POSTGRAD. MED. J. (1962), 38, 150

ENDEMIC FLUOROSISWith Particular Reference to Dental and Systemic Intoxication

AMARJIT SINGH, M.D., M.R.C.P. (Lond.)Professor of Medicine

SUNDER J. VAZIRANI, B.D.S., D.O.S., M.S., F.I.C.D.Professor of Oral Surgery

S. S. JOLLY, M.D.Assistant Professor of Medicine

B. C. BANSAL, M.B.Registrar, Central Registration

VVith the technical assistance of 0. C. MATHUR, M.Sc.*(Department of Medicine and Dentistry, Medical College, Patiala)

THE-studies of the toxic effects of fluoride on thehuman system have evoked a very lively interestthroughout the world because the public healthprogrammes of fluoridation for the prevention ofdental caries have always considered the risk of aremote cumulative intoxication. However, theindices of early intoxication are very poorly de-fined. The affinity of fluoride for the bones isacknowledged by everybody, but there is nouniversal agreement on its effects on other systemsof the body-particularly when it has been spreadover a number of years.We have had a unique opportunity of studying

the toxic potentialities of this ion because thereexists an extensive belt of 'endemic fluorosis' inthe southern parts of Punjab (India) mainly affect-ing the rural population. As already reported,people in these villages get their drinking watersupply mostly from wells in which the fluorinecontent is high (varying from 2.5 to I4 parts permillion-Singh, Jolly and Bansal, I96I; Singh andJolly, I96I). The soil of this area is sandy andthe temperature goes pretty high (iI6°-II7° F.)in the summer.The skeletal and neurological features of en-

demic fluorosis have already been described(Singh, Jolly and Bansal, I96I; Singh and Jolly,I96I; Singh, Dass, Hayreh and Jolly, I96I).The bones, due to heavy and irregular fluoride

deposition, become grotesque and markedly ir-regular in their contours (Figs. i and 2). The

* The biochemical investigations pertaining to thiswork were entirely carried out by Mr. Mathur.

sites of muscular and tendinous insertions arerendered abnormally prominent by excessive peri-osteal reaction with development of multipleexostoses which can be clinically palpated inmany cases. The greatest changes are observedin the spine, particularly in the cervical region.The vertebrx show altered proportions andmeasurements in all planes, but the striking ab-normality is the gross reduction of the antero-posterior diameter of the spinal canal and inter-vertebral foramina accounting for the neuro-logical features of a radiculo-myelopathy. In oneof our cases it was reduced to 3 mm. at the levelof the third and fourth cervical vertebra (Fig. 3).It is evident that with this degree of narrowingcompression of the cord is inevitable.The radiological features of fluorosis are charac-

teristic and diagnostic (M0ller and Gudjonsson,I932). Sclerosis of bones is observed throughoutthe skeleton, with calcification of ligaments andmuscular attachments.The most pronounced changes are seen in the

vertebral column with marked osteosclerosis andirregular osteophyte formation resulting in beak-like lipping and a chalky-white ground-glassappearance (Fig. 4).The osteosclerosis and irregular calcification is

evident in all the other bones of the body, particu-larly along the attachment of muscles and tendonsin the limb bones, in the interosseous membranesand around the joint capsules (Fig. 5).

It is proposed in this paper to record some ofour observations on dental fluorosis and also thesystemic effects of fluorine intoxication.

March I 962 SINGH AND OTHERS: Endemic Flutorosis

xk

FIG. i.-The pelvis from a case of fluorosis showingirregular bone deposition with calcification of theacetabulum.

.I

FIG. 2.-Femora from a case of fluorosis showingirregular bone deposition along the insertion oftendons.

Methods and MaterialFor this purpose we selected Papra, a village in

the Sangrur district of Punjab, where the level offluorine in drinking water was appreciably high(varying from 9.I to io.6 p.p.m.). This villagehas a total population of 667 individuals living inI12 houses. An effort was made to examine allthe residents who -were available at the time ofsurvey. The study comprised of complete dental

FIG. 3 -Fourth cervical vertebra from a case of fluorosisshowing a huge exostosis projecting into the spinalcanal thereby reducing the antero-posteriordiameter to only 3 mm.

..e;

FIG. 4.-Radiograph of the lumbar spine showingosteosclerosis with calcification of inter-vertebralligaments and irregular bone deposition in thetransverse processes.

152 POSTGRADUATE MEDICAL JOURNATL March i962

!. ..:..9.. .-.

....... ............... ..

..,....

a.................

W .-'.

FIG. 5.-Roentgenograph of the chest showing a chalky-white bony cage in contrast to the radio-translucentlungs.

and systemic examination, roentgenographicstudies of skeleton and teeth and biochemicalstudies, wherever indicated.

Dental FluorosisMottled enamel or dental fluorosis is a well-

recognized entity. It has been shown that if aperson resides in an area having a fluoride contentof more than i p.p.m. during the period oferuption of his teeth, he will most probablydevelop mottled enamel. On the other hand, ifan individual were to move to an endemic localityafter the period of development of the enamel ofhis teeth, there will be no mottling. Thus mottlingof dental enamel has become one of the first andearliest visible signs of chronic fluorine intoxi-cation; it is usually regarded as a sensitive diag-nostic criterion and has been accepted as an indexof fluorosis (Day, I940; Dean, I936 and I943;McKay, I9 I 6).

In our recent paper (Singh and others, ig6ib)on skeletal fluorosis and its neurological compli-cations, it was observed that in 25% of the 46cases showing obvious skeletal signs of seriousfluoride intoxication, there was no evidence ofdental mottling even though the fluorine contentofi the- drinking water- was as much- as- I4 p.p.m.In view of this report, Holman (i96i) questioned

the accuracy of 'mottled enamel' as an index ofendemic fluorosis.To evaluate the exact incidence of dental

fluorosis and its relation to skeletal fluorosis acareful field survey of the human population wascarried out in the above village where the fluorinecontent of the drinking water ranges from 9.I2to io.68 p.p.m.

Results of the Present SurveyA total of 302 individuals was examined, out

of which I5 were edentulous and are not includedin the subsequent analysis. Of the remaining 287persons, 170 were males and II7 females ofdifferent age-groups, as shown in Table i.The population was grouped into residents

(257) and non-residents (30), and into thosehaving a deciduous (49) or permanent (238)dentition. By residents we mean those personswho were born and brought up in the endemicarea. Non-residents were those who eithermigrated as refugees or as brides into the villageafter the age of 14 or IS years. Deciduous denti-tion age ranged from o-5 years and permanentdentition 6 years and above.The dental changes were grouped into three

grades, and in order to standardize our study wefollowed the same grades as described by Siddiqui(1955):

Grade I: White opacities or patches on theenamel; very faint yellow line across theenamel.

Grade II: A distinct brown stain.Grade III: Besides the well-established brown

line, considerable pitting all over the enamelsometimes with chipped-off edges.

The population was examined with the mouthmirror and probe in the daylight.

Incidence of Mottled Enamel in ChildrenForty-eight children (I7.I% of the total popu-

lation) in the age-group of 0-5 years were exam-ined. They were all residents of the village. Outof these, 40 (8i.6%) showed mottled enamel,whereas the remaining 9 (i8.4%) had none. Out,of the 40 positive cases, 80% were in grade -I2 5% in grade II, and I7.5% in grade III dentalfluorosis.

Incidence of Mottled Enamel in AdultsThe permanent dentition group, i.e. aged 6

and above, consisted of 238 persons, out of which30 were non-residents. Among 2o8 residents,204 (98.I%) were suffering from mottled enameland only 4 (44..%) were free from dental fluorosis.The mottling was most evident on the labialsurface of the upper and anterior teeth- Out ofthese 204 adults I9.2% were in grade I, z6.S%

March I962 SINGH AN! OTHERS: Endemic Fluorosis T53

in grade II, and 54% in grade III, as shown inTable I.

TABLE I

GRADING OF DENTAL PIGMENTATION

Grade Grade GradeDeciduous Total I II III

Age o-5 years 40 32 7

Permanent 204 39 55 110

Age Group6-io 50 9 9 32I11-20 56 3 II 4221-30 38 I I 15 I231-40 27 12 9 641-50 I6 2 8 65I-60 12 2 3 761-70 5 .;

Incidence of Skeletal Fluorosis in Relation toMottled EnamelOut of the total village population only 107

individuals submitted themselves voluntarily forthe whole skeleton to be radiographed. On roent-genographic evaluation 93 showed skeletal fluorosisand I4 did not. There were only 4 resident caseswhich did not show mottled enamel but hadskeletal fluorosis (see Table z).

Incidence of CariesIt has been observed that mottled teeth are

more resistant to caries than normal teeth (Arm-strong and Brekhus, I938). From our investigationwe found that out of 287 individuals surveyed,only 4 had caries (I.4% of the total populationinvestigated).

Dental Roentgenographic ChangesDuring our study we came across the autopsy

material of a proved fluorotic case (Singh andothers, I962). The teeth showed generalizedfluorosis grade II. On gross examination the moststriking change was observed in the root portionof every tooth. The root surfaces were irregularand rough and revealed heavy deposits of calcifiedmasses in the form of excessive amounts offluorine osteocementum at the apical region ofthe teeth (see Fig. 6). We have not come across

... .....

FIG. 6. Teeth from a case of fluorosis showing irregularbone deposition near the roots of the teeth.

any similar published report in the dental litera-ture on fluorosis (Stones, 1957; Thoma andGoldman, I960). Therefore, it was decided thatin the present survey we should X-ray the teethalso along with other parts of the skeleton forevidence of endemic fluorosis. The plan was toradiograph the anterior upper and lower incisorsand the left and right lower molars because it waseasy to angulate these areas with the portablefield X-ray apparatus. For dental X-ray we usedthe dental cone. On a voluntary basis 86 personssubmitted thenmselves for the dental X-ray.As seen roentgenographically the following

three features were noted, namely, osteosclerosis,cementosis, and periapical root resorption (Figs.7 and 8).In a typical case abnormally dense bone was

noted. There was a gradual resorption of theroot-apex and often the root appeared evenlyresorbed, resembling in appearance post-operativeapicectomy, though sometimes the resorption wasirregular. Also it indicates that new bone hadbeen deposited in the area previously occupiedby the root and this was lined by a cortical layeradjoining the periodontal membrane.

Hypercementosis or cementum hyperplasia wasevident on careful examination.Out of 86 persons whose teeth were X-rayed,

68 showed osteosclerosis of the jaw bone, 41

TABLE 2DENTAL CHANGES IN 93 CASES OF SKELETAL FLUOROSIS (63 MALE, 30 FEMALE)

Total Age group-numberof cases 11-20 21-30 31-40 41-50 5 -60 61-70

Dental pigmentation 74 7 21 20 I3 7 *6No pigmentation 9-

Resi.dents'(4) 2 -?Non-'reside'nt's )(1 ) -7 4 3-

154 POSTGRADUATE MEDICAL JOURNAL March I962

........ ... w:.:.........:......

..........:.

.......W

FIG. 7.-Skiagram of the teeth from a case of fluorosisshowing resorption of the roots.

showed cementosis, and in 29 cases various degreesof root resorption were recorded in the molarand incisor teeth. A higher incidence of rootresorption was marked in the lower first per-manent molars. Next in order of frequency werethe upper lower central incisors and secondmolars. The early root resorption changes weredetectable in age-group as early as I5-20 years.Radiological skeletal changes were noted at anage as early as i 8 years.

Systemic InvestigationsSporadic reports of systemic intoxication by

fluoride have been published. It is believed tolower the general nutritional status and is par-ticularly toxic for the thyroid, kidneys and cardio-vascular system. In order to detect any suchsystemic and visceral manifestations, we studiedthe village population in detail.On general physical examination there appeared

to be no evidence of under-development or undueanremia or sign of any unusual nutritional defi-ciency among the people of the affected area.On the contrary, the rural population in theBhatinda district, where the fluoride content ofwater is fairly high, is one of the tallest and best-built in the country. They are mostly Jat Sikhsand well known for their sturdy constitution,which is probably their racial characteristic.Similarly, there was no evidence of any sign ofgoitre or other thyroid disorder in the affectedpopulation. A portion of Punjab is affected byendemic goitre, but this belt extends along itsnorth-western border along the edge of theHimalayas, while on the contrary, the fluorosisbelt extends along the southern border of Punjab.

Detailed examination of the cardiovascularsystem, including electrocardiography, revealed

.i

Fice. 8.-Skiagram of the teeth -from a case of fluorosisshowing hyper-cementosis.

no evidence of ischaemic heart disease in thepeople examined. Similarly, examination of othersystems was unrewarding. A plain skiagram ofthe urinary tract was taken in most of the caseswith negative results. We have come across onlyone case of renal calculus out of a total of i 6oX-ray positive cases of skeletal fluorosis. Theurine, though normal on routine physical, chemi-cal and microscopic examination, showed a rathercharacteristic change in colour on standing: itwas noticed that urine on standing for 6-8 hourschanged its colour to dark brown from abovedownwards. This gives a resemblance to theurine of cases of alkaptonuria on casual examina-tion. Luckily a case of ochronosis with a classicalclinical picture was available for comparison dur-ing the course of this study. Urine from thealkaptonuric patient when made alkaline turnedblack immediately on account of the conversionof homogentisic acid to melanin. The colour ofthe urine from the fluorotic patients, however, didnot change colour immediately on addition ofalkali. Further chemical tests for homogentisicacid (Harrison, I957) were applied to thesesamples and also proved to be negative.A detailed study of the urine was also made for

the excretion of total nitrogen, amino-acid nitro-gen, and for tyrosine and its metabolites. For thispurpose 34 cases of fluorosis selected at randomfrom our present series were examined. An in-creased excretion of amino acids was found in allthe cases. The detailed results are tabulated inTable 3.

DiscussionDental roentgenographic investigation features

two important findings, root resorption andhypercementosis. A partial review of the litera-

March i962 SINGH AND OTHERS: Endemic Fluorosis

TABLE 3TWENTY-FOUR HOURS' URINARY EXCRETION OF AMINO ACIDS IN CASES OF FLuOROSIS

Total Amino acid Amino N x I00 Tyrosine andnitrogen nitrogen its metabolites

(g./24 hour) (mg./24 hour) Total N (mg. %)

Normal values .. .. .. .. 6-I2 50-150 0.5-1.5 0-25Mean values (fluorotic patients) .. 8.723 272.01 3. II 40.3Range (fluorotic patients) .. .. 6.138- 1.276 I88.2-402.76 1.95-4.22 30.6-54.6Standard deviations .. .. .. 1.254 57.77 o.6732 6.78

ture reveals no mention of the above findings indental fluorosis (Stafne, 1959; Stones, 1957;Thoma and Goldman, I960).

Resorption of the roots of teeth most oftenoccurs as a result of local factors, although itmay also be caused by general systemic disease.The most common local factors are trauma andpressure. Resorption that results from traumaticocclusion or from orthodontic appliances is notuncommon and is generally recognized. How-ever, Stafne (1959) pointed out that resorptionalso occurs as a result of pressure exerted by im-pacted teeth, tumours and osteosclerosis.As far as hypercementosis is concerned, our

observation is further confirmed by recent studiesby Yoon, Brudevoid, Smith, Gardner and Soni(I960). It has been shown that deposition offluorine varies, not only in different skeletoncomponents but in different regions of the indi-vidual bones (Gardner, Smith, Hodge, Brudevoidand Eldredge, I959, Wallace, I954; Zipkin,McClure and Leone, 1958). In view of thesefindings Yoon and his group (I960) studiedthe deposition of fluorine in different parts ofalveolar bone and of the teeth. They have re-ported that the most notable finding in theirstudy was the greater concentration of fluorine inthe cementum than in the lamina dura and theother portions of the alveolar bone. Usuallyteeth so affected are asymptomatic, retain theirvitality and are rarely lost as a result of theresorption. In our study no subjective symp-toms were revealed in the population investigated.

Paget's disease or osteitis deformans also givesthe same roentgenographic appearance as recordedin endemic dental fluorosis. As seen roentgeno-graphically, Paget's disease shows a ground-glassappearance, evidence of resorption of the roots ofthe teeth and deposition of excess of cementumon the roots of the teeth.

Differential diagnosis can be established only ifwe examine carefully the presence of periodontalmembrane and the lamina dura. The lamina duraand periodontal membrane is present in endemicdental fluorosis and absent in Paget's disease.

It will further be observed that out of 107people X-rayed, 93 showed evidence of skeletal

fluorosis in this small village. Out of these therewere four who, though residents of the placesince birth, had skeletal involvement but did nothave any dental mottling on most careful examina-tion. There were i 5 more cases with radiologicallypositive skeletal fluorosis but no dental mottling.These were, however, non-residents, having mi-grated to the village after the age of 14 years.This should provide some answer to the con-troversy started by Holman (I96I) regarding thesensitivity of dental mottling as an index offluoride intoxication in an endemic area.

In this connection there is another observationmade by us that all the skeletal fluorosis cases,including i9 with no dental mottling, showed ondental X-ray, osteosclerosis, root resorption andhypercementosis. We feel that X-ray of theteeth and jaws gives an even more sensitive indexof fluorosis than mere mottling of the enamel.

Sporadic reports of systemic manifestationsother than skeletal and dental changes in fluorineintoxicants have been published from time totime.Symptoms relating to general nutrition, anamia,

thyroid, skin, neuromuscular, cardiac, respiratory,gastro-intestinal and urinary systems have beenreported by different workers (Waldbott, I955,1956, 1957, I96I; Takamori and others, I956;Siddiqui, 1955; Silva, Chapedi and Pedace, 1940;Rao, 1955; Raffaele, 1944).The strong affinity of fluorine for calcium is

believed to interfere with calcium metabolism.Its affinity for other metals, especially magnesiumand manganese, has been accounted for by itsinterference with certain enzymes.

In our series, however, we failed to comeacross any such visceral or systemic manifestationexcept the change in the colour of the urine onstanding. This has also been reported by Panditand Rao (1940) in experimental fluorosis in mon-keys. They suggested that this may be due to theexcretion of homogentisic acid and metabolites oftyrosine. Our studies, however, show that thechemical present in the urine which is responsiblefor the change of colour is not homogentisic acidbut some other metabolite of tyrosine as indicatedby the increase in 24 hours' urinary excretion of

156 POSTGRADUATE MEDICAL JOURNAL March I962

tyrosine derivatives. Further, our observations ofincreased excretion of total amino-acids in theurine in fluorosis cases also indicates that fluoridesare probably excreted in organic molecular formin combination with amino-acids. We are carryingout further work on experimental animals toconfirm our preliminary observations. It is alsopossible that the absence of visceral toxic effectsin endemic fluorosis may be due to this mechanismof excretion. Damage to the kidney and otherorgans in experimental fluorosis is well known.The absence of such manifestation in endemicfluorosis may be due to the gradual detoxicationand excretion of fluorides by the conversion intothis organic molecular form in combination with-amino-acids. Our observations that skeletalfluorosis is more common among the poor in therendemic area may also be thus explained becauseof the lesser amount of amino-acids available forexcretion in poor and under-nourished people.It is also possible that the pigment in mottledteeth may be of the same nature as that excretedin the urine, viz. some metabolite of tyrosine.This, however, needs confirmation.

Finally it will be interesting to point out thepreventive measures that are being adopted in the

endemic area. In the village of Papra, to whichthe present report relates, deep drilling at oneplace at a depth of 250 feet has yielded water con-taining only i p.p.m. of fluorine, as compared toabout 9-IO p.p.m. in ten superficial wells, whichwere so far the source of drinking water. In theother villages, canal water after due purificationis being utilized because its fluorine content hasbeen found to be only 0-5 p.p.m.

SummaryA careful survey of an isolated community in

an endemic fluorosis area has been carried outspecially to evaluate the relative incidence ofdental fluorosis compared to skeletal fluorosiswith the following observations:-

(i) Dental mottling, although a very sensitiveindex, may be absent in a small number ofskeletal-positive cases.

(2) Some useful radiological features of dentalfluorosis have been revealed.

(3) Biochemical examination of the urine incases of fluorosis has given some interesting cluesto further studies in the mode of fluoride excretion.

(4) 'The absence of any other manifestation oftoxic systemic effects is stressed.

REFERENCESARMSTRONG, W. D., and BREKHUS, P. J. (1938): Relationship of Fluorine Content of Enamel and Resistance to Dental

Decay, J. dent. Res., 17, 301.DAY, C. D. M. (I940): Chronic Endemic Fluorosis in Northern India, Brit. Dent. J., 68, 409.DEAN, H. T. (I936): Chronic Endemic Dental Fluorosis (Mottled Enamel), J. Amer. med. Ass., 107, 1269.

and ARNOLD, F. A. (1943): Endemic Dental Fluorosis or Mottled Teeth, Ibid., 30, 1278.GARDNER, D. E., SMITH, F. A., HODGE, H. C., BRUDEVOID, F., and ELDREDGE, D. M. (1959): Distribution of

Fluoride in the Normal Dog Femur, Y. Appl. Physiol., I4, 427.HARRISON, G. (I957): Chemical Methods in Clinical Medicine, p. 252. London: J. A. Churchill & Co.HOLMAN, R., WILSON, D. C., and GRIFFITH, G. W. (I961): Skeletal Fluorosis, Lancet, i, 399, 449, So6.McKAY, F. S., and BLACK, G. V. (I9I6): Mottled Teeth, Dental Cosmos., 58, I29.PANDIT, C. G., and RAO, D. N. (1940): Endemic Fluorosis in India-Experimental Production of Fluorine Intoxication

in Monkeys (Macca Radiata), Indian 3t. med. Res., 28, 559.RAFFAELE, J. F. (1944): La Fluorosis. Buenos Aires: El Atenco.RAO, S. V. (I955): Fluorosis Causing Paraplegia, Y'. Indian med. Prof., 2, 780.SIDDIQUI, A. H. (1955): Fluorosis in Nalgonda District, Hyderabad-Deccan, Brit. med. 5'., ii, I408-1413.SILVA, L. L., CHAPEDI, E., and PEDACE, E. A. (1940): Fluorosis and Tuberculosis, Sem. mid. (B. Aires), 47,

14I3-1434.SINGH, A., JOLLY, S. S., and BANSAL, B. C. (I96Ia): Skeletal Fluorosis and its Neurological Complications, Lancet, i, I97.

- (i96ib): Endemic Fluorosis with Particular Reference to Fluorotic Radiculo-Myelopathy, Quart. 5'. Med.N.S., 30, 357., DASS, R., HAYREH, S. S., and JOLLY, S. S. (I962): Anthropometric Measurements in a Case of Fluorosis. In thepress.

STAFNE, E. C. (1959): Oral Roentgenographic Diagnosis, pp. III-II3. Philadelphia: W. B. Saunders.STONES, H. H. (1957): Oral and Dental Diseases, pp. 125-I82. London: E. & S. Livingstone.TAKAMORI, T. (I955): Recent Studies on Fluorosis-Jokushima, 5. exp. Med., 2, 25.THOMA, K. H., and GOLDMAN, H. M. (I960): Oral Pathology, pp. 103-IIO. St. Louis: C. V. MosbyWALDBOTT, G. L. (1955): Chronic Fluorine Intoxication from Drinking Water, Int. Arch. Allergy, 7, 70.- (1956): Incipient Fluoride Intoxication from Drinking Water, Acta. med. Scand., x56, 157.

(1957): Tetaniform Convulsions Precipitated by Fluoridated Drinking Water, Confin. neurol. (Basel), I7, 339.(I96I): The Physiologic and Hygienic Aspects of Absorption of Inorganic Fluorides, Arch. Environmental Health,2, 59-155.

WALLAcE-DuRBIN, P. (1954): The Metabolism of Fluorine in the Rat Using F I8 as a Tracer, 5'. dent. Res., 33, 789.YOON, S. H., BRUDEVOID, F., SMITH, F. A., GARDNER, D. E., and SONI, N. (I960): Distribution of Fluorine in Teeth

and Alveolar Bone, 5'. Amer. dent. Ass., 6I, 565.ZIPKIN, I., McCLuRE, F. J., and LEONE, M. C. (1958): Fluoride Deposition in Human Bones After Prolonged Ingestion

of Fluoride, in Drinking Water, Publ. Hlth Rep. (Wash.), 73, 732.