Report on Carcinogens, Fourteenth Edition For Table of Contents, see home page: http://ntp.niehs.nih.gov/go/roc Nickel Compounds and Metallic Nickel caused tumors at tissue sites other than the lung; in particular, be- nign or malignant adrenal-gland tumors (pheochromocytoma) were Introduction observed in rats (NTP 1996a,b). Injection of rodents with various nickel compounds was repeatedly shown to cause dose-dependent Nickel compounds and metallic nickel have many industrial and com- increases in tumors in several species and at several different sites. mercial applications, including use in stainless steel and other nickel Subcutaneous, intramuscular, intraperitoneal, subperiosteal, intra- alloys, catalysts, batteries, pigments, and ceramics. Nickel and Cer- femoral, intrapleural, intracerebral, intrarenal, intratesticular, and in- tain Nickel Compounds were listed in the First Annual Report on Car- traocular injections of nickel compounds all caused cancer (usually cinogens (1980) as reasonably anticipated to be human carcinogens. sarcoma) at the injection site. Injection of nickel also produced dis- Nickel compounds as a class were first listed as known to be human tant tumors of the liver in some strains of mice. IARC concluded that carcinogens in the Tenth Report on Carcinogens (2002); this listing there was sufficient evidence of the carcinogenicity of several nickel supersedes the listing of “certain nickel compounds” and applies to compounds (monoxides, hydroxides, and crystalline sulfides) in ex- all members of the class. Metallic nickel was reevaluated in 2000 and perimental animals (IARC 1990). remains listed as reasonably anticipated to be a human carcinogen. Soluble nickel acetate is a complete transplacental carcinogen in Nickel alloys were reviewed in 2000 but were not recommended for rats. Brief exposure of pregnant rats to nickel acetate by intraper- listing in the Report on Carcinogens (see Appendix C). itoneal injection during pregnancy caused pituitary cancer in the The profiles for nickel compounds and metallic nickel follow this offspring. Transplacental exposure to nickel acetate followed by ex- introduction. The evidence for carcinogenicity from cancer studies in posure of the offspring to barbital (a known tumor promoter) caused experimental animals and humans is discussed separately for nickel kidney tumors (renal cortical and pelvic tumors) (Diwan et al. 1992). compounds and metallic nickel. However, most of the information In adult rats, injection of soluble nickel salts followed by barbital ex- on mechanisms of carcinogenesis, properties, use, production, ex- posure caused kidney cancer (renal cortical adenocarcinoma) that posure, and regulations is common to both nickel compounds and frequently metastasized to the lung, liver, and spleen (Kasprzak et metallic nickel and therefore is combined into one section following al. 1990). the discussions of cancer studies. Metallic Nickel Nickel Compounds CAS No. 7440-02-0 No separate CAS No. assigned for nickel compounds as a class Reasonably anticipated to be a human carcinogen Known to be human carcinogens First listed in the First Annual Report on Carcinogens (1980) First listed in the Tenth Report on Carcinogens (2002) Also known as Ni Carcinogenicity Carcinogenicity Nickel compounds are known to be human carcinogens based on suf- Metallic nickel is reasonably anticipated to be a human carcinogen ficient evidence of carcinogenicity from studies in humans, includ- based on sufficient evidence of carcinogenicity from studies in -ex ing epidemiological and mechanistic studies. The combined results perimental animals. of epidemiological studies, mechanistic studies, and cancer studies in rodents support the concept that nickel compounds generate nickel Cancer Studies in Experimental Animals ions in target cells at sites critical for carcinogenesis, thus allowing Metallic nickel caused tumors in two rodent species, at several differ- consideration and evaluation of these compounds as a single group. ent tissue sites, and by several different routes of exposure. In both Cancer Studies in Humans rats and hamsters, metallic nickel powder caused tumors when ad- ministered by intratracheal instillation or by subcutaneous, intra- Several epidemiological cohort studies of workers exposed to vari- muscular, or intraperitoneal injection. Intratracheal instillation of ous nickel compounds showed an elevated risk of death from lung metallic nickel powder primarily caused adenocarcinoma, whereas cancer and nasal cancer. Although the precise nickel compound re- injection most frequently caused sarcoma, demonstrating that me- sponsible for the carcinogenic effects in humans is not always clear, tallic nickel can induce both epithelial and connective-tissue tumors studies indicate that nickel sulfate and the combinations of nickel (IARC 1973, 1976, 1990). sulfides and oxides encountered in the nickel-refining industry cause cancer in humans. The International Agency for Research on Cancer Cancer Studies in Humans concluded that there was sufficient evidence of the carcinogenicity The available epidemiological studies of workers exposed to metal- of nickel compounds encountered in the nickel-refining industry in lic nickel are limited by inadequate exposure information, low ex- humans (IARC 1990). In an additional study, nickel-refinery work- posure levels, short follow-up periods, and small numbers of cases. ers exposed primarily to soluble nickel compounds had a significant excess risk of lung cancer, and smoking and nickel exposure had a synergistic effect on cancer risk (Anderson et al. 1996). These work- Nickel Compounds and Metallic Nickel ers also had an excess risk of nasal cancer. Studies on Mechanisms of Carcinogenesis Cancer Studies in Experimental Animals The available evidence suggests that metallic nickel has carcinogenic In rats and in some studies with mice, inhalation or intratracheal in- properties because it can slowly dissolve in the body and release ionic stillation of nickel subsulfide or nickel oxide led to dose-related in- nickel, an active genotoxic and carcinogenic form of nickel. There is duction of benign and malignant lung tumors, including carcinoma no evidence to suggest that the mechanisms by which nickel causes (IARC 1990, NTP 1996a,b). Inhalation of nickel compounds also tumors in experimental animals would not also operate in humans. National Toxicology Program, Department of Health and Human Services Report on Carcinogens, Fourteenth Edition Many studies in cultured rodent and human cells have shown that Nickel sulfides are insoluble in water, and some occur in more a variety of nickel compounds, including both soluble and insoluble than one form. Nickel subsulfide (α form) occurs as lustrous pale- forms of nickel, caused genetic damage, including DNA strand breaks, yellowish or bronze crystals that are soluble in nitric acid. Nickel sul- mutations, chromosomal damage, cell transformation, and disrupted fide occurs in three forms (α, β, and amorphous) as dark-green to DNA repair. Chromosomal aberrations have been observed in hu- black crystals or powder. Nickel disulfide occurs as black crystals or mans occupationally exposed to nickel. Nickel can bind ionically to powder and decomposes at temperatures above 400°C (IARC 1990). cellular components, including DNA. The reduction-oxidation activ- Nickel salts are green to yellow crystals that generally are solu- ity of the nickel ion may produce reactive oxygen species that attack ble in water and decompose when heated. Nickel acetate occurs as a DNA, and exposure to nickel ion in vitro or in vivo can result in pro- dull-green powder that effloresces somewhat in air. It is available as duction of 8-hydroxy-2′-deoxyguanosine in target tissues for cancer the tetrahydrate at greater than 97% purity. Nickel chloride occurs caused by nickel (IARC 1990, Kasprzak et al. 1990). as yellow (anhydrous) or green (hexahydrate) deliquescent crystals. The carcinogenic potency of various nickel compounds varies It is soluble in ethanol and ammonium hydroxide and insoluble in widely, based on solubility properties and speciation. Studies indi- ammonia. The hexahydrate form is available as a laboratory reagent cate that soluble nickel salts can be complete carcinogens (Diwan at greater than 99% purity or as industrial products containing ap- et al. 1992) or initiators of carcinogenesis (Kasprzak et al. 1990) at proximately 24.7% nickel. Nickel sulfate occurs as yellow, green, or tissue sites distant from the site of administration, which confirms blue crystals and is available in anhydrous, hexahydrate, or heptahy- that ionic nickel is the carcinogenic species. Differences in the po- drate forms. The hexahydrate melts at 53.3°C and the heptahydrate tency of nickel compounds may relate to the specific properties of the at 99°C; both forms are available at greater than 99% purity. Nickel compounds that affect the availability of ionic nickel at target sites. carbonate occurs as light-green rhombic crystals. It is practically in- The listings of nickel compounds and metallic nickel are based on a soluble in water but soluble in dilute acids and ammonia. Laboratory large body of scientific evidence supporting the concept that nickel reagent grades contain 45% or 47.5% nickel, and industrial grades con- ion is carcinogenic. The hazard associated with a particular nickel tain approximately 45% nickel (IARC 1990, HSDB 2009). compound is related largely to the compound’s propensity to release Nickel carbonyl