Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. 
Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. What was reviewed?
This review article, Carcinogenicity Assessment of Selected Nickel Compounds (Oller, Costa, & Oberdörster, 1997), systematically examined human epidemiological studies, animal inhalation studies, and in vitro experiments to clarify the carcinogenic potential of three representative nickel compounds: nickel subsulfide (Ni₃S₂), high-temperature green nickel oxide (NiO), and nickel sulfate hexahydrate (NiSO₄·6H₂O). The authors integrated toxicological, mechanistic, and epidemiological evidence into a unified model explaining how different nickel species produce distinct carcinogenic outcomes depending on solubility, bioavailability, and capacity to induce genetic or epigenetic alterations.
Who was reviewed?
The review synthesized findings from diverse cohorts of approximately 140,000 nickel industry workers across the United States, Canada, England, Wales, Norway, Finland, and New Caledonia. It also incorporated multiple animal models (rats, mice, and hamsters) tested in long-term inhalation bioassays by the National Toxicology Program (NTP) and other laboratories, alongside cellular and molecular data from in vitro assays of DNA damage, transformation, and oxidative stress. Regulatory bodies such as IARC, EPA, and ACGIH were also considered for their differing classifications of nickel compounds.
Most Important Findings
| Compound | Findings |
|---|---|
| Nickel subsulfide (Ni₃S₂) | Strong evidence of carcinogenicity in rats exposed by inhalation, producing dose-dependent lung tumors. Rats were consistently more susceptible than mice or hamsters. Mechanistically, Ni₃S₂ dissolves inside cells, efficiently delivering Ni²⁺ ions to the nucleus, leading to epigenetic silencing of tumor suppressor genes and induction of chromosomal aberrations. Human cohort studies linked high-level exposure (>10 mg Ni/m³) to lung and nasal cancers in refinery workers. |
| High-temperature nickel oxide (green NiO) | Weak to moderate evidence of carcinogenicity, primarily in rats. Tumor development correlated with impaired particle clearance, chronic inflammation, and macrophage activation rather than direct genotoxicity. NiO has very low solubility, making Ni²⁺ less bioavailable. Carcinogenic effects may appear only at high, overtly toxic exposures, suggesting a possible threshold. Human data indicated increased respiratory cancers in workers exposed to oxidic nickel dust at high levels. |
| Nickel sulfate hexahydrate (NiSO₄·6H₂O) | No carcinogenic activity detected in long-term inhalation studies in rats or mice, despite causing noncancerous lung inflammation, fibrosis, and hyperplasia. Soluble nickel enters cells inefficiently in vivo, is rapidly cleared, and fails to reach nuclear DNA in sufficient concentrations. Nonetheless, NiSO₄ can stimulate cell proliferation and may enhance the carcinogenic effects of insoluble nickel compounds or other co-exposures. Epidemiological evidence for soluble nickel alone was inconsistent, with risk possibly attributable to mixed exposures. |
Key implications
For regulatory frameworks such as the Heavy Metal Tested and Certified (HTMC) program, this review highlights the necessity of compound-specific assessment rather than treating all nickel species as equivalent. Nickel subsulfide should be prioritized as a confirmed human carcinogen with stringent exposure limits. High-temperature nickel oxide presents risk only at concentrations causing chronic lung inflammation, suggesting a threshold effect. Nickel sulfate hexahydrate is not independently carcinogenic but may act as a promoter in mixed exposures, requiring careful monitoring in occupational environments. Research gaps include understanding particle size effects, synergistic interactions, and species differences in susceptibility. Practically, certification programs must mandate speciation data, particle characterization, and biological markers of exposure to strengthen regulatory accuracy and worker protection.
Citation
Oller AR, Costa M, Oberdörster G. Carcinogenicity assessment of selected nickel compounds.Toxicol Appl Pharmacol. 1997;143(1):152-166. doi:10.1006/taap.1996.8075.
Nickel is a widely used transition metal found in alloys, batteries, and consumer products that also contaminates food and water. High exposure is linked to allergic contact dermatitis, organ toxicity, and developmental effects, with children often exceeding EFSA’s tolerable daily intake of 3 μg/kg bw. Emerging evidence shows nickel crosses the placenta, elevating risks of preterm birth and congenital heart defects, underscoring HMTC’s stricter limits to safeguard vulnerable populations.
