Hydrogen Peroxide Emulsions

by Harry R. Elden, Ph.D., consultant, Elden Associates, Inc., Miami, FL
and
Ted Kalli, AURA Research, Ltd., Marmora, NJ

INTRODUCTION

Skin is at the end of blood circulation and in vivo oxygen delivery even though epidermal cells are exposed to the atmosphere. A few cosmetic class products have proposed to improve hypoxic shin condition that increases with age. An efficient formulation concept is that based on dilute hydrogen peroxide, but skeptics hastily rally caution against dangers of lipoperoxidation they envision accompanying topical hydrogen peroxide.

This article briefly reviews the need to improve skin oxygenation to overcome intermittent and progressive hypoxia. Published studies (Oak Ridge National Laboratory) show that dilute hydrogen peroxide is not a major threat to epidermal cell integrity when compared to benzoyl peroxide.

SYSTEMIC PHYSIOLOGY

It has been known for some time that oxygen uptake decreases with aging (Dobeln et al., 1967) at submaximal and maximal work loads. A mathematical equation relates maximal oxygen uptake (V) to work load (L), Heart rate (H) and age (A):

V = 1.29 [ L / (H - 60) ] exp ( -0.00884 A )

Asrand (1967) also showed that aerobic work capacity and many co-related physiological functions all decline with increasing age beyond peak performances attained post-adolescence. Generally, the human body improves its aerobic competence until late teens/early twenties, then declines.

Impediments to oxygenation exist at several points between lungs and cells. While blood is a hydraulic conductance for oxygen, transfer of oxygen to and from red blood cells is impeded by plasma constituents. Navari, Gainer and Hall (1970) showed that plasma proteins and other constituents generate liquid structures that slow down oxygen free-diffusion. Oxygen, glucose and carbon dioxide have impaired diffusion through human plasma with normal range of protein concentrations. Chisolm et al. (1970), then showed that free-diffusion of oxygen in plasma decreases linearly with aging, while concentration of cholesterol increases with aging.

SKIN HYPOXIA

Skin is vulnerable to hypoxia because it is the terminal organ for oxygen delivery, its metabolic rate is transient due to environmental temperature and autonomic system responses to stress deprive skin oxygen.

Functional perfusion reserve, i.e., reactive hyperemia following release of occlusion, is less for older than for younger human subjects. Xakellis et al. (1993) showed that compression prompts a compensatory increased circulation in skin which increases with duration of compression. Older persons show impaired compensation to compression of blood flow. Findings are of importance to understanding mechanisms of decubitus ulcer formation in compressed and compromised skin.

Transcutaneous oxygen and carbon dioxide have been measured in situ in human skin. Dowd et al. (1983) showed a statistical distribution of partial pressure oxygen for normal and ischaemic skin. Low end of normal skin overlaps upper end of ischaemic skin, suggesting that human skin in situ has a wide range of ortho/hypoxia under ordinary conditions.

Matsen et al. (1982) showed that elevation of upper limbs against gravity markedly decreased skin oxygen while breathing ambient atmosphere. Evans and Nalyor (1967) showed, however, that inhaling oxygen markedly raised skin tissue oxygen at top and base of an induced blister. Thus, skin circulation and oxygen are highly sensitive to environmental factors.

The most insidious impairment of skin oxygenation is due to cigarette smoking; Soffer (1986). Inhalation of nicotine-containing smoke, either primary or second-hand causes the release of vasopressin, a powerful vasoconstrictor. Waeber et al. (1984) showed that cigarette smoking markedly decreased skin blood flow and oxygenation.

These early studies amply show that skin blood flow and oxygenation declines with aging, depends on limb position/occlusion and is impaired further by environmental pollutants (cigarette smoking). Consequences lead to exacerbation of decubitus ulcers and impaired wound healing.

A highly relevant further observation is that cigarette smoking increases the perception of agedness, based upon aesthetic perceptions of the human face. Studies done by Borkan and Norris (1980) at the Gerontology Research Center, National Institute of Aging indicated that faces judged to look functionally older were accompanied by numerous older sub-systems in the body. Circulation and oxygenation of skin are vital to physiological health and to aesthetic perceptions of wellness, fitness, vitality and beauty. Clearly, there is a need to enhance otherwise compromised oxygen tension of mature adult and aging human skin.

ENHANCED OXYGENATION

Scientific evidence strongly encourages the development of ways to enhance oxygenation of skin, and perhaps all other organs as well. Several means exist to accomplish this objective, but one with the longest history of safety is to apply stabilized hydrogen peroxide lotions to the skin.

Critics of this cosmetic formulation concept raise a cry against adding (hydrogen) peroxide to the skin, but say nothing about the widespread use of (benzoyl) peroxide. This article addresses benefits vs. risks of hydrogen peroxide cosmetic formulation, and cites evidence that strongly supports immediate and longer term safety.

Is there a beneficial response to topical hydrogen peroxide? The first step in benefit is to determine extent to which oxygen tension is raised by topical hydrogen peroxide. Extensive unreported studies clearly show that topical hydrogen peroxide is decomposed by contact with skin; closed and open wounds. Oxygen tension rises to a peak and descends slowly to baseline. Time course for this event is on the order of 100-minutes for an FDA cosmetic class formulation.

Oxygen does not dissipate immediately upon release from hydrogen peroxide. Lipid solubility of molecular oxygen favors retention in non-aqueous skin depots.

PHYSIOLOGICAL AND BIOCHEMICAL MODELS

Biochemical studies of skin oxygenation can be standardized by two physiological treatment modalities. It is well known that inhaling orthobaric oxygen raises concentrations of oxygen in plasma and thereby elevates concentrations of oxygen in end-organ skin. By extension, exposure of a limb or entire body to hyperbaric oxygen further elevates plasma oxygen and that of the skin. Responses to topical cosmetic formulation can be compared with skin oxygenated at ortho and hyperbaric conditions.

A third method illustrates the rapidity which dilute stabilized hydrogen peroxide cosmetic lotions reacts with the skin. It has been reported that white spots appear at pressure sites when subjects recline on sunbeds for UVA photo tanning; Tegner (1990).White spots due to cutaneous hypoxia are prevented by pre-treating sites with 1% hydrogen peroxide cream just minutes prior to UVA exposure.

This comment is not intended to encourage artificial tanning, but refers to studies that can be confirmed using standard solar simulators and pressure on skin. Clearly, oxygen is delivered rapidly and it becomes involved immediately in cellular biochemical reactions.

Laboratory measurements can be done conveniently with transcutaneous oxygen meter as used in respiratory physiology skin oxygen tension increases with topical application of oxygen delivery cosmetic formulations. Few studies exist in the literature, however, on benefits of topical oxygenation. They are anticipated by numerous testimonial, anecdotal and clinical perceptions of improvement.

The lack of formal study is not due to the difficulty in measuring skin oxygen. Nor, is there uncertainty about stability of up to 4% hydrogen peroxide cosmetic formulations. There is skepticism, perhaps cynicism, regarding safety attending topical hydrogen peroxide. And there is general lack of appreciating the physiology of mature, adult and aging skin. Otherwise, there would be a major effort to improve blood circulation and oxygenation in adult skin.

On balance, it is necessary to evaluate the risk-potential of topical hydrogen peroxide, since free radical reactions are possible and hazardous.

PROTECTION IN PLACE

Cellular systems are protected in vivo to a substantial degree against free radicals generated by cellular basal metabolism. Catalase, superoxide dismutase, glutathione, vitamin E and vitamin C are part of the body's natural protective system. Skin cells are particularly well protected against hydrogen peroxide mediated free radicals because topical hydrogen peroxide does not exist very long in situ.

Upon application of stabilized hydrogen peroxide cosmetic products, catalase breaks up hydrogen peroxide releasing oxygen which dissolves in lipid regions of skin surface. Oxygen then equilibrates with aqueous phase and is dispersed by blood and lymphatic circulations.

Peak levels of tissue oxygen attained by topical cosmetic formulations approximates that produced desirably by orthobaric inhalation and hyperbaric treatment. An added safety feature of cosmetic application is that only skin surface is exposed, allowing dilution by distribution to other tissues.

PROTECTION BY FORMULATIONS - VITAMINS E AND C

Cosmetic class formulations of hydrogen peroxide should contain vitamin E and C to block free radical production. This does not interfere with direct production and utilization of oxygen. Anti-oxidant agents add protection to epidermal cells beyond that intended for unreacted hydrogen peroxide. Another feature of cosmetic formulations is that the formula pH should be near that of the acid mantle. This protects skin and also stabilizes hydrogen peroxide against spontaneous decomposition.

Hydrogen peroxide (3%) is distributed to mass market consumers as an acid-stabilizes solution. These solutions are safe and effective disinfectant and cleansing agents for open wounds in human subjects. Topical hydrogen peroxide remains safe and effective for open wounds and also for use in dental products, even thought the same hydrogen peroxide is capable of generating free radicals.

SUBSTANTIATION OF SAFETY

Vitamin E and C effectively block free radical mediated lipoperoxidation in vivo and in vitro. An outstanding in vitro study by Nike et al. (1984) shows that oxidation of methyl linoleate in solution is inhibited by vitamins E and C. Kinetic mechanisms of initiation, propagation and termination have been delineated and measured in this detailed study.

Literature distributed by Hoffman-La Roche, Inc., shows about a 50% reduction in lipoperoxidation by TBA assay of MDA produced by irradiating mouse epidermal cells: see report by Pugliese (1985).

Another Hoffman-La Roche report, Elden (1988), shows distribution of topical vitamin E linoleate into lipid components of the epidermis; viz., ceramide, cholesterol and cholesterol ester fractions.

These reports amply demonstrate protection against excessive lipoperoxidation by vitamins E and C at concentrations used to formulate topical stabilized hydrogen peroxide emulsions; see AURA research, Ltd.

TUMOR PRODUCTION - PEROXIDES

Strongest evidence favoring safety of topical hydrogen peroxide is that provided by Biology Division, Oak Ridge National Laboratory. Klien-Szanto and Slaga (1982) studied tumor protection in mouse skin treated with benzoyl, lauroyl and hydrogen peroxides at 10, 20 and 40 mg. doses for 25 weeks.

These peroxides were incomplete carcinogens, but benzoyl and lauroyl peroxide were effective tumor promoters in a two-stage (DMBA) carcinogenesis protocol. Hydrogen peroxide was ineffective as complete carcinogen and inducer. Thus, hydrogen peroxide was not observed to be a potent tumor promoter. Benzoyl peroxide, while not a complete carcinogen or inducer is well known as a tumor promoter.

SUMMARY COMMENTS

Cosmetic class hydrogen peroxide emulsions are an economical and effective source of oxygen for hypoxic adult skin. Oxygen is released rapidly upon topical application which decreases remaining hydrogen peroxide. Solubility of oxygen in lipid domains of epidermal cells does not raise concentrations higher than attained by ortho and hyperbaric oxygenations. vitamins E and C protect epidermal cells against lipoperoxidation, and are included in hydrogen peroxide cosmetic emulsions.

Hydrogen peroxide is FDA safe and effective as and anti-infective and cleansing agent for open wounds. It is used extensively in dental products. Years of use by mass market consumers have not revealed dangerous side effects that would prohibit continues application to skin surface.

Upon comparison with benzoyl peroxide, hydrogen peroxide is much less a risk for tumor induction and promotion of epidermal skin cells. Benzoyl peroxide is of such far greater risk that the FDA Anti-Acne Final Monograph removed benzoyl peroxide from safe and effective classification. Efficacy is not the issue; safety is being reviewed extensively with animal studies to determine its risk for long term human use.

REFERENCES:

1. W. Von Dobelin, A. Astrand and A. Bergstrom. An Analysis of Age and Other Factors Related to Maximal Oxygen Uptake. J. Appl. Physiol. 22(5) 934-938 (1967).

2. I. Astrand. Aerobic Work Capacity; Its Relation to Age, Sex and Other Factors. Circulation Research XX and XXI, I - 211 (1967).

3. R. N. Navari, J. L. Gainer and K. R. Halt. Blood Oxygenation, D. Hershey (Editor) Plwnum Press, NY (1970).

4. G. M. Chisolm, E. N. Terrado and J. L. Gainer. Physiological Transport in Relation to Aging. Nature 230: 390-391 (1971).

5. G. C. Xakellis, R. A. Flantz, M. Arteaga and S. Meletiou. Dermal Blood Flow Response to Constant Pressure in Healthy Older and Younger Subjects. J. Gerontol. 48: No. 1, M6 - M9 (1993).

6. G. S. E. Dowd, K. Linge and G. Bently. Measurement of Trancutaneous Oxygen Pressure in Normal and Ischaemic Skin. J. Bone Joint Surg. 65b: 79 (1983).

7. F. A. Matsen, C. R. Wyss and C. W. Simmons. The Effects of Compression and Elevation on Circulation to Skin of the hand as Reflected by Transcutaneous Oxygen. Plastic Reconstr. Surg. 69: No.1, 86 (1982).

8. N. T. S. Evans and P. F. D. Naylor. The Oxygen Tension Gradient Across Human Epidermis. Resp. Physiol. 3: 38 (1967).

9. B. Waeber, M. D. Schaller, J. Nussberger, J. P. Bussien, K. G. Hofbauer and H. R. Brunner. Skin Blood Flow Reduction Induced by Cigarette Smoking; Role of Vasopressin. Am. J. Physiol. 247 (Heart Circ. Physiol. 16): H895 (1984).

10. A. Soffer. (Editorial) Smoker's Faces: Who are the Smokers: Arch. Intem. Med 146: 1496 (1986).

11. H. Daniell. Smoker's Wrinkles. A Study of the Epidemiology of "Crows Feet". Ann. Intern. Med. 75: 873 (1971).

12. D. P. Kadunce, R. Burr, R. Gress, R. Kanner, J.L. Lyon and J.J. Zone. Cigarette Smoking: Risk Factor for Premature Facial Wrinkling. Ann. Intern. Med. 114: 840 (1991).

13. G. Borkan and A. H. Norris. Assessment of Biological Age Using a Profile of Physical Parameters. J. Gerntol. 35: 177 (1980).

14. E. Tegner and A. Bjomberg. Hydrogen Peroxide Cream for the Prevention of White Pressure Areas in UVA Sunbeds. Acta. Derm. Venerol. (Stockh). 70: 75 (1990).

15. E. Niki, T. Saito, A. Kawakami and Y. Kamiya. Inhibition of Oxidation of Methyl Linoleate in Solution by Vitamin E and Vitamin C. J. Biol. Chem. 249: 4177 (1984).

16. P. Pugliese. Vitamin E Acetate: Reduction of Lipid Peroxidation. Report for Hoffam-La Roche, Inc., Nutley, NJ (1985).

17. H. R. Elden. Vitamin E Linoleate: Penetration and Incorporation into Lipids of Mouse Epidermis. Report for Hoffman-La Roche, Inc., Nutley, NJ (1988).

18. A. J. W. Klien-Stanto and T. J. Olasa. Effects of Peroxides on Rodent Skin: Epidermal Hyperplasia and Tumor Promotion. J. Invest. Dermatol. 79: 30 (1982).