Eye Make-up Products and Dry Eye Disease: A Mini Review

ABSTRACT

Dry eye disease (DED), a multifactorial condition of the tear film and ocular surface, is one of the leading reasons for patients seeking eye care. Despite the multiple toxic ingredients of eye make-up products and their long-term application close to the ocular surface, few studies have analyzed their role in initiating and worsening DED. Females and the elderly experience the highest prevalence of DED and may be particularly vulnerable to the effects of eye make-up. The multifactorial nature of DED and common mechanisms behind several ocular surface diseases make it difficult to link a particular ingredient-driven mechanism to DED. Therefore, here, we list potential responses to eye cosmetics that may be involved in DED development. The first part of this review introduces the anatomy of the eye and DED, the second section explains the classification of eye cosmetic products, and the final part discusses the undesired effects under physical, pathogenic, and chemical insults.

KEYWORDS:

• Eye make-up products
• eye cosmetics
• dry eye disease

Introduction

The cosmetics industry has been experiencing a steady increase in production and sales in recent years. To expand sales, companies have aimed at broader age groups (e.g., the elderly), increased marketing of anti-aging products, and considered the cultural/ethnic differences in cosmetic usage, habits, and beliefs.¹ As a result, cosmetic use spans a wide spectrum of ages and sexes in everyday life² as well as the TV and film industries.³ However, its application is particularly widespread among women.^2,4 From a long list of raw ingredients, cosmetics typically contain preservatives, vehicles, antioxidants, humectants, fragrances, ultraviolet absorbers, emollients, emulsifiers, acrylates, and dyes.⁵ Some of these ingredients pose a health risk to consumers (for a review, see references.^6–9)

Among potential sites of reaction to ingredients in the body, the eye and periorbital region are considered particularly sensitive due to their position and anatomy. The application of eye cosmetics to increase beauty and attractiveness¹⁰ may come at the cost of discomfort, allergic reactions, and ocular changes.¹¹ Eye make-up products are known to cause inflammation,^11,12 affect lipid layer quality and influence ocular comfort¹² and are key factors in the initiation and/or exacerbation of dry eye disease (DED).¹³

Dry eye, a multifactorial condition, is characterized by symptoms of dryness and irritation of the ocular surface due to alterations in the quality or quantity of the tear film. It can be experienced at any age, but DED is particularly widespread among women and the elderly. It has been estimated that 5–50% of the population suffer from this disease,¹⁴ making it one of the most common ocular conditions. DED causes a quality-of-life burden on sufferers, and its scale imposes considerable economic and medical resource usage.^15,16

Several reviews have addressed the effect of eye cosmetic constituents on the ocular surface, leading to various ocular conditions.^11,12,17,18 However, the multifactorial nature of DED makes it difficult to link a particular ingredient-driven mechanism to this condition. In addition, there are common mechanisms behind several ocular surface diseases. Therefore, here, we list the potential responses to eye cosmetics that may be involved in the development of dry eye.

The first part of this paper introduces the anatomy of the eye and DED. The second section provides an outline of the classification of eyelash cosmetics and eyelid cosmetic products. Finally, undesired effects are discussed under physical, pathogenic, and chemical insults in the third part. The terms cosmetic and make-up are used interchangeably in this review, as they are in the general population, although technically, the former includes a wide spectrum of items such as personal care products.⁵ Additionally, the use of contact lenses was not the focus of this work.

Anatomy of eye and periorbital area

The anatomy of the human face can be classified into upper, middle, and lower regions. The eye and periorbital area are housed in the upper face, where make-up products are generally applied (Figure 1). Therefore, anatomical knowledge is necessary to understand how cosmetics affect the eye.

Figure 1. Anatomy of internal and external parts of eye and periorbital area, and points for eye makeup along with the artificial eyelash, adhesive and remover.

Eyelid

The eyelid, a thin layer of skin, primarily protects the eye against mechanical trauma.¹⁹ Another vital responsibility of the eyelid is related to tears by supplying essential nutrients and helping with even tear distribution over the eye, followed by drainage through the lacrimal puncta. Additionally, the eyelid maintains the globe in the correct position within the orbit and controls the amount of light entering the eye via squinting.²⁰ The eyelids comprise 5 layers: skin (epidermis and dermis), subcutaneous tissue, muscular layer, and tarsal plate.²¹

Eyelid margin

The margin of the eyelid with ~2 mm thickness is divided by a grey line into two regions, where posteriorly it is covered with conjunctival epithelium and anteriorly with cutaneous epidermis.²² This margin is the place of transition from the nonkeratinized-columnar epithelium of the conjunctiva to the keratinized-stratified squamous epithelium of the skin, referred to as the mucocutaneous junction.²³ The former region encompasses meibomian gland orifices, whereas the latter holds the eyelashes.²⁴

Eyelashes

Eyelashes (cilia) protect the eye from potential incoming danger through the reflective response, defend the eye against particles using its curved shape, help to keep the moisture of the eye by minimizing airflow, filter out sunlight, and provide natural beauty. There are typically 2–3 rows of lashes on each lid rim. The upper eyelashes differ in number (100–150), length (8–12 mm), and shape (curved upward) compared to the lower ones (50–75 and 6–8 mm, respectively). With a normal lifetime of 5–12 months, the eyelashes grow ~0.15 mm per day, depending on age and the physical health of individuals. The eyelashes are housed in the muscular layer and are typically concomitant with two glands of Zeis (modified sebaceous gland) and often the apocrine gland of Moll (a modified sweat gland).²⁴

Meibomian glands

Meibomian glands (tarsal glands) secrete the tear film outer layer lipids and attenuate the evaporation of the aqueous phase, lubricate the corneal surface during blinking, retain the near-perfect optical surface necessary for visual acuity, seal the opposing lid margins during sleep, and create a protective barrier against microorganisms and particles. They are composed of 30–40 (upper lid) and 20–25 (lower lid) individual grape-like clusters in the tarsal plate, between the eyelashes and the bulbar conjunctiva. The glands of meibum constantly synthesize and secrete a complex mixture containing lipids (e.g., cholesterol, wax esters, diesters, triacylglycerol, free fatty acids, and phospholipids) and proteins (e.g., keratins, lactoferrin, lipophillins, lipocalins, phospholipid transfer proteins, surfactant proteins, and proteoglycans).^25,26

Conjunctiva

The conjunctiva protects the soft tissues of the orbit and eyelid, maintains the aqueous and mucous layers of the tear film, is involved in immune protection, lubricates the eye, and supplies oxygen. It is a thin, highly vascularized transparent mucous membrane lining the inner surface from the corneoscleral limbus to the eyelid margins and caruncle. The conjunctiva comprises an anterior stratified columnar epithelium containing numerous unicellular mucous glands (goblet cells) and a lamina propria composed of connective tissue with blood vessels, nerves, and glands. Three distinct regions of the conjunctiva are the bulbar (white sclera), forniceal (junction zone), and palpebral (inner surface of eyelid). The accessory lacrimal exocrine glands of Krause and Wolfring are located deep within the superior fornix and slightly above the superior border of the tarsus, respectively.^27,28

Corneal epithelium

The corneal epithelium is a barrier to water, chemicals, and microorganisms. It also provides a smooth reflective surface, protects the underlying layers from injury, and contributes to the immune response via its dendritic Langerhans cells. As an outermost layer of the cornea, the epithelium is located above the Bowman’s membrane, stroma, Descemet’s membrane, and endothelium. Its uniform structure comprises a basal layer of cylindric cells, a wing cell layer, and a surface layer of flat cells with ultrastructural microplicae and microvilli. The corneal epithelium is divided into central and peripheral regions. The epithelium of the peripheral cornea has 7–10 cell layers and holds melanocytes or Langerhans cells. In contrast, no such cells exist in the 5–7 layers of the central corneal epithelium.^28,29

Tear film

The tear film lubricates, nourishes, and protects the ocular surface. It is a transparent fluid comprising ~98% water, with the remainder composed of electrolytes, lipids, and proteins. Based on a 3-layered structure (Figure 1), a traditional model, the tear film consists of (1) an outer lipid layer secreted by meibomian glands to reduce water evaporation, (2) an intermediate aqueous layer produced by the lacrimal glands and accessory lacrimal glands of Krause and Wolfring to supply oxygen and nutrients, and (3) an inner mucus layer produced by goblet and epithelial cells of the conjunctiva to attach and spread the tears evenly. However, the Tear Film and Ocular Surface Society Dry Eye Workshop (TFOS DEWS II) depicts the tear film as a 2-layered interactive structure composed of a mucoaqueous layer and a lipid layer. Tears are classified as basal, closed eye, emotional, and reflex types according to their mode of production.^30,31

Nasolacrimal duct

Tear fluid and particles attached to the ocular surface are drained by the nasolacrimal duct into the inferior meatus of the nose. Anatomically, the lacrimal passages are divided into bony and membranous lacrimal sections. The latter include the lacrimal canaliculi, lacrimal sac, and the nasolacrimal duct. The last two parts are lined by a double-layered epithelium containing superficial columnar cells and basal flattened cells. Goblet cells may also be present in the epithelial layer. During blinking, tears are wiped and pushed into the lacrimal puncta, small openings located in the nasal upper and lower eyelids. The punctum ends in the canaliculus, where the fluid drains into the lacrimal sac followed by the nasolacrimal duct canal before reaching the nasal cavity.³¹

Dry eye disease

The normal tear film is pivotal for ocular surface health and clear vision. Any alteration in the quality or quantity of the tear film may result in DED. DED symptoms vary and include discomfort, dryness, irritation, burning, stinging, gritty/foreign body sensation, and blurred vision. DED can vary from mild signs and symptoms to severe pain with the deterioration of visual function. The associated decreased quality of life and increased consumption of medical resources impose considerable cost to patients, families, and society.^14,32

In 2017, TFOS DEWS II defined DED as “a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles”.³³ In addition, the Asian Dry Eye Society provided an alternative definition for DED as “a multifactorial disease characterized by unstable tear film causing a variety of symptoms and/or visual impairment, potentially accompanied by ocular surface damage”.³⁴

A clinically relevant classification has been used by a TFOS DEWS II report for DED. It includes two major classes: aqueous-deficient dry eye (ADDE) and evaporative dry eye (EDE). ADDE involves the failure of lacrimal secretion caused mainly by Sjögren and non-Sjögren lacrimal disease, whereas EDE is the excessive tear loss from the ocular surface mostly due to meibomian gland dysfunction or abnormal blink patterns. The combination of these two classes also exists among DED patients.^35,36

The main aspects involved in DED are ocular-surface hyperosmolarity and inflammation, which may act together or independently. The pathogenesis of DED is mediated by various cellular and molecular components such as cytokines, chemokines, metalloproteinases, and their receptors. Hyperosmolarity caused by dysfunctional tear secretion (ADDE) and/or excessive water evaporation (EDE) leads to an inflammatory cascade followed by a vicious circle. The process can be initiated and/or worsened by intrinsic (e.g., ocular disease and immune-mediated conditions) and extrinsic (e.g., chemical, environmental, and pathogenic insults) factors.^37,38

Eye cosmetics

Historically, cosmetics have been used by civilizations in religious rituals throughout the ancient world. The main goals were to improve beauty, promote health, and indicate social class. The eyes, often referred to as the windows to the soul and a powerful communication tool, were at the center of attention in this process. Therefore, various make-up mixtures with specific natural colors, trends, and styles have been applied for accentuating them. For instance, the use of black pigments made of ashes, soot, and antimony in the form of kohl has been documented in the early Bronze Age (c. 4000–1500 BCE), old Middle East (ancient Egypt and Mesopotamia), classical Greece, and antiquated Rome to darken the lashes, eyelids, and eyebrows.^11,17 For millennia, stretching from ~4000 BCE through to the 21st century, the development of eye cosmetics progressed substantially. Consequently, different products with a broad range of ingredients under diverse categories have been introduced and utilized in myriad ways. Table S1 shows the common classes of materials used in different forms of eye cosmetics.

Classification

Eyelash cosmetics

Eyelash cosmetics comprise a range of products, including mascara and eyelash dye. These products perform differently depending on their formulation, material, and/or design (Figure 1).

Mascara

Mascara is utilized to make the eyes appear bigger and form an intense look by darkening, stretching, and thickening the eyelashes. For dramatizing the eyes and enhancing contrast between the iris and sclera, different colors are added to the preparation. Mascara is primarily available as shades of blacks and browns, but also purples, blues, greens, yellows, and pinks. For those interested in lengthening without darkening, unpigmented products are sold on the market.³⁹

Mascara has been produced in a variety of forms, including cakes (or blocks), creams, gels, and low viscosity liquids with diverse ingredients (Table S2). Cake mascara was originally a mixture of soap and pigment, which is stamped into blocks. Two major disadvantages of this product are: 1) the requirement of a wet brush to make a paste before its application and 2) smudging and running of the formed film on the lashes with tears, perspiration, or rain due to its water solubility. Although improved water-resistant cakes are made by adding waxes, consumers prefer to use either cream or liquid forms instead. The next product, cream mascara, soon gained considerable attention because of its ease of application and less tendency to run with moisture and form clumps on the lashes. This form of mascara typically comprises dispersions of waxes and pigments in water, with a final consistency similar to vanishing cream. The cream texture with a substantial water-holding property permits to include natural and synthetic film formers to improve adhesion. However, this ability comes at the cost of shortening the application time owing to clump formation following water evaporation. Therefore, liquid in several types has found its way into mascara formulations. Liquid mascara, the most popular modern form, is divided into water-based (waxes (e.g., carnauba wax and beeswax), pigments, and resin dissolved in water), non-water-based (e.g., candelilla wax and ozokerite, pigments, and petroleum distillates) and water/non-water-based hybrid products. The latter intend to combine the beneficial effects, such as short drying time and waterproofness, from the two other categories.^40,41

Several factors, including the desired effect, type of eyelashes, and health status of consumers, play important roles in the choice of a suitable mascara. For a make-up effect, the design of the applicator brush and the diameter of the aperture are apparently as important as the formulation of the mascara. Hence, the market success of cream and particularly liquid mascaras has partly been due to the advent of the automatic applicator, spiral-tipped wand, or wand and brush applicator.^11,42

Eyelash dye and tint

Eyelash dye and tint involve the application of permanent and semi-permanent colorants onto the lashes to make them appear darker and thicker. The color can last for several weeks (tinting) or longer (dyeing) depending on several factors, such as the health of lashes, type of dye, skill of beauty staff, color used, application of other eye cosmetics, exposure to the sun, type of detergent, and water temperature during washing. Although fashion trends tend to dictate followers, the dyeing and tinting may also be used by individuals with naturally light-colored lashes, canities (hair greying), and vitiligo (skin pigment loss). Due to potential eye damage, the authorities have tightened regulations on colorants for coloring eyelashes. For example, the U.S. Food and Drug Administration (USFDA) has not approved any natural or synthetic color additives,^17,40 and the EU Commission has recently allowed only relatively few ingredients for professional use in accordance with the Scientific Committee on Consumer Safety (SCCS/1553/15): the oxidative hair dye substances toluene-2,5-diamine, p-aminophenol, 2-methylresorcinol, tetraaminopyrimidine sulfate, hydroxyethyl-p-phenylenediamine sulfate, and 2-amino-3-hydroxypyridine.

Eyelid cosmetic products and removers

Eyelid cosmetics are applied around the eyes to enhance the appearance by making them look big, bold, and attractive. The most popular products in this category are eyeliner and eyeshadow, and to enable them to be more easily wiped off, eye make-up remover products may be applied.

Kohl, eyeliner, and tattooing

Kohl (surma/al-kahal/kajal), one of the primitive forms of cosmetics for eyelid margins, is still popular in some parts of Africa and Asia. It is a blend of a natural lead compound, galena (lead sulphide), sulfur, antimony, carbon, iron, and chromium. Eyeliner, the modern form, is used to make the eyes bolder with illusive shapes and sizes. Based on fashion trends, it is applied outside the lash line, on the inner lid area closer to the eye, or along the waterline.^11,43

Eyeliner can be found in the form of a cake, liquid, cream/gel, or pencil with different formulations. Cake eyeliner has similar ingredients to powdered eye shadow (Table S3) but contains surfactants for making a paste once water is added. Similar to its corresponding mascara, a wet brush is required for making and transferring the paste. Additionally, the formed pigmented film on eyelid margins is prone to smudging due to its water solubility. Although the cake form is still available, liquid eyeliner is a dominant substitute in today’s market. Liquid eyeliner formulations can be roughly categorized into two different types; water-resistant and waterproof. Intensely pigmented blends (or emulsions) in water or any other solvents represent the chemical backbone of the former compared to organic solvents or an anhydrous base in the latter case. These are applied using a fine (felt-tip) pen-like applicator or brush. Gel eyeliner has much in common with liquid eyeliner, except that it is more viscous, needs to be layered by a separate brush applicator from a pot container, holds up well and gives more control of the outcome by tending to go on sheer, and moves better with the delicate skin around the eye. Another product, pencil (or soft crayon) eyeliner, is popular because of its ease of application. Supplied in either a mechanical plastic or wooden case, it is a mixture of waxes (natural and synthetic), pigments, oils (mineral or vegetable), and emollients, such as lanolin derivatives.^39,44,45

Permanent eyeliner tattooing, also referred to as blepharopigmentation, has gained increasing attention in recent decades. It obviates the need for the daily application of eyeliner make-up and provides wearers with an enhanced dull eye. The most common pigment used in this process is black, but some others, such as navy blue, green, and brown, are also available. The micropigmentation technique is performed by implantation of dye into the superficial dermis layer at a constant depth using a tattoo machine.^40,46,47

Eyeshadow

Eyeshadow is applied to eyelids and below the eyebrows for creating depth and dimension to the eyes, making them and/or their color stand out and become more attractive. Compared to other facial make-up products, the formulation of eyeshadows requires special care to prevent scratches, infections, irritation, and toxic effects due to soft-thin skin type and proximity to the eyes.

A variety of products in the form of a paste, cream (or gel), stick (or crayon), pencil, liquid, and powder has been introduced to the market over recent decades (Table S3). Paste, the early form of eyeshadow, was popular before the Second World War. It mainly suffered from settling of its high portion of waxes or oils into eyelid creases, leading to the formation of lines. Although the release of emulsion creams offered a less greasy product, the water content necessitated preservatives against bacterial contamination and sealed packaging to reduce drying out. The anhydrous cream form, also termed cream-to-powder eyeshadow, was a highly effective alternative because it is transformed into a super soft powder following application. The high viscosity of the dehydrated emulsions assists with the uniform distribution of colorants into the cream base. However, their wearing time is short because of potential migration into the eyelid folds. In addition, these emulsions are prone to easily melt on the eyelids in hot weather. A variation on the cream-based shadow is the gel, where waxes are replaced with clay gelling agents for the thickening of oils. Among anhydrous eyeshadows, sticks and pencils have always been attractive to consumers because they can be easily carried around as well as their ease of application, are independent of brushes/applicators, and are available in long-wearing formulae. Crayon eyeshadow, their modified version, has gained even more popularity due to its wider diameter and softer property. Liquid eyeshadows are also considered convenient products to use. They are typically highly pigmented, set quickly, and sold in a sleek tube with a fluffy wand/doe foot applicator. Powder eyeshadows, either loose or pressed, are the most common form on the market. Both have similar ingredients, except that binders are added to the latter to hold the particles together.^39,44 Recent modifications have offered baked eyeshadows, in which the prepared formula is heated in an oven/furnace rather than being pressed.

Eye make-up remover

Eye make-up remover enables applied cosmetics on the eye and surrounding area to be more easily wiped off. Chemically, such removers follow the general principle of solubility referred to as “like dissolves like”, in which substances with similar chemical characteristics are dissolved in each other.⁸ Therefore, water alone is insufficient to effectively remove cosmetics containing lipophilic compounds,¹¹ requiring surfactants/emulsifiers in oil-based or oil-free formulations.⁴⁴ The remover comes in different forms, including oils, creams, balms, foams, sticks, micellar water, and saturated pads/wipes. The use of diverse raw materials in these products (Table S4) provides consumers with a variety of options based on the biocompatibility of the ingredients, effectiveness of the products, and convenience of application.^1,45

Other products

Artificial eyelash, adhesive, and remover

These are not classed as cosmetic products under EC Regulation 1223/2009 but fall under the General Product Safety Regulation. Eyelash extensions and false eyelashes are used to create bold and attractive looks by modifying the length, volume, curl, and thickness of natural lashes. Extensions are individually adhered fibers in close proximity to the base of each natural lash using a special adhesive, whereas false (strip) ones are glued on top of them. These extensions are semi-permanent and last for several weeks, but false lashes are one-time use with the possibility of being reused 2–3 times. They are popular among those with healthy as well as damaged eyelashes resulting from negligent home care, inappropriate application of cosmetics, use of low-quality make-up products, and disease.⁴⁸

Both natural (e.g., silk, mink, human, and horsehair) and synthetic (e.g., polybutylene terephthalate) materials are used in the production of artificial eyelashes. The choice of adhesive depends essentially on the biological response of the wearer, type of chemicals used in false eyelashes, and the physical properties of glue after drying, such as good attachment and long retention.⁴⁰ Cyanoacrylate-based adhesives (Table S5), previously used for biomedical applications,⁴⁹ are widely marketed in response to the increasing global demand for eyelash treatment.⁵⁰ They are sold under different categories, such as surgical (medical), rubber latex, and sensitive/allergic (e.g., formaldehyde- and latex-free) glues. Each type of artificial eyelash has its own method of removal. For extensions, organic solvent-(liquid), cream-, gel-, and oil-based removers are available (Table S6). Besides, the natural oils such as olive, almond, and coconut often break down adhesive bonds and, therefore, are considered a safe and economical option. The oil-based removers and natural oils are also the method of choice for false eyelashes. However, specifically designed oil-free products, as well as steaming, are substitute methods for ensuring that lashes remain intact for future reuse.

In addition to the above-mentioned products, some others, such as eyelash growth-stimulating sera, primers, concealers, foundations, setting creams, face powders, bronzers, facial masks, and anti-aging gels/creams may be applied on the eyelids and periorbital area. Although each one has its own list of ingredients, they may have some in common with the popular eye cosmetics discussed above.

Undesired effects

A range of adverse effects on the ocular surface, tear film, and lids are associated with the use of eye make-up products. For example, mechanical trauma, tear film destabilization, immunological response, toxicity, and infection driven by ocular cosmetics may lead to inflammation,^11,12 a key contributing factor to the vicious dry eye circle.¹³ This process is serious in female populations because they are dominant in both presenting DED and consuming beauty products. The elderly, another sensitive population with frequent prevalence of DED, have also been targeted by cosmetic companies in recent years.¹ In youth, eye make-up products are also increasingly used to enhance natural beauty and simulate attractive characteristics.⁵¹ The potential risk of utilizing eye cosmetics by teens to develop DED at a far earlier age is an intriguing area of research that could be explored in further studies.

Physical insults

Physical insult or mechanical trauma refers to any physical injury caused by a direct insult or blow to the eye, ranging from mild to severe. The well-known cosmetics-related corneal trauma among wearers involves poking the eye with a mascara applicator wand.¹² The use of a pin on the clumpiest sections of eyelashes after applying liquid mascara also risks mechanical trauma to the eye. Open wounds could be an entry point for pathogens and are an infection risk. The presence of fine nylon fibers in, for example, the base coat of two-step mascara for lash lengthening may irritate the ocular surface by being loosened and falling on it.¹¹ The direct application of eyeliner to the lid rim may block the orifices of the meibomian glands.^51,52 Additionally, sharp pencil eyeliners can scratch the eye, although wooden cases produce less pressure than plastic ones.³⁹ The particles from eyeshadow can distribute on the tear film and may affect its stability along with increased debris formation risk.⁵² Any changes in the volume, length (e.g., artificial lashes), and curl (e.g., lash lifting) of natural lashes can interfere with their functions with respect to debris-deflecting attributes and limiting tear evaporation.^53,54 For instance, lengthening the eyelashes by the application of mascara or artificial lashes (or a combination of both) channels flow towards the ocular surface and causes stress.⁵⁴ Moreover, the natural lashes attached to extensions could fall off and cause irritation due to excessive force being applied during make-up removal by wiping (particularly waterproof make-up), inappropriate artificial lash removal, and/or poor sleeping posture (particularly on the abdomen).

Pathogenic insults

The microbiome is a collective term to describe a community of microorganisms, such as bacteria, fungi, and viruses, inhabiting a common niche such as the human body.⁵⁵ However, this term has been widely used for the inhabiting bacteria and distinguished from two others by the terms mycobiome and virome.⁵⁶ Several eye-associated microorganisms and parasites, with internal (e.g., lids, skin, nasopharynx, and birth canal) or external (e.g., water, soil, and atmosphere) origins impact ocular surface physiology both in health and disease.⁵⁷

Since the pioneering work of Keilty,⁵⁸ there has been increasing interest in identifying the structure and composition of the ocular surface bacterial inhabitants using different methods (Table S7). Despite technical challenges, the dominant bacterial genera present in a normal individual were shown to be Corynebacterium, Acinetobacter, Pseudomonas, Staphylococcus, Propionibacterium, and Streptococcus, co-occurring with the abundant Bacillus.⁵⁹ In contrast to bacteria, few studies have investigated fungal^60–63 and viral^60,64,65 communities of the human eyes. Additionally, the interactions between bacteriophages and mucosal surfaces^66,67 for eye health and disease is an interesting subject that requires further research.

The bacterial profile of the ocular surface was shown to be affected by dry eye in several studies (Table 1). However, there was no general agreement on the prevalence of isolates due to differences in sample size, detection method (culture vs. 16S rRNA gene analysis), and dry eye diagnostic criteria.⁶⁸ It was hypothesized that changes in the quantity and quality of DED patients’ tear films, preventing normal tear turnover, would alter the spectrum of the ocular surface flora.⁶⁹ On the other hand, the microbial components such as ligands (e.g., flagellin A and lipopolysaccharide) and lipoteichoic acids influence the production of mucin, particularly MUC2 and MUC5A, resulting in epithelial stress and activation of adaptive immunity.⁷⁰ Therefore, a better understanding of microbial communities’ distribution on the ocular surface could be of substantial significance in the treatment of DED.⁷¹

Table 1. Changes in bacterial flora on human ocular surface of non-DED and DED subjects

Subjects	Sampling	Detection method	Non-DED vs. DED
n = 66 (Non-DED) and n = 12 (DED)	Conjunctiva	Culture-based	Staphylococcus epidermidis (type VI), Micrococcus and Diphtheroids were absent in DED compared to non-DED	Seal et al ^Citation72
n = 16 (Non-DED) and n = 12 (DED)	Swab: Posterior lid margin and inferior conjunctival sac; Impression cytology: bulbar conjunctiva	Culture-based and culture-independent 16S rRNA gene analysis	Bacillus sp., Propionbacterium acnes and Klebsiella oxytoca were only identified in DED subjects, whereas Erwinia sp. only in non-DED	Graham et al ^Citation73
n = 56 (Non-DED) and n = 67 (DED)	Swab: Conjunctiva	Culture-based	No significant difference in the isolation rates between non-DED and DED, but the latter presented significantly higher incidence of fluoroquinolone-resistant methicillin-sensitive coagulase-negative Staphylococcus and fluoroquinolone-resistant methicillin-resistant coagulase-negative Staphylococcus	Hori et al^Citation69
n = 54 (Non-DED) and n = 35 (DED)	Swab: Superior and inferior palpebral, caruncle, and fornix conjunctiva	Culture-independent 16S rRNA gene analysis	Bacteroidia and Bacteroidetes were enriched in DED subjects but Pseudomonadaceae, Pseudomonas, Gammaproteobacteria and Proteobacteria had lower relative abundance compared to non-DED	Li et al ^Citation68
n = 36 (Non-DED) and n = 36 (DED)	Collection of closed eye tears in sterile saline	Culture-independent 16S rRNA gene analysis	Relatively unaffected microbial communities of non-DED and DED by daily eye wash, but univariate analysis detected the most significant differences in the abundance of MLE112, Lactobacillaceae, Streptococcus, Sphingobium, Caldicoprobacter and Anaerococcus	Willis et al^Citation74
n = 28 (Non-DED) and n* = 18 + 21 (DED)	Swab: Inferior fornix conjunctiva	Culture-independent 16S rRNA gene analysis	Decreased microbiota diversity with different composition in DED patients vs. controls. >75% of DED subjects shared Enhydrobacter, Brevibacterium, Staphylococcus, Streptococcus and Cutibacterium. Pseudomonas was identified as a bacterial biomarker for controls and Bacilli for patients with DED	Andersson et al ^Citation75

*Aqueous tear-deficient dry eye patients with (n = 18) and without ocular graft-versus-host disease (n = 21).

Eyes, particularly dry eyes, are at the risk of harmful microbial infection from eye cosmetics.^53,76 These products provide a good medium for their growth, and contamination is facilitated by mishandling during production, inadequate preservatives, poor personal hygiene, long-term usage, multiple consumers, and product modification by users, such as adding water to mascara.⁷⁷ Among pathogens, significant attention has been paid to bacteria (Table 2), and scientists have been able to, for example, isolate Bacillus, which is hazardous to human health.⁷⁸ As Table 1 shows, Bacillus has not been identified on non-DED individuals; however, it was among the only identified species in DED subjects⁷³ (Table 1). Andersson, et al.⁷⁵ identified Bacillus as a bacterial biomarker for patients with DED. It can be seen from Table 2 that it has been screened in different eye make-up products in several studies. In contrast, little has been done for fungal^76,79-81 contamination and, to our knowledge, nothing for viral contamination.

Table 2. Bacterial contamination of commercially available eye makeup products

Product	Taxa	Country	Reference
Eyeshadow	Staphylococcus, Micrococcus, Corynebacterium, Acinetobacter, Bacillus, Moraxella	USA	Dawson and Reinhardt^Citation82
Mascara, eyeshadow and face cream	Pseudomonas aeruginosa, Citrobacter freundii, Klebsiella pneumoniae, Escherichia coli, Enterobacter agglomerans, Staphylococcus epidermidis, Micrococcus sp.	Egypt	Abdelaziz et al ^Citation83
Kohl	Bacillus spp., Staphylococcus spp., Pseudomonas spp., Proteus vulgaris, Serratia marcescens	Jordan	Abdelaziz and Alkofahi^Citation84
Mascara	Staphylococcus epidermidis, Streptococcus sp.	USA	Pack et al ^Citation76
Mascara, eyeliner and eyeshadow	– Staphylococcus aureus, Staphylococcus warneri, Staphylococcus epidermidis, Bacillus cereus, Bacillus megaterium, Klebsiella pneumonia	Egypt	El-Bazza et al ^Citation81
Kohl	Escherichia coli, Staphylococcus sp.	India	Guleria^Citation85
Mascara	Staphylococcus, proteus, Escherichia coli, Shigella, Citrobacter, Klebseilla, Pseudomonas aeruginosa	Iraq	Baqer et al ^Citation79
Mascara and eyeliner	Acinetobacter, Escherichia coli, Bacillus, Pseudomonas, Staphylococcus, Streptococci, Klebsiella, Citrobacter, Salmonella, Alcanigenes	Iran	Dadashi and Dehghanzadeh^Citation80
Kohl, mascara, eyeshadow and eyeliner	Bacillus cereus, Bacillus sp., Chromobacterium violaceum, Pseudomonas aeruginosa, Listeria monocytogenes	India	Nandi and Mandal^Citation86
Kohl, mascara, eyeliner and eyeshadow	Salmonella, Escherichia coli, Staphylococcus epidermis, Staph aureus	Saudi Arabia	Eldesoukey et al ^Citation87
Mascara and eyeliner	Pluralibacter gergoviae, Staphylococcus saprophyticus, Cryptococcus diffluens, Micrococcus luteus, Burkholderia vietnamiensis, Bacillus muralis, Staphylococcus capitis	UK	Bashir and Lambert^Citation88
Mascara	Staphylococcus epidermidis, Candida albicans	Saudi Arabia	Noor et al ^Citation89

The wearers of eye cosmetics, particularly oil-based products, tend to present higher rates of demodex mites.⁹⁰ This common parasitosis within eyelash follicles is responsible for duct blockage.⁵¹ These mites are highly prevalent in the older population with dry eye and specifically manifest symptoms of itching and cylindrical dandruff.⁹¹

Chemical insults

Many hazardous cosmetic ingredients and their effects on the human ocular surface^11,12,17,18 and body (e.g.,^6–9) have been previously reviewed. Among the mechanisms behind chemical insults, inflammatory responses play a central role. DED could develop secondary to inflammatory response.⁹²

The ocular immunologic defense encompasses innate, adaptive, and mucosal components. The latter contains conjunctiva- and lacrimal drainage-associated lymphoid tissue, together forming the ocular surface-associated lymphoid tissue, part of a larger common secretory immune system from the gastrointestinal-respiratory-genitourinary tracts. The ocular surface immune system is closely regulated and carefully controlled by the innate and adaptive immune responses.^27,93 The cosmetics-induced immune response in the eye primarily affects the eyelid, tear film, conjunctiva, and cornea.⁹⁴

The eyelid, similar to skin across the body, may develop contact allergy (a delayed-type hypersensitivity; type IV) when exposed to a sufficient concentration of an allergen, such as some preservatives, fragrances, antioxidants, emollients, resins, pearlescent additives, and pigments containing nickel. Following re-exposure, symptoms of irritant or allergic contact dermatitis, including rash, blisters, wheals, urticarial, itchy, and burning skin appear within 24–72 h.^7,44,95,96 Mechanistically, it consists of afferent (also termed induction or sensitization) phase and efferent (elicitation or challenge) phases. During the first step, skin dendritic cells are activated by a contact allergen and maturated before migrating to local lymph node(s) to stimulate antigen-specific T cells. During the second stage, subsequent encounters with the same chemical trigger the recruitment of the primed T cells to the affected location, followed by a local antigen-specific response. Because typically small compounds (<500 Da in size) can induce contact dermatitis, the process is believed to be mediated by hapten/carrier peptide complexes.⁹⁵ The allergen source of initial or subsequent exposures might be directly from eye cosmetics or indirectly from other products such as hair/eyebrow dyes, eyelash curlers, make-up removers, facial cleansers, shampoos/conditioners (rinsed off during showers), make-up sponges, and allergens transferred from the hands.⁹⁷

In addition to cell-mediated allergic reactions (Type IV), the eyelids may manifest immediate hypersensitivity (Type I) in the form of immunological contact urticaria after exposure to some hair dyes, antimicrobial agents/preservatives, fragrances, and plant- or animal-derived cosmetic ingredients.⁹⁸ The mechanism involves the formation of a specific IgE molecule-antigen complex on the mast cell surface at the site of exposure, which results in redness and edema along with extracutaneous symptoms (e.g., conjunctivitis) within 30–60 min (or exceptionally later) due to the release of histamine. Patients with atopic dermatitis are prone to such an immunological reaction.⁹⁹

Externally applied eye make-up products could migrate across the eyelid margin onto the ocular surface.¹⁰⁰ Such contamination is higher among make-up users who use eye drops at the same time.¹⁰¹ Within the tear film, one mechanism suggests that the pro-inflammatory effects are driven by hyperosmolarity after the accumulation of hydrophilic components within the aqueous-mucin phase.¹⁰⁰ However, this suggestion was based on benzalkonium chloride, an abandoned chemical in eye make-up products today.¹⁰² For the cornea and conjunctiva, the drifted make-up materials may cause irritation. Although it is not well understood, the mechanism may involve eye irritation induced by various chemical classes: cell membrane lysis, saponification, coagulation, and actions on macromolecules.¹⁰³ It has also been suggested that the migrated ingredients may provide an additional entry point to the DED vicious circle by activating ocular surface inflammatory pathways.¹²

The immune system affects and partly controls the neuroendocrine network of tear secretion. The neuronal and hormonal (androgens mainly) regulation acts through the hypothalamic-pituitary-gonadal axis for the production of tears and their contents (e.g., immunoglobulins, lymphocytes, and proteins). Therefore, any disruption of the immuno-neuro-hormonal system function may result in tear film changes with consequences of DED.¹⁰⁴ For instance, the secretion of the tear film’s lipid layer may be interrupted after exposure of the meibomian gland to, for example, retinoic acid derivates, the key components for anti-aging products around the eye.¹⁰⁵ Mechanistic studies have revealed that the androgen receptor is suppressed at mRNA and protein levels,^106,107 and retinol dehydrogenase-4 is inhibited¹⁰⁸ by them.

The chronic inflammatory infiltrate (mostly lymphocytes and neutrophils) has been seen in accumulated black pigments containing high levels of lead in the lacrimal sac and surrounding tissue in several kohl consumers.¹⁰⁹ In other studies, kohl use was shown to be associated with high blood lead concentration and low hemoglobin levels.^110,111 Lead, similar to other heavy metals, is toxic^6,112; however, no corneal toxicity in humans has been linked to it.¹¹ According to EC Regulation 1223/2009, lead and its compounds are prohibited in cosmetics.

Although some ingredients, such as preservatives, in cosmetics are known to adversely affect biological systems,⁹ particularly the eyes,¹¹ the lack of evidence and/or their very low levels in final products have not convinced regulatory agencies to ban them. For example, parabens (methylparaben, ethylparaben), phenoxyethanol, and chlorphenesin have been reported to be toxic to immortalized human meibomian gland epithelial cells.¹¹³ In addition, methylparaben and ethylparaben have been associated with the signs and symptoms of DED.¹¹⁴

Conclusions and future work

A range of adverse effects on the ocular surface, tear film, and lid are associated with the use of eye make-up products. For example, physical, pathogenic, and chemical insults driven by these products may lead to inflammation. Dry eye, a multifactorial disease, could develop secondary to the inflammatory response. This disease is most prominent in women, a dominant population both in presenting DED and consuming beauty products. The elderly, a sensitive population with a frequent prevalence of DED, are also at risk owing to their increased consumption of such products. Although the regulatory agencies are continually reviewing ingredients, it is also the responsibility of the manufacturers to ensure the clinical safety of their formulations’ constituents. On the other hand, eye care practitioners must be updated about newly released products, and consumers/patients should increase their awareness. Considering the widespread use of these products, further research on a broader range of eye cosmetics with long-term exposure and potential mixture toxicity would assist in establishing more effective safety guidelines. There is an apparent lack of studies on DED and eye make-up products.

Author contributions

Conceptualization and Writing – Original Draft Preparation: M.Y. (Toxicologist), Writing – Review: K.B.P.E (Chemist), T.P.U. (Ophthalmologist).

Acknowledgments

The authors thank Sara Tellefsen for her assistance in drawing the illustrations.

Disclosure statement

No potential conflict of interest was reported by the author(s)

Supplementary materials

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This research received no external funding.