194 Research review Combined toxicity of fluoride and cadmium 194

Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek

July-September 2016

COMBINED TOXICITY OF FLUORIDE AND CADMIUM

Tomasz Olszowski,a Maciej Sikora,b,c Dariusz Chlubekc
Szczecin and Kielce, Poland

ABSTRACT: Fluoride (F-)

and cadmium (Cd) are toxicants found ubiquitously in the
human environment. The aim of this review was to identify and characterize studies
that attempted to determine the combined toxicity of F- and Cd. The effects of F- and
Cd on liver and kidney (with a special focus on chronic kidney disease of unknown
etiology), bone, tooth enamel, dental caries, and brain were taken into consideration.
Based on the results of the studies described in this review, various types of
combined toxicity of F- and Cd might occur: additive, synergistic, or antagonistic,
with the latter two being true interactions. However, the type of combined action
occurring seems to depend on many factors, such as which toxic effect is
considered, the dose levels of F- and Cd and their dose ratio, exposure duration,
presence of other elements, etc. Moreover, when analyzing the combined toxic
effects of F- and Cd, the possible interactions of these toxicants with other elements
(e.g., fluoride with aluminum and arsenic; cadmium with lead, arsenic, zinc,
selenium, and calcium) should also be taken into consideration. We also may not
exclude the independent action of F- and Cd on some selected functions/health
outcomes. Due to the huge gaps in knowledge, additional studies are required to
address this important public health issue, i.e., the combined effects of exposure to
these common environmental toxicants, especially among people with high
exposure to these elements.

Keywords: Cadmium; Fluoride; Toxicity.

INTRODUCTION
Fluoride (F-) and cadmium (Cd) are toxicants found ubiquitously in human
environment. The main sources of exposure to Cd include ingestion of food,
inhalation of ambient air, ingestion of drinking water, and tobacco smoking,1
while for F- they are ingestion of drinking water and non-dairy beverages,
consumption of some foodstuffs, the use of F-containing dental products
(including toothpastes), and inhalation of indoor air.2
Cd and F- coexist in the environment. For example, F- and Cd co-occur in
drinking water.3-5 Mullenix demonstrated that Cd is found as an contaminant of
some F- additives used for drinking water fluoridation,4 such as hydrofluorosilicic
acid. However, the Cd concentration was below the established method detection
limit (MDL) in 2325% of raw samples of the additives and it remained
insignificant.4 Similarly, according to the NSF Fact Sheet on Fluoridation
Products (2013) none of 216 samples from 20072011 had detectable levels of Cd
as compared to 1% of samples from 20002006 with detectable Cd levels.6 The
majority of fluoridation products do not contribute measurable amounts of Cd to
the drinking water.6

aDepartment
of Hygiene and Epidemiology, Pomeranian Medical University, Szczecin, Poland;
bDepartment
of Maxillofacial Surgery, Hospital of the Ministry of Interior, Kielce, Poland;
cDepartment of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin,

Poland. For correspondence: D Chlubek, Department of Biochemistry and Medical Chemistry,

Pomeranian Medical University, Szczecin, Poland; e-mail: dchlubek@pum.edu.pl
195 Research review Combined toxicity of fluoride and cadmium 195
Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek
July-September 2016

Fluoride and cadmium have some features in common, i.e., a broad distribution
in the environment, similar sources of exposure, a long half-life in the human
organism, a high level of toxicity to humans, similar target organs for their
toxicities (e.g., liver, kidney, and brain), and similar clinical symptoms in the teeth
and bones of people intoxicated.1,2,7-10
Various types of combined toxic action of metal compounds can be identified:
independent action, additivity, synergism, potentiation, and antagonism.11 A
number of reviews have been published that dealt with the toxicity of Cd 7,12-17
and/or the toxicity of F-.8,9,12,13,17,18 However, to our knowledge, there is no
review dedicated solely to the effects of the combined action of these elements.
Therefore, the aim of this review was to identify and characterize studies that
attempted to determine the combined toxicity of F- and Cd, including interactions
between them. The following aspects will be reviewed: the effects of F- and Cd on
liver and kidney (with a special focus on chronic kidney disease of unknown
etiology), bone, tooth enamel, dental caries, and the brain and cognitive functions.
HEPATIC AND RENAL EFFECTS
Zhang et al. examined the chronic effects of Cd and F- on liver and kidney
function in male rats.19 Animals were exposed to Cd in a dose of 50 mg/L or F- in
a dose of 100 mg/L or to a combination of both elements in drinking water for 12
weeks. The following parameters were assessed: serum alanine aminotransferase
(ALT) and aspartate aminotransferase (AST) activities (a measure of liver
function), 2-microglobulin and albumin in urine (a measure of kidney injury),
and superoxide dismutase (SOD) activity and malondialdehyde (MDA) level in
kidney and liver (a measure of oxidative stress). Significantly higher serum ALT
activity was found in the group of rats treated with either F- or Cd as compared to
the control. The effect of co-exposure to F- and Cd on ALT activity appeared to be
synergistic.19 Urinary 2-microglobulin levels were significantly higher in the F-
group and in the Cd group compared to the control group. The combined action of
Cd and F- resulted in a significantly higher 2-microglobulin content in the
combination group as compared to the either F- or the Cd groups.19 Exposure to
either F- or Cd caused significantly decreased SOD activities and significantly
increased MDA levels in both the kidney and liver of the rats as compared to the
control group. Combined exposure to Cd and F- resulted in significantly lower
SOD activities and significantly higher MDA content in the kidney and liver as
compared to the control, F-, and Cd groups.19 Based on these results and
histological analyses, the authors came to the conclusion that combined exposure
to Cd and F- caused more severe liver and kidney damage as compared to Cd or F-
exposure alone.19
In another study, Adachi et al. examined the acute toxicity of cadmium fluoride
(CdF2) after intravenous administration in rats.20 In the mentioned study, the
following parameters were assessed: serum hepatic enzyme activities, serum
glucose concentration, blood urea nitrogen (BUN) and creatinine concentration,
serum electrolyte levels such as potassium, calcium and phosphates, and urine
volume.20 The authors demonstrated that CdF2 in a dose of 2.67 mg/kg body
196 Research review Combined toxicity of fluoride and cadmium 196
Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek
July-September 2016

weight (bw) and 4.01 mg/kg bw caused severe hepatic damage as confirmed by
significantly increased activities of AST and ALT and decreased serum glucose
concentration compared to the saline group.20 CdF2 administration resulted also in
renal injury as confirmed by increased BUN and decreased urine volume
compared to the saline group. However, the acute renal failure due to CdF2
exposure was unlikely to result from the effects of F-, because the BUN and urine
volume in the NaF group and in the saline group did not differ significantly. CdF2
exposure caused also abnormal changes in the serum electrolytes, which was
probably the effect of ionized F.20 In the conclusion of their study, Adachi et al. are
of the opinion that CdF2 has the strongest lethal and hepatic toxicity among all Cd-
containing compounds.20
Another issue worth discussing is the potential role of Cd and F- exposure in
drinking water in causation of chronic kidney disease of unknown etiology
(CKDu).5,21-24 Wasana et al. demonstrated a strong positive correlation between
the presence of F-, Cd, and water hardness in drinking water and the prevalence of
CKDu in Sri Lanka, indicating the synergistic effect of these factors for the
etiology of the disease.5 The other studies gave divergent results. Jayatilake et al.
conducted a cross-sectional study to determine the prevalence of CKDu and the
risk factors for that disease.22 Based on the obtained results, i.e., significantly
higher urinary excretion of Cd in CKDu patients and the dose-effect relationship
between Cd level in urine and CKDu stages, the authors suggested that exposure
to Cd was a risk factor for the pathogenesis of CKDu.22 However, Chandrajith et
al. exclude Cd as a contributing factor to CKDu and show that no single
geochemical parameter could be clearly and directly related to CKDu in Sri Lanka.
The authors suggest that a unique hydrogeochemistry of drinking water might be
closely associated with the incidence of disease.21 Rango et al. suggest the
presence of non-water sources of toxic chemicals such as Cd, As, Pb, and U in the
region from food and other sources (for example tobacco consumption).23
Wanigasuriga, in a review article, concludes that the etiology of CKDu in Sri
Lanka is multifactorial, with one or more environmental agents being involved in
addition to genetic predisposition.24
BONE AND DENTAL EFFECTS
As regards the effects of F- and Cd in combination on bone, only one study can
be identified in literature so far,25 although the influence of either Cd or F- alone
on bone was discussed in other studies.10,12,13,17,26-29
Tang et al. conducted a pilot study in a fluorotic rural area of China and
demonstrated that naturally occurring Cd in areas with endemic fluorosis
associated with coal combustion acts as a critical but hidden health hazard that
may underlie the risk of F-.10 Since the symptoms of either F- or Cd intoxication
are similar in bone and teeth, the occurrence of dental and skeletal health problems
in the population from the study area has been explained entirely by fluorosis,
without taking into consideration the contribution of Cd.10 For example, half of
the urine samples of local residents from the study area had F- levels within the
197 Research review Combined toxicity of fluoride and cadmium 197
Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek
July-September 2016

normal range for a non-exposed population, whereas all the urine samples had Cd
levels higher than in the control and non-exposed population.10
Chen et al. examined the effects of subchronic (12 weeks) exposure to F- in a
dose of 20 mg/L, Cd in a dose of 50 mg/L, or their combination via drinking water
on bone in male rats.25 The authors suggested that F- might influence the Cd
absorption in the gut, since the blood Cd level of rats treated with F- and Cd in
combination was higher than in rats treated with Cd only. The vertebral bone
mineral density (BMD) of rats exposed to Cd decreased significantly (by about
9%) compared to the control. The BMD in rats exposed to F- increased
insignificantly (3%) relative to control. However, the BMD of rats co-exposed to
both F- and Cd was significantly higher as compared to rats exposed to Cd only.25
Based on the results presented above, one can suggest that there is an antagonistic
interaction between Cd and F- in their effects on BMD. The authors conclude that
F- could reverse the decrease of vertebral BMD caused by Cd.25
Chen et al. also assessed the mechanical property of the femur, i.e., bending
strength, bending load, and elastic modulus. Exposure to F- and Cd, either alone or
in combination, resulted in a worsening of all the analyzed parameters relative to
the control. The combined exposure to F- and Cd slightly decreased the bending
strength and elastic modulus of femur compared to rats exposed to Cd alone.25
The serum levels of tartrate-resistant acid phosphatase 5b (Tracp-5b), measured by
the enzyme immunoassay method, in rats exposed to Cd and F- or their
combination, were significantly higher than in the control group. The Tracp-5b
level in the Cd+F- group was higher than in the F- or Cd groups, indicating
excessive osteoclast formation and bone resorption.25 One can speculate on the
occurrence of an additive effect of Cd and F- on serum Tracp-5b levels.
Exposure to F- and Cd is one of the environmental risk factors for osteoporosis
and osteomalacia.9,12,28,29 Kakei et al. examined the effect of Cd ions on crystal
formation in developing rat tooth enamel.28 Three-week-old male rats were
exposed to Cd in a dose of 100 mg/L via drinking water for 5 weeks. Since the
basic mechanism of crystal formation is the same in enamel, dentin, and bone, the
results can be extrapolated to bone.28 The authors demonstrated Cd-induced
perforations in the developing tooth enamel and concluded that Cd inhibited the
crystal nucleation process.28 Moreover, the authors found that the catalytic activity
of carbonic anhydrase, a critical enzyme in the initiation of the crystal nucleation
process, in the Cd-exposed rats declined significantly to 30% of that in the control
rats.28 Kakei et al. concluded that impaired mineralization may be one of the
causal factors of osteoporosis.28
In another study, Kakei et al. investigated the effects of F ions on crystal
formation in rat hard tissues.26 Similarly to Cd, F ions were found to interrupt the
crystal nucleation process.26 Fluoride, even at low concentrations, interfered with
the synthesis of carbonic anhydrase, thus indirectly affecting crystal formation.26
Kakei et al. suggested that F- intake has harmful effects on both tooth and bone
formation,26 and questioned the use of F- in the treatment of osteoporosis, since
exposure to F- might accelerate osteoporotic changes in postmenopausal women.29
198 Research review Combined toxicity of fluoride and cadmium 198
Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek
July-September 2016

Kakei et al. also compared the harmfulness of F- and Cd on the crystal

nucleation process of developing rat tooth enamel.27 Rats received water
containing either F- (2 mg/L) or Cd (20, 40, and 100 mg/L). The authors
demonstrated similar harmfulness of 2 mg/L F- and 40 mg/L Cd on the crystal
nucleation process, suggesting that F- harmfulness to hard tissue formation was 20
times greater than that of Cd.27 However, it is worth noting the other studies
indicating that F-, apart from some toxic effects at high doses, might be beneficial
for bone (or hard tissues) at low doses.12,13 Taking into consideration the results of
the studies discussed in this review, we speculate that the combined toxic action of
F- and Cd, in terms of bone and tooth formation, might be additive, especially at
higher doses of these agents.
EFFECTS ON DENTAL CARIES
Another aspect of a possible interaction between F- and Cd could be their effect
on dental caries. In 1980, Shearer et al. investigated the effect of Cd on caries and
the cariostatic properties of F- in rats.30 In the first experiment, the following doses
of Cd (as cadmium chloride) were administered to rats at their tooth
developmental period: 0.25, 0.50, and 0.75 mg Cd/kg bw.30 The experiment
demonstrated the caries-promoting effect of Cd in female rats: the number of
carious lesions was proportional to the Cd dose.30 In the second experiment, the
effects of developmental Cd on the cariostatic properties of post-developmental F-
(15 mg F-/L added to drinking water of pups after weaning) were examined.30 For
the first time, the interaction between Cd and F- on the caries scores was shown:
Cd exposure during tooth development caused partial negation of caries
prevention by F- in both male and female rats, i.e., enamel caries scores in the F-
+0.50 mg Cd/kg bw group and buccal and enamel caries scores in the F-+0.75 mg
Cd/kg bw group were significantly higher as compared to the F- groups.30 Based
on the results obtained, one can suggest that the effect of Cd and F- on caries
scores involves the occurrence of an antagonistic interaction between Cd and F-.
In another study, Shearer et al. investigated the effects of post-developmental
exposure to Cd on caries and the cariostatic properties of F- in rats.31 In one of the
experiments, the authors demonstrated the lack of a significant influence of post-
developmental Cd (30 and 50 mg/L in drinking water) on the number of carious
lesions in male rats.31 The addition of 30 or 50 mg Cd/L to fluoridated (10 mg F-/
L) drinking water did not alter significantly the cariostatic properties of F-.31
Based on the results of two studies by Shearer et al.,30,31 the authors suggested that
exposure to Cd during the period of tooth development is critical for caries
promotion by Cd.31
In turn, in a cross-sectional study carried out among US children aged 612 yr,
Arora et al. examined the association of environmental Cd exposure with dental
caries.32 The authors found that such an exposure was significantly associated
with caries scores in the deciduous teeth of children with low environmental
tobacco smoke (ETS) exposure.32 An interquartile range (IQR) increase in
creatinine-corrected Cd concentrations (0.21 g/g creatinine) corresponded to a
30% increase in the odds of having experienced caries (prevalence odds ratio (OR)
199 Research review Combined toxicity of fluoride and cadmium 199
Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek
July-September 2016

= 1.30; 95% CI, 1.011.67). The authors of that study were concerned that the
consumption of fluoridated water might be the confounding factor for the
observed association.32 However, based on sensitivity analyses, it appeared
unlikely that the differences in water fluoridation could explain the observed
association between Cd exposure and dental caries experience.32
NEUROTOXIC EFFECTS
Another problem of F- and Cd toxicity of particular concern, might be their
potential combined neurotoxic effects. Cd and F- were found to be neurotoxic.7-
9,14-16,18,33-39
Since these two toxicants might reach the fetus/infant/child via
different routes (mothers milk, maternal blood or drinking water, and food and air
later in life), and no barrier (such as the placenta, mammary gland, or blood-brain
barrier) offers complete protection from their exposure, they may accumulate in
brain resulting in neurotoxic effects.9,14 Unfortunately, to our knowledge, none of
studies examined the combined neurotoxic effects of Cd and F-. We were able to
identify only studies that concentrated on either the neurotoxic effects of cadmium
7,14-16,33,35,36,38,39
or the neurotoxic effects of fluoride. 8,9,18,37
A very important issue is the suspected developmental neurotoxicity of Cd and
- 15,18,34,36,37
F. Choi et al. conducted a systematic review and meta-analysis of
published studies to assess the effect of exposure to F- on childrens
neurodevelopment.18 The authors included 27 eligible epidemiological studies in
their meta-analysis. They found the standardized weighted mean difference in IQ
scores between the exposed and the reference populations of children, across
studies that gave the average difference in standard deviations (SDs), was 0.45
SDs (95% CI: 0.56, 0.35) using a random-effects model, which means that
children living in areas with a high F- exposure had significantly lower IQ scores
as compared to children living in low-F- areas.18,40 For commonly used IQ scores
with a mean of 100 and a SD of 15, 0.45 SDs is equivalent to 6.75 points (rounded
to 7 points).40 The results therefore showed an average IQ decrement of about 7
points in children with increased F- exposure40 and point to the possibility of
adverse effects of F- exposure on childrens neurodevelopment.18 Such result also
raises questions about the legitimacy and safety of drinking water fluoridation in
some areas of the world.
Rodriguez-Barranco et al. conducted a systematic review and meta-analysis to
evaluate the association of exposure to Cd with neurodevelopment and behavioral
disorders in children.15 Of the six studies that met the authors inclusion criteria,
only two found such association.15,33,39 However, these studies were of high
methodological quality.33,39 Tian et al. in a prospective cohort study demonstrated
a lower full-score IQ and performance IQ at 4 years of age in children who had
higher concentrations of Cd in the cord blood at birth.39 Bao et al. in a cross-
sectional study found that higher Cd levels in the hair of children, aged 716 years,
were associated with a higher frequency of withdrawal, social problems, and
attention problems.33
Some authors link exposure to multiple environmental factors, including Cd and/
or F-, with learning-memory ability depression,35,41 autism,34,38 cognitive
200 Research review Combined toxicity of fluoride and cadmium 200
Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek
July-September 2016

impairment, 3,16 and neurodegenerative diseases such as Alzheimers disease and

Parkinsons disease.42
Ciesielski et al. assessed the association between urinary Cd concentrations
among US children, aged 615 years, and reported learning disability.35 The
authors found a significantly higher odds ratio for learning disability for children
in the highest quartile of urinary Cd compared with those in the lowest quartile
(OR=3.21, 95% CI: 1.43, 7.17), suggesting that children with higher urinary Cd
levels may have an increased risk of learning disability.35 Kaoud and Kalifa
examined the effects of exposure to F (100 mg NaF/L), Cd (100 mg CdCl2/L), and
arsenic (50 mg As2O3/L) in drinking water on the learning-memory ability in
rats.41 The authors demonstrated that the learning-memory ability of rats treated
with either fluoride, cadmium, or arsenic was depressed as compared to the control
group.41
Blaylock focuses in his review article on the role of excitotoxic food additives
and suggests that they have synergistic effects with other environmental toxins
(such as fluoride, lead, cadmium, and aluminum) on the pathological and
biochemical changes characteristic of autism spectrum disorders (ASD).34 Roberts
et al. examined the hypothesis that perinatal exposure to air pollutants is associated
with ASD in the children of the participants of the Nurses Health Study II.38 They
found that perinatal exposure to the highest versus the lowest quintile of Cd was
significantly associated with ASD (OR=1.5).38 The authors of the cited study
concluded that perinatal exposure to such air pollutants as diesel, lead, manganese,
and cadmium may increase the risk of ASD.38
Sanders et al. performed a literature search for epidemiological studies
(published between 2009 and 2015) examining the association of prenatal and
childhood metal exposures (mainly cadmium or manganese) and metal mixtures
with childrens cognitive outcomes.16 The authors suggest that prenatal/childhood
Cd exposure may be associated with poorer cognition but also emphasize the need
for further studies.16 Emsley et al. evaluated the association of concentrations of
several elements (cadmium, fluoride, calcium, iron, lead, selenium, and zinc) in
drinking water with cognitive function among elderly residents (n=1016) in rural
China.3 Fluoride showed a significant positive linear relation with cognitive
function (p=0.02). However, the effect of F- appeared to be insignificant after the
adjustment for the other analyzed elements. Cd appeared not to exert a significant
effect on cognitive function in univariate analysis, but the results from the mixed
effects models demonstrated that the interaction between Cd and zinc on cognitive
function was significant, even after the adjustment for the elements that were
correlated with zinc.3
CONCLUSION
To sum up, based on the results of the studies described in this review, various
types of combined toxicity of Cd and F- might occur: additive, synergistic, or
antagonistic, with the latter two being true interactions. Such effects relate to the
liver, kidney function (including CKDu), bones, teeth (including dental caries),
and the brain. However, the type of combined action occurring seems to depend on
201 Research review Combined toxicity of fluoride and cadmium 201
Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek
July-September 2016

many factors, such as which toxic effect is considered, the dose levels of Cd and F-
and their dose ratio, exposure duration, and the presence of other elements, etc. 43
Moreover, when analyzing the combined toxic effects of F- and Cd, the possible
interactions of these toxicants with other elements (e.g., F- with aluminum and
arsenic, Cd with lead, arsenic, zinc, selenium, and calcium) should also be taken
into consideration.3,43-49 In addition, we may not exclude the independent action
of F- and Cd on some selected functions/health outcomes. Due to the huge gaps in
our knowledge, additional studies are required to address this important public
health issue, i.e., the combined effects of exposure to these common
environmental toxicants, especially among people with a high exposure to them.
REFERENCES
1 IARC. Cadmium and cadmium compounds. IARC Monographs on the evaluation of
carcinogenic risks to humans 2012, 100C. Available from: http://monographs. iarc.fr/ENG/
Monographs/vol100C/mono100C-8.pdf
2 Liteplo R, Gomes R, Howe P, Malcolm H. Environmental health criteria 227. Fluorides.
Geneva: WHO; 2002. Available from: http://apps.who.int/iris/bitstream/10665/ 42415/1/
WHO_EHC_227.pdf
3 Emsley CL, Gao S, Li Y, Liang C, Ji R, Hall KS, et al. Trace element levels in drinking water
and cognitive function among elderly Chinese. Am J Epidemiol 2000;151(9):913-20.
4 Mullenix PJ. A new perspective on metals and other contaminants in fluoridation chemicals.
Int J Occup Environ Health 2014; 20(2):157-66.
5 Wasana HM, Aluthpatabendi D, Kularatne WM, Wijekoon P, Weerasooriya R, Bandara J.
Drinking water quality and chronic kidney disease of unknown etiology (CKDu): synergic
effects of fluoride, cadmium and hardness of water. Environ Geochem Health
2016;38(1):157-68.
6 National Sanitation Foundation. NSF Fact Sheet on Fluoridation Products 2013. Available
from: http://www.nsf.org/newsroom_pdf/NSF_Fact_Sheet_on_Fluoridation.pdf
7 Bernhoft RA. Cadmium toxicity and treatment. Scientific World Journal 2013 Jun
3;2013:394652. doi:10.1155/2013/394652.
8 Ghosh A, Mukherjee K, Ghosh SK, Saha B. Sources and toxicity of fluoride in the
environment. Res Chem Intermed 2013;39:2881-915.
9 Perumal E, Paul V, Govindarajan V, Panneerselvam L. A brief review on experimental
fluorosis.Toxicol Lett 2013;223(2):236-51.
10 Tang J, Xiao T, Wang S, Lei J, Zhang M, Gong Y, et al. High cadmium concentrations in
areas with endemic fluorosis: a serious hidden toxin? Chemosphere 2009;76(3):300-5.
11 Nordberg GF, Gerhardsson L, Mumtaz M, Ruiz P, Fowler BA. Interactions and mixtures in
metal toxicology. In: Nordberg GF, Fowler BA, Nordberg M, editors. Handbook on the
toxicology of metals. 4th ed. Vol I: General considerations. Amsterdam: Academic Press as
an imprint of Elsevier; 2015. pp. 213-38.
12 Aaseth J, Boivin G, Andersen O. Osteoporosis and trace elements: an overview. J Trace
Elem Med Biol 2012;26(2-3):149-52.
13 Dermience M, Lognay G, Mathieu F, Goyens P. Effects of thirty elements on bone
metabolism. J Trace Elem Med Biol 2015;32:86-106.
14 Mndez-Armenta M, Ros C. Cadmium neurotoxicity. Environ Toxicol Pharmacol
2007;23(3):350-8.
202 Research review Combined toxicity of fluoride and cadmium 202
Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek
July-September 2016

15 Rodrguez-Barranco M, Lacasaa M, Aguilar-Garduo C, Alguacil J, Gil F, Gonzlez-

Alzaga B, Rojas-Garca A. Association of arsenic, cadmium and manganese exposure with
neurodevelopment and behavioral disorders in children: a systematic review and meta-
analysis. Sci Total Environ 2013;454-455:562-77.
16 Sanders AP, Claus Henn B, Wright RO. Perinatal and childhood exposure to cadmium,
manganese, and metal mixtures and effects on cognition and behavior: a review of recent
literature. Curr Environ Health Rep 2015; 2 (3): 284-94.
17 Zofkov I, Nemcikova P, Matucha P. Trace elements and bone health. Clin Chem Lab Med
2013; 51(8):1555-61.
18 Choi AL, Sun G, Zhang Y, Grandjean P. Developmental fluoride neurotoxicity: a systematic
review and meta-analysis. Environ Health Perspect 2012;120 (10):1362-8.
19 Zhang J, Song J, Zhang J, Chen X, Zhou M, Cheng G, Xie X. Combined effects of fluoride
and cadmium on liver and kidney function in male rats. Biol Trace Elem Res 2013;
155(3):396-402.
20 Adachi K, Dote T, Dote E, Mitsui G, Kono K. Strong acute toxicity, severe hepatic damage,
renal injury and abnormal serum electrolytes after intravenous administration of cadmium
fluoride in rats. J Occup Health 2007;49(3):235-41.
21 Chandrajith R, Nanayakkara S, Itai K, Aturaliya TN, Dissanayake CB, Abeysekera T, et al.
Chronic kidney diseases of uncertain etiology (CKDue) in Sri Lanka: geographic distribution
and environmental implications. Environ Geochem Health 2011;33(3):267-78.
22 Jayatilake N, Mendis S, Maheepala P, Mehta FR, CKDu National Research Project Team.
Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a
developing country. BMC Nephrol 2013;14:180.
23 Rango T, Jeuland M, Manthrithilake H, McCornick P. Nephrotoxic contaminants in drinking
water and urine, and chronic kidney disease in rural Sri Lanka. Sci Total Environ 2015; 518-
519:574-85.
24 Wanigasuriya K. Update on uncertain etiology of chronic kidney disease in Sri Lanka's
north-central dry zone. MEDICC Rev 2014;16(2):61-5.
25 Chen X, Qin B, Li X, Jin T, Zhu G, Zhou W, Wang Z. Effects of fluoride and cadmium co-
exposure on bone in male rats. Biol Trace Elem Res 2013;154(3):396-402.
26 Kakei M, Sakae T, Yoshikawa M, Tamura N. Effect of fluoride ions on apatite crystal
formation in rat hard tissues. Ann Anat 2007;189(2):175-81.
27 Kakei M, Sakae T, Mishima H, Yoshikawa M.Comparison of harmfulness between fluoride
and cadmium ions on the crystal nucleation process. Bone 2009; 44 (Suppl 2):S414.
28 Kakei M, Sakae T, Yoshikawa M. Mechanism of cadmium induced crystal defects in
enveloping rat tooth enamel. Proc Jpn Acad Ser B Phys Biol Sci 2009;85(10):500-7.
29 Kakei M, Yoshikawa M, Mishima H. Fluoride exposure may accelerate the osteoporotic
change in postmenopausal women: animal model of fluoride-induced osteoporosis. Adv
Tech Biol Med 2016;4:170.
30 Shearer TR, Britton JL, DeSart DJ, Johnson JR. Influence of cadmium on caries and the
cariostatic properties of fluoride in rats. Arch Environ Health 1980;35(3):176-80.
31 Shearer TR, Britton JL, DeSart DJ. Influence of post-developmental cadmium on caries and
cariostasis by fluoride. Environ Health Perspect 1980; 34:219-32.
32 Arora M, Weuve J, Schwartz J, Wright RO. Association of environmental cadmium
exposure with pediatric dental caries. Environ Health Perspect 2008;116(6):821-5.
203 Research review Combined toxicity of fluoride and cadmium 203
Fluoride 49(3 Pt 1):194-203 Olszowski, Sikora, Chlubek
July-September 2016

33 Bao QS, Lu CY, Song H, Wang M, Ling W, Chen WQ, et al. Behavioural development of
school-aged children who live around a multi-metal sulphide mine in Guangdong province,
China: a cross-sectional study. BMC Public Health 2009; 9:217.
34 Blaylock RL. A possible central mechanism in autism spectrum disorders, part 3: the role of
excitotoxin food additives and the synergistic effects of other environmental toxins. Altern
Ther Health Med 2009;15(2):56-60.
35 Ciesielski T, Weuve J, Bellinger DC, Schwartz J, Lanphear B, Wright RO. Cadmium
exposure and neurodevelopmental outcomes in U.S. children. Environ Health Perspect
2012;120(5):758-63.
36 Gorini F, Muratori F, Morales MA. The role of heavy metal pollution in neurobehavioral
disorders: a focus on autism. Rev J Autism Dev Disord 2014;1:354-72.
37 Grandjean P, Herz KT. Trace elements as paradigms of developmental neurotoxicants:
lead, methylmercury and arsenic. J Trace Elem Med Biol 2015;31:130-4.
38 Roberts AL, Lyall K, Hart JE, Laden F, Just AC, Bobb JF, et al. Perinatal air pollutant
exposures and autism spectrum disorder in the children of Nurses' Health Study II
participants. Environ Health Perspect 2013;121(8):978-84.
39 Tian LL, Zhao YC, Wang XC, Gu JL, Sun ZJ, Zhang YL, Wang JX. Effects of gestational
cadmium exposure on pregnancy outcome and development in the offspring at age 4.5
years. Biol Trace Elem Res 2009;132(1-3):51-9.
40 Choi AL, Zhang Y, Sun GF, Bellinger DC, Wang KL, Yang XJ, et al. Association of lifetime
exposure to fluoride and cognitive functions in Chinese children: a pilot study. Neurotoxicol
Teratol 2015;47:96-101.
41 Kaoud H, Kalifa B. Effect of fluoride, cadmium and arsenic intoxication on brain and
learningmemory ability in rats. Toxicol Lett 2010;196S:S53.
42 Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. Environmental pollutants as risk
factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell
Neurosci 2015;9:124.
43 Varaksin AN, Katsnelson BA, Panov VG, Privalova LI, Kireyeva EP, Valamina IE,
Beresneva OY. Some considerations concerning the theory of combined toxicity: a case
study of subchronic experimental intoxication with cadmium and lead. Food Chem Toxicol
2014;64:144-56.
44 Brzska MM, Moniuszko-Jakoniuk J. Interactions between cadmium and zinc in the
organism. Food Chem Toxicol 2001;39(10):967-80.
45 Chouhan S, Flora SJ. Arsenic and fluoride: two major ground water pollutants. Indian J Exp
Biol 2010;48(7):666-78.
46 Diacomanolis V, Noller BN, Ng JC. Bioavailability and pharmacokinetics of arsenic are
influenced by the presence of cadmium. Chemosphere 2014;112:203-9.
47 Goyer RA. Toxic and essential metal interactions. Annu Rev Nutr 1997;17:37-50.
48 Lubkowska A, yluk B, Chlubek D. Interactions between fluorine and aluminum. Fluoride
2002; 35(2):73-7.
49 Zwolak I, Zaporowska H. Selenium interactions and toxicity: a review. Selenium interactions
and toxicity. Cell Biol Toxicol 2012; 28(1):31-46.

Copyright 2016 The International Society for Fluoride Research Inc.

www.fluorideresearch.org www.fluorideresearch.com www.fluorideresearch.net
Editorial Office: 727 Brighton Road, Ocean View, Dunedin 9035, New Zealand