Katerina Damevska1, Suzana Nikolovska1, Jana Kazandjieva2, Bisera Kotevska Trifunova3, and Georgeta Bocheva4
1 University Clinic of Dermatology, Ss Cyril and Methodius University, Skopje, Republic of Macedonia
2 Department of Dermatology, Medical University, Sofia, Bulgaria
3 Department of Dermatology, Tokuda Hospital, Sofia, Bulgaria
4 Department of Pharmacology and Toxicology, Medical University, Sofia, Bulgaria
Environmental Pollution and Its Effects on the Skin
The deleterious effects of environmental pollution on human health have been consistently documented in many epidemiologic studies worldwide. The World Health Organization estimated that environmental risk factors such as air, water and soil pollution, climate change, and ultraviolet (UV) radiation contribute to more than 100 diseases .
The term “exposome” was coined in 2005 by the American cancer epidemiologist Christopher Wild to highlight the importance of the environment to human health. The concept of the “exposome” refers to the totality of environmental exposure, from conception to death .
Environmental pollution is defined as the addition of any substance or form of energy to the environment at a rate faster than the environment can accommodate it by dispersion, decomposition, recycling, or storage in some harmless form. Pollutants can be naturally occurring substances or energies, or xenobiotics, chemical compounds with artificial chemical structure, to which organisms have not adjusted through prior evolution. Depending on the component that is being polluted, pollution may be classified as air pollution, water pollution, soil pollution, noise pollution, or radiation pollution .
Air pollution is a mixture of pollutants of variable physical as well as chemical composition. Worldwide, the air pollutants of concern include particulate matter (PM), ground‐level ozone (O3), carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), lead, volatile organic compounds (VOCs), and carbon disulfide (CS2). Criteria pollutants are those found in relatively high concentrations. They are typically monitored via a network of monitoring stations. Hazardous air pollutants are pollutants that are found in trace concentrations, but may cause acute irritations or serious health effects, such as cancer or birth defects. Examples of hazardous air pollutants include benzene, perchlorethylene, and methylene chloride .
PM is a complex mixture of small particles and liquid droplets, composed of acids, organic chemicals, metals, and soil or dust particles. In general, these particles are divided into three major categories based on their size. Particles designated as PM2.5 (fine particles) have a diameter of less than or equal to 2.5 μm. Particles with a diameter between 2.5 and 10 μm are designated as PM10 (coarse) particulates. Ultrafine particles or nanoparticles (PM0.1) have diameter smaller than 0.1 μm . Currently PM0.1 are emerging as the most abundant particulate pollutants in urban and industrial areas. They remain in the atmosphere for long periods, and invade the indoor air environment .
PM could enter the skin either through hair follicles or transepidermally. Their ability to disturb the skin barrier depends on physicochemical characteristics. PM induces cutaneous damage not only directly, once particles reach deeper layers in the epidermis, but also indirectly, triggering a signaling pathway. PM‐induced skin damage involves both oxidative stress and inflammation, two closely related processes, each of which can be easily induced by the other. In addition, nanoparticles can serve as carriers for organic chemicals and metals that are capable of localizing in mitochondria and generating reactive oxygen species (ROS) . It remains unclear whether PM10 are able to penetrate the stratum corneum. It is equally unclear whether the nanoparticle penetration process is the same as the one involved in the alveolar epithelium.
Ozone is a reactive environmental oxidant which induces antioxidant depletion as well as lipid and protein oxidation in the stratum corneum. Skin exposure to high levels of O3 also induces damage to the deeper layers of the skin via the signal transduction mechanism even when there is no percutaneous penetration to the deeper skin layers . Ozone exposure has been associated with comedogenesis, wrinkling and extrinsic skin aging, urticaria, eczema, contact dermatitis, and rashes .
SO2 is a highly irritating, colorless, soluble gas with a pungent odor. The sources of SO2 include the burning of fossil fuels that contain sulfur, especially in diesel engines. The principal sources of CO in urban areas are automobiles, industrial processes, and the burning of fossil fuels. It is suggested that these oxides may induce inflammation of the skin in a similar fashion as that in the respiratory system .
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants generated primarily during the incomplete combustion of organic materials. Routes of exposure include ingestion, inhalation, and skin contact. PAHs are highly lipophilic and therefore easily penetrate the skin barrier. Mixtures of PAHs are also known to cause skin irritation and inflammation. Anthracene, benzo(a)pyrene, and naphthalene are direct skin irritants and sensitizers. PAHs pollution also results in an unbalancing Th2‐mediated inflammation. Moreover, in vitro and in vivo studies in B cells show PAHs interfere with antigen‐presenting processes, inducing an Ig class switch (from G to E). Many PAHs have toxic and mutagenic properties. Finally, PAHs promote carcinogenetic mechanisms, unbalancing pro‐ and antiapoptotic cell signals .
CS2 is a volatile, inflammable liquid with a sweet aromatic odor. CS2 is used mainly as an industrial chemical for the manufacture of rayon, cellophane, and carbon tetrachloride, as well as in the production of rubber chemicals and pesticides. The release of CS2 from industrial processes is almost exclusively to the air. Inhalation is the main route of CS2 absorption in both occupational and environmental exposure.
VOCs are a large group of chemicals characterized by low vapor pressure at ambient temperature. The number of VOCs is extremely high and includes, in addition to hydrocarbons, oxygen species such as ketones, aldehydes, alcohols, acids, and esters. VOCs include formaldehyde, toluene, ethylbenzene, xylene, and extremely hazardous substances such as benzene, vinyl chloride, and 1,2 dichloroethane. In addition, many compounds react with other air pollutants, contributing to the formation of photochemical smog. The major sources of indoor VOCs are latex paints, adhesives, flooring materials, wallpapers, new furnishings, and photocopy machines. Formaldehyde and other VOCs are considered among the main causes of airborne dermatitis and aggravation of atopic dermatitis (AD) .
Heavy metals are commonly found in PM. They often pollute the soil and water reservoirs, and can enter the food chain. The most frequent elements are lead, mercury, manganese, chromium, and arsenic. Many elements have demonstrated procarcinogenetic mechanisms. DNA repair malfunctions and pro‐ and antiapoptotic gene imbalances are the most frequent mutations induced by heavy metals .
UV radiation is responsible for the majority of environmentally induced skin pathologies, including premature aging, as well as a heightened risk of skin cancers. It is estimated that UV exposure is associated with 65% of melanoma cases and 90% of nonmelanoma skin cancers. Carcinogenesis mediated by UV radiation involves complex pathways, including those of apoptosis, DNA repair, checkpoint signaling, metabolism, and inflammation. Ultraviolet A (UVA) and ultraviolet B (UVB) damage DNA through different mechanisms: UVB is largely absorbed by epidermal cellular components, while UVA radiation penetrates into the basal layer of the epidermis and dermal fibroblasts .
UV‐induced inflammatory responses result in increased levels of cyclooxygenase‐2 (COX‐2) and prostaglandin (PG) metabolites. Among them, PGE2 is the most reactive metabolite and is considered to play a key role in UV‐induced immunosuppression .
Chronic sun exposure could be especially dangerous in patients with hypothyroidism because it could lead to exhaustion of the antioxidant defense of the skin, which is generally reduced in hypothyroidism .
There is an increasing interest in the interaction the sun’s UV spectrum has with the various pollutants in the atmosphere. The link between ground‐level ozone, UV irradiation, and skin carcinogenesis has been demonstrated in a large number of epidemiological studies. For every 1% decrease in ozone there is a 2% increase in UVB irradiance, and therefore a 2% increase in skin cancer is predicted .
Furthermore, it is well known that UV radiation is an essential driver of the generation of ground‐level ozone and some PM, including sulfate, nitrate, and organic aerosols. Several studies have demonstrated that UVA in combination with common environmental pollutants, like PAHs, significantly increase photodamage of the skin .
Water and Food Pollution
Human exposure to waterborne contaminants can include: direct exposure through ingestion, dermal contact, inhalation of aerosols, indirect exposure through foods contaminated by irrigation water or water used for aquaculture, and contaminated seafood. Acute exposure to water contaminants can cause irritation or inflammation of the eyes, nose, skin, and the gastrointestinal system. However, the greatest health effects are due to chronic exposure to pesticides, copper, or heavy metals in drinking water.
Some dermatological disorders may be related to the following food contaminants: pesticides, food additives, packaging materials, agricultural and veterinary chemical residues, biological agents, including microorganisms, viruses and parasites, cooking‐related artifacts, mycotoxins, and plant and marine toxins .
Mechanism of Skin Damage
In 2014, Krutmann et al. suggested that each individual air pollutant has most likely a specific, toxic action on the skin . However, associations between environmental pollution and certain dermatological disorders are complex and often poorly characterized. Levels of exposure, for example, are often uncertain or unknown, and exposures may occur via a range of pathways. In addition, individual pollutants may be implicated in a wide range of effects, whereas few diseases are directly attributable to single pollutants (e.g. chloracne caused by halogenated aromatic compounds). In many cases, the combined effects of two or more pollutants are more severe or even qualitatively different from the individual effects of separate pollutants. Biomarkers may be used for determining exposure to some chemicals. However, for many substances, biological monitoring is impracticable.
Despite the complex constitution of air pollution, classic studies have revealed inflammation and oxidative stress as common mechanisms of air pollution‐induced damage. It has also been proposed that environmental toxicants exert their effects at multiple points across human development, a theory labeled “the multiple hit hypothesis” .
Pollutants such as diesel‐exhaust particles (DEPs) have been shown to induce a strong inflammatory response in human skin cells, including a significant increase in IL‐8 production . This data is supported further by findings that DEPs increase expression of NF‐kB, which regulates the expression of proinflammatory cytokines in mouse epidermal cells .
In addition, PMs and heavy metals have been shown to increase gene expression of proinflammatory cytokines in human epidermal cells .
One of the mechanisms by which ambient air pollution can induce skin damage includes activation of the aryl hydrocarbon receptor (AhR) . Additionally, PAH, by binding to AhRs on keratinocytes and melanocytes, may lead to an increased production of ROS which is associated with premature skin aging [16, 22]. To neutralize oxidative stress, the keratinocytes also express nuclear factor‐erythroid 2‐related factor‐2 (NRF2), which is a master switch for antioxidant signaling. In particular, there is a cross‐talk between AhR and NRF2, which mutually increases or decreases their activation states . Tauchi et al. engineered a line of transgenic mice expressing an activated AhR in the absence of ligand stimulation. The activation of AhR led to development of pruritic skin rashes and inflammation that mimicked AD . These studies suggest that air pollution induces a proinflammatory state in the epidermis, which may change epidermal differentiation and affect the immunological barrier of the skin .
Skin Microbiome and Pollution
Recent advances in next‐generation sequencing technology, along with the development of bioinformatics tools, have provided unique insights into the skin microbiome. Many of the studies to date have focused on the composition of the microbial community, and understanding its role in homeostasis and disease pathogenesis. New research data confirms the microbiome’s potential to impact several skin disorders, including AD, psoriasis, opportunistic infections, acne, and rosacea. It is still unclear whether the changes in the microbiome are the cause or consequence of disease development.
As our primary interface with the external environment, the biodiversity of skin habitats is heavily influenced by the biodiversity of the ecosystems in which we reside . The skin is an exposed organ and it is reasonable to theorize that the pollutants, UV radiation, or low‐dose exposure to some prevalent environmental chemicals (phthalates, parabens, triclosan) may modify the skin microbiome. In view of this, investigating these microbiome–environment interactions is a critical next step for microbiome research.
Petra et al. hypothesized that exposure to UV radiation could directly alter the microbial communities on the skin, by producing microbial photoproducts such as pyrimidine dimers and/or 6–4 photoproducts, leading to microbial killing. At subtoxic levels, UV radiation may initiate a pathogen‐associated molecular pattern (PAMP) response, leading to inflammation and altered immune response .
In addition, lung and gut studies confirm the ability of the microbiome to alter the absorption and biotransformation of environmental chemicals. The manner in which the skin microbiome influences environmental pollution remains to be studied.
Air Pollution and Skin Disease
Although AD, eczema, skin cancer, acne, and skin aging are currently the dermatological disorders for which a strong link to environmental pollution has been established, many other skin disorders can be caused or exacerbated by environmental exposure.
Epidemiological observations support the role of outdoor and indoor pollution for the increasing prevalence of AD. A variety of air pollutants, such as VOCs, benzene, formaldehyde, tobacco smoke, toluene, nitrogen dioxide, and PMs, act as risk factors for the development or aggravation of AD . These air pollutants probably induce oxidative stress, leading to skin barrier dysfunction and immune dysregulation. A significant correlation was found between the daily concentration of PM, and the presence and severity of AD symptoms [28, 29]. Huss‐Marp et al. observed that airborne VOC increased transepidermal water loss (TEWL) and dermal blood flow in the presence of house dust mite allergens .
Furthermore, due to the impairment of the natural skin barrier in AD, airborne particles may easily penetrate into the epidermis leading to airborne contact dermatitis (ABCD). When airborne proteins (house dust mites, cockroach, pet dander, and multiple pollens) have entered the deeper layers of the skin, AD may be worsened by the inherent proteolytic activity of these proteins via the activation of protease‐activated receptor 2 (PAR‐2), and by the direct binding of immunoglobulin E (IgE) antibodies, initiating type I hypersensitivity reaction .
Recent advances in understanding the mechanism of air‐pollution‐induced AD include artemin expression and AhR activation. According to Hidaka et al. AhR, a transcription factor activated by air pollutants, induces the expression of artemin in keratinocytes, which induces hyper‐innervation of the epidermis. Subsequent scratching leads to barrier damage and an increased penetration of antigens, which enhances sensitization .
Airborne Contact Dermatitis
Airborne dermatoses include skin disorders related to external factors (physical and chemical agents, and various particles of plant and animal origins) transported in the surrounding air. The harmful agents can enter the environment in many different ways: vapors, droplets, or solid particles. ABCD can be classified into five types: airborne irritant contact dermatitis, airborne allergic contact dermatitis, airborne phototoxic reactions, airborne photoallergic reactions, and airborne contact urticaria .