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= A clastogen is an agent that can cause one
of two types of structural changes. A clastogen can cause
breaks in chromosomes that result in the gain, loss, or
rearrangements of chromosomal segments. A clastogen can
also cause sister chromatid exchanges, which are "homologous
chromatid strand interchanges and reunions [that occur]
during DNA replication" (Thilly & Call, 1986, p. 181)
= of or relating to substances that are toxic to cells.
= Toxic to the fetus.
= Describes a poisonous substance which harms an organism
by damaging its DNA.
= capable of inducing mutation (used mainly of extracellular
factors such as X-rays or chemical pollution)
Sister chromatid exchange
(SCE) is a sophisticated cytomolecular
technique that is commonly applied in a search for clastogenicity
or genotoxicity. A clastogen is any environmental agent
that causes damage to genetic material and may include
carcinogens. An SCE analysis will tell us whether the
chromosomes and thus DNA of a particular interest group
has undergone some genetic damage compared to a control
Each chromosome comprises two sister chromatids
which are genetically identical. In the SCE technique,
one sister chromatid is stained dark and the other one
pale. In a normal healthy person it is not unusual for
the sister chromatids of one chromosome to break and swap
pieces with each other (see Figure below). This is called
sister chromatid exchange (SCE) and providing the number
of SCEs do not go beyond a certain threshold, this is
not considered to be harmful. Many studies have shown,
however, that any increase in frequency of SCEs beyond
the threshold indicates that something in that persons
existence is or has caused genetic damage, which can lead
to ill health. Many environmental agents, at home or at
work, can increase the number of SCEs, for example, UV
light, X-rays, nicotine and alcohol , to name a very limited
Note: The following is a limited selection of abstracts from 1994
Due to length, we present this as a separate section
• Click here to return to the same
section for fluorine & organofluorine pesticides.
When time allows more information will be added.
Effect of antioxidants, oxidants,
metals and saliva on cytotoxicity induction
by sodium fluoride.
T, Morshed SR, Otsuki S, Takayama F, Satoh T, Hashimoto K, Yasui
T, Ogawa S, Kanegae H, Yokote Y, Akahane K, Kashimata M, Satoh K,
Department of Dental Pharmacology, Meikai University School of Dentistry,
Sakado, Saitama, Japan.
have recently found that millimolar concentrations of sodium fluoride
(NaF) induced apoptotic cell death, characterized by caspase activation
and DNA fragmentation, in tumor cell lines.
This finding paved the way to investigating the interaction between
NaF and the oral environment. As an initial step, we investigated
redox compounds, metals and saliva, which may modify the cytotoxic
activity of NaF against a human oral squamous cell carcinoma cell
line (HSC-2). The minimum exposure time to NaF required for cytotoxicity
induction was 8 hours. Noncytotoxic concentrations of antioxidants
(sodium ascorbate, gallic acid, epigallocatechin gallate, chlorogenic
acid, curcumin, superoxide dismutase, catalase), oxidants (hydrogen
peroxide, sodium hypochlorite), metals (CuCl, CuCl2, FeCl2, FeCl3,
CoCl2) or saliva neither protected against, nor enhanced the cytotoxic
activity of NaF. Cytotoxic concentrations of these compounds produced
somewhat additive, but not synergistic, effects on the cytotoxicity
of NaF. ESR analysis demonstrated that NaF did not apparently change
the radical intensity of sodium ascorbate and gallic acid, measured
under alkaline conditions. During the cell death induction in human
promyelocytic leukemia HL-60 cells by NaF, the consumption of glucose
rapidly declined, followed by a decline in the consumption of major
amino acids. The present study suggests that
the cytotoxic activity of NaF is not regulated by the redox mechanism,
but rather linked to the rapid decline in glucose consumption at
PMID: 14666669 [PubMed - in process]
Zhonghua Yu Fang Yi Xue Za Zhi. 2002 Jul;36(4):222-4.
[Studies on DNA damage
and apoptosis in rat brain induced by fluoride]
[Article in Chinese]
Chen J, Chen X, Yang K, Xia T, Xie H.
Department of Environmental Health, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan 430030, China.
OBJECTIVE: To explore the DNA damage effects and apoptosis in brain
cells of rats induced by sodium fluoride.
METHODS: SD rats were divided into two groups, i.e. control group
and fluoride treated group, which were injected intraperitoneally
with distilled water and sodium fluoride (20 mg.kg(-1).d(-1)) respectively.
On the hand, 5 mmol/L NaF were used in in vitro study. Single Cell
Gel Electrophosis (SCGE or Comet Assay) was utilized to measured
DNA damage and apoptosis was detected by the TUNEL method and Flow
RESULTS: The DNA damage in pallium neurons
in rats of the fluoride group was much more serious compared with
those of the control group, with the Ridit value being 0.351
and 0.639 respectively (P < 0.01) in vivo, and 0.384 4 and 0.650
1 respectively (P < 0.01) in vitro. TUNEL
positive cells were found in pallium, hippocampus and cerebellar
granule cells in rats of fluoride group, whereas those in the control
group were rare. It was demonstrated by FCM results that the
percentages of apoptotic cells both in pallium and hippocampus were
significantly higher (P < 0.01) in rats of fluoride group (27.12
+/- 3.08, 34.97 +/- 5.46) than those in control group (4.63 +/-
0.98, 5.35 +/- 0.79), (P < 0.01).
CONCLUSION: Sodium fluoride could induce DNA
damage and apoptosis in rats brain.
PMID: 12411198 [PubMed - indexed for MEDLINE]
Epidemiol 2001 Jul;11(4):170-9.
analysis of cancer incidence rates and water fluoride in the U.S.A.
based on IACR/IARC (WHO) data (1978-1992). International Agency
for Research on Cancer
K, Akiniwa K, Narita K.
Age-specific and age-standardized rates (ASR) of registered cancers
for nine communities in the U.S.A. (21.8 million inhabitants, mainly
white) were obtained from IARC data (1978-82, 1983-87, 1988-92).
The percentage of people supplied with "optimally"
fluoridated drinking water (FD) obtained from the Fluoridation
Census 1985, U.S.A. were used for regression analysis of incidence
rates of cancers at thirty six sites (ICD-WHO, 1957). About two-thirds
of sites of the body (ICD) were associated positively with FD, but
negative associations were noted for lip cancer, melanoma of the
skin, and cancers of the prostate and thyroid gland. In digestive
organs the stomach showed only limited and small intestine
no significant link. However, cancers of the
oral cavity and pharynx, colon and rectum, hepato-biliary and urinary
organs were positively associated with FD. This was also
the case for bone cancers in male,
in line with results of rat experiments. Brain
tumors and T-cell system Hodgkin's disease, Non-Hodgkin lymphoma,
multiple myeloma, melanoma of the skin and monocytic leukaemia were
also correlated with FD. Of the 36 sites, 23 were positively
significant (63.9%), 9 not significant (25.0%) and 4 negatively
significant (11.1%). This may indicate a complexity of mechanisms
of action of fluoride in the body, especially in view of the coexising
positive and negative correlations with the fluoridation index.
The likelihood of fluoride acting as a genetic cause of cancer requires
[PubMed - indexed for MEDLINE]
chromatid exchange frequency and chromosome aberrations
in residents of fluoride endemic regions of south Gujarat
Joseph, PK Gadhia (a)
(a) For Correspondence:
Department of Biosciences, South Gujarat University Surat 395 007,
Gujarat, India. E-mail: email@example.com
Peripheral blood lymphocytes of residents of three villages and
one nearby township in South Gujarat with fluoride
concentrations in the drinking water of 1.56 - 3.46 and 0.6 - 0.8
ppm, respectively, were examined for their frequency of sister chromatid
exchanges (SCE) and chromosome aberrations. The rates of SCEs and
chromosome aberrations in persons living in one of the endemic villages
were significantly higher than in the
others, and their lymphocytes were more susceptible to the clastogen
Chinese Journal of Endemiology
effects of high fluoride on micronucleus
rate in humans and mice
- As cited and abstracted
in Fluoride 2001; 34(1):80
Zhou H-L, Yang Q, et al.
Objective: The human
body and the mice were regarded as suitable subjects to study the
effects of high-fluoride on micronucleus rate in mammalian animals.
Methods: In a test on
the human body, the micronucleus rate of 51 adults from a high-fluoride
area was compared with the micronucleus rate of 24 adults from a
low-fluoride area. In a test on mice, the experimental group drank
fluoride water, and the control group drank tap water. Differences
were examined for significance by the chi-squared test.
Results: The micronucleus
rate of adults from the high-fluoride area was higher than that
of adults in the low-fluoride area, and the difference was sig-nificant
(P<0.05). The micronucleus rate of mice drinking high-fluoride water
was higher than that of the control group, and the difference was
also signifi-cant (P<0.05).
intake increases the miconucleus rate in mammals, and can damage
chromosomes. Fluoride may therefore be mutagenic.
Toxicol In Vitro 2000
Morphological transformation and effect on gap junction intercellular
communication in Syrian hamster embryo cells as screening tests
for carcinogens devoid of mutagenic activity.
E, Mikalsen SO, Sanner T.
Department of Environmental and Occupational Cancer, Institute for
Cancer Research, The Norwegian Radium Hospital, N-0310, Oslo, Norway.
A large fraction of chemicals observed to cause cancer in experimental
animals is devoid of mutagenic activity. It is therefore
of importance to develop methods that can be used to detect and
study environmental carcinogenic agents that do not interact directly
with DNA. Previous studies have indicated that induction of in vitro
cell transformation and inhibition of gap junction intercellular
communication are endpoints that could be useful for the detection
of non-genotoxic carcinogens. In the present work, 13 compounds
[chlordane, Arochlor 1260, di(2-ethylhexyl)phthalate, 1,1,1-trichloro-2,
2-bis(4-chlorophenyl)ethane, limonene, sodium
fluoride, ethionine, o-anisidine, benzoyl peroxide, o-vanadate,
phenobarbital, 12-O-tetradecanoylphorbol 13-acetate and clofibrate]
have been tested for their ability to induce morphological transformation
and affect intercellular communication in Syrian hamster embryo
cells. The substances were selected on the basis of being proven
or suspected non-genotoxic carcinogens, and thus difficult to detect
in short-term tests. The data show that nine of the 13 compounds
induced morphological transformation, and seven of the 13 inhibited
intercellular communication in hamster embryo cells. Taken together,
12 of the 13 substances either induced transformation or caused
inhibition of communication. The data suggest that the combined
use of morphological transformation and gap junction intercellular
communication in Syrian hamster embryo cells may be beneficial when
screening for non-genotoxic carcinogens.
PMID: 10793297 [PubMed - indexed for MEDLINE]
As cited on Toxnet DART.
Down syndrome births and their estimated occurrence due to water
of Internal Medicine and Biostatistics, Tokyo University Medical
School, Tokyo, Japan. Source:
Down syndrome (DS) birth rates (BR) as a function of maternal age
exhibit a relatively flat linear regression line for younger mothers
and a fairly steep one for older mothers with the second line intersecting
the first line a little above maternal age 30. Consequently, overall
DS-BR for all maternal ages are not a very reliable parameter for
detecting environmental influences, since they may be strongly affected
by the ratio of the number of younger to older mothers. For this
reason, data for mothers under age 30 were selected to detect an
association between water fluoridation and DS for which the lower
maternal age regression would be a much smaller contributing factor.
The early research of I Rapaport indicating a link between fluoride
in drinking water and Down syndrome was followed by studies claiming
there was no such association. Application of sound methodology
to the data in those later investigations shows that none of the
criticisms against Rapaport's work are valid. For example, in the
data of J D Erickson on maternal age-specific DS births in Metropolitan
Atlanta, Georgia, when the three youngest maternal age subgroups
are reasonably combined into single groups for areas with and without
water fluoridation, a highly significant association (P less than
0.005) is revealed between fluoridated water and DS births.
It also appears that the dose-response line (DRL) or DS-BR for daily
fluoride intake may have no allowable level that does not induce
fluoride-linked DS births. Therefore fluoride may be one of the
major causes of DS other than aging of mothers. The number
of excess DS births due to water fluoridation is estimated to be
several thousand cases annually throughout the world.
Arch Toxicol 1996;70(3-4):249-51
cell death following exposure to fluoride
in rat alveolar macrophages.
S, Ando M.
Regional Environment Division, National Institute for Environmental
Studies, Ibaraki, Japan.
Since inhaled fluoride is implicated in the
acute respiratory failure, cytotoxic effects of fluoride
on alveolar macrophages, primary target cells of inhaled
toxicants, were investigated. The LC50 of sodium
fluoride was estimated to be 0.41 mM, while 1 mM sodium chloride,
bromide and iodide had virtually no effects on the viability of
alveolar macrophages. Photomicroscopic observation
revealed that nuclei of the fluoride-exposed alveolar macrophages
were fragmented. The ladder formation was observed when DNA
isolated from fluoride-exposed alveolar
macrophages was electrophoresed in agarose gel.
These results suggest that cytotoxicity of fluoride is associated
with apoptosis in rat alveolar macrophages.
PMID: 8825685 [PubMed - indexed for MEDLINE]
Mutat Res 1996
activity of sodium fluoride to rat vertebral body-derived
cells in culture.
Mihashi M, Tsutsui T.
Department of Pharmacology,
School of Dentistry at Tokyo, Nippon Dental University, Japan.
The US National Toxicology Program has shown equivocal evidence
of carcinogenic activity of sodium fluoride
(NaF) in male F344/N rats based on
the occurrence of five osteosarcomas in treated animals. In the
study the osteosarcomas developed mainly in the rat vertebrae. To
provide a possible mechanistic basis for the observed tumors, the
genotoxic effects of NaF on the possible target organ of
NaF carcinogenesis were examined. Rat
vertebral body-derived (RVBd) cells were established from trabecular
bone of vertebral bodies of a male F344/N rat 6 weeks of age and
treated with NaF. RVBd cells in secondary
culture exhibited a high level of alkaline phosphatase (ALP) activity
when the cells at confluence were assayed by ALP staining. When
the histochemical examination was performed on RVBd cell colonies,
most of the colonies were stained positively for ALP. Confluent
RVBd cells were responsive to 10(-8) M 1 alpha.25-dihydroxyvitamin
D3 with a 7.7-fold increase in osteocalcin production over base
line values. The von Kossa staining demonstrated that in the presence
of 2 mM beta-glycerophosphate, RVBd cells that were allowed to grow
past confluence for approximately 2 months formed mineralized nodules.
When RVBd cells in tertiary culture were treated with
NaF at 0.5-2.0 mM for 24-72 h, the growth and/or survival
of the treated cells was reduced in a dose-dependent manner. Significant
increases in the frequencies of chromosome aberrations were induced
in a dose- and treatment time-dependent fashion when NaF
was administered to RVBd cells at 0.5 and 1.0 mM for 24 and 48 h.
The results indicate that NaF is genotoxic
to rat vertebrae, providing a possible mechanism for the vertebrae,
as a target organ of NaF carcinogenesis.
PMID: 8637511 [PubMed - indexed for MEDLINE]
Mutat Res 1995
aberrations in cultured rat bone marrow
cells treated with inorganic fluorides.
Department of Biological Sciences, Yarmouk University, Irbid, Jordan.
The genotoxic effects of inorganic fluorides were investigated by
treating cultured rat bone marrow cells with varying concentrations
(0.1-100 microM) of potassium fluoride (KF)
and sodium fluoride (NaF) for different durations (12, 24
and 36 h) and measuring the incidence of cells with aberrations
and number of breaks per cell. Both forms of fluoride were found
to be weak mutagens relative to the positive control N-methyl-N-nitro-N-nitrosoguanidine
(MNNG). A specificity of fluoride ion in inducing
chromosome aberrations (CA) was indicated by the observation that
both NaF and KF behaved almost equivalently in this study and at
significantly higher variations from the results with potassium
chloride (KCl) and sodium chloride (NaCl).
7753108 [PubMed - indexed for MEDLINE]
the human erythrocyte membrane protein SH binding site property
with exposure to fluoride and three strong mutagens
YY, Li XJ, Xin WJ
Beijing Municipal Research
Institute of Environemental Protection, Fu Wai Avenue, Beijing 100037,
Summary: The effects
of three strong mutagens (potassium bichromate, mitomycin C, and
colchicine) and fluoride on the human erythrocyte membrane protein
SH binding site property have been studied by using the maleimide
nitroxide-ESR technique. The results indicate that in singular and
combined treatments with mutagens, the ratio of weakly to strongly
immobilized component protein is altered. It
is possible that the inhibition in the cytogenetic response is induced
by the interaction of fluoride with the other chemicals.
There is a dose and temperature dependence of both the singular
and the combined action of the mutagen on the membrane protein.
and sister chromatid
exchange frequency in endemic fluorosis
and Y Wu
Inner Mongolia Sanitary
and Anti-epeidemic Station, Hohhot 010020, China
of the Hohhot Region in Inner Mongolia who drink high-fluoride (4-15
mg/L) water were compared for their micronucleus (MN) rate and sister
chromatid exchange (SCE) frequency in their peripheral blood lymphocytes.
In persons with fluorosis as well as those
considered "healthy", the MN rate and SCE frequency were
significantly higher (t test) than in a neighbouring control group
drinking low-fluoride water.
observations on alterations in rabbit ovary DNA and RNA content
in experimental fluorosis
Abstract: Summary. Forty-eight
albino rabbits were administered fluorde as sodium fluoride subcutaneously
in daily doses of 5, 10, 20, and 50 mg/kg body weight for three
and a half months. Twelve controls received 1 cc distilled water/kg
body weight/day for the same period. Ovaries from the control and
fluoridated animals were analysed for DNA and RNA content.
The experimental animals showed significant depletion (P < 0.001)
of ovarian DNA and RNA compared to the controls. The data indicate
that fluoride inhibits nucleic acid synthesis in the ovary. The
findings also suggest that fluoride acts directly on DNA to produce
structural changes in ovarian tissue which were subsequently confirmed
by histopathological examination of control and treated animals.
Further studies are desirable to define the possible role of fluoride
in causing deleterious effects on reproduction such as delayed oestrus,
repeated failure to conceive, and lowered viability detected earlier
in experimental animals.