Review of Antioxidant and Cytoprotective Effects of Molecular Hydrogen: 3 Papers Accepted by Medical Gas Research | MiZ and Keio University

Lead Paragraph

Three review papers on the antioxidant and cytoprotective effects of molecular hydrogen (H2) by a research group from MiZ Corporation (Kamakura City, Kanagawa Prefecture) and Keio University have been accepted (in press) by the international peer-reviewed journal "Medical Gas Research." The three reviews, centered on the common mechanism by which hydrogen selectively converts highly cytotoxic hydroxyl radicals (•OH) into water molecules (H2O), provide a unified overview of cellular damage from environmental radiation, mitochondrial redox biology, and the role of •OH in cancer initiation, proliferation, and metastasis. This press release introduces the abstracts of each review prior to their official publication and reiterates our proposal for safe hydrogen inhalation, which is essential for disseminating these findings to society.

Abstract of This Research

- Paper 1: Presented a new perspective that hydrogen can suppress oxidative damage caused by •OH from environmental radiation (cosmic rays and natural radiation).

- Paper 2: Positioned hydrogen as a "smart antioxidant" that exhibits no reductive effects under physiological conditions, selectively eliminating only •OH while maintaining mitochondrial function and normal redox signaling.

- Paper 3: Proposed a new hypothesis that cancer cell escape from hydroxyl radical hotspots within tumors can be suppressed by scavenging •OH.

- The three reviews unified different domains—environmental radiation, mitochondrial oxidative stress, and cancer initiation, proliferation, and metastasis—through the common mechanism of "selective •OH scavenging."

- Low-concentration hydrogen inhalation, where the device output concentration is maintained below the verified inhalation environment value of 10% by volume, poses no explosion risk and is a prerequisite for the societal implementation of applied research.

Background: Hydroxyl Radicals (•OH) and Molecular Hydrogen

Hydroxyl radicals (•OH) are the most potent reactive oxygen species, indiscriminately damaging DNA, lipids, and proteins, and are implicated in aging, neurodegenerative diseases, carcinogenesis, and ischemia-reperfusion injury. No endogenous enzymes directly scavenge •OH. Molecular hydrogen (H2), on the other hand, easily penetrates cell and mitochondrial membranes and has been reported to have a selective antioxidant effect by reacting with •OH deep within cells to convert it into water (H2O). Furthermore, it has been pointed out that H2 is unlikely to disrupt normal redox signaling or electron transport chains under physiological conditions.

Meanwhile, in 2015, MiZ Corporation announced that based on a review of existing literature on hydrogen inhalation and empirical studies assuming an inhalation environment, an explosion risk arises when the hydrogen concentration exceeds 10% by volume in a normal environment. This 10% by volume is an empirically verified value assuming an inhalation environment, distinct from the lower explosion limit under ideal conditions (Ichikawa et al., 2026).

Definitions of Terms

Reductive Stress

A state where the intracellular NAD(P)H/GSH ratio is excessively shifted towards the reduced side due to excessive intake of antioxidants, disrupting mitochondrial electron transport chains and redox signaling. A concept complementary to oxidative stress.

Hydroxyl Radical Hotspot

Regions within a tumor where the •OH concentration is locally elevated due to Fenton reactions, etc. Extending the hydrogen peroxide hotspot model by Ueda et al. (Nat Cell Biol 2025), Ichikawa et al. (2026 in press) proposed the possibility that cancer cell escape from these regions contributes to metastasis.

Hydrogen Inhaler

Devices that generate hydrogen gas (H2) through water electrolysis and deliver it into the body via a respiratory interface. The selection of device output concentration is a design variable that determines safety. MiZ Corporation advocates for a design that maintains the device output concentration at or below the verified inhalation environment value of 10% by volume (Ichikawa et al., 2026).

Verified Inhalation Environment Value (10% by Volume)

The empirically verified threshold for explosion risk in a hydrogen inhalation environment (exceeding 10% by volume). This value was announced by MiZ Corporation in 2015 based on a review of existing literature and empirical studies assuming an inhalation environment, taking into account inhalation-specific conditions such as the device outlet, exhalation pathway, human body, and device design (Ichikawa et al., 2026).

Classical Lower Flammable Limit (LFL) 4% by Volume

A value reported by Coward & Jones (1952) in U.S. Bureau of Mines Bulletin 503. It is the theoretical minimum concentration measured under conditions of pre-mixed hydrogen and air in a closed vertical tube at 1 atmosphere and room temperature, ignited statically, where upward flame propagation can be sustained. It primarily targets closed system scenarios such as containers, pipelines, and mines.

Relationship Between LFL 4% and Verified Value 10%

The hydrogen inhalation environment is an open system where hydrogen gas generated by water electrolysis at atmospheric pressure is continuously released into the air, diffused and diluted with room air, and supplied to the inhalation pathway as a flowing gas. This fundamentally differs in three aspects—spatial conditions, mixing state, and flow state—from the measurement conditions of the classical LFL, which assumes pre-mixed static gas in containers and pipelines. Both are distinct indicators measuring different physical conditions, and safety evaluation of hydrogen inhalers should be based on the verified value of 10% by volume.

Key Findings of the 3 Reviews

Paper 1: Environmental Radiation Damage and Cellular Homeostasis

Paper 1, "Hydrogen: A Potential Guardian Against Environmental Radiation Damage," presents the perspective that cosmic and natural radiation, to which we are routinely exposed, can generate •OH in the body, and the accumulation of DNA and mitochondrial damage may contribute to aging and intractable diseases. It discusses the potential for hydrogen, which diffuses widely within cells, to selectively scavenge •OH, suppress radiation-induced oxidative damage, and thereby maintain cellular homeostasis, contribute to the health of astronauts, and prevent cerebrovascular diseases (Figure 1). This review offers a perspective of suppressing the accumulation of cellular damage upstream, rather than through senolytics (removal of senescent cells).

Figure 1: Hydrogen may maintain cellular homeostasis by scavenging hydroxyl radicals generated by environmental radiation to which we are routinely exposed.

Paper 2: Hydrogen as a Smart Antioxidant

Paper 2, "Smart Antioxidant Molecular Hydrogen: A New Paradigm for Mitigating Oxidative Stress in Mitochondrial Redox Biology," is a review that re-examines oxidative stress countermeasures from the perspective of mitochondrial redox biology. It has been pointed out that conventional antioxidants, when taken in excess, can disrupt the electron transport chain and redox balance, leading to "reductive stress." In contrast, hydrogen exhibits no reductive effects under physiological conditions and selectively scavenges •OH while preserving normal redox signaling, thus positioning it as a "smart antioxidant" (Figure 2). This paper presents a new antioxidant strategy for oxidative stress-related diseases.

Figure 2: Excessive vitamin intake may lead to "reductive stress" that disrupts the electron transport chain. In contrast, hydrogen converts hydroxyl radicals to water without disrupting the electron transport chain, protecting cells from oxidative stress.

Paper 3: New Hypothesis for Suppressing Cancer Initiation, Proliferation, and Metastasis

Paper 3, "Molecular Hydrogen as a Selective Hydroxyl Radical Scavenger," presents a new hypothesis that the selective scavenging of •OH by hydrogen can unify the explanation for cancer initiation, proliferation, and metastasis. Starting from the model of cancer cell escape from hydrogen peroxide hotspots within tumors by Ueda et al. (Nat Cell Biol 2025), this paper proposes that •OH is the factor driving this escape, and that hydrogen can suppress metastasis by converting it to water (Figure 3). It also presents hypotheses for suppressing carcinogenesis by inhibiting DNA damage and for suppressing tumor proliferation by inhibiting •OH-dependent proliferation signals.

Figure 3: In hydrogen peroxide hotspots within tumors, hydroxyl radicals are generated by the Fenton reaction. This paper proposes the hypothesis that metastasis is an "escape response" from oxidative stress, and that hydrogen selectively scavenges hydroxyl radicals to alleviate stress within the tumor, thereby suppressing metastasis.

Molecular Mechanism Underlying the 3 Reviews and Transition to Safe Hydrogen Inhalation

Transition to Safe Hydrogen Inhalation - A Prerequisite for Applied Research

For the societal implementation of the antioxidant and cytoprotective applications of hydrogen proposed in the three reviews, avoiding explosion risks during hydrogen inhalation is essential. Multiple explosion accidents, with static electricity presumed as the ignition source, have been reported with high-concentration hydrogen inhalers (67-100% device output concentration), and cases of in-body hydrogen explosions causing complex facial fractures, lung damage, massive bleeding, and respiratory failure have also been reported in the literature. In January 2026, MiZ Corporation and Keio University et al. published a paper academically verifying these accidents (Ichikawa et al., 2026).

Accident Cases of High-Concentration Hydrogen Inhalers (Consumer Affairs Agency Data)

The Consumer Affairs Agency's Accident Information Database System reports multiple accidents that occurred while using hydrogen inhalers with device output concentrations of 67-100% by volume. These include not only explosions of the device itself but also in-body hydrogen explosions in the nasal cavity, airways, and lungs:

- Complex Facial Fractures (February 2025, Esthetic Salon, Case No. 508163) https://www.jikojoho.caa.go.jp/ai-national/accident/detail/508163?kind=1&menu=nolink

- Rupture of Internal Organs (October 2024, Home, Case No. 496203) https://www.jikojoho.caa.go.jp/ai-national/accident/detail/496203?kind=1&menu=nolink

- Bronchial Perforation and Massive Bleeding (September 2024, Home, Case No. 496928) https://www.jikojoho.caa.go.jp/ai-national/accident/detail/496928?kind=1&menu=nolink

- Facial Bone Fractures (January 2024, Home, Case No. 478324) https://www.jikojoho.caa.go.jp/ai-national/accident/detail/478324?kind=1&menu=nolink

- Tinnitus due to Device Lid Ejection (February 2016, Case No. 264488) https://www.jikojoho.caa.go.jp/ai-national/accident/detail/264488?kind=1&menu=nolink

- Hearing Loss due to Device Rupture (January 2015, Case No. 248208) https://www.jikojoho.caa.go.jp/ai-national/accident/detail/248208?kind=1&menu=nolink

In a scholarly paper, the Emergency and Critical Care Center of Ebina General Hospital reported in 2024 a case of a breast cancer patient who developed lung contusion centered in the alveoli (inhalation burn lung injury) during combined hyperthermia and hydrogen inhalation therapy.

Anticipated Questions and Answers (Q&A)

Q1: What is the safe hydrogen concentration for inhalation?

A: The empirically verified threshold for explosion risk in an inhalation environment is above 10% by volume. This value was announced by MiZ Corporation in 2015, and maintaining the device output concentration at or below 10% by volume is an indicator for ensuring safety (Ichikawa et al., 2026).

Q2: What should I look for when choosing a hydrogen inhaler?

A: The primary check is that the device output concentration is maintained at or below the verified inhalation environment value of 10% by volume. Serious accidents, including in-body explosions, have been reported in the Consumer Affairs Agency data bank for high-concentration hydrogen inhalers with device output concentrations reaching 67-100% by volume (Case Nos. 508163, 496203, 496928, 478324, etc.), and ventilation, humidification, and static control around the device alone cannot prevent accidents. It is recommended to choose equipment that employs "inherently safe design" to maintain the output concentration below the explosion limit at the design stage.

Q3: I heard the upper flammable limit (UFL) for hydrogen is 75%. Is 100% pure hydrogen not safe because it exceeds the UFL?

A: Even with a device output of 100% pure hydrogen, it is not safe. At the device outlet, 100% hydrogen comes into contact with ambient air, creating a concentration gradient from 100% to 0% at the outlet interface. Therefore, a layer passing through the explosive range (10-75%) will inevitably exist. In the nasal cavity, airways, and lungs, mixing with exhaled and inhaled air locally creates concentrations within the explosive range, and an explosion can occur with a weak ignition source such as static electricity or frictional heat. The UFL of 75% is a measurement for pre-mixed static gas in a closed space and is not directly applicable to inhalation environments with dynamic mixing from device output → atmospheric diffusion → inhalation pathway (Kurokawa et al., 2015; Kurokawa et al., 2019; Ichikawa et al., 2023, 2026).

Q4: What is the difference between the classical lower flammable limit (LFL) of 4% and the 10% in this study?

A: The classical LFL of 4% by volume (Coward & Jones, 1952) is the theoretical minimum value under conditions of a closed vertical tube, pre-mixed, static gas, and upward flame propagation, primarily targeting closed system scenarios such as containers, pipelines, and mines. In contrast, the verified inhalation environment value of 10% by volume is a practical threshold assuming an open space, continuous dilution, and inhalation environment as a flowing gas at atmospheric pressure. Both are distinct indicators measuring different physical conditions, and safety evaluation of hydrogen inhalers should be based on the verified value of 10% by volume.

Q5: Can humidification and ventilation prevent the explosion risk of high-concentration hydrogen inhalers?

A: These measures only have a supplementary effect on the conditions around the device. Once the emitted hydrogen gas reaches inside the human body, surrounding measures cannot eliminate the explosion risk. The fundamental solution is a design that maintains the device output concentration itself at or below the verified inhalation environment value of 10% by volume.

Discussion and Societal Significance

The three reviews position the central action of hydrogen as "selective scavenging of •OH," unifying cellular damage from environmental radiation (Paper 1), mitochondrial oxidative stress (Paper 2), and cancer cell escape from the oxidative stress environment within tumors (Paper 3) under a single molecular mechanism. The perspective of positioning hydrogen as a selective antioxidant strategy that does not cause reductive stress provides a new hypothetical framework for oxidative stress-related diseases. For the societal implementation of applied research, a transition to low-concentration hydrogen inhalation, where the device output concentration is maintained at or below the verified inhalation environment value of 10% by volume, is a prerequisite.

References and Sources

Three Review Papers (Medical Gas Research, in press)

- Hydrogen: A Potential Guardian Against Environmental Radiation Damage.

- Smart Antioxidant Molecular Hydrogen: A New Paradigm for Mitigating Oxidative Stress in Mitochondrial Redox Biology.

- Molecular Hydrogen as a Selective Hydroxyl Radical Scavenger: A Missing Link in the Suppression of Cancer Initiation, Growth and Metastasis.

Citations for Paper 3

- Ueda Y, et al. (2025). Nature Cell Biology, 27(3): 530-543.

Peer-reviewed papers related to MiZ Corporation's "Low-Concentration Hydrogen Safety" (2015-2026, 4 papers)

- Kurokawa R, Seo T, Sato B, Hirano S, Sato F (2015). Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation. Medical Gas Research, 5: 13. DOI: 10.1186/s13618-015-0034-2. PMC: https://pmc.ncbi.nlm.nih.gov/articles/PMC4620630/

- Kurokawa R, Hirano S, Ichikawa Y, Matsuo G, Takefuji Y (2019). Preventing explosions of hydrogen gas inhalers. Medical Gas Research, 9(3): 160-162. DOI: 10.4103/2045-9912.266996. PMC: https://pmc.ncbi.nlm.nih.gov/articles/PMC6779006/

- Ichikawa Y, Hirano S, Sato B, Yamamoto H, Takefuji Y, Satoh F (2023). Guidelines for the selection of hydrogen gas inhalers based on hydrogen explosion accidents. Medical Gas Research, 13(2): 43-48. DOI: 10.4103/2045-9912.344972. PMC: https://pmc.ncbi.nlm.nih.gov/articles/PMC9555030/

- Ichikawa Y, Sato B, Takefuji Y, Satoh F (2026). Preventable in-body hydrogen explosions from high-concentration H2 inhalers in Japan—Switch to safe, low-concentration hydrogen therapy. International Journal of Risk and Safety in Medicine, 2026 Jan 5: 9246479251414573. DOI: 10.1177/09246479251414573. https://journals.sagepub.com/doi/10.1177/09246479251414573

Company Information

Company Name: MiZ Corporation

Official Website: https://e-miz.co.jp/

Location: 2-19-15 Ofuna, Kamakura City, Kanagawa Prefecture, 247-0056

Phone Number: 0467-53-7511

Reference Link | About Awareness Activities

To support safe choices for general consumers and healthcare facility managers, MiZ Corporation distributes awareness materials titled "First Steps in Choosing a Hydrogen Inhaler - Organizing Your Thoughts." It explains accident cases of high-concentration hydrogen inhalers, the rationale for safe concentrations, and the transition to low-concentration hydrogen inhalation with academic evidence.

▼Awareness Distribution Page

How to Safely Choose a Hydrogen Inhaler | Accident Reports and Prevention Measures for High-Concentration Hydrogen Inhalers (MiZ)

https://e-miz.co.jp/pressrelease/pressrelease15.html