Smoking tobacco is the single largest cause of preventable death around the world. With more than 7 million premature deaths due to smoking including second-hand smoke yearly, the menace of smoking is far away from being tamed and is estimated to reach a massive 8 million by 2030.

The newest smoking products are Electronic Nicotine Delivery Systems (ENDS) or Alternative Nicotine Delivery Systems (ANDS) and Vaporised Nicotine Products (VNPs), popularly known as e-cigarettes and e-hookahs. These devices heat liquid propylene glycol or glycerol or their combination, to create an aerosol that contains nicotine which is inhaled.

Since its invention by Hon Lik in 2003, and its subsequent commercial launch in 2006, there has been an alarming increase in the consumption of e-cigarettes. In 2015 alone their global sale was at least US$ 3.5 billion with the majority of it coming from the western countries where significant percentage up to 21% of the smokers and recent ex-smokers use ENDS.

Although pitched and extensively marketed to be an effective tool against tobacco dependency, its use has not been as tightly regulated as with the nicotine replacement therapies. There has been a significant proportion of previous non-smokers and long-term ex-smokers currently using e-cigarettes which rather suggests it as an alternative tobacco delivery system.

The harmful effects of ENDS can be broadly classified into two types as the harmful effects due to nicotine consumption and the direct use of ENDS by the individual. Although there have been guidelines and recommendations to not allow the ENDS liquid to contain more than 20mg/ml of nicotine, there is great heterogeneity in the concentration of nicotine in ENDS globally.

Studies done on chronic ENDS users by Vansickle et al proved beyond doubt that chronic use of ENDS can achieve a steady continuous plasma concentration of at least 16ngm/ml with 10 puffs of e-cigarettes after one hour. This study refuted the earlier claims that e-cigarette did not cause raised nicotine levels in the blood which perhaps was only for the earlier ENDS devices and definitely not true of the second and third generation ENDS.

Further studies by Flouris et al checked the cotinine levels, which is the chief metabolite of nicotine in blood and did found significantly higher levels than compared to the baseline. Present-day 3rd generation e-cigarettes have matched their conventional counterparts both in delivering adequately equal nicotine to the blood and also achieving the level of dependency and withdrawal symptoms.

Nicotine acts by three major mechanisms namely the ganglionic transmission, secondly by the Nicotinic acetylcholine receptors (nAChRs) which act on chromaffin cells through catecholamines, and lastly central nervous system (CNS) stimulation of nAChRs. Nicotine increases the activity of the prefrontal cortex in the brain and visual cortex. It increases oxidative stress and neuronal apoptosis, DNA damage, reactive oxygen species and lipid peroxide increase.

Following below are the various health-related adverse effects of nicotine.

Immediate toxicity: Irritation and burning sensation in the mouth and throat, increased salivation, nausea, abdominal pain, vomiting and diarrhoea. The increased rate of respiration causes hypothermia, a hypercoagulable state, decreases skin temperature, and increases the blood viscosity. In severe poisoning, there are tremors, prostration, cyanosis, dyspnoea, convulsion, death may occur from paralysis of respiratory muscles or a central respiratory failure with an LD50 in adults of around 30-60 mg of nicotine.

Addiction: The US surgeon general report in 2010 has stated nicotine to be as addictive as cocaine or heroin. It simulated dopaminergic transmission which in turn stimulates the reward centre and is responsible for the mood elevation and apparent improvement in cognitive function, chronic stimulation causes desensitization of the GABAnergic neurons to dopamine and thus results in addiction and dependency. Furthermore, it mutates the CYP2A6 gene and leads to inheritable dependence to nicotine.

Metabolism: It increases glycogen synthesis due to adrenoceptor stimulation which leads to a reduction in the fasting blood glucose levels. It also causes lipolysis thus decreasing body weight. Nicotine affects insulin resistance and predisposes to metabolic syndrome and diabetes.

Carcinogenesis: Although not classified as a carcinogen on its own by the IARC, nicotine acts by stimulation of nAChRs on cells which causes initiation and progression of cancer, by the receptor-mediated effect to achieve the survival of damaged epithelial cells. Further, the nitration of nicotine in the oral cavity and GI tract causes the formation of highly carcinogenic compounds like nicotine-derived nitrosamine ketone (NNK) and N- nitrosonornicotine (NNN).

Cardiovascular: Nicotine causes catecholamine release both locally and systemically leading to an increase in heart rate, blood pressure and cardiac contractility, further it reduces the myocardial oxygen delivery resulting in acute myocardial ischemia on chronic use. In patients with coronary heart diseases, nicotine worsens the ischemia and also produces transient ischemia even without changes in heart rate and blood pressure.

Respiratory: Nicotine plays a role in the development of emphysema in smokers, by decreasing elastin in the lung parenchyma and increasing the alveolar volume. Nicotine stimulates vagal reflex and parasympathetic ganglia and causes an increased airway resistance by causing bronchoconstriction.

Gastro-intestinal (GI): It acts on the cyclo-oxygenase pathway and thus has been strongly associated with gastro-oesophagal Reflux Disease (GERD) and peptic ulcers. Furthermore, it decreases the intestinal motility and increases the incidence of resistant Helicobacter pylori infection.

Ophthalmic: Nicotine has been associated with retinal neovascularization and thus increases the risk of age-related macular degeneration in adults. This results in increased and accelerated cataract formation.

Renal: Nicotine causes COX-2 isoform induction which causes increased glomerular inflammation, acute glomerulonephritis and ureteral obstruction. This chronically leads to increased risk of chronic kidney disease.

Male reproductive system: Nicotine causes impairment of Nitrous Oxide synthesis, Nitrous oxide plays a crucial role in generating immediate penile vasodilatation and corpus cavernosum relaxation causing penile erection. Thus it results in erectile dysfunction and moreover, the seminiferous tubules degeneration caused by nicotine causes decreased spermatogenesis.

Female reproductive system: Nicotine causes chronic anovulation and irregular menstrual cycles by increasing the follicle-stimulating hormone levels and decrease estrogen and progesterone levels. Nicotine treated oocytes show disrupted shape and surface and delayed maturation. Maternal nicotine consumption leads to lower levels of ACTH and cortisol and thus associated with an increased incidence of intrauterine growth restriction, still birth, miscarriages and mental retardation.

Adverse effects of ENDS have been documented by various studies in the last decade. Although many of the adverse effects are similar to those inflicted by conventional smoking there are others which are specific to e-cigarettes. These adverse effects can be further classified into three major categories namely the health effects of the product itself (e-liquid and aerosol), secondly the public health associated effects and thirdly the hazardous effects of device failure itself.

The following are the documented direct adverse effects of e-cigarettes:

1. Non-standard production of e-liquid and aerosols from unlicensed manufactures results in widespread adulteration and high concentration of Nicotine. There have been at least 460 brands of e-cigarettes sold world-wide with most of them unregulated.
2. Although propylene glycol has been considered safe for inhalation in human, it has been reported to cause chronic respiratory disorders in children and theatre personnel exposed to the stage fog, leading to decreased lung function, rhinitis, asthma, eczemas and dryness of upper aero digestive tract.
3. Uchiyama et al. demonstrated that 70% of examined e-cigarette brands contained or generated carbonyl compounds such as formaldehyde, acetaldehyde, acrolein, crotonaldehyde and methylglyoxal which have shown to have a role in epithelial mucosal injury and disruption of the normal upper aero digestive tract leading to carcinogenesis. Volatile organic compounds (VOCs) such as benzene, acrylonitrile, ethylbenzene, styrene and toluene were found in e-cigarette aerosol as well.
4. Acrolein which is toxic by-product of glycerol has been found in many brands of ENDS. Although the amount of acroline in e-cigarettes is much lower than conventional smoking, Faroon et al stated that it induces the respiratory, ocular, and gastrointestinal irritations by inducing the release of peptides at the nerve terminals. There has been a dose-related decrease in substance P between 22 and 249 ppm of acrolein for 10 min. In animal models, it has been also shown to induce mild nasal epithelial dysplasia, necrosis, and focal basal cell metaplasia of the upper aero- digestive tract.
5. The impurities of e-cigarettes are significantly lower compared to conventional cigarettes but nevertheless, the flavouring substance, metal impurities and by-products of heating coils and other tobacco carcinogens have been found, hence the long term effects of this could be deleterious.
6. Review of medical literature is replete reports of pneumonia, acute asymptomatic atrial fibrillation, increased airway resistance and bronchial irritation.
7. Maternal e-cigarette smoking has been associated with decreasing in lung volume of foetus and pulmonary resistance, accompanied with decreased static and dynamic lung compliance almost similar to conventional cigarettes.
8. Studies have documented raised liver biomarkers aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) on exposure of e-cigarettes.
9. Recently E-cigarettes have been shown to significantly affect the CNS resulting in chronic neuropathy.

There have been device-related problems associated with e-cigarettes like facial burns caused by battery burst and explosion of the device, there have been reports of infant chocking due to the ENDS device as well.

The adverse effects on public health due to smoking behaviours and use of e-cigarettes have been also very alarming. Although extensive long term studies are needed to conclusively prove these, they are accepted as the possible fallouts by many of the public health advocates and the current trends in its usage prove these:

• ENDS gives the non-smoker or the ex-smoker an opportunity to indulge in smoking which is portrayed as less harmful
• There would be an indirect rise in the prevalence of smoking conventional cigarettes by making smoking acceptable were ever banned.
• There would be migration of the adolescent e-smoker to a conventional smoker in adulthood.
• There would be no actual reduction or cessation of nicotine dependency as the possible benefit as most data suggest a steady rise in the prevalence of e-cigarette use.

While discussing the benefits of e-cigarettes it is important to highlight one of the most cited literature which is from the Public Health England, published in February 2018 as a detailed evidence based review.

This 243-page report is famous for the headline stating E-cigarettes are around 95% less harmful than tobacco. This was publicized in media and other sources, however, there were quite a few glaring shortcomings of this review, the figure of 95% less harmful was derived from a report by Nutt et al.

This report by Nutt et al was based on an assessment of e-cigarettes as compared to nicotine-containing products by a group of Independent Scientific Committee on Drugs which was founded by him, the authors of this paper had a serious conflict of interest associations, one being the consultant to a firm distributing e-cigarettes.

In excessively dependent individuals there has been shown that multi-modality delivery system of nicotine replacement helps in smoking cessation when administered under the supervision of a medical practitioner. There is little knowledge about the harmful effects of ENDS. Most of the available studies are non-standardized and only report acute adverse effects. Long-term effects of ENDS have not been studied.

This distorted information led to a general understanding of the civil society that e-cigarettes are a harmless and safe alternative.

ENDS have been propagated as a safe alternative to smoking. However, they pose a great threat to individual health and public health in general. The nicotine dependence, increased prevalence, smoking-associated adverse effects and the rebirth of casual smoking through e-cigarettes is unacceptable to the decades of tobacco control policies and public health initiatives.

With large data available on its adverse effects and the potential benefits it appears that the harmful effects outweigh the potential benefits. Hence the widespread use of e-cigarettes needs to be strictly regulated and an impending epidemic of a new form of tobacco consumption controlled.

Courtesy: The Leaflet