Cosmeceuticals: A Review of the Scientific Evidence

Molly Wanner, MD/MBA

Disclosures

I have the following relevant financial relationship with a commercial interest to

disclose:

Scientific Advisory Board, Nu Skin

Grand funding, Solta

Investment, Clarity Cosmetics

What Is a Cosmeceutical?

Drugs: Mitigate, prevent, or treat disease. Affect body structure.

Cosmetic: A product intended to improve appearance with NO effect on structure and function of skin

“Cosmeceuticals” = Cosmetic

6 out of 10 people believe that over the counter products are regulated

Federal Food, Drug and Cosmetic Act (1938)

• Ingredients in cosmetics and personal care products are NOT obliged to FDA standard regulatory practices (with exception of food color additives)

• FDA prohibits adulterated or misbranded products

Cosmetics Are Not Regulated

What does this mean?

• FDA cannot require companies to submit pre-marketing safety data

• FDA cannot require companies to report any side effects of products reported by consumers

• Instead, monitoring is performed by the Personal Care Products Counsel

-Sponsored by cosmetics industry

Savvy Consumers Started Asking Questions

Modmarcc.com

Are my products safe?

Do my products work?

Are My Products Safe?

The Clean Cosmetics movement

The search for “non toxic” products

“Clean” Cosmetics: The “Bad” List

Methylisothiazolinone (MI), methylchloroisothiazolinone (MCI), Vitamin A derivatives, fragrance mix, phenoxyethanol, petroleum distillates, formaldehydes, triclosan and triclocarban, toluene, resorcinol, petroleum distillates, butylated hydroxyanisole (BHA), boric acid and sodium borate, phthalates, placenta extract, parabens, phenoxyethanol, PEGs and ceteareth(1,4-dioxane), formaldehydes, coal tar ingredients (including aminophenol, diaminobenzene and phenylenediamine), petroleum distillates, placenta extract

What Is Toxic?

• Toxicity depends on dosage (concentration and absorption)

• There is too much of a good thing.

– Fat soluble vitamins A, D, E, K are stored

– Chronic excessive supplementation can lead to coma or death

• “Natural” ≠ non toxic

– Poison Ivy is “natural”

“Clean” Cosmetics: Let’s See the Science

Commonly avoided chemicals grouped into three categories: irritants/allergens, potential endocrine disruptors, potential carcinogens

PubMed Search performed for chemicals in each above category, with attention to:

• Type of study/study subjects (human data available?)

• Dose (relevant to routine exposure?)

• Route of administration (topical?)

Arrived at a “shortlist” of chemicals that may be worth avoiding

Dr. Neera Nathan

Clean Cosmetics3 Categories of “Bad” Ingredients

CarcinogensEndocrine

Disruptors

Allergens

Irritants

Allergens and Irritants Commonly avoided in “Clean” products

• Formaldehyde

• Fragrance

• Methylisothiazone (MI)

• Methylchloroisothiazolinone (MCI)

• Phenoxyethanol

• Petroleum distillates

• Vitamin A

Allergens

Irritants

Allergens and Irritants What does the science back up avoiding?

• Formaldehyde – hair straightener

• Fragrance

• Methylisothiazone (MI) - preservative

• Methylchloroisothiazolinone (MCI) - preservative

• Phenoxyethanol

• Petroleum distillates

• Vitamin A

Allergens

Irritants

Allergens of the year

Allergens and Irritants What can stay in the cosmetic bag?

• Formaldehyde

• Fragrance

• Methylisothiazone (MI)

• Methylchloroisothiazolinone (MCI)

• Phenoxyethanol

• Petroleum distillates

• Vitamin A

Allergens

Irritants

Endocrine DisruptorsImitate hormones & interfere with normal signaling of chemical messengers

Endocrine

Disruptors

DES (Diethylstilbestrol)Endocrine disruptor in Medical History

• Synthetic estrogen given orally to women in 1940s to 1970s to prevent miscarriage

• Linked to clear cell adenocarcinoma of the vagina and cervix in daughters of women who received this medication

Endocrine DisruptorsWhat does the science back up avoiding?

Commonly avoided in “Clean” products

• Triclosan and triclocarbon

• Parabens

• Phthalates

• Toluene

• Resorcinol

• Petroleum

• Butylated hydroxyanisole

• Boric acid and sodium borate

• Placenta extract

• Phenoxyethanol

Endocrine

Disruptors

?

More research is needed.

More Research Is NeededToxicity depends on concentration and absorption

• Most studies performed in vitro and in animals

• In animal studies, ingredients studied at high doses, orally or subcutaneously

• In human studies, source is unclear, not specifically topical, conflicting studies

Endocrine Disruptors

• Parabens –preservative, antimicrobial

• Phthalates – softener in shampoos and nail polish

• Triclosan and triclocarbon –antimicrobial in toothpaste and deodorant

• Universal

• Many sources

• Absorbed through skin

• Animal studies

• Difficult to link to topicals

• No definitive link to human disease

ParabensPreservative in cosmetics, moisturizers, shampoos, food additives, food packaging, pharmaceuticals

• Penetrate skin. 99% rapidly metabolized in skin to weaker metabolite.

• Weak estrogen

– 4 most common parabens 10,000 less potent than estradiol

Fransway AF et al. Paraben Toxicology. Dermatitis 2019; 30: 32-45.Fransway AF et al. Parabens: Contact (Non)allergen of the year. Dermatitis 2018.Final amended report of safety assessment of methylparaben, ethylparaben, propylparaden, isopropylparaben, and benzylparaben as used in cosmetic products. Inter J Toxicology 2008; 27: 1-82.Darbre et al. J applied toxicology 2014; 34: 925-938.Harley et al. Human reproduction 2019; 34: 109-117.

In Vivo Studies of Parabens ConflictAre parabens endocrine disruptors?

• 338 children in farmworkingcommunity

• Increased urinary levels of methylparaben associated with shift (1.3-1.5 months) in pubarche (pubic hair appearance) and <1 month (menarche)

• 1239 girls in NYC, Cincinnati, San Francisco: No impact on puberty

• Human studies: no impact on semen quality or sperm DNA

Harley et al. Association of phthalates, parabens and phenols in personal care products with pubertal timing in girls and boys. Human reproduction 2019; 34: 109-117. Wolff MS et al. Environmental Phenols and Pubertal Development in Girls. Environ Int 2015; 84: 174-180.Nishihama Y et al. Paraben exposure and semen quality of Japanese male partners of subfertile couples. Environ Health Prev Med 2017; 7: 22-5.

YES NO

Phthalate “Tha-leit”Enhance flexibility of plastic (“plasticizers”), food wrappers, flooring,

medical devices, toys, lacquers, varnish, personal care products

• Phthalates can be absorbed through the skin

– Baby lotion in infants<8 months& powder > 8 months

• Not all phthalates are alike

– In personal care products, diethyl phthalate (DEP) most common in US

– DEP does not have hormonal activity

– Long side chain phthalates have weak hormone activity at high doses Witorsch RJ and Thomas JA. Personal care products and endocrine disruption. Crit Rev Toxic 2010; 40: 1-30.

Janjua NR. Urinary excretion of phthalates and paraben after repeated whole-body topical application in humans. Int J andrology 2008; 31: 118-130.Sathyanarayana S et al. Baby Care Products. Pediatrics 2008; 121: 260-8.Sathyanarayana S et al. Baby Care Products: Possible sources of infant phthalate exposure. Pediatrics 2008; 121: 260-268.

DEPNo hormone activity

DEHPWeak hormone activity

Long side chain

PhthalateEndocrine disruption potential?

• Inverse association of concentration with breast development (Wolff)

• Possible association of DEHP on male genitalia (Swan)

• No association in pubertal timing in girls or boys (Harley)

Witorsch RJ and Thomas JA. Personal care products and endocrine disruption. Crit Rev Toxic 2010; 40: 1-30.Wolff MS. Investigation of relationships between urinary biomarkers of phytoestrogens, phthalates and phenols and pubertal stages in girls. Environ Health Perspect 2010; 118: 1939-1046.Harley et al. Association of phthalates, parabens, and phenols found in personal care products with pubertal timing in girls and boys.Human Reproduction 2019; 34: 109-117.Swan SH. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints. Environ Red 2008; 108: 177-184.

YES NO

Long side chainWeak hormone activityHigh doses impact rat fertility

TriclosanAntibacterial and antifungal deodorants,

toothpaste, clothing, household items

• Animal studies show dose dependent impact on thyroid– Rat study: Dose dependent

decrease of T4 with oral triclosan

• RCT of 132 subjects and 0.3% triclosan in toothpaste – no impact on thyroid

• Human studies conflict

Zorrilla LM et al. The effects of triclosan on puberty and thyroid hormones in males wistar rats. Tox Sciences 2009: 107: 56-64.Cullinan MP et al. Long term use of triclosan toothpaste and thyroid function Science of the Total Environment 2012; 416: 75-79.Mihaich E et al. Hypothesis-driven weight of evidence analysis of endocrine disruption potential: a case study with triclosan. Critical reviews in toxicology 2017 47: 263-285Deierlein AL et al Phenol concentrations during childhood and subsequent measures of adiposity among young girls. Am J Epid 2017; 186: 581-592.Li S et al. Urinary triclosan concentrations are inversely associated with body mass index and waist circumference in US general population: experience in NHANES 2003-2010. Int J Hyg Environ Health 2015; 218: 401-406.

YES NOAvoid?

Potential CarcinogensCommonly avoided in “Clean” products

• Formaldehyde

• Coal tar ingredients

• Petroleum

• 1-4 dioxane

• Placenta extract

Carcinogens

Potential CarcinogensWhat does the science back up avoiding?

Formaldehyde

• Linked to cancer in animals and humans in high doses including topical occupational exposure

• Labeled a known carcinogen by NIH National Toxicology Program

Formaldehyde

25,619 workers in the formaldehyde industry: link between formaldehyde and nasopharyngeal cancerBeane Freeman LE. Mortality from solid tumors amount workers in formaldehyde industries.: An update of the NCI cohort. Am J Indus Med 2013; 56: 1015-1026.

Coal Tar

1,4 dioxane

Petroleum

distillates

Placenta

extract

Coal Tar

Formaldehyde

1,4 dioxane

Petroleum

distillates

Placenta

extract

Potential CarcinogensWhat can we leave in the bag?

Coal Tar

– Industrial use linked to cancer~“chimney sweeps”– Cohort study of 13,200patients did not increaserisk of malignancies

Potential CarcinogensWhat can we leave in the bag?

Coal Tar

Formaldehyde

1,4 dioxane

Petroleum

Distillates?

Placenta

extract

Potential CarcinogensWhat can we leave in the bag?

• CRUDE petroleum on the skin of 50 mice increased skin cancer

• Cosmetics have highly refined petroleum distillates– Poly aromatic

hydrocarbons are not present (known carcinogen)

• 4 Human studies: petrolatum stays in superficial skin due to size

Clark CR, Walter MK, Ferguson PW, Katchen M. Comparative dermal carcinogenesis of shale and petroleum-derived distillates. Toxicol Ind Health 1988; 4: 11-22. Rawlings AV and Lombard KJ. A review on the extensive skin benefits of mineral oil. In J Cos Sci 2012; 34: 511-518.Petry T et al. Review of data on the dermal penetration of mineral oils and waxes used in cosmetic applications. Tox Letters 2017;280: 70-78.

PetroleumDistillates

Mineral oilLight mineral oilHeavy mineral oilLiquid ParaffinMineral oil mistParaffin oil

Petrolatum liquidPetroleum oilParaffinum liquidum

Potential CarcinogensWhat can we leave in the bag?

Coal Tar

Formaldehyde

1,4 dioxane

Refined

Petroleum

Placenta

extract

Potential CarcinogensWhat can we leave in the bag?

More data

More data

Do My Products Work?

Modmarcc.com

Are my products safe?

Do my products work?

Common Cosmeceuticals

• Vitamins A, B, C

• Growth Factors

• Peptides

• Sugars

Koo E, Kimball A, and Wanner M. Cosmeceuticals. In: Griffiths C, Barker J, Bleiker T, Chalmers R, and Creamer D Eds. Rook’s Textbook of Dermatology, 9th Edition. Wiley-Blackwell, 2016.

Absorbed?Biologic

effect?

Clinical

effect? Yes

Do My Products Work?

Absorbed?Biologic

effect?

Clinical

effect?Recommend

Absorbed?

Absorption (J) = Permeability coefficient * Concentration

(Partition coefficient*Diffusion coefficient/Length of path of diffusion)

Concentration and Molecular Weight Influences Absorption

<500

dalton

Hydrophilic – lipophilic balance

Non ionized

Non polar

pH

DOES MY PRODUCT WORK?Can Vitamin A be absorbed through the skin?

Vitamin A: Tretinoin Is Our Gold Standard for Photoaging

• 6 double blind, controlled studies

• 2 largest trials – 619 subjects

– Followed for 6 months

– 86% had global improvementvs 44% control

Weinstein GD et al. Arch Derm 1991Olsen EA. JAAD 1992. Wanner et al. JDD 2015; 14: 13-18.

OTC Vitamin A: Retinaldehyde Induces Retinoic Acid Activity in Humans More Than Retinol

Retinol

Retinaldehyde(Retinal)

All transretinoic acid(Tretinoin)

Duell EA et al. Extraction of human epidermis treated with retinol yields retro-retinoids in addition to free retinol and retinyl esters.JID 1996; 107: 178-182.Saurat JH et al. Topical retinaldehyde on human skin: biologic effects and tolerance. JID 1994; 103: 770-774.

Vitamin A – Retinaldehyde Reduces Fine Lines

• 125 subjects, retinaldehyde 0.05 vstretinoin 0.05 vsplacebo

• Silicone replicas of crows feet

• Improvement of photoaging

Creidi P et al. Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. JAAD 1998; 39: 960-5.

Tretinoin RA Placebo

Retinol Reduces Fine Lines

• Retinol 0.4% (36 subjects): -1.64 point improvement wrinkles vs control on 9 pt scale (statistically significant)

• Concentration in cosmeceuticals can be as low as 0.08%

Lee et al. A newly synthesized photostable retinol derivative (retinyl N-formyl aspartamate) for photodamaged skin: profilometricevaluation of 24-week study. J. Am. Acad. Dermatol. 2006;55:220–4.Manela-Azulay M, Bagatin E. Cosmeceutical vitamins. Clin Dermatol 2009; 27: 469-74.Kafi et al. Improvement of naturally aged skin with Vitamin A (retinol). Arch Derm 2007; 143: 606-612.

My Approach to Vitamin A

• Retinaldehyde when can not tolerate tretinoin

• Concentration matters

Vitamin B3

Niacin

Nicotinic acid

Nicotinamide

/

Niacinamide

Inositol

hexanicotinate

Does My Product Work?Vitamin B3

Vitamin B3

• Precursors of NAD(H) and NADP(H) enzymes –oxidative metabolism

• +ceramides and keratinocyte differentiation

Can Vitamin B3 Be Absorbed Through the Skin?

Vitamin B3 Improves Skin Barrier Function

Placebo

5% myristyl nicotinate(nicotinic acid derivative)

Increases skin thicknessPromotes epidermal differentiationDecreases TEWL

Jacobson EL et al. A topical lipophilic niacin derivative increases NAD, epidermal differentiation and barrier function In photodamaged skin. Exp Dermatol 2007; 16: 490-499.Bermudez Y et al. Nicotinic acid receptor abnormalities in human skin cancer. Plos One 2011; 6: 1-10.

Vitamin B3: 4-5% Niacinamide Improves Acne, Photoaging and Melasma

50 subjects5% reduction in wrinkles vs control

Photoaging

27 subjects44% improved on niacinamide vs 55% hydroquinone

Melasma

Acne

80 subjectsImproved, not as much as 1% clindamycin

Reduced brown spots

Before After

My Approach to Vitamin B3

Sensitive skin and photoagingMoisturizer or spray for Acne

4% concentration, pH 4-7

Antioxidant Collagen Vitamin C

DOES MY PRODUCT WORK?Can Vitamin C be absorbed through the skin?

Vitamin C Absorption Maximized at Concentration of 20% and pH Less Than 3.5

Pinnell et al. Topical L-ascorbic acid: Percutaneous absorption studies. Dermatol Surg 2001; 27:137-42.

Ferulic Acid Stabilizes Vitamin C

– After 2 months, 0% of L-ascorbic acid remained

– >90% L-ascorbic acid present at 2 months when formulated with Ferulic acid

Pinnell et al. Dermatol Surg 2001; 27:137-42

Lin et al. JID 2005; 125:xi-xiii.

Austria R et al. J Pharm Biomed Anal 1997: 795-801.

Concentration Matters for Collagen Stimulation

Increase collagen15% Vit C increased collagen I and III in skin biopsies by 20%-25% (p<0.06)

5% Vitamin C no effect in skin biopsies

Lin et al. JAAD 2003; 48:866-74.

Nusgens et al. JID 2001; 116: 853-859.Placzek M et al. JID 2004; 124: 304-307.

Vitamin C Is Photoprotective

10% Vit C15% Vit C

Valacchi et al. Protective effects of topical vitamin C compound mixturesAgainst ozone-induced damage in human skin. JID 2017; 137: 1373-1375.

Increases sun protection

Lin et al. JID 2005; 125:xi-xiii.

Clinical Studies:Vitamin C and Photoaging

• 3 studies, 10-20 subjects, 1 RCT

• Improvement statistically significant, but variable

Traikovich SS. Arch Otolaryngol Head Neck Surg 1999; 125; 1091-8.

Fitzpatrick et al. Dermatol Surg 2002; 28: 231-236.

Humbert 2003. Exp Dermatol 2003; 12: 237-244.

My Approach to Vitamin C

• Photoprotective effects>morning

• Dark bottle, small opening

• Ideal pH 3.5 (sting) > not for sensitive skin

• Concentration in 10-15% range

• Formulation with ferulic acid may be helpful

Should I Use This Product?What does the science support?

NO

• Formaldehyde

• Fragrance

• Methylisothiazone (MI)

• Methylchloroisothiazolinone (MCI)

YES

• Retinol or Retinaldehyde

• Niacinamide or nicotinic acid

• Ascorbic acid