Environ Monit Assess (2017) 189: 579
https://doi.org/10.1007/s10661-017-6288-5
Dental fluorosis, nutritional status, kidney damage,
and thyroid function along with bone metabolic indicators
in school-going children living in fluoride-affected hilly areas
of Doda district, Jammu and Kashmir, India
Arjun L. Khandare & Shankar Rao Gourineni &
Vakdevi Validandi
Received: 16 June 2017 / Accepted: 5 October 2017 / Published online: 23 October 2017
# Springer International Publishing AG 2017
Abstract A case-control study was undertaken among
the school children aged 8–15 years to know the pres-
ence and severity of dental fluorosis, nutrition and kid-
ney status, and thyroid function along with bone meta-
bolic indicators in Doda district situated at high altitude
where drinking water was contaminated and heat stress.
This study included 824 participants with an age of 8–
15 years. The results of the study reviled that dental
fluorosis was significantly higher in affected than con-
trol area children. Urinary fluoride was significantly
higher (p < 0.05) in affected children as compared to
the control area school children. Nutritional status of
affected children was lower than control area children.
The chronic kidney damage (CKD) was higher in af-
fected than control school children. Thyroid function
was affected more in affected than control area schools.
Serum creatinine, total alkaline phosphatase, parathy-
roid hormone, 1, 25(OH)2 vitamin D, and osteocalcin
were significantly higher in affected school children
(p < 0.05) as compared to control school children,
whereas there was no significant difference in triiodo-
thyronine (T3), thyroxine (T4), and 25-OH vitamin D
among the two groups. There was a significant decrease
in thyroid-stimulating hormone (TSH) in the affected
area school children compared to control. In conclusion,
A. L. Khandare (*) : S. R. Gourineni : V. Validandi
Department of Food Toxicology, Indian Council of Medical
Research, Food and Drug Toxicology Research Center, National
Institute of Nutrition, Jamai-Osmania, Hyderabad, Telangana
500007, India
e-mail: alkhandare@yahoo.com
fluorotic area school children were more affected with
dental fluorosis, kidney damage, along and some bone
indicators as compared to control school children.
Keywords Fluoride . Urinary fluoride . Dental
fluorosis . Glomerular filtration rate . 1,25(OH)2
vitamin D
Introduction
Fluoride (F) intake in permissible limit (< 1 ppm)
through water prevents the formation of dental caries
(Petersen and Lennon 2004). However, exposure to high
F (>1 ppm) can generate several alterations. Chronic
fluoride poisoning is a worldwide health problem that
occurs in endemic areas where the fluoride content in
drinking water is above the optimal level (> 1 ppm)
(Xiang et al. 2010). The World Health Organization
(WHO) referred to fluoride above 1.0–1.5 mg/L in
drinking water, especially drawn from the groundwater
of areas of granite rock, result in pathological changes in
teeth causing dental fluorosis (DF), which is categorized
by light yellow to brown-black horizontal lines on the
teeth surface and chipped off edges (Pérez-Pérez et al.
2017).It is known that high intake of F for long time
produces bone damage and kidney damage and lowers
the intelligent quotient (IQ) in children (Das and
Mondal 2016; Ranjith 2015; Qin et al. 2009).
The high-risk areas of F concentrations are mostly
located in arid and semi-arid regions that are charac-
terized by a rapid rate of chemical weathering of
579 Page 2 of 8
geological resources (Rango et al. 2012). In the hu-
man body, the total fluoride ingested remains for a
long time; however, approximately 80% of fluoride is
excreted mainly through urine; the rest of it is
absorbed into body tissues from where it is released
very slowly (WHO 1996). The excreted fluoride
through urine can be considered as biomarkers of
fluoride and it serve to identify deficient or excessive
consumption and bioavailability of fluoride in the
body (Watanable et al. 1994). Among the various
biomarkers of fluoride exposure, the urinary fluoride
(UF) was considered to be the best indicator of fluo-
ride exposure because it can be collected noninva-
sively and systematically reflects the burden of fluo-
ride exposure through all the sources (diet and water).
Hence, special attention has been given to it as a
biomarker, and is used as an indirect indicator of
fluoride exposure.
There is a limited data on the prevalence and severity
of fluorosis in the hilly and disturbed area of Doda
district, Jammu and Kashmir, India. There is no systemic
study on nutritional status, dental fluorosis, kidney, and
thyroid and bone metabolic indicators in the area of Doda
district, Jammu and Kashmir, affected with fluorosis.
Hence, the present descriptive study has been undertaken
to plan appropriate intervention strategies in the future.
Materials and methods
Study design
The detailed case-control study was undertaken to cover
10 schools in Doda district of Jammu and Kashmir out
of which 8 rural (affected; F = 1.43 to 3.84 mg/L) and 2
urban (control; F = < 1 mg/L). The school-going chil-
dren were divided into 2 categories: control and affected
based on their drinking water fluoride levels.
The Doda district lies within latitude 32°25′00″ and
34°14′00″ N and 75°00″ and 76°45′30″ E and has an
average elevation of 1107 m (3631 ft). This case-control
study has been conducted in an endemic fluorosis area
of Jammu and Kashmir State where geogenic concen-
tration of F in groundwater was high (1.153 to
27.216 mg/L) (Inder et al. 2000) and known to be
endemic for dental fluorosis (Thakuria 2007).
All the participants were born and had resided in
the area since their birth. An appropriate question-
naire was administered to all the participants at the
Environ Monit Assess (2017) 189: 579
time of admission to collect demographic data. Di-
agnosis of dental fluorosis was performed by clinical
examination through oral examination of each stu-
dent, by a dental specialist (from local hospital) in
the common room of the school, with the subject
seated in a chair in bright daylight. The dental spe-
cialist used a mirror and a sterile dental probe for
oral examination. The presence and severity of den-
tal fluorosis were recorded. The Dean index was
used to determine the grade of dental fluorosis
(Dean 1942) which was selected because of its ac-
curacy to identify DF severity. Anthropometric mea-
sures such as weight and height were recorded, and
body mass index (BMI) was calculated. Water sam-
ples from all drinking water sources were collected
from the selected control and affected villages in
clean, high-density polyethylene bottles. First morn-
ing spot urine samples were collected in polyethyl-
ene containers and stored, adding 2 to 4 drops of
toluene as a preservative and transported to labora-
tory, NIN, Hyderabad and stored at 4 °C till
analysis.
Twelve-hour fasting blood samples were collected
in a serum vacutainer (Vacuette, Greiner Bio-one,
Austria). Serum was separated by centrifugation at
3000 rpm for 20 min and stored in an ice-lined
refrigerator (ILR) at 4 °C in the district hospital.
The samples were transferred to the laboratory at
NIN, Hyderabad in cold condition using vaccine
carrier and kept at − 80 °C until further analysis.
Biochemical parameters in serum
Serum samples were analyzed for biochemical parame-
ters such as creatinine and alkaline phosphatase (ALP)
using ACE Alera Auto analyzer, Alfa Wassermann, Inc.,
USA. Serum Osteocalcin was analyzed using BMicro
Vue^ Osteocalcin Immune Assay kit supplied by Quidel
Corporation, USA. Parathyroid hormone (PTH), 25-OH
and 1, 25 (OH)2 vitamin D, and T3 and T4 levels in
serum were measured by using DiaSorin kits supplied
by DiaSorin Minnesota, USA. Thyroid-stimulating hor-
mone (TSH) was measured by Immunoradiometric as-
say (IRMA) kit, DiaSorin, Saluggia (VC) Italy.
Drinking water and UF concentrations were analyzed
using fluoride-specific ion electrode, (Orion 9609) (Tusl
1970) which was calibrated with fresh, serially diluted
standard solutions. During the measurement, ionic strength
buffer solution was added to each sample for analysis.
Environ Monit Assess (2017) 189: 579
The BMI was calculated by the formula,
BMI ¼ weight in kg=ðheight in meterÞ2
The status of kidney damage was assessed by
glomerular filtration rate (GFR) and it was calcu-
lated by the Bedside Schwartz Formula (Schwartz
et al. 1976),

rosis, only 56 were affected (12.5%); most of them were
GFR mL=min=1:73 m2
¼ ð0:41  height in cmÞ=creatinine in mg=dL:
Written informed consent was obtained from all the
participants or by their school Head Master in case they
were minors. All data were managed to ensure the
protection of individual rights and maintain confidenti-
ality. This study was approved by the Institutional Hu-
man Ethics Committee, National Institute of Nutrition,
Hyderabad, India (Protocol No. 18/2013/I).
Statistical analysis
Results are presented as means and standard deviations
between the observed values. Relationships between
water fluoride level with prevalence and severity of
fluorosis, fluoride exposure dose, were assessed by lin-
ear regression analysis. The statistical differences be-
tween the bone metabolic indicators of control and
affected group children were quantitatively assessed by
the statistical parameters such as correlation coefficient
(r), Fisher-ratio (F-ratio), and one-way ANOVA. All
statistical analyses were performed by Microcal-Origin
version 6. p < 0.05 was considered as statistically
significant.
Results
Prevalence of dental fluorosis
The study population consisted of 824 participants with
379 from affected area [boys193 (50.9%); girls
186(49.1%)] and 445 from control area [boys 301
(67.6%); girls 144 (32.3%)]. Out of 379 from affected
area, 48% were affected by different grades of dental
fluorosis; boys and girls were equally affected. Out of 8
affected schools, 2 schools belong to Malwas and
Golibagh having high drinking water fluoride
(> 3 ppm). In these village schools, more than 95%
Page 3 of 8 579
students were affected with different grades of dental
fluorosis (out of 33 students 32 were affected, 12 in
grade I, 4 in grade II, 8 in grade III, and 8 were in grade
IV) (Fig. 1). Two schools named Green Model School
and Govt. Higher Secondary School having average
drinking water fluoride 1.13 ppm (0.32–1.18 ppm) were
considered as control schools. Out of 445 students ex-
amined for clinical signs and symptoms of dental fluo-
in grade I and 6 students were in grade II. The commu-
nity fluorosis index (CFI) for affected and control area
was calculated and given in Table 1. There were no
significant differences observed in the extent of preva-
lence and severity of dental fluorosis among the boys
and girls (p < 0.680) in affected areas (Table 1).
Figure 2a–d illustrates that the increase in water fluoride
levels in study areas quantitatively enhances the fluoride
exposure dose, prevalence of fluorosis, and CFI values,
respectively.
Nutritional status
To know the nutritional status, the BMI was calculated
and it was ranged from 14.59 to 18.70 for the age groups
of 6 to 15 years in boys of affected area, whereas 15.87
to 18.71 for same age groups of control area. However,
affected area boys aged 11and 12 years BMI was 16.15
and 16.28, which was low as compared to control area
boys (BMI = 17.03 and 17.49). BMI for girls from
affected and control schools ranged from 15.40 to
20.47 for the age groups 6 to 15 years, whereas 15.37
to 19.74 for same age groups from control area.
Fig. 1 Dental fluorosis in the affected area school children of
Doda district
579 Page 4 of 8 Environ Monit Assess (2017) 189: 579

Table 1 Water fluoride levels, prevalence of fluorosis, and community fluorosis index (CFI) in normal and high fluoride areas

Areas Water fluoride level Gender No. of children classified according to Dean’s classification Prevalence of CFI
(mg/L) fluorosis (%)
0 0.5 1 1.5 2 3 4

Control area 1.13 ± 0.42 Boys 220 45 20 11 5 0 0 27 0.23

Doda Girls 99 24 16 4 1 0 0 31 0.25
High fluoride areas 1.85 ± 0.25 Boys 26 0 3 2 0 0 1 19 0.31
Ganega Girls 21 0 2 0 1 0 1 16 0.32
Arnora 2.04 ± 0.49 Boys 4 2 6 3 1 0 0 75 0.84*
Girls 6 0 4 2 2 0 0 57 0.79*
Ghat 2.05 ± 0.51 Boys 71 7 21 12 9 5 1 44 0.63*
Girls 64 15 17 17 13 6 1 52 0.74*
Malvas 3.12 ± 0.10 Boys 0 0 1 1 0 3 1 100 2.58*
Girls 1 0 2 0 2 0 6 91 2.73*
Golibagh 3.84 ± 0.01 Boys 0 1 1 2 2 2 4 100 2.54*
Girls 0 0 0 1 0 1 2 100 3.13*

*Statistically significant (p < 0.05)

Fluoride exposure dose (mg kg d )
-1

(Y = -13.27 + 31.0477 X, r = 0.8929, p = 0.0166)

0.35 (Y = -0.117 + 0.0999 X, r = 0.8704, p = 0.024)
-1

0.30 100
Prevalence of fluorosis (%)

0.25 A B
80
0.20
60
0.15

0.10 40

0.05
20
0.00
1.0 1.5 2.0 2.5 3.0 3.5 4.0 1.0 1.5 2.0 2.5 3.0 3.5 4.0
-1 -1
water fluoride level (mg L ) water fluoride level (mg L )

(Y = -1.438 + 1.153 X, r = 0.9540, p = 0.0031) Y = 0.297 + 8.2406 X, r = 0.7822, p = 0.0660

Community Fluorosis Index (CFI)

Community Fluorosis Index (CFI)

3.0 3.0

2.5 C 2.5

2.0
D
2.0

1.5 1.5

1.0 1.0

0.5 0.5

0.0 0.0
1.0 1.5 2.0 2.5 3.0 3.5 4.0 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35
-1 -1 -1
water fluoride level (mg L ) Fluoride exposure dose (mg kg d )

Fig. 2 a–d Linear correlations between water fluoride levels with fluoride exposure dose (a), prevalence of fluorosis (%) (b) and CFI (c),
and relationship between CFI and fluoride exposure dose (d)
Environ Monit Assess (2017) 189: 579
Table 2 Levels of fluoride exposure dose, urinary fluoride, serum creatinine, GFR, and chronic kidney disease stages in control and affected
groups of children (values represent mean±standard deviation)
Group Fluoride exposure dose Urinary fluoride level
(mg/kg/d) (mg/L)
Control 0.05 ± 0.01 1.91 ± 0.64
Affected 0.09 ± 0.02† 3.28 ± 1.71†
Normal range 0.05–0.07 ≤ 1.5
*Chronic kidney disease
†
Statistically significant (p < 0.05)
Blood and urinary parameters
Fluoride exposure was significantly higher (p < 0.05) in
the affected area school children than the control area
(Table 2). The UF was significantly higher in the affected
area school children than the control. Creatinine, alkaline
phosphatase, osteocalcin, parathyroid hormone, and 1,
25-(OH)2 vitamin D in the affected area school children
were significantly higher than the controls (Tables 2 and
3). There was a significant reduction (p < 0.001) in GFR
in the affected area school children (30 units less) than the
control (Table 2). In both the areas, serum 25-OH vitamin
D was lower than the normal range. Serum TSH levels in
the affected area school children were significantly lower
than the control area children (p < 0.02). There was no
significant difference in serum T3 (p = 0.9731) and
thyroxine (T4) level (p = 0.103) in control and affected
school children (Table 4).
Discussion
According to the prevalence and severity of fluorosis
based on the CFI levels (> 0.6), fluorosis is considered
to be a public health problem in affected villages (Arnora,
Ghat, Malvas, and Golibagh) of Doda district (Table 1).
An average of 77% prevalence of dental fluorosis was
observed among the children where the fluoride level
was 2 to 4 ppm in affected villages. As per the regression
analysis, an increase of 1 mg/L fluoride level in drinking
water consequently increases the fluoride exposure dose
at about 0.1 mg/kg/d which elevates the extent of prev-
alence of fluorosis about 31% among the children in
study areas of Doda district (Fig. 2a–d). However, the
fluoride level in drinking water of Doda town was less
than the permissible limit (< 1.5 mg/L); however, there
was a considerable prevalence of fluorosis (29%) and this
Page 5 of 8 579
Serum creatinine GFR CKD* stage
(mg/dL) (mL/min/1.73m2)
0.45 ± 0.16 120.9 ± 27.4 Normal
0.85 ± 0.35† 84.1 ± 33.1† Stage 2
0.5–1.2 ≥ 90 Normal
may be due to black tea consumption, known to contrib-
ute fluoride (Waugh et al. 2016). The extent of preva-
lence of fluorosis in Doda district (high altitude) was
considerably higher when it was compared with the plain
areas with similar drinking water fluoride levels which
was also reported elsewhere (Hou et al. 2014; Kececi
et al. 2014).This may be due to the alteration in acid-base
balance caused by hypobaric hypoxia among the resi-
dents in high-altitude areas, which increase the retention
of fluoride in body due to lesser excretion through urine
which enhances the risk of fluorosis which was also
reported by Whitford (1999).
In the present study, we found there was no much
difference in BMI of the school children from control
and affected areas. However, the reports available in the
literature contradict with each other. A positive correla-
tion was observed between BMI and drinking water
fluoride levels (Das and Mondal 2016). In another study
conducted in Delhi, India, found there was no signifi-
cant association of disease with gender, source of drink-
ing water, and with BMI (Tiwari et al. 2010).
In the present study, UF levels of affected children
was 3.28 ± 1.71 mg/L, whereas water fluoride level
ranged from 1.5 to 4.0 mg/L was comparable with the
previous studies conducted by Ding et al. (2011). Kid-
ney is a site of active excretion and excretes 50–80% of
fluoride from all sources of exposure (Spencer et al.
1969). High UF in the affected group of children reflects
high exposure of fluoride (drinking water and tea). In
other Indian studies, of aged 6 to 18 years, the highest
UF concentration reported was 17 mg/L when fluoride
water concentration was of 2.11 mg/L (Das and Mondal
2016) whereas in other study, individuals aged 11–
16 years, an average UF was 2.35 mg/L (Singh et al.
2007). These variations might be due to different use
and consumption practices of water and other sources of
fluoride like tea and black salt among populations.
579 Page 6 of 8
Table 3 Levels of alkaline phosphatase, osteocalcin, PTH, 25-(OH)-vitamin D, and 1, 25 (OH)2 vitamin D in serum of control and affected
group of children (values represent mean±standard deviation)
Group Osteocalcin Parathyroid hormone (PTH) Alkaline phosphatase 25-(OH) vitamin D (ng/mL) 1, 25-(OH)2 vitamin D
(ng/mL) (pg/mL) (IU/L)
Control 14.7 ± 3.3 27 ± 5 266 ± 70
Affected 31.3 ± 13.2* 49 ± 12* 401 ± 125*
Normal range 9.0–42.0 13–54 98–279
*Statistically significant (p < 0.05)
Previous studies demonstrated that the intake of ex-
cess fluoride can enhance the occurrence of renal failure
by damaging tubular epithelial cells in the kidney lead-
ing to chronic kidney diseases (Juncos and Donadio
1972; Ludlow et al. 2007; Xiong et al. 2007). In the
present study, a significant increase in serum creatinine
due to a considerable reduction in GFR in affected
children indicates damage of the kidney. According to
the GFR level (< 90 mL/min/1.73m2) estimated among
the affected children indicated that they are in the
second-stage chronic kidney diseases. This may be due
to higher altitude, heat stress, and contaminated water in
the area which has been reported in earlier studies
(Lunyera et al. 2016). The impaired kidney function
further enhances the retention of fluoride in the body
and increases the risk of fluorosis which correlates with
earlier study (Xiong et al. 2007).
It is known that the excess fluoride in drinking water
elevates serum alkaline phosphatase and osteocalcin, in
turn, increases osteoblastic activity and bone formation
in children in high-fluoride endemic areas (Johnson
et al. 1979; Khandare et al. 2005; Ross and Knowlton
1998). The same was observed in the present study in
the affected area children indicating the enhanced oste-
oblastic activity which may increase fracture risk.
Earlier study has demonstrated elevated levels of
PTH (Khandare et al. 2005) in the fluoride endemic
areas, the same holds good in the present study also.
Table 4 Levels of thyroxine (T4) and triiodothyronine (T3), thyroid-stimulating hormone (TSH) in serum of control and affected group of
children (values represent mean±standard deviation)
Group Thyroxine
(T4) (μg/dL)
Control 16.9 ± 1.6
Affected 16.1 ± 2.9
Normal range 6.1–11.8
*Statistically significant (p < 0.05)
Environ Monit Assess (2017) 189: 579
(pg/mL)
13.0 ± 7.6 98.8 ± 38.1
9.8 ± 5.9 146.2 ± 38.8*
30–74 24–86
The increase in PTH may be due to maintain the calcium
(Ca) homeostasis in blood (Gupta et al. 2001). In India,
Ca deficiency is rampant irrespective of fluorotic or
non-fluorotic areas. In fluorotic area, there is an addi-
tional demand of Ca because of false bone formation
which also shows increase in alkaline phosphatase and
osteocalcin in the present study. To increase the absorp-
tion of Ca at the intestine, the conversion of 25-hydroxy
vitamin D to 1,25-dihydroxy vitamin D was increased
(Shankar et al. 2013). In addition, lesser exposure to
sunlight at high-altitude areas may create the deficiency
of vitamin D level (25-hydroxy vitamin D) (Dusso et al.
2011); however, the same was not seen in the present
study. The increased 1,25-dihydroxy vitamin D in the
present study might be to maintain the Ca homeostasis.
Excess F exposure in the high-altitude area children
(commonly deficient of iodine) elevates the risk of hypo-
function of thyroid glands (Mordes et al. 1983; Rastogi
et al. 1977). The significantly decreased levels of TSH in
the affected children may be due to the excess F intake.
The excess F intake which competitively affects the
iodine absorption might have inhibited its activities in
thyroid glands to release TSH. Additionally, the excess F
affects the catabolism (deiodination process) of conver-
sion from T4 to T3, leads to a deficiency in T3 (the active
form of thyroid hormone) (Singh et al. 2014). In the
present study, the deiodination of T4 to T3 might have
been inhibited by F which is indicated by the low levels
Triiodothyronine (T3) Thyroid-stimulating
(ng/mL) hormone (TSH) (mU/L)
0.68 ± 0.35 3.4 ± 0.5
0.63 ± 0.24 2.9 ± 0.6*
0.8–2.0 0.3–4.0
Environ Monit Assess (2017) 189: 579
of T3 in affected area children compared to control.
These thyroid hormone disturbances among the
fluorosis-affected children show the vulnerability to thy-
roid hormone deficiency created health risks such as low
IQ, deaf-mutism, and cretinism in children have been
reported earlier (Saxena et al. 2012; Susheela et al. 2005).
Conclusion
Increase in water fluoride levels in study areas en-
hances the fluoride exposure dose, prevalence of
fluorosis, CFI, urinary F, alkaline phosphatase,
osteocalcin, PTH, and TSH. There was no signifi-
cant difference in nutrition status from control and
affected children; however, significant increase in
serum creatinine was observed and may be due to
a considerable reduction in GFR in affected children
indicating partial damage of the kidney. The in-
crease in PTH and 1,25-(OH)2 vitamin D shows
Ca deficiency in affected area than the controls.
The fluoride altered thyroid hormone levels in the
affected area children compared to controls. To pro-
tect the health of the young children in affected hilly
areas of Doda district, the immediate intervention
with safe drinking water supply is advised.
Acknowledgements The authors thank the BIndian Council of
Medical Research^ for funding the study. The authors also ac-
knowledge the encouragement and guidance of the director-in-
charge, National Institute of Nutrition.
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