Halitosis - Part I

by Drs. Evi Stamou and Moshe Davidovitch

INTRODUCTION

Oral malodor, halitosis, fetor ex ore, or as it is commonly referred to as "bad breath"(1) is a common human condition (2), which affects a large portion of the population. It primarily affects the adult population (2,3,7) and is an unpleasant problem most people try to avoid(4). Halitosis is a lyrical term derived from the Latin halitus (breath) and the greek suffix osis (condition, action of a pathologic process)(4). Bad breath is not a modern phenomenon. It has been discussed in the Jewish Talmud, as well by Greek and Roman writers. Islam also stresses fresh breath in the context of good oral hygiene (5).

The consequences of halitosis may be more than social; its presence may reflect serious local or systemic conditions (6). However, physicians tend to view this as a dental condition, which causes those most often to refer patients with this problem to a dentist. When halitosis is a dental problem the profession should recognise and recommend therapy to address it (4).

A significant number of people complain of having bad breath, however, this is usually based on some self-conscious rationalization without actually suffering from the condition. Few studies exist which have documented the prevalence of halitosis in the general population. The preponderance of the currently available information regarding the distribution of halitosis has been derived from selected groups presenting voluntarily to a dentist, implying self-knowledge of their condition. More accurate information regarding distribution of halitosis is required in order to better understand this condition and contribute to its differential diagnosis.

The causes of halitosis can be divided into two categories: Physiologic (oral) (4), and pathologic (systemic) (7). Oral malodor is a subject of considerable interest, yet scientific advances have been stymied by the lack of simplified instrumentation and the need for detailed molecular studies that dissect the component species of oral gases (8).

Evaluation of expired air:

According to Delanghe et al.,87% of malodor originates from the mouth(9). The simplest way to distinguish oral from non-oral sources of maloder is to compare the smell coming from the mouth with that exiting the nose(5). Any potential nasal source of malodor is differentially diagnosed by directing the subject to seal the mouth and exhale only through the nose. A potential oral source of malodor is detected by directing the patient to pinch the nose closed and exhale through the mouth(10).

Pungent odor from the expired air can indicate lesions or disease of the nasopharynx, nose or sinuses. The nasopharynx is a common site of bacterial colonization contributing to bad breath. Any condition that alters the mucous membrane of the nose including atrophic rhinitis or rhinitis medicametosa can contribute to bacterial overgrowth and malodor. Chronic sinusitis, unilateral choanal atresia and nasal foreign bodies also cause halitosis(10).

If the same malodour is detected from both nasally and orally expired air, a systemic or respiratory tract source should be suspected(10). Malodor can be an early symptom of nasal tumors. Referral to an otolaryngologist is indicated if infection, foreign body or neoplasm of these structures is suspected.

A more noxious odour found in the orally expired air than air expired nasally can indicate an oral, oropharyngeal, hypopharyngeal or, rarely, a gastric source (10).

Physiologic causes of malodour:

Physiologic etiology of halitosis is most frequently found to be caused or arising directly within the oral cavity. (11) An investigation by Sulser indicated that slightly more than half of the study sample had offensive breath at some time during a given day(12).

A state of hunger(8,12,13) may be associated with breath and mouth odours. This is related to the stagnation which may occur in the mouth due to the lack of activity related to mastication. In addition, a factor related to an increased incidence of oral odour production are age-related systemic changes, as well as the normal daily cycle of metabolic activity time of day(13).

Reduced saliva production during sleep

In all individuals, regardless of age or health status of the oral tissues, the most intense oral malodor is exhibited after prolonged periods of reduced salivary flow(7), increased oral alkalinity(4,7,8,10)(like following fasting, during sleep)(7,14) and abstinence from food and liquid(7). This is accentuated in cases with any type of active periodontal inflammatory process (6). When there is no flow of saliva, putrefaction of the retained exfoliated oral epithelial cells and other debris causes an unpleasant odour, which quickly disappears after resumption of normal salivary flow (4). When whole saliva is allowed to stagnate for 24 hours at 37°C, the formation of odour is coincident with an increase by 3 orders of magnitude of odour-generating organisms over the number initially present in the fresh sample. Where there is little saliva, gram-positive organisms were found to be 20-100 times more numerous than gram-negative organisms. In areas such as the gingival crevice, where one would expect salivary stagnation to occur, gram-negative organisms were found to be ten times more numerous than the gram-positive organisms (13).

It is not surprising to find that bacterial populations vary within different microenvironments in the mouth. Intrinsic malodor is readily produced by microorganisms in localized areas within the mouth where saliva stagnation commonly occurs. Such malodor does not occur in areas of copious flow of saliva. A change to a more acidic pH or the presence of small amounts of glucose can affect the metabolism of the oral flora in a way that results in the formation of non-odorous end products. An acidic pH prevents the formation of odorous metabolic products by inactivating the enzymes required in the putrefaction of amino acids(13).

Even though most studies suggest that bad breath levels are inversely related to saliva flow, (4,5,7,10,11,12,13,15) the implication is that when saliva dries out on oral surfaces, a range of volatile sulphur compounds (VSC), and other analogous compounds (i.e. non sulphur containing gases like cadaverine, putrescine etc.), are released(5). Conversely, mastication increases saliva flow, with concomitant cleansing of the oral cavity causing a reduction in malodor(5). When saliva flow is lowest, for instance during sleep or after fasting, the incidence of bad breath increases(11).

When a subject is sleeping or not eating, the saliva flow decreases and pooled saliva undergoes alteration in the balance of its microflora. The pH of the pooled saliva rises above 7 and enzymatic breakdown occurs, making the saliva itself odiferous. Bacterial overgrowth and breakdown of this organic matter cause morning breath(6).

Despite these observations, two clinical studies did not support any association between salivary flow rate and levels of oral malodor in the populations studied(2,16). One possible explanation could be that malodor arises primarily in an alkaline environment, whereas the saliva of people with xerostomia often is acidic(5).

Physiologic oral malodor is transient in duration as it can be controlled to varying degrees in most individuals by oral hygiene measures, such as tooth brushing, dental prophylaxis, tongue scraping and rinsing with antiseptic mouth washes(7).

Food

Bacteria are essential in production of intrinsic malodor but not all malodors emanating from the mouth are caused by microorganisms. Food intake can affect the production of breath and mouth odors as well(9). Common examples would include the extrinsic odor of onion, alcoholic beverages, and garlic (13). Foods and beverages such as these produce volatile fatty acids or other malodorous substances that are excreted through the lungs during normal breathing (4).

Physiological halitosis is temporary and occurs when volatile odoriferous hematologically borne substances from foods(6) and beverages are released into the lungs (4,6).Metabolites of certain foods such as onions, garlic, ethyl alcohol(4,6,10,17) and cured meats (i.e. pastrami),(4) are absorbed in the intestine, metabolised in the liver, released into the blodstream(10) excreted through the lungs,(4,6,10) resulting in a characteristic halitosis(4,6).

Smoking

There is no doubt that the smoking of tobacco products influences breath odour (4,9). Excessive smoking has been reported to directly cause oral malodor(14). Tobacco smoke itself contains VSC's (18). Cigarette odour can linger for more than a day after smoking. In some cases, one can detect the odor of cigarette smoke on the breath of people who do not smoke but are continually exposed in a passive fashion (5). However, whether this is considered halitosis is more subjective than anything else. For example, if both partners of a couple smoke they will usually not notice each other's smoking-related bad breath(4)

Menstruation

It has been reported that during menstruation (4,6,8) or certain menstrual cycles(Massler, Emslie and Bolden, 1951)(11), some women have bad breath. This is most likely secondary to hormonal changes (4). The results of a study by Tonzetich, Peti and Huggins (1978) provided a satisfactory explanation of this phenomenon when they reported finding distinct variations of hydrogen sulfide, methyl mercaptan and dimethyl sulfide in mouth air during different stages of the menstrual cycle(11).

Pathologic causes of halitosis

Non-oral(Systemic) causes of halitosis

Odors can be derived from the mouth, the lungs, and the nasal passages. Any putrefaction in the lungs or in the nasal passages would also give off odiferous substances during the flow of air in the process of breathing (12).

Pathologic odors are more intense, persistent and characteristic of specific disorders (19) i.e. "ketonic" breath in diabetics (6,11,14,16). An acetone smell was once considered a diagnostic indication for uncontrolled diabetes, but very few cases have been detected in this manner (C. Hollenberg, M.D., personal communication,1990)(5). However, since many diabetics are currently monitored and treated for hyperglycemia, 'ketonic' breath is no longer commonly observed.

A patient with an esophageal or cardiospasm can, on rare occasions, present for medical and/or dental evaluation with bad breath as the initial symptom. Schiffman stated that specific odors can be associated with infectious, nutritional, and mental diseases (10).

Nasal passage involvement is the most common source of non-oral etiologies of bad breath. Nasal odor may be indicative of a frank nasal infection, such as sinusitis, or a problem affecting airflow or mucous secretions, such as polyps. In some cases craniofacial anomalies, such as cleft palate may be involved (5).

A group of congenital genetic defects resulting in errors of metabolism that are associated with an enzyme deficiency or transport problem may cause malodour (19). One such, albeit rare, metabolic condition that leads to perception on the part of the patient of a foul "fishy" odour or taste is trimethylaminuria(TMAU)(5). Patients with TMAU report a persistent bad "flavor", odor, and/or taste (19).

Uremia can cause a fishy ammonia-like smell to the breath(17). In this instance the breath is altered by a metabolic defect which results in an excess of trimethylamine which is also present in sweat, and urine. In normal individuals, TMA is converted in the liver to odorless products that are excreted in the urine and feces. This defect appears to be inherited as an autosomal recessive trait and is thought to occur in 1 in 5000 births. The persistent foul taste/odor reported by these patients may be due to the presence of trimethylamine. However, excess amounts of other volatiles in the saliva and lung air of these patients are also seen. Data shows that there is a relationship between metabolic disorders known to produce an excess of volatile organic compounds with both altered chemosensation and longstanding idiopathic oral malodour production (19).

Facial injuries, cosmetic surgery, radiation, and chemotherapy may affect the olfactory epithelium located on the dorsal aspect of the nose, the nasal epithelium, and superior turbinates. This may result in an altered sense of taste and smell which will effect the perception of malodour (20).

Disorders of the upper respiratory tract

An oral breathing pattern: Breathing through the mouth causes bad breath because the amount of saliva in the mouth is reduced by evaporation(4).

Sinusitis: Chronic suppurative sinusitis may produce a foul-smelling purulent exudate (4,20,21). The tendency of very young children to insert foreign bodies into their nostrils is a common cause of offensive odour that comes from the nose yet appears to emanate from the entire body(5).

Foreign bodies(4,20): Long-standing nasal discharge that is unilateral and accompanied by a foul odour should be considered to be due to a foreign body until proven otherwise(4).

Atrophic rhinitis (ozema): The inability of the nasal mucosa to cleanse itself because of atrophic changes or ciliary destruction results in the accumulation of dried nasal secretions that become infected

Tuberculosis: Tuberculosis of the nose usually affects the cartilaginous septum just behind the vestibule and causes malodour(4).

Syphilis: Syphilis of the nose may cause halitosis through gumma formation, which usually affects the nasal bones and surrounding tissues, thereby causing necrosis and an offensive odour (4).

Rhinoscleroma: This is a protracted condition which has been associated with, but not proven to be caused by, the rhiniscleroma bacillus. The lesions are granulomatous and hypertrophic, and they usually become infected and malodorous(4).

Adenoiditis: Adenoiditis may cause halitosis if the nasal passages become obstructed so that it is necessary to breath through the mouth, or because a purulent exudate is produced (4).

Nasopharngeal abscess: A midline nasopharyngeal pouch may be present either as a congenital defect (a remnant of Rathke's pouch) or, more commonly, as a result of adhesions in the adenoid furrows(4).

Carcinoma of the larynx(4,19): Ulcerative and necrotic lesions of invasive carcinoma usually become infected with aerobic and anaerobic bacteria. These secondary infections result in halitosis as well (4).

Infection of larynx: Laryngeal infections produce malodor that emanates from the oral cavity(19).

Other diseases of the respiratory tract, such as neoplasms, can cause bad breath. In addition, bronchitis, pneumonia (10), bronchial and lung infections(5,10) and bronchiectasis cause foul odours in expired air. Foul smelling sputum and noxious expired air are also characteristic physical findings (10).

Disorders of the lower respiratory tract

Pulmonary abscess: A lung abscess which is often accompanied by fever, a productive cough and pleuritic pain can also be detected early because it sometimes causes halitosis as one of its first symptoms (4).

Carcinoma of the lung: Cancerous destruction of healthy tissue and its secondary infection by (anaerobic) bacteria, often produce bad breath(4).

Other: Bronchiectasis, necrotizing pneumonitis and empyema may all be associated with halitosis (4).

Salivary gland dysfunction (4) or aplasia (14): Any condition that decreases salivary flow (i.e. dehydration, the use of anticholinergic drugs, radiotherapy of the head and neck region, Sjogren's syndrome (sicca syndrome), may be associated with halitosis (4,14). Peritonsillar abscess:

A peritonsillar abscess usually produces temporary halitosis because it also causes a foul smelling purulent exudate (4).

Retropharyngeal abcess: Halitosis usually occurs in patients with a retropharyngeal abscess (4).

Tonsils: The role of tonsils in chronic bad breath is not at all clear(5).There is a controversy in the literature regarding the association between tonsils and halitosis. According to Attia et al. and Clark et al., cryptic tonsilopathy contributes to halitosis (4, 6). Repeated infections of the tonsils and adenoids causes chronic follicular tonsillitis. Deep crypts form on the surfaces of these lymphoid tissues providing niches(6) for the collection of food (6,10), saliva, and necrotic matter(6). Large tonsils with prominent crypts allow exfoliated epithelial cells to accumulate and mix with the saliva, which results in fermentation and putrefaction(4). If natural mechanisms do not cleanse the crypts, such collections form tonsilloliths(6), which can migrate to the surface of the tongue (5) and are capable of causing halitosis(6). However, according to Rosenberg, even though these tonsilloliths themselves do emit a foul odour, particularly when pressed, they are not necessarily a significant source of bad breath (5).

Carcinoma of the tonsil or pharynx: Ulceration and necrosis of tissue with secondary infection is common in carcinomas of the tonsil and will cause halitosis(4).

Oropharynx: Bacterial, fungal or viral infections of the oropharynx can contribute to oral malodors(10).

Gangrenous angina: Usually gangrenous angina involves the pharynx, the tonsils and the soft palate (4).

Disorders of gastrointestinal tract

The contribution to halitosis of pathologic states below the gastroesophageal junction is not a universally accepted concept. Numerous reports in the literature describe halitosis associated with gastric carcinoma, hiatus hernia (4) and pyloric stenosis, esophagitis as well as with enteric infections (4,6).

Gastric/stomach odours are not considered a significant contributing factor to oral odour. This is because the esophagus is normally a collapsed tube and only during eructation would odiferous gases be expelled into the mouth from the stomach(13).

Contrary to common thinking, bad breath originating in the gastrointestinal tract is considered to be extremely rare. The esophagus is normally collapsed and closed, and although the occasional belch may carry odor up from the stomach, the possibility of air escaping continuously is remote(5).

Other non-oral disorders which cause pathological malodor are: chronic renal failure(fishy odour) (5,6,19),cirrhosis of liver (19),hepatic failure(4,6,10), various carcinomas, metabolic dysfunctions and biochemical disorders, can result in bad breath(4,5), weight loss, fever, joint pains and alcohol abuse suggest a primary systemic cause for the halitosis, such as sepsis and dehydration, agranulocytosis, carcinoma(4). However, all these diseases taken together affect only a very small percentage of people experiencing oral malodor(5).

Systemic diseases

Conditions such as leukemia and agranulocytosis are usually characterized by severe buccal manifestations similar to those of periodontitis. Necrotizing inflammation of the gingivae and buccal mucosa and a decreased flow of saliva usually cause halitosis(4).

Drugs

Pharmacologic agents(4,14,21) can either alter the senses of taste and/or smell (e.g. lithium salts, penicillamine, griseofulvin and thio-carbamide), thus causing subjective halitosis (4). In addition, these can be excreted in the breath(17) (e.g., dimethyl sulfoxide), which produces an odour similar to stale seafood.

The use of drugs such as lithium, penicillamine and griseolfuvine may cause subjective halitosis. Dimethyl sulfoxide causes objective halitosis(4) and anticholinergic drugs may cause halitosis(6,17) by decreasing the flow of saliva and encouraging microorganisms to grow(20).

Many drugs produce xerostomia (6,20), and it is suspected that bad breath is inversely related to salivary flow(20). The drugs that produce xerostomia include analgesics, antidepressants,antihypertensives,psychotherapeutics(20), sublingual isosorbide(17)and numerous others(20).

Reduced salivary flow (xerostomia)(10,11,14) which contributes to production of oral malodor, can also be caused by:

Dehydration states (10,14)

Aging (10,16)

Anemia (10)

Hypovitaminosis (10)

Diabetes (10,14)

Emotional stress (10,14)

Metabolic disease (10,14)

Inflammatory or autoimmune disease of salivary glands (10)

Mechanical blockage (10)

Malignancy (10)

Multiple sclerosis (10)

AIDS (10)

Head and neck (10)

Irradiation (10)

Medications (10)

Mouth breathing

Menopause (14)

Chronic use of inhaled corticosteroids in asthmatic patients can lead to a change in the balance of the microenvironment of respiratory tract flora, contributing to the development of oropharyngeal candidiasis. Oral candidiasis can be caused by local or systemic factors, and is commonly seen in patients receiving chronic steroid therapy, broad spectrum antibiotics, suffering from cancer, diabetes, xerostomia or who are immunocompromised, immunosuppressed or have a debilitating disease(10). Drug specific halitosis(10,14) is also associated with iodine-based medications, amyl nitrate and chloral hydrate (10).

Functional abnormalities

In many cases, patients report that they suffer from halitosis although none can be detected (4). These patients suffer from halitophobia (imaginary bad breath) (9), and exhibit excessive fear of having bad breath (20). Subjective halitosis may occur as a manifestation of a mental disorder, usually a psychosis. This condition can be confirmed as part of a psychological examination (4).

Yet imaginary halitosis may be worse than real halitosis for it can become an obsession that dominates the affected person's life, even turning them into social outcasts(17).The current success rate in treating such individuals is low and indicates the need for collaboration with psychological and/or psychiatric counselling(9).These patients may have a variety of psychopathologic symptoms(20). In patients with depression (4,17), halitosis is usually just one of many somatic complaints(4). The most extreme of these cases may be diagnosed as having a body dysmorphic disorder (20).

Malasi and others have reported convictions of malodors associated with overvalued ideas, depression, schizophrenia and organic brain syndrome. They also stated that the olfactory hallucination may be a rationalization for difficulties in interpersonal relationships or a manifestation of low self-esteem (10).

Part II will be available soon......

REFERENCES

1 Kozlovsky A., Gordon D., Gelertner I., Loesche W.T., and Rosenberg M.: Correlation between the BANA test and oral malodor parameters. J Dent Res 73: 1036, 1994

2 Rosenberg, M., Kulkarni, G.V., Bosy A., and McCulloch C.A.G.: Reproducibility and sensitivity of oral malodor measurements with a portable sulphide monitor, J Dent Res 70:1436, 1991

3 Rosenberg M., Septon I.,Eli I., Bar-Ness R.,Gelernter I., Brenner S., and Gabbay J.: Halitosis measurement by an industrial sulfide monitor. J Periodontol 62:487,1991

4 Attia EL., Marshall KG.: Halitosis. Can Med Assoc J 126:1281,1982

5 Rosenberg M.: Clinical assessment of bad breath: Current concepts. JADA 127: 475,1996

6 Nachnani S. and Clark G. T.: Halitosis: A Breath of fresh air. CID 25 (Suppl 2):218, 1997

7 Tonzetich J.: Production and origin of oral malodor: A review of mechanisms and methods of analysis, J Periodontol48: 13,1977

8 Rosenberg M. and McCulloch C.A.G.: Measurement of Oral malodor: Current methods and future prospects. J Periodontol 63: 776, 1992.

9 Quirynen M., Mongardini C., and Van Steenberghe D.: The effect of a 1- Stage Full-Mouth disinfection on Oral Malodor and Microbial Colonization of the tongue in periodontitis patients. A pilot study. J Periodontol 69: 374, 1998 1

0 McDowell J., Kassebaum D.: Diagnosing and treating halitosis JADA, 124:55, 1993

11 Tonzetich J.: Oral malodour: an indicator of health status and oral cleanliness. Int Dent J 28:309, 1978

12 Sulser G. F., Brening R. H., and Fosdick L. S.: Some conditions that effect the odor concentration of breath. J Dent Res 18:355, 1939

13 McNamara T.F., Alexander J.F., and Lee M. and Plains M.: The role of microorganisms in the production of oral malodour. Oral Surg.34:41, 1972

14 Lu D.P.: Halitosis: an etiologic classification, a treatment approach, and prevention.Oral Surg Oral Med Oral Patho 54:521, 1982

15 Kleinberg I., Westbay G.: Salivary and metabolic factors involved in oral malodor formation. J Periodontol 63:768, 1992

16 Bosy A., Kulkarni G.V., Rosenberg M., and McCulloch C.A.G.: Relationship of oral malodor to periodontitis: Evidence of independence in discrete subpopulations. J Periodontol, 65:37, 1994.

17 Hawkins C.: Real and imaginary halitosis. Br Med J, 294:200, 1987

18 Miyazaki H., Sakao S., Katoh Y., Takehara T.:Correlation between volatile sulphur compounds and certain oral health measurements in the general polulation. J Periodontol 66:679, 1995

19 Preti G.,Clark L., Cowart B.J., Feldman R.S., Lowry L.D.,Weber E., and Young I. M.: Non-oral etiologies of oral malodor and altered chemosensation. J Periodontol 63:790, 1992

20 Neiders M., Ramos B.: Operation of bad breath clinics Quintessence International, 30:295, 1999

21 Amir E., Shimonov R., Rosenberg M.: Halitosis in children The Journal of Pediatrics, 134:338,1999

22 Malasi T.H., El-Hilu S.R., Mizra I.A. and Fakhr El-Islam M.:Olfactory Delusional Syndrome with various aetiologies. British Journal of Psychiatry 156:256, 1990.

23 Waler S.M.: The effects of some metal ions on volatile sulfur-containing compounds originating from the oral cavity Acta Odontol Scand 55:261, 1997

24 Tonzetich J, Ng SK.: Reduction of malodour by oral cleaning procedures Oral Surg Med Oral Path 42:172,1976.

25 Yaegaki K. and Sanada K.: Biochemical and clinical factors influencing oral malodor in periodontal patients. J Periodontol 63: 783, 1992

26 Loesche W.J.: The effect of antimicrobial mouthrinses on oral malodor and their status relative to US food and drug administration regulations. Quintessence International 30:311,1999

27 Rosenberg M., Leib E.: Experiences of an Israeli malodor clinic. In: Bad breath: Research Perspectives. Ramot publishing, Tel-Aviv University; pp.139, 1997

28 Yaegaki K, Sanada K.: Volatile sulfur compounds in mouth air from clinically healthy subjects and patients with periodontal disease.J Periodont Res 27:233,1992.

29 Miyazaki H, Fujita C, Soh I, Takehara T.: Relationship between volatile sulphur compounds and oral conditions in the general Japanese population.In: van Steenberghe D. Rosenberg M.eds. Bad breath, A Multidisciplinary approach. Leuven: Leuven University Press; 165,1996

30 Rosenberg M., Gelernter I., Barki M., and Bar-Ness R.: Day-long reduction of oral malodor by a two-phase oil: water mouthrinse as compared to chlorehexidine and placebo rinses. J Periodontol 63:39,1992

31 Kostelc JG, Preti G, Zelson NH, Stoller NH, Tonzetich J.: Salivary volatiles as indicators of periodontitis. J Periodont Res 15:185, 1980

32 Crohn BB.: Halitosis in relation to oral diagnosis. Am J Orthodontics Oral Surg 28:109, 1942.

33 Delanghe G, Ghyselen J. Feenstra L. van Steenberghe D.: Experiences of a Belgian multidisciplinary breath odor clinic. In: van Steenberghe D. Rosenberg M, eds. Bad Breath. A multidisciplinary Approach. Leuven: Leuven University Press: 1996; 199

34 Kostelc JG., Preti G., Zelson PR, Brauner L., Baechni P.: Oral odor in early experimental gingivitis. J Periodont Res 19:303,1984

35 Willis C. L., Gibson G.R., Holt J., Allison C.: Negative correlation between oral malodour and numbers and activities of sulphate-reducing bacteria in the human mouth. Archives of Oral Biology 44: 665, 1999

36 Sterer N., Greenstein B.N., Rosenberg M.: ß-Galactosidase activity in saliva is associated with oral malodor. J Dent Res 81:182, 2002

37 Bhide V. M., Smith L., Overall C. M., Birek P., and McCulloch C.A.G.: Use of a flourogenic septapetide matrix metalloproteinase assay to assess responses to periodontal treatment. J of Periodontol, 71:690, 2000

38 Lindhe J.: Textbook of Clinical Periodontology, Pg.76, Fig.2-10a

39 Lindhe J.: Textbook of Clinical Periodontology, Pg.76, Fig.2-9

40 Rosenberg M.: Bad Breath, Research Perspectives, Ramot Publishing, Tel-Aviv University, 3, 1997

40 Zhu W. Sha Y., Chung-Hua Kou Chiangi, Hsuch Tsa Chih.: The relationship between oral malodor, VSCs levels in the mouth air with periodontitis and tongue coating. Chinese Journal of Stomatology 37(4):300,2002

41 Lucas V., Omar J., Vieira A., Roberts G.J.: The relationship between odontogenic bacteremia and orthodontic treatment procedures. EJO 24: 293, 2002.

42 Rosenberg M.,Kozlovsky A., Wind Y., Mindel E.: Self-assessment of oral malodor 1 year following initial consultation. Quintessence International 30:324, 1999