Peer Review: Chlorine Dioxide: A Potential Gaseous Bactericide and Its Application in Food and Biomedical Industries

Peer Review: Chlorine Dioxide: A Potential Gaseous Bactericide and Its Application in Food and Biomedical Industries

Overview

The article by Shi et al. (2022) reviews the antimicrobial properties of chlorine dioxide (ClO2) gas and its applications in food preservation and biomedical contexts, including sterilization and potential therapeutic uses. The authors compile data from various studies to highlight ClO2’s efficacy against bacteria, fungi, and viruses, emphasizing its advantages (e.g., broad-spectrum activity, low residue) and limitations (e.g., corrosiveness, toxicity). While the review provides a useful overview of ClO2’s applications, it suffers from significant methodological and interpretive flaws, including the omission of critical chemical parameters like oxidation-reduction potential (ORP), inappropriate comparisons between environmental and physiological conditions, and a lack of critical analysis of safety data. These issues undermine the article’s scientific rigor and applicability to biomedical contexts.

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Strengths

1. Comprehensive Scope: The review covers a wide range of ClO2 applications, from food safety (e.g., fruit preservation, poultry processing) to biomedical uses (e.g., sterilization, oral hygiene), making it a valuable resource for interdisciplinary researchers.
2. Mechanistic Insights: The article provides a detailed explanation of ClO2’s antimicrobial mechanisms, including disruption of cell membranes, inhibition of protein synthesis, and oxidative damage to DNA/RNA. This enhances the understanding of its efficacy.
3. Acknowledgment of Limitations: The authors note practical challenges, such as ClO2’s corrosiveness, instability, and potential toxicity at high concentrations, which provides some balance to the discussion.
4. Literature Synthesis: The review cites a broad range of studies (e.g.,,,,,) to support claims about ClO2’s efficacy, demonstrating an effort to integrate existing research.

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Major Concerns and Methodological Issues

1. Omission of Oxidation-Reduction Potential (ORP)

The article fails to address the role of oxidation-reduction potential (ORP) in ClO2’s antimicrobial activity, particularly in physiological contexts. This is a significant oversight for the following reasons:

• Critical Parameter: ORP is a key determinant of ClO2’s oxidative capacity, which drives its antimicrobial effects. In the body, ORP is tightly regulated (e.g., -200 to +200 mV in cellular environments) and varies significantly between tissues (e.g., blood, gut, skin). The article does not discuss how physiological ORP affects ClO2’s efficacy or stability.
• Impact on Biomedical Claims: The review suggests ClO2’s potential for biomedical applications (e.g., oral rinses, wound treatment) without considering how the body’s redox environment might neutralize or enhance ClO2’s activity. For example, high levels of reducing agents (e.g., glutathione, ascorbic acid) in tissues could quench ClO2, reducing its efficacy.
• Recommendation: The authors should include a discussion of ORP, referencing studies that measure ClO2’s oxidative potential in physiological conditions (e.g., simulated body fluids). They should also address how ORP variations in vivo might limit or alter ClO2’s antimicrobial effects compared to in vitro or environmental settings.

2. Inappropriate Comparison of Physiological and Wastewater Conditions

The article frequently draws parallels between ClO2’s efficacy in wastewater treatment and its potential in biomedical applications, which is problematic:

• Issue: The chemical environment of wastewater (e.g., high organic load, variable pH, and presence of chemical sludge) is vastly different from the human body (e.g., buffered pH ~7.4, complex redox systems, and enzymatic activity). For instance, Section 4.2 cites wastewater studies to support ClO2’s antimicrobial efficacy but does not acknowledge that these conditions are not comparable to physiological settings.
• Impact: This comparison overstates ClO2’s applicability to biomedical contexts. Wastewater studies often use high ClO2 concentrations (e.g., 10–100 ppm) that would be toxic in vivo. The article fails to address how factors like blood proteins, mucus, or tissue antioxidants might interact with ClO2, potentially reducing its efficacy or generating harmful byproducts (e.g., chlorite, chlorate).
• Recommendation: The authors should clearly delineate environmental and physiological applications, avoiding direct comparisons. They should include data from studies conducted in biologically relevant conditions (e.g., cell cultures, animal models) to support biomedical claims and discuss potential interactions with bodily components.

3. Lack of Critical Safety Analysis

• Issue: While the article mentions ClO2’s toxicity risks (e.g., respiratory irritation, cytotoxicity at high concentrations), it does not critically evaluate safety data for biomedical applications. For example, Section 5.2 discusses ClO2’s use in oral rinses and wound sprays but cites studies with limited safety assessments (e.g., small sample sizes, short-term exposure). No mention is made of long-term toxicity, systemic absorption, or potential carcinogenic effects of ClO2 byproducts (e.g., chlorite).
• Recommendation: Include a dedicated section on ClO2’s toxicology, summarizing data on acute and chronic effects, safe concentration ranges

4. Inadequate Discussion of ClO2 Stability and Delivery

• Issue: The article does not adequately address ClO2’s chemical instability (e.g., volatility, photodegradation, reactivity with organic matter), which is critical for its practical application. For example, Section 3 mentions ClO2’s advantages over chlorine but does not discuss challenges in maintaining stable concentrations in gaseous or aqueous forms, especially in complex environments like the body or food matrices.
• Impact: Without addressing stability, the review overestimates ClO2’s feasibility for applications like wound sprays or food preservation. For instance, ClO2’s rapid decomposition in the presence of organic matter (e.g., blood, food residues) could reduce its efficacy or require frequent reapplication, which is not discussed.
• Recommendation: Include a section on ClO2’s chemical stability, discussing factors like pH, temperature, and organic load. Provide examples of delivery systems (e.g., stabilized aqueous solutions, controlled-release gels) that mitigate instability, with references to relevant studies.

5. Overreliance on In Vitro and Environmental Data

• Issue: The review heavily relies on in vitro and environmental studies (e.g., wastewater, surface disinfection) to support claims about ClO2’s biomedical potential, with limited reference to in vivo or clinical data. For example, Section 5.2 cites in vitro studies on ClO2’s antiviral effects but includes only one small-scale human study on oral rinses.
• Impact: This limits the generalizability of the findings to biomedical contexts, where factors like tissue penetration, systemic clearance, and immune responses play significant roles. The lack of clinical data undermines the article’s claims about ClO2’s “promising” therapeutic potential.
• Recommendation: Prioritize in vivo and clinical studies to support biomedical applications. Where such data are lacking, acknowledge this as a research gap and call for further investigation rather than extrapolating from in vitro results.

6. Methodological Gaps in Cited Studies

• Issue: The review does not critically evaluate the quality of cited studies. For example, some referenced studies (e.g.,,,,,) use inconsistent ClO2 concentrations, lack controls, or employ non-standardized methods for measuring antimicrobial efficacy. The article presents these findings uncritically, without discussing methodological limitations.
• Impact: This reduces the reliability of the review’s conclusions, as the synthesized data may be based on flawed or incomparable studies. For instance, MIC values for ClO2 vary widely across studies, but no attempt is made to explain these discrepancies.
• Recommendation: Critically assess the methodology of cited studies, noting limitations such as small sample sizes, lack of controls, or inconsistent ClO2 measurement. Use this to contextualize findings and highlight areas for methodological improvement.

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Minor Concerns

1. Clarity and Organization: The article is verbose and could be more concise, particularly in Sections 3 and 4, which repeat points about ClO2’s advantages. Subheadings are not always clearly defined, making it difficult to follow transitions between topics (e.g., from food to biomedical applications).
2. Figure and Table Quality: Figures (e.g., Figure 1 on ClO2’s antimicrobial mechanism) are simplistic and lack quantitative data. Tables summarizing applications (e.g., Table 1) could include more details, such as specific ClO2 concentrations or exposure times.
3. Citation Precision: Some citations are vague or outdated. For example, references to early studies on ClO2’s use in water treatment (e.g., 1970s) could be supplemented with more recent data to reflect current practices.

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Overall Assessment

The review by Shi et al. (2022) provides a broad overview of ClO2’s antimicrobial properties and applications, but its scientific rigor is compromised by significant flaws. The omission of ORP as a critical parameter, inappropriate comparisons between wastewater and physiological conditions, and lack of critical safety analysis are particularly concerning, as they undermine the article’s relevance to biomedical applications. Additional issues, such as reliance on in vitro data, inadequate discussion of ClO2 stability, and uncritical use of cited studies, further weaken the manuscript. While the topic is timely and relevant, the review fails to provide a balanced, evidence-based synthesis.

Recommendations for Revision

1. Incorporate ORP: Discuss the role of ORP in ClO2’s antimicrobial activity, particularly in physiological contexts, with references to studies in relevant conditions.
2. Avoid Inappropriate Comparisons: Clearly separate environmental and biomedical applications, using biologically relevant data to support therapeutic claims.
3. Strengthen Safety Analysis: Include a comprehensive discussion of ClO2’s toxicology, with data on safe concentrations, long-term effects, and byproduct risks.
4. Address Stability: Detail ClO2’s chemical instability and propose solutions for maintaining efficacy in practical applications.
5. Prioritize Clinical Data: Emphasize in vivo and clinical studies, acknowledging gaps where data are lacking.
6. Critique Cited Studies: Evaluate the quality of referenced studies, noting methodological limitations to contextualize findings.

Recommendation

Major Revision Required: The article has the potential to contribute to the literature on ClO2 but requires substantial revisions to address methodological oversights, improve critical analysis, and ensure relevance to biomedical applications. The authors should revise the manuscript to incorporate physiological parameters (e.g., ORP), use appropriate data, and critically evaluate safety and stability before resubmission.

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Specific Concern

We identified two critical flaws: the omission of ORP and the inappropriate comparison between wastewater and physiological conditions. ORP is essential for understanding ClO2’s oxidative activity in the body, where redox homeostasis differs significantly from environmental systems. The article’s failure to address this limits its applicability to biomedical contexts. Similarly, equating wastewater treatment (with high organic loads and extreme chemical conditions) to in vivo environments is misleading, as factors like tissue antioxidants, pH buffering, and systemic clearance drastically alter ClO2’s behavior. These issues reflect a broader lack of rigor in contextualizing ClO2’s biomedical potential.

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