Salivary flow patterns and the health of hard and soft oral tissues Colin Dawes JADA 2008;139(suppl

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Salivary flow patterns and the health of hard and soft oral tissues
Colin Dawes, BSc, BDS, PhD

he three paired major salivary glands are the parotid, submandibular and sublingual. Their ducts open opposite the second maxillary molar, at the side of the lingual frenum and in the lingual sulcus. In addition, there are many minor salivary glands, whose ducts open onto most areas of the oral mucosa except the area covering the dorsum of the tongue, the anterior part of the hard palate and the gingivae. The combined secretions from these various glands are termed whole saliva. When flow is unstimulated, the parotid, submandibular, sublingual and minor mucous glands (MMGs) contribute about 25 percent, 60 percent, 7 to 8 percent and 7 to 8 percent, respectively, to whole saliva, but when flow is stimulated, the parotid glands contribution increases by at least 10 percent.1-4 Because saliva from the various glands enters the mouth at several locations, it is not well-mixed. The enzyme amylase is secreted primarily by the parotid glands, and, by using amylase as a marker for parotid saliva, Sas and Dawes5 found that they could calculate the percentage contribution of parotid saliva to whole saliva sampled at several sites. The table shows the mean results when salivary flow

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ABSTRACT

CON

IO N

Background. This nonsystematic review N C U summarizes the effects of saliva on some of the A ING EDU 2 RT diseases affecting the hard and soft oral tissues. ICLE Results. Saliva enters the mouth at several locations, and the different secretions are not well-mixed. Saliva in the mouth forms a thin film, the velocity of which varies greatly at different sites. This variation appears to account for the site specificity of smoothsurface caries and supragingival calculus deposition. Saliva protects against dental caries, erosion, attrition, abrasion, candidiasis and the abrasive mucosal lesions seen commonly in patients with hyposalivation. These effects are the result of salivas being a source of the acquired enamel pellicle; promoting the clearance of sugar and acid from the mouth; being supersaturated with respect to tooth mineral; containing buffers, urea for plaque base formation, and antibacterial and antifungal factors; and lubricating the oral mucosa, making it less susceptible to abrasive lesions. Clinical Implications. For optimal oral health, people should keep food and liquids in the mouth as briefly as possible. The most important time for toothbrushing is just before bedtime, because salivary flow is negligible during sleep and the protective effects of saliva are lost. Chewing sugar-free gum or sucking on sugar-free candies stimulates salivary flow, which benefits hard and soft oral tissues in many ways. Key Words. Pellicle; caries; calcium; phosphate; flow rate; supersaturation; attrition; abrasion; erosion; salivary film; clearance; lubrication; antibacterial factors; calculus; gastroesophageal reflux disease. JADA 2008;139(5 suppl):18S-24S.
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Dr. Dawes is a professor emeritus, Department of Oral Biology, Faculty of Dentistry, University of Manitoba, 780 Bannatyne Ave., Winnipeg, Manitoba, Canada R3E 0W2, e-mail Colin_Dawes@ umanitoba.ca. Address reprint requests to Dr. Dawes.

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was unstimulated and when it was stimulated by gum chewing. Even during gum chewing, which might have been expected to mix the different secretions well, little parotid saliva reached the anterior parts of the mouth. Thus, different sites in the mouth are exposed to different fluid environments. Whole saliva contains components in addition to salivary secretions, including gingival crevicular fluid, leukocytes, epithelial cells and microorganisms, as well as, possibly, food debris, blood and viruses. These sources of enzymes initiate the breakdown of several proteins secreted by the salivary glands.6
SALIVARY FLOW RATE

TABLE

Percentage contribution of parotid saliva to unstimulated and stimulated whole saliva at different sites.*
ORAL SITE PERCENTAGE CONTRIBUTION Unstimulated Saliva Whole Saliva (Entire Mouth) Buccal Maxillary Molars Palatal Maxillary Molars Lingual Mandibular Molars Palatal Maxillary Incisors Lingual Mandibular Incisors Buccal Maxillary Incisors 30.1 56.1 24.7 20.4 8.5 5.0 2.8 Dawes.5 Stimulated Saliva 35.6 61.3 31.9 28.9 17.2 9.4 6.7

The salivary flow rate is influenced by a large number of factors, including the degree of hydration, body position, exposure to light, previous stimulation, circadian and circannual rhythms, gland size and drug use.7 The unstimulated flow rate averages 0.3 to 0.4 milliliter per minute, but the range is wide. Unfortunately, dentists do not routinely measure the salivary flow rate of their patients, so when a patient complains of experiencing a dry mouth, there are no baseline data for comparison. During sleep, the salivary flow rate is negligible.8 Unstimulated flow rates of less than 0.1 mL/minute are considered evidence of hyposalivation. The main factors responsible for a decreased flow rate are therapeutic drugs, particularly when multiple drugs are used9; Sjgren syndrome; and radiation treatment for head and neck cancer.10 The latter two conditions are not common, and therapeutic drug use is the typical cause of dry mouth. Several hundred such drugs cause the condition as an adverse effect,11 although 20 percent of the population experience dry mouth on occasion9 as do 30 percent of people older than 65 years.10 Several studies have been conducted to determine the effects of various stimuli on the salivary flow rate and many have reported flow rates of less than 2 mL/minute.7 However, Watanabe and Dawes12 found that when subjects ate several foods, the mean flow rates during chewing varied between 3.15 and 4.94 mL/minute, while infusion of 5 percent citric acid into the mouth elicited a flow rate of 7.07 mL/minute. Taste stimulation is a much more effective salivary stimulus than is chewing alone.13 The same authors estimated that the total volume of saliva secreted each day is about 600 mL.13

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* Adapted with permission of Elsevier from Sas and

For patients with severe dry mouth, pilocarpine and cevimeline may enhance salivary secretion, provided some residual secretory tissue remains.10 More commonly, however, patients can chew sugar-free gum or those with temporomandibular joint disorders can suck on sugar-free candy to stimulate salivary flow sufficiently to help relieve the dryness. With gum chewing, the flow rate peaks at about 6 mL/minute in the first minute. Across the next 15 minutes, it decreases to a plateau of about 1 mL/minute, well above the normal unstimulated flow rate, and this rate can be maintained for two hours or more.14
SALIVARY COMPONENTS

Proteins. Recent developments in proteomics have resulted in the identification of a large number of different proteins, both in whole saliva and in secretions from individual glands. The technique uses an initial separation of proteins by means of electrophoresis or chromatography, isolation of small groups of proteins or their constituent peptides and, after further separation by means of chromatography, identification of the peptides via mass spectrometry. From a database of the peptides in known proteins, researchers ABBREVIATION KEY. Ca: Calcium. Cl: Chloride.
HCO3: Bicarbonate. IgA: Immunoglobulin A. IgG: Immunoglobulin G. K: Potassium. MMG: Minor mucous gland. Na: Sodium. Pi: Inorganic phosphate. Resid: Minimum saliva volume. sIgA: Secretory immunoglobulin A. Vmax: Maximum saliva volume.
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people, because many of the protein families exhibit 35 genetic polymorphisms. Salivary Flow Rate (mL/Minute) Electrolytes. The main Na (mmoI/L) 6 30 electrolytes in whole saliva K (mmoI/L) include sodium, potassium, Ca (mmoI/L) 5 25 calcium, magnesium, chlo CI (mmoI/L) ride, bicarbonate, phosphate, HCO (mmoI/L) 4 20 thiocyanate and fluoride. The P (mmoI/L) concentrations of both elec 3 15 trolytes and proteins are influenced by such factors as 2 the glandular source, flow 10 rate, duration of stimulation, 1 biological rhythms, nature of 5 the stimulus and various hor 0 mones.7 The figure shows the 0 changes in the main salivary -5 0 5 10 15 20 electrolyte concentrations of TIME (MINUTES) 12 subjects while they chewed a sugar-free gum for 20 minutes.18 Saliva is hypotonic Figure. Changes in the salivary flow rate and main electrolytes in whole saliva secreted over 20 with respect to plasma, so minutes in 12 subjects while they chewed a piece of sugar-free gum, preceded by a five-minute collection of unstimulated saliva. mmol/L: Millimoles/liter. mL: Milliliters. Na: Sodium. K: Potassium. there is always a tendency for Ca: Calcium. Cl: Chloride. HCO3: Bicarbonate. Pi: Inorganic phosphate. Source: Dawes and Dong.18 the water in saliva to be absorbed across the oral then can identify the proteins present in saliva. mucosa, as discussed in detail elsewhere.19 The presence of certain proteins in saliva may be Of the salivary electrolytes, calcium, phospredictive of squamous cell carcinoma.15 phate, bicarbonate and fluoride are of particular Researchers have identified as many as 309 importance for oral health. Although the calcium proteins in whole saliva6,16 and 130 in the concentration in major salivary gland secretions acquired enamel pellicle.17 However, proteomics is less than that in plasma, the phosphate concencannot be used to identify the concentrations of tration is much higher, except in the MMG secrethe individual proteins, many of which are pretions. The net effect is that saliva, even that from sent in only trace amounts. In fact, more than 95 the MMGs, is supersaturated with respect to percent of salivary protein is from the major salihydroxyapatite, the main mineral of teeth. Thus, vary protein families, which include acidic and tooth mineral will not dissolve in saliva or plaque basic proline-rich proteins, amylase, high- and fluid (which is even more supersaturated than low-molecular-weight mucous glycoproteins saliva during fasting), unless the saliva or plaque (MUC5B and MUC7), agglutinins, cystatins, hisis acidified. tatins and statherin.6 After protein synthesis in Bicarbonate in saliva is the main buffer the salivary glands, many of these proteins against acid, but it is only really effective at high undergo posttranslational modifications, which salivary flow rates because its concentration include glycosylation, acylation, deamidization, increases markedly with the flow rate (Figure). sulfation, phosphorylation and proteolysis, before Because MMG secretions contain no bicarthey enter the mouth. The main contributor to bonate,20 they are poorly buffered, even when flow salivary viscosity is the mucous glycoprotein is stimulated. The fluoride concentration in saliva MUC5B, secreted primarily by MMGs, and it is low, about 1 micromole per liter (0.02 parts per exhibits great heterogeneity in its glycosylation million), but this helps keep the saliva somewhat pattern.6 In a given person, the proportions of difmore supersaturated with respect to fluorapatite ferent proteins in saliva from a particular gland than to hydroxyapatite.21 appear to be independent of the nature of the Small molecules. Urea is present in whole stimulus. However, differences exist among saliva at a concentration of about 2 to 4 mil7

mL/MINUTE

mmoI/L

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limole/L, depending on the amount of protein in the diet, but it is more than 5 mmol/L in MMG secretions.22 Urea is split by bacterial ureases to form ammonia and carbon dioxide, and the ammonia causes the plaque pH to be higher than that of unstimulated saliva.23
SALIVA AS A THIN FILM

The volume of saliva in the mouth before and after swallowing averages about 1.1 and 0.8 mL, respectively.24 Using the mean surface area of the mouth (215 square centimeters) and assuming that saliva is spread evenly throughout the mouth, Collins and Dawes25 calculated that it must be present as a thin film (between 70- and 100-micrometers thick). Wolff and Kleinberg26 showed that the film varies in thickness, being thickest on the posterior tongue and thinnest on the hard palate.26 In people experiencing dry mouth, the film on the hard palate was thinner than 10 m.26 When salivary flow is unstimulated, the velocity of the film varies about 10-fold in different regions of the mouth. Lingual to the mandibular incisors, the velocity is estimated to be about 8 mm/minute, but it is only 0.8 mm/ minute buccal to the maxillary incisors,27 where the fluid contains mainly the viscous MMG secretions. When flow is stimulated via gum chewing or candy consumption, the velocity becomes high on the lingual surfaces of the teeth (> 300mm/ minute), but it increases only slightly on the buccal surfaces, except where parotid saliva enters the mouth.27,28 The film flows toward the pharynx.
SALIVARY CLEARANCE

late salivary flow if their concentrations are above the taste threshold. This will shorten the half-time until the flow rate decreases to the unstimulated flow rate. Some materials, such as fluoride or chlorhexidine, have the ability to bind to oral structures, which greatly prolongs their clearance half-time. Because the clearance half-time is much shorter than the time required for any microorganism to divide into two, these microorganisms cannot survive in the mouth unless they have the ability to bind to oral tissues.30 Most of the microorganisms in saliva are not free but are bound to desquamated oral epithelial cells. In the mouth, there is an equilibrium between the number of free microorganisms in saliva and the number bound to oral epithelial cells or to the teeth.
PROTECTION AGAINST HARD-TISSUE LOSS

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The Dawes model of oral clearance29 mimics the action of an incomplete siphon, with the minimum salivary volume (Resid) being the residual volume in the mouth after swallowing (mean, 0.8 mL), and the maximum salivary volume (Vmax) being the volume just before swallowing (mean, 1.1 mL). When the unstimulated flow rate is 0.3 mL/minute, the model yields a clearance half-time of 2.2 minutes, which means that the concentration of any extraneous component of saliva, such as glucose, will tend to decrease by one-half in that time. Patients with a lower unstimulated flow rate or higher Resid and Vmax values will have longer clearance times. When substances such as sugar or acid are placed in the mouth, they will stimu-

Tooth substance may be lost by means of abrasion, attrition, erosion and dental caries. Abrasion. This process is due to the action of foreign bodies rubbing against the teeth, and it may occur in people who use abrasive toothpastes or toothbrushes or have certain habits, such as pipe smoking. Because most of the foods we eat are not abrasive, foods are not a common source of abrasive enamel loss. The protective effect of saliva is due to its forming the acquired enamel pellicle, which is a renewable lubricant, because when the abraded surface is exposed to saliva again, the pellicle begins to re-form within seconds. Attrition. This process is due to repeated contact between opposing teeth, and it is a natural feature of aging. However, grossly excessive wear may occur in people with bruxism. Again, the protective effect of saliva is the result of its ability to form the acquired enamel pellicle, which acts as a lubricant to reduce frictional wear. Erosion. Enamel is susceptible to acid dissolution when the pH of its fluid environment is less than the critical pH below which the fluid is unsaturated with respect to tooth mineral.31 For saliva, the critical pH with respect to tooth mineral is between 5.5 and 6.5, and it is inversely related to the concentrations of calcium and phosphate in the saliva.32 Erosion is caused by the action of extrinsic acid on the teeth, and there are many possible sources of such acid, including gastroesophageal reflux disease, bulimia, acidic soft drinks, sports drinks, fruit juices, wine, exposure to acid fumes in the workplace, acidic medicaJADA, Vol. 139 http://jada.ada.org May 2008 21S

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ments such as aspirin and improperly chlorinated swimming pools.33 Saliva protects against acid erosion in several ways but, unfortunately, not effectively. First, the acquired pellicle provides some protection,34,35 but to a small degree, because it is only about 1 m thick. Second, saliva acts as a diluent of the acid. However, because the residual volume is only about 0.8 mL, this often is not effective when, for instance, a person consumes a mouthful of soft drink that has a pH of 2.8. Third, salivary clearance removes the acid gradually via the swallowing process. Fourth, saliva contains bicarbonate and phosphate buffers. However, when acid is taken into the mouth, only unstimulated saliva is present initially, and this is poorly buffered compared with stimulated saliva. Fifth, the saliva is supersaturated with respect to tooth mineral, and the calcium and phosphate that it contains tend to reduce the rate of enamel dissolution. Acid in the mouth will stimulate the flow of saliva, which improves the effectiveness of factors two through five. Because of salivas supersaturation with respect to tooth mineral, slightly softened enamel may experience remineralization, particularly in the presence of fluoride.33 However, this process is inhibited by the acquired enamel pellicle. The pellicle also prevents the continuous enlargement of the teeth in the supersaturated saliva. When a dentist acid etches a tooth before placing a resin-based composite restoration, the phosphoric acid dissolves the first few micrometers of the enamel and creates an irregular surface. Acid etching also removes the acquired enamel pellicle, which otherwise would interfere with the mechanical bonding of the composite to the enamel. Because pellicle begins to re-form within seconds of enamels exposure to saliva, the clinician should not allow saliva to contact acidetched enamel before placing the resin-based composite restoration. Dental caries. Caries is initiated beneath dental plaque by acidogenic microorganisms that have been exposed to fermentable carbohydrate. The critical pH for the fluid phase of dental plaque has been calculated to be as low as 5.1, because plaque fluid contains more calcium and phosphate than does saliva.31 However, when plaque is exposed to sugar, its pH may decrease to as low as 4.0 within a few minutes, which leads to continued mineral dissolution until the plaque pH rises above the critical pH. This decrease and
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subsequent increase in pH is termed the Stephan curve.36 People with a low salivary flow rate are particularly susceptible to caries because of the development of deeper Stephan curves and, therefore, the loss of many protective effects of saliva, as described below. Sugar clearance. Saliva is responsible for sugar clearance from the mouth, which is increased by an increased flow rate and low Resid and Vmax values. The rate of clearance varies markedly at different oral sites and is fastest lingual to the mandibular incisors and slowest on the buccal surfaces of the teeth (except buccal to the maxillary molars). Acid clearance. Saliva is responsible for acid clearance from dental plaque, which depends primarily on the velocity of the salivary film flowing over the plaque. Again, there is marked site specificity, and the velocity is highest in the same locations where sugar clearance is fastest. These two factors seem to explain why smooth-surface caries is more prevalent on buccal surfaces than on lingual surfaces.28 Urea. Saliva is a source of urea. Results from a modeling study suggest that the salivary concentration is sufficient to raise the plaque pH minimum after a sucrose rinse by at least one-half of a pH unit.37 Remineralization. Salivas supersaturation with respect to tooth mineral allows remineralization of teeth with early carious lesions. With each intake of fermentable carbohydrate, caries tends to progress, while teeth tend to remineralize between meals and, in particular, when plaque is removed. This process is promoted when salivary flow is stimulated by chewing sugar-free gum or consuming sugar-free hard candies.
PROTECTION AGAINST SOFT-TISSUE DAMAGE

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Resistance to physical damage. The mucous glycoproteins of saliva, such as MUC5B, MUC7 and proline-rich glycoproteins, play a major role in lubricating oral tissues. This lubrication reduces trauma to soft tissues during mastication, swallowing and speaking. These glycoproteins also help maintain an intact layer of saliva (the salivary film) in contact with the oral mucosa, which prevents it from drying out. When salivary flow is low, areas of the mucosa become dried out and are much more susceptible to abrasion (for example, by dentures). The residual volume of saliva buffers hot and cold food and

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drink, which otherwise might cause thermal damage to the oral mucosa. Some of the salivary proteins, notably the basic proline-rich proteins, have the ability to bind the tannins in such materials as red wine, tea and strawberries, which reduces the binding of tannins to the oral mucosa and their absorption from the gastrointestinal tract.38 Tannins have the ability to inhibit several digestive enzymes, such as trypsin, and to precipitate other proteins. The presence of basic proline-rich proteins in saliva enables us to avoid most of the deleterious effects of tannins.38 Antibacterial and antifungal effects. The number of bacteria in saliva may reach 109/mL, and typically they are cleared by the swallowing process. In patients with a low unstimulated salivary flow rate, clearance of bacteria and desquamated epithelial cells is reduced greatly, increasing the tendency for halitosis to develop, especially before breakfast (because salivary flow has been reduced further during sleep).10 An important feature of having a continuous flow of unstimulated saliva into the mouth is that it reduces the probability that oral bacteria will be able to ascend the salivary ducts and infect the glands. Although saliva contains several antibacterial factors, such as lysozyme, the typical oral flora are not affected significantly by them. These proteins may repel transient bacterial invaders; however, saliva also contains several histidine-rich proteins, termed histatins, which have strong antifungal activity.39 People with hyposalivation are more susceptible to fungal infections, usually with Candida albicans.10 Amylase, in addition to catalyzing the hydrolysis of 1 4 glycosidic linkages in starch, has the ability to bind certain oral microorganisms such as Streptococcus gordonii, S. mitis and S. oralis.40 MUC5B and agglutinin have similar abilities,41,42 and Murray and colleagues41 have suggested that the formation of bacterial aggregates would facilitate bacterial clearance if the aggregates were less able than single microorganisms to bind to the teeth. Saliva contains several cystatins that inhibit cysteine proteases, proteolytic enzymes produced by several oral pathogens. Whether these enzymes have a clinically significant protective effect in the mouth is unclear.43 Two types of immunoglobulin primarily are in whole saliva: secretory immunoglobulin A (sIgA) and immunoglobulin G (IgG). sIgA is a dimer of

IgA as well as two other protein molecules, namely J chain and secretory component. The latter two are believed to reduce the rate of proteolytic breakdown of sIgA in the mouth. The J chain and dimer of IgA are synthesized by plasma cells in the salivary glands. As they are transported through the salivary acinar cells on their way to the lumen of the gland, they become attached to secretory component, which is synthesized by the acinar cells, to form sIgA.44 IgG enters whole saliva mainly via gingival crevicular fluid. These immunoglobulins are able to bind some soluble and particulate antigens, including some bacteria and viruses, and they may take part in adaptive immunity. However, patients with selective IgA deficiency usually do not exhibit increased evidence of oral disease, possibly because a compensatory increase in salivary immunoglobulin M occurs.44,45 HIV. Several types of salivary proteins, such as the mucins, inhibit HIV infections by interacting with the virus.46 Thus, unlike vaginal and rectal epithelia, an intact oral epithelium rarely is a site of HIV transmission. However, chronic HIV infection leads to impaired immune responses in the mouth, and xerostomia frequently occurs.46 Periodontal disease. Little evidence exists that saliva has a direct influence on periodontal disease, probably because it does not enter the periodontal pocket, where periodontal pathogens are located. Because of the net outward flow of the gingival crevicular fluid, saliva does not penetrate the gingival crevice and, thus, the antibacterial components of saliva are unable to affect the bacteria there.47 However, in patients with a reduced salivary flow rate, bacterial clearance is reduced, and more bacteria will be in the saliva to colonize the oral tissues. Supragingival calculus, which contributes to gingivitis by virtue of the plaque layer on its irregular surface, forms predominantly lingual to the mandibular anterior teeth. This is primarily because sugar clearance is most rapid in that location, and the salivary film velocity there is the highest in the mouth. Therefore, after a person consumes sugar, the Stephan curves there will be shallow, and plaque fluid there will tend to remain supersaturated with respect to the minerals in calculus.28,48 Hence, the mineral in the calculus underlying the plaque in that location seldom tends to dissolve.
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CONCLUSION

For optimal oral health, food and drink should remain in the mouth for as short a time as possible. The most important time for people to brush their teeth is just before bedtime, because salivary flow is negligible during sleep and the protective effects of saliva are lost. Chewing sugar-free gum or consuming sugar-free candies stimulates salivary flow, which benefits hard and soft oral tissues in many ways.
Disclosure: Dr. Dawes has conducted studies supported by the Wm. Wrigley Jr. Company, Chicago, and has been a consultant for the Wm. Wrigley Jr. Company. 1. Schneyer LH, Levin LK. Rate of secretion of individual salivary gland pairs of man under conditions of reduced exogenous stimulation. J Appl Physiol 1955;7(5):508-512. 2. Schneyer LH, Levin LK. Rate of secretion of exogenously stimulated salivary gland pairs of man. J Appl Physiol 1955;7(6):609-613. 3. Shannon IL. Parotid fluid flow rate as related to whole saliva volume. Arch Oral Biol 1962;7(3):391-394. 4. Dawes C, Wood CM. The contribution of oral minor mucous gland secretions to the volume of whole saliva in man. Arch Oral Biol 1973;18(3):337-342. 5. Sas R, Dawes C. The intra-oral distribution of unstimulated and chewing-gum-stimulated parotid saliva. Arch Oral Biol 1997;42(7): 469-474. 6. Helmerhorst EJ, Oppenheim FG. Saliva: a dynamic proteome. J Dent Res 2007;86(8):680-693. 7. Dawes C. Factors influencing salivary flow rate and composition. In: Edgar M, Dawes C, OMullane D, eds. Saliva and Oral Health. 3rd ed. London: British Dental Association; 2004:32-49. 8. Schneyer LH, Pigman W, Hanahan L, Gilmore RW. Rate of flow of human parotid, sublingual, and submaxillary secretions during sleep. J Dent Res 1956;35(1):109-114. 9. Nederfors T, Isaksson R, Mrnstad H, Dahlf C. Prevalence of perceived symptoms of dry mouth in an adult Swedish population: relation to age, sex and pharmacotherapy. Community Dent Oral Epidemiol 1997;25(3):211-216. 10. Turner MD, Ship JA. Dry mouth and its effects on the oral health of elderly people. JADA 2007;138(suppl 9):15S-20S. 11. Sreebny LM, Schwartz SS. A reference guide to drugs and dry mouth: 2nd edition. Gerodontology 1997;14(1):33-47. 12. Watanabe S, Dawes C. The effects of different foods and concentrations of citric acid on the flow rate of whole saliva in man. Arch Oral Biol 1988;33(1):1-5. 13. Watanabe S, Dawes C. A comparison of the effects of tasting and chewing foods on the flow rate of whole saliva in man. Arch Oral Biol 1988;33(10):761-764. 14. Dawes C, Kubieniec K. The effects of prolonged gum chewing on salivary flow rate and composition. Arch Oral Biol 2004;49(8):665-669. 15. Hu S, Yu T, Xie Y, et al. Discovery of oral fluid biomarkers for human oral cancer by mass spectrometry. Cancer Genomics Proteomics 2007;4(2):55-64. 16. Hu S, Xie Y, Ramachandran P, et al. Large-scale identification of proteins in human salivary proteome by liquid chromatography/mass spectrometry and two-dimensional gel electrophoresis-mass spectrometry. Proteomics 2005;5(6):1714-1728. 17. Siqueira WL, Zhang W, Helmerhorst EJ, Gygi SP, Oppenheim FG. Identification of protein components in in vivo human acquired enamel pellicle using LC-ESI-MS/MS. J Proteome Res 2007;6(6): 2152-2160. 18. Dawes C, Dong C. The flow rate and electrolyte composition of whole saliva elicited by the use of sucrose-containing and sugar-free chewing-gums. Arch Oral Biol 1995;40(8):699-705. 19. Dawes C. How much saliva is enough for avoidance of xerostomia? Caries Res 2004;38(3):236-240. 20. Dawes C, Wood CM. The composition of human lip mucous gland secretions. Arch Oral Biol 1973;18(3):343-350. 21. Pan HB, Darvell BW. Solubility of calcium fluoride and fluorapatite by solid titration. Arch Oral Biol 2007;52(9):861-868.

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