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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

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

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

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

Integrated Risk Information System

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

Last updated on Tuesday, March 13, 2012

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__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).

__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)

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

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

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

Substance Name — Cadmium

CASRN — 7440-43-9

Not available at this time.

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_II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Cadmium

CASRN — 7440-43-9

Last Revised — 06/01/1992

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

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

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

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

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

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

breathed. The third form in which risk is presented is a drinking water or air concentration providing

cancer risks of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods used to

develop the carcinogenicity information in IRIS are described in The Risk Assessment Guidelines of

1986 (EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries developed since

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

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

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

carcinogenicity.

_II.A. Evidence for Human Carcinogenicity

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

Classification — 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 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

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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).

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

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

_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:

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.

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).

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

__II.D.1. EPA Documentation

Source Document — U.S. EPA, 1985

The Addendum to the Cadmium Health Assessment has received both Agency and external review.

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

Agency Work Group Review — 11/12/1986

Verification Date — 11/12/1986

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

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

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

_III. [reserved]

_IV. [reserved]

_V. [reserved]

_VI. Bibliography

Substance Name — 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.

_VI.B. Inhalation RfC References

None

_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.

Cadmium (CASRN 7440-43-9) | IRIS | US EPA http://www.epa.gov/iris/subst/0141.htm

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Date Section Description

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.

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.

_VII. Revision History

Substance Name — Cadmium

CASRN — 7440-43-9

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

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

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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

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.

_VIII. Synonyms

Substance Name — Cadmium

CASRN — 7440-43-9

Last Revised — 03/31/1987

7440-43-9

C.I. 77180

Cadmium

KADMIUM

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Carcinogenicity

Assessment for

Lifetime Exposure

Evidence for Human

Carcinogenicity

Weightof-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

Discussion of

Confidence

EPA

Documentation,

Review and,

Contacts

Bibliography

Revision History

Synonyms

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