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 information 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 inhalation 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 subgroups) that is likely to be without an 

appreciable risk of deleterious effects during a lifetime. An RfD can be derived from a no-observedadverse-effect level (NOAEL), lowest-observed-adverse-effect level (LOAEL), or benchmark dose, with 

uncertainty factors generally applied to reflect limitations of the data used. The inhalation RfC 

(expressed in units of mg of substance/m3 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 systemic 

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 continuous exposure throughout the duration 

specified. RfDs and RfCs are generally used in noncancer health assessments.
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Arsenic, inorganic (http://www.epa.gov/iris/subst/0278.htm)

Arsenic, inorganic (CASRN 7440-38-2) 

Reference Dose for Chronic Oral Exposure (RfD)

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

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

0278 

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

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

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

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

Assessment for Lifetime Exposure) present the conclusions that were reached during the 

assessment development process. Supporting information and explanations of the methods used to 

derive the values given in IRIS are provided in the guidance documents located on the IRIS 

website. 

STATUS OF DATA FOR Arsenic, inorganic

File First On-Line 02/10/1988

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
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Last Revised — 02/01/1993

The oral Reference Dose (RfD) is based on the assumption that thresholds exist for certain toxic 

effects such as cellular necrosis. It is expressed in units of mg/kg-day. In general, the RfD is an 

estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the 

human population (including sensitive subgroups) that is likely to be without an appreciable risk of 

deleterious effects during a lifetime. Please refer to the Background Document for an elaboration of 

these concepts. RfDs can also be derived for the noncarcinogenic health effects of substances that 

are also carcinogens. Therefore, it is essential to refer to other sources of information concerning 

the carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for potential 

human carcinogenicity, a summary of that evaluation will be contained in Section II of this file. 

NOTE: There was not a clear consensus among Agency scientists on the oral RfD. Applying the 

Agency's RfD methodology, strong scientific arguments can be made for various values within a 

factor of 2 or 3 of the currently recommended RfD value, i.e., 0.1 to 0.8 ug/kg/day. It should be 

noted, however, that the RfD methodology, by definition, yields a number with inherent uncertainty 

spanning perhaps an order of magnitude. New data that possibly impact on the recommended RfD 

for arsenic will be evaluated by the Work Group as it becomes available. Risk managers should 

recognize the considerable flexibility afforded them in formulating regulatory decisions when 

uncertainty and lack of clear consensus are taken into account. 

__I.A.1. Oral RfD Summary

Critical Effect Experimental Doses* UF MF RfD

Hyperpigmentation,

keratosis and 

possible vascular

complications

Human Chronic

oral exposure

Tseng, 1977; 

Tseng et al., 1968

NOAEL: 0.009 mg/L

converted to 0.0008

mg/kg-day

LOAEL: 0.17 mg/L converted

to 0.014 mg/kg-day

3 1 3E-4

mg/kg-day

*Conversion Factors -- NOAEL was based on an arithmetic mean of 0.009 mg/L in a range of arsenic concentration of 0.001 to 

0.017 mg/L. This NOAEL also included estimation of arsenic from food. Since experimental data were missing, arsenic 

concentrations in sweet potatoes and rice were estimated as 0.002 mg/day. Other assumptions included consumption of 4.5 L 

water/day and 55 kg bw (Abernathy et al., 1989). NOAEL = [(0.009 mg/L x 4.5 L/day) + 0.002 mg/day] / 55 kg = 0.0008 mg/kg-
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day. The LOAEL dose was estimated using the same assumptions as the NOAEL starting with an arithmetic mean water 

concentration from Tseng (1977) of 0.17 mg/L. LOAEL = [(0.17 mg/L x 4.5 L/day) + 0.002 mg/day] / 55 kg = 0.014 mg/kg-day.

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

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

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

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

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

The data reported in Tseng (1977) show an increased incidence of blackfoot disease that increases 

with age and dose. Blackfoot disease is a significant adverse effect. The prevalences (males and 

females combined) at the low dose are 4.6 per 1000 for the 20-39 year group, 10.5 per 1000 for 

the 40-59 year group, and 20.3 per 1000 for the >60 year group. Moreover, the prevalence of 

blackfoot disease in each age group increases with increasing dose. However, a recent report 

indicates that it may not be strictly due to arsenic exposure (Lu, 1990). The data in Tseng et al. 

(1968) also show increased incidences of hyperpigmentation and keratosis with age. The overall 

prevalences of hyperpigmentation and keratosis in the exposed groups are 184 and 71 per 1000, 

respectively. The text states that the incidence increases with dose, but data for the individual 

doses are not shown. These data show that the skin lesions are the more sensitive endpoint. The 

low dose in the Tseng (1977) study is considered a LOAEL. 

The control group described in Tseng et al. (1968; Table 3) shows no evidence of skin lesions and 

presumably blackfoot disease, although this latter point is not explicitly stated. This group is 

considered a NOAEL.

The arithmetic mean of the arsenic concentration in the wells used by the individuals in the NOAEL 

group is 9 ug/L (range: 1-17 ug/L) (Abernathy et al., 1989). The arithmetic mean of the arsenic 

concentration in the wells used by the individuals in the LOAEL group is 170 ug/L (Tseng, 1977; 

Figure 4). Using estimates provided by Abernathy et al. (1989), the NOAEL and LOAEL doses for 

both food and water are as follows: LOAEL - [170 ug/L x 4.5 L/day + 2 ug/day (contribution of 

food)] x (1/55 kg) = 14 ug/kg/day; NOAEL - [9 ug/L x 4.5 L/day + 2 ug/day (contribution of food)] 

x (1/55 kg) = 0.8 ug/kg/day. 

Although the control group contained 2552 individuals, only 957 (approximately 38%) were older 

than 20, and only 431 (approximately 17%) were older than 40. The incidence of skin lesions 

increases sharply in individuals above 20; the incidence of blackfoot disease increases sharply in 

individuals above 40 (Tseng, 1968; Figures 5, 6 and 7). This study is less powerful than it appears 

at first glance. However, it is certainly the most powerful study available on arsenic exposure to 

people. 
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This study shows an increase in skin lesions, 22% (64/296) at the high dose vs. 2.2% (7/318) at 

the low dose. The average arsenic concentration in the wells at the high dose is 410 ug/L and at the 

low dose is 5 ug/L (Cebrian et al., 1983; Figure 2 and Table 1) or 7 ug/L (cited in the abstract). The 

average water consumption is 3.5 L/day for males and 2.5 L/day for females. There were about an 

equal number of males and females in the study. For the dose estimates given below we therefore 

assume an average of 3 L/day. No data are given on the arsenic exposure from food or the body 

weight of the participants (we therefore assume 55 kg). The paper states that exposure times are 

directly related to chronological age in 75% of the cases. Approximately 35% of the participants in 

the study are more than 20 years old (Figure 1). 

Exposure estimates (water only) are: high dose - 410 ug/L x 3 L/day x (1/55 kg) = 22 ug/kg/day; 

low dose - 5-7 ug/L x 3 L/day x (1/55 kg) = 0.3-0.4 ug/kg/day. 

The high-dose group shows a clear increase in skin lesions and is therefore designated a LOAEL. 

There is some question whether the low dose is a NOAEL or a LOAEL since there is no way of 

knowing what the incidence of skin lesions would be in a group where the exposure to arsenic is 

zero. The 2.2% incidence of skin lesions in the low-dose group is higher than that reported in the 

Tseng et al. (1968) control group, but the dose is lower (0.4 vs. 0.8 ug/kg/day). 

The Southwick et al. (1983) study shows a marginally increased incidence of a variety of skin 

lesions (palmar and plantar keratosis, diffuse palmar or plantar hyperkeratosis, diffuse 

pigmentation, and arterial insufficiency) in the individuals exposed to arsenic. The incidences are 

2.9% (3/105) in the control group and 6.3% (9/144) in the exposed group. There is a slight, but 

not statistically significant increase in the percent of exposed individuals that have abnormal nerve 

conduction (8/67 vs. 13/83, or 12% vs. 16% (Southwick et al., 1983; Table 8). The investigators 

excluded all individuals older than 47 from the nerve conduction portion of the study. These are the 

individuals most likely to have the longest exposure to arsenic. 

Although neither the increased incidence of skin lesions nor the increase in abnormal nerve 

conduction is statistically significant, these effects may be biologically significant because the same 

abnormalities occur at higher doses in other studies. The number of subjects in this study was 

insufficient to establish statistical significance. 

Table 3 (Southwick et al., 1983) shows the annual arsenic exposure from drinking water. No data 

are given on arsenic exposure from food or the body weight (assume 70 kg). Exposure times are 

not clearly defined, but are > 5 years, and dose groups are ranges of exposure. 

Exposure estimates (water only) are: dosed group - 152.4 mg/year x 1 year/365 days x (1/70) kg 

= 6 ug/kg/day; control group - 24.2 mg/year x year/365 days x (1/70) kg = 0.9 ug/kg/day. 
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. (1983) study; the incidence of abnormal nerve 

conduction in the control group is higher than that from the low-dose group in the Hindmarsh et al. 

(1977) study described below. The control dose is comparable to the dose to the control group in 

the Tseng et al. (1968) and Hindmarsh et al. (1977) studies. The dosed group may or may not be a 

LOAEL, since it is does not report statisically significant effects when compared to the control. 

This study shows an increased incidence of abnormal clinical findings and abnormal 

electromyographic findings with increasing dose of arsenic (Hindmarsh et al., 1977; Tables III and 

VI). However, the sample size is extremely small. Percentages of abnormal clinical signs possibly 

attributed to As were 10, 16, and 40% at the low, mid and high doses, respectively. Abnormal EMG 

were 0, 17 and 53% in the same three groups. 

The exact doses are not given in the Hindmarsh et al. (1977) paper; however, some well data are 

reported in Table V. The arithmetic mean of the arsenic concentration in the high-dose and middose wells is 680 and 70 ug/L, respectively. Figure 1 (Hindmarsh et al., 1977) shows that the 

average arsenic concentration of the low-dose wells is about 25 ug/L. No data are given on arsenic 

exposure from food. We assume daily water consumption of 2 liters and body weight of 70 kg. 

Exposure times are not clearly stated. 

Exposure estimates (water only) are: low - 25 ug/L x 2 L/day x (1/70) kg = 0.7 ug/kg/day; mid -

70 ug/L x 2 L/day x (1/70) kg = 2 ug/kg/day; high - 680 ug/L x 2 L/day x (1/70) kg = 19 

ug/kg/day. 

The low dose is a no-effect level for abnormal EMG findings. However, because there is no 

information on the background incidence of abnormal clinical findings in a population with zero 

exposure to arsenic, there is no way of knowing if the low dose is a no-effect level or another 

marginal effect level for abnormal clinical findings. The low dose is comparable to the dose received 

by the control group in the Tseng (1977) and Southwick et al. (1983) studies. 

The responses at the mid dose do not show a statistically significant increase but are part of a 

statistically significant trend and are biologically significant. This dose is an equivocal 

NOAEL/LOAEL. The high dose is a clear LOAEL for both responses. 

As discussed previously there is no way of knowing whether the low doses in the Cebrian et al. 

(1983), Southwick et al. (1983) and Hindmarsh et al. (1977) studies are NOAELs for skin lesions 

and/or abnormal nerve conduction. However, because the next higher dose in the Southwick and 

Hindmarsh studies only shows marginal effects at doses 3-7 times higher, the Agency feels 

comfortable in assigning the low doses in these studies as NOAELs. 
7

The Tseng (1977) and Tseng et al. (1968) studies are therefore considered superior for the 

purposes of developing an RfD and show a NOAEL for a sensitive endpoint. Even discounting the 

people < 20 years of age, the control group consisted of 957 people that had a lengthy exposure to 

arsenic with no evidence of skin lesions. 

The following is a summary of the defined doses in mg/kg-day from the principal and supporting 

studies: 

1) Tseng (1977): NOAEL = 8E-4; LOAEL = 1.4E-2

2) Cebrian et al. (1983): NOAEL = 4E-4; LOAEL = 2.2E-2 

3) Southwick et al. (1983): NOAEL = 9E-4; LOAEL = none (equivocal effects at 6E-3) 

4) Hindmarsh et al., 1977: NOAEL = 7E-4; LOAEL = 1.9E-2 (equivocal effects at 2E-3) 

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

UF — The UF of 3 is to account for both the lack of data to preclude reproductive toxicity as a 

critical effect and to account for some uncertainty in whether the NOAEL of the critical study 

accounts for all sensitive individuals. 

MF — None 

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

Ferm and Carpenter (1968) produced malformations in 15-day hamster fetuses via intravenous 

injections of sodium arsenate into pregnant dams on day 8 of gestation at dose levels of 15, 17.5, 

or 20 mg/kg bw. Exencephaly, encephaloceles, skeletal defects and genitourinary systems defects 

were produced. These and other terata were produced in mice and rats all at levels around 20 

mg/kg bw. Minimal effects or no effects on fetal development have been observed in studies on 

chronic oral exposure of pregnant rats or mice to relatively low levels of arsenic via drinking water 

(Schroeder and Mitchner, 1971). Nadeenko et al. (1978) reported that intubation of rats with 

arsenic solution at a dose level of 25 ug/kg/day for a period of 7 months, including pregnancy, 

produced no significant embryotoxic effects and only infrequent slight expansion of ventricles of the 

cerebrum, renal pelves and urinary bladder. Hood et al. (1977) reported that very high single oral 

doses of arsenate solutions (120 mg/kg) to pregnant mice were necessary to cause prenatal fetal 

toxicity, while multiple doses of 60 mg/kg on 3 days had little effect. 

Extensive human pharmacokinetic, metabolic, enzymic and long-term information is known about 

arsenic and its metabolism. Valentine et al. (1987) established that human blood arsenic levels did 
8

not increase until daily water ingestion of arsenic exceeded approximately 250 ug/day 

(approximately 120 ug of arsenic/L. Methylated species of arsenic are successively 1 order of 

magnitude less toxic and less teratogenic (Marcus and Rispin, 1988). Some evidence suggests that 

inorganic arsenic is an essential nutrient in goats, chicks, minipigs and rats (NRC, 1989). No 

comparable data are available for humans. 

__I.A.5. Confidence in the Oral RfD

Study — Medium

Database — Medium

RfD — Medium

Confidence in the chosen study is considered medium. An extremely large number of people were 

included in the assessment ( > 40,000) but the doses were not well-characterized and other 

contaminants were present. The supporting human toxicity database is extensive but somewhat 

flawed. Problems exist with all of the epidemiological studies. For example, the Tseng studies do 

not look at potential exposure from food or other source. A similar criticism can be made of the 

Cebrian et al. (1983) study. The U.S. studies are too small in number to resolve several issues. 

However, the database does support the choice of NOAEL. It garners medium confidence. Medium 

confidence in the RfD follows. 

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

Source Document — This assessment is not presented in any existing U.S. EPA document.

This analysis has been reviewed by EPA's Risk Assessment Council on 11/15/1990. This assessment 

was discussed by the Risk Assessment Council of EPA on 11/15/1990 and verified through a series 

of meetings during the 1st, 2nd and 3rd quarters of FY91.

Other EPA Documentation — U.S. EPA, 1984, 1988 

Agency Work Group Review — 03/24/1988, 05/25/1988, 03/21/1989, 09/19/1989, 08/22/1990, 

09/20/1990 

Verification Date — 11/15/1990 

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

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

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

request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-

1676.
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__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).

Top of page

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

Substance Name — Arsenic, inorganic

CASRN — 7440-38-2

Not available at this time.

Top of page

_II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Arsenic, inorganic

CASRN — 7440-38-2

Last Revised — 04/10/1998

Section II provides information on three aspects of the carcinogenic assessment for the substance 

in question; the weight-of-evidence judgment of the likelihood that the substance is a human 

carcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. 

The quantitative risk estimates are presented in three ways. The slope factor is the result of 

application of a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. The 

unit risk is the quantitative estimate in terms of either risk per ug/L drinking water or risk per 

ug/cu.m air breathed. The third form in which risk is presented is a drinking water or air 

concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale 

and methods used to develop the carcinogenicity information in IRIS are described in The Risk 

Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the IRIS Background Document. IRIS 

summaries developed since the publication of EPA's more recent Proposed Guidelines for 

Carcinogen Risk Assessment also utilize those Guidelines where indicated (Federal Register 

61(79):17960-18011, April 23, 1996). Users are referred to Section I of this IRIS file for 

information on long-term toxic effects other than carcinogenicity. 
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_II.A. Evidence for Human Carcinogenicity

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

Classification — A; human carcinogen

Basis — based on sufficient evidence from human data. An increased lung cancer mortality was 

observed in multiple human populations exposed primarily through inhalation. Also, increased 

mortality from multiple internal organ cancers (liver, kidney, lung, and bladder) and an increased 

incidence of skin cancer were observed in populations consuming drinking water high in inorganic 

arsenic.

__II.A.2. Human Carcinogenicity Data

Sufficient. Studies of smelter worker populations (Tacoma, WA; Magma, UT; Anaconda, MT; 

Ronnskar, Sweden; Saganoseki-Machii, Japan) have all found an association between occupational 

arsenic exposure and lung cancer mortality (Enterline and Marsh, 1982; Lee-Feldstein, 1983; 

Axelson et al., 1978; Tokudome and Kuratsune, 1976; Rencher et al., 1977). Both proportionate 

mortality and cohort studies of pesticide manufacturing workers have shown an excess of lung 

cancer deaths among exposed persons (Ott et al., 1974; Mabuchi et al., 1979). One study of a 

population residing near a pesticide manufacturing plant revealed that these residents were also at 

an excess risk of lung cancer (Matanoski et al., 1981). Case reports of arsenical pesticide 

applicators have also corroborated an association between arsenic exposure and lung cancer (Roth, 

1958). 

A cross-sectional study of 40,000 Taiwanese exposed to arsenic in drinking water found significant 

excess skin cancer prevalence by comparison to 7500 residents of Taiwan and Matsu who 

consumed relatively arsenic-free water (Tseng et al., 1968; Tseng, 1977). Although this study 

demonstrated an association between arsenic exposure and development of skin cancer, it has 

several weaknesses and uncertainties, including poor nutritional status of the exposed populations, 

their genetic susceptibility, and their exposure to inorganic arsenic from non-water sources, that 

limit the study's usefulness in risk estimation. Dietary inorganic arsenic was not considered nor was 

the potential confounding by contaminants other than arsenic in drinking water. There may have 

been bias of examiners in the original study since no skin cancer or preneoplastic lesions were seen 

in 7500 controls; prevalence rates rather than mortality rates are the endpoint; and furthermore 

there is concern of the applicability of extrapolating data from Taiwanese to the U.S. population 

because of different background rates of cancer, possibly genetically determined, and differences in 

diet other than arsenic (e.g., low protein and fat and high carbohydrate) (U.S. EPA, 1988). 

A prevalence study of skin lesions was conducted in two towns in Mexico, one with 296 persons 

exposed to drinking water with 0.4 mg/L arsenic and a similar group with exposure at 0.005 mg/L. 
11

The more exposed group had an increased incidence of palmar keratosis, skin hyperpigmentation 

and hypopigmentation, and four skin cancers (histologically unconfirmed) (Cebrian et al. (1983). 

The association between skin cancer and arsenic is weak because of the small number of cases, 

small cohort size, and short duration follow-up; also there was no unexposed group in either town. 

No excess skin cancer incidence has been observed in U.S. residents consuming relatively high 

levels of arsenic in drinking water but the numbers of exposed persons were low (Morton et al., 

1976; Southwick et al., 1981). Therapeutic use of Fowler's solution (potassium arsenite) has also 

been associated with development of skin cancer and hyperkeratosis (Sommers and McManus, 

1953; Fierz, 1965); several case reports implicate exposure to Fowler's solution in skin cancer 

development (U.S. EPA, 1988). 

Several follow-up studies of the Taiwanese population exposed to inorganic arsenic in drinking 

water showed an increase in fatal internal organ cancers as well as an increase in skin cancer. Chen 

et al. (1985) found that the standard mortality ratios (SMR) and cumulative mortality rates for 

cancers of the bladder, kidney, skin, lung and liver were significantly greater in the Blackfoot 

disease endemic area of Taiwan when compared with the age adjusted rates for the general 

population of Taiwan. Blackfoot disease (BFD, an endemic peripheral artery disease) and these 

cancers were all associated with high levels of arsenic in drinking water. In the endemic area, SMRs 

were greater in villages that used only artesian well water (high in arsenic) compared with villages 

that partially or completely used surface well water (low in arsenic). However, dose-response data 

were not developed (Chen et al. 1985). 

A retrospective case-control study showed a significant association between duration of consuming 

high-arsenic well water and cancers of the liver, lung and bladder (Chen et al., 1986). In this study, 

cancer deaths in the Blackfoot disease endemic area between January 1980 and December 1982 

were chosen for the case group. About 90% of the 86 lung cancers and 95 bladder cancers in the 

registry were histologically or cytologically confirmed and over 70% of the liver cancers were 

confirmed by biopsy or à-fetoprotein presence with a positive liver x-ray image. Only confirmed 

cancer cases were included in the study. A control group of 400 persons living in the same area was 

frequency-matched with cases by age and sex. Standardized questionnaires of the cases (by proxy) 

and controls determined the history of artesian well water use, socioeconomic variables, disease 

history, dietary habits, and lifestyle. For the cancer cases, the age-sex adjusted odds ratios were 

increased for bladder (3.90), lung (3.39), and liver (2.67) cancer for persons who had used artesian 

well water for 40 or more years when compared with controls who had never used artesian well 

water. Similarly, in a 15-year study of a cohort of 789 patients of Blackfoot disease, an increased 

mortality from cancers of the liver, lung, bladder and kidney was seen among BFD patients when 

compared with the general population in the endemic area or when compared with the general 

population of Taiwan. Multiple logistic regression analysis to adjust for other risk factors including 

cigarette smoking did not markedly affect the exposure-response relationships or odds ratios (Chen 

et al., 1988).
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 bladder, kidney, skin, lung, liver and prostate (Wu et al., 1989). An ecological study 

of cancer mortality rates and arsenic levels in drinking water in 314 townships in Taiwan also 

corroborated the association between arsenic levels and mortality from the internal cancers (Chen 

and Wang, 1990). 

Chen et al.(1992) conducted a recent analysis of cancer mortality data from the arsenic-exposed 

population to compare risk of various internal cancers and compare risk between males and 

females. The study area and population have been described by Wu et al. (1989). It is limited to 42 

southwestern coastal villages where residents have used water high in arsenic from deep artesian 

wells for more than 70 years. Arsenic levels in drinking water ranged from 0.010 to 1.752 ppm. The 

study population had 898,806 person-years of observation and 202 liver cancer, 304 lung cancer, 

202 bladder cancer and 64 kidney cancer deaths. The study population was stratified into four 

groups according to median arsenic level in well water ( < 0.10 ppm, 0.10- 0.29 ppm, 0.30-0.59 

ppm and 60+ ppm), and also stratified into four age groups ( < 30 years, 30-49 years, 50-69 years 

and 70+ years). Mortality rates were found to increase significantly with age for all cancers and 

significant dose- response relationships were observed between arsenic level and mortality from 

cancer of the liver, lung, bladder and kidney in most age groups of both males and females. The 

data generated by Chen et al. (1992) provide evidence for an association of the levels of arsenic in 

drinking water and duration of exposure with the rate of mortality from cancers of the liver, lung, 

bladder, and kidney. Dose-response relationships are clearly shown by the tabulated data (Tables 

II-V of Chen et al., 1992). Previous studies summarized in U.S. EPA (1988) showed a similar 

association in the same Taiwanese population with the prevalence of skin cancers (which are often 

non-fatal). Bates et al. (1992) and Smith et al. (1992) have recently reviewed and evaluated the 

evidence for arsenic ingestion and internal cancers. 

__II.A.3. Animal Carcinogenicity Data

Inadequate. There has not been consistent demonstration of carcinogenicity in test animals for 

various chemical forms of arsenic administered by different routes to several species (IARC, 1980). 

Furst (1983) has cited or reviewed animal carcinogenicity testing studies of nine inorganic arsenic 

compounds in over nine strains of mice, five strains of rats, in dogs, rabbits, swine and chickens. 

Testing was by the oral, dermal, inhalation, and parenteral routes. All oxidation states of arsenic 

were tested. No study demonstrated that inorganic arsenic was carcinogenic in animals. 

Dimethylarsonic acid (DMA), the end metabolite predominant in humans and animals, has been 

tested for carcinogenicity in two strains of mice and was not found positive (Innes et al., 1969); 

however, this was a screening study and no data were provided. The meaning of non-positive data 

for carcinogenicity of inorganic arsenic is uncertain, the mechanism of action in causing human 

cancer is not known, and rodents may not be a good model for arsenic carcinogenicity testing. 
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., 1982, 1984). 

__II.A.4. Supporting Data for Carcinogenicity 

A retrospective cohort mortality study was conducted on 478 British patients treated between 

1945-1969 with Fowler's solution (potassium arsenite). The mean duration of treatment was 8.9 

months and the average total oral consumption of arsenic was about 1890 mg (daily dose x 

duration). In 1980, 139 deaths had occurred. No excess deaths from internal cancers were seen 

after this 20-year follow-up. Three bladder cancer deaths were observed (1.19 expected, SMR 2.5) 

(Cuzick et al., 1982). A recent follow-up (Cuzick et al., 1992) indicated no increased mortality from 

all cancers but a significant excess from bladder cancer (5 cases observed/1.6 expected; SMR of 

3.07). A subset of the original cohort (143 persons) had been examined by a dermatologist in 1970 

for signs of arsenicism (palmar keratosis). In 1990, there were 80 deaths in the subcohort and 11 

deaths from internal cancers. All 11 subjects had skin signs (keratosis-10, hyperpigmentation-5 and 

skin cancer-3). A case-control study of the prevalence of palmar keratoses in 69 bladder cancer 

patients, 66 lung cancer patients and 218 hospital controls (Cuzick et al., 1984), indicated an 

association between skin keratosis (as an indicator of arsenic exposure) and lung and bladder 

cancer. Above the age of 50, 87% of bladder cancer patients and 71% of lung cancer patients but 

only 36% of controls had one or more keratoses. Several case reports implicate internal cancers 

with arsenic ingestion or specifically with use of Fowler's solution but the associations are tentative 

(U.S. EPA, 1988).

Sodium arsenate has been shown to transform Syrian hamster embryo cells (Dipaolo and Casto, 

1979) and to produce sister chromatid-exchange in DON cells, CHO cells, and human peripheral 

lymphocytes exposed in vitro (Wan et al., 1982; Ohno et al., 1982; Larramendy et al., 1981; 

Andersen, 1983; Crossen, 1983). Jacobson-Kram and Montalbano (1985) have reviewed the 

mutagenicity of inorganic arsenic and concluded that inorganic arsenic is inactive or very weak for 

induction of gene mutations in vitro but it is clastogenic with trivalent arsenic being an order of 

magnitude more potent than pentavalent arsenic.

Both the pentavalent and trivalent forms of inorganic arsenic are found in drinking water. In both 

animals and humans, arsenate (As+5) is reduced to arsenite (As+3) and the trivalent form is 

methylated to give the metabolites mononomethylarsinic acid (MMA) and dimethylarsonic acid 

(DMA) (Vahter and Marafante, 1988). The genotoxicity of arsenate (As+5) and arsenite (As+3) and 

the two methylated metabolites, MMA and DMA were compared in the thymidine kinase forward 

mutation assay in mouse lymphoma cells (Harrington-Brock et al. 1993; Moore et al., 1995, in 

press). Sodium arsenite (+3) and sodium arsenate (+5) were mutagenic at concentration of 1-2 

ug/mL and 10-14 ug/mL, respectively, whereas MMA and DMA were significantly less potent, 

requiring 2.5-5 mg/mL and 10 mg/mL, respectively, to induce a genotoxic response. Based on 

small colony size the mutations induced were judged chromosomal rather than point mutations. The 
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 abberation response with DMA was insufficient to consider 

it a clastogen. Since arsenic exerts its genotoxicity by causing chromosomal mutations, it has been 

suggested by the above authors that it may act in a latter stage of carcinogenesis as a progressor, 

rather than as a classical initiator or promotor (Moore et al., 1994). A finding which supports this 

process is that arsenate (8-16 uM) and arsenite (3 uM) have been shown to induce 2-10 fold 

amplification of the dihydrofolate reductase gene in culture in methotrexate resistant 3T6 mouse 

cells (Lee et al., 1988). Although the mechanism of induction in rodent cells is not known, gene 

amplification of oncogenes is observed in many human tumors. Inorganic arsenic has not been 

shown to mutate bacterial strains, it produces preferential killing of repair deficient strains 

(Rossman, 1981). Sodium arsenite (As+3) induces DNA-strand breaks which are associated with 

DNA-protein crosslinks in cultured human fibroblasts at 3 mM but not 10 mM (Dong and Luo, 1993) 

and it appears that arsenite inhibits the DNA repair process by inhibiting both excision and ligation 

(Jha et al., 1992; Lee-Chen et al., 1993). 

The inhibitory effect of arsenite on strand-break rejoining during DNA repair was found to be 

reduced by adding glutathione to cell cultures (Huang et al., 1993). The cytotoxic effects of sodium 

arsenite in Chinese hamster ovary cells also has also found to correlate with the intracellular 

glutathione levels (Lee et al., 1989). 

In vivo studies in rodents have shown that oral exposure of rats to arsenate (As+5) for 2-3 weeks 

resulted in major chromosomal abnormalities in bone marrow (Datta et al., 1986) and exposure of 

mice to As (+3) in drinking water for 4 weeks (250 mg As/L as arsenic trioxide) caused 

chromosomal aberrations in bone marrow cells but not spermatogonia (Poma et al., 1987); 

micronuclei in bone marrow cells were also induced by intraperitoneal dosing of mice with arsenate 

(DeKnudt et al., 1986; Tinwell et al., 1991). Chromosomal aberrations and sister chromatid 

exchange have been seen in patients exposed to arsenic from treatment with Fowler's solution 

(Burgdorf et al., 1977) and subjects exposed occupationally (Beckman et al., 1977) but no increase 

in either endpoint was seen in lymphocytes of subjects exposed to arsenic in drinking water (Vig et 

al., 1984). 

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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 quadratic model fitting of the data 

were conducted. The maximum likelihood estimate (MLE) of skin cancer risk for a 70 kg person 

drinking 2 L of water per day ranged from 1E-3 to 2E-3 for an arsenic intake of 1 ug/kg/day. 

Expressed as a single value, the cancer unit risk for drinking water is 5E-5 per (ug/L). Details of the 

assessment are in U.S. EPA (1988).
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 present. 

__II.B.3. Additional Comments (Carcinogenicity, Oral Exposure)

Eastern Research Group, under contract to EPA, convened an Expert Panel on Arsenic 

Carcinogenicity on May 21 and 22, 1997 (Eastern Research Group, 1997). The Expert Panel 

believed that, "it is clear from epidemiological studies that arsenic is a human carcinogen via the 

oral and inhalation routes (p. 20)." They also concluded, "that one important mode of action is 

unlikely to be operative for arsenic". The panel agreed that arsenic and its metabolites do not 

appear to directly interact with DNA (pp. 30-31)." In addition, the panel agreed that, "for each of 

the modes of action regarded as plausible, the dose-response would either show a threshold or 

would be nonlinear (p. 31)". The panel agreed, however, "that the dose-response for arsenic at low 

doses would likely be truly nonlinear, i.e., with a decreasing slope as the dose decreased. However, 

at very low doses such a curve might be linear but with a very shallow slope, probably 

indistinguishable from a threshold (p. 31)."

__II.B.4. Discussion of Confidence (Carcinogenicity, Oral Exposure)

This assessment is based on prevalence of skin cancer rather than mortality because the types of 

skin cancer studied are not normally fatal. However, competing mortality from Blackfoot disease in 

the endemic area of Taiwan would cause the risk of skin cancer to be underestimated. Other 

sources of inorganic arsenic, in particular those in food sources have not been considered because 

of lack of reliable information. There is also uncertainty on the amount of water consumed/day by 

Taiwanese males (3.5 L or 4.5 L) and the temporal variability of arsenic concentrations in specific 

wells was not known. The concentrations of arsenic in the wells was measured in the early 1960s 

and varied between 0.01 and 1.82 ppm. For many villages 2 to 5 analyses were conducted on well 

water and for other villages only one analysis was performed; ranges of values were not provided. 

Since tap water was supplied to many areas after 1966, the arsenic-containing wells were only used 

in dry periods. Because of the study design, particular wells used by those developing skin cancer 

could not be identified and arsenic intake could not be assigned except by village. Several 

uncertainties in exposure measurement reliability existed and subsequent analysis of drinking water 

found fluorescent substances in water that are possible confounders or caused synergistic effects. 

Uncertainties have been discussed in detail in U.S. EPA (1988). Uncertainties in exposure 

measurement can affect the outcome of dose- response estimation.

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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; Higgins, 1982; Enterline and Marsh, 

1982

Ambient Unit Risk Estimates (per μg/cu.m)

Exposure

Source

Study Unit Risk Geometric Mean

Unit Risk

Final Estimated

Geometric Mean

Unit Risk

Anaconda

smelter

Brown and Chu

Lee-Feldstein

Higgins et al.

1.25E-3

2.80E-3

4.90E-3

2.56E-3 4.29E-3

ASARCO

smelter

Enterline & Marsh 6.81E-3

7.60E-3

7.19E-3

4.29E-3
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 expected 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 (Carcinogenicity 

Assessment)

__II.D.1. EPA Documentation

U.S. EPA. 1984, 1988, 1993

A draft of the 1984 Health Assessment Document for Inorganic Arsenic was independently reviewed 

in public session by the Environmental Health Committee of the U.S. EPA Science Advisory Board on 

September 22-23, 1983. A draft of the 1988 Special Report on Ingested Inorganic Arsenic; Skin 

Cancer; Nutritional Essentiality was externally peer reviewed at a two-day workshop of scientific 

experts on December 2-3, 1986. A draft of the Drinking Water Criteria Document for Arsenic was 

reviewed by the Drinking Water Committee of the U.S. EPA Science Advisory Board on March 10, 

1993. The comments from these reviews were evaluated and considered in the revision and 

finalization of these reports. 

__II.D.2. 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 Arsenic 

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

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

(202)566-1676.

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

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

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

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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

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of Research and Development, U.S. EPA. Memorandum to P. Cook, Office of Drinking Water, U.S. 

EPA and P. Preuss, Office of Regulatory Support 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 prenatal 

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

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

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

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

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

Scientific Publishing Company, Princeton, NJ. p. 133-158. 

Nadeenko, V.G., V. Lenchenko, 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. Recommended Dietary Allowances, 10th ed. Report of the 

Food and Nutrition Board, National Academy of Sciences, Washington, National Academy Press, 

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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. Prepared by the Office of 

Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research 

Triangle Park, NC. EPA 600/8-83-021F. 

U.S. EPA. 1988. Quantitative Toxicological Evaluation of Ingested Arsenic. Office of Drinking Water, 

Washington, DC. (Draft)

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_VI.B. Inhalation RfD References

None

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_VI.C. Carcinogenicity Assessment References

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22

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Mexico. Human Toxicol. 2: 121-133. 

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25

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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. EPA600/1-81-064. 

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. 

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

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

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

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

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

Park, NC. 

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

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

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

Draft. 

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

Chem. 66: 105-119. 

Vig, B.K., M.L. Figueroa, M.N. Cornforth, S.H. Jenkins. 1984. Chromosome studies in human 

subjects chronically exposed to arsenic in drinking water. Am. J. Ind. Med. 6(5): 325-338. 

Wan, B., R.T. Christian and S.W. Soukup. 1982. Studies of cytogenetic effects of sodium arsenicals 

on mammalian cells in vitro. Environ. Mutag. 4: 493-498. 

Welch, K., I. Higgins, M. Oh and C. Burchfield. 1982. Arsenic exposure, smoking, and respiratory 

cancer in copper smelter workers. Arch. Environ. Health. 37(6): 325-335. 

Wu, M-M., T-L. Kuo, Y-H Hwang and C-J. Chen. 1989. Dose-response relation between arsenic 

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

130(6): 1123-1132.

Top of page

_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 Regulatory Actions, and Supplementary 

Data were removed from IRIS on or before April 1997. IRIS users were directed 

to the appropriate EPA Program Offices for this information.

04/10/1998 II.B.3 Added discussion on expert panel workshop 

02/11/2000 II.C.2 Corrected alignment of unit risks in table with corresponding studies

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

II.D.2.

Screening-Level Literature Review Findings message has been added.

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

Top of page
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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30

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 Summary of Risk Estimates

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 Additional Comments

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Bibliography

Revision History

Synonyms

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

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Last updated on Thursday, August 09, 2012
31

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

Cadmium (CASRN 7440-43-9) 

Reference Dose for Chronic Oral Exposure (RfD)

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

Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment 

development process. Supporting information and explanations of the methods used to derive the 

values given in IRIS are provided in the guidance documents located on the IRIS website. 

STATUS OF DATA FOR Cadmium

File First On-Line 03/31/1987 

Category (section) Status Last Revised

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 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

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 renal 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 mg 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 toxicity 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 model 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 this 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 considered 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).

Top of page

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

Substance Name — Cadmium

CASRN — 7440-43-9

Not available at this time.

Top of page

_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 estimates are presented in three ways. The slope factor is the result of application of 

a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. The unit risk is the 

quantitative estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m air breathed. 

The third form in which risk is presented is a drinking water or air concentration providing cancer risks 

of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods used to develop the 

carcinogenicity information in IRIS are described in The Risk Assessment Guidelines of 1986 

(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries developed since the 

publication of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment also utilize 

those Guidelines where indicated (Federal Register 61(79):17960-18011, April 23, 1996). Users are 

referred to Section I of this IRIS file for information on long-term toxic effects other than 

carcinogenicity. 
35

_II.A. Evidence for Human Carcinogenicity

__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 evidence 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. The 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 presence 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 were, 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 al. (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). Intratracheal 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, testicular) 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 mice 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. Positive 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 aberrations 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). 

Top of page

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

Not available. There are no positive studies of orally ingested cadmium suitable for quantitation. 

Top of page

_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 — Thun 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 from 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 fume 

and cadmium oxide). 

Top of page

_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 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]
39

_VI. Bibliography 

Substance Name — Cadmium

CASRN — 7440-43-9

Last Revised — 10/01/1989

_VI.A. Oral RfD References

Foulkes, E.C. 1986. Absorption 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 Report 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 -- recommendations. 

Vol. 1. Geneva, Switzerland.

Top of page

_VI.B. Inhalation RfC References

None

Top of page
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 cadmium 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, March 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-strand 

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 in 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. Presented 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.

Top of page

_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 being 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

Top of page

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

 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
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

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http://www.epa.gov/iris/subst/0141.htm

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Last updated on Thursday, August 09, 2012
45

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

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

Reference Dose for Chronic Oral Exposure (RfD)

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

page to learn more.

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 

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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 

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. 
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 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

None Reported

Rat, 1-year drinking 

water study

MacKenzie et al., 1958 

NOAEL: 25 mg/L of chromium

as K2CrO4

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 studies. 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 K2CrO4) 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 K2CrO4), 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 K2CrO4) 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 examined 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 "apparently, 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 K2CrO4) in drinking water for 4 years. The calculated doses were 

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 (K2Cr2O7), sodium dichromate (Na2Cr2O7), potassium chromate (K2Cr2O4), 

and sodium chromate (Na2CrO4). 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 with 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 observed 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 significant 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 

dichromate 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 15-400 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-rump 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 fetal 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 

ossification 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 37 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 are 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 

exposures 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 exposure 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 allergic contact dermatitis 

is an inflammatory response mediated by the immune system. Allergic contact dermatitis is a cellmediated immune response that occurs in a two-step process. In the first step (induction), 

chromium is absorbed into the skin and triggers 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 chromium 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 concentrations 

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-lifetime 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 Identification 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 assessment 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 studies 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 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). 

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 effects 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) 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 (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. 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.

__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).

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 generally expressed in 

units of mg/m3. 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 

Concentrations 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 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.B.1. Inhalation RfC Summary

Critical Effect Experimental Doses* UF 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/m3

7.14 E-4 mg/m3(adj.) 

90 1 8E-6

mg/m3

(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/m3

0.034 mg/m3(adj.) 

300 1 1E-4 

mg/m3

*Conversion Factors and Assumptions — Breathing rate for 8-hour occupational exposure = 10 m3; breathing rate for 24-hour 

continuous exposure = 20 m3; 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 exposures 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 reported 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 hexavalent 
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 studies 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 interviewed 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-exposure group (8-hr TWA below 0.002 mg/m3, N=19) and a 

high-exposure group (8-hr TWA above 0.002 mg/m3, 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 selected as 

controls for lung functionmeasurements. Smoking habits of workers were evaluated as part of the 

study.

At mean exposures below 0.002 mg/m3, 4/19 workers from the low-exposure group of subjective 

nasal symptoms. Atrophied nasal mucosa were reported 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/m3 complained of subjective symptoms. At mean concentrations of 0.002 

mg/m3 or above, approximately 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 nasal 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 results were 

within normal limits.

The authors concluded that 8-hour mean exposures to chromic acid above 0.002 mg/m3 may cause 

a transient decrease in lung function, and that short-term exposures to greater than 0.02 mg/m3

may cause septal ulceration and perforation. Based on the results of this study, a LOAEL of 0.002 

mg/m3can 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/m3, nasal septum 

ulceration 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/m3 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 m3)

MVh is the breathing volume for a 24 hour continuous exposure (20 m3)

The LOAEL of 0.002 mg/m3 based on a TWA exposure to chromic acid is converted to a LOAEL for 

continuous exposure of 7.14 E-4 mg/m3. 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 applied 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 the LOAEL of 7.14E-4 mg/m3 generates an RfC of 8 E-6 

mg/m3for 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 following 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)/m3 22 hr/day, 7 days/wk for 30-90 days. Chromiuminduced effects occurred in a strong 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 

significant dose-dependent leukocytosis following subacute exposures. Mean lung weights were 

significantly increased at exposure levels of 0.1 mg/m3following 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 effects 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)/m3, 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/m3. Differences in the mean total 

serum immunoglobulin were also significant at exposures above 0.025 mg/m3, while exposures to 

aerosol concentrations greater than 0.1 mg/m3resulted in depression of the immune system 

stimulation. The immune stimulating effect of subchronic exposure 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/m3chromium. 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/m3the 

phagocytic activity of the alveolar macrophages increased; however, subchronic exposure at 0.2 

mg/m3 decreased this function significantly. The spleen T-lymphocyte subpopulation was stimulated 

by subchronic exposure to 0.2 mg/m3 chromium, and serum contents of triglycerides and 

phospholipids differed significantly from controls (p < 0.05) at this concentration. 

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 pulmonary injury and chronic lung inflammation, which 

may lead to the onset of pulmonary fibrosis (Henderson, 1988). While these studies present dosedependent results on sensitive indicators of lower respiratory toxicity, potential upper respiratory 

impacts resulting 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 corresponding 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 regression, yielding maximum likelihood estimates of 0.036 - 0.078 mg/m3 and BMCs of 

0.016 - 0.067 mg/m3. Malsch et al. (1994) applied dosimetric adjustments and uncertainty factors 

to determine a RfC based on the following equation: 

RfC = 

BMC x RDDR

UFA x UFF x UFH

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

 UFA is a threefold uncertainty factor to account for pharmacodynamicdifferences not 

addressed by the RDDR

 UFF is a threefold uncertainty factor to account for extrapolating from subchronic to 

chronic exposures; and

 UFH 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 pattern 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/m3 and 0.39 for dose levels of 0.1-

0.4 mg/m3) and the geometric standard deviation (1.63 for dose levels of 0.05-0.1 mg/m3 and 1.72 

for dose levels of 0.1-0.4 mg/m3) of the particulates reported in Glaser et al. (1990). A 3.16-fold 

uncertainty factor (midpoint between 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-dependent fashion from 0.05 to 

0.4 mg/m3sodium dichromate, and this endpoint generated the lowest BMC (0.016 mg/m3) and 

RfC (3.4 E-4 mg/m3). 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 prevention 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 

immunological 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 considered 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 factor 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 poor 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 for 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 exposures 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 

accounted for by the RDDR, an additional 10-fold uncertainty factor to account for the less-thanlifetime 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/m3for 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 exposed 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 

experienced 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) should 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 chromium 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 this 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 chosen 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 characterization.

(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 effects 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 Review 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 

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).

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 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 Hotline 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)566-1749 (fax), or hotline.iris@epa.gov (Internet address).

Top of page

_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 

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/m3 air breathed. The third form in which risk is presented is a concentration of the chemical in 

drinking water 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

__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 

carcinogen 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 across 

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 bioassays, 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 subcutaneous 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 intracellular 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 damage. 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 trivalent 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 specific 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 cancer 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. Within 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 from 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 (hexavalent), 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 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 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 those 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 consistently 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 animal 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 dichromate 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) compounds (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 P450 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 (1O2) (Kawanishi et al., 

1986). A variety of DNA lesions are formed during the reduction of Cr(VI) to Cr(III), including DNA 

strand breaks, alkali-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 damage 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; Petrilli 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), while 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 primary 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 clastogenic 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 treatmentrelated 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.

Top of page

_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. 

Top of page

_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/m3)

E-5 (1 in 100,000) 8E-4 (μg/m3)

E-6 (1 in 1,000,000) 8E-5 (μg/m3)

__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/m3) 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 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 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 were 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 

concentration 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)

Results 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 use 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. 

Top of page

_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 incorporated 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)

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 

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 chromiumpassivated metal. Contact Derm 19:175-179.

Burrows, D; Adams, 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 of 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 chromium 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 potassium 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):167-178.

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 17:145-219.

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 Environmental

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 References

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 toxicity--

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: Raven 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 relationship 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 

effects 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 

Service, 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 Pharmacol 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 deficiency 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

Alderson, 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 

Schizosaccharomyces 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 chromate 

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-cancer 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 105:183-188.

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 Wistar 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 plant. 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 the 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 oxidative 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, Socialmedizin, 

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) Effects 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 chromium is decreased by microsomal 

metabolism. Naturvissenschaften 65:207-208.

Machle, W; Gregorius, F. (1948) Cancer of the respiratory system in the United States chromateproducing industry. Public Health Rep 63(35):1114-1127.

Maltoni, C. (1974) Occupational 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 Hazards 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 chromium. 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 Health (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. Thorax 

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; DeFlora, 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 58:167-178.

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-

163.

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):835-838.

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 employment as reflected by a 

cohort of chromate workers. Am J Public Health 56(2):218-229.

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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.

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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.

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chromate-producing industry in Hokkaido, Japan. Presented at International Congress on 

Occupational Health.

Top of page

_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 Pilot 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.

Top of page

_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

Top of page

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Reference Dose for Chronic Oral Exposure (RfD)

 Oral RfD Summary 

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78

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 Inhalation RfC Summary

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

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

Reference Dose for Chronic Oral Exposure (RfD)

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

page to learn more.

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 documents 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 substance is included in the IRIS database 

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

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

Assessment for Lifetime Exposure) present the conclusions that were reached during the 

assessment development process. Supporting information and explanations of the methods used to 

derive the values given in IRIS are provided in the guidance documents located on the IRIS 

website. 

STATUS OF DATA FOR 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 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

Developmental

neuropsychological 

impairment

Human epidemiological 

studies (Grandjean et al., 

1997; Budtz-Jørgensen et 

al., 1999a)

Benchmark Dose: BMDL05

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 concentrations 

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-observedadverse-effect level (NOAEL/LOAEL) approach to analyze the neurological effects 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 developmental 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 

with 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 Zealand. 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 independent 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 38 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 precludes 

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 fit 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 P0 = 0.05 was used: that is, the cutoff for abnormal response was set at the lowest 5% 

(5th percentile) of children. 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 5th percentile are considered significantly 

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 doubling of the number of children with a 

response at the 5th 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 (BMDL05) (the 

lower 95% confidence limit of the BMD05) was calculated for each endpoint described above from 

the three studies. 

DOSE CONVERSION

The biomarker of choice for the Faroese data was cord blood, 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 mercury 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 (Ginsberg 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)
84

 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 BMDL05. 

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 supported 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 Study 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) reported 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 203Hg-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; the 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 published 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 logtriangular distribution. The median value was 5.9% or 0.059, close to the values of 0.05 used in the 

MSRC and by other groups (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 from 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 from 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 constant 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 half-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 alternative 

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-1for the 

Al-Shahristani data alone; the combined data set mean elimination constant was 0.014 days-1. 

The decision to select 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. Nevertheless, 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 (0.013 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) used 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 they 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, women 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 range 

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= (BMDL05 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 of 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 

were 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 original 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 exposure 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 

measure, 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 based 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 data 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 Endpointa

Full Cohort Adjusted for 

PCBs 

Low-PCB 

Tertile

BMD05(BMDL05)

b BMD05 (BMDL05) BMD05 (BMDL05)

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)

aCPT = Continuous Performance Test; BNT = Boston Naming Test; CVLT = California Verbal 

Learning Test.

bBMDs are calculated under the assumption that 5% of the responses will be abnormal in 

unexposed subjects (P0 = 0.05), assuming a doubling of the excess risk (BMR = 0.05). 

Source: E. Budtz-Jørgensen, Copenhagen University, 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 BMDL05s from a number of endpoints in terms of cord-blood mercury. These tests 

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 Faroe 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 study; 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 BMDL05s and Corresponding RfDs from Faroes, New Zealand, and NRC 

Integrative Analysisa

Testb

BMDL05 ppb 

mercury 

cord

Ingested 

dose

μg;/kg/dayc

RfD 

μg/kg/dayd

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

Testb

BMDL05 ppb 

mercury 

cord

Ingested 

dose

μg;/kg/dayc

RfD 

μg/kg/dayd

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

aBMDL05s 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.

bBNT = 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 using 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 three 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 concentration (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 50th

percentile/99th percentile ranged from 1.7 to 3.3. Using maternal blood as the starting point, the 

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-blood 

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.,1991; 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 mercury. 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-fetal pairs. Vahter et al. (2000) reported the 5th and 

95th 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 the 

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 that 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 

uncertainty. 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 analysis 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 with 

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 methylmercury 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 subgroup 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 identified 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 increased 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. Salonen 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 al. 

(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 deficits 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 more 

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 exposed 

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 (Newland 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 on 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 exposure 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 

exposed 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) reported 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 derivation. 

__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 cordblood mercury. 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 μg/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 determining 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 determined 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 determined 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 BMDL10 (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 250:1 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 

neurotoxic 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, 1988). 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, revealed 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 delayed 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 combined 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 based 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 oral 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 of 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 analysis 

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 same 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 methylmercury 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. To 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 review 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 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 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

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

Substance Name — Methylmercury (MeHg) 

CASRN — 22967-92-6

Not available at this time.

Top of page

_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 substance is a human 

carcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. 

The quantitative risk estimates are presented in three ways. The slope factor is the result of 

application of a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. The 

unit risk is the quantitative estimate in terms of either risk per ug/L drinking water or risk per 

ug/cu.m air breathed. The third form in which risk is presented is a drinking water or air 

concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale 

and methods used to develop the carcinogenicity information in IRIS are described in The Risk 

Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the IRIS Background Document. IRIS 

summaries developed since the publication of EPA's more recent Proposed Guidelines for 

Carcinogen Risk Assessment also utilize those Guidelines where indicated (Federal Register 
98

61(79):17960-18011, April 23, 1996). Users are referred to Section I of this IRIS file for 

information on long-term toxic effects other than carcinogenicity. 

_II.A. Evidence for Human Carcinogenicity

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

Classification — C; possible human carcinogen 

Basis — Based on inadequate 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 

single 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 cancer 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 studies 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, 

however, 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 (methylmercury 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 in 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 ratios 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 

neoplasms 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 methylmercury 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 (inhabited 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 believed 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 1970-1981, 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 cirrhosis. 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 cancer). 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 frames (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 

unrelated 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 preceding 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, 

healthy 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 of 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, criteria 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 other 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 conducted 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 interviews. Control groups from the same 

region of the country were matched to cases based on vital status. A total of 402 cases of softtissue sarcoma and (among persons not exposed to phenoxyacetic acid herbicides) 128 cases of 

malignant lymphoma were reported. 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 strains 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 

indicate 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/group) 

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 groups, 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 of 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 incidences 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 proximal 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 chloride (>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 males, 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, respectively, 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 females 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 (classified 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-, midand high-dose females, 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 control, 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 died 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, 10 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 study. 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 males 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 observed. 

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/group 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 approximately 

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. Body 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 lesions 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); parathyroid 

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 middose males and exceeded in high-dose males and high-dose females. 

No tumor data were reported in a study using Wistar rats (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 of 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 sexes 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 

rats 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 were 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 lesions 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 mice (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 received 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 from controls. Significant reductions in body weight were reported in highdose 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 methylmercury (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 Data 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 specified) 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 related 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 appears 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 peripheral 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 mutagenic 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 with 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 (1975) 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 methylmercury (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 

Salmonella 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 nondisjunction 

(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 methylmercury. 

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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 highdose 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 methylmercury 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 tumors 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 nonfederal 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 these 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 conducted 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 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 
107

Substance Name — Methylmercury (MeHg) 

CASRN — 22967-92-6 

Last Revised — 07/27/2001

_VI.A. Oral RfD References

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Al-Shahristani, H; Shihab, KM. (1974) Variation of biological half-life of methyl mercury in man. 

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Amin-Zaki, L; Elhassani, S; Majeed, MA; et al. (1974) Intra-uterine methylmercury poisoning in 

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Baglan RJ; Brill, AB; Schulert, A; et al. (1974) Utility of placental tissue as an indicator of trace 

element exposure to adult and fetus. Environ Res 8:64-70. 

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181:230-241. 

Berglund, F; Berlin, M; Birke, G; et al. (1971) Methyl mercury in fish: a toxicologic- epidemiologic 

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women measured by radiochromium cell-labeling and hematocrit. J Clin Invest 41:2182-2190. 

Budtz-Jørgensen, E; Keiding, N; Grandjean, P; et al. (1999a) Methylmercury neurotoxicity 

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Budtz-Jørgensen, E; Keiding, N; Grandjean, P. (1999b) Benchmark modeling of the Faroese 

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Budtz-Jørgensen, E; Grandjean, P; Keiding, N; et al. (2000) Benchmark dose calculations of 

methylmercury-associated neurobehavioral deficits. Toxicol Lett 112-113:193-199. 

Burbacher, TM; Grant, KS; Mottet, NK. (1986). Retarded object permanence development in 

methylmercury exposed Macaca fascicularis infants. Dev Psychobiol 22:771-776. 

Burbacher, TM; Mohamed, MK; Mottett, NK. (1988) Methyl mercury effects on reproduction and 

offspring size at birth. Reprod Toxicol 1:267-278. 

Burbacher, TM; Rodier, PM; Weiss, B. (1990a) Methylmercury developmental neurotoxicity: a 

comparison of the effects in humans and animals. Neurotoxicol Teratol 12:191-202. 

Burbacher, TM; Sackett, GP; Mottet, NK. (1990b) Methylmercury effects on the social behavior of 

Macaca fascicularis infants. Neurotoxicol Teratol 12:65-71. 

Clewell, HJ; Gearhart, JM; Gentry, PR; et al. (1999) Evaluation of the uncertainty in an oral 

reference dose for methylmercury due to interindividual variability in pharmacokinetics. Risk Anal 

19:547-558. 

Davidson, P; Myers, G; Cox, C; et al. (1995) Longitudinal neurodevelopmental study of Seychellois 

children following in utero exposure to methylmercury from maternal fish ingestion: outcomes at 19 

and 29 months. NeuroToxicology 16:677-688. 

Davidson, PW; Myers, GJ; Cox, C; et al. (1998) Effects of prenatal and postnatal methylmercury 

exposure from fish consumption 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-blood. Sci 

Total Environ 3(3):275-277. 

Ershow, AG; Canter, KP. (1989) Total water and tapwater intake in the United States: populationbased estimates of quantities and sources. Life Sciences Research Office, Federation of American 

Societies for Experimental Biology, Bethesda, MD. (Prepared under NCI #263-MD-810264.) 

Fujita, M; Takabatake, E. (1977) Mercury levels in human maternal and neonatal blood, hair and 

milk. Bull Environ Contam Toxicol 18(2):205-209. 

Fukuda, Y; Ushijima, K; Kitano, T. (1999) An analysis of subjective complaints in a population living 

in a methylmercury-polluted area. Environ Res 81:100-107. 
109

Fuyuta, M; Fujimoto, T; Hirata, S. (1978) Embryotoxic effects of methylmercuric chloride 

administered to mice and rats during organogenesis. Teratology 18(3):353-366. 

Fuyuta, M; Fujimoto, T; Kiyofuji, E. (1979) Teratogenic effects of a single oral administration of 

methylmercuric chloride in mice. Acta Anat (Basel) 104(3):356-362. 

Gilbert, SG; Grant-Webster, KS. (1995) Neurobehavioral effects of developmental methylmercury 

exposure. Environ Health Perspect 103 Suppl. 6:135-142. 

Ginsberg, GL; Toal, BF. (2000) Development of a single-meal fish consumption advisory for 

methylmercury. Risk Anal 20:41-47. 

Grandjean, P; Weihe, P; White, R; et al. (1997) Cognitive deficit in 7-year-old children with prenatal 

exposure to methylmercury. Neurotoxicol Teratol 20:1-12. 

Gunderson, VM; Grant, KS; Fagan, JF. (1986) The effect of low-level prenatal methylmercury 

exposure on visual recognition memory of infant crab-eating macaques. Child Dev 57:1076-1083. 

Gunderson, VM; Grant-Webster, KS; Burbacher, TM; et al. (1988) Visual recognition memory 

deficits in methylmercury-exposed Macaca fascicularis infants. Neurotoxicol Teratol 10:373-379. 

Hansen, JE; Tarp, U; Bohm, J. (1990) Prenatal exposure to methyl mercury among Greenlandic 

Polar Inuits. Arch Environ Health 45:355-358. 

Harrison, KA. (1966) Blood volume changes in normal pregnant Nigerian women. J Obstet Gynaec 

Br Cwlth 73:717-723. 

Hirano, M; Mitsumori, K; Maita, K; et al. (1986). Further carcinogenicity study on methylmercury 

chloride in ICR mice. Nipon Juigaku Zasshi (Jpn J Vet Sci) 48(1):127-135. 

Huff, RL; Feller, DD. (1956) Relation of circulating red cell volume to body density and obesity. J 

Clin Invest 35:1-10. 

Hughes, JA; Annau, Z. (1976) Postnatal behavioral effects in mice after prenatal exposure to 

methylmercury. Pharmacol Biochem Behav 4(4):385-391. 

Inouye, M; Kajiwara, Y. (1988). Developmental disturbances of the fetal brain in guinea pigs caused 

by methylmercury. Arch Toxicol 62(1):15-21. 

Kershaw, TG; Clarkson, TW; Dhahir, PH. (1980) The relationship between blood levels and the dose 

of methylmercury in man. Arch Environ Health 35(1):28-36. 
110

Khera, KS. (1973) Reproductive capability of male rats and mice treated with methylmercury. 

Toxicol Appl Pharmacol 24(2):167-177. 

Kinjo, Y; Higashi, H; Nakano, A; et al. (1993) Profile of subjective complaints and activities of daily 

living among current patients with Minamata disease after 3 decades. Environ Res 63(2):241-251. 

Kjellstrom, T; Kennedy, P; Wallis, S; et al. (1986) Physical and mental development of children with 

prenatal exposure to mercury from fish. Stage 1: Preliminary test at age 4. Natl Swed Environ 

Protec Bd, Rpt 3080 (Solna, Sweden). 

Kjellstrom, T; Kennedy, P; Wallis, S; et al. (1989) Physical and mental development of children with 

prenatal exposure to mercury from fish. Stage 2: Interviews and psychological tests at age 6. Natl 

Swed Environ Prot Bd, Rpt 3642 (Solna, Sweden). 

Kuntz, WD; Pitkin, RM; Bostrom, A; et al. (1982) Maternal and cord-blood background mercury 

levels: a longitudinal surveillance. Am J Obstet Gynecol 143:440-443. 

Kuhnert, PM; Kuhnert, BR; Erhard, P (1981) Comparison of mercury levels in maternal-blood, fetal 

cord-blood, and placental tissues. Am J Obstet Gynecol. 139(2):209-213. 

Lauwerys, R; Buchet, JP; Roels, H; et al. (1978) Placental transfer of lead, mercury, cadmium, and 

carbon monoxide in women. I. Comparison of the frequency distributions of the biological indices in 

maternal and umbilical cord-blood. Environ Res 15(2):278-289. 

Lee, JH; Han, DH. (1995). Maternal and fetal toxicity of methylmercuric chloride administered to 

pregnant Fischer 344 rats. J Toxicol Environ Health 45(4):415-425. 

Marsh, DO; Clarkson, TW; Cox, C; et al. (1987) Fetal methylmercury poisoning: relationship 

between concentration in single strands of maternal-hair and child effects. Arch Neurol 44:1017-

1022. 

Miettinen, JK; Rahola, T; Hattula, T; et al. (1971). Elimination of 203-Hg methylmercury in man. 

Ann Clin Res 3:116-122. 

Mitsumori, K; Hiarano, M; Ueda, H; et al. (1990) Chronic toxicity and carcinogenicity of 

methylmercury chloride in B6C3F1 mice. Fundam Appl Toxicol 14:179-190. 

Myers, GJ; Marsh, DO; Cox, C; et al. (1995a) A pilot neurodevelopmental study of Seychellois 

children following in utero exposure to methylmercury from a maternal fish diet. Neurotoxicology 

16(4):629-638. 
111

Myers, GJ; Marsh, DO; Davidson, PW. (1995b) Main neurodevelopmental study of Seychellois 

children following in utero exposure to methylmercury from a maternal fish diet: outcome at six 

months. Neurotoxicology 16(4):653-664. 

Myers, GJ; Davidson, PW; Cox, C; et al. (1995c) Neurodevelopmetnal outcomes of Seychellois 

children sixty-six months after in utero exposure to methylmercury from a maternal fish diet: pilot 

study. Neurotoxicology 16(4):639-652. 

Myers, GJ; Davidson, PW; Shamlaye, CF; et al. (1997) Effects of prenatal methylmercury exposure 

from a high fish diet on developmental milestones in the Seychelles Child Development Study. 

Neurotoxicology 18(3):819-830. 

National Center for Health Statistics (NCHS). (1995) [Section 4.2.3, body weight]. 

Newland, CM; Rasmussen, EB. (2000) Aging unmasks adverse effects of gestational exposure to 

methylmercury in rats. Neurotoxicol Teratol 22. 

Nishima, T; Ikeda, S; Tada, T; et al. (1977) Mercury content levels in mother and newborn and 

their interrelation. Ann Rep Tokyo Metro Res Lab PH 28:215-220. 

National Research Council (NRC). (2000) Toxicological effects of methylmercury. Committee on the 

Toxicological Effects of Methylmercury, Board on Environmental Studies and Toxicology, 

Commission on Life Sciences, National Research Council. Washington, DC: National Academy Press. 

Ong, CN; Chia, SE; Foo, SC; et al. (1993) Concentrations of heavy metals in maternal and umbilical 

cord-blood. Biometals 6:61-66. 

Pitkin, RM; Bahns, JA; Filer, LJ, Jr; et al. (1976) Mercury in human maternal and cord-blood, 

placenta, and milk. Proc Soc Exp Biol Med 151(3):565-567. 

Ramirez, GB; Cruz, MCV; Pagulayan, O; et al. (2000) The Tagum Study: I. Analysis and clinical 

correlates of mercury in maternal and cord-blood, breast milk, meconium, and infants' hair. 

Pediatrics 106:774-781. 

Retzlaff, JA; Tauxe, WN; Khely, JM; et al. (1969) Erythrocyte volume, plasma volume, and lean 

body mass in adult men and women. Blood 33:649-664. 

Rice, DC. (1989) Delayed neurotoxicity in monkeys exposed developmentally to methylmercury. 

Neurotox 10:645-650. 
112

Rice, DC. (1996) Sensory and cognitive effects of developmental methylmercury exposure in 

monkeys, and a comparison to effects in rodents. Neurotoxicology 17:139-154. 

Rice, DC. (1998) Age-related increase in auditory impairment in monkeys exposed in utero plus 

postnatally to methylmercury. Toxicol Sci 44(2):191-196. 

Rice, DC; Gilbert, SG. (1982) Early chronic low-level methylmercury poisoning in monkeys impairs 

spatial vision. Science 216:759-761. 

Rice, DC; Gilbert, SG. (1990) Effects of developmental exposure to methylmercury on spatial and 

temporal visual function in monkeys. Toxicol Appl Pharmacol 102:151-163. 

Rice, DC; Gilbert, SG. (1992) Exposure to methylmercury from birth to adulthood impairs highfrequency hearing in monkeys. Toxicol Appl Pharmacol 102:151-163. 

Rice, DC; Gilbert, SG. (1995) Effects of developmental methylmercury exposure or lifetime lead 

exposure on vibration sensitivity function in monkeys. Toxicol Appl Pharmacol 134(1):161-169. 

Rice, DC; Hayward, S. (1999) Comparison of visual function at adulthood and during aging in 

monkeys exposed to lead or methylmercury. Neurotoxicology 20:767-784. 

Salonen, JT; Seppanen, K; Nyyssonen, K; et al. (1995) Intake of mercury from fish, lipid 

peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in 

Eastern Finnish men. Circulation 91(3):645-655. 

Sherlock, JC; Lindsay, DG; Hislop, J; et al. (1982) Duplication diet study on mercury intake by fish 

consumers in the United Kingdom. Arch Environ Health 37(5):271-278. 

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 blood, 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 10:370-375. 

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 methylmercury: 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 Office, 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 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. 
114

U.S. EPA. (1987) Peer Review Workshop on Mercury Issues. 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 for 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-blood. 

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 Sci 27(2):135-141.

Top of page

_VI.B. Inhalation RfC References

None

Top of page

_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 risk 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: 103-109. 

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 exposure 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 activities 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 chloride 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 mutagenicity 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 to 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. Environ. 

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. Zawidzka. 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: Mercury 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. Methylmercury 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, Environmental 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. Prepared 

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. 1984b. 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, Washington, 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 Assessment 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, Switzerland: 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: Dose-response relationship between SCE and 

seal diet, smoking, and blood cadmium and mercury concentrations. Sci. Total Environ. 48: 81-94. 

Top of page

_VII. Revision History

Substance Name — 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 has been added.

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

Top of page

_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 for Chronic Oral Exposure (RfD)

 Oral RfD Summary 

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 Confidence in the Oral RfD

 EPA Documentation and Review

Reference Concentration for Chronic Inhalation Exposure (RfC)

 Inhalation RfC Summary

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 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

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 Summary of Risk Estimates

 Dose-Response Data

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121

Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure

 Summary of Risk Estimates

 Dose-Response Data

 Additional Comments

 Discussion of Confidence

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122

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

Nickel, soluble salts (CASRN Various) 

Reference Dose for Chronic Oral Exposure (RfD)

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 during the assessment 

development process. Supporting information and explanations of the methods used to derive the 

values given in IRIS are provided in the guidance documents located on the IRIS website. 

STATUS OF DATA FOR 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 assumption 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 (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious 

effects during a lifetime. Please refer to the Background Document for an elaboration of these 

concepts. RfDs can also be derived for the noncarcinogenic health effects of substances that are also 

carcinogens. Therefore, it is essential to refer to other sources of information concerning the 

carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for potential human 

carcinogenicity, a summary of that evaluation will be contained in Section II of this file. 

__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 highdose male and female rats were significantly decreased compared with controls. Body weight was also 

reduced at 1000 ppm. This reduction was significant 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 ratios 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 this 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/kg/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) or 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) 

administered 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 consumption 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 indicated 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 lower 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 Additional 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 dietary 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 laboratory 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-ofevidence from these studies indicates that ingested nickel may invoke an eruption or worsening of 

eczema; however, a dose-response relationship 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 quantitative 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 study 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 study (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 satellite 

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 performed 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 effects 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 

development 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 

offspring (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-generation 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 

compared 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 environmentally 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 inadequate) 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 

concentrations 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 increased 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, 

particularly 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 other 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 following 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 doseresponse 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 aggravation 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 treatment. 

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 of 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 individuals 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 may 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 day 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 was 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 considered 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 developed 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 of 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 occurred 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 

confidence 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 Toxicologic 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 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).

Top of page

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

Substance Name — Nickel, soluble salts

CASRN — Various

Not available at this time.

Top of page

_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 hand 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. Antabuse 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 Perspectives. 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. Dermatol. 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 reactivity 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: Fertility 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 deficiency 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. Perinatal 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 Technology, Washington, DC.

Top of page

_VI.B. Inhalation RfD References

None

Top of page

_VI.C. Carcinogenicity Assessment References

None

Top of page

_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 were 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 Program.

Top of page

_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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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

 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
135

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

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136

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

Selenium and Compounds (CASRN 7782-49-2) 

Reference Dose for Chronic Oral Exposure (RfD)

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

Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment 

development process. Supporting information and explanations of the methods used to derive the 

values given in IRIS are provided in the guidance documents located on the IRIS website. 

STATUS OF DATA FOR 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 expressed 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 deleterious 

effects during a lifetime. Please refer to the Background Document for an elaboration of these 

concepts. RfDs can also be derived for the noncarcinogenic health effects of substances that are also 

carcinogens. Therefore, it is essential to refer to other sources of information concerning the 

carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for potential human 

carcinogenicity, a summary of that evaluation will be contained in Section II of this file. 

__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. Electrolytes 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) study 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 

commonly 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 possible 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 intake 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 with 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 CNS 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, 

1989). 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 samples 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 (prothrombin 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 concentration) 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 

factor 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. Additional 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 demonstrated 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 made 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 Rij 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 plateaus 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) reported 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 high 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 well 

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 hepatotoxicity 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 toxicity. 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 insufficient 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 consuming 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 findings 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 feeding 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 

selenodiglutathione 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 several 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 further 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 dimethylaminoazobenzeneinduced 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 

incorporated 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 selenium 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 selenite 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 of 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 teratogenic 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 to 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 hatch. 

The developmental toxicity of selenomethionine was investigated by Tarantal et al. (1991) in nonhuman 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 selenomethionine 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 treatmentrelated 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 utilization 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 of 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 survivors 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 were 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 accounted 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 epidemiologic 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 confidence 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 

contractor 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).

Top of page

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

Substance Name — Selenium and Compounds

CASRN — 7782-49-2

Not available at this time. 

Top of page

_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 three aspects of the carcinogenic assessment for the substance in 

question; the weight-of-evidence judgment of the likelihood that the substance is a human 

carcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. The 

quantitative risk estimates are presented in three ways. The slope factor is the result of application of 

a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. The unit risk is the 

quantitative estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m air breathed. 

The third form in which risk is presented is a drinking water or air concentration providing cancer risks 

of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods used to develop the 

carcinogenicity information in IRIS are described in The Risk Assessment Guidelines of 1986 

(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries developed since the 

publication of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment also utilize 

those Guidelines where indicated (Federal Register 61(79):17960-18011, April 23, 1996). Users are 

referred to Section I of this IRIS file for information on long-term toxic effects other than 

carcinogenicity. 

NOTE: This assessment is for 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 selenium 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 nested 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 (Shamberger 
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 subjects 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 between cancer death rates and the selenium concentrations in foliage 

plants of several Canadian provinces. The human cancer death rate in provinces with seleniumcontaining plants was 122.2 +/- 7.8 (presumably per 100,000 population although this was not 

specified), 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 the 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 would 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 correlated 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 

cancer (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 pain 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 animal 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 hepatocellular 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 control 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. Selenite 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 achieved 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 significantly 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 groups 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 time 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 increase 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

controls. 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 controls. 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 selenium- (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 dependent 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 selenite 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 another 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 rats 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-blood cultures; sodium 

selenate was not mutagenic in this assay (Ray and Altenburg, 1980). 

Top of page

_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, Review, 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 (Carcinogenicity 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 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)

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, New 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. and 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 Biomedicine, 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 etiologic 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 toenails 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 Biology 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 

embryotoxicity 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. Factors 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. Selenium: 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. Science. 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 receiving 

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 and 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. Selenium 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. FASEB 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 

seleniferous 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. 

Top of page

_VI.B. Inhalation RfC References

None

Top of page

_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 

experimental 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. Mutat. 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. Calvery. 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 valence 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 tumors 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 tumors. 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 Symposium on SeleniumTellurium 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. Possible 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. Selenium 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. EPA. 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 440/5-80-070. 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 Emergency 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 Assessment 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. 

Top of page

_VII. Revision History

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.

Top of page

_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 [German]

 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

 EPA Documentation and Review

Reference Concentration for Chronic Inhalation Exposure (RfC)

 Inhalation RfC Summary

 Principal and Supporting Studies

 Uncertainty and Modifying Factors

 Additional Studies/Comments

 Confidence in the Inhalation RfC

 EPA Documentation and Review

Carcinogenicity Assessment for Lifetime Exposure

Evidence for Human Carcinogenicity

 Weight-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

 Discussion of Confidence

 EPA Documentation, Review and, Contacts

Bibliography

Revision History

Synonyms

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160

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

Zinc and Compounds (CASRN 7440-66-6) 

Reference Dose for Chronic Oral Exposure (RfD)

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

Assessment for Lifetime Exposure) present the conclusions that were reached during the 

assessment development process. Supporting information and explanations of the methods used to 

derive the values given in IRIS are provided in the guidance documents located on the IRIS 

website. 

STATUS OF DATA FOR Zinc and Compounds

File First On-Line 02/01/1991

Category (section) Status 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 risk of adverse health effects over a lifetime. 

It is derived from a statistical lower confidence limit on the benchmark dose (BMDL), a noobserved-adverse-effect level (NOAEL), a lowest-observed-adverse-effect level (LOAEL), or another 

suitable point of departure, 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 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.

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-day

3 0.3

mg/kgday

* 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 reported 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 female 

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, 

development, 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 examine 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 individuals 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 neuropsychological 

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 malformations, 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 intrauterine 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 20th 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 increased 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 measure 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 1982-1986 [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 plasma 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 could 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 in 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 weight 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 activity 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 reported 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 were 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 metabolic 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 supplemented 

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 additional 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 changes 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 extracellular 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. 

Alcohol 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 contrasts 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 those 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 plasma 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 

difference 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 decrease 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 reversed with high-zinc treatment, resulting in lower total 

cholesterol. LDL-cholesterol changes were similar to the total cholesterol changes, while HDLcholesterol, very low density lipoprotein-cholesterol, and triglycerides were not affected. Zinc 

supplementation 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 expression 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 phlebotomy.

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 adult males), the studies of Yadrick et al. 

(1989), Fischer et al. (1984), Davis et al. (2000) and Milne et al. (2001) were selected as coprincipal studies.1

1

The studies by Davis et al. (2000) and Milne et al. (2001) were approved by the Institutional Review 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. 1984; 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 (UFA) 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 (UFS) was not necessary. Zinc is an essential 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 resulting in toxic effects in healthy non-pregnant adult humans consuming 

an average American diet.

A database uncertainty factor (UFD) to account for uncertainties due to lack of information in the 

database was not necessary. The database contains a considerable 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 (UFL) was determined not 

to be necessary. The RfD was based 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 (UFH) 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 

zinc. 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 UFH of 3 was applied, based on four different 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 reverse 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 an 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 enhancement 

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-blind 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 given 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, occurred 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 plasma level of 

LDL-cholesterol in females only. An inverse linear relationship between plasma zinc levels and LDLcholesterol 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 two 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 were 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 data. 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 study 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 years, 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 blood cell counts were significantly lower in women, but not in men, in the zinctreated 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 variation 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 subjects 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 HDLcholesterol for the 75-mg supplement group between 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 from 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 zinc, 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 zinc 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-cholesterol 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 correlate 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 supplemented 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/kgday 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 ED50 for low ceruloplasmin levels was approximately 125 ppm. Dose-related 

decreases in the activities 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 oxidase 

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/kg 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 noted 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 recently-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 for 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 overall 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-high 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 Review 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 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 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), (202) 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 limit on the benchmark concentration (BMCL), a noobserved-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 used. 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/m3) 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 

Concentrations 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 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 Summary

Not available at this time.

Available 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 subchronic 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 (Inhalation 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 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 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).

Top of page

_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 Guidelines 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/m3 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 occupationallyexposed 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 toxicological 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/kgday) as zinc sulfate in drinking 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 weight 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 increases 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 

lymphoma 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 water, 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 strains 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 in 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 were 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, 1979; 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.

Top of page

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

Not applicable.

Top of page

_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 Documentation

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 ReviewSummary of Comments and 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 males. 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 disease 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 copper-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; James, 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 postmenopausal 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 Work 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 effect 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.

Sandstead, 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 Systems 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) Zinc: 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 females. Am J Clin Nutr 49:145-150.

Top of page

_VI.B. Inhalation RfC References

Not Applicable.
178

Top of page

_VI.C. Carcinogenicity 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 zinc. 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.

Top of page

_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.

Top of page

_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

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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

Reference Concentration for Chronic Inhalation Exposure (RfC)

 Inhalation RfC Summary

 Principal and Supporting Studies

 Uncertainty and Modifying Factors

 Additional Studies/Comments

 Confidence in the Inhalation RfC

 EPA Documentation and Review

Carcinogenicity Assessment for Lifetime Exposure

Evidence for Human Carcinogenicity

 Weight-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 History

Synonyms

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182

Lead and Lead Compounds (inorganic) (http://www.epa.gov/iris/subst/0277.htm)

Lead and compounds (inorganic) (CASRN 7439-

92-1)

Reference Dose for Chronic Oral Exposure (RfD)

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

Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment 

development process. Supporting information and explanations of the methods used to derive the 

values given in IRIS are provided in the guidance documents located on the IRIS website. 

STATUS OF DATA FOR 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 is 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/iris/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 overt 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 (Centers 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 research. 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 Standards (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 (07/08/1985 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-evaluate 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 noncancer 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 those 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 potential 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 during 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 inappropriate 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 methods 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 limits 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 report 

"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 concern 
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 level 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 inherent 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 source. 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 these 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 caseby-case evaluation of the relative contributions of relevant lead exposures in a particular setting. The 

Superfund Program has guidelines for identifying lead-contaminated soil 

(http://www.epa.gov/superfund/programs/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 with 
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 uses 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 described 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 paint 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). 

Top of page

_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 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. 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 thresholds 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 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.B.1. Inhalation RfC Summary

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 RfC)
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). 

Top of page

_II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Lead and compounds (inorganic)

CASRN — 7439-92-1

Section II Last Revised — II.A. introductory 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 water 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 several 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 studies 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 mortality 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 (1975) 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 cancer (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

Sufficient. 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. The 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 

rats 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. (1985), 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 renal 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-Dawley 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 carcinoma; 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 mortality. 

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 (DiPaolo 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 vivo 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 associated with the regulation of gene expression 

(U.S. EPA, 1986b). 

Top of page

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

Not available.

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 knowledge 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 

literature 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 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 (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

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_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 evaluation 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. Lane. 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 calcium 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. Toxicol. 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. Jones. 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 with 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