Skin cancers can be categorized into two main groups: cutaneous malignant melanoma and non-melanoma skin cancer (NMSC). NMSC, predominantly formed of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), is the most commonly identified cancer, making up approximately one-third of all malignant tumors diagnosed globally each year.1,2 BCC represents almost 80% of all NMSC cases detected each year,3 with SCC making up the remaining 20%.4,5 Melanoma, an aggressive type of skin cancer arising from melanocytes, accounts for under 5% of all skin cancer cases but poses a substantial threat. If left untreated, melanoma, responsible for 75% of all deaths related to skin cancer, has the ability to metastasize to different areas of the body.6,7 Collectively, melanoma and NMSC impose a substantial economic and health burden, which is anticipated to keep increasing in the future.

Arsenic has been used as a medicine (Fowler's solution) for the treatment of syphilis, malaria and psoriasis for the past two centuries.8 However, after 30-years of treatment, patients developed multiple skin cancers.9 Subsequent research has progressively demonstrated that long-term chronic exposure to arsenic can result in a range of cancers, including skin, lung,10,11 and, to a lesser extent, liver, kidney, and bladder cancers.12–14 Consequently, many arsenic-containing drugs have been restricted or phased out entirely. The International Agency for Research on Cancer (IARC) classifies arsenic as a Group I human carcinogen.15 Nonetheless, Arsenic is commonly found in soils, sediments, and groundwater, either occurring naturally or as a result of human activities such as food preparation, industrial processes, mining and pesticide use. Humans can be exposed to arsenic through various pathways.16 According to recommendations from the World Health Organization (WHO), the level of arsenic in drinking water should not exceed 10 μg/L.17 However, this guideline is often increased to 50 μg/L in numerous developing nations.18 Globally, more than 100 million individuals are at risk of consuming arsenic levels over 50 μg/L in their drinking water.19 Average dietary exposure to inorganic Arsenic (iAs) ranges from 0.1 to 3.0 μg/kg per day in Europe, Asia, and the United States.20 The National Research Council (NRC) Risk Assessment from 2001 suggests that even exposure to lower concentrations of arsenic poses a relatively high risk of cancer.21

Extensive research has been conducted on the association between exposure to arsenic and NMSC.22–28 Multiple epidemiological investigations have established a association between exposure to arsenic and a heightened likelihood of developing NMSC in different locations such as Taiwan, Mexico, Bangladesh, and Chile.29–31 Research in Taiwan31,32 revealed a significant dose-response relationship for this association, while other studies did not observe such an effect.23,25,26,28 Conversely, research on the potential association between melanoma and exposure to arsenic has yielded divergent findings.22,33–38 While some studies indicate a possible association between arsenic exposure and a heightened likelihood of developing skin cancer, the definitive nature of this link is still debated. To investigate this potential association more thoroughly, a meta-analysis was carried out to systematically review existing data concerning arsenic exposure and its association to skin cancer, encompassing both melanoma and non-melanoma cases.

This groundbreaking meta-analysis is the initial study to investigate the association between exposure to arsenic and the likelihood of developing skin cancer, encompassing both melanoma and non-melanoma varieties. Firstly, the research examined 12 papers, comprising prospective and case-control studies involving 48,003 participants, offering some evidence of an association between exposure to arsenic and a heightened likelihood of developing skin cancer. Secondly, the quantification of arsenic exposure in the reviewed literature presents distinct advantages, such as the precise identification of biomarkers, including arsenic concentrations in water, urine, and toenails. Additionally, the use of semi-quantitative three-level scales (low, medium, high) for quantification enhances the research potential of the data. Thirdly, previous studies that did not meet the authors’ criteria also supported these findings. For example, one study showed a significant association between inorganic Arsenic (iAs) and BCC, even at average water iAs concentrations below 40 ug/L.45 A separate investigation conducted in the United States revealed a 1.5 times increased likelihood of developing SCC due to exposure to arsenic in rice, in contrast to individuals who did not consume rice.46 Moreover, research carried out in Bangladesh through a cohort study established a direct association between the levels of arsenic in water and the occurrence of melanoma, BCC and SCC.47 In a meta-analysis, Shuai et al.48 found that arsenic exposure was associated with an increased risk of melanoma, with a pooled OR of 1.47 (95% CI 1.01–2.13). The results from previous studies, along with the meta-analysis, consistently indicate the possibility of a positive association between exposure to arsenic and the heightened risk of melanoma, BCC, and SCC. Additionally, the assessment using funnel plots and Begg's test did not show any significant evidence of small study effects. Subgroup and sensitivity analyses consistently indicated strong correlations.

The present study has several limitations. In the meta-analysis, the authors observed a notable degree of heterogeneity, which remained evident even following subgroup and sensitivity analyses. While such variability is not uncommon in similar studies, it is likely rooted in underlying differences across the literature, including population characteristics, adjustments for confounding variables, methodologies for determining outcomes, and approaches to assessing exposure. Due to the restricted quantity of research papers accessible, the authors were unable to perform stratified examinations according to levels of exposure to arsenic in the urine, arsenic in water, or exposure in the workplace. Additionally, combined estimates of arsenic concentrations across different exposure media may result in misclassification of exposure. Self-reported assessments through questionnaires are susceptible to memory bias, while data from biological samples, water, or air analysis may be subject to inaccuracies, potentially affecting the reliability of the association between arsenic exposure and the risk of developing skin cancer. Ultimately, personal protection measures, skin type, population mobility, and socioeconomic factors also represent significant potential confounding variables. The accuracy of a meta-analysis is contingent upon the quality of the underlying research. In case-control studies, key issues such as recall bias, varying measurement criteria, and residual confounders contribute to the risk of bias. While literature quality assessments and bias risk evaluations indicate that most studies have made adjustments for potential bias-inducing factors, the findings of meta-analyses may still be influenced. Due to the lack of high-quality studies that can effectively control for these bias factors, and because the results of studies with small sample sizes or statistical insignificance are often not easy to publish, the results of meta-analyses may still be affected and tend to report positive results. Therefore, the authors must be cautious in interpreting these results.

The precise molecular mechanisms involved in arsenic carcinogenesis are still being actively researched. It is widely acknowledged that arsenic exerts its toxicity through various pathways, such as inducing oxidative stress,49 immune dysfunction,50 genotoxicity,51 impairing DNA repair,10,52 and disrupting signal transduction.53 It is believed that these procedures play a crucial role in the formation of skin cancer following arsenic exposure.

Arsenic triggers oxidative stress through the upregulation of Nicotinamide Adenine Dinucleotide Phosphate Oxidase (NADPHO), which results in the production of Reactive Oxygen Species (ROS). These ROS disturb the equilibrium of nitric oxide and glutathione, essential antioxidants, and affect other proteins responsible for redox homeostasis.49,54 The formation of ROS triggers the activation of transcription factors like AP-1 and NF-κB, resulting in the excessive production of pro-inflammatory factors, which can enhance cell proliferation and potentially initiate carcinogenesis.55

Arsenic exposure activates the unfolded protein response signaling pathway, which impairs both innate and adaptive immunity by reducing immune cell function and number, creating a microenvironment conducive to tumor development.51 Within cells, arsenic metabolism involves key enzymes like Adenine nucleoside Methionine (SAM). Depletion of SAM due to arsenic-induced ROS leads to the methylation of inorganic arsenic into methylated forms. These methylated arsenic compounds further deplete SAM and can methylate DNA in an unregulated fashion, altering intracellular gene expression and potentially promoting carcinogenesis.51,56 Additionally, arsenic disrupts cellular DNA repair mechanisms, such as base excision, mismatch repair and nucleotide excision, mainly by interfering with ATP and interacting with complexes likepoly-ADP ribose polymerase, O6-methyl-guanine-DNA methyltransferase and DNA polymerase β.10,52 Impairment of these repair pathways may compromise genomic stability and disrupt normal cancer-related gene expression. Recent research indicates that arsenic triggers the Hippo pathway, which is critical for the survival and growth of cells. Arsenic modulates Hippo pathway activity by upregulating key proteins like Large Tumor Suppressor Kinase 1/2 (LATS1), Salvador homologue-1 (Sav1) and ste20-like kinase 1/2 (Mst1), which are known to play roles in various cancers, including skin cancer.53,57

This study demonstrates an association between arsenic exposure and the risk of skin cancer (both melanoma and non-melanoma), regardless of the exposure route ‒ whether through inhalation, ingestion, or dermal contact. This finding could have significant implications for patient education initiatives, enhancing public awareness of skin cancer prevention and consequently reducing both its health and economic burdens. Furthermore, it may serve as a valuable reference for professionals involved in mitigating occupational exposure. However, the study's limitations highlight the need for future research. There is a clear necessity for more rigorous prospective studies that can better control potential confounding variables to understand the precise impact of arsenic on skin cancer risk. Additionally, evaluating the response to different doses will provide a more robust scientific basis for creating regulations on arsenic levels in a variety of sources, including drinking water, soil, air, and food. Drawing from the latest studies, the authors’ recommendation is to initiate proactive measures aimed at not only validating arsenic as a contributing element to skin cancer but also crafting successful preventative tactics for areas plagued by chronic arsenic exposure.

Lijiao He: 0009-0004-7736-7342

Meiying Wei: 0009-0002-6913-8027

Qikui Yang: 0009-0009-1511-2199

Yun Huang: 0009-0005-1781-710X

Zuyuan Wei: 0009-0004-2411-3437

None declared.

Lijiao He: Conceptualization; methodology; software; investigation; formal analysis; writing-original draft.

Meiying Wei: Data curation; software; validation.

Qikui Yang: Visualization.

Yun Huang: Software; validation.

Zuyuan Wei: Conceptualization; supervision; writing-review & editing.

None declared.