TOXICITY OF COSMECEUTICALS - NOT TO BE IGNORED

The consumer-manufacturer enthusiasm revolving around cosmeceuticals has unfortunately eventuated into addition f many chemicals as additives in the commercially available preparations to enhance their properties, qualities, significance, performance, and viability.[15] In the following section, we mention the established/potential toxicity of some important chemical ingredients frequently used in cosmeceuticals:

1,4-dioxane (C4H8O2, dioxane) - It is an ether with emulsifying, detergent, and solvent properties making it a preferred additive in shampoos, mouthwashes, and kinds of toothpaste. Accidental significant exposure to this chemical by ingestion/other modes of consumption at levels beyond standard lab animals' threshold can act as a potent carcinogen eliciting cancer of breast, skin, and liver; potent inducer of irritation in the nasal cavity and tumors in the liver of animals, and endocrine disruption properties of 1,4-dioxane in animals. Fortunately, there is no proof of genotoxicity effects on the human reproductive system to date.[16]

Formaldehyde and paraformaldehyde - Formaldehyde, commonly used as its 37% concentrated solution 'formalin' and paraformaldehyde, are popular preservatives in various cosmetic products, including liquid soaps and shampoos. Since inhalation constitutes the most common route of exposure, this set of preservatives are considered one of the most common indoor contaminants. The toxic properties of formaldehyde and derivatives include - pro-allergenicity, carcinogenicity, mutagenicity, and high-level exposure correlates to an increased risk of developing myeloid leukemia.[17] Additional issues concerning these chemicals include -  ophthalmic irritation and nose and throat irritations, amongst others.

Parabens -  Parabens are esters of p-hydroxybenzoic acid. They have extensive use as preservatives in cosmetics, cleansing products, and moisturizers. Methylparaben, ethylparaben, benzyl paraben, butylparaben, and propylparaben are common congeners used. Although they have a good safety profile, their continuous high-dose application may exert a potential menace to human health. Recently, research ash identified ill-effects of parabens - on male reproductive health (damage to spermatozoa),[18] detection of parabens in the mammary gland and breast cancer tissues,[19] genotoxic effects of paraben on peripheral human lymphocytes[16]. Since 2011, the Danish Environmental Protection Agency (EPA) also banned the use of butyl and propylparaben in cosmetic products for children under three years owing to their harmful consequences for newborns and children.[16]

The list of such additives with potential or established toxicity profile is enormous and beyond the scope of this chapter; and includes benzalkonium chloride, imidazolidinyl urea, and diazolidinyl urea, trace metals, phthalates, isothiazolinone derivatives, phenoxyethanol and many more. Readers are advised to refer to an exhaustive review devoted to his aspect for further details.[16]

The same molecule could be a cosmetic constituent in one concentration, while it could be used as a cosmeceutical in another like salicylic acid in lower concentrations are used in cosmetics, but 2% salicylic acid used in creams have a completely different effect. Similarly, kojic acid is used in many cosmetic creams in lower concentrations, while in concentrations of 2 to 5%, it attains the status of a cosmeceutical.[20]

The evaluation of the biological characteristics of the active ingredients in cosmeceuticals, especially for organic sources like marine extracts, depends on the selection of an appropriate EXTRACTION process.[21]  The quality of the end product depends majorly on a properly conceived and executed extraction technique. Of course, other factors that are of vital importance in determining the end product include various physicochemical properties of the source material, the type, and concentration of the extracting solvent, the ambient pH, temperature, and pressure conditions of the extraction methodology amongst others.

The extraction techniques divide into conventional or classical, and the novel or modern approaches.

CONVENTIONAL EXTRACTION METHODS [21]:

(1) Hydro-distillation 

(2) Soxhlet extraction

(3) Maceration

(4) Percolation

(5) Infusion

(6) Decoction

(7) Hot continuous extraction

Of the above, Soxhlet extraction has been the conventional methodology, especially for plant/marine-derived sources. However, the need for pre-digestion by acids with consequent time consumption is a major limiting factor. Other limitations of the above-mentioned conventional extraction techniques include the requirement of high purity solvents, low extraction yield, decomposition of thermolabile ingredients, and long extraction periods.  The novel non-conventional (modern) extraction techniques were developed to overcome some/most of these limitations. Further, since modern technologies comply with the U.S. Environmental Protection Agency (EPA) standards, they are considered eco-friendly or 'green.'   A detailed discussion of each of the modern technologies and evaluation methodologies for individual cosmeceuticals is beyond the scope of this CME chapter. Thus interested readers are advised to refer to comprehensive articles authored on this subject.[21][22]

MODERN EXTRACTION METHODS [21]:

(1) Superficial-fluid extraction (SFE)

(2) Pressurized-liquid extraction (PLE)

(3) Enzyme-assisted extraction (EAE)

(4) Microwave-assisted  extraction (MAE)

EVALUATION OF COSMECEUTICALS

The father of 'cosmeceuticals,' Dr. Albert Kligman, suggested three crucial questions to be answered to ascertain the claimed physiological/biological/therapeutic effect of a cosmeceutical product [23][24]:

1. Is the active ingredient able to penetrate the stratum corneum (SC) and be deliverable in sufficient concentrations to its intended skin target over a time course consistent with its mechanism of action?

2. Does the active ingredient possess a known specific biochemical mechanism of action in the target cell or tissue in human skin?

3. Are there published, double-blind, peer-reviewed, placebo-controlled, statistically significant, clinical trials to substantiate the efficacy claims?

PENETRATION ACROSS STRATUM CORNEUM(SC):

Penetration of ingredients across the SC, a robust barrier to prevent transepidermal water loss (TEWL), is the first hurdle to be overcome. Proteins, peptides, sugars, and nucleic acids with molecular weights >1000kDa and highly charged molecules find it difficult to penetrate an intact SC. The penetrating behavior of an active ingredient can undergo evaluation:

(1) in vitro

(2) ex vivo, and

(3) in vivo

Basic Principle - The published human stratum corneum permeability coefficient (Kp, often expressed as log Kp) has been used for ages by investigators to develop models to predict skin permeability.[25] The most commonly used device for in vitro diffusion and for determining penetration through skin consists of the Franz-type diffusion cell or its modifications.[25] For in vitro studies, this barrier can consist of an artificial skin construct (ASC). Ex vivo studies employ either animal skin, human cadaver skin, or bovine udder skin (BUS) as the barrier.[26]

For human in vivo penetration studies, tape stripping, or advanced spectroscopic methods, e.g., ATR (attenuated total reflection) spectroscopy is an option. A more advanced in vivo technique is microdialysis.[27] Some newer approaches include - principal components analysis (PCA), probabilistic analyses, fuzzy modeling, artificial neural network (ANN) modeling, and biopartitioning micellar chromatography, amongst others.[25] The development of newer carrier systems and techniques with nanoparticulation, ionto- and electroporation, liposomes, etc. have not only revolutionized the approach to enhance smooth percutaneous absorption of desirable ingredients but have correspondingly lead to the development of more sophisticated evaluation techniques.

BIOENGINEERING TESTS FOR DRUG TARGET IDENTIFICATION 

Various bioengineering techniques have been employed to determine the specific drug target within the skin. Some of these include[28][29][30][31]:

(1) Evaporimetry - for measurement of cosmeceutical impact on reducing TEWL

(2) Corneometry - conductivity of skin to a low electric current to evaluate skin water content

(3) Profilometry - to evaluate skin texture and improvement in skin elasticity and fine wrinkles

(4) Laser Doppler flowmetry - to evaluate erythema indices using the Doppler effect to measure the cutaneous blood flow

(5) A-scan ultrasound imaging - to ascertain the 'skin thickening' claims of cosmeceuticals

CLINICAL TRIALS FOR SUBSTANTIATION OF CLAIMS

This is perhaps the most important aspect of evaluation, but it is not an entity in isolation, rather an amalgamation of basic, translational, and clinical trial data on a cosmeceutical. Ideally, clinical trials should prefer noninvasive instruments to measure parameters such as TEWL, corneometry, skin elasticity, colorimetry, profilometry, and other techniques to approve or disprove efficacy claims. Pre-treatment and post-treatment photography is essential but not adequate in isolation owing to pitfalls in standardized clinical photography. Further, the study design should include a large cohort as feasible, be controllable through a placebo, or another entity with well-established effects. Randomization, statistical analyses, and well-defined objective outcome measures are also criteria. 

The traditional way of histology to demonstrate the effects of a product is ideal but suffers from logistic issues. In contrast, dermoscopy and/or confocal microscopy are novel and validated tools for better assessment than gross photography and are preferred over histology by study subjects and/or volunteers owing to their non-invasive trait.[32]

Cosmaceuticals have been used in a variety of therapeutic indications like[33][34]:

1) Skin lightening or depigmenting

2) Sunscreens

3) Moisturization

4) Anti-wrinkle/aging effects

5) Scar-reduction

6) Antioxidants

7) Hair strengthening, hair fall arrest, hair growth stimulation, textural hair improvement

8) Treatment of specific disorders, e.g., acne, rosacea, melasma

9) Miscellaneous uses

• Atopic dermatitis

• Contact dermatitis

• Drug eruption

• Erythema infectiosum

• Erythema multiforme

• Folliculitis

• Guttate psoriasis

• Insect bites

• Keratosis pilaris

• Nummular eczema

• Tinea corporis

• Urticaria

Although there is a relative lack of patient studies and trials (primarily stemming from the definition-related issues of regulatory authorities), attempts are being actively pursued to draft well-designed and controlled trials to compare the safety and efficacy of various cosmeceuticals and their constituents for specific indications.[35]

There is generally no fixed duration or dosage of any cosmeceutical. Providers familiar with the use, efficacy, and safety profile of different cosmeceuticals use their preferred products for specific indications. The dose and duration of therapy while planning the treatment for a particular condition may be highly variable and depends on various factors including patient, condition, ingredients, evidence (if available) of efficacy, safety, tolerability,  and clinician's personal preference based on experience.[35]

A general approach of using cosmeceuticals for anti-aging purposes is suggested:

(1) CLEANSERS - Use of a gentle cleanser containing cetyl alcohol and stearyl alcohol for sensitive skin - this is typically a lather free cleanser and does not leave the face dry. For patients with oily skin, a mild exfoliating cleanser containing a low percentage of alpha-hydroxy acids (AHA), e.g. lactic acid 5%, or a combination [glycolic 1%-2%, Salicylic 1-2%, mandelic 2-5%] may be preferred. For patients with severe tendency of facial oiliness, a stronger face wash containing higher percentages of the AHAs and surfactants may be used.

(2) SUN PROTECTION - The key to anti-aging, prevention of unwanted pigmentation and prevention of post-treatment hyperpigmentation is effective sun protection. In addition to physical measures of sun-protection, the use of a broad-spectrum sunscreen with an SPF of at least 30 must be applied as per the modified teaspoon rule (MTSR), which means that one teaspoon (=5 ml) should be applied to the face + scalp + neck,  left arm/ forearm, right arm/forearm, and two teaspoons each to the right thigh/leg, torso, and left thigh/leg. [36] The first cote must be on the skin at least 25-30 minutes prior to expected sun-exposure and should be repeated every 2-3 hourly, depending on the prevalent seasonal and weather conditions. Sun-screen must be applied around the year, even indoors.

(3) VITAMIN A based topicals - Retinoids are the natural and synthetic derivatives of vitamin A and maybe a part of OTC cosmeceuticals or prescription topical medication. Retinoic acid (RA), and the synthetic higher generation retinoids such as adapalene, tazarotene, and bexarotene are registered prescription drugs. The retinoids that are typically a component of topical cosmeceutical include retinyl esters, retinol (ROL), and retinaldehyde (RAL). [37] In the skin, ROL is oxidized to RAL, and RAL to RA; the latter being the biologically active form of vitamin A. Topical cosmeceuticals containing ROL and RAL are expected to work after getting metabolized to RA by the effect of the skin enzyme cytochrome P-450-dependent RA 4-hydroxylase (CP450-RAH). Studies have shown that the threshold concentration of RAL and ROLessential for adequate percutaneous penetration and metabolism to RA is around 0.025%. [38]  Thus, a minimum concentration of 0.025% of ROL or RAL is typically present in retinoid containing cosmeceuticals. The anti-aging effects of daily night-time retinoid application include a reduction in the roughness of the skin, evening out of the mottled pigmentation, and gradual reduction of fine rhytides. It must be noted that while the concentration of retinoids in cosmeceuticals does not give as good results as the higher permissible concentration in pharmaceutical topicals, the consumers of the former are usually satisfied with the effects obtained with cosmeceutical-range retinoids. [22].

(4) ADJUVANTS -

• Topical nicotinamide, a form of vitamin B3 is known to exert pleiotropic effects over the aging skin including improved epidermal barrier, direct reduction of hyperpigmentation, repair the outcome of solar damage such as redness/blotchiness, improve skin elasticity, and reduce fine rhytides in addition to its antioxidant property. A specific property of niacinamide is in the reduction of age-related yellowing of the skin that stems from the Maillard reaction, which involves spontaneous oxidation and glycation of proteins. The reaction progresses with aging and the resulting cross-linked proteins give a yellowish hue to the aged skin. [39][40]  Niacinamide undergoes an oxidoreductive transformation, and its antioxidants forms, NADH and NADPH can inhibit the Maillard reaction, and by extrapolation, reduce skin yellowing.   It is important to note that the other form of vitamin B3, nicotinic acid also has anti-aging potential. However, it causes intense vasodilation resulting in skin flushing; a side-effect that bothers most consumers. That is why the efficacy of niacinamide has been studied much more than nicotinic acid as a topical cosmeceutical agent. Niacinamide used as 2%, 2.5%, and 5% has been found to provide acceptable anti-aging effects to the consumers. [41][39][41]
• Soy derivatives - The major pharmacologically active components of soy proteins include phospholipids, essential fatty oils, isoflavones, and the enzymes soybean trypsin inhibitor (STI) and Bowman-Birk inhibitor (BBI). Topical isoflavones constitute the most effective component of soy that exerts multiple anti-aging effects via anti-oxidative mechanisms, stimulation of neocollagenesis, and enhancing moisturization of the skin.  and their ability to reduce ROS, stimulate collagen synthesis, and increase the moisture content of the skin. Soy isoflavones metabolize into genistein and daidzein, which serve as phytoestrogens (plant-derived compounds with a weak pro-estrogenic effect). The thinner collagen-deficient dermis in postmenopausal women is considered to be due to the withdrawal of the favorable effect of estrogens. Akin to the effect of topical estrogen in retarding collagen loss and skin thinning, these soy derivatives have a similar potential of providing the anti-aging effect to the post-menopausal skin via estrogenic stimulation. Additionally. the enzymes STI and BBI contribute towards a reduction in skin hyperpigmentation. Recently, a novel soy-based moisturizer was found to be efficacious in improving dullness of skin, mottled pigmentation, fine rhytides, and overall skin tone after 12 weeks of use in 65 women with moderate facial photodamage.  [42]
• Green Tea - Green tea is the least processed form of the leaves and buds of the tea plant. Compared to black and white tea, green tea contains the highest amount of the polyphenol epigallocatechin-3-gallate (EGCG), in addition to epicatechin, and epicatechin-3-gallate (ECG). Green tea polyphenols exert anti-aging effects through their anti-inflammatory and antioxidant effects via scavenging of free radicals.   Several in vivo and in vitro studies have suggested the potential of green tea supplementation in stimulating synthesis of collagen and elastin fiber content in the dermis and suppression of MMP-3 enzyme, a collagenase with a resultant anti-wrinkle effect. [43]
• Ascorbic acid and derivatives - Vitamin C is one of the strongest natural anti-oxidants of the human body. It has been shown in many trials to possess potent antiaging property, effected by stabilization and stimulation of collagen synthesis, and decreasing collagen degradation. Additionally, it reduced hyperpigmentation through its inhibitory effect on melanin synthesis. It works synergistically with vitamin E as an anti-oxidant unit, as the former acts as the primary replenisher of the latter. Among the various available forms, L-ascorbic acid is the most biologically active. However, L-ascorbic acid shows poor penetration into the skin owing to it being hydrophilic and unstable, unable to penetrate the hydrophobic stratum corneum.  Reducing the acidity of L-ascorbic acid to a pH below 3.5 is an effective method of improving its stability and permeability. This has shown to greatly aid its penetration, largely because of the transformation from the charged to the uncharged form of the molecule.4 In one example of the currently available L-ascorbic acid product (SkinCeuticals, L’Oreal, New York, New York), the addition of ferulic acid aids in both stabilization of the molecule and achieving an acidity of a pH below 3.5.5 Two other common topical formulations of vitamin C include ascorbyl-6-palmitate and magnesium ascorbyl phosphate (MAP). Unlike L-ascorbic acid, which is hydrophilic and unstable, both ascorbyl-6-palmitate and MAP are lipophilic, esterified forms of vitamin C, which are stable at neutral pH.6 Examples of other stable, esterified derivatives of vitamin C are disodium isostearyl 2-0 L-ascorbyl phosphate, ascorbic acid sulphate, and tetraisopalmitoyl ascorbic acid. However, one study showed that daily application of MAP, ascorbyl-6-palmitate, and other ascorbic acid derivatives did not increase the levels of L-ascorbic acid in the skin.4 The optimal concentration of vitamin C depends on its formulation. In most cases, for a product to be of biological significance, it needs to have a vitamin C concentration higher than eight percent.4 Studies have shown that a concentration above 20 percent does not increase its biological significance and, conversely, might cause some irritation.4 Reputable products of vitamin C available today are, therefore, in the range of 10 to 20 percent.

Although the detailed discussion on toxicity profile of cosmeceuticals paints a gloomy picture, in essence, most of the meticulously manufactured cosmeceuticals have good tolerance and require (if at all) minor management approaches for the typically mild and transient adverse effects like a burning sensation, irritation, erythema, PIH, etc. Most of these various side effects are manageable with physician experience, if using mild concentrations, and with early intervention.

It is not possible to prognosticate in general, the outcome of a particular skin issue amenable to improvement with cosmeceuticals. Every skin has different reactivity, response patterns, and a tendency to develop adverse effects to both pharmaceutical topicals as well as cosmeceuticals. The prognosis after recommended use of cosmeceutical(s) for melasma, e.g., would depend upon the:

(1) Disease characteristics - Depth of melasma, the activity of melanocytes, factors (like hormonal pills) that may antagonize the effect of cosmeceuticals

(2) Patient factors - Skin sensitivity and tolerance to the cosmeceutical, compliance, and adherence to treatment, concomitant meticulous use of sun protection, affordability to maintain the long-term effect, etc.

(3) Cosmeceutical factors - quality, cutaneous bioequivalence of brands, cost, effect, tolerance, the possibility of long-term adverse effects, etc.

Thus, the use of cosmeceuticals requires careful individualization in each patient based on all the above factors.

Aids like dermoscopy may aid in the preferential selection of a particular cosmeceutical based on the findings, e.g., melasma showing brown pigmented structures may be amenable to short term use of moderate-strength cosmeceuticals, while stronger treatment may be necessary for deep melasma.[44] A de novo melasma with prominent vascular changes may improve more with tranexamic acid-based preparations instead of hydroquinone.

Although complications can be severe like anaphylactic shock, burns, PIH, or milder and transient like irritant dermatitis, contact allergic dermatitis etc.,  by and large the short-term complications with most of the cosmeceuticals are rare, provided they are used in moderation and as per the prescribing physician's advice with essential precautions followed by the patients.

1) The patient must be informed that these are not drugs per se, and these cosmeceuticals are not a substitute for pharmaceutical-grade dermatological topicals. As a corollary, the time taken for improvement may be more.

2) A very common issue that has become daunting for a practicing dermatologist is that the patient seeking improvement in his/her skin texture/tone/pigmentation/hair loss etc. often approaches the dermatologist enquiring about branded cosmeceuticals that they have been using in the past. The dermatologist should make an attempt to verify the contents of the creams, lotions, and other products being used by the patient, and allow or stop their use depending on the patient's condition, tolerance, and the impact of them being in addition to the planned topicals to be prescribed. A cost factor assumes importance here since the majority of cosmeceuticals are not inexpensive. Thus the treating dermatologist should prescribe cost-effective topicals and have a duration in mind for which it should/can be used. The cosmeceutical may have to be changed depending on the improvement or lack thereof, and if any concomitant drugs (like oral isotretinoin) or physical procedures (peels/laser toning) are planned.

3) There is another facet to the cost-related aspect of cosmeceuticals - Patients often insist on continuing to use 'expensive' skin-care products 'gifted' or 'bought' by them It is prudent to explain to the patient that in your opinion, what will help and what may not.

4) Similarly, often, patients ascribe a new problem, e.g., acneiform eruption to the prescribed cosmeceutical. If the clinician is convinced that this cannot be the result of the prescribed topical, counsel, and observe. If the issue persists or worsens, it is advisable to stop all applications and consider doing a patch test. In patients with known sensitive skin, always advise any new topical to be first tested as a patch over a small area of the face or away from the face for 2 to 3 days, and if tolerated, then only go ahead with the therapy. Short contact therapy has been found very useful in certain situations, especially with topical retinoids and AHA-based lotions. The patient with sensitive skin should be advised to start with short duration exposure (5 to 15 min) followed by rinse off and generous use of a moisturizer.

5) Patient compliance - Checking for patient's compliance of using all the prescribed medicines is essential on each visit. Often patients apply retinoids religiously at night but forget to use the sunscreen in the day time as advised. This is a common reason for otherwise unexplainable reactions like redness, aggravated by sun exposure.

6) Undisclosed applications/parlor procedures - The clinician must determine (especially with relatively stronger agents like retinoids) that the patient is not using additional undisclosed skincare products. These agents can include astringents, toners, SA-based face-washes, or taking parlor treatments like facials, bleaching, 'cleansing' etc. since the latter may result in an unwanted complication that the patient often tends to blame on the doctor's prescribed topical instead of his/her own 'mild' skincare products.

The healthcare industry is becoming increasingly commercialized. New, untested molecules or those with a very weak level of evidence receive aggressive promotion. This industrial behavior can affect the patients (through product advertisements on TV and social media) as well as dermatologists (tall claims by medical reps). While there is no denying that cosmeceuticals constitute possibly over 40% of a specialist's prescription, the dermatologist should exercise great caution before endorsing a product. Attempt to search for the highest level of evidence published and safety-associated trials on a few patients with consent should be the approach towards a newly launched cosmeceutical. Members of the healthcare team must ask about the patient's concomitant treatment, including unrevealed home-based therapies (which often includes irritants) such as face-masks, toners, astringents, and most dreaded, steroidal creams to ensure best and safe outcome with treatment.

To ensure public safety, an interprofessional team that includes a pharmacist, primary care provider, and nurse practitioner should educate patients about the benefits/harms of a cosmeceutical. Further, the cost implications of long term use for maintenance should be discussed at some point in time during the therapeutic regime. The patient should always receive information about alternative or adjuvant treatment options, whether drugs/physical procedures or injectables. Finally, patients should understand about the existence of fake, counterfeit, and bogus cosmeceuticals on the market.

All members of the interprofessional team, from the family physician (including NPs and PAs), the dermatologist, the nursing staff, and the pharmacist, need to have a thorough understanding of these agents. This knowledge will permit team members to determine which agents the patient may be using (since many of them are available over the counter), and communicate with each other to ensure minimal adverse events or interactions with other cosmeceuticals or even actual medications. With each member weighing in and communicating across disciplines, the interprofessional team can better achieve optimal results. Specialty care dermatology and plastic surgery nurses educate and monitor patients, providing feedback to team members. Pharmacists check for drug-drug interactions and also provide education. [Level V]

The healthcare industry needs to take a proper judgment on the judicious use of these agents, which may qualify as drugs. Eventually, their efficacy must be tested. Also, their potency should be compared to other drugs before we start prescribing them as dermatologists and physicians till then, research needs to be increased, and patient education is a must.

Lastly, in the current era of social media and internet serving as sources of primary-skin-care for many patients, dispelling the myths and tall claims sourced from these has become an essential duty of the dermatologist. Remember, the dermatologist is the doctor. The patient lured by the gentlemen pickpockets of social media are innocent and often amenable to transformation with proper counseling. But this requires patience on behalf of the doctor as much as the patient himself/herself.