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DERMATOLOGIC ASPECTS OF COSMETICS
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COSMETICS A Dermatologist Looks to the Future: Promises and Problems Albert M. Kligman, MD, PhD
The cosmetic industry is a huge worldwide business, destined to grow rapidly owing to its universal appeal for improving the quality of life. In the United States, more money is spent on skin and hair care products than on education. There are more Avon ladies in Brazil than enlisted personnel in the army. Demographic changes are partly responsible for this enormous outlay of money to look and feel better. The postwar generation of buby boomers is aging, with wrinkles and blotches clear signs of mortal decay and the inevitable despoilation of appearance. The boomer generation has money, is obsessed with youth, is health conscious, and knows that it will live a lot longer than their grandparents. They are the antiaging generation and are determined to look young and sexy until death. An incredible array of products are available to combat the ravages of time and to prevent premature aging. The fashion magazines and the mass media are awash in advertisements that promise eternal youth and happiness. The cosmetic industry is extremely competitive and is dominated by less than a half-dozen juggernauts that use every legal means to capture and hold market share.
Consumers do not understand that cosmetics, in contrast to drugs, are not regulated by agencies such as the U.S. Food and Drug Administration (FDA). No premarketing proof of efficacy or safety is required. This is afYeefor-all situation in which claims can be made, often by unscrupulous start-ups, that lie clearly in the domain of fantasy and humbuggery. These powerful new winds of commerce are blowing up a set of new problems that need to be addressed honestly. COSMECEUTICALS
The author coined the term cosmeceuticals 20 years ago before an annual meeting of the Society of Cosmetic Chemists.’ To the author’s astonishment, a storm of protest broke out immediately. The author was denounced as a traitor to the industry because he seemed to be inviting the FDA to regulate cosmetics in the same way as drugs, a long, expensive process that would hurt innovation and slow down the flow of exciting new products into the marketplace. The author’s intent was simply to point out that the definition of a cosmetic in the 1938 Act of Congress was scientifically untenable
From the Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
DERMATOLOGIC CLINICS VOLUME 18 NUMBER 4 OCTOBER 2000
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and archaic. That statute held that cosmetics were simply for adornment and beautification and by law must not affect the structure and function of skin. This wording established that cosmetics could be used for camouflage and improved appearance but had to be completely inert and pharmacologically inactive. If it could be shown that a cosmetic had some biologic effect, strict reading of the statute would require its reclassification as a drug. There were only two polar categories: cosmetics and drugs. Drugs were intended to prevent and treat disease. No cosmetic could mention the possibility that it did something beneficial to health, even if nothing more than preserving healthy skin. In the 60 years since the act was passed, clinicians learned that nearly every substance can affect the structure and function of skin measurably, under certain circumstances. For example, the innocuousness of water seems beyond question. All living cellular processes occur in a milieu of water. Water can be quite harmful to skin under certain circumstances, however. Occupational dermatologists have long known that chronic exposure to water in wet-work situations predisposes to chemical injury and contributes to the production and persistence of a variety of chronic dermatoses. Familiar examples include bartenders, cannery workers, hairdressers, and multiparous housewives. With the advent of sophisticated, modern technologies, it has been shown that an occlusive exposure of normal skin to water for 48 hours results in a series of striking changes, including increased blood flow; cytotoxic changes to keratinocytes, Langerhans' cells, and melanocytes (shown by transmission electron microscopy); an inflammatory dermal infiltrate; a loosening of the cohesion of corneocytes; and opening up of empty domains (lacunae) in the intercellular spaces between corneocytes, which promotes permeability to potentially toxic substances.2 It is postulated that these dramatic but largely subclinical changes result from the rapid swelling of the horny layer with the release of preformed mediators of inflammation that are stored in the horny layer. Powerful new tools in the era of nanotechnology have made it possible to detect biolog-
ically significant changes that previously were hidden. This is the domain of invisible dermatology, in which most of the important early changes in the pathogenesis of diverse disorders are occult and become known only when powerful new instruments are employed. An arsonal of noninvasive bioengineering instruments exists that make it possible to monitor the changes that occur when seemingly benign exogenous substances, such as cosmetics and toiletries, are applied to normal skin. The author argued that it was scientifically silly to pretend that cosmetics did not do anything and that cosmetics might be doing lots of good things that could improve the quality of skin. The cosmetic industry could now make legitimate claims of functional activity, and a new era could begin, consonant with scientific reality. Although controversy and confusion still persist, the term cosmeceuticals has permanently entered the vocabulary and is used throughout the world.'j Cosmeceuticals are topical agents that are distributed across a broad spectrum of materials lying somewhere between pure cosmetics (lipstick and rouge) and pure drugs (antibiotics, corticosteroids). They partake of both categories. Some cosmetics are closer to the drug pole, and some drugs are closer to the cosmetic pole. The term cosmeceutical has no legal status. Its prominence is due to its operational usefulness. Most products made by manufacturers of cosmetics are cosmeceuticals. They do something beyond improving appearance through concealment and camouflage. The term cosmeceutical has stimulated marketing professionals to offer a number of seman& -variations, denoting functional activity, for example, as follows: 1. Performance cosmetics 2. Dermatocosmetics 3. Bioactives 4. Functional cosmetics 5. Neoceuticals
These terms apparently have such resonance that analogous terms have been created for foods and supplements that are deemed to promote health and well-being, for example, neutraceuticals. A flood of new materials can be
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incorporated into cosmetics under the rubric of cosmeceuticals. The cosmetic industry is not subject to federal regulations under FDA rules. There is no requirement to show premarketing safety or efficacy. An infinitude of materials deriving from the sea, plants, animals, minerals, and thousands of synthetic chemicals can be incorporated into cosmetics. In this free-for-all environment, the claims for these ingredients cover the range from the credible to the fantastic, from sense to nonsense, from fact to fraud. Provided that no drug claims are made and no one is seriously injured, the field is open for full exploitation by marketers not constrained by ethical standard^.^ Competition for market share has created a near-maniacal marketplace where in the name of science preposterous promises are made to credulous consumers. This opendoor policy has led to situations in which some regulatory action within the industry or by federal authorities is indicated; otherwise, one may envision a backlash of disbelief that undermines the credibility and integrity of the cosmetic industry. Some prominent examples follow.
HERBS Herbal texts list thousands of plant-derived materials that date back thousands of years and can be found in all cultures. For every known malady, there are herbal remedies, especially from China, whch are now being rediscovered, often under the now respectable name of alternative or cornplementay rnedicine. The great resurgence of interest in herbal remedies and the incorporation of herbs in cosmetics stem from popular beliefs that have great appeal to modern consumers. The first belief goes under the salutary name of natural. Many supposedly educated consumers, especially the younger constituency, are suspicious of the myriads of synthetic substances made by the chemical industry, which they see as polluting the environment and poisoning humans. This doctrine of chemophobia is a mobilizing mantra for many environmentalists with many links to the green movement. These consum-
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ers scrupulously avoid agents that are not natural and have been produced in a laboratory. They intuitively equate natural with safety and wholesomeness. The assumption that natural equates to safety is ridiculous and irrational. In regard to skin, nothing is more destructive to appearance than natural sunlight, the cause of premature aging with its repertoire of despoilations, such as wrinkles, blotches, sallowness, and laxity. Sunlight causes more cases of skin cancer than all other cancers combined. Other natural toxins are the heavy metals, such as mercury and arsenic, all quite natural, which for centuries poisoned millions of sufferers of various skin diseases, especially victims of syphilis. Some of the most lethal toxins are natural, such as botulinus toxin, which has come to international prominence as a menace in chemical warfare. Many proponents of natural products believe that the vitamin C in citrus fruits is somehow different than synthetic vitamin C. This irrational devotion to the natural knows no bounds and, surprisingly, has more adherence among college graduates than high-school dropouts. This concern for the benefits of the natural applies equally to foods; devotees believe that the foods grown by organic farming are healthier and safer than those grown with chemical fertilizers. There are innumerable serious problems with the expanding incorporation of herbs in cosmetics, not the least of which is the complete lack of quality control, identification and quantification of the active ingredients, mode of preparation, and presence of potentially harmful ingredients. Another problem has come to light that has serious safety overtones for an unsuspecting public. Not only is the composition of unregulated herbs unknown, but also an unscrupulous merchant can add components secretly that can increase efficacy but that are actually drugs, in violation of the statutory laws. There are now proven instances of adulteration in which medium-potency anti-inflammatory corticosteroids have been included in herbal concoctions. The label does not list the corticosteroid ingredient, and the consumer is never told about steroid atrophy and addiction after long-term use.
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Large amounts of Oriental herbs, whose composition is largely unknown, are taken orally in the belief that safety has been proved by their having been used for thousands of years. Not all herbs can be discredited peremptorily, but the toxic effects of many are coming gradually to light. The most serious adverse effects of some well-known herbs include end-stage renal disease and death. There is no limit to the amount of herbal cocktails that consumers can buy.
TOPICAL VITAMINS Many Americans take an extraordinary number of vitamins on a daily basis, often in amounts hundreds of times greater than the daily recommended requirements. This irrational vitamania is mostly harmless for watersoluble vitamins but can produce serious, lifethreatening side effects in the case of the readily absorbed fat-soluble ones, such as vitamins A, D, and E. A new marketing ploy on the part of some manufacturers of cosmetics exploits the high popularity of vitamins by including these in a large array of cosmeceuticals, under the aegis of bioactives. In this case, the benefits that are touted are targeted to skin, especially improving appearance by combating the aging process. Vitamins are favorite ingredients of antiaging skin care products. These formulations may contain every known vitamin, in association with a multitude of minerals, micronutrients, antioxidants, Chinese herbs, and other unpronounceable, nonexistent chemicals. These megacocktails of antiaging cosmeceuticals are largely harmless but are an insult to the consumer and do no credit to the credibility and integrity of the cosmetic industry.
Vitamin A Vitamins are named alphabetically in the order of their discovery. Vitamin A was synthesized more than 50 years ago. The parent compound is retinol, which the body metabolizes to retinoic acid. The latter is now known everywhere as a pharmacologic agent that can partially reverse the cutaneous stigmata
of excessive exposure to the sun (photoaging). Retinoic acid is a drug that can be obtained only by prescription. Substances that have activity similar to vitamin A are generically known as retinoids. Retinol, the vitamin itself, has grandfather status and is exempt from FDA regulations. Retinol has been incorporated into many skin care products, hoping to benefit from the positive pharmacologic image of retinoids. Most can be dismissed as useless. The doses are usually homeopathic. Retinol is exceedingly unstable. For most of these products, data supporting efficacy in reducing the signs of photodamage are nonexistent. Most are worthless. Retinyl acetate, another metabolic derivative of retinol, is incorporated into innumerable products under the banner of retinoids. The author’s studies show that it totally lacks retinoid activity, although it is inexpensive and harmless. Retino1 is a prodrug that can be converted to retinoic acid by skin. In stable formulations and in appropriate concentrations, it can produce retinoid effects. Few formulations meet this standard. Many well-formulated skin care products, regardless of their ingredients, can improve the appearance of photodamaged skin. In the skin care business, there are no placebos because the basic formulations generally are good moisturizers and enjoy the long-standing benefits of emollients in moderating common skin conditions. The rogue marketer rarely can be discovered. The consumer experiences some benefit willy-nilly, especially if the formulation has agreeable sensory properties, such as slip, nontackiness, rub in, and fragrance.
Vitamin C At least a half-dozen companies offer products in which the chief active ingredient is vitamin C. (Note vitamin C also benefits by being natural). A great deal is known about vitamin C. Its absence in the diet causes scurvy. It plays a crucial role in the synthesis of collagen, the fibrous material that makes up about 95% of the dermal matrix and whose loss with photoaging mainly accounts for laxity and sagging of skin. That being
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the case, one can make out a great story for incorporating vitamin C in products for muture skin, a euphemism for photodegraded facial skin. Vitamin C tissue levels decrease with age, and local application could result in concentrations in the skin far greater than can be attained by oral consumption of inordinately high doses. Theoretically the administration of vitamin C topically is reasonable and scientifically explicable for correcting sagging, wrinkled, photoaged skin. The problem lies in the proof of performance. The warriors in the vitamin C battles furnish consumers with seductive technical information, singling out specific attributes of their particular products. For example, product A may be vitamin C in a lipophilic form, which logically promotes its penetration through the stratum corneum barrier, attaining high tissue levels. The supplier of product B uses an ester derivative of vitamin C that is said to be converted to the biologically active form after application to the skin. There are other formulations in which pH and special vehicles have been manipulated to create products that are reputed to have the highest capacity to synthesize and replace lost collagen. Also, a barrage of irrelevant in vitro studies show that fibroblasts fed vitamin C produce greater amounts of procollagen. Vitamin C is grandfathered, and manufacturers are not required to provide proof of efficacy. The consumer has no way of expressing an informed opinion regarding the superiority of one product over another or whether any vitamin C product owes its presumed antiaging effect to the presence of vitamin c. The literature does not, in the author’s opinion, contain a single study that provides unassailable proof of efficacy. Clinical judgments alone are worthless. A good moisturizing cream, such as nonmedicated Nivea Cream, now 100 years old, also improves wrinkles, blotchiness, and firmness. The requirements for indisputable proof are formidable, as for drugs, and include double-blind, vehicle-controlled, randomized studies, preferably with outside surveillance. No vitamin C product has met these criteria.
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Antioxidants The theoretic importance of antioxidants in preventing tissue damage has been appreciated for more than 50 years. Antioxidants have been the subject matter of thousands of reports that cover such broad areas as cancer, wound repair, inflammation, and amelioration of the aging process. Antioxidants have the property of scavenging highly reactive oxygen species, the so-called free radicals, which are known to be capable of degrading lipid constituents of cell membranes, proteins, and DNA. Vitamin E is perhaps the best known of the free radical scavengers, alongside vitamin C and, to a lesser extent, vitamin A. Vitamin E taken orally is highly popular as a dietary supplement. Numerous articles have been published in peer-reviewed journals, including the most prestigious ones, that purport to provide evidence that vitamin E is beneficial in such varied disorders as heart disease, Alzheimer’s disease, macular degeneration of the retina, and senescent changes in body organs. No consensus exists regarding the value of vitamin E, including high doses of vitamin E in the diet, to combat any of the conditions in which a scientific case could be made for its well-known free radical scavenging activity. The case for vitamin E supplementation is subjudice. High doses, which many prefer, can be harmful. The same situation prevails in the case of vitamin E-containing antiaging skin care products, of which there are now hundreds in the marketplace. As with vitamin C, the story is a good one theoretically, but proof lies in performance and not in casuistic pseudoscientific rationalizations. Several books tout antioxidants for a wide variety of skin conditions. It is known that vitamin C and vitamin E stored in the horny layer are degraded by UV light and can be depleted in photodamaged skin. It seems reasonable to replace these deficiencies in a convenient manner by incorporating them into moisturizers that individuals use every day as a matter of good grooming. Also, endogenous antioxidants such as superoxide dismutase have a solid sound that educated consumers like to look for in the labels. Superoxide dismutase
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is a protein that has no chance of achieving biologically active concentrations in skin. Nonetheless, it is present in innumerable formulations anyway. The supporting evidence for the efficacy of another antioxidant, lipoic acid, derives from in vitro studies, which do not translate into clinical practice. Reports of the value of antioxidants in skin care formulations cannot stand up to critical scrutiny as having met the rigorous standards of proof of efficacy. Topical antioxidants appear not to be harmful, however.
THERAPEUTIC COSMETOLOGY (DERMATOCOSMETOLOGY)
In keeping with the trend to produce biologically active products that improve the structure and function of skin, it is timely to envision a new mission and role for the cosmetic industry. Cosmetic firms intuitively shy away from promoting products that treat skin diseases, which is seen as the domain of the medical profession. The reality is that the industry already produces therapeutic products, whether or not these are called over-thecounter drugs or are regarded as cosmeceuticals. The exact category depends not so much on the active ingredients, which may be identical, but rather what the label says regarding the intended use. Acne vulgaris epitimizes the problems and possibilities. Most adolescents experience some degree of acne and usually go to the drugstore rather than consult a physician for treatment. Acne, although a genuine pathologic process, is dominantly a cosmetic problem, which despoils appearance and affects psychosocial behavior negatively. For the affected individual, there is no such thing as mild acne. Two pustules and three comedones may ruin the life of an emotionally vulnerable individual. Drugstore therapy is just as effective for moderating mild-to-moderate acne as a visit to the dermatologist. Salicylic acid is an excellent comedolytic agent that prevents comedones, the primary event in the pathogenesis of acne. It is available in many agreeable forms to suit every kind of personal preference (i.e., creams, gels, solutions, and lotions). Salicylic acid mild washes can be combined effectively
with topicals. Also, there is an array of benzoyl peroxide products, which have an unmatched capacity to eliminate the follicular population of Propionibacterium acnes, the organism responsible for converting comedones into inflammatory lesions (papulopustules), which may leave scars. Benzoyl peroxide is far more effective than the topical antibiotics that dermatologists prescribe to suppress P. acnes. I? acnes does not become resistant to benzoyl peroxide, which is a major problem with antibiotics. The combined use of benzoyl peroxide and salicylic acid attacks acne at two of its most vulnerable points, the formation of comedones and the suppression of I? acnes. Over-thecounter products provide self-treatment of the vulgar forms of moderate acne, treatments that are at least as effective as most physicians can provide with expensive prescriptions. The introduction of film-forming polymers to extract microcomedones qualifies as a breakthrough in cosmetic technology. Formerly, dermatologists used cyanoacrylate polymer (Krazy Glue) to seep into the follicles and harden into a film, which then could be lifted off to pull out I? acnes-laden horny plugs. With products such as Biore, the process has been simplified greatly because all one has to do is wet the skin and apply a polymer-impregnated patch for about 15 minutes. Other polymers are in development. This novel technology is an invitation for the industry to consider the exciting possibility of moving into a new but related territory where it already has the resource to expand its traditional services, a field that might be called diagnostic cosmetology. For example, prepubertal children, as young as age 8 for girls, who show subclinical microcomedones are destined to develop clinical acne and visible comedones (whiteheads and blackheads) 4 to 5 years later. High-risk children, whose mother, father or both had scarring acne, can be tested periodically with polymer-impregnated patches starting at age 7, keeping an archival record of the results. If crops of microcomedones start to appear on the nose at age 8, 9, or 10, comedolytic treatment can be inaugurated. Prevention of disease is always
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more desirable than treatment. The latter can be viewed as a failure of prevention. Another diagnostic technique can be used to predict which children are likely to develop clinical acne. Sebutapes (CuDerm, Dallas, TX) are prepackaged adhesive-coated disks that yield black-and-white pore prints of sebum droplets. Sebum output is low in children but increases when the glands begin to respond to androgens at prepuberty in girls, even before menstruation. The presence of numerous droplets, especially with copious outlet, presages the early development of clinical acne. It is not too far-fetched to envision the time when a company will create an educational program to head off acne, producing diagnostic kits of Sebutapes and polymer patches, along with treatment cosmetics based on salicylic acid and benzoyl peroxide therapies. Rosacea is another serious cosmetic disorder that is not only an embarrassment when the face turns bright red, but also threatens the quality of life because of its emotional impact. The red face syndrome mainly afflicts women and is growing in prevalence among adults. An ambitious, enterprising, innovative cosmetic company could take up an active position that could be extremely helpful to rosacea sufferers. Two openings can be envisioned. The first is therapeutic based on the fact that the current topical treatments prescribed by physicians are far from satisfactory. Ancient formulations containing 5% to 10% elemental sulfur are probably more consistently effective than pharmacologic agents approved by the FDA. Colloidal sulfur, rather than the elementary sulfur in current products, is more effective because of its small particle size. The problem is that sulfur stinks, is irritating, and is cosmetically unattractive. Over-the-counter sulfur is an unpatentable substance. It is precisely the cosmetic industry that has the technical know-how to solve each one of the above-mentioned negative features of sulfur. An encapsulating system, such as liposomes, microsponges, or nanospheres, could be used to entrap sulfur and to release it slowly to avoid a bolus effect, while making it less malodorous. Sulfur is an ancient ingredient that may prove to have therapeutic properties if it could be made palatable to the
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consumer, a fact well within the capabilities of the modern cosmetic industry. Is it more than folklore that accounts for the widespread use of sulfur over centuries for the treatment of acne and rosacea? Rosacea offers another great possibility to the new field of diagnostic cosmetology. The diagnostic hallmark of rosacea is long-lasting blushing, triggered by a variety of factors. Girls who are flusher-blushers in adolescence are at high risk of developing rosacea when they reach their 30s and 40s. A drop of a vasodilating substance, such as sorbic acid (a familiar preservative), applied to the cheek provokes a spreading erythema that may last 15 to 20 minutes in a prerosacea flusher. Sorbic acid could be incorporated into a small adhesive disc similar to Sebutape, making it easy to apply the patch for a prescribed time and follow the pattern and intensity of the erythema. Treatment could be started in adolescence, long before the clinical stigmata of rosacea become apparent. With patients playing a greater role as partners in treatment programs, these devices could have a great future in identifying individuals who are at high risk for developing common skin diseases, not excluding atopic dermatitis, another growing problem throughout the world. There is no reason why the cosmetic industry should not play an influential role in this new field of preventive dermatology. MISCELLANEOUS INGREDIENTS
The ingenuities of some cosmetic manufacturers are great, and so is the number of exotic ingredients that are appearing in topical antiaging products. Most of these are marketed without proof of efficacy or safety. The inventory of such substances is endless. The sea contains thousands of mostly unexplored materials that are now appearing in cosmetics. There are hundreds of thousands of plants, most of them unclassified, providing an endless source of new ingredients. This is traditionally an attractive area because plants have been the source of drugs that have benefited humans immensely (e.g., digitalis and morphine). Botanicals have come to the fore,
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providing a source of new bioactives that might match the benefits that have been achieved by pharmacologists. As always, the proof is in the performance. There are an endless number of ingredients derived from animal sources: hormones, such as melatonin, dehydroepiandrosterone, and estrogens, enzymes, such as telomerase, which has created a sensation by promising an extension of human longevity; fats (from exotic animals such as the emu); placenta; growth factors; cytokines; chicken embryos; and transforming growth factor, a wonder drug that supposedly allows wounds to heal without scarring, as in fetal skin, which is rich in transforming growth factor-p. Because all of these ingredients are natural and exempt from regulation by the FDA, how long will it be before these will enrich antiaging topicals? Finally, there are luxury high-end cosmetics that cater to people who believe that value is proportional to price. These examples are ludicrous and include such ingredients as caviar and gold dust, at prices exceeding $200 per ounce. There is no known relationship between price and function in any category of cosmetics. There is no justification for the American credo that more is better. One example is cited of a newly successful product that illustrates the limit in absurdity has not yet been reached. This boutique-type formulation contains the following active ingredients: (1) 8 antioxidants, (2) 11 vitamins, (3) 12 minerals, (4) 6 hydroxy acids, (5) 21 Chinese herbs, (6) 6 sunscreens, (7) 3 enzymes, (8) 2 phytoestrogens, (9) 6 marine principals, and (10) 4 plant anti-idammatories. If this cosmetic was classified as a drug, it would take more than $3 billion and two lifetimes to prove according to FDA rules that each ingredient contributed to the overall performance.
PSEUDO-ISSUES
Marketing and merchandising in the ebullient, fast-track competitive cosmetic industry plays such an enormous role in capturing the market share that some insidious and egregious practices have practically become an obsession. These are disguised under the eu-
phemism of creative marketing, in which leading celebrities receive salaries orders of magnitude greater than the sober scientist who creates and validates new products. These practices speak unfavorably on the industry and lead many to question whether standards of ethical conduct can be violated indefinitely, without a damaging backlash of publicity. The obvious instances of phony, unmeritorious issues include the following.
Negative Advertising Negative advertising plays into the hands of misinformed chemophobic consumers who are certain that some ingredients in skin care products are harmful and should be eliminated. Industry often caters to this irrational end, and the ploy of the marketers is to emphasize blatantly what is not in the product; for example, lanolin-free, fragrance-free, preservative-free. Allergen-free is designed for sensitive skin. Such warnings come with no evidence that such products are safer for people with sensitive skin. Some dermatologists have made a career of reporting the supposedly high frequency of contact allergy resulting from cosmetics, sometimes arguing that 10% of users may have become sensitized to one or more components. These political toxicologists do a great disservice to an industry whose safety record is exemplary. Many patients with various problems believe they have sensitive skin when this cannot be validated by testing. They buy products for sensitive skin, which generally cost more. Lanolin allergy, in particular, is a fiction of the political toxicologists who do not understand the limitations of patch testing and who fail to recognize the frequency of false-positive patch tests in patients with chronic dermatoses, who compose a small segment of consumers. Tons of lanolin are sold worldwide every year with an extremely low incidence of contact allergy. Contact allergy to preservatives and fragrances can be a problem in patients with chronic skin disorders, but these are special cases and not representative of the general population. Lacking are corresponding figures for an unselected, normal population.
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No manufacturer selling products on a global scale could afford to put a product on the market in which the prevalence reached 1 in a 1000 (0.1%) much less 15%. At that rate, the incidence of contact allergy would be 1000 for every 1 million users, a prohibitively high level that would require pulling the product off the market to avoid litigation. These criticisms do not argue against the worthiness of providing fragrance-free and preservativefree products for individuals who are truly allergic. Fragrances are a much enjoyed and pleasing feature of the products into which they are incorporated. Overall the risks are low and the benefits great. Preservatives are a prerequisite for most cosmetic creams, which are water-containing emulsions in which bacteria can thrive. Poor preservation is a danger to health, as has been evident in the case of contamination by gram-negative organisms in sick and immunosuppressed patients. Patients who are sensitive to preservatives should have access to preservative-free products.
Claim Substantiation: The Bioengineering Paradox
Responsible manufacturers of cosmetics appreciate the importance of supporting their claims by credible procedures that meet the international rules of scientific evidence. The last 2 decades have witnessed the emergence of the new specialty of bioengineering, in which the principles of material science are applied to skin with the intent of providing quantitative objective proof of efficacy, rather than relying on subjective criteria, which may be irrelevant and misleading. Nearly 100 bioengineering devices exist for measuring some physical feature of skin. The familiar ones include (1) the Evaporimeter (Servomed, Sweden), to measure transepidermal water loss; (2) ultrasound scans, to estimate dermal thickness; (3) laser-Doppler velocimetry, to measure blood flow; (4) estimation of the hydration of the stratum corneum by electric conductance; (5) biomechanical properties, such as viscoelasticity; (6) thermography; and (7) chromammetry.
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These devices not only furnish quantitative data on some particular property of human skin but also have the advantage of being noninvasive, replacing procedures such as biopsy, which are not only disagreeable to subjects, but also may leave scars and unsightly hypopigmentations or hyperpigmentations. These instruments have become convenient and powerful in delineating a defined physical feature of skin, with high precision and reproducibility. In the proper hands, noninvasive bioengineering methods are extremely valuable for obtaining a battery of diverse measurements that characterize the structure and function of skin obtainable in no other way. As with all powerful tools, however, bioengineering methods can be manipulated to obtain results that are not only misleading, but also specious. The game of claim substantiation is a sophisticated one in which unscrupulous manufacturers exploit bioengineering techniques to prove every claim that the marketers need to show superiority over a competitive product. Statis tical significance deriving from reams of numbers is not the same as clinical significance. Anyone can place a probe on the skin and make a measurement. It takes a knowledgeable scientist to know exactly what is being measured, to know how to interpret the result, and to understand its relevance. Each device is monodirectional and measures one defined function, whereas it may require a battery of instruments to capture multidirectional effects. The misuse of bioengineering methods to substantiate false claims does not necessarily involve chicanery or overt dishonesty. It is simply a matter of choosing the right instruments to obtain the desired, predetermined result. After making a battery of measurements using different instruments, it usually turns out that some are favorable in support of the claims and others are unfavorable, that is, counterproductive. It is not difficult to imagine which data are presented to the world and which are kept out of sight. FUTURE POSSIBILITIES Petrolatum
Petrolatum is the king of moisturizers and emollients. Why not develop a synthetic pet-
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rolatum with chemically defined ingredients instead of the mishmash petrolatum that contains hundreds if not thousands of hydrocarbons, most of which escape identification. New technology is beginning to meet the challenge of creating nongreasy, nontacky topical drugs that often have to be used for long periods. A corticosteroid cream has come on the market that is delivered as a fastbreaking foam that is esthetically agreeable and promotes penetration.
Perfect Sunscreen Solar radiation encompasses an exceedingly broad range of frequencies: UV-B, UVA I and 11, visible light, and the infrared (the last-mentioned accounting for 40% of the total flux). Infrared (heat) can cause severe photodamage ending in cancers and can act synergistically with UV-B and UV-A to promote photodamage. Most current sunscreens have gaps that allow certain wavelengths to pass through. Broad-spectrum sunscreens as currently understood include UV-B and UV-A radiation but ignore the infrared. Infrared can be blocked by ultrafine zinc and titanium dioxide. The currently available agents tend to be cosmetically unacceptable by imparting a whitish color to the skin, however. The technology exists to overcome this esthetic defect by using high-energy pulses to break down the oxides into particles of a nanometer size that leave no unsightly residue after being rubbed in. Sunscreens are becoming available in Europe that are approaching true broad-spectrum protection. The cosmetic industry deserves great praise for its great achievements in the sunscreen market.
Tars For hundreds of years, coal tars were the mainstay for treating chronic dermatoses in the presteroid era. They are the ultimate examples of substances that sting, stain, and smell. The fact is, however, they still have a place in the over-the-counter treatment of psoriasis, dandruff, and other common problems. They also have some unexplained anti-
inflammatory activity as well as being antipruritic. Could the cosmetic industry help the pharmaceutical industry clean up coal tars? HEURISTICS VERSUS HEDONICS
The paradox of heuristics versus hedonics is rarely discussed, but in the new age of bioactives and functional cosmetics it constitutes a significant problem. This tension arises because consumers desire products that are pleasant, are enjoyable, are easy to apply, feel good, look good, are mild (nonirritating), and furnish a full range of sensory satisfactions. Active products may be antithetic to hedonics because they are specifically designed to achieve a corrective, beneficial effect. As they become more functional, they become less pleasing and rank poorly in premarketing tests in which panelists give undue emphasis on esthetic and sensory properties. The marketing decision in this conflict usually is determined in favor of hedonics based on the operative rule that ”consumers won’t buy products they don’t like.” This is a reality that cannot be ignored completely but comes at a high cost when the benefit that is sought is sacrificed in favor of pleasing the customer. This situation may mean that the producer has to educate the consumer and to explain why the product has some downsides. For example, it is easy to make antiaging retinoids less irritating-decrease the concentration, but then the product becomes less effective. This tactic may be successful from the standpoint of sales based on the fact that consumers often cannot discern true differences in efficacy, especially if the vehicle is enriched in traditional emollients. Cosmetics, in contrast to drugs, do not qualify as placebos. They nearly always have an appreciable beneficial effect. Hydroxy acids, such as lactic acid and salicylic acid, furnish another compelling example. Among other things, these are exfoliants that remove coarse superficial scales from rough-dry skin. They become active if the pH is lowered, but they also become more irritating at the low pH values at which they work best. The cheap solution is to raise the pH to the point where they still work a little
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but are less likely to produce stinging and burning. Sophisticated formulators usually arrive at some compromise, depending on the products that are to be mass marketed or targeted to salons, dermatologists, or spas. Now that cosmetics have ascended to the bioactive, functional category, it is timely to ask whether aromachology will soon be promoted to a similarly respectable position. The concept of using fragrances to alter moods and behaviors is as old as civilization. Evidence is accumulating that certain odors can jog memory, enhance cognitive performance, and produce a state of tranquility. Some fragrances are associated with localized patterns of brain activity that now can be recorded by modern imaging techniques. All that is needed is for the science to supplement the smell. The selection of a fragrance for a given soap and moisturizer may then depend less on hedonics than on desired psychologic effects. Osmoceuticals may be the next great wave in the sea of cosmeceuticals. CONCLUSION
The major manufacturers produce an array of products that contribute enormously to the daily satisfactions and pleasures of modern life. These products are tested routinely for safety and often test marketed to ensure that consumers will perceive claimed benefits. The central issues raised in this article relate to the problems that come from an essentially unregulated marketplace. No one wants to see cosmetics regulated as drugs; still, there
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is a need for some middle ground or compromise. Europeans are ahead in this regard. The EEC publishes directives on the standards that manufacturers are required to meet regarding safety and claims? These directives do not have the backing of strict laws for enforcement, but the industry makes serious efforts to cooperate. There are advisory committees made up of academics and industry scientists who meet regularly with the European commission to revise and implement standards. Self-regulation has not worked well in the booming capitalistic economy of the United States. The self-imposed safety record is a credit to the industry. The next stage is an agenda to set reasonable policies for claim substantiation. Academics must participate in this development and work at educating the public. Finally, as regards the future, the author recommends Skin: Interface of a Living System: Perspective for Skin Care in the Future.4
References 1. Kligman AM: Hydration injury to the skin. In Vander Walk DG, Maibach HI (eds): The Irritant Contact Dermatitis Syndrome. Boca Raton, FL, CRC Press, 1996, pp 187-194 2. Kligman AM: Cosmeceuticals as a third category. Cosmetics and Toiletries 113:33-40, 1998 3. Rogiers V Efficacy claims of cosmetics in Europe must be scientifically substantiated from 1997 on. Skin Res Techno1 1344-48, 1997 4. Tagami H, Parrish JA, Ozawa T Skin: Interface of a Living System: Perspectives for Skin Care in the Future. New York, Elsevier, 1998
Address reprint requests to Albert M. Kligman, MD, PhD Department of Dermatology University of Pennsylvania 226 Clinical Research Building 415 Curie Boulevard Philadelphia, PA 19104
DERMATOLOGIC ASPECTS OF COSMETICS
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COSMETICS A Dermatologist Looks to the Future: Promises and Problems Albert M. Kligman, MD, PhD
The cosmetic industry is a huge worldwide business, destined to grow rapidly owing to its universal appeal for improving the quality of life. In the United States, more money is spent on skin and hair care products than on education. There are more Avon ladies in Brazil than enlisted personnel in the army. Demographic changes are partly responsible for this enormous outlay of money to look and feel better. The postwar generation of buby boomers is aging, with wrinkles and blotches clear signs of mortal decay and the inevitable despoilation of appearance. The boomer generation has money, is obsessed with youth, is health conscious, and knows that it will live a lot longer than their grandparents. They are the antiaging generation and are determined to look young and sexy until death. An incredible array of products are available to combat the ravages of time and to prevent premature aging. The fashion magazines and the mass media are awash in advertisements that promise eternal youth and happiness. The cosmetic industry is extremely competitive and is dominated by less than a half-dozen juggernauts that use every legal means to capture and hold market share.
Consumers do not understand that cosmetics, in contrast to drugs, are not regulated by agencies such as the U.S. Food and Drug Administration (FDA). No premarketing proof of efficacy or safety is required. This is afYeefor-all situation in which claims can be made, often by unscrupulous start-ups, that lie clearly in the domain of fantasy and humbuggery. These powerful new winds of commerce are blowing up a set of new problems that need to be addressed honestly. COSMECEUTICALS
The author coined the term cosmeceuticals 20 years ago before an annual meeting of the Society of Cosmetic Chemists.’ To the author’s astonishment, a storm of protest broke out immediately. The author was denounced as a traitor to the industry because he seemed to be inviting the FDA to regulate cosmetics in the same way as drugs, a long, expensive process that would hurt innovation and slow down the flow of exciting new products into the marketplace. The author’s intent was simply to point out that the definition of a cosmetic in the 1938 Act of Congress was scientifically untenable
From the Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
DERMATOLOGIC CLINICS VOLUME 18 NUMBER 4 OCTOBER 2000
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and archaic. That statute held that cosmetics were simply for adornment and beautification and by law must not affect the structure and function of skin. This wording established that cosmetics could be used for camouflage and improved appearance but had to be completely inert and pharmacologically inactive. If it could be shown that a cosmetic had some biologic effect, strict reading of the statute would require its reclassification as a drug. There were only two polar categories: cosmetics and drugs. Drugs were intended to prevent and treat disease. No cosmetic could mention the possibility that it did something beneficial to health, even if nothing more than preserving healthy skin. In the 60 years since the act was passed, clinicians learned that nearly every substance can affect the structure and function of skin measurably, under certain circumstances. For example, the innocuousness of water seems beyond question. All living cellular processes occur in a milieu of water. Water can be quite harmful to skin under certain circumstances, however. Occupational dermatologists have long known that chronic exposure to water in wet-work situations predisposes to chemical injury and contributes to the production and persistence of a variety of chronic dermatoses. Familiar examples include bartenders, cannery workers, hairdressers, and multiparous housewives. With the advent of sophisticated, modern technologies, it has been shown that an occlusive exposure of normal skin to water for 48 hours results in a series of striking changes, including increased blood flow; cytotoxic changes to keratinocytes, Langerhans' cells, and melanocytes (shown by transmission electron microscopy); an inflammatory dermal infiltrate; a loosening of the cohesion of corneocytes; and opening up of empty domains (lacunae) in the intercellular spaces between corneocytes, which promotes permeability to potentially toxic substances.2 It is postulated that these dramatic but largely subclinical changes result from the rapid swelling of the horny layer with the release of preformed mediators of inflammation that are stored in the horny layer. Powerful new tools in the era of nanotechnology have made it possible to detect biolog-
ically significant changes that previously were hidden. This is the domain of invisible dermatology, in which most of the important early changes in the pathogenesis of diverse disorders are occult and become known only when powerful new instruments are employed. An arsonal of noninvasive bioengineering instruments exists that make it possible to monitor the changes that occur when seemingly benign exogenous substances, such as cosmetics and toiletries, are applied to normal skin. The author argued that it was scientifically silly to pretend that cosmetics did not do anything and that cosmetics might be doing lots of good things that could improve the quality of skin. The cosmetic industry could now make legitimate claims of functional activity, and a new era could begin, consonant with scientific reality. Although controversy and confusion still persist, the term cosmeceuticals has permanently entered the vocabulary and is used throughout the world.'j Cosmeceuticals are topical agents that are distributed across a broad spectrum of materials lying somewhere between pure cosmetics (lipstick and rouge) and pure drugs (antibiotics, corticosteroids). They partake of both categories. Some cosmetics are closer to the drug pole, and some drugs are closer to the cosmetic pole. The term cosmeceutical has no legal status. Its prominence is due to its operational usefulness. Most products made by manufacturers of cosmetics are cosmeceuticals. They do something beyond improving appearance through concealment and camouflage. The term cosmeceutical has stimulated marketing professionals to offer a number of seman& -variations, denoting functional activity, for example, as follows: 1. Performance cosmetics 2. Dermatocosmetics 3. Bioactives 4. Functional cosmetics 5. Neoceuticals
These terms apparently have such resonance that analogous terms have been created for foods and supplements that are deemed to promote health and well-being, for example, neutraceuticals. A flood of new materials can be
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incorporated into cosmetics under the rubric of cosmeceuticals. The cosmetic industry is not subject to federal regulations under FDA rules. There is no requirement to show premarketing safety or efficacy. An infinitude of materials deriving from the sea, plants, animals, minerals, and thousands of synthetic chemicals can be incorporated into cosmetics. In this free-for-all environment, the claims for these ingredients cover the range from the credible to the fantastic, from sense to nonsense, from fact to fraud. Provided that no drug claims are made and no one is seriously injured, the field is open for full exploitation by marketers not constrained by ethical standard^.^ Competition for market share has created a near-maniacal marketplace where in the name of science preposterous promises are made to credulous consumers. This opendoor policy has led to situations in which some regulatory action within the industry or by federal authorities is indicated; otherwise, one may envision a backlash of disbelief that undermines the credibility and integrity of the cosmetic industry. Some prominent examples follow.
HERBS Herbal texts list thousands of plant-derived materials that date back thousands of years and can be found in all cultures. For every known malady, there are herbal remedies, especially from China, whch are now being rediscovered, often under the now respectable name of alternative or cornplementay rnedicine. The great resurgence of interest in herbal remedies and the incorporation of herbs in cosmetics stem from popular beliefs that have great appeal to modern consumers. The first belief goes under the salutary name of natural. Many supposedly educated consumers, especially the younger constituency, are suspicious of the myriads of synthetic substances made by the chemical industry, which they see as polluting the environment and poisoning humans. This doctrine of chemophobia is a mobilizing mantra for many environmentalists with many links to the green movement. These consum-
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ers scrupulously avoid agents that are not natural and have been produced in a laboratory. They intuitively equate natural with safety and wholesomeness. The assumption that natural equates to safety is ridiculous and irrational. In regard to skin, nothing is more destructive to appearance than natural sunlight, the cause of premature aging with its repertoire of despoilations, such as wrinkles, blotches, sallowness, and laxity. Sunlight causes more cases of skin cancer than all other cancers combined. Other natural toxins are the heavy metals, such as mercury and arsenic, all quite natural, which for centuries poisoned millions of sufferers of various skin diseases, especially victims of syphilis. Some of the most lethal toxins are natural, such as botulinus toxin, which has come to international prominence as a menace in chemical warfare. Many proponents of natural products believe that the vitamin C in citrus fruits is somehow different than synthetic vitamin C. This irrational devotion to the natural knows no bounds and, surprisingly, has more adherence among college graduates than high-school dropouts. This concern for the benefits of the natural applies equally to foods; devotees believe that the foods grown by organic farming are healthier and safer than those grown with chemical fertilizers. There are innumerable serious problems with the expanding incorporation of herbs in cosmetics, not the least of which is the complete lack of quality control, identification and quantification of the active ingredients, mode of preparation, and presence of potentially harmful ingredients. Another problem has come to light that has serious safety overtones for an unsuspecting public. Not only is the composition of unregulated herbs unknown, but also an unscrupulous merchant can add components secretly that can increase efficacy but that are actually drugs, in violation of the statutory laws. There are now proven instances of adulteration in which medium-potency anti-inflammatory corticosteroids have been included in herbal concoctions. The label does not list the corticosteroid ingredient, and the consumer is never told about steroid atrophy and addiction after long-term use.
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Large amounts of Oriental herbs, whose composition is largely unknown, are taken orally in the belief that safety has been proved by their having been used for thousands of years. Not all herbs can be discredited peremptorily, but the toxic effects of many are coming gradually to light. The most serious adverse effects of some well-known herbs include end-stage renal disease and death. There is no limit to the amount of herbal cocktails that consumers can buy.
TOPICAL VITAMINS Many Americans take an extraordinary number of vitamins on a daily basis, often in amounts hundreds of times greater than the daily recommended requirements. This irrational vitamania is mostly harmless for watersoluble vitamins but can produce serious, lifethreatening side effects in the case of the readily absorbed fat-soluble ones, such as vitamins A, D, and E. A new marketing ploy on the part of some manufacturers of cosmetics exploits the high popularity of vitamins by including these in a large array of cosmeceuticals, under the aegis of bioactives. In this case, the benefits that are touted are targeted to skin, especially improving appearance by combating the aging process. Vitamins are favorite ingredients of antiaging skin care products. These formulations may contain every known vitamin, in association with a multitude of minerals, micronutrients, antioxidants, Chinese herbs, and other unpronounceable, nonexistent chemicals. These megacocktails of antiaging cosmeceuticals are largely harmless but are an insult to the consumer and do no credit to the credibility and integrity of the cosmetic industry.
Vitamin A Vitamins are named alphabetically in the order of their discovery. Vitamin A was synthesized more than 50 years ago. The parent compound is retinol, which the body metabolizes to retinoic acid. The latter is now known everywhere as a pharmacologic agent that can partially reverse the cutaneous stigmata
of excessive exposure to the sun (photoaging). Retinoic acid is a drug that can be obtained only by prescription. Substances that have activity similar to vitamin A are generically known as retinoids. Retinol, the vitamin itself, has grandfather status and is exempt from FDA regulations. Retinol has been incorporated into many skin care products, hoping to benefit from the positive pharmacologic image of retinoids. Most can be dismissed as useless. The doses are usually homeopathic. Retinol is exceedingly unstable. For most of these products, data supporting efficacy in reducing the signs of photodamage are nonexistent. Most are worthless. Retinyl acetate, another metabolic derivative of retinol, is incorporated into innumerable products under the banner of retinoids. The author’s studies show that it totally lacks retinoid activity, although it is inexpensive and harmless. Retino1 is a prodrug that can be converted to retinoic acid by skin. In stable formulations and in appropriate concentrations, it can produce retinoid effects. Few formulations meet this standard. Many well-formulated skin care products, regardless of their ingredients, can improve the appearance of photodamaged skin. In the skin care business, there are no placebos because the basic formulations generally are good moisturizers and enjoy the long-standing benefits of emollients in moderating common skin conditions. The rogue marketer rarely can be discovered. The consumer experiences some benefit willy-nilly, especially if the formulation has agreeable sensory properties, such as slip, nontackiness, rub in, and fragrance.
Vitamin C At least a half-dozen companies offer products in which the chief active ingredient is vitamin C. (Note vitamin C also benefits by being natural). A great deal is known about vitamin C. Its absence in the diet causes scurvy. It plays a crucial role in the synthesis of collagen, the fibrous material that makes up about 95% of the dermal matrix and whose loss with photoaging mainly accounts for laxity and sagging of skin. That being
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the case, one can make out a great story for incorporating vitamin C in products for muture skin, a euphemism for photodegraded facial skin. Vitamin C tissue levels decrease with age, and local application could result in concentrations in the skin far greater than can be attained by oral consumption of inordinately high doses. Theoretically the administration of vitamin C topically is reasonable and scientifically explicable for correcting sagging, wrinkled, photoaged skin. The problem lies in the proof of performance. The warriors in the vitamin C battles furnish consumers with seductive technical information, singling out specific attributes of their particular products. For example, product A may be vitamin C in a lipophilic form, which logically promotes its penetration through the stratum corneum barrier, attaining high tissue levels. The supplier of product B uses an ester derivative of vitamin C that is said to be converted to the biologically active form after application to the skin. There are other formulations in which pH and special vehicles have been manipulated to create products that are reputed to have the highest capacity to synthesize and replace lost collagen. Also, a barrage of irrelevant in vitro studies show that fibroblasts fed vitamin C produce greater amounts of procollagen. Vitamin C is grandfathered, and manufacturers are not required to provide proof of efficacy. The consumer has no way of expressing an informed opinion regarding the superiority of one product over another or whether any vitamin C product owes its presumed antiaging effect to the presence of vitamin c. The literature does not, in the author’s opinion, contain a single study that provides unassailable proof of efficacy. Clinical judgments alone are worthless. A good moisturizing cream, such as nonmedicated Nivea Cream, now 100 years old, also improves wrinkles, blotchiness, and firmness. The requirements for indisputable proof are formidable, as for drugs, and include double-blind, vehicle-controlled, randomized studies, preferably with outside surveillance. No vitamin C product has met these criteria.
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Antioxidants The theoretic importance of antioxidants in preventing tissue damage has been appreciated for more than 50 years. Antioxidants have been the subject matter of thousands of reports that cover such broad areas as cancer, wound repair, inflammation, and amelioration of the aging process. Antioxidants have the property of scavenging highly reactive oxygen species, the so-called free radicals, which are known to be capable of degrading lipid constituents of cell membranes, proteins, and DNA. Vitamin E is perhaps the best known of the free radical scavengers, alongside vitamin C and, to a lesser extent, vitamin A. Vitamin E taken orally is highly popular as a dietary supplement. Numerous articles have been published in peer-reviewed journals, including the most prestigious ones, that purport to provide evidence that vitamin E is beneficial in such varied disorders as heart disease, Alzheimer’s disease, macular degeneration of the retina, and senescent changes in body organs. No consensus exists regarding the value of vitamin E, including high doses of vitamin E in the diet, to combat any of the conditions in which a scientific case could be made for its well-known free radical scavenging activity. The case for vitamin E supplementation is subjudice. High doses, which many prefer, can be harmful. The same situation prevails in the case of vitamin E-containing antiaging skin care products, of which there are now hundreds in the marketplace. As with vitamin C, the story is a good one theoretically, but proof lies in performance and not in casuistic pseudoscientific rationalizations. Several books tout antioxidants for a wide variety of skin conditions. It is known that vitamin C and vitamin E stored in the horny layer are degraded by UV light and can be depleted in photodamaged skin. It seems reasonable to replace these deficiencies in a convenient manner by incorporating them into moisturizers that individuals use every day as a matter of good grooming. Also, endogenous antioxidants such as superoxide dismutase have a solid sound that educated consumers like to look for in the labels. Superoxide dismutase
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is a protein that has no chance of achieving biologically active concentrations in skin. Nonetheless, it is present in innumerable formulations anyway. The supporting evidence for the efficacy of another antioxidant, lipoic acid, derives from in vitro studies, which do not translate into clinical practice. Reports of the value of antioxidants in skin care formulations cannot stand up to critical scrutiny as having met the rigorous standards of proof of efficacy. Topical antioxidants appear not to be harmful, however.
THERAPEUTIC COSMETOLOGY (DERMATOCOSMETOLOGY)
In keeping with the trend to produce biologically active products that improve the structure and function of skin, it is timely to envision a new mission and role for the cosmetic industry. Cosmetic firms intuitively shy away from promoting products that treat skin diseases, which is seen as the domain of the medical profession. The reality is that the industry already produces therapeutic products, whether or not these are called over-thecounter drugs or are regarded as cosmeceuticals. The exact category depends not so much on the active ingredients, which may be identical, but rather what the label says regarding the intended use. Acne vulgaris epitimizes the problems and possibilities. Most adolescents experience some degree of acne and usually go to the drugstore rather than consult a physician for treatment. Acne, although a genuine pathologic process, is dominantly a cosmetic problem, which despoils appearance and affects psychosocial behavior negatively. For the affected individual, there is no such thing as mild acne. Two pustules and three comedones may ruin the life of an emotionally vulnerable individual. Drugstore therapy is just as effective for moderating mild-to-moderate acne as a visit to the dermatologist. Salicylic acid is an excellent comedolytic agent that prevents comedones, the primary event in the pathogenesis of acne. It is available in many agreeable forms to suit every kind of personal preference (i.e., creams, gels, solutions, and lotions). Salicylic acid mild washes can be combined effectively
with topicals. Also, there is an array of benzoyl peroxide products, which have an unmatched capacity to eliminate the follicular population of Propionibacterium acnes, the organism responsible for converting comedones into inflammatory lesions (papulopustules), which may leave scars. Benzoyl peroxide is far more effective than the topical antibiotics that dermatologists prescribe to suppress P. acnes. I? acnes does not become resistant to benzoyl peroxide, which is a major problem with antibiotics. The combined use of benzoyl peroxide and salicylic acid attacks acne at two of its most vulnerable points, the formation of comedones and the suppression of I? acnes. Over-thecounter products provide self-treatment of the vulgar forms of moderate acne, treatments that are at least as effective as most physicians can provide with expensive prescriptions. The introduction of film-forming polymers to extract microcomedones qualifies as a breakthrough in cosmetic technology. Formerly, dermatologists used cyanoacrylate polymer (Krazy Glue) to seep into the follicles and harden into a film, which then could be lifted off to pull out I? acnes-laden horny plugs. With products such as Biore, the process has been simplified greatly because all one has to do is wet the skin and apply a polymer-impregnated patch for about 15 minutes. Other polymers are in development. This novel technology is an invitation for the industry to consider the exciting possibility of moving into a new but related territory where it already has the resource to expand its traditional services, a field that might be called diagnostic cosmetology. For example, prepubertal children, as young as age 8 for girls, who show subclinical microcomedones are destined to develop clinical acne and visible comedones (whiteheads and blackheads) 4 to 5 years later. High-risk children, whose mother, father or both had scarring acne, can be tested periodically with polymer-impregnated patches starting at age 7, keeping an archival record of the results. If crops of microcomedones start to appear on the nose at age 8, 9, or 10, comedolytic treatment can be inaugurated. Prevention of disease is always
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more desirable than treatment. The latter can be viewed as a failure of prevention. Another diagnostic technique can be used to predict which children are likely to develop clinical acne. Sebutapes (CuDerm, Dallas, TX) are prepackaged adhesive-coated disks that yield black-and-white pore prints of sebum droplets. Sebum output is low in children but increases when the glands begin to respond to androgens at prepuberty in girls, even before menstruation. The presence of numerous droplets, especially with copious outlet, presages the early development of clinical acne. It is not too far-fetched to envision the time when a company will create an educational program to head off acne, producing diagnostic kits of Sebutapes and polymer patches, along with treatment cosmetics based on salicylic acid and benzoyl peroxide therapies. Rosacea is another serious cosmetic disorder that is not only an embarrassment when the face turns bright red, but also threatens the quality of life because of its emotional impact. The red face syndrome mainly afflicts women and is growing in prevalence among adults. An ambitious, enterprising, innovative cosmetic company could take up an active position that could be extremely helpful to rosacea sufferers. Two openings can be envisioned. The first is therapeutic based on the fact that the current topical treatments prescribed by physicians are far from satisfactory. Ancient formulations containing 5% to 10% elemental sulfur are probably more consistently effective than pharmacologic agents approved by the FDA. Colloidal sulfur, rather than the elementary sulfur in current products, is more effective because of its small particle size. The problem is that sulfur stinks, is irritating, and is cosmetically unattractive. Over-the-counter sulfur is an unpatentable substance. It is precisely the cosmetic industry that has the technical know-how to solve each one of the above-mentioned negative features of sulfur. An encapsulating system, such as liposomes, microsponges, or nanospheres, could be used to entrap sulfur and to release it slowly to avoid a bolus effect, while making it less malodorous. Sulfur is an ancient ingredient that may prove to have therapeutic properties if it could be made palatable to the
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consumer, a fact well within the capabilities of the modern cosmetic industry. Is it more than folklore that accounts for the widespread use of sulfur over centuries for the treatment of acne and rosacea? Rosacea offers another great possibility to the new field of diagnostic cosmetology. The diagnostic hallmark of rosacea is long-lasting blushing, triggered by a variety of factors. Girls who are flusher-blushers in adolescence are at high risk of developing rosacea when they reach their 30s and 40s. A drop of a vasodilating substance, such as sorbic acid (a familiar preservative), applied to the cheek provokes a spreading erythema that may last 15 to 20 minutes in a prerosacea flusher. Sorbic acid could be incorporated into a small adhesive disc similar to Sebutape, making it easy to apply the patch for a prescribed time and follow the pattern and intensity of the erythema. Treatment could be started in adolescence, long before the clinical stigmata of rosacea become apparent. With patients playing a greater role as partners in treatment programs, these devices could have a great future in identifying individuals who are at high risk for developing common skin diseases, not excluding atopic dermatitis, another growing problem throughout the world. There is no reason why the cosmetic industry should not play an influential role in this new field of preventive dermatology. MISCELLANEOUS INGREDIENTS
The ingenuities of some cosmetic manufacturers are great, and so is the number of exotic ingredients that are appearing in topical antiaging products. Most of these are marketed without proof of efficacy or safety. The inventory of such substances is endless. The sea contains thousands of mostly unexplored materials that are now appearing in cosmetics. There are hundreds of thousands of plants, most of them unclassified, providing an endless source of new ingredients. This is traditionally an attractive area because plants have been the source of drugs that have benefited humans immensely (e.g., digitalis and morphine). Botanicals have come to the fore,
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providing a source of new bioactives that might match the benefits that have been achieved by pharmacologists. As always, the proof is in the performance. There are an endless number of ingredients derived from animal sources: hormones, such as melatonin, dehydroepiandrosterone, and estrogens, enzymes, such as telomerase, which has created a sensation by promising an extension of human longevity; fats (from exotic animals such as the emu); placenta; growth factors; cytokines; chicken embryos; and transforming growth factor, a wonder drug that supposedly allows wounds to heal without scarring, as in fetal skin, which is rich in transforming growth factor-p. Because all of these ingredients are natural and exempt from regulation by the FDA, how long will it be before these will enrich antiaging topicals? Finally, there are luxury high-end cosmetics that cater to people who believe that value is proportional to price. These examples are ludicrous and include such ingredients as caviar and gold dust, at prices exceeding $200 per ounce. There is no known relationship between price and function in any category of cosmetics. There is no justification for the American credo that more is better. One example is cited of a newly successful product that illustrates the limit in absurdity has not yet been reached. This boutique-type formulation contains the following active ingredients: (1) 8 antioxidants, (2) 11 vitamins, (3) 12 minerals, (4) 6 hydroxy acids, (5) 21 Chinese herbs, (6) 6 sunscreens, (7) 3 enzymes, (8) 2 phytoestrogens, (9) 6 marine principals, and (10) 4 plant anti-idammatories. If this cosmetic was classified as a drug, it would take more than $3 billion and two lifetimes to prove according to FDA rules that each ingredient contributed to the overall performance.
PSEUDO-ISSUES
Marketing and merchandising in the ebullient, fast-track competitive cosmetic industry plays such an enormous role in capturing the market share that some insidious and egregious practices have practically become an obsession. These are disguised under the eu-
phemism of creative marketing, in which leading celebrities receive salaries orders of magnitude greater than the sober scientist who creates and validates new products. These practices speak unfavorably on the industry and lead many to question whether standards of ethical conduct can be violated indefinitely, without a damaging backlash of publicity. The obvious instances of phony, unmeritorious issues include the following.
Negative Advertising Negative advertising plays into the hands of misinformed chemophobic consumers who are certain that some ingredients in skin care products are harmful and should be eliminated. Industry often caters to this irrational end, and the ploy of the marketers is to emphasize blatantly what is not in the product; for example, lanolin-free, fragrance-free, preservative-free. Allergen-free is designed for sensitive skin. Such warnings come with no evidence that such products are safer for people with sensitive skin. Some dermatologists have made a career of reporting the supposedly high frequency of contact allergy resulting from cosmetics, sometimes arguing that 10% of users may have become sensitized to one or more components. These political toxicologists do a great disservice to an industry whose safety record is exemplary. Many patients with various problems believe they have sensitive skin when this cannot be validated by testing. They buy products for sensitive skin, which generally cost more. Lanolin allergy, in particular, is a fiction of the political toxicologists who do not understand the limitations of patch testing and who fail to recognize the frequency of false-positive patch tests in patients with chronic dermatoses, who compose a small segment of consumers. Tons of lanolin are sold worldwide every year with an extremely low incidence of contact allergy. Contact allergy to preservatives and fragrances can be a problem in patients with chronic skin disorders, but these are special cases and not representative of the general population. Lacking are corresponding figures for an unselected, normal population.
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No manufacturer selling products on a global scale could afford to put a product on the market in which the prevalence reached 1 in a 1000 (0.1%) much less 15%. At that rate, the incidence of contact allergy would be 1000 for every 1 million users, a prohibitively high level that would require pulling the product off the market to avoid litigation. These criticisms do not argue against the worthiness of providing fragrance-free and preservativefree products for individuals who are truly allergic. Fragrances are a much enjoyed and pleasing feature of the products into which they are incorporated. Overall the risks are low and the benefits great. Preservatives are a prerequisite for most cosmetic creams, which are water-containing emulsions in which bacteria can thrive. Poor preservation is a danger to health, as has been evident in the case of contamination by gram-negative organisms in sick and immunosuppressed patients. Patients who are sensitive to preservatives should have access to preservative-free products.
Claim Substantiation: The Bioengineering Paradox
Responsible manufacturers of cosmetics appreciate the importance of supporting their claims by credible procedures that meet the international rules of scientific evidence. The last 2 decades have witnessed the emergence of the new specialty of bioengineering, in which the principles of material science are applied to skin with the intent of providing quantitative objective proof of efficacy, rather than relying on subjective criteria, which may be irrelevant and misleading. Nearly 100 bioengineering devices exist for measuring some physical feature of skin. The familiar ones include (1) the Evaporimeter (Servomed, Sweden), to measure transepidermal water loss; (2) ultrasound scans, to estimate dermal thickness; (3) laser-Doppler velocimetry, to measure blood flow; (4) estimation of the hydration of the stratum corneum by electric conductance; (5) biomechanical properties, such as viscoelasticity; (6) thermography; and (7) chromammetry.
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These devices not only furnish quantitative data on some particular property of human skin but also have the advantage of being noninvasive, replacing procedures such as biopsy, which are not only disagreeable to subjects, but also may leave scars and unsightly hypopigmentations or hyperpigmentations. These instruments have become convenient and powerful in delineating a defined physical feature of skin, with high precision and reproducibility. In the proper hands, noninvasive bioengineering methods are extremely valuable for obtaining a battery of diverse measurements that characterize the structure and function of skin obtainable in no other way. As with all powerful tools, however, bioengineering methods can be manipulated to obtain results that are not only misleading, but also specious. The game of claim substantiation is a sophisticated one in which unscrupulous manufacturers exploit bioengineering techniques to prove every claim that the marketers need to show superiority over a competitive product. Statis tical significance deriving from reams of numbers is not the same as clinical significance. Anyone can place a probe on the skin and make a measurement. It takes a knowledgeable scientist to know exactly what is being measured, to know how to interpret the result, and to understand its relevance. Each device is monodirectional and measures one defined function, whereas it may require a battery of instruments to capture multidirectional effects. The misuse of bioengineering methods to substantiate false claims does not necessarily involve chicanery or overt dishonesty. It is simply a matter of choosing the right instruments to obtain the desired, predetermined result. After making a battery of measurements using different instruments, it usually turns out that some are favorable in support of the claims and others are unfavorable, that is, counterproductive. It is not difficult to imagine which data are presented to the world and which are kept out of sight. FUTURE POSSIBILITIES Petrolatum
Petrolatum is the king of moisturizers and emollients. Why not develop a synthetic pet-
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rolatum with chemically defined ingredients instead of the mishmash petrolatum that contains hundreds if not thousands of hydrocarbons, most of which escape identification. New technology is beginning to meet the challenge of creating nongreasy, nontacky topical drugs that often have to be used for long periods. A corticosteroid cream has come on the market that is delivered as a fastbreaking foam that is esthetically agreeable and promotes penetration.
Perfect Sunscreen Solar radiation encompasses an exceedingly broad range of frequencies: UV-B, UVA I and 11, visible light, and the infrared (the last-mentioned accounting for 40% of the total flux). Infrared (heat) can cause severe photodamage ending in cancers and can act synergistically with UV-B and UV-A to promote photodamage. Most current sunscreens have gaps that allow certain wavelengths to pass through. Broad-spectrum sunscreens as currently understood include UV-B and UV-A radiation but ignore the infrared. Infrared can be blocked by ultrafine zinc and titanium dioxide. The currently available agents tend to be cosmetically unacceptable by imparting a whitish color to the skin, however. The technology exists to overcome this esthetic defect by using high-energy pulses to break down the oxides into particles of a nanometer size that leave no unsightly residue after being rubbed in. Sunscreens are becoming available in Europe that are approaching true broad-spectrum protection. The cosmetic industry deserves great praise for its great achievements in the sunscreen market.
Tars For hundreds of years, coal tars were the mainstay for treating chronic dermatoses in the presteroid era. They are the ultimate examples of substances that sting, stain, and smell. The fact is, however, they still have a place in the over-the-counter treatment of psoriasis, dandruff, and other common problems. They also have some unexplained anti-
inflammatory activity as well as being antipruritic. Could the cosmetic industry help the pharmaceutical industry clean up coal tars? HEURISTICS VERSUS HEDONICS
The paradox of heuristics versus hedonics is rarely discussed, but in the new age of bioactives and functional cosmetics it constitutes a significant problem. This tension arises because consumers desire products that are pleasant, are enjoyable, are easy to apply, feel good, look good, are mild (nonirritating), and furnish a full range of sensory satisfactions. Active products may be antithetic to hedonics because they are specifically designed to achieve a corrective, beneficial effect. As they become more functional, they become less pleasing and rank poorly in premarketing tests in which panelists give undue emphasis on esthetic and sensory properties. The marketing decision in this conflict usually is determined in favor of hedonics based on the operative rule that ”consumers won’t buy products they don’t like.” This is a reality that cannot be ignored completely but comes at a high cost when the benefit that is sought is sacrificed in favor of pleasing the customer. This situation may mean that the producer has to educate the consumer and to explain why the product has some downsides. For example, it is easy to make antiaging retinoids less irritating-decrease the concentration, but then the product becomes less effective. This tactic may be successful from the standpoint of sales based on the fact that consumers often cannot discern true differences in efficacy, especially if the vehicle is enriched in traditional emollients. Cosmetics, in contrast to drugs, do not qualify as placebos. They nearly always have an appreciable beneficial effect. Hydroxy acids, such as lactic acid and salicylic acid, furnish another compelling example. Among other things, these are exfoliants that remove coarse superficial scales from rough-dry skin. They become active if the pH is lowered, but they also become more irritating at the low pH values at which they work best. The cheap solution is to raise the pH to the point where they still work a little
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but are less likely to produce stinging and burning. Sophisticated formulators usually arrive at some compromise, depending on the products that are to be mass marketed or targeted to salons, dermatologists, or spas. Now that cosmetics have ascended to the bioactive, functional category, it is timely to ask whether aromachology will soon be promoted to a similarly respectable position. The concept of using fragrances to alter moods and behaviors is as old as civilization. Evidence is accumulating that certain odors can jog memory, enhance cognitive performance, and produce a state of tranquility. Some fragrances are associated with localized patterns of brain activity that now can be recorded by modern imaging techniques. All that is needed is for the science to supplement the smell. The selection of a fragrance for a given soap and moisturizer may then depend less on hedonics than on desired psychologic effects. Osmoceuticals may be the next great wave in the sea of cosmeceuticals. CONCLUSION
The major manufacturers produce an array of products that contribute enormously to the daily satisfactions and pleasures of modern life. These products are tested routinely for safety and often test marketed to ensure that consumers will perceive claimed benefits. The central issues raised in this article relate to the problems that come from an essentially unregulated marketplace. No one wants to see cosmetics regulated as drugs; still, there
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is a need for some middle ground or compromise. Europeans are ahead in this regard. The EEC publishes directives on the standards that manufacturers are required to meet regarding safety and claims? These directives do not have the backing of strict laws for enforcement, but the industry makes serious efforts to cooperate. There are advisory committees made up of academics and industry scientists who meet regularly with the European commission to revise and implement standards. Self-regulation has not worked well in the booming capitalistic economy of the United States. The self-imposed safety record is a credit to the industry. The next stage is an agenda to set reasonable policies for claim substantiation. Academics must participate in this development and work at educating the public. Finally, as regards the future, the author recommends Skin: Interface of a Living System: Perspective for Skin Care in the Future.4
References 1. Kligman AM: Hydration injury to the skin. In Vander Walk DG, Maibach HI (eds): The Irritant Contact Dermatitis Syndrome. Boca Raton, FL, CRC Press, 1996, pp 187-194 2. Kligman AM: Cosmeceuticals as a third category. Cosmetics and Toiletries 113:33-40, 1998 3. Rogiers V Efficacy claims of cosmetics in Europe must be scientifically substantiated from 1997 on. Skin Res Techno1 1344-48, 1997 4. Tagami H, Parrish JA, Ozawa T Skin: Interface of a Living System: Perspectives for Skin Care in the Future. New York, Elsevier, 1998
Address reprint requests to Albert M. Kligman, MD, PhD Department of Dermatology University of Pennsylvania 226 Clinical Research Building 415 Curie Boulevard Philadelphia, PA 19104