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.
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).
Nickel is a naturally occurring metal existing in various mineral forms and may be found throughout the environment including rivers, lakes, oceans, soil, air, drinking water, plants, and animals. Soil and sediment are the primary receptacles for nickel, but mobilization may occur depending on physico-chemical characteristics of the soil (ATSDR 1988, USAF 1990). Nickel is used in a wide variety of metallurgical processes such as electroplating and alloy production as well as in nickel-cadmium batteries. Some evidence suggests that nickel may be an essential trace element for mammals (Goyer 1991). As for most metals, the toxicity of nickel is dependent on the route of exposure and the solubility of the nickel compound (Coogan et al. 1989).
Pulmonary absorption is the major route of concern for nickel-induced toxicity. Nickel may be absorbed as the soluble nickel ion (Ni+2) while sparingly soluble nickel compounds may be phagocytized. The chemical form and its deposition site (determined by size, shape, density, and electrical charge of the nickel particles) in the lungs will affect the extent of absorption (ATSDR 1988). Nickel may be removed from portions of the respiratory tract via mucociliary transport resulting in the material entering the gastrointestinal tract. Although nickel is poorly absorbed from the gastrointestinal tract, dietary exposure and exposure via drinking water provide most of the intake of nickel and nickel compounds (Coogan et al. 1989, Goyer 1991). As reviewed by the EPA (1986), humans and animals absorb approximately 1-10% of dietary nickel. Similar values were reported for drinking water exposure and gavage administration (ATSDR 1988). Nickel metal is poorly absorbed dermally but some nickel compounds such as nickel chloride or nickel sulfate can penetrate occluded skin resulting in up to 77% absorption within 24 hours (ATSDR 1988).
Nickel is readily distributed throughout the body but may be affected by route of exposure, the chemical form, and time after exposure (Coogan et al. 1989). Although the kidney and lungs are the primary sites of accumulation of nickel, other organs such as the spleen, liver, heart and testes may also accumulate the metal to a much lesser extent. Nickel is known to bind to specific proteins and/or amino acids in the blood serum and the placenta. These ligands are instrumental in the transport and distribution of nickel in the body. Nickel distribution may be altered by the formation of lipophilic nickel complexes.
Nickel is not destroyed in the body, but its chemical form may be altered. The metabolism of nickel is most appropriately viewed in light of its binding to form ligands and its transport throughout the body. Much of the toxicity of nickel may be associated with its interference with the physiological processes of manganese, zinc, calcium, and magnesium (Coogan et al. 1989). Various disease states (myocardial infarction and acute stroke) and injuries (burn injury) are associated with altered transport and serum concentrations of nickel (ATSDR 1988).
Nickel is excreted in the urine and feces, but because it is poorly absorbed, most ingested nickel is excreted in the feces. It has been reported that fecal nickel is usually about 100 times that of urinary nickel and represents the removal of unabsorbed nickel (ATSDR 1988, Goyer 1991). Furthermore, nickel that is absorbed is excreted primarily in the urine (ATSDR 1988). Urinary nickel levels of 0.4-6.0 µg/L in nonexposed, healthy adults were reported by Sunderman et al. (1986a, 1989) while levels as high as 400 µg/L were reported by Sunderman et al. (1986b) for workers occupationally exposed to nickel and nickel compounds.
In a study of nickel-chromium electroplaters, White and Boran (1994) noted that urinary nickel is a valid and sensitive (0.6 µg nickel/L urine) method of monitoring occupational exposure to soluble nickel salts. Nickel may also be excreted in the hair and sweat (ATSDR 1988).
The acute lethality of nickel following oral exposure is dependent upon the chemical form of nickel. A fatal case of nickel poisoning was reported for a 2 ½-year-old girl who had ingested 15 g of nickel sulfate (Daldrup et al. 1983). The cause of death was cardiac arrest. Death due to nickel-induced Adult Respiratory Distress Syndrome (ARDS) was reported for a worker spraying nickel using a thermal arc process (Rendall et al. 1994). Death occurred 13 days following 90-minute exposure to an estimated nickel concentration of 382.1 mg/m3; total nickel intake was estimated at nearly 1 g. Nausea, vomiting, abdominal pain, diarrhea, headache, cough, shortness of breath, and giddiness were reported for workers of an electroplating plant who drank water contaminated with nickel chloride and nickel sulfate (1.63 g/L) (Sunderman et al. 1988). Signs and symptoms of toxicity lasted for up to 2 days with uneventful recoveries for all 32 workers. The nickel doses were estimated to be 0.5 to 2.5 g, serum nickel concentrations were 13 to 1340 µg/L, and urinary nickel concentrations were 0.15 to 12 mg/g creatinine.
Some studies have provided information indicating the aggravation of nickel-induced dermatitis in women following exposure to dietary nickel (ATSDR 1988).
Oral LD50 values for rats range from 67 mg nickel/kg for nickel sulfate hexahydrate to >9000 mg nickel/kg for nickel powder (ATSDR, 1988). Generally, soluble nickel compounds are more toxic than insoluble compounds. A 2-week exposure of rats to 1000 ppm nickel chloride in the drinking water resulted in excessive mortality (RTI 1987).
3.1.2 Subchronic Toxicity
No data were available regarding the toxicity of nickel or nickel compounds in humans following subchronic oral exposure.
With the exception of vomiting during the initial phase of exposure to the highest dose, exposure of dogs to dietary nickel sulfate hexahydrate (100, 1000, or 2500 ppm) for 2 years failed to produce significant signs of compound-related toxicity (Ambrose et al. 1976).
A 91-day study using rats given nickel chloride hexahydrate by gavage at doses of 5, 35, or 100 mg nickel/kg/day resulted in the death of all rats in the high-dose group by day 78, in an increase in white blood cell counts for those in the 35 mg/kg/day group at an interim sacrifice, and an elevated platelet count and decreased blood glucose level in the 35 mg/kg group at final sacrifice (American Biogenics Corp. 1986).
Renal tubular degeneration was reported for rats receiving dietary nickel acetate (0.1 to 1.0%) for several weeks.
No studies were available regarding the toxicity of nickel or nickel compounds in humans following chronic oral exposure.
No studies were available that examined the chronic oral systemic toxicity of nickel or nickel compounds in animals.
No studies were available that addressed the developmental/reproductive toxicity of orally administered nickel or nickel compounds.
Research Triangle Institute (1987) conducted a multigeneration study using rats exposed to nickel chloride in the drinking water at nickel concentrations of 50, 250, or 500 ppm (equivalent to 7.3, 30.8, or 51.6 mg nickel/kg/day). The highest exposure produced maternal toxicity characterized by a decrease in body weight and decreased absolute and relative liver weights of the dams. A decrease in the number of live pups per litter, an increase in pup mortality, and a decrease in the average body weight of the pups was noted for the F1a and F1b generations of the 500 ppm test group. Following statistical analyses, both the 50 and 250 ppm exposures were considered to be a no-observed-adverse-effect level (NOAEL).
ORAL RfDs: 2E-2 mg/kg/day (soluble nickel salts) (EPA 1994)
UNCERTAINTY FACTOR: 300
NOAEL: 100 ppm (5 mg/kg/day)
ORAL RfDc: 2E-2 mg/kg/day (soluble nickel salts) (EPA 1995)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: 3
NOAEL: 100 ppm (5 mg/kg/day)
LOAEL: 1000 ppm (50 mg/kg/day)
Data base: Medium
VERIFICATION DATE: 07/16/87
PRINCIPAL STUDY: Ambrose et al. 1976
COMMENTS: The RfD is based on decreased organ and body weights of rats receiving dietary nickel sulfate hexahydrate (100 ppm equivalent to a dose of 5 mg/kg/day) for 2 years. An uncertainty factor of 100 reflects interspecies extrapolation and protection of sensitive populations. A modifying factor of three was applied to account for the absence of definitive reproductive/developmental studies.
Acute inhalation exposure to nickel carbonyl results in initial headache, nausea, vomiting, and chest pain, progressing to hyperpnea, cyanosis, respiratory failure, and death if the exposure is severe (Goyer 1991). A lowest toxic concentration (TCLo) of 7 mg/m3 for nickel carbonyl has been reported (Sax and Lewis 1989).
Asthmatic disease resulting from inhalation exposure to nickel and nickel compounds has been reported for nickel-plating workers and stainless steel welders (ATSDR 1988). Nicklin and Nielsen (1994) categorized these responses as (1) a rapid onset attack (antibody-mediated Type I hypersensitivity) associated with acute bronchospasm, (2) a late response reaction at 6-12 hours after exposure (antigen-antibody immune complex-mediated inflammatory reaction), and 3) a mixed or combined response.
Acute inhalation toxicity studies in animals have provided LCLo values ranging from 0.97 mg/m3 for 6-hour exposure of rats to nickel subsulfate to 15 mg/m3 (time not specified) for guinea pigs exposed to nickel dust (USAF 1990). Acute toxic effects will be dependent upon the chemical form, exposure concentration, and exposure duration.
Several studies summarized in ATSDR (1988) indicated that 2-hour exposure of mice to nickel chloride at concentrations of 0.25 to 0.50 mg nickel/m3 caused a suppression of immune responses.
In an evaluation of workers welding high-nickel alloys, it was reported that 6-week exposure to nickel fumes (0.07 to 1.1 mg nickel/m3) caused an increase in airway and eye irritations, headaches, and tiredness (Akesson and Skervfing 1985).
A number of studies have examined the toxic effects of short-term exposure of animals to various chemical forms of nickel (ATSDR 1988). Exposure of rats and mice to aerosols of nickel sulfate hexahydrate (0.7 to 13.5 mg nickel/m3) for 12 days resulted in pulmonary inflammation, degenerative changes in the bronchiolar mucosa, and atrophy of the olfactory epithelium (Benson et al. 1988). Another study using the same protocol and nickel subsulfate (0.4, 0.9, 1.8, 2.7, 3.7, or 7.3 mg nickel/m3) showed that exposure to 5 mg Ni3S2 (3.7 mg nickel/m3) caused necrotizing pneumonia, emphysema, and fibrosis in both rats and mice (Benson et al. 1987). Degeneration of the olfactory epithelium was reported for the rats and mice exposed to concentrations 1.2 mg/m3 (0.9 mg nickel/m3). Inhalation exposure of rats to nickel chloride (0.109 mg nickel/m3) produced hyperplastic changes in the bronchial epithelium and increased mucus secretion (Bingham et al. 1972). Similar effects have been observed for rabbits inhaling nickel dust for 3-8 months (Curstedt et al. 1983, 1984; Johansson et al. 1983).
A 13-week inhalation study conducted by the Inhalation Toxicology Research Institute compared the effects of exposure of rats and mice to nickel sulfate hexahydrate, nickel subsulfate, and nickel oxide at occupationally relevant exposure concentrations. Severity of inflammation and fibrosis of the lungs and alveolar macrophage hyperplasia corresponded to the water solubility of the nickel compounds with nickel sulfate being the most toxic, followed by nickel subsulfate and nickel oxide (Dunnick et al. 1989). Biochemical indexes of pulmonary toxicity (lactate dehydrogenase and beta-glucuronidase activity; total protein levels) indicated the order of toxicity to be NiSO4 > Ni3S2 > NiO (Benson et al. 1989). Varying degrees of immunological effects in mice were also noted for these three compounds, with effects depending on dose and physicochemical form (Haley et al. 1990). The investigators concluded that inhalation of these nickel compounds at occupationally relevant concentrations can result in significant alterations of pulmonary and systemic immune defenses.
The immunotoxic effects of nickel compounds have been affirmed by other investigators. Haley et al. (1990) reported immunotoxic effects in mice following 13-week exposures to various nickel compounds. Nickel subsulfide (1.8 mg nickel/m3) decreased activity levels of natural killer cells while both nickel oxide (0.47, 2.0, and 7.9 mg nickel/m3) and nickel subsulfate (0.45 and 1.8 mg nickel/m3) inhibited phagocytic ability of alveolar macrophages. In studies with mice and rats, Smialowicz et al. (1984, 1985, 1987) found that nickel chloride affected T-cell-mediated immune responses (but not humoral immune responses) and that natural killer cells were target cells of the immunotoxic effects of nickel.
Most chronic inhalation exposures involve occupational exposure to nickel dust or nickel vapors resulting from welding nickel alloys. Generally, chronic inhalation exposure to nickel dusts and aerosols contribute to respiratory disorders such as asthma, bronchitis, rhinitis, sinusitis, and pneumoconiosis (USAF 1990). Chronic exposure to nickel and nickel compounds have been implicated in carcinogenic responses as discussed in Sect. 4.2.
A 31-month exposure of rats to nickel oxide (0.06 or 0.20 mg nickel/m3) resulted in the development of focal septal fibrosis and histological changes indicative of alveolar proteinosis (Takenaka et al. 1985). A lifetime exposure of rats to nickel oxide (42 mg nickel/m3) produced emphysema and other proliferative and inflammatory changes (Wehner et al. 1975).
No clinical evidence of developmental or reproductive toxicity were reported for women working in a nickel refinery (Warner et al. 1979). More recently, however, Chashschin et al. (1994) reported on 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 versus 8-9% in nonexposed workers) and an increased incidence of nonspecified structural malformations (17% vs 6%) was also reported.
A reduction in fetal body weight was observed for pregnant rats exposed to nickel oxide (1.3 or 2.5 mg/m3) throughout gestation (Weischer et al. 1980). The number of fetuses per litter was unaffected. Benson et al. (1988) reported degeneration of the germinal epithelium of testes in rats exposed to nickel sulfate at concentrations 7 mg/m3 ( 1.6 mg nickel/m3) for 12 days. Similar effects were observed for mice and rats exposed to nickel subsulfate at concentrations of 2.5 mg/m3 ( 1.8 mg nickel/m3) (Benson et al. 1987).
Subchronic and chronic inhalation RfCs for soluble nickel salts are currently under review by the RfD/RfC Work Group (EPA 1995).
Nickel-induced contact dermatitis is well documented for humans and is the most prevalent effects of nickel in humans (ATSDR 1988). Both occupational and nonoccupational exposures are common, the latter involving commodities such as eating utensils, coins, jewelry, and tools. Data indicate women to be at greater risk for dermatitis of the hands, possibly due to more frequent contact with nickel-containing items. No dose-response data are available for nickel sensitivity reactions.
Nickel sensitivity has not been adequately demonstrated in animals (ATSDR 1988), and no information was available regarding other acute effects following dermal exposure to nickel or nickel compounds.
No information was available on the subchronic toxicity of nickel or nickel compounds in humans or animals by other routes of exposure.
No information was available on the chronic toxicity of nickel or nickel compounds in humans or animals by other routes of exposure.
No definitive information was available. Mathur et al. (1977) reported that application of nickel sulfate hexahydrate (60 or 100 mg/kg/day for 30 days) to the shaved backs of rats resulted in tubular damage of the testes and sperm degeneration. However, the effects may have been due to ingestion of the compound during grooming.
1. Kidney: Although not documented for humans, parenteral administration studies in animals have verified the nephrotoxicity of nickel and nickel compounds (ATSDR 1988, USAF 1990).
2. Blood: Alterations in white blood cell counts of mice and decreased hematocrit in rats have been reported following gavage administration of nickel chloride (USAF 1990).
1. Skin: Some studies are available documenting the aggravation of nickel-induced dermatitis in women following exposure to dietary nickel.
2. Cardiovascular system: Anecdotal information suggested that very high (15 g) acute doses of nickel sulfate may cause cardiac arrest.
1. Respiratory tract: Inhalation of nickel or nickel compounds may cause respiratory conditions such as asthma, bronchitis, rhinitis, sinusitis, and pneumoconiosis. Inhalation of nickel carbonyl may be fatal. The nature and severity of the adverse effects may vary depending on the specific nickel compound and the duration of exposure.
2. Immune system: Exposure of mice to nickel subsulfide decreased activity levels of natural killer cells, and both nickel oxide (0.47-7.9 mg nickel/m3) and nickel subsulfide (0.45-1.8 mg nickel/m3) inhibited phagocytic ability of alveolar macrophages. Exposure of rats and mice to nickel chloride inhibited T-cell-mediated immune responses.
1. Testes: Degeneration of the germinal epithelium of the testes was observed in rats exposed to nickel sulfate at concentrations 7 mg/m3 ( 1.6 mg nickel/m3) for 12 days.
No information was available on the carcinogenicity of nickel or nickel compounds in humans following oral exposure.
Although several studies have been conducted assessing the carcinogenic potential of nickel compounds following oral exposure, the studies suffered from inadequate design (ATSDR 1988).
Several epidemiologic studies have investigated the potential carcinogenicity of inhaled nickel and nickel compounds (ATSDR 1988). Based on analyses of studies completed prior to 1975, the National Academy of Sciences (NAS 1975) concluded that nickel refinery workers demonstrated an increase in the incidence of pulmonary and nasal cavity cancers, specifically epidermoid, anaplastic, and pleomorphic cancers. Enterline and Marsh (1982) showed that there was an excess risk of nasal sinus cancer in nickel refinery workers. The standardized mortality ratio (SMR) was 2443.
Doll et al. (1977) also reported an excess of lung and nasal cancer among nickel refinery workers. The incidence was virtually eliminated after the implementation of respirators.
Magnus et al. (1980) studied workers from several job categories in a nickel refinery and found an increase in the risk of nasal cancer in all jobs, with the highest risk being in roasting/smelting jobs and for electrolysis workers. The authors also reported that smoking and nickel exposure appeared to be additive in their carcinogenic potential.
For epidemiologic studies on stainless steel welders, Langård (1994) noted that it was not possible to determine whether exposure to nickel or chromium VI was a greater factor in the reported increased cancer incidences for this occupational group. Additionally, Easton et al. (1994) noted that currently available data and analyses would not allow for a valid association of a specific nickel compound with the observed cancer incidences. In the absence of more definitive data, it is assumed that exposure to any nickel compound with a particle size small enough to reach nasal and bronchial tissue may constitute a respiratory cancer hazard.
Although data are not available to positively identify which nickel compounds are responsible for inducing carcinogenic responses in humans, recent analyses have indicated nickel oxide, subsulfate, and soluble nickel to be likely candidates (Roberts et al. 1994).
In an inhalation study by Ottolenghi et al. (1974), rats of both sexes were exposed to nickel subsulfate (0.97 mg nickel/m3) for 78 to 84 weeks followed by a 30-week observation period. Relative to controls, there was an increase in the incidence of adenomas and adenocarcinomas in the nickel-exposed rats.
Sunderman et al. (1959) showed that repeated inhalation exposures of rats to nickel carbonyl (0.03 or 0.06 mg/L) over a 1-year period resulted in an increased incidence of tumors relative to controls. Lifetime inhalation exposure of rats to nickel carbonyl vapor (0.6 mg/L for 30 minutes or 0.03 mg/L, three times/week) resulted in pulmonary carcinomas and metastases (Sunderman and Donnelly 1965). Lau et al. (1972) induced malignant tumors at various sites in rats injected with nickel carbonyl.
No information was available on the carcinogenicity of nickel or nickel compounds in animals by other routes of exposure.
Classification--A, Human carcinogen (EPA 1995)
Basis--Increased risks of lung and nasal cancer in humans exposed to nickel refinery dust, most of which is believed to be nickel subsulfate; increased tumor incidences in several species and strains of animal for multiple routes of administration; positive results in genotoxicity assays.
Nickel refinery dust:
Classification--A, Human carcinogen (EPA 1995)
Basis--Epidemiologic studies in several different countries showed nickel refinery dust to cause lung and nasal tumors in nickel sulfide matte refinery workers; animal data showed an increased incidence of carcinomas in rats following administration via inhalation or injection.
Classification--B2, Probable human carcinogen (EPA 1995)
Basis--Observation of pulmonary carcinomas and malignant tumors at various sites in rats administered nickel carbonyl by inhalation and intravenous injection, respectively; nickel administered as nickel carbonyl binds to DNA.
The EPA has not evaluated soluble nickel salts for potential human carcinogenicity.
No slope factors for carcinogenicity of nickel and nickel compounds through ingestion have been calculated.
SLOPE FACTORS: 8.4E-01 (mg/kg/day)-1 (nickel refinery dust) (EPA 1994)
1.7E+0 (mg/kg/day)-1 (nickel subsulfide) (EPA 1994)
No slope factors have been calculated for other nickel compounds.
PRINCIPAL STUDY: Data sets from several occupational exposure studies were used and are described in EPA (1986).
VERIFICATION DATE: 04/01/87
UNIT RISKS: 4.8E-4 (µg/m3)-1 (nickel subsulfide) (EPA 1995)
2.4E-4 (µg/m3)-1 (nickel refinery dust) (EPA 1995)
Nickel refinery dust is a mixture of many nickel moieties, and the identity of the specific carcinogenic nickel species is not known.
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