The Risk Assessment Information System

Toxicity Profiles

Condensed Toxicity Summary for NICKEL AND NICKEL COMPOUNDS

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

JULY 1995

Prepared by: Robert A. Young, Ph.D., D.A.B.T., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory*, Oak Ridge, Tennessee.

Prepared for: Oak Ridge Reservation Environmental Restoration Program.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

Nickel is a naturally occurring element that may exist in various mineral forms. It is used in a wide variety of applications including metallurgical processes and electrical components, such as batteries (ATSDR 1988, USAF 1990). Some evidence suggests that nickel may be an essential trace element for mammals.

The absorption of nickel is dependent on its physicochemical form, with water soluble forms being more readily absorbed. The metabolism of nickel involves conversion to various chemical forms and binding to various ligands (ATSDR 1988). Nickel is excreted in the urine and feces with relative amounts for each route being dependent on the route of exposure and chemical form. Most nickel enters the body via food and water consumption, although inhalation exposure in occupational settings is a primary route for nickel-induced toxicity.

In large doses (>0.5 g), some forms of nickel may be acutely toxic to humans when taken orally (Daldrup et al. 1983, Sunderman et al. 1988). Oral LD50 values for rats range from 67 mg nickel/kg (nickel sulfate hexahydrate) to >9000 mg nickel/kg (nickel powder) (ATSDR 1988). Toxic effects of oral exposure to nickel usually involve the kidneys with some evidence from animal studies showing a possible developmental/reproductive toxicity effect (ATSDR 1988, Goyer 1991).

Inhalation exposure to some nickel compounds will cause toxic effects in the respiratory tract and immune system (Smialowicz et al. 1984, 1985, 1987; ATSDR 1988; Goyer 1991). Inhalation LC50 values for animals range from 0.97 mg nickel/m3 for rats (6-hour exposure) to 15 mg nickel/m3 for guinea pigs (time not specified) (USAF 1990). Acute inhalation exposure of humans to nickel may produce headache, nausea, respiratory disorders, and death (Goyer 1991, Rendall et al. 1994). Asthmatic conditions have also been documented for inhalation exposure to nickel (Goyer 1991). Soluble nickel compounds tend to be more toxic than insoluble compounds (Goyer 1991). In addition, nickel carbonyl is known to be extremely toxic to humans upon acute inhalation exposure (Goyer 1991).

Data on nickel-induced reproductive/developmental effects in humans following inhalation exposure are equivocal. No clinical evidence of developmental or reproductive toxicity were reported for women working in a nickel refinery (Warner et al. 1979), but Chashschin et al. (1994) reported possible reproductive and developmental effects in humans of occupational exposure to nickel (0.13-0.2 mg nickel/m3). Although not validated by quantitative epidemiologic data or statistical analyses, the authors reported an apparently abnormal increase in spontaneous and threatening abortions (16-17% in nickel-exposed workers vs 8-9% in nonexposed workers), and an increased incidence of non-specified structural malformations (17% vs 6%) was reported also. Furthermore, sensitivity reactions to nickel are well documented and usually involve contact dermatitis reactions resulting from contact with nickel-containing items such as cooking utensils, jewelry, coins, etc. (ATSDR 1988).

A chronic (EPA 1995) and subchronic (EPA 1994) oral reference dose (RfD) of 0.02 mg/kg/day for soluble nickel salts is based on changes in organ and body weights of rats receiving dietary nickel sulfate hexahydrate (5 mg/kg/day) for 2 years. A no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effects level (LOAEL)

of 5 mg/kg/day and 50 mg/kg/day, respectively, were reported in the key study (Ambrose et al. 1976). An uncertainty factor of 300 reflects interspecies extrapolation uncertainty, protection of sensitive populations, and a modifying factor of 3 for a database deficient in reproductive/developmental studies.

An inhalation reference concentration (RfC) for soluble nickel salts is under review by the RfD/RfC Work Group (EPA 1995) and currently is not available.

The primary target organs for nickel-induced systemic toxicity are the lungs and upper respiratory tract for inhalation exposure and the kidneys for oral exposure (ATSDR 1988, Goyer 1991). Other target organs include the cardiovascular system, immune system, and the blood.

Epidemiologic studies have shown that occupational inhalation exposure to nickel dust (primarily nickel subsulfate) at refineries has resulted in increased incidences of pulmonary and nasal cancer (NAS 1975, Enterline and Marsh 1982, ATSDR 1988). Inhalation studies using rats have also shown nickel subsulfate or nickel carbonyl to be carcinogenic (Sunderman et al. 1959, Sunderman and Donnelly 1965, Ottolenghi et al. 1974). Based on these data, the EPA (1995) has classified nickel subsulfate and nickel refinery dust in weight-of-evidence group A, human carcinogen. Carcinogenicity slope factors of 1.7E+0 and 8.4E-01 (mg/kg/day)-1 and unit risks of 4.8E-04 (µg/m3)-1 and 2.4E-04 (µg/m3)-1 have been calculated for nickel subsulfide and nickel refinery dust, respectively (EPA 1994, 1995). Based on an increased incidence of pulmonary carcinomas and malignant tumors in animals exposed to nickel carbonyl by inhalation or by intravenous injection, this compound had been placed in weight-of-evidence group B2, probable human carcinogen (EPA 1995). No unit risk values were available for nickel carbonyl. Recent analyses of epidemiologic data, however, indicate that definitive identification of a specific nickel compound as the causative agent is not yet possible (Easton et al. 1994, Langård 1994, Roberts et al. 1994).

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Last Updated 2/13/98

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