Concern regarding halitosis is estimated to be the third most frequent reason for people to seek dental care, following tooth decay and periodontal disease . Compared with tooth decay and periodontal disease, there are a diverse number of causes of halitosis. Table 1 shows a commonly used classification of halitosis [2 – 4]. Obvious bad breath is termed genuine halitosis, which is classified as physiological and pathological halitosis. Pathological halitosis is further sub-classified into halitosis as a result of oral and extra-oral causes. Physiological and oral pathological halitosis occur in the oral cavity, and comprise 85% or more of genuine halitosis [5, 6]. Physiological halitosis generally occurs at the time of waking or starving, and likely results from increased microbial metabolic activity that is aggravated by a physiological reduction in salivary flow, oral cleaning, and inadequate mouth cleaning before sleep or after eating . Clinical causes of oral pathological halitosis include poor oral hygiene, tongue debris, periodontitis, inadequately fitted restorations, deep caries, endodontic lesions, ulceration, and low salivary flow [7 – 11]. The most common malodorous compounds that cause oral-derived malodor are volatile sulfur compounds (VSCs) such as hydrogen sulfide (H2S) and methyl mercaptan (CH3SH), which are associated with microbial amino acid metabolism [12, 13]. Halitosis derived from extra-oral causes is less common, but causes include respiratory disorders, gastrointestinal diseases, metabolic disorders, and drugs [2 – 4]. The smell of gases that have accumulated in organs during respiratory disorders and gastrointestinal diseases can be emitted directly from the oral cavity and nose. Malodorous components caused by some metabolic disorders and drugs circulate in the bloodstream and are exhaled in the breath after alveolar gas exchange. Components of extra-oral malodor include those due to disease, such as acetone in uncontrolled diabetes and trimethylamine in trimethylaminuria (“fish odor syndrome” ). Dimethyl sulfide (CH3SCH3), a VSC, is the main contributor to extra-oral or blood-borne halitosis via an as-yet-unknown metabolic disorder . Some patients that complain of halitosis do not have bad breath. Although pseudo-halitosis is not diagnosed as a psychiatric disorder, some patients with this condition exhibit neurotic tendencies more frequently than do patients with genuine halitosis . Halitophobia is characterized by a patient’s persistent belief that he or she has halitosis, despite reassurance, treatment, and counseling. Many patients with halitophobia have slight bad breath at their first visit to a dental clinic. However, the presence of a mental condition together with bad breath has been suggested in these individuals.
|Genuine halitosis||Obvious malodor, and of an intensity beyond the socially acceptable level is perceived.|
|Physiological halitosis (TN-1)||Malodor arises through putrefactive processes within the oral cavity. No specific diseases or pathological conditions that could cause halitosis are found.|
|Oral (TN-1 and TN-2)||Halitosis caused by a disease or a pathological condition that causes malfunction of the oral tissues.|
|Extra-oral (TN-1 and TN-3)||Malodor that originates from a respiratory system, gastrointestinal tract, metabolic disorders, or drugs.|
|Pseudo-halitosis (TN-1 and TN-4)||No objective evidence of malodor, although the patient thinks they have it.|
|Halitophobia (TN-1 and TN-5)||The patient persists in believing they have halitosis despite reassurance, treatment, and counseling.|
All patients that complain of halitosis should receive an explanation of halitosis and instructions for oral hygiene (TN-1; Table 2) . Further professional instruction, education, and reassurance are necessary for patients with pseudo-halitosis (TN-4). Professional cleaning and treatment of oral diseases are performed in patients with oral pathological halitosis (TN-2), and treatment and control of the systemic causative disease by a physician or medical specialist is provided for patients with extra-oral pathological halitosis (TN-3). Medical treatment by a psychological specialist is required for the treatment of halitophobia, regardless of the presence of bad breath (TN-5).
|TN-1||Explanation of halitosis and instructions for oral hygiene.|
|TN-2||Oral prophylaxis, professional cleaning, and treatment for oral diseases, particularly periodontal diseases.|
|TN-3||Referral to a physician or medial specialist.|
|TN-4||Explanation of the examination data, further professional instructions, education, and reassurance.|
|TN-5||Referral to a clinical psychologist, psychiatrist, or other psychological specialist.|
Most genuine halitosis occurs in the oral cavity, and is known as oral-derived malodor. As mentioned above, VSCs are produced during the metabolism of the sulfur-containing amino acids cysteine and methionine by bacteria [12, 13]. Gram-negative anaerobes in the oral cavity are important producers of VSCs. Periodontopathic bacteria isolated from subgingival plaques, such as
2. Chemical agents
Chlorhexidine (CHX), cetylpyridinium chloride (CPC), triclosan, zinc ions (Zn2+), and chlorine dioxide (ClO2) are all known to inhibit oral malodor [23, 24]. In many cases, these active ingredients have been used in mouthwashes and dentifrices, both individually and in combinations. CHX digluconate has been used most frequently to treat oral cavities as an active ingredient in mouthwash that is designed to reduce dental plaque and oral bacteria. CHX is used in mouthwashes at 0.12% or 0.2%, and a previous study revealed that these two concentrations of CHX had an identical effect on gingival inflammation . Young et al.  evaluated the inhibitory effects of CHX, CPC, and Zn2+on VSC production. Data revealed that 0.2% CHX and 1% Zn2+exhibited excellent inhibitory effects, and had similar effects on VSC production; however, the two agents had different anti-VSC kinetics. Briefly, 0.2% CHX had a sustained inhibitory effect, whereas Zn2+had an immediate effect. In contrast, 0.2% CPC had only a mild inhibitory effect on VSC production. These ingredients are found in commercial mouthwashes, often in combination. Roldán et al.  compared five commercial mouthwashes in a randomized, double-blind, crossover trial: 0.12% CHX alone, 0.12% CHX plus 5% alcohol, 0.12% CHX plus 0.05% CPC, 0.12% CHX plus sodium fluoride, and a combination of 0.05% CHX, 0.05% CPC, and 0.14% Zn2+. In this study, the combination of 0.12% CHX plus 0.05% CPC resulted in the greatest reduction in oral bacterial numbers. In contrast, the combination of 0.05% CHX, 0.05% CPC and 0.14% Zn2+provided the most immediate reduction in VSC levels. Zn2+can be effective in reducing the activity of VSCs directly, in addition to its antimicrobial effect . It has been reported that a combination of Zn2+and CHX or CPC inhibited VSC formation synergistically . ClO2 and chlorite anion (ClO2-) also oxidize VSCs directly into non-malodorous products, which consumes the amino acids that act as precursors to VSCs [30, 31]. A randomized double-blind crossover placebo-controlled clinical trial found that mouth rinsing with ClO2 effectively reduced morning malodor for 4 h in healthy volunteers . Triclosan is a broad-spectrum antibacterial agent that blocks lipid synthesis in susceptible bacteria . A double-blind, crossover, randomized study comparing the VSC-reducing effects of mouthwashes on morning bad breath in healthy subjects reported that VSC formation was inhibited by, in descending order, mouthwashes containing 0.12% CHX gluconate, 0.03% triclosan, essential oils, and 0.05% CPC .
However, there are concerns regarding the potential side effects of these chemical agents. The use of 0.2% CHX results in an unpleasant bitter taste, perturbs taste, causes desquamative lesions and soreness of the oral mucosa, and yellow/brown staining of the teeth and dorsum of the tongue . Hypersensitivity to CHX is rare, but several immediate-type allergies such as contact urticarial, occupational asthma, and anaphylactic shock have been reported [36, 37]. In Japan, based on these reports, the concentration of CHX used near a wound is limited to 0.05%, which is lower than its effective concentration. Recently, the possibility that triclosan is hazardous to human health has been suggested. Several studies reported that triclosan might contribute to bacterial resistance to antibiotics, or interfere with endocrine functions in rats [38, 39]. The US Food and Drug Administration (FDA) named triclosan in the National Toxicology Program (NTP) for toxicological evaluation.
3. Naturally derived compounds (Table 3)
3.1. Natural botanical extracts
Due to the increase in health consciousness, many flavors and natural botanical extracts have been added to foods and medicine to reduce oral malodor. In addition, the effects of natural botanical extracts on oral malodor have been evaluated in randomized controlled trials.
Eucalyptus extract is one of the four active ingredients of Listerine® mouthwash (Pfizer Inc., Morris Plains, NJ, USA), which was created in 1879 and was formulated originally as a surgical antiseptic. It has antibacterial activity against several periodontopathic bacteria including
The catechins present in green tea have
Pericarp extracts of
Hinokitiol (β-thujaplicin), a component of essential oils isolated from Cupressaceae, shows antibacterial activity against various bacteria, including periodontopathic bacteria and fungi [50, 51], and has been used as a therapeutic agent against periodontal disease and oral
Actidinine is a cysteine protease derived from the kiwi fruit. Tongue coating is understood to be an important factor in oral malodor and is composed of proteins [22, 53]. The effect of a tablet containing actidinine on oral malodor was evaluated in a double-blind, randomized crossover trial . The subjects sucked the tablets three times per day for 1 week. VSC levels and tongue-coating ratios decreased significantly on the first day in both the test and placebo groups immediately after taking a tablet. VSC levels were significantly lower after 7 days only in the test group. There was no significant reduction in tongue-coating ratios in either group after 7 days of use.
3.2. Salivary components
Saliva contains a variety of antimicrobial proteins including lactoferrin, peroxidase, lysozyme, and secretory immunoglobulin A. Lactoferrin is an iron-binding glycoprotein that chelates two ferric ions per molecule, and decreases bacterial growth, biofilm development, iron overload, reaction oxygen formation, and inflammatory processes . Salivary peroxidase, in the presence of H2O2 and SCN-, can reversibly inhibit bacterial enzyme and transport systems by oxidizing the sulfhydryl groups of proteins . A reduction in salivary flow might inhibit antimicrobial defense systems in saliva. A relationship between low salivary flow and the generation of H2S and CH3SH in mouth air has been reported previously .
The effect of a tablet containing lactoferrin and lactoperoxidase purified from bovine milk on oral malodor was evaluated in a randomized, double-blind, crossover, placebo-controlled clinical trial . According to that study, CH3SH levels were significantly lower in the test group compared with the placebo group 10 min after taking a tablet. The median CH3SH concentration in the test group was below the olfactory threshold between 10 min and 2 h, whereas the level in the placebo group was above the threshold throughout the experimental period.
3.3. Probiotic bacteria
The use of probiotics as preventative and therapeutic products for oral healthcare is a novel antimicrobial approach that has been proposed as an alternative to chemotherapeutics. Probiotics are defined as “live microorganisms that confer a health benefit on the host when administered in adequate amounts” by the World Health Organization and the Food and Agriculture Organization of the United States (http://www.who.int/foodsafety/fs_management/en/probiotic_guidelines.pdf). Probiotics have been used traditionally to treat diseases related to the gastrointestinal tract. Recently, the use of such probiotics to improve oral health has attracted increasing attention, although this field is still in its infancy. Nevertheless, there are several reports related to the use of probiotics to ameliorate oral malodor.
Kang et al. isolated three peroxide-generating lactobacilli, identified as
Chemical agents have been used widely to prevent and treat oral malodor. However, long-term use of some antiseptic agents such as CHX might result in complications such as staining of teeth and the development of microbial resistance. In addition, recent studies have raised concern regarding the potentially harmful effects of triclosan on the human body. These phenomena and consumers’ increasing health consciousness have led to the development of alternative antimicrobial approaches, including herbs, natural botanical extracts, salivary components, and probiotics. Diverse natural products have been marketed as effective for preventing and treating oral malodor, and an increasingly diverse range of strategies for oral malodor is available. However, few studies have demonstrated effectiveness of new products against oral malodor clinically. Furthermore, most studies evaluated the short-term effects of products on oral malodor, either immediately or only a few weeks after taking the products. However, the products used for preventing and treating oral malodor, including mouthwash, toothpaste, tablets, and lozenges, are generally used for the long term. Therefore, the long-term effects of agents on oral malodor, as well as their safety and side effects, should be evaluated in randomized controlled trials.
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