5.2 Chemical factors

Usually, this kind of injuries occur during accidents (drinking, spilling) or when the dentist is not careful enough. The oral mucosa is sensitive to burning both by acids and bases as well as by salts of heavy metals. This group of factors also includes the effects of some treatment agents applied locally (in the past, e.g. arsenic), or generally. The chemical factors contain among other things the effects of smoking and action of compounds formed by erosion of metals used in the dental practice.

5.2.1 Stomatitis due to corrosive substances (burning)


Those typically occur due to the accidents in laboratories, improper handling of the chemicals in the clinical practices, or as a result of harmful effects of chronic exposure to corrosive chemicals in the working environment. The action of acids or bases leads (depending on the concentration and duration of exposure) to the development of necroses of various depths that originally manifest as pale spots on the tissue. Acids cause a circumscribed delimited coagulation necrosis, the colour of the damaged mucosa depends on the used chemical (nitric acid- yellowish; hydrochloric acid – white; sulphuric acid – black. When the tissue is burnt by bases, the surface is usually greyish and mushy (liquefactive necrosis). When the necroses separate, painful ulcers appear that heal only with difficulty and leave scars. When chronic exposure occurs, damage to the mucosa of the eye and nose is the most prominent while on the oral mucosa, hyperkeratotic changes can be observed.

Th.: The most important rule is to neutralize the agent as quickly as possible. When the burn was caused by an acid, a 5% sodium bicarbonate solution is used while when the agent was a base, the best course of action is to rinse the mouth repeatedly by a solution of citric acid. If those (or similar) chemicals are not available, it is important to at least keep rinsing the mouth with water for 20 minutes. Other measures include protection from secondary infection and painkillers.

5.2.2 Toxic effects of xenobiotics


Xenobiotics are substances that are not formed in the human organism but possess pharmacological (medicines), endocrine or toxic effects affecting the organism. In the oral cavity, xenobiotics may affect:

  1. the oral mucosa – lichenoid reaction, EEM, pigmentation, gingival hyperplasia and bleeding, mucositis and non-specific ulcerations (Fig. 7).

  2. salivary glands – xerostomia, ptyalism, induration and/or pain in the salivary glands.

  3. hard tissues – caries, discoloration of teeth, alveolitis, osteonecrosis of the jaw.

  4. non-specific inflammations – changes in the taste perception, halitosis, neuropathy, motility disorders, infections.

Unwanted effects of medications may also cause variable mucosal and dermal changes. Various mechanisms can be involved in the drug-induced pathogenesis (general toxic effects, drug interactions, immunopathological effects, allergic, provoking an autoimmune disease). .

Fig. 7: Xenobiotics-induced diseases of the oral cavity

The problems can be provoked by an abnormally high drug dosage, although even therapeutic doses can elicit pathological processes. Complications after the use of ATBs manifesting as dysmicrobia (dysbalance of the microbial equilibrium of the digestive tract caused by ATB-induced destruction of the physiological microflora) is a typical example of such process. Dysmicrobia can subsequently facilitate the development of a superinfection, i.e., of proliferation of pathogenic microorganisms insensitive to the particular ATB (e.g. proliferation of yeasts after ATB therapy).

The method of the exposure to the xenobiotics also plays a role. A direct contact with the oral mucosa can cause local irritation, allergic reaction or other pathological processes. Drugs administered as inhalation preparations may lead to disorders of taste perception. Drug-abusing individuals (e.g. cocaine) can after a long-term oral or nasal application suffer with serious damage to the tissues of the oral cavity, even to perforation of the hard palate.

Swellings in the oral cavity can be caused e.g. by cardiac medications (ACE inhibitors), ATBs, barbiturates, NSAIDs. The symptoms usually appear within minutes to hours after administration of the respective drug. ACE inhibitors can induce a non-allergic intraoral swelling caused by a change in levels of locally released bradykinin. Although such swelling can be usually observed during the first weeks of therapy, it is not uncommon that it only appears after a longer period of using.

Individuals taking multiple medications or their excessive doses have a higher risk of developing drug-induced xerostomia due to the synergistic effects of the active substances. Smoking, alcohol abuse and/or long-term usage of caffeine-containing drinks also add to the burden and affect the moisture of the oral mucosa.

Drug-induced gingival hyperplasia is a relatively common condition, usually manifesting

1-3 months after the initiation of the therapy with a new drug. First, it appears on the interdental papillae, especially frontally, a generalized affliction of the entire gingiva is nevertheless not uncommon. Typically, this type of gingival affliction results from the use of calcium channel blockers, cyclosporine or hydantoinates.

Drug-induced discolorations (pigmentations) of the mucosa can be caused by a direct stimulation of melanocytes to melanin production, by storage of pigmented drug metabolites, or by a combination of both. Usually, such pigmentation occurs in the centre of the posterior part of the hard palate, is bluish-black to brown and can be bilateral. During HIV treatment with antiretrovirotics, diffuse oral discolorations can occur. Pigmentations of the tongue (and hard dental tissues) was also observed after the use of tetracyclines.

Drug-induced stomatitis of toxic origin

In comparison to the allergic form of drug-induced stomatitis (see Chapter 6.1.1), the inflammatory component is less pronounced while tiny erosions and haemorrhages are more prominent. The symptoms are rather localized. The physiological coating of the tongue is typically reduced or completely suppressed and the mucosa on the remaining islands (patches) of the coating on the tongue surface bears signs of hyperkeratotic changes. The diagnosis of drug-induced exanthemas can be facilitated by a parallel occurrence of skin problems. Reasons of toxic reactions may include too high dosage of the drug, reduced tolerance of the organism to the drug or accumulation of the medicine in the organism during long-term use. Mixed toxic-allergic manifestations combine symptoms of both types, the clinical picture therefore contain both inflammatory and non-inflammatory manifestations. Smooth tongue with inflammation can be observed, which however do not combine with hyperkeratotic manifestations. Tiny erosions in a certain area resulting from disintegration of the capillaries (arteriolitis) in the affected area are the most common manifestation. If larger vessels are affected, extensive necroses can occur. Th:

Dif. dg.: It is especially difficult to distinguish this type of stomatitis from enanthemas associated with infectious diseases that may be almost indistinguishable from drug-induced stomatitis (a general examination usually helps as infectious diseases are typically associated with the alteration of the patient’s general condition).

Th: The most important therapeutic step is, if possible, discontinuation of the respective medicine that is identified as the causal factor of the drug-induced stomatitis (which of course must be preceded by discussion with the attending physician).

Erosions and ulcerations

Some medicines used for treatment of myeloproliferation diseases may be toxic for the oral mucosa (e.g. methotrexate, daunomycin, cyclophosphamide, 6 mercaptopurine). Clinical manifestations include extensive painful erosions covered with fibrin pseudomembranes on the buccal, vestibular or labial mucosa, on the palate or pharynx that can become infected with candida. Severe dysphagia is often present. Ulceration or epithelial necrosis can also develop as a result of taking over-the-counter drugs (such as aspirin) and various antiseptics that are getting into a direct contact with the oral mucosa. Most commonly, labial mucosa is affected, followed by buccal mucosa and palate.

There is still a lot of controversy regarding drug-induced tumours. The use of strong immunosuppressants and/or their long-term use is likely to increase the risk of initiation and development of a malignant disease (Yuan a Woo, 2015).

Many drug-induced oral reactions may clinically, histopathologically and even immunopathologically resemble idiopathic OLP, EEM, pemphigus, pemphigoid or LE. Any site of the oral cavity may be affected, most commonly affected sites however include the buccal mucosa, lateral sides of the tongue and alveolar mucosa. Lesions can be either solitary or multiple.

OLP-like drug-induced reactions were originally described as reactions to antimalarial drugs; nowadays, however, cardiac medications are most commonly associated with this problem, along with NSAIDs and peroral antidiabetic drugs. Both lichenoid papuloreticular and erosive manifestations can be observed. In contrast with a bilateral occurrence in idiopathic OLP, drug-induced lichenoid reactions usually manifest by unilateral erosions.

Drug-induced EEM represents approximately 25 % of all cases of this affliction. Similar to the idiopathic or postinfectious (often with HSV etiology) cases, the disease has a quick onset with a variable clinical picture that can vary from lesions limited to the oral mucosa up to an extensive general affliction of the mucosas and skin all over the body. Drug-induced EEM is often associated with ATB therapy, antihyperuricemics and barbiturates. More serious forms of EEM include Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome) that are much more frequently drug-induced than „normal“ EEM and can be life-threatening.

Drug-induced pemphigus can take a form of pemphigus vulgaris or pemphigus foliaceus. Drugs inducing this problem usually contain a thiol bond. Drug-induced pemphigoid-like reactions may either manifest solely on the oral mucosa or affect also other mucosas and skin. Most commonly, they occur after derivatives of thiols and/or sulfonamides. Clinically, relatively large vesicles or bullae appear that have a tendency to burst and turn into extensive erosions and shallow ulcerations that are often covered by a fibrinous pseudomembrane. The gingiva is often affected by desquamative gingivitis with a notable erythema, erosions and epithelial peeling (of the vesicular roofs).

Drug-induced lupus erytematosus (LE) is a well-known adverse reaction that can arise following the use of more than 70 drugs, most commonly of procainamide, hydralazine, penicillamine and chlorpromazine. Erosions or ulcerative lesions can occur on the palatal or buccal mucosa as well as on the gingiva or alveolus.

Drugs known to induce diseases of oral mucosa, xerostomia or changes in taste perception are listed in the Appendix 1 (Kalmar, 2016).

5.2.3 Tobacco abuse-associated changes of the oral mucosa

Smoking represents the most harmful form of tobacco abuse (when compared with chewing and snuff). Several hundred substances have been identified in the tobacco smoke, many of which are toxic and carcinogenic for the oral mucosa. A parallel alcohol consumption further pronounces those negative effects. Over the last years, many studies reported adverse effects even of e-cigarettes on the oral mucosa (Bardellini et al., 2018). Although they do not contain tar-like substances formed during tobacco burning, their cartridges contain besides nicotine also many other chemical compounds.

Smoking-associated changes of the oral mucosa include smoker’s melanosis and leukokeratosis that are considered benign. Leukoplakia (see Chapter 7.1) is another type of lesion, the occurrence of which can be associated with smoking – it is much more common in smokers than in non-smokers and is considered as precancerous lesion. The most serious disease developing due to smoking is the squamous cell carcinoma. Tobacco abuse also constitutes one of predisposing factors for development of oral candidosis and acute necrotizing ulcerative gingivitis.

Smoker's melanosis


This condition represents a melanin hyperpigmentation of the oral cavity in heavy smokers developing due to irritation of melanocytes by substances from the cigarette smoke (which stimulate melanin synthesis). It especially affects the vestibular part of gingiva, to a lesser degree also the buccal mucosa.

Smoker's leukokeratosis (stomatitis fumantium, leukokeratosis nicotinica palati)


It appears in some smokers as a result of a long-term tobacco abuse (especially of cigarette smoking), which leads to a chronic, toxic-mechanical irritation of the palatal mucosa. This in turn leads to a higher keratinization of the mucosal epithelium manifesting as whitish discoloration and inflammatory reaction of the salivary gland orifices both on the soft and hard palate. Those changes may also be a reason for development of small elevations – papules with a central dip or dots representing erythematous orifices of minor salivary glands. In case of smoking cessation, those lesions can disappear.

Histology: Histopathologically, no dysplastic changes are present, only a simple hyperkeratosis (not parakeratosis) is observed. It can however coincide with leukoplakia in smokers.

Th.: A biopsy is not necessary, a long-term observation due to a possible risk of development of leukoplakia or squamous cell carcinoma is however recommended. When removing the etiological factor, the hyperkeratosis can regress spontaneously.

Smoking related leukoplakia


Smoking related leukoplakia appears predominantly on the floor of the oral cavity and buccal mucosa in the region of corners of the mouth. The risk of malignant transformation is the highest in female smokers with lesions located on the inferior surface of the tongue or on the floor of the oral cavity (Slezák a Ryška, 2006).

Squamous cell carcinoma of the oral cavity


Smoking is one of the predominant etiological factors of this malignant epithelial tumour. In some patients, it may appear as a consequence of smoking-related leukoplakia, it is however more commonly formed „de novo“. Alcohol abuse in smokers significantly increases the risk of the carcinoma development.

5.2.4 Exogenous pigmentations

In this type of pigmentation, the pigment originates externally (Fig. 8). The discoloration of the dorsum of the tongue may be a result of some pigment-containing foods (liquorice), frequent use of mouthwashes (especially CHX-containing brands), smoking and pigment-producing microorganisms (that have proliferated during dysbiosis caused e.g. by some antibiotics. Some medications can also cause mucosal pigmentation. The mechanisms of action may include the aforementioned effects of ATBs on microbial balance, presence of metallic salts that may constitute a component of some drugs, or a direct deposition of insoluble pigmented complexes into the mucosa/bone.

Tattoo of the oral mucosa is caused by direct implantation of pigments into the submucosal connective tissue (pen or pencil injury, artistic tattoo).

Fig. 8: Etiology of exogenous pigmentations

Amalgam tattoo


Amalgam tattoo is an exogenous pigmentation of grey-bluish-black colour developing after an injury of the oral mucosa (e.g. during tooth preparation with amalgam filling) leading to a subsequent incorporation of metallic particles into the tissue.

Metallic gingival pigmentations


Metallic gingival pigmentations result from corrosion of some metals used in dentistry in the region of the dento-gingival junction and they manifest as a grey-black line along the gingiva (in the cervical region), usually on the cervix of devitalized repaired teeth (metallic fillings, crowns, build-ups). A blue-greyish line along the gingiva is typical in chronic heavy metal poisoning (especially when associated with professional exposure due to the work without protective devices or due to the accumulation of drugs in the organism). During exposure to heavy metals, their derivatives are getting into the blood circulation and subsequently into the sulcular fluid. A site with a chronic inflammation (such as gingivitis) then represents a preferential site for precipitation of metal sulphides in the subepithelial connective tissues that in effect becomes pigmented.

Pigmentations caused by heavy metals and their salts

Heavy metals and their salts enter the organism and tissues most commonly orally, parenterally or traumatically.


Chronic lead poisoning is very characteristic. Lead binds to red blood cells (basophilic stippling of erythrocytes caused by lead (II) phosphate on their surface) and accumulates in all organs and particularly in bones. In the oral cavity, insoluble lead (II) sulphide forms a grey or blue-black margin on the gingiva which cannot be removed mechanically. Other symptoms include metallic taste in the mouth and increased salivation.


In the past, bismuth compounds were used in the treatment of syphilis. In the oral cavity, the chronic exposure manifested by the characteristic grey-blue discolouration of the marginal gingiva resembling mercury poisoning. Nowadays, bismuth intoxication is extremely rare.


Mercury poisoning (mercurialism) also used to be relatively frequent during the syphilis treatment in the past. Nowadays, the exposure is typically due to inhalation of mercury vapours. In the oral cavity, stomatitis with increased salivation and a grey-blue discolouration of the gingiva is characteristic for this problem. Similar to lead, the patient may feel metallic taste.


Gold accumulates in tissues in particular where colloidal gold solutions have been applied parenterally for treatment of rheumatoid arthritis. A blue-violet discolouration of the gingival mucosa (chrysocyanosis) is typical of chronic gold exposure.


It enters the organism orally (e.g. when using colloidal silver) or as a component of amalgams or prosthetic metal alloys (Koldan, Aurix). Exposure to silver may result in argyrosis – a distinct grey discolouration of the skin and gingiva. Bluish hyperpigmentations also occur as a result of traumatic tattoo of the oral mucosa. The presence of the metallic material in the soft tissues can be proved by X ray. It is important to emphasize that with the exception of completely clear and unambiguous cases of amalgam tattoo, any dark pigmentation of lips and oral mucosa must be histopathologically examined; this is especially true about the lesions present on the palate or the alveolar process of the maxilla.