Ocular conditions and dry eye due to traditional and new forms of smoking: A review

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Review article

Ocular conditions and dry eye due to traditional and new forms of smoking: A review Dimitra Makryniotia,*,1, Zoi Zagoritib, Constantinos Koutsojannisc, Philip B. Morgand, George Lagoumintzisa,b,1 a

School of Health Rehabilitation Sciences, University of Patras, Psaron 6, GR 25100, Aιgio, Greece Department of Pharmacy, Laboratory of Molecular Biology and Immunology, University of Patras, University Campus, GR26504, Patras, Greece c Department of Physiotherapy, Laboratory of Health Physics and Computational Intelligence, School of Health Rehabilitation Sciences, University of Patras, Psaron 6, GR 25100, Aιgio, Greece d Eurolens Research, Division of Pharmacy and Optometry, The University of Manchester, Carys Bannister Building, Dover Street, Manchester, M13 9PL, United Kingdom b

A R T I C LE I N FO

A B S T R A C T

Keywords: Electronic cigarettes Conventional cigarettes Nicotine uptake Dry eye disease Smoking Vaping

Addiction to cigarette smoking has high prevalence rates recorded worldwide. Smoking has been linked to several life-threatening systemic conditions such as cancer, heart attack and stroke, in addition to a range of ocular pathologies. In recent years, electronic cigarettes (EC) have emerged as alternatives to smoking. ECs are nicotine delivery devices which produce an aerosol by heating, rather than combusting, a liquid which contains nicotine, flavours and preservatives. This review focuses on the association of traditional and new forms of smoking with dry eye disease, contact lens wear and four other common ocular diseases: cataract, age-related macular degeneration, glaucoma and Graves’ ophthalmopathy. It is concluded that smoking and vaping appear as a risk factor for the aforementioned ocular conditions. An evidence-based, clear link between cigarette smoking, or EC vaping and ocular problems is yet to be discovered.

1. Introduction Tobacco consumption is one of the main causes of morbidity and mortality globally [1] with cigarette smoke being a rich source of heavy metals and other toxic elements [2]. Consequently, various pathological conditions are associated with smoking such as cancer, heart attacks and strokes [3–5]. The prevalence of smoking among adults was estimated as 19.2 % of the general population in 2019, with substantial regional variations [1]. According to the World Health Organization (WHO) report on the global tobacco epidemic, the prevalence rates for cigarette smoking for the United Kingdom is 15.1 %, for the United States of America 19.9 % and for Australia 14.9 %, while it rises to 35 % in the tobacco producing country of Greece [1]. According to the WHO, tobacco ultimately kills as many as half of its users - more than seven million human beings each year. More than six million of those deaths are the result of direct tobacco use, whilst around 890,000 are due to non-smokers being exposed to ‘second-hand’ smoke. In Europe, it is anticipated that tobacco smoking accounts for 700,000 deaths each year, with an associated cost greater than 100 billion euros [6].

In addition to its association with systemic disorders and conditions, smoking has been linked to various eye pathologies [7,8], including dry eye disease, which is a significant healthcare problem affecting millions of people [9]. However, the association between smoking and ocular disease is not well recognized by the public [8,10–12]. In the last decade, electronic nicotine delivery systems (ENDS), such as electronic cigarettes (ECs), have been introduced as a potentially healthier alternative to conventional cigarettes. This drew the attention of WHO, who included ECs in their 2019 global report on smoking and tobacco use. There is no estimate on a global EC use, probably because out of 195 countries studied, only 39 provided data. The prevalence of ECs use though in United Kingdom is 5.5 %, in Australia 3.2 % and in Greece 1.9 % [1]. ECs are battery-powered devices which deliver the stimulant nicotine to users by producing a heated vapour which is inhaled. This process is commonly referred to as vaping [13]. The vapour may contain nicotine and various fruit and other flavours but does not contain tobacco, or other tobacco combustion byproducts. Although ECs owe their popularity to the absence of the harmful chemicals that are

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Corresponding author. E-mail addresses: [email protected] (D. Makrynioti), [email protected] (Z. Zagoriti), [email protected] (C. Koutsojannis), [email protected] (P.B. Morgan), [email protected] (G. Lagoumintzis). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.clae.2020.02.009 Received 30 July 2019; Received in revised form 24 January 2020; Accepted 16 February 2020 1367-0484/ © 2020 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Dimitra Makrynioti, et al., Contact Lens and Anterior Eye, https://doi.org/10.1016/j.clae.2020.02.009

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some toxic chemicals are released in the EC vapour as well, but their levels are substantially lower compared with tobacco smoke [41], and in some cases (such as nitrosamines) are comparable to the amounts found in pharmaceutical nicotine products [42]. There is ongoing debate within the public health community as to whether ECs have a potential role in smoking cessation [43,44]; whether use of ECs can reduce harm for individual users; whether widespread use of the devices has the potential to reduce or increase population-level harm; and how to best regulate ECs to minimize both individual and population-level harm [45]. Producing nicotine aerosol from a solution, rather than burning tobacco, gives rise to fewer harmful substances than cigarette smoke for both users and non-users [46], but the long-term effects of ECs use are still under investigation. Because the health risks associated with vaping are likely to be smaller, some experts advocate wider availability and softer regulation, and consider ECs to have great potential in helping smokers quit or switch to a harm-reducing way of consuming nicotine [47,48]. Others call for application of the ‘precautionary principle’ in public health, and argue that it is not consistent with public health policy to allow ECs into the market, until robust evidence supporting the safety of ECs and their efficacy in reducing harm would be available [49,50]. They cite the addictiveness of nicotine and the potential for harm from ongoing use of ECs, compared with complete cessation of all nicotine and tobacco products [45]. There are also concerns that ECs will be used in combination with tobacco products, or that ex-smokers will re-initiate their nicotine addiction or return to smoking [50,51], particularly if exposed to EC advertising that may be perceived as being glamorous [52]. Other serious issues include the possibilities that ECs might promote nicotine use among non-smokers, especially children; serve to renormalize smoking; or serve as a gateway to the use of combustible cigarettes or illicit drugs [50,53,54].

identified in the tobacco smoke, there is still a debate about their safety. In this review, we focus on the effects of smoking conventional cigarettes and using ECs, particularly with regard to dry eye disease and other ocular conditions. 2. Conventional cigarettes There are about 1.2 billion smokers worldwide [14]. Cigarette smoke causes the intake of heavy metals and toxic mineral elements and can be divided into mainstream smoke, which is inhaled by smokers from the burning tobacco and side stream smoke, which is emitted into the surrounding air during puffs [3]. It is known that tobacco smoke is a toxic and carcinogenic mixture that contains almost 5,000 chemicals and consists of both vapour and particulate phases [15,16]. Some components, such as CO and CO2 are found in the vapour phase, while others, such as phytosterols, are found in the particulate phase. Other compounds, such as phenol and cresols, are found in both phases [15]. More than seventy human carcinogens have been identified in tobacco smoke [17]. The best known component of tobacco is nicotine, a psychoactive chemical, but the risk of long term nicotine intake is still being researched. Almost every organ of the body is affected [9] by the significant toxicity of smoking. The negative effects on human health include cancerous and non-cancerous lung diseases, other forms of cancer, atherosclerotic diseases of the heart and blood, damage of the reproductive system and interaction with some therapeutic drugs [18,19]. It is also responsible for dyslipidemia, high-density lipoprotein (HDL) reduction and concomitant increase of low-density lipoprotein (LDL) and triglycerides which, in turn, can lead to more rapid thromboembolism [20,21]. Furthermore, smoking tends to affect the immune responses of smokers, causing tissue damage and inflammation. At molecular and cellular levels, the smoking process, in addition to causing hypoxia and oxidative stress, triggers the production of proinflammatory cytokines and autoantibodies [22]. Autoimmune diseases such as rheumatoid arthritis, Crohn’s disease and multiple sclerosis are associated with smoking [23–25].

4. Smoking and health hazards As previously mentioned, the global tobacco epidemic is a major issue [1]. To sum up, smoking increases the risk of various types of cancer (mainly lung cancer), and cardiovascular and respiratory diseases, reduces fertility and is associated with increased levels of stroke, deafness, blindness, osteoporosis, back pain and peripheral vascular disease. Furthermore, smokers die about 10 years younger than nonsmokers, on average [55].

3. Electronic cigarettes An EC device is comprised of a battery, as a power unit, and an atomizer that includes the heating coil, which produces steam. Most commonly, e-liquids contain water, nicotine, vegetable glycerin (VG), propylene glycerol (PG) and a mix of flavouring additives, in variable concentrations, in order to achieve the desired taste while vaping [26]. ECs can deliver nicotine, hence managing the chemical part of the addiction, and, at the same time, they offer sensory and motor stimuli much like smoking. ECs offer an alternative method of nicotine delivery and are used by consumers to reduce, or fully substitute, the smoking of conventional cigarettes. The ability of ECs to deliver nicotine whilst retaining the ‘look and feel’ of conventional cigarettes has led to success in the reduction of conventional cigarette consumption [27]. Awareness and use of ECs has grown exponentially over the past few years [28,29]. A number of surveys and studies of users have shown that many smokers succeed in quitting smoking with the use of ECs, while randomized controlled trials have shown modest health benefits [30–33]. According to Farsalinos and co-authors [27], an estimated 48.5 million people have used ECs in all member states of the EU. Existing evidence indicates that EC use is a far less harmful alternative to smoking [34–36]. Nevertheless, the latest studies report somewhat harmful levels of toxic chemicals in heated tobacco products/ e-cigarettes [37,38] and similar adverse events [39], as well as a higher level of addiction to e-cigarettes when compared to traditional cigarettes [40]. There is no tobacco and no combustion involved in EC use though; therefore, regular vapers may avoid several harmful toxic chemicals that are typically present in the smoke of tobacco cigarettes. Indeed,

5. Smoking and ocular conditions Research data suggest that active and passive smoking are both risk factors for many ophthalmological disorders, such as development of dry eye, anterior ischemic optic neuropathy, age related macular degeneration (AMD), cataract, thyroid ophthalmopathy, open angle glaucoma, diabetic retinopathy or even blindness; furthermore, strabismus in the offspring of pregnant smokers has been reported [7,9,56–58]. Although these conditions can be triggered by other reasons, smoking is considered an important factor and its effects are doserelated [9,59]. However, the public awareness of the relationship between smoking and eye diseases, some of which may even result in blindness, is lower than other smoking related diseases [10–12]. 5.1. Dry eye disease Dry eye disease is a serious multifactorial healthcare problem that affects millions of people [60]. According to the definition given in the Tear Film & Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II): “Dry eye is 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” [60]. It is commonly due to dysfunction of 2

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the tear film, related to a deficiency in tear volume or excessive tear evaporation. This disorder is characterized by inflammation of the ocular surface and the lacrimal glands and the most common clinical symptoms are ocular burning, foreign body sensation and stinging, photophobia, blurred vision and susceptibility to eye infections [9,61]. The TFOS DEWS II epidemiology of dry eye suggests that dry eye disease affects between 5–50 % of the population worldwide and its prevalence is increasing [62]. In a recently published study, increasing prevalence in the United States was reported regardless of demographic grouping [63]. Dry eye has also been associated with a higher prevalence of depression and suicidal ideation [64–67]. Cigarette smoking is suggested to be one of the risk factors for the development of dry eye symptoms [68,69]. Satici and co-authors [70] report the negative effects of cigarette smoke on the ocular surface and tear film and they attribute the very first report of cigarette smoke aggravating dry eye symptoms to Arffra in 1991 [70]. Later, in 2005, Yoon and co-authors [71] suggested that cigarette smoke decreases the quantity and quality of tear secretion and this can lead to ocular surface damage and dry eye disease. Also, several pathological conditions of dry eye, including chronic inflammation of the ocular surface and decreased sensitivity of the cornea and conjunctiva are caused by smoking [72]. In addition to these, tobacco smoke induces ocular discomfort [71]. Chronic smoking may also be linked to meibomian gland dysfunction, which is associated with dry eye disease [73]. One Japanese study reported that 25–40 % of employees encountered tobacco smoke in their work environment, while 25 % of this group suffered from dry eye disease [9]. Weber, who first reported these percentages in 1984, adds that there is a positive correlation between the concentration and exposure duration to smoke and eye/nose/throat irritation and eye blink rate [74] Environmental exposure to smoke has also been linked further to dry eye symptoms [9,75] as has passive smoking [76,77], even in children [78]. On the contrary, several studies report no significant association with dry eye disease [65,69,79] and no effect on tear meniscus or break up time results [80], or even an increase in the total and reflex tear secretion [70,71]. Smoking is sometimes considered to be a risk factor for dry eye disease [81,82] but despite reports associating it with ocular surface discomfort, a clear link with dry eye disease has not yet been established [67,68,71,83–86]. The latest DEWSII report, for example, mentions the effects of smoking on dry eye [87] but concludes that it constitutes an “inconclusive” risk factor for dry eye disease [83].

5.3. Age-related macular degeneration Age-Related Macular Degeneration (AMD) is a common eye condition, which leads to vision loss among people aged 50 and older [94,95]. The term itself represents a collective designation for a variety of degenerative changes in the macula [96,97]. AMD alone does not lead to complete loss of vision, but can interfere with simple everyday activities such as driving and reading, as it leads to color perception loss and image distortion. In some cases progression is slow and vision loss can take a long time, while in others, the disease progresses faster, affecting vision in one or both eyes. AMD results from changes in the retina and its associated tissues and smoking is postulated to be one of the most controllable factors underlying these changes [95,98–100]. Oxidative stress derived from free-radicals that damage proteins, lipids, and possibly, mitochondrial DNA, is thought to contribute to the malfunction of the retinal pigment epithelium (RPE), affecting its ability to phagocytize cellular products. In turn, this leads to accumulation of debris that interferes with nutrient exchange between the RPE and the choriocapillaris [101]. The macula is a likely target for oxidative stress as it is exposed to light, has high metabolic rate and high concentration of fatty acids. Although the macula is very rich in antioxidative capacity, with the presence of various antioxidant nutrients and enzymes, smoking acts to lower the levels of these agents in plasma. More directly, it also reduces macular pigment optical density. This carotenoid based pigmentation offers dual protection by virtue of its role in filtering short wavelength light and being actively antioxidant and so, a reduction in its abundance might be expected to reduce the overall effectiveness of the macular defenses [102,103]. Indeed, antioxidant supplements and zinc may delay the progression of some signs of AMD [104]. Smoking has been shown to reduce the volume of blood flowing through the choroidal vessels [105]. This may be contributory in AMD, where vascular insufficiency is thought to be an important factor in reducing the local capacity to dispose of cellular waste. It is likely that multiple pathways are responsible for the degenerative changes that occur in the macula with age and a reasonable basis exists for presuming that smoking operates through one or more of these pathways to accelerate, or magnify, these effects. 5.4. Glaucoma Glaucoma is a disease characterized by loss of retinal ganglion cells, probably through a variety of mechanisms. The two main types of primary glaucoma are primary open-angle glaucoma and angle closure glaucoma. Glaucoma results in damage of the optic nerve and vision loss and it is the third leading cause of blindness worldwide [88]. In the majority of cases, the damage to the optic nerve is linked to raised intraocular pressure. If not successfully treated, glaucoma can result in permanent vision loss. Commonly, treatments attempt to reduce intraocular pressure with eye drops, laser treatment or surgery. Numerous epidemiological studies have demonstrated a range of strength of association between smoking and glaucoma [106–115], with most suggesting that smoking increases the likelihood of glaucoma [112]. Current research evidence is inadequate though to infer the presence or absence of a strong causal relationship between smoking and glaucoma and further work is needed in this area.

5.2. Cataract Cataract is the clouding of the ocular crystalline lens with this loss of transparency leading to decreased vision; it represents one of the main causes of blindness worldwide [88–90]. Although cataract development is multi-factorial, several hypotheses and research findings have proposed an association between cigarette smoking and cataract [89–91]. Cigarette smoke contains a huge number of aromatic compounds and trace metals that are harmful for lens proteins but studies on their bio-dynamics and potential mechanisms responsible for cataract formation are challenging. It has been postulated that cadmium, lead, thiocyanate and aldehydes in cigarette smoke lead to damage in the lens [92]. Though thiocyanate levels were not measured in smokers’ lenses they were found to be elevated in blood, leading to the suggestion that it may have caused carbamylation of lens proteins (crystallins) and other enzymes. Blood and lenses from cataract surgery patients, who were also smokers, exhibited highly dose dependent accumulations of cadmium compared to non-smokers [93].

5.5. Graves’ ophthalmopathy Graves’ disease is an inflammatory disorder of the thyroid [116] related to a range of genetic and environmental factors. Graves’ ophthalmopathy is characterized by proptosis (protrusion of the eyeball), diplopia (double vision), optic neuropathy, and conjunctival and periorbital inflammation [117]. Although the exact pathogenic mechanism of the disease at molecular and cellular level is not yet completely understood, it seems to involve the deposition of collagen and 3

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glycosaminoglycans from orbital fibroblasts to the muscles, which results in the enlargement and fibrosis of the ocular compartments [118,119]. Data suggest an autoimmune basis for Graves’ ophthalmopathy, as well [116,120,121]. An increased risk among smokers for developing the ocular complications of Graves' disease has been reported. For example, cigarette smoking is the major preventable factor for Graves’ ophthalmopathy, with incidence approximately 8-fold higher in smokers vs nonsmokers, and the risk proportional to the number of cigarettes smoked daily [122]. Smoking is suggested to be associated with autoimmune diseases due to non-specific suppression of T-cell activation, reduction of natural killer T cells and impairment of humoral and cell-mediated immunity [22]. Moreover, smokers with Graves’ ophthalmopathy respond less well to immunosuppressive therapies compared to non-smokers [123]. The association between Graves’ ophthalmopathy and smoking suggests the involvement of additional factors to immune suppression, such as direct effects of cigarette toxins [124]. Lacheta et al. recently presented a review on the immunological aspects of Graves’ Ophthalmopathy, where orbital fibroblasts and putative autoantigents are mainly considered [125]. Yet, the mechanism by which smoking may cause or aggravate Graves’ ophthalmopathy is unknown and further research is needed.

7. ECs and health hazards Reports of fires and burn injuries, ascribed mainly to EC battery explosions, are growing in numbers, probably due to the fact that the popularity and use of ECs has increased worldwide [146–153]. In the UK, about 113 fires caused by e-cigarettes over a three-year period (2013–2015), have been reported, while there have been over 16,000 smoking related fires over the same period. These reports indicate that, while ECs do cause combustive problems, these events are quite rare relative to those associated with smoking. Nevertheless, in US hospital emergency departments, between 2015 and 2017, an analysis of ECs explosion and burn injuries concluded that past reports appeared to have significantly underestimated the actual numbers of events. As those with less severe injuries may not present in emergency departments, the true number of cases is likely to exceed these primary estimates [154]. Regarding the site of burn injuries associated with EC batteries, it was found that the lower extremities and hands were most frequently involved. Nearly 50 % of the reported incidents required surgical management as a result of the depth of injury [153]. Many of the EC related burn injuries presenting to US emergency departments in 2016 occurred to the upper leg/lower trunk and were as a result of devices being carried in users’ pockets [155]. There have also been case reports of EC explosions causing fractures [156] and ocular injuries [157,158]. Although ECs manufacturers have tried to attribute blame for explosions to the user for charging the devices improperly, a 2017 report from the US Fire Administration found that only 25 % of explosions occurred during the charging process [146]. Sixty-two per cent of the devices exploded when being carried in a pocket or being actively in use. Etiologically, these accidents seem to be related to the shape and construction of ECs, wherein the lithium-ion battery is installed in a cylindrical tube. Internal pressure, generated by battery failures, forces the battery out of the tube at the weakest points, which are at either end [146]. As a consequence, it would be prudent to avoid ECs powered by lithium-ion batteries.

6. Smoking and contact lens wear Epidemiological studies that have examined the links between contact lens wear and smoking, suggest that there is a higher risk of ocular irritation among smokers [126–130]. More important is the relationship between smoking and corneal infection (microbial keratitis) which is the major concern amongst contact lens practitioners [131,132] Microbial keratitis incidence for contact lens wearers is low but consistent over the years [128]. The disease can vary significantly in severity [133] and can ultimately lead to blindness via corneal opacification [134] or even endophtalmitis and enuclation. Zapp et al. in their work report a 7.2 % development of endophtalmitis after microbial keratitis in their subjects; additionally, when they studied the severe microbial keratitis cases in the hospital, they found a lower transformation rate of 0.29 % from microbial keratitis to endophtalmitis overall (11 out of 3773 cases) [135]. Despite its severity, microbial keratitis, if diagnosed and treated early, can result in no longterm effects of corneal integrity [136]. Contact lens wearers who are smokers show approximately a 3x higher risk of microbial keratitis and 4x higher risk of corneal infiltrates [127–130,137–141]. These studies suggest the excess risk is mainly due to behavioral issues, or poor hygiene among contact lens weares and smokers. Another point of view suggests that lipopolysaccharides that contaminate tobacco smoke can easily travel from tobacco to smokers hands and then the contact lens and consequently reach the eye. There, they may initiate an immune response, in a similar way that they induce proliferative changes in the airway of smokers [142–144]. As mentioned above, smoking may be associated with dry eye [83,86,87] and of course, soft contact lens wear is itself a risk factor for dry eye disease [83]. Dissociating these relationships is problematic because reports exploring links between both contact lens wear and smoking and dry eye disease in the same subjects are limited. In a study performed in 2010 in Japan, Ward et al. reported significantly worse tear evaporation rates, tear break up times and corneal staining in soft contact lens wearers versus non-wearers, when they were passively exposed to only five minutes of cigarette smoke [77]. Tityal et al. in a multivariate analysis on risk factors for dry eye disease, correlate smoking and contact lens usage and report “increased odds of developing severe DED (P < 0.001)” among smokers [145]. On the contrary, Lee et al. in 2012 reported a lack of association when studying dry eye severity under smoking and/or contact lens wearing conditions [69].

7.1. ECs and aerosol pollutants Due to the recent introduction of ECs to the market, there is limited literature in controlled studies on the safety of long-term use of ECs. A recent study suggests similar changes in acute respiratory response after exposure to e-cigarette use or tobacco cigarette smoke [159]. However, since ECs do not generate the smoke that is produced by burning tobacco, their use is generally accepted as likely to be less harmful than smoking conventional cigarettes [32,160,161]. Apart from related serious burn and fire accidents, other short-term adverse effects of exposure to ECs are usually mild and transient, and may include nausea, vomiting, mouth and airway irritation, chest pain and palpitations. [162]. ECs deliver nicotine by creating an aerosol of ultrafine particles, but due to the variability and chemical complexity of fine particles and uncertainty regarding the specific components responsible for toxicity, it is unknown whether ECs have health effects and toxicity similar to the ambient fine particles generated by conventional cigarette smoke or second-hand smoke [51,163]. This issue is further confounded by the absence of regulatory and manufacturing controls, which has allowed potentially harmful variability to occur in terms of both the concentrations and constituents of key components. Users should be aware that the actual contents may thus be significantly different from those marked on the packaging [164,165]. 8. ECs vaping and ocular conditions Current knowledge about ECs and related “harm reduction” products is very limited and the long-term effects are yet to be established. However, there are some early indications that ECs can cause irritation 4

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with dry eye in only one report [166] and with general eye irritation in two [178,179]. Vaping and cataract are possibly correlated, hypothetically due to the toxic compounds found in EC vapour, but a clear, causal route has yet to be reported. Some evidence exists connecting vaping with AMD, glaucoma, Graves’ ophthalmopathy and contact lens related complications but the literature relating to health problems in general, and ocular conditions in particular, is currently limited. Otherwise, the human hazard posed by EC use is mainly that of burns, due to battery overheating.

to the eyes in the form of dry eye, cataract or other ocular irritation. Yet, there are still many factors that require rationalization and serious consideration before firm conclusions can be drawn in relation to these products. 8.1. Dry eye disease It appears that there has been only one published study on EC and dry eye disease to date [166]. According to Md Isa et al. (2019), vaping was correlated with poor tear film quality and symptomatic dry eye [166]. The authors suggested that: “high vaping voltage may have aggravated the dry eye syndrome because of hazardous by-products from pyrolysis of the e-liquid constituents” and they recommended further investigation of the ocular surface cells and molecules to provide a better understanding of the vaping effect to eye health [166].

Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing Interest

8.2. Cataract None. Despite the presence of studies on tobacco consumption and cataract formation, there is currently no direct evidence linking cataract and EC use. In early studies though, which compared tobacco smoke and EC aerosols, lower levels (9 to 450-fold lower) of potentially toxic compounds (e.g., formaldehyde, acetaldehyde, acrolein, and toluene) were reported to be present in ECs aerosol [160,167–170] This suggests that ECs may be less harmful to lens proteins than cigarette smoke, potentially reducing the risk of cataract; although further study is required in this area. Cataract caused by smoking might also have an alternative route, i.e. by lowering the levels of antioxidants [171]. In vitro studies have shown that exposure to e-liquids or aerosols induces oxidative stress to certain cell types at lower levels than those commonly produced by conventional cigarettes [172,173]. Although the association between elevated oxidative stress, or lower antioxidant levels, and cataract development is controversial (as the antioxidant pathway responsible for lens damage has not yet been determined), a few studies have reported on the antioxidant levels in the lens, blood or serum of those with cataractous eyes [174–177]. Further research on smoking/vaping, oxidative stress and cataract is required.

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8.3. Other ocular conditions Among other potential health risks of ECs use that have been identified in recent years, one review notes that exposure to propylene glycol, one of the major constituents of e-liquid refills, can cause eye irritation [178,179]. 9. Conclusion This work has reviewed the relationships between traditional and new ways of nicotine uptake and a range of ophthalmic diseases. The relationship between smoking and dry eye disease remains unproven [83] although stronger relationships are evident for cataract, AMD, glaucoma and Graves’ ophthalmopathy. A detailed causal pathway between smoking and any of these diseases has yet to be established however. Smoking is strongly associated with higher risks of microbial keratitis and corneal infiltrates in contact lens wearers. Independently, smoking is associated with ocular irritation in contact lens wear and so, potentially, smoking and contact lens wear combined may increase the risk of ocular irritation. This hypothesis requires further investigation. Vaping is a recently introduced method of nicotine delivery. As such, research is actively being pursued on its safety and impact on human health. As there is no tobacco in ECs, unquestionably the harmful toxic chemicals of traditional cigarette smoking are avoided. Whether there are residual effects of EC vapour inhalation remains to be seen, however. Up to the present time, vaping has been correlated 5

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