acidulated fluor

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PEDIATRICDENTIS[RY/Copyright ~198SbyThe American Academy f Pediatric Dentistry

Volume 7 Number 3

The caries-preventive effects of full- and half-strengthtopical acidulated phosphate fluoride

Patricia P. Hagan, DDS, MSR. Gary Rozier, DDS, MPHJames W. Bawden, DDS, MS, PhDAbstract

Due o concernsabout the potential for acute toxicityfollowing professional application of topical fluoride, thisclinical trial was undertaken o determine f half-strengthacidulated phosphate luoride (APF)wouldbe as clinicallyeffective in reducing caries as the currently used 1.23%APF. Three hundred and sixteen junior high schoolstudents, 11-15 years of age, living in a nonfluoridatedarea were assigned randomly o 1 of 3 groups: a 1.23%APF hixotropic gel group, a 0.6% APF hixotropic gelgroup, or a placebo gel control group.Visual and tactile dental examinations, toothbrush andfloss prophylaxis, and topical application of assignedgelwere performed wice annually for each child. After 24months, both the 1.23% APF group and the 0.6% APFgroup experienced tatistically significant (p < 05) cariesincrement reductions whencompared o the contro!group. Although he 2 fluoride-treated groups experiencedcaries incrementreductions that were not statisticallydifferent from each other, there was a tendency for thehalf-strength fluoride (0.6%APF) o be less effective,especially in reducing pit and fissure caries. Thus, whilea half-strength fluoride gel maybe effective in reducingcaries in selected cases whereacute fluoride toxicity is ofspecial concern, these findings suggest that someeffectiveness in pit and fissure caries prevention maybesacrificed. Therefore, his clinical trial does not supportwidespreadreduction of fluoride content to 0.6% F- intwice-annual, professionally applied topical fluorideformulations.

The results of previous clinical trials have shownthat the use of acidulated phosphate fluoride (APF)gels containing 1.23% fluoride (F-) on a twice-annualbasis is effective in preventing dental caries. ~-3 How-ever, recent studies have shown that a considerableamount of fluoride may be ingested during the course

of a standard professional topical fluoride application,5and that plasma fluoride levels achieved after suchan application may reach potentially toxic levels.-8Acute fluoride toxicity is of particular concern whenadministering a topical fluoride treatment to the smallchild patient because of the exposure to a relativelyhigher fluoride dose per body weight than in the caseof an adult receiving the same treatment. Since mostcurrently used gels are both flavored and acidulated,salivation is stimulated and swallowing of this excesssaliva-fluoride mixture generally occurs during gelapplication. The amount ingested by a young childmaybe increased if the child is unable to use a salivaejector effectively.This potential for toxicity would be diminished ifthe fluoride concentration of the currently used 1.23%APF gels could be reduced without compromisingclinical effectiveness. Due o differences in conditionsunder which clinical studies are conducted, the clin-ical effect of variations in fluoride concentration can-not be determined by comparing the results obtainedin independent trials. As a result, the lowest fluorideconcentration that achieves optimum clinical effec-tiveness when applied twice annually has not beenestablished.Evidence exists, however, to support the idea thata lower concentration than the current standard 1.23%APFgel may be effective. All the current theories ofmechanismof action of topical fluorides including re-mineralization, reduction of enamel solubility andantibacterial action, propose that lower concentra-tions of fluoride would suffice for these effects.-12Fluoride gels of different concentrations ranging from0.25 to 1.25% F- have been tested in the rat modeland all were found to be significantly effective in in-hibiting caries. 13 In a previously reported clinical trial

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in which a high-release 1.23% fluoride solution wascompared with a gel that released only half as muchfluoride, both agents were found to be equally effec-tive in reducing caries when the agents were appliedtwice annually. 3 However, the vehicles were not thesame and that variable may have been a factor.Although such supporting evidence exists, no clin-ical trials directly comparing the caries reducing ef-fects of twice-annual, professionally applied topicalgels of varying fluaride concentrations have been re-ported. This controlled clinical trial was designed tocompare directly the caries-preventive effects of anAPF opical gel containing the standard 1.23% F- withthose of a gel containing a reduced fluoride concen-tration (0.6% F-) when the agents were applied twiceannually in a child population.Methods and Materials

The initial study sample consisted of 428 seventhgrade students in nonfluoridated ( < 0.2 ppmF-) areasof Guilford County, North Carolina. Studentsundergoing fixed orthodontic appliance therapy wereexcluded from the study since the presence of bandedappliances would not allow adequate examination andwould interfere with the direct contact between enameland fluoride. Students who returned a permissionslip were assigned randomly to 1 of 3 groups of equalsize: those to be treated with a 1.23% APFgel (GroupA); those to be treated with a 0.6% APF gel (GroupB); and those to receive a placebo gel containing nofluoride (Group C).At the beginning of the study in March, 1981, eachchild received a dental prophylaxis, a dental exami-nation, and an application of his assigned gel. Theseprocedures were repeated every 6 months (_+ 3 weeks)for 2 years. To obtain subject demographic data andascertain the extent of the childs dental care and pastfluoride exposure, a questionnaire was mailed to theparents of each participant.Prior to examina~tion and gel application, each sub-jects teeth were stained with a disclosing solution.~The stained plaque was removed with a soft bristlebrush b and unwaxed dental floss b by dental hygienestudents or dental assistants who were familiar withthe study protocol. No prophylaxis paste or dentifricewas used in the prophylaxis procedure.A single examiner (PH) performed all dental ex-aminations. Portable dental chairs and lights were setup in the schools for the procedures. The teeth weredried with compressed air prior to the examinations.Front surface mirrors and sharp #23 explorers were

Trace Dental Disclosing Solution -- Lorvic Corp: St. Louis, MO.Oral B 40 Toothbrushes and Oral B Unwaxed Dental Floss --Coopercare, Inc: Fairfield, NJ.

used to perform the visual and tactile examinations.Radiographs were not taken. The DMFS ndex wasused as the measurement of caries experience. Theexaminer adhered to the DMFS riteria set forth bythe Caries Measurement Task Group~a as modifiedby the NIDR for the National Dental Caries Preva-lence Survey. ~s Only erupted, permanent teeth wereincluded in the study. Third molars were excludedfrom the data.

The data for each child were recorded by trainedindividuals on separate forms designed for ease ofrecording as well as for facilitating subsequent dataentry into a computer. Results from prior examina-tions were not available to the examiner during thecourse of the study. All data were edited before, dur-ing, and after entry into the computer by means oflogical checks by a dentist (PH). The edited data thenwere processed using a Statistical Analysis System(SAS) package.6Following plaque removal and examination, thesubjects received a 4-min topical application of theirassigned gel. Approximately 2.5 ml of the appropri-ate gel was placed into the trough of disposable styr-ofoam trays ~ by trained dental personnel. The studyfollowed the classic double-blind protocol in that theexaminer, subjects, and dental auxiliaries were una-ware of which agent was applied in each subject. All

gels were packaged in plain containers labeled onlywith an identifying code letter. The code was brokenonly after data collection was completed. Group Areceived an application of a 1.23% F- APF hixotropicgel; d Group B received an application of a 0.6% FoAPF thixotropic gel; a and Group C received an ap-plication of a placebo thixotropic gel. d To minimizepotential bias, the placebo gel was similar to the fluo-ride gels in color, odor, and physical appearance butcontained no fluoride or acid. Prior to placing thefluoride trays firmly onto the dental arches, the teethwere dried with compressed air or cotton gauze. Asaliva ejector was placed sublingually to remove ex-cess saliva and fluoride. Participants were allowed toexpectorate into a disposable bowl after the trays wereremoved and each child then was instructed not toeat or drink for 30 min. Students were observed forat least 15 min following gel applications for any signsof acute toxicity such as nausea or vomiting.

The data collected were evaluated statistically todetermine the significance of DMFSncrement dif-Centrays - Pacemaker orp: (Coopercare,nc).All gels were manufacturedor this study by Pacemaker orp:(Coopercare,nc). Themanufacturerf the gels used n this studyhad no regulatoryor administrative ole in the planning r im-plementation f the study or in the analysis of results. Afterreceipt from he manufacturer,luoride release from he gels wasmeasured ccording o the flow dialysis method f Congleton tal.7

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ferences using analysis of variance (ANOVA).M Dif-ferences were regarded as significant at the 95%confidence level. Only data from subjects who fin-ished the 2-year study were included in the data anal-ysis.Results

Of the 428 subjects who received parental permis-sion to participate and who were initially examined,316 remained in the study after 24 months. Most ofthose not reexamined had moved to other locations.Participant attrition rates were not significantly dif-ferent among groups and ranged from 24 to 26%. Theage of the participants at the baseline examinationranged from 11 to 15 years with a mean age of 12.5for all subjects. Seventy-three per cent of the samplepopulation received regular dental care defined as atleast I dental visit per year. There were no significantdifferences (p > 0.05) among groups with respectage, race, sex, regularity of dental care, school loca-tion, or previous exposure to fluorides as determinedby chi-square tests for homogeneity.The baseline DMFS cores for the individuals whodropped out of the study were similar across all groupsand similar to the baseline DMFS cores based on ttests (p > 0.05). Table 1 shows the average baselineDMFS core for the 316 students who completed thestudy. The baseline DMFScore for the 1.23% F- APFgroup (Group A) was higher than for the othergroups, but the difference was not statistically sig-nificant according to ANOVAesting (p = 0.49).Table 1 also displays the observed 24-month DMFSincrements for the 3 groups. Differences in the ob-served mean baseline DMFS cores among groupsindicated the possible use of analysis of covariance(ANOCOV) ith this data when determining the sig-nificance of DMFSncrement differences. 18,19 How-ever, since the baseline DMFS cores were notsignificantly different from each other, ANOVA asdeemed appropriate.Statistical comparisons of DMFSncrements usingANOVAhowed that after 24 months children whohad received the full- or half-strength fluoride treat-

ments (Groups A and B, respectively) twice annuallyexperienced significantly less decay than did childrenin the control group (Group C). Although the 24-month DMFS ncrement in Group A (1.23% APF) wassmaller than the DMFSncrement in Group B (0.6%APF), a significant difference between the two treat-ment groups could not be detected (p = 0.66).The 95% confidence interval shown in Table 1 in-dicates the range of likely percentage caries reductionoutcomes if the investigation were to be repeated.The width of the confidence interval denotes the levelof precision achieved by the study design. 2~ The widerthe confidence interval, the less precise the study inthose areas of analysis.Figure 1 is a graphic display of observed mean,cumulative 6-month DMFS ncrements for the 3groups. The 2 fluoride-treated groups (Groups A andB) had smaller cumulative DMFSncrements than thecontrol group at each examination, with the greatest

difference occurring between the 18- and 24-monthexaminations.To determine whether the protection conferred bythe fluoride gels varied by type of surface, the overallmean DMFSncrement for each group after 24 monthswas separated into its pit and fissure and smoothsurface components as shown in Table 2. Occlusalsurfaces of molars and premolars, lingual surfaces ofmaxillary molars, and buccal surfaces of mandibularmolars were considered pit and fissure surfaces. Allother surfaces were designated as smooth surfaces.After 2 years, both fluoride groups had smaller DMFincrements for both surface types when compared tothe control. In comparing percentage differences withthe control, both fluoride gels appeared to be moreeffective on smooth surfaces. However, when actualnet DMFS ncrements according to surface type arecompared, it is apparent that more pit and fissuresurfaces were protected from decay than smooth sur-faces in both treatment groups. It is clear that in all3 groups, pit and fissure surfaces accounted for themajority of the DMFS aseline and 24-month incre-ment scores.Figure 2 demonstrates a tendency for the higherconcentration fluoride gel (A = 1.23% F- APF) to

TABLE. MeanDMFSaselineand24-MonthncrementScores or Control Group GroupC) and he Fluoride-TreatedGroups95%Confi-dence24-Month p-Value ANOVA Interval orBaseline DMFSncrement for 24-Month % DMFS Percentage e-Group N DMFS SEM) SEM Increment Reduction ductionA 108 5.05 (0.47) 3.08 (0.37) 0.015 30 10,4 to 49.6B 105 4,41 {0.43) 3,31 (0.38) 0,046 25 3.6 to 46.4C 103 4.41 (0.48) 4.40 (0.38) ..................

Group A - 1.23% F; Group B = 0.6% F.

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A CONTROL GROUP; N= 1030 0,6% F-APF GROUP; N=I05 1.23% F-~,PF GROUP; N=I08]: SEM

6 12 18 2IME IN MONTHS

F~G1. CumulativeDMFSncrements for control group, 1.23%F- APF-treatedgroup and 0.6%F- APF-treatedgroup.

more effective on pit and fissure surfaces than thelower concentration gel (B = 0.6% F- APF). On smoothsurfaces, however, this was not the case. The totaldifference in effectiveness between the 2 fluoride gelsoccurred mostly in the pit and fissure lesions. A sta-tistically significant reduction in pit and fissure cariesoccurred in the full-strength fluoride group (p = 0.01),

but not in the half-strength group when compared tothe controls (Table 2). However, this represents onlya trend and not a conclusive result since neither fluo-ride gel performed significantly superior to the otheron either surface type according to ANOVAesting.

Although more than 1000 applications of fluoride-containing gel were conducted during the course ofthis study, only 3 episodes of nausea or vomitingoccurred within the 15 min subsequent to gel appli-cation. All 3 episodes occurred in participants in GroupA (1.23% F-). None of the 3 individuals reported hav-ing symptoms prior to gel application.

Fluoride release from both fluoride-containing thix-otropic gels as measured by continuous flow dialysiswith subsequent measurement by fluoride ion elec-trode showed that the 0.6% F- APF gel released halfas much fluoride ion as did the 1.23% F- APF gel inthe first 5 min. The placebo gel released only a neg-ligible level of fluoride ion.

As a measure of examiner reliability, the frequencyof diagnostic reversals was determined. A diagnosticreversal was defined as a tooth which was diagnosedas carious on the baseline examination and as soundon the 24-month examination. After the frequency ofreversals was determined, a reversal rate for the ex-aminer was calculated. 22 In all groups the proportionof teeth reversing from decayed to sound to thosethat potentially could have reversed (decayed-to-soundplus decayed-to-decayed) was less than 0.002%. Dueto the low reversal rate, actual differences in incre-mental caries scores between control and test groupswere affected insignificantly.Discussion

The results of this study show that after 2 yearsboth the full- and half-strength fluoride regimens were

TABtE2. MeanDMFS aseline and 24-Month Increment Scores by Surface Type According to GroupSmooth urfaces % DMFBaseline 24-Month DMF Smooth Sur-DMF SmoothSurface ANOVA face

Group SmoothSurfaces (SEM) Increment (SEM) p-Value Reduction95% ConfidenceInterval for

Percenta6eReductionA (N=108) 0.62 (0.14) 0.72 (0.17) 0.20 30.1 --13 to 73B (N=105) 0.50 (0.13) 0.55 (0.17) 0.06 46.7 13.4 to 80C (N=103) 0.60 (0.18) 1.03 (0.17) ..................

Group

Pit andFissure urfacesBaseline DMF 24-Month DMF % DMFPit & Fissure P & F Surfaces ANOVA P & F SurfaceSurfaces (SEM) Increment (SEM) p-Value Reduction95%ConfidenceInterval forPercenta6e Reduction

A 4.43 (0.40) 2.37 (0.27) 0.01 29.7B 3.90 (0.36) 2.76 (0.28) 0.13 18.1C 3.81 (0.38) 3.37 (0.28) ........2.3 to 47.7-3.56 to 39.56

Group A = 1.23% APF: Group B = 0.67% APF; Group C = Control.

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1.50O

.oo:~0~-J 0.75

o.5ohz 0.25

I-] 1.23% F-APF GROUP 0.6% F-APF GROUP

Smooth Pit 8 ~ Fissure DMFSSurfaces Surfaces (total)

FIG2. Meanifferences n net DMFurface ncrementsf thefluoride-treated groups GroupA = 1.23% - APF;Group= 0.6%F- APF) rom the contro] group (GroupC) afteryears.effective in controlling decay, and neither regimenwas significantly superior to the other. The differencebetween the full- and half-strength groups was only0.23 DMF urfaces over the 2-year period. Thus, it isdoubtful whether the overall benefits to Group A (fullstrength) can be considered to be significantly greateron a clinical level than the benefits to Group B (halfstrength) in this study. Despite the unimpressive sizeof the overall difference between the 2 fluoride groups,certain study limitations and tendencies in the datashould be discussed before conclusions are drawn.

First, 73%of the subjects in the study reported thatthey were receiving regular dental care. An unde-fined number of these subjects received regular full-strength (1.23% F-) fluoride applications from theirdentists, thus substantially contaminating the half-strength (Group B) and control (Group C) groups.This well may have resulted in reduced caries incre-ments in these 2 groups and minimized the differencebetween them and the full-strength group (Group A.)The true effect of such contamination, however, can-not be defined clearly in this study.

Second, when the caries-inhibiting benefits of thefluoride gels were evaluated by surface type, an in-teresting tendency emerged. After 2 years, the full-strength fluoride gel showed a tendency to be moreeffective on pit and fissure surfaces than the half-strength gel. It is interesting that although the 2 fluo-

ride gels were not significantly different from eachother in their effectiveness on pit and fissure sur-faces, the full-strength fluoride group experienced asignificantly lower caries increment on these surfacesthan the control, but the half-strength fluoride groupdid not (Table 2).Laboratory studies concerning topical fluorides ef-fect on sound and carious enamel always have beenperformed on smooth surfaces. Thus, much of therationale for attempting to reduce fluoride concentra-tion without loss of effectiveness is based on smoothsurface data. It is obvious that there are differencesin the nature of the caries process between smoothand pit and fissure surfaces, and perhaps caries in-hibition on the different surface types requires dif-ferent fluoride concentrations for optimumeffectiveness. It would seem reasonable to expect thata higher concentration of fluoride would produce ahigher diffusion gradient which would favor pene-tration of fluoride ion through the distances involvedin the pits and fissures to reach the caries-active site.In the case of smooth surface caries, the diffusiondistances normally would be much less. In fact, lab-oratory studies on smooth surface enamel indicatethat fluoride uptake in sound enamel is nearly thesame for the 2 fluoride concentrations used in thisstudy. 1~ Ifi vitro studies on incipient smooth surfacecarious lesions suggest that a low concentration offluoride ion is as effective as a high concentration inremineralizing such lesions. ~ Similar studies have notbeen done on pit and fissure surfaces.

Thus, from a mechanistic point of view, it seemslogical that the higher concentration of fluoride ap-plied twice a year may be more effective in prevent-ing pit and fissure caries than a lower concentrationof gel due to the distances the fluoride must travel tocontact the enamel in the tortuous pits and fissures.On smooth surfaces, however, the higher concentra-tion gel would not seem to have a theoretical advan-tage and the results of this study support thathypothesis, if the majority of carious lesions in schoolchildren continues to occur on pit and fissure surfacesas a national trend, the effect of any caries inhibitingagent on these surfaces will become increasingly moreimportant.In a previously reported study that explored theeffectiveness of 1.23% APF opicals, ~ results revealedthat effectiveness against pit and fissure caries in-creased in the third year. Perhaps if the present studyhad run longer, a true difference between the full-and half-strength fluorides effect on pit and fissuresurfaces would have emerged.Because of these considerations, one should notconclude on the basis of this study that a 0.6% F-APFgel is as effective in reducing caries on all sur-

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faces as a 1.23% F-. APF gel when they are appliedtwice annually. This is particularly true with respectto the prevention of pit and fissure caries. Additionalstudies need to be conducted to better define the ef-fects of fluoride concentrations in such systems.The small sample size of this study allowed inclu-sion of only 1 reduced fluoride concentration testgroup. A larger sample would allow several fluorideconcentrations to be tested on a head-to-head basisto aid in establishing the lowest concentration in twice-annual topicals that would still provide optimumclinical effectiveness. Care should be taken in suchfuture studies to evaluate the effects of fluoride con-centration by tooth surface type. The informationgained from additional studies would be importantfrom the mechanistic as well as the clinical stand-point.To summarize, the results of this clinical trial in-dicate that a significant degree of caries preventioncan be obtained using the 0.6% F- agent twice a year,aside from the possibility that it is not as effective asthe 1.23% F- gel on pit and fissure surfaces. In caseswhere potential toxicity is of particular concern, onemay choose to use a 0.6% F- agent and substantiallyreduce the exposure to fluoride ingestion whileknowing that some effectiveness in caries preventionmaybe sacrificed.Conclusions

Both the full- (1.23% F- APF)and half-strength (0.6%F- APF) gels were effective in reducing the caries in-crement in our sample of adolescents. There wereindications that the full-strength agent is more effec-tive in reducing pit: and fissure caries.In selected cases where acute fluoride toxicity andexposure to high levels of fluoride are of special con-cern, the reduced strength concentration gel (0.6% F-APF) can be used and may be expected to impartsignificant caries-reducing effect.Additional clinical studies evaluating several dif-ferent fluoride concentrations should be conductedgiving special attention to the evaluation of treatmenteffects by surface type before widespread changes inprofessionally applied topical fluoride formulationsare made.This study was supporled in part by PHS grant RR05333.The authors acknowledge Ms. Georgeann Dunko-Nine for man-uscript preparation, Ms. Virginia Swecker for illustrations, andThomas G. Deaton for laboratory analysis of the fluoride contentof the gels. The authors also thank the dental hygiene studentsfrom Guilford Technical Institute and the dental assistants anddental hygiene students from UNCSchool of Dentistry for theirassistance in this project. The authors express our appreciation toMs. Diane Ramsey and Mr. Ed Stanek in the computer organiza-tion and statistical analysis of the data. The authors acknowledge

the Division of Dental Health of North Carolina for providing thedental equipment used in this project. The authors also thankCoopercare for supplying the fluoride and placebo gels, tooth-brushes, and floss, Finally, the authors thank the students andfaculty at Northeast, Northwest and Southeast Junior High Schoolsfor their participation in this project.

Dr. Hagan s an assistant professor, pediatric dentistry, School ofDentistry, West Virginia University, Morgantown, West Virginia26506-6305. Dr Rozier is an associate professor, health policy andadministration, School of Public Health; and Dr. Bawden s AlumniDistinguished Professor, pediatric dentistry, The University of NorthCarolina at Chapel Hill. Reprint requests should be sent to Dr.Hagan.

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2. lngraham RQ, Williams JE: An evaluation of the utility ofapplication and cariostatic effectiveness of phosphate fluo-rides in solution and gel states. J Tenn State Dent Assoc 50:5-12, 1970.3. Cobb HB, Rozier RG, Bawden JW: A clinical study of thecaries-preventive effects of an APF solution and an APF hix-otropic gel. Pediatr Dent 2:263-66, 1980.

4. LeCompte EJ, Doyle TE: Oral fluoride retention followingvarious topical application techniques in children. J Dent Res61:236, 1982.

5. OwenD, Morris M, Adir J, Bakker V: Monitoring ingestionand urinary excretion of topical fluoride. |ADR Program andAbstracts, no. 1256, 1979.

6. Ekstrand J, Koch G: Systemic fluoride absorption followingfluoride gel application. J Dent Res 59:1067, 1980.

7. Ekstrand J, Koch G, Lindgren LE, Petersson LG: Pharmacookinetics of fluoride gels in children and adults. Caries Res15:213-20, 1981.

8. Van Dyke RA: Fluoride from anesthetics and its conse-quences, in Continuing Evaluation of the Use of Fluorides,Johansen E, Taves DR, Olsen TO, eds. Boulder, Colorado;Westview Press, 1979.

9. Shannon IL, Edmonds EJ: Effect of pH and fluoride concen-tration on enamel solubility reduction by APF solutions. DentHyg 52:231-35, 1978.

10. Silverstone LM: Remineralization phenomena. Caries Res11:59-84, 1977.

11. Dijkman AG, Tak J, Arends J: Comparison of fluoride uptakeby human enamel from acidulated phosphate fluoride gelswith different fluoride concentrations. Caries Res 16:197-200,1982.

12. Messer HH: The anticaries actions of topical fluorides. North-west Dent 57:354-57, 1978.13. Hefti A: Effect of topical fluoride gel applications on cariesincidence in rats. Caries Res 16:77-79, 1982.

14. ADA ouncil on Dental Therapeutics: Proceedings of theConference on the Clinical Testing of Cariostatic Agents. Chi-cago: ADA, 1972.

15. NIDR: Calibration Manual for the National Dental CariesPrevalence Survey. National Caries Program. Prepared byN1DR nd Westat Staff, 1979.

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Horowitz HS: Measurement and expression of treatment ef-fects in caries clinical trials. J Dent Res 63:709-12, 1984.Heifetz SB, Meyers RJ, Kingman A: A comparison of the an-ticaries effectiveness of daily and weekly rinsing with sodiumfluoride solution: final results after three years. Pediatr Dent4:300-303, 1982.

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