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, authored by Salnikow and Zhitkovich (2008), comprehensively examined the genetic and epigenetic mechanisms of carcinogenesis and cocarcinogenesis caused by nickel (Ni), arsenic (As), and chromium (Cr). It focused on how these heavy metals exert carcinogenic effects not primarily through direct mutagenesis, but rather through epigenetic modifications, DNA repair inhibition, and activation of stress and hypoxic signaling pathways. The paper synthesizes evidence from epidemiological studies, in vitro and in vivo animal models, and mechanistic experiments to clarify how these persistent environmental pollutants contribute to cancer risk in exposed human populations.
Who was reviewed?
The review drew from multiple sources, including epidemiological cohorts of exposed workers (e.g., nickel refinery workers, populations consuming arsenic-contaminated water, and industrial workers exposed to Cr(VI)), experimental rodent and cell models, and translational human studies involving biomarker analysis. Humans exposed through occupational inhalation or environmental contamination, particularly populations in industrial regions and areas with arsenic-laced drinking water, were central to the evidence base. Laboratory models allowed the authors to probe cellular signaling, DNA methylation, and histone modifications, while clinical epidemiological studies confirmed carcinogenic risks at both occupational and environmental exposure levels.
Most important findings
| Mechanism/Exposure | Key Findings |
|---|---|
| Nickel (Ni) | Carcinogenic largely via epigenetic silencing (DNA methylation, histone modifications), not direct mutagenesis. Nickel exposure activates hypoxic signaling through HIF-1 stabilization, alters iron metabolism, and depletes ascorbate. Ni acts as a cocarcinogen by inhibiting DNA repair pathways, increasing susceptibility to other carcinogens. |
| Arsenic (As) | Cr(VI) is strongly linked to lung and nasal cancers in workers. Once inside cells, Cr(VI) is reduced to Cr(III), generating Cr-DNA adducts, DNA-protein crosslinks, and strand breaks. Ascorbate is a dominant reducer, paradoxically enhancing mutagenicity. Cr(VI) carcinogenesis is associated with microsatellite instability and loss of mismatch repair (MMR), resulting in a mutator phenotype. Even revised OSHA standards leave residual excess cancer risks. |
| Chromium (Cr, mainly Cr(VI)) | All three metals amplify the effects of other carcinogens by impairing DNA repair, stabilizing damaged DNA structures, and altering the process of apoptosis. These synergistic effects demonstrate that metal exposures can multiply risks from chemical or physical carcinogens. |
| Cocarcinogenesis (all metals) | All three metals amplify the effects of other carcinogens by impairing DNA repair, stabilizing damaged DNA structures, and altering apoptosis. These synergistic effects demonstrate that metal exposures can multiply risks from chemical or physical carcinogens. |
Key implications
This review has critical implications for the Heavy Metal Tested and Certified (HTMC) program. Evidence shows that even low-level chronic exposure to nickel, arsenic, and chromium poses carcinogenic risks via epigenetic changes and cocarcinogenesis. Certification should move beyond concentration limits to include biomarkers such as DNA methylation and histone modifications. Applications span nickel alloy industries, arsenic-contaminated water, and chromium-based manufacturing. Research gaps remain on dose-response, transgenerational effects, and nutrient interactions. Regulators should enforce stricter exposure limits, biomonitoring, and mechanistic biomarkers within HTMC standards to capture risks missed by conventional thresholds.
Citation
Salnikow K, Zhitkovich A. Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: Nickel, arsenic, and chromium.Chem Res Toxicol. 2008;21(1):28-44. doi:10.1021/tx700198a
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.
