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Caution Needed in Fluoride and Osteosarcoma Study

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Chester W Douglass at Harvard University
Chester W Douglass
Kaumudi J Joshipura at Ahmedabad University
Kaumudi J Joshipura
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LETTER TO THE EDITOR
Caution needed in fluoride and osteosarcoma study
Chester W. Douglass Æ Kaumudi Joshipura
Received: 3 January 2006 / Accepted: 12 January 2006
Ó Springer 2006
This issue of Cancer Causes and Controls includes a paper
with results from an analysis of a subset of participants in
our ongoing study of fluoride and osteosarcoma. The paper,
‘‘Age-specific fluoride exposure in drinking water and
osteosarcoma’’, presents a partial view of this ongoing
study. We would like to advise the readers to be especially
cautious when interpreting the findings of this paper for
several reasons. The authors themselves have already
raised a flag of caution in their final paragraph with the note
that they are aware of additional findings from other inci-
dent cases that appear not to replicate the findings from the
cases presented in their paper.
The Harvard School of Dental Medicine study of fluo-
ride and osteosarcoma has been a 15-year collaboration
among NIEHS, NCI, NIDCR, and Harvard. Two sets of
cases have been collected each with their own control
groups. The study started in 1992. The first set of cases was
recruited from existing cases between 1989 and 1992, and
the second set of cases was recruited from new incident
cases between 1993 and 2000. The Bassin et al paper
reports age-specific results among only the cases from 1989
to 1992. We are also finding some positive associations
between fluoride and osteosarcoma in the overall (not age-
specific) analysis of the first set of cases. However, our
preliminary findings from the overall analysis of the second
set of cases (1993–2000) do not appear to replicate the
overall findings from the first part of the study. Our find-
ings currently being prepared for publication, do not sug-
gest an overall association between fluoride and
osteosarcoma. This seems particularly important since the
cases had been accrued essentially from the same hospitals
within the same orthopedic departments with the same
providers, and the same pathology departments making the
diagnosis of the osteosarcoma and also using similar
methods of fluoride exposure.
In addition to fluoride intake history, many of the cases
and controls that were accrued in the 1993–2000 time
period agreed to provide bone specimens. The cases pro-
vided bone that was obtained proximal to the osteosarcoma
lesion as well as from their contra lateral hip. The control
group of non-osteosarcoma cancer patients provided bone
specimens. Our preliminary analysis of the fluoride content
of the bone specimens suggests that the fluoride level
within the bone is not associated with excess risk of oste-
osarcoma. We are grateful to Dr. Bassin and her coauthors
for mentioning at the end of their paper that we are not
finding a positive association from the bone specimens in
the second set of cases.
Obtaining and analyzing sufficient numbers of bone
specimens has been a laborious and a time consuming
effort by many people throughout the hospitals and
research teams. The analysis of these specimens has
included quality control procedures on laboratory tech-
niques, pilot studies to test reliability, many runs of small
batches of specimens, the double checking of specimen
transport procedures, and the preparation of data sets for
analysis.
We are now in the possession of the complete analytic
data sets and are pursuing previously planned analysis and
comparisons with the earlier set of collected cases. We
C. W. Douglass (&) Æ K. Joshipura
Harvard School of Dental Medicine, Boston, MA, USA;
Harvard School of Public Health, Boston, MA, USA
e-mail: chester_douglass@hsdm.harvard.edu
Tel.: +1-617-432-1456
Fax: +1-617-432-0047
K. Joshipura
University of Puerto Rico, Medical Sciences Campus, San Juan,
Puerto Rico
Cancer Causes Control (2006) 17:481–482
DOI 10.1007/s10552-006-0008-8
123
have delayed publication of all the major findings until we
found replication or lack of replication of the earlier po-
sitive findings. Our role model in this process has been Sir
Richard Doll, whose first publication associating smoking
with illness was rejected for publication until it could be
replicated (New York Times, July 26, 2005). It was too
important and too unexpected to be published on its own.
Professor Doll did replicate his initial findings; we appar-
ently have not and the bone specimens seem to corroborate
the lack of an association between the fluoride content in
drinking water and osteosarcoma in the new cases. Inter-
estingly, the NIEHS replication of their own earlier study
that found excess osteosarcoma in male rats was recently
presented on the NIEHS web site [1]. The findings of their
second study do not replicate their original widely quoted
National Toxicology Program study [2]. Drinking water
with very high fluoride content was not found to be asso-
ciated with osteosarcoma in either male or female rats.
A parallel analysis of age-specific exposure to fluoride,
especially during growth periods, is also being pursued by
our study team in the second set of cases of our study.
Accordingly, readers are cautioned not to generalize and
over-interpret the results of the Bassin et al. paper and to
await the publications from the full study, before making
conclusions, and especially before influencing any related
policy decisions.
References
1. The National Toxicology Program (NTP). Supplemental 2-year
study of sodium fluoride in male F344 rats (CAS No. 7681–49–4)
2. National Toxicology Program (1990) Toxicology and carcino-
genesis of sodium fluoride in F344 TN rats and B 6C3FL mice.
Technical Report Services 393, NIH Publication No. 90–2848
482 Cancer Causes Control (2006) 17:481–482
123
... Des facteurs environnementaux peuvent aussi augmenter le risque de développement d'ostéosarcome. C'est le cas des radiations ionisantes ainsi que des agents alkylants [121]. Des analyses sanguines, permettant l'étude de marqueurs biochimiques sériques peuvent également être réalisées à des fins diagnostiques et pronostiques [139,140]. ...
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... Findings on human populations often show mixed results; therefore further data are needed before a conclusion on the likelihood of F À causing cancer can be reached (Takahashi, Akiniwa, & Narita, 2001). Although the literature suggests that school-aged children are more vulnerable to the carcinogenic effects of F À , more studies are required to conclude any assessment within this context (Bassin, 2001;Douglass & Joshipura, 2006). ...
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Fluoride (F⁻) originating from many natural geologic sources and anthropogenic activities has imposed a substantial environmental health risk. More than 200 million people from more than 35 nations are at risk of fluorosis, thus increasing the global attention paid to F⁻ research. The present study reviews the mechanisms of F⁻ ingestion from possible sources and exposures, correlating possible health effects by extensively surveying the literature. The relationship between F⁻ levels in drinking water and dental and skeletal fluorosis has been studied for decades. However, several alternative routes of exposure, such as food and other supplements, influence fluorosis incidence and hinder benchmarking of fluorosis levels with F⁻ concentrations in drinking water. Deposition of F⁻ in developing teeth, accompanied by the loss of matrix protein, leads to deformities in tooth enamel and dentin. Skeletal fluorosis results from the strong and irreversible inclusion of F⁻ in the deeper parts of bone and causes increased bone mass and density along with enlarged joints. This review article also describes extensive in vivo or in vitro studies of F⁻ ingestion in laboratory animals and the correlation of F⁻ exposure with several health effects.
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... Temperature and pH value are the most important features of the environment which affect the metabolic activity, growth, nutrition and human reproduction. Studies have shown that chlorine and fluorine contents in the water are associated with heart disease, senility, and cancer of the liver, pancreas, colone, urinary tract (McDonagh et al. 2000) and in particular osteosarcomas (Douglas and Joshipura 2006;Comber et al. 2011;Kim et al. 2011). Water hardness is influenced by the presence of dissolved calcium and magnesium salts. ...
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... Studies conducted of human populations have yielded mixed results, including those that suggest a positive association between fluoride ingestion and osteosarcoma [49,50,136,137], those that show no relationship [92,[138][139][140][141][142], and even some that found negative correlations [142,143]. Recent work suggests that certain subgroups (e.g., boys aged 6-8) might be more susceptible to the carcinogenic effects of fluoride than the overall population [144], but more research is needed to confirm these conclusions [145]. There is also a possibility that fluoride ingestion might increase kidney and bladder cancer rates based on the tendency for hydrogen fluoride, a caustic and potentially toxic substance, to form under the acid conditions found in urine. ...
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Technical Report
Full-text available
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Groundwater is one of a common source for drinking. In recent times, there is a dramatically concerned about the quality of drinking water in coastal area. The purpose of the research is to investigate the quality of drinking groundwater and potential of fluoride contamination in groundwater, coastal regions of Cambodia. The determination of fluoride concentration was used spectrophotometric method, whilst other parameters such as temperature, pH, oxidation reduction potential, electrical conductivity, total dissolve solids, salinity, followed standard methods. Analytically, the results indicate that pH 22.73% of tube and dug wells was impermissible to the Cambodia drinking water quality standard. The significant difference between pH of tube and dug wells was not detected in coastal groundwater. Turbidity 31.82% of tube and dug wells does not follow the Cambodia drinking water quality standard and was also not significantly different between tube and dug well. The tube and dug wells TDS 13.64% was not met the Cambodia drinking water quality standard and not significantly different among them. The Fluoride concentration was determined in between 0.00 mg. L- and 1.33 mg. L-. The fluoride concentration is under the permissible standard of the Cambodia drinking water quality standard. However, its concentration seems to promote the dental caries for the consumers. As a consequence, the suggestions from this research is to study further the exact source of fluoride in coastal area. Even though the research was brought into being minor harmfulness to people to this coastal area; however, the local authority should get involved in this issue to keep tracking the change of this area. Furthermore, they should have any solution to those people who live near the shoreline to approach the fresh water appropriately.
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... The effect sizes observed in our analysis were much lower than those reported among boys of comparable ages in Bassin et al. [13]. In addition, the findings of the Bassin et al. study were based on preliminary results, and an analysis of bone fluoride concentrations (rather than drinking water fluoride) for a second set of patients from the same source yielded no significant association between bone fluoride levels and risk of osteosarcoma [18,19]. Hoover et al. [12] analyzed SEER incidence data and found that childhood osteosarcomas appeared to be more prominent in fluoridated areas than in non-fluoridated areas; however, the increases in osteosarcoma observed in fluoridated areas were not related to the timing of fluoridation and were thus not thought to be due to fluoridation of public drinking water [12]. ...
Fluoride exposure in public drinking water and childhood and adolescent osteosarcoma in Texas
Article
Full-text available
  • Jul 2016
  • CANCER CAUSE CONTROL
PURPOSE: The purpose of this study was to examine the association between fluoride levels in public drinking water and childhood and adolescent osteosarcoma in Texas; to date, studies examining this relationship have been equivocal. Using areas with high and low naturally occurring fluoride, as well as areas with optimal fluoridation, we examined a wide range of fluoride levels in public drinking water. METHODS: This was a population-based case-control study, with both cases and controls obtained from the Texas Cancer Registry. Eligible cases were Texas children and adolescents <20 years old diagnosed with osteosarcoma between 1996 and 2006. Controls were sampled from children and adolescents diagnosed with either central nervous system (CNS) tumors or leukemia during the same time frame. Using geocoded patient addresses at the time of diagnosis, we estimated patients' drinking water fluoride exposure levels based on the fluoride levels of their residence's public water system (PWS). Unconditional logistic regression models were used to assess the association between osteosarcoma and public drinking water fluoride level, adjusting for several demographic risk factors. RESULTS: Three hundred and eight osteosarcoma cases, 598 leukemia controls, and 604 CNS tumor controls met selection criteria and were assigned a corresponding PWS fluoride level. PWS fluoride level was not associated with osteosarcoma, either in a univariable analysis or after adjusting for age, sex, race, and poverty index. Stratified analyses by sex were conducted; no association between PWS fluoride level and osteosarcoma was observed among either males or females. CONCLUSIONS: No relationship was found between fluoride levels in public drinking water and childhood/adolescent osteosarcoma in Texas.
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... An association between fluoride and osteosarcoma is biologically plausible, since bones readily take up much of the fluoride ingested; children/adolescents are often diagnosed around the time of the pubertal growth spurt, when osteoblastic activity is particularly high. While there has been one recent report of an association of osteosarcoma in males with earlier exposure to fluoridated water (Bassin et al. 2006), most available scientific evidence strongly suggests that community water fluoridation is not associated with osteosarcoma (Douglass and Joshipura 2006, Kim et al. 2011, Levy and Leclerc 2012, Blakey et al. 2014. ...
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Osteosarcoma: A comprehensive review of management and treatment strategies
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Osteosarcoma, a bone cancer usually seen in children and young adults, is generally a high-grade malignancy presented by extreme metastases to the lungs. Osteosarcoma has a tendency for appearing in bones with rapid growth rate. The etiology of osteosarcoma is multifaceted and poorly understood. A molecular consideration of this disease will lead to a directed tumor treatment. The present treatment for osteosarcoma comprises of an arrangement of systemic chemotherapy and wide surgical resection. Survival rate is increased by the progress of destructive systemic chemotherapies. So, the development of new treatment approaches for metastatic osteosarcoma is essential. Immunomodulation has been used in clinical settings. Through targeting surface antigens expressed on tumor cells, particular antibodies and exploitation of cellular immunotherapy against sarcomas have been confrmed to be effective as cancer therapeutics. In this article, we have reviewed epidemiology, etiology, pathogenesis, diagnosis, and treatment of osteosarcoma and we have focused on different methods of immunotherapy including vaccines, cell-based immunotherapy, cytokines, and monoclonal antibodies
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Osteosarcoma: A comprehensive review of management and treatment strategies
Article
  • Oct 2020
  • Ann Diagn Pathol
Osteosarcoma, a bone cancer usually seen in children and young adults, is generally a high-grade malignancy presented by extreme metastases to the lungs. Osteosarcoma has a tendency for appearing in bones with rapid growth rate. The etiology of osteosarcoma is multifaceted and poorly understood. A molecular consideration of this disease will lead to a directed tumor treatment. The present treatment for osteosarcoma comprises of an arrangement of systemic chemotherapy and wide surgical resection. Survival rate is increased by the progress of destructive systemic chemotherapies. So, the development of new treatment approaches for metastatic osteosarcoma is essential. Immunomodulation has been used in clinical settings. Through targeting surface antigens expressed on tumor cells, particular antibodies and exploitation of cellular immunotherapy against sarcomas have been confrmed to be effective as cancer therapeutics. In this article, we have reviewed epidemiology, etiology, pathogenesis, diagnosis, and treatment of osteosarcoma and we have focused on different methods of immunotherapy including vaccines, cell-based immunotherapy, cytokines, and monoclonal antibodies.
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Reversible fluoride chemosensor for the development of multi-input molecular logic gates
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A potential rhodamine derived chemosensor was synthesized for the quantitative colorimetric detection of F¯ ions in real-time and to design multiple-input logic gates at the molecular level. Bottom-up fabrication techniques to design logic gates using chemical inputs has been initiated since a decade now and shown immense promise of reducing the size of microprocessors even smaller, as the chemical signals are at the molecular level. The chemosensor exhibited a change in color from pale yellow to dark yellow for F¯ ion. However, upon adding Cu2+ ion to the same solution exhibited pink coloration. This change in color and absorbance were used to develop chemical input logic gates. Further, the color change trend could be reversed for sixteen cycles with the alternative addition of F¯ and Cu2+ ions. Moreover, the chemosensor was used to design combinational three input logic gates by adding Cu2+, F¯ and Ni2+ ions. In addition, UV-Vis titrations and 1H NMR titrations were carried out to understand the color change and binding mechanism. Furthermore, chemosensor was investigated for its ability to detect F¯ ions in real-time samples.
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Toxicology and carcinogenesis of sodium fluoride in F344 TN rats and B 6C3FL mice
  • Jan 1990
  • 90-2848
National Toxicology Program (1990) Toxicology and carcinogenesis of sodium fluoride in F344 TN rats and B 6C3FL mice. Technical Report Services 393, NIH Publication No. 90–2848