low
- ex posure group (8
- hr TWA below 0.002 mg/m 3 , N=19) and a high
- exposure group (8
- hr TWA above 0.002 mg/m 3 , N=24). Exposure measurements using personal air samplers were performed for 84 subjects in the study on 13 different days. Exposure for the remaining 20 workers was assumed to be similar to that measured for workers in the same area. Nineteen office employees were used as controls for nose and throat symptoms. A group of 119 auto mechanics whose lung function had been evaluated by similar techniques was se lected as controls for lung functionmeasurements. Smoking habits of workers were evaluated as part of the study. At mean exposures below 0.002 mg/m 3 , 4/19 workers from the low
- exposure group of subjective nasal symptoms. Atrophied nasal mucosa were report ed in 4/19 subjects from this group and 11/19 had smeary and crusty septal mucosa, which was statistically higher than controls. No one exposed to levels below 0.001 mg/m 3 complained of subjective symptoms. At mean concentrations of 0.002 mg/m 3 or above, a pproximately one
- third of the subjects had reddened, smeary, or crusty nasal mucosa. Atrophy was seen in 8/24 workers, which was significantly different from controls. Eight subjects had ulcerations in the nasal mucosa and five had perforations of the nasa l septum. Atrophied nasal mucosa was not observed in any of the 19 controls, but smeary and crusty septal mucosa occurred in 5/19 controls.
Short
- term effects on pulmonary function were evaluated by comparing results of tests taken on Monday and Thursday among exposed groups and controls. No significant changes were seen in the

### 54

low
- exposure group or the control group. Nonsmokers in the high
- exposure group experienced significant differences in pulmonary function measurements from the controls, but the resu lts were within normal limits.
The authors concluded that 8
- hour mean exposures to chromic acid above 0.002 mg/m 3 may cause a transient decrease in lung function, and that short
- term exposures to greater than 0.02 mg/m 3 may cause septal ulceration and per foration. Based on the results of this study, a LOAEL of 0.002 mg/m 3 can be identified for incidence of nasal septum atrophy following exposure to chromic acid mists in chromeplating facilities. At TWA exposures greater than 0.002 mg/m 3 , nasal septum ulcer ation and perforations occurred in addition to the atrophy reported at lower concentrations. The LOAEL is based on an 8
- hour TWA occupational exposure. The LOAEL is adjusted to account for continuous exposure according to the following equation:

LOAELc = 0.002 mg/m 3 x (MVho/MVh) x 5 days/7 days
where: LOAELc is the LOAEL for continuous exposure MVho is the breathing volume for an 8 hour occupational exposure (10 m 3 ) MVh is the breathing volume for a 24 hour continuous exposure (20 m 3 )
The LOAEL of 0.002 mg/m 3 based on a TWA exposure to chromic acid is converted to a LOAEL for continuous exposure of 7.14 E
- 4 mg/m 3 . An uncertainty factor of 3 is applied to the LOAEL to extrapolate from a subchronic to a chronic exposure, an uncertainty factor of 3 is appli ed to account for extrapolation from a LOAEL to a NOAEL, and an uncertainty factor of 10 is applied to the LOAEL to account for interhuman variation. The total uncertainty factor applied to the LOAEL is 90. Application of the uncertainty factor of 90 to th e LOAEL of 7.14E
- 4 mg/m 3 generates an RfC of 8 E
- 6 mg/m 3 for upper respiratory effects caused by chromic acid mists and dissolved hexavalent chromium aerosols. (2) Cr (VI) Particulates: Two studies provide high
- quality data on lower respiratory effects f ollowing exposures to chromium particulates (Glaser et al., 1985, 1990). Glaser et al. (1990) exposed 8
- week
- old male Wistar rats to sodium dichromate at 0.05
- 0.4 mg Cr(VI)/m 3 22 hr/day, 7 days/wk for 30
- 90 days. Chromium
induced effects occurred in a st rong dose
- dependent manner. The authors observed obstructive respiratory dyspnea and reduced body weight following subacute exposure at the higher dose levels. The mean white blood cell count was increased at all doses (p < 0.05) and was related to signifi cant dose
- dependent leukocytosis following subacute exposures. Mean lung weights were significantly increased at exposure levels of 0.1 mg/m 3 following both the subacute and subchronic exposures. Accumulation of macrophages was seen in all of the exposure groups and was

### 55

postulated to be a chromium
- specific irritation effect that accounted for the observed increases in lung weights. Focal inflammation was observed in the upper airways following the subchronic exposure, and albumin and lactate dehydrogenase ( LDH) in bronchioalveolar lavage fluid (BALF) were increased following the exposure. The authors concluded that chromium inhalation induced pneumocyte toxicity and suggested that inflammation is essential for the induction of most chromium inhalation effect s and may influence the carcinogenicity of Cr(VI) compounds. Glaser et al. (1985) exposed 5
- week
- old male Wistar rats to aerosols of sodium dichromate at concentrations ranging from 0.025 to 0.2 mg Cr(VI)/m 3 , 22 hr/day in subacute (28 day) or subchronic (90 day) protocols. Chromium
- induced effects occurred in a dose
- dependent manner. Lung and spleen weights were significantly increased (p < 0.005) after both subacute and subchronic exposures at concentrations greater than 0.025 mg/m 3 . Differences in the m ean total serum immunoglobulin were also significant at exposures above 0.025 mg/m 3 , while exposures to aerosol concentrations greater than 0.1 mg/m 3 resulted in depression of the immune system stimulation. The immune stimulating effect of subchronic expos ure was not reversed after 2 mo of fresh air regeneration. Bronchoalveolar lavage (BAL) cell counts were significantly decreased following subchronic exposure to levels above 0.025 mg/m 3 chromium. The number of lymphocytes and granulocytes showed a slight but significant increase in the lavage fluids of the subacute and subchronically exposed groups. At subacute exposure concentrations up to 0.05 mg/m 3 the phagocytic activity of the alveolar macrophages increased; however, subchronic exposure at 0.2 mg/m 3 decreased this function significantly. The spleen T
- lymphocyte subpopulation was stimulated by subchronic exposure to 0.2 mg/m 3 chromium, and serum contents of triglycerides and phospholipids differed significantly from controls (p < 0.05) at this concent ration. Together, these studies provide useful information on chromium exposure
- related impacts including lung and spleen weight, LDH in BALF, protein in BALF, and albumin in BALF. The cellular content of BALF is considered representative of initial pulm onary injury and chronic lung inflammation, which may lead to the onset of pulmonary fibrosis (Henderson, 1988). While these studies present dose
dependent results on sensitive indicators of lower respiratory toxicity, potential upper respiratory impacts r esulting from the exposures were not addressed. Glaser et al. (1990) state that the upper respiratory tract was examined, but these data were not reported. One approach for development of an RfC using the data of Glaser et al. (1985, 1990) was offered by Malsch et al. (1994), who generated an inhalation RfC for chromium dusts using a benchmark concentration (BMC) approach. The Agency developed its RfC for particulates based on this approach. After excluding exposures for periods of less than 90 days from the BMC analysis, Malsch et al. (1994) developed BMCs for lung weight, LDH in BALF, protein in BALF, albumin in BALF, and spleen weight. The Malsch et al. (1994) analysis defined the benchmark concentration as the 95% lower confidence limit on the dose cor responding to a 10% relative change in the endpoint compared to the control. Dose
- effect data were adjusted to account for discontinuous exposure (22 hr/day) and the maximum likelihood model was used to fit continuous data to a polynomial mean

### 56

response reg ression, yielding maximum likelihood estimates of 0.036
- 0.078 mg/m 3 and BMCs of 0.016
- 0.067 mg/m 3 . Malsch et al. (1994) applied dosimetric adjustments and uncertainty factors to determine a RfC based on the following equation:
RfC = BMC x RDDR UF A x UF F x UF H

where:



###  RfC is the inhalation reference concentration


###  BMC is the benchmark concentration (lower 95% confidence limit on thedose corresponding to a 10% relative change in the endpoint compared to the control)


###  RDDR is the regional deposited dose ratio to account for pharmacokineticdifferences between species


###  UF A is a threefold uncertainty factor to account for pharmacodynamicdifferences not addressed by the RDDR


###  UF F is a threefold uncertainty factor to account for e xtrapolating from subchronic to chronic exposures; and


###  UF H is a 10
- fold uncertainty factor to account for the variation in sensitivity among members of the human population The RDDR factor is incorporated to account for differences in the deposition patter n of inhaled hexavalent chromium dusts in the respiratory tract of humans and the Wistar rat test animals (Jarabek et al., 1990). The RDDR of 2.1576 was determined based on the mass median aerodynamic diameter (0.28 μm for dose levels of 0.05
- 0.1 mg/m 3 and 0.39 for dose levels of 0.1
- 0.4 mg/m 3 ) and the geometric standard deviation (1.63 for dose levels of 0.05
- 0.1 mg/m 3 and 1.72 for dose levels of 0.1
- 0.4 mg/m 3 ) of the particulates reported in Glaser et al. (1990). A 3.16
- fold uncertainty factor (midpoint b etween 1 and 10 on a log scale) was incorporated to account for the pharmacodynamic differences not accounted for by the RDDR. An additional 3.16
- fold uncertainty factor was incorporated to account for the less
- than
- lifetime exposure in Glaser et al. (1990 ), and a 10
- fold uncertainty factor was applied to account for variation in the human population. A total uncertainty factor of 100 was applied to the BMC in addition to the RDDR. Glaser et al. (1990) reported that LDH in BALF increased in a dose
- depende nt fashion from 0.05 to 0.4 mg/m 3 sodium dichromate, and this endpoint generated the lowest BMC (0.016 mg/m 3 ) and RfC (3.4 E
- 4 mg/m 3 ). LDH in BALF is considered the among the most sensitive indicators of potential lung toxicity (Henderson, 1984, 1985, 1988 ; Beck et al., 1982; Venet et al., 1985), as LDH is found extracellularly after cell damage and BALF is the closest site to the original lung injury. LDH in BALF may also reflect chronic lung inflammation, which may lead to pulmonary fibrosis through preve ntion of the normal repair of lung tissue (Henderson, 1988). Several uncertainties must be addressed with regard to the BMC and RfC developed by Malsch et al.

### 57

(1994). Potentially important endpoints, including upper airway effects and potential renal or i mmunological toxicity, were not addressed in the Glaser et al. (1985, 1990) studies and could not be included in the BMC analysis. While LDH in BALF resulted in the lowest BMC and RfC, all of the effects noted in Glaser et al. (1985, 1990) can be considere d indicative of an inflammatory response, and might be equally suited to development of the RfC. LDH in BALF did not generate the best fit on the regression curve of the endpoints considered in the BMC analysis. In addition, the threefold uncertainty facto r accounting for the use of a subchronic study may not be sufficiently protective for long
- term effects. While the analysis acknowledged the importance of particle size and airway deposition in the development of the RDDR, the potential impact of different particle sizes in respiratory toxicity by hexavalent chromium particulates was not addressed. Several of these uncertainties were conservatively addressed in the analysis of Malsch et al. (1994). LDH in BALF generated the lowest estimate of the BMC from the effects noted by Glaser et al. (1985, 1990). This effect can be considered to be indicative of cell damage that occurs prior to fibrosis, as LDH appears in BALF following cell lysis. While the Malsch et al. (1994) analysis demonstrated a relatively po or curve fit for this endpoint, the model generated a conservative fit in the data that is unlikely to overestimate the BMC. LDH in BALF as reported in Glaser et al. (1990) is considered to be an acceptable endpoint for development of an RfC for inhalation of hexavalent chromium particulates, and Malsch et al. (1994) used a reasonable approach for development of a BMC based on this endpoint. The threefold uncertainty factor used by Malsch et al. (1994) to account for the subchronic study is insufficient fo r development of the RfC for inhalation of chromium particulates. Glaser et al. (1985) demonstrated that at the end of the 90
- day exposure period, chromium was still accumulating in the lung tissue of the test animals, suggesting that lower long
- term expos ures might lead to accumulation of a critical concentration in the lung. Subchronic studies also may not adequately predict the presence of inflammatory effects from lower long
- term exposures. The Agency has therefore determined that a 10
- fold uncertainty factor accounting for the use of a subchronic study is more appropriate in this case for the development of an RfC for inhalation of chromium particulates. Selection of a threefold uncertainty factor to account for the pharmacodynamic differences not acc ounted for by the RDDR, an additional 10
- fold uncertainty factor to account for the less
- than
lifetime exposure in Glaser et al. (1990), and a 10
- fold uncertainty factor to account for variation in the human population generates a total uncertainty factor of 300. Application of the total uncertainty factor of 300 and the RDDR of 2.1576 to the BMC generated by Malsch et al. (1994) based on LDH in BALF (Glaser et al., 1990) results in an RfC of 1 E
- 4 mg/m 3 for inhalation of hexavalent chromium particulates.

### 58

__I.B.3. Uncertainty and Modifying Factors (Inhalation RfC)

See discussion above. (1) Chromic acid mists and dissolved Cr (VI) aerosols: UF = 90. MF = 1. (2) Chromium (VI) particulates: UF = 300. MF = 1 

### __I.B.4. Additional Studies/Comments (Inhalation RfC)
There is considerable uncertainty with regard to the relevance of the nasal septum atrophy endpoint observed in the chromeplating industry to exposure to hexavalent chromium in the environment. The effects were observed in chromeplaters who were expo sed to chromic acid mists near the plating baths. Environmental exposures would most likely occur through contact with hexavalent chromium dusts, and exposures to chromic acid mists in the environment is considered to be unlikely. An additional uncertainty is related to the determination of dose in the Lindberg and Hedenstierna study. Nasal septum atrophy in this study was related to TWA exposures to chromic acid. The most significant effects (nasal septum perforation) were observed in workers who experienc ed peak excursions to levels considerably greater than the TWA. It is uncertain whether the peak excursion data or the TWAs are more appropriate for the determination of dose in this study. The RfC based on the data of Lindberg and Hedenstierna (1983) shou ld only be used to address exposures to chromic acid and dissolved hexavalent chromium aerosols. Nasal mucosal irritation, atrophy, and perforation have been widely reported following occupational exposures to chromic acid mists and dissolved hexavalent c hromium aerosols. Glaser et al. (1990) did not report on upper respiratory effects following exposure of rats to sodium dichromate. The RfC based on the data of Glaser et al. should only be used to address inhalation of Cr(VI) particulates.
The RfCs in t his IRIS Summary were added in 1998. The previous RfC section for hexavalent chromium in IRIS was empty. For more detail on other Hazard Identification Issues, exit to the toxicological review, Section 4.7 (PDF)
.

### 59

__I.B.5. Confidence in the Inhalation RfC
(1) Chromic acid mists and dissolved Cr (VI) aerosols: Study

— Low Database

— Low RfC
-- Low
The overall confidence in this RfC assessment is low. Confidence in the ch osen study is low because of uncertainties regarding the exposure characterization and the role of direct contact for the critical effect. Confidence in the database is low because the supporting studies are equally uncertain regarding the exposure charact erization. (2) Chromium (VI) particulates: Study

— Medium RfC

— Medium The overall confidence in this RfC assessment is medium. Confidence in the chosen study is medium because of uncertainties regarding upper respiratory, reproductive, and renal effect s resulting from the exposures. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)
. 

### __I.B.6. EPA Documentation and Re view of the Inhalation RfC

Source Document
— U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS Summary. A record of these comments is includ ed as an appendix to the Toxicological Review of Acetonitrile in Support of Summary Information (a PDF document) on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, External Peer Review -- Summary of Comments and Disposition (PDF)
.

Agency Consensus Date
— 04/28/1998 Screening
- Level Literature Review Findings

— A screening
- level review conducted by a n EPA contractor of the more recent toxicology literature pertinent to the RfC for Chromium (VI)

### 60

conducted in August 2003 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotli ne at hotline.iris@epa.gov or 202
- 566
- 1676. 

### __I.B.7. EPA Contacts (Inhalation RfC)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566
- 1676 (phone), (202)56 6
- 1749 (fax), or hotline.iris@epa.gov (Internet address).

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### _II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name: Chromium (VI) CASRN: 18540
- 29
- 9 Last Revised

— 09/03/1998 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 carcin ogen, 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 t he risk per (mg/kg)/day. The unit risk is the quantitative estimate in terms of either risk per μg/L drinking water or risk per μg/m3 air breathed. The third form in which risk is presented is a concentration of the chemical in drinking water or air associ ated with 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 Sect ion 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
Under the current guidelines (EPA, 1986), Cr(VI) is classified as Group A
- known human carcinogen by the inhalation route of exposure. Carcinogenicity by the oral route of exposure cannot be determined and is classified as Group D.

### 61

Under the proposed guidelines (EPA, 1996), Cr(VI) would be characterized as a known human carci nogen by the inhalation route of exposure on the following basis. Hexavalent chromium is known to be carcinogenic in humans by the inhalation route of exposure. Results of occupational epidemiologic studies of chromium
- exposed workers are consistent acros s investigators and study populations. Dose
- response relationships have been established for chromium exposure and lung cancer. Chromium
- exposed workers are exposed to both Cr(III) and Cr(VI) compounds. Because only Cr(VI) has been found to be carcinogenic in animal studies, however, it was concluded that only Cr(VI) should be classified as a human carcinogen. Animal data are consistent with the human carcinogenicity data on hexavalent chromium. Hexavalent chromium compounds are carcinogenic in animal bioa ssays, producing the following tumor types: intramuscular injection site tumors in rats and mice, intrapleural implant site tumors for various Cr(VI) compounds in rats, intrabronchial implantation site tumors for various Cr(VI) compounds in rats, and subcu taneous injection site sarcomas in rats. In vitro data are suggestive of a potential mode of action for hexavalent chromium carcinogenesis. Hexavalent chromium carcinogenesis may result from the formation of mutagenic oxidatitive DNA lesions following in tracellular reduction to the trivalent form. Cr(VI) readily passes through cell membranes and is rapidly reduced intracellularly to generate reactive Cr(V) and Cr(IV) intermediates and reactive oxygen species. A number of potentially mutagenic DNA lesions are formed during the reduction of Cr(VI). Hexavalent chromium is mutagenic in bacterial assays, yeasts, and V79 cells, and Cr(VI) compounds decrease the fidelity of DNA synthesis in vitro and produce unscheduled DNA synthesis as a consequence of DNA damag e. Chromate has been shown to transform both primary cells and cell lines. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)
. For more detail on other Hazard Identification Issues, exit to the toxicological review, Section 4.7 (PDF)
. 

### __II.A.2. Human Carcinogenicity Data
Occupational exposure to chromium compounds has been studied in the chromate production, chromeplating and chrome pigment, ferrochromium production, gold mining, leather tanning, and chrome alloy production industries. Workers in the chromate industry are exposed to both trivalen t and hexavalent compounds of chromium. Epidemiological studies of chromate production plants in Japan, Great Britain, West

### 62

Germany, and the United States have revealed a correlation between occupational exposure to chromium and lung cancer, but the specif ic form of chromium responsible for the induction of cancer was not identified (Machle and Gregorius, 1948; Baejter, 1950a,b; Bidstrup, 1951; Mancuso and Hueper, 1951; Brinton et al., 1952; Bidstrup and Case, 1956; Todd, 1962; Taylor, 1966; Enterline, 1974 ; Mancuso, 1975; Ohsaki et al., 1978; Sano and Mitohara, 1978; Hayes et al., 1979; Hill and Ferguson, 1979; Alderson et al., 1981; Haguenor et al., 1981; Satoh et al., 1981; Korallus et al., 1982; Frentzel
- Beyme, 1983; Langard and Vigander, 1983; Watanabe and Fukuchi, 1984; Davies, 1984; Mancuso, 1997). Mancuso and Hueper (1951) conducted a proportional mortality study of a cohort of chromate workers (employed for > l year from 1931
- 1949 in a Painesville, OH chromate plant) in order to investigate lung ca ncer associated with chromate production. Of the 2,931 deaths of males in the county where the plant is located, 34 (1.2%) were due to respiratory cancer. Of the 33 deaths among the chromate workers, however, 6 (18.2%) were due to respiratory cancer. Withi n the limitations of the study design, this report strongly suggested an increased incidence of respiratory cancer in the chromate
- production plant. In an update of the Mancuso and Hueper (1951) study, Mancuso (1975) followed 332 of the workers employed f rom 1931
- 1951 until 1974. By 1974, > 50% of this cohort had died. Of these men, 63.6%, 62.5%, and 58.3% of the cancer deaths for men employed from 1931
- 1932, 1933
- 1934, and 1935
- 1937, respectively, were due to lung cancer. Lung cancer death rates increased by gradient of exposure to total chromium, and significant deposition of chromium was found in the lungs of workers long after the exposure ceased. Mancuso (1975) reported that these lung cancer deaths were related to insoluble (trivalent), soluble (hexav alent), and total chromium exposure, but the small numbers involved make identification of the specific form of chromium responsible for the lung cancer uncertain. Mancuso (1997) recently updated this study, following the combined cohort of 332 workers un til 1993. Of 283 deaths (85% of the cohort identified), 66 lung cancers were found (23.3% of all deaths and 64.7% of all cancers). Lung cancer rates clearly increased by gradient level of exposure to total chromium. The relationship between gradient level of exposure and lung cancer rates is less clear for trivalent and hexavalent chromium. The rates of lung cancer within the cohort are consistent with those reported in Mancuso (1975), and provide further support for the cancer risk assessment based on thos e data. Studies of chrome pigment workers in the United States (Hayes et al., 1989), England (Davies, 1984, 1979, 1978), Norway (Langard and Vigander, 1983; Langard and Norseth, 1975), and in the Netherlands and Germany (Frentzel
- Beyme, 1983) have consist ently demonstrated an association between occupational chromium exposure (predominantly to Cr [VI]) and lung cancer. Several studies of the chromeplating industry have demonstrated a positive relationship between

### 63

cancer and exposure to chromium compounds (Royle, 1975; Franchini et al., 1983; Sorahan et al., 1987). 

### __II.A.3. Animal Carcinogenicity Data
Animal data are consistent with the findings of human epidemiological studies of hexavalent chromium. Hexavalent chromium compounds were carcinogenic in ani mal assays producing the following tumor types: lung tumors following inhalation of aerosols of sodium chromate and pyrolized Cr(VI)/Cr(III) oxide mixtures in rats (Glaser et al., 1986), lung tumors following intratracheal administration of sodium dichroma te in rats (Steinhoff et al., 1983), intramuscular injection site tumors in Fischer 344 and Bethesda Black rats and in C57BL mice (Furst et al., 1976; Maltoni, 1974, 1976; Payne, 1960a; Hueper and Payne, 1959); intrapleural implant site tumors for various Cr(VI) compounds in Sprague
- Dawley and Bethesda Black rats (Payne, 1960b; Hueper 1961; Hueper and Payne, 1962), intrabronchial implantation site tumors for various Cr(VI) compounds in Wistar rats (Levy and Martin, 1983; Laskin et al., 1970; Levy, as quoted in NIOSH, 1975), and subcutaneous injection site sarcomas in Sprague
- Dawley rats (Maltoni, 1974, 1976). Inflammation is considered to be essential for the induction of most chromium respiratory effects and may influence the carcinogenicity of Cr(VI) compo unds (Glaser et al., 1985). 

### __II.A.4. Supporting Data for Carcinogenicity
Metabolism and genotoxicity. Hexavalent chromium is rapidly taken up by cells through the sulfate transport system (Sugiyama, 1992). Once inside the cell, Cr(VI) is quickly reduced to the trivalent form by cellular reductants, including ascorbic acid, glutathione and flavoenzymes (cytochrome P
450 and glutathione reductase), and riboflavin (De Flora et al., 1989; De Flora et al., 1990; Sugiyama, 1992). The intracellular reduction of Cr(VI) generates reactive Cr(V) and Cr(IV) intermediates as well as hydroxyl free radicals (OH) and singlet oxygen ( 1 O 2 ) (Kawanishi et al., 1986). A variety of DNA lesions are formed during the reduction of Cr(VI) to Cr(III), including DNA strand breaks, a lkali
- labile sites, DNA
- protein and DNA
- DNA crosslinks, and oxidative DNA damage, such as 8
- oxo - deoxyguanosine (Klein et al., 1992; Klein et al., 1991; De Flora et al., 1990). The relative importance of the different chromium complexes and oxidative DNA da mage in the toxicity of Cr(VI) is unknown. A large number of chromium compounds have been assayed with in vitro genetic toxicology assays. In general, hexavalent chromium is mutagenic in bacterial assays whereas trivalent chromium is not (Lofroth, 1978; P etrilli and DeFlora, 1977, 1978). Likewise Cr(VI), but not Cr(III), was mutagenic in yeasts (Bonatti et al., 1976) and in V79 cells (Newbold et al., 1979). Cr(III) and (VI) compounds decrease the fidelity of DNA synthesis in vitro (Loeb et al., 1977), whil e Cr(VI) compounds inhibit replicative DNA synthesis in mammalian cells (Levis et al., 1978) and produce unscheduled DNA synthesis, presumably repair synthesis, as a consequence of DNA damage (Raffetto, 1977). Chromate has been shown to transform both prim ary cells and cell lines (Fradkin

### 64

et al., 1975; Tsuda and Kato, 1977; Casto et al., 1979). Chromosomal effects produced by treatment with chromium compounds have been reported by a number of authors; for example, both Cr(VI) and Cr(III) salts were clastoge nic for cultured human leukocytes (Nakamuro et al.,1978). In dogs (2/group) exposed to potassium dichromate in drinking water at concentrations up to 11.2 ppm for 4 years, gross and microscopic examination of all major organs revealed no treatment
related lesions (Anwar et al., 1961). The small number of animals and the relatively short exposure duration relative to the lifespan of the dog precludes a conclusion regarding a possible carcinogenic response. There are no other long
- term studies of ingested Cr (VI). Cr(VI) is readily converted to Cr(III) in vivo, but there is no evidence that Cr(III) is oxidized to Cr(VI) in vivo. Cr(III) is an essential trace element.

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### _II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure
The oral carcinogenicity of Cr(VI) cannot be determined. No data were located in the available literature that suggested that Cr(VI) is carcinogenic by the oral route of exposure.

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### _II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure __II.C.1. Summary of Risk Estimates
___ II.C.1.1. Air Unit Risk

— 1.2E
- 2 per (μg/cu.m)
Source: Mancuso, 1975

### 65

___ II.C.1.2. Extrapolation Method

— Multistage, extra risk Air Concentrations at Specified Risk Levels:

Risk Level Concentration
E
- 4 (1 in 10,000) 8E
- 3 (μg/m 3 )
E
- 5 (1 in 100,000) 8E
- 4 (μg/m 3 )
E
- 6 (1 in 1,000,000) 8E
- 5 (μg/m 3 )


### __II.C.2. Dose - Response Data for Carcinogenicity, Inhalation Exposure
Tumor type
-- lung cancer Test animals

— human Route
— inhalation, occupational exposure Source
-- Mancuso, 1975

Subject age (years) Exposure Level midrange (μg/m 3 ) Deaths From Lung Cancer Person - Years
50 5.66 25.27 46.83 3 6 6 1,345 931 299
60 4.68 20.79 39.08 4 5 5 1,063 712 211
70 4.41 21.29 2 4 401 345


### __II.C.3. Additional Comments (Carcinogenicity, Inhalation Exposure)
Mancuso (1997) recently updated the study of Mancuso (1975), following the combined cohort of 332 workers until 1993. Of 283 deaths (85% of the cohort identified), 66 lung cancers were found (23.3% of all deaths and 64.7% of all cancers). Lung cancer rates clearly increased by gradient level of exposure to total chromium. The rel ationship between gradient level of exposure and lung cancer rates is less clear for trivalent and hexavalent chromium. The rates of lung cancer within the cohort are consistent with those reported in Mancuso (1975), and provide further support for the can cer risk assessment based on those data.

### 66

The cancer mortality in Mancuso (1975) was assumed to be due to Cr(VI), which was further assumed to be no less than one
- seventh of total chromium. It was also assumed that the smoking habits of chromate workers we re similar to those of the U.S. white male population. Trivalent chromium compounds have not been reported as carcinogenic by any route of administration.
The unit risk should not be used if the air concentration exceeds 8E
- 1 μg/m3, since above this con centration the unit risk may not be appropriate. The carcinogenicity section of this IRIS Summary was updated in 1998; however, the quantitative results have not been modified. 

### __II.C.4. Discussion of Confidence (Carcinogenicity, Inhalation Exposure)

Resu lts of studies of chromium exposure are consistent across investigators and countries. A dose relationship for lung tumors has been established. Theassumption that the ratio of Cr(III) to Cr(VI) is 6:1 may lead to a sevenfold underestimation of risk. The u se of 1949 hygiene data (Bourne and Yee, 1950), which may underestimate worker exposure, may result in an overestimation of risk. Further overestimation of risk may be due to the implicit assumption that the smoking habits of chromate workers were similar to those of the general white male population, since it is generally accepted that the proportion of smokers is higher for industrial workers than for the general population.

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### _II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment) __II.D.1. EPA Documentation

Source Document
— U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporate d in finalization of this IRIS Summary. A record of these comments is included as an appendix to the Toxicological Review of Acetonitrile in Support of Summary Information (a PDF document) on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998).

### 67

To review this appendix, exit to the toxicological review, Appendix A, External Peer Review -- Summary of Comments and Disposition (PDF)
. Other EPA Documentation

— U.S. EPA. (1984) Health assessment document for chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA/600/8
- 83
- 014F. 

### __II.D.2. EPA Review (Carcinogenicity Assessment)
Agency consensus date
-- 04/28/1998
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 Chromium (VI) conducted in August 2003 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 202
- 566
- 1676. 

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

Pleas e 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).

Top of page



### _III. [reserved] _IV. [reserved] _V. [reserved]
_VI. Bibliography
Chromium (VI) CASRN
— 18540
- 29
- 9 Last Revised

— 09/03/1998 

### _VI.A. Oral RfD References
Anwar, RA; Langham, FF; Hoppert, CA; et al. (1961) Chronic toxicity studies. III. Chronic toxicity of cadmium and chromium in dogs. Arch Environ 3:456
- 460.

### 68

Bruynzeel, DP; Hennipman, G; van Ketel, WG. (1988) Irritant contact dermatitis and chromium
passivated metal. Contact Derm 19:175
- 179.
Burrows, D; A dams, RM. (1990) In: Occupational skin disease, 2nd ed., Adams, RM, d. Philadelphia: W.B. Saunders, pp. 349
- 386. Cronin, E. (1980) Contact dermatitis. New York: Churchill Livingstone, pp. 287
- 390. Elbetieha, A; Al
- Hamood, MH. (1997) Long
- term exposure of male and female mice to trivalent and hexavalent chromium compounds: effect on fertility. Toxicology 116:19
- 47. Fregert, S. (1981) Chromium valencies and cement dermatitis. Br J Dermatol 105 (suppl. 21):7
- 9. Gruber, JE; Jennette, KW. (1978) Metabolism o f the carcinogen chromate by rat liver microsomes. Biochem Biophys Res Commun 82(2):700
- 706. Hunter, D. (1974) The diseases of occupations, 5th ed. Boston: Little, Brown. Junaid, M; Murthy, RC; Saxena, DK. (1996) Embryotoxicity of orally administered chr omium in mice: exposure during the period of organogenesis. Toxicol Lett 84:143
- 148. Kanojia, RK; Junaid, M; Murthy, RC. (1996) Chromium induced teratogenicity in female rat. Toxicol Lett 89:207
- 213. MacKenzie, RD; Byerrum, RU; Decker, CF; et al. (1958) Chronic toxicity studies. II. Hexavalent and trivalent chromium administered in drinking water to rats. Am Med Assoc Arch Ind Health 18:232
- 234. National Toxicology Program (NTP). (1996a) Final Report. Potassium dichromate (hexavalent): The effects of pot assium dichromate on Sprague
- Dawley rats when administered in the diet. December 13, 1996. National Toxicology Program (NTP). (1996b) Final Report. Potassium dichromate (hexavalent): The effects of potassium dichromate in BALB/c mice when administered in the diet. November 27, 1996. National Toxicology Program (NTP). (1997) Final Report. Potassium dichromate (hexavalent): Reproductive assessment by continuous breeding when administered to BALB/c mice in the diet. February 18, 1997. Petrilli, FL; DeFlora, S. (1977) Toxicity and mutagencity of hexavalent chromium on Salmonella

### 69

typhimurium. Appl Environ Microbiol 33(4):805
- 809. Petrilli, FL; DeFlora, S. (1978) Oxidation of inactive trivalent chromium to the mutagenic hexavalent form. Mutat Res 58(2
- 3):167
- 1 78. Polak, L. (1983) Immunology of chromium. In: Chromium: metabolism and toxicity. Burrows, D, ed. Boca Raton, FL: CRC Press, pp. 51
- 135. Polak, L; Turk, JL; Frey, FR. (1973) Studies on contact hypersensitivity to chromium compounds. Progr Allergy 17:14 5
- 219. Spruit, D; van Neer, FCJ. (1966) Penetration rate of Cr(III) and Cr(VI). Dermatological 132:179
- 182. U.S. Environmental Protection Agency (U.S. EPA). (1984) Health effects assessment for hexavalent chromium. Prepared by the Office of Health and En vironmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. (1985) Drinking water health advisory for chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Drinking Water, Washington, DC. U.S. EPA. (1998) Toxicological review of hexavalent chromium. Available online at http://www.epa.gov/iris
. Zhang, J; Li, X. (1987) Chromium pollution of soil and water in Jinzhou. J of Chinese Preventive Med 21:262
- 264.

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### _VI.B. Inhalation RfC R eferences
Beck, BD; Brain, JD; Bohannon, DE. (1982) An in vivo hamster bioassay to assess the toxicity of particles for the lungs. Toxicol Appl Pharmacol 66:9
- 29. Cohen, SR; Davis, DM; Kramkowski, RS. (1974) Clinical manifestations of chronic acid toxicit y -- Nasal lesions in electroplate workers. Cutis 13:558
- 568.

### 70

Glaser, U; Hochrainer, D; Kloppe, H; et al. (1985) Low level chromium (VI) inhalation effects on alveolar macrophages and immune function in Wistar rats. Arch Toxicol 57(4):250
- 256. Glaser, U; Hochrainer, D; Steinhoff, D. (1990) Investigation of irritating properties of inhaled Cr(VI) with possible influence on its carcinogenic action. In: Environmental Hygiene II. Seemayer, NO; Hadnagy, W, eds. Berlin/New York: Springer
- Verlag. Henderson, RF. (1984) Use of bronchoalveolar lavage to detect lung damage. Environ Health Perspect 56:115
- 129. Henderson, RF. (1988) Use of bronchoalveolar lavage to detect lung damage. In: Toxicology of the lung. Gardner, DE; Crapo, JD; Masaro, EJ, eds., New York: Rave n Press. Henderson, RF; Benson, JM; Hahn, FF. (1985) New approaches for the evaluation of pulmonary toxicity: bronchoalveolar lavage fluid analysis. Fundam Appl Toxicol 5:451
- 458. Lees, PSJ; Gibb, HJ; Rooney, BC. (1995) Derivation of exposure
- response re lationship for chromium from historic exposure data. 11th International Symposium of Epidemiology in Occupational Health, the Netherlands, September 1995. Lindberg, E; Hedensteirna, G. (1983) Chrome plating: Symptoms, finding in the upper airways and effe cts on lung function. Arch Environ Health 38:367
- 374. Lucas, JB; Kramkowski, RS. (1975) Health Hazard Evaluation Report No. 74
- 87
- 221. Cincinnati, OH. Health Hazard Evaluation Branch, U.S. Department of Health, Education, and Welfare, Public Health Servic e, Center for Disease Control. National Institute for Occupational Safety and Health. Malsch, PA; Proctor, DM; Finley, BL. (1994) Estimation of a chromium inhalation reference concentration using the benchmark dose method: a case study. Regul Toxicol Phar macol 20:58
- 82. U.S. EPA. (1998) Toxicological review of hexavalent chromium. Available online at http://www.epa.gov/iris
. Venet, A; Clavel, F; Israel
- Biet, D; et al. (1985) Lung in acquired immune deficie ncy syndrome: Infectious and immunological status assessed by bronchioalveolar lavage. Bull Eur Physiopathol Respir 21:535
- 543.

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### 71

_VI.C. Carcinogenicity Assessment References

Ald erson, MR; Rattan, NS; Bidstrup, L. (1981) Health of workmen in the chromate
- producing industry in Britain. Br J Ind Med 38:117
- 124. Baetjer, AM. (1950a) Pulmonary carcinoma in chromate workers. In: A review of the literature and report of cases. Arch Ind Hyg Occup Med 2(5):487
- 504. Baetjer, AM. (1950b) Pulmonary carcinoma in chromate workers. II. Incidence on basis of hospital records. Arch Ind Hyg Occup Med 2(5):505
- 516. Bidstrup, PL. (1951) Carcinoma of the lung in chromate workers. Br J Med 8:302
- 305
. Bidstrup, PL; Case, RAM. (1956) Carcinoma of the lung in workmen in the bichromates
- producing industry in Great Britain. Br J Ind Med 13:260
- 264. Bonatti, S; Meini, M; Abbondandolo, A. (1976) Genetic effects of potassium dichromate in Schizosaccharomyc es pombe. Mutat Res 38:147
- 150. Bourne, HG, Jr; Yee, HT. (1950) Occupational cancer in a chromate plant
- an environmental appraisal. Ind Med Surg 19(12):563
- 567. Brinton, HP; Frasier, ES; Koven AL. (1952) Morbidity and mortality experience among chromat e workers. Public Health Rep 67(9):835
- 847. Casto, BC; Meyers, J; DiPaolo, JA. (1979) Enhancement of viral transformation for evaluation of the carcinogenic or mutagenic potential of inorganic metal salts. Cancer Res 39:193
- 198. Davies, JM. (1978) Lung
- c ancer mortality in workers making chrome pigments. Lancet 1:384. Davies, JM. (1979) Lung cancer mortality of workers in chromate pigment manufacture: An epidemiological survey. J Oil Chem Assoc 62:157
- 163. Davies, JM. (1984) Lung cancer mortality among workers making lead chromate and zinc chromate pigments at three English factories. Br J Ind Med 41:158
- 169. De Flora, S; Wetterhahn, KE. (1989) Mechanisms of chromium metabolism and genotoxicity. Life Chem Rep 7:169
- 244. De Flora, S; Bagnasco, M; Serra, D; et al. (1990) Genotoxicity of chromium compounds: a review. Mutat Res 238:99
- 172.

### 72

Enterline, PE. (1974) Respiratory cancer among chromate workers. J Occup Med 16:523
- 526. Fradkin, A; Janoff, A; Lane, BP; et al. (1975) In vitro transformation of BHK21 cells grown in the presence of calcium chromate. Cancer Res 35:1058
- 1063.
Frentzel
- Beyme, R. (1983) Lung cancer mortality of workers employed in chromate pigment factories. A multicentric European epidemiological study. J Cancer Res Clin Oncol 105:183
- 18 8. Furst, A; Schlauder, M; Sasmore, DP. (1976) Tumorigenic activity of lead chromate. Cancer Res 36:1779
- 1783. Glaser, U; Hochrainer, D; Kloppel, H; et al. (1986) Carcinogenicity of sodium dichromate and chromium(VI/III) oxide aerosols inhaled by male Wi star rats. Toxicology 42:219
- 232. Haguenor, JM; Dubois, G; Frimat, P; et al. (1981) Mortality due to bronch
- pulmonary >cancer in a factory producing pigments based on lead and zinc chromates. In: Prevention of occupational cancer - International symposium , occupational safety and health series 46. Geneva, Switzerland: International Labour Office, pp. 168
- 176. (French). Hayes, RB; Lilienfeld, AM; Snell, LM. (1979) Mortality in chromium chemical production workers: a prospective study. Int J Epidemiol 8(4): 365
- 374. Hayes, RB; Sheffet, A; Spirtas, R. (1989) Cancer mortality among a cohort of chromium pigment workers. Am J Ind Med 16:127
- 133. Hill, WJ; Ferguson, WS. (1979) Statistical analysis of epidemiological data from chromium chemical manufacturing plan t. J Occup Med 21:103
- 106. Hueper, WC. (1961) Environmental carcinogenesis and cancers. Cancer Res 21:842
- 857. Hueper, WC; Payne, WW. (1962) Experimental studies in metal carcinogenesis: Chromium, nickel, iron, and arsenic. Arch Environ Health 5:445
- 462
. Hill, WJ; Ferguson, WS. (1979) Statistical analysis of epidemiological data from a chromium chemical manufacturing plant. J Occup Med 21(2):103
- 106. Kawanishi, S; Inoue, S; Sano, S. (1986) Mechanism of DNA cleavage induced by sodium chromate (VI) in th e presence of hydrogen peroxide. J Biol Chem 261:5952
- 5958. Klein, CB; Frenkel, K; Costa, M. (1992) Chromium mutagenesis in transgenic gpt+ Chinese hamster

### 73

cell lines. Environ Mol Mutagen 19:29a. Klein, CB; Frenkel, K; Costa, M. (1991) The role of oxidat ive processes in metal Carcinogenesis. Chem Res Toxicol 4:592
- 604. Korallus, U; Lange H; Ness, A; et al. (1982) Relationships between precautionary measures and bronchial carcinoma mortality in the chromate
- producing industry. Arbeitsmedizin, Socialmedizi n, Preventivmedizin. 17(7):159
- 167. (German
- Eng. summary) Langard, S; Norseth, T. (1975) A cohort study of bronchial carcinomas in workers producing chromate pigments. Br J Ind Med 32:62
- 65. Langard, S; Vigander, T. (1983) Occurrence of lung cancer in workers in producing chromium pigments. Br J Ind Med 40:71
- 74. Laskin, S; Kuschner, M; Drew, RT. (1970) Studies in pulmonary carcinogenesis. In: Hanna, Jr., MG;, Nettesheim, P; and Gilbert, JR, eds. Levis, AG; Buttignol, M; Bianchi, V; et al. (1978) Eff ects of potassium dichromate on nucleic acid and protein syntheses and on precursor uptake in BHK fibroblasts. Cancer Res 38:110
- 116. Levy, LS; Martin, PA. (1983) The effects of a range of chromium
- containing materials on rat lung. Sponsored by Dry Color Manufacturers' Association and others. (Unpublished) Loeb, LA; Sirover, MA; Agarwal, SS. (1977) Infidelity of DNA synthesis as related to mutagenesis and carcinogenesis. Adv Exp Biol Med 91:103
- 115. Lofroth, G. (1978) The mutagenicity of hexavalent chrom ium is decreased by microsomal metabolism. Naturvissenschaften 65:207
- 208. Machle, W; Gregorius, F. (1948) Cancer of the respiratory system in the United States chromate
producing industry. Public Health Rep 63(35):1114
- 1127. Maltoni, C. (1974) Occupatio nal carcinogenesis. Excerpta Med Int Congr Ser 322:19
- 26. Maltoni, C. (1976) Predictive value of carcinogenesis bioassays. Ann NY Acad Sci 271:431
- 443. Mancuso, TF. (1975) Consideration of chromium as an industrial carcinogen. International Conference on Heavy Metals in the Environment, Toronto, Ontario, Canada, October 27
- 31. pp. 343
- 356.

### 74

Mancuso, TF. (1997) Chromium as an industrial carcinogen: Part 1. Am J Ind Med 31:129
- 139. Mancuso, TF; Hueper, WC. (1951) Occupational cancer and other health Hazard s in a chromate plant: A medical appraisal. In: Lung cancers in chromate workers. Ind Med Surg 20(8):358
- 363. Nakamuro, K; Yoshikawa, K; Sayato, Y; et al. (1978) Comparative studies of chromosomal aberration and mutagenicity of trivalent and hexavalent ch romium. Mutat Res 58:175
- 181. Newbold, RF; Amos, J; Connell, JR. (1979) The cytotoxic, mutagenic and clastogenic effects of chromium
- containing compounds on mammalian cells in culture. Mutat Res 67:55
- 63. National Institute for Occupational Safety and H ealth (NIOSH). (1975) Criteria for a recommended standard occupational exposure to chromium (VI). U.S. Department of Health, Education, and Welfare, Washington, DC. Ohsaki, Y; Abe, S; Kimura, K; et al. (1978) Lung cancer in Japanese chromate workers. Thor ax 33:372
- 374. Payne, WW. (1960a) The role of roasted chromite ore in the production of cancer. Arch Environ Health 1:20
- 26. Payne, WW. (1960b) Production of cancers in mice and rats by chromium compounds. Arch Ind Health 21:530
- 535. Petrilli, FL; DeFlo ra, S. (1977) Toxicity and mutagenicity of hexavalent chromium on Salmonella typhimurium. Appl Environ Microbiol 33(4):805
- 809. Petrilli, FL; DeFlora, S. (1978) Oxidation of inactive trivalent chromium to the mutagenic hexavalent form. Mutat Res 58:167
- 17 8. Raffetto, G; Parodi, S; Parodi, C; et al. (1977) Direct interaction with cellular targets as the mechanism for chromium carcinogenesis. Tumori 63:503
- 512. Royle, H. (1975) Toxicity of chromic acid in the chromium plating industry. Environ Res 10:141
- 1 63. Sano, T; Mitohara, I. (1978) Occupational cancer among chromium workers. Jpn J Chest Dis 37(2):90
- 101.

### 75

Satoh, K; Fukuda, Y; Torii, K; et al. (1981) Epidemiologic study of workers engaged in the manufacture of chromium compounds. J Occup Med 23(12):83 5
- 838. Sorahan, T; Burgess, DC; Waterhouse, JA. (1987) A mortality study of nickel/chromium platers. Br J Ind Med 44:250
- 258. Steinhoff, S; Gad, SC; Hatfield, GK; et al. (1983) Listing sodium dichromate and soluble calcium chromate for carcinogenicity in rats. Bayer AG Institute of Toxicology. (Unpublished) Sugiyama, M. (1992) Role of physiological antioxidants in chromium (VI)
- induced cellular injury. Free Rad Biol Med 12:397
- 407. Taylor, FH. (1966) The relationship of mortality and duration of employ ment as reflected by a cohort of chromate workers. Am J Public Health 56(2):218
- 229. Todd, GE. (1962) Tobacco manufacturer's standing committee research papers. No. 1. Statistics of Smoking in the United Kingdom, 3rd ed. Tobacco Research Council, London. Tsuda, H; Kato, K. (1977) Chromosomal aberrations and morphological transformation in hamster embryonic cells treated with potassium dichromate in vitro. Mutat Res 46:87
- 94. U.S. EPA. (1984) Health assessment document for chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA/600/8
- 83
- 014F. U.S. EPA. (1998) Toxicological review of hexavalent chromium. Available online at http://www.epa.gov/iris
. Watanabe, S; Fukuchi, Y. (1975) An epidemiological survey on lung cancer in workers of a chromate
- producing industry in Hokkaido, Japan. Presented at International Congress on Occupational Health.

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### _VII. Revision History
Chromium (VI) CASRN
— 18540
- 29
- 9

### 76 Date Section Description 09/30/1987 II.A.1. Citation corrected 03/01/1988 II.C.4. Confidence statement revised 03/01/1988 II.D.3. Contacts switched 03/01/1988 III.A. Health Advisory added 12/01/1989 I.B. Inhalation RfD now under review 06/01/1990 II.A.1. Basis
- Text revised 06/01/1990 II.B. Text revised 06/01/1990 IV.A.1. Area code for EPA contact corrected 06/01/1990 IV.F.1. EPA contact changed 06/01/1990 VI. Bibliography on
- line 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 03/01/1991 II.A.1 Text revised 03/01/1991 II.A.4. Text revised 03/01/1991 II.B. Text revised 01/01/1992 I.A.7. Secondary contact change 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 06/01/1992 All CASRN corrected from 7440
- 47
- 3 to 18540
- 29
- 9 09/01/1994 I.A.6. Work group review date added 02/01/1995 I.A. RfD noted as pending change: Work Grp Mtg on 08/03/1994
08/01/1995 I.A.,

I.A.6., I.B. 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 Pilo t Program replaced the

### 77 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. 12/01/1996 I.A.7. Secondary contact removed 09/03/1998 I., II., VI. Revised RfD, RfC, carcinogenicity assessment, refs.

10/28/2003 I.A.6.,

I.B.6., II.D.2. Screening
- Level Literature Review Findings message has been added.

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### _VIII. Synonyms
Chromium (VI) CASRN
— 18540
- 29
- 9 Last Revised

— 03/31/1987



###  18540
- 29
- 9


###  7440
- 47
- 3


###  Chromic ion


###  Chromium


###  Chromium, ion


###  Chromium (VI)


###  Chromium (VI) ion

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Chronic Health Hazards for Non - Carcinogenic Effects

Reference Dose for Chronic Oral Exposure (RfD)



###  Oral RfD Summary 

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### 78  Additional Studies/Comments 

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###  Inhalation RfC Summary 

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- of
- Evidence Characterization 

###  Huma n Carcinogenicity Data 

###  Animal Carcinogenicity Data 

###  Supporting Data for Carcinogenicity

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###  Summary of Risk Estimates 

###  Dose
- Response Data 

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### 79  EPA Home 

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- Is Last updated on Thursday, August 09, 2012

### 80

Mercury (as methyl mercury) ( http://www.epa.gov/iris/subst/0073.htm ) 

# Methylmercury (MeHg) (CASRN 22967 - 92 - 6)

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

Note: A Support Document for Methylmercury can be found on EPA's Office of Water Web site. The Summary and Response to the Peer Review for Methylmercury is also available in Adobe PDF format (23 Pages, 63 Kbytes).

Similar d ocuments can be found in the List of Available IRIS Toxicological Reviews.
0073 Methylmercury (MeHg); CASRN 22967 - 92 - 6
Human health assessment information on a chemical su bstance 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 prov ided in the guidance documents located on the IRIS website
. STATUS OF DATA FOR Methylmercury
File First On - Line 01/31/1987 Category (section) Status Last Revised Oral RfD Assessment (I.A.) on - line 07/27/2001 Inhalation RfC Assessment (I.B.) no data 07/27/2001 Carcinogenicity Assessment (II.) on - line 05/01/1995

### 81

_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects _I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name

— Methylmercury (MeHg) CASRN
— 22967
- 92
- 6 Last Revised

— 07/27/2001 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 lifet ime. 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. 

### __I.A.1. Oral RfD Summary

Critical Effect Experi mental Doses* UF MF RfD

Developmental neuropsychological impairment Human epidemiological studies (Grandjean et al., 1997; Budtz
- Jørgensen et al., 1999a) Benchmark Dose: BMDL 05 range of 46
- 79 ppb in maternal blood for different neuropsychological effects in the offspring at 7 years of age, corresponding to a range of maternal daily intakes of 0.857
- 1.472 μg/kg
- day 10 1 1E
- 4 mg/kg
- day (0.0001 mg/kg
- day)

*Conversion Factors and Assumptions

— Maternal daily dietary intake levels were used as the dose surrogate for the observed developmental effects in the children exposed in utero. The daily dietary intake levels were calculated from blood concentrat ions measured in the mothers with supporting additional values based on their hair concentrations. This conversion is explained in the text below. A benchmark dose approach (BMD) was used rather than a no
- observed
- adverse
- effect level/lowest

- observed
adverse
- effect level (NOAEL/LOAEL) approach to analyze the neurological e ffects in children as the response variable. This analysis is also explained in the text below.

### 82

This assessment updates the 1995 RfD assessment on IRIS and is the same as the RfD that was based on the study of a poisoning episode in Iraq in which developme ntal neurotoxicity was observed following ingestion of methylmercury
- treated grain (Marsh et al., 1987). 

### __I.A.2. Principal and Supporting Studies (Oral RfD)
Congress directed EPA, through the House Appropriations Report for Fiscal Year 1999, to contract w ith the National Research Council (NRC), a body of the National Academy of Sciences, to evaluate the available data on the health effects of methylmercury, with particular emphasis on new data since the publication of the Mercury Study Report to Congress ( MSRC) (U.S. EPA, 1997). NRC was asked to provide recommendations regarding issues relevant to the derivation of an appropriate RfD for methylmercury. The NRC report, "Toxicological Effects of Methylmercury," was released to the public on July 11, 2000 (NRC , 2000). This assessment reported here relied on the quantitative analyses performed by the NRC, as described in that report. Methylmercury is a highly toxic substance; a number of adverse health effects associated with exposure to it have been identified in humans and in animal studies. Most extensive are the data on neurotoxicity, particularly in developing organisms. The nervous system is considered to be the most sensitive target organ for which there are data suitable for derivation of an RfD.
There are three epidemiological studies for which quantitative analyses have become available since EPA's derivation of an RfD in 1995 (NRC, 2000). These longitudinal, developmental studies were conducted in the Seychelles Islands, the Faroe Islands, and New Zea land. The subjects of the Seychelles longitudinal prospective study were 779 mother
- infant pairs from a fish
- eating population (Myers et al., 1995a
- c, 1997; Davidson et al., 1995, 1998). Infants were followed from birth to 5.5 years of age, and assessed at various ages on a number of standardized neuropsychological endpoints. The independent variable was maternal
- hair mercury levels. The Faroe Islands study was a longitudinal study of about 900 mother
- infant pairs (Grandjean et al., 1997). The main independ ent variable was cord
- blood mercury; maternal
- hair mercury was also measured. At 7 years of age, children were tested on a variety of tasks designed to assess function in specific behavioral domains. The New Zealand study was a prospective study in which 3 8 children of mothers with hair mercury levels during pregnancy greater than 6 ppm were matched with children whose mothers had lower hair mercury levels (Kjellstrom et al., 1989, 1986). At 6 years of age, a total of 237 children were assessed on a number of neuropsychological endpoints similar to those used in the Seychelles study (Kjellstrom et al., 1989). The Seychelles study yielded scant evidence of impairment related to in utero methylmercury exposure, whereas the other two studies found dose
- related effects on a number of neuropsychological endpoints. In the assessment described here, emphasis is placed on the results of the Faroe Islands study, the larger of the two studies that identified methylmercury
- related developmental neurotoxicity. Supporting evidence from the New Zealand study provides assurance that choosing this focus is the appropriate strategy

### 83

for protecting public health. In addition, of all three studies an integrative analysis is set out later in this assessment report.
EPA chose BMD analysis as the most appropriate method of quantifying the dose
- effect relationship in these studies, which was also the recommendation of the NRC (2000). EPA chose the K power model for BMD analysis, with the constraint that K >= 1, such that the model pr ecludes supralinearity. There is no identified mechanism by which methylmercury would produce a supralinear response; therefore the K power model was thought to have more biological plausibility compared with other models. A power of 1 provided the best fi t of the Faroese data using the K power model (Budtz
- Jørgensen et al., 1999b, 2000), so this model was used in this RfD derivation. A value of P 0 = 0.05 was used: that is, the cutoff for abnormal response was set at the lowest 5% (5 th percentile) of childr en. Most human characteristics, including children's neurodevelopmental abilities, have an approximately bell
- shaped or "normal" distribution. Generally speaking, children who function at or below approximately the 5 th percentile are considered significant ly developmentally compromised for the ability that is being measured (e.g., IQ < 75, or comparable standard scores for more specific abilities such as attention, language, or memory). A BMR of 0.05 was chosen for this assessment, which would result in a d oubling of the number of children with a response at the 5 th percentile of the population. This choice was particularly appropriate, because effects were identified on a number of neuropsychological endpoints in the offspring at approximately the same body burden in the mother. A benchmark dose lower limit (BMDL 05 ) (the lower 95% confidence limit of the BMD 05 ) was calculated for each endpoint described above from the three studies.

DOSE CONVERSION
The biomarker of choice for the Faroese data was cord bloo d, and the BMDLs were reported in units of ppb mercury in cord blood. In order to calculate an RfD, it is necessary to convert this figure to an ingested daily amount that would result in exposure to the developing fetus at the BMDL level in terms of ppb m ercury in blood. EPA chose the one
- compartment model for dose conversion for this RfD. This model has shown reasonably good fit to data on mercury blood
- level changes in human subjects during and after consumption of methylmercury
- contaminated fish (Ginsbe rg and Toal, 2000). The model is described by the formula below: d= (c x b x V)/(A x f x bw) μg/kg/day

where



###  d = daily dietary intake (expressed as μg of methylmercury)


###  c = concentration in blood (expressed as μg/L)

### 8 4  b = elimination constant (expressed as days - 1 )


###  V = volume of blood in the body (expressed as liters)


###  A = absorption factor (expressed as a unitless decimal fraction)


###  f = fraction of absorbed dose taken up by blood (unitless)


###  bw = body weight (expressed in kg)
In this one
- compartment model, all maternal compartments are compressed to one: namely, blood. It is assumed that the blood methylmercury concentration is at steady state. Concentration in blood (c)
The concentration in blood corresponds to the BMDL 05 . Fraction of mercury in diet that is absorbed (A) After administration of radiolabeled methylmercuric nitrate in water to three healthy volunteers, uptake was reported to be >95 % (Aberg et al., 1969). This value is suppor ted by experiments involving human volunteers conducted by Miettinen et al. (1971). It is generally believed that absorption of ingested methylmercury is high and not likely to vary a great deal. An absorption factor of 0.95 was used as in the Mercury Stud y Report to Congress (U.S. EPA, 1997). Fraction of the absorbed dose that is found in the blood (f) Currently, four published reports address the fraction of absorbed methylmercury dose distributed to blood volume in humans. Kershaw et al. (1980) reporte d an average fraction of 5.9% of absorbed dose in total blood volume, based on a study of five adult male subjects who ingested methylmercury
- contaminated tuna. In a group of nine male and six female volunteers who had received 203 Hg
- methylmercury in fish, approximately 10% of the total mercury body burden was present in 1 L of blood in the first few days after exposure; this amount dropped to approximately 5% over the first 100 days (Miettinen et al., 1971). In another study, an average value of 1.14% for the percentage of absorbed dose per kg of blood was derived from data on subjects who consumed a known amount of methylmercury in fish over a 3
- month period (Sherlock et al., 1984). Average daily intake in the study ranged from 43 to 233 μg/day, and there was a dose
- related effect on percentage of absorbed dose that ranged from 1.03% to 1.26% in 1 L of blood. Smith et al. (1994) administered radiolabeled methylmercury to seven subjects. The paper presented published modeled data rather than observations; th e mean fraction of absorbed dose in blood was 7.7% (SD, 0.88%). Stern (1997) noted that although the Smith et al. (1994) and Kershaw et al. (1980) data could be fit by a log
- normal distribution, the data sets were too small for a reasonable determination of the underlying distributions. Stern used the mean and standard deviation of those two data sets for average parameter values as inputs to the log
- normal distribution; the average of the means is

### 85

0.067. Swartout and Rice (2000) used the observations publ ished by Kershaw et al. (1980), Miettinen et al. (1971), and Sherlock et al. (1984) as adjusted for 5 L of blood as inputs with a log
triangular distribution. The median value was 5.9% or 0.059, close to the values of 0.05 used in the MSRC and by other gro ups (e.g., Berglund et al., 1971; WHO, 1990). EPA chose to use the median value of 0.059 published by Swartout and Rice (2000) for f in the dose conversion. Elimination constant (b) Currently, five studies report clearance half
- times for methylmercury f rom blood or hair: Miettinen et al. (1971), Kershaw et al. (1980), Al
- Shahristani et al. (1974), Sherlock et al. (1984), and Smith et al. (1994). The clearance half
- lives for blood in these reports are quite variable, ranging from 32 to 189 days. In the Al
- Shahristani et al. (1974) study, 10% of the sample population had mercury half
- lives of 110 to 120 days. Average mercury half
- lives as gleaned from the five publications are 45 to 70 days. The MSRC (U.S. EPA, 1997) used an average elimination constant fro m four of the studies (data from Smith et al. [1994] were not used). The corresponding elimination constant of 0.014 days - 1 also was noted to be the average of individual values reported for 20 volunteers ingesting from 42 to 233 μg mercury/day in fish for 3 months (Sherlock et al., 1982). Swartout and Rice (2000) applied a log
- triangular distribution to the data from the five extant studies. They noted that the distribution was highly skewed and that the median was 53 days; the corresponding elimination c onstant was 0.013 days - 1

. Stern (1997) discussed the variability in the data sets. His analysis of variance indicated significant differences among the sets, which were eliminated when the Al
- Shahristani data were removed. The author observed that the hal f
- lives reported by Al
- Shahristani were larger than those observed in the other studies. Stern offers the opinion that this difference may result from relatively large size of the Al
- Shahristani data set as compared with the others. Stern says that an alte rnative explanation is that the Al
- Shahristani data reflect a genetic polymorphism in the metabolism occurring with higher frequency in the Iraqi population, which was the subject of this study. In his analyses, Stern (1997) treated the Al
- Shahristani data both separately and in combination with the data from the other four studies. He reported a mean elimination constant of 0.011 days - 1 for the Al
- Shahristani data alone; the combined data set mean elimination constant was 0.014 days - 1

. The decision to sel ect point estimates for dose conversion parameters was done in this assessment with the acknowledgment that some of the variability around these parameters would be truncated. This loss was compensated for by using a pharmacokinetic uncertainty factor. Nev ertheless, it did not seem prudent to select a point estimate, which is meant to reflect a population's central tendency, from one data set only. The two central tendency estimates of Swartout and Rice (2000) and Stern (1997) were very close in value (0.01 3 versus 0.014); the differences presumably

### 86

resulted from the application of different distribution types. In this assessment the value of 0.014 days - 1 was used for b in the dose conversion. Volume of blood in the body (V) Stern (1997) cited three studies (Brown et al., 1962; Retzlaff et al., 1969; Huff and Feller, 1956) wherein correlation of body weight and blood volume were demonstrated. All studies were of U.S. women, presumably not pregnant at the time of the study. The mean blood volumes for each study were 3.58 L, 3.76 L, and 3.49 L, respectively; the mean of the combined data set is 3.61 L. If one assumes a 30% increase in blood volume with pregnancy, this would be 4.67 L. In their analysis, Swartout and Rice (2000) u sed data from a cohort of 20 pregnant Nigerian women (Harrison, 1966). Whole
- blood volumes in the third trimester ranged from 4 to 6 L; the mean and median were both 5 L. Although 5 L is somewhat higher than the blood volume estimated from three studies of U.S. women, it is a reasonable value to use for V
. Body weight (bw) Swartout and Rice (2000) in their distributional analysis used the body weight data collected on the cohort of 20 pregnant Nigerian women (Harrison, 1966); this was the data set that th ey used for blood volume. Body weight during the third trimester of pregnancy ranged from 49.5 kg to 73.9 kg, with a geometric mean of 55 kg. Stern (1997) used the Third National Health and Nutritional Survey (NHANES III) data for women 18 to 40 years old (NCHS, 1995). The mean weight was 66.6 kg and the 50th percentile value was 62.8 kg. The EPA Methodology for Deriving Ambient Water Quality Criteria for the Protection of Human Health (U.S. EPA, 2000) also cites NHANES III data; in the agency document, wom en of childbearing age were considered to be between the ages of 15 and 44 years old. The median body weight in this group was 63.2 kg and the mean was 67.3 kg. EPA also cites the earlier analyses of Ershow and Canter (1989); they do not state the age rang e but give a median of 64.4 kg and a mean of 65.8 kg. The recommendation in the EPA Methodology was to use a body weight value of 67 kg for a pregnant woman on the basis of the relatively current data from NHANES III. This value was used for body weight in the dose conversion. Dose conversion using the one - compartment model d= (c x b x V)/(A x f x bw)
d= (BMDL 05 μg/L x 0.014days - 1 x 5L)/(0.95 x 0.059 x 67 kg)

BMD ANALYSIS OF THE FAROE ISLANDS STUDY The Faroe cohort was exposed to polychlorinated biphenyls (PCBs) as well as to methylmercury. An association was identified between PCB levels in cord tissue and four measures for which an effect

### 87

of methylmercury also was identified (Grandjean et al., 1997 ). Analyses performed by the Faroe investigators indicate that the effects of methylmercury and PCBs are independent of each other (Budtz
- Jørgensen et al., 1999a). Further, NRC presented an analysis of benchmark analyses designed to explore the influence o f PCBs (Table 1). PCB measurements were made on cord tissue taken from about one
- half of the Faroese cohort (about 450 children) and the "adjusted for PCBs" values are based on those children for whom PCB cord tissue levels and cord
- blood mercury levels we re available. PCB
- adjusted analyses also were conducted of children in the lowest tertile with respect to PCB levels, which reduced the number of children studied to about 150. No clear pattern arose from a comparison of the PCB
- adjusted analyses and the o riginal results. The observed variability probably was no more than that which would be expected to exist by chance alone. This analysis provides compelling evidence that the effects of methylmercury identified in this study are not the consequence of expo sure to PCBs.
BMD ANALYSIS OF ALL THREE EPIDEMIOLOGICAL STUDIES Benchmark dose analyses were performed for a number of endpoints from all three studies (Faroe Islands, Seychelles, New Zealand) (NRC, 2000, Chapter 7). NRC estimated a central tendency meas ure, equivalent to a BMD, across all three studies for all endpoints that were identified as significant in the Faroe Islands and New Zealand studies, and for all endpoints at 5.5 years of age in the Seychelles study. They also determined a lower limit bas ed on a theoretical distribution of BMDs, which is the logical equivalent of a BMDL.
NRC also used a hierarchical random
- effect model to reduce random variation in the estimate for these same endpoints from all three studies (NRC, 2000, Table 7
- 5, pp. 290
- 294). Additionally, this analysis was used in calculating BMD and BMDLs for the most sensitive and median endpoints from both the Faroe Islands and New Zealand studies (NRC, 2000, Table 7
- 6, p. 294). This approach also allowed an integrative analysis of d ata from all three studies.

### 88

Table 1. BMD (BMDL) Estimates from the Faroe Islands Study with and without Adjustment for PCBs and in the Subset of Children Whose PCB Exposure Was Low (calculated using the K
- power model)

Exposure Endpoint a Full Cohort Ad justed for PCBs Low - PCB

Tertile
BMD 05 (BMDL 05 ) b BMD 05 (BMDL 05 ) BMD 05 (BMDL 05 ) Maternal
- hair (ppm) Finger tapping 20 (12) 17 (9) 7 (4)

CPT reaction time 18 (10) 27 (11) 13 (5)

BNT 15 (10) 24 (10) 21 (6) CVLT: delayed recall 27 (14) 39 (12) 32 (7)
Cord blood (ppb) Finger tapping 140 (79) 149 (66) 41 (24)

CPT reaction time 72 (46) 83 (49) 53 (28)

BNT 85 (58) 184 (71) 127 (40) CVLT: delayed recall 246 (103) 224 (78) 393 (52)

a CPT = Continuous Performance Test; BNT = Boston Naming Test; CVLT = California Verbal Learning Test. b BMDs are calculated under the assumption that 5% of the responses will be abnormal in unexposed subjects (P 0 = 0.05), assuming a doubling of the excess risk (BMR = 0.05).
Source: E. Budtz
- Jørgensen, Copenhagen Univ ersity, N. Keiding, Copenhagen University, and P. Grandjean,University of Southern Denmark, unpublished material, April 28, 2000, in Table 7
- 4, p. 289, NRC 2000. Table 2 presents BMDL 05 s from a number of endpoints in terms of cord
- blood mercury. These tes ts are all indications of neuropsychological processes involved in a child's ability to learn and process information. The BMDLs for these scores are all within a relatively close range. They were converted using a one
- compartment model to an ingested dose of methylmercury that would result in the cord
- blood level. The last column shows the corresponding RfD from application of a UF of 10 (see next section). The calculated RfD values converge at the same point: 0.1 μg/kg/day. Among the endpoints from the Fa roe Islands study were three deviations from 0.1 μg/kg/day: 0.2 μg/kg/day

### 89

for the CVLT entire cohort and 0.05 μg/kg/day for CPT and Finger Tapping, the lowest PCB tertile. EPA also calculated geometric means from the four endpoints from the Faroe Islands s tudy; RfDs were 0.1 μg/kg/day based on these calculations. For the New Zealand study smoothed values, both the median value and the results of the McCarthy Perceived Performance test yielded RfDs of 0.05 μg/kg/day, and the McCarthy Motor Test yields an RfD of 0.1 μg/kg/day. Based on the integrative analysis of all three studies, the RfD would be 0.1 μg/kg/day Table 2. Comparison of BMDL 05 s and Corresponding RfDs from Faroes, New Zealand, and NRC Integrative Analysis a

Test b BMDL 05 ppb mercury cord Ingested

dose μg;/kg/day c RfD

μg/kg/day d

BNT Faroes
Whole cohort 58 1.081 0.1
PCB
- adjusted 71 1.323 0.1
Lowest PCB 40 0.745 0.1
CPT Faroes
Whole cohort 46 0.857 0.1
PCB
- adjusted 49 0.913 0.1
Lowest PCB 28 0.522 0.05
CVLT Faroes
Whole cohort 103 1.920 0.2
PCB
- adjusted 78 1.454 0.1
Lowest PCB 52 0.969 0.1 Finger Tap Faroes
Whole cohort 79 1.472 0.1
PCB
- adjusted 66 1.230 0.1
Lowest PCB 24 0.447 0.05

### 90 Test b BMDL 05 ppb mercury cord Ingested

dose μg;/kg/day c RfD

μg/kg/day d

Geometric mean Faroes
Whole cohort 68 1.268 0.1
PCB
- adjusted 65 1.212 0.1
Lowest PCB 34 0.634 0.1
Smoothed values
BNT Faroes 48 0.895 0.1
CPT Faroes 48 0.895 0.1
CVLT Faroes 60 1.118 0.1 Finger Tap Faroes 52 0.969 0.1
MCCPP New Zealand 28 0.522 0.05
MCMT New Zealand 32 0.596 0.1
Median values
Faroes 48 0.895 0.1
New Zealand 24 0.447 0.05 Integrative All endpoints 32 0.596 0.1

a BMDL 05 s from NRC (2000), Tables 7
- 4, 7
- 5, 7
- 6. Hair mercury was converted to blood mercury using a250:1 ratio (WHO, 1990) and an assumption of equivalent maternal and cord levels. b BNT = Boston Naming Test; CPT = Continuous Performance Test; CVLT = California Verbal Learning Test;MCCPP = McCarthy Perceived Performance; MCMT = McCarthy Motor Test.
c Calculated using a one
- compartment model. d Calculated usin g an UF of 10.

### 91

Rather than choose a single measure for the RfD critical endpoint, EPA based this RfD for thisassessment on several scores from the Faroes measures, with supporting analyses from the New Zealandstudy, and the integrative analysis of all thr ee studies. 

### __I.A.3. Uncertainty and Modifying Factors (Oral RfD)

UF = 10.

MF = 1. In its report, NRC presented an analysis of the interindividual variability in the ingested dose of methylmercury corresponding to a given maternal
- blood or hair
- mercury c oncentration (NRC, 2000, pp.83
- 95). NRC cited two analyses of the variability and uncertainty in the ingested dose estimates based on the one
- compartment model (Stern, 1997; Swartout and Rice, 2000) as well as similar analysis of a PBPKmodel (Clewell et al ., 1999). In general, all three analyses found similar ranges of variability due to pharmacokinetic factors. The ratios of estimated ingested doses at the 50 th percentile/99 th percentile ranged from 1.7 to 3.3. Using maternal blood as the starting point, t he consolidated range from the three analyses is 1.7 to 3.0. Investigators have found that the placenta is not a barrier to the transfer of methylmercury from the mother to the developing fetus. Typically, a strong correlation exists between maternal
- bloo d mercury concentrations and fetal
- blood mercury concentrations, as shown by cord
- blood. A review of the literature identified 21 studies that reported cord
- blood mercury and maternal blood mercury data (Amin
- Zaki et al., 1974; Baglan et al., 1974; Dennis and Fehr, 1975; Pitkin et al., 1976; Kuhnert et al., 1981; Nishima et al., 1977; Lauwerys et al., 1978; Fujita and Takabatake, 1977; Kuntz et al., 1982; Tsuchiya et al., 1984; Truska et al., 1989; Sikorski et al., 1989; Hansen et al., 1990; Soong et al.,19 91; Soria et al., 1992; Ong et al., 1993; Akagi et al., 1997; Yang et al., 1997; Ramirez et al., 2000; Bjerregaard and Hansen, 2000; Vahter et al., 2000). Overall, data from these studies indicate that cord
- blood mercury is higher than maternal blood mercu ry. The composite ratio from the studies reporting methylmercury concentrations indicates that the cord
- blood: maternal blood ratio is around 1.7. These values are ratios of means and do not reflect the full range of variability in the individual mother
- fe tal pairs. Vahter et al. (2000) reported the 5 th and 95 th percentiles of cord:maternal Hg to be 0.88 and 3.1. Individual data were available from Fujita and Takabatake (1997); ratios calculated from these data ranged from 0.78 to 4.36.
EPA has chosen not to make a numerical adjustment between cord
- blood and maternal
- blood mercury. At this time the relationship between cord
- blood and maternal
- blood mercury is considered subject to variability and uncertainty, and is to be included in the determination of th e uncertainty factor (UF).

### 92

CHOICE OF UNCERTAINTY FACTOR An RfD is based on human data, so an interspecies UF was not needed. The points of departure were the BMDL for a number of endpoints from the Faroe Islands study, with supporting analyses from the New Zealand study, and an integrative analysis of all three recent large epidemiological studies. RfDs derived from these BMDLs all converged on the same value; this convergence provides reassurance that additional UFs, other than for intraspecies variability, are not needed. Further, no issues were identified tha t indicated the need for a modifying factor (i.e., MF = 1). The two major phenomena included in the intraspecies UF for methylmercury were interindividual toxicokinetic variability in ingested dose estimation and pharmacodynamic variability and uncertaint y. For the former, EPA relied in part on the NRC analyses of variability in the pharmacokinetic factors underlying the conversion of a biomarker level of methylmercury to an ingested daily dose of methylmercury that corresponds to that level. EPA chose not to make a numerical adjustment in the dose conversion for the potential differences between cord
- and maternal
- blood mercury levels, but rather toconsider them additional aspects of toxicokinetic variability and uncertainty.
A quantitative uncertainty an alysis of toxicodynamics was not possible. However, the population of the Faroe Islands is descended from Scandinavian stock that settled many generations ago, and is extremely homogeneous. The average toxicodynamic response of this population compared wit h that of the United States, which is genetically much more diverse, is unknown. Similarly, the relative variability of different populations also is unknown. A threefold UF for toxicodynamic variability and uncertainty was applied. In calculating the met hylmercury RfD for this assessment, a composite UF of 10 was used. This choice was made to account for the following factors:
1. Pharmacokinetic variability and uncertainty in estimating an ingested mercury dose from cord
- blood mercury concentration: a factor of 3 was applied. 2. Pharmacodynamic variability and uncertainty: a factor of 3 was applied. Choosing an overall UF of 10 is supported by additional analyses of the Faroese neuropsychological data, wherein the observations made of the most highly exposed sub group were excluded from the model (Grandjean et al., 1997). Associations remained significant when the part of the cohort with maternal
- hair mercury concentrations greater than 10 ppm was excluded from the analyses. This finding indicates that it would be reasonable to expect some percentage of the population to show effects at or below 10 ppm hair mercury, or at levels at or below 40 ppb cord
- blood. It is also important to note that no evidence of a threshold arose for methylmercury
- related neurotoxicity within the range of exposures in the Faroe Islands study. This lack is indicated by the

### 93

fact that, of the K power models, K = 1 provided a better fit for the endpoint models than did highervalues of K.

ADDITIONAL IDENTIFIED DATA GAPS
Areas were identifi ed that require additional research and/or analysis.
Cardiovascular effects There are two recently published studies show an association between low
- level methylmercury exposure and cardiovascular effects. Sørensen et al. (1999) reported that in a study of 1,000 7
- year - old Faroese children, diastolic and systolic blood pressures i ncreased by 13.9 and 14.6 mm Hg, respectively, as the cord
- blood mercury increased from 1 to 10 μg/L. They also reported a 47% decrease in heart rate variability (an indication of cardiac autonomic control) for the same increase in cord
- blood mercury. Salo nen et al. (1995) reported effects in adults from a study of 1,833 Finnish men. Over the 7
- year observation period, men with hair mercury in the highest tertile (2 ppm or higher) had a 2.0 times greater risk of acute myocardial infarction than the rest of the study population. Persistent and delayed neurotoxicity Another area of concern is the onset or exacerbation of neurological deficits in aging populations previously exposed to methylmercury. In a follow
- up study of the Minamata population, Kinjo et a l. (1993) reported a high prevalence of sensory disturbance in people with Minamata disease (MD). Also evaluated were "acts of daily living" (ADL) that included the abilities to independently eat, bathe, wash, dress, and use the toilet. The prevalence of d eficits was relatively greater in persons with MD compared with controls as a function of increasing age. In other words, exposure to methylmercury three decades earlier accelerated the aging process in aged individuals relative to younger ones. Fukuda et al. (1999) evaluated adults who lived in a methylmercury
- polluted area near Minamata City in Japan's Kumamoto Prefecture but who were not designated MD patients; the authors then compared them with age
- matched adults. Complaints that were significantly mor e frequent in methylmercury
- contaminated areas included heart palpitation, dysesthesia, staggering when standing, resting and intention tremor in the hands, dizziness (especially when standing), low
- tone tinnitus, low
- pain sensation in hands and legs, and (among women only) loss of touch sensations in hands and legs. Animal studies lend support to the conclusion that methylmercury can have delayed effects that are uncovered with age. Spyker (1975) identified neurological and immune impairment in mice expos ed prenatally to methylmercury as they approached 1 year of age. Rats exposed to methylmercury in utero through 16 days of age exhibited a decline in performance in a task that required a substantial motor output at an earlier age than did control rats (Ne wland and Rasmussen, 2000).

### 94

Rice and colleagues (Rice, 1998, 1989; Rice and Hayward, 1999) identified accelerated aging of sensory system function in a series of studies in monkeys exposed during development to methylmercury. All of these observations are consistent with a hypothesis that either developmental or adult exposure to methylmercury can have adverse long
- term sequelae that may not be detected for years or decades following cessation of exposure. However, these effects cannot be quantified based o n available data. Reproductive effects
Short
- term, high
- dose studies in rodents and guinea pigs have reported low sperm counts, testicular tubule atrophy, reduced litter size, decreased fetal survival, resorptions, and fetal malformations following expos ure to methylmercury (Khera, 1973; Lee and Han, 1995; Hughes and Annau, 1976; Fuyuta et al., 1978, 1979; Hirano et al., 1986; Mitsumori et al., 1990; Inouye and Kajiwara, 1988; Suter, 1975). No studies have been done of reproductive deficits in humans expo sed to low
- dose methylmercury, nor have there been any standard, two
- generation reproductive studies. Bakir et al. (1973) noted a small number of pregnant women in the Iraqi population exposed to methylmercury in treated grain. Burbacher et al. (1988) repo rted decreased conception rates, early abortions, and stillbirths in monkeys treated with methylmercury, but at higher doses than those at which behavioral deficits were identified in the offspring. Rice (1996) also found no effect on time to pregnancy or viability of offspring at doses that produced neurotoxicity in the offspring. The available evidence therefore suggests that the developing nervous system is more sensitive to methylmercury than is reproductive competence. The database upon which this RfD is based is considered to be of high quality and extensive. The effects of methylmercury on other organ systems, such as the kidney and liver, are well documented and occur at higher exposures than the effects on the nervous system. Further, data from the most sensitive subpopulation for nervous system effects, the fetus, is the basis for this RfD. It is therefore considered that no additional UF(s) is warranted at this time. However, as additional data become available, they may be used in future RfD deri vation. 

### __I.A.4. Additional Studies/Comments (Oral RfD)
In a second Faroese cohort recruited from children born between 1994 and 1995 (Steurwald et al.,2000), decreases in neurologic optimality score (NOS) were associated with increasing cord
blood mercur y. This association remained statistically significant after adjustment for confounders (including cord and maternal serum PCB levels). There was an exposure
- related decrease in NOS as cord
- blood levels increased from less than 10 μg/L to greater than 40 μ g/L. This finding indicates a dose
- dependent effect at levels as low as (or lower than) those for which neuropsychological deficits were reported in the study of 7
- year - old children (Grandjean et al., 1997). The size of this study was relatively small (N = 182) and identified subtle changes at a very early developmental

### 95

period, the clinical implications of which are less clear than the changes found in the study of 7
- year - olds. The Marsh et al. (1987) study, chosen as the most appropriate one for determini ng the RfD derived by EPA for methylmercury in 1995 (U.S. EPA, 1995), reported clinical neurologic signs in 81 mother
- and
- child pairs. Maternal
- hair mercury concentrations were the exposure metric. Concentrations ranging from 1 to 674 ppm mercury were dete rmined from X
- ray fluorescent spectrometric analysis of selected regions of maternal scalp. These were correlated with clinical signs observed in the affected members of the mother
- child pairs. The hair concentration for developmental effects was determine d by application of a BMD approach. The analysts considered the combined incidence of all neurological effects in children exposed in utero. A Weibull model for extra risk was used to determine the BMD; in current terminology, this was a BMDL 10 (95% lower confidence limit on the dose corresponding to a 10% risk level). This level was calculated to be 11 ppm mercury in maternal
- hair (11 mg/kg hair). The BMD of 11 ppm maternal
- hair mercury was converted to an exposure level of 44 μg mercury/L blood using a 25 0:1 ratio as described in the MSRC (U.S. EPA, 1997, pp. 6
- 22
- 6
- 23). It is informative to compare RfDs derived from animal studies with those derived from the epidemiological literature. RfDs derived from monkey studies are particularly relevant, as the ne urotoxic effects produced by developmental methylmercury exposure in monkeys are similar to those identified in humans (Burbacher et al., 1990a; Gilbert and Grant
- Webster, 1995). Studies at the University of Washington were of a relatively large cohort of macaque monkeys whose mothers were exposed throughout pregnancy to 50 μg/kg/day of methylmercury. The studies revealed deficits on cognitive tests during infancy, which may represent retarded development (Burbacher et al., 1986; Gunderson et al., 1986, 198 8). These methylmercury
- exposed monkeys also displayed aberrant play and social behavior (Burbacher et al., 1990b). Studies at the Canadian Health Protection Branch in the same species of monkey, dosed with 50 μg/kg/day from birth to 7 years of age, reveal ed visual, auditory, and somatosensory deficits, including evidence of delayed neurotoxicity identified in middle age (Rice and Gilbert, 1995, 1992, 1982; Rice, 1989). Research in a cohort of monkeys dosed beginning in utero and continuing until 4 years of age revealed similar sensory system impairment (Rice and Hayward, 1999; Rice, 1998; Rice and Gilbert, 1995, 1990). Three individuals dosed at 10 or 25 μg/kg/day all exhibited impaired function in at least one sensory system in addition to evidence of dela yed neurotoxicity (Rice, 1998). In none of these studies was a NOAEL identified. Reference doses derived from these data would yield an RfD of 0.05 μg/kg/day from the in utero and postnatal exposure studies, and an RfD as low as 0.01 μg/kg/day based on com bined in utero and postnatal exposure (Rice, 1996). The doses would be based on an UF of 10 to extrapolate from a LOAEL to a NOAEL and an UF of 10 to extrapolate from animals to humans. Gilbert and Grant
- Webster (1995) suggested an RfD of 0.025 μg/kg/day b ased on the same data.

### 96

__I.A.5. Confidence in the Oral RfD
Study

— High Database

— High RfD

— High The overall confidence in this RfD assessment is high. Three high
- quality epidemiological studies have been published since the last derivation of the ora l RfD in 1995. Two of the studies (Faroe Islands, New Zealand) reported effects on a number of neuropsychological endpoints, whereas the third (Seychelles Islands) reported no effects related to in utero exposure to methylmercury. Benchmark dose analysis o f a number of endpoints from both the New Zealand and Faroe Islands study converged on an RfD of 0.1 μg/kg
- day, as did the integrative analysis combining all three studies. Although there was coexposure to PCBs in the Faroe Islands study, statistical analy sis indicated that the effects of PCBs and methylmercury were independent. Moreover, benchmark dose analysis of the endpoints that were significantly associated with methylmercury yielded RfDs that were approximately the same when corrected for PCBs. The s ame was true when the analysis was or based on the subset of the cohort in the lowest tertile with respect to PCB levels, as compared with the full cohort. These findings provide further evidence that the identified effects are in fact the result of methyl mercury exposure. The RfD used in this assessment report is the same as that derived in 1995 based on a study of a poisoning episode in Iraq. Experimental studies in monkeys also support the quantitative estimate of the RfD based on a NOAEL/LOAEL approach . Thus, there is a wealth of data from both epidemiological and experimental studies that converges on the derived RfD of 0.1 μg/kg/day. 

### __I.A.6. EPA Documentation and Review of the Oral RfD

Source Document
— U.S. EPA, 2001 All reviewers' comments have been carefully evaluated and considered in the revision and finalization of this IRIS Summary. A record of these comments is summarized in the IRIS documentation files. T o review, exit to the Summary and Response to the Peer Review for Methylmercury document (PDF)
. Other EPA Documentation

— U.S. EPA, 1980, 1984, 1987, 1988, 1995
Consensus Date
- 06/19/2001 Screening
- Level Literature Review Findings

— A screening
- level re view conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Methylmercury conducted in September 2002 did not identify any critical new studies. IRIS users who know of

### 97

important new studies may provide that informa tion to 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).

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

Substance Name

— Methylmercury (MeHg) CASRN
— 22967
- 92
- 6
Not available at this time.

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### _II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name

— Methylmercury (MeHg) CASRN
— 22967
- 92
- 6 Last Revised

— 05/01/1995 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 s ubstance 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 proce dure 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 concentrati on 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 Backgroun d 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

### 98

61(79):17960
- 18011, April 23, 1996). Users are referred to Se ction 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

— C; possible human carcinogen

Basis
— Based on inadeq uate data in humans and limited evidence of carcinogenicity in animals. Male ICR and B6C3F1 mice exposed to methylmercuric chloride in the diet had an increased incidence of renal adenomas, adenocarcinomas and carcinomas. The tumors were observed at a sing le site and in a single species and single sex. The renal epithelial cell hyperplasia and tumors were observed only in the presence of profound nephrotoxicity and were suggested to be a consequence of reparative changes in the cells. Several nonpositive ca ncer bioassays were also reported. Although genotoxicity test data suggest that methylmercury is capable of producing chromosomal and nuclear damage, there are also nonpositive genotoxicity data. 

### __II.A.2. Human Carcinogenicity Data
Inadequate. Three stud ies were identified that examined the relationship between methylmercury exposure and cancer. No persuasive evidence of increased carcinogenicity attributable to methylmercury exposure was observed in any of the studies. Interpretation of these studies, ho wever, was limited by poor study design and incomplete descriptions of methodology and/or results. Tamashiro et al. (1984) evaluated the causes of death in 334 subjects from the Kumamoto Prefecture who had been diagnosed with Minamata disease (methylmercu ry poisoning) and died between 1970 and 1980. The subjects involved fishermen and their families who had been diagnosed with the disease; thus, Minamata disease was used as a surrogate for methylmercury exposure. The controls were selected from all deaths that had occurred in the same city or town as the cases and were matched on the basis of sex, age at death (within 3 years) and year of death; two controls were matched to each subject. Malignant neoplasms were designated as the underlying cause of death i n 14.7% (49/334) of the subjects and 20.1% (134/668) of the controls. For 47 subjects in which Minamata disease was listed as the underlying cause of death, the investigators reanalyzed the mortality data and selected one of the secondary causes to be the underlying cause of death in order to allow examination of the subjects and controls under similar conditions and parameters. The three subjects for which Minamata disease was listed as the only cause of death were excluded from further analysis. Using the Mantel
- Haenzel method to estimate odds ratios, no significant differences were observed between the subjects and controls with respect to the proportion of deaths due to malignant neoplasms among males, females or both sexes

### 99

combined. The estimated odds r atios and 95% confidence intervals were 0.84 (0.49
- 1.43), 0.58 (0.28
- 1.21) and 0.75 (0.50
- 1.11) for males, females and both sexes combined. Similarly, no increases in odds ratio were observed among the subjects relative to the controls when malignant neopl asms were identified as a secondary cause of death or were listed on death certificates as one of the multiple causes of death. These data suggest that cancer incidence was not increased in persons with overt signs of methylmercury poisoning when compared with persons for whom no diagnosis of methylmercury poisoning had been made. Interpretation is limited by potential bias in designating the cause of death among patients with known Minamata disease and by the uncertainty regarding the extent of methylmercu ry exposure and undiagnosed Minamata disease among the controls. In a subsequent study, Tamashiro et al. (1986) compared the mortality patterns (between 1970 and 1981) among residents of the Fukuro and Tsukinoura districts in the Kumamoto Prefecture (inhab ited mainly by fishermen and their families) with that of age
- matched residents of Minamata City (also in the Kumamoto Prefecture) who died between 1972 and 1978. In this study, high exposure to methylmercury was inferred from residence in a district belie ved to have higher intake of local seafood. By contrast, in the 1984 study described above, high methylmercury exposure was inferred from a diagnosis of Minamata disease. A total of 416 deaths were recorded in the Fukuro and Tsukinoura districts in 1970
- 19 81, and 2325 deaths were recorded in Minamata City in 1972
- 1978. No statistically significant increase in the overall cancer mortality rate was observed; however, an increase in the mortality rate due to liver cancer was observed (SMR, 207.3; 95% CI, 116.0
- 341.9). Analysis of mortality by sex showed a statistically significant increase in the rate of liver cancer only among males (SMR, 250.5; 95% CI, 133.4
- 428.4). Males also had statistically significant higher mortality due to chronic liver disease and cir rhosis. The authors note that these results should be interpreted with caution because the population of the Fukuro and Tsukinoura districts had higher alcohol consumption and a higher prevalence of hepatitis B (a predisposing factor for hepatocellular can cer). Interpretation of these results is also limited by an incomplete description of the methodology used to calculate the SMRs; it is unclear whether the study authors used appropriate methods to compare mortality data collected over disparate time frame s (12 years for exposed and 7 years for controls). In a study from Poland, Janicki et al. (1987) reported a statistically significant increase in mercury content of hair in leukemia patients (0.92 +/
- 1.44 ppm [sic]; n=47) relative to that in healthy unre lated patients (0.49 +/
- 0.41 ppm; n=79). Similarly, the mercury content in the hair of a subgroup of leukemia patients (0.69 +/
- 0.75; n=19) was significantly greater than that in healthy relatives who had shared the same residence for at least 3 years pr eceding the onset of the disease (0.43 +/
- 0.24 ppm; n=52). When patients with specific types of leukemia were compared with the healthy unrelated subjects (0.49 +/
- 0.41 ppm; n=79), only those with acute leukemia (type not specified; 1.24 +/
- 1.93 ppm; n= 23) had a significantly increased hair mercury content. No significant differences in hair mercury content were observed in 9 patients with chronic granulocytic leukemia or 15 patients with chronic lymphocytic leukemia when compared with the unrelated, hea lthy controls. The authors inferred that acute leukemia was associated with increased level of mercury in hair. This study is of limited use for cancer risk assessment because of the following:

### 100

uncertainty regarding the correlation between the chronology o f incorporation of mercury in the hair and onset of the disease; the small population studied; the failure to describe adequately the characteristics of the leukemia patients or healthy controls (age distribution, length of residence in the region, criteri a for inclusion in the study); uncertainty regarding the source of mercury exposure (the authors presumed that exposure was the result of use of methylmercury
- containing fungicides); and the failure to address exposure to other chemicals or adjust for othe r leukemia risk factors. Furthermore, the variability of hair mercury content was large, and the mean hair mercury levels were within normal limits for all groups. Thus, the statistical significance may have been due to chance. The carcinogenic effects of organomercury seed dressing exposure were investigated in a series of case - control studies for incidence of soft
- tissue sarcomas (Eriksson et al., 1981, 1990; Hardell and Eriksson, 1988) or malignant lymphomas (Hardell et al., 1981). These studies were co nducted in Swedish populations exposed to phenoxyacetic acid herbicides or chlorophenols (the exposures of primary interest in the studies), organomercury seed dressings, or other pesticides. Exposure frequencies were derived from questionnaires and/or int erviews. Control groups from the same region of the country were matched to cases based on vital status. A total of 402 cases of soft
tissue sarcoma and (among persons not exposed to phenoxyacetic acid herbicides) 128 cases of malignant lymphoma were repor ted. In each study, the odds ratio for exposure to organomercury in seed dressings and the incidence of sarcoma or lymphoma was either <1.0 or the range of the 95% confidence interval for the odds ratio included 1.0; therefore, no association was indicated for organomercury exposure and soft
- tissue sarcoma or malignant lymphoma. The study subjects were likely to have experienced exposures to the other pesticides and chemicals. 

### __II.A.3. Animal Carcinogenicity Data
Limited. Three dietary studies in two stra ins of mice indicate that methylmercury is carcinogenic. Interpretation of two of the positive studies was complicated by observation of tumors only at doses that exceeded the MTD. A fourth dietary study in mice and four dietary studies in rats failed to i ndicate carcinogenicity associated with methylmercury exposure. Interpretation of four of the nonpositive studies was limited because of deficiencies in study design or failure to achieve an MTD. Methylmercuric chloride (> 99% pure) was administered in the diet at levels of 0, 0.4, 2 or 10 ppm (0, 0.03, 0.15 and 0.73 (mg/kg)/day in males and 0, 0.02, 0.11 and 0.6 (mg/kg)/day in females) to 60 ICR mice/sex/group for 104 weeks (Hirano et al., 1986). Interim sacrifices (6/sex/g roup) were conducted at 26, 52 and 78 weeks. Complete histopathological examinations were performed on all animals found dead, killed in extremis or killed by design. Mortality, group mean body weights and food consumption were comparable to controls. The first renal tumor was observed at 58 weeks in a high
- dose male, and the incidence of renal epithelial tumors (adenomas or adenocarcinomas) was significantly increased in high
- dose males (1/32, 0/25, 0/29 and 13/26 in the control, low
- , mid
- and high
- dose g roups, respectively). Ten of the 13 tumors in high
- dose

### 101

males were adenocarcinomas. These tumors were described as solid type or cystic papillary types of adenocarcinomas. No invading proliferation into the surrounding tissues was observed. The incidence o f renal epithelial adenomas was not significantly increased in males, and no renal adenomas or adenocarcinomas were observed in any females studied. Focal hyperplasia of the tubular epithelium was reported to be increased in high
- dose males (13/59; other i ncidences not reported). Increases in non
- neoplastic lesions in high
- dose animals provided evidence that an MTD was exceeded. Non
- neoplastic lesions reported as increased in treated males included the following: epithelial degeneration of the renal proxim al tubules; cystic kidney; urinary cast and pelvic dilatation; and decreased spermatogenesis. Epithelial degeneration of the renal proximal tubules and degeneration or fibrosis of the sciatic nerve was reported in high
- dose females. Methylmercuric chlorid e (>99% pure) was administered in the diet at levels of 0, 0.4, 2 or 10 ppm (0, 0.3, 0.14 and 0.69 (mg/kg)/day in males and 0, 0.03, 0.13 and 0.60 (mg/kg)/day in females) to 60 B6C3F1 mice/sex/group for 104 weeks (Mitsumori et al., 1990). In high
- dose male s, a marked increase in mortality was observed after week 60 (data presented graphically; statistical analyses not performed by authors). Survival at study termination was approximately 50, 60, 60 and 20% in control, low
- , mid
- and high
- dose males, respect ively, and 58, 68, 60 and 60% in control, low
- , mid
- and high
- dose females, respectively. The cause of the high mortality was not reported. At study termination, the mean body weight in high
- dose males was approximately 67% of controls and in high
- dose fem ales was approximately 90% of controls (data presented graphically; statistical analyses not performed by study authors). The incidence of focal hyperplasia of the renal tubules was significantly increased in high
- dose males (14/60; the incidence was 0/60 in all other groups). The incidence of renal epithelial carcinomas (classified as solid or cystic papillary type) was also significantly increased in high
- dose males (13/60; the incidence was 0/60 in all other groups). The incidence of renal adenomas (cla ssified as solid or tubular type) was also significantly increased in high
- dose males; the incidence was 0/60, 0/60, 1/60 and 5/60 in control, low
- , mid
- and high
- dose males, respectively, and 0/60, 0/60, 0/60 and 1/60 in control low
- , mid
and high
- dose f emales, respectively. No metastases were seen in the animals. The incidences of a variety of non
- neoplastic lesions were increased in the high
- dose mice including the following: sensory neuropathy; neuronal necrosis in the cerebrum; neuronal degeneration in the cerebellum; and chronic nephropathy of the kidney. Males exhibited tubular atrophy of the testis (1/60, 5/60, 2/60 and 54/60 in control, low
- , mid
- and high
- dose, respectively) and ulceration of the glandular stomach (1/60, 1/60, 0/60 and 7/60 in co ntrol, low
- , mid
- and high
- dose males, respectively). An MTD was achieved in mid
- dose males and high
- dose females. High mortality in high
- dose males indicated that the MTD was exceeded in this group. Mitsumori et al. (1981) administered 0, 15 or 30 ppm of methylmercuric chloride (>99% pure) in the diet (0, 1.6 and 3.1 (mg/kg)/day) to 60 ICR mice/sex/group for 78 weeks. Interim sacrifices of up to 6/sex/group were conducted at weeks 26 and 52. Kidneys were microscopically examined from all animals that di ed or became moribund after week 53 or were killed at study termination. Lungs from mice with renal masses and renal lymph nodes showing gross abnormalities were also

### 102

examined. Survival was decreased in a dose
- related manner; at week 78 survival was 40, 1 0 and 0% in control, low
- and high
- dose males, respectively, and 55, 30 and 0%, in control, low
- and high
- dose females, respectively (statistical analyses not performed). The majority of high
- dose mice (85% males and 98% females) died by week 26 of the st udy. Examination of the kidneys of mice that died or were sacrificed after 53 weeks showed a significant increase in renal tumors in low
- dose males (13/16 versus 1/37 in controls). The incidence of renal epithelial adenocarcinomas in control and low
- dose m ales was 0/37 and 11/16, respectively. The incidence of renal epithelial adenomas in control and low
- dose males was 1/37 and 5/16, respectively. No renal tumors were observed in females in any group. No metastases to the lung or renal lymph nodes were obse rved. Evidence of neurotoxicity and renal pathology were observed in the treated mice at both dose levels. The high mortality in both groups of treated males and in high
- dose females indicated that the MTD was exceeded in these groups. (Note: Hirano et al . (1986) was a followup to this study.) Mitsumori et al. (1983, 1984) administered diets containing 0, 0.4, 2 or 10 ppm of methylmercuric chloride (0, 0.011, 0.05 and 0.28 (mg/kg)/day in males; 0, 0.014, 0.064 and 0.34 (mg/kg)/day in females) to 56/sex/gr oup Sprague
- Dawley rats for up to 130 weeks. Interim sacrifices of 10/group (either sex) were conducted at weeks 13 and 26 and of 6/group (either sex) at weeks 52 and 78. Mortality was increased in high
- dose males and females. At week 104, survival was app roximately 55, 45, 75 and 10% in control, low
- , mid
- and high
- dose males, respectively, and 70, 75, 75 and 30% in control, low
- , mid
- and high
- dose females, respectively (data presented graphically). All males in the high
- dose group had died by week 119. B ody weight gain was significantly decreased in high
- dose males starting after week 44 and females after 44 weeks (approximately 10
- 20%, data presented graphically). No increase in tumor incidence was observed in either males or females. Noncarcinogenic les ions that were significantly increased in high
- dose rats included the following: degeneration in peripheral nerves and the spinal cord (both sexes); degeneration of the proximal tubular epithelium (both sexes); severe chronic nephropathy (females); parathy roid hyperplasia (both sexes); polyarteritis nodosa and calcification of arterial wall (females); fibrosis of bone (females); bile duct hyperplasia (males); and hemosiderosis and extramedullary hematopoiesis in the spleen (males). Mid
- dose males exhibited significantly increased degeneration of the proximal tubular epithelium and hyperplasia of the parathyroid. An MTD was achieved in mid
dose males and exceeded in high
- dose males and high
- dose females. No tumor data were reported in a study using Wistar ra ts (Munro et al., 1980). Groups of 50 Wistar rats/sex/dose were fed diets containing methylmercury; doses of 2, 10, 50 and 250 (ug/kg)/day were fed for 26 months. High
- dose female rats exhibited reduced body weight gains and showed minimal clinical signs o f neurotoxicity; however, high
- dose male rats showed overt clinical signs of neurotoxicity, decreased hemoglobin and hematocrit values, reduced weight gains and significantly increased mortality. Histopathologic examination of the high
- dose rats of both se xes revealed demyelination of dorsal nerve roots and peripheral nerves. Males showed severe dose
- related kidney damage, and females had minimal renal damage.

### 103

No increase in tumor incidence or decrease in tumor latency was observed in another study using r ats of an unspecified strain (Verschuuren et al., 1976). Groups of 25 female and 25 male rats were administered methylmercuric chloride at dietary levels of 0, 0.1, 0.5 and 2.5 ppm (0, 0.004, 0.02 and 0.1 (mg/kg)/day) for 2 years. No significant effects we re observed on growth or food intake except for a 6% decrease (statistically significant) in body weight gain at 60 weeks in high
- dose females. Survival was 72, 68, 48 and 48% in control, low
- , mid
- and high
- dose males, respectively, and 76, 60, 64 and 56% in control, low
- , mid
- and high
- dose females, respectively (statistical significance not reported). Increases in relative kidney weights were observed in both males and females at the highest dose. No effects on the nature or incidence of pathological les ions were observed, and tumors were reported to have been observed with comparable incidence and latency among all of the groups. This study was limited by the small sample size. No increase in tumor incidence was observed in a study using white Swiss mic e (Schroeder and Mitchener, 1975). Groups of mice (54/sex/group) were exposed until death to methylmercuric acetate in the drinking water at two doses. The low
- dose group received 1 ppm methylmercuric acetate (0.19 (mg/kg)/day). The high
- dose group receive d 5 ppm methylmercuric acetate (0.95 (mg/kg)/day) for the first 70 days and then 1 ppm thereafter, due to high mortality (21/54 males and 23/54 females died prior to the dose reduction). Survival among the remaining mice was not significantly different fro m controls. Significant reductions in body weight were reported in high
dose males (9
- 15% lower than controls) and high
- dose females (15
- 22% lower than controls) between 2 and 6 months of age. After dying, mice were weighed and dissected; gross tumors were counted, and limited histopathologic sections were made of heart, lung, liver, kidney and spleen for microscopic examination. This study is limited because complete histological examinations were not performed.
No increase in tumor incidence was observed in a multiple
- generation reproduction study using Sprague
- Dawley rats (Newberne et al., 1972). Groups of rats (30/sex) were given semisynthetic diets supplemented with either casein or a fish protein concentrate to yield dietary levels of 0.2 ppm methylme rcury (0.008 (mg/kg)/day). Another group of controls received untreated rat chow. Rats that received diets containing methylmercury during the 2
- year study had body weights and hematology comparable to controls. Detailed histopathological analyses revealed no lesions of the brain, liver, or kidney that were attributable to methylmercury exposure. Mortality data were not presented. Interpretation of these data is limited by the somewhat small group sizes and failure to achieve an MTD. 

### __II.A.4. Supporting D ata for Carcinogenicity
Blakley (1984) administered methylmercuric chloride to female Swiss mice (number/group not specified) in drinking water at concentrations of 0, 0.2, 0.5 or 2.0 mg/L for 15 weeks (approximately 0, 0.03, 0.07 and 0.27 (mg Hg/kg)/day) . At the end of week 3, a single dose of 1.5 mg/kg of urethane was administered intraperitoneally to 16
- 20 mice/group. No effects on weight

### 104

gain or food consumption were observed. Lung tumor incidence in mice not administered urethane (number/group not spe cified) was less than one tumor/mouse in all groups. Statistically significant trends for increases in the number and size of lung adenomas/mouse with increasing methylmercury dose were observed; the number of tumors/mouse was 21.5, 19.4, 19.4 and 33.1 in control, low
- , mid
- and high
- dose mice, respectively, and the tumor size/mouse was 0.70, 0.73, 0.76 and 0.76 mm in control, low
- , mid
- and high
- dose mice, respectively. The study authors suggest that the increase in tumor number and size may have been rela ted to the immunosuppressive activity of methylmercury. It should be noted that this study is considered a short
- term bioassay, and pulmonary adenomas were the only tumor type evaluated. Humans ingesting methylmercury
- contaminated foods have been reported to experience chromosomal aberrations (Skerfving et al., 1970, 1974) or SCE (Wulf et al., 1986); however, interpretation of these studies is limited by methodological deficiencies. As reviewed in WHO (1990), methylmercury is not a potent mutagen but appe ars to be capable of causing chromosome damage and nuclear perturbations in a variety of systems. In Bacillus subtilis, methylmercury produced DNA damage (Kanematsu et al., 1980). Methylmercury produced chromosomal aberrations and aneuploidy in human perip heral lymphocytes (Betti et al., 1992), SCE in human lymphocytes (Morimoto et al., 1982), and DNA damage in human nerve and lung cells as well as Chinese hamster V
- 79 cells and rat glioblastoma cells (Costa et al., 1991).
Bone marrow cells of cats treated with methylmercury in a study by Charbonneau et al. (1976) were examined by Miller et al. (1979). The methylmercury treatment resulted in an increased number of nuclear abnormalities and an inhibition of DNA repair capacity. Methylmercury induced a weak m utagenic response in Chinese hamster V
- 79 cells (Fiskesjo, 1979). Methylmercury also induced histone protein perturbations and influenced factors regulating nucleolus
- organizing activity (WHO, 1990). Moreover, methylmercury has been reported to interfere w ith gene expression in cultures of glioma cells (WHO, 1990). Mailhes (1983) reported a significant increase in the number of hyperploid oocysts in Lak:LVG Syrian hamsters fed methyl mercury; however, no evidence of chromosomal damage was reported. Suter (1 975) concluded that strain
- specific differences exist with respect to the ability of methylmercury to produce dominant lethal effects in mice. Nondisjunction and sex
- linked recessive lethal mutations were observed in Drosophila melanogaster treated with me thylmercury (Ramel, 1972 as cited in U.S. EPA, 1985). Methylmercury produced single strand breaks in DNA in cultured L5178Y cells (Nakazawa et al., 1975). Negative studies have also been reported. Methylmercury acetate was reported to be negative in a Sal monella typhimurium assay and a mouse micronucleus assay (Heddle and Bruce, 1977, as reported in Jenssen and Ramel, 1980). Methylmercury was not mutagenic and did not cause recombination in Saccharomyces cerevisiae but did slightly increase chromosomal non disjunction (Nakai and Machida, 1973). Matsumoto and Spindle (1982) reported no significant increase in SCE

### 105

in developing mouse embryos; they did report, however, that the developing mouse embryos were highly sensitive to in vitro treatment with methylmerc ury.

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### _II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure
None. The two studies by Mitsumori et al. (1981, 1990) were limited by high mortality in the high
dos e males, the only group to exhibit a statistically significant increase in tumor incidence. Tumors were observed only in those dose groups in which the MTD had been exceeded. The study by Hirano et al. (1986) was not limited by low survival, but the tumors were observed in conjunction with nephrotoxicity and, thus, their incidence may have been a high
- dose phenomenon that would not be expected to occur at low doses. The tumors appeared to originate from focal hyperplasia of the tubular epithelium induced as a reparative change. The hyperplasia was not observed in tubular epithelium that was undergoing early degenerative changes. Thus, the tumors may not occur where degenerative changes do not occur. The genotoxicity data indicate that methylmercury is not a potent mutagen but may produce chromosomal damage; these data do not support a hypothesis that methylmercury is a genotoxic carcinogen. It appears, rather, that methylmercury exerts its carcinogenic effect only at high dose, at or above an MTD. Because the linearized multistage procedure is based on the assumption of linearity at low doses, the relevance of deriving a slope factor based on data for which a threshold may exist is questionable. It is likely that systemic non
- cancer effects would be seen at m ethylmercury exposures lower than those required for tumor formation. Long
- term administration of methylmercury to experimental animals produces overt symptoms of neurotoxicity at daily doses an order of magnitude lower than those required to induce tumor s in mice.

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### _II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure

None.

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### 106

_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment) __II.D.1. EPA Documentation

Source Documents
-- U.S. EPA, 1995 This IRIS Summary is included in The Mercury Study Report to Congress which was reviewed by OHEA and EPA's Mercury Work Group in November 1994. An Interagency Review by scientists from other federal agencies took place in January 1995. The report was also reviewed by a panel of non
federal external scientists in January 1995 who met in a public meeting on January 25
- 26. All reviewers comments have been carefully evaluated and considered in the revision and finalization of this IRIS summary. A record of thes e comments is summarized in the IRIS documentation files. 

### __II.D.2. EPA Review (Carcinogenicity Assessment)
Agency Work Group Review

— 03/03/1994
Verification Date

— 03/03/1994 Screening
- Level Literature Review Findings

— A screening
- level review conduct ed by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Methylmercury conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that infor mation to 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 gene ral, at (202)566
- 1676 (phone), (202)566
- 1749 (FAX) or hotline.iris@epa.gov (internet address).

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### _III. [reserved] _IV. [reserved] _V. [ reserved]
_VI. Bibliography

### 107

Substance Name

— Methylmercury (MeHg) CASRN
— 22967
- 92
- 6 Last Revised

— 07/27/2001 

### _VI.A. Oral RfD References
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- 344.

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- 688. Davidson, PW; Myers, GJ; Cox, C; et al. (1998) Effects of prenatal and postnatal methylmercury exposure from fish consumptio n on neurodevelopment: outcomes at 66 months of age in the Seychelles child development study. JAMA 280:701
- 707. Dennis, CA; Fehr F. (1975) The relationship between mercury levels in maternal and cord
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- 810264.) Fujita, M; Takabatake, E. (1977) Mercury levels in human maternal and neonatal blood, hair and milk. Bull Environ Contam Toxicol 18(2):205
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- 278. Sherlock, J; Hislop, J; Newton, D; et al. (1984) Elevation of mercury in human blood from controlled chronic ingestion of methylmercury in fish. Hum Toxicol 3:117
- 131. Sikorski, R; Paszkowski, T; Slawinski, P; (1989) The intrapartum content of toxic metals in maternal
- blood and umbilical cord
- blood. Ginekol Pol 60(3):151
- 155. Smith, JC; Allen, PV; Turner, MD; et al. (1994) The kinetics of intravenously administered methylmercury in man. Toxicol Appl Pharmacol 128:251
- 256. Soong, Y
- K ; Tseng, R; Liu, C; et al. (1991) Lead, cadmium, arsenic and mercury levels in maternal and fetal cord
- blood. J Formosan Med Assoc 90:59
- 65.

### 113

Soria, ML; Sanz, P; Martinez, D; et al. (1992) Total mercury and methylmercury in hair, maternal and umbilical blo od, and placenta from women in the Seville area. Bull Environ Contam Toxicol 48:494
- 501. Sørensen, N; Murata, K; Budtz
- Jørgensen, E; et al. (1999) Prenatal methylmercury exposure as a cardiovascular risk factor at seven years of age. Epidemiology 10:370
- 3 75. Spyker, JM. (1975) Assessing the impact of low level chemicals on development: behavioral and latent effects. Fed Proc 34(9):1835
- 1844. Stern, AH. (1997) Estimation of the interindividual variability in the one
- compartment pharmacokinetic model for m ethylmercury: implications for the derivation of a reference dose. Regul Toxicol Pharmacol 25:277
- 288. Steurwald, U; Weibe, P; Jorgensen, K; (2000) Maternal seafood diet, methylmercury exposure, and neonatal neurologic function. J Pediatr 136(5):599
- 605. Suter, KE. (1975) Studies on the dominant lethal and fertility effects of the heavy metal compounds methyl mercuric hydroxide, mercuric chloride, and cadmium chloride in male and female mice. Mutat Res 30:365
- 374. Swartout, J; Rice, G. (2000) Uncertainty analysis of the estimated ingestion rates used to derive the methylmercury reference dose. Drug Clin Toxicol 23(1):293
- 306. Truska, P; Rosival, I; Balazova, G; et al. (1989) Placental concentrations of cadmium, lead, and mercury in mothers and their newborns. J Hyg Epidemiol Microbiol Immunol 33(2):141
- 147. Tsuchiya, H; Mitani, K; Kodama, T; et al. (1984) Placental transfer of heavy metals in normal pregnant Japanese women. Arch Environ Health 39(1):11
- 17. U.S. EPA. (1980) Ambient Water Quality Criteria Document for Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Of fice, Cincinnati, OH for the Office of Water Regulation and Standards, Washington, DC. EPA/440/5
- 80/058. NTIS PB 81
- 117699. U.S. EPA. (1984) Mercury Health Effects Update: Health Issue Assessment. Final Report. Prepared by the Office of Health and Environ mental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA/600/8
- 84/019F. NTIS PB81
- 85
- 123925.

### 114

U.S. EPA. (1987) Peer Review Workshop on Mercury Issu es. Environmental Criteria and Assessment Office, Cincinnati, OH. Summary report. October 26
- 27. U.S. EPA. (1988) Drinking Water Criteria Document for Inorganic Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. EPA/600/X
- 84/178. NTIS PB89
- 192207. U.S. EPA. (1995) Mercury Study Report to Congress. Office of Research and Development, Washington, DC. External Review Draft. EPA/ 600/P
- 94/002Ab. U.S. EPA. (1997) Mercury Study Report to Congress. Office of Research and Development, Washington, DC. December, 1997. U.S. EPA. (2001) Water Quality Criterion for the Protection of Human Health: Methylmercury Chapter 4: Risk Assessment f or Methylmercury. Office of Science and Technology, Office of Water. Vahter, M; Akesson, A; Lind, B; et al. (2000) Longitudinal study of methylmercury and inorganic mercury in blood and urine of pregnant and lactating women, as well as in umbilical cord
- b lood. Environ Res 84:186
- 194. WHO (World Health Organization). (1990) Environmental Health Criteria 101: Methylmercury. Geneva. Yang, J; Jiang, Z; Wan, Y; et al. (1997) Maternal
- fetal transfer of metallic mercury via the placenta and milk. Ann Clin Lab S ci 27(2):135
- 141.

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### _VI.B. Inhalation RfC References

None

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### _VI.C. Carcinogenicity Assessment References
Betti, C., T. Davini and R. Barale. 1992. Genotoxic activity of methyl mercury chloride and dimethyl mercury in human lymphocytes. Mutat. Res. 281(4): 255 260.

### 115

Blakley, B.R. 1984. Enhancement of urethane
- induced adenoma formation in Swiss mice exposed to methylmercury. Can. J. Comp. Med. 48: 299 302. Charbonneau, S.M., I.C. Munro, E.A. Nera et al. 1976. Chronic toxicity of methylmercury in the adult cat. Toxicology. 5: 337
- 349. Costa, M., N.T. Christie, O. Cantoni, J.T. Zelikoff, X.W. Wang and T.G. Rossman. 1991. DNA damage by mercury compounds: An overview. In: Advances in Mercury Toxicity, T. Suzuki, N. Imura and T.W. Clarkson, Ed. Plenum Press, New York, NY. p. 255
- 273. Eriksson, M., L. Hardell, N.O. Berg, T. Moller and O. Axelson. 1981. Soft
- tissue sarcomas and exposure to chemical substances: A case
- referent study. Br. J. Ind. Med. 38: 27 33. Eriksson, M., L. Hardell and H.
- O. Adami. 1990. Exposure to dioxins as a ris k factor for soft
- tissue sarcoma: A population
- based case
- control study. J. Natl. Cancer Inst. 82(6): 486 490. Fiskesjo, G. 1979. Two organic mercury compounds tested for mutagenicity in mammalian cells by use of the cell line V 79
- 4. Hereditas. 90: 103
- 1 09. Hardell, L. and M. Eriksson. 1988. The association between soft
- tissue sarcomas and exposure to phenoxyacetic acids. A new case
- referent study. Cancer. 62: 652 656. Hardell, L., M. Eriksson, P. Lenner and E. Lundgren. 1981. Malignant lymphoma and exp osure to chemicals, especially organic solvents, chlorophenols and phenoxy acids: A case
- control study. Br. J. Cancer. 43: 169 176. Heddle, J.R. and W.R. Bruce. 1977. Comparison of the micronucleus and sperm assay for mutagenicity with the carcinogenic ac tivities of 61 different agents. In: Origins of Human Cancer, H.H. Hiatt, J.D. Watson, J.A. Winsten, Ed. Vol. 4. Cold Spring Harbor Conferences. Hirano, M., K. Mitsumori, K. Maita and Y. Shirasu. 1986. Further carcinogenicity study on methylmercury chlori de in ICR mice. Jpn. J. Vet. Sci. 48(1): 127 135. Janicki, K., J. Dobrowolski and K. Krasnicki. 1987. Correlation between contamination of the rural environment with mercury and occurrence of leukemia in men and cattle. Chemosphere. 16: 253 257.
Jenssen, D. and C. Ramel. 1980. The micronucleus test as part of a short
- term mutagenicity test program for the prediction of carcinogenicity evaluated by 143 agents tested. Mutat. Res. 75: 191 202.

### 116

Kanematsu, N., M. Hara and T. Kada. 1980. Rec assay and mutagen icity studies on metal compounds. Mutat. Res. 77: 109
- 116. Mailhes, J.B. 1983. Methylmercury effects on Syrian hamster metaphase II oocyte chromosomes. Environ. Mutagen. 5: 679
- 686. Matsumoto, N. and A. Spindle. 1982. Sensitivity of early mouse embryos t o methylmercury toxicity. Toxicol. Appl. Pharmacol. 64: 108
- 117. Miller, C.T., Z. Zawidska, E. Nagy and S.M. Charbonneau. 1979. Indicators of genetic toxicity in leukocytes and granulocytic precursors after chronic methylmercury ingestion by cats. Bull. E nviron. Contam. Toxicol. 21: 296
- 303. Mitsumori, K., K. Maita, T. Saito, S. Tsuda and Y. Shirasu. 1981. Carcinogenicity of methylmercury chloride in ICR mice: Preliminary note on renal carcinogenesis. Cancer Lett. 12: 305 310. Mitsumori, K., K. Takahashi , O. Matano, S. Goto and Y. Shirasu. 1983. Chronic toxicity of methylmercury chloride in rats: Clinical study and chemical analysis. Jpn. J. Vet. Sci. 45(6): 747
- 757. Mitsumori, K., K. Maita and Y. Shirasu. 1984. Chronic toxicity of methylmercury chloride in rats: Pathological study. Jpn. J. Vet. Sci. 46(4): 549
- 557. Mitsumori, K., M. Hirano, H. Ueda, K. Maita and Y. Shirasu. 1990. Chronic toxicity and carcinogenicity of methylmercury chloride in B6C3F1 mice. Fund. Appl. Toxicol. 14: 179 190.
Morimoto, K ., S. Iijima and A. Koizumi. 1982. Selenite prevents the induction of sister
- chromatid exchanges by methyl mercury and mercuric chloride in human whole
- blood cultures. Mutat. Res. 102: 183
- 192. Munro, I., E. Nera, S. Charbonneau, B. Junkins and Z. Zawidzk a. 1980. Chronic toxicity of methylmercury in the rat. J. Environ. Pathol. Toxicol. 3: 437
- 447. Nakai, S. and I. Machida. 1973. Genetic effect of organic mercury on yeast. Mutat. Res. 21(6): 348. Nakazawa, N., F. Makino and S. Okada. 1975. Acute effects of mercuric compounds on cultured mammalian cells. Biochem. Pharmacol. 24: 489
- 493. Newberne, P.M., O. Glaser and L. Friedman. 1972. Chronic exposure of rats to methyl mercury in fish protein. Nature. 237: 40
- 41.

### 117

Ramel, C. 1972. Genetic effects. In: Merc ury in the Environment
- An Epidemiological and Toxicological Appraisal, L. Friberg and J. Vostal, Ed. CRC Press, Cleveland, OH. p. 169
- 181. (Cited in U.S. EPA, 1985). Schroeder, H. and M. Mitchener. 1975. Life
- time effects of mercury, methyl mercury, and nine other trace metals in mice. J. Nutr. 105: 452 458. Skerfving, S., K. Hansson and J. Lindsten. 1970. Chromosome breakage in humans exposed to methyl mercury through fish consumption. Arch. Environ. Health. 21: 133
- 139. Skerfving, S., K. Hansson, C. Mangs, J. Lindsten and N. Ryman. 1974. Methylmercury
- induced chromosome damage in man. Environ. Res. 7: 83
- 98. Suter, K.E. 1975. Studies on the dominant
- lethal and fertility effects of the heavy metal compounds methylmercuric hydroxide, mercuric chloride, and cadmium chloride in male and female mice. Mutat. Res. 30: 365
- 374. Tamashiro, H., M. Arakaki, H. Akagi, M. Futatsuka and L.H. Roht. 1984. Causes of death in Minamata disease: Analysis of death certificates. Int. Arch. Occup. Environ. Health. 54: 135
- 146. Tamashiro H., Arakaki M., Futatsuka M. and E.S. Lee. 1986. Methylme rcury exposure and mortality in southern Japan: A close look at causes of death. J. Epidemiol. Comm. Health. 40: 181
- 185. U.S. EPA. 1980. Ambient Water Quality Criteria Document for Mercury. Prepared by the Office of Health and Environmental Assessment, E nvironmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulation and Standards, Washington, DC. EPA/440/5
- 80/058. NTIS PB81
- 117699. U.S. EPA. 1984a. Mercury Health Effects Update: Health Issue Assessment. Final Report. Prepa red by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA/600/8
- 84/019F. NTIS PB81
- 85
- 123925.
U.S. EPA. 198 4b. Health Effects Assessment for Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. EPA/540/1086/042. NTIS PB86
- 134533/AS. U.S. EPA. 1988. Drinking Water Criteria Document for Inorganic Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washingt on, DC. EPA/600/X
- 84/178. NTIS PB89
- 192207.

### 118

U.S. EPA. 1993. Summary Review of Health Effects Associated with Mercuric Chloride: Health Issue Assessment (Draft). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Asse ssment Office, Cincinnati, OH for the Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA/600/R
- 92/199. U.S. EPA. 1995. Mercury Study Report to Congress. Office of Research and Development, Washington, DC. External Review Draft. EPA/600/P
- 94/002Ab. Verschuuren, H.G., R. Kroes, E.M. Den Tonkelaar et al. 1976. Toxicity of methylmercury chloride in rats. III. Long
- term toxicity study. Toxicology. 6: 107 123. WHO (World Health Organization). 1990. Methyl mercury. Vol. 101. Geneva, S witzerland: World Health Organization, Distribution and Sales Service, International Programme on Chemical Safety. Wulf, H.C., N. Kromann, N. Kousgaard, J.C. Hansen, E. Niebuhr and K. Alboge. 1986. Sister chromatid exchange (SCE) in Greenlandic eskimos: D ose - response relationship between SCE and seal diet, smoking, and blood cadmium and mercury concentrations. Sci. Total Environ. 48: 81
- 94.

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### _VII. Revision History

Substance Nam e — Methylmercury (MeHg) CASRN
— 22967
- 92
- 6
Date Section Description 12/01/1988 I.A. Principal study citations added 02/01/1989 I.A. Oral RfD summary is being reevaluated 08/01/1991 VI. Bibliography on
- line 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory Action section on
- line 03/01/1994 I.A.6. Work group review date added 04/01/1994 II. Carcinogenicity assessment now under review

### 119

09/01/1994 I.A.6. Work group review date added 10/01/1994 I.A.6. Work group review dates added 11/01/1994 I.A.6. Work group review date added 12/01/1994 I.A.6. Work group review date added 05/01/1995 I.A. Oral RfD summary replaced; new RfD 05/01/1995 VI.A. Oral RfD references replaced 05/01/1995 II. Carcinogenicity assessment on
- line 05/01/1995 VI.C. Carcinogenicity assessment references on
- line 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. 07/27/2001 I.A.,

VI.A. Oral RfD Summary and references replaced

07/31/2001 VI.A. references corrected 12/03/2002 I.A.6.,

II.D.2. Screening
- Level Literature Review Findings message ha s been added.

04/05/2011 I.A.2. Edits made to dose conversion equations.

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### _VIII. Synonyms

Substance Name

— Methylmercury (MeHg) CASRN
— 22967
- 92
- 6 Last Revised

— 07/27/2001



###  22967
- 92
- 6


###  MeHg


###  Methylmercury


###  Methylmercury II


###  Mercury(1+), methyl
-

### 120  Mercury (1+), Methyl
- , Ion


###  Methyl Mercury


###  Methylmercury (II) Cation


###  Methylmercury Ion

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Reference Dose f or Chronic Oral Exposure (RfD)



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- Response Data 

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### 121 Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure



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### 122

Nickel (as soluble salts) ( http://www.epa.gov/iris/subst/0271.htm ) 

# Nickel, soluble salts (CASRN Various)

0271 Nickel, soluble salts; CASRN Various 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 duri ng 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
.
ST ATUS OF DATA FOR Nickel, soluble salts
File First On - Line 09/30/1987

Category (section) Status Last Revised Oral RfD Assessment (I.A.) on - line 12/01/1996 Inhalation RfC Assessment (I.B.) no data Carcinogenicity Assessment (II.) message 08/01/1994


### _I. Chronic Health Hazard Assessments for Noncarcinogenic Effects _I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name

— Nickel, soluble salts CASRN
— Various Last Revised

— 12/01/1996 The oral Reference Dose (RfD) is based on the assumptio n that thresholds exist for certain toxic

### 123

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 (in cluding 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 ef fects 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. 

### __I.A.1. Oral RfD Summary

Critical Effect Experimental Doses* UF MF RfD

Decreased body and organ weights
Rat Chronic Oral Study Ambrose et al., 1976 NOAEL: 100 ppm diet (5 mg/kg/day) LOAEL: 1000 ppm diet (50 mg/kg/day) 300 1 2E
- 2 mg/kg/day

*Conversion Factors

-- 1 ppm = 0.05 mg/kg/day (assumed rat consumption) 

### __I.A.2. Principal and Supporting Studies (Oral RfD)
Ambrose, A.M., D.S. Larson, J.R. Borzelleca and G.R. Hennigar, Jr. 1976. Long
- term toxicologic assessment of nickel in rats and dogs. J. Food Sci. Technol. 13: 181
- 187. Ambrose et al. (1976) reported the results of a 2
- year feeding study using rats given 0, 100, 1000 or 2500 ppm nickel (estimated as 0, 5, 50 and 125 mg Ni/kg bw) in the diet. Body weights in the high
dose male and female rats were significantly decreased compared with controls. Body weight was also reduced at 1000 ppm. This reduction was si gnificant for females at week 6 and from weeks 26 through 104, whereas males showed body weight reduction only at 52 weeks. Groups of female rats on the 1000 or 2500 ppm nickel diets (50 and 125 mg Ni/kg bw) had significantly higher heart
- to
- body weight ra tios and lower liver
- to
- body weight ratios than controls. No significant effects were reported at 100 ppm (5 mg Ni/kg bw). The dose of 1000 ppm (50 mg Ni/kg bw) represents a LOAEL for this study, while the dose of 100 ppm (5 mg Ni/kg bw) is a NOAEL. In thi s study, 2
- year survival was poor, particularly in control rats of both sexes (death: 44/50), raising some concern about the interpretation of the results of this study. A subchronic study conducted by American Biogenics Corp.

### 124

(ABC, 1986) also found 5 mg/k g/day to be a NOAEL, which supports the Ambrose et al. (1976) chronic NOAEL of 5 mg/kg/day. Dietary exposure of dogs to 2500 ppm Ni (about 63 mg/kg/day) resulted in depressed body weight gain; no effects were seen at either 100 ppm (about 2.5 mg/kg/day) o r 1000 ppm Ni (about 25 mg/kg/day) in the diet (Ambrose et al., 1976). This study demonstrates that rats are the more sensitive of the two species. ABC (1986) conducted the 90
- day study with nickel chloride in water (0, 5, 35 and 100 mg/kg/day) administer ed by gavage to both male and female CD rats (30 animals/sex/group). The data generated in this study included clinical pathology, ophthalmological evaluations, serum biochemistry, body and organ weight changes and histopathological evaluations of selected organs (heart, kidney, liver). The body weight and food consumption values were consistently lower than those of controls for the 35 and 100 mg/kg/day dosed males. Female rats in both high
- dose groups had lower body weights than controls, but food consum ption was unaffected by the test article. Clinical signs of toxicity, such as lethargy, ataxia, irregular breathing, cool body temperature, salivation and discolored extremities, were seen primarily in the 100 mg/kg/day group; these signs were less severe in the 35 mg/kg/day group. The 5 mg/kg/day group did not show any significant clinical signs of toxicity. There was 100% mortality in the high
- dose group; 6/30 males and 8/30 females died in the mid
- dose group (35 mg/kg/day). Histopathologic evaluation ind icated that deaths of 3/6 males and 5/8 females in the mid
- dose group were due to gavage errors. At sacrifice, kidney, liver and spleen weights for 35 mg/kg/day treated males and right kidney weights for 35 mg/kg/day treated females were significantly lowe r than controls. Based on the results obtained in this study, the 5 mg/kg/day nickel dose was a NOAEL, whereas 35 mg/kg/day was a LOAEL for decreased body and organ weights. 

### __I.A.3. Uncertainty and Modifying Factors (Oral RfD)

UF
— An uncertainty factor of 10 is used for interspecies extrapolation and 10 to protect sensitive populations. An additional uncertainty factor of 3 is used to account for inadequacies in the reproductive studies (RTI, 1987; Ambrose et al., 1976; Smith et al., 1990) (see Additiona l Comments section). During the gestation and postnatal development of F1b litters in the RTI (1987) study, temperatures were about 10 degrees F higher than normal at certain times, which makes evaluation of this part of the reproductive study impossible. In the Ambrose et al. (1976) study, statistical design limitations included small sample size and use of pups rather than litters as the unit for comparison. There were also problems with the statistical analysis of the Smith et al. (1990) study.
The Ni d ietary study by Ambrose et al. (1976) identifying a NOAEL of 100 ppm (5 mg/kg/day) is supported by the subchronic gavage study in water (ABC, 1986), which indicated the same NOAEL (5 mg/kg/day).

### 125

MF
— None 

### __I.A.4. Additional Studies/Comments (Oral RfD)

In addition to the effects on organ weights described in the critical study, two other sensitive endpoints exist: neonatal mortality and dermatotoxicity. While no reproductive effects have been associated with nickel exposure to humans, several studies in la boratory animals have demonstrated fetotoxicity. These studies are described below. Following the reproductive studies is a discussion of nickel
- induced dermatotoxicity in hypersensitive humans. While nickel has long been recognized as a contact irritant, many studies have also demonstrated dermal effects in sensitive humans resulting from ingested nickel. The weight
- of
evidence from these studies indicates that ingested nickel may invoke an eruption or worsening of eczema; however, a dose
- response relatio nship is difficult to establish. A few representative studies and review articles are cited below. While the systemic toxicity data (as manifested in organ weight changes) was used as the critical study for the RfD determination, the reproductive/fetotoxicity and the dermatotoxicity were both considered as possible endpoints upon which to base the quant itative risk assessment of nickel. The data for effects on the latter two endpoints do not demonstrate consistent dose
- response relationships, and in both cases the available studies are sufficiently flawed so as to prevent their selection as the basis for the oral RfD. It is noted, however, that the RfD based on the Ambrose et al. (1976) study is considered to be protective of all endpoints with the possible exception of hypersensitive individuals as described below.
In addition to the 2
- year feeding stud y used as the basis for the RfD, Ambrose et al. (1976) also reported reproductive toxicity of nickel. The study had some statistical design limitations including small sample size and use of pups rather than litters as the unit for comparison. Furthermore, the results were equivocal and did not clearly define a NOAEL or LOAEL. Because nickel was administered in a laboratory chow diet rather than drinking water, quantifying analogous nickel exposure via drinking water was problematic.

In a 2
- generation stud y (RTI, 1987) nickel chloride was administered in drinking water to male and female CD rats (30/sex/dose) at dose levels of 0, 50, 250 and 500 ppm (0, 7.3, 30.8 and 51.6 mg/kg/day, estimated) for 90 days before breeding (10 rats/sex/group comprised a satel lite subchronic nonbreeder group). At the 500 ppm dose level there was a significant decrease in the Po maternal body weight, along with absolute and relative liver weights. Thus, 250 ppm (30.8 mg/kg/day) was a NOAEL for Po breeders. Histopathology was per formed for liver, kidney, lungs, heart, pituitary, adrenals and reproductive organs to make this assessment. This NOAEL is higher than the NOAEL derived from the chronic Ambrose et al. (1976) and subchronic gavage (ABC, 1986) assays.

### 126

In the RTI (1987) F1a generation (postnatal days 1
- 4) at the 500 ppm dose level the number of live pups/litter was significantly decreased, pup mortality was significantly increased, and average pup body weight was significantly decreased in comparison with controls. Similar e ffects were seen with F1b litters of Po dams exposed to 500 ppm nickel. In the 50 and 250 ppm dose groups increased pup mortality and decreased live litter size was observed in the F1b litters. However, these effects seen with F1b litters are questionable because the room temperature tended to be 10 degrees F higher than normal at certain times (gestation
- postnatal days) along with much lower levels of humidity. As evidenced in the literature, temperatures that are 10 degrees F above normal during fetal dev elopment cause adverse effects (Edwards, 1986). Therefore, the above results seen at 50 and 250 ppm cannot be considered to be genuine adverse effects. F1b males and females of the RTI (1987) study were randomly mated on postnatal day 70 and their offspri ng (F2a and F2b) were evaluated through postnatal day 21. This phase included teratological evaluations of F2b fetuses. Evaluation of the data indicated that the 500 ppm dose caused significant body weight depression of both mothers and pups, and increased neonatal mortality during the postnatal development period. The intermediate dose, 250 ppm nickel, produced transient depression of maternal weight gain and water intake during gestation of the F2b litters. The 50 ppm nickel exposure caused a significant increase in short ribs (11%). However, since this effect was not seen in both the higher dose groups, the reported incidence of short ribs in the 50 ppm group is not considered to be biologically significant. Schroeder and Mitchener (1971) conducted a 3
- g eneration study in which 5 mating pairs of rats were provided drinking water containing 5 mg Ni/L (estimated as 0.43 mg/kg bw). Results of this study indicated significant increases in neonatal mortality and in the number of runts born to exposed rats comp ared with controls. The major weakness of this study, however, is that the end result is based on a total of five matings. The matings were not randomized and the males were not rotated. The Schroeder and Mitchener (1971) study was conducted in an environm entally controlled facility where rats had access to food and water containing minimal levels of essential trace metals. Because of the interactions of nickel with other trace metals, the restricted exposure to trace metals (chromium was estimated as inade quate) may have contributed to the toxicity of nickel. Smith et al. (1990) also studied the reproductive and fetotoxic effects of nickel. Four groups of 34 female Long
- Evans rats were given drinking water containing nickel chloride in the following concen trations of nickel: 0, 10, 50 or 250 ppm (0, 1.3, 6.8 or 31.6 mg/kg/day) for 11 weeks prior to mating and during two successive gestation periods (G1, G2) and lactation periods (L1, L2). Maternal body weight gain was reduced during G1 in mid
- and high
- dose females. The reproductive performance of the exposed rats was not affected. Pup birth weight was unaltered by treatment, and weight gain was reduced only in male pups exposed to 50 ppm nickel during L1. The most significant toxicological finding was the i ncreased incidence of perinatal mortality. The proportion of dead pups per litter was elevated at the high dose in L1 and at 10 and 250 ppm in L2. While the perinatal

### 127

mortality reported in this study is consistent with other reproductive studies on nickel, it is hard to define a NOAEL and LOAEL because of the absence of a clear dose
- response trend at the lower doses. Many studies have been published regarding nickel sensitivity in humans. Of the general population, approximately 8
- 10% of women and 1
- 2% of men demonstrate a sensitivity to nickel as determined by a patch test (North American Contact Dermatitis Group, 1973; Prystowsky et al., 1979). Initial sensitization to nickel is believed to result from dermal contact, but recurring flares of eczema, parti cularly of the hands, may be triggered by ingestion. The human studies described below are difficult to interpret for several reasons: very small numbers of subjects (mostly women already determined to be sensitive to nickel by a patch test) were used in the studies; many investigators reported a placebo effect; many studies were not conducted in a double
- blind manner, thereby introducing investigator bias; and it was often not specified whether subjects had been fasted overnight or whether there were othe r dietary restrictions. It is important to note that the way in which nickel is consumed may greatly affect its bioavailability. Sunderman et al. (1989) demonstrated that 27+/
- 17% of the nickel in drinking water was absorbed by healthy humans whereas only 0.7+/
- 0.4% of the same dose of nickel ingested in food was absorbed (a 40
- fold difference). One final point to bear in mind in interpreting these studies is that the subjects were generally given a bolus dose of nickel. The absorption and biokinetics follo wing such an exposure may be quite different from an exposure which is given incrementally throughout the day. Following an overnight fast, groups of 5 nickel
- sensitive women were given 100 mL of water along with one oral dose of nickel sulfate containing 0.6, 1.25 or 2.5 mg nickel (Cronin et al., 1980). The clinical response was observed for the next 24 hours. Worsening of hand eczema was reported in 2/5 female subjects that received 0.6 mg, 3/5 at 1.25 mg and 5/5 at 2.5 mg. Erythema was observed in 1/5 ( 0.6 mg), 4/5 (1.25 mg) and 4/5 (2.5 mg) women. While there appears to be a good dose
response relationship, this study did not report controls. The response observed at the lowest dose may well be within background levels.
Numerous other studies have been conducted to attempt to establish the relationships between nickel exposure and dermal irritation. Kaaber et al. (1978, 1979) reported worsening of eczema following an oral challenge with 2.5 mg nickel. In the 1978 study, 17/28 subjects experienced aggrav ation of dermatitis following nickel ingestion. Nine of the 17 that experienced adverse effects from the nickel found that their condition improved when they adopted a low nickel diet. In the 1979 study 9/14 subjects responded negatively to nickel treatmen t. Studies conducted by Gawrodger et al. (1986), Burrows et al. (1981) and Jordan and King (1979) offer different results. Jordan and King's double blind, placebo controlled investigation suggested that 0.5 mg supplement to a normal diet was safe with the possible exception of extremely sensitive individuals. Gawrodger et al. (1986) reported that 5/10 women responded to both the 0.4 and 2.5 mg doses of nickel, but 10/26 also reacted to a placebo. They determined the LOAEL of their experiment

### 128

to be 5.6 mg o f nickel, a dose at which 100% of the women responded. Burrows et al. (1981) administered 0.5 mg nickel twice a day on two consecutive days to 22 patients, each of whom served as her own control. There was no significant difference between the number of in dividuals responding to a placebo as compared to nickel. However, the placebo response was high (12/22). The authors concluded that there is probably no connection between nickel in an ordinary diet and exacerbation of dermatitis but that a higher level ma y aggravate dermatitis in some individuals. Nielsen (1989) describes a study in which 12 nickel
- sensitive women were challenged for a 4
- day period with a diet providing 490 ug Ni/day. No changes were observed before the start of the nickel challenge to da y 0 (start of challenge). On day 4, the eczema of 6 patients was considered to be worse according to both the patients' impressions and a dermatologist's evaluation. The delayed reaction in this study may be attributed to the fact that the dose of nickel w as ingested in the diet throughout the day as opposed to studies which employed a bolus dose. This difference may greatly affect the pharmacokinetics of ingested nickel. While the previous studies on humans with a hypersensitivity to nickel were considere d in developing the RfD, none of them were adequate to serve as the basis for the quantitative risk assessment. The RfD is believed to be set at a level which would not cause individuals to become sensitized to nickel; however, those who have already devel oped a hypersensitivity (e.g., from a dermal exposure) may not be fully protected. One final point to bear in mind in establishing an RfD for nickel is that nickel has been shown to be an essential trace element for several animal species. Rats deprived o f nickel exhibit retarded growth and low hemoglobin levels (Schnegg and Kirchgessner, 1977). A requirement for nickel has not been conclusively demonstrated in humans, but nickel is considered to be a normal constituent of the diet. Typical daily intake of nickel ranges from 100
- 300 ug/day. 

### __I.A.5. Confidence in the Oral RfD
Study

— Low Database

— Medium RfD

— Medium The chronic study (Ambrose et al., 1976) was properly designed and provided adequate toxicological endpoints; however, high mortality occurr ed in the controls (44/50). Therefore, a low confidence is recommended for the study. The database provided adequate supporting subchronic studies, one by gavage and the other in drinking water (Po animals of the RTI subchronic study, 1986). A medium confi dence level in the database is recommended since there are inadequacies in the remaining reproduction data.

### 129

__I.A.6. EPA Documentation and Review of the Oral RfD

Source Document
— U.S. EPA, 1986, 1991 The information contained in the Quantification of T oxicologic Effects for Nickel was reviewed by the Science Advisory Board in August 1990.
Other EPA Documentation

— None Agency Work Group Review

— 04/16/1987, 05/20/1987, 07/16/1987, 05/17/1990, 08/14/1991
Verification Date

— 07/16/1987 

### __I.A.7. EPA Con tacts (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).

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

Substance Name

— Nickel, soluble salts CASRN
— Various
Not available at this time.

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### _II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name

— Nickel, soluble salts CASRN
— Various The U.S. EPA has not evaluated soluble salts of nickel, as a class of compounds, for potential human carcinogenicity. However, nickel refinery dust and specific nickel compounds
- nickel carbonyl and nickel subsulfide
- have been evaluated. Summaries of these evaluations are on IRIS.

### 130 Top of page



### _III. [reserved] _IV. [reserved] _V. [reserved]
_VI. Bibliography

Substance Name

— Nickel, soluble salts CASRN
— Various Last Revised

— 01/01/1992 

### _VI.A. Oral RfD References
Ambrose, A.M., P.S. Larson, J.R. Borzelleca and G.R. Hennigar, Jr. 1976. Long
- term toxicologic assessment of nickel in rats and dogs. J. Food Sci. Technol. 13: 181
- 187. ABC (American Biogenics Corp.). 1986. Ninety
- day gavage study in albino rats using nickel. Draft Final Report submitted to Research Triangle Institute , P.O. Box 12194, Research Triangle Park, NC 27709. Burrows, D., S. Creswell and J.D. Merrett. 1981. Nickel, hands and hip prostheses. Br. J. Dermatol. 105: 437
- 444. Cronin, E., A. Di Michiel and S.S. Brown. 1980. Oral nickel challenge in nickel
- sensitive women with hand eczema. In: Nickel Toxicology, S.S. Brown and F.W. Sunderman Jr., Ed. Academic Press, New York. p. 149
- 152. Edwards, M.J. 1986. Hyperthermia as a teratogen: A review of experimental studies and their clinical significance. Terat. Carcin. Mutagen. 6: 563
- 582. Gawkrodger, D.J., S.W. Cook, G.S. Fell and J.A.A. Hunter. 1986. Nickel dermatitis: The reaction to oral nickel challenge. Br. J. Dermatol. 115: 33
- 38. Jordan, W.P. and S.E. King. 1979. Nickel feeding in nickel
- sensitive patients with h and eczema. J. Am. Acad. Dermatol. 1(6): 506
- 508. Kaaber, K., N.K. Veien and J.C. Tjell. 1978. Low nickel diet in the treatment of patients with chronic nickel dermatitis. Br. J. Derm. 98: 197
- 201.

### 131

Kaaber, K., T. Menne, J.C. Tjell and N. Veien. 1979. Anta buse treatment of nickel dermatitis. Chelation

- a new principle in the treatment of nickel dermatitis. Contact Derm. 5: 221
- 228. Nielsen, G.D. 1989. Oral challenge of nickel
- allergic patients with hand eczema. In: Nickel and Human Health: Current Perspect ives. Advances in Environmental Science and Technology, E. Nieboer and A. Aitio, Ed. John Wiley and Sons, Inc., New York, NY. Chapter 16: 1. North American Contact Dermatitis Group. 1973. Epidemiology of contact dermatitis in North America: 1972. Arch. Der matol. 108: 537
- 540. Prystowsky, S.D., A.M. Allen, R.W. Smith, J.H. Nonomura, R.B. Odom and W.A. Akers. 1979. Allergic contact hypersensitivity to nickel, neomycin, ethylenediamine and benzocaine. Relationships between age, sex, history, exposure and react ivity to standard patch tests and use tests in a general population. Arch. Dermatol. 115(8): 959
- 962. RTI (Research Triangle Institute). 1987. Two generation reproduction and fertility study of nickel chloride administered to CD rats in drinking water: Fer tility and reproductive performance of the Po generation (Part II of III) and F1 generation (Part III of III). Final study report. Report submitted to Office of Solid Waste Management, U.S. EPA, Washington, DC. Schnegg, A. and M. Kirchgessner. 1977. Ni def iciency and its effect on metabolism. In: Trace Element Metabolism in Man and Animals, Vol. 3, M. Kirchgessner, Ed. Freising
- Weihenstephan: Tech. Univ. Munich West Germany. p. 236
- 243. Schroeder, H.A. and M. Mitchener. 1971. Toxic effects of trace elements on the reproduction of mice and rats. Arch. Environ. Health. 23: 102
- 106. Schroeder, H.A., J.J. Balassa and I.H. Tipton. 1962. Abnormal trace elements in man
- nickel. J. Chronic Dis. 15: 51. Smith, M.K., J.A. George, H.F. Stober and G.L. Kimmel. 1990. Pe rinatal toxicity associated with nickel chloride exposure. Fund. Appl. Toxicol. Preliminary unpublished draft. Sunderman Jr., F.W., S.M. Hopfer, K.R. Sweeney, A.H. Marcus, B.M. Most and J. Creason. 1989. Nickel absorption and kinetics in human volunteers. Proc. Soc. Exp. Biol. Med. 191: 5
- 11. U.S. EPA. 1986. Health Assessment Document for Nickel. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. (Final Report). EPA/600/8
- 83/012FF.

### 132

U.S. EPA. 1991. Quantification of Toxicologic Effects for Nickel. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water, Office of Science and Technolo gy, Washington, DC.

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### _VI.B. Inhalation RfD References

None

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### _VI.C. Carcinogenicity Assessment References

None

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### _VII. Revision History

Substance Name

— Nickel, soluble salts CASRN
— Various
Date Section Description 03/01/1988 I.A.2. Text clarified paragraph 1 12/01/1989 I.B. Inhalation RfD now under review 04/01/1990 I.A. ABC, 1986 corrected to U.S. EPA, 1986 04/01/1990 VI. Bibliography on
- line 06/01/1990 I.A. Oral RfD summary noted as pending change 06/01/1990 IV.F.1. EPA contact changed

### 133

09/01/1991 I.A. Oral RfD no longer pending change; no changes made 12/01/1991 I.A.3. Text revised; additional study added 12/01/1991 I.A.4. Text significantly revised; additional studies added 12/01/1991 VI.A. Oral RfD references revised to reflect new text 01/01/1992 I.A.4. Citation year corrected for Schnegg and Kirchgessner 01/01/1992 IV. Regulatory actions updated 01/01/1992 VI.A. Citation year corrected for Schnegg and Kirchgessner 03/01/1994 II. Carcinogenicity assessment now under review 08/01/1994 II. Message added 08/01/1994 II. Work group review date added 05/01/1995 All CAS Registry Number changed to Various 08/01/1995 I.B., II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that we re not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 12/01/1996 I.A.7. Primary contact removed 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. 12/10/1998 I., II. This chemical is being reassessed under the IRIS Progra m.

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### _VIII. Synonyms

Substance Name

— Nickel, soluble salts CASRN
— Various Last Revised

— 09/30/1987

### 134

 7440
- 02
- 0


###  C.I. 77775


###  NICHEL


###  Nickel


###  Nickel, soluble salts

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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

Ref erence 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

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- of
- Evidence Characterization 

###  Human Carcinogenicity Data 

###  Animal Carcinogenicity Data 

###  Supporting Data for Carcinogenicity

Quantitative Estimate of Carcinogenic Risk from Oral Exposure



###  Summary of Risk Estimates 

###  Dose
- Response Data 

###  Additional Comments 

###  Discussion of Confidence

### 135

Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure



###  Summary of Risk Estimates 

###  Dose
- Response Data 

###  Additional Comments 

###  Discussion of Confidence 

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### 136

Selenium ( http://www.epa.gov/iris/subst/0472.htm ) 

# Selenium and Compounds (CASRN 7782 - 49 - 2)

0472 Selenium and Compounds; CASRN 7782 - 49 - 2 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 . Secti ons 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 meth ods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website
. STATUS OF DATA FOR Selenium and Compounds
File First On - Line 03/01/1991 Category (section) Status Last Revised Oral RfD Assessment (I.A.) on - line 09/01/1991 Inhalation RfC Assessment (I.B.) no data Carcinogenicity Assessment (II.) on - line 07/01/1993


### _I. Chronic Health Hazard Assessments for Noncarcinogenic Effects _I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name

— Selenium and Compounds CASRN
— 7782
- 49
- 2 Last Revised

— 09/01/1991 The oral Reference Dose (RfD) is based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. It is ex pressed in units of mg/kg
- day. In general, the RfD is an

### 137

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 dele terious 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. 

### __I.A.1. Oral RfD Summary

Critical Effect Experimental Doses* UF MF RfD

Clinical selenosis Human Epidemiological Study Yang et al., 1989b NOAEL: 0.015 mg/kg/day LOAEL: 0.023 mg/kg/day 3 1 5E
- 3 mg/kg/day

* Conversion Factors: NOAEL (0.853 mg/day) and LOAEL (1.261 mg/day) calculated from regression analysis (log Y = 0.767log X

- 2.248, where Y = blood selenium and X = selenium intake) as detailed in Yang et al. (1989a) based upon the correlation (r = 0 .962) between dietary selenium intake and blood selenium level for data showing incidence of clinical selenosis in adults based on an average adult body weight of 55 kg (Yang et al., 1989b). 

### __I.A.2. Principal and Supporting Studies (Oral RfD)
Yang, G., S. Yin , R. Zhou, et al. 1989b. Studies of safe maximal daily dietary Se
- intake in a seleniferous area in China. II. Relation between Se
- intake and the manifestation of clinical signs and certain biochemical alterations in blood and urine. J. Trace Elem. Electro lytes Health Dis. 3(2): 123
- 130. Yang et al. (1989b), in a follow
- up to an earlier study (Yang et al., 1983), studied a population of approximately 400 individuals living in an area of China with unusually high environmental concentrations of selenium (Se ). The subjects were evaluated for clinical and biochemical signs of Se intoxication. Three geographical areas with low, medium and high selenium levels in the soil and food supply were chosen for comparison in the studies. The earlier Yang et al. (1983) s tudy was conducted in response to endemic selenium intoxication in two separate areas with sample sizes of only 6 and 3. Comparisons were then made to a selenium
- adequate area (n=8) and low
- selenium area (n=13). The Yang et al. (1989a,b) studies provide a much larger sample size and include additional analysis of

### 138

tissue selenium levels. This allows a more accurate estimation of the dose
- response relationship observed for selenium toxicity. Selenium levels in soil and approximately 30 typical food types com monly eaten by the exposed population showed a positive correlation with blood and tissue Se levels. The daily average Se intakes, based on lifetime exposure, 70, 195 and 1438 ug for adult males and 62, 198 and 1238 ug for adult females in the low
- , medium
- and high
- selenium areas, respectively. Significant correlations demonstrated between Se concentrations of various tissues were used to estimate the minimal daily Se intake values that elicited various alterations in biochemical parameters indicative of p ossible Se
- induced liver dysfunction (i.e., prolongation of clotting time and serum glutathione titer) and clinical signs of selenosis (i.e., hair or nail loss, morphological changes of the nails, etc.). In this manner, a marginal safe level of daily Se i ntake was estimated. Analysis of the results indicated that perisistent clinical signs of selenosis were observed only in 5/349 adults, a potentially sensitive subpopulation. The blood selenium concentration in this group ranged from 1.054 to 1.854 mg/L w ith a mean of 1.346 mg/L. Clinical signs observed included the characteristic "garlic odor" of excess selenium excretion in the breath and urine, thickened and brittle nails, hair and nail loss, lowered hemoglobin levels, mottled teeth, skin lesions and CN S abnormalities (peripheral anesthesia, acroparesthesia and pain in the extremities). Alterations in the measured biochemical parameters occurred at dietary intake levels of 750
- 850 ug/day. These alterations were described as a delay in prothrombin time, i .e., increase in blood coagulation time and reduction in blood glutathione concentration. However, these indicators were poorly characterized and are not typically used as an index for clinical selenosis resulting from chronic exposure to selenium (NAS, 19 89). Based upon the blood selenium levels shown to reflect clinical signs of selenium intoxication, a whole blood selenium concentration of 1.35 mg/L corresponding to 1.261 mg of daily selenium intake is indicative of the lowest correlative selenium intake causing overt signs of selenosis. The next lowest whole blood selenium concentration of 1.0 mg/L, corresponding to 0.853 mg selenium/day, produces no clinical signs of selenosis. The NOAEL for this study is 0.85 mg Se/day and the LOAEL is 1.26 mg Se/day. A group of 142 volunteers in South Dakota and Wyoming were recruited by Longnecker et al. (1991) at random from households listed in a telephone directory or from ranches with suspected high selenium intake based on previous cases of livestock selenosis. The geographical areas were chosen because of known seleniferous topsoil and high concentrations of selenium in plants and food. The subjects were followed for 1 year and completed health questionnaires, underwent physical examinations, provided blood samp les for clinical assessment, and provided blood, urine, toenails and duplicate
- plate food collections for selenium analysis. The average selenium intake was 239 ug/day, approximately 2
- 3 times higher than the national average. The concentration of selenium in whole blood, serum, urine and toenails and the amount in diet were highly correlated. Blood selenium concentration was highly correlated with selenium intake. The correlation was very similar to that reported by Yang et al. (1989a). Liver function (pro thrombin time and alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase and alkaline phosphatase), hematologic functon (leukocyte count, hemoglobin and hematocrit) and clinical chemistry (sodium, potassium and

### 139

chloride concentrati on) were not found to be altered as a result of selenium intake. High regression coefficient predictor variables for selenium toxicity (muscle twitching, paresthesia, nail loss, nail lines, hair loss and garlic breath) were not found in increased frequency for this population. No signs of selenium toxicity were found in this population, including individuals whose selenium intake was as high as 724 ug/day. This report corroborates that of Yang et al. (1989b), which showed that a selenium intake of up to 853 ug/day is not associated with characteristic nail or hair loss typical of selenium intoxication. 

### __I.A.3. Uncertainty and Modifying Factors (Oral RfD)

UF
— An uncertainty factor of 3 was applied to the NOAEL to account for sensitive individuals. A full f actor of 10 was not deemed necessary since similar NOAELs were identified in two moderately
- sized human populations exposed to selenium levels in excess of the RDA throughout a lifetime without apparent clinical signs of selenosis.

MF
— None 

### __I.A.4. Addi tional Studies/Comments (Oral RfD)
The essentiality for selenium has been well
- documented in livestock based upon the alleviation of specific deficiency conditions by selenium supplementation of the diet (Combs and Combs, 1986). Selenium has been clearly d emonstrated to be a cofactor of glutathione peroxidase, a hydrogen and lipid peroxide reducing enzyme and is therefore essential (Rotruck et al., 1973). Human requirements for selenium were not conclusively established until 1979 when an association was ma de between low selenium status and cardiomyopathy (Keshan disease) in China for young children and women of child
- bearing age (Keshan Disease Research Group, 1979a,b). More recently, iatrogenic episodes of selenium deficiency have been reported in patients receiving intravenous total parenteral administration of feeding solutions devoid of selenium. Symptoms included low glutathione peroxidase activity and low selenium levels in erythrocytes (Levander and Burk, 1986), muscular weakness and discomfort (van R ij et al., 1979) and cardiomyopathy (Johnson et al., 1981). It is important to note that glutathione peroxidase activity is a valid indicator of human selenium status only in populations with relatively low selenium intakes, since the enzyme activity plate aus at adequate selenium intake levels (Whanger et al., 1988), thereby precluding the use of this biochemical indicator under excessive selenium intake situations. The NAS (1989) has determined the recommended dietary allowance for selenium to be 0.87 ug/ kg, or approximately 70 and 55 ug/day for the reference adult North American male and female, respectively. Requirements for selenium increase during pregnancy to 65 ug/day and for lactation to 75 ug/day. Selenium requirements for infants and children vary according to age. However, based on the reference weights of NHANES II, these populations demonstrate an increased requirement per unit weight relative to adults. For infants, the selenium requirement is 1.67 ug/kg and for children the

### 140

requirement ranges from 1.07
- 1.53 ug/kg. It should be noted that the most recent RDA for selenium did not consider the 1989 results of Yang et al. (1989a,b) discussed above, but an earlier preliminary report by the same authors (Yang et al., 1983). Yang et al. (1983) report ed clinical signs of selenosis (i.e., loss of hair and nails) in approximately 50% of a population of 248 inhabitants living in Enshi County, Hubei Province of the People's Republic of China. Selenosis was reported in the highest selenium contaminated area where the average daily Se intake was 5.0 mg/day (range 3.2
- 6.7), but no selenosis occurred when the average intake was 0.750 mg/day (range 0.240
- 1.51). These estimates, however, were based upon estimates of intake from only 6 and 3 inhabitants in the hig h and low contaminated areas, respectively. Yang et al. (1989b) reported prolonged clotting time and serum glutathione and these biochemical changes were indicated as adverse effects of selenium exposure. Glutathione is a strong nucleophile that reacts wel l with soft electrophiles and is an important conjugate
- forming compound for the detoxification and excretion of electrophilic metabolites and metabolically produced oxidizing agents. If glutathione is depleted or markedly reduced in the liver, the hepatot oxicity of these compounds would likewise be expected to be enhanced (Ketterer et al., 1983). However, the significance of decreased serum glutathione is not well characterized and should not be used in this context as a biochemical marker of selenium toxi city. Likewise, there is no indication that prothrombin activity is affected by excess selenium administration (Longnecker et al., 1991). Furthermore, the description of this effect in Yang et al. (1989b) was based on a population for which there is insuff icient documentation of normal clotting times in the general Chinese population. Selenium toxicity has been clinically described according to three types: acute selenosis, subacute selenosis and chronic selenosis. The acute condition is caused by consumin g relatively high amounts of selenium over a short period of time. After the onset of this condition, walking becomes unsteady, cyanosis of the mucous membranes occurs and labored breathing is usually seen sometimes resulting in death. Pathological finding s include congestion of the liver, endocarditis and myocarditis, degeneration of the sooth musculature of the gastrointestinal tract, gallbladder and bladder, and erosion of the long bones (Francke and Moxon, 1936). Subacute selenosis occurs from exposure to large doses of Se over a longer period of time resulting in neurological dysfunction (impaired vision, ataxia, disorientation) and respiratory distress. It is typically seen most frequently in grazing livestock fe eding upon Se
- accumulating plants and has been referred to as "blind staggers" (Rosenfeld and Beath, 1964). Prolonged exposure to more moderate levels of selenium result in skin lesions involving alopecia, hoof necrosis and loss, emaciation and increased serum transaminases and alkaline phosphatase in animals. In man, the condition is characterized by chronic dermatitis, fatigue, anorexia, gastroenteritis, hepatic degeneration, enlarged spleen and increased concentrations of Se in the hair and nails (Harr and Muth, 1972).

### 141

Selenium exists naturally in a number of oxidation states, thereby accounting for the different forms of selenium important to living organisms by oral ingestion. In the
- 2 oxidation state, selenium can be found as hydrogen selenide (H2Se ), sodium selenide (Na2Se), di
- [(CH3)2Se] and trimethyl selenium [(CH3)3Se] and various selenoamino acids such as selenomethionine, selenocysteine, Se
- methyl selenocysteine, selenocystathionine and selenotaurine. Elemental selenium and the dipeptide seleno diglutathione have an oxidation state of 0. In the +4 oxidation state, selenium can exist as selenium dioxide (SeO2), selenious acid (H2SeO3) or as sodium selenite (Na2SeO3). Finally, in its most oxidized state (+6), selenium can be found as selenic acid ( H2SeO4) or as sodium selenate (Na2SeO4). The toxicity of selenium has been consistently well documented. However, some early studies reported that selenium may be a carcinogen. Nelson et al. (1943) showed that rats fed diets containing Se as seleniferous wheat developed hepatic tumors and low
- grade carcinomas in 11/53 animals. This work has subsequently been criticized due to low
- protein content and relatively high levels of Se in the diet (5, 7 or 10 ppm Se), a poorly characterized source of selenium, and in general poor experimental design. The authors reported no encapsulation or metastases and in fact noted their own difficulty in determining the difference between hyperplasia and tumor. Another early investigation by Seifter et al. (1946) reported seve ral thyroid tumors and adenomatous hyperplasia in livers of rats fed 0.05% bis
- 4
- acetylaminophenyl selenium dihydroxide for 105 days. This organic selenium compound was suspected of having goitrogenic properties but its carcinogenic effect has not been fu rther confirmed to be attributable to the selenium in the molecule. The first animal experiment which demonstrated anticarcinogenic effects of selenium was performed by Clayton and Baumann (1949). An approximate 50% reduction in dimethylaminoazobenzene
in duced tumor incidence occurred in rats fed a diet supplemented with 5 ppm Se as selenite. Additional evidence subsequently reported, further illustrated the inhibitory effect of selenium on transplantable tumors in rats (Weisberger and Suhrland, 1956a) and leukemia in humans (Weisberger and Suhrland, 1956b). The National Cancer Institute sponsored an extensive study on selenium toxicity in rats in order to resolve the issue of selenium carcinogenicity. Diets containing up to 8 ppm selenium did not increase tumor incidence (Tinsley et al., 1967; Harr et al., 1967). Since 1970, there has been an increased interest in characterizing the anti
- carcinogenic and anti
- tumorigenic properties of selenium. The number of reports characterizing these properties are too numerous to discuss in detail here. The reader is referred to a review by Milner and Fico (1987) for a more comprehensive treatment of the database. The essentiality and toxicity of selenium varies according to the valence state of selenium when incorpora ted into biomolecules and the form in which selenium is fed or administered. This is especially true when comparing the LD50 value as an index of toxicity for the various selenium compounds. Although it is difficult to make an assessment for several seleni um compounds by a similar mode of administration in a common species, there is general agreement that sodium selenite, sodium selenate, selenomethionine and selenoglutathione are among the more toxic species (Combs

### 142

and Combs, 1986). The relative potency of systemic toxicity for selenium compounds is also similar in experiments examining potency of anti
- tumorigenic activity. In vitro examination of potency of effect of selenium compounds on incubated Ehrlich ascites tumor cells (EATC) showed that sodium sele nite is more efficacious in significantly reducing EATC viability than an equivalent concentration of sodium selenate. Although selenium dioxide, selenomethionine and selenocystine ultimately decreased viability of the EATC, nearly 50% more incubation time was required for the same effect (Poirier and Milner, 1979). The same authors investigated the relative potency of various selenium compounds administered intraperitoneally on EATC growth in vivo. Sodium selenite and selenodiglutathione (an intermediate o f selenium metabolism) were the most effective forms of selenium in preventing EATC propagation. Sodium selenide, dimethyl selenide and selenocystine were not effective in inhibiting EATC growth (Poirier and Milner, 1983). Similar relative potency results have been reported in in vitro systems for canine mammary cells (Fico et al., 1986) and human mammary cells (Watrach et al., 1984). Since selenium has been reported to cause growth retardation, decreased fertility, embryotoxicity, fetotoxicity and teratog enic effects in animals, Yang et al. (1989b) made the following observations: Malformation in chickens hatched from locally produced eggs did occur; however, teratogeneic effects in human infants were never seen in this area although Se has been reported t o be transmitted through the placenta to the fetus in animals. These findings confirm those reported by Yang et al. (1983) in which chicken eggs from this same area were reported to have very low hatchability and some deformed embryos in those that did hat ch. The developmental toxicity of selenomethionine was investigated by Tarantal et al. (1991) in non
human primates. Forty pregnant long
- tailed macaques were dosed daily by nasogastric intubation with 0, 0.025, 0.150 or 0.3 mg selenium/kg as selenomethion ine through gestational days 20
- 50. Dams were examined clinically and the pregnancies of two to three dams within each test group were followed to term (gestational day 165). All other dams were hysterectomized on gestational day 100. Neonates delivered at term were examined for morphometric, neurologic, behavioral and ophthalmologic effects on days 1, 8, 15, 22 and 30. Pregnancy loss among treated animals was not significantly different from concurrent or historical controls. No statistically significant t reatment
related effects were observed at necropsy on gestational day 100. There were no significant maternal or fetal developmental effects or teratogenesis found up to 0.3 mg/kg selenium, the highest dose tested. Halverson et al. (1966) fed 60
- 70 g male , post
- weanling Sprague
- Dawley rats selenium as selenite or seleniferous wheat ad libitum at 1.6, 3.2, 4.8, 6.4, 8.0, 9.6 or 11.2 ppm of selenium (13, 27, 40, 67, 81 or 94 ug/kg/day, respectively). Levels of selenium up to 4.8 ppm showed no effect. At 8.0 ppm selenium as seleniferous wheat, there was an observed decrease in liver weight, increase in spleen weight, and decrease in hemoglobin. Mortality was observed in the groups fed 8.0, 9.6 and 11.2 ppm selenium as seleniferous wheat at incidences of 1/8, 5 /8 and 8/8, respectively. The incidences of mortality reported for groups fed 8.0 and 9.6 ppm selenium as selenite were 1/8 and 1/10,

### 143

respectively. A significant growth reduction was reported for both selenium sources at 6.4 ppm and higher, although feed u tilization was not decreased. No other effects were reported for the rats fed sodium selenite. Schroeder and Mitchener (1971) administered 3 ppm selenium as selenate (390 ug/kg/day) to CD mice through four generations. Maternal effects were not observed. There was a significant increase in young deaths in the F1 generation and an increase in numbers of runts in generations F1 through F3. By the F3 generation there was also a decrease in breeding events. Rosenfeld and Beath (1954) administered selenium as potassium selenate to sires and pregnant rats through five breeding cycles at 1.5, 2.5 or 7.5 ppm selenium (75, 125 or 375 ug/kg/day). No effect was observed on reproduction, the number of young reared or on the reproduction of two successive generations o f dams and sires in groups receiving 1.5 ppm selenium. In the group receiving 2.5 ppm selenium, the was a 50% reduction in the number of young reared. At 7.5 ppm there was a decrease in fertility of the females but not males, a decrease in the number of su rvivors and a reduction in the rate of growth in the young. Nobunaga et al. (1979) administered 3 or 6 ppm selenium (390 or 780 ug/kg/day, respectively) as selenite to IVCS mice for 30 days prior to mating and throughout gestation. On day 18 of gestation, maternal mice were sacrificed and the embryos removed. Number of litters, total implants, total implants per dam, dead fetuses, dead embryos, resorptions, surviving fetuses (% to total implants), litter size, gross malformations and skeletal anomalies wer e not significantly different for either selenium
- treated or control mice. The only significant effect noted was a decrease in the body weight of surviving fetuses in mice given 6 ppm selenium. 

### __I.A.5. Confidence in the Oral RfD
Study

— Medium Database

— High RfD

— High Confidence in the chosen principal study is medium. Although this is a human epidemiological study in which a sizable population with sensitive subpopulations was studied, there are still several possible interactions that were not fully a ccounted for, e.g., fluoride intake and protein status. Also, except for clinical signs of selenosis there are no other reliable indicators, biochemical or clinical, of selenium toxicity. Confidence in the database is high because many animal studies and e pidemiologic studies (reviewed by Combs and Combs, 1986) support the principal study. An additional human study with a freestanding NOAEL (Longnecker et al., 1991) strongly corroborates the NOAEL identified in the principal study. Therefore, high confidenc e in the RfD is selected based upon support of the critical study and the high level of confidence in the database.

### 144

__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.
Other EPA Documentation

— U.S. EPA, 1985 Agency Work Group Review

— 01/20/1988, 03/22/1989, 09/21/1989, 11/14/1990, 03/27/1991
Verification Date

— 03/27/1991 Screening
- Level Literature Review Findings

— A screening
- level review conducted by an EPA con tractor of the more recent toxicology literature pertinent to the RfD for Selenium and Compounds 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).

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

Substance Name

— Selenium and Compounds CASRN
— 7782
- 49
- 2
Not available at this time.

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### _II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name

— Selenium and Compounds CASRN
— 7782
- 49
- 2 Last Revised

— 07/01/1993

### 145

Section II provides information on thre e 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 quan titative 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 carc inogenicity 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 Asse ssment 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.
NOTE: This assessment is f or the following compounds: Selenium (CASRN 7782
- 49
- 2); sodium selenate (CASRN 13410
- 01
- 0); sodium selenite (CASRN 10102
- 18
- 8); selenious acid (CASRN 7783
- 00
- 8); selenic acid (CASRN 7783
- 08
- 6); sodium selenide (CASRN 1313
- 85
- 5). 

### _II.A. Evidence for Human Carcinogenicity __II.A.1. Weight - of - Evidence Characterization

Classification

— D; not classifiable as to carcinogenicity in humans

Basis
— Based on inadequate human data and inadequate evidence of carcinogenicity in animals. The evidence for various selen ium compounds in animal and mutagenicity studies is conflicting and difficult to interpret; however, evidence for selenium sulfide is sufficient for a B2 (probable human carcinogen) classification. 

### __II.A.2. Human Carcinogenicity Data
Inadequate. Data on the potential carcinogenicity of selenium and various selenium compounds in humans are inadequate. Epidemiological studies have evaluated selenium in blood and cancer death rates in areas of high vs. low naturally
- occurring selenium. However, these studies have limited value because they do not assess specific selenium compounds or correlate exposure with cancer risk. Several investigators have studied the association between serum selenium and the risk of cancer through prospective, case
- control and neste d case
- control studies. Analysis of blood serum levels indicated that patients with cancer, particularly gastrointestinal cancer, prostatic cancer, or Hodgkin's lymphoma, had significantly lower blood selenium levels in blood than healthy patients (Shambe rger

### 146

et al., 1973; Salonen et al., 1984; Kok et al., 1987; Willet et al., 1983; Willet and Stampfer, 1986). The risk of cancer for men (Kok et al., 1987) or for all subjects (Willet et al., 1983) in the lowest quintile of serum selenium was twice that of s ubjects with higher levels. Geographic correlational studies have compared cancer mortality in areas of high vs. low levels of naturally
- occurring selenium. In an ecological study Shamberger and Frost (1969) reported that an inverse relationship existed b etween cancer death rates and the selenium concentrations in foliage plants of several Canadian provinces. The human cancer death rate in provinces with selenium
containing plants was 122.2 +/
- 7.8 (presumably per 100,000 population although this was not s pecified), while in the provinces devoid of these plants, the human death rate was 139.9 +/
- 4.0. In an ecological study Shamberger and Willis (1971) reported that there was a correlation between decreased cancer death rates in humans and an increase in t he selenium in the forage crops in California. In high
- selenium areas (selenium 0.11 ppm of forage crops) the cancer death rate per 100,000 was 141.2. In the medium
- selenium areas (0.05
- 0.10 ppm) the cancer death rate was 190.1. In low
- selenium areas (0.02
- 0.05 ppm) the cancer death rate was 233.0. Shamberger and Willis (1971) also investigated the ratio of observed to expected cancer death rates by anatomic site for men in 17 paired cities including high
- and low
- selenium areas. The anatomic sites that wou ld come into contact with dietary selenium, such as pharynx, esophagus, stomach, bladder and intestine, showed a substantially lower rate ratio in the high
- selenium cities than in the low
- selenium cities. Other ecological and prospective studies have corr elated an increased incidence of colon, breast and other forms of cancer in humans in geographic areas where selenium is deficient and a lowered cancer incidence with higher selenium concentrations (Schrauzer and Ishmael, 1974; Shamberger, 1976; Schrauzer et al., 1976; Jansson et al., 1978; Yang et al., 1983). In a study of approximately 300 employees exposed to selenium (form not specified) in a rectifier (electronics) process over a 26
- year period, only 17 deaths occurred, 6 of which were because of canc er (Glover, 1970). This number, however, is not statistically different from the 5.1 deaths expected based on national mortality rates. The source of the mortality rates was not specified. Several toxic effects including pulmonary irritation, epigastric pa in and dermal irritation and dermatitis were associated with selenium exposure in men, but no carcinogenic effect was reported. 

### __II.A.3. Animal Carcinogenicity Data
Inadequate. The carcinogenicity of selenium compounds has been evaluated in several anima l studies. However, the data are conflicting and difficult to interpret because of apparent anticarcinogenic activity and high toxicity of some selenium salts. In addition, comparison of the available data is difficult because several different salts with varying degrees of bioavailability were used in the assays.

In a 2
- year dietary study reported by Nelson et al. (1943), Osborne
- Mendel rats (sex not specified) were fed selenium in the form of seleniferous corn or wheat or ammonium potassium selenide at 5
- 10

### 147

ppm. Survival was lower in the treated rats; 53/126 (42%) rats fed selenium survived 18 months or longer compared with 14/18 (78%) control rats. Of the 53 surviving selenium
- treated rats, 43 (81%) developed liver cirrhosis and 11 (21%) developed hepato cellular adenoma or carcinoma. All 11 animals with tumors also had liver cirrhosis. None of the 14 control animals surviving 2 years developed liver tumors. Only pooled group data were reported and no statistical analysis was reported. No tumors developed in a total of 1437 Wistar rats fed sodium selenite or sodium selenate in the diet at levels of 0.5
- 16 ppm for their lifetime (Harr et al., 1967; Tinsley et al., 1967). Nonneoplastic liver effects such as hyperemia, cellular degeneration, binucleation, and mild proliferation of hepatocytes were observed at concentrations of 4 ppm and higher.
Long
- Evans rats (approximately 50/sex/group at study initiation) received 2 ppm (as selenium) sodium selenate or sodium selenite in drinking water for 1 year, then 3 ppm for the remainder of the study (Schroeder and Mitchener, 1971). The treatment of the c ontrol group was not discussed. The animals were observed for the duration of their natural lifespan, approximately 36 months, although one selenate
- treated female lived for 5 years. Selenite produced 50% mortality in males by 58 days. At this time, 2 ppm selenate was substituted for selenite in the male group. The concentration of selenium was raised to 3 ppm in this group when the animals were 1 year old; however, the high mortality rendered the group size too small for further statistical analysis. Selen ite produced 50% mortality in females by 348 days; selenite
- treated females were sacrificed at 23 months due to high mortality. Selenate produced 50% mortality in females by 1014 days and in males by 962 days. In the control groups 50% mortality was achie ved by 872 and 853 days in females and males, respectively. Survival of rats receiving selenate was comparable to controls and median lifespan was increased by >100 days. Body weights of treated males were comparable to controls throughout the study. Body weights of females fed selenate were significantly greater than controls at 24 and 36 months; body weights of females fed selenite were significantly less than controls at all times but 18 months. Incidence of all tumors and of malignant tumors was signif icantly increased in the selenate
- treated rats compared with the controls. Incidence of all tumors in controls, selenate
- and selenite
- treated rats was 20/65 (30.8%), 30/48 (62.5%) and 4/32 (12.5%), respectively. Incidence of malignant tumors in the same g roups was 11/65 (16.9%), 20/48 (41.7%) and 4/32 (12.5%), respectively. The earliest tumor occurred on day 833 in the control males, on day 633 in the control females, on day 344 in selenate males and on day 633 in selenate females. The shortened survival t ime of the selenite groups was thought to be responsible for the small number of tumors. This study is considered inadequate because only the heart, lung, liver, kidney and spleen tissues from animals necropsied were examined histologically, and an increas e in longevity was observed in selenate
- treated female rats. Schroeder and Mitchener (1972) administered 3 ppm sodium selenate or sodium selenite in drinking water to Swiss mice (50/sex/group). Body weights of selenate
- treated animals were comparable to

### 148

c ontrols. Body weights of males fed selenite were significantly increased compared with controls, but body weights of females fed selenite were significantly decreased compared with controls. Longevity in males fed selenate was increased compared with contr ols. Longevity in females fed selenate increased, but longevity in females fed selenite decreased compared with controls. When compared to controls, there was no significant increase in total tumor incidence or malignant tumor incidence observed in seleniu m - (form not specified) treated mice. In the control group 23/119 (19%) had tumors (10/119 (8%) malignant tumors). Selenium
- fed mice showed 13/88 (15%) tumors (all were malignant). In selenium
- treated group 8/13 malignancies were lymphoma or leukemia, 4/13 were papillary or alveologenic adenocarcinoma and 1/13 an osteosarcoma. In the control group there were two incidences of lymphoma or leukemia, 7 of lung carcinoma and 1 carcinoma of unknown origin. The 13 benign tumors included breast and ovary tumors. 

### __II.A.4. Supporting Data for Carcinogenicity
Selenium is an essential micronutrient for several species, including humans, and is part of several enzymes such as glutathione peroxidase, an enzyme involved in cellular defense against oxidative damage, and heme oxidase. While low doses of selenium are essential, high doses of selenium or a deficiency of dietary selenium may cause a toxic response. Additionally, selenium may be protective against tumor development. The greatest daily exposure to selenium is via food. Bioavailability of selenium is depend ent on numerous factors, including the intake levels, chemical form and nutritional status. Organic forms of selenium are more bioavailable than inorganic forms; selenates and selenites are the inorganic forms more readily absorbed. Sodium selenate and sel enite are soluble in water, but the extent to which they are absorbed dermally or through the gastrointestinal tract has not been fully elucidated (U.S. EPA, 1989). Shamberger (1985) reported that the oral administration of 0.1
- 6 ppm or dermal application of 0.005% of selenium reduced incidences of skin, liver, tracheal, intestinal and lung tumors induced by several carcinogens in rats, mice and hamsters. Shamberger theorized that selenium may reduce cellular damage caused by peroxidation of fat. In anothe r study, natural killer (NK) cell activity was significantly increased in female rats administered 0.5 or 2.0 ppm selenium (sodium selenate) in the drinking water for 10 weeks (Koller et al., 1986), suggesting to the authors that NK
- sensitive tumors may be prevented by using selenium therapy. Data on the mutagenicity of selenium and its compounds are equivocal. Selenate and selenite (12 uM) were mutagenic in a reverse mutation assay using Salmonella typhimurium strains TA98, TA100 and TA1537 (Noda et al., 1979) in the absence of rat hepatic homogenates. In a second assay, sodium selenate, but not sodium selenite, was mutagenic; the S. typhimurium strains used were not reported (Lofroth and Ames, 1978). Selenite (selenious acid and sodium selenite) produced DNA damage in Bacillus subtilis strains 17A and 45T; however, selenate (selenic acid and sodium selenate) was negative in the Rec assay (Nakamuro et al., 1976).

### 149

Sodium selenide, sodium selenite, and sodium selenate (in order of decreasing activity) caused an increase in unscheduled DNA synthesis in the presence or absence of glutathione in Chinese hamster ovary cells at concentrations of 1.0E
- 4 M (Whiting et al., 1980). Increased chromosomal aberrations were also produced by sodium selenite at E
- 5 M in rat lymphocytes (Newton and Lilly, 1986) and by sodium selenite, selenious acid, selenic acid, and selenium oxide at 2.6E
- 6 M in human lymphocytes (Nakamuro et al., 1976). Sodium selenite produced an increase in chromosomal aberrations in the bone marrow of r ats administered a total of 10
- 12 mg/kg intravenously (near
- lethal doses) (Newton and Lilly, 1986). Selenium (elemental), selenium dioxide, sodium selenide, and sodium selenite (in order of decreasing activity) induced an increase in SCEs in human whole
- bl ood cultures; sodium selenate was not mutagenic in this assay (Ray and Altenburg, 1980).

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### _II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure

None

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### _II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure

None

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### _II.D. EPA Documentation, Re view, and Contacts (Carcinogenicity Assessment) __II.D.1. EPA Documentation

Source Document
— U.S. EPA, 1980, 1984, 1989 The 1989 Health and Environmental Effects Document on Selenium and Compounds has received OHEA review.

### 150

__II.D.2. EPA Review (Carcin ogenicity Assessment)
Agency Work Group Review

— 11/09/1989, 03/07/1990
Verification Date

— 03/07/1990 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 Selenium and Compounds conducted in September 2002 did not identify any cri tical new studies. IRIS users who know of important new studies may provide that information to 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).

Top of page



### _III. [reserved] _IV. [reserved] _V. [reserved]
_VI. Bibliography

Substance Name

— Selenium and Compounds CASRN
— 7782
- 49
- 2 Last Revised

— 06/01/1991 

### _VI.A. Oral RfD References
Clayton, C.C. and C.A . Baumann. 1949. Diet and azo dye tumors: Effect of diet during a period when the dye is not fed. Cancer Res. 9: 575
- 582. Combs, G.F. and S.B. Combs. 1986. Effects of Selenium Excesses, Chapter 11. In: The Role of Selenium in Nutrition. Academic Press, Ne w York. p. 463
- 525. Fico, M.E., K.A. Poirier, A.M. Watrach, M.A. Watrach and J.A. Milner. 1986. Differential effects of selenium on normal and neoplastic canine mammary cells. Cancer Res. 46: 3384
- 3388.

### 151

Francke, K.W. and A.L. Moxon. 1936. A comparison of the minimum fatal doses of selenium, tellurium, arsenic and vanadium. J. Pharmacol. Exp. Ther. 58: 454
- 459. Halverson, A.W., I.S. Palmer and P.L. Guss. 1966. Toxicity of selenium to post
- weanling rats. Toxicol. Appl. Pharmacol. 9: 477
- 484.
Harr, J.R. an d O.H. Muth. 1972. Selenium poisoning in domestic animals and its relationship to man. Clin. Toxicol. 5(2): 175
- 186. Harr, J.R., J.F. Bone, I.J. Tinsley, P.H. Weswig and R.S. Yamamoto. 1967. Selenium toxicity in rats. II. Histopathology. In: Selenium in B iomedicine, O.H. Muth, Ed. AVI, Westport, CT. p. 153
- 178. Johnson, R.A., S.S. Baker, J.T. Fallon, et al. 1981. An occidental case of cardiomyopathy and selenium deficiency. N. Engl. J. Med. 304(20): 1210
- 1212. Keshan Disease Research Group of the Chinese Academy of Medical Sciences. 1979a. Observations on effect of sodium selenite in prevention of Keshan disease. Chin. Med. J. 92(7): 471
- 476. Keshan Disease Research Group of the Chinese Academy of Medical Sciences. 1979b. Epidemiologic studies on the eti ologic relationship of selenium and Keshan disease. Chin. Med. J. 92(7): 477
- 482. Ketterer, B., B. Coles and D.J. Meyer. 1983. The role of glutathione in detoxication. Environ. Health Perspect. 49: 59
- 69. Levander, O.A. and R.F. Burk. 1986. Report on the 1986 A.S.P.E.N. Research Workshop on Selenium in Clinical Nutrition. J. Parenter. Enteral Nutr. 10(6): 545
- 549. Longnecker, M.P., P.R. Taylor, O.A. Levander et al. 1991. Selenium in diet, blood, and toenai ls in relation to human health in a seleniferous area. Am. J. Clin. Nutr. 53: 1288
- 1294. Milner, J.A. and M.E. Fico. 1987. Selenium and tumorigenesis. In: Selenium in Biology and Medicine: Proceedings of the Third International Symposium on Selenium in Bi ology and Medicine, G.F. Combs Jr., J.E. Spallholz, O.A. Levander and J.E. Oldfield, Ed. Van Nostrand Reinhold, New York. p. 1034
- 1043. NAS (National Academy of Sciences). 1989. Recommended Dietary Allowances, 10th ed. National Academy Press, Washington, DC. p. 217
- 224. Nelson, A.A., O.G. Fitzhugh and H.O. Calvery. 1943. Liver tumors following cirrhosis caused by selenium in rats. Cancer Res. 3: 230
- 236.

### 152

Nobunaga, T., H. Satoh and T. Suzuki. 1979. Effects of sodium selenite on methylmercury embryotoxici ty and teratogenicity in mice. Toxicol. Appl. Pharmacol. 47(1): 79
- 88. Poirier, K.A. and J.A. Milner. 1979. The effect of various seleno
- compounds on Ehrlich ascites tumor cells. Biol. Trace Elem. Res. 1: 25
- 34. Poirier, K.A. and J.A. Milner. 1983. Fact ors influencing the antitumorigenic properties of selenium in mice. J. Nutr. 113: 2147
- 2154. Rosenfeld, I. and O.A. Beath. 1954. Effect of selenium on reproduction in rats. Proc. Soc. Exp. Biol. Med. 87: 295
- 297. Rosenfeld, I. and O.A. Beath. 1964. Selen ium: Geobotany, Biochemistry, Toxicity and Nutrution. Academic Press, New York. p. 198
- 208. Rotruck, J.T., A.L. Pope, H.E. Ganther, A.B. Swanson, D.G. Hafeman and W.G. Hoekstra. 1973. Selenium: Biochemical role as a component of glutathione peroxidase. Sc ience. 179: 588
- 590. Schroeder, H.A. and M. Mitchener. 1971. Toxic effects of trace elements on the reproduction of mice and rats. Arch. Environ. Health. 23(2): 102
- 107. Seifter, J., W.E. Ehrich, G. Hudyma and G. Mueller. 1946. Thyroid adenomas in rats r eceiving selenium. Science. 103(2687): 762. Tarantal, A.F., C.C. Willhite, B.L. Lasley et al. 1991. Developmental toxicity of L
- selenomethionine in Macaca fascicularis. Fund. Appl. Toxicol. 16: 147
- 160. Tinsley, I.J., J.R. Harr, J.F. Bone, P.H. Weswig an d R.S. Yamamoto. 1967. Selenium toxicity in rats. I. Growth and longevity. In: Selenium in Biomedicine, O.H. Muth, Ed. AVI, Westport, CT. p. 141
- 152. U.S. EPA. 1985. Health Effects Assessment for Selenium (and Compounds). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. NTIS PB
- 86
- 134699/AS. van Rij, A.M., C.D. Thomson, J.M. McKenzie and M.F. Robinson. 1979. Seleniu m deficiency in total parenteral nutrition. Am. J. Clin. Nutr. 32: 2076
- 2085. Watrach, A.M., J.A. Milner, M.A. Watrach and K.A. Poirier. 1984. Inhibition of human breast cancer cells by selenium. Cancer Lett. 25: 41
- 47.

### 153

Weisberger, A.S. and L.G. Suhrland . 1956a. Studies on analogues of L
- cysteine and L
- cystine. II. The effect of selenium cystine on Murphy lymphosarcoma tumor cells in the rat. Blood. 11: 11
- 18. Weisberger, A.S. and L.G. Suhrland. 1956b. Studies on analogues of L
- cysteine and L
- cystine. III. The effect of selenium cystine on leukemia. Blood. 11: 19
- 30. Whanger, P.D., M.A. Beilstein, C.D. Thomson, M.F. Robinson and M. Howe. 1988. Blood selenium and glutathione peroxidase activity of populations in New Zealand, Oregon and South Dakota. FAS EB J. 2(14): 2996
- 3002. Yang, G., S. Wang, R. Zhou and S. Sun. 1983. Endemic selenium intoxication of humans in China. Am. J. Clin. Nutr. 37: 872
- 881. Yang, G., R. Zhou, S. Yin, et al. 1989a. Studies of safe maximal daily dietary selenium intake in a sel eniferous area in China. I. Selenium intake and tissue levels of the inhabitants. J. Trace Elem. Electrolytes Health Dis. 3(2): 77
- 87. Yang, G., S. Yin, R. Zhou, et al. 1989b. Studies of safe maximal daily dietary Se
- intake in a seleniferous area in China . II. Relation between Se
- intake and the manifestation of clinical signs and certain biochemical alterations in blood and urine. J. Trace Elem. Electrolytes Health Dis. 3(2): 123
- 130.

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### _VI.B. Inhalation RfC References

None

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### _VI.C. Carcinogenicity Assessment References
Glover, J.R. 1970. Selenium and its industrial toxicology. Ind. Med. Surg. 39(1): 26
- 30. Harr, J.R., J.F. Bone, I.J. Tinsley, P.H. Weswig and R.S. Yamamoto. 1967. Selenium toxicity in rats. II. Histopathology. In: Selenium in Biomedicine, O.H. Muth, J.E. Oldfield, P.H. Weswig, Ed. Proc. 1st Int. Symp., Oregon State University, 1966. AVI Publishing Co., Westport, Conn. p. 153
- 178. (Cited in U.S. EPA, 1989)

### 154

Jansson, B., M.M. Jacobs and A.C. Griffin. 1978. Gastrointestinal cancer: Epidemiology and experiment al studies. Adv. Exp. Med. Biol. 91: 305
- 322. Kok, F.J., A.M. De Bruijn, A. Hofman, R. Vermeeren and H.A. Valkenburg. 1987. Is serum selenium a risk factor for cancer in men only? Am. J. Epidemiol. 125(1): 12
- 16. Koller, L.D., J.H. Exon, P.A. Talcott, C. A. Osborne and G.M. Henningsen. 1986. Immune responses in rats supplemented with selenium. Clin. Exp. Immunol. 63: 570
- 576. Lofroth, G. and B.N. Ames. 1978. Mutagenicity of inorganic compounds in Salmonella typhimurium: Arsenic, chromium and selenium. Mut at. Res. 53: 65
- 66. Nakamuro, K., K. Yoshikawa, Y. Sayato, H. Kurata, M. Tonomura and A. Tonomura. 1976. Studies on selenium
- related compounds. V. Cytogenetic effect and reactivity with DNA. Mutat. Res. 40: 177
- 184. Nelson, A.A., O.G. Fitzhugh and H.O. C alvery. 1943. Liver tumors following cirrhosis caused by selenium in rats. Cancer Res. 3: 230
- 236. (Cited in U.S. EPA, 1989) Newton, M.F. and L.J. Lilly. 1986. Tissue
- specific clastogenic effects of chromium and selenium salts in vivo. Mutat. Res. 169: 61
- 69. Noda, M., T. Takano and H. Sakurai. 1979. Mutagenic activity of selenium compounds. Mutat. Res. 66: 175
- 179. Ray, J.H. and L.C. Altenburg. 1980. Dependence of the sister
- chromatid exchange
- inducing abilities of inorganic selenium compounds on the va lence state of selenium. Mutat. Res. 78: 261
- 266. Salonen, J.T., G. Alfthan, J.K. Huttunen and P. Puska. 1984. Association between serum selenium and the risk of cancer. Am. J. Epidemiol. 120(3): 342
- 349. (Cited in U.S. EPA, 1989) Schrauzer, G.N. and D. Ishmael. 1974. Effects of selenium and of arsenic on the genesis of spontaneous mammary tumors in inbred C3H mice. Ann. Clin. Lab. Sci. 4: 441
- 447. Schrauzer, G.N., D.A. White and C.J. Schneider. 1976. Inhibition of the genesis of spontaneous mammary tumo rs in C3H mice: Effect of selenium and of selenium
- antagonistic elements and their possible role in human breast cancer. Bioinorg. Chem. 6: 265
- 270. Schroeder, H.A. and M. Mitchener. 1971. Selenium and tellurium in rats: Effect on growth, survival and tum ors. J. Nutr. 101: 1531
- 1540.

### 155

Schroeder, H.A. and M. Mitchener. 1972. Selenium and tellurium in mice: Effects on growth, survival and tumors. Arch. Environ. Health. 24: 66
- 71. Shamberger, R.J. 1976. Selenium in health and disease. Proceedings of the Sympo sium on Selenium
Tellurium in the Environment. Industrial Health Foundation, Inc., Pittsburgh, PA. p. 253
- 267. Shamberger, R.J. 1985. The genotoxicity of selenium. Mutat. Res. 154: 29
- 48. (Cited in U.S. EPA, 1989) Shamberger, R.J. and D.V. Frost. 1969. P ossible protective effect of selenium against human cancer. Can. Med. Assoc. J. 100: 682. Shamberger, R.J. and C.E. Willis. 1971. Selenium distribution and human cancer mortality. Crit. Rev. Clin. Lab. Sci. 2: 211
- 221. Shamberger, R.J., E. Rukovena, A.K. Longfield et al. 1973. Antioxidants and cancer. I. Selenium in the blood of normals and cancer patients. J. Natl. Cancer Inst. 50(4): 863
- 870. Tinsley, I.J., J.R. Harr, J.F. Bone, P.H. Weswig and R.S. Yamamoto. 1967. Se lenium toxicity in rats. I. Growth and longevity. In: Selenium in Biomedicine, O.H. Muth, J.E. Oldfield, P.H. Weswig, Ed. Proc. 1st Int. Symp., Oregon State University, 1966. AVI Publishing Co., Westport, Conn. p. 141
- 152. (Cited in U.S. EPA, 1989)

U.S. E PA. 1980. Ambient Water Quality Criteria for Selenium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Quality Planning and Standards, Washington, DC. EPA 4 40/5
- 80
- 070. NTIS PB 81
- 117814. U.S. EPA. 1984. Health Effects Assessment for Selenium (and Compounds). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergenc y and Remedial Response, Washington, DC. EPA/540/1
- 86
- 058. NTIS PB 86
- 134699. U.S. EPA. 1989. Health and Environmental Effects Document for Selenium and Compounds. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and A ssessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. Whiting, R.F., L. Wei and H.F. Stich. 1980. Unscheduled DNA synthesis and chromosome aberrations induced by inorganic and organic selenium compounds in the presence of glutathione. Mutat. Res. 78: 159
- 169.

### 156

Willett, W.C. and M.J. Stampfer. 1986. Selenium and human cancer. Acta Pharmacol. Toxicol. Suppl. 59: 240
- 247. Willett, W.C., B.F. Polk, J.S. Morris et al. 1983. Prediagnostic serum selenium and risk of cancer. Lancet. 2: 130
- 134. Yang, G., S. Wang, R. Zhou and S. Sun. 1983. Endemic selenium intoxication of humans in China. Am. J. Clin. Nutr. 37: 872
- 881.

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### _VII. Revision H istory

Substance Name

— Selenium and Compounds CASRN
— 7782
- 49
- 2
Date Section Description 03/01/1991 II. Carcinogenicity assessment on
- line 03/01/1991 VI. Bibliography on
- line 06/01/1991 II.A.2. Para 4: Correct Shamber&Willis to Shamberger&Willis 06/01/1991 I.A. Oral RfD summary on
- line 06/01/1991 VI.A. Oral RfD references added 09/01/1991 I.A.2. Paragraph 2, line 2: number corrected to 5/349 09/01/1991 I.A.3. Text revised 09/01/1991 I.A.5. Confidence in RfD changed; text revised 01/01/1992 IV. Regulatory Action section on
- line 07/01/1993 II.D.3. Primary contact's phone number changed 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.

### 157

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

II.D.2. Screening
- Level Literature Review Findings message has been added.

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### _VIII. Synonyms

Substance Name

— Selenium and Compounds CASRN
— 7782
- 49
- 2 Last Revised

— 03/01/1991



###  7782
- 49
- 2


###  Selenium


###  C.I. 77805


###  Caswell No. 732


###  ELEMENTAL SELENIUM


###  EPA Pesticide Chemical Code 072001


###  HSDB 4493


###  SELEN [Polish]


###  Selenio [Spanish]


###  Selenium


###  SELENIUM ALLOY


###  SELENIUM BASE


###  SELENIUM DUST


###  SELENIUM ELEMENTAL


###  SELENIUM HOMOPOLYMER


###  UN 2658


###  13410
- 01
- 0


###  Selenic acid, disodium salt


###  Caswell No. 791


###  Disodium selenate


###  EPA Pesticide Chemical Code 072002


###  Natriumseleniat [Ger man]


###  NSC 378348


###  Selenic acid, disodium salt


###  Sodium selenate


###  10102
- 18
- 8


###  Selenious acid, disodium salt


###  DISODIUM SELENITE


###  DISODIUM SELENIUM TRIOXIDE


###  HSDB 768


###  Natriumselenit [German]


###  SELENIOUS ACID, DISODIUM SALT


###  SODIUM SELENITE


###  UN 2630


###  7783
- 00
- 8


###  Selenious acid

### 158

 HSDB 6065


###  MONOHYDRATED SELENIUM DIOXIDE


###  Selenious Acid


###  7783
- 08
- 6


###  Selenic acid


###  Acide selenique [French]


###  Acido selenico [Spanish]


###  HSDB 675


###  Selenic acid


###  UN 1905


###  1313
- 85
- 5


###  Sodium selenide [Na2Se]


###  Disodium monoselenide


###  Sodium selenide

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Chronic Health Hazards for Non - Carcinogenic Effects

Reference Dose for Chronic Oral Exposure (RfD)



###  Oral RfD Summary 

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###  Uncertainty and Modifying Factors 

###  Additional Studies/Comments 

###  Confidence in the Oral RfD 

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Reference Concentration for Chronic Inhalation Exposure (RfC)



###  Inhalation RfC Summary 

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###  Uncertainty and Modifying Factors 

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###  Confidence in the Inh alation RfC 

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Evidence for Human Carcinogenicity



###  Weight
- of
- Evidence Characterization 

###  Human Carcinogenicity Data 

###  Animal Carcinogenicity Data 

###  Supporting Data for Carcinogenicity

### 159

Quantitative Estimate of Carcinogenic Risk from Oral Exposure



###  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 

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### 160

Zinc and Zinc Compounds ( ht tp://www.epa.gov/iris/subst/0426.htm ) 

# Zinc and Compounds (CASRN 7440 - 66 - 6)

Note: A TOXICOLOGICAL REVIEW is available for this chemical in Adobe PDF Format (83 Pages, 520 Kbytes). Similar documents can be found in the List of Available IRIS Toxicological Reviews
. Links to spe cific pages in the toxicological review are available throughout this summary. To utilize this feature, your Web browser and Adobe program must be configured properly so the PDF displays within the browser window. If your browser and Adobe program need con figuration, please go to EPA's PDF page for instructions
.
0426 Zinc and Compounds; CASRN 7440 - 66 - 6; 08/03/2005
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 . Secti ons 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 meth ods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website
. STATUS OF DATA FOR Zinc and Compounds
File First On - Line 02/01/1991

Category (section) Statu s Last Revised Oral RfD Assessment (I.A.) on - line 08/03/2005 Inhalation RfC Assessment (I.B.) No data Carcinogenicity Assessment (II.) on - line 08/03/2005

### 161

_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects _I.A. Reference Dose for Chronic Oral Exposure (RfD)
Zinc and Compounds CASRN
— 7440
- 66
- 6 Section I.A. Last Revised

— 08/03/2005 The RfD is an estimate of a daily oral exposure to the human population (including susceptible subgroups) that is likely to be without an appreciable ri sk of adverse health effects over a lifetime. It is derived from a statistical lower confidence limit on the benchmark dose (BMDL), a no
observed
- adverse
- effect level (NOAEL), a lowest
- observed
- adverse
- effect level (LOAEL), or another suitable point of dep arture, with uncertainty/variability factors applied to reflect limitations of the data used. The RfD is intended for use in risk assessments for health effects known or assumed to be produced through a nonlinear (possibly threshold) mode of action. It is expressed in units of mg/kg
- day. Please refer to the guidance documents at http://www.epa.gov/iris/backgrd.html for an elaboration of these concepts. Since RfDs can be derived for the noncarcinogenic healt h effects of substances that are also carcinogens, it is essential to refer to other sources of information concerning the carcinogenicity of this chemical substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a summa ry of that evaluation will be contained in Section II of this file. This RfD replaces the previous RfD of 0.3 mg/kg
- day entered on IRIS 02/01/1991. The new RfD is based on additional data from more recent studies using a sensitive endpoint in a variety of human subjects. 

### __I.A.1. Oral RfD Summary Critical Effect Experimental Doses* UF RfD

Decreases in erythrocyte Cu, Zn
- superoxide dismutase (ESOD) activity in healthy adult male and female volunteers Yadrick et al., 1989 Fischer et al., 1984 Davis et al., 2000 Milne et al., 2001 NOAEL: NONE LOAEL: 0.91 mg/kg
- da y 3 0.3 mg/kg
day

* Conversion Factors and Assumptions

- The dose conversion factor was based on reference adult body weights for the appropriate gender. Total dose was derived from estimations from the FDA Total Diet Study for 1982

- 1986 (Pennington et al., 1989), plus repo rted supplemental dose. For example, for the Yadrick et al. (1989) study, the supplemental dose of 50 mg/day

### 162 was added to the average daily intake of 9.38 mg/day, giving a total intake of 59.38 mg/day. Dividing this by a reference fem ale body weight of 60 kg results in a mean zinc intake of 0.99 (1.0) mg/kg

- day. The principal studies identified effect levels of 0.81 mg Zn/kg

- day (Davis et al., 2000; Milne et al., 2001), 0.94 mg Zn/kg

- day (Fischer et al., 1984), and 0.99 mg Zn/kg

- day (Yadrick et al., 1989). Since the four studies have similar methodologies and outcomes with regard to effects, they were averaged together to obtain the LOAEL (0.81+0.94+0.99=2.74/3=0.91 mg/kg

- day). 

### __I.A.2. Principal and Supporting Studies (Oral RfD)

Zinc is an essential element required as part of a healthy diet. The zinc content of a typical mixed diet of North American adults is approximately 10
- 15 mg/day (IOM, 2001). The FDA's Total Diet Study (Pennington et al., 1989) found zinc intakes of 7.25, 9.74, 15.42, 9.38, and 15.92 mg/day in children (2 years of age), girls (14
- 16 years), boys (14
- 16 years), women (25
- 30 years), and men (25
- 30 years), respectively. The recommended dietary allowances (RDAs) for zinc for the year 2000 (IOM, 2001) are 11 mg/day for adult males and 8 mg/ day for adult females (not pregnant or lactating). The RfD for zinc is based on human clinical studies to establish daily nutritional requirements. Zinc is an essential trace element that is crucial to survival and health maintenance, as well as growth, de velopment, and maturation of developing organisms of all animal species. Thus, insufficient as well as excessive oral intake can cause toxicity and disease and a quantitative risk assessment must take essentiality into account. The principal studies examin e dietary supplements of zinc and the interaction of zinc with other essential trace metals, specifically copper, to establish a safe daily intake level of zinc for the general population, including pregnant women and children, without compromising normal health and development. A wide range of clinical symptoms have been associated with zinc deficiency in humans (Abernathy et al., 1993; Prasad, 1993; Sandstead, 1994; Walsh et al., 1994). The clinical manifestations of severe zinc deficiency, seen in indivi duals with an inborn error of zinc absorption or in patients receiving total parenteral nutrition with inadequate levels of zinc, include bullous pustular dermatitis, diarrhea, alopecia, mental disturbances, and impaired cell
- mediated immunity resulting in intercurrent infections. Symptoms associated with moderate zinc deficiency include growth retardation, male hypogonadism, skin changes, poor appetite, mental lethargy, abnormal dark adaptation, and delayed wound healing. Neurosensory changes, impaired neu ropsychological functions, oligospermia, decreased serum testosterone, hyperammonemia, and impaired immune function (alterations in T
- cell subpopulations, decreased natural killer cell activity) have been observed in individuals with mild or marginal zinc deficiency. As reviewed by Mahomed et al. (1989), severe zinc deficiency in animals has been associated with reduced fertility, fetal nervous system malformations, and growth retardation in late pregnancy. In humans, labor abnormalities, congenital malform ations, and preterm labor have been reported in otherwise healthy women with low maternal serum zinc concentrations. Numerous studies have

### 163

examined pregnancy outcomes following zinc supplementation. For example, Simmer et al. (1991) found significant intra uterine growth retardation and fewer inductions of labor (generally associated with poor fetal growth), and non
- statistically significant increases in birth weight and placental weights in zinc
- deficient women receiving a supplement containing 100 mg zinc citrate (22.5 mg zinc) (these women were receiving the supplement because they were determined to be at risk of delivering small
- for
- gestational age babies). However, Mahomed et al. (1989) did not find any statistically significant differences in gestation duration, details of labor and delivery, fetal development, or neonatal health among 246 randomly selected pregnant women receiving 20 mg Zn/day as zinc sulfate tablets beginning before the 20 th week of pregnancy as compared to 248 women receiving placebo tablets. While the zinc supplement and placebo group had marginal zinc intake (approximately 10 mg/day) prior to supplementation, the zinc supplementation did not appear to influence pregnancy outcome. Reduced copper status has been associated with increa sed zinc intake. In studies in which the interactions of excess zinc with copper were measured, there was a consistent decrease in erythrocyte Cu, Zn
- superoxide dismutase (ESOD) activity. Thus, copper status and ESOD activity are considered a sensitive mea sure of the effects of high levels of zinc exposure. The study of Yadrick et al. (1989) exposed a group of healthy adult women to 50 mg supplemental Zn/day; adding in an average daily dietary consumption of 9.38 mg/day (from the FDA Total Diet Study from 1 982
- 1986 [Pennington et al., 1989]), the total exposure level from the Yadrick et al. (1989) study was 59.38 mg Zn/day, or 0.99 mg/kg
- day assuming a reference female body weight of 60 kg. ESOD activity declined over the 10
- week supplementation period and, at 10 weeks, was significantly different ( p <0.05) from values during the pretreatment period. By 10 weeks, ESOD activity had declined to 53% of pretreatment levels. Change in enzyme activity is considered a better indicator of altered copper status than a measure of metal concentration in tissue or plasma. This has been documented by studies in rats which were fed copper
- deficient or high
- zinc diets, in which treatment
- related changes in copper metalloenzyme activity are greater and precede changes in plasm a or tissue levels of copper (L'Abbe and Fischer, 1984a, b). Ceruloplasmin concentrations were not altered. Serum zinc was significantly increased. There was also a significant decline in serum ferritin and hematocrit values at 10 weeks. Such a decrease co uld pose a significant risk to the iron status of women. Fischer et al. (1984) instructed groups of 13 healthy adult male volunteers to take capsules containing 0 (cornstarch) or 25 mg supplemental zinc (as zinc gluconate) twice daily for 6 weeks. Adding i n an average daily dietary consumption of 15.92 mg Zn/day (from the FDA Total Diet Study from 1982
- 1986 [Pennington et al., 1989]), the total exposure level from Fischer et al. (1984) was 65.92 mg Zn/day, or 0.94 mg/kg
- day assuming a reference male body we ight of 70 kg. Nonfasting blood samples were taken at the beginning and at biweekly intervals and tested for measures of copper status. Plasma copper levels and levels of ferroxidase activity did not change during the course of the study. However, ESOD act ivity decreased after 4 weeks in the supplement group and

### 164

was significantly lower than controls by 6 weeks. An inverse correlation between plasma zinc levels and ESOD activity was also observed at 6 weeks. Davis et al. (2000) and Milne et al. (2001) have r eported the results of exposure of a group of postmenopausal women (aged 50
- 76, mean of 64.9 ± 6.7 years) to varying concentrations of zinc and copper in the diet. Average height was 159.6 ± 7.6 cm, and mean body weight was 65.1 ± 9.5 kg. These studies wer e conducted in a hospital metabolic ward where patients or human volunteers are maintained under strict environmental and dietary control to monitor dietary intake with collection of biological samples for metabolic studies. Subjects were kept in a metabol ic ward for a 200 day period, and fed a controlled basal diet that contained 0.6 mg Cu/day and 3 mg Zn/day. For the first ten days, all subjects consumed an equilibration diet, which consisted of the basal diet supplemented with 1.4 mg Cu/day (2 mg total) and 6 mg Zn/day (9 mg total). Following the initial 10
- day equilibration, one group (n=12) was exposed to a diet containing basal diet supplemented with 0.4 mg Cu/day (1.0 mg Cu/day total) and the other group (n=13) was fed the basal diet supplemented with 2.4 mg Cu/day (3.0 mg Cu/day total). The remaining 190 days were divided into two 90
- day study periods for both groups: the Cu
- supplemented basal diet with no zinc supplement was fed for the first 90
- day period and the Cu
- supplemented basal diet supplemen ted with 50 mg Zn/day (for a total of 53 mg Zn/day; a total average daily dose of 0.81 mg Zn/kg
- day using a mean body weight of 65.1 kg provided in the manuscripts) was fed for the second 90
- day period. The two 90
- day periods were separated by an additiona l equilibration period, identical to the one performed at the beginning of the study. During each of the equilibration periods, and twice monthly during the exposure periods, blood was drawn from the subjects after an overnight fast, and evaluated for chan ges in cells and cell elements (erythrocytes, platelets, mononuclear cells, neutrophils), plasma and blood levels of copper and zinc, and a variety of blood proteins and factors (alkaline phosphatase activity, superoxide dismutase activities [ESOD and extr acellular Cu, Zn
- superoxide dismutase (EC
- SOD)], 5'
- nucleotidase activity, triiodothyronine, thyroxine, and thyroid
- stimulating hormone levels, and amyloid precursor protein levels). Copper and zinc levels were determined for urine, feces, and diet. Alcoho l tolerance tests were performed at the end of the first equilibration period and at the end of the low
- and high
- zinc exposures. Data were analyzed by a two
- way (dietary zinc and copper) repeated
- measures analysis of variance (ANOVA), and Tukey's contrast s were used to test for differences among means. Plasma zinc concentrations were significantly lower, relative to the equilibration levels, and platelet zinc concentrations tended to be lower, though not significantly, in subjects fed 3 mg Zn/day than in t hose fed 53 mg Zn/day; plasma zinc was not lowered from equilibration levels when subjects were fed 3 mg Zn/day, but was elevated in those fed 53 mg Zn/day. Zinc supplementation increased Zn levels in the feces and urine, but did not appear to affect plasm a Cu levels. Neither erythrocyte zinc levels nor erythrocyte membrane zinc concentrations were significantly altered by changes in dietary zinc. High
- zinc subjects showed significant increases in bone
- specific alkaline

### 165

phosphatase activity, relative to the equilibration period, but not in plasma alkaline phosphatase or erythrocyte membrane alkaline phosphatase. Zinc supplementation significantly increased mononuclear white cell 5'
- nucleotidase activity and decreased plasma 5'
- nucleotidase activity; the diff erence in 5'
- nucleotidase activity was apparent when subjects were fed the high
- copper diet, but not when they were fed the low
- copper diet. EC
- SOD activity, but not ESOD activity, was significantly increased by zinc supplementation; this was more apparent in the low
- copper group. ESOD activity was significantly decreased relative to equilibration levels in low
- copper subjects and significantly increased in high
- copper subjects; in both cases, zinc supplementation caused a statistically insignificant decrea se in ESOD activity. Erythrocyte glutathione peroxidase activity was increased by low dietary zinc and decreased by high dietary zinc; however, the decrease did not result in a return to initial equilibration activity. Plasma free thyroxine concentrations, but not total thyroxine concentrations, were significantly increased in the zinc
- supplemented groups; no other effects on thyroid
- related endpoints were noted. During the low
- zinc period, there was an increase in total cholesterol; this increase was rever sed with high
- zinc treatment, resulting in lower total cholesterol. LDL
- cholesterol changes were similar to the total cholesterol changes, while HDL
cholesterol, very low density lipoprotein
- cholesterol, and triglycerides were not affected. Zinc supplement ation significantly decreased platelet amyloid precursor protein expression in subjects fed the low
- copper diet; however, technical concerns prevented many of these samples from being properly analyzed, so the sample size for amyloid precursor protein expr ession was very small. Most indicators of iron status were not affected by the changes in dietary zinc or copper; the exception was a small drop in hemoglobin levels, which the investigators attributed to the effects of accumulated blood loss from phleboto my. As the four studies identified physiological changes on similar, sensitive endpoints (indicators of body copper status) at similar dose levels (0.81
- 0.99 mg Zn/kg
- day) in a variety of human subject groups (postmenopausal females, adult females, and adu lt males), the studies of Yadrick et al. (1989), Fischer et al. (1984), Davis et al. (2000) and Milne et al. (2001) were selected as co
principal studies. 1

1 The studies by Davis et al. (2000) and Milne et al. (2001) were approved by the Institutional Revie w boards of the University of North Dakota and the US Department of Agriculture and followed Guidelines of the Department of Health and Human Services and the Helsinki Declaration regarding the use of human subjects. The study by Yadrick et al. (1989) was approved by the Institutional Review Board of Oklahoma State University and informed consent was obtained from each participant. Finally, the study by Fischer et al. (1984) was approved by the Human Studies Committee of the Health Protection Branch, Health and Welfare Canada, and a consent form was signed by all participants.

__I.A.3. Uncertainty Factors (Oral RfD)

UF=3

### 166

In selecting the point of departure for the RfD, the effect levels from the co
- principal studies (Yadrick et al. 1989; Fischer et al. 19 84; Davis et al. 2000 and Milne et al. 2001) were averaged (0.81+0.94+0.99=2.74/3=0.91 mg/kg
- day), since they have similar methodologies and outcomes with regards to effects. An interspecies uncertainty factor (UF A ) was not necessary for extrapolation from an animal study to the human population. The principal studies were conducted in human volunteers. An uncertainty factor to account for extrapolation from a subchronic study to estimate chronic exposure conditions (UF S ) was not necessary. Zinc is an essen tial element and therefore, chronic exposures of zinc are required for proper nutrition. The RfD is expected to be without adverse effects when consumed on a daily basis over the life
- span of the individual, neither inducing nutritional deficiency nor resu lting in toxic effects in healthy non
- pregnant adult humans consuming an average American diet. A database uncertainty factor (UF D ) to account for uncertainties due to lack of information in the database was not necessary. The database contains a considera ble number of well
- conducted human studies in a diverse group of human subjects. There are numerous reproductive and developmental toxicity studies performed in different species. Animal studies demonstrate that effects on reproductive and/or developmental endpoints are observed at doses higher than the zinc supplemental dosages associated with ESOD activity and copper homeostasis. An uncertainty factor for extrapolation from a minimal LOAEL to a NOAEL (UF L ) was determined not to be necessary. The RfD was b ased on a minimal effect level for a sensitive biological indicator, decreased ESOD activity, which is a measure of zinc associated alterations in copper homeostasis that could lead to oxidative tissue damage. A threefold intraspecies uncertainty factor (U F H ) was used to account for variability in susceptibility in human populations. For zinc, and other nutritionally required elements, it is important that the RfD not be set at a value that would suggest that people should consume diets with insufficient zi nc. Nutritional studies have established a baseline and the use of a greater UF would place some sensitive humans in the possible position of either exceeding the RfD or not obtaining sufficient zinc. Therefore, a UF H of 3 was applied, based on four differ ent studies with moderate duration in the most sensitive humans and consideration of a substance which is an essential dietary nutrient. 

### __I.A.4. Additional Studies/Comments (Oral RfD)
Zinc is essential for the function of more than 300 enzymes, including alkaline phosphatase, alcohol dehydrogenase, Cu, Zn
- superoxide dismutase, carboxypeptidase, delta
- aminolevulinic acid dehydratase, carbonic anhydrase, ribonucleic acid polymerase, and r everse transcriptase (Vallee and Falchuk, 1993; Sandstead, 1994). Zinc is also involved in DNA and RNA synthesis and cell

### 167

proliferation. Zinc coordinates with cysteine and histidine residues of certain peptides and produces a tertiary structure which has a n affinity for unique segments of DNA in promoter gene regions, including zinc finger protein domains, the most common zinc motif, and the zinc thiolate cluster (Prasad and Nath, 1993; Walsh et al., 1994). Other physiological roles of zinc include enhancem ent of the affinity of growth hormone for its binding receptors, modulation of synaptic transmissions by interacting with specific sites on ionotrophic neurotransmitter receptor proteins, and induction of metallothionein (Walsh et al., 1994).
In a double
- b lind crossover trial, Samman and Roberts (1987, 1988) gave zinc sulfate tablets (150 mg supplemental zinc/day in three divided doses at mealtimes) to healthy adult volunteers (21 men and 26 women) for 6 weeks. Identical capsules containing lactose were giv en to the same group of volunteers for 6 weeks as the placebo). Using the reported average body weights, the zinc doses averaged 2 mg Zn/kg
- day for men and 2.5 mg Zn/kg
- day for women. Adverse symptoms, including abdominal cramps, vomiting, and nausea, occu rred in 84% of women and 18% of men. Five females withdrew from the trial because of gastric irritation. A dose
- related increase in clinical symptoms was observed when doses were expressed on a mg/kg
- day basis. Ingestion of zinc tablets alone (contrary to recommended instructions) or with small meals increased the incidence of adverse effects. Zinc administration for 6 weeks had no effect on plasma levels of copper, total cholesterol, or HDL
- cholesterol in males or females, but significantly decreased the p lasma level of LDL
- cholesterol in females only. An inverse linear relationship between plasma zinc levels and LDL
cholesterol levels was found in the females. Hematocrit values were unaffected by zinc ingestion in males and females and specific measures of copper status (ferroxidase activity of serum ceruloplasmin, antioxidant activity of ESOD) were apparently unaffected in males. However, females, who received higher mg/kg
- day doses of zinc than males, exhibited a significant reduction in the activity of t wo copper metalloenzymes: serum ceruloplasmin and ESOD. Possible explanations for the discrepancy between these results for the male subjects and those reported by Fischer et al. (1984) may be differences in the composition of the diets of test subjects (e .g., high phytic acid content), decreased zinc absorption with higher doses, body weight, etc. Hale et al. (1988) carried out an epidemiological study of the effect of zinc supplements on the development of cardiovascular disease in elderly subjects who we re participants in an ongoing longitudinal geriatric health screening program. Noninstitutionalized, ambulatory subjects between the ages of 65 and 91 (average 78) years were evaluated using questionnaire, electrocardiogram, hematological, and drug
- use dat a. A group of subjects (38 women and 31 men) which had ingested zinc supplements (20 to 150 mg supplemental zinc/day) for at least one year was compared to a control group (1195 women and 637 men) from the same screening program. Approximately 85% of the s tudy group reported taking <50 mg supplemental zinc/day. For the 15% that reported an average intake of 60
- 150 mg supplemental zinc/day, the average duration was 8 years. The overall duration of zinc usage by the study group was: <=2 years, 30%; >2<=10 yea rs, 55%; and >10 years, 15%. Based on the results of the questionnaire, the incidence of anemia was reported to decrease with increasing zinc dose. There were no differences between zinc
- treated and control

### 168

groups with respect to electrocardiogram results or the incidence of adverse cardiovascular events (heart attack, heart failure, hypertension, or angina). The zinc group had a lower mean serum creatinine, lower total serum protein, lower serum uric acid, and a higher mean corpuscular hemoglobin. Red bloo d cell counts were significantly lower in women, but not in men, in the zinc
treated group. Groups of 9, 13, or 9 healthy white men were administered 0, 50, or 75 mg/day supplemental zinc as zinc gluconate, respectively, for 12 weeks (Black et al., 1988). The subjects were given instructions to avoid foods high in calcium, fiber, and phytic acid, dietary constituents that are known to decrease zinc absorption. Subjects were also told to restrict their intake of zinc
- rich foods in order to minimize the varia tion in daily dietary zinc. Three
- day dietary records were collected on a biweekly basis. The records indicated that the dietary zinc intakes of the three treatment groups were 12.5, 14.0, and 9.5 mg Zn/day for the groups receiving the 0, 50, and 75 mg/day supplements, respectively. Thus, based on the average body weights for each treatment group, total zinc intakes were 0.16, 0.85, and 1.10 mg zinc/kg
- day for the 0, 50, and 75 mg/day groups, respectively. Biweekly blood samples were collected from all subj ects and analyzed for total cholesterol, HDL
- cholesterol, LDL
- cholesterol, triglycerides, zinc, and copper. Urinary zinc and copper values were also determined. There was a general decline in the mean serum HDL
cholesterol for the 75
- mg supplement group be tween weeks 6 and 12. HDL values for this group were significantly lower than those for the placebo group at weeks 6 and 12 ( p <0.05). When the mean HDL
- cholesterol level of these subjects was compared to population percentile norms, there was a decline fro m the 92nd to the 77th percentile (Simko et al., 1984) in 6 weeks, followed by a relative stabilization of HDL values for the remaining 6
- week test period. There was also a decline in the HDL values for the 50
- mg group between weeks 8 through 12; however, this decline was not significantly different from that for the controls until the 12th week of treatment. Over the 12
- week period, the HDL values for the 50
- mg supplemental zinc group declined from the 90th to the 77th population percentile norms. Serum zi nc, copper, total cholesterol, LDL
- cholesterol, and triglycerides did not appear to be affected by treatment. In another study, 12 healthy men (23 to 35 years) with normal serum cholesterol levels received a zinc sulfate capsule twice a day with meals (160 mg supplemental zinc/day or ~2 mg supplemental zinc/kg
- day, assuming a 70 kg reference body weight) for 5 weeks and 8 subjects received placebo capsules (Hooper et al., 1980). Fasting lipid levels were measured weekly for 7 weeks and at week 16 in the zin c group, and biweekly for 6 weeks in the control group. There were no statistically significant differences in total serum cholesterol, triglycerides, and LDL
- cholesterol between the zinc and control groups. After 5 weeks of zinc ingestion, serum HDL
- chole sterol had been reduced by 17%. Although no further zinc was administered, the serum HDL
- cholesterol level continued to decline and was reduced by 26% at week 7, relative to the values for the placebo group. The rise in plasma zinc concentration did not co rrelate with the fall in HDL
- cholesterol. Serum HDL
- cholesterol returned to near baseline levels 11 weeks after the end of zinc supplementation.

### 169

In a study by L'Abbe and Fischer (1984a), groups of 10 weanling male Wistar rats were fed a basal diet suppleme nted with 0, 15, 30, 60, 120, or 240 ppm zinc as zinc sulfate for 6 weeks; the 30 ppm group served as the control group. Using a reference body weight of 0.217 kg and food intake of 0.020 kg/day (U.S. EPA, 1988), daily doses of 1.4, 2.8, 5.5, 11, and 22 mg supplemental Zn/kg
day were estimated. Although a linear relationship between zinc intake and serum ceruloplasmin levels was not established, the number of animals with abnormal ceruloplasmin levels increased with increasing doses. Abnormal ceruloplasmin levels were observed in 0, 0, 11, 30, and 100% of the animals in the 0, 15, 30, 60, 120, and 240 ppm groups, respectively. The study authors estimated that the ED 50 for low ceruloplasmin levels was approximately 125 ppm. Dose
- related decreases in the activ ities of liver Cu, Zn
- superoxide dismutase and heart cytochrome c oxidase were observed at dietary zinc levels greater than 30 ppm, reaching statistical significance in the 120 and 240 ppm groups. Heart Cu, Zn
- superoxide dismutase and liver cytochrome c ox idase activities were not affected. In a second study, L'Abbe and Fischer (1984b) fed groups of 10 weanling male Wistar rats diets containing normal (30 mg zinc/kg diet) or supplemented (240 mg zinc/kg diet) zinc (as zinc sulfate) and normal (6 mg copper/k g diet) or deficient (0.6 mg copper/kg diet) copper for up to 6 weeks. Groups of rats were sacrificed at 2, 4, and 6 weeks. Blood, heart, and liver samples were collected for analysis. No significant differences in body weight or food consumption were note d among treated groups. Similarly, no differences were seen in hemoglobin levels. Serum and heart copper levels were significantly decreased in rats fed either zinc
- supplemented or copper
- deficient diets. In both the high
- zinc and copper
- deficient groups, the activities of serum ceruloplasmin, liver and heart Cu, Zn
- superoxide dismutase, and liver and heart cytochrome c oxidase were significantly reduced relative to control animals by 2 weeks of exposure, and remained reduced throughout the study.
The recen tly
- derived recommended dietary allowances (IOM, 2001) are 11 mg/day for men and 8 mg/day for women (not pregnant or lactating). Using reference body weights of 70 kg for men and 60 kg for women, these equate to 0.16 mg/kg
- day for men and 0.13 mg/kg
- day fo r women. Therefore, recommendation of a risk value below the range of 0.13
- 0.21 mg/kg
- day, which represent both the daily intake levels necessary for normal health and the average daily intake of the U.S. population, is contraindicated.
For more detail on Susceptible Populations, exit to the toxicological review, Section 4.9 (PDF)
. 

### __I.A.5. Confidence in the Oral RfD
Study

— Medium
- to
- high Data Base
— High RfD

— Medium
- to
- high

### 170

The over all confidence in this RfD assessment is medium
- to
- high because the principal studies are well
- conducted clinical studies with relevant biochemical parameters investigated in both males (Fischer et al., 1984) and females (Davis et al., 2000; Milne et al., 2001; Yadrick et al., 1989), but had a limited number of study subjects. The confidence in the overall database is high because there are several available suitable human studies that are of moderate duration. Chronic animal data are limited. Medium
- to
- hig h confidence in the RfD follows. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)
. 

### __I.A.6. EPA Documentation and Rev iew of the Oral RfD

Source Document
— U.S. EPA (2005) This assessment was peer reviewed by external scientists. Comments from the peer reviewers were evaluated carefully and considered by the Agency during the finalization of this assessment. A record of t hese comments is included in Appendix A of the Toxicological Review of Zinc and Compounds (U.S. EPA, 2005). To review this appendix, exit to the toxicological review, Appendix A: Exte rnal Peer Review - Summary of Comments and Disposition (PDF)
. Agency Completion Date
-- 7/29/2005 

### __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), (2 02) 566
- 1749 (fax), or hotline.iris@epa.gov (email address).

Top of page



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

Zinc and Compounds CASRN
— 7440
- 66
- 6 Section I.B. Last Revised

— 08/03/2005 The RfC is an estimate of a daily inhalation exposure to the human population (including susceptible subgroups) that is likely to be without an appreciable risk of adverse health effects over a lifetime. It is derived from a statistical lower confidence li mit on the benchmark concentration (BMCL), a no
observed
- adverse
- effect level (NOAEL), a lowest
- observed
- adverse
- effect level (LOAEL), or another

### 171

suitable point of departure, with uncertainty/variability factors applied to reflect limitations of the data u sed. The RfC considers toxic effects for both the respiratory system (portal
- of
- entry) and for effects peripheral to the respiratory system (extrarespiratory effects). The inhalation RfC (generally expressed in units of mg/m 3 ) is analogous to the oral RfD and is similarly intended for use in risk assessments for health effects known or assumed to be produced through a nonlinear (possibly threshold) mode of action. Inhalation RfCs are derived according to Methods for Derivation of Inhalation Reference Concen trations and Application of Inhalation Dosimetry (U.S. EPA, 1994). Since RfCs can also be derived for the noncarcinogenic health effects of substances that are carcinogens, it is essential to refer to other sources of information concerning the carcinogeni city of this chemical 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. 

### __I.B.1. Inhalation RfC Summary

Not available at this time.
Availa ble data are not suitable for the derivation of an RfC for zinc. A number of case reports of metal fume fever have been reported in humans; however, exposure levels are not known. The data in animals are limited to a few studies of acute duration; no subch ronic or chronic inhalation studies of zinc are available at this time. 

### __I.B.2. Principal and Supporting Studies (Inhalation RfC)
Not applicable. __I.B.3. Uncertainty Factors (Inhalation RfC) Not applicable. 

### __I.B.4. Additional Studies/Comments (Inhalati on RfC)
Not applicable. 

### __I.B.5. Confidence in the Inhalation RfC
Not applicable.

### 172

__I.B.6. EPA Documentation and Review of the Inhalation RfC

Source Document
— U.S. EPA (2005) This assessment was peer reviewed by external scientists. Comments from the peer reviewers were evaluated carefully and considered by the Agency during the finalization of this assessment. A record of these comments is included in Appendix A of the Toxicol ogical Review of Zinc and Compounds (U.S. EPA, 2005). To review this appendix, exit to the toxicological review, Appendix A: External Peer Review - Summary of Comments and Disposition ( PDF)
. Agency Completion Date

— 7/29/2005 

### __I.B.7. EPA Contacts (Inhalation RfC)
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 (email address).

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### _II. Carcinogenicity Assessment for Lifetime Exposure
Zinc and Compounds CASRN
— 7440
- 66
- 6 Section II. Last Revised

— 08/03/2005 This section 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 and inhalation exposure. Users are referred to Section I of this file for information on long
- term toxic effects other than carcinogenicity. The rationale and methods used to develop the carcinogenicity information in IRIS are described in the Guideli nes for Carcinogen Risk Assessment (U.S. EPA, 2005). The quantitative risk estimates are derived from the application of a low
- dose extrapolation procedure, and are presented in two ways to better facilitate their use. First, route
- specific risk values are presented. The "oral slope factor" is an upper bound on the estimate of risk per mg/kg
- day of oral exposure. Similarly, a "unit risk" is an upper bound on the estimate of risk per unit of concentration, either per μg/L drinking water (see Section II.B.1.) or per μg/m 3 air breathed (see Section II.C.1.). Second, the estimated concentration of the chemical substance in drinking water or air when associated with cancer risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000 is also provided.

### 173

_II.A. Evidence for Human Carcinogenicity __II.A.1. Weight - of - Evidence Characterization

Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is inadequate information to assess carcinogenic potential of zinc, because studies of humans occupationally
ex posed to zinc are inadequate or inconclusive, adequate animal bioassays of the possible carcinogenicity of zinc are not available, and results of genotoxic tests of zinc have been equivocal. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)
. For more detail on Susceptible Populations, exit to the tox icological review, Section 4.9 (PDF)
. 

### __II.A.2. Human Carcinogenicity Data
Inadequate. There are no reports on the possible carcinogenicity of zinc and compounds per se in humans. Case studies have been used to evaluate the effects of zinc administered for therapeutic reasons. There are reports which compare zinc levels in normal and cancerous tissue. Studies of occupational exposure to zinc compounds have also been conducted, but have limited value because they do not correlate exposure with cancer risk.



### _ _II.A.3. Animal Carcinogenicity Data
Inadequate. In a 1
- year study, an unspecified number of newborn Chester Beatty stock mice (sex not reported) were administered 0, 1000, or 5000 ppm zinc (approximately 0, 170, or 850 mg/kg
day) as zinc sulfate in drinki ng water (Walters and Roe, 1965). A separate group of mice received zinc oleate in the diet at an initial dose of 5000 ppm supplemental zinc. This dose was reduced to 2500 ppm after 3 months and to 1250 ppm after an additional 3 months because of mortality due to anemia. An epidemic of ectromelia, a natural mouse pathogen and an orthopoxvirus, caused the deaths of several mice during the first 8 weeks; consequently, additional control and test
- diet groups were established. There was no difference in body we ight gain between control and treated groups, except for the dietary zinc group which became anemic. Survival was not reported in treated groups compared with control groups. In mice administered zinc oleate in the diet, no statistically significant increa ses in liver tumors were observed. The hepatoma incidences in the control, low
- dose drinking water, high
- dose drinking water, and test
- diet groups were 3/24 (12.5%), 3/28 (10.7%), 3/22 (13.6%), and 7/23 (30.4%), respectively. Incidences of malignant lympho ma in the control, low
- dose drinking water, high
- dose drinking water, and test
- diet groups were 3/24 (12.5%), 4/28 (14.3%), 2/22 (9%), and 2/23 (8.7%), respectively. Incidences of lung adenoma in the control, low
- dose drinking water, high
- dose drinking wat er, and test
- diet groups

### 174

were 10/24 (41.7%), 9/28 (32.1%), 5/22 (22.7%), and 9/23 (39.1%), respectively. None of these were significantly elevated in a statistical analysis performed by the EPA. Halme (1961) exposed tumor
- resistant and tumor
- susceptible st rains of mice to zinc in drinking water. In a 3
- year, five
- generation study, zinc chloride was added to the water of tumor
- resistant mice (strain not specified); the groups received 0, 10, 20, 50, 100, or 200 mg Zn/L. Most of the tumors occurred in the 10
- and 20
- mg Zn/L dose groups. No statistical analyses and no individual or group tumor incidence data were reported. In the tumor
- susceptible mice, strains C3H and A/Sn received 10
- 29 mg Zn/L in their drinking water for 2 years; 33/76 tumors were observed i n the C3H strain (31 in females) and 24/74 tumors were observed in the A/Sn strain (20 in females). However, this study provided no support for carcinogenicity since no statistical analyses were performed and no individual or group tumor incidence data wer e reported. 

### __II.A.4. Supporting Data for Carcinogenicity
Either zinc deficiency or excessively high levels of zinc may enhance susceptibility to carcinogenesis, whereas supplementation with low to moderate levels of zinc may offer protection (Mathur, 197 9; Woo et al., 1988). For example, zinc deficiency enhanced carcinomas of the esophagus induced by methylbenzylnitrosamine (Fong et al., 1978) but retarded the development of cancer of the oral cavity induced by 4
- nitroquinoline
- N
- oxide (Wallenius et al., 1979). Thus, zinc's modifying effect on carcinogenesis may depend both on the dose of zinc and the identity of the carcinogen being affected. The mutagenicity of zinc, particularly in Salmonella typhimurium , appears to depend greatly on the chemical form.

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### _II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure
Not applicable.

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### _II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure
Not applicable.

### 175 Top of page



### _II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment) __II.D.1. EPA Do cumentation

Source Document
— U.S. EPA (2005) This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS Summary. A record of these comments is included in Appendix A of the Toxicological Review of Zinc and Compounds (U.S. EPA, 2005). To review this appendix, exit to the toxicological review, Appendix A: External Peer Review Summary of Comments an d Disposition (PDF)
. 

### __II.D.2. EPA Review (Carcinogenicity Assessment)
Agency Consensus Date
— 7/29/2005 

### __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 (email address).

Top of page



### _III. [reserved] _IV. [reserved] _V. [reserved]
_VI. Bibliography
Zinc and Compounds CASRN
— 7440
- 66
- 6 Section VI. Last Revised

— 08/03/2005

### 176

_VI.A. Oral RfD References
Abernathy, CO; Cantilli, R; Du, JT; et al. (1993) Essentiality versus toxicity: some considerations in the risk assessment of essential trace elements. In: Saxena, J.; ed. Hazard assessment of chemicals. Vol. 8. Bristol, PA: Taylor & Francis Inc; pp. 81
- 113. Black, MR; Medeiros, DM; Brunett, E; et al. (1988) Zinc supplements and serum lipids in young adult white mal es. Am J Clin Nutr 47:970
- 975. Davis, CD; Milne, DB; Nielsen, FH. (2000) Changes in dietary zinc and copper affect zinc
- status indicators of postmenopausal women, notably, extracellular superoxide dismutase and amyloid precursor proteins. Am J Clin Nutr 71 :781
- 788. Fischer, PW; Giroux, A; L'Abbe, MR. (1984) Effect of zinc supplementation on copper status in adult man. Am J Clin Nutr 40:743
- 746. Hale, WE; May, FE; Thomas, RG; et al. (1988) Effect of zinc supplementation on the development of cardiovascular d isease in the elderly. J Nutr Elder 8:49
- 57. Hooper, PL; Visconti, L; Garry, PJ; et al. (1980) Zinc lowers high
- density lipoprotein
- cholesterol levels. J Am Med Assoc 244:1960
- 1961. IOM (Institute of Medicine). (2001) Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; pp. 442
- 501. L'Abbe, MR; Fischer, PW. (1984a) The effects of dietary zinc on the activity of c opper - requiring metalloenzymes in the rat. J Nutr 114:823
- 828. L'Abbe, MR; Fischer, PW. (1984b) The effects of high dietary zinc and copper deficiency on the activity of copper
- requiring metalloenzymes in the growing rat. J Nutr 114:813
- 822. Mahomed, K; Ja mes, DK; Golding, J; et al. (1989) Zinc supplementation during pregnancy: a double blind randomized controlled trial. Br Med J 299:826
- 830. Milne, DB; Davis, CD; Nielsen, FH. (2001) Low dietary zinc alters indices of copper function and status in postmenop ausal women. Nutrition 17:701
- 708. Pennington, JA; Young, BE; Wilson, DB. (1989) Nutritional elements in U.S. diets: results from the Total Diet Study, 1982 to 1986. J Am Diet Assoc 89:659
- 664.

### 177

Prasad, A. (1993) Essentiality and toxicity of zinc. Scand J W ork Environ Health 19(Suppl 1):134
- 6.:134
- 136. Prasad, R; Nath, R. (1993) Zinc transport in monkey renal brush border membrane vesicles and its interaction with cadmium: a kinetic study. J Trace Elem Exp Med 6:95
- 107. Samman, S; Roberts, DC. (1987) The eff ect of zinc supplements on plasma zinc and copper levels and the reported symptoms in healthy volunteers. Med J Aust 146:246
- 249. Samman, S; Roberts, DC. (1988) The effect of zinc supplements on lipoproteins and copper status. Atherosclerosis 70:247
- 252.

S andstead, H. (1994) Understanding zinc: recent observations and interpretations. J Lab Clin Med 124:322
- 327. Simko, MD; Cowell, C; Gilbride, JA; eds. (1984) Nutrition assessment: a comprehensive guide for planning intervention.. Rockville, MD: Aspen System s Corp.
Simmer, K; Lort
- Phillips, L; James, C; et al. (1991) A double
- blind trial of zinc supplementation in pregnancy. Eur J Clin Nutr 45:139
- 144. U.S. EPA (Environmental Protection Agency). (1988) Recommendations for and documentation of biological values for use in risk assessment. EPA/600/6
- 87/008. Available from: NTIS, Springfield, VA; PB
- 88179874/AS. Vallee, BL; Falchuk, KH. (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79
- 118. Walsh, CT; Sandstead, H; Prasad, A; et al. (1994) Z inc: health effects and research priorities for the 1990s. Environ Health Perspect 102(Suppl 2):5
- 46.:5
- 46. Yadrick, MK; Kenney, MA; Winterfeldt, EA. (1989) Iron, copper, and zinc status: response to supplementation with zinc or zinc and iron in adult fema les. Am J Clin Nutr 49:145
- 150.

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### _VI.B. Inhalation RfC References
Not Applicable.

### 178 Top of page



### _VI.C. Carcinog enicity Assessment References
Fong, LY; Sivak, A; Newberne, PM. (1978) Zinc deficiency and methylbenzylnitrosamine
- induced esophageal cancer in rats. J Natl Cancer Inst 61:145
- 150. Halme, E. (1961) On the carcinogenic effect of drinking water containing zi nc. Vitalstoffe 6:59
- 66. [German with English translation] Mathur, A; Wallenius, K; Abdulla, M. (1979) Influence of zinc on onset and progression of oral carcinogenesis in rats. Acta Odontol Scand 37:277
- 284. U.S. EPA. (2005) Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC. EPA/630/P
- 03/001F. Available from: http://www.epa.gov/iris/backgrd.html
. Wallenius, K; Mathur, A; Abdulla, M. (1979) Effect of different levels of dietary zinc on development of chemically induced oral cancer in rats. Int J Oral Surg 8:56
- 62. Walters, M; Roe, FJ. (1965) A study of the effects of zinc and tin administered orally to mice over a prolonged period. Food Cosmet Toxicol 3:271
- 276.
Woo, YT; Lai, DY; Arcos, JC; et al; eds. (1988) Natural, metal, fiber and macromolecular carcinogens. In: Chemical induction of cancer: structural bases and biological mechanisms. Vol. IIIC. San Diego, CA: Academic Press; pp. 488
- 489.

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### _VII. Revision History
Zinc and Compounds CASRN
— 7440
- 66
- 6 File First On
- Line
— 02/01/1991
Date Section Description 02/01/1991 II. Carcinogenicity assessment on
- line

### 179

02/01/1991 VI. Bibliography on
- line 01/01/1992 IV. Regulatory Action section on
- line 10/01/1992 I.A. Oral RfD summary on
- line 10/01/1992 VI.A. Oral RfD references on
- line 4/01/1997 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. 12/10/1998 I., II. This chemical is being reassessed under the IRIS Program. 08/03/2005 I., II.,

VI. RfD, RfC, and cancer sections updated.

04/03/2007 VI.C. Modified the reference to the Guidelines for carcinogen risk assessment.

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### _VIII. Synonyms
Zinc and Compounds CASRN
— 7440
- 66
- 6 Section VIII. Last Revised

— 08/03/2005



###  7440
- 66
- 6


###  Zinc


###  Asarco L 15


###  Blue powder


###  Cinc [Spanish]


###  EMANAY ZINC DUST


###  GRANULAR ZINC


###  HSDB 1344


###  JASAD


###  Lead refinery vacuum zinc


###  Merrillite


###  UN 1436


###  ZINC DUST


###  ZINC POWDER


###  ZINC, ashes


###  ZINC, powder or dust, non
- pyrophoric


###  ZINC, powder or dust, pyrophoric

### 180 Top of page

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Chronic Health Hazards for Non - Carcinogenic 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

Ref erence 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
- of
- Evidence Characterization 

###  Human Carcinogenicity Data 

###  Animal Carcinogenicity Data 

###  Supporting Data for Carcinogenicity

Quantitative Estimate of Carcinogenic Risk from Oral Exposure



###  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

### 181  Discussion of Confidence 

###  EPA Documentation, Review and, Contacts

Bibliography

Revision Hist ory

Synonyms

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### 182



## L e a d a n d L e a d C o m p o u n d s ( i n o r g a n i c ) ( http://www.epa.gov/iris/subst/0277.htm ) 

# Lead and compounds (inorganic) (CASRN 7439 - 92 - 1)

0277 Lead and compounds (inorganic); CASRN 7439 - 92 - 1 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 . Sec tions 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 me thods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website
. STATUS OF DATA FOR Lead and compounds (inorganic)
File First On - Line 03/01/1988

Category (section) Status Last Revised Oral RfD Assessment (I.A.) discussion 07/08/2004 Inhalation RfC Assessment (I.B.) no data Carcinogenicity Assessment (II.) on - line 11/01/1993


### _I. Chronic Health Hazard Assessments for Noncarcinogenic Effects _I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name

— Lead and compounds (inorganic) CASRN
— 7439
- 92
- 1 Section I.A. Last Revised

— 07/08/2004

### 183

In general, the oral Reference Dose (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. The RfD i s based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis and is expressed in units of mg/kg
- day. Please refer to the guidance documents at http://www.epa.gov/ir is/backgrd.html for an elaboration of these concepts. Since RfDs can be derived for the noncarcinogenic health effects of substances that are also carcinogens, it is essential to refer to other sources of information concerning the carcinogenicity of this chemical 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. 

### __I.A.1. Oral RfD Summary
Health effects associated with exposure to inorganic lead and compounds include, but are not limited to, neurotoxicity, developmental delays, hypertension, impaired hearing acuity, impaired hemoglobin synthesis, and male reproductive impairment. Importantly, many of lead's health effects may occur without o vert signs of toxicity. Lead has particularly significant effects in children, well before the usual term of chronic exposure can take place. Children under 6 years old have a high risk of exposure because of their more frequent hand
- to
- mouth behavior (Cen ters for Disease Control and Prevention (CDC), 1991: http://www.cdc.gov/nceh/lead/publications/books/plpyc/contents.htm ). EPA considered providing an RfD for inorganic lead in 1985, and concluded that it was inappropriate to develop an RfD, as documented online in the following statement in 1988: A great deal of information on the health effects of lead has been obtained through decades of medical observation and scientific r esearch. This information has been assessed in the development of air and water quality criteria by the Agency's Office of Health and Environmental Assessment (OHEA) in support of regulatory decision
- making by the Office of Air Quality Planning and Standar ds (OAQPS) and by the Office of Drinking Water (ODW). By comparison to most other environmental toxicants, the degree of uncertainty about the health effects of lead is quite low. It appears that some of these effects, particularly changes in the levels of certain blood enzymes and in aspects of children's neurobehavioral development, may occur at blood lead levels so low as to be essentially without a threshold. The Agency's RfD Work Group discussed inorganic lead (and lead compounds) at two meetings (07/0 8/1985 and 07/22/1985) and considered it inappropriate to develop an RfD for inorganic lead. EPA is not providing a review of current literature concerning the health effects of lead at this time (June, 2004), given the ongoing effort of the CDC to re
- eval uate the blood lead level of concern (CDC, 2004: http://www.cdc.gov/nceh/lead/spotLights/changeBLL.htm ). A screening
- level review of the

### 184

more recent toxicology literature pertinent to no ncancer effects associated with oral exposure to Lead and compounds (inorganic) was conducted by an EPA contractor in September 2002, and identified one or more significant new studies since the 1985 assessment. IRIS users may request the references for th ose studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566
- 1676. Current knowledge of lead pharmacokinetics indicates that risk values derived by standard procedures would not truly indicate the potent ial risk, because of the difficulty in accounting for pre
- existing body burdens of lead. Lead bioaccumulates in the body, primarily in the skeleton. Lead body burdens vary significantly with age, health status, nutritional state, maternal body burden durin g gestation and lactation, etc. For this reason, and because of the continued apparent lack of threshold (CDC, 2004: http://www.cdc.gov/nceh/lead/spotLights/changeBLL.htm ), it is still i nappropriate to develop reference values for lead. The purpose of this 2004 update is to assist IRIS users in finding relevant risk information and risk assessment methods that have been developed within EPA for media
- specific applications. Most of these m ethods focus on blood lead levels, through the development of several media
- specific lead exposure levels for risk management and regulatory purposes. Further information on these lead risk assessment methods and tools is described in Section 1.A.4. 

### __I.A. 2. Principal and Supporting Studies (Oral RfD)
Not applicable. 

### __I.A.3. Uncertainty and Modifying Factors (Oral RfD)
Not applicable. 

### __I.A.4. Additional Studies/Comments (Oral RfD)
As noted above, EPA is not providing a review of current literature at this time. In addition to information developed by CDC and the Agency for Toxic Substances and Disease Registry (ATSDR), described below, EPA has developed a number of lead exposure lim its in support of regulatory decision
- making, and has developed methods to assess risk from lead in situations not covered by these limits, also described below. The CDC identified 10 μg/dL as the blood lead level of concern in children in their 1991 repor t "Preventing Lead Poisoning in Young Children" ( http://www.cdc.gov/nceh/lead/publications/books/plpyc/contents.htm ), and provided risk management options for categories of blood lead levels higher than 10 μg/dL. In view of the fact that health effects were and continue to be identified below the level of concern, the CDC convened an Advisory Committee on Childhood Lead Poisoning Prevention to consider whether the level of co ncern

### 185

should be changed. The Advisory Committee's progress reports can be found at http://www.cdc.gov/nceh/lead/ACCLPP/acclpp_main.htm . At this time, CDC has not changed the blood lead lev el of concern for three reasons (March 23, 2004, http://www.cdc.gov/nceh/lead/spotLights/changeBLL.htm :



###  "No effective clinical interventions are known to lower blood lead levels for children with levels less than 10 μg/dL or to reduce the risks for adverse developmental effects."


###  "Children cannot be accurately classified as having blood lead levels above or below 10 μg/dL because of the inaccuracy inhere nt in laboratory testing."


###  "Finally, there is no evidence of a threshold below which adverse effects are not experienced. Thus, any decision to establish a new level of concern would be arbitrary and provide uncertain benefits." In addition to the ongoing CDC effort, the ATSDR is mandated by Congress under CERCLA (1980) and SARA (1986) to develop toxicological profiles for all hazardous waste sites on the National Priorities List (NPL) (PB/99/166704, NTIS PB
- 99
- 66704; http://www.atsdr.cdc.gov/toxprofiles/tp13.html ). Lead is the most common toxic metal at these sites. The ATSDR Toxicological Profile for Lead was last updated in 1999. EPA has developed a number of lead exposure levels in support of regulatory decision
- making, which limit the amount of lead that can be present in various environmental media. Under the National Primary Drinking Water Regulations, EPA established a Maximum Contaminant Level (MCL) for lead in drinking water due to any s ource. Under the Toxic Substances Control Act (TSCA) as amended by the Residential Lead
- Based Paint Hazard Reduction Act, EPA established standards for lead in paint, house dust, and outdoor soil. The following links provide more information:
Action level for lead in drinking water: http://www.epa.gov/safewater/mcl.html#mcls Regulation for lead in paint housedust, and outdoor soil: http://www.epa.gov/lead/regulations.html#paint National ambient air quality standard: http://www.epa.gov/ttn/naaqs/ Note that additional relevant information will be found by following links provided at t hese websites, such as dose
- response relationships relating blood lead levels to changes in IQ (children) and hypertension (men). Due to the likelihood of simultaneous exposure to various sources of lead, EPA recommends a case
by
- case evaluation of the rel ative contributions of relevant lead exposures in a particular setting. The Superfund Program has guidelines for identifying lead
- contaminated soil ( http://www.epa.gov/superfund/progra ms/lead/products.htm ), and facilitates site
- specific risk assessments at contaminated waste sites on the National Priority List, where the major sources of soil contamination are activities such as disposal of mining and manufacturing wastes contaminated w ith

### 186

lead and deposition of lead from air, rather than presence of lead
- based paint in residences (see: http://www.epa.gov/superfund/programs/lead/trwhome.htm ). The Superfund Program use s the Integrated Exposure Uptake Biokinetic (IEUBK) Model for Lead in Children. The IEUBK Model provides estimates of the risk of elevated blood lead associated with particular combinations of relevant sources of lead exposure. This interactive model is de scribed in more detail and provided for downloading at http://www.epa.gov/superfund/programs/lead/products.htm . Note that the IEUBK model was used in direct support of the lead
- based p aint regulation cited above. The Superfund Program has also developed an Adult Lead Model, for use when lead exposures to adults, especially pregnant women, are of greater concern. This model is described and provided for downloading at http://www.epa.gov/superfund/programs/lead/adult.htm
. EPA maintains a lead resources page ( http://www.epa.gov/lead/index.html ). Links are provided to many other EPA offices, government agencies, and other organizations involved in efforts to reduce exposure to lead in the environment. 

### __I.A.5. Confidence in Risk Values
Not applicable. 

### __I.A.6. EPA Documentation and Review of the Oral RfD
Agency Completion Date
- 05/26/2004 

### __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 (email address).

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

Substance Name

— Lead and compounds (inorganic) CASRN
- 7439
- 92
- 1 In general, the Reference Concentration (RfC) is an estimate (with uncertainty spannin g perhaps an order of magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The

### 187

RfC considers toxic effects for both the respiratory system (portal
- of
- entry) and for effects peripheral to the respiratory system (extrarespiratory effects). The inhalation RfC (generally expressed in units of mg/m3) is analogous to the oral RfD and is likewise based on the assumption that thres holds exist for certain toxic effects such as cellular necrosis. Inhalation RfCs are derived according to the Interim Methods for Development of Inhalation Reference Doses (EPA/600/8
- 88/066F, 1989) and subsequently, according to Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry (EPA/600/8
- 90/066F, 1994). Since RfCs can also be derived for the noncarcinogenic health effects of substances that are carcinogens, it is essential to refer to other sources of in formation concerning the carcinogenicity of this chemical 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. 

### __I.B.1. Inhalation RfC Summar y
No RfC is available. See Section I.A. for additional information. 

### __I.B.2. Principal and Supporting Studies (Inhalation RfC)
Not applicable. 

### __I.B.3. Uncertainty and Modifying Factors (Inhalation RfC)
Not applicable. 

### __I.B.4. Additional Studies/Comments (Inhalation RfC)
Not applicable. 

### __I.B.5. Confidence in the Inhalation RfC
Not applicable. 

### __I.B.6. EPA Documentation and Review of the Inhalation RfC
Agency Completion Date
-- Not applicable. 

### __I.B.7. EPA Contacts (Inhalation R fC)

### 188

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 (email address).

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### _II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name

— Lead and compounds (inorganic) CASRN
— 7439
- 92
- 1 Section II Last Revised

— II.A. introduc tory paragraph revised 07/08/2004. II.A.1
- II.D. last revised 11/01/1993 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 μg/L drinking water or risk per μg/cu.m air breathed. The third form in which risk is presented is a concentration of the chemical in drinking wa ter or air associated with 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
Note that the National Toxicology Program's Report on Carcinogens Review Committee has recommended that lead and lead compounds be considered "reasonably anticipated to be human carcinogens" ( http://ntp
- server.niehs.nih.gov/NewHomeRoc/roc11Bkgrnd2003.html ; July 2003). Also, the International Agency for Research on Cancer (IARC) has undertaken a reevaluation of lead's carcinogenicity ( http://monographs.iarc.fr/ENG/Monographs/vol87/index.php ). 

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

Classification

— B2; probable human carcinogen

### 189

Basis
— Sufficient animal evidence. Ten rat bioassays and one mouse assay have shown statistically significant increases in renal tumors with dietary and subcutaneous exposure to several soluble lead salts. Animal assays provide reproducible results in sev eral laboratories, in multiple rat strains with some evidence of multiple tumor sites. Short term studies show that lead affects gene expression. Human evidence is inadequate. 

### __II.A.2. Human Carcinogenicity Data
Inadequate. There are four epidemiologic st udies of occupational cohorts exposed to lead and lead compounds. Two studies (Dingwall
- Fordyce and Lane, 1963; Nelson et al., 1982) did not find any association between exposure and cancer mortality. Selevan et al. (1985), in their retrospective cohort mo rtality study of primary lead smelter workers, found a slight decrease in the total cancer mortality (SMR=95). Apparent excesses were observed for respiratory cancer (SMR=111, obs=41, p>0.05) and kidney cancer (SMR=204, obs=6, p>0.05). Cooper and Gaffey (1 975) and Cooper (1985 update) performed a cohort mortality study of battery plant workers and lead smelter workers. They found statistically significant excesses for total cancer mortality (SMR=113, obs=344), stomach cancer (SMR=168, obs=34), and lung canc er (SMR=124, obs=109) in the battery plant workers. Although similar excesses were observed in the smelter workers, they were not statistically significant. Cooper and Gaffey (1975) felt it was possible that individual subjects were monitored primarily on the basis of obvious signs of lead exposure, while others who showed no symptoms of lead poisoning were not monitored. All of the available studies lacked quantitative exposure information, as well as information on the possible contribution from smoking. All studies also included exposures to other metals such as arsenic, cadmium, and zinc for which no adjustment was done. The cancer excesses observed in the lung and stomach were relatively small (<200). There was no consistency of site among the various studies, and no study showed any dose
- response relationship. Thus, the available human evidence is considered to be inadequate to refute or demonstrate any potential carcinogenicity for humans from lead exposure. 

### __II.A.3. Animal Carcinogenicity Data

Suff icient. The carcinogenic potential of lead salts (primarily phosphates and acetates) administered via the oral route or by injection has been demonstrated in rats and mice by more than 10 investigators. The most characteristic cancer response is bilateral renal carcinoma. Rats given lead acetate or subacetate orally have developed gliomas, and lead subacetate also produced lung adenomas in mice after i.p. administration. Most of these investigations found a carcinogenic response only at the highest dose. Th e lead compounds tested in animals are almost all soluble salts. Metallic lead, lead oxide and lead tetraalkyls have not been tested adequately. Studies of inhalation exposure have not been located in the literature.

### 190

Azar et al. (1973) administered 10, 50, 100, and 500 ppm lead as lead acetate in dietary concentrations to 50 rats/sex/group for 2 years. Control rats (100/sex) received the basal laboratory diet. In a second 2
- year feeding study, 20 rats/group were given diets containing 0, 1000, and 2000 ppm lead as lead acetate. No renal tumors were reported in the control groups or in treated animals of either sex receiving 10 to100 ppm. Male rats fed 500, 1000, and 2000 ppm lead acetate had an increased renal tumor incidence of 5/50, 10/20, and 16/20, while 7/20 females in the 2000 ppm group developed renal tumors. The Azar et al. (1973) study is limited by the lack of experimental detail. The possibility of environmental contamination from lead in the air or drinking water was not mentioned. The strain of r ats used was not specified in the study, but the Health Effects Assessment for Lead (U.S. EPA, 1984) indicates the rats were Wistar strain. The weight gain at 1000 and 2000 ppm was reported to be depressed, but details were not given. Kasprzak et al. (198 5), in investigating the interaction of dietary calcium on lead carcinogenicity, fed 1% lead subacetate (8500 ppm Pb) to male Sprague
- Dawley rats in the diet for 79 weeks. Of the rats surviving (29/30) in this treatment group beyond 58 weeks, 44.8% had ren al tumors. Four rats had adenocarcinomas; the remaining nine had adenomas. Bilateral tumors were noted. No renal tumors were noted among the controls. As part of a study to determine interactions between sodium nitrite, ethyl urea and lead, male Sprague
- D awley rats were given lead acetate in their drinking water for 76 weeks (Koller et al., 1986). The concentration of lead was 2600 ppm. No kidney tumors were detected among the 10 control rats. Thirteen of 16 (81%) lead
- treated rats had renal tubular carcin oma; three tumors were detected at 72 weeks and the remainder detected at the termination of the study. Van Esch and Kroes (1969) fed basic lead acetate at 0, 0.1%, and 1.0% in the diet to 25 Swiss mice/sex/group for 2 years. No renal tumors developed in the control group, but 6/25 male mice of 0.1% basic lead acetate group had renal tumors (adenomas and carcinomas combined). In the 1.0% group, one female had a renal tumor. The authors thought that the low incidence in the 1.0% group was due to early morta lity. Hamsters given lead subacetate at 0.5% and 1% in the diet had no significant renal tumor response (Van Esch and Kroes, 1969). 

### __II.A.4. Supporting Data for Carcinogenicity
Lead acetate induces cell transformation in Syrian hamster embryo cells (Di Paolo et al., 1978) and also enhances the incidence of simian adenovirus induction. Lead oxide showed similar enhanced adenovirus induction (Casto et al., 1979).

### 191

Under certain conditions lead compounds are capable of inducing chromosomal aberrations in vi vo and in tissue cultures. Grandjean et al. (1983) showed a relationship between sister chromatid exchange and lead exposure in exposed workers. Lead has been shown, in a number of DNA structure and function assays, to affect the molecular processes associ ated with the regulation of gene expression (U.S. EPA, 1986b).

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### _II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure

Not ava ilable. Quantifying lead's cancer risk involves many uncertainties, some of which may be unique to lead. Age, health, nutritional state, body burden, and exposure duration influence the absorption, release, and excretion of lead. In addition, current knowl edge of lead pharmacokinetics indicates that an estimate derived by standard procedures would not truly describe the potential risk. Thus, the Carcinogen Assessment Group recommends that a numerical estimate not be used.

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### _II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure

Not available.

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### _II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment) __II.D.1. EPA Documentation

Source Document
— U.S. EPA, 1984, 1986, 1989 U.S. EPA, 1989 has received OHEA and SAB review. The 1986 Air Quality Criteria Document for Lead has received Agency and External Review.

### 192

__II.D.2. EPA Review (Carcinogenicity Assessment)

Verification Date

— 05/04/1988 Screening
- Level Literature Review Findings

— A screening
- level review of the more recent toxicology litera ture pertinent to the cancer assessment for Lead and compounds (inorganic), conducted by an EPA contractor in September 2002, did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS H otline 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
- 16 76 (phone), (202)566
- 1749 (fax), or hotline.iris@epa.gov (email address).

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### _III. [reserved] _IV. [reserved] _V. [reserved]
_VI. Bibliography

Substance Name

— Lead and compounds (inorganic) CASRN
— 7439
- 92
- 1 Section V.I. Last Revised

— 07/08/2004 

### _VI.A. Oral RfD References

None.

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### _VI.B. Inhalation RfC References

None.

### 193 Top of page



### _VI.C. Carcinogenicity Assessment References
Anderson, E.L., and CAG (Carcinogenic Assessment Group). 1983. Quantitative approaches in use to assess cancer risk. Risk Analysis. 3: 277
- 295. Azar, A., H.J. Trochimowicz and M.E. Maxfield. 1973. Review of lead studies in animals carried out at Haskell Laboratory
- Two year feeding study and response to hemorrhage study. In: Barth D., A. Berlin, R. Engel, P. Recht and J. Smeets, Ed. Environmental health aspects of lead: Proceedings International Symposium; October 1972; Amsterdam, The Netherlands. Commission of the European Communities, Luxemberg. p. 199
- 208. Casto, B.C., J. Meyers and J.A. DiPaolo. 1979. Enhancement of viral transformation for e valuation of the carcinogenic or mutagenic potential of inorganic metal salts. Cancer Res. 39: 193
- 198. Cooper, W.C. 1985. Mortality among employees of lead battery plants and lead producing plants, 1947
- 1980. Scand. J. Work Environ. Health. 11: 331
- 345. Cooper, W.C. and W.R. Gaffey. 1975. Mortality of lead workers. In: Proceedings of the 1974 Conference on Standards of Occupational Lead Exposure, J.F. Cole, Ed., February, 1974. Washington, DC. J. Occup. Med. 17: 100
- 107. Dingwall
- Fordyce, I. and R.E. Lan e. 1963. A follow
- up study of lead workers. Br. J. Ind. Med. 20: 313
- 315. DiPaolo, J.A., R.L. Nelson and B.C. Casto. 1978. In vitro neoplastic transformation of Syrian hamster cells by lead acetate and its relevance to environmental carcinogenesis. Br. J. Cancer. 38: 452
- 455. Grandjean, P., H.C. Wulf and E. Niebuhr. 1983. Sister chromatid exchange in response to variations in occupational lead exposure. Environ. Res. 32: 199
- 204. Kasprzak, K.S., K.L. Hoover and L.A. Poirier. 1985. Effects of dietary calc ium acetate on lead subacetate carcinogenicity in kidneys of male Sprague
- Dawley rats. Carcinogenesis. 6(2): 279
- 282. Koller, L.D., N.I. Kerkvliet and J.H. Exon. 1986. Neoplasia induced in male rats fed lead acetate, ethyl urea and sodium nitrate. Toxico l. Pathol. 13: 50
- 57.

### 194

Nelson, D.J., L. Kiremidjian
- Schumacher and G. Stotzky. 1982. Effects of cadmium, lead, and zinc on macrophage
- mediated cytotoxicity toward tumor cells. Environ. Res. 28: 154
- 163. Selevan, S.G., P.J. Landrigan, F.B. Stern and J.H. J ones. 1985. Mortality of lead smelter workers. Am. J. Epidemiol. 122: 673
- 683. U.S. EPA. 1984. Health Effects Assessment for Lead. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington, DC. EPA/540/1
- 86/055. NTIS PB85
- 163996/AS. U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Environmental Protection Agency, Washington, DC. 51 FR 33992
- 34003.
U.S. EPA. 1986b. Air Quality Criteria Document for Lead. Volumes III, IV. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC, for the Office of Air Quality Planning and Standards. EPA
- 600/8
- 83 /028dF. U.S. EPA. 1989. Evaluation of the potential carcinogenicity of lead and lead compounds: In support of reportable quantity adjustments pursuant to CERCLA Section 102. Prepared by the Office of Health and Environmental Assessment, Washington, DC. EPA /600/8
- 89/045A. (External Review Draft). Van Esch, G.J. and R. Kroes. 1969. The induction of renal tumors by feeding of basic lead acetate to mice and hamsters. Br. J. Cancer. 23: 265
- 271.

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### _VII. Revision History

Substance Name

— Lead and compounds (inorganic) CASRN
— 7439
- 92
- 1 File First On
- Line 03/01/1988
Date Section Description 09/26/1988 II. Carcinogen summary on
- line 02/01/1989 IV.B.1. Effect level corrected in discussion

### 195

06/01/1989 II.D.3. Primary contact changed 06/01/1989 IV.A.1. Reference corrected
- changed number for part in CFR 12/01/1989 II.A.3. Last paragraph
- Correct Van Esch 1969 citation 12/01/1989 VI. Bibliography on
- line 07/01/1990 I.A. Changed contact J. Cohen's office and telephone number 07/01/1990 IV.F.1. EPA contact changed 02/01/1991 I.A. Message revised to include new EPA document 02/01/1991 I.A. EPA contacts changed 05/01/1991 II.A. Text edited 01/01/1992 IV. Regulatory actions updated 06/01/1992 IV.B.2. MCL monitoring reqs. and BAT corrected 07/01/1993 II.D.3. Secondary contact's phone number changed 07/01/1993 VI.C. References alphabetized correctly 11/01/1993 II.D.1. U.S. EPA 1987 replaced with 1989; rev. state. revised 11/01/1993 VI.C. U.S. EPA 1987 deleted; U.S. EPA 1989 added 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. 12/03/2002 I.A.,

II.D.2. Screening
- Level Literature Review Findings message has been added.

07/08/2004 I.A.,

I.B., II. Previous reference value discussions replaced with links to EPA websites

containing regulatory information and other websites wi th risk assessment information; cancer discussion retained, added links to agencies conducting reviews of lead carcinogenicity.

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### 196

_VIII. Synonyms

Substance Name

— Lead and compounds (inorganic) CASRN
— 7439
- 92
- 1 Last Revised

— 07/08/2004



###  7439
- 92
- 1


###  Lead


###  Lead and compounds


###  plumbum