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, “Metals and molecular carcinogenesis” by Zhu and Costa (2020), comprehensively examines the molecular mechanisms by which specific heavy metals contribute to carcinogenesis. The authors focus on Group 1 carcinogenic metals as classified by the International Agency for Research on Cancer (IARC): arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr), and nickel (Ni). Through an extensive synthesis of epidemiological, experimental, and mechanistic studies, the review explores how these metals induce cancer via genotoxic, epigenetic, and cellular signaling pathways. Key molecular mechanisms include DNA repair inhibition, chromosomal instability, oxidative stress, DNA methylation changes, histone modifications, microRNA dysregulation, competition with essential metal ions, and interference with cancer-related signaling networks. The review also highlights the relevance of exposure routes (occupational, environmental, dietary) and discusses emerging concepts such as metal-induced suppression of autophagy and carcinogenesis through histone variant imbalances.
Who was reviewed?
The reviewed literature encompasses a wide range of human epidemiological studies, in vivo animal models, and in vitro cellular and molecular research. Human subjects include populations exposed to heavy metals through contaminated drinking water, industrial workplaces, and food sources, as well as individuals with genetic susceptibilities to metal toxicity (e.g., HLA-DP alleles in beryllium exposure). Animal studies include rodents and primates experimentally exposed to metals to evaluate toxicity and carcinogenicity. Cell-based studies utilize various primary and immortalized cell lines to dissect the molecular events underpinning metal-induced carcinogenesis. The review also integrates genetic, epigenetic, and biochemical investigations to elucidate both general and metal-specific carcinogenic pathways.
Most important findings
The review identifies both shared and unique mechanisms by which arsenic, beryllium, cadmium, chromium, and nickel induce carcinogenesis:
| Metal | Key Carcinogenic Mechanisms |
|---|---|
| Arsenic | Inhibits DNA repair, induces chromosomal instability, generates ROS; alters DNA methylation, histones, microRNAs; SLBP depletion → histone mRNA errors (shared with Cd & Ni). |
| Beryllium | Immune-mediated hypersensitivity → CBD, lung granulomas; HLA-DP Glu69 susceptibility; limited genotoxicity in vivo; animal carcinogenicity stronger. |
| Cadmium | ROS generation, DNA repair inhibition, metalloestrogen activity; zinc displacement → transcription/DNA repair disruption; epigenetic changes → tumor suppressor silencing. |
| Chromium (Cr(VI)) | Enters cells → Cr(III) → DNA adducts/crosslinks; ROS generation; DNA/histone methylation & acetylation changes; silences repair/tumor suppressor genes. |
| Nickel | Insoluble particulates release Ni²⁺; mimics hypoxia via HIF-1α stabilization; epigenetic effects: chromatin condensation, gene silencing, histone deacetylation, altered non-coding RNA. |
| Shared | Oxidative stress, metal ion displacement, autophagy suppression; protective agents: selenium, curcumin, sulforaphane. |
Key implications
For heavy metal certification programs such as HTMC, this review emphasizes the complex, multifaceted carcinogenic mechanisms of Group 1 metals. Regulatory standards should address not only acute toxicity but also chronic, low-dose exposures that produce cumulative genotoxic and epigenetic effects. Rigorous evaluation of both soluble and insoluble metal forms, alongside consideration of genetic susceptibility (e.g., HLA alleles for beryllium), is essential. Risk assessments should integrate molecular biomarkers, including DNA methylation, histone modifications, and microRNA alterations. Current permissible exposure limits may require reassessment in light of epigenetic and autophagy-related effects, which can occur at sub-toxic doses. Future frameworks should also consider mixed-metal exposures. These insights can guide the development of more sensitive, mechanism-informed testing protocols for certification and public health protection.
Citation
Zhu, Y., & Costa, M. (2020). Metals and molecular carcinogenesis. Carcinogenesis, 41(9), 1161–1172. https://doi.org/10.1093/carcin/bgaa076
Cadmium is a persistent heavy metal that accumulates in kidneys and bones. Dietary sources include cereals, cocoa, shellfish and vegetables, while smokers and industrial workers receive higher exposures. Studies link cadmium to kidney dysfunction, bone fractures and cancer.
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.
