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Cited by 37Skin Protection and AgingNeutrophil, Myeloperoxidase and Oxidative MechanismsNonmelanoma Skin Cancer Studies

Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer

Open access
Snell, Jeremy A., Jandova, Jana, Wondrak, Georg T.·2022·Frontiers in Oncology
DOI 10.3389/fonc.2022.887220PMC PMC9106365
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Abstract

A multitude of extrinsic environmental factors (referred to in their entirety as the ‘skin exposome’) impact structure and function of skin and its corresponding cellular components. The complex (i.e. additive, antagonistic, or synergistic) interactions between multiple extrinsic (exposome) and intrinsic (biological) factors are important determinants of skin health outcomes. Here, we review the role of hypochlorous acid (HOCl) as an emerging component of the skin exposome serving molecular functions as an innate immune factor, environmental toxicant, and topical chemopreventive agent targeting solar UV-induced skin cancer. HOCl [and its corresponding anion (OCl-; hypochlorite)], a weak halogen-based acid and powerful oxidant, serves two seemingly unrelated molecular roles: (i) as an innate immune factor [acting as a myeloperoxidase (MPO)-derived microbicidal factor] and (ii) as a chemical disinfectant used in freshwater processing on a global scale, both in the context of drinking water safety and recreational freshwater use. Physicochemical properties (including redox potential and photon absorptivity) determine chemical reactivity of HOCl towards select biochemical targets [i.e. proteins (e.g. IKK, GRP78, HSA, Keap1/NRF2), lipids, and nucleic acids], essential to its role in innate immunity, antimicrobial disinfection, and therapeutic anti-inflammatory use. Recent studies have explored the interaction between solar UV and HOCl-related environmental co-exposures identifying a heretofore unrecognized photo-chemopreventive activity of topical HOCl and chlorination stress that blocks tumorigenic inflammatory progression in UV-induced high-risk SKH-1 mouse skin, a finding with potential implications for the prevention of human nonmelanoma skin photocarcinogenesis.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review positions hypochlorous acid (HOCl) as an underappreciated component of the "skin exposome," functioning simultaneously as a myeloperoxidase-derived innate immune factor, a freshwater/topical disinfectant, and—per the authors' recent work—a topical photo-chemopreventive agent. It synthesizes the physicochemical, biochemical, and signaling literature on HOCl-driven chlorination stress and argues for further development of controlled topical HOCl interventions against solar UV-induced skin cancer.

Key findings

  • HOCl is a weak acid (pKa = 7.46) existing at near-equimolar ratio with its anion OCl⁻ at physiological pH, with redox potentials of E0' = +1.48 V (HOCl) and +0.9 V (OCl⁻); OCl⁻ absorbs maximally at 292 nm (ε = 378), covering the solar UVB and UVA-II regions, so photolysis is pH-dependent.
  • Chlorination stress modifies amino acids/peptides/proteins (e.g., dichloro-tyrosine, methionine sulfoxide, cysteine sulfenic/sulfinic/sulfonic acid), unsaturated lipids and cholesterol (forming chlorohydrin stereoisomers), and nucleic acids (e.g., 8-chlorodeoxyadenosine, 8-chlorodeoxyguanosine, 5-chlorodeoxyuridine via spontaneous deamination), with mutagenic/genotoxic potential.
  • Key protein targets include IKK (Cys114/115 oxidation, attenuating psoriasis), GRP78 (Lys353 chloramine adduction), HSA (N-chlorination), and Keap1/NRF2; N-chlorotaurine modulates IL-6 (Met161, Trp157) and NF-κB via IκB Met45 oxidation.
  • In the authors' SKH-1 high-risk mouse model, topical HOCl blocked UV-induced tumorigenic progression and inflammatory gene expression (Ptgs2, Il19, Tlr4), confirmed by 3-chloro-tyrosine immunohistochemistry; topical HOCl also suppressed UV-induced AP-1 activation in AP-1 transgenic luciferase-reporter mice.

Methods

  • Narrative review article (Frontiers in Oncology, 2022), synthesizing published literature on HOCl chemistry, innate immunity, water disinfection, biomolecular targets, antagonists, and organ toxicity.
  • No new primary data are reported; the authors summarize their own prior experimental work in reconstructed human epidermis, SKH-1 hairless mice, and AP-1 transgenic luciferase-reporter mice (citing Jandova et al., Redox Biol 2021).
  • Thematic organization covers physicochemical properties, biomolecular targets, endogenous/phytochemical/synthetic HOCl antagonists, signaling pathways (p53, Keap1/NRF2, HSF1, IKK/NFκB, AP-1, MAPKs), human target organs, and therapeutic/chemopreventive opportunities.

Limitations

  • Stated by the paper: the specific mechanistic involvement of NFκB and AP-1 in HOCl-induced attenuation of UV-induced skin inflammatory gene expression and carcinogenesis "remains to be elucidated"; the role of photolysis in mediating biological HOCl-based chlorination stress "remains to be explored"; and translatability of the mouse findings to photodamaged human skin is conditional ("If translatable to photodamaged human skin").
  • Evident from the text: as a narrative review, it presents no systematic search strategy, no quantitative synthesis, and no primary human data; the chemopreventive claim rests largely on the authors' own murine and organotypic studies, and the authors note that dose regimens and extended-release formulations still need to be developed to avoid HOCl-induced tissue damage and irritation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fonc.2022.887220

Cites

184 of 184 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 176 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Co-exposure studies combining topical HOCl and UV in SKH-1 hairless mouse skin revealed that the HOCl-induced cutaneous stress response blocks redox and inflammatory gene expression elicited by subsequent acute solar UV exposure.

    “Co-exposure studies (combining topical HOCl and UV) performed in SKH-1 hairless mouse skin revealed that the HOCl-induced cutaneous stress response blocks redox and inflammatory gene expression elicited by subsequent acute solar UV exposure.”
    Quote in the paperSubstantial claim
  • Findingown data

    In AP-1 transgenic SKH-1 luciferase-reporter mice, topical HOCl suppressed UV-induced inflammatory signaling assessed by bioluminescent imaging and gene expression analysis, documenting HOCl-antagonism of solar UV-induced AP-1 activation.

    “In AP-1 transgenic SKH-1 luciferase-reporter mice, topical HOCl suppressed UV-induced inflammatory signaling assessed by bioluminescent imaging and gene expression analysis documenting HOCl-antagonism of solar UV-induced AP-1 activation.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Common environmental toxicants such as heavy metals (e.g. cadmium), metalloids (e.g. arsenic), and organic xenobiotics (e.g. benzo[a]pyrene, TCDD) are established potentiators of solar UV damage and skin carcinogenesis.

    “common environmental toxicants such as heavy metals (e.g. cadmium), metalloids (e.g. arsenic), and organic xenobiotics (e.g. benzo[a]pyrene, TCDD) are established potentiators of solar UV damage and skin carcinogenesis (21–23).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Cope, 2003, Exposure to Soil Contaminated With an Environmental PCB/PCDD/PCDF Mixture Modulates Ultraviolet Radiation-Induced Non-Melanoma Skin Carcinogenesis in the Crl:SKH1-hrBR Hairless Mouse, Cancer Lett source

      Not checked in the free run.

    • cites [22] Burns, 2004, Arsenic-Induced Enhancement of Ultraviolet Radiation Carcinogenesis in Mouse Skin: A Dose-Response Study, Environ Health Perspect source

      Not checked in the free run.

    • cites [23] Wang, 2005, Combined Subcarcinogenic Benzo[a]Pyrene and UVA Synergistically Caused High Tumor Incidence and Mutations in H-Ras Gene, But Not P53, in SKH-1 Hairless Mouse Skin, Int J Cancer source

      Not checked in the free run.

  • Premisecitation

    HOCl serves as an innate immune factor acting as a myeloperoxidase (MPO)-derived microbicidal factor.

    “as an innate immune factor [acting as a myeloperoxidase (MPO)-derived microbicidal factor]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Kishimoto, 2015, Effect of pH and Moar Ratio of Pollutant to Oxidant on a Photochemical Advanced Oxidation Process Using Hypochlorite, Environ Technol source

      Not checked in the free run.

    • cites [38] Remucal, 2016, Emerging Investigators Series: The Efficacy of Chlorine Photolysis as an Advanced Oxidation Process for Drinking Water Treatment, Environ Sci Water Res Technol source

      Not checked in the free run.

  • Premisecitation

    HOCl has been identified as an environmental toxicant relevant to cutaneous exposures.

    “Recently, hypochlorous acid (HOCl) has been identified as an environmental toxicant relevant to cutaneous exposures (34–36).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [34] Richardson, 2010, What's in the Pool? A Comprehensive Identification of Disinfection by-Products and Assessment of Mutagenicity of Chlorinated and Brominated Swimming Pool Water, Environ Health Perspect source

      Not checked in the free run.

    • cites [35] Leung, 2013, Topical Hypochlorite Ameliorates NF-kappaB-Mediated Skin Diseases in Mice, J Clin Invest source

      Not checked in the free run.

    • cites [36] Jandova, 2021, Topical Hypochlorous Acid (HOCl) Blocks Inflammatory Gene Expression and Tumorigenic Progression in UV-Exposed SKH-1 High Risk Mouse Skin, Redox Biol source

      Not checked in the free run.

  • May combine two claims. 21
  • Classified as probably not a substantial claim. 22

  • May combine two claims.

    Findingown data

    In the SKH-1 high-risk mouse model of UV-induced human keratinocytic skin cancer, topical HOCl blocked tumorigenic progression and inflammatory gene expression (Ptgs2, Il19, Tlr4), confirmed by immunohistochemical analysis including 3-chloro-tyrosine-epitopes.

    “Remarkably, in the SKH-1 high-risk mouse model of UV-induced human keratinocytic skin cancer, relevant to actinic keratosis and subsequent malignant progression, topical HOCl blocked tumorigenic progression and inflammatory gene expression (Ptgs2, Il19, Tlr4), confirmed by immunohistochemical analysis including 3-chloro-tyrosine-epitopes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    UVB (290-320 nm) is thought to cause direct structural damage to DNA in the form of epidermal cyclobutane pyrimidine dimers (CPDs) and other photoproducts.

    “UVB (290-320 nm) is thought to cause direct structural damage to DNA in the form of epidermal cyclobutane pyrimidine dimers (CPDs) and other photoproducts.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Wondrak, 2006, Endogenous UVA-Photosensitizers: Mediators of Skin Photodamage and Novel Targets for Skin Photoprotection, Photochem Photobiol Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    HOCl and OCl- absorb solar UVB photons and can undergo photolysis.

    “Another important physico-chemical feature of HOCl and its corresponding anion [OCl- (hypochlorite)], relevant to environmental co-exposure scenarios, is its ability to absorb solar UVB (290-320 nm) photons and, as a consequence, undergo photolysis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    The major anti-microbially active species is thought to be HOCl compared to the hypochlorite anion, consistent with the half-cell oxidation-reduction potentials and an increased ability of the uncharged HOCl species to penetrate cell walls and membranes of pathogens.

    “the major anti-microbially active species is thought to be HOCl (compared to the hypochlorite anion), consistent with the half-cell oxidation-reduction potentials and an increased ability of the uncharged HOCl species to penetrate cell walls and membranes of pathogens.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Smoking accelerates skin aging.

    “smoking (an external exposomal factor) accelerates skin aging (intrinsic factor) (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Morita, 2009, Molecular Basis of Tobacco Smoke-Induced Premature Skin Aging, J Investig Dermatol Symp Proc source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intrinsic genetic alterations that impair DNA repair capacity are associated with an increased UV-induced skin cancer incidence, as substantiated by xeroderma pigmentosum patients with excision repair deficiencies underlying a pronounced increase in skin cancer risk.

    “intrinsic genetic alterations that impair DNA repair capacity are associated with an increased UV-induced skin cancer incidence as substantiated paradigmatically by xeroderma pigmentosum patients with excision repair deficiencies underlying a pronounced increase in skin cancer risk (32, 33).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Martens, 2020, Sunlight, Vitamin D, and Xeroderma Pigmentosum, Adv Exp Med Biol source

      Not checked in the free run.

    • cites [33] Rizza, 2021, Xeroderma Pigmentosum: A Model for Human Premature Aging, J Invest Dermatol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    HOCl and its conjugated base represent a potent oxidizing redox system [E0' = +0.9 (OCl-); E0' = +1.48 V (HOCl)] under physiological conditions.

    “HOCl and its conjugated base represent a potent oxidizing redox system [E0’ = +0.9 (OCl-); E0’ = +1.48 V (HOCl)] under physiological conditions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HOCl serves as a chemical disinfectant used in freshwater processing on a global scale, including drinking water safety and recreational freshwater use.

    “as a chemical disinfectant used in freshwater processing on a global scale, both in the context of drinking water safety and recreational freshwater use.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Kishimoto, 2015, Effect of pH and Moar Ratio of Pollutant to Oxidant on a Photochemical Advanced Oxidation Process Using Hypochlorite, Environ Technol source

      Not checked in the free run.

    • cites [38] Remucal, 2016, Emerging Investigators Series: The Efficacy of Chlorine Photolysis as an Advanced Oxidation Process for Drinking Water Treatment, Environ Sci Water Res Technol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HOCl/OCl− serves as an endogenous microbicidal agent, generated by myeloid lineage-derived effector cells including neutrophils.

    “The potent oxidant HOCl/OCl− serves as an endogenous microbicidal agent, generated by myeloid lineage-derived effector cells (including neutrophils).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Hawkins, 2020, Hypochlorous Acid-Mediated Modification of Proteins and its Consequences, Essays Biochem source

      Not checked in the free run.

    • cites [48] Davies, 2021, Myeloperoxidase: Mechanisms, Reactions and Inhibition as a Therapeutic Strategy in Inflammatory Diseases, Pharmacol Ther source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Physicochemical properties including redox potential and photon absorptivity determine the chemical reactivity of HOCl towards select biochemical targets such as proteins, lipids, and nucleic acids.

    “Physicochemical properties (including redox potential and photon absorptivity) determine chemical reactivity of HOCl towards select biochemical targets [i.e. proteins (e.g. IKK, GRP78, HSA, Keap1/NRF2), lipids, and nucleic acids]”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Human skin photoaging represents the overlap of intrinsic factors such as cellular senescence as a function of chronological age and structural/functional alterations due to environmental solar exposure.

    “human skin photoaging represents the overlap of intrinsic factors (such as cellular senescence as a function of chronological age) and structural/functional alterations due to environmental solar exposure (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Gromkowska-Kepka, 2021, The Impact of Ultraviolet Radiation on Skin Photoaging - Review of In Vitro Studies, J Cosmet Dermatol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    HOCl maximally absorbs at 237 nm and 289 nm with molar extinction coefficients of 102 and 36.1, respectively; OCl- maximally absorbs at 292 nm with a molar extinction coefficient of 378.

    “HOCl maximally absorbs at 237 nm and 289 nm with molar extinction coefficients of 102 and 36.1, respectively; OCl- maximally absorbs at 292 nm with a molar extinction coefficient of 378.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HOCl and its corresponding anion OCl- are a weak halogen-based acid and a powerful oxidant.

    “HOCl [and its corresponding anion (OCl-; hypochlorite)], a weak halogen-based acid and powerful oxidant, serves two seemingly unrelated molecular roles”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Kishimoto, 2015, Effect of pH and Moar Ratio of Pollutant to Oxidant on a Photochemical Advanced Oxidation Process Using Hypochlorite, Environ Technol source

      Not checked in the free run.

    • cites [38] Remucal, 2016, Emerging Investigators Series: The Efficacy of Chlorine Photolysis as an Advanced Oxidation Process for Drinking Water Treatment, Environ Sci Water Res Technol source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Most solar UV energy incident on human skin derives from the deeply penetrating UVA region (≥95%, 320-400 nm) and is not directly absorbed by DNA.

    “Most of the solar UV energy incident on human skin derives from the deeply penetrating UVA region (≥ 95%, 320-400 nm) not directly absorbed by DNA”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Upon reaction with nitrite, formation of nitryl chloride and chlorine nitrite might occur, reactions relevant to inflammatory protein nitration.

    “upon reaction with nitrite, formation of nitryl chloride and chlorine nitrite might occur, reactions relevant to inflammatory protein nitration (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Eiserich, 1996, Formation of Nitrating and Chlorinating Species by Reaction of Nitrite With Hypochlorous Acid. A Novel Mechanism for Nitric Oxide-Mediated Protein Modification, J Biol Chem source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Little molecular research exploring the potentially adverse cutaneous and systemic effects resulting from exposure to HOCl-disinfectants during recreational swimming pool use has been conducted.

    “however, little molecular research exploring the potentially adverse cutaneous and systemic effects resulting from exposure to HOCl-disinfectants during recreational swimming pool use has been conducted.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    As a result of UV-driven photolysis, generation of hydroxyl and chlorine radicals has been documented, a reaction of potential relevance to environmental co-exposure scenarios where solar photons in the UVB range might cause HOCl/OCl- degradation with formation of reactive free radical species consistent with the extensive UVB absorptivity of OCl-.

    “as a result of UV-driven photolysis generation of hydroxyl and chlorine radicals has been documented, a reaction of potential relevance to environmental co-exposure scenarios where solar photons in the UVB range might cause HOCl/OCl- degradation with formation of reactive free radical species consistent with the extensive UVB absorptivity of OCl- (38).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Remucal, 2016, Emerging Investigators Series: The Efficacy of Chlorine Photolysis as an Advanced Oxidation Process for Drinking Water Treatment, Environ Sci Water Res Technol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Chloramine formation involves the HOCl-dependent derivatization of primary and secondary biological amines as contained in small biochemicals such as histamine and taurine and macromolecules such as proteins.

    “Chloramine formation involves the HOCl-dependent derivatization of primary and secondary biological amines as contained in small biochemicals (such as histamine and taurine) and macromolecules (proteins etc.) (62–64).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62] Daumer, 2000, Chlorination of Pyridinium Compounds. Possible Role of Hypochlorite, N-Chloramines, and Chlorine in the Oxidation of Pyridinoline Cross-Links of Articular Cartilage Collagen Type II During Acute Inflammation, J Biol Chem source

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    • cites [63] Wastensson, 2020, Inorganic Chloramines: A Critical Review of the Toxicological and Epidemiological Evidence as a Basis for Occupational Exposure Limit Setting, Crit Rev Toxicol source

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    • cites [64] Gottardi, 2013, N-Chloramines, a Promising Class of Well-Tolerated Topical Anti-Infectives, Antimicrob Agents Chemother source

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  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    It seems reasonable to expect synergistic molecular interactions that drive HOCl-potentiation of sun damage in exposed individuals.

    “it seems reasonable to expect synergistic molecular interactions that drive HOCl-potentiation of sun damage in exposed individuals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GRP78 modification through chloramine adduction (Lys 353) has been suggested to modulate autophagy and apoptosis in A549 lung cancer cells.

    “GRP78 (glucose-regulated protein 78, HSPA5) modification through chloramine adduction (Lys 353) has been suggested to modulate autophagy and apoptosis in A549 lung cancer cells”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Ulfig, 2021, The Effects of Neutrophil-Generated Hypochlorous Acid and Other Hypohalous Acids on Host and Pathogens, Cell Mol Life Sci source

      Not checked in the free run.

    • cites [86] Ning, 2019, Inhibiting Lysine 353 Oxidation of GRP78 by a Hypochlorous Probe Targeting Endoplasmic Reticulum Promotes Autophagy in Cancer Cells, Cell Death Dis source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Taurine formation occurs via enzyme-catalyzed cysteine transformation through intermediate generation of L-cysteine sulfinic acid and hypotaurine.

    “Taurine formation occurs as the result of enzyme-catalyzed cysteine transformation through intermediate generation of L-cysteine sulfinic acid and hypotaurine ( Figure 4B ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Figure 4B

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Chlorination byproducts including organohaloacetic acids and trihalomethanes and chlorite are subject to strict EPA regulation due to potential adverse health effects.

    “Importantly, chlorination byproducts (CBPs) including organohaloacetic acids and trihalomethanes (formed due to the presence of dissolved organic matter) and chlorite are subject to strict EPA regulation due to potential adverse health effects (122, 123).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [122] Srivastav, 2020, Disinfection by-Products in Drinking Water: Occurrence, Toxicity and Abatement, Environ Pollut source

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    • cites [123] Li, 2018, Drinking Water Disinfection Byproducts (DBPs) and Human Health Effects: Multidisciplinary Challenges and Opportunities, Environ Sci Technol source

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  • May combine two claims.

    Premisecitation

    Chlorination of PPCPs including sunscreen ingredient avobenzone is associated with formation of a dichloro-species, and cosmetics are equally subject to chlorination with unexplored effects on human health.

    “Likewise, chlorination of PPCPs including sunscreen ingredients such as the common UVA-sunscreen avobenzone are associated with formation of a dichloro-species, and cosmetics are equally subject to chlorination with unexplored effects on human health (16, 130–135).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [16] Juliano, 2017, Cosmetic Ingredients as Emerging Pollutants of Environmental and Health Concern, A Mini-Rev Cosmetics source

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    • cites [130] Zhuang, 2013, Stability and Toxicity of Selected Chlorinated Benzophenone-Type UV Filters in Waters, Acta Chim Slov

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    • cites [131] Crista, 2015, Degradation in Chlorinated Water of the UV Filter 4-Tert-Butyl-4'-Methoxydibenzoylmethane Present in Commercial Sunscreens, Environ Technol source

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    • cites [132] Sharifan, 2016, UV Filters Interaction in the Chlorinated Swimming Pool, a New Challenge for Urbanization, a Need for Community Scale Investigations, Environ Res source

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    • cites [133] Zhang, 2016, Chlorination of Oxybenzone: Kinetics, Transformation, Disinfection Byproducts Formation, and Genotoxicity Changes, Chemosphere source

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    • cites [134] Wang, 2017, Stability and Removal of Selected Avobenzone's Chlorination Products, Chemosphere source

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    • cites [135] Yang, 2018, Chlorination and Chloramination of Benzophenone-3 and Benzophenone-4 UV Filters, Ecotoxicol Environ Saf source

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  • May combine two claims.

    Premisecitation

    Mutagen X is a disinfection byproduct derived from humic acids, not regulated by EPA, with suspected involvement in cancer risk elevation associated with consumption of chlorinated drinking water, attributed to genotoxicity surpassing that of currently regulated CBPs.

    “For example, mutagen X (3-chloro-4-(dichloromethyl)-5-hydroxy-5H-furan-2-one) is a disinfection byproduct derived from humic acids, not regulated by EPA, with suspected involvement in cancer risk elevation associated with consumption of chlorinated drinking water, an effect attributed to genotoxicity surpassing that of currently regulated CBPs (including chloroform and bromodichloromethane) (125).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Bagheban, 2019, Investigation of the Effective Factors on the Mutagen X Formation in Drinking Water by Response Surface Methodology, J Environ Manage source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Molecular chlorination stress relevant to human health originates from HOCl (among other endogenous hypohalous acids including HOI and HOBr, formed mostly in innate immunity) and is complemented by exposure to HOCl and related derivatives from exogenous sources.

    “Molecular chlorination stress relevant to human health originates from HOCl (among other endogenous hypohalous acids including HOI and HOBr, formed mostly in the context of innate immunity) and is complemented by exposure to HOCl (and related derivatives) originating from exogenous sources.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HOCl-modification of deoxyadenosine forms 8-chlorodeoxyadenosine, and HOCl-modification of deoxyguanosine forms 8-chlorodeoxyguanosine.

    “HOCl-modification of deoxyadenosine forms 8-chlorodeoxyadenosine, and HOCl-modification of deoxyguanosine forms 8-chlorodeoxyguanosine.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Trichloroisocyanuric acid and its di-chloro-analogue are EPA-approved under FIFRA, used globally for drinking water and freshwater disinfection, offering increased photostability and sustained HOCl release.

    “Interestingly, trichloroisocyanuric acid as well as its di-chloro-analogue are EPA-approved under FIFRA (Federal Insecticide, Fungicide, and Rodenticide Act) regulations, used globally for drinking water and freshwater disinfection (such as in swimming pools), offering increased photostability and sustained HOCl release (44, 121).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Wahman, 2018, Chlorinated Cyanurates: Review of Water Chemistry and Associated Drinking Water Implications, J Am Water Works Assoc source

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    • cites [121] Suppes, 2014, Assessment of Swimmer Behaviors on Pool Water Ingestion, J Water Health source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Out of more than six hundred halogenation byproducts identified to date, only eleven are currently subject to strict EPA regulation.

    “Strikingly, out of more than six hundred halogenation byproducts identified as of to date, only eleven are currently subject to strict EPA regulation (124).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Muellner, 2007, Haloacetonitriles vs. Regulated Haloacetic Acids: Are Nitrogen-Containing DBPs More Toxic, Environ Sci Technol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    N-chlorotaurine is a chlorinated adduct with attenuated reactivity, interpreted as an intermediate step facilitating extension of the phagocytic activity range, enabling enhanced stability and diffusion, spatially amplifying the range of oxidative antimicrobial effects.

    “The consequent formation of N-chlorotaurine, representing a chlorinated adduct with attenuated reactivity, has also been interpreted as an intermediate step facilitating the extension of the phagocytic activity range, enabling enhanced stability and diffusion, spatially amplifying the range of oxidative antimicrobial effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Gottardi, 2002, Chemical Properties of N-Chlorotaurine Sodium, a Key Compound in the Human Defence System, Arch Pharm (Weinheim) source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the lung, exposure to chlorination stressors has long been associated with a role in chronic inflammatory diseases of the respiratory system.

    “In the lung, exposure to chlorination stressors has long been associated with a role in chronic inflammatory diseases of the respiratory system (137, 144–148).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [137] Zhu, 2008, Identification of Nrf2-Dependent Airway Epithelial Adaptive Response to Proinflammatory Oxidant-Hypochlorous Acid Challenge by Transcription Profiling, Am J Physiol Lung Cell Mol Physiol source

      Not checked in the free run.

    • cites [144] Van Den Broucke, 2018, Irritant-Induced Asthma to Hypochlorite in Mice Due to Impairment of the Airway Barrier, Arch Toxicol source

      Not checked in the free run.

    • cites [145] Thickett, 2002, Occupational Asthma Caused by Chloramines in Indoor Swimming-Pool Air, Eur Respir J source

      Not checked in the free run.

    • cites [146] Venglarik, 2003, Hypochlorous Acid Alters Bronchial Epithelial Cell Membrane Properties and Prevention by Extracellular Glutathione, J Appl Physiol (1985) source

      Not checked in the free run.

    • cites [147] Bougault, 2009, Asthma, Airway Inflammation and Epithelial Damage in Swimmers and Cold-Air Athletes, Eur Respir J source

      Not checked in the free run.

    • cites [148] Li, 2015, Health Effects From Swimming Training in Chlorinated Pools and the Corresponding Metabolic Stress Pathways, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the gastrointestinal tract, chlorination-associated changes have been substantiated, potentially impacting microbiome and barrier function, occurrence and severity of inflammatory pathology, and malignant progression.

    “Likewise, in the gastrointestinal tract, chlorination-associated changes have been substantiated, potentially impacting microbiome and barrier function, occurrence and severity of inflammatory pathology, and malignant progression (153–157).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [153] Dias, 2018, Changes in Mouse Gut Bacterial Community in Response to Different Types of Drinking Water, Water Res source

      Not checked in the free run.

    • cites [154] Fish, 2020, Unchartered Waters: The Unintended Impacts of Residual Chlorine on Water Quality and Biofilms, NPJ Biofilms Microbiomes source

      Not checked in the free run.

    • cites [155] Sasada, 2015, Chlorinated Water Modulates the Development of Colorectal Tumors With Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice, PloS One source

      Not checked in the free run.

    • cites [156] El-Tawil, 2016, Colorectal Cancers and Chlorinated Water, World J Gastrointest Oncol source

      Not checked in the free run.

    • cites [157] Prochazka, 2019, Global Transcriptional Analysis of Nontransformed Human Intestinal Epithelial Cells (FHs 74 Int) After Exposure to Selected Drinking Water Disinfection By-Products, Environ Health Perspect source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There are concerns that innate or environmental chlorination stress might be related to the occurrence of lung malignancy related to genotoxic effects.

    “Moreover, there are concerns that innate or environmental chlorination stress might be related to the occurrence of lung malignancy related to genotoxic effects (86, 151, 152).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [86] Ning, 2019, Inhibiting Lysine 353 Oxidation of GRP78 by a Hypochlorous Probe Targeting Endoplasmic Reticulum Promotes Autophagy in Cancer Cells, Cell Death Dis source

      Not checked in the free run.

    • cites [151] Kogevinas, 2010, Genotoxic Effects in Swimmers Exposed to Disinfection by-Products in Indoor Swimming Pools, Environ Health Perspect source

      Not checked in the free run.

    • cites [152] Vizcaya, 2013, Risk of Lung Cancer Associated With Six Types of Chlorinated Solvents: Results From Two Case-Control Studies in Montreal, Canada, Occup Environ Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hepatic toxicity related to chlorination stress, particularly in the context of environmental exposure to chlorination byproducts, has been documented extensively.

    “Hepatic toxicity related to chlorination stress, particularly in the context of environmental exposure to chlorination byproducts, has been documented extensively.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [158] Chang, 1981, Effects of Acute Administration of Chlorinated Water on Liver Lipids, Lipids source

      Not checked in the free run.

    • cites [159] Plaa, 2000, Chlorinated Methanes and Liver Injury: Highlights of the Past 50 Years, Annu Rev Pharmacol Toxicol source

      Not checked in the free run.

    • cites [160] Faustino-Rocha, 2016, Trihalomethanes in Liver Pathology: Mitochondrial Dysfunction and Oxidative Stress in the Mouse, Environ Toxicol source

      Not checked in the free run.

    • cites [161] Zheng, 2021, Effects of Environmental Contaminants in Water Resources on Nonalcoholic Fatty Liver Disease, Environ Int source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inhalational HOCl formulations are now undergoing clinical trials for prophylaxis and treatment of COVID-related respiratory infectious illness.

    “In the context of pulmonary exposure, it is noteworthy that inhalational HOCl formulations are now undergoing clinical trials for prophylaxis and treatment of COVID-related respiratory infectious illness (ClinicalTrials.gov Identifier: NCT04684550).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites NCT04684550

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute kidney injury, glomerulonephritis, diabetic nephropathy, and bladder cancer have been associated with exposure to pathological chlorination stress.

    “Among other pathologies, acute kidney injury, glomerulonephritis, diabetic nephropathy, and bladder cancer have been associated with exposure to pathological chlorination stress (110, 162–166).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [110] Madu, 2015, Pyridoxamine Protects Proteins From Damage by Hypohalous Acids In Vitro and In Vivo, Free Radic Biol Med source

      Not checked in the free run.

    • cites [162] Peck, 2011, Spectrum of Sodium Hypochlorite Toxicity in Man-Also a Concern for Nephrologists, NDT Plus source

      Not checked in the free run.

    • cites [163] Brown, 2015, Hypohalous Acids Contribute to Renal Extracellular Matrix Damage in Experimental Diabetes, Diabetes source

      Not checked in the free run.

    • cites [164] Afshinnia, 2017, Myeloperoxidase Levels and Its Product 3-Chlorotyrosine Predict Chronic Kidney Disease Severity and Associated Coronary Artery Disease, Am J Nephrol source

      Not checked in the free run.

    • cites [165] Parvez, 2019, Exposure Characterization of Haloacetic Acids in Humans for Exposure and Risk Assessment Applications: An Exploratory Study, Int J Environ Res Public Health source

      Not checked in the free run.

    • cites [166] Evlampidou, 2020, Trihalomethanes in Drinking Water and Bladder Cancer Burden in the European Union, Environ Health Perspect source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    If translatable to photodamaged human skin, these observations provide novel insights on molecular consequences of chlorination stress not only relevant to environmental exposure but indicative of a potential photo-chemopreventive utility for topical intervention targeting early (actinic keratosis) and advanced stages of nonmelanoma skin cancer.

    “If translatable to photodamaged human skin, these observations provide novel insights on molecular consequences of chlorination stress not only relevant to environmental exposure but indicative of a potential photo-chemopreventive utility for topical intervention targeting early (actinic keratosis) and advanced stages of nonmelanoma skin cancer.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The observations from cutaneous organotypic and murine models are translatable to photodamaged human skin.

  • May combine two claims.

    Premisecitation

    HOCl activity as a natural adjuvant through induction of adaptive immunity by HOCl-dependent oxidation of N-linked carbohydrates in glycoprotein, subsequently enhancing scavenger receptor uptake by antigen presenting cells, has been demonstrated, linking HOCl-potentiation of innate and adaptive immunity.

    “Likewise, activity as a natural adjuvant (through induction of adaptive immunity by HOCl-dependent oxidation of N-linked carbohydrates in glycoprotein), subsequently enhancing scavenger receptor uptake by antigen presenting cells, has been demonstrated, linking HOCl-potentiation of innate and adaptive immunity (180).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [180] Prokopowicz, 2010, Hypochlorous Acid: A Natural Adjuvant That Facilitates Antigen Processing, Cross-Priming, and the Induction of Adaptive Immunity, J Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HOCl-induced increased immunogenicity of proteins and enhanced uptake by dendritic cells have been observed.

    “With relevance to cancer-directed preventive and potentially therapeutic activity, an HOCl-induced increased immunogenicity of proteins and enhanced uptake by dendritic cells have been observed (179).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Biedron, 2015, Oxidation by Neutrophils-Derived HOCl Increases Immunogenicity of Proteins by Converting Them Into Ligands of Several Endocytic Receptors Involved in Antigen Uptake by Dendritic Cells and Macrophages, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Chlorination stress associated with HOCl/OCl- exposure originating from innate and environmental sources has now been identified as a double-edged molecular sword, mediating essential functions in innate immunity towards microbial attack and exerting effects that are either detrimental or therapeutic to human health, particularly in the context of skin anti-inflammatory and cancer photochemoprevet

    “Chlorination stress associated with HOCl/OCl- exposure originating from innate and environmental sources has now been identified as a double-edged molecular sword, mediating essential functions in the context of innate immunity towards microbial attack and exerting effects that are either detrimental or therapeutic to human health, particularly in the context of skin anti-inflammatory and cancer”
    Quote in the paperSubstantial claim
39 of 39

  • The authors state this as an assumption.

    The observations from cutaneous organotypic and murine models are translatable to photodamaged human skin.

    “If translatable to photodamaged human skin, these observations provide novel insights on molecular consequences of chlorination stress not only relevant to environmental exposure but indicative of a potential photo-chemopreventive utility for topical intervention targeting early (actinic keratosis) and advanced stages of nonmelanoma skin cancer.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • HOCl is a weak halogen-based acid and a powerful chlorination agent, containing one labile proton (pKa = 7.46) that dictates co-existence between acid and conjugated base under physiological conditions at near equimolar ratio.

    “HOCl is a weak halogen-based acid and a powerful chlorination agent, that contains one labile proton (pKa = 7.46) dictating the co-existence between acid and conjugated base under physiological conditions at near equimolar ratio.”

    From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [157]

  • HOCl and its conjugated base HOCl/OCl− represent a potent oxidizing redox system under physiological conditions and serve as an endogenous microbicidal agent generated by myeloid lineage-derived effector cells.

    “HOCl and its conjugated base HOCl/OCl− represent a potent oxidizing redox system [E0′ = +0.9 (OCl-); E0′ = +1.48 V (HOCl)] under physiological conditions, and serves as an endogenous microbicidal agent, generated by myeloid lineage-derived effector cells (including neutrophils) [157].”

    From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [157]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure 3 assigns the same identifiers to different compounds

    Minor

    Figure 3 uses identifiers (6) and (7) for two cholesterol derivatives, then reuses them for phosphatidylserine and phosphatidylserine chloramine.

  • Conflicting extinction coefficients for hypochlorite

    Minor

    Figure 2 reports a molar extinction coefficient of 365 for OCl- at 292 nm, while the text reports 378 for the same species at the same wavelength.

2 of 2

Cites

1 retracted

Flagged first, then by citations

1 of the 185 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Snell, J. A., Jandova, J., & Wondrak, G. T.
Affiliations
University of Arizona (US)
Corresponding author
Wondrak, Georg T.
ORCID
Wondrak, Georg T.
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2022-04-29
Volume
12
Pages
887220-887220
ISSN
2234-943X (ISSN-L)
DOI
10.3389/fonc.2022.887220
PMC
PMC9106365
OpenAlex
W4225123753
Cited by
37
References
185
Citations by year
2026: 5 · 2025: 13 · 2024: 12 · 2023: 3 · 2022: 4
FWCI
1.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Institutes of Health (1R01CA229418, 1R21ES029579, 1P01CA229112, ES007091, ES006694, CA023074)
Topics
  • Health Sciences › Medicine › Dermatology › Skin Protection and Aging
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
Keywords
hypochlorous acid, hypochlorite, chemoprevention, innate immunity, myeloperoxidase, non-melanoma skin cancer, oxidative stress, inflammation, drinking water disinfection

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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