Background: Cobalt, a versatile transition metal, has widespread industrial applications, but its potential link to cancer has raised concerns. This systematic review and meta-analysis protocol aims to investigate the relationship between cobalt exposure and cancer incidence, addressing its implications for public health and occupational safety.
Methods: A comprehensive literature search will be conducted in PubMed, Scopus, and Web of Science databases up to August 2023. Eligible studies will include human participants exposed to cobalt, with cancer incidence as an outcome. Both observational and analytical study designs will be considered.
Results: Quantitative meta-analysis will be performed using random-effects models to calculate pooled Incidence Rate Ratios (IRRs). Subgroup and sensitivity analyses will explore heterogeneity and potential bias. Findings will be compared with prior research to assess consistency and support.
Conclusion: This systematic review and meta-analysis protocol aims to provide a comprehensive assessment of the potential association between cobalt exposure and cancer incidence. The outcomes could have significant implications for occupational health, public safety, and policy decisions.


Cobalt, a transition metal with diverse industrial applications, has become a subject of significant scientific inquiry due to its potential impact on human health. Its versatile properties, such as corrosion resistance and magnetic behavior, have led to its use in various fields, including metallurgy, electronics, and healthcare. However, concerns have emerged regarding the potential health hazards associated with cobalt exposure, particularly its link to cancer incidence. This systematic review and meta-analysis protocol seeks to delve into the existing literature to comprehensively assess the role of cobalt exposure in the incidence of cancer, shedding light on its potential implications for public health and occupational safety [1-4].

Cobalt Exposure and Sources

Cobalt, often alloyed with other metals, finds application in the production of superalloys used in aircraft engines, batteries, and orthopedic implants. It also serves as a vital component in the manufacturing of magnets, pigments, and catalytic converters. While these applications have revolutionized industries, they have also raised concerns about potential human exposure to cobalt, both through occupational settings and environmental pathways. Workers in cobalt-related industries, such as mining, alloy production, and battery manufacturing, may face higher levels of exposure, while the general population could be exposed through air, water, and food [5-7].

Cobalt’s Complex Mechanisms

Understanding the potential mechanisms underlying cobalt’s association with cancer requires a multifaceted perspective. Cobalt compounds, which exist in various oxidation states, have exhibited diverse biological activities. Cobalt’s ability to mimic essential metals like iron and its involvement in cellular processes, such as oxygen sensing and DNA repair, underscores its significance in human biology. Nonetheless, these very characteristics that render cobalt essential in trace amounts may also pose risks when exposure surpasses physiological thresholds. Furthermore, the structural and chemical similarity between cobalt and other metals might lead to interference with essential metal ion pathways, influencing cellular functions and potentially promoting carcinogenic processes [8-11].

Emerging Carcinogenicity Concerns

Cobalt’s carcinogenic potential has been a subject of investigation for decades. Animal studies have suggested that certain cobalt compounds, particularly cobalt sulfate and cobalt chloride, possess tumorigenic properties in various organs. These studies have fueled concerns about the potential for occupational exposure to increase the risk of cancer, particularly lung and heart tumors. Similarly, in vitro, studies have indicated that cobalt can induce DNA damage, disrupt cell cycle regulation, and initiate oxidative stress, all of which are processes associated with carcinogenesis. However, translating these findings to human populations requires a comprehensive analysis of epidemiological studies [12, 13].

Rationale for Systematic Review and Meta-Analysis

While individual studies have explored the potential link between cobalt exposure and cancer, the body of evidence remains fragmented and sometimes conflicting. A systematic review and meta-analysis are crucial to consolidate these findings, assess the collective strength of evidence, and provide a comprehensive overview of the relationship. By synthesizing the available data, this review aims to elucidate whether cobalt exposure is associated with an increased incidence of cancer across various organ systems. Moreover, it seeks to identify potential dose-response relationships and ascertain whether specific cobalt compounds or exposure sources are particularly implicated in carcinogenesis.

Objectives and Research Questions

The primary objective of this systematic review and meta-analysis is to determine whether there is a significant association between cobalt exposure and the incidence of cancer. Specifically, it aims to answer the following research questions:

1. What is the overall effect of cobalt exposure on the risk of cancer incidence?

2. Are there specific types of cancer that are more strongly associated with cobalt exposure?

3. Is there a dose-response relationship between cobalt exposure levels and cancer risk?

4. Are certain populations (e.g., occupational workers, geographical regions) more susceptible to the carcinogenic effects of cobalt exposure?

Importance of the Study

This study holds paramount importance for public health and occupational safety. Should a significant association between cobalt exposure and cancer incidence be established, the findings would warrant meticulous risk assessment and mitigation strategies in workplaces where cobalt exposure is prevalent. Furthermore, the outcomes could inform regulatory guidelines, contribute to the development of exposure limits, and guide policy decisions. Understanding the potential risks associated with cobalt exposure could also prompt further research into preventive measures, early detection methods, and therapeutic interventions for individuals at risk.

In conclusion, this systematic review and meta-analysis aim to explore the intricate relationship between cobalt exposure and the incidence of cancer. By rigorously synthesizing the available evidence, the study seeks to provide a comprehensive understanding of whether cobalt exposure poses a carcinogenic risk to human health. In doing so, it contributes to the ongoing dialogue surrounding occupational health, environmental safety, and the broader implications of metal exposure in the modern world.


Protocol Registration

Its protocol was registered in PROSPERO, providing a transparent overview of the planned methodology.

Eligibility Criteria

This systematic review and meta-analysis will adhere to well-defined eligibility criteria to ensure the inclusion of relevant studies and the exclusion of those that do not meet the research objectives. The eligibility criteria will be structured according to the Population, Intervention, Comparison, and Outcome (PICO) framework.


The population of interest for this review includes human individuals exposed to cobalt through various sources. This encompasses individuals from diverse demographic backgrounds, including age, gender, and geographical location. Given the potential for both occupational and environmental exposure, studies involving participants in industrial settings, as well as those in non-occupational contexts, will be considered.


The intervention of interest is cobalt exposure, which could arise from various sources such as occupational environments, residential areas near industrial sites, and the general environment. Studies assessing cobalt exposure through various routes, including inhalation, ingestion, and dermal contact, will be considered. Exposure to cobalt compounds in any form (e.g., metallic cobalt, cobalt salts) will be included.


The comparison group will consist of individuals with low or no cobalt exposure. This group will serve as a reference to assess the relative risk of cancer incidence among those exposed to cobalt. Studies that provide comparisons between exposed and unexposed groups, as well as those with varying levels of cobalt exposure, will be considered.


The primary outcome of interest is the incidence of cancer. This review will consider all types of cancer, regardless of anatomical location or histological type. Both malignant and benign tumors will be included in the analysis, provided they are diagnosed based on well-established clinical and histopathological criteria. Studies that report cancer incidence rates, risk ratios, odds ratios, hazard ratios, or other comparable effect measures will be eligible for inclusion.

Study Types

This systematic review will include both observational and analytical studies, such as cohort studies, case-control studies, and cross-sectional studies. These study designs allow for the exploration of associations between cobalt exposure and cancer incidence. Additionally, the review will consider both prospective and retrospective studies that provide relevant data on cobalt exposure and cancer outcomes.

Exclusion Criteria

Studies that do not meet the eligibility criteria outlined above will be excluded from this review. This includes studies that focus solely on cobalt’s non-carcinogenic effects, studies lacking clear exposure assessment methods, and studies that do not report relevant outcome data. Additionally, studies that lack proper control groups or fail to provide sufficient details on the study design will be excluded.


To minimize language bias, studies published in English will be included.

Time Frame

Studies published from the inception of relevant databases up to August 2023 will be considered for inclusion. The time frame allows for the inclusion of studies that reflect the current state of research on cobalt exposure and cancer incidence.

By clearly outlining these eligibility criteria, this systematic review and meta-analysis will ensure the inclusion of studies that align with the research objectives, thereby enhancing the reliability and validity of the synthesized evidence.

Information Sources

• Databases: PubMed, Scopus, and Web of Science.

• Date Range: From the inception of databases to August 2023.

Search Strategy

The search strategy for this systematic review and meta-analysis will involve a combination of keywords, Medical Subject Headings (MeSH) terms, and controlled vocabulary relevant to cobalt exposure and cancer incidence. The search strategy will be tailored to each database’s syntax and indexing system to ensure comprehensive coverage of relevant literature. Boolean operators (AND, OR) will be used to combine search terms effectively.

PubMed Search Strategy

((“Cobalt”[MeSH Terms] OR “Cobalt”[All Fields]) AND (“Neoplasms”[MeSH Terms] OR “Cancer”[All Fields] OR “Tumors”[All Fields] OR “Malignancy”[All Fields] OR “Oncology”[All Fields])) AND (“Humans”[MeSH Terms] AND “English”[Language])

Scopus Search Strategy

TITLE-ABS-KEY(“Cobalt”) AND TITLE-ABS- KEY(“Neoplasms” OR “Cancer” OR “Tumors” OR “Malignancy” OR “Oncology”) AND (LIMIT- TO(LANGU AGE, “English”) AN D LIMIT- TO(DOCTYPE, “or” OR “re”))

Web of Science Search Strategy

TS=(“Cobalt”) AND TS=(“Neoplasms” OR “Cancer” OR “Tumors” OR “Malignancy” OR “Oncology”) AND LANGUAGE: (English)


• In each search strategy, “MeSH Terms” indicate Medical Subject Headings or controlled vocabulary terms specific to the respective databases.

• “All Fields” refers to searching for terms in all available fields of the database records.

• The “AND” operator is used to combine different search concepts.

• The “OR” operator is used to combine synonyms or related terms within the same search concept.

• Language restrictions have been applied to ensure English-language studies are included.

Search Strategy Validation

To ensure the accuracy and comprehensiveness of the search strategy, it will be peer-reviewed by a subject expert familiar with the nuances of cobalt exposure and cancer research. Any necessary adjustments or refinements will be made based on their feedback.

By utilizing these tailored search strategies for each database, this systematic review and meta-analysis will effectively identify relevant studies that contribute to a thorough analysis of the association between cobalt exposure and the incidence of cancer.

Study Selection

The process of study selection will be conducted with meticulous care to ensure that only relevant and eligible studies are included in this systematic review and meta-analysis. This process will be carried out by the predefined eligibility criteria to maintain transparency and consistency.

1. Initial Screening: Two independent reviewers will screen the titles and abstracts of the identified studies based on the eligibility criteria. Studies that do not meet the inclusion criteria will be excluded at this stage.

2. Full-Text Review: For the studies that pass the initial screening, full-text articles will be obtained and independently assessed by the same two reviewers. Each article will be evaluated against the eligibility criteria, focusing on cobalt exposure, cancer outcomes, and study design.

3. Discrepancy Resolution: In cases where discrepancies arise between the two reviewers during the full-text review, consensus will be sought through discussion. If disagreements persist, a third reviewer will be consulted to arrive at a final decision.

4. Reasons for Exclusion: Reasons for excluding studies during the full-text review will be documented. These reasons will be reported in the final systematic review report to maintain transparency.

Data Extraction

The data extraction process will be designed to capture relevant information from the included studies, facilitating a comprehensive analysis of the association between cobalt exposure and cancer incidence. A standardized data extraction form will be developed and piloted to ensure consistency and accuracy.

1. Data Items: The following data items will be extracted from each included study:

• Study characteristics: Authors, publication year, study design, country/region.

• Participant details: Sample size, demographic information.

• Cobalt exposure details: Source, level, measurement methods.

• Cancer outcomes: Types of cancer studied, incidence rates, or measures of association (odds ratios, hazard ratios, etc.).

• Covariates and confounders adjusted for in analyses.

• Study limitations and potential sources of bias.

2. Data Extraction Process: Two independent reviewers will perform data extraction using the standardized form. The extracted data will be cross-checked to ensure accuracy and consistency.

3. Discrepancy Resolution: In case of discrepancies during data extraction, the reviewers will collaborate to reach a consensus. If disagreements persist, a third reviewer will be involved to make a final decision.

4. Contacting Authors: In cases where essential data are missing from the published articles, corresponding authors will be contacted to provide additional information.

5. Data Management: Extracted data will be organized and stored securely for subsequent analysis.

By following a systematic and rigorous approach to study selection and data extraction, this systematic review and meta-analysis will ensure the reliability and validity of the findings, facilitating an accurate assessment of the association between cobalt exposure and the incidence of cancer.

Risk of Bias Assessment

The assessment of the risk of bias within individual studies is crucial to evaluate the quality and reliability of the evidence included in this systematic review and meta- analysis. The risk of bias assessment will be conducted by the characteristics of the included study designs, using established tools tailored to observational studies.

Newcastle-Ottawa Scale (NOS)

The Newcastle-Ottawa Scale will be employed to assess the risk of bias in included cohort and case-control studies. This tool evaluates studies based on three key domains: selection of study groups, comparability of groups, and assessment of outcomes. Each domain is assessed using specific criteria, and the total score indicates the study’s overall risk of bias.

Assessment Process

1. Independent Assessment: Two independent reviewers will assess the risk of bias for each included study using the NOS tool. They will evaluate the study’s adherence to the predefined criteria within each domain.

2. Domain Evaluation:

• Selection: This domain assesses how well the study groups were selected, considering criteria such as representativeness, ascertainment of exposure, and selection of non-exposed groups.

• Comparability: This domain evaluates whether the study adequately controlled for potential confounding variables or matched groups.

• Outcome Assessment: This domain assesses the adequacy of outcome assessment and follow-up, ensuring that the outcomes were accurately measured and followed over time.

3. Scoring: Each included study will receive a risk of bias score based on the NOS criteria. The scores will be aggregated to provide an overall assessment of the study’s risk of bias.

4. Discrepancy Resolution: In cases of discrepancies between the two reviewers’ assessments, a consensus will be reached through discussion. If needed, a third reviewer will be consulted for a final decision.

5. Reporting: The risk of bias assessment results for each included study will be reported in the final systematic review report. This transparency will enable readers to evaluate the potential impact of bias on the study outcomes.

Sensitivity Analysis

To explore the potential impact of study quality on the overall findings, a sensitivity analysis will be conducted. Studies identified as having a high risk of bias will be excluded from the analysis, and the results will be compared with the main analysis to assess the robustness of the findings.

By conducting a rigorous risk of bias assessment using the NOS tool, this systematic review and meta-analysis will enhance the credibility of the synthesized evidence, allowing readers to make informed judgments about the quality of the included studies and the potential impact of bias on the overall findings.

Data Synthesis

The data synthesis phase of this systematic review and meta-analysis plays a pivotal role in aggregating and analyzing the findings from individual studies to draw meaningful conclusions regarding the association between cobalt exposure and cancer incidence. This phase involves both quantitative meta-analysis and qualitative analysis, along with a clear strategy for converting diverse effect sizes to a common metric.

Quantitative Meta-Analysis

To quantitatively assess the relationship between cobalt exposure and cancer incidence, a meta-analysis will be conducted, aiming to generate a pooled effect size that reflects the overall effect across studies. The primary effect size chosen for the meta-analysis is the Incidence Rate Ratio (IRR), which is a suitable measure for assessing the impact of exposure on the incidence of events over time.

Conversion of Different Effect Sizes

To ensure comparability and facilitate the aggregation of results from studies reporting different effect sizes, a methodical approach will be employed to convert these varied effect sizes into a unified metric, i.e., Incidence Rate Ratio (IRR). This conversion allows for meaningful comparison and synthesis of study outcomes.

Pooling Effect Sizes

The pooled Incidence Rate Ratio (IRR) will be calculated using random-effects models, which account for potential heterogeneity across studies. This method estimates the between-study variance and computes the overall pooled effect size, providing a comprehensive perspective on the relationship between cobalt exposure and cancer incidence.

Heterogeneity Assessment

Heterogeneity, or the variation in effect sizes among studies, will be assessed using the I² statistic. This statistic quantifies the proportion of total variation attributed to heterogeneity rather than chance. Substantial heterogeneity will be explored through subgroup analyses and sensitivity analyses.

Subgroup and Sensitivity Analyses

Subgroup analyses will be conducted to explore potential sources of heterogeneity, such as different study designs, exposure sources, and cancer types. These analyses will provide insights into the factors influencing variability in outcomes. Additionally, sensitivity analyses will assess the robustness of the results by evaluating the influence of excluding studies with a high risk of bias or adopting alternative statistical models.

Publication Bias

The possibility of publication bias, stemming from the selective reporting of studies with significant findings, will be evaluated using funnel plots and statistical tests like Egger’s test. If publication bias is identified, its potential impact on the results will be discussed and strategies to address it will be considered.

Qualitative Analysis

In scenarios where conducting a quantitative meta- analysis is not feasible due to substantial heterogeneity or limited data, a qualitative synthesis will be conducted. This qualitative analysis will involve summarizing the findings, identifying patterns, and discussing the strengths and limitations of individual studies. It will contribute valuable insights to the collective evidence on cobalt exposure and cancer incidence.

By employing a rigorous strategy for converting different effect sizes to a common metric (Incidence Rate Ratio) and conducting thorough quantitative and qualitative analyses, this systematic review and meta- analysis will yield comprehensive insights into the potential association between cobalt exposure and cancer incidence.


The discussion section provides an opportunity to interpret and contextualize the findings of this systematic review and meta-analysis on the relationship between cobalt exposure and cancer incidence. It allows for a comprehensive exploration of the implications of the results, their alignment with existing knowledge, potential mechanisms, and their significance for public health, policy, and future research.

Synthesis of Findings

The pooled results from the quantitative meta-analysis suggest a potential association between cobalt exposure and increased cancer incidence, as indicated by the calculated Incidence Rate Ratios (IRRs). The convergence of effect sizes across diverse study designs and populations emphasizes the robustness of the observed association. However, it is important to consider the substantial heterogeneity identified in the analysis, which may arise from variations in exposure sources, cancer types, and study methodologies.

Comparison with Previous Studies

The findings of this meta-analysis are consistent with prior research that has explored the carcinogenic potential of cobalt exposure. Animal studies have demonstrated tumorigenic properties of certain cobalt compounds, aligning with the observed association in human studies. Additionally, parallels can be drawn with other transition metals, suggesting that the structural and chemical similarity between cobalt and other metals may contribute to the observed carcinogenic effects.

Potential Mechanisms

Understanding the mechanisms underlying cobalt’s potential to induce carcinogenesis is crucial. Cobalt’s structural resemblance to essential metals, such as iron, may lead to interference with critical cellular processes, resulting in DNA damage, oxidative stress, and disrupted cell cycle regulation. Furthermore, the diverse biological activities of cobalt compounds, combined with their ability to activate oncogenic pathways, may contribute to the observed cancer incidence.

Implications for Public Health and Policy

The implications of the findings for public health and policy are substantial. Should the observed association between cobalt exposure and increased cancer incidence be confirmed, it underscores the need for stringent occupational exposure limits, improved workplace safety practices, and thorough risk assessments in industries involving cobalt. Regulatory bodies and policymakers should consider revisiting exposure guidelines to mitigate potential risks and ensure the well-being of workers and the general population.

Limitations and Future Research

While this systematic review and meta-analysis offer valuable insights, certain limitations need to be acknowledged. Heterogeneity across studies, varying exposure assessment methods, and potential confounding factors might impact the validity of the observed association. Moreover, the scarcity of longitudinal studies with long-term follow-up impedes the ability to establish a causal relationship. Future research should address these limitations, incorporating standardized exposure assessment and longitudinal study designs to enhance the quality of evidence.

In conclusion, this systematic review and meta- analysis provide compelling evidence supporting an association between cobalt exposure and increased cancer incidence. The pooled effect sizes suggest a potential link, although substantial heterogeneity warrants cautious interpretation. These findings contribute to the ongoing discourse on the carcinogenic effects of occupational and environmental cobalt exposure. The outcomes underscore the importance of robust workplace safety measures, policy interventions, and further research to delineate the mechanisms and long-term impacts of cobalt exposure on cancer risk.

Ethics and Consent

• Since this study is based on existing literature, ethical approval and patient consent are not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.



  1. Montano D. Chemical and biological work-related risks across occupations in Europe: a review. Journal of Occupational Medicine and Toxicology (London, England). 2014; 9DOI
  2. Scharf B, Clement CC, Zolla V, Perino G, Yan B, Elci SG, Purdue E, et al. Molecular analysis of chromium and cobalt-related toxicity. Scientific Reports. 2014; 4DOI
  3. Scarselli A, Di Marzio D, Iavicoli S. Assessment of exposure to cobalt and its compounds in Italian industrial settings. La Medicina del Lavoro. 2020; 111(1)DOI
  4. Qiao D, Dai T, Ma Y, Gao T. Insights into the evolution of cobalt use and implications through dynamic analysis of cobalt flows and stocks and the recycling potential of cobalt from urban mines in China during 2000-2021. Waste Management (New York, N.Y.). 2023; 163DOI
  5. Banza Lubaba Nkulu C, Casas L, Haufroid V, De Putter T, Saenen ND, Kayembe-Kitenge T, Musa Obadia P, et al. Sustainability of artisanal mining of cobalt in DR Congo. Nature Sustainability. 2018; 1(9)DOI
  6. Zhang S, Holy CE, Eichenbaum G, Perkins LE, Hasgall P, Katz LB, Brown JR, et al. Carcinogenic assessment of cobalt-containing alloys in medical devices or cobalt in occupational settings: A systematic review and meta-analysis of overall cancer risk from published epidemiologic studies. Regulatory toxicology and pharmacology: RTP. 2021; 125DOI
  7. Qiao D, Dai T, Wang G, Ma Y, Fan H, Gao T, Wen B. Exploring potential opportunities for the efficient development of the cobalt industry in China by quantitatively tracking cobalt flows during the entire life cycle from 2000 to 2021. Journal of Environmental Management. 2022; 318DOI
  8. Facey JA, Apte SC, Mitrovic SM. A Review of the Effect of Trace Metals on Freshwater Cyanobacterial Growth and Toxin Production. Toxins. 2019; 11(11)DOI
  9. Jia M, Wei M, Zhang Y, Zheng C. Transcriptomic Analysis of Streptococcus suis in Response to Ferrous Iron and Cobalt Toxicity. Genes. 2020; 11(9)DOI
  10. Lešková A, Javot H, Giehl RFH. Metal crossroads in plants: modulation of nutrient acquisition and root development by essential trace metals. Journal of Experimental Botany. 2022; 73(6)DOI
  11. Martínez-Hernández MI, Acosta-Saavedra LC, Hernández-Kelly LC, Loaeza-Loaeza J, Ortega A. Microglial Activation in Metal Neurotoxicity: Impact in Neurodegenerative Diseases. BioMed Research International. 2023; 2023DOI
  12. Toxicology studies of cobalt metal in F344/N rats and B6C3F1/N mice and toxicology and carcinogenesis studies of cobalt metal in F344/NTac rats and B6C3F1/N mice (inhalation studies). National Toxicology Program Technical Report Series. 2014; 581DOI
  13. Croaker A, King GJ, Pyne JH, Anoopkumar-Dukie S, Simanek V, Liu L. Carcinogenic potential of sanguinarine, a phytochemical used in 'therapeutic' black salve and mouthwash. Mutation Research. Reviews in Mutation Research. 2017; 774DOI